Acromelic acid synthesis

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... 

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. 

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. 

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

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. ... 

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),... 

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. 

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. 

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

An analogous synthesis of acromelic acid B 6 was also attempted using enamide 185. C-2 methyl ester reduction and hydroxyl-directed enamide hydrogenation proceeded smoothly giving a 10 1 mixture of C-4 epimeric catechols, 197 and 198 (Scheme 74). 

The mixture of catechols was subjected to the lead tetraacetate cleavage conditions, giving the corresponding muconates (197 only shown) which were reoxidized and esterified to the corresponding C-2 methyl esters (199 only shown), again with no C-2 epimerization observed. Unfortunately, the hydrolysis with concomitant pyrone formation gave rise to a complex mixture of products, ruling out this method for the synthesis of acromelic acid B 6 (Scheme 75—major isomers only shown). 

This chapter reviews recent developments in the synthesis of both naturally occurring and unnatural acromelic acids, important members of the kainoid class of neuroexcitatory nonproteinogenic amino acid. 

Several synthetic targets have been attacked by exploitation of this methodology examples include an enantiospecific synthesis of acromelic acid A and a formal synthesis of physovenine (equations 186 and 187)362. Recent work has focused on rendering the radical generation and addition processes catalytic in cobalt successes have been achieved by using more readily reduced cobaloxime complexes and carefully controlled conditions363. 

Hashimoto, K., Konno, K., Shirahama, H., and Matsumoto, T., Synthesis of acromelic acid B, a toxic principle of Clitocybe acromelalga, Chem. Lett., 1399, 1986. 

In terms of modified operational procedures for the transformation, in their route to (-)-kainic acid, Ogasawara and co-workers performed a tandem Chugaev elimination-intramolecular ene reaction and found sodium hydrogen carbonate to be a beneficial additive.27 Derivative 35 was heated in refluxing diphenyl ether and in the presence of sodium hydrogen carbonate. This furnished tricyclic system 36, which was converted to (-)-kainic acid. They later extended this procedure for the synthesis of the acromelic acids.28... 

In a similar manner, these researchers have also synthesized [48] a C-8 side-chain analog 60 of domoic acid using a cobalt-mediated cyclization-elimination sequence on the iodide 59 (Scheme 22). They extended this methodology to an enantiospecific total synthesis of acromelic acid A 64, a potent neurotoxin obtained from poisonous mushrooms [46]. The cornerstone of their synthetic strategy was a cobalt-mediated radical cyclization of the substrate 61 which was prepared from the epoxy alcohol in optically pure form. Treatment of 61 with cobalt(I) afforded 62, which was converted to the natural product 64 via pyridone 63 using routine functional group manipulation (Scheme 23). 

Scheme 23. Cobalt-mediated synthesis of acromelic acid...

Scheme 88. Synthesis of acromelic acids A and B from a mutual intermediate aldehyde.

Azomethine ylides are another class of powerful nitrogen-based 1,3-dipoles, which provide access to pyrrolidines. An illustration of their use in stereoselective synthesis [53] was reported by Takano, starting from aziridine 28 (Scheme 18.7) [54]. Thermally induced electrocyclic ring-opening generated dipole 29 in situ, which then participated in a stereospecific cycloaddition process to give 30 in >95 5 dr. This key intermediate was subsequently transformed into acromelic acid A (31), an amino acid with important neurochemical properties. 

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