Peptide Synthesis Using Unprotected Amino Acids

The mandatory use of Nα-protecting group for amino acids, which invokes protection and deprotection operations and imposes a significant negative effect on environment sustainable development, constitutes the essential principle of peptide synthesis. Using unprotected amino acids for peptide synthesis represents an ideal and attractive greening strategy. However, this strategy has been unsuccessful for more than 60 years owing to the severe epimerization that occurs during N→C peptide chain elongation. The first general unprotected amino acid strategy was developed in this study by employing a ynamide coupling reagent, which successfully addressed the notorious epimerization issue. This step- and atom-economic strategy is not only effective for synthesizing dipeptides but also adaptable to longer peptides containing more than two amino acids. The synthetic application of this method was exemplified by successful syntheses of a range of peptide active pharmaceutical ingredients (APIs). It is foreseeable that this study will bring about disruptive technologies to both academia and industry.