Synthesis of Macrocyclic Peptides via Photochemical Radical Thiol–yne Reaction

Peptide macrocyclization offers a versatile method for enhancing peptide stability, cell permeability, and biological activity. Herein, we report a radical-mediated, thiol-yne process for peptide macrocyclization, furnishing vinyl sulfide products. Our robust methodology enables the formation of cyclic peptides under mild conditions, generating a disulfide bioisostere to a range of biologically relevant neuropeptides, identifying a novel vinyl sulfide analogue of oxytocin with enhanced potency and redox stability over the parent compound. Cyclization was achieved using UV-A or blue LED irradiation, in either organic or aqueous solvents. The adaptation of the methodology for late-stage modification of cyclic peptides using maleimide tags is also described, underscoring the broad utility of the method.