cis -1-Aminoindan-2-ol in Asymmetric Syntheses · cis-1-amino-indan-2-ol derived catalysts and auxiliaries. The present review is intended to focus on the cis-1-aminoindan-2-ol derived

937

REVIEW

1. Introduction

Stereochemically defined synthesis of organic moleculesin enantiomerically pure form is one of the most importantareas in organic synthesis.

1

With the unprecedented ad-vances in molecular biology and modern spectroscopictechniques, the pathogenesis of many complex human dis-eases is now well understood at the molecular level. Inaddition, a growing number of new complex natural prod-ucts with important biological functions have been isolat-ed and characterized. Concurrent to these remarkableachievements came new challenges and opportunities inasymmetric synthesis. The design and synthesis of en-zyme inhibitors and receptor agonists or antagonists, veryoften targets a molecular probe that contains multiple ste-reocenters. For meaningful biological studies, the prepa-ration of such molecules in enantiomerically pure form ishighly desirable if not mandatory. Therefore, the develop-ment of methodologies for efficient asymmetric synthesisis of great interest in the field of medicinal chemistry andrelated disciplines.

The sophistication of asymmetric synthesis has nowreached the point that many complex organic moleculescan be synthesized with near complete enantioselectivity.Indeed, several asymmetric transformations can be car-ried out with enantio- or diastereoselectivities rivaling en-zymatic transformations. The development of asymmetriccatalysts or ‘abiological catalysts’ for asymmetric hydro-genation with chiral bis(phosphine)rhodium complexes,

2

asymmetric dihydroxylations,

3

asymmetric epoxidationof allylic alcohols,

4

asymmetric epoxidation of unfunc-tionalized olefins,

5

and asymmetric reductions with chiraloxazaborolidines

6

are examples of the sophistication of

cis

-1-Aminoindan-2-ol in Asymmetric Syntheses

Arun K. Ghosh,*

a

Steve Fidanze,

a

Chris H. Senanayake

b

a

Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA

b

Sepracor Inc, Chemical Research and Development, 111 Locke Drive, Marlbrough, MA 01752, USAFax +1(312)9960431; E-mail: [email protected]

Received 26 February 1998; revised 19 March 1998

Dedicated to the memory of Professor Wolfgang Oppolzer for his invaluable contributions in the field of asymmetric synthesis

catalytic asymmetric synthesis. Also, the development ofchiral auxiliaries for asymmetric

syn

-aldol reactions,

7

asymmetric alkylations,

8

asymmetric Diels–Alder reac-tions,

9

and asymmetric conjugate additions

10

has reachedlevels of diastereoselectivity of >99:1. One of the key ad-vantages of abiological systems over enzymatic transfor-mations is that either enantiomer of the target moleculecan be conveniently synthesized by the proper choice ofcatalyst or auxiliary.

Further development of asymmetric chiral catalysts andauxiliaries in the areas of novel asymmetric reactions,substantive enhancement of stereocontrol, efficiency andready accessibility of the chiral templates will be of enor-mous benefit to synthetic communities. The

α

-amino acidderived amino alcohols have been utilized in numerousefficient auxiliary-directed and catalytic asymmetrictransformations.

11

However, development of catalysts orauxiliaries that are not derived from natural amino acidsoften renders advantage in terms of manipulation of struc-tural properties, conformational rigidities and availabilityof either enantiomer for asymmetric synthesis. In the con-text of design and synthesis of potent, selective and orallyactive HIV-protease inhibitors for the treatment of AIDS,the researchers at Merck Research Laboratories first dem-onstrated the utility of

(1S, 2R)-

1-aminoindan-2-ol as aneffective ligand for protease inhibitors in 1990.

12

Subse-quently, the clinically effective protease inhibitor indi-navir was discovered which incorporates this importantamino alcohol into its structure.

13

In combination with re-verse transcriptase inhibitors, indinavir was approved bythe U.S. Food and Drug Administration in 1996 for treat-ment of AIDS under the trade name of Crixivan

®

.

14

Nu-merous effective syntheses and resolutions of cis-1-amino-

Abstract:

A review on

cis

-1-aminoindan-2-ol derived asymmetricsyntheses is described.

Key words:

asymmetric synthesis, 1-aminoindan-2-ol, protease,inhibitor

1. Introduction2. Aminoindanol-Based Chiral Catalysts and Auxiliaries3. Syntheses of Aminoindanol4. Applications of Aminoindanol as Chiral Auxiliaries 4.1. Aldol and Homoaldol Reactions4.2. Diels–Alder Reactions4.3. Reduction of

α

-Keto Esters

4.4. Miscellaneous Reactions 5. Applications of Aminoindanol as Ligands in Asymmetric

Catalysis 5.1. Catalytic Asymmetric Reductions5.2. Chiral Bis(oxazoline) Ligands (Inda-Box) 5.2.1. Diels–Alder Reactions5.2.3. Hetero Diels–Alder reactions5.2.4 Cyclopropanation Reactions5.2.5. Free Radical Conjugate Additions6. Aminoindanol in HIV-Protease Inhibitor Synthesis7. Conclusion

938

Arun K. Gosh, Steve Fidanze, Chris H. Senanayake SYNTHESIS

indan-2-ol have been developed in this context and eitherenantiomer is readily available. Since its discovery as aligand for HIV-protease inhibitors,

cis

-1-aminoindan-2-olhas become a vital source of enantio- and diastereoselec-tivity in asymmetric synthesis.

cis

-Aminoindanol is struc-turally related to phenylglycinol, and indeed is often usedas a phenylglycinol surrogate. The advantage of amino-indanol over phenylglycinol is that aminoindanol is con-formationally constrained by the methylene link betweenthe aromatic ring and the alcohol moiety. This rigid skel-eton is the key to the high selectivities often obtained withaminoindanol-based catalysts and auxiliaries. The rigidskeleton often limits transition state geometries far moreeffectively than corresponding phenylglycinol-based cat-alysts and auxiliaries. As either enantiomer of aminoin-danol is now commercially available, syntheses usingaminoindanol-based catalysts or auxiliaries can be tai-lored to produce either enantiomer of the target mole-cule.

15

Already, many impressive asymmetric syntheticmethodologies have been recorded utilizing

cis

-1-amino-

indan-2-ol derived catalysts and auxiliaries. The presentreview is intended to focus on the

cis

-1-aminoindan-2-olderived asymmetric syntheses and their applications in or-ganic synthesis.

2. Aminoindanol-Based Chiral Catalysts and Auxiliaries

Enantiomerically pure

cis

-1-aminoindan-2-ol

(1)

and itsderivatives have been utilized in numerous asymmetricsyntheses since 1991. These auxiliaries and catalysts areshown in Figure 1. One of the early uses of

cis

-amino-indanol

1

in asymmetric synthesis was reported by Didieret al. as a ligand for chiral oxazaborolidine based reduc-tions of ketones.

16

The Sepracor group later developedligands

3–10

for oxazaborolidine reductions of

α

-chloro-acetophenone.

17

cis

-1-Aminoindan-2-ol derived tetrahy-dro-4

H

-oxazinone

2

was investigated for synthesis of

α

-amino acids.

18

Ghosh et al. developed auxiliaries

11–16

for asymmetric reductions of

α

-keto esters,

19

asymmetric

Biographical Sketches

Arun K. Ghosh

was born in India in 1958. He received his Ph.D. from the Universityof Pittsburgh under the supervision of Professor Alan P. Kozikowski (1985). Followinghis postdoctoral studies at Harvard University with Professor E. J. Corey (1985–1988),he joined the department of Medicinal Chemistry at Merck Research Laboratories as aSenior Research Chemist in 1988. He moved to University of Illinois at Chicago in 1994as an Assistant Professor. He is currently Associate Professor of Organic and BioorganicChemistry.

Steve Fidanze

was born in Chicago, Illinois in 1969. He studied chemistry at the Uni-versity of Illinois at Urbana-Champaign where he received his B.S. in chemistry in 1992.In 1996, he joined Professor Ghosh’s group and is currently working for his Ph.D. on thedevelopment of asymmetric syntheses and their applications in bioactive natural prod-ucts. He is the recipient of 1997 University Graduate Fellowship from the University ofIllinois at Chicago.

Chris H. Senanayake

was born in Sri Lanka. He obtained his Ph.D. from Wayne StateUniversity under the guidance of Professor James H. Rigby in 1987. He remained atWayne State as a postdoctoral fellow with Professor Carl R. Johnson (1987–1989). In1989, he moved to Dow Chemical Co. as a Senior Research Chemist and in 1990, hejoined the Merck Process Research Group as a Senior Research Chemist. In 1996, hemoved to Sepracor Inc. as Director of Chemical Process Research.

939

cis

-1-Aminoindan-2-ol in Asymmetric SynthesesJuly 1998

Diels–Alder reactions,

20

and for asymmetric

syn

-aldol re-actions.

21

Ghosh et al. also demonstrated the utility ofchiral sulfonamides

11

and

15

in ester derived titanium-enolate based stereoselective asymmetric

syn

- and

anti

-aldol reactions.

22

Ghosh et al. and Davies et al. indepen-dently developed bis(oxazoline) ligands

17

23

and

18

24

forcatalytic asymmetric Diels–Alder reactions. The bis(ox-azoline) ligand

17

was utilized by Ghosh et al. in asym-metric hetero Diels–Alder reactions.

25

Davies et al. alsodeveloped py-box ligand

19

for asymmetric cyclopropa-nations.

26

Armstrong has developed auxiliary

20

forasymmetric homoaldol reactions.

27

3. Syntheses of Aminoindanol 1

The synthesis of racemic

cis

-1-aminoindan-2-ol

(1)

wasreported in 1951 by Lutz and Wayland.

28

As shown inScheme 1,

trans

-2-bromoindan-1-ol

(21)

was treated withexcess ammonia to form

trans

-1-aminoindan-2-ol

(22)

.This reaction presumably proceeds via an indene oxide in-termediate, which is then opened by ammonia. Treatmentwith 4-nitrobenzoyl chloride afforded the correspondingamide

23

. Reaction of

23

with thionyl chloride gave thecorresponding

cis

-oxazoline

24

. Acidic hydrolysis of

24

furnished racemic

cis

-1-aminoindan-2-ol

(1)

.

Heathcock and co-workers have synthesized racemic

cis

-aminoindanol

1

from indene via iodine isocyanate addi-tion to indene as depicted in Scheme 2.

