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Deconstructive diversification of cyclic amines

Nature (2018) | Download Citation

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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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.

Author information

Author notes

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

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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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.

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).

Corresponding author

Correspondence to Richmond Sarpong.

Supplementary information

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    This file contains Supplementary Text and Data – see contents page for details

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DOI

https://doi.org/10.1038/s41586-018-0700-3

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