Troubleshooting When Using γ‑Valerolactone (GVL) in Green Solid-Phase Peptide Synthesis

The synthesis of peptides for both research and API production is conveniently carried out using the solid-phase strategy. However, the main drawback of this approach is the large amounts of hazardous solvents required. In this regard, several pharmaceutical industries participating in the ACS Green Chemistry Institute Pharmaceutical Roundtable have shown interest in identifying green solvents for solid-phase peptide synthesis. In a previous study, our group proposed γ-valerolactone (GVL) as a replacement for the hazardous DMF. However, during Fmoc removal of the less hindered Gly residue, acylation with GVL can take place. Here we demonstrate that this side reaction can be circumvented by the incorporation of the corresponding dipeptides that carry Gly as the C-terminal. These dipeptides were conveniently prepared using CTC resin, which can be reused after activation. Using this strategy, GVL proved to be slightly superior to DMF for the synthesis of the demanding ABRF 1992 peptide, which contains five Gly residues.