A Versatile Strategy for Head-to-Tail Macrocyclization and Traceless Backbone Editing of Short Peptides

The efficient synthesis of short, head-to-tail macrocyclic peptides remains a fundamental challenge in chemical biology and drug discovery, particularly for homochiral sequences lacking turn-inducing residues. We hypothesized that thioimidates─a dynamic, backbone-localized functional group with a near 1:1 cis/trans-isomeric equilibrium─could promote macrocyclization by biasing the formation of preorganized conformers while also enhancing peptide solubility. Herein, we demonstrate that incorporation of a single thioimidate dramatically improves the efficiency of macrocyclization, enabling high-yielding cyclizations of tetra- and pentapeptides that fail under conventional conditions. A mild Ag(I)-mediated protocol then converts the thioimidate to the native amide, allowing access to previously inaccessible macrocyclic peptides. Post cyclization, the thioimidate also serves as a versatile and traceless branch point for backbone editing, furnishing native and ¹⁸O-isotopically labeled amides, in addition to thioamides, amidines, and secondary amine pseudopeptides from a common precursor. These transformations expand the structural and functional diversity of macrocyclic peptides using readily implementable synthetic workflows that are compatible with SPPS, thereby positioning thioimidates as a powerful platform to access previously inaccessible cyclic peptide scaffolds.