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Peroxy Natural Products D. A. Casteel Division of Medicinal and Natural Products Chemistry, College o f Pharmacy, University of lo wa, Iowa City, Iowa 52242, USA

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Reviewing the literature to December 1990

1 2 2.1 2.2 2.3 3 3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.3 3.4 3.5 4 5 6

Introduction Marine Metabolites Fatty Acid Derived Peroxy Ketals 1,2-Dioxane Carboxylates Other Marine Metabolites Terrestrial Sources Small Molecules, Hemiterpenes, and Monoterpenes Sesquiterpenes Nerolidol and Davanone Derivatives Bisabolene Derivatives Germacranes and Germacranolides Eudesmanes and Eudesmanolides Guaianes and Guaianolides Other Sesquiterpenes Diterpenes Triterpenes Others Steroidal Peroxides Arachidonic Acid Metabolites References

1 Introduction This report covers the literature up to 1990, although selected papers appearing in 1991 are cited. Many of the compounds have been described in reviews on the various structural classes : monoterpenes,'. ~esquiterpenes,~-~ diterpenoids,1°-13 sesterterpenoids, l4 and triterpenoids. is. l6 Peroxy compounds have been included in reviews on marine natural products17 22 as well as in other reviews.2326

2 Marine Metabolites 2.1 Fatty Acid Derived Peroxy Ketals The first peroxy marine metabolite to be isolated was the peroxy ketal chondrillin ( l).27 The compound was isolated from a sponge of the genus Chondriffu, and the structure was deduced from spectroscopic data along with a series of chemical transformations. The authors were unable to assign the relative or absolute stereochemistries at C-6 but proposed an S configuration for C-3 based on C D and ORD studies. Chondrillin was later isolated from another sponge, Pfukortis litu.". 29 From NOE measurements, these workers28 discerned that the C-3 proton and the methoxy group were in a cis relationship. Chondrillin possesses an IC,, of 5 ,ug/ml in an in vitro antitumour assay against P388 cells.28 The epimer of chondrillin, plakorin (2), has been isolated from a Pfukortis sp. and the structure was determined by NMR studies." Plakorin is a potent activator of sarcoplasmic reticulum Ca"-ATPase and may provide a valuable chemical tool for the study of Ca2+transport. Plakorin also exhibited activity in vitro against murine lymphoma L1210 cells (IC5, = 0.85 ,ug/ml) and human epidermoid carcinoma KB cells (1C5" = 1.8 ,ug/ml).31 Both chondrillin and plakorin were isolated from Pfukortis lira along with related unsaturated derivative^.^^ Compounds (3) and (4), and ( 5 ) and (6) were shown to be cisltrans isomeric 289

pairs by a comparison of NMR data. These workers tested chondrillin ( 1 ) and ( 5 ) for cytotoxicity towards P388 cells and found ED,,'s > 10 ,ug/ml, in contrast to the values cited above. In another report, the prolific P. fitu produced peroxy ketal compounds with shorter fatty chains.28Compounds (7)-( 10) were shown to possess the plakorin relative configuration about the peroxy ring by NOE studies; they varied in the length and degree of unsaturation in the side-chain. A Xestospangiu sp. was the source for two isomeric peroxy ketals with longer unsaturated fatty chains.32Xestin B ( 1 1) was shown to possess the same relative configuration as chondrillin but with an unsaturated C,, framework. Xestin A (12) had a configuration at C-3 identical with (1 1) and was shown to be the C-6 epimer. In vitro assays against P388 cells gave IC,,'s of 0.3 pg/ml for xestin A and 3 pg/ml for xestin B. Although xestin B was inactive at 5,ug/ml against other tumor lines, xestin A exhibited strong activity. A chemical synthesis of (7) and its C-6 epimer has been reported.33The key transformation in the seven-step sequence involved the photo-oxygenation of an acetoxy diene. The final product was a separable mixture of the epimers. Researchers28have observed that chondrillin is found in both P. fitu (order Homosclerophorida, family Plakinidae) and Chondriflu sp. (order Hadromerida, family Chondrosiidae), two unrelated sponges, while Xestospongiu sp. (order Nepheliospongia, family Nepheliospongiidae) is the source for the epimeric xestins. In addition, a plakinid sponge ( P . hufichondrioides) and a chondrosiid sponge (Chondrosiu coffectrix) both contain branched-chain cyclic peroxides. The conclusion is that no taxonomic significance can be attributed to the type of peroxide produced. Little attention has been given to the biogenesis of these peroxy esters. The co-occurrence of epimeric mixtures of compounds in one species led some researches to speculate that biological singlet oxygen cycloaddition to a methoxy diene may lead to the cyclic structures. This supposition is supported by the concomitant isolation of products attributable to the scission of the peroxide bond and further transformation.j2

2.2 1,ZDioxane Carboxylates A wide variety of marine compounds with the unifying features of an acetate or propionate chain attached at the 3-position to a I ,2-dioxane have been isolated. Many are norterpenoids. Muqubilin (1 3), isolated from a Priunos sp., was one of the first examples.34The norsesterterpene structure was deduced from NMR data and analysis of decomposition products, although no stereochemistry was reported. The corresponding methyl ester (14) was also found as a component of the extract. Later workers isolated a compound they named prianicin A from Priunos which was shown to be identical with (13)."" They proposed sterochemical details which were later corrected when muqubilin was r e - i ~ o l a t e d . ~ ~ Muqubilin (13) was reported to exhibit 100 YOinhibition of cleavage of fertilized sea-urchin eggs at 16 , ~ g / m I It . ~ was ~ tested against beta haemolytic Streptococcus and found to be 4 times more effective than tetracycline, although it was virtually inactive against a variety of Gram-negative bacteria.35Against 31-2

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R =H (14) R = M e




(7) 1


(19) R = H

(22) R = M e

(20) R = H (23) R = M e


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I (27)

(29) R = H (31) R = M e

Saccharonzyces cerevisiae, ( 13) was somewhat more effective than mycostatin. A geometric isomer of muqubilin (15) was isolated from a Latrunculia sp. and characterized as its methyl e ~ t e r . ~The ’ absolute sterochemistry of (15 ) was assigned as 2S73S,6Sbased on Horeau analysis and C D measurements. Use of the magnitude and direction of the optical rotation for (13) in comparison to several related systems allowed these workers to assign an absolute stereochemistry of 2S73R,6S. A norditerpene, methyl nuapapuanoate ( I 6), was found in addition to muqubilin in another examination of an undescribed Prianos sp.36 The structure and relative stereochemistry were assigned by NMR spectroscopy studies. A second norditerpene, (17), was isolated from a Latrunculia SP.~’The skeleton was assigned by lH and 13C NMR and the stereochemistry was reported as 2S,3 R,6S. The related sesterterpene ( I 8) was recovered from the same source and possessed the 2S73S,6S absolute c~nfiguration.~’ The investigation of the ichthyotoxic fraction of Sigrnosceptrella laevis produced two acidic compounds, sigmosceptrellin A (19) and B (20).38 Sigmosceptrellin A was characterized as its methyl ester and the structure was elucidated through chemical modifications and NMR studies. The relative stereochemistry was assigned based on an X-ray crystal structure of a derivative. Further work on the species lead to the isolation of another member of the series from the crude extract, sigmosceptrellin C (21), as well as the methyl esters of (19) and (20), (22) and (23).39Sigmosceptrellins B and C were determined to be stereoisomers of (19) and an X-ray crystal structure determination was carried out on a derivative of (20).40A related compound, called prianicin B, was isolated from a Prianos sp. and was determined to be identical to sigmosceptrellin B although the structure reported had a different relative c ~ n f i g u r a t i o nSigmosceptrellin .~~ B (prianicin B) possessed antibiotic and antifungal proper tie^.^^ The absolute configuration of the sigmosceptrellins has been the source of some confusion due to the different results obtained by the use of different procedures. The configuration of (20) was originally assigned based on a positive Cotton effect in the CD of a keto d e r i ~ a t i v eCompounds .~~ (19) and (21) were then correlated to (20). Later, use of the Horeau asymmetric esterification procedure returned evidence for the assignment of the opposite absolute configuration for (20).3i Some clarity was gained by the isolation of a norsesterterpene peroxide (24) from Mycale aizcorina, the methyl ester of which exhibited spectroscopic characteristics identical to the methyl ester of sigmosceptrellin A (19) but possessed an optical rotation opposite in sign.3i 41 A comparison of the ORD curves of the two esters confirmed the enantiomeric relationship. Final confirmation was obtained by comparison of a degradation fragment from (24) with an identical fragment prepared by

