44

Tetrahedron 63 (2007) 2745–2785

Tetrahedron report number 791

Application of hydrolytic kinetic resolution (HKR) in thesynthesis of bioactive compounds

Pradeep Kumar,* Vasudeva Naidu and Priti Gupta

Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India

Received 6 December 2006

Available online 8 January 2007

In memory of my mentor Professor Arya K. Mukerjee

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27461.1. Jacobsen’s HKR procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27471.2. Jacobsen’s catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27471.3. Oligomeric Jacobsen’s Co(salen) catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2748

2. Halogenated epoxides or epihalohydrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27482.1. Muconin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2748

3. Glycidol ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27483.1. 12(R)-HETE, 12(S)-HETE, 2H2-12(R)-HETE, and LTB4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27483.2. CMI-977 (LDP-977) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27503.3. 7(S),17(S)-Resolvin D5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27503.4. (S)-Atenolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27513.5. (S)- and (R)-Naftopidil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27513.6. (S)-Betaxolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2752

4. Aliphatic/aromatic epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27524.1. (R)-(�)-Phenylephrine hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27524.2. E type 1 phytoprostanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27534.3. Massoialactone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27534.4. iso-Cladospolide B and cladospolide B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27534.5. Neoglycolipid analogs of glycosyl ceramides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27544.6. Bicyclic g-lactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27544.7. C13–C22 fragment of amphidinolide T2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27554.8. Dihydrobenzofurans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27554.9. Spongiacysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27574.10. Astrocyte activation suppressor, ONO-2506 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27574.11. (S)-2-Tridecanyl acetate: sex pheromone of Douglas-fir cone gall midge,

Contarinia oregonensis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2757

Keywords: Hydrolytic kinetic resolution; Terminal epoxides; Bis-epoxides; meso-Epoxides; Natural products; Synthesis; Biological activity.Abbreviations: Ac, acetyl; AD, asymmetric dihydroxylation; AE, asymmetric epoxidation; Bn, benzyl; NBS, N-bromosuccinimide; Boc, t-butoxycarbonyl;t-Bu, tert-butyl; m-CPBA, m-chloroperbenzoic acid; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane; DHP, dihydropyran; DIBAL-H,diisobutylaluminum hydride; DIAD, diisopropylazodicarboxylate; DIPEA, diisopropylethylamine; DMAP, dimethylaminopyridine; DMF, dimethylform-amide; 2,2-DMP, 2,2-dimethoxypropane; DMPU, N,N0-dimethylpropyleneurea; DMSO, dimethyl sulfoxide; Et, ethyl; HMPA, hexamethylphosphoramide;IBX, 2-iodoxybenzoic acid; Im, imidazole; LAH, lithiumaluminumhydride; LTB4, leukotriene-B4; LiHMDS, lithium hexamethyldisiloxane; Me, methyl;MEM, methoxyethoxymethyl; MOM, methoxymethyl; PBu3, tributylphosphine; Ph, phenyl; PMB, p-methoxybenzyl; PPTS, pyridinium p-toluenesulfonate;RCM, ring-closing metathesis; TBAF, tetrabutylammonium fluoride; TBDMS, tert-butyldimethylsilyl; TBME, tert-butyl methyl ether; TES, triethylsilyl;TEMPO, 2,2,6,6,-tetramethyl-1-piperidinyloxy; Tf, triflate; THP, tetrahydropyran; TMEDA, N,N,N0,N0-tetramethylenediamine; TMS, trimethylsilyl; TBDPS,tert-butyldiphenylsilyl; Ts, p-toluenesulfonyl; TsIm, tosylimidazole.* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629; e-mail: [email protected]

0040–4020/$ - see front matter � 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2006.12.015

mailto:[email protected]

2746 P. Kumar et al. / Tetrahedron 63 (2007) 2745–2785

5. Dialkyl-substituted epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27585.1. Taurospongin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2758

6. Amine-substituted epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27596.1. b-Adrenergic blocking agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27596.2. 1-[2-Hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one . . . . . . . . . . . . . . . . . . . . 2759

7. Epoxides bearing a carbonyl functionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27597.1. Fostriecin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27597.2. C1–C19 fragment of ulapualide A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27607.3. Epothilone A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27607.4. N-Substituted 4-hydroxypyrrolidin-2-one . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2762

8. Mono- and bis-epoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27638.1. Insect pheromones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2763

9. Multifunctionalized epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27649.1. Corossolin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27649.2. Aminohydroxyiminocarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27649.3. (+)-Allosedamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27659.4. Tarchonanthuslactone and cryptocarya diacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27659.5. (2R,7S)-Diacetoxytridecane: sex pheromone of the aphidophagous gall midge,

Aphidoletes aphidimyza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27669.6. Cryptocarya diacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27669.7. (+)-Boronolide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27679.8. Polyene-polyol macrolide RK-397 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27679.9. Macroviracin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27689.10. (5S,7R)-Kurzilactone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27699.11. (�)-Indolizidine 223AB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27699.12. Optically active 1,4-anhydropentitols and 2,5-anhydrohexitols . . . . . . . . . . . . . . . . . . . . . . . 27709.13. C3–C14 fragment of antitumor agent, laulimalide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27719.14. Hemibrevetoxin B: synthesis of a key intermediate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27719.15. (4R)-Hydroxy analogs of Annonaceous acetogenins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2772

10. Miscellaneous epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277310.1. (R)-2-Amino-1-hydroxyethylphosphonic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277310.2. Enantiomeric 2,3-epoxypropylphosphonates and (S)-phosphocarnitine . . . . . . . . . . . . . . . . . 277310.3. Oxacyclic ring systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277310.4. Monofluorinated analogs of (lyso)phosphatidic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277310.5. Chiral (a,a-difluoroalkyl)phosphonate analogs of (lyso)phosphatidic acid . . . . . . . . . . . . . 277410.6. 7(S),16(R),17(S)-Resolvin D2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277410.7. (�)-Galantinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277510.8. (4R,9Z)-Octadec-9-en-4-olide, the female sex pheromone of Janus integer . . . . . . . . . . . . . . . 277510.9. (+)-Sch 642305 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277610.10. hNK-1 receptor antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277610.11. L-Carnitine and a-lipoic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277710.12. C20–C26 building block of halichondrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277710.13. (S)-Propranolol and (R)-9-[2-(phosphonomethoxy)propyl]adenine (R-PMPA) . . . . . . . . . . . . . . 277710.14. Total synthesis of (+)-brefeldin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277810.15. C1–C16 fragment of bryostatins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277810.16. Pyrinodemin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277910.17. Combinatorial synthesis of natural product-like molecules . . . . . . . . . . . . . . . . . . . . . . . . . . 277910.18. (S)-(�)-Zearalenone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278010.19. trans-2,5-Disubstituted morpholines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2780

11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2780Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2781References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2781Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2785

1. Introduction

The search for new and efficient methods for the synthesis ofoptically pure compounds has been an active area of researchin organic synthesis. Amongst various syntheses, the enan-tioselective syntheses of complex natural products contain-ing multiple stereocenters are often the most challenging.

The asymmetric catalysis provides a practical, cost effectiveand efficient synthesis of such molecules. Furthermore, theenantioselective synthesis of natural products by a catalyticprocess assumes significance since isolation from naturalsources can only be accomplished in minute quantities.The use of catalytic methods not only provides an easy ac-cess to an enantiomerically pure product but also permits

P. Kumar et al. / Tetrahedr

maximum variability in product structure with regard tostereochemical diversity, which is particularly important formaking various synthetic analogs required for biological ac-tivity. While tremendous advances have been made in asym-metric synthesis, substrate driven or catalytically inducedresolution of racemates is still the most important industrialapproach to the synthesis of enantiomerically pure com-pounds. In a kinetic resolution process, one of the enantio-mers of the racemic mixture is transformed to the desiredproduct while the other is recovered unchanged.

Epoxides are versatile building blocks that have been exten-sively used in the synthesis of complex organic compounds.Their utility as valuable intermediates has further expandedwith the advent of asymmetric catalytic methods for theirsynthesis.1 The terminal epoxides are a most important sub-class of these compounds, but no general and practicalmethods were available for their synthesis in enantiomeri-cally pure form. Hydrolytic kinetic resolution (HKR) devel-oped by Jacobsen has emerged in recent times as a powerfultool to synthesize both terminal epoxides and their corre-sponding diols in highly enantiomerically pure form.2 Theprocess uses water as the only reagent, no added solvent,and low loading of recyclable chiral cobalt-based salen com-plexes to afford the terminal epoxides and 1,2-diol in highyield and high enantiomeric excess. With the advent of theHKR method, synthetic organic chemists have graduallyadopted this as the method of choice for the preparation ofa variety of terminal epoxides in enantio-enriched form.During the last couple of years, the main emphasis hasbeen on the application of this novel reaction and thereforethe main aim of this review is to cover its growing applica-tions in target-oriented synthesis. The compounds coveredare classified into 10 categories, which are based on thesynthesis of enantiopure epoxides as chiral building blocksprepared through the HKR method. These epoxides werecarried through various organic transformations to the targetmolecules. In this article, an attempt has been made to pres-ent the subject in an integrated form and in its proper per-spective.

1.1. Jacobsen’s HKR procedure

In the HKR method a racemic epoxide is treated with ap-prox. half an equivalent of water either neat or with onlyapprox. 10 mol % of a solvent in the presence of Jacobsen’s(salen)Co(III)–OAc (1a or 1b) catalyst (Fig. 1) to producehighly enantio-enriched epoxide and 1,2-diol in almostequal amounts (Scheme 1). The epoxide and diol productsdiffer greatly in their physical characteristics allowing easyseparation to give two highly useful enantiomerically pureproducts.

Thus, the salient features of the HKR method include the fol-lowing: the high accessibility of racemic terminal epoxides;

applicability to a wide range of racemic terminal epoxides,most of which are quite inexpensive; access to highly enan-tio-enriched products in close to theoretical yields; a practi-cal and scaleable protocol; the low loading (0.2–2 mol %)and recyclability of commercially available catalysts at lowcost; the use of water as the nucleophile for epoxide ringopening; and the ease of product separation from unreactedepoxide due to large boiling point and polarity differences.Many chiral building blocks based on HKR technology havebeen developed. Some of these include propylene oxide,methyl glycidate, epichlorohydrin, and 3-chloro-1,2-pro-panediol.3

1.2. Jacobsen’s catalyst

Both the enantiomers of (salen)Co(II) complex 1 (Fig. 1) areavailable commercially4 or they can be prepared from thecommercially available ligands using Co(OAc)2.3 TheCo(II) complex 1 is catalytically inactive. The active stateof the Jacobsen’s catalyst requires the +3 oxidation state ofcobalt, not the +2 state of the pre-catalyst. Thus, the Co(II)complex must be subjected to one-electron oxidation to pro-duce a (salen)Co(III)–X complex (X¼anionic ligand) priorto the HKR. The conversion of inactive Co(II) salen into ac-tive Co(III) salen is simply achieved in situ on a small scale;a solution of the Co(II) salen pre-catalyst is directly exposedto air in the presence of acetic acid. Thus, 2 mol of Co(II)pre-catalyst, 2 mol of acetic acid and a half mole of oxygenare converted into 2 mol of Co(III) catalyst and 1 mol of wa-ter. A much more desirable approach would be to generateand isolate Co(III) salen allowing its direct use in HKRreactions.5 Thus, the parent salen system 2 on treatmentwith Co(II)acetate tetrahydrate in excess acetic acid withan air sparge gives the Co(III) salen 1a as a crystalline solid(Scheme 2). It is also possible to recycle the catalyst after thereoxidation. The solid residue obtained after the product sep-aration in the HKR reaction is found to have the characteris-tic red-brick color of the reduced (salen)Co(II) complex.Reoxidation with air and AcOH leads to the catalyst with un-diminished levels of reactivity and selectivity.2 The 2,2-di-substituted epoxides are unreactive under HKR conditionswith catalyst 1, however, the kinetic resolution in the pres-ence of (salen)Cr catalysts 1c and 1d with HN3 proved tobe successful.5d,e Chromium(salen) complexes (1c and 1d)are indeed a highly effective catalysts for the enantioselec-tive ring opening of epoxides with Me3SiN3. This reactionis notable not only for its high enantioselectivity and the

RO

RO

R

RO

R

++H2OH2O1a1b

OH OHOHHO

Scheme 1. Hydrolytic kinetic resolution (HKR) reaction.

2747on 63 (2007) 2745–2785

H H

t-Bu t-Bu

H H

t-Bu t-BuOAc

H H

t-Bu t-Bu

NNH H

O

t-Bu

O

t-BuN3

Cr

(R,R)-SalenCo (III) OAc complex (1a)

t-Bu t-Bu

(S,S)-SalenCo (III) OAc complex (1b)

t-Bu t-Bu t-But-Bu

(R,R)-SalenCrN3 complex (1c)

t-But-Bu

(S,S)-SalenCrN3 complex (1d)(R) / (S)SalenCo (II) complex (1)

NN

O ON3

CrNN

O OCo

OAc

NN

O OCo

NN

O OCo

t-Bu t-Bu

H H

t-Bu t-Bu

Figure 1. Jacobsen catalysts.


excess AcOH, airCo(OAc)2.4H2O

2 1a

NNH H

O

t-Bu

O

t-BuOAc

t-Bu t-Bu

NNH H

OH

t-Bu

HO

t-Bu

t-Bu t-BuCo

Scheme 2.

synthetic utility of its products but also for its remarkableefficiency as a catalytic process.

1.3. Oligomeric Jacobsen’s Co(salen) catalyst

The HKR reaction is second order in catalyst. This motivatedthe Jacobsen group to identify a means for fixing or linkingtwo or more Co(salen) units in close proximity to decreasethe catalyst requirements by making the reaction pseudofirst-order with respect to Co(salen) units. This led to thebreakthrough in this area with the discovery of so-calledoligomeric Co(salen) catalyst system6 1e (Fig. 2). This sys-tem is much easier to synthesize than previous ones due to alocally symmetric Co(salen) unit. The oligomeric Co(salen)displays a dramatic reactivity increase on a per Co(salen)unit basis, and a 50-fold decrease in oligomeric catalyst ascompared to the normal Co(salen) system using a typicalepoxide. With the oligomeric catalyst, the product puritywas consistently higher than that observed with the parentCo(III)-salen.

2. Halogenated epoxides or epihalohydrins

2.1. Muconin

Muconin 3 is a novel tetrahydropyran-bearing acetogeninisolated from Rollinia mucosa that has exhibited potent andselective in vitro cytotoxicities against pancreatic and breasttumor cell lines.7 Jacobsen and co-workers developed a con-vergent approach to the synthesis of 3 by assembly of readilyaccessible chiral building blocks.8 Retrosynthesis of the tar-get molecule 3 resulted in four fragments (Scheme 3). Thesefragments were conveniently prepared in high enantiomeric

RSO3

N O

O

N O

O

O

O O

O

NOt-Bu

O

NOt-Bu

O

O

O

t-Bu

t-Bu

1en

O3SR CoCo

Figure 2. Oligomeric Jacobsen’s Co(salen) catalyst (1e).

purity by HKR of the commercially available racemic termi-nal oxides such as tetradecene oxide, epichlorohydrin, andpropylene oxide. In order to prepare the key fragment 4,(R)-tetradecane-1,2-diol 6 was synthesized in 90% yieldand >99% ee from HKR of (�)-tetradecene oxide using0.5 mol % of catalyst 1b in TBME and 0.5 equiv of H2O.This was converted into the required acid 12 by selectiveprotection of the secondary hydroxyl group, oxidation, andvinyl Grignard reaction. The coupling of the acid 12 withpyranol 7, prepared through the hetero-Diels–Alder reac-tion,9 resulted in 15, which was eventually transformed intothe key fragment 4 in several steps. To synthesize the keyfragment 5, (R)-epichlorohydrin 8 was readily prepared in>99% ee and 82% of theoretical yield by HKR of racemicepoxide using 0.5 mol % of catalyst 1b and 0.55 equiv ofwater. This compound was converted into the TBS-protectediodohydrin 18 by copper(I)-catalyzed epoxide ring openingusing a Grignard reaction. Lactone 19 was readily preparedin quantitative yield from phenylthioacetic acid and (S)-pro-pylene oxide, the latter obtained through HKR in 98% ee and95% yield. Alkylation of the enolate derived from 19 withiodohydrin 18 afforded 20 in 81% yield. The key fragmentcoupling was accomplished by hydroboration of 20 andtransmetalation followed by addition of aldehyde 4 to theresulting vinylzinc derivative. The addition product was, how-ever, obtained as a mixture of diastereomers. Finally, thedesired C(12)-(S)-stereochemistry was installed by means ofa Swern oxidation/Zn(BH4)2 reduction sequence. Subsequentsynthetic manipulation led to the synthesis of 3 (Scheme 4).

3. Glycidol ethers

3.1. 12(R)-HETE, 12(S)-HETE, 2H2-12(R)-HETE, andLTB4

12(R)-HETE 29 is found in high concentrations in psoriasislesions and is formed by the cytochrome P-450 pathway.10

Me

M

OTBS

O

OPhS

OOOOH

O

MeOHOH

OOMe

OTBS O

H

H25C12

OHOH

O

O

OP ClO Me

O

+

+

8

10

muconin 3

4

45

6 7 8 9

+

Scheme 3. Retrosynthetic analysis for muconin.

2749P. Kumar et al. / Tetrahedron 63 (2007) 2745–2785

H25C12O

H25C12

OMOMOH

H25C12

OMOM

O CO2H

TMSO

OMe

OOPBB

H

O

OH

OPBB

ClO

IOTBS

MeO O

Me O

O

PhS

Me

OOH25C12

OTBS

OPBB

OOOTBS OH OTBS

O

O

Me

PhSMe

ClO

MeOO

O

H

OTBS

OTBSO

PhS

Me

O

BrTMS

+

muconin

76%

i) TEMPO, NaOClii) CH2=CHMgBr

68%10 11 12

13

4

8

14

(S)-9

8

22 12 4

36

3

HKR 1b 82%, 99%ee

95%, 98%ee

HKR 1b

i) LDA, Phenylthioacetic acid (17)ii) PTSA, Benzene

99%

418

15

20

21

7

19±9

±8

16

10

4

i) 1b

ii) CH(OMe)3iii) DIBAL-H

iii) NaHiv) ICH2CO2Na

Scheme 4.

