Article | Published:

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

Nature Chemistry volume 2, pages 735740 (2010) | Download Citation

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.

  • Compound C15H11NO

    (E)-3-Benzylidene-2-oxindole

  • Compound C10H10BrNO2

    N-(4-Bromobenzylidene)-glycine methyl ester

  • Compound C25H21BrN2O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H21BrN2O3

    Methyl (2’R,3R,4’S,5’R)-2’-(4-bromophenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C26H23BrN2O4

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-4’-(4-methoxyphenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H20BrFN2O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-4’-(4-fluorophenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H20BrFN2O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-4’-(3-fluorophenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H20BrFN2O3

    Methyl (2’R,3S,4’S,5’R)-2’-(4-bromophenyl)-4’-(2-fluorophenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H19Br2ClN2O3

    Methyl (2’R,3S,4’R,5’R)-2’,4’-bis(4-bromophenyl)-5-chloro-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C29H24BrF4N3O3

    Methyl (2’R,3S,4’S,5’R)-2’-(4-bromophenyl)-4’-(2,3,5,6-tetrafluoro-4-(pyrrolidin-1-yl)phenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C23H19BrN2O4

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-4’-(2-furyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C21H19BrN2O5

    Dimethyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-4’,5’-dicarboxylate

  • Compound C23H25BrN2O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-2-oxo-4’-isobutyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C28H27BrN2O6

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromophenyl)-4’-(3,4,5-trimethoxyphenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C28H27BrN2O6

    Methyl rel-(2’S,3S,4’R,5’S)-2’-(4-bromophenyl)-4’-(3,4,5-trimethoxyphenyl)-2-oxo-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C26H21F3N2O3

    Methyl (2’R,3S,4’R,5’R)-2-oxo-4’-phenyl-2’-[4-(trifluoromethyl)phenyl]-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C26H21N3O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-cyanophenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H21ClN2O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-chlorophenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H20BrFN2O3

    Methyl (2’R,3S,4’R,5’R)-2’-(4-bromo-3-fluorophenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H20Cl2N2O3

    Methyl (2’S,3S,4’R,5’R)-2’-(2,3-dichlorophenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C26H23BrN2O5

    Methyl (2’S,3S,4’R,5’R)-2’-(2-bromo-3-hydroxy-4-methoxyphenyl)-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

  • Compound C25H28N2O3

    Methyl (2’R,3S,4’R,5’R)-2’-cyclohexyl-2-oxo-4’-phenyl-1,2-dihydrospiro[indole-3,3’-pyrrolidine]-5’-carboxylate

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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).

Author information

Affiliations

  1. Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany

    • Andrey P. Antonchick
    • , Claas Gerding-Reimers
    • , Slava Ziegler
    •  & Herbert Waldmann
  2. Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany

    • Andrey P. Antonchick
    • , Claas Gerding-Reimers
    •  & Herbert Waldmann
  3. Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany

    • Daniel Rauh
  4. Universität Konstanz, Konstanz Research School Chemical Biology, 78457 Konstanz, Germany

    • Mario Catarinella
  5. Technische Universität Dortmund, Fakultät Chemie, Anorganische Chemie, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany

    • Markus Schürmann
    •  & Hans Preut

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Herbert Waldmann.

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DOI

https://doi.org/10.1038/nchem.730

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