Alkylation Reactions

A common feature of many natural products containing phenolic rings is the introduction of alkyl groups at nucleophilic sites. Obviously, the phenol groups themselves are nucleophilic, and with a suitable alkylating agent, O-alkyl derivatives may be formed (see page 12), e.g. the O -methylation of emodin to physcion (Figure 3.30). However, a phenol group also activates the ring carbons at the ortho and para positions, so that these positions similarly become susceptible to alkylation, leading to C-alkyl derivatives. The meta oxygenation pattern, which is a characteristic feature of acetate-derived phenolics, has the effect of increasing this nucleophilicity considerably, and the process of C-alkylation is very much facilitated (see page 12). Suitable natural alkylating agents are S-adenosylmethionine (SAM), and dimethylallyl diphosphate (DMAPP). Other polyprenyl diphos-phate esters may also be encountered in biological alkylation reactions (e.g. see vitamin K, page 159). A minor inconsistency has been discovered, in that, while C-alkylation with dimethylallyl and higher diphosphates is mediated after the initial polyketide cyclization product is liberated from the enzyme, there are several examples where C-methylation undoubtedly occurs before release of any aromatic compound from the enzyme. 5-methylorsellinic acid (Figure 3.36) is a simple C-methylated analogue of orsellinic acid found in Aspergillus flaviceps, and the extra methyl is derived from SAM. However, orsellinic acid is not a precursor of 5-methylorsellinic acid and it is proposed that the poly-ß-keto ester is therefore methylated as part of the series of reactions catalysed by the synthase complex (Figure 3.36). Similarly, 5-methylorsellinic acid, but not orsellinic acid is a precursor of mycophenolic acid* in Penicillium brevicompactum (Figure 3.36). However, C-alkylation by farnesyl diphosphate (see page 191) proceeds after the aromatization step, and a phthalide intermediate is the substrate involved. The phthalide is a lactone derived from 5-methylorsellinic acid by hydroxylation of its starter methyl group and reaction with the end-

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