Fluorinated acyclo-C-nucleoside analogues from glycals in two steps

A convenient two-step strategy is reported for the synthesis of fluorinated optically pure acyclo-C-nucleoside analogues starting from simple glycals. In the first step, benzyl- or p-methoxybenzyl-protected glycals are treated with trifluoroacetic anhydride, bromodifluoroacetyl chloride, trichloroacetyl chloride, and perfluorooctanoyl chloride, respectively, in the presence of Et3N. This one-pot procedure yields 1,2-unsaturated sugars (1,5-anhydro-3,4,6-tri-O-benzyl (or p-methoxybenzyl) 2-deoxy-2-perhalogenoacyl-d-arabino / lyxo-hex-1-enitols 4–9) acylated at C-2. In the second step, a selective ring transformation is induced by treatment of the C-acylated glycals with bis-nucleophiles (hydrazine, phenylhydrazine, o-phenylenediamine, hydroxylamine). In particular, 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-trifluoroacetyl-d-arabino-hex-1-enitol (4) and 1,5-anhydro-2-deoxy-2-trifluoroacetyl-3,4,6-tri-O-(p-methoxybenzyl)-d-arabino-hex-1-enitol (8) were reacted with these nucleophiles generating the final C-nucleoside analogues of pyrazole (10, 11, and 12), diazepine (13), and isoxazole (15), respectively, containing a carbohydrate side chain linked to the heterocyclic ring.