合成路线:Previously,it was reported that D-ribose was synthesized from D-xylose,the epimer of D-ribose,via a stereoselective oxidation-reduction procedure,albeit in low yield.This strategy was adapted to prepare the L-ribose derivative (V) for the practical synthesis of L-FMAU as well as related nucleosides.After pyridinium dichromate (PDC) oxidation,ketone (III) was reduced to an alcohol using NaBH4.It should be mentioned that due to the stereoelectronic effects of the 1,2-O-isopropylidene group,the hydride preferentially attacks from the beta-face.After a series of reactions,compound (V) was obtained and treated with saturated hydrogen chloride in CH2Cl2 at 0 C followed by the migration of the benzoyl group and treatment with SO2Cl2 and imidazole in DMF/CH2Cl2 to give a imidazolyl intermediate.The imidazole derivative was fluorinated with a mixture of KHF2 and 48% HF/H2O to give 1,3,5-tri-O-benzoyl-2-fluoro-alpha-L-arabinofuranose,which was converted to bromosugar (VI) using 45% HBr/AcOH.Without further purification,the bromosugar was condensed with silylated thymine in anhydrous CHCl3 in refluxing conditions to give protected L-FMAU with high stereoselectivity,which was further treated with NH3/CH3OH for debenzoylation to give L-FMAU.Due to the availability and high cost of L-xylose,however,we have developed another procedure from L-arabinose.L-Arabinose is a natural sugar with reasonable cost.The anomeric position was protected with a benzyl group in acidic conditions to the pyranose form and the vicinal cis-hydroxy groups were protected with an isopropylidene group.In similar conditions as for L-xylose,PDC was used for the oxidation reaction to obtain ketone (IV),which was reduced with NaBH4 in methanol with high stereoselectivity as described for L-xylose.After deprotection of compound (IV) using 4% CF3CO2H,the resulting L-ribose was sequentially treated with 1% HCl/MeOH,BzCl/pyridine and H2SO4/AcO/AcOH to obtain compound (V).The remaining steps to L-FMAU were the same as described for the L-xylose route.
参考文献标题:Fluorocarbohydrates in synthesis.An efficient synthesis of 1-(2-deoxy-2-fluoro-?D-arabinofuranosyl)-thymine (?D-FMAU)
文献作者:Brundidge; Tann,C.H.; Brodfuehrer,P.R.; et al.
参考来源:J Org Chem 1985,503644-6
合成路线:Previously,it was reported that D-ribose was synthesized from D-xylose,the epimer of D-ribose,via a stereoselective oxidation-reduction procedure,albeit in low yield.This strategy was adapted to prepare the L-ribose derivative (V) for the practical synthesis of L-FMAU as well as related nucleosides.After pyridinium dichromate (PDC) oxidation,ketone (III) was reduced to an alcohol using NaBH4.It should be mentioned that due to the stereoelectronic effects of the 1,2-O-isopropylidene group,the hydride preferentially attacks from the beta-face.After a series of reactions,compound (V) was obtained and treated with saturated hydrogen chloride in CH2Cl2 at 0 C followed by the migration of the benzoyl group and treatment with SO2Cl2 and imidazole in DMF/CH2Cl2 to give a imidazolyl intermediate.The imidazole derivative was fluorinated with a mixture of KHF2 and 48% HF/H2O to give 1,3,5-tri-O-benzoyl-2-fluoro-alpha-L-arabinofuranose,which was converted to bromosugar (VI) using 45% HBr/AcOH.Without further purification,the bromosugar was condensed with silylated thymine in anhydrous CHCl3 in refluxing conditions to give protected L-FMAU with high stereoselectivity,which was further treated with NH3/CH3OH for debenzoylation to give L-FMAU.Due to the availability and high cost of L-xylose,however,we have developed another procedure from L-arabinose.L-Arabinose is a natural sugar with reasonable cost.The anomeric position was protected with a benzyl group in acidic conditions to the pyranose form and the vicinal cis-hydroxy groups were protected with an isopropylidene group.In similar conditions as for L-xylose,PDC was used for the oxidation reaction to obtain ketone (IV),which was reduced with NaBH4 in methanol with high stereoselectivity as described for L-xylose.After deprotection of compound (IV) using 4% CF3CO2H,the resulting L-ribose was sequentially treated with 1% HCl/MeOH,BzCl/pyridine and H2SO4/AcO/AcOH to obtain compound (V).The remaining steps to L-FMAU were the same as described for the L-xylose route.
参考文献标题:Synthesis of D-ribose from D-xylose
文献作者:Oka,K.; Wada,H.
参考来源:Yakugaku Zasshi 1963,83890-1
产品链接: CAS No. 163252-36-6››