(Digital Presentation) Electrochemical Peptide Synthesis Utilizing Triphenylphosphine (Ph₃P) in a Biphasic System

Abstract

Recently, peptides have been recognized as candidates for medium molecular medicines, which refers to pharmaceutical compounds whose molecular weights are roughly in the 1000 to 5000 range. This class of medicines has more specificity and fewer side effects than conventional small molecular medicines. However, an amount of waste derived from coupling reagents is regarded as a serious drawback of peptide synthesis from a green chemistry viewpoint.1 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 1. M. C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou, S. G. Koenig, J. D. Hayler, M. R. Hickey, S. Hughes, M. E. Kopach, G. Moine, P. Richardson, F. Roschangar, A. Steven and F. J. Weiberth, Green Chem., 2018, 20, 5082–5103. 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. Figure 1