In polypeptide synthesis, the initial consideration for using anhydride can be traced back to Theodor Curtius' early research about benzoylacetic acid synthesis in 1881. Besides the benzoylacetic acid is gained, BZ-Glyn-OH(n=2-6) is obtained in the reaction from the aminoacetic acid silver and benzoyl chloride. In the early days, when it is treated with benzoyl chloride, N-benzoylacetic acid or N-benzoyl peptide formed the reactive intermediate asymmetric anhydrideand reacted with benzoic acid.
About 70 years later, Theodor Wieland took advantage of these discoveries to use mixed anhydride for contemporary polypeptide synthesis. At present, in addition to this method, the N-carboxylic anhydride (NCA, Leuchs anhydrides) formed in the molecule by symmetric anhydride and carboxyl of carbamic acid, which is also condensed by peptide. It should be mentioned that asymmetrical anhydride is often involved in the acylation of biochemical reactions.