(30) R = H (32) R = Me

asymmetric synthesis, the results supporting the data from the Horeau experiments.42 The assignments are secured as 2R,3R,6R,9R,lOS,13S,18S for (19), 2R,3S,6R,9R7lOS,13S,18S for (20), 2S,3R76R,9R,IOS, 13S,18s for (21) and 2S73S,6S,9S,10R,13R,18R for (24).37 Two other norsesterterpenes, isomeric with (24), were also recovered from the extracts of Mycale ~ n c o r i n aCompounds .~~ (25) and (26) were isolated as their methyl esters and characterized by comparison with co-occurring (24). The overall structure and absolute stereochemistry of (25) were confirmed by acid catalyzed conversion of (24) into a compound identical with (25) in all respects including optical rotation. The bicyclic portion of (26) was identified as a trans-labdane type in contrast to the clerodane compounds previously recovered. The absolute stereochemistry of (26) was assigned by assuming the additive nature of the optical rotations for two insulated chiral portions, and was determined to be 2S,3S76S,9R,13R,18s based on a series of compounds with known configuration. Another clerodane- type cyclic peroxide (27) was isolated from Mycale s p ~ n g i o s a .A~ ~novel norsesterterpenoid compound (28) with a rearranged skeleton somewhere between clerodane and labdane was also identified. In the case of (27) the relative stereochemistry at C-2 and C-3 was determined to be erythro and a small-scale Horeau experiment suggested a tentative assignment as 2R,3R,6S. Insufficient material precluded a similar examination of (28). No information about the relative or absolute relationships in the bicyclic portions was reported. The marine sponge Latrunculia brevis has produced additional norsesterterpene cyclic peroxides. The crude extract contained trunculin A (29) and trunculin B (30) along with their corresponding methyl esters, (31) and (32).44 X-Ray analysis of each ester provided complete relative stereostructures. The absolute configuration of each was determined by Horeau analysis of derived alcohols and established as 3R for both compounds. The carboxylic acids (29) and (30) displayed antimicrobial activity in standard disk assays but the esters were inactive.


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(36) R = Me (37) R = H


(43) (45)

R =H R = Me

(40) R = Me (41) R = H

(44) R = H (46) R = Me

Three more trunculins were isolated from Latrunculia sp. : trunculin C methyl ester (33), trunculin D methyl ester (34) and trunculin E (35).45 An X-ray structural analysis of (33) confirmed the relative relationships that had been determined by spectroscopic means. Analysis of a derived diol gave evidence that these trunculins were of the same enantiomeric series as those previously isolated. The structure of compound (34) was established based on its spectroscopic properties, its similarities to (33), and its facile conversion into (33) by treatment with p-toluenesulfonic acid. Trunculin E (35) was studied as its methyl ester, and the stereochemistry, while not unambiguous, was proposed based on the common biosynthetic origin of the three compounds. The authors observed that compound (33) might be derived from (35) by a series of 1,2migrations. Of these compounds, only trunculin E, the free acid, was active in antimicrobial assays. The structure of plakortin (36), a metabolite of Plakortis halichondrioides, was elucidated from spectroscopic data and degradation The relative stereochemistry around the peroxy ring was proposed based on information from lanthanide-induced shift experiments ; the configuration of the side-chain was not determined. Plakortin and its free acid (37) were found as constituents of Plakortis z~ggompha.~' Although plakortin was essentially bioinactive, the carboxylic acid (37) was shown to inhibit S. cerevisiae, P. atrovenetum, and B. sub tilis. The C-3 epimer of plakortin (38) was a constituent of Plakortis zyggompha and P. halichondrioides. P. halichondrioides contained, in addition, 9,1O-dihydro-3-epiplakortin (39) and three cyclic peroxy compounds having a related skeleton (40), its corresponding free acid (41), and (42).4*These compounds were characterized by interpretation of spectroscopic data and from chemical transformations.


There remains some ambiguity in the structure of the sidechains of (40) and (42) and the stereochemistry, other than at C-2 and C-3, could not be determined. The authors comment on the probable biosynthesis of this group of compounds from simple carboxylic acids via the polyketide pathway. The presence of metabolites with different skeletons in the same sponge was surprising. Extraction of a frozen, lyophilized, sample of Chondrosia collectrix provided two epimeric peroxy acids (43) and (44) and their esters (45) and (46).49 Samples that had been stored in ethanolic solution did not contain peroxides, but related ketals and hemiketals were recovered. The stereochemistry of the major ester (45) was assumed to be the same as that found in plakortin (36). All four compounds were reported as having mild antibacterial activity. Three compounds containing an aromatic ring in the sidechain have been isolated. The lactone (47) and the carboxylic acid (48) were constituents of Plakortis halichondrioides.". Both were relatively unstable and no stereochemical information was available for (47) due to decomposition. Studies on the methyl ester of acid (48) allowed the assignment of the 3epiplakortin relative stereochemistry.4K The third aromatic cyclic peroxide, plakinic acid B (49), was a product of a unnamed genus of the Fdmily Plakinidae.47The compound was characterized as its methyl ester and the structure of the side-chain was deduced from degradative experiments. The relative stereochemistry of plakinic acid B was assigned based on coupling constants assuming a chair conformation. Compound (49) was an active antifungal agent in disk assays against S. cerevisiae and P. atroveneturn. Plakortis angulospicdatus provided two additions to the group of cyclic peroxides, these possessing unsaturation in the peroxy ring.51 Compounds (50) and (51) were analyzed by

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95 OOH

(58) R = OOH

spectroscopic examination of their methyl esters. Conclusive evidence for the relative stereochemistry was not found in difference NOE experiments. Both the acids had an MIC of I .6 ,ug/ml in a disk assay against Candida albicans and were also active against Aspergillus nidulans and B. subtilis. Cytotoxicity tests revealed that the acids and the esters gave IC,,'s of 0.2-0.9 ug/ml against P388 cells.

2.3 Other Marine Metabolites Two examples of naturally occurring 1,2-dioxoIanes are known."' Both compounds were isolated from an unnamed sponge of the family Plakinidae. Plakinic acid A (52) was characterized as its methyl ester but no information was available as to the stereochemistry. Although the ester was inactive, the acid (52) was an active antifungal agent in disk assays against S. cerevisiae and P. atroveneturn. A note added in proof reports the isolation of compound ( 5 3 ) from the same Plakinidae sponge. Denticulatolide (54),an ichthyotoxic cembranolide diterpene containing a cyclic peroxide, was isolated from Lohophj~turn d e n t i c u l ~ t u mExtensive .~~ spectroscopic studies gave an overall picture of the structure but an X-ray crystal study of a derivative provided the details of regiochemistry and relative stereochemistry. A conformational study of denticulatolide

was carried out because of the unusual location and geometry of the double Chrornodoris funerea, a nudibranch, was the source for furodysinin hydroperoxide (55).54 The structural assignment was made by X-ray analysis of a single crystal. Compound ( 5 5 ) could be prepared from furodysinin, a furanosesquiterpene, by reaction with singlet oxygen in the presence of a sensitizer in methanolic solution; the synthetic sample was identical to the natural product in all respects including optical rotation. From an examination of the components of a species of Dysidea (sponge), which is a probable food source for the nudibranch, the authors propose that C. funerea accumulates furodysinin from the diet and oxidizes it to ( 5 9 , perhaps via an endoperoxide. Furodysinin hydroperoxide was very active in a fish feeding-inhi bi tion assay. Clavularia koellikeri was the source of a trinorguaiane hydroperoxide, clavukerin C (56).j5 The absolute stereochemistry was assigned and a biosynthetic pathway from farnesyl pyrophosphate was proposed. Clavukerin C was synthesized and the structure confirmed by photosensitized oxygenation of clavukerin A, a related la-H hydrocarbon metabolite, by allylic rearrangement. The diterpenoid neoconcinndiol hydroperoxide (57) was found as a constituent of Laurencia snyderi~e.~" The final structural assignment was accomplished by an X-ray crystallographic study. The suggestion was made that (57) arises from the brominated natural product concinndiol, also from L. snyderiae, by solvolytic ring contraction and oxygenation to yield the rearranged allylic hydroperoxide. Another diterpenoid hydroperoxide was isolated from an undescribed species of Pseudopterogorgia (58).57The structure and absolute configuration were assigned by spectroscopic studies and by comparison to related compounds from the same extract. The authors propose a series of steps involving oxidation and acid catalyzed rearrangement to account for the formation of the tertiary hydroperoxide in (58).



