Studies towards syntheses of kainic acid

Abstract

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.