不对称Henry反应催化剂的设计、合成及其在药物中间体中的应用

发布时间：2018-06-25 00:47

本文选题：Henry反应 + 不对称催化　；参考：《河北大学》2014年硕士论文

【摘要】：手性化合物对于化学和医学具有非常重要的意义。获得单一手性化合物的方法有很多，比如：手性拆分、自然界中提取、不催对称合成等。从工业生产的角度来看，其中不对称催化反应作为获得光学纯化合物的一种手段在众多方法中最具有原子经济性，同时也最具有挑战性。催化不对称Henry反应是重要的构筑碳碳键的方法。其β-硝基醇催化产物可以方便的转化为相应的手性醛、酮、羧酸、α-氨基醇等一系列有机合成的重要中间体。因此进一步深入研究不对称Henry反应具有重要的理论意义和应用前景。根据文献调研我们发现有三种类型的催化剂被应用于不对称Henry反应中。其中包括：金属配合物催化剂、有机小分子催化剂、季铵盐类催化剂。基于前人的工作，我们以色氨酸为原料设计合成了一系列的新的催化剂并且把他们应用于不对称Henry反应的研究中。其主要内容是：以L-色氨酸为原料，合成了两种不同类型的配体，并把它们与不同的金属盐配位后，研究其在催化醛与硝基烷烃的不对称Henry反应中的应用。研究结果发现了一个高效的催化配体4a，在最优条件下（-30oC，IPA为溶剂，100%DIPEA为添加剂，5%CuCl2.H2O为金属盐，），Cu(II)/4a配合物能高效地催化醛与硝基甲烷的反应，并且对芳香醛、脂肪醛都有很好的选择性，，ee值高达98%，以及99%的产率。在此基础上我们还研究了Cu(II)/4a配合物催化醛与硝基乙烷的不对称Henry反应。研究结果表明，Cu(II)/4a配合物对于醛与硝基乙烷的反应依然有很高的催化活性（产率99%），但是其对映选择性效果却不理想（dr=1：4.4； ee=30、23%）。同时，在我们把4a与金属盐络合物应用于(-)-denopamine中间体的合成中，取得了优秀的效果，其产率达到了90%，ee值高达98%。研究结果证明：我们所设计合成的新手性催化剂能高效、高对映选择性地催化不对称Henry反应。催化剂合成简便，成本低廉，用量低，金属Cu盐毒性低且对水空气不敏感，相应的催化产物具有很重要的实用价值。因此，该催化剂在工业领域具有很高的应用前景，同时也为催化不对称Henry反应的研究提供了一条新的路径。
[Abstract]:Chiral compounds are of great significance in chemistry and medicine. There are many methods to obtain single chiral compounds, such as chiral resolution, extraction from nature, asymmetric synthesis and so on. From the point of view of industrial production, asymmetric catalytic reaction as a means of obtaining optical pure compounds is the most atomic economy and the most challenging among many methods. Catalytic asymmetric Henry reaction is an important method to construct carbon and carbon bond. The catalytic products of 尾 -nitroalcohol can be easily converted into a series of important intermediates in organic synthesis, such as chiral aldehydes, ketones, carboxylic acids, 伪 -amino alcohols, etc. Therefore, the further study of asymmetric Henry reaction has important theoretical significance and application prospect. According to literature review, we found that three types of catalysts were used in asymmetric Henry reaction. These include: metal complex catalyst, organic small molecule catalyst, quaternary ammonium salt catalyst. Based on previous work, we designed and synthesized a series of new catalysts using tryptophan as raw material and applied them to the study of asymmetric Henry reaction. The main contents are as follows: two kinds of ligands were synthesized from L-tryptophan and coordinated with different metal salts to study their application in the asymmetric Henry reaction of aldehydes with nitroalkanes. It was found that a highly efficient catalytic ligand (4a) can efficiently catalyze the reaction of aldehydes with nitromethane under the optimum conditions (-30oCnIPA as solvent, 100DIPEA as additive, 5CuCl2.H2O as metal salt,) Cu (II) / 4a, and aromatic aldehydes. Aliphatic aldehydes have a high selectivity of 98% and yield of 99%. On this basis, we have also studied the asymmetric Henry reaction of aldehyde with nitroethane catalyzed by Cu (II) -4a complex. The results show that the cu (II) / 4a complex still has high catalytic activity (yield 99%) for the reaction of aldehyde with nitroethane, but its enantioselectivity effect is not ideal (drine 1: 4.4; Eee 30% 23%). At the same time, in the synthesis of (-) -denopamine intermediates with 4a and metal salts, excellent results have been obtained. The yield of 4a is up to 90% and the yield is as high as 98%. The results show that the new catalyst we designed and synthesized can catalyze asymmetric Henry reaction with high efficiency and high enantioselectivity. The synthesis of the catalyst is simple, low cost, low dosage, low toxicity of metal Cu salt and insensitive to water and air. The corresponding catalytic products have very important practical value. Therefore, the catalyst has a high application prospect in the industrial field, and also provides a new way for the study of asymmetric Henry reaction.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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