Recent Advances in Bioconjugation of Aromatic Amino Acid Residues by a Reactivity‐Guided Approach

The bioconjugation of aromatic amino acids has emerged as a powerful strategy in chemical biology, drug discovery, and biomolecular research. Beyond the classical targeting of cysteine and lysine, aromatic amino acids residues offer higher selectivity owing to their lower abundance and critical roles in intermolecular interactions. Current synthetic approaches include substitution reactions, addition reactions, free-radical reactions, metal-catalyzed transformations, and biocatalytic approaches, enabling precise and versatile modifications in cells, tissues, and at the proteome level. In recent years, transition-metal catalysis and radical processes have dominated the field, with particular emphasis on tyrosine and tryptophan. This review provides a critical analysis of advances from the past 3 years, categorizing methodologies by reaction mechanism and highlighting how the intrinsic reactivity of aromatic amino acids can be harnessed for site-selective functionalization, ultimately expanding the accessible chemical space across all these residues.