Total Synthesis of Gagunin E

加古宁E的全合成

• 批准号: 437106685
• 负责人: Professor Dr. Martin Hiersemann
• 金额: --
• 依托单位: Forschungsgebiet Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/437106685?language=en
• 关键词: Total; Synthesis; Gagunin

The intricate structure of the unique marine diterpenoid gagunin E rests on a rare homoverrucosane scaffold of extraordinary molecular complexity. The molecular architecture of gagunin E is characterized by a pentahydroxylated and fourfold esterificated tricyclic AB-cis-BC-trans configured cyclohepta[e]hydrindane skeleton. This curved backbone is decorated by two angular methyl groups on the convex and an isopropyl group on the concave face. Furthermore, ten chirality centers in very close proximity are integral part of the homoverrucosane scaffold. Gagunin E exerts a significant biological activity (LC50 = 0.03 mg/mL, 49 nM, against the human myelogenous leukemia cell line K562) but access to the natural product from the natural source is severely limited (3 mg from 1.8 kg of the dried sponge). Here, we propose a research project aimed at the enantioselective total synthesis of gagunin E. Several key objectives will be addressed, for instance: (i) we envision to establish an unprecedented variant of a H(ydroxyl)D(directed)D(iels)A(alder) reaction to assemble the pivotal AB-cis hydrindanoid segment of gagunin E; (ii) we intend to assign the currently unknown absolute configuration of gagunin E by total synthesis; (iii) we will continue our collaborative efforts to explore the MDR modulating properties of gagunin E and its derivatives; (iv) we are seeking to launch collaborative efforts to shed light on the molecular mode of action of gagunin E against K562, embarking with the working hypothesis that gagunin E represents a Bcr-Abl tyrosine-kinase inhibitor.

独特的海洋二萜加古宁 E 的复杂结构依赖于具有非凡分子复杂性的稀有高聚壳烷支架。加古宁 E 的分子结构特征为五羟基化和四酯化三环 AB-顺式-BC-反式配置的环庚[e]茚满骨架。这种弯曲的主链由凸面上的两个有角甲基和凹面上的异丙基装饰。此外，十个非常接近的手性中心是高聚壳烷支架的组成部分。 Gagunin E 具有显着的生物活性（针对人骨髓性白血病细胞系 K562，LC50 = 0.03 mg/mL，49 nM），但从天然来源获取天然产物的机会受到严重限制（从 1.8 kg 干燥海绵中提取 3 mg）。在这里，我们提出了一个针对加古宁 E 对映选择性全合成的研究项目。将解决几个关键目标，例如：（i）我们设想建立一种前所未有的 H(ydroxyl)D(directed)D(iels)A(alder) 反应变体，以组装加古宁 E 的关键 AB-cis Hydrindanoid 片段； (ii) 我们打算通过全合成来确定目前未知的加古宁 E 的绝对构型； (iii) 我们将继续合作探索加古宁 E 及其衍生物的 MDR 调节特性； (iv) 我们正在寻求开展合作，以阐明加古宁 E 对抗 K562 的分子作用模式，并以加古宁 E 代表 Bcr-Abl 酪氨酸激酶抑制剂的工作假设为出发点。