Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines

由游离醇和 Boc 保护的胺引导的 Pd 催化 C(sp3)-H 官能化

• 批准号: 10606508
• 负责人: Daniel Aaron Strassfeld
• 金额: $ 6.95万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606508
• 关键词: Acceleration; Acids; Address; Alcohols; Amides; Amines; Binding; Biological; Carbamates; Charge; Chemical Structure; Chemistry; Compensation; Complex; Development; Environment; Equilibrium; Excision; Failure; Family; Future; Goals; Growth; Health; Human; Hydrogen Bonding; Hydroxyl Radical; Knowledge; Ligands; Mentorship; Metals; Methodology; Methods; Modification; Molecular; National Institute of General Medical Sciences; Outcome; Palladium; Pharmaceutical Chemistry; Postdoctoral Fellow; Production; Pyridones; Reaction; Research; Research Design; Research Institute; Role; Site; Structure; Synthesis Chemistry; Transition Elements; Validation; Work; alcohol free; base; carbene; carboxylate; carboxylation; catalyst; chelation; dehydrogenation; deprotonation; design; driving force; functional group; methyl group; novel; novel therapeutics; professor; small molecule; small molecule therapeutics; success; tool

PROJECT SUMMARY/ABSTRACT Subtle structural modifications have the potential to dramatically alter the biological activity of small molecules. Consequently, the development of synthetic methods that allow for selective molecular editing has the potential to greatly accelerate the design and synthesis of novel therapeutics. Transition-metal catalyzed C– H functionalization is a particularly compelling approach, as it circumvents the requirement for prior activation at the site of functionalization. However, C–H activation typically requires a high degree of preorganization of the agostic interaction between the metal and the target bond, usually through coordination of the metal to a directing group. Unfortunately, efforts to use common functional groups and commonly used protecting groups to direct C(sp3)–H activation have met with limited success. Instead, specially designed directing groups are often necessary, limiting the synthetic utility of existing C–H functionalization methodologies. In the proposed research, ligands will be designed to enable the use of common, weakly coordinating L-type donors, such as alcohols and carbamates, as directing groups for C(sp3)–H activation. We hypothesized that two main factors are responsible for the failure of existing ligands to promote these reactions: the intrinsically weak binding of these functional groups to Pd, and the focus on L,X chelates in recent ligand design efforts, which are expected to disfavor agostic complex formation with L-type directing groups due to the lack of charge balance within the complex. Thus, we propose to design novel bis-anionic ligands, structures that are currently underexplored in C–H activation chemistry, containing an internal base that can participate in C–H activation via concerted metalation-deprotonation. In order to compensate for the weak coordination of the desired directing groups to Pd, the proposed ligands will be designed to stabilize substrate-Pd complexes through the secondary coordination sphere by serving as H-bond acceptors or donors matched to the desired directing group. In Aim 1, which is strongly supported by preliminary results, we will develop ligands that can enable alcohol-directed C(sp3)–H functionalizations through two reaction manifolds: C–H dehydrogenation reactions to form allylic alcohols, which are exceedingly versatile synthetic intermediates, and direct C(sp3)–H arylations. Aim 2 will extend this ligand design strategy to develop α-arylations of Boc-amines, with a particular focus on methylene C–H activation in saturated N-Boc azacycles. The successful realization of these aims will provide powerful new synthetic methodologies, directly facilitating the design and synthesis of novel therapeutics. In addition, validation of the underlying hypotheses and ligand design strategy will afford a conceptual advance that will contribute to the continued development of the field of C–H activation. The proposed work will be carried out under the mentorship of Professor Jin-Quan Yu, a preeminent scholar in the field of transition-metal catalyzed C–H functionalization. The intellectual environment in the Yu lab and The Scripps Research Institute is ideally suited to enable the successful execution of these aims.

项目摘要/摘要 微妙的结构修饰有可能显着改变小分子的生物活性， 分子。因此，允许选择性分子编辑的合成方法的开发已经成为可能。 极大地加速新型治疗方法的设计和合成的潜力。过渡金属催化的C- H功能化是一种特别引人注目的方法，因为它避免了在 功能化的场所。然而，C-H活化通常需要高程度的预组织化， 金属和目标键之间的agostic相互作用，通常是通过金属的配位到一个定向的 组不幸的是，使用常见的官能团和常用的保护基团来指导 C（sp3）-H激活的成功率有限。相反，专门设计的指导小组往往是 这是必要的，限制了现有C-H官能化方法的合成效用。 在拟议的研究中，配体将被设计为能够使用常见的弱配位L-型 供体，如醇和氨基甲酸酯，作为C（sp3）-H活化的导向基团。我们假设 两个主要因素是现有配体不能促进这些反应的原因： 这些官能团与Pd的弱结合，以及在最近的配体设计工作中对L，X螯合物的关注， 由于缺乏电荷，预期其不利于与L-型导向基团形成Agostic复合物 复杂的平衡。因此，我们建议设计新的双阴离子配体，其结构目前是 在C-H活化化学中探索不足，含有一个内部碱基，可以通过以下方式参与C-H活化 协同金属化-去质子化。为了弥补所需的指导的弱协调 基团的Pd，所提出的配体将被设计为通过二级反应稳定底物-Pd络合物。 通过充当与所需导向基团匹配的H-键受体或供体，可以将配位球引入。在目标1中， 这是强烈支持的初步结果，我们将开发配体，可以使酒精定向 通过两种反应歧管的C（sp3）-H官能化：C-H脱氢反应以形成烯丙基 醇，这是非常通用的合成中间体，和直接C（sp3）-H芳基化。目标2将 将这种配体设计策略扩展到开发Boc-胺的α-芳基化，特别关注亚甲基 饱和N-Boc氮杂环中的C-H活化。这些目标的成功实现将为我们提供强大的新动力。 合成方法，直接促进新治疗剂的设计和合成。此外，验证 潜在的假设和配体设计策略将提供一个概念上的进步，这将有助于 C-H活化领域的持续发展。 建议的工作将在杰出学者于金泉教授的指导下进行 在过渡金属催化的C-H官能化领域。Yu实验室的智力环境， 斯克里普斯研究所是理想的适合，使这些目标的成功执行。