Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis.
Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis.
复制标题
DOI：
10.1038/nature10647
复制
发表时间：
2011-12-08
期刊：
影响因子：
64.8
通讯作者：
MacMillan, David W. C.
中科院分区：
文献类型：
--
作者：
Nagib, David A.;MacMillan, David W. C.
现代药物发现依赖于合成方法的不断发展来解决与新药物设计相关的许多挑战。其中一项挑战来自于体内细胞色素 P450 氧化酶对药物的酶促代谢，该酶利用单电子氧化机制快速修饰小分子以促进其排泄。防止体内代谢的常用合成策略涉及将吸电子功能（例如三氟甲基（CF3）基团）掺入候选药物中。 CF3 基团在药物化学领域享有特殊的地位，因为它与小分子的结合通常可以通过促进与靶标的静电相互作用、改善细胞膜通透性和增加药物氧化代谢的稳健性来增强功效。尽管常见的药效基团通常在芳香系统中带有 CF3 基序，但获得此类类似物通常需要在多步合成序列开始时掺入 CF3 基团或替代部分。在这里，我们报告了一种温和、操作简单的策略，通过使用商业光催化剂和家用灯泡的自由基介导机制，对未活化的芳烃和杂芳烃进行直接三氟甲基化。我们通过将 CF3 添加到许多杂芳族和芳香族体系中，证明了这种转化的广泛实用性。广泛使用的药剂的直接三氟甲基化的例子也显示了药物化学的益处和对后期药物开发的适用性。
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 metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF3) group, into drug candidates. The CF3 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 metabolism of the drug. Although common pharmacophores often bear CF3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF3 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 CF3 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.
登录
查看更多内容
影响因子：
1.6
作者：
KAMIGATA, N;FUKUSHIMA, T;YOSHIDA, M
通讯作者：
YOSHIDA, M
影响因子：
1.9
作者：
Wiehn, Matthias S.;Vinogradova, Ekaterina V.;Togni, Antonio
通讯作者：
Togni, Antonio
影响因子：
21.8
作者：
Yoon, Tehshik P.;Ischay, Michael A.;Du, Juana
通讯作者：
Du, Juana
影响因子：
4.9
作者：
Xu, Jun;Luo, Dong-Fen;Liu, Lei
通讯作者：
Liu, Lei
DOI：
10.1039/p19940001339
发表时间：
1994-05-21
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
影响因子：
--
作者：
KAMIGATA, N;OHTSUKA, T;SHIMIZU, T
通讯作者：
SHIMIZU, T