Diastereodivergent Synthesis of Multi-Substituted Cyclohexanes via Alkene Hydroamidation

The construction of three-dimensional (3D) organic molecular structures is pivotal in modern organic chemistry. For disubstituted cyclohexanes, substituent orientation dictates thermodynamic stability, physicochemical properties, and biological activities, but precise stereocontrol of saturated cycloalkane substituents is challenging. Hydrogenation of substituted cyclohexanones/cyclic imines is a classic model for multi-substituted cyclohexane stereochemistry, in which stereoselectivity is governed by steric and electronic effects. In contrast, stereocontrol of exocyclic C=C bonds remains a major hurdle. Herein, we achieved diastereodivergent hydroamidation of methylenecyclohexanes: a nickel catalytic system efficiently synthesizes 1,4-cis/trans and 1,3-cis/trans isomers, while a cobalt system realizes 1,2-cis/trans stereodivergence. The core achievement lies in the differentiated active catalytic species strategy, which precisely regulates the spatial structure and electronic properties of metal-hydride or metal-functional group species. This work broadens the chemical space for multi-substituted cyclohexane synthesis, provides a powerful tool for the preparation of sp3-rich drug molecules, and offers an important case for research on substituted cyclohexane stereochemistry.