An improved method for the synthesis of nucleoside triphosphate analogues.

[reaction: see text] Nucleoside monophosphates, when activated by trifluoroacetic anhydride and N-methylimidazole, efficiently couple with a variety of electron-deficient diphosphonates in a reproducible and efficient manner (<2 h, >72% isolated yield). Unlike traditional methods for the preparation of nucleoside 5'-beta,gamma-methylenetriphosphate analogues, there is no requirement for predrying, or conversion to specific salt forms, of commercially available nucleoside monophosphate starting materials.