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Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids

Abstract

α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of unnatural amino acids is often desirable for modulating chemical, physical and pharmaceutical properties. Here we report a protocol for the economical and practical synthesis of optically active α-amino acids based on an unprecedented stereocontrolled 1,3-nitrogen shift. Our method employs abundant and easily accessible carboxylic acids as starting materials, which are first connected to a nitrogenation reagent, followed by a highly regio- and enantioselective ruthenium- or iron-catalysed C(sp3)–H amination. This straightforward method displays a very broad scope, providing rapid access to optically active α-amino acids with aryl, allyl, propargyl and alkyl side chains, and also permits stereocontrolled late-stage amination of carboxylic-acid-containing drugs and natural products.

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Fig. 1: Stereocontrolled nitrene C(sp3)–H insertions for the synthesis of α-amino acids.
Fig. 2: Investigation of the reaction mechanism.
Fig. 3: Summary of proposed simplified mechanism.

Data availability

All relevant data supporting the findings of this study, including experimental procedures and compound characterization, NMR and HPLC are available within the article and its Supplementary Information.

References

  1. Saghyan, A. S. & Langer, P. Asymmetric Synthesis of Non-proteinogenic Amino Acids (Wiley-VCH, 2016).

    Book  Google Scholar 

  2. Nájera, C. & Sansano, J. M. Catalytic asymmetric synthesis of α-amino acids. Chem. Rev. 107, 4584–4671 (2007).

    PubMed  Article  CAS  Google Scholar 

  3. Janey, J. M. Recent advances in catalytic, enantioselective α aminations and α oxygenations of carbonyl compounds. Angew. Chem. Int. Ed. 44, 4292–4300 (2005).

    CAS  Article  Google Scholar 

  4. Bøgevig, A., Juhl, K., Kumaragurubaran, N., Zhuang, W. & Jørgensen, K. A. Direct organo-catalytic asymmetric α-amination of aldehydes—a simple approach to optically active α-amino aldehydes, α-amino alcohols, and α-amino acids. Angew. Chem. Int. Ed. 41, 1790–1793 (2002).

    Article  Google Scholar 

  5. List, B. Direct catalytic asymmetric α-amination of aldehydes. J. Am. Chem. Soc. 124, 5656–5657 (2002).

    CAS  PubMed  Article  Google Scholar 

  6. Kumaragurubaran, N., Juhl, K., Zhuang, W., Bøgevig, A. & Jørgensen, K. A. Direct l-proline-catalyzed asymmetric α-amination of ketones. J. Am. Chem. Soc. 124, 6254–6255 (2002).

    CAS  PubMed  Article  Google Scholar 

  7. Morrill, L. C., Lebl, T., Slawin, A. M. Z. & Smith, A. D. Catalytic asymmetric α-amination of carboxylic acids using isothioureas. Chem. Sci. 3, 2088–2093 (2012).

    CAS  Article  Google Scholar 

  8. Dequirez, G., Pons, V. & Dauban, P. Nitrene chemistry in organic synthesis: still in its infancy? Angew. Chem. Int. Ed. 51, 7384–7395 (2012).

    CAS  Article  Google Scholar 

  9. Park, Y., Kim, Y. & Chang, S. Transition metal-catalyzed C–H amination: scope, mechanism, and applications. Chem. Rev. 117, 9247–9301 (2017).

    CAS  PubMed  Article  Google Scholar 

  10. Ju, M. & Schomaker, J. M. Nitrene transfer catalysts for enantioselective C–N bond formation. Nat. Rev. Chem. 5, 580–594 (2021).

    CAS  Article  Google Scholar 

  11. Nägeli, I. et al. Rhodium(II)-catalyzed CH insertions with {[(4-nitrophenyl)sulfonyl]imino}phenyl-λ3-iodane. Helv. Chim. Acta 80, 1087–1105 (1997).

    Article  Google Scholar 

  12. Zhou, X.-G., Yu, X.-Q., Huang, J.-S. & Che, C.-M. Asymmetric amidation of saturated C–H bonds catalysed by chiral ruthenium and manganese porphyrins. Chem. Commun. 2377–2378 (1999).

  13. Kohmura, Y. & Katsuki, T. Mn(salen)-catalyzed enantioselective C–H amination. Tetrahedron Lett. 42, 3339–3342 (2001).

    CAS  Article  Google Scholar 

  14. Yamawaki, M., Tsutsui, H., Kitagaki, S., Anada, M. & Hashimoto, S. Dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate]: a new chiral Rh(II) catalyst for enantioselective amidation of C–H bonds. Tetrahedron Lett. 43, 9561–9564 (2002).

    CAS  Article  Google Scholar 

  15. Liang, C. et al. Efficient diastereoselective intermolecular rhodium-catalyzed C–H amination. Angew. Chem. Int. Ed. 45, 4641–4644 (2006).

    CAS  Article  Google Scholar 

  16. Nishioka, Y., Uchida, T. & Katsuki, T. Enantio- and regioselective intermolecular benzylic and allylic C–H bond amination. Angew. Chem. Int. Ed. 52, 1739–1742 (2013).

