Phosphite-Mediated Peptide Bond Formation through Fragment Condensation

Triaryl phosphites are attracting attention as environmentally friendly reagents for condensation reactions, particularly for peptide bond formation. Peptide fragment condensation is an efficient strategy for the synthesis of oligopeptides. Because most bioactive peptides are oligopeptides, parallel synthesis via fragment condensation could improve operational efficiency and reduce the use of excess reagents and solvents. However, activation of the C-terminus can promote epimerization at the adjacent stereocenter through oxazolone formation. In this study, we applied tri(p-tolyl)phosphite to oligopeptide synthesis by peptide fragment condensation. This method suppressed epimerization even during fragment condensation and was applicable to a variety of peptides bearing diverse functional groups, including bioactive peptides. Furthermore, some amino acids with unprotected side chains were compatible with this reaction. The utility of this approach was validated through the synthesis of hexapeptide-10 in 10 steps with a 55% overall yield.