tricyclic sesquiterpenes from marine originau.edu.sy/images/files/ipubs/2017/m.kousara-2.pdf ·...

Tricyclic Sesquiterpenes from Marine OriginFranck Le Bideau,*,† Mohammad Kousara,†,‡ Li Chen,† Lai Wei,† and Francoise Dumas*,†

†BioCIS, Faculty of Pharmacy, Universite Paris-Sud, CNRS, Universite Paris-Saclay, 92290, Chatenay-Malabry, France‡Faculty of Pharmacy, Al Andalus University, P.O. Box 101, Tartus, Al Qadmus, Syria

*S Supporting Information

ABSTRACT: The structure elucidation, biosynthesis, and biological activity of marinecarbotricyclic sesquiterpene compounds are reviewed from the pioneering results to theend of 2015. Their total syntheses with a particular emphasis on the first syntheses,enantiomeric versions, and syntheses that led to the revision of structures orstereochemistries are summarized. Overall, 284 tricyclic compounds are classified intofused, bridged, and miscellaneous structures based on 54 different skeletal types.Tricyclic sesquiterpenes constitute an important group of natural products. Theirstructural diversity and biological activities have generated further interest in the field ofdrug discovery research, although the exact mechanisms of action of these species arenot well known. Furthermore, these tricyclic structures, according to their chemicalcomplexity, are a source of inspiration for chemists in the field of total synthesis for thedevelopment of innovative methodologies.

CONTENTS

1. Introduction 61112. Isolation, Structural Determination, and Biosyn-

thesis 61112.1. Fused Carbocycles 6111

2.1.1. 5/5/4, 5/4/5 Tricyclic Skeletons: Bourbo-nane and Kelsoane 6111

2.1.2. 5/5/5 Tricyclic Skeletons: Hirsutane, Iso-hirsutane, Capnellane, and Silphiperfo-lane 6112

2.1.3. 6/5/3, 5/6/3, 5/3/6 Tricyclic Skeletons:Cycloeudesmane, Calenzanane, Sha-gane, and Cubebane 6114

2.1.4. 6/5/4 Tricyclic Skeletons: Viridiane, Punc-taporane and Perforetane 6116

2.1.5. 6/5/5 Tricyclic Skeleton: Probotryane 61162.1.6. 6/6/3 Tricyclic Skeletons: Aristolane,

Maaliane, and Laurobtusane 61162.1.7. 6/6/4 Tricyclic Skeleton: Paralemnane 61182.1.8. 7/5/3 Tricyclic Skeletons: Africanane,

Aromadendrane, and Neomerane 61182.1.9. 7/6/3 Tricyclic Skeleton: Capillosanane 61202.1.10. 8/4/3 Tricyclic Skeleton: Norantipa-

thane 61212.2. Bridged Carbocycles 6121

2.2.1. Tricyclic Decane Skeletons: Ylangane,Copaane, Sinularane, Trachyopsane, Pu-pukeanane, Allopupukeanane, Abeopu-pukeanane, Neopupukeanane, Sativane,and Isosativane 6121

2.2.2. Tricyclic Undecane Skeletons: Acantho-dorane, Isotenerane, Quadrane or Sub-erosane, Paesslerane, Longibornane,Rumphellane, Strepsesquitriane, andCedrane 6123

2.2.3. Tricyclic Dodecane Skeletons: Caryolane,Isocaryolane, Clovane, Penicibilane,Lemnafricanane, Isoparalemnane, Rho-dolaurane, Gomerane, and Omphalane 6124

2.3. Miscellaneous Carbocycles: Inflatane, Cyclo-laurane, and Cyclococane 6125

3. Biological Activity 61263.1. Cytotoxic and Antitumor Activity 61263.2. Antibacterial Activity 61303.3. Other Biological Activities 6132

4. Synthesis 61334.1. Fused Carbocycles 6133

4.1.1. Kelsoene 61334.1.2. Capnellene and Corresponding Diols 61334.1.3. Silphiperfolanes 61354.1.4. Cycloeudesmanes and Cubebanes 61364.1.5. Aristolanes and Maalianes 61384.1.6. Africananes and Aromadendranes 6138

4.2. Bridged Tricyclic Sesquiterpenes 61414.2.1. Tricyclic Decane Skeleton 61414.2.2. Tricyclic Undecane Skeleton 61434.2.3. Tricyclic Dodecane Skeleton 6146

4.3. Miscellaneous Tricyclic Sesquiterpenes 61465. Conclusion 6146Associated Content 6147

Received: July 29, 2016Published: April 5, 2017

Review

pubs.acs.org/CR

© 2017 American Chemical Society 6110 DOI: 10.1021/acs.chemrev.6b00502Chem. Rev. 2017, 117, 6110−6159

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http://dx.doi.org/10.1021/acs.chemrev.6b00502

Supporting Information 6147Author Information 6147

Corresponding Authors 6147ORCID 6147Notes 6147

Acknowledgments 6147Abbreviations 6148References 6148

1. INTRODUCTION

Sesquiterpenes could be seen as a class of very old compounds,especially when looking to their terrestrial members. However,their occurrence is still expanding due to growing interest in themarine biodiversity and the importance of natural products indrug discovery.1 They thus represent an important class ofnatural products,2 identified from all kingdoms of life.3 Many ofthese compounds display a wide range of biological activitiessuch as anti-HIV, antitumor, antibiotic, antiviral, immunosup-pressive, cytotoxic, insecticidal, and antifungal activities and havestimulated research for druggable analogs.4−11 Known sesqui-terpenes are derived metabolically from some 300 distinct C15-hydrocarbon skeletons, which in turn are produced from thesingle substrate farnesyl diphosphate (FPP) by the action ofsesquiterpene synthases.12,13 Each cyclization reaction in thesebiosynthetic cascades is initiated by the formation andpropagation of highly reactive carbocation intermediates.14,15

Not surprisingly, covering 70% of the surface of the planet,oceans are the source of an extremely rich biodiversity. Lifeappearance in the marine environment is dated approximately 4billion years ago, whereas the first known terrestrial species areaged 400 million years, and consequently, this difference leadstoday to a greater diversity of phyla in the marine world. Inaddition to this longer evolution timeline, the huge variations intemperature, pressure, and light from the sea surface to theseabed16 may also explain the richness of the marine world incomparison with the terrestrial world.A large number of living organisms shows biochemical

properties that could lead to major advances in the field ofmedicinal chemistry and understanding of human diseases andtheir treatments. In the same way as terrestrial plants, which haveinspired numerous drug discoveries, marine organisms representan impressive source of original molecules which have thepotential to lead to new therapeutic findings.17 Currently, few ofthem are commercially available as drugs, and others are at anadvanced stage of clinical trials.18,19

More than 25 000 marine natural substances have beendescribed,20 a limited number in comparison with their terrestrialcounterparts. This is due to the late development in divingtechnologies and subsequent difficult access to marine species.Marine metabolites often display peculiar structures due to theirenvironment. They incorporate elements such as chlorine,bromine, and to a lesser extent boron, silicon, phosphorus,iodine, and arsenic, as well as the chemical functions such asisonitrile, thiocyanate, or formamide.21 Most of them wereisolated from sponges, algae, corals, and other invertebrates,which mainly adopt biologically active compounds as chemicaldefenses owing to their lack of physical protection againstpredators. Because they rapidly dilute when in the marineenvironment, these chemical defenses need to be highly toxic,which could give them an advantage in the field of drug discovery.Among these compounds, tricyclic sesquiterpenes constitute

an important group of natural products showing structural

diversity and for some of them interesting biologicalactivities.7,9,22−24

In this review, tricyclic sesquiterpenes from marine environ-ment will be considered, excluding their heterocyclic counter-parts.25 Halogenated sesquiterpenes of marine origin were, inpart, recently compiled.26,27 Structural characterization, biosyn-thesis, and biological activity of the species will be commented onwhen appropriate. Total syntheses, either racemic or asymmetric,with particular emphasis on the first syntheses and syntheses thatled to the revision of structures or stereochemistry attributionswill be described focusing on the key step and/or introduction ofchirality. The present review covers the subject from thepioneering results (early 1970s) to the end of 2015.In the second and fourth parts of this review, fused carbocycles

were classified according to the increasing sizes of their rings (5/5/4, 5/5/5, 6/5/3, ...), whatever their relative positions. Forinstance, 5/5/4 and 5/4/5 tricyclic structures are reported in thesame section, even if they are separately treated and appear indifferent schemes. Bridged carbocycles are sorted according tothe number of carbon atoms found in their skeletons: tricyclicdecane, undecane, and dodecane. Both bridged and fused all-carbon carbocycle structures reported in this review can bedescribed in accordance with IUPAC atom numbering28 asillustrated in Figures 1 and 2, but numbering resulting frombiosynthetic considerations or from common usage29 is alsoutilized in the manuscript. Skeleton family names (Figures 1 and2) are given when known (in black). Since the authors did notcoin names for several skeletons, we herewith named them (inblue) based on the corresponding metabolite names or on thenames of the species they are extracted from. Compoundstructures described all along this manuscript whose ACs havenot been determined are arbitrarily drawn under oneenantiomeric form. In these cases, the associated optical rotationsigns, when specified, are those of the corresponding isolatedproducts, irrespective of their ACs.

2. ISOLATION, STRUCTURAL DETERMINATION, ANDBIOSYNTHESIS

2.1. Fused Carbocycles

2.1.1. 5/5/4, 5/4/5 Tricyclic Skeletons: Bourbonane andKelsoane. From the dichloromethane solubles of the tropicalmarine sponge Cymbastela hooperi collected at Kelso reef (GreatBarrier Reef, Australia), novel terpenoid metabolites wereisolated after repeated HPLC separations.30 One of these,(−)-bourbon-11-ene 1, named inconveniently prespatane owingto its unsaturated nature, was structurally unprecedented in themarine literature (Figure 3). It is the enantiomer of (+)-bourbon-11-ene 2, a constituent of the terrestrial leafy liverwortCalypogeiamulleriana whose AC was determined by comparison of itshydrogenation product which is identical to the product obtainedby hydrogenation of (−)-β-bourbonene 3.31An investigation of the Formosan soft coral Nephthea erecta

(Green Island, Taiwan)32 led to the isolation of the bourbonanederivatives (+)-8-β-hydroxyprespatane 4 and (+)-8-β-hydro-peroxyprespatane 5 of unknown absolute configuration with adecahydrocyclobutadicyclopentane skeleton (Figure 3).From the tropical Australian marine sponge C. hooperi,

(+)-kelsoene 6 possessing an unusual tricyclo[6.2.0.02,5]decaneskeleton was the first marine isolated member of a new class ofsesquiterpenes, the kelsoanes (Figure 4).30 Structural elucidationof this linearly fused carbotricyclic system previously found in thesesquiterpenoid sulcatine G33 relied on incisive spectral analyses.

Chemical Reviews Review

DOI: 10.1021/acs.chemrev.6b00502Chem. Rev. 2017, 117, 6110−6159

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Kelsoene 6, also called tritomarene, was isolated from culturedcells of terrestrial liverworts Ptychanthus straitus,34 Calypogeiamuelleriana,31 Tritomaria quinquedentata,35 and later from theFormosan soft coral N. erecta.32 The syntheses of (+)- and(−)-kelsoene 6 from enantiomerically pure (R)-(+)-pulegone 7(see section 4.1.1) showed that the AC assigned earlier36 needsto be reversed as (1R,2S,5R,6R,7R,8S) for the naturally occurringkelsoene as represented by (+)-6 (Figure 4).37 In 2014, thisfamily expanded with the discovery of kelsoenethiol 8 and thecorresponding ether dimer 9, isolated from the Formosan softcoral N. erecta (Green Island, Taiwan) and whose relativeconfigurations were elucidated through extensive spectroscopicanalyses, including 2D NMR spectroscometry, ESI orbitrapmass, and quantum chemical calculations.38 (−)-Bourbon-11-ene 1 and (+)-kelsoene 6were also found in the volatiles releasedfrom marine Streptomyces sp., strain GWS-BW-H5, isolated fromthe North Sea.39

The labeling pattern of kelsoene 6 and bourbon-11-ene 1biosynthesized from exogenous 2H- and 13C-labeled mevalonate10 through FPP 11 suggested that these compounds are,respectively, biosynthesized from alloaromadendranyl 13 and 14guaianyl cations.34,40 Nevertheless, the assumption that thesecompounds came, respectively, from the (R)- and (S)-12enantiomers was postulated before correction of the AC of(+)-6; therefore, they are probably both formed via thegermacradienyl cation (S)-12 (Scheme 1).2.1.2. 5/5/5 Tricyclic Skeletons: Hirsutane, Isohirsu-

tane, Capnellane, and Silphiperfolane. The new sesqui-terpenes (−)-hirsutanol A 15, hirsutanol B 16, (+)-hirsutanol C17, and (−)-hirsutanol F 18, also named gloeosteretriol, wereisolated from salt water cultures of an unidentified fungusseparated from an Indo-Pacific sponge of the genus Haliclona(Figure 5).41 AC of the latter, isolated from a marine-derivedfungus Chondrostereum sp., collected from the soft coral

Sarcophyton tortuosum (South China Sea) together withhirsutanol A and (+)-hirsutanol E 19, was recently unambigu-ously established by X-ray diffraction study,42 but its opticalrotation was found opposite to the one isolated from theterrestrial Gloeostereum incarnatum.43 ACs of (−)-hirsutanols A15 and C 17 were also ascertained by X-ray crystallography, theoptical rotation sign for marine compound (+)-17 beingopposite to the one isolated from the edible mushroom G.incarnatum.44

(+)-Hirsutanol C 17 and five new sesquiterpenes, chon-drosterins A−E 20−24 of unknown ACs, were isolated frompotato dextrose culture of the marine fungus Chondrostereum sp.,collected from the soft coral S. tortuosum (South China Sea).45

Among them, (+)-chondrosterin E 24 possesses a rare46,47

rearranged hirsutane skeleton resulting from migration of amethyl group from C2 to C6 and previously namedisohirsutane.41 (−)-Chondrosterins I 25 and J 26 extractedfrom a culture of the same fungus in another media containingglycerol as the carbon source were found to possess thisparticular skeleton.48 Eventually two other known hirsutanes ofunknown ACs, (+)-incarnal 2749 and (−)-arthrosporone 28,46

were isolated from the same fungus.50

Soft corals of the genus Capnella are rich sources ofsesquiterpenes with the capnellane framework (Figure 6),which serve as chemical defense agents within the coral reefbiomass toward algae andmicrobial growth, and to prevent larvaesettlement.Δ9(12)-Capnellene 29, the simplest metabolite of the soft coral

Capnella imbricata collected offMaluku (Leti Island, Indonesia)was isolated in 1978.51 The most abundant terpenoid of thiscoral, (+)-Δ9(12)-capnellene-3β,8β,10α-triol 30, was character-ized in 1974,52 and its structure and AC were later confirmed byX-ray crystallography.53 This compound was also found in aspecimen at the same location together with (+)-Δ9(12)-

Figure 1. Fused sesquiterpene skeletons found in this review along with the nor-sesquiterpene skeleton norantipathane. Atom numbering is inaccordance with IUPAC numbering. Skeleton names in black were already reported in the literature; those in blue were named in this review.



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capnellene-5α,8β,10α-triol 31, (+)-Δ9(12)-capnellene-8β,10α-diol 32, and Δ9(12)-capnellene-2ε,8β,10α-triol 33, whose ACswere not determined.54

Two new capnellane sesquiterpenes, (+)-capnellen-8β-ol 34bearing no hydroxy group at the C10 position and (+)-3β-acetoxycapnellene-8β,10α,14β-triol 35 along with compound(+)-32, were characterized55 from an Indonesian specimen of C.imbricata in the Molucca Sea (Mayu Island), while the tetraol(+)-Δ9(12)-capnellene-3β,8β,10α,14β-tetraol 36 was found in aspecimen collected off Leti Island.56 Eight acetylated capnellenes37−44were extracted from colonies ofC. imbricata living aroundLaing Island (Papua, New Guinea).57 It was demonstrated that

the contents of sun-dried specimen extracts differ from thecorresponding fresh extracts carried out immediately aftercollection: in the former, acetate hydrolysis produced bysubstrate specific hydrolases occurs, leading to the correspondingfree alcohols which can be thus considered as artifacts.Three related acetylated capnellenes (+)-45−47 and one

peculiar capnellene (−)-48 bearing an acetylated hydroxyfunction at the C13 position of undetermined ACs were recently

Figure 2. Bridged and miscellaneous sesquiterpene skeletons found in this review. Atom numbering is in accordance with IUPAC numbering. Skeletonnames in black were already reported in the literature; those in blue were named in this review.

Figure 3. Bourbonanes from marine (1, 4, and 5) and terrestrial (2 and3) origins.

Figure 4. Structure and AC of kelsoene 6, kelsoene thiol 8, and dimer 9.



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identified together with compounds (+)-32 and (−)-41 from thesoft coralDendronephthya rubeola (Bali, Indonesia).58 (+)-Δ9(12)-Capnellene-8β,10α-diol 32 was also isolated from the soft coralCapnella sp. (Green Island, Taiwan)59 and from extracts of theFormosan soft coral Paralemnala thyrsoides.60 Six new capnellenesesquiterpenes 49−54 were collected from the soft coral C.imbricata (Green Island, Taiwan) together with (+)-32, (+)-34,and (−)-41,61 while the tetraol (+)-55 was characterized from C.imbricata (Laing Island, Indonesia).62

(−)-Subergorgic acid 56, a marine sesquiterpene based on asilphiperfolane tricyclo[6.3.0.01,5]undecane framework, was firstisolated in 1985 from the gorgonian Subergorgia suberosa (SouthChina Sea) (Figure 7)63 and later from S. suberosa (Mandapamcoast, Tamil Nadu, India)64 from the South China Sea gorgonian

Echinogorgia pseudossapo,65 and from Isis hippuris (Green Island,Taiwan).66 It was also found together with methyl subergorgate57 and methyl 2β-hydroxysubergorgate 58 in the gorgonianMenella sp. collected off South China Sea (Meishan Island).67

Chemical study of a methanolic extract of an Indian Oceangorgonian coral S. suberosa led to the isolation of (−)-56 togetherwith the four related silphiperfolanes 57−60.68 (−)-Subergorgicacid 56 and compounds (−)-57, (−)-59, and (−)-60 were alsofound together with (−)-2β-acetoxysubergorgic acid 61 andsubergorgiol 62 ([α]31D 0°) from Taiwanese collections of S.suberosa.69 Recently, sesquiterpenes (−)-56 and 58−62,70 whoseACs were determined on the basis of circular dichroism,Mosher’s method, and through chemical conversions, and(−)-suberosanone C 6371 were characterized from the samespecies collected off South China Sea. In the late 1980s,sesquiterpenes (−)-6472 and (−)-6573 were identified fromtropical algae Laurencia majuscula collected from the coastalwaters of North Queensland (Australia). AC of compound 64was not determined, while the structure of 65 was later correctedand its AC secured by total synthesis (Scheme 17).74 Compound64 was also found in the red alga Laurencia dendroidea from thesoutheastern Brazilian coast,75 and in Laurencia rigida (CapeBanks, Sydney, Australia).76

2.1.3. 6/5/3, 5/6/3, 5/3/6 Tricyclic Skeletons: Cyclo-eudesmane, Calenzanane, Shagane, and Cubebane. Redseaweeds in the genus Laurencia are a rich source of secondarymetabolites of varied and often unusual structures.77 The firstmarine origin example (+)-66 of a 6,8-cycloeudesmanesesquiterpene, brominated at C-1 (Figure 8), was isolated fromthis genus,78 and most cycloeudesmanes so far reported belongto the 1,3-class 67 and 2,4-class 68, characterized from terrestrialplants.79 The only nonhalogenated cycloeudesmane of marineorigin, (−)-cycloeudesmol 69, was identified from the red algaeChondria oppositiclada Dawson (Puerto Penasco, Mexico)80 andlater from Laurencia nipponica (Hokkaido, Japan).81 The AC aswell as correction of the structure originally proposed80 for thiscompound were determined by crystallographic study.82

Debromoisocalenzanol (−)-70 (Figure 9) was isolated fromthe red seaweed Laurencia microcladia collected in Elba Island,83

with the brominated compound (+)-7184 and the namecalenzanane attributed to their new skeleton. Two similarcompounds (−)-shagene A 72 and (+)-shagene B 73, bearingtheir cyclopropane unit at the cycle junction, were recentlyisolated from an undescribed Antarctic octocoral collected nearthe South Georgia Islands (Figure 9).85

A biosynthetic pathway to shagenes was proposed (Scheme 2)through formation of caryophyllyl cation 74, which could betransformed into 75 via a 1,2-H shift. Proton abstraction fromthis species could generate triene 76, which could undergo aproton-mediated ring closure to form carbocation 77, followedby a second proton abstraction to form diene 78, a possibleprecursor of shagenes.(+)-Cubebol 79 (Figure 10) was found in a soft coral of the

Cespitularia genus collected in Orpheus Island (Palm IslandGroup, Townsville, Australia) in 1983.86 Radiolabeled experi-ments led on Cespitularia sp. showed that cubebol wassynthesized by this soft coral.87 Its enantiomer (−)-79 whoseAC was established by total synthesis starting from (−)-trans-caran-2-one (Scheme 19),88 was also obtained from the brownalgae Taonia atomaria (Rovinj, Croatia).89 (−)-4-Epicubebol 80was also found in this seaweed and in the brown algaeDictyopterisdivaricata (Okanamura, Japan) with four other sesquiterpenes:the methyl ethers (−)-81 and (−)-82, (−)-β-cubebene 83, and

Scheme 1. Plausible Biosynthetic Pathway to (+)-Kelsoene 6and (−)-Bourbon-11-ene 1

Figure 5. Marine hirsutanes and isohirsutanes.



