杂芳族N-氧化物,以其高度极性的N-O键和坚固的结构而闻名,自发现米诺地尔以来,表现出显著的生物活性,并在各种药物开发项目中发挥了关键作用。此外,杂芳族N-氧化物,具有轴向手性双芳基骨架,是有机合成中不可缺少的路易斯碱催化剂和配体。尽管它们很重要,合成这些手性化合物具有挑战性,需要手性起始材料或拆分过程。催化策略依赖于杂芳族N-氧化物化合物的官能化,导致骨骼多样性相对有限的产品。这项研究介绍了一种通过从头杂芳族N-氧化物环形成来合成联芳基N-氧化物的Cu催化的偏选择性方法。这种温和有效的方法实现了优异的立体选择性(高达99:1er),能够用新型杂芳族支架生产广泛的N-氧化物。轴向手性N-氧化物产物3f表现出作为路易斯碱催化剂的高立体选择性和可循环利用性。此外,产品3e对三阴性乳腺癌具有良好的治疗效果,MDA-MB-231和MDA-MB-468细胞的IC50值为4.8和5.2μm,分别。这项研究不仅推进了具有挑战性的手性杂芳族N-氧化物的合成,而且还鼓励在发现生物活性小分子方面进一步探索N-氧化物实体。
Heteroaromatic N-oxides, renowned for their highly polar N─O bond and robust structure, exhibit significant bioactivities and have played a pivotal role in various drug development projects since the discovery of Minoxidil. Moreover, heteroaromatic N-oxides, featuring axially chiral biaryl frameworks, are indispensable as Lewis base catalysts and ligands in organic synthesis. Despite their importance, synthesizing these chiral compounds is challenging, necessitating chiral starting materials or resolution processes. Catalytic strategies rely on the functionalization of heteroaromatic N-oxide compounds, leading to products with a relatively limited skeletal diversity. This study introduces a Cu-catalyzed atroposelective method for synthesizing biaryl N-oxides via de novo heteroaromatic N-oxide ring formation. This mild and efficient approach achieves excellent stereoselectivities (up to 99:1 er), enabling the production of a wide array of N-oxides with novel heteroaromatic scaffolds. The axially chiral N-oxide product 3f demonstrates high stereoselectivity and recyclability as a Lewis base catalyst. Additionally, product 3e exhibits promising therapeutic efficacy against triple-negative breast cancer, with IC50 values of 4.8 and 5.2 µm in MDA-MB-231 and MDA-MB-468 cells, respectively. This research not only advances the synthesis of challenging chiral heteroaromatic N-oxides but also encourages further exploration of N-oxide entities in the discovery of bioactive small molecules.