Abstract
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 (1–3). 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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Sandler, M. and Smith, H. J. (1989) Design of Enzyme Inhibitors as Drugs, Oxford, Oxford, UK, pp. 573–649.
Rich, D. H. (1990) Peptidase Inhibitors, in Comprehensive Medicinal Chemistry (Sammes, P. G., ed.), Pergamon, Oxford, UK, pp. 391–441.
Gante, J. (1994) Peptidomimetics-tailored enzyme inhibitors. Angew. Chem. Int. Ed. Engl. 33, 1699–1720.
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.
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.
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.
Diederich, A. M. and Ryckman, D. M. (1993) Stereoselective synthesis of a hydroxyethylene fipeptide isostere. Tetrahedron Lett. 34, 6169–6172.
Jones, D. M., Nilsson, B., and Szelke, M. (1993) A short, stereocontrolled synthesis of hydroxyethylene dipeptide isosteres. J. Org. Chem. 58, 2286–2290.
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.
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.
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.
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.
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.
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.
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.
Lygo, B. (1992) Use of an alanine derived β-ketosulfone in the synthesis of peptide isosteres. Synlett 793–795.
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.
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.
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.
Still, W. C, Kahn, M., and Mitra, A. (1978) A rapid chromatographic method. J. Org. Chem. 43, 2923–2925.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Humana Press Inc., Totowa, NJ
About this protocol
Cite this protocol
Hoffman, R.V., Tao, J. (1999). Synthesis of Cbz-Protected Ketomethylene Dipeptide Isosteres. In: Kazmierski, W.M. (eds) Peptidomimetics Protocols. Methods in Molecular Medicine™, vol 23. Humana Press. https://doi.org/10.1385/0-89603-517-4:103
Download citation
DOI: https://doi.org/10.1385/0-89603-517-4:103
Publisher Name: Humana Press
Print ISBN: 978-0-89603-517-1
Online ISBN: 978-1-59259-605-8
eBook Packages: Springer Protocols