Iridoids

Iridoids are monoterpenes with a carbocyclic five-membered ring. Their designation is derived from iridodial, a constituent of the defence secretions of ants of the genus Iridomyrmex, 

Iridoids are plant products, but are formed also in some animals. 

Iridodial is derived from geranyl pyrophosphate. 10-Hydroxynerol is an important intermediate (Fig. 104). 

On the one hand 10-hydroxynerol may be oxidized to the trialdehyde la which may also occur in the form of the enol Ib. The equilibrium between la, Ib, and Ic may explain why (in contrast to all other groups of terpenes) C-8 and C-10 of geranyl pyrophosphate lose their identity during the biosynthesis of many iridoids, e.g., during the formation of loganin. 

On the other hand 10-hydroxynerol may be dehydrogenated to 10-oxonerol, which via the dialdehyde III is reductively cyclized to iridodial without any randomization. 

Cyclopentanes, Iridoids.—A very useful review of the biosynthesis of the known sweroside-, morroniside-, and oleuropein-type secoiridoid glucosides, together with the biosynthesis of alkaloidal glucosides which can be regarded as secoiridoid 

Matsui, Agric. and Biol. Chem. (Japan), 1976, 40, 153. 

The essential oil from Lippia citriodora (oil of verbena) has yielded the four cyclopentanes (94 X = Me)—(96) as minor componentsTeucrium marum yields the two known dialdehydes (94 X = CHO) together with dolicholactone (97) and allodolicholactone (98) which may arise by biogenetic-type Cannizzaro reactions from(94 X = CHO).  

Thirty-three known iridoid and secoiridoid glucosides have been analysed by gas chromatography of their trimethylsilyl derivatives. G.c.-m.s. analysis of several representative compounds e.g. 4-CO2H, 4-C02Me, 4-unsubstituted) demonstrated the feasibility of iridoid-containing plant extract analysis and resulted in the identification of secologanoside 11-methyl ester (99 R = H, X = CH2) from Lonicera morrowii the sixth paper in a series of chemotaxonomic studies on iridoids illustrates the need for accurate analysis of minor components.  

Cyclopentanes, Iridoids.— Two papers report the analysis and separation of iri-doids. -  

The characterization of tran, fraws-dolichodial (118) from Iridomyrmex humilis has been reported (c/. Vol. 6, p. 25), and chrysomelidial (119) and plagiolactone (120 the assigned absolute stereochemistry is tentative) are present in the defensive secretion of Plagiodera versicolora.  

New Ci5 iridoid glucosides, occurring as minor components, are bartsioside, or 6-deoxyaucubin (121 X = H, R = /3-Glu), from Bartsia trixago, linaride, or 10-deoxyaucubin (122), from Linaria muralis, and a third picroside, 6 -(4-hydroxy- 

The full paper on the synthesis of onikulactone and mitsugashiwalactone (Vol. 7, p. 24) has been published.Whitesell reports two further useful sequences (cf. Vol. 7, p. 26) from accessible bicyclo[3,3,0]octanes which may lead to iridoids (123 X=H2, Y = H) may be converted into (124) via (123 X = H2, Y = C02Me), the product of ester enolate Claisen rearrangement of the derived allylic alcohol and oxidative decarboxylation/ whereas (123 X = 0, Y = H) readily leads to (125), a known derivative of antirride (126) via an alkylation-dehydration-epoxi-dation-rearrangement sequence. Aucubigenin (121 X = OH, R = H), which is stable at —20°C and readily obtained by enzymic hydrolysis of aucubin (121 X = OH, R = j8-Glu), is converted by mild acid into (127) ° with no dialdehyde detected sodium borohydride reduction of aucubigenin yields the non-naturally occurring isoeucommiol (128 X=H,OH) probably via the aldehyde (128 X = O).  

New Ci6 iridoid glucosides include mussaenoside (129 X = H, R = Me) and shanzhiside methyl ester (129 X = OH, R = Me) from Mussaenda parviftora and M. shikokiana, ipolamiidoside (28 X = H, R = Ac), the acetate of ipolamiide (28 X = R = H), whose stereochemistry is now assigned (c/. Vol. 6, p. 24), from Lamium amplessicaule, and another component from Phlomis fruticosa (cf. Vol. 

