Asymmetric Construction of Benzylic Stereocenters via Reductive Copper Catalysis

还原铜催化不对称构建苄基立构中心

• 批准号: 9203629
• 负责人: Michael Thomas Pirnot
• 金额: $ 2.32万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-16 至 2017-06-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203629
• 关键词: Agrochemicals; Alkanes; Alkenes; Alkylation; Architecture; Area; Biological; Bromides; Carbon; Catalysis; Cell Membrane Permeability; Chemicals; Chemistry; Collection; Complex; Copper; Coupling; Crystallization; Development; Electron Spin Resonance Spectroscopy; Employment; Environment; Foundations; Generations; Half-Life; Human body; Injection of therapeutic agent; Investigation; Iodides; Kinetics; Ligands; Magnetism; Methodology; Methods; Modeling; Modernization; Molecular; Natural Products; Nuclear; Organic Synthesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Process; Property; Protocols documentation; Reaction; Research; Roentgen Rays; Silanes; Societies; Sodium Chloride; Source; Styrenes; Technology; Time; Ursidae Family; Work; aryl halide; computer studies; design; drug candidate; drug synthesis; metal complex; novel; public health relevance; spectroscopic survey

 DESCRIPTION (provided by applicant): The development of milder and more efficient methods towards complex molecule construction is a vibrant area of research within organic synthesis. In particular, certain structural motifs have achieved a privileged status within organi chemistry, due to their seemingly ubiquitous presence in bioactive molecules. For example, the benzylic carbon stereocenter is a common motif found in medicinal agents, agrochemicals, and natural product isolates. The substitution and functionality provided on the carbon framework can profoundly alter cell membrane permeability, half-life time of the molecule in a biological environment, and potency of a drug within the human body. Thus, the generation of a broad catalytic platform for this motif would be highly desirable. Recent advances in copper(I) hydride chemistry have demonstrated the potential of this catalytic platform for producing diastereoenriched and enantioenriched molecules under mild conditions with inexpensive sources of copper and silane. Still, significant advances could be achieved with this chemistry towards other asymmetric methodologies. Two specific aims outlined in this proposal detail two transformations that are catalyzed through reductive copper catalysis: enantioselective hydroarylation and enantioselective benzylic alkylation. The starting material proposed is styrene, a class of molecules produced on a millions of tons scale each year, and a variety of commercially available or easy-to-produce electrophilic sources. Lastly, mechanistic investigations will be pursued to isolate any competent intermediates in the catalytic cycle, identify the presence of any Cu(II)/Cu(III) or radical intermediates, and to develop a stereochemical model. Computational, kinetic, and spectroscopic investigations will, in turn, be applied to second-generation ligand framework synthesis and the expansion of this asymmetric methodology to other classes of olefins.

 描述（由申请人提供）：开发更温和、更有效的复杂分子构建方法是有机合成领域的一个充满活力的研究领域，特别是，某些结构基序由于其看似独特的性质而在有机化学中取得了特权地位。例如，苄基碳立构中心是药物、农用化学品和天然产物分离物中常见的基序，碳框架上的取代和提供的功能可以深刻地改变细胞膜。因此，非常需要为该基序生成广泛的催化平台。 氢化铜（I）化学的最新进展证明了该催化平台在温和条件下利用廉价的铜和硅烷来源生产非对映体富集和对映体富集分子的潜力，并且该化学可以在其他不对称方法方面取得重大进展。该提案中概述的具体目标详细介绍了通过还原铜催化催化的两种转化：对映选择性加氢芳基化和对映选择性苄基烷基化。提出的材料是苯乙烯，一类每年生产数百万吨规模的分子，以及各种市售或易于生产的亲电子来源。 最后，将进行机理研究以分离催化循环中的任何有效中间体，识别任何 Cu(II)/Cu(III) 或自由基中间体的存在，并开发立体化学模型。反过来，可应用于第二代配体框架合成，并将这种不对称方法扩展到其他类别的烯烃。