Chiral Catalysts Designed to Catalyze Organic Reactions

 描述(由申请人提供)：本提案侧重于将非共价催化中的新机理见解应用于发现合成有用的碳-碳键形成反应。我们概述了催化阴离子中间体的周环反应、缩醛的活化和立体控制的取代反应(包括C-糖基化反应)以及从叔醇构建四元立体中心的全新方法。在每个目标中，提出的反应流形都基于从广泛的初步调查中收集到的坚实的机理基础。在我们对周环反应的研究中，我们探索了前手性阴离子中间体反应的立体选择性是否可以利用离子对催化的原理来控制。为了实现这一目标，我们将设计能够结合阴阳离子的多官能团氢键供体催化剂，以激活中间碱金属-烯醇和/或烷氧离子对，并促进它们随后的重排中的对映诱导。这一原理将被应用于开发催化不对称酯烯醇化爱尔兰-克莱森重排和阴离子氧-钴重排的方法。在第二个目标中，我们寻求开发新的方法来产生和随后的立体控制的加成，从稳定的缩醛前体生成的氧卡宾离子结合使用氢键供体催化剂和三氟化三烷基硅基助剂。我们已经发现，手性方酰胺催化剂能激活三氟化硅 生成一种络合物，其中酰胺N-H键参与三氟化硅的结合，方酰胺羰基中的一个与硅阳离子配位；这种电荷分离的中间体显示出相对于三氟化硅酸盐的显着增强的Lewis酸性。我们将把这一观点应用于缩醛的对映选择性C-C键取代反应和催化剂控制的非对映选择性C-糖基化反应。在第三个目标中，我们将阴离子结合催化的原理应用于通过生成和控制捕获叔碳正离子来立体选择性地构建四元中心。基于对阴离子提取的大量定量研究，我们已经确定了能够产生不稳定的叔碳正离子并允许它们被以-C为中心的弱亲核亲核分子选择性捕获的新型氢键供体催化剂。这一反应性原理将在苄基和烯丙基叔阳离子的立体选择性烷基化以及类似于由萜类环酶促进的阳离子环化反应的背景下得到发展。这项工作的直接成果将是由小分子手性催化剂推动的有价值的新的碳-碳键形成反应，这些小分子手性催化剂通过非共价相互作用网络与高活性的离子中间体接触。更广泛地说，这项工作将为未来仿生策略在催化剂设计中的应用提供基础。

 DESCRIPTION (provided by applicant): This proposal is focused on the application of new mechanistic insights in non-covalent catalysis to the discovery of synthetically useful carbon-carbon bond-forming reactions. We outline entirely new approaches to catalysis of pericyclic reactions of anionic intermediates, to activation and stereocontrolled substitution reactions of acetals including C-glycosylation reactions, and to the construction of quaternary stereocenters from tertiary alcohols. In each aim, the proposed reaction manifolds are based on a firm mechanistic foundation gleaned from extensive preliminary investigations. In our studies of pericyclic reactions, we explore whether the stereoselectivity of reactions of prochiral anionic intermediates may be controlled using the principles of ion-pairing catalysis. To accomplish this aim we will design polyfunctional H-bond donor catalysts capable of dual anion- and cation-binding to activate the intermediate alkali metal-enolate and/or alkoxide ion pairs and to facilitae enantioinduction in their subsequent rearrangements. This principle will be applied to the development of catalytic asymmetric methods for the ester-enolate Ireland-Claisen and anionic oxy-Cope rearrangements. In a second aim, we seek to develop new methodologies for the generation of and subsequent stereocontrolled additions to oxocarbenium ions generated from stable acetal precursors utilizing hydrogen-bond donor catalysts in conjunction with trialkylsilyl triflate promoters. We have discovered that chiral squaramide catalysts activate silyl triflates to generate a complex wherein the amide N-H bonds participate in triflate binding and one of the squaramide carbonyls coordinates the silylium cation; this charge- separated intermediate displays remarkably heightened Lewis acidity relative to silyl triflates alone. We will apply this insight to enantioselective C-C bond-forming substitutions of acetals and catalyst-controlled diastereoselective C-glycosylation reactions. In a third aim, we apply the principles of anion-binding catalysis to stereoselective construction of quaternary centers via the generation and controlled trapping of tertiary carbocations. Based on extensive quantitative studies of anion abstraction, we have identified new classes of H-bond donor catalysts capable of generating unstabilized tertiary carbocations and of allowing their selective capture by weakly nucleophilic -C-centered nucleophiles. This reactivity principle will be developed in the context of steroselective alkylations of benzylic and allylic tertiary cations, and to cationic cyclization reactions analogous to those promoted by terpene cyclases. The direct output of the work described in this proposal will be valuable new carbon-carbon bond-forming reactions promoted by small-molecule, chiral catalysts that engage highly reactive ionic intermediates through networks of non-covalent interactions. More broadly, this work will provide a foundation for future applications of biomimetic strategies in catalyst design.