Cyclopentanes, Iridoids.—The nomenclature, structure, and methods of isolation of iridoid glucosides have been reviewed 167 the occurrence of iridoids in the angio-sperms has also been reviewed.168 

Sticher and U. Junod-Busch, Pharm. Acta Helv., 1975, 50, 127. 

R = Ac) from Barleria prionitis.189 Interest continues in iridoid glycosides from Valerianaceae. Three examples are now known with glucose linked to the C-ll rather than the C-l hydroxy-group they are patrinoside (100) from Patrinia scabiosaefolia,190 the previously unreported villoside (101),191 and valerosidate 

Reagents i, SOCl2-C6H6 ii, CH2N2 iii, hv, MeCN-H20 iv, B2H6-THF v, 1.5N NaOH  

Inouye and T. Nishioka, Chem. and Pharm. Bull. (Japan), 1973, 21, 497. 

Cyclopentanes, including Iridoids.—A summary of the botanical distribution, structure, and properties of the iridoids and seco-iridoids has been compiled, including about 80 natural products.  

The full paper concerning galiridoside, isolated from Galeopsis tetrahit (see Vol. 1, p. 18), has appeared. A thorough study of ca. 40 species of various Valerianaceae has shown that the valepotriates, the main component of which is 

A preliminary report has appeared from Wolinsky s laboratory concerning the cyclization of methyl ( )-epoxycitronellate (80) by the action of sodium hydride in dimethylformamide. This leads to the two lactones [(81) and (82)] and three unsaturated acids [(83)—(85)], the acids being formed via the action of sodium methoxide on the lactones. This reaction has led to a synthesis of dihydronepetalactone [the cis,cis,trans-S-meihy isomer of (74) and (75)].  

Tanaka, T. Katagiri, and K. Ozawa, Bull. Chem. Soc. Japan, 1971,44, 130. 

The colorants from saffron have enjoyed good technological success as colorants and spices but their high price has led to searches for other sources of the same pigments. The pigments, but not the flavor, can be obtained in much larger quantities from the fmits of the gardenia or Cape jasmine plant.33 

The geniposides from gardenia were found to have some hepatoxicity due to the aglycone genipin produced by hydrolysis of the geniposides.34 The yellow, green, red, and blue colorants were studied extensively and were found to be safe for human consumption as food colorants.35,36 

The yellow crocins from gardenia have received some success for the same colorant applications as saffron,37 but the iridoid derivatives have not received the same promotion. The range of colorants available from the same source would seem to make them attractive possibilities. 

SCHEME 6.7 Limonene (16) as a precursor for different oxygenated monoterpenes. 

SCHEME 6 Biosynthetic pathways toward carane- and thujane-type monoterpenes. 

SCHEME 6.9 Biosynthetic pathways toward important bicyclic monoterpenes. 

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Introduction of Nitrogen into a Terpenoid Skeleton. The acetate-derived fragments (35) mevalonic acid (30), which yields isopentenyl pyrophosphate (31) and its isomer, 3,3-dimethyl ally pyrophosphate (32) a dimeric C -fragment, geranyl pyrophosphate (33), which gives rise to the iridoid loganin (34) and the trimer famesyl pyrophosphate (35), which is also considered the precursor to C q steroids, have already been mentioned (see Table 3... 

From the plant Escallonia pulvemlenta (Escalloniaceae), which grows in Chile, an iridoid gluco-side of elemental composition CigZ/j On was isolated. Formula / gives the structure of the iridoid glucoside skeleton... 

The iridoid monoterpenoid part of the strueture C-1-C-9-C-5-C-6-C-7 (B) is eonfirmed by the HH COSY plot ... 

Scheme 3 RCM of a diene with trisubstituted and gem-disubstituted double bond en route to iridoid natural products [23]...

Icacinaceae are a moderate-sized, primarily tropical family consisting of 52 genera, many of which are monotypic, and 300 species. Additional background on taxonomic problems surrounding the family can be found in the 1991 paper by Kaplan et al. Chemical data have been used by Dahlgren (1980) to assess these relationships with related families, but the application involved simple presence or absence data (iridoids) and did not touch upon the dynamic nature of the pathways involved. 

The solubility of iridoids depends on their state (free, glycosylated, acetylated), but usually they are extracted with polar solvents methanol, ethanol, aqueous alcohols, and rarely acetone. Iridoid glycosides are more or less stable some of them are very sensitive to acids and alkalis. Some iridoid glycosides such as aucubin suffer color modification after chemical or enzymatic hydrolysis they give first a blue to green... 