29

Treatment of in-dene with iodine isocyanate prepared in situ by reaction ofiodine and silver cyanate in ethanol afforded

trans

-1-(ethoxycarbonylamino)-2-iodoindan

(26)

. Pyrrolysis of

26

in refluxing diglyme afforded the corresponding

cis

-oxazolidinone

27

. Basic hydrolysis of

27

yielded racemic

cis

-aminoindanol

1

.

Ghosh et al. have synthesized racemic aminoindanol bystereoselective reduction of

α

-hydroxy oxime-ether

30

which was obtained from indan-1-one

(28)

.

30

As shownin Scheme 3, treatment of

28

with potassium hydroxide

Figure 1.

Auxiliaries and Catalysts Used in Asymmetric Synthesis

Aminoindanol has also been used extensively in the asym-metric syntheses of several HIV-protease inhibitors. (1

S

,2

R

)-

cis

-aminoindanol was first introduced as a ligand forprotease inhibitors in 1990.

12 Intensive research effortsresulted in Crixivan®.14 Four of the five stereocenters inCrixivan® are set by aminoindanol: two in aminoindanolitself and two by chirality transfer processes in the synthe-sis of Crixivan®.

Scheme 1

Scheme 2

940 Arun K. Gosh, Steve Fidanze, Chris H. Senanayake SYNTHESIS

and iodobenzenediacetate in methanol according to the pro-cedure of Moriarty et al. yielded the corresponding 2-hy-droxy-1-dimethyl ketal 29.31 Acidic hydrolysis followed byreaction of the resulting α-hydroxy ketone with benzyl-oxyamine hydrochloride in pyridine afforded the mixtureof oximes 30. Reduction of 30 with borane-THF complexgave an 88:12 mixture of cis- and trans-aminoindanols. Arelated asymmetric reduction of keto oxime ethers cata-lyzed by oxazaborolidine-borane complex in the tetraloneseries has been reported by Tillyer and co-workers.32

Laksman and Zajc prepared cis-aminoindanol 1 from cis-indandiol 31 as outlined in Scheme 4.33 Reaction of 31with α-acetoxyisobutyryl chloride afforded the trans-chloroacetate 32. The stereo and regiochemical outcomeof this reaction is dictated by initial formation of an ace-toxonium species which is attacked by the chloride at themost stable carbocationic site, giving the trans-chloro-acetate 32.34 Treatment of 32 with lithium azide in DMFyielded the cis-azido acetate 33. Removal of acetate groupby hydrolysis with sodium methoxide, followed by hydro-genation of the resulting cis-azido alcohol afforded the ra-cemic cis-aminoindanol 1.

An early synthesis from the Merck group35 used a modifi-cation of the method of Lutz and Wayland.28 As shown inScheme 5, racemic 2-bromoindan-1-ol (21) was first re-acted with concentrated ammonium hydroxide. The re-sulting trans-aminoindanol 22 was then treated with ben-zoyl chloride followed by thionyl chloride to provide the

oxazoline 34. Hydrolysis of oxazoline 34 with 6 N sulfu-ric acid at reflux afforded the racemic cis-aminoindanol.Resolution of the racemic amino alcohol was carried outby reaction of Boc-phenylalanine followed by removal ofthe Boc-group with trifluoroacetic acid and chromato-graphic separation of the corresponding phenylalanineamide 35.36 Hydrolysis of 35 with sodium methoxidegave optically pure (1S, 2R)-aminoindanol (1).

An enantioselective synthesis of either isomer of cis-amino-indanol was reported by Didier et al. using baker’s yeastreduction.16 As depicted in Scheme 6, baker’s yeast re-duction of 1-(methoxycarbonyl)-indan-2-one 36 resultedin formation of optically active hydroxy ester 37 with99.5% ee and >99% de. The ester was then hydrolyzedusing pig liver esterase (PLE), and the resulting acid 38subjected to a Curtius rearrangement with diphenylphos-phoryl azide to give oxazolidinone 40.37 Basic hydrolysisresulted in optically pure (1R, 2S)-aminoindanol 1 . Hy-drolysis of hydroxy ester 37 with aqueous sodium hydrox-ide gave a 2:1 mixture of cis- and trans- hydroxy acids, ofwhich only the trans- isomer 39 was isolated in pure form.This isomer was then subjected to a Curtius rearrange-ment with diphenylphosphoryl azide in ethanol to providethe ethyl carbamate 41.37 Treatment with thionyl chlorideafforded the oxazolidinone, which was hydrolyzed withpotassium hydroxide to provide (1S, 2R)-aminoindanol 1.

Boyd has oxidized 2-bromoindan with whole cell culturesof Pseudomonas putida UV4 to enantiomerically pure(1S, 2R)-cis-2-bromoindan-1-ol (43).38 This cis-bromo-indanol 43 was then converted to both enantiomers of cis-aminoindanol 1 and ent-1. As illustrated in Scheme 7, di-rect application of a Ritter reaction with sulfuric acid inacetonitrile followed by basic hydrolysis with potassiumhydroxide as described by Senanayake et al. afforded (1S,2R)-aminoindanol 1.39 Inversion of the C-1 center by me-sylation followed by treatment with potassium hydroxideto effect inversion and epoxidation afforded (1R, 2S)-in-dene oxide 44. A Ritter reaction followed by hydrolysis of

Scheme 3

Scheme 4

Scheme 5

941cis-1-Aminoindan-2-ol in Asymmetric SynthesesJuly 1998

the resulting oxazoline with potassium hydroxide yielded(1R, 2S)-1-aminoindan-2-ol (ent-1).

Ogasawara and Takahashi 40 and Ghosh et al. 41 haveindependently resolved trans-1-azidoindan-2-ol withPseudomonas sp. Amano lipase. As shown in Scheme 8,treatment of indene with NBS in THF/water affordedtrans-bromohydrin 21. Reaction of racemic 21 with sodi-um hydroxide yielded the corresponding epoxide, whichwas opened with sodium azide to give racemic azido alco-hol 45. Treatment of 45 with Lipase PS and vinyl acetatein tert-butyl methyl ether gave 48% of (1S, 2S)-azido in-danol 46 in >99% ee and 49% of (1R, 2R)-azido acetate 47in 98% ee.40 Inversion of C-2 center of alcohol 46 wascarried out by reaction with mesyl chloride and triethyl-

amine followed by displacement of the resulting mesylatewith cesium acetate in toluene in the presence of 18-crown-6 to provide acetate derivative 48 in 64% yield.Alternatively, Mitsunobu inversion of the alcohol 46 withp-nitrobenzoic acid, diethyl azodicarboxylate, and triphe-nylphosphine afforded the azido ester 49 in 75% yield. Es-ter hydrolysis of 49 with sodium methoxide afforded azi-do alcohol 50 which upon hydrogenation over palladiumon carbon afforded (1S, 2R)-aminoindanol 1. The azidoacetate 47 was hydrolyzed with potassium carbonate inmethanol to give azido alcohol ent-46. (1R, 2S)-1-Amino-indan-2-ol (ent-1) was synthesized from ent-46 via a sim-ilar reaction sequence as described above (Scheme 8).

Ghosh’s synthesis of enantiopure aminoindanol proceedsvia direct epoxidation of indene with MCPBA, followedby opening of the racemic epoxide 44 with sodium azideto give racemic trans-azidoindanol 45 (Scheme 9).41 Reso-lution of 45 was carried out with immobilized Lipase PSon Celite,42 and isopropenyl acetate in dimethoxyethane,yielding 46% of (1S, 2S)-azidoindanol 46 and 44% of (1R,2R)-azido acetate 47, both in >96% ee. The resulting azi-doindanols 46 and ent-46 were each hydrogenated in thepresence of diethylpyrocarbonate. The respective carba-mates 51 and ent-51 were treated with thionyl chloride toafford the corresponding oxazolidinones. Basic hydroly-sis of the resulting oxazoldinone with potassium hydrox-ide afforded the respective optically pure aminoindanols 1and ent-1.

Scheme 6

Scheme 7 Scheme 8


Senanayake et al. have developed one of the most practi-cal syntheses of either enantiomer of cis-aminoindanol.39,

43 The key step involves Jacobsen epoxidation of indeneto optically active indene oxide.44 As shown in Scheme10, the epoxidation is carried out with 0.7 mol% (S,S)-(salen)Mn(III)Cl, 3 mol% 4-(3-phenylpropyl)pyridine N-oxide (P3NO), and 1.5M aqueous NaOCl in chloroben-zene. Indene oxide ent-44 is produced in 89% yield and88% ee under these conditions. Detailed mechanistic stud-ies have revealed that P3NO serves several purposes inthis epoxidation: (i) P3NO is the axial ligand on manga-nese and stabilizes the catalyst while increasing the rate ofthe reaction, and (ii) P3NO assists in drawing the activeoxidant, HOCl, into the organic layer. The same studyshowed that oxidation of the manganese catalyst is therate-limiting step.45 Furthermore, hydroxide concentra-tion in the aqueous layer has been shown to be of criticalimportance; commercial 2 M NaOCl typically is 0.03–0.18 M in hydroxide. Raising this value to 0.3 M helpedto stabilize the hypochlorite, and also helped prevent theside reaction of oxidation of P3NO to isonicotinic acid andbenzoic acid.43

In the Merck process, chiral indene oxide ent-44 is thentreated with oleum in acetonitrile in a Ritter reaction, pro-ducing the corresponding methyl oxazoline 53. Studieshave shown that this reaction proceeds through a cyclicsulfate intermediate 52, then on to the favored cis-5,5 ringsystem.39 The oxazoline 53 is hydrolyzed with water, thenfractionally crystallized with l-tartaric acid to yield (1S,

2R)-aminoindanol in 50% overall yield from indene, andin >99% ee. This sequence also proceeds through optical-ly pure indene oxide.

4. Applications of Aminoindanol as Chiral Auxiliaries

Amino alcohols derived from α-amino acids have beenutilized in numerous efficient asymmetric syntheses.11

The development of new chiral auxiliaries that are not de-rived from natural amino acids however, offers opportuni-ties in terms of manipulation of structural properties andconformational rigidities necessary for a particular asym-metric process.46 Conformationally constrained cyclicamino alcohol derived ligands and chiral auxiliaries are ofparticular interest since the transition state leading toasymmetric induction may be somewhat more predict-able. The conformational rigidity of cis-1-aminoindan-2-ols (1) has been already exploited in a number of efficientasymmetric processes both as covalently bound chiralauxiliaries as well as ligands in asymmetric catalysis asdescribed in the following sections.

