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Organocatalysis –A New Tool for Industry
The Royal Society of Chemistry SymposiumCatalysts for Change
2
What is my mission
What is organocatalysis
To present an overview organocatalytic reactions
To show the synthesis of optically active building blocksand their application
To use simple and easy available starting compoundsand catalysts
3
Organocatalysis
Advantagesa) Easy to prepareb) Easy to handle – water, airc) Easy to scale upd) No metal contaminatione) Easy screeningf) “More flexible” than metal
catalysisg) More complex reactions
and multiple stereocenter formation
Disadvantagesa) High catalyst loadingsb) ”Premature”
4
Organocatalysis - activation
N
R
enamine iminium
N
R
dienamine SOMO
cinchona alkaloids/PTC
proton activation
N
OMe
H
N
OH
Quinine
O
RR
XH
XH
O
R
XH
XH
R1
N
R
N
R
R* R*
R* R*
5
An “old” example – Warfarin – from lab to humans
100% atom economic, one-step synthesis of optically active anticoagulants
100% atom economic, one-step synthesis of optically active anticoagulants
O O
OH Ph OWarfarin
sold as racemate for 40 years
Activity: (S)-enantiomer is about 5 times higher than the activity of the (R)-enantiomer, and the enantiomers are metabolized by different metabolic pathways.
Different half-lives of the enantiomers: 21-43 and 37-89 h for (S)- and (R)-warfarin, respectively.
Problem: patients are responding very differently to racemic warfarin.
Treatment of patients with optically pure warfarin will reduce the dose problem. Advantage: weak patients, unable to tolerate the stronger racemic or (S)-warfarin,could be treated with the milder (R)-warfarin.
The most important advantage of administrating optically pure warfarin is the possibility of eliminatingdrug-drug interactions, which represents another serious problem with racemic warfarin, as the cytochromeP-450 enzyme responsible for metabolising warfarin is also metabolizing other drugs
S-Warfarin metabolized by cytochrome P450
6
P. A Willams et al. Nature, 2003, 424, 464P. A Willams et al. Nature, 2003, 424, 464
7
Development of catalysts
O O
OH Ph O
O
OH
O
O
Ph+Chiral amines
1) SOCl22) MeNH2
COOH
NH2 NH2
O NHMe
Quant. >90%
NH2
NHMe
Quant.
O
COOHNH
NMe
COOH
LiAlH4
L-phenylalanine
NH
NMe
COOH
NH
HNPh
PhCOOH 96% yield
82% ee/>99% ee
85% yield70% ee/>99% ee
Catalyst can be reusedwithout drop in yield and ee
NH2
NH2
Quant.
O
COOH
NH
HN
COOH
WO 2003/050105Halland, Hansen, Jørgensen Angew. Chem. Int. Ed. 2003, 42, 4955
8
Variation of enones and coumarins
O O
OH O
Me
Cl
O O
OH O
Me
NO2
O O
OH O
Me
OMe
O O
OH O
Me
S
68% yield87% ee
81% yield83% ee
91% yield82% ee
78% yield79% ee
O O
OH O
Me
81% yield83% ee
O O
OH O
Me
99% yield84% ee
Me
O O
OH O
Me
77% yield83% ee
Me Me
O O
OH O
Me
O
75% yield76% ee
O O
OH O
84% yield82% ee
Me
O O
OH O
71% yield85% ee
Me
Me
O O
OH O
12% yield84% ee
Cl
O O
OH O
Me
N
68% yield87% ee
Me O O
O
Me
S
OH
O
O
MeO
OH
O
O
Me
MeO
OH
76% yield85% ee
81% yield85% ee
84% yield78% ee
9
Aldehyde activation
Aldehydes
10
H-Bonding directing vs. steric shielding
Y
XN
R
N
R
YX
XH
O
H(S)R
XYH O
H(R)R
XYH
From aboveRe-face attack
From belowSi-face attack
H-bonding directing Steric shielding
11
Catalyst design
Marigo, Wabnitz, Fielenbach, Jørgensen Angew. Chem. Int. Ed. 2005, 44, 792Franzén, Marigo, Fielenbach, Wabnitz, Kjærsgaard, Jørgensen J. Am. Chem. Soc. 2005, 127, 18296
