Illicium sesquiterpenes are a large number of biologically active secondary metabolites which are isolated from Illicium species of plants and well known for their activity of neurite outgrowth in cultured neurons. Compared to various studies of bioactivity and synthesis of the illicium sesquiterpenes, there are very few discussions in their biosynthetic pathways. Herein, we report a plausible comprehensive biosynthetic pathway of illicium sesquiterpenes and a synthetic route to illisimonin A and merrilactone A based on it. We think that most of the illicium sesquiterpenes' carbon scaffolds could be synthesized from dicarbonyl derivative of allo-cedrane via retro-Dieckmann condensation, oxidative cleavage and aldol reaction at suitable oxidation states in Nature. The common intermediate for illisimonin A and merrilactone A similar to the dicarbonyl derivative of allo-cedrane was assembled by an intramolecular desymmetrizing reductive Heck reaction. A new type of chiral phosphine ligands was developed to achieve the asymmetric intramolecular desymmetrizing reductive Heck reaction, and a maximum of 82% ee was obtained. The syntheses of illisimonin A and merrilactone A confirmed the key transformations of the proposed biosynthetic pathway.
目前合成的一个潮流是专注在碳骨架比较小,但是氧化态非常高的天然产物。此处阳铭老师课题组选取了一类倍半萜分子,具有多样的氧化态分布。下图为该类分子的生源转化关系:
逆合成分析如下图所示,作者选取了生源合成的中间体骨架7,如上图所示,将两个天然产物逆推至简单的中间体26。随后设计了一步非常大胆的跨环Heck,构建了这个中心高张力的骨架。 问[Pd(PPh3)4]catalyzed Tsuji-Trost allylation的a步骤的催化循环? 问Grubbs催化剂的结构是什么? 问作者尝试对31的羰基进行保护,但是失败了,为什么? 问32到33的转换还可以通过什么途径实现? 问常规在烯丙基化这步g,应该是可以构建绝对手性,实现手性的引入,但作者为什么没有在这一步这样做?难点是什么? 问反应i能发生的必要条件是什么? 问反应i的过程是什么? 问a步的反应面选择性? 问36到37的转化机理是什么? 问CAN脱保护的机理是什么? 问38向39的转化过程中,为什么要加ptsa? 问39向40的转化过程? 问40向41的转化过程? 问42向43的转化机理? 问最后一步的反应机理,用44的优势在哪里? 问在46向47的转化过程中,为什么CAN脱保护后,没有形成分子内的半缩酮? 问反应48向49的转化过程?非常聪明的做法! 问49向50的过程,手性控制?
基于对该类分子的生源合成途径的探究,作者设计了一条bio-inspired的合成路线:针对生源合成中propose的高级中间体,设计路线,随后再进行多样性合成。最终,通过高超的氧化态操作技巧,作者成功地完成了这两类分子的全合成。 其中,最为惊叹的是碳环骨架的合成,断键极具想象力,最近余金泉老师有篇nature,science和这个思路也比较像。 同时这类分子的合成已经有很多课题组报道过了,之后有机会做一个集锦对比各条路线。 |
|