Synthesis of nucleoside 3′-phosphonates via 3′-keto nucleosides

Abstract

Nucleophilic addition of diethyl phosphite anion to several 2′- or 3′-keto nucleosides results in an efficient synthesis of 2′-hydroxy-2′-phosphono- or 3′-hydroxy-3′-phosphononucleosides. The stereochemistry of one such adduct, 3′α-diethylphosphono-3′β-hydroxy-5′-O-tritylthymidine, was determined by single crystal diffraction analysis. When the 5′-hydroxyl group is protected with groups that are not sterically demanding, the 3′ geminal hydroxy phosphonates undergo radical deoxygenation under modified Barton conditions to afford the reduced compounds in good yields. Removal of the remaining hydroxyl protecting groups, and hydrolysis of the phosphonate acid esters, then gives the parent nucleoside 3′-phosphonic acids.