Phenolic Oxidative Coupling

C-Methylation also features in the biosynthesis of usnic acid (Figure 3.41), an antibacterial metabolite found in many lichens, e.g. Usnea and Clado-nia species, which are symbiotic combinations of alga and fungus. However, the principal structural modification encountered involves phenolic oxidative coupling (see page 28). Two molecules of methylphloracetophenone are incorporated, and these are known to derive from a pre-aromatization methylation reaction and not by methylation of phloracetophenone (Figure 3.41). The two molecules are joined together by an oxida-tive coupling mechanism which can be rationalized via the one-electron oxidation of a phenol group in methylphloracetophenone giving free radical A, for which resonance forms B and C can be written. Coupling of B and C occurs. Only the left-hand ring can subsequently be restored to aromaticity by keto - enol tautomerism, this state being denied to the right-hand ring because coupling occurred on to the methyl-containing position para to the original phenol. Instead, a het-erocyclic ring is formed by attack of the phenol on to the enone system (see khellin, above). The outcome of this reaction is enzyme controlled, since two equivalent phenol groups are present as potential nucleophiles, and two equivalent enone systems are also available. Therefore, four different products could be formed, but only one is actually produced. Loss of water then leads to usnic acid.

Phenolic oxidative coupling is widely encountered in natural product biosynthesis, and many other examples are described in subsequent sections. A further acetate-derived metabolite formed as a result of oxidative coupling is the antifungal agent griseofulvin* (Figure 3.42) synthesized by cultures of Penicillium griseofulvin. The sequence of events leading to griseofulvin has now been established in detail, and the pathway also includes O-methylation steps and the introduction of a halogen (chlorine) atom at one of the nucleophilic sites, which is represented as involving the electrophile Cl+ (Figure 3.42).

Y^rrr

SEnz

C-methylation prior Claisen reaction,

O O to cyclization o O aromatization

SAM vJkA.

OH O

SEnz

OH O

OH O

HO "OH

methylphloracetophenone

HO "OH

SEnz methylphloracetophenone one-electron oxidation to free radical resonance forms of free radical j|

OH O

OH O

resonance forms of free radical j|

OH HO

nucleophilic attack on to enone system O

OH HO

OH HO

OH HO

Figure 3.41

OH O

OH O

Figure 3.41

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