Avoiding the Hidden Costs of Peptide Synthesis: THIQ in DMI as an Alternative Fmoc-Deprotection Reagent

For over half a century, piperidine in N,N-dimethylformamide (PPR/DMF) has served as the gold standard for fluorenylmethyloxycarbonyl (Fmoc) deprotection in solid-phase peptide synthesis (SPPS), praised for its cost-effectiveness and robust performance. However, shifting priorities now place greater emphasis on occupational health, environmental impact, and production safety rather than simply minimizing raw material costs. As peptide synthesis scales up, it faces increasing global regulatory pressures. Traditional PPR/DMF reagents, known for their strong odor, instability, and poor material compatibility, are increasingly unsuited to modern peptide synthesis requirements. This study identifies tetrahydroisoquinoline in N,N′-dimethylimidazolidinone (THIQ/DMI) as a viable alternative, providing comparable deprotection efficiency while mitigating these drawbacks. Our findings suggest that, despite the apparent affordability and efficiency of PPR/DMF, the hidden costs associated with its use render THIQ/DMI a more sustainable and economically favorable choice.