Regio- and Enantioselective Enzymatic Reduction

Comparison of analytical data of the products (R) -2b and (R) -2c with literature data (NMR, [a]) clearly proved the formation of R-configured [S in the case of 2a, 

R = Cl] 5-hydroxy-P-keto isomers of high optical purity. Neither the P-hydroxy-5-keto regioisomer nor p,5-di-hydroxy esters could be detected by NMR and GC-MS analysis of the crude enzymatic products. 

The enzyme recLBADH is the first catalyst that has been found to allow the highly regio- and enantioselective synthesis of 5-hydroxy-P-keto esters by reduction of the respective diketo esters. This enzymatic reaction is of enormous preparative value. The substrates are readily available by acylation of P-keto ester bisenolates and the reaction only requires a simple batch technique which is easy to scale up. Reduction of the chlorinated compound la has been performed routinely on a 75 g scale in our laboratory (8 L fed batch), yielding (S)-2a in an isolated yield of 84% [10]. 

In order to synthesize the R-enantiomer of hydroxy keto ester 2a we reinvestigated the baker s yeast reduction of 3,5-dioxoesters [7]. The chlorinated diketo 

A set of Saccharomyces cerevisiae reductases was screened in collaboration with J. D. Stewart s group (University of Florida). Itwas demonstrated that diketo ester la is accepted as substrate by at least three different NADP(H)-dependent reductases of this microorganism. Application of a cell-free system in preparative batches using enzyme-coupled coenzyme regeneration afforded (R)-2a with more than 99% enantiomeric excess [13]. 

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Substituted 1,3-diols are valuable intermediates in the synthesis of drugs and natural products [18]. Starting from the regio- and enantioselective enzymatic reduction of diketo esters described above, various methods to obtain enantio-merically pure 3,5-dihydroxy esters were developed. 

Scheme 2.2.7.11 Chiral building blocks evolved from diketo ester la via regio- and enantioselective enzymatic reduction.

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