Biphasic electrochemical peptide synthesis

The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint. To overcome this issue, we report an electrochemical peptide synthesis in a biphasic system. Anodic oxidation of triphenylphosphine (Ph3P) generates a phosphine radical cation, which serves as the coupling reagent to activate carboxylic acids, and produces triphenylphosphine oxide (Ph3P]O) as a stoichiometric byproduct. In combination with a soluble tag-assisted liquid-phase peptide synthesis, the selective recovery of desired peptides and Ph3P]O was achieved. Given that methods to reduce Ph3P]O to Ph3P have been reported, Ph3P]O could be a recyclable byproduct unlike byproducts from typical coupling reagents. Moreover, a commercial peptide active pharmaceutical ingredient (API), leuprorelin, was successfully synthesized without the use of traditional coupling reagents.

Automated summary

An electrochemical peptide synthesis method has been developed to activate carboxylic acids in a biphasic system, with the stoichiometric byproduct Ph3P]O being recycled back into triphenylphosphine. This innovative approach not only reduces waste derived from coupling reagents, but also successfully synthesized a commercial peptide active pharmaceutical ingredient (API) leuprorelin without traditional coupling reagents.