C-Terminal Functionalization Methods of Amino Acids, Peptides, and Proteins.

The functionalization of the C-terminus of amino acids, peptides, and proteins has been extensively studied for more than 150 years and is central to modern peptide synthesis. While most functionalization methods target the N-terminus or reactive residues, such as lysine, cysteine, or tyrosine, the chemo- and regioselective modification of the C-terminus remains relatively underdeveloped. In this review, we discuss strategies for C-terminal activation and functionalization, including classical coupling reagents, enzymatic modifications, photo- and electrochemical decarboxylation, and emerging catalytic approaches. Recent atom-efficient advances in the field that describe protective group-free syntheses while minimizing epimerization and improving chemo- and regio-selectivity are discussed enabling the modification of complex peptides and proteins. Furthermore, current limitations and remaining challenges in achieving general, selective, and broadly applicable C-terminal functionalization methods are highlighted.