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Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

机译：芳烃和杂芳烃的三氟甲基化通过光氧化还原催化

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摘要

Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion. A commonly used synthetic strategy to protect against in vivo metaboh'sm involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF_3) group, into drug candidates. The CF_3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metaboh'sm of the drug. Although common pharmacophores often bear CF_3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF_3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF_3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability, to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.
机译：现代药物发现依赖于合成方法的不断发展，以解决与新药物设计相关的许多挑战。细胞色素P450氧化酶在体内通过酶促药物代谢产生了此类挑战，该酶使用单电子氧化机制快速修饰小分子以促进其排泄。防止体内代谢障碍的常用合成策略涉及将吸电子官能团（例如三氟甲基（CF_3）基团）结合到候选药物中。 CF_3基团在药物化学领域中享有特权，因为将其掺入小分子中通常可以通过促进与靶标的静电相互作用，改善细胞膜通透性以及增强对药物氧化代谢的耐受性来提高功效。尽管常见的药效基团通常在芳族系统中带有CF_3基序，但要获得此类类似物，通常需要在多步合成序列的开始处并入CF_3基团或替代基团。在这里，我们报告了一种温和的，操作简单的策略，可通过自由基介导的机制，使用市售光催化剂和家用灯泡，直接将未活化的芳烃和杂芳烃进行三氟甲基化。我们通过将CF_3添加到许多杂芳族和芳族体系中，证明了这种转化的广泛用途。通过广泛处方的药物直接三氟甲基化的例子，也显示了对药物化学和对后期药物开发的适用性。

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  • 来源
    《Nature》 |2011年第7376期|p.224-228|共5页
  • 作者

    David A. Nagib; David W. C. MacMillan;

  • 作者单位

    Merck Center for Catalysis at Princeton University, Department of Chemistry, 192 Frick Laboratory, Princeton, New Jersey 08540, USA;

    Merck Center for Catalysis at Princeton University, Department of Chemistry, 192 Frick Laboratory, Princeton, New Jersey 08540, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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