Asymmetric synthesis of conformationally and topographically constrained amino acids as peptidomimetics: An approach to design and synthesis of opioid receptor selective ligands

Persistent Link:
http://hdl.handle.net/10150/280393
Title:
Asymmetric synthesis of conformationally and topographically constrained amino acids as peptidomimetics: An approach to design and synthesis of opioid receptor selective ligands
Author:
Xiong, Chiyi
Issue Date:
2003
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:
As part of continuing efforts to obtain backbone and side chain conformationally constrained, novel amino acids,¹⁻⁷ we have successfully developed the asymmetric synthesis of β-phenyl-substituted cysteine, tryptophan, and serene derivatives. In this approach, the key intermediate, enantiomerically pure 3-phenylaziridine-2-carboxylic ester, was prepared from an α, β-unsaturated ester by employing the Sharpless asymmetric dihydroxylation. The aziridine was treated with 4-methoxybenzylthiol, indole, and acetic acid to give β-phenyl-substituted cysteine, tryptophan, and serine, respectively, in a clean S(N)2 type ring opening at the C3 position. This methodology was readily extended to provide a general approach to the synthesis of optically pure anti- and syn-β-substituted cysteines. We also described an effective means to synthesize 8-phenyl-substituted thiaindolizidinone amino acids through a convergent strategy. β-Phenyl-substituted cysteine benzyl esters were prepared according to our new protocol developed above. The doubly protected glutamic acid gamma-aldehyde was prepared according to a known procedure. The key step was the condensation of the aldehyde with β-phenyl-substituted cysteines to afford novel 8-phenylthiaindolizidinone amino acids as epimers at the bridgehead, which can be readily separated. These novel 8-phenylthiaindolizidinone amino acids, which are constrained β-turn dipeptide mimetics, were incorporated into Leu-enkephalin peptides as a replacement of the dipeptide Gly³-Phe⁴ to afford individual isomers of Leu-enkephalin analogues. The conformationally restricted nature of these analogues rendered them amenable to conformational analysis in solution because they are less subject to dynamic averaging than are more the flexible linear compounds.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Chemistry, Biochemistry.; 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 conformationally and topographically constrained amino acids as peptidomimetics: An approach to design and synthesis of opioid receptor selective ligandsen_US
dc.creatorXiong, Chiyien_US
dc.contributor.authorXiong, Chiyien_US
dc.date.issued2003en_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.abstractAs part of continuing efforts to obtain backbone and side chain conformationally constrained, novel amino acids,¹⁻⁷ we have successfully developed the asymmetric synthesis of β-phenyl-substituted cysteine, tryptophan, and serene derivatives. In this approach, the key intermediate, enantiomerically pure 3-phenylaziridine-2-carboxylic ester, was prepared from an α, β-unsaturated ester by employing the Sharpless asymmetric dihydroxylation. The aziridine was treated with 4-methoxybenzylthiol, indole, and acetic acid to give β-phenyl-substituted cysteine, tryptophan, and serine, respectively, in a clean S(N)2 type ring opening at the C3 position. This methodology was readily extended to provide a general approach to the synthesis of optically pure anti- and syn-β-substituted cysteines. We also described an effective means to synthesize 8-phenyl-substituted thiaindolizidinone amino acids through a convergent strategy. β-Phenyl-substituted cysteine benzyl esters were prepared according to our new protocol developed above. The doubly protected glutamic acid gamma-aldehyde was prepared according to a known procedure. The key step was the condensation of the aldehyde with β-phenyl-substituted cysteines to afford novel 8-phenylthiaindolizidinone amino acids as epimers at the bridgehead, which can be readily separated. These novel 8-phenylthiaindolizidinone amino acids, which are constrained β-turn dipeptide mimetics, were incorporated into Leu-enkephalin peptides as a replacement of the dipeptide Gly³-Phe⁴ to afford individual isomers of Leu-enkephalin analogues. The conformationally restricted nature of these analogues rendered them amenable to conformational analysis in solution because they are less subject to dynamic averaging than are more the flexible linear compounds.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectChemistry, Biochemistry.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.proquest3107054en_US
dc.identifier.bibrecord.b44667061en_US
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