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: 9421133
• 负责人: Michael Thomas Pirnot
• 金额: $ 0.03万
• 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 2018-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9421133
• 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; 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（由适用提供）：米勒的开发和更有效的复杂分子构造方法是有机合成中的一个充满活力的研究领域。特别是，由于它们在生物活性分子中看似无处不在，某些结构基序在组织化学中获得了特权状态。例如，苯基碳立体中心是在医疗剂，农业化学和天然产物分离株中发现的常见基序。碳框架上提供的替代和功能可以深刻地改变细胞膜的渗透性，在生物学环境中分子的半衰期时间以及人体中药物的效力。这是高度可取的。 铜（i）氢化物化学的最新进展证明了这种催化平台在轻度条件下具有廉价的铜和硅烷源，在轻度条件下产生映射和映射分子的潜力。尽管如此，通过这种化学反应针对其他不对称方法可以取得重大进步。该提案细节中概述了两个通过减少铜催化而催化的特定目标：对映选择性水溶性和对映选择性苯并醇。提出的起始材料是苯乙烯，每年以数百万吨比例生产的一类分子，以及各种市售或易于生产的亲电源。 最后，将寻求机械投资，以隔离催化周期中的任何有能力的中间体，确定任何CU（II）/CU（III）或激进中间体的存在，并开发立体化学模型。反过来，计算，动力学和光谱投资将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。