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Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling

Nature volume 505, pages 386–390 (2014)Cite this article

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An Erratum to this article was published on 26 February 2014

Abstract

Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of α-olefins1, none of these catalytic enantioselective processes results in chain-extending carbon–carbon bond formation to the terminal carbon2,3,4,5,6. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), uses low loadings (1–2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

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Figure 1: The diboration/cross-coupling (DCC) strategy and potential applications.
Figure 2: Observations on the Pd-catalysed cross-coupling of 1,2-bis(boronates) with bromobenzene.
Figure 3: Mechanistic considerations for the cross-coupling rate enhancement observed with 1,2-bis(boronates).
Figure 4: Tandem single-pot DCC provides a new route to enantiomerically enriched benzylic alcohols from terminal alkenes.
Figure 5: The DCC tandem sequence provides access to synthetically useful chiral homoallylic alcohols that are not readily prepared by carbonyl allylation reactions.
Figure 6: DCC tandem reactions provide short new synthesis routes to important medicinal agents.

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Acknowledgements

This research was supported by the US National Institutes of Health, Institute of General Medical Sciences (grant GM-59417). S.N.M. and C.H.S. were supported by John LaMattina graduate fellowships. We thank Allychem for providing B2(pin)2.

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Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Scott N. Mlynarski, Christopher H. Schuster & James P. Morken

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  1. Scott N. Mlynarski
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Contributions

S.N.M. and C.H.S. developed the procedure for the DCC reaction and collected the data in Figs 2b and 4. S.N.M. conducted the studies in Figs 5 and 6 and conducted the isotope labelling experiment in Fig. 3. J.P.M. conceived and designed the studies, planned the research and wrote the manuscript with assistance from C.H.S.

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Correspondence to James P. Morken.

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The authors declare no competing financial interests.

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Mlynarski, S., Schuster, C. & Morken, J. Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling. Nature 505, 386–390 (2014). https://doi.org/10.1038/nature12781

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