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

Abstract

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 Et 3N. 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.