苦参生物碱的结构修饰与改造研究
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摘要
在化学尤其是有机化学研究中，天然产物化学长期以来一直占据着非常重要的地位，不仅是因为天然产物研究给有机化学家带来的巨大的挑战，而且是因为天然药物的研究成果能极大的改善人们的身体健康状况，因而和人们的生活息息相关。在药物研究方面，迄今为止在临床应用的药物中，有三分之一以上源自天然产物。我国天然产物资源丰富，种类繁多，中医药利用历史悠久。因而从事天然产物研究具有得天独厚的条件。天然产物历来都是我国有机化学家研究的重要对象，尤其是生物碱类天然药物，由于其广泛而优异的活性一直以来都是化学家和药理学家研究的热点。
生物碱一般是指植物中除蛋白质、肽类、氨基酸及维生素B外的含氮的有机化合物。它是科学家们研究的最早的一类有生物活性的天然有机化合物，而且生物碱类化合物大多具有良好的生物活性。这类化合物往往是许多药用植物，包括许多中草药的有效成分。目前国内外对生物碱的研究如火如荼，近年来，由于分离纯化、结构鉴定、生物活性导向跟踪等方面技术上的长足进步，结构新颖、活性高的生物碱不断被发现，其数目不断增加。对已发现的生物碱的结构修饰与改性研究是天然药物研究的另一个重要的方面。因此为了进一步提高苦参生物碱的药理活性，我们对苦参碱进行了初步的结构修饰与改造研究，合成出了几种结构新颖的苦参碱的衍生物，论文主要分为以下四个部分：
第一章首先就天然药物的研究现状及生物碱的研究进展进行了文献总结，重点介绍了当前对生物碱研究的一些新的方法、理念以及有关天然产物结构修饰与改造的原理；对我们的研究对象苦参碱的生物学特征和广泛的药理活性也做了详细的介绍，并就目前的研究情况做了总结。
第二章以槐果碱为起始化合物，以形成多元醇为目的同时又可以增大苦参碱的水溶性，我们设计了对槐果碱的α，β-不饱和双键进行双羟化氧化，成功的合成出了13，14-二羟基苦参碱，并且对产物结构进行了表征。
第三章中，应用组合化学中多组分反应的高效性、原子经济性的原则，同时又能体现出绿色无污染、对环境友好的有机合成理念，我们以槐果碱为原料，成功的提出了一个新颖、高效、绿色的一锅法合成二硫代(N，N-二烃基)氨基甲酸苦参碱酯的方法，合成出了两个结构新颖的苦参碱衍生物。反应过程中避免了使用一些毒性的有机溶剂如氯仿、DMF、DMSO等，同时反应也不需要加入任何的金属催化剂。我们还从可能的反应机理上解释了水在反应中的双重作用。该反应除了具有不需要催化剂、对有些胺类产率较高、反应清洁等优点外，还具有后处理过程简单的优点。产物的结构经二维核磁共振图谱表征及X射线单晶衍射测定，为我们的预期产物。
第四章中仍以槐果碱为起始反应物，应用经典的Michael加成反应的原理，我们试验了在槐果碱的α，β-不饱和内酰胺的双键上进行亲核加成。反应中槐果碱作为电子受体，当用乙酰乙酸乙酯或硝基甲烷作为电子供体时，实验结果显示，槐果碱的反应活性较低，产率相比较典型的α，β-不饱和醛酮做电子受体时的反应偏低。通过对该反应的研究，我们补充了Michael反应的应用范围，取得了预期的成果。
Nature Pharmacological chemistry play an important role in chemistry, especially in organic chemistry at all time, not only because the study of nature pharmacological chemistry can take tremendous challenge to organic chemists, but also because the result of which can improve people's health situation greatly, so it has a close relationship with us. As far as the study of drugs is concerned, more than one third of the clinical drugs were derived from natural products so far. There is a great variety of the resources of natural products in our country which has been applied to Chinese traditional medicine for a long time. Chinese organic chemists always regard the natural products as significant targets of research because of the ascendant conditions. The natural products of alkaloids are especially listed among the hottest point by the chemists and pharmacologists for its broadly and excellently pharmacological activities at all times.
