Shikimic add

The Claisen rearrangement has attracted special attention because of the pronounced solvent dependence of the reaction [92] and the biochemically important Claisen rearrangement of chorismate to prephenate in the shikimic add pathway [93] (Fig. 12). Both aspects of the reaction have been studied recently using DFT methods. 

E. Haslam, Shikimic Add Metabolism and Metabolites, Wiley, New York, 1993. 

The simultaneous and selective protection of the two equatorial hydroxyl groups in methyl dihydroquinate [11L1, Scheme 3.111 j as the butane-2,3-diace-tal 111 2 was a key strategic feature in a synthesis of inhibitors of 3-dehydroqui-nate synthase.205 Later in the synthesis, deprotection of intermediate 111.4 required three steps (a) hydrolysis of the trimethylsilyl ether and the butane-2,3-diacetal with trifluoroacetic acid (b) cleavage of the isopropyl phosphonate with bromotrimethylsilane and (c) hydrolysis of the methyl ester with aqueous sodium hydroxide. Compound 111 1 has also been used in the synthesis of inhibitors 3-dehydroquinate dehydratase206 and influenza neuraminadase207-208 as well as shikimic add derivatives.209 210... 

Further support for the conclusion that two molecules of shikimic acid are involved in phenazine biosynthesis comes from the incorporation of >-[1,6,7,- CaJshikimic acid [as (134)] into phenazine-1-carboxylic acid (138) in Pseudomonas aureofaciens with close to a fifth of the activity present in the carboxy-group, as required if two molecules of shikimic acid are involved [however, the same result would have been obtained if only one molecule of shikimic add was implicated provided that a symmetrical intermediate of type (139) was also involved in the elaboration of (138)]. 

A further family of aromatic compounds produced by lichens is derived from shikimic add via phenylalanine and is exemplified by vulpinic acid (7.55), which was isolated from Letharia vulpina. Vulpinic acid has been synthesized by the lead tetra-acetate oxidation of polyporic acid. Lichens also produce some alkylated citric acid derivatives such as lichesterinic acid (7.56) and some sterols. 

Karpf, M. and Trussardi, R. (2006) Process for the preparation of 4,5-diamino shikimate add derivatives. US Patent Application, 20060047002. 

Sebacic add dinitrile, 50, 20 SELECTIVE a-BROMINATION OF AN ARALKYL KETONE WITH PHENYLTRIMETHYLAMMO-NIUM TRIBROMIDE 2-BRO-MOACETYL-6-METHOXY-NAPHTHALENE AND 2,2-DI-BROMOACETYL-6-METHOXY-NAPHTHALENE,53, 111 Shikimic add, SO, 27 Silver benzoate, as catalyst in decomposition of diazoketones, 50,... 

The predominant organic adds in commonly consumed fruit are citric and/or malic acids. Actinidia fruits are unusual in that quinic acid levels are similar to that of citric add as the predominant organic add. Although the nutritional importance of quinic add has not been established, it is an intensely interesting compound because it is a key intermediate for aromatic compound biosynthesis via the shikimic add pathway. Moreover, quinic add is a component of several potent free radical scavengers, including chlorogenic add. 

The biosynthesis of the aromatic amino acids proceeds via shikimic acid. [56] The starting point is erythrose-4-phosphate, which is produced in the Calvin cycle. The enzyme-catalysed aldol condensation with phosphoenol pyruvate leads to a heptulose, 3-deoxy-(D)-arahino-heptulonic add 7-phosphate. Elimination of phosphate produces an enol, which is converted hy a further aldol condensation into 3-dehydroquinic acid. Elimination of water and reduction then yield shikimic add. 

The effect of addition of amino acids to medium 3 (which already contains aspartate, arginine, and histidine as nitrogen sources) was studied by Cheng et al. (76). Of 18 amino acids tested at 1 g/liter, only L-lysine showed a marked stimulation of both volumetric and specific rapamycin production. Its effect was maximal at 10 g/liter, the highest concentration examined. Lysine stimulation is probably due to its conversion to pipccolic acid, a precursor of rapamycin (58). Suppression of rapamycin production was observed with L-methionine and L-phenylalanine. Since methionine is a rapamycin precursor (20), it is peculiar that it interferes with rapamycin formation. However, for some unknown reason, methionine often suppresses formation of antibiotics for which it acts as precursor (77-80). One possibility for phenylalanine suppression of rapamycin formation was considered to be feed-back inhibition of shikimic add formation, since shikimate is a precursor of rapamycin (20), However, in a recent study (81) demonstrating stimulation of rapamycin biosynthesis by exogenous shikimate (57 mM), it was also shown that shikimate does not reverse phenylalanine interference. 

