Desymmetrization of <i>meso</i> -Pyrrolidines via Oxoammonium-Catalyzed Enantioselective Hydride Transfer

We report the oxidative desymmetrization of urea-protected pyrrolidines via site-selective hydride transfer from enantiotopic C-H bonds. The optimal oxoammonium-peptide conjugate catalyst provided over 90% <i>ee</i> across all tested pyrrolidines, providing products that can readily undergo subsequent N-deprotection and other derivatization reactions to form medicinally relevant compounds. We isolated key on-cycle catalytic intermediates, which allowed us to elucidate both the mechanism of catalytic activation and the origin of stereochemical induction in detail. In particular, a stereochemical model for asymmetric induction emerged from analyzing a covalent catalyst-substrate adduct, which served as an isolable analog of the enantiodetermining transition state. In this model, a tight hydrogen bond between the urea protecting group and the peptide directs the asymmetric hydride transfer.