基于有机硼与重氮反应中间体捕捉的多组分反应研究

Multi-component reaction has attracted considerable attention owning to its high efficiency for improving drug synthesis process and constructing small molecular libraries with complexity as well as skeletal diversity. Trapping the reactive intermediate is a crucial strategy in developing novel multi-component reactions, but the reported reactive intermediates are quite limited. Our group has disclosed that under the catalysis of transition metals the diazo compounds could react with a series of nucleophiles （such as alcohols, amines and electron rich aromatics）to generate reactive ylides or zwitterionic intermediates in situ, which undergo further transformations including Mannich addition , Michael addition and Aldol addition. Based on these assumptions, our group has reported several multi-component reactions, which could used in constructing highly functionalized small molecular libraries. We propose that the combination of diazo compounds and organoboron compounds may react with other chemical reagents. By changing reaction conditions, choosing suitable catalysts, and the order of adding reagents we have a chance to control the reaction selectivity, in the meantime we can further understand the mechanism of reactions by analysis of the byproducts. Finally, these new developed multi-component reactions will be used in constructing small molecular libraries and broadening the diazo chemistry as well as organoboron chemistry, which will absolutely benefit both industry and fundamental research.

多组分反应可用于优化药物合成工艺和高效构建结构复杂多样化合物库，因而备受关注。捕捉“活泼中间体”是发展新型多组分反应的关键，但目前已报道的“活泼中间体”种类非常有限。本课题组发现重氮在过渡金属的催化下产生的金属卡宾与一些亲核试剂（如胺、醇以及富电子芳烃等）可以原位生成的活泼叶立德以及两性离子中间体，进而发生Mannich加成、Michael加成以及Aldol加成等，以此为基础发展了一系列新型多组分反应。我们提出重氮化合物和有机硼试剂新生成的有机硼中间体可以与其他试剂发生捕捉反应，发展新型的多组分反应。通过调节反应条件，筛选催化剂以及优化加料顺序实现对反应选择性的控制，同时对反应过程中产生的副产物分析检测以达到深入理解反应机理的目的。最终，将发展的新型多组分反应用于一些结构复杂多样的化合物库的构建，同时此项目可以丰富有机硼化学，促进重氮化学研究，具有非常重要应用与学术价值。

绿色精准合成是当今合成化学最具挑战性课题之一，开发高效高选择性新反应是绿色精准合成的核心。其中，多组分反应可以将三个或三个以上反应物通过一锅煮的方法获得目标产物，一步形成多个化学键，具有原子、步骤经济性，大大节约反应成本，可用于优化药物合成工艺和高效构建结构复杂多样化合物库，因而备受当代合成化学家的广泛关注。重氮化合物是一类重要的有机合成砌块，可作为卡宾的前体，广泛用于多组分反应的中间组分将不同的组分连接起来。在本项目中，我们成功实现了不同种类的重氮化合物，以及多种亲核试剂或亲电试剂的新型多组分反应。另外，我们还成功实现了自由基介导的重氮化合物参与的多组分反应，这类多组分反应与之前基于金属卡宾过程的发展具有良好互补性，具有很广的官能团忍受性。项目按照原计划书进行，进展顺利。此项目的研究成果可以进一步拓展重氮化合物的应用，为其他用于构建有价值的化合物骨架的新型多组分反应提供参考。