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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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.
The authors declare no competing financial interests.
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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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