Bertelsen, Jørgensen, Chem. Soc. Rev. 2009 Advanced article
12
Catalyst synthesis and properties
NH OH
ArAr
TMSOTf, Et3N
NH OTMS
ArAr
>98% yield
NH OTMS
ArArO
NN
NS
PhO
SPh+
Ar =
R
R
1. The TMS-group can be installed in one single quantitative step.
2. The catalyst is soluble in the most common organic solvents.
3. The reaction can be easily followed by 1H NMR spectroscopy.
R Taft E’sValue
ee[%]
H 0 77
CH3 - 1.24 90
CF3 - 2.40 98
Franzén, Marigo, Fielenbach, Wabnitz, Kjærsgaard, Jørgensen J. Am. Chem. Soc. 2005, 127, 18296Focus review: Mielgo, Palomo, Chem Asian J. 2008, 3, 922
13
α-Functionalization of aldehydes
Feature article: Marigo, Jørgensen Chem. Commun. 2006, 2001Bertelsen, Nielsen, Jørgensen Angew. Chem. Int. Ed. 2007, 46, 7356
14
α-Amination reactions
Bøgevig, Kumagurubaran, Juhl, Zhuang, Jørgensen Angew. Chem. Int. Ed. 2002, 41, 1790List J. Am. Chem. Soc. 2002, 124, 5656
Ketones: Kumagurubaran, Juhl, Zhuang, Bøgevig, Jørgensen J. Am. Chem. Soc. 2002, 124, 6254
15
New catalyst and scope
Franzén, Marigo, Fielenbach, Wabnitz, Kjærsgaard, Jørgensen J. Am. Chem. Soc. 2005, 127, 18296
16
α-Sulfenylation reactions
Ar = 3,5-(CF3)2-PhO
R
+
O
R
S
NH
Ar
OTMSAr
N NN
SPh
PhOH
R
SPhNaBH4
R Yield[%]
ee[%]
i-Pr 81 98
Me 60 95
Et 85 96
Bn 94 97
Allyl 64 96
t-Bu 83 95
Marigo, Wabnitz, Fielenbach, Jørgensen Angew. Chem. Int. Ed. 2005, 44, 792
17
α-Fluorination
O
HR
NaBH4NH
F -source
R*
O
HF
R
OHF
R* *
Direct use in pharmaceuticals,agro and material science
Problem-challenge:α-Fluoro aldehydes are unstable and very volatile –racemization – the high electronegativity of F
Enders, Hüttl Synlett, 2005, 991Marigo, Fielenbach, Braunton, Kjærsgaard, Jørgensen Angew. Chem. Int. Ed. 2005, 44, 3703
Steiner, Mase, Barbas Angew. Chem. Int. Ed. 2005, 44, 3706Beeson, MacMillan J. Am. Chem. Soc. 2005, 127, 8826
18
Scope of the reaction
O
HR
NaBH4
NH O
HF
R
OHF
R* *N
SO2Ph
SO2Ph
RPrBuHexBn(CH2)3BnCyt-Bu1-Ad
Yield>95>9055647469>9075
Ee9691969193969796
Cat. loading:down to 0.25 mol%
F
ArAr
OTMS
NFSI
19
Propagylic and allylic fluorides
20
Propagylic fluorides
O
R
SO2N3
NH
O
P(OMe)2O O R
F R = Bn, 56%, 92% eeR = alkyl, 65-67%, 93-99% eeR = (CH2)3CO2Me, 57%, 80% ee
NH
ArAr
OTMS
(1 mol%)Ar = 3,5-(CF3)2C6H3
NFSI
R
FPh S N3
Sodium-ascorbateCuSO4-4 H2O1:1 t-BuOH:H2O
S NNN F
R
1) Cp2ClZr, 2) I2Bn
