基于genepolide全合成的不对称D-A反应研究

发布时间：2018-03-08 14:15

本文选题：Genepolide　切入点：二倍半萜　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：萜类化合物是自然界中广泛分布的一大类天然产物,结构特点新颖且具有多样的生物活性,一直是生物医学和化学界关注的重点。近年来,许多有机化学家们都纷纷致力于复杂萜类物质的全合成研究之中,二倍半萜作为一种特殊的萜类物质,虽然在数量上相对较少,但是其表现出的优秀的生理药理活性使其具有很重要的商业价值。迄今为止,关于二倍半萜类物质的提取分离并延伸到全合成研究的并不算多,2008年Appendino小组从山苦艾中发现的二倍半萜化合物Genepolide是一种结构新颖且活性价值很高的物质,具有倍半萜烯γ-内酯类新型骨架结构,形式上可以通过倍半萜物质木香烃内酯和月桂烯通过两分子的D-A反应得到,至今尚未有该分子相关的合成报道,我们小组尝试了对其进行全合成方面的研究。之前的研究报道了关于Genepolide全合成的不可行性,并通过不对称D-A反应的失败尝试,推测其仅仅为天然存在的物质,不能通过人工合成的方法获得。幸运的是,我们小组在进行Genepolide全合成过程中,也尝试了其关键中间体D-A反应,并通过不断地条件筛选,最终成功得到了所需要的加成产物。所以我们同时开展了两个方面的工作:一方面是通过逆合成分析得到一个较优的中间体合成过程,即从山道年出发经过七步反应得到了关键的D-A反应合成中间体。另一方面,鉴于之前已经尝试出中间体与双烯的D-A反应可行性,在此基础上我们进行了不对称D-A反应的方法学研究,对底物结构进行了改变与修饰、对双烯体的不同类型进行筛选以及对D-A反应条件进行了优化,试图筛选得到一个最佳的D-A加成反应条件,在此过程中我们成功合成了一些加成产物,将其作为此D-A反应可行性的一个佐证。最后,我们将中间体继续往下开展了 Genepolide的全合成研究,通过九步反应得到了 Cope重排的前体化合物,虽然在进行最后一步重排时始终没有得到想要的结果,但是后续工作仍在不断地尝试之中。并且之前报道中认为不可发生的D-A反应,已经被证实可行,这也使得Genepolide的后续全合成研究变得明朗许多,同时也给今后的天然产物全合成工作带来一定的借鉴意义。
[Abstract]:Terpenoids are a kind of natural products which are widely distributed in nature. The structure of terpenoids is novel and has a variety of biological activities, which has been the focus of biomedical and chemical fields. Many organic chemists have devoted themselves to the study of the synthesis of complex terpenoids. As a special kind of terpenoids, the diploid sesquiterpenes are relatively small in quantity. But its excellent physiological and pharmacological activity makes it of great commercial value. Few studies have been conducted on the extraction, isolation and extension of diploid sesquiterpenes to total synthesis. In 2008, the diploid diterpenoid compound Genepolide, which was discovered by the Appendino team from Herba vermouth, was a novel and highly active substance. It has a new framework structure of sesquiterpene 纬 -lactone, which can be obtained through D-A reaction of sesquiterpene substances such as xylinolactone and lauryl in the form of sesquiterpene. So far, there has been no report on the synthesis of this molecule. Our team tried to study it in terms of total synthesis. Previous studies reported on the infeasibility of total synthesis of Genepolide, and through failed attempts at asymmetric D-A reactions, we speculated that it was only a natural substance. It can't be obtained by synthetic method. Fortunately, our team also tried its key intermediate D-A reaction during the whole synthesis of Genepolide, and it was screened by constant conditions. Finally, we got the desired addition product. So we did two things at the same time: on the one hand, we got a better intermediate synthesis process by inverse synthesis analysis. On the other hand, given the feasibility of the D-A reaction between the intermediate and the diene, we have already tried out the feasibility of the D-A reaction between the intermediate and the diene. On this basis, we studied the methodology of asymmetric D-A reaction, modified and modified the substrate structure, screened different types of dienes and optimized the conditions of D-A reaction. We tried to screen out an optimal condition for D-A addition reaction. In the process, we successfully synthesized some addition products as a proof of the feasibility of the D-A reaction. Finally, We carried on the whole synthesis of Genepolide from the intermediate, and we got the precursor compound of Cope rearrangement through nine steps, although we never got the desired result in the last step of the rearrangement. But the follow-up work is still under way. And the D-A reaction, which was previously reported as not to happen, has been proven to be feasible, which has made it much clearer to follow up on the full synthesis of Genepolide. At the same time, it also brings some reference to the whole synthesis of natural products in the future.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O629

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