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(−)-α-cubebene 84 possessing the cubebane skeleton.90 (+)-α-Cubebene 84 was also isolated from the gorgonian Pseudoplex-aura porosa.91

Two new sesquiterpenes (+)-cubebenone 85 and thecubebane derivative (+)-86 (Figure 10) were, respectively,characterized from an extract of the nudibranch Leminda millecra

(Algoa Bay, South Africa)92 and the soft coralGersemia rubiformis(Atlantic Ocean, New Foundland, Canada).93

The structure of the nitrogeneous isothiocyanato cubebanederivative (−)-87 found in an Okinawan marine sponge(Iriomote Island, Japan) of the genus Stylissa has beenestablished from NMR studies94 to be the 2-epimer of (−)-88reported from the sponge Axinyssa aplysinoides (Ant Atoll,Pohnpei, Federated States of Micronesia).95 Recently, (+)-13-isocyanocubebane 89, whose AC was not determined, wasisolated from the nudibranch Phyllidia ocellata collected inMudjimba Island (Mooloolaba, Australia).96

Figure 6. Marine capnellanes.

Figure 7. Marine silphiperfolanes.

Figure 8. Isocycloeudesmane and cycloeudesmanes.

Figure 9. Marine calenzanane and shaganes.

Scheme 2. Proposed Biosynthetic Pathway to Shagenes 72and 73



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2.1.4. 6/5/4 Tricyclic Skeletons: Viridiane, Punctapor-ane and Perforetane. An unusual sesquiterpene, (+)-viridia-nol 90 (Figure 11), based on a 4,5,6 tricyclic skeleton namedviridiane, was isolated from the red seaweed Laurencia viridis.97

Two new caryophyllane-based sesquiterpenoids named(−)-punctaporonin L 91 and (+)-punctaporonin M 92 wereobtained from the fermentation broth of the sponge-derivedfungusHansfordia sinuosae isolated from the sponge Niphates sp.collected off Southern China Sea (Figure 11).98

The AC of (−)-91, featuring a new skeleton namedpunctaporane, was attributed by comparison of the sign andmagnitude of its optical rotation with the one of thecorresponding tetraol 6-hydroxypunctaporonin E of terrestrialorigin,99 whose AC was determined by X-ray diffraction study.Perforatone 93 was found for the first time in Laurencia

perforata collected off Corralejos, Fuerteventura (CanaryIslands), in 1975,100,101 but its relative stereochemistry was

revised in 2002102 to the correct structure (+)-perforatone 94,following extensive NMR analysis of this compound extractedfrom Laurencia obtusa collected off the coasts of Milos Island(Aegean Sea, Greece) together with metabolites 95−98. ACs ofthese compounds have not yet been determined. In the sameseries, compound (−)-99, whose AC was ascertained by X-raydiffraction study, was produced by Laurencia tenera collected offFlorence Bay (Magnetic Islands)103 and (−)-tenerol acetate 100extracted from L. tenera (Townsville region of the Great BarrierReef, Australia).104

Eventually metabolites (+)-101 together with (−)-perforatol102 were, respectively, identified from the sea hare Aplysiapunctata collected at Porto San Paolo (Olbia, Sardinia, Italy)105

and the red alga L. obtusa (coastal rocks of Serifos in the AegeanSea, Greece).106

2.1.5. 6/5/5 Tricyclic Skeleton: Probotryane. Thecarbotricyclic probotryane sesquiterpene (+)-103 (Figure 12)

was found in an extract from the mitosporic fungusGeniculosporium sp., which was associated with a marine redalga of the Polysiphonia genus (Ahrenshoop, Germany).107

Structural studies did not allow determination of the relativeconfiguration at C15.

2.1.6. 6/6/3 Tricyclic Skeletons: Aristolane, Maaliane,and Laurobtusane. (+)-10-Hydroxyaristolan-9-one 104,(+)-aristol-8(9)-en-1-one 105, and aristol-9(10)-en-1-one 106,previously synthesized (Scheme 22),108,109 were obtained fromthe red alga Laurencia similis (Hainan Island, China) togetherwith the known aristol-1(10),8-diene 107, 1(10)-8-aristoladiene108, aristol-1(10)-en-9-one 109 (gansongone), and (+)-9β-aristol-1(10)-en-9-ol 110 (Figure 13).110,111Metabolites(+)-105, (+)-110, and (−)-aristolone 111 were later found inthe same marine organism.112 Interestingly, (−)-111 was knownmuch earlier from the roots of Aristochia debilis,113 while itsenantiomer (+)-111 (α-ferulone) was identified in the fruitingbodies of the basidiomycete Russula lepida114 and from theliverwort Porella cordeana.115 (−)-Aristolone 111 was alsoisolated from the AcOEt extract of the soft coral N. erecta(Green Island, Taiwan)116 and the corresponding enantiomerfrom Nephthea chabrolii (Pingtung County, Taiwan).117

The enantiomer (−)-112 of the known terrestrial (+)-1(10)-aristolene (calarene) 112118 was found in the gorgonianPseudopterogorgia americana (Bermuda and Florida Keys),119 inthe yellow and gray morphs of the soft coral Parerythropodiumfulvum fulvum (Gulf of Eilat, Red Sea),120 and in the marine redalga Laurencia decumbens collected in South China Sea watersoffshore (Weizhou Island),121 as well as in the volatiles releasedfrom a marine Streptomyces sp., strain GWS-BW-H5, isolatedfrom the North Sea.39

(−)-Aristolone 111was isolated from the AcOEt extract of thesoft coral N. erecta (Green Island, Taiwan)122 and thecorresponding enantiomer from N. chabrolii (Pingtung County,Taiwan).123 The aristolanes (+)-104−(+)-110 and (−)-aristo-lone 111were characterized from a sample of the marine red alga

Figure 10. Marine cubebane sesquiterpenes.

Figure 11. Viridianol, punctaporanes, and perforetanes.

Figure 12. Probotryane.



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L. similis (Sanya Bay, Hainan, China),124 and compounds(+)-110 and (−)-111 were also found in Laurencia sp. collectedin South China Sea.125 (+)-9-Aristolene 113was one of the activecomponents isolated from the marine sponge Acanthellacavernosa (Hachijo-jima Island, Japan)126 and from thegorgonian P. americana (Bermuda and Florida Keys),119 whilethe corresponding enantiomer (−)-113 was found in a soft coralof the Nephthea genus (Andaman and Nicobar group of islands,Indian Ocean).127 ACs of 111, 112, and 113 were determinedearlier in 1962128 on the basis of indirect correlations withterrestrial maaliol of known AC.129

Extraction of the sponge Axinyssa isabela (Isla Isabel, Gulf ofCalifornia, Mexico) led to the isolation of the aristolanesesquiterpene axinysones A−E 114−117 and (+)-axinynitrileA 118.130 The ACs of (+)-axinysones A 114 and B 115 wereassigned by Mosher’s method, while that of the unusual nitrile-containing aristolane (+)-118 was determined through itssynthesis from (+)-aristolone 111. Recently, (−)-debilon 119,a known terrestrial sesquiterpene,131 was isolated from the redalga Laurencia complanata (southwest coast of Madagascar).132

Studies of the Australian soft coral Lemnalia humesi afforded twonew sesquiterpenes (+)-120 and (+)-121, containing thearistolane skeleton and whose ACs were determined by chemicalconversion into the known (+)-9-aristolene 113.133 Compounds(+)-110, (+)-111, (+)-115, and (+)-nardostachnol 122 werecharacterized from a Bornean red algal population of L. similis,134

while the only aristolane (−)-123 showing a functionalization ofits gem dimethyl group was isolated from an Indonesian octocoralLemnalia africana (Pohnpei, Micronesia).135

An investigation of the extracts from Mediterranean spongeAxinella cannabina (Bay of Taranto, southern Italy) furnished thenew sesquiterpenes 124−126 of unknown ACs, with themaaliane skeleton and bearing an isonitrile, isothiocyanate, or

formylamino function (Figure 14).136 Compounds (+)-127 and(+)-128 were isolated from Southern California (Scripps

Canyon, La Jolla and Point Loma, San Diego) nudibranchCadlina luteomarginata.137 Their relative stereochemistry wasdeduced through NMR studies and confirmed by X-raydiffraction analysis of the derivative 129, obtained by acidichydrolysis of 127. Compounds (+)-127−(+)-129 were found inthe skin extract of the Northeastern Pacific nudibranch C.luteomarginata (Graham Islands, British Columbia), also 127 and129 in its associated sponge Acanthella sp. (Figure 11).138

Compound (−)-128 was characterized from the marine spongeAcanthella pulcherrima (Weed Reef, Darwin, Australia),139 fromAcanthella sp. (Ximao Island, Hainan, China)140 and from themarine sponge Axinyssa sp. collected either offOne Tree, HeronIslands (Great Barrier Reef, Australia),141 or in Japan (TsutsumiIsland).142

The corresponding enantiomer (+)-128, also called epipolasinA, was identified from the sponge Epipolasis kushimotoensiswhereit coexists with the related (+)-epipolasin-A thiourea 130143 andin the sponge A. cavernosa (Heron Island, Great Barrier Reef,Australia).144 Its AC was deduced from circular dichroismexperiments done on a derived product and comparison withmaaliol. Compounds (+)-111 and (−)-128 were isolated fromAxinyssa sp. collected at the Gulf of California.145 (+)-γ-Maaliene131 is a constituent of the gorgonian P. americana (Bermuda andFlorida Keys).119 Maaliane-type sesquiterpenes (+)-132 and(+)-3-maalien-1-ol 133 were obtained from the gorgonaceaClavularia koellikeri (Ishigaki Island, Okinawa, Japan).146

Mosher’s method defined the absolute stereochemistry of 133,which on acetylation gave 132.147

Compound (−)-1(R)-bromo-ent-maaliol 134 was extractedfrom the calcareous alga Neomeris annulata, collected off theshallow inshore waters of Bermuda.148 Its AC was determined bycomparison of the product obtained through bromineelimination with the known (+)-maaliol.Investigation of the red alga L. obtusa (Castelluccio, Eastern

Sicily) afforded an unprecedented and rare minor metabolite 135(Figure 14) named (+)-laurobtusol,149 whose relative stereo-chemistry was assigned based on computational processing of thelanthanide-induced shifts in the 1H NMR spectra and molecularmechanics calculations but not yet confirmed through totalsynthesis.150 A plausible biogenetic route to this compound fromhumulene starting with the α-humulyl cation151 was proposed.

Figure 13. Aristolanes.

Figure 14. Maalianes and laurobtusol.



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Maalianes differ from aristolanes only by the nature of thesubstitution of their identical 6,6,3 skeleton at the C10 and C5positions, reflecting the possible biosynthetic origin (Scheme 3)

they have in common.152 Thus, germacradienyl cation (R)-12could furnish the bicyclogermacrene 136 by loss of a proton,generating the cyclopropane unit (Scheme 3). (+)-1(10)-Aristolene 112 could arise by successive H+-mediated C2−C7ring closure, 1,3-H shift, 1,2-Me migration, and loss of H+,implying the cations 137, 138, and 139, while maaliane 140 is theresult of hydride attack on 138.39

2.1.7. 6/6/4 Tricyclic Skeleton: Paralemnane. (−)-Paral-emnanol 141 (Figure 15), characterized from the soft coral P.thyrsoides (Green Island, Taiwan), possesses a very peculiarskeleton, which has never been encountered in other naturalsources.153

2.1.8. 7/5/3 Tricyclic Skeletons: Africanane, Aromaden-drane, and Neomerane. (+)-Africanol 142 was isolated in1974 from the soft coral L. af ricana (Leti Island, Maluku,Indonesia).154 X-ray diffraction studies confirmed its decahydro-1H-cyclopropa[e]azulene core structure and determined its ACas depicted in Figure 16.155 A biosynthetic pathway to africanol142 from α-humulene has been proposed.154 Its analog(+)-isoafricanol 143 was later found in the red alga Laurenciamariannensis (Hainan and Weizhou Islands, China).156

(+)-Δ9(15)-Africanene 144 was concomitantly reported for thefirst time from the soft corals of the genus Sinularia collected offtwo different locations: Sinularia erecta (Gulf of Eliat, RedSea)157 and Sinularia polydactyla (Laing Island, Papua NewGuinea).158 Its AC was determined by application of the octantrule on a derived ketone. It was later found in the soft coralsSinularia leptoclados (coast of Mandapam, Mannar Island),159

Sinularia capillosa (Sanya Bay, South China Sea),160 Sinularia sp.(Putti Island and Kurshide Island, Mandapam Coast, IndianOcean),161,162 Sinularia conferta (Andaman and Nicobar

Islands),163 Sinularia hirta (Andaman and Nicobar Islands, atthe juncture of the Bay of Bengal and Andaman Sea),164 Sinulariakavarattiensis (Mandapam coast, India),165,166 Lobophytumpaucif lorum (Havalock Island, Indian Ocean),167 and Lobophy-tum strictum (Andaman and Nicobar Islands).168

It was also isolated together with the known terrestrialsesquiterpene (+)-Δ7(8)-africanene 145 (1-africanene) from theaeolid nudibranch Phyllodesmium magnum collected from SouthChina Sea169 and the soft coral Sinularia dissecta (MadapamCoast, India).170 A study of the latter also afforded (+)-144171

together with the oxygenated africananes 146 and 147 and(+)-(9S)-africanane-9,15-diol 148.172,173 Compounds 144 and148−151 were isolated from Sinularia intacta collected from theMoyli Island (Gulf of Mannar, Indian Ocean).174 AC of (+)-150as drawn was ascertained by comparison with the productresulting from the oxidation of (+)-144. Four africananesesquiterpenes 144, 146, 148, and 150 were also characterizedfrom South China Sea soft coral Sinularia numerosa.175

Compound 146 reported as (+)-10α-hydroxy-Δ9(15)-africaneneis likely to be the 10β enantiomer, with a 1R configuration of theafricanane skeleton as drawn in Figure 16.174 (+)-Ophiocericacid 152, whose absolute stereochemistry was not assigned, wasidentified from the aquatic fungus Ophioceras venezuelense(Heredia, Costa Rica).176

(+)-Palustrol 153, an aromadendrane tricyclic sesquiterpenebearing an angular hydroxy group (Figure 17), was identifiedusing an interactive computer program in extracts of a marineXeniid (Cespitularia subviridis) collected at Albatros Rocks(Seychelles Islands).177 This class of natural products isstructurally characterized by the fusion of a hydroazulenenucleus to a cyclopropane ring. The AC of (+)-palustrol 153was later determined by X-ray diffraction analysis of thecorresponding autoxidation product.178 (+)-Palustrol 153, themajor metabolite of the hexane extract of this soft coral, wasfound together with (−)-viridiflorol 154 and (+)-ledol 155,which have, respectively, opposite and identical configurationsthan their terrestrial counterparts.179 (+)-Palustrol was alsorecently isolated from a Bornean soft coral Capnella sp.(Mantanani Island, Sabah, Malaysia)180 and from the Red Seasoft corals Sarcophyton trocheliophorum181 and Sarcophytonglaucum.182

Sesquiterpene (+)-156 and the first natural nor-aromanden-drane (−)-157 were identifed from the EtOAc solubles of themethanol extract of the Okinawan soft coral C. koellikeri(Okinawa, Japan).146 While the AC of 156 was proposedbased on comparison with the maalianes 132 and 133 found

Scheme 3. Proposed Biosynthetic Pathways to Maalianes andAristolanes

Figure 15. Paralemnanol.

Figure 16. Africananes.



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concomitantly, that of 157, previously reported as a(+)-synthetic intermediate prepared from (+)-aromaden-drene,183 followed from comparison of the [α]D with literaturevalues, was therefore established as (−)-(1S,4R,5R,6S,7S)-157.(+)-Cyclocolorenone 158 (Figure 17), previously known as aterrestrial metabolite, was isolated from the soft coralN. chabrolii(Sinyaru Island, Indonesia)184 and later, together with itsanalogue (+)-1α-hydroxycyclocolorenone 159, from the softcoral Nephthea sp. (Andaman and Nicobar Islands, IndianOcean).185

The Formosan soft coral Clavularia inf lata var. luzonianacollected off Green Island (Taiwan) was the source of threearomadendranes 160, 161, and 162.186 ACs of (+)-160 and(+)-161 were determined as 3R using Mosher’s method. Marinesesquiterpene (+)-161 is the enantiomer of (−)-3β-hydrox-yspathulenol obtained from the terrestrial Chilean liverwort,Lepicolea ochroleuca.187

Two aromadendranediols possessing a trans ring junctionbetween C1 and C5, (+)-4α,7β-aromadendranediol 163 and(−)-4α,7α-aromadendranediol 164 (Figure 17), whose oppositeenantiomers were later found in the South China Sea gorgonianMelitodes squamata,188 and one minor compound (−)-165possessing the corresponding cis junction were isolated from the

soft coral Sinularia mayi (Nias Island, Indonesia) together withthe major component (−)-aromadendrene 166.189 Its epimer(+)-alloaromadendrene 167 was found in extracts of a marineXeniid (C. subviridis)179 and in Sarcophyton acutangulum(Ishigaki Island, Okinawa, Japan).190 Compound (−)-166 wasalso extracted from the Australian marine red alga Laurenciaf iliformis.191 (−)-Lochmolins E 168, F 169, C 170, D 171, and B172, whose ACs were not determined, were recently isolatedfrom a Taiwanese soft coral Sinularia lochmodes.192 Sesquiter-penes (−)-163, (−)-173, (−)-174, and (−)-175 werecharacterized from the ethanol extract of an Indian specimenof the soft coral Sinularia maxima (Havelock Island, IndianOcean).193 Metabolite (−)-163, (+)-spathulenol 176, and(+)-11-epispathulenol 177 obtained from Taonia lacheana(Lachea Island, Italy) represent the first aromadendranesesquiterpenes isolated from brown algae.194 (+)-Spathulenol176 was also isolated from S. kavarattiensis (Mandapam Coast,India)165,166 and from the lipophilic extract of the soft coral P.fulvum fulvum (Phantom Island, North Queensland, Australia)together with the corresponding acetate (−)-178 and the knownterrestrial195 tridensenone 179.196 Compound (−)-180, bearingan original fulvene moiety, probably responsible for the color of

Figure 17. Aromadendranes.



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the yellow morph it belongs to, was identified from the soft coralP. fulvum fulvum (Gulf of Eilat, Red Sea).120

Extracts of the nudibranch L. millecra (Coffee Bay, SouthAfrica) afforded (+)-squamulosone 181, also called millecrone-B.197 Spicules from soft corals were found in the digestive glandof L. millecra, suggesting a dietary origin of this secondarymetabolite. Examination of this nudibranch from Algoa Bay(South Africa) also afforded (+)-181 as the major metabolite.92

The red alga Laurencia subopposita, collected in La Jolla (SanDiego, CA, USA), contained a variety of metabolites from whichthe quaternary allylic alcohols (−)-182 and (−)-183 werediscovered.198 The only known marine origin aromadendranebearing a substituted methyl in the C12 position (−)-184(Figure 17) was isolated from C. koellikeri collected around LaingIsland (Papua NewGuinea).199 A peculiar dimeric structure 185,named (+)-halichonadin E, bearing both aromadendrane andeudesmane skeletons linked by a urea function, was characterizedfrom a marine sponge Halichondria sp., collected off Unten Port(Okinawa, Japan).200

Formation of (+)-alloaromadendrene 167 can arise bysuccessive proton-mediated C1−C7 ring closure starting from136 and loss of H+, implying the cation 186 (Scheme 4).40

Nitrogeneous compounds (Figure 18), among them sesqui-terpenes bearing isonitrile, isocyano, isothiocyanato, or for-mamide functional groups, are commonly encountered in themarine world.201 The only example of a tricyclic sesquiterpenebearing a primary amine function, (+)-halichonadin F 187, wasisolated from the marine sponge Halichondria sp. collected offUnten Port (Okinawa, Japan) together with an unusualcopper(I) complex of the eudesmane halichonadin C.202 Therelative configurations of compounds (−)-188, (−)-189, and190 characterized from the toxic extract of the marine spongeAcanthella acuta, collected off the Mediterranean Sea (Banyuls,France),203,204 were later corrected by chemical correlation withpalustrol 153.178

Compounds (−)-188 and (−)-189were also isolated from thesame sponge but in a different location (Bay of Napoli),205 andcompound 189 was later found in a specimen of A. aplysinoides(Pohnpei).95 A chemical study of an extract from the Spanishdancer nudibranch Hexabranchus sanguineus, collected in theSouth China Sea was the source of the new aromadendranesesquiterpene (+)-191 as the main metabolite.206 Its AC wastenuously proposed based upon comparison of the sign of itsexperimental optical rotation with palustrol’s one. A chemicalstudy of the Vietnamese nudibranch mollusk Phyllidiellapustulosa207 afforded (+)-(10R)-isothiocyanato-allo-aromaden-drane 192, whose AC was determined by comparison with itssemisynthetic enantiomer,208 together with (−)-188 and(−)-189. Such aromadendrane structure, bearing nitrogenoussubstituents in the C10 position, was first found in the1970s209,210 in compounds 193−195 and later in compounds

196−198,211 isolated from the marine sponge A. cannabinacollected off the coast of Taranto (Italy). Compounds (−)-189and (−)-197 were also extracted from the sponge Axinyssa sp.collected off Tsutsumi Island (Japan),142 and Acanthella sp. wasshown to produce metabolites (+)-192 (Yalong Bay, Hainan,China)212 and (+)-192 together with (−)-197 and (+)-199(Ximao Island, Hainan, China).140

Sesquiterpene (+)-195 was found in the nudibranch H.sanguineus,206 collected in the South China Sea, and compounds188−190, (−)-axisothiocyanate 194, and (−)-197 were alsoisolated from specimens of the Indo-Pacific sponge A. cavernosacollected from locations along the eastern coastline ofAustralia.213 Metabolite (−)-188 was extracted from thenudibranch P. ocellata collected in Mudjimba Island (Mooloo-laba, Australia)96 and found together with 197 from the marinesponge A. pulcherrima collected off Weed Reef (Australia).139

Sesquiterpenes 192−194 were found in the marine sponge A.cavernosa collected off Hachijo-jima Island (Japan),126,214 whilethe nudibranch P. pustulosa found in the same location produced(+)-axisonitrile 193.215 The nitrogenous sesquiterpene bearing aformamide substituent, (+)-axamide 195, was also recentlycharacterized from the Thai marine sponge Halichondria sp. (PPIsland, Andaman Sea, South Thailand).216 The new sesquiter-pene isothiocyanate, named (+)-epipolasin B 199, was found inthe sponge E. kushimotoensis where it co-occurs with the relatedepipolasinthiourea B 200. Their stereochemistry, relative andabsolute, was deduced from chemical correlation to (−)-ar-omadendrene 166.143Metabolites (+)-201 and (−)-202, bearinga peculiar CH2NH(CH2)2Ph group, were identified in the SouthChina Sea gorgonian M. squamata.186

(−)-Neomeranol 203, also possessing a rare structure, wasobtained from extracts of the calcareous alga N. annulatacollected off the shallow inshore waters of Bermuda,148 and itsAC was elucidated by a modified Horeau’s method.217

2.1.9. 7/6/3 Tricyclic Skeleton: Capillosanane. (+)-Cap-illosanane V 204 (Figure 19), isolated from the soft coral S.

