Preparation of cyclic 2',3'-carbamate derivatives of erythromycin macrolide antibiotics.
Tricarbonylation of clarithromycin has been effected in a one-pot reaction with phosgene. The 11,12-diol moiety was closed into a cyclic carbonate, while the dimethylamino alcohol of the desosamine sugar was cyclised with loss of a methyl group to form a cyclic 2',3'-carbamate. The 4'' hydroxyl group in clarithromycin was converted into a chloroformate group and subsequently to an allyl carbonate which on Pd-catalysis furnished a novel N-demethylclarithromycin 2',3'-carbamate-11,12-carbonate. Hydrolytic removal of the cladinose sugar and a subsequent oxidation furnished the corresponding ketolide. The 11,12-cyclic carbonate moiety was cleaved by sodium azide to the 10,11-anhydro-9-ketone. 11-N-Arylated cyclic 11,12:2',3'-dicarbamate derivatives were prepared in a copper(I) chloride aided reaction between aryl isocyanates and 10,11-anhydro 9-ketones. The products are novel N-arylated-N'-demethylated 11,12:2',3'-dicarbamate ketolides derived from clarithromycin.
Heggelund
Audun
A
Department of Chemistry, University of Oslo, N-0315 Oslo, Norway.
Undheim
Kjell
K
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002219:Carbamates; D018942:Macrolides; D004917:Erythromycin