The Kinetic Resolution of Epoxides

The kinetic resolution (KR) of racemic mixtures of terminal epoxide catalyzed by chiral metal Salen complexes, such as Cr(Salen) and Co(Salen) (Salen = N,N-bis(3,5-di-tert-butyl-salicylidene)-l,2-cyclohexene diamine), is of great interest in many total syntheses of natural products and drugs. Both Co(Salen) and Cr(Salen) 

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TONs up to 9000 [11c]. Of potential interest is the use of ionic liquids which allow recycling of the catalyst (cf. Section 3.1.1.2.2) [33]. SALEN complexes are also eminently suitable for the kinetic resolution of epoxides [12 u] especially promising for commercial applications is hydrolytic ring-opening using Co/ SALEN complexes [34] (42 5). a,jff-Unsaturated ketones can be epoxidized with hydrogen peroxide in presence of a polypeptide catalyst with ee values up to >98% [35]. 

The kinetic resolution of epoxide-bearing substrates has also been achieved... 

The kinetic resolution of epoxide-bearing substrates has also been achieved via a biotransformation different from hydrolysis. Thus, Weijer et al. [141]... 

Jacobsen and Ready <0IJA2687> have reported on the development of a highly aetive cyclic oligosalen catalyst (66), which is remarkably effective in promoting the asymmetric ring opening of epoxides by water and alcohols. For example, exposure of the notoriously recalcitrant substrate cyclohexene oxide (67) to water in methylene chloride/acetonitrile and 1.5 mol% of catalyst 66 led to smooth conversion to the chiral diol 68 in 98% yield and 94% ee. This catalyst is also effective in the kinetic resolution of epoxides with alcohols (i.e., 69 71)<01JA2687>. 

Jacobsen also showed that 2,2-disubstituted epoxides underwent kinetic resolution catalyzed by (salen)Cr-N3 complex 3 under conditions virtually identical to those employed with monosubstituted epoxides (Scheme 7.34) [64]. Several epoxides in this difficult substrate class were obtained with high ees and in good yields, as were the associated ring-opened products. The kinetic resolution of TBS-... 

In sharp contrast, Bartoli showed that the (salen) Co catalyst system could be applied to the kinetic resolution of terminal epoxides with unprotected tert-butyl carbamate as nucleophile with extraordinarily high selectivity factors (Scheme 7.40) [72]. Excellent yields and selectivities are also obtained with use of ethyl, Cbz,... 

One way of overcoming these problems is by kinetic resolution of racemic epoxides. Jacobsen has been very successful in applying chiral Co-salen catalysts, such as 21, in the kinetic resolution of terminal epoxides (Scheme 9.18) [83]. One enantiomer of the epoxide is converted into the corresponding diol, whereas the other enantiomer can be recovered intact, usually with excellent ee. The strategy works for a variety of epoxides, including vinylepoxides. The major limitation of this strategy is that the maximum theoretical yield is 50%. 

Another application of salen ligands is the hydrolytic kinetic resolution of epoxides (Scheme 3). For this purpose cobalt complexes are efficient, and fiu-... 

Biocatalytic hydrolysis or transesterification of esters is one of the most widely used enzyme-catalyzed reactions. In addition to the kinetic resolution of common esters or amides, attention is also directed toward the reactions of other functional groups such as nitriles, epoxides, and glycosides. It is easy to run these reactions without the need for cofactors, and the commercial availability of many enzymes makes this area quite popular in the laboratory. 

Scheme 20. Jacobsen s sequential use of catalytic asymmetric reactions, including his Cr-catalyzed kinetic resolution of epoxides in the total synthesis of taurospongin A (1998).

Sharpless "asymmetric epoxidation" has been used in the enantioselective synthesis of several natural products, including the kinetic resolution of allylic alcohols [11] and the creation of ... 

The above-mentioned facts have important consequences on the stereochemical outcome of the kinetic resolution of asymmetrically substituted epoxides. In the majority of kinetic resolutions of esters (e.g. by ester hydrolysis and synthesis using lipases, esterases and proteases) the absolute configuration at the stereogenic centre(s) always remains the same throughout the reaction. In contrast, the enzymatic hydrolysis of epoxides may take place via attack on either carbon of the oxirane ring (Scheme 7) and it is the structure of the substrate and of the enzyme involved which determine the regioselec-tivity of the attack [53, 58-611. As a consequence, the absolute configuration of both the product and substrate from a kinetic resolution of a racemic... 

