Iridoid Glycosides and Aglycones as Chiral Synthons, Bioactive

Chapter 26

Iridoid Glycosides and Aglycones as Chiral Synthons, Bioactive Compounds, and Lepidopteran Defenses

Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: November 28, 1988 | doi: 10.1021/bk-1988-0380.ch026

Frank R. Stermitz Department of Chemistry, Colorado State University, Fort Collins, CO 80523 Iridoid glycosides are relatively widely distributed among families of several higher plant orders and are often present in amounts reaching several percent of the plant dry weight. The high plant concentration of several iridoids has resulted in their use as starting materials for subsequent conversion to substituted cyclopentanes, such as prostaglandin synthons. Some iridoid glycosides have been shown to have antibiotic, antioxidant, plant growth inhibiting or antitumor properties, but these seem to be mainly a property of the aglycone. The bitter taste of iridoids is responsible for their utilization by Lepidoptera as defensive substances and such iridoids have been found in a number of boldly-patterned insect larvae. Iridoids are higher plant biosynthetic derivatives of 2, the hemiacetal form of an enol of iridoidal, 1. Iridoids generally occur in the plant as a glucosides, such as 3, but are occasionally encountered as glycosides of other sugars. Many iridoids occur as oxidized derivatives of 3, where the C-4 methyl has been replaced by an aldehyde, carboxylic acid, or carbomethoxy group. The C-4 decarboxylated compounds are also common. Most iridoids are, in addition, further oxidized in the cyclopentane ring. In some plant families, the cyclopentane ring has been cleaved to yield secoiridoids related to secologanin, 4, which is an important biosynthetic precursor of indole alkaloids and a useful, commercially available synthon. Known iridoids and secoiridoids from plants now number over 300. A recent review (1) with 200 references provided background information as well as a comprehensive discussion of iridoid biosynthesis.

3

4

The present review, which will be illustrative rather than comprehensive, focuses on aspects of recent work showing that iridoids can be exploited as chiral synthons, on recent reports of biological activity of some iridoids and their aglycones, and on some of our own results on iridoid sequestration by aposematic (warningly-patterned or colored) insects. 0097-6156/88/0380-0397$06.00/0 ° 1988 American Chemical Society

In Biologically Active Natural Products; Cutler, H.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

398

BIOLOGICALLY ACTIVE NATURAL PRODUCTS

Iridoids as Useful Chiral Synthons By early 1986 18 papers and 4 patents had appeared in which naturally-occurring iridoids were utilized as chiral starting materials for the preparation of prostanoid synthons or prostaglandins (2). The three iridoids most commonly used have been aucubin, 5, asperuloside, 6, and catalpol, 7. The Italian group has generally used


ο

1 2 R C O O M e ; R = OH 1=

8 R, = CH ; R = OH

2

3

2

13 R, =COOH;R = H 2

14 R = COOMe; R = Η 1

2

5, obtained in 2% yield from the readily available ornamental shrub Aucuba japonica (2). In another case (3), 5, was obtained from Eucommia ulmoides (Eucommiaceae). Derivatives of 6 have been obtained from Asperula odorosa (Rubiaceae). Weinges and co-workers have generally used 7 and recently reported (4) a 1.6% yield of pure 7 by hydrolysis of the natural catalpol esters from Picrorhiza kurrooa (Scrophulariaceae). Thus, 800 g of pure catalpol was obtained from 50 kg of dried plant after ester hydrolysis, activated charcoal absorption, desorption and alumina chromatography. Catalpol (5a) and aucubin (5b) have been converted to (-)-jasmonate or analogs. Although it has apparently not yet been utilized synthetically, antirrhinoside, 8, might be valuable, perhaps in the preparation of 11-methylprostaglandins (6). Many common snapdragons (Antirrhinum sp.) contain high levels of 8 and might be exploited as iridoid sources. I recently soaked 100 g of fresh plant material of a closely related taxon, Maurandya antirrhiniflora, in methanol for two days, evaporated the methanol, extracted the residue with water, washed the water with ether, evaporated the water and triturated the residue with absolute methanol. Evaporation of the methanol yielded 2g of solid 8 which was greater than 90% pure by nmr analysis. Thus, if one is able to work with fresh plant material even higher yields of an exploitable iridoid might be achievable since plant drying has sometimes been found to result in a decrease in extractable iridoids. Just as secologanin, 4, is a precursor of indole alkaloids, iridoids are both biosynthetically and synthetically convertible to pyridine monoterpene alkaloids. As a recent example of conversion, we isolated both penstemonoside, 9, and rhexifoline, 10,fromseveral Castilleja (Scrophulariaceae) species and were able to convert 9 to 10 (7). The pharmacological properties of pyridine monoterpene