Its enantiomer, 12(S)-HETE 30, the major 12-lipoxygenasemetabolite in platelets,11a has been found to play a centralrole in various stages of metastatic processes in tumors andis therefore a potential target for an anticancer treatment.12(S)-HETE inhibits tumor cell adhesion to endothelialcells.11b LTB4 32, a metabolite of arachidonic acid, is a po-tent chemotactic agent for human eosinophils and neutro-phils and a modulator of inflammatory responses.12 It also

has high antiviral activity comparable with antiviral drugssuch as acyclovir or ganciclovir13 toward DNA viruses aswell as retroviruses including HIV-1 and HIV-2.

The total syntheses of these molecules from racemic glyci-dol were reported by Spur and co-workers.14 As shown inScheme 5, the key steps employed were the hydrolytickinetic resolution of racemic TES-glycidol, and the selective

OH OH

CO2H

PO

OTBDPSCO2MeMeO

MeO

LDA, THF, -78 °C - RTI2, CH2Cl2H2, Lindlar cat.TBAF, THF, 0 °C LTB4 32

31

(R)-25

OTESO

TESOOH

OH

CO2H

OTESH

O

OTESO

OHO OTES

OOTES

O

OTESH

O

1-heptyne, n-BuLi

BF3.Et2O, THF, -78 °C

1. TESCl, imidazole Et3N, DMF2. Swern oxidation

Ph3P = CH-CHO

KHMDS, HMPA,THF, -78 °C

2. H2, Lindlar cat (Pd/CaCO3, Py, hexane3. PPTS, MeOH4. 1 N, LiOH, THF/MeOH, CO2 12 (R)-HETE 29

12 (S)-HETE 30

(R)-24

(S)-24

(R)-27

(S)-27

28

1b

1a

H2O, ether

H2O, ether(±)-23

TESCl, cat DMAPEt3N, DCM0 °C22

(R)-23

(S)-23

(R)-23

(S)-23

(R)-25

(S)-25

26

COOMeI- Ph3P+

Scheme 5.


oxidation of primary silyl ethers in the presence of second-ary ones under Swern conditions. Subsequent Wittig reac-tion and selective reduction of the triple bond to a cis- ortrans-double bond resulted in the desired target compounds.

3.2. CMI-977 (LDP-977)

CMI-977, (2S,5S)-trans-5-[(4-fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, renamed lateras LDP-977 40, is a promising candidate for chronicasthma,15 being developed by Cytomed Inc., USA. Thesynthesis reported by Gurjar and co-workers16 began withHKR of a glycidyl ether (�)-33 (prepared by ring openingof (�)-epichlorohydrin with p-fluorophenol in the presenceof a base), which provided the enantiopure epoxide (S)-33and the (R)-diol (R)-34 in 46% yield each. The epoxide(R)-33 obtained from the diol (R)-34 was subjected to allylGrignard reaction to afford 35. Subsequent ozonolysis,

F

OO

F

OOH

OH

F

OO

+

1a

t-BuOH-H2O0 °C-rt, 5 h46% each

±33

(S)-33

(R)-34

F

OOH

OH

F

OO

F

OOBs

F

OOBs

OH

F

OOBs

OHO

OOHH

F

1. TMSCl, CH3C(OMe)3 CH2Cl22. K2CO3 MeOH 91%

1. allylmagnesium bromide ether, CuCN,84%

AE

(R)-34(R)-33

35

36

37

38

92%

2. PhSO2Cl, Et3N, DMA 92%

OOHH

F

N OO

O

O

OPh

Ph

OOHH

FNOH

NH2

O

39

CMI-977 40

Scheme 6.

two-carbon homologation by Wittig, reduction to allylicalcohol followed by Sharpless epoxidation furnished theepoxy alcohol 37. Its conversion into a-chloro oxirane,a tandem double elimination and concomitant intramolecu-lar nucleophilic substitution yielded the THF/acetylene de-rivative 38, which was converted into the target moleculeCMI-977 40 over several steps (Scheme 6).

3.3. 7(S),17(S)-Resolvin D5

Resolvins, a new class of lipid mediators, are known tohave anti-inflammatory activities in the pico- or nanomolarrange.17 The first total synthesis of 7(S),17(S)-resolvinD5, a lipid mediator derived from docosahexaenoic acid,was accomplished by Spur and Rodriguez.18 A convergentapproach was employed to assemble the molecule, whichmainly involved the Takai olefination to construct the transdouble bond, Lindlar reduction for the cis double bond, pal-ladium-catalyzed Sonogashira coupling for the constructionof the ene–yne moiety, and the simultaneous deprotectionand ester cleavage with lipase from Candida rugosa.

As outlined in Scheme 7, the enantiopure benzyl glycidylether (R)-41 was prepared by HKR in >99% ee following aliterature method.3 The C1–C9 fragment 45 was obtainedfrom (R)-41 and commercially available 2-(4-pentynyloxy)-tetrahydro-2H-pyran 4219 (Scheme 7). The ring opening ofepoxide (R)-41 with lithium acetylide of 42 under Yamaguchiconditions afforded 43, which was carried through severaltransformations including Takai olefination to yield the re-quired fragment 45. Following a similar sequence of reac-tions, the C15–C22 fragment 48 was synthesized from thechiral glycidyl ether (R)-41 as outlined in Scheme 8. The cou-pling of 48 with 2 equiv of 1-trimethylsilyl-1,4-pentadiyne4920 gave exclusively the trans-ene-diyne 51 after cleavageof the terminal TMS group. The target compound, resolvin53, was finally obtained by the Pd-catalyzed second couplingof 45 with 51 followed by selective hydrogenation, deprotec-tion, and saponification (Scheme 9).

OO O

O

OO OTHP

OOH OTHP

OCO2Me

OBz

CO2Me

OBz

I

+

n-BuLi,BF3Et2OTHF, -70 °C85%

1. BzCl, Py, 92%2. PPTS MeOH, 88%

3. Jones oxidation4. 10% TMSCl, MeOH 2,2-DMP, 93%5. H2, Lindlar cat., 98%

1a

±41 (R)-41

45%

42

43

44

45

99% ee

(R)-41

Scheme 7.


3.4. (S)-Atenolol

(S)-Atenolol 61 is a b-blocker, and is used in the treatmentof hypertension and ocular delivery for glaucoma.21 Itsasymmetric synthesis was reported by Bose and Narsaiahin 2005.22 The terminal epoxide 58 was prepared from 4-hy-droxyl acetophenone 54 using a sequence of reactions asshown in Scheme 10 and (�)-58 was subjected to HKR us-ing catalyst 1a to give the (S)-epoxide (S)-58 in 46% yieldand 94% ee. The (S)-epoxide was converted into (S)-atenolol61 using standard transformations.

3.5. (S)- and (R)-Naftopidil

Naftopidil (67 and 68) is a vasodilator from the piperazinederivative series.23 It is a novel a1-adrenoreceptor antagonist

OO O

OH

HOOBz

OBz

I

1-butyne, n-BuLi THF, -70 °C

1. BzCl, pyridine,94%

2. H2, Lindlar cat., 96%3. EtSH, AlCl3, 85%

(R)-41 46

47

48

80%

Scheme 8.

(a1-blocker), renal urologic drug. Bose and co-workers24

have successfully carried out the HKR of racemic a-naph-thyl glycidyl ether (prepared from a-naphthol and epichloro-hydrin) using the catalyst 1a, which provided theenantiomerically pure (S)-naphthyl glycidyl ether (S)-62and (R)-1-naphthyl glycerol 63. Piperazine derivative 66was obtained from the coupling of O-anisidine and bis(2-chloroethyl)amine hydrochloride 65, which was preparedfrom diethanolamine 64. The enantiomerically pure (S)-and (R)-naftopidil was synthesized by opening of the

OBz

I

OBz

OBz

OBz

CO2Me

OH

CO2H

OH

+

(i) Pd(PPh3)4, CuI n-PrNH2, 50%

49 50

51(ii) AgNO3, MeOH

52

7(S),17(S)-resolvin D5 53

Lipase

75%

TMS

Scheme 9.

O

H2N

O

OHN

O

S

N

HO HO HO

O

O

OMe

O

MeO

OO

MeO

OO

O

MeO

OO

O

MeO

OOH

OH

OO

MeO

OH

O

MeO

OO

+1a

isopropylaminewater, reflux, 78%

Ph3P, DEADBenzene, 83.7%

NH4OH, MeOH, 72%

allyl bromide,acetoneK2CO3

m-CPBACH2Cl2

Sulfurmorpholine

i) ethanolic-NaOHii) MeOH-thionyl chloride

100 °C

(S)-atenolol 61

5455 56

57

(±)-58

(S)-58

(R)-59

60 (R)-58

86%83%

87%

84%

H

NH

Scheme 10.


corresponding pure terminal epoxide with 1-(2-methoxy-phenyl)piperazine (Scheme 11).

HO NH

HO

Cl NH.HCl

Cl

NOMe NH O N

NOH

MeO

OO

OOH

OH

O

O

H

45% yield 45% yield

74% 85%

93%

SOCl2, benzeneO-Anisidineaq. NaHCO3

+ 1a

(±)-62 (S)-62 63

6465

66

(S)-62

(S)-naftopidil 67

O OHOH

OO

O NN

MeO

OHiPrOH, reflux

DEAD, Ph3Pbenzene

63 (R)-62

66

90% (R)-naftopidil 68

87%

Scheme 11.

3.6. (S)-Betaxolol

(S)-Betaxolol 75 is a b-adrenergic antagonist25 used in thetreatment of cardiovascular disorders such as hypertension,cardiac arrhythmia, angina pectoris, and open-angleglaucoma.26 Its synthesis was accomplished by Gurjar andco-workers27a starting from the commercially available 2-(4-hydroxyphenyl)ethanol 69. This was converted into theglycidol derivative 73 in several steps, which was subjectedto HKR to afford the (S)-epoxide (S)-73 in 99% ee and 43%yield and the (R)-diol (R)-74 in 92% ee and 47% yield. Theepoxide ring opening with isopropylamine led to the targetcompound, (S)-betaxolol 75, in 76% yield (Scheme 12).

Similarly, other glycidol ethers prepared through HKR havebeen employed in the synthesis of a various biologicallyimportant compounds such as fluoroalanines27b and phor-boxazoles.27c

4. Aliphatic/aromatic epoxides

4.1. (R)-(L)-Phenylephrine hydrochloride

(R)-(�)-Phenylephrine hydrochloride 79 is a clinically po-tent adrenergic agent and b-receptor sympathomimeticdrug, exclusively marketed in the optically active form.28

Gurjar and co-workers29 devised a route for its asymmetricsynthesis based on hydrolytic kinetic resolution of the sty-rene oxide derivative (�)-77. As shown in Scheme 13, thesynthesis began with m-hydroxybenzaldehyde 76, which

was converted into the required epoxide after hydroxyl pro-tection and subsequent treatment with trimethylsulfoxoniumiodide in the presence of NaH/DMSO. The epoxide (�)-77was subjected to HKR using (R,R)-salen Co(III) acetatecomplex 1a to give the (R)-styrene oxide, (R)-77, in 45%yield and 97% ee and (S)-diol (S)-78 in 48% yield and95% ee. Subsequent treatment with methylamine/HCl re-sulted in (R)-(�)-phenylephrine hydrochloride 79 in 97% ee.

OH

OH

O

OBn

O

OBn

O

O

O

OO

i) BnBr KOH 90%ii) allyl bromide KOtBu DMSO 98%

i) diethyl zinc diiodomethane

i) Raney Ni MeOH, H2, 86%

ii) allyl bromide KOH, 95%

m-CPBA

69 70 71

72

95%

75%

(±)-73

O

OO

O

OO

O

OOH

OH

O

OOH

NH

+1a

99% ee, 43% yield 92% ee, 47% yield

(S)-betaxolol 75

isopropylamine, CH2Cl2

(±)-73

(S)-73 (R)-74

76%

Scheme 12.

OH

OH HN CH3

CHO

OH OMEM

O

OMEM

O

76

1a

(±) 77

Yield 45%ee 97%

Yield 48%ee 95%(R)-77 (S)-78

(R)-77 (R)-(-)-phenylephrine hydrochloride

OMEM

OHOH

OMEM

O

+

i) MEMClDIPEA, DCM95%

ii) (CH3)3S(O)INaH, DMSO75%

HCl

79

Scheme 13.


4.2. E type 1 phytoprostanes

The first total synthesis of two E type phytoprostanes 91 and92 was reported by Spur and Rodriguez.30 Phytoprostanesare known to cause tissue irritation and contribute to allergicreactions in human beings. The synthesis involved two-component coupling of a chiral hydroxycyclopentenone de-rivative with a trans-vinyl iodide and subsequent syntheticmanipulations. As illustrated in Scheme 14, the synthesisof the optically active pure iodovinyl side chain started fromthe kinetic resolution of racemic 1,2-epoxybutane 80 usingthe S,S-salen-Co catalyst 1b to give the diol 81 in 99% eeand 47% yield. Hydroxyl protection, selective oxidation toaldehyde followed by a Takai reaction yielded the requiredside chain 84. The racemic hydroxycyclopentenone 88 wasobtained from the reaction of furan 85 and mixed anhydrideof azelaic monomethyl ester 86 in water under reflux usinga catalytic amount of chloral. The rac-hydroxycyclopente-none 88 was easily converted into the chiral intermediatesin >97% ee by lipase. The synthesis of target compounds91 and 92 was achieved by two-component coupling follow-ing a series of synthetic transformations (Scheme 15).

OHO

OH

TESOOTES

OTES

O

HOTES

I

TESClimidazole

CrO3.2PyCH2Cl2

CrCl2, CHI3THF

(±)-80 81

99% ee47% yield

82

83 84

65%

75%1b

Scheme 14.

O

HOOH

COOHO

HOOH

COOH

OHOOC COOMe

OO

COOMe

HO

O

COOMe

HO

O

COOMe

AcO

O

COOMe

OTES

I

ent-phytoprostane E1 91 16 epi-phytoprostane E1 92

+

i) ClCH2COCl, Et3Nii) cat. BF3.Et2O, CCl4 77%

Lipase (PPL), vinyl acetatechromatographic separation

8586

87

88

89 90

84

Scheme 15.

4.3. Massoialactone

A practical and efficient enantioselective synthesis of both(R)- and (S)-massoialactone 98 was achieved by Kumar andco-workers.31 The key steps in the synthesis included theHKR of a racemic epoxyheptane and ring-closing metathesisof homoallylic alcohol-derived acrylate esters using Grubb’scatalyst. Thus, as depicted in Scheme 16, the synthesis of thetarget molecule 98 started from 1-heptene 93, which wasepoxidized with m-CPBA and then subjected to HKR using1a (0.5 mol %) and water (0.55 equiv) to give the R-epoxide,(R)-94, in 45% yield and >99% ee and (S)-diol 95 in 43%yield with 99.5% ee. Opening of the R-epoxide, (R)-94,with lithium acetylide and hydrogenation followed by ring-closing metathesis resulted in (R)-massoialactone 98. The(S)-diol 95 was converted into the cyclic sulfate 99. It wasopened with lithium acetylide and converted into the homo-allylic alcohol. The synthesis of (S)-massoialactone wasachieved using a similar sequence of reactions as shownabove.

O

OHOH

O +

93 (±)-94

(R)-94

45% yield

95

43% yield

m-CPBA92%

1a

OOH

O

O

O

O

H2 (1 bar)Pd/BaSO4, 92%

Acryloyl chlorideEt3N

0 °C, 89%

(R)-massoialactone

LiacetylideethylenediamineDMSO, 86%

(R)-94(R)-96

(R)-97 (R)-98

RCM84%

OHOH

OH

O

OO

O

OS

O

OO

SOCl2, Et3N, CH2Cl2 99%RuCl3, NaIO4

Acryloyl chlorideEt3N

RCM

(S)-98

95

ii) H2 (1 bar)Pd/BaSO4 86%

i) Li acetylideethylenediamine80%

99

(S)-96

(S)-97 (S)-massoialactone

100%

84%

85%

Scheme 16.

4.4. iso-Cladospolide B and cladospolide B

The novel hexaketide compounds, iso-cladospolide and cla-dospolide, were isolated from the fungal isolate, I96S215.32

They have plant growth retardant activity toward rice seed-lings.33 Kumar and Pandey accomplished the total synthesisof iso-cladospolide B and cladospolide B from commer-cially available propylene oxide employing Jacobsen’s


HKR, a Sharpless asymmetric dihydroxylation, and Yama-guchi macrolactonization as the key steps.34a The chainlengthening of (R)-propylene oxide, prepared throughHKR, by Grignard, Sharpless asymmetric dihydroxylation,and iterative Wittig reaction followed by acid-inducedYamaguchi lactonization resulted in iso-cladospolide B 104and cladospolide B 106 (Scheme 17). The stereochemistryof the carbon bearing a methyl substituent was derivedfrom HKR while the other two centers were established bySharpless asymmetric dihydroxylation.

OOTPS

OBn

OTPS O

OEt

OTPS O

OEtOH

OH

O

OH OH

O

OH

(R)-9

Grignard, 77%

protection, 95%100

101

102103

94%

3% MeOH/HCl77%

iso-cladospolide B 104

OTPS

O O

OEt

O

O

O

AD

O OOH

OH

O

OH103

i) LiOH, MeOH/H2Oii) TBAF

88%

cladospolide B 106

105

Scheme 17.

