Interaction of the N-(tert-butylsulfinyl)imine of Trifluoropyruvate with Diazomethane as a Convenient Synthetic Approach to Enantiomeric Trifluoromethylamino Acids

Authors

  • Roman M. Zakharko Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine
  • Yuliya V. Rassukana Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0003-3101-9911

DOI:

https://doi.org/10.24959/ophcj.25.343956

Keywords:

amino acids, trifluoromethyl, diazomethane, enantiomeric, tert-butylsulfinyl, imine

Abstract

The interaction of enantiomerically pure N-tert-butylsulfinyl imines of trifluoropyruvate with diazomethane has been studied. It has been shown that there is the [3+2]-cycloaddition at the initial step with the formation of diastereomeric trifluoromethyltriazoline carboxylates in the ratio of 5.6:1. Treating the triazoline carboxylates with trifluoroacetic acid yielded optically pure aziridine carboxylates, which were subsequently converted into their corresponding acids. When subjected to hydrochloric acid in an ethereal solution, trifluoromethylaziridines underwent ring-opening and the sulfinyl group removal, producing α-chloromethylamino acids. The study also demonstrates the potential use of these aziridinecarboxylic acids in the peptide synthesis.

Supporting Agency

  • The work was supported by the National Academy of Sciences of Ukraine (grant No. 0124U002052).

