Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl-alpha-l-lyxopyranosyl]thymine.
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-alpha-l-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested that this nucleoside would show the (4)C(1) conformation in contrast to anhydrohexitol nucleosides (1) whose most stable conformation is (1)C(4). 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 alpha-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-alpha-l-lyxopyranose with beta-tributylstannyl styrene. This allowed stereoselective beta-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/reduction (OsO(4), NaIO(4)/NaBH(4)) 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 SnCl(2) 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 ((4)C(1)).
Vanheusden
Veerle
V
Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Gent, Belgium.
Busson
Roger
R
Herdewijn
Piet
P
Van Calenbergh
Serge
S
D002236:Carbohydrate Conformation; D009705:Nucleosides / Q000138:chemical synthesis*; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
C499199:1-(2,4-dideoxy-4-C-hydroxymethyl-alpha-l-lyxopyranosyl)thymine; D009705:Nucleosides; D013941:Thymine