Similarly, both (R)- and (S)-propylene oxide preparedthrough HKR have been employed in the synthesis of avariety of other biologically important compounds such asneocarazostatin,34b nonactin,34c elecanacin,34d (+)-pelorusideA34e and carquinostatin A.34f

4.5. Neoglycolipid analogs of glycosyl ceramides

Glycosphingolipids or glycosyl ceramides are constituentsof animal cell membranes consisting of various oligosaccha-rides bound to ceramides by a glycosidic bond. They serveas identifying markers and regulate cellular recognition,growth, and development.35 Boullanger and co-workers36

synthesized four different types of glycosyl ceramide ana-logs having D-galactose or 2-acetamido-2-deoxy-D-glucosestarting from an epoxide and employing hydrolytic kineticresolution (HKR) as a key step.

As depicted in Scheme 18, (�)-1,2-epoxyhexadecane, (�)-107, was subjected to hydrolytic kinetic resolution with wa-ter (0.55 equiv) in THF in the presence of (R,R) catalyst 1a toafford the R-epoxide, (R)-107, and S-diol, (S)-108, in 48 and37% yields, respectively, with >95% ee. Similarly, by using1b catalyst S-epoxide, (S)-107, and R-diol, (R)-108, wereobtained in the same yields. Treatment of (S)-108 withPPh3/DIAD and TMSN3 gave an inseparable mixture ofregioisomers (20:1), (R)-109 and (S)-110, in good yield.After desilylation, the two isomers were separated bycolumn chromatography. Next, (R)-112 and (S)-111 wereprepared from (R)-108 using a similar sequence of reactions.Finally, galactosylation and glycosylation led to the ceram-ides (R)-115, (S)-115, (R)-117, and (S)-117 in good yields(Scheme 19).

4.6. Bicyclic g-lactones

Kitching and co-workers developed a new synthesis of somebicyclic g-lactones from parasitic wasps (Hymenoptera:

C14H29O

C14H29O

C14H29

OHHO

C14H29O

C14H29

OHHO

C14H29Me3SiON3

C14H29

OSiMe3

N3C14H29Me3SiO

N3

C14H29

OSiMe3

N3

C14H29HON3

C14H29

OHN3

C14H29HON3

C14H29

OHN3

++

(R)-107 (48%) (S)-107 (48%)

i) PPh3, DIADii) (CH3)3SiN3

mixture 20:1

+

mixture 20:1

+

i) PPh3, DIADii) (CH3)3SiN3

(R)-111 (86%) (S)-112 (5%) (S)-111 (86%) (R)-112 (5%)

(±)-107

(R)-109 (S)-110

1b1a

(R)-108 (37%)(S)-108 (37%)

(S)-109 (R)-110

Scheme 18.


Braconidae).37 The authors have employed a palladium(II)-catalyzed hydroxycyclization–carbonylation–lactonizationsequence with appropriate pent-4-ene-1,3-diols providingefficient access to the bicyclic g-lactones. The ene-diols121a,b were visualized as immediate precursors for thePd-catalyzed cyclization. The ene-diols 121a,b, in turn, wereprepared starting from racemic 1,2-epoxyhexane 118a/1,2-epoxyoctane 118b, which were subjected to HKR using 1bcatalyst to afford the (S)-epoxide 118a/118b in 33% yieldand (R)-1,2-hexanediol 119a/octanediol 119b in 40% yield(Scheme 20). The treatment of S-epoxide with vinylmagne-sium bromide delivered the homoallylic alcohols, which, astheir THP ethers, were ozonized and again reacted with

OC14H29

RO

OR OR

OR

N3

OC14H29

N3RO

OR OR

OR

OC14H29

HO

OH OH

OH

NHCOC15H31

OC14H29

HO

OH OH

OH

NHCOC15H31

RO

OR OR

OR

R = Bz or Ac

(R)-111, TMSOTf (cat)CH2Cl2, 0 °C

(S)-111, TMSOTf (cat)CH2Cl2, 0 °C

(R)-114

(S)-114

(R)-115

(S)-115

113

OAcAcO

AcOAcO

AlocHNO

C14H29

NHCOC15H31

HOHO

HO

AcHN

OC14H29

NHCOC15H31

HOHO

HO

AcHN

(R)-109

116

(R)-117

(S)-117

(S)-109

OC(NH)CCl3

Scheme 19.

vinylmagnesium bromide. Deprotection afforded the ene-diols 121a,b, which were successfully converted into thedesired lactones 122 and 123 by Pd-catalyzed reactions(Scheme 21).

4.7. C13–C22 fragment of amphidinolide T2

Amphidinolide is a recently discovered molecule withpotent biological activity and, therefore, it has attracteda lot of attention from organic chemists worldwide.38 Asa result, several total or partial syntheses of thismolecule have appeared in the literature. Jamison andco-workers accomplished the synthesis of the C13–C22fragment of amphidinolide T2 131 via nickel-catalyzedreductive coupling of an alkyne and a terminal epoxide.39

The authors explored several routes to the synthesis of enan-tiomerically enriched epoxide 128a, but the use of HKR wasmost satisfactory to separate the mixture of diastereomericepoxides.

The HKR of a stereorandom mixture of 1,5-hexadienediepoxides (125/meso-125/ent-125¼1:2:1)40 provided theepoxide 125 with >99% ee in only two steps from 1,5-hexadiene 124. However, the subsequent reduction of 125with both Red-Al and DIBAL-H resulted in a low yieldof 126a due to rapid cyclization via attack of the hydroxylgroup on the epoxide giving undesired tetrahydrofuran126b (Scheme 22). Further, the addition of allylmagnesiumchloride to S-propylene oxide followed by TBS protectionand epoxidation with m-CPBA (1:1 dr) provided the desiredmixture of epoxides in 38% yield over three steps. The twodiastereomers were chemically separated by subjectingthem again to HKR to afford 128a in >98% diastereoselec-tivity, albeit in low yield. The nickel-catalyzed coupling ofalkyne 12941 and epoxide gave the desired alcohol in >95:5dr and 39% yield, representing rapid access to a significantfragment of amphidinolide T2 131.

4.8. Dihydrobenzofurans

Enantiomerically enriched dihydrobenzofuran derivativesare an important class of biologically active compounds,42

e.g., arthrographol shows antifungal properties,43 whilemegapodiol44 and conocarpan45 exhibit antileukemic andanticancer activity, respectively.

The enantioselective synthesis of 1-benzyloxy-2-oxiranyl-methylbenzenes, precursors for dihydrobenzofurans, wasreported by Bhoga using the HKR method.46 As shown in

RO

RO

R

OHHO

R

OHHO R

O

+

i) Et3N, DCMH2O, RuCl3NaIO4

ii) LiBriii) 20% H2SO4iv) MeOH, K2CO3

(R)119a

(R)119b

(S)118a

(S)118b

(R)-118a-b

1b

(R)-119a-b

R = (CH2)3CH3 118a

R = (CH2)5CH3 118b

RO

R

OTHPi) O3, DCM

RO

ii) NH4Cl.H2Oiii) DHP.PPTS iii) MeOH, Amberlite

(S)-118a-b

(R)-118a-b

120a-b (S)-121a-b

(R)-121a-b

R

OH OH

MgBrCuI, -43 °C

i)

MgBrii) , H3O+R

OH OHHKR

IR-120A

Scheme 20.


R

OH OH

R

OH OH

R

OH OH

R

OH OH

OO O

HR

H

H

OOO

RH

H

H

OOO

HR

H

H

OO O

RH

H

H

OO O

HR

H

H

OOO

RH

H

H

OOO

HR

H

H

OO O

RH

H

H

R = (CH2)3CH3

R = (CH2)5CH3

R = (CH2)5CH3

R = (CH2)3CH3

(S)-121a

etc.

etc.

(R)-121a

(S)-121b

(R)-121b

(3aS,5S,6aS)-Cis-(122) >98%ee

(3aR,5S,6aR)-Trans-(122) >98%ee

(3aS,5S,6aS)-Cis-(123) >98%ee

(3aR,5R,6aR)-Cis-(123) >80%ee

(3aS,5R,6aS)-Trans-(122) >98%ee

(3aR,5R,6aR)-Cis-(122) >98%ee

(3aR,5S,6aR)-Trans-(123) >98%ee

(3aS,5R,6aR)-Trans-(123) >90%ee

Pd (II) Pd (II)

Pd (II)Pd (II)

Scheme 21.

Scheme 23, the HKR substrate was prepared from o-allyl-phenols 132a–c by their conversion into the correspondingo-allylbenzyl ethers followed by epoxidation withdimethyldioxirane to give the racemic 1-benzyloxy-2-

MeO

Me

OTBS Me

OTBS

O

Me

OTBS

O

MeOHMe

Ph

OTBS

TBSO

TBSO

Me Ph

Me

OTBS

OMe

OTBS

O

O

O

O

O

OMe

OHO Me

HO

O

M

1412

18

1

7

e CH2

Me

O

O

HO

HO

O

Me

Me

i) allyl magnesium

amphidinolide T2 131

bromidecat. CuBrii) TBSCl, imid.

+m-CPBA

(S)-9 127

128a

128b

130

67% 67%

50%7%

Ni(cod)2 10 mol%PBu3 20 mol%

Et3 B, 35%

129

128a: 128b, 1:1 128a

1a

8%

> 95: 5 dr

+

m-CP Red-AlBA 1a

CH2Cl2

CH2Cl2125, meso-125, ent-125

(1:2:1)

124 125

126a 126b

Scheme 22.

oxiranylmethylbenzenes, 133a–c. The HKR using the chiralsalen cobalt complex 1a gave the optically active pure(R)-epoxides 134a–c and the (S)-1,2-diols 135a–c in80–90% and 78–85% ee, respectively. Using a similar se-quence of reactions, the o-allylnaphthol 136 was convertedinto the racemic epoxide (�)-137, which, on HKR underidentical conditions, gave the (R)-epoxide (R)-137 and (S)-1,2-diol (S)-138 in 80 and 78% ee, respectively. Subsequentintramolecular epoxide opening followed by in situ cycliza-tion resulted in the target molecules 139 and 140(Scheme 24).

OH

R1

R3

R2

R4

OBnO

R1

R3

R2

R4

OBnO

R1

R3

R2

R4

OBn

OHOH

R1

R3

R2

R4

132a : R1 = R2 = R4 = H; R3 = NO2132b : R1 = R2 = R4 = H; R3 = CH3132c : R1 = CH3; R3 = Cl; R2 = R4 = H

ii) BnBr/K2CO3

ii) Oxone/acetone/ CH3CN

134a : 85% ee134b : 90% ee134c : 80% ee

135a : 80% ee135b : 85% ee135c : 78% ee

+

133a-c

1a

OHO

OBnO

OBnHO

OH

OBn

1a

+

(78% ee)(80% ee)136 (±)-137 (R)-137 (S)-138

Scheme 23.


4.9. Spongiacysteine

Spongiacysteine 141 (Fig. 3), a novel cysteine derivative,was isolated from marine sponge Spongia sp.47 It showsantimicrobial activity against rice blast fungus Pyriculariaoryzae (IC90¼100 ppm). Kigoshi and co-workers elucidatedthe gross structure and absolute stereostructure by spectro-scopic analysis and total synthesis starting from the chiralpool starting material, N-methylcysteine, and using HKR

OOBn

R1

R2

R3

R4

OOH

O

OH

139a : R1= R2 = R4 = H; R3 = NO2 (92% ee)139b : R1= R2 = R4 = H; R3 = CH3 (89% ee)139c : R1 = CH3; R2 = R4 = H; R3 = Cl (85% ee)

10% Pd-C/MeOH

10% Pd-C/MeOH

K2CO3/Et3N

K2CO3/Et3NH2/12 h, 68%(R)-137

(R)-134 a-c

140

R1

R2

R3

R4

OBnO

Scheme 24.

NS

O CO2H

OHH

OH

spongiacysteine (141)

3''1''

2'

1'

2

5

Figure 3.

HN

SHCO2H

NSH

O CO2H

O O

OH OHO

NS

O CO2H OH OH

NS

O CO2H

OHH

OH

isovaleroylchloridePy, rt, 30 min23%

0 °C to rt22 h, 35%, >99% ee

(+)-144

i) lithium acetylide EDA complex 99%ii) MeI, n-BuLi 92%

142 143

145 146

143 + 146

+

1 M NaOH THF-H2O

50 °C, 16 h

41%

147

iii) Lindlar catalyst 83%

(±)-144

1a, H2O

Spongiacysteine (141)

Scheme 25.

and diastereoselective epoxidation as the key steps.48 Asdepicted in Scheme 25, 1,2-epoxypentane (�)-144 was sub-jected to hydrolytic kinetic resolution with H2O catalyzed by1a to provide the optically active epoxide (+)-144, which, onring opening with lithium acetylide followed by methylationand partial hydrogenation, furnished the homoallylic alcohol145 in 83% yield. The epoxide 146 derived from 145 by dia-stereoselective epoxidation was coupled with cysteine deriv-ative 143 leading to the target molecule 141 along withregioisomer 147.

4.10. Astrocyte activation suppressor, ONO-2506

ONO-2506 (152) delays the expansion of cerebral infarctionby modulating the activation of astrocytes through inhibi-tion of S-100b synthesis. It has been developed as a noveltherapeutic agent for stroke, amyotrophic lateral sclerosis,Alzheimer’s disease, and Parkinson’s disease.49 Hasegawaand co-workers50 developed a new process for the synthesisof ONO-2506 using the hydrolytic kinetic resolutionmethod. Racemic 1,2-epoxyoctane (�)-148 was subjectedto HKR using 1a catalyst to give the (R)-epoxide(R)-148 with >99% ee. Opening of the R-epoxide withethylmagnesium bromide, tosylation by directly quenchingwith tosyl chloride, and cyanation with acetone cyanohydrinfollowed by hydrolysis resulted in ONO-2506 (152)(Scheme 26).

O

CN

CONH2CO2H

O

OTs

1a

>99.5% ee

acetone cyanohydrin (2 eq)THF/DMI (7/3)

85.6% 97.1% ee

K2CO330% aq. H2O2

MeOHDMSO70%

i) EtMgCl cat. CuCl

ii) TsCl

99% eerecrystallization

99.8% ee

(±)-148 (R)-148

149150

151ONO-2506 (152)

LiOH

Scheme 26.

4.11. (S)-2-Tridecanyl acetate: sex pheromone ofDouglas-fir cone gall midge, Contarinia oregonensis

Gries and co-workers51a identified compound 154 (Fig. 4)as the sex pheromone of the female Douglas-fir cone

OAc

OAc

(S)-2-tridecanyl acetate (154)

(Z,Z)-4,7-tridecadien-2-yl acetate (153)

Figure 4.


gall midge, C. oregonensis. They synthesized (S)-2-tride-canyl acetate 154 employing hydrolytic kinetic resolutionas the key step. As depicted in Scheme 27, 1,2-epoxytride-cane (�)-155 was subjected to HKR using H2O (0.55 equiv)and catalyst 1a for three days at room temperature to give theR-epoxide (R)-155, which was separated from the S-diol 156by flash chromatography. Ring opening of epoxide (R)-155with LAH followed by acetylation gave the target molecule,(S)-2-tridecanyl acetate 154, in 47% overall yield and with91.3% ee. The hydrolytic kinetic resolution of epoxide(�)-155 with 1b catalyst in a similar manner gave the (R)-2-tridecanyl acetate in 47% yield with 91.3% ee.

Similarly, other aliphatic epoxides prepared through HKRhave been employed in the synthesis of a variety ofbiologically important compounds such as pamamycin-607,51b Annonaceous acetogenins,51c and trisubstituted tet-rahydrofurans.51d

O

O

HOOH

OAc

+

1a (0.4 mol%), THFH2O, (0.55 equiv), 72 h

i) LAHii) Ac2O, Py

47%91.3% ee

(S)-2-tridecanyl acetate 154

(±)-155

(R)-155

156

(R)-155

Scheme 27.

5. Dialkyl-substituted epoxides

5.1. Taurospongin A

Taurospongin A 157 (Fig. 5) is a structurally interesting fattyacid derivative isolated recently from the Okinawan marinesponge Hippospongia sp. It is found to exhibit remarkabledual activity as a potent inhibitor of both DNA polymeraseb and HIV reverse transcriptase.52 Jacobsen and Lebel haveaccomplished the total synthesis of taurospongin.53 The retro-synthetic analysis reveals that the chiral component (S)-158,one of the key intermediates in the synthesis, can be derivedfrom the 2,2-disubstituted epoxide (�)-158. While the Co-salen catalyst has been successfully used for the resolutionof a wide variety of monosubstituted terminal epoxides, 2,2-disubstituted epoxides, e.g., (�)-158, failed to react underHKR conditions. In contrast, kinetic resolution with salenCr catalyst 1d and TMSN3 proved to be successful, providingthe desired enantio-enriched epoxide (S)-158 in 37% yieldand 97% ee (Scheme 28). The epoxide was carried through aseries of transformations to eventually complete the synthesisof the target molecule, taurospongin A 157 (Scheme 29).

157

HO3SHN

O OH O O

O O 14

1 3 7 9

Figure 5. Taurospongin A.

TBSOO

TBSOO

TBSO

OHN3

1d,TMSN3 (0.65 eq)i-PrOH (0.65 eq)

TBME, 0 °C, rt+

(S)-158

37% yield, 97% ee(±)-158 159

Scheme 28.

TBSOO

TBSO

OTES

OO

MeO

O

MeO

OTBS

TBSO

OTESO OTBS

TBSO

OTESOTBSOH

O

O

OH OAc OTBS

NH

NPh

PhRu

O

O

OH O O

O O

O

O

HO3SHN

O OH O

O

HO O

99% ee

ii) TESOTf2,6-lutidine, 97%

i) HF.py, THFii) DIC, i-Pr2NEt, DMAP, CH2Cl2

(R,R)-164 (2 mol%)(S)-158160

161162

163165

166

Ts

i) BINAP, 92%

II) TBSCl, 91%

78%

94%

168

taurospongin A 157

14

1 3 7 9

14 167

i) n-BuLi, BF3.Et2OTHF, -78 °C, 81%

14

Scheme 29.


