Glycerol derived solvents for sustainable and more efficient peptide synthesis

Abstract: Peptides are reshaping the pharmaceutical landscape, yet chemical manufacturing mainly hinges on the dipolar aprotic solvents N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP) which are toxic to both humans and the environment. We introduce trioxabicyclooctanes (TBOs), tunable dipolar solvents made in two steps from bio glycerol, as drop in replacements. The lead TBO solvent, MTBO, accelerates couplings and enables reducing amino acid equivalents from 2.0 to 1.1, while maintaining performance. In the synthesis of difficult sequences in batch (Barstar[75–90], 68% vs 65% in DMF) and in flow (Neurokinin A, 68% vs 51% in DMF), crude purities are improved compared to DMF. Practical handling includes moderate boiling points and viscosities, and benign toxicology. Technoeconomic analysis shows that the two-step process can lead to pricing competitive to DMF. Our findings show how waste-glycerol can be turned into performant DMF replacements without relying on N or S atoms, for SPPS, and the broader chemical industry.