Chemoenzymatic 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 synthesis of phenol diarylamines. Non-heme diiron N-oxygenase AzoC, which catalyzes the oxidization of amines to nitroso groups for azoxymycin biosynthesis in Streptomyces chattanoogensis, is engineered as a catalyst. This synthetic method tolerates a broad range of phenol and aniline substrates. The mechanistic study indicates that the enzymatically formed nitroso intermediate coupled to phenoxide facilitates the nonenzymatic diarylamine synthesis. Our study suggests that diarylamines can be enzymatically synthesized in aqueous solutions and highlights the synthetic potential of non-heme diiron N-oxygenases.