Synthesis of Dipeptides with Ψ[CH20] Amide Bond Mimetics

  • Wieslaw M. Kazmierski
  • Paul C. Fritch
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 23)


This chapter describes the synthetic procedures leading to ether dipeptide isosteres of the Phe-ψ[CH2O]-spiro-Cx (9a–9e, Fig. 1) and Phe-ψ[CH2O]-Allylglycine (13, Fig. 2). Development of methods which lead to mimetics of amide bonds is central to the conversion of peptide leads into pharmaceutically viable molecules. Our strategy utilizes template 1, which provides derivatives 6b–6e upon alkylation with I, Cl-alkanes (C3–C6). Subsequent Finklestein conversion to iodides 7b–7e is then followed by cyclization to spirocyclic derivatives 5b–5e (Fig. 3).
Figure 1.

Synthesis of Phe ψ[CH2O]Spiro isosteres 9a–9e.

Figure 2.

Synthesis of Phe ψ[CH2O]Allylglycine 13

Figure 3.

Synthesis of morpholinones 5b–5e.


Organic Phase General Procedure Amide Bond Sodium Hydride Cerium Ammonium Nitrate 
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.
    TenBrink, R. E., Pals, D. T., Harris, D. W., and Johnson, G. A. (1988) Renin inhibitors containing ψ[CH2O] pseudopeptide inserts. J. Med. Chem. 31, 671–677.CrossRefGoogle Scholar
  2. 2.
    TenBrink, R. E. (1987) A method for the preparation of stereochemically defined ψ/[CH2O] pseudodipeptides. J. Org. Chem. 52, 418–422.CrossRefGoogle Scholar
  3. 3.
    Anthony, N. J., Gomez, R. P., Holtz, W. J., Murphy, J. S., Ball, R. G., and Lee, T.-J. (1995) Pseudo-allylic A1,3 strain as a conformational control element: stereoselective synthesis of ψ[CH2O] pseudopeptides. Tetrahedron Lett. 22, 3821–3824.CrossRefGoogle Scholar
  4. 4.
    Norman, B. H. and Kroin, J. S. (1995) Stereoselective synthesis of novel methylene ether dipeptide isosteres. Tetrahedron Lett. 36, 4151–4154.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 1999

Authors and Affiliations

  • Wieslaw M. Kazmierski
    • 1
  • Paul C. Fritch
    • 1
  1. 1.Department of Medicinal ChemistryGlaxo Wellcome Research and DevelopmentResearch Triangle Park

Personalised recommendations