Cobalt-Catalyzed Enantioselective Hydroalkylation of Oxa- or Azabicyclic Alkenes

作者：Xuyang Liu, Jia-Wang Wang, Deguang Liu, Jun Liu, Can Zhao, Yao Chen, Peng-Jie Yang, Zili Ren, Quan Gao, Yan Li, Xi Lu, Haiqun Cao, Yao Fu · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.5c13397 · 被引用次数：11 · 研究领域：Catalytic C–H Functionalization Methods、Synthetic Organic Chemistry Methods、Organoboron and organosilicon chemistry

Bridged bicyclic structures, exemplified by rigid oxa- and azabicyclic alkanes, are pivotal scaffolds in drug design and natural product synthesis due to their three-dimensional architecture and inherent ring strain. Functionalization of readily available bicyclic alkenes provides a potential pathway to synthesizing molecules with complex cyclic structures. However, strained bicyclic alkenes exhibit thermodynamic reactivity driven by strain energy release, which predominantly favors ring-opening pathways. In contrast, ring-retentive hydroalkylation─a direct method for synthesizing complex bridged bicyclic architectures─remains underdeveloped. Here, we present a cobalt-catalyzed enantioselective hydroalkylation strategy for bicyclo[2.2.1]alkenes that enables ring-retentive addition while constructing tertiary carbon stereocenters within oxa- or azabicyclic frameworks. Mechanistic investigations revealed that the hydrometalation of alkenes serves as the selectivity-determining step, where noncovalent interactions between the catalyst and substrate govern stereoisomeric differentiation. The protocol demonstrates broad compatibility with diverse alkyl iodides and bicyclo[2.2.1]alkenes, facilitating late-stage functionalization of bioactive molecules and enabling the efficient synthesis of antifungal agents with potent activity.