ASYMMETRIC SYNTHESIS OF VANCOMYCIN ANTIBIOTICS

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The first member of the vancomycin family of peptide antibiotics was isolated in 1956, and the progenitor of the family, vancomycin, has been in clinical use for more than twenty-five years as an antibiotic of last resort. The continuing objective of this research program is to develop an efficient approach to the synthesis of the principal members of the vancomycin family of antibiotics. Accordingly, we will pursue a laboratory synthesis of vancomycin aglycone and the related congeners orienticin C, ristocetin and aridicin A. In conjunction with the execution of these objectives, we will develop new methods for the asymmetric synthesis of complex amino acids and cyclic peptides. In addition, we propose to develop new methodology for the oxidative macrocyclization of phenol-containing peptides to form macrocyclic diphenyl ethers and biphenyls, critical constituents of the vancomycin skeleton. The successful development of this methodology will enable us to pursue a biogenetically modeled synthesis of virtually any member of the vancomycin family. Finally, the full stereochemical assignments of all members of this family of antibiotics rests on NMR spectroscopy, and as such must be considered as tentative. During the course of this project we intend to confirm (correct) the absolute stereochemical assignments of the principal members of this family by total synthesis.