Anacardic acids synthesis

Souto, J.A., Conte, M., Alvarez, R., Nebbioso, A., Carafa, V., Altucci, L. et al. (2008) Synthesis ofbenzamides related to anacardic acid and their histone acetyltransferase (HAT) inhibitory activities. ChemMedChem, 3, 1435-1442. 

The initial application to the synthesis of anacardic acid-8Z,l lZ-diene, used the synthons, ArCi — ArC7 - ArCio — ArCis [114,236]. 

Subsequently, this approach to the synthesis of C15 phenolic lipids consisted in the route ArCi - ArCis. It has proved generally convenient for the synthesis of the unsaturated anacardic acids. From the methodological view it is also an aspect of the use of acyclic intermediates discussed in the next section since the starting material ethyl 2-methoxy-6-methylbenzoate is prepared from ethyl acetoacetate. 

Scheme 3. Synthesis of anacardic acid 8(Z),1 l(Z)-diene and C14 reactant stereoisomers...

Scheme 3 depicts, for anacardic acid diene, the synthesis of H, by the alkylation method with a Q4 halide and the synthesis of co-hydroxy C14 the side-chains for the 8,11-diene and its stereoisomers namely (A) 7Z,10Z, (B) 7Z,10E, (C) 7E,10E and (D) 7E,10Z.. The 1-iodo derivatives of each were obtained as for route (a). This methodology has been applied to the synthesis of Fig (2)-3, anacardic acid 8(Z),ll(Z),14-triene as shown in Scheme 4. Strategies for obtaining side-chains for the stereoisomers of the triene have been described [2,114].

Anacardic acid 8Z,11Z,14-triene Scheme 4. Synthesis of Anacardic acid 8Z),1 l(Z),14-triene... 

The first synthesis modelled on biomimetic lines was directed to obtaining anacardic acids by way of polyketides [237] and later to a (17 l)-orsellinic acid [43]. A less complicated approach based on the Michael addition of ethyl acetoacetate and ethyl octadec-2-enoate, has led to a C15 orsellinic acid, Fig (4)-56, 2,4-dihydroxy-6n-pentadecylbenzoic, considered to be the biogenetic precursor of the cashew phenols [238], notably cardol, by decarboxylation. The use of bromine at the aromatisation stage in this synthesis precluded the extension of the method to components with unsaturated side-chains, although bromination with copper(ii)bromide and thermal debromination offers an alternative procedure. In a more recent approach, by the use of an oxazole intermediate and its addition to ethyl acetoacetate, (15 0) and (15 1) anacardic acid have been obtained [239] as shown in Scheme 5a, b. The 8(Z),1 l(Z)-diene and 8(Z),1 l(Z),14-triene have also been synthesised [240] by way of ethyl 6-(7-formylheptyl)-2-methoxybenzoate (C), prepared from acyclic sources, rather than, as in previous work, by semisynthesis from the ozonisation of urushiol. 

Alkylation routes have been used for the monoenes in this group. Thus, ethyl 2-methoxy-6-methylbenzoate as the carbanion (formed from lithium di-isopropylamide) has been alkylated with (Z) 1-bromotetradec-7-ene in the presence of hexamethylphosphoric triamide. Demethylation with lithium t-butytthiolate yielded (15 1)-anacardic acid (ref. 114). A more activated benzyl group having an adjacent sulphur atom was used for a synthesis of the 10(Z)-isomer of ginkgolic acid in the following way (ref. 8). 

In the triene series for the synthesis of the stereoisomers of (15 3)-anacardic acid, namely the 8(Z),11(Z),14 8(E),11(E),14 8(Z),11(E),14 and 8(Z),11(E),14 compounds by the alkylation of the ArC., intermediate (ethyl 2-methoxy-6-methybenzoate) with a 0 4 component these boration methods have been of value as an addition to selective catalytic hydrogenation and the use of terminal trimethylsilylation (ref. 167). At this stage for synthetic purposes the selective reductive use of boration methods has been mainly exploited. The chief use of combined addition/alkylation procedures is for obtaining 8(E), and 11 (E) isomers. For this, the sequence of synthons, for the side chain has to follow the different series, Ar9->ArCi2->ArCi5. 

Since cardanols can be obtained from anacardic acids and cardols from orsellinic acids, the methods outlined have a general applicability to a range of phenolic lipids. Reference has been made largely to the phenols of the Anacardiacae but the methods are likely to be applicable to other phenolic systems, and those with methylene-interrupted structures at different side-chain positions. Alkynes and phosphorans have both proved invaluable in synthetic studies but attention should be drawn to the very elegant use of ailenic compounds in the polyethenoid (arachidonic) series (ref. 168) which has a potential application with phenolic lipids. Methods for the synthesis of leukotrienes are also relevant for the methylene group-interrupted structures of phenolic lipids (169). 

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