Work

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

Year: 2025

Type: article

Abstract: 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 remains a great challenge due to the lack of strategic routes to the multiple contiguous chiral centers, particularly in case of thermodynamically unstable cis-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 N-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 N-acylaziridine undergoes HFIP-promoted regio- and diastereoselective ring-opening with pendant arene or heteroarene nucleophiles to deliver condensed δ-lactam products with excellent anti-selectivity.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c14319