Organocatalytic C-H Bond Activation

有机催化C-H键活化

• 批准号: 8712665
• 负责人: Justin Thomas Malinowski
• 金额: $ 4.99万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712665
• 关键词: Address; Area; Biological Assay; Biological Factors; Carbon; Catalysis; Chemicals; Complex; Coupling; Cysteine; Drug Targeting; Electrons; Future; Goals; Hydrogen; Hydrogen Bonding; Investigation; Lead; Methane; Methods; Mind; Natural Product Drug; Nature; Organic Synthesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Protocols documentation; Reaction; Reagent; Research; Source; Sulfhydryl Compounds; System; Technology; Temperature; Testing; Transition Elements; analog; base; catalyst; design; improved; method development; novel; operation; planetary Atmosphere; programs; public health relevance; scaffold; screening; toxic metal

DESCRIPTION (provided by applicant): The objective of this research program is to address a longstanding carbon-carbon bond formation problem using a novel, synergistic catalysis mode. C-H activation is a leading area of modern chemical research with extraordinary promise. Successful functionalization of unreactive carbons in a selective manner could fundamentally impact retrosynthetic analysis of natural product and drug targets, enabling drastically simplified syntheses. Herein we present a novel construction of a ubiquitous moiety in Nature - the aliphatic-aryl C-C bond. Our approach harnesses a radical coupling strategy recently discovered by the merger of two distinct catalysis modes which act in concert to achieve selective C-H bond arylation. Previously, this bond formation could only be accomplished with transition-metal catalysis with the requirement of two stoichiometric prefunctionalized reagents and careful reaction conditions. In our analysis, this venerable strategy could be improved significantly with the elimination of both toxic metal byproducts and activated substrates. Additionally, an improved protocol under ambient conditions would largely benefit the practitioner. Central to this new mode of activation is an organocatalyzed hydrogen atom abstraction triggered by photoredox catalysis, which results in the catalytic activation of each reaction partner. Upon their formation, the two components engage in radical-radical coupling to provide the desired product from simple, commercial materials under mild reaction conditions. We will begin with the benzylic substrate class and electron-deficient arenes. The diaryl methane products obtained are prevalent in drug molecule scaffolds and natural products. This technology would enable facile syntheses as well as open access to analogues in an effort to improve bioactivity and/or selectivity of medicinal agents. After optimization of the initial protocol, we propose expansion of this reaction manifold to the allylic substrate class - a prevalent organic building block. We also disclose a desymmetrization strategy for asymmetric induction using symmetrical or meso substrates, further increasing reaction utility. With the goal of ease of operation in mind, these reactions will be performed under ambient atmosphere and temperature. The two catalyst classes (photoredox and thiol organocatalyst) are commercially available and will be used out of the bottle. Additionally, reaction substrates and coupling partners require no synthesis or preactivation, are widely available, and will be used as received.

描述（由申请人提供）：该研究计划的目标是使用新型协同催化模式解决长期存在的碳-碳键形成问题。 C-H活化是现代化学研究的一个领先领域，具有非凡的前景。以选择性方式成功功能化非反应性碳可能会从根本上影响天然产物和药物靶标的逆合成分析，从而大大简化 综合。 在此，我们提出了自然界中普遍存在的部分的新结构——脂肪族芳基C-C键。我们的方法利用了最近发现的一种激进的偶联策略，该策略通过合并两种不同的催化模式来协同作用以实现选择性的 C-H 键芳基化。以前，这种键的形成只能通过过渡金属催化来完成，需要两种化学计量的预官能化试剂和谨慎的反应条件。在我们的分析中，通过消除有毒金属副产物和活化底物，可以显着改进这一古老的策略。此外，在环境条件下改进的方案将大大有利于从业者。 这种新激活模式的核心是光氧化还原催化触发的有机催化氢原子提取，从而导致每个反应伙伴的催化激活。形成后，两种组分进行自由基-自由基偶联，在温和的反应条件下由简单的商业材料提供所需的产物。我们将从苄基底物类和缺电子芳烃开始。所得二芳基甲烷产物普遍存在于药物分子支架和天然产物中。该技术将使合成变得容易，并开放类似物的获取，以努力提高药物的生物活性和/或选择性。在优化初始方案后，我们建议将该反应歧管扩展到烯丙基底物类 - 一种普遍的有机构建块。我们还公开了使用对称或内消旋底物进行不对称诱导的去对称化策略，进一步提高了反应效用。 考虑到易于操作的目标，这些反应将在环境气氛和温度下进行。两种催化剂（光氧化还原催化剂和硫醇有机催化剂）均已市售，并且将直接开瓶使用。此外，反应底物和偶联配偶体不需要合成或预激活，可广泛使用，并且将按收到时使用。