Sharma Manik, Pascoe Cameron A, Jones Stacey K, Barthel Sophia G, Davis Katherine M, Biegasiewicz Kyle F
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
School of Molecular Sciences, Arizona State University, Tempe, Arizona 85281, United States.
J Am Chem Soc. 2025 Mar 26;147(12):10698-10705. doi: 10.1021/jacs.5c01175. Epub 2025 Mar 12.
The enzymatic synthesis of heterocycles is an emerging biotechnology for the sustainable construction of societally important molecules. Herein, we describe an enzyme-mediated strategy for the oxidative dimerization of thioamides enabled by enzymatic halide recycling by vanadium-dependent haloperoxidase enzymes. This approach allows for intermolecular biocatalytic bond formation using a catalytic quantity of halide salt and hydrogen peroxide as the terminal oxidant. The established method is applied to a diverse range of thioamides to generate the corresponding 1,2,4-thiadiazoles in moderate to high yields with excellent chemoselectivity. Mechanistic experiments suggest that the reaction proceeds through two distinct enzyme-mediated sulfur halogenation events that are critical for heterocycle formation. Molecular docking experiments provide insight into reactivity differences between biocatalysts used in this study. Finally, the developed biocatalytic oxidative dimerization is applied to a preparative scale chemoenzymatic synthesis of the anticancer agent penicilliumthiamine B. These studies demonstrate that enzymatic halide recycling is a promising platform for intermolecular bond formation.
杂环的酶促合成是一种新兴的生物技术，用于可持续构建具有社会重要性的分子。在此，我们描述了一种酶介导的策略，用于硫代酰胺的氧化二聚反应，该反应由钒依赖性卤过氧化物酶的酶促卤化物循环实现。这种方法允许使用催化量的卤化物盐和过氧化氢作为终端氧化剂进行分子间生物催化键的形成。所建立的方法应用于多种硫代酰胺，以中等至高收率生成相应的1,2,4-噻二唑，具有优异的化学选择性。机理实验表明，该反应通过两个不同的酶介导的硫卤化事件进行，这对杂环形成至关重要。分子对接实验深入了解了本研究中使用的生物催化剂之间的反应性差异。最后，所开发的生物催化氧化二聚反应应用于抗癌剂青霉硫胺B的制备规模化学酶促合成。这些研究表明，酶促卤化物循环是分子间键形成的一个有前途的平台。
