金属和手性仲胺共催化的不对称三组分反应研究

发布时间：2018-04-04 12:58

本文选题：多组分反应　切入点：重氮化合物　出处：《华东师范大学》2017年博士论文

【摘要】：多组分反应是高效构建复杂分子的有效方法,但是实现多组分反应的不对称催化具有很大挑战。因为相比于两组分反应,多组分反应的新增组分增加了过渡态的可能构象,对立体选择性控制要求更高。我们课题组一直以来致力于亲电试剂捕捉活泼叶立德或两性离子对中间体的多组分反应,并已经成功开发了过渡金属/手性Lewis酸共催化体系和过渡金属/手性Br(?)nsted酸共催化体系,取得很好的立体选择性控制。但是对于过渡金属/手性碱共催化体系,由于碱易与金属配位使其失去分解重氮的能力而一直没有成功实现。本论文成功开发出过渡金属/手性仲胺共催化体系用于不对称Michael型三组分反应,二芳基脯胺醇硅醚类手性仲胺共催化剂的使用克服了过渡金属与胺类催化剂的相互淬灭作用。反应中,过渡金属缓慢分解重氮形成金属卡宾,进而与醇、吲哚或芳胺反应生成叶立德或两性离子对中间体,接下来被手性仲胺活化的α,β-不饱和醛捕捉,延迟的质子转移后得到手性三组分产物,反应的对映选择性很高。这个催化体系的成功开发,为我们课题组的不对称三组分反应提供新的思路。论文第一章介绍多组分反应,从多组分反应发展史、不对称多组分反应角度简单介绍多组分反应的优势以及不对称多组分反应的实现策略。同时也介绍了金属卡宾、重氮化合物、叶立德和两性离子对中间体在有机反应中的应用。最后介绍基于捕捉活泼叶立德或两性离子对中间体的三组分反应,详细阐述不对称aldol型多组分反应、不对称Mannich型多组分反应以及不对称Michael型多组分反应的实现策略(过渡金属/手性Lewis酸共催化策略和过渡金属/手性Br(?)nsted酸共催化策略)并指出存在的挑战和亟待解决的问题,为本论文的研究方向提供研究背景。在论文第二章中,我们设计并实现了过渡金属/手性碱共催化体系用于α,β-不饱和醛、重氮化合物和醇的不对称Michael型三组分反应,解决了过渡金属与胺类共催化剂的兼容性问题。为了使亚胺阳离子生成速率和羟基叶立德中间体生成速率相匹配,将传统的醋酸铑换成过渡金属铱复合物,再与手性仲胺组成共催化体系,成功实现了 α,β-不饱和醛对羟基叶立德的不对称捕捉反应,得到邻位具有两个手性中心的1,2,5-三醇衍生物,反应取得了令人满意的收率和对映选择性,但是非对映选择性有待进一步提高。在论文第三章中,为了解决该反应的非对映选择性问题,我们将底物醇换成吲哚,设想通过增加底物的立体位阻实现非对映选择性控制。通过一系列条件优化,反应的dr值被提高到78:22,部分解决了非对映选择性问题,对映选择性和收率良好,得到一系列具有良好生物活性的手性吲哚衍生物。在论文第四章中,从产物结构多样性和有用性的角度考虑,同时也期望进一步提高反应的非对映选择性,我们将该共催化体系用于α,β-不饱和醛对铵基叶立德的捕捉反应,成功构建了含三个手性中心的吡咯烷骨架。吡咯烷骨架在天然生物碱、生物活性化合物和药物中是一类重要的核心骨架,也是有机合成中构建杂环化合物的重要结构砌块。机理研究证明三组分产物是热力学控制的。该反应通过可逆的氮杂aldol反应将热力学不稳定的非对映异构体全部转化成热力学稳定的非对映异构体,获得了极高的非对映选择性。至此,我们彻底解决了反应的非对映选择性问题。在论文第五章中,对全文进行总结。论文第六章是实验部分,体现全文实验的一般信息,底物和催化剂的制备方法以及各章节具体实验操作和化合物表征数据。
[Abstract]:Multicomponent reaction is an effective method for efficient construction of complex molecules, but the realization of multicomponent reaction asymmetric catalysis is a big challenge. As compared to the two component reaction, multi component reaction of the new group increased the conformation transition state, higher control requirements on the stereochemistry of our group has been committed. To capture the active electrophiles ylides or zwitterionic intermediates of multicomponent reactions, and has successfully developed a transition metal / chiral Lewis acid co catalyst system and transition metal / chiral Br (?) nsted Acid Co catalyst system, achieved very good enantioselectivity. But for transition metal / chiral alkali the catalytic system, due to alkali metal coordination and easily lose its ability to break down heavy nitrogen and has not been successful. The successful development of transition metal / chiral secondary amine Co catalyst system for asymmetric Michael Type three component reaction, using two aryl prolinol silyl ether chiral secondary amine Co catalyst to overcome the mutual quenching of transition metal and amine catalyst. Quenching reactions, transition metal slow decomposition of diazo forming metal CABBEEN, and alcohol, indole or aromatic amine reaction or zwitterionic Ye de for intermediates, chiral secondary amine is then activated alpha, beta unsaturated aldehyde capture, delay the proton transfer after three chiral component products, the enantioselectivity of the reaction is very high. The successful development of this catalytic system for the asymmetric, our group of three component reaction provides a new idea in the first chapter of this paper. The multicomponent reactions, divided the history of the development of response from the multi group, asymmetric multicomponent reaction point introduces