Tricyclic Sesquiterpenes from Marine Origin - Chemical Reviews

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Tricyclic Sesquiterpenes from Marine Origin Franck Le Bideau,*,† Mohammad Kousara,†,‡ Li Chen,† Lai Wei,† and Françoise Dumas*,† †

BioCIS, Faculty of Pharmacy, Université Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-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 marine carbotricyclic sesquiterpene compounds are reviewed from the pioneering results to the end of 2015. Their total syntheses with a particular emphasis on the first syntheses, enantiomeric versions, and syntheses that led to the revision of structures or stereochemistries are summarized. Overall, 284 tricyclic compounds are classified into fused, bridged, and miscellaneous structures based on 54 different skeletal types. Tricyclic sesquiterpenes constitute an important group of natural products. Their structural diversity and biological activities have generated further interest in the field of drug discovery research, although the exact mechanisms of action of these species are not well known. Furthermore, these tricyclic structures, according to their chemical complexity, are a source of inspiration for chemists in the field of total synthesis for the development of innovative methodologies.

CONTENTS 1. Introduction 2. Isolation, Structural Determination, and Biosynthesis 2.1. Fused Carbocycles 2.1.1. 5/5/4, 5/4/5 Tricyclic Skeletons: Bourbonane and Kelsoane 2.1.2. 5/5/5 Tricyclic Skeletons: Hirsutane, Isohirsutane, Capnellane, and Silphiperfolane 2.1.3. 6/5/3, 5/6/3, 5/3/6 Tricyclic Skeletons: Cycloeudesmane, Calenzanane, Shagane, and Cubebane 2.1.4. 6/5/4 Tricyclic Skeletons: Viridiane, Punctaporane and Perforetane 2.1.5. 6/5/5 Tricyclic Skeleton: Probotryane 2.1.6. 6/6/3 Tricyclic Skeletons: Aristolane, Maaliane, and Laurobtusane 2.1.7. 6/6/4 Tricyclic Skeleton: Paralemnane 2.1.8. 7/5/3 Tricyclic Skeletons: Africanane, Aromadendrane, and Neomerane 2.1.9. 7/6/3 Tricyclic Skeleton: Capillosanane 2.1.10. 8/4/3 Tricyclic Skeleton: Norantipathane 2.2. Bridged Carbocycles 2.2.1. Tricyclic Decane Skeletons: Ylangane, Copaane, Sinularane, Trachyopsane, Pupukeanane, Allopupukeanane, Abeopupukeanane, Neopupukeanane, Sativane, and Isosativane

2.2.2. Tricyclic Undecane Skeletons: Acanthodorane, Isotenerane, Quadrane or Suberosane, Paesslerane, Longibornane, Rumphellane, Strepsesquitriane, and Cedrane 2.2.3. Tricyclic Dodecane Skeletons: Caryolane, Isocaryolane, Clovane, Penicibilane, Lemnafricanane, Isoparalemnane, Rhodolaurane, Gomerane, and Omphalane 2.3. Miscellaneous Carbocycles: Inflatane, Cyclolaurane, and Cyclococane 3. Biological Activity 3.1. Cytotoxic and Antitumor Activity 3.2. Antibacterial Activity 3.3. Other Biological Activities 4. Synthesis 4.1. Fused Carbocycles 4.1.1. Kelsoene 4.1.2. Capnellene and Corresponding Diols 4.1.3. Silphiperfolanes 4.1.4. Cycloeudesmanes and Cubebanes 4.1.5. Aristolanes and Maalianes 4.1.6. Africananes and Aromadendranes 4.2. Bridged Tricyclic Sesquiterpenes 4.2.1. Tricyclic Decane Skeleton 4.2.2. Tricyclic Undecane Skeleton 4.2.3. Tricyclic Dodecane Skeleton 4.3. Miscellaneous Tricyclic Sesquiterpenes 5. Conclusion Associated Content

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Received: July 29, 2016 Published: April 5, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.chemrev.6b00502 Chem. Rev. 2017, 117, 6110−6159

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diversity and for some of them interesting biological activities.7,9,22−24 In this review, tricyclic sesquiterpenes from marine environment will be considered, excluding their heterocyclic counterparts.25 Halogenated sesquiterpenes of marine origin were, in part, recently compiled.26,27 Structural characterization, biosynthesis, and biological activity of the species will be commented on when appropriate. Total syntheses, either racemic or asymmetric, with particular emphasis on the first syntheses and syntheses that led to the revision of structures or stereochemistry attributions will be described focusing on the key step and/or introduction of chirality. The present review covers the subject from the pioneering 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. For instance, 5/5/4 and 5/4/5 tricyclic structures are reported in the same section, even if they are separately treated and appear in different schemes. Bridged carbocycles are sorted according to the number of carbon atoms found in their skeletons: tricyclic decane, undecane, and dodecane. Both bridged and fused allcarbon carbocycle structures reported in this review can be described in accordance with IUPAC atom numbering28 as illustrated in Figures 1 and 2, but numbering resulting from biosynthetic considerations or from common usage29 is also utilized in the manuscript. Skeleton family names (Figures 1 and 2) are given when known (in black). Since the authors did not coin names for several skeletons, we herewith named them (in blue) based on the corresponding metabolite names or on the names of the species they are extracted from. Compound structures described all along this manuscript whose ACs have not been determined are arbitrarily drawn under one enantiomeric form. In these cases, the associated optical rotation signs, when specified, are those of the corresponding isolated products, irrespective of their ACs.

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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 the marine biodiversity and the importance of natural products in drug discovery.1 They thus represent an important class of natural products,2 identified from all kingdoms of life.3 Many of these compounds display a wide range of biological activities such as anti-HIV, antitumor, antibiotic, antiviral, immunosuppressive, cytotoxic, insecticidal, and antifungal activities and have stimulated research for druggable analogs.4−11 Known sesquiterpenes are derived metabolically from some 300 distinct C15hydrocarbon skeletons, which in turn are produced from the single substrate farnesyl diphosphate (FPP) by the action of sesquiterpene synthases.12,13 Each cyclization reaction in these biosynthetic cascades is initiated by the formation and propagation 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. Life appearance in the marine environment is dated approximately 4 billion years ago, whereas the first known terrestrial species are aged 400 million years, and consequently, this difference leads today to a greater diversity of phyla in the marine world. In addition to this longer evolution timeline, the huge variations in temperature, pressure, and light from the sea surface to the seabed16 may also explain the richness of the marine world in comparison with the terrestrial world. A large number of living organisms shows biochemical properties that could lead to major advances in the field of medicinal chemistry and understanding of human diseases and their treatments. In the same way as terrestrial plants, which have inspired numerous drug discoveries, marine organisms represent an impressive source of original molecules which have the potential to lead to new therapeutic findings.17 Currently, few of them are commercially available as drugs, and others are at an advanced stage of clinical trials.18,19 More than 25 000 marine natural substances have been described,20 a limited number in comparison with their terrestrial counterparts. This is due to the late development in diving technologies and subsequent difficult access to marine species. Marine metabolites often display peculiar structures due to their environment. 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 as isonitrile, thiocyanate, or formamide.21 Most of them were isolated from sponges, algae, corals, and other invertebrates, which mainly adopt biologically active compounds as chemical defenses owing to their lack of physical protection against predators. Because they rapidly dilute when in the marine environment, 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

2. ISOLATION, STRUCTURAL DETERMINATION, AND BIOSYNTHESIS 2.1. Fused Carbocycles

2.1.1. 5/5/4, 5/4/5 Tricyclic Skeletons: Bourbonane and Kelsoane. From the dichloromethane solubles of the tropical marine sponge Cymbastela hooperi collected at Kelso reef (Great Barrier Reef, Australia), novel terpenoid metabolites were isolated after repeated HPLC separations.30 One of these, (−)-bourbon-11-ene 1, named inconveniently prespatane owing to its unsaturated nature, was structurally unprecedented in the marine literature (Figure 3). It is the enantiomer of (+)-bourbon11-ene 2, a constituent of the terrestrial leafy liverwort Calypogeia mulleriana whose AC was determined by comparison of its hydrogenation product which is identical to the product obtained by hydrogenation of (−)-β-bourbonene 3.31 An investigation of the Formosan soft coral Nephthea erecta (Green Island, Taiwan)32 led to the isolation of the bourbonane derivatives (+)-8-β-hydroxyprespatane 4 and (+)-8-β-hydroperoxyprespatane 5 of unknown absolute configuration with a decahydrocyclobutadicyclopentane skeleton (Figure 3). From the tropical Australian marine sponge C. hooperi, (+)-kelsoene 6 possessing an unusual tricyclo[6.2.0.02,5]decane skeleton was the first marine isolated member of a new class of sesquiterpenes, the kelsoanes (Figure 4).30 Structural elucidation of this linearly fused carbotricyclic system previously found in the sesquiterpenoid sulcatine G33 relied on incisive spectral analyses. 6111


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

Sarcophyton tortuosum (South China Sea) together with hirsutanol A and (+)-hirsutanol E 19, was recently unambiguously established by X-ray diffraction study,42 but its optical rotation was found opposite to the one isolated from the terrestrial Gloeostereum incarnatum.43 ACs of (−)-hirsutanols A 15 and C 17 were also ascertained by X-ray crystallography, the optical rotation sign for marine compound (+)-17 being opposite to the one isolated from the edible mushroom G. incarnatum.44 (+)-Hirsutanol C 17 and five new sesquiterpenes, chondrosterins A−E 20−24 of unknown ACs, were isolated from potato 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 a methyl group from C2 to C6 and previously named isohirsutane.41 (−)-Chondrosterins I 25 and J 26 extracted from a culture of the same fungus in another media containing glycerol as the carbon source were found to possess this particular skeleton.48 Eventually two other known hirsutanes of unknown ACs, (+)-incarnal 2749 and (−)-arthrosporone 28,46 were isolated from the same fungus.50 Soft corals of the genus Capnella are rich sources of sesquiterpenes with the capnellane framework (Figure 6), which serve as chemical defense agents within the coral reef biomass toward algae and microbial growth, and to prevent larvae settlement. Δ9(12)-Capnellene 29, the simplest metabolite of the soft coral Capnella imbricata collected off Maluku (Leti Island, Indonesia) was isolated in 1978.51 The most abundant terpenoid of this coral, (+)-Δ9(12)-capnellene-3β,8β,10α-triol 30, was characterized in 1974,52 and its structure and AC were later confirmed by X-ray crystallography.53 This compound was also found in a specimen at the same location together with (+)-Δ9(12)-

Kelsoene 6, also called tritomarene, was isolated from cultured cells of terrestrial liverworts Ptychanthus straitus,34 Calypogeia muelleriana,31 Tritomaria quinquedentata,35 and later from the Formosan 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 needs to be reversed as (1R,2S,5R,6R,7R,8S) for the naturally occurring kelsoene as represented by (+)-6 (Figure 4).37 In 2014, this family expanded with the discovery of kelsoenethiol 8 and the corresponding ether dimer 9, isolated from the Formosan soft coral N. erecta (Green Island, Taiwan) and whose relative configurations were elucidated through extensive spectroscopic analyses, including 2D NMR spectroscometry, ESI orbitrap mass, and quantum chemical calculations.38 (−)-Bourbon-11ene 1 and (+)-kelsoene 6 were also found in the volatiles released from marine Streptomyces sp., strain GWS-BW-H5, isolated from the North Sea.39 The labeling pattern of kelsoene 6 and bourbon-11-ene 1 biosynthesized from exogenous 2H- and 13C-labeled mevalonate 10 through FPP 11 suggested that these compounds are, respectively, biosynthesized from alloaromadendranyl 13 and 14 guaianyl cations.34,40 Nevertheless, the assumption that these compounds came, respectively, from the (R)- and (S)-12 enantiomers was postulated before correction of the AC of (+)-6; therefore, they are probably both formed via the germacradienyl cation (S)-12 (Scheme 1). 2.1.2. 5/5/5 Tricyclic Skeletons: Hirsutane, Isohirsutane, Capnellane, and Silphiperfolane. The new sesquiterpenes (−)-hirsutanol A 15, hirsutanol B 16, (+)-hirsutanol C 17, and (−)-hirsutanol F 18, also named gloeosteretriol, were isolated from salt water cultures of an unidentified fungus separated from an Indo-Pacific sponge of the genus Haliclona (Figure 5).41 AC of the latter, isolated from a marine-derived fungus Chondrostereum sp., collected from the soft coral 6112


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Figure 2. Bridged and miscellaneous sesquiterpene skeletons found in this review. Atom numbering is in accordance with IUPAC numbering. Skeleton names 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 and 3) origins.

capnellene-5α,8β,10α-triol 31, (+)-Δ9(12)-capnellene-8β,10αdiol 32, and Δ9(12)-capnellene-2ε,8β,10α-triol 33, whose ACs were not determined.54 Two new capnellane sesquiterpenes, (+)-capnellen-8β-ol 34 bearing no hydroxy group at the C10 position and (+)-3βacetoxycapnellene-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 a specimen collected off Leti Island.56 Eight acetylated capnellenes 37−44 were extracted from colonies of C. imbricata living around Laing Island (Papua, New Guinea).57 It was demonstrated that

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

the contents of sun-dried specimen extracts differ from the corresponding fresh extracts carried out immediately after collection: in the former, acetate hydrolysis produced by substrate specific hydrolases occurs, leading to the corresponding free alcohols which can be thus considered as artifacts. Three related acetylated capnellenes (+)-45−47 and one peculiar capnellene (−)-48 bearing an acetylated hydroxy function at the C13 position of undetermined ACs were recently 6113


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Echinogorgia pseudossapo,65 and from Isis hippuris (Green Island, Taiwan).66 It was also found together with methyl subergorgate 57 and methyl 2β-hydroxysubergorgate 58 in the gorgonian Menella sp. collected off South China Sea (Meishan Island).67 Chemical study of a methanolic extract of an Indian Ocean gorgonian coral S. suberosa led to the isolation of (−)-56 together with the four related silphiperfolanes 57−60.68 (−)-Subergorgic acid 56 and compounds (−)-57, (−)-59, and (−)-60 were also found together with (−)-2β-acetoxysubergorgic acid 61 and subergorgiol 62 ([α]31D 0°) from Taiwanese collections of S. suberosa.69 Recently, sesquiterpenes (−)-56 and 58−62,70 whose ACs were determined on the basis of circular dichroism, Mosher’s method, and through chemical conversions, and (−)-suberosanone C 6371 were characterized from the same species collected off South China Sea. In the late 1980s, sesquiterpenes (−)-6472 and (−)-6573 were identified from tropical algae Laurencia majuscula collected from the coastal waters of North Queensland (Australia). AC of compound 64 was not determined, while the structure of 65 was later corrected and its AC secured by total synthesis (Scheme 17).74 Compound 64 was also found in the red alga Laurencia dendroidea from the southeastern Brazilian coast,75 and in Laurencia rigida (Cape Banks, Sydney, Australia).76 2.1.3. 6/5/3, 5/6/3, 5/3/6 Tricyclic Skeletons: Cycloeudesmane, Calenzanane, Shagane, and Cubebane. Red seaweeds in the genus Laurencia are a rich source of secondary metabolites of varied and often unusual structures.77 The first marine origin example (+)-66 of a 6,8-cycloeudesmane sesquiterpene, brominated at C-1 (Figure 8), was isolated from this genus,78 and most cycloeudesmanes so far reported belong to the 1,3-class 67 and 2,4-class 68, characterized from terrestrial plants.79 The only nonhalogenated cycloeudesmane of marine origin, (−)-cycloeudesmol 69, was identified from the red algae Chondria oppositiclada Dawson (Puerto Penasco, Mexico)80 and later from Laurencia nipponica (Hokkaido, Japan).81 The AC as well as correction of the structure originally proposed80 for this compound were determined by crystallographic study.82 Debromoisocalenzanol (−)-70 (Figure 9) was isolated from the red seaweed Laurencia microcladia collected in Elba Island,83 with the brominated compound (+)-7184 and the name calenzanane attributed to their new skeleton. Two similar compounds (−)-shagene A 72 and (+)-shagene B 73, bearing their cyclopropane unit at the cycle junction, were recently isolated from an undescribed Antarctic octocoral collected near the South Georgia Islands (Figure 9).85 A biosynthetic pathway to shagenes was proposed (Scheme 2) through formation of caryophyllyl cation 74, which could be transformed into 75 via a 1,2-H shift. Proton abstraction from this species could generate triene 76, which could undergo a proton-mediated ring closure to form carbocation 77, followed by a second proton abstraction to form diene 78, a possible precursor of shagenes. (+)-Cubebol 79 (Figure 10) was found in a soft coral of the Cespitularia genus collected in Orpheus Island (Palm Island Group, Townsville, Australia) in 1983.86 Radiolabeled experiments led on Cespitularia sp. showed that cubebol was synthesized by this soft coral.87 Its enantiomer (−)-79 whose AC was established by total synthesis starting from (−)-transcaran-2-one (Scheme 19),88 was also obtained from the brown algae Taonia atomaria (Rovinj, Croatia).89 (−)-4-Epicubebol 80 was also found in this seaweed and in the brown algae Dictyopteris divaricata (Okanamura, Japan) with four other sesquiterpenes: the methyl ethers (−)-81 and (−)-82, (−)-β-cubebene 83, and

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

Figure 5. Marine hirsutanes and isohirsutanes.

identified together with compounds (+)-32 and (−)-41 from the soft coral Dendronephthya rubeola (Bali, Indonesia).58 (+)-Δ9(12)Capnellene-8β,10α-diol 32 was also isolated from the soft coral Capnella sp. (Green Island, Taiwan)59 and from extracts of the Formosan soft coral Paralemnala thyrsoides.60 Six new capnellene sesquiterpenes 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 a silphiperfolane tricyclo[6.3.0.01,5]undecane framework, was first isolated in 1985 from the gorgonian Subergorgia suberosa (South China Sea) (Figure 7)63 and later from S. suberosa (Mandapam coast, Tamil Nadu, India)64 from the South China Sea gorgonian 6114


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Figure 6. Marine capnellanes.

Figure 9. Marine calenzanane and shaganes.

Scheme 2. Proposed Biosynthetic Pathway to Shagenes 72 and 73

Figure 7. Marine silphiperfolanes.

(Algoa Bay, South Africa)92 and the soft coral Gersemia rubiformis (Atlantic Ocean, New Foundland, Canada).93 The structure of the nitrogeneous isothiocyanato cubebane derivative (−)-87 found in an Okinawan marine sponge (Iriomote Island, Japan) of the genus Stylissa has been established from NMR studies94 to be the 2-epimer of (−)-88 reported from the sponge Axinyssa aplysinoides (Ant Atoll, Pohnpei, Federated States of Micronesia).95 Recently, (+)-13isocyanocubebane 89, whose AC was not determined, was isolated from the nudibranch Phyllidia ocellata collected in Mudjimba Island (Mooloolaba, Australia).96

Figure 8. Isocycloeudesmane and cycloeudesmanes.

(−)-α-cubebene 84 possessing the cubebane skeleton.90 (+)-αCubebene 84 was also isolated from the gorgonian Pseudoplexaura porosa.91 Two new sesquiterpenes (+)-cubebenone 85 and the cubebane derivative (+)-86 (Figure 10) were, respectively, characterized from an extract of the nudibranch Leminda millecra 6115


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revised in 2002102 to the correct structure (+)-perforatone 94, following extensive NMR analysis of this compound extracted from Laurencia obtusa collected off the coasts of Milos Island (Aegean Sea, Greece) together with metabolites 95−98. ACs of these compounds have not yet been determined. In the same series, compound (−)-99, whose AC was ascertained by X-ray diffraction study, was produced by Laurencia tenera collected off Florence Bay (Magnetic Islands)103 and (−)-tenerol acetate 100 extracted from L. tenera (Townsville region of the Great Barrier Reef, Australia).104 Eventually metabolites (+)-101 together with (−)-perforatol 102 were, respectively, identified from the sea hare Aplysia punctata collected at Porto San Paolo (Olbia, Sardinia, Italy)105 and the red alga L. obtusa (coastal rocks of Serifos in the Aegean Sea, Greece).106 2.1.5. 6/5/5 Tricyclic Skeleton: Probotryane. The carbotricyclic probotryane sesquiterpene (+)-103 (Figure 12)

Figure 10. Marine cubebane sesquiterpenes.

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

Figure 12. Probotryane.

was found in an extract from the mitosporic fungus Geniculosporium sp., which was associated with a marine red alga of the Polysiphonia genus (Ahrenshoop, Germany).107 Structural studies did not allow determination of the relative configuration 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 from the red alga Laurencia similis (Hainan Island, China) together with the known aristol-1(10),8-diene 107, 1(10)-8-aristoladiene 108, aristol-1(10)-en-9-one 109 (gansongone), and (+)-9βaristol-1(10)-en-9-ol 110 (Figure 13). 110,111 Metabolites (+)-105, (+)-110, and (−)-aristolone 111 were later found in the same marine organism.112 Interestingly, (−)-111 was known much earlier from the roots of Aristochia debilis,113 while its enantiomer (+)-111 (α-ferulone) was identified in the fruiting bodies of the basidiomycete Russula lepida114 and from the liverwort Porella cordeana.115 (−)-Aristolone 111 was also isolated from the AcOEt extract of the soft coral N. erecta (Green Island, Taiwan)116 and the corresponding enantiomer from Nephthea chabrolii (Pingtung County, Taiwan).117 The enantiomer (−)-112 of the known terrestrial (+)-1(10)aristolene (calarene) 112118 was found in the gorgonian Pseudopterogorgia americana (Bermuda and Florida Keys),119 in the yellow and gray morphs of the soft coral Parerythropodium f ulvum f ulvum (Gulf of Eilat, Red Sea),120 and in the marine red alga Laurencia decumbens collected in South China Sea waters offshore (Weizhou Island),121 as well as in the volatiles released from a marine Streptomyces sp., strain GWS-BW-H5, isolated from the North Sea.39 (−)-Aristolone 111 was isolated from the AcOEt extract of the soft coral N. erecta (Green Island, Taiwan)122 and the corresponding enantiomer from N. chabrolii (Pingtung County, Taiwan).123 The aristolanes (+)-104−(+)-110 and (−)-aristolone 111 were characterized from a sample of the marine red alga

Figure 11. Viridianol, punctaporanes, and perforetanes.

Two new caryophyllane-based sesquiterpenoids named (−)-punctaporonin L 91 and (+)-punctaporonin M 92 were obtained from the fermentation broth of the sponge-derived fungus Hansfordia sinuosae isolated from the sponge Niphates sp. collected off Southern China Sea (Figure 11).98 The AC of (−)-91, featuring a new skeleton named punctaporane, was attributed by comparison of the sign and magnitude of its optical rotation with the one of the corresponding tetraol 6-hydroxypunctaporonin E of terrestrial origin,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 (Canary Islands), in 1975,100,101 but its relative stereochemistry was 6116


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

Figure 14. Maalianes and laurobtusol.

Canyon, La Jolla and Point Loma, San Diego) nudibranch Cadlina luteomarginata.137 Their relative stereochemistry was deduced through NMR studies and confirmed by X-ray diffraction analysis of the derivative 129, obtained by acidic hydrolysis of 127. Compounds (+)-127−(+)-129 were found in the skin extract of the Northeastern Pacific nudibranch C. luteomarginata (Graham Islands, British Columbia), also 127 and 129 in its associated sponge Acanthella sp. (Figure 11).138 Compound (−)-128 was characterized from the marine sponge Acanthella pulcherrima (Weed Reef, Darwin, Australia),139 from Acanthella sp. (Ximao Island, Hainan, China)140 and from the marine sponge Axinyssa sp. collected either off One Tree, Heron Islands (Great Barrier Reef, Australia),141 or in Japan (Tsutsumi Island).142 The corresponding enantiomer (+)-128, also called epipolasin A, was identified from the sponge Epipolasis kushimotoensis where it coexists with the related (+)-epipolasin-A thiourea 130143 and in the sponge A. cavernosa (Heron Island, Great Barrier Reef, Australia).144 Its AC was deduced from circular dichroism experiments done on a derived product and comparison with maaliol. Compounds (+)-111 and (−)-128 were isolated from Axinyssa sp. collected at the Gulf of California.145 (+)-γ-Maaliene 131 is a constituent of the gorgonian P. americana (Bermuda and Florida Keys).119 Maaliane-type sesquiterpenes (+)-132 and (+)-3-maalien-1-ol 133 were obtained from the gorgonacea Clavularia 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 extracted from the calcareous alga Neomeris annulata, collected off the shallow inshore waters of Bermuda.148 Its AC was determined by comparison of the product obtained through bromine elimination 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 stereochemistry was assigned based on computational processing of the lanthanide-induced shifts in the 1H NMR spectra and molecular mechanics calculations but not yet confirmed through total synthesis.150 A plausible biogenetic route to this compound from humulene starting with the α-humulyl cation151 was proposed.

Figure 13. Aristolanes.

L. similis (Sanya Bay, Hainan, China),124 and compounds (+)-110 and (−)-111 were also found in Laurencia sp. collected in South China Sea.125 (+)-9-Aristolene 113 was one of the active components isolated from the marine sponge Acanthella cavernosa (Hachijo-jima Island, Japan)126 and from the gorgonian P. americana (Bermuda and Florida Keys),119 while the corresponding enantiomer (−)-113 was found in a soft coral of the Nephthea genus (Andaman and Nicobar group of islands, Indian Ocean).127 ACs of 111, 112, and 113 were determined earlier in 1962128 on the basis of indirect correlations with terrestrial maaliol of known AC.129 Extraction of the sponge Axinyssa isabela (Isla Isabel, Gulf of California, Mexico) led to the isolation of the aristolane sesquiterpene axinysones A−E 114−117 and (+)-axinynitrile A 118.130 The ACs of (+)-axinysones A 114 and B 115 were assigned by Mosher’s method, while that of the unusual nitrilecontaining aristolane (+)-118 was determined through its synthesis from (+)-aristolone 111. Recently, (−)-debilon 119, a known terrestrial sesquiterpene,131 was isolated from the red alga Laurencia complanata (southwest coast of Madagascar).132 Studies of the Australian soft coral Lemnalia humesi afforded two new sesquiterpenes (+)-120 and (+)-121, containing the aristolane skeleton and whose ACs were determined by chemical conversion into the known (+)-9-aristolene 113.133 Compounds (+)-110, (+)-111, (+)-115, and (+)-nardostachnol 122 were characterized from a Bornean red algal population of L. similis,134 while the only aristolane (−)-123 showing a functionalization of its gem dimethyl group was isolated from an Indonesian octocoral Lemnalia africana (Pohnpei, Micronesia).135 An investigation of the extracts from Mediterranean sponge Axinella cannabina (Bay of Taranto, southern Italy) furnished the new sesquiterpenes 124−126 of unknown ACs, with the maaliane skeleton and bearing an isonitrile, isothiocyanate, or 6117


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Maalianes differ from aristolanes only by the nature of the substitution of their identical 6,6,3 skeleton at the C10 and C5 positions, reflecting the possible biosynthetic origin (Scheme 3) Scheme 3. Proposed Biosynthetic Pathways to Maalianes and Aristolanes

Figure 16. Africananes.

