Recent Advances in Flavin-Dependent Halogenase Biocatalysis: Sourcing, Engineering, and Application

Abstract

The introduction of a halogen atom into a small molecule can effectively modulate its properties, yielding bioactive substances of agrochemical and pharmaceutical interest. Consequently, the development of selective halogenation strategies is of high technological value. Besides chemical methodologies, enzymatic halogenations have received increased interest as they allow the selective installation of halogen atoms in molecular scaffolds of varying complexity under mild reaction conditions. Today, a comprehensive library of aromatic halogenases exists, and enzyme as well as reaction engineering approaches are being explored to broaden this enzyme family’s biocatalytic application range. In this review, we highlight recent developments in the sourcing, engineering, and application of flavin-dependent halogenases with a special focus on chemoenzymatic and coupled biosynthetic approaches.

Biocatalysis making waves in organic chemistry

“…C-H bonds have been receiving an increasing interest from the academic community. 232,233 Today, a range of highly selective halogenases (halogenating monooxygenases) and haloperoxidases are available. Scheme 27 gives a representative overview over the biocatalytic halogenation reactions available today.…”

Exploring the Biocatalytic Potential of Fe/α‐Ketoglutarate‐Dependent Halogenases

“…α‐Ketoglutarate‐dependent halogenases (αKGHs), which are the focus of this Concept paper, harness a radical mechanism, while the other known halogenases either follow an electrophilic or a nucleophilic mechanism. Even though the catalytic cycle of the latter two enzyme families has been extensively reviewed elsewhere, a brief overview of nature's alternative halogenation approaches is helpful to contextualize the unique synthetic advantages attainable through the halogenation strategy employed by αKGHs.…”

Recent Advances in Synthetic Application and Engineering of Halogenases

“…[7][8][9] In recent years, identification, application and engineering of halogenases has attracted growing interest with an increasing significance for site-selective CÀ H functionalization. [10,11] The broad utility of halogenated compounds in synthesis has promoted extensive efforts in development and optimization of alternative routes towards halogenation providing a safe and selective approach for the synthesis of haloarenes under benign reaction conditions. In living systems, a diverse array of halogenases catalyzes the incorporation of halogens.…”

“…S E Ar is a widely‐applied reaction type for arene functionalization that is of major importance for the synthesis of bulk and fine chemicals, yet control of regioselectivity and introduction of the halogen atom at electronically and mechanistically disfavored positions remain challenging . In recent years, identification, application and engineering of halogenases has attracted growing interest with an increasing significance for site‐selective C−H functionalization . The broad utility of halogenated compounds in synthesis has promoted extensive efforts in development and optimization of alternative routes towards halogenation providing a safe and selective approach for the synthesis of haloarenes under benign reaction conditions.…”