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Synthesis of the C1–C13 fragment of eribulin mesylate has been accomplished. It features a highly stereoselective construction of a trans-dihydropyran framework using three key reactions: (1) Sharpless epoxidation, (2) regioselective ring opening, and (3) olefin metathesis.

A highly diastereoselective and efficient convergent synthesis of mupirocin H starting from (+)-(R)-Roche ester was achieved. Grubbs cross metathesis was employed as the key step in the pathway to generate an important E-olefin intermediate. Other processes utilized in the route include a Pd-catalysed stereoselective substitution reaction of a cis epoxide, Sharpless epoxidation followed by Red-Al promoted epoxide ring opening, and Seebach methylation and a TEMPO/BAIB mediated oxidation-lactonization sequence. Finally, we observed that mupirocin H inhibits SbnE, a synthetase required for staphyloferrin B biosynthesis.

α-Acetoxy aldehydes or α-acetoxy ketones can be efficiently synthesized by treating 2,3-epoxy primary alcohols with lead tetraacetate. The reaction, which proceeds with complete regio- and stereoselectivity facilitates the enantioselective synthesis of α-acetoxy carbonyl compounds from allyl alcohols, via Sharpless epoxidation. Cyclic β-hydroxy ethers, with an oxygenated five-, six- or seven-membered ring, are transformed into α-acetoxy ethers.

Total synthesis of (+)-dienomycin C was achieved via Sharpless asymmetric epoxidation, Pd-catalyzed hydrogenolysis with formic salt, and Pd(II)-catalyzed cyclization of urethane.

The natural products, (−)-frontalin and (+)- exo -isobrevicomin were synthesized employing Sharpless asymmetric epoxidation and ZrCl 4 -catalyzed intramolecular acetalization as the key steps. (−)-Frontalin was synthesized in three steps with a 61.4% overall yield and 89.9% ee and (−)- exo -isobrevicomin also obtained in an overall satisfactory yield of 10.1% and 97% ee. We have also synthesized the volatile contributor of beer aroma in a 96% ee.

The enantioselective total synthesis of idesolide has been accomplished in 20% overall yield from a known allylic alcohol by a nine-step sequence involving the Sharpless asymmetric epoxidation as the source of chirality and an efficient NaHCO 3 -promoted dimerization of the monomeric form of idesolide as the key transformation.

An efficient protocol for the asymmetric synthesis of triacetyl- d - erythro -sphingosine and D-1-deoxyallonojirimycin has been developed starting from commercially available propargyl alcohol. The key steps involved Sharpless asymmetric epoxidation and Miyashita C2 selective endo -mode azide opening of the 2,3-epoxy alcohol.

A highly stereoselective asymmetric total synthesis of marine polypropionate (−)-baconipyrone C has been achieved. Utilization of desymmetrization technique to create five stereogenic centres, Sharpless epoxidation, Gilman's reaction and resolution of methyl group using enzyme PS-C is the highlight of the synthesis.

The preparation of the key intermediate in the synthesis of the DNA damaging fragment of the anticancer antibiotic leinamycin starting from geraniol is described. The synthetic sequence involves the building of a quaternary asymmetric center through kinetic resolution through Sharpless epoxidation followed by the regioselective opening of the resultant enantiomerically pure hydroxyepoxide and intramolecular Wittig–Horner olefination.

Stereoselective synthesis of the C18–C34 fragment of antascomicin A is described. Construction of the C27–C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson–Claisen rearrangement, which was converted to iodide 2 by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18–C34 fragment.

A propionate-derived polyketide building block A whose 2-methyl-1,3-diol moiety was built by a Ti(III)-mediated ring opening reaction of a trisubstituted 2,3-epoxy alcohol precursor was employed as a common starting material for the syntheses of highly substituted tetrahydropyrans 1-5, the first one being the C20-C28 fragment of cytotoxic natural products, phorboxazoles.

