Ring-expanded nucleoside analogues. 1,3-dioxan-5-yl pyrimidines

1,3-Dioxan-5-yl pyrimidine nucleoside analogues, higher homologues of antiviral and anticancer 1,3-dioxolanes, were prepared from bis-1,3-tritylglycerol and 3-benzoylated bases (uracil, 5-fluorouracil, thymine). Mitsunobu condensation, deprotection, and cycloacetalization gave cis/trans mixtures of 2,5-disubstituted-1,3-dioxanes in which the desired cis stereoisomers predominated. Cytosine derivatives could not be obtained in this manner; N-4-benzoylcytosine afforded an O-2 alkylated Mitsunobu product that rearranged to an O-2-(2,3-dihydroxypropyl)cytosine on detritylation with aqueous acetic acid. Cytosine and 5-fluorocytosine nucleosides were therefore prepared from the corresponding uracils via their 1,2,4-triazole derivatives. H-1 NMR data established the conformational preference for equatorial 2'-hydroxymethyl and axial 5'-base in the cis isomers; the trans compounds were diequatorial. Despite their conformations, the cis nucleosides showed no antiviral activity.