Kainic acid derivatives

Diastereoselective hydroformylation can be achieved in special cases through passive substrate control in which conformational preferences are transferred in the corresponding selectivity-determining hydrometalation step [4-6]. A recent example is the highly diastereoselective hydroformylation of a kainic acid derivative (Scheme 17) [64], The selective formation of the major diastereomer has been explained via a reactive substrate conformation in which allylic 1,2-strain has been minimized. In this situation the czs-positioned methylene carbonylmethoxy group controls the catalyst attack to occur from the si face exclusively. 

Scheme 17 Diastereoselective hydroformylation of a kainic acid derivative relying on passive substrate control...

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>. 

The rearrangement of allylic esters obtained from )5-amino acids was investigated by Knight et al. during their syntheses of kainic acid derivatives [123]. They subjected different protected j8-alanine esters 211 to the typical Ireland-Claisen conditions, and by far the best results are obtained with the N-Boc-protected substrates (Scheme 5.2.67, Table 5.2.22). In the case of the Z-protected derivatives only low yields are isolated along with other materials which appeared to arise from metal-... 

ScHWARCz, R., ScHOLZ, D., and Coyi.e, J. T., 1978a, Structure-activity relations for the neurotoxicity of kainic acid derivatives and glutamate analogues. Neuropharmacology 17 145-151. 

An efficient stereodivergent entry to (—) a-kainic acid derivatives involves the intramolecular cyclization of the allene 183 to give the cycloadduct 184 in 57 % yield... 

If the alkenes and acetylenes that are subjected to the reaction mediated by 1 have a leaving group at an appropriate position, as already described in Eq. 9.16, the resulting titanacycles undergo an elimination (path A) as shown in Eq. 9.58 [36], As the resulting vinyltitaniums can be trapped by electrophiles such as aldehydes, this reaction can be viewed as an alternative to stoichiometric metallo-ene reactions via allylic lithium, magnesium, or zinc complexes (path B). Preparations of optically active N-heterocycles [103], which enabled the synthesis of (—)-a-kainic acid (Eq. 9.59) [104,105], of cross-conjugated trienes useful for the diene-transmissive Diels—Alder reaction [106], and of exocyclic bis(allene)s and cyclobutene derivatives [107] have all been reported based on this method. 

The main lines of this approach were later embodied in an enantioselective synthesis of (—)-a-allokainic acid (Scheme 34) (179). The sole stereo center of die ene reaction starting material was derived from a glutamic acid derivative (132) to avoid loss of optical activity via double bond migration (see Scheme 33), the a acid function of kainic acid had to be reduced before the pyrolysis step... 

ASP is caused by eating shellfish contaminated with one or more of three domoic acid derivatives, which are excitatory neurotoxic amino acids (Baden and Trainer, 1993). Domoic acid is produced by the diatom Nitzchia pungens and accumulates in mussels, specifically Mytilus edulis (Baden and Trainer, 1993). Domoic acid is similar in structure to the excitatory dicarboxylic amino acid, kainic acid, and has an antagonistic effect at the glutamate receptor. Both... 

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. 

Hashimoto K., Watanabe K., Nishimura T., Iyo M., Shirayama Y., and Minabe Y. (1998). Behavioral changes and expression of heat shock protein hsp-70 mRNA, brain-derived neurotrophic factor mRNA, and cyclooxygenase-2 mRNA in rat brain following seizures induced by systemic administration of kainic acid. Brain Res. 804 212-223. 

Cyclopentyl sulfonamide derivatives, (I), prepared by Cantrell (1) were effective as AMPA and kainic acid receptor repotentiators and used in treating depression and related psychiatric disorders. 

Mono-, (III), and difluoro-sulfonamide derivatives, (IV), prepared by Bender (3) and Aikins (4), respectively, were effective in reactivating and resensitizing AMPA and kainic acid receptors to glutamate. 

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. 

They are not excessively used in medicinal chemistry. Divinyl oxide is an excellent general anesthetic but it polymerizes easily and forms peroxides. Stabilization of the compound is usually achieved by addition of 0.01% of Ai-phenyl a-naphtylamine. On the other hand, compounds such as kainic acid, vinylbital, quinine, 17a-vinyl-testosterone, compound SKF 100 047, and vigabatrin (Figure 20.16) are perfectly stable vinyl derivatives. 

In the first method for preparing kainic acid the key intermediate is 4,5-disub-stituted piperidin-2-one (60) which was obtained by two different methods (Scheme 3) [91]. The piperidin-2-one (60) is brominated to form the monobromo derivative... 

In terms of modified operational procedures for the transformation, in their route to (-)-kainic acid, Ogasawara and co-workers performed a tandem Chugaev elimination-intramolecular ene reaction and found sodium hydrogen carbonate to be a beneficial additive.27 Derivative 35 was heated in refluxing diphenyl ether and in the presence of sodium hydrogen carbonate. This furnished tricyclic system 36, which was converted to (-)-kainic acid. They later extended this procedure for the synthesis of the acromelic acids.28... 

Intramolecular ene reactions take place readily, even with compounds containing a normally unreactive enophile. The cyclization is parhcularly effective for the formation of hve-membered rings, although six-memhered rings can also be formed from appropriate unsaturated compounds. The geometrical constraints imposed on the transition state often result in highly selective reactions. For example, the homoallylic alcohol 242 with an axial alcohol substituent was the exclusive product from the cyclization of the unsaturated aldehyde 241 (3.157). In a synthesis of the neuroexcitatory amino acid (—)-a-kainic acid 245, the diene 243, itself prepared from (5)-glutamic acid, was cyclized to the pyrrolidine derivative 244 with almost complete stereoselectivity (3.158). ... 

In September 2007, following my nomination as a university lecturer at the University of Strasbourg, I joined the laboratory of Dr. Andre Mann in the faculty of pharmacy at Strasbourg. The recent work of this laboratory concerned the reaction of hydroformylation. They had just published an article on the synthesis of derivatives of kainic acid by cyclohydrocarbonylation (CHC) in collaboration with Professor Ojima, and another on olefin hydroa minomethylations assisted by microwave irradiation with Professor Taddei. One year before my arrival, a research student had the role of continuing... 

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