Oxidative Rearrangement of Indoles Enabled by Promiscuous Cryptic Halogenation with Vanadium-Dependent Haloperoxidases

The 2-oxindole class of heterocycles are privileged structural components in natural products and biologically active compounds. One of the most attractive methods for accessing 2-oxindoles is through direct oxidation of indoles, but current methods rely on the use of chemical oxidizing agents that lead to the generation of harmful waste products or biocatalytic methods using enzymes with a limited substrate scope. Herein, we describe the development and application of a general biocatalytic platform for the oxidative rearrangement of indoles using enzymatic halide recycling with vanadium-dependent haloperoxidases (VHPOs) facilitated by a catalytic quantity of halide salt and hydrogen peroxide as the terminal oxidant. This catalytic system is effective for the oxidative rearrangement of indoles into 2-oxindoles and 2-spirooxindoles. The developed protocol has been applied in multienzymatic and chemoenzymatic synthesis, late-stage functionalization of biologically active molecules, tryptophan-selective peptide modification, and gram-scale syntheses of coerulescine and horsfiline.