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：
8766428
负责人：
Daniel John Weix
金额：
$ 4.8万
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/8766428
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 键形成反应彻底改变了学术界和工业界小分子的发现和合成，但过渡金属催化的全部潜力现在经常因需要预先形成的有机金属试剂而受到限制。很少有这样的试剂可以在商业上买到，因为它们的合成并不简单，而且许多试剂的稳定性有限。这些限制对药物发现和生物化学产生了影响，因为许多潜在的重要分子在被认为太耗时而无法制造时就不会被制造出来。该问题的一个潜在解决方案是用亲电子试剂（例如实验室稳定且丰富的有机卤化物）替代亲核有机金属试剂。该计划的长期目标是开发偶联两个或多个亲电子试剂的新催化反应，以及阐明控制这些还原偶联反应中选择性和反应性的因素。在拟议的拨款中，将为两种最重要的 C-C 键形成反应类型开发还原替代方案：交叉偶联和共轭加成。这项工作的指导机制假设是，第一行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个氧化加成来实现两个亲电子试剂的偶联。尽管几乎肯定涉及自由基中间体，但这些过渡金属催化的反应可以通过选择金属和配体来调节。因此，所开发的反应将为更好地研究其他金属的双电子过程提供补充反应性。根据强有力的初步数据，该提案的具体目标是：（1）开发直接还原交叉偶联反应，从简单的有机卤化物或拟卤化物形成Csp3-Csp2键，并更好地理解转化机制； (2) 创建形成Csp3-Csp3键的直接还原偶联方法； (3)将还原偶联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，申请人的实验室都发现了一种有前途的催化剂系统，该系统将成为开发几种通用方法的基础。该方法具有创新性，因为它专注于开发完全避免中间有机金属试剂的新反应。已经确定了克服交叉选择性和反应性挑战的策略，这些挑战以前阻碍了进展。通过研究不同机制的反应，拟议的研究为关键的 C-C 键形成反应以及以前不可能的新键结构的显着改进提供了机会。这项研究意义重大，因为它有望扩大由市售材料快速制造的分子数量。从长远来看，这种易于获取的分子多样性的扩展将使分子生物学和药理学的发现成为可能，从而直接影响人类健康。