Enzymatic Halogenation: A Timely Strategy for Regioselective C−H Activation

Abstract

Halogenating enzymes are increasingly attracting attention for biocatalytic C-H functionalization. Despite its importance for synthetic chemistry, selective introduction of halogens using conventional approaches often remains challenging, whereas biocatalysis offers excellent catalyst-controlled selectivity without requiring protecting groups or hazardous reagents. Owing to the high prevalence of halogenated secondary metabolites, a still growing repertoire of halogenases has been identified. Recently, flavin-dependent tryptophan halogenases came into focus for synthetic use. Nevertheless, these enzymes still suffer from severe deficiencies. Herein, current attempts in optimizing tryptophan halogenases have been compiled. Enzyme discovery, structure elucidation and mechanisms are reviewed with focus on biosynthesis of halogenated arenes. Emphasis is also given to random and rational engineering, high-throughput screening and implementation of halogenases into one-pot processes.

Flavin‐Dependent Halogenases from Xanthomonas campestris pv. campestris B100 Prefer Bromination over Chlorination

“…[4] Halogenated secondary metabolites with antibacterial, antifungal, or antitumor activity have been isolated from different organisms like bacteria, fungi, algae or plants, [5][6][7][8] which sparked investigations on their bio-synthesis, in particular on the key step, the enzymatic halogenation. [9] As chloride is the most abundant halide in the geosphere, chlorinated natural products prevail over other halogenated compounds. Enzymatic halogenation follows different chemical strategies and the halogenases can thus be classified according to their mechanisms of action.…”

“…While haloperoxidases use hydrogen peroxide for that purpose, [14] flavin-dependent halogenases convert molecular oxygen into a flavin hydroperoxide intermediate. [9] Recently, enzymes have been getting more and more involved in chemical conversions due to their remarkable specificity and selectivity. The selective halogenation of non-activated CH bonds that only relies on halide salts and oxygen under ambient conditions certainly is a 'dream reaction' of organic chemistry.…”

Bergmann Medal: R. T. Raines / Bergmann Young Investigator Award: C. Schnepel / Bessel Award: S. T. Liddle

“…His recent investigations include the discovery and engineering of various biocatalysts along with the development of novel enzyme functions towards multistep reaction cascades. He reported in Angewandte Chemie on a fluorescence screening for halogenases based on Suzuki cross‐coupling suitable to evolve enzyme efficiency, and he published a Minireview in Chemistry—A European Journal on the significance of halogenating enzymes for synthesis …”

The Mechanism of Sugar C−H Bond Oxidation by a Flavoprotein Oxidase Occurs by a Hydride Transfer Before Proton Abstraction

“…The high efficiency and selectivity of these enzymes can eliminate the cost of product purification and environmental cleanup that is generally required for harsh chemical processes. These factors have led to the increased use of enzymes as biocatalysts in both preparative and industrial scale applications …”

“…These factorsh ave led to the increasedu se of enzymesa sb iocatalystsi nb oth preparative and industrial scale applications. [9,[15][16][17] The functionalization of CÀHb onds throughahydride transfer mechanism, as occurs in various enzymes, has received significant attention in theoretical and experimental investigations, [18][19][20][21][22][23] because understanding the reaction mechanisms underlying CÀHo xidation in these enzymes is instrumental for devising efficient industrial biocatalysts. CÀHb ond oxidation can be catalyzedb ym any flavoenzymes by the simple transfer of ah ydride equivalent to their flavin cofactors such as those in the reactions of alcohold ehydrogenase, [24] choline oxidase, [25] choline dehydrogenase, [26] amine oxidases, [27,28] vanillyl-alcohol oxidase, [29] aryl-alcohol oxidase, [30] cholesterol oxidase, [31] 5-hydroxymethylfurfural oxidase, [32] ands ugar oxidase.…”