Synthesis of viridiofungins and zaragozic acids, cholesterol synthesis inhibitors

胆固醇合成抑制剂viridiofungins和zaragozic酸的合成

• 批准号: 09470487
• 负责人: HATAKEYAMA Susumi
• 金额: $ 5.63万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-09470487/
• 关键词: viridiofungin; zaragozic acid; sphingo lipid synthesis inhibition; antibacterial activity; squalene synthase inhibition; asymmetric synthesis; dialkenylcarbinol; dihydroxylation; ビリジオフンジン天然物; ビリジオフンジンAエステル; キラル合成; 絶対構造の決定

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.

由于其有效的角鲨烯合酶抑制活性，viridiofungins和zaragigic酸作为开发有效降低胆固醇药物的主要化合物而备受关注。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。Viridiofungin A 与 viridiofundin B 和 C 一起从绿色木霉 Pers（真菌、丝菌纲）菌株中分离出来。这些 viridiofungin 具有独特的结构，包括具有C-16长链的常见柠檬酸部分和芳香族氨基酸残基，例如酪氨酸、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viridiofungin A三甲酯，这使我们能够确定其绝对构型为3S、4S、2'S。对于zaragozic酸，我们设想了一种依赖于前所未有的二烯基甲醇双二羟基化的新策略。我们首先检查了各种二烯基甲醇的双羟基化以检查非对映选择性。结果，我们发现该反应以中等至优异的非对映选择性发生，并且主要非对映异构体具有合成萨拉戈酸所需的构型。现在我们正在基于上述策略进行萨拉戈酸A的合成。

项目成果

江角朋之: "Synthesis of Viridiofungin A Trimethyl Ester and Detetmination of the Absolute Structure of Viridiofungin A" Tetrahedron Letters. 39(印刷中). (1998)

Tomoyuki Esumi：“Viridiofungin A 三甲酯的合成和 Viridiofungin A 绝对结构的测定”Tetrahedron Letters 39（出版中）。

江角朋之: "Synthesis of Viridiofungin A Trimethyl Ester and Determination of the Absolute Structure of Viridiofungin A"Tetrahedron Letters. 39. 877-880 (1998)

Tomoyuki Esumi：“Viridiofungin A 三甲酯的合成和 Viridiofungin A 绝对结构的测定”Tetrahedron Letters 39. 877-880 (1998)。

Tomoyuki Esumi: "Synthesis of viridiofungin A Trimetyl Ester and Determination of the Absolute Structure of Viridiofungin A"Tetrahedron Letters. 39. 877-880 (1998)

Tomoyuki Esumi：“viridiofungin A 三甲基酯的合成和 Viridiofungin A 绝对结构的测定”四面体字母。

江角朋之: "Synthesis of Viridiofungin A Trimethyl Ester and Determination of the Absolute Structure of Viridiofungin A" Tetrahedron Letters. 39. 877-880 (1998)

Tomoyuki Esumi：“Viridiofungin A 三甲酯的合成和 Viridiofungin A 绝对结构的测定”Tetrahedron Letters 39. 877-880 (1998)。