Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions (Administrative/Equipment Supplement)

开发黄素蛋白作为不对称自由基反应的催化剂（管理/设备补充）

基本信息

批准号：
9895080
负责人：
Todd Kurt Hyster
金额：
$ 8.61万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-02-28
项目状态：
已结题

项目摘要

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. !

7。项目摘要本提案中描述的工作旨在应对控制的长期挑战自由基中间体介导的合成有价值反应的对映选择性和调节选择性。在这项工作，广泛的底物允许黄酮酶与三种新型机制结合形成以实现蛋白质活性位点内结合的以底物为中心的自由基。第一个机制涉及从假体黄素辅因子到位于蛋白质活性位点内的底物的电子转移。这种方法使形成α-酰基自由基用于各种C – C键形成反应能够选择性合成生物学重要性的碳环和杂环基序。第二个涉及利用结合对所选底物氧化还原电位的影响。在底物中轴承刘易斯基本功能组，在蛋白质活性位点内的结合使底物更容易减少。我们发现，当使用弱还原时，可以将选择性自由基形成定位于与蛋白活性位点结合的底物。这种反应性使酮自由基的形成用于耦合与电子贫穷的伴侣，例如有价值的杂环。最后，使用疏水染料能够与蛋白质结合，我们发现可以选择性地将自由基形成定位于酶结合基材。该方法可以选择性形成C – C键。这些方法和特定目的中提出的目标有可能简化生物问题的综合和药物靶标，为人类健康和相关的生物医学带来重大好处。呢