Propylphosphonic Anhydride (T3P®) as Coupling Reagent for Solid‐Phase Peptide Synthesis

Abstract Amidation is the predominant reaction within the pharmaceutical setting, and it is attracting greater attention due to the increased demand for therapeutic peptides. The high therapeutic efficacy and safety profile of peptides have placed these molecules in prime position within the pharmaceutical arena, which is reflected by these molecules receiving several approvals from various regulatory agencies each year. In this context, the demand for developing efficient strategies for peptide synthesis has also risen. Although propylphosphonic anhydride (T3P®), which has been recently proposed as a green coupling reagent, has shown good performance in solution, it has never been applied to solid‐phase peptide synthesis (SPPS). Here we test the use of T3P® for SPPS. Satisfactory yields were achieved with a mild activation protocol. Various green solvents were tested and proved to be compatible with this coupling reagent. Several commonly used reagents cause allergic reactions or are susceptible to explosion under certain conditions. To overcome these issues, we propose T3P® as a potential alternative coupling reagent in SPPS.