A direct α-hydroxylation of racemic 2-hydroxymethyl ketones with the Sharpless epoxidation catalyst resulted in α,β-dihydroxy ketones in high ee (up to 97%) and in moderate to good isolated yield (up to 58%).

Cryptophycin fragment A was prepared in 11 steps from protected methyl (R)-mandelate 4. A diastereoselective addition of magnesium acetylide to methyl mandelate and a Sharpless epoxidation followed by regioselective opening of the resulting epoxide allowed the synthesis of this intermediate in high diastereomeric purity.

A new method for the enantioselective synthesis of N-Boc-α,α-disubstituted α-amino acids has been developed. The starting materials are diastereomerically pure 3,3-disubstituted allyl alcohols, prepared by DIBAL-H reduction of the corresponding unsaturated esters derived from carbocupration of an acetylenic ester or from Wadsworth–Emmons olefination of a ketone. Sharpless epoxidation of the allylic alcohols provided enantiomerically enriched epoxy alcohols that were submitted to nucleophilic ring-opening under Crotti's conditions (N3Na/LiClO4) to give 3-azido-1,2-diols. Hydrogenation and in situ protection provided the N-Boc-3-amino-1,2-diols that were oxidatively cleaved to the α,α-disubstituted N-Boc-α-amino acids. Protected α-methyl-α-phenylglycine and α-methylisoleucine have been prepared by this methodology.

Highly enantio- and diastereoselective routes to 2-hydroxymethylquinuclidines have been developed. Key steps involve the use of Sharpless dihydroxylation or Sharpless epoxidation to introduce the asymmetry with high stereocontrol, and formation of the quinuclidine ring systems via cyclisation of epoxy amines.

Methylenolactocin. an antitumour antibiotic, has been synthesised through an efficient radical cyclisation process on a chiral iodo acetylenic ester. Chiral iodohydrins may be formed by regioselective opening of a chiral epoxy ester, prepared by Sharpless epoxidation. C-2 opening is achieved with TMSCl/Nal and C-3 attack with Mgl 2 . Subsequent esterification of the 2-iodo compound by reaction with substituted propynoyl triflates gives the key lodo acetylenic esters. This route is highly adaptable to the synthesis of analogues.

The C 19 -C 32 segment 10 of swinholide A was prepared in 15 steps (8% yield, 82% ds) from (±)- 16 . Key steps include ( i ) the Sharpless epoxidation, 16 → 17 , ( ii ) the acetal allylation, 15 → 23 , ( iii ) the anti aldol addition, 13 + 14 → 12 , and ( iv ) the alkene hydroboration, 30 → 31 . The swinholides are a series of complex polyketide macrodiolides, which display potent cytotoxicity against a variety of human tumour cell lines. 1,2 Swinholide A, isolated from the marine sponge Theonella swinhoei , was first reported as an antifungal agent by Carmely and Kashman in 1985.1 Using NMR methods and chemical

We describe one synthesis of ( S )-fenfluramine and several syntheses of its precursors ( R )- and ( S )-1-(metatrifluoromethylphenyl) propan-2-ols. They were obtained from the asymmetric epoxidation of the primary allylic alcohol 5 and from the kinetic resolution with asymmetric epoxidation of the secondary allylic alcohol 6 .

A synthetic approach to the marine alkaloid Zoanthamine is outlined. Starting with (-)- perilly alkohol, the C-11 to C-20 fragment 9b has been synthesized in 12 operations and > 30% overall yield. Model studies for a proposed intramolecular Diels-Alder strategy are also described.

