Utility of azolium triflates as promoters for the condensation of a nucleoside phosphoramidite and a nucleoside in the Agrawal's stereoselective synthesis of nucleoside phosphorothioates

This paper demonstrates that some azolium triflates, such as N-phenylimidazolium Inflate, benzimidazolium triflate and N-methylbenzimidazolium triflate, are more useful than 1H-tetrazole as promoters for the stereoselective condensation of a 5'-O-free nucleoside and a stereochemically pure 5'-O-(p,p'-.dimethoxytrityl)-3'-O-{(4R)-1H,3H-pyrrolo[1,2-c]-1,3,2- oxazaphospholidin}-2-y1 2'-deoxyribonucleoside (Rc-1) or 5'-O-(p,p'-dimethoxytrityl)-3'-O-{(4S)-1H,3H-pyrrolo[1,2-c]-1,3,2- oxazaphospholidin}-2-y1 2'-deoxyribonucleoside (Sc-2) (Ag-rawal strategy). The azolium triflates allowed the stereoselective formation of an internucleotide phosphorothioate bond via the above-described condensation using a stereochemically pure phosphoramidite, followed by sulfurization using bis[3-triethoxysilylpropyl]tetrasulfide. The highest diastereoexcess values of the products in the synthesis of dideoxyribonucleoside phosphorothioates using a suitable azolium triflate such as benzimidazolium triflate, N-methylbenzimidazolium triflate or N-phenylimidazolium triflate were 90-96% in solution phase or 80-88% in solid phase; these values were higher than those obtained in the synthesis using 1H-tetrazole as a promoter for the condensation of a nucleoside phosphoramidite and a nucleoside. This paper also describes that studies on the absolute configurations of stereogenic phosphorus atoms in the phosphoramidites Rc-1 and Sc-2 by means of two different existing methods, i.e., the Beaucage method, gave contrary conclusions, and thus the configurations should be determined by an absolutely reliable method, such as X-ray analysis. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)