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Review ArticleAsymmetric Organocatalysis at the Serviceof Medicinal Chemistry
Alfredo Ricci
Department of Industrial Chemistry ldquoToso Montanarirdquo School of Science University of Bologna V Risorgimento 440136 Bologna Italy
Correspondence should be addressed to Alfredo Ricci alfredomarcoricciuniboit
Received 4 December 2013 Accepted 30 December 2013 Published 11 March 2014
Academic Editors J M Campagne G Li J C Menendez and L Wang
Copyright copy 2014 Alfredo RicciThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
The application of the most representative and up-to-date examples of homogeneous asymmetric organocatalysis to the synthesisof molecules of interest in medicinal chemistry is reported The use of different types of organocatalysts operative via noncovalentand covalent interactions is critically reviewed and the possibility of running some of these reactions on large or industrial scale isdescribed A comparison between the organo- and metal-catalysed methodologies is offered in several cases thus highlighting themerits and drawbacks of these two complementary approaches to the obtainment of very popular on market drugs or of relatedkey scaffolds
1 Introduction
Over the past ten years the field of enantioselective organ-ocatalysis has had a significant impact on chemical synthesis[1 2] Currently asymmetric organocatalysis is recognized[3] as an independent synthetic tool besides asymmetricmetallic catalysis and enzymatic catalysis for the synthesisof chiral organic molecules Multiple advantages comparedwith the other two catalytic domains are the reasons for therapid growth and acceptance of organocatalysis In generalorganocatalysts are air- and moisture-stable and thus inert-equipments such as vacuum lines or glove boxes are notnecessary They are easy to handle even on large scale andrelatively less toxic compared to transition metals Moreoverfrequently the reactions are conducted undermild conditionsand high concentrations thus avoiding the use of largeamounts of solvents and minimizing waste
The organocatalysts can be classified by means of theirinteractionswith the substrate or ldquomode of actionrdquo as covalentor noncovalent catalysts (Figure 1)
In covalent organocatalysis a new covalent bond betweenthe catalysts and the substrate is formed as in the case ofaminocatalysis [4] and carbenes [5] leading to a strong inter-action between the substrate and the reagent in the reaction
In the case of noncovalent interactions between the substrateand the catalyst the activation of the substrate occurs viaweak binding exemplified by hydrogen bonding [6] or ionicinteraction as in the case of phase transfer catalysis [7]
The field of asymmetric organocatalysis has enjoyedphenomenal growth in the past 15 years [8ndash10] and duringthe ldquogolden agerdquo [11] of organocatalysis many researchersfrom academia and chemical industry were involved in thisfield with most efforts focused on the development of novelorganocatalysts new reactivities and asymmetric method-ologies Moreover current developments in the field of thesynthesis of structurally complex andor polyfunctionalizedmolecules indicate that chemists have adopted the funda-mental principles of biosynthesis as synthetic strategic keyelements for their synthetic approaches [12] Among thesecascade reactions [13 14] employing a single catalyst capableof promoting each single step have gained in the recent yearsan important role in the efficient and rapid generation ofmolecules with complex architectures generally correlatedwith specificity of action and potentially useful biologicalproperties [15] Organocatalysts turn out to be particularlyfavourable when used in catalytic cascade reactions becausethey allow distinct modes of activation which can often becombined [16 17]
Hindawi Publishing CorporationISRN Organic ChemistryVolume 2014 Article ID 531695 29 pageshttpdxdoiorg1011552014531695
2 ISRN Organic Chemistry
ldquoSynzymesrdquosimple molecules which mimic enzyme functions
Organocatalysis
Noncovalent organocatalysis Covalent organocatalysisnew covalent bond formationweak interactions
AminesHydrogen bonds
Ionic interactionsCarbenes
OP
O O
O H
R
R
NH
NH
S
NH
NH OTMS
PhPh
NH
NO
N
HOH
NN F
F
FF
F
F3C
CF3
N+
BF4minus
+N
NMe2
Brminus
CO2H
Figure 1 General classification of the activation mode of several representative classes of molecules in organocatalysis
Despite their great development the application oforganocatalyticmethodologies to the synthesis of active com-pounds in medicinal chemistry in the past years has rarelybeen reported However in most recent years organocat-alytic methodologies for the synthesis of enantioenrichedmolecules for medicinal chemistry purposes have been gain-ing momentum being particularly attractive for the prepara-tion of compounds that do not tolerate metal contaminationIn academia several groups have made a remarkable effortto show the great applicability of organocatalysts to the totalsynthesis of bioactive natural products [18] and of drugs[19] most of them currently available in the market such asoseltamivir warfarin paroxetine baclofen and maravirocThese efforts mainly focused on the removal of barriersfor scale-up by addressing issues such as catalyst loadingproduct inhibition substrate scope and bulk availability ofdesigner catalysts which have drawn the attention of the com-panies [20 21] that have begun to incorporate organocatalysisas a synthetic tool in some industrial scale processes [22 23]
In this review some of the most recent representativeapplications of asymmetric organocatalysis to medicinalchemistry will be highlighted Not only the access to marketavailable drugs but also the access to drug candidates tomedicinal scaffolds and to promising new compoundswhosebiological profile has not yet been fully explored will bereviewed In some cases a comparison between organo-and metal-catalysed methodologies aimed at the obtainmentof the same medicinal targets will be reported and a few
interesting industrial examples of the use of organocatalysisin medicinal chemistry taken from the literature will bediscussed as well
2 Discussion
21 Noncovalent Organocatalysis
211 Hydrogen Bonding Catalysis This ubiquitous interac-tion is one of the central forces in Nature As an individualhydrogen bonds are feeble and quite easy to break Howeverwhen acting together they become much stronger and leaneach otherThis phenomenon is called ldquocooperativityrdquo (1 + 1 ismore than 2) Some of themany vital functions that hydrogenbonds fulfil in biological systems are shown in Figure 2
The simultaneous donation of two hydrogen bonds leadsto a highly successful strategy for electrophilic activationincreased strength and directionality relative to single hydro-gen bonds Therefore asymmetric catalysis via noncovalentbond interactions such as hydrogen bonding turns out to bea powerful synthetic strategy
Original achievements regarding bis-hydrogen bondcomplexes have been reported through the years It is worthnoting that this two-point binding is a powerful strategy bothinmetal-centered catalysis and in organocatalysis as shown inFigure 3
However whereas coordination to a chiral Lewis acidimposes limitations upon substrate structure any Lewis
ISRN Organic Chemistry 3
Organization andbase pairing of DNA and RNA
Maintenance of the form and thefunction of most biological systems
Secondary and tertiarystructure of proteins
Catalytic cycle ofvarious enzymes
Figure 2 Some of the vital functions that hydrogen bonds fulfil inbiological systems
O OH H O
OO
Kellyrsquos bisphenol
N NH H
Etterrsquos urea
HO
H
HO
H
Jorgensenrsquoshydration model
N
O
N
O
Cu
O O
N NH H
X
Y
O
Me3C CMe3
Figure 3 Original achievements regarding bis-hydrogen-bondedcomplexes
base is in principle capable of engaging bifurcated hydrogenbonds so that this catalytic strategy has potential as ageneral paradigm for synthesis Thiourea catalysts designedby Sigman and Jacobsen [24] and Corey and Grogan [25]as well as minimal peptides introduced by Davie et al [26]appeared together with many others during the last decadethey all fall into this class of catalysts These structuresare highly modular and can be readily modified and finelytuned Many organocatalysts have been recognized to bereminiscent of natural enzymes in their mode of actionand substrate interactionactivation [27] Their use in severalbioinspired methodologies has led to envisaging efficientsynthetic routes leading among the others to the obtainmentof target compounds of interest in medicinal chemistry
In the biosynthesis of fatty acids and polyketides theactive site of polyketide synthase (PKS) clearly highlights thekey role displayed by hydrogen bonds (Scheme 1) [28]
The possibility of mimicking the hydrogen bond inter-actions of PKSrsquos with a simple organic molecule (ldquohunt forsmallest enzymesrdquo according to Schreiner) has been shown
feasible by using double hydrogen bond-based organocata-lysts The potential of this strategy has been appreciated bysynthetic chemists for many years and has been widely usedin asymmetric catalysis [29]
The application of the enantioselective decarboxylativereaction of malonic half thioesters (MAHTs) to the synthesisof medicinal targets is exemplified by the synthesis of GABAreceptor antagonists 3 and 4 using I and II as the organocata-lysts (Scheme 2) The 120574-nitrothioesters 1 and 2 easily achiev-able through these organocatalytic approaches occurringunder mild conditions and tolerating both moisture andair are versatile building blocks for further modificationsAmong them the formation of 120574-butyrolactams by reductionof the nitro group followed by intramolecular cyclizationleads to intermediates en route to the antidepressant (R)-Rolipram [30] 3 and to gram scale synthesis and transforma-tion to (S)-baclofensdotHCl 4 a GABA receptor antagonist usedin the treatment of spasticity [31]
Several enantioselective syntheses of GABA receptorshave been reported based on the use of a metalligand assem-bly as the catalyst system So far (Scheme 3) the Rh(acac)-catalyzed asymmetric 14-additions of arylboronic acids to 4-aminobut-23-enoic acid derivatives led to (minus)-(R)-baclofenent-4 and to (minus)-(R)-rolipram 3 in high yields and excellentenantioselectivities [32]However the use of inert atmosphere(argon) and the to some extent difficult purification byflash chromatography prevent this methodology to be easilyapplied on large scale
