Wen Yu-Hua, Yang Fengrui, Li Shuai, Yao Xuebiao, Song Jin, Gong Liu-Zhu
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.
MOE Key Laboratory for Cellular Dynamics and Hefei National Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
J Am Chem Soc. 2023 Feb 13. doi: 10.1021/jacs.2c12648.
Spirooxindoles have emerged as promising architectures for engineering biologically active compounds. The diastereodivergent construction of unique scaffolds of this type with full control of continuous chiral centers including an all-carbon quaternary stereogenic center is yet to be developed. Here, we report an unprecedented diastereodivergent desymmetric [3 + 3] annulation of oxabicyclic alkenes with enals enabled by N-heterocyclic carbene (NHC)/Rh cooperative catalysis, leading to a series of enantiomerically enriched spirooxindole lactones with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >95:5 dr). The combined catalyst system comprises a rhodium complex that controls the configuration at the electrophilic carbon and an NHC catalyst that controls the configuration at the nucleophilic oxindole-containing carbon; thus, four stereoisomers of the spirooxindole products can be readily obtained simply by switching the configurations of the two chiral catalysts. Transformations of the chiral spirooxindoles delivered synthetically useful compounds. Importantly, those chiral spirooxindoles arrested mammalian cells in mitosis and exhibited potent antiproliferative activities against HeLa cells. Significantly, both absolute and relative configurations exert prominent effects on the bioactivities, underscoring great importance of catalytic asymmetric diastereodivergent synthesis beyond creating useful tools for the exploration of structure-activity relationships.
螺环氧化吲哚已成为构建生物活性化合物的有前景的结构单元。目前尚未开发出能完全控制包括全碳季碳立体中心在内的连续手性中心的此类独特骨架的非对映选择性构建方法。在此，我们报道了一种前所未有的通过N - 杂环卡宾（NHC）/铑协同催化实现的氧杂双环烯烃与烯醛的非对映选择性去对称[3 + 3]环化反应，得到了一系列对映体富集的螺环氧化吲哚内酯，具有优异的对映选择性（高达>99% ee）和非对映选择性（高达>95:5 dr）。组合催化剂体系包括控制亲电碳构型的铑配合物和控制含亲核氧化吲哚碳构型的NHC催化剂；因此，只需切换两种手性催化剂的构型，就能轻松得到螺环氧化吲哚产物的四种立体异构体。手性螺环氧化吲哚的转化生成了具有合成用途的化合物。重要的是，那些手性螺环氧化吲哚使哺乳动物细胞停滞在有丝分裂期，并对HeLa细胞表现出强大的抗增殖活性。值得注意的是，绝对构型和相对构型都对生物活性有显著影响，这突出了催化不对称非对映选择性合成的重要性，其意义远不止于为探索构效关系创造有用工具。
