A Modular Chemoenzymatic Cascade Simplifies Divergent Synthesis of Natural and Unnatural Benzylisoquinoline Alkaloids

Conventional chemical or biological synthetic methods often encounter challenges in conveniently preparing chiral natural and unnatural products with the same skeleton at a scalable level, due to their complexity with numerous chiral centers or uncharacterized enzymes. Herein, a simplified modular chemoenzymatic platform is designed featuring a streamlined four-enzyme cascade coupled with a chemical module that involves one or two chemical steps. This platform enables the divergent synthesis of structurally diverse natural and unnatural benzylisoquinoline alkaloids (BIAs), including 1-benzylisoquinoline, protoberberine, morphinan, and aporphine alkaloids. Moreover, the enantioselectivity of the chiral BIAs is up to 99% ee. The titer of papaverine reaches an impressive 2.83 g L^-1, demonstrating substantial industrial potential. Overall, this work establishes a paradigm for constructing modular chemoenzymatic platforms that simplify the production of structurally diverse natural and unnatural products for drug development.