Synthesis and properties of 2'-deoxy-2'-alpha-C-branched nucleosides and nucleotides

Four functionalized 2'-deoxy-2'-alpha-C-branched nucleosides, namely, 2'-deoxy-2'-alpha-C-(carboxymethyl)-uridine, 2'-deoxy-2'-alpha-acetamidouridine, 2'-deoxy-2'-alpha-C-(hydroxyethyl)uridine, and 2'-deoxy-2'-alpha-C-(2,3-dihydroxypropyl)uridine, have been prepared. Conversion of these nucleosides to their appropriately protected phosphoramidites, followed by tetrazole-induced reaction with 2',3'-di-O-acetyluridine, oxidation, and subsequent deprotection furnished the corresponding dinucleoside monophosphates. During the oxidation of the amide-derived phosphite, partial dehydration occurred to give a mixture of the amide- and nitrile-containing dimers. Interestingly, the ratio of amide to nitrile could be largely controlled by choice of oxidant. The hydroxyethyl- and dihydroxypropyl-modified dimers were particularly resistant to snake venom phosphodiesterase-catalyzed hydrolysis (relative half-lives of 129 and 120, respectively, in comparison to UpU). It is anticipated that these nucleoside analogues will ultimately be used in the construction of ribozymes containing enhanced functionality and nuclease resistance.