FI
Bn
FPh
CuI, PhBr
O
R
organocatalysis One-pot reaction:R = Bn (50% over three steps)
Bn
FCuI, MeCN
NBn
Ph ClO
NBn
O
PhF
Bn
,
Jiang, Falcicchio, Jensen, Paixão, Bertelsen, Jørgensen J. Am. Chem. Soc. 2009, 131, 7153
21
Mechanism
NH
ArAr
OTMS
N
ArAr
OTMS
R1
N
ArAr
OTMS
R1
N
ArAr
OTMS
R1
F
O
R1 F
R1
Ph3P=CHCO2Me
MeO
O
N2
P(OMe)2O
N2
P(OMe)2O
- AcOMe
O PPh3
CO2MeR1
F
R1
CO2Me
F
O
PPh3O-
O P(OMe)2
N2
R1
F
O
R1
FH
R1
F
- N2NFSI
OP(OMe)2O O
NH
SO2N3
+
O2P(OMe)2-
NN
47-53% yield93-96% ee
22
α-Chlorination of aldehydes
Brochu, Brown, MacMillan J. Am. Chem. Soc. 2004, 126, 4108Halland, Braunton, Bachmann, Marigo, Jørgensen J. Am. Chem. Soc. 2004, 126, 4790
Ketones see: Marigo, Bachmann, Halland, Braunton, Jørgensen Angew. Chem. Int. Ed. 2004, 43, 5507
23
Variation in aldehydes
+
Cat(10 mol%)
OH
R
NCS
OCl
RCH2Cl2,rt 1-10h
NH
CONH2 NH
Ph Ph
Yield9999959395907575
RMeEt
i-Prt-Bu
n-HexAllyl
CH2Ph(CH2)2OTBS
Ee7580879570747885
Yield-
9090-
99908295
Ee-
9594-
95959581
24
Synthetic manipulations
O
R
O
RHO TMSCHN2
O
RMeO
NaBH4
OH
R
n-Hexyl
O
KMnO4
Cl
Cl Cl
Cl
R = Bn, 95% eeR = t-Bu, 95% eeR = n-Hexyl, 95% eeR = Et, 95% ee
95% ee
KOH
R = Et, 95% eeR = i-Pr, 94% eeR = n-Hexyl, 95% eeR = (CH2)2OTBS, 85% ee
O
EtMeO
R>90%
>90%
R = N3, 95% eeR = NH2, 95% ee
OH
Et
N3
OH
Et
NH2H2, Pd/C
95% ee 95% ee
NaN3
N3
O
RHO
Cl Prepared in multi-tons scale/year
OH
Et
NH2NH
Et
HOHN Et
OH
One of the most important amino alcohols
ACIE 2004, 43, 788Tuberculostatic
etambutol
25
α-Arylation
OH
OH
OR O
HO
OH +
O
O
Chiralamine
catalyst
R'
R' R'
R
Mechanism – two catalytic cycles
Aleman, Cabrera, Maerten, Overgaard, Jørgensen Angew. Chem. Int. Ed. 2007, 46, 5520
26
α-Arylation of aldehydes
OO
OH
R
OHO
OR'
NH
EtOH or H2O
O
O
O
O
(20 mol%)
R'
O
O
ClO
O
MeCl Me
PhPh
OTMS
O
OH
R
OH
R = alkyl86% - quant yield96 - >99% ee
O
OH
i-Pr
OH
52% yield99% ee
O
OH
R
OH
R = alkyl65-95% yield96 - >99% ee
Cl
O
OH
R
OH
R = alkyl72-85% yield>98% ee
MeCl Me
R
27
Application - α-methylene-δ-lactones and δ-lactams
NR2
O
R1
O
O
R1
O
O
H
H
H3C
O
OO
O
H
OH
O
O OOH3C
H
O
H
HCH3
CO2H
OO
O O
OO
OHH
O
H
O
OH
OH
Albrecht, Richter, Krawczyk, Jørgensen J. Org. Chem. 2008, 73, 8337
28
α-Methylene-δ-lactones and δ-lactams
29
From α- to β-functionalization
Jorge Cham – www.phdcomics.com
30
Aldehyde activation
α,β-Unsaturated aldehydes
N R*
H2O
R
N R*
R
N R*
R
NH
R*
H
H
H
Nucleophile
O
HR
O
HR
H2O
N
N
N
31
β-Functionalization of α,β-unsaturated aldehydes
O
NH
Ar
OTMSAr+
>20:1 (E):(Z); 97% eeJACS 2009, 131, in press
R
O
R CH(CO2R)2
95% eeACIE 2006, 45, 4305
O
R
95% eeHayashi: ACIE 2006, 45, 6853
O
R
95% eeHayashi: OrgLett 2007, 9, 2859
N O
O
R
Z
R1
96% eeChow: TetLett 2007, 48, 277
Cordova: TetLett 2007, 48, 5701
NH
CO2Et
CO2Et
R
R1
O
98% eeCordova: TetLett 2007, 48, 6252
O
R NHPg
98% eeChemEurJ 2007, 13, 9068
Cordova: ChemCommun 2007, 849
O
R NHAr
94% eeACIE 2007, 46, 1983
O
R O
97% eeJACS 2007, 129, 1536
Pg
O
R S
97% eeJACS 2005, 127, 15710
Pg
O
R P(OR)2
97% eeMelchiorre: ACIE 2007, 46, 4504Cordova: ACIE 2007, 46, 4507
JOC 2007, 72, 8893
X
O
R
96% eeJACS 2008, 130, 12031
NH2C
R1COOH
O
R
97% eeJACS 2009,131, in press
R1
O
R R1
32
Application
NH
R1
OR2
N
CO2R3
R1
PGO
CO2R3
R1
CO2R3
OCO2R3
R1
CO2R3
O
O
CO2R3
R1
O
NH
F
O
O
Paroxetine
NH
Fermoexetine
OMe NH
Cl
O
O
Rosche-1Peptidomimetic inhibitor
Brandau, Landa, Franzén, Marigo, Jørgensen Angew. Chem. Int. Ed. 2006, 45, 4305
33
Application
R1
O
CO2R2R2O2C R1 CO2R2
CO2R2
ONH OTMS
ArAr
Ar = 3,5-(CF3)2-Ph 86-94% ee
O
CO2MeO
R
O
O
O OMe
OMe
R
R = H, 57%, 90% ee, dr >99:1R = Br, 49%, 93% ee, dr >99:1
a) NaCNBH3, AcOH, THFb) SiO2, CH2Cl2
O
O
O OBn
OBn
F CO2Bn
N
Ph
O
NH
F
O
OO
1/2 HCl
N
Ph
OH
a b c,d,e
F F
Synthesis of (-)-paroxetine: a) PhCH2NH2, NaBH(OAc)3, dioxane, 70%;b) LiAlH4, THF; c) MsCl, NEt3, toluene; d) sesamol, NaH, DMF, 60 °C;e) i) H2, 5% Pd/C; ii) HCl.
34
Optically active 3,4-dihydropyran derivatives
Franke, Richter, Jørgensen Chem. Eur. J. 2008, 14, 6317
N
R
OTMS
ArAr
N
R
OTMS
ArArAttack from
Re-face(below)
H2O
N
R
OTMS
ArAr
NH OTMS
ArAr
O
R
H2O
O
O
O
O
OH
O
OHO
OR
OAcO
OR
Acetylation
+OR
O
O
O
O
AcO
R2) Ac2O, Et3N, DMAP,
n
n
R = Ar: 65-95%, 82-90% eeR = Alkyl: 74-85%, 84-96% ee
Ar = 3,5-(CF3)2C6H3PhCO2H (10 mol%)
NH
ArAr
OTMS
35
Optically active 1,4-dihydropyridines
O
R1R3
OCOR2
N
R4
R1HCOR2
R3
Ar = 3,5-(CF3)2C6H3PhCO2H (10 mol%) NH2-R4, CaCl2
NH
ArAr
OTMS
33-60% yield64-92% ee
OEtO
O
* OEtOH
O
Mg(ClO4)2
N
Ph
EtHCOMe
Me 90% ee
90% yield82% ee
Franke, Johansen, Bertelsen, Jørgensen Chem. Asian J. 2008, 3, 196
36
Application to amino acid synthesis
NO
O
R3
R2
**R2H
OR1
H2N CO2HR1 H
O+
Organocatalysis
*R2
H2N CO2H
StreckerreactionR1 N
