The cinnamic acids also feature in the pathways to other metabolites based on C6C3 building blocks.
Pre-eminent amongst these, certainly as far as nature is concerned, is the plant polymer lignin, a strengthening material for the plant cell wall which acts as a matrix for cellulose microfibrils (see page 473). Lignin represents a vast reservoir of aromatic materials, mainly untapped because of the difficulties associated with release of these metabolites. The action of wood-rotting fungi offers the most effective way of making these useful products more accessible. Lignin is formed by phenolic oxidative coupling of hydroxycin-namyl alcohol monomers, brought about by perox-idase enzymes (see page 28). The most important of these monomers are 4-hydroxycinnamyl alcohol (p-coumaryl alcohol), coniferyl alcohol, and sinapyl alcohol (Figure 4.15), though the monomers used vary according to the plant type. Gymnosperms polymerize mainly coniferyl alcohol, dicotyledonous plants coniferyl alcohol and sinapyl alcohol, whilst monocotyledons use all three alcohols. The alcohols are derived by reduction of cinnamic acids via coenzyme A esters and aldehydes (Figure 4.17), though the substitution patterns are not necessarily elaborated completely at the cinnamic acid stage, and coenzyme A esters and aldehydes may also be substrates for aromatic hydroxylation and methylation. Formation of the coenzyme A ester facilitates the first reduction step by introducing a better leaving group (CoAS-) for the NADPH-dependent reaction. The second reduction step, aldehyde to alcohol, utilizes a further molecule of NADPH and is reversible. The peroxidase enzyme then achieves one-electron oxidation of the phenol group. One-electron oxidation of a simple phenol allows delocalization of the unpaired electron, giving resonance forms in which the free electron resides at positions ortho and para to the oxygen function (see page 29). With cinnamic acid derivatives, conjugation allows the unpaired electron to be delocalized also into the side-chain (Figure 4.18). Radical pairing of resonance structures can then provide a range of dimeric systems containing reactive quinoneme-thides, which are susceptible to nucleophilic attack from hydroxyl groups in the same system, or by external water molecules. Thus, coniferyl alcohol monomers can couple, generating linkages as exemplified by guaiacylglycerol p-coniferyl ether (P-arylether linkage), dehydrodiconi-feryl alcohol (phenylcoumaran linkage), and
radical pairing ,OH
HO y OMe O
OMe nucleophilic attack of water on to quinonemethide
nucleophilic attack of water on to quinonemethide
radical pairing OH
OMe radical pairing OH
OMe enolization OH
OMe nucleophilic attack of hydroxyl on to quinonemethide
OH OMe guaiacylglycerol P-coniferyl ether
of hydroxyl on to quinonemethide
OMe dehydrodiconiferyl alcohol
radical pairing o>H®
0 1 r©io nucleophilic attack of hydroxyls on to quinonemethides
OMe dehydrodiconiferyl alcohol
phenolic oxidative coupling
phenolic oxidative coupling a.
coniferyl alcohol hoX>
OH this step probably involves ring opening to the quinonemethide followed by reduction OMe
modification of aromatic substitution oxidation of one CH2OH to CO2H, then lactone ring oxidation of one CH2OH to CO2H, then lactone ring
MeO y OMe OMe
MeO y OMe OMe desoxypodophyllotoxin
podophyllotoxin intestinal bacteria
secoisolariciresinol diglucoside enterodiol enterolactone
pinoresinol (resinol linkage). These dimers can react further by similar mechanisms to produce a lignin polymer containing a heterogeneous series of inter-molecular bondings as seen in the various dimers. In contrast to most other natural polymeric materials, lignin appears to be devoid of ordered repeating units, though some 50 -70% of the linkages are of the P-arylether type. The dimeric materials are also found in nature and are called lignans. Some authorities like to restrict the term lignan specifically to molecules in which the two phenylpropane units are coupled at the central carbon of the side-chain, e.g. pinoresinol, whilst compounds containing other types of coupling, e.g. as in guaiacylglycerol P-coniferyl ether and dehydrodiconiferyl alcohol, are then referred to as neolignans. Lignan/neolignan formation and lignin biosynthesis are catalysed by different enzymes, and a consequence is that natural lignans/neolignans are normally enantiomerically pure because they arise from stereochemically controlled coupling. The control mechanisms for lignin biosynthesis are less well defined, but the enzymes appear to generate products lacking optical activity.
Further cyclization and other modifications can create a wide range of lignans of very different structural types. One of the most important of the natural lignans having useful biological activity is the aryltetralin lactone podophyl-lotoxin (Figure 4.19), which is derived from coniferyl alcohol via the dibenzylbutyrolactones matairesinol and yatein, cyclization probably occurring as shown in Figure 4.19. Matairesinol is known to arise by reductive opening of the furan rings of pinoresinol, followed by oxidation of a primary alcohol to the acid and then lactonization. The substitution pattern in the two aromatic rings is built up further during the pathway, i.e. matairesinol ^ yatein, and does not arise by initial coupling of two different cinnamyl alcohol residues. The methylenedioxy ring system, as found in many shikimate-derived natural products, is formed by an oxidative reaction on an ortho-hydroxymethoxy pattern (see page 27). Podophyllotoxin and related lignans are found in the roots of Podophyllum* species (Berberi-daceae), and have clinically useful cytotoxic and anticancer activity. The lignans enterolactone and enterodiol (Figure 4.20) were discovered in human urine, but were subsequently shown to be derived from dietary plant lignans, especially secoisolariciresinol diglucoside, by the action of intestinal microflora. Enterolactone and enterodiol have oestrogenic activity and have been implicated as contributing to lower levels of breast cancer amongst vegetarians (see phyto-oestrogens, page 156).
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