Many natural products are produced by the coupling of two or more phenolic systems, in a process readily rationalized by means of free radical reactions. The reactions can be brought
Baeyer-Villiger oxidations nucleophilic attack of peracid on to carbonyl
carbonyl reforms: alkyl group migrates from carbon to adjacent oxygen
Phenolic oxidative coupling
resonance-stabilized free radical
OH H® V ^ - e Ay resonance-stabilized free radical
ether linkage ortho-ortho coupling ortho-para coupling para-para coupling
ortho-ortho coupling ortho-para coupling para-para coupling
about by oxidase enzymes, including peroxidase and laccase systems, known to be radical generators. Other enzymes catalysing phenolic oxidative coupling have been characterized as cytochrome P-450-dependent proteins, requiring NADPH and O2 cofactors, but no oxygen is incorporated into the substrate. A one-electron oxidation of a phenol gives the free radical, and the unpaired electron can then be delocalized via resonance forms in which the free electron is dispersed to positions ortho and para to the original oxygen function (Figure 2.26). Coupling of two of these mesomeric structures gives a range of dimeric systems as exemplified in Figure 2.26. The final products indicated are then derived by enolization, which restores aromaticity to the rings. Thus, carbon-carbon bonds involving positions ortho or para to the original phenols, or ether linkages, may be formed. The reactive dienone systems formed as intermediates may in some cases be attacked by other nucleophilic groupings, extending the range of structures ultimately derived from this basic reaction sequence.
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