Scheme 4. Possible Biosynthetic Pathway to(+)-Alloaromadendrene 167 Figure 18. Nitrogenous aromadendranes, allo-aromadendranes, and

neomerane.



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capillosa (Sanya Bay, South China Sea), possesses a very peculiarskeleton which has never been encountered in other naturalsources.160

2.1.10. 8/4/3 Tricyclic Skeleton: Norantipathane. Theweak antibacterial (+)-rumphellolide F 205 (Figure 20), a rare

nor-sesquiterpene alcohol with a cyclopropane ring, was isolatedfrom the Taiwanese soft coral Rumphella antipathies.218 It waspreviously obtained by chemical synthesis on base treatment ofkobusone, a caryophyllene-derived epoxy ketone.219

2.2. Bridged Carbocycles

2.2.1. Tricyclic Decane Skeletons: Ylangane, Copaane,Sinularane, Trachyopsane, Pupukeanane, Allopupukea-nane, Abeopupukeanane, Neopupukeanane, Sativane,and Isosativane. (−)-Lemnalol 206 (Figure 21), an ylangene-type sesquiterpenoid whose AC was established by the 1H NMRlanthanide-induced shift method and X-ray crystallographicanalyses, was first found in the Japanese soft coral Lemnalia tenuis(Okinawa, Japan),220 and later (−)-(1S,2S,4R,6S,7R,8S)-4α-formyloxy-β-ylangene 207 was isolated from the soft coralLemnalia f lava (Green Island, Taiwan) along with (−)-lemnalol206 and (+)-cervicol 208.60 Metabolites 206 and 208−210 werecharacterized from the methylene chloride solubles of theFormosan soft coral Lemnalia cervicorni (Green Island,Taiwan).221 Extract of the soft coral S. mayi (Nias Island,Indonesia) was shown to contain (+)-β-copaene 211 as majormetabolite along with (+)-α-copaene 212.189 The knownterrestrial antipode (−)-212 was found in the marine alga D.divaricata.222 The tricyclo[4.4.0.02,7]decane skeleton was alsorecently found in philippinlins A (−)-213 and B (+)-214, whichwere isolated from the soft coral Lemnalia philippinensis collectedoff the coast of Lanyu (Taiwan) together with (−)-lemnalol206.223 (+)-β-Copaene 211 was also detected in Eunicea succineacollected off St. Croix (United States) and South Caicos (UnitedKingdom) islands,224 Eunicea palmeri, P. porosa, P. wagenaari, andPseudoplexora sp.225 This metabolite was erroneously reported as(+)-β-ylangene having an isomeric isopropyl group at C8.226

Such core structures were eventually isolated from the Red Seasoft coral Dendronephthya sp. (coast of Hurghada, Egypt) incompounds (−)-215, (−)-216, and (−)-217, respectively,named dendronephthol A, B, and C.227 (−)-Sinularene 218was the most abundant sesquiterpene hydrocarbon extractedfrom the soft coral S. mayi (Eastern reef of Telukdalam, NiasIsland, Indonesia).189,228 The corresponding 12-acetoxysinular-

ene (−)-219, whose structure was determined by an X-raydiffraction study, was identified from Clavularia inf tata (LaingIsland, Papua New Guinea).199

The nitrogenous sesquiterpenes 220−222 (Figure 21) werereported from the Palauan sponge A. (= Trachyopsis)aplysinoides.229,230 Bioassay-guided isolation of the nudibranchPhyllidia varicosa (Shimokoshiki-jima Island, Japan) allowedidentification of (+)-2-isocyanotrachyopsane 223 with goodantifouling activity.231 ACs for compounds (−)-221 and (+)-223were later assigned via total enantioselective syntheses (Scheme30) leading, respectively, to the same [(−)-221] and theopposite [(−)-223] enantiomers.232(−)-(1R,3S,5R,6S,7S,9R)-9-Isocyanopupukeanane 224233 and

its C2 isomer 225234 were found in both the nudibranch P.varicosa and its prey, the spongeHymeniacidon sp., as a mixture ofvolatile substances lethal to fish and crustaceans. Circulardichroism measurements and X-ray diffraction data establishedthe ACs of the two metabolites.

Figure 19. Capillosanane.

Figure 20. Rumphellolide F.

Figure 21. Compounds of marine origin possessing a tricyclic decaneskeleton.



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[13C]-Labeled 225 was encased in gelatin capsules andembedded in a live Hymeniacidon sponge in the ocean for 7−14 days incubation.235 Analysis by gas chromatography/massspectrometry of the presence of 225 and the related 2-formamidopupukeanane 226 and 2-isothiocyanopupukeanane227 in the isolated extracts showed that the isocyano group wasthe precursor of the formamido and isothiocyano groups, thereverse reactions did not take place, and the sponge did notutilize formate in the isocyano biosynthesis. It was also shownthat extraction of the sponge Ciocalypta sp. (Hawai)236 andAxynissa n. sp. (Australia)237 incubated with [14C]-labeledsodium cyanide resulted in radioactive 225, thus suggesting theexistence of cyanide ions of metabolic origin. Compound(−)-226 was recently isolated from the nudibranch Phyllidiacodestis Bergh collected off Koh-Ha Islets (Krabi Province,Thailand) together with the abeopupukeanane (+)-228.238 Co-occurrence of (−)-9-isocyanopupukeanane 224 and its C-9epimer (+)-229 was observed in the nudibranch Phyllidiabourguini collected from Hachijo-jima Island (Japan).239

Compounds 224 and 229 were also found in P. pustulosacollected off Hachijo-jima Island (Japan).215

An epimeric mixture of two new 9-thiocyanatopupukeananesesquiterpenes 230 and 231 (Figure 21) obtained from themethanol extract of the nudibranch P. varicosa and its sponge-prey Axinyssa aculeata collected off the coral reefs of PramukaIsland (Thousand Islands National Park, Indonesia)240 was alsofound in nudibranch mollusk P. pustulosa (offshore, Vietnam).207

Compound (−)-224 was found in the marine sponge Axinyssasp. collected off either One Tree or Heron Islands (Great BarrierReef, Australia) along with (−)-232 and (−)-233.141 This last

metabolite was previously reported from the sponge A.aplysinoides (Ant Atoll, Pohnpei, Federated States of Micronesia)together with (+)-227.95 Crude extracts of the tropical marinesponge of the genus Axinyssa (Gun Beach, Guam) deterredfeeding in the common pufferfishCanthigaster solandri. However,the only constituent of the sponge to be available in sufficientquantities for the bioassay, (+)-5-isothiocyanatopupukeanane234, failed to deter feeding when tested at a relatively highconcentration.241 The marine sesquiterpene (−)-2-thiocyanato-neopupukeanane 233 with the coexisting isomeric naturalproduct (−)-235 were isolated from sponges Phycopsis terpnisfrom Okinawa (Japan) and in an unidentified species fromPohnpei.242 The correct stereochemistry of (−)-233 wasdetermined based on NMR studies done on this compoundisolated from A. aplysinoides (Palau)95 and later confirmed bytotal synthesis (Scheme 31) and X-ray diffraction study.243

Ciocalypta sp., a sponge from the south shore of O’ahu (Hawaii),was found to produce the isocyanosesquiterpene (+)-236, whoseAC was not determined.244

The biosynthetic origins of the isocyanide and isothiocyanategroups in 9-isocyanopupukeanane 224 and 9-isothiocyanatopu-pukeanane 232 were investigated by incorporation of thecorresponding [14C]-labeled compounds independently intothe sponge Axinyssa sp.245,246 After 21 days in aerated seawater,extraction of the sponge incubated with [14C]-labeled 224([14C]-labeled 232) gave the radioactive compound 232 (theradioactive compound 224) clearly indicating that these twometabolites can be interconverted by the sponge, in contra-diction with the experiments previously conducted oncompound 225.235

Scheme 5. Possible Biosynthetic Pathway to α-Copaene 212 and Pupukeanane Derivatives



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After mass cultivation, the fungus Drechslera dematioideaisolated from the inner tissue of the marine red alga Liagoraviscida collected off the Mediterranean Sea (Moraira, Spain),investigated for its secondary metabolite content, afforded(−)-cis-sativene diol 237 and (−)-isosativenetriol 238,247

whose ACs were determined based on the previously isolatedterrestrial sativene.248 The allopupukeanane derivative (+)-239was found in the nudibranch P. pustulosa collected off Hachijo-jima Island (Japan).215

The biosynthetic pathway to α-copaene 212 could beexplained (Scheme 5)39 starting from cation (S)-12, whichafter hydride migration and subsequent deprotonation could givegermacrene 240. Under its transoid conformation, this lastspecies could lead by ring closure to muurolenyl cation 241,which could afford through a second cyclization step cation 242,a possible precursor to 212. Cation (S)-12 could also furnish α-amorphene 245 by 1,3-hydride migration and subsequent ringclosure to give 244 and proton loss.249 Subsequent C−C shiftscould afford cations 247, 248, and 249 as precursors of,respectively, the pupukeanane, abeopupukeanane, and neo-pupukeanane series.238

2.2.2. Tricyclic Undecane Skeletons: Acanthodorane,Isotenerane, Quadrane or Suberosane, Paesslerane,Longibornane, Rumphellane, Strepsesquitriane, andCedrane. (+)-Acanthodoral 250 (Figure 22) is a sesquiterpenealdehyde characterized from the nudibranch Acanthodorisnanaimoensis collected in Barkley Sound, British Columbia.250

Natural acanthodoral 250 is likely to have a dextrorotatoryoptical rotation on the basis of biogenetic considerations,although its optical rotation has not been determined due tothe difficulty of purification and the extremely small quantity (7mg/100 animals) coupled with the high volatility of this minorcomponent. Its absolute stereochemistry was postulated basedon its synthesis (see section 4.2.2).251 The bridged sesquiter-pene, (−)-4-hydroxy-1,8-epi-isotenerone 251, was isolated fromthe red alga L. perforata (Magnetic Island, Australia),252 while itsunstable brominated analog (−)-252was obtained from L. teneracollected off Florence Bay (Magnetic Islands, Australia).103

(+)-Suberosenone 253, the first quadrane-type253 sesquiter-pene of marine origin, was one of the three cytotoxic compoundscharacterized from the gorgonian S. suberosa in 1996.254 Fiveadditional suberosane sesquiterpenes possessing the same denseskeleton, (−)-suberosenol A 254, (−)-suberosenol B 255,(−)-suberosenol A acetate 256, (−)-suberosenol B acetate257, and (+)-suberosanone 258, were later isolated from thegorgonian I. hippuris collected off the Southeast coast ofTaiwan.66 The rare sesquiterpene alkaloid (+)-259255 wasreported as a mildly cytotoxic metabolite isolated from thegorgonian S. suberosa (China) together with (−)-suberosenol A254.70 The latter was also found in the gorgonian Menella sp.collected off Meishan Island (South China Sea).67 The relativeconfiguration at C2 of (+)-259 was later corrected (as drawn inFigure 22) based on the isolation from the same species (S.suberosa) of the corresponding purine metabolite (+)-260.256

The 1R ACs of suberosenone 253, suberosanone 258, andsuberosenol A acetate 256 have been proposed via densityfunctional theory calculations of their optical rotation,257 but ACof (+)-suberosanone was recently reversed based on its totalsynthesis (see section 4.2.2, Scheme 39). (+)-Suberosenone 253was also identified from Alertigorgia sp. collected off the east sideof Joseph Bonaparte Gulf (Northern Territories, Australia)together with the peculiar dimer (+)-alertenone 261.258

Although the biosynthesis of terrestrial metabolite quadrone

was explored, there was only one biosynthetic proposal regardingthe suberosanes that were shown to be linked to silphinanes viathe presilphiperfolan-8-yl carbocation before their isolation frommarine natural sources (see Scheme 37).259

In the course of the search of minor bioactive metabolites fromdeep-water marine invertebrates, paesslerins A 262 and B 263(Figure 22) were isolated from the sub-Antarctic soft coralAlcyonium paessleri (South Georgia Islands) collected by nettingat around −200 m. Their structures with an unprecedentedtricyclic 2,8,8,10-tetramethyltricyclo[4.3.2.02,5]undecane skele-ton named paesslerane were elucidated by spectroscopictechniques.260 However, from synthetic studies directed to thestereoselective formation of highly substituted bicyclo[4.2.0]-octane framework as found in paesslerin, it has been made clearthat a revision of the structure of natural paesslerin A isrequired.261 These compounds show moderate cytotoxicity inpreliminary assays. The tricyclic sesquiterpene (+)-isoculmorin264, isolated from the culture broth of marine fungusKallichroma tethys (Figure 22),262 exhibited a longibornaneskeleton but differs from culmorin 265263,264 and all other knownculmorin derivatives of terrestrial origin265 in that it lacks ahydroxy or keto group at C-11. A sesquiterpene possessing a newcarbon skeleton named rumphellane, (−)-rumphellaoic acid A266, was recently characterized from the gorgonian coral R.antipathies collected off the coast of Pingtung (Taiwan).266 ItsAC was not established. (+)-Strepsesquitriol 267 possessing a

Figure 22. Compounds of marine origin possessing a tricyclic undecaneskeleton.



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rare strepsesquitriane skeleton was identified from the deep-sea-derived actinomycete Streptomyces sp. SCSIO 10355, collected inthe Bay of Bengal (Indian Ocean).267 Its AC was determined byNMR analysis and theoretical optical rotation derived fromquantum-chemical calculations. The diastereoisomeric cedranes(+)-α-pipitzol 268 and (−)-β-pipitzol 269 were found in plantsof the genus Perezia268 before their recent identification from thesoft coral Pseudopterogorgia rigida, collected in the Caribbean Sea(United States).269 Their relative stereochemistry was laterconfirmed through an X-ray diffraction study.270

Isotope incorporation studies271 with A. nanaimoensis wereconsistent with the proposed biosynthetic pathway250 toacanthodoral 250. Thus, FPP 11 could give diene 270 andthen cation 271 via two consecutive cyclizations (Scheme 6).Acanthodoral 250 could then arise directly from this cation orthrough formation of aldehyde 272.

2.2.3. Tricyclic Dodecane Skeletons: Caryolane, Iso-caryolane, Clovane, Penicibilane, Lemnafricanane, Iso-paralemnane, Rhodolaurane, Gomerane, and Ompha-lane. Isolation of the cytotoxic caryolane sesquiterpene (−)-273along with inactive analogs (−)-274 and (−)-275 possessing atricyclo[6.3.1.02,5]dodecane skeleton was reported in 1988 froma New Zealand marine sponge of the genus Eurypon (Figure23).272 It was postulated that 274 and 275 could result fromartifacts arising during the isolation procedure by oxidation of theallylic alcohol group in 273 followed by conjugate addition ofwater or methanol to the enone intermediate.During a collection of marine sponges off the Mercury Islands,

New Zealand, some different but related compounds wereobtained from a specimen of the same species. Separation of thecrude hexane extract, which had significant antimicrobial activity,resulted in isolation of the antimicrobial sesquiterpene (−)-273together with the inactive sesquiterpenes (−)-274 and(−)-276−(−)-278.273 Structures of the new sesquiterpenes276−278 were determined by spectroscopic methods, but theirACs were not determined.Compound (+)-279 of unknown AC was recently isolated

from the gorgonian coral R. antipathies, collected off the water ofTaiwan (Pingtung).274 The nitrogenous metabolites (−)-280−282, whose ACs were established based on X-ray crystallographicanalysis, were recently characterized from the nudibranch P.ocellata collected offMudjimba Island (Mooloolaba, Australia).96

The new clovane derivatives (−)-283,275 (−)-rumphellclo-vanes D−E 284−285,276 (−)-clovan-2,9-dione 286,276 and(+)-rumphellclovane B 287277 were reported as marine naturalproduct extracted from the gorgonian coral R. antipathiescollected off the southern coast of Taiwan.

(+)-Penicibilaenes A 288 and B 289, incorporating atricyclo[6.3.1.01,5]dodecane skeleton, named penicibilane, wererecently isolated from the fungus Penicillium bilaiae MA-267collected from the rhizospheric soil of themarine mangrove plantLumnitzera racemosa at Hainan Island (South China).278 TheirACs were established by X-ray analysis. From the soft coral L.af ricana collected off south Kenya was found (−)-lemnafricanol290 of unknown AC, and a possible biogenetic pathway wassuggested starting from 1(10)-aristolane.279 (−)-Paralemnanone291 and (+)-isoparalemnanone 292 (Figure 23) epimeric atC12, whose ACs were established by application of Mosher’smethod, were isolated from the soft coral P. thyrsoides (GreenIsland, Taiwan).153

A possible pathway to caryolene 298 and caryol-7-en-6α-ol273 was proposed based on DFT calculations.280,281 Anasynchronous [2 + 2] cycloaddition could provide cation 294through 293 starting from FPP 11 (Scheme 7). This cation couldthen be transformed, under basic conditions, into diene 295whose protonation could generate cation 296. Cyclization into297 and subsequent proton loss could result in caryolene 298and its corresponding functionalized derivatives.Five halogenated tricyclic sesquiterpenes (Figure 24) of

marine origin built on the rhodolaurane skeleton have beendescribed to date. Among them, rhodolauradiol 299 and(+)-rhodolaureol 300 were found in an unidentified alga of thegenus Laurencia282 and from L. obtusa collected off Lanzarote(Canary Islands).283 Their absolute configurations weredetermined through X-ray diffraction analysis of syntheticallyrelated compounds. (+)-Isorhodolaureol 301, whose ACwas notdetermined, was isolated from L. majuscula collected off Zoe Bay(Hinchinbrook Island, North Queensland).72 Its structure wasconfirmed by synthetic transformations which led to enone 302,identical with the known oxidized form of 300. Compound 304

Scheme 6. Possible Biosynthetic Pathway to Acanthodoral250

Figure 23.Marine compounds possessing a tricyclic dodecane skeleton.



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was characterized from L. mariannensis collected off Hainan andWeizhou Islands (China).156 It could nevertheless be an artifactof the isolation of 303 concomitantly found in this alga, whichwas shown to rearrange into 304 on silica gel, as previouslyshown in a biomimetic synthetic study en route to rhodolaureoland rhodolauradiol.284

Compounds (−)-305, (+)-306, and (+)-307, whose ACs werenot determined, belong to a new class of sesquiterpenes namedgomerane, based on the location (La Gomera, Canary Islands)where the red alga L. majuscula containing these metabolites wascollected.285 It was later shown that epimeric gomerones 306 and307 had been interchanged in their assignments via totalsynthesis of the former.286

The bridged tricyclo[7,2,1,01,6]dodecane compound (+)-gui-marediol monoacetate 308 resulted from acetylation of oneextract of the red seaweed Laurencia sp.287 Its skeleton wasdesigned as guimarane and its AC ascertained by X-ray diffractionanalysis. (−)-Dactylomelatriol 309, sharing the same skeleton

but with the different name omphalane, was later characterizedfrom the sea hare Aplysia dactylomela collected off the southerncoast of La Gomera (Canary Islands).288

2.3. Miscellaneous Carbocycles: Inflatane, Cyclolaurane,and Cyclococane

Aromatic tricyclic sesquiterpenoid (−)-debromolaurinterol 310and the corresponding brominated compound (+)-laurinterol311 (Figure 25) were first mentioned in 1966, as produced by

Laurencia intermedia collected at Oshoro Bay (Hokkaido,Japan),289,290 before being reattributed to Laurencia okamurai,291

this last species also furnishing compound (+)-312. AC ofcompound (+)-311 was determined later from the same samplevia an X-ray diffraction study.292 Metabolites (−)-310 and(+)-311 were also extracted from the same species collected indifferent locations: Hakata-shima, Inland Sea of Japan,293 andNyudogatane, Okino-shima, Tosa Province (Japan), togetherwith (+)-313.294 (−)-Debromolaurinterol 310 was found inLaurencia f lexilis collected off Barrio Pangil (Curimao, LlocosNortes, Philippines).295

(−)-Cyclolaurene 314, referred to as a rare cuparanesesquiterpene derivative, was isolated together with brominatedanalogs (−)-cyclolaurenol 315 and (−)-cyclolaurenol acetate316 from the sea hare A. dactylomela collected off Kohama Island(Okinawa, Japan).296 Its AC was deduced from chemicalinterconversion to the cyclolaurane-type sesquiterpene (−)-lau-requinone 321 characterized from red alga Laurencia nidif icacollected off the coast of Goza (Japan) together with compounds(−)-310 and (+)-311.297 Dimer (+)-322 was later identifiedfrom the same source298 and from the red alga Laurencia tristicha

Scheme 7. Possible Biosynthetic Pathway to Caryolane 273

Figure 24. Halogenated marine rhodolauranes, gomeranes, andomphalanes possessing a tricyclic dodecane skeleton and sesquiterpene303.