R1 R2
R3
+aa
Alkylation of-substituted
glycine imines
b
b
N CO2R4
R1
R3 + R2 X CN
C-4
+
(10 mol%)Ar = 3,5-(CF3)2C6H3
rac
OR1 NO
O
Ph
i-BuOR1
N
OO
Ph i-Bu
NH
Ar
OTMSAr
C-4R1: aryl: dr up to 20:1, 94%R1: alkyl: dr up to 7:1, 94%
+
(10 mol%)Ar = 3,5-(CF3)2C6H3
rac
OR1 NO
O
Ph2HC
MeOR1
N
OO
Ph2HC Me
NH
Ar
OTMSAr
R1: aryl: dr up to 20:1, 96%R1: alkyl: dr up to >20:1, 94%
Cabrera, Reyes, Alemán, Mielli, Jørgensen J. Am. Chem. Soc. 2008, 208, 12031
37
Application to amino acid synthesis
Ph3P=CHCO2Me
CH2Cl2, rt
OR1
N
OR2R3
O
R1
N
OR2R3
O
CO2Me
60-92% yield
R1
R3COHN
R2
O
OMeTMSCl
MeOH, rt
CO2Me
50-99% yield
OR1
N
OR2R3
ONCOR3
OHR2
R1
R1 = n-Pr, R2 = i-Bu, R3 = Ph (71% yield)R1 = Et, R2 = i-Bu, R3 = o-ClC6H4 (90% yield)
MeO2CTMSCl
MeOH, rt
OR1
R2CO2MeR3COHN
carbapenem antibioticsintermediate
38
Application to amino acid synthesis
On-PrN
Oi-Bu
Ph
O
N
n-Pr
PhCOHNi-Bu
ONHp-Ts
NHNHSO2Tol
p-TsNHNH2
H2O
NNHSO2Toln-PrN
Oi-Bu
Ph
O
p-TsNHNH2a
b
Path a
Path b
N
n-Pr
PhCOHNi-Bu
ONHp-Ts
NHNHSO2Toln-PrN
Oi-Bu
Ph
O
NHNHSO2Tol
p-TsNHNH2
H2O
p-TsNHNH2
N
n-Pr
PhCOHNi-Bu
ONHp-Ts
OH
60 cyclic depsipeptidesf rom cyanobacter
39
Application to amino acid synthesis
NaBH4,MeOH
NaBH4,MeOH
OR2
NHCOPhR1
MeO2C
t = 10 min t = 24 h
R1
N
OR2R3
O
CO2Me
R1 = n-Pr (75% yield)R1 = (Z)-n-hex-3-enyl (65% yield)
R1
PhCOHN i -Bu
OH
CO2Me
R1 = n-Pr, R2 = i-Bu (80% yield)R1 = Et, R2 = MeSCH2CH2 (40% yield)
MeOH, 24 h
NaBH4 Pyran: carbohydrates, alkaloids,polyether antibiotics, and pheromones
40
N-Heterocycle conjugate addition to α,β-unsaturated aldehydes
Dinér, Nielsen, Marigo, Jørgensen Angew. Chem. Int. Ed. 2007, 46, 1983
41
β-Hydroxylation of α,β-unsaturated aldehydes
R
O
HO R
O
O
Pg
Chiralamine
catalystR
OH
O
Pg
NaBH4
MeOHPg
MeOH
Pd(OH)2/C, H2
R
OH
OHin situ
+
R
O
HO Pg+R
O
OPg
R
HO O Pg
Bertelsen, Dinér, Johansen, Jørgensen J. Am. Chem. Soc. 2007, 129, 1536
42
β-Hydroxylation of α,β-unsaturated aldehydes
R
O HON
R
O
ONPhCO2H (10 mol%)
R
OH
ON
NaBH4
MeOH
R1
R3 R2
Ar = 3,5-(CF3)2-Ph
R3 R1
R2
R1R3
R2
NH
ArAr
OTMS
anitinflamatory agentspenicillin and cephalosporin analoguessex phermone analogues
Et
O
ON
72% yield95% ee
Me
O
ON
72% yield95% ee
Hep
O
ON
64% yield95% ee
i-Pr
O
ON
62% yield97% ee
EtO2C
O
ON
60% yield88% ee
43
Asymmetric epoxidations
NH
OTMSAr
Ar
R1 H2O2H
O
R1 H
OO
Yield8090656390758560
