Modular Chemoenzymatic Cascade for Highly Diastereo- and Enantioselective Synthesis of 1,3-Disubstituted Tetrahydroisoquinolines

Abstract

1,3-Disubstituted tetrahydroisoquinolines (THIQs) are widespread structural skeletons among alkaloid natural products with diverse biological activities. The lack of their unambiguous biosynthetic pathways to produce these structures has, however, impeded their efficient production through environmentally friendly biosynthesis. Herein, a modular chemoenzymatic cascade has been developed to circumvent this limitation for the synthesis of various 1,3-disubstituted THIQs bearing two stereo carbon centers with high diastereo- and enantioselectivities after the semirational design of the imine reductase SnIR. More importantly, the preparative stereodivergent synthesis of both cis- and trans-1,3-disubstituted THIQs is achieved through the plug-and-play strategy. Therefore, this work highlights the promising potential of modular chemoenzymatic strategies for the preparation of a series of value-added products and derivatives through synthetic biology.