异腈参与的惰性键活化与含氮杂环构建

Nitrogen-containing heterocycles represent a catagory of compounds that contain diverse biological activities and material properties as well as acting as important building blocks for natural products and can be used as ligands for asymmetric synthesis. However, despite of many synthetic efforts, the development of a generally applicable approach for the highly efficient and selective synthesis of these compounds remains elusive. In this context, finding new approachs to construct nitrogen-containing heterocycles, in a prompt and efficient way, still remains both challenging and of great value. Transition metal-catalyzed functionalization of chemically inert bonds has attracted tremendous interest as a valuable tool for the construction of heterocycles. As a unique building block, isocyanides are highly potent reagents for the development of multicomponent reactions (MCRs) to generate heterocyclic systems or natural product-like compounds. Recently, metal-catalyzed reactions with isocyanides has invoked evergrowing synthetic efforts and continued to be an active and rewarding research area. In this proposal, we will fully develop the chemically inert bonds activation with isocyanides from easily available starting materials based on unique properties of isocyanides. More attentions will be paid to solve some key scientific problems related to isocyanides, for example, non-precious metal catalyzed reactions, the high degrees of chem-, regio- and enantioselective reactions of C(sp3)-H bond activation with isocyanides, multi-centered reactions, and new types of reactions using isocyanides as ligands or additives. By given approaches, versatile and highly functionalized nitrogen-containing heterocycles could be developed with high efficience and selectivity through chemical bonds insertion and annulation reactions. The mechanistic studies for these reactions will be speculated accordingly by using quantum computational method together with experimental technics. Furthermore, the generated drug-like chemical libraries will be used for specific biological targets and this strategy will be applied for the efficient total synthesis of some bioactive natural products.

含氮杂环具有较特殊的生物活性和材料性能，而传统的合成方法效率较低。利用过渡金属催化的C-H键官能团化反应来构建各类含氮杂环，目前已引起广泛的关注并得到迅速发展。作为一个不可替代的合成子，异腈已被广泛应用于各类含氮杂环的合成中，但涉及惰性键活化的反应还有待深入。本项目将基于异腈特殊的物理和化学性质，在前期工作的基础上，系统地研究异腈参与的惰性键活化反应。我们将着力研究并解决目前异腈化学研究中涉及的几个关键科学问题：1）挖掘和发现新的廉价金属催化体系和新试剂来促进异腈参与的反应；2）探讨基于C(sp3)-H 键活化的化学和立体选择性问题；3）深入研究异腈作为一类新的金属配体或添加剂的相关反应及机理。基于所发展的含氮杂环构建新方法，我们将拓宽其在复杂天然产物的全合成以及特定药物分子的后期衍生化方面的应用。通过对反应所涉及的化学过程和反应机理的研究，为异腈化学的进一步深入研究提供新的内容和思路。

含氮杂环在有机合成、药物化学以及材料化学中具有较高的学术和应用价值，但传统的合成方法一般效率较低。利用过渡金属催化的惰性键官能团化反应来构建各类含氮杂环，已成为重要的合成策略而得到广泛引用，但异腈参与的惰性键活化反应还有待深入。本项目在实施过程中利用惰性键活化反应，发展了一些高效、新颖的有机合成新方法，构建了多个含氮分子库，并研究了其在抗肿瘤和材料性能等方面的应用。项目从以下几个方面开展了研究工作：(1)异腈参与的惰性键活化反应。通过异腈对环状或开链杂原子邻位C(sp3)-H键的连续插入，完成了具有叔碳中心的氰基亚胺或α-羰基-氰基亚胺等化合物的高效构建；实现了多取代α-酰氧基丙烯酰胺类烯烃和C9-烷基化的菲啶衍生物的直接合成；基于异腈的特殊配位能力及还原能力，首次实现了惰性硫酸铜中硫酸根阴离子的磺化反应。同时，我们还研究了这些反应在抗结直肠癌和聚集诱导发光效应等方面的应用。(2)硝酸铜参与的烯烃或炔烃的碳-碳键断裂反应。利用硝酸铜作为新颖的氧化腈前体，从简单的炔烃-炔烃、烯烃-烯吖内酯或烯烃-烯烃出发，经碳-碳键断裂反应和环化反应，合成了一系列具有潜在生物活性的(二氢)异噁唑类化合物；同时，硝酸铜可作为硝酸酯源或硝基源，实现了烯烃或炔烃的双官能团化反应。(3)基于惰性碳-杂键和氢-杂键断裂的杂环化合物构建。基于铜催化惰性C-H键氧化关环反应，高效构建了噌啉类化合物，并在反应中同时实现了罕见的惰性C-O键、C-F键以及C-N键的高选择性断裂；合成了具有较高挑战性、带有碗状结构的高张力三硫/硒/碲/硅/锗杂素馨烯衍生物，并对合成的化合物进行了相关光学性质研究。