Synthesis of 2'-β-Fluoro- and 3'-α-Fluoro-Substituted Guanine Nucleosides. Effects of Sugar Conformational Shifts on Nucleophilic Displacement of the 2'-Hydroxy and 3'-Hydroxy Group with DAST

Article abstract of DOI:10.1021/jo00052a055

Tritylation of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)guanosine (4) with TrCl/DMAP followed by TrCl/AgNO3 afforded a mixture of isomeric 3',5'-di-O-trityl and 2',5'-di-O-trityl derivatives 6 and 7, which were separated on a silica gel column to give 6 and 7 in 40percent and 50percent yield, respectively.Upon treatment with DAST, 6 was converted into the corresponding 2'-β-fluoro nucleoside 8 in 43percent yield.Deprotection of the 2-N-acetyl group occurred during the reaction.Removal of the 6-O-NPE group from 8 with DBU/pyridine, followed by detritylation with CF3COOH/CHCl3, gave F-ara-G (1b) in good yield.The same treatment of 7 with DAST did not lead to nucleophilic substitution with fluoride ion, but only decomposition took place.Treatment of the 2',5'-di-O-trityl nucleoside 7 with CF3SO2Cl/DMAP in CH2Cl2, followed by PhCO2K/HMPA, afforded the corresponding xylofuranosyl derivative 16 along with 6-O-deprotected nucleoside 19.The 6-O-NPE group was completely removed in the reaction of triflate nucleoside 15 with CH3CO2Na/HMPA.The obtained diacetyl nucleoside 20 under hydrolysis with Et3N/MeOH/H2O gave 9-(2,5-di-O-trityl-β-D-xylofuranosyl)guanine (22).Upon reaction of derivative 22 with DAST no formation of the desired 3'-fluoro nucleoside 23 was observed, but only decomposition took place.When, however, the triflate nucleoside 15 was treated with CH3COONa in DMF instead of HMPA the corresponding diacetyl nucleoside 17 with intact 6-O-NPE group was obtained.This compound was hydrolyzed with Et3N/MeOH/H2O to give the 2-N-acetyl derivative 18, which was smoothly converted into the desired 3'-α-fluoro-substituted nucleoside 24 in 76percent yield.Again, removal of the 2-N-acetyl group occured during the reaction with DAST.Compound 24 was deprotected with DBU/pyridine followed by CF3COOH/CHCl3 to give 3'-fluoro-3'-deoxyguanosine in good yield (3b).In a similar manner the O²,O⁵,N⁶-tritrityladenosine (25) was converted into the corresponding 3'-deoxy-3'-fluoroadenosine (3a).