A-Allokainic acid

The known anthelmintic properties of the seaweed Digenea simplex Agardh were traced back to a-kainic acid (75) after several decades of intense work by Japanese workers (117, 118). A structure was rapidly proposed for this relatively small molecule (C10H15NO4) on the basis of chemical (119) and X-ray evidence (120). a-Allokainic acid was isolated soon after from the same source, and its structure was established as 76 (121, 122). 

Two types of ring contractions have been used in the synthesis of pyrrolidines. The older one, an analogous Favorskii process, is the key step of Honjo s a-allokainic acid synthesis. The general lines of this approach are given in Scheme 29 (173). 

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... 

This sequence was obviously not amenable to a synthesis of optically active a-allokainic acid given the fact that an aminomalonate group was necessary. After unfruitful assays with menthyl esters, the Swiss group was rewarded by the discovery that the phenylmenthyl group (180) brings sufficient asymmetry to the reaction intermediate to afford products with a high percentage of favorable diastereoisomer (Scheme 35) (181). 

Pyrrolidines are attainable by [3 + 2] cycloaddition of azomethine ylides and olefins one such reaction is exemplified by a total synthesis of a-allokainic acid (Scheme 36) (182). 

In many cases, allenes are used as creative solutions to problems encountered using more saturated counterparts. This is the situation in Chevliakov and Montgomery s approach to (-)-a-kainic acid (131) [31]. They reported a late-stage common intermediate 132 that could be taken on to both (-)-a-kainic acid (131) and (+)-a-allokainic acid (133) (Scheme 19.25). Intermediate 132 was to be obtained from enyne 134. Indeed, treatment of 134 to conditions developed in their laboratories afforded the desired carboannulation to give 135. However, this pyrrole could only be taken on to (+)-a-allokainic acid (133) owing to reduction of the olefin affording... 

Asymmetric ene reactions.5 A key step in an asymmetric synthesis of the amino diacid (+ )-a-allokainic acid (5) involves an intramolecular ene reaction of the (Z)-diene 2, in which the enophile is a (Z)-( —)-8-phenylmenthyl acrylate unit. In the presence of (C2H5)2A1C1, (Z)-2 cyclizes to the two pyrrolidines 3 and 4 in the ratio of... 

The ability of the alga Digenea simplex to combat intestinal worms has been exploited for many years in Japan.28 The active component has been shown to be (-)-a-kainic acid 2 [NB not (+)-a-allokainic acid 3] and similar properties have been reported for (-)-domoic acid 4.4b Insecticidal and/or anthelmintic properties of the acromelic acids have not been reported to date. 

An analogous result had previously been reported by Ito and co-work-ers in a racemic synthesis of a-allokainic acid.70 Unsaturated derivative 103 was reduced under heterogeneous hydrogenation conditions to give a 1 19 ratio of epimers 104 105 in an overall 90% yield, the C-2 methyl ester influencing the stereoselectivity (Scheme 44). 

Oppolzer and Sammes independently developed a route to a-allokainic acid (72) based on the thermal ene reactions of (Z)-alkene (69) and ( )-alkene (73). Pyrolysis of (69) for 5 min at 180 C or 80 h at 70 C gives a 3 1 mixture of (70) and (71). Reaction of (73) under similar conditions gives a 1 1 mixture of (70) and (71). The trans isomer (70) was converted to a-allokainic acid (72) by hydrolysis and decarboxylation. Oppolzer found that EtAlCh catalyzed ene reactions of these esters proceed at very low temperature with improved selectivity for the desired trans isomer (70). Treatment of (69) at -78 °C with 3 equiv. of EtAlCh for 8 h or 20 equiv. of EtAlCh for 5 min gives only (70). Treatment of (73) at -35 C with EtAlCh gives a 89 11 mixture of (70) and (71). At least three equiv. of EtAlCh are needed to complex fully the ester groups in (69) and (73). The ene reactions of (69) and (73) differ from most ene reactions of 1,6-dienes in that rran5-pyrrolidines are the exclusive or major products. 

Oppolzer and cowoikers have developed an enantioselective version of this reaction which permits the synthesis of (+)- and (-)-a-allokainic acid from (76) and (77), respectively. - Treatment of (-)-8-phe-nylmenthyl ester (74) with EtAlCh at -78 C gives a 95 5 mixture of (76) and (77). Treatment of (-)-8-phenylmenthyl ester (75) with EtAlCh at -35 C gives an 11 89 mixture of (76) and (77). Oppolzer and Mirza used C labeling to establish that the hydrogen is transferred exclusively from the frons-methyl group of (69). This result precludes a stepwise mechanism with a free cationic intermediate which should transfer hydrogen equally from both methyl groups. 

Natural (+)-a-allokainic acid 132 comes from anti-136 by two simple steps in 73% yield. The stereochemistry of the final centre is under thermodynamic control. 

Scheme 43 Synthesis of (-)-a-kainic acid and (+)-a-allokainic acid...

The alkyl-cobalt addition-elimination (cobalt group transfer) sequence has been used by Baldwin and Li during the enantiospecific synthesis of (-)-a-kainic acid (58a) and (-)-a-allokainic acid (58b). These reactions proceed via the carbon-centered... 

The fundamental principles of asymmetric synthesis employed throughout also apply to ene reactions. Chiral additives, chiral auxiliaries, and the preparation of chirons all lead to good enantioselectivity when applied to the ene reactions. Most chiral ene reactions seem to involve addition of a chiral catalyst or the use of a chiral auxiliary. Oppolzer et al. utilized a chiral auxiliary in 713 to prepare 714 (90 % de) in a synthesis of (+)-a-allokainic acid.515 Yamamoto used the chiral aluminum catalyst 715 for the intermolecular ene reaction of 1,6-dichlorobenzaldehyde and 2-phenylthio-l-propene to give 716 in 96% yield (65 % ee).5i6 These catalysts are similar to those used in Section 11.9.B. A similar titanium catalyst (717) was used to couple methylenecyclohexane and methyl glyoxalate, giving 89% of 718 (98 % ee). The titanium catalyst... 

The epimeric (+)-a-allokainic acid was constructed by the unsaturated imide/ alkyne alkylative coupling of 9 with trimethylaluminum in 73% yield and 97 3 diastereoselectivity (Scheme 8.11) [33]. This was followed by silyl to carbonate protecting group transposition, stereoselective aUylic reduction, and removal of protecting groups to afford (+)-a-allokainic acid. The complementary nature of these two stereodivergent approaches allowed access to both epimeric natural products. 

---