Lewis碱催化贫电子环丙烷的开环串联反应及其在5/7/6环系紫杉烷二萜天然产物合成中的应用

The past decades have witnessed spectacular developments in Lewis base catalysis, but those transformations based on n-sigma* activation of carbon-carbon bonds present a significant challenge and have rarely been explored. By virtue of the special structure of electron-poor cyclopropanes, in this program we will design and develop their ring-opening tandem reactions via n-sigma* activation with Lewis base catalysis, and explore their applications in the synthesis of complex molecules. On one hand, under the catalysis of tertiary phosphines or amines, the ring-opening reactivity of electron-poor cyclopropanes and derivatives will be investigated toward rearrangement reactions and intermolecular annulations with electrophiles or nucleophiles. Asymmetric versions will also be studied by utilizing cooperative catalysis with chiral secondary amines. On the other hand, using a novel phosphine-catalyzed rearrangement of vinylcyclopropylketones to cycloheptenones as a key step, in combination with classic organic reactions, we will focus on the total synthesis of Taxchinin A, a member of taxoid diterpene natural products of 5/7/6 ring system with highly important antitumor activity. On the basis of preliminary work, this project combines advances in both reaction discovery and natural product synthesis, which will enrich the mode of Lewis base catalysis and ring-opening activity of cyclopropanes, and provide useful synthetic methodologies for important ring structures as well as supply a strategy toward the total synthesis of taxoid diterpene natural products of 5/7/6 ring system.

Lewis碱催化在近年来获得迅速发展，但针对碳碳键n-sigma*活化的催化反应研究非常欠缺并存在挑战。本项目借助于贫电子环丙烷的结构特性，设计、发展其在Lewis碱催化下以n-sigma*活化实现的开环串联反应，并将之应用于复杂分子的合成当中。一方面，系统研究叔膦、叔胺催化贫电子环丙烷衍生物的扩环重排反应，及与亲电、亲核试剂的分子间环化反应，并采用手性仲胺协同催化等策略发展不对称转化。另一方面，基于原创性叔膦催化乙烯基环丙基酮重排为环庚烯酮的反应作为关键步骤，结合其它经典有机反应，开展具有重要抗肿瘤活性的5/7/6环系紫杉烷二萜天然产物Taxchinin A的全合成研究。基于前期工作基础，本项目融合新反应探索与天然产物全合成，有助于丰富Lewis碱催化反应模式和环丙烷开环反应途径，可望发展重要环状分子的合成方法学并提供5/7/6环系紫杉烷二萜天然产物的全合成策略。

根据项目研究计划，本项目采用Lewis碱催化手段活化缺电子环丙烷衍生物，发展了若干开环串联/环化反应: 1)实现了叔膦催化亚甲基环丙基酮新颖多样的开环重排反应，分别实现三、四取代呋喃和多取代共轭烯烃的合成；2)实现了叔膦催化环丙烯酮与醛、β-酮酯、亚胺、异氰酸酯、碳二亚胺等的[3 + 2]环化反应，为合成丁烯内酯、丁烯内酰胺、马来酰胺及其衍生物等生物活性分子提供了新的策略；3)发展了叔膦催化环丙烯酮与氧、氮、硫亲核试剂的开环加成反应，为α,β-不饱和酯、酰胺、硫酯的合成提供了简单高效的方法；4)实现了DMAP催化溴代酮与环丙烯酮的[3 + 3]环化反应，高效合成了吡喃酮化合物。通过密度泛函理论计算(DFT)、控制实验、核磁跟踪实验、高分辨质谱等方式对上述反应进行研究，提出并验证了反应机制。以上Lewis碱催化环丙烷衍生物的开环反应，丰富了Lewis碱催化的反应模式，拓展了环丙烷化学的研究范畴，同时为多种重要分子的高效构筑提供了新的方法。此外，在药物活性分子合成方面，发展了磷叶立德与两分子异氰酸酯的一锅法串联反应，快速构建了具有重要生物活性的4-喹诺酮分子骨架。