SYNTHESIS OF 6-SUBSTITUTED THYMINE 2′-DEOXY-2′-FLUORO-D-ARABINOFURANOSYL NUCLEOSIDES

Abstract

New 6-fluorothymine 2′-deoxy-2′-fluoro-D-arabinofuranosyl nucleosides were prepared by the silyl method starting from persilylated 6-fluorothymine and 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide. A mixture of benzoylated N(1)-β- and α-anomeric 6-fluorothymine 2′-fluorodeoxy arabinonucleosides was obtained by refluxing in CHCl3 with
a 34  % yield. 6-Substituted (OMe, NH2) thymine 2′-deoxy-2′-fluoro-D-arabinonucleosides were prepared by the treatment of individually protected N(1)-α/β-D-arabinosides with methanolic ammonia. It is shown that mild deprotection of the benzoyl groups of intermediate 6-fluorothymine β-nucleoside using LiOH monohydrate in a mixture of acetonitrile-water resulted in the target nucleoside in good yields (82  %). An approach to the synthesis of 2′-fluoro-6,3′-O-α-D-anhydronucleosides was developed as a result of the intramolecular substitution reaction of the fluorine atom at the C(6)-position of the heterocycle by the C(3′)-hydroxyl group of an intermediate deprotected nucleoside during the removal of the protective groups of 6-fluorothymine N(1)-α-arabinonucleoside under the basic reaction conditions. The structures of all synthesized nucleosides were proved by UV-, NMR-, CD- and mass-spectroscopy.