【摘要】：硝基烯化合物是一類重要的含氮有機(jī)物,是有機(jī)合成中重要的反應(yīng)合成子,可以作為Michael加成反應(yīng)受體和構(gòu)筑多環(huán)吡咯類化合物的關(guān)鍵中間體。不對(duì)稱Michael加成反應(yīng)是構(gòu)建C-C鍵最有效的有機(jī)合成方法之一,醛與硝基烯的不對(duì)稱Michael加成產(chǎn)物是合成多種手性藥物和天然產(chǎn)物分子的重要原料。L-脯氨酰胺是催化不對(duì)稱Michael加成反應(yīng)的重要手性催化劑之一。開(kāi)展新型L-脯氨酰胺催化的醛與硝基烯的不對(duì)稱Michael加成反應(yīng)的方法學(xué)研究,并基于硝基烯構(gòu)筑多環(huán)吡咯骨架、進(jìn)一步實(shí)現(xiàn)多環(huán)吡咯類化合物庫(kù)的構(gòu)建具有重要的研究意義。本文綜述了硝基烯化合物、不對(duì)稱Michael加成反應(yīng)及多環(huán)吡咯化合物的研究概況,開(kāi)展了6個(gè)新型脯氨酰胺類手性催化劑的設(shè)計(jì)、合成、及其在醛與硝基烯的不對(duì)稱Michael加成反應(yīng)中催化應(yīng)用的方法學(xué)研究,并基于硝基烯開(kāi)展多組分“一鍋法”反應(yīng)實(shí)現(xiàn)多環(huán)吡咯類化合物的合成研究。論文從廉價(jià)的N-Boc-氨基酸、N-Boc-L-脯氨酸出發(fā),與二苯基甲胺、三苯基甲胺等原料經(jīng)過(guò)酰胺化、脫Boc保護(hù)基等步驟高效地合成6個(gè)新型的L-脯氨酰胺催化劑。并開(kāi)展了該類手性催化劑在醛與硝基烯的不對(duì)稱Michael加成反應(yīng)中催化應(yīng)用的方法學(xué)研究。在最優(yōu)反應(yīng)條件下,催化劑160在醛與硝基烯的不對(duì)稱Michael加成反應(yīng)中表現(xiàn)出了理想的催化活性和立體選擇性。反應(yīng)以82%-94%的產(chǎn)率、60:40-99:1的非對(duì)映異構(gòu)體選擇性和85%-99%對(duì)映異構(gòu)體選擇性合成了17個(gè)不對(duì)稱Michael加成產(chǎn)物(圖1)。該研究可以為新型手性催化劑的發(fā)現(xiàn)、應(yīng)用及小分子不對(duì)稱催化及部分手性藥物的研發(fā)提供一定理論指導(dǎo)。圖1 L-脯氨酰胺160催化應(yīng)用于醛與硝基烯的不對(duì)稱Michael加成反應(yīng)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組分“一鍋法”反應(yīng),建立了構(gòu)筑多環(huán)吡咯類化合物庫(kù)高效的合成方法。在最佳反應(yīng)條件下,以81%-91%的產(chǎn)率合成了22個(gè)新型多環(huán)吡咯衍生物(圖2)。所有化合物通過(guò)核磁共振碳譜、核磁共振氫譜、高分辨質(zhì)譜、紅外光譜、熔點(diǎn)等進(jìn)行結(jié)構(gòu)表征。通過(guò)反應(yīng)的普適性和底物的多樣性的研究表明,硝基烯化合物(172)的芳環(huán)上帶有Cl、Br、CF3等吸電子基時(shí)有利于反應(yīng)的進(jìn)行(產(chǎn)率84%-89%)。該反應(yīng)同樣適用于具有供電子取代基(CH3、OCH3)的硝基烯化合物參與多組分反應(yīng)。該合成方法對(duì)不同結(jié)構(gòu)的氨基酸(62)化合物具有優(yōu)異的普適性,X為CH2、S、(CH2)2時(shí)都以理想的產(chǎn)率合成了對(duì)應(yīng)的多環(huán)吡咯類衍生物。該研究可以為新型多環(huán)吡咯類化合物庫(kù)的建立及新型藥物分子的發(fā)現(xiàn)奠定基礎(chǔ)。圖2新型多環(huán)吡咯類化合物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
【學(xué)位授予單位】：云南師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：O626.13;O621.25

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