Sustainable Fragment Peptide Synthesis (SFPS): Leveraging Oxyma as a Dual Resin Cleavage-Peptide Coupling Agent

Coupling of fully protected peptide fragments (FPPFs) released off acid labile polymer supports such as 2-chlorotrityl chloride (CTC) resin is a powerful peptide synthesis approach used from R&D to manufacturing type 2 diabetes/obesity drugs on a ton scale. Nevertheless, cleavage of acid labile FPPF resins typically entails PFAS-classified TFA as a reagent and suspected carcinogen DCM as a solvent while necessitating laborious work-ups and isolations. Here, in an approach we term sustainable fragment peptide synthesis (SFPS), a cleavage of FPPFs off 2-chlorotrityl (2-CT) resin was carried out using coupling additive ethyl cyanohydroxyiminoacetate (Oxyma) in EtOAc. The cleaved FPPF was not isolated but rather coupled with another peptide resin using a carbodiimide as a coupler and Oxyma from the cleavage as an additive. Showcasing the power of SFPS, a two Cys-(Trt) containing FPPF resin formed by a process leveraging Oxyma as a dual cleavage-coupling agent was cyclized to a disulfide containing FPPF resin which upon an Oxyma-induced cleavage afforded a disulfide containing FPPF, opening the door to the world of modular SFPS as a means of accessing a variety of complex peptide architectures.