Figure 25. Miscellaneous marine tricyclic sesquiterpenes.



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collected off the coast of Naozhou Island (Zhanjiang City,China) together with the new compound (+)-317.299

Another cuparane-derived compound (−)-318 with a cyclo-laurane skeleton was also found in the red alga L. tristichacollected off Pingyu Island (South China Sea) together with(−)-310, (+)-312, (−)-316, (+)-laurinterol acetate 319, and(−)-323300 and also together with (−)-310, (+)-311, and(+)-319 from the sea hare Aplysia kurodai collected off ToyamaBay (Japan).301 Cyclolaurane dimer (−)-323 was previouslyobtained106 with (+)-311 from L. microcladia collected at ChiosIsland in the North Aegean Sea, but its structure was erroneouslydrawn as 324, which corresponds to an achiral meso compoundresulting from the ortho coupling of (−)- and (+)-laurinterol311.(+)-Laurinterol 311 (Figure 25) was also extracted from L.

nidif ica collected off Kahala Reef on the island of Oahu(Hawaii),302 from the red algae Marginisporum aberrans,Amphiroa zonata, and the calcareous alga Corallina piluliferacollected at Cape Omaezaki (Shizuoka Prefecture, Japan),303

from the red alga Laurencia pacif ica,304 from Laurencia sp.collected from Tsubota (Miyake-jima Island, Tokyo),305 from L.okamurai collected off Nanji Island (Zhejiang Province,China),306 and from the digestive gland of the sea hare Aplysiacalifornia collected in La Jolla and Cardiff (California).307

Cyclolauranes (cuparanes) (−)-310 and (+)-317, (−)-318,and (+)-319 were also characterized from the red alga L.okamurai collected off the coast of Nanji Island (East ChinaSea),308 while 310−312 and (−)-323 were produced by the redalga L. tristicha collected off Shanwei (Guangdong Province ofChina).309

Compound (−)-320 is the only tricyclic sesquiterpene bearingtwo different halogen atoms (bromine and iodide). It was foundin L. microcladia collected at Chios Island (North Aegean Sea,Greece) together with (+)-312 and the new dimer (−)-325.310The relative stereochemistry found in 325 following NOE studyled to a surprising structure involving epimerization of thelaurinterol motif at C7. Compounds 310−321 and the relateddimers 322−325 are found to possess either a cuparane or acyclolaurane-type skeleton. We propose cyclolaurane to namethis skeletal type, having an extra bond between C12 and C10relative to the cuparane skeleton.Sesquiterpene (−)-326 with a new fused/joined carbon

skeleton made of two cyclopropane rings, one being fused to acyclobutane ring, was identified in the course of bioguidedfractionation with cytotoxic assay of the Formosan Soft Coral C.inf lata var. luzoniana (Figure 25) collected off Green Island(Taiwan), along with three new aromandendranes 160−162 andfour cytotoxic diterpenes.186 This first in class inflatane (−)-326was however not cytotoxic to P-388 and HT-29 cells.

(+)-Bromocyclococanol 327, built on a novel skeleton namedcyclococane and whose AC was not determined, was isolatedfrom L. obtusa collected in Cayo Coco (Cuba).311

3. BIOLOGICAL ACTIVITY

3.1. Cytotoxic and Antitumor Activity

Cytotoxicity toward a wide range of cancer cell lines (Tables1−7) was the prevalent kind of biological activity reported fortricyclic sesquiterpenes of marine origin, usually expressed as50% of the effective dose (ED50), inhibitory concentration(IC50), growth inhibition (GI50, this value emphasizes thecorrection for the cell count at time zero), lethal concentration(LC50), or cytotoxic concentration (CC50) and ordered in eachentry by increasing numbers and references. Among the 284identified metabolites, 79 products incorporating 17 differentskeletons were tested against 54 cancer cell lines (Tables 1−7).Cytotoxic activities against seven human colon cancer cell lines

(Table 1) were evaluated, HT-29 being predominantly studied.The most potent among these 79 compounds belongs to thesuberosane family. They showed good [(−)-255, 9.5 μM] toexcellent ED50 values in the nanomolar range [(−)-254 and(−)-258, 0.023 nM; (−)-256, 1.4 nM; (−)-257, 19 nM] in thiscell line.66 Kelsoenes 630 and 8 exhibited moderate to goodactivity (15.6 and 7.6 μM, respectively).32,38 Compound (+)-4was shown to have no activity (ED50 > 45 μM), emphasizing theimportance of the peroxide function in the same kelsoene seriesas found in (+)-5, which exhibited good (2.1 μM) activity againstHT-29 cell line.32 In the ylangane series, contrary to the bridgedcompound (−)-lemnalol 206 which demonstrated a moderatecytotoxic activity (ED50 = 10.5 μM), compounds (+)-208,(−)-209, and (+)-210 exhibited no activity (ED50 > 100 μM).221

The hydroxy group at the C4 position, only found for compound206, thus seems to play a role in the cytotoxic efficiency. Last,compounds (+)-312, (−)-320, (−)-325,310 and (+)-160−162,186 showed weak (from 78.4 to >300 μM) and no activity,respectively, against HT-29 cell line. The good to moderatecytotoxicity (2.2−20.3 μM) observed in the hirsutane series forcompounds (−)-15,42 20,45 and (+)-2750 against SW480,SW620, and LoVo cell lines could be explained by the presenceof an electrophilic α-methylene cyclopentenone group in thesecompounds, while in the same series, compounds (+)-17,50

(−)-18, (+)-19,42 and (−)-22−2350 lacking this functionalgroup were found inactive.However, (+)-isohirsutane 24 bearing such functionality

exhibited no activity toward LoVo cell lines.50 No activity(IC50 > 4500 μM) was reported for capnellen-8β-ol 34 contraryto its analogue (+)-Δ9(12)-capnellene-8β,10α-diol 32, whichdemonstrates a moderate activity (IC50 = 63 μM) against HT115cell lines and a good activity (IC50 = 0.16 μg/mL) toward WiDr

Table 1. Cytotoxic Activities toward Human Colon Cancer Cell Lines

cell lines cytotoxic activities

HT-29 (+)-5 ED50 = 0.5 μg/mL (2.1 μM), (+)-6 ED50 = 3.2 μg/mL (15.6 μM), (+)-4 ED50 > 10 μg/mL (>45.4 μM),32 (−)-8 ED50 = 1.8 μg/mL (7.6 μM),38

(+)-160−(+)-162, (−)-326 no activity,186 (−)-206 ED50 = 10.5 μM, 208−210 ED50 > 100 μM,221 (−)-254 ED50 < 5 × 10−6 μg/mL (<22.7 × 10−6 μM),(−)-255 ED50 = 2.1 μg/mL (9.5 μM), (−)-256 ED50 = 3.6 × 10−4 μg/mL (1.4 × 10−3 μM), (−)-257 ED50 = 5.0 × 10−3 μg/mL (19 × 10−3 μM), (−)-258ED50 < 5.0 × 10−6 μg/mL (<22.7 × 10−6 μM),66 (+)-312 IC50 = 98.7 μM, (−)-320 IC50 = 78.4 μM, (−)-325 IC50 > 300 μM310

SW480 (−)-15 ED50 = 3.03 ± 0.07 μg/mL (12.3 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>196 μM)42

SW620 (−)-15 ED50 = 0.58 ± 0.09 μg/mL (2.3 μM)42

LoVo (−)-15 ED50 = 5.01 ± 0.38 μg/mL (20.3 μM),42 (+)-20 IC50 = 5.47 μM,45 (+)-27 IC50 = 2.16 μM, (+)-17, (−)-22, (−)-23, and (+)−24 IC50 > 200 μM50

HT115 (+)-32 IC50 = 63 μM, 34 IC50 > 4500 μM55

WiDr (+)-32 IC50 = 0.16 μg/mL (0.7 μM)59

Col2 (−)-64 inactive, (−)-65 ED50 = 17.8 μg/mL (80.1 μM), (+)-301 and (−)-310 ED50 > 20 μg/mL (>100 μM)312



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cell lines.55 These two structures differ solely by the presence ofan H atom or a hydroxy group at the C2 position. Compounds(+)-301 and (−)-310 were found inactive (ED50 > 100 μM),while compound (−)-65 showed a moderate activity towardCol2 cell line.312

Biological activities against human breast cancer wereevaluated on MCF7, MDA-MB-231, MDA-MB-435, andMDA-MB-453 cell lines (Table 2). In the hirsutane andcapnellane series, (+)-incarnal 27 (IC50 = 4.6 μM),50

(−)-hirsutanol A 15 (ED50 = 10.4 μM),42 and (+)-32 (IC50 =93 μM)55 showed good to weak activities toward MCF7 cell,while their analogs (−)-hirsutanol F 18,42 (+)-hirsutene triol19,42 (+)-capnellen-8β-ol 34,55 and (+)-3β-acetoxycapnellene-8β,10α,14β-triol 3555 were found inactive. No activity towardMCF7 cells were detected for compounds (+)-110, (+)-111,(+)-115, and (+)-122 in the aristolane series,134 and weak to noactivity (78.4 to >100 μM) was observed for cyclolauranes(+)-312, (−)-320, and (−)-325.310 (+)-Suberosenone 253 wasshown to have in vivo antitumor activity (IC50 = 2 μM), while itsdimer (+)-alertenone 261 exhibited a lowest cytotoxicity (IC50 =91.6 μM) against MCF7 cell line, implanted subcutaneously, andintraperitoneally in mice, as well as against A549, HOP-92, SF-295, SF539, SNB19, LOX, M14, MALME-31, and OVCAR celllines (IC50 = 79.6 to >227.5 μM).258 The latter was presented as astorage nontoxic form of (+)-suberosenone 253, which could bea chemical defensive agent of the gorgonian.(−)-Hirsutanol A 15 was shown to have good antitumor

activities toward MDA-MB-231 (ED50 = 5.4 μM), MDA-MB-435 (ED50 = 1.8 μM), and MDA-MB-453 (ED50 = 4.4 μM) celllines, while its analogs (−)-18 and (+)-19 exhibited no activity(ED50 > 200 μM) against these cell lines.42

The nitrogenous aromadendrane (+)-195 exhibited very weak(IC50 = 94.2 μM) activity against the human breast carcinomaMDA-MB-231 cell line.216 The bridged tricyclic structure(−)-philippinlin A 213 tested against this cell line showedweak activity (IC50 = 69 μM), while its analogs (+)-lemnalol 206

and (+)-philippinlin B 214 showed no activity.223 (+)-Sub-erosane alkaloid 259 showed moderate cytotoxicity (IC50 = 23.1μM),255 whereas its purine analogue (+)-260 showed weakcytotoxicity (data not provided) toward the same cell line.256

Moderate activity (38.8 and 47 μM) for compounds (+)-301and (−)-310 and low activity (ED50 > 60 μM) for compound(−)-65 were determined in the breast cancer cell line, ZR-75-1.312

Capnellenes (+)-32 and (+)-34 showed weak (IC50 = 51 and68 μM) to good activities (IC50 = 0.7 and 4.6 μM) against humanleukemia HL-60 and K562 cell lines, respectively (Table 3).55

The activity of (+)-Δ9(12)-capnellene-8β,10α-diol 32 was never-theless not confirmed later (GI50 = 67.4± 2.5 μM) in a study alsoshowing that capnellenes (−)-41 (GI50 = 70.9 ± 2.7 μM) and(+)-47 (GI50 = 62.2 ± 2.7 μM) exhibited weak cytotoxicitieswhile (+)-45 (GI50 = 126.9 ± 0.2 μM), (+)-46 (GI50 = 142.0 ±4.7 μM), and (−)-48 (GI50 = 126.9 ± 3.0 μM/l) were not activetoward K562 cell lines.58 Their analog (+)-3β-acetoxycapnel-lene-8β,10α,14-triol 35 showed moderate (IC50 = 24 μM) andno activity (IC50 = 713 μM) against human K562 and HL-60leukemia cell lines, respectively.55 Compounds (+)-110 and(+)-122 proved to bemoderately effective (LC50 = 22.7 μM) and(−)-111 and (+)-115 not active against human ATL cell line,134

and no activity (>100 μM) was noted for (−)-65 and (−)-310toward human BC-1 cell line.312

Aromadendranes (+)-160−(+)-162186 and aristolanes(+)-110, (−)-111, (+)-115, and (+)-122 were reported asweakly or noncytotoxic (>100 μM) to murine P-388 cell line.134

Derivatives (+)-5, (+)-6,32 and (−)-838 proved to be goodantileukemic agents with ED50 values in the range of 1.3−12.8μM against murine cancer cell line P-388, while (−)-subergorgicacid 5666 and (−)-debilon 119131 exhibited a weaker activity(>50 μM) toward the same cell line. In the ylangane series,(−)-lemnalol 206 once again showed moderate activity towardthis cell line (ED50 = 16.3 μM) in comparison with its congeners208−210, which were found inactive.221 Excellent activities

Table 2. Antitumor Activities toward Human Breast Cancer Cell Lines


MCF7 (−)-15 ED50 = 2.55 ± 0.41 μg/mL (10.4 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-27 IC50 = 4.57 μM,50 (+)-32 IC50 = 93 μM,(+)-34 IC50 > 4500 μM, (+)-35 IC50 = 1029 μM,55 110 and 122 LC50 = 25 μg/mL (113.4 μM), 111 and 115 no activity,134 (+)-253 IC50 = 0.43 μg/mL (2 μM), (+)-261 IC50 = 40 μg/mL (91.6 μM),258 (+)-312 IC50 = 104.1 μM, (−)-320 IC50 = 86.3 μM, (−)-325 IC50 > 300 μM310

MDA-MB-231 (−)-15 ED50 = 1.34± 0.19 μg/mL (5.4 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-195 IC50 94.2 μM,216 (−)-213 IC50 = 16.3 μg/mL (69 μM), (+)-206 and (+)-214 no activity,223 (+)-259 IC50 = 8.87 μg/mL (23.1 μM)255

MDA-MB-435 (−)-15 ED50 = 1.82 ± 0.37 μg/mL (7.4 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM)42

MDA-MB-453 (−)-15 ED50 = 1.08 ± 0.10 μg/mL (4.4 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM)42

ZR-75-1 (−)-64 inactive, (−)-65 ED50 = 10.4 μg/mL (46.8 μM), (+)-301 ED50 > 20 μg/mL (>60 μM), (−)-310 ED50 = 8.4 μg/mL (38.8 μM)312

Table 3. Cytotoxic Activities toward Human and Mouse Leukemia Lymphoma Cancer Cell Lines

cell types cell lines cytotoxic activities

human HL-60 (+)-32 IC50 = 51 μM, (+)-34 IC50 = 68 μM, (+)-35 IC50 = 713 μM55

human K562 (+)-32 IC50 = 0.7 μM, (+)-34 IC50 = 4.6 μM, (+)-35 (IC50 = 24 μM),55 (+)-32 GI50 = 67.4 ± 2.5 μM, (−)-41 GI50 = 70.9 ± 2.7 μM, (+)-47 GI50 =62.2 ± 2.7 μM, (+)-45 GI50 = 126.9 ± 0.2 μM, (+)-46 GI50 = 142.0 ± 4.7 μM, (−)-48 GI50 = 126.9 ± 3.0 μM58

human ATL (+)-110 and (+)-122 LC50 = 5 μg/mL (22.7 μM), (−)-111 and (+)-115 no activity134

human BC-1 (−)-64 inactive, (−)-65 and (−)-310 ED50 > 20 μg/mL (>100 μM)312

murine P-388 (+)-5 ED50 = 0.3 μg/mL (1.3 μM), (+)-6 ED50 = 2.8 μg/mL (1.4 μM),32 (−)-8 ED50 = 3.03 μg/mL (12.8 μM),38 (−)-56 ED50 = 13.3 μg/mL (53.6μM),66 (−)-119 IC50 = 13.0 μg/mL (55.5 μM),131 (+)-110 and (+)-122 LC50 = 25 μg/mL (113.5 μM), (−)-111 and (+)-115 no activity,134 (+)-160−(+)-162, (−)-326 no activity,186 (−)-206 ED50 = 16.3 μM, 208−210 ED50 > 100 μM,221 (−)-254 ED50 < 5.0 × 10−6 μg/mL (<22.7 × 10−6 μM),(−)-255 ED50 < 3.4 μg/mL (15.4 μM), (−)-256 ED50 = 7.6× 10−3 μg/mL (29× 10−3 μM), (−)-257 ED50 = 7.4× 10−2 μg/mL (0.3 μM), (−)-258 ED50< 5.0× 10−6 μg/mL (<22.7× 10−6 μM).66 (−)-65 ED50 > 5 μg/mL (>22.5 μM), (+)-301 ED50 = 2.8 μg/mL (8.4 μM), (−)-310 ED50 > 5 μg/mL (>22.1μM)312

murine L1210 (+)-130 ED50 = 4.1 μg/mL (10.6 μM), (+)-200 ED50 = 3.7 μg/mL (9.6 μM)143

murine MOLT-3 (+)-195 IC50 = 57 μM216

murine L5178Y (−)-215 ED50 = 8.4 μg/mL (33.3 μM), (−)-217 ED50 = 6.8 μg/mL (25.5 μM)227



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toward murine P-388 cell line were observed in the suberosaneseries for (−)-suberosenone 254 (ED50 < 0.023 nM),(−)-suberosenol B acetate 256 (ED50 = 29 nM), (−)-sub-erosenol A acetate 257 (ED50 = 0.3 μM), and (−)-suberosanone258 (ED50 < 0.023 nM), while (−)-suberosenol A 255 (ED50 <15.4 μM) was only moderately cytotoxic.66 Eventuallycompounds (+)-301 (ED50 = 8.4 μM), (−)-65, and (−)-310(ED50 > 20 μM) showed good to moderate activity against thiscell line.312

(+)-Epipolasin-A thiourea 130 and (+)-epipolasin-B thiourea200, differing by their structures but with the same thioureagroup, were shown to have good in vitro cytotoxic activities(ED50 = 9.6−10.6 μM) toward L1210.143 The formamidoaromadendrane (+)-195 has a moderate activity (IC50 = 57 μM)against MOLT-3 cells.216

Sesquiterpenes (−)-215 and (−)-217 were found to bemoderately active against L5178Y cells with ED50 values of 33.3and 25.5 μM, respectively.227

Among the tricyclic sesquiterpenes of marine origin testedagainst human epidermoid KB cancer cell line, hirsutanes(+)-27,50 (+)-32,59 and (−)-silphiperfolane 65312 were moder-ately active (25.6−46 μM), while compounds (−)-1 and(+)-6,325 (−)-141, (−)-291, and (+)-292,153 and (+)-301 and(−)-310312 were inactive (ED50 or IC50 > 60 μM) (Table 4).Compound (−)-65 was also slightly active (46 μM), but (−)-64and (+)-301 were inactive against the human epidermoid A431

cell line.312 In the cyclolaurane series, compound (−)-310showed a moderate cytotoxic activity (ED50 = 35.6 μM)312

contrary to (+)-312, (−)-320, and (−)-325, which were foundinactive (ED50 > 90 μM) in this cell line.310

Hirsutanes (−)-18 and (+)-19, lacking an electrophilic α-methylene cyclopentenone group, were inactive (ED50 > 200μM) toward nasopharyngeal (CNE1, CNE2,50 and SUNE 142)and lung cancer (A549)42 cell lines, while the correspondingclose analogs (−)-15, (+)-20, and (+)-27 bearing this motifdemonstrated good cytotoxic activities against the last cell linewith ED50 or IC50 in the range of 2.4−12.4 μM

42,45,50 (Table 4).Against A549 cancer cell line, compounds (+)-195,216 (−)-206,and (+)-214223 were not cytotoxic (IC50 > 100 μM) andcompounds (−)-91, (+)-92,98 and (−)-213223 showed weakcytotoxic activity with IC50 values >10 μM. The nitrogeneousaromadendrane (+)-192 provided good cytotoxicity (IC50 = 7.5μM) against this cell line,212 but the most efficient compoundstoward this cell line were found in the suberosane series, withexcellent to good activities found for (−)-254 (ED50 = 23.1 nM),(−)-255 (ED50 = 0.9 μM), (−)-256 (ED50 = 0.3 μM), (−)-257(ED50 = 1.4 μM), and (−)-258 (ED50 = 23.1 μM).66

(+)-Suberosenone 253 showed moderate (IC50 = 7.5 μM) topotent cytotoxic (IC50 = 0.5 μM) activity toward A549 andHOP-92 cell lines, respectively.258

