Cobalt-Catalyzed Enantioselective Hydroalkylation of Oxa- or Azabicyclic Alkenes

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.