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Gagunin E的复杂结构取决于罕见的同种分子复杂性的稀有同源性造成的支架。 Gagunin E的分子结构的特征是五氢氧化和四倍酯的三环AB-CIS-CIS-CIS-CIS-CIS-BC-TRANS构造了CycloHepta [E] Hydrindane骨骼。该弯曲的主链由凸面上的两个角甲基和凹面上的异丙基进行装饰。此外，在非常紧密的近端中，十个手性中心是同种群脚手架的组成部分。 Gagunin E具有重要的生物学活性（LC50 = 0.03 mg/ml，49 nm，针对人脊髓性白血病细胞系K562），但从天然来源访问天然产物的距离受到严重限制（从1.8 kg干燥的海绵中获得3 mg）。在这里，我们提出了一个研究项目，旨在解决Gagunin E的对映选择性总合成。 （ii）我们打算通过总合成分配当前未知的Gagunin E绝对配置； （iii）我们将继续我们的协作努力，以探索Gagunin E及其衍生物的MDR调节属性； （iv）我们正在寻求发起协作努力，以阐明Gagunin E对K562的分子作用方式，并以一种工作假设为基础，即Gagunin E代表了BCR-Abl酪氨酸激酶抑制剂。