【作者】 陈霞；

【导师】 张勇慧； 罗增伟；

【作者基本信息】 华中科技大学 ， 药物化学， 2021， 博士

【摘要】 2,3-萘二甲酰亚胺、芳基二氢萘和琥珀酰亚胺骨架,是三种非常重要的骨架类型。2,3-萘二甲酰亚胺可用作荧光标记材料和环境敏感型的荧光探针,用于药物及药理活性分子在体内的成像分析等;芳基二氢萘和琥珀酰亚胺骨架可见于一些有药理活性的分子和天然产物或者药物结构中。因此,这三类骨架的构建对于生物化学和药物化学领域具有重要的意义。然而,现已有的合成这几类化合物的方法面临着路线繁琐、产率低和官能团的兼容性差等不足,在一定程度上限制了其应用。因此,继续开发新的、高效和具有宽广底物适用范围的合成方法仍然非常重要。近年来,绿色化学深受广大化学合成工作者们的青睐,不仅因为其能降低反应的成本,更重要的是能减少合成过程中过渡金属催化剂的使用,从而减少对环境造成的污染。本论文提出了三种骨架——2,3-萘二甲酰亚胺、芳基二氢萘和琥珀酰亚胺的合成方法,并开展了与其相关的应用方面的研究,为具有应用价值和潜在的药理活性的这几类化合物的合成提供了绿色的合成方案。本论文基于酰亚胺对炔基具有一定的活化作用;结合底物所具备的合适的空间构型,实现了苯乙烯-炔-酰亚胺化合物在无金属催化剂的作用下通过发生分子内的二脱氢Diels-Alder反应合成2,3-萘二甲酰亚胺。该方法无需使用昂贵或者有毒的金属催化剂和配体,具有高原子经济性,反应条件温和,官能团的兼容性好等特点,为荧光物质2,3-萘二甲酰亚胺的合成提供了一条简便和温和的合成路线。基于上述炔酰亚胺片段促进的温和条件下的分子内二脱氢Diels-Alder反应的研究,结合芳基二氢萘骨架在天然产物和生物活性物质中广泛存在的研究背景。本文进一步开展了苯乙烯-炔类型的底物发生分子内的二脱氢Diels-Alder反应的研究,为重要的骨架类型——芳基二氢萘的合成提供了一个可替换的和绿色的合成方案。基于炔酰亚胺促进的苯乙烯-炔化合物发生分子内的二脱氢Diels-Alder反应的研究,结合琥珀酰亚胺类化合物在药物和药理活性物质中的重要应用。本文实现了含有炔酰亚胺片段的1,6-烯炔底物在无金属催化剂的作用下,在相对温和的条件下发生分子内Alder-ene反应合成琥珀酰亚胺;该方法可以很好地完成复杂天然产物和药理活性分子在后期阶段进行的结构上的修饰,避免了化学合成过程中金属残留的问题,不仅为琥珀酰亚胺类化合物的构建提供了一条绿色经济的合成路线,而且也为炔酰亚胺促进的其它烯炔类型的底物发生环化反应奠定了基础。更多还原

【Abstract】 2,3-Naphthalimide,aryldihydronaphthalene and succinimide skeletons are three very important skeleton types.2,3-Naphthalimide can be used as a fluorescent labeling material and environmentally sensitive fluorescent probes for imaging analysis of drug molecules and pharmacologically active molecules in vivo,etc.;Aryldihydronaphthalene and succinimide skeletons can be found in some pharmacologically active molecules and natural products or drug structures.Therefore,the construction of these three types of frameworks is of great significance to the fields of biochemistry and medicinal chemistry.However,the existing methods for synthesizing these types of compounds are suffered from cumbersome routes,low yields and poor compatibility of functional groups,which limits its’ applications to a certain extent.Therefore,it is still very important to develop a new method with high efficiency and wide substrate scope.In recent years,green chemistry has been favored by the majority of chemical synthetic researchers,not only because it can reduce the cost of the reaction,but more importantly,it can reduce the use of transition metal catalysts in the synthetic process,thereby reducing environmental pollution.Three synthetic approaches for the construction of 2,3-naphthalimide,aryldihydronaphthalene and succinimide compounds were proposed,and related applications of these methods were conducted.The research provides green and practical synthetic routes for the construction of these types of compounds with potential pharmacological activities and medicinal values.The thesis is based on the certain activation effect of the imide fragment to the alkynyl group and a suitable substrate configuration,which can promote the synthesis of 2,3-Naphthalimide via an intramolecular didehydro-Diels-Alder(DDDA)reaction of styrene-yne-imide compounds.This method avoids the utilization of expensive or toxic metal catalysts and ligands,and features in high atom economy,mild reaction conditions and good compatibility with different functional groups,which provides a simple and mild synthetic pathway for the fluorescence 2,3-naphthalimides.Based on the research on the intramolecular DDDA reaction under mild reaction conditions,which are promoted by the above-mentioned propiolimide fragment,together with the research background that the aryldihydronaphthalene skeleton is widely existed in natural products and biologically active substances.In this paper,the investigation on the dehydro-Diels-Alder reaction from the styrene-alkynes,which offers an alternative and green synthesis process for the construction of the important aryldihydronaphthalene skeletons.Based on the study of the intramolecular DDDA reaction of styrene-ynes promoted by the propiolimide fragment,together with the important application of the succinimide skeletons in drugs and pharmacologically active substances.In this paper,we realized the synthesis of succinimide skeletons via an intramolecular Alder-ene reaction through the propiolimide compounds containing 1,6-enynes moieties under relatively mild and metal-free conditions;this method can fulfill the structural modification of complex natural products and pharmacologically active molecules in the late stages,avoiding the problem of metal residues in the chemical synthesis process,which not only provides a green and economical synthetic apprach for the construction of succinimide compounds,and also laid the foundation for the cyclization of other enyne type substrates promoted by the propiolimide moiety.更多还原