细胞松弛素多聚体及抗疟疾天然产物spiroaxillarone A的全合成

	细胞松弛素多聚体及抗疟疾天然产物spiroaxillarone A的全合成
	龙先文
导师	邓军
关键词	细胞松弛素多聚体，仿生全合成，[5+2]环加成反应，抗疟疾活性，硫Michael加成 Merocytochalasan, Biomimetic synthesis, [5+2] Cycloaddition, Antimalarial, Thiol-Michael addition
摘要	结构复杂多样的天然产物一直是药物发现的重要来源，然而由于其自然来源有限，极大地限制了后续的相关研究，因此，如何简洁、高效地大量获得天然产物及其类似物成为天然产物化学、药物化学、有机化学和化学生物学的重要研究内容。本论文以此重要问题为导向，采用生源启发的合成策略对细胞松弛素多聚体以及抗疟疾天然产物spiroaxillarone A进行了全合成研究。本论文主要包括以下三个部分内容。第一部分：系统的总结了国内外多个课题组的研究工作，以期在前人的工作的基础上实现该类分子更简洁、更高效全合成。第二部分：细胞松弛素多聚体因其新颖的结构和显著的抗肿瘤生物活性吸引着众多合成化学家和药理学家的关注，其多环系、连续季碳中心的复杂化学结构给有机合成化学家带来了极大的挑战，迄今为止仍未有全合成的报道。因此，如何通过已有的化学手段以及发展新的化学合成方法来实现这类分子的全合成对揭示其生物合成途径以及后续药物化学、药理学研究具有重大的意义。我们从简单的手性片段出发，以分子间HWE反应，Diels-Alder反应和分子内HWE反应为关键反应，最长线性步骤10-11步完成了aspochalasins D，B的首次规模化全合成。随后基于生源启发的网络分析策略，采用酸催化的苯并呋喃Diels-Alder反应，邻苯三酚[5+2]环加成反应，光引发的[2+2]环加成串联α-羟基酮重排反应以及PMe3介导的类MBH反应完成了十余个细胞松弛素多聚体的首次全合成。第三部分：近年来，随着疟原虫新耐药性的出现，可用于疟疾治疗的药物种类和数量极其有限。因此针对产生耐药性的疟原虫虫株，开发新型的抗疟疾药物成为广大药物化学家亟需解决的重要问题。Spiroaxillarone A是从鞘苞花（Cyanotis axillaris）中分离出的一种含有新型对称螺环双萘结构的天然产物。对恶性疟原虫有显著的抗疟活性（IC50 = 2.32 μM），有望成为潜在的新型抗疟疾药物。实现该分子的全合成有助于阐明该分子的生物合成路径以及为后续抗疟疾先导化合物的研究奠定坚实的合成基础。我们以可逆的硫杂Michael加成和邻苯醌烯醇Michael加成反应为关键反应，从商业可得的3,4-二羟基苯甲醛出发，经6步以22%的总收率完成了spiroaxillaroneA的高效全合成。; Natural products with complex and diverse structures are the important source of drug discovery. However, the related research has been greatly limited attributed to their rare natural sources. Therefore, how to obtain large scale of natural products and their analogs in concise and efficient manners has become an important research field in natural product chemistry, medicinal chemistry, organic chemistry and chemical biology. In this paper, guided by this important question, the total synthesis of merocytochalasan and antimalarial spiroaxillarone A was achieved using a bioinspired synthetic strategy. The dissertation includes the following three chapters. The first chapter: We summarizes the research work of several research groups, realize the more efficient synthesis molecules on the basis of previous work. The second chapter: Merocytochalasans has attracted extensive attention from synthetic chemists and pharmacologists due to novelty structure and significant antitumor biological activity. No total synthesis has been reported so far. Its complex polycyclic system, continuous quaternary carbon poses challenges to organic synthetic chemists. It is of great significance to complete the total synthesis of merocytochalasans through existing chemical methods and the development of new chemical synthesis methods. We completed the scalable total synthesis of aspochalasin D and B in the longest linear step 10-11 via intermolecular HWE reaction, Diels-Alder reaction and intramolecular HWE reaction from known chiral fragments. Based on bioinspired network analysis, ten different merocytochalasans was obtained in 4–5 steps from aspochalasin D and epicoccine by using bioinspired Diels-Alder and [5+2] cycloaddition reaction, sunlight-promoted [2+2] cycloaddition and subsequent acyloin rearrangement cascade, and PMe3 initiated MBH-type reaction. The third chapter: With the emergence of new drug resistance of Plasmodium in recent years, the drugs can be used for malarial treatment are limited. Therefore, developing new antimalarial drugs for drug-resistant Plasmodium strains has become an urgent problem for medicinal chemists. Spiroaxillarone A contained unique spirobisnaphthalene, which exhibited significant antimalarial activity against P. falciparum with an IC50 value of 2.32 μM, making it a potential lead compound for antimalarial drugs. Achieveing the total synthesis of this molecule will help to clarify the biosynthetic pathway, provide synthetic foundation for the subsequent research on anti-malarial lead compounds. We have accomplished the total synthesis of (±)-spiroaxillarone A in six steps with an overall yield of 22% from commercially available 3,4-dihydroxybenzaldehyde, the key reaction included reversible sulfa-Michael addition and an enol?Michael addition to o-quinone
语种	中文
	2022-05
学位授予单位	中国科学院大学
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75135
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	龙先文. 细胞松弛素多聚体及抗疟疾天然产物spiroaxillarone A的全合成[D]. 中国科学院大学,2022.

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