The synthesis and structural characterization of both diastereomers of 5′-(hydroxymethyl)-6,5′-cyclo-2′,5′-dideoxyuridine cyclonucleosides

Abstract

A concise synthesis of both C5′ diastereomers of 5′-(hydroxymethyl)-6,5′-cyclo-2′,5′-dideoxyuridine is presented. Individual crystal structures of the fully deprotected S- and R-stereoisomers indicate that the addition of a methylene group between the C5′ and O5′ positions of 6,5′-cyclo-2′-deoxyuridine increases the distance between the nucleobase and backbone. The resulting nucleosides adopt a conformation that more closely mimics A-form rather than B-form nucleotides. Nucleotides of 5′(R)-(hydroxymethyl)-6,5′-cyclo-2′,5′-dideoxyuridine were successfully incorporated into DNA oligonucleotides during automated synthesis, but full-length oligonucleotides were not obtained after post-synthetic cleavage from the solid support due to a base-catalyzed strand cleavage at the site of insertion.