基于硝基烯化合物的不对称Michael加成及多环吡咯类化合物的合成研究

发布时间：2019-04-03 15:42

【摘要】：硝基烯化合物是一类重要的含氮有机物,是有机合成中重要的反应合成子,可以作为Michael加成反应受体和构筑多环吡咯类化合物的关键中间体。不对称Michael加成反应是构建C-C键最有效的有机合成方法之一,醛与硝基烯的不对称Michael加成产物是合成多种手性药物和天然产物分子的重要原料。L-脯氨酰胺是催化不对称Michael加成反应的重要手性催化剂之一。开展新型L-脯氨酰胺催化的醛与硝基烯的不对称Michael加成反应的方法学研究,并基于硝基烯构筑多环吡咯骨架、进一步实现多环吡咯类化合物库的构建具有重要的研究意义。本文综述了硝基烯化合物、不对称Michael加成反应及多环吡咯化合物的研究概况,开展了6个新型脯氨酰胺类手性催化剂的设计、合成、及其在醛与硝基烯的不对称Michael加成反应中催化应用的方法学研究,并基于硝基烯开展多组分“一锅法”反应实现多环吡咯类化合物的合成研究。论文从廉价的N-Boc-氨基酸、N-Boc-L-脯氨酸出发,与二苯基甲胺、三苯基甲胺等原料经过酰胺化、脱Boc保护基等步骤高效地合成6个新型的L-脯氨酰胺催化剂。并开展了该类手性催化剂在醛与硝基烯的不对称Michael加成反应中催化应用的方法学研究。在最优反应条件下,催化剂160在醛与硝基烯的不对称Michael加成反应中表现出了理想的催化活性和立体选择性。反应以82%-94%的产率、60:40-99:1的非对映异构体选择性和85%-99%对映异构体选择性合成了17个不对称Michael加成产物(图1)。该研究可以为新型手性催化剂的发现、应用及小分子不对称催化及部分手性药物的研发提供一定理论指导。图1 L-脯氨酰胺160催化应用于醛与硝基烯的不对称Michael加成反应Fig.1 L-prolinamide 160 catalyzed aldehyde and nitroene asymmetric Michael addition reaction基于硝基烯、手性氨基酸和苊醌的多组分“一锅法”反应,建立了构筑多环吡咯类化合物库高效的合成方法。在最佳反应条件下,以81%-91%的产率合成了22个新型多环吡咯衍生物(图2)。所有化合物通过核磁共振碳谱、核磁共振氢谱、高分辨质谱、红外光谱、熔点等进行结构表征。通过反应的普适性和底物的多样性的研究表明,硝基烯化合物(172)的芳环上带有Cl、Br、CF3等吸电子基时有利于反应的进行(产率84%-89%)。该反应同样适用于具有供电子取代基(CH3、OCH3)的硝基烯化合物参与多组分反应。该合成方法对不同结构的氨基酸(62)化合物具有优异的普适性,X为CH2、S、(CH2)2时都以理想的产率合成了对应的多环吡咯类衍生物。该研究可以为新型多环吡咯类化合物库的建立及新型药物分子的发现奠定基础。图2新型多环吡咯类化合物190的合成Fig.2 Synthesis of Novel Polycyclic Pyrrole Compounds 190
[Abstract]:Nitroenes are important nitrogen-containing organic compounds and are important reaction synthesizers in organic synthesis. They can be used as Michael adduct receptors and key intermediates for the construction of polycyclic pyrrole compounds. Asymmetric Michael addition reaction is one of the most effective organic synthesis methods to construct C C bond. The asymmetric Michael addition of aldehydes and nitroenes is an important raw material for the synthesis of chiral drugs and natural product molecules. L-proline is one of the important chiral catalysts for asymmetric Michael addition reaction. It is of great significance to study the asymmetric Michael addition reaction of aldehydes and nitroenes catalyzed by new L-proline, and to construct the polycyclic pyrrole skeleton based on nitroene to further realize the construction of polycyclic pyrrole compound library. In this paper, the research situation of nitroene compounds, asymmetric Michael addition reaction and polycyclic pyrrole compounds were reviewed. Six new chiral catalysts of prolyl amide were designed and synthesized. And its application in the asymmetric Michael addition reaction of aldehyde and nitroene, and the synthesis of polycyclic pyrrolides based on the multi-component "one-pot method" reaction of nitrotene and its catalytic effect on the synthesis of polycyclic pyrrolides were studied in this paper. In this paper, six novel L-proline catalysts were synthesized from cheap N-Boco-amino acid and N-Boco-L-proline with diphenylmethylamine and triphenylmethylamine by amidation and deamination of Boc protection groups. The application of this kind of chiral catalysts in asymmetric Michael addition of aldehyde to nitroene was studied. Under the optimum reaction conditions, the catalyst 160 exhibited ideal catalytic activity and stereoselectivity in the asymmetric Michael addition reaction of aldehyde and nitroene. Seventeen asymmetric Michael addition products were synthesized in 82% / 94% yield, 60 / 40 / 99 / 1 non-enantiomer selectivity and 85% / 99% enantiomeric selectivity (Fig. 1). This study can provide some theoretical guidance for the discovery and application of new chiral catalysts, the asymmetric catalysis of small molecules and the research and development of some chiral drugs. Fig. 1 the asymmetric Michael addition of aldehydes and nitroenes catalyzed by L-proline 160 Fig.1 L-prolinamide 160 catalyzed aldehyde and nitroene asymmetric Michael addition reaction based on the multi-component "one-pot" reaction of nitroenes, chiral amino acids and acenaphthene quinones, An efficient synthesis method for constructing a library of polycyclic pyrrolides was established. Under the optimum reaction conditions, 22 novel polycyclic pyrrole derivatives were synthesized in 81% / 91% yield (Fig. 2). All the compounds were characterized by NMR, 1H NMR, high resolution mass spectrometry, infrared spectroscopy, melting point and so on. Through the study of the universality of the reaction and the diversity of the substrate, it was found that the aromatic ring of nitroene with Cl,Br,CF3 isoelectronic group was favorable for the reaction (the yield was 84% / 89%). The reaction is also suitable for multi-component reactions of nitroenes with electron-donor substituents (CH3,OCH3). The synthesis method has excellent universality for amino acid (62) compounds with different structures. The corresponding polycyclic pyrrole derivatives have been synthesized in ideal yield at X = CH2,S, (CH2) 2. This study may lay a foundation for the establishment of a new polycyclic pyrrolidine compound library and the discovery of novel drug molecules. Fig. 2 Synthesis of novel polycyclic pyrrole compounds Fig.2 Synthesis of Novel Polycyclic Pyrrole Compounds 190
【学位授予单位】：云南师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626.13;O621.25

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