有机不对称催化合成二氢香豆素和α,α-双取代非天然α-氨基酸酯

发布时间：2018-01-06 16:27

本文关键词：有机不对称催化合成二氢香豆素和α,α-双取代非天然α-氨基酸酯　出处：《湖北工业大学》2017年硕士论文　论文类型：学位论文

【摘要】：第一部分二氢香豆素作为许多天然产物的核心骨架由于其多样的结构性和生物活性吸引了越来越多的关注。不同种类的二氢香豆素衍生物显示出多样的生物活性,部分已当作药物候选物,因此这类化合物的合成具有非常重要的意义。二氢香豆素的许多合成方法都已报道,但是用高效温和的有机不对称催化合成方式尤为瞩目。在给体/受体观念的指导下,邻位上连有吸电子基团的苯酚发生[4+2]环加成反应是合成二氢香豆素骨架最常用的策略。尽管已经有一些比较好的合成例子,但是开发出一种新的合成策略去构建包含多功能转变基团的光学纯二氢香豆素始终是一个比较有挑战性的课题。在此,我们报道了在这一领域的最新研究成果,通过有机催化萘酚和3-三氟亚乙基吲哚酮的傅克烷基化/内酯化反应(新颖的[3+3]合成策略)合成二氢香豆素。我们发现该反应仅需要2.5 mol%的奎宁衍生的四方胺催化剂就能以较好的效果(up to 99%yield and up to 98%ee,20:1 d.r.)得到α-芳基-β-CF3-二氢香豆素类化合物。在温和条件下酚羟基进攻吲哚酮的酰胺键发生内酯化反应,这种分子内酰胺键断裂后发生内酯化的反应代表了合成二氢香豆素的新方法。更为重要的是将具有药学活性的CF3引入到具有重要生物活性的二氢香豆素中,它可以增加母体化合物的代谢稳定性和生物利用率。为了进一步研究该不对称傅克烷基化/内酯化反应,我们对加成产物做了一些具有代表性的衍生,这些化合物均具有潜在的生物活性。第二部分高度对映选择性的α,α-双取代的α-氨基酸衍生物广泛存在于天然产物、药物分子和多功能材料中,在有机合成化学中,它也具有广泛的应用前景。有机催化亲核试剂对映选择性加成到α-酮酯提供了一种高效制备光学纯α-手性季碳中心氨基酸衍生物的方法。而吲哚和α-酮酯的不对称氮杂傅克烷基化可以得到一系列连有吲哚和含有手性季碳中心的α-氨基酸类化合物。这类化合物可以用来合成很多天然产物和药物分子。因此,我们报道了手性磷酸作用下吲哚和芳基环α-酮酯发生对映选择性氮杂傅克烷基化反应,以较好的反应条件(up to 85%yield and up to93%ee)得到α,α-双取代非天然α-氨基酸酯衍生物。最后,我们对加成产物做了一些具有代表性的衍生转变,它可以用来合成α-氨基酸酯。
[Abstract]:Part one: dihydrocoumarin, as the core skeleton of many natural products, has attracted more and more attention because of its diverse structure and biological activity. Different kinds of dihydrocoumarin derivatives show various biological activities. . Some have been used as drug candidates, so the synthesis of these compounds is of great significance. Many synthesis methods of dihydrocoumarin have been reported. Under the guidance of donor / acceptor concept, phenol with electron-absorbing groups on the ortho site is produced. [42] Cycloaddition reaction is the most commonly used strategy for the synthesis of dihydrocoumarin skeleton, although there are some good examples of synthesis. However, the development of a new synthesis strategy to construct optical pure dihydrocoumarin containing multifunctional transition groups has always been a challenging issue. In this paper, we report the latest research results in this field. Fourier alkylation / internal esterification of naphthol with 3-trifluoroethylindolone catalyzed by organic catalyst (novel. [Synthesis of dihydrocoumarin. We found that only 2.5 mol% Quinine derivative catalyst was needed for the synthesis of dihydrocoumarin. Up to 99 yield and up to 98. 伪 -aryl- 尾 -CF3-dihydrocoumarin compounds were obtained from 20: 1 d.r.) the amide-bonds of phenolic hydroxyl groups attacking indole ketones were esterified internally under mild conditions. The lactone reaction after the break of the molecular lactam bond represents a new method for the synthesis of dihydrocoumarin. More importantly, CF3 with pharmacological activity is introduced into dihydrocoumarin with important biological activity. It can increase the metabolic stability and bioavailability of the parent compounds. In order to further study the asymmetric Fourier alkylation / internal esterification reaction, we have made some representative derivatives of the addition products. These compounds have potential biological activities. The second part of the highly enantioselective 伪, 伪 -disubstituted 伪 -amino acid derivatives are widely found in natural products, drug molecules and multifunctional materials. In organic synthesis chemistry. It also has a wide application prospect. The enantioselective addition of organic catalytic nucleophilic reagent to 伪 -ketone ester provides an efficient method for the preparation of optically pure 伪 -chiral quaternary carbon-centered amino acid derivatives, while indoles and 伪 -keto esters. A series of 伪 -amino acid compounds with indole and chiral quaternary carbon centers can be obtained by asymmetric aza-Fourier alkylation. These compounds can be used to synthesize many natural products and drug molecules. The enantioselective aza-Fourier alkylation of indoles and aryl cyclic 伪 -ketones with chiral phosphoric acid was reported. 伪, 伪 -disubstituted unnatural 伪 -amino acid ester derivatives were obtained by yield up up to93 under better reaction conditions. Finally, 伪, 伪 -disubstituted natural 伪 -amino acid ester derivatives were obtained. We have made some representative derivatives of addition products, which can be used to synthesize 伪-amino acid esters.
【学位授予单位】：湖北工业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O621.251;O629

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