Late-Stage Functionalization of Peptides on Solid-Phase via Photochemical Decarboxylative Arylation

Late-stage functionalization of specific residues in a peptide provides a fast and straightforward method to unnatural amino acids. Here we provide a protocol for the photochemical conversion of redox-active esters formed from aspartic acid and glutamic acid. The reaction involves the formation of an electron-donor acceptor complex using the Hantzsch ester, which leads to radical decarboxylation under irradiation with purple light. The formed carbon radical then adds to a Nickel aryl bromide complex to facilitate C-C cross coupling. By using widely available aryl bromides a broad scope of unnatural aromatic amino acids can be accessed. Since all steps take place on solid support, the protocol is rapid and easy to perform.