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Deconstructive diversification of cyclic amines

Nature volume 564, pages 244–248 (2018)Cite this article

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An Author Correction to this article was published on 01 April 2020

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Abstract

Deconstructive functionalization involves carbon–carbon (C–C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis1 and olefin metathesis2,3 have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C(sp3)–C(sp3) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp3)–N and C(sp3)–C(sp3) single-bond cleavage followed by C(sp3)–halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides.

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Fig. 1: Development of a deconstructive halogenation of cyclic amines.
Fig. 2: Scope of the cyclic amine in the deconstructive halogenation reaction.
Fig. 3: Applications of deconstructive halogenation.
Fig. 4: Deconstructive chlorination of l-proline-containing peptides.

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Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information, or from the corresponding author upon reasonable request.

Change history

  • 01 April 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH; NIGMS RO1 086374). J.B.R. thanks the NIH for a graduate diversity supplement fellowship (NIGMS RO1 086374). Y.K. thanks the Japan Society for the Promotion of Science (JSPS) for an Overseas Research Fellowship. L.T.G. thanks LMU PROSA and DAAD for financial support. We thank J. Derrick for assistance with electrochemical measurements.

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  1. These authors contributed equally: Jose B. Roque, Yusuke Kuroda

Authors and Affiliations

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

    Jose B. Roque, Yusuke Kuroda, Lucas T. Göttemann & Richmond Sarpong

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  1. Jose B. Roque
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  2. Yusuke Kuroda
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Contributions

J.B.R. and Y.K. conceived the research and designed the experiments. J.B.R., Y.K. and L.T.G. performed the experiments. R.S. directed the project. J.B.R., Y.K. and R.S. wrote the manuscript.

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Correspondence to Richmond Sarpong.

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Competing interests

J.B.R., Y.K., L.T.G. and R.S. are listed as inventors on an initial patent application describing the silver-mediated deconstructive halogenation of cyclic amines and subsequent transformations (052103-515P01US).

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Roque, J.B., Kuroda, Y., Göttemann, L.T. et al. Deconstructive diversification of cyclic amines. Nature 564, 244–248 (2018). https://doi.org/10.1038/s41586-018-0700-3

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