Montua Nicolai, Sewald Norbert
Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, 33615, Bielefeld, Germany.
Chembiochem. 2024 Dec 2;25(23):e202400496. doi: 10.1002/cbic.202400496. Epub 2024 Oct 27.
Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.
黄素依赖性卤化酶（FDHs）是研究最为广泛的卤化酶，在生物转化应用中显示出巨大潜力。这些酶利用氯离子、溴离子或碘离子作为卤素供体，催化富电子芳基部分的需氧卤化反应，在此过程中需要化学计量的FADH。这使得FDH催化的芳基卤化成为合成芳基卤化物的一种高度选择性且环境友好的工具。而芳基卤化物反过来又作为过渡金属催化的用于形成碳 - 碳键的交叉偶联反应的有价值中间体。先前的研究广泛使用这种方法将小分子卤化，作为过渡金属催化的交叉偶联反应进行后期功能化的构建模块。基于这些结果，在过去两年中，有几个研究团队成功地将这项研究扩展到了蛋白质靶点。他们的工作表明了一种新兴的生物共轭方法，即利用后期生物催化卤化结合生物正交的铃木 - 宫浦交叉偶联反应。由于连接生成的联芳基部分的碳 - 碳键的稳定性以及后期酶促修饰的简便性，同时在温和条件下保持优异的选择性，这种策略可能为现有方法提供一种有吸引力的替代方案。
