Acromelic acids

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... 

Structurally rather complicated target molecules can be synthesized with the aid of thi-olate 1,6-addition reactions to acceptor-substituted dienes as well. For example, a richly functionalized proline derivative with a 2,4-pentadienal side chain was converted into the corresponding 6-phenylthio-3-hexen-2-one derivative by 1,6-addition of phenylthiolate, treatment of the adduct with methyl lithium and oxidation (equation 46)127. The product was transformed into acromelic acid A, the toxic principle of clitocybe acromelalga ichimura. Similarly, the 1,6-addition reaction of cesium triphenylmethylthiolate to methyl 2,4-pentadienoate served for the construction of the disulfide bridge of the macrobicyclic antitumor depsipeptide FR-901,228128. 

From recent literature it must be coneluded that mushrooms of the genera Inocybe and Clitocybe contain toxic components that are different from muscarine. The severe symptoms reported of an Israeli ehild poisoned with /. tristis therefore departed from what is known of musearine poisoning (Amitai et al., 1982). The toxic activities of C. acromelalga and C. amoenolens, two Clitocybe species containing clitidine and acromelic acid A, respectively, were studied in rats (Fukuwatari et al., 2001 Saviuc et al., 2003). 

Acromelic acid A (260), isolated from Clitocybe acromelaga, displays the most potent polarizing effect of aU known kainoids. By application of the same intramolecular aziridine thermolysis route described above, Takano et al. (80) outlined a concise entry into such compounds. Thermolysis of the chiral aziridine 261, derived from (5)-0-benzylglycidol in 1,2-dichlorobenzene at 200 °C, furnished the single reaction product 262 in 73% yield. The complete control over the... 

The Co(I) reduction of alkyl iodides which afford nucleophilic radicals has proven useful in a synthesis of acromelic acid A [139]. In a sense contrapolarization is involved and a Michael addition follows. 

The most important feature of organocobalt cyclizations is that a variety of functionalized products can be obtained, depending on the nature of the substrate and the reaction conditions. The most common transformation has been formation of an alkene by cobalt hydride elimination. Alkenes are often formed in situ during the photolysis, and with activated alkene acceptors the formation of these products by cobalt hydride elimination is very facile. Scheme 31 provides a representative example from the work of Baldwin and Li.143 The alkene that is formed by cobalt hydride elimination maintains the correct oxidation state in the product (54) for formation of the pyrimidone ring of acromelic acid. Under acidic conditions, protonation of the cyclic organocobalt compound may compete 144 however, if protonated products are desired, the cyclization can probably be conducted by the reductive method with only catalytic quantities of cobalt (see Section 4.2.2.2.2). 

This chapter covers recent developments in the synthesis of kainoids and kainoid analogues, particularly concentrating on the highly neuroexcitatory acromelic acids. The synthetic work involves the development of a short and versatile route to such derivatives starting from relatively cheap and readily available trcms-4-hy-droxy-L-proline. Syntheses of naturally occurring kainoids and synthetic analogues are covered. 

A number of kainoids have been isolated from the poisonous Japanese mushroom, Clitocybe acromelalga. Acromelic acid A 5 and acromelic acid B 6 were isolated from this source by Shirahama and co-workers6 in 1983, their structures being confirmed from total syntheses by Takano et al.7,8 and semisynthetic approaches by Shirahama.9-11 More recently, an additional three acromelates have been isolated acromelic acids C... 

This review covers mainly advances in the synthesis of naturally occurring acromelic acids and unnatural analogues, centering around... 

A similar cyclization sequence, incorporating a functionalized pyridine-containing unit rather than an isoprenoid derivative, is thought to give rise to the acromelic acids. It has been suggested that the various... 

Stizolobinic acid 15 has been formally proposed as a biosynthetic precursor to acromelic acid A 520 and, importantly, radiolabeling studies have shown that it is derived biosynthetically from L-dopa.21... 

The chemical viability of the L-dopa diol cleavage process involved in the generation of the acromelic acid C-4 substituents has been examined in a biomimetic sense by Baldwin s group in syntheses of stizolobic acid 16,22 3-(6-carboxy-2-oxo-4-pyridyl)alanine 17,22 and stizolobinic acid 1523 (Figure 5). 

An analogous biomimetic route to stizolobinic acid 15, the biosynthetic side chain precursor to acromelic acid A 5, was also carried out.23 Iron(III)-catalyzed peracetic acid cleavage of the catechol portion of 23 gave alanyl muconic acid 24 which was cyclized and concomitantly deprotected to (i)-stizolobinic acid 15 (Scheme 5). Use of Schollkopf bislactim ether methodology26 also allowed the formation of enan-tiomerically pure 15 by an analogous route. 

These results lend strong support to the L-dopa diol cleavage proposal for the biosynthesis of acromelic acid C-4 pyridone moieties. 

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. 

Of the naturally occurring kainoids, the most potent neuroexcitatory activity has been observed for the acromelic acids, and hence, much synthetic activity has been undertaken in this area. Synthetic studies have been reported, not only on the naturally occurring derivatives 5-9, but also on modified derivatives containing a number of differing aromatic substituents in the C-4 position. 

The high potency of the o-anisyl derivative 26 had been noted earlier,32,33 and so far, no natural or unnatural kainoid with higher neuroexcitatory behavior has been reported. This review covers recent progress made toward a general synthesis of this important class of kainoid, which will be referred to as acromelic acid analogues. ... 

For a full review of previous acromelic acid and other kainoid syntheses, the reader is directed to Ref. 1. Only syntheses important in the context of our work will be covered here. For convenience, the syntheses can be divided into two categories ... 

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. 

For the analogous synthesis of acromelic acid A 5, a more complex precursor 30 was prepared for cobaloxime-mediated cyclization.35 This yielded pyrrolidine derivative 31 in a 64% yield as a 1 1 mixture of the two side-chain double bond diastereoisomers (Scheme 7). The C-4 epimer was obtained in an 11% yield (i.e., a 6 1 ratio of C-4 epimers),... 

With all four of the required protected acromelic acid analogues 106, 160,161,162 and 112 to 115 available in reasonable quantities as single diastereoisomers along with the C-4 epimers 116 to 119, it only remained to carry out global deprotection. 

So far, the results suggested a versatile synthesis of C-4 aryl kainoid analogues (or acromelic acid analogues) had been developed. In summary form, the most efficient synthesis achieved involves 12 steps from rrtww-4-hydroxy-L-proline 34 (Scheme 62). This route allows access to these biologically important molecules on a relatively large scale. 

To test the versatility of our synthetic scheme, it only remained to apply it to naturally occurring acromelic acids. 

H. An Efficient Synthesis of Acromelic Acid A and an Approach to Acromelic Acid B... 

It was decided to make an attempt to combine the successful biomimetic pyridone syntheses described in the section on Biosynthesis of Acromelic Acids with the newly developed general kainoid synthesis in the preparation of acromelic acids A 5 and B 6. 

Muconate 188 was cyclized under strongly acidic conditions with concomitant deprotection to the required pyrone 189 which was quantitatively ammonolyzed to give so-called alb- acromelic acid A 190 (Scheme 69). It is worth noting the excellent overall yield achieved for the construction of the C-4 pyridone moiety from the starting protected catechol. 

Given the success of this biomimetic synthesis, attention was turned to the natural isomer acromelic acid A 5. 

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