Advances in the synthesis of cyclic peptides, pseudopeptides, and peptoids by CuAAC-mediated macrocyclization

Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) stands as paradigmatic reaction within the click chemistry expansive repertoire. This bio-orthogonal transformation generates 1,4-disubstituted 1,2,3-triazole linkages serving as privileged disulfide bridge and peptide-bond mimetics. In this review, we comprehensively examine the use of CuAAC for constructing macrocyclic peptides, pseudopeptides, and peptoids, particularly emphasizing both homodetic and heterodetic architectures. We critically analyze innovative synthetic strategies enabling efficient macrocyclization, mechanistic principles governing regioselective triazole formation, and practical solutions for suppressing di- and oligomerization side-reactions. Furthermore, we highlight how strategic incorporation of triazole can fine-tune macrocycle conformation and enhance biological properties compared with their linear precursors. This review ultimately provides researchers with a strategic framework for using the remarkable efficiency and precision of CuAAC in macrocyclic peptide-based drug discovery and biomaterial engineering.