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Issue 9, 1993
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Origin of regioselectivity in the O-methylation of erythromycin as elucidated with the aid of computational conformational space search

Abstract

Contrasting regioselectivities reported in the O-methylation of 2′,4″-bis(O-trimethylsilyl)erythromycins (preferentially at 11-OH for the erythromycin A 2, but almost exclusively at 6-OH for the erythromycin B 3 and the 9-allyloxyiminoerythromycin A 4) have been studied with the aid of a computational conformational space search technique. Low-energy conformers were exhaustively generated for the model erythronolides 5(ENA), 6(ENB) and 7(ENA oxime) using a new algorithm (CONFLEX) coupled with MM2 geometry-optimization. Hundreds of conformers thus generated were classified into clusters based on the conformation of the 14-membered lactone ring. Examination of stable conformers in the more abundant 17 clusters revealed key features relevant to the O-methylation reaction: the orientation of α-hydrogen atom at C(11) and the network of internal hydrogen bonds that occur among hydroxy groups at C(6), C(11), C(12), and carbonyl groups at C(1), C(9). Clusters were then merged according to these reactivity criteria into three bundles; ‘6-OH reactive’, ‘11-OH reactive’ and ‘inactive’. The trend in the combined populations in these bundles agree with the observed regioselectivity in the O-methylation reaction.

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Article type: Paper
DOI: 10.1039/P29930001647
J. Chem. Soc., Perkin Trans. 2, 1993, 1647-1654

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    Origin of regioselectivity in the O-methylation of erythromycin as elucidated with the aid of computational conformational space search

    H. Gotō, Y. Kawashima, M. Kashimura, S. Morimoto and E. Ōsawa, J. Chem. Soc., Perkin Trans. 2, 1993, 1647
    DOI: 10.1039/P29930001647

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