基于有機(jī)催化不對(duì)稱Michael-Aldol串聯(lián)反應(yīng)合成多功能手性六元環(huán)
發(fā)布時(shí)間：2018-08-26 15:32
【摘要】：有機(jī)催化指的是只存在有機(jī)小分子參與的反應(yīng),相對(duì)于金屬催化以及酶催化有著獨(dú)特的優(yōu)勢(shì):有機(jī)催化適用范圍廣;不含金屬,環(huán)保無毒;催化劑的使用量極少,節(jié)約成本。近年來通過有機(jī)催化合成光學(xué)活性的化合物成為了一種重要的方法,尤其是以脯氨酸衍生物作為催化劑催化的不對(duì)稱Michael-Aldol串聯(lián)反應(yīng)經(jīng)過幾十年的發(fā)展,使得該類反應(yīng)在有機(jī)合成領(lǐng)域得到了廣泛的發(fā)展。串聯(lián)反應(yīng)指的是在反應(yīng)過程中可以逐步形成多個(gè)共價(jià)鍵,并且在反應(yīng)過程中不需要進(jìn)行中間體分離的反應(yīng),反應(yīng)底物中可以含有多種官能團(tuán),并且可以同時(shí)發(fā)生化學(xué)轉(zhuǎn)化,對(duì)于合成復(fù)雜手性分子具有重要的作用。串聯(lián)反應(yīng)在有機(jī)合成應(yīng)用中具有較大的優(yōu)勢(shì):由于是一鍋法,所以反應(yīng)中不需要進(jìn)行中間體的分離;反應(yīng)一般發(fā)生在分子內(nèi)部,所以加快了反應(yīng)速度;減少了操作步驟;提高了原子利用率。六元環(huán)狀化合物是許多天然產(chǎn)物和藥物的中間體,具有良好的生物活性。但是對(duì)于怎樣根據(jù)不對(duì)稱有機(jī)催化的串聯(lián)反應(yīng)高效、快速地構(gòu)建多手性中心的六元環(huán)狀化合物仍然是一個(gè)難題。近年來,文獻(xiàn)報(bào)道了以脯氨酸衍生物為催化劑,通過不對(duì)稱有機(jī)催化的Michael-Aldol串聯(lián)反應(yīng),可以獲得高對(duì)映選擇性的六元環(huán)衍生物,但是產(chǎn)率卻只有30-40%,同時(shí)反應(yīng)中包含過多的有毒以及不穩(wěn)定底物,因此對(duì)于在工業(yè)化上的應(yīng)用還不足以滿足要求。本論文以脯氨酸衍生物二苯基脯胺醇三甲基硅醚為催化劑,β-硝基苯乙烯和3-芐氧基丙醛為原料,通過有機(jī)催化Michael-Aldol串聯(lián)反應(yīng)構(gòu)建了具有多取代的三個(gè)手性中心環(huán)己烯醛衍生物,得到的產(chǎn)率和對(duì)映選擇性比之前有了較大的提高。實(shí)驗(yàn)還通過對(duì)反應(yīng)溶劑、添加劑、催化劑類型、催化劑用量、反應(yīng)時(shí)間、原料配比和反應(yīng)溫度在內(nèi)的反應(yīng)條件進(jìn)行了優(yōu)化,最終確定了該反應(yīng)的最佳條件:溫度為0℃,正己烷為溶劑(3 mL),二苯基脯胺醇三甲基硅醚催化劑(20 mol%),3-芐氧基醛與硝基苯乙烯摩爾比為2.5,反應(yīng)時(shí)間24 h。另外對(duì)不同的醛進(jìn)行了底物擴(kuò)展,發(fā)現(xiàn)醛保護(hù)基上含有吸電子基團(tuán)的底物很難與共軛硝基反應(yīng),苯甲�；Ｗo(hù)的醛也只能在異丙醇溶劑中發(fā)生反應(yīng)。然后我們還對(duì)苯基上不同取代基的底物進(jìn)行了擴(kuò)展,產(chǎn)物的對(duì)映選擇性(ee值)都在99%以上,收率在62-76%。最后反應(yīng)考察了本實(shí)驗(yàn)的Michael-Aldol串聯(lián)反應(yīng)機(jī)理。
[Abstract]:Organic catalysis refers to the reaction in which only small organic molecules are involved. Compared with metal catalysis and enzyme catalysis, organic catalysis has unique advantages: wide application range of organic catalysis; no metal, environmental protection and non-toxic; the use of catalyst is very small and cost saving. In recent years, the synthesis of optically active compounds by organic catalysis has become an important method, especially the asymmetric Michael-Aldol series reaction catalyzed by proline derivatives has been developed for decades. This kind of reaction has been widely developed in the field of organic synthesis. A series reaction is a reaction in which multiple covalent bonds can be gradually formed during the reaction, and no intermediate separation is required during the reaction. The substrate can contain multiple functional groups and can be chemically converted at the same time. It plays an important role in the synthesis of complex chiral molecules. Series reaction has great advantages in organic synthesis application: because it is a one-pot process, there is no need for separation of intermediates in the reaction, reaction usually takes place inside the molecule, so the reaction rate is accelerated, and the operation steps are reduced. The atomic utilization rate is improved. Six-member cyclic compounds are intermediates of many natural products and drugs with good biological activity. However, it is still a difficult problem how to quickly construct multichiral hexagonal cyclic compounds based on asymmetric organic catalytic series reactions. In recent years, it has been reported that proline derivatives can be synthesized by asymmetric organic catalytic Michael-Aldol series reaction, and high enantioselectivity of hexagonal ring