Diastereodivergent Desymmetric Annulation to Access Spirooxindoles: Chemical Probes for Mitosis

Spirooxindoles have emerged as promising architec-tures for engineering biologically active compounds. The diaster-eodivergent 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.

Automated summary

In this study, a unique catalytic synthesis method was reported, which involved diastereodivergent [3 + 3] annulation of oxabicyclic alkenes with enals enabled by N-heterocyclic carbene (NHC)/Rh cooperative catalysis. Enantiomerically enriched spirooxindole lactones were obtained with excellent enantioselectivities and diastereoselectivities. These compounds showed significant effects on cell division and exhibited potent antiproliferative activities against HeLa cells. The absolute and relative configurations of the stereoisomers also played a crucial role in their bioactivities, highlighting the importance of catalytic asymmetric diastereodivergent synthesis in exploring structure-activity relationships.