9

10

11

alkaloids have been but little explored, although most have been isolated from pharmacologically active plants (8). Many of the pyridine monoterpenes occur as such in the plant, while others, such as cantleyine, 11, have been found several


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399

times in different plant species, but always as artifacts arising from the use of ammonia in the isolation procedure. Other "alkaloids" reported from iridoidcontaining plants can also arise as artifacts of the isolation procedure (9). In general, extensive use of iridoids as chiral synthons will depend on the availability of an easily grown plant species containing the desired iridoid (or iridoid ester) as a major component. When the desired iridoid is not a major component, separation of individual compoundsfromeach other and from contaminating sugars in the extracts may be tedious and time-consuming.


Iridoid and Iridoid Aglycone Biological Activity As has been pointed out (1), one important factor leading to a doubling of the known iridoid glycosides from 158 in 1980 (10) to over 300 by 1986 has been their common occurrence in folk medicinal plants. This has led to many new isolations and a renewed interest in biological activity studies. Several recent reports have focussed on the activity of the iridoid glucosides relative to the activity of their aglycones. In only rare instances have iridoid aglycones related to 2 been isolated from plants, although compounds linked at C-l to alcohols other than sugars, or further transformation products of 2 (such as lactones or cyclic ethers) are known (10). The relative plant proportions of iridoid aglycone vs. glycoside are essentially unknown since normal isolation procedures probably result in the decomposition of the relatively unstable aglycone (11). Recently, however, an isolation technique involving CH2CI2 liquid-liquid extraction of an aqueous iridoid glycoside enzymatic hydrolysis reaction mixture has yielded pure aglycones in high yield (12). In this work, the antimicrobial activity of aucubin aglycone against moulds and bacteria, but not yeasts, was clearly established. Other research groups had previously studied the antimicrobial activity of aucubin and other iridoids (12). It had been shown (13) in a study involving 21 iridoids, that iridoid glycoside antimicrobial activity was only observable after treatment with β-glucosidase. A similar study was reported on antitumor activity. Five isolated and Si gel purified aglycones showed activity against leukemia P388, while none of the glucosides were active (14). The most active were 5 aglycone and (especially) scandoside methyl ester aglycone, 12. A patent was recently issued (15) for use of 12 as a chiral synthon for preparation of other antitumor compounds. Several iridoids isolatedfromGarrya elliptica, including geniposidic acid, 13, and its aglycone were shown to inhibit the growth of wheat embryos (16). 13 has also been shown to be the active antioxidant in a methanol extract of Plantago COOMe

Oglu 15

asiatica Linne (17). The activity was superior to that of d/-a-tocopherol against air oxidation of linoleic acid. Also present in the extract were aucubin, geniposide, 14, and gardenoside, 15, but these were much less active than 13. The aglycone of 13 was not studied. In each of these cases, the aglycones may not be the active species themselves. Biological activity might instead stem from the aglycone-derived, highly electrophilic oxonium ion, 16. There are, however, a number of other biologically-active compounds which contain highly substituted 5,6-fusedringsand


400


iridoid aglycones could be bioisosters of these. An example is provided by the important indolizidine swainsonine, 17.

