Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

项目摘要 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。这 这项工作将开发在蛋白质活性部位产生自由基中间体的新机制。 将进行蛋白质的进化，以提高反应的化学、区域和对映体选择性。 在它们的蛋白质活性部位内进行。在前一个资金阶段的研究结果的基础上，我们将制定 硝酸盐与卤代烷的偶联反应。这些反应有两种可能的产物：氧化还原- 中性反应制备手性𝛼-叔基硝基烷烃和还原偶联制备交叉偶联 产品。我们将设计有利于每一种结果的催化剂。其次，我们将开发一种区域选择性耦合 烷基与芳烃的结合。在这个项目中，我们将设计蛋白质支架以支持功能化 使用现有合成方法未触及的位置。第三，我们将探索烯烃 去功能化。在一个歧管中，我们将氧化自由基中间体形成碳正离子，这可以是 与各种亲核试剂一起淬火。在第二种方法中，我们将利用微笑的重新安排来进行激进的 终止。这些方法将使高取代度产品的快速合成成为可能，同时也使 用于精确控制C-C键形成的立体中心的立体化学的催化剂的发展-- 形成事件。在这个应用中，我们还将开发一种使用氧化引发自由基的新策略 脱羧基。该活化模式将应用于仲胺的合成。最后，我们会 创建生物催化交叉偶联反应，其中烷基化黄素加合物模拟 有机金属中间体。这种方法将使羧酸和卤代烷的偶联不需要 使用一种金属蛋白。总而言之，这些方法和在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，对人类健康产生重大好处 以及相关的生物医学科学。

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.