Greener Solid Phase Peptide Synthesis: Improved Procedure for Distributed Drug Discovery in Undergraduate Laboratories

We report a revised solid-phase peptide synthesis (SPPS) protocol for the Distributed Drug Discovery (D3) program that integrates green chemistry principles into the undergraduate laboratory setting. The updated protocol replaces hazardous solvents and reagents with greener and more accessible alternatives: ethyl acetate, 4-methylpiperidine, and T3P. This updated protocol reduces total solvent use by approximately 20%, lowers costs, and minimizes health and environmental risks, while achieving the requisite product yields and purities for biological screening. The revised experiment was implemented in second-semester organic chemistry courses, where students successfully synthesized fluorophenylalanine-derived dipeptides and analyzed products using TLC, LC-MS, and 1H NMR. A green chemistry worksheet was created as a complementary classroom activity to teach sustainability principles in the context of peptide synthesis. This work demonstrates a scalable approach to combining authentic drug discovery research with sustainable laboratory practices, providing a model for course-based undergraduate research experiences that promote both technical skill development and environmental responsibility.