Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate.

( 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.