Catalytic Site-Selective Thiocarbonylations and Deoxygenations of Vancomycin Reveal Hydroxyl-Dependent Conformational Effects

• Published in: Journal of the American Chemical Society Vol. 134; no. 23; pp. 9755 - 9761
• Main Authors: Fowler, Brandon S, Laemmerhold, Kai M, Miller, Scott J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.06.2012; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Chemistry; Chemistry, Multidisciplinary; Crystallography, X-Ray; Enterococcaceae - drug effects; Humans; Isomerism; Models, Molecular; Molecular Conformation; Oxygen - chemistry; Physical Sciences; Science & Technology; Staphylococcal Infections - drug therapy; Staphylococcus aureus - drug effects; Sulfhydryl Compounds - chemistry; Vancomycin - chemistry; Vancomycin - pharmacology; GLYCOPEPTIDE ANTIBIOTICS; AMINO-ACID; ANTIBIOTIC VANCOMYCIN; RISTOCETIN-A; NATURAL-PRODUCTS; ALA-D-ALA; ERYTHROMYCIN-A; BINDING; DERIVATIVES; RADICAL REACTIONS
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja302692j

We have examined peptide-based catalysts for the site-selective thiocarbonylation of a protected form of vancomycin. Several catalysts were identified that either enhanced or altered the inherent selectivity profile exhibited by the substrate. Two catalysts, one identified through screening and another through rational design, were demonstrated to be effective on 0.50-g scale. Deoxygenations led ultimately to two new deoxy-vancomycin derivatives, and surprising conformational consequences of deoxygenation were revealed for one of the new compounds. These effects were mirrored in the biological activities of the new analogues and support a structural role for certain hydroxyls in the native structure.