Synthesis of - -a-Kainic Acid

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). 

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. 

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. 

Xia, Q. Ganem, B. Asymmetric total synthesis of (-)-a-kainic acid using an enantioselective, metal-promoted ene cyclization. Org. Lett. 

This reaction was applied to an asymmetric total synthesis of (+)-a-kainic acid [103] (Eq. 79). 

Oppolzer and coworkers used an intramolecular ene reaction as the key step in the synthesis of a-kainic acid (81). Thermolysis of diene (78) at 180 C results in reversible isomerization to diene (79), which undergoes an intramolecular ene reaction to give the expected cis-substituted pyrrolidine (80) in 90% yield. Hydrolysis gives a-kainic acid (81) in 60% yield. This approach was extended to the synthesis of (-)-a-kainic acid. Thermolysis of (82) for 40 h at 130 "C gives the key intermediate (83) in 75% yield. 

B. Ganem and co-workers accomplished the asymmetric totai synthesis of (-)-a-kainic acid using an enantioselective, metai-promoted ene cyclization. The chirai bis-oxazoiine-magnesium perchlorate system strongly favored the formation of the c/s-diastereomer in the cyclization. Enantiomerically pure kainic acid was synthesized from readily available starting materials on a 1-2 g scale in six steps in an overall yield of greater than 20%. 

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. 

Cyclization. If a proper leaving group is present at an allylic position of a 1,6-diene, an opportunity for elimination exists after formation of a bicyclic titanacycle. The resulting alkyltitanium species may be functionalized. A synthesis of (—)-a-kainic acid has been developed accordingly. 

An intramolecular Claisen rearrangement was the key step in the enantiospecific synthesis of (—)-a-kainic acid. The silylation of the azalactone (141) gave the intermediate ketene silyl ether, which upon warming underwent a [3,3] Claisen rearrangement to furnish the pyrrolidine (142), via a boatlike transition state (Scheme 11) <87CC1220,91JCS(Pl)705>. 

Barco, A., Benetti, S., Spalluto. G., Casolari, A., Pollini, G.P., and Zanirato, V. (1992) A new approach to kainoids through tandem Michael reaction methodology application to the enantioselective synthesis of (-E) and (-)-a-allokainic acid and to the formal synthesis of ( )-a-kainic acid./. Org. Chem., 57, 6279-6286. 

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. 

Bachi, M.D. and Melman, A. (1998) Enantioseledive total synthesis of (—)-a-kainic acid. PureAppl. Chem., 70, 259-262. 

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