Copper-Catalyzed Asymmetric Nitrenoid Transfer to Access Fused δ-Lactams via HFIP-Assisted Aziridination and Cascade Cyclization

Aza-steroids and terpenoid alkaloids are prominent entities of biorelevant ring-fused azacycles with significant pharmaceutical applications. Despite their importance, synthetic approaches to these complex molecules remain a great challenge due to the lack of strategic routes to the multiple contiguous chiral centers, particularly in the case of thermodynamically unstable <i>cis</i>-ring frameworks. Herein, we report a Cu-catalyzed asymmetric cascade cyclization of arylalkenyl dioxazolones to access ring-fused δ-lactams. It is initiated to form a bicyclic <i>N</i>-acylaziridine intermediate to involve a concerted transition state, allowing an asynchronous C-N bond formation on the open-shell singlet surface. This key reactivity is enabled by 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), which stabilizes the reactive Cu-acylnitrenoid intermediate via inner-sphere hydrogen bonding. The resulting <i>N</i>-acylaziridine undergoes HFIP-promoted regio- and diastereoselective ring-opening with pendant arene or heteroarene nucleophiles to deliver condensed δ-lactam products with excellent <i>anti</i>-selectivity.