Benzoic Acids From C6c3 Compounds

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Some of the simple hydroxybenzoic acids (C6Ci compounds) such as 4-hydroxybenzoic acid and gallic acid can be formed directly from intermediates early in the shikimate pathway, e.g. 3-dehydroshikimic acid or chorismic acid (see page 121), but alternative routes exist in which cinnamic acid derivatives (C6C3 compounds) are cleaved at the double bond and lose two carbons from the side-chain. Thus, 4-coumaric acid may act as a precursor of 4-hydroxybenzoic acid, and ferulic acid may give vanillic acid (4-hydroxy-3-methoxybenzoic acid) (Figure 4.26). A sequence analogous to that involved in the P-oxidation of fatty acids (see page 18) is possible, so that the double bond in the coenzyme A ester would be hydrated, the hydroxyl group oxidized to a ketone, and the P-ketoester would then lose acetyl-CoA by a reverse Claisen reaction, giving the coenzyme A ester of 4-hydroxybenzoic acid. Whilst this sequence has been generally accepted, newer evidence supports another side-chain cleavage mechanism, which is different from the fatty acid P-oxidation pathway (Figure 4.26).

Coenzyme A esters are not involved, and though a similar hydration of the double bond occurs, chain shortening features a reverse aldol reaction, generating the appropriate aromatic aldehyde. The corresponding acid is then formed via an NAD+-dependent oxidation step. Thus, aromatic aldehydes such as vanillin, the main flavour compound in vanilla (pods of the orchid Vanilla planiflora; Orchidaceae) would be formed from the correspondingly substituted cinnamic acid without proceeding through intermediate benzoic acids or esters. Whilst the substitution pattern in these C6C1 derivatives is generally built up at the C6C3 cinnamic acid stage, prior to chain shortening, there exists the possibility of further hydroxylations and/or methylations occurring at the C6C1 level, and this is known in certain examples. Salicylic acid (Figure 4.27) is synthesized in microorganisms directly from isochorismic acid (see page 124), but can arise in plants by two other mechanisms. It can be produced by hydrox-ylation of benzoic acid, or by side-chain cleavage of 2-coumaric acid, which itself is formed by an ortho-hydroxylation of cinnamic acid. Methyl sal-icylate is the principal component of oil of win-tergreen from Gaultheria procumbens (Ericaceae), used for many years for pain relief. It is derived by

co2h

COSCoA

HSCoA ATP

HSCoA ATP

COSCoA

COSCoA

HOx h2o

R = H, 4-coumaric acid R = H, 4-coumaroyl-CoA R = OMe, ferulic acid R = OMe, feruloyl-CoA

CO2H

reverse aldol

reverse aldol

benzaldehyde R = OMe, vanillin

NAD+

benzaldehyde R = OMe, vanillin

co2h

NAD+

P-oxidation pathway, as in fatty acid metabolism (Figure 2.11)

HSCoA

CH3COSCoA

reverse Claisen co2h

COSCoA

benzoic acid R = OMe, vanillic acid

CO2H hydroxylation CO2H methylation C02Me

salicylic acid

methyl salicylate

CO2H

benzoic acid

CO2H

salicylic acid

methyl salicylate

OCOCH3

side-chain cleavage

OCOCH3

aspirin (acetylsalicyclic acid)

hydroxylation hydroxylation

2-coumaric acid

CO2H

side-chain cleavage

CHO glucosylation CHO reduction CH2OH

salicylaldehyde

Figure 4.27

UDPGlc

UDPGlc

OGlc

OGlc

OGlc salicin

OGlc

2-coumaric acid salicylaldehyde

Figure 4.27

salicin

SAM-dependent methylation of salicylic acid. The salicyl alcohol derivative salicin, found in many species of willow (Salix species; Salicaceae), is not derived from salicylic acid, but probably via gluco-sylation of salicylaldehyde and then reduction of the carbonyl (Figure 4.27). Salicin is responsible for the analgesic and antipyretic effects of willow barks, widely used for centuries, and the template for synthesis of acetylsalicylic acid (aspirin) (Figure 4.27) as a more effective analogue.

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