title: Synthesis of clarithromycin ketolides chemically modified at the unreactive C10-methyl group.
abstract: Chemoselective substitutions in the C10-methyl group of erythromycin A ketolides is reported. The C10-methyl group in the clarithromycin derived substrate 10,11-anhydro-O6-methyl-descladinosylerythromycin was activated by conversion into an allyl acetate and thereafter to the corresponding allylic cyanide. Both the allylic acetate and the cyanide reacted with carbonyldiimidazole and ammonia to afford a C11,C12-cyclic carbamate with concurrent elimination of the allylic function to yield a methylene α,β-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C-N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the formation of the 10-substituent. Stereoselective cycloaddition with trimethylsilyldiazomethane afforded a spirane where the C10 carbon of the macrolide skeleton had become a quaternary spirocarbon. Antibacterial in vitro data for a selected group of compounds against strains of respiratory pathogens S. pneumoniae and S. aureus are reported. Most of the compounds tested showed improved activities over CLA as a reference compound against efflux resistant S. pneumoniae as well as against efflux and inducibly resistant strains of S. aureus.
authors.affiliation: C10 Pharma AS, Oslo, Norway.
authors.forename: Hany Fakhry
authors.initials: HF
authors.lastname: Anwar
authors.affiliation: C10 Pharma AS, Oslo, Norway.
authors.forename: Mioara
authors.initials: M
authors.lastname: Andrei
authors.affiliation: Department of Chemistry, University of Oslo, N-0315 Oslo, Norway. Electronic address: kjell.undheim@kjemi.uio.no.
authors.forename: Kjell
authors.initials: K
authors.lastname: Undheim
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D017291:Clarithromycin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048628:Ketolides / Q000138:chemical synthesis* / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D017291:Clarithromycin
keywords: Allylic substitutions; Antibacterials; C10-aminomethyl-3-ketolides; In vitro MIC data; NCS acetoxylation; Stereoselectivity; Syntheses