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Umpolung reactivity in amide and peptide synthesis

Abstract

The amide bond is one of nature’s most common functional and structural elements, as the backbones of all natural peptides and proteins are composed of amide bonds. Amides are also present in many therapeutic small molecules. The construction of amide bonds using available methods relies principally on dehydrative approaches, although oxidative and radical-based methods are representative alternatives. In nearly every example, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon–nitrogen bond-forming step. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products. Preliminary observations support a mechanism in which the polarities of the two reactants are reversed (German, umpolung) during carbon–nitrogen bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods.

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Figure 1
Figure 2: Amide and peptide synthesis.
Figure 3
Figure 4
Figure 5: Stereoselective peptide synthesis.
Figure 6: Enantioselective peptide synthesis.

References

  1. Valeur, E. & Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 38, 606–631 (2009)

    CAS  Article  Google Scholar 

  2. Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85, 2149–2154 (1963)

    CAS  Article  Google Scholar 

  3. Merrifield, R. B. Solid phase peptide synthesis. II. The synthesis of bradykinin. J. Am. Chem. Soc. 86, 304–305 (1964)

    CAS  Article  Google Scholar 

  4. Bode, J. W. Emerging methods in amide- and peptide-bond formation. Curr. Opin. Drug Disc. Dev. 9, 765–775 (2006)

    CAS  Google Scholar 

  5. Saxon, E., Armstrong, J. I. & Bertozzi, C. R. A “traceless” Staudinger ligation for the chemoselective synthesis of amide bonds. Org. Lett. 2, 2141–2143 (2000)

    CAS  Article  Google Scholar 

  6. Saxon, E. & Bertozzi, C. R. Cell surface engineering by a modified Staudinger reaction. Science 287, 2007–2010 (2000)

    ADS  CAS  Article  Google Scholar 

  7. Saxon, E. et al. Investigating cellular metabolism of synthetic azidosugars with the Staudinger ligation. J. Am. Chem. Soc. 124, 14893–14902 (2002)

    CAS  Article  Google Scholar 

  8. Nilsson, B. L., Kiessling, L. L. & Raines, R. T. Staudinger ligation: a peptide from a thioester and azide. Org. Lett. 2, 1939–1941 (2000)

    CAS  Article  Google Scholar 

  9. Kohn, M. & Breinbauer, R. The Staudinger ligation — a gift to chemical biology. Angew. Chem. Int. Edn 43, 3106–3116 (2004)

    Article  Google Scholar 

  10. Dawson, P. E., Muir, T. W., Clarklewis, I. & Kent, S. B. H. Synthesis of proteins by native chemical ligation. Science 266, 776–779 (1994)

    ADS  CAS  Article  Google Scholar 

  11. Cho, S. H., Yoo, E. J., Bae, L. & Chang, S. Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water. J. Am. Chem. Soc. 127, 16046–16047 (2005)

    CAS  Article  Google Scholar 

  12. Cassidy, M. P., Raushel, J. & Fokin, V. V. Practical synthesis of amides from in situ generated copper(I) acetylides and sulfonyl azides. Angew. Chem. Int. Edn 45, 3154–3157 (2006)

    CAS  Article  Google Scholar 

  13. Gunanathan, C., Ben-David, Y. & Milstein, D. Direct synthesis of amides from alcohols and amines with liberation of H2 . Science 317, 790–792 (2007)

    ADS  CAS  Article  Google Scholar 

  14. Nordstrom, L. U., Vogt, H. & Madsen, R. Amide synthesis from alcohols and amines by the extrusion of dihydrogen. J. Am. Chem. Soc. 130, 17672–17673 (2008)

    CAS  Article  Google Scholar 

  15. Yoo, W. J. & Li, C. J. Highly efficient oxidative amidation of aldehydes with amine hydrochloride salts. J. Am. Chem. Soc. 128, 13064–13065 (2006)

    CAS  Article  Google Scholar 

  16. Gao, J. & Wang, G. W. Direct oxidative amidation of aldehydes with anilines under mechanical milling conditions. J. Org. Chem. 73, 2955–2958 (2008)

    CAS  Article  Google Scholar 

  17. Chan, W. K., Ho, C. M., Wong, M. K. & Che, C. M. Oxidative amide synthesis and N-terminal alpha-amino group ligation of peptides in aqueous medium. J. Am. Chem. Soc. 128, 14796–14797 (2006)

    CAS  Article  Google Scholar 

  18. Bode, J. W., Fox, R. M. & Baucom, K. D. Chemoselective amide ligations by decarboxylative condensations of N-alkylhydroxylamines and alpha-ketoacids. Angew. Chem. Int. Edn 45, 1248–1252 (2006)

    CAS  Article  Google Scholar 

  19. Li, X. C. & Danishefsky, S. J. New chemistry with old functional groups: on the reaction of isonitriles with carboxylic acids — a route to various amide types. J. Am. Chem. Soc. 130, 5446–5448 (2008)

    CAS  Article  Google Scholar 

  20. Ono, N. The Nitro Group in Organic Synthesis (Wiley-VCB, 2001)

    Book  Google Scholar 

  21. Westermann, B. Asymmetric catalytic aza-Henry reactions leading to 1,2-diamines and 1-,2-diaminocarboxylic acids. Angew. Chem. Int. Edn 42, 151–153 (2003)

    CAS  Article  Google Scholar 

  22. Palomo, C., Oiarbide, M. & Mielgo, A. Unveiling reliable catalysts for the asymmetric nitroaldol (Henry) reaction. Angew. Chem. Int. Edn 43, 5442–5444 (2004)