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

ARO reaction with phenols and alcohols as nucleophiles is a logical extension of HKR of epoxides to synthesize libraries of stereochemically defined ring-opened products in high optical purity. To this effect Annis and Jacobsen [69] used their polymer-supported Co(salen) complex 36 as catalyst for kinetic resolution of epoxides with phenols to give l-aiyloxy-2-alcohols in high yield, purity and ee (Scheme 17). Conducting the same reaction in the presence of tris(trifluoromethyl)methanol, a volatile, nonnucleophilic protic acid additive accelerates KR reaction with no compromise with enantioselectivity and yield. Presumably the additive helped in maintaining the Co(III) oxidation state of the catalyst. 

Choi, S. D. Kim, G. J. (2004) Enantioseleetive hydrolytie kinetic resolution of epoxides eatalyzed by chiral Co(III) salen eomplexes immobilized in the membrane reaetor., Catal. Lett., 92 35-40. 

This screening system has also been applied successfully in the directed evolution of enantioselective EHs acting as catalysts in the kinetic resolution of chiral epoxides 95,96) (Section IV.A.4). Moreover, the firm Diversa has applied the MS-based method in the desymmetrization of a prochiral dinitrile (l,3-dicyano-2-hydroxypropane) catalyzed by mutant nitrilases 46). In this industrial application, one of the nitrile moieties was labeled selectively with as in N-17, which means that the two pseiido-eaaniiovaenc products (S)- N-18 and (J )-18 differ by one mass unit. This is sufficient for the MS system to distinguish between the two products quantitatively 46). 

The epoxidation procedure can also be utilized for the kinetic resolution of secondary allylic alcohols 39 as shown by Sharpless and coworkers (Scheme 59) ". For example, secondary allylic alcohol 39j can be epoxidized very rapidly by using the Sharpless... 

Heterogenization of homogeneous metal complex catalysts represents one way to improve the total turnover number for expensive or toxic catalysts. Two case studies in catalyst immobilization are presented here. Immobilization of Pd(II) SCS and PCP pincer complexes for use in Heck coupling reactions does not lead to stable, recyclable catalysts, as all catalysis is shown to be associated with leached palladium species. In contrast, when immobilizing Co(II) salen complexes for kinetic resolutions of epoxides, immobilization can lead to enhanced catalytic properties, including improved reaction rates while still obtaining excellent enantioselectivity and catalyst recyclability. 

In the realm of hydrolytic reactions, Jacobsen has applied his work with chiral salen complexes to advantage for the kinetic resolution of racemic epoxides. For example, the cobalt salen catalyst 59 gave the chiral bromohydrin 61 in excellent ee (>99%) and good yield (74%) from the racemic bromo-epoxide 60. The higher than 50% yield, unusual for a kinetic resolution, is attributed to a bromide-induced dynamic equilibrium with the dibromo alcohol 62, which allows for conversion of unused substrate into the active enantiomer <99JA6086>. Even the recalcitrant 2,2-disubstituted epoxides e.g., 64) succumbed to smooth kinetic resolution upon treatment with... 

The C = C bond in the hydroxy allylic system of a fluoroalkanol can be selectively epoxidized without affecting the hydroxy group. Enantioselective epoxidation of racemic unsaturated fluoro alcohols by using the chiral Sharpless reagent can be exploited for the kinetic resolution of enantiomers. The recovered stereoisomer (e.g., 1) has 14-98% enantiomeric excess.165... 

Thiols may be enantioselectiveiy added in a conjugate fashion to a,p-unsaturated carbonyl compounds in the presence of chiral hydroxyamine catalysts e.g. chinchona alkaloids).242,244 249 252-261-269 In some cases ee of up to >80% were achieved e.g. Scheme 77).242-261-262 This methodology was utilized for the kinetic resolution of compound rat-86 Scheme 34) in a multigram scale.94 Related enantioselective 1,4-additions of thioacetates270-271 and selenophenols272 to enones are also known. Epoxidations, based on the asymmetric nucleophilic addition of peroxide anions to enones, are discussed separately.273... 

The rationale that explains the kinetic resolution of the 1-monosubstituted allylic alcohols predicts that a 1,1-disubstituted allylic alcohol will be difficult to epoxidize with the Ti-tartrate catalyst. In practice, the epoxidation of 1,1-dimethylallyl alcohol (88) with a stoichiometric quantity of the Ti-tartrate complex is very slow, and no epoxy alcohol is isolated... 

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