Synthesis of Nucleoside 5'-O-(1,3-Dithiotriphosphates) and 5'-O-(1,1-Dithiotriphosphates)

Article abstract of DOI:10.1021/jo00005a023

The synthesis of 3'-deoxy-3'-azidothymidine 5'-O-(1,3-dithiotriphosphate) (5) as the first example of a nucleoside 5'-O-(1,3-dithiotriphosphate) is described. 2-Chloro-4H-1,3,2-benzodioxaphosphorin-4-one phosphitylates the 5'-hydroxy group of 3'-deoxy-3'-azidothymidine to form intermediate 1.Reaction of 1 with thiopyrophosphate (9) and sulfur results in the formation of an unseparable mixture of 3'-deoxy-3'-azidothymidine 5'-O-(1,3-dithiotriphosphate) (5) and 3'-deoxy-3'-azidothymidine 5'-O-(1,2-dithiotriphosphate) (3).Selective hydrolysis of 5 allows isolation of 3.However, reaction of 1 with P¹-O-(cyanoethyl)-P¹-thiopyrophosphate (8) and sulfur produced the diastereomers of 5 in good yield.Compound 8 is prepared by reaction of 3-hydroxyproprionitrile with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, pyrophosphate, and sulfur to yield 10, which is ring opened to 8 by reaction with ethylenediamine.Hydrolysis of this compound leads to 9.An alternative route to nucleoside 5'-O-(1,3-dithiotriphosphates) consists of reacting a nucleoside 5'-O-(1-thiocyclotriphosphate) such as 13 with Li2S.This reaction, when performed in pyridine/dioxane, leads to a mixture of the nucleoside 5'-O-(1,3-dithiotriphosphate) and the nucleoside 5'-O-(1,1-dithiotriphosphate).The latter is the only nucleotide product when the reaction is carried out in DMF.