New Photocatalytic Coupling Reactions to Prepare Bioactive Molecules

这项研究计划的首要目标是发现新的催化合成方法。 生物活性目标，既有天然的，也有非天然的。我们之前已经报道了酚类化合物的合成 脂类天然产物和合成两类多环萜烯的努力，以及制备 项目2中所描述的光催化研究中所用的钴配合物的合成。 这项提案中描述的目标包括将作为机械探测器进行研究的分子。 神经变性和病毒性疾病，以及可能提供新治疗机会的线索。我们是 以特定的具有生物活性的结构基序为靶标的研究方法，如氨基金刚烷 和柠檬苦素类天然产物，以及催化方法设计，适用于广泛 化学目标的光谱。这些方法背后的使能技术是光催化，它 利用光能驱动复杂的催化过程。光催化继续提供新的 以其他方式很难或不可能访问的机制和转换。了解 这些过程的管理原则使我们能够将这种洞察力应用于发现新的、广泛有用的东西 合成方法。 取代金刚烷存在于多种具有重要功能的分子中，包括 临床批准的治疗阿尔茨海默氏症和病毒性疾病的药物，然而有效的合成仍然是 挑战。在项目1中，将通过新的氨基烷基化反应获得新的氨基金刚烷衍生物 反应和新的催化策略，实现与现有的互补的独特的选择性 接近了。这里描述的独特策略包括对新的和 建立了氢原子转移方法，为选择合适的HAT催化剂提供了必要的指导方针 不同的底物类别。在项目2中，一种受生物化学启发的新型极性/自由基交叉流形 将开发一系列维生素B12，以有效使用廉价和容易获得的生物活性酒精 分子结构。这些方法将被应用于合成有前景的天然产物目标。 比如具有神经保护作用的柠檬苦素。柠檬苦素类化合物的神经保护活性研究 非常重要，因此将探索获得这些分子和 用于作用机制研究的衍生物。总体而言，这里描述的概念将提供一般 用于快速构建药效团和生物活性天然产物衍生物的平台 立即被生物医学研究人员部署。

The overarching goal of this research program is to discover new catalytic methods for the synthesis of biologically active targets, both natural and unnatural. We have previously reported the synthesis of phenolic lipid natural products and efforts toward two families of polycyclic terpenes, as well as a general process for the synthesis of the cobalt complexes used in the photocatalytic investigations described in Project 2. The targets described in this proposal include molecules that will serve as mechanistic probes to study neurodegeneration and viral diseases, as well as leads that may provide new therapeutic opportunities. We are investigating methods to target specific structural motifs with established biological activity, such as amino-adamantanes and limonoid natural products, as well as catalytic methods designed to apply to a broad spectrum of chemical targets. The enabling technology behind these methods is photocatalysis, which harnesses light energy to drive complex catalytic processes. Photocatalysis continues to provide new mechanisms and transformations that are difficult or impossible to access otherwise. Understanding the governing principles of these processes allows us to apply that insight to the discovery of new, broadly useful synthesis methods. Substituted adamantanes appear in a wide variety of molecules with important function including clinically approved drugs for Alzheimer’s dementia and viral diseases, however efficient synthesis remains a challenge. In Project 1, new amino-adamantane derivatives will be accessed through a new aminoalkylation reaction and new catalytic strategies that enable unique selectivity that is complementary to existing approaches. The unique strategies described here include a detailed study of the selectivity of new and established H-atom transfer methods, providing guidelines necessary for selecting the proper HAT catalyst for different substrate classes. In Project 2, a novel polar/radical crossover manifold inspired by the biochemistry of vitamin B12 will be developed for the efficient use of inexpensive and readily available alcohols for bioactive molecule construction. These methods will be applied to the synthesis of promising natural product targets such as the neuroprotective limonoids. The investigation of the neuroprotective activity of limonoids is of central importance, therefore alternative pathways will be explored to access to these molecules and derivatives for mechanism of action studies. Overall, the concepts described here will provide general platforms for the rapid construction of pharmacophores and bioactive natural product derivatives that can be immediately deployed by biomedical researchers.