Hetidine型C20-二萜生物碱Talassamine的仿生合成研究

Recently, studies on the total syntheses of complex diterpenoid alkaloids have been the focuses and challenges in the community of natural organic chemistry. Atisine-type, hetidine-type, and spiramine-subtype alkaloids belong to the category of C20-diterpenoid alkaloid, which are closely related to each other in terms of structure. A new biogenetic pathway that the spiramine skeleton might serve as a bridge between atisine- and hetidine-type alkaloids is postulated in this project. Based on the proposal and our previous work, the present study aims at achieving the first biomimetic total synthesis of hetidine-type C20-diterpenoid alkaloid Talassamine, by way of atisine and spiramine intermediates. The atisine core could be efficiently assembled through an oxidative dearomatization/ intramolecular Diels-Alder cycloaddition (IMDA) cascade, followed by a key radical-mediated amide oxidation process to afford the spiramine framework. Construction of C14-C20 bond is envisioned to be realized via an aza-Prins cyclization, giving access to the hexacyclic skeleton of hetidine. In addition, starting from a common intermediate, total synthesis of the natural product Spiramine D could be accomplished as well. The research of this work may provide a crucial clue on the aspect of the biosynthesis of hetidine-type C20-diterpenoid alkaloids. Moreover, the preparation of corresponding natural products and their analogs sets the stage for an in-depth exploration of the biological functions and applications.

近年来，针对复杂二萜生物碱的全合成是当前天然有机化学界的研究热点和难点之一。申请人在本项目中创新性地提出Spiramine亚型骨架可能是生源上连接Atisine及Hetidine型C20-二萜生物碱的桥梁这一新的生源合成假设。在此推测及前期工作的基础上，本研究拟通过氧化去芳香化/分子内DA环加成串联反应构建Atisine骨架，进一步经自由基介导的酰胺氧化形成缩醛胺得到Spiramine亚型分子，最后借助氮杂Prins环化策略连接C14-C20键，实现首例Hetidine型C20-二萜生物碱Talassamine的仿生合成；由共同的中间体出发同时可完成Spiramine亚型化合物Spiramine D的合成。该研究对于探索Hetidine型C20-二萜生物碱可能的生源合成机理具有重要的指导意义；另一方面，通过相应天然产物及类似物的制备，为进一步考察其潜在的生物学功能提供了关键的物质基础。

二萜生物碱及对应的二萜类化合物是生物合成上相互关联的一大家族的天然产物，其集中分布于毛茛科(Ranunculaceae)乌头属(Aconitum)、翠雀属(Delphinium)和飞燕草属(Consolida)等植物类群中。其中的Atisine型、Ajaconine亚型、Hetidine型及Denudatine型四类C20-二萜生物碱结构上具有多环笼状的三维骨架。本项目通过挖掘上述四类生物碱结构间的内在生源关系，发展了一条通用且仿生的合成路线，实现了相关天然产物的全合成。取得的重要结果包括：1) 利用氧化去芳香化/分子内Diels-Alder环加成串联反应、酰胺α-位C–H氧化反应、氮杂Prins及氮杂pinacol偶联反应为关键步骤，实现了四类目标生物碱骨架的合成；2) 完成了相关天然产物gymnandine 和dihydroajaconine的全合成；3) 通过类似的氧化去芳香化/分子内Diels-Alder环加成串联反应策略，实现了乌头二萜化合物atropurpuran的全合成。在此项目的支持下，发表标注基金号的SCI论文5篇，其中包括一篇《Nature Commun.》，一篇《Angew. Chem. Int. Ed.》和一篇《Nat. Prod. Rep.》等。此项目的开展从化学合成的角度验证了四类C20-二萜生物碱的生源关系，并为后续相关化合物的生物学功能和机理研究奠定了物质基础。