Epoxy esters, resolution

In another approach, the alcohol moiety, formed by an enzymatic hydrolysis of an ester, can act as a nucleophile. In their synthesis of pityol (8-37a), a pheromone of the elm bark beetle, Faber and coworkers [17] used an enzyme-triggered reaction of the diastereomeric mixture of ( )-epoxy ester 8-35 employing an immobilized enzyme preparation (Novo SP 409) or whole lyophilized cells of Rhodococcus erythro-polis NCIMB 11540 (Scheme 8.9). As an intermediate, the enantiopure alcohol 8-36 is formed via kinetic resolution as a mixture ofdiastereomers, which leads to the diastereomeric THF derivatives pityol (8-37a) and 8-37b as a separable mixture with a... 

The example we show here is the resolution of a racemic mixture of epoxy-esters according to the following reaction ... 

In the case of biocatalysis, enzymes [3] and catalytic antibodies [4] have attracted most attention. Since enzymes are inherently the more active catalysts, they have been used most often. Indeed, many industrial processes for the enantioselective production of certain chiral intermediates are based on the application of enzymes, as in the lipase-catalyzed kinetic resolution of an epoxy-ester used in the production of the anti-hypertensive therapeutic Diltiazem [5]. Recently, it has been noted that there seems to be a trend in industry to use enzymes more often than in the past... 

An alternative approach is to perform a resolution of the epoxy ester (10), which can be accomplished with a lipase from Serratia marcescens (Scheme 2) [30,31]. This approach allows for resolution of an early intermediate that can then be used to prepare just the desired diastereoisomer. Alternatives are to resolve precursors to the epoxy functionality [32]. 

The types of enzymes used by organic chemists vary widely and include such well-known biocataiysts as lipases, esterases, oxidoreductases, oxinitrilases, transferases and aldolases [4]. An example which illustrates the industrial application of a lipase concerns the kinetic resolution of a chiral epoxy ester used as the key intermediate in the synthesis of the calcium antagonist Diltiazem, a major therapeutic in the treatment of high blood pressure [6] (Fig. 1). In developing the industrial process for the production of this drug, many different lipases were screened, but only the bacterial lipase from Serratia marescens showed both a sufficiently high activity and enantioselectivity. The intermediate is produced industrially on a scale of 50 tons/year. 

Scheme 2.55 Resolution of epoxy esters by porcine pancreatic lipase...

Scheme 2.71 Lipase-catalyzed resolution of an epoxy-ester on industrial scale...

Both saturated (50) and unsaturated derivatives (51) are easily accepted by lipases and esterases. Lipase P from Amano resolves azide (52) or naphthyl (53) derivatives with good yields and excellent selectivity. PPL-catalyzed resolution of glycidyl esters (54) is of great synthetic utiUty because it provides an alternative to the Sharpless epoxidation route for the synthesis of P-blockers. The optical purity of glycidyl esters strongly depends on the stmcture of the acyl moiety the hydrolysis of propyl and butyl derivatives of epoxy alcohols results ia esters with ee > 95% (30). 

The stereochemistry of each enantiomer separated by the chiral HPLC has been studied after methanolysis of the epoxy ring. Examining the H NMR data of esters of the produced methoxyalcohols with (S)- and (R)-a-methoxy-a-(tri-fluoromethyl) phenylacetic acid by a modified Mosher s method [181], it has been indicated that the earlier eluting parent epoxides are (3S,4R)-, (6S,7R)-, and (9R,10S)-isomers (Table 7) [75, 76, 179]. The above three chiral HPLC columns show different resolution abilities but a different elution order is not observed. The resolution profile by the reversed-phase OJ-R column has been generalized with molecular shapes of the epoxy compounds considering the... 

Palomo JM, Munoz G, Fernandez-Lorente G et al. (2003) Modification of Mucor miehei lipase properties via directed immobilization on different heterofunctional epoxy resins. Hydrolytic resolution of (R,S)-2-butyroyl-2-phenylacetic acid. J Mol Catal B Enzym 21 201-210 Palomo JM, Ortiz C, Fernandez-Lorente G et al. (2005) Lipase-lipase interaction as a new tool to immobilize and modulate the lipase properties. Enzyme Microb Technol 36 447-454 Park EY, Sato M, Kojima S (2006) Fatty acid methyl ester production using Upase-immobilizing silica particles with different particle sizes and different specific surface areas. Enzyme Microb Technol 39(4) 889-896... 

Renewed development and marketing effort is expected with brominated epoxy oligomers, now in the hands of Resolution Performance Products, following a sell-off from Shell. These materials are well established for thermosets, such as epoxy resins, phenolics, and vinyl esters, but modified grades have recently been introduced aiming at thermoplastics, such as styrenic and (significantly, because of its potential in electrical and electronics equipment) ABS. Thermoplastic polyesters, elastomers, and polyolefins can also be flame retarded with these materials which have a bromine content of 50-60% weight... 

Sharpless early investigations of epoxidation reactions of secondary allylic alcohols were accompanied by an intriguing observation the enantiomeric alcohols display substantial rate differences in the epoxidation event. This allowed a kinetic resolution process to be considered [78, 79]. As showcased in Equation 12, the racemic substrate 56 features four diastereotopic olefin faces and its epoxidation represents a particularly interesting case [79]. As anticipated, the more nucleophilic, disubstituted olefin displays greater reactivity in the epoxidation to give 58 in > 95 % ee. As is generally the trend for metal-catalyzed epoxidation of allylic alcohols, the anti epoxy alcohol 58 is preferentially formed. Kinetic studies have shown that the use of bulkier tartrate esters, such as diisopropyl tartrate (57), generally further enhances the rate differences between two enantiomeric allylic alcohols [19]. 

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