Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Angew Chem Int Ed Engl. 2024 Mar 22;63(13):e202317860. doi: 10.1002/anie.202317860. Epub 2024 Feb 19.
Single component flavin-dependent halogenases (FDHs) possess both flavin reductase and FDH activity in a single enzyme. We recently reported that the single component FDH AetF catalyzes site-selective bromination and iodination of a variety of aromatic substrates and enantioselective bromolactonization and iodoetherification of styrenes bearing pendant carboxylic acid or alcohol substituents. Given this inherent reactivity and selectivity, we explored the utility of AetF as catalyst for alkene and alkyne C-H halogenation. We find that AetF catalyzes halogenation of a range of 1,1-disubstituted styrenes, often with high stereoselectivity. Despite the utility of haloalkenes for cross-coupling and other applications, accessing these compounds in a stereoselective manner typically requires functional group interconversion processes, and selective halogenation of 1,1'-disubstituted olefins remains rare. We also establish that AetF and homologues of this enzyme can halogenate terminal alkynes. Mutagenesis studies and deuterium kinetic isotope effects are used to support a mechanistic proposal involving covalent catalysis for halogenation of unactivated alkynes by AetF homologues. These findings expand the scope of FDH catalysis and continue to show the unique utility of single component FDHs for biocatalysis.
单组分黄素依赖型卤化酶（FDH）在单个酶中同时具有黄素还原酶和 FDH 活性。我们最近报道，单组分 FDH AetF 可以催化各种芳香族底物的选择性溴化和碘化，以及带有侧羧酸或醇取代基的苯乙烯的对映选择性溴内酯化和碘醚化。鉴于这种固有反应性和选择性，我们探索了 AetF 作为烯烃和炔烃 C-H 卤化催化剂的用途。我们发现 AetF 可以催化一系列 1,1-二取代苯乙烯的卤化，通常具有高立体选择性。尽管卤代烯烃在交叉偶联和其他应用中很有用，但以立体选择性方式获得这些化合物通常需要官能团转化过程，并且 1,1'-二取代烯烃的选择性卤化仍然很少见。我们还确定 AetF 和这种酶的同源物可以卤化末端炔烃。突变研究和氘动力学同位素效应用于支持涉及 AetF 同源物对未活化炔烃的共价催化的卤化的机理建议。这些发现扩展了 FDH 催化的范围，并继续展示了单组分 FDH 在生物催化中的独特用途。
