Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

7.项目总结 本提案中描述的工作旨在解决长期存在的挑战，即控制 自由基中间体介导的合成有价值反应的对映体选择性和区域选择性。在……里面 这项工作，广泛底物允许的黄素酶与三种新的自由基机制相结合 形成以底物为中心的自由基，结合在蛋白质活性部位内。第一个机制 包括从黄素辅因子假体到位于蛋白质活性部位的底物的电子转移。 该方法能够形成用于各种C-C成键反应的α-酰基自由基 能够选择性地合成具有生物重要性的碳环和杂环基序。第二 包括利用结合对选定底物的氧化还原电位的影响。在衬底中 带有Lewis碱性官能团，结合在蛋白质活性部位内使底物更容易 减少。我们发现，当使用弱还原剂时，选择性自由基的形成可以局部化到 与蛋白质活性部位结合的底物。这种反应性使得能够形成用于偶联的酮基自由基 与药物上有价值的杂环等电子贫乏的配对。最后，使用疏水染料 能够与蛋白质结合，我们发现自由基的形成可以选择性地定位于酶结合 底物。这种方法能够选择性地形成C-C键。总的来说，这些方法和 在具体目标中提出的目标有可能简化生物探针和 药物靶点，对人类健康和相关的生物医学科学产生重大益处。 好了！

7. Project Summary The work described in this proposal aims to address the longstanding challenge of controlling the enantioselectivity and regioselectivity of synthetically valuable reactions mediated by radical intermediates. In this work, broadly substrate permissive flavoenzymes are coupled with three novel mechanisms for radical formation to achieve substrate-centered radicals bound within protein active sites. The first mechanism involves electron transfer from a prosthetic flavin cofactor to substrates located within the protein active site. This approach enables the formation of α-acyl radicals for use in various C–C bond-forming reactions enabling the selective synthesis of carbocyclic and heterocyclic motifs of biological importance. The second involves exploiting the impact that binding has on the redox potential of a chosen substrate. In substrates bearing Lewis basic functional groups, binding within the protein active site makes the substrate easier to reduce. We have found that when weak reductants are used, selective radical formation can be localized to substrates bound to the protein active site. This reactivity enables the formation of ketyl radicals for coupling with electron poor partners such as medicinally valuable heterocycles. Finally, using hydrophobic dyes capable of binding to proteins, we found that radical formation can be selectively localized to enzyme bound substrates. This method enables the selective formation of C–C bonds. Together, these methods and the goals proposed in the Specific Aims have the potential to streamline the synthesis of biological probes and drug targets, creating a significant benefit to human health and associated biomedical sciences. !