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Photochemical single-step synthesis of β-amino acid derivatives from alkenes and (hetero)arenes

Nature Chemistry volume 14, pages 1174–1184 (2022)Cite this article

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Abstract

β-Amino acids are frequently found as important components in numerous biologically active molecules, drugs and natural products. In particular, they are broadly utilized in the construction of bioactive peptides and peptidomimetics, thanks to their increased metabolic stability. Despite the number of methodologies established for the preparation of β-amino acid derivatives, the majority of these methods require metal-mediated multistep manipulations of prefunctionalized substrates. Here we disclose a metal-free, energy-transfer enabled highly regioselective intermolecular aminocarboxylation reaction for the single-step installation of both amine and ester functionalities into alkenes or (hetero)arenes. A bifunctional oxime oxalate ester was developed to simultaneously generate C-centred ester and N-centred iminyl radicals. This mild method features a remarkably broad substrate scope (up to 140 examples) and excellent tolerance of sensitive functional groups, and substrates that range from the simplest ethylene to complex (hetero)arenes can participate in the reaction, thus offering a general and practical access to β-amino acid derivatives.

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Fig. 1: Synthesis of β-amino acid derivatives.
Fig. 2: Synthetic applications.
Fig. 3: Mechanistic investigations.
Fig. 4: Proposed reaction mechanism and density functional theory calculations.

Data availability

Materials and methods, experimental procedures, mechanistic studies, computational studies, sensitivity assessment and NMR spectra are available in the Supplementary Information. CIF crystallographic data files and xyz coordinates of the optimized structures are available as Supplementary Files. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2113934 (1), 2113935 (S1), 2115949 (S3) and 2114975 (138). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Amino Acid Market Research Report by Product Type, Source, Application, and Region-Global Forecast to 2026—Cumulative Impact of COVID-19 (Research And Markets, accessed 30 October 2021); https://www.researchandmarkets.com/reports/4905142/amino-acid-market-research-report-by-product#tag-pos-3

  2. Cardillo, G. & Tomasini, C. Asymmetric synthesis of ß-amino acids and α-substituted β-amino acids. Chem. Soc. Rev. 25, 117–128 (1996).

    Article  CAS  Google Scholar 

  3. Juaristi, E. & Soloshonok, V. A. Enantioselective Synthesis of β-Amino Acids (Wiley, 2005).

  4. Kudo, F., Miyanaga, A. & Eguchi, T. Biosynthesis of natural products containing β-amino acids. Nat. Prod. Rep. 31, 1056–1073 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Spiteller, P. Amino Acids, Peptides and Proteins in Organic Chemistry (Wiley, 2009).

  6. Cabrele, C., Martinek, T. A., Reiser, O. & Berlicki, L. Peptides containing β‑amino acid patterns: challenges and successes in medicinal chemistry. J. Med. Chem. 57, 9718–9739 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Seebach, D. & Gardiner, J. β-peptidic peptidomimetics. Acc. Chem. Res 41, 1366–1375 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Wang, L., Mao, Y., Wang, Z., Ma, H. & Chen, T. Advances in biotechnological production of β‑alanine. World J. Microbiol. Biotechnol. 37, 79 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Zrenner, R. H. et al. A functional analysis of the pyrimidine catabolic pathway in arabidopsis. New Phytol. 183, 117–132 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miltenberger, K. Ullmann’s Encyclopedia of Industrial Chemistry—Hydroxycarboxylic Acids, Aliphatic (Wiley, 2000).

  11. Weiner, B., Szymański, W., Janssen, D. B., Minnaard, A. J. & Feringa, B. L. Recent advances in the catalytic asymmetric synthesis of β-amino acids. Chem. Soc. Rev. 39, 1656–1691 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Rulev, R. Y. Aza-Michael reaction: achievements and prospects. Russ. Chem. Rev. 80, 197–218 (2011).

    Article  CAS  Google Scholar 

  13. Qian, B., Chen, S., Wang, T., Zhang, X. & Bao, H. Iron-catalyzed carboamination of olefins: synthesis of amines and disubstituted β‑amino acids. J. Am. Chem. Soc. 139, 13076–13082 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Bruneau, C., Renaud, J.-L. & Jerphagnon, T. Synthesis of β-amino acid derivatives via enantioselective hydrogenation of β-substituted-β-(acylamino)acrylates. Coord. Chem. Rev. 252, 532–544 (2008).

