Clarithromycin macrolides modified by unsaturation at the C10-position

Abstract

Methodologies for the synthesis of C10- C -unsaturated clarithromycin congeners have been developed from corresponding C10-methyl erythromycin A ketolides. Activation of the unreactive C10-methyl group and subsequent Pd-catalyzed cross-coupling reactions afford novel C-10-unsaturated clarithromycins for antibacterial screening programs. By related methodology azides can be prepared and used for the preparation of corresponding 1,2,3-triazoles by click chemistry. The work demonstrates the importance of transition metal catalysis in natural product semi-synthesis and potential SAR studies. The in vitro MIC values from screening the products against strains of respiratory pathogens of S. pneumoniae and S. aureus indicate that the new antibacterials are close to equipotent with the clarithromycin reference compound. • A series of C10-alkenyl clarithromycin ketolides were prepared. • Syntheses of C10- C -unsaturated clarithromycins were achieved by Pd-promoted catalysis. • In vitro MIC values are reported. • MIC data indicated that clarithromycin and C10- C -unsaturated analogues had a comparable potency.