Islands),163 Sinularia hirta (Andaman and Nicobar Islands, at the juncture of the Bay of Bengal and Andaman Sea),164 Sinularia kavarattiensis (Mandapam coast, India),165,166 Lobophytum paucif lorum (Havalock Island, Indian Ocean),167 and Lobophytum strictum (Andaman and Nicobar Islands).168 It was also isolated together with the known terrestrial sesquiterpene (+)-Δ7(8)-africanene 145 (1-africanene) from the aeolid nudibranch Phyllodesmium magnum collected from South China Sea169 and the soft coral Sinularia dissecta (Madapam Coast, 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 and 148−151 were isolated from Sinularia intacta collected from the Moyli Island (Gulf of Mannar, Indian Ocean).174 AC of (+)-150 as drawn was ascertained by comparison with the product resulting from the oxidation of (+)-144. Four africanane sesquiterpenes 144, 146, 148, and 150 were also characterized from South China Sea soft coral Sinularia numerosa.175 Compound 146 reported as (+)-10α-hydroxy-Δ9(15)-africanene is likely to be the 10β enantiomer, with a 1R configuration of the africanane skeleton as drawn in Figure 16.174 (+)-Ophioceric acid 152, whose absolute stereochemistry was not assigned, was identified from the aquatic fungus Ophioceras venezuelense (Heredia, Costa Rica).176 (+)-Palustrol 153, an aromadendrane tricyclic sesquiterpene bearing an angular hydroxy group (Figure 17), was identified using an interactive computer program in extracts of a marine Xeniid (Cespitularia subviridis) collected at Albatros Rocks (Seychelles Islands).177 This class of natural products is structurally characterized by the fusion of a hydroazulene nucleus to a cyclopropane ring. The AC of (+)-palustrol 153 was later determined by X-ray diffraction analysis of the corresponding autoxidation product.178 (+)-Palustrol 153, the major metabolite of the hexane extract of this soft coral, was found together with (−)-viridiflorol 154 and (+)-ledol 155, which have, respectively, opposite and identical configurations than their terrestrial counterparts.179 (+)-Palustrol was also recently isolated from a Bornean soft coral Capnella sp. (Mantanani Island, Sabah, Malaysia)180 and from the Red Sea soft corals Sarcophyton trocheliophorum181 and Sarcophyton glaucum.182 Sesquiterpene (+)-156 and the first natural nor-aromandendrane (−)-157 were identifed from the EtOAc solubles of the methanol extract of the Okinawan soft coral C. koellikeri (Okinawa, Japan).146 While the AC of 156 was proposed based on comparison with the maalianes 132 and 133 found

they have in common.152 Thus, germacradienyl cation (R)-12 could 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−C7 ring closure, 1,3-H shift, 1,2-Me migration, and loss of H+, implying the cations 137, 138, and 139, while maaliane 140 is the result of hydride attack on 138.39 2.1.7. 6/6/4 Tricyclic Skeleton: Paralemnane. (−)-Paralemnanol 141 (Figure 15), characterized from the soft coral P. thyrsoides (Green Island, Taiwan), possesses a very peculiar skeleton, which has never been encountered in other natural sources.153

Figure 15. Paralemnanol.

2.1.8. 7/5/3 Tricyclic Skeletons: Africanane, Aromadendrane, and Neomerane. (+)-Africanol 142 was isolated in 1974 from the soft coral L. af ricana (Leti Island, Maluku, Indonesia).154 X-ray diffraction studies confirmed its decahydro1H-cyclopropa[e]azulene core structure and determined its AC as depicted in Figure 16.155 A biosynthetic pathway to africanol 142 from α-humulene has been proposed.154 Its analog (+)-isoafricanol 143 was later found in the red alga Laurencia mariannensis (Hainan and Weizhou Islands, China).156 (+)-Δ9(15)-Africanene 144 was concomitantly reported for the first time from the soft corals of the genus Sinularia collected off two different locations: Sinularia erecta (Gulf of Eliat, Red Sea)157 and Sinularia polydactyla (Laing Island, Papua New Guinea).158 Its AC was determined by application of the octant rule on a derived ketone. It was later found in the soft corals Sinularia leptoclados (coast of Mandapam, Mannar Island),159 Sinularia capillosa (Sanya Bay, South China Sea),160 Sinularia sp. (Putti Island and Kurshide Island, Mandapam Coast, Indian Ocean),161,162 Sinularia conferta (Andaman and Nicobar 6118


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Figure 17. Aromadendranes.

soft coral Sinularia mayi (Nias Island, Indonesia) together with the major component (−)-aromadendrene 166.189 Its epimer (+)-alloaromadendrene 167 was found in extracts of a marine Xeniid (C. subviridis)179 and in Sarcophyton acutangulum (Ishigaki Island, Okinawa, Japan).190 Compound (−)-166 was also extracted from the Australian marine red alga Laurencia f iliformis.191 (−)-Lochmolins E 168, F 169, C 170, D 171, and B 172, whose ACs were not determined, were recently isolated from a Taiwanese soft coral Sinularia lochmodes.192 Sesquiterpenes (−)-163, (−)-173, (−)-174, and (−)-175 were characterized from the ethanol extract of an Indian specimen of the soft coral Sinularia maxima (Havelock Island, Indian Ocean).193 Metabolite (−)-163, (+)-spathulenol 176, and (+)-11-epispathulenol 177 obtained from Taonia lacheana (Lachea Island, Italy) represent the first aromadendrane sesquiterpenes isolated from brown algae.194 (+)-Spathulenol 176 was also isolated from S. kavarattiensis (Mandapam Coast, India)165,166 and from the lipophilic extract of the soft coral P. f ulvum f ulvum (Phantom Island, North Queensland, Australia) together with the corresponding acetate (−)-178 and the known terrestrial195 tridensenone 179.196 Compound (−)-180, bearing an original fulvene moiety, probably responsible for the color of

concomitantly, that of 157, previously reported as a (+)-synthetic intermediate prepared from (+)-aromadendrene,183 followed from comparison of the [α]D with literature values, was therefore established as (−)-(1S,4R,5R,6S,7S)-157. (+)-Cyclocolorenone 158 (Figure 17), previously known as a terrestrial metabolite, was isolated from the soft coral N. chabrolii (Sinyaru Island, Indonesia)184 and later, together with its analogue (+)-1α-hydroxycyclocolorenone 159, from the soft coral Nephthea sp. (Andaman and Nicobar Islands, Indian Ocean).185 The Formosan soft coral Clavularia inf lata var. luzoniana collected off Green Island (Taiwan) was the source of three aromadendranes 160, 161, and 162.186 ACs of (+)-160 and (+)-161 were determined as 3R using Mosher’s method. Marine sesquiterpene (+)-161 is the enantiomer of (−)-3β-hydroxyspathulenol obtained from the terrestrial Chilean liverwort, Lepicolea ochroleuca.187 Two aromadendranediols possessing a trans ring junction between C1 and C5, (+)-4α,7β-aromadendranediol 163 and (−)-4α,7α-aromadendranediol 164 (Figure 17), whose opposite enantiomers were later found in the South China Sea gorgonian Melitodes squamata,188 and one minor compound (−)-165 possessing the corresponding cis junction were isolated from the 6119


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the yellow morph it belongs to, was identified from the soft coral P. f ulvum f ulvum (Gulf of Eilat, Red Sea).120 Extracts of the nudibranch L. millecra (Coffee Bay, South Africa) afforded (+)-squamulosone 181, also called millecroneB.197 Spicules from soft corals were found in the digestive gland of L. millecra, suggesting a dietary origin of this secondary metabolite. 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 (San Diego, CA, USA), contained a variety of metabolites from which the quaternary allylic alcohols (−)-182 and (−)-183 were discovered.198 The only known marine origin aromadendrane bearing a substituted methyl in the C12 position (−)-184 (Figure 17) was isolated from C. koellikeri collected around Laing Island (Papua New Guinea).199 A peculiar dimeric structure 185, named (+)-halichonadin E, bearing both aromadendrane and eudesmane skeletons linked by a urea function, was characterized from a marine sponge Halichondria sp., collected off Unten Port (Okinawa, Japan).200 Formation of (+)-alloaromadendrene 167 can arise by successive proton-mediated C1−C7 ring closure starting from 136 and loss of H+, implying the cation 186 (Scheme 4).40 Scheme 4. Possible Biosynthetic Pathway to (+)-Alloaromadendrene 167

Figure 18. Nitrogenous aromadendranes, allo-aromadendranes, and neomerane.

196−198,211 isolated from the marine sponge A. cannabina collected off the coast of Taranto (Italy). Compounds (−)-189 and (−)-197 were also extracted from the sponge Axinyssa sp. collected off Tsutsumi Island (Japan),142 and Acanthella sp. was shown 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 compounds 188−190, (−)-axisothiocyanate 194, and (−)-197 were also isolated from specimens of the Indo-Pacific sponge A. cavernosa collected from locations along the eastern coastline of Australia.213 Metabolite (−)-188 was extracted from the nudibranch P. ocellata collected in Mudjimba Island (Mooloolaba, Australia)96 and found together with 197 from the marine sponge 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 while the nudibranch P. pustulosa found in the same location produced (+)-axisonitrile 193.215 The nitrogenous sesquiterpene bearing a formamide substituent, (+)-axamide 195, was also recently characterized from the Thai marine sponge Halichondria sp. (PP Island, Andaman Sea, South Thailand).216 The new sesquiterpene isothiocyanate, named (+)-epipolasin B 199, was found in the sponge E. kushimotoensis where it co-occurs with the related epipolasinthiourea B 200. Their stereochemistry, relative and absolute, was deduced from chemical correlation to (−)-aromadendrene 166.143 Metabolites (+)-201 and (−)-202, bearing a peculiar CH2NH(CH2)2Ph group, were identified in the South China Sea gorgonian M. squamata.186 (−)-Neomeranol 203, also possessing a rare structure, was obtained from extracts of the calcareous alga N. annulata collected off the shallow inshore waters of Bermuda,148 and its AC was elucidated by a modified Horeau’s method.217 2.1.9. 7/6/3 Tricyclic Skeleton: Capillosanane. (+)-Capillosanane V 204 (Figure 19), isolated from the soft coral S.

Nitrogeneous compounds (Figure 18), among them sesquiterpenes bearing isonitrile, isocyano, isothiocyanato, or formamide functional groups, are commonly encountered in the marine world.201 The only example of a tricyclic sesquiterpene bearing a primary amine function, (+)-halichonadin F 187, was isolated from the marine sponge Halichondria sp. collected off Unten Port (Okinawa, Japan) together with an unusual copper(I) complex of the eudesmane halichonadin C.202 The relative configurations of compounds (−)-188, (−)-189, and 190 characterized from the toxic extract of the marine sponge Acanthella acuta, collected off the Mediterranean Sea (Banyuls, France),203,204 were later corrected by chemical correlation with palustrol 153.178 Compounds (−)-188 and (−)-189 were also isolated from the same sponge but in a different location (Bay of Napoli),205 and compound 189 was later found in a specimen of A. aplysinoides (Pohnpei).95 A chemical study of an extract from the Spanish dancer nudibranch Hexabranchus sanguineus, collected in the South China Sea was the source of the new aromadendrane sesquiterpene (+)-191 as the main metabolite.206 Its AC was tenuously proposed based upon comparison of the sign of its experimental optical rotation with palustrol’s one. A chemical study of the Vietnamese nudibranch mollusk Phyllidiella pustulosa207 afforded (+)-(10R)-isothiocyanato-allo-aromadendrane 192, whose AC was determined by comparison with its semisynthetic enantiomer,208 together with (−)-188 and (−)-189. Such aromadendrane structure, bearing nitrogenous substituents in the C10 position, was first found in the 1970s209,210 in compounds 193−195 and later in compounds 6120


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capillosa (Sanya Bay, South China Sea), possesses a very peculiar skeleton which has never been encountered in other natural sources.160

Figure 19. Capillosanane.

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

Figure 20. Rumphellolide F.

nor-sesquiterpene alcohol with a cyclopropane ring, was isolated from the Taiwanese soft coral Rumphella antipathies.218 It was previously obtained by chemical synthesis on base treatment of kobusone, a caryophyllene-derived epoxy ketone.219 2.2. Bridged Carbocycles

2.2.1. Tricyclic Decane Skeletons: Ylangane, Copaane, Sinularane, Trachyopsane, Pupukeanane, Allopupukeanane, Abeopupukeanane, Neopupukeanane, Sativane, and Isosativane. (−)-Lemnalol 206 (Figure 21), an ylangenetype sesquiterpenoid whose AC was established by the 1H NMR lanthanide-induced shift method and X-ray crystallographic analyses, was first found in the Japanese soft coral Lemnalia tenuis (Okinawa, Japan),220 and later (−)-(1S,2S,4R,6S,7R,8S)-4αformyloxy-β-ylangene 207 was isolated from the soft coral Lemnalia f lava (Green Island, Taiwan) along with (−)-lemnalol 206 and (+)-cervicol 208.60 Metabolites 206 and 208−210 were characterized from the methylene chloride solubles of the Formosan 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 major metabolite along with (+)-α-copaene 212.189 The known terrestrial antipode (−)-212 was found in the marine alga D. divaricata.222 The tricyclo[4.4.0.02,7]decane skeleton was also recently found in philippinlins A (−)-213 and B (+)-214, which were isolated from the soft coral Lemnalia philippinensis collected off the coast of Lanyu (Taiwan) together with (−)-lemnalol 206.223 (+)-β-Copaene 211 was also detected in Eunicea succinea collected off St. Croix (United States) and South Caicos (United Kingdom) islands,224 Eunicea palmeri, P. porosa, P. wagenaari, and Pseudoplexora 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 Sea soft coral Dendronephthya sp. (coast of Hurghada, Egypt) in compounds (−)-215, (−)-216, and (−)-217, respectively, named dendronephthol A, B, and C.227 (−)-Sinularene 218 was the most abundant sesquiterpene hydrocarbon extracted from the soft coral S. mayi (Eastern reef of Telukdalam, Nias Island, Indonesia).189,228 The corresponding 12-acetoxysinular-

Figure 21. Compounds of marine origin possessing a tricyclic decane skeleton.

ene (−)-219, whose structure was determined by an X-ray diffraction study, was identified from Clavularia inf tata (Laing Island, Papua New Guinea).199 The nitrogenous sesquiterpenes 220−222 (Figure 21) were reported from the Palauan sponge A. (= Trachyopsis) aplysinoides.229,230 Bioassay-guided isolation of the nudibranch Phyllidia varicosa (Shimokoshiki-jima Island, Japan) allowed identification of (+)-2-isocyanotrachyopsane 223 with good antifouling activity.231 ACs for compounds (−)-221 and (+)-223 were later assigned via total enantioselective syntheses (Scheme 30) leading, respectively, to the same [(−)-221] and the opposite [(−)-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 sponge Hymeniacidon sp., as a mixture of volatile substances lethal to fish and crustaceans. Circular dichroism measurements and X-ray diffraction data established the ACs of the two metabolites. 6121


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

[13C]-Labeled 225 was encased in gelatin capsules and embedded in a live Hymeniacidon sponge in the ocean for 7− 14 days incubation.235 Analysis by gas chromatography/mass spectrometry of the presence of 225 and the related 2formamidopupukeanane 226 and 2-isothiocyanopupukeanane 227 in the isolated extracts showed that the isocyano group was the precursor of the formamido and isothiocyano groups, the reverse reactions did not take place, and the sponge did not utilize formate in the isocyano biosynthesis. It was also shown that extraction of the sponge Ciocalypta sp. (Hawai)236 and Axynissa n. sp. (Australia)237 incubated with [14C]-labeled sodium cyanide resulted in radioactive 225, thus suggesting the existence of cyanide ions of metabolic origin. Compound (−)-226 was recently isolated from the nudibranch Phyllidia codestis Bergh collected off Koh-Ha Islets (Krabi Province, Thailand) together with the abeopupukeanane (+)-228.238 Cooccurrence of (−)-9-isocyanopupukeanane 224 and its C-9 epimer (+)-229 was observed in the nudibranch Phyllidia bourguini collected from Hachijo-jima Island (Japan).239 Compounds 224 and 229 were also found in P. pustulosa collected off Hachijo-jima Island (Japan).215 An epimeric mixture of two new 9-thiocyanatopupukeanane sesquiterpenes 230 and 231 (Figure 21) obtained from the methanol extract of the nudibranch P. varicosa and its spongeprey Axinyssa aculeata collected off the coral reefs of Pramuka Island (Thousand Islands National Park, Indonesia)240 was also found in nudibranch mollusk P. pustulosa (offshore, Vietnam).207 Compound (−)-224 was found in the marine sponge Axinyssa sp. collected off either One Tree or Heron Islands (Great Barrier Reef, 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 marine sponge of the genus Axinyssa (Gun Beach, Guam) deterred feeding in the common pufferfish Canthigaster solandri. However, the only constituent of the sponge to be available in sufficient quantities for the bioassay, (+)-5-isothiocyanatopupukeanane 234, failed to deter feeding when tested at a relatively high concentration.241 The marine sesquiterpene (−)-2-thiocyanatoneopupukeanane 233 with the coexisting isomeric natural product (−)-235 were isolated from sponges Phycopsis terpnis from Okinawa (Japan) and in an unidentified species from Pohnpei.242 The correct stereochemistry of (−)-233 was determined based on NMR studies done on this compound isolated from A. aplysinoides (Palau)95 and later confirmed by total 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, whose AC was not determined.244 The biosynthetic origins of the isocyanide and isothiocyanate groups in 9-isocyanopupukeanane 224 and 9-isothiocyanatopupukeanane 232 were investigated by incorporation of the corresponding [14C]-labeled compounds independently into the 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 (the radioactive compound 224) clearly indicating that these two metabolites can be interconverted by the sponge, in contradiction with the experiments previously conducted on compound 225.235 6122


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After mass cultivation, the fungus Drechslera dematioidea isolated from the inner tissue of the marine red alga Liagora viscida 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 isolated terrestrial sativene.248 The allopupukeanane derivative (+)-239 was found in the nudibranch P. pustulosa collected off Hachijojima Island (Japan).215 The biosynthetic pathway to α-copaene 212 could be explained (Scheme 5)39 starting from cation (S)-12, which after hydride migration and subsequent deprotonation could give germacrene 240. Under its transoid conformation, this last species 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 αamorphene 245 by 1,3-hydride migration and subsequent ring closure to give 244 and proton loss.249 Subsequent C−C shifts could afford cations 247, 248, and 249 as precursors of, respectively, the pupukeanane, abeopupukeanane, and neopupukeanane series.238 2.2.2. Tricyclic Undecane Skeletons: Acanthodorane, Isotenerane, Quadrane or Suberosane, Paesslerane, Longibornane, Rumphellane, Strepsesquitriane, and Cedrane. (+)-Acanthodoral 250 (Figure 22) is a sesquiterpene aldehyde characterized from the nudibranch Acanthodoris nanaimoensis collected in Barkley Sound, British Columbia.250 Natural acanthodoral 250 is likely to have a dextrorotatory optical rotation on the basis of biogenetic considerations, although its optical rotation has not been determined due to the difficulty of purification and the extremely small quantity (7 mg/100 animals) coupled with the high volatility of this minor component. Its absolute stereochemistry was postulated based on its synthesis (see section 4.2.2).251 The bridged sesquiterpene, (−)-4-hydroxy-1,8-epi-isotenerone 251, was isolated from the red alga L. perforata (Magnetic Island, Australia),252 while its unstable brominated analog (−)-252 was obtained from L. tenera collected off Florence Bay (Magnetic Islands, Australia).103 (+)-Suberosenone 253, the first quadrane-type253 sesquiterpene of marine origin, was one of the three cytotoxic compounds characterized from the gorgonian S. suberosa in 1996.254 Five additional suberosane sesquiterpenes possessing the same dense skeleton, (−)-suberosenol A 254, (−)-suberosenol B 255, (−)-suberosenol A acetate 256, (−)-suberosenol B acetate 257, and (+)-suberosanone 258, were later isolated from the gorgonian I. hippuris collected off the Southeast coast of Taiwan.66 The rare sesquiterpene alkaloid (+)-259255 was reported as a mildly cytotoxic metabolite isolated from the gorgonian S. suberosa (China) together with (−)-suberosenol A 254.70 The latter was also found in the gorgonian Menella sp. collected off Meishan Island (South China Sea).67 The relative configuration at C2 of (+)-259 was later corrected (as drawn in Figure 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, and suberosenol A acetate 256 have been proposed via density functional theory calculations of their optical rotation,257 but AC of (+)-suberosanone was recently reversed based on its total synthesis (see section 4.2.2, Scheme 39). (+)-Suberosenone 253 was also identified from Alertigorgia sp. collected off the east side of Joseph Bonaparte Gulf (Northern Territories, Australia) together with the peculiar dimer (+)-alertenone 261.258 Although the biosynthesis of terrestrial metabolite quadrone

Figure 22. Compounds of marine origin possessing a tricyclic undecane skeleton.

was explored, there was only one biosynthetic proposal regarding the suberosanes that were shown to be linked to silphinanes via the presilphiperfolan-8-yl carbocation before their isolation from marine natural sources (see Scheme 37).259 In the course of the search of minor bioactive metabolites from deep-water marine invertebrates, paesslerins A 262 and B 263 (Figure 22) were isolated from the sub-Antarctic soft coral Alcyonium paessleri (South Georgia Islands) collected by netting at around −200 m. Their structures with an unprecedented tricyclic 2,8,8,10-tetramethyltricyclo[4.3.2.02,5]undecane skeleton named paesslerane were elucidated by spectroscopic techniques.260 However, from synthetic studies directed to the stereoselective formation of highly substituted bicyclo[4.2.0]octane framework as found in paesslerin, it has been made clear that a revision of the structure of natural paesslerin A is required.261 These compounds show moderate cytotoxicity in preliminary assays. The tricyclic sesquiterpene (+)-isoculmorin 264, isolated from the culture broth of marine fungus Kallichroma tethys (Figure 22),262 exhibited a longibornane skeleton but differs from culmorin 265263,264 and all other known culmorin derivatives of terrestrial origin265 in that it lacks a hydroxy or keto group at C-11. A sesquiterpene possessing a new carbon skeleton named rumphellane, (−)-rumphellaoic acid A 266, was recently characterized from the gorgonian coral R. antipathies collected off the coast of Pingtung (Taiwan).266 Its AC was not established. (+)-Strepsesquitriol 267 possessing a 6123


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rare strepsesquitriane skeleton was identified from the deep-seaderived actinomycete Streptomyces sp. SCSIO 10355, collected in the Bay of Bengal (Indian Ocean).267 Its AC was determined by NMR analysis and theoretical optical rotation derived from quantum-chemical calculations. The diastereoisomeric cedranes (+)-α-pipitzol 268 and (−)-β-pipitzol 269 were found in plants of the genus Perezia268 before their recent identification from the soft coral Pseudopterogorgia rigida, collected in the Caribbean Sea (United States).269 Their relative stereochemistry was later confirmed through an X-ray diffraction study.270 Isotope incorporation studies271 with A. nanaimoensis were consistent with the proposed biosynthetic pathway250 to acanthodoral 250. Thus, FPP 11 could give diene 270 and then cation 271 via two consecutive cyclizations (Scheme 6). Acanthodoral 250 could then arise directly from this cation or through formation of aldehyde 272. Scheme 6. Possible Biosynthetic Pathway to Acanthodoral 250

Figure 23. Marine compounds possessing a tricyclic dodecane skeleton.

