Photoredox Catalysis for Chemical Synthesis

化学合成中的光氧化还原催化

• 批准号: 8220903
• 负责人: David W MacMillan
• 金额: $ 29.19万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220903
• 关键词: Aldehydes; Alkylation; Amination; Amines; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Area; Benign; Biological; Biological Factors; Carbon; Catalysis; Characteristics; Chemicals; Complex; Coupled; Development; Discipline; Electron Transport; Electrons; Exhibits; Family; Generic Drugs; Grant; Household; Hydrogen Bonding; Investigation; Kinetics; Light; Lignans; Mainstreaming; Malignant Neoplasms; Mediating; Methodology; Methods; Mitotic Activity; Molecular; Pharmacologic Substance; Process; Property; Protocols documentation; Reaction; Reagent; Research; Research Personnel; Research Project Grants; Research Proposals; Route; Savings; Series; Source; System; Technology; Therapeutic; Time; Viral; Visible Radiation; catalyst; chemical synthesis; cost; dimer; innovation; insight; interest; novel; operation; programs; public health relevance; scaffold; tool; tumor

DESCRIPTION (provided by applicant): The objective of this research proposal is to invent new catalytic synthetic methods or strategies that allow access to structural and stereochemical motifs, which, although common among anti-viral, anti-cancer, anti-bacterial and anti-inflammatory medicinal agents, cannot be readily accessed using conventional methods. In this endeavor, we target processes that are readily applied within the related discipline of photoredox catalysis and therefore will have a direct and immediate impact on the accessibility of new carbon-carbon bonds frequently found in molecular scaffolds that have established biological importance. Our intent is to develop operationally trivial synthetic methods of broad utility and function that will ultimately provide new chemical tools for the diverse range of biomedical researchers that utilize molecule construction. As a consequence, this core research will prove valuable within the therapeutic realm. Despite the identification of photoredox catalysis as an important chemical strategy over the past ten years, the vast potential of these simple and widely available catalysts is largely unexplored. However, many of these photoredox active catalysts can engage in single electron transfer reactions upon treatment with only visible light, indicating that their incorporation into mainstream utilization offers savings in cost, time, energy and operation complexity. This proposal outlines the development of an innovative and general strategy for photoredox catalysis that enables readily accessible complexes, activated by only a simple and inexpensive household light source, to function as catalysts for a wide range of transformations. When coupled with well-established organocatalysis protocols, this strategy provides an effective and robust catalyst system that can effect high levels of asymmetric induction across a broad spectrum of chemical processes. During the tenure of this granting period, the value of this new chemical strategy will be demonstrated in the context of the first examples of enantioselective photoredox mediated ?-aldehyde (1) alkylations, (2) trifluoromethylations, (3) perfluoroalkylations, (4) benzylations, and (5) aminations, as well as photoredox mediated (6) aryl trifluoromethylations and (7) C-H bond arylations. Although each of these transformations yield important structural scaffolds, the enantioselective installation of trifluoromethyl substituents offers a milestone in pharmaceutical synthesis, where this functionality is frequently exploited. Lignans represent a unique family of structurally complex non-symmetrical phenylpropanoid dimers that exhibit remarkable biological properties across a broad spectrum of pharmacological screens (anti-viral, anti-tumor and anti-mitotic activity). This proposal outlines an innovative application of the photoredox organocatalysis activation strategy towards the rapid construction of lignan architectures. Having demonstrated the utility of these photoredox mediated transformations, the scope of this catalytic methodology will be applied to the highly expeditious one-pot synthesis of (-)-yatein. This new methodology will be further employed as a template for subsequent complex target syntheses endeavors. PUBLIC HEALTH RELEVANCE: The objective of this research is to establish a synthetic protocol whereby a simple and inexpensive household light source will initiate the catalytic formation of structural motifs that are integral components in many medicinal agents, but that are not currently accessible using known chemical methods.

描述（由申请人提供）：本研究提案的目的是发明新的催化合成方法或策略，允许获得结构和立体化学基序，尽管这些基序在抗病毒、抗癌、抗菌和抗炎药物中很常见，但使用常规方法无法轻易获得。在这项奋进中，我们的目标是在光氧化还原催化的相关学科中容易应用的过程，因此将对在已建立生物重要性的分子支架中经常发现的新碳-碳键的可及性产生直接和直接的影响。我们的目的是开发具有广泛实用性和功能的操作上简单的合成方法，最终为利用分子构建的各种生物医学研究人员提供新的化学工具。因此，这项核心研究将在治疗领域证明是有价值的。 尽管在过去的十年中，光氧化还原催化被认为是一种重要的化学策略，但这些简单且广泛可用的催化剂的巨大潜力在很大程度上尚未开发。然而，这些光氧化还原活性催化剂中的许多在仅用可见光处理时可以参与单电子转移反应，这表明将它们并入主流利用中可以节省成本、时间、能量和操作复杂性。该提案概述了光氧化还原催化的创新和一般战略的发展，使易于获得的复合物，激活只有一个简单和廉价的家用光源，作为催化剂的广泛的转换。当与成熟的有机催化方案结合时，该策略提供了有效且稳健的催化剂系统，其可以在广谱化学过程中实现高水平的不对称诱导。在此授予期间的任期内，这种新的化学策略的价值将在对映选择性光氧化还原介导的？醛（1）烷基化，（2）三氟甲基化，（3）全氟烷基化，（4）苄基化，和（5）胺化，以及光氧化还原介导的（6）芳基三氟甲基化和（7）C-H键芳基化。虽然这些转换产生重要的结构支架，三氟甲基取代基的对映选择性安装提供了一个里程碑，在药物合成中，这种功能经常被利用。木脂素代表了结构复杂的非对称苯丙素二聚体的独特家族，其在广泛的药理学筛选（抗病毒、抗肿瘤和抗有丝分裂活性）中表现出显著的生物学特性。该提案概述了一个创新的应用程序的光氧化还原有机催化活化策略对木脂素架构的快速建设。已经证明了这些光氧化还原介导的转化的实用性，这种催化方法的范围将被应用于（-）-yatein的高度快速的一锅法合成。这种新的方法将进一步作为模板，为后续的复杂目标合成的努力。 公共卫生相关性：本研究的目的是建立一种合成方案，通过该方案，简单且廉价的家用光源将启动结构基序的催化形成，所述结构基序是许多药剂中不可或缺的组分，但目前使用已知的化学方法无法获得。