Chelation‐Assisted Metal‐Catalyzed Ligation and Cleavage Reactions for Chemical Biology

While bioorthogonal click chemistry has transformed chemical biology, chelation‐assisted transition‐metal catalysis has emerged as a powerful yet still underexplored alternative tool for studying biological processes. This review provides a comprehensive overview of recent chelation‐assisted methodologies involving designed coordinating substrates to enable the reactivity of metals such as Cu, Ru, and Pd within complex biological media. By pre‐organizing the catalytic center, chelating scaffolds effectively overcome the kinetic barriers and improve biocompatibility. These systems have been successfully used in site‐selective ligation for the synthesis of functional bioconjugates through chelation‐assisted cycloadditions or cross metathesis, but also in chelation‐assisted decaging reactions for the cleavage of protecting groups for controlled “turn‐on” bioactivities. These methodologies demonstrate robust utility across both in vitro and, in a few examples, in vivo applications, highlighting the strong potential of chelation‐assisted strategies in facilitating biocompatible, metal‐catalyzed transformations within the complexity of biological environments.