Novel enzymatic reduction of α-amido- and α-cyanoalkyl-β-keto esters catalyzed by ketoreductases

Abstract

An enzymatic approach for the asymmetric reduction of α-amido- and α-cyanoalkyl-β-keto esters has been developed. We have shown that NADPH-dependent ketoreductases can catalyze these transformations with excellent activity and high stereoselectivity, leading to optically pure β-hydroxy-α-amido esters as well as optically pure β-hydroxy-α-cyanoalkyl esters. With this method tert-butyl 2-acetamido-3-hydroxy-4-methylpentanoate, a valuable chiral intermediate for the synthesis of lactacystin, was obtained in high yield and excellent anti-diastereoselectivity. The ketoreductase catalyzed reduction of α-cyanomethyl- and α-cyanoethyl-β-keto esters to form the corresponding optically pure β-hydroxy esters, which are chiral intermediates for the synthesis of optically pure α-substituted γ-butyro and δ-valerolactams, was accomplished in high yield and high stereoselectivity leading to one stereoisomer out of four (>99 % de, >99 % ee, >99 % conversion).