A Multitasking Vanadium-Dependent Chloroperoxidase as an Inspiration for the Chemical Synthesis of the Merochlorins

The vanadium-dependent chloroperoxidase Mcl24 was found to mediate a complex series of transformations in the biosynthesis of the merochlorin natural products. This unprecedented enzyme catalyzes a site-selective naphthol chlorination followed by an oxidative dearomatization/cyclization cascade to generate the stereochemically complex carbon framework of the merochlorins. We have developed a parallel chemical chlorination protocol inspired by the enzyme activity, which enabled a concise total synthesis of the merochlorins. Furthermore, the chemical transformation sheds light on the mechanistic details of the enzyme. Ongoing structural and biochemical investigations of Mcl24 suggest a significantly different mode of action compared to other known vanadium-dependent haloperoxidases.