Complementation of Biotransformations with Chemical C-H Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals
Complementation of Biotransformations with Chemical C-H Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals
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DOI：
10.1021/ja405471h
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发表时间：
2013-08-21
影响因子：
15
通讯作者：
Toure, B. Barry
中科院分区：
文献类型：
--
作者：
Genovino, Julien;Luetz, Stephan;Toure, B. Barry
生物体液中药物代谢物的分离、定量和表征仍然具有挑战性。快速获得氧化药物可以促进代谢物鉴定，并使早期药理学和毒性研究成为可能。在此，我们比较了使用奥卡西平、萘普生和早期化合物（酞嗪1）的经典和新的化学C-H氧化方法的生物转化。这些研究表明，生物转化的制备效率低，化学方法无法氧化复杂的药物。我们还公开了一种有氧催化方案（CuI/air）来氧化药物中的叔胺和苄基CH。该反应耐受广泛的功能，并表现出高水平的化学选择性，这通常不是由C-H键的强度来解释，而是由个体结构的化学型来解释。这项研究代表了建立化学工具包（化学转化）的第一步，该工具包可以选择性地氧化复杂药物中的C-H键并快速递送药物代谢物。
The isolation, quantitation, and characterization of drug metabolites in biological fluids remain challenging. Rapid access to oxidized drugs could facilitate metabolite identification and enable early pharmacology and toxicity studies. Herein, we compared biotransformations to classical and new chemical C-H oxidation methods using oxcarbazepine, naproxen, and an early compound hit (phthalazine 1). These studies illustrated the low preparative efficacy of biotransformations and the inability of chemical methods to oxidize complex pharmaceuticals. We also disclose an aerobic catalytic protocole (CuI/air) to oxidize tertiary amines and benzylic CH's in drugs. The reaction tolerates a broad range of functionalities and displays a high level of chemoselectivity, which is not generally explained by the strength of the C-H bonds but by the individual structural chemotype. This study represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites.