Modeling the selective methylation in the synthesis of clarithromycin

Abstract

The synthesis of clarithromycin from erythromycin A oxime derivatives has been investigated in order to improve the antibacterial and pharmacokinetic properties of erythromycin A. In this study, the protection and the methylation reactions of each of the hydroxy groups in erythromycin A have been analyzed computationally by the AM1 method by using erythromycin A 9-[O-(dimethylthexylsilyl)oxime] in the gas phase. Our results have shown the protection of the C-2′ and C-4″ hydroxy groups to be faster than for the other hydroxy groups, in agreement with the experimental studies. Furthermore, methylation of the hydroxy group on C-6 was found to be preferred over that of the other hydroxy groups.