Concise synthesis of chiral tricyclic γ-lactams via synergistic isothiourea/Ir catalyzed asymmetric [3 + 2] annulation.

Accessing trans-fused N-fused tricyclic frameworks with multiple contiguous stereocenters remains a major challenge in synthesis. We report a synergistic isothiourea/Ir-catalyzed [3 + 2] annulation of arylacetic acid esters with azabenzonorbornadienes, providing trans-fused tricyclic γ-lactams with three contiguous tertiary stereocenters in high regio-, enantio-, and diastereoselectivity. The method tolerates diverse arylacetates, heterocycles, and pharmaceutically relevant carboxylates, and is amenable to gram-scale synthesis. Mechanistic studies support a cooperative cycle involving C1-ammonium enolate formation and enantioselective SN2' attack on the Ir-activated azabenzonorbornadiene. Downstream functionalizations, including epoxidation, hydrogenation, and amino alcohol formation, demonstrate the versatility of the products. This work establishes a concise and efficient platform for constructing sterically challenging trans-fused tricyclic γ-lactams, highlighting the potential of synergistic catalysis for complex stereocontrolled transformations.