A (59) R=OOH

(60) R = A c (61) R = M e 0


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(73)R = H (74) R = A c

Nephtheoxydiol (59) is a cytotoxic germacrane hydroperoxide isolated from Nephthea sp." The structure was deduced from detailed NMR studies and the absolute stereochemistry was confirmed by NOE measurements and an application of the Horeau method to the corresponding alcohol. Further confirmation of the structure was obtained by synthesis of (59) through a sensitized photo-oxygenation of 4R-hydroxy7s-germacra- 1(lO)E,SE-diene. Two peroxylactones, (60) and (61), were isolated from the brown seaweed Taonia a t ~ m a r i a The . ~ ~ structure of (60) was elucidated by an X-ray analysis and the absolute configuration is proposed based on biogenetic considerations. From the brown algae Sphaerotrichia divaricata, two toxins were isolated that may be the cause of human intoxications known as 'mozuku' poisoning.60 The algal samples did not always produce toxin(s); the authors suggest that the toxin, or its precursor appears only at certain stages of the life-cycle and requires specific conditions of temperature. Later workers isolated a compound from unpurified stock diethyl ether with spectroscopic characteristics identical to those of toxin A.61 The structure (I-ethoxyethy1)hydroperoxide(62) was proposed ; toxin B may be the peroxy hydrate of acetaldehyde. Similar toxic fractions were also recovered from Cladosiphon okamuranus, Analipus japonicus, and Gracilariopsis chorda60

3 Terrestrial Sources 3.1 Small Molecules, Hemiterpenes, and Monoterpenes A number of esters containing a hydroperoxy group have been isolated from Anthemis nobilis (roman chamomile).62 Compounds (63) and (64) incorporate the hydroperoxy group in the acid portion of the molecule while (65) and (66) are angelate derivatives with the hydroperoxy function in the alcohol. The latter two compounds possess modest antibacterial activity. The structures of all four compounds were confirmed by synthesis. Mutisin spiiiosa was the source for several monoterpene



(75) R = H (76) R = Me



hydroperoxides (67)-(71).63 It was suggested that (70), (71), and (68) were most likely derived from linalyl, geranyl, and 2,3dihydrogeranyl acetates, respectively. Compound (7 1) was subsequently isolated from the aerial parts of Eriocephalus kingesii as well.64An interesting linalol derivative, (72), is a constituent of Ferreyanthus rugosus.65 Artemzsia sp. have been the source for additional monoterpene hydroperoxides. A . aucheri elaborates highly oxygenated geraniol derivatives (73)-(76).66 Compound (75) is the 5,6-cis isomer of (74), and has undergone an intramolecular hemiketal formation. Two santolinatriene hydroperoxides with unpleasant odours, (77) and (78), were isolated from the aerial parts of A . lancea6' The structures were elucidated by spectroscopic means as (3R,4S)-isolyratyl hydroperoxide A and (3R,4R)-isolyratyl hydroperoxide B, respectively. Other naturally occurring peroxy monoterpenes include the chrysanthemol derivative (79), obtained from Eriocephalus k i n g e ~ i i trans-Pinocarveyl .~~ hydroperoxide ( S O ) was isolated

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Table 1 Sources of Ascaridole (87)

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(83) cis (84) trans




Chenop odium ambr 0sioides Chenopodium ant helmint icum Chenopodium botrys Croton afinis mucronifolius Pepper essential oil Peumus boldus Ledum hypoleucum Ledum palustre angustum Siphonostegia chinensis Vitex agnus-cast us Zanthoxylum bungeanum

76-78 79 80 81 82 83 84 85 86 87 88




(86)R = H (87) R = A c

from A . nobilis and prepared by synthesis.62The structure of acetylsaturejol, from Satureja gilliessi, was confirmed by an X ray crystallographic study of the peroxy hemiketal menthane derivative (81).'j8 Oil of chenopodium has been used as a remedy for worms, particularly ascarides, in humans for centuries even though its ' O Chemical investigations toxic effects have taken their of the essential oil of Chenopodium ambrosioides began in the early 1900s. Schimmel & Co. reported on the fractionation of the oil into a major portion which was named a~caridole'~ and which possessed the medicinal activity associated with cheno" Chemical investigations then showed that podium ascaridole was a naturally occurring organic peroxide (82).73-75 Ascaridole has since been found as a constituent of a number of plant species which are listed in Table 1. A number of reports have appeared over the years on various methods for determining the amount of ascaridole in chenopodium 0il,8g-g'its p~rification,'~and physical properties.71*g3. 94 The chemistryg5and photochemistryg6 of ascaridole have been reviewed. Synthetic ascaridole was originally isolated from an auto-oxidized sample of a-terpinene." Since that time, several photo-oxygenation methods have been explored for the preparation of (82) from a - t e ~ p i n e n elol .~~ In addition to its use against internal worms, ascaridole was found to exhibit other a c t i v i t i e ~ . ~It~ is ~ weakly - ' ~ ~ carcinogenic in a skin application assay with rni~e.~O~-~O' When tested as an antimalarial, compound (82) displayed activity in vitro but was inactive in vivo.los The lack of optical activity in natural ascaridole supports an argument for a non-enzymic origin. log Nevertheless, its rare occurrence relative to a-terpinene, its most reasonable biosynthetic precursor, suggests an enzymic action specific to a few species.'lo A soluble iodide peroxidase isolated from homogenates of C. ambrosioides fruit and leaves seems to be involved in a peroxide transfer reaction initiated by peroxidase-generated I' for the conversion of a-terpinene to ascaridole. log Chenopodium multlJidum was the source for both the cis-(83) and trans-(84)isomers of the 3,6-endoperoxide of phellandrene ;

no ascaridole was detected. ll1 Phellandrene endoperoxide has also been reported from the aerial parts of Callilepis laureola although no stereochemistry was indicated. 112Mikania saltensis provided (84)which was suggested as the biosynthetic precursor to other highly oxygenated menthane derivatives.l13 Both stereoisomers have been obtained by the photo-oxidation of aphellandrene. 114

3.2 Sesquiterpenes 3.2.1 Nerolidol and Davanone Derivatives Several hydroperoxy derivatives of nerolidol have been isolated. Compound (85) was found to be a constituent of Schistostephium crataegiyolium"5 and Pentzia albida. 'I6 The aerial parts of Pentzia albida also provide the related ketone (86).lI6 The corresponding acetate (87) was isolated from Artemisia santolinifolia.l17 The cyclic nerolidol derivative fercoperol (88) was isolated from Ferula communis and the structure determined by spectroscopic methods although no sterochemical assignments were possible.11s Compound (89) was originally isolated from the aerial parts of Artemisia inculta and given the name arteincultone; no sterochemistry was r e ~ 0 r t e d . l Later, '~ (89) was found to be the major constituent of the flowers of Tanacetum vulgare. The stereochemistry of arteincultone was proposed to be as shown based on the biogenetic relationship of (89) to the other constituents of T. vulgare and by synthesis of the compound from ( + )-davanone by photo-oxygenation. l Z o Arternisia judaica'21 and A . maritima122are also sources of (89). A related peroxy hemiketal, (90), was present in the leaves and flowers of T. vulgare and its synthesis by photo-oxygenation of (+)davanone was reported.120 Artemisia muritima produced the unusual five-membered ring peroxy hemiketal (9 1). 1 2 2 3.2.2 Bisabolene Derivatives The simple endoperoxide of bisabolene (92) has been isolated from Rudbeckiu laciniata'23 and Senecio desfontainei. l Z 4 A


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(98)R = Val' (99)R = Tigl


(103) R = Val'

(100) R = Val' (101) R =Tigl


(1 09)


