Macrocyclizations toward the assembly of Tyr-linked cyclopeptides

The synthesis of cyclic peptides remains an unmet challenge of capital importance within medicinal chemistry and drug discovery. In recent years, numerous macrocyclization strategies have been developed, often relying on the coupling of amino acids such as tryptophan, lysine, and cysteine. However, ring-closing approaches that directly involve a tyrosine (Tyr) residue have received comparatively little attention. This review provides a critical analysis of advances from the last years within the assembly of cyclopeptides through transformations in which the phenolic side-chain of the Tyr unit plays a direct role in the cyclization step. • Cyclic peptide synthesis remains a major challenge in medicinal chemistry and drug discovery. • Classical macrocyclization methods often rely on amino acids like tryptophan, lysine, and cysteine. • Tyrosine-involved cyclization strategies have been relatively underexplored compared to other amino acids. • This review analyzes recent advances in cyclopeptide synthesis where the phenolic side chain of tyrosine directly participates in the cyclization step.