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.