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Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters

Nature Chemistry volume 6, pages 584–589 (2014)Cite this article

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Abstract

The cross-coupling of boronic acids and related derivatives with sp2 electrophiles (the Suzuki–Miyaura reaction) is one of the most powerful C–C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

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Figure 1: Proposed method for stereospecific coupling of boronic esters with an illustration of previous literature and key results.
Figure 2: Range of secondary and tertiary boronic esters tested in this study.
Figure 3: Possible reaction pathways for the reactions of aryl–boronate complexes with electrophiles, illustrated with [Br+].

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Acknowledgements

We thank the Engineering and Physical Sciences Research Council (EP/I038071/1) and the European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support. A.B. thanks the Marie Curie Fellowship program (EC FP7 No 329578). We thank H. Mayr, V. Rawal and J. N. Harvey for useful discussions.

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  1. School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK

    Amadeu Bonet, Marcin Odachowski, Daniele Leonori, Stephanie Essafi & Varinder K. Aggarwal

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  1. Amadeu Bonet
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  2. Marcin Odachowski
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Contributions

D.L. and V.K.A. designed the project and wrote the manuscript. A.B. and M.O. contributed intellectually and practically to the laboratory experiments, S.E. performed preliminary computational studies and was involved in the mechanistic discussions.

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Correspondence to Varinder K. Aggarwal.

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Bonet, A., Odachowski, M., Leonori, D. et al. Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters. Nature Chem 6, 584–589 (2014). https://doi.org/10.1038/nchem.1971

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