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Title Asymmetric Syntheses of Analogs of Kainic Acid
URL
Publication Date
Degree PhD
Discipline/Department Chemistry
Degree Level doctoral
University/Publisher Florida International University
Abstract Kainic acid has been used for nearly 50 years as a tool in neuroscience due to its pronounced neuroexcitatory properties. However, the significant price increase of kainic acid resulting from the disruption in the supply from its natural source, the alga Digenea Simplex, as well as inefficient synthesis of kainic acid, call for the exploration of functional mimics of kainic acid that can be synthesized in a simpler way. Aza kainoids analog could be one of them. The unsubstituted aza analog of kainoids has demonstrates its ability as an ionotropic glutamate receptor agonist and showed affinity in the chloride dependent glutamate (GluCl) binding site. This opened a question of the importance of the presence of one nitrogen or both nitrogens in the aza kainoid analogs for binding to glutamate receptors. Therefore, two different pyrrolidine analogs of kainic acid, trans-4-(carboxymethyl)pyrrolidine-3-carboxylic acid and trans-2-carboxy-3-pyrrolidineacetic acid, were synthesized through multi-step sequences. The lack of the affinity of both pyrrolidine analogs in GluCl binding site indicated that both nitrogens in aza kainoid analogs are involved in hydrogen bonding with receptors, significantly enhancing their affinity in GluCl binding site. Another potential functional mimic of kainic acid is isoxazolidine analogs of kainoids whose skeleton can be constituted directly via a 1, 3 dipolar cycloaddition as the key step. The difficulty in synthesizing N-unsubstituted isoxazolidines when applying such common protecting groups as alkyl, phenyl and benzyl groups, and the requirement of a desired enantioselectivity due to the three chiral ceneters in kainic acid, pose great challenges. Hence, several different protected nitrones were studied to establish that diphenylmethine nitrone may be a good candidate as the dipole in that the generated isoxazolidines can be deprotected in mild conditions with high yields. Our investigations also indicated that the exo/endo selectivity of the 1, 3 dipolar cycloaddition can be controlled by Lewis acids, and that the application of a directing group in dipolarophiles can accomplish a satisfied enantioselectivity. Those results demonstrated the synthesis of isoxazoldines analogs of kainic acid is very promising.
Subjects/Keywords Kainic Acid; Pyrrolidine; Dipolar cycloaddition; Asymmetric; Exo/Endo; Isoxazolidine; Mosher method
Contributors Kathleen S. Rein; David Becker; Kevin O'Shea; Philip Stoddard; Waston Lees
Country of Publication us
Record ID oai:digitalcommons.fiu.edu:etd-1866
Repository fiu
Date Retrieved
Date Indexed 2020-01-06
Created Date 2012-11-02 07:00:00

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…to establish that diphenylmethine nitrone may be a good candidate as the dipole in that the generated isoxazolidines can be deprotected in mild conditions with high yields. Our investigations also indicated that the exo/endo selectivity of the 1, 3…

…38 9. The affinity of trans CPAA 38 evaluated in AMPA and chloride dependant glutamate binding sites .......................................................................................................................42 10. Exo/endo selectivity in…

…synthesis of 29 given a proposed regioselectivity ................45 11. Sustmann’s classification of 1, 3-dipolar cycloaddtions..............................................48 12. Exo/endo selectivity using oxazolidinone alkene dipolarophiles…

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