New green base for Fmoc removal in solid-phase peptide synthesis: 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), a promising sustainable alternative to piperidine

Developing greener synthetic methodologies requires replacing hazardous reagents with more sustainable alternatives. In solid-phase peptide synthesis (SPPS), piperidine is the standard base for Fmoc group removal, but its toxicity, environmental concerns, and regulatory restrictions have prompted the search for safer substitutes. This study evaluates various green bases based on their GSK greenness score and chemical–physical properties similar to piperidine. Their performance was assessed through deprotection kinetics tests in different green solvents, followed by efficiency evaluations in solid-phase synthesis. Among the tested bases, DBN demonstrated the highest efficiency, achieving rapid Fmoc removal at the lowest concentration across all green solvents. Additionally, DBN effectively minimized side reactions such as racemization, particularly in Anisole/NOP (75:25). Finally, DBN was tested in the synthesis of a model peptides, yielding comparable results to piperidine. These findings highlight DBN as a promising green alternative for SPPS, contributing to the advancement of more sustainable peptide synthesis strategies.