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(申请人提供)：这项研究提案的目标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、抗细菌和消炎药物中很常见，但不能用传统方法容易地获得。在这项工作中，我们的目标是在光氧化还原催化相关学科中容易应用的过程，因此将直接和立即影响新的碳-碳键的可获得性，这些新的碳-碳键经常出现在已确定生物重要性的分子支架中。我们的目的是开发操作上微不足道的合成方法，具有广泛的实用性和功能，最终将为利用分子结构的各种生物医学研究人员提供新的化学工具。因此，这项核心研究在治疗领域将被证明是有价值的。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，但这些简单而广泛使用的催化剂的巨大潜力在很大程度上还没有被开发出来。然而，许多这些光氧化还原活性催化剂在仅用可见光处理后就可以进行单电子转移反应，这表明它们融入主流利用可以节省成本、时间、能源和操作复杂性。这项提议概述了开发一种创新和一般的光氧化还原催化战略，使仅由简单和廉价的家用光源激活的容易获得的络合物能够用作各种转化的催化剂。当与成熟的有机催化协议相结合时，该策略提供了一个有效和强大的催化剂系统，可以在广泛的化学过程中实现高水平的不对称诱导。在本授权期内，这一新的化学策略的价值将在第一批对映体选择性光氧化还原介导的β-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键芳基化的背景下得到证明。虽然每一次转化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，这一功能经常被利用。木脂素是一类结构复杂的非对称苯丙烷二聚体，在广泛的药理筛选中表现出显著的生物学特性(抗病毒、抗肿瘤和抗有丝分裂活性)。这项提案概述了光氧化还原有机催化活化策略在快速构建木脂素结构方面的创新应用。在展示了这些光氧化还原介导的转化的有效性之后，该催化方法学的范围将被应用于(-)-叶酸的一锅法的快速合成。这一新的方法将进一步用作后续复杂目标合成努力的模板。 与公共健康相关：这项研究的目标是建立一种合成方案，根据该方案，一种简单且廉价的家用光源将启动结构基元的催化形成，这些结构基元是许多药物中不可或缺的成分，但目前无法使用已知的化学方法获得。