Unusual amidation reaction of asparagine-containing glycopeptide antibiotics in the presence of (benzotriazole-1-yl)oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP)

Abstract

The coupling reagent (benzotriazole-1-yl)oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) is widely used for the synthesis of different peptides and their amides, particularly carboxamides of glycopeptide antibiotics of the vancomycin or teicoplanin groups. The amidation reaction of the carboxyl group of the seventh amino acid residue (AA7) in antibiotics in the presence of PyBOP is not usually accompanied by the formation of significant amounts of byproducts. However, the amidation of eremomycin (I) with bulky amines (e.g., decyl amine and adamantyl amine) in the presence of PyBOP at pH ∼8.5 (Et3N or (i-Pr)2EtN) yielded N-unsubstituted carboxamide of eremomycin (Ia) as an admixture. The interaction of asparagine-containing antibiotics (eremomycin or vancomycin) with the excess of PyBOP and Et3N (pH ∼8.5) in the absence of amine or ammonia led to the formation of still larger amounts of corresponding unsubstituted AA7-amides (∼20%). Their structure was determined by 1H NMR and ESI MS methods and confirmed by comparing with authentic samples. It is assumed that the amide group of the asparagine residue (AA3) is the source of ammonia in the unususal amidation reaction of Asn-containing antibiotics.