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

2013; American Chemical Society; Volume: 135; Issue: 33 Linguagem: Inglês

10.1021/ja405471h

1943-2984

Julien Genovino, Stephan Lütz, Dalibor Sameš, B. Barry Touré,

Oxidative Organic Chemistry Reactions

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.