Enantioselective Synthesis of Unnatural Carbamate-Protected α-Alkyl Amino Esters via N-H Bond Insertion Reactions

We have developed a method for highly enantioselective N-H bond insertion reactions of alpha-alkyl-alpha-diazoacetates and various carbamates cooperatively catalyzed by TpCu, where Tp = (hydrotris(4,5-bromopyrazolyl)borate), and a chiral spiro phosphoric acid. These reactions provide straightforward access to unnatural optically active N-carbonate alpha-alkyl-alpha-amino esters, which are widely used in artificial peptide synthesis. This mild method uses readily available starting materials and features a broad substrate scope, good functional group tolerance, good to high yields (58-88%), and high enantioselectivities (90-96% ee). The combination of the neutral copper catalyst TpCu and the chiral spiro phosphoric acid ensures the success of the reaction by inhibiting a beta-H migration reaction of a copper carbene intermediate and by promoting enantioselective proton transfer to an enolate intermediate.