Baeyer enantioselective enzyme

Directed Evolution of Enantioselective Enzymes for Catalysis in Baeyer-Villiger Reactions... 

Camell and co-workers have recently applied lipase-catalysed resolution to formally desymmetrize prochiral ketones that would not normally be considered as candidates for enzyme resolution, through enantioselective hydrolysis of the chemically prepared racemic enol acetate. " For example, an NK-2 antagonist was formally desymmetrized by this approach using Pseudomonas fluorescens hpase (PFL) (Scheme 1.40). By recychng the prochiral ketone product, up to 82 % yields of the desired (5)-enol acetate (99 % ee) could be realized. This method offers a mild alternative to methodologies such as base-catalysed asymmetric deprotonation, which requires low temperature, and biocatalytic Baeyer-Villiger oxidation, which is difficult to scale up. 

Since the isolation of the oxygenating enzyme and recycling of the cofactor is still difficult for large-scale preparations, the use of whole microorganisms would seem to be advantageous. Whole cells of Acinetobacter are well suited for enantioselective Baeyer-Villiger oxidation of cyclic ketones when a lactone hydrolase inhibitor is used or a hydrolase deficient mutant is... 

A preparatively useful synthesis of (R)-lipoic acid involves Baeyer-Villiger monooxygenase-catalyzed biotransformation of 2-(2-acetoxyethyl)cyclohexanone 351 to the key precursor, that is, chiral lactone 352 (Scheme 68) < 1997BMCL253, 1995CC1563>. The enzyme-catalyzed lactone 352 was then converted by a standard reaction procedure into the desired acid on enantioselective esterification of racemic lipoic acid, using C. rugosa lipase. 

Apart from the asymmetric metal catalysis, enantioselective Baeyer-Villiger oxidations mediated by enzymes have been known for some time [32,33,34]. Both whole-cell cultures and isolated enzymes, usually flavin-dependent monooxygenases, can be used to oxidize ketones enantioselectively. For future improvements in the asymmetric Baeyer-VilHger oxidation the use of chiral Lewis acids in combination with an appropriate oxidant seems worthy of intensive investigation. 

The Baeyer-Villiger reaction can be carried out using isolated enzymes or whole cell systems. Biotransformations of simple cyclic ketones are most effective. For example, 4-methylcyclohexanone is oxidized with high enantioselectivity by using cyclohexanone monooxygenase (6.64). 

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