Inverse Peptide Synthesis Using Transient Protected Amino Acids.

The mandatory protection of the α-amino group of α-amino acids in peptide synthesis invokes protection and deprotection operations and imposes great negative effect on sustainable development. Using unprotected amino acids for peptide synthesis represents an attractive greening strategy but has been kept unsuccessful for more than 60 years because of the severe epimerization encountered in N → C peptide chain elongation. This challenge has been overcome by ynamide coupling reagent employing a transient protection strategy. This article describes a practical protocol for inverse peptide elongation using unprotected amino acids. In this method, transient protection, activation, aminolysis, and in situ deprotection were performed in one pot, and thus avoiding the purification of intermediates. The application potential of this method was exemplified by the long peptide synthesis and solid-phase peptide synthesis.