导向生物碱多样性合成的几类方法学研究

发布时间：2018-03-24 13:39

本文选题：生物碱合成　切入点：菲啶酮　出处：《华东师范大学》2017年博士论文

【摘要】：方法学和全合成是有机化学研究的两个重要分支。方法学研究重点在于新颖合成方法的发展和反应机制的探索,而全合成研究则侧重于天然产物或重要药物分子的多步合成策略的建立。二者本质上休戚相关,高效的合成方法学的建立可以大大简化天然产物全合成的步骤,另一方面全合成则是检验方法学高效性和应用性的试金石,只有普适性好,选择性高的方法学才可能被成功地运用到天然产物合成当中。本文围绕"方法学导向生物碱多样性合成"这一主题,研究了平面类生物碱菲啶酮、吖啶酮以及立体生物碱氢化吲哚类生物碱的骨架构建方法,主要开展了以下几个方面的研究:1)配体调控区域选择性一碳源插入实现菲啶酮和吖啶酮的多样性合成;2)苯炔参与的多组分C-H活化反应构建菲啶酮类天然产物骨架;3)天然氨基酸手性源构建氢化吲哚骨架及ETP类天然产物多样性单体的合成。具体介绍如下:(1)配体调控的区域选择性一碳源插入实现菲啶酮和吖啶酮的多样性合成菲啶酮(phenanthridinone)和吖啶酮(acridone)是两类重要的天然产物骨架。含有这两类结构的化合物具有多种重要药物活性,并且有一些已成为临床候选药物。除此之外,吖啶酮还是很多光催化剂、发光材料的骨架。因其广泛的应用性,菲啶酮和吖啶酮的合成方法引起了广大化学家关注。通过对菲啶酮和吖啶酮结构的反合成分析,这两类化合物的结构可以通过苯炔、一氧化碳和邻碘苯胺三个组分的组合选择性转化获得。采用配体促进CO插入和氟化试剂调控苯炔释放速度的方式,可以实现反应路径"双向开关"的调控性:在无外加配体参与的条件下得到菲啶酮类化合物,而在双磷配体dppm的参与下生成吖啶酮类化合物。通过这一 "双向开关",可以合成多个菲啶酮和吖啶酮类天然产物以及类似物。核磁跟踪实验直观反映了不同氟化试剂和添加剂对苯炔释放速率的影响,进而揭示配体加速作用和苯炔释放速率控制是实现反应选择性的本质。(2)苯炔参与的多组分C-H活化反应高效构建菲啶酮类天然产物骨架之前的研究发现邻碘苯胺、苯炔和CO的三组分反应可以用来建立菲啶酮这一重要生物碱骨架。但是邻碘苯胺的使用降低了该反应的原子经济性,并且限制了底物普适性。如果能用苯胺代替邻碘苯胺,利用C-H活化策略来实现菲啶酮的合成,则可在一定程度上解决这个问题。然而,苯炔作为一种超高活性的反应中间体,能否顺利的和惰性C-H键活化过程兼容,是一个巨大挑战。利用氟化铜作为氟化试剂,可以实现苯炔的"缓释",使得苯炔与C-H活化匹配成为了可能。以这种方法,多种商业可得的原料经过自由组合,即可成功地构建菲啶酮类化合物,避免了传统方法中的预官能团化过程,提高菲啶酮类化合物合成方法的原子经济性和步骤经济性。这一方法还被成功运用于天然产物合成当中,进一步证明了该方法的实用性。机理实验确定了八元环Pd(Ⅱ)中间体是该反应的关键中间体,并且氟化铜条件下苯炔的"缓释"也对反应的顺利进行起到了帮助作用。(3)天然氨基酸手性源构建氢化吲哚骨架及ETP类天然产物多样性单体的合成氢化吲哚骨架广泛的存在于立体型生物碱分子结构当中如ETP类天然产物、白坚木属生物碱、石蒜科生物碱和百部属生物碱等都含有这一骨架。在构建氢化吲哚天然产物骨架的过程中,我们发展了 L-焦谷氨酸衍生的烯胺与香豆酸甲酯的Diels-Alder反应。利用L-焦谷氨酸的手性团诱导,以高产率(4步84%),高非对映选择性(大于10:1)实现了具有氢化吲哚骨架的关键中间体的构建。该反应可以实现20克级规模制备关键中间体,这为以氢化吲哚为主题骨架的天然产物的多样性合成奠定了基础。在随后的探索中,通过官能团转化,可以实现ETP类天然产物的共同中间体的合成,这也标志着焦谷氨酸衍生的烯胺与香豆酸甲酯的不对称Diels-Alder反应方法学在构建氢化吲哚类天然产物骨架的成功应用。
[Abstract]:The methodology and synthesis are two important branches of organic chemistry. The methodology focuses on exploring the development of novel synthetic methods and reaction mechanism, establish multi step synthesis strategy is focused on the total synthesis of natural products or drug molecules. Two essentially bound together in a common cause high efficient synthetic method, study the establishment of steps can greatly simplify the synthesis of natural products, on the other hand is the touchstone of efficient total synthesis and application test methodology, only good universality, high selectivity to method could be successfully applied to natural product synthesis. This paper focuses on the "methodological diversity oriented synthesis." the theme of the plane alkaloids phenanthridinone, acridone alkaloids and construction method of three-dimensional hydrogenation of indole type alkaloids, mainly carried out the following studies: 1) with Synthesis of the diversity of phenanthridinone and acridinone inserted a selective control of regional carbon source; 2) the phenylacetylenic involved multicomponent C-H activation reaction to construct phenanthridines ketones natural products skeleton; 3) natural amino acid chiral source of synthetic indole skeleton and hydrogenated natural product ETP diversity monomers are presented concretely. Are as follows: (1) a carbon source region selective ligand regulated insert to achieve diversity phenanthridinone and acridinone synthesis phenanthridinone (phenanthridinone) and acridone (acridone) are two kinds of important natural products. This framework contains a compound of two kinds of structure has many important pharmacological activities, and some have been become a clinical drug candidate. In addition, acridones still a lot of photocatalyst, luminescent materials of the skeleton. Because of its wide application, synthesis methods of phenanthridinone and acridinone aroused concern of chemists. The phenanthridone and acridine The retrosynthetic analysis pyridone structure. The structure of these two