Stereochemistry of internucleotide bond formation by the H-phosphonate method. 7. Stereoselective formation of ribonucleoside (RP)- and (SP)-3′-H-phosphonothioate monoesters

Ribonucleoside 3′-H-phosphonothioate monoesters exist in the form of (RP)- and (SP)-diastereomers. In order to obtain them in good yields and in high stereochemical purity, stereoselective strategies for their preparation were investigated. For the synthesis of the (RP)-isomer, a stereoselective sulfhydrolysis of an activated nucleoside H-phosphonate was developed, while the monoesters with an (SP)-configuration were prepared by asymmetric transformation of diastereomeric mixtures of nucleoside 3′-H-phosphonothioates using either a condensation with 9-fluorenemethanol, followed by β-elimination, or via pivaloylation-hydrolysis reaction sequence. A tentative assignment of the absolute configurations of the obtained diastereomers of 3′-H-phosphonothioate esters was carried out via a stereochemical correlation analysis.

Graphical abstractDiastereoselective preparation of nucleoside (RP)- and (SP)-3′-H-phosphonothioate monoesters and tentative assignment of their configuration are described.Figure optionsDownload full-size imageDownload as PowerPoint slide