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.

手性氮桥环骨架（chiral N-bridged cyclic scaffolds）在药理学相关物质中的广泛分布，源于其多维度的生物功能特性，尤其在优势天然产物结构骨架中尤为显著。尽管中心手性化学领域已取得诸多进展，但由于缺乏高效合成方法，精准且快速构建兼具完美对映控制与高度结构多样性的轴手性氮桥环骨架，在很大程度上仍未得到充分开发。本文报道了一种前所未有的Rh(I)/二烯（diene）催化的芳基硼酸与β-羟基-α-重氮羰基化合物的卡宾偶联反应，通过远程控制的去对称化策略，构建了一系列多样化的三维非阻转异构型轴手性亚烷基氮桥环[3.2.1]与[3.3.1]环系。该简便方法无需氧化还原条件，对多种底物展现出广泛的适用性（含超过50个反应实例），同时在化学选择性与对映选择性上实现了优异的控制：最高产率可达97%，多数产物的对映体过量值为95%~99%。通过后续衍生化过程进一步验证了此类化合物的合成实用性，可模块化组装得到具有明确构型轴手性的新型氮桥双环骨架。