4.1. Aldol and Homoaldol Reactions

Ghosh et al. have first demonstrated that the potential of(1S, 2R)-cis-aminoindanol derived chiral oxazolidinone16 in asymmetric syn-aldol reactions.21 As shown inScheme 11, propionyl imide 56 provided a similar level ofdiastereoselectivities and isolated yields as the valinol orphenylalaninol derived auxiliaries developed by Evans.7

Scheme 9

Scheme 10


An advantage of the aminoindanol derived auxiliary isthat both enantiomers are readily available.15 The synthe-sis of the auxiliary is carried out by treatment of amino-indanol with disuccinimidyl carbonate in the presence oftriethylamine. Aldol condensation and hydrolytic removalof the chiral auxiliary are then carried out under standardconditions.7, 21 A list of representative aldol reactions isshown in Scheme 11. Aldol condensation with various al-dehydes proceeded with complete diastereofacial selec-tivity (>99% de).

This aminoindanol derived auxiliary has been used in sev-eral syntheses. The C11-C15 segment of tylosin has beensynthesized by use of the corresponding crotonyl oxazo-lidinone, as shown in Scheme 12.21 Treatment of crotonyloxazolidinone 59 with dibutylboron triflate and triethyl-amine, followed by propionaldehyde afforded aldol pro-duct 60. The auxiliary was removed by LAH reduction tothe corresponding diol 61. A series of standard syntheticsteps gave the C11-C15 tylosin intermediate synthesized byNicolaou and co-workers.47

Aminoindanol based chiral oxazolidinone has also beenutilized in the enantioselective total synthesis of hapalosin65.48 Hapalosin is a novel cyclodepsipeptide isolated fromthe blue-green alga Hapalosiphon welwitschii. This mol-ecule has shown important multidrug-resistance reversingactivity.49 As shown in Scheme 13, aldol condensation ofN-propionyl oxazolidinone 56 and octanaldehyde, fol-

lowed by hydrolysis of the aldol condensation product 63with lithium hydroperoxide provided the key synthetic in-termediate 64 for the enantioselective total synthesis ofhapalosin.

The C-6 amine stereochemistry of nucleoside antibioticsinefungin 69 was set by a highly diastereoselective allyl-ation (>99% de) of a (1S, 2R)-1-aminoindan-2-ol derivedoxazolidinone 66 followed by a Curtius rearrangement ofthe resulting acid 68 (Scheme 14).50 The C-9 amino acid

Scheme 11

Scheme 12

Scheme 13

Scheme 14


stereochemistry of sinefungin (69) was established by arhodium chiral bis(phosphine)-catalyzed asymmetric hy-drogenation of an α-acylaminoacrylate derivative.51

The (1S, 2R)-1-aminoindan-2-ol derived oxazolidinonehas also recently been utilized in the synthesis of the coreunit of the HIV protease inhibitor Saquinavir®.52 As de-picted in Scheme 15, N-acylation was carried out with thepivalic anhydride of hydrocinnamic acid and N-lithio-oxazolidinone. Aldol reaction with benzyloxyacetalde-hyde followed by lithium hydroperoxide hydrolysis af-forded the key acid intermediate 73. This intermediatewas converted by several standard synthetic steps to hy-droxyethylamine dipeptide isostere 74.53

Ghosh and Onishi have developed N-tosyl-aminoindanolas a chiral auxiliary in an interesting ester derived titan-ium enolate based anti selective aldol reaction.22 Whilestereoselective generation of syn-aldol products54 has be-come very sophisticated, the development of correspond-ing enantioselective anti-aldol methodologies55 has re-ceived much less attention. As shown in Scheme 16, thechiral sulfonamide ent-11 is readily prepared by reactionof cis-aminoindanol with tosyl chloride in the presence oftriethylamine and 4-(dimethylamino)pyridine. The sul-fonamide derivative ent-11 is O-acylated by propionylchloride, or with the corresponding acid in the presence ofdicyclohexylcarbodiimide and 4-(dimethylamino)pyri-dine.22 The titanium enolate is formed by titanium tetra-chloride and diisopropylethylamine. This enolate is thenadded to a solution of aldehyde precomplexed to titaniumtetrachloride to yield the anti-aldol product, as shown inScheme 16.22a

The stereochemical outcome of these reactions has beenrationalized in terms of a Zimmerman–Traxler type tran-

sition state model A, as shown in Figure 2.22, 56 The modelis derived based on the following assumptions; that thegeometry of the titanium enolate is Z, the titanium enolateis a seven-membered metallocycle with a chair-like con-formation and a second titanium metal is involved in thetransition state where it is chelated to the indanyloxygroup as well as to the aldehyde carbonyl in a six mem-bered chair-like transition state. The involvement of twotitanium metal atoms is supported by the fact that thetitanium enolate derived from 75a does not react with al-dehydes without precomplexation with TiCl4. Based onthis possible transition state assembly, we subsequentlyhypothesized that the incorporation of a chelating substit-uent on the aldehyde side chain would adopt a transitionstate model B and thereby alter the stereochemical out-

Scheme 15

Scheme 16

Figure 2. Zimmerman–Traxler Type Transition States


come from an anti-aldol to a syn-aldol product. It shouldbe noted that the present syn-stereoselectivity can also beexplained by an acyclic transition state similar to that pro-posed by Gennari et al.57 As shown in Scheme 17, the reactions of the titanium enol-ates derived from esters ent-75 a–c with three representa-tive bidentate oxyaldehydes such as benzyloxyacetalde-hyde, benzyloxypropionaldehyde and benzyloxybutyral-dehyde proceeded with excellent syn-diastereoselectivity(up to 99% de) with good to excellent isolated yields(Scheme 17).22b Thus, with proper choice of chiral tem-plate and aldehyde one can prepare either syn- or anti-aldol product in a stereopredictable fashion.

These reactions have been used in the asymmetric synthe-sis of a hydroxyethyl(sulfonamide) dipeptide isostere, andalso a hydroxyethylene dipeptide isostere as depicted inScheme 18.58 Aldol reaction of hydrocinnamate ester ent-75b with benzyloxyacetaldehyde produced the syn-aldolproduct 78d in 97% yield as a single diastereomer. Re-moval of the chiral auxiliary with lithium hydroperoxidefollowed by a series of standard synthetic steps resulted inthe hydroxyethyl(sulfonamide) isostere 83.59 Similarly,aldol reactions with E-cinnamaldehyde provided a singlediastereomer in 48% yield. Precomplexing the aldehydewith dibutylboron triflate instead of titanium tetrachlorideincreased the yield to 68%. However, the anti:syn diaste-reoselectivity was 6.1:1.60 Hydrolytic removal of thechiral auxiliary, followed by several standard syntheticsteps provided hydroxyethylene isostere 82. The γ-lactone

81 and the sulfonamide isostere 83 are the intermediatesof numerous potent and selective inhibitors of HIV pro-tease and other aspartyl proteases.58, 61 The main advan-tage of the present synthesis is that the side chain substi-tutents of either isostere are not limited to amino acid de-rived side chains.62

Armstrong et al. have shown that isopropylidene aminoin-danol is an excellent chiral auxiliary for stereocontrolledhomoaldol reactions, as depicted in Scheme 19.27 The ti-tanium homoenolate species was formed by sonication ofthe corresponding iodide with Zn/Cu couple to form thezinc homoenolate, followed by transmetallation withdichlorotitanium diisopropoxide.27a Reaction with Boc-phenylalaninal provided product 87a as a single isomer in55% yield. An improved method of forming the ho-moenolate involved treating the hydrocinnamate amidewith BuLi, then with di(iodomethyl)zinc in the presenceof benzyloxylithium.27b The mechanism of formation ofthe zincate is thought to proceed via stereoselective 1,2-migration of a zincate dianion, along with loss of lithiumiodide to give the zincate anion. The stereoselective mi-gration sets the absolute configuration of the α-center.Transmetallation with trichlorotitanium isopropoxide,then addition of aldehyde, affords the homoaldol products87. Representative examples are shown in Scheme 19.

4.2. Diels–Alder Reactions

Merck researchers have used the previously described21

oxazolidinone derived from aminoindanol as a chiral aux-iliary for Diels–Alder reactions.63 The auxiliary was pre-pared from aminoindanol and triphosgene, then acylatedwith acryloyl anhydride or crotonyl anhydride. Diels–Al-

Scheme 17

Scheme 18


der reactions with isoprene and piperylene were studiedunder various conditions. The results are shown inScheme 20. N-Acyl oxazolidinones were also prepared forthe corresponding 6- and 7- membered ring homologs,and for phenylglycinol. In each case, low levels of stereo-control were observed (30–35% de), demonstrating theimportance of the rigidity of the aminoindanol platform.

Ghosh has shown that 1-(arylsulfonamido)indan-2-ols areexcellent chiral auxiliaries for Diels–Alder reactions.20

The aryl sulfonamides were prepared as previously de-scribed.22 O-Acylation is carried out with acryloyl chlo-ride and triethylamine. Reaction with cyclopentadieneand a variety of Lewis acids demonstrated the syntheticutility of this auxiliary. endo/exo-Ratios of >99:1, andendo diastereoselectivities from 86:14 to 96:4 were ob-served, along with good to excellent yields, as shown inScheme 21.

4.3. Reduction of α-Keto Esters

The use of 1-arylsulfonamido-2-aminoindanols as chiralauxiliaries for the stereoselective reduction of α-keto es-ters was demonstrated by Ghosh and Chen.19 As shown inScheme 22, several hydride reagents and reaction condi-tions were examined. Although the selectivity using sodi-um borohydride was poor (2:1), the use of bulky alkyl hy-dride reagents afforded good to excellent selectivities,ranging from 4:1 to as high as >99:1. Indeed, reductionusing L-selectride and zinc chloride afforded products99a–b in 96% yield and >99:1 diastereoselectivity. Re-duction with L-selectride and zinc chloride afforded 99cin 90% yield and 49:1 diastereoselectivity. Results of thereductions using various hydride reagents and aryl sul-fonamides are shown in Scheme 22.

