Alkaloids from Polyketides

Biosynthesis of adaline (107) may be carried out via intermediate 456 from polyketide origin. A possible biogenetic interrelationship between adaline (107) and the coccinelline-type alkaloids (Scheme 57), suggested by Tursch et al. 

The examples cited highlight the state of the art in the solid phase synthesis of natural products ranging from alkaloids to polyketides and terpene derived structures. While the well optimized protocols of peptide and DNA synthesis allow for over 50 steps to be carried out linearly on solid phase, the efficacy of solid phase transformations for the larger repertoire of reactions (albeit less optimized) generally limits the length of a synthesis to a range of 10-12 steps with the current technologies. 

Only three macrolides have been isolated from lichens (Table VII). On the other hand, plants produce about 700 macrolides (Table VIII), but most of them are macrodiolides or macrotriolides such as tannins and alkaloids (e.g., pyrroliz-idines). Their biosynthetic pathways are quite different from polyketide macrolides. A small group of monolactone macrolides has up to 19-membered ring lactones. Some of them have a musky odor. 

The H. a. are pseudoalkaloids, their carbon skeletons do not originate from amino acid metabolism but rather from polyketide metabolism (figure). Coniine is a highly toxic alkaloid and is rapidly resorbed by mucous membranes and intact skin. It acts at first as a stimulant for motoric nerve endings followed by cu-rare type paralysis of striated musculature. Death follows after 0.5-5 h in full consciousness through par-... 

Biological Activity of Tropane Alkaloids Distribution of Tropane Alkaloids Piperidine Alkaloids Alkaloids from Piper Species Piperine Alkaloids Involving Condensation with Acetate/Malonate Sedum Alkaloids Lobelia Alkaloids Lycopodium Alkaloids Piperidine Alkaloids in Insects Polyketide-Derived Alkaloids Coniine... 

Very few alkaloids of polyketide origin are known in nature, particularly in woody plants. Pinidine is one of them. This alkaloid has been isolated from the needles of the Pinaceae species Pinus jeffreyi, P. subiniana, and P. torreyana (153, 154). 

Polyketide-Derived Alkaloids from Coniothyrium cereale... 

Some ants make products reminiscent of the coccinellid alkaloids. Three indolizidines are known from the venom gland of Monomorium pharaonis (Figure 9.10), and a pyrrolizidine from a Solenopsis ant has been known for some time. They would appear to be formed from polyketides or fatty acids as in the case of the coccinellines. More pyr-rolizidines and indolizidines with two alkyl and alkenyl groups have been found in Monomorium and Solenopsis species. Tetraponerine ants smear the venom of their poison glands onto prey. The venom consists of tricyclic alkaloids called tetraponerines (Figure 9.10). They are divided... 

In addition, it has been discovered that there are naturally occurring enzymes that facilitate Diels-Alder type reactions within certain metabolic pathways and that enzymes are also instrumental in forming polyketides, isoprenoids, phenylpropanoids, and alkaloids (de Araujo et al., 2006). Agresti et al. (2005) identified ribozymes from RNA oligo libraries that catalyzed multiple-turnover Diels-Alder cycloaddition reactions. 

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). 

Overall, however, the immensity of temperate land corresponds to a most various secondary metabolic production, different from that of tropical land. The most renowned alkaloids belong to the morphine class (Chart 6.2.A1), and, in combination with isoprenoids, to the ergot and triterpene classes (Chart 6.2. A2). Prominent in the peptides are the cyclosporins (the first of which was isolated from a fiingus collected in Norway), streptogramins, and P-lactams (Chart 6.2.P). The isoprenoids are represented by pyrethrin monoterpenes, cedrane sesquiterpenes, ginkgolide and taxane diterpenes, ophiobolane sesterterpenes, and arborane and amyrin-like triterpenes (Chart 6.2.1). In the polyketides, epothilones, recently discovered from Myxobacteria, and the long known rapamycin, are two prominent classes of macrolides (Chart 6.2.FA/PO/C). 

One current estimate of NP diversity totals ryo.ooo different structures, yet this huge chemical diversity is generated from only a few biochemical pathways that branch from the metabolism shared by most organisms. About 60% of the known NP diversity comes from one ancient pathway (the isoprenoids or terpenoids), another 30% comes from some other ancient pathways related to each other (the polyphenols, phenylpropanoids or polyketides) and less than 10% of NPs (alkaloids) comes from a more diverse family of pathways. There seems to be a rough correlation between the number of species possessing one pathway and the total diversity of NPs made by that route. Consequently, the minor groups of NPs that comprise less than 1% of the total NP diversity (e.g., the glucosinolates) tend to be restricted to a small number of species. 

There are several classes of alkaloids. Among these are purines such as xanthine and caffeine, ter-penes (Chapter 22), polyketides (Chapter 21), and alkaloids derived from amino acids. The basic amino acids ornithine, arginine, histidine, and lysine as well as the aromatic amino acids, anthranilate, and nicoti-nate are some of the starting materials.199 201 Robinson202 203 in 1917 recognized that many alkaloids are derived directly from aromatic amino acids. He proposed that alkaloids arise from Mannich reactions (Eq. 25-12) in which an amine and an aldehyde (probably through a Schiff base) react with a nucleophilic carbon such as that of an enolate anion. Many of the... 

The polyketide synthases responsible for chain extension of cinnamoyl-CoA starter units leading to flavonoids and stilbenes, and of anthraniloyl-CoA leading to quinoline and acridine alkaloids (see page 377) do not fall into either of the above categories and have now been termed Type TTT PKSs. These enzymes differ from the other examples in that they are homodimeric proteins, they utilize coenzyme A esters rather than acyl carrier proteins, and they employ a single active site to perform a series of decarboxylation, condensation, cyclization, and aromatization reactions. 

Biosynthesis of Polyketides Phenolic Compounds derived from Shikimate. The Biosynthesis of CB - Cjg Terpenoid Compounds Trrterpenoids Steroids, and Carotenoids Non-protein Amino-acids, Cyanogenic Glycosides, and Glucosinolates Biosynihesis of Alkaloids. 

The biosynthetic studies undertaken to date on microbial marine natural products well illustrate the diversity of metabolic pathways encountered in cultured marine bacteria. Examples include brominated alkaloids such as pentabromopseudiline (Structure 2.1),19 polyketide or mixed polyketide metabolites such as oncorhyncholide (Structure 2.2),20 aplasmomycin (Structure 2.3),21 and andrimid (Structure 2.4),22 or the cyclic depsipeptide salinamide A (Structure 2.5).23 As researchers continue to define more specific culture media and a wider range of marine bacteria from diverse habitats are successfully placed into culture, the true biosynthetic potential of these prolific and adaptable microorganisms can be explored. 

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