SYNTHESIS OF 2'-BETA-FLUORO-SUBSTITUTED NUCLEOSIDES BY A DIRECT APPROACH

Recent research activities directed toward the synthesis of 2'-beta-fl uoro-substituted nucleosides by nucleophilic displacement of an activa ted 2'-hydroxy group of preformed ribonucleosides are reviewed. In the pyrimidine-C-nucleoside area, direct fluorination of a 4,5'-anhydro-C -nucleoside triflate with TASF afforded the desired 2'-beta-fluoro-1-m ethyl-psi-uridine (C-FMAU). A similar strategy in regular pyrimidine s eries by using the corresponding 2,5'-O-, 2,3'-O- and 5',6-anhydro nuc leoside derivatives did not give the desired fluoro-containing product s. An interesting triflyl migration was discovered when a triflate nuc leoside was treated with LiCl in HMPA. The carbocyclic analog of the a denosine containing a fluorine in the 2'-beta configuration was prepar ed from O5, O3', N6-tribenzoylaristeromycin in reaction with DAST. A s imilar treatment of purine nucleosides led to decomposition. When, how ever, inosine, adenosine and guanosine were tritylated at the 3',5' po sitions of the sugar moiety and suitably protected at the base, the co rresponding 2'-beta-fluoro-substituted arabino-nucleosides were obtain ed by treatment with DAST in moderate to good yields. Deprotection aff orded 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 the sugar and the effect of C- 3'-endo to C-2'-endo conformational shift on the reaction course of 2' -hydroxyl group with DAST is discussed.