Scheme 19

Scheme 20

Scheme 21


The high degree of stereoselection associated with thisasymmetric reduction can be attributed to the chelation ofcarbonyl oxygens with a metal ion. As shown in Figure 3,in the α-keto esters 97a, reduction by L-Selectride mostlikely proceeds through the s-cis conformation 101 be-cause of the metal chelation. The presence of the vicinaltoluenesulfonamide blocks the approach of the hydridefrom the re-face and therefore, si-face hydride attackleads to the preferential formation of 99 a–c. Consistentwith this rationale, a more sterically demanding 1-naph-thalenesulfonamide bearing chiral auxiliary 97b, has ex-hibited an even higher degree of stereoselection. The ste-reoselectivity has been reversed by using an additive tochelate the metal ion, such as K-selectride with 18-crown-

6. This leads to predominately re-face attack of the hy-dride which proceeds through the s-trans conformation102.

4.4. Miscellaneous Reactions

An asymmetric [2,3]-sigmatropic rearrangement of amideenolates of 103 containing isopropylidene aminoindanolas chiral auxiliary has been described by Kress et al.64 Asshown in Scheme 23, the diastereomeric ratio of 104:105of the reaction has been shown to be a function of thecounter ion. The syn-stereoselectivity increased in the or-der K < Na < Li < Zr. Using HMPA along with LiHMDShas given the optimal combination of selectivity and yield.Although the selectivity was greater with the zirconiumenolate than the lithium enolate, the yield was much low-er. Increased amounts of the HMPA additive resulted inslightly increased syn-selectivity. The rearrangement pro-ceeds with good to excellent diastereoselectivity, as wellas in good yield.

The scope and utility were further examined with amide-acetonides 106a–e as depicted in Scheme 24. The rear-rangement was carried out under similar conditions as de-scribed above. In general, trans-disubstituted olefinexhibited excellent syn-diastereoselectivity. Unsubstitut-ed allyl ether 106d furnished greater than 98% 2R selec-tivity.

Scheme 22

Figure 3. Conformations 101 and 102 During L-Selectride Reduction

Scheme 23


Asymmetric synthesis of α-amino acids via electrophilicamination has been demonstrated by Zheng and Armstrongand coworkers.65 The electrophile used was lithium tert-bu-tyl-N-tosyloxycarbamate. The reaction proceeds via a lithi-um enolate, which was transmetallated with copper(I) cy-anide. Zinc and lithium enolates were also tested for thisreaction, but no product was observed. The amide cupratethus generated adds to the electrophile in good yield, andwith excellent diastereoselectivity, as shown in Scheme 25.The chiral auxiliary was then removed with 6 N HCl.

5. Applications of Aminoindanol as Ligands in Asym-metric Catalysis

5.1. Catalytic Asymmetric Reductions

Enantioselective reduction of prochiral ketones by usingoxazaborolidines as the chiral catalyst has been one of themost spectacular advances in organic synthesis.6,66 In thiscontext, catalytic efficiency of chiral oxazaborolidines de-rived from numerous natural and unnatural amino alcoholshave been examined.67 cis-Aminoindanol has been used asa ligand for chiral oxazaborolidine reduction of several ke-tones. The use of cis-aminoindanol used as a ligand forchiral oxazaborolidine reductions of ketones was first ex-plored by Didier et al.16 As shown in Scheme 26, severalchiral cyclic and acyclic amino alcohols were tested for theasymmetric reduction of acetophenone in stoichiometricamounts. In selected instances, substoichiometric amountsof ligands were examined. In all cases, reactions proceededwith good yields and aminoindanol 1 derived catalyst af-forded the highest enantioselectivity (87%).

Asymmetric reduction of anti-acetophenone oxime meth-yl ether was also investigated by Didier et al.16 As out-lined in Scheme 27, good to excellent yields were reportedin all cases, when a stoichiometric amount of ligand wasutilized. The highest enantioselectivities were observedfor 1-(N-methylamino)cyclopentan-2-ol ligand 114a(95%), and for aminoindanol 1 (94.5%). However, use ofa substoichiometric amount of ligands 1, 114a, and 115aall resulted in decreased enantioselectivities, as shown inScheme 27.

Scheme 24

Scheme 25

Scheme 26


Sepracor researchers have developed practical catalystsystems derived from optically active cis-aminoindanol.17

As shown in Scheme 28, several oxazaborolidine catalystsbased on aminoindanol were investigated. The B-methyloxazaborolidines 4, 6–10 were prepared from amino-indanol and the corresponding N-alkylated aminoindanols(for catalysts 6–10) were prepared by reductive aminationof the corresponding aldehydes. The B-methyl oxaza-borolidene ligands 4, 6–10 were prepared by reaction ofthe corresponding N-alkyl aminoindanol with trimethyl

boroxine. The B-hydrogen oxazaborolidene ligand 3 wasprepared in situ. These ligands were studied in the reduc-tion of α-chloroacetophenone. The B-methyl oxazaboro-lidine catalysts 4 and ent-4 were found to be the most se-lective, as shown in Scheme 28. The incorporation of anadditional coordinating heteroatom to the N-alkyl groupgreatly decreased the enantioselectivity (ligands 9–10).

As shown in Scheme 29, several other aromatic ketoneswere then examined using catalyst 4.17 All reactions werecarried out using 5–10 mol% of catalyst. The α-halogen-ated ketones were reactive enough to be completely con-sumed at –20˚C. Less reactive methyl and ethyl ketonesrequired a temperature of 0˚C to be completely reduced.All reductions proceeded with >95% isolated yields, andenantioselectivities ranging from 80–96% ee. The morereactive α-halogenated ketones generally proceeded withhigher enantioselectivities than the ketones which re-quired higher temperatures to react to completion.

Reduction of several cyclic and acyclic ketones with amino-indanol and borane-methyl sulfide complex was studiedby Umani-Ronchi et al.68 The results are shown inScheme 30. Catalytic amounts (5-10 mol%) of amino-indanol are treated with borane-methyl sulfide complex toprovide the oxazaborolidene in situ. Isolated yields wereat least 89%, and enantioselectivities were all >85%. Thehighest enantioselectivities were observed with cyclic andhindered ketones, as shown in Scheme 30.

The proposed mechanism of reduction involves initial ad-dition of borane to aminoindanol, with the loss of twomoles of hydrogen to form the oxazaborolidine. A secondmolecule of borane coordinates to the nitrogen with atrans-relationship to the indanyl substituent. The ketonecarbonyl coordinates to the boron center providing a pos-sible boat-like transition state 125 or a chair-like transitionstate as shown in Figure 4. In either case, intramolecularhydride attack by the re-face of the ketone is most prob-able. The boat-like transition state 125 is thought to bemore accessible than the chair-like transition state 126.68

Scheme 27

Scheme 28

Scheme 29


Asymmetric addition of diethyl zinc to aromatic alde-hydes with 6 mol% N-alkyl aminoindanol was also exam-ined by Umani-Ronchi et al.68 As illustrated in Scheme 31,the N-dibutyl- or N-diallylaminoindanol (129a or ent-

129a and 129b or ent-129b, respectively) were preparedby alkylation with the corresponding iodide in the pres-ence of sodium carbonate. Addition of 2 equivalents ofdiethylzinc with 0.6 mol% ligand to a solution of aldehydegave the corresponding chiral alcohol in good yield. How-ever, enantioselectivities were only fair, ranging from 40–50% ee as shown in Scheme 31.

The researchers in Sepracor laboratories have recently uti-lized oxazaborolidine catalyst ent-4 in the asymmetricsynthesis of R,R-formoterol, a β2-agonist for the treat-ment of asthma and bronchitis.69 As shown in Scheme 32,asymmetric reduction of bromo ketone 130 with (1R,2S)-B-methyl oxazaborolidine ent-4 (20 mol%) and borane/tetrahydrofuran complex resulted in bromohydrin 131 in98% yield and 96% ee. A series of standard synthetictransformations yields R,R-formoterol (133).

A detailed study was conducted to determine optimal con-ditions for the reduction of ketone 130.70 As depicted inScheme 33, both B-methyl and B-hydrogen oxazaboro-lidines 4 and 3 were studied, using various temperatures

Scheme 30

Figure 4. Transition States 125 and 126

Scheme 31

Scheme 32

Scheme 33


and borane reagents. Although several reactions yieldedenantioselectivities of >90%, the highest enantiomeric ex-cess was observed using B-methyl oxazaborolidine 4 at–10˚C, using borane/methyl sulfide as the active reduc-tant. These conditions afforded an enantioselectivity of96%. The optimal temperature using borane-tetrahydrofu-ran complex with ligand 4 was also –10˚C, with an enan-tioselectivity of 95% ee. The optimal conditions usingligand 3 were the use of borane/THF complex at 0˚C.With either 5 or 10 mol% catalyst, the enantioselectivitywas 93%. However, using borane-methyl sulfide com-plex, the optimal temperature for ligand 3 was 25˚C, withan enantioselectivity of 90% ee.

cis-Aminoindanol has been shown to be an excellentligand for transfer hydrogenation of several aromatic ke-tones.71 As outlined in Scheme 34, reduction of the ketonein isopropanol in the presence of 1 mol% ligand,2.5 mol% potassium hydroxide, and 0.25 mol% [RuCl2-(arene)]2 afforded the corresponding alcohols in goodyield and generally high enantioselectivity when cis-ami-noindanols were employed. In comparison, using phe-nylglycinol 136 or N-methyl aminoindanol 137 as ligandprovided much lower enantioselectivities (23 and 27% ee).