(+)-Penicibilaenes A 288 and B 289, incorporating a tricyclo[6.3.1.01,5]dodecane skeleton, named penicibilane, were recently isolated from the fungus Penicillium bilaiae MA-267 collected from the rhizospheric soil of the marine mangrove plant Lumnitzera racemosa at Hainan Island (South China).278 Their ACs were established by X-ray analysis. From the soft coral L. af ricana collected off south Kenya was found (−)-lemnafricanol 290 of unknown AC, and a possible biogenetic pathway was suggested starting from 1(10)-aristolane.279 (−)-Paralemnanone 291 and (+)-isoparalemnanone 292 (Figure 23) epimeric at C12, whose ACs were established by application of Mosher’s method, were isolated from the soft coral P. thyrsoides (Green Island, Taiwan).153 A possible pathway to caryolene 298 and caryol-7-en-6α-ol 273 was proposed based on DFT calculations.280,281 An asynchronous [2 + 2] cycloaddition could provide cation 294 through 293 starting from FPP 11 (Scheme 7). This cation could then be transformed, under basic conditions, into diene 295 whose protonation could generate cation 296. Cyclization into 297 and subsequent proton loss could result in caryolene 298 and its corresponding functionalized derivatives. Five halogenated tricyclic sesquiterpenes (Figure 24) of marine origin built on the rhodolaurane skeleton have been described to date. Among them, rhodolauradiol 299 and (+)-rhodolaureol 300 were found in an unidentified alga of the genus Laurencia282 and from L. obtusa collected off Lanzarote (Canary Islands).283 Their absolute configurations were determined through X-ray diffraction analysis of synthetically related compounds. (+)-Isorhodolaureol 301, whose AC was not determined, was isolated from L. majuscula collected off Zoe Bay (Hinchinbrook Island, North Queensland).72 Its structure was confirmed by synthetic transformations which led to enone 302, identical with the known oxidized form of 300. Compound 304

2.2.3. Tricyclic Dodecane Skeletons: Caryolane, Isocaryolane, Clovane, Penicibilane, Lemnafricanane, Isoparalemnane, Rhodolaurane, Gomerane, and Omphalane. Isolation of the cytotoxic caryolane sesquiterpene (−)-273 along with inactive analogs (−)-274 and (−)-275 possessing a tricyclo[6.3.1.02,5]dodecane skeleton was reported in 1988 from a New Zealand marine sponge of the genus Eurypon (Figure 23).272 It was postulated that 274 and 275 could result from artifacts arising during the isolation procedure by oxidation of the allylic alcohol group in 273 followed by conjugate addition of water or methanol to the enone intermediate. During a collection of marine sponges off the Mercury Islands, New Zealand, some different but related compounds were obtained from a specimen of the same species. Separation of the crude hexane extract, which had significant antimicrobial activity, resulted in isolation of the antimicrobial sesquiterpene (−)-273 together with the inactive sesquiterpenes (−)-274 and (−)-276−(−)-278.273 Structures of the new sesquiterpenes 276−278 were determined by spectroscopic methods, but their ACs were not determined. Compound (+)-279 of unknown AC was recently isolated from the gorgonian coral R. antipathies, collected off the water of Taiwan (Pingtung).274 The nitrogenous metabolites (−)-280− 282, whose ACs were established based on X-ray crystallographic analysis, were recently characterized from the nudibranch P. ocellata collected off Mudjimba Island (Mooloolaba, Australia).96 The new clovane derivatives (−)-283,275 (−)-rumphellclovanes D−E 284−285,276 (−)-clovan-2,9-dione 286,276 and (+)-rumphellclovane B 287277 were reported as marine natural product extracted from the gorgonian coral R. antipathies collected off the southern coast of Taiwan. 6124


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

Scheme 7. Possible Biosynthetic Pathway to Caryolane 273

2.3. Miscellaneous Carbocycles: Inflatane, Cyclolaurane, and Cyclococane

Aromatic tricyclic sesquiterpenoid (−)-debromolaurinterol 310 and the corresponding brominated compound (+)-laurinterol 311 (Figure 25) were first mentioned in 1966, as produced by

Figure 25. Miscellaneous marine tricyclic sesquiterpenes. Figure 24. Halogenated marine rhodolauranes, gomeranes, and omphalanes possessing a tricyclic dodecane skeleton and sesquiterpene 303.

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 of compound (+)-311 was determined later from the same sample via an X-ray diffraction study.292 Metabolites (−)-310 and (+)-311 were also extracted from the same species collected in different locations: Hakata-shima, Inland Sea of Japan,293 and Nyudogatane, Okino-shima, Tosa Province (Japan), together with (+)-313.294 (−)-Debromolaurinterol 310 was found in Laurencia f lexilis collected off Barrio Pangil (Curimao, Llocos Nortes, Philippines).295 (−)-Cyclolaurene 314, referred to as a rare cuparane sesquiterpene derivative, was isolated together with brominated analogs (−)-cyclolaurenol 315 and (−)-cyclolaurenol acetate 316 from the sea hare A. dactylomela collected off Kohama Island (Okinawa, Japan).296 Its AC was deduced from chemical interconversion to the cyclolaurane-type sesquiterpene (−)-laurequinone 321 characterized from red alga Laurencia nidifica collected off the coast of Goza (Japan) together with compounds (−)-310 and (+)-311.297 Dimer (+)-322 was later identified from the same source298 and from the red alga Laurencia tristicha

was characterized from L. mariannensis collected off Hainan and Weizhou Islands (China).156 It could nevertheless be an artifact of the isolation of 303 concomitantly found in this alga, which was shown to rearrange into 304 on silica gel, as previously shown in a biomimetic synthetic study en route to rhodolaureol and rhodolauradiol.284 Compounds (−)-305, (+)-306, and (+)-307, whose ACs were not determined, belong to a new class of sesquiterpenes named gomerane, based on the location (La Gomera, Canary Islands) where the red alga L. majuscula containing these metabolites was collected.285 It was later shown that epimeric gomerones 306 and 307 had been interchanged in their assignments via total synthesis of the former.286 The bridged tricyclo[7,2,1,01,6]dodecane compound (+)-güimarediol monoacetate 308 resulted from acetylation of one extract of the red seaweed Laurencia sp.287 Its skeleton was designed as güimarane and its AC ascertained by X-ray diffraction analysis. (−)-Dactylomelatriol 309, sharing the same skeleton 6125


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Table 1. Cytotoxic Activities toward Human Colon Cancer Cell Lines cell lines HT-29

SW480 SW620 LoVo HT115 WiDr Col2

cytotoxic activities (+)-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 ( 50 μg/mL (>196 μM)42 (−)-15 ED50 = 0.58 ± 0.09 μg/mL (2.3 μM)42 (−)-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 (+)-32 IC50 = 63 μM, 34 IC50 > 4500 μM55 (+)-32 IC50 = 0.16 μg/mL (0.7 μM)59 (−)-64 inactive, (−)-65 ED50 = 17.8 μg/mL (80.1 μM), (+)-301 and (−)-310 ED50 > 20 μg/mL (>100 μM)312

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

collected off the coast of Naozhou Island (Zhanjiang City, China) together with the new compound (+)-317.299 Another cuparane-derived compound (−)-318 with a cyclolaurane skeleton was also found in the red alga L. tristicha collected 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 Toyama Bay (Japan).301 Cyclolaurane dimer (−)-323 was previously obtained106 with (+)-311 from L. microcladia collected at Chios Island in the North Aegean Sea, but its structure was erroneously drawn as 324, which corresponds to an achiral meso compound resulting from the ortho coupling of (−)- and (+)-laurinterol 311. (+)-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 pilulifera collected 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 Aplysia california 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 China Sea),308 while 310−312 and (−)-323 were produced by the red alga L. tristicha collected off Shanwei (Guangdong Province of China).309 Compound (−)-320 is the only tricyclic sesquiterpene bearing two different halogen atoms (bromine and iodide). It was found in L. microcladia collected at Chios Island (North Aegean Sea, Greece) together with (+)-312 and the new dimer (−)-325.310 The relative stereochemistry found in 325 following NOE study led to a surprising structure involving epimerization of the laurinterol motif at C7. Compounds 310−321 and the related dimers 322−325 are found to possess either a cuparane or a cyclolaurane-type skeleton. We propose cyclolaurane to name this skeletal type, having an extra bond between C12 and C10 relative to the cuparane skeleton. Sesquiterpene (−)-326 with a new fused/joined carbon skeleton made of two cyclopropane rings, one being fused to a cyclobutane ring, was identified in the course of bioguided fractionation 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 and four cytotoxic diterpenes.186 This first in class inflatane (−)-326 was however not cytotoxic to P-388 and HT-29 cells.

3. BIOLOGICAL ACTIVITY 3.1. Cytotoxic and Antitumor Activity

Cytotoxicity toward a wide range of cancer cell lines (Tables 1−7) was the prevalent kind of biological activity reported for tricyclic sesquiterpenes of marine origin, usually expressed as 50% of the effective dose (ED50), inhibitory concentration (IC50), growth inhibition (GI50, this value emphasizes the correction for the cell count at time zero), lethal concentration (LC50), or cytotoxic concentration (CC50) and ordered in each entry by increasing numbers and references. Among the 284 identified metabolites, 79 products incorporating 17 different skeletons 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 the suberosane family. They showed good [(−)-255, 9.5 μM] to excellent ED50 values in the nanomolar range [(−)-254 and (−)-258, 0.023 nM; (−)-256, 1.4 nM; (−)-257, 19 nM] in this cell line.66 Kelsoenes 630 and 8 exhibited moderate to good activity (15.6 and 7.6 μM, respectively).32,38 Compound (+)-4 was shown to have no activity (ED50 > 45 μM), emphasizing the importance of the peroxide function in the same kelsoene series as found in (+)-5, which exhibited good (2.1 μM) activity against HT-29 cell line.32 In the ylangane series, contrary to the bridged compound (−)-lemnalol 206 which demonstrated a moderate cytotoxic 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 compound 206, 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 moderate cytotoxicity (2.2−20.3 μM) observed in the hirsutane series for compounds (−)-15,42 20,45 and (+)-2750 against SW480, SW620, and LoVo cell lines could be explained by the presence of an electrophilic α-methylene cyclopentenone group in these compounds, while in the same series, compounds (+)-17,50 (−)-18, (+)-19,42 and (−)-22−2350 lacking this functional group 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 contrary to its analogue (+)-Δ9(12)-capnellene-8β,10α-diol 32, which demonstrates a moderate activity (IC50 = 63 μM) against HT115 cell lines and a good activity (IC50 = 0.16 μg/mL) toward WiDr 6126


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Table 2. Antitumor Activities toward Human Breast Cancer Cell Lines cell lines MCF7 MDA-MB-231 MDA-MB-435 MDA-MB-453 ZR-75-1

cytotoxic activities (−)-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 (−)-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 (−)-15 ED50 = 1.82 ± 0.37 μg/mL (7.4 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM)42 (−)-15 ED50 = 1.08 ± 0.10 μg/mL (4.4 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM)42 (−)-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

human human

HL-60 K562

human human murine

ATL BC-1 P-388

murine murine murine

L1210 MOLT-3 L5178Y

cytotoxic activities (+)-32 IC50 = 51 μM, (+)-34 IC50 = 68 μM, (+)-35 IC50 = 713 μM55 (+)-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 (+)-110 and (+)-122 LC50 = 5 μg/mL (22.7 μM), (−)-111 and (+)-115 no activity134 (−)-64 inactive, (−)-65 and (−)-310 ED50 > 20 μg/mL (>100 μM)312 (+)-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 (53.6 μM),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 (22.5 μM), (+)-301 ED50 = 2.8 μg/mL (8.4 μM), (−)-310 ED50 > 5 μg/mL (>22.1 μM)312 (+)-130 ED50 = 4.1 μg/mL (10.6 μM), (+)-200 ED50 = 3.7 μg/mL (9.6 μM)143 (+)-195 IC50 = 57 μM216 (−)-215 ED50 = 8.4 μg/mL (33.3 μM), (−)-217 ED50 = 6.8 μg/mL (25.5 μM)227

cell lines.55 These two structures differ solely by the presence of an 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 toward Col2 cell line.312 Biological activities against human breast cancer were evaluated on MCF7, MDA-MB-231, MDA-MB-435, and MDA-MB-453 cell lines (Table 2). In the hirsutane and capnellane series, (+)-incarnal 27 (IC 50 = 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 triol 19,42 (+)-capnellen-8β-ol 34,55 and (+)-3β-acetoxycapnellene8β,10α,14β-triol 3555 were found inactive. No activity toward MCF7 cells were detected for compounds (+)-110, (+)-111, (+)-115, and (+)-122 in the aristolane series,134 and weak to no activity (78.4 to >100 μM) was observed for cyclolauranes (+)-312, (−)-320, and (−)-325.310 (+)-Suberosenone 253 was shown to have in vivo antitumor activity (IC50 = 2 μM), while its dimer (+)-alertenone 261 exhibited a lowest cytotoxicity (IC50 = 91.6 μM) against MCF7 cell line, implanted subcutaneously, and intraperitoneally in mice, as well as against A549, HOP-92, SF295, SF539, SNB19, LOX, M14, MALME-31, and OVCAR cell lines (IC50 = 79.6 to >227.5 μM).258 The latter was presented as a storage nontoxic form of (+)-suberosenone 253, which could be a 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-MB435 (ED50 = 1.8 μM), and MDA-MB-453 (ED50 = 4.4 μM) cell lines, 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 carcinoma MDA-MB-231 cell line.216 The bridged tricyclic structure (−)-philippinlin A 213 tested against this cell line showed weak activity (IC50 = 69 μM), while its analogs (+)-lemnalol 206

and (+)-philippinlin B 214 showed no activity.223 (+)-Suberosane alkaloid 259 showed moderate cytotoxicity (IC50 = 23.1 μM),255 whereas its purine analogue (+)-260 showed weak cytotoxicity (data not provided) toward the same cell line.256 Moderate activity (38.8 and 47 μM) for compounds (+)-301 and (−)-310 and low activity (ED50 > 60 μM) for compound (−)-65 were determined in the breast cancer cell line, ZR-751.312 Capnellenes (+)-32 and (+)-34 showed weak (IC50 = 51 and 68 μM) to good activities (IC50 = 0.7 and 4.6 μM) against human leukemia HL-60 and K562 cell lines, respectively (Table 3).55 The activity of (+)-Δ9(12)-capnellene-8β,10α-diol 32 was nevertheless not confirmed later (GI50 = 67.4 ± 2.5 μM) in a study also showing that capnellenes (−)-41 (GI50 = 70.9 ± 2.7 μM) and (+)-47 (GI50 = 62.2 ± 2.7 μM) exhibited weak cytotoxicities while (+)-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 active toward K562 cell lines.58 Their analog (+)-3β-acetoxycapnellene-8β,10α,14-triol 35 showed moderate (IC50 = 24 μM) and no activity (IC50 = 713 μM) against human K562 and HL-60 leukemia cell lines, respectively.55 Compounds (+)-110 and (+)-122 proved to be moderately 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 (−)-310 toward human BC-1 cell line.312 Aromadendranes (+)-160−(+)-162 186 and aristolanes (+)-110, (−)-111, (+)-115, and (+)-122 were reported as weakly or noncytotoxic (>100 μM) to murine P-388 cell line.134 Derivatives (+)-5, (+)-6,32 and (−)-838 proved to be good antileukemic agents with ED50 values in the range of 1.3−12.8 μM against murine cancer cell line P-388, while (−)-subergorgic acid 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 toward this cell line (ED50 = 16.3 μM) in comparison with its congeners 208−210, which were found inactive.221 Excellent activities 6127


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Table 4. Cytotoxic Activities toward Human Epidermoid, Nasopharyngeal, and Lung Cancer Cell Lines cell lines epidermoid KB

epidermoid A431 nasopharyngeal CNE1 nasopharyngeal CNE2 nasopharyngeal SUNE1 lung A549

lung HOP-92 lung Lu1

cytotoxic activities (+)-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 (>85 μM),153 (−)-1 and (+)-6 IC50 > 20 μg/mL (>98 μM),325 (−)-64 inactive, (−)-65, ED50 = 10.4 μg/mL (46 μM), (+)-301 and (−)-310 ED50 > 20 μg/mL (>60 μM)312 (−)-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 = 93.4 μM, (−)-320 IC50 = 92.4 μM, (−)-325 IC50 > 300 μM310 (−)-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 (−)-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 (−)-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 (−)-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 (−)-91 and (+)-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 (+)-253 IC50 = 0.11 μg/mL (0.5 μM), (+)-261 IC50 = 45 μg/mL (103 μM)258 (−)-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 Cell Lines cancer type

a

cell lines

cytotoxic activities

CNS CNS CNS glioblastoma medulloblastoma melanoma melanoma melanoma melanoma

SF295a SF539a SNB19a U-373a Daoya LOXa M14a MALME-3Ma Mel-2a

melanoma cholangiocarcinoma

B16b HuCCA-1a

(+)-253 IC50 = 0.03 μg/mL (0.14 μM), (+)-261 IC50 = 35 μg/mL (79.6 μM)258 (+)-253 IC50 = 0.002 μg/mL (9.2 × 10−3 μM), (+)-261 IC50 = 35 μg/mL (79.6 μM)258 (+)-253 IC50 = 0.006 μg/mL (27.5 × 10−3 μM), (+)-261 IC50 = 45 μg/mL (102.4 μM).258 (+)-301 ED50 > 20 μg/mL (>60 μM), (−)-310 ED50 > 20 μg/mL (>90 μM)312 (−)-141 ED50 > 20 μg/mL (>90 μM), (−)-291 and (+)-292 ED50 > 20 μg/mL (>85 μM)153 (+)-253 IC50 = 0.006 μg/mL (27.5 × 10−3 μM), (+)-261 IC50 > 100 μg/mL (>227.5 μM)258 (+)-253 IC50 = 0.010 μg/mL (45.8 × 10−3 μM), (+)-261 IC50 = 40 μg/mL (91.6 μM)258 (+)-253 IC50 = 0.008 μg/mL (36.6 × 10−3 μM), (+)-261 IC50 = 40 μg/mL (91.6 μM)258 (−)-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 (−)-15 IC50 = 25.6 μM, (−)-17 IC50 > 200 μM, (+)-27 IC50 = 14.4 μM44 (+)-195 IC50 > 100 μM216

Human cell line. bMurine cell line.

cell line.312 In the cyclolaurane series, compound (−)-310 showed a moderate cytotoxic activity (ED50 = 35.6 μM)312 contrary to (+)-312, (−)-320, and (−)-325, which were found inactive (ED50 > 90 μM) in this cell line.310 Hirsutanes (−)-18 and (+)-19, lacking an electrophilic αmethylene cyclopentenone group, were inactive (ED50 > 200 μM) toward nasopharyngeal (CNE1, CNE2,50 and SUNE 142) and lung cancer (A549)42 cell lines, while the corresponding close analogs (−)-15, (+)-20, and (+)-27 bearing this motif demonstrated good cytotoxic activities against the last cell line with ED50 or IC50 in the range of 2.4−12.4 μM42,45,50 (Table 4). Against A549 cancer cell line, compounds (+)-195,216 (−)-206, and (+)-214223 were not cytotoxic (IC50 > 100 μM) and compounds (−)-91, (+)-92,98 and (−)-213223 showed weak cytotoxic activity with IC50 values >10 μM. The nitrogeneous aromadendrane (+)-192 provided good cytotoxicity (IC50 = 7.5 μM) against this cell line,212 but the most efficient compounds toward this cell line were found in the suberosane series, with excellent 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) to potent cytotoxic (IC50 = 0.5 μM) activity toward A549 and HOP92 cell lines, respectively.258

toward murine P-388 cell line were observed in the suberosane series for (−)-suberosenone 254 (ED50 < 0.023 nM), (−)-suberosenol B acetate 256 (ED50 = 29 nM), (−)-suberosenol A acetate 257 (ED50 = 0.3 μM), and (−)-suberosanone 258 (ED50 < 0.023 nM), while (−)-suberosenol A 255 (ED50 < 15.4 μM) was only moderately cytotoxic. 66 Eventually compounds (+)-301 (ED50 = 8.4 μM), (−)-65, and (−)-310 (ED50 > 20 μM) showed good to moderate activity against this cell line.312 (+)-Epipolasin-A thiourea 130 and (+)-epipolasin-B thiourea 200, differing by their structures but with the same thiourea group, were shown to have good in vitro cytotoxic activities (ED50 = 9.6−10.6 μM) toward L1210.143 The formamido aromadendrane (+)-195 has a moderate activity (IC50 = 57 μM) against MOLT-3 cells.216 Sesquiterpenes (−)-215 and (−)-217 were found to be moderately active against L5178Y cells with ED50 values of 33.3 and 25.5 μM, respectively.227 Among the tricyclic sesquiterpenes of marine origin tested against human epidermoid KB cancer cell line, hirsutanes (+)-27,50 (+)-32,59 and (−)-silphiperfolane 65312 were moderately 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 (−)-64 and (+)-301 were inactive against the human epidermoid A431 6128


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Hepa59T/VGH A435 SK-Hep1 G402 A2780 OVCAR-3 PC3 LnCaP HeLa

KB-V1

hepatic hepatic hepatic renal ovarian ovarian prostate prostate cervical

cervical

(−)-15 ED50 = 0.90 ± 0.19 μg/mL (3.6 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM)42 (−)-15 IC50 = 2.49 ± 0.13 μg/mL (10.1 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-195 IC50 = 66.2 μM,216 (−)-213 IC50 = 16.0 μg/mL (67.7 μM), 206 and (+)-214 no activity223 (−)-15 IC50 = 6.11 ± 0.41 μg/mL (24.8 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-27 IC50 = 23.36 μM,50 (−)-91 and (+)-92 IC50 > 10 μM,98 (+)-104 IC50 > 10 μg/mL (>42 μM), (+)-105, 106, 109 and (−)-111 IC50 > 10 μg/mL (>46 μM), 107 and 108 IC50 > 10 μg/mL (>49 μM), (+)-110 IC50 > 10 μg/mL (>45 μM)124 (−)-141 ED50 > 20 μg/mL (>90 μM), (−)-291 and (+)-292 ED50 > 20 μg/mL (>85 μM)153 (+)-260 weak activity256 (−)-168−(−)-172 no activity192 (+)-32 IC50 = 42−51 μM, (+)-34 IC50 > 4.5 mM, (+)-35 IC50 = 52 μM55 (+)-32 IC50 = 9.7 μM, (+)-34 IC50 = 6.6 μM, (+)-35 IC50 = 32 μM,55 (−)-91 and (+)-92 IC50 > 10 μM98 (+)-253 IC50 = 0.02 μg/mL (91.6 × 10−3 μM)258 (+)-312 IC50 = 75.2 μM, (−)-320 IC50 = 88.5 μM, (−)-325 IC50 > 300 μM310 (−)-64 inactive, (−)-65 and (−)-310 ED50 > 20 μg/mL (>90 μM), (+)-301 ED50 > 20 μg/mL (>60 μM)312 (−)-15 ED50 = 8.27 ± 0.71 μg/mL (33.6 μM), (−)-18 and (+)-19 ED50 > 50 μg/mL (>200 μM),42 (+)-32 CC50 = 7.6 ± 0.8 μM,58 (+)-32 IC50 = 3.56 μg/mL (15.1 μM),59 41 CC50 = 9.4 ± 1.0 μM, 45−48 CC50 > 125 μM,58 (−)-57 ED50 = 4.3 μg/mL (16.4 μM),314 (+)-110, (−)-111, (+)-115 and (+)-122 no activity,134 (−)-87 IC50 = 57.8 μM,94 (−)-141 ED50 > 20 μg/mL (>90 μM), (−)-291 and (−)-292 ED50 > 20 μg/mL (>85 μM),153 (+)-163 and (−)-164 IC50 > 200 μg/mL (>840 μM),188 (−)-168−(−)-172 no activity,192 (+)-195 IC50 = 96.2 μM,214 215-217 no activity,227 (+)-310 IC50 = 18 μg/mL (83.2 μM), (−)-318 IC50 > 50 μg/mL (>193 μM).301 (+)-312 IC50 = 114.6 μM, (−)-320 IC50 = 81.4 μM, (−)-325 IC50 > 300 μM310 (−)-64 inactive, (−)-65 (parent cell line) 8.0 μg/mL (36 μM), (drug resistant cell line) 5.5 μg/mL (24.7 μM), (+)-301 ED50 > 20 μg/mL (>60 μM), (−)-310 ED50 > 20 μg/mL (>90 μM)312 Hep3B HepG2 Bel-7402 hepatic hepatic hepatic

cell lines cancer type

Table 6. Cytotoxic Activities toward Human Hepatic, Renal, Ovarian, Prostate, and Cervical Cancer Cell Lines

Compounds (−)-64, (−)-65, (+)-301, and (−)-310 exhibited no 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 noncytotoxic against 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 shown to 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 were reported for (−)-310 (ED50 = 21.3 μM), (−)-65 (ED50 = 54.4 μM), and (+)-301 (ED50 > 60 μM) (Table 5).312 (−)-Hirsutanol A 15 and (+)-incarnal 27, incorporating an electrophilic α-methylene cyclopentenone motif, exhibited moderate antiproliferative activity toward murine B16 melanoma cells (IC50 = 25.6 μM), while their analog (−)-hirsutanol C 17 was inactive against the same cell line (IC50 > 200 μM) (Table 5).44 Nitrogenous aromadendrane (+)-195 was inactive (IC50 > 100 μM) against human HuCCA-1 cell line.216 (−)-Paralemnanol 141, (−)-paralemnanone 291, and (−)-isoparalemnanone 292 were shown to be noncytotoxic against human medulloblastoma Daoy (ED50 > 85 μM)153 as well as (+)-301 and (−)-310 (ED50 > 85 μM) against glioblastoma U-373 cancer cell lines (Table 5).312 (−)-Hirsutanol A 15 exhibited good to moderate activity toward human hepatic Hep3B, HepG2, and Bel-7402 cancer cell lines with ED50 or IC50 values varying from 3.6 to 24.8 μM (Table 6) 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 HepG2 cell lines223 (Table 6). When submitted for a cytotoxicity assay against the cancer cell line BEL7402, aristolanes 104−111 were found to be inactive (IC50 > 40 μM).124 Compounds (+)-27 (IC50 = 23.4 μM), (−)-91, and (+)-92 (IC50 > 10 μM)98 showed moderate to weak activity against the same cell line. Compounds (−)-141, (−)-291, and (+)-292 were found to be noncytotoxic toward hepathic Hepa59T/VGH cell line,153 as well as (−)-168−(−)-172 against SK-Hep1cell line (Table 6).192 Capnellenes diol (+)-32 and triol acetate (+)-35 showed moderate activities (IC50 = 42−52 μM) toward human renal G402 cancer cell line (Table 6), while the corresponding alcohol (+)-34 was inactive (IC50 > 4.5 mM).55 Better results were found for these compounds toward human ovarian A2780 cancer cell line with IC50 values ranging between 6.6 and 32 μM.55 Compound (+)-253 was the only tricyclic sesquiterpene of marine 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) toward prostate PC3 and cervical HeLa cell lines, while compounds (+)-312 and (−)-320 were reported to be weakly active toward PC3 (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 exhibited no 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


