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.
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.
About the Authors
T. S. Bozhok
Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus
Belarus
Researcher
Belarus
Researcher
E. N. Kalinichenko
Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus
Belarus
Corresponding Member, D. Sc. (Chemistry), Deputy Director
Belarus
Corresponding Member, D. Sc. (Chemistry), Deputy Director
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