Asymmetric Capture of Carbocations: Novel Access to Benzylic Stereogenicity

碳阳离子的不对称捕获：获得苄基立体异构性的新途径

• 批准号: 7541539
• 负责人: Robert R Knowles
• 金额: $ 4.48万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541539
• 关键词: Address; Anions; Binding; Carbon; Catalysis; Cations; Chloride Ion; Chlorides; Class; Complex; Development; Electrostatics; Elements; Event; Face; Facility Construction Funding Category; Future; Halogens; Ions; Kinetics; Knowledge; Light; Methodology; Object Attachment; Organic Chemistry; Organic Synthesis; Pharmacologic Substance; Process; Public Health; Range; Reaction; Reporting; Research; Resolution; Scheme; Solutions; Structure; Thiourea; Work; base; catalyst; concept; design; ionization; novel; nucleophilic substitution; physical property; small molecule

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.

描述（由申请人提供）：在有机化学中所有经典的反应中间体中，碳正离子可以说是研究最全面和理解最透彻的。然而，尽管在了解它们的反应性方面取得了进展，三价碳正离子（碳离子）在现代有机合成中，特别是在不对称催化中，一直没有得到系统的充分利用。考虑到它们作为反应性、前手性、叔碳亲电试剂的杰出合成潜力，这一点尤其令人惊讶。离散碳正离子的不对称捕获将代表一个对映选择性亲电反应的新平台，并且考虑到碳正离子易于与广泛的亲核试剂反应的既定倾向，它有可能允许许多不同键类型的不对称构建。本研究将集中于发展新型硫脲催化的仲、叔苄基卤化物的不对称亲核取代反应，通过稳定的碳正离子中间体进行。最近的研究表明，硫脲催化氯酰胺和氯缩醛中弱碳卤化物键的可逆电离，产生一个瞬态离子对，其中包含一个酰基或氧羰基离子和一个手性硫脲？氯络合物反离子。这种手性阴离子配合物已经证明了将高度对映选择性的tr -亲核试剂添加到这些活性阳离子中间体上的能力，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，以适应稳定的苯基碳正离子，并进一步完善这些反应被认为是运作的机制框架。如果成功，这一策略将代表催化不对称合成苯基立体性的一个强大的和潜在的普遍进步。强调指出，这项工作还需要研究一些基本问题，如动态形成的离子对的溶液结构和碳-卤素键的亲电活化的能量学。阐明该过程的机制方面将为不对称反离子催化领域的未来发展铺平道路。从公共卫生的角度来看，这一提议的意义在于它创造了一个共同的反应性平台，从中可以不对称地产生一系列苯基立体中心。大多数现代药物都是手性小分子，在这个亚群中，苯基立体中心具有显著的特征。因此，设计针对这类重要的手性中心的新形式的不对称催化有望使新型药物制剂的开发成为可能。