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Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions

Abstract

Organofluorine compounds are central to modern chemistry, and broadly applicable transformations that generate them efficiently and enantioselectively are in much demand. Here we introduce efficient catalytic methods for the addition of allyl and allenyl organoboron reagents to fluorine-substituted ketones. These reactions are facilitated by readily and inexpensively available catalysts and deliver versatile and otherwise difficult-to-access tertiary homoallylic alcohols in up to 98% yield and >99:1 enantiomeric ratio. Utility is highlighted by a concise enantioselective approach to the synthesis of the antiparasitic drug fluralaner (Bravecto, presently sold as the racemate). Different forms of ammonium–organofluorine interactions play a key role in the control of enantioselectivity. The greater understanding of various non-bonding interactions afforded by these studies should facilitate the future development of transformations that involve fluoroorganic entities.

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Figure 1: Ammonium–organofluorine affinity in enantioselective organoboron addition to trifluoromethyl ketones.
Figure 2: Catalytic enantioselective allyl additions to trifluoromethyl phenyl ketones.
Figure 3: Catalytic enantioselective allenyl additions to trifluoromethyl phenyl ketones.
Figure 4: Dependence of enantioselectivity on the number and positioning of the fluorine atoms in a ketone substrate.
Figure 5: Enantioselective synthesis of the antiparasitic drug fluralaner.

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Acknowledgements

This research was supported by a grant from the National Institutes of Health (GM-57212). D.L.S. and S.T. were partially supported as an AstraZeneca graduate fellow and a Swiss National Science Foundation postdoctoral fellow, respectively. We are grateful to E. M. Vieira, H. Wu, C. Qin, X. Shen and F. Romiti for helpful suggestions and discussions.

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K.A.L. and D.L.S. developed the catalytic enantioselective transformations and analysed the results regarding various interactions; K.A.L. carried out the experiments reported in Fig. 5; S.T. made the initial observations. DFT calculations were designed and performed by S.T., F.H. and F.W.v.d.M. D.W.R. developed the silyl-substituted catalyst. A.H.H. designed and directed the investigations and composed the manuscript with revisions provided by the other authors.

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Correspondence to Amir H. Hoveyda.

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Crystallographic data for compound 17. (CIF 661 kb)

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Lee, K., Silverio, D., Torker, S. et al. Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions. Nature Chem 8, 768–777 (2016). https://doi.org/10.1038/nchem.2523

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