Akuammiline天然产物是一类单萜吲哚生物碱，近年来成为科学研究的热点。其结构特点是以氢化咔唑为基本骨架，含有复杂的笼状结构、多样的桥环与稠环体系以及多个手性中心。研究显示该类天然产物具有多种生物学活性，如抗肿瘤和抗炎活性等。受其合成上的挑战性与显著的生物活性所吸引，该家族天然产物受到世界范围的广泛关注。自从该家族成员vincorine的全合成被首次报道后，陆续有几个该家族的天然产物被化学全合成，并在合成过程中发展出了多种新颖高效的合成策略。 根据骨架中N4连接位置的不同，akuammiline生物碱可分为三类，包括N4-C2、N4-C3和N4-C14的连接方式，之前的研究都是针对含有N4-C2或N4-C3连接的天然产物。本论文首先实现了calophyline A的全合成，该天然产物是已发现的唯一含有N4-C14连接方式的akuammiline生物碱；接下来，我们发展了针对不同骨架类型（N4-C2、N4-C3和N4-C14）akuammiline天然产物的通用性合成策略。 我们对calophyline A的全合成路线包括以下关键反应：利用氮杂频哪醇重排反应高效构建关键的[3.2.2]氮杂桥环骨架与季碳中心，通过Heck反应构建其6/5/6/5稠环体系，后期通过高难度的aldol关环串联反应生成另一个季碳中心并完成氧杂[3.2.1]桥环的构建。基于上述路线，我们实现了该天然产物的首次化学全合成，并且证明了我们前期发展的氮杂频哪醇重排策略在复杂分子合成中的实用性。 接下来，我们通过选择性的骨架迁移，实现了对不同骨架类型akuammiline生物碱的通用性合成策略。我们设计与合成了一个含有N4-C14连接方式的通用中间体，进而通过二碘化钐介导的骨架迁移，成功实现了对N4-C2和N4-C3两种环系的构建。基于上述环迁移策略，我们完成了对calophyline A的改进型全合成、对deformylcorymine的首次化学全合成以及对天然产物strictamine的全合成。 本论文不仅实现了含有N4-C14类骨架akuammiline生物碱calophyline A的首次全合成，还发展了针对不同骨架类型该家族天然产物的通用性合成策略，进而实现了天然产物deformylcorymine和strictamine的全合成。我们的工作填补了N4-C14类akuammiline生物碱的合成研究空白，并为该家族天然产物的集体性合成与多样性修饰提供了新的策略。我们相信上述工作可以为进一步研究该家族天然产物的生物学活性提供化学基础。
The akuammiline natural products are a family of monoterpene indole alkaloids that have become the popular research area in recent years. Their structure features include the hydrocarbazole scaffold, rigid and cagelike framework, the bridged polycyclic ring system, and multiple stereogenic centers. Scientists have also identified their wide range of biological properties, which span from anti-cancer to anti-inflammatory effects. The synthetic challenges of akuammiline natural products, coupled with their versatile bioactivities, have attracted the attention of chemists worldwide for many years. Since the first total synthesis of vincorine was reported, several members of this alkaloid family have been successfully synthesized, highlighting the power of a variety of novel synthetic strategies. According to the ring connectivity around N4, these natural products can be divided into three subclasses with N4?C2, N4?C3, and N4?C14 linkages. While previous studies mainly focus on the synthesis of natural products belonging to the former two subclasses, in this dissertation we first describe the total synthesis of calophyline A with a N4-C14 linkage and later a unified strategy to construct all the ring connectivities (N4?C2, N4?C3, and N4?C14) of akuammiline natural products. Our synthetic route to calophyline A features several key transformations, including an aza-pinacol rearrangement to construct the nitrogen-containing bridged [3.2.2] bicycle, a Heck cyclization to assemble the fused 6/5/6/5 ring system, and a challenging late-stage aldol reaction to generate both a neopentyl quaternary stereogenic center and an oxygencontaining bridged [3.2.1] bicycle. Our studies represent the first total synthesis of this complex natural product and successfully demonstrate the synthetic utility of our previously developed aza-pinacol rearrangement in natural product total synthesis. A unified synthetic strategy to structurally diverse akuammiline alkaloids by selective ring migrations has been realized. A common synthetic precursor containing the N4?C14 linkage was synthesized and used for the SmI2 facilitated selective ring migrations, generating the N4-C2 and N4-C3 linkage respectively. Our strategy led to an improved total synthesis of calophyline A, the first total synthesis of deformylcorymine and the total synthesis of strictamine. In brief summary, we have achieved the first total synthesis of calophyline A, the only member of akuammiline alkaloids with the unique N4?C14 linkage. In addition, we have developed a unified strategy via selective ring migrations for the total synthesis of structurally diverse akuammiline alkaloids, including deformylcorymine and strictamine. Our works fill the gaps in the synthesis of akuammiline alkaloids and provide a unified solution for the collective synthesis of akuammiline alkaloids, which we believe would lay the foundation for the further exploration of the versatile biological activities of the natural products in this family.
