Mechanistic insights into NHC/Cu catalyzed asymmetric synthesis of spirooxindoles: origins of enantioselectivity and diastereoselectivity

Abstract

Density functional theory (DFT) calculations were conducted to elucidate the mechanism of NHC/Cu catalyzed enantioselective annulation between isatin-derived enals and ethynyl carbonates, enabling the asymmetric synthesis of spirooxindole δ-lactones with vicinal all-carbon quaternary stereocenters. The catalytic process involves four key stages: (i) generation of an azolium homoenolate intermediate IM3 via NHC-mediated nucleophilic addition to enal 1a; (ii) [Cu]-catalyzed decarboxylation of ethynyl carbonate 2a to afford the copper-alkynyl intermediate IM7; (iii) stereoselective C–C bond formation between IM3 and IM7, followed by a two-water-mediated enol–keto tautomerization yielding the ketone intermediate IM10; and (iv) NEt₃-promoted deprotonation, intramolecular cyclization, and proton transfer affording the product spirooxindole δ-lactone 3a. Notably, both the enantio- and diastereoselectivity-determining step and the rate-determining step occur in Stage III. Furthermore, DIAS and QTAIM analyses of four stereoisomeric transition states identified TS5(S,R) as the most favorable, exhibiting the lowest free energy barrier and multiple stabilizing non-covalent interactions (C–H⋯π, C–H⋯O, C–F⋯π, and Cu⋯H), rationalizing the observed high stereoselectivity. Water molecules are shown to play a crucial role in lowering the barrier of the rate-determining step by enhancing electrostatic, orbital, and dispersion interactions. This study not only deepens the mechanistic understanding of cooperative NHC/Cu catalysis but also provides valuable theoretical guidance for rational designing of next-generation asymmetric annulation reactions.