基于活化C(SP3)-H键的新型串联反应的发展及其单萜吲哚生物碱全合成应用研究

Comparing to stepwise process, multistep, one-pot reaction (tandem reaction) strategies are being increasingly applied to the synthesis of natural products and derivatives, not only due to their elegance, but also because of their efficiency and economy in terms of reagent consumption and purification. The environmental concern and the demand for more efficient and environmentally benign chemical processes calls for the further development of such synthetic strategies and tactics as we move into a new age of chemical synthesis. In this manner, development of new tandem reactions based on redox-neutral C(Sp3)-H bonds functionalization, which benefits from significant atom and redox-economy, provides an intriguing strategy in complex molecular synthesis expeditions. In this proposal, a challenging and unprecedented tandem reaction strategy based on intramolecular capture of 1, 4-dipole intermediate generated by C(Sp3)-H 6-endo-dig/trig [1, 5]-hydride shift will be developed. This new methodology will find broad applications in the concise total synthesis of representative members of bio-significant and structurally complex monoterpene indole alkaloids, such as vellosimine, strychnine and aspidophytine.

相比分步式反应，多步一锅式串联反应由于能高效环保地快速完成复杂分子骨架的构建而在天然产物及其衍生物合成中运用日益广泛。其中，发展基于C(Sp3)-H键活化的新型串联反应将为复杂分子经济性合成提供“绿色”手段。本项目中，申请人拟发展一种基于捕获6-endo-dig/trig型[1, 5]-负氢分子内转移(C(Sp3)-H键活化)产生的1, 4-偶极中间体的多步一锅式新型串联反应，在完成典型性代表夹竹桃科和马钱子科吲哚生物碱骨架高效构建的基础上，实现以vellosimine、strychnine、 aspidophytine等为代表的具有复杂结构和重要生理活性的单萜吲哚生物碱家族代表成员的全合成。

相比分步式反应，多步一锅式串联反应由于能高效环保地快速完成复杂分子骨架的构建而在天然产物和其衍生物合成中运用越来越广泛。发展基于C（Sp3）—H键活化的新型串联反应为复杂分子的高效合成提供符合上述标准的解决方案。基于对铜催化的环丙醇开环对亚胺的加成的发现，我们发展了一种新颖的C-H键氧化/环丙醇开环加成串联反应，实现了广泛存在于天然产物的氮杂双环[3.3.1]壬烷桥环骨架的高效构建。以此为关键反应，我们实现了萝芙木生物碱 suaveoline、五个sarpagine类型生物碱和三个koumine类型生物碱全合成，为后续开展该类天然产物的活性研究奠定了物质基础。研究意义在于：1）首次实现环丙醇对亚胺离子的加成；2）发展了一种全新的构建氮杂双环[3.3.1]壬烷桥环骨架的方法。