Enantioselective synthesis of structurally diverse aryl γ-/δ- lactones using an engineered carbonyl reductase

Abstract

Optically pure aryl γ-/δ-lactones are valuable building blocks in the organic synthesis of natural products and pharmaceutical compounds. The asymmetric reduction of aryl keto acids or esters using carbonyl reductase provides a green and atom-economic synthetic route to these molecules. However, this method is still challenging due to the substantial steric hindrance of substrates, which has limited its practical application. Herein, we report the engineering of a carbonyl reductase SmCRV4, which showed excellent enantioselectivity (99% (S)) for methyl 3-benzoyl propionate (1a), to obtain the mutant SmCRW6 by directed evolution. The specific activity and catalytic efficiency of SmCRW6 towards 1a were 4.9-fold and 3.2-fold higher than those of the parent SmCRV4, respectively. The mutant SmCRW6 showed a broad substrate scope (26 examples) with improvement in specific activity and enantioselectivity for most substrates. Finally, 7 chiral aryl lactones and 10 aliphatic lactones were prepared using lyophilized enzyme powder. In scaled-up synthesis, three aryl γ-/δ-lactones were prepared with > 97% conversions, 76 − 88% yields and ee up to > 99%, and the highest space-time yield (STY) of 28.2 g L−1 h−1 reported so far for (S)-γ-phenyl-γ-butyrolactone was obtained through biocatalysis.