Prephenic acid synthesis

Functionality can be built into either the diene or dienophile for purposes of subsequent transformations. For example, in the synthesis of prephenic acid, the diene has the capacity to generate an enone. The dienophile contains a sulfoxide substituent that is subsequently used to introduce a second double bond by elimination. 

The preparation of a key intermediate in an imaginative synthesis of prephenic acid is depicted below. Write a series of equations showing the important steps and intermediates in this process. Indicate the reagents required to bring about the desired... 

The ring of anthranilic acid, like that of prephenic acid, is derived, in appropriate bacterial extracts, from shikimate 5-phosphate, the amino group originating in the amide nitrogen of glutamine. An oxidation-reduction appears to be involved in this synthesis, since diphosphopyridine nucleotide is a required cofactor. At least one other cofactor, present in yeast extract and so far unidentified, is also required. 

Figure 4. Enzymes of Rhizobium (a) and Lemna (b) proposed as sites of glyphosate inhibition of aromatic amino acid synthesis. Abbreviations CM, chorismate mutase PDH, prephenate dehydrogenase and PD, prephenate dehydratase.

This new route to cyclohexadienones has been used in a total synthesis of the disodium salt of prephenic acid (2j, an unstable intermediate in biosynthesis of various phenols. The first attempt used the dienophile 3 in which the potential... 

Because shikimic acid does not enter into mammalian metabolism, its synthesis and use are clear targets at which to aim selective toxicity. In bacteria, shikimic acid arises by cyclization of the carbohydrate 3-deoxy-2-oxo-D- mAzVzoheptulosonic acid 7-phosphate, which is formed by the condensation of erythrose 4-phosphate and phosphoenolpyruvic acid. Shikimic acid undergoes biosynthesis to chorismic acid (4.55) which is the enolpyruvic ether of raw5-3,4-dihydroxy cyclohexa-1,5-diene-1-carboxylic acid. As its name indicates, this acid sits at a metabolic fork, the branches of which lead to prephenic acid, to phenylalanine (and hence to tyrosine), to anthranilic acid (and hence tryptophan), to ubiquinone, vitamin K, and/ -aminobenzoic acid (and hence folic acid). 

Danishefsky and Hirama have published a neat total synthesis of the disodium salt of prephenic acid (24), a central intermediate in the shikimic acid biosynthetic pathway.The key step involves a Diels-Alder reaction between the diene (22) and the unsaturated lactone (23). A crucial feature of this synthesis is the simultaneous protection of both the C-lO-carboxy and C-8-keto functions as a methoxy-lactone, allowing umasking in a single step by alkaline hydrolysis. 

The structure of prephenic acid actually represents two stereoisomers. I was no longer able any more to try solving this problem unpublished mechanistic interpretation of some observations did suggest the stereochemistry later on shown to be the correct one, but at this stage, my active participation in research on the shikimate pathway came to an end. Fortunately, the stereochemistry of prephenic acid was elucidated by Plieninger, who also did much pioneering work on the total synthesis, which he achieved in 1978 independently, Danishefsky and Hirama succeeded in synthesizing prephenic acid. 

Organic synthesis has made significant contributions to the study of the shikimate pathway, including the total synthesis of arogenate (Fig. 4) by Danishefsky s group. This synthesis relies on the Diels-Alder strategy used earlier in Danishefsky s synthesis of prephenic acid. ... 

DANISHEFSKY, S., M. HIRAMA, N. FRITSCH, J. CLARDY. 1979. Synthesis of disodium prephenate and disodium epiprephenate. Stereochemistry of prephenic acid and an observation on the base-catalyzed rearrangements of prephenic acid to p-hydroxyphenyllactic acid. J. Am. Chem. Soc. 101 7013-7018. 

The terminal stage of the synthesis has had some light cast upon it by the results of enzyme studies. It has been shown that prephenic acid is an intermediate in the path from phenylalanine to tyrosine. Moreover, phenylpyruvic acid also lies along the pathway of phenylalanine synthesis. 

Origin of the side chain of the aromatic amino acids and of prephenic acid from a three-carbon glycolytic intermediate was established by isotopic results as previously mentioned. Evidence of this is that the / -carbon of tyrorine is derived about equally and almost entirely from C-1 and 6 of glucose (217), and that the o-carbon was h hly labeled while the /3-carbon was unlabeled in tyrorane derived from pyruvate-a-C (219). Synthesis of prephenic acid presumably results from condensation of a pyruvate moiety with a cyclic intermediate beyond shikimic acid that has lost two hydroxyl groups. 

This route, often called the shikimic acid pathway involves the condensation of phosphoenolpyruvate (2) and a 4-carbon sugar erythrose-4-phosphate (1) which is derived from the pentose phosphate pathway. The product of this reaction is converted to shikimic acid (3). Phosphorylation of shikimic acid to yield 5-phosphoshikimic acid (4) is followed by the addition of another molecule of phospho-enol pyruvate (2) which results in the synthesis of prephenic acid (5). Aromatization of the prephenic acid can give rise to phenylpyruvic acid (6) which upon transamination becomes phenylalanine. The carbon skeletons of the other aromatic amino acids, tryptophane and tyrosine are also synthesised via the shikimic acid pathway as is lignin and many of the aromatic secondary products described in Chapter 6. 

Chorismate is converted to prephenate (the precursor of phenylalanine and tyrosine) and anthranilate (the precursor of tryptophan). (Chorismate can also be converted to 4-hydroxybenzoic acid, the precursor of the ubiquinones. 4-Hydroxyphenylpyruvate is also a precursor in the synthesis of plastoquinone and various tocopherols.) PRPP is an abbreviation for phosphoribosylpyrophosphate. 

Cycloaddition of the diene 20 with dienophiles bearing a phenyl sulfoxide substituent leads, after elimination of phenyl sulfenic acid and hydrolysis, to a 4,4-disubstituted cyclohexadienone or a substituted phenol product. For example, an elegant synthesis of disodium prephenate 34 makes use of this chemistry... 

The pivotal position occupied by chorismic acid in the shikimic acid pathway has been established in several higher plants as well as microorganisms (Fig. 2) (Edwards and Jackman, 1965 Cotton and Gibson, 1968 Schmit and Zalkin, 1969 Gilchrist et al., 1972). By action of chorismate mutase [Fig. 3 (8)], chorismate is converted to prephenate which is subsequently metabolized by two independent pathways [Fig. 3 (9 and 11)] to form phenylalanine and tyrosine. Alternatively, chorismate serves as a substrate for anthranilate synthase, the first enzyme in the pathway branch leading to the synthesis of tryptophan [Fig. 4 (13)]. 

---