Enabling Triplet-Energy Transfer via NHC Catalysis

项目概要： 立体选择性合成是评价候选药物的关键。在上个世纪， 社会对热反应的立体控制的理解已经相当成熟。相比之下， 用于控制光化学转化的立体化学的方法仍然不发达，尽管 合成有机光化学的重要性日益增加。克服这一限制的必要条件是更深层次的 了解光活化机制以及有机分子的物理性质和 催化剂可用于促进对映选择性途径。 该建议概述了一种方法，通过该方法可以实现廉价烯烃的光激发， 卡宾催化剂、光敏剂和可见光。这将使化学原料直接参与 在对映选择性光环化加成反应中， 组在两个具体目标中的第一个目标中，将通过评估制定本提案的概念 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的研究奠定基础。 环加成反应一旦确定了这一办法的可行性，就将界定其范围和限制。 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 以前惰性的烷基取代的底物。这一建议的成果将直接有利于药物 通过建立一个强大的新工具来构建新领域的生物活性分子， 化学空间和基础，以评估因素，驱动选择性在一个新的模式的选择。

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.