6. Amine-substituted epoxides

6.1. b-Adrenergic blocking agents

b-Adrenergic blocking agents of the 3-(aryloxy)-2-hydroxy-N-isopropylamine type 169 (Fig. 6) are a group of drugs, thebiological activity of which resides almost exclusively inthe (S)-enantiomer. Hou and co-workers have developed aconcise, divergent, five-step synthesis of three b-adrenergicblocking agents in high enantiomeric excess using (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine as the keyintermediate.54 As illustrated in Scheme 30, N-benzyl-N-isopropylallylamine (prepared from the reaction of N-benz-yl-N-isopropylamine and allyl bromide) was treated withwater in the presence of Li2PdCl4/CuCl2 at�10 �C in DMF,followed by decomplexation of CuCl2 from the chlorohy-droxylation product with an excess of Na2S$9H2O, to givethe amine-substituted epoxide 172 in high yield. This wassubjected to HKR using 0.55 equiv water catalyzed by0.01 equiv of 1b to provide (S)-N-benzyl-N-isopropyl-2,3-epoxypropylamine 173 in 40% yield and >99% ee anddiol 174 in 51% yield and 90.6% ee. Further, the authorshave observed that, if the benzylcarbonate protecting group(Cbz) replaced the benzyl group, the HKR was not satisfac-tory and only 45% yield of the epoxypropylamine could beobtained with 47% ee. This means that the amino group mayplay a role in this reaction. The epoxypropylamine 173 wasthen reacted with phenol in refluxing NEt3 followed by de-benzylation with 10% Pd/C to give the target molecules169a–c in essentially quantitative yield (Scheme 31).

6.2. 1-[2-Hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one

Compound 177 belongs to a class of antiarrhythmic drugsand also showed hypotensive effects and a1 and a2 ad-renergic blocking activities.55 Malawska and co-workersdeveloped an asymmetric synthesis of 1-[2-hydroxy-3-(4-

ArO NHOH

ArOH β-blocker

169a : α-Naphthol propranolol

169b : Guaiacol (2-methoxyphenol) moprolol

169c : m-Cresol (3-methylphenol) toliprolol

169

Figure 6.

NCuCl2

OHCl

Li2PdCl4(10%)

CuCl2DMF,-10 °CH2O

+

Yield: 40%ee: >99.0%

Yield: 40%ee: >90.6%

170171

83% yieldfrom 146

172 173 174

1b

172

BnNBn

NO

Bn

NO

Bn

N OHOHBn

NO

Bn

Na2S.9H2O

Scheme 30.

phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one 177 usingAD or hydrolytic kinetic resolution methods.56 The enantio-mers of compound 177, which were obtained by HKR,showed a higher ee than those which were synthesized byAD and epoxidation. As depicted in Scheme 32, racemic175 was subjected to HKR in the presence of 1a/1b andwater to give the R/S-epoxide, which, on treatment withphenylpiperazine, furnished the desired product (R)-(�)-177in 96% ee and (S)-(�)-177 in 64% ee.

N

O

O

N

O

ON

O

OHOH

N

O

ON

O

OHOH

N NN

OH

O

+ +

1b1a

(±)-175

(S)-176 (R)-176(S)-175(R)-175

(R)-(-)-177 ee = 96% (S)-(+)-177 ee = 64%

Scheme 32.

7. Epoxides bearing a carbonyl functionality

7.1. Fostriecin

Fostriecin (CI-920) 178 is a structurally interesting antitu-mor agent that was isolated in 1983 by scientists at WarnerLambert–Parke Davis.57 It displayed in vitro activity againsta broad range of cancerous cell lines as well as in vivo anti-tumor activity.58 A new synthesis of this molecule reportedby Jacobsen and Chavez59 involves the assembly of fourfragments (179–182) of similar complexity (Scheme 33).Epoxyketone 181 played a central role, serving as the sourceof the C9 stereocenter. The racemic 181 was prepared easily

NH

OOH

OMeNH

OOH

NH

OOH

ArOH,Et3Nreflux

a. ArOH= 1-Naphthol, 86%

b. ArOH = 2-Methoxyphenol,92%

c. ArOH = 3-Methylphenol, 92%

H2, Pd/C, EtOH, 100%



169a (S)-propranolol

169b (S)-moprolol

169c (S)-toliprolol

173

NO

Bn

Scheme 31.


from the inexpensive methyl vinyl ketone.60 However, thepreparation of enantio-enriched 181 proved to be challeng-ing by HKR. Under standard conditions, precipitation ofthe catalyst as the reduced [salen Co(II)] complex was ob-served with low substrate conversions. However, when thereaction was carried out under an atmosphere of oxygen in-stead of nitrogen or air, reduction of the catalyst was avoidedand the HKR proceeded to completion, affording (+)-181 in>99% ee and 40% yield (Scheme 34). To install the

ORO M

Bu3Sn

OTBDPS

Me

O

O

OBn

+ +

+

+

179180

(+)-181 182

183 184

fostriecin (CI-920) 178

S SH

TMS

H

O

OOOHMe

NaHO3PO OH OH1

58

9 11

TIPS

Scheme 33. Retrosynthetic analysis for fostriecin (CI-920).

OBn

OH

BnO

OOOTESMe

OTBSOH

I

OCr

N

Me

O

Cl

Me

O

O Me

O

OMe

O

OHOH

C6H13 CH C6H13

Me OH

O

OOOHMe

NaHO3PO OH OH

+ii) TBAFiii) TsOHiv) recrystallization 65%

>99% ee184

189

183

188

1f

185

+1b (2 mol%)HOAc (4 mol%)

O2 balloon5-25 °C, 48 h

40% yield, >99% ee(±)-181 (+)-181

186

i) [Cp2Zr(H)Cl] CH2Cl2

ii) Me2Zn, -78 °Ciii) R-3, RT

d.r. > 30:1187

178

15

89 11

fostriecin (CI-920)

H

O

TIPS

-C

Scheme 34.

stereochemistry of the C-8 tert-hydroxyl group, the couplingreaction of 183 and 184 using the Wipf procedure resulted inthe required product 188, which was carried through a seriesof transformations to furnish, eventually, the target mole-cule, fostriecin 178.

7.2. C1–C19 fragment of ulapualide A

Ulapualide A 190 (Fig. 7), first isolated from the red eggmasses of the nudibranch Hexabranchus sanguineus, be-longs to a unique family of tris-oxazole-containing metabo-lites.61 It exhibits inhibitory activity against L1210 leukemiacell proliferation and also displays ichthyotoxic and antifun-gal properties. Asymmetric synthesis of a C1–C19 fragmentof ulapualide A was reported by Panek and Celatka62a inwhich a C3 hydroxyl-bearing stereocenter was establishedby Jacobsen’s hydrolytic kinetic resolution of a terminal ep-oxide. As shown in Scheme 35, the synthesis of the C1–C6subunit 193 began by HKR of the readily available racemicepoxide (�)-191 with 1a to provide the (R)-epoxide (R)-191in 94% yield and 99% ee. The epoxide ring opening with vi-nylmagnesium bromide, protection of the hydroxyl group asthe TBS ether followed by oxidative cleavage of the terminalolefin, and Takai iodo-olefination provided the C1–C6 frag-ment 193 as a 5:1 mixture of isomers. The C7–C19 subunit197 was constructed starting from a-benzyloxyacetaldehydethrough a series of transformations. The coupling of the twofragments was accomplished through a Kishi–Nozaki reac-tion to afford the desired C1–C19 fragments 199 of the targetmolecule 190.

Mycalolide A was also synthesized by using the sameepoxide 191.62b

7.3. Epothilone A

Epothilones A and B 200 and 201 (Fig. 8), a new class ofmacrolides, which were isolated by Hofle and co-workers,63

have attracted much attention among synthetic organicchemists, due to their high antitumor activity. Liu and co-workers accomplished the total synthesis of epothilone Abased on simple asymmetric catalytic reactions and througha stereospecific a-epoxidation of 3-O-PMB epothilone C ina total of 25 steps and 4.4% overall yield.64 The synthesiswas accomplished by the coupling of four fragments andthe chiral centers were introduced by asymmetric catalyticreactions. The synthesis of one of the fragments is basedon Jacobsen’s HKR and methoxycarbonylation of the chiral

H N

O

O O

Me

Me

Me Me

OAc OMe

Me

N

O

N O

NO

MeO

O

OH

OMe

35 19

9

1

3190

Figure 7. Ulapualide A.


MOMO

H

H

OBnO BnO

BF3.Et2O, -35 °CNH2CO2

tBu73%

Me

SiPhMe2

CO2Me

NHBOC

MeCO2Me

O OTBDPSI

tBuO

tBuOCrCl2/NiCl2 (99.9.0.1)THF/DMSO (3:1 v/v)78%

194

195

196

197

193

199

N

O

N O

NO

MeOOTBDPS

MOMON

O

N O

NO

MeO

O

MOMO

tBuO

198

N

O

N O

NO

MeOHOTBDPSO

OOO

OO OTBDPS

O OTBDPSI

i) Vinylmagnesium bromide, Cu(I)I, 76%

ii) TBDPSCl, Im 98%

i) O3, Me2S

ii) CHI3, Cr2Cl2 (±)-191

0.5 mol% 1a

94%, 99% ee (R)-191

192

193

76% two stepstBuO

tBuOtBuO

tBuO

Scheme 35.

terminal epoxide. As shown in Scheme 36, the vinyl ketone20265 was epoxidized with oxone to give the racemic epox-ide (�)-203, which was subjected to HKR conditions to af-ford the desired chiral epoxyketone (R)-203 in>99% ee and48% yield and the chiral diol 204 in 90% ee and 40.5% yield,which was easily converted into the required epoxyketone(R)-203 with an additional three steps. Regioselective carbo-methoxylation of the chiral terminal epoxyketone in thepresence of Co2(CO)8 as catalyst and 3-hydroxypyridineas co-catalyst afforded the b-hydroxyl ester 205. Hydroxylprotection as the silyl ether and subsequent saponificationprovided the desired keto acid 206 as one of the fragment re-quired for the synthesis of the target molecule. The synthesisof the acetylide segment 210 was accomplished startingfrom geraniol according to a modified previously reportedsynthesis.66,67 Similarly, another epoxide 213 was obtainedin 98% ee employing a Sharpless epoxidation strategy fromcrotyl alcohol.68 The modified Wittig reagent 216 was easilysynthesized from 1,3-dichloroacetone using a literature pro-cedure.69 Coupling of these fragments following a series oftransformations led to the target molecule, epothilone A 200(Scheme 37).

O

O OH O

OH

S

N

OR

R = H epothilone A : 200

R = Me epothilone B : 201

Figure 8.

O OO

OO

OOH

HO

OOH

O

O

OOTBS

HO

O OOTBSOTBS

Oxone, NaHCO3

acetone/H2O(1:1)

1b +

5 mol% Co2(CO)810 mol% 3-hydroxypyridene750 psi CO, 65 °C

i) TBSOTf2,6-lutidine96.4% ii) NaOH

95%

202 (±)-203

(R)-203

204

205

206207

85.6%

48% yield 99% ee

40.5% yield90% ee

(R)-203

OH OH

O

O

O

OH ORO O

BnO

NH2

S S

NR

O

Cl

Cl

Ref 66

Ref 68

Ref 69

209210

Ref 67

212 213

216

208

211

214

215

R = PBu3Cl+ -

Scheme 36.


O

O

OOTBS

S

N

O

OH

OOPMB

S

N

OTBS

HO O

OH

OOPMB

S

N

OTBS

HO

O

OTBS

OOPMB

S

N

O

O

OTBS

OOPMB

S

N

O

O

O OH O

OH

S

N

O

O

O OH O

OH

S

N

+

LDA, THF

+

epothilone C 221epothilone A 200

210217

206

218a

218b

219 220

Scheme 37.

7.4. N-Substituted 4-hydroxypyrrolidin-2-one

Optically active 4-substituted pyrrolidin-2-ones can be foundin various biologically active compounds, e.g., CS-834,222a, an oral carbapenem antibiotic,70 rolipram 222b, an an-tidepressant agent,71 and oxiracetame 222c, a nootropic drugfor the Alzheimer’s disease72 (Fig. 9). Ahn and co-workers73

developed the asymmetric synthesis of active 4-substitutedpyrrolidin-2-ones using hydrolytic kinetic resolution as thekey step. As depicted in Scheme 38, crotyl chloride 223was esterified followed by oxidation with m-CPBA to affordthe HKR substrate (�)-225. This was subjected to HKRusing 0.5 equiv of water catalyzed by 1a to provide theR-epoxide (R)-225 in 84% yield and 99% ee. The epoxide(R)-225 was then reacted with glycinamide hydrochloride228 followed by cyclization to give the target molecule

NH

O

O

ON O

HO

O

NH2

NH

NS

OH

O

H H

OO

O

O

O

222a222b 222c

CS-834 rolipram oxiracetame

Figure 9.

(R)-222c in 45–50% yield. Similarly, (R)-227 was synthe-sized by the reaction of epoxide (R)-225 and benzylaminein 47% yield.

O

OO N O

HO

H2NNH2

O

O

HN

OH

OONH2

N O

HO

NH2

O

Cl

O

O

O

O

OO

O

OO

O

OOHHO

benzene

NaHCO3/EtOH

+

EtOH/reflux

(R)-225

228

(R)-229 (R)-222c

(R)-227

+

iso-PrOHTEAbenzene

m-CPBA

1a

(R)-225 (S)-226

(±)-225223 224

benzylamine

HCl

CHCl3

Scheme 38.


(COH

(CH2)7OBnH2)7

OBn

(CH2)7OBn

(CH2)7OBn

(CH2)7OAc

OH(CH2)7 OBn

O(CH2)5

(R)-231

233a 234 235

233b 236 237

99%

MsCl then Me2CuLi

60%

EtMgBr, CuI

62%

MsCl then Me2CuLi

40%(R)-231

Me2CuLi

(CH2)7 OBn

(CH2)7 OBn

(CH2)7 OBn

O

O

HOOH

m-CPBA+

230 (±)-231

(R)-231

(S)-232

78%48% yield

46% yield

1a

Scheme 39.

8. Mono- and bis-epoxide

8.1. Insect pheromones

Kitching and Chow have studied the HKR of functionalizedmono- and bis-epoxide.74 The synthetic utility of productssuch as epoxides, diols, epoxydiols, and tetrols obtained inhigh enantiomeric excess was further demonstrated by theirefficient transformations to important insect pheromones. Asillustrated in Scheme 39, the benzyl ether of undecen-10-ol230 was epoxidized to furnish the HKR substrate (�)-231.This, on reaction with 0.5 mol % of 1a and 0.55 mol equivwater for 20–24 h, gave the R-epoxide (R)-231 and theS-diol (S)-232. Further synthetic manipulation afforded the(R)-acetate 235. The acetate 235 is a pheromone fromthe smaller tea tortrix moth (Adoxophyes sp.), with the(R)-enantiomer slightly more bioactive than the (S)-enantio-mer. Similarly, the methyl ketone 237 was obtained by

processing the epoxide (R)-231 through a series of transfor-mations, as shown in Scheme 39.

An important component from ant-lions (Euroleon nostrasand Grocus bore) is (R)-(�)-(Z)-undec-6-en-2-ol (nostrenol)242. Its synthesis began with the chemoselective epoxida-tion of enyne 238. HKR of epoxide (�)-239 furnished the(S)-epoxide (S)-239 with 95% ee. Ti-mediated stereospecificZ-reduction of the protected alcohol led to the (R)-(�)-pheromone 242 (Scheme 40).

The same authors have further explored the HKR of bis-epoxides, as depicted in Scheme 41. The racemic bis-epox-ide 243 was exposed to 1a and 0.8 equiv H2O to provide(2R,8R)-bis-epoxide 244 (24%), epoxydiol 245 (46%), andtetrol 246 (15%). The epoxydiol 245 was carried througha series of transformations to afford (1R,7R)-1,7-dimethyl-nonyl propanoate 249, the female-produced sex pheromone

C4H9 C4H9 O

C4H9 O

C4H9OH

OH

C4H9 OTHP C4H9

OH

+

m-CPBA1b

238 (±)-239

(S)-239

240

43% yield

242241

i) NaBH4, 73%ii) DHP, H+84%

(S)-239

Scheme 40.

(CH2)3O O

(CH2)3O O

(CH2)3O

OHOH (CH2)3

OHOH

OHHO

(CH2)3

OHO

O(CH2)3

OO

(CH2)3

OCOEt

+ +

245

1a

243244 245 246

24% 46% 15%

247248 249

DMP, H+78%

Me2CuLi98%

MsCl then Me2CuLi

70%

(CH2)3O

(CH2)3

OH

(CH2)3

O

245

H2C=CH(CH2)2MgBrCuI, 34%

250 251

252

i) MsCl then Me2CuLi, 53%

ii) PdCl2, CuCl, 74%

Scheme 41.


of the Western corn rootworm (Diabrotica virgifera). Thesame epoxydiol 245 provided the bioactive (6R,12R)-6,12-dimethylpentadecan-2-one 252, the female-produced phero-mone of the banded cucumber beetle (Diabrotica balteata)by the procedure summarized above.

HKR of the bis-epoxide of dodeca-1,11-diene 253 affordedthe epoxydiol 255, which has been converted into the(2S,11S)-2,11-diacetoxytridecane 258, a sex pheromonecomponent of the female pea midge, Contarinia pisi,a serious pest of commercial peas (Scheme 42).

(CH2)6O O

(CH2)6O O

(CH2)6O

OHOH

2)6

OHOH(CH

OHHO

253

254

255

256

23%

26%

12%

+

+

1b

(CH2)6

OO

OR(CH2)6

OAcOAc255

257 258

Scheme 42.

Scheme 43 illustrates the application of bis-epoxide 259and epoxydiol 260 prepared by the HKR of bis-epoxidehepta-1,6-diene with 1.4 mol % 1a and 1.0 mol equiv H2O.Routes to (4R,8R)-4,8-dimethyldecanal (tribolure) 263, animportant pheromone component of several Tribolure sp. in-cluding the red flour and confused flour beetles, and the C2-symmetric dimethylalkanes 262a,b, pheromone componentsof female spring hemlock looper (Lambdina athasaria) andfemale stable flies (Stomoxys calcitrans), respectively, havebeen developed. Tetrol 261 was converted into C2-symmet-ric piperidines 264.

