Efficient Synthesis of 5-(β-D-Ribofuranosyl)nicotinamide and Its α-Isomer

Condensation of 2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-D-ribonolactone (3) with 3-cyano-5-lithiopyridine afforded 1-(3-cyanopyridin-5-yl)-2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-β-D-ribofuran-1-ulose (5a), which was reduced with NaBH₄ to a 1:1 allo/altro mixture of 5-[2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-Dpentitol-1-yl]-3-cyanopyridine (7a). The isomers were chromatographically separated. Treatment of allo-7a with TsOH/MeOH gave 5-(2,3-O-isopropylidene-D-allo-pentitol-1-yl)-3-cyanopyridine (allo-8a), which was acetonated to give 5-(2,3:4,5-di-O-isopropylidene-D-o(Zo-pentitol-1-yl)-3-cyanopyridine (allo-9a). Mesylation of allo-9a to allo-10 followed by acid hydrolysis with CF₃CO₂H/CHCl₃ afforded 5-(α-D-ribofuranosyl)-3-cyanopyridine (11a). The β-isomer la was synthesized in a similar manner from altro-7a. Inversion of the configuration at the C-1 position of 6-(2,3:4,5-di-O-isopropylidene-D-allo-pentitol-1-yl)-2-bromopyridine (allo-9b) into the corresponding altro isomer altro-9b was achieved albeit in modest yield (24%) by mesylation of allo-9b to allo-10b followed by treatment with potassium superoxide. Interconversion of altro-9a or -9b into the corresponding allo derivatives was readily achieved in excellent yield by oxidation with CrO₃/pyridine/Ac₂O to the corresponding keto intermediates 19 followed by borohydride reduction. Treatment of the 1-O-mesylate allo-10b with NaN₃ in DMF afforded the corresponding 1-azido-1-deoxy altro derivative (17). Similar treatment of the 1-O-triflyl derivatives allo-15a,b with NaN₃ or NaOAc in DMF surprisingly afforded allo-9a,b in good yield.