1.异噁唑啉并苯并氧杂卓类化合物的合成研究 2.均相Au（Ⅰ）催化在有机合成中的应用研究

【作者】 王冠；

【导师】 王全瑞；

【作者基本信息】 复旦大学 ， 有机化学， 2011， 博士

【摘要】 苯并氧杂卓类化合物是一类非常重要的化合物,以生物碱的形式广泛存在于自然界中。该类化合物具有较好的生理活性,在临床中主要表现为中枢神经系统(CNS)方面的活性。由于现代都市化进程加快,使得人们的压力越来越大,造成越来越多的人们有抑郁的倾向。所以天然的该类化合物无论是从数量还是活性方面都越来越不能满足人们的需求。这就需要有机化学家和药物学家通过有机合成的方法制备新型的该类化合物,期望能够获得具有更好的抗抑郁活性的药物。这项研究主要包括两方面：第一,通过对苯环或氧杂卓环进行修饰,来构建新型的治疗中枢神经系统的药物。第二,通过在苯并氧杂卓双环体系上引入第三个环来构建三环体系。从文献报道看研究主要采用的是第一种方法。我们则利用第二种方法来研究合成新型的CNS药物。在临床中表现出较好的抗抑郁活性的另-类杂环化合物就是异噁唑啉类化合物,所以我们希望将两种活性较好的结构单元融合在一起,构建异噁唑啉并苯并氧杂卓类化合物,期望获得更新颖的三环系化合物。金催化是当今有机化学领域研究的热点课题之一。特别是近十几年来,均相金催化成了构建未知结构和发展新型有机反应机理的有力手段。其中环加成反应和环异构化反应是两类广受关注的反应。正因为此,我们在本论文中研究了均相金催化的联烯基醚与二烯体之间的环加成反应和新型均相金催化Rautenstrauch重排反应,并分别对反应的机理进行了深入探讨。在本论文的第一章,我们对论文所涉及的两个课题进行了文献综述。首先介绍了异噁唑啉并苯并氧杂卓类化合物的研究意义,列举了它们的合成方法。然后,我们从金催化的背景介绍和均相金催化[4+2]环加成反应现状两方面分别介绍了相应领域的研究背景。最后,我们介绍了均相金催化的Rautenstrauch重排反应的发展现状,分析了均相金催化反应在复杂天然产物全合成中的巧妙应用。在本论文的第二章中首先通过苯乙醛制备一系列1-(4-溴-1-丁烯基)-苯(45)。然后又由他们和水杨醛类化合物(46)通过醚化反应制备2-(4-苯基-3-丁烯氧基)-苯甲醛(47),之后再将其肟化得到一系列苯甲醛肟类化合物(48)。最后以苯甲醛肟(48a)为模板底物,通过文献上报道的反应条件,一步制备三环体系,得到目标产物-异噁唑啉并苯并氧杂卓类化合物(49)。该反应是通过1,3-偶极环加成反应实现的,条件温和,收率良好。在本论文的第三章中我们介绍了金催化的联烯基醚与二烯体之间的[4+2]环加成反应。首先,我们制备了一系列的不同取代的联烯基醚(77)。然后我们选取77a和环戊二烯作为模板反应底物对该反应的条件进行筛选。继而我们对该反应的底物进行了拓展,以证明该反应的通用性。接着我们对反应的机理进行了深入的研究。研究表明该反应很可能是通过一个协同的[4+2]环加成反应来进行的。我们成功实现了二烯体78在反应体系中捕获金催化剂和77原位生成的烯丙叉氧鎓离子中间体84发生正常电子需求的Diels-Alder反应,高选择性地合成取代的环已烯醚类化合物79。对于含供电子基取代的环戊二烯78b-d,反应以非常优秀的产率得到以Z构型为主环加成产物79i-n。对于环戊二烯78a,反应以良好的产率得到以Z构型为主环加成产物79a-g。对于含供电子基取代的开链二烯体78e-j,反应可以中等的产率选择性地得到Z构型的环加成反应产物79o-z。该反应在二氯甲烷中进行,催化剂用量小,室温下3分钟即可完成。该方法具有收率高,选择好,条件温和,底物适用性好的优点。在本论文的第四章中,我们研究了均相金催化Rautenstrauch重排反应。我们首先介绍了一系列环丙基炔丙酯32的制备方法。接着,通过条件的筛选对反应底物进行了拓展。然后我们对该反应的机理进行了深入的研究,证明了存在非经典碳正离子的合理性。整体上该金催化的均相Rautenstrauch重排反应具有高效、快速且反应条件温和的特点,可以方便地合成官能团化的环已烯酮类化合物91。我们还合成了具有光学活性的底物环丙基炔丙酯(1S,2S)-120,并将该底物用于研究该重排反应的手性传递作用。通过对反应的条件进行筛选,实现了手性信息在一定程度上的传递,合成了具有光学活性的环已烯酮(S)-121和环辛烯酮122。产物的绝对构型通过测定圆二色谱并与理论拟合进行确定。论文第五章实验部分记录了所有化合物的合成方法和步骤,并用通过IR、NMR、GC-MS和HRMS等方法进行了表征。部分典型的新化合物还附了谱图。更多还原

