[Unusual amidation reaction of Asn-containing glycopeptide antibiotics using the coupling reagent PyBOP]

The coupling reagent PyBOP is widely used for the synthesis of different peptides and their amides, particularly for carboxamides of glycopeptide antibiotics of vancomycin or teicoplanin groups. The amidation reaction of the peptide core of the glycopeptide antibiotic eremomycin (I) with highly reactive amines in the presence of PyBOP is usually not accompanied by the formation of side products. However, the amidation of I with bulky amines (e.g., decyl amine and adamantyl amine) in the presence of PyBOP and Et3N or di-(i-Pr)2EtN (pH - 8.5) yielded N-unsubstituted carboxamide of eremomycin (Ia) as an admixture. The reaction of (I) or vancomycin (II) with an excess of PyBOP and Et3N (pH - 8.5) without addition of an amine or ammonia gave a mixture of products which contained higher amounts of the corresponding N-unsubstituted carboxamides (-20%). The structures of the samples of Ia and vancomycin amide (IIa) were proved by 1H NMR and ESI MS methods and confirmed by comparing with the authentic samples.