Synthesis of Carminic Acid

Synthesis has usually followed on from full structural elucidation although from the commercial viewpoint the apparent abundant natural source, in the present case of cochineal, would not be a spur towards this objective. However experience in a number of areas shows that the availability and price of natural products are capricious matters subject to a number of vagaries including human factors as well as variations of nature. A spiralling price of cochineal in the mid eighties made total synthesis appear a more viable commercial proposition than purely an academic goal. 

In our own work (ref.39) the methyl, ethyl and benzyl esters of coccinellic anhydride methyl ether were prepared by the Dlels-Alder reaction of 2-chloro and2-bromomaleicanhydride with 3-alkoxy carbonyl-2,4-bistrimethylsiloxypenta-1,3-diene (R = Me,Et,Bn) rather than by the lengthy procedure used formerly (ref. 214). Nevertheless the Friedel-Crafts reaction of these esters with 1,4-dihydroxybenzene to afford finally 6-deoxykermesic add could not be effected. 

Reagents (i) TMSCI, EtjN, (ii) 2-Clmaleicanhydride, PhMe,A OiOHsO  

Regiospecific syntheses of kermesic add were developed both based primarily on the Diels-Alder reaction. In the first (ref. 215) methyl diacetylacetate was converted to to the enol methyl ether which was silylated to give 4-methoxy-3-methoxycarbonyl-2-trimethylsiloxypenta-2,5-diene (A). Diels-Alder addition to 2,6-dichloronaphthazarin afford, after methylation and nucleophilic displacement of 

Reagents 0) TMSCI, Et3N,ZnCl2, (ii) A,PhMe,A, (ii ) NaOMe,DMF,Civ)B, PhMe,A, (V) DMS, KjCOg, PhMe 

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Cochineal pigments are extracted from dried bodies of female insects with water or with ethanol the result is a red solution that is concentrated in order to obtain the 2 to 5% carminic acid concentration customary for commercial cochineal. For carmine lakes, the minimum content of carminic acid is 50%. An industrial procedure applied in Spain uses ammonium hydroxide as the extracting agent and phosphoric acid as the acidifying agent. For analytical purposes the extraction is carried out with 2 N HCl at 100°C. The chemical synthesis of carminic acid has also been reported and is the subject of European and United States patents. ... 

AUevi, P et al.. Synthesis of carminic acid, the colourant principle of cochineal, J. Chem. Soc. Perkin Trans., 1, 575, 1998. 

Due to the spiraling price of cochineal in the mid eighties, synthesis of carminic acid appeared to be a viable commercial proposition. This seemed at first to be readily soluble simply by the glucosylation of kermesic acid, a process conceived to be the probable biosynthetic pathway. However, numerous studies of this potential route had no useful outcome (ref. 85). Nevertheless in view of the failure of several routes from different retrosynthetic... 

Even if alizarin had served its time as a dyestuff for textiles, natural cochineal still finds broad application as a colourant for foodstuffs. Given the high expenditure required for isolation of the natural product, a ftiUy synthetic preparation of nature-identical kermesic and carminic acids can be attractive if one takes into account that higher prices can be realised for food colourants than for textile dyes. In this connection, the first total synthesis of carminic acid has been described by John Tyman and Pietro AUevi. [62,63]... 

Carminic acid, the active colourant principle of cochineal, is employed in the form of its derivatives, notably, the aluminium chelate which is obtained by semi-synthesis. 

Vanscheeuwijck, P.M., A. Teredesai, P.M. Terpstra, J. Verbeeck, P. Kuhl, B. Gerstenberg, S. Gebel, and E.L. Carmines Evaluation of the potential effects of ingredients added to cigarettes. Part 4 Subchronic inhalation studies Food Chem. Toxicol. 40 (2002) 113-131. Akimoto, H., A Kawai, H. Nomura, M. Nagao, T. Kawachi, and T. Sugimura Synthesis of potent mutagens in tryptophan pyrolysates Chem. Lett. (1977) 1061. Appleton, B.S. Levulinic acid pyrolysis Memorandum, 1986, March 3, see www.rjrtdocs.com 511373917 -3917. 

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