基于α-重氮酮的生成新途径与原位捕获策略构建碳/杂环结构体的研究

The effectiveness of discovering leading compounds by high-throughput drug screening highly depends on the number and quality of the compounds in the compound library, and the quality of the compound is primarily determined by their structural diversity. Therefore, building a compound library with large number of molecules and considerable structural diversity is not only a fundamental work for pesticide and pharmaceutical research, but also a major subject of drug synthesis. In this project, arylglyoxal monohydrate, p-toluenesulfonyl hydrazide, and cesium carbonate are treated as multicomponent reagents, in which the highly reactive α-diazoketone intermediate is formed in situ via a series of self-organized transformation. Based on the strategies of in-situ trapping and diversity-oriented synthesis (DOS), a wide variety of trappers are designed to trap the α-diazoketone intermediate. Thus, with the consideration of the requirement for functional groups and the principles of different reaction types, this project is expected to develop new types of diversity-oriented reaction systems and novel methods for the constructing of small molecule library. Moreover, new reaction modes are expected to be established for the synthesis of different carbon-heterocyclic structures, thus providing a high-quality compound library for related bioactivity studies.

通过高通量药物筛选发现先导化合物(leading compounds)的有效性取决于化合物样品库中化合物的数量与质量，而化合物样品的质量主要由化合物结构的多样性来决定，因此，构建一个分子结构丰富，数量庞大的高品质化合物样品库是农药及医药研发的基础，也是药物合成研究的一大核心课题。本项目以“酮醛一水合物、对甲苯磺酰肼、Cs2CO3”为一个“多组分试剂系统（Multicomponent Reagents）”，历经一系列自序化的反应转化而在现场形成一个具有广泛反应活性的α-重氮酮活泼中间体,基于原位捕获与多样性导向合成策略，结合不同反应类型所需的活性功能团和各种环加成的组装原理去设计捕获子对其进行原位捕获，从而形成一个多样性导向的新型反应系统，探索出一个新型小分子化合物库的构建方法，同时，期冀为一系列碳/杂环结构体的合成建立新颖的多组分反应模式，并为相关生物活性筛选研究提供一个优质的化合物样本库

碳/杂环化合物是具有广泛生理活性的分子结构体，多样性导向合成(diversity-oriented synthesis, DOS)策略成为构建小分子化合物库的一种重要手段。可以说，设计和寻找一个具有广泛反应活性的分子片段作为关键的高活性亚稳态结构体，是多样性导向合成策略得以实现、分子库得以建立的核心目标和媒介。该课题研究了从“多组分反应”延伸出形式上的“多组分试剂”，即由一个多组分反应产生一个高活性的试剂——亚稳态的高反应活性中间体；然后按照串级反应的原理设计出不同的捕获子，基于原位捕获的手段来构建各种碳/杂环，从而形成一个多样性导向的自组织反应系统，以期获得一个结构丰富的分子库，进一步丰富了自分类反应网络的研究内容。相继以芳基甲酮为起始，基于芳基酮醛以及α-重氮酮的原位捕获策略构建了30余种合成杂环结构体的反应，同时实现了多种天然产物的一锅全合成。项目执行期间在国际权威期刊发表研究型论文40余篇，总引用次数为959次。并培养博士毕业生7个，硕士毕业生6个，共有5人获得国家奖学金。产生了良好的社会效益，体现出较高的学术价值，所得到的研究成果完成了预定目标。