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

摘要

Adenosine 5u0001-thiophosphoimidazolide (Imp(S)A) was prepared from adenosine, thiophosphoryl trichloridenand imidazole. It hydrolyzed four times more slowly than the corresponding adenosine 5u0001-phosphoimidazolide.nEpimerization between the diastereomers of Imp(S)A took place more quickly than the hydrolysis of Imp(S)Anin aqueous solution. The uranyl ion catalyzed polymerization of Imp(S)A in neutral aqueous solution yielded,npreferentially, a series of 5u0001-thiophosphorylated 2u0001-5u0001 linked thiophosphate oligoadenylates with Rp configuration.nThe corresponding adenosine 5u0001-thiophosphobenzimidazolide (Bzimp(S)A) was prepared in a similar way, and Rpnand Sp diastereomers of Bzimp(S)A were separated by HPLC. (Sp)-Bzimp(S)A was polymerized by the uranyl ionncatalyst efficiently giving 2u0001-5u0001 linked (Rp)-thiophosphate oligoadenylates up to a hexamer with both high regio- andnstereoselectivity. On the other hand, uranyl-ion catalyzed polymerization of (Rp)-Bzimp(S)A proceeded inefficiently,nand 2u0001-5u0001 linked (Sp)-thiophosphate di- and triadenylates were formed with low stereoselectivity. The polymerizationntook place by an S2 reaction pathway with inversion of the thiophosphoryl group of Imp(S)A or Bzimp(S)A.nThe mechanistic role of the uranyl ion in this regio- and stereocontrolled polymerization is described briefly.