Iridoids and their related alkaloids are widely spread in angiosperms and are found in 13 orders and 70 families including Rutales, Buxales, Hamamelidales, Comales, Loasales, Gentianales, etc. Important iridoids are loganin, found in high amounts in Strychnos nux-vomica and in Catharanthus roseus, and secologanin found especially in Caprifoliaceae. 

Jensen, S.R., Plant iridoids, their biosynthesis and distribution in angiosperms, in Ecological Chemistry and Biochemistry of Plant Terpenoids, Harbome, J.B. et al., Eds., Clarendon Press, Oxford, 1991, 133. 

Contin, A. et al.. The iridoid glucoside secologanin is derived from the novel triose phosphate/pyruvate pathway in a Catharantus roseus cell culture, FEES Lett., 434, 413, 1998. 

Konoshima, T. et al.. Cancer chemopreventive activity of an iridoid glycoside, 8-acetylharpagide, fvom Ajuga decumbens. Cancer I tt., 157, 87, 2000. 

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. 

Francis, F.J., Caramel, brown polyphenols and iridoids, in Colorants, Eagan Press, St. Paul, MN, 83,1999. 

The family Hamamelidaceae consists of 26 genera and about 100 species of shrubs or tress known to contain tannins and iridoids. The leaves are alternate, simple, and often palmately lobed. The flowers are small and appear in spikes. The fruits are woody, capsular, and scepticidal. In Western medicine, the dried leaves of Hamamelis virginiana (hamamelis, British Pharmaceutical Codex, 1963), yielding not less that 20% of alcohol (45%)-soluble extractive, have been used as astringents for the treatment of hemorrhoids. Hamamelis water (British Pharmaceutical Codex, 1969) made from the stems has been used as a cooling application to sprains and bruises and as a styptic remedy. It is also used in cosmetics and as active ingredient of eye lotions. 

Defensive substances are often general irritants that can be used in a variety of contexts. For example, the alloxystine wasps (Cynipoidea), all hyperpara-sitoids of other hymenopteran parasitoids, produce a large number of compounds in their cephalic (mainly mandibular) glands. These compounds include m/p-xylol, 6-methylhept-5-en-2-one 16, various iridoids 21 and frans-dihydro-nepetalactone 22 [46,73]. 

Detection of the hyperparasitoid by the primary parasitoid has also been recently described. The parasitoid Aphidius uzbekistanikus detects trans-fused iridoids 21 produced by females of the hyperparasitoid A. victrix as part of their defensive cephalic gland secretion. The iridoids cause avoidance behavior in A. uzbekistanikus [46]. 

The number of natural products containing these tricyclic systems is relatively small, viz. a few alkaloids from marine (compound 293), fungal (compound 282), amphibian (compound 395), insect (compound 387), and plant sources (compound 288) and also some iridoid molecules (compounds 98-100). Some of those Myrmkaria alkaloids (from ants Section 12.16.6.5.2) which contain the 5 5 6 fused-ring system are perhaps the most extensively studied of these natural products, with several successful syntheses now recorded. 

Hoye and Richardson have published an ingeneous synthesis of the tricyclic iridoid sarracenin (170) which relied on the Paterno-Buchi cycloaddition between acetaldehyde and cyclopentadiene as the intial step (Scheme 38)79. This reaction provided a 5 1 mixture of adducts 166a and 166b. The major adduct was opened with camphor-10-sulfonic acid (CSA) in methanol and the alcohol was tosylated to give 167. Displacement with malonate 168 and decarboalkoxylation/demethylation steps gave 169. Ozonolysis, reductive workup and acid-catalyzed acetalization then furnished 170. 

The facile conversion of carbonyl groups into lactones via cyclobutanones offers many opportunities for synthetic applications considering the importance of butanol-ides in natural products synthesis. The iridoids vividly illustrate this potential. Allamandin (163) 135 c) and its dehydrated relative plumericin (164) 135 d), compounds possessing antifungal, antibacterial, and antitumor activity, pack a great deal of... 

Fig. 8.5 Top. Some flavonoid pigments in gardenia. Bottom. Six of the nine iridoid...

FRANCIS, F. J. Caramel, Brown Polyphenols, and Iridoids. Chap. 10 in Colorants, Eagen Press, St. Paul, MN, 1999, pp. 83-8. 

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