Chemical Control Methods for Intramolecular Ring-Closing Selectivity in Peptide Macrocyclization

Peptide macrocyclization is a pivotal strategy in the development of bioactive cyclic peptides, yet achieving precise intramolecular ring-closing selectivity remains a formidable synthetic challenge. Multiple competing reaction pathways, including undesired intermolecular oligomerization, self-cyclization at alternative nucleophilic sites, and epimerization, frequently compromise the yield and fidelity of the desired macrocyclic product. To elucidate the primary factors governing intramolecular ring-closing selectivity during peptide macrocyclization and the underlying mechanistic principles, this review systematically examines the effects of precursor conformation, the presence of multiple reactive sites, and competitive side reactions on ring-closing behavior. Drawing upon a comprehensive analysis of recent literature, we outline three principal regulatory strategies: conformational pre-organization through template-assisted or solvent-mediated folding, reaction site orientation via protecting group adjustment and steric shielding, and reaction system control encompassing reagent selection, temperature optimization, and solvent engineering. The analysis reveals that these distinct regulatory approaches operate by modulating spatial accessibility, site-specific reactivity, and kinetic competition, respectively, and that their overall effectiveness is jointly constrained by ring size and sequence characteristics. Appropriately matching regulatory methods to the structural features of the target peptide significantly enhances the selectivity and controllability of the desired ring closure. This review provides a practical framework for the rational design of selective peptide macrocyclization protocols and highlights emerging opportunities in the field.