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3.6 Halogenases

DOI: 10.1055/sos-SD-216-00195

Grüschow, S.; Smith, D. R. M.; Gkotsi, D. S.; Goss, R. J. M.Science of Synthesis: Biocatalysis in Organic Synthesis, (20153313.

General Introduction

The introduction of a halogen into a molecule can be beneficial. Halogens often have profound effects on the physical properties of molecules by changing lipophilicity, electronics, and compound stability. Halogenation of a drug or agrochemical can affect bioactivity by altering the binding of drugs to their targets. Furthermore, increased lipophilicity may influence the bioavailability of a compound, and by blocking metabolic sites the half-life of the compound may be significantly increased.[‌1‌] A further use of halogens is to offer a chemical handle by which to derivatize the target compound without the need for protecting groups.[‌2‌] Nature provides many examples of halogen-containing natural products where most of the halogens are installed in a highly regiospecific manner, and some must have arisen through stereoselective enzymatic halogenation. For example, obtusenyne and maʼilione are isolated from Laurencia,[‌3‌,‌4‌] halomon from Portieria,[‌5‌] and the fimbrolides, such as 4-bromo-3-butyl-5-(dibromomethylene)furan-2(5H)-one, from Delisea[‌6‌] (Scheme 1), and further examples are given throughout this section. It is attractive to explore whether the catalytic potential that is offered by nature might be harnessed for synthetic purposes. In this section, we will briefly outline the issues of chemical halogenation, and then present an overview of the current understanding of halogenating enzymes and their applications.

Scheme 1 Natural Products from Marine Red Algae[‌3‌‌6‌]

Chemical halogenation by the direct use of dihalogens, often in conjunction with catalytic Lewis acids, is well established and widely applied in industry. However, this approach is far from ideal and is generally not applicable to the synthesis of fine chemicals at a laboratory scale due to issues with regioselectivity, stereoselectivity, and the handling of corrosive halogen gases.[‌7‌] As a result of the continuing desire to incorporate halogenated moieties in organic synthesis, a wide range of reagents and techniques have become available to more elegantly install these features. Synthetic targets are accessed via the halogenation of multiple bonds, aromatic systems, or activated carbon centers, or through eliminative processes such as halo-dehydroxylation.[‌8‌]

Whilst elemental bromine and iodine can be handled with relative ease in a standard synthetic laboratory, it is often preferable to use alternative sources of these halogens, ideally crystalline, bench-stable reagents. As elemental chlorine and especially fluorine are reactive and corrosive gases, working with these elements requires the use of specialized apparatus. To counter these difficulties, approaches such as the in situ generation of reactive halogenating species and halogen carrier reagents have seen widespread use.[‌8‌‌11‌] Perhaps reflecting the extreme difficulty of working with elemental fluorine in particular, a wide range of more readily handled fluorinating reagents are available, including diethylaminosulfur trifluoride (DAST) and aminodifluorosulfinium tetrafluoroborate (XtalFluor) reagents. However, the degree to which these alternative reagents are environmentally preferable or cost effective at the industrial scale is debatable.[‌9‌]

The stereoselective halogenation of alkenes and activated carbon centers is an emerging field of research, and elegant asymmetric transformations are continually reported in the literature.[‌12‌‌14‌] Approaches include the use of chiral catalysts and auxiliaries[‌15‌,‌16‌] alongside the development of chiral halogenating agents.[‌17‌,‌18‌] Diastereoselective intramolecular halocyclizations are better established and offer an attractive approach to the introduction of structural complexity, however enantioselective halocyclizations remain less common. A number of intermolecular alkene halogenations have been reported, using both stoichiometric and catalytic reagents, but asymmetric halogenation remains an area of work under development, and so far these reactions usually lack generality.[‌15‌,‌16‌]

Chemical and enzymatic strategies for halogenation are complementary; the chemical strategies can lack selectivity but are often widely applicable, whereas enzymatic halogenation can show exquisite regio- and stereoselectivity but have a more limited substrate scope. In the following sections enzymatic methods for electrophilic, nucleophilic, and radical halogenation are discussed.