Total Synthesis of Gagunin E

独特的海洋二萜gagunin E的复杂结构依赖于一种罕见的homoverrucosane支架的非凡的分子复杂性。gagunin E的分子结构特征为五羟基化和四重取代的三环AB-顺式-BC-反式构型的环庚并[e]氢茚满骨架。这个弯曲的骨架由凸面上的两个有角的甲基和凹面上的异丙基修饰。此外，非常接近的十个手性中心是高金刚烷骨架的组成部分。Gagunin E具有显著的生物活性（LC 50 = 0.03 mg/mL，49 nM，对人骨髓性白血病细胞系K562），但从天然来源获得天然产物受到严重限制（从1.8 kg干燥海绵中获得3 mg）。本文提出了一个对映选择性全合成gagunin E的研究项目。几个关键目标将得到解决，例如：（i）我们设想建立一个前所未有的H（羟基）D变体（ii）我们打算通过全合成来确定目前未知的gagunin E的绝对构型;（iii）我们会继续合作研究gagunin E及其衍生物调节多药耐药的特性;（iv）我们正在寻求开展合作努力，以阐明gagunin E对K562的分子作用模式，开始工作的假设，即gagunin E代表Bcr-Abl酪氨酸激酶抑制剂。

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.