Advancing Sustainable Synthesis of Cyclic Peptides by Integrating Aqueous Fmoc/ t -Bu Solid-Phase Peptide Synthesis with Disulfide Bond Formation and TFA/PFAS-Free Resin Cleavage

Universal Fmoc/t-Bu solid-phase peptide synthesis (SPPS) has long been intertwined with harmful substances such as dimethylformamide (DMF) and PFAS-classified trifluoroacetic acid (TFA). Having eliminated DMF and TFA from peptide synthesis by aqueous SPPS (ASPPS) [Pawlas, J.; Rasmussen, J. H. Circular Aqueous Fmoc/t-Bu Solid-Phase Peptide Synthesis. ChemSusChem 2021, 14, 3231-3236] and Brønsted acid-Lewis acid-induced resin cleavage [Pawlas, J.; André, C.; Rasmussen, J. H.; Ludemann-Hombourger, O. Brønsted Acid-Lewis Acid (BA-LA) Induced Final Deprotection/Peptide Resin Cleavage in Fmoc/t-Bu Solid-Phase Peptide Synthesis: HCl/FeCl₃ and AcOH/FeCl₃ as Viable PFAS-Free Alternatives for TFA. Org. Lett. 2024, 26, 6787-6791], we now report that ASPPS can be integrated with disulfide formation and TFA/PFA-free cleavage toward a new platform for sustainable synthesis of cyclic peptides, illustrated by synthesizing labor suppressant atosiban by both on-resin cyclization/cleavage and cleavage/solution cyclization approaches.