Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate

Xiaofeng Lin; Yixuan Li; Zefei Xu; Shanshan Yu; Jinhui Feng; Aipo Diao; Peiyuan Yao; Qiaqing Wu; Dunming Zhu

doi:10.1021/acs.orglett.4c01079

Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate

Org Lett. 2024 May 15. doi: 10.1021/acs.orglett.4c01079. Online ahead of print.

Authors

Xiaofeng Lin^{1

2}, Yixuan Li^{2

3}, Zefei Xu², Shanshan Yu^{2

3}, Jinhui Feng^{2

3}, Aipo Diao¹, Peiyuan Yao^{2

3}, Qiaqing Wu^{2

3}, Dunming Zhu^{2

3}

Affiliations

¹ School of Biotechnology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China.
² Key Laboratory of Engineering Biology for Low-carbon Manufacturing, National Engineering Research Center of Industrial Enzymes, National Center of Technology Innovation for Synthetic Biology, Tianjin Engineering Research Center of Biocatalytic Technology, and Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.

PMID: 38747552
DOI: 10.1021/acs.orglett.4c01079

Abstract

(S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline ((S)-1-(4-methoxybenzyl)-OHIQ) is the key intermediate of the nonopioid antitussive dextromethorphan. In this study, (S)-IR61-V69Y/P123A/W179G/F182I/L212V (M4) was identified with a 766-fold improvement in catalytic efficiency compared with wide-type IR61 through enzyme engineering. M4 could completely convert 200 mM of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline into (S)-1-(4-methoxybenzyl)-OHIQ in 77% isolated yield, with >99% enantiomeric excess and a high space-time yield of 542 g L^-1 day^-1, demonstrating a great potential for the synthesis of dextromethorphan intermediate in industrial applications.