OHOH

OHHO N

HORRO

259

260 263

261

264

262a: R= CH3(CH2)5262b: R= CH3(CH2)13

OOH

OHCHO

O OR R

Scheme 43.

9. Multifunctionalized epoxides

9.1. Corossolin

Annonaceous acetogenins (AAs) are a relatively new classof natural products, which have been isolated from thetropical and subtropical plants of the Annonaceae family.

They are characterized by the presence of one or more tetra-hydrofuran rings together with a terminal a,b-unsaturatedg-lactone on a 35- or 37-carbon chains. A majority of thesecompounds exhibit high cytotoxicity and immunomodulat-ing activities, which make them potential parasiticidal,insecticidal, and powerful tumoricidal agents.75 Wu andco-workers devised a new synthetic strategy of a key inter-mediate for corossolin 265 (Fig. 10) using hydrolytic kineticresolution of epoxides.76

The substrate for HKR, the racemic epoxide 268, was pre-pared from alcohol 266,77 as shown in Scheme 44. The ep-oxide 268 was subjected to HKR using 1a (0.5 mol %) andwater (0.55 equiv) to yield epoxide 269 (46%) and diol270 (38%). Treatment of the epoxide 269 with lithiumtrimethylsilylacetylide gave the diastereomerically pure(99%) 271, a key intermediate for corossolin.

HOOTHP

CO2Me

O

O

OAc

O

O

O

O

O

O

O

O

OHHO

OHO

O

Methyl undec-10-enoate Ref 77

+

271

i) Ac2O, Py, 91%

ii) 10% H2SO4, THF 83%

m-CPBA, CH2Cl2

trimethylsilylacetyleneBF3.Et2O, -78 °C

1a

266

267

268

270

91%

46% yield

38% yield

269

269

n-BuLi

Scheme 44.

9.2. Aminohydroxyiminocarenes

Lochy�nski and co-workers developed a stereoselective HKRprocess for diastereomeric mixtures of epoxyiminocareneintermediates, which was applied as the first step in the syn-thesis of novel chiral aminohydroxyiminocarene derivativesKP-23 with local anesthetic activity.78 As shown in Scheme45, (�)-cis-carene-4-one oxime 274 is readily availablefrom (+)-3-carene 272 by a three-step pathway: stereoselec-tive borohydration–oxidation followed by Brown–Garg oxi-dation, and reduction of ketone 273 with hydroxylaminehydrochloride. The reaction of racemic epichlorohydrin

OC12H25

OH OH

OHO

O265

Figure 10.


with 274 gave a diastereomeric mixture (R,S)-275, whichwas subjected to HKR on reaction with water catalyzed bya (salen)Co(III)complex. A mixture of the 1,2-diol (S)-276(97% ee) and unreacted epoxide (R)-275 (99% ee) wasobtained after 7 h using catalyst 1a in 76% yield. Diol (S)-276 was converted into the epoxy isomer (S)-275 in 71%yield under Mitsunobu conditions. Similarly, HKR of (�)-275 by the use of catalyst 1b required a longer reactiontime (20 h), affording the desired epoxide in moderate yield(56%). Both (R)- and (S)-epoxy compounds were reactedwith an excess of isopropylamine followed by treatmentwith anhydrous ethereal HCl to give the crystalline, water-soluble hydrochlorides, KP-23R$HCl (R)-277 and KP-23S$HCl (S)-277 (Scheme 46).

NOH N

OO

272 273

274 (±)-275

ORS R

Scheme 45.

9.3. (D)-Allosedamine

A concise synthesis of (+)-allosedamine was developed byChang and Kang79 using HKR and ring-closing metathesisas the key steps. The authors have employed HKR to installboth the stereocenters. As shown in Scheme 47, the synthesisbegan with (+)-styrene epoxide 278,3 which can be obtainedon a gram scale via a hydrolytic kinetic resolution of racemicstyrene epoxide. Opening of the epoxide was achieved byusing cuprate reagents derived from tetravinyltin to givethe homoallylic alcohol 279. Subsequent epoxidation withperacid or peroxide under various conditions gave the dia-stereomeric mixture of products. After protection of thefree hydroxyl group of the epoxide, the MOM ethers 280were subjected to HKR with catalyst 1a (1 mol %), aceticacid (4 mol %), and water (0.55 equiv) in THF at room

temperature to give the enantiomerically pure epoxide 281in >98% ee and 44% yield. The diol 282 was isolated in47% yield as a single diastereomer. Epoxide opening ofthe oxirane 281 with a vinyl Grignard reagent, introductionof the required amino group at the homoallylic positionthrough mesylate, and, finally, ring closure by RCM led tothe synthesis of the target molecule 285 (Scheme 48).

Ph

O OH

Ph

OMOM

Ph

OOMOM

Ph

O OMOM

Ph

OH

OH

(CH2=CH)4Sn/MeLi/CuCN

+

THF, -78 °C to 0 °C

i) m-CPBA94%

ii) MOMCl DIPEA 95%

1a

278 279

280 281 282

53%

44% 47%

Scheme 47.

OMOM

Ph

OOMOM

Ph

OH

MOMO

Ph

N

Ph

NOH

MgBr

281283

284

CuBr/Me2S

70%

(+)-allosedamine 285

Scheme 48.

9.4. Tarchonanthuslactone and cryptocarya diacetate

Optically active syn- and anti-1,3-polyols/5,6-pyrones areubiquitous structural motifs in various biologically activecompounds.80 Tarchonanthuslactone 294 and cryptocaryadiacetate 300 are such examples. Short and practical enan-tioselective syntheses of these molecules were achieved byKumar and co-workers in high diastereomeric excess usingJacobsen’s hydrolytic kinetic resolution, diastereoselectiveiodine-induced electrophilic cyclization, and ring-closingmetathesis as the key steps.81

The commercially available racemic propylene oxide (�9)was subjected to HKR to afford the enantiomerically pure

NO

O

NO

OHOH

NO

O

NO

OHNH

NO

O

NO

OHOH

NO

OHNH

1a,THF, 0 °C to rtH2O, 7 h, 76% +

>97% ee 99% ee

DEADPh3P

+

>97% ee

1b

>97% ee

(±)-275 (S)-276 (R)-275

(S)-275

KP-23S (S)-277 KP-23R (R)-277

(R)-276

THF, 0 °C to rtH2O, 7 h, 56%

i-PrNH2

i-PrNH2

Scheme 46.


(R)-9 and (S)-9 propylene oxides, which were reacted with avinyl Grignard to give the homoallylic alcohols 287. Subse-quent iterative epoxidation of the homoallylic alcohol fol-lowed by HKR gave the diastereomerically pure epoxide288 (Scheme 49). Ring opening of the epoxide 288 with avinyl Grignard generated the second stereocenter (Scheme50). In the case of cryptocarya diacetate, the third stereo-center was generated via iodine-induced diastereoselectiveelectrophilic cyclization to give the syn-configuration. Thesyn- and anti-configuration of the hydroxyl functionalitycan be manipulated by the use of a 1a or 1b Jacobsen’s cat-alyst in the resolution step. The conversion of the hydroxylgroup into acrylate and subsequent ring-closing metathesisgave the target molecules, tarchonanthuslactone 294(Scheme 50) and cryptocarya diacetate 300 (Scheme 51).

9.5. (2R,7S)-Diacetoxytridecane: sex pheromone of theaphidophagous gall midge, Aphidoletes aphidimyza

Gries and co-workers82 identified and synthesized the sexpheromone, (2R,7S)-diacetoxytridecane 305, from femalesof the aphidophagous midge, A. aphidimyza, which was

OO

O OPO

OH

MgBr

MgBr

(S)-287a : P = H

(S)-287b : P = TBS

(R)-287a : P = H

(R)-287b : P = TBS

(R)-9

(S)-9

(R)-287

(S)-287

m-CPBA

m-CPBA

TBSCl95%

TBSCl95%

89% 96%

87% 96%

OOH

OH

OH OP

OOOH

OH+

1a

±9

+1b

(R)-286 (S)-9 (R)-9 (S)-286

OTBSO

OTBS OH

OH

OTBSO

OTBSO

OTBS OH

OHOTBS

O

+1b

(S)-287b ent-288 ent-289

+1a

(R)-287b 288 289

Scheme 49.

OTBSO

OTBS OH OTBS O

O

OH O

O

O

O

O

OHO

HO

MgBr

OH

OTBSO

TBSO

288290

291

Acryloyl chloride

292

293

86% 89%

tarchonanthuslactone 294

293

Scheme 50.

evidenced by females releasing a sex pheromone to attractmates. As shown in Scheme 52, the ring opening of (R)-pro-pylene oxide with 4-penten-1-ylmagnesium bromide fol-lowed by epoxidation of the resulting secondary alcoholswith m-CPBA afforded the HKR substrate 302 in good yield.The epoxides 302 were subjected to hydrolytic kinetic reso-lution with H2O using a 1a catalyst to yield the four isomersof 1,2-epoxy-7-hydroxyoctane 303 in good yield and withgood diastereoselectivity. Opening of these epoxides withamylmagnesium bromide and subsequent acetylation fur-nished all four isomers of the sex pheromone 305.

OBrMg

OH

OH

O

OH

OHOH

OH

O

OCOCH3

OCOCH3

OH

O

THF, -20 °C+

99% ee

i) C5H11MgBr, CuI

ii) Ac2O, Py35%

+

(R)-9 301

302

303

304

303

(2R,7S)-diacetoxytridecane 305

1a

m-CPBA

CH2Cl2, 85%

CuI

Scheme 52.

9.6. Cryptocarya diacetate

Krishna and Reddy employed a combination of HKR andstereoselective reduction of ketones as the key steps forthe construction of a 1,3-polyol moiety, which was subse-quently transformed into (+)-cryptocarya diacetate.83 Asshown in Scheme 53, the epoxide 306 was obtained throughHKR of the racemic epoxide, which was treated with a vinylGrignard to give the homoallylic alcohol 307. Hydroxyl pro-tection as its TBS ether, reductive ozonolysis of olefin to an

OTBSO OTBS OH OTBS O

O

O

OTBS O

O

OI

OTBS OPO

OTBS OTBS OHOTBS OTBS O

O

OAc OAc O

O

MgBr

MgBr

ent-288 ent-290

296

295

IBr, PhMeK2CO3, MeOH

Acryloylchloride

298

299

82%

(Boc)2OCH3CN

90%

81%, two step

81% 82%

TBSCl297a : P = H

297b : P = TBS

cryptocarya diacetate 300

Scheme 51.


aldehyde followed by allylation with allyl bromide/Zn gavethe homoallylic alcohol in 82% yield. Subsequent PCCoxidation followed by desilylation afforded the b-hydroxylketone 308, which, on selective reduction with NaBH4 inthe presence of a chelating agent, B(Et)2OMe, resulted in ex-clusive formation of the syn-1,3-diol (>98% de). Hydroxy-group protection as acetonide and epoxidation yielded theepoxide 310, which, on HKR with 0.55 equiv of water using1a catalyst, provided the enantiomerically pure epoxide 311(de 94%) and diol 312 in 43% yield each. The epoxide wassmoothly converted into the target molecule 300 in severalsteps through synthetic manipulation.

OOBn OBn

OH

OBn

OTBSO

OBn

O O

OBn

O OO

OBn

O OO

OBn

O OOHHO

O

O

OAcOAc

+

i) Vinylmagnesium bromide

i) TBSCl, Im , 82%ii) O3, CH2Cl2, -78 °C

iii) allyl bromide Zn, 82%iv) PCC oxidation 72%

ii) B(Et)2OMe, NaBH4, THF 75%

ii) 2,4-DMP 94%

Oxone, acetoneNaHCO3,EDTA (cat) 1a

306 307

308309

310

312

cryptocarya diacetate 300

74%

i) HF-Py 63%

311

311

73%

Scheme 53.

9.7. (D)-Boronolide

a-Pyrones possessing polyhydroxy or polyacetoxy sidechains are an important class of heterocycles because of theirusefulness as biologically active compounds. Examples ofsuch compounds include (+)-boronolide 317. This com-pound has antimalarial properties and is isolated from thespecies, Tetradenia fruticosa84 and Tetradenia barberae,85

which have been used as a local folk medicine in Madagas-car and South Africa.86 Kumar and Naidu87 developed an in-novative route for the total synthesis of (+)-boronolidestarting from valeraldehyde. The key steps include a Sharp-less asymmetric hydroxylation, a chelation-controlled vinylGrignard followed by asymmetric epoxidation, HKR, anda ring-closing metathesis. Scheme 54 highlights its synthesisinvolving the resolution of multifunctionalized epoxidesby HKR to obtain the enantiomerically pure epoxides. Thus,the HKR substrate 314 prepared in a multistep sequencefrom valeraldehyde 313 was subjected to HKR with 1a(0.5 mol %) and water (0.4 equiv) to yield the epoxide(2R,3R,3R,5S)-315 in 94% yield (as calculated from 80%epoxide) and diol (2S,3R,3R, 5S)-316 in 90% yield (as calcu-lated from 20% other epoxide). The epoxide 315 was furtherconverted into the target molecule by vinyl Grignard andring-closing metathesis.

9.8. Polyene-polyol macrolide RK-397

McDonald and Burova reported the total synthesis of thenatural product RK-397, an antifungal compound, which isbased on a new synthetic strategy for assembling polyacetatestructures, by efficient cross coupling of nucleophilic termi-nal alkyne modules with electrophilic epoxides bearing an-other alkyne at the opposite terminus.88 The retrosyntheticstrategy (Scheme 55) reveals that the target molecule canbe constructed from four principal modules: a polyene pre-cursor for carbons 3–9, and three alkyne-terminated modulesfor carbons 10–16, 17–22, and 23–31. The authors have em-ployed HKR methods to synthesize modules C17–C22 andC10–C16.

OR

OR OR

R'

OOR

R'

OR'

OR

XOR

OR

OROROR OROROR

O

O

OH OH OH OH OH OH

OH

OHO

O

16

10

2223

2

39

16

10

2223

RK-397 318

320

321

322 323

1731

31 17

319

Y

[P](O)

Scheme 55. Retrosynthetic analysis for polyene-polyol macrolide RK-397.

The C23–C31 module was prepared from isobutyraldehydein several steps as shown in Scheme 56. As depicted in

H

O

OMOM

OMOM

OTBS

O

OMOM

OMOM

OTBS

OH

OH

OMOM

OMOM

OTBS

O

O

OAc

OAc

OAc

O

+

1a, 42 h

94% yield 90% yield

(+)-boronolide 317

313

314

315

316

Scheme 54.


Scheme 57, the C17–C22 module was prepared startingfrom the (S)-enynol 327. Epoxidation of either the silyl orp-methoxybenzyl ether 327 gave 328 as a ca. 1:1 mixtureof diastereomers, and a single diastereomer was preparedby the HKR procedure. Similarly, the seven-carbon C10–C16 module was constructed from (R)-epichlorohydrin andcopper bromide-promoted addition of vinylmagnesium bro-mide to give 331, which was converted into the enynol 332.The epoxidation with or without hydroxyl protection re-sulted in a mixture of diastereomers in different proportions.The compound 333, as a mixture of diastereomers, whensubjected to HKR gave the enantiomerically pure epoxide334 as a single diastereomer, which was easily separatedfrom the more polar diol 335 (Scheme 58). The alkynyl alco-hol obtained from alkyne–epoxide couplings was convertedinto the 1,3-diols by a sequence of hydroxyl-directed hydro-silylation, C–Si bond oxidation, and stereoselective ketonereduction, and these were finally converted into the targetcompound in several steps (Scheme 59).

9.9. Macroviracin A

Macroviracin A, a 42-membered macrodiolide core consist-ing of a C22 fatty acid dimer possessing D-glucose residues,

OPMBnH

OO

31O

H

OR

COOMe

325 a: R= H b: R= PMBn c: R= TBS

326324

Scheme 56. Synthesis of C23–C31 module.

OR

TMS22

17

OROHHO

TMS

ORO

TMS22

17

ORO

m-CPBA+1b

a: R= TBSb: R= PMB

328

329

330

79%

327

TMS22

17


was isolated from the mycelium extracts of Streptomyces sp.BA-2836.89 This type of natural product exhibits powerfulantiviral activity against herpes simplex virus type 1(HSV-1) and varicella zoster virus (VZV). Takahashi andco-workers90 synthesized the C2-symmetric macrodiolidecore 339 of macroviracin A in a single step by the intramo-lecular macrodimerization of the C22-hydroxy carboxylicacid 340 (Scheme 60). The acid 340 was synthesizedthrough a series of reactions such as coupling of acetylenewith epoxide and stereoselective glycosidation. The right-half epoxide 343 can be synthesized through hydrolytic ki-netic resolution. As shown in Scheme 61, olefin 346 wassynthesized from methyl ester 344 by reduction and tosyla-tion followed by chain extension with 1-pentenylmagnesiumbromide. The epoxide 347 derived from m-CPBA oxidationof 346 was subjected to hydrolytic kinetic resolution with0.9% 1a catalyst in the presence of water (0.65 equiv) atroom temperature to give the epoxide 343 in 44% yield

OPMB

TMSO

OR

TMS

O

2217

OPMBn

OOOH OR

TMS

336

31 2322

17

R = TBS or PMBn

OPMBn

OO OPMBn

H

OO

OPMBn

OO OPMBnOO

OH

OPMB

TMS

OPMBnH

OO+

3123 21

17

3123 21

17 16

10

RK-397

BuLi, THF31

326 329

337

334

338

318

BF3.Et2O

Scheme 59. Coupling of various modules and completion of RK-397 syn-thesis.

OCl

O

OPMB

TMSO

OPMB

TMS OH

OH

+

i) vinylMgBr, 84%

ii) KOH, 81%

TMS-acetylene/BuLi/BF3.Et2O

m-CPBA, CH2Cl2i) NaH, PMBnCl 73%

331 332

333

334

335

75%

77%

32% yield

47% yield

(R)-8

ii) 1b (polymer supported)

OPMB

TMSO

OH

TMS



and diol 348 in 44% yield with >99% optical purity. Theleft-half segment 342, which was synthesized in severalsteps, was coupled with epoxide under Yamaguchi

OO

OMPM

O MeO O

OBn

OBn

OBnOBn

OO

OMPM

OBnBnO

BnO

OMe

OBn

OO

MeHOOC

MPMO OBn

OH

BnOBnO OBn

MeO

OBn

TBDPSO Me

OMPM OBnOH

2

4

4

2

4 15

342 343

341

340

339

4

TBDPSO

OMPM

4

Scheme 60. Retrosynthetic analysis for macrodiolide core unit of macro-viracin A.

