Structural Modifications Anthraquinones

A number of natural anthraquinone derivatives are also excellent examples of acetate-derived structures. Endocrocin (Figure 3.29) found in species of Pénicillium and Aspergillus fungi is formed by folding a polyketide containing eight C2 units to form the periphery of the carbon skeleton. Three aldol-type condensations would give a hypothetical intermediate 1, and, except for a crucial carbonyl oxygen in the centre ring, endocrocin results by enolization reactions, one of which involves the vinylogous enolization —CH2-CH=CH-CO-->

-CH=CH-CH=C(OH)-. The additional car-bonyl oxygen must be introduced at some stage aldol reactions - H2O

O O O hypothetical intermediate 1

O O O hypothetical intermediate 1

u enolizations oxidation

enolizations oxidation

OH O OH endocrocin decarboxylation n facilitated by II- CO2

ortho-hydroxyl

OH O OH endocrocin decarboxylation n facilitated by II- CO2

ortho-hydroxyl

OH O OH emodin

OH O OH emodin

O-methylation of phenol i

YYYY

SEnz

NADPH O

NADPH

NADPH O

O O O hypothetical intermediate 2

co2h

O O O hypothetical intermediate 2

-H2O enolization oxidation - CO2

-H2O enolization oxidation - CO2

OH O OH

chrysophanol

OH O OH

chrysophanol

NADPH

NADPH reduces carbonyl

NADPH reduces carbonyl

O O O hypothetical intermediate 2

co2h

O O O hypothetical intermediate 2

-H2O enolization 2 x oxidation

O OH

O OH

OH O OH islandicin

OH O OH islandicin i

OH O

OH O OH

aloe-emodin oxidation of methyl to alcohol

OH O

OH O OH

aloe-emodin oxidation of alcohol to acid

CO2H

OH O OH rhein

CO2H

OH O OH rhein

OH O OH

physcion

OH O OH

physcion

Figure 3.29

during the biosynthesis by an oxidative process, for which we have little information. Emodin, a metabolite of some Penicillium species, but also found in higher plants, e.g. Rhamnus and Rumex species, would appear to be formed from endocrocin by a simple decarboxylation reaction. This is facilitated by the adjacent phenol function (see page 20). O-Methylation of emodin would then lead to physcion. Islandicin is another anthraquinone pigment produced by Penicillium islandicum, and differs from emodin in two ways.

One hydroxyl is missing, and a new hydroxyl has been incorporated adjacent to the methyl. Without any evidence for the sequence of such reactions, the structure of intermediate 2 shows the result of three aldol condensations and reduction of a carbonyl. A dehydration reaction, two oxidations, and a decarboxylation are necessary to attain the islandicin structure. In chrysophanol, aloe-emodin, and rhein, the same oxygen function is lost by reduction as in islandicin, and decarboxylation also occurs. The three compounds are interrelated by a sequential oxidation of the methyl in chrysophanol to a hydroxymethyl in aloe-emodin, and a carboxyl in rhein.

These structural modifications undergone by the basic polyketide are conveniently considered under two main headings, according to the timing of the steps in the synthetic sequence. Thus, 'missing' oxygen functions appear to be reduced out well before the folded and cyclized polyketide is detached from the enzyme, and are mediated by a reductase component of the enzyme complex during chain elongation before the cycliza-tion reaction. On the other hand, reactions like the decarboxylation, O-methylation, and sequential oxidation of a methyl to a carboxyl are representative of transformations occurring after the cyclization reaction. It is often possible to demonstrate these later conversions by the isolation of enzymes catalysing the individual steps. Most of the secondary transformations are easily rationalized by careful consideration of the reactivity conferred on the molecule by the alternating and usually phenolic oxygenation pattern. These oxygens activate adjacent sites creating nucleophilic centres. Introduction of additional hydroxyl groups ortho or para to an existing phenol will be facilitated (see page 26), allowing the extra hydroxyl of islandicin to be inserted, for example. Ortho- or para-diphenols are themselves susceptible to further oxidation in certain circumstances, and may give rise to o- and p-quinones (see page 25). The quinone system in anthraquinones is built up by an oxidation of the central cyclohexadienone ring, again at a nucleophilic centre activated by the enone system. Methyls on an aromatic ring are also activated towards oxidation, facilitating the chryso-phanol ^ aloe-emodin oxidation, for example. Decarboxylation, e.g. endocrocin ^ emodin, is readily achieved in the presence of an ortho phenol function, though a para phenol can also facilitate this (see page 20).