5.2 Chiral Bis(oxazoline) Ligands (Inda-Box)

The utilities of C2-symmetric chiral bis(oxazoline)ligands in numerous catalytic asymmetric processes havebeen well documented since 1989.72 The C2-symmetricbis(oxazoline) ligands were designed based upon thesemicorrin platform pioneered by Pfaltz et al.,73 Masam-une et al. first demonstrated the utility of bis(oxazoline)-Cu(II) complexes in enantioselective cyclopropanationreaction.74 In 1991, Corey et al. first demonstrated the cat-alytic potential of bis(oxazoline)-metal complexes in enan-tioselective Diels–Alder reactions.75 Evans et al. have alsodocumented the utility of bis(oxazoline)-Cu complexes innumerous intermolecular and intramolecular Diels–Alderreactions.76 In 1996, Ghosh et al., 23 and the Merck group24

independently reported on the use of aminoindanol derivedbis(oxazoline)-metal complexes as catalysts for asymmet-ric Diels–Alder reactions. The synthesis of bis(oxazoline)ligand 17 is shown in Scheme 35. Treatment of malononi-trile with anhydrous HCl in ethanol afforded the amide enolether dihydrochloride 138.77 Condensation of the imidatesalt with optically active amino alcohol furnished thebis(oxazoline) ligands 17 and ent-17 (inda-box) in multi-gram quantities in 60–65% yield.23

Constrained bis(oxazoline) ligand 18 was prepared by theMerck group by using a Ritter type reaction.24 As shownin Scheme 36, reaction of optically active 1S, 2R-indan-diol and dinitriles in the presence of trifluoromethane-sulfonic acid afforded various bis(oxazoline) derivatives.The use of malonitrile with indandiol afforded the bis(ox-azoline) 17 in 60% yield and the corresponding monoox-azoline in 10% yield. Alternatively, reaction of dimethylmalonitrile resulted in bis(oxazoline) 18 in only 30% yieldand the corresponding mono(oxazoline) was obtained asthe major product. Dimethyl bis(oxazoline) 18 was pre-pared by dialkylation of the parent bis(oxazoline) 17 withLDA and methyl iodide. Spiro bis(oxazoline) ligands140a–d were also prepared by alkylation of 17 with thecorresponding terminal diiodides.78

Py-box ligand 19 has also been made from aminoindanoland 2,6-pyridine dicarbonyl dichloride 141 as shown inScheme 37.26 Reaction of 141 with (1S, 2R)-aminoin-Scheme 34

Scheme 35


danol in the presence of potassium bicarbonate in isopro-pyl acetate provided the corresponding bis-hydroxy-amide. Cyclization of bis-hydroxyamide by treatmentwith BF3•OEt2 at 120˚C furnished the py-box ligand 19.This protocol is convenient for the synthesis of other con-strained py-box ligands derived from cyclic cis-aminoalcohol with retention of configuration.

5.2.1 Diels–Alder Reactions

The Merck group disclosed the use of several bis(oxazo-line) ligands with copper(II) triflate in Diels–Alder react-ions of cyclopentadiene with acryloyl-N-oxazolidinone142.79 The results are summarized in Scheme 38. Ligand18, which forms a six-membered copper chelate, has beenshown to be the most selective of the ligands studied.Ligands 145a–d, which form 7 or 8 membered metal che-lates, were far less selective. These ligands are postulatedto have increased flexibility over the ligand 18, whichlowers the enantioselectivity.

Ghosh et al. have investigated ligands 17 and ent-17 withcopper(II) and magnesium as Lewis acid in the reaction ofcyclopentadiene with several N-acyl oxazolidinones.23

These results are summarized in Scheme 39. A reversal ofenantioselectivity was shown between copper and magne-

sium complexes. Excellent enantioselectivities were ob-served using copper(II) as Lewis acid. Moderate enantio-selectivities were observed using magnesium as Lewisacid. Diels–Alder reaction of acryloyl-N-oxazolidinone142 and cyclopentadiene in the presence of 10 mol% cation-ic aqua complex80 derived from bis(oxazoline) ent-17 andCu(ClO4)2•6H2O afforded cycloadduct 147a in 98% ee.81

These results have been rationalized in terms of a squareplanar conformation of copper, and s-cis conformation ofthe dieneophile.23, 76a In this model, endo-si-face attack bythe diene is preferred. The reversal caused by use of mag-nesium complexes has been rationalized in terms of a

Scheme 36

Scheme 37

Scheme 38

Scheme 39


Corey–Ishihara transition state model,75b which assumestetrahedral magnesium geometry. This leaves the endo-re-face less hindered for attack by the diene (Figure 5).

Merck researchers have examined the effect of bite angleof the bis(oxazoline) catalyst on the enantioselectivity ofthe Diels–Alder reaction between cyclopentadiene andacryloyl-N-oxazolidinone.78 Again, copper(II) triflate isthe Lewis acid, and ligands 18 and 140a–d were examined(Scheme 40). The bite angle was calculated using the mo-

lecular mechanics program OPTIMOL.82 As shown inScheme 40, the larger the bite angle, the better the enantio-selectivity. For example, cyclopropyl bis(oxazoline)ligand 140a has afforded the best enantioselectivity stud-ied (96% ee), and also has the largest bite angle. The roleof the conformation of the aromatic ring has also beenstudied.83 Ligands 150a,b were prepared from 1-amino-tetrahydronaphthalen-2-ol, and ligands 151a,b were pre-pared from phenylglycinol. Diels–Alder reaction of cy-clopentadiene and acryloyl-N-oxazolidinone, with copper(II) triflate as Lewis acid, was examined. All the confor-mationally constrained aminoindanol-based ligands 18and 140a–e have demonstrated far better enantioselectiv-ities than either tetrahydronaphthalene ligands 150a,b orphenylglycinol ligands 151a,b. Indeed, the highest enan-tioselectivity observed with any of these four ligands was49%. The greater enantioselectivities have been attributedto the conformational rigidity of aminoindanol over tet-rahydronaphthalene or the phenyl group.

5.2.2. Hetero Diels–Alder Reactions

Ghosh et al. have investigated asymmetric hetero Diels–Alder reactions of Danishefsky’s diene and glyoxylate es-ters.25a As shown in Scheme 41, ligands 152, 153, andent-17 were studied using copper(II) triflate as Lewisacid. Aminoindanol derived ligand ent-17 afforded thehighest yields and enantioselectivities. A modest reversalof enantioselectivity was again observed with magnesiumcomplexes. This reaction proceeds in a stepwise mannervia Mukaiyama aldol reaction, followed by ring closing

Figure 5. Transition Models 148 and 149

Scheme 40 Scheme 41


with trifluoroacetic acid. Indeed, the Mukaiyama aldolproduct and the dihydropyrone were both observed beforetreatment with trifluoroacetic acid.84 Previous rigorousinvestigations by Danishefsky et al. have described theimmense synthetic utility of this reaction.85

Hetero Diels–Alder reactions of Danishefsky’s diene andeither benzyloxyacetaldehyde or 1,3-dithiane carboxalde-hyde also provided the corresponding cycloadduct in highenantiomeric excess. As depicted in Scheme 42, confor-mationally constrained inda-box ligands 17 and ent-17 ex-hibited better enantioselectivity than the phe-box ligand152 and the bu-box ligand 153.25b The C3-C14 segment ofthe antitumor macrolide Laulimalide,86 was synthesizedby utilizing dihydropyran 157. As shown, reaction ofDanishefsky’s diene with benzyloxyacetaldehyde, using5 mol% copper(II) triflate and 6 mol% ent-17 provided di-hydropyrone 157 in 76% yield and 85% ee. A series ofstandard synthetic steps gave the C3-C14 segment of Lau-limalide, protected as the MOM ether.25b

5.2.3. Cyclopropanation Reactions

Bis(oxazoline)-metal complex catalyzed enantioselectivecyclopropanation reactions of various alkyl diazoacetateand a variety of olefins were previously studied by a num-ber of research groups.87 Davies et al. have examined

Ru(II)-pybox complexes 19 and 162–164 for the cyclo-propanation of styrene (Scheme 43).83 Reaction of ethyldiazoacetate with styrene in the presence of 0.2 mol%[RuCl2(p-cymene)]2 and 0.8 mol% pybox ligand affordedcyclopropane 161 in moderate yield and fair to good enan-tioselectivity. Interestingly, py-box ligand 162 gave thebest yields, diastereoselectivities, and trans-enantioselec-tivities compared to conformationally constrained py-inda-box ligand 19.

5.2.4 Free Radical Conjugate Additions

Chiral bis(oxazoline)-metal complex catalyzed enantio-selective free radical carbon-carbon bond forming reac-tions have been described by Porter et al. and Sibi et al.88

Recently, Sibi et al. have investigated various bis(oxazo-line) ligands for free radical conjugate additions to cin-namates using oxazolidinone template 146b.89 Stoichio-metric amounts of metal-ligand complexes derived from anumber of bis(oxazoline) ligands and a variety of Lewisacids including MgBr2, MgI2, Mg(OTf)2, Mg(ClO4)2 andZn(OTf)2 were examined. The ligand-metal complexes ofMgI2 afforded good to excellent enantioselectivities andisolated yields as shown in Scheme 44 and Table 25.89a

The cyclopropyl bis(oxazoline) ligand 140a was most ef-fective in providing maximum enantioselectivity. The useof 20-50 mol% ligand at –78˚C resulted in at least 88%chemical yield and greater than 96% product enantiose-lectivites. The use of 30 mol% catalyst at temperaturesranging from –20 to 25˚C also afforded excellent yields(at least 87%) and enantioselectivities (at least 93% ee). In

Scheme 42

Scheme 43


comparison, conjugate additions to the pyrazole templateusing stoichiometric amounts of zinc(II) triflate andligand afforded moderate enantioselectivities at best.89b

6. Aminoindanol in HIV-Protease Inhibitor Synthesis

Much of the explosion of interest in the chemistry of ami-noindanol is a direct result of its use as an amino acid sur-rogate for HIV-protease inhibitors. Numerous potent andselective HIV protease inhibitors incorporating (1S, 2R)-aminoindanol were designed and synthesized by the re-searchers at Merck Research Laboratories.35, 90 These ef-forts have culminated the discovery of a clinically ef-fective protease inhibitor indinavir which has been ap-proved by the U.S. Food and Drug Administration for thetreatment of AIDS in a combination therapy with reversetranscriptase inhibitors under the trade name Crixivan®.14

In the clinical setting, Crixivan® has shown remarkableevidence of effectiveness.91 As many as 90% of the clin-ical-trial participants who received Crixivan® have shownreduced viral load and increased CD4

+ lymphocytecounts. There are five stereogenic centers in indinavir and

cost effective synthesis of such inhibitor is one of the big-gest challenges in asymmetric synthesis. In current com-mercial synthesis, of the five chiral centers in indinavir,two are in aminoindanol, and two more chiral centers areset by the chirality in aminoindanol. The design ofaminoindanol as a ligand in HIV-protease inhibitor led tothe discovery of potent inhibitor L-685,434 (167) withan enzyme inhibitory potency of (IC50) value of 0.35 nMand antiviral potency (CIC95) of 400 nM.12 However,L-685,434 suffered from aqueous insolubility and inade-quate antiviral potency. Attempts were made to improvesolubility and antiviral potency by adding hydrophilicsubstituents to each of the two phenyl rings in L-685,434.These investigations resulted in the discovery of two po-tent inhibitors, L-689,502 (168, IC50 = 0.45 nM; CIC95=6–50 nM)35 and L-693,549 (169, IC50 = 0.1 nM; MIC100 =25–50 nM).92 As shown in Figure 6, each inhibitor con-tains a polar, hydrophilic substituent on the 4-position ofthe P1’ phenyl ring.

