Chemical modification of erythromycins. II. Synthesis and antibacterial activity of O-alkyl derivatives of erythromycin A.

A series of O-alkyl erythromycin A derivatives have been synthesized and their antibacterial activities compared with those of erythromycin A (1) and 6-O-methylerythromycin A (3). Methylation of the hydroxyl groups of erythromycin A analogue proceeded stepwise by the two main pathways beginning at the C-6 and C-11 positions, individually. O-Alkylation, other than methylation, took place at the C-11 hydroxyl group exclusively. Among O-alkyl derivatives, 6,12-di-O-methylerythromycin A (5) showed comparable in vitro antibacterial activity to those of 1 and 3. 11-O-Methylerythromycin A (8) was slightly less active than 1. O-Methylation at the C-4" position resulted in a decrease of antibacterial activity.