Synthesis of β-triphosphotriester pronucleotides.

Dinucleoside phosphorochloridite were synthesized from phosphorus trichloride and three nucleoside analogues, 3'-fluoro-2',3'-dideoxythymidine (FLT), 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), and 2',3'-dideoxy-3'-thiacytidine (3TC), in a multistep synthesis. Polymer-bound N-Boc p-acetoxybenzyl 5'-O-2'-deoxythymidine was reacted with dinucleoside phosphorochloridite in the presence of 2,6-lutidine, followed by the reaction with dodecyl alcohol and 5-(ethylthio)-1H-tetrazole, oxidation with tert-butyl hydroperoxide, and acidic cleavage, respectively, to afford the β-triphosphotriester derivatives containing three different nucleosides.