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and (−)-methyl subergorgate 57314 provided good activity with ED50 values between 7.6 and 16.4 μM, while metabolites (−)-87,94 (+)-195,216 and (+)-310301 were found to display weak 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 (Table 7).58 Compound (+)-144 was shown to possess moderate activity against EAC and DLAT cell lines,159 while (+)-153 had a good activity against EAC.181

results which showed an activity of (+)-incarnal 27 toward these organisms (respectively, 51.2, 25.6, and >400 μM).49 (−)-Subergorgic acid 56 was reported to be active against Proteus vulgaris and 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, Pseudomonas lachrymans, Agrobaterium tumefaciens, and Ralstonia solanacearum), and Gram-positive bacteria (Bacillus thuringensis, S. aureus, B. subtilis, and Staphylococcus hemolyticus) with MIC values ranging from 16 to >128 μg/mL (Table 8). Silphiperfolanes (−)-58 and (−)-59 specifically inhibited S. aureus, whereas the corresponding analogs bearing a carboxylic acid at C13 such as 56, 60, and 61 were inactive (MIC > 128 μg/ mL), thus showing the importance of the methyl ester unit in the inhibitory effect against this bacteria. Subergorgiol 62 inhibited all these bacteria with MIC ranging from 16 to 32 μg/mL, while suberosane 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) toward P. lachrymans, R. solanacearum, and S. hemolyticus with MIC > 128 μg/mL.70 (−)-Cycloeudesmol 69 was found to significantly inhibit S. aureus 12600 and to possess in vitro activity against Salmonella choleraesuis, Mycobacterium smegmatis, and Candida albicans but no activity against E. coli.319 Compound 64 was found to be inactive against M. bovis BCG (IC50 = 204.6 ± 7.6 μM),320 Bacillus megaterium, and E. coli.76 The methanol fraction of L. complanata containing (−)-debilon 119 was reported to possess antimicrobial activity against Bacillus 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), Micrococcus spp., Acinetobacter spp., Klebsiella pneumoniae, Pseudomonas aeruginosa, and E. coli.181 Since separation of pupukeanane epimers 230 and 231 was not successful, they were tested as a mixture 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 (−)-273 was shown to inhibit the growth of S. aureus at 100 μg/disk.273 Compounds (+)-110 and (+)-122 showed moderate (MIC = 50 and 20 μg/disc, respectively) activities toward S. aureus and Streptococcus pyrogenes, respectively, while their analogs (−)-111 and (+)-115 showed no activity against these bacteria.134 Metabolite (+)-115 was alone in this series to present a low activity toward Staphylococcus sp. (MIC= 75 μg/disc). Compound (+)-111 showed low activity (MIC = 150 μg/ disc), and compounds (+)-110, (+)-115, and (+)-122 showed no activity against Salmonella enteritidis.134 (−)-Debromolaurinterol 310 and its acetate (−)-318 were found to be active against S. aureus at 50 μg/disk.301 (−)-Debromolaurinterol 310 was found to exhibit complete inhibition after 48 h of S. aureus and C. albicans at 10−30 μg/mL and M. smegmatis at 10−50 μg/mL and has no effect on the culture of Salmonella coleraesuis or E. coli up to 1 mg/mL.319 Compounds (−)-91 and (+)-92 showed weak inhibitory effects against the bacterial strains of E. coli, S. aureus, B. thuringensis, and B. subtilis with MIC values more than 125 μM.98 Compounds (+)-288 and (+)-289 showed no potent activity against human and aquapathogenic microbes Aeromonas hydrophila, Edwardsiella tarda, E. coli, S. aureus, Vibrio alginolyticus, V. anguillarum, V. harveyi, and V. parahemolyticus with MIC > 64 μg/mL.278

Table 7. Cytotoxic Activities toward Murine Fibroblast L-929, Ehrlich Ascites Carcinoma (EAC), and Dalton’s Lymphoma Ascites Tumor (DLAT) Cell Lines cell lines


L-929

(+)-47 GI50 = 99.1 ± 1.8 μM, (+)-32 GI50 = 6.8 ± 0.8 μM, (−)-41 GI50 = 20.9 ± 1.1 μM58 (+)-144 ED100 = 10 μg/mL (48.9 μM)159 (+)-153 LD50 = 2.8 μM181 (+)-144 ED100 = 10 μg/mL (48.9 μM)159

EAC DLAT

As described above, the great diversity of suberosane compounds displaying impressive cytotoxic activities toward several 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 functional modifications generated from one structure to another, implying in particular the alternate presence and absence of stereogenic centers in the C2 and C3 positions, suggesting a highly selective enzymatic cellular target. Contrary to the previous reported results,66,255,258 (−)-suberosanone 258 was recently shown313 to have 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 of apoptosis and autophagic cell death by increasing reactive oxygen species.314−316 3.2. Antibacterial Activity

The study of natural products, especially from terrestrial plants and fungi, has long been the source of antibiotic compounds. The tricyclic all-carbon sesquiterpene structures of marine origin were less tested for their antibacterial activities. Assessment of their antimicrobial action by the classical methods used the disk method (expressed as inhibition zone diameter in millimeters at a given concentration for the disc impregnation: in millimeters at a given weight of tested compound in grams)317 and the microdilution method or the agar well diffusion method (expressed as minimum inhibitory concentration (MIC) in concentration unit for 24 or 48 h incubation or minimum bactericidal concentration (MBC) in concentration unit).318 (−)-Hirsutanols A 15 and F 18 were found to be active against Bacillus subtilis.41 Hirsutanols A 15 and C 17 and (+)-incarnal 27 showed no activity toward B. subtilis, Staphylococcus aureus, and Escherichia coli (MIC > 100 μM)44 in contradiction with previous 6130


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Table 8. Antibacterial Activitya microorganism B. subtilis sp. B. subtilis ATCC 6633 B. subtilis ATCC 70385 B. subtilis CMCC 63501 B. megaterium S. aureus sp. S. aureus FDA 209P S. aureus ATCC 25923 S. aureus 12600 S. aureus ATCC 11632 S. aureus 6538 MRSA Streptococcus pyogenes X. vesicatoria ATCC 11633 P. lachrymans ATCC 11921 A. tumefaciens ATCC 11158 R. solanacearum ATCC 11696 and ATCC 11696 B. thuringiensis NS B. thuringiensis ATCC 10792 S. hemolyticus ATCC 29970 S. enteritidis S. choleraesuis M. smegmatis C. albicans 10231 C. albicans CA-5 C. albicans NS B. cereus ATCC 13061 S. pneumoniae NS S. pneumoniae ATCC 6301 S. epidermidis Micrococcus spp. Acinetobacter spp. K. pneumoniae P. aeruginosa A. hydrophila V. alginolyticus V. anguillarum V. harveyi V. parahemolyticus E. tarda E. coli E. coli ATCC 8739 E. coli NIHJ JC-2 A. agilis Alteromonas sp. A. beijerinckii E. amylovora

antibacterial activities (−)-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 (+)-27 MIC = 51.2 μM49 (−)-15, (−)-17 and (+)-27 MIC > 100 μM44 (−)-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 (−)-64 no activity76 (+)-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 (+)-110 and (−)-111 MIC = 50 μg/disk (+)-115 and (+)-122 no activity,134 (+)-273 > 64 μg/mL (>270 μM), (+)-274 MIC > 64 μg/mL (>230 μM).278 115 MIC = 75 μg/disk, (+)-110, (−)-111 and (+)-122 no activity134 (+)-27 MIC = 25.6 μM49 (−)-56 MIC > 16 μg/mL (>64.4 μM), (−)-58 MIC = 16 μg/mL (60 μM), (−)-59 MIC = 8 μg/mL (26.1 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 = 64 μg/mL (290 μM)70 (−)-69 MIC 48 h = 10−50 μg/mL (45−225 μM), (−)-310 MIC 48 h = 10−30 μg/mL (46−138 μM)319 (−)-119 6 mm132 (−)-15, (−)-17 and (+)-27 MIC > 100 μM,44 (−)-310 MIC 48 h = 10−30 μg/mL (46−138 μM)319 (+)-153 8 ± 1.4 mm181 (+)-110 and (−)-111 MIC = 20 μg/disk, (+)-115 and (+)-122 no activity.134 (−)-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 (72.6 μM)70 (−)-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 (−)-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 = 32 μg/mL (145.2 μM)70 (−)-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 (−)-91 and (+)-92 MIC > 125 μM98 (−)-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 = 64 μg/mL (290.4 μM)70 (−)-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 (−)-111 MIC = 150 μg/disk, (+)-110, (+)-115 and (+)-122 no activity.134 (−)-69 MIC 48 h = 50−100 μg/mL (225−450 μM), (−)-310 MIC 48 h > 1000 μg/mL (>4600 μM)319 (−)-69 MIC 48 h = 10−50 μg/mL (45−225 μM), (−)-310 MIC 48 h = 10−50 μg/mL (46−231 μM)317 (−)-69 MIC 48 h = 10−50 μg/mL (45−225 μM), (−)-310 MIC 48 h = 10−50 μg/mL (46−231 μM)319 (−)-310 MIC 48 h = 10−30 μg/mL (46−138 μM)319 230/231 (30:70) MA240 (−)-119 7.5 mm132 (+)-153 10 ± 1.1 mm181 (−)-119 6 mm132 (+)-153 8 ± 1.2 mm181 (+)-153 8 ± 0.5 mm181 (+)-153 8 ± 1.12 mm181 (+)-153 11 ± 1.0 mm181 (+)-27 MIC > 100 μg/mL (>400 μM),49 (+)-153 10 ± 0.5 mm181 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278 (+)-288 MIC > 64 μg/mL (>270 μM), (+)-289 MIC > 64 μg/mL (>230 μM)278 (+)-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 (−)-15, (−)-17 and (+)-27 MIC > 100 μM44 (+)-27 MIC > 100 μg/mL (>409 μM)49 (+)-311 (MIC = 5 μg/disk)321 (+)-311 (MIC = 5 μg/disk)321 (+)-311 (MIC = 15 μg/disk)321 (+)-311 MIC = 5 μg/disk)321 6131


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Table 8. continued microorganism M. bovis BCG a

antibacterial activities (−)-64 IC50 = 204.6 ± 7.6 μM320

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

falciparum malaria parasite Dd2 line (IC50 = 0.36 ± 0.05 and 0.83 ± 0.25 μM, respectively) and against chloroquine sensitive P. falciparum malaria parasite 3D7 line (IC50 = 0.30 ± 0.09 and 0.29 ± 0.07 μM, respectively).96 No antimalarial activity was detected against P. falciparum clones D6 and W2 (IC50 > 1000 ng/mL) for silphiperfolanes (−)-64, (−)-65, perforetane (−)-99, (+)-isorhodolaureol 301 and cyclolaurane (−)-310.312 Several derivatives demonstrate potential as analgesics capable of attenuating neuropathic pain. Such compounds have been shown in vivo to reduce proteins mediating inflammation, tumor necrosis facor alpha (TNFα), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). (+)-Strepsesquitriol 267 was shown to moderately inhibit lipopolysaccharide-stimulated TNFα production in RAW264.7 macrophages at a concentration of 100 μM (35.4% inhibition, p < 0.01), which was superior to 60.6% inhibition for the positive control, N-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK).267 Primary anti-inflammatory results showed that (+)-32 significantly inhibited iNOS and COX-2 proteins expression reducing, respectively, their levels by 216.9 ± 5.1% and 67.6 ± 13.1%.60 Compounds (+)-32, (−)-41, and (+)-54 were shown to significantly reduce the levels of the iNOS protein (1.2 ± 0.1, 54.4 ± 12.0, and 34.8 ± 10.2, respectively) at concentrations of 10 μM.61 Compounds (+)-32 and 41 significantly reduced the levels of COX-2 protein (24.8 ± 7.5 and 62.9 ± 13.7, respectively) at a concentration of 10 μM. At the same concentration, the other isolated capnellenes (+)-34 and 49− 53 did not inhibit iNOS and COX-2 protein expression.61 In vivo, (−)-Δ9,12-capnellene-8β,10α-diol 41 inhibited hyperalgesia behavior in the mouse model for neuropathic pain in a dosedependent manner.326 The triquinane derivative (−)-64 was found to be active against 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 f usca) and no activity toward several fungi (Ustilago violacea, Mycotypha microspora, Eurotium repens, and Fusarium oxysporum).76 Contrary to (−)-shagene B 73 which showed no activity (>20 μg/mL), (−)-shagene A 72 was found to be active against Leishmania donovani, with no toxicity against the mammalian host, showing the importance of the methoxy substituent at the C8 position.85 Compound (+)-103 produced partial inhibition against C. f usca growth (10 mm inhibition zone diameter at 5 mg/mL).107 (−)-Paralemnanone 291 and (−)-isoparalemnanone 292 were found to inhibit the LPS-induced pro-inflammatory proteins 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 141 did not inhibit the COX-2 expression but was able to reduce expression of iNOS (66 ± 4.6%) by LPS treatment.153 The antiinflammatory activities of compounds 168−172 through the accumulation of pro-inflammatory iNOS and COX-2 proteins in RAW264.7 macrophage cells were evaluated.192 It was found that these compounds did not reduce the accumulation of iNOS

Compound (+)-311 was found to display a marked antibiotic activity against S. aureus283 and a potent one against B. subtilis,303 but no experimental details were furnished. It was also shown to display 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 Alcaligenes aquamarines, Halobacterium sp., and Halococcus sp.321 3.3. Other Biological Activities

(−)-Subergorgic acid 56 was shown to inhibit larval settlement of Balanus amphitrite and the bryozoan Bugula neritina with EC50 values of 1.2 and 3.2 μg/mL, respectively.322 Compounds (+)-113, (+)-192, and (+)-194 were found to inhibit the larval attachment and provoke the metamorphosis of the barnacle B. amphitrite.126 It was shown that compounds (−)-223, (−)-233, and (−)-235 inhibited settlement and metamorphosis of cyprid larvae 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 Locusta migratoria, its activity being reinforced in the presence of (+)-ferruginol, a diterpene found in the same extract of Cryptomeria japonica.323 (−)-Cubebol 79, found in the same Japanese cedar, was also shown to inhibit the feeding behavior of Acusta despesta at 120 μg/mL.324 A mixture of maalianes 127 and 128 was reported to be toxic for goldfish Carassius auratus at 100 μg/mL and effective as antifeedant against this goldfish at 10 μg/mg in food pellets. Because these metabolites are found only in the dorsum, which is exposed to potential predators, they appear as belonging to the chemical defense of the nudibranch C. luteomarginata they originated from.137 The isonitrile aromadendrane (−)-188 showed toxicity for the fish Lebistes reticulatus (LD 30 mg/ mL), suggesting that it may be involved in the defense mechanisms of the sponge A. acuta it was extracted from.203 The corresponding derivatives (−)-189 and 190 were found to be nontoxic to fish L. reticulatus and have been proposed to be the result of a detoxification process.204 Since separation of the 9-thiocyanatopupukeananes 230 and 231 was not successful, both compounds were tested as epimeric mixtures (monitored by GC). A decrease in brine shrimp mortality (from 90% to 35%) was observed when decreasing the proportion of 231 in bioassays (from 230:231 = 30:70 to 50:50), thus showing the greater toxicity of epimer 231.240 The toxicity of (−)-lemnafricanol 290 on brine shrimp larvae was evaluated through its LC50 value of 0.32 μM.279 (+)-Penicibilaenes A 288 and B 289 were tested against plant pathogenic fungi Alternaria brassicae, Colletotrichum gloeosporioides, Fusarium graminearum, and Gaeumannomyces graminis. Both of them exhibited selective activity against C. gloeosporioides with MIC values of 1.0 and 0.125 μg/mL, respectively, thus indicating that acetylation at the C4 position likely enhanced the activity.278 (−)-Subergorgic acid 56 was reported to be active against Rhizopus oryzae at 200 μg/mL without further detail.64 (−)-Bourbon-11-ene 1 was found to have no activity toward the malaria parasite Plasmodium falciparum.325 Nitrogenous metabolites (−)-281 and (−)-282 showed activity against P. 6132


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

protein induced by LPS. Compounds (−)-168 and (−)-170 were found to reduce the accumulation of LPS-induced COX-2 to 8.7 ± 4.5%, 61.0 ± 6.0%, and 83.4 ± 6.4%, respectively, at 10 μM. At a concentration of 100 μM, compounds 168−170 were shown 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 the iNOS 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-2 protein (67.6 ± 13.1%, 25.0 ± 6.7%, 108.3 ± 0.9%, and 94.3 ± 3.2% respectively) in comparison with LPS alone. These results show that 32 and 206 significantly inhibited iNOS and COX-2 proteins expression, while 207 did not inhibit COX-2 protein expression but significantly inhibited iNOS protein expression, and 208 exhibited no discernible anti-inflammatory activity against LPS-stimulated RAW 264.7 macrophages.60 (−)-Lemnanol 206 was shown to produce anti-inflammatory and analgesic effects in carrageenan-injected rats.327 (+)-Caryophyllene 279 showed inhibitory effects on the generation of superoxide anions (inhibition rates = 42.22%) and the release of elastase (inhibition rates = 42.10%) by human neutrophils at a concentration of 37.6 μM (10 μg/mL).274 (+)-Δ9(12)-Capnellene-8β,10α-diol 32 and acetylated capnellene (−)-41 were found to have antineuro-inflammatory and antinociceptive properties in IFN-γ-stimulated microglial cells and in neuropathic rats, respectively, and could therefore serve as useful lead compounds in the search for new therapeutic agents for treatment of neuro-inflammatory diseases.326 Clovane sesquiterpene (−)-283 displayed a 14.8% inhibitory effect on elastase release by human neutrophils at a concentration of 10 μg/mL.275 Compound (−)-284 was found to display a 4.3% inhibitory effect on superoxide anion generation by human neutrophils at 10 μg/mL.277 Contrary to compounds 284 and 285, clovane sesquiterpene (−)-286 was found to display significant inhibitory effects on the generation of superoxide anion (IC50 = 2.72 ± 0.93 μg/mL) and the release of elastase by human neutrophils (IC50 = 6.73 ± 0.85 μg/mL).276 Compounds 94−98 were shown to have no antiviral activities against 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) herpes simplex virus-1 KOS (ACVr), vesicular stomatitis virus, Coxsackie virus B4, respiratory syncytial virus, parainfluenza-3 virus, reovirus-1, Sindbis virus, and Punta Toro virus.102

Scheme 8. First Racemic and Corresponding Enantioselective Syntheses of Kelsoene 6

through a [2 + 2] photocycloaddition in the presence of trans1,2-dichloroethylene to deliver 331 in very good yield (85%). In this cycloaddition, the alkene approaches by the less hindered face of the diquinane moiety, with a total stereoselective control. Subsequent functional group manipulations next led to the methyl ketone 332 in good overall yield (OY) (42.3% 8 steps) whose methylenation was eventually realized using Wittig’s conditions (80% yield). An enantioselective version of this racemic synthesis was revisited 2 years later by the same team (Scheme 8).333 Lipase-catalyzed kinetic resolution of rac-diol 329 provided ready access to (+)-329 and the corresponding diacetate (+)-333 in high ee, whose transformations into the corresponding kelsoene enantiomers (+)-6 and (−)-6 were achieved following the racemic strategy in 17−18 steps (Scheme 8). 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 by bromination and Favorskii rearrangement into cis-pulegonic acids 336, separated by column chromatography from its trans isomer. Tricyclic compound 337 was next obtained in five steps through bicyclic enone 330 as one enantiomer (yields and experimental parts were not given). The following transformations (337 → 332) were in accordance with the racemic syntheses (Scheme 8) with slight modifications of the last step, implying Cp2TiMe2334 as the methylenation agent. Determination of the AC of natural kelsoene was first established by X-ray diffraction analysis of a tosylate 336 derived from enone 330 and then by comparison of the respective optical rotations of the synthetic and natural kelsoene synthesized. 4.1.2. Capnellene and Corresponding Diols. Capnellene 29 and its hydroxy derivatives, which belong to the linearly fused

4. SYNTHESIS Total syntheses, either racemic or asymmetric with a particular emphasis on the first syntheses and syntheses that led to the revision of structures or stereochemistry attributions, will be described in this section, covering the subject from the early 1970s (pioneering results) to the end of 2015. A systematic and chronological update of the synthesis of all tricyclic sesquiterpenes working from 1979 to 1994328 as well as of the synthetic approaches to triquinanes329 were published among others. 4.1. Fused Carbocycles

4.1.1. Kelsoene. Owing to its interesting [5.3.0.02,5]decane structure incorporating six contiguous stereogenic centers including 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 in 1999,331,332 starting from cyclooctadiene 328, which was first transformed into the bicyclooctane 329 in two steps and 67% 6133


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

Scheme 11. First Racemic Synthesis of Capnellene Diol 32

This bisallylic diol was synthesized starting from the BC bicyclic ketone 343, which led to acetylenic derivative 346 in three steps and 65.6% OY. After cyclization using sodium naphthalene radical, the resulting allylic alcohol 347 was oxidized into 348 in 40% yield. Generation of the corresponding mesylate followed by its displacement with potassium superoxide in the presence of 18-crown-6344 was the only successful and stereospecific way to the 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 reacted with levulinic acid 350 under acid catalysis to afford the enantiomerically 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 alcohols 353 and 354 through 4 steps (71.8% yield), implying reduction of the lactam part among others. Both alcohols 353 and 354 furnished the same compound 355 in, respectively, 89% and 74% yields, the configuration of the CHOH in the β-alcohol 354 being inversed via a Mitsunobu reaction. Seven steps were eventually required to provide 356 (67.8% yield), which was cyclized into (+)-29 according to a procedure previously 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 vinylcyclopropane−cyclopentene rearrangement of the bicyclic alcohol 358, obtained from the natural (+)-3-carene 357 (Scheme 13).348,349 This rearrangement delivered a mixture of diastereoisomers 359 and 360 in 75% yield. Subsequent transformations of this mixture allowed elimination of the undesired alcohol 360, leading to 361 in 39.8% yield over four steps. The next step was a ring-expansion reaction with ethyl diazoacetate in the presence of SbCl5 furnishing the enantiomerically pure enone (−)-362, which was shown to be a capnellene precursor in a racemic synthesis of this compound.350 Another formal synthesis leading to 362 reported 3 years later351 begins with the silylated cyclopentanone 364, obtained in three steps from enantiomerically pure cyclohexenone 363352 (Scheme 13). The following compound 365 was synthesized in six steps (29.6% OY) and transformed into the target bicyclic enone 362 in 51.8% OY through a four-step sequence involving cyclization. A synthesis of natural (−)-capnellene 29 based on enantiomerically pure oxodicyclopentadiene (−)-366 was reported in 1996 (Scheme 14).353 This compound was transformed into ketone 367 in five steps and 38.8% OY, whose retro-Diels−Alder reaction provided bicyclic enone

triquinane sesquiterpene family, have drawn the interest of synthetic chemists for decades.335−339 They possess a geminal methyl unit at Cl and an angular methyl group at C4 (Scheme 10). Scheme 10. First Racemic Syntheses of Capnellene 29

Two racemic syntheses of capnellene 29 were reported concomitantly in 1981 for the first time and confirmed the cis,anti,cis relative configuration of the natural product (Scheme 10). One340 is based on a 1,3-diyl trapping341 of the intermediate 340, generated under THF reflux from 339, itself obtained starting from acid 338 in 4 steps and 44% OY. Subsequent functional group manipulations next led to (±)-29 in 4% yield over three steps. The other one (Scheme 10)342 began with the transformation of cyclopentenaldehyde 342 into the BC bicyclic unit 343 in four steps and 64.6% OY. The keto-aldehyde 344 obtained in four steps and 44.5% OY from 343 was cyclized via an intramolecular aldol condensation to furnish the ABC tricyclic unit 345 (79% yield), which was easily converted by hydrogenation 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 6134


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

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

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

(−)-362 and formal access to the desired target. Ketone 367 was also the precursor of (−)-capnellene 29 following a longer and lesser efficient synthesis (11 steps, 16.8% OY). The only catalytic asymmetric synthesis of this natural compound was reported the same year, implying an elegant tandem Heck reaction−carbanion capture sequence starting from enol triflate 368 to afford the bicyclic diene 369 in 77% yield and 87% ee (Scheme 14).354 Enantioselectivity in this process was induced by the presence of (S)-BINAP as a ligand for palladium. It was next transformed into iodide 370 (six steps and 78.2% OY), the precursor of alcohol 371 incorporating the third cycle A, through a radical process and subsequent alcohol deprotection in 96% OY. The geminal dimethyl group was then introduced by cyclopropanation followed by catalytic hydrogenolysis, which furnished alcohol 372 in 76% OY. Final deshydration allowed the synthesis of natural (−)-capnellene 29 in 78% yield and 87% ee. 4.1.3. Silphiperfolanes. Two racemic syntheses of subergorgic acid 56, an interesting structure incorporating five contiguous stereogenic centers including two quaternary carbon centers, were reported (Scheme 15). The first one355 was based on intramolecular alkylation and subsequent transformations within a functionalized spiro[4,5]dec-6-en-8-one 374, obtained in eight steps and 24.2% OY starting from spiranic enone ketal 373, which afforded 5,5,6 tricyclic olefinic ketone 375 (three steps, 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 subergorgic acid 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 378 and angular 379 tetracyclic adducts in a single step following a highly diastereoselective (de >98%) intramolecular [3 + 2] photocycloaddition, starting from arene−olefin ketal 377, itself prepared from bromoxylene and 3-methyl-pent-4-enal. These adducts were obtained in 42% yield (61% brsm), the angular derivative 379 precursor of subergorgic acid being the minor one (378:379 = 64:36). It could be processed in seven steps (11 from bromotoluene) and 24.4% OY into (±)-56 according to previous routes. The only enantioselective total synthesis of subergorgic acid reported to date357 (Scheme 16) was based on the lipase6135


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(−)-Silphiperfolan-6-ol 65 was another silphiperfolane to draw synthetic chemists’ attention. It was the subject of the only asymmetric synthesis reported to date,74 which confirmed its AC. This synthesis began with the formation of diazo ketone 390 in six steps and 25.8% yield from enantiomerically pure (R)(+)-limonene 389 (Scheme 17). Construction of the second cycle then led via anhydrous copper sulfate-copper catalyzed intramolecular cyclopropanation to the tricyclic adduct 391 in good yield (76%). After a four-step sequence, done in a 54.6% global yield, a 1:2 mixture of diastereoisomers 392 and the desired product 393 was obtained. The major isomer 393 was next transformed (2 steps, 81% yield) into the diazo compound 394, which afforded the triquinane species 395 in 84% yield, via a highly regioselective insertion of the corresponding rhodium carbenoid into the C−H bond of the tertiary methyl group at the ring junction. Subsequent functional group manipulations provided in four steps and 51.6% OY an inseparable mixture of the desired target (−)-65 and its diastereoisomer 396 together with the corresponding dehydrated compounds 397 and 398. Since it was observed that dehydration of 396 was relatively faster than dehydration of (−)-65, the latter was purified by treatment of this mixture with 3 N hydrochloric acid, which gave a mixture of 397, 398 (60%), and unreacted (−)-65 (18%), eventually separated by flash chromatography. 4.1.4. Cycloeudesmanes and Cubebanes. Among the two racemic syntheses of cycloeudesmol 69 reported to date,358,359 the first one358 (Scheme 18) was the more efficient and the shortest one. This synthesis started with a six-step preparation of ketoester 400 from tosylhydrazone 399 (38.4% OY) and relied on an olefin−ketocarbene cyclopropanation of 400 as a key step, which allowed concomitant formation of two cycles in one step to afford 401 in 56% yield. Cycloeudesmol synthesis 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 fisrt one88,361 (Scheme 19), which allowed confirmation of the ACs of the targets, started with the transformation of (−)-trans-caran-2one 402 into spirolactone 403 in three steps and 16% yield. This

