Exploiting the Intrinsic Peroxidase Activity of Unspecific Peroxygenase for the Oxidative Cyclization of Ortho‐Substituted Phenols

Fungal unspecific peroxygenases (UPOs) have emerged as powerful catalysts for diverse oxidation reactions. While previous studies have predominantly focused on their native mono(per)oxygenase activity, their full catalytic potential remains underexplored. Herein, we demonstrate that the intrinsic peroxidative activity of UPOs can be effectively leveraged for the straightforward synthesis of benzoxazole compounds. Using the unspecific peroxygenase from Agrocybe aegerita, a broad range of ortho-patterned phenolic substrates were efficiently converted into high-value benzoxazoles with conversions of up to 99% under the neat reaction conditions. The enzyme exhibited superior catalytic performance compared to the well-established horseradish peroxidase. Mechanistic studies demonstrated that phenoxyl radicals generated by UPO's intrinsic peroxidase activity are essential for benzoxazole formation. This work not only presents a mild and efficient synthetic route to benzoxazoles but also expands the known reactivity and oxidative chemistry of UPOs.