Of shikimic acid

The first known pseudo-hexose, pseudo-a-DL-toZopyranose (34) was prepared by reduction of the keto-acid monoacetate (30) 26, 27). This intermediate, which had been used by Daniels, Doshi, and Smissman (9, JO) for a synthesis of shikimic acid, is prepared from the Diels-Alder adduct (31) of 2-acetoxyfuran and maleic anhydride, by a remarkable series of transformations. 

Figure 1. Biosynthetic pathway for production of shikimic acid pathway-derived phenolic compounds in higher plants.

I, 7-diphosphate.170 1 (f> This tetrose phosphate is involved with phosphoenol pyruvate in the formation of shikimic acid via 3-deoxy-2-keto-D-ara6ino-heptonic acid 7-phosphate and, hence, of aromatic compounds.170(d) A synthesis of the tetrose phosphate has been described.170 1 Aldolase shows a high affinity for the heptulose diphosphate and, compared with that for D-fructose 1,6-diphosphate, the rate of reaction is about 60 %. The enzyme transaldolase, purified 400-fold from yeast, catalyzes the following reversible reaction by transfer of the dihydroxyacetonyl group.l70(o>... 

Shikimic acid is isolated from Chinese star anis, Illicium verum, and quinic acid is extracted from the bark of Cinchona trees. Although both compounds can be found in many other plants, their isolation and purification are cumbersome. A fermentation production process of shikimic acid from other renewables such as glucose seems to be successful [46]. 

Approaches to oseltamivir phosphate (1) that were independent of ( )-shikimic acid as the raw material were also evaluated. The furan-ethyl acrylate Diels-Alder approach is shown in Scheme 7.8 (Abrecht et al., 2001, 2004). The zinc-catalyzed Diels-Alder reaction between furan and ethyl acrylate was heated at 50°C for 72 h to provide a 9 1 mixture favoring exo-isomer rac-43 over the enJo-isomer. The enJo-isomer was kinetically preferred, but with increased reaction times an equilibrium ratio of 9 1 was achieved favoring the thermodynamically preferred exo-isomer rac-43. The optical resolution of rac-43 was achieved via enantioselective ester hydrolysis using Chirazyme L-2 to give (—)-43 in 97%... 

Applications of the inhibition of enzymes of the shikimic pathway have given rise to the synthesis of numerous fluorinated derivatives of shikimic acid, especially for applications in crop sciences (bactericides, fungicides, herbicides). " Due to the lack of precise data on the inhibition mechanism, these examples are not considered here. 

The shikimate pathway was identified through the study of ultraviolet light-induced mutants of E. coli, Aerobacter aerogenes, and Neurospora. In 1950, using the penicillin enrichment technique (Chapter 26), Davis obtained a series of mutants of E. coli that would not grow without the addition of aromatic substances.4 5 A number of the mutants required five compounds tyrosine, phenylalanine, tryptophan, p-aminobenzoic acid, and a trace of p-hydroxybenzoic acid. It was a surprise to find that the requirements for all five compounds could be met by the addition of shikimic acid, an aliphatic compound that was then regarded as a rare plant acid. Thus, shikimate was implicated as an intermediate in the biosynthesis of the three aromatic amino acids and of other essential aromatic substances.6 7... 

The mutants that grew in the presence of shikimic acid evidently had the biosynthetic pathway blocked... 

As an example of conversion of complex 111 to 113, optically pure complex 126 was used for the enantioselective total synthesis of shikimic acid (129) [30]. The hydroxy-substituted diene complex 127 was prepared from 126. Silylation and decomplexation of 127 gave 128. Stereoselective dihydroxylation of the more reactive double bond of the decomplexed silyl ether derivative 128, followed by desilylation afforded (—)-methyl shikimate (129). 

The stereoselective cis diacetoxylation of 5-carbomethoxy-l,3-cyclohexadiene (146) has been applied to the synthesis of /-shikimic acid (147). 

The essential stages of the multistep route used by nature to synthesize aromatic amino acids were elucidated in the 1950s by studies on mutant bacteria (e.g. Aerobacter and Escheridiia coi) the cyclization of D-glucose (17) to 5-dehy-droquinic acid (18) and the formation of shikimic acid (19) [28], The first aromatic compound in the reaction chain is anthranilic acid (20) ... 

In Scheme 1.2 one possible retrosynthetic analysis of the unnatural enantiomer of shikimic acid, a major biosynthetic precursor of aromatic a-amino acids, is sketched. Because cis dihydroxylations can be performed with high diastereoselectiv-ity and yield, this step might be placed at the end of a synthesis, what leads to a cyclohexadienoic acid derivative as an intermediate. Chemoselective dihydroxylation of this compound should be possible, because the double bond to be oxidized is less strongly deactivated than the double bond directly bound to the (electron-withdrawing) carboxyl group. 

