【摘要】：有機催化指的是只存在有機小分子參與的反應,相對于金屬催化以及酶催化有著獨特的優(yōu)勢:有機催化適用范圍廣;不含金屬,環(huán)保無毒;催化劑的使用量極少,節(jié)約成本。近年來通過有機催化合成光學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稱Michael-Aldol串聯反應經過幾十年的發(fā)展,使得該類反應在有機合成領域得到了廣泛的發(fā)展。串聯反應指的是在反應過程中可以逐步形成多個共價鍵,并且在反應過程中不需要進行中間體分離的反應,反應底物中可以含有多種官能團,并且可以同時發(fā)生化學轉化,對于合成復雜手性分子具有重要的作用。串聯反應在有機合成應用中具有較大的優(yōu)勢:由于是一鍋法,所以反應中不需要進行中間體的分離;反應一般發(fā)生在分子內部,所以加快了反應速度;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物和藥物的中間體,具有良好的生物活性。但是對于怎樣根據不對稱有機催化的串聯反應高效、快速地構建多手性中心的六元環(huán)狀化合物仍然是一個難題。近年來,文獻報道了以脯氨酸衍生物為催化劑,通過不對稱有機催化的Michael-Aldol串聯反應,可以獲得高對映選擇性的六元環(huán)衍生物,但是產率卻只有30-40%,同時反應中包含過多的有毒以及不穩(wěn)定底物,因此對于在工業(yè)化上的應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,通過有機催化Michael-Aldol串聯反應構建了具有多取代的三個手性中心環(huán)己烯醛衍生物,得到的產率和對映選擇性比之前有了較大的提高。實驗還通過對反應溶劑、添加劑、催化劑類型、催化劑用量、反應時間、原料配比和反應溫度在內的反應條件進行了優(yōu)化,最終確定了該反應的最佳條件: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,反應時間24 h。另外對不同的醛進行了底物擴展,發(fā)現醛保護基上含有吸電子基團的底物很難與共軛硝基反應,苯甲�；Ｗo的醛也只能在異丙醇溶劑中發(fā)生反應。然后我們還對苯基上不同取代基的底物進行了擴展,產物的對映選擇性(ee值)都在99%以上,收率在62-76%。最后反應考察了本實驗的Michael-Aldol串聯反應機理。
[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：2205333