Intermolecular Asymmetric Stetter Reaction Catalyzed by Nucleophilic Carbenes

描述(由申请人提供)：新反应的发现促进了新药物实体和有希望的新疗法的发展。这一建议将寻求应用新型手性有机盐来催化碳-碳键的对映选择性形成。立体化学致密的功能与一个靶点的生物特异性的提高有关。该研究计划包括研究Stetter反应的机理，以推进目前诱导不对称分子间Stetter反应的方法学。Stetter反应在Michael受体和乙醛衍生的酰基阴离子当量之间创建了一个新的碳-碳键。对该反应的详细机理研究将有助于深入了解催化循环中的中间体和转化。这些信息随后将为分子间协议的设计提供基础。分子间反应性的方法包括改变我们现有的三氮唑盐上的取代基，通过空间体积效应和电子效应来激发对映体选择性。我们还建议通过使用各种新的底物来影响反应过程，例如亚胺作为亲核前体，联烯作为亲电受体。还提出了Michael受体的Lewis酸活化方法。这些目标的成功实现将允许一种新的反应流形和一种新的策略来解决与药物靶标合成方法相关的分子复杂性问题。

DESCRIPTION (provided by applicant): The discovery of new reactions facilitates the development of new drug entities and promising new therapeutics. This proposal will seek to apply novel chiral organic salts to catalyze the enantioselective formation of carbon-carbon bonds. Stereochemically dense functionality is associated with improved biological specificity for one target. The research plan involves investigating the Stetter mechanism in order to advance current methodology to induce the asymmetric intermolecular Stetter reaction. The Stetter reaction creates a new carbon-carbon bond between a Michael acceptor and an acyl anion equivalent derived from an aldehyde. A detailed mechanistic study of this reaction will provide insight into the intermediates and transformations within the catalytic cycle. This information will subsequently present the basis for the design of an intermolecular protocol. Approaches to intermolecular reactivity include the changing of substituents on our current triazolium salts to invoke enantioselectivity through both steric bulk and electronic effects. We also propose to affect the course of the reaction by using a variety of new substrates, such as imines as nucleophilic precursors and allenes as electrophilic acceptors. Lewis acid activation of the Michael acceptor is also proposed. Successful realization of these goals will allow a new reaction manifold and a novel strategy to solving problems of molecular complexity relevant to synthetic approaches to pharmaceutical targets.