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Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst

Nature Chemistry volume 3, pages 473–477 (2011)Cite this article

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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.

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Figure 1: Overview of spirooxindoles and a strategy for their preparation.
Figure 2: Further exploration of substrates involving methyleneindolinone esters.
Figure 3: Preparation of enantiomer (1R,2R,3S,4R)-3b.
Figure 4: Investigation of a different protecting group and deprotection of bispirooxindole.

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Acknowledgements

The authors acknowledge the Skaggs Institute for Chemical Biology for funding. N.R.C. thanks Fundação para a Ciência e Tecnologia (SFRH/BPD/46589/2008) for financial support. The authors also thank A.L. Rheingold for X-ray crystallographic analysis.

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Authors and Affiliations

  1. The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Bin Tan, Nuno R. Candeias & Carlos F. Barbas III

  2. Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa

    Nuno R. Candeias

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  1. Bin Tan
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Contributions

B.T. and N.C. designed and carried out the chemical experiments. C.B. designed the experiments and supervised the project. All authors discussed the results, contributed to writing the manuscript, and commented on the manuscript.

Corresponding author

Correspondence to Carlos F. Barbas III.

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The authors declare no competing financial interests.

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Crystallographic data for compound 3e (CIF 22 kb)

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Crystallographic data for compound 3p (CIF 29 kb)

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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

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