Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Deconstructive diversification of cyclic amines

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

This article has been updated


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

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.


  1. Bailey, P. S. The reactions of ozone with organic compounds. Chem. Rev. 58, 925–1010 (1958).

    CAS  Article  Google Scholar 

  2. Hoveyda, A. H. & Zhugralin, A. R. The remarkable metal-catalysed olefin metathesis reaction. Nature 450, 243–251 (2007).

    ADS  CAS  Article  Google Scholar 

  3. Vougioukalakis, G. C. & Grubbs, R. H. Ruthenium-based heterocyclic carbene-coordinated olefin metathesis catalysts. Chem. Rev. 110, 1746–1787 (2010).

    CAS  Article  Google Scholar 

  4. Galloway, W. R. J. D., Isidro-Llobet, A. & Spring, D. R. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat. Commun. 1, 80 (2010).

    ADS  Article  Google Scholar 

  5. Chen, W., Ma, L., Paul, A. & Seidel, D. Direct α-C–H bond functionalization of unprotected cyclic amines. Nat. Chem. 10, 165–169 (2018).

    CAS  Article  Google Scholar 

  6. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    CAS  Article  Google Scholar 

  7. Sun, H., Tawa, G. & Wallqvist, A. Classification of scaffold-hopping approaches. Drug Discov. Today 17, 310–324 (2012).

    CAS  Article  Google Scholar 

  8. Hu, Y., Stumpfe, D. & Bajorath, J. Recent advances in scaffold hopping. J. Med. Chem. 60, 1238–1246 (2017).

    CAS  Article  Google Scholar 

  9. Shawcross, A. P. & Stanforth, S. P. Reaction of N-nitroaryl-1,2,3,4-tetrahydroisoquinoline derivatives with oxygen. J. Heterocycl. Chem. 27, 367–369 (1990).

    CAS  Article  Google Scholar 

  10. Han, G., McIntosh, M. C. & Weinreb, S. M. A convenient synthetic method for amide oxidation. Tetrahedr. Lett. 35, 5813–5816 (1994).

    CAS  Article  Google Scholar 

  11. Ito, R., Umezawa, N. & Higuchi, T. Unique oxidation reaction of amides with pyridine-N-oxide catalyzed by ruthenium porphyrin: direct oxidative conversion of N-acyl-l-proline to N-acyl-l-glutamate. J. Am. Chem. Soc. 127, 834–835 (2005).

    CAS  Article  Google Scholar 

  12. Kaname, M., Yoshifuji, S. & Sashida, H. Ruthenium tetroxide oxidation of cyclic N-acylamines by a single layer method: formation of ω-amino acids. Tetrahedr. Lett. 49, 2786–2788 (2008).

    CAS  Article  Google Scholar 

  13. Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

    ADS  CAS  Article  Google Scholar 

  14. Henninot, A., Collins, J. C. & Nuss, J. M. The current state of peptide drug discovery: Back to the future? J. Med. Chem. 61, 1382–1414 (2018).

    CAS  Article  Google Scholar 

  15. Yu, C. et al. Selective ring-opening of N-alkyl pyrrolidines with chloroformates to 4-chlorobutyl carbamates. J. Org. Chem. 82, 6615–6620 (2017).

    CAS  Article  Google Scholar 

  16. Roque, J. B., Kuroda, Y., Göttemann, L. T. & Sarpong, R. Deconstructive fluorination of cyclic amines by carbon–carbon cleavage. Science 361, 171–174 (2018).

    ADS  CAS  Article  Google Scholar 

  17. Wang, Z. et al. Silver-catalyzed decarboxylative chlorination of aliphatic carboxylic acids. J. Am. Chem. Soc. 134, 4258–4263 (2012).

    CAS  Article  Google Scholar 

  18. Anderson, J. M. & Kochi, J. K. Silver(i)-catalyzed oxidative decarboxylation of acids by peroxydisulfate. Role of silver(ii). J. Am. Chem. Soc. 92, 1651–1659 (1970).

    CAS  Article  Google Scholar 

  19. Dai, C., Meschini, F., Narayanam, J. M. R. & Stephenson, C. R. J. Friedel–Crafts amidoalkylation via thermolysis and oxidative photocatalysis. J. Org. Chem. 77, 4425–4431 (2012).

    CAS  Article  Google Scholar 

  20. Po, H. N. Heterocyclic and macrocyclic amine complexes of silver(ii) and silver(iii). Coord. Chem. Rev. 20, 171–195 (1976).

    CAS  Article  Google Scholar 

  21. Edwards, J. O. & Gallopo, A. R. Kinetics and mechanisms of the spontaneous and metal-modified oxidations of ethanol by peroxydisulfate ion. J. Org. Chem. 36, 4089–4096 (1971).

    CAS  Article  Google Scholar 

  22. Tan, X. et al. Silver-catalyzed decarboxylative bromination of aliphatic carboxylic acids. Org. Lett. 19, 1634–1637 (2017).

    CAS  Article  Google Scholar 

  23. Reddy, D. N. & Prabhakaran, E. N. Synthesis and isolation of 5,6-dihydro-4H-1,3-oxazine hydrobromides by autocyclization of N-(3-bromopropyl)amides. J. Org. Chem. 76, 680–683 (2011).

    CAS  Article  Google Scholar 

  24. Bandarage, U. K. & Davies, R. J. A new synthesis of spiropyrrolidine–tetralones via an unexpected formal ring-contraction of 4-disubstituted piperidine to 3-disubstituted pyrrolidine. Tetrahedr. Lett. 51, 6415–6417 (2010).

    CAS  Article  Google Scholar 

  25. Aldmairi, A. H., Griffiths-Jones, C., Dupauw, A., Henderson, L. & Knight, D. W. Piperidines from acid-catalysed cyclisations: pitfalls, solutions and a new ring contraction to pyrrolidines. Tetrahedr. Lett. 58, 3690–3694 (2017).

    CAS  Article  Google Scholar 

  26. Sengupta, S. & Mehta, G. Late stage modification of peptides via C–H activation reactions. Tetrahedr. Lett. 58, 1357–1372 (2017).

    CAS  Article  Google Scholar 

  27. Wang, F., He, Y., Tian, M., Zhang, X. & Fan, X. Synthesis of α-formylated N-heterocycles and their 1,1-diacetates from inactivated cyclic amines involving an oxidative ring contraction. Org. Lett. 20, 864–867 (2018).

    CAS  Article  Google Scholar 

  28. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).

    CAS  Article  Google Scholar 

  29. Shechter, Y., Burstein, Y. & Patchornik, A. Selective oxidation of methionine residues in proteins. Biochemistry 14, 4497–4503 (1975).

    CAS  Article  Google Scholar 

  30. Lin, S. et al. Redox-based reagents for chemoselective methionine bioconjugation. Science 355, 597–602 (2017).

    ADS  CAS  Article  Google Scholar 

Download references


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

Authors and Affiliations



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.

Corresponding author

Correspondence to Richmond Sarpong.

Ethics declarations

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).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Roque, J.B., Kuroda, Y., Göttemann, L.T. et al. Deconstructive diversification of cyclic amines. Nature 564, 244–248 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Cyclic Amines
  • Scaffold Hopping
  • Deconstructive Strategy
  • Single Bond Cleavage
  • Proline-containing Peptides

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing