Stereoselective synthesis of three isomers of tert-butyl 5-hydroxy-4-methyl-3-oxohexanoate through alcohol dehydrogenase-catalyzed dynamic kinetic resolution

Abstract

Regioselective reduction of the 5-keto group of tert-butyl 4-methyl-3,5-dioxohexanoate (1) leads to a stereodiad of tert-butyl 5-hydroxy-4-methyl-3-oxohexanoate (2). Alcohol dehydrogenases from Lactobacillus brevis (LBADH), Rhodococcus sp. (RS 1-ADH) and Saccharomyces cerevisiae (YGL157w) reduce 1 under dynamic kinetic resolution conditions, thereby establishing two chiral carbons with a single reduction step. While it had been shown previously that LBADH reduction of 1 stereoselectively leads to syn-(4S,5R)-2, alcohol dehydrogenase-mediated dynamic kinetic resolution now allows easy access to syn-(4R,5S)-2 (RS 1-ADH; 97.6% ee, syn:anti = 92:8, 66% conversion, 37% isolated yield) and anti-(4S,5S)-2 (YGL157w; 90% ee, anti:syn = 93:7, 64% conversion, 42% isolated yield), as well. Thus three out of four possible stereoisomers were formed selectively upon reduction of 1. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.