Masato Kashimura

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 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.

Chemical Modification of Erythromycins. X. Removal of Benzyloxycarbonyl and 2-Chlorobenzyl Groups of Erythromycin Derivatives by Use of Catalytic Transfer Hydrogenation

The benzyloxycarbonyl and the 2-chlorobenzyl groups of ethythromycin derivatives were easily removed by catalytic transfer hydrogenation (CTH). Their deprotection reaction was dependent on both the hydrogen donor and the solvent for use. Application of CTH to removal of the protective groups is discussed