An alternative metal-catalysed system [33] in whichthe potential for scale-up is clear is shown in Scheme 4and appears highly competitive with the organocatalysedapproach The chiral Lewis acid-catalyzed Michael additionof diethyl malonate to fully elaborated nitrostyrene 5 allowsthe nitroester 6 that upon reduction and saponification leadsto the target compound 3 Both enantiomers of rolipram 3can be accessed in a total of six steps and at 10 gram scale withexcellent overall yields of 76 and without chromatography
The use of magnesium is preferable to many other metalcatalysts since toxicity issues are avoided The dependenceon solvents such as chloroform does however raise in thismethod toxicological and environmental issues
The range of applications of bioinspired decarboxylativereactions is witnessed by the very recent [34] hydrogen-bonddirected enantioselective decarboxylative Mannich reactionof keto acids with ketimines Under the action of saccharide-derived amino thioureas as chiral catalysts (III) this reactionthat can be run on a gram scale without any detriment on thereaction outcome leads to the expected trifluoromethylated34-dihydro-quinazolin-2(1H)-one rings in very high yieldsand up to 99 ee The potential application of this decar-boxylativeMannich reaction in the domain of pharmaceuticsis demonstrated in a new and efficient and shortcut synthesisof the anti-HIV drug DPC083 7 shown in Scheme 5 Hereinthe crucial role of the hydrogen bond interactions in buildinga complex rigid architecture responsible for the high stereos-electivity is highlighted
Hydrogen bond-based organocatalysis also plays a pri-mary role in the synthesis of low molecular weight drug can-didates The aza-Henry reaction (nitro-Mannich reaction)
4 ISRN Organic Chemistry
NHN H
As nO
NH
H
HisS
Cys
S
O
O
O
CoA
cisthis
asn
RNO
S O
O
R
N
N
H
NO
H
H
Chiralspacer R
S
O RO(minus)O(minus)
(minus)O (+)
(+)
(+)
R998400
NO2
Scheme 1 Activation of MAHT in the active of PKA synthase and in the chiral core of the organocatalyst
X
Y
+
NH
O
NH
OO
3-(R)-rolipram
NH
OCl
4-(S)-baclofenHCl
X = HY = Cl
X = OBnY = OMe
67 yield97 ee
S
O
OBn
Up to 97 yieldand 90 ee
82 yield 90 ee5 gr scale
S
O
Cl1
2
S
MeO
MeO
MeOMeO
MeO
O
OH
O
NNH
N
O
H
OMe
OMe
OMe
N
NNH
N
NH
OO
Cat II
Cat II 5 mol Cat I 20 mol
Cat I
Cl
HO
CF3
CF3
CF3
NO2
NO2
NO2
CF3
Raney-NiH2
H3PO4 64
NH2HCl
HO2C
Scheme 2 Synthesis of GABA receptors via hydrogen bonds directed organocatalysis mimicry of polyketide synthase
BINAP base+
(R)-baclofen ent 4
Up to 96 yield
OH
Cl
O
80 overall yield89 ee
OOMe
OMeOMe
NHO
(R)-rolipram 357 overall yield84 ee
OO
DioxaneH2O
Rh(acac)(C2H4)2R2R1N
R2R1N
R4R4
R3
R3
2M NaOH MeOH rt
TFA CH2Cl2 rt 2h
12h HCl Et2O rt 24h
(+)H3NCl(minus)
B(OH)2
Et3N toluene rfx 20h
Scheme 3 Metal-catalysed synthesis of GABA receptors
ISRN Organic Chemistry 5
CHOHO
MeOMeO
MeO
MeO
Ligand (55 mol)
NMM (6 mol)mol sieves rt
95 yield on 10 g scale 96 ee
NHNH O
NaOH TsOH
OMe
O
EtO
O
(R)-rolipram
Ligand
92 three steps
56
3
N
OO
N
EtO
O
OEt
O
OC4H9
NO2
NO2
OC4
4
H9
OC4H9
EtO2C
Ra-NiH2
H3PO
CO2Et
C4H9O
Mg(OTf)2 (5mol)
Scheme 4 Scalable metal-catalysed synthesis of both enantiomers of rolipram
N
N N
NH
O
O
N
NH
PMBPMB
PMB
PMB
PMB
O
OHN
NH
O
N
NH
O
+Cat 10 mol+
MeOH RT (2) TFA anisole
(Z)-DPC 08326 96 ee
(E)-DPC 08353 96 ee
O
N
NO
Cl
Cl
Cl Cl
Cl
Cl
OOAc
AcO
OAc
OAcN N
S
H H
N
H
Ar
O
OH
7
IIIO
OH
OF3C
F3C
F3C
F3C
CF3
CF3
(minus)O
(+)
R998400
NaBH4
(1) 220ndash230∘CHMPA
THF minus20∘C 48h
Scheme 5 Hydrogen-bonding assembly between organocatalyst ketimine and 120573-ketoacid in the preparation of the anti-HIV drug DPC 083
was used by Xu and coworkers [35] for the short asymmet-ric synthesis of the chiral piperidine derivative CP-999948 (Scheme 6) The previous asymmetric syntheses of thispotent neurokin-1 receptor antagonist were mainly basedon the use of metal complexes as catalysts but sufferedfrom several drawbacks for example low overall yield andenantioselectivity or a lengthy synthetic route Notably theorganocatalysed Takemotorsquos synthesis proceeded in five stepswithout the need to separate the diastereomeric intermediatesthat were cyclized as a mixture The catalyst employed wasa chiral thiourea IV which served as an activator of boththe nitroalkane and imine reactants The transition state isrelatively complex and is dominated by hydrogen-bondinginteractions
The simultaneous donation of two hydrogen bonds hasalso proven to be a highly successful strategy for electrophilicactivation in enzymes with an ldquooxyanion holerdquo having apostulated role in the stabilization of many high-energytetrahedral intermediates [36] It appears that living systemsdiscovered and made use of these interactions in the ubiq-uitous useful ring-forming Diels-Alder reaction eons agofor the construction of complex natural products so thatthe prospect of discovering a Diels-Alderase mimic wouldbe especially exciting Following this concept and inspiredby the antibody 13G5-catalyzed Diels-Alder cycloadditionof acrylamide with a carbamate (Scheme 7) taking placevia a cooperative multiple hydrogen bond coordination toboth diene and dienophile [37] a catalytic asymmetric
6 ISRN Organic Chemistry
H MeO
HN
HN
Ph
Ph
PhMeO
MeO
Boc
Boc
Ph
PhNH
HN
OMe
++
(i) TFA
80
80
75
Epimerization andreduction
Cat IV 10 mol
83 ee
95 ee
cistrans 191
Reductive amination of
HN
S
HN
Cat IV8 (minus)-CP-99 994
NBoc
F3C
F3C
NMe2
NO2
NO2
NH2
NO2
NO2
CH2Cl2 minus20∘C
(ii) K2CO3
o-MeOC6H4CHO
NH
NH
Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist
O
NH
R
H ONN
N NH H
57-His
HO
O
Asp-102O
NR
O
Ser-195
NN
Gly-193Gly-193 Ser-195Ser-195
Ser-195
N NH H
57-His
HO
O
Asp-102 (+)
H
HOxyanion hole
Serine protease
HN
O
O Ar
O
Antibody 13G5pH 74
+
95 ee 49 1 dr
N
O O Ar
HOO H
L36-Tyr
O
N
Asn-91L
H H
O
O Asp-50H
N(CH3)2
N(CH3)2
H2O 37∘C
(minus)
(minus)
(minus)
(minus)
NHCO2CH2Ar
CON(CH3)2
R998400
R998400
Scheme 7 Occurrence of the oxyanion hole in enzymatic processes
cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities
A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common
scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)
The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective
ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
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Carbohydrate Chemistry
International Journal of
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
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2 ISRN Organic Chemistry
ldquoSynzymesrdquosimple molecules which mimic enzyme functions
Organocatalysis
Noncovalent organocatalysis Covalent organocatalysisnew covalent bond formationweak interactions
AminesHydrogen bonds
Ionic interactionsCarbenes
OP
O O
O H
R
R
NH
NH
S
NH
NH OTMS
PhPh
NH
NO
N
HOH
NN F
F
FF
F
F3C
CF3
N+
BF4minus
+N
NMe2
Brminus
CO2H
Figure 1 General classification of the activation mode of several representative classes of molecules in organocatalysis
Despite their great development the application oforganocatalyticmethodologies to the synthesis of active com-pounds in medicinal chemistry in the past years has rarelybeen reported However in most recent years organocat-alytic methodologies for the synthesis of enantioenrichedmolecules for medicinal chemistry purposes have been gain-ing momentum being particularly attractive for the prepara-tion of compounds that do not tolerate metal contaminationIn academia several groups have made a remarkable effortto show the great applicability of organocatalysts to the totalsynthesis of bioactive natural products [18] and of drugs[19] most of them currently available in the market such asoseltamivir warfarin paroxetine baclofen and maravirocThese efforts mainly focused on the removal of barriersfor scale-up by addressing issues such as catalyst loadingproduct inhibition substrate scope and bulk availability ofdesigner catalysts which have drawn the attention of the com-panies [20 21] that have begun to incorporate organocatalysisas a synthetic tool in some industrial scale processes [22 23]
In this review some of the most recent representativeapplications of asymmetric organocatalysis to medicinalchemistry will be highlighted Not only the access to marketavailable drugs but also the access to drug candidates tomedicinal scaffolds and to promising new compoundswhosebiological profile has not yet been fully explored will bereviewed In some cases a comparison between organo-and metal-catalysed methodologies aimed at the obtainmentof the same medicinal targets will be reported and a few
interesting industrial examples of the use of organocatalysisin medicinal chemistry taken from the literature will bediscussed as well
2 Discussion
21 Noncovalent Organocatalysis
211 Hydrogen Bonding Catalysis This ubiquitous interac-tion is one of the central forces in Nature As an individualhydrogen bonds are feeble and quite easy to break Howeverwhen acting together they become much stronger and leaneach otherThis phenomenon is called ldquocooperativityrdquo (1 + 1 ismore than 2) Some of themany vital functions that hydrogenbonds fulfil in biological systems are shown in Figure 2
The simultaneous donation of two hydrogen bonds leadsto a highly successful strategy for electrophilic activationincreased strength and directionality relative to single hydro-gen bonds Therefore asymmetric catalysis via noncovalentbond interactions such as hydrogen bonding turns out to bea powerful synthetic strategy
Original achievements regarding bis-hydrogen bondcomplexes have been reported through the years It is worthnoting that this two-point binding is a powerful strategy bothinmetal-centered catalysis and in organocatalysis as shown inFigure 3
However whereas coordination to a chiral Lewis acidimposes limitations upon substrate structure any Lewis
ISRN Organic Chemistry 3
Organization andbase pairing of DNA and RNA
Maintenance of the form and thefunction of most biological systems
Secondary and tertiarystructure of proteins
Catalytic cycle ofvarious enzymes
Figure 2 Some of the vital functions that hydrogen bonds fulfil inbiological systems
O OH H O
OO
Kellyrsquos bisphenol
N NH H
Etterrsquos urea
HO
H
HO
H
Jorgensenrsquoshydration model
N
O
N
O
Cu
O O
N NH H
X
Y
O
Me3C CMe3
Figure 3 Original achievements regarding bis-hydrogen-bondedcomplexes
