Cyclization reactions, biosynthesis

Alternative, also stereoselective, routes to allenic steroids take advantage of cationic cyclization reactions [108] or [2,3]-sigmatropic rearrangements [109]. For example, the allenic Michael acceptor 112 was prepared with 57% chemical yield by reaction of mestranol (111) with diethyl chlorophosphite and was found to inhibit the sterol biosynthesis of the pathogen responsible for Pneumocystis carinii pneumonia (PCP), the most abundant AIDS-related disease (Scheme 18.36) [110]. 

These processes are normally enzyme-catalyzed. Purefy ctemical processes are seldom encountered with carbon conq)ounds in nature. The few exceptions include the very act of phenol coupling (by which racemic compounds are obtained), cyclization reactions ofpolyprenyl compoimds (which benefit from the preferred conformation of the reaction partners, suitable for the cyclization, Wendt 2000), and Diels-Alder cycloadditions. The latter have been advocated for the biosynthesis of celastroidine A (= volubilide) from a lupane triterpene and an abietane diterpene in two different plants, Hippocratea celastroides Kunth from Mexico (Jimenez-Estrada 2000) and Hippocratea volubilis Linnaeus (Alvarenga 2000). 

As we shall see, cyclization reactions of this general type seem to be important in terpene biosynthesis. The 6,7-trans-farnesol has been shown to have hormone action in some insects. It acts to regulate the changes from caterpillar to cocoon to moth. 

A modified Pechmann cyclization reaction of resorcinol and acrylic acid is catalyzed by silica nanocomposites to afford 7-hydroxydihydrocoumarin in good yield <2003JM0315>. A study concerning the biosynthesis of 7-hydro-xydihydrocoumarin from a catechol precursor is available <2005CC666>. 

In these cases the formal //-ammo acid relationship often is a result of late stage condensation or cyclization reactions (e.g. Mannich-type, Pictet-Spengler) within the biosynthesis Typical examples are cocaine and correlated tropane alkaloids, Catharanthus alkaloids or Iboga alkaloids like heyneanine. 

WILLIAMS, D. C., WILDUNG, M. R., JIN, A. Q. W., DALAL, D., OLIVER, J. S., COATES, R. M., CROTEAU, R., Heterologous expression and characterization of a "pseudomature" form of taxadiene synthase involved in paclitaxel (Taxol) biosynthesis and evaluation of a potential intermediate and inhibitors of the multistep diterpene cyclization reaction, Arch. Biochem. Biophys., 2000, 379, 137-146. 

A beautiful example of electrocyclic reactions at work is provided by the chemistry of the endiandric acids. This family of natural products, of which endiandric acid D is one of the simplest, is remarkable in being racemic—most chiral natural products are enantiomerically pure (or at least enantiomerically enriched) because they are made by enantiomerically pure enzymes (we discuss all this in Chapter 45). So it seemed that the endiandric acids were formed by non-enzymatic cyclization reactions, and in the early 1980s their Australian discoverer, Black, proposed that their biosynthesis might involve a series of electrocyclic reactions, starting from an acyclic polyene precursor. 

Cyclization of an allylic pyrophosphate is a key step in the biosynthesis of most monoterpenes. Early hypotheses concerning the nature of the acyclic precursor and the cyclization process are first described, and chemical models for the cyclization presented. Following a review of several representative cyclase enzymes and the reactions that they catalyze, a series of stereochemical and mechanistic experiments with partially purified cyclases are reported. The results of these studies have allowed a detailed description of events at the active site and the formulation of a unified stereochemical scheme for the multistep isomerization-cyclization reaction by which the universal precursor geranyl pyrophosphate is transformed to cyclic monoterpenes. 

Biosynthetic experiments with variously labelled acetate units and [methyl- C] methionine established that the carbon skeleton of mevinolin was formed from nine acetate units, with the extra methyl group arising from methionine. The ester arose from two acetate units and a methionine. The oxygen atoms of the side chain at C-11, C-13 and C-15 were derived from the original acetate units whilst that at C-8 came from oxygen of the air. The cyclization reaction to form the bicyclic carbon skeleton may be a Diels-Alder cyclization (4.93 4.94). These are biosynthetically rather unusual. In the late stages of the biosynthesis, 4ot,5-dihydromonacolin L (4.95) is hydroxylated and dehydrogenated to form mevinolin. 

Arachidonic acid (22) is a polyunsaturated fatty acid that plays a special role as a synthetic intermediate in plants and animals (Mann et al., 1994). As shown in Figure 6.6, allylic oxidation at the 11th carbon of the chain leads to the hydroperoxide (23). Further oxidation (at the 15th carbon) with two concomitant cyclization reactions gives the cyclic peroxide (24). This is a key intermediate for the biosynthesis of prostaglandins such as 6-ketoprostaglandin Fjj, (25) and... 

The biochemistry and enzymology of CHS and its closely related plant PKSs have been extensively studied [72, 75]. The native enzymes have been isolated from various plants [70,71,73,74,124,125,127,128], and the recombinant proteins have been produced in E. coli and purified [71,76,124,125,132-135,139]. The active site for the condensation reaction has been mapped to a single Cys residue [132]. The dimeric nature of CHS and STS has been established with each homodimer to constitute two active sites [76,127,133]. The subtle differences among the CHS and STS proteins have been compared, which seems to have a profoimd effect on substrate specificity and regiospedfidty for the condensation and cyclization reactions, respectively [74, 127, 128, 133, 134]. The interactions between CHS and other proteins, such as KR [133,136-139] and methylmalonyl CoA-specific condensing enzyme [76], have been examined to account for the biosynthesis of deoxychalcones and methylchalcones. 

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