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...