Synthetic Applications The stereocontrol associated with the palladium-catalyzed 1,4-diacetoxylation is useful in synthetic applications. An example is the cis-1,4-diacetoxylation of 5-carbomethoxy-l,3-cyclohexadiene and subsequent transformation of the diacetate to shikimic add (Eq. (11.36)) [57b]. 

Qnnamaldehyde s formation from shikimic add utilizes one of only two biogenetic routes in nature that lead to the aromatized benzene ring (the other pathway is found in the acetogenins and produces secondary metabolites like usnic acid see Experiment [llA]).The shikimic acid route contributes to a class of metabolites called the phenylpropanes (Ph—C3), of which cinnamaldehyde is one of a limited number of simple end products. Another close relative is, for example, eugenol from oil of cloves. 

CI.ll Tamiflu (Oseltamivir), C16H28N2O4, is a drug that is used to treat influenza. The preparation of Tamiflu begins with the extraction of shikimic add from the seedpods of the Chinese spice, star anise. From 2.6 g of star anise, 0.13 g of shikimic acid can be obtained and used to produce one capsule containing 75 mg of Tamiflu. The usual adult dosage for treatment of influenza is 75 mg of Tamiflu twice daily for 5 days. (2.7, 6.5,7.2,7.3,7.4,7.5)... 

Organic acids have been named both as the anionic form (e.g. shikimate) and as the free acid (e.g. shikimic add) to accord with the context of the discussion. Where the emphasis in the text is largely chemical, they are named as adds but where the emphasis is biochemical and the transformations most probably involve the anion of the acid, they are named as anions. 

Shikimic add was first described as a natural product from the plant Illicium religiosum Sieb. by Eykmann in 1885 and it was from the Japanese name of this plant, shikimi-no-ki, that the name shikimic acid was derived. Eykmann s own investigations coupled with the detailed structural emd stereochemical studies of Fischer and Dangschat " , Freudenberg and Karrer led to the formulation of both (—)-shikimic acid and the closely related natural product (—)-quinic acid as (4) and (5) respectively. Fischer and Dangschat also remarked on the close structural similarity of known aromatic... 

Mutant strains of Escherichia coli and Aerobacter aerogenes were described which had a quintuple requirement of aromatic substrates (L-phenylalanine, L-tyrosine, L-tryptophan, 4-amino-benzoate and 4-hydroxybenzoate) for growth. Certain of these mutants were found to accumulate (—)-shikimic acid (4) in their culture filtrates and other mutants, blocked in earlier reactions in the pathway, were able to utilise (—)-shikimic acid (4) to replace the aromatic sutetrates. These observations established with great probability that (—)-shikimic add was a common precursor for each of these aromatic compounds. Experiments of this type permitted each of the intermediate in the common pathway, 3-dehydroquinic add (10), 3-dehydroshikimic add (11), (—)-shikimic add (4), shikimic add-3-phosphate (12), 5-enolpyruvylshikimic add-3-phosphate (13) and chorismic acid (14), to be isolated and characterised and for the pathway... 

This pattern of labelling, when it was analysed, prompted Sprinson to propose that in Escherichia coli (—)-shikimic add was biosynthesised from a three carbon fragment of glycolysis (8) and a four carbon sugar (7) which was derived from the pentose phosphate pathway of carbohydrate metabolism. 

The identification of these two precursors was greatly fadlitated by experiments at the enzymic level and by the observation that cell free extracts of Escherichia coli 83-24 were able to convert various sugar phosphates and in particular D-altroheptulose-7-phosphate to (—)-shikimic add, albeit in low yields ( — 5 per emit). When D-altroheptulose-7-phosphate and D-fructose-1,6-diphosphate were... 

There is little doubt that lignin is ultimately a product of the shikimate pathway of metabolism and that the lignin building units, the hydroxycinnamyl alcohols (70-72), are derived from the corresponding cinnamic adds by reductive means. Several workers have for example observed that [ Q-shikimic add is readily metabolised... 

Salicylic Acid.—It has recently been demonstrated (see last year s Report ) that whereas 6-methylsalicylic acid in both micro-organisms and higher plants is acetate-derived, salicylic add itself is formed in both groups of organisms by the shikimic add pathway. Further confirmation of this has come from Marshall and Ratledge, who have studied the enzymology of biosynthesis of salicylic acid in Mycobacterium smegmatis. These authors isolated the enzyme salicylate synthetase, which catalyses the last step (see Scheme 1) in synthesis of salicylic acid (1) from isochorismic add (2), formed in turn from chorismic (3) and shikimic adds (4). The enzyme has no cofactor requirements and converts (2) directly into (1). No evidence could be obtained for the presence in bacterial cultures of the possible intermediate 2,3-dihydroxy-2,3-dihydrobenzoic add. 

Plouvier, V. The Study of Quinic and Shikimic Adds, Bergenin and Heterosides from Some Hamamelideae. C.R. hebd, seances Acad. Sci. 252, 599 (1961). 

---