Investigating green ethers for the precipitation of peptides after global deprotection in solid-phase peptide synthesis

Diethyl ether and methyl tert-butyl ether are the solvents most widely used for peptide precipitation after global deprotection in the last step of solid-phase peptide synthesis. Here we report peptide precipitation with the greener solvent cyclopentyl methyl ether. In addition to its preferable environmental, and health and safety (EHS) characteristics, cyclopentyl methyl ether does not have any handling difficulties and shows great stability in acidic media, thereby minimizing the possibility of fuelling side reactions. Peptides precipitated with either diethyl ether and cyclopentyl methyl ether showed identical HPLC profiles. This observation thus indicates that the use of the greener ether is not detrimental for the quality of the final product. Furthermore, cyclopentyl methyl ether and diethyl ether produced a similar amount of precipitated peptide. Therefore, we conclude that cyclopentyl methyl ether can efficiently replace the hazardous diethyl and tert-butyl methyl ethers for the precipitation of peptides after global deprotection.