若干含6-6或5-7碳骨架萜类天然产物的全合成研究

Terpenes are an important class of secondary metabolites, which constitute the most diverse structures among different classes of natural products. Either 6-6 or 5-7 carbon frameworks are very common structural motif in terpenoids. We have developed very facile construction of 6-6 carbon ring systems in one step through aldol-Henry reaction cascade and further more developed an approach for easy preparation of 5-7 carbon ring system via stereospecific rearrangement. In this application, we are going to extent the application of our chemistry to explore the total syntheses of five Cadinanes and two Guaianes, as well as aplyviolene and longefolene. We expected to develop rapid construction of the complex core of Cadinanes in 2-3 steps and finish all five family members in 5-7 steps through a common intermediate. As for pleocarpenene and pleocarpenone, we plan to use a known intermediate from our previous total synthesis to finish them in short steps with straight-forward chemical transformations. In the retrosynthetic analysis of aplyviolene, we proposed novel bond disconnection to greatly simplify the complex diterpenes to easily accessable target. We also would like to explore a new synthetic strategy to synthesize longifolene, a historically important sesquiterpenes. The new strategy features a cross-ring radical addition to alkyne to form the external methylene through a cis-fused 5-7 carbon skeleton. All these will add new synthetic tools and new strategies into the world of terpenoids chemistry.

6-6或5-7碳骨架是萜类化合物中比较常见的骨架类型。我们发展了快捷方便的aldol-Henry串联反应一步生成6-6环系，并进一步通过重排反应生成5-7碳骨架的方法。本申请拟利用此方法学来探索五个杜松烷，两个愈创木烷，以及二萜aplyviolene和倍半萜长叶烯的全合成。我们有望简单高效的在2-3步得到有连续四个手性中心的杜松烷的核心骨架，并在5-7步完成全部五个家族成员的不对称全合成；通过已经获取的便宜易得中间体，我们希望利用简单的化学转化完成愈创木烷pleocarpenene和pleocarpenone的全合成；在对aplyviolene全合成的构想中，提出新颖的断键和简化方式，拟用简短的步骤实现这个复杂二萜化合物的合成；对长叶烯的全合成将探索一种新颖的断键方式，用跨环自由基加成反应从5-7顺式并环底物一步完成长叶烯的全合成。这些工作将为萜类天然产物的合成提供新的合成策略与方法学。

本项目在我们自身发展的aldol-Henry串联反应基础上完成了若干结构罕见，反式萘烷碳骨架桥头带有叔碳羟基的杜松类天然产物的不对称简短全合成；该串联反应与立体专一性重排反应组合应用，高效构筑长叶烯中的顺式[5，7]-碳环体系，并在跨环自由基加成策略的指导下，完成了长叶烯的快速合成；在isoleptographiol和leptographiol的不对称合成中，将两个镜像异构体都利用起来，转化为相同光学活性中间体的理念和应用在有机立体化学概念上是一次很有意思的实践，对立体化学的灵活应用有很大的启发性和指导意义；我们发展了利用便宜易得的手性源化合物香芹酮快速立体选择性构筑在天然产物中广泛存在的含多个立体化学中心的六元碳环的“seeding & growing”合成策略。利用此策略，我们从香芹酮出发只用15步左右就实现了复杂天然产物indoxamycin A和B的全合成；考虑到立体化学环境复杂的六元碳环在天然产物中大量存在的客观事实，我们预计该合成策略将很大程度的为诸多复杂结构的天然产物的合成提供解决方案；复杂海绵烷二萜类天然产物因为其生物合成中多种多样的氧化重排反应的发生，导致其环系结构复杂多样，在合成上有很大的难度和挑战感。我们发展的串联逆D-A，ene反应策略很好的解决了该类二萜中广泛存在的内酯骨架单元的快速构筑，为此类天然产物的高效合成打下了坚实的基础。