    CAS  Article  Google Scholar 

  17. Höke, T., Herdtweck, E. & Bach, T. Hydrogen-bond mediated regio- and enantioselectivity in a C–H amination reaction catalysed by a supramolecular Rh(II) complex. Chem. Commun. 49, 8009–8011 (2013).

    Article  CAS  Google Scholar 

  18. Nasrallah, A. et al. Catalytic enantioselective intermolecular benzylic C(sp3)–H amination. Angew. Chem. Int. Ed. 58, 8192–8196 (2019).

    CAS  Article  Google Scholar 

  19. Jin, L.-M., Xu, P., Xie, J. & Zhang, X. P. Enantioselective intermolecular radical C–H amination. J. Am. Chem. Soc. 142, 20828–20836 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Liang, J.-L., Yuan, S.-X., Huang, J.-S., Yu, W.-Y. & Che, C.-M. Highly diastereo- and enantioselective intramolecular amidation of saturated C–H bonds catalyzed by ruthenium porphyrins. Angew. Chem. Int. Ed. 41, 3465–3468 (2002).

    CAS  Article  Google Scholar 

  21. Milczek, E., Boudet, N. & Blakey, S. Enantioselective C–H amination using cationic ruthenium(II)–pybox catalysts. Angew. Chem. Int. Ed. 47, 6825–6828 (2008).

    CAS  Article  Google Scholar 

  22. Ichinose, M. et al. Enantioselective intramolecular benzylic C–H bond amination: efficient synthesis of optically active benzosultams. Angew. Chem. Int. Ed. 50, 9884–9887 (2011).

    CAS  Article  Google Scholar 

  23. Zalatan, D. N. & Du Bois, J. A chiral rhodium carboxamidate catalyst for enantioselective C–H amination. J. Am. Chem. Soc. 130, 9220–9221 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Lang, K., Torker, S., Wojtas, L. & Zhang, X. P. Asymmetric induction and enantiodivergence in catalytic radical C–H amination via enantiodifferentiative H-atom abstraction and stereoretentive radical substitution. J. Am. Chem. Soc. 141, 12388–12396 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Park, Y. & Chang, S. Asymmetric formation of γ-lactams via C–H amidation enabled by chiral hydrogen-bond-donor catalysts. Nat. Catal. 9, 219–227 (2019).

    Article  CAS  Google Scholar 

  26. van Vliet, K. M. & de Bruin, B. Dioxazolones: stable substrates for the catalytic transfer of acyl nitrenes. ACS Catal. 10, 4751–4769 (2020).

    Article  CAS  Google Scholar 

  27. Zheng, Y. et al. Octahedral ruthenium complex with exclusive metal-centered chirality for highly effective asymmetric catalysis. J. Am. Chem. Soc. 139, 4322–4325 (2017).

    CAS  PubMed  Article  Google Scholar 

  28. Zhou, Z. et al. Catalytic enantioselective intramolecular C(sp3)–H amination of 2-azidoacetamides. Angew. Chem. Int. Ed. 58, 1088–1093 (2019).

    CAS  Article  Google Scholar 

  29. Zhou, Z. et al. Enantioselective ring-closing C–H amination of urea derivatives. Chem 6, 2024–2034 (2020).

    CAS  Article  Google Scholar 

  30. Thirumurugan, P., Matosiuk, D. & Jozwiak, K. Click chemistry for drug development and diverse chemical–biology applications. Chem. Rev. 113, 4905–4979 (2013).

    CAS  PubMed  Article  Google Scholar 

  31. Ueno, K. et al. 6,11-Dihydro-11-oxodibenz[b,e]oxepinacetic acids with potent antiinflammatory activity. J. Med. Chem. 19, 941–946 (1976).

    CAS  PubMed  Article  Google Scholar 

  32. Krupp, P. J. et al. Sodium [o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (GP 45 840), a new non-steroidal anti-inflammatory agent. Experientia 29, 450–452 (1973).

    CAS  PubMed  Article  Google Scholar 

  33. Bauer, I. & Knölker, H.-J. Iron catalysis in organic synthesis. Chem. Rev. 115, 3170–3387 (2015).

    CAS  PubMed  Article  Google Scholar 

  34. Liu, Y. et al. Iron- and cobalt-catalyzed C(sp3)–H bond functionalization reactions and their application in organic synthesis. Chem. Soc. Rev. 49, 5310–5358 (2020).

    CAS  PubMed  Article  Google Scholar 

  35. Hong, Y., Jarrige, L., Harms, K. & Meggers, E. Chiral-at-iron catalyst: expanding the chemical space for asymmetric earth-abundant metal catalysis. J. Am. Chem. Soc. 141, 4569–4572 (2019).

    CAS  PubMed  Article  Google Scholar 

  36. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. Gormisky, P. E. & White, M. C. Catalyst-controlled aliphatic C–H oxidations with a predictive model for site-selectivity. J. Am. Chem. Soc. 135, 14052–14055 (2013).

