Orsellinic acid synthesis

Tetraacetic acid (or a biological equivalent) has been suggested as an intermediate in the biosynthesis of phenolic natural products. Its synthesis has been described, as has its ready conversion to orsellinic acid. Suggest a mechanism for formation of orsellinic acid under the conditions specified. 

Cell-free systems capable of in vitro synthesis of 6-methylsalicylic acid (6-MS A) and a related tetraketide, orsellinic acid, were developed long before the advent of recombinant DNA technologies in the field of natural product biosynthesis [113-115] (Fig. 5). Since then, the biosynthetic mechanisms and molecular recognition features of 6-methylsalicylic acid synthase (6-MSAS) have been extensively studied. 6-MSAS initiates synthesis with an acetyl group derived from acetyl Co A, extends the polyketide chain to a tetraketide via three decar-boxylative condensations of malonyl CoA-derived extender units, and uses NADPH to specifically reduce one of resulting carbonyls to a hydroxyl group. In its natural producer, Penicillium patulum, the product, 6-MSA is subsequently glycosylated to form the antibiotic patulin [116]. 

Money, Scott and coworicers utilized a similar strategy of protecting the labile polyketcxie as a pyrone ring. As shown in equation (150), pyranopyrone (133) reacts with aqueous base to give orsellinic acid, presumably by way of the intermediate triketo diacid (134). 4 procedure was found to be quite general equation (151) shows a further application in the synthesis of pinosylvin, (135). ... 

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. 

The facile decarboxylation of resorcinol carboxylic acids and notably of orsellinic acids in alkaline solution poses a problem during their syntheses in high yield. For this reason the synthesis of alkoxycarbonyl derivatives is usually adopted followed by acidic hydrolysis. The removal of the protective acetyl groups in the compound shown was effected preferentially without hydrolysis of the ester group. Methyl 2,6-diacetoxybenzoate in toluene saturated with water when add to a catalyst (prepared from 4-toluenesulphonic acid monohydrate and silica gel) and stirr at 86°C during 6 hours, afford methyl... 

There has been considerable activity in the synthesis of orsellinic acids in the past decade. On account of their ready decarboxylation all these procedures also give access to 5-alkylresorcinols. These routes are summarised in the scheme shown. Homologous alkyl acetoacetates (R = R = alkyl) with thallium ethoxide or sodium hydride followed by reaction with diketene (route a) afford the corresponding homologous alkyl orsellinates (ref.23). In a related method (route b) methyl orsellinate (R = Me) results from the interaction of the monoanion with the dianion of methyl acetoacetate (ref.24). 

In the Michael addition procedure for orsellinic acid itself (ref.30) the dihydro intermediate was aromatised by a bromination/dehydrobromination step which was obviated in the preceding example by the incorporation of an acetoxy group. Complete aromatisation is also achieved by the use of an acetylenic intermediate as seen in the following case of the synthesis of 2,4-diethoxycarbonyl-3,5-dihydroxybiphenyl (ref.31). 

Other routes to the parent orsellinic acid have been listed (ref. 119). Cycloaromatisation reactions have been employed for the synthesis of 2-hydroxy-6-methylbenzoic acid and for the 4-methyl isomer as shown in the scheme The syntheses which are claimed to be regiospecific involve two different pathways in the reaction of 4-methoxybut-3-en-2-one with the bis-trimethylsilyl ether of 1-methoxybuta-1,3-diene, dependent on the conditions used (ref. 120). 

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). 

Looking at this problem as if it were a chemical synthesis, we could disconnect orsellinic acid by aldol style chemistry. 

Orsellinic acid (V) and altemariol (a heptaketide) are both formed directly from thioester substrates by acyl transferase and condensation reactions, without the intervention of reductive steps. Orsellinic acid may be considered the simplest phenol in the biogenetic sense, and the mechanism of its synthesis could prove an excellent model for these systems. 

For those engaged in the structure determination of natural products there is a security to be found in structures which can be correlated with simple repeating units. So the repeating isoprene unit found in the terpenes (Chapter 4) has been invaluable in structure assignment. At the turn of the century Collie [6, 7] recognized that many natural products contained within them the [CH2-CO] unit and that this could be exploited in chemical synthesis, as in the conversion of dehydroacetic acid 3.2) via 3.3) into orsellinic acid 3.4),... 

Durrani AA, Tyman JHP (1980) Long-chain phenols. Part 16. A novel synthesis of homologous orsellinic acids and their methyl ethers. J Chem Soc Perkin Trans 1 1658-1666... 

Griffin DA, Staunton J (1975) A novel biogenetic-type synthesis of an orsellinic acid derivative. Chem Commun 675-676... 

Kloss RA, Clayton D (1965) A synthesis of orsellinic acid. J Org Chem 30 3566... 

Santessson J (1970c) Syntheses of orsellinic acid and related compounds. Acta Chem Scand 24 3373-3378 Santesson J, Sundholm G (1968) Chemical studies on lichens. 14. Syntheses and chlorinations of norlichexanthone. Ark Kemi 30 427-431 Santesson J, Wachtmeister CA (1969) Chemical studies on lichens. 15. 2,4-Dichloro-6-methoxy-l,3-dihydroxy-8-methylxanthone (thiophaninic acid) from Pertusaria flavicans. Ark Kemi 30 445-448 Sargent MV (1980) Synthesis of grisa-2, 5 -dien-3,4 -diones by intramolecular ipsosubstitution. Chem Commim 285... 

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