Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products

Abstract

In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3′-pyrrolidinyl spirooxindoles—which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1–3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF6(CH3CN)4. Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity.

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Figure 1: Structures of a representative bioactive natural product structure with 3,3′-pyrrolidinyl-spirooxindole and a non-natural bioactive compound.
Figure 2: Representative enantioselective 1,3-dipolar cycloaddition between an arylidene oxindole and an amino acid ester imine in the presence of a chiral catalyst, and proposed rational for the observed stereocontrol.
Figure 3: Biological evaluation of cycloadduct (−)-6k.

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Acknowledgements

The authors thank T. U. Mayer for helpful discussions and B. Vogelstein for the HCT116 p53+/+ and p53 −/− cell lines. This work was supported by the German Federal Ministry for Education and Research through the German National Genome Research Network-Plus (NGFN-Plus) (Grant No. BMBF 01GS08102).

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A.P.A. designed and carried out chemical experiments. C.G-R. and M.C. performed biological and biochemical experiments. M.S. and H.P. carried out the X-ray crystallographic analysis. H.W., D.R. and S.Z. designed experiments and supervised the project. All authors discussed the results and commented on the manuscript. H.W., D.R., S.Z. and A.P.A. wrote the manuscript.

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Correspondence to Herbert Waldmann.

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The authors declare no competing financial interests.

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Crystallographic data for compound 5a (CIF 19 kb)

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Antonchick, A., Gerding-Reimers, C., Catarinella, M. et al. Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nature Chem 2, 735–740 (2010). https://doi.org/10.1038/nchem.730

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