Regio- and stereocontrolled synthesis of 2′-5′ linked phosphorothioate oligoadenylates by uranyl ion catalyst in aqueous solution

Abstract

Adenosine 5′-thiophosphoimidazolide (Imp(S)A) was prepared from adenosine, thiophosphoryl trichloride and imidazole. It hydrolyzed four times more slowly than the corresponding adenosine 5′-phosphoimidazolide. Epimerization between the diastereomers of Imp(S)A took place more quickly than the hydrolysis of Imp(S)A in aqueous solution. The uranyl ion catalyzed polymerization of Imp(S)A in neutral aqueous solution yielded, preferentially, a series of 5′-thiophosphorylated 2′-5′ linked thiophosphate oligoadenylates with R_p configuration. The corresponding adenosine 5′-thiophosphobenzimidazolide (Bzimp(S)A) was prepared in a similar way, and R_p and S_p diastereomers of Bzimp(S)A were separated by HPLC. (S_p)-Bzimp(S)A was polymerized by the uranyl ion catalyst efficiently giving 2′-5′ linked (R_p)-thiophosphate oligoadenylates up to a hexamer with both high regio- and stereoselectivity. On the other hand, uranyl-ion catalyzed polymerization of (R_p)-Bzimp(S)A proceeded inefficiently, and 2′-5′ linked (S_p)-thiophosphate di- and triadenylates were formed with low stereoselectivity. The polymerization took place by an SN₂ reaction pathway with inversion of the thiophosphoryl group of Imp(S)A or Bzimp(S)A. The mechanistic role of the uranyl ion in this regio- and stereocontrolled polymerization is described briefly.