Table 4. Cytotoxic Activities toward Human Epidermoid, Nasopharyngeal, and Lung Cancer Cell Lines


epidermoid KB (+)-27 IC50 = 28.55 μM,50 (+)-32 IC50 = 6.06 μg/mL (25.6 μM),59 (−)-141 ED50 > 20 μg/mL (>90 μM), (−)-291 and (+)-292 ED50 > 20 μg/mL (>85μM),153 (−)-1 and (+)-6 IC50 > 20 μg/mL (>98 μM),325 (−)-64 inactive, (−)-65, ED50 = 10.4 μg/mL (46 μM), (+)-301 and (−)-310ED50 > 20 μg/mL (>60μM)312

epidermoid A431 (−)-64 inactive, (−)-65 ED50 = 6.9 μg/mL (46 μM), (+)-301 ED50 > 20 μg/mL (>60 μM), (−)-310 ED50 = 7.7 μg/mL (35.6 μM),312 (+)-312 IC50 = 93.4μM, (−)-320 IC50 = 92.4 μM, (−)-325 IC50 > 300 μM310

nasopharyngealCNE1

(−)-15 ED50 = 2.48 ± 0.32 μg/mL (10.1 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 27 IC50 = 8.33 μM50

nasopharyngealCNE2

(−)-15 ED50 = 3.13 ± 0.29 μg/mL (12.7 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-20 IC50 = 4.95 μM,45 (+)-27 IC50 = 6.07 μM50

nasopharyngealSUNE1

(−)-15 ED50 = 0.87 ± 0.10 μg/mL (3.5 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 27 IC50 = 3.99 μM50

lung A549 (−)-15 ED50 = 2.97 ± 0.31 μg/mL (12.1 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-20 IC50 = 2.45 μM,45 27 IC50 = 12.37 μM,50 (−)-91and (+)-92 IC50 values > 10 μM,98 (+)-192 IC50 = 1.98 μg/mL (7.5 μM),212 (+)-195 IC50 > 100 μM,216 (−)-213 IC50 = 15.8 μg/mL (66.8 μM), (−)-206 and(+)-214 no activity,223 (+)-253 IC50 = 1.63 μg/mL (7.5 μM), (+)-261 IC50 = 40 μg/mL (91.6 μM),258 (−)-254 ED50 = 5.1× 10−3 μg/mL (23.1 × 10−3 μM),(−)-255 ED50 = 0.2 μg/mL (0.9 μM), (−)-256 ED50 = 8.0 × 10−2 μg/mL (0.3 μM), (−)-257 ED50 = 0.36 μg/mL (1.4 μM), (−)-258 ED50 = 3.6 × 10−2 μg/mL (0.2 μM)66

lung HOP-92 (+)-253 IC50 = 0.11 μg/mL (0.5 μM), (+)-261 IC50 = 45 μg/mL (103 μM)258

lung Lu1 (−)-64 inactive, (−)-65 and (−)-310 ED50 > 20 μg/mL (>90 μM), (+)-301 ED50 > 20 μg/mL (>60 μM)312

Table 5. Cytotoxic Activities toward Human and Murine CNS, Melanoma, Cholangiocarcinoma, and Glioblastoma Cancer CellLines

cancer type cell lines cytotoxic activities

CNS SF295a (+)-253 IC50 = 0.03 μg/mL (0.14 μM), (+)-261 IC50 = 35 μg/mL (79.6 μM)258

CNS SF539a (+)-253 IC50 = 0.002 μg/mL (9.2 × 10−3 μM), (+)-261 IC50 = 35 μg/mL (79.6 μM)258

CNS SNB19a (+)-253 IC50 = 0.006 μg/mL (27.5 × 10−3 μM), (+)-261 IC50 = 45 μg/mL (102.4 μM).258

glioblastoma U-373a (+)-301 ED50 > 20 μg/mL (>60 μM), (−)-310 ED50 > 20 μg/mL (>90 μM)312

medulloblastoma Daoya (−)-141 ED50 > 20 μg/mL (>90 μM), (−)-291 and (+)-292 ED50 > 20 μg/mL (>85 μM)153

melanoma LOXa (+)-253 IC50 = 0.006 μg/mL (27.5 × 10−3 μM), (+)-261 IC50 > 100 μg/mL (>227.5 μM)258

melanoma M14a (+)-253 IC50 = 0.010 μg/mL (45.8 × 10−3 μM), (+)-261 IC50 = 40 μg/mL (91.6 μM)258

melanoma MALME-3Ma (+)-253 IC50 = 0.008 μg/mL (36.6 × 10−3 μM), (+)-261 IC50 = 40 μg/mL (91.6 μM)258

melanoma Mel-2a (−)-64 inactive, (−)-65 ED50 = 12.1 μg/mL (54.4 μM), (+)-301 ED50 > 20 μg/mL (>60 μM), (−)-310 ED50 = 4.6 μg/mL(21.3 μM)312

melanoma B16b (−)-15 IC50 = 25.6 μM, (−)-17 IC50 > 200 μM, (+)-27 IC50 = 14.4 μM44

cholangiocarcinoma HuCCA-1a (+)-195 IC50 > 100 μM216

aHuman cell line. bMurine cell line.



6128


Compounds (−)-64, (−)-65, (+)-301, and (−)-310 exhibitedno activity, with ED50 > 60 μM against the lung Lu1 cell line(Table 4).312

(−)-Paralemnanol 141, (−)-paralemnanone 291, and(−)-isoparalemnanone 292 were found to be noncytotoxicagainst KB (Table 4), human medulloblastoma Daoy (Table 5),HeLa, and human liver carcinoma Hepa59T/VGH (Table 6)(ED50 > 20 μg/mL).153

(+)-Suberosenone 253, despite its great instability, was shownto display excellent cytotoxicity toward human CNS (SF295,SF539, SNB19) and melanoma (LOX, M14, MALME-3M)cancer cell lines with IC50 from 9.2 nM to 0.14 μM (Table 5).258

Moderate and no activity against melanoma Mel-2 werereported for (−)-310 (ED50 = 21.3 μM), (−)-65 (ED50 = 54.4μM), and (+)-301 (ED50 > 60 μM) (Table 5).312

(−)-Hirsutanol A 15 and (+)-incarnal 27, incorporating anelectrophilic α-methylene cyclopentenone motif, exhibitedmoderate antiproliferative activity toward murine B16melanomacells (IC50 = 25.6 μM), while their analog (−)-hirsutanol C 17was inactive against the same cell line (IC50 > 200 μM) (Table5).44

Nitrogenous aromadendrane (+)-195was inactive (IC50 > 100μM) against human HuCCA-1 cell line.216 (−)-Paralemnanol141, (−)-paralemnanone 291, and (−)-isoparalemnanone 292were shown to be noncytotoxic against human medulloblastomaDaoy (ED50 > 85 μM)153 as well as (+)-301 and (−)-310 (ED50> 85 μM) against glioblastoma U-373 cancer cell lines (Table5).312

(−)-Hirsutanol A 15 exhibited good to moderate activitytoward human hepatic Hep3B, HepG2, and Bel-7402 cancer celllines with ED50 or IC50 values varying from 3.6 to 24.8 μM(Table6) contrary to its analogs (−)-18 and (+)-19 (ED50 > 200 μM).42

Weak activities were reported for nitrogenous aromadendrane(+)-195 (IC50 = 66.2 μM)216 and (−)-213 (IC50 = 67.7 μM),223

and no activities were reported for (−)-lemnalol 206 and(+)-philippinlins-B 214 against human cancer hepatic HepG2cell lines223 (Table 6). When submitted for a cytotoxicity assayagainst the cancer cell line BEL7402, aristolanes 104−111 werefound to be inactive (IC50 > 40 μM).124 Compounds (+)-27(IC50 = 23.4 μM), (−)-91, and (+)-92 (IC50 > 10 μM)98 showedmoderate to weak activity against the same cell line.Compounds (−)-141, (−)-291, and (+)-292were found to be

noncytotoxic toward hepathic Hepa59T/VGH cell line,153 aswell as (−)-168−(−)-172 against SK-Hep1cell line (Table 6).192Capnellenes diol (+)-32 and triol acetate (+)-35 showed

moderate activities (IC50 = 42−52 μM) toward human renalG402 cancer cell line (Table 6), while the corresponding alcohol(+)-34was inactive (IC50 > 4.5 mM).55 Better results were foundfor these compounds toward human ovarian A2780 cancer cellline with IC50 values ranging between 6.6 and 32 μM.55

Compound (+)-253 was the only tricyclic sesquiterpene ofmarine origin tested against ovarian OVCAR cancer cell line,showing an excellent cytotoxic activity (IC50 = 91.6 nM).258

Dimer (−)-325 appeared inactive (IC50 > 300 μM) towardprostate PC3 and cervical HeLa cell lines, while compounds(+)-312 and (−)-320 were reported to be weakly active towardPC3 (IC50 = 75.2 and 88.5 μM, respectively) and HeLa (IC50 =114.6 and 81.4 μM, respectively) cell lines (Table 6).310

Compounds (−)-64, (−)-65, (+)-301, and (−)-310 exhibitedno cytotoxic activity toward prostate LnCaP cell line with ED50 >60 μM.312

Concerning cervical cancer HeLa cell line, (+)-Δ9(12)-capnellene-8β,10α-diol 32,59 acetylated capnellene (−)-41,58 Table6.CytotoxicActivitiestowardHum

anHepatic,R

enal,O

varian,P

rostate,andCervicalC

ancerCellL

ines

cancer

type

celllines

cytotoxicactivities

hepatic

Hep3B

(−)-15

ED50=0.90

±0.19

μg/m

L(3.6μM

),(−

)-18

and(+)-19

ED50>50

μg/m

L(>200μM

)42

hepatic

HepG2

(−)-15

IC50=2.49

±0.13

μg/m

L(10.1μM

),(−

)-18

and(+)-19

ED50>50

μg/m

L(>200μM

),42(+)-195IC

50=66.2μM

,216(−

)-213IC

50=16.0μg/m

L(67.7μM

),206and(+)-214no

activity

223

hepatic

Bel-7402

(−)-15

IC50=6.11

±0.41

μg/m

L(24.8μM

),(−

)-18

and(+)-19

ED50>50

μg/m

L(>200μM

),42(+)-27

IC50=23.36μM

,50(−

)-91

and(+)-92

IC50>10

μM,98

(+)-104IC

50>10

μg/m

L(>42

μM),(+)-105,106,109and(−

)-111IC

50>10

μg/m

L(>46

μM),107and108IC

50>10

μg/m

L(>49

μM),(+)-110IC

50>10

μg/m

L(>45

μM)124

hepatic

Hepa59T

/VGH

(−)-141ED

50>20

μg/m

L(>90

μM),(−

)-291and(+)-292ED

50>20

μg/m

L(>85

μM)153

hepatic

A435

(+)-260weakactivity

256

hepatic

SK-H

ep1

(−)-168−

(−)-172no

activity

192

renal

G402

(+)-32

IC50=42−51

μM,(+)-34IC

50>4.5mM,(+)-35IC

50=52

μM55

ovarian

A2780

(+)-32

IC50=9.7μM

,(+)-34IC

50=6.6μM

,(+)-35IC

50=32

μM,55

(−)-91

and(+)-92

IC50>10

μM98

ovarian

OVCAR-3

(+)-253IC

50=0.02

μg/m

L(91.6×10

−3μM

)258

prostate

PC3

(+)-312IC

50=75.2μM

,(−)-320IC

50=88.5μM

,(−)-325IC

50>300μM

310

prostate

LnCaP

(−)-64

inactive,(−

)-65

and(−

)-310ED

50>20

μg/m

L(>90

μM),(+)-301ED

50>20

μg/m

L(>60

μM)312

cervical

HeLa

(−)-15

ED50=8.27

±0.71

μg/m

L(33.6μM

),(−

)-18

and(+)-19

ED50>50

μg/m

L(>200μM

),42(+)-32

CC50=7.6±0.8μM

,58(+)-32

IC50=3.56

μg/m

L(15.1μM

),5941

CC50=9.4±1.0μM

,45−48

CC50>125μM

,58(−

)-57

ED50=4.3μg/m

L(16.4μM

),314(+)-110,(−

)-111,(+)-115and(+)-122no

activity,134(−

)-87

IC50=57.8μM

,94(−

)-141ED

50>20

μg/m

L(>90

μM),(−

)-291

and(−

)-292ED

50>20

μg/m

L(>85

μM),153(+)-163and(−

)-164IC

50>200μg/m

L(>840μM

),188(−

)-168−

(−)-172no

activity,192(+)-195IC

50=96.2μM

,214215-217no

activity,227(+)-310

IC50=18

μg/m

L(83.2μM

),(−

)-318IC

50>50

μg/m

L(>193μM

).301(+)-312IC

50=114.6μM

,(−)-320IC

50=81.4μM

,(−)-325IC

50>300μM

310

cervical

KB-V1

(−)-64

inactive,(−

)-65

(parentcellline)

8.0μg/m

L(36μM

),(drugresistantcellline)

5.5μg/m

L(24.7μM

),(+)-301ED

50>20

μg/m

L(>60

μM),(−

)-310ED

50>20

μg/m

L(>90

μM)312



6129


and (−)-methyl subergorgate 57314 provided good activity withED50 values between 7.6 and 16.4 μM, while metabolites(−)-87,94 (+)-195,216 and (+)-310301 were found to displayweak cytotoxicity (IC50 = 57.8, 96.2, and 83 μM). Compounds(−)-18, (+)-19,42 (+)-45−47, (−)-48,58 (+)-110, (−)-111,(+)-115, (+)-122,134 (−)-141,153 (+)-163, (−)-164,188(−)-168−172,192 (−)-215-217,227 (−)-291, (+)-292,153 and(−)-318301 exhibited no activity against this cell line (Table 6).Compound (−)-65 was reported as being moderately active

against cervical KB-V1 cell line (24.7−36 μM), while (−)-64,(+)-301, and (−)-310 had no activity toward this cell line (ED50> 60 μM) (Table 6).312

Good to weak activities were detected for (+)-32 (GI50 = 6.8±0.8 μM/l), (−)-41 (GI50 = 20.9 ± 1.1 μM), and (+)-47 (GI50 =99.1 ± 1.8 μM) toward murine fibroplast L-929 cell line (Table7).58 Compound (+)-144 was shown to possess moderateactivity against EAC and DLAT cell lines,159 while (+)-153 had agood activity against EAC.181

As described above, the great diversity of suberosanecompounds displaying impressive cytotoxic activities towardseveral different cell lines (A-549, HOP-92, SF-295, SF-539,SNB-19, LOX, M14, MALME-3M, OVCAR-3, and MCF7)could be questionable owing to the fundamental functionalmodifications generated from one structure to another, implyingin particular the alternate presence and absence of stereogeniccenters in the C2 and C3 positions, suggesting a highly selectiveenzymatic cellular target. Contrary to the previous reportedresults,66,255,258 (−)-suberosanone 258 was recently shown313 tohave no significant toxicity toward HL60, KB, MCF7, MCR5,A549, and HT29 cell lines.Eventually it was also shown that (−)-hirsutanol A 15

significantely inhibited tumor growth through induction ofapoptosis and autophagic cell death by increasing reactive oxygenspecies.314−316

3.2. Antibacterial Activity

The study of natural products, especially from terrestrial plantsand fungi, has long been the source of antibiotic compounds. Thetricyclic all-carbon sesquiterpene structures of marine originwere less tested for their antibacterial activities. Assessment oftheir antimicrobial action by the classical methods used the diskmethod (expressed as inhibition zone diameter inmillimeters at agiven concentration for the disc impregnation: in millimeters at agiven weight of tested compound in grams)317 and themicrodilution method or the agar well diffusion method(expressed as minimum inhibitory concentration (MIC) inconcentration unit for 24 or 48 h incubation or minimumbactericidal concentration (MBC) in concentration unit).318

(−)-Hirsutanols A 15 and F 18were found to be active againstBacillus subtilis.41 Hirsutanols A 15 and C 17 and (+)-incarnal 27showed no activity toward B. subtilis, Staphylococcus aureus, andEscherichia coli (MIC > 100 μM)44 in contradiction with previous

results which showed an activity of (+)-incarnal 27 toward theseorganisms (respectively, 51.2, 25.6, and >400 μM).49 (−)-Sub-ergorgic acid 56 was reported to be active against Proteus vulgarisand E. coli at 200 μg mL−1 without further detail.64 It was also,with its reduced form 62, their analogs 58−62, and(−)-suberosenol A 254, evaluated against several bacteria,70

including Gram-negative ones (Xanthomanes vesicatoria, Pseudo-monas lachrymans, Agrobaterium tumefaciens, and Ralstoniasolanacearum), and Gram-positive bacteria (Bacillus thuringensis,S. aureus, B. subtilis, and Staphylococcus hemolyticus) with MICvalues ranging from 16 to >128 μg/mL (Table 8).Silphiperfolanes (−)-58 and (−)-59 specifically inhibited S.aureus, whereas the corresponding analogs bearing a carboxylicacid at C13 such as 56, 60, and 61 were inactive (MIC > 128 μg/mL), thus showing the importance of the methyl ester unit in theinhibitory effect against this bacteria. Subergorgiol 62 inhibitedall these bacteria with MIC ranging from 16 to 32 μg/mL, whilesuberosane 254 showed good to moderate activities against X.vesicatoria, A. tumefaciens, S. aureus, Bacillus thuringiensis, and B.subtilis with 16 < MIC < 64 μg/mL and no activity (NA) towardP. lachrymans, R. solanacearum, and S. hemolyticus with MIC >128 μg/mL.70 (−)-Cycloeudesmol 69 was found to significantlyinhibit S. aureus 12600 and to possess in vitro activity againstSalmonella choleraesuis, Mycobacterium smegmatis, and Candidaalbicans but no activity against E. coli.319

Compound 64 was found to be inactive againstM. bovis BCG(IC50 = 204.6 ± 7.6 μM),320 Bacillus megaterium, and E. coli.76

The methanol fraction of L. complanata containing (−)-de-bilon 119 was reported to possess antimicrobial activity againstBacillus cereus, S. aureus, Streptococcus pneumoniae, and C.albicans.132 (+)-Palustrol 153 showed antimicrobial activities(Table 8) against S. pneumoniae, Staphylococcus epidermidis,Micrococcus spp., methicillin-resistant S. aureus (MRSA), Micro-coccus spp., Acinetobacter spp., Klebsiella pneumoniae, Pseudomo-nas aeruginosa, and E. coli.181 Since separation of pupukeananeepimers 230 and 231 was not successful, they were tested as amixture and found to be weakly and moderately active against B.subtilis and C. albicans at a dose level of 20 μg, respectively.240

The alcohol (−)-273was shown to inhibit the growth of S. aureusat 100 μg/disk.273

Compounds (+)-110 and (+)-122 showed moderate (MIC =50 and 20 μg/disc, respectively) activities toward S. aureus andStreptococcus pyrogenes, respectively, while their analogs (−)-111and (+)-115 showed no activity against these bacteria.134

Metabolite (+)-115 was alone in this series to present a lowactivity toward Staphylococcus sp. (MIC= 75 μg/disc).Compound (+)-111 showed low activity (MIC = 150 μg/disc), and compounds (+)-110, (+)-115, and (+)-122 showedno activity against Salmonella enteritidis.134

(−)-Debromolaurinterol 310 and its acetate (−)-318 werefound to be active against S. aureus at 50 μg/disk.301

(−)-Debromolaurinterol 310 was found to exhibit completeinhibition after 48 h of S. aureus and C. albicans at 10−30 μg/mLand M. smegmatis at 10−50 μg/mL and has no effect on theculture of Salmonella coleraesuis or E. coli up to 1 mg/mL.319

Compounds (−)-91 and (+)-92 showed weak inhibitory effectsagainst the bacterial strains of E. coli, S. aureus, B. thuringensis, andB. subtilis with MIC values more than 125 μM.98 Compounds(+)-288 and (+)-289 showed no potent activity against humanand aquapathogenic microbes Aeromonas hydrophila, Edward-siella tarda, E. coli, S. aureus, Vibrio alginolyticus, V. anguillarum, V.harveyi, and V. parahemolyticus with MIC > 64 μg/mL.278

Table 7. Cytotoxic Activities towardMurine Fibroblast L-929,Ehrlich Ascites Carcinoma (EAC), and Dalton’s LymphomaAscites Tumor (DLAT) Cell Lines


L-929 (+)-47 GI50 = 99.1 ± 1.8 μM, (+)-32 GI50 = 6.8 ± 0.8 μM, (−)-41GI50 = 20.9 ± 1.1 μM58

EAC (+)-144 ED100 = 10 μg/mL (48.9 μM)159

(+)-153 LD50 = 2.8 μM181

DLAT (+)-144 ED100 = 10 μg/mL (48.9 μM)159



6130


Table 8. Antibacterial Activitya

microorganism antibacterial activities

B. subtilis sp. (−)-15 and (−)-18 NA at 200 μg/disc,41 230/231 (30:70) WA,240 (−)-310 10 mm at 50 μg/disk, (−)-318 6 mm at 50 μg/disk,301 (−)-91 and(+)-92 MIC > 125 μM98

B. subtilis ATCC6633

(+)-27 MIC = 51.2 μM49

B. subtilis ATCC70385

(−)-15, (−)-17 and (+)-27 MIC > 100 μM44

B. subtilis CMCC63501

(−)-56 MIC > 16 μg/mL (>64.4 μM), (−)-58 MIC > 16 μg/mL (>60 μM), (−)-59 MIC > 16 μg/mL (>52 μM), (−)-60 MIC > 16 μg/mL(>64 μM), (−)-61 MIC > 16 μg/mL (>55 μM), 62 MIC = 16 μg/mL (72.6 μM), (−)-254 MIC = 63 μg/mL (285.9 μM)70