For a concise and practical synthesis of this class of pro-tease inhibitors, diastereoselective alkylations of chiralamide enolate derived from (1S, 2R)-aminoindanol wereinvestigated by Askin et al.93 As depicted in Scheme 45,alkylation of N-hydrocinnamoyl aminoindanol acetonide84a with methyl iodide provided alkylation product 84hin 76% yield and 97:3 diastereomeric ratio. This diastere-oselective alkylation protocol was conveniently employedin the synthesis of (1S, 2R)-aminoindanol containingpseudo-C2 symmetric inhibitor 171. The alkylation of theamide enolate of 84a was carried out with 0.5 equivalentsof 3-iodo-2-(iodomethyl)prop-1-ene, to afford the alkyl-ation product 170 in 74% yield. Ozonolysis of 170 fol-lowed by reductive workup with borohydride and subse-quent deprotection of the isopropylidene group affordedto pseudo-C2 symmetric inhibitor 171.94

The synthesis of protease inhibitors 167-169 containinghydroxyethylene isostere were efficiently carried out asshown in Scheme 46. Reaction of 2 equivalents of BuLi ina mixture of 1 equivalent of known95 epoxide 172 and 1equiv of amide at –78 to –25˚C for 2 h furnished the ep-oxide opening product 173 in >90% yield and >99:1 dia-stereoselectivity. Presumably, lithium carbamate salt of

Scheme 44Figure 6. Structures of Inhibitors 167–169


172 activated the epoxide toward the electrophilic ep-oxide opening. The removal of the isopropylidene groupof 173 by treatment with camphorsulfonic acid in metha-nol provided the protease inhibitor 167 in excellent yield.Protease inhibitors 168 and 169 were also prepared con-veniently with appropriate substitution at the 4-position ofthe amide 84a.93

As shown in Figure 7, (1S, 2R)-aminoindanol was also in-corporated in a number of different dipeptide isosteres. Atyrosine-proline hydroxyethylene isostere containingaminoindanol as a ligand was synthesized however, thiscompound 174 was not very potent (IC50=110 nM).96 The

researchers at Upjohn also incorporated aminoindanolinto a dihydroxyethylene isostere providing protease in-hibitor 175 (Ki = 200 nM).97 Compared to inhibitors 167–169, both enzyme inhibitory and antiviral potencies of in-hibitor 175 were poor.97 (1S,2R)-Aminoindanol contain-ing inhibitor 176 with greatly reduced peptide characterhas also been synthesized.98 However, enzyme inhibitoryor antiviral potencies of this inhibitor has not been report-ed. Incorporation of 3(S)-tetrahydrofuranyl urethane inplace of Boc-functionality in 167 resulted inhibitor 177(IC50

< 0.03 nM; CIC95= 3 nM) with remarkable enhance-ment of both enzyme inhibitory and antiviral potencies.99

In 1994, Merck researchers disclosed the synthesis andpharmacological properties of a novel (1S,2R)-aminoin-danol containing protease inhibitor, L-735,524 (180)which eventually became the current therapeutic agentCrixivan®.14, 90 Inhibitor L-735,524 evolved from a struc-ture-based designed strategy in which features of the in-hibitor 167 and Ro 31-8959 (178, Saquinavir®)100 werecombined as shown in Figure 8. The lead inhibitor 179incorporating N-tert-butylcarbonyl-(4a(S)-8a(S)-decahy-droisoquinoline was systematically modified using vari-ous cyclic amines to produce L-735,524 with a 2(S)-(N-tert-butylcarbonyl)piperazine moiety. Numerous N-sub-stituents to this piperazine were investigated prior to thediscovery of Crixivan®.90

For industrial production of Crixivan, Merck researchersdeveloped a novel alkylation-epoxidation sequence whichutilizes the existing chirality of (1S,2R)-aminoindanol to

Scheme 45

Scheme 46

Figure 7. Structures of Different Dipeptide Isosteres


set two of the three remaining chiral centers.101 As shownin Scheme 47, diastereoselective allylation of the lithiumenolate of 84a with allyl bromide afforded the allylationproduct 181 in 94% yield and 96:4 diastereoselectivity.102

Treatment of 181 with N-chlorosuccinimide/sodium io-dide in a two-phase isopropyl acetate/sodium hydrogencarbonate mixture afforded iodohydrin 182 in 92% yield.Reaction of iodohydrin 182 with sodium methoxide inTHF afforded the corresponding oxirane 183 in 99% yieldand impressive diastereoselectivity of 97:3.

As shown in Scheme 48, the reaction is proposed to pro-ceed via cyclic imidate intermediate 184.102b A1,3 strainbetween the benzyl group and amine substituents forcesthe benzyl group to a pseudoaxial position. This results ina high bias for the 2,4-trans product. Hydrolysis of thiscyclic imidate proceeds through intermediate 185 in twodifferent pathways, depending upon the reaction condi-tions. Use of acidic media or unbuffered conditions resultsin formation of the iodolactone 186 (path A). Mildly basichydrolysis with sodium bicarbonate results in the forma-tion of iodohydrin amide 182 in excellent yields (path B).Rossen et al. at Merck recently reported an operationallysimple electrochemical epoxidation of 181 which provid-ed the epoxide 183 in excellent yield (86%) and high di-astereofacial selectivity (94:6).103

The 2(S)-piperazine carboxamide fragment of Crixivan®

is synthesized from cyanopyrazine 187. As shown inScheme 49, hydrolysis of nitrile 187 with tert-butyl ace-tate and sulfuric acid, followed by catalytic hydrogenationof the aromatic ring affords racemic piperazine carbox-amide 188. Selective crystallization as the bis(l-pyro-glutamic) acid salt gives (S)-piperazine carboxamide 190in 47% yield and 86% ee. The R-isomer 189 is recycled bybase catalyzed racemization. The S-isomer is treated withdi-tert-butyl dicarbonate and potassium hydroxide to af-ford the Boc-protected piperazine 191.104 Merck research-ers have also developed an enantioselective route to 191by asymmetric hydrogenation of the correspondingtetrahydropyrazine derivative with 2 mol% [(R)-BI-NAP(COD)Rh]OTf catalyst.105

To complete the synthesis of Crixivan®, epoxide 183 wasreacted with with Boc-piperazine 191 in refluxing metha-

Figure 8. Structural Features of Indinavir (180)

Scheme 47

Scheme 48


nol and the resulting epoxide opening was subjected totreatment of HCl gas to effect the deprotection of the Bocand acetonide protecting groups (Scheme 50). Treatmentof piperazine derivative 192 with 3-picolyl chloride in sul-furic acid provided indinavir sulfate 180 in 75% yieldfrom the epoxide. The overall yield for the process fromaminoindanol is 56%.104

Researchers at Merck laboratories have continued tosearch for more effective protease inhibitors incorporat-ing aminoindanol as the P2’-ligand.106, 107 As shown inFigure 9, replacement of both P1’ and P3 substituents ofindinavir with pyridylmethyl and [3,2-b]thienothiophenemoieties resulted in inhibitor 193 (L-748,496, IC50=0.12nM; IC95 = 6-12 nM).106 This inhibitor is reported to bemore potent than indinavir in cell culture assay and alsothe compound has exhibited excellent pharmacokineticproperties in laboratory animals.106 Merck researchershave also attempted to replace the picolyl piperazine frag-

ment with several aromatic substituents.107 The lowestIC50 observed with this strategy was 1.7 nM for inhibitor194 (antiviral potency, CIC95 = 400 nM). Lehr et al. atSandoz have incorporated aminoindanol into a 2-hetero-substituted-4-amino-3-hydroxy-5-phenylpentanoic acid(AHPPA) isostere.108 The most potent of these inhibitors,195, only showed an IC50 of 47 nM.

7. Conclusion

This review reports on recent developments on the use ofcis-1-aminoindan-2-ol (1) in asymmetric synthesis. Sincethe discovery of cis-1-aminoindan-2-ol (1) as a ligand forHIV-protease inhibitors in 1990, its use in asymmetricsynthesis has blossomed. cis-1-Aminoindan-2-ol basedchiral auxiliaries have proven to be effective for asymmet-ric reductions, aldol reactions, homoaldol reactions, alkyl-ations, and Diels–Alder reactions. Furthermore, cis-1-aminoindan-2-ol derived chiral catalysts have been shownto be effective for asymmetric reductions, Diels–Alderand hetero Diels–Alder reactions, and conjugate radicaladditions. It should also be noted that related cis-2-ami-noindan-1-ol derivatives have been found to be efficientchiral auxiliaries for asymmetric syn-aldol, Diels–Alderreactions as well as chiral ligands for asymmetric reduc-tions.109 The use of cis-1-aminoindan-2-ol (1) as a keyinducer of asymmetry in the synthesis of the HIV-proteaseinhibitor Crixivan® has demonstrated its utility on an in-dustrial scale. However, many potential applications ofcis-aminoindanols and related cyclic amino alcohols insynthesis have yet to be explored. Hopefully, this review

Scheme 49

Scheme 50

Figure 9. Structures of 193–195


will help to stimulate the creativity and ingenuity of syn-thetic organic chemists to find novel applications of cis-1-aminoindan-2-ol (1) in organic synthesis.

Financial support of our work by the National Institute of Health(GM 55600) is gratefully acknowledged. We thank Merck ResearchLaboratories, Sepracor Inc. and BASF, Germany for providing usoptically active aminoindan-2-ol used for our studies. The authorsalso thank Professor George Gould for helpful discussions.

(1) For recent reviews, see: Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Sey-den-Penne, J., Ed.; Wiley Interscience: New York, 1995. Stereoselective Synthesis; Nogradi, M., Ed.; VCH Publishers:New York, 1995.Asymmteric Catalysis in Organic Synthesis, Noyori, R.; WileyInterscience: New York, 1994.Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Pu-blishers: New York, 1993, and references cited therein.

(2) Takaya, H.; Ohta, T.; Noyori, R. Asymmetric hydrogenation. InCatalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Pu-blishers: New York, 1993; pp 1–39.

