jo040130g_si_001.pdf (961.28 kB)

Synthesis and Conformational Analysis of 1-[2,4-Dideoxy-4-C-hydroxymethyl-α-l-lyxopyranosyl]thymine

Download (961.28 kB)
journal contribution
posted on 25.06.2004, 00:00 by Veerle Vanheusden, Roger Busson, Piet Herdewijn, Serge Van Calenbergh
Previously different types of nucleosides with a six-membered carbohydrate moiety have been evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with a 1,4-substitution pattern like 1-[2,4-dideoxy-4-C-hydroxymethyl-α-l-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this nucleoside would show the 4C1 conformation in contrast to anhydrohexitol nucleosides (1) whose most stable conformation is 1C4. The key to the synthesis of 4 involves the stereoselective introduction of the hydroxymethyl group onto the C-4 carbon of the pyranose sugar. Attempts to achieve this via hydroboration/oxidation of a C-4‘-exocyclic vinylic intermediate selectively yielded the undesired α-directed hydroxymethyl group. Therefore, we envisaged another approach in which the C-4 substituent was introduced upon treatment of 2,3-O-isopropylidene-1-O-methyl-4-O-phenoxythiocarbonyl-α-l-lyxopyranose with β-tributylstannyl styrene. This allowed stereoselective β-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/reduction (OsO4, NaIO4/NaBH4) into the desired 4-hydroxymethyl group (20). The resulting 1-O-methyl-2,3,6-tri-O-acetyl-protected sugar was coupled with silylated thymine, using SnCl2 as Lewis acid (22). After suitable protection, Barton deoxygenation of the 2‘-hydroxyl function of the obtained ribo-nucleoside yielded the desired 2‘-deoxynucleoside 4, indeed showing the expected equatorial orientation of the thymine ring (4C1).

History

Exports