Synthesis of Adenine Nucleosides with a Reactive (<i>β</i>-Iodovinyl)sulfone or (<i>β</i>-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA

Abstract

Iodosulfonylation of an ethynyl group at the C2 position of 2′-deoxyadenosine or adenosine with TsI provides (E)-2-(β-iodovinyl)sulfones. The latter undergo nucleophilic substitution with amines via an addition–elimination to give β-sulfonylvinylamines (enamines). Acid-catalyzed hydrolysis of the β-sulfonylvinylamines provides 2-(β-keto)sulfones, mechanistically different probes that react with alkyl halides, resulting in α-alkylation. Adenine nucleosides with a β-ketosulfone group at C2, during conversion to their 5′-triphosphate form, undergo an unexpected conversion to 2-carboxylic acid nucleotides. The 5′-triphosphate of 2′-deoxyadenosine-2-carboxylic acid was incorporated by a human DNA polymerase into a one-nucleotide gap DNA substrate.

Keywords

• nucleosides
• purines
• halosulfonylation of alkynes
• (<i>β</i>-halovinyl)sulfones
• (<i>β</i>-keto)sulfones
• <i>β</i>-sulfonylvinylamines