Polyketide terpenes

Scheme 2.175. Domino Knoevenagel/hetero-Diels-Alder reaction for the construction of "polyketide" terpenes.

Hoffmann and coworkers have elaborated an appealing three-component domino Knoevenagel/hetero-Diels-Alder procedure [395]. These authors converted cy-clohexane-l,3-dione, formaldehyde and several as dienophiles acceptor serving monoterpenes into a variety of polyketide terpenes of type 2-790 (Scheme 2.175). 

Over the past quarter-century more than 10,000 compounds have been reported from marine-derived organisms. These compounds encompass a wide variety of chemical structures including acetogenins, polyketides, terpenes, alkaloids, peptides and many compounds of mixed biosynthesis. A number of excellent books and reviews document the diversity of both structures and bioactivities which have been observed for marine-derived compounds. ... 

Natural products come in enormous variety, but fall mainly into four types alkaloids, polyketides, terpenes, and steroids... 

Despite the thousands of secondary metabolites made by microorganisms, they are synthesized from only a few key precursors in pathways that comprise a relatively small number of reactions and which branch off from primary metabolism at a limited number of points. Acetyl-CoA and propionyl-CoA are the most important precursors in secondary metabolism, leading to polyketides, terpenes, steroids, and metabolites derived from fatty acids. Other secondary metabolites are derived from intermediates of the shikimic acid pathway, the tricarboxylic acid cycle, and from amino acids. The regulation of the biosynthesis of secondary metabolites is similar to that of the primary processes, involving induction, feedback regulation, and catabolite repression [6]. 

The three main groups of secondary metabolites (polyketides, terpenes and alkaloids) are all represented in marine fungi. Their distribution is still uncertain but tends to be non-homogeneous between the two main fungal divisions. Ascomycotina seems to contain preferentially polyketides and alkaloids, whereas the main terpenes identified to date were isolated from Deuteromycotina (Table XX). 

A variety of monoterpenes take part in a hetero Diels-Alder reaction with the oxabutadiene derivative formed from 1,3-cyclohexanedione and formaldehyde, giving polyketide terpene frameworks by a one-pot regio-, chemo- and stereoselective reaction. Amongst the products accessible by this route is the oxapropellane (4) (94H661). 

Asymmetric synthesis ch41 and protect sensitive functional groups How to make and manipulate sugars and their derivatives Lipids form the basis of membrane structures The main sorts of natural products are alkaloids, polyketides, terpenes, and steroids Alkaloids are amines made from amino acids Fatty acids are built up from acetyl CoA and malonyl CoA subunits ... 

When considering the formation of naturally occurring substances, whether simple amino-acids, sugars, or complex proteins, alkaloids, polyketides, terpenes or steroids, it should be remembered that all the reactions involved follow the normal laws of chemistry. One of the fascinating areas of chemistry today is trying to understand how these biosynthetic reactions occur. How it is that reactions we find extremely difficult in the laboratory are accomplished efficiently and quickly at room temperature and near neutral pH inside cells What kinds of organic chemical reactions can be used in living cells ... 

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. 

Chemical structure can often be used by itself to recognize a secondary metabolite because of their common biosynthetic origin Terpenes and polyketides, for... 

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). 

Fatty acids. Lipids, Secondary polyketides Mevalonate, Steroids, Carotenoids, Terpenes... 

Mycotoxins are, in general, low molecular weight, non-antigenic fungal secondary metabolites formed by way of several metabolic pathways, e.g. the polyketide route (aflatoxins), the terpene route (trichothecenes), the amino acid... 

Assign each of these natural products to a general class (such as amino acid metabolite, terpene, polyketide) explaining what makes you choose that class. Then assign them to a more specific part of the general class (for example, tetraketide, sesquiterpene). 

Similar to other natural products, phytotoxins are classified on the basis of their structural types considering their biosynthetic pathways. Among various phytotoxin families, polyketides including aromatic and reduced polyketides, peptides including diketopiperazines, and terpenes are most frequently described in the literature. In this section, representative phytotoxins that are well-characterized biosynthetically and physiologically will be introduced. 

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

Type III polyketide synthases (PKSs) generate a diverse array of natural products by condensing multiple acetyl units from malonyl-CoA to specific starter substrates (1,2). The homodimeric enzymes orchestrate a series of acyltransferase, decarboxylation, condensation, cyclization, and aromatizatidn reactions at two functionally independent active sites. Due to their ability to vary either the starter molecule or the type of cyclization and the number of condensations, they are, along with terpene synthases, one of the major generators of carbon skeleton diversity in plant secondary metabolites (i). Among the starter substrates used, benzoyl-CoA is a rare starter molecule. It is utilized by bacterial type I PKSs to form soraphen A, enterocin and the wailupemycins (4). in plants, benzoyl-CoA is the starter unit for two type III PKSs, benzophenone synthase (BPS) and biphenyl synthase (BIS), both of which were cloned in our laboratory. 

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. 

The past decade has seen an explosion in our understanding of enzyme pathways through which natural products are produced [6, 7]. For example, linear non-ribosomal peptide (NRP), polyketide (PK), and terpenoid (terpene) scaffolds are usually assembled from amino acids (isopenicillin) [8], acyl-CoAs (erythromycin) [9], and pentenyl pyrophosphates (artemisinin), respectively [10] (Scheme 8.1). These... 

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