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

## TL;DR

This review discusses recent methods for modifying aromatic amino acids in biomolecules using their natural reactivity, enabling precise chemical changes for research and drug development.

## Contribution

The paper introduces a reactivity-guided approach for site-selective modification of aromatic amino acids, expanding chemical possibilities in bioconjugation.

## Key findings

- Transition-metal catalysis and radical processes are dominant in modifying tyrosine and tryptophan.
- Aromatic amino acids offer higher selectivity due to their lower abundance and key roles in molecular interactions.
- Recent methods enable precise modifications at the cellular, tissue, and proteome levels.

## Abstract

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.

This review highlights recent advances in the bioconjugation of aromatic amino acids residues, focusing on strategies that leverage their inherent chemical reactivity to enable precise and versatile modifications of biomacromolecules, illustrating relevant applications.© 2025 WILEY‐VCH GmbH