构建芳香稠杂环的新方法及其在抗肿瘤药物中的应用

Fused heteroaromatic compounds have a wide range of applications in pharmaceuticals, photovoltaic material and so on, due to their distinctive structures. They are traditionally synthesized by intramolecular functionalization of aryl halides or sp2 C-H. These traditional methods are generally disadvantageous because of aromatic precursors as starting materials, costly transition metals as catalysts and inefficiency in producing aromatic fused heterocycles possessing an electron withdraw group. It is an important scientific issue in organic chemistry to develop novel green and efficient procedures for the synthesis of fused aromatic heterocycles. This project aims at establishing novel procedures to construct fused heteroaromatic compounds through oxidative cyclization/dehydrogenation of cyclohexenones or cyclohexanones fused to aromatic rings. Under oxidative conditions, cyclic ketone go through a cyclization reaction using carbony carbon and a-carbon to give a aromatic heterocycle and then undergo a dehydrogenative aromatization to produce fused heteroaromatic compounds. This study not only establishes a new method for the synthesis of fused aromatic heterocycles, but also provides a series of novel unique fused aromatic heterocycles. These skeletons will be tested for antitumor activities to seek new antitumor lead compounds.

芳香稠杂环化合物因具有独特的化学电子性能而在医药、光电材料等领域有着广泛应用。目前合成芳香稠杂环的主要方法是在过渡金属催化下分子内芳基卤的官能团化或分子内的SP2 C-H官能团化。这些传统的方法均以芳香性前体为原料，其来源受到限制，大多需要价格昂贵的过渡金属催化剂，也无法在杂环上引入吸电子基。发展绿色、高效的合成芳香稠杂环的新方法是有机化学中重要的科学问题。本项目拟开展由非芳香性的环己烯酮或与芳环稠合的环己酮通过氧化环化/脱氢芳构化构建芳香稠杂环的研究。在氧化条件下，环酮的羰基碳、α-碳与双功能试剂通过环化反应形成一个芳杂环，然后脱氢芳构化形成稠合的芳杂环。本项目的研究不仅可以建立一个在温和条件下由非芳香性原料合成芳香稠杂环的绿色高效的新方法，还可以构建一系列新型的结构独特的芳香稠杂环化合物。在此基础上，对这些芳香稠杂环化合物进行抗肿瘤活性筛选，期望从中找到活性好的新型先导化合物。

研究了通过氧化环化/脱氢芳构化来构建喹啉、苯并吖啶、苯并嘧唑并[2, 1-b]萘并噻唑、苯并嘧唑并[2, 1-b]苯并噻唑等芳香稠杂环化合物，合成2-氨基噻唑衍生物并进行抗肿瘤性能测试。结果表明，喹啉杂环可以由苯胺与烯丙醇通过氧化环化来合成，而很多杂环并合的六元环脱氢芳构化困难，并不存在活性“苄位”碳；另外，所合成的2-氨基噻唑衍生物对白血病细胞562表现出较强的抑制作用。本研究结果为芳香杂环的合成提供了新方法，揭示了脱氢芳构化的一些内在规律；并对从杂环化合物筛选发现新的抗肿瘤先导化合物具有一定的借鉴和指导意义。