ORIGIN OF REGIOSELECTIVITY IN THE O-METHYLATION OF ERYTHROMYCIN AS ELUCIDATED WITH THE AID OF COMPUTATIONAL CONFORMATIONAL SPACE SEARCH

Contrasting regioselectivities reported in the O-methylation of 2',4'' -bis(O-trimethylsilyl)erythromycins (preferentially at 11-OH for the e rythromycin 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-ene rgy conformers were exhaustively generated for the model erythronolide s 5 (ENA), 6 (ENB) and 7 (ENA oxime) using a new algorithm (CONFLEX) c oupled with MM2 geometry-optimization. Hundreds of conformers thus gen erated 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-methylat ion reaction: the orientation of alpha-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 t hen merged according to these reactivity criteria into three bundles; '6-OH reactive', '11-OH reactive' and 'inactive'. The trend in the com bined populations in these bundles agree with the observed regioselect ivity in the O-methylation reaction.