16

17


Iridoid Sequestration and Aposematic Lepidopteran Larvae Several recent reports detail the acquisition and sequestration of bitter tasting iridoid glucosides by lepidopteran larvae feeding on iridoid-containing plant species (18, 19, 20, 21). The known cases of sequestration were recently summarized (22). We have discovered additional examples involving some lepidopteran species having particularly boldly-patterned and/or highly colored larval stages, but cryptic imagos. Poole first described the remarkable similarity between last-instar larval color patterns (black and white longitudinal stripes, with gold-yellow spots) of Meris alticola Hulst and Neoterpes graefiaria (Hulst), geometrid moths known from Arizona (23). We collected M. alticola larvae on Penstemon virgatus, raised them to cryptic adults and analyzed adults, empty pupal cases, cocoon silk and emitted meconium for catalpol. A Neoterpes graefiaria female adult was collected at a uv light in southern Arizona. After the female had oviposited, eggs were collected, hatched and the larvae raised on P. barbatus (23). Larvae, pupal cases, meconium and adults were again analyzed for catalpol. Adult males of both species contained low amounts of catalpol, while meconium and the pupal cases were high in catalpol. Although only one adult female was available (of Meris alticola), a high level of catalpol was found in the abdomen, but not in other parts. We presume catalpol to be an important constituent of the eggs. Manipulation of N. graefiaria larvae resulted in a reflex bleeding emission, which had a high catalpol concentration. We have suggested that larval Mullerian mimicry, based on the sequestered bitter iridoid catalpol, may be involved with these two geometrids (24). The vine snapdragon, Maurandya antirrhiniflora, a common wildflower in the southwest U.S., is host to another geometrid, Meris paradoxa Rindge, and also to a noctuid moth, Oncocnemis (Lepopolys) perscripta. The strikingly colored and boldly-patterned larvae of these insects have cryptic adult stages. The previously uninvestigated hostplant was found to contain 2% wet weight of antirrhinoside and this iridoid was also found to be present in relatively high concentration in the larvae, but not adults of both species. M. paradoxa emits a yellow liquid via reflex bleeding and this also contained antirrhinoside. Thus the aposematic larva/cryptic adult predator avoidance strategy noted (18) for Ceratomia catalpae (Sphingidae), a catalpol sequester, has been extended to several additional Lepidoptera. A number of evolutionary aspects of the "profitability" of such strategies have recently been discussed (25). Our field work indicates that the iridoid content of the insect larvae and adults is not deterrent to ants or spiders, which can be major predators. It seems likely that vertebrate predators provided the selection pressures resulting in the development of the aposematic patterns. There is evidence that some iridoidcontaining lepidoptera are unpalatable to birds (26, 27), but effects on other possible vertebrate predators (such as mice or lizards) are unknown. In wild-collected and lab raised insects, sequestered iridoid content is commonly 2-4% of the insect dry weight and values as high as 10% have been found. In view of some of the other biological activities described above (antioxidant, antimicrobial, for example) it is conceivable that the iridoids could play additional roles in insect survival besides that


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of a prédation defense. If this were the primary selection pressure which resulted in iridoid sequestration, one might, however, expect completely cryptic specialists on iridoid-containing plants to also store these substances. The only case we have studied so far is that of the plume moth Amblyptilia (Platyptilia) pica, which is a specialist on many iridoid-containing Scrophulariaceae, but which is cryptic in both larval and adult stages. These larvae excrete iridoids in the frass and none can be found in adult insects (28).


Addendum As a continuation of some earlier work, a very recent report (29) described a new preparation of a prostanoid intermediate starting from the iridoid glucoside loganin. A complete literature review, supplementary to that quoted above (2), is presented on such synthetic uses of iridoids. Acknowledgment Preparation of this review was supported by grant CHE-8521382 from the National Science Foundation. Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Bull.

17. 18. 19.

