Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural prod
Author: ["Andrey P. Antonchick","Claas Gerding-Reimers","Mario Catarinella","Markus Schürmann","Hans Preut","Slava Ziegler","Daniel Rauh","Herbert Waldmann"]
Publication: Nature Chemistry
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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. A Lewis-acid-catalysed 1,3-dipolar cycloaddition provides rapid access to a variety of substituted spirooxindoles. Initial cellular evaluations supports the view that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry, and decorated with assorted substituents, will be a rich source of compounds with diverse bioactivity.
Cite this article
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