To address this issue, we have developed an electrochemical peptide synthesis utilizing triphenylphosphine (Ph3P) in a biphasic system (MeCN-c-Hex).2 Anodic oxidation of Ph3P generates a phosphine radical cation, which serves as the coupling reagent to activate carboxylic acids followed by peptide bond formation and production of triphenylphosphine oxide (Ph3PO) as a stoichiometric byproduct.3 Given that methods to reduce Ph3PO to Ph3P have been reported,4 Ph3P can be a recyclable byproduct unlike byproducts from typical coupling reagents.
In the optimized condition, we found that all canonical amino acids can be applied to electrochemical peptide bond formation and succeeded in the selective recovery of desired peptides and Ph3PO in combination with a soluble tag-assisted liquid-phase peptide synthesis. Moreover, a commercial peptide active pharmaceutical ingredient (API), leuprorelin, was successfully synthesized without the use of traditional coupling reagents.
Reference
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2. S. Nagahara, Y. Okada, Y. Kitano, K. Chiba, Chem. Sci., 2021, 12, 12911–12917.
3. A. Palma, J. Cardenas and B. A. Frontana-Uribe, Green Chem., 2009, 11, 283–293.
4. D. Hérault, D. H. Nguyen, D. Nuel and G. Buono, Chem. Soc. Rev., 2015, 44, 2508–2528.