Studies On The Total Synthesis Of 3-C-ethynyl-3-fluoro-β-D-nucleosides

Side effects and emergence of drug-resistant mutants continue to be a critical problem with the antiviral and anticancer nucleosides chemotherapeutic agents. Therefore, the development of structurally new nucleoside derivatives which have potential antiviral and anticancer activities and low toxicity as well as novel resistant profiles are in demand. This paper launches an investigation on the total synthesis of novel 3-C-ethynyl-3-fluoro-β-D-nucleosides mainly including the following:1. The synthesis of 3β-C-ethynyl sugarsAccording to the literature, the 3β-C-ethynyl sugars were synthesized from D-xylose in five steps by a known procedure. The D-xylose was subjected to the protecting reaction with acetone/conc.H2SO4/anhydrous CuSO4 followed by the partly deprotecting reaction with diluted hydrochloride to give the compound (3). The resulting product (3) was further treated with 4-chloro-benzoyl chloride to afford the sugar (4). The compound (4) was oxidized to furnish the keto sugar (5) which was further converted to 3β-C-ethynyl sugar (6) with ethynyl magnesium bromide. The structure of 3β-C-ethynyl sugars was confirmed by comparing their melting point with those in the literature.2. The synthesis of the glycosyl donor—1-O-acetyl-3-C-ethynyl-3-fluoro sugar (12)The 3β-C-ethynyl sugar (6) was benzoylated to give the compound (7) which was further treated with HCl in aqueous MeOH to afford the 3β-C-ethynyl-1-methyl sugar (8). Then the sugar was converted to the 3-C-ethynyl-3-fluoro-1-methyl sugar (9) with DAST. Treatment of sugar (9) with AcOH/Ac2O/H2SO4 afforded the 1-O-acetyl-3-C-ethynyl-3-fluoro sugar (12). The structure and configuration of (7), (8), (9), (12) was identified by NMR combined with the anomeric effect in the carbohydrate chemistry. A neighbouring group participation pathway was proposed for the formation of 3-C-ethynyl-3-fluoro-1-methyl sugar (9).3. The synthesis of the 3-C-ethynyl-3-fluoro-β-D-nucleosidesThe coupling reaction between the glycosyl donor (12) and various bases was studied. A series of protected 3-C-ethynyl-3-fluoro-β-D-nucleosides were obtained through the Silyl-Hilbert-Johnon reaction catalyzed by the F-C catalyst (Lewis acid SnCl4 or TMSOTf). The protected nucleosides were converted to the nucleosides under different conditions including a bicyclic nucleoside (15-OMe). We suggest a possible pathway whereby the 6-chloropurine reacts with the glycosyl donor to give the the N(7)-isomer. A plausible intramolecular cyclization induced by fluorine mechanism was proposed for the formation of (15-OMe).