The alkaloids refer to some organic compounds which contain nitrogen atom except proteins, peptides, amino acids and vitamin B. It is a kind of pharmacologically active nature organic compounds and is earliest investigated by scientists. For the most of the compounds like alkaloids show excellent pharmacological activity, they are usually the effective components in many medical plants including many Chinese traditional medicines. The researches on alkaloids are undergoing actively in the domestic and in the foreign countries at present. Because the technology of separation, purification, character and biological activity's tracing have made great progress, some alkaloids with novel structures and excellent pharmacological activities were found continuously. The modification of alkaloids' structure which had been confirmed is an important field in the study of natural medicine. We aimed to further improve the pharmacological activities of the matrine, and some primitive modification to the structure of matrine was carried out. As a result, several novel derivatives of matrine were synthesized. This thesis comprises four parts shown as follows:
In the first chapter, we summarized the studying progress of the natural medicine and the alkaloids firstly, emphasizing to introduce the new methods and ideas in the research of the alkaloids. We also introduced matrine's biological character and its comprehensive pharmacological activities in detail, and the summary of its presently studying progress was made as well.
In the second chapter, for the good solubility of anticipated product we design an experiment in which sophocarpine was taken as the initiative material to be oxidized by potassium permanganate and the dihydroxylation product: 13, 14-dihydroxymatrine was given out successfully. The final product was determined by several methods.
In the third chapter, according to the rule of high efficiency, atom economy in the combinatorial chemistry as well as green, zero pollution and environmentally benign idea in organic synthesis, we success to design an experiment to synthesize two novel derivatives of matrine. The method was confirmed to be a novel, high efficiency, green protocol for one-pot preparation of matrine dithiocarbamate. This protocol avoids the use of some toxic organic solvents, such as chloroform, DMF or DMSO, and some catalysts. The plausible dual role of water in promoting the reaction is rationalized by the mechanism we have described. In addition to the above advantages, the metal-free, non-hazardous and mild experimental conditions, simple experimental procedures, easy workup also show great superiority in this experiment. The desired products were confirmed by two-dimensional NMR spectrum and x-Ray single crystal diffraction anylysis etc.
In the last chapter, with an attempt to apply the classic principle of Michael addition we still use the initiative material sophocarpine and try to make it as an electron acceptor and nitrocarbol or acetacetic ester as an electron donor in this reaction. The result has shown that the sophocarpine has poor reaction activity, and the yield was lower than the reaction in which the electron donor wereα,β-unsaturated aldehydes orα,β-unsaturated ketones. We broadened the application range of Michael addition reaction and get what we have anticipated through our study.
生物碱一般是指植物中除蛋白质、肽类、氨基酸及维生素B外的含氮的有机化合物。它是科学家们研究的最早的一类有生物活性的天然有机化合物，而且生物碱类化合物大多具有良好的生物活性。这类化合物往往是许多药用植物，包括许多中草药的有效成分。目前国内外对生物碱的研究如火如荼，近年来，由于分离纯化、结构鉴定、生物活性导向跟踪等方面技术上的长足进步，结构新颖、活性高的生物碱不断被发现，其数目不断增加。对已发现的生物碱的结构修饰与改性研究是天然药物研究的另一个重要的方面。因此为了进一步提高苦参生物碱的药理活性，我们对苦参碱进行了初步的结构修饰与改造研究，合成出了几种结构新颖的苦参碱的衍生物，论文主要分为以下四个部分：
第一章首先就天然药物的研究现状及生物碱的研究进展进行了文献总结，重点介绍了当前对生物碱研究的一些新的方法、理念以及有关天然产物结构修饰与改造的原理；对我们的研究对象苦参碱的生物学特征和广泛的药理活性也做了详细的介绍，并就目前的研究情况做了总结。
第二章以槐果碱为起始化合物，以形成多元醇为目的同时又可以增大苦参碱的水溶性，我们设计了对槐果碱的α，β-不饱和双键进行双羟化氧化，成功的合成出了13，14-二羟基苦参碱，并且对产物结构进行了表征。
第三章中，应用组合化学中多组分反应的高效性、原子经济性的原则，同时又能体现出绿色无污染、对环境友好的有机合成理念，我们以槐果碱为原料，成功的提出了一个新颖、高效、绿色的一锅法合成二硫代(N，N-二烃基)氨基甲酸苦参碱酯的方法，合成出了两个结构新颖的苦参碱衍生物。反应过程中避免了使用一些毒性的有机溶剂如氯仿、DMF、DMSO等，同时反应也不需要加入任何的金属催化剂。我们还从可能的反应机理上解释了水在反应中的双重作用。该反应除了具有不需要催化剂、对有些胺类产率较高、反应清洁等优点外，还具有后处理过程简单的优点。产物的结构经二维核磁共振图谱表征及X射线单晶衍射测定，为我们的预期产物。
第四章中仍以槐果碱为起始反应物，应用经典的Michael加成反应的原理，我们试验了在槐果碱的α，β-不饱和内酰胺的双键上进行亲核加成。反应中槐果碱作为电子受体，当用乙酰乙酸乙酯或硝基甲烷作为电子供体时，实验结果显示，槐果碱的反应活性较低，产率相比较典型的α，β-不饱和醛酮做电子受体时的反应偏低。通过对该反应的研究，我们补充了Michael反应的应用范围，取得了预期的成果。
