Rh(I)-Catalyzed Modular Synthesis of Axially Chiral Alkylidene Azacycloalkanes

The structural prevalence of chiral N-bridged cyclic scaffolds in pharmacologically relevant substances originates from their multifaceted biofunctional capacities, particularly in privileged natural product architectures. Despite advances in central chirality, the precise and expeditious construction of axially chiral N-bridged cyclic scaffolds with impeccably full enantiocontrol and highly structural diversity remains largely underexploited due to the lack of efficient synthetic methods. Here, we disclose an unprecedented Rh­(I)/diene-catalyzed carbene coupling reaction of arylboronic acid with β-hydroxy α-diazocarbonyl compounds through a remotely controlled desymmetrization strategy, furnishing a diverse array of three-dimensional nonatropisomeric axially chiral alkylidene N-bridged [3.2.1] and [3.3.1] ring systems. This straightforward methodology operates without redox requirements, demonstrating extensive applicability across diverse substrates (>50 examples) while maintaining exceptional control of chemo- and enantioselectivity (up to 97% yield, mostly 95–99% ee). The synthetic utility of these compounds was further validated via sequential elaboration processes, allowing for modular assembly of novel N-bridged bicyclic systems with configurationally defined axial chirality.