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 triflate, benzimidazolium triflate and N ‐methylbenzimidazolium triflate, are more useful than 1 H ‐tetrazole as promoters for the stereoselective condensation of a 5′‐ O ‐free nucleoside and a stereochemically pure 5′‐ O ‐( p , p ′‐dimethoxytrityl)‐3′‐ O ‐{(4 R )‐1 H ,3 H ‐pyrrolo[1,2‐ c ]‐1,3,2‐oxazaphospholidin}‐2‐yl 2′‐deoxyribonucleoside ( R c‐ 1 ) or 5′‐ O ‐( p , p ′‐dimethoxytrityl)‐3′‐ O ‐{(4 S )‐1 H ,3 H ‐pyrrolo[1,2‐ c ]‐1,3,2‐oxazaphospholidin}‐2‐yl 2′‐deoxyribonucleoside ( S c‐ 2 ) (Agrawal 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 1 H ‐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 R c‐ 1 and S c‐ 2 by meansof 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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)