Transaminase‐Triggered Cascades for the Synthesis and Dynamic Kinetic Resolution of Chiral <i>N</i>‐Heterocycles

Abstract Biocatalysis is now a well‐established branch of catalysis and the growing toolbox of natural, evolved and designer enzymes is enabling chemistry previously deemed inaccessible. However, most enzyme methodologies have been developed for functional group interconversions, such as the conversion of a ketone into an amine or alcohol, and do not result in the generation of significant 3D molecular complexity. The application of enzyme‐triggered reaction cascade methodologies has the potential to transform simple substrates into complex sp 3 ‐rich molecules in one step. Herein, we describe a single‐step biocatalytic route to high‐value, complex indolizidine, and quinolizidine alkaloids, which relies on a transaminase‐triggered double intramolecular aza‐Michael reaction. This approach allows access to architecturally complex, natural‐product‐like N ‐heterocycles and reveals intriguing examples of diastereoselectivity in these enzyme‐triggered reactions. Significantly, we demonstrate an elegant example of a biocatalytic cascade where the transaminase plays a dual role in generating complex N ‐heterocycles and where a retro‐double intramolecular aza‐Michael reaction mediates a dynamic kinetic resolution and enables the isolation of sp 3 ‐rich indolizidine diastereoisomers containing five stereocenters, as single isomers.