Sharma Manik, Patton Zoe E, Shoemaker Carlie R, Bacsa John, Biegasiewicz Kyle F
Department of Chemistry, Emory University, 1515 Dickey Dr, Atlanta, GA, 30322.
School of Molecular Sciences, Arizona State University, 551 E University Dr, Tempe, AZ, 85281.
Angew Chem Int Ed Engl. 2024 Dec 9;63(50):e202411387. doi: 10.1002/anie.202411387. Epub 2024 Oct 30.
Nitrogen-containing compounds are valuable synthetic intermediates and targets in nearly every chemical industry. While methods for nitrogen-carbon and nitrogen-heteroatom bond formation have primarily relied on nucleophilic nitrogen atom reactivity, molecules containing nitrogen-halogen bonds allow for electrophilic or radical reactivity modes at the nitrogen center. Despite the growing synthetic utility of nitrogen-halogen bond-containing compounds, selective catalytic strategies for their synthesis are largely underexplored. We recently discovered that the vanadium-dependent haloperoxidase (VHPO) class of enzymes are a suitable biocatalyst platform for nitrogen-halogen bond formation. Herein, we show that VHPOs perform selective halogenation of a range of substituted benzamidine hydrochlorides to produce the corresponding N'-halobenzimidamides. This biocatalytic platform is applied to the synthesis of 1,2,4-oxadiazoles from the corresponding N-acylbenzamidines in high yield and with excellent chemoselectivity. Finally, the synthetic applicability of this biotechnology is demonstrated in an extension to nitrogen-nitrogen bond formation and the chemoenzymatic synthesis of the Duchenne muscular dystrophy drug, ataluren.
含氮化合物是几乎每个化学工业中都很有价值的合成中间体和目标产物。虽然氮-碳键和氮-杂原子键形成的方法主要依赖于亲核氮原子的反应性，但含氮-卤键的分子在氮中心允许亲电或自由基反应模式。尽管含氮-卤键化合物的合成用途不断增加，但其合成的选择性催化策略在很大程度上仍未得到充分探索。我们最近发现，依赖钒的卤过氧化物酶（VHPO）类酶是用于形成氮-卤键的合适生物催化剂平台。在此，我们表明VHPO对一系列取代的盐酸苯甲脒进行选择性卤化，以产生相应的N'-卤代苯并咪唑酰胺。该生物催化平台被应用于从相应的N-酰基苯甲脒高产率且具有优异化学选择性地合成1,2,4-恶二唑。最后，这种生物技术的合成适用性在氮-氮键形成的扩展以及杜兴氏肌肉营养不良症药物阿他鲁伦的化学酶促合成中得到了证明。