compounds by phenylacetylenic, carbon monoxide and o-iodine aniline in combination with selective three components. The conversion ligand promotes CO insertion and regulation phenylacetylenic fluorinating reagent release speed, control can realize the reaction path of "two-way switch": in the absence of plus get phenanthridines ketones ligands under the conditions of generating acridone compounds in diphosphine ligand DPPM participation. Through the "two-way switch" that can synthesize multiple phenanthridinone and acridones natural products and analogs. Magnetic tracking experiments directly reflects the effects of different additives and release fluoride reagent the rate of benzyne, which reveals the ligand acceleration and phenylacetylenic release rate control is essential to achieve selectivity. (2) the phenylacetylenic in multicomponent C-H activation, Gou Jianfei pyridine ketone Prior to the study of natural products found skeleton o-iodine aniline, phenylacetylenic and CO three component reaction can be used to establish the phenanthridone this important alkaloid skeleton. But using o-iodine aniline reduces the atom economy of the reaction, and has limited substrate universality. If you can use aniline instead of o-iodine aniline. The activation strategy to achieve the synthesis of phenanthridinone by C-H, can solve this problem to some extent. However, the phenylacetylenic as a high active reaction intermediate, smooth and inert C-H bond activation process compatible, is a huge challenge. The use of copper fluoride as fluorinating reagent, can realize the phenylacetylenic "slow release", the phenylacetylenic and C-H activation, as possible. In this way, a variety of commercially available materials through the free combination, can be successfully constructed phenanthridines ketones, avoid pre functional groups in the traditional method. Cheng, improve the synthesis method of phenanthridine ketones atom economy and economic steps. This method has been successfully applied to the synthesis of natural products, to further prove the practicality of the method. The mechanism of experiment to determine the eight membered ring intermediate Pd (II) is a key intermediate of the reaction, and under the condition of copper fluoride phenylacetylenic "slow release" of reaction smoothly helped. (3) the synthesis of hydrogenated natural amino acid chiral source to construct indole skeleton indole skeleton and ETP hydrogenated natural product diversity monomer exists in a wide range of stereo type alkaloid molecular structure of natural products such as ETP, Aspidosperma alkaloids, alkaloids and red spider lily, Stemona alkaloid contain a skeleton. In the process of constructing natural products in the hydrogenation of indole skeleton, we developed the L- enamine pyroglutamic acid and p-coumaric acid methyl ester Diels-Alde R. L- reaction using chiral pyroglutamic acid induced with high yield (4 step 84%), high diastereoselectivity (more than 10:1) construct the key intermediate with hydrogenated indole skeleton. The reaction can be realized by the key intermediate 20 gram scale preparation, laid the foundation for the synthesis of diversity the theme of the hydrogenation of indole skeleton of natural products. In the subsequent exploration, through the functional transformation, synthesis of common intermediates can achieve ETP class of natural products, which also marks the asymmetric Diels-Alder reaction method of pyroglutamic acid enamine and p-coumaric acid methyl ester in the successful application of construction of hydrogenated indole skeleton of natural products.

【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O629.3

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