【作者】 余述燕；

【导师】 姚祝军；

【作者基本信息】 南京大学 ， 有机化学， 2013， 博士

【摘要】 苯并异吡喃氧鎓是一类结构特殊且性质活泼的化学中间体,而其四氟硼酸盐固体却可以在空气环境下稳定存在。无论是由邻炔基苯甲醛在亲电试剂(具有Lewis酸性的过渡金属或者具有亲电性的卤正离子)催化条件下现场形成的苯并异吡喃盐中间体,还是稳定的苯并异吡喃四氟硼酸盐(ICTBs),都具有启动多种类型串联反应的能力,快速地构建一系列具有复杂结构的化合物,在各种研究中具有重要的应用价值。从结构特点及电子因素方面考察,苯并异吡喃盐是一类特殊的缺电子的氧杂双烯体,目前已报道的反应多是关于其与富电子化合物之间的作用,一定程度上限制了它的应用范围。其次,由于苯并异毗喃盐化学性质相当活泼,而原位生成的苯并异吡喃盐中间体的金属中心离反应中心较远,采用经典的金属与手性配体结合的策略,难以获得理想的不对称催化的效果,导致对其对映选择性反应的研究一直以来缺乏有效的控制手段和方法。鉴于本课题组在苯并异吡喃盐化学上的浓厚兴趣以及研究基础,希望通过合理的设计和仔细的探索,为以上两方面问题提供一条可行的解决方案,促进苯并异吡喃盐化学的进一步发展。本论文的主要内容和创新点包括：1.通过苯乙烯型底物中邻位羟基的引入,以C-1位O-糖苷化启动后继的Michacel加成和aldol缩合形成串联反应历程,实现了苯并异吡喃四氟硼酸盐与缺电子烯烃的形式上[4+2]环加成反应。该方法的优点在于不需要任何金属试剂的辅助,可以一步高效地构建含多立体中心(包括季碳中心)的并环或者桥环结构的化合物。在扩大苯并异吡喃盐的应用范围的同时,为合成具有多取代四氢萘或者二氢萘骨架结构的化合物提供了一条简便的合成方法。2.设计合成了两种手性催化剂,并希望借助催化剂与稳定的ICTBs之间的弱相互作用(静电作用和П-П相互作用),实现ICTBs与烯烃之间的不对称[4+2]环加成反应；利用手性Bronsted酸催化邻炔基苯甲醛化合物原位形成苯并异吡喃盐中间体,在配对手性负离子的诱导下,以中等的对映选择性实现了苯并异吡喃盐与烯烃的不对称[4+2]环加成反应；3.设计并发展了过渡金属Pd(OAc)2和手性磷酸Trip的协同催化模式,以令人满意的对映选择性首次实现了基于苯并异吡喃盐中间体的环异构化-[4+2]环加成-亲核取代串联反应的不对称控制。该金属/有机协同催化模式通过配位离子的交换以及底物与催化剂间的氢键作用,将两种独立的底物和两个催化剂整合到一个共同“超分子”不对称环境中,从而引导高度立体选择性地发生“分子内”[4+2]环加成反应。利用该方法可以高效、高立体选择性地构建含多立体中心(包括季碳中心)的桥环化合物,在天然产物鬼臼毒素类似物的合成中具有潜在的应用价值。初步的机理研究表明,Pd(OAc)2中等程度的Lewis酸性、磷酸Trip的双功能化特征以及合适的Bronsted酸性是获得理想的对映选择性的关键。更多还原

【Abstract】 Isochromenyliums are a type of reactive intermediates, while recent research found that their tetrafluorobrates (ICTBs) are air-and moisture-stable. Both the isochromenyliums formed in situ by treatment of o-alkynylbenzaldehydes with certain electronphilic catalysts (lewis acidic transition metal or electronphilic X+) and stable ICTBs have been found to exhibit diverse and flexible reaction behaviors through various cascade transformations, generating unique and complex compound in a simple and efficient manner. Structrually, isochromenylium could be regarded as an electron-deficient oxa-diene equivalent, and the early reaction partners were restricted to electron-rich substrates. On the other hand, the traditional metal/chrial ligand complexes could not afford satisfactory asymmetric transformations owing to isochromenyliums’high reactivity and the lack of enough asymmetric induction resulting from the remote distance between chiral and reaction centers. And so, enantioselective transformations based on the planar isochromenyliums are still a challenge in organic chemistry. Based on our research interests and experience on ischoromenyliums, rational designs were proposed and careful explorations were attempted with aim to resolve the above two problems. The important points of this thesis work were as follows: In the first part, electronically unfavorable formal [4+2]-cyclization reactions between isochromenylium tetrafluoroborates and electrondeficient olefins have been achieved by assistance of a phenolic hydroxyl group in the olefin substrates. The newly developed cascade methodology is initiated by an intermolecular C-1O-glycosylation, and completed with an intramolecular Michael addition and an aldol condensation. The developed cascade methodology is advantageous in ease of operations, metal-free conditions, and high efficiency to generate corresponding2-oxabicyclo[3.3.1]nonane derivatives with multiple stereogenic centers including the quaternary carbons, and thus will be useful in future applications to the synthesis of bioactive natural products and drug-like molecules.The enantioselective addition of olefins to ICTBs was attempted based on the weak intermolecular interaction between catalysts and ICTBs. After a number of experiments, the asymmetric Diels-Alder reaction of olefins and in situ formed isochromenyliums was examined under the catalysis of Bransted acids. Moderate enantioselectivity was achieved and it was believed to stem from the asymmetric induction by chiral counteranion.The first catalytic asymmetric oxa Diels-Alder/nucleophilic substitution cascade reaction based on isochromenylium intermediate has been established with good to excellent enantioselectivities (up to>99.5%ee) in a broad spectrum of substrates. A cooperative binary catalysis with Pd(OAc)2and (5)-Trip successful assembled two separated substrates into an effective supramolecular asymmetric environment to facilitate the "intramolecular" oxa Diels-Alder cycloaddition through exchange of coordinating encounter anion followed by hydrogen bond formation. The mechanism study revealed that the appropriate acidity of Pd(OAc)2, bifunctional catalytic property and appropriate acidity of Trip were necessary for sastifactory stereoselectivity. The developed enantioselective cascade reaction has shown great efficiency in establishing densely multiple stereogenic centers including quaternary carbons and variable bridged ring systems, and thus provides an efficient one-step access to a new class of enantiopure conformation-constrained natural product-like tetrahydronaphthalene derivatives of medicinal interest such as podophyllotoxin analogues.更多还原