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Greening the Solid-Phase Peptide Synthesis Process. 2-MeTHF for the Incorporation of the First Amino Acid and Precipitation of Peptides after Global Deprotection

Abstract:

In solid-phase peptide synthesis, dichloromethane is the predominant solvent used to incorporate the first amino acid on a 2-chlorotrityl chloride resin (via nucleophilic substitution) and Wang resin (via activation with carbodiimide in the presence of 4-dimethylaminopyridine). However, legal authorities have restricted the use of this solvent, as it is considered hazardous and a potential occupational carcinogen. Therefore, there is a need for an alternative that is easy to handle and poses less risk for the environment and more importantly for human health. Herein, we describe 2-methyltetrahydrofuran as a greener alternative for the incorporation of the first protected amino acids on both 2-chlorotrityl chloride and Wang resins. The amounts of several amino acids loaded on 2-chlorotrityl chloride and Wang resins using dry dichloromethane or 2-methyltetrahydrofuran were comparable. In addition, the use of 2-methyltetrahydrofuran rendered acceptable racemization and dipeptide formation in the case of Wang resin. This solvent can also be used to replace diethyl ether and tert-butyl methyl ether in the peptide precipitation step performed after final global deprotection. On the basis of our findings, 2-methyltetrahydrofuran emerges as a good alternative to the hazardous solvents currently used for amino acid incorporation and peptide precipitation. Furthermore, taking into account that 2-methyltetrahydrofuran proved effective for the elongation of the peptide in a solid-phase mode, we propose 2-methyltetrahydrofuran as a universal solvent for all solid-phase peptide synthesis steps, namely, incorporation of the first amino acid, assembly of the peptide chain, and precipitation of the final peptide.