Synthesis of kainic acid

This was our initial plan, and we set about making the starting materials 37 or 87. We used the cumyl group as a readily removable bulky protecting substituent, but we found that while the amide 85 could be readily, if slowly, benzylated, it was surprisingly much harder to alkylate with a p-methoxy substituted benzyl halide than its naphthamide 

We were eager to apply this reaction to the real synthesis, but since the lactone product of the Baeyer-Villiger reaction, and each intermediate 

As before, ring opening of the lactone 98 required careful control to prevent epimerisation, and indeed migration of Boc to the primary hydroxyl group of 99, but NaOMe in methanol at -78 °C gave the alcohol 99 essentially quantitatively. 

Future prospects the domoic/isodomoic acid family 

I am grateful to all the talented co-workers who have pushed forward our work on these cyclisation reactions to this point, namely Anjum Ahmed, Ryan Bragg, Samreen Yasin, Kirill Tchabanenko, Christel Menet, Savroop Purewal and Katherine Hebditch. 

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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... 

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>. 

Greenwood, E.S., Hitchcock, P.B., and Parsons, P.J. (2003) Studies towards a total synthesis of kainic acid. Tetrahedron, 59, 3307-3314. 

This methodology has been applied to the synthesis of an advanced intermediate 211 related to the natural product (—)-a-kainic acid. The required stannane 210 was prepared in several steps from /3-lactam 209. Disappointingly, the major diastereoisomer (with respect to the new stereogenic centre) of the desired pyrrolidine 211 was not the expected one for similar cyclizations and has not the required stereochemistry across C-3 and C-4 for the synthesis of kainic acid (Scheme 56)95. Attempts to alter the stereoselectivity by changing the solvent were unsuccessful. The authors reasoned that if the intramolecular carbolithiation reaction takes place through a six-membered chair-shaped transition state, then different conformations must be preferred for the two different cyclizations leading to the cis-and frans-diastereoisomers of 211. 

In the laboratory of J.C. Anderson, the total synthesis of (+)-kainic acid was accomplished relying on a route that utilized an aza-[2,3]-Wittig rearrangement as the key step to install the correct relative stereochemistry between C2 and C3. The C4 stereocenter was established via an iodolactonization reaction. 

Viderson, J. C., Whiting, M. Total Synthesis of ( )-Kainic Acid with an /tza-[2,3]-Wittig Sigmatropic Rearrangement as the Key Stereochemical Determining Step. J. Org. Chem. 2003, 68, 6160-6163. 

Scheme 14. Synthesis of kainic acids based on the rearrangement of an allyl sulfone...

An interesting synthesis of kainic acid > mide, which undergoes cyclization to form a... 

Scheme 10-lW Synthesis of kainic acid in which Bachi and Melman used intramolecular nucleophile delivery. 

For a similar tether-mediated intramolecular dipolar cycloaddition approach to the synthesis of (-)-kainic acid S. Takano, Y. Iwabuchi, K. Ogasawara, J. Chem. Soc., Chem. Com-mun. 1988, 1204-1206. 

Figure 8.1 illustrates some structures synthesized from 65 or its pinanediol analog. Structure 66 was prepared in an incomplete synthesis directed toward leuconolide [44]. Structure 67 is enantiomeric to the steric relationships of kainic acid [45], and 68 was prepared in an attempted synthesis of kainic acid [46]. 

Enines derived from allylic substitution products by propargylation offer many possibilities in organic synthesis. We have pursued Au-catalyzed cycloadditions with carbonyl compounds [31], enyne metathesis reactions in combination with Diels-Alder reactions [32], and a Pauson-Khand reaction as part of a synthesis of kainic acid [33]. The latter synthesis is described in Scheme 11.16 as a ret-rosynthetic scheme. The Ir-catalyzed allylic amination under in situ conditions proceeded with excellent enantioselectivity. Overall, our synthesis required 12 steps and gave a total yield of 12%. 

Scheme 11.16 Retrosynthetic analysis of the synthesis of (-)-kainic acid [TBDPS = Si(f-BujMej].

Alkene Metathesis Synthesis of Kainic Acid, Pladienolide B and Amphidinolide Y... 

SCHEME 17.12. Synthesis of ( )-kainic acid using an auxiliary-controlled aza-[2,3]-Wittig... 

Naito et al. used an addition-cyclization-ffagmentation radical process in the synthesis of kainic acid. The radical reaction was induced by a thiyl radical and only required a catalytic amount of PhSH as a result of the pathway of the domino process (121 122, Scheme 25.58). 

Miyata, 0., Ozawa, Y Ninomiya, I., and Naito, T. (2000) Radical cydization in heterocycle synthesis. Part 10 a concise synthesis of (—)-kainic acid via sulfanyl radical addition-cyclization-elimination reaction. Tetrahedron, 56, 6199-6207. 

Sakaguchi, H., Tokuyama, H., and Fukuyama, T. (2007) Stereocontrolled total synthesis of (—)-kainic acid. Org. Lett., 9,1635-1638. 

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