Enabling Triplet-Energy Transfer via NHC Catalysis

项目总结： 立体选择性合成是评价候选药物的关键。在上个世纪， 社区对热反应立体控制的理解已经显著成熟。相比之下，战略 控制光化学转化的立体化学仍然不发达，尽管 合成有机光化学日益重要。克服这一限制所不可或缺的是一个更深层次的 了解有机分子的光活化机理和光物理性质 可以利用催化剂来促进对映体选择性途径。 这项建议概述了一种廉价的烯烃的光激发方法。 卡宾催化剂、光敏剂和可见光。这将允许直接使用化学原料 在不对称光环加成反应中生成含有药物相关官能团的环丁烷 组。在两个具体目标中的第一个目标中，这项提案的概念将通过评估来发展 关键活性中间体的机理和物理性质，以及使 光激发。这些基础性研究将为推进不对称催化反应奠定基础。 环加成反应。一旦确定了该方法的可行性，就将确定范围和限制。 在第二个具体目标中，将进行新催化剂的第一性原理设计，以从 以前的惰性类烷基取代底物。这项提议的成果将直接惠及该药物 通过建立一个强大的新工具来在新的区域构建生物活性分子的发现过程 化学空间和评估在新的光催化模式中驱动选择性的因素的基础。

PROJECT SUMMARY: Stereoselective synthesis is critical for the assessment of drug candidates. Over the last century, the community understanding of stereocontrol of thermal reactions has matured significantly. By contrast, strategies for controlling the stereochemistry of photochemical transformations remain underdeveloped, despite the growing importance of synthetic organic photochemistry. Integral to overcoming this limitation is a deeper understanding of photoactivation mechanisms and how the photophysical properties of organic molecules and catalysts can be harnessed to promote enantioselective pathways. This proposal outlines a means by which photoexcitation of inexpensive alkenes can be accomplished with a carbene catalyst, photosensitizer, and visible light. This will allow chemical feedstocks to be directly engaged in enantioselective photocycloadditions to generate cyclobutanes containing medicinally relevant functional groups. In the first of two Specific Aims, the concept of this proposal will be developed through an assessment of the mechanism and of the physical properties of the key reactive intermediate and the features that enable photoexcitation. These fundamental studies will lay the groundwork to advance asymmetric catalysis of the cycloaddition reactions. Upon establishment of the viability of the approach, scope and limitations will be defined. In the second Specific Aim, a first-principles design of new catalysts will be performed to elicit reactivity from previously inert classes of alkyl-substituted substrates. The fruition of this proposal will directly benefit the drug discovery process by establishing a powerful new tool to construct biologically active molecules in new areas of chemical space and a basis to assess the factors that drive selectivity in a new mode of photocatalysis.