Complementation of Biotransformations with Chemical C鈥揌 Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals

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• 作者：Julien Genovino ; Stephan L眉tz ; Dalibor Sames ; B. Barry Tour茅
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：August 21, 2013
• 年：2013
• 卷：135
• 期：33
• 页码：12346-12352
• 全文大小：462K
• 年卷期：v.135,no.33(August 21, 2013)
• ISSN：1520-5126

文摘

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鈥揌 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鈥檚 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鈥揌 bonds but by the individual structural chemotype. This study represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C鈥揌 bonds in complex pharmaceuticals and rapidly deliver drug metabolites.