Scheme 15. Racemic Syntheses of Subergorgic Acid 56

promoted hydrolysis of the racemic chloroacetate 381, easily obtained in two steps and over 86% yield from 1,3-cyclopentanedione 380, which furnished enantiomerically pure alcohol (−)-382 and chloroacetate (+)-381. The latter was then transformed, through alcohol (+)-382, into diquinane (+)-383 in four steps and 52.1% OY. This compound was submitted to a tandem diastereoselective Michael addition process−enolate trapping by TMSCl to provide silyl enol ether 384 in 90% yield. Cyclization and subsequent functional group manipulations next led to tricyclic ketal (−)-385 in four steps and 20.3% OY. Seven more steps (34.0% OY) were necessary to transform the ketal into an olefin and the silylated alcohol into a α-keto enoate in (+)-386, suitable for introduction of the 15 carbon atom of the sesquiterpene skeleton, via a Michael addition of a methyl group and subsequent transformations into (−)-387 (four steps, 64.4% OY). Compound 388 was further elaborated in five steps and 78.6% OY and eventually easily transformed in natural subergorgic acid (−)-56 in three additional steps and 78.6% OY via oxidation, Michael addition, and saponification. Scheme 16. Enantioselective Synthesis of Subergorgic Acid (−)-56

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

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

Scheme 18. First Racemic Synthesis of Cycloeudesmol 69

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

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

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

cally pure enyne ketone 408 was obtained in 6 steps and 48.4% OY, which by three more steps (77.8% OY), including a highly diastereoselective Noyori’s transfer hydrogenation, led to acetylenic acetate 409, the desired precursor for the PtCl2catalyzed 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 found that the less basic MeCeCl2 behaved exceptionally well in the next step, probably avoiding competing enolization, for the synthesis of (−)-cubebol 79 in comparison with the direct 6137


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reported addition of MeLi.88 Additionally, more efficient access to (−)-α-cubebene 84 was also reported in two steps through the enol triflate 411 and 81.9% yield. In the course of the study of chirality transfer during the enynol cycloisomerization process, a similar strategy was concomitantly reported364,365 starting with the synthesis of a 1:2 mixture of inseparable pivalates 412 and 413 prepared from (+)-(R,R)tetrahydrocarvone 407 (7 steps, 55% OY). Enriched mixtures of 412 and 413 of variable composition (70:30 to 98:2) were submitted to Pt-, Au-, or Cu-catalyzed face-selective enyne cycloisomerizations to give after separation of the wrong diastereomer at C6−C10 generated from epimeric pivaloyl enyne 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 was recently reported (Scheme 20).366 Epoxide 415, obtained in five steps and 8.7% OY from (−)-menthone 414, was deprotonated with LTMP to stereoselectively provide via an electrophilic carbenoid intermediate, the tricyclic alcohol 416 in 90% yield. This compound was eventually easily converted into (−)-cubebol 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 was reported in 1969 (Scheme 21).367 Olefinic acid 418 prepared in

Scheme 22. Hemisyntheses of Aristolanes 106, 107, 108, and 122

Scheme 21. Racemic Synthesis of Aristolone 111

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

21.9% OY over seven steps was transformed into the corresponding intermediate diazo compound suitable for copper-catalyzed intramolecular cyclopropanation leading to a mixture of (±)-aristolane 111 (46%) and its diastereomer 419 (20%), reflecting the 2:1 facial selectivity of the cyclopropanation step. 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)-aristolene 112 led to hydroperoxide 420 and a small amount of a mixture of aristoladienes 107 and 108 (Scheme 22), while the same reaction involving Rose Bengal gave compound 122, which was oxidized into 106,109 together with another allylic alcohol (8.5%), which was oxidized to known terrestria1 metabolite (10)-aristolene-2one.368 4.1.6. Africananes and Aromadendranes. Since africanol’s AC determination through X-ray diffraction studies,155 one enantioselective369 and three racemic syntheses370−372 were reported prior to publication of an elegant and efficient enantioselective process based on a Mo-catalyzed asymmetric olefin metathesis (Scheme 23).373 Norbornenone 421 was thus easily transformed (81%) into diene 422, which was submitted to asymmetric ring-opening metathesis/ring-closing metathesis (AROM/RCM) conditions in the presence of chiral Mo catalyst 423 to afford the bicyclic adduct 424 in excellent yield (97%). Subsequent functional group manipulations provided in three steps and 82.6% OY the bicyclic olefin 425, which was submitted

to catalytic hydroformylation reaction to provide a 1:1 separable mixture of regioisomeric aldehydes 426 and 427 in 97% combined yield. The mixture was next reduced (NaBH4) and the regioisomeric alcohol separated and processed in four more steps and 21.3% OY from the aldehydes 426 and 427 to give alcohol 428, a precursor to (+)-africanol 142 as previously reported in a racemic synthesis372 of this natural product. The first semisynthesis of (−)-aromadendrene 166 was described in the 1960s using (−)-perillaldehyde 429 as the 6138


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

chiral source (Scheme 24).374 Construction of the cyclopropane unit was first accomplished by bromation and subsequent basecatalyzed cyclization leading to bicyclic aldehyde 430 in 41% yield. A Wittig reaction then allowed quantitative formation of diene 431, which underwent a Diels−Alder cycloaddition with acrolein leading to the tricyclic olefin 432 (73% OY). Subsequent functional group manipulations provided in four steps and 66.2% OY 1,2-tosylate alcohol 433, which quantitatively rearranged over chromatography on alumina to afford the tricyclo[6.3.0.02,4]undecanone 434, a precursor of the desired natural aromadendrene (−)-166 via a second Wittig procedure (53% yield). This work brought a correction to the first reported stereochemistry for compound 166375 and ascertained its AC as 1S,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 catalysis to give cycloheptenone 436. Compound 437 was next obtained in 6 steps and 33.3% OY and then under intramolecular aldol condensation, delivering tricyclic cyclopentenone 438 in 84% yield. Stereoselective methylation of the latter followed by epimerization led through the common intermediate 439 to the desired targets (+)-166 and (−)-167 in 79.1% yield. Trans and cis 5,7 ring junctions were next introduced by direct hydrogenation of enone 439 over Pd/C affording ketone 440 or via reduction of its corresponding tosyl hydrazone leading to olefin 441. Subsequent functional group transformations of 440 and 441 gave, 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 LiAlH4 into C10 epimeric diols (−)-163, (−)-164, (−)-443, and Scheme 25. Semisyntheses of Aromadendrane Diols (−)-163 and (−)-164

(−)-446. It is worth noting that (−)-163 is the antipode of the natural product found in S. mayi, while (−)-164 found in the same organism has the correct AC: finding two antipodal frameworks inside the same species, if intriguing, is nevertheless not without precedent.378 In order to ascertain their ACs, a series of aromadendrane type compounds (+)-154, (−)-155, (+)-157, (−)-163, (−)-167, (+)-174, and (+)-176 was obtained starting from aromadendrene (+)-166, (Scheme 26).183 (+)-Aromadendrene 166 was first transformed via ozonolysis into ketone 447, whose epimerization through the corresponding silyl enol ether furnished quantitatively 448 via crystallization in MeOH in the presence of Et3N. Reaction of the latter with 6139


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

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

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

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 epox6140


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reported (Scheme 29).382 Four steps were thus necessary to generate 468 in 63.6% OY, which was cyclized in the presence of SmI2 to afford diol 469 bearing two hydroxy groups in favorable configuration for further syn elimination, allowing formation of the E-olefin geometry in the acid-sensitive target (+)-bicyclogermacrene 136 (66% yield). Acid exposure (HSCN) of this compound furnished (+)-ledene 471 through cation 470, and subsequent 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 be explained by rearrangement of 472. This intermediate is nevertheless not the most obvious one owing to steric hindrance generated by the cyclopropane unit, which should favor epoxidation in a trans position or on the other double bond of the bicyclic unit.

adduct led to 4α,7β-aromadendranediol (−)-163 in 44% yield. Eventually (+)-157 was epimerized into 449, whose subsequent protection as a silyl ether, MeMgI attack, and deprotection furnished (+)-174 in 79% yield. The first enantioselective synthesis of (−)-aromadendrane diol 164 was reported in 2009379 via an impressive cascade of three reactions involving metal and organocatalysts 450, 451, and 452 (Scheme 27). Compounds 453 and crotonaldehyde 454 were first submitted to metathesis reaction conditions using Grubbs II catalyst 450, leading transitorily to ketoaldehyde 455. Success of the following organo-cascade sequence then relied on the use of the dual-system 451/452 with the imidazolidinone 451 generating an iminium intermediate 457 prone to nucleophilic attack of the furan 456, while proline 452 was at the origin of the enamine 458, which led through intramolecular cyclization 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 460 via hydrogenation, subsequent reduction, and protection in 80.7% OY. Construction of the seven-membered ring was then realized after double-Wittig olefination and metathesis to produce 461 (56.2% yield), whose transformation into (−)-aromadendrane diol 164 was done by introduction of the gem-dimethyl cyclopropane unit via a two-step sequence involving diastereoselective addition of dibromocarbene, treatment with Me2CuLi and MeI, and subsequent deprotection in 88.4% OY. The second enantioselective synthesis of (−)-aromadendrane diol 164 was recently reported380 based on the gold-catalyzed cyclization of compound 464, obtained in four steps and 62% yield from 463 (Scheme 28). In the presence of 2 mol %

4.2. Bridged Tricyclic Sesquiterpenes

4.2.1. Tricyclic Decane Skeleton. Since its isolation and determination of its AC through an X-ray study,228 many racemic syntheses 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 The biogenetic relationship between the marine sesquiterpenes neopupukeananes and trachyopsanes was ascertained by a biomimetic rearrangement employed as the key step for the enantioselective 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/intramolecular Michael addition sequence between (−)-carvone 473 and methyl methacrylate, which allowed access to the bicyclic structure 474 in 65% yield (Scheme 30). Rhodium-catalyzed cyclization of an intermediate diazoketone obtained from 474 furnished the tricyclic dione 475 in 81% yield, whose successive reductions gave 476 (two steps, 89% OY). Under acidic conditions, this keto alcohol 476 provided, through the neopupukeanane-type 477 and trachyopsane-type 478 cations, the tricyclic structure 479 in 87% yield. The latter compound was eventually transformed into the natural (−)-2-formylaminotrachyopsanes 221 in three steps and 83.7% OY, whose tosylation afforded the corresponding (−)-2-isocyanotrachyopsanes 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 was thus determined.394−396 The corrected relative stereochemistry95 of compound 233 was confirmed by an enantiospecific synthesis of both enantiomeric forms of this natural product (Scheme 31).397 Reductive ozonolysis of 475 furnished 482, whose epimerization at the C9 position was led in basic media to provide a 1:1 mixture of diastereoisomers 482 and 483 (85% yield) separated by flash chromatography. The latter was next transformed in two steps into (−)-484, and subsequent functional group modifications led to the corresponding enantiomer (+)-233 of the natural product together with a major rearranged product 485. Synthesis of the natural enantiomer began with the double-Michael addition (Scheme 30) applied to dihydrocarvone 486 which, contrary to carvone 473, led to a 3:1 mixture of diastereoisomers 487 and 488 next transformed into a separable mixture of product ketol 489 and diol 490 in three steps and 61.7% yield. Compound 490

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

JohnPhos catalyst 462, the linear 14 carbon unit 464 was transformed into the tricyclic aromadendrene structure 466 in 56% yield, probably through allylic alcohol nucleophilic attack of the intermediate 465. Selective epoxidation of 466 from the less hindered face, followed by opening of the generated epoxide and allyl 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 6141


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

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

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 to give the tetracyclic adduct 500 in 86% yield. Tricyclic olefin 501 was next obtained in six steps and 66.6% OY and then transformed into 2-isocyanoallopupukeanane 239 through formation of formamide 502 (63% yield). Several syntheses, including one enantioselective route,405,406 of cis-sativenediol 237 were also reported.407−410 Asymmetric access to this compound (Scheme 34) was accomplished starting from (+)-dihydrocarvone 503 of known absolute configuration, which was transformed into the bicyclic structure 504 via deprotonation, addition of the resulting anion onto 1-chloropentan-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 methylenation afforded compound 506 in 76% yield. A carbonyl intramolecular condensation of the latter then afforded the bicyclic compound 507 in 76% yield, and 8 more steps413,414 were needed to deliver

was eventually oxidized into (+)-484 (95%), a precursor of the natural metabolite (−)-2-thiocyanoneopupukeanane 233. Two racemic syntheses of (±)-9-isocyanopupukeanane 224 were concomitantly reported in 1979 (Scheme 32). The first one398 was based on the base-catalyzed cyclization of ketone 492 obtained in four steps and 9.6% OY from the hydrindanone 491 to deliver 493 (75% yield), which was transformed in the desired target with two additional steps (yield not given). The second one (Scheme 32)399 relied on the intramolecular Diels−Alder cyclization of diene olefin 495 (diastereomeric composition not given) synthesized in four steps and 39.2% OY from allylic alcohol 456, which gave quantitatively the tricyclic ketoalcohols 496 which was transformed in seven more steps to achieve the synthesis of 224 in 17.5% yield. Racemic synthesis of the neopupukeanane derivative 236 based on the same strategy was reported later,400 and two other racemic syntheses of this pupukeanane-type structure were also described.401,402 Only one racemic synthesis of (±)-2-isocyanoallopupukeanane 239 has been reported to date (Scheme 33).403,404 Lactone 498, prefiguring the final cyclopentane−cyclohexane-bridged 6142


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

Scheme 33. Racemic Synthesis of 2-Isocyanoallopupukeanane 239

Scheme 34. Enantioselective Access to (+)-cis-Sativenediol 237

the alcohol 508 in 17.9% yield. Oxidation (Collin’s reagent), intramolecular Prins reaction (CF3CO2H), and subsequent oxidation (excess of Collin’s reagent) of the resulting alcohol group furnished compound 509 in 55% yield.415 Hydroxylation of the adjacent position of the keto group in 509 followed by reduction of the resulting hydroxy ketone afforded a 1:1 mixture of (+)-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 was the subject of one enantioselective synthesis (Scheme 35).251 Compound 511 (>96% ee), easily obtained through resolution of its racemate form using (S)-1-phenylethylamine,416 was converted into 512 in three steps and 58.5% OY. Palladiummediated metal−ene reaction next allowed cyclization into 513 (50% yield), whose esterification and subsequent cyclopropanation afforded tricyclic compound 514 in 92% yield. Ring expansion via solvolysis of the gem-dibromocyclopropane unit in the presence of a nucleophilic arene thiol then provided the vinyl bromide 515 in 94% yield, whose subsequent functional group transformation gave seleno ester 516 after three steps and 67%

OY. The acyl radical generated from 516 under nonreductive conditions induced a regioselective cyclization to provide tricyclic ketone 517 in 85% yield, which was subsequently transformed into diazoketone 518 through four steps and 42.2% OY.

Scheme 32. Racemic Syntheses of 9-Isocyanopupukeanane 224

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yield), obtained upon irradiation of compound 520 (35% yield, separated from another isomer in equal amount) prepared from o-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 to afford a 8:1 mixture of α-terrecyclene 524 and silphinene 522 (81% combined yield). Upon hydroboration reaction conditions and subsequent oxidation, α-terrecyclene 524 led to suberosanone 258 in 79.7% yield. Stereoselective epoxidation of 524 gave the α-epoxide 525 in 86% yield, which eventually provided suberosenol B 255 via β-elimination in the presence of Et2NLi and 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 was proposed (Scheme 37). Cation 526 obtained by 1,2 shift from

Scheme 35. Enantioselective Synthesis of (+)-Acanthodoral 250

Scheme 37. Proposed Biosynthesis of α-Terrecyclene 524

Photo-Wolff rearrangement of compound 518 allowed construction of the strained bicyclo[3.1.1]heptane framework into ester 519 almost quantitatively (Scheme 35). Subsequent reduction and oxidation furnished (+)-acanthodoral 250 in 79.7% yield. Racemic syntheses of suberosanone 258, suberosenol B 255, and the corresponding acetate 257 were remarkably reported417,418 prior to their isolation as natural products66 (Scheme 36) in the course of biogenetic relationship studies between silphinene 522 and the terrestrial secondary metabolite quadrone. First, the synthesis of silphinene 522 was performed according to a previously described three-step synthesis419 via reductive cleavage of a tetracyclic [3 + 2] cycloadduct 521 (66%

caryophyllenyl cation 74 could rearrange via π-cyclization to give the 527 and presilphiperfolan-8-yl carbocation 528 through a 1,3-hydride migration. Three consecutive 1,2 shifts delivering successively silphin-1-yl cation 529 and the carbocations 530 and 531 could furnish α-terrecyclene 524, precursor of the natural metabolites 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 was published (Scheme 38) but it is only recently421 that an enantioselective route to this compound and suberosanone 258 was 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, itself obtained from dimedone 532 in two steps and 39% OY.422 The key step was performed using tin hydride to generate radical 535 with an unexpected selectivity presumably due to the conformational preference of the butynyl chain with a silyloxy group in 535 toward cyclization, leading to 536. This latter intermediate then underwent a rearrangement into 537 and subsequent cyclization providing access to the expected tricyclic diol 538 after destanylation over silica gel and deprotection. A further functional group manipulation of tricyclic unit 538 to reach the target suberosenone 238 necessitates a 17-step sequence (3.8% OY) through ketone 539 and enone 540 to install an axial methyl group at C8 and set the exomethylene ketone at C2−C3 (quadrone numbering). The enantioselective route to suberosenone 253 and suberosanone 258 started with the 3-step synthesis of compound 541 from dimedone 532 in 62.3% OY (Scheme 39).421−424 Chirality was next introduced via a hyperbaric asymmetric Michael addition in 59.9% yield, implying transient formation of the enamine generated from 541 and (R)-1-phenylethylamine,

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

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Scheme 38. First Racemic Synthesis of Suberosenone 253

Highly chemoselective intramolecular cyclization via a silver trifluoroacetate-mediated α-alkylation then furnished the bicyclic ketone 544 in 87% yield, and a second cyclization was next accomplished by an intramolecular aldol condensation of the diketone issued from 544 via a Wacker transformation to provide the tricyclic enone 545 (two steps and 68.9% yield). Compound 545 was eventually modified to separately deliver (+)-suberosenone 253 (three steps and 34.6% yield) and (+)-suberosanone 258 (two steps and 88% yield). The optical rotation sign of (+)-suberosanone 258 was opposite to that of the natural product, isolated from I. hippuris,66 which is thus the first example of quadrane-type natural product not related to the 1R configurational series. On the opposite, the optical rotation sign of synthetic (+)-suberosenone 253 was found to be identical to the natural product’s one extracted from S. suberosa,254 confirming its AC previously determined via density functional theory calculations of optical rotation.257 Syntheses of synthetic (−)-suberosenone 253, (+)-suberosenol A 254, and natural (−)-suberosanone 258 following the same strategy313 and of (+)-suberosanone 258 via an elegant dualorganocatalyzed reaction425 were recently reported but lies beyond 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 by several syntheses,427,428 only one giving access to the enantiomer (+)-265.429

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

which led to exclusive formation of keto-ester 542, whose subsequent functional group transformations delivered silyl enol ether 543 after 6 steps and 86.5% OY. Scheme 40. Racemic Synthesis of Gomerone 306

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4.2.3. Tricyclic Dodecane Skeleton. Racemic synthesis of gomerone C 306 (Scheme 40) was recently published, and its relative stereochemistry was subsequently revised.286 Catalyzed Diels−Alder reaction between silyloxydiene 546 and alkene 547 furnished the bicyclic structure 548 in 69% yield, whose relative configuration was confirmed via X-ray crystallography. Compound 548 was next converted into 549 in 8 steps and 41.2% yield. Five more steps in an overall yield of 65% were then necessary to provide 550, whose cyclization through a Conia−ene-type reaction generated 551 in good yield (65%) as a logical precursor of the desired target 306, eventually obtained by chlorination in 67% yield.

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

4.3. Miscellaneous Tricyclic Sesquiterpenes

Only one racemic synthesis of cyclolaurene 314 has been reported to date (Scheme 41)430 based on the CuSO4-catalyzed Scheme 41. Racemic Synthesis of Cyclolaurene 314

intramolecular cyclization of the diazoketone 553, derived from ketone 552 (5 steps), into a mixture of the tricyclic structures 554 (28% OY). Three more steps were necessary to generate the natural product target in only 16.9% OY, owing to the low diastereoselectivity obtained in the key cyclization step. The asymmetric synthesis of natural (−)-laurequinone 321 based on an intramolecular Heck reaction and a carbene insertion as the key step was reported in 1998 (Scheme 42).431 This compound possesses two consecutive quaternary carbons included in a triad of three contiguous stereogenic centers and is therefore a candidate of choice in the field of modern organic synthesis. Optically active acid 555, easily prepared by optical resolution, was transformed into the ester 556 via its corresponding acyl chloride in 69% yield. Intramolecular Heck reaction delivered the tricyclic 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 and reduction in 34% OY. Oxidation of 310 eventually furnished the natural compound (−)-laurequinone 321 in 60% yield.

Figure 26. Repartition of genus and species containing carbotricyclic sesquiterpenes.

A limited number of halogenated molecules were found in this category. These compounds did not necessarily share their skeletons with the nonhalogenated compounds as exemplified by the rhodolaurane, gomerane, cyclococane, and omphalane halogenated sesquiterpene classes (Figure 24). The other ones were found in the cyclolaurane (9 compounds), perforetane (10 compounds), isocycloeudesmane (1), calenzanane (1), maaliane (1), and neomerane (1) skeletal classes. These halogenated compounds mainly (28/34) originated from the genus Laurencia, but the lack of studies does not make it possible to draw any conclusions concerning their biosynthesis or their ecological significance. The presence of nitrogen atoms in isonitrile, isothiocyanate, and N-formylamino groups is another original characteristic found in some of these marine structures. Peroxide

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

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functions in some of these compounds are also rarely found in terrestrial sesquiterpenes. One of the intriguing observations is that some marine sequiterpenes are optical antipodes of the corresponding terrestrial compounds, such as (−)-bourbon-11ene 1, (−)-1(10)-aristolene 112, (+)-γ-maaliene 131, (+)-palustrol 153, (−)-viridiflorol 154, and β-copaene 211, while others are present as enantiomeric pairs, such as (+)- and (−)-128, or (−)-163 and (+)-164. Beyond that the biosynthesis of antipodal sesquiterpenes is of considerable fundamental interest. From a structural point of view, these tricyclic sesquiterpenes have a higher degree of complexity than bicyclic C15-based molecules and therefore represent a greater challenge ahead for their structural investigation and total synthesis. As in the case of countless secondary metabolites produced by marine organisms, unprecedented carbon skeletons of the sesquiterpene class were discovered from marine life forms. Among the 54 skeletal types encountered in the carbotricyclic sesquiterpenes compiled in this review, approximately one-half (26) are unprecedented tricyclic skeletons, 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 unique representative of new natural product classes. Interestingly, this field of research has witnessed continuous attention over the past decades as reflected by a constant number of publications in the area since the 1960s.21 Sesquiterpene metabolites isolated from marine organisms exhibit various biological activities, for example, antifouling, ichthyotoxic, antialgal, cytotoxic, antibiotic, antifungal, antiparasitic, and anti-inflammatory activities. Nowadays, none of these tricyclic marine sesquiterpenes have been able to reach the preclinical marine pharmaceutical pipeline, despite highly interesting biological activities.433,434 However, apart from (+)-suberosanone 258, whose tremendous cytotoxic activities were not retained by the synthetic compound,313,421 other suberosanes should deserve further synthetic studies, as well as bourbonane (+)-5, hirsutane (−)-15, and capnellane (+)-32 displaying micromolar cytotoxic activities. Beside their cytotoxic evaluation, other biological activities were tested with some success. Furthermore, many of the compounds compiled in this review have not been assessed in biological assays. Often the limited supply of promising secondary metabolites extracted from their natural sources is a major hurdle to their pharmaceutical development. Nonetheless, strategies aimed to overcome this problem are being developed.435 Their structural diversity and great biological potential as pharmacological agents make them ideal candidates in the fields of drug discovery research, total synthesis, and medicinal chemistry. The discovery and total synthesis of new structures of potential biological interest will surely accentuate and stimulate the development of innovative synthetic methods. Interest in this field has remained very high and could increase as long as exploration of this rich reservoir of fascinating natural products still remains active itself.21,436

Table 9. Distribution of Skeletal Types in (Terrestrial + Marine) versus Marine Organisms skeletons found in terrestrial and marine organisms

skeletons found only in marine organisms

fused bourbonane kelsoane hirsutane isohirsutane capnellane silphiperfolane cycloeudesmane cubebane punctaporane probotryane aristolane maaliane africanane aromadendrane neomerane

isocycloeudesmane calenzanane shagane viridiane perforetane laurobtusane paralemnane capillosanane norantipathane

ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrev.6b00502. Nonhalogenated and halogenated carbotricyclic sesquiterpenes with their biological testing sorted by marine organisms; fused skeletons with highlighted numbering and connective bonds according to IUPAC rules to name tricyclic skeletons; bridged and miscellaneous skeletons with highlighted numbering and connective bonds according to IUPAC rules to name tricyclic skeletons (PDF)

bridged skeletons ylangane copaane sinularane pupukeanane sativane quadrane (suberosane) longibornane rumphellane cedrane caryolane isocaryolane clovane lemnafricanane

trachyopsane allopupukeanane abeopupukeanane neopupukeanane isosativane acanthodorane isotenerane paesslerane strepsesquitriane penicibilane isoparalemnane rhodolaurane gomerane omphalane (güimarane) miscellaneous skeletons cyclolaurane inflatane cyclococane

AUTHOR INFORMATION Corresponding Authors

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

Françoise Dumas: 0000-0002-2828-3124 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS Authors are thankful to BioCIS, University Paris-Sud, Centre National de la Recherche Scientifique (CNRS) & Université 6147


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Paris-Saclay (France) for their financial support during the time devoted 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 Daniela Ceccarelli (Magnetic Island, Australia) for the picture of Acropora echinata and I. hippuris, Pr Catherine Jeannot for proofreading the manuscript, and Barbara Dumas for the graphics.

