Biocatalytic Atroposelective Synthesis of Axially Chiral Styrenes via Dynamic Kinetic Resolution
Abstract
Abstract Enzymatic synthesis of atropisomers has recently attracted considerable research attention, with most studies focusing on axially chiral biaryls. We report a less explored atroposelective dynamic kinetic resolution (DKR) of nonbiaryl styrenes catalyzed by imine reductases (IREDs) and alcohol dehydrogenases (ADHs). The IR189 wild type enzyme was identified to be highly active and selective; furthermore, the inversion of atroposelectivity was achieved with protein engineering. Additionally, two ADHs with enantio‐complementary selectivity for the reductive DKR were identified and applied in the synthesis of axially chiral styrenes. Both IREDs and ADHs exhibited broad substrate scope, affording up to 99:1 e.r. and 99% yields for up to 29 examples. Scaled‐up reactions and derivatization of optically pure products demonstrated the synthetic utility of these axially chiral styrenes. Molecular recognition mechanisms were elucidated by molecular dynamics (MD) simulations. The current strategy expands the scope of enzymatic DKR of atropisomeric compounds and significantly advances the field of biocatalytic synthesis of axially chiral compounds.
Article Details
Authors (12)
Pengpeng Zhang
College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
Zhuangfei Tian
NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 P.R. China
Congcong Li
Runze Meng
State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology
Bowen Zhang
Xinzhuo Liu
Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 P.R. China
Junkuan Li
Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 P.R. China
Ge Qu
School of Materials Science and Engineering
Nicholas J. Turner
Department of Chemistry, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.
Bo Yuan
Haigen Fu
State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology
Zhoutong Sun
Tianjin Institute of Industrial Biotechnology of Chinese Academy of Sciences National Technology Innovation Center of Synthetic Biology Tianjin P. R. China