Synthesis of Cbz-Protected Ketomethylene Dipeptide Isosteres

  • Robert V. Hoffman
  • Junhua Tao
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 23)


Ketomethylene peptide isosteres have been the focus of a variety of synthetic studies because of their potential as therapeutic agents in the treatment of medical conditions mediated by proteases (1, 2, 3). The dipeptide core units 1 are chemically characterized by a 1,4-disposition of the carbonyl groups (ketone and carboxylate) and have an alkyl group at C-2 that is a chiral center. Protecting groups at amino nitrogen (typically carbamate such as Cbz or Boc) and the carboxyl group (typically ester) are usually present to make processing easier but must be readily and independently removable to permit extension in either the N-terminal or C-terminal directions (Fig. 1).

Figure 1.


Flash Chromatography Normal Reaction Time Methyl Lactate Major Diastereomer Lithium Enolate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Sandler, M. and Smith, H. J. (1989) Design of Enzyme Inhibitors as Drugs, Oxford, Oxford, UK, pp. 573–649.Google Scholar
  2. 2.
    Rich, D. H. (1990) Peptidase Inhibitors, in Comprehensive Medicinal Chemistry (Sammes, P. G., ed.), Pergamon, Oxford, UK, pp. 391–441.Google Scholar
  3. 3.
    Gante, J. (1994) Peptidomimetics-tailored enzyme inhibitors. Angew. Chem. Int. Ed. Engl. 33, 1699–1720.CrossRefGoogle Scholar
  4. 4.
    Deziel, R., Plante, R., Caron, V., Grenier, L., Llinas-Brunet, M., Duceppe, J.-S., Malenfant, E., and Moss, N. (1996) A practical and diastereoselective synthesis of ketomethylene dipeptide isosteres of the type AAψ[COCH2]Asp. J. Org. Chem. 61, 2901–2903.CrossRefGoogle Scholar
  5. 5.
    Casimir, J. R., Turetta, C, Ettouati, L., and Paris, J. (1995) First application of the Dakin-West reaction to Fmoc chemistry: syntyhesis of the ketomethylene tripeptide F-moc-Na-Asp(tBu)-(R(S)Tyr(tBu)ψPCO-CH2)Gly-OH. Tetrahedron Lett. 36, 4797–4800.Google Scholar
  6. 6.
    Baker, W. R. and Pratt, J. K. (1993) Dipeptide isosteres. 2: synthesis of hydroxyethylene dipeptide isostere diastereomers from a common γ-lactone intermediate. Preparation of renin and HIV-1 protease inhibitor transition state mimics. Tetrahedron 49, 8739–8756.CrossRefGoogle Scholar
  7. 7.
    Diederich, A. M. and Ryckman, D. M. (1993) Stereoselective synthesis of a hydroxyethylene fipeptide isostere. Tetrahedron Lett. 34, 6169–6172.CrossRefGoogle Scholar
  8. 8.
    Jones, D. M., Nilsson, B., and Szelke, M. (1993) A short, stereocontrolled synthesis of hydroxyethylene dipeptide isosteres. J. Org. Chem. 58, 2286–2290.CrossRefGoogle Scholar
  9. 9.
    D’Aniello, F. and Taddei, M. (1992) A Stereoselective method of the preparation of HIV-1 protease inhibitors based on the Lewis acid mediated reaction of allylsilanes and N-Boc-α-amino aldehydes. J. Org. Chem. 57, 5247–5250.CrossRefGoogle Scholar
  10. 10.
    Vara Prasad, J. V. N., and Rich, D. H. (1991) Synthesis of hydroxyethylene dipeptide isosteres that mimic a cyclic amino acid at the PI′ subsite. Tetrahedron Lett. 32, 5857–5860.Google Scholar
  11. 11.
    DeCamp, A. E., Kawaguchi, A. T., Volante, R. P., and Shinkai, I. (1991) Stereocontrolled addition of propionate homoenolate equivalents to chiral amino aldehydes. Tetrahedron Lett. 32, 1867–1870.CrossRefGoogle Scholar
  12. 12.
    Hoffman, R. V. and Kim, H.-O. (1992) A simple synthetic approach to Cbz-Phe-ψ-(CH2)Gly-Pro-OMe and related peptide isosteres. Tetrahedron Lett. 33, 3579–3582.CrossRefGoogle Scholar
  13. 13.
    Gonzalez-Muniz, R., Garcia-Lopez, M. T., Gomez-Monterrey, I., Herranz, R., Jimeno, M. L., Suarez-Gea, M. L., Johansen, N. L., Madsen, K., Thøgersen, H., and Suzdak, P. (1995) Ketomethylene and (Cyanomethylene)amino pseudo-peptide analogues of the C-terminal hexapeptide of neurotensin. J. Med. Chem. 38, 1015–1021.CrossRefGoogle Scholar
  14. 14.
