Synthesis of methylene-bridged analogues of nicotinamide riboside, nicotinamide mononucleotide and nicotinamide adenine dinucleotide

P. Lipka, A. Ztorski, K. A. Watanabe, K. W. Pankiewicz

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5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-3(R)-(nicotinamid-2-y lmethyl)-D-ribofuranose (11a) and -3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (11b) were prepared by condensation of 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-erythro-3-pentul ofuranose (10) with lithiated (LDA) 2-methylnicotinamide and 6-methylnicotinamide, respectively, and then deprotected to give 1,2-O-isopropylidene-3-(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose (12a) and 1,2-O-isopropylidene-3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (12b). Benzoylation as well as phosphorylation of compounds 12 afforded the corresponding 5-O-benzoate (13b) and 5-O-monophosphates (14a and 14b). Treatment of 13b with CF3COOH/H2O caused 1,2-de-O-isopropylidenation with simultaneous cyclization to the corresponding methylene-bridged cyclic nucleoside - 3',6-methylene-1-(5-O-benzoyl-β-D-ribofuranose)-3-carboxamidopyridini um trifluoro-acetate (8b) - restricted to the 'anti' conformation. In a similar manner compounds 14a and 14b were converted into conformationally restricted 2,3'-methylene-1-(β-D-ribofuranose)-3-carboxamidopyridinium-5'-monoph osphate (9a-'syn') and 3',6-methylene-1-(β-D-ribofuranose)-3-carboxamidopyridinium-5'-monoph osphate (9b-'anti') respectively. Coupling of derivatives 12a and 12b with the adenosine 5'-methylenediphosphonate (16) afforded the corresponding dinucleotides 17. Upon acidic 1,2-de-O-isopropylidenation of 17b, the conformationally restricted P1-[6,3'-methylene-1-(β-D-ribofuranos-5-yl)-3-carboxamidopyridinium] -P2-(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 dinucleotides, i.e. P1-[3(R)-nicotinamid-6-ylmethyl-D-ribofuranos-5-yl]-P2-(adenosin-5'- yl)methylenediphosphonate (19b). In a similar manner, treatment of 17a with CF3COOH/H2O and HPLC purification afforded the corresponding dinucleotide 19a.

Original languageEnglish (US)
Pages (from-to)149-167
Number of pages19
JournalNucleosides and Nucleotides
Issue number1-3
StatePublished - 1996
Externally publishedYes


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