dr93:791:990:1095:597:398:294:490:10
ee9697969896969496
R1
Pho-NO2-Pho-Me-Php-Cl-PhEti -PrCH2OBnCO2Et
H2O2
H
O
H
OO
75% yield85% ee
Marigo, Franzén, Poulsen, Zhuang, Jørgensen J. Am. Chem. Soc. 2005, 127, 6964
44
Organocatalytic leaving group strategy
Jiang, Elsner, Jensen, Falcicchio, Marcos, Bertelsen Jørgensen Angew. Chem. Int. Ed. early view
45
Scope
H
O
R
NO
R
OH
O
CO2Et
NH
CO2Et
NO2N
NH
ArAr
OTMS
t-But-Bu
Br Br
O
66-90% yielddr: >20:1
92-96% ee
H
O
R
NO
R
NHBn
O
CO2Et
NH
CO2Et
NO2
NNH
ArAr
OTMS
t-But-Bu
Br Br
O
NH2Bn
MgSO4
47-57% yielddr: >20:1
81-86% ee
NH
CO2tBu
NO2
ArAr
OTMS
CsOH.H2O
H
ONO
OH
O
CO2tBuR HO
R
N
MeO
MeOtBu
tBu
OMe
BrAr
Ar
H2O265-71% yield
dr: 4:194-99% ee
46
Potential
47
Organocatalyzed multicomponent reactions
NAr
OTMSAr
H2O
R
NAr
OTMSAr
R
NAr
OTMSAr
R
NH
ArAr
OTMS
H
H
H
Nuc
O
HR
O
HR
H2O
Nuc
Elec
Nuc
ElecNuc
Elec
Yang, Hechavarria, List J. Am. Chem. Soc. 2005, 127, 15036Huang, Walji, Larsen, MacMillan J. Am. Chem. Soc. 2005, 127, 15051
Marigo, Schulte, Franzén, Jørgensen J. Am. Chem. Soc. 2005, 127, 15710
48
Organocatalytic domino Michael-aldol reactions
EWGO
EWGO
R2+
Cl
HO
Aldol
O
R2
EWGO
R2
E1cB
Michael
Cl
O R2
Cl
SN2
EWGO
Cl
O R2
O
Marigo, Bertelsen, Landa, Jørgensen J. Am. Chem. Soc. 2006, 128, 5475
49
Scope
50
How to have six and 1 out of 64!
+ O
MeO
O O
OMe
HO
HO
R1
6 stereocenters1 out of 64 stereoisomers
CO2Me
CO2Me
MeO2C
CO2MeO
R1
O
MeO
O O
OMe
NH
OTMSPh
Ph1)
2)
3 (10 mol%)PhCO2H (10 mol%)toluene, r.t., 16 h
Piperidine (20 mol%)MeOH, 40 oC, 1 h
One-Pot
CO2MeHO
CO2MeHO
CO2MeEt
MeO2C
CO2MeHO
CO2MeHO
CO2MeEtO2CMeO2C
CO2MeHO
CO2MeHO
CO2MePh
MeO2C
48% yielddr >99:194% ee
38% yielddr >99:189% ee
70% yielddr >99:194% ee
Bertelsen, Johansen, Jørgensen Chem. Commun. 2008, 3016
51
Acknowledgements
Lukasz Albrecht, José Alman, Stephan Bachmann, Søren Bertelsen
Alan Braunton, Anders Bøgevig, Patrick Boltze, Armando Carlone,
Silvia Canrera, Peter Dinér, Petteri Elsner, Johan Franzén,
Doris Fielenbach, Aurelia Falcicchio, Patrick Francke,
Kim L. Jensen, Hao Jiang, Rasmus L. Johansen, Anne Kjærsgaard,
k, Nagaswamy Kumargubaran, Aitor Landa,
Mauro Marigo, Eddy Maerten, Andrea Mielli, Martin Nielsen,
Maorio Paxio, Thomas Poulsen, Efraim Reyes,
Bo Richter, Tobias Schulte, Tobias Wabnitz, Wei Zhuang
X-ray: Jacob Overgaard
Carlsbergfondet