    Article  CAS  Google Scholar 

  15. Kobayashi, S., Mori, Y., Fossey, J. S. & Salter, M. M. Catalytic enantioselective formation of C–C bonds by addition to imines and hydrazones: a ten-year update. Chem. Rev. 111, 2626–2704 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Meyer, C. C., Ortiz, E. & Krische, M. J. Catalytic reductive aldol and Mannich reactions of enone, acrylate, and vinyl heteroaromatic pronucleophiles. Chem. Rev. 120, 3721–3748 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Podlech, J. & Seebach, D. The Arndt–Eistert reaction in peptide chemistry: a facile access to homopeptides. Angew. Chem. Int. Ed. 34, 471–472 (1995).

    Article  CAS  Google Scholar 

  18. Cheng, J., Qi, X., Li, M., Chen, P. & Liu, G. Palladium-catalyzed intermolecular aminocarbonylation of alkenes: efficient access of β‑amino acid derivatives. J. Am. Chem. Soc. 137, 2480–2483 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Davies, J. et al. Ni-catalyzed carboxylation of aziridines en route to β‑amino acids. J. Am. Chem. Soc. 143, 4949–4954 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Xuan, J. & Xiao, W.-J. Visible-light photoredox catalysis. Angew. Chem. Int. Ed. 51, 6828–6838 (2012).

    Article  CAS  Google Scholar 

  21. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Silvi, M. & Melchiorre, P. Enhancing the potential of enantioselective organocatalysis with light. Nature 554, 41–49 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Stephenson, C. R. J., Yoon, T. & MacMillan, D. W. C. Visible Light Photocatalysis in Organic Chemistry (Wiley, 2018).

  26. Strieth-Kalthoff, F., James, M. J., Teders, M., Pitzer, L. & Glorius, F. Energy transfer catalysis mediated by visible light: principles, applications, directions. Chem. Soc. Rev. 47, 7190–7202 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Zhou, Q.-Q., Zou, Y.-Q., Lu, L.-Q. & Xiao, W.-J. Visible-light-induced organic photochemical reactions through energy-transfer pathways. Angew. Chem. Int. Ed. 58, 1586–1604 (2019).

    Article  CAS  Google Scholar 

  28. Strieth-Kalthoff, F. & Glorius, F. Triplet energy transfer photocatalysis: unlocking the next level. Chem 6, 1888–1903 (2020).

    Article  CAS  Google Scholar 

  29. Teders, M. et al. The energy-transfer-enabled biocompatible disulfide–ene reaction. Nat. Chem. 10, 981–988 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Ma, J. et al. Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes. Science 371, 1338–1345 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang, H.-M., Bellotti, P., Ma, J., Dalton, T. & Glorius, F. Bifunctional reagents in organic synthesis. Nat. Rev. Chem. 5, 301–321 (2021).

    Article  CAS  Google Scholar 

  32. Pitzer, L., Schäfers, F. & Glorius, F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations. Angew. Chem. Int. Ed. 58, 8572–8576 (2019).

    Article  CAS  Google Scholar 

  33. Silverman, R. B. From basic science to blockbuster drug: the discovery of lyrica. Angew. Chem. Int. Ed. 47, 3500–3504 (2008).

    Article  CAS  Google Scholar 

  34. Purdy, R. H., Morrow, A. L., Moore, P. H. & Paul, S. M. Stress-induced elevations of γ-aminobutyric acid type A receptor-active steroids in the rat brain. Proc. Natl Acad. Sci. USA 88, 4553–4557 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wille, U. Radical cascades initiated by intermolecular radical addition to alkynes and related triple bond systems. Chem. Rev. 113, 813–853 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Xiong, T. & Zhang, Q. Recent advances in the direct construction of enantioenriched stereocenters through addition of radicals to internal alkenes. Chem. Soc. Rev. 50, 8857–8873 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Monos, T. M., McAtee, R. C. & Stephenson, C. R. J. Arylsulfonylacetamides as bifunctional reagents for alkene aminoarylation. Science 361, 1369–1373 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Constantin, T. et al. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides. Science 367, 1021–1026 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Bunescu, A., Abdelhamid, Y. & Gaunt, M. J. Multicomponent alkene azido-arylation by anion-mediated dual catalysis. Nature 598, 597–603 (2021).

    Article  PubMed  Google Scholar 

  40. Fische, H. The persistent radical effect: a principle for selective radical reactions and living radical polymerizations. Chem. Rev. 101, 3581–3610 (2001).

