Aromatic natural products

Kuzuyama T, Noel JP, Richard SB (2005) Structural basis for the promiscuous biosynthetic preny-lation of aromatic natural products. Nature 435(7044) 983-987... 

Shikimates, which include phenylalanine, tyrosine, tryptophan, and their derivatives, are represented by many aromatic natural products, including hydroquinones found inbrownalgae such as Sargassum (Segawaand Shirahama 1987). Flavonoids are a structural class of shikimates found in plants, including isoflavonoids or neo-flavonoids, as is the y-pyrone (coumarin) core structure (Knaggs 2003). 

In the next chapter you will see how hydroxylation of benzene rings plays an important part in the biosynthesis of alkaloids and other aromatic natural products. 

Aromatic natural products of polyketide origin are less prevalent in plants compared with microorganisms. The majority of the plant constituents that contain aromatic stmctures are known to arise from the shikimate pathway (see below). Unlike those derived from the shikimate pathway, aromatic products of the polyketide pathway invariably contain a meta oxygenation pattern because of their origin from the cyclization of polyketides. Phenolic compounds such as chrysophanol-anthrone (Bl), and emodin-anthrone (B2), and the anthraquinones, aloe-emodin (B3) and emodin (B4) (Fig. 2), are products of the polyketide pathway and are found to occur in some plants of the genera Cassia (Leguminosae) (21), Rhamnus (Rhamnaceae) (22), and Aloe (Liliaceae) (23). The dimer of emodin-anthrone (B2), namely hypericin, (B5) is a constituent of the antidepressant herbal supplement, St. John s wort (Hypericumperforatum, Hy-pericaceae) (24). 

The shikimate pathway links the metabolism of carbohydrates to the biosynthesis of aromatic natural products via aromatic amino acids. This pathway, which is found only in plants and microorganisms, provides a major route to aromatic and phenolic natural products in plants. To date, over 8,000 phenolic natural products are known, which accounts for about 40% of organic carbon circulating in the biosphere. Although the bulk of plant phenolics are components of cell wall stmctures, many phenolic natural products are known to play functional roles that are essential for the survival of plants. 

Coumestans represented by 321 are an oxygenated class of aromatic natural products, which have phytoalexin and estrogenic activities. From the biogenetic point of view, 321 will be formed from two units, 4-hydroxycoumarin (322) and catechol. Thus, the first synthesis of 321 was carried out by an electrochemical method. Catechol was initially oxidized to o-quinone, which was attacked by 322 to afford 321 in 95% yield (Scheme 69). ... 

NATURAL PRODUCTS 1270 Steroids 1297 Terpenes 1306 Aromatic Natural Products... 

CioHioOa, Mr 226.19. Crystallizes as a monohydrate, mp. 148-149°C, [a]c -295.5° (HjO). In bacteria, fungi, and higher plants C. is an important intermediate in the biosynthesis of aromatic natural products via the shikimic acid pathway. The biosynthesis proceeds via shikimic acid - shikimic acid 3-phosphate -> 5-0-(l-carboxyvinyl)-shikimic acid 3-phosphate - chorismic acid. 

CgHgOi, Mr 168.15, needles, mp. 176 °C (anhydrous), 186-189 °C (monohydrate), soluble in water and alcohol. The phenolcarboxylic acid O. represents an important intermediate in the biosynthesis of aromatic natural products from polyketides. 

C,oH oOg, Mu 226.19. P. is unstable in the free form and undergoes decarboxylation with elimination of water to give phenylpyruvic acid. It is an intermediate in the biosynthesis of many aromatic natural products by the shikimate pathway (see chorismic acid, shi-kimic acid). The biosynthesis of P. proceeds from chorismic acid by enzyme-catalyzed [3,3]sigmatropic rearrangement (Claisen rearrangement) under the action of chorismate mutase (EC 5.4.99.5). 

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

Except for the construction of isoprenyl aromatic natural products, the Claisen rearrangement of allyl phenyl ethers has been relatively little exploited in natural product synthesis. The potential value of the reaction, however, has now been demonstrated in a synthesis of (+)-latifine (128). Thus, the allyl phenol ether (125) was found to re-arrange smoothly in refluxing N,N-dimethylaniline to give (125) in 75% yield, which was then elaborated to the natural product via the amine (12 ) in a further seven steps. 

Carbohydrates include saccharides and polysaccharides, or sugars and starches, and cellulosic or lignin type biotnolecules. They consist mostly of aliphatic cyclic groups with attached OH groups and ether linkages. Lignin is representative of aromatic natural product compounds. Thus, the bands normally associated with these functional groups may be observed in the near-infrared (NIR) spectra of carbohydrate molecules. 

Late-stage ligand-accelerated inter-molecular oleflnation via Pd-mediated C—H activation was utilized toward the convergent construction of the biologically relevant aromatic natural product (+)-lithospermic acid (58) (Scheme 3.34). Subsequent functionalization completed the natural product in efficient 12 steps for the longest linear sequence in 11% overall yield from commercially available o-eugenol. 

Ultraviolet-visible (UV-Vis) spectroscopy (281, 337) is one of the oldest spectroscopic techniques and hence one of the first to be applied to structure determination. The substitution pattern of many aromatic natural products - flavonoids being an excellent example (241) - are still determined by UV-Vis spectroscopy including acid-based-, and aluminum trichloride-induced shifts of absorbance bands (227, 288, 343, 389). Adduct formation of the purine and pyrimidine bases are also investigated by UV-Vis spectroscopy (352), and solvent-induced shifts are often useful tools of structure determination for many other classes of compounds. There remains, however, a wealth of uncovered information in the UV-Vis spectra of natural products masked by broad, overlapping bands with little or no fine structure. 

This section has dealt with a diversity of compounds of very different structural types and of different biogenetic origins. Some types of compounds have been investigated in more detail than others. This situation does not reflect the relative importance of the compounds but rather the academic interest of natural product chemists. The literature is, of course, not covered completely since the intention has been to emphasize common constituents or constituents of general interest. Additional references to recent work on some of the classes of compounds, discussed in this section, can be obtained from a comprehensive review on benzenoid and polycyclic aromatic natural products by Simpson (108). 

Simpson T J 1987 Benzenoid and polycyclic aromatic natural products. Nat Prod Rep 4 639-676... 

Type II PKS Systems in Bacteria Many bio-medicaUy important aromatic natural products are derived from bacterial type II PKSs [23]. Within these biosynthetic machineries, individual enzymes form a functional complex, the so-called minimal PKS. This is composed of a KSot/KSp heterodimer and a dissociated ACP that serves as product tether (cf. Scheme 2.3b). ACP loading with building blocks is catalyzed by a malonyl-CoA ACP transacylase (MAT), an activity that can be provided by FabD from fatty acid... 

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