base is in principle capable of engaging bifurcated hydrogenbonds so that this catalytic strategy has potential as ageneral paradigm for synthesis Thiourea catalysts designedby Sigman and Jacobsen [24] and Corey and Grogan [25]as well as minimal peptides introduced by Davie et al [26]appeared together with many others during the last decadethey all fall into this class of catalysts These structuresare highly modular and can be readily modified and finelytuned Many organocatalysts have been recognized to bereminiscent of natural enzymes in their mode of actionand substrate interactionactivation [27] Their use in severalbioinspired methodologies has led to envisaging efficientsynthetic routes leading among the others to the obtainmentof target compounds of interest in medicinal chemistry
In the biosynthesis of fatty acids and polyketides theactive site of polyketide synthase (PKS) clearly highlights thekey role displayed by hydrogen bonds (Scheme 1) [28]
The possibility of mimicking the hydrogen bond inter-actions of PKSrsquos with a simple organic molecule (ldquohunt forsmallest enzymesrdquo according to Schreiner) has been shown
feasible by using double hydrogen bond-based organocata-lysts The potential of this strategy has been appreciated bysynthetic chemists for many years and has been widely usedin asymmetric catalysis [29]
The application of the enantioselective decarboxylativereaction of malonic half thioesters (MAHTs) to the synthesisof medicinal targets is exemplified by the synthesis of GABAreceptor antagonists 3 and 4 using I and II as the organocata-lysts (Scheme 2) The 120574-nitrothioesters 1 and 2 easily achiev-able through these organocatalytic approaches occurringunder mild conditions and tolerating both moisture andair are versatile building blocks for further modificationsAmong them the formation of 120574-butyrolactams by reductionof the nitro group followed by intramolecular cyclizationleads to intermediates en route to the antidepressant (R)-Rolipram [30] 3 and to gram scale synthesis and transforma-tion to (S)-baclofensdotHCl 4 a GABA receptor antagonist usedin the treatment of spasticity [31]
Several enantioselective syntheses of GABA receptorshave been reported based on the use of a metalligand assem-bly as the catalyst system So far (Scheme 3) the Rh(acac)-catalyzed asymmetric 14-additions of arylboronic acids to 4-aminobut-23-enoic acid derivatives led to (minus)-(R)-baclofenent-4 and to (minus)-(R)-rolipram 3 in high yields and excellentenantioselectivities [32]However the use of inert atmosphere(argon) and the to some extent difficult purification byflash chromatography prevent this methodology to be easilyapplied on large scale
An alternative metal-catalysed system [33] in whichthe potential for scale-up is clear is shown in Scheme 4and appears highly competitive with the organocatalysedapproach The chiral Lewis acid-catalyzed Michael additionof diethyl malonate to fully elaborated nitrostyrene 5 allowsthe nitroester 6 that upon reduction and saponification leadsto the target compound 3 Both enantiomers of rolipram 3can be accessed in a total of six steps and at 10 gram scale withexcellent overall yields of 76 and without chromatography
The use of magnesium is preferable to many other metalcatalysts since toxicity issues are avoided The dependenceon solvents such as chloroform does however raise in thismethod toxicological and environmental issues
The range of applications of bioinspired decarboxylativereactions is witnessed by the very recent [34] hydrogen-bonddirected enantioselective decarboxylative Mannich reactionof keto acids with ketimines Under the action of saccharide-derived amino thioureas as chiral catalysts (III) this reactionthat can be run on a gram scale without any detriment on thereaction outcome leads to the expected trifluoromethylated34-dihydro-quinazolin-2(1H)-one rings in very high yieldsand up to 99 ee The potential application of this decar-boxylativeMannich reaction in the domain of pharmaceuticsis demonstrated in a new and efficient and shortcut synthesisof the anti-HIV drug DPC083 7 shown in Scheme 5 Hereinthe crucial role of the hydrogen bond interactions in buildinga complex rigid architecture responsible for the high stereos-electivity is highlighted
Hydrogen bond-based organocatalysis also plays a pri-mary role in the synthesis of low molecular weight drug can-didates The aza-Henry reaction (nitro-Mannich reaction)
4 ISRN Organic Chemistry
NHN H
As nO
NH
H
HisS
Cys
S
O
O
O
CoA
cisthis
asn
RNO
S O
O
R
N
N
H
NO
H
H
Chiralspacer R
S
O RO(minus)O(minus)
(minus)O (+)
(+)
(+)
R998400
NO2
Scheme 1 Activation of MAHT in the active of PKA synthase and in the chiral core of the organocatalyst
X
Y
+
NH
O
NH
OO
3-(R)-rolipram
NH
OCl
4-(S)-baclofenHCl
X = HY = Cl
X = OBnY = OMe
67 yield97 ee
S
O
OBn
Up to 97 yieldand 90 ee
82 yield 90 ee5 gr scale
S
O
Cl1
2
S
MeO
MeO
MeOMeO
MeO
O
OH
O
NNH
N
O
H
OMe
OMe
OMe
N
NNH
N
NH
OO
Cat II
Cat II 5 mol Cat I 20 mol
Cat I
Cl
HO
CF3
CF3
CF3
NO2
NO2
NO2
CF3
Raney-NiH2
H3PO4 64
NH2HCl
HO2C
Scheme 2 Synthesis of GABA receptors via hydrogen bonds directed organocatalysis mimicry of polyketide synthase
BINAP base+
(R)-baclofen ent 4
Up to 96 yield
OH
Cl
O
80 overall yield89 ee
OOMe
OMeOMe
NHO
(R)-rolipram 357 overall yield84 ee
OO
DioxaneH2O
Rh(acac)(C2H4)2R2R1N
R2R1N
R4R4
R3
R3
2M NaOH MeOH rt
TFA CH2Cl2 rt 2h
12h HCl Et2O rt 24h
(+)H3NCl(minus)
B(OH)2
Et3N toluene rfx 20h
Scheme 3 Metal-catalysed synthesis of GABA receptors
ISRN Organic Chemistry 5
CHOHO
MeOMeO
MeO
MeO
Ligand (55 mol)
NMM (6 mol)mol sieves rt
95 yield on 10 g scale 96 ee
NHNH O
NaOH TsOH
OMe
O
EtO
O
(R)-rolipram
Ligand
92 three steps
56
3
N
OO
N
EtO
O
OEt
O
OC4H9
NO2
NO2
OC4
4
H9
OC4H9
EtO2C
Ra-NiH2
H3PO
CO2Et
C4H9O
Mg(OTf)2 (5mol)
Scheme 4 Scalable metal-catalysed synthesis of both enantiomers of rolipram
N
N N
NH
O
O
N
NH
PMBPMB
PMB
PMB
PMB
O
OHN
NH
O
N
NH
O
+Cat 10 mol+
MeOH RT (2) TFA anisole
(Z)-DPC 08326 96 ee
(E)-DPC 08353 96 ee
O
N
NO
Cl
Cl
Cl Cl
Cl
Cl
OOAc
AcO
OAc
OAcN N
S
H H
N
H
Ar
O
OH
7
IIIO
OH
OF3C
F3C
F3C
F3C
CF3
CF3
(minus)O
(+)
R998400
NaBH4
(1) 220ndash230∘CHMPA
THF minus20∘C 48h
Scheme 5 Hydrogen-bonding assembly between organocatalyst ketimine and 120573-ketoacid in the preparation of the anti-HIV drug DPC 083
was used by Xu and coworkers [35] for the short asymmet-ric synthesis of the chiral piperidine derivative CP-999948 (Scheme 6) The previous asymmetric syntheses of thispotent neurokin-1 receptor antagonist were mainly basedon the use of metal complexes as catalysts but sufferedfrom several drawbacks for example low overall yield andenantioselectivity or a lengthy synthetic route Notably theorganocatalysed Takemotorsquos synthesis proceeded in five stepswithout the need to separate the diastereomeric intermediatesthat were cyclized as a mixture The catalyst employed wasa chiral thiourea IV which served as an activator of boththe nitroalkane and imine reactants The transition state isrelatively complex and is dominated by hydrogen-bondinginteractions
The simultaneous donation of two hydrogen bonds hasalso proven to be a highly successful strategy for electrophilicactivation in enzymes with an ldquooxyanion holerdquo having apostulated role in the stabilization of many high-energytetrahedral intermediates [36] It appears that living systemsdiscovered and made use of these interactions in the ubiq-uitous useful ring-forming Diels-Alder reaction eons agofor the construction of complex natural products so thatthe prospect of discovering a Diels-Alderase mimic wouldbe especially exciting Following this concept and inspiredby the antibody 13G5-catalyzed Diels-Alder cycloadditionof acrylamide with a carbamate (Scheme 7) taking placevia a cooperative multiple hydrogen bond coordination toboth diene and dienophile [37] a catalytic asymmetric
6 ISRN Organic Chemistry
H MeO
HN
HN
Ph
Ph
PhMeO
MeO
Boc
Boc
Ph
PhNH
HN
OMe
++
(i) TFA
80
80
75
Epimerization andreduction
Cat IV 10 mol
83 ee
95 ee
cistrans 191
Reductive amination of
HN
S
HN
Cat IV8 (minus)-CP-99 994
NBoc
F3C
F3C
NMe2
NO2
NO2
NH2
NO2
NO2
CH2Cl2 minus20∘C
(ii) K2CO3
o-MeOC6H4CHO
NH
NH
Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist
O
NH
R
H ONN
N NH H
57-His
HO
O
Asp-102O
NR
O
Ser-195
NN
Gly-193Gly-193 Ser-195Ser-195
Ser-195
N NH H
57-His
HO
O
Asp-102 (+)
H
HOxyanion hole
Serine protease
HN
O
O Ar
O
Antibody 13G5pH 74
+
95 ee 49 1 dr
N
O O Ar
HOO H
L36-Tyr
O
N
Asn-91L
H H
O
O Asp-50H
N(CH3)2
N(CH3)2
H2O 37∘C
(minus)
(minus)
(minus)
(minus)
NHCO2CH2Ar
CON(CH3)2
R998400
R998400
Scheme 7 Occurrence of the oxyanion hole in enzymatic processes
cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities
A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common
scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)
The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective
ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 3
Organization andbase pairing of DNA and RNA
Maintenance of the form and thefunction of most biological systems
Secondary and tertiarystructure of proteins
Catalytic cycle ofvarious enzymes
Figure 2 Some of the vital functions that hydrogen bonds fulfil inbiological systems
O OH H O
OO
Kellyrsquos bisphenol
N NH H
Etterrsquos urea
HO
H
HO
H
Jorgensenrsquoshydration model
N
O
N
O
Cu
O O
N NH H
X
Y
O
Me3C CMe3
Figure 3 Original achievements regarding bis-hydrogen-bondedcomplexes
base is in principle capable of engaging bifurcated hydrogenbonds so that this catalytic strategy has potential as ageneral paradigm for synthesis Thiourea catalysts designedby Sigman and Jacobsen [24] and Corey and Grogan [25]as well as minimal peptides introduced by Davie et al [26]appeared together with many others during the last decadethey all fall into this class of catalysts These structuresare highly modular and can be readily modified and finelytuned Many organocatalysts have been recognized to bereminiscent of natural enzymes in their mode of actionand substrate interactionactivation [27] Their use in severalbioinspired methodologies has led to envisaging efficientsynthetic routes leading among the others to the obtainmentof target compounds of interest in medicinal chemistry
In the biosynthesis of fatty acids and polyketides theactive site of polyketide synthase (PKS) clearly highlights thekey role displayed by hydrogen bonds (Scheme 1) [28]
The possibility of mimicking the hydrogen bond inter-actions of PKSrsquos with a simple organic molecule (ldquohunt forsmallest enzymesrdquo according to Schreiner) has been shown
feasible by using double hydrogen bond-based organocata-lysts The potential of this strategy has been appreciated bysynthetic chemists for many years and has been widely usedin asymmetric catalysis [29]
