抗疟活性天然产物spiroaxillarone A的合成路线开发

	抗疟活性天然产物spiroaxillarone A的合成路线开发
	张敏
导师	邓军
关键词	螺二萘 Spirobisnaphthalenes Spiroaxillarone A Spiroaxillarone A 全碳螺烷 Carbocyclic spirane 抗疟活性 Antimalarial activity 仿生合成 Biomimetic synthesis
摘要	Spiroaxillarone A是从鞘苞花（Cyanotis axillaris）中分离得到的一类具有独特对称螺二萘结构单元的天然产物，其具有显著的抗疟活性（IC50 = 2.32 μM, against Plasmodium falciparum）。我们课题组开发了一条spiroaxillarone A的仿生合成路线，关键步骤包括：分子间乙硫醇对α,β -不饱和酮的加成、邻苯醌的双 1,4-Michael加成以及β -乙硫醇消除。本论文具体包括以下三章内容：第一章综述了螺环季碳的不对称合成方法。螺环化合物大量存在于天然产物及药物分子中，且螺环骨架及潜在的生物活性多样性，吸引了一大批天然产物合成化学家的关注。随着金属催化与有机小分子催化领域的迅速发展，螺环化合物季碳立体中心的催化不对称合成也取得了很大的成功。本文首先从合成螺环化合物的前体底物的六种大类型分类，再针对手性金属催化和有机小分子催化这两个小类型，加以分析和介绍，从而揭示其在含有螺环骨架天然产物合成中的高效性与实用性。第二章作者主要阐述了天然产物spiroaxillarone A合成路线的开发。基于该分子可能的生源合成途径，我们课题组以 6 步 22%的收率实现了spiroaxillarone A的仿生合成，合成亮点有两处：一是铁氰化钾介导的邻苯酚氧化去芳构化串联双 1,4-Michael加成，快速构建螺二萘分子骨架；二是在三乙胺条件下，乙硫醇发生 β -消除，逆迈克加成形成了α,β -不饱和双键。本论文的研究工作亮点在于探索了一种邻苯酚氧化去芳构化串联双 1,4-Michael加成螺环化的策略，实现了核心螺环骨架的构建以及完成了抗疟活性天然产物spiroaxillarone A的全合成工作。第三章为本论文实验部分，详细论述了论文中重要化合物合成实验的具体规范操作和其相关谱图数据。; Spiroaxillarone A, a novel symmetrical spirobisnaphthalene natural product with significant antimalarial activity (IC50 = 2.32 μM, against Plasmodium falciparum), was isolated from aerial part of cyanotis axillaris. A bioinspired strategy is described for total synthesis of spiroaxillarone A by our group. The key steps include an intermolecular ethanethiol 1,4-Michael addition of unsaturated ketones, double o-quinone 1,4-Michael addition, and subsequent β -ethanethiol elimination. This thesis specifically includes the following three chapters: In chapter one, we summarize synthetic strategies about catalytic enantioselective assembly of spirocyclic molecules featuring a spiro quaternary carbon stereocenter. Spirocycles are one of important skeletons due to their unique structure and being a frequent occurrence of natural products. Moreover, unique structural features of spirocyclic compounds have been used for the synthesis of new ligands and catalysts. Both chiral metal catalysis and organocatalysis exhibited great potential to access to various spirocycles with a spiro quaternary carbon stereocenter through catalytic enantioselective strategies. This thesis is organized by the types of substrates, using as the material for spirocycles, further subdivided by two types of catalysts, chiral metal catalysis and organocatalysis. The synthetic strategies show the advantages of the molecular high efficiency and practicality in the synthesis of natural products containing spirocyclic skeletal system. In chapter two, we mainly elaborate the exploration of the synthetic route of natural product spiroaxillarone A. Based on the biosynthetic pathway given in the separation literature, the biomimetic synthesis of (±)-spiroaxillarone A was achieved in six steps with an overall yield of 22% by our group. There are two highlights in the synthesis. To construct the spironaphthalene skeleton, a potassium ferricyanide-mediated cascade reaction - oxidative dearomatization of o-phenol and subsequently double 1,4-Michael addition reaction turns out to be the best way. Second, β-ethanethiol elimination helps the formation of α, β -unsaturated double bond through an ethanethiol-involved reversible sulfa-Michael addition under the condition of triethylamine. The highlight of this paper includes a potassium ferricyanide-mediated cascade reaction, which was proceeded by oxidative dearomatization of o-phenol and subsequently double 1,4-Michael addition spiro cyclization. Finally, we realized the construction of core spirocyclic skeleton and afforded the total synthesis of antimalarial natural product spiroaxillarone A. In chapter three, we will detail the experimental part of this thesis, which concludes the specific standard operation of synthesis and their related NMR spectral data.
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/151853/75097
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	张敏. 抗疟活性天然产物spiroaxillarone A的合成路线开发[D]. 中国科学院大学,2022.

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