Synthesis of hydroxylated derivatives of topiramate, a novel antiepileptic drug based on d-fructose: Investigation of oxidative metabolites

To corroborate the structures of two monohydroxylated metabolites of topiramate (1), we synthesized four monosaccharide derivatives from d-fructose: 4,5-O-[(1R∗)- and 4,5-O-[(1S∗)-1-hydroxymethylethylidene]-2,3-O-isopropylidene-β-d-fructopyranose sulfamates (2a and 2b); 2,3-O-[(1R∗)- and 2,3-O-[(1R∗)-1-hydroxymethylethylidene]-4,5-O-isopropylidene-β-d-fructopyranose sulfamates (3a and 3b). The route to 2a and 2b was brief and straightforward, while that to 3a and 3b was more involved. In the latter case, the d-fructose bis-acetal 10 was benzylated and converted to a monoacetal dibenzoate (14) (50% yield), which was then transacetalized to give a mixture of 4,5-dibenzoyl-2,3-O-[(1R∗)- and 4,5-dibenzoyl-2,3-O-[(1S∗)-1-benzyloxymethylethylidene]-β-d-fructopyranose (16a and 16b) (22%). The individual diastereomers were separated and processed via ester saponification, acetonation, sulfamoylation, and hydrogenolysis into 3a (36%) and 3b (27%). Structure 2b was confirmed for one oxidative metabolite, but the other metabolite was found not to correspond with either 2a, 3a, or 3b. On the basis of CI-MS and 1H NMR data, a (2-hydroxy-1,4-dioxano)pyran structure, 4, is proposed for this unidentified metabolite.