Nature Pharmacological chemistry play an important role in chemistry, especially in organic chemistry at all time, not only because the study of nature pharmacological chemistry can take tremendous challenge to organic chemists, but also because the result of which can improve people's health situation greatly, so it has a close relationship with us. As far as the study of drugs is concerned, more than one third of the clinical drugs were derived from natural products so far. There is a great variety of the resources of natural products in our country which has been applied to Chinese traditional medicine for a long time. Chinese organic chemists always regard the natural products as significant targets of research because of the ascendant conditions. The natural products of alkaloids are especially listed among the hottest point by the chemists and pharmacologists for its broadly and excellently pharmacological activities at all times.
The alkaloids refer to some organic compounds which contain nitrogen atom except proteins, peptides, amino acids and vitamin B. It is a kind of pharmacologically active nature organic compounds and is earliest investigated by scientists. For the most of the compounds like alkaloids show excellent pharmacological activity, they are usually the effective components in many medical plants including many Chinese traditional medicines. The researches on alkaloids are undergoing actively in the domestic and in the foreign countries at present. Because the technology of separation, purification, character and biological activity's tracing have made great progress, some alkaloids with novel structures and excellent pharmacological activities were found continuously. The modification of alkaloids' structure which had been confirmed is an important field in the study of natural medicine. We aimed to further improve the pharmacological activities of the matrine, and some primitive modification to the structure of matrine was carried out. As a result, several novel derivatives of matrine were synthesized. This thesis comprises four parts shown as follows:
In the first chapter, we summarized the studying progress of the natural medicine and the alkaloids firstly, emphasizing to introduce the new methods and ideas in the research of the alkaloids. We also introduced matrine's biological character and its comprehensive pharmacological activities in detail, and the summary of its presently studying progress was made as well.
In the second chapter, for the good solubility of anticipated product we design an experiment in which sophocarpine was taken as the initiative material to be oxidized by potassium permanganate and the dihydroxylation product: 13, 14-dihydroxymatrine was given out successfully. The final product was determined by several methods.
In the third chapter, according to the rule of high efficiency, atom economy in the combinatorial chemistry as well as green, zero pollution and environmentally benign idea in organic synthesis, we success to design an experiment to synthesize two novel derivatives of matrine. The method was confirmed to be a novel, high efficiency, green protocol for one-pot preparation of matrine dithiocarbamate. This protocol avoids the use of some toxic organic solvents, such as chloroform, DMF or DMSO, and some catalysts. The plausible dual role of water in promoting the reaction is rationalized by the mechanism we have described. In addition to the above advantages, the metal-free, non-hazardous and mild experimental conditions, simple experimental procedures, easy workup also show great superiority in this experiment. The desired products were confirmed by two-dimensional NMR spectrum and x-Ray single crystal diffraction anylysis etc.
In the last chapter, with an attempt to apply the classic principle of Michael addition we still use the initiative material sophocarpine and try to make it as an electron acceptor and nitrocarbol or acetacetic ester as an electron donor in this reaction. The result has shown that the sophocarpine has poor reaction activity, and the yield was lower than the reaction in which the electron donor wereα,β-unsaturated aldehydes orα,β-unsaturated ketones. We broadened the application range of Michael addition reaction and get what we have anticipated through our study.
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