The application of the enantioselective decarboxylativereaction of malonic half thioesters (MAHTs) to the synthesisof medicinal targets is exemplified by the synthesis of GABAreceptor antagonists 3 and 4 using I and II as the organocata-lysts (Scheme 2) The 120574-nitrothioesters 1 and 2 easily achiev-able through these organocatalytic approaches occurringunder mild conditions and tolerating both moisture andair are versatile building blocks for further modificationsAmong them the formation of 120574-butyrolactams by reductionof the nitro group followed by intramolecular cyclizationleads to intermediates en route to the antidepressant (R)-Rolipram [30] 3 and to gram scale synthesis and transforma-tion to (S)-baclofensdotHCl 4 a GABA receptor antagonist usedin the treatment of spasticity [31]
Several enantioselective syntheses of GABA receptorshave been reported based on the use of a metalligand assem-bly as the catalyst system So far (Scheme 3) the Rh(acac)-catalyzed asymmetric 14-additions of arylboronic acids to 4-aminobut-23-enoic acid derivatives led to (minus)-(R)-baclofenent-4 and to (minus)-(R)-rolipram 3 in high yields and excellentenantioselectivities [32]However the use of inert atmosphere(argon) and the to some extent difficult purification byflash chromatography prevent this methodology to be easilyapplied on large scale
An alternative metal-catalysed system [33] in whichthe potential for scale-up is clear is shown in Scheme 4and appears highly competitive with the organocatalysedapproach The chiral Lewis acid-catalyzed Michael additionof diethyl malonate to fully elaborated nitrostyrene 5 allowsthe nitroester 6 that upon reduction and saponification leadsto the target compound 3 Both enantiomers of rolipram 3can be accessed in a total of six steps and at 10 gram scale withexcellent overall yields of 76 and without chromatography
The use of magnesium is preferable to many other metalcatalysts since toxicity issues are avoided The dependenceon solvents such as chloroform does however raise in thismethod toxicological and environmental issues
The range of applications of bioinspired decarboxylativereactions is witnessed by the very recent [34] hydrogen-bonddirected enantioselective decarboxylative Mannich reactionof keto acids with ketimines Under the action of saccharide-derived amino thioureas as chiral catalysts (III) this reactionthat can be run on a gram scale without any detriment on thereaction outcome leads to the expected trifluoromethylated34-dihydro-quinazolin-2(1H)-one rings in very high yieldsand up to 99 ee The potential application of this decar-boxylativeMannich reaction in the domain of pharmaceuticsis demonstrated in a new and efficient and shortcut synthesisof the anti-HIV drug DPC083 7 shown in Scheme 5 Hereinthe crucial role of the hydrogen bond interactions in buildinga complex rigid architecture responsible for the high stereos-electivity is highlighted
Hydrogen bond-based organocatalysis also plays a pri-mary role in the synthesis of low molecular weight drug can-didates The aza-Henry reaction (nitro-Mannich reaction)
4 ISRN Organic Chemistry
NHN H
As nO
NH
H
HisS
Cys
S
O
O
O
CoA
cisthis
asn
RNO
S O
O
R
N
N
H
NO
H
H
Chiralspacer R
S
O RO(minus)O(minus)
(minus)O (+)
(+)
(+)
R998400
NO2
Scheme 1 Activation of MAHT in the active of PKA synthase and in the chiral core of the organocatalyst
X
Y
+
NH
O
NH
OO
3-(R)-rolipram
NH
OCl
4-(S)-baclofenHCl
X = HY = Cl
X = OBnY = OMe
67 yield97 ee
S
O
OBn
Up to 97 yieldand 90 ee
82 yield 90 ee5 gr scale
S
O
Cl1
2
S
MeO
MeO
MeOMeO
MeO
O
OH
O
NNH
N
O
H
OMe
OMe
OMe
N
NNH
N
NH
OO
Cat II
Cat II 5 mol Cat I 20 mol
Cat I
Cl
HO
CF3
CF3
CF3
NO2
NO2
NO2
CF3
Raney-NiH2
H3PO4 64
NH2HCl
HO2C
Scheme 2 Synthesis of GABA receptors via hydrogen bonds directed organocatalysis mimicry of polyketide synthase
BINAP base+
(R)-baclofen ent 4
Up to 96 yield
OH
Cl
O
80 overall yield89 ee
OOMe
OMeOMe
NHO
(R)-rolipram 357 overall yield84 ee
OO
DioxaneH2O
Rh(acac)(C2H4)2R2R1N
R2R1N
R4R4
R3
R3
2M NaOH MeOH rt
TFA CH2Cl2 rt 2h
12h HCl Et2O rt 24h
(+)H3NCl(minus)
B(OH)2
Et3N toluene rfx 20h
Scheme 3 Metal-catalysed synthesis of GABA receptors
ISRN Organic Chemistry 5
CHOHO
MeOMeO
MeO
MeO
Ligand (55 mol)
NMM (6 mol)mol sieves rt
95 yield on 10 g scale 96 ee
NHNH O
NaOH TsOH
OMe
O
EtO
O
(R)-rolipram
Ligand
92 three steps
56
3
N
OO
N
EtO
O
OEt
O
OC4H9
NO2
NO2
OC4
4
H9
OC4H9
EtO2C
Ra-NiH2
H3PO
CO2Et
C4H9O
Mg(OTf)2 (5mol)
Scheme 4 Scalable metal-catalysed synthesis of both enantiomers of rolipram
N
N N
NH
O
O
N
NH
PMBPMB
PMB
PMB
PMB
O
OHN
NH
O
N
NH
O
+Cat 10 mol+
MeOH RT (2) TFA anisole
(Z)-DPC 08326 96 ee
(E)-DPC 08353 96 ee
O
N
NO
Cl
Cl
Cl Cl
Cl
Cl
OOAc
AcO
OAc
OAcN N
S
H H
N
H
Ar
O
OH
7
IIIO
OH
OF3C
F3C
F3C
F3C
CF3
CF3
(minus)O
(+)
R998400
NaBH4
(1) 220ndash230∘CHMPA
THF minus20∘C 48h
Scheme 5 Hydrogen-bonding assembly between organocatalyst ketimine and 120573-ketoacid in the preparation of the anti-HIV drug DPC 083
was used by Xu and coworkers [35] for the short asymmet-ric synthesis of the chiral piperidine derivative CP-999948 (Scheme 6) The previous asymmetric syntheses of thispotent neurokin-1 receptor antagonist were mainly basedon the use of metal complexes as catalysts but sufferedfrom several drawbacks for example low overall yield andenantioselectivity or a lengthy synthetic route Notably theorganocatalysed Takemotorsquos synthesis proceeded in five stepswithout the need to separate the diastereomeric intermediatesthat were cyclized as a mixture The catalyst employed wasa chiral thiourea IV which served as an activator of boththe nitroalkane and imine reactants The transition state isrelatively complex and is dominated by hydrogen-bondinginteractions
The simultaneous donation of two hydrogen bonds hasalso proven to be a highly successful strategy for electrophilicactivation in enzymes with an ldquooxyanion holerdquo having apostulated role in the stabilization of many high-energytetrahedral intermediates [36] It appears that living systemsdiscovered and made use of these interactions in the ubiq-uitous useful ring-forming Diels-Alder reaction eons agofor the construction of complex natural products so thatthe prospect of discovering a Diels-Alderase mimic wouldbe especially exciting Following this concept and inspiredby the antibody 13G5-catalyzed Diels-Alder cycloadditionof acrylamide with a carbamate (Scheme 7) taking placevia a cooperative multiple hydrogen bond coordination toboth diene and dienophile [37] a catalytic asymmetric
6 ISRN Organic Chemistry
H MeO
HN
HN
Ph
Ph
PhMeO
MeO
Boc
Boc
Ph
PhNH
HN
OMe
++
(i) TFA
80
80
75
Epimerization andreduction
Cat IV 10 mol
83 ee
95 ee
cistrans 191
Reductive amination of
HN
S
HN
Cat IV8 (minus)-CP-99 994
NBoc
F3C
F3C
NMe2
NO2
NO2
NH2
NO2
NO2
CH2Cl2 minus20∘C
(ii) K2CO3
o-MeOC6H4CHO
NH
NH
Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist
O
NH
R
H ONN
N NH H
57-His
HO
O
Asp-102O
NR
O
Ser-195
NN
Gly-193Gly-193 Ser-195Ser-195
Ser-195
N NH H
57-His
HO
O
Asp-102 (+)
H
HOxyanion hole
Serine protease
HN
O
O Ar
O
Antibody 13G5pH 74
+
95 ee 49 1 dr
N
O O Ar
HOO H
L36-Tyr
O
N
Asn-91L
H H
O
O Asp-50H
N(CH3)2
N(CH3)2
H2O 37∘C
(minus)
(minus)
(minus)
(minus)
NHCO2CH2Ar
CON(CH3)2
R998400
R998400
Scheme 7 Occurrence of the oxyanion hole in enzymatic processes
cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities
A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common
scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)
The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective
ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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4 ISRN Organic Chemistry
NHN H
As nO
NH
H
HisS
Cys
S
O
O
O
CoA
cisthis
asn
RNO
S O
O
R
N
N
H
NO
H
H
Chiralspacer R
S
O RO(minus)O(minus)
(minus)O (+)
(+)
(+)
R998400
NO2
Scheme 1 Activation of MAHT in the active of PKA synthase and in the chiral core of the organocatalyst
X
Y
+
NH
O
NH
OO
3-(R)-rolipram
NH
OCl
4-(S)-baclofenHCl
X = HY = Cl
X = OBnY = OMe
67 yield97 ee
S
O
OBn
Up to 97 yieldand 90 ee
82 yield 90 ee5 gr scale
S
O
Cl1
2
S
MeO
MeO
MeOMeO
MeO
O
OH
O
NNH
N
O
H
OMe
OMe
OMe
N
NNH
N
NH
OO
Cat II
Cat II 5 mol Cat I 20 mol
Cat I
Cl
HO
CF3
CF3
CF3
NO2
NO2
NO2
CF3
Raney-NiH2
H3PO4 64
NH2HCl
HO2C
Scheme 2 Synthesis of GABA receptors via hydrogen bonds directed organocatalysis mimicry of polyketide synthase
BINAP base+
(R)-baclofen ent 4
Up to 96 yield
OH
Cl
O
80 overall yield89 ee
OOMe
OMeOMe
NHO
(R)-rolipram 357 overall yield84 ee
OO
DioxaneH2O
Rh(acac)(C2H4)2R2R1N
R2R1N
R4R4
R3
R3
2M NaOH MeOH rt
TFA CH2Cl2 rt 2h
12h HCl Et2O rt 24h
(+)H3NCl(minus)
B(OH)2
Et3N toluene rfx 20h
Scheme 3 Metal-catalysed synthesis of GABA receptors
ISRN Organic Chemistry 5
CHOHO
MeOMeO
MeO
MeO
Ligand (55 mol)
NMM (6 mol)mol sieves rt
95 yield on 10 g scale 96 ee
NHNH O
NaOH TsOH
OMe
O
EtO
O
(R)-rolipram
Ligand
92 three steps
56
3
N
OO
N
EtO
O
OEt
O
OC4H9
NO2
NO2
OC4
4
H9
OC4H9
EtO2C
Ra-NiH2
H3PO
CO2Et
C4H9O
Mg(OTf)2 (5mol)
Scheme 4 Scalable metal-catalysed synthesis of both enantiomers of rolipram
N
N N
NH
O
O
N
NH
PMBPMB
PMB
PMB
PMB
O
OHN
NH
O
N
NH
O
+Cat 10 mol+
MeOH RT (2) TFA anisole
(Z)-DPC 08326 96 ee
(E)-DPC 08353 96 ee
O
N
NO
Cl
Cl
Cl Cl
Cl
Cl
OOAc
AcO
OAc
OAcN N
S
H H
N
H
Ar
O
OH
7
IIIO
OH
OF3C
F3C
F3C
F3C
CF3
CF3
(minus)O
(+)
R998400
NaBH4
(1) 220ndash230∘CHMPA
THF minus20∘C 48h
Scheme 5 Hydrogen-bonding assembly between organocatalyst ketimine and 120573-ketoacid in the preparation of the anti-HIV drug DPC 083
was used by Xu and coworkers [35] for the short asymmet-ric synthesis of the chiral piperidine derivative CP-999948 (Scheme 6) The previous asymmetric syntheses of thispotent neurokin-1 receptor antagonist were mainly basedon the use of metal complexes as catalysts but sufferedfrom several drawbacks for example low overall yield andenantioselectivity or a lengthy synthetic route Notably theorganocatalysed Takemotorsquos synthesis proceeded in five stepswithout the need to separate the diastereomeric intermediatesthat were cyclized as a mixture The catalyst employed wasa chiral thiourea IV which served as an activator of boththe nitroalkane and imine reactants The transition state isrelatively complex and is dominated by hydrogen-bondinginteractions