(3) (a) Kolb, H.C.; VanNieuwenhze, M.S.; Sharpless, K. B. Chem.Rev. 1994, 94, 2483.(b) Johnson, R. A.; Sharpless, K. B. In Catalytic AsymmetricSynthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993;pp 227–272. (c) Lohray, B. B. Tetrahedron: Asymmetry 1992, 3, 1317, andreferences cited therein.

(4) (a) Sharpless, K. B. Tetrahedron 1994, 50, 4235. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic AsymmetricSynthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993;pp 103-158.

(5) Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,Ed.; VCH Publishers: New York, 1993; pp 159-202.

(6) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.1987, 109, 5551.(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,V. K. J. Am. Chem. Soc. 1987, 109, 7927. (c) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3,1475. (d) Singh, V. K. Synthesis 1992, 605, and references cited there-in.

(7) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.1983, 13, 1. (b) Evans, D. A. Aldrichimia Acta. 1982, 15, 23. (c) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.1981, 103, 2127.

(8) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.1982, 104, 1737.

(9) (a) Oppolzer, W. Angew. Chem. 1984, 96, 840; Angew. Chem.Int. Ed. Engl. 1984, 23, 876. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.1988, 110, 1238.

(10) (a) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19,227. (b) Oppolzer, W.; Kingma, A. J.; Poli, G. Tetrahedron 1989, 45,479.

(11) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,835, and references cited therein.

(12) Lyle, T. A.; Wiscount, C. M.; Guare, J. P.; Thompson, W. J.;Anderson, P. S.; Darke, P. L.; Zugay, J. A.; Emini, E. A.;Schlief, W. A.; Quintero, J. C.; Dixon, R. A. F.; Sigal, I. S.;Huff, J. R. J. Med. Chem. 1991, 34, 1228.

(13) Vacca, J. P.; Dorsey, B. D.; Guare, J. P.; Holloway, M. K.;Hungate, R. W.; EP 5 411 68 A1, Merck & Co Inc. (1993);Chem. Abstr. 1994, 120, 54 552.

(14) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDa-niel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.;Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Con-dra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.;Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff,J. R. Proc. Natl. Acad. Sci. USA. 1994, 91, 4096.

(15) Enantiomerically pure cis-1-aminoindan-2-ol is available fromAldrich Chemical Co., Milwaukee, WI. For a highlight of cis-1-aminoindan-2-ol in synthesis, see, Senanayake, C. H. Aldrichi-mica Acta, 1998, P-3.

(16) Didier, E.; Loubinoux, B.; Ramos Tombo, G. M.; Rihs, G.Tetrahedron 1991, 47, 4941.

(17) Hong, Y.; Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron Lett.1994, 35, 6631.

(18) Oxazinone 2 was prepared according to the procedure of Willi-ams, R. M.; Zhai, W. Tetrahedron 1988, 44, 5425. Synthesisof α-amino acids utilizing oxazinone 2 is currently in progress;Ghosh, A. K.; Cho, H, unpublished results.

(19) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 6811.(20) Ghosh, A. K.; Mathivanan, P. Tetrahedron: Asymmetry 1996, 7,

375.(21) Ghosh, A. K.; Duong, T. T.; McKee, S. P. Chem. Comm. 1992,

1673.(22) (a) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527.

(b) Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetra-hedron Lett. 1997, 38, 7171.

(23) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron Lett.1996, 37, 3815.

(24) Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T.R.; Reider, P. J. Tetrahedron Lett. 1996, 37, 813.

(25) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishnan, K.Tetrahedron: Asymmetry 1996, 7, 2165. (b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. TetrahedronLett. 1997, 38, 2427.

(26) Davies, I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J.J. Org. Chem. 1996, 61, 9629.

(27) (a) Armstrong III, J. D.; Hartner Jr., F. W.; DeCamp, A. E.; Vo-lante, R. P.; Shinkai, I. Tetrahedron Lett. 1992, 33, 6599. (b) McWilliams, J. C.; Armstrong III, J. D.; Zheng, N.; Bhupa-thy, M.; Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1996,118, 11970.

(28) Lutz, R. E.; Wayland Jr., R. L. J. Am. Chem. Soc. 1951, 73, 1639.(29) Hassner, A.; Lorber, M. E.; Heathcock, C. J. Org. Chem. 1967,

32, 540.(30) Ghosh, A. K.; McKee, S. P.; Sanders, W. M. Tetrahedron Lett.

1991, 32, 711.(31) Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981,

22, 1283. (b) Moriarty, R. M.; Prakash, O.; Thachet, C. T. Syn. Comm.1984, 14, 1373.

(32) Tillyer, R. D.; Boudreau, C.; Tschaen, D.; Dolling, U.-H.; Rei-der, P. J. Tetrahedron Lett. 1995, 36, 4337.

(33) Laksman, M. K.; Zajc, B. Tetrahedron Lett. 1996, 37, 2529.(34) Greenberg, S.; Moffatt, J. G. J. Am. Chem. Soc. 1973, 95, 4016.(35) Thompson, W. J.; Fitzgerald, P. M. D.; Holloway, M. K.; Emi-

ni, E. A.; Darke, P. L.; McKeever, B. M.; Schleif, W. A.; Quin-tero, J. C.; Zugay, J. A.; Tucker, T. J.; Schwering, J. E.;Homnick, C. F.; Nunberg, J.; Springer, J. P.; Huff, J. R. J. Med.Chem. 1992, 35, 1685.

(36) Rittle, K. E.; Evans, B. E.; Bock, M. G.; Dipardo, R. M.; Whit-ter, W. L.; Homnick, C. F.; Veber, D. F.; Freidinger, R. M.Tetrahedron Lett. 1987, 28, 521.

(37) (a) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30,2151.


(b) Grunewald, G. L.; Ye, Q. J. Org. Chem. 1988, 53, 4021. (c) Ghosh, A. K.; McKee, S. P.; Thompson, W. J.; Darke, P. L.;Zugay, J. C. J. Org. Chem. 1993, 58, 1025.

(38) Boyd, D. R.; Sharma, N. D.; Bowers, N. I.; Goodrich, P. A.;Groocock, M. R.; Blacker, A. J.; Clarke, D. A.; Howard, T.;Dalton, H. Tetrahedron: Asymmetry 1996, 7, 1559.

(39) Senanayake, C. H.; Roberts, F. E.; DiMichele, L. M.; Ryan, K.M.; Liu, J.; Fredenburgh, L. E.; Foster, B. S.; Douglas, A. W.;Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett.1995, 36, 3993.

(40) Ogasawara, K.; Takahashi, M. Synthesis 1996, 954.(41) Ghosh, A. K.; Kincaid, J. F.; Haske, M. G. Synthesis 1997, 541.(42) (a) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 505.

(b) Bianchi, D.; Cesti, P.; Battistel, E. J. Org. Chem. 1988, 53,5531.

(43) Senanayake, C. H.; Smith, G. B.; Ryan, K. M.; Fredenburgh, L.E.; Liu, J.; Roberts, F. E.; Hughes, D. L.; Larsen, R. D.; Ver-hoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1996, 37, 3271.

(44) (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng,L. J. Am. Chem. Soc. 1991, 113, 7063. (b) Jacobsen, E. N.; Larrow, F. J. J. Am. Chem. Soc. 1994, 116,12129, and references cited therein.

(45) Hughes, D. L.; Smith, G. B.; Liu, J.; Dezeny, G. C.; Senanaya-ke, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org.Chem. 1997, 62, 2222.

(46) (a) Curran, D. P.; Jeong, K.-S.; Heffner, T. A.; Rebek, Jr., J.J. Am. Chem. Soc. 1989, 111, 9238. (b) Boeckman, Jr., R. K.; Liu, Y. J. Org. Chem. 1996, 61, 7984;(c) Palomo, C.; Oiarbide, M.; Gonzalez, A.; Garcia, J. M.;Berree, F. Tetrahedron Lett. 1996, 37, 4565, and also seeRef. 1.

(47) (a) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc.1982, 104, 2027. (b) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. ibid. 1982, 104,2030.

(48) Ghosh, A. K.; Liu, W.; Xu, Y.; Chen, Z. Angew. Chem. 1996,108, 73; Angew. Chem. Int. Ed. Engl. 1996, 35, 74.

(49) Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M.L.; Smith, C. D. J. Org. Chem. 1994, 59, 7219.

(50) Ghosh, A. K.; Liu, W. J. Org. Chem. 1996, 61, 6175.(51) (a) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D.; Wein-

kauff, D. J. J. Am. Chem. Soc. 1975, 97, 2567. (b) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman,G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946, andalso see Ref. 2.

(52) Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J. Org. Chem. 1997,62, 6080.

(53) (a) Ghosh, A. K.; Kincaid, J. F.; Walters, D. E.; Chen, Y.;Chaudhuri, N. C.; Thompson, W. J.; Culberson, C.; Fitzgerald,P. M. D.; Lee, H. Y.; McKee, S. P.; Munson, P. M.; Duong, T.T.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.; Axel, M. G.; Lin,J.; Huff, J. R. J. Med. Chem. 1996, 39, 3278. (b) Rich, D. H.; Sun, C.-Q.; Vara Prasad, J. V. N.; Pathiasseril, A.;Toth, M. V.; Marshall, G. R.; Clare, M.; Mueller, R. A.; Houseman,K. J. Med. Chem. 1991, 34, 1222, and references cited therein.

(54) For references for syn-aldol methodologies, see: (a) Kim, B.-M.; Williams, S. F.; Masamune, S. In Comprehen-sive Organic Synthesis; Trost, B. M.; Fleming, I.; Eds.; Perga-mon Press; Oxford, 1991; Vol 2 (Heathcock, C. H., Ed.),Chapter 1.7, 239. (b) Franklin, A. S.; Paterson, I.; Contemp. Org. Synth. 1994, 317and references cited therein.

(55) For references for anti-aldol methodologies, see: (a) Fleming, I. In Comprehensive Organic Synthesis, Vol 2;Heathcock, C. H., Ed., Pergamon Press; Oxford, 1991; pp 563. (b) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,119, 2586, and references cited therein.

(56) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,1920.

(57) Gennari, C.; Cozzi, G. J. Org. Chem. 1988, 53, 4015, and refe-rences cited therein.

(58) Ghosh, A. K.; Fidanze, S., submitted to J. Org. Chem.(59) Vazquez, M. L.; Bryant, M. L.; Clare, M.; DeCrescenzo, G. A.;

Doherty, E. M.; Freskos, J. N.; Getman, D. P.; Houseman, K. A.;Julien, J. A.; Kocan, G. P.; Mueller, R. A.; Shieh, H-S.; Stallings,W. C.; Stegeman, R. A.; Talley, J. J. J. Med. Chem. 1995, 38, 581.

