Synthesis of viridiofungins and zaragozic acids, cholesterol synthesis inhibitors

由于具有较强的角鲨烯合成酶抑制活性，病毒菌素和杂环酸作为开发有效降胆固醇药物的先导化合物而备受关注。在本研究中，我们旨在开发合成这些化合物家族的有效方法。病毒菌素A是从一株绿色木霉(真菌，丝孢菌)中与病毒菌素B和C一起分离得到的。这些病毒菌素具有独特的结构，包括具有C-16长链的普通柠檬酸部分和芳香族氨基酸残基，如酪氨酸、苯丙氨酸和色氨酸。然而，这些化合物的绝对结构尚未确定。在这项研究中，我们首次合成了病毒菌素A三甲酯，使我们能够确定其绝对构型为3S，4S，2‘S。对于Zaragozic酸，我们设想了一种新的策略，该策略依赖于前所未有的二烯基甲醇的双羟基化。我们首先考察了各种二烯基甲醇的双羟化反应，以考察其非对映选择性。结果表明，该反应具有中等到极好的非对映选择性，主要的非对映异构体具有较好的构型，可用于合成杂环酸。现在，我们正在基于上述策略进行扎拉戈齐酸A的合成。

Both viridiofungins and zaragogic acids have attracted much attention as leading compounds for developing an effective cholesterol lowering drug because of their potent squalene synthase inhibitory activity. In this research, we aimed to develop efficient methods for the syntheses of these families of compounds.Viridiofungin A was isolated from a strain of Trichoderma viride Pers.(Fungi, Hyphomycetes) together with viridiofundin B and C.These viridiofungins have unique structures consisting of a common citric acid moiety having C-16 long chain and an aromatic amino acid residue such as tyrosine, phenylalanine, and tryptophane. However, the absolute structures of these compounds were not determined. In this research, we achieved the first synthesis of viridiofungin A trimethyl ester which allowed us to determine its absolute configuration to be 3S, 4S, 2'S.For zaragozic acids, we envisaged a new strategy which relies on unprecedented double dihydroxylation of dialkenylcarbinols. We first examined double hydroxylation of various dialkenylcarbinols to check the diastereoselectivity. As a result, we found that this reaction took place with moderate to excellent diastereoselectivity and the major diastereoisomer possessed desirable configuration for the synthesis of zaragozic acids. Now we are carrying out the synthesis of zaragozic acid A based on the above-mentioned strategy.