NUCLEOSIDE H-PHOSPHONATES .12. SYNTHESIS OF NUCLEOSIDE 3'-(HYDROGEN-PHOSPHONOTHIOATE) MONOESTERS VIA PHOSPHINATE INTERMEDIATES

Reactions of phosphinic acid with suitably protected nucleosides in the presence of condensing agents have been studied using 31P NMR spectroscopy. It was found that rapid disproportionation of phosphinic acid occurring during course of the reactions can be avoided if the proper ratio of the reactants is chosen, and the phosphinate esters can be produced quantitatively. The utility of phosphinate esters as synthetic intermediates was demonstrated by designing a convenient method for the preparation of nucleoside H-phosphonothioates. It consists of the in situ formation of nucleoside phosphinates from phosphinic acid and appropriate nucleosides in the presence of a condensing agent, followed by their oxidation with elemental sulfur. Ribo- and deoxyribonucleoside 3’-H-phosphonothioates have been synthesized in ~80-90% yield using this method. © 1990, American Chemical Society. All rights reserved.