Asymmetric synthesis of chi-constrained pyroglutamic acids, glutamic acids and prolines for peptides and peptidomimetics
AdvisorHruby, Victor J.
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PublisherThe University of Arizona.
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AbstractThe recent upsurge of interest in the peptide-based drug molecules has been accompanied by a great deal of attention to the design of stereochemically defined non-proteinogenic amino acids. As a continuous effort to develop efficient syntheses of χ-constrained amino acids in our group, we recently have developed a practical methodology for the asymmetric synthesis of substituted pyroglutamic acid, glutamic acid and proline analogues, which are of important use in examining the relationships between conformation and bioactivities of biologically important peptides (e.g. DPDPE, α-MSH). The key step in this method is an asymmetric Michael addition reaction between a chiral Ni(II)-complex of the glycine Schiff base (S)-NiGlyBPB, and derivatives of α,β-unsaturated carboxylic acids. This new method is the first highly diastereoselective, room temperature, organic base-catalyzed, asymmetric Michael addition reaction. Excellent chemical yields and diastereoselectivity, along with the simplicity of experimental procedure, renders the present method of immediate use for preparation of various novel beta-substituted pyroglutamic acids, glutamic acids and prolines. Decomposing the resulting addition products in acidic medium, followed by neutralizing with ammonia, gave optically pure substituted pyroglutamic; acids in good yields (>80%). The substituted pyroglutamic acids were converted to the corresponding substituted glutamic acids by hydrolysis in 6N HCl, or to substituted proline analogues by selective reduction of amide carbonyl group to a methylene group. Both novel substituted glutamic acids and prolines are being incorporated into biologically important peptide MT-II analogues for structure-activity studies.
Degree ProgramGraduate College