Novel Cost-Effective Methanephosphonoanilidothioate Approach to the Stereoselective Synthesis of Dinucleoside (3‵,5‵)-Methanephosphonates

Abstract

A new method of stereoselective preparation of di(2‵-deoxy or 2‵-OMe)ribonucleoside (3‵,5‵)-methanephosphonate 5 is presented. The DBU/LiCl-assisted reaction of 5‵-O-DMT-(2‵-deoxy or 2‵-OMe)ribonucleoside 3‵-0-(S-alkyl methanephosphonothioate) 9 with 5‵-OH nucleosides proceeds with full stereospecificity, giving 5 in moderate to good yield. The conversion of 5‵-O-DMT-(2‵-deoxy or 2‵-OMe)ribonucleoside 3‵-methanephosphonoanilidothioates 8 and 3‵-O-methanephosphonoanilidates 10 by means of NaH/CX₂ (X = O,S) followed by S-alkylation leads to monomers 9, with the possibility of use of both separated diastereomers of 8 for the preparation of one selected diastereomer of 5. The relative configuration at the P atom in 2‵-OMe and deoxynucleoside derivatives of compounds 9 was established by means of stereoselective degradation of nucleoside 3‵-O-methanephosphonothioates 11 (precursors of 9) with nuclease P1.