B. megaterium (−)-64 no activity76

S. aureus sp. (+)-153 11 ± 1.0 mm,181 230/231 (30:70) no activity,238 (−)-273 active at 100 μg/disk,273 (−)-91 and (+)-92 MIC > 125 μM,98,314 (+)-110and (−)-111 MIC = 50 μg/disk (+)-115 and (+)-122 no activity,134 (+)-273 > 64 μg/mL (>270 μM), (+)-274 MIC > 64 μg/mL (>230μM).278 115 MIC = 75 μg/disk, (+)-110, (−)-111 and (+)-122 no activity134

S. aureus FDA 209P (+)-27 MIC = 25.6 μM49

S. aureus ATCC25923

(−)-56MIC > 16 μg/mL (>64.4 μM), (−)-58MIC = 16 μg/mL (60 μM), (−)-59MIC = 8 μg/mL (26.1 μM), (−)-60MIC > 16 μg/mL (>64μM), (−)-61 MIC > 16 μg/mL (>55 μM), 62 MIC = 16 μg/mL (72.6 μM), (−)-254 MIC = 64 μg/mL (290 μM)70

S. aureus 12600 (−)-69 MIC 48 h = 10−50 μg/mL (45−225 μM), (−)-310 MIC 48 h = 10−30 μg/mL (46−138 μM)319

S. aureus ATCC11632

(−)-119 6 mm132

S. aureus 6538 (−)-15, (−)-17 and (+)-27 MIC > 100 μM,44 (−)-310 MIC 48 h = 10−30 μg/mL (46−138 μM)319

MRSA (+)-153 8 ± 1.4 mm181

Streptococcuspyogenes

(+)-110 and (−)-111 MIC = 20 μg/disk, (+)-115 and (+)-122 no activity.134

X. vesicatoria ATCC11633


P. lachrymansATCC 11921

(−)-56 MIC > 16 μg/mL (>64.4 μM), (−)-58 MIC > 16 μg/mL (>60 μM), (−)-59 MIC > 16 μg/mL (>52 μM), (−)-60 MIC > 16 μg/mL(>64 μM), (−)-61 MIC > 16 μg/mL (>55 μM), 62 MIC = 32 μg/mL (145.2 μM), (−)-254 MIC > 16 μg/mL (>72 μM)70

A. tumefaciensATCC 11158


R. solanacearumATCC 11696 andATCC 11696

(−)-56 MIC > 16 μg/mL (>64.4 μM), (−)-58 MIC > 16 μg/mL (>60 μM), (−)-59 MIC > 16 μg/mL (>52 μM), (−)-60 MIC > 16 μg/mL(>64 μM), (−)-61 MIC > 16 μg/mL (>55 μM), 62 MIC = 16 μg/mL (72.6 μM), (−)-254 MIC > 16 μg/mL (>145.2 μM)70

B. thuringiensis NS (−)-91 and (+)-92 MIC > 125 μM98

B. thuringiensisATCC 10792


S. hemolyticusATCC 29970

(−)-56 MIC > 16 μg/mL (>64.4 μM), (−)-58 MIC > 16 μg/mL (>60 μM), (−)-59 MIC > 16 μg/mL (>52 μM), (−)-60 MIC > 16 μg/mL(>64 μM), (−)-61 MIC > 16 μg/mL (>55 μM), 62 MIC = 16 μg/mL (72.6 μM), (−)-254 MIC > 16 μg/mL (>145.2 μM)70

S. enteritidis (−)-111 MIC = 150 μg/disk, (+)-110, (+)-115 and (+)-122 no activity.134

S. choleraesuis (−)-69 MIC 48 h = 50−100 μg/mL (225−450 μM), (−)-310 MIC 48 h > 1000 μg/mL (>4600 μM)319

M. smegmatis (−)-69 MIC 48 h = 10−50 μg/mL (45−225 μM), (−)-310 MIC 48 h = 10−50 μg/mL (46−231 μM)317

C. albicans 10231 (−)-69 MIC 48 h = 10−50 μg/mL (45−225 μM), (−)-310 MIC 48 h = 10−50 μg/mL (46−231 μM)319

C. albicans CA-5 (−)-310 MIC 48 h = 10−30 μg/mL (46−138 μM)319

C. albicans NS 230/231 (30:70) MA240

B. cereus ATCC13061

(−)-119 7.5 mm132

S. pneumoniae NS (+)-153 10 ± 1.1 mm181

S. pneumoniaeATCC 6301

(−)-119 6 mm132

S. epidermidis (+)-153 8 ± 1.2 mm181

Micrococcus spp. (+)-153 8 ± 0.5 mm181

Acinetobacter spp. (+)-153 8 ± 1.12 mm181

K. pneumoniae (+)-153 11 ± 1.0 mm181

P. aeruginosa (+)-27 MIC > 100 μg/mL (>400 μM),49 (+)-153 10 ± 0.5 mm181

A. hydrophila (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278

V. alginolyticus (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278

V. anguillarum (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278

V. harveyi (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278

V. parahemolyticus (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278

E. tarda (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278

E. coli (+)-27 MIC > 400 μM,49 (−)-64 no activity,76 (+)-153 11 ± 1.0 mm,181 (−)-310 MIC 48 h > 1000 μg/mL (>4600 μM),319 (−)-91 and(+)-92 MIC > 125 μM,98 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM),278 (+)-311 MIC = 5 μg/disk321

E. coli ATCC 8739 (−)-15, (−)-17 and (+)-27 MIC > 100 μM44

E. coli NIHJ JC-2 (+)-27 MIC > 100 μg/mL (>409 μM)49

A. agilis (+)-311 (MIC = 5 μg/disk)321

Alteromonas sp. (+)-311 (MIC = 5 μg/disk)321

A. beijerinckii (+)-311 (MIC = 15 μg/disk)321

E. amylovora (+)-311 MIC = 5 μg/disk)321



6131


Compound (+)-311 was found to display a marked antibioticactivity against S. aureus283 and a potent one against B. subtilis,303

but no experimental details were furnished. It was also shown todisplay activity against Alteromonas sp. (MIC = 5 μg/disk),Azomonas agilis (MIC = 5 μg/disk), Azobacter beijerinckii (MIC =15 μg/disk), Erwinia amylovora MIC = 5 μg/disk), and E. coli(MIC = 5 μg/disk) and no activity toward Alcaligenesaquamarines, Halobacterium sp., and Halococcus sp.321

3.3. Other Biological Activities

(−)-Subergorgic acid 56was shown to inhibit larval settlement ofBalanus amphitrite and the bryozoan Bugula neritina with EC50values of 1.2 and 3.2 μg/mL, respectively.322 Compounds(+)-113, (+)-192, and (+)-194 were found to inhibit the larvalattachment and provoke the metamorphosis of the barnacle B.amphitrite.126 It was shown that compounds (−)-223, (−)-233,and (−)-235 inhibited settlement and metamorphosis of cypridlarvae of B. amphitrite with IC50 values of 0.33, 4.6, and 2.3 μg/mL, respectively.231

(−)-Cubebol 79 was revealed as antifeedant against Locustamigratoria, its activity being reinforced in the presence of(+)-ferruginol, a diterpene found in the same extract ofCryptomeria japonica.323 (−)-Cubebol 79, found in the sameJapanese cedar, was also shown to inhibit the feeding behavior ofAcusta despesta at 120 μg/mL.324

A mixture of maalianes 127 and 128 was reported to be toxicfor goldfish Carassius auratus at 100 μg/mL and effective asantifeedant against this goldfish at 10 μg/mg in food pellets.Because these metabolites are found only in the dorsum, which isexposed to potential predators, they appear as belonging to thechemical defense of the nudibranch C. luteomarginata theyoriginated from.137 The isonitrile aromadendrane (−)-188showed toxicity for the fish Lebistes reticulatus (LD 30 mg/mL), suggesting that it may be involved in the defensemechanisms of the sponge A. acuta it was extracted from.203

The corresponding derivatives (−)-189 and 190 were found tobe nontoxic to fish L. reticulatus and have been proposed to be theresult of a detoxification process.204

Since separation of the 9-thiocyanatopupukeananes 230 and231 was not successful, both compounds were tested as epimericmixtures (monitored by GC). A decrease in brine shrimpmortality (from 90% to 35%) was observed when decreasing theproportion of 231 in bioassays (from 230:231 = 30:70 to 50:50),thus showing the greater toxicity of epimer 231.240 The toxicityof (−)-lemnafricanol 290 on brine shrimp larvae was evaluatedthrough its LC50 value of 0.32 μM.279

(+)-Penicibilaenes A 288 and B 289 were tested against plantpathogenic fungi Alternaria brassicae, Colletotrichum gloeospor-ioides, Fusarium graminearum, and Gaeumannomyces graminis.Both of them exhibited selective activity against C. gloeosporioideswith MIC values of 1.0 and 0.125 μg/mL, respectively, thusindicating that acetylation at the C4 position likely enhanced theactivity.278

(−)-Subergorgic acid 56 was reported to be active againstRhizopus oryzae at 200 μg/mL without further detail.64

(−)-Bourbon-11-ene 1 was found to have no activity towardthe malaria parasite Plasmodium falciparum.325 Nitrogenousmetabolites (−)-281 and (−)-282 showed activity against P.

falciparummalaria parasite Dd2 line (IC50 = 0.36± 0.05 and 0.83± 0.25 μM, respectively) and against chloroquine sensitive P.falciparummalaria parasite 3D7 line (IC50 = 0.30± 0.09 and 0.29± 0.07 μM, respectively).96

No antimalarial activity was detected against P. falciparumclones D6 and W2 (IC50 > 1000 ng/mL) for silphiperfolanes(−)-64, (−)-65, perforetane (−)-99, (+)-isorhodolaureol 301and cyclolaurane (−)-310.312Several derivatives demonstrate potential as analgesics capable

of attenuating neuropathic pain. Such compounds have beenshown in vivo to reduce proteins mediating inflammation, tumornecrosis facor alpha (TNFα), cyclooxygenase-2 (COX-2), andinducible nitric oxide synthase (iNOS). (+)-Strepsesquitriol 267was shown to moderately inhibit lipopolysaccharide-stimulatedTNFα production in RAW264.7 macrophages at a concentrationof 100 μM (35.4% inhibition, p < 0.01), which was superior to60.6% inhibition for the positive control, N-p-tosyl-L-phenyl-alanine chloromethyl ketone (TPCK).267

Primary anti-inflammatory results showed that (+)-32significantly inhibited iNOS and COX-2 proteins expressionreducing, respectively, their levels by 216.9 ± 5.1% and 67.6 ±13.1%.60 Compounds (+)-32, (−)-41, and (+)-54were shown tosignificantly reduce the levels of the iNOS protein (1.2 ± 0.1,54.4 ± 12.0, and 34.8 ± 10.2, respectively) at concentrations of10 μM.61 Compounds (+)-32 and 41 significantly reduced thelevels of COX-2 protein (24.8 ± 7.5 and 62.9 ± 13.7,respectively) at a concentration of 10 μM. At the sameconcentration, the other isolated capnellenes (+)-34 and 49−53 did not inhibit iNOS and COX-2 protein expression.61 Invivo, (−)-Δ9,12-capnellene-8β,10α-diol 41 inhibited hyperalgesiabehavior in the mouse model for neuropathic pain in a dose-dependent manner.326

The triquinane derivative (−)-64 was found to be activeagainst both the Leishmania amazonensis promastigote (IC50 =43.8 μg/mL) and the amastigote (IC50 = 48.7 ± 3.7 μg/mL)forms.75 It was also shown to possess a moderate antialgal activity(inhibition zone = 0.2 cm at 40 μg for Chlorella fusca) and noactivity toward several fungi (Ustilago violacea, Mycotyphamicrospora, Eurotium repens, and Fusarium oxysporum).76

Contrary to (−)-shagene B 73 which showed no activity (>20μg/mL), (−)-shagene A 72 was found to be active againstLeishmania donovani, with no toxicity against the mammalianhost, showing the importance of the methoxy substituent at theC8 position.85

Compound (+)-103 produced partial inhibition against C.fusca growth (10 mm inhibition zone diameter at 5 mg/mL).107

(−)-Paralemnanone 291 and (−)-isoparalemnanone 292were found to inhibit the LPS-induced pro-inflammatoryproteins iNOS (respectively, to 48.7 ± 11.2% and 70.6 ±3.8%) and COX-2 (respectively, to 73± 3.1% and 68.5± 10.1%)expression at a concentration of 10 μM. (−)-Paralemnanol 141did not inhibit the COX-2 expression but was able to reduceexpression of iNOS (66 ± 4.6%) by LPS treatment.153 The anti-inflammatory activities of compounds 168−172 through theaccumulation of pro-inflammatory iNOS and COX-2 proteins inRAW264.7 macrophage cells were evaluated.192 It was found thatthese compounds did not reduce the accumulation of iNOS

Table 8. continued

microorganism antibacterial activities

M. bovis BCG (−)-64 IC50 = 204.6 ± 7.6 μM320

aMA: moderately active. NA: no activity or not active. WA: weakly active.



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protein induced by LPS. Compounds (−)-168 and (−)-170were found to reduce the accumulation of LPS-induced COX-2to 8.7 ± 4.5%, 61.0 ± 6.0%, and 83.4 ± 6.4%, respectively, at 10μM. At a concentration of 100 μM, compounds 168−170 wereshown to reduce the levels of induced COX-2 to 1.7± 1.3%, 17.6± 2.2%, 32.8 ± 3.2%, and 71.3 ± 7.2%, respectively.192

Metabolites (+)-32 and 206−208 reduced the levels of theiNOS protein at a concentration of 10 μM (13.1 ± 2.1%, 2.0 ±0.8%, 70.0 ± 7.0%, and 103.0 ± 4.3%, respectively) and COX-2protein (67.6 ± 13.1%, 25.0 ± 6.7%, 108.3 ± 0.9%, and 94.3 ±3.2% respectively) in comparison with LPS alone. These resultsshow that 32 and 206 significantly inhibited iNOS and COX-2proteins expression, while 207 did not inhibit COX-2 proteinexpression but significantly inhibited iNOS protein expression,and 208 exhibited no discernible anti-inflammatory activityagainst LPS-stimulated RAW 264.7 macrophages.60

(−)-Lemnanol 206 was shown to produce anti-inflammatoryand analgesic effects in carrageenan-injected rats.327 (+)-Car-yophyllene 279 showed inhibitory effects on the generation ofsuperoxide anions (inhibition rates = 42.22%) and the release ofelastase (inhibition rates = 42.10%) by human neutrophils at aconcentration of 37.6 μM (10 μg/mL).274

(+)-Δ9(12)-Capnellene-8β,10α-diol 32 and acetylated capnel-lene (−)-41 were found to have antineuro-inflammatory andantinociceptive properties in IFN-γ-stimulated microglial cellsand in neuropathic rats, respectively, and could therefore serve asuseful lead compounds in the search for new therapeutic agentsfor treatment of neuro-inflammatory diseases.326

Clovane sesquiterpene (−)-283 displayed a 14.8% inhibitoryeffect on elastase release by human neutrophils at a concentrationof 10 μg/mL.275 Compound (−)-284 was found to display a4.3% inhibitory effect on superoxide anion generation by humanneutrophils at 10 μg/mL.277 Contrary to compounds 284 and285, clovane sesquiterpene (−)-286 was found to displaysignificant inhibitory effects on the generation of superoxideanion (IC50 = 2.72 ± 0.93 μg/mL) and the release of elastase byhuman neutrophils (IC50 = 6.73 ± 0.85 μg/mL).276

Compounds 94−98 were shown to have no antiviral activitiesagainst human immunodeficiency virus [HIV-1 (IIIB), HIV-2(ROD)], herpes simplex virus-1 (KOS), herpes simplex virus-2(G), vaccinia virus, thymidine kinase2-deficient (TK2) herpessimplex virus-1 KOS (ACVr), vesicular stomatitis virus,Coxsackie virus B4, respiratory syncytial virus, parainfluenza-3virus, reovirus-1, Sindbis virus, and Punta Toro virus.102

4. SYNTHESIS

Total syntheses, either racemic or asymmetric with a particularemphasis on the first syntheses and syntheses that led to therevision of structures or stereochemistry attributions, will bedescribed in this section, covering the subject from the early1970s (pioneering results) to the end of 2015. A systematic andchronological update of the synthesis of all tricyclic sesquiter-penes working from 1979 to 1994328 as well as of the syntheticapproaches to triquinanes329 were published among others.

4.1. Fused Carbocycles

4.1.1. Kelsoene. Owing to its interesting [5.3.0.02,5]decanestructure incorporating six contiguous stereogenic centersincluding one quaternary carbon center at the C2 position,kelsoene 6 has been the subject of five syntheses to date.330

The first racemic synthesis of kelsoene 6 was reported in1999,331,332 starting from cyclooctadiene 328, which was firsttransformed into the bicyclooctane 329 in two steps and 67%

yield (Scheme 8). Compound 329 was then modified to affordenone 330, allowing introduction of the cyclobutane ring

through a [2 + 2] photocycloaddition in the presence of trans-1,2-dichloroethylene to deliver 331 in very good yield (85%). Inthis cycloaddition, the alkene approaches by the less hinderedface of the diquinane moiety, with a total stereoselective control.Subsequent functional group manipulations next led to themethyl ketone 332 in good overall yield (OY) (42.3% 8 steps)whose methylenation was eventually realized using Wittig’sconditions (80% yield). An enantioselective version of thisracemic synthesis was revisited 2 years later by the same team(Scheme 8).333 Lipase-catalyzed kinetic resolution of rac-diol329 provided ready access to (+)-329 and the correspondingdiacetate (+)-333 in high ee, whose transformations into thecorresponding kelsoene enantiomers (+)-6 and (−)-6 wereachieved following the racemic strategy in 17−18 steps (Scheme8).AC of the natural (+)-kelsoene 6 was determined the same

year by asymmetric synthesis of its antipode, starting from (R)-(+)-pulegone 334 (Scheme 9),37 which was transformed bybromination and Favorskii rearrangement into cis-pulegonicacids 336, separated by column chromatography from its transisomer. Tricyclic compound 337 was next obtained in five stepsthrough bicyclic enone 330 as one enantiomer (yields andexperimental parts were not given). The following trans-formations (337 → 332) were in accordance with the racemicsyntheses (Scheme 8) with slight modifications of the last step,implying Cp2TiMe2

334 as the methylenation agent. Determi-nation of the AC of natural kelsoene was first established by X-raydiffraction analysis of a tosylate 336 derived from enone 330 andthen by comparison of the respective optical rotations of thesynthetic and natural kelsoene synthesized.

4.1.2. Capnellene and Corresponding Diols. Capnellene29 and its hydroxy derivatives, which belong to the linearly fused

Scheme 8. First Racemic and Corresponding EnantioselectiveSyntheses of Kelsoene 6



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triquinane sesquiterpene family, have drawn the interest ofsynthetic chemists for decades.335−339 They possess a geminalmethyl unit at Cl and an angular methyl group at C4 (Scheme10).

