Catalytic Approaches to C-C Bond Formation Using Alkyl Halides

使用卤代烷形成 C-C 键的催化方法

• 批准号: 9033923
• 负责人: Erik John Alexanian
• 金额: $ 36.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033923
• 关键词: Alkenes; Amides; Area; Biological Sciences; Biology; Carbon Monoxide; Catalysis; Chemicals; Coupling; Development; Esters; Foundations; Goals; Health; Hybrids; Investigation; Ketones; Link; Metals; Methods; Organic Synthesis; Organometallic Chemistry; Outcome; Palladium; Pathway interactions; Pattern; Pharmacologic Substance; Process; Public Health; Reaction; Reagent; Research; Science; Structure; Transition Elements; Variant; Work; base; carbonyl compound; chemical synthesis; drug synthesis; forging; innovation; next generation; novel strategies; small molecule; small molecule therapeutics; tool

DESCRIPTION (provided by applicant): The utility of chemical synthesis in health-related research is closely tied to the efficient and selective construction of C-C bonds. Transition metal catalysis has introduced many C-C bond-forming transformations that would be challenging to accomplish via alternative means. Despite these advances, the general use of alkyl halides in catalytic, intermolecular C-C bond-forming reactions is limited to cross-coupling using stoichiometric organometallic reagents. This gap in reaction development limits the use of alkyl halides in C-C bond formation that would streamline drug synthesis and provide access to medicinally valuable functionalized small molecules. The long-term goal of this research is to introduce new catalytic C-C bond-forming reactions involving the direct coupling of alkyl electrophiles and widely available chemical feedstocks. The overall objective of this research is to develop new catalytic reactions of alkyl halides and alkenes or CO, including asymmetric variants. Synthetic studies and detailed experimental mechanistic analysis will be pursued to identify prevailing reaction pathways and avenues for further optimization. Our research is based on the central hypothesis that metal-catalyzed reactions involving hybrid organometallic-radical reactivity open the door to a wide variety of unique C-C bond-forming reactions. Transition-metal-promoted radical processes are well precedented, but the potential of this reactivity in organic synthesis is largely unrealized. Our initial work has demonstrated the power of this approach for accessing new catalytic transformations applicable to synthetically valuable carbo- and heterocycles. The rationale of the proposed research is that these fundamental C-C bond-forming reactions will enable new approaches to small molecule synthesis and facilitate access to a diverse array of functionalized compounds valuable in health-related research. This work involves three specific aims: (1) to develop intermolecular alkyl-Heck and carbonylative alkyl-Heck cross-couplings, (2) to perform detailed mechanistic investigations of alkyl-Heck processes, and (3) to develop enantioselective carbonylations of unactivated alkyl halides. Under the first aim, we will develop a general, intermolecular, catalytic coupling of unactivated alkyl halides and alkenes, providing a variety of valuable unsaturated products. In the second aim, we will study the reaction pathways involved in alkyl-Heck transformations to provide a mechanistic foundation for further reaction development. Under the third aim, we will develop a general catalytic asymmetric synthesis of carbonyl compounds via the carbonylation of alkyl electrophiles. We will extend this manifold to the enantioselective synthesis of α-chiral esters, amides, and ketones. Our proposed research is innovative because it aims to develop new C-C bond-forming strategies using simple alkyl halides by harnessing unique organometallic-radical reactivity in palladium catalysis. These contributions are significant because they will offer practical, catalytic processes for the intermolecular formation of C-C bonds applicable to broad classes of small molecules valuable to the biomedical sciences.

描述（由适用提供）：化学合成在与健康相关研究中的实用性与C-C键的有效和选择性结构紧密相关。过渡金属催化引入了许多C-C键形成转换，这些转化将是通过替代手段来实现的挑战。尽管有这些进展，但在催化，分子间C-C键形成反应中的一般使用仅限于使用化学计量有机试剂进行交叉偶联。反应发展的这种差距限制了在C-C键形成中使用酒精卤化物的使用，该卤化物将简化药物合成并提供对药物有价值的功能化小分子的访问。这项研究的长期目标是引入新的催化C-C键形成反应，涉及酒精电池直接偶联和广泛可用的化学原料。这项研究的总体目的是开发烷基卤化物和烷烃或CO的新催化反应，包括不对称变体。将进行合成研究和详细的实验机械分析，以确定盛行的反应途径和途径以进一步优化。我们的研究基于以下中心假设：金属催化反应涉及杂交有机自由基反应性，为各种独特的C-C键形成反应打开了大门。过渡金属促进的自由基过程是良好的，但是这种反应性在有机合成中的潜力在很大程度上是未实现的。我们的最初工作证明了这种方法可以访问适用于合成有价值的碳和异环的新催化转化的力量。拟议研究的基本原理是，这些基本的C-C形成反应将使小分子合成的新方法在与健康相关的研究中促进访问一系列功能化化合物的价值。这项工作涉及三个具体的目的：（1）开发分子间烷基 - 赫克和羰基 - 甲基交叉耦合，（2）以执行烷基 - 赫克过程的详细机械投资，以及（3）开发未激活烷基卤化物的对映体性羰基化。在第一个目的下，我们将开发出未激活的烷基卤化物和烷烃的一般，分子间的催化耦合，从而提供各种有价值的不饱和产品。在第二个目标中，我们将研究与酗酒转化有关的反应途径，为进一步的反应发展提供机械基础。在第三个目标下，我们将通过酒精电池的羰基化开发一种对羰基化合物的一般催化不对称合成。我们将将这一歧管扩展到α-手续酯，酰胺和酮的对映选择性合成。我们提出的研究具有创新性，因为它旨在通过利用钯催化中独特的有机基反应性来利用简单的烷基卤化物制定新的C-C键形成策略。这些贡献之所以重要，是因为它们将为C-C键的分子间形成提供实用的催化过程，适用于适用于生物医学科学有价值的大型小分子。