Solvent-Enabled Organocatalyst-Assisted Enantioselective Regiodivergent Cascade Reactions: Overriding Intrinsic Reactivity of Vinylogous Pyrazolones

Enantioselective regiodivergent cascade reactions remain a significant challenge due to the dual requirement of achieving precise control over both regioselectivity and stereoselectivity. Herein, a quinine-derived bifunctional catalyst-driven strategy is presented for constructing the diverse asymmetric polycyclic spiro-pyrazolone scaffolds in a cascade manner. The cascade reaction is initiated by the asymmetric vinylogous Michael addition (VMA) of arylidene pyrazolones to the indandione-derived acceptors, followed by regioselective transformations that lead to structurally diverse products. The divergent reaction outcomes are governed by the interaction between the in situ generated conjugate acid of the catalyst and the anionic intermediate (VMA adduct). These outcomes are further modulated by adjustments in the reaction conditions, particularly the polarity of the solvent. In toluene, the reaction predominantly yields the cage product with excellent regio- and enantioselectivity via a cascade pathway involving asymmetric VMA/acetalization/oxa-Michael/Michael addition. In contrast, in MeCN, the reaction proceeds through an asymmetric VMA/proton transfer/aldol/acetalization, furnishing the fused product. Mechanistic studies reveal that the formation of the fused product involves an unusual and reversible reaction pathway. Specifically, the catalyst-controlled 1,6-conjugate addition of 1,3-indandione to the diene intermediate occurs under optimal conditions. This strategy demonstrates a versatile foundation for asymmetric regiodivergent cascade reactions.