ACH-126445, L-I-OddU
Chemical Name: (2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-iodouracil
项目整合开发状态: Preclinical
项目研究机构: University of Georgia (Originator), Yale University (Originator), Achillion (Licensee)
合成路线:L-Gulono-gamma-lactone (I) was reduced with DIBAL and then protected as the diisopropylidene ketal (III).This was converted to 1,6-anhydrogulopyranose (IV) upon treatment with 0.5N HCl.Subsequent oxidative cleavage of (IV) with NaIO4,followed by reduction with NaBH4 provided triol (V),which was protected as the isopropylidene derivative (VI) with acetone and TsOH.Condensation of (VI) with benzoyl chloride in the presence of pyridine yielded benzoate ester (VII).Then,ketal deprotection of (VII) afforded diol (VIII).Oxidative treatment with NaIO4/RuO2 produced acid (IX),and further oxidative decarboxylation with Pb(OAc)4 furnished dioxolanyl acetate (X).5-Iodouracil (XI) was silylated using hexamethyldisilazane and a catalytic amount of (NH4)2SO4.The resulting silylated uracil (XII) was coupled with dioxolanyl acetate (X) in the presence of trimethylsilyl triflate to afford an anomeric mixture of nucleosides (XIII).Title compound was then obtained by deprotection of the benzoate ester of the mixture (XIII) with methanolic ammonia,followed by chromatographic isolation of the desired L-anomer.
📌 参考资料/链接：
参考文献标题:Structure-activity relationships of L-dioxolane uracil nucleosides as anti-epstein barr virus agents
文献作者:Lin,J.S.; Kira,T.; Gullen,E.; Choi,Y.; Qu,F.; Chu,C.K.; Cheng,Y.C.
参考来源:J Med Chem 1999,42(12),2212
📄 详细内容
合成路线:L-Gulono-gamma-lactone (I) was reduced with DIBAL and then protected as the diisopropylidene ketal (III).This was converted to 1,6-anhydrogulopyranose (IV) upon treatment with 0.5N HCl.Subsequent oxidative cleavage of (IV) with NaIO4,followed by reduction with NaBH4 provided triol (V),which was protected as the isopropylidene derivative (VI) with acetone and TsOH.Condensation of (VI) with benzoyl chloride in the presence of pyridine yielded benzoate ester (VII).Then,ketal deprotection of (VII) afforded diol (VIII).Oxidative treatment with NaIO4/RuO2 produced acid (IX),and further oxidative decarboxylation with Pb(OAc)4 furnished dioxolanyl acetate (X).5-Iodouracil (XI) was silylated using hexamethyldisilazane and a catalytic amount of (NH4)2SO4.The resulting silylated uracil (XII) was coupled with dioxolanyl acetate (X) in the presence of trimethylsilyl triflate to afford an anomeric mixture of nucleosides (XIII).Title compound was then obtained by deprotection of the benzoate ester of the mixture (XIII) with methanolic ammonia,followed by chromatographic isolation of the desired L-anomer.
参考文献标题:L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: Asymetric synthesis and structure - Activity relationships
文献作者:Kim,H.O.; Schinazi,R.F.; Shanmuganathan,K.; Jeong,L.S.; Beach,J.W.; Nampalli,S.; Cannon,D.L.; Chu,C.K.
参考来源:J Med Chem 1993,36(5),519