The simultaneous donation of two hydrogen bonds hasalso proven to be a highly successful strategy for electrophilicactivation in enzymes with an ldquooxyanion holerdquo having apostulated role in the stabilization of many high-energytetrahedral intermediates [36] It appears that living systemsdiscovered and made use of these interactions in the ubiq-uitous useful ring-forming Diels-Alder reaction eons agofor the construction of complex natural products so thatthe prospect of discovering a Diels-Alderase mimic wouldbe especially exciting Following this concept and inspiredby the antibody 13G5-catalyzed Diels-Alder cycloadditionof acrylamide with a carbamate (Scheme 7) taking placevia a cooperative multiple hydrogen bond coordination toboth diene and dienophile [37] a catalytic asymmetric
6 ISRN Organic Chemistry
H MeO
HN
HN
Ph
Ph
PhMeO
MeO
Boc
Boc
Ph
PhNH
HN
OMe
++
(i) TFA
80
80
75
Epimerization andreduction
Cat IV 10 mol
83 ee
95 ee
cistrans 191
Reductive amination of
HN
S
HN
Cat IV8 (minus)-CP-99 994
NBoc
F3C
F3C
NMe2
NO2
NO2
NH2
NO2
NO2
CH2Cl2 minus20∘C
(ii) K2CO3
o-MeOC6H4CHO
NH
NH
Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist
O
NH
R
H ONN
N NH H
57-His
HO
O
Asp-102O
NR
O
Ser-195
NN
Gly-193Gly-193 Ser-195Ser-195
Ser-195
N NH H
57-His
HO
O
Asp-102 (+)
H
HOxyanion hole
Serine protease
HN
O
O Ar
O
Antibody 13G5pH 74
+
95 ee 49 1 dr
N
O O Ar
HOO H
L36-Tyr
O
N
Asn-91L
H H
O
O Asp-50H
N(CH3)2
N(CH3)2
H2O 37∘C
(minus)
(minus)
(minus)
(minus)
NHCO2CH2Ar
CON(CH3)2
R998400
R998400
Scheme 7 Occurrence of the oxyanion hole in enzymatic processes
cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities
A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common
scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)
The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective
ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
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Analytical ChemistryInternational Journal of
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Journal of
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Quantum Chemistry
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Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 5
CHOHO
MeOMeO
MeO
MeO
Ligand (55 mol)
NMM (6 mol)mol sieves rt
95 yield on 10 g scale 96 ee
NHNH O
NaOH TsOH
OMe
O
EtO
O
(R)-rolipram
Ligand
92 three steps
56
3
N
OO
N
EtO
O
OEt
O
OC4H9
NO2
NO2
OC4
4
H9
OC4H9
EtO2C
Ra-NiH2
H3PO
CO2Et
C4H9O
Mg(OTf)2 (5mol)
Scheme 4 Scalable metal-catalysed synthesis of both enantiomers of rolipram
N
N N
NH
O
O
N
NH
PMBPMB
PMB
PMB
PMB
O
OHN
NH
O
N
NH
O
+Cat 10 mol+
MeOH RT (2) TFA anisole
(Z)-DPC 08326 96 ee
(E)-DPC 08353 96 ee
O
N
NO
Cl
Cl
Cl Cl
Cl
Cl
OOAc
AcO
OAc
OAcN N
S
H H
N
H
Ar
O
OH
7
IIIO
OH
OF3C
F3C
F3C
F3C
CF3
CF3
(minus)O
(+)
R998400
NaBH4
(1) 220ndash230∘CHMPA
THF minus20∘C 48h
Scheme 5 Hydrogen-bonding assembly between organocatalyst ketimine and 120573-ketoacid in the preparation of the anti-HIV drug DPC 083
was used by Xu and coworkers [35] for the short asymmet-ric synthesis of the chiral piperidine derivative CP-999948 (Scheme 6) The previous asymmetric syntheses of thispotent neurokin-1 receptor antagonist were mainly basedon the use of metal complexes as catalysts but sufferedfrom several drawbacks for example low overall yield andenantioselectivity or a lengthy synthetic route Notably theorganocatalysed Takemotorsquos synthesis proceeded in five stepswithout the need to separate the diastereomeric intermediatesthat were cyclized as a mixture The catalyst employed wasa chiral thiourea IV which served as an activator of boththe nitroalkane and imine reactants The transition state isrelatively complex and is dominated by hydrogen-bondinginteractions
The simultaneous donation of two hydrogen bonds hasalso proven to be a highly successful strategy for electrophilicactivation in enzymes with an ldquooxyanion holerdquo having apostulated role in the stabilization of many high-energytetrahedral intermediates [36] It appears that living systemsdiscovered and made use of these interactions in the ubiq-uitous useful ring-forming Diels-Alder reaction eons agofor the construction of complex natural products so thatthe prospect of discovering a Diels-Alderase mimic wouldbe especially exciting Following this concept and inspiredby the antibody 13G5-catalyzed Diels-Alder cycloadditionof acrylamide with a carbamate (Scheme 7) taking placevia a cooperative multiple hydrogen bond coordination toboth diene and dienophile [37] a catalytic asymmetric
6 ISRN Organic Chemistry
H MeO
HN
HN
Ph
Ph
PhMeO
MeO
Boc
Boc
Ph
PhNH
HN
OMe
++
(i) TFA
80
80
75
Epimerization andreduction
Cat IV 10 mol
83 ee
95 ee
cistrans 191
Reductive amination of
HN
S
HN
Cat IV8 (minus)-CP-99 994
NBoc
F3C
F3C
NMe2
NO2
NO2
NH2
NO2
NO2
CH2Cl2 minus20∘C
(ii) K2CO3
o-MeOC6H4CHO
NH
NH
Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist
O
NH
R
H ONN
N NH H
57-His
HO
O
Asp-102O
NR
O
Ser-195
NN
Gly-193Gly-193 Ser-195Ser-195
Ser-195
N NH H
57-His
HO
O
Asp-102 (+)
H
HOxyanion hole
Serine protease
HN
O
O Ar
O
Antibody 13G5pH 74
+
95 ee 49 1 dr
N
O O Ar
HOO H
L36-Tyr
O
N
Asn-91L
H H
O
O Asp-50H
N(CH3)2
N(CH3)2
H2O 37∘C
(minus)
(minus)
(minus)
(minus)
NHCO2CH2Ar
CON(CH3)2
R998400
R998400
Scheme 7 Occurrence of the oxyanion hole in enzymatic processes
cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities
A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common
scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)
The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective
ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
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Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
6 ISRN Organic Chemistry
H MeO
HN
HN
Ph
Ph
PhMeO
MeO
Boc
Boc
Ph
PhNH
HN
OMe
++
(i) TFA
80
80
75
Epimerization andreduction
Cat IV 10 mol
83 ee
95 ee
cistrans 191
Reductive amination of
HN
S
HN
Cat IV8 (minus)-CP-99 994
NBoc
F3C
F3C
NMe2
NO2
NO2
NH2
NO2
NO2
CH2Cl2 minus20∘C
(ii) K2CO3
o-MeOC6H4CHO
NH
NH
Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist
O
NH
R
H ONN
N NH H
57-His
HO
O
Asp-102O
NR
O
Ser-195
NN
Gly-193Gly-193 Ser-195Ser-195
Ser-195
N NH H
57-His
HO
O
Asp-102 (+)
H
HOxyanion hole
Serine protease
HN
O
O Ar
O
Antibody 13G5pH 74
+
95 ee 49 1 dr
N
O O Ar
HOO H
L36-Tyr
O
N
Asn-91L
H H
O
O Asp-50H
N(CH3)2
N(CH3)2
H2O 37∘C
(minus)
(minus)
(minus)
(minus)
NHCO2CH2Ar
CON(CH3)2
R998400
R998400
Scheme 7 Occurrence of the oxyanion hole in enzymatic processes
cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities
A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common
scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)
The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective
ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
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Carbohydrate Chemistry
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Advances in
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
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ISRN Organic Chemistry 7
CycloadditionsSynthetic elaboration ofvinyl indole derivatives
Het
NH
R
Ph
Natural product from algae
NH
OMeOMe
Antibiotic action
Carbazoles
NH
R
Antitumoral action
N
Me
Me
MeMeMe
NH
NMe
Pyridocarbazoles
R1
R2O
R3
Figure 4 Biological activity of ring-fused indoles
N
N
N
NN
S
H
O
X HH
N
N
O
O
R
X
O
O
R-N
[4 + 2]
X = Boc Ts or Me racemic mixturesX = H high enantioselectivities
Lewis base activationincrease in the HOMO energyof the diene
Broensted acid activationlowering in the LUMOenergy of the dienophile
N
N
NH N
H
S
H
O
Cat V
CF3
CF3
CF3
CF3
lowast
lowastlowast
Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles
double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives
Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly
enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities
212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
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[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
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[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
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[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
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[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
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ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
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[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
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[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
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[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
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[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
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[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
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[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
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[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
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[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
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[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
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Quantum Chemistry
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Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
8 ISRN Organic Chemistry
N NPh
O
O
H
HHN NPh
O
O
H
H N NPh
O
O
H
HHO
N
O
OH
H
HCl 9
quant97 ee
97 ee
88 yield95 5 dr
HCl 5 M TFA
(ii) Acetone CNDEAD Ph3P(iii) HClMeOH
93 eeN
H
N
H
H
Tubifolidine 11
Indoline 10tetra-H-carbazole 9
(ent)
68 yield 94 ee
N
RH
HH
H
Reference [43]
CF3
CO2Me
(i) LiAlH4
H2 PdC
Scheme 9 Synthetic elaborations of the vinylindole cycloadducts
N
Cl
Cl
Cl
Cl
Cl
MeO
MeO
O
O O
O
MeO
O O
N
N
O
O
NOH
OH
HN
H
N 3 steps
4 steps
+
Cat IV 10 mol
85
Cascade sequence
75 ee
(minus)-epibatidine
NH
NH
S
Cat IV
12
15
1413
NO2
NO2
NO2
NO2
NMe2
CF3
lowastlowastlowast
F3C
Toluene 0∘C
KOH EtOH 0∘C
Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15
[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies
have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs
Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
Journal of
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
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Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
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Quantum Chemistry
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Organic Chemistry International
