Studies on Selectivity of O-Methylation of Erythromycin Derivatives Based on Molecular Mechanics and Molecular Orbital Methods

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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.
公益社団法人日本薬学会の論文
1990-06-25