Skeleton-Divergent Access to Chiral Bridged/Fused Azaheterocycle-Tetrahydrofurans via Bimetallic Catalysis and Cascade Annulation

Chiral N -heterocycles and tetrahydrofuran units are privileged scaffolds prevalent in numerous bioactive molecules. Bridged piperidine-tetrahydrofuran and fused pyrrolidine-tetrahydrofuran architectures are especially noteworthy due to their structural complexity and biological relevance. While established methods exist for synthesizing individual heterocycles such as pyrrolidines, piperidines, or tetrahydrofurans, efficient strategies to access chiral azaheterocycle-tetrahydrofuran frameworks—particularly those with fused or bridged three-dimensional topologies—remain underdeveloped and challenging. Herein, we report a modular and stereoselective strategy for the synthesis of these scaffolds via bimetallic Cu/Ir-catalyzed asymmetric allylation and acid-promoted cascade annulation. Using tert -butyl ether-containing serine-derived aldimine esters and allylic carbonates, this method enables divergent access to two distinct classes of complex heterocycles: bridged piperidine-tetrahydrofurans bearing three skipped stereocenters via a 6- endo -trig cyclization, while fused pyrrolidine-tetrahydrofurans through an unexpected stereoconvergent 5- exo -trig cyclization. Key challenges, including competing cyclization pathways and stereochemical integrity, were addressed through rational design and optimization. The transformation exhibits broad substrate scope, good functional group tolerance, and high stereoselectivity. Gram-scale reactions and further derivatizations highlight the practical utility and synthetic versatility of this methodology, providing efficient access to biologically relevant heterocycles and offering important insights into controlling reactivity and stereochemistry in complex cascade annulations.