Polyketides types

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]. 

Scheme 8.29 Kishi s approach for the construction of the C19-C26 polyketide-type segment of rifamycin S.

There are at least three types of PKS. Type I PKSs catalyze the biosynthesis of macrolides such as erythromycin and rapamycin. As modular enzymes, they contain separate catalytic modules for each reaction catalyzed sequentially in the polyketide biosynthetic pathway. Type II PKSs have only a few active sites on separate polypeptides, and the active sites are used iteratively, catalyzing the biosynthesis of bacterial aromatic polyketides. Type III are fungal PKSs they are hybrids of type I and type II PKSs [49,50]. 

In the 1970s the biosynthesis of cannabinoids was investigated with radiolabeling experiments. 14C-labeled mevalonate and malonate were shown to be incorporated into tetrahydrocannabinolic acid and cannabichromenic acid at very low rates (< 0.02%). Until 1990 the precursors of all terpenoids, isopentenyl diphosphate and dimethyl-allyl diphosphate were believed to be biosynthesized via the mevalonate pathway. Subsequent studies, however, proved that many plant terpenoids are biosynthesized via the recently discovered deoxyxylulose phosphate pathway (Eisenreich et al., 1998 Rohmer, 1999). It was shown that the Cio-terpenoid moiety of cannabinoids is biosynthesized entirely or predominantly (>98%) via this pathway (Fellermeister et al., 2001). The phenolic moiety is generated by a polyketide-type reaction sequence. 

Polyketides. These pyranones combine with carbanions obtained from orsellinic acid derivatives to afford polyketide-type compounds. ... 

The stereochemical outcome of the addition of carbanions to ketones yielding tertiary alcohols (or secondary alcohols in the case of aldehydes) is variable and depends on the substrate, the counterion and the solvent. Numerous applications of this strategy to natural product synthesis from carbohydrates can be found in the literature and this approach was fruitful in pioneering syntheses of polyketide-type products. Here again, the template effect of the sugar plays a tremendous role in the stereochemical outcome of the reaction. Chelation controlled nucleophilic addition can also be used to form chiral centers in a highly predictable way. 

The labeling pattern of the (3 lactone moiety could be easily explained by Claisen condensation of octanoyl-CoA (33) with 3-hydroxy-5,8-tetradecanoyl-CoA (32) obtained by (3 oxidation of linoleic acid, as opposed to polyketide-type biosynthesis from low-molecular-weight fragments64... 

Over the past decade the enantio- and diastereo-selective aldol methodology has been developed mainly with the purpose of synthesizing polyketide-type natural products such as macrolides and iono-phore antibiotics. These natural products have the basic structural units that result from propionate and acetate addition a-methyl-P-hydroxycarbonyl (27a-d) and (3-hydroxycarbonyl (28a and 28b). Discussions on the construction of these units will be followed by comments on the stereoselective assembly... 

Since the PKS (polyketide synthase) gene cluster for actinorhodin (act), an antibiotic produced by Streptomyces coelicolor[ 109], was cloned, more than 20 different gene clusters encoding polyketide biosynthetic enzymes have been isolated from various organisms, mostly actinomycetes, and characterized [98, 100]. Bacterial PKSs are classified into two broad types based on gene organization and biosynthetic mechanisms [98, 100, 102]. In modular PKSs (or type I), discrete multifunctional enzymes control the sequential addition of thioester units and their subsequent modification to produce macrocyclic compounds (or complex polyketides). Type I PKSs are exemplified by 6-deoxyerythronolide B synthase (DEBS), which catalyzes the formation of the macrolactone portion of erythromycin A, an antibiotic produced by Saccharopolyspora erythraea. There are 7 different active-site domains in DEBS, but a given module contains only 3 to 6 active sites. Three domains, acyl carrier protein (ACP), acyltransferase (AT), and P-ketoacyl-ACP synthase (KS), constitute a minimum module. Some modules contain additional domains for reduction of p-carbons, e.g., P-ketoacyl-ACP reductase (KR), dehydratase (DH), and enoyl reductase (ER). The thioesterase-cyclase (TE) protein is present only at the end of module 6. 

A number of combinatorial-based syntheses have been reported. Andrus et al. prepared a solution-phase indexed combinatorial library of nonnatural polyenes such as 291 for multidrug resistance reversal.298 This library was formed by modification of R and R. Ellman and co-workers reported a combinatorial library of synthetic receptors targeting vancomycin-resistant bacteria,209 and Paterson et al. prepared polyketide-type libraries by iterative asymmetric aldol reactions on solid support.2l0 Rieser et al. used combinatorial liquid-phase synthesis to prepare [1,4]-oxazepine-7-ones by the Baylis-Hillman reaction (see sec. 9.7.B).2H Schreiber and co-workers reported the synthesis and evaluation of a library of polycyclic small molecules for use in chemical genetic assays.2 2 Bauer et al. reported a library of N-substituted 2-pyrazoline compounds... 

T. M. Harris and C. M. Harris, Synthesis of Polyketide-type Aromatic Natural Products by Biogenetically Modelled Routes , Tetrahedron, 1977, 33, 2159. 

Evaluation of the above-described experiments led to polyketide-type pathways for the biosynthesis of the side chain units of 220 and 221, differing in the nature of the chain starter and extension units. In the case of 220, the upper side chain (C-1-C-13 ) was predicted to arise from an acetate starter unit that is elongated by condensation with one malonyl-CoA and three methylmalonyl-CoA ( propionate ) units. For 221, in the upper chain (Cl -C13 ), the starter unit was presumed to be... 

Diverse polyketide-type libraries were synthesized using a-chiral aldehydes attached by a silyl linker to a hydromethylpolysyrene resin (Figure 11.24). " Aldol chain extension with chiral ketone modules, and subsequent ketone reduction and manipulation on the solid support led to elaborated stereopentad sequences found in natural products such as 6-deoxyerythronolide B and discoder-molide. Based on the biosynthesis of erythromycin, the same methodology was used in the combinatorial synthesis of polyketide sequence mimetics with a great variety of chain-extending units. " ... 

Paterson, L, Donghi, M., and Gerlach, K., A combinatorial approach to polyketide-type hbraries by iterative asymmetric aldol reactions performed on sohd-support, Angew. Chem. Int. Ed. Engl., 39, 3315, 2000. 

Sandifer RM, Harris TM (1979) Biogenetically Modelled Synthesis of Polyketide-type Xanthones. J Chem Soc Chem Comm 442... 

Schaberle, T.F., Goralski, E Neu, E., Erol, O., Holzl, G., Dormann, P., Bierbaum, G., and Kdnig, G.M. (2010) Marine myxobacteria as a source of antibiotics - Comparison of physiology, polyketide-type genes and antibiotic production of three new isolates of Enhygromyxa salina. Mar. Drugs, 8, 2466-2479. 

The culture of strain CNC-651 of a fungus of the genus Phoma, collected from a hypersaHne pond (11.5%) in the Bahamas, resulted in the isolation of a cyclic carbonate, phomoxin, and two related polyketide-type derivatives. Despite the presence of many oxygen atoms, these derivatives have no specific activity (Liu, Jensen, and Fenical, 2003). 

Several new acids related to spiculoic add A were found subsequently in the species Plakortis zyggompha harvested in Martinique. These contain all the original skeleton of trans-hydrindan-2-one and a detailed structural study has revealed the definitive stereochemistry of all compounds of this family (Berrue et al, 2005a, 2007). AH of these polyketide-type derivatives are moderately cytotoxic or antimycobacterial. 

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