Asymmetric Construction of Benzylic Stereocenters via Reductive Copper Catalysis

 描述(由申请人提供)：开发更温和和更有效的方法来构建复杂的分子是有机合成中一个充满活力的研究领域。特别是，某些结构基序已经在有机化学中获得了特权地位，因为它们似乎无处不在地存在于生物活性分子中。例如，苄基碳立体中心是药剂、农用化学品和天然产品分离株中常见的基序。碳骨架上的取代和官能团可以深刻地改变细胞膜的通透性、分子在生物环境中的半衰期以及药物在人体内的效力。因此，为这个基序生成一个广泛的催化平台将是非常可取的。 铜(I)氢化物化学的最新进展表明，该催化平台有可能在温和的条件下，以廉价的铜和硅烷为源，生成非对映富集型和对映富集型分子。尽管如此，这种化学可以在其他不对称方法上取得重大进展。该提案中概述的两个具体目标详细说明了通过还原铜催化的两种转化：对映体选择性氢芳基化和对映体选择性苄基烷基化。提出的起始材料是苯乙烯，这是一类每年生产数百万吨规模的分子，以及各种商业上可获得的或易于生产的亲电源。 最后，将进行机理研究，以分离催化循环中任何合格的中间体，确定任何铜(II)/铜(III)或自由基中间体的存在，并开发立体化学模型。计算、动力学和光谱研究将依次应用于第二代配体骨架的合成和将这种不对称方法扩展到其他类型的烯烃。

 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.