(2) Fraga, B. M. Natural Sesquiterpenoids. Nat. Prod. Rep. 2013, 30, 1226−1264 and references therein. (3) In Dictionary of Natural Products on CD-ROM; Buckingham, J., Ed.; Chapman & Hall: London, 1998; Vol. 6.1. (4) Spivey, A. C.; Weston, M.; Woodhead, S. Celastraceae Sesquiterpenoids: Biological Activity and Synthesis. Chem. Soc. Rev. 2002, 31, 43−59. (5) Yang, X. L.; Zhang, J.-Z.; Luo, D. Q. The Taxonomy, Biology and Chemistry of the Fungal Pestalotiopsis Genus. Nat. Prod. Rep. 2012, 29, 622−641. (6) Orofino Kreuger, M. R.; Grootjans, S.; Biavatti, M. W.; Vandenabeele, P.; D’Herde, K. Sesquiterpene Lactones as Drugs with Multiple Targets in Cancer Treatment: Focus on Parthenolide. AntiCancer Drugs 2012, 23, 883−1001. (7) Tanasova, M.; Sturla, S. J. Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents. Chem. Rev. 2012, 112, 3578− 3610. (8) Gliszczyńska, A.; Brodelius, P. E. Sesquiterpene Coumarins. Phytochem. Rev. 2012, 11, 77−96. (9) Durán-Peña, M. J.; Botubol Ares, J. M.; Hanson, J. R.; Collado, I. G.; Hernández-Galán, R. Biological Activity of Natural Sesquiterpenoids Containing a Gem-Dimethylcyclopropane Unit. Nat. Prod. Rep. 2015, 32, 1236−1248. (10) Elissawy, A. M.; El-Shazly, M.; Ebada, S. S.; Singab, A. N. B.; Proksch, P. Bioactive Terpenes from Marine-Derived Fungi. Mar. Drugs 2015, 13, 1966−1992. (11) Bartikova, H.; Hanusova, V.; Skalova, L.; Ambroz, M.; Bousova, I. Antioxidant, Pro-Oxidant and Other Biological Activities of Sesquiterpenes. Curr. Top. Med. Chem. 2014, 14, 2478−2494. (12) Miller, D. J.; Allemann, R. K. Sesquiterpene Synthases: Passive Catalysts or Active Players? Nat. Prod. Rep. 2012, 29, 60−71. (13) Nay, B.; Evanno, L. Biomimetic Rearrangements of Complex Terpenoids. In Biomimetic Organic Synthesis; Poupon, E.; Nay, B., Eds.; Wiley-VCH: Weinheim, 2011; Vol. 2, pp 397−431. (14) Lin, X.; Hopson, R.; Cane, D. E. Genome Mining in Streptomyces coelicolor: Molecular Cloning and Characterization of a New Sesquiterpene Synthase. J. Am. Chem. Soc. 2006, 128, 6022−6023. (15) Christianson, D. W. Structural Biology and Chemistry of the Terpenoid Cyclases. Chem. Rev. 2006, 106, 3412−3442. (16) Thornburg, C. C.; Zabriskie, T. M.; McPhail, K. L. Deep-Sea Hydrothermal Vents: Potential Hot Spots for Natural Products Discovery? J. Nat. Prod. 2010, 73, 489−499. (17) Mayer, A. M. S.; Rodríguez, A. D.; Taglialatela-Scafati, O.; Fusetani, N. Marine Pharmacology in 2009−2011: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action. Mar. Drugs 2013, 11, 2510−2573. (18) Murti, Y.; Agrawal, T. Marine Derived PharmaceuticalsDevelopment of Natural Health Products from Marine Biodiversity. Int. J. Chem. Technol. Res. 2010, 2, 2198−2217. (19) Jaspars, M.; De Pascale, D.; Andersen, J. H.; Reyes, F.; Crawford, A. D.; Ianora, A. The Marine Biodiscovery Pipeline and Ocean Medicines of Tomorrow. J. Mar. Biol. Assoc. U. K. 2016, 96, 151−158. (20) Kornprobst, J.-M. Encyclopedia of Marine Natural Products; WileyBlackwell: Oxford, 2010. (21) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R. Marine Natural Products. Nat. Prod. Rep. 2016, 33, 382− 431 and references therein. (22) Gomes, N. G. M.; Lefranc, F.; Kijjoa, A.; Kiss, R. Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents? Mar. Drugs 2015, 13, 3950−3991. (23) Hegazy, M. E. F.; Mohamed, T. A.; Alhammady, M. A.; Shaheen, A. M.; Reda, E. H.; Elshamy, A. I.; Aziz, M.; Paré, P. W. Molecular Architecture and Biomedical Leads of Terpenes from Red Sea Marine Invertebrates. Mar. Drugs 2015, 13, 3154−3181. (24) Wei, W.-C.; Sung, P.-J.; Duh, C.-Y.; Chen, B.-W.; Sheu, J.-H.; Yang, N.-S. Anti-Inflammatory Activities of Natural Products Isolated

ABBREVIATIONS AC absolute configuration AIBN azo-bis-isobutyronitrile BINAP 2,2′-bis(diphénylphosphino)-1,1′-binaphtyle brsm based on recovered starting material CC cytotoxic concentration CD circular dichroism COX cyclooxygenase CSA camphorsulfonic acid m-CPBA 3-chloroperbenzoic acid DBU diazabicycloundecene de diastereomeric excess DMAP 4-(dimethylamino)pyridine EDA ethylenediamine ED effective dose ee enantiomeric excess FPP farnesyl diphosphate GC gas chromatography GI growth inhibition HIV human immune virus HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HPLC high-performance liquid chromatography iNOS inducible nitric oxide synthase IC inhibitory concentration IFN interferon IUPAC International Union of Pure and Applied Chemistry LD lethal dose LPS lipopolysaccharide LTMP lithium 2,2,6,6-tetramethylpiperidide MA moderately active MIC minimal inhibitory concentration MIC 48 h concentration for complete inhibition after 48 h incubation Ms mesyl NA no activity OY overall yield PCC pyridinium chlorochromate sp species or not specified spp Latin abbreviation for multiple (plural) species TBSOTf tert-butyldimethylsilyl triflate TES triethylsilyl pTSA p-toluene sulfonic acid THF tetrahydrofuran TMS trimethylsilyl Ts tosyl WA weak activity REFERENCES (1) Horta, A.; Alves, C.; Pinteus, S.; Pedrosa, R. The Marine Origin of Drugs. In Phycotoxins, Chemistry and Biochemistry; Botana, L. M., Alfonso, A., Eds.; John Wiley & Sons, Ltd.: Chichester, UK, 2015; pp 293−316. 6148


Chemical Reviews

Review

from Soft Corals of Taiwan between 2008 and 2012. Mar. Drugs 2013, 11, 4083−4126. (25) Dumas, F.; Kousara, M.; Chen, L.; Wei, L.; Le Bideau, F. Non Halogenated Heterotricyclic Sesquiterpenes from Marine Origin I: Fused systems. In Studies in Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science Publishers: Amsterdam, Netherlands, 2017; Vol. 52, pp 269−302. (26) Dembitsky, V. M.; Tolstikov, G. A. Natural Halogenated Sesquiterpenes from Marine Organisms. Chem. Sustain. Dev. 2004, 12, 1−12. (27) Wang, B.-G.; Gloer, J. B.; Ji, N.-Y.; Zhao, J.-C. Halogenated Organic Molecules of Rhodomelaceae Origin: Chemistry and Biology. Chem. Rev. 2013, 113, 3632−3685. (28) Moss, G. P. Extension and Revision of the Von Baeyer System for Naming Polycyclic Compounds (Including Bicyclic Compounds). Pure Appl. Chem. 1999, 71, 513−529. (29) Blunt, J. W.; Munro, M. H. Dictionary of Marine Natural Products with CD-ROM; CRC Press, 2007. Structural types available on the world wide web at http://dmnp.chemnetbase.com/intro/DMNP_ StructuralTypes.pdf. (30) König, G. M.; Wright, A. D. New and Unusual Sesquiterpenes: Kelsoene, Prespatane, Epi-γ-Gurjunene, and T-Cadinthiol, from the Tropical Marine Sponge Cymbastela hooperi. J. Org. Chem. 1997, 62, 3837−3840. (31) Warmers, U.; Wihstutz, K.; Bülow, N.; Fricke, C.; König, W. A. Sesquiterpene Constituents of the Liverwort Calypogeia muelleriana. Phytochemistry 1998, 49, 1723−1731. (32) Cheng, S.-Y.; Dai, C.-F.; Duh, C.-Y. Sesquiterpenoids and Artificial 19-Oxygenated Steroids from the Formosan Soft Coral Nephthea erecta. J. Nat. Prod. 2007, 70, 1449−1453. (33) Arnone, A.; Nasini, G.; de Pava, O. V. Secondary Mould Metabolites: Part 45. Isolation and Structure Elucidation of Sulcatine G, a Novel Sesquiterpene from Laurilia sulcata. J. Chem. Soc., Perkin Trans. 1 1993, 2723−2725. (34) Nabeta, K.; Yamamoto, K.; Hashimoto, M.; Koshino, H.; Funatsuki, K.; Katoh, K. Biosynthesis of Kelsoene in Cultured Cells of Liverworts Ptychanthus striatus. Chem. Commun. 1998, 1485−1486. (35) Warmers, U.; König, W. A. (−)-7-Epi-Isojunenol and (+)-7-Epijunenol, Constituents of the Liverwort Tritomaria quinquedentata. Phytochemistry 1999, 52, 1519−1524. (36) Nabeta, K.; Yamamoto, K.; Koshino, H.; Fukui, H.; Fukushi, Y.; Tahara, S. Absolute Configuration of Kelsoene and Prespatane. Biosci., Biotechnol., Biochem. 1999, 63, 1772−1776. (37) Fietz-Razavian, S.; Schulz, S.; Dix, I.; Jones, P. G. Revision of the Absolute Configuration of the Tricyclic Sesquiterpene (+)-Kelsoene by Chemical Correlation and Enantiospecific Total Synthesis of Its Enantiomer. Chem. Commun. 2001, 2154−2155. (38) Cheng, S.-Y.; Shih, N.-L.; Hou, K.-Y.; Ger, M.-J.; Yang, C.-N.; Wang, S.-K.; Duh, C.-Y. Kelsoenethiol and Dikelsoenyl Ether, Two Unique Kelsoane-Type Sesquiterpenes, from the Formosan Soft Coral Nephthea erecta. Bioorg. Med. Chem. Lett. 2014, 24, 473−475. (39) Dickschat, J. S.; Martens, T.; Brinkhoff, T.; Simon, M.; Schulz, S. Volatiles Released by a Streptomyces Species Isolated from the North Sea. Chem. Biodiversity 2005, 2, 837−865. (40) Nabeta, K.; Yamamoto, M.; Fukushima, K.; Katoh, K. Biosynthesis of Kelsoene and Prespatane in Cultured Cells of the Liverwort Ptychanthus striatus. J. Chem. Soc., Perkin Trans. 1 2000, 2703− 2708. (41) Wang, G.-Y.-S.; Abrell, L. M.; Avelar, A.; Borgeson, B. M.; Crews, P. New Hirsutane Based Sesquiterpenes from Salt Water Cultures of a Marine Sponge-Derived Fungus and the Terrestrial Fungus Coriolus consors. Tetrahedron 1998, 54, 7335−7342. (42) Li, H.-J.; Lan, W.-J.; Lam, C.-K.; Yang, F.; Zhu, X. F. Hirsutane Sesquiterpenoids from the Marine-Derived Fungus Chondrostereum sp. Chem. Biodiversity 2011, 8, 317−324. (43) Gao, J.; Yue, D. C.; Cheng, K. D.; Wang, S. C.; Yu, K. B.; Zheng, Q. T.; Yang, J. S. Gloeosteretriol, a new Sesquiterpene from the Fermentation Products of Gloeostereum incarnatum S. Ito et Imai. Acta Pharm. Sin. 1992, 27, 33−36.

(44) Asai, R.; Mitsuhashi, S.; Shigetomi, K.; Miyamoto, T.; Ubukata, M. Absolute Configurations of (−)-Hirsutanol A and (−)-Hirsutanol C Produced by Gloeostereum Incarnatum. J. Antibiot. 2011, 64, 693−696. (45) Li, H.-J.; Xie, Y.-L.; Xie, Z.-L.; Chen, Y.; Lam, C.-K.; Lan, W.-J. Chondrosterins A−E, Triquinane-Type Sesquiterpenoids from Soft Coral-Associated Fungus Chondrostereum sp. Mar. Drugs 2012, 10, 627−638. (46) Hellwig, V.; Dasenbrock, J.; Schumann, S.; Steglich, W.; Leonhardt, K.; Anke, T. New Triquinane-Type Sesquiterpenoids from Macrocystidia cucumis (Basidiomycetes). Eur. J. Org. Chem. 1998, 1998, 73−79. (47) Shindo, M.; Sato, Y.; Shishido, K. An Ynolate-Initiated Tandem Process Giving Cyclopentenones: Total Synthesis of Cucumin E. Tetrahedron Lett. 2002, 43, 5039−5041. (48) Li, H.-J.; Jiang, W.-H.; Liang, W.-L.; Huang, J.-X.; Mo, Y.-F.; Ding, Y.-Q.; Lam, C.-K.; Qian, X.-J.; Zhu, X.-F.; Lan, W.-J. Induced Marine Fungus Chondrostereum sp. as a Means of Producing New Sesquiterpenoids Chondrosterins I and J by Using Glycerol as the Carbon Source. Mar. Drugs 2014, 12, 167−175. (49) Takazawa, H.; Kashino, S. Incarnal. A New Antibacterial Sesquiterpene from Basidiomycetes. Chem. Pharm. Bull. 1991, 39, 555−557. (50) Li, H.-J.; Chen, T.; Xie, Y.-L.; Chen, W.-D.; Zhu, X.-F.; Lan, W.-J. Isolation and Structural Elucidation of Chondrosterins F-H from the Marine Fungus Chondrostereum sp. Mar. Drugs 2013, 11, 551−558. (51) Ayanoglu, E.; Gebreyesus, T.; Beechan, C. M.; Djerassi, C.; Kaisin, M. Terpenoids LXXV. Δ9(12)-Capnellene, a New Sesquiterpene Hydrocarbon from the Soft Coral Capnella imbricata. Tetrahedron Lett. 1978, 19, 1671−1674. (52) Kaisin, M.; Sheikh, Y. M.; Durham, L. J.; Djerassi, C.; Tursch, B.; Daloze, D.; Braekman, J. C.; Losman, D.; Karlsson, R. Capnellane - a New Tricyclic Sesquiterpene Skeleton from the Soft Coral Capnella imbricata. Tetrahedron Lett. 1974, 15, 2239−2242. (53) Karlsson, R. The Structure and Absolute Configuration of Δ9(12)Capnellene-3β,8β,10α-Triol. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1977, 33, 1143−1147. (54) Sheikh, Y. M.; Singy, G.; Kaisin, M.; Eggert, H.; Djerassi, C.; Tursch, B.; Daloze, D.; Braekman, J. C. Chemical Studies of Marine Invertebrate-XIV. Four Representatives of a Novel Sesquiterpene Classthe Capnellane Skeleton. Tetrahedron 1976, 32, 1171−1178. (55) Morris, L. A.; Jaspars, M.; Adamson, K.; Woods, S.; Wallace, H. M. The Capnellenes Revisited: New Structures and New Biological Activity. Tetrahedron 1998, 54, 12953−12958. (56) Sheikh, Y. M.; Djerassi, C.; Braekman, J. C.; Daloze, D.; Kaisin, M.; Tursch, B.; Karlsson, R. Terpenoids-LXXII: Chemical Studies of Marine invertebrates-XXVI Δ9(12)-Capnellene-3β,8β,10α, 14-Tetrol, a Novel Polyoxygenated Sesquiterpene from the Alcyonarian Capnella imbricata. Tetrahedron 1977, 33, 2115−2117. (57) Kaisin, M.; Braekman, J. C.; Daloze, D.; Tursch, B. Novel Acetoxycapnellenes from the Alcyonacean Capnella imbricata. Tetrahedron 1985, 41, 1067−1072. (58) Grote, D.; Hänel, F.; Dahse, H.-M.; Seifert, K. Capnellenes from the Soft Coral Dendronephthya rubeola. Chem. Biodiversity 2008, 5, 1683−1693. (59) Shen, Y.-C.; Tzeng, G.-L.; Kuo, Y.-H.; Khalil, A. T. Cytotoxic Activity of Capnellene-8β,10α-Diol Derivatives from a Taiwanese Soft Coral Capnella sp. J. Chin. Chem. Soc. 2008, 55, 828−833. (60) Cheng, S.-Y.; Lin, E.-H.; Huang, J.-S.; Wen, Z.-H.; Duh, C.-Y. Ylangene-Type and Nardosinane-Type Sesquiterpenoids from the Soft Corals Lemnalia f lava and Paralemnalia thyrsoides. Chem. Pharm. Bull. 2010, 58, 381−385. (61) Chang, C.-H.; Wen, Z.-H.; Wang, S.-K.; Duh, C.-Y. Capnellenes from the Formosan Soft Coral Capnella imbricata. J. Nat. Prod. 2008, 71, 619−621. (62) Kaisin, M.; Tursch, B.; Declercq, J. P.; Germain, G.; Van Meerssche, M. Chemical Studies of Marine Invertebrates. XL. Δ9(12)Capnellene-2β,5α,8β,10α-Tetrol, a New Sesquiterpene Alcohol from the Soft Coral Capnella imbricata. Bull. Soc. Chim. Belg. 1979, 88, 253− 258. 6149


Chemical Reviews

Review

(63) Groweiss, A.; Fenical, W.; Cun-Heng, H.; Clardy, J.; Zhongde, W.; Zhongnian, Y.; Kanghou, L. Subergorgic Acid, a Novel Tricyclopentanoid Cardiotoxin from the Pacific Gorgonian Coral Subergorgia suberosa. Tetrahedron Lett. 1985, 26, 2379−2382. (64) Subrahmanyam, C.; Kumar, S. R.; Reddy, G. D. Bioactive Compounds from the Indian Ocean Gorgonian Subergorgia suberosa (Pallas). Indian J. Chem., Sect B 2005, 44B, 2186−2188. (65) Gao, C.-H.; Wang, Y.-F.; Li, S.; Qian, P.-Y.; Qi, S.-H. Alkaloids and Sesquiterpenes from the South China Sea Gorgonian Echinogorgia pseudossapo. Mar. Drugs 2011, 9, 2479−2487. (66) Sheu, J.-H.; Hung, K.-C.; Wang, G.-H.; Duh, C.-Y. New Cytotoxic Sesquiterpenes from the Gorgonian Isis hippuris. J. Nat. Prod. 2000, 63, 1603−1607. (67) Guo, Z.; Chai, X.; Yang, B.; Zhou, X.; Liu, Y.; Tu, P. Sesquiterpenoids from a South China Sea Gorgonian Menella sp. J. Chin. Pharm. Sci. 2013, 22, 282−285. (68) Parameswaran, P. S.; Naik, C. G.; Kamat, S. Y.; Puar, M. S.; Das, P.; Hegde, V. R. Studies on the Secondary Metabolites from the Indian Gorgonian Subergorgia suberosa: Isolation and Characterization of Four Analogues of the Cardiotoxin Subergorgic Acid. J. Nat. Prod. 1998, 61, 832−834. (69) Wang, G.-H.; Ahmed, A. F.; Kuo, Y.-H.; Sheu, J.-H. Two New Subergane-Based Sesquiterpenes from a Taiwanese Gorgonian Coral Subergorgia suberosa. J. Nat. Prod. 2002, 65, 1033−1036. (70) Huang, Q.; Cheng, W.; Long, H.; Liu, H.; van Ofwegen, L.; Lin, W. Subergane-Type Sesquiterpenes from Gorgonian Coral Subergorgia suberosa with Antibacterial Activities. Helv. Chim. Acta 2015, 98, 1202− 1209. (71) Zhang, J.; Liang, Y.; Li, L.-C.; Xu, S.-H. Suberosanones A-C, New Metabolites Possessing Cyclopentenone System from the South China Sea Gorgonian Coral Subergorgia suberosa. Helv. Chim. Acta 2014, 97, 128−136. (72) Coll, J. C.; Wright, A. D. Tropical Marine Algae. III. New Sesquiterpenes from Laurencia majuscula (Rhodophyta, Rhodophyceae, Ceramiales, Rhodomelaceae). Aust. J. Chem. 1989, 42, 1591−1603. (73) Wright, A. D.; Coll, J. C.; Price, I. R. Tropical Marine Algae, VII. The Chemical Composition of Marine Algae from North Queensland Waters. J. Nat. Prod. 1990, 53, 845−861. (74) Srikrishna, A.; Nagaraju, G.; Sheth, V. M. Enantiospecific First Total Synthesis of (6S,7R)-Silphiperfolan-6-ol. Tetrahedron 2012, 68, 2650−2656. (75) da Silva Machado, F. L.; Pacienza-Lima, W.; Rossi-Bergmann, B.; de Souza Gestinari, L. M.; Fujii, M. T.; Campos de Paula, J.; Costa, S. S.; Lopes, N. P.; Kaiser, C. R.; Soares, A. R. Antileishmanial Sesquiterpenes from the Brazilian Red Alga Laurencia dendroidea. Planta Med. 2011, 77, 733−735. (76) Kö nig, G. M.; Wright, A. D. Laurencia rigida: Chemical Investigations of Its Antifouling Dichloromethane Extract. J. Nat. Prod. 1997, 60, 967−970. (77) Ji, N.-Y.; Wang, B.-G. Nonhalogenated Organic Molecules from Laurencia Algae. Phytochem. Rev. 2014, 13, 653−670. (78) Guella, G.; Skropeta, D.; Mancini, I.; Pietra, F. The First 6,8Cycloeudesmane Sesquiterpene from a Marine Organism: the Red Seaweed Laurencia microcladia from the Baia di Calenzana, Elba Island. Z. Naturforsch. 2002, 57b, 1147−1151. (79) Wu, Q.-X.; Shi, Y.-P.; Jia, Z.-J. Eudesmane Sesquiterpenoids from the Asteraceae Family. Nat. Prod. Rep. 2006, 23, 699−734. (80) Fenical, W.; Sims, J. J. Cycloeudesmol, an Antibiotic Cyclopropane Containing Sesquiterpene from the Marine Alga, Chondria oppositiclada Dawson. Tetrahedron Lett. 1974, 15, 1137−1140. (81) Suzuki, T.; Kikuchi, H.; Kurosawa, E. (E)-γ-Bisabolen-8,9Epoxide and Isocycloeudesmol, Two New Sesquiterpenoids from the Red Alga Laurencia nipponica Yamada. Chem. Lett. 1980, 9, 1267−1270. (82) Suzuki, T.; Furusaki, A.; Kikuchi, H.; Kurosawa, E. The Absolute Configuration of Cycloeudesmol from the Red Alga Laurencia nipponica Yamada. Tetrahedron Lett. 1981, 22, 3423−3426. (83) Guella, G.; Skropeta, D.; Mancini, I.; Pietra, F. Calenzanane Sesquiterpenes from the Red Seaweed Laurencia microcladia from the Bay of Calenzana, Elba Island: Acid-Catalyzed Stereospecific Con-

version of Calenzanol into Indene- and Guaiazulene-Type Sesquiterpenes. Chem. - Eur. J. 2003, 9, 5770−5777. (84) Guella, G.; Skropeta, D.; Breuils, S.; Mancini, I.; Pietra, F. Calenzanol, the First Member of a New Class of Sesquiterpene with a Novel Skeleton Isolated from the Red Seaweed Laurencia microcladia from the Bay of Calenzana, Elba Island. Tetrahedron Lett. 2001, 42, 723− 725. (85) von Salm, J. L.; Wilson, N. G.; Vesely, B. A.; Kyle, D. E.; Cuce, J.; Baker, B. J. Shagenes A and B, New Tricyclic Sesquiterpenes Produced by an Undescribed Antarctic Octocoral. Org. Lett. 2014, 16, 2630−2633. (86) Bowden, B. F.; Coll, J. C.; Tapiolas, D. M. Studies of Australian Soft Corals. XXX. A Novel Trisnorsesquiterpene from a Cespitularia Species and the Isolation of Guaiazulene from a Small Blue Alcyonium Species. Aust. J. Chem. 1983, 36, 211−214. (87) Dai, M. C.; Garson, M. J.; Coll, J. C. Biosynthetic Processes in Soft Coral. I. A Comparison of Terpene Biosynthesis in Alcyonium molle (Alcyoniidae) and Heteroxenia sp. (Xeniidae). Comp. Biochem. Physiol., Part B 1991, 99, 775−783. (88) Tanaka, A.; Tanaka, R.; Uda, H.; Yoshikoshi, A. Synthesis of Cubebane-Type Sesquiterpenoids and the Stereochemistry of Cubebol. J. Chem. Soc., Perkin Trans. 1 1972, 1721−1727. (89) De Rosa, S.; De Giulio, A.; Iodice, C.; Zavodink, N. Sesquiterpenes from the Brown Alga Taonia atomaria. Phytochemistry 1994, 37, 1327−1330. (90) Suzuki, M.; Kowata, N.; Kurosawa, E. Epicubebol and Related Sesquiterpenoids from the Brown Alga Dictyopteris divaricata. Bull. Chem. Soc. Jpn. 1981, 54, 2366−2368. (91) Weinheimer, A. J.; Schmitz, F. J.; Ciereszko, L. S. Chemistry of Coelenterates. VII. The Occurrence of Terpenoid Compounds in Gorgonians. In Drugs Sea, Transactions from the Drugs from the Sea Symposium.; Freudenthal, H. D., Ed.; Marine Technololgy Society: Washington, D.C, 1968; pp 135−140. (92) McPhail, K. L.; Davies-Coleman, M. T.; Starmer, J. Sequestered Chemistry of the Arminacean Nudibranch Leminda millecra in Algoa Bay, South Africa. J. Nat. Prod. 2001, 64, 1183−1190. (93) Williams, D. E.; Andersen, R. J.; Kingston, J. F.; Fallis, A. G. Minor Metabolites of the Cold Water Soft Coral Gersemia rubiformis. Can. J. Chem. 1988, 66, 2928−2934. (94) Mitome, H.; Shirato, N.; Miyaoka, H.; Yamada, Y.; van Soest, R. W. M. Terpene Isocyanides, Isocyanates, and Isothiocyanates from the Okinawan Marine Sponge Stylissa sp. J. Nat. Prod. 2004, 67, 833−837. (95) He, H.-Y.; Salva, J.; Catalos, R. F.; Faulkner, D. J. Sesquiterpene Thiocyanates and Isothiocyanates from Axinyssa aplysinoides. J. Org. Chem. 1992, 57, 3191−3194. (96) White, A. M.; Pierens, G. K.; Skinner-Adams, T.; Andrews, K. T.; Bernhardt, P. V.; Krenske, E. H.; Mollo, E.; Garson, M. J. Antimalarial Isocyano and Isothiocyanato Sesquiterpenes with Tri- and Bicyclic Skeletons from the Nudibranch Phyllidia ocellata. J. Nat. Prod. 2015, 78, 1422−1427. (97) Norte, M.; Fernandez, J. J.; Souto, M. L. Viridianol, a Rearranged Sesquiterpene with a Novel Carbon Skeleton from Laurencia viridis. Tetrahedron Lett. 1994, 35, 4607−4610. (98) Wu, Z.; Liu, D.; Proksch, P.; Guo, P.; Lin, W. Punctaporonins H− M: Caryophyllene-Type Sesquiterpenoids from the Sponge-Associated Fungus Hansfordia sinuosae. Mar. Drugs 2014, 12, 3904−3916. (99) Deyrup, S. T.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T. Caryophyllene Sesquiterpenoids from a Fungicolous Isolate of Pestalotiopsis disseminata. J. Nat. Prod. 2006, 69, 608−611. (100) González, A. G.; Aguiar, J. M.; Martin, J. D.; Norte, M. Three New Sesquiterpenoids from the Red Alga Laurencia perforata. Tetrahedron Lett. 1975, 16, 2499−2502. (101) Gonzáles, A. G.; Darias, J.; Martin, J. D. Biomimetic Interconversion of two New Types of Metabolite from Laurencia perforata. Tetrahedron Lett. 1977, 18, 3375−3378. (102) Iliopoulou, D.; Roussis, V.; Pannecouque, C.; De Clercq, E.; Vagias, C. Halogenated Sesquiterpenes from the Red Alga Laurencia obtusa. Tetrahedron 2002, 58, 6749−6755. (103) Coll, J. C.; Skelton, B. W.; White, A. H.; Wright, A. D. Tropical Marine Algae. V. The Structure Determination of Two Novel 6150


