Enzymatic Halogenation of Tryptophan on a Gram Scale

Halogenated arenes are important building blocks in medicinal and agrochemistry. Chemical electrophilic aromatic halogenation requires molecular halogen, whereas FAD‐dependent halogenases form halogenated arenes with high regioselectivity while only halide salts and O₂ are required. This reaction proceeds at room temperature in aqueous media. However, enzymatic halogenation is considered inefficient, mainly because halogenases are not stable. Thus, the preparative application remained elusive. We were able to show that the long‐term stability and, hence, the preparative efficiency of the tryptophan‐7‐halogenase RebH can be significantly improved by immobilization together with the other enzymes required for cofactor regeneration. We established a facile scalable method suitable for the halogenation of tryptophan and its derivatives on a gram scale using a solid, multifunctional, and recyclable biocatalyst; this immobilization strategy might also be applicable for other FAD‐dependent halogenases.