MeMeO2C

OBn

MeTsO

OBn

Me

OBn

Me

OBnO

Me

OBnOHHO

i) LAH, 94%

ii) P-TsCl, Py 77%

1-pentenylmagnesiumbromide, CuI99%

m-CPBA

87%

tert-butylmethyl etherrt

343 +

44% 44%

346

344 345

347

348

1a

H2O

TBDPSO

OMPM

Me

OH OBn

O

O Me

OBn

OBn

OBnOBn

O

O

OMPM

HO

OH

3

TBDPSO

OMPM

3 342

342 + 343

n-BuLiBF3.Et2O

91%4

339 +

351

349

350

2

352

Scheme 61.

conditions to afford the coupling product 351 in 91% yield,which was converted into the target molecule 339 in severalsteps.

9.10. (5S,7R)-Kurzilactone

Tae and Kim synthesized enantiomerically pure syn- andanti-2-silyloxy-1-oxiranyl-4-pentenes by using the HKRmethod, which was used in the total synthesis of (5S,7R)-kurzilactone 360 having strong cytotoxicity against KBcells.91 The authors have developed a route to synthesizeboth syn- and anti-1,3-diol in the desired fashion using theHKR method. As shown in Scheme 62, the syn-epoxide(�)-354 was prepared from 1,6-heptadien-4-ol using a liter-ature procedure.92 The anti-epoxide (�)-356 was generatedby a Mitsunobu inversion reaction of (�)-354. The racemicTBS-protected epoxides (�)-358 and (�)-357 were thenprepared for the HKR studies. Treatment of syn-epoxides(�)-358 with 1a (0.3–0.5 mol %) and H2O (0.8 equiv) atroom temperature led to the formation of epoxide (�)-358in 42–48% yield and in 98–99% ee. The diol 359 was formedin 48–49% yield and 93–94% ee. In contrast, HKR of anti-epoxide (�)-357 under the same conditions yielded the ep-oxide (69–88% ee). A subsequent ring-opening reaction ofepoxide with the acyl anion equivalent and RCM led to thesynthesis of (5S,7R)-kurzilactone 360.

OHOH

O

OTBSO

ORO

OTBSO

1. n-BuLi, THF CO2 then I2 (84%)

2. 1N KOH/THF(1:1) n-Bu4NI (cat.) (99%) Ph3P, DIAD

(p-NO2)PhCO2HTHF (98%)

TBSCl imidazole DMF (97%)

TBSCl, imidazoleDMF (97%)

353

(±)-355

(±)-356

(±)-358

(±)-357

R= O2CPh(p-NO2)R= H (95%)

K2CO3MeOH

(±)-354

OTBSO

OTBSO OTBS

HOOH

OTBSO OTBS

O

O OH O

O

+1a

4 steps(89%)

1. p-TsCl, Et3Nn-Bu2SnOCH2Cl2 (98%)

2. NaH THF (87%)

(5S,7R)- kurzilactone 360

(±)-358

(-)-358 359

(+)-357 (+)-358

H2O

Scheme 62.

9.11. (L)-Indolizidine 223AB

(�)-Indolizidine 223AB (361) is an alkaloid isolated fromthe skin of the neotropical dart-poison frogs belonging to thegenus Dendrobates.93 Smith and Kim94 have accomplished


the total synthesis of (�)-indolizidine 223AB (361) exploit-ing a three-component linchpin coupling of silyldithiane 364with epoxide 365 and a known aziridine 363,95 followed bya one-pot sequential cyclization in an overall yield of 10%in the longest linear sequence (Scheme 63). The epoxide365 was constructed by exploiting Carreira alkyne method-ology96 followed by HKR. As shown in Scheme 64, 4-pentenal366 was treated with 1-butyne via a Carreira protocol usingJiang ligand (�)-36797 followed by hydroxyl protection asits TBS ether. Subsequent treatment with m-CPBA and hy-drogenation furnished 369 as a 1:1 diastereomeric mixture.HKR of 369 using 1a catalyst furnished the desired epoxide365 along with diol 370 in high diastereomeric excess. Theundesired diol 370 was converted into the desired epoxide365 by conventional methods. A three-component linchpincoupling of silyldithiane 364 with epoxide 365 as the firstelectrophile and aziridine 363 as the second electrophile fur-nished 362, which, on cyclization in a one-pot sequential

N

H

SS

TBS

OTBSO

NTs

SS

TsHNTBSO

OTBS

361

+ +

362

363 364 365

Scheme 63. Retrosynthetic analysis for (�)-indolizidine 223AB.

O

OTBS

HO

O2N

N

OH

OTBS

O

OTBS

O

OTBS

HOOH

(-)-367, toluene, rt, 83%

(-)-367

(-)-368

> 99% ee

i) TBSOTf 98%ii) m-CPBA 78%ii) H2, Pd/C 92%

1a

THF

+

49% 47%

366

(+)-370(+)-365

369

Zn(OTf)2, 1-butyne, TEA

S S

TBS

SS

TBSOOTBS

N

H

i) t-BuLi, Et2O -78 to -45 °Cii) (+)-365, -78 °C to -25 °C 5 hiii) (-)-363, HMPA/Et2O, -78 °C to 0 °C

362 +

(-)-37156% 24%

362

364

361

(-)-indolizidine 223AB

Scheme 64.

manner followed by reductive removal of the dithiane,gave the target molecule 361.

9.12. Optically active 1,4-anhydropentitols and2,5-anhydrohexitols

Kakuchi and co-workers98 synthesized chiral anhydroalditolalcohols in extremely high enantiomeric excess using hydro-lytic kinetic resolution. They studied diastereoselective cy-clizations of 1,2:5,6-dianhydro-3,4-di-O-methyl-D-glucitol(372) and the regio- and stereoselective cyclizations ofC2-symmetric dianhydrosugars such as 1,2:5,6-dianhydro-3,4-di-O-methyl-D-mannitol (373) and 1,2:5,6-dianhydro-3,4-di-O-methyl-L-arabinitol (375) using catalysts 1a and1b (Fig. 11). These reactions arise from the enantioselectivehydrolysis of one of the epoxides, followed by cyclization ofthe resulting diol into the other epoxide. The dianhydrosugar372 possesses two epoxy groups, the reactivities of whichare non-equivalent. In the cyclization of 372 using water(1.1 equiv) in the presence of 1a (0.5 mol %) at room tem-perature, the color of the reaction mixture changed fromdark to light brown as the reaction proceeded (the reactionresults are summarized in Table 1). The reaction using 1awas complete in 3 h, while 1b needed about 51 h. The cycli-zation of 373 with 1a proceeded rapidly at room temperatureand produced 380, 381, and 382 in 57.2, 27.9 and 5.9%yields, respectively, while with 1b no product was obtained(the reaction results are summarized in Table 2). The cycli-zation of 374 with 1a proceeded with no products, whilewith 1b only the five-membered ring compound 380 was

O

O

OMeMeO

O

OMeMeO

O O

OMeMeO

O

O

O

OMe

372 373 374 375

Figure 11. Structures of meso-diepoxides.

Table 1. Cyclization of 1,2:5,6-dianhydro-3,4-di-O-methyl-D-glucitol (372)using chiral (salen)Co(III)–OAc and other conditions

Catalyst Time (h) T (�C) Yield (%)

376 378 377 379

1a 3 rt 89.3 4.1 3.3 0.21b 51 rt 3.7 81.4 0.1 2.7HCl 24 rt 37.0 35.2 10.3 9.8KOH 24 60 47.3 35.9 8.5 6.6None (H2O) 7 100 46.5 17.9 21.5 8.3

Table 2. Cyclization of 1,2:5,6-dianhydro-3,4-di-O-methyl-D-mannitol(373) and 1,2:5,6-dianhydro-3,4-di-O-methyl-L-iditol (374) using (salen)-Co(III)–OAc

Substrate Catalyst Time (h) Yield (%)

380 381 382

373 1a 3 57.2 27.9 5.91a 3 30.4 35.0 6.81b 6 0 0 0

374 1a 6 0 0 01b 48 49.1 0 0


formed. The cyclization of 375 with 1b proceeded smoothlyto afford 383 in 85% yield, while no reaction was observedwith 1a (Scheme 65).

O

OHMeO

OMe

HO

OHMeO

OMe

HO O

OMeO

OMe

OH

HO

OMeO

OMe

OH

OH

372

1a

1b

+

89.3% (d.e. 91.2%) 3.3% (d.e. 88.6%)376 377

372

81.4% (d.e. 91.3%) 2.7% (d.e. 92.9%)378 379

O

OMe OH

OH

OMeO

OMe

HO OH O

MeO

OMeHO

OH OMeO

OMe

O

375

373

1a

+ +

380 381 382

57.2% 27.9% 5.9%

No reaction

383

1b1a

Scheme 65.

9.13. C3–C14 fragment of antitumor agent, laulimalide

Laulimalide 384, isolated from various marine sponges,99

shows microtubule stabilization in eukaryotic cells and isdistinguished by an unusually high antitumor activity againstmultidrug resistant cells lines.100 Mulzer and co-workers101

synthesized the C3–C14 fragment of laulimalide from natu-rally occurring (�)-citronellal using hydrolytic kinetic reso-lution (HKR) (Scheme 66). As shown in Scheme 67,aldehyde 387 was converted into a racemic epoxide 388via Corey’s sulfonium ylide addition, and this was subjected

H

O

Me

Me

OMOM

OTBDPS

OOH

H

O

MeBr

HHTESO

2 23 219

1715

3 5 9

11

1

14

(-)-citronellal 387386

385

laulimalide 384

Me

OHO

OH

O

O O Me

H

H H

2 23 219

1715

1

11

5 931

Scheme 66. Retrosynthetic analysis for C3–C14 fragment of antitumoragent, laulimalide.

to HKR using H2O (0.5 equiv) catalyzed by 1a in TBME for48 h to give the epoxide 389 and diol 390 in 41 and 42%yields, respectively, and in good diastereoselectivity. Thering opening of epoxide 389 with ethyl propiolate followedby partial hydrogenation and in situ cyclization furnished thelactone 391 in quantitative yield. Lactone 391 was furtherconverted into the desired C3–C14 fragment 386 in severalsteps.

9.14. Hemibrevetoxin B: synthesis of a key intermediate

Polycyclic ether marine natural products, such as ciguat-oxins (e.g., CTX1B), brevetoxins, and yessotoxin originatedfrom the ‘red tides’ of marine unicellular algae as potentneurotoxins that bind to a common site of, and activate, volt-age-sensitive sodium channels.102 Nelson and co-workers103

synthesized an intermediate 393 for hemibrevetoxin B 392(Fig. 12) by desymmetrization of a centrosymmetric diepox-ide 394, which can be synthesized by cyclization of an epoxycarbonyl compound 395, which, in turn, could be synthe-sized from the corresponding alkene 396 (Scheme 68).

O

OO

O

O H

Me

Me

H

O

O

O H

Me

Me

H O

O

O

R

RO

O

O

R

R

392

393 394

395396

SR

Scheme 68. Retrosynthetic analysis for a key intermediate of hemibreve-toxin B.

As shown in Scheme 69, the trans-epoxide 395 was synthe-sized from the g,d-unsaturated enone 397 in several steps,and this was cyclized with PPTS in methanol to give the

Me

O

Me

O

Me

HO

HO

Me

O O

387 +

388390389

386

i) trimethylsulfonium iodide, KOH 95% 1a

H2O, TBME22 °C, 48 h

42% 41%

ethyl propiolaten-BuLi, BF3.Et2O91%

390

391

Scheme 67.

O

O

O

OHO

Me

H HH

HH H

OH

OHC

Me

392

AB

CD

Figure 12.


O O

O

NCO2Et

O

O

O

OO

E:Z 2:1

i) (E)-1,4-dibromobut-2-ene MeCN

ii) HCliii) NaOHiv) HCl 70%

E-400

398

m-CPBACH2Cl296%

trans- 395

397

399

Scheme 69.

O

OO

O

O

H

H

OMe

OMe

O

OO O

O

H

H

OMe

OMe

O

O

H

H

OMe

OMe

trans-395

PPTSMeOH

85%

395; E:Z 2:1

PPTSMeOH

402

+

401

401

O

O

H

H

OMe

OMe

O

O

H

H

Me

Me

Me3Si

O

O

H

H

Me

Me

Me3Si

404, >100:1

cat. Me3SiOTfCH2Cl290%

405, >100:1

cat. Me3SiOTfCH2Cl292%

401

401

403a

403b

O

O

H

H

Me

MeO

O

O

O

O H

Me

Me

H O

O

O

O H

Me

Me

HOH

OH

O

O

O H

Me

Me

HOH

O2CPh

O

O

O H

Me

Me

HO

O

i) O3, CH2Cl2 -78 °C

406

Me3S(O) I, NaHDMSO

394; d.r. 20:1

20 mol% 1a

1.1 eq. H2O

MeCN-CH2Cl2

407, >95% ee408

393

>98%

PhCOClEt3N

70%

cat. PPTS98%

ii) Me2S 98%

75%

(MeO)2CMe2

Scheme 70.

thermodynamically more stable centrosymmetric diacetal401. Centrosymmetric diacetal 401 was subjected to two-directional nucleophilic substitution using a range of nucleo-philes such as allylic silane, or propargylsilane to give thecentrosymmetric diTHPs 404 and 405, respectively, with>100:1 diastereoselectivities. Ozonolysis of diallene 405followed by treatment with dimethylsulfonium ylide gavethe diepoxide 394 as a 20:1 mixture of centrosymmetricand unsymmetrical diastereomers. Finally, a wide range ofsolvents were used for desymmetrization of bis-epoxide394 by hydrolytic kinetic resolution. The best results wereobtained when HKR was carried out in the presence of water(1.1 equiv) and 1:1 acetonitrile/dichloromethane catalyzedby 1a (20 mol %) to furnish the diol 407 in 98% yield and95% ee, which was converted into the key intermediate393 in essentially quantitative yield (Scheme 70).

9.15. (4R)-Hydroxy analogs of Annonaceous acetogenins

Yao and co-workers104a devised a new synthesis for the(4R)-hydroxylated analogs of an Annonaceous acetogenin-mimicking compound on the basis of the naturally occurringAnnonaceous acetogenin, bullatacin 409d (Fig. 13). Prelim-inary screening of this mimicking compound showed an en-hancement effect against HCT-8 and HT-29, compared withthose of 409c. The target compound 409e was synthesizedbased on a two-directional C-alkylation of 1,7-octadiyne417 with epoxides 413 and 416 as key steps. As shown inScheme 71, the intermediate 413 was synthesized by HKRof the racemic epoxide 412.

The butenolide unit 411 was synthesized from 410 by analdol reaction with (S)-O-tetrahydropyranyl lactol followedby acid-catalyzed THP cleavage, in situ lactonization, andb-elimination. The racemic epoxide derived from olefin411 by m-CPBA oxidation was subjected to HKR in thepresence of water (0.55 equiv) catalyzed by 1b to afford413 in 43% yield with 99% de and diol 414 in 50% yieldwith 70% de. The other epoxide 416 was synthesized fromglyceraldehyde in several steps. The epoxide ring openingwith diyne 417 and further manipulations led to the targetmolecule 409e.

Similarly, the epoxide 413 was employed in the synthesisof several other acetogenins such as longimicin C104b andmurisolins.104c

409a (15R,22R)409b (15S,22R)409c (15R,22S)

bullatacin 409d

409e

OOH

OHO

OMe O

OH5 5

OOH

O

OMe O

OH5 5

OOOH

OHO

OMe

OH5 5

Figure 13.


10. Miscellaneous epoxides

10.1. (R)-2-Amino-1-hydroxyethylphosphonic acid

Wyatt and Blakskjaer105 have shown for the first time that theHKR method can be successfully applied to diethyl oxirane-phosphonate 419, which could provide an easy access to auseful new homochiral building block. Accordingly, theracemic epoxide 419 was subjected to HKR in the presenceof the catalyst 1a (0.05 mmol) and H2O (4.44 mmol) at20 �C for four days (Scheme 72). This resulted in the isola-tion of enantiomerically pure epoxide (R)-419 in 39% yieldas a single isomer. The enantiomeric purity of the epoxidewas checked by its conversion into a single diastereomerby its reaction with (R)/(S)-1-phenylethylamine or 1,10-car-bonyldiimidazole. Opening of the resultant (R)-epoxide bybenzylamine followed by phosphate ester hydrolysis, andhydrogenolysis resulted in the protozoal plasma membranecomponent, (R)-2-amino-1-hydroxyethylphosphonic acid420.

P(OH)2

OH

NH2 O

OP(OEt)2

H

O

OP(OEt)2

O

1a,H2O (0.8 equiv)20 °C, 4 days

39% yield(±)-419 (R)-419 420

Scheme 72.

10.2. Enantiomeric 2,3-epoxypropylphosphonatesand (S)-phosphocarnitine

Enantiomeric 2,3-epoxypropylphosphonates are useful three-carbon phosphonate chirons for the synthesis of variousphosphonate analogs, e.g., phosphocarnitine,106a phos-phonic acid antibiotics FR-33289 and FR-33699,106b andisosteres of glycerophosphoric acid.106c Wr�oblewski andHalajewska-Wosik107 synthesized enantiomeric (S)-phos-phocarnitine, based on the hydrolytic kinetic resolution ofdiethyl 2,3-epoxypropylphosphonate.

