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Theoretical study of selective methylation in the synthesis of azithromycin

Duran, Dilek and Aviyente, Viktorya and Baysal, Canan (2004) Theoretical study of selective methylation in the synthesis of azithromycin. Journal of computer-aided molecular design, 18 (1). pp. 1-11. ISSN 0920-654X (Print) 1573-4951 (Online)

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Official URL: http://dx.doi.org/10.1023/B:JCAM.0000022560.75389.c5

Abstract

Azithromycin is a 15-membered macrolide antibiotic which is active in vitro against clinically important gram-negative bacteria. In this study, the selectivity of the methylation mechanism was analyzed computationally on the 2'-OCbz-3'-NMeCbz derivative of azithromycin in vacuum and in DMF. We have shown that the methylation of the hydroxy group on C-6 is energetically unfavorable compared to the other hydroxy groups in vacuum; the softness values further showed that the C-6 anion is not reactive towards CH3I in the methylation mechanism. To understand the effect of the solvent on the methylation process, detailed molecular dynamics simulations were performed in DMF using the anions at the C-4", C-6, C-11 and C-12 positions. We find the conformations of the anions not to be affected by the presence of the solvent. The radial distribution functions of the solvent molecules around the O- of the anions demonstrate that DMF molecules cluster around the C-6 anion. The relative strength of the anion-solvent interactions reveal that the solvent molecules provide the largest stabilization to the C-6 anion and prevent the methylation at this position. The latter descriptor was found to be an important factor in explaining the experimentally observed selectivity towards the methylation of the C-4", C-6, C-11 and C-12 anions.

Item Type:Article
Uncontrolled Keywords:azalide antibiotics; conformational analysis; methylation; molecular dynamics; solvent effect
Subjects:Q Science > QD Chemistry
ID Code:364
Deposited By:Canan Atılgan
Deposited On:16 Feb 2007 02:00
Last Modified:25 May 2011 14:14

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