Collect. Czech. Chem. Commun. 1990, 55, 2521-2536

Synthesis of 5'-O-phosphonomethyl derivatives of pyrimidine 2'-deoxynucleosides

Marcela Krečmerová, Hubert Hřebabecký and Antonín Holý

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


Reaction of sodium salt of 3-N,3'-O-bis(benzyloxymethyl)-2'-deoxyuridine (X) and 3-N,3'-O-bis(benzyloxymethyl)-2'-deoxythymidine (XI) with diethyl p-toluenesulfonyloxymethanephosphonate in dimethylformamide afforded diesters of the respective 5'-O-phosphonomethyl derivatives XII and XVII. Diethyl esters of 5'-O-phosphonomethyl-2'-deoxynucleosides XV and XIX, obtained after hydrogenolytic removal of the benzyloxymethyl groups, were converted into free 2'-deoxy-5'-O-phosphonomethyluridine (XVI) and a mixture of anomeric 1-(2-deoxy-5-O-phosphonomethyl-β-D-erythro-pentofuranosyl)thymines (XXIIIa, XXIIIb), respectively. Analogously, 2'-deoxy-5'-O-phosphonomethylcytidine (XXXIV) was prepared from 4-N-benzoyl-2'-deoxy-3'-O-(tetrahydro-2H-pyran-2-yl) cytidine (XXX) via diethyl ester of 2'-deoxy-5'-O-phosphonomethylcytidine (XXXIII). This compound reacted with bromotrimethylsilane to give compound XXXIV without anomerization and nucleoside bond cleavage. Condensation of the protected nucleosides X and XI with dibenzyl p-toluenesulfonyloxymethanephosphonate afforded dibenzyl esters of the corresponding 5'-O-phosphonomethyl derivatives XIII and XVIII. The free 5'-O-phosphonomethyl derivatives XVI and XXIIIa were obtained from XIII and XVIII by catalytic hydrogenation.