Group Transfer to an Aliphatic Bond: A Biomimetic Study Inspired by Nonheme Iron Halogenases

Amy Timmins,Sam P De Visser,Matthew G Quesne,Tomasz Borowski

doi:10.1021/acscatal.8b01673

Abstract

In this work, we predict a group-transfer reaction to an aliphatic substrate on a biomimetic nonheme iron center based on the structural and functional properties of nonheme iron halogenases. Transferring groups other than halogens to C–H bonds on the same catalytic center would improve the versatility and applicability of nonheme iron halogenases and enhance their use in biotechnology; however, few studies have been reported on this matter. Furthermore, very few biomimetic models are known that are able to transfer halogens or other groups to aliphatic C–H bonds. To gain insight into group transfer to an aliphatic C–H bond, we performed a detailed computational study on a biomimetic nonheme iron complex and studied the reactivity patterns with a model substrate (ethylbenzene). In particular, we investigated the reaction mechanisms of [FeIV(O)(TPA)X]+, TPA = tris(2-pyridylmethy1)amine, and X = Cl, NO2, N3 with ethylbenzene leading to 1-phenylethanol and 1-phenyl-1-X-ethane products. Interestingly, we find...

Highlights

In Nature, halogenases catalyze the addition of a halogen atom to a wide variety of molecular scaffolds including aromatic and heterocyclic rings, olefinic sites, and unactivated aliphatic carbon centers.[1]
The halogen-transfer enzymes are subdivided into several classes, the largest being the haloperoxidases that utilize hydrogen peroxide and react on either a heme, a vanadium cofactor, or a flavin group to halogenate a variety of electron-rich carbon centers.2b,3 In addition to these haloperoxidases, there is a second group of halogen-transfer enzymes, namely the αketoglutarate dependent halogenases, that react through a radical mechanism
In natural halogenases and biomimetic halogenase systems, several mechanisms were proposed for the bifurcation pathways leading to substrate hydroxylation and halogenation; see Scheme 2.11,16,19 To find out whether nitration and azidation would be possible on the same iron(IV)−oxo complex, we investigated the same reaction scheme for these processes for the reaction of ethylbenzene by [FeIV(O)(TPA)(X)]+ with X = NO2−/N3−

Summary

Introduction

In Nature, halogenases catalyze the addition of a halogen atom to a wide variety of molecular scaffolds including aromatic and heterocyclic rings, olefinic sites, and unactivated aliphatic carbon centers.[1] more than 4500 naturally occurring halogenated compounds have been identified already.[2] The halogen-transfer enzymes are subdivided into several classes, the largest being the haloperoxidases that utilize hydrogen peroxide and react on either a heme, a vanadium cofactor, or a flavin group to halogenate a variety of electron-rich carbon centers.2b,3 In addition to these haloperoxidases, there is a second group of halogen-transfer enzymes, namely the αketoglutarate (αKG) dependent halogenases, that react through a radical mechanism. Experimental studies showed the αKG-dependent halogenases to react via a rate-determining hydrogen atom abstraction from aliphatic (sp3-hybridized) carbon atoms.[4] The αKG-dependent oxidases are an extremely diverse and useful class of biocatalysts, with members of this superfamily involved in biological pathways as varied as antibiotic biosynthesis and toxin metabolism.[5]

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