Abstract
The need to replace natural amino acids in peptides with nonproteinogenic counterparts in order to obtain drug-like target molecules has stimulated a great deal of innovation on several fronts (1–3). One of the more exciting areas of research in drug design has been the synthesis of so-called secondary structure peptidomimetic molecules that are expected to have the same therapeutic effects as natural peptide counterparts, with the added advantage of metabolic stability (4,5). Of particular interest to us has been the replacement of a dipeptide motif in a given natural substrate with a constrained or rigidified counterpart that stimulates β-turn formation (6,7). In particular, we have been investigating the generation of a general synthetic pathway towards a variety of substituted peptidomimetic core structures. Various appendages could then be attached to these central core units either by standard iterative conditions or, more preferably, by using combinatorial techniques. This chapter will describe the preparation of one such novel peptidomimetic nucleus and its elaboration to a fully extended β-turn peptidomimetic.
Keywords
- Combine Organic
- Boron Trifluoride Etherate
- Ethylcarbodiimide Hydrochloride
- Saturated Aqueous NaHCO3
- Tetrabutylammonium Iodide
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.
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Liskamp, R. M. J. (1994) Conformational restricted amino acids and dipeptides, (non) peptidomimetics and secondary structure mimetics. Reel. Trav. Chim. Pays-Bas 113, 1–19.
Adang, A. E. P., Hermkens, P. H. H., Linder, J. T. M., Ottenheijm, H. C. J., and van Staveren, C. J. (1994) Case histories of peptidomimetics: progression from peptides to drugs. Reel. Trav. Chim. Pays-Bas. 113, 63–78.
Giannis, A. and Kolter, T. (1993) Peptidomimetics for receptor ligands—discovery, development, and medical perspectives. Angew. Chem. Int. Ed. Engl. 32, 1244–1267.
Kahn, M., ed. (1993) Peptide secondary structure mimetics. Tetrahedron 50, 49, 3433–3689.
Hanessian, S., McNaughton-Smith, G. A., Lombart, H. G., and Lubell, W. D. (1996) Design and synthesis of conformationally constrained amino acids as versatile scaffolds and peptidomimetics. Tetrahedron 53, 12789–12854.
Hanessian, S. and Ronan, B. (1994) Design and synthesis of a prototype model antagonist of tachykinin NK-2 Receptor. Bioorg. Med. Chem. Lett. 4, 1397–1400.
Hanessian, S. and McNaughton-Smith, G. A. (1996) A versatile synthesis of a β-turn peptidomimetic scaffold: an approach towards a designed model antagonist of the tachykinin NK-2 receptor. Bioorg. Med. Chem. Lett. 6, 1567–1572.
Woo, K.-C. and Jones, K. (1991) Asymmetric synthesis from a-amino acids; some reactions of (S)-pyroglutamate Tetrahedron Lett. 32, 6949–6952
Casiraghi, G. and Spanu, P. (1995) Furan-, pyrrole-, and thiophene-based silyloxydienes for synthesis of densely functionalised homochiral compounds. Synthesis 607–626.
Boeckman, R. K. and Potenza, J. C. (1985) Catechol boron halides: mild and selective reagents for cleavage of common protecting groups. Tetrahedron Lett. 26, 1411–1414.
Czernecki, S., Georgoulis, C., Provelenghiou, C., and Fusey, G. (1976) Nouvelle méthode de benzylation ďhydroxyles glucidiques encombrés. Tetrahedron Lett. 39, 3535–3536.
Hartwig, W. and Born, L. J. (1987) Diastereoselective and enantioselective total synthesis of the heptaprotective agent clausenamide. J. Org. Chem. 52, 4352–4358.
Hughes, D. L. (1992) The Mitsunobu reaction. Org. React. 42, 335–657.
Bowers, A., Halsall, T. G., Jones, E. R. H., and Lemin, A. J. (1953). The chemistry of the triterpenes and related compounds. Part XVIII. Elucidation of the structure of polyporenic acid C. J. Chem. Soc. 2548–2556.
Coste, J. and Campagne, J.-M. (1995) A propos de ľestérification des acides carboxylic par le BOP ou le PyBOP. Tetrahedron Lett. 36, 4253–4256.
Ireland, R. E. and Longbin, L. (1993) An improved procedure for the preparation of the Dess-Martin periodinane. J. Org. Chem. 58, 2899.
Sajiki, H. (1995) Selective inhibition of benzyl ether hydrogenolysis with Pd/C due to the presence of ammmonia, pyridine or ammonium acetate. Tetrahedron Lett. 36, 3465–3468.
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© 1999 Humana Press Inc., Totowa, NJ
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Hanessian, S., McNaughton-Smith, G. (1999). Synthesis of a Versatile Peptidomimetic Scaffold. In: Kazmierski, W.M. (eds) Peptidomimetics Protocols. Methods in Molecular Medicine™, vol 23. Humana Press. https://doi.org/10.1385/0-89603-517-4:161
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DOI: https://doi.org/10.1385/0-89603-517-4:161
Publisher Name: Humana Press
Print ISBN: 978-0-89603-517-1
Online ISBN: 978-1-59259-605-8
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