N-heterocyclic carbene catalyzed [2+3] annulation reaction for the synthesis of trifluoroethyl 3,2′-spirooxindole γ-lactam

Asymmetric catalytic processes promoted by N-heterocyclic carbenes (NHCs) hold great potential for the sustainable preparation of chiral molecules. However, catalyzing the reactions by manipulating the reactive intermediates is challenging. We report herein that the known NHC-catalyzed [3 + 2] annulation reaction between ketimine and enal can also be turned into a [2 + 3] annulation reaction for the highly enantioselective direct synthesis of trifluoroethyl 3,2 '-spirooxindole gamma-lactams (4) through timely catalysis of the intermediates. DFT calculations revealed that this transformation included the key step of the nucleophilic attack of the Breslow intermediate M2 derived from NHC and enal (2) to the unattacked ketimine (1). Our study demonstrates that it is possible to tune the desired selectivities through the dynamic catalysts of the reactive intermediates. The addition of NHC catalysts in enals reverses normal reactivity by the formation of Breslow intermediates that act as prenucleophiles, which enable asymmetric selective intermolecular [2 + 3] annulation reaction with ketimines.