    CAS  Article  Google Scholar 

  23. Palomo, C., Oiarbide, M. & Laso, A. Recent advances in the catalytic asymmetric nitroaldol (Henry) reaction. Eur. J. Org. Chem.2561–2574 (2007)

  24. Marques-Lopez, E., Merino, P., Tejero, T. & Herrera, R. P. Catalytic enantioselective aza-Henry reactions. Eur. J. Org. Chem.2401–2420 (2009)

  25. Grobel, B. T. & Seebach, D. Umpolung of reactivity of carbonyl-compounds through sulfur-containing reagents. Synthesis 357–402 (1977)

  26. Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Edn Engl. 18, 239–258 (1979)

    Article  Google Scholar 

  27. Seebach, D. & Corey, E. J. Generation and synthetic applications of 2-lithio-1,3-dithianes. J. Org. Chem. 40, 231–237 (1975)

    CAS  Article  Google Scholar 

  28. Ballini, R. & Petrini, M. Recent synthetic developments in the nitro to carbonyl conversion (Nef reaction). Tetrahedron 60, 1017–1047 (2004)

    CAS  Article  Google Scholar 

  29. Pinnick, H. W. The Nef reaction. Org. React. 38, 655–792 (1990)

    CAS  Google Scholar 

  30. Kovacic, P., Lowery, M. K. & Field, K. W. Chemistry of N-bromamines and N-chloramines. Chem. Rev. 70, 639–665 (1970)

    CAS  Article  Google Scholar 

  31. Erdik, E. & Ay, M. Electrophilic amination of carbanions. Chem. Rev. 89, 1947–1980 (1989)

    CAS  Article  Google Scholar 

  32. Gauthier, J. Y. et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 18, 923–928 (2008)

    CAS  Article  Google Scholar 

  33. Palmer, J. T. et al. Design and synthesis of tri-ring P-3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K. J. Med. Chem. 48, 7520–7534 (2005)

    CAS  Article  Google Scholar 

  34. Grayson, E. J. & Davis, B. G. A tuneable method for N-debenzylation of benzylamino alcohols. Org. Lett. 7, 2361–2364 (2005)

    CAS  Article  Google Scholar 

  35. Stenmark, H. G., Brazzale, A. & Ma, Z. Biomimetic synthesis of macrolide/ketolide metabolites through a selective N-demethylation reaction. J. Org. Chem. 65, 3875–3876 (2000)

    CAS  Article  Google Scholar 

  36. Katoh, T. et al. Selective C–N bond oxidation: demethylation of N-methyl group in N-arylmethyl-N-methyl-α-amino esters utilizing N-iodosuccinimide (NIS). Tetrahedr. Lett. 49, 598–600 (2008)

    CAS  Article  Google Scholar 

  37. Zhong, Y.-L. et al. Practical and efficient synthesis of N-halo compounds. Tetrahedr. Lett. 46, 1099–1101 (2005)

    CAS  Article  Google Scholar 

  38. Williams, R. M. & Hendrix, J. A. Asymmetric synthesis of arylglycines. Chem. Rev. 92, 889–917 (1992)

    CAS  Article  Google Scholar 

  39. Nugent, B. M., Yoder, R. A. & Johnston, J. N. Chiral proton catalysis: a catalytic enantioselective direct aza-Henry reaction. J. Am. Chem. Soc. 126, 3418–3419 (2004)

    CAS  Article  Google Scholar 

  40. Wilt, J. C., Pink, M. & Johnston, J. N. A diastereo- and enantioselective synthesis of α-substituted anti-α,β-diaminophosphonic acid derivatives. Chem. Commun. 4177–4179 (2008)

  41. Singh, A. & Johnston, J. N. A diastereo- and enantioselective synthesis of α-substituted syn-α,β-diamino acids. J. Am. Chem. Soc. 130, 5866–5867 (2008)

    CAS  Article  Google Scholar 

  42. Shen, B. & Johnston, J. N. A formal enantioselective acetate Mannich reaction: the nitro functional group as a traceless agent for activation and enantiocontrol in the synthesis of β-amino acids. Org. Lett. 10, 4397–4400 (2008)

    CAS  Article  Google Scholar 

  43. Singh, A., Yoder, R. A., Shen, B. & Johnston, J. N. Chiral proton catalysis: enantioselective Bronsted acid catalyzed additions of nitroacetic acid derivatives as glycine equivalents. J. Am. Chem. Soc. 129, 3466–3467 (2007)

    CAS  Article  Google Scholar 

  44. Davis, T. A., Wilt, J. C. & Johnston, J. N. Bifunctional asymmetric catalysis: amplification of Brønsted basicity can orthogonally increase the reactivity of a chiral Brønsted acid. J. Am. Chem. Soc. 132, 2880–2882 (2010)

    CAS  Article  Google Scholar 

  45. Wong, F. T., Patra, P. K., Seayad, J., Zhang, Y. & Ying, J. Y. N-heterocyclic carbene (NHC)-catalyzed direct amidation of aldehydes with nitroso compounds. Org. Lett. 10, 2333–2336 (2008)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the Vanderbilt Institute of Chemical Biology, and in part (catalyst preparation and development) by the NIH (GM084333 and Chemistry-Biology Interface training grant T32 GM065086 in support of D.M.M.).

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Contributions

The reaction was conceptualized and reduced to practice by B.S. and J.N.J. Experiments were performed by B.S. (mechanism and scope) and D.M.M. (scope). The manuscript was prepared by J.N.J. with input from all coauthors.

Corresponding author

Correspondence to Jeffrey N. Johnston.

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The authors declare no competing financial interests.

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Shen, B., Makley, D. & Johnston, J. Umpolung reactivity in amide and peptide synthesis. Nature 465, 1027–1032 (2010). https://doi.org/10.1038/nature09125

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