Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

7.项目摘要 本提案中所述的工作旨在解决控制 自由基中间体介导的合成有价值的反应的对映选择性和区域选择性。在 这项工作，广泛的底物允许黄素酶与三种新的机制相结合， 形成以实现结合在蛋白质活性位点内的以底物为中心的自由基。第一机构 涉及电子从辅黄素辅因子转移到位于蛋白质活性位点内的底物。 这种方法能够形成α-酰基自由基，用于各种C-C键形成反应 能够选择性合成具有生物学重要性的碳环和杂环基序。第二 涉及利用结合对所选底物的氧化还原电位的影响。在基板中 带有刘易斯碱性官能团，结合在蛋白质活性位点内使底物更容易 减少。我们已经发现，当使用弱还原剂时，选择性自由基的形成可以局限于 底物结合到蛋白质活性位点。该反应性使得能够形成用于偶联的酮基自由基 与贫电子的伙伴如有药用价值的杂环。最后，使用疏水染料 能够结合蛋白质，我们发现，自由基的形成可以选择性地定位到酶结合 印刷受体.这种方法能够选择性地形成C-C键。总之，这些方法和 具体目标中提出的目标有可能简化生物探针的合成， 药物靶点，为人类健康和相关生物医学科学带来重大益处。 !

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. !