Kainoid amino acids are a family of none proteinogenic pyrrolidine dicarboxylic acids with similar structures and can be viewed as conformationally restricted analogues of the mammalian neurotransmitter L-glutamic acid. As the parent structure of the kainoid amino acid family, (–)-kainic acid has attracted tremendous attention because of its neuroexcitatory properties in neuropharmacology to mimic the disease states of epilepsy, Alzheimer’s disease, and Huntington’s chorea. In this thesis, a formal synthesis of (±)-kainic acid has been achieved, via a Lewis acid-catalyzed carbonyl ene cyclization as the key step, from simple starting materials 3.1 (Scheme 1). In the key step, quantitative yield of cyclization was achieved by utilizing 0.3 equivalents of Gd(OTf)3 as the catalyst in anhydrous DCM, yielding key intermediate 3.25. Moreover, the Lewis acid-catalyzed enantioselective carbonyl ene cyclization of α-keto amides (Scheme 2) represents a powerful method for the preparation of substituted pyrrolidinones. [Cu(S,S)-phenyl](SbF6)2 was found to be the most efficient chiral Lewis acid, and high yields, excellent enantioselectivity were obtained in the products. The substrate scope, reaction mechanism, diastereoselectivity and enantioselectivity of the reaction have also been systematically investigated by both experimental and computational chemistry approaches. Finally, a formal synthesis of (–)-kainic acid have been accomplished via Lewis acid-promoted PhSe group transfer radical cyclization as key the step (Scheme 3). (–)-8-Phenylmenthol was employed as a chiral auxiliary in cyclization precursor 5.13 to control the diastereoselectivity and enantioselectivity of the radical cyclization. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Thesis--University of Florida. / Description based on print version record. Typescript. Vita. Includes bibliographical references (leaves 84-89).

(2S)-trans-4-Hydroxyproline has been studied as a chiral template for the preparation of kainoids. Conversion to protected 4-ketoproline derivatives has allowed functionalisation at C-3 to be investigated. Although the tendency to epimerisation has caused problems, we have successfully introduced a variety of alkyl side chains with cis stereochemistry at this position. Functionalisation of the 3-alkyl-4-ketoprolines at C-4 has been investigated and a method has been found to prepare compounds which are functionalised stereospecifically at both C-3 and C-4. These have potential for study as kainate analogues. During our studies on the synthesis of kainoids, an unusually stereospecific deuteriation has been discovered. We have exploited this in a synthesis of (2S,3S)-[3- 2Ht]-proline, (2S,3R)-[3-2Ht]-proline and (2S)-[3,3-2H21-proline.

We have developed an one-pot reaction procedure to polysubstituted pyroglutamates with three contiguous chiral centers. The results were applied to the synthetic studies toward kainic acid and lycorane.

Attempts were made to synthesise a conformationally restricted analogue of kainic acid wherein the double bond was confined in a ring-system. The stratagem involved an intramolecular Diels-Alder reaction but could not be tested as the precursors to the cycloaddition reaction could not be prepared. Attempts were made to develop a general route to kainic acid and analogues by employing a 1,3-dipolar cycloaddition reaction between aziridines and olefins. Triazolines were used as a precursor to aziridines because of the ease of formation from alkyl azides and olefins. The required dipolar cycloaddition was found to occur but produced various side-products from the triazoline thermolysis. The subsequent Grignard reaction on the cycloaddition product gave problems as the compound epimerised under basic conditions and did not undergo reaction with methyl Grignard or methyl lithium. An attempt to prepare kainic acid and analogues by an intramolecular 1,3-dipolar cycloaddition or a 1,3-sigmatropic shift reaction failed when the basic precursors for the reaction could not be prepared.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [86]-98).

Thesis (Ph. D.)--Cornell University, August, 2008. / Vita. Includes bibliographical references (leaves 196-242).

Compared with saline injected controls, rats with bilateral injections of kainic acid (KA) in the dorsal striatum showed temporary aphagia and adipsia, long-lasting body weight decreases, increased locomotor response to d-amphetamine, increased spontaneous nocturnal locomotor activity, increased resistance to extinction, impaired acquisition and retention of avoidance behavior and increased latencies to leave start boxes in various mazes. The KA injections resulted in loss of local neurons in the dorsal striatum, with no appreciable damage either to dopaminergic terminals or to extrinisic myelinated axons, thus supporting both the selective neurotoxic action of KA on neuronal perikarya and the proposed similarity of KA-induced striatal lesions with those found in the caudate-putamen of patients with Huntington's disease (HD). The present results demonstrate that KA striatal lesioned rats also show behavioral and pharmacological similarities with HD patients. In addition, they support the view that HD is characterized by a "subcortical dementia syndrome". A review of HD is also presented. / Medicine, Faculty of / Graduate

Phenylethanolamine-N-methyltransferase (PNMT) activity is located in a subpopulation of amacrine cells in the inner nuclear layer of the rat retina. Kainic, quisqualic, and ibotenic acids, all of which are analogues of glutamic acid, were injected intravitreally to the right and saline to the contralateral left eyes of adult male rats in order to determine the effect of these agents upon retinal PNMT activity. Animals were sacrificed 1 week later for tissue removal. The effect of these agents was measured by radiometric assay for PNMT. The fall in PNMT activity was used to measure the sensitivity of the PNMT-containing cells to these agents. Kainic acid was the most potent, producing the greatest reduction in PNMT activity in the smallest doses. Quisqualic acid was intermediate in potency to that of kainic and ibotenic acids. Ibotenic acid reduced PNMT activity only in extremely high doses. The PNMT-containing cells are sensitive to the toxic actions of kainic and quisqualic acids, but relatively insensitive to the actions of ibotenic acid.

We have explored a formal [3+2] strategy that is synthetically useful for constructing polysubstituted pyroglutamates with three contiguous chiral centers in one step. Base-induced coupling/cyclization reactions of a-sulfonylacetamide with various ethyl (Z)-2-bromo-2-propenoates have been carried out. This reaction with high diastereoselectivity has been applied to the synthesis of Rolipram, Chlorpheg, Baclofen, Pseudoheliotridane and Kainic acid.