C‐Terminal Functionalization Methods of Amino Acids, Peptides, and Proteins

ABSTRACT 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.