    Lygo, B. and Rudd, C. N. (1995) Synthesis of Xaa-Gly-Xaa’ keto-methylene tripeptide isosteres incorporating phenylalanine, tyrosine, and valine units. Tetrahedron Lett. 36, 3577–3580.CrossRefGoogle Scholar
  15. 15.
    Lagu, B. R. and Liotta, D. C.(1994) Diastereoselective synthesis of the key lactone intermediate for the preparation of hydroxyethylene dipeptide isosteres. Tetrahedron Lett. 35, 547–550.CrossRefGoogle Scholar
  16. 16.
    Lygo, B. (1992) Use of an alanine derived β-ketosulfone in the synthesis of peptide isosteres. Synlett 793–795.Google Scholar
  17. 17.
    Askin, D., Wallace, M. A., Vacca, J. P., Reamer, R. A., Volante, R. P., and Shinkai, I. (1992) Highly diastereoselective alkylations of chiral amide enolates new routes to hydroxyethylene dipeptide isostere inhibitors of HIV-1 protease. J. Org. Chem. 57, 2771–2773.CrossRefGoogle Scholar
  18. 18.
    Hoffman, R. V. and Kim, H.-O. (1993) A new chiral alkylation methodology for the synthesis of 2-alkyl-4-ketoacids in high optical purity using 2-triflyloxy esters. Tetrahedron Lett. 34, 2051–2054.CrossRefGoogle Scholar
  19. 19.
    Hoffman, R. V. and Kim, H.-O. (1995) The stereoselective synthesis of 2-alkyl-γ-ketoacid and heterocyclic ketomethylene peptide isostere core units using chiral alkylation by 2-triflyloxy esters. J. Org. Chem. 60, 5107–5113.CrossRefGoogle Scholar
  20. 20.
    Still, W. C, Kahn, M., and Mitra, A. (1978) A rapid chromatographic method. J. Org. Chem. 43, 2923–2925.CrossRefGoogle Scholar
  21. 21.
    Harris, B. D., Bhat, K. L., and Jouille, M. M. (1987) Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett.. 25, 2837–2840.CrossRefGoogle Scholar
  22. 22.
    Hamada, Y., Kando, Y., Shibata, M, and Shioiri, T. (1989) Efficient total synthesis of didemnins A and B. J. Am. Chem. Soc., 111, 669–673.CrossRefGoogle Scholar
  23. 23.
    Hoffman, R. V. and Kim, H.-O. (1992) Preparation of (2R)-2-azidoesters from 2(p-Nitrobenzenesulfonyl)oxy esters and their use as protected amino acid equivalents for the synthesis of di-and tripeptides containing d-amino acid constituents. Tetrahedron 48, 3007–3013.CrossRefGoogle Scholar
  24. 24.
    Xiang, Y. B., Snow, K., and Belley, M. (1993) α-(Arylsulfonamido)borneols as auxilaries in asymmetric synthesis: an efficient and highly stereoselective method for the reduction of α-ketoesters. J. Org. Chem. 58, 993–994.CrossRefGoogle Scholar
  25. 25.
    Kempf, D. J., Codacovi, L., Wang, X. C, Kohlbrenner, W. E., Wideburg, N. E., Saldiver, A., Vasavannonda, S., Marsh, K. C, Bryant, P., Sham, H. L., Green, B. E., Betebenner, D. A., Erickson, J., and Norbeck, D. W. (1993) Symmetry-based inhibitors of HIV protease, structure-activity studies of acylated 2,4-diamino-1,5-diphenyl—3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol. J. Med. Chem. 36, 320–330.CrossRefGoogle Scholar
  26. 26.
    Jendralla, H., Henning, R., Seuring, B., Herchen, J., Kulitzscher, B., and Wunner, J. (1993) Short and efficient large scale synthesis of (R)-2-benzylsuccinic acid 4-[4-(BOC-amino)-1-piperidide] monoamide: N-terminal component of renin inhibitors by asymmetric hydrogenation. Synlett 155–157.Google Scholar
  27. 27.
    Thompson, W. J., Ghosh, A. K., Holloway, M. K., Lee, H. Y., Munson, P. M., Schwering, J. E., Wai, J., Darke, P. L., Zugay, J., Emini, E. A., Schlief, W. A., Huff, J. R., and Anderson, P. A. (1993) 3′-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease. J. Am. Chem. Soc, 115, 801–803.CrossRefGoogle Scholar
  28. 28.
    Beckett, R. P., Brown, P. D., Crimmin, M. J., and Galloway, W. A. (1993) Paper No. 147, Medicinal Chemistry, 204th National Meeting of the American Chemical Society, Denver, CO.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 1999

Authors and Affiliations

  • Robert V. Hoffman
    • 1
  • Junhua Tao
    • 1
  1. 1.Department of Chemistry and BiochemistryNew Mexico State UniversityLas Cruces

Personalised recommendations