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方法

基本信息

批准号：
7738892
负责人：
Robert R Knowles
金额：
$ 4.76万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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性中间体中，碳含量可以说是最全面的研究和良好的理解。然而，尽管在理解其反应性方面所取得的所有进展，但在现代有机合成中，尤其是在不对称的催化中，三价碳化离子（碳离子）已被系统地利用。鉴于它们的出色合成潜力是反应性，亲手性的第三级电力，这尤其令人惊讶。离散碳酸盐的不对称捕获将代表一个新型的对映选择性亲电反应性的平台，并且有可能使许多不同键类型的不对称结构具有不对称的结构，因为碳化碳的倾向可以轻松地与广泛的核生物反应。拟议的研究将重点介绍新型硫库催化的不对称，亲核取代反应的二次和三级苯基卤化物，并通过稳定的碳酸盐中间体进行。最近的工作表明，thioureas催化了氯酰胺和氯环中弱碳键键的可逆电离，从而产生了一个瞬时离子对，该离子对含有酰基铵或氧化物离子和手性硫脲？这种手性阴离子复合物已证明能够将TR-核粉高度对映选择性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结构。拟议的研究将旨在扩展该阴离子抽象/反子催化的概念，以适应稳定的苯并碳化碳的化合物，并进一步完善据信这些反应可起作用的机械框架。如果成功，此策略将代表苯并立体源性的催化不对称合成中的强大且潜在的一般进步。人们强调的是，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以及碳释放键的亲电激活的能量。阐明该过程的机械方面将为未来不对称抗衡催化领域的未来进步铺平道路。公共卫生相关性从公共卫生的角度来看，该提案的意义在于，它创建了一个共同的反应平台，从中可以从中不对称产生一系列苯并立体中心。大多数现代药物是手性的小分子，在此子集中，苯并立体中心是突出的。因此，设计针对这一重要类手性中心的新形式的不对称催化形式有望使新药剂的开发能够简化和简化新的药物的发展。