Zn-Catalyzed Nicotinate-Directed Transamidations in Peptide Synthesis

A chemoselective and catalytic transamidation for peptide synthesis is described. Transamidation under Zn catalysis is chemoselectively achieved by amino acid amide/peptidic amide derivatization with a tert-butyl nicotinate (tBu nic) directing group. The directing group could be easily introduced on protected amino acid amides via Pd-catalyzed amidation with tBu 2-chloronicotinate (tBu NicCl). Under standard peptide coupling/deprotection conditions, the tBu nic equipped amino acid amides proved to be fully inert allowing to be easily built-in in complex molecules. The disclosed method was evaluated in the synthesis of diverse dipeptides, in dipeptide segment coupling, in side chain modification of a solid supported tetra/pentapeptide, and in the macrocyclization of a heptapeptide.