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Enantioselective transition-metal catalysis via an anion-binding approach

Nature volume 616, pages 84–89 (2023)Cite this article

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Abstract

Asymmetric transition-metal catalysis represents a powerful strategy for accessing enantiomerically enriched molecules1,2,3. The classical strategy for inducing enantioselectivity with transition-metal catalysts relies on direct complexation of chiral ligands to produce a sterically constrained reactive metal site that allows formation of the major product enantiomer while effectively inhibiting the pathway to the minor enantiomer through steric repulsion4. The chiral-ligand strategy has proven applicable to a wide variety of highly enantioselective transition-metal-catalysed reactions, but important scenarios exist that impose limits to its successful adaptation. Here, we report a new approach for inducing enantioselectivity in transition-metal-catalysed reactions that relies on neutral hydrogen-bond donors (HBDs)5,6 that bind anions of cationic transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other non-covalent interactions7,8,9. A cooperative anion-binding effect of a chiral bis-thiourea HBD is demonstrated to lead to high enantioselectivity (up to 99% enantiomeric excess) in intramolecular ruthenium-catalysed propargylic substitution reactions10. Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the HBD and the metal complex that underlie enantioinduction and the acceleration effect.

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Fig. 1: Strategies in asymmetric transition-metal catalysis.
Fig. 2: Reaction optimization and representative products of the stereoselective propargylic substitution reaction.
Fig. 3: Study of the mode of interaction between HBDs and diruthenium complexes in the stereoselective propargylic substitution.
Fig. 4: Study of non-covalent interactions responsible for enantioselectivity and rate acceleration.

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The data that support the findings in this work are available within the paper and Supplementary Information.

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Acknowledgements

This work was supported by the National Institutes of Health through grant no. GM43214, NSF predoctoral fellowship (DGE1745303) and Bristol-Myers Squibb Graduate Research fellowship to J.M.O., and Alfred Bader Fellowship in Chemistry to P.V. We thank S.-L. Zheng (Harvard University) for determination of the X-ray crystal structures, Q. Li for assistance with catalyst synthesis, and D. Diaz, J. Gair, C. Wagen and J. Wong for helpful discussions.

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  1. These authors contributed equally: John M. Ovian, Petra Vojáčková

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  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    John M. Ovian, Petra Vojáčková & Eric N. Jacobsen

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E.N.J. conceived the work, P.V. and J.M.O. designed and conducted the experiments, E.N.J. supervised and directed the research, and all authors wrote the manuscript.

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Correspondence to Eric N. Jacobsen.

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Ovian, J.M., Vojáčková, P. & Jacobsen, E.N. Enantioselective transition-metal catalysis via an anion-binding approach. Nature 616, 84–89 (2023). https://doi.org/10.1038/s41586-023-05804-3

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