Kainoids

Pyroglntamic acid is a useful starting material for the synthesis of several naniral products, such as pyrtolidme alkaloids, kainoids, and other unnaniral amino acids. Interesting chemose-lecdve Michael additions of anions derived from pyroglntamates have been reported fsee Eqs. 4.54 and4.55. ... 

The hydrogenolysis proceeds usually with inversion on Pd. This ability of Pd was used for stereospecific hydrogenation of a lactone during the synthesis of a phenyl kainoid on 10% Pd(OH2)/C in AcOEt at 40°C (Scheme 4.44).214... 

Novel C-4 thiazole kainoid analogues have been synthesised from kainic acid 43. This was converted into the a-bromoketone 44 in three steps, which reacted with thioamides and thioureas to form thiazole and aminothiazole heterocycles 45. All the synthesised thiazole kainic acid derivatives exhibited strong binding to the kainate receptors <00BMCL309>. 

Moloney and co-workers (64) also made use of the morpholinone template in the synthesis of analogues of the kainoid group of amino acids. Treatment of the template under the conditions reported by Harwood furnished the expected adducts. In keeping with earlier observations, the reaction proceeded with complete facial selectivity generating the new C(3) stereogenic center with complete control. 

Acromelic acid A (260), isolated from Clitocybe acromelaga, displays the most potent polarizing effect of aU known kainoids. By application of the same intramolecular aziridine thermolysis route described above, Takano et al. (80) outlined a concise entry into such compounds. Thermolysis of the chiral aziridine 261, derived from (5)-0-benzylglycidol in 1,2-dichlorobenzene at 200 °C, furnished the single reaction product 262 in 73% yield. The complete control over the... 

Baldwin, J.E. Fryer, A.M. Pritchard, G.J. (2000) Novel C-4 heteroaromatic kainoid analogues a parallel synthesis approach. Bioorg. Med. Chem. Lett., 10, 309-11. 

TOTAL SYNTHESIS OF KAINOIDS BY DEAROMATIZING ANIONIC CYCLIZATION... 

Our early work on kainoid synthesis was conducted in the racemic series while we were still establishing a reliable method for carrying out the asymmetric cyclisation, and we made both 2 and kainic acid 1 in racemic form first, later developing an asymmetric version of the entire synthesis of 1 and of the synthesis of a key intermediate for 2. 

The red alga Digenea simplex has been used for the treatment of roundworm disease for centuries. Its active principle is kainic acid. The related domoic acid is a constituent of another red alga, Chondria armata, used for the same purpose. These compounds, known as kainoids, are potent neurotoxins and excitatory amino acids. Kainoids are important tools in neurophysiological research. Domoic acids are also produced by diatoms and were responsible for the shellfish poisonings known as amnesic shellfish poisonings that occurred in Canada in 1987. 

This chapter covers recent developments in the synthesis of kainoids and kainoid analogues, particularly concentrating on the highly neuroexcitatory acromelic acids. The synthetic work involves the development of a short and versatile route to such derivatives starting from relatively cheap and readily available trcms-4-hy-droxy-L-proline. Syntheses of naturally occurring kainoids and synthetic analogues are covered. 

The kainoids are a well-known group of naturally occurring, nonpro-teinogenic amino acids of general structure 1 (Figure 1). They vary only in the nature of the C-4 substituent (which is always attached to the pyrrolidine ring via an sp2 center) and the absolute configuration at this position. All of the isolated derivatives exhibit S absolute stereochemistry at C-2 and a trans relative disposition of the C-2 and C-3 substituents. 

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