(60) Mechanistic details of this reaction is the subject of ongoing in-vestigation in our laboratory, Ghosh, A. K.; Fidanze, S., unpu-blished results.

(61) Greenlee, W. J.; J. Med. Res. Rev. 1990, 10, 173, and referencescited therein.

(62) For previous nonamino acid derived synthesis, see: (a) Ghosh, A. K.; McKee, S. P.; Thompson, W. J. J. Org. Chem.1991, 56, 6500.(b) Ghosh, A. K.; McKee, S. P.; Lee, H. Y.; Thompson, W. J.J. Chem. Soc., Chem. Commun. 1992, 273, and Ref. 52.

(63) Davies, I. W.; Senanayake, C. H.; Castonguay, L.; Larsen, R.D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36,7619.

(64) Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetra-hedron Lett. 1997, 38, 2633.

(65) Zheng, N.; Armstrong III, J. D.; McWilliams, C.; Volante, R. P.Tetrahedron Lett. 1997, 38, 2817.

(66) Itsuno, S.; Sakurai, Y.; Ito, A.; Hirao, A; Nakahama, S. Bull.Chem. Soc. Jpn. 1987, 60, 395, and references cited therein.

(67) (a) Wallbaum, S.; Martens, J. Tetrahedron:Asymmetry 1992, 3, 1475.(b) Deloux, L.; Srebnlk, M. Chem. Rev. 1993, 93, 763, and re-ferences cited therein.

(68) DiSimone, B.; Savoia, D.; Tagliavini, E.; Umani-Ronchi, A.Tetrahedron: Asymmetry 1995, 6, 301.

(69) Hett, R.; Fang, Q. K.; Gao, Y.; Hong, Y.; Butler, H. T.; Nie, X.;Wald, S. A. Tetrahedron Lett. 1997, 38, 1125.

(70) Hett, R.; Senanayake, C. H.; Wald, S. A. Submitted to Tetrahe-dron.

(71) Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62,5226.

(72) Ghosh, A. K.; Mathivanan, P; Cappiello, J. Tetrahedron:Asymmetry 1998, 9, 1.

(73) (a) Pfaltz, A. Acta Chem. Scan. 1996, 50, 189. (b) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. (c) Pfaltz, A. Chimia 1990, 44, 202.

(74) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. TetrahedronLett. 1990, 31, 6005.(b) Lowenthal, R. E.; Masamune, S. Tetrahedron Lett. 1991, 32,7373.

(75) (a) Corey E. J.; Imai, N.; Zhang, H. J. Am. Chem. Soc. 1991,113, 728.(b) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807.

(76) (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc.1993, 115, 6460. (b) Evans, D.A.; Kozlowski, M. C.; Tedrow, J. S. TetrahedronLett. 1996, 37, 7481. (c) Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786,and references cited therein.

(77) Hall, J.; Lehn, J. M.; DeCian, A.; Fischer, J. Helv. Chim. Acta.1991, 74, 1.

(78) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake, C. H.;Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Chem Soc.Chem. Commun. 1996, 1753.

(79) Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T.R.; Reider, P. J. Tetrahedron Lett. 1996, 37, 1725.

(80) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.; Wa-da, E.; Curran, D. P. J. Org. Chem. 1997, 62, 6454.


(81) Ghosh, A. K.; Cappiello, J.; Cho, H. Unpublished work.(82) Holloway, M. K.; Wai, J. M.; Halgren, T. A.; Fitzgerald, P. M.

D.; Vacca, J. P.; Dorsey, B. D.; Levin, R. B.; Thompson, W. J.;Chen, L. J.; deSolms, S. J.; Gaffin, N.; Ghosh, A. K.; Giuliani,E. A.; Graham, S. L.; Guare, J. P.; Hungate, R. W.; Lyle, T. A.;Sanders, W. M.; Tucker, T. J.; Wiggins, M.; Wiscount, C. M.;Woltersdorf, O. W.; Young, S. D.; Darke, P. L.; Zugay, J. A.J. Med. Chem. 1995, 38, 305.

(83) Davies, I. W.; Gerena, L.; Cai, D.; Larsen, R. D.; Verhoeven, T.R.; Reider, P. J. Tetrahedron Lett. 1997, 38, 1145.

(84) (a) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett.1992, 33, 6907. (b) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc.1994, 116, 2811. (c) Motoyama, Y.; Mikami, K. J. Chem. Soc. Chem. Commun.1994, 1563. (d) Keck, G. E.; Li , X-Y.; Krishnamurthy, D. J. Org. Chem.1995, 60, 5998, and references cited therein.

(85) For synthetic application of wide variety of dihydropyranones,see: (a) Danishefsky, S. J. Aldrichim. Acta 1986, 19, 59. (b) Bednarski, M. D.; Lyssikatos, J. P. Compr. Org. Synth.

1991, 2, 661.(86) (a) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53,

3642. (b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul,V. J. J. Org. Chem. 1988, 53, 3644.

(87) (a) Evans, D. A.; Woerpel, K. A.; Scott, M. J. Angew. Chem.1992, 104, 439; Angew. Chem. Intl. Ed. Engl. 1992, 31, 430.(b) Gant, T. G.; Noe, M. C.; Corey, E. J. Tetrahedron Lett. 1995,36, 8745. (c) Pfaltz, A. Acta Chem. Scand. 1996, 50, 189, and referencescited therein.

(88) (a) Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc.1995, 117, 11029.(b) Sibi, M. P.; Ji, J.; Wu, J-H.; Gurtler, S.; Porter, N. A. J. Am.Chem. Soc. 1996, 118, 9200.

(89) (a) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800. (b) Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron Lett. 1997, 38,5955.

(90) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Gua-re, J. P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.;Quintero, J. C.; Lin, J. H.; Chen, I.-W.; Holloway, M. K.; Fitz-gerald, P. M. D.; Axel, M. G.; Ostovic, D.; Anderson, P. S.;Huff, J. R. J. Med. Chem. 1994, 37, 3443, and references citedtherein.

(91) (a) First HIV Protease Inhibitors Approved by FDA. AntiviralAgents Bull. 1995, 8 (12) 353. (b) Cohen, J. Science, 1996, 272, 1882.

(92) Young, S. D.; Payne, L. S.; Thompson, W. J.; Gaffin, N.; Lyle,T. A.; Britcher, S. F.; Graham, S. L.; Schultz, T. H.; Deana, A.A.; Darke, P. L.; Zugay, J.; Schleif, W. A.; Quintero, J. C.; Emi-ni, E. A.; Anderson, P. S.; Huff, J. R. J. Med. Chem. 1992, 35,1702.

(93) Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; Volan-te, R. P.; Shinkai, I. J. Org. Chem. 1992, 57, 2771.

(94) Bone, R.; Vacca, J. P.; Anderson, P. S.; Holloway, M. K. J. Am.Chem. Soc. 1991, 113, 9382.

(95) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J. P.;Hirshfield, J.; Veber, D. F.; J. Org. Chem. 1985, 50, 4615, andalso see Ref. 58.

(96) Thompson, W. J.; Ball, R. G.; Darke, P. L.; Zugay, J. A.; Thies,J. E. Tetrahedron Lett. 1992, 33, 2957.

(97) Thaisrivongs, S.; Turner, S. R.; Strohbach, J. W.; TenBrink, R.E.; Tarpley, W. G.; McQuade, T. J.; Heinrickson, R. L.; To-masselli, A. G.; Hui, J. O.; Howe, W. J. J. Med. Chem. 1993,36, 941.

(98) Dorsey, B. D.; Plzak, K. J.; Ball, R. G. Tetrahedron Lett. 1993,34, 1851.

(99) Ghosh, A. K.; Thompson, W. J.; McKee, S. P.; Duong, T. T.;Lyle, T. A.; Chen, J. C.; Darke, P. L.; Zugay, J. A.; Emini, E.A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem.1993, 36, 292.

(100) Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A.V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.;Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.;Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D. L.;Thomas, G. J.; Machin, P. J. Science 1990, 248, 358.

(101) Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K. M.;Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35, 673.

(102) (a) Maligres, P. E.; Upadhyay, V.; Rossen, K.; Cianciosi, S. J.;Purick, R. M.; Eng, K. K.; Reamer, R. A.; Askin, D.; Volante,R. P.; Reider, P. J. Tetrahedron Lett. 1995, 36, 2195. (b) Maligres, P. E.; Weissman, S. A.; Upadhyay, V.; Cianciosi,S. J.; Reamer, R. A.; Purick, R. M.; Sager, J.; Rossen, K.; Eng,K. K.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron1996, 52, 3327.

(103) Rossen, K.; Volante, R. P.; Reider, P. J.; Tetrahedron Lett.1997, 38, 777.

(104) (a) Reider, P. J. Chimia 1997, 51, 306. (b) Davies, I. W.; Reider, P. J. Chem. & Ind. (London) 1996,412.

(105) Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.; Askin,D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1995, 36, 6419.

(106) Dorsey, B. D.; McDaniel, S. L.; Levin, R. B.; Vacca, J. P.; Dar-ke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Lin, J. H.;Chen, I.-W.; Holloway, M. K.; Anderson, P. S.; Huff, J. R.Bioorg. & Med. Chem. Lett. 1994, 4, 2769.

(107) Coburn, C. A.; Young, M. B.; Hungate, R. W.; Isaacs, R. C. A.;Vacca, J. P.; Huff, J. R. Bioorg. & Med. Chem. Lett. 1996, 6,1937.

(108) Lehr, P.; Billich, A.; Charpiot, B.; Ettmayer, P.; Scholz, D.;Rosenwirth, B.; Gstach, H. J. Med. Chem. 1996, 39, 2060.

(109) (a) Hashimoto, Y.; Kai, A.; Saigo, K. Tetrahedron Lett. 1995,36, 8821. (b) Sudo, A.; Saigo, K. Tetrahedron: Asymmetry 1996, 7, 2939.(c) Sudo, A.; Saigo, K. Chem. Lett. 1997, 97, and referencescited therein.

Documents

cis -1-Aminoindan-2-ol in Asymmetric Syntheses · cis-1-amino-indan-2-ol derived catalysts and auxiliaries. The present review is intended to focus on the cis-1-aminoindan-2-ol derived