Re-evaluating the stability of COMU in different solvents

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• COMU (Oxyma-based uronium coupling reagent) offers advantages like solubility and water-soluble byproducts.
• Classical benzotriazole reagents have limitations, including hydrolytic instability in DMF, restricting automated peptide synthesis.
• Hydrolytic instability of COMU in DMF limits its application in automated peptide synthesizers.

Purpose of the Study:

• To evaluate the hydrolytic stability of COMU in alternative solvents: γ-valerolactone (GVL), acetonitrile (ACN), and N-formylmorpholine (NFM).
• To compare the hydrolytic stability of COMU in these solvents against its stability in DMF.
• To assess the feasibility of using COMU in GVL or ACN for synthesizing complex peptides.

Main Methods:

• Hydrolytic stability of COMU was assessed after 24 hours in GVL, ACN, NFM, and DMF.
• Quantitative analysis of COMU remaining in each solvent was performed.
• Synthesis of challenging decapeptides (Aib-ACP and JR) using COMU in GVL or ACN was conducted.

Main Results:

• COMU exhibited significantly higher hydrolytic stability in GVL (88%) and ACN (89%) compared to DMF (14%) after 24 hours.
• Successful synthesis of the Aib-ACP decapeptide and JR decapeptide was achieved using COMU dissolved in GVL or ACN.
• Fmoc amino acids were effectively dissolved in DMF during the peptide synthesis experiments.

Conclusions:

• GVL and ACN are superior solvents to DMF for maintaining COMU's hydrolytic stability.
• COMU dissolved in GVL or ACN is a viable and effective reagent for automated peptide synthesis, overcoming DMF limitations.
• This finding expands the utility of COMU for efficient and reliable peptide synthesis, particularly in automated platforms.