Keto-fluorothiopyranosyl nucleosides: a convenient synthesis of 2- and 4-keto-3-fluoro-5-thioxylopyranosyl thymine analogs.

A novel series of fluorinated keto-β-d-5-thioxylopyranonucleosides bearing thymine as the heterocyclic base have been designed and synthesized. Deprotection of 3-deoxy-3-fluoro-5-S-acetyl-5-thio-d-xylofuranose (1) and selective acetalation gave the desired isopropylidene 5-thioxylopyranose precursor 3. Acetylation and isopropylidene removal followed by benzoylation led to 3-deoxy-3-fluoro-1,2-di-Ο-benzoyl-4-O-acetyl-5'-thio-d-xylopyranose (6). This was condensed with silylated thymine and selectively deacetylated to afford 1-(2'-Ο-benzoyl-3'-deoxy-3'-fluoro-5'-thio-β-d-xylopyranosyl)thymine (8). Oxidation of the free hydroxyl group in the 4'-position of the sugar led to the formation of the target 4'-keto compound together with the concomitant displacement of the benzoyl group by an acetyl affording, 1-(2'-O-acetyl-3'-deoxy-3'-fluoro-β-d-xylopyranosyl-4'-ulose)thymine (9). Benzoylation of 3 and removal of the isopropylidene group followed by acetylation, furnished 3-deoxy-3-fluoro-1,2-di-Ο-acetyl-4-O-benzoyl-5'-thio-d-xylopyranose (12). Condensation of thiosugar 12 with silylated thymine followed by selective deacetylation led to the 1-(4'-Ο-benzoyl-3'-fluoro-5'-thio-β-d-xylopyranosyl)thymine (14). Oxidation of the free hydroxyl group in the 2'-position and concomitant displacement of the benzoyl group by an acetyl gave target 1-(4'-O-acetyl-3'-deoxy-3'-fluoro-β-d-xylopyranosyl-2'-ulose)thymine (15).