Synthesis of 4‐Epoxy‐4‐c‐methyleneglycosylceramides, Potential Glycosyltransferase Inhibitors

Abstract

AbstractD‐Glucose was transformed into the 4‐deoxy‐4‐C‐methylene derivative 1. Dihydroxylation of 1 and then selective O‐tosylation afforded 4‐C‐(tosyloxymethyl)glucoside 3. Subsequent hydrogenolytic O‐debenzylation, selective O‐acetylation, treatment with a base, selective removal of the anomeric O‐acetyl group, and then treatment with trichloroacetonitrile in the presence of a base furnished 4‐epoxy‐4‐C‐methyleneglucosyl donor 7 (α,β mixture). Reaction of 7 with 3‐O‐acyl‐protected azidosphingosines 8a–c in the presence of Et2O.BF3 gave β‐glycosides 9a–c. Compounds 9a–c were transformed into the corresponding glucosylceramide derivatives 10a–c by treatment with triphenylphosphane/water and acyl anhydrides. Satisfactory removal of the O‐benzoyl protective group was difficult; however, O‐acetyl and O‐isobutyryl protective groups could be removed by methanolysis, thus affording from 10b, c the target molecules 11 and 12 with varying alkyl‐chain length. The epoxide 16 with galacto configuration, readily obtained from 1, on treatment with p‐toluenesulfonic acid furnished 4‐C‐(tosyloxymethyl)galactoside 18; this was transformed, as outlined for 3, into the target molecules 25b, c having galacto configuration in the sugar moiety.