Synthesis of clarithromycin ketolides chemically modified at the unreactive C10-methyl group
| Autor: | Kjell Undheim, Hany Fakhry Anwar, Mioara Andrei |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Allylic rearrangement
Ketolides Spectrometry Mass Electrospray Ionization Staphylococcus aureus Ketone Stereochemistry Cyanide Proton Magnetic Resonance Spectroscopy Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests 010402 general chemistry 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Clarithromycin Drug Discovery Methylene Carbon-13 Magnetic Resonance Spectroscopy Molecular Biology chemistry.chemical_classification 010405 organic chemistry Organic Chemistry 0104 chemical sciences Anti-Bacterial Agents Streptococcus pneumoniae chemistry Allyl acetate Molecular Medicine Trimethylsilyldiazomethane Carbonyldiimidazole Methyl group |
| Zdroj: | Bioorganicmedicinal chemistry. 25(8) |
| ISSN: | 1464-3391 |
| Popis: | 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- O 6 -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 . |
| Databáze: | OpenAIRE |
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