O

O

O

O

O

O

O

O

O

O O

O

HOOH

+

i) LDA, THF-HMPA (S)-O-tetrahydropyranyl lactol

ii) 10% H2SO4 THF, rtiii) (CF3CO)2O, Et3N 60%

m-CPBA 86%

1b

43%, 99% de 50%, 70% de

410

411 412

413 414

OO

CHO5Me O

OMOMO

O

OOH

Me OOMOM

5 409e

n-BuLiBF3.Et2O80%

415416

417

418

413

Scheme 71.

As shown in Scheme 73, hydrolytic kinetic resolution ofthe racemic epoxide (�)-421 using 1a (0.2 mol %) in thepresence of water (0.55 equiv) afforded epoxide (S)-421 in34% yield with 94% ee and diol (R)-422 in 31% yieldwith 86% ee. Ring opening of the epoxide (S)-421 withMgBr2, followed by bromide substitution with Me3N andhydrolysis, furnished the target molecule (S)-426. Attemptsto cleave the epoxide (S)-421 with aqueous trimethylaminegave the eliminated product 427 as a major component(60%), together with (S)-428 (20%) and some unidentifiedproducts.

10.3. Oxacyclic ring systems

Gopalan and co-workers108 prepared a number of chiral1,2-dihydroxysulfones in high enantiomeric excess bythe HKR method.76 The (�)-epoxysulfones preparedfrom u-phenylsulfonyl-1-alkenes by the oxidation withm-CPBA were stirred at room temperature in the presenceof 1b catalyst (1.0 mol %) and H2O (0.55 equiv). The prod-uct 1,2-diols and the unreacted epoxides were separated bysilica gel chromatography. As shown in Scheme 74, theintramolecular cyclization reaction of the acyl and ethoxy-carbonyl derivatives of these dihydroxysulfones has beenexploited to access a variety of functionalized chiralnon-racemic cyclic ethers and lactones such as 434, 436,and 437.

10.4. Monofluorinated analogs of (lyso)phosphatidicacid

(Lyso)phosphatidic acid 441 (LPA, 1- or 2-acyl-sn-glycerol3-phosphate) (Fig. 14) is a naturally occurring phospholipid.It has received increasing attention due to a variety ofbiological responses that it evokes including platelet aggre-gation, smooth muscle contraction, changes in cell morpho-logy, and mitogenesis.109 Prestwich and co-workers have

HO HP(O)(OEt)2Br

HO HP(O)(OEt)2Bn2N

+1a (0.2 mol%)

H2O (0.55 equiv.)

82% ee(S)-421 44%

Bn2NH, 60 °C

20 h(S)-421

(S)-421

421

MgBr2diethyl ether 45% Me3N

in EtOH/H2O

12 M HClH2O

(R)-424

(S)-425 (S)-426

(S)-421

Me3N, 45%aqueoussolution

+

427 (S)-428

(R)-422

423

O HP(O)(OEt)2

H OHP(O)(OEt)2HO

P(O)(OEt)2O

P(O)(OEt)2O H

P(O)(OEt)2O H

HO HP(O)(OEt)2Me3N+

Br– HO HP(O)(OH)OMe3N+

_

HO P(O)(OEt)2HO H

P(O)(OEt)2Me3N+

_OH

Scheme 73.


reported the synthesis of the target molecules and relatedanalogs.110 Scheme 75 illustrates the synthesis and HKRof fluorophosphonate epoxides. The HKR substrate wasprepared in four steps in the following manner. Thecommercially available diethyl dibromofluoromethyl-phosphonate 442 was converted into iodomonofluoro-methylphosphonate 443 by tributylphosphine reductionand iodine quench of the intermediate zinc species. ThePd-catalyzed addition of 443 to allyl alcohol gave thecorresponding iodohydrin 444, which, on treatment withK2CO3/MeOH at room temperature, provided the desiredracemic oxide 445 in good yield. The reaction of racemicepoxide 445 with 0.45 equiv of H2O in a minimum volumeof THF in the presence of 1a (1.0 mol %) gave the diol447a in 90% ee and 73% isolated yield. Similarly, catalyst1b provided the opposite configuration of the diol in 89%ee and 90% yield. These diols were smoothly convertedinto sn-1-O-acyl-a-fluoromethylenephosphonate analogs448a,b by regioselective acylation of the primary hydroxylgroup.

OO

O

O

PhSO2 OEt

OHOH

PhSO2

PhSO2

OHOH PhSO2

OPhSO2

O

PhSO2

O

O

O

O

O

PhSO2 OTBDMS

OH

PhSO2

O

O C3H7

O

OHOH

PhSO2

O CH2OH

PhSO2

O

O

OH

PhSO2

OHOH

PhSO2

Butyryl chlorideEt3N, Bu2SnO, CH2Cl2, 0 °C430 435

436

437

n

n+

n

430 431

n

429 (n = 1-3, 9)

1b

Butyrylchloride

Et3NCH2Cl2

1.1 eq LHMDSTHF

-78 °C

i) TsOH PhHii) KOH THF

430432

433 434

n

n

n

n

n

430

n

n

Scheme 74.

F OO

P OH

OOH

R

O

O OF

P OH

OOH

O

R

OOH

O

R P OH

OOH

FO O

OH

P OH

OOH

O

R

438 439

440 441

Figure 14.

Br Br

PO

FOEtOEt

PO

FOEtOEt

I

OH

PO

OEtOEt

FHO

I

PO

OEtOEt

FO

442 443

444 445

2 Steps

K2CO3, MeOH

68%

Pd(PPh3)4

PO

OEtOEt

FO

PO

OEtOEt

FO

PO

OEtOEt

FHO

OH

PO

OEtOEt

FO

PO

OEtOEt

FHO

OH

1a ++

445

446b

447b

446a

447a

1b

PO

OEtOEt

FHO

OH

PO

OHOH

FO

OHOR

PO

OEtOEt

FHO

OH

PO

OHOH

FO

OHOR

447a 448a

447b 448b

Scheme 75.

10.5. Chiral (a,a-difluoroalkyl)phosphonateanalogs of (lyso)phosphatidic acid

The same authors have reported the resolution of 1,1-di-fluoro-3,4-epoxy-butylphosphonate (prepared in a similarmanner as described above) by the HKR method.111 This ex-ample constitutes the first application of HKR in a substratecontaining both fluorine and phosphonate functionalities. Asshown in Scheme 76, the reaction of racemic epoxide (�)-452 with 0.45 equiv of H2O in THF in the presence of 1a(1.0 mol %) gave the diol 453a in 99% ee and 69% yield.Similarly, the catalyst 1b provided the opposite configura-tion of the diol 453b in 99% ee and 70% yield. The diolwas transformed into the target molecule 456 by regioselec-tive acylation of the primary alcohol.

10.6. 7(S),16(R),17(S)-Resolvin D2

7(S),16(R),17(S)-Resolvin D2 is a new class of lipid media-tor derived from docosahexaenoic acid that possesses potentanti-inflammatory and immunoregulatory activities. Spurand Rodriguez have accomplished the first total synthesisof this molecule encompassing the hydrolytic kinetic resolu-tion of a terminal epoxide combined with a chiral pool strat-egy.112 The chiral center at C-7 was obtained via HKR ofa terminal epoxide, whereas the centers at C-16 and C-17were installed by the chiral pool strategy. As shown inScheme 77, alkylation of the dimagnesium complex of pen-tynoic acid 457 with allyl bromide in the presence of a cata-lytic amount of CuBr/Me2S followed by in situ esterificationgave the ester 459. Subsequent epoxidation with m-CPBAfurnished the epoxide (�)-460. The epoxide (�)-460 wassubjected to HKR in the presence of 5% of catalyst 1a to


give the diol 461 in>94% ee. The other enantiomer was ob-tained in>95% ee employing the catalyst 1b. The chiral diolthus obtained was converted into the C1–C9 fragment 463

ICF2 P

O

O

OCF2 P

O

O

O

IHO

OCF2

P

O

O

O

OH451

(±)-452

79%

72%

450

449

Pd(PPh3)4

K2CO3

MeOH

OCF2 P

O

O

OO

CF2 P

O

O

O

CF2 P

O

OOHHO

O

CF2 P

O

OOHHO

O

OCF2 P

O

O

O+

+1b 1a

453b

454a

(±)-452

453a

454b

CF2 P

O

OOHHO

OCF2 P

O

ONaOHO

ONa

O

C17H33

CF2 P

O

ONaOO

ONa

O

C17H33

OC17H33

453a455

456

Scheme 76.

COOH Br CO2Me

OCOOMe

COOMeO

COOMe

OHHO

OTESO

HCOOMe

OTES

COOMeI

O O

O O

OTES

CO2Me

HO OH

OH

CO2H

HO OH

OH

CO2Me

+

+

7(S),16(R),17(S)-resolvin D2 467

457 458 459

(±)-460

461

(R)-460

462

463

464

465

10

11

716 17

i) MeMgBr

ii) TMSCl 2,2-DMP

m-CPBA 1a

CrCl2,CHI3

Pd(PPh3)4CuIn-Pr NH2benzene

466

Scheme 77.

through series of organic transformations and finally cou-pled with the C10–C22 fragment 464 to afford the targetmolecule, 7(S),16(R),17(S)-resolvin D2 467.

10.7. (L)-Galantinic acid

(�)-Galantinic acid 473, a non-proteogenic amino acid, isa constituent of the peptide antibiotic, galantin I, whichwas isolated from the culture broth of Bacillus pulvifa-ciens.113 Raghavan and co-workers developed a stereoselec-tive synthesis of (�)-galantinic acid, which includes thehydrolytic kinetic resolution of a racemic epoxide and regio-and stereoselective heterofunctionalizations of an olefinusing a pendant sulfinyl group as the nucleophile as thekey steps.114 As illustrated in Scheme 78, the HKR of theracemic epoxide 468115 with 1b afforded the optically pureepoxide (S)-468 in 42.5% yield along with the diol 469(49%). Triethylamine-promoted opening of epoxide (S)-468by thiophenol gave the homopropargyl alcohol 470. Depro-tection of the PMB group, reduction of the resulting prop-argyl alcohol with LiAlH4, and protection of the hydroxylgroup as the silyl ether followed by oxidation of sulfidewith NaIO4 yielded an equimolar, inseparable mixture ofsulfoxides 471, which were converted into the target mole-cule, (�)-galantinic acid 473, over several steps.

OPMBO

OPMBO

OPMBOH

HO

OPMBOH

PhS

SOTPS

OTPS

O

Ph

O

N3

O OOH

OH OH

NH2

HO2C

+

PhSH, Et3N

(±)-468

469

(S)-468

470

471

472 473galantinic acid

1b

49%

42.5%

85%

Scheme 78.

10.8. (4R,9Z)-Octadec-9-en-4-olide, the femalesex pheromone of Janus integer

(4R,9Z)-Octadec-9-en-4-olide 480 is a female-specific andantennally active compound from the female currant stemgirdler, J. integer Norton, a pest of redcurrant in NorthAmerica.116 It was then found to be the sex pheromone ofthat insect. Mori has developed a multi-gram synthesis ofthis pheromone by employing Sharpless asymmetric dihy-droxylation (AD) and Jacobsen’s hydrolytic kinetic resolu-tion (HKR).117

Scheme 79 illustrates the synthesis and purification by reso-lution. Commercially available hex-5-en-1-ol 474 was con-verted into the corresponding iodide 475 via the tosylate.


Alkylation of dec-1-yne with n-butyllithium followed bySharpless AD with AD-mix b gave the crystalline (R)-diol478 in about 75% ee and 84% yield. This was convertedinto the epoxide (R)-479 by the method of Kolb and Sharp-less.118 Compound 479 obtained in 87% ee was subjected tofurther purification by HKR in the presence of 0.7 mol % of1a and 0.4 equiv of water for three days at room temperatureto give (R)-479 in 96% ee and 72% yield. Further syntheticmanipulations led to the formation of the target molecule480.

OH I

nC8H17

OH

nC8H17

OH

nC8H17

O

nC8H17

O

OO

nC8H17

nC8H C17 CHii) NaI, DMF nBuLi

i) AD-mix β

1a

96% ee

87% ee

474 475

477478

(R)-479

(R)-479480

i) TsCl

92% 71%

72%

476

(4R,9Z)-octadec-9-en-4-olide 480

Scheme 79.

10.9. (D)-Sch 642305

(+)-Sch 642305 (481) is a bicyclic macrolide, isolated fromPenicillium verrucosum (culture ILF-16214),119 which in-hibits bacterial DNA primase with an EC50 value of70 mM. It also inhibits HIV-1 Tat, a regulatory protein re-quired for viral replication.120 Snider and Zhou121 accom-plished the total synthesis of (+)-Sch 642305 usinga transannular Michael reaction of 482 with NaH in THF,Yamaguchi macrolactonization, and hydrolytic kinetic reso-lution of racemic epoxide (�)-489 as the key steps (Scheme80). As shown in Scheme 81, 7-octenal was treated withLiC^CTMS to afford the propargyl alcohol, which, on sub-sequent PCC oxidation, gave 487. Dioxolane formation andTMS deprotection gave 488 in 89% yield. The racemicepoxide formed by oxidation of 488 with m-CPBA wassubjected to HKR with 0.5 equiv of water catalyzed by anoligomeric (salen)Co(III) catalyst in MeCN to give (R)-489 in 46% yield with 92.5% ee. The epoxide was openedwith hydride using NaBH4. Further synthetic manipulationled to the formation of the target molecule 481 in 1.6%overall yield.

O

O Me

O

OR

OOMeHO

OTBDPS

CO2H

CO2EtOHC

481 482

485

486

483

O

OOTBS

OH

O

O (CH2)5

CO2EtOTBS

484

O

O Me

O

OHH

H1

3 56

79

11

13

(CH2)5

Scheme 80. Retrosynthetic analysis for (+)-Sch 642305.

10.10. hNK-1 receptor antagonist

The neuropeptide, substance P, has been found to preferen-tially bind to the human neurokinin-1 (hNK-1) receptor.122

The hNK-1 receptor is involved in a wide array of biologicalfunctions, and it has been suggested that modulating the inter-action between substance P and the hNK-1 receptor may affectnumerous and diverse disease states.123 Tetrahydropyran 494has been identified as one such selective hNK-1 receptor an-tagonist.124 Nelson and co-workers have developed a newand concise synthesis of this hNK-1 receptor antagonist, whichinvolved an a-alkoxy sulfonate as a key intermediate.125 Theepoxide (R)-491 required for the synthesis of the key interme-diate was prepared by HKR of a terminal epoxide 491.

As shown in Scheme 82, treatment of the alkene 490 withbenzyl chloride followed by epoxidation with m-chloroper-benzoic acid afforded the racemic epoxide (�)-491, whichreadily underwent hydrolytic kinetic resolution with 1.5 mol %catalyst 1a and 50 mol % H2O. The required epoxide (R)-491 was conveniently separated from the newly formed anti-pode (S)-492 by distillation. The enantiomeric excess of theepoxide was found to be >99%. The synthesis of the targetmolecule 494 was achieved by the epoxide ring openingand through several subsequent organic transformations.

7-octenalii) PCC 83%

i) ethylene glycol HC(OMe)3

ii) K2CO3 MeOH 89%

m-CPBA 1e

MeCN0.55 equiv. H2O

99%, racemic

46%, 92.5% ee481

(±)-489

488

487

(R)-489

(+)-Sch 642305

O

TMS

i) BuLi, TMSC CH

O

O

OO

O

OO

O

OTBSO

O

HOCO2Et

484

(CH2)5

(CH2)5 (CH2)5

(CH2)5 (CH2)5

Scheme 81.

OH OBn

O

OBn

O

OBn

HO

OH

OBn

PMPO

OH O O

MeCF3

CF3

N

CO2Me

H

i) BnCl, NaOH

ii) m-CPBA

1a, DCMHOAc, H2OTHF

+

(R)-491

(±)-491 (R)-491 (S)-492

493

hNK-1 receptor antagonist 494

490

+

-

Scheme 82.

P. Kumar et al. / Tetrahedr

10.11. L-Carnitine and a-lipoic acid

Bose and co-workers126 developed a general and practicalapproach for the synthesis of the biologically importantnatural products, L-carnitine 496 and a-lipoic acid 497(Fig. 15), by synthesizing C-4 chiral building blocks throughhydrolytic kinetic resolution (HKR). (R)-Carnitine 496,127

also known as vitamin BT, plays an important role in b-oxi-dation of fatty acids, acting as a carrier of fatty acids over themitochondrial membrane, while a-(R)-lipoic acid 497 is animportant protein-bound coenzyme and growth factor foundin animal tissues, plants, and microorganisms. As shown inScheme 83, racemic epoxide (�)-491 was subjected to HKRusing H2O (0.5 equiv) catalyzed by 1a to afford a mixtureof R-epoxide (R)-491 in 47% yield (96% ee) and 1,2-diol(S)-492 in 43% yield. Hydrogenolysis of the benzyl etherfollowed by oxidation and opening of the epoxide withNH4OH furnished 496. Regiospecific opening of epoxide(R)-491 with but-3-enylmagnesium bromide furnished 499,which was converted into a-lipoic acid 497 in several steps(Scheme 84).

S S

CO2HH

OHCOO¯H3N+

OHCOO¯Me3N+

495 496

497

Figure 15.

BnOO

BnOO

BnO

OHOH

BnOO

+1a (0.5 mol%)H2O (0.55 eq.)

Ph3P, DIADC6H6, reflux

(S)-491 94%

(±)-491 (R)-491 (S)-492

Scheme 83.

OBnO

OHO

BnOO

BnO

OH

BnOOH

OBn

HO

OH

CO2Me

OHOH

but-3-enylMgBrLi2CuCl4

90%

H2, Pd/CEtOH

i) RuCl3 NaIO4

ii) conc NH4OH

MeIbase

(R)-lipoic acid, 497

(R)-491 498

496 495

(R)-491 499

500

501

COO¯COO¯ H3N+H3N+

Scheme 84.

