基于有机催化不对称Michael-Aldol串联反应合成多功能手性六元环
发布时间：2018-08-26 15:32
【摘要】：有机催化指的是只存在有机小分子参与的反应,相对于金属催化以及酶催化有着独特的优势:有机催化适用范围广;不含金属,环保无毒;催化剂的使用量极少,节约成本。近年来通过有机催化合成光学活性的化合物成为了一种重要的方法,尤其是以脯氨酸衍生物作为催化剂催化的不对称Michael-Aldol串联反应经过几十年的发展,使得该类反应在有机合成领域得到了广泛的发展。串联反应指的是在反应过程中可以逐步形成多个共价键,并且在反应过程中不需要进行中间体分离的反应,反应底物中可以含有多种官能团,并且可以同时发生化学转化,对于合成复杂手性分子具有重要的作用。串联反应在有机合成应用中具有较大的优势:由于是一锅法,所以反应中不需要进行中间体的分离;反应一般发生在分子内部,所以加快了反应速度;减少了操作步骤;提高了原子利用率。六元环状化合物是许多天然产物和药物的中间体,具有良好的生物活性。但是对于怎样根据不对称有机催化的串联反应高效、快速地构建多手性中心的六元环状化合物仍然是一个难题。近年来,文献报道了以脯氨酸衍生物为催化剂,通过不对称有机催化的Michael-Aldol串联反应,可以获得高对映选择性的六元环衍生物,但是产率却只有30-40%,同时反应中包含过多的有毒以及不稳定底物,因此对于在工业化上的应用还不足以满足要求。本论文以脯氨酸衍生物二苯基脯胺醇三甲基硅醚为催化剂,β-硝基苯乙烯和3-苄氧基丙醛为原料,通过有机催化Michael-Aldol串联反应构建了具有多取代的三个手性中心环己烯醛衍生物,得到的产率和对映选择性比之前有了较大的提高。实验还通过对反应溶剂、添加剂、催化剂类型、催化剂用量、反应时间、原料配比和反应温度在内的反应条件进行了优化,最终确定了该反应的最佳条件:温度为0℃,正己烷为溶剂(3 mL),二苯基脯胺醇三甲基硅醚催化剂(20 mol%),3-苄氧基醛与硝基苯乙烯摩尔比为2.5,反应时间24 h。另外对不同的醛进行了底物扩展,发现醛保护基上含有吸电子基团的底物很难与共轭硝基反应,苯甲酰基保护的醛也只能在异丙醇溶剂中发生反应。然后我们还对苯基上不同取代基的底物进行了扩展,产物的对映选择性(ee值)都在99%以上,收率在62-76%。最后反应考察了本实验的Michael-Aldol串联反应机理。
[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，
本文编号：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，
本文编号：2205333
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