Asymmetric total synthesis of (-)-alpha-Kainic acid. Metal-promoted variants of the Passerini reaction for the synthesis of functionalized heterocycles.

摘要

(−)-α-Kainic acid 1 belongs to a family of natural products, named kainoid amino acids. As a powerful neuroexcitant, kainic acid is a valuable research tool used by neuroscientists to study brain disorders. From both the structural and biological perspectives, kainic acid has stimulated enormous interest among synthetic chemists. About 50 syntheses of 1 have been published, whereas none has been found to be practical on a preparative scale. In 2000, a worldwide shortage of kainic acid prompted searches for alternative sources. Synthetic strategies towards 1 have been studied. A route from dienamide 99 using an enantioselective ene reaction led to a short and efficient asymmetric synthesis of 1 in six laboratory operations on a 1–2 g scale from readily available starting materials in an overall yield exceeding 20%. Moreover, the zirconium-mediated Strecker reaction, which represents an outgrowth of earlier amide-to-imine methodology developed in our laboratory, proved synthetically useful for the construction of proline derivatives. The preparation of 5,5-dimethylproline and (2S,5S)-pyrrolidine-2,5-dicarboxylic acid was also achieved in good yield.; The Passerini reaction, a multi-component condensation, provides access to α-acyloxycarboxamides in one step. The Lewis acid-promoted Passerini reaction has been known for some time, whereas few developments have been reported for the asymmetric Passerini reaction. The synthetic utility of the Passerini reaction has prompted studies on metal-promoted Passerini reactions. A Zn(OTf)₂-TMSCl mediated two-component variant of the Passerini reaction was developed for the construction of substituted oxazoles in 1–2 steps starting from readily available materials. A new four-component condensation reaction for the synthesis of trisubstituted oxazoles has been developed. The possibility of effecting asymmetric Zn(OTf)₂-TMSCl mediated Passerini reactions using chiral ligands was also investigated.