SYNTHESIS OF METHYLENE-BRIDGED ANALOGS OF NICOTINAMIDE RIBOSIDE, NICOTINAMIDE MONONUCLEOTIDE AND NICOTINAMIDE ADENINE-DINUCLEOTIDE

3(R)-(nicotinamid-2-ylmethyl)-alpha-D-ribofuranose (11a) and 3(R)-(nic otinamid-6-ylmethyl)-alpha-D-ribofuranose (11b) were prepared by conde nsation of O-isopropylidene-alpha-D-erythro-3-pentulofuranose (10) wit h lithiated (LDA) 2-methylnicotinamide and 6-methylnicotinamide, respe ctively, and then deprotected to give ropylidene-3-(R)-(nicotinamid-2- ylmethyl)-alpha-D- 3(R)-(nicotinamid-6-ylmethyl)-alpha-D-ribofuranose (12b). Benzoylation as well as phosphorylation of compounds 12 afforde d the corresponding 5-O-benzoate (13b) and 5-O-monophosphates (14a and 14b). Treatment of 13b with CF3COOH/H2O caused 1,2-de-O-isopropyliden ation with simultaneous cyclization to the corresponding methylene-bri dged cyclic nucleoside - nzoyl-beta-D-ribofuranose)-3-carboxamidopyrid inium trifluoro-acetate (8b) - restricted to the ''anti'' conformation . In a similar manner compounds 14a and 14b were converted into confor mationally restricted -(beta-D-ribofuranose)-3-carboxamidopyridinium-5 '- monophosphate (9a - ''syn'') and ,6-methylene-1-(beta-D-ribofuranos e)-3-carboxamido - pyridinium-5'monophosphate (9b - ''anti'') respecti vely. Coupling of derivatives 12a and 12b with the adenosine 5'-methyl enediphosphonate (16) afforded the corresponding dinucleotides 17. Upo n acidic 1,2-de-O-isopropylidenation of 17b, the conformationally rest ricted dinium]-P-2-(adenosin-5'-yl)methylenediphosphonate 18b -''anti' ' was formed. Compound 18b was found to be unstable. Upon addition of water 18b was converted into the anomeric mixture of acyclic dinucleot ides, i.e. -5-yl]-P-2-(adenosin-5'-yl)-methylenediphosphonate (19b). I n a similar manner, treatment of 17a with CF2COOH/H2O and HPLC purific ation afforded the corresponding dinucleotide 19a.