Modular Synthesis of Chiral Multi-Substituted Cyclohexanes via Cobalt-Catalyzed Enantioselective Desymmetrizing Hydroalkylation

Chiral, multi-substituted six-membered carbocycles with high sp 3 character are privileged frameworks in pharmaceuticals, agrochemicals, and natural products, owing to their enhanced binding affinity, metabolic stability, and three-dimensional molecular recognition. However, the enantioselective construction of such densely functionalized all-carbon rings bearing multiple C(sp 3 ) stereocenters remains a major synthetic challenge. Here, we report a cobalt-catalyzed asymmetric remote hydroalkylation of cyclohexene derivatives, enabling modular and enantioselective access to multisubstituted, chiral six-membered carbocycles. This transformation proceeds under mild conditions with excellent regio- and enantioselectivity, allowing for precise distal stereocontrol across a broad substrate scope. The resulting products feature high Fsp 3 content and are readily amenable to diversification via radical C–C coupling, photoredox transformations, or Curtius rearrangement. This work provides a powerful strategy for the streamlined synthesis of sp 3 -rich, stereochemically complex carbocycles, expanding the synthetic toolbox for 3D molecular architectures in drug and materials discovery.