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Skeletal editing through direct nitrogen deletion of secondary amines

Nature volume 593, pages 223–227 (2021)Cite this article

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An Author Correction to this article was published on 11 July 2022

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Abstract

Synthetic chemistry aims to build up molecular complexity from simple feedstocks1. However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space2,3. Here we report a reaction that ‘deletes’ nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon–carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon–carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon–carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.

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Fig. 1: Background.
Fig. 2: Development of an anomeric amide reagent.
Fig. 3: Scope of the nitrogen-deletion reaction promoted by reagent 1c.
Fig. 4: Mechanistic experiments.

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Data availability

All data are available from the corresponding author upon reasonable request.

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References

  1. Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1995).

  2. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  Google Scholar 

  3. Huigens, R. W., III et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem. 5, 195–202 (2013).

    Article  CAS  Google Scholar 

  4. Szpilman, A. M. & Carreira, E. M. Probing the biology of natural products: molecular editing by diverted total synthesis. Angew. Chem. Int. Ed. 49, 9592–9628 (2010).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Mahjour, B., Shen, Y., Liu, W. & Cernak, T. A map of the amine–carboxylic acid coupling system. Nature 580, 71–75 (2020).

    Article  ADS  CAS  Google Scholar 

  8. Cao, Z.-C. & Shi, Z.-J. Deoxygenation of ethers to form carbon–carbon bonds via nickel catalysis. J. Am. Chem. Soc. 139, 6546–6549 (2017).

    Article  CAS  Google Scholar 

  9. Roque, J. B., Kuroda, Y., Göttemann, L. T. & Sarpong, R. Deconstructive diversification of cyclic amines. Nature 564, 244–248 (2018).

    Article  ADS  CAS  Google Scholar 

  10. Smaligo, A. J. et al. Hydrodealkenylative C(sp3)–C(sp2) bond fragmentation. Science 364, 681–685 (2019).

    Article  ADS  CAS  Google Scholar 

  11. Fier, P. S., Kim, S. & Maloney, K. M. Reductive cleavage of secondary sulfonamides: converting terminal functional groups into versatile synthetic handles. J. Am. Chem. Soc. 141, 18416–18420 (2019).

    Article  CAS  Google Scholar 

  12. Xu, Y. et al. Deacylative transformations of ketones via aromatization-promoted C–C bond activation. Nature 567, 373–378 (2019).

    Article  ADS  CAS  Google Scholar 

  13. Silva Jr, L. F. in Stereoselective Synthesis of Drugs and Natural Products Vol. 1 (eds Andrushko, N. & Andrushko, V.) Ch. 18 (Wiley, 2013).

  14. Donald, J. R. & Unsworth, W. P. Ring-expansion reactions in the synthesis of macrocycles and medium-sized rings. Chem. Eur. J. 23, 8780–8799 (2017).

    Article  CAS  Google Scholar 

  15. Glover, S. A. Anomeric amides — Structure, properties and reactivity. Tetrahedron 54, 7229–7271 (1998).

    Article  CAS  Google Scholar 

  16. Glover, S. A. & Mo, G. Hindered ester formation by SN2 azidation of N-acetoxy-N-alkoxyamides and N-alkoxy-N-chloroamides—novel application of HERON rearrangements. J. Chem. Soc., Perkin Trans. 2 1728–1739 (2002).

    Article  Google Scholar 

  17. Hinman, R. L. & Hamm, K. L. The oxidation of 1,1-dibenzylhydrazines. J. Am. Chem. Soc. 81, 3294–3297 (1959).

    Article  CAS  Google Scholar 

  18. Hinsberg, W. D. & Dervan, P. B. Synthesis and direct spectroscopic observation of a 1,1-dialkyldiazene. Infrared and electronic spectrum of N-(2,2,6,6-tetramethylpiperidyl)nitrene. J. Am. Chem. Soc. 100, 1608–1610 (1978).

    Article  CAS  Google Scholar 

  19. Kuznetsov, M. A. & Ioffe, B. V. The present state of the chemistry of aminonitrenes and oxynitrenes. Russ. Chem. Rev. 58, 732 (1989).

    Article  ADS  Google Scholar 

  20. Urry, W. H., Kruse, H. W. & McBride, W. R. Novel organic reactions of the intermediate from the two-electron oxidation of 1,1-dialkyl hydrazines in acid. J. Am. Chem. Soc. 79, 6568–6569 (1957).

    Article  CAS  Google Scholar 

  21. Lemal, D. M. & Rave, T. W. Diazenes from Angeli’s Salt. J. Am. Chem. Soc. 87, 393–394 (1965).

    Article  CAS  Google Scholar 

  22. Zou, X., Zou, J., Yang, L., Li, G. & Lu, H. Thermal rearrangement of sulfamoyl azides: reactivity and mechanistic study. J. Org. Chem. 82, 4677–4688 (2017).

    Article  CAS  Google Scholar 

  23. Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    Article  CAS  Google Scholar 

  24. Berger, K. J. & Levin, M. D. Reframing primary alkyl amines as aliphatic building blocks. Org. Biomol. Chem. 19, 11–36 (2021).

