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

Abstract

A novel series of fluorinated keto-beta-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-O-benzoyl-4-O-acetyl-5'-thio-D-xylopyranose (6). This was condensed with silylated thymine and selectively deacetylated to afford 1-(2'-O-benzoyl-3'-deoxy-3'-fluoro-5'-thio-beta-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-b-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-O-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'-O-benzoyl-3'-fluoro-5'-thio-beta-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-b-D-xylopyranosyl-2'-ulose) thymine (15). (C) 2011 Elsevier Ltd. All rights reserved.