Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N‐heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N‐tosylaziridines by [3+3] annulation with isatin‐derived enals, leading to highly enantioenriched N‐tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.
Despite that asymmetric stereodivergent synthesis has experienced great success to provide unusual processes for the creation of chirality complexity, concepts appliable to asymmetric stereodivergent catalysis are still limited. The dependence on the unusual capacity of each catalyst to precisely control the reactive site planar in the region poses unparalleled constraints on this field. Here, we first demonstrate that the chiral Cu-allenylidene species can participate in the stereodivergent propargylic alkylation of enals, in concert with chiral N-heterocyclic carbenes (NHCs). Thus, all four stereoisomers were obtained with excellent enantioselectivity and diastereoselectivity (up to >99% e.e. and >95:5 d.r.) from the same starting materials by simply altering chiral Cu-Pybox complex and NHC combinations. The rich chemistry workable in the products enables the structurally diverse synthesis of chiral functional molecules and holds great potential in alkaloid synthesis, as showcased by the preparation of the key building block to access (-)-perophoramidine.
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.
Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N‐heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N‐tosylaziridines by [3+3] annulation with isatin‐derived enals, leading to highly enantioenriched N‐tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.
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