Synthesis of a Versatile Peptidomimetic Scaffold
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, 2, 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.
KeywordsCombine Organic Boron Trifluoride Etherate Ethylcarbodiimide Hydrochloride Saturated Aqueous NaHCO3 Tetrabutylammonium Iodide
- 4.Kahn, M., ed. (1993) Peptide secondary structure mimetics. Tetrahedron 50, 49, 3433–3689.Google Scholar
- 5.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.Google Scholar
- 9.Casiraghi, G. and Spanu, P. (1995) Furan-, pyrrole-, and thiophene-based silyloxydienes for synthesis of densely functionalised homochiral compounds. Synthesis 607–626.Google Scholar
- 13.Hughes, D. L. (1992) The Mitsunobu reaction. Org. React. 42, 335–657.Google Scholar
- 14.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.Google Scholar