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Abstract
Single-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole structural motif is common to a range of bioactive compounds; however, asymmetric synthesis of this motif is complicated due to the presence of multiple chiral centres. The development of organocatalytic cascade reactions has proven to be valuable for the construction of several chiral centres in one step. Here, we describe a newly designed organocatalytic asymmetric domino Michael–aldol reaction between 3-substituted oxindoles and methyleneindolinones that affords complex bispirooxindoles. This reaction was catalysed by a novel multifunctional organocatalyst that contains tertiary and primary amines and thiourea moieties to activate substrates simultaneously, providing extraordinary levels of stereocontrol over four stereocentres, three of which are quaternary carbon stereocentres. This new methodology provides facile access to a range of multisubstituted bispirocyclooxindole derivatives, and should be useful in medicinal chemistry and diversity-oriented syntheses of this intriguing class of compounds. Spirooxindoles are important structural motifs found in an array of bioactive compounds. Here a Michael–aldol domino reaction for the construction of bispirooxindoles is presented, creating four stereocentres, including three quaternary carbon centres. Novel multifunctional organocatalysts have been developed for this transformation.Cite this article
Tan, B., Candeias, N. & Barbas, C. Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst. Nature Chem 3, 473–477 (2011). https://doi.org/10.1038/nchem.1039 