Atropselective macrocyclization of diaryl ether ring systems: application to the synthesis of vancomycin model systems.
Vancomycin is the last line of defense available in the clinic for treating multidrug-resistant bacterial infections. Vancomycin contains two 16-membered diaryl ether macrocycles, each of which contains a stereogenic axis across the diaryl ether linkage. Since an effective total synthesis of vancomycin requires that these stereogenic axes be formed in a stereoselective manner, we have developed an atropselective variation of the triazene mediated diaryl ether forming reaction. This variation introduced an energetic penalty into the transition state of the undesired atropisomer. This reaction is used to synthesize the C-O-D diaryl ether macrocycle found in vancomycin with high diastereoselectivity (de > 90%), providing the naturally occurring atropisomeric configuration.
Nicolaou
K C
KC
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. kcn@scripps.edu
Boddy
Christopher N C
CN
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003198:Computer Simulation; D003500:Cyclization; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D014640:Vancomycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry
D000900:Anti-Bacterial Agents; D014640:Vancomycin