Asymmetric synthesis of chi-constrained pyroglutamic acids, glutamic acids and prolines for peptides and peptidomimetics

Persistent Link:
http://hdl.handle.net/10150/280129
Title:
Asymmetric synthesis of chi-constrained pyroglutamic acids, glutamic acids and prolines for peptides and peptidomimetics
Author:
Cai, Chaozhong
Issue Date:
2001
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The 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.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Organic.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
Hruby, Victor J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleAsymmetric synthesis of chi-constrained pyroglutamic acids, glutamic acids and prolines for peptides and peptidomimeticsen_US
dc.creatorCai, Chaozhongen_US
dc.contributor.authorCai, Chaozhongen_US
dc.date.issued2001en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.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.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Organic.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorHruby, Victor J.en_US
dc.identifier.proquest3010201en_US
dc.identifier.bibrecord.b4161138xen_US
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