Chiral Isourea-Catalyzed Enantioselective Carbene Insertion into an N–H Bond through a Double Proton-Transfer Process

The development of novel chiral catalysts and the discovery of new mechanisms remain central to the advancement of asymmetric catalysis. Chiral hydrogen-bond-donor (HBD) catalysts have proven to be effective for mediating asymmetric proton-transfer reactions and are therefore widely applied in enantioselective N-H bond insertions. Herein, inspired by biological processes, we report a class of chiral isourea catalysts that enable highly enantioselective amide N-H insertion with α-alkyl diazo esters. Mechanistic and computational studies uncovered an unprecedented double proton-transfer mechanism, which is brought about by the unique properties of the isourea catalyst and forms the basis for the catalyst's exceptional reactivity and enantioselectivity.