Understanding Coupling Reactions of Heteroaryls

项目摘要 杂联芳基是一类重要的亚结构，存在于大量的生物活性物质中。 活性分子和FDA批准的药物。这些支架通常是通过 传统的交叉耦合策略。不幸的是，这些协议对于 杂芳基片段的掺入。这里提出的工作目标是制定一个 对杂芳烃交叉偶联反应的基本理解。我们还旨在 将我们的发现应用于开发新的高效和可预测的交叉偶联反应 杂芳族偶联伴侣。这项工作最终将允许合成和药用 化学家设计可预测和可靠的合成策略，以生物学方式获得这些化合物。 相关中间体和目标化合物。我们最近发现了场效应的邻位- 取代基作为脱羧和氧化速率的主要预测因子， 苯甲酸的脱羧偶联（ODC）反应。第一阶段的研究将 将这种预测能力扩展到杂芳族羧酸酯的ODC反应， 苯甲酸酯而不具有通常所需的邻位取代基。我们假设新的配体 可以设计支架以减轻这些反应中对邻位取代基的需要， 场效应参数描述了贯穿空间的影响。在我们研究的最后阶段， 我们将把这些新的配体结构应用于其他类型的交叉偶联反应， 历史上受到相关邻位取代基限制。发展大 一系列可预测和可靠的交叉偶联反应，可广泛有效地用于 （杂）芳族偶联配偶体的范围是重要的，因为它提供了获得大的 生物相关核心结构库。因此，发展一个基本的 了解这些和其他偶联反应的趋势和局限性， 杂芳烃将允许现有的和正在开发的合成方法适用于 构建复杂的和药学相关的结构。

Project Summary Heterobiaryls are an important class of substructures found in a large number of biologically active molecules and FDA approved drugs. These scaffolds are typically constructed through traditional cross-coupling strategies. Unfortunately, these protocols are inefficient for the incorporation of heteroaryl fragments. The objective of the work proposed here is to develop a fundamental understanding of the cross-coupling reactions of heteroarenes. We also aim to apply our findings to the development of new efficient and predictable cross-coupling reactions of heteroaromatic coupling partners. This work will ultimately allow synthetic and medicinal chemists to design predictable and reliable synthetic strategies to access these biologically relevant intermediates and target compounds. We recently identified the field effect of ortho- substituents as being a dominant predictor in the rate of decarboxylation and oxidative decarboxylative coupling (ODC) reactions of benzoic acids. The first phase of research will extend this predictive power to the ODC reactions of heteroaromatic carboxylates and benzoates without the typically required ortho-substituents. We hypothesize that new ligand scaffolds can be designed to mitigate the need for ortho-substituents in these reactions because the field effect parameter describes a through-space influence. In the final phase of our study, we will apply these new ligand structures to other classes of cross-coupling reactions that have historically suffered from related ortho-substituent limitations. The development of a large collection of predictable and reliable cross-coupling reactions that operate efficiently for a broad scope of (hetero)aromatic coupling partners is significant because it provides access to a large library of biologically relevant core structures. Thus, the development of a fundamental understanding of the trends and limitations in these and other coupling reactions of heteroarenes would allow existing and developing synthetic methods to be adapted for the construction of complex and pharmaceutically relevant structures.