A Novel Synthesis of 2‘-Modified 2‘-Deoxy-4‘-thiocytidines from d-Glucose1

Abstract

Novel 2‘-deoxycytidine antimetabolites, specifically several 2‘-modified 2‘-deoxy-4‘-thiocytidines, were synthesized as potential new antineoplastic agents. Methyl 3-O-benzylxylofuranoside was converted to a 1,4-anhydro-4-thioarabitol 24. Protection of the primary alcohol of 24 gave a common intermediate (15) which was useful for the synthesis of various 2‘-modified 2‘-deoxy-4‘-thionucleosides. Oxidation of the secondary hydroxyl group of 15, followed by the Wittig reaction or treatment with (diethylamido)sulfur trifluoride (DAST) produced 2-deoxy-2-methylene (26) and 2-deoxy-2,2-difluoro (34) derivatives, respectively. Unique Pummerer-type glycosylation between the corresponding sulfoxides and trimethylsilylated N⁴-acetylcytosine produced 2‘-deoxy-2‘-methylene- (10) and 2‘-deoxy-2‘,2‘-difluoro-4‘-thiocytidines (11). On the other hand, treatment of 15 with DAST introduced a fluorine atom with retention of the 2‘-stereochemistry, yielding 40. In contrast, the Mitsunobu reaction of 3-O-benzoyl derivative 53 which was obtained from 15 in five steps, using diphenylphosphoryl azide gave azide derivative 54 with inverted stereochemistry. These derivatives were converted to the corresponding 1-O-acetyl derivatives via the usual Pummerer rearrangement, which were in turn used to synthesize 4‘-thiocytidines 12 and 58. Among the 2‘-modified 4‘-thiocytidines obtained, 2‘-methylene (10) and 2‘-fluoro (12) derivatives were found to have potent antineoplastic properties in vitro.