multicomponent reactions and the advantages of asymmetric multicomponent reactions. The implementation strategy also introduced the CABBEEN diazo compounds, metal, Ye Lide And the application of zwitterionic intermediates in organic reactions. Finally capture the lively ylides or zwitterionic intermediate three component reaction based on the detailed introduction, asymmetric aldol type multicomponent reactions, asymmetric Mannich type multicomponent reaction and asymmetric Michael type multicomponent reaction strategy (transition metal / catalytic CO chiral Lewis acid method and transition metal / chiral Br (?) nsted Acid co catalyzed) strategy and points out some challenges and problems, provide the research background for the research direction of this thesis. In the second chapter, we design and transition metal / chiral alkali catalyst system for the realization of alpha, beta unsaturated aldehydes, asymmetric Michael type diazo compound and alcohol three component reaction, solves the compatibility problem of transition metal and amine Co catalyst. In order to make the iminium cation formation rate and hydroxyl ylide Between generation rate matching, will replace the traditional rhodium acetate of transition metal iridium complexes, and the chiral secondary amine consists of catalytic system, the successful implementation of the alpha, beta unsaturated hydroxyl of asymmetric ylides aldehyde capture reaction, two chiral centers 1,2,5- three alcohol derivatives with ortho reaction, obtained satisfactory yield and enantioselectivity, but the diastereoselectivity needs to be further improved. In the third chapter, in order to solve the diastereoselectivity of the reaction, we will change into alcohol indole, envisaged by the steric hindrance of substrate increasing realization of diastereoselective control through a series of optimization. And the Dr value of the reaction was increased to 78:22, partly solves the diastereoselectivity problem, good enantioselectivity and yield, get a series of good biological activity of chiral indole derivatives in the fourth chapter, Considering the structure of the product diversity and usefulness perspective, we also expect to further improve the response of diastereoselectivity, we will be the CO catalytic system for alpha, beta unsaturated aldehyde capture reaction of ammonium ylide, was successfully constructed with three chiral centers of pyrrolidine pyrrolidine skeleton. In the natural alkaloid, biologically active compounds and drugs is an important kind of framework structure is an important block in organic synthesis of heterocyclic compounds. The construction mechanism showed that three component products. The reaction is thermodynamically controlled by reversible aza aldol reaction thermodynamic unstable diastereomers into the thermodynamic stability of the diastereomers, gained high diastereoselectivity. Thus, we completely solve the reaction diastereoselectivity problem. In the fifth chapter, summarizes the theory. The sixth chapter is the experimental part, which embodies the general information of the full-text experiment, the preparation methods of substrate and catalyst, and the specific operation and compound characterization data of each chapter.

【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.251

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