(110) R = OTigl (111)LOB"'

related nor-sesquiterpene, senedigitalen- 1,4-endoperoxide (93), was isolated from another Senecio species, S. paludaflnis. 123 An inseparable mixture of two bisabolol hydroperoxides, (94) and (95), was isolated from Schistostephium crataegif o 1 i ~ m . l 'The ~ mixture was reduced with triphenylphosphine to the corresponding hydroxy compounds, which could be separated and identified although the stereochemistry at C-7 and C- 10 could not be determined. Pentacalia andicola produced two related, more highly oxygenated, compounds (96) and (97).lZ5 Six hydroperoxides (98)-( 103) were recovered from the aerial parts of Senecio pampeanus. lZ6 The structures and stereochemistries were assigned by spectroscopic investigations and by correlation to other bisabolene derivatives and to the related hydroxy compounds that were isolated at the same time. Two cyclic compounds containing a bisabolene skeleton have been isolated from the roots of the plant yingzhao (Artabotrys uncinatus or A . hexapetalus), which has been used as a folk treatment for malaria. Yingzhaosu A (104) was first isolated and the structure proposed in 1979.12'3128 A synthesis of (104) from (-)-carvone has recently appeared.129The structure and stereochemistry of yingzhaosu C (105) were determined by spectroscopic methods, by derivization, and by conversion to a known Both compounds are active antimalarials. ln8.131

(106)R = O O H

(112) R = 0+OH




3.2.3 Germacranes and Germucranolides A hydroperoxide derived from germacrene D (106) was isolated . ~ ~ lactone ~ crispolide (107), from Senecio g l ~ n d u l o s o - p i l o s u sThe from Tanacetum vulgare, contains a modified germacrane skeleton.13"Although the relative stereochemistry of (107) was not unambiguously determined by NMR, an X-ray crystal structure determination of the diacetate confirmed the relationships shown.134Crispolide might arise by an acid catalyzed transannular cyclization of peroxyparthenolide ( 108), which in turn may be derived from parthenolide, a compound which is the main sesquiterpene lactone from T. vulgare, by photooxygenation. The 601,12-germacranolide, peroxycostunolide (verlotorin, 109) has been recovered from a number of sources. It was first isolated from Artemisia ~erlotorurn,~~' although the structure was later corrected when it was re-isolated from Magnolia grandzjlora. 136. 137 Another source is Eriocephalus kingesii.64 Peroxyparthenolide (108) was isolated along with (109) from M . grandzjlora. 136, 13' Ester derivatives of peroxycostunolide were isolated from Ferreyanthus rugosus ( I 10) and (1 1 1),65Eupatorium sachalinense (1 12, peroxysachalinin),''' Cassinia subtropica ( 1 1 3),13' Liriodendron tulipifera (seeds and leaves) (1 14, peroxyferolide),l4".141 and Anthemis nobilis (1 15, lp-hydroperoxyisonobilin).", l a 2 The synthesis of peroxysachalinin (1 12) was accomplished by photosensitized oxygenation of eupatorio-

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(121) R = H (123) R = MeAcr








(120) R = H (122) R = MeAcr





% O H




picrin.138 Peroxyferolide (1 14) possesses cytotoxic activity against KB cells with an ED,, of 0.29 , ~ g / m l . l ~ ~ A series of hydroperoxides containing the 8a,12-germacranolide skeleton have also been isolated. The two hydroperoxides ( 1 16) and (1 17) were isolated as an inseparable mixture from Calea szyszylowiczii.la3 After reduction with triphenylphosphine, the corresponding hydroxy compounds were purified and identified separately. Although neither ( 1 18) nor ( 1 19) were isolated in pure form from Calea szyszlowiczii, the presence of these materials was proposed based on the isolation of a number of decomposition products.143 The germacranolides (120) and (1 2 1) were isolated from four sources : Schistostephium ~rataegifolium,~'~ Mikania goya~ ~ ~related zensis, M . pohlii,144 and Cassinia ~ u b t r o p i c a .The esters, (122) and (123) were also constituents of Schistostephium crataegifolium. 11' 3.2.4 Eudesmanes und Eudesmanolides The simple eudesm-5,7-diene endoperoxide (1 24) was isolated from Isocorna coronopfolia. la5The authors suggest that reaction of the diene with oxygen would occur from the a-face since the /%face is hindered by the presence of the methyl groups at C-4 and C-10. The eudesmol hydroperoxide (125) was found to be



a constituent of Artemisia d o u g l a ~ i a n a ' and ~ ~ Eriocephalus africanus.64The fresh rhizomes of Alpiniajaponica provided the 10-epi-eudesmol derivatives (126) and ( 127).147These compounds might arise by an ene reaction of 10-epi-y-eudesmol with singlet oxygen ; indeed, photo-oxygenation of 1 0-epi-yeudesmol gave a 5 : 1 mixture of (126) and (127). The cuathemone derivatives (128) and ( 1 29), allylic isomers of each other, were isolated from the aerial parts of Blumea Both may be derived from the related A7.I2 compound by reaction with oxygen. A similar pair of hydroperoxides, odontin (130) and odonticin (13 l), was identified as constituents of the whole plant of Pluchea arguta.lagP . arguta also provided argutinin ( 132).I5O Verbesina species are characterized by the presence of cinnamates of eudesmanes. It is perhaps not surprising, therefore, that (1 33) was isolated from V. subcordata. 1 5 1 An ene reaction of the corresponding A3-eudesmane would account for the formation of (133). A similar reaction may also be responsible for the formation of ( 1 34)-( 136) although the precursor needed would be a 5,lO-bis-epi-eudesmane derivative. Compounds (1 34)-( 136) were isolated from the aerial parts of Ambrosia artemisioides.152 The eudesmane benghalensin A (1 37), from Meriandra benghalensis, contains an unusual type of 172-dioxane ring system. 153 An X-ray structural analysis



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-O H













confirmed the structure and the relative and absolute stereochemistry. Benghalensin A was tested against human and murine malaria parasites and found to be inactive. log Seven costic acid derivatives, (138)-( 144), containing a 5ahydroperoxy group were isolated from Eriocephalus pauperr i m u ~The . ~ ~complex mixture could not be separated as the free acids and the compounds were purified and characterized as their methyl esters. The stereochemistry was assigned based on NOE data. Hydroperoxy derivatives of Sp,12-eudesmanolides are represented by a number of compounds related to telekin (or, equivalently, 5a-hydroxy-isoalantolactone).Compounds (145) and (146) were isolated from Artemisia ~ m b e l l i f o r m i sas~ well ~~ as from Calea szyszylowiczii. 143 Another Artemisia species, A . iwayomogi, yielded five hydroperoxy eudesmanolides, (147)-( 15l).'li A group of related eudesmanolides (152)(15 5 ) with oxygenation at the C- 14 position were isolated from Eriocephalus a f r i ~ a n u sAmbrosia .~~ artemisioides was the source for the 15-acetoxy derivative (1 56).152 8a,12-Eudesmanolides are reported from Gnephosis arachnoidea (157),155 Calea szyszylowiczii (158) and (159),lg3 and Artemisia pectinata (160).156In two of the cases, however, it was suggested that these compounds are simply artefacts arising from the reaction of a corresponding A4-eudesmanolide with oxygen.'55,156


wo Three 2a,5a-endoperoxides, (16 I)-( 163), which possess the 6a, 12-eudesmanolide structure were isolated from Artemisia herba-alba. 15i The stereochemistry of the peroxy bridge was first deduced from NOE measurements; an X-ray structural analysis confirmed the structure of (161). All three compounds were synthesized by photo-oxygenation of the corresponding 2,4-dien- 1-ones. Artemisia judaica is the source for the epimeric hydroperoxide derivatives of vulgarin (164)121.l S 8 and (1 65).15*

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HO' %o

Since these compounds co-occur with dihydrosantamarin, the authors speculate that they are formed by oxidation of dihydrosantamarin at C-1 followed by an ene reaction with oxygen. These lactones are reported to have cytotoxic activity.'*ja



3.2.5 Guaiunes and Guaianolides A group of guaiane 6,lO-endoperoxides has been isolated from Alpinia species. A . japonica provided (166) ( h a n a l p i n ~ l ) , ~ ~ ~ (167) (hanalpinone), 160 and ( I 68) (isohanalpinone)160while A . intermedia yielded those three and three others, (169) (hanalhave been discovered. Brocchia cinerea is the source for (17.5)l'j4 pinol peroxide), (1 70) (isohanalpinol), and ( 1 7 1) (aokumano1).161 while compounds (1 76)-( 178) were isolated from Serratula Hanalpinone (167) was synthesized by reaction of (166) with latifolia. 165 These later three compounds could be derived from pyridinium chlorochromate.15'. 162 The structure of (17 1) was pseudoivalin by reaction with oxygen. confirmed by X-ray analysis and a biogenetic scheme was A large number of peroxy 6a,12-guaianolides have been proposed that involved sequential oxidations of a guaiane-6,9isolated from various sources. The structures of the compounds are summarized in Table 2 while the sources are summarized in diene precursor.161An X-ray crystallographic study established the structure of a related secoguaiane, alpinolide peroxide Table 3. (172), also a constituent of A . japonica.'60 The original report of the structure of compound (218) proposed a P-dioxi bridge.17' Later workers, in studies of The aerial parts of Liabum floribundum afforded two guaiane similar compounds, suggested that the structure be revised to endoperoxides, (173) and ( 174)?j3 Reaction of the correthat with an a-dioxi bridge.175They further offered that the sponding guaiadienes with oxygen was proposed as the likely dioxi bridge in (219) was most probably P as originally biogene tic pathway . reported. Four hydroperoxides with the SP, 12-guaianolide framework