    Article  Google Scholar 

  41. Leifert, D. & Studer, A. The persistent radical effect in organic synthesis. Angew. Chem. Int. Ed. 59, 74–108 (2020).

    Article  CAS  Google Scholar 

  42. Su, Y.-L. et al. Radical-mediated strategies for the functionalization of alkenes with diazo compounds. J. Am. Chem. Soc. 142, 13846–13855 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Patra, T., Bellotti, P. & Glorius, F. Photosensitized intermolecular carboimination of alkenes through persistent radical effect. Angew. Chem. Int. Ed. 59, 3172–3177 (2020).

    Article  CAS  Google Scholar 

  44. Karageorgis, G., Warriner, S. & Nelson, A. Efficient discovery of bioactive scaffolds by activity-directed synthesis. Nat. Chem. 6, 872–876 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Zhang, X. et al. A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C−H arylation. Nat. Chem. 10, 540–548 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Khan, M. U. et al. Synthesis and characterization of metabolites and potential impurities of balsalazide disodium, an anti-inflammatory drug. Synth. Commun. 40, 2241–2253 (2010).

    Article  CAS  Google Scholar 

  47. Desai, A. A. Sitagliptin manufacture: a compelling tale of green chemistry, process intensification, and industrial asymmetric catalysis. Angew. Chem. Int. Ed. 50, 1974–1976 (2011).

    Article  CAS  Google Scholar 

  48. Nikitas, N. F., Gkizis, P. L. & Kokotos, C. G. Thioxanthone: a powerful photocatalyst for organic reactions. Org. Biomol. Chem. 19, 5237–5253 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Kudisch, M., Lim, C.-H., Thordarson, P. & Miyake, G. M. Energy transfer to Ni–amine complexes in dual catalytic, light-driven C–N cross-coupling reactions. J. Am. Chem. Soc. 141, 19479–19486 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Patra, T., Mukherjee, S., Ma, J., Strieth-Kalthoff, F. & Glorius, F. Visible-light-photosensitized aryl and alkyl decarboxylative functionalization reactions. Angew. Chem. Int. Ed. 58, 10514–10520 (2019).

    Article  CAS  Google Scholar 

  51. Patra, T., Das, M., Daniliuc, C. G. & Glorius, F. Metal-free, photosensitized oxyimination of unactivated alkenes with bifunctional oxime carbonates. Nat. Catal. 4, 54–61 (2021).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Ma, X. Zhang, X. Yu, T. Hu (all WWU) and S. Chang (KAIST) for helpful assistance and discussion. Generous financial support from the Alexander von Humboldt Foundation and the Deutsche Forschungsgemeinschaft (SFB 858) is gratefully acknowledged. H.K. thanks the Institute for Basic Science (IBS-R010-D1) in the Republic of Korea for financial support.

Author information

Authors and Affiliations

  1. Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Münster, Germany

    Guangying Tan, Mowpriya Das, Peter Bellotti, Constantin Daniliuc & Frank Glorius

  2. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science, Daejeon, South Korea

    Hyeyun Keum

  3. Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, South Korea

    Hyeyun Keum

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  1. Guangying Tan
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Contributions

F.G. and G.T. conceived the project. G.T., M.D. and P.B. performed the synthetic experiments. H.K. performed the density functional theory calculations. C.D. analysed the X-ray structures. G.T., M.D., H.K. and F.G. supervised the research and wrote the manuscript with contributions from all the authors.

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Correspondence to Frank Glorius.

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The authors declare no competing interests.

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Nature Chemistry thanks Gabriela Oksdath-Mansilla and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–14 and Tables 1–4. Experimental data, synthesis and characterization data, supplementary discussion, computational and procedural details, x-ray crystallographic data, NMR spectra.

Supplementary Data 1

Crystallographic data for compound 1; CCDC reference 2113934.

Supplementary Data 2

Crystallographic data for compound 138; CCDC reference 2114975.

Supplementary Data 3

Crystallographic data for compound S1; CCDC reference 2113935.

Supplementary Data 4

Crystallographic data for compound S3; CCDC reference 2115949.

Supplementary Data 5

Cartesian coordinates for all calculated structures.

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Tan, G., Das, M., Keum, H. et al. Photochemical single-step synthesis of β-amino acid derivatives from alkenes and (hetero)arenes. Nat. Chem. 14, 1174–1184 (2022). https://doi.org/10.1038/s41557-022-01008-w

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