Asymmetric Capture of Carbocations: Novel Access to Benzylic Stereogenicity

描述(由申请人提供)：在有机化学中所有经典的活性中间体中，碳正离子可以说是研究最广泛和理解最好的。然而，尽管在理解它们的反应性方面取得了所有的进展，但在现代有机合成中，特别是在不对称催化中，三价碳正离子(卡宾离子)一直没有得到系统的利用。鉴于它们作为反应性、亲手性、叔碳亲电试剂的杰出合成潜力，这一点尤其令人惊讶。对离散碳正离子的不对称捕获将代表一种新的对映选择性亲电反应平台，并且考虑到碳正离子容易与各种亲核试剂反应的既定倾向，该平台有可能允许许多不同类型的键的不对称结构。拟议的研究将集中于开发新型的硫脲催化的不对称亲核取代反应，通过稳定的碳正离子中间体进行仲苯基卤化物和叔基苯卤化物的亲核取代反应。最近的研究表明，硫脲催化氯酰胺和氯缩醛中弱碳-卤键的可逆电离，生成一个瞬时离子对，其中包含一个酰亚胺或氧卡宾离子和一个手性硫脲氯络离子。这种手性阴离子络合物能够将Tr-亲核试剂定向到这些反应性阳离子中间体上，从而导致新的碳-碳键的不对称结构。拟议的研究将旨在扩展阴离子提取/反离子催化的概念，以适应稳定的苄基碳正离子，并进一步完善这些反应所在的机理框架。如果成功，这一策略将代表着在催化不对称合成苄基立体活性方面取得的强有力的和潜在的普遍进展。强调指出，这项工作还需要研究基本问题，如动态形成的离子对的溶液结构和碳-卤键亲电活化的能量学。阐明该过程的机理将为未来不对称反离子催化领域的进展铺平道路。公共卫生相关性从公共卫生的角度来看，这项提议的意义在于它创建了一个共同的反应性平台，人们可以从该平台不对称地产生一系列苄基立体中心。大多数现代药物都是手性小分子，在这一子集中，苄基立体中心是突出的特征。因此，针对这类重要的手性中心设计新的不对称催化形式有望使新药物的开发变得顺畅。

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.