Table 2 6a, 12-Guaianolides 14

(OH O+OH 0

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f!JJo 0


Double bonds



Arborescin derivative Bishopsolicepolide derivative Bishopsolicepolide derivative Bishopsolicepolide derivative Rupicolin-A derivative Bishopsolicepolide derivative Rupicolin-A derivative Rupicolin-A derivative Rupicolin-A derivative Rupicolin-A derivative Rupicolin-A derivative Peroxyeupahakonin- A Ligustrin derivative Rupicolin-B derivative Rupicolin-B derivative Peroxyeupahakonin- B Arborescin derivative Arborescin derivative Parishin A derivative Tanaparthin derivative Dihydrobishopantholide derivative Bishopantholide derivative

2-3, 10-14 1-13 2-3, 10-14, 2-3, 10-14, 1-13 2--3, 10-14, 1-13 2-3, 9-10, 1 -13 1-13 2-3, 10-14, 2-3, 9-10, 1 -13 2-3, 9-10, 11-13 2-3, 9-10, 11-13 3 4 , 9-10, 11-13 3 4 , 9-10, 11-13 3-4, 9-10, 11-13 3-4, 9-10, 11-13 3 4 , 10-14, 11-13 3-4, 10-14, 11-13 3 4 , 10-14, 11-13 2-3 4-5 4-5, 11-13 2-3, 11-13 2-3

Ia-OH ; 4 a - 0 0 H ; 1 la 1a-OH ; 4 a - 0 0 H ; 8a-OAc 1Z-OOH ; 4 a - 0 0 H ; SE-OAC 1a-OOH ; 4 a - 0 0 H ; 8a-OH 1a-OOH ; 4P-OH ; 8a-OAc 1a-OOH ; 4a-OH ; 8a-OAc Ia-OH ; 4P-00H ; 8a-OAc Ia-OOH ; 4a-OOH ; 8a-OAc 1a-OOH ; 4P-00H ; Sa-OAc l a - 0 0 H ; ~z-OAC 1a-OOH ; 8a-OH Ia-OOH; 8p-0R1 l a - 0 0 H ; 8P-OR2 1a-OOH : 8a-OH 1a-OOH ; 8x-OAc 1 a-OOH ; 8P-OR' 1a, I0a-epoxy ; 4 a - 0 0 H ; 11a 1a, 10a-epoxy ; 3 - 0 0 H ; 1 1a 1a-H ; 3 a - 0 0 H ; 1Oa-OH la-H ; 4a-OOH ; IOa-OH la-H ; 4 a - 0 0 H ; ~ z - O A CIOa-OH ; ; 1 la

166 167, 168 168 168 168 167. 168 168 168 168 115, 17, 167-169 168, 69 170 171 168, 69 115, 17, 167-169 170 166 166 64 64 64


I ~,2a-epoxy ; 3a,4a-epoxy ; 8a-OAc ; IOa-OOH la,2a-epoxy; 3a,4a-epoxy ; ~ x - O A C10a-OOH ; ; I la: 1a,4a-dioxi ; 10a-OH la,4a-dioxi; 8a-OProp; 1Oa-OH 1a,4a-dioxi ; 9a-OAc ; IOa-OH la,4a-dioxi ; 9a-OH ; 1Oa-OAc laAa-dioxi; 8a-OAc; IOP-OOH 1a,4a-dioxi ; 8a-OAc ; 1Oa-00H 1r,4a-dioxi ; 2P,3P-epoxy ; 8a-OAc; 1Oa-00H la,4a-dioxi; 8a-OiBu; 10a-OH : 1 la la,4a-dioxi ; 8a-OiVal ; 10a-OH ; 1 1a la,4a-dioxi; 8a-MeBu; 10a-OH; 1 l a 1a,4a-dioxi ; 8a-OTigl ; IOa-OH ; 1 l a la,4a-dioxi ; 8a-OProp ; 1Oa-OH ; 1 1a 1a,4a-dioxi : 8a-OAng ; IOa-OH ; 1 1a 1,8,4P-dioxi; IOa-OH 1/3,4/3-dioxi; 8a-OAc ; IOa-OH 1,4,4P-dioxi; 8a-OAc ; 1Oa-OH ; 1 1a la,4a-dioxi ; 9a-OAng ; IOa-OH 1P,4/I-dioxi ; 9a-OAng ; 1OP-OH 1/3,4P-dioxi; 8a-OH : 9a-OAng ; 1Oa-OH


Bishopantholide derivative Tanaparthin-a-peroxide Tanaparthin derivative Apresin Isoapressin 1O-Epibishopantholide Bishopantholide Epoxybishipantholide

2-3, 2-3, 2-3, 2-3, 2-3, 2-3, 11-13

Epiezomontanin derivative Epiezomontanin derivative Epiezomontanin derivative Epiezomontanin derivative Epiezomontanin derivative Epiezomontanin derivative Tanaparthin-P-peroxide Ezomontanin Dihydroezomontanin Athanadregeolide 10-Epiathanadregeolide 8a-Hydroxy athanadregeolide 4a-H ydroperox yromanolide

2-3 2-3 2-3 2-3 2-3 2-3 2-3, 2-3, 2-3 2-3, 2-3, 2-3,

11-13 11-13 11-13 11-13 11-13 11-13

11-13 11-13 11-13 11-13 11-13

2--3, 10-14, 11-13

3.2.6 Other Sesquiterpenes The tertiary hydroperoxide (222), an ivangulin derivative, was isolated from Gnephosis arachnoidea, although the authors suggest that the compound may be an artefact from an ene reaction of oxygen with a r e 1 a t i ~ e . The l ~ ~ configuration at C-10 was proposed as a-OOH based on hinderance from the plactone moiety. Arternisia filifoliu was the source for an interesting longibornan endoperoxide, (223).17s A biosynthetic scheme was proposed that accounted for the presence of several longibornane metabolites as well as the endoperoxide. Two cadinene carboxylic acids, (224) and (225), were constituents of Heterotheca latifolia; they were isolated and characterized as their methyl The configurations at C-10 and C-9 were A53l0

1a,5z-H ; 4 a - 0 0 H ; 8a-OAng

168 116, 172, 173 146 174, 175 174 168 167, 168 167 116, 146 116, 146 116, 146 146 146 116 173 176 176 175, 177 177 177 62

assigned by a shifting of proton signals in the NMR and from steric considerations, respectively. An aristolane hydroperoxide was isolated from Aristolochiu debilis.lsO An unambiguous assignment could not be made from the spectroscopic data; an X-ray analysis gave (226) as the structure. Compound (226) could also be prepared from 1(1 O)-aristolen-2-one by reaction with oxygen. Obviously, oxidation opposite to the cyclopropane ring is preferred. One of the earlier peroxy natural products to be isolated was nardosinone (227).lS1 It was a constituent of Nardostuchjjs chinensis, N , juturnansi, and Chinese spikenard oi1.182-184 The structure was determined through spectroscopic studies and by chemical t r a n s f ~ r m a t i o n slS6 . ~The ~ ~ ~absolute configuration of (227) was determined by chemical correlation1s7 and later


Table 3 Sources for 6a,12-guaianolides Source Achillea depressa Achillea ligustica Anthemis nobilis Artemisia adamsii Artemisia ufra

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aoA aoAc 6 OOH


Artemisia douglasiana Artemisia feddei Artemisia gmelinii A r temisia mom tuna A thanasia dregeana Bishopan th us soliceps Cacosmia rugosa Eriocephalus giessi Eriocephalus SQ. Eupa t or ium chinense H y menopappus scuhiosaeus Otanthus maritimus


