Search

Direct O-methylation of various derivatives of 9-deoxo-8a- and 9a-aza-8a-homo-erythromycin (2′,3′-bis-Cbz protected) gives 6-OMe derivatives only in a small number of special cases. The 6-OMe-azalides can, however, be synthesized beginning from clarithromycin.

A series of O-Me derivatives of 9-deoxo-8a-aza-8a-homoerythromycin has been prepared and evaluated for antibacterial activity. The relative rates of methylation of the four available hydroxyls (4″, 6, 11 and 12) in 2′, 3′ -bis-Cbz protected 9-deoxo-8a-aza-8a-homoerythromycin were compared to those given in a published report for the similarly protected 9a-azalide. An incongruity in the results prompted reinvestigation of the O-methylation of the 9a-azalide, and an error in structure assignment in the published report was discovered: the compound reported as the 6-OMe-9a-azalide has been determined to be the 12-OMe derivative.

The preparation and biological activity of the novel aza macrolides 6, 8, 11–13 and 15–20 are reported. These analogs display in vitro antibacterial properties that are superior to erythromycin A.

The (9E)-oxime of erythromycin A (1) was isomerized to the (9Z)-isomer 2 in the presence of strong base. Stereospecific Beckmann rearrangement of the (9Z)-oxime led to a series of novel 8a-aza-8a- homoerythromycin A derivatives. In vitro data is provided that shows the 8a-methyl derivative 10 to be equally active with its positional isomer azithromycin.