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实用性与C-C键的高效和选择性构建密切相关。过渡金属催化已经引入了许多C-C键形成转化，这些转化通过替代手段来实现将是具有挑战性的。尽管有这些进展，烷基卤化物在催化的、分子间C-C键形成反应中的一般用途限于使用化学计量的有机金属试剂的交叉偶联。反应发展中的这一差距限制了烷基卤化物在C-C键形成中的使用，这将简化药物合成并提供获得有药用价值的官能化小分子的途径。本研究的长期目标是引入新的催化C-C键形成反应，涉及烷基亲电试剂和广泛可用的化学原料的直接偶联。本研究的总体目标是开发新的烷基卤化物和烯烃或CO的催化反应，包括不对称变体。将进行合成研究和详细的实验机理分析，以确定主要的反应途径和进一步优化的途径。我们的研究是基于一个中心假设，即金属催化的反应，涉及混合有机金属自由基的反应性打开了大门，以各种各样的独特的C-C键形成反应。过渡金属促进的自由基过程是很好的先例，但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。我们的初步工作已经证明了这种方法的力量，用于访问新的催化转化适用于合成有价值的碳环和杂环。拟议研究的基本原理是，这些基本的C-C键形成反应将使小分子合成的新方法成为可能，并有助于获得在健康相关研究中有价值的各种功能化化合物。这项工作包括三个具体目标：（1）发展分子间烷基-Heck和羰基化烷基-Heck交叉偶联，（2）进行详细的烷基-Heck过程的机理研究，和（3）发展未活化的烷基卤化物的对映选择性羰基化。在第一个目标下，我们将开发一个通用的，分子间的，未活化的烷基卤化物和烯烃的催化偶联，提供各种有价值的不饱和产物。在第二个目标中，我们将研究烷基Heck转化的反应途径，为进一步的反应发展提供机理基础。第三个目标是通过烷基亲电试剂的羰基化反应，发展一种通用的催化不对称合成羰基化合物的方法。我们将把这一方法推广到α-手性酯、酰胺和酮的对映选择性合成。我们提出的研究是创新的，因为它的目的是开发新的C-C键形成策略，利用简单的烷基卤化物在钯催化独特的有机金属自由基反应。这些贡献是重要的，因为它们将提供实用的，催化过程的分子间形成的C-C键适用于广泛类别的小分子生物医学科学的价值。