derivatives can be obtained. But the yield is only 30-400.At the same time the reaction contains too many toxic and unstable substrates, so the application in industrialization is not enough to meet the requirements. In this paper, three chiral cyclohexenal derivatives with multiple substitutions were synthesized by Michael-Aldol series reaction with proline derivative diphenyl propanol trimethylsilyl ether as catalyst, 尾 -nitrostyrene and 3-benzyloxypropionaldehyde as raw materials. The yield and enantioselectivity were greatly improved than before. The reaction conditions such as solvent, additive, type of catalyst, amount of catalyst, reaction time, ratio of raw material and reaction temperature were optimized. The optimum reaction conditions were determined as follows: temperature 0 鈩，
本文編號(hào)：2205333
[Abstract]:Organic catalysis refers to the reaction in which only small organic molecules are involved. Compared with metal catalysis and enzyme catalysis, organic catalysis has unique advantages: wide application range of organic catalysis; no metal, environmental protection and non-toxic; the use of catalyst is very small and cost saving. In recent years, the synthesis of optically active compounds by organic catalysis has become an important method, especially the asymmetric Michael-Aldol series reaction catalyzed by proline derivatives has been developed for decades. This kind of reaction has been widely developed in the field of organic synthesis. A series reaction is a reaction in which multiple covalent bonds can be gradually formed during the reaction, and no intermediate separation is required during the reaction. The substrate can contain multiple functional groups and can be chemically converted at the same time. It plays an important role in the synthesis of complex chiral molecules. Series reaction has great advantages in organic synthesis application: because it is a one-pot process, there is no need for separation of intermediates in the reaction, reaction usually takes place inside the molecule, so the reaction rate is accelerated, and the operation steps are reduced. The atomic utilization rate is improved. Six-member cyclic compounds are intermediates of many natural products and drugs with good biological activity. However, it is still a difficult problem how to quickly construct multichiral hexagonal cyclic compounds based on asymmetric organic catalytic series reactions. In recent years, it has been reported that proline derivatives can be synthesized by asymmetric organic catalytic Michael-Aldol series reaction, and high enantioselectivity of hexagonal ring derivatives can be obtained. But the yield is only 30-400.At the same time the reaction contains too many toxic and unstable substrates, so the application in industrialization is not enough to meet the requirements. In this paper, three chiral cyclohexenal derivatives with multiple substitutions were synthesized by Michael-Aldol series reaction with proline derivative diphenyl propanol trimethylsilyl ether as catalyst, 尾 -nitrostyrene and 3-benzyloxypropionaldehyde as raw materials. The yield and enantioselectivity were greatly improved than before. The reaction conditions such as solvent, additive, type of catalyst, amount of catalyst, reaction time, ratio of raw material and reaction temperature were optimized. The optimum reaction conditions were determined as follows: temperature 0 鈩，
本文編號(hào)：2205333
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