构建2(lH)-喹啉酮/香豆素螺环及稠环的新方法及其在抗肿瘤药物中的应用

发展高效、高选择性的串联反应构筑类天然活性杂环是当今有机化学的前沿领域之一。针对目前2(1H)–喹啉酮和香豆素螺环/稠环化合物的结构类型不足，前期合成方法存在底物局限性、反应条件苛刻、反应步骤多及产率低等亟需解决的问题，本项目在前期研究叠氮-烯烃串联新反应的基础上，拟发展叠氮缀合的天然分子片与烯烃的串联成环反应。以具有潜在抗肿瘤活性的2(1H)–喹啉酮和香豆素为基础骨架，通过Michael加成反应在其C-4位引入叠氮基团，探索在过渡金属催化下与烯烃的定位串联螺环/稠环化反应，用于快速高效地构建结构多样的2(1H)–喹啉酮和香豆素的螺环及稠环化合物。本项目的研究不仅可以建立一个由叠氮-烯烃串联反应高效合成螺环/稠环的新方法，还可以构建一系列结构独特的新型螺环/稠环化合物。并进一步对这些螺环/稠环化合物进行抗肿瘤活性筛选，从中找到活性好的先导化合物，为新型抗肿瘤药物的研究奠定基础。

Development of efficient and high selective tandem reactions to construct natural heterocyclic analogues with bioactivity has been highlighted as one of research frontier. At present, spiro/fused-ring compounds containing 2(lH)-quinolinone or coumarin moiety are inadequate, and methods reported for this research area generally require special substrates, harsh reaction conditions, multi-step synthesis, often resulting in low product yields. This proposal focuses on these urgent problems. On the basis of some azide-alkene new cascade reactions founded recently in our group, 2(lH)-quinolinone and coumarin, which have potential anticancer activity, are modified to conjugate with functional azide group at the C4 position via Michael addition. Then, these azide-conjugated natural molecules and alkenes proceed via transition metal catalyzed spiro/fused cyclization reactions. These new reactions will be used to construct structurally diverse 2(lH)-quinolinone and coumarin spiro/fused-ring compounds rapidly and effectively. This study not only establishes a new method for the synthesis of spiro/fused-ring compounds through azide-alkene cascade reactions, but also provides a series of novel unique spiro/fused-ring compounds. These skeletons will be further tested for antitumor activities to seek new antitumor lead compounds, and provide a foundation for the study of novel antitumor drugs.