Enhancing Atom Economy via Minimal Protection-Liquid Phase Peptide Synthesis (MP-LPPS) Using TBDC Salts/Oxyma Pure

The expansion of the oligopeptides segment in the pharmaceutical industry has driven increased efforts toward the development of sustainable and efficient synthetic methods consistent with modern green chemistry principles. The success of hybrid synthesis shifted the target from long linear sequences in SPPS or LPPS to short highly pure oligomers averaging 10–15 amino acids. Within this framework, liquid-phase peptide synthesis (LPPS) and solution-phase peptide synthesis (SolPPS) have gained increasing importance in recent years. Herein, we report the use of N-(3-(dimethylamino)propyl)-N′-tert-butylcarbodiimide tosylate (TBDC•TsOH) as a coupling reagent that improves atom economy (AE) and reduces process mass intensity (PMI) in MP-LPPS. This protocol eliminates chlorinated solvents and avoids the need for side-chain protection of arginine, histidine, tyrosine, and tryptophan. Challenging peptide sequences were obtained in high yield and purity using 2-methyltetrahydrofuran (2-MeTHF) as primary solvent in MP-LPPS. The broad solubility of TBDC•TsOH enables its application in solution-phase coupling as an alternative to N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC•HCl). Overall, these results consistently increased the sustainability of TAG-assisted Liquid-Phase Peptide Synthesis.