Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

黄素蛋白作为不对称自由基反应催化剂的开发

• 批准号: 10895748
• 负责人: Todd Kurt Hyster
• 金额: $ 27.81万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10895748
• 关键词: Development; Flavoproteins; Catalysts; Asymmetric; Radical

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. This work will develop novel mechanisms for generating free radical intermediates within protein active sites. Evolution of the protein will be conducted to enhance the chemo-, regio-, and enantioselectivity of the reactions performed within their protein active site. Building on findings in the previous funding period, we will develop couplings reactions between nitronates and alkyl halides. These reactions have two possible products: a redox- neutral reaction to afford chiral 𝛼-tertiary nitroalkanes and a reductive coupling to prepare cross-coupled products. We will design catalysts to favor each outcome. Secondly, we will develop a regioselective coupling of alkyl radicals with arenes. In this project, we will engineer the protein scaffold to favor functionalization at positions that are untouched using existing synthetic methods. Thirdly, we will explore alkene difunctionalization. In one manifold, we will oxidize radical intermediates to form carbocations which can be quenched with various nucleophiles. In a second approach, we will exploit Smiles rearrangements for radical termination. These approaches will enable the rapid synthesis of highly substituted products while also enabling the development of catalysts to precisely control the stereochemistry of stereocenters formed in C–C bond- forming events. In this application, we will also develop a new strategy for radical initiation using oxidative decarboxylation. This activation mode will be applied to the synthesis of secondary amines. Finally, we will create a biocatalytic cross-coupling reaction, where alkylated flavin adducts mimic the reactivity of organometallic intermediates. This method will enable the coupling of carboxylic acids and alkyl halides without using a metalloprotein. 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.

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。这 工作将开发出新的机制，用于在蛋白质活性部位生成自由基中间体。 将进行蛋白质的进化，以增强反应的化学，区域和对映选择性 在其蛋白质活性部位进行。在上一个资金期间的发现的基础上，我们将发展 硝酸盐和烷基卤化物之间的耦合反应。这些反应有两个可能的产品：氧化还原 中性反应提供手性的𝛼前硝基烷烃和降​​低的耦合以制备交叉耦合 产品。我们将设计催化剂以偏爱每个结果。其次，我们将开发一个监管耦合 带有烷基的烷基自由基。在这个项目中，我们将设计蛋白质支架以偏爱功能化 使用现有的合成方法未经影响的位置。第三，我们将探索 调节性。在一个歧管中，我们将氧化自由基中间体形成碳酸化 用各种核透明质淬灭。在第二种方法中，我们将利用微笑重排来进行激进 终止。这些方法将使高度替代产品的快速合成，同时也可以 催化剂的发展以精确控制C – C键形成的立体化学的立体化学 形成事件。在此应用程序中，我们还将制定一种使用氧化的新策略，用于激进启动 脱羧。这种激活模式将应用于次级胺的合成。最后，我们会的 创建生物催化交叉偶联反应，其中烷基化黄素加合物模仿了反应性 有机中间体。此方法将使羧酸和醇卤化物的偶联 使用金属蛋白。这些方法和特定目的中提出的目标都有潜力 简化生物问题和药物靶标的综合，为人类健康带来重大好处 和相关的生物医学科学。