Investigation of the Optimal Phosphine for Improved Electrochemical Peptide Synthesis

Abstract

Peptides have been expected to be medicines with higher specificity and fewer side effects than conventional medicines. However, a longstanding problem that the huge amount of waste is produced in synthetic process is not resolved. One of the causes is use of coupling reagents. Although they facilitate efficient peptide bond formation, byproducts lead to accumulation of waste. To address the issue, we developed electrochemical peptide synthesis using triphenylphosphine (Ph3P) as a coupling reagent. Anodic oxidation of Ph3P generates radical cation to activate carboxylic acids and promote peptide bond formation, producing triphenylphosphine oxide (Ph3PO). Since the reduction of Ph3PO to Ph3P is achieved in various ways, Ph3P have a potential to be a recyclable coupling reagent, which would be one of the solutions. Actually, we succeeded in development of an electrochemical peptide synthesis applicable to all of canonical amino acids and recovering method of Ph3PO. Nevertheless, we found that this method is difficult to use for highly sterically hindered amino acids. To improve the reaction efficiency, we examined various phosphine derivatives instead of Ph3P. We will present our recent improvement of the electrochemical peptide synthesis and nature of phosphine radical cations in detail.