一些基于联烯的反应和不对称联烯基化反应研究

发布时间：2018-03-14 06:18

  本文选题：联烯　切入点：金催化环化　出处：《浙江大学》2017年博士论文　论文类型：学位论文

【摘要】：联烯是一类含有独特的累积二烯结构的化合物,广泛地存在于天然产物和药物分子中。到目前为止,至少有220种含有联烯结构片段的天然产物被分离和鉴定出来。利用联烯独特的反应活性,可以以优秀的区域和立体选择性去构筑各种各样的分子。同时联烯可以作为关键的中间体应用到复杂分子和天然产物的合成中。因此,联烯所具有的独特的物理、生物和化学性质吸引了越来越多的化学家的广泛关注。基于此,我博士期间的研究工作主要围绕着基于金催化联烯醇环化反应的天然咔唑生物碱的全合成、联烯与有机锌试剂的共轭加成反应和钯催化的不对称联烯基化反应展开。本论文分为以下三部分:第一部分:天然咔唑生物碱的全合成研究。天然咔唑生物碱因为具有潜在的生物活性,一直受到人们广泛的关注。在此,我们完成了天然咔唑生物碱3-甲基-2-轻基咔挫、girinimbine、murrayacine、mukoenine-A 和 heptaphylline 的全合成,反应规模均在克级以上。其中,中间体3-甲基-9-苄基-2-甲氧基咔唑是通过我们组发展的金催化的吲哚取代联烯醇的环化反应制备的;苯硼酸参与的与α,β-不饱和醛的环加成反应是合成girinimbine和murrayacine的关键步骤;销催化的O-烯丙基化/Claisen重排反应是合成mukoenine-A和heptaphylline的最有效的方法。第二部分:2,3-联烯醛与有机锌试剂的共轭加成反应研究。高区域、高立体选择性地合成四取代烯烃一直是有机合成方法学中的一项挑战。已有的一些合成四取代烯烃的方法,诸如酮的烯化反应,烷烃的消除反应,烯烃复分解反应以及烯烃的C-H官能团化反应等均容易得到区域异构体或立体异构体的混合物。在此,我们通过有机锌试剂对2,3-联烯醛的共轭加成反应,发展了一种实用的制备单一构型的四取代烯醛的方法。通过机理研究,我们发现反应首先生成了共轭二烯醇锌中间体,用醋酸淬灭反应后,区域专一的发生氧质子化,得到1,3-共轭二烯醇中间体,再经历六元环状过渡态发生独特的分子内1,5-氢迁移,立体专一地生成四取代烯醛。利用这一方法,可以高效地构筑一系列具有单一构型的四取代烯烃。第三部分:钯催化的不对称联烯基化反应研究。目前关于构筑含有一种手性中心(中心手性或轴手性)化合物的方法已有大量报道,但如何通用、高效的构筑含有多种手性中心(中心手性和轴手性)的化合物仍然是一项挑战,也是现阶段不对称化学研究的重点。钯催化的不对称联烯基化反应已经被广泛地应用于含有轴手性或中心手性的联烯的合成中,但至今为止,利用这一不对称催化反应一步构建同时含有轴手性和中心手性的联烯仍然没有实现。在此,我们利用单一手性配体催化的外消多取代联烯基醋酸酯与一系列亲核试剂的不对称联烯基化反应,实现了联烯分子中轴手性和中心手性的同时控制,发展了一种高效、实用的一步构建同时含有轴手性和中心手性的光学活性联烯的新方法。
[Abstract]:Allene is a kind of compound containing the cumulative diene unique structure, widely exists in natural products and drugs. So far, there are at least 220 kinds of natural products containing allene structure fragments were isolated and identified. The unique reactivity of allenic molecules can use, with excellent regioselectivity and stereoselectivity to build a variety of allenes. At the same time can be used as intermediates for the application of key to the synthesis of complex molecules and natural products. Therefore, allenes has unique physical, biological and chemical properties has attracted more and more attention of chemists. Based on this, my doctoral project mainly focused on the total synthesis of gold catalysis enol cyclization of natural carbazole alkaloids based on conjugated dienes and associated organic zinc reagent addition reaction and palladium catalyzed asymmetric Olefination of the expansion. The following three parts: the first part: Study on the total synthesis of natural carbazole alkaloids. Natural carbazole alkaloid because of potential biological activity, has been paid more attention. Here, we finished the natural carbazole alkaloid 3- methyl -2- light based girinimbine, click file, murrayacine, total synthesis of mukoenine-A and heptaphylline, are in the scale of reaction g or more. Among them, the intermediate 3- methyl -9- benzyl -2- methoxyl carbazole by gold catalyzed the development of our group with indole substituted enol cyclization preparation; arylboronic acid and alpha, beta unsaturated aldehyde cycloaddition reaction is the key step in the synthesis of girinimbine and murrayacine; O- allylation of /Claisen rearrangement reaction catalyzed by pin is the most effective method for the synthesis of mukoenine-A and heptaphylline. The second part: Study on addition reaction of 2,3- conjugated olefine aldehyde and organic zinc reagent. Area, synthesis of four substituted olefins has been a challenge in the organic synthesis method with high stereoselectivity. Some synthesis of four substituted olefins, Olefination reaction such as ketone and alkane elimination reaction of olefin metathesis, olefin C-H functionalization reaction was easy to get a mixture of regioisomers or stereoisomers. Here, we through the organic zinc reagent conjugated to 2,3- allene aldehydes, the development of a practical method for the preparation of single configuration of four substituted aldehyde. Through the mechanism research, we found that the first reaction has become two conjugated enol intermediates with acetic acid zinc, quenching reaction after the regional oxygen protonation specificity, 1,3- conjugated two enol intermediates, then six membered cyclic transition state has unique intramolecular 1,5- hydrogen migration, generating four substituted aldehydes to stereospecific. Using this party Method can effectively construct a series with a single configuration of four substituted olefins. The third part: palladium catalyzed asymmetric Olefination research. Currently on building containing a chiral center (the center of chiral and axial chiral compounds have been reported) a lot of method, but how to build a universal, efficient (containing multiple chiral centers the center of chiral and axial chiral compounds) is still a challenge, but also the study of asymmetric chemical synthesis. At this stage the focus of allenic palladium catalyzed asymmetric Olefination reaction has been widely used in chiral or with axial center hand of the, but so far, the asymmetric catalytic reaction step at the same time construct containing axial chiral chiral allenes and the center is still not implemented. Here, we use a single chiral ligand catalyzed the elimination of polysubstituted allenyl acetate and a series of nucleophiles not The symmetric dienylation reaction controlled the axial and central chirality of the ene molecules simultaneously. An efficient and practical new method for constructing optical active ene containing both axial and central chirality has been developed.

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.251
，

本文编号：1610002