A Chemoenzymatic Strategy for Efficient Synthesis of Aporphine Alkaloids

Aporphine alkaloids (APAs) are renowned for their diverse pharmacological activities, but their practical preparation is hindered by challenges, such as poor chiral control and low coupling efficiency, making their production largely dependent on plant extraction. Here, we present a streamlined, modular chemoenzymatic strategy that integrates biocatalysis with photoinduced coupling to efficiently synthesize both natural and unnatural APAs from inexpensive, readily available substrates. This platform employs a sequential enzymatic reaction using engineered imine reductase and cocaine N-methyltransferase to convert 2’-halogenated 1-benzyl-dihydroisoquinolines into (S)-1-benzyl-tetrahydroisoquinoline precursors, followed by catalyst-free photoinduced coupling to construct diverse APA frameworks. Notably, the highly efficient method enables the gram-scale synthesis of (S)-nuciferine in just four steps, demonstrating its practical applicability. By simplifying complex synthesis, enhancing stereoselectivity, and reducing reliance on rare plant sources, this approach offers a powerful platform for APA production and serves as a broadly applicable model for the synthesis of related complex natural products.