Chemical Reviews

Review

Sesquiterpenes from the Red Alga Laurencia tenera (Rhodophyceae, Ceramiales, Rhodomelaceae). Aust. J. Chem. 1989, 42, 1695−1703. (104) Wright, A. D.; König, G. M.; Sticher, O.; Rüegger, H. The Application of Two-Dimensional Nuclear Magnetic Resonance Methodologies to the Structure Solution of the New Natural Product Tenerol Acetate from Laurencia tenera. Phytochem. Anal. 1992, 3, 263− 269. (105) Findlay, J. A.; Li, G. Novel Terpenoids from the Sea Hare Aplysia punctata. Can. J. Chem. 2002, 80, 1697−1707. (106) Kladi, M.; Xenaki, H.; Vagias, C.; Papazafiri, P.; Roussis, V. New Cytotoxic Sesquiterpenes from the Red Algae Laurencia obtusa and Laurencia microcladia. Tetrahedron 2006, 62, 182−189. (107) Krohn, K.; Dai, J.; Flörke, U.; Aust, H.-J.; Dräger, S.; Schulz, B. Botryane Metabolites from the Fungus Geniculosporium sp. Isolated from the Marine Red Alga Polysiphonia. J. Nat. Prod. 2005, 68, 400−405. (108) Rücker, G.; Kretzschmar, U. 9-Aristolen-1α-ol und 1.2.9.10Tetradehydro-Aristolan, Neue Sesquiterpene Mit einem AristolanGerüst. Liebigs Ann. Chem. 1971, 748, 214−217. (109) Takeshita, H.; Shimooda, I.; Hatsui, T. Synthetic Photochemistry. XXI. The Sensitized Photooxygenation of Calarene. A Facile Hock Cleavage of an Allylhydroperoxide and Structure Revision for Aristolenols. Bull. Chem. Soc. Jpn. 1980, 53, 3721−3722. (110) Ji, N. Y.; Li, X. M.; Ding, L. P.; Wang, B. G. Two New Aristolane Sesquiterpenes from Laurencia similis. Chin. Chem. Lett. 2007, 18, 178− 180. (111) Ji, N. Y.; Li, X. M.; Ding, L. P.; Wang, B. G. Aristolane Sesquiterpenes and Highly Brominated Indoles from the Marine Red Alga Laurencia similis (Rhodomelaceae). Helv. Chim. Acta 2007, 90, 385−391. (112) Li, C.-S.; Li, X. M.; Cui, C.-M.; Wang, B. G. Brominated Metabolites from the Marine Red Alga Laurencia similis. Z. Naturforsch., B: J. Chem. Sci. 2010, 65, 87−89. (113) Kariyone, T.; Naito, S. Components of Aristolochia debilis. J. Pharm. Soc. Jpn. 1955, 75, 1511−1516; Chem. Abstr. 1956, 50, 10684a. (114) Vidari, G.; Che, Z.; Garlaschelli, L. New Nardosinane and Aristolane Sesquiterpenes from the Fruiting Bodies of Russula lepida. Tetrahedron Lett. 1998, 39, 6073−6076. (115) Harrigan, G. G.; Ahmad, A.; Baj, N.; Glass, T. E.; Gunatilaka, A. A. L.; Kingston, D.G. I. Bioactive and Other Sesquiterpenoids from Porella Cordeana. J. Nat. Prod. 1993, 56, 921−925. (116) Cheng, S.-Y.; Wen, Z.-H.; Wang, S.-K.; Chiang, M. Y.; El-Gamal, A. A. H.; Dai, C.-F.; Duh, C.-Y. Revision of the Absolute Configuration at C(23) of Lanostanoids and Isolation of Secondary Metabolites from Formosan Soft Coral Nephthea erecta. Chem. Biodiversity 2009, 6, 86− 95. (117) Su, J.-H.; Dai, C.-F.; Huang, H.-H.; Wu, Y.-C.; Sung, P.-J.; Hsu, C.-H.; Sheu, J.-H. Terpenoid-Related Metabolites from a Formosan Soft Coral Nephthea chabrolii. Chem. Pharm. Bull. 2007, 55, 594−597. (118) Narayanan, C. S.; Kulkarni, K. S.; Vaidya, A. S.; Kanthamani, S.; Lakshmi Kumari, G.; Bapat, B. V.; Paknikar, S. K.; Kulkarni, S. N.; Kelkar, G. R.; Bhattacharyya, S. C. Terpenoids-XLVI Components of Indian Valerian Root Oil. Tetrahedron 1964, 20, 963−968. (119) Weinheimer, A. J.; Washecheck, P. H.; van der Helm, D.; Hossain, M. B. The Sesquiterpene Hydrocarbons of the Gorgonian, Pseudopterogorgia americana, the Nonisoprenoid β-Gorgonene. Chem. Commun. 1968, 4, 1070−1071. (120) Green, D.; Kashman, Y.; Benayahu, Y. Secondary Metabolites of the Yellow and Gray Morphs of the Soft Coral Parerythropodium f ulvum f ulvum: Comparative Aspects. J. Nat. Prod. 1992, 55, 1186−1196. (121) Ji, N.-Y.; Li, X.-M.; Cui, C.-M.; Wang, B.-G. Terpenes and Polybromoindoles from the Marine Red Alga Laurencia decumbens (Rhodomelaceae). Helv. Chim. Acta 2007, 90, 1731−1736. (122) Cheng, S.-Y.; Wen, Z.-H.; Wang, S.-K.; Chiang, M. Y.; El-Gamal, A. A. H.; Dai, C.-F.; Duh, C.-Y. Revision of the Absolute Configuration at C(23) of Lanostanoids and Isolation of Secondary Metabolites from Formosan Soft Coral Nephthea erecta. Chem. Biodiversity 2009, 6, 86− 95.

(123) Su, J.-H.; Dai, C.-F.; Huang, H.-H.; Wu, Y.-C.; Sung, P.-J.; Hsu, C.-H.; Sheu, J.-H. Terpenoid-Related Metabolites from a Formosan Soft Coral Nephthea chabrolii. Chem. Pharm. Bull. 2007, 55, 594−597. (124) Su, H.; Shi, D.-Y.; Li, J.; Guo, S.-J.; Li, L.-L.; Yuan, Z.-H.; Zhu, X.B. Sesquiterpenes from Laurencia similis. Molecules 2009, 14, 1889− 1897. (125) Su, S.; Sun, W.-S.; Wang, B.; Cheng, W.; Liang, H.; Zhao, Y.-Y.; Zhang, Q.-Y.; Wu, J. A Novel Brominated Cuparene-Derived Sesquiterpene Ether from the Red Alga Laurencia sp. J. Asian Nat. Prod. Res. 2010, 12, 916−920. (126) Hirota, H.; Tomono, Y.; Fusetani, N. Terpenoids with Antifouling Activity Against Barnacle Larvae from the Marine Sponge Acanthella cavernosa. Tetrahedron 1996, 52, 2359−2368. (127) Anjaneyulu, A. S. R.; Krishna Murthy, M. V. R. Two New Terpenoid Derivatives from a New Soft Coral Species of the Nephthea Genus of the Indian Ocean. Indian J. Chem., Sect B 2000, 39, 42−56. (128) Büchi, G.; Greuter, F.; Tokoroyama, T. Terpenes-XVII. Structure of Calarene and Stereochemistry of Aristolone. Tetrahedron Lett. 1962, 3, 827−833. (129) Bates, R. B.; Büchi, G.; Matsuura, T.; Shaffer, R. R. Terpenes. XI. 1 The Total Synthesis of Maaliol. J. Am. Chem. Soc. 1960, 82, 2327− 2337. (130) Zubia, E.; Ortega, M. J.; Carballo, J. L. Sesquiterpenes from the Sponge Axinyssa isabela. J. Nat. Prod. 2008, 71, 2004−2010. (131) Itokawa, H.; Masuyama, K.; Morita, H.; Takeya, K. Cytotoxic Sesquiterpenes from Nardostachys chinensis. Chem. Pharm. Bull. 1993, 41, 1183−1184. (132) Rahelivao, M. P.; Gruner, M.; Andriamanantoanina, H.; Andriamihaja, B.; Bauer, I.; Knölker, H.-J. Red Algae (Rhodophyta) from the Coast of Madagascar: Preliminary Bioactivity Studies and Isolation of Natural Products. Mar. Drugs 2015, 13, 4197−4216. (133) Bowden, B. F.; Coll, J. C.; Mitchell, S. J. Studies of Australian Soft Corals. XVI. Two New Sesquiterpenes from Lemnalia humesi. Aust. J. Chem. 1980, 33, 681−684. (134) Kamada, T.; Vairappan, C. S. New Bioactive Secondary Metabolites from the Bornean Red Alga, Laurencia similis (Ceremiates). Nat. Prod. Commun. 2013, 8, 287−288. (135) Jurek, J.; Scheuer, P. J. Sesquiterpenoids and Norsesquiterpenoids from the Soft Coral Lemnalia af ricana. J. Nat. Prod. 1993, 56, 508− 513. (136) Ciminiello, P.; Fattorusso, E.; Magno, S.; Mayol, L. Sesquiterpenoids Based on the Epi-Maaliane Skeleton from the Marine Sponge Axinella cannabina. J. Nat. Prod. 1985, 48, 64−68. (137) Thompson, J. E.; Walker, R. P.; Wratten, S. J.; Faulkner, D. J. A Chemical Defense Mechanism for the Nudibranch Cadlina luteomarginata. Tetrahedron 1982, 38, 1865−1873. (138) Burgoyne, D. L.; Dumdei, E. J.; Andersen, R. J. Acanthenes A to C: a Chloro, Isothiocyanate, Formamide Sesquiterpene Triad Isolated from the Northeastern Pacific Marine Sponge Acanthella sp. and the Dorid Nudibranch Cadlina luteomarginata. Tetrahedron 1993, 49, 4503−4510. (139) Capon, R. J.; MacLeod, J. K. New Isothiocyanate Sesquiterpenes from the Australian Marine Sponge Acanthella pulcherrima. Aust. J. Chem. 1988, 41, 979−983. (140) Yan, X.-H.; Zhu, X.-Z.; Yu, J.-L.; Jin, D.-Z.; Guo, Y.-W.; Mollo, E.; Cimino, G. 3-Oxo-Axisonitrile-3, a New Sesquiterpene Isocyanide from the Chinese Marine Sponge Acanthella sp. J. Asian Nat. Prod. Res. 2006, 8, 579−584. (141) Simpson, J. S.; Garson, M. J.; Hooper, J. N. A.; Cline, E. I.; Angerhofer, C. K. Terpene Metabolites from the Tropical Marine Sponge Axinyssa sp. nov. Aust. J. Chem. 1997, 50, 1123−1127. (142) Kodama, K.; Higuchi, R.; Miyamoto, T.; Van Soest, R. W. M. (−)-Axinyssene: A Novel Cytotoxic Diterpene from a Japanese Marine Sponge Axinyssa Sp. Org. Lett. 2003, 5, 169−171. (143) Tada, H.; Yasuda, F. Metabolites from the Marine Sponge Epipolasis kushimotoensis. Chem. Pharm. Bull. 1985, 33, 1941−1945. (144) Dumdei, E. J.; Flowers, A. E.; Garson, M. J.; Moore, C. J. The Biosynthesis of Sesquiterpene Isocyanides and Isothiocynanates in the Marine Sponge Acanthella cavernosa (Dendy); Evidence for Dietary 6151


Chemical Reviews

Review

Transfer to the Dorid Nudibranch Phyllidiella pustulosa. Comp. Biochem. Physiol., Part A 1997, 118, 1385−1392. (145) Zubía, E.; Ortega, M. J.; Hernández-Guerrero, C. J.; Carballo, J. L. Isothiocyanate Sesquiterpenes from a Sponge of the Genus Axinyssa. J. Nat. Prod. 2008, 71, 608−614. (146) Iguchi, K.; Fukaya, T.; Yasumoto, A.; Watanabe, K. New Marine Sesquiterpenoids and Diterpenoids from the Okinawan Soft Coral Clavularia koellikeri. J. Nat. Prod. 2004, 67, 577−583. (147) For an exception to the Mosher’s rule, see: Potin, D.; Dumas, F.; d’Angelo, J. New Chiral Auxiliaries: Their Use in the Asymmetric Hydrogenation of β-Acetamidocrotonates. J. Am. Chem. Soc. 1990, 112, 3483−3486. (148) Barnekow, D. E.; Cardellina, J. H., II; Zektzer, A. S.; Martin, G. E. Novel Cytotoxic and Phytotoxic Halogenated Sesquiterpenes from the Green Alga Neomeris annulata. J. Am. Chem. Soc. 1989, 111, 3511−3517. (149) Caccamese, S.; Amico, V.; Neri, P.; Foti, M. The Structure of Laurobtsusol, a New Rearranged Sesquiterpenoid from the Mediterranean Red Alga Laurencia obtusa. Tetrahedron 1991, 47, 10101−10108. (150) Blanchfield, J. T.; Chow, S.; Bernhardt, P. V.; Kennard, C. H. L.; Kitching, W. Concerning the Proposed Structure of (+)-Laurobtusol: Spectral Discrepancies with Synthetic, Racemic Stereoisomers. Aust. J. Chem. 2004, 57, 673−676. (151) Hamlin, T. A.; Hamann, C. S.; Tantillo, D. J. Delocalization of Charge and Electron Density in the Humulyl Cation-Implications for Terpene Biosynthesis. J. Org. Chem. 2015, 80, 4046−4053. (152) Rücker, G. Sesquiterpenes. Angew. Chem., Int. Ed. Engl. 1973, 12, 793−806. (153) Huang, H.-C.; Wen, Z.-H.; Chao, C.-H.; Ahmed, A. F.; Chiang, M. Y.; Kuo, Y.-H.; Hsu, C.-H.; Sheu, J.-H. Novel Sesquiterpenoids from the Formosan Soft Coral Paralemnalia thyrsoides. Tetrahedron Lett. 2006, 47, 8751−8755. (154) Tursch, B.; Braekman, J. C.; Daloze, D.; Fritz, P.; Kelecom, A.; Karlsson, R.; Losman, D. Chemical Studies of Marine Invertebrates. VIII. Africanol, an Unusual Sesquiterpene from Lemnalia af ricana. Tetrahedron Lett. 1974, 15, 747−750. (155) Karlsson, R. Measurements of Bijvoet Differences. Structure and Absolute Configuration of Africanol, a Sesquiterpene. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1976, 32, 2609−2614. (156) Ji, N.-Y.; Li, X.-M.; Li, K.; Ding, L.-P.; Gloer, J. B.; Wang, B.-G. Diterpenes, Sesquiterpenes, and a C15-Acetogenin from the Marine Red Alga Laurencia mariannensis. J. Nat. Prod. 2007, 70, 1901−1905. (157) Kashman, Y.; Bodner, M.; Finer-Moore, J. S.; Clardy, J. Δ9(15)Africanene, a New Sesquiterpene Hydrocarbon from the Soft coral Sinularia erecta. Experientia 1980, 36, 891−892. (158) Braekman, J. C.; Daloze, D.; Tursch, B.; Hull, S. E.; Declercq, J.P.; Germain, G.; Van Meerssche, M. Chemical Studies of Marine Invertebrates. XXXVIII. Δ9(15)-Africanene, a New Sesquiterpene Hydrocarbon from Sinularia polydactyla (Coelenterata, Octocorallia, Alcyonaceae). Experientia 1980, 36, 893−893. (159) Bala Show Reddy, G.; Venkata Rao, D.; Bheemasankara Rao, C.; Dhananjaya, N.; Kuttan, R.; Babu, T. D. Isolation and Structural Determination of New Sphingolipids and Pharmacological Activity of Africanene and Other Metabolites from Sinularia leptoclados. Chem. Pharm. Bull. 1999, 47, 1214−1220. (160) Chen, D.; Cheng, W.; Liu, D.; van Ofwegen, L.; Proksch, P.; Lin, W. Capillosananes S−Z, New Sesquiterpenoids from the Soft Coral Sinularia capillosa. Tetrahedron Lett. 2014, 55, 3077−3082. (161) Anjaneyulu, A. S. R.; Krishnamurthy, M. V. R.; Rao, G. V. Rare Aromadendrane Diterpenoids from a New Soft Coral Species of Sinularia Genus of the Indian Ocean. Tetrahedron 1997, 53, 9301−9312. (162) Ammanamanchi; Anjaneyulu, S. R.; Sarada, P. Bishomoisomandapamate, a New Tetracyclic Diterpenoid from a New Species of the Sinularia Genus of the Indian Ocean. J. Chem. Res., Synop. 1999, 600−601. (163) Anjaneyulu, A. S. R.; Rao, G. V. New Cembranoid Diterpenes from the Soft Coral Sinularia conferta of the Andaman and Nicobar Group of Islands. Indian J. Chem., Sect. B 1996, 35, 826−831.

(164) Anjaneyulu, A. S. R.; Rao, G. V.; Kameswara, R. N. S. Sesqui- and Diterpenoids of the Soft Coral Sinularia hirta of the Andaman and Nicobar Islands. Indian J. Chem., Sect. B 1996, 35, 815−818. (165) Rajaram, S.; Ramesh, D.; Ramulu, U.; Anjum, M.; Kumar, P.; Murthy, U. S. N.; Altaf Hussain, M.; Narahari Sastry, G.; Venkateswarlu, Y. Chemical Examination of the Soft Coral Sinularia kavarattiensis and Evaluation of Anti-Microbial Activity. Indian J. Chem., Sect B 2014, 53, 1086−1090. (166) Goud, T. V.; Reddy, N. S.; Krishnaiah, P.; Venkateswarlu, Y. Spathulenol: A Rare Sesquiterpene from Soft Coral Sinularia kavarattiensis. Biochem. Syst. Ecol. 2002, 30, 493−495. (167) Anjaneyulu, A. S. R.; Rao, G. V.; Raju, K. V. S.; Murthy, M. V. R. K. Two New Lobane Derivatives from the Soft Coral Lobophytum paucif lorum of the Havelock Island of the Indian Ocean. Indian J. Chem., Sect. B 1995, 34, 1074−1079. (168) Anjaneyulu, A. S. R.; Rao, G. V.; Prakash, C. V. S. A New Cembranoid Diterpene from the Soft Coral, Lobophytum strictum of the Andaman and Nicobar Islands. Indian J. Chem., Sect. B 1994, 33, 1165− 1169. (169) Mao, S.-C.; Gavagnin, M.; Mollo, E.; Guo, Y.-W. A New Rare Asteriscane Sesquiterpene and Other Related Derivatives from the Hainan Aeolid Nudibranch Phyllodesmium magnum. Biochem. Syst. Ecol. 2011, 39, 408−411. (170) Reddy, N. S.; Goud, T. V.; Venkateswarlu, Y. Seco- Sethukarailin, a Novel Diterpenoid from the Soft Coral Sinularia dissecta. J. Nat. Prod. 2002, 65, 1059−1060. (171) Ramesh, P.; Reddy, N. S.; Rao, T. P.; Venkateswarlu, Y.; Reddy, M. V. R.; Faulkner, D. J. Rameswaralide, a Novel Diterpenoid from the Soft Coral Sinularia dissecta. Tetrahedron Lett. 1998, 39, 8217−8220. (172) Ramesh, P.; Reddy, N. S.; Rao, T. P.; Venkateswarlu, Y. New Oxygenated Africanenes from the Soft Coral Sinularia dissecta. J. Nat. Prod. 1999, 62, 1019−1021. (173) Ramesh, P.; Ravikanth, V.; Venkateswarlu, Y. New Sesquiterpenoid from the Soft Coral Sinularia dissecta. Indian J. Chem., Sect. B 2001, 40, 867−868. (174) Anjaneyulu, A. S. R.; Gowri, P. M.; Krishna Murthy, M. V. R. New Sesquiterpenoids from the Soft Coral Sinularia intacta of the Indian Ocean. J. Nat. Prod. 1999, 62, 1600−1604. (175) Qin, M.; Li, X.; Wang, B. Cembranoid, Steroid, and Sesquiterpenoid Derivatives from the South China Sea Soft Coral Sinularia numerosa. Chin. J. Chem. 2012, 30, 1278−1282. (176) Reátegui, R. F.; Gloer, J. B.; Campbell, J.; Shearer, C. A. Ophiocerins A−D and Ophioceric Acid: Tetrahydropyran Derivatives and an Africane Sesquiterpenoid from the Freshwater Aquatic Fungus Ophioceras venezuelense. J. Nat. Prod. 2005, 68, 701−705. (177) Cheer, C. J.; Smith, D. H.; Djerassi, C.; Tursch, B.; Braekman, J. C.; Daloze, D. Applications of Artificial Intelligence, for Chemical Inference-XXI. Chemical Studies of Marine Invertebrates-XVII. The Computer-Assisted Identification of (+)-Palustrol in the Marine Organism Cespitularia sp., aff. Tetrahedron 1976, 32, 1807−1810. (178) Braekman, J. C.; Daloze, D.; Stoller, C.; Declercq, J. P. The Configuration of Palustrol and Related Compounds. Bull. Soc. Chim. Belg. 1989, 98, 869−875. (179) Braekman, J. C.; Daloze, D.; Ottinger, R.; Tursch, B. Chemical Studies of Marine Invertebrates. XXXVII. On the Absolute Configuration of Aromadendrane Sesquiterpenes from the Soft Coral Cespitularia aff. Experientia 1977, 33, 993−993. (180) Phan, C.-S.; Ng, S.-Y.; Kim, E.-A.; Jeon, Y.-J.; Palaniveloo, K.; Vairappan, C. S. Capgermacrenes A and B, Bioactive Secondary Metabolites from a Bornean Soft Coral, Capnella sp. Mar. Drugs 2015, 13, 3103−3115. (181) Al-Footy, K. O.; Alarif, W. M.; Asiri, F.; Aly, M. M.; Ayyad, S.-E. N. Rare Pyrane-Based Cembranoids from the Red Sea Soft Coral Sarcophyton trocheliophorum as Potential Antimicrobial-Antitumor Agents. Med. Chem. Res. 2015, 24, 505−512. (182) Abdel-Lateff, A.; Alarif, W. M.; Ayyad, S.-E. N.; Al-Lihaibi, S. S.; Basaif, S. A. New Cytotoxic Isoprenoid Derivatives from the Red Sea Soft Coral Sarcophyton glaucum. Nat. Prod. Res. 2015, 29, 24−30. 6152