Two racemic syntheses of capnellene 29 were reportedconcomitantly in 1981 for the first time and confirmed thecis,anti,cis relative configuration of the natural product (Scheme10). One340 is based on a 1,3-diyl trapping341 of the intermediate340, generated under THF reflux from 339, itself obtainedstarting from acid 338 in 4 steps and 44% OY. Subsequentfunctional group manipulations next led to (±)-29 in 4% yieldover three steps. The other one (Scheme 10)342 began with thetransformation of cyclopentenaldehyde 342 into the BC bicyclicunit 343 in four steps and 64.6% OY. The keto-aldehyde 344obtained in four steps and 44.5% OY from 343 was cyclized viaan intramolecular aldol condensation to furnish the ABC tricyclicunit 345 (79% yield), which was easily converted by hydro-genation and subsequent methylenation into the desired target(±)-29 in 60% yield.The first synthesis of the Δ9(12)-capnellene-8β-10α-diol 32

began with the synthesis of its C8 epimer 348 (Scheme 11).343

This bisallylic diol was synthesized starting from the BC bicyclicketone 343, which led to acetylenic derivative 346 in three stepsand 65.6% OY. After cyclization using sodium naphthaleneradical, the resulting allylic alcohol 347 was oxidized into 348 in40% yield. Generation of the corresponding mesylate followedby its displacement with potassium superoxide in the presence of18-crown-6344 was the only successful and stereospecific way tothe desired diol, delivering (±)-32 in 40% yield.345

AC of natural (−)-capnellene 29 was established in 1990(Scheme 12) through the synthesis of its enantiomer (+)-29.346

Chirality found its origin in (S)-valinol 349, which was reactedwith levulinic acid 350 under acid catalysis to afford theenantiomerically pure bicyclic lactam 351 (ee > 99%) in 86%yield. This lactam was next transformed in five steps and 78.2%yield into 352, which led to a mixture of the epimeric alcohols353 and 354 through 4 steps (71.8% yield), implying reductionof the lactam part among others. Both alcohols 353 and 354furnished the same compound 355 in, respectively, 89% and 74%yields, the configuration of the CHOH in the β-alcohol 354 beinginversed via a Mitsunobu reaction.Seven steps were eventually required to provide 356 (67.8%

yield), which was cyclized into (+)-29 according to a procedurepreviously reported in a racemic synthesis of capnellene,347

completing this first asymmetric synthesis in 20 steps and 14.1%OY.A formal asymmetric synthesis of natural (−)-capnellene 29

was reported in 1991, based on the photoinduced vinyl-cyclopropane−cyclopentene rearrangement of the bicyclicalcohol 358, obtained from the natural (+)-3-carene 357(Scheme 13).348,349 This rearrangement delivered a mixture ofdiastereoisomers 359 and 360 in 75% yield. Subsequenttransformations of this mixture allowed elimination of theundesired alcohol 360, leading to 361 in 39.8% yield over foursteps. The next step was a ring-expansion reaction with ethyldiazoacetate in the presence of SbCl5 furnishing the enantiomeri-cally pure enone (−)-362, which was shown to be a capnelleneprecursor in a racemic synthesis of this compound.350

Another formal synthesis leading to 362 reported 3 yearslater351 begins with the silylated cyclopentanone 364, obtained inthree steps from enantiomerically pure cyclohexenone 363352

(Scheme 13). The following compound 365 was synthesized insix steps (29.6% OY) and transformed into the target bicyclicenone 362 in 51.8% OY through a four-step sequence involvingcyclization.A synthesis of natural (−)-capnellene 29 based on

enantiomerically pure oxodicyclopentadiene (−)-366 wasreported in 1996 (Scheme 14).353 This compound wastransformed into ketone 367 in five steps and 38.8% OY,whose retro-Diels−Alder reaction provided bicyclic enone

Scheme 9. Enantioselective Hemisynthesis of (−)-Kelsoene 6

Scheme 10. First Racemic Syntheses of Capnellene 29

Scheme 11. First Racemic Synthesis of Capnellene Diol 32



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(−)-362 and formal access to the desired target. Ketone 367 wasalso the precursor of (−)-capnellene 29 following a longer andlesser efficient synthesis (11 steps, 16.8% OY).The only catalytic asymmetric synthesis of this natural

compound was reported the same year, implying an eleganttandem Heck reaction−carbanion capture sequence startingfrom enol triflate 368 to afford the bicyclic diene 369 in 77% yieldand 87% ee (Scheme 14).354 Enantioselectivity in this processwas induced by the presence of (S)-BINAP as a ligand forpalladium. It was next transformed into iodide 370 (six steps and78.2% OY), the precursor of alcohol 371 incorporating the thirdcycle A, through a radical process and subsequent alcoholdeprotection in 96% OY. The geminal dimethyl group was thenintroduced by cyclopropanation followed by catalytic hydro-genolysis, which furnished alcohol 372 in 76% OY. Finaldeshydration allowed the synthesis of natural (−)-capnellene 29in 78% yield and 87% ee.4.1.3. Silphiperfolanes. Two racemic syntheses of sub-

ergorgic acid 56, an interesting structure incorporating fivecontiguous stereogenic centers including two quaternary carboncenters, were reported (Scheme 15). The first one355 was basedon intramolecular alkylation and subsequent transformationswithin a functionalized spiro[4,5]dec-6-en-8-one 374, obtainedin eight steps and 24.2% OY starting from spiranic enone ketal373, which afforded 5,5,6 tricyclic olefinic ketone 375 (threesteps, 61.3%OY). Construction of ring C by ring contraction was

next performed via aldol condensation of dialdehyde 376,generated from 375 in 68% yield, to give racemic subergorgicacid 56 in two steps and 75.5% OY.The second racemic synthesis (Scheme 15),356 although not as

efficient in terms of yield, allowed construction of the linear 378and angular 379 tetracyclic adducts in a single step following ahighly diastereoselective (de >98%) intramolecular [3 + 2]photocycloaddition, starting from arene−olefin ketal 377, itselfprepared from bromoxylene and 3-methyl-pent-4-enal. Theseadducts were obtained in 42% yield (61% brsm), the angularderivative 379 precursor of subergorgic acid being the minor one(378:379 = 64:36). It could be processed in seven steps (11 frombromotoluene) and 24.4%OY into (±)-56 according to previousroutes.The only enantioselective total synthesis of subergorgic acid

reported to date357 (Scheme 16) was based on the lipase-

Scheme 12. Asymmetric Synthesis of Non-Natural Capnellene (+)-29

Scheme 13. Formal Synthesis and Enantioselective Synthesesof Natural (−)-Capnellene 29

Scheme 14. Enantioselective and Catalytic EnantioselectiveSyntheses of Natural (−)-Capnellene 29



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promoted hydrolysis of the racemic chloroacetate 381, easilyobtained in two steps and over 86% yield from 1,3-cyclo-pentanedione 380, which furnished enantiomerically purealcohol (−)-382 and chloroacetate (+)-381. The latter wasthen transformed, through alcohol (+)-382, into diquinane(+)-383 in four steps and 52.1% OY. This compound wassubmitted to a tandem diastereoselective Michael additionprocess−enolate trapping by TMSCl to provide silyl enol ether384 in 90% yield. Cyclization and subsequent functional groupmanipulations next led to tricyclic ketal (−)-385 in four steps and20.3% OY. Seven more steps (34.0% OY) were necessary totransform the ketal into an olefin and the silylated alcohol into aα-keto enoate in (+)-386, suitable for introduction of the 15carbon atom of the sesquiterpene skeleton, via aMichael additionof a methyl group and subsequent transformations into (−)-387(four steps, 64.4% OY). Compound 388 was further elaboratedin five steps and 78.6% OY and eventually easily transformed innatural subergorgic acid (−)-56 in three additional steps and78.6% OY via oxidation, Michael addition, and saponification.

(−)-Silphiperfolan-6-ol 65 was another silphiperfolane todraw synthetic chemists’ attention. It was the subject of the onlyasymmetric synthesis reported to date,74 which confirmed its AC.This synthesis began with the formation of diazo ketone 390 insix steps and 25.8% yield from enantiomerically pure (R)-(+)-limonene 389 (Scheme 17). Construction of the secondcycle then led via anhydrous copper sulfate-copper catalyzedintramolecular cyclopropanation to the tricyclic adduct 391 ingood yield (76%). After a four-step sequence, done in a 54.6%global yield, a 1:2 mixture of diastereoisomers 392 and thedesired product 393 was obtained.The major isomer 393 was next transformed (2 steps, 81%

yield) into the diazo compound 394, which afforded thetriquinane species 395 in 84% yield, via a highly regioselectiveinsertion of the corresponding rhodium carbenoid into the C−Hbond of the tertiary methyl group at the ring junction.Subsequent functional group manipulations provided in foursteps and 51.6% OY an inseparable mixture of the desired target(−)-65 and its diastereoisomer 396 together with thecorresponding dehydrated compounds 397 and 398. Since itwas observed that dehydration of 396 was relatively faster thandehydration of (−)-65, the latter was purified by treatment of thismixture with 3 N hydrochloric acid, which gave a mixture of 397,398 (60%), and unreacted (−)-65 (18%), eventually separatedby flash chromatography.

4.1.4. Cycloeudesmanes and Cubebanes. Among thetwo racemic syntheses of cycloeudesmol 69 reported todate,358,359 the first one358 (Scheme 18) was the more efficientand the shortest one. This synthesis started with a six-steppreparation of ketoester 400 from tosylhydrazone 399 (38.4%OY) and relied on an olefin−ketocarbene cyclopropanation of400 as a key step, which allowed concomitant formation of twocycles in one step to afford 401 in 56% yield. Cycloeudesmolsynthesis was next achieved through four more steps and 81%OY.(−)-Cubebol 79 and (−)-α-cubebene 84 were the subject of

five asymmetric syntheses and one racemic route.360 The fisrtone88,361 (Scheme 19), which allowed confirmation of the ACs ofthe targets, started with the transformation of (−)-trans-caran-2-one 402 into spirolactone 403 in three steps and 16% yield. This

Scheme 15. Racemic Syntheses of Subergorgic Acid 56

Scheme 16. Enantioselective Synthesis of Subergorgic Acid (−)-56



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lactone 403 was next modified to give the tricyclic ketone 405 inthree steps including a copper-catalyzed intramolecular cyclo-propanation from the intermediate 404 in a modest 11.2% yieldpartly due to the poor facial diastereoselectivities obtained in thatprocess. Compound 405 was eventually transformed into(−)-cubebol 79 with methyl Grignard reagent in 44% yield.Dehydration (with thionyl chloride in pyridine) of this speciesled to a mixture (7:2) of (−)-α-cubebene 84 and its epimer β-cubebene 406 separated by GC without mention of the yield.This strategy, which had the merit of being the first reportedaccess to these natural products, is relatively inefficient (OY =0.8% for (−)-79) and, moreover, requires separation of productsby preparative GC on many stages.

A second similar and no more efficient synthesis was reportedin 1976,362 but it took four more decades363 before a renewedinterest for the total syntheses of such natural products. Startingfrom (+)-tetrahydrocarvone 407 (Scheme 20), the enantiomeri-

cally pure enyne ketone 408 was obtained in 6 steps and 48.4%OY, which by three more steps (77.8% OY), including a highlydiastereoselective Noyori’s transfer hydrogenation, led toacetylenic acetate 409, the desired precursor for the PtCl2-catalyzed enyne cycloisomerization to furnish in excellent yield(92%) and with a total stereoselectivity the enol acetate 410,which was easily saponified into ketone 405. It was next foundthat the less basic MeCeCl2 behaved exceptionally well in thenext step, probably avoiding competing enolization, for thesynthesis of (−)-cubebol 79 in comparison with the direct

Scheme 17. Semisynthesis of (−)-Silphiperfolan-6-ol 65

Scheme 18. First Racemic Synthesis of Cycloeudesmol 69

Scheme 19. First Semisynthesis of (−)-Cubebol 79 and (−)-α-Cubebene 84

Scheme 20. Formal Semisyntheses of (−)-Cubebol 79 and(−)-α-Cubebene 84



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reported addition of MeLi.88 Additionally, more efficient accessto (−)-α-cubebene 84was also reported in two steps through theenol triflate 411 and 81.9% yield.In the course of the study of chirality transfer during the enynol

cycloisomerization process, a similar strategy was concomitantlyreported364,365 starting with the synthesis of a 1:2 mixture ofinseparable pivalates 412 and 413 prepared from (+)-(R,R)-tetrahydrocarvone 407 (7 steps, 55% OY). Enriched mixtures of412 and 413 of variable composition (70:30 to 98:2) weresubmitted to Pt-, Au-, or Cu-catalyzed face-selective enynecycloisomerizations to give after separation of the wrongdiastereomer at C6−C10 generated from epimeric pivaloylenyne 37, and saponification, tricyclic ketone 405 in 72% yield.Although less efficient, an original strategy based on an

intramolecular cyclopropanation of an α-lithiated epoxide wasrecently reported (Scheme 20).366 Epoxide 415, obtained in fivesteps and 8.7% OY from (−)-menthone 414, was deprotonatedwith LTMP to stereoselectively provide via an electrophiliccarbenoid intermediate, the tricyclic alcohol 416 in 90% yield.This compound was eventually easily converted into (−)-cube-bol 79 by oxidation and subsequent nucleophilic attack in 80.7%yield.4.1.5. Aristolanes and Maalianes. Racemic synthesis of

aristolane 111 starting from β-ketoaldehyde enol 417 wasreported in 1969 (Scheme 21).367 Olefinic acid 418 prepared in

21.9% OY over seven steps was transformed into thecorresponding intermediate diazo compound suitable forcopper-catalyzed intramolecular cyclopropanation leading to amixture of (±)-aristolane 111 (46%) and its diastereomer 419(20%), reflecting the 2:1 facial selectivity of the cyclopropanationstep.Aristol-9-en-1-one 106 and aristol-1,9-diene 108 were,

respectively, hemisynthesized starting from 9-aristolen-1α-ol(+)-122 by oxidation and dehydration (Scheme 22).108

Methylene Blue-sensitized oxidation of (+)-1(10)-aristolene112 led to hydroperoxide 420 and a small amount of a mixture ofaristoladienes 107 and 108 (Scheme 22), while the same reactioninvolving Rose Bengal gave compound 122, which was oxidizedinto 106,109 together with another allylic alcohol (8.5%), whichwas oxidized to known terrestria1 metabolite (10)-aristolene-2-one.368

4.1.6. Africananes and Aromadendranes. Since africa-nol’s AC determination through X-ray diffraction studies,155 oneenantioselective369 and three racemic syntheses370−372 werereported prior to publication of an elegant and efficientenantioselective process based on a Mo-catalyzed asymmetricolefin metathesis (Scheme 23).373 Norbornenone 421 was thuseasily transformed (81%) into diene 422, which was submitted toasymmetric ring-opening metathesis/ring-closing metathesis(AROM/RCM) conditions in the presence of chiral Mo catalyst423 to afford the bicyclic adduct 424 in excellent yield (97%).Subsequent functional group manipulations provided in threesteps and 82.6% OY the bicyclic olefin 425, which was submitted

to catalytic hydroformylation reaction to provide a 1:1 separablemixture of regioisomeric aldehydes 426 and 427 in 97%combined yield. The mixture was next reduced (NaBH4) andthe regioisomeric alcohol separated and processed in four moresteps and 21.3% OY from the aldehydes 426 and 427 to givealcohol 428, a precursor to (+)-africanol 142 as previouslyreported in a racemic synthesis372 of this natural product.The first semisynthesis of (−)-aromadendrene 166 was

described in the 1960s using (−)-perillaldehyde 429 as the

Scheme 21. Racemic Synthesis of Aristolone 111

Scheme 22. Hemisyntheses of Aristolanes 106, 107, 108, and122

Scheme 23. Enantioselective Synthesis of (+)-Africanol 142



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chiral source (Scheme 24).374 Construction of the cyclopropaneunit was first accomplished by bromation and subsequent base-catalyzed cyclization leading to bicyclic aldehyde 430 in 41%yield. A Wittig reaction then allowed quantitative formation ofdiene 431, which underwent a Diels−Alder cycloaddition withacrolein leading to the tricyclic olefin 432 (73%OY). Subsequentfunctional group manipulations provided in four steps and 66.2%OY 1,2-tosylate alcohol 433, which quantitatively rearrangedover chromatography on alumina to afford the tricyclo-[6.3.0.02,4]undecanone 434, a precursor of the desired naturalaromadendrene (−)-166 via a second Wittig procedure (53%yield). This work brought a correction to the first reportedstereochemistry for compound 166375 and ascertained its AC as1S,4S,5S,6R,7S.In the 1990s, (+)-166 and its epimer (−)-167 were

synthesized from natural (+)-3-carene 357 (Scheme 24)376,377

which was first transformed into cyclopropane 435 (3 steps,63.3% yield) prior to cyclization (82% yield) under acid catalysisto give cycloheptenone 436. Compound 437 was next obtainedin 6 steps and 33.3% OY and then under intramolecular aldolcondensation, delivering tricyclic cyclopentenone 438 in 84%yield. Stereoselective methylation of the latter followed byepimerization led through the common intermediate 439 to thedesired targets (+)-166 and (−)-167 in 79.1% yield.Trans and cis5,7 ring junctions were next introduced by direct hydrogenationof enone 439 over Pd/C affording ketone 440 or via reduction ofits corresponding tosyl hydrazone leading to olefin 441.Subsequent functional group transformations of 440 and 441gave, respectively, (+)-166 (six steps, 51.4% OY) and (−)-167(four steps, 77.8% OY).Epoxidations of (+)-spathunelol 176 or its corresponding

dehydration product 444 obtained in 70% yield, respectively,afforded 442 and 445 as mixtures of C10 epimeric epoxides

(Scheme 25),189 easily transformed in the presence of LiAlH4into C10 epimeric diols (−)-163, (−)-164, (−)-443, and

(−)-446. It is worth noting that (−)-163 is the antipode of thenatural product found in S. mayi, while (−)-164 found in thesame organism has the correct AC: finding two antipodalframeworks inside the same species, if intriguing, is neverthelessnot without precedent.378

In order to ascertain their ACs, a series of aromadendrane typecompounds (+)-154, (−)-155, (+)-157, (−)-163, (−)-167,(+)-174, and (+)-176 was obtained starting from aromaden-drene (+)-166, (Scheme 26).183

(+)-Aromadendrene 166 was first transformed via ozonolysisinto ketone 447, whose epimerization through the correspond-ing silyl enol ether furnished quantitatively 448 via crystallizationin MeOH in the presence of Et3N. Reaction of the latter with

Scheme 24. Semisyntheses of Aromadendrene (−)-166, (+)-166, and (−)-167

Scheme 25. Semisyntheses of Aromadendrane Diols (−)-163and (−)-164



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MeLi gave (−)-ledol 155 in 91% yield. Peterson olefination

reaction conditions applied to ketone 448 avoided epimerization

of this compound at C8 using Wittig conditions to furnish

(−)-alloaromadendrene 167 in 91% yield. Subsequent epox-

idation and reduction of the latter gave a 1:4 separable mixture of

(+)-viridiflorol 154 and (−)-155 in 89% yield. Ketone 447 was

also oxidized into (+)-157 (40% yield), whose olefination

afforded (+)-spathulenol 176. Epoxidation and reduction of this

Scheme 26. Semisyntheses of Aromadendranes (+)-154, (−)-155, (+)-157, (−)-163, (−)-167, (+)-174, and (+)-176

Scheme 27. First Enantioselective Synthesis of (−)-Aromadendrane Diol 164



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adduct led to 4α,7β-aromadendranediol (−)-163 in 44% yield.Eventually (+)-157 was epimerized into 449, whose subsequentprotection as a silyl ether, MeMgI attack, and deprotectionfurnished (+)-174 in 79% yield.The first enantioselective synthesis of (−)-aromadendrane

diol 164 was reported in 2009379 via an impressive cascade ofthree reactions involving metal and organocatalysts 450, 451,and 452 (Scheme 27). Compounds 453 and crotonaldehyde 454were first submitted to metathesis reaction conditions usingGrubbs II catalyst 450, leading transitorily to ketoaldehyde 455.Success of the following organo-cascade sequence then relied onthe use of the dual-system 451/452 with the imidazolidinone451 generating an iminium intermediate 457 prone tonucleophilic attack of the furan 456, while proline 452 was atthe origin of the enamine 458, which led through intramolecularcyclization to the bicyclic structure 459 in 64% yield, 95%enantiomeric excess (ee), and 67% diastereomeric excess (de).The latter was next converted into cyclopentane dialdehyde 460via hydrogenation, subsequent reduction, and protection in80.7% OY. Construction of the seven-membered ring was thenrealized after double-Wittig olefination and metathesis toproduce 461 (56.2% yield), whose transformation into(−)-aromadendrane diol 164 was done by introduction of thegem-dimethyl cyclopropane unit via a two-step sequenceinvolving diastereoselective addition of dibromocarbene, treat-ment with Me2CuLi and MeI, and subsequent deprotection in88.4% OY.The second enantioselective synthesis of (−)-aromadendrane

diol 164 was recently reported380 based on the gold-catalyzedcyclization of compound 464, obtained in four steps and 62%yield from 463 (Scheme 28). In the presence of 2 mol %

JohnPhos catalyst 462, the linear 14 carbon unit 464 wastransformed into the tricyclic aromadendrene structure 466 in56% yield, probably through allylic alcohol nucleophilic attack ofthe intermediate 465. Selective epoxidation of 466 from the lesshindered face, followed by opening of the generated epoxide andallyl cleavage with Li in ethylenediamine, gave the desired target(−)-aromadendrane diol 164 in 51.5% yield and 74% ee.(+)-Spathulenol 176 was prepared for the first time by

stereoselective ozonization of (+)-aromadendrene 166.381

An interesting biomimetic approach to the syntheses of(−)-palustrol 153 and (+)-spathulenol 176 was recently

reported (Scheme 29).382 Four steps were thus necessary togenerate 468 in 63.6% OY, which was cyclized in the presence ofSmI2 to afford diol 469 bearing two hydroxy groups in favorableconfiguration for further syn elimination, allowing formation ofthe E-olefin geometry in the acid-sensitive target (+)-bicyclo-germacrene 136 (66% yield). Acid exposure (HSCN) of thiscompound furnished (+)-ledene 471 through cation 470, andsubsequent Mukaiyama’s cobalt-catalyzed phenylsilane/O2

hydration383 allowed formation of (−)-palustrol 153 in 45%OY. Epoxidation of (+)-bicyclogermacrene 136 led to(+)-spathulenol 176 in 57% yield, whose formation could beexplained by rearrangement of 472. This intermediate isnevertheless not the most obvious one owing to steric hindrancegenerated by the cyclopropane unit, which should favorepoxidation in a trans position or on the other double bond ofthe bicyclic unit.