167 117 I76 177 169 64

64 170 171





(230) R=C02H

(231) R = OTigl


Pentziu ulhida Schistostephiurn rotundfolium Tanacetum par thenium



"3. 0




confirmed by X-ray* Nardosinone can be synthesized from gansongone by auto-oxidation.lag.lgoA related aristolane, kanshone B (228), was also isolated from N . chinensis and found to possess weak antihepatotoxic activity.la4 Three humulene hydroperoxides, (229)-(23 I), were re~~ covered from the aerial parts of Heterotheca v i l l o s ~ . 'The crude extract was treated with diazomethane to afford the

II 0

corresponding methyl esters which could be characterized by NMR techniques. Perhaps the most famous peroxy natural product, and certainly the most promising therapeutically, is qinghaosu (artemisinin, arteannuin, 232). The discovery of the compound was a result of explorations into the chemical bases for traditional Chinese medicinal practices. l Z a131* l g 4 The struclg6 and ture was proposed based on spectroscopic data1g5confirmed by a single crystal X-ray A detailed analysis of the NMR spectra of (232) has appeared.lg9 Isolated from Artemisia a ~ l n u aqinghaosu ,~~~ is an extremely potent antimalarial agent with low human toxicity.200It has been used in the treatment of several thousand malaria patients in China, including those with chloroquine-resistant strains of Plasmodium falciparum.201The mechanism of action of (232) is believed to involve oxidant stress to which the malarial parasites are particularly sensitive.lo8.202 Qinghaosu is also a selective phytoto~in.~~~ A number of syntheses of qinghaosu have been reported. Some approaches have utilized precursors such as artemisinic less-complex acid204 209 while others started from material^.^^^-^^^ The production of (232) in tissue culture has been reviewed.216,217 Artemisinic acid has been proposed as the biosynthetic precursor for qinghaosu. 218 -220 Many derivatives of qinghaosu have been prepared and tested for antimalarial activity.'04-221 225 The types of analogues studied include the desmethylZzfi and de-ethano and esters of dihydroqinghaosu, from reduction of the lactone."8 232 Of particular interest is the ethyl acetal of dihydroqinghaosu, a ~ t e e t h e r . ~ ~ ~ - ~ ~ ~ General reviews on qinghaosu have appeared,lg2.194.237 239 as have reviews of its pharmacology. 240-242 Qinghaosu has also been isolated from Artemisia ~ p i a c e aand ~ ~A~. lance^.^^ The related exo-methylene lactone artemisitene (233) was a constituent of Artemisia annua as well.244Its synthesis from (232) has been reported.245





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(242) R = H (243) R = AC


C02H I





p.... H06


3.3 Diterpenes The flowers of Greek tobacco, Nicotiana tabacum, afforded six cembranic diterpenoid hydroperoxides (234)-(239).246-247 The first five compounds were characterized by spectroscopic studies and by obvious similarities to the corresponding triols which had been previously isolated from tobacco. Further confirmation of the structures was obtained by biomimetic synthesis. Sensitized photo-oxygenation of cembratriendiols with known configuration yielded a mixture of ene reaction products from which hydroperoxides identical with the natural materials were The sixth cembrene hydroperoxide, (239), was found to be an inhibitor of indole-3-acetic acid activity; its structure was established by an X-ray crystallographic study.247 Jatropha grossidentata has been used in folk medicine and its root bark provided two peroxyketals with the rare rhamnofolane skeleton (240) and (241).248The authors suggest that these compounds arise from a cycloaddition of oxygen from the /3- and a-sides of the corresponding em-methylene ketone ; although such 2 + 2 + 2 reactions are not common, the cycloaddition may proceed due to the rigid arrangement of the double bonds. An abietane endoperoxide (242) was isolated from Safvia oxyodon along with its acetate (243).249The crude acids were converted to their methyl esters for purification and characterization. A cytotoxic labdane peroxy hemiacetal, coronarin B (244), was isolated from the rhizomes of Hedychium coronarium, a species used for rheumatism in No sterochemistry was assigned for the peroxy ring. Coronarin B had an IC,, value of 2.7 pg/ml against hamster V-79 cells. Gutierrezia

x spathufata was the source of the ent-labdane endoperoxide (245) which was isolated as its methyl ester.251The absolute configuration was determined by transformation to known compounds and measurement of the Cotton effect. Two labdane hydroperoxides, (246) and (247), were constituents of Zxiolaena feptolepi~.'~'The authors speculated that these materials were also ent-labdanes because of the presence of such in a related genus.

3.4 Triterpenes The nor-triterpene peroxide baccatin (248) was isolated from the benzene extract of the bark of Sapium b a c c a t ~ m The .~~~ presence of a taraxerane system and the overall structure was deduced from proton NMR data and biogenetic considerations. Photo-oxidation of the corresponding diene gave a peroxide identical with baccatin. Maytenus diversifolia was the source for maytensicolin-A

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0 O O



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H N-C0,Me







(249), a hydroperoxide containing the 28-norfriedelan-3-one system. A single crystal X-ray analysis established the structure and stereochemistry. The unusual cycloartane peroxyacetal(250) was a constituent of Litzdheirnera fe.Yana.')"" The general structure and partial stereochemistry were assigned by spectroscopic techniques ; an X-ray study provided complete relative and absolute configuration by correlations of the observed Cotton effect. The crude ethereal extract of the seeds of Pseudolarix kaen7pf>ri, which showed significant cytotoxic activity, was the source of two peroxy triterpenes. The structure and stereochemistry of both pseudolarolide H (25 1)256fz and pseudowere determined from spectral data and single larolide I (252)2.36" crystal X-ray analyses. "j4

3.5 Others Peroxyauraptenol(253) was isolated from the leaves of Murravn e.Yoticu.2." The structure was determined by analysis of spectroscopic data and by conversion of the compound into the known hydroxy derivative auraptenol by reaction with triphenyl phosphine. The authors propose the S-configuration for the asymmetric centre based on the negative optical rotation value. The seeds of the tree Marnrnea anzericana contain an array of substituted coumarins ; three peroxy coumarin derivatives were isolated from the extract.'58,25gCompounds (254) and (255) were isolated as a mixture in a 3: 1 ratio. The hydroperoxide (256) was recovered in pure form as a crystalline solid. Both the

(257) R' = Et, R2 = Me (258) R' = M e , R 2 = E t


mixture of (254) and (255) and pure (256) were optically active. The authors do not know whether the products result from metabolism within the seeds or are formed during isolation. Although M . arnmicana seeds are insecticidal, none of these compounds possessed this activity. Eucalyptus grandis contained a group of peroxy hemi ketals, The (257)-(259), which inhibited root formation in structure of (257) was determined by an X-ray crystal analysis. The remaining two compounds were assigned based on the first. Compounds (257) and (258) are interconvertible, with a 1 : 1 equilibrium mixture arising in a methanol solution in thc course of 48 hours. The lack of optical purity in the compounds suggested either a non-enzymic step in their biosynthesis or the peroxidation of precursors during isolation. The authors found no evidence for the latter. Peroxy-Y base (260) has been isolated from the tRNA's of mammalian liver2". "" and most probably from wheat-germ.2":' The structure was derived from spectroscopic The plant Lupinus luteus provided a larger amount of the material for more extensive characterization."" Evcn though Y base itself was also isolated, the authors believe (260) to be a real constituent of the plant and not artefactual. This compound appears to bc the only peroxide containing nitrogen heterocycle. Biosynthetic studies on Y base in yeast have shown that the highly modified base is derived from guanine?";' and it would not be unreasonable to assume that (260) is also formed from guanine. The fermentation broth of an AcfinomadurLt sp. produces a



dimeric anthrone peroxide, oxanthromicin (26 1).266An X-ray study of a single crystal established the structure but the absolute configuration remains to be defined. As (261) is optically active, the stereochemistry of both monomeric units must be identical and an enzymic oxidation is suggested. Oxanthromicin possesses good in vitro activity against dermatophytes and moderate activity against Candida sp. Compound (261) is unique in being the only example to date of a non-cyclic dialkyl peroxy natural product.