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 9
OCl Cl
O
Ph PhPh
C l Me MeO
O
O
HO
MeCl
50 aq NaOH
60 overall
95 yield92 ee
(+)-indacrinone
N
Cat V
Cat V
OH
N
O
OHClCl
H
10 mol17 1816
MeOMeO
MeO
C l C l
20∘C 18h
CF3CF3
N(+)
N(+)Br(minus)
Br(minus)
Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18
O
MeO
MeO
O O
HOOC-O
O
N
OH
NHH
H
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl
(+)
Cat VI
Cat 55 mol
Toluene RT 15 h
O
+
92 yield 100 g scale40 ee
19
20 21
(minus)
Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis
18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process
Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions
Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20
The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis
The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
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Analytical ChemistryInternational Journal of
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Journal of
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Quantum Chemistry
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Organic Chemistry International
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
10 ISRN Organic Chemistry
O
O
NaOH tolueneCat VII (8 mol)
O
HO
HO
OPh
OPh O
+MeO
Cl
O
HOCl
OCl
Cl
Cl
NOH
OH
R
Cat VIIR = 2-naphtylmethyl
252423
22
N(+)
Br(minus)
Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573
O N
Cat (10 mol)
toluene RT 48 h O N
R
NaOH THF
COOH COOHR
Cl BaclofenCat VIII 54 yield97 ee (S)
94 ee (R)
91 ee (S)
89 ee (R)Cat ent-VIII 66 yield
(S)-(+)-4 HCl(R)-(minus)-4 HCl
N
NHO HOH
H
N
N
H
H
Cat ent-VIIICat VIII
+
26R
CF3CF3 (+)(+)Br(minus)
Cl(minus)
Br(minus)
F3CF3C
NO2
NO2
CH3-NO2 O2NO2N(+)H3N
Cat VIII R = 4-ClC6H4
Cat ent-VIII R = 4-ClC6H4
87ndash89100∘C
K2CO3 (5 equiv)
87ndash89
Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4
In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1
The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology
213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids
catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)
Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology
In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
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[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
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[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
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[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
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[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
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ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
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[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
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[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
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[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
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[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
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Analytical Methods in Chemistry
Journal of
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
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Analytical ChemistryInternational Journal of
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Quantum Chemistry
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Organic Chemistry International
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 11
NH
H
N
NH
H
N
OMeOMe
ORORO
AB
ElectrophileR1
R2
(+)
Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair
Cat IX
N
S
O
NS
O
NH
Cat IX (20 mol)
Yields 67ndash94dr 75 25ndash98 2ee 80ndash99
N Ts Ts+
292827 SEtSEt
N
TMSO N
H
R = i-Pr i-Bu R = aryl heteroaryl
Et2O 20∘C 16h R1
1
R1
R2
R2
2
Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction
offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs
Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)
In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into
dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34
Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting
12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Carbohydrate Chemistry
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Journal of
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Advances in
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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CatalystsJournal of
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12 ISRN Organic Chemistry
HNXO O
O O
N H
O X
SHNN
+ Catalyst
Lawessonrsquosreagent
Toluenereflux
(i) MeI
(96 compounds)
N
NHO
HO
H
H
H
NH
H
H
(+)-cinchonine
(minus)-cinchonidine
Cat X
Cat XI
Cat
34
3032
33
31
R2
R2
R1
R1
R1
R3R3
R4
R3
R2OC
R2OC
(ii) NH2R5
OR2C
SO2Ar
NHR5
N Cat
NN
R1
R4
R3
OH
NN
R1
R4
R3
O
Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep
N
CHO
NHO
HO O
N
O
N
OMeOMeOMe
OMe
OMe
+5 steps
(minus)-Huperzine A45
AcONa AcOH
7764 ee
N
NH
OH
N
NHHO
HO
N
OMe
O
O
Intermediate ionic complex(minus)-cinchonidine XI
minus+
(minus)-cinchonidine
36
37
35NH2CO2Me
CO2Me
CO2Me120
∘C 24hDCM 10d minus10∘C
Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence
from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst
214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to
the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs
The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Journal of
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Analytical ChemistryInternational Journal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 13
N
F
NH
F
N
OF
NH
OFF
OO
OHP
O
Cat XIII
NH
H H
OEt
OEt
EtO
EtO
Et Et
t-But-Bu
O O
NH
H HO O
12 equivCat 1 mol
24 equivCat 1 mol
79 yield 96 ee
67 yield 93 ee
N
O
F
(R)-Flumequine 43
(R)-Levofloxacine 44
37 41
40
4238
39
O
N
F
COOH
COOH
O
N
N
SiPh3
SiPh3
CH2Cl2 RT 48h
PhH 60∘C 14h
Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44
N
O
O
NH
H H
OEtEtO
Me Me
O O
NH
O
O
N
O
O
Me
OO P
O
OH
Cat XIV
94
Galipinine 48
95
91 ee47
45
46
(i) CH2O AcOH(ii) NaBH4
1mol cat XIV PhH 60∘C
Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction
the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)
The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps
Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine
species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains
Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important
14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
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[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
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[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
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[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
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ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
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[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
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[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
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[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
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[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
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[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
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[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
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[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
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Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Analytical ChemistryInternational Journal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
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14 ISRN Organic Chemistry
O O
X
+ N
X
H
P
O
O H+ O
O
HN
X
Condensation
Yield up to 86Up to 97 ee
10 mol
OO
OHP
O
Cat XV
Cat XV
X = O S
52
51
535049
54
O
NH
NH
O
R3O2C
H2N R1
R1
R1
OR3
OR3R2
R1 R2
R2
NH2
NH2 CH2Cl2 25∘C
lowast
lowast
ROlowastRO
R1 = Ar AlkR2 = AlkR3 = Alk
Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction
pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)
An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope
22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]
221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic
reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis
Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)
The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis
A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
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Carbohydrate Chemistry
International Journal of
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 15
HN HO
OR
O
N HO
HOHO
HO
HO
HO
HOOH OH
OH
RCHO
N HO
O
N HO
NO
O
R H
O H
N HO
O
R
N HO
R
R2
R2
R2
R2
R2
R2
R2 R2
R1
R1
R1
R1
R1R1
R1R1
H2O
H2O
+
+
minus
minus
=|=
Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction
N
NH
O Me
MeMe
Me
Me
Me
Ph Ph
N
NH
OMe
I-generation II-generation
O + Lewis acid (LA) OLA
O + NR
R
X
XVI XVII
120575
120575
minus
minus+
+
R2N middot HX
Scheme 22 Iminium activation through LUMO lowering
The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart
[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]
An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well
16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
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[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
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ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
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[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
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[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
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16 ISRN Organic Chemistry
Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis
O O+
OCatalyst
cocatalystconditions
O O
O
NH
HN
Ph
Ph
Ph Ph
Ph
PhPh
Ph
Ph
Ph
Ph
Ph
Ph
XVIII
N
MeO
NH
XXIV
XIX
NNH H
OO
HNNH
XXVI
XX XXII
Warfarin
N
XXI
N
NH
O
BrBr
Br
Br
XXIII
OH
OH
OHOH
XXV
NH2
NH2
NH2
NH2
NH2NH2
NH2
NH2
H2NSO3Li
NHP(O)Ph2
lowast
CO2H
Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0
∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40
∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported
demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1
The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis
is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
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Carbohydrate Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Analytical ChemistryInternational Journal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 17
N
O
OH
O
+
Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway
mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]
Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)
A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)
Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)
A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)
Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
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Journal of
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Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Analytical ChemistryInternational Journal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
18 ISRN Organic Chemistry
NO
NF
FN
ON
NH
NHOH
Telcagepant
NO
FF HN N
O
+
F3C F3C
NH2
Scheme 23 Retrosynthetic disconnection of Telcagepant
FF CHO CHO
+
(6 equiv)
Cat (5 mol)
aq THF
NH
OH
PhPh
TMSClimidazole
NH
OTMS
PhPh
Cat XXVII
FF
73 assay yield95 ee
55 56CH3NO2
NO2t-BuCO2H (5mol)B(OH)3(50mol)
Scheme 24 Organocatalysed Michael addition
Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid
Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use
The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical
need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed
The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)
An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)
The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets
ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
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Carbohydrate Chemistry
International Journal of
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Advances in
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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ElectrochemistryInternational Journal of
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ISRN Organic Chemistry 19
FF
(i) n-BuLi
(ii) Acrolein
THFwater
FF
OH
TEMPO (1 mol)NaOCl NaBr F
F CHO
CHO
Organocatalyticstep
FF
86 7395 ee
Pyrrolidine (35 mol)
DMA
FF
NHAc
NHAc NHAc
NHAc
FF
i-PrOAcHeptane
ZE gt 99 1ZE 94 6ee gt 99
9391
95
48 overall yieldfrom difluorobenzene
5758
55
56
NO2NO2 NO2
CO2Hn-Bu3NH+
n-Bu3N
COminus2
NaO2C CO2Na CO2HH2SO4
HO2C
DMA 15∘C
THF minus55∘C
K2HPO4 MTBE(iii) H2SO4
Scheme 25 Large scale preparation of 58
FF
LiCl (03 equiv)
i-PrOHF
F (ii) NaOH
FF
HN
95
83
95
95
DMAP (5 mol)
NO
FF NHAc
NHAc
NHAc NHAc NHAc
NO
FF
aq DMSONaOH
73 overall yieldfrom the enamide
(i) HCl aq i-PrOH
(ii) HCl MTBEN
OF
F
(ii) Piperidine(iii) KOt-Bu EtOH
HN N NHO
NO
NF
FN
ON
OH
Telcagepant potassium saltEtOH solvategt998 puritygt999 ee
626160
5957
NO2 NH2CF3
CO2H
F3C
F3C F3C F3C
CO2i-Pr CO2i-Pr
95∘C Clminus
NH3+
(i) CDI Et3NTHF 60∘C
(i) CF3CH2OTfEt3N 50ndash60∘C
H2SO4 (25 equiv)H2 (50ndash100 psig)
35ndash50∘C
Pd(OH)2C
t-BuCOCl Et3N
NminusK+
middotEtOH
i-PrOAc 35∘C
Scheme 26 Second part of the synthesis of Telcagepant
CHO
CHO CHO
CHOHOOC COOH
+
+
(route a)
(route b)
83 overall yield
Up to 75 yield and 95 ee
64 65
66
NHBoc NHBocCO2Me
RHN
OHNH
PhPh
OTMS NOR OH NH
P
NH2
R = Cbz Boc C6H11-CO C6F2H9-COR1
R1R1
R1
= Ph p-Br-Ph napht
Mo(CO)6
CO2Me
Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes
20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
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Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Journal of
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Analytical ChemistryInternational Journal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
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20 ISRN Organic Chemistry
NN
NN
F F
Ph
O NH
Maraviroc (UK-427 857)69
Figure 7 The structure of maraviroc (69)
Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee
Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)
In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities
The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters
Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization
Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
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[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
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[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
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[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
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ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
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[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
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[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
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[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
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Analytical ChemistryInternational Journal of
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Journal of
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Quantum Chemistry
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Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 21
HNN
NNF F
Ph
Ph
O NHHN
OHO
O
+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii
Conditions i ii = 78 80 ee3 steps 53 overall yield
Conditions ii iv = 78 92 ee3 steps 45 overall yield
67
68
69
CHO
Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h
Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc
EtO
EtOH
NH
Ph
Ph Ph
O O
F
O
HN OHO
F
N O
Ph
Ph
F
OH
N O
F
O
OO
F
O
HO
N O
F
+
(minus)-paroxetine
+Route a
Route b
72 86 ee
76
84 90 ee
10 mol cat XXVIII
Cat XXVIII
20 mol cat XXVII
rfx
72
70
71
NH
ArAr
OTMS
BnO2C
CF3CH2OH
CO2Bn
CO2BnCO2Bn
CO2R
CO2Bn
BH3 THF rt
LiAlH4 THF
Ar = 35 minus(CF3)2Ph
Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis
of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion
Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with
a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82
This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Chemistry
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Analytical Methods in Chemistry
Journal of
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
22 ISRN Organic Chemistry
O
NH
O
Et
Et
Et
Cl
Cl
Cl
ClCl
N
N
OMe
HCat XXIX+ Cat XXIX 20 mol
MDM2-p53
NH
O
NH
NH
Et
O
NH
NCl
O Ar
Ar
Ar
HCat
Cat
+ Cat
O
IntramolecularMichael addition
Michael addition
70 yield45 1 dr84 ee
74
7773
7576
NH2
o-FC6H4CO2H (30mol)Toluene 1M 40
∘ 72h
Ominus
+
Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole
OH
O
+
NH
PhPh
OTMS
1 mol
toluene RT 6 hO
O
syn anti 78 197 ee
PO
EtOEtO
O
p-TolSHO
S
56 yield over the three one pot steps
(i) TFA tolueneRT 4 h thenevaporation
RT 30 min thenevaporation
toluene RT 20 min OS
O
RT 48 h thenevaporation
AcHN
OS
(i) Zn TMSCl
2 h then
AcHN
O
81 yield over the six one-pot steps
+
OOH
O
+
Evaporationthen EtOH RT
10 min O
78 79 a
79 c
79 b
80 81
82 83 (minus)-oseltamivir 84
XXVII
NO2
NO2NO2NO2
NO2
N3
NO2
NO2NO2
NH2
CO2Et
CO2Et
CO2EtCO2Et
CO2Et
CO2Et CO2Et CO2Et
CO2EtCO2Et
P(O)(OEt)2
P(O)(OEt)2
O2N
t-BuO2Ct-BuO2Ct-BuO2C
t-BuO2C t-BuO2C
t-BuO2C
t-BuO2C
ClCH2CO2H (20mol)
(ii) (COCl)2 toluene
(iii) TMSN3 pyridineAcOH Ac2O
Cs2CO3
0∘C to RT 4h
minus15∘C 36h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 9h
Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
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Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
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Journal of
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Analytical ChemistryInternational Journal of
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Quantum Chemistry
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CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 23
OH
O
+
NH
PhPh
O
AcHN
AcHNAcHN
AcHN
O
P
O
then EtOH 1 h
10 mol
OS
(i) Zn TMSCl
2 h then
O
28 yield on gram scale
O
NHAc
XXVII
85
84
EtO
EtOCO2Et
CO2EtCO2Et
CO2EtCs2CO3
0∘C 3 h
NO2NO2
NO2
NH2
NO2
p-TolSHminus15
∘C 36h
(minus)-oseltamivir
HCO2H (30mol)ClC6H5 20∘C 15h
EtOH 70∘C
NH3 0∘C 10min(ii) K2CO3 RT 14h
OSiPh2Me
Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84
zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation
A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation
In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant
interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide
3 Concluding Remarks
Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram
The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a
24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
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[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
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Carbohydrate Chemistry
International Journal of
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Advances in
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Quantum Chemistry
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ElectrochemistryInternational Journal of
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24 ISRN Organic Chemistry
partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper
References
[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006
[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004
[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011
[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012
[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009
[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008
[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010
[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008
[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007
[11] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004
[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009
[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006
[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007
[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003
[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006
