On-Resin Synthesis and Diversification of Macrocyclic Disulfide Bridge Peptidomimetics via Bifunctional...

Cyclic peptides represent an important class of therapeutic molecules, however, often require late-stage functionalization to address suboptimal pharmacokinetic properties. Solid phase bifunctional cyclization strategies that enable both macrocyclization and diversification within a single scaffold remain limited. Herein, we report a general on-resin platform that exploits the 5-iodo-1,4-triazole as a bifunctional macrocyclic disulfide bridge mimetic, enabling modular late-stage modification of cyclic peptides. The methodology was demonstrated across a diverse panel of peptides spanning 6-12 residue macrocycles, incorporating varied amino acid side chains, N-terminal protecting groups, and peptide topologies. Formation of the 5-iodo-1,4-triazole was compatible with functionally diverse sequences under Fmoc-based solid-phase peptide synthesis conditions, highlighting the robustness of the cyclization strategy. Optimization of on-resin Suzuki-Miyaura cross-coupling significantly reduced reaction times while maintaining high conversions, enabling efficient aryl diversification of the triazole linkage. To expand structural scope, a complementary on-resin Sonogashira cross-coupling protocol was developed, allowing direct installation of alkyl linkers, functional handles, and biologically relevant motifs that are inaccessible through aryl-based cross-coupling alone. Together, these orthogonal palladium-catalyzed transformations establish a unified, operationally simple platform for the synthesis and late-stage diversification of cyclic peptidomimetics, providing rapid access to structurally diverse macrocyclic peptides relevant to chemical biology and medicinal chemistry.