It is now appreciated that the assembly of the anthraquinone skeleton (and related polycyclic structures) is achieved in a step-wise sequence. After the polyketide chain is folded, the ring at the centre of the fold is formed first, followed in turn by the next two rings. The pathway outlined for the biosynthesis of endocrocin and emodin is shown in Figure 3.30. Mechanistically, there is little difference between this and the speculative pathway of Figure 3.29, but the sequence of reactions is altered. Decarboxylation appears to take place before aromatization of the last-formed ring system, and tetrahydroanthracene intermediates such as atrochrysone carboxylic acid and atrochrysone are involved. These dehydrate to the anthrones endocrocin anthrone and emodin anthrone, respectively, prior to introduction of the extra carbonyl oxygen as a last transformation in the production of anthraquinones. This oxygen is derived from O2.

Note that many other natural anthraquinone structures are not formed via the acetate pathway, but by a more elaborate sequence involving shiki-mate and an isoprene unit (see page 158). Such structures do not contain the characteristic meta oxygenation pattern, and often have oxygenation in only one aromatic ring (see page 164).

Emodin, physcion, chrysophanol, aloe-emodin, and rhein form the basis of a range of purgative anthraquinone derivatives found in long-established laxatives such as Senna*, Cascara*, Frangula*, Rhubarb*, and Aloes*. The free anthra-quinones themselves have little therapeutic activity and need to be in the form of water-soluble glycosides to exert their action. Although simple anthraquinone O-glycosides are present in the drugs, the major purgative action arises from compounds such as cascarosides, e.g. cascaro-side A (Figure 3.33), which are both O- and C-glycosides, and sennosides, e.g. sennoside A (Figure 3.33), which are dianthrone O-glycosides. These types of derivative are likely to be produced from intermediate anthrone structures. This could act as substrate for both O- and C-glucosylation, employing the glucose donor UDPglucose (see page 29), and would generate a cascaroside structure (Figure 3.31). Alternatively, a one-electron oxidation allows oxidative coupling (see page 28) of two anthrone systems to give a dianthrone (Figure 3.32). This can be formulated as direct oxidation at the benzylic — CH2-, or via the anthra-nol, which is the phenolic tautomer of the anthrone (Figure 3.32). Glycosylation of the dianthrone system would then give a sennoside-like product. However, further oxidative steps can create a dehydrodianthrone, and then allow coupling of the aromatic rings through protohypericin to give a naphthodianthrone, e.g. hypericin (Figure 3.32). The reactions of Figure 3.32 can be achieved

TYYY

aldol - H2O enolization

SEnz

aldol - H2O enolization

aldol

enolization

aldol

enolization

NADPH

SEnz

SEnz

SEnz

SEnz

CO2H

OH O OH chrysophanol anthrone

CO2H

OH O OH chrysophanol anthrone

OH O OH chrysophanol

OH O OH chrysophanol

aldol

SEnz

SEnz

OH O OH aloe-emodin

hydrolysis from enzyme

hydrolysis from enzyme

CO2H OH OH O

atrochrysone carboxylic acid

OH O OH aloe-emodin

endocrocin anthrone endocrocin

CO2H

OH O OH rhein

CO2H

OH O OH rhein

OH OH O

atrochyrsone

OH O OH emodin anthrone

OH O OH emodin

MeO SAM

MeO SAM

OH O OH

physcion

OH OH O

atrochyrsone

OH O OH emodin anthrone

OH O OH emodin

OH O OH

physcion

Figure 3.30

OH O OH

OH O OH

aloe-emodin anthrone

2 x UDPGlc

GlcO O OH

aloe-emodin anthrone

GlcO O OH

OH OH

Anthron Glucose Reaktion

cascaroside

OH OH

cascaroside

OH OH

NADPH

aldol

OH O OH

OH O OH

emodin anthrone tautomerism

OH OH OH

emodin anthrone tautomerism

OH OH OH

emodin anthranol OH O OH

HO HO

emodin anthranol OH O OH

HO HO

OH O OH hypericin

OH O OH

OH O OH

OH O OH

OH O OH protohypericin

Figure 3.32

radical coupling x 2

OH O OH

HO HO

OH O OH

HO HO

Emodin Dianthrone
OH O OH emodin dianthrone

OH O OH

OH O OH

OH O OH protohypericin

Figure 3.32

HO HO

OH O OH

HO HO

OH O

OH O

chemically by passing air into an alkaline solution of emodin anthrone. Hypericin is found in cultures of Dermocybe fungi, and is also a constituent of St John's Wort, Hypericum perforatum (Gut-tiferae/Hypericaceae), which is a popular herbal medicine in the treatment of depression. The naphthodianthrones have no purgative action, but hypericin can act as a photosensitizing agent in a similar manner to furocoumarins (see page 146). Thus ingestion of hypericin results in an increased absorption of UV light and can lead to dermatitis and burning. Hypericin is also being investigated for its antiviral activities, in particular for its potential activity against HIV.

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