【Abstract】 The benzoxepine nucleus represents an important motif which occurs as alkaloids in nature, and exhibit a wide spectrum of biological activities. Nowadays many drugs in clinical which are used as therapy of centre neural system diseases contain a benzoxepine skeleton. With the modern quick urbanized course increasing number of citizens suffer from more or less depressed illness. So there is a need to develop new methods for the synthesis of novel analog. In the present, the two methods frequently exploited include the modification of the benzene ring on benzoxepine motif and addition of a third heterocycle ring to the benzoxepine. However, a literature survey suggests that the latter one has relatively less investigated. The reported methods include ring enlargement and intermolecular 1,3-dipolar cycloaddition, while the intramolecular cycloaddition less investigated. On the other hand, the isoxazoline motif also exhibits interesting biological activities. Therefore, the synthesis of unprecedented isoxazoline anellated benzoxepines constitute one of our research topics aimed at developing new tricyclic compounds with potential CNS activities.Nowadays, homogeneous gold catalysis has aroused considerable research efforteds in organic and theoretical communites. A literature survey revealed that the filed of gold catalysis has mainly been restricted on the use as heterogeneous catalysts for a long time. However, the situation has been changed since 1990s. Homogeneous gold catalysis has been recognized as a powerful synthetic tool to access unprecedented structural and mechanistic diversity in the past decade. In particular, Au-catalyzed intramolecular cyclizations and cycloisomerization has been extensively investigated. Thus in the present dissertation, we studied on the cationic gold(I)-catalyzed intermolecular [4+2] cycloaddition between dienes and allenyl ethers as well as gold catalysis homo-Rautenstrauch rearrangement.The first chapter is a brief review. The synthesis and application of benzoxepinoisoxazoles and related heterocycles were summarized. The homogeneous gold catalyzed synthetic transformations with emphasis on gold-catalyzed [4+2] cycloaddition and the gold catalyzed homo-Rautenstrauch rearrangement were reviewed. The gold catalysis strategy that allows quick access to complex natured products was also discussed.In chapter 2, a series of 1-(4-bromobut-1-enyl)benzenes (45) were prepared from 2-phenylacetaldehyde. Williamson ether synthesis of salicyl aldehyde (46) with 45 afforded 2-(4-phenylbut-3-enyloxy)benzaldehydes (47). 2-((E)-4-phenylbut-3-enyloxy)benzaldehyde oxime (48) were prepared from 47 by condensation with hydroxyamine hydrochloride. In the presence of NaOCl,48a underwent intramolecular 1,3-dipolar cycloaddition to furnish the novel tricyclic compound 49a-f. The yields were generally moderate to good and the reaction condition was mild.In Chapter 3, we have succeeded in the gold(I)-catalyzed intermolecular [4+2] cycloaddition between dienes and allenyl ethers. The synthesis begin with the preparation of a series of allenyl ethers (77) from propargyl ethers. We chose the reaction of 77a and cyclopentadiene as a model to screen the optimal condition. Then the substrates were expanded to different types of allenyl ethers and dienes to investigate the scope and limitations of this cycloaddition. As for the mechanism of the cycloaddition, we postulated that they follow a concerted [4+2] cycloaddition. This work realized a Diels-Alder reaction with nomal electron-demand by trapping Au-stabilized allylidene oxonium 84 with diene 78. This methodology represents an unprecedented strategy to access unique cyclohexene derivatives 79. For cyclopentadienes that bear an electron-donatimg group 78b-d, the Z-configured products Z-79i-n were obtained in excellent yield. For the parent cyclopentadiene 78a, the reaction could also proceed smoothly in good yield. However, linear dienes substituted with electron-donating group 78e-j, furnished the Z-79o-z in moderate yields. This unique [4+2] cycloaddition proceeded in general at room temperature and went to completion in several minutes under a low dosage of catalysts.In Chapter 4, a new Au-catalyzed homo-Rautenstrauch rearrangement was developed. The work commenced with the synthesis of a series of cyclopropylpropargylic esters (32). Different cyclopropy alkynyl ester substrates 32 were investigated to study the scope and limitations under variable conditions. Then we focus on the mechanism of the Rautenstrauch rearrangement. The concept of carbocation was applied to account for the observed unusual reactivity of cyclopropylpropargylic esters 32. In general, the gold catalyzed rearrangement was highly efficient, rapid under mild conditions. In addition, enantiomerically enriched cyclohexenones (S)-121 was prepared by the gold-catalyzed cycloisomerization of optically active propargyl acetates (1S,2S-120). Although the rearrangements are cationic in nature, some degree of chirality transfer in these reactions suggests that gold-stabilized nonclassical carbocations with a certain configurational stability are involved. The absolute configurations of the products were determined by measurement and theoretical stimulation of their ECD.Chapter 5 is the experimental section, which record the experimental details of the synthesis. New compounds have been characterized by IR, NMR, GC-MS and HRMS analysis.更多还原