Collect. Czech. Chem. Commun. 1982, 47, 3447-3463

Preparation of 5'-O-phosphonylmethyl analogues of nucleoside-5'-phosphates, 5'-diphosphates and 5'-triphosphates

Antonín Holý and Ivan Rosenberg

Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, 166 10 Prague 6


Reaction of a trialkyl phosphite (VI) or sodium salt of dialkyl phosphite (V) with bromomethyl acetate afforded dialkyl acetoxymethanephosphonates VII which were alcoholyzed to dialkyl hydroxymethanephosphonates VIII. Tosylation of the compounds VIII gave dialkyl p-toluenesulfonyloxymethanephosphonates IX which on reaction with 2',3'-O-isopropylideneribonucleosides (I), 2',3'-O-ethoxymethyleneribonucleosides (XI) or 3'-O-tetrahydropyranyl-2'-deoxyribonucleosides in the presence of sodium hydride, followed by acid hydrolysis, were converted into alkyl esters of 5'-O-phosphonylmethylnucleosides XII. Treatment of compounds XII with trimethylsilyl iodide led to 5'-O-phosphonylmethylnucleosides II and XIV. The ribo derivatives II were also obtained in low yields by reaction of compounds I with sodium chloromethanephosphonate in the presence of sodium hydride. Compound II reacted with morpholine in the presence of N,N'-dicyclohexylcarbodiimide to give morpholides XV which on treatment with phosphate afforded 5'-O-phosphorylphosphonylmethylribonucleosides XVI. Analogously, 5'-O-diphosphorylphosphonylmethylribonucleosides XVII were obtained from the derivatives XV by reaction with diphosphate. The compounds II are resistant towards E. coli alkaline phosphomonoesterase and snake venom and bull semen 5'-nucleotidase. E. coli alkaline phosphomonoesterase degrades the compounds XVI and XVII to compounds II and inorganic phosphate.