Green Solid-Phase Peptide Synthesis: Oxyma-Triggered Spectrophotometric Monitoring of Residual Piperidine

Solid-phase peptide synthesis (SPPS) is an efficient platform technology for synthesizing synthetic peptides but has an environmental downside due to the use of vast amounts of toxic solvents. In recent years, a big effort has been made to replace these solvents with more environmentally benign alternatives; however, this work has not had a significant effect on reducing the PMI and carbon footprint of SPPS. Herein, we demonstrate that by adding a low concentration of Oxyma Pure to the waste stream after Fmoc-removal, a simple real-time online UV–vis monitoring system can quantify piperidine with the needed sensitivity. In addition to the potential for reducing washing volumes after Fmoc-removal, this inexpensive and easy-to-implement process analytical tool allows the determination of completed washing by visual inspection due to the yellow color of Oxyma Pure in the presence of piperidine. Moreover, manual sampling of the waste stream is not needed, which reduces the overall process time. Importantly, the methodology was found to be compatible with green SPPS performed in 10–50% DMSO in the EtOAc mixtures.