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Updated: Jan 15, 2026
Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
Copper-Catalyzed Asymmetric Nitrenoid Transfer to Access Fused δ-Lactams via HFIP-Assisted Aziridination and Cascade
Suhyeon Kim1,2, Eleonora Tufano3, Matteo Barilli3
1Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, South Korea.
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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 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.
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