Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

三氟甲基化 化学 药效团 光催化 药物发现 药物开发 部分 药品 小分子 催化作用 组合化学 三氟甲基 立体化学 药理学 生物化学 有机化学 医学 光催化 烷基
作者
David A. Nagib,David W. C. MacMillan
出处
期刊:Nature [Nature Portfolio]
卷期号:480 (7376): 224-228 被引量:1240
标识
DOI:10.1038/nature10647
摘要

A simple and mild strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes that acts via a radical-mediated mechanism and uses commercial photocatalysts. Premature metabolic decomposition can stop potentially promising drugs from reaching their intended targets. One way of blocking this metabolism involves the addition of a trifluoromethyl (CF3) group to aromatic or heteroaromatic moieties in a candidate drug molecule. David Nagib and David MacMillan report a new method for this synthesis that is more economical than current methods in terms of both raw materials and energy input. They use an energy-saving compact fluorescent light bulb to excite a variety of commercially available photocatalysts, which promote the addition of CF3 to unactivated arenes and heteroarenes through a radical-mediated mechanism. The potential of the method is demonstrated by the trifluoromethylation of three molecules: a uracil analogue, a precursor of the acetylcholinesterase inhibitor donepezil and a vitamin (flavone). Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents1. 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 excretion2. 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 candidates3. 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 drug4,5,6. 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.
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