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）：在有机化学中的所有经典反应中间体中，碳阳离子可以说是研究最全面、理解最透彻的。然而，尽管在理解其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，一直没有得到充分利用。鉴于它们作为反应性、前手性、叔碳亲电子试剂的突出合成潜力，这一点尤其令人惊讶。离散碳阳离子的不对称捕获将代表一种对映选择性亲电子反应性的新平台，并且考虑到碳阳离子容易与各种亲核试剂发生反应的既定倾向，该平台有可能允许许多不同键类型的不对称结构。拟议的研究将重点开发新型硫脲催化的仲和叔苄基卤化物的不对称亲核取代反应，通过稳定的碳阳离子中间体进行。最近的工作表明，硫脲催化氯酰胺和氯缩醛中弱碳卤化物键的可逆电离，产生含有酰亚胺或氧碳鎓离子和手性硫脲氯化物络合物抗衡离子的瞬态离子对。这种手性阴离子配合物已证明能够将 Tr 亲核试剂高度对映选择性加成到这些反应性阳离子中间体上，从而形成新的碳-碳键的不对称结构。拟议的研究旨在扩展阴离子提取/抗衡离子催化的概念，以适应稳定的苄基碳正离子，并进一步完善这些反应被认为运行的机制框架。如果成功，该策略将代表苯甲基立体异构性催化不对称合成方面的强大且潜在的普遍进展。需要强调的是，这项工作还需要检查基本问题，例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。阐明该过程的机理将为不对称反离子催化领域的未来进展铺平道路。公共卫生相关性 从公共卫生的角度来看，该提案的重要性在于它创建了一个通用的反应平台，人们可以从中不对称地生成一系列苄基立体中心。大多数现代药物都是手性小分子，在这个子集中，苯甲基立构中心具有显着的特征。因此，设计针对这一类重要的手性中心的新型不对称催化有望促进并简化新药剂的开发。