Synthesis of 2′-β-fluoro-substituted nucleosides by a direct approach

Recent research activities directed toward the synthesis of 2′-β-fluoro-substitutednucleosides by nucleophilic displacement of an activated 2′-hydroxy group of preformedribonucleosides are reviewed. In the pyrimidine-C-nucleoside area, direct fluorination ofa 4,5′-anhydro-C-nucleoside triflate with TASF afforded the desired 2′-β-fluoro-1-methyl-ψ-uridine (C-FMAU). A similar strategy in regular pyrimidine series by using the corresponding2,5′-O-, 2,3′-O- and 5′,6-anhydro nucleoside derivatives did not give thedesired fluoro-containing products. An interesting triflyl migration was discovered whena triflate nucleoside was treated with LiCl in HMPA. The carbocyclic analog of theadenosine containing a fluorine in the 2′-β configuration was prepared from O^5′, O^3′, N⁶-tribenzoylaristeromycin in reaction with DAST. A similar treatment of purine nucleosidesled to decomposition. When, however, inosine, adenosine and guanosine were tritylatedat the 3′,5′ positions of the sugar moiety and suitably protected at the base, thecorresponding 2′-β-fluoro-substituted arabino-nucleosides were obtained by treatmentwith DAST in moderate to good yields. Deprotection afforded the desired F-ara-H,F-ara-A and F-ara-G. The role of the bulky trityl groups at the 3′,5′ positions of thesugar and the effect of C-3′-endo to C-2′-endo conformational shift on the reaction courseof 2′-hydroxyl group with DAST is discussed.