To a suspension of shikimic acid (25 g, 144 mmol, Aldrich) in methanol (300 ml) was added p-toluenesulfonic acid (274 mg, 1.44 mmol, 1 mol %) and the mixture was heated to reflux for 2 h. After adding more p-toluenesulfonic acid (1 mol %) the reaction was refluxed for 26 h and was evaporated. The crude methyl ester (28.17 g) was suspended in acetone (300 ml) and was treated with dimethoxypropane (35 ml, 288 mmol) and was stirred at room temperature for 6 h and then was evaporated. The crude product was dissolved in ethyl acetate (400 ml) and was washed with saturated NaHC03 (3 times 125 ml) and saturated NaCI. The organic phase was dried (MgS04), filtered, and evaporated to afford crude 7-hydroxy-2,2-dimethyl-3a,6,7,7a-... 

On the other hand, 65 (R=MOM), obtained through 63-65 (R=MOM) by employing the same sequence involving RCM, was converted into 66 on sequential diastereoselective epoxidation, protection and oxidation. On treatment with DBU, 66 afforded 67 serving as the precursor of (-)-shikimic acid (Scheme 18).26... 

Subsequently, Posner published the completely regioselective and highly stereoselective cyclo additions of racemic 3-(p-tolylsulfinyl)-2-pyrone (141) (Scheme 70) with 1,1-dimethoxyethylene [133],vinylether,and vinylthioethers [134]. With the first dienophile, the best diastereoselectivity (an 88 12 ratio of the two endo-adducts) was achieved at room temperature in toluene or hexane as the solvent (48 h). A 10 1 endo/exo mixture of cycloadducts was obtained with vinyl-ether in the presence of ZnBr2 as the catalyst, whereas a total endo selectivity was observed in reactions of 141 with vinylthioethers [134] conducted under high pressures. The bridged bicyclic lactone cycloadducts 142 have been used as versatile synthons in the synthesis of shikimic acid derivatives. Although enantio-merically pure samples of compound 141 could be obtained [134] it was not used as a starting material for asymmetric Diels-Alder reactions (the low yield of (S)-141 precluded this). 

Two main attributes are ascribed to natural shikimic acid the first, of practical nature, is related to its use as a chiral source for asymmetric synthesis, the second, of biochemical prominence, is connected to the key role it exerts in the production of benzenoid rings of natural aromatic amino acids and other important metabolites [45]. The biological relevance of shikimic acid and the challenging nature of its multichiral structure have motivated an active search for the development of viable asymmetric syntheses of this compound and novel structural variants [46],... 

Campbell, M.M. et al. The Biosynthesis and Synthesis of Shikimic Acid, Chorismic Acid, and Related Compounds. 1993 [45]... 

Jiang, S. et al. Chemical Synthesis of Shikimic Acid and Its Analogues. 1998 [46]... 

Star anise belongs to a family of spices with a rich history. In addition to its traditional uses, it has multiple applications in botany, chemistry, pharmacology and therapy. The spice is back in the region as an ingredient of the drug to fight bird flu. It is also the primary source of shikimic acid used to pro-... 

Wang, X.Q., Guo, Y.J. and Yang, C.S. (2001) Determination of shikimic acid in fruit of llliciaceae plants by HPLC with diode-array detection. Zhongguo Zhong Yao Za Zhi 26(7), 447 449. 

Different silylating agents have been utilized for the preparation of TMS derivatives of phenolic acids and related substances. Shyluk et al. [162] used the following procedure for the GC of shikimic acid and related compounds. A 2-mg amount of the acid was dissolved in 0.5 ml of dry acetone and 0.2 ml of HMDS and 0.1 ml of TMCS were added. After shaking for 30 min the mixture was allowed to stand for 10 min and 1 /al was injected into the chromatograph. SE-30, QF-1 and XE-60 were used as stationary phases. 

All numbers refer to the carbon atoms of shikimic acid)... 

II. Discovery of the Role of Shikimic Acid in the Formation of Aromatic Compounds. 237... 

Formation of Shikimic Acid in Cell-free Extracts. 245... 

VII. Conversion of Shikimic Acid to Aromatic Amino Acids. 259... 

When such strains as E. coli 83-24, which are blocked after shikimic acid, were grown on minimal medium plus aromatic supplement, they accumulated 400-800 mg. of shikimic acid per liter, together with variable amounts of shikimate 5-phosphate. Since no mutants that are blocked between shikimic acid and its phosphorylated form were found, it was considered that the phosphate ester is not on the main path of biosynthesis. As will be pointed out later, enzymic studies showed that shikimate 5-phosphate is actually an intermediate between shikimate and the aromatic compounds. It would appear, therefore, that the block in such strains as E. coli 83-24 is probably immediately after shikimate 5-phosphate. With filtrates from this organism, methods were developed for the isolation of pure shikimate and for its stepwise degradation. ... 

The next stage in the formation of the aromatic amino acids involves the conversion of shikimic acid to prephenic acid (XV) and anthranilic acid (XVI). The conversion of prephenic acid to phenylalanine and t3Tosine, and that of anthranilic acid to tryptophan are fairly well understood and... 

The known intermediates and reactions, considered above, indicate that the conversion of shikimic acid to the aromatic amino acids takes place without rearrangement of the carbon atoms of the ring. Some studies of the incorporation of labeled precursors into the aromatic amino acids have been entirely in accord with this conclusion other studies have not. This discrepancy has been briefly reviewed, but not resolved. 

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