Regioselective reductive transamination of peptidic amides enabled by a dual Zr(IV)–H catalysis

Summary

An amide group, which is a common structural motif of peptides and biologically active molecules, is a highly attractive target for catalytic transformations. Despite its high synthetic potential, the chemical inertness of the amide bond, owing to its resonance stabilization, has rendered this approach challenging. Existing catalytic modes essentially include metal-catalyzed carbon–nitrogen bond activation, transamidation, and catalytic amide reduction. Herein, we report an unprecedented protocol of catalytic reductive transamination of amides to amines of exchanged identities. Through the intermediacy of aminals, combinations of amides with a wide range of external amines lead to a variety of mono- and diamines in good yields with high compatibility of functional groups and retentions of chirality. Regioselective post-modifications of oligomeric peptide derivatives bearing multiple amide motifs have also been realized, and the origin of site-selectivity has been explained by both experimental studies together with DFT calculations.