title: Synthesis of 14,15-dehydroerythromycin A ketolides: effects of the 13-substituent on erythromycin tautomerism.
abstract: A ketolide was prepared from 14,15-dehydroerythromycin A by two different routes. The first approach involving oxidation of the 3-OH of 3-descladinosyl-14,15-dehydroerythromycin A 2'-O-acetate gave unexpectedly high levels of 3,11-double oxidation. This may be due to greater formation of the 9,12-hemiketal in 14,15-dehydroerythromycin A and concomitant exposure of the 11-OH group for oxidation. NMR studies of 14,15-dehydroerythromycin A support this hypothesis, revealing a 9:1 ratio of 9-ketone to 9,12-hemiketal in CDCl3 and a 1:1 ratio in CD3OD as contrasted with the corresponding tautomer ratios of 30:1 in CDCl3, and 6: 1 in CD3OD with erythromycin A. Alteration of the 13-substituent on the erythronolide A ring from ethyl to vinyl thus favors formation of the 9,12-hemiketal. A second route to the ketolides was developed based on these findings, in which the 11-OH is eliminated prior to oxidation of the 3-OH.
authors.affiliation: Department of Chemistry, Kosan Biosciences, Inc, Hayward, CA 94545, USA.
authors.forename: M
authors.initials: M
authors.lastname: Fardis
authors.forename: G W
authors.initials: GW
authors.lastname: Ashley
authors.forename: J R
authors.initials: JR
authors.lastname: Carney
authors.forename: D T
authors.initials: DT
authors.lastname: Chu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006094:Gram-Positive Bacteria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin