Polyether polyketides

Polyketide Biosynthesis, Enediyne Polyketides Polyketide Biosynthesis, Aromatic Polyetides Polyketide Biosynthesis, Modular Polyketide Synthases Polyketide Biosynthesis, Polyethers Polyketides as Drugs... 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Microalgae produce many potent natural products in the form of complex polycyclic polyethers, a type of polyketide. The ladder-like polyether brevetoxin B (Fig. 1.8a) (Lin et al. 1981) is representative of a host of such toxins, which include cigua-toxin (Scheuer et al. 1967), yessotoxin (Murata et al. 1987), maitotoxin (Murata et al. 1993), gambieric acids (Murata et al. 1992), and azaspiracid (Satake et al. 1998). Brevetoxin B, one of the causitive agents of red tide poisoning, can be isolated from... 

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin A (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [1,2]. Because of their biological potency, members of this structural class as well as the aromatic polycyclic products of type II polyketide-synthases, tetracyclines and anthara-cyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [1,2],... 

Selected examples of other biocatalytic asymmetric oxidations are shown in Figure 20.10. In the area of the polyether ionophore monensin a recently proposed mechanism of oxidative cycUzation of a linear polyketide intermediate by four enzymes, the products of monBI, monBll, monCI, and monCII, has been supported experimentally by analysis of a biosynthetic gene cluster [110] and the accumulation of an B,F,F-triene, when oxidative cydization was blocked [111]. 

A diverse array of polyketide metabolites are found in marine organisms, which range from simple oxylipins to highly complex polyethers and macrolides. Particularly intriguing are ladder-shaped polyethers of dinofragellate origin and sponge macrolides. 

Azaspiracids [azaspiracid-1 (18)] are another class of highly unusual polyketide polyethers originally isolated from Irish mussels that caused azaspiracid shellfish poisoning (5). They are produced by the dinoflagellate Protoperidinium crassipes. A similar class of polyether toxins named pinnatoxins [pinnatoxin A (19)] were reported from the bivalve Pinna pectinata a closely related species P. attenuata is known to cause food poisoning in China. Pinnatoxins are likely of dinoflagellate origin and activate Ca channels (15). 

This review covers the biosynthesis of terrestriai and marine polyethers and discusses their biologic properties and the molecular genetics and enzymology of the proteins responsible for their formation. The biosynthesis of monensin, nanchangmycin, nonactin, and the marine polyether ladders are discussed in detail. Novel enzymes found only in type I polyketide polyether gene clusters that are responsible for the epoxidation and cyclization of polyene biosynthetic intermediates are described. The macrotetrolide biosynthetic gene cluster, which is an ACP-less type II polyketide synthase that functions noniteratively is reviewed. 

J, Leadlay PF, Spencer JB. Evidence that a novel thioesterase is responsible for polyketide chain release during biosynthesis of the polyether ionophore monensin. ChemBioChem 2006 7 1435— 1442. 

For a review on polyether biosynthesis (as well as polyketides and mixed NRPS/PKS metabolites) Hill AM. The biosynthesis, molecular genetics and enzymology of the polyketide-derived metabolites. Nat. Prod. Rep. 2006 23 256-320. 

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