Kainic acid synthesis

Me2BBr, CH2CI2, —78°, 45 min, 100% yield. These conditions were chosen when conventional acid-catalyzed hydrolysis resulted in aldehyde epimerization during a kainic acid synthesis. ... 

Suggest a synthesis for amine (5), needed to make the potent neuronal excitant a-kainic acid. ... 

Pyrrolidine 2-548e was used as substrate for the synthesis of the natural product a-kainic acid [286, 287]. 

The synthesis of kainic acid, acromelic acid, and related compounds such as domoic acid has been the subject of considerable investigation.125 A simple and direct route to neurophysi-ologically active kainic acid analogs has been reported, as shown in Scheme 10.21.126... 

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 low percentage of obtaining products belonging to the a-kainic acid series (at best 50%) was attributed to unfavorable transition states with repulsion between one of the aminomalonate ester groups and the isoprenyl chain. These difficulties were circumvented by using a simple a-amino ester (131) in lieu of the aminomalonate group this has led to a simple synthesis of a-kainic acid (Scheme 33) (178). 

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... 

A novel Ni(cod)2-catalyzed allene/alkene cyclization has been utilized in the synthesis of (-)-a-kainic acid (Scheme 16.88) [96], A stereocontrolled metallacycle would be generated via coordination of Ni(0) species to both an alkene of the enone and a proximal allenyl double bond followed by oxidative cyclization of the Ni(0) complex. The metallacycle would be transformed into the product through transmetallation of Me2Zn and ensuing reductive elimination. 

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>. 

Xia, Q. Ganem, B. (2001) Asymmetric taal synthesis of (-)-o-kainic acid using an aiantioselective, metal-promoted ene cyclization. Org. Lett., 3, 485-7. 

Thus, (2R)-pumiliotoxin C (214) has been prepared from (R)-norvaline (212). The asymmetric center in the triene (213) controls the configuration at three carbon atoms 210). a-Kainic acid, isolated from the algae Digena simplex and Centrocerus clavulatum, was prepared by total synthesis. Its enantioselective synthesis involved a stereocon trolled intramolecular cycloaddition of a (S)-glutamic acid211). Asymmetric cycloadditions also play a decisive role in the synthesis of chiral cytochalasins. In this case 212> the primary chiral information was carried by (S)-alanine and (S)-phenylalanine, respectively. 

The intramolecular ene reaction [198] proceeds in good reioselectivity if either the ene or the enophile component is linked to polarizable groups. Based on the direction of polarization an excellent synthesis of (—)-a-kainic acid [199] has been designed. 

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. 

Many of these effects can still be observed after pretreatment with kainic acid in the neostriatum (113). This treatment degenerates the neostriatal efferent pathways and by consequence also the neostriatal efferent part(s) of the nigrostriatal loop. Apparently postsynaptic dopamine receptors, if located on these striatonigral neurons play only a minor role in the regulation of dopamine synthesis and turnover in dopaminergic neurons and the major role has to be attributed to dopaminergic autoreceptors. 

Combination of 26 with pericyclic reaction led to a diastereocontrolled synthesis of anthelmintic (-)-kainic acid and anticholinergic (-)-physostigmine and (-)-physovenine. Thermolysis of 68, obtained from (+)-26 furnished diastereoselectively 69 by intramolecular ene reaction. (-)-Kainic acid was obtained from 69 through a sequence of several steps of reactions (Scheme 19).27... 

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