CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, P. R. China.
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, P. R. China.
J Am Chem Soc. 2022 Nov 2;144(43):19932-19941. doi: 10.1021/jacs.2c08090. Epub 2022 Oct 21.
Searching for efficient strategies to access structurally novel aminoindolines is of great significance for drug discovery. However, catalytic asymmetric de novo construction of aminoindoline scaffolds with functionality primed for diversification still remains elusive. Here, we report a Cu-catalyzed asymmetric cyclization of ethynyl benzoxazinones with amines, producing chiral 3-aminoindolines in good yield and with high enantioselectivity (up to 97% yield and 98:2 er). Moreover, a radical-mediated sulfonyl migration of these products was unexpectedly found, further affording new chiral 3-aminoindolines bearing alkenyl sulfonyl groups with retained enantiopurity (up to 84% yield and 98:2 er). Bioactivity evaluations indicate that these 3-aminoindolines show notable antitumor activities and chirality is proven to have a significant impact on their antitumor activity.
寻找有效的策略来获得结构新颖的氨基吲哚啉对于药物发现具有重要意义。然而，具有功能多样性潜力的氨基吲哚啉支架的催化不对称从头构建仍然难以捉摸。在这里，我们报告了一种铜催化的炔基苯并恶嗪酮与胺的不对称环化反应，以高产率和高对映选择性（高达 97%的产率和 98:2 的对映选择性）得到手性 3-氨基吲哚啉。此外，还意外地发现了这些产物的自由基介导的砜基迁移，进一步得到了保留对映纯度的新型手性 3-氨基吲哚啉，具有烯基砜基（高达 84%的产率和 98:2 的对映选择性）。生物活性评价表明，这些 3-氨基吲哚啉具有显著的抗肿瘤活性，并且手性被证明对其抗肿瘤活性有重大影响。