[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010
[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007
[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013
[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004
[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008
[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011
[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012
[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998
[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999
[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007
[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012
[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000
[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014
[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007
ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Carbohydrate Chemistry
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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Quantum Chemistry
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Organic Chemistry International
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CatalystsJournal of
ElectrochemistryInternational Journal of
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ISRN Organic Chemistry 25
[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011
[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003
[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002
[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013
[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005
[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002
[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995
[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008
[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002
[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997
[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007
[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009
[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998
[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004
[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis
of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008
[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005
[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008
[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997
[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999
[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003
[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004
[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004
[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010
[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010
[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013
[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984
[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986
[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986
[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008
[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009
[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003
26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
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Analytical Methods in Chemistry
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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
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CatalystsJournal of
ElectrochemistryInternational Journal of
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26 ISRN Organic Chemistry
[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010
[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981
[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004
[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004
[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011
[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011
[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998
[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004
[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004
[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005
[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011
[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010
[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986
[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992
[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction
organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006
[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006
[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005
[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008
[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008
[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974
[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971
[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000
[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004
[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000
[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002
[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002
[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002
[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002
[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005
[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 27
[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002
[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003
[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005
[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004
[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001
[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000
[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996
[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006
[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003
[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003
[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006
[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010
[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011
[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011
[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012
[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective
Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013
[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007
[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009
[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009
[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007
[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007
[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010
[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010
[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008
[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007
[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008
[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005
[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005
[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
28 ISRN Organic Chemistry
[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008
[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010
[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000
[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002
[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000
[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002
[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009
[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006
[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008
[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010
[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009
[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002
[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000
[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007
[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003
[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005
[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008
[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003
[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009
[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997
[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993
[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006
[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008
[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006
[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006
[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009
[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010
[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010
[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012
[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
ISRN Organic Chemistry 29
short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012
[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012
[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013
[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009
[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006
[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010
[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Submit your manuscripts athttpwwwhindawicom
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Inorganic ChemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
International Journal ofPhotoenergy
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Carbohydrate Chemistry
International Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in
Physical Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom
Analytical Methods in Chemistry
Journal of
Volume 2014
Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
SpectroscopyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Chromatography Research International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Applied ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Theoretical ChemistryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Spectroscopy
Analytical ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Quantum Chemistry
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Organic Chemistry International
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
CatalystsJournal of
ElectrochemistryInternational Journal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014