Asymmetric Capture of Carbocations: Novel Access to Benzylic Stereogenicity

描述（由申请人提供）：在有机化学中的所有经典反应性中间体中，碳正离子可以说是研究最全面和理解最透彻的。然而，尽管在理解它们的反应性方面取得了所有进展，但三价碳阳离子（碳正离子）在现代有机合成中，特别是在不对称催化中，系统地利用不足。鉴于它们作为反应性、前手性、叔碳亲电试剂的突出合成潜力，这是特别令人惊讶的。离散碳阳离子的不对称捕获将代表对映选择性亲电反应性的新平台，并且鉴于碳阳离子易于与广泛的亲核试剂反应的既定倾向，该平台具有允许许多不同键类型的不对称构建的潜力。拟议的研究将集中在开发新的硫脲催化的不对称，亲核取代反应的仲和叔苄基卤化物，通过稳定的碳阳离子中间体进行。最近的工作表明，硫脲催化氯代酰胺和氯缩醛中的弱碳卤键的可逆电离，产生含有酰基或氧代碳正离子和手性硫脲的瞬态离子对？氯络合物这种手性阴离子络合物已经证明了能够直接将Tr-亲核试剂高度对映选择性地添加到这些反应性阳离子中间体中，从而导致新的碳-碳键的不对称构建。拟议的研究将旨在扩展这种概念的阴离子抽象/反催化，以适应稳定的苄基碳正离子，并进一步完善这些反应被认为是操作的机制框架。如果成功的话，这一策略将代表一个强大的和潜在的一般进展，催化不对称合成的苄基立体。它强调，这项工作也将需要检查的基本问题，如动态形成的离子对的溶液结构和亲电激活的碳-卤键的能量。阐明该过程的机理方面将为不对称反相催化领域的未来进展铺平道路。从公共卫生的角度来看，这一建议的重要性在于，它创造了一个共同的反应平台，人们可以从中不对称地产生一系列苄基立体中心。大多数现代药物是手性小分子，并且在这一子集中，苄基立构中心的特征突出。因此，设计针对这类重要手性中心的新形式的不对称催化有望使新药剂的开发成为可能并简化其开发。

DESCRIPTION (provided by applicant): Of all the classical reactive intermediates in organic chemistry, carbocations are arguably the most comprehensively studied and well understood. Yet, for all the advances made in understanding their reactivity, trivalent carbocations (carbenium ions) have been systematically underutilized in modern organic synthesis, and in asymmetric catalysis in particular. This is especially surprising in light of their outstanding synthetic potential as reactive, pro-chiral, tertiary carbon electrophiles. The asymmetric capture of a discrete carbocation would represent a novel platform of enantioselective electrophilic reactivity, and one that has the potential to allow for the asymmetric construction of many different bond types given the established propensity of carbocations to react readily with a wide range of nucleophiles. The proposed research will focus on the development of novel thiourea-catalyzed asymmetric, nucleophilic substitution reactions of secondary and tertiary benzylic halides, proceeding through stabilized carbocation intermediates. Recent work has demonstrated that thioureas catalyze the reversible ionization of weak carbon-halide bonds in chloroamides and chloroacetals, creating a transient ion pair containing an acyliminium or oxocarbenium ion and a chiral thiourea?chloride complex counterion. This chiral anionic complex has demonstrated the ability to direct highly enantioselective additions of Tr-nucleophiles to these reactive cationic intermediates, resulting in the asymmetric construction of new carbon-carbon bonds. The proposed research will aim to extend this concept of anion abstraction/counterion catalysis to accommodate stabilized benzylic carbocations and to further refine the mechanistic framework within which these reactions are believed to operate. If successful this strategy will represent a powerful and potentially general advance in the catalytic asymmetric synthesis of benzylic stereogenicity. It is emphasized that this work would also necessitate the examination of fundamental problems, such as the solution structures of dynamically formed ion-pairs and the energetics of electrophilic activation of carbon-halogen bonds. Elucidating the mechanistic aspects of the process will pave the way for future advances in the field of asymmetric counterion catalysis. PUBLIC HEALTH RELEVANCE The significance of this proposal from a perspective of public health is that it creates a common platform of reactivity from which one could asymmetrically generate an array of benzylic stereocenters. The majority of modern medicinal agents are chiral small molecules, and within this subset the benzylic stereocenter is featured prominently. As such, devising new forms of asymmetric catalysis that target this important class of chiral center promises to enable and streamline the development of new pharmaceutical agents.