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4 Steroidal Peroxides Peroxy derivatives of steroids have been isolated from a number of marine sources as well as from terrestrial fungi. The derivatives are most commonly 5a,8a-endoperoxides with variations in the side-chains of sterols. Ergosterol peroxide (262) (5a,8a-epidioxyergosta-6,24-dien3/1-01) is perhaps the only peroxy natural product that can truly be described as ubiquitous. It was originally prepared by synthesis'6i and efforts to characterize the compound and its structure have been reviewed.95 Wieland discovered (262) in 1947 as a constituent of Aspergillus fumigatus.268Since that time, it has been isolated from a number of fungal species, lichens, micro-organisms, plants, and marine sources. The natural sources of (262) are summarized in Table 4. The occurrence of sterols including (262) in fungi has been reviewed.308 Compounds (262), its 3-acetate, and its 3pmethoxymethyl ether have been prepared by synthesis.loO306. 30y There have been no authentic reports of 5/3,8/3-endoperoxides, although one publication erroneously identified (263) as 5/3,8/3ergosterol peroxide before the authors uncovered their own mistake.303,310 It has been suggested that the a-epidioxy sterols arise from a more sterically favoured attack of oxygen on the a-face of a diene."'l Ergosterol peroxide is not the only steroidal endoperoxide known, however. A whole series of compounds with various side-chains have also been isolated and characterized, mainly from marine sources. Steroid endoperoxides can be divided into two series that differ in the presence or absence of a 9( 11) double bond. The structures and natural sources of epidioxy sterols are summarized in Table 5 and Figure 1. A novel steroid peroxide related to (263) but bearing a keto group at the 12 position has been isolated from the fungus Fusarium monilforme (28 Several of the compounds are very similar in structure and details of stereochemistry and connectivity were not always obvious. An example is the epimeric pair (262) and (270). There were considerable differences in the 360 MHz NMR spectra of the Comparison of an authentic sample of (262) allowed for assignment of (270). In (269), (272), (273), (277), and (279), the methyl signals were not well enough separated to assign the connectivity of the side-chain; the authors could not exclude with certainty methyl or ethyl substitution at carbons other than C-24. although on the grounds of analogy, alkylation of C-24 seemed most likely.275The geometry of (274) was reported as Z by correlation with fucosterol by one set of although others who isolated (274) did not address the issue. In addition to the recovery of mixtures of known sterol peroxides from various marine sources, one group of researchers also isolated but did not characterize fatty acid esters of the same as well as saturated sterol peroxides."' The linoleate ester of ergosterol peroxide (282) has been isolated from Ganoderrna lucidurn."' Ergosterol peroxide (262) was at one time thought to be only an artefact, since older extracts of Piptoporus betulinus or Daedalea quercina gave peroxide but fresh samples did not."' Similarly, (262) was isolated from Aspergillusflavus only when operations were carried out in the presence of An investigation of the conversion of ergosterol into its epidioxide (262) in two unrelated fungi demonstrated that both chemical (photo-oxidation) and enzymic pathways were operative."' Later workers argued for epidioxy sterols as true natural

Table 4 Sources of ergosterol peroxide (262) Source Acremonium luzulae Aclinia equina Adularia sp. Alternaria dianthicolu Ananas comosus Arenaria kansuensis Ascidiu nigra Asperg illus f u m igatus Axinella cannabina Cantharellus cibarius Claviceps purpurea, ergoty grain Dendrogyra cylindrus Daedalea quercinu Dunaliella salina Euglena grucilus Fusurium monilforme Fusarium osysporum Ganoderma lucidum Guignardia laricina Haliclona rubens Heterohasidion tasmanica Hypogymnia vittata Hyrtios sp. In on o t us radiu t us Ircinia campana Ircinia fuscicula ta Lamprrromyces japonicus Peltigera aphthosa and P. dolichorrhiza Penicillium rubrum Penicillium sclero tigenum Pisolithus tinctorius Pleraphysilla papyracea Pycnoporus sanguineus Raphidostila incisa Rhizoctonia repens Saccharomyces cerevisiae Scleroderma aurantium Tethva auruntia Thalysius jun iperina Trichophyton schonleini Virgularia sp.

Ref. 269 270 27 1 272 273 274 275 268 276 277 278 275 279 280 28 1 282 283, 284 285-287 288 289 290 29 1 292 293 289 289 294 295 296. 297 298 299 300 30 1 302 303 304 305 306

275 307 27 1


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Table 5 Steroidal endoperoxides and their natural sources Compound Source



Actinia equina Ascidia nigra Dendrogyra cylindrus Hyrtios sp. Thalysias juniperina

270 275 275 292 275


Actinia equina Adalaria sp. Anodonta cygnea Aplysia dactylomela Aplysia depilans Aplysia juliana Aplysia punctata Ascidia nigra Ascidiella aspersa Dendrodoa grossularia Dendrogyra cylindrus Fish- Liver homogenates Hyrtios sp. Metridium senile Tethya aurantia Thalysias juniperina Virgularia sp.

270 27 1 313 275 313 315 313, 315 275 313 313 275 318 292 319 306 275 27 1

Adalaria sp. Ascidia nigra Axinellu cannabina Dendrodoa grossularia Dendrogyra cylindrus Hyrtios sp. Metridium senile Pleraphysilla papyracea Raph idos t ila incisa Rhalysias juniperina Virgulariu sp.

27 1 275 276 313 275 292 319 300 302 275 27 I


Adalaria sp. Metridium senile Virgularia sp.

27 1 319 27 1


Aplysia punctata Dendrodoa grossularia

313, 315 313


Actinia equina Anodonta cygnea Aplysia dactylomela Ascidia nigra Dendrogyra cylindrus Hyrtios sp. Thalysias juniperina Virgularia sp.

270 313 275 275 27 5 292 275 27 1

Ascidia nigra Dendrogyra cylindrus Hjrtios sp. Thulysius juniperina

275 275 292 275

Actinia equina Adalaria sp. Ascidia nigra Dendrodoa grossularia Metridium senile Tethya aurantia Thalysias juniperina

270 27 1 275 313 319 306 275

Actinia equinu Adalaria sp. Anodonta cygnea Aplysia ductylomela Ascidia nigra

270 27 1 313 275 275





products based on the fact that other extracts from similar organisms using the same experimental techniques did not lead to the isolation of epidioxy Indeed, a number of other marine species were examined for the presence of epidioxy sterols to no avai1.270,313 Samples doped with ergosterol and fractionated showed no ergosterol peroxide excluding the

Compound Source



Dendrodoa grossularia Dendr ogyra cylindr us Hyrtios sp. Lophogorgia platycados Metridium senile Tethya aurantia Thalysias juniperina Virgularia sp.

313 275 292 318 319 306 275 27 1

Actinia equina Adalaria sp. Ascidia nigra Dendr ogyra cy 1indr us Dunaliella salina Hyrtios sp. Metridium senile Raphidost ila incisa Pleraphysilla papyracea Thalys ias juniper ina Virgularia sp.

270 27 1 27 5 275 280 292 319 302 300 275 27 1

Actinia equina Ascidia nigra Dendrodoa grossularia Dendrogyra cylindrus

270 275 313 275

Actinia equina Anodonta c-ygnea Aplysia dactylomela Aplysia juliana Aplysia punctata Ascidia nigra Ciona intestinulis Dendrodoa grossulariu Dendrogyra cylindrus Hyrtios sp. Metridium senile Phallusia mamilluta Thalysias juniper ina

270 313 275 315 313, 315 275 316 313 275 292 319 316 275

Ascidia nigra Den dr og,vra cy 1indr us Ganoderma lucidum Guignardia laricina Phallusia mamillata Rhizoctonia repens Scleroderma aurantium Thalysias juniperina

27 5 275 285 288 316 303, 310 305 275

Ascidia nigra Dendrogyra cylindrus Hyrtios sp. Thalysias juniperina

275 275 292 275

Anodonta cygnea Ascidia nigra Dendrogyra cylindrus Metridium senile Thalysias juniperina

313 275 275 319 275

Ascidia nigra Phallusia mam illa ta

275 316

Anodonta cygnea Ascidia nigra Phallusia mamillutu Dendrogyra cylindrus Thalysias juniperina

313 27 5 316 275 275

Metridium senile


possibility that the occurrence of (262) was artefactual.2R0 Several workers noted the care that was taken in the processing of samples to ensure that any epidioxy sterols isolated were in fact true r n e t a b o l i t e ~Extraction . ~ ~ ~ ~ ~ in ~ ~the dark,316or use of an argon atmosphere,313did not alter the nature or amounts of endoperoxides isolated.

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(272) R =



(273) R =

-i.)U -

(274)R =

**-A -


(276) R = -'.*

(278) R = =


(277) R =

(263) R =


(279) R =

Figure 1


(280) R =



Steroidal endoperoxide structures.

