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: 10585465
• 负责人: Todd Kurt Hyster
• 金额: $ 6.12万
• 依托单位: CORNELL 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585465
• 关键词: Active Sites; Address; Alcohols; Alkenes; Alkylation; Amines; Amino Acids; Binding; Biological; Carboxylic Acids; Chemicals; Complex; Coupled; Coupling; Decarboxylation; Development; Directed Molecular Evolution; Drug Targeting; Electrons; Engineering; Environment; Enzymes; Event; Evolution; Flavins; Flavoproteins; Free Radicals; Funding; Goals; Health; Human; Hydrogen; Mediating; Medicine; Metalloproteins; Methods; Mixed Function Oxygenases; Molecular; Mutagenesis; Nitrogen Dioxide; Outcome; Oxidation-Reduction; Oxidoreductase; Phase; Positioning Attribute; Process; Protein Engineering; Proteins; Reaction; Research; Scaffolding Protein; Science; Site; Smiling; Technology; Transition Elements; Work; adduct; catalyst; chemical synthesis; design; interest; manufacture; nitroalkane; novel; oxidation; permissiveness; stereochemistry; tertiary amine; tool

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.

项目概要 本提案中描述的工作旨在解决控制 由自由基中间体介导的具有合成价值的反应的对映选择性和区域选择性。 这项工作将开发在蛋白质活性位点内产生自由基中间体的新机制。 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 基于之前资助期间的发现，我们将在其蛋白质活性位点内进行开发。 硝基化合物和卤代烷之间的偶联反应有两种可能的产物：氧化还原-。 中性反应得到手性𝛼-叔硝基烷烃和还原偶联制备交叉偶联 其次，我们将设计有利于每种结果的催化剂。 在这个项目中，我们将设计蛋白质支架以利于功能化。 第三，我们将探索烯烃。 在一种方式中，我们将氧化自由基中间体形成碳正离子，其可以是 在第二种方法中，我们将利用微笑重排进行激进的反应。 这些方法将能够快速合成高度取代的产物，同时也能够实现。 开发催化剂以精确控制C-C键中形成的立体中心的立体化学 在此应用中，我们还将开发一种利用氧化进行自由基引发的新策略。 最后，我们将这种活化模式应用到仲胺的合成中。 创建生物催化交叉偶联反应，其中烷基化黄素加合物模仿 该方法无需使用有机金属中间体即可实现羧酸和卤代烷的偶联。 使用金属蛋白，这些方法和具体目标中提出的目标具有潜力。 简化生物探针和药物靶标的合成，为人类健康创造重大利益 以及相关的生物医学科学。