Photoredox Catalysis for Chemical Synthesis

化学合成中的光氧化还原催化

• 批准号: 7865525
• 负责人: David W MacMillan
• 金额: $ 29.62万
• 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/7865525
• 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）：本研究计划的目的是发明新的催化合成方法或策略，以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、抗菌和抗病毒药物中很常见，但炎症药物，无法使用常规方法轻易获得。在这一努力中，我们的目标是在光氧化还原催化相关学科中易于应用的过程，因此将对在已确定生物学重要性的分子支架中常见的新碳-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被证明是有价值的。 尽管在过去十年中光氧化还原催化被认为是一种重要的化学策略，但这些简单且广泛使用的催化剂的巨大潜力在很大程度上尚未得到开发。然而，许多这些光氧化还原活性催化剂仅用可见光处理即可参与单电子转移反应，这表明将它们纳入主流应用可以节省成本、时间、能源和操作复杂性。该提案概述了光氧化还原催化的创新和通用策略的发展，该策略使易于获得的复合物仅由简单且廉价的家用光源激活，即可作为各种转化的催化剂。当与完善的有机催化方案相结合时，该策略提供了有效且稳健的催化剂系统，可以在广泛的化学过程中实现高水平的不对称诱导。在此授权期间，这种新化学策略的价值将在对映选择性光氧化还原介导的α-醛（1）烷基化，（2）三氟甲基化，（3）全氟烷基化，（4）的第一个例子中得到证明。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。尽管这些转化中的每一个都产生了重要的结构支架，但三氟甲基取代基的对映选择性安装在药物合成中提供了一个里程碑，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，在广泛的药理学筛选（抗病毒、抗肿瘤和抗有丝分裂活性）中表现出显着的生物学特性。该提案概述了光氧化还原有机催化激活策略在快速构建木脂素结构方面的创新应用。在证明了这些光氧化还原介导的转化的效用后，这种催化方法的范围将应用于 (-)-yatein 的高度快速的一锅合成。这种新方法将进一步用作后续复杂目标合成工作的模板。 公共健康相关性：本研究的目的是建立一个合成方案，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，这些结构基序是许多药物的组成部分，但目前使用已知的化学方法无法获得。