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Enantioselective α-functionalizations of ketones via allylic substitution of silyl enol ethers

Nature Chemistry volume 11, pages 177–183 (2019)Cite this article

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Abstract

The enantioselective construction of carbon–heteroatom and carbon–carbon bonds that are alpha to ketones leads to the formation of substructures that are ubiquitous in natural products, pharmaceuticals and agrochemicals. Traditional methods to form such bonds have relied on combining ketone enolates with electrophiles. Reactions with heteroatom-based electrophiles require special reagents in which the heteroatom, which is typically nucleophilic, has been rendered electrophilic by changes to the oxidation state. The resulting products usually require post-synthetic transformations to unveil the functional group in the final desired products. Moreover, different catalytic systems are typically required for the reaction of different electrophiles. Here, we report a strategy for the formal enantioselective α-functionalization of ketones to form products containing a diverse array of substituents at the alpha position with a single catalyst. This strategy involves an unusual reversal of the role of the nucleophile and electrophile to form C–N, C–O, C–S and C–C bonds from a series of masked ketone electrophiles and a wide range of conventional heteroatom and carbon nucleophiles catalysed by a metallacyclic iridium catalyst.

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Fig. 1: Typical approaches to the α-functionalization of ketones and our design of an alternative strategy involving a reversal of the origin of the nucleophile and electrophile.
Fig. 2: Importance of the protecting group.
Fig. 3: Selected transformations of the allylic substitution products.

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Data availability

All relevant data are available with the manuscript, in the Supplementary Information files.

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Acknowledgements

Financial support for this work was provided by the National Institutes of Health (GM-55382). Z.-T.H. thanks a joint postdoc fellowship from Pharmaron and Shanghai Institute of Organic Chemistry (SIOC). We thank Sophie I. Arlow for assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, CA, USA

    Zhi-Tao He & John F. Hartwig

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Contributions

Z.-T.H. and J.F.H. conceived and designed the project. Z.-T.H. performed the experiments and collected and analysed the data. J.F.H. directed the project. Z.-T.H. and J.F.H. co-wrote the manuscript.

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Correspondence to John F. Hartwig.

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Supplementary information

Details of experiments for reaction development, experimental procedures, characterization data of all new molecules, spectra and references.

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He, ZT., Hartwig, J.F. Enantioselective α-functionalizations of ketones via allylic substitution of silyl enol ethers. Nature Chem 11, 177–183 (2019). https://doi.org/10.1038/s41557-018-0165-x

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