Enantioselective synthesis of aziridine-fused polycyclic architectures via a catalytic asymmetric aza-Darzens reaction and reductive cyclization

Abstract

Aziridine-fused polycyclic architectures are prevalent in biological and natural molecules, but the asymmetric synthesis of such strained frameworks with multiple chiral centers is highly challenging and has not yet been achieved. Herein, we disclose a two-step approach for the asymmetric synthesis of aziridine-fused polycyclic molecules bearing the heterotricyclo[4.3.0.0^2,9]decane skeleton. The core aziridine ring was first formed by a chiral phosphoric acid-catalyzed asymmetric aza-Darzens reaction of quinoxalin-2(1H)-ones with α-diazoacetates. Subsequent LiAlH₄-mediated reductive cyclization constructed the tetrahydrofuran ring, simultaneously establishing the 6–5–3 tricyclic system with stereochemical retention. Moreover, the target products can be obtained by a one-pot sequential reaction procedure. This method affords chiral aziridine-fused polycyclic molecules with high enantioselectivity and diastereoselectivity (up to 96% ee, >20 : 1 dr) over a broad substrate scope. This finding also establishes a general strategy for the asymmetric construction of polycyclic fused skeletons.