A synthesis of 9-(2-Deoxy-2-fluoro-β-d-arabinofuranosyl)adenine and Hypoxanthine. An Effect of C3′-Endo to C2′-Endo Conformational Shift on the Reaction Course of 2′-Hydroxyl Group with DAST

O³′,O⁵′,N⁶-Tritrityladenosine (6), 3′,5′-di-O-trityl-N¹-benzylinosine (15), and 3′,5′-di-O-tritylinosine (18) were prepared and subjected to nucleophilic reaction with DAST. Thus, 6 afforded 2′-β-fluorine-substituted nucleoside 11 along with the isomeric 2-deoxy-2-(N-trityladenin-3-yl)-3,5-di-O-trityl-α-d-arabinofuranosyl fluoride (12). Nucleoside 15, under the same treatment with DAST, gave the desired 2′-fluoroarabino derivative 16 exclusively in high yield. Although 18 was converted into the 2′-β-fluoro product 19 under the similar conditions, the yield was low. A plausible mechanism of formation of 12 is discussed. Deprotection of 11 and 16 afforded the desired 9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine (1) and -hypoxanthine (2), respectively, in high yield. The conformational influence of sugar protecting groups on the rate of nucleophilic substitution against elimination is discussed. Treatment of O³′,O⁵′,N¹-benzylinosine (20) with DAST afforded only the elimination products 9-(3′,5′-di-O-benzyl-β-d-erythro-pent-2-enofuranosyl)-1-benzylhypoxanthine (22) and 3-(benzyloxy)-2-[(benzyloxy) methyl]furan (23). On the other hand, 9-(3,5-di-O-trityl-β-d-arabinofuranosyl)adenine (26) (prepared from 6 by triflyation followed by NaOAc treatment and deacetylation) afforded a mixture from which 2′-deoxy-2′-fluoroadenosine (27) and 9-(2-deoxy-3,5-di-O-trityl-d-erythro-pent-1-enofuranosyl)-N⁶-trityladenine (28) were isolated in 60 and 30% yield, respectively. O²′,O⁵′,N⁶-Tritrityladenosine (7) was selectively detritylated with HCO₂H/Et₂O to give O²′,N⁶-ditrityladenosine (30), which, upon treatment with benzyl chloride/KOH, afforded 3′.5′-di-O-benzyl-O²′,N⁶-ditrityladenosine (31). 9-(3,5-Di-O-benzyl-β-d-arabinofuranosyl)adenine (35) was prepared from 31 by further detritylation with CF₃CO₂H/CHCl₃ and triflylation followed by NaOAc treatment and deacetylation of the product. Treatment of 35 with DAST followed by hydrogenolytic debenzylation afforded 2′-deoxy-2′-fluoroadenosine (3) in high yield. The three-step synthesis described herein, albeit about 10% overall yield, is far superior to the currently available multistep procedures which give the desired 2′-fluoroarabinosylpurines in much less overall yields.