Polyketide derivatives

Methyl 6-methylsalicylate is the trail pheromone of some ants, it is also found in carabid beetle, 6-methylsalicylaldehyde in the defensive secretion of a cerambycid beetle, and 6-methylsalicylic acid is made by some Penicillium moulds. Orsellinic acid and 6-methylsalicylic acid are 

Given the structure of a substance we can usually work back to the polyketide from which it must be derived. When side chains occur in acetogenins, these are always derived from the tail of the polyketide, never the carboxylic acid head . The carbonyl oxygen nearest to the 

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Leighton and coworkers [217] have also used this approach to develop efficient strategies for the synthesis of polyketide-derived natural products [218]. A main motif of these compounds is a skipped polyol structure, as in 6/2-94 this can easily be prepared by a novel Rh-catalyzed domino reaction of a diallylsilyl ether in the presence of CO, followed by a Tamao oxidation [219]. Thus, reaction of, for example, the silane 6/2-93, which is readily prepared from the corresponding ho-... 

An unusual class of heterocydes are polyketide-derived macrodiolide natural produds. The groups of Porco and Panek have recently shown that stereochemically well-defined macrodiolides of this type can be obtained by cyclodimerization (transesterification) of non-racemic chiral hydroxy esters (Scheme 6.154) [301]. Preliminary experiments involving microwave irradiation demonstrated that exposing dilute solutions of the hydroxy ester (0.02 m) in chlorobenzene to sealed-vessel microwave irradiation conditions (200 °C, 7 min) in the presence of 10 mol% of a distannoxane transesterification catalyst led to a 60% isolated yield of the 16-mem-bered macrodiolide heterocycle. Conventional reflux conditions in the same solvent (0.01 m in the hydroxy ester) provided a 75% yield after 48 h at ca. 135 °C. 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

Another important class of anti-infective natural products introduced in recent years is the avermectins, polyketide-derived macrolides that were originally isolated from several species of Streptomyces. The major drug in this class, ivermectin, was originally developed to treat and control nematodes and parasites in livestock. In recent years, however, the potential of ivermectin for the treatment of human disease has also been realized, and it is now used to treat onchocerciasis (river blindness), a disease that afflicts 40 million people worldwide (De Smet, 1997). 

Substituted 5-methylene-l,3-dk>xepines 38 are converted into vinyl acetals 39 by Ni catalysts bearing (R,R)-DuPHOS or (R,R)-ChiraPHOS as chiral ligands (Scheme 11) [16]. Similarly high enantioselectivity can be achieved with 5-methyl-ene-l,3-dioxanes as substrates [17]. Chiral Ru-catalysts are less efficient [18]. Cyclic acetals obtained are an useful starting material for preparation of macrolide antibiotics and other polyketide-derived natural products. 

The polyketide-derived aryl C-glycoside natural products have a variety of interesting biological activities, most notably antitumor activity (7). The defining feature of members of this class is a carbon-carbon bond linking a polycyclic aromatic "aglycone" and the anomeric carbon of a carbohydrate (Figure 1). 

Su et al. [53] used allylsilanes having C-centered chirality and a distannoxane transesterification catalyst [54] in a sequence of transesterification reactions to rapidly assemble a set of stereochemically diverse macrodiolides reminiscent of polyketide-derivative natural products. Figure 15.20 summarizes the synthesis of stereochemically well defined 14- and 16-member macrodiolides 20.4 and 20.5, resembling known polyketide-derived natural products, from hydroxyl esters 20.2 and 20.3. The feasibility of cyclodimeriztion was studied using different solvents and variable concentrations. Reactions were affected by the choice of the solvent. 

Monanchorin (120), which has been isolated from the sponge Monanchora unguiculata [238], is the last example of polyketide-derived guanidines. 

Although the clinical use of polyketide-inspired pharmaceuticals has been appreciated for decades, polyketide-derived metabolites have been recognized recently for their role in bacterial virulence. For example, the pathogenesis of Mycobacterium ulcerans, the causative agent of the devastating skin disease known as Buruli ulcer, is the result of the secretion of... 

The epothilones 6 (and Fig. la), which are produced by So-rangium cellulosum, are mixed NRPS-polyketide derived natural products that possess potent antitumor activity. Interestingly,... 

Hill AM. The biosynthesis, molecular genetics and enzymology of the polyketide-derived metabolites. J. Nat. Prod. 2006 23 256-320. 

Differentiation inducing factors (DIFs see Table 1, column 4) are polyketide-derived signaling molecules critical for... 

As shown below, the attack of epoxide 6 with lithium dimethylcuprate is a key step of Hanessian et al. s erythronolide synthesis [23]. This methodology was also applied to the preparation of other polyketide-derived macrolides. Specific to erythronolide, introduction of the methyl group at C2 was achieved according to Scheme 11.3. 

Oikawa, Y, Nishi, T, Yonemitsu, O, Chiral synthesis of polyketide-derived natural product. Chemical correlation of chiral synthons, derived from D-glucose for the synthesis of erythromycin A, with chemical cleavage products of the natural antibiotic, J. Chem. Soc., Perkin. Trans. 1, 27-33, 1985. 

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