Peptide Coupling Reagents, More than a Letter Soup

The procedures used to combine two amino acid residues to form a peptide are referred to as coupling methods. Coupling involves attack by the amino group of one residue at the carbonyl carbon atom of the carboxy-containing component that has been activated by the introduction of an electron-withdrawing group. Several parameters are used to control racemization during peptide-coupling reactions. A key issue is the use of an appropriate N-protecting group. It is pertinent to remember that two types of acyl groups are involved in couplings, namely, those originating from an N-alkoxycarbonylamino acid and those from a peptide. The most traditional approach used to form peptide bonds is the carbodiimide method, using dicyclohexylcarbodiimide. A unique approach to peptide synthesis is the preparation of a derivative of the N- alkoxycarbonylamino acid that is stable enough to be stored and yet reactive enough to combine with an amino group when the two are mixed.