    Article  CAS  Google Scholar 

  25. Plunkett, S., Basch, C. H., Santana, S. O. & Watson, M. P. Harnessing alkylpyridinium salts as electrophiles in deaminative alkyl–alkyl cross-couplings. J. Am. Chem. Soc. 141, 2257–2262 (2019).

    Article  CAS  Google Scholar 

  26. Brown, H. C. & Okamoto, Y. Electrophilic substituent constants. J. Am. Chem. Soc. 80, 4979–4987 (1958).

    Article  CAS  Google Scholar 

  27. Banert, K. et al. Steric hindrance underestimated: it is a long, long way to tri-tert-alkylamines. J. Org. Chem. 83, 5138–5148 (2018).

    Article  CAS  Google Scholar 

  28. Procopiou, G., Lewis, W., Harbottle, G. & Stockman, R. A. Cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane. Org. Lett. 15, 2030–2033 (2013).

    Article  CAS  Google Scholar 

  29. Chandrasekaran, R. Y. & Wager, T. T. Histamine-3 receptor modulators. US patent US2005171181A1 (2005).

  30. Wager, T. T. et al. Discovery of two clinical histamine H3 receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764). J. Med. Chem. 54, 7602–7620 (2011).

    Article  CAS  Google Scholar 

  31. Taylor, E. C. in Successful Drug Discovery (eds Fischer, J. & Rotella, D. P.) 157–180 (John Wiley & Sons, Ltd, 2015).

  32. Barrett, T. N., Braddock, D. C., Monta, A., Webb, M. R. & White, A. J. P. Total synthesis of the marine metabolite (±)-polysiphenol via highly regioselective intramolecular oxidative coupling. J. Nat. Prod. 74, 1980–1984 (2011).

    Article  CAS  Google Scholar 

  33. Moy, B., Kirkpatrick, P., Kar, S. & Goss, P. Lapatinib. Nat. Rev. Drug Discov. 6, 431–432 (2007).

    Article  CAS  Google Scholar 

  34. Ayer, W. A. & Habgood, T. E. in The Alkaloids: Chemistry and Physiology Vol. 11 (ed. Manske, R. H. F.) Ch. 12, 459–510 (Academic Press, 1968).

  35. Münch, G. et al. The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation. J Neural Transm. Park. Dis. Dement. Sect. 8, 193–208 (1994).

    Article  Google Scholar 

  36. De Almeida, M. V. et al. Preparation and thermal decomposition of N,N′-diacyl-N,N′-dialkoxyhydrazines: synthetic applications and mechanistic insights. J. Am. Chem. Soc. 117, 4870–4874 (1995).

    Article  Google Scholar 

  37. Glover, S. A. et al. The HERON reaction — origin, theoretical background, and prevalence. Can. J. Chem. 83, 1492–1509 (2005).

    Article  CAS  Google Scholar 

  38. Strick, B. F., Mundal, D. A. & Thomson, R. J. An oxidative [2,3]-sigmatropic rearrangement of allylic hydrazides. J. Am. Chem. Soc. 133, 14252–14255 (2011).

    Article  CAS  Google Scholar 

  39. Nwachukwu, C. I., McFadden, T. P. & Roberts, A. G. Ni-catalyzed iterative alkyl transfer from nitrogen enabled by the in situ methylation of tertiary amines. J. Org. Chem. 85, 9979–9992 (2020).

    Article  CAS  Google Scholar 

  40. Newcomb, M. in Encyclopedia of Radicals in Chemistry, Biology and Materials (eds Chatgilialoglu, C. & Studer, A.) (Wiley, 2012).

  41. Herk, L., Feld, M. & Szwarc, M. Studies of “Cage” Reactions. J. Am. Chem. Soc. 83, 2998–3005 (1961).

    Article  CAS  Google Scholar 

  42. Carpenter, B. K. Dynamic behavior of organic reactive intermediates. Angew. Chem. Int. Ed. 37, 3340–3350 (1998).

    Article  Google Scholar 

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Acknowledgements

We thank D. Nagib, F. D. Toste, M. Johnson and Z. Wickens for discussions. Financial support for this work was provided by start-up funding from the University of Chicago.

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  1. These authors contributed equally: Balu D. Dherange, Kathleen J. Berger

Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Sean H. Kennedy, Balu D. Dherange, Kathleen J. Berger & Mark D. Levin

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Contributions

S.H.K., K.J.B. and B.D.D. designed and conducted experiments, and collected and analysed the data. M.D.L. supervised the research, conceived of the project and wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Mark D. Levin.

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Competing interests

Reagent 1c is under development for commercialization with Sigma-Aldrich (product number 919799), but the authors have retained no financial interest and no patents have been filed.

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Supplementary Information

This file contains Supplementary Sections 1-59, including Supplementary Materials and Methods, Procedures, Supplementary Figures 1-17, Supplementary References and NMR Spectra data – see contents page for details.

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Kennedy, S.H., Dherange, B.D., Berger, K.J. et al. Skeletal editing through direct nitrogen deletion of secondary amines. Nature 593, 223–227 (2021). https://doi.org/10.1038/s41586-021-03448-9

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