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New Photocatalytic Coupling Reactions to Prepare Bioactive Molecules

制备生物活性分子的新光催化偶联反应

基本信息

批准号：
10620275
负责人：
David Martin
金额：
$ 37.45万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

项目摘要

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.

这项研究计划的首要目标是发现新的催化方法，用于合成生物活性目标，包括天然的和非天然的。我们以前曾报道过酚的合成脂质天然产物和对两个多环萜烯家族的努力，以及制备多环萜烯的一般方法。项目2中描述的用于光催化研究的钴络合物的合成。的在这项提议中描述的目标包括将作为研究机制探针的分子，神经变性和病毒性疾病，以及可能提供新的治疗机会的线索。我们研究靶向具有既定生物活性的特定结构基序的方法，如氨基金刚烷和柠檬酸类天然产物，以及催化方法，旨在适用于广泛的化学目标的光谱这些方法背后的支持技术是可编程逻辑器件，利用光能驱动复杂的催化过程。光催化继续提供新的这些机制和转变很难或不可能以其他方式获得。了解这些过程的指导原则使我们能够将这种洞察力应用于发现新的，广泛有用的合成方法取代的金刚烷出现在具有重要功能的多种分子中，包括临床批准的药物阿尔茨海默氏痴呆症和病毒性疾病，但有效的合成仍然是一个问题。挑战.在项目1中，新的氨基金刚烷衍生物将通过新的氨基烷基化反应获得。反应和新的催化策略，使独特的选择性，是补充现有的接近。这里描述的独特策略包括对新的和新的选择性的详细研究。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，不同的基底类别。在项目2中，一个新颖的极性/自由基交叉流形的灵感来自于生物化学维生素B12将被开发用于有效利用廉价和容易获得的醇用于生物活性分子结构这些方法将应用于有前景的天然产物目标物的合成例如神经保护性柠檬苦素。柠檬苦素类化合物的神经保护活性的研究是因此，将探索替代途径以获得这些分子，用于作用机制研究的衍生物。总的来说，这里描述的概念将提供一般的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。