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Copper-catalyzed asymmetric conjugate addition of alkylzirconium reagents to cyclic enones to form quaternary centers

Nature Protocols volume 9, pages 104–111 (2014)Cite this article

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Abstract

This protocol describes the catalytic asymmetric formation of all-carbon quaternary centers—a distinctive feature of many natural products and pharmaceuticals—via conjugate addition of alkylzirconium reagents to a tertiary enone. This methodology uses alkenes as starting materials and enables the incorporation of functional groups. The alkylzirconium reagent is generated in situ by mixing the alkene with the Schwartz reagent. The alkylzirconium is added to a solution containing a copper-ligand complex, and then the enone is added to the mixture. The addition of pent-4-en-1-ylbenzene to 3-methyl-2-cyclohexenone is detailed herein as a generic example. This procedure works at room temperature (∼25 °C), and it is scalable to at least 1.5 g. The setup of the reaction takes 3–5 h and the reaction goes to completion within 4–20 h.

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Figure 1
Figure 2: General reaction schemes.
Figure 3: Reaction conditions used in our research group.
Figure 4: The Schwartz reagent.
Figure 5: Appearance of copper solution.
Figure 6: Sequence of procedures implemented in Steps 10–13.
Figure 7

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Acknowledgements

We thank the UK Engineering and Physical Sciences Research Council for generous support of this research in the form of a Career Acceleration Fellowship to S.P.F. (EP/H003711/1).

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  1. Philippe M C Roth and Mireia Sidera: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Oxford, UK

    Philippe M C Roth, Mireia Sidera, Rebecca M Maksymowicz & Stephen P Fletcher

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  1. Philippe M C Roth
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Contributions

P.M.C.R., M.S. and R.M.M. conducted the experiments. All authors designed the experiments and analyzed the data. S.P.F. guided the research. P.M.C.R., M.S. and S.P.F. wrote the manuscript. All authors contributed to discussions.

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Correspondence to Stephen P Fletcher.

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The authors are all named as inventors on a UK patent application filed by Isis Innovation, which is the technology transfer arm of the University of Oxford.

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Synthesis of diphenyl isopropyl binol phosphoramidite ligand A (PDF 106 kb)

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Roth, P., Sidera, M., Maksymowicz, R. et al. Copper-catalyzed asymmetric conjugate addition of alkylzirconium reagents to cyclic enones to form quaternary centers. Nat Protoc 9, 104–111 (2014). https://doi.org/10.1038/nprot.2013.169

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