Synthetic studies on natural products using a new approach via Diels-Alder reaction and fragmentation reaction

使用 Diels-Alder 反应和裂解反应新方法进行天然产物的合成研究

• 批准号: 11672124
• 负责人: NAGAOKA Hiroto
• 金额: $ 2.24万
• 依托单位: MEIJI PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672124/
• 关键词: zaragozic acids; synthesis; 7-oxabicycol[2.2.1]hepta-2,5-diene; Diels-Alder reaction; fragmentation reaction; 7-oxabicyclo[2.2.1]heptane; 不斉加水分解; Zaragozic Acids; 7-オキサビシクロ[2.2.1]ヘプタン誘導体; 2,8-オキサビシクロ[3.2.1]オクタン誘導体

Zaragozic acids (squalestatins), a family of structurally related fungal metabolites isolated from different organisms by three independent groups in 1992, have been found to be potent inhibitors of squalene synthase and farnesyl-protein transferase. These compounds share a common 2,8-dioxabicyclo[3.2.1]octane core and differ in two lipophilic side chains (e.g., zaragozic acid A). A number of reports about their synthesis reflected their unique structures and biological activities. Their most characteristic feature is the highly oxygenated hydrophilic core bearing six contiguous chiral carbon atoms. Total syntheses of zaragozic acids have been reported by several groups, however, various synthetic approaches continue to be investigated. We developed a new synthetic route for construction of the core moiety of zaragozic acids from a furan derivative. This synthesis involves two crucial steps for the regio- and stereoselective introduction of oxygen functionalities into the C(3), C(4), C(6) and C(7) positions on 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative which was obtained by Diels-Alder reaction of 2,5-disubstituted furan with dimethyl, and Grob fragmentation-reduction-iodo acetalization reaction of 7-oxabicyclo[2.2.1]heptane derivative to give 2,8-dioxabicyclo[3.2.1]octane ring system. In addition, hydrolysis of symmetrical esters in 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative by pig liver esterase (PLE) gave half ester in good yield (70% ee).

1992年，三个独立的研究小组从不同的生物体中分离出了一系列结构相关的真菌代谢产物，即萨拉戈萨酸（Zaragozic acids，squalestatins），它们被发现是角鲨烯合成酶和法尼基蛋白转移酶的有效抑制剂。这些化合物共有一个共同的2，8-二氧杂双环[3.2.1]辛烷核，不同之处在于两个亲脂性侧链（例如，萨拉戈萨酸A）。大量的合成报道反映了它们独特的结构和生物活性。它们最典型的特征是带有六个连续手性碳原子的高度氧化的亲水性核。几个研究小组已经报道了萨拉戈萨酸的全合成，然而，各种合成方法仍在研究中。我们开发了一种新的合成路线，用于从呋喃衍生物构建萨拉戈萨酸的核心部分。该合成包括两个关键步骤，即在7-氧杂双环[2.2.1]庚-2，5-二烯衍生物的C（3）、C（4）、C（6）和C（7）位上区域和立体选择性地引入氧官能团，该衍生物是通过2，5-二取代呋喃与二甲基，7-氧杂双环[2.2.1]庚烷衍生物经Grob断裂-还原-碘缩醛化反应得到2，8-二氧杂双环[3.2.1]辛烷环系。此外，猪肝酯酶（PLE）水解7-氧杂双环[2.2.1]庚-2，5-二烯衍生物中的对称酯，以良好的产率（70%ee）得到半酯。

项目成果

Haruta Koshimizu: "A New Synthetic Route for Construction of the Core of Zaragozic Acids"Tetrahedron Letters. 40・14. 2777-2780 (1999)

Haruta Koshimizu：“构建萨拉戈兹酸核心的新合成路线”Tetrahedron Letters 40・14 2777-2780（1999）。

Haruta Koshimizu, Tomo Baba, Takehiko Yoshimitsu, and Hiroto Nagaoka: "A New Synthetic Route for Construction of the Core of Zaragozic Acids"Tetrahedron Letters. 40. 2777-2780 (1999)

Haruta Koshimizu、Tomo Baba、Takehiko Yoshimitsu 和 Hiroto Nagaoka：“构建萨拉戈兹酸核心的新合成路线”四面体字母。