Biocatalytic reduction of beta,delta-diketo esters: A highly stereoselective approach to all four stereoisomers of a chlorinated beta,delta-dihydroxyhexanoate

A stereoselective chemoenzymatic synthesis of all four stereoisomers of ter t-butyl 6-chloro-3,5-dihydroxyhexanoate (6a) is presented. The key step of the sequence is a highly regio- and enantioselective single-site reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (1 a) by two enantiocomplementary biocatalysts. Alcohol dehydrogenase from Lactobacillus brevis (recLBADH) a fforded a 72% yield of enantiopure tert-butyl (S)-6-chloro-5-hydroxy-3-oxoh exanoate [(S)-2a]. The enantiomer (R)-2a was prepared with 90-94% ee by Bak er's yeast reduction in a biphasic system (50% yield). Both biotransformati ons were performed on a gram scale. The P-keto group of the enantiomeric de lta -hydroxy-beta -keto esters 2a thus obtained was reduced by syn- and ant i-selective borohydride reductions. Permutation of the reduction methods yi elded all four stereoisomers of the crystalline target compound 6a (greater than or equal to 99.3% ce, dr greater than or equal to 205:1), which is a versatile 1,3-diol building block. recLBADH accepts a variety of beta,delta -diketo esters as was determined in a photometric assay. tert-Butyl 3,5-di oxohexanoate (1b) and tert-butyl 3,5-dioxoheptanoate (1c) were reduced on a preparative scale as well to afford the corresponding delta -hydroxy-beta -keto esters (R)-2b and (R)-2c with 99.4% ee and 98.1 % ee, respectively.