Inouye, H.; Uesato, S. Prog. Chem. Nat. Prod. 1986, 50, 169-236. Bernini, R.; Davini, E.; Iavarone, C.; Trogolo, C. J. Org. Chem. 1986, 51, 4600-4603. Bonini, C.; Iavarone, C.; Trogolo, C.; DiFabio, R. J. Org. Chem. 1985, 50, 958-861. Weinges, K.; Haremsa, S.; Huber-Patz, U.; Jahn, R.; Rodewald, H.; Irngartinger, H.; Jaggy, H.; Melzer, E. Liebigs Ann. Chem. 1986, 46-53. a) Weinges, K.; Gethoeffer, H.; Huber-Patz, U.; Rodewald, H.; Irngartinger, H. Liebigs Ann. Chem. 1987, 361-366. b) Davini, E.; Iavarone, C.; Trogolo, C. Heterocycles 1988, 22, 57-61. Bonaides, F.; Gubbiotti, Α.; Bonini, C. Gazz. Chim. Ital. 1985,115,45-48. Roby, M.R.; Stermitz, F.R. J. Nat. Prod. 1984, 47, 854-857. Cordell, G.A. in The Alkaloids: Academic Press: New York, 1977; Vol. 16, p. 432. Stermitz, F.R.; Harris, G.H. Tetrahedron Lett. 1985, 26, 5251-5252. El-Naggar, L.J.; Beal, J.L. J. Nat. Prod. 1980, 43, 649-707. Bianco, Α.; Guiso, M.; Iavarone, C.; Passacantilli, P.; Trogolo, C. Tetrahedron 1977,33,847-850. Davini, E.; Iavarone, C.; Trogolo, C.; Aureli, P.; Pasolini, B. Phytochemistry 1986,25,2420-2422. Ishiguro, K.; Yamaki, M.; Takagi, S. Yakugaku Zasshi 1982, 102, 755. Ishiguro, K.; Yamaki, M.; Takagi, S.; Ikeda, Y.; Kawakami, K.; Ito, K.; Nose, T. Chem. Pharm. Bull. 1986,34,2375-2379. Isoe, Y.; Takemoto, T.; Inaba, H.; Kan, K. Jpn. Kokai Tokkvo Koho JP 62 53, 982 (CA107, 134198). Cameron, D.W.; Feutrill, G.I.; Perlmutter, P.; Sasse, J.M. Phytochemistry 1984, 23, 533-535. Toda, S.; Miyase, T.; Arichi, H.; Tanizawa, H.; Takino, Y. Chem. Pharm. 1985,33,1270-1273. Bowers, M.D.; Puttick, G.M. J. Chem. Ecol. 1986, 12, 169-178. Stermitz, F.R.; Gardner, D.R.; Odendaal, F.J.; Ehrlich, P.R. J. Chem. Ecol. 1986, 12, 1459-1468.



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20. 21. 22. 23. 24. 25. 26. 27. 28.

Gardner, D.R.; Stermitz, F.R. J. Chem. Ecol. 1988, 14, in press. Franke, Α.; Rimpler, H.; Schneider, D. Phytochemistry 1987, 26, 103-106. Bowers, M.D. in Chemistry and Evolution. K. Spencer, Ed., 1988, in press. Poole, R.W. J. KansasEnt..Soc.1970, 42, 292-297 Stermitz, F.R.; Gardner, D.R.; McFarland, N. J. Chem. Ecol. 1988, 14, 435-441 Leimar, Ο.; Enquist, M.; Sillen-Tullberg, Β. Am. Nat. 1987,128,469-490. Bowers, M.D. Evolution 1980, 34, 586-600. Bowers, M.D. Evolution 1981,35,367-375. Stermitz, F.R.; Harris, G.H.; Wang, J. Biochem. Syst. Ecol. 1986, 14, 499-

29.

Berkowitz, W.F.; Arafat, A.F. J. Org. Chem. 1988, 52, 1100-1102.

RECEIVED April

5, 1988


Iridoid Glycosides and Aglycones as Chiral Synthons, Bioactive

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