Iv. Introduction 8886 Chemical Synthesis of Chiral Epoxides 8887 1. Epoxidation of olefins with per&d8 8887 1.1. Enantioselective epoxidation of alkenes 8887 1.2. Enantioselective epoxidation of allylic alcohols 8888 1.3. Conclusion 8889 2. Epoxidation catalyzed by metals: Sharpless method 8889 2.1. Use of transition metals 8889 2.2. Pmcursors of the Sharpless reagent 8889 2.3. The Sharpless reaction 8891 2.4. Conclusion 8894 3. Epoxidation catalyzed by metalloporphyrins 8894 4. Other methods 8898 4.1. From chit-al precursors 8898 4.2. Use of phase-transfer catalysts 8899 4.3. Use of chiral reagents 8900 5. Conclusion 8901 Biological Synthesis of Chiral Epoxides 8901 1. Direct stereospecific epoxidation 8901 1.1. Isolated monooxygenases: the cytochromes P-450 8902 1.2. Bacterial monooxygenases 8906 1.3. Monooxygenases from other microorganisms 8912 1.4. Conclusion 8912 2. Indirect epoxidation 8912 2.1. Use of peroxidases 8912 2.2. Other methods 8915 2.3. Conclusion 8917 3. Enzymatic resolution 8917 3.1. use of lipases 8917 3.2. Enantioselective degradation of epoxides 8918 3.3. Conclusion 8921 4. Conclusion 8921 Conclusion 8921

The optically active taxol A-ring unit 3 was synthesized in 11 steps from 2-isopropyl-2-propenol. The stereogenic centers were introduced via the asymmetric glyoxylate-ene reaction and the Sharpless asymmetric epoxidation reaction.

Chiral synthesis of canadensolide has been achieved by using the Sharpless kinetic resolution of the 2-furylcarbinol derivative( 11 ), followed by its oxidative conversion into the corresponding pyranone( 12 ) as key reactions.

The enantioselective synthesis of mexiprostil (16R-16-methoxy-16-methyl PGE1 methyl ester) is described. The assembly of the prostaglandin framework has been accomplished by the three component coupling process, via consecutive linking of the ω and α-sidechain to unsubstituted (R)-4-hydroxy-2-cyclopentenone, and alternatively by a conjugate addition of the ω-side chain to a (R)-4-hydroxy-2-cyclopentenone in which the α-side chain is already incorporated. The required lower side chain building block is prepared enantioselectively from nerol utilising the Sharpless epoxidation reaction.

A new asymmetric synthesis of both erythro and threo aldols (β-siloxy aldehydes) has been developed based on the respective stereocontrolled rearrangement of optically active threo and erythro epoxy silyl ethers with stoichiometric use of exceptionally bulky, oxygenophilic methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) under mild conditions. The observed stereoselectivity varies with the electronic effect of silyl substituents rather than their steric effect, and the more electron-withdrawing triphenylsilyl group exhibits better selectivity than trialkylsilyl group. Since enantiomeric erythro and threo epoxy silyl ethers are readily accessible by Sharpless asymmetric epoxidation, this method allows the practical asymmetric synthesis of four possible aldol isomers with high selectivity.

By starting from the N-alkenylurethane 4, the epoxy urethane ent-5, and the pyrrolidine ent-6 available from the Katsuki-Sharpless kinetic resolution of N-benzyloxycarbonyl-3-hydroxy-1-pentenylamine (2) has been elaborated (−)-supinidine (1).

A new, stereocontrolled rearrangement of epoxy silyl ethers leading to β-siloxy aldehydes has been effected with stoichiometric use of exceptionally bulky, oxygenophilic methylaluminum bis(4-bromo-2,6-di-trert-butylphenoxide) (MABR) under mild conditions. Used in combination with the Sharpless asymmetric epoxidation of allylic alcohols, this rearrangement represents a new approach to the synthesis of various optically active β-hydroxy aldehydes, useful intermediates in natural product synthesis. The modified organoaluminum reagent, MABR is also applicable to the transformation of a variety of simple epoxides to carbonyl compounds with high efficiency and selectivity. Further, the catalytic version for the rearrangement of epoxy silyl ethers as well as simple epoxides has been newly devised. The scope and limitation of this catalytic method has been clarified with various epoxy substrates.

