Chemoenzymatic Cascade Synthesis of Phenol Diarylamine Using Non-Heme Diiron N-Oxygenase

Abstract Diarylamines are important moieties in organic materials and bioactive molecules. The traditional synthetic approach to diarylamines is metal catalysis in organic solvents. Herein, we report the chemoenzymatic cascade synthesis of phenol diarylamines. Non-heme diiron N-oxygenase AzoC, which catalyzes the oxidization of amines to nitroso groups for azoxymycins biosynthesis in Streptomyces chattanoogensis, is engineered as a catalyst. This synthetic method bears a broad range of phenol and aniline substrates. Mechanistic study indicates that the enzymatically formed nitroso intermediate couple to phenoxide facilitates the non-enzymatic diarylamine synthesis. Our study suggests that diarylamines can be enzymatic synthesized in aqueous solutions and highlights the synthetic potential of non-heme diiron N-oxygenases.