Coumarins

The hydroxylation of cinnamic acids ortho to the side-chain as seen in the biosynthesis of salicylic acid is a crucial step in the formation of a group of cinnamic acid lactone derivatives, the coumarins. Whilst the direct hydroxylation of the aromatic ring of the cinnamic acids is common, hydrox-ylation generally involves initially the 4-position para to the side-chain, and subsequent hydrox-ylations then proceed ortho to this substituent (see page 132). In contrast, for the coumarins, hydroxylation of cinnamic acid or 4-coumaric acid can occur ortho to the side-chain (Figure 4.28). In the latter case, the 2,4-dihydroxycinnamic acid produced confusingly seems to possess the meta hydroxylation pattern characteristic of phenols derived via the acetate pathway. Recognition of the C6C3 skeleton should help to avoid this confusion. The two 2-hydroxycinnamic acids then suffer a change in configuration in the side-chain, from the trans (E) to the less stable cis (Z) form. Whilst trans - cis isomerization would be unfavourable in the case of a single isolated double bond, in the cinnamic acids the fully conjugated system allows this process to occur quite readily, and UV irradiation, e.g. daylight, is sufficient to produce equilibrium mixtures which can be separated (Figure 4.29). The absorption of energy promotes an electron from the n-orbital to a higher energy state, the n*-orbital, thus temporarily destroying the double bond character and allowing rotation. Loss of the absorbed energy then results in reformation of the double bond, but in the cis-configuration. In conjugated systems, the n-n* energy difference is considerably less than with a non-conjugated double bond. Chemical lactoniza-tion can occur on treatment with acid. Both the trans-cis isomerization and the lactonization are enzyme-mediated in nature, and light is not necessary for coumarin biosynthesis. Thus, cinnamic acid and 4-coumaric acid give rise to the coumarins coumarin and umbelliferone (Figure 4.28). Other coumarins with additional oxygen substituents on the aromatic ring, e.g. aesculetin and scopoletin, appear to be derived by modification of umbellif-erone, rather than by a general cinnamic acid to coumarin pathway. This indicates that the hydrox-ylation meta to the existing hydroxyl, discussed above, is a rather uncommon occurrence.

Coumarins are widely distributed in plants, and are commonly found in families such as the Umbelliferae/Apiaceae and Rutaceae, both in the free form and as glycosides. Coumarin itself is cr-

cinnamic acid

CO2H

2-coumaric acid trans-cis isomerization CO2H

lactone formation

2-coumaric acid

CO2H

CO2H

coumarin

coumarin

4-coumaric acid

XX"

2,4-dihydroxy-cinnamic acid

CO2H

CO2H

CO2H

HO ^ O O umbelliferone

HO ^ O O umbelliferone

MeO.

scopolin

scopolin

scopoletin

scopoletin

Figure 4.28

CO2H

CO2H

Figure 4.29

CO2H

Figure 4.29

HO ^ O O aesculetin

HO ^ O O aesculetin

O O coumarin

O O coumarin

OGlc (E)-2-coumaric acid glucoside

O Glc

(Z)-2-coumaric acid glucoside

CO2H

OGlc (E)-2-coumaric acid glucoside enzymic hydrolysis

O O coumarin

O O coumarin

CO2H

O Glc

(Z)-2-coumaric acid glucoside

Figure 4.30

found in sweet clover (Melilotus species; Legu-minosae/Fabaceae) and contributes to the smell of new-mown hay, though there is evidence that the plants actually contain the glucosides of (E)- and (Z)-2-coumaric acid (Figure 4.30), and coumarin is only liberated as a result of enzymic hydrolysis and lactonization through damage to the plant tissues during harvesting and processing (Figure 4.30). If sweet clover is allowed to ferment, 4-hydroxycoumarin is produced by the action of microorganisms on 2-coumaric acid (Figure 4.31) and this can react with formaldehyde, which is usually present due to micro-bial degradative reactions, combining to give dicoumarol. Dicoumarol* is a compound with pronounced blood anticoagulant properties, which can cause the deaths of livestock by internal bleeding, and is the forerunner of the warfarin* group of medicinal anticoagulants.

Many other natural coumarins have a more complex carbon framework and incorporate extra carbons derived from an isoprene unit (Figure 4.33). The aromatic ring in umbelliferone is activated at positions ortho to the hydroxyl group and can thus be alkylated by a suitable alkylating agent, in this case dimethylallyl diphosphate. The newly introduced dimethylallyl

COSCoA

lactone formation and enolization

aldol reaction; it may help to consider the diketo tautomer

COSCoA

O O 4-hydroxycoumarin

O O 4-hydroxycoumarin

HCHO

HCHO

O O O' O dicoumarol

Figure 4.31

dehydration follows

dehydration follows nucleophilic attack on to the enone system

c&Dto

O O O' O dicoumarol

Figure 4.31

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