Studies on selectivity of O-methylation of erythromycin derivatives based on molecular mechanics and molecular orbital methods.

Abstract

The regioselectivity of O-methylation of the C6- and C11-hydroxyl groups of 2', 4"-O-bis(trimethylsilyl)erythromycin A (3, TMS-EM-A) and that in the case of 2', 4"-O-bis(trimethylsilyl)erythromycin B (4, TMS-EM-B) were examined in relation to the ease of deprotonation and the stability of the anion state. O-Metylation of 3 gave 11-methoxy-TMS-EM-A (5) and 6-methoxy-TMS-EM-A (6) in the ratio of ca.3 : 1, whereas that of 4 gave predominantly 6-methoxy-TMS-EM-B (7). To understand how the steric and electronic structures of EM-A (1) and EM-B (2) affect the selectivities, we carried out theoretical calculations using a semi-empirical molecular orbital method, MNDO. From the frontier electronic density of the lowest unoccupied molecular orbital (LUMO), it was suggested that the activities of deprotonation at the C11-hydroxyl groups of 3 and 4 are higher than those of the C6-hydroxyl groups. On the other hand, it was shown from the total energies of the molecules that the C6-O- -derivatives (3a and 4a) of 3 and 4 are more stable than the C11-O- -derivatives (3b and 4b). The difference of total energies between 4a and 4b is greater than that of 3a and 3b by 5.1kcal/mol, suggesting the possibility of hydrogen bonding between C11-O- and C12-OH of 3b.