L-a-Kainic acid

Further reactions of 66 resulting in the formation of L-a-kainic acid are described in scheme 4. 

For example, L-a-kainic acid, obtained from the red algae Digenea simplex (Rhodomelaceae), in ht not be regarded as an alkaloid. However,... 

Kirihata, M., Kaziwara, T, Kawashima, Y, and Ichimoto, 1. (1991) An effident synihesis of (-l-)-a-kainic acid using a 3-hydroxyallylglycine derivative as a common building block. Agric. Biol. Chem., 55, 3033-3037. 

The biogenetic pathway to (-)-a-kainic acid 2 and (-)-domoic acid 4 has been proposed to involve a condensation between an isoprenoid unit 10 and a -activated 5-glutamate unit 11 (Scheme l).14... 

Watkins, J.C. Excitatory amino acids" McGeer, E.G. Olney, J.W. McGeer P.L. Eds Kainic acid as a tool in neurobiology, Raven Press, New York, 1978, p.37-69. 

Cossy has reported a synthesis of a-kainic acid that establishes the stereogenic centers on a preformed pyrrolidine ring (Eq. 20) [40], Thus, ketone 57 was prepared from L-pyroglutamic acid in 11 steps. Samarium iodide-mediated cyclization of 57 gave 58 as a mixture of stereoisomers at the carbinol carbon. Dehydration gave 59, and a 6-step sequence, starting with oxidative cleavage of the double bond, provided a-kainic acid. One notable aspect of this synthesis is the use of an enamide as a free-radical acceptor in the key cyclization. This process has been used in a number of alkaloid syntheses as will be seen in the next section. 

Jakus J, Stransky A, Poliacek I, Barani H, Bosel ova L (1998) Effects of medullary midUne lesions on cough and other airway reflexes in anaesthetized cats. Physiol Res 47 203-213 Jakus J, Stransky A, Poliacek I, Barani H, Bosel ova L (2000) Kainic acid lesions to the lateral tegmental field of medulla Effects on cough, expiration and aspiration reflexes in anesthetized cats. Physiol Res 49 387-398... 

Total syntheses of (—)-a-kainic acid (2S-carboxy-4S-(l-methylethenyl)-3S-pyrrolidineacetic acid) 12EJ04661. 

The plane structure of kainic acid was determined by three independent research groups by three different methods, and resulted in identical chemical structure [5-7].The stereochemistry ofi-a-kainic acid and of L-a-allokainic acid was determined by the total synthesis of the respective alkaloids [8,9]. 

Knight et al. employed a related rearrangement in the synthesis of (-)-a-kainic acid (Scheme4.100). The lactone starting material is derived from L-aspartic acid (92). 

The last example used a simple amino alcohol (3-aminopropanol, 6.283) as a starting material. Reaction of ethyl bromoacetate gave 6.284. Swem oxidationi i of the alcohol gave an aldehyde, and Wittig olefinationi l gave ethyl 5-(N-benzoyl-N-carboethoxymethyl)pent-2E-enoate (j6.285), which was converted to a-kainic acid. 

Hanessian, S. and Ninkovic, S. (1996) Stereoselective synthesis of ( )-a-kainic acid and (-l-)-a-allokainic acid via trimethylstannyl-mediated radical carbocyclization and oxidative destannylation. /. Otg. Chem., 61, 5418-5424. 

Miyata, O., Ozawa, Y., Ninomiya, L, and Naito, T. (1997) An enantioselective synthesis of (—)-a-kainic acid via thiyl radical addition-cyclization-elimination reaction. Synlett, 275-276. 

Takeuchi, H., et al., Elfects of alpha-kainic acid, domoic acid and their derivatives on a molluscan giant neuron sensitive to beta-hydroxy-L-glutamic acid, Eur. J. Pharmacol, 102, 2, 325, 1984. 

There are two examples in which the carboxylic group is first reduced to an alcohol. In this manner a multistep transformation yielded kainic acid 7 with the correct configuration at all three chiral centers (82JA4978). A similar reaction afforded (-)- or (+ )-lram-2,5-dimethylpyrrolidine from L- or D-Ala (87TL2083). 

An intermolecular [2+2] photocycloaddition of 2,2-dimethyl-l,3-dioxin-4-one and A -methyldihydropyrrole was the key step in the synthesis of kainic acid analogs. The cyclobutane intermediate was hydrolyzed with sodium methoxide to give ketoester 181 in good yield (Scheme 40) <2002SL167, 2003T3307>. 

Farooqui A. A., Ong W. Y., and Horrocks L. A. (2004). Neuroprotection abilities of cytosolic phospholipase A2 inhibitors in kainic acid-induced neurodegeneration. Curr. Drug Targets Cardiovasc. Haematol. Disord. 4 85-96. 

In other recent examples, l,3-dioxin-4-ones have been employed in synthetic efforts to prepare solanoeclepin A and kainic acid, modifications of which were previously mentioned (Schemes 6.31 and 6.33) [89, 91]. 

Hampson, D.R., Huang, X.P., Wells, J.W, Walter, J.A., and Wright, J.L. 1992. Interaction of domoic acid and several derivatives with kainic acid and AMPA binding sites in rat brain. Eur J Pharmacol 218, 1-8. 

Willoughby, J.O., Mackenzie, L., Medvedev, A., and Hiscock, J.J. 1997. Fos induction following systemic kainic acid early expression in hippocampus and later widespread expression correlated with seizure. Neuroscience 77, 379-392. 

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