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）：本研究计划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、抗菌和抗炎药物中很常见，但使用传统方法无法轻易获得。在这项努力中，我们的目标是在光氧化还原催化的相关学科中很容易应用的过程，因此将对在分子支架中经常发现的新碳-碳键的可及性产生直接和立即的影响，这些碳-碳键已经建立了生物学重要性。我们的目的是开发具有广泛用途和功能的操作简单的合成方法，最终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尚未得到开发。然而，许多这些光氧化还原活性催化剂在仅用可见光处理时可以进行单电子转移反应，这表明将其纳入主流利用可以节省成本、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一般策略的发展，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，即可作为广泛转化的催化剂。当与完善的有机催化协议相结合时，该策略提供了一个有效且强大的催化剂系统，可以在广泛的化学过程中实现高水平的不对称诱导。在此授权期内，这种新化学策略的价值将在第一个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，(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。虽然每一种转化都产生重要的结构支架，但三氟甲基取代基的对映选择性安装在药物合成中是一个里程碑，在药物合成中这种功能经常被利用。木脂素代表了一个独特的结构复杂的非对称苯丙二聚体家族，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。本提案概述了光氧化还原有机催化激活策略在木脂素结构快速构建中的创新应用。在证明了这些光氧化还原介导转化的实用性之后，这种催化方法的范围将应用于(-)-yatein的高度快速的一锅合成。这种新方法将被进一步用作后续复杂目标合成工作的模板。