The Journey of Schinortriterpenoid Total Syntheses
The Journey of Schinortriterpenoid Total Syntheses
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五香三萜全合成之旅
DOI：
10.1021/acs.accounts.8b00569
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发表时间：
2019
影响因子：
18.3
通讯作者：
Yang Zhen
中科院分区：
文献类型：
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作者：
Yang Zhen
五味子科植物是传统中草药的重要组成部分，常用于治疗各种疾病。因此，这些五味子科植物是发现新的化学实体和开发新的治疗药物的宝贵资源。近二十年来，五味子科植物中具有生物活性和结构新颖的三萜化合物的鉴定取得了长足的进展。特别是，孙和他的同事已经成功地从五味子科中分离出了100多种北三萜。其中一些北三萜对肝炎、肿瘤和HIV-1有很强的抑制活性。然而，这些北三萜在五味子科植物中的天然稀缺性阻碍了它们的分离和进一步的生物医学开发，它们的生物合成尚未完全阐明。因此，开发高效、简化的全合成这些具有重要药用价值的北三萜是十分重要和紧迫的。这样的合成将为详细的生物学研究提供充足的材料，并为新的合成类似物和探针分子提高其生物学功能和阐明其作用方式提供材料。然而，由于其结构的新颖性和复杂性，这些北三萜天然产物的全合成对合成化学家来说是一个重大的挑战，尽管有机合成，特别是全合成在20世纪和21世纪初取得了进展。因此，需要发明和发展新的合成方法和策略，以促进这些北三萜天然产物的全合成。考虑到这一点，自2003年Sun及其同事分离出micrandilactone A(1)以来，我们的团队已经花了15年的时间（Sun et al.Org）。let .2003, 5, 1023−1026)，致力于合成研究，以期开发全合成三萜的方法和策略。在这种情况下，诸如硫脲/ pd催化的烷基羰基环化和硫脲/共催化的Pauson-Khand反应等方法已经被开发出来，以形成这些复杂目标分子的关键环体系和立体中心。这些方法的进步使我们通过分支定向策略首次合成了具有不同结构特征的schindilactone A (2), lancifodidiactone G acetate (6a), 19- dehydroxyisandilactone A(9)和prodidilactone G（10）。在我们的全合成活动中发展的化学不仅帮助我们处理了在合成四个目标分子时遇到的各种挑战，而且还为合成其他天然存在的三萜及其衍生物开辟了新的途径，这可能会产生具有改进的生物功能的分子和工具化合物，从而能够阐明其作用机制或潜在的细胞靶标。本帐户突出了我们的三萜合成的化学演变。
ConspectusPlants in the Schisandraceae family are important components of the traditional Chinese herbal medicines and are often used to treat various illnesses. Therefore, these Schisandraceae plants are valuable sources for the discovery of new chemical entities for novel therapeutic development. Considerable progress has been made in the identification of bioactive and structurally novel triterpenoids from the Schisandraceae family in the past two decades. In particular, Sun and co-workers have successfully isolated over 100 nortriterpenoids from the Schisandraceae family. Some of these nortriterpenoids have strong inhibitory activities toward hepatitis, tumors, and HIV-1. However, the natural scarcity of these nortriterpenoids in the Schisandraceae plants has hampered their isolation and further biomedical development, and their biosynthesis has not been fully elucidated. It is therefore important and urgent to develop efficient and streamlined total syntheses of these medicinally important nortriterpenoids. Such syntheses will provide sufficient materials for detailed biological studies as well as new synthetic analogues and probe molecules to improve their biological functions and elucidate their mode of actions. However, because of their structural novelty and complexity, the total syntheses of these nortriterpenoid natural products present a significant challenge for synthetic chemists, despite the progress made in organic synthesis, particularly total synthesis, in the 20th century and since the beginning of the 21st century. New synthetic methodologies and strategies therefore need to be invented and developed to facilitate the total syntheses of these nortriterpenoid natural products. With this in mind, our group has spent the last 15 years, ever since the isolation of micrandilactone A (1) by Sun and co-workers in 2003 (Sun et al.Org. Lett.2003, 5, 1023−1026), working on synthetic studies with a view to developing methods and strategies for the total syntheses of schinortriterpenoids. Enabling methods such as a thiourea/Pd-catalyzed alkocycarbonylative annulation and a thiourea/Co-catalyzed Pauson–Khand reaction have been developed under these circumstances to form the key ring systems and stereocenters of these complex target molecules. These methodological advances have led us to the first total syntheses of schindilactone A (2), lancifodilactone G acetate (6a), 19-dehydroxyarisandilactone A (9), and propindilactone G (10) with diverse structural features via a branching-oriented strategy. The chemistry developed during our total synthesis campaign has not only helped us to deal with various challenges encountered in the syntheses of the four target molecules, but has also opened up new avenues for synthesizing other naturally occurring schinortriterpenoids and their derivatives, which will likely result in molecules with improved biological functions and tool compounds to enable elucidation of their mechanism of actions or potential cellular targets. This Account highlights the chemistry evolution of our schinortriterpenoid syntheses.