Polyketides

Polyketide Compounds from Unusual Starter Units Methylenebisphloroglucinols and Related Compounds Polyketides from Lichens Mycotoxins 

Polyketide or polyacetate compounds are derived from ace-tate-malonate pathways and, in terms of biosynthesis, are related to fatty acids. Polyketides are assembled by condensation of acetate and malonate units however, in contrast to fatty acid biosynthesis, the carbonyl groups may not be reduced and intermediate compounds typically condense to produce aromatic ring systems, usually with phenolic substitutions (Packter, 1980). 

Many polyketides have pronounced physiological effects and several are important antibiotics. 

Few areas of natural products chemistry have seen as many major advances in the study of biosynthetic pathways as have occurred in polyketide compounds. Birch and Donovan (1953) demonstrated that a wide range of structural types are derived from acetate (later shown to be acetate and malonate). In experiments witfi deuterated precursors, acetate serves preferentially as a starter unit for the formation of 6-methylsalicylic acid in Penicillium griseofulvum (Simpson, 1983). Thus, polyketides are derived from the same precursors as fatty acids and the initial step seems to be similar (Fig. 5.1). Extensive purifrcation of 6-methylsalicylate synthetase from Penicillium patulum has been performed. This enzyme system is distinct and separable from the co-occurring fatty acid synthetase and has a molecular weight approximately half that of the former enzyme. NADPH is required as a coenzyme for methylsalicylate synthetase from this source (O Hagan, 1990 Packter, 1980). 

CH3C(CH2C) CH2CCoA bound on enzyme surface 

Acetic acid is found in living systems as its coenzyme A ester(J.7). This is a reactive thioester and is a pivotal compound in biosynthesis. On the one hand, it is involved in the formation of the important long-chain fatty acids and their transformation products (Section 1.1.2). On the other hand, 3.1) is the source of small fragments 

For those engaged in the structure determination of natural products there is a security to be found in structures which can be correlated with simple repeating units. So the repeating isoprene unit found in the terpenes (Chapter 4) has been invaluable in structure assignment. At the turn of the century Collie [6, 7] recognized that many natural products contained within them the [CH2-CO] unit and that this could be exploited in chemical synthesis, as in the conversion of dehydroacetic acid 3.2) via 3.3) into orsellinic acid 3.4), 

The Birch hypothesis initiated many studies on polyketide biosynthesis using [ C]acetate, studies which have recently been extended 

Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM), Biosystems Chemistry, Technische Universitdt MUnchen, Munich, Germany 

Equally impressive as the polyketide structural and functional diversity are the enzymatic machineries that evolved to produce these fascinating secondary metabolites. 

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products, First Edition. Edited by Alexandres L. Zografos. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

SCHEME 2.1 Selection of structurally and functionally diverse polyketide natural products 1-8. 

Although the organization of PKSs into types I to III will continue to be challenged by newly discovered systems that do not match the scheme [37, 38], it is extremely useful to explain fundamental differences in polyketide biosynthetic 

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The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

Biosynthetic studies using acetate (Ac), propionate (Pr), and butyrate (Bu) revealed the polyketide nature of aurodox which has the composition Pr(Ac)g for the goldinamine skeleton C-7 to C-25 and the composition Bu(Ac) for the C-27 to C-39 carbon chain of goldinonic acid. In contrast to the methyl branch at C-8, those at C-19 and C-21 are methionine-derived as are all remaining methyl groups (52,53). The biogenetic origin of the pyridone moiety is not clear. 

The overall biosynthetic pathway to the tetracychnes has been reviewed (74). Studies (75—78) utilising labeled acetate and malonate and nmr analysis of the isolated oxytetracycline (2), have demonstrated the exclusive malonate origin of the tetracycline carbon skeleton, the carboxamide substituent, and the folding mode of the polyketide chain. Feeding experiments using [1- 02] acetate and analysis of the nmr isotope shift effects, led to the location of... 

Figure 4 Halogenated terpenoid and polyketide metabolites isolated from red algae in the genera Laureucia and Plocamium...

Role of polyketide synthases in biosynthesis of some heterocycles, in particular macrolides 97CRV2465. 

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.

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

The acetate labeling results clearly demonstrated a polyketide origin for the naphthoate fragment. This resulted in the hypothesis that the first enzyme-free intermediate in azinomycin biosynthesis would be naphthoate 102, with condensation to fonn a polyketone chain, reduction, cyclization, and dehydration/aromati-... 

It is very likely that a similar Type I polyketide synthase constructs the naphthoate fragment of azinomycin B. This will be a very interesting enzyme to study, since it will need to perform an unprecedented three regioselective reduction reactions, as well as controlling the polyketide chain length and directing its cycliza-tion. 

It is likely that the biosynthesis of 113 is directed by a hybrid polyketide syn-thase/nonribosomal peptide synthetase enzyme system, as indicated in Figure 11.19. 

The biosynthesis of maduropeptin has not been studied in detail, but an iterative type I polyketide synthase gene predicted to be responsible for forming the enediyne core structure has been identified [188]. 

These mesylates, in turn, can be converted to enantioenriched allenyltin, zinc, and indium reagents which add to aldehydes with excellent diastereo-and enantioselectivity to afford either syn- or anti-homopropargylic alcohols or allenylcarbinols (eq 2, 3, and 4).3 4 Adducts of this type serve as useful intermediates for the synthesis of polyketide and hydrofuran natural products.5... 

Sheiko SS, Moller M (2001) Hyperbranched Macromolecules Soft Particles with Adjustable Shape and Capability to Persistent Motion. 212 137-175 Shen B (2000) The Biosynthesis of Aromatic Polyketides. 209 1-51 Shinkai S, see James TD (2002) 218 159-200 Shirakawa E, see Hiyama T (2002) 219 61-85 Shogren-Knaak M, see Imperial B (1999) 202 1-38 Sinou D (1999) Metal Catalysis in Water. 206 41-59... 

A considerable number of mycotoxins that show high toxicity to vertebrates and/ or invertebrates are produced by organisms associated with crop plants (Flannigan 1991). There are many known cases of human poisoning caused by such compounds. There are three broad categories of mycotoxins represented here, based on the structures of the intermediates from which these secondary metabolites are derived. They are (1) compounds derived from polyketides, (2) terpenes derived from mevalonic acid, and (3) cyclic peptides and derivatives thereof. 

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