Elevating 1-tert-Butyl-3-ethylcarbodiimide (TBEC) as a Reagent for Sustainable Peptide Synthesis: Quality Assessment and Minimizing Racemization, Precipitation, and Radical-Induced Side Reactions by TBEC/Oxyma Couplings in an Environmentally Sensible Solvent

The finding that the widely used peptide coupling reagents DIC and Oxyma form the toxic H-CN (McFarland, A. D. Org. Process Res. Dev. 2019, 23, 2099) has prompted studies aimed at H-CN minimization, attained, for example, by solvent engineering (Erny, M. Org. Process Res. Dev. 2020, 24, 1341) and by substituting DIC with TBEC (Manne, S. R. Org. Process Res. Dev. 2022, 26, 2894). Here, an integrated study of TBEC/Oxyma as peptide couplers is reported, focusing not only on the performance of TBEC in the couplings but also on its cost, hazards associated with its use, sustainability of the route of synthesis, the end of life strategies, as well as the potential impact of impurities in the reagent on the synthesis. TBEC/Oxyma-mediated peptide couplings in NBP/EtOAc (1:4) proceeded with minimal racemization, free of precipitation, and radical side reactions irrespective of TBEC quality. These results hold great promise for broad adoption of TBEC/Oxyma in suitable green media as a coupling strategy for sustainable peptide synthesis from an R&D lab to a manufacturing plant.