Chiral Catalysts Designed to Catalyze Organic Reactions

 描述（由申请人提供）：该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。我们概述了阴离子中间体的周环反应的催化，缩醛的活化和立体控制的取代反应，包括C-糖基化反应，和从叔醇的季立体中心的建设的全新方法。在每一个目标中，所提出的反应歧管都是基于从广泛的初步调查中收集到的坚实的机械基础。在周环反应的研究中，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用离子对催化原理来控制。为了实现这一目标，我们将设计多官能H-键供体催化剂，能够双阴离子和阳离子结合，以激活中间体碱金属烯醇化物和/或醇盐离子对，并促进其随后的重排对映体诱导。这一原则将适用于酯烯醇化物Ireland-Claisen和阴离子氧Cope重排的催化不对称方法的发展。在第二个目标中，我们寻求开发新的方法，用于生成和随后的立体控制添加到从稳定的缩醛前体产生的氧碳正离子，利用氢键供体催化剂与三烷基甲硅烷基三氟甲磺酸酯促进剂。我们已经发现，手性方酰胺催化剂活化三氟甲磺酸甲硅烷基酯， 生成络合物，其中酰胺N-H键参与三氟甲磺酸酯键合，并且方酰胺羰基之一与甲硅烷基阳离子配位;相对于单独的甲硅烷基三氟甲磺酸酯，这种电荷分离的中间体显示出显著提高的刘易斯酸性。我们将把这一认识应用于缩醛的对映选择性C-C键形成取代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阳离子来立体选择性地构建季中心。基于对阴离子提取的广泛定量研究，我们已经确定了新的H-键供体催化剂类别，其能够产生不稳定的叔碳阳离子，并允许它们被弱亲核性的以N-C为中心的亲核试剂选择性捕获。这种反应性的原则将开发的上下文中的立体选择性烷基化的苄基和烯丙基叔阳离子，和阳离子环化反应类似于那些促进萜烯环化酶。本提案中描述的工作的直接输出将是由小分子手性催化剂促进的有价值的新的碳-碳键形成反应，该催化剂通过非共价相互作用网络与高活性离子中间体接合。更广泛地说，这项工作将为未来的仿生策略在催化剂设计中的应用奠定基础。

 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.