Development of Flavoproteins as Catalysts for Asymmetric Radical Reactions

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。这 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选择性、区域选择性和对映选择性 在其蛋白质活性位点内进行。根据上一个资助期的研究结果， 硝基膦酸盐和烷基卤化物之间的偶联反应。这些反应有两种可能的产物：氧化还原- 中性反应得到手性N-叔硝基烷烃，还原偶联得到交叉偶联的 产品.我们将设计催化剂，以促进每一个结果。其次，我们将开发一种区域选择性偶联 烷基与芳烃的反应。在这个项目中，我们将设计蛋白质支架，使其有利于功能化， 使用现有的合成方法未触及的位置。第三，我们将探索烯烃 双功能化在一个流形中，我们将氧化自由基中间体以形成碳阳离子， 用各种亲核试剂淬灭。在第二种方法中，我们将利用Smiles重排进行激进的 终止这些方法将使得能够快速合成高度取代的产物，同时还使得能够 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， 形成事件。在本申请中，我们还将开发一种新的策略，使用氧化引发自由基 脱羧作用这种活化方式将应用于仲胺的合成。最后我们将 产生生物催化交叉偶联反应，其中烷基化黄素加合物模拟 有机金属中间体该方法将使得羧酸和烷基卤化物的偶联能够进行， 使用金属蛋白。总之，这些方法和具体目标中提出的目标有可能 简化生物探针和药物靶标的合成，为人类健康创造重大利益 和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.