A-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]. 

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. 

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. 

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

Previous work in Baldwin s group based around cobalt(I)-mediated cyclization had led to syntheses of (-)-a-kainic acid 2, (+)-allokainic acid 3,34 and acromelic acid A 5.35 A cobaloxime-mediated cyclization of 27 gave the separable pyrrolidines 28 and 29, suitable for conversion to (-)-a-kainic acid 2 and (+)-allokainic acid 3, respectively.34 In this instance, the required stereoisomer 28 for the preparation of (-)-a-kainic acid 2 predominated in a ratio of 28 29,1.7 1 (Scheme 6). Both 28 and 29 were carried through to the respective kainoids 2 and 3. In this case, asymmetry was introduced at a very early stage in the synthesis via a Sharpless asymmetric epoxidation. 

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

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. 

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%. 

Scheme 21. Synthesis of precursors to (-)-a-kainic acid and (-)-a-allokainic acid by cobalt group transfer protocol...

This methodology was used as the key eyclization step in the stereo- and enan-tioselective synthesis of ( + )- and (-)-a-kainic acid 43, the prototype of a group of neuroexeitatory amino aeids that are important substrates in physiological and pharmacological studies of the central nervous system [22e-f], One of the major obstacles in the synthesis of kainic aeid is the establishment of the 3,4-c/5-stereochemistry. This was overcome by using on the pyrroline intermediate 42 a... 

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. 

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