生源启发的Lycodoline型和Fawcettimine型石松科生物碱合成研究

发布时间：2018-04-26 11:23

本文选题：石松科生物碱 + 串联反应　；参考：《兰州大学》2017年博士论文

【摘要】：石松属包含上千个不同的种,且在全世界范围均有分布。石松作为药用植物,在世界上有着悠久的历史。从石松中分离得到的生物碱更是结构多样、生物活性显著,由于石松科生物碱的这些特性,它一直吸引着诸多合成化学家和药物化学家的研究兴趣。本学位论文着重于围绕着lycodoline型和Fawcettimine型石松科生物碱的生源启发的全合成。以lycojaponicumin D的仿生合成为驱动,以lycodoline为基础,设计、发展了串联的碎裂化/Mannich环化反应,实现了由lycodoline到lycojaponicumin D的生源启发的仿生转化,建立了6/6/6/6骨架结构和5/7/6/6四环体系的重排联系。基于对称化切断的策略,发展了新颖的Pd介入的串联氧化脱氢/hetero-Michael加成反应,实现了双环[3.3.1]体系桥头C?H的官能团化,为发展基于Saugesa-Ito氧化的串联反应提供了新的机遇。以lycodoline为契机的发散式合成,总共实现了9个石松科天然产物碱、4类天然石松科生物碱的合成,其中lycojaponicumin D和6个lycodoline型石松科生物碱(lycoposerramine G,miyoshianine A,obscurumine A,serratezomine C,huperzine O,and 12-epilycodoline)属于首次全合成报道。本论文主要包含以下三个部分:第一章:系统地介绍了石松科生物碱的分离、活性、分类及部分合成工作。第二章:以lycojaponicumin D生源启发的仿生合成为动力,设计发展了“串联的碎裂化/Mannich环化反应”,实现了lycaponicumin D的全合成报道。在基于对称性切断策略,设计发展了新颖的“串联氧化脱氢/hetero-Michael加成反应”,为张力桥环体系中桥头C?H键的杂原子官能团化提供了新方法。在此基础上结合“串联还原胺化/桥头胺解反应”,简洁高效地实现了lycodoline的克级化学合成。第三章:采用两种不同的策略尝试12-epilycodoline的全合成研究,并最终通过羟基消除和烯烃水合的方式,完成了12-epilycodoline的首次合成。同时基于lycodoline的发散式合成,完成了4个lycodoline型石松科生物碱以及4个类天然产物的合成。第四章:针对fawcettimine类石松科生物碱的合成,首先尝试了aza-semipinacol重排反应的仿生合成策略。随后设计了以Pauson?Khand插羰环化为关键反应的汇聚式合成路线,并对关键的Pauson?Khand反应做了初步的化学探讨。
[Abstract]:Pinus contains thousands of different species and is distributed all over the world. Pine, as a medicinal plant, has a long history in the world. The alkaloids isolated from Pinus lanceolata have various structures and remarkable biological activities. Because of these properties of alkaloids, they have attracted the research interest of many synthetic chemists and pharmaceutical chemists. This dissertation focuses on the total synthesis of biogenic alkaloids of lycodoline type and Fawcettimine type of Pinaceae. Based on the bionic synthesis of lycojaponicumin D and lycodoline, a series of fragmentation / Mannich cyclization reaction was designed and developed. The bionic transformation inspired by lycodoline to lycojaponicumin D was realized, and the skeleton structure of 6 / 6 / 6 / 6 and the rearrangement of 5 / 7 / 6 / 6 four-ring system were established. Based on the strategy of symmetry cutting, a novel series oxidative dehydrogenation / hetero-Michael addition reaction involving PD was developed, and the functionalization of Con H at the bridgehead of bicyclic [3.3.1] system was realized, which provided a new opportunity for the development of series reaction based on Saugesa-Ito oxidation. A total of 9 natural alkaloids of Pinaceae were synthesized by using lycodoline as the opportunity of divergent synthesis. Lycojaponicumin D and 6 lycodoline type alkaloids of Pinaceae, lycojaponicumin D and 6 lycodoline type alkaloids of Pinaceae Gobsoserramine, are reported for the first time in the total synthesis of Chuperzine and 12-epilycodolineine, among which lycojaponicumin D and 6 lycodoline type alkaloids of Pinaceae are reported for the first time in the total synthesis report of Chuperzine and 12-epilycodoline.Aobscuranine Aobsratezomine Chuperzine and 12-epilycodoline are reported for the first time. This paper mainly includes the following three parts: chapter 1: the separation, activity, classification and partial synthesis of alkaloids of Pinaceae are introduced systematically. Chapter 2: based on the bionic synthesis inspired by lycojaponicumin D, the series fragmentation / Mannich cyclization reaction is designed and developed, and the full synthesis report of lycaponicumin D is realized. Based on the symmetry cut-off strategy, a novel "series oxidative dehydrogenation / hetero-Michael addition reaction" was designed and developed, which provides a new method for the functionalization of the C ~ (+) H bond at the bridgehead in the tension bridge ring system. Combined with series reduction amination / bridgehead amination reaction, lycodoline was synthesized succinctly and efficiently. Chapter 3: two different strategies were used to study the total synthesis of 12-epilycodoline. Finally, the first synthesis of 12-epilycodoline was completed by hydroxyl elimination and olefins hydration. At the same time, based on the divergent synthesis of lycodoline, four lycodoline alkaloids and four natural products were synthesized. Chapter 4: in view of the synthesis of fawcettimine alkaloids, the bionic synthesis strategy of aza-semipinacol rearrangement reaction was first tried. Then a convergent synthesis route with Pauson?Khand intercalated carbonyl ring as the key reaction was designed and the key Pauson?Khand reaction was preliminarily studied.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O629.3

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