Acetate pathways, natural products

Additional hypotheses concerning prostaglandin biosynthesis in P. homomalla resulted from isolation of 11R-HETE (76) from the polar lipid fraction [95]. Apparently, 11R-HETE (76) is also a minor product of incubations of arachidonic acid with acetone powder preparations of P. homomalla [95], In this alternate hypothesis (Scheme 8), an 11-hydroxy or 11-hydroperoxy-8,9-allene oxide intermediate is formed from a sequence of oxidations at C8 and Cll. Opening of the allene oxide to a transient C8 earboeation induces eycli-zation with a consequent addition of water to C15. This proposed pathway leads initially to formation of PGE2 (16 or 38), which following acetylation, elimination of acetic acid from Cl 1-12, and esterification, forms the observed major natural product in the coral, 15-acetoxy methyl PGA2 (36 or 54). Notably, if... 

Of the four major classes of biochemicals (carbohydrates, proteins, nucleic acids and lipids), experiments have shown that the first three classes could have arisen through prebiotic chemistry. Although the biosynthesis of many natural products can be traced back to acetate (e.g. fatty acids, terpenes and polyketide biosynthesis) or amino acids (e.g. alkaloid biosynthesis), there are many whose biosynthetic origins are either obscure or result from a complex combination of pathways (Fig. 2). 

The flavonoids, which comprise the largest group of these natural products, are derived from a mixed acetate-shikimate pathway. A shikimate-derived C6-C3 unit combines with a six-carbon polyketide chain to provide the open-chain precursor (685) of the group. The derivation of p-hydroxycinnamic add (p-coumaric acid), the C6-C3 component, from shikimic acid proceeds through chorismic acid, prephenic acid and phenylalanine. 

The macrolide antibiotics provide us with excellent examples of natural products conforming to the acetate pathway, but composed principally of propionate units, or mixtures of propionate and acetate units. The macrolides are a large family of compounds, many with antibiotic activity, characterized by a macrocyclic lactone ring, typically 12, 14, or 16 membered, reflecting the number of units utilized. Zear-alenone (Figure 3.59), a toxin produced by the... 

Many other natural products contain terpenoid elements in their molecules, in combination with carbon skeletons derived from other sources, such as the acetate and shikimate pathways. Many alkaloids, phenolics, and vitamins discussed in other chapters are examples of this. A particularly common terpenoid fragment in such cases is a... 

Natural Products Originating from Acetate and Shikimic Acid Pathways... 

Mevalonic acid, a six-carbon building block, is made up from three molecules of the most basic two-carbon precursor, acetyl-CoA. The mevalonate pathway, which involves the intermediary of mevalonic acid, directs acetate into a series of natural products different from those derived directly from the acetate pathway and includes terpenoids and steroids. Terpenoids constitute the most chemically diverse and one of the largest groups of plant natural products, and therefore a detailed discussion on this group of natural products is warranted. 

Myriaporones are a class of natural compounds that were first isolated in 1995 and show antitumor activity against some cancer cell lines. From their structures it is assumed that they stem from the polyketide biosynthesis pathway. It has been argued that the somewhat unusual exo-methylene group at C-6 in myriaporones 1 (1) and 2 (2) is a result of the isolation process via elimination of an acetate group rather than a part of the actual natural product. ... 

Among the marine natural products shown in Fig. (4), predehydrovenustatriol acetate (16) presents an attractive structural feature in regards to its biogenesis. The absence of the A-ring and the presence of the trisubstituted double bond between C2 and C3 points to a step-wise biosynthetic pathway this subject is discussed in the next section of this Chapter. Laurencia viridis has also been the source of thyrsenol A (19) and thyrsenol B [20, Fig. (5)]. Both of these compounds display an unusual enol ether moiety in the C-ring [11]. 

Lipids are natural products derived from polyketides which are originated from the acetate pathway. The term lipid has traditionally... 

Flavonoids are a large class of plant natural products of low molecular weight. Over 3,000 different flavonoids have been chemically characterised and novel ones are still being reported. Flavonoids are aromatic molecules synthesised from the amino acid phenylalanine and an acetate-derived precursor as malonyl-coenzyme A (Fig. 11.1) (Winkel-Shirley 2001). This reaction is carried out by the enzyme chalcone synthase (CHS) to produce chalcone. The chalcone can subsequently be isomerised by the enzyme chalcone flavone isomerase (CHI) to yield a flavanone. From these intermediates the pathway diverges into several side branches yielding different subclasses of flavonoids, as summarised in Fig. 

The nature of the biosynthetic pathway to sambucinol (81) is controversial. Trichodiene and isotrichool (52) are proven precursors in F. culmorum (225), as are apotrichool (85) (226) and 3-deoxysambucinol (80) (285). Another precursor is 2a,13-dihydroxyapotrichothecene (84) (227), which has not yet been isolated as a natural product but which should be readily obtainable from 11-epiisotrichodiol (143) by mechanism F, Scheme 3. Apotrichodiol (86) is converted photochemically in solution at room temperature into the acetal (92) (211), a likely precursor of sporol (91). Similar photochemical reactions with 2a-hydroxyapo-trichothecenes, which could lead to deoxysambucinol (80) (mechanism F), have not been reported. 

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). 

Acetals incorporated in aimelated five-membered rings are prominent examples in natural products such as, for instance, aflatoxins. A new route to this structural motif weaving the different reactivities of a furan core into a reaction pathway was... 

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