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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References
Li, J. W. H. & Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).
Kumar, K. & Waldmann, H. Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. 48, 3224–3242 (2009).
Harvey, A. L. Natural products in drug discovery. Drug Discovery Today 13, 894–901 (2008).
Ganesan, A. The impact of natural products upon modern drug discovery. Curr. Opin. Chem. Biol. 12, 306–317 (2008).
Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007).
Koch, M. A. et al. Charting biologically relevant chemical space: A structural classification of natural products (SCONP). Proc. Natl Acad. Sci. USA 102, 17272–17277 (2005).
Nören-Müller, A. et al. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc. Natl Acad. Sci. USA 103, 10606–10611 (2006).
Kaiser, M., Wetzel, S., Kumar, K. & Waldmann, H. Biology-inspired synthesis of compound libraries. Cell. Mol. Life Sci. 65, 1186–1201 (2008).
Galliford, C. V. & Scheidt, K. A. Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem. Int. Ed. 46, 8748–8758 (2007).
Marti, C. & Carreira, E. M. Construction of spiro[pyrrolidine-3,3′-oxindoles] - recent applications to the synthesis of oxindole alkaloids. Eur. J. Org. Chem. 2209–2219 (2003).
Ding, K. et al. Structure-based design of potent non-peptide MDM2 inhibitors. J. Am. Chem. Soc. 127, 10130–10131 (2005).
Ding, K. et al. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J. Med. Chem. 49, 3432–3435 (2006).
Shangary, S. et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl Acad. Sci. USA 105, 3933–3938 (2008).
Ashimori, A. & Overman, L. E. Catalytic asymmetric-synthesis of quarternary carbon centers - palladium-catalyzed formation of either enantiomer of spirooxindoles and related spirocyclics using a single enantiomer of a chiral diphosphine ligand. J. Org. Chem. 57, 4571–4572 (1992).
Trost, B. M. & Brennan, M. K. Asymmetric syntheses of oxindole and indole spirocyclic alkaloid natural products. Synthesis 3003–3025 (2009).
Chen, X. H., Wei, Q., Luo, S. W., Xiao, H. & Gong, L. Z. Organocatalytic synthesis of spiro[pyrrolidin-3,3′-oxindoles] with high enantiopurity and structural diversity. J. Am. Chem. Soc. 131, 13819–13825 (2009).
Filippone, S., Maroto, E. E., Martin-Domenech, A., Suarez, M. & Martin, N. An efficient approach to chiral fullerene derivatives by catalytic enantioselective 1,3-dipolar cycloadditions. Nature Chem. 1, 578–582 (2009).
Lopez-Perez, A., Adrio, J. & Carretero, J. C. Bis-sulfonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3 + 2] cycloaddition of azomethine ylides. J. Am. Chem. Soc. 130, 10084–10085 (2008).
Cabrera, S., Arrayas, R. G. & Carretero, J. C. Highly enantioselective copper(I)-fesulphos-catalyzed 1,3-dipolar cycloaddition of azomethine ylides. J. Am. Chem. Soc. 127, 16394–16395 (2005).
Cabrera, S., Arrayas, R. G., Martin-Matute, B., Cossio, F. P. & Carretero, J. C. Cu-I-fesulphos complexes: efficient chiral catalysts for asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Tetrahedron 67, 6587–6602 (2007).
Zeng, W., Chen, G. Y., Zhou, Y. G. & Li, Y. X. Hydrogen-bonding directed reversal of enantioselectivity. J. Am. Chem. Soc. 129, 750–751 (2007).
Wang, C. J., Liang, G., Xue, Z. Y. & Gao, F. Highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides catalyzed by copper(I)/TF-BiphamPhos complexes. J. Am. Chem. Soc. 130, 17250–17251 (2008).
Yan, X. X. et al. A highly enantio- and diastereoselective Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes. Angew. Chem. Int. Ed. 45, 1979–1983 (2006).
Pandit, B. et al. Structure-activity-relationship studies of conformationally restricted analogs of combretastatin A-4 derived from SU5416. Bioorg. Med. Chem. 14, 6492–6501 (2006).
Sun, L. et al. Synthesis and biological evaluations of 3-substituted indolin-2-ones: A novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J. Med. Chem. 41, 2588–2603 (1998).
Vivanco, S. et al. Origins of the loss of concertedness in pericyclic reactions: Theoretical prediction and direct observation of stepwise mechanisms in [3 + 2] thermal cycloadditions. J. Am. Chem. Soc. 122, 6078–6092 (2000).
Cui, C. B., Kakeya, H. & Osada, H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 52, 12651–12666 (1996).
Sebahar, P. R., Osada, H., Usui, T. & Williams, R. M. Asymmetric, stereocontrolled total synthesis of (+) and (−)-spirotryprostatin B via a diastereoselective azomethine ylide [1,3]-dipolar cycloaddition reaction. Tetrahedron 58, 6311–6322 (2002).
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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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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DOI: https://doi.org/10.1038/nchem.730
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