Monoterpenes and Iridoids

Monoterpenes and iridoids are important classes of secondary metabolites, and their biosynthesis as well as total synthesis approaches to access these compounds has attracted the interest of chemists for a long time. This overview will summarize the most important biosynthesis pathways and in addition will illustrate how one of the most important recent developments in organic chemistry, asymmetric organocatalysis, contributed in the development of total synthesis approaches toward these compounds. Therefore, a comprehensive introduction to asymmetric organocatalysis will be given as well. However, it should be noted that the applicability of this methodology to the synthesis of natural products is of course not only limited to monoterpenes and iridoids but holds much promise for other classes of primary and secondary metabolites as well. 

The biosynthetic pathways leading to the formation of (mono)terpenes by different organisms have been systematically investigated in the past [1 ]. As already discussed in the preceding chapter, the biosynthesis sequence conunences with formation of the two key building blocks isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2) either via the mevalonate or the mevalonate-independent pathway [1, 3, 4]. These two compounds represent the activated isoprene units that can be assembled and 

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products, First Efiition. Edited by Alexaiifiros L. Zografos. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

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Monoterpenes and iridoids are very important natural products, and the biosynthetic pathways toward these compounds are nowadays well understood. We choose this class of secondary metabolites to highlight the potential of asymmetric organocatalysis for the total synthesis of complex natural products. Asymmetric organocatalysis has been one of the most exciting fields in organic chemistry over the last decades, and we hope that we have been able to illustrate how diverse and powerful this methodology can be with respect to different activation modes that are possible and different substance classes that can be easily accessed thereby. 

In plant plastids, GGPP is formed from products of glycolysis and is eight enzymatic steps away from central glucose metabolism. The MEP pathway (reviewed in recent literature - ) operates in plastids in plants and is a preferred source (non-mevalonate) of phosphate-activated prenyl units (IPPs) for plastid iso-prenoid accumulation, such as the phytol tail of chlorophyll, the backbones of carotenoids, and the cores of monoterpenes such as menthol, hnalool, and iridoids, diterpenes such as taxadiene, and the side chains of bioactive prenylated terpenophe-nolics such as humulone, lupulone, and xanthohumol. The mevalonic pathway to IPP that operates in the cytoplasm is the source of the carbon chains in isoprenes such as the polyisoprene, rubber, and the sesquiterpenes such as caryophyllene. 

The CNS-depressant component of valerian is still unknown. Thus far, three major constituents of valerian have been identified the volatile or essential oil, containing sesquiterpenes and monoterpenes, nonglycosidic iridoid esters (valepotriates), and a small number of alkaloids (2). Valepotriates are unstable compounds and are easily hydrolyzed by heat and moisture (22). In addition, valepotriates are not water soluble, and aqueous extracts contain... 

Iridoids are derivatives of monoterpenes and occur usually, but not invariably, as glycosides.100,101 Structurally, they are cyclopentano [r] pyran monoterpenoids and they provide a biogenetical and chemotaxonomical link between terpenes and alkaloids. The cleavage of the cyclopentane ring of iridoids produces secoiridoids.10... 

The CNS depressant component of valerian is still unknown. Thus far, three major constituents of valerian have been identified the volatile or essential oil, containing sesquiterpenes and monoterpenes, nonglycosidic iridoid esters (valepotriates), and a small number of alkaloids (Anonymous, 1991). Valepotriates are unstable compounds and are easily hydrolyzed by heat and moisture (Wagner et al., 1998). In addition, valepotriates are not water soluble, and aqueous extracts contain small amounts (Wagner et al., 1998). For example, the aqueous extract used in the study by Balderer and Borbely, described previously, was analyzed using thin-layer chromatography (TLC), and no valepotriates were detectable. Furthermore, valepotriates are not well absorbed orally (Tyler, 1993). Therefore, the likelihood that valepotriates are a major contributor to valerian s effects is questionable. Because of the low amount of alkaloid present in preparations, their contribution is also questionable (Houghton,... 

CioH.jN, Mr 147.22, oil, bp. 100-103 °C(1 kPa),[a]i, -7.2° (CHCI3), a monoterpene alkaloid ( iridoids) from the east Asian creeper Actinidia polygama and other Actinidiaceae, Bignoniaceae, and Valerianaceae. It is a component of the defensive secretion of black beetles, ants, grasshoppers, and flies. Only the (5) enantiomer occurs in nature. A. exhibits antimicrobial properties and a deterrent effect against birds and arthropods , while cats are strongly attracted Synthesis There are various syntheses of the racemate and the unnatural (/I) enantiomer, but only three for the (5) enantiomer. The biosynthesis presumably proceeds from iridodial. 

Monoterpene and indole alkaloids are frequently derived from iridoid monoterpene precursors (Inouye, 1991). 

Plants in the Comanae, Gentiananae, and Loasanae, in general, contain both normal iridoid monoterpenes and secoiridoids. Plants in the Lamianae contain not only many normal iridoid monoterpenes but also those in which C-11 is decarboxylated. They lack secoiridoids. Plants of the Ericanae do not exhibit a clear pattern. Iridoid compounds with 8-P-stereochemistry were assumed to derive from pathways associated with secoiridoid biosynthesis, whereas those with 8-a-stereochemistry were associated with the route involving C-11 decarboxylation (Jensen, 1991). Some exceptions... 

The order Gentianales (Apocynaceae, Gentianaceae, Lo-ganiaceae, Rubiaceae, and Theligonaceae) contains normal iridoid monoterpenes and secoiridoids, as well as iridoid-derived alkaloids in families other than the Asclepiadaceae. Multiple types of alkaloids are found in the Apocynaceae (indole and steroidal types), the Loganiaceae, and Rubiaceae (emetine, quinine, and indole types). 

Five-membered rings are present, for example, in the physiologically important prostanoids as well as in monoterpenes, the iridoids, in the antibiotic hirsutic acid and in nepetalactone, an essential oil from catmint. 

Plant feeding insects are able to store host plant monoterpenes and use the compounds in their own defense. Pine sawfly larvae store mono- and diterpenes of host plant resin for defensive purposes (see diterpenes). Larvae of Chrysomelid leaf beetles feeding on Salix and Populus are able to store and sequester precursors of iridoids (cyclopentane monoterpenoids) derived from host plant. In addition to this sequestration iridoids may even have a dual origin as larvae of Plagiodera versicolora and Phratora laticollis have the potential to de novo produce iridoids from the precursors in their food [8]. 

Terpenoids, which include in particular tetraterpenoid and some other pigments derived from tetraterpenes, known as carotenoids, monoterpenic pigments iridoids and certain other coloured compounds. 

Iridoid monoterpenes called iridoids are a group derived from the skeleton of the hydrocarbon iridane (9-206). Their usual structure is represented by the formula 9-207. The opening of a cyclopentane ring and introduction of various functional groups (mainly by oxidation) yields secoiridoids (9-208), which include many bitter substances of plants. 

Phosphinothioic amides are highly effective reagents for the alkylidenation of ketones, and the method has been developed as a means of methylenation coupled with optical resolution. The reaction of the anion of the phosphinothioic amide (21) gives the diastereoisomeric mixture (22), which, after separation, can be converted into the optically active olefins (23). The method has been applied to the synthesis of the (+)- and ( —)-iridoid monoterpene hop ether (24), and can be extended to alkylidenation with resolution. 

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