Prephenic acid

Phenylalanine- and Tyrosine-Derived Alkaloids. Carbohydrate metaboHsm leads via a seven-carbon sugar, ie, a heptulose, derivative to shikimic acid [138-59-0] (57), C H qO, which leads in turn to prephenic acid [126-49-8] (58), (43). 

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. 

Preparative chromatography, 6 374, 385 Preparative high performance liquid chromatography, 6 441 Prephenic acid, 2 83-84 Prepolymers, 24 705... 

Table 1 Kinetic and thermodynamic parameters for the spontaneous, enzyme-catalysed and antibody-catalysed conversion of chorismic acid [23] into prephenic acid [24],...

Claisen rearrangement chorismic acid to prephenic acid... 

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

The biogenetic pathway proposed by Chakraborty for the formation of carbazole (1) and 3-methylcarbazole (2) proceeds through Af-phenylated anthranilic acid (406). This hypothesis is based on aromatic C-methylation of aniline with methionine, and originates from anthranilic acid (397) and prephenic acid (404). Until now, there are no N-phenylated anthranilic acid derivatives known naturally, therefore, this hypothesis is lacking substantial biogenetic evidence. However, the isolation of carbazole (1), 3-methylcarbazole (2), and several derivatives of 3-methylcarbazole... 

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 flavonoids, which comprise the largest group of these natural products, are derived from a mixed acetate-shikimate pathway. A shikimate-derived C6-C3 unit combines with a six-carbon polyketide chain to provide the open-chain precursor (685) of the group. The derivation of p-hydroxycinnamic add (p-coumaric acid), the C6-C3 component, from shikimic acid proceeds through chorismic acid, prephenic acid and phenylalanine. 

A thoroughly investigated reaction on the biosynthetic pathway to aromatics is the [3+3]-sigmatropic Claisen rearrangement from chorismic acid to prephenic acid (Figure 18.8). 

Returning to the main course of the shikimate pathway, a singular rearrangement process occurs transforming chorismic acid into prephenic acid... 

Pathways to the aromatic amino acids L-pheny-lalanine and L-tyrosine via prephenic acid may vary according to the organism, and often more than one route may operate in a particular species according to the enzyme activities that are available (Figure 4.12). In essence, only three reactions are involved, decarboxylative aromatization,... 

FIGURE 3.1 The biosynthetic pathway from chorismate to L-phenylalanine in Escherichia coli K12. The mnemonic of the genes involved are shown in parentheses below the enzymes responsible for each step. Compound 1 is L-phenylalanine, 2 is chorisimic acid, 3 is prephenic acid, and 4 is phenylpyruvic acid. 

We have arrived at prephenic acid, which as its name suggests is the last compound before aromatic compounds are formed, and we may call this the end of the shikimic acid pathway. The final stages of the formation of phenylalanine and tyrosine start with aromatization. Prephenic acid is unstable and loses water and CO2 to form phenylpyruvic acid. This a-keto-acid can be converted into the amino acid by the usual transamination with pyridoxal. 

Among the more interesting reactions involved in making all three of these natural products are the loss of ammonia from phenylalanine to give an alkene and the introduction of extra OH groups around the benzene rings. We know how a para OH of Tyr is introduced directly by the oxidation of prephenic acid before decarboxylation and it is notable that the extra oxygen functionalities appear next to that point. This is a clue to the mechanism of the oxidation. 

On standing in alkali in the laboratory, prephenic acid rearranges to 4-hydroxyphenyl-lactic acid with specific incorporation of deuterium label as shown. Suggest a mechanism, being careful to draw realistic conformations. 

These properties, combined with the fact that the second methoxyl group is not attached to the benzene ring and must, therefore, be derived from the dihydroxyphenylalanine (or prephenic acid) precursor, suggest the presence in rhynchophylline of a /3-methoxyacrylic ester residue. Convincing support for this conclusion is provided by a comparison of the UV- and IR-spectra of rhynchophylline with those of appropriate model compounds. Thus, the UV-spectrum of rhynchophylline is identical with the summation spectrum of 3-ethyloxindole and ethyl jS-ethoxy-a-methylacrylate (74), and it is also closely similar to that of formosanine. The IR-absorption of rhynchophylline in the carbonyl region also resembles that of formosanine, except that rhynchophylline exhibits an additional band, of medium intensity, at 1645 cm-1 this band, however, is also present in the spectrum of ethyl jS-ethoxy-a-methylacrylate. 

Pseudoakuammicine is the first racemic base to be discovered in the strychnine-yohimbine series of alkaloids, and the question of its origin naturally arises. The only stage in the extraction of Picralima seeds during which racemization of akuammicine might have occurred involved prolonged percolation with hot methanol however, as already discussed, akuammicine is not racemized under these conditions but suffers a more extensive decomposition. In any event, such a racemization would necessarily involve fission of the 3,7 and 15,16 bonds, followed by a nonspecific resynthesis, which is considered to be a very unlikely possibility. It was therefore suggested that, in the plant, pseudoakuammicine is produced by a nonspecific biosynthesis this would accord with its formation from a tryptophan-phenylalanine precursor, but not from an optically pure prephenic acid derivative (40). 

Finally, the possible biogenesis of echitamine remains for discussion (88). This can readily be rationalized, using as an intermediate a base such as geissoschizine (LX), one of the hydrolytic fission products of the alkaloid geissospermine. Geissoschizine can clearly be obtained from tryptamine and dihydroxyphenylalanine or prephenic acid by a route which has many analogies in indole alkaloid chemistry. Dehydrogenation... 

Biogenetically, this interesting variant on the heteroyohimbine theme could originate from tryptamine and either dihydroxyphenylalanine (Robinson) or prephenic acid (LXXV) (Wenkert) as example, a possible route from prephenic acid via the seco-prephenate-formaldehyde unit (LXXVI) (97) is outlined below. A vital feature in this proposal (and... 

The mode of biosynthesis of none of these alkaloids is known but, in the case of the iboga group, some guesses have been made (39, 63, 64), all of which start from the amino acids, tryptophan and dihydroxy-phenylalanine, and involve a fission of the latter s aromatic ring. A more sophisticated approach (65), starting from precursors of the aromatic amino acids, namely shikimic and prephenic acids, is apparently not in agreement with recent work on other indole alkaloids (66). The genesis of most indole alkaloids appears to stem from tryptophan and three... 

Fig. 8.15 Biosynthesis of L-Phe. Compounds EPSP, 5-enol-pyruvoylshikimic acid-3-phosphate CHA, chorismic acid PPA, prephenic acid PPY, phenylpyruvic acid S3P, shikimic acid 3-phosphate.

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... 

---