Chemical Reviews

Review

(183) Gijsen, H. J. M.; Wijnberg, J. B. P. A.; Stork, G. A.; de Groot, A.; de Waard, M. A.; van Nistelrooy, J. G. M. The Synthesis of Mono- and Dihydroxy Aromadendrane Sesquiterpenes, Starting from Natural (+)-Aromadendrene-III. Tetrahedron 1992, 48, 2465−2476. (184) Handayani, D.; Edrada, R. A.; Proksch, P.; Wray, V.; Witte, L.; van Ofwegen, L.; Kunzmann, A. New Oxygenated Sesquiterpenes from the Indonesian Soft Coral Nephthea chabrolii. J. Nat. Prod. 1997, 60, 716−718. (185) Rao, C. B.; Sekhar, V. C.; Sarvani, B.; Rao, D. V. A New Oxygenated Tricyclic Sesquiterpene from a Soft Coral of Nephthea Species of Andaman and Nicobar Coasts of Indian Ocean. Indian J. Chem., Sect. B 2004, 43, 1329−1331. (186) Wang, S.-K.; Huang, M.-J.; Duh, C.-Y. Cytotoxic Constituents from the Formosan Soft Coral Clavularia inf lata var. luzoniana. J. Nat. Prod. 2006, 69, 1411−1416. (187) Liu, H.-J.; Wu, C.-L.; Becker, H.; Zapp, J. Sesquiterpenoids and Diterpenoids from the Chilean Liverwort Lepicolea ochroleuca. Phytochemistry 2000, 53, 845−849. (188) Huang, L.-S.; He, F.; Huang, H.; Zhang, X.-Y.; Qi, S.-H. Carbamate Derivatives and Sesquiterpenoids from the South China Sea Gorgonian Melitodes squamata. Beilstein J. Org. Chem. 2012, 8, 170−176. (189) Beechan, C. M.; Djerassi, C.; Eggert, H. Terpenoids-LXXIV. The Sesquiterpenes from the Soft Coral Sinularia mayi. Tetrahedron 1978, 34, 2503−2506. (190) Yasumoto, M.; Mada, K.; Ooi, T.; Kusumi, T. New Terpenoid Components from the Volatile Oils of the Soft Corals Clavularia viridis and Sarcophyton acutangulum. J. Nat. Prod. 2000, 63, 1534−1536. (191) Rochfort, S. J.; Capon, R. J. Parguerenes Revisited: New Brominated Diterpenes from the Southern Australian Marine Red Alga Laurencia f iliformis. Aust. J. Chem. 1996, 49, 19−26. (192) Tseng, Y.-J.; Shen, K.-P.; Lin, H.-L.; Huang, C.-Y.; Dai, C.-F.; Sheu, J.-H. Lochmolins A−G, New Sesquiterpenoids from the Soft Coral Sinularia lochmodes. Mar. Drugs 2012, 10, 1572−1581. (193) Anjaneyulu, A. S. R.; Sagar, K. S.; Venugopal, M. J. R. V. Terpenoid and Steroid Constituents of the Indian Ocean Soft Coral Sinularia maxima. Tetrahedron 1995, 51, 10997−11010. (194) Tringali, C.; Piattelli, M.; Spatafora, C. Sesquiterpenes and Geranylgeranylglycerol from the Brown Algae Taonia lacheana and Taonia atomaria f. ciliata: their Chemotaxonomic Significance. Phytochemistry 1995, 40, 827−831. (195) Toyota, M.; Asakawa, Y.; Takemoto, T. Sesquiterpenes from Japanese Liverworts. Phytochemistry 1981, 20, 2359−2366. (196) Wessels, M.; König, G. M.; Wright, A. D. 3-Acetoxyspathulenol, a New Aromadendrane-Type Natural Product from the Soft Coral Parerythropodium f ulvum. J. Nat. Prod. 2001, 64, 370−372. (197) Pika, J.; Faulkner, D. J. Four Sesquiterpenes from the South African Nudibranch Leminda millecra. Tetrahedron 1994, 50, 3065− 3070. (198) Wratten, S. J.; Faulkner, D. J. Metabolites of the Red Alga Laurencia subopposita. J. Org. Chem. 1977, 42, 3343−3349. (199) Braekman, J. C.; Daloze, D.; Dupont, A.; Tursch, B.; Declercq, J. P.; Germain, G.; Van Meersschf, M. Chemical Studies of Marine Invertebrates-XLIII. Novel Sesquiterpenes from Clavularia inf lata and Clavularia koellikeri (Coelenterata, Octocorallia, Stolonifera). Tetrahedron 1981, 37, 179−186. (200) Kozawa, S.; Ishiyama, H.; Fromont, J.; Kobayashi, J. Halichonadin E, a Dimeric Sesquiterpenoid from the Sponge Halichondria Sp. J. Nat. Prod. 2008, 71, 445−447. (201) Garson, M. J.; Simpson, J. S. Marine Isocyanides and Related Natural Products-Structure, Biosynthesis and Ecology. Nat. Prod. Rep. 2004, 21, 164−179. (202) Ishiyama, H.; Kozawa, S.; Aoyama, K.; Mikami, Y.; Fromont, J.; Kobayashi, J. Halichonadin F and the Cu(I) Complex of Halichonadin C from the Sponge Halichondria sp. J. Nat. Prod. 2008, 71, 1301−1303. (203) Braekman, J. C.; Daloze, D.; Deneubourg, F.; Huysecom, J.; Vandevyver, G. 1-Isocyanoaromadendrane, a New Isonitrile Sesquiterpene from the Sponge Acanthella acuta. Bull. Soc. Chim. Belg. 1987, 96, 539−543.

(204) Braekman, J. C.; Daloze, D.; Moussiaux, B.; Stoller, C.; Deneubourg, F. Sponge Secondary Metabolites: New Results. Pure Appl. Chem. 1989, 61, 509−512. (205) Mayol, L.; Piccialli, V.; Sica, D. Nitrogenous Sesquiterpenes from the Marine Sponge Acanthella acuta: Three New IsocyanideIsothiocyanate Pairs. Tetrahedron 1987, 43, 5381−5388. (206) Zhang, W.; Gavagnin, M.; Guo, Y.-W.; Mollo, E.; Ghiselin, M. T.; Cimino, G. Terpenoid Metabolites of the Nudibranch Hexabranchus sanguineus from the South China Sea. Tetrahedron 2007, 63, 4725− 4729. (207) Lyakhova, E. G.; Kolesnikova, S. A.; Kalinovskii, A. I.; Stonik, V. A. Secondary Metabolites of the Vietnamese Nudibranch Mollusk Phyllidiella pustulosa. Chem. Nat. Compd. 2010, 46, 534−538. (208) Da Silva, C. C.; Almagro, V.; Zukerman-Schpector, J.; Castellano, E. E.; Marsaioli, A. J. An Easy Route to (−)-10 (R)Isothiocyanoaromadendrane and (−)-10 (S)-Isothiocyanoalloaromadendrane. J. Org. Chem. 1994, 59, 2880−2881. (209) Fattorusso, E.; Magno, S.; Mayol, L.; Santacroce, C.; Sica, D. Isolation and Structure of Axisonitrile-2. A New Sesquiterpenoid Isonitrile from the Sponge Axinella cannabina. Tetrahedron 1974, 30, 3911−3913. (210) Fattorusso, E.; Magno, S.; Mayol, L.; Santacroce, C.; Sica, D. New Sesquiterpenoids from the Sponge Axinella cannabina. Tetrahedron 1975, 31, 269−270. (211) Ciminiello, P.; Fattorusso, E.; Magno, S.; Mayol, L. New Nitrogenous Sesquiterpenes Based on Alloaromadendrane and EpiEudesmane Skeletons from the Marine Sponge Axinella cannabina. Can. J. Chem. 1987, 65, 518−522. (212) Sun, J.-Z.; Chen, K.-S.; Yao, L.-G.; Liu, H.-L.; Guo, Y.-W. A New Kalihinol Diterpene from the Hainan Sponge Acanthella sp. Arch. Arch. Pharmacal Res. 2009, 32, 1581−1584. (213) Jumaryatno, P.; Stapleton, B. L.; Hooper, J. N. A.; Brecknell, D. J.; Blanchfield, J. T.; Garson, M. J. A Comparison of Sesquiterpene Scaffolds across Different Populations of the Tropical Marine Sponge Acanthella cavernosa. J. Nat. Prod. 2007, 70, 1725−1730. (214) Fusetani, N.; Wolstenholme, H. J.; Shinoda, K.; Asai, N.; Matsunaga, S.; Onuki, H.; Hirota, H. Two New Sesquiterpenes Isocyanides and a Sesquiterpene Thiocyanate from the Marine Sponge Acanthella cf. cavernosa and the Nudibranch Phyllidia ocellata. Tetrahedron Lett. 1992, 33, 6823−6826. (215) Fusetani, N.; Wolstenholme, H. J.; Matsunaga, S.; Hirota, H. Two New Sesquiterpenes Isonitriles from the Nudibranch Phyllidia pustulosa. Tetrahedron Lett. 1991, 32, 7291−7294. (216) Prawat, H.; Mahidol, C.; Wittayalai, S.; Intachote, P.; Kanchanapoom, T.; Ruchirawat, S. Nitrogenous Sesquiterpenes from the Thai Marine Sponge Halichondria sp. Tetrahedron 2011, 67, 5651− 5655. (217) Barnekow, D. E.; Cardellina, J. H. Determining the Absolute Configuration of Hindered Secondary Alcohols-A Modified Horeau’s Method. Tetrahedron Lett. 1989, 30, 3629−3632. (218) Sung, P.-J.; Chuang, L.-F.; Kuo, J.; Chen, J.-J.; Fan, T.-Y.; Li, J.-J.; Fang, L.-S.; Wang, W.-H. Rumphellolides A-F, Six New CaryophyllaneRelated Derivatives from the Formosan Gorgonian Coral Rumphella antipathies. Chem. Pharm. Bull. 2007, 55, 1296−1301. (219) Hinkley, S. F. R.; Perry, N. B.; Weavers, R. T. Base Treatment of Kobusone Revisited. Tetrahedron 1997, 53, 7035−7044. (220) Kikuchi, H.; Tsukitani, Y.; Yamada, Y.; Iguchi, K.; Drexler, S. A.; Clardy, J. A New Sesquiterpenoid from the Soft Coral Lemnalia tenuis Verseveldt. Tetrahedron Lett. 1982, 23, 1063−1066. (221) Duh, C.-Y.; El-Gamal, A. A. H.; Song, P.-Y.; Wang, S.-K.; Dai, C.F. Steroids and Sesquiterpenoids from the Soft Corals Dendronephthya gigantea and Lemnalia cervicorni. J. Nat. Prod. 2004, 67, 1650−1653. (222) Irie, T.; Yamamoto, K.; Masamune, T. Sesquiterpenes from Dictyopteris divaricata. Bull. Chem. Soc. Jpn. 1964, 37, 1053−1055. (223) Xio, Y.-J.; Su, J.-H.; Chen, B.-W.; Tseng, Y.-J.; Wu, Y.-C.; Sheu, J.-H. Oxygenated Ylangene-Derived Sesquiterpenoids from the Soft Coral Lemnalia philippinensis. Mar. Drugs 2013, 11, 3735−3741. (224) Gopichand, Y.; Ciereszko, L. S.; Schmitz, F. J.; Switzner, D.; Rahman, A.; Hossain, M. B.; van der Helm, D. Further Studies of the 6153


Chemical Reviews

Review

Terpenoid Content in the Gorgonian Eunicea succinea: 12, 13Bisepieupalmerin, a New Cembranolide. J. Nat. Prod. 1984, 47, 607− 614. (225) Ciereszko, L. S.; Karns, T. K. B. In Biology and Gelogy of Coral Reefs; Jones, O. A., Endeon, R., Eds.; Academic Press: New York, 1973; p 183. (226) Tursch, B.; Braekman, J. C.; Daloze, D.; Kaisin, M. Terpenoids from Coelenterates. In Marine Natural Products V2: Chemical And Biological Perspectives; Scheuer, P., Ed.; Elsevier, 2012; p 257. (227) Elkhayat, E. S.; Ibrahim, S. R. M.; Fouad, M. A.; Mohamed, G. A. Dendronephthols A−C, New Sesquiterpenoids from the Red Sea Soft Coral Dendronephthya sp. Tetrahedron 2014, 70, 3822−3825. (228) Beechan, C. M.; Djerassi, C. Terpenoids LXXIII. Sinularene, a Sesquiterpene Hydrocarbon Based on a Novel Skeleton from the Soft Coral Sinularia mayi. Tetrahedron Lett. 1977, 18, 2395−2398. (229) He, H.-Y.; Faulkner, D. J.; Shumsky, J. S.; Hong, K.; Clardy, J. A Sesquiterpene Thiocyanate and Three Sesquiterpenes Isothiocyanates from the Sponge Trachyopsis aplysinoides. J. Org. Chem. 1989, 54, 2511− 2514. (230) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Bean, M. F.; Faucette, L.; Johnson, R. K.; Haltiwanger, R. C.; Eggleston, D. S. Two New Nitrogenous Sesquiterpenes from the Sponge Axinyssa aplysinoides. J. Nat. Prod. 1997, 60, 507−510. (231) Okino, T.; Yoshimura, E.; Hirota, H.; Fusetani, N. New Antifouling Sesquiterpenes from Four Nudibranchs of the Family Phyllidiidae. Tetrahedron 1996, 52, 9447−9454. (232) Srikrishna, A.; Ravi, G.; Venkata Subbaiah, D. R. C. Enantioselective First Total Syntheses of 2-(Formylamino)trachyopsane and Ent-2-(Isocyano)trachyopsane via a Biomimetic Approach. Synlett 2009, 2009, 32−34. (233) Burreson, B. J.; Scheuer, P. J.; Finer, J.; Clardy, J. 9Isocyanopupukeanane, a Marine Invertebrate Allomone with a New Sesquiterpene Skeleton. J. Am. Chem. Soc. 1975, 97, 4763−4764. (234) Hagadone, M. R.; Burreson, B. J.; Scheuer, P. J.; Finer, J. S.; Clardy, J. Defense Allomones of the Nudibranch Phyllidia varicosa Lamarck 1801. Helv. Chim. Acta 1979, 62, 2484−2494. (235) Hagadone, M. R.; Scheuer, P. J.; Holm, A. On the Origin of the Isocyano Function in Marine Sponges. J. Am. Chem. Soc. 1984, 106, 2447−2448. (236) Karuso, P.; Scheuer, P. J. Biosynthesis of Isocyanoterpenes in Sponges. J. Org. Chem. 1989, 54, 2092−2095. (237) Simpson, J. S.; Garson, M. J. Thiocyanate Biosynthesis in the Tropical Marine Sponge Axinyssa n. sp. Tetrahedron Lett. 1998, 39, 5819−5822. (238) Jaisamut, S.; Prabpai, S.; Tancharoen, C.; Yuenyongsawad, S.; Hannongbua, S.; Kongsaeree, P.; Plubrukarn, A. Bridged Tricyclic Sesquiterpenes from the Tubercle Nudibranch Phyllidia coelestis Bergh. J. Nat. Prod. 2013, 76, 2158−2161. (239) Fusetani, N.; Wolstenholme, H. J.; Matsunaga, S. CoOccurrence of 9-Isocyanopupukeanane and Its C-9 Epimer in the Nudibranch Phyllidia bourguini. Tetrahedron Lett. 1990, 31, 5623−5624. (240) Yasman, Y.; Edrada, R. A.; Wray, V.; Proksch, P. New 9Thiocyanatopupukeanane Sesquiterpenes from the Nudibranch Phyllidia varicosa and Its Sponge-Prey Axinyssa aculeata. J. Nat. Prod. 2003, 66, 1512−1514. (241) Marcus, A. H.; Molinski, T. F.; Fahy, E.; Faulkner, D. J. 5Isothiocyanatopupukeanane from a Sponge of the Genus. J. Org. Chem. 1989, 54, 5184−5186. (242) Pham, A. T.; Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Uchida, T.; Tanaka, J.-I.; Higa, T. Two Marine Sesquiterpene Thiocyanates. Tetrahedron Lett. 1991, 32, 4843−4846. (243) Srikrishna, A.; Gharpure, S. J.; Venugopalan, P. Stereochemistry of the Marine Sesquiterpene 2-Thiocyanatoneopupukeanane: Crystal Structure of Neopupukean-2-yl 4-Nitrobenzoate. Indian J. Chem., Sect. B 2003, 42, 129−134. (244) Karuso, P.; Poiner, A.; Scheuer, P. J. Isocyanoneopupukeanane, a New Tricyclic Sesquiterpene from a Sponge. J. Org. Chem. 1989, 54, 2095−2097.

(245) Simpson, J. S.; Garson, M. J. Advanced Precursors in Marine Biosynthetic Study. Part 2: The Biosynthesis of Isocyanides and Isothiocyanates in the Tropical Marine Sponge Axinyssa n. sp. Tetrahedron Lett. 2001, 42, 4267−4269. (246) Simpson, J. S.; Garson, M. J. Biosynthetic Pathways to Isocyanides and Isothiocyanates; Precursor Incorporation Studies on Terpene Metabolites in the Tropical Marine Sponges Amphimedon terpenensis and Axinyssa n. sp. Org. Biomol. Chem. 2004, 2, 939−948. (247) Osterhage, C.; König, G. M.; Höller, U.; Wright, A. D. Rare Sesquiterpenes from the Algicolous Fungus Drechslera dematioidea. J. Nat. Prod. 2002, 65, 306−313. (248) Nukina, M.; Hattori, H.; Marumo, S. Cis-Sativenediol, a Plant Growth Promotor, Produced by Fungi. J. Am. Chem. Soc. 1975, 97, 2542−2543. (249) Bülow, N.; König, W. A. The Role of Germacrene D as a Precursor in Sesquiterpene Biosynthesis: Investigations of Acid Catalyzed, Photochemically and Thermally Induced Rearrangements. Phytochemistry 2000, 55, 141−168. (250) Ayer, S. W.; Andersen, R. J.; He, C. H.; Clardy, J. Acanthodoral and Isoacanthodoral, Two Sesquiterpenoids with New Carbon Skeletons from the Dorid Nudibranch Acanthodoris nanaimoensis. J. Org. Chem. 1984, 49, 2653−2654. (251) Zhang, L.; Koreeda, M. Total Synthesis of (+)-Acanthodoral by the Use of a Pd-Catalyzed Metal-Ene Reaction and a Nonreductive 5Exo-Acyl Radical Cyclization. Org. Lett. 2004, 6, 537−540. (252) Wright, A. D.; Goclik, E.; Kö nig, G. M. Three New Sesquiterpenes from the Red Alga Laurencia perforata. J. Nat. Prod. 2003, 66, 435−437. (253) Presset, M.; Coquerel, Y.; Rodriguez, J. Quadrane Sesquiterpenes: Natural Sources, Biology, and Syntheses. Eur. J. Org. Chem. 2010, 2010, 2247−2260. (254) Bokesch, H. R.; McKee, T. C.; Cardellina, J. H., II; Boyd, M. R. Suberosenone, a New Cytotoxin from Subergorgia Suberosa. Tetrahedron Lett. 1996, 37, 3259−3262. (255) Qi, S.-H.; Zhang, S.; Li, X.; Li, Q.-X. A Cytotoxic Sesquiterpene Alkaloid from the South China Sea Gorgonian Subergorgia suberosa. J. Nat. Prod. 2005, 68, 1288−1289. (256) Qi, S.-H.; Zhang, S.; Huang, H. Purine Alkaloids from the South China Sea Gorgonian Subergorgia suberosa. J. Nat. Prod. 2008, 71, 716− 718. (257) Stephens, P. J.; McCann, D. M.; Devlin, F. J.; Smith, A. B. Determination of the Absolute Configurations of Natural Products via Density Functional Theory Calculations of Optical Rotation, Electronic Circular Dichroism, and Vibrational Circular Dichroism: The Cytotoxic Sesquiterpene Natural Products Quadrone, Suberosenone, Suberosanone, and Suberosenol A Acetate. J. Nat. Prod. 2006, 69, 1055−1064. (258) Bokesch, H. R.; Blunt, J. W.; Westergaard, C. K.; Cardellina, J. H.; Johnson, T. R.; Michael, J. A.; McKee, T. C.; Hollingshead, M. G.; Boyd, M. R. Alertenone, a Dimer of Suberosenone from Alertigorgia sp. J. Nat. Prod. 1999, 62, 633−635. (259) Bohlmann, F.; Jakupovic, J. Neue Sesquiterpen-Kohlenwasserstoffe Mit Anomalen Kohlenstoffgerüst Aus Silphium-Arten. Phytochemistry 1980, 19, 259−265. (260) Rodríguez Brasco, M. F.; Seldes, A. M.; Palermo, J. A. Paesslerins A and B: Novel Tricyclic Sesquiterpenoids from the Soft Coral Alcyonium paessleri. Org. Lett. 2001, 3, 1415−1417. (261) Inanaga, K.; Takasu, K.; Ihara, M. Rapid Assembly of Polycyclic Substances by a Multicomponent Cascade (4 + 2)−(2 + 2) Cycloadditions: Total Synthesis of the Proposed Structure of Paesslerin A. J. Am. Chem. Soc. 2004, 126, 1352−1353. (262) Alam, M.; Jones, E. B. G.; Hossain, M. B.; van der Helm, D. Isolation and Structure of Isoculmorin from the Marine Fungus Kallichroma tethys. J. Nat. Prod. 1996, 59, 454−456. (263) Barton, D. H. R.; Werstiuk, N. H. The Constitution and Stereochemistry of Culmorin. Chem. Commun. 1967, 30−31. (264) Barton, D. H. R.; Werstiuk, N. H. Sesquiterpenoids. Part XIV. The Constitution and Stereochemistry of Culmorin. J. Chem. Soc. C 1968, 148−155. 6154


Chemical Reviews

Review

(265) Kasitu, G. C.; ApSimon, J. W.; Blackwell, B. A.; Fielder, D. A.; Greenhalgh, R.; Miller, J. D. Isolation and Characterization of Culmorin Derivatives Produced by Fusarium culmorum CMI 14764. Can. J. Chem. 1992, 70, 1308−1316. (266) Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Fang, L.-S.; Wen, Z.H.; Chen, J.-J.; Wu, Y.-C.; Sung, P.-J. Rumphellaoic Acid A, a Novel Sesquiterpenoid from the Formosan Gorgonian Coral Rumphella antipathies. Mar. Drugs 2014, 12, 5856−5863. (267) Yang, X.-W.; Peng, K.; Liu, Z.; Zhang, G.-Y.; Li, J.; Wang, N.; Steinmetz, A.; Liu, Y. Strepsesquitriol, a Rearranged Zizaane-Type Sesquiterpenoid from the Deep-Sea-Derived Actinomycete Streptomyces sp. SCSIO 10355. J. Nat. Prod. 2013, 76, 2360−2363. (268) Walls, F.; Padilla, J.; Joseph-Nathan, P.; Giral, F.; Romo, J. The Structure of α and β-Pipitzols. Tetrahedron Lett. 1965, 6, 1577−1582. (269) Georgantea, P.; Ioannou, E.; Vagias, C.; Roussis, V. Bisabolane and Chamigrane Sesquiterpenes from the Soft Coral Pseudopterogorgia rigida. Phytochem. Lett. 2014, 8, 86−91. (270) Evans, S. V.; Yee, V. C.; Garcia-Garibay, M.; Trotter, J. Structure of a Mixed Crystal of α-Pipitzol and β-pipitzol (1:1), C15H20O3.C15H20O3. Acta Crystallogr. 1994, C50, 278−281. (271) Graziani, E. I.; Andersen, R. J. Investigations of Sesquiterpenoid Biosynthesis by the Dorid Nudibranch Acanthodoris nanaimoensis. J. Am. Chem. Soc. 1996, 118, 4701−4702. (272) Barrow, C. J.; Blunt, J. W.; Munro, M. H. G. Sesquiterpenes from a New Zealand Sponge of the Genus Eurypon. Aust. J. Chem. 1988, 41, 1755−1761. (273) Kernan, M. R.; Cambie, R. C.; Bergquist, P. R. Chemistry of Sponges, X. New Sesquiterpenes from a Marine Sponge of the Genus Eurypon. J. Nat. Prod. 1990, 53, 1353−1356. (274) Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Chen, J.-J.; Fang, L.S.; Wen, Z.-H.; Wang, Y.-B.; Wu, Y.-C.; Sung, P.-J. Rumphellols A and B, New Caryophyllene Sesquiterpenoids from a Formosan Gorgonian Coral, Rumphella antipathies. Int. J. Mol. Sci. 2014, 15, 15679−15688. (275) Chung, H.-M.; Chen, Y.-H.; Hwang, T.-L.; Chuang, L.-F.; Wang, W.-H.; Sung, P.-J. Rumphellclovane A, a Novel Clovane-Related Sesquiterpenoid from the Gorgonian Coral Rumphella antipathies. Tetrahedron Lett. 2010, 51, 2734−736. (276) Chung, H.-M.; Su, J.-H.; Hwang, T.-L.; Li, J.-J.; Chen, J.-J.; Chen, Y.-H.; Chang, Y.-C.; Su, Y.-D.; Chen, Y.-H.; Fang, L.-S.; Sheu, J.-H.; Wang, W.-H.; Sung, P.-J. Rumphellclovanes C−E, New Clovane-Type Sesquiterpenoids from the Gorgonian Coral Rumphella antipathies. Tetrahedron 2013, 69, 2740−2744. (277) Chung, H.-M.; Hwang, T.-L.; Chen, Y.-H.; Su, J.-H.; Lu, M.-C.; Chen, J.-J.; Li, J.-J.; Fang, L.-S.; Wang, W.-H.; Sung, P.-J. Rumphellclovane B, a Novel Clovane Analogue from the Gorgonian Coral Rumphella antipathies. Bull. Chem. Soc. Jpn. 2011, 84, 119−121. (278) Meng, L.-H.; Li, X.-M.; Liu, Y.; Wang, B.-G. Penicibilaenes A and B, Sesquiterpenes with a Tricyclo[6.3.1.0 1,5 ]dodecane Skeleton from the Marine Isolate of Penicillium bilaiae MA-267. Org. Lett. 2014, 16, 6052−6055. (279) Bishara, A.; Yeffet, D.; Sisso, M.; Shmul, G.; Schleyer, M.; Benayahu, Y.; Rudi, A.; Kashman, Y. Nardosinanols A-I and Lemnafricanol, Sesquiterpenes from Several Soft Corals, Lemnalia sp., Paralemnalia clavata, Lemnalia af ricana, and Rhytisma f ulvum f ulvum. J. Nat. Prod. 2008, 71, 375−380. (280) Nguyen, Q. N. N.; Tantillo, D. J. Caryolene-Forming Carbocation Rearrangements. Beilstein J. Org. Chem. 2013, 9, 323−331. (281) Hong, Y. J.; Tantillo, D. J. Feasibility of Intramolecular Proton Transfers in Terpene Biosynthesis - Guiding Principles. J. Am. Chem. Soc. 2015, 137, 4134−4140. (282) González, A. G.; Martín, J