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Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation

Nature volume 517, pages 351–355 (2015)Cite this article

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Abstract

The development of new reactions forming asymmetric carbon–carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers1. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy—dynamic kinetic asymmetric transformation—involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield2,3. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes4,5. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge6,7,8,9. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods.

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Figure 1: Asymmetric allylic alkylation (AAA) procedures.
Figure 2: Dynamic kinetic AAA with alkylzirconium nucleophiles generated from alkenes.
Figure 3: Scale-up and applications of the method to access tricyclic structures and natural products.
Figure 4: Mechanistic analysis.

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Acknowledgements

We acknowledge financial support from the EPSRC (EP/H003711/1, a Career Acceleration Fellowship to S.P.F.). B. Odell and T. Claridge are thanked for assistance with the NMR experiments.

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  1. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK,

    Hengzhi You, Emeline Rideau, Mireia Sidera & Stephen P. Fletcher

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  1. Hengzhi You
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Contributions

H.Y., E.R. and M.S. performed the experiments. All authors contributed to designing, analysing and discussing the experiments; S.P.F. conceived the work and guided the research. S.P.F. wrote the manuscript with assistance from H.Y. All authors contributed to discussing and editing the manuscript.

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Correspondence to Stephen P. Fletcher.

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Competing interests

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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You, H., Rideau, E., Sidera, M. et al. Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation. Nature 517, 351–355 (2015). https://doi.org/10.1038/nature14089

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