SNAR-BASED MACROCYCLIZATION - AN APPLICATION TO THE SYNTHESIS OF VANCOMYCIN FAMILY MODELS

The first examples of macrocyclization using the intramolecular SNAr reaction are reported. The method has allowed the efficient preparation of the elusive 16-membered macrocyclic COD and DOE rings related to vancomycin. The mild conditions used allow the incorporation of very racemization-prone amino acids, such as p-methoxyphenylglycine, into the peptide chain. After serving as an activator, the nitro group ortho to the diaryl ether linkage is converted either into a chlorine or a hydrogen atom, thus achieving the substitution pattern found in the vancomycin family of glycopeptides. When compound 20 was submitted to the same macrocyclization conditions, two atropisomers 21 and 22 were isolated and characterized.