Catalytic Approaches to C-C Bond Formation Using Alkyl Halides

描述(申请人提供)：化学合成在与健康相关的研究中的效用与有效和选择性地构建C-C键密切相关。过渡金属催化引入了许多C-C键形成的转化，这些转化很难通过替代方法来实现。尽管取得了这些进展，但在催化的分子间C-C键形成反应中，烷基卤化物的一般用途仅限于使用化学计量比的有机金属试剂进行交叉偶联。反应发展的这一差距限制了烷基卤化物在C-C键形成中的使用，C-C键的形成将简化药物合成，并提供获得具有医学价值的功能化小分子的途径。这项研究的长期目标是引入新的催化C-C键形成反应，涉及烷基亲电体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。将进行综合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，即涉及有机金属-自由基反应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已经得到了很好的先例，但这种反应在有机合成中的潜力在很大程度上还没有实现。我们的初步工作证明了这种方法的力量，以获得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，并有助于获得一系列在健康相关研究中有价值的官能化化合物。这项工作涉及三个具体目标：(1)发展分子间的烷基-Heck和羰基化的烷基-Heck交叉偶联；(2)对烷基-Heck过程进行详细的机理研究；(3)发展未活化的烷基卤化物的对映选择性羰化反应。在第一个目标下，我们将开发未活化的烷基卤化物和烯烃的一般、分子间、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转化中涉及的反应途径，为进一步的反应发展提供机理基础。在第三个目标下，我们将开发一种通用的催化不对称合成烷基亲电化合物的方法。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。我们提出的研究是创新的，因为它旨在通过利用钯催化中独特的有机金属-自由基反应性来开发使用简单的烷基卤化物的新的C-C键形成策略。这些贡献意义重大，因为它们将为分子间C-C键的形成提供实用的催化过程，适用于对生物医学科学有价值的广泛类别的小分子。

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.