*2.1. Discovery, Structure, and Some Properties*

The key member of the kainoid family, kainic acid (**2**) [(–)α-kainic acid], sometimes referred to as digenic acid, was isolated by Japanese chemists in the 1950 s from aqueous extracts of the red macroalga Diginea simplex (Floridiophyceae, Ceramiales, Rhodomelaceae). Compound **2** in these extracts was used as a vermifuge in the traditional medicine of East Asian countries for over a thousand years [7]. In 1953, Murakami and co-authors [8] showed this acid to be the most active anthehelmintic agent from this alga and named it kainic acid after Kaininso, the Japanese name of this alga. The structures of this compound and its isomer, allo-kainic acid (**6**), were established by X-ray analysis of the zinc salt of kainic acid and, later of kainic and allokainic acids themselves [9,10]. Compound (**2**) was also detected in several other species of lower macrophytes such as the red alga Centroceras clavulatum [9] and others [11]. The Corsican moss Alsidium helminthochorton [12] contains kainic acid (**2**), allokainic acid (**6**), and α-kainic acid lactone (**7**) (Figure 2) along with a peptide of 37 amino acids including two kainic acid residues. A mutant strain of the alga Palmaria palmata was found to produce high levels of kainic acid [13]. Chemical transformation of **2** provided several additional compounds of this series such as isokainic acid (**8**) [12].

**Figure 2.** Some compounds closely related to kainic acid (**6**–**8**).

A new stage in the fundamental research of kainic acid came when its most interesting property, the ability to specifically activate a subgroup of glutamic acid receptors, was discovered in the early 1970s. Later, these receptors were named kainate receptors (KARs) [14–16]. Kainic acid is one of the best natural agonists of KARs. It causes the influx of cellular Ca2<sup>+</sup> ions, production of reactive oxygen species, and mitochondrial dysfunctions that leads to neuronal apoptosis and necrosis. Hyperstimulation of KARs is involved in the pathogenesis of various neurodegenerative disorders such as epilepsy, Hantington's chorea, and stroke. These properties of **2** and its application in experimental neurobiology and pharmacology have attracted much attention and stimulated development of different approaches to synthesize this excitatory acid and related compounds. In 1995, after the discovery of better anthelmintics than **2**, the production of this acid as anthehelmintic in Taiwan was stopped. However, application in experimental pharmacology continued to require increasing amounts of this compound, and it began to be produced not only from algae, but also by synthesis. In the early 2000s, its price increased more than 50 times, to \$100 per 10 mg [17]. In 2012, Evens and Inglesby [18] noted that kainic acid had an estimated market value of 1 billion USA \$ per annum. The price of synthetic (−)-α-kainic acid from Sigma-Aldrich in January 2012 was \$750/50 mg and increased up to \$1749/50 mg by May 2020. The deficit and the exceptionally high price of this product necessitated development of optimal schemes for its complete syntheses, the number of which has increased significantly in the recent decade.