(282)R = linoleoyl On the other hand, although both (262) and (263) were isolated from extracts of Usnea.florida, the authors believe the compounds to be artefacts, arising from the presence of the corresponding diene precursors in the crude material. 3 2 3 In

contrast, some workers have postulated the presence of epidioxy sterols based on the isolation of unusual 5cc-methoxyster01s.~~~ The role of epidioxy sterols in biosynthetic pathways has been a controversial issue. Some have argued for a dietary origin, some for their derivation from A5s7-stero1precursors, and others for their role as precursors to A5,'-stero1s. To address the question in a marine organism, Riguera and co-workers examined the steroid fractions of Actinia equina and its primary food source, Mytilus edulis (mussels).2io Although M . edulis does not contain any epidioxy steroids, the steroid side-chains present in M . edulis correspond very well to the side-chains found in the epidioxy sterols of A . equina. A . equina is not able to biosynthesize sterols de novo from simple precursors. An experiment using ['4C]cholesterol demonstrated that in vivo transformation of steroids into epidioxy steroids does occur in A . equina and supports a dietary origin for those metabolites. Anodonta cygnea and an unidentified Black Sea sponge were both studied in experiments using lJC-labelled cholesterol ; labelled sterol peroxides were isolated. The authors conclude that sterol peroxides were not a result of an auto-oxidation during the isolation procedure and did not come from the diet but were the result of biological oxidation of sterols in the organisms.312These experiments suggested that the biosynthetic pathway is cholesterol to sterol peroxide with the possibility of a sterol as an intermediate rather than with the sterol peroxide as a precursor to dienes. Several Ass7 sterols were isolated from Axinella cannabina along with the corresponding epidioxy sterols, perhaps with the

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former being the biosynthetic precursors of the latter.276The in vivo transformation of As to A, steroids is known to proceed via the intermediate diene.325 Alternatively, it has been suggested that (262) is formed from lanosterol and may be the precursor to Ergosterol peroxide may also be a biosynthetic intermediate in the formation of cerevister~l.~"~ 30s When rat or trout liver homogenates were incubated with inhibitors of the conversion of 7-dehydrocholesterol to cholesterol, compound (265) was isolated, suggesting that the epidioxy sterol is in the direct biosynthetic On the other hand, incubation of labelled (265) with rat liver homogenates did not produce labelled 7-dehydrocholesterol or c h o l e ~ t e r o l The . ~ ~ ~question whether epidioxy sterols play an intermediate role in the biosynthesis of sterols in Baker's yeast,328or whether they arise from A'.7 sterols as in fungi,"' is still not Study of the incorporation of tritium-labelled sterols into an ergosterone derivative by Penicillium rubrum demonstrated that steroidal epidioxides can be metabolized in a biosynthetic Ig7 pathway but that several pathways must be Peroxy sterols have also been suggested as precursors for various epoxy and keto sterols and not an metabolic ' deadends .2 7 5 , 3 2 9 Support was gained for this assertion by an incubation of (262) with Mycobacterium crj~stallophagumwhich resulted in the recovery of isomerized epoxides and d i o l ~ . ~A~ O problem with this suggestion is that the side-chains of epidioxy sterols and of other sterols within the same organisms rarely correspond.2i0 The co-occurrence of steroidal peroxides and A4.7-3,6-diketones in Raphidostila incisa is of interest and suggests that the latter might be biogenetically derived from the former.30s Compound (265) has been suggested as an intermediate in the non-photochemical formation of vitamin D, in fish livers."" A structural role has been proposed for the sterol peroxides (262) and (273) in the halotolerant alga Dunaliella salina. The compounds were isolated in a 1 : 1.43 ratio and accounted for nearly 22 Yo of the lipid composition of the plasma membrane.280 Their presence may contribute to the unusual permeability properties of the membrane structure. Several of the sterol endoperoxides have been synthesized : (263),316(263 acetate),"' (275),314,316 (265),306. 314 (272),306and (268).313.315 Two steroidal hydroperoxides have been identified from natural sources. The first was isolated in 1960 from Aesculus lzippocaslanum (horse chestnut) and the structure was determined to be 3cz,22r-dihydroxy-7cz-hydroperoxy-24[ethylcholesta-5(6)-ene (283).332 The second was isolated from the tunicates Phallusia mamillata and Ciona intestinalis and was identified as 24hydroperoxy-24-vinylcholesterol(284).333Compound (284) is not believed to be an artefact since the isolation was carried out with fresh animals quickly in the dark. The synthesis and cytotoxicity of (284) were also Compound (284) was prepared by reaction of fucosterol with photochemically generated singlet oxygen along with small amounts of an allylic regioisomer. An ID,, of 2 ,ug/ml was obtained for (284) when tested against L 1210 leukaemia cells. Ergosterol peroxide (262) 7

and 9,11-dehydroergosterol peroxide (263) displayed modest phytoxicity in a lettuce-seedling assay."8" The degradation of cholesterol involves oxidation with both singlet and triplet molecular oxygen to give initially the 5a-,7a-, and 7P-hydroperoxides which subsequently decay to other oxygenated derivatives.335

5 Arachidonic Acid Metabolites No discussion of peroxy natural products would be complete without mention of the peroxy metabolites of arachidonic acid. Arachidonic acid is converted by several distinct pathways to prostaglandins, thromboxanes, prostacyclins, and leukotrienes. Of note here is that the biosynthetic pathways to the prostaglandins and the leukotrienes proceed through hydroperoxy and/or endoperoxy intermediates. A number of reviews and monographs on the arachidonic acid metabolites have appeared over the years.336 Early studies on the biosynthesis of prostaglandins demonstrated that molecular oxygen was the source of incorporated oxygen337and that two of the oxygen atoms, those at sites 9 and 11, derived from the same molecule of o ~ y g e n . ~This '$~ observation lead to a hypothesis on the intermediacy of peroxide compounds in the formation of prostaglandin^.^^^ 340 Two unstable intermediates were detected, recovered, and identified as prostaglandin en doper oxide^."^^ 3 4 3 The overall biosynthetic sequence may be described as follows (Scheme 1). Arachidonic acid is converted into the prostaglandins by the action of the enzyme prostaglandin endoperoxide synthase (PES).344.'345 The cyclo-oxygenase activity of the enzyme inserts two molecules of oxygen into arachidonate to yield a 15hydroperoxy-9,ll -endoperoxide with a substituted cyclopentane ring (PGG,). A peroxidase activity of PES reduces the 15-hydroperoxy group to a 15-hydroxy group (PGH,). The two enzymic activities reside on a single protein346348 but can be selectively d e a c t i ~ a t e d .Further ~ ~ ~ . ~transformations ~~ convert PGH, into the other prostaglandins, the prostacyclins, and the t h r o m b o x a n e ~ .The ~ ~ ~ prostaglandin endoperoxides clearly demonstrate biological activity and are not merely biosyn t hetic intermediate^.^", 343*3 5 2

Action by another set of enzymes leads to the formation of leukotriene biosynthetic intermediates. Lipoxygenase enzymes act on arachidonate to yield a variety of hydroperoxyeicosatetraenoic acids ( H P E T E S ) . Depending ~~~ on the source of the lipoxygenase enzyme, the hydroperoxy group may be inserted into the 5, 12, 15, and perhaps the 8, 9, and 11 positions.35J The oxygenated carbon is asymmetric and the absolute configuration of the resulting HPETE depends on the site of hydroperoxidation and the source of the lipoxygenase enzyme.355 5-HPETE is further metabolized to the corresponding hydroxyeicosatetraenoic acid (5-HETE) by way of an epoxy intermediate (LTA,) and from there on to the family of leukotrienes by hydrolysis and addition of amino acid r e ~ i d u e s . In ~ ~a ~similar , ~ ~ ~manner, 15-HPETE is converted into trihydroxylated metabolites called lipoxins while 12HPETE gives rise to epoxyhydroxyeicosatrienoic acids known as h e p ~ x i l i n s .356 ~~~,


308 prostaglandin endoperoxide synthase (c yclooxygenase)

arachidonic acid











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prostaglandin endoperoxide synthase (peroxidase)


leukotriene A synthase

5-li poxygenase



C02H ~



leukotie nes


prostaglandin H2 thromboxanes




Arachidonic acid metabolites Scheme 1

Acknowledgment. The assistance of Ms Jean Sevcik and Mr Steven Shepardson is greatly appreciated.

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