Reductive Coupling Reactions: Trading Organometallic Reagents for Organic Halides

还原偶联反应：用有机金属试剂换取有机卤化物

基本信息

批准号：
8281424
负责人：
Daniel John Weix
金额：
$ 29.02万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281424
关键词：
Academia Address Air Alcohols Alkanesulfonates Alkenes Alkynes Biochemistry Carbon Monoxide Catalysis Chemistry Chloride Ion Chlorides Collection Coupled Coupling Cross Reactions Cyclization Data Development Dimerization Electron Transport Electrons Esters Event Exclusion Goals Grant Health Health Sciences Human Hydrocarbons Industry Investigation Ketones Laboratories Ligands Light Lighting Mediating Metals Methods Mission Molecular Molecular Biology Molecular Probes Nickel Nitrogen Organic Synthesis Outcome Pharmaceutical Preparations Pharmacology Procedures Process Public Health Reaction Reagent Reducing Agents Reliance Research Solutions System Techniques Time Transition Elements Translating United States National Institutes of Health Work aryl halide base catalyst cost design drug discovery empowered experience functional group improved innovation interest prevent programs small molecule

项目摘要

DESCRIPTION (provided by applicant): Catalytic C-C bond forming reactions have revolutionized the discovery and synthesis of small molecules in academia and industry, but the full potential of transition-metal catalysis is now frequently limited by the need for pre-formed organometallic reagents. Few such reagents are commercially available because their synthesis is not trivial and many of the reagents have limited stability. These limitations have consequences for drug discovery and biochemistry because many potentially important molecules are not made when they are deemed too time consuming to access. One potential solution to this problem is the replacement of nucleophilic organometallic reagents with electrophiles, such as organic halides, which are bench stable and plentiful. This program's long-term goals are the development of new catalytic reactions that couple two or more electrophiles as well as the illumination of the factors which control selectivity and reactivity in these reductive coupling reactions. In the proposed grant, reductive alternatives will be developed for two of the most important types of C-C bond forming reactions: cross-coupling and conjugate addition. The guiding mechanistic hypothesis for this work is that the single-electron chemistry of first-row transition metals will enable the coupling of two electrophiles by allowing multiple oxidative additions to occur at a single metal center. Although radical intermediates are almost certainly involved, these transition-metal catalyzed reactions can be tuned through choice of metal and ligand. Thus, the reactions developed will provide a complementary reactivity to the better studied two-electron processes of other metals. Following up on strong preliminary data, the specific aims of the proposal are to: (1) develop direct reductive cross-coupling reactions that form Csp3- Csp2 bonds from simple organic halides or pseudohalides and better understand the mechanism of the transformation; (2) create direct reductive coupling methods that form Csp3-Csp3 bonds; and, (3) extend the concept of reductive coupling to include the coupling of organic halides with carbon monoxide, alkenes, and alkynes. Under each aim a promising catalyst system has been discovered in the applicant's laboratory that will become the basis for the development of several general methods. The approach is innovative because it focuses on the development of new reactions that completely avoid intermediate organometallic reagents. Strategies to overcome the challenges of cross-selectivity and reactivity have been identified that have previously prevented progress. By investigating reactions with different mechanisms, the proposed research presents the opportunity for dramatic improvements in critical C-C bond-forming reactions as well as new bond constructions that were not previously possible. The proposed research is significant because it is expected to expand the number of molecules that can be rapidly made from commercially available materials. In the long run, this expansion of readily accessible molecular diversity will enable discoveries in molecular biology and pharmacology that will directly impact human health.

描述（由申请人提供）：催化C-C键形成反应已彻底改变了学术界和工业中小分子的发现和合成，但是现在过渡金属催化的全部潜力通常受到需要预先形成的器官测量试剂的需求的限制。由于其合成不是微不足道的，而且许多试剂的稳定性有限，因此很少有此类试剂可获得市售。这些局限性对药物发现和生物化学产生了后果，因为当它们被认为太耗时而无法获得时，就不会产生许多潜在的重要分子。解决此问题的一种潜在解决方案是用电力剂（例如有机卤化物）替代了亲核有机金属试剂，这些试剂稳定而丰富。该计划的长期目标是开发新的催化反应，这些反应将两个或多个或多个电力液以及控制这些还原性偶联反应中选择性和反应性的因素照明。在拟议的赠款中，将为C-C键形成反应的两种最重要类型开发还原替代方法：交叉耦合和偶联物。这项工作的指南机械假设是，首先过渡金属的单电子化学将通过允许在单个金属中心发生多种氧化添加来实现两个电力的偶联。尽管几乎可以肯定地涉及自由基中间体，但可以通过选择金属和配体来调整这些过渡金属催化的反应。因此，发展的反应将为其他金属的两电子过程提供互补的反应性。遵循强大的初步数据，该提案的具体目的是：（1）形成直接还原性交叉偶联反应，这些反应形成来自简单有机卤化物或伪黑甲化的CSP3-CSP2键，并更好地理解转化的机制；（2）创建形成CSP3-CSP3键的直接还原耦合方法；（3）将还原耦合的概念扩展到包括有机卤化物与一氧化碳，烯烃和炔烃的偶联。在每个目标下，在申请人的实验室中发现了一个有希望的催化剂系统，该系统将成为开发几种通用方法的基础。这种方法具有创新性，因为它着重于完全避免中间有机金属试剂的新反应的发展。已经确定了克服交叉选择性和反应性挑战的策略，这些策略以前阻止了进步。通过研究不同机制的反应，拟议的研究为关键C-C键形成反应以及以前无法实现的新键结构的急剧改善提供了机会。拟议的研究很重要，因为预计它将扩大可以通过市售材料迅速制成的分子数量。从长远来看，易于获得的分子多样性的扩展将使分子生物学和药理学的发现直接影响人类健康。