Synthesis of fluorosugar analogues of 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole as antivirals with potentially increased glycosidic bond stability

The metabolic instability in vivo of the glycosidic bond of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole, 2,5,6-trichloro-1-(3-deoxy-3-fluoro-beta-D-ribofuranosyl)benzimidazole, and 2-bromo-5,6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3'5'-dinitryl derivatives, which were fluorinated with DAST and deprotected to yield 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) and 2,5,6-trichloro-1(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low over yield (5%) of 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5,6-trichlorobenzimidazole was condensed with 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.