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（由申请人提供）：化学合成在健康相关研究中的应用与 C-C 键的高效和选择性构建密切相关。过渡金属催化引入了许多 C-C 键形成转变，而通过替代方法很难实现这些转变。尽管取得了这些进展，卤代烷在催化分子间 C-C 键形成反应中的一般用途仅限于使用化学计量有机金属试剂的交叉偶联。反应开发中的这一差距限制了卤代烷在 C-C 键形成中的使用，而 C-C 键的形成可以简化药物合成并提供具有药用价值的功能化小分子。这项研究的长期目标是引入新的催化 C-C 键形成反应，涉及烷基亲电子试剂和广泛可用的化学原料的直接偶联。这项研究的总体目标是开发卤代烷和烯烃或CO的新催化反应，包括不对称变体。将进行综合研究和详细的实验机制分析，以确定主要的反应途径和进一步优化的途径。我们的研究基于这样一个中心假设：涉及混合有机金属自由基反应性的金属催化反应为各种独特的 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有先例的，但这种反应性在有机合成中的潜力很大程度上尚未实现。我们的初步工作证明了这种方法在实现适用于具有合成价值的碳环和杂环的新催化转化方面的力量。拟议研究的基本原理是，这些基本的 C-C 键形成反应将为小分子合成提供新方法，并有助于获得对健康相关研究有价值的各种功能化化合物。这项工作涉及三个具体目标：(1) 开发分子间烷基-Heck 和羰基化烷基-Heck 交叉偶联，(2) 对烷基-Heck 过程进行详细的机理研究，(3) 开发未活化烷基卤化物的对映选择性羰基化。在第一个目标下，我们将开发未活化的卤代烷和烯烃的通用分子间催化偶联，提供各种有价值的不饱和产品。第二个目标是研究烷基-Heck转化中涉及的反应途径，为反应的进一步发展提供机理基础。在第三个目标下，我们将通过烷基亲电子试剂的羰基化开发羰基化合物的通用催化不对称合成。我们将把这个流形扩展到 α-手性酯、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金属自由基反应性，使用简单的烷基卤化物开发新的 C-C 键形成策略。这些贡献意义重大，因为它们将为分子间形成 C-C 键提供实用的催化过程，适用于对生物医学有价值的广泛小分子。