4.2. Bridged Tricyclic Sesquiterpenes

4.2.1. Tricyclic Decane Skeleton. Since its isolation anddetermination of its AC through an X-ray study,228 many racemicsyntheses of sinularene 218384−390 were reported to date,however without enantioselective synthesis of this compound.The same finding holds for lemnalol 206 and β-copaene 211,which were the subject of only racemic syntheses.391−393 Thebiogenetic relationship between the marine sesquiterpenesneopupukeananes and trachyopsanes was ascertained by abiomimetic rearrangement employed as the key step for theenantioselective first total syntheses of the marine sesquiterpenes(−)-2-(formylamino)-trachyopsane 221 and (+)-ent-2-(isocyano)trachyopsane 223 (Scheme 30).232

This synthesis began with an intermolecular/intramolecularMichael addition sequence between (−)-carvone 473 andmethyl methacrylate, which allowed access to the bicyclicstructure 474 in 65% yield (Scheme 30). Rhodium-catalyzedcyclization of an intermediate diazoketone obtained from 474furnished the tricyclic dione 475 in 81% yield, whose successivereductions gave 476 (two steps, 89% OY). Under acidicconditions, this keto alcohol 476 provided, through theneopupukeanane-type 477 and trachyopsane-type 478 cations,the tricyclic structure 479 in 87% yield. The latter compound waseventually transformed into the natural (−)-2-formylamino-trachyopsanes 221 in three steps and 83.7% OY, whosetosylation afforded the corresponding (−)-2-isocyanotrachyop-sanes 223, opposite to the natural metabolite,229 in 92% yield.Synthesis of (−)-4-thiocyanatoneopupukeanane 235 was

achieved in 21.6% yield and 11 steps from 474, and its AC wasthus determined.394−396

The corrected relative stereochemistry95 of compound 233was confirmed by an enantiospecific synthesis of bothenantiomeric forms of this natural product (Scheme 31).397

Reductive ozonolysis of 475 furnished 482, whose epimerizationat the C9 position was led in basic media to provide a 1:1 mixtureof diastereoisomers 482 and 483 (85% yield) separated by flashchromatography. The latter was next transformed in two stepsinto (−)-484, and subsequent functional groupmodifications ledto the corresponding enantiomer (+)-233 of the natural producttogether with a major rearranged product 485. Synthesis of thenatural enantiomer began with the double-Michael addition(Scheme 30) applied to dihydrocarvone 486 which, contrary tocarvone 473, led to a 3:1 mixture of diastereoisomers 487 and488 next transformed into a separable mixture of product ketol489 and diol 490 in three steps and 61.7% yield. Compound 490

Scheme 28. Second Enantioselective Synthesis of(−)-Aromadendrane Diol 164



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was eventually oxidized into (+)-484 (95%), a precursor of thenatural metabolite (−)-2-thiocyanoneopupukeanane 233.Two racemic syntheses of (±)-9-isocyanopupukeanane 224

were concomitantly reported in 1979 (Scheme 32). The firstone398 was based on the base-catalyzed cyclization of ketone 492obtained in four steps and 9.6% OY from the hydrindanone 491to deliver 493 (75% yield), which was transformed in the desiredtarget with two additional steps (yield not given).The second one (Scheme 32)399 relied on the intramolecular

Diels−Alder cyclization of diene olefin 495 (diastereomericcomposition not given) synthesized in four steps and 39.2% OYfrom allylic alcohol 456, which gave quantitatively the tricyclicketoalcohols 496 which was transformed in seven more steps toachieve the synthesis of 224 in 17.5% yield. Racemic synthesis ofthe neopupukeanane derivative 236 based on the same strategywas reported later,400 and two other racemic syntheses of thispupukeanane-type structure were also described.401,402

Only one racemic synthesis of (±)-2-isocyanoallopupukea-nane 239 has been reported to date (Scheme 33).403,404 Lactone498, prefiguring the final cyclopentane−cyclohexane-bridged

skeleton, was obtained in 56% yield via a ring-expansion process,starting from ester 497.Seven further steps provided olefinic enone 499 in 30.4% yield

engaged in an intramolecular hetero-Diels−Alder reaction togive the tetracyclic adduct 500 in 86% yield. Tricyclic olefin 501was next obtained in six steps and 66.6% OY and thentransformed into 2-isocyanoallopupukeanane 239 throughformation of formamide 502 (63% yield).Several syntheses, including one enantioselective route,405,406

of cis-sativenediol 237 were also reported.407−410 Asymmetricaccess to this compound (Scheme 34) was accomplished startingfrom (+)-dihydrocarvone 503 of known absolute configuration,which was transformed into the bicyclic structure 504 viadeprotonation, addition of the resulting anion onto 1-chloro-pentan-3-one, and dehydration in 27% overall yield.411

Compound 505 was next obtained412 in 4 steps and 81.9%yield. Its ozonolysis, subsequent oxidation, and methylenationafforded compound 506 in 76% yield. A carbonyl intramolecularcondensation of the latter then afforded the bicyclic compound507 in 76% yield, and 8 more steps413,414 were needed to deliver

Scheme 29. Biomimetic Approach to (−)-Palustrol 153 and (+)-Spathulenol 176

Scheme 30. Semisynthetic and Biomimetic Approach to Trachyopsanes (−)-221 and (+)-223 and Neopupukeanane (−)-235



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the alcohol 508 in 17.9% yield. Oxidation (Collin’s reagent),intramolecular Prins reaction (CF3CO2H), and subsequentoxidation (excess of Collin’s reagent) of the resulting alcoholgroup furnished compound 509 in 55% yield.415 Hydroxylationof the adjacent position of the keto group in 509 followed byreduction of the resulting hydroxy ketone afforded a 1:1 mixtureof (+)-cis-sativenediol 237 and its epimer 510 in 66.6% yield.4.2.2. Tricyclic Undecane Skeleton. Acanthodoral 250,

bearing a highly strained bicyclo[3.1.1]heptane framework wasthe subject of one enantioselective synthesis (Scheme 35).251

Compound 511 (>96% ee), easily obtained through resolutionof its racemate form using (S)-1-phenylethylamine,416 wasconverted into 512 in three steps and 58.5% OY. Palladium-mediated metal−ene reaction next allowed cyclization into 513(50% yield), whose esterification and subsequent cyclopropana-tion afforded tricyclic compound 514 in 92% yield. Ringexpansion via solvolysis of the gem-dibromocyclopropane unit inthe presence of a nucleophilic arene thiol then provided the vinylbromide 515 in 94% yield, whose subsequent functional grouptransformation gave seleno ester 516 after three steps and 67%

OY. The acyl radical generated from 516 under nonreductiveconditions induced a regioselective cyclization to providetricyclic ketone 517 in 85% yield, which was subsequentlytransformed into diazoketone 518 through four steps and 42.2%OY.

Scheme 31. Semisynthesis of (+)- and (−)-2-Thiocyanoneopupukeanane 233

Scheme 32. Racemic Syntheses of 9-Isocyanopupukeanane 224

Scheme 33. Racemic Synthesis of 2-Isocyanoallopupukeanane239

Scheme 34. Enantioselective Access to (+)-cis-Sativenediol237



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Photo-Wolff rearrangement of compound 518 allowedconstruction of the strained bicyclo[3.1.1]heptane frameworkinto ester 519 almost quantitatively (Scheme 35). Subsequentreduction and oxidation furnished (+)-acanthodoral 250 in79.7% yield.Racemic syntheses of suberosanone 258, suberosenol B 255,

and the corresponding acetate 257 were remarkably re-ported417,418 prior to their isolation as natural products66

(Scheme 36) in the course of biogenetic relationship studiesbetween silphinene 522 and the terrestrial secondary metabolitequadrone. First, the synthesis of silphinene 522 was performedaccording to a previously described three-step synthesis419 viareductive cleavage of a tetracyclic [3 + 2] cycloadduct 521 (66%

yield), obtained upon irradiation of compound 520 (35% yield,separated from another isomer in equal amount) prepared fromo-bromotoluene and 6-methyl-5-hepten-2-one in 97% yield.The unstable α-mesylate 523 was next produced in three steps

and 21% OY and then submitted to solvolysis in formic acid toafford a 8:1 mixture of α-terrecyclene 524 and silphinene 522(81% combined yield). Upon hydroboration reaction conditionsand subsequent oxidation, α-terrecyclene 524 led to suber-osanone 258 in 79.7% yield. Stereoselective epoxidation of 524gave the α-epoxide 525 in 86% yield, which eventually providedsuberosenol B 255 via β-elimination in the presence of Et2NLiand suberosenol B acetate 257 via subsequent acetylation (79%yield).On the basis of these synthetic results and on earlier studies,259

biosynthetic access to the carbon skeleton of suberosane wasproposed (Scheme 37). Cation 526 obtained by 1,2 shift from

caryophyllenyl cation 74 could rearrange via π-cyclization to givethe 527 and presilphiperfolan-8-yl carbocation 528 through a1,3-hydride migration. Three consecutive 1,2 shifts deliveringsuccessively silphin-1-yl cation 529 and the carbocations 530 and531 could furnish α-terrecyclene 524, precursor of the naturalmetabolites 478, 480, and 481 as previously shown (Scheme 35),after subsequent proton elimination.In 2000,420 the racemic synthesis of suberosenone 253 based

on an elegant tandem free radical cyclization−rearrangement waspublished (Scheme 38) but it is only recently421 that anenantioselective route to this compound and suberosanone 258was reported (Scheme 39).Preparation of the required bis-acetylenic silyl enol ether 534

was done in 10 steps and 23.6% OY from ketoester 533, itselfobtained from dimedone 532 in two steps and 39% OY.422 Thekey step was performed using tin hydride to generate radical 535with an unexpected selectivity presumably due to the conforma-tional preference of the butynyl chain with a silyloxy group in 535toward cyclization, leading to 536. This latter intermediate thenunderwent a rearrangement into 537 and subsequent cyclizationproviding access to the expected tricyclic diol 538 afterdestanylation over silica gel and deprotection.A further functional groupmanipulation of tricyclic unit 538 to

reach the target suberosenone 238 necessitates a 17-stepsequence (3.8% OY) through ketone 539 and enone 540 toinstall an axial methyl group at C8 and set the exomethyleneketone at C2−C3 (quadrone numbering).The enantioselective route to suberosenone 253 and

suberosanone 258 started with the 3-step synthesis of compound541 from dimedone 532 in 62.3% OY (Scheme 39).421−424

Chirality was next introduced via a hyperbaric asymmetricMichael addition in 59.9% yield, implying transient formation ofthe enamine generated from 541 and (R)-1-phenylethylamine,

Scheme 35. Enantioselective Synthesis of (+)-Acanthodoral250

Scheme 36. First Racemic Syntheses of Suberosanone 258,Suberosenol B 255, and Suberosenol Acetate B 257

Scheme 37. Proposed Biosynthesis of α-Terrecyclene 524



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which led to exclusive formation of keto-ester 542, whosesubsequent functional group transformations delivered silyl enolether 543 after 6 steps and 86.5% OY.

Highly chemoselective intramolecular cyclization via a silvertrifluoroacetate-mediated α-alkylation then furnished the bicyclicketone 544 in 87% yield, and a second cyclization was nextaccomplished by an intramolecular aldol condensation of thediketone issued from 544 via aWacker transformation to providethe tricyclic enone 545 (two steps and 68.9% yield). Compound545 was eventually modified to separately deliver (+)-sub-erosenone 253 (three steps and 34.6% yield) and (+)-sub-erosanone 258 (two steps and 88% yield). The optical rotationsign of (+)-suberosanone 258 was opposite to that of the naturalproduct, isolated from I. hippuris,66 which is thus the first exampleof quadrane-type natural product not related to the 1Rconfigurational series. On the opposite, the optical rotationsign of synthetic (+)-suberosenone 253was found to be identicalto the natural product’s one extracted from S. suberosa,254

confirming its AC previously determined via density functionaltheory calculations of optical rotation.257

Syntheses of synthetic (−)-suberosenone 253, (+)-suberose-nol A 254, and natural (−)-suberosanone 258 following the samestrategy313 and of (+)-suberosanone 258 via an elegant dual-organocatalyzed reaction425 were recently reported but liesbeyond the scope of this review as published in 2016.The first formal synthesis426 of racemic culmorin 265 from

tetrahydroeucarvone (12 steps and 0.5% OY) was followed byseveral syntheses,427,428 only one giving access to the enantiomer(+)-265.429

Scheme 38. First Racemic Synthesis of Suberosenone 253

Scheme 39. First Enantioselective Syntheses of(+)-Suberosenone 253 and (+)-Suberosanone 258

Scheme 40. Racemic Synthesis of Gomerone 306



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4.2.3. Tricyclic Dodecane Skeleton. Racemic synthesis ofgomerone C 306 (Scheme 40) was recently published, and itsrelative stereochemistry was subsequently revised.286

Catalyzed Diels−Alder reaction between silyloxydiene 546and alkene 547 furnished the bicyclic structure 548 in 69% yield,whose relative configuration was confirmed via X-ray crystallog-raphy. Compound 548 was next converted into 549 in 8 stepsand 41.2% yield. Five more steps in an overall yield of 65% werethen necessary to provide 550, whose cyclization through aConia−ene-type reaction generated 551 in good yield (65%) as alogical precursor of the desired target 306, eventually obtained bychlorination in 67% yield.4.3. Miscellaneous Tricyclic Sesquiterpenes

Only one racemic synthesis of cyclolaurene 314 has beenreported to date (Scheme 41)430 based on the CuSO4-catalyzed

intramolecular cyclization of the diazoketone 553, derived fromketone 552 (5 steps), into a mixture of the tricyclic structures554 (28%OY). Three more steps were necessary to generate thenatural product target in only 16.9% OY, owing to the lowdiastereoselectivity obtained in the key cyclization step.The asymmetric synthesis of natural (−)-laurequinone 321

based on an intramolecular Heck reaction and a carbeneinsertion as the key step was reported in 1998 (Scheme 42).431

This compound possesses two consecutive quaternary carbonsincluded in a triad of three contiguous stereogenic centers and istherefore a candidate of choice in the field of modern organicsynthesis.Optically active acid 555, easily prepared by optical resolution,

was transformed into the ester 556 via its corresponding acylchloride in 69% yield. Intramolecular Heck reaction delivered thetricyclic structure 557 as a mixture of double-bond regioisomers.Five steps (40.6%) were necessary to afford 558, which gave(−)-debromolaurinterol 310 after carbene insertion andreduction in 34% OY. Oxidation of 310 eventually furnishedthe natural compound (−)-laurequinone 321 in 60% yield.

5. CONCLUSION

The earliest of marine-derived tricyclic sesquiterpene wasreported by Irie et al. from the brown alga D. divaricata andlater confirmed as (−)-α-copaene 212.222 A half-century later,tricyclic sesquiterpenes having an all-carbon skeleton constitute alarge group of 284 natural products obtained from many speciesof marine origin covered in this review. Only a few of them (28)bear halogen atoms. Indeed, marine organisms have beenconsidered as a gold mine with respect to great potentialregarding their secondary metabolites. Thus far, thesesesquiterpenes have been isolated from 124 species, belongingto 62 genera and 8 marine phyla,432 the sponges (Porifera), thecoelenterates (Cnidaria), the mollusks (Mollusca), the brownalgae (Ochrophyta), the red algae (Rhodophyta), the calcareousalgae (Chlorophyta), the fungi (Fungi), and the bacteria(Actinobacteria) (Figure 26). Although these studies arefragmentary, corals (coelenterates) are the most prolific sourceof these metabolites.

A limited number of halogenated molecules were found in thiscategory. These compounds did not necessarily share theirskeletons with the nonhalogenated compounds as exemplified bythe rhodolaurane, gomerane, cyclococane, and omphalanehalogenated sesquiterpene classes (Figure 24). The other oneswere found in the cyclolaurane (9 compounds), perforetane (10compounds), isocycloeudesmane (1), calenzanane (1), maaliane(1), and neomerane (1) skeletal classes. These halogenatedcompoundsmainly (28/34) originated from the genus Laurencia,but the lack of studies does not make it possible to draw anyconclusions concerning their biosynthesis or their ecologicalsignificance. The presence of nitrogen atoms in isonitrile,isothiocyanate, and N-formylamino groups is another originalcharacteristic found in some of these marine structures. Peroxide

Scheme 41. Racemic Synthesis of Cyclolaurene 314

Scheme 42. Enantioselective Synthesis of (−)-Debromolaurinterol 310 and (−)-Laurequinone 321

Figure 26. Repartition of genus and species containing carbotricyclicsesquiterpenes.



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functions in some of these compounds are also rarely found interrestrial sesquiterpenes. One of the intriguing observations isthat some marine sequiterpenes are optical antipodes of thecorresponding terrestrial compounds, such as (−)-bourbon-11-ene 1, (−)-1(10)-aristolene 112, (+)-γ-maaliene 131, (+)-pal-ustrol 153, (−)-viridiflorol 154, and β-copaene 211, while othersare present as enantiomeric pairs, such as (+)- and (−)-128, or(−)-163 and (+)-164. Beyond that the biosynthesis of antipodalsesquiterpenes is of considerable fundamental interest.From a structural point of view, these tricyclic sesquiterpenes

have a higher degree of complexity than bicyclic C15-basedmolecules and therefore represent a greater challenge ahead fortheir structural investigation and total synthesis. As in the case ofcountless secondary metabolites produced by marine organisms,unprecedented carbon skeletons of the sesquiterpene class werediscovered from marine life forms. Among the 54 skeletal typesencountered in the carbotricyclic sesquiterpenes compiled in thisreview, approximately one-half (26) are unprecedented tricyclicskeletons, defining new classes of sesquiterpenoids (Table 9),like those found in (−)-paralemnanol 141, (−)-neomeranol 203,(+)-capillosanane V 204, (+)-rumphellolide 205, and (+)-strep-

sesquitriol 267, some of these compounds being the uniquerepresentative of new natural product classes.Interestingly, this field of research has witnessed continuous

attention over the past decades as reflected by a constant numberof publications in the area since the 1960s.21

Sesquiterpene metabolites isolated from marine organismsexhibit various biological activities, for example, antifouling,ichthyotoxic, antialgal, cytotoxic, antibiotic, antifungal, antipar-asitic, and anti-inflammatory activities. Nowadays, none of thesetricyclic marine sesquiterpenes have been able to reach thepreclinical marine pharmaceutical pipeline, despite highlyinteresting biological activities.433,434 However, apart from(+)-suberosanone 258, whose tremendous cytotoxic activitieswere not retained by the synthetic compound,313,421 othersuberosanes should deserve further synthetic studies, as well asbourbonane (+)-5, hirsutane (−)-15, and capnellane (+)-32displaying micromolar cytotoxic activities. Beside their cytotoxicevaluation, other biological activities were tested with somesuccess. Furthermore, many of the compounds compiled in thisreview have not been assessed in biological assays. Often thelimited supply of promising secondary metabolites extractedfrom their natural sources is a major hurdle to theirpharmaceutical development. Nonetheless, strategies aimed toovercome this problem are being developed.435 Their structuraldiversity and great biological potential as pharmacological agentsmake them ideal candidates in the fields of drug discoveryresearch, total synthesis, and medicinal chemistry. The discoveryand total synthesis of new structures of potential biologicalinterest will surely accentuate and stimulate the development ofinnovative synthetic methods. Interest in this field has remainedvery high and could increase as long as exploration of this richreservoir of fascinating natural products still remains activeitself.21,436

ASSOCIATED CONTENT*S Supporting Information

The Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.chem-rev.6b00502.

Nonhalogenated and halogenated carbotricyclic sesqui-terpenes with their biological testing sorted by marineorganisms; fused skeletons with highlighted numberingand connective bonds according to IUPAC rules to nametricyclic skeletons; bridged and miscellaneous skeletonswith highlighted numbering and connective bondsaccording to IUPAC rules to name tricyclic skeletons(PDF)

AUTHOR INFORMATIONCorresponding Authors

*E-mail: [email protected].*E-mail: [email protected]

Francoise Dumas: 0000-0002-2828-3124Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTSAuthors are thankful to BioCIS, University Paris-Sud, CentreNational de la Recherche Scientifique (CNRS) & Universite

Table 9. Distribution of Skeletal Types in (Terrestrial +Marine) versus Marine Organisms

skeletons found in terrestrial and marineorganisms

skeletons found only in marineorganisms

fusedbourbonane isocycloeudesmanekelsoane calenzananehirsutane shaganeisohirsutane viridianecapnellane perforetanesilphiperfolane laurobtusanecycloeudesmane paralemnanecubebane capillosananepunctaporane norantipathaneprobotryanearistolanemaalianeafricananearomadendraneneomerane

bridged skeletonsylangane trachyopsanecopaane allopupukeananesinularane abeopupukeananepupukeanane neopupukeananesativane isosativanequadrane (suberosane) acanthodoranelongibornane isoteneranerumphellane paessleranecedrane strepsesquitrianecaryolane penicibilaneisocaryolane isoparalemnaneclovane rhodolauranelemnafricanane gomerane

omphalane (guimarane)miscellaneous skeletons

cyclolauraneinflatanecyclococane



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http://pubs.acs.org

http://pubs.acs.org/doi/abs/10.1021/acs.chemrev.6b00502

http://pubs.acs.org/doi/abs/10.1021/acs.chemrev.6b00502

http://pubs.acs.org/doi/suppl/10.1021/acs.chemrev.6b00502/suppl_file/cr6b00502_si_001.pdf

mailto:[email protected]

mailto:[email protected]

http://orcid.org/0000-0002-2828-3124


Paris-Saclay (France) for their financial support during the timedevoted to this contribution. M.K. thanks the Faculty of Tishreen(Syria), L.C and L.W. thank the Chinese Scholarship Council (P.R. China) for financial support. We warmly thank Dr DanielaCeccarelli (Magnetic Island, Australia) for the picture ofAcropora echinata and I. hippuris, Pr Catherine Jeannot forproofreading the manuscript, and Barbara Dumas for thegraphics.

ABBREVIATIONS

AC absolute configurationAIBN azo-bis-isobutyronitrileBINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphtylebrsm based on recovered starting materialCC cytotoxic concentrationCD circular dichroismCOX cyclooxygenaseCSA camphorsulfonic acidm-CPBA 3-chloroperbenzoic acidDBU diazabicycloundecenede diastereomeric excessDMAP 4-(dimethylamino)pyridineEDA ethylenediamineED effective doseee enantiomeric excessFPP farnesyl diphosphateGC gas chromatographyGI growth inhibitionHIV human immune virusHMDS hexamethyldisilazaneHMPA hexamethylphosphoramideHPLC high-performance liquid chromatographyiNOS inducible nitric oxide synthaseIC inhibitory concentrationIFN interferonIUPAC International Union of Pure and Applied ChemistryLD lethal doseLPS lipopolysaccharideLTMP lithium 2,2,6,6-tetramethylpiperidideMA moderately activeMIC minimal inhibitory concentrationMIC 48 h concentration for complete inhibition after 48 h

incubationMs mesylNA no activityOY overall yieldPCC pyridinium chlorochromatesp species or not specifiedspp Latin abbreviation for multiple (plural) speciesTBSOTf tert-butyldimethylsilyl triflateTES triethylsilylpTSA p-toluene sulfonic acidTHF tetrahydrofuranTMS trimethylsilylTs tosylWA weak activity

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