The asymmetric Sharpless epoxidation of divinylcarbinol (1), a secondary, achiral allylic alcohol, is described in detail. The epoxidation proceeds with high enantio-control and diastereo-selection. The resulting 1,2-epoxy-4-pentene-3-ols 2 are equilibrated to afford the internal epoxides 5. Hydrolysis of the regioisomers 2 and 5, respectively, furnishes opposite enantiomers of erythro-4-pentenitols 3 with high selectivity. Several derivatives of 3 are described, as well as results of a less stereoselective route - from D-glyceraldehyde acetonide (10) - providing NMR data of the threo series. -The acute toxicity of divinylcarbinol (1) is reported, along with the mutagenicity of 1, L-2 and L-5 as determined by Ames tests.

Asymmetric synthesis of (-)-dehydroclausenamide 1 by scheme 2 was reported. Sharpless epoxidation was applied to cinnamyl alcohol for introduction of two desired chiral centers and the potential hydroxyl group. The key intermediate, γ-lactam (-)-5, was obtained by regio-selective intramolecular cyclization of (-)-6. Subsequent stereo-selective reduction was achieved by reducing C3-tetrahydropyranyl ether of (-)- 5. The title natural product was then obtained by successive tosylation, hydrolysis and cyclization.

The natural mosquito oviposition attractant pheromone,(-)-(5R,6S)- 6-acetoxy-5-hexadecanolide ( 1 ) was synthesized from readily available 1,2-cyclohexanediol, using kinetic resolution of cyclic allylic alcohol by modified Sharpless asymmetric epoxidation reagent as the key step.

Simple, concise first, enantioselective total synthesis of 1 has been achieved. The route utilised is an attractive alternative to conventional synthetic methods employed in the synthesis of fatty acids, by using Sharpless kinetic resolution of allyl propargyl alcohols.

The orthoesters, 4a and 4b were obtained from treatment of methyl-7,13E-labdadien-17-oate, 3, under Sharpless asymmetric epoxidation conditions . The hydrolysis followed by dehydration of the orthoesters led to the synthesis of two new diterpenic acids isolated from Halimium viscosum : 14R,15-dihydroxy-7,13(16)-labdadien-17-oic and 14S,15.dihydroxy-7, 13(16)-labdadien-17-oic.

A series of 1,2-bis-methylenecycloalkane monoepoxides(2a-e)was prepared from the related 12-to 16-membered cyclic ketones. Reduction with lithium in ammonia afforded the corresponding trans-and cis-2-methylcycloalkenylmethanols (3a/4a-3e/4e) in ratios of 92:8-78:22. Sharpless epoxidation of these allylic alcohols with 0.6 equivalents of the reagent prepared from titanium isopropoxlde, (+)-diisopropyl tartrate, and t-butylhydroperoxide gave rise to a mixture of the epoxy alcohols 6a-e and recovered allylic alcohols. In the case of the 12- to 14-membered cycloalkenes the recovered alcohols 3a-c were optically active. The 15- and 16-membered cases 3d and e were racemic. Barriers to jump rope rotation were calculated by means of the Still Macro Model program.

The synthesis of the C14-C23 macrocyclic subunit of cytochalasin B from pulegone is described. The key feature of this synthesis is the photo-induced rearrangement of epoxy diazomethyl ketone E to a γ-hydroxy alkenoic ester (Scheme 2). The intermediate epoxy alcohol F was prepared using the asymmetric Sharpless epoxidation. Considerable attention was given to the preparation of allylic alcohol 14, having a t-butyldimethylsilyloxy protecting function, as starting material for the asymmetric epoxidation, however, several unforeseen difficulties were encountered (Schemes 3 and 4). Satisfactory results were obtained using the methoxy group as protecting function (Scheme 5). The allylic alcohol 22 was prepared from bromide 20 by chain lengthening with propargyl alcohol. The Sharpless epoxidation of 22 took place with high induction. Conversion to epoxy ester 24, to diazo ketone 25 and photo-rearrangement to 26 and deprotection to give 28, completes the sequence.

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.