We describe a novel approach to the chemical ligation of peptide segments with no protecting groups and no activation of the C-alpha-carboxyl group. The key reaction of this approach is based on the intramolecular O,N-acyl transfer reaction to achieve high effective molarity so that two closely neighbored functional groups can react efficiently and selectively with each other. The specificity of this approach is contributed by the facile ring formation between the carboxyl component bearing an ester glycolaldehyde and the amino component bearing a 1,2-amino thiol group such as a N-terminal cysteine residue. The feasibility of this scheme was verified by model studies on small compounds and the synthesis of a pentadecapeptide.