10.12. C20–C26 building block of halichondrins

Halichondrin B, a polyether macrolide, isolated from a vari-ety of sponge genera,128 displays an in vitro IC50 value of0.3 nM against L1210 leukemia and remarkable in vivoactivities against various chemoresistant human solid tumorxenografts.129 Kishi and co-workers130 developed a generalmethodology for the synthesis of the C20–C26 buildingblock of halichondrin. As shown in Scheme 85, the epoxide(�)-506 derived from olefin 505 was subjected to hydrolytickinetic resolution using water catalyzed by 1a to give theoptically active epoxide (R)-506 in good yield. Opening ofthe epoxide with propargyl triethylsilyl (TES) ether 507 un-der Yamaguchi conditions followed by hydrostannation andiodine quenching furnished a 55:6:2:1 mixture of all fourpossible products, with the desired product 509 as the majorisomer. Further synthetic manipulation yielded the targetintermediate 510.131

O

O

O

MeH

TBSO

TBSOH

MeR

OMPMO

MeH

H

OMPM

CHO

I

MeR

MsO

38 30

25

30

502

i) Ni(II)/Cr(II)-mediated couplingii) base-induced cyclization

503

504

TrisylOI

OHOTBS

OTBS OTBSO

OTBSO

OTBSOH

HO

I

OHOTBS

Me

m-CPBA

90%

1a

BuLi, BF3.Et2O87%

509

505 (±)-506 (R)-506

508

510

507TESOCH2C CH

Scheme 85.

10.13. (S)-Propranolol and (R)-9-[2-(phosphonometh-oxy)propyl]adenine (R-PMPA)

Jacobsen and co-workers have developed a (salen)Cr-cata-lyzed 1c epoxide ring-opening reaction of a racemic epoxideleading to the efficient synthesis of 1-azido-2-trimethylsiloxy-alkanes (Scheme 86). The viability of this strategy isillustrated in the practical synthesis of (S)-propranolol, awidely used antihypertensive agent, and (R)-9-[2-(phospho-nomethoxy)propyl]adenine (R-PMPA), a compound recentlydemonstrated to display prophylactic activity against SIVinfection.132

The treatment of neat racemic propylene oxide with0.5 equiv of TMSN3 in the presence of (salen)CrN3 complex1d (1 mol %) resulted in the clean conversion to a mixture ofepoxide and ring-opened product, 1-azido-2-trimethylsiloxy-propane, in 97% ee and in essentially quantitative yieldafter 18 h at 0 �C. Thus, the kinetic resolution of the racemicepoxide derived from chlorohydrin and 1-naphthol afforded

2777on 63 (2007) 2745–2785


the corresponding azido silyl ether 511 in 74% yield andin 93% ee. In a one-pot, two-step procedure, transformationto (S)-propranolol 512 was accomplished by desilylationfollowed by azide reduction and in situ reductive alkylation.The synthesis of (R)-PMPA was effected similarly in ahighly efficient manner via kinetic resolution of propyleneoxide, as shown in Scheme 86. A desilylation–reductionsequence yielded the synthetically important amino alcohol,(R)-1-amino-2-propranolol 514, in excellent yield. Furthertransformation of this compound to (R)-PMPA 516 wasaccomplished using known methods by conversion of theamine into an adenine base133 followed by alkylation ofthe alcohol and standard deprotection of the phosphonate.134

10.14. Total synthesis of (D)-brefeldin A

Brefeldin A 517 (Fig. 16) was first isolated from Penicilliumdecumbens,135 and shows a range of biological activitiessuch as antifungal,136 antiviral,137 antitumor,138 and nemato-cidal activities.139

Wu and co-workers140 developed a convergent synthesisthrough Michael addition between cyclopentenone 524and vinyl iodide 521. The key intermediate cyclopentenone524 was synthesized in several steps from 522, which wasreadily prepared from the corresponding acid. The vinyl

MeO TMSO

MeN3

HO

HO

Me

N

NN

N

Me

OOH

NH

OOTMS

N3

N

NN

N

NH2

NH2

NH2

O

Me

PO

(R)-9[2-(phosphonomethoxy)propyl]adenine

i) CSA, MeOH, 92%

ii) 10%Pd/C, MeOH, H2, 91%(±)-9 513 514

515

516

(S)-propranolol 512

i) EtOH CSA

ii) 5 mol% PtO2acetone, H291%

511

1d

(OH)2

R

OR

OTMS

N3

OTMS

RN3 R

O+

1c 1d

TMSN3 TMSN3S R

Scheme 86.

XY

OHO

O

H

H

1

1510

47

517a : X = H, Y = OH517b : X = OH, Y = H

Figure 16.

iodide 521 fragment was prepared from the known alkene518 by hydrolytic kinetic resolution. The epoxide (�)-519formed from alkene 518 with m-CPBA was subjected toHKR using 1a in the presence of water at 25 �C to affordthe R-epoxide (R)-519 in 44% yield with >99% ee. In thisreaction, the author observed that, if benzyl was replacedwith benzoyl, the enantiomeric excess was lowered to 97%under the same conditions. The R-epoxide (R)-519 was hy-drogenated to give the hydroxy compound in 90% yield.The benzyl ether formed from the secondary hydroxy groupwas hydrolyzed followed by tosylation. Replacement withlithium acetylide and further manipulation gave the vinyliodide 521. Final coupling of both fragments led to thetarget molecule over several steps (Scheme 87).

BzO BzO

O

BzO

O H

OH

BzOI

OBn

NSSS

OS O

O

OTBS

OBnO

OTBS

OBn

O

HOTBS

H

H

OBnO

OBn

m-CPBA

95%

Pd-C/H2

90%44%

ee >99%

Bn

524

518 (±)-519

520

(R)-519

1a

521

522 523

n-BuLi/521

CuCN/MeLi93%

525

517a: X = H, Y = OH517b: X = OH, Y = H

XY

OHO

O

H

H

1

1510

47

Scheme 87.

10.15. C1–C16 fragment of bryostatins

Bryostatins were isolated from the marine bryozoan Bugulaneritna Linn. and Amathia convoluta. These bryostatinsand related biologically active marine macrolides exhibitexceptional antineoplastic activity against lymphocyticleukemia and ovarian carcinoma,141 and inhibit the tumorpromotion of phorbols related to protein kinase C.142 Yadavand co-workers143a synthesized the C1–C16 fragment ofbryostatins using hydrolytic kinetic resolution, a Horner–Wadsworth–Emmons coupling reaction, and 1,4-Michael-type cyclization as the key steps. As shown in Scheme 88,the synthesis of the C1–C9 fragment started with hydrolytickinetic resolution of racemic epoxide (�)-491 with catalyst1b to give the chiral epoxide (S)-491 in 47% yield and 97%ee. The epoxide (S)-491 was opened with THP-protectedpropargyl alcohol. Further synthetic manipulations afforded


the fragment 529. The C10–C16 fragment 531 was synthe-sized from dimethyl 1,3-acetonedicarboxylate 530 in severalsteps and was coupled with 529 by Horner–Wadsworth–Emmons olefination to furnish the a,b-unsaturated ketone532, which was converted into the target intermediate 533(Scheme 89).

OOBn O

OBn OBnOHHO+

1b

43%97% ee

0.55 equiv. H2O0 °C to rt12 h

(±)-491(S)-491 (R)-492

Scheme 88.

OBnTHPO

OBnTHPO

OH OTIPSOBn OBnOBn OBn

HO

OBnOOO

P

OMeO

MeO

OBn

O

CO2MeMeO2C O OMOMO

TBSO

CHO

(S)-491

n-BuLi, BF3.Et2O90%ii) NaH, BnBr

i)i) PTSA, MeOH

ii) LAH, THF reflux

531

529

526

527 528

530

O OMOMO

TBSO O OO OBnOBn

O

OO O

OHH MeO

OMOM

OBnOBn

531 + 529

533

532

Scheme 89.

A similar application of this epoxide has been reported in thesynthesis of (�)-salicylihalamides A and B.143b

10.16. Pyrinodemin A

Pyrinodemin A 540 is a bis-3-alkylpyridine, which wasisolated from the Okinawan marine sponge Amphimedonsp.144 Because of its interesting cytotoxicity toward murineleukemia L1210 and KB epidermoid carcinoma cells andthe uncertainty in its absolute stereochemistry, Lee andco-workers145 established the absolute configuration bysynthesis of pyrinodemin A 540 via a nitrone, which couldbe derived from an aldehyde. As shown in Scheme 90, theepoxide (R)-534 was obtained through the HKR of the race-mic epoxide 534, which was treated with lithium trimethyl-silylacetylide to afford the secondary alcohol 535. Removalof the trimethylsilyl group, hydroxyl protection as itsTBDPS ether followed by alkylation of acetylene with1,7-dibromoheptane in the presence of n-BuLi and DMPU

furnished compound 536 in 81% yield. Semi-hydrogenationof the triple bond followed by treatment with lithiated3-picoline, deprotection of the primary silyl ether, andsubsequent IBX oxidation furnished the aldehyde 538 in88% yield. The aldehyde 538 was further converted intothe target molecule 540 in a few steps through syntheticmanipulations.

OTBDPS OTBDPSO

OTBDPSO

OTBDPS

OHMe3Si

OTBDPS

OTBDPSBr

N

N

NO

HH

BrOTBDPS

OTBDPS

m-CPBA

98% 47%

trimethylsilylacetylenen-BuLi, BF3.Et2O94%

i) K2CO3, MeOH 89%

ii) TBDPSOTf 98%iii) n-BuLi, DMPU Br(CH2)7Br 81%

6

Lindlar catalystH2

99%

538

539 (known)

5 5

534 (±)-534

1a

(R)-534 535

536

537

pyrinodemin A 540

5

OTBDPS

N

O7

N

NH

HO6

Scheme 90.

10.17. Combinatorial synthesis of natural product-likemolecules

Porco and co-workers146 have reported the use of the dioxa-spiro[5,5]undecane (spiroketal) moiety as a rigid-core tem-plate for elaboration using parallel synthesis techniques. Inthis paper, they have used the scaffold to generate a smallcombinatorial library of natural product-like molecules.The synthesis of functionalized spiroketals 548, 549, and550 could be achieved from spiroketal ketone 547, which,in turn, was prepared from condensation of chiral ketone545 and aldehyde 545a using standard reaction sequences.As shown in Scheme 91, hydroxyl ketone fragment 544was synthesized by HKR. The epoxide (�)-541 was sub-jected to HKR using 1b and water (0.55 equiv) to yield ep-oxide (S)-541 in 85% yield. The treatment of epoxide with2-methyl-1,3-dithiane 542 provided the hydroxyl dithiane543, which was converted into silyl-protected hydroxyl ke-tone 544 in two steps. Enolization of 544 followed by con-densation with aldehyde 545a under Mukaiyama reactionconditions gave 546, which, on further synthetic manipula-tions, gave the spiroketal scaffold and highly functionalizedmolecules.


10.18. (S)-(L)-Zearalenone

Zearalenone 557, also known as RRL and F-2 toxin, is a po-tent estrogenic metabolite, isolated from the mycelia of thefungus Gibberella zeae.147 F€urstner and co-workers148 ac-complished the total synthesis of (S)-(�)-zearalenone 557using a ring-closing metathesis and HKR as the key steps.As shown in Scheme 92, racemic epoxide (�)-553 (preparedfrom 1-cyano-4-pentene 551 in two steps) was subjected toHKR using 1b catalyst and water (2 equiv) to give the re-quired epoxide (S)-553 in optically pure form (ee>99%).Reaction of (S)-553 with LiBEt3H afforded the alcohol554, which, on esterification with salicylic acid derivative555 under Mitsunobu conditions followed by ring-closingmetathesis, gave the target molecule 557.

10.19. trans-2,5-Disubstituted morpholines

In the course of a large-scale preparation of trans-2,5-disub-stituted morpholine derivatives required for solid-phase syn-thesis of a library of saframycin analogs,149 Myers andLanman150 established a simple route for their synthesisstarting from readily available, enantiomerically pure start-ing materials. As depicted in the Scheme 93, the racemicepoxide 559 (derived from olefin 558 by m-CPBA oxidation)was subjected to hydrolytic kinetic resolution in the

O OH

H Me

S S

S SOH

Me

TBDPSO

Me

O

1b

H2O, AcOHTHF, 0 °C to rt

n-BuLi, THFHMPA73%

85%(±)-541 (S)-541

543544

542

TBDPSO OSiMe3

MeMe

TBDPSO O OHO

O

O

O

TBSO

HO

O O NH

O

O

ON

O

OMe

NH

OPh

HO2C

N OMe

OHO

ONH

OPh

HO2C

OO CHO

547 548

i) KHMDS, THF -78 °C, 1.5 hii) TMSCl, -78 °C 2 h, 98%

545a, -78 °CBF3.Et2O1.5 h65%

+

(2 : 1)549 550

545

546

545a

O

OO

HO

H1H2

Scheme 91.

presence of water (0.55 equiv) catalyzed by 1b to form theS-epoxide (S)-559 in 46% yield with 98% ee and R-diol560 in 50% yield. (S)-Epoxide (S)-559 on ring openingwith amino alcohols 561 and 565 followed by N-protection,selective hydroxy activation, ring closure, and N-deprotec-tion gave the trans-2,5-disubstituted morpholines 564 and566, respectively, in excellent yields.

TBSO TBSOO

TBSOO

TBSOOH

OH

NH2

CH3OH

TBSONH

OH

OHCH3

TBSONH

CH3O

NH2

OHPh

TBSONH

OPh

TBSON

OH

OHCH3

+

+1b (0.2 mol%)

H2O (0.55 equiv.)0 to 23 °C 46% (98% ee) 50%

97 °C99%

+

TsClEt3N

77%

i) NaH, THF TsIm, THF

ii) Na, NH3 EtOH

99%

100%

m-CPBA94%558 (±)-559

(S)-559 560

(S)-559

561

562

563564

(S)-559

565

566

Ts

n-PrOH

Scheme 93.

11. Conclusions

As evidenced by the foregoing discussion, one of the mosteffective and recent methods for obtaining several classesof chiral building blocks is Jacobsen’s hydrolytic kineticresolution (HKR). The method provides general access tomany chiral epoxides and 1,2-diols that are otherwise

CN

O

O OO O OO

O OOH

4-pentenylmagnesiumbromide, Et2O70%

i) ethylene glycol PPTS, 4 h 98%ii) m-CPBA 41%

1b

H2O (2 equiv)THF, 67 h

41%, > 99% ee

LiBEt3H, THF1 h, 95%

554

(S)-553rac-553

551552

OH

OMe

MeO

OH

OO O

OH

OMe

MeO

O

O

OH

HO

O

O

O

555

PPh3, DEADEt2O, 88%

556

(S)-(-)-zearalenone 557

554 +

Scheme 92.


difficult to obtain in high conversions and enantiopuritiesfrom inexpensive racemic starting materials. We have shownin this review that the HKR method has broad applications inorganic synthesis. In particular, it is quite useful in the syn-thesis of biologically active products. The synthesis of chiralbuilding blocks by the HKR method is a blossoming fieldand there is enormous scope for using this method in the syn-thesis of diverse compounds, which may have applicationsas biologically active agents. In view of the easy availabilityof the chiral ligand and the simplicity of the reaction withwater being used as the nucleophile, they will continue toplay an important role in asymmetric synthesis and judiciousapplication of the knowledge in this area will give the de-sired result. We anticipate many more applications to emergein the near future and this review just presents the state ofthe art knowledge on how a synthetic organic chemist canexploit this novel tool for the total synthesis of complexnatural products.

Acknowledgements

The financial support by the Department of Science andTechnology (Grant No. SR/S1/OC-40/2003) is gratefullyacknowledged. We thank Dr. M. K. Gurjar, Head, Division ofOrganic Chemistry: Technology for constant support andencouragement. This is NCL communication No. 6698.

References and notes

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Biographical sketch


Pradeep Kumar was born and grew up in India. He received his both B.Sc.

and M.Sc. degrees from Gorakhpur University. Gorakhpur (UP). In 1981, he

obtained his Ph.D. degree from BHU, Varanasi (UP) under the supervision

of Late Professor Arya K. Mukerjee. Subsequently he joined National

Chemical Laboratory, Pune, India in 1982. He is currently working in the

Division of Organic Chemistry: Technology as Scientist F since 2003. He

has visited Germany and worked in the group of Professor H. J. Bestmann

at the Institute of Organic Chemistry, University of Erlangen, Nuernberg

during 1988–1990 as DAAD fellow and later as Alexander von Humboldt

fellow with Professor Richard R. Schmidt at the University of Konstanz,

Germany (1996–1997) and with Professor Martin E. Maier at the University

of Tuebingen, Germany (2003). Recently he spent three months (September–

November, 2006) as a visiting scientist in Professor Joerg Rademann’s group

at Leibniz Institute for Molecular Pharmacology (FMP), Berlin (Germany).

He has published over hundred papers and a few review articles in interna-

tional journals of repute. His research interest includes development of

new methodologies, synthesis of biologically active natural products, and

solid catalyst induced synthetic organic transformations.

Priti Gupta was born in Maudaha, Hamirpur district, Uttar Pradesh, India.

She received her B.Sc. degree from Lucknow University, Lucknow in 1996

and M.Sc. degree in Organic Chemistry from Lucknow University, Luck-

now, UP in 1998 and was awarded McMohan gold medal for her academic

excellence. She joined Ph.D. program under the guidance of Dr. Pradeep

Kumar in the Division of Organic Chemistry: Technology, National Chem-

ical Laboratory, Pune in 2002 with a research fellowship awarded by UGC.

Presently, she is continuing as a Senior research fellow in this division. Her

research focuses on asymmetric synthesis of biologically active natural

products.

Vasudeva Naidu Sagi was born in Tirupathi, Chittor district, Andhra Pradesh,

India. He received his B.Sc. degree from Osmania University, Hyderabad in 1995

and M.Sc. degree in Organic Chemistry from National Institute of Technology,

Warangal, Andhra Pradesh in 1998. He joined Ph.D. program under the guidance

of Dr. Pradeep Kumar in the Division of Organic Chemistry: Technology, National

Chemical Laboratory, Pune in 2000 with a research fellowship awarded by CSIR.

He has been awarded the Keerti Sangoram Endowment Award (best research

scholar of the year 2005) in Chemical Sciences. He has completed his work and

presently, he is in the process of writing his thesis. His research focuses on

asymmetric synthesis of biologically active natural products.

44

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