Stereoselective Synthesis of Three Isomers of tert ‐Butyl 5‐Hydroxy‐4‐methyl‐3‐oxohexanoate through Alcohol Dehydrogenase‐Catalyzed Dynamic Kinetic Resolution

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 ‐(4 S ,5 R )‐ 2 , alcohol dehydrogenase‐mediated dynamic kinetic resolution now allows easy access to syn ‐(4 R ,5 S )‐ 2 (RS 1‐ADH; 97.6% ee , syn : anti =92:8, 66% conversion, 37% isolated yield) and anti ‐(4 S ,5 S )‐ 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 .