Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis

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Science  11 May 2018:
Vol. 360, Issue 6389, pp. 638-642
DOI: 10.1126/science.aar7941

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H-bond to deliver fluoride

Simple fluoride salts are theoretically convenient reagents for carbon-fluorine bond formation. In practice, they are often insoluble in the solvents that dissolve their reaction partners. Pupo et al. developed urea-based catalysts that make fluoride soluble through hydrogen bonding. Moreover, their chiral substituents bias the reaction toward one of two mirror image products of C–F bond formation. This strategy should be applicable to the asymmetric addition of other salts, too.

Science, this issue p. 638


Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility. Here, we report that merging hydrogen bonding and phase-transfer catalysis provides an effective mode of activation for nucleophiles that are insoluble in organic solvents. This catalytic manifold relies on hydrogen bonding complexation to render nucleophiles soluble and reactive, while simultaneously inducing asymmetry in the ensuing transformation. We demonstrate the concept using a chiral bis-urea catalyst to form a tridentate hydrogen bonding complex with fluoride from its cesium salt, thereby enabling highly efficient enantioselective ring opening of episulfonium ion. This fluorination method is synthetically valuable considering the scarcity of alternative protocols and points the way to wider application of the catalytic approach with diverse anionic nucleophiles.

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