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.