Diastereodivergent Desymmetric Annulation to Access Spirooxindoles: Chemical Probes for Mitosis

Abstract

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.

Synergistic Catalysis Involving Palladium for Stereodivergent Csp3–Csp3 Coupling Reactions

“…It would be more appealing if less active but readily available simple alkenes or alkynes could undergo Csp3–Csp3 coupling reactions for stereodivergent synthesis. Another challenge is that while iridium- and palladium-involved synergistic catalyses have proven to be successful in stereodivergent synthesis, expanding the scope to other transition-metal-related synergistic catalysis is attractive. − Additionally, despite the achievements in constructing vicinal stereocenters, the stereodivergent preparation of 1, n -remote multistereocenters with a single transformation is still limited. − Finally, gaining mechanistic insights into the origins of the stereochemistry, especially understanding how the two catalysts cooperate with each other in the synergistic system, is highly desirable. However, due to the complexity of the system, theoretical studies in this field are still in their infancy. − …”

Synergistic Dual Catalysis in Stereodivergent Synthesis

“…The same group also disclosed the feasibility of merging NHC catalysis with Rh-catalyzed asymmetric ring-opening (ARO) reactions (Scheme ). Transition-metal-catalyzed ARO reactions proceeded through the generation of an electrophilic species (for example, Rh- 62 ) via desymmetric oxidative addition of low valent transition-metal into a bridge-head C–O bond. Gong and co-workers demonstrated that the key intermediate Rh- 62 could be trapped by an NHC-homoenolate 63 , and the two thus-generated stereocenters in this coupling step were almost fully and independently controlled by Rh­(I)/ L13 and NHC 50 , respectively.…”

Recent Advances in Nucleophilic Lewis Base‐Catalyzed Cycloadditions for Synthesis of Spirooxindoles

“…It is worth pointing out that four stereoisomers of the spirooxindole products were obtaineded with high diastereoselectivity and enantioselectivity by only switching the enantiomeric pairs of the two catalysts (Scheme 57). [96] Control experiments suggested that the competing ligation between the NHC catalyst and the rhodium center probably occurred to somewhat quench the catalytic activity of the rhodium complex and NHC. In addition, biological investigations revealed this novel class of spirooxindoles inhibiting mitotic progression against HeLa cells.…”