Shikimic acid, synthesis

Diacetoxylation of various conjugated dienes including cyclic dienes has been extensively studied. 1,3-Cyclohexadiene was converted into a mixture of isomeric l,4-diacetoxy-2-cyclohexenes of unknown stereochemistry[303]. The stereoselective Pd-catalyzed 1,4-diacetoxylation of dienes is carried out in AcOH in the presence of LiOAc and /or LiCI and beiizoquinone[304.305]. In the presence of acetate ion and in the absence of chloride ion, /rau.v-diacetox-ylation occurs, whereas addition of a catalytic amount of LiCl changes the stereochemistry to cis addition. The coordination of a chloride ion to Pd makes the cis migration of the acetate from Pd impossible. From 1,3-cyclohexadiene, trans- and ci j-l,4-diacetoxy-2-cyclohexenes (346 and 347) can be prepared stereoselectively. For the 6-substituted 1,3-cycloheptadiene 348, a high diaster-eoselectivity is observed. The stereoselective cij-diacetoxylation of 5-carbo-methoxy-1,3-cyclohexadiene (349) has been applied to the synthesis of dl-shikimic acid (350). 

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. 

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>... 

Precursors of phenylpropanoids are synthesized from two basic pathways the shikimic acid pathway and the malonic pathway (see Fig. 3.1). The shikimic acid pathway produces most plant phenolics, whereas the malonic pathway, which is an important source of phenolics in fungi and bacteria, is less significant in higher plants. The shikimate pathway converts simple carbohydrate precursors into the amino acids phenylalanine and tyrosine. The synthesis of an intermediate in this pathway, shikimic acid, is blocked by the broad-spectrum herbicide glyphosate (i.e., Roundup). Because animals do not possess this synthetic pathway, they have no way to synthesize the three aromatic amino acids (i.e., phenylalanine, tyrosine, and tryptophan), which are therefore essential nutrients in animal diets. 

Deoxy-araWno-heptulosonic acid 7-phosphate (10) is a metabolic intermediate before shikimic acid in the biosynthetic pathway to aromatic amino-acids in bacteria and plants. While (10) is formed enzymically from erythrose 4-phosphate (11) and phosphoenol pyruvate, a one-step chemical synthesis from (11) and oxalacetate has now been published.36 The synthesis takes place at room temperature and neutral pH... 

In acyclic systems the 1,4-relative stereoselectivity was controlled by the stereochemistry of the diene. Thus, oxidation of (E,E)- and (E,Z)-2,4-hexadienes to their corresponding diacetates affords dl (>88% dl) and mesa (>95% me so) 2,5-diacetoxy-3-hexene, respectively. A mechanism involving a t vans-accto xy pal I adation of the conjugated diene to give an intermediate (rr-allyljpalladium complex, followed by either a cis or trans attack by acetate on the allyl group, has been suggested. The cis attack is explained by a cis migration from a (cr-allyl)palladium intermediate. The diacetoxylation reaction was applied to the preparation of a key intermediate for the synthesis of d/-shikimic acid, 3,... 

Phenylalanine Ammonia-Lyase. The building units of lignin are formed from carbohydrate via the shikimic acid pathway to give aromatic amino acids. Once the aromatic amino acids are formed, a key enzyme for the control of lignin precursor synthesis is phenylalanine ammonia-lyase (PAL) (1). This enzyme catalyzes the production of cinnamic acid from phenylalanine. It is very active in those tissues of the plant that become lignified and it is also a central enzyme for the production of other phenylpropanoid-derived compounds such as flavonoids and coumarins, which can occur in many parts of the plant and in many different organs (35). Radioactive phenylalanine and cinnamic acid are directly incorporated into lignin in vascular tissue (36). 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

Scheme 7.1. Gilead synthesis of GS-4071 (7) from (-)-shikimic acid (8).

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 final example described in this chapter is that done by Schriebej and co-workers. They used a scaffold with multivariant sites derived from shikimic acid. However, the end products of their synthesis were compact, highly functionalized structures reminiscent of alkaloids.34 An objective of this study was to produce a very large number of compounds for miniaturized cell-based assays. In fact, about 2 million compounds were made. 

Wood, H. B. Ganem, B. Short Chemical Synthesis of (-)-Chorismic Acid from (-)-Shikimic Acid, J. Am. Chem. Soc. 1990,112, 8907. 

The ester-substituted complex (34) has been used in synthesis of (+)- and (-)-shikimic acid, an important intermediate in the biosynthesis of aromatic compounds, as well as stereospecifically deuterium labeled shikimic acid.60 Addition of hydroxide anion to (+)-(34) gives the diene complex (+)-(182),... 

Evans, and later j0rgensen, studied the counterion effect of these Cj-symmetric bis(oxa-zoline)/Cu(II) complexes, and found that the counterion structure dramatically affected the catalytic efficiency, and SbFg- was the best among the anions examined (SbF6>PF6>OTf>BF4) [27,28] (Eq. 8A.15). This cationic bis(oxazoline)/Cu(II) catalyst has been successfully applied to asymmetric synthesis of enr-A1 -tetrahydrocannabinol [29] and enf-shikimic acid [30]. 

Usami Y, Horibe Y, Takaoka I, Ichikawa H, Arimoto M (2006) First Total Synthesis of (-)-Pericosine A from (-)-Shikimic Acid Structure Revision and Determination of the Absolute Configuration of Antitumour Natural Product Pericosine A. Synlett 1598... 

Humphreys JL, Lowes DJ, Wesson KA, Whitehead RC (2006) Arene cw-Dihydrodiols -Useful Precursors for the Preparation of Antimetabolites of the Shikimic Acid Pathway Application to the Synthesis of 6,6-Difluoroshikimic Acid and (6S)-6-Fluoroshikimic Acid. Tetrahedron 62 5099... 

In addition to acetyl-CoA, shikimic acid, mevalonic acid, and deoxyxylulose phosphate, other building blocks based on amino acids are frequently employed in natural product synthesis. Peptides, proteins, alkaloids, and many antibiotics are derived from amino acids, and the origins of the most important amino acid components of these are briefly indicated in Figure 2.1. Intermediates from the glycolytic pathway and the Krebs cycle are used in constructing many of them, but the aromatic amino acids phenylalanine, tyrosine,... 

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