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References

  1. Bégué, J.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine, 1st ed.; Wiley, 2008. https://doi.org/10.1002/9780470281895.
  2. Zanda, M. Trifluoromethyl Group: An Effective Xenobiotic Function for Peptide Backbone Modification. New J. Chem. 2004, 28 (12), 1401. https://doi.org/10.1039/b405955g.
    |
  3. Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Léger, S.; Li, C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as Amide Isosteres in Inhibitors of Cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15 (21), 4741 – 4744. https://doi.org/10.1016/j.bmcl.2005.07.071.
    | |
  4. Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.; Léger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Thérien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The Discovery of Odanacatib (MK-0822), a Selective Inhibitor of Cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18 (3), 923 – 928. https://doi.org/10.1016/j.bmcl.2007.12.047.
    | |
  5. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58 (21), 8315 – 8359. https://doi.org/10.1021/acs.jmedchem.5b00258.
    | |
  6. Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116 (2), 422 – 518. https://doi.org/10.1021/acs.chemrev.5b00392.
    | |
  7. Han, J.; Remete, A. M.; Dobson, L. S.; Kiss, L.; Izawa, K.; Moriwaki, H.; Soloshonok, V. A.; O’Hagan, D. Next Generation Organofluorine Containing Blockbuster Drugs. J. Fluorine Chem. 2020, 239, 109639. https://doi.org/10.1016/j.jfluchem.2020.109639.
    |
  8. Sakai, T.; Yan, F.; Kashino, S.; Uneyama, K. Asymmetric Reduction of 2-(N-Arylimino)-3,3,3-Trifluoropropanoic Acid Esters Leading to Enantiomerically Enriched 3,3,3-Trifluoroalanine. Tetrahedron 1996, 52 (1), 233 – 244. https://doi.org/10.1016/0040-4020(95)00866-7.
    |
  9. Pajkert, R.; Röschenthaler, G.-V. Synthesis of Novel α-CF3-Trifluoroalanine Derivatives Containing N-(Diethoxyphosphoryl)Difluoroacetyl Group. J. Fluorine Chem. 2010, 131 (12), 1362–1367. https://doi.org/10.1016/j.jfluchem.2010.09.010.
    |
  10. Cherednichenko, A. S.; Bezgubenko, L. V.; Rusanov, E. B.; Onys’ko, P. P.; Rassukana, Y. V. Enantiomeric N - Tert -Butylsulfinyl Imines of Methyl Trifluoropyruvate: Promising Building Blocks in Asymmetric Synthesis of α-Trifluoromethylated Amino Acids and Derivatives. ChemistrySelect 2020, 5 (43), 13569 – 13574. https://doi.org/10.1002/slct.202003500.
    |
  11. Rassukana, Y. Methyl α-Iminotrifluoropropionate: A Novel Convenient Building Block for the Preparation of Functionalized Derivatives Bearing a Trifluoroalanine Residue. Synthesis 2011, 2011 (21), 3426 – 3428. https://doi.org/10.1055/s-0030-1260249.
    |
  12. Rassukana, Y. V.; Yelenich, I. P.; Synytsya, A. D.; Onys’ko, P. P. Fluorinated NH-Iminophosphonates and Iminocarboxylates: Novel Synthons for the Preparation of Biorelevant α-Aminophosphonates and Carboxylates. Tetrahedron 2014, 70 (18), 2928 – 2937. https://doi.org/10.1016/j.tet.2014.03.030.
    |
  13. Rassukana, Y. V.; Bezgubenko, L. V.; Onys’ko, P. P.; Synytsya, A. D. Cycloaddition of N-Substituted Imines of Trifluoropyruvate with Diazomethane: Efficient Synthesis of 2-(Trifluoromethyl)Aziridine-2-Carboxylates. J. Fluorine Chem. 2013, 148, 14 – 18. https://doi.org/10.1016/j.jfluchem.2013.01.019.
    |
  14. Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V. Cycloaddition Reactions of Methyl 2-N-Trifluoroacetyliminotrifluoropropionate. Russ. Chem. Bull. 1988, 37 (1), 122 – 126. https://doi.org/10.1007/BF00962670.
    |
  15. Rassukana, Y. V.; Bezgubenko, L. V.; Stanko, O. V.; Rusanov, E. B.; Kulik, I. B.; Onys’ko, P. P. Diastereoselective Cycloaddition of (S)-N-(1-Phenylethylimino)Trifluoropropionate and Trifluoroethylphosphonate with Diazomethane. Tetrahedron: Asymmetry 2017, 28 (4), 555 – 560. https://doi.org/10.1016/j.tetasy.2017.03.009.
    |
  16. Kadaba, P. K. Rational Drug Design and the Discovery of the Δ2-1,2,3-Triazolines, A Unique Class of Anticonvulsant and Antiischemic Agents. Curr. Med. Chem. 2003, 10 (20), 2081 – 2108. https://doi.org/10.2174/0929867033456765.
    | |
  17. Marsini, M. A.; Reeves, J. T.; Desrosiers, J.-N.; Herbage, M. A.; Savoie, J.; Li, Z.; Fandrick, K. R.; Sader, C. A.; McKibben, B.; Gao, D. A.; Cui, J.; Gonnella, N. C.; Lee, H.; Wei, X.; Roschangar, F.; Lu, B. Z.; Senanayake, C. H. Diastereoselective Synthesis of α-Quaternary Aziridine-2-Carboxylates via Aza-Corey–Chaykovsky Aziridination of N - Tert -Butanesulfinyl Ketimino Esters. Org. Lett. 2015, 17 (22), 5614 – 5617. https://doi.org/10.1021/acs.orglett.5b02838.
    | |
  18. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2 : A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42 (2), 339 – 341. https://doi.org/10.1107/S0021889808042726.
    |
  19. Sheldrick, G. M. SHELXT – Integrated Space-Group and Crystal-Structure Determination. Acta Crystallogr., Sect. A:Found. Adv. 2015, 71 (1), 3 – 8. https://doi.org/10.1107/S2053273314026370.
    |
  20. Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr., Sect. C:Struct. Chem. 2015, 71 (1), 3 – 8. https://doi.org/10.1107/S2053229614024218.
    | |

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Published

2025-10-10

How to Cite

(1)
Zakharko, R. M.; Rassukana, Y. V. Interaction of the N-(tert-butylsulfinyl)imine of Trifluoropyruvate With Diazomethane As a Convenient Synthetic Approach to Enantiomeric Trifluoromethylamino Acids. J. Org. Pharm. Chem. 2025, 23, 43-49.

Issue

Vol. 23 No. 3 (2025)

Section

Original Researches

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