    CAS  PubMed  Article  Google Scholar 

  38. Mitra, M. et al. Highly enantioselective epoxidation of olefins by H2O2 catalyzed by a non-heme Fe(II) catalyst of a chiral tetradentate ligand. Dalton Trans. 48, 6123–6131 (2019).

    CAS  PubMed  Article  Google Scholar 

  39. Poli, R. & Harvey, J. N. Spin forbidden chemical reactions of transition metal compounds. New ideas and new computational challenges. Chem. Soc. Rev. 32, 1–8 (2003).

    CAS  PubMed  Article  Google Scholar 

  40. Harvey, J. N., Poli, R. & Smith, K. M. Understanding the reactivity of transition metal complexes involving multiple spin states. Coord. Chem. Rev. 238-239, 347–361 (2003).

    CAS  Article  Google Scholar 

  41. Yersin, H. & Humbs, W. Spatial extensions of excited states of metal complexes. Tunability by chemical variation. Inorg. Chem. 38, 5820–5831 (1999).

    CAS  Article  Google Scholar 

  42. Maestre, L., Sameera, W. M. C., Díaz-Requejo, M. M., Maseras, F. & Pérez, P. J. A general mechanism for the copper- and silver-catalyzed olefin aziridination reactions: concomitant involvement of the singlet and triplet pathways. J. Am. Chem. Soc. 135, 1338–1348 (2013).

    CAS  PubMed  Article  Google Scholar 

  43. Jung, H., Keum, H., Kweon, J. & Chang, S. Tuning triplet energy transfer of hydroxamates as the nitrene precursor for intramolecular C(sp3)–H amidation. J. Am. Chem. Soc. 142, 5811–5818 (2020).

    CAS  PubMed  Article  Google Scholar 

  44. Ess, D. H. & Houk, K. N. Theory of 1,3-dipolar cycloadditions: distortion/interaction and frontier molecular orbital models. J. Am. Chem. Soc. 130, 10187–10198 (2008).

    CAS  PubMed  Article  Google Scholar 

  45. Krenske, E. H. & Houk, K. N. Aromatic interactions as control elements in stereoselective organic reactions. Acc. Chem. Res. 46, 979–989 (2013).

    CAS  PubMed  Article  Google Scholar 

  46. Wheeler, S. E. Understanding substituent effects in noncovalent interactions involving aromatic rings. Acc. Chem. Res. 46, 1029–1038 (2013).

    CAS  PubMed  Article  Google Scholar 

  47. Wheeler, S. E. & Bloom, J. W. G. Toward a more complete understanding of noncovalent interactions involving aromatic rings. J. Phys. Chem. A 118, 6133–6147 (2014).

    CAS  PubMed  Article  Google Scholar 

  48. Isidro-Llobet, A., Álvarez, M. & Albericio, F. Amino acid-protecting groups. Chem. Rev. 109, 2455–2504 (2009).

    CAS  PubMed  Article  Google Scholar 

  49. Blaskovich, M. A. T. Unusual amino acids in medicinal chemistry. J. Med. Chem. 59, 10807–10836 (2016).

    CAS  PubMed  Article  Google Scholar 

  50. Agostini, F. et al. Biocatalysis with unnatural amino acids: enzymology meets xenobiology. Angew. Chem. Int. Ed. 56, 9680–9703 (2017).

    CAS  Article  Google Scholar 

  51. Drienovská, I. & Roelfes, G. Expanding the enzyme universe with genetically encoded unnatural amino acids. Nat. Catal. 3, 193–202 (2020).

    Article  CAS  Google Scholar 

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Acknowledgements

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 883212). Funding was also provided by the Deutsche Forschungsgemeinschaft (Me 1805/15-1). S.C. thanks Oberlin College for financial support. DFT calculations were performed using the SCIURus, the Oberlin College HPC cluster (NSF MRI 1427949), and the startup allocations awarded by Extreme Science and Engineering Discovery Environment (XSEDE TG-CHE200100).

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Authors

Contributions

E.M. and S.C. wrote the manuscript. E.M. and C.-X.Y. conceived the project and devised the experiments for the ruthenium catalysis. E.M. and X.S. devised the experiments for the iron catalysis. C.-X.Y. carried out the initial experiments and developed the ruthenium catalysis. X.S. developed the iron catalysis. S.C. performed the DFT calculations.

Corresponding authors

Correspondence to Shuming Chen or Eric Meggers.

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Competing interests

E.M., C.-X.Y. and X.S. are named inventors on a European patent application (EP22163544.4) filed by the University of Marburg on the synthesis of α-amino acids via 1,3-nitrogen migration. S.C. declares no competing interests.

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Nature Chemistry thanks Trevor Hamlin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Tables 1 and 2, Figs. 1 and 2, experimental procedures and characterization data, mechanistic studies, computational data and NMR spectra.

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Ye, CX., Shen, X., Chen, S. et al. Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids. Nat. Chem. 14, 566–573 (2022). https://doi.org/10.1038/s41557-022-00895-3

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