CuH‐Catalyzed Asymmetric Desymmetrization of Cyclobutenes via Stereodivergent Hydroamination

Enantioenriched multisubstituted aminocyclobutanes (ACBs) are prevalent in numerous promising drug candidates due to their favorable pharmacological attributes. However, the catalytic asymmetric synthesis of multisubstituted ACBs remains underdeveloped. To tackle this challenge, this article presents the CuH‐catalyzed asymmetric hydroamination of cyclobutenes through a desymmetrization approach. This protocol efficiently yields a diverse array of trisubstituted ACBs with high yields and excellent diastereo, as well as enantioselectivities. Significantly, the diastereoselectivity of the reaction can be finely tuned by altering the ligand, thereby enabling the stereodivergent synthesis of related bioactive compounds. The practical utility of this method is further underscored by a series of subsequent transformations of the products, which include the first asymmetric synthesis of two pharmaceutically active molecules. Moreover, density functional theory calculations have been employed to elucidate the pivotal role of ligands in achieving the stereodivergence of the reaction.