根据HCMV蛋白酶晶体结构和拟肽类抑制剂与酶复合物的晶体结构数据，设计了拟肽类HCMV蛋白酶抑制剂化合物库Ⅰ，并拟采取液相组合方式，通过两步策略，首先由四种构建块分子：羧酸、胺、醛或酮和异腈，经Ugi四组分缩合反应生成Ⅱ，然后氧化来合成化学库。介绍其中最重要的构建块异腈Ⅲ的前体Ⅳ的合成。首先将酒石酸二乙酯由相应胺进行酰胺化产生酒石酸二酰胺Ⅴ。酒石酸二酰胺用过碘酸氧化裂解产生乙醛酸酰胺Ⅵ，然后不经分离，直接在KF-氧化铝的催化下完成硝基乙烷的加成。由此生成的2-羟基-3-硝基丁酰胺Ⅶ可经Zn+NH4Cl或Zn+NH4Cl+催化量10%Pd-C还原为2-羟基-3-氨基丁酰胺Ⅷ，再经过氨基的甲酰化生成2-羟基-3-甲酰胺基丁酰胺Ⅳ。但是在甲酸乙酯存在下，用H2/Pd-C对Ⅶ的硝基进行还原，得到的Ⅷ中的氨基可当即被甲酰化，使由Ⅶ到Ⅳ的两步反应一步完成。%The human cytomegalovirus(HCMV)is a member of the herpesvirusfamily infecting 40%～80% of the general population.HCMV can cause fatal infections in immunocompromised individuals.HCMV encodes a serine protease that is essential for viral replication and is a potential target for antiviral drug development.In this paper a peptidomimetic library Ⅰ for HCMV protease inhibitor was designed based on the interactions between the protease active site and its peptidomimetic inhibitors.The library was synthesized in the manner of liquid-phase combinatorial synthesis,by a two-step strategy.Firstly by the Ugi four-component condensation reaction,from four kinds of building blocks-carboxylic acids,amines,aldehydes or ketones and isocyanides,then followed by oxidation of the product Ⅱ to form the library.The isocyanide Ⅲ was the most important block for building up the library.The syntheses of the former compounds Ⅳ of the isocyanides were described.Tartaric acid diamides Ⅴ were obtained first from diethyl tartrate in good yield.The oxidative scission of Ⅴ by periodic acid gave glycoxylic amides Ⅵ,which were then nitroethylated immediately without working up and produce 2-hydroxy-3-nitrobutyric amide Ⅶ catalyzed by KF-alumina.The nitro group of Ⅶ was then reduced by Zn+NH4Cl or Zn+NH4Cl+catalytic amount of 10%Pd-C to yield 2-hydroxy-3-aminobutyric amide Ⅶ,and followed by formylation of the amino group to give 2-hydroxy-3-formamidobutyric amide Ⅴ.With the occurrence of H2/Pd-C and ethyl formic ester,the reduction of the nitro group and the formylation of the amino group could be finished in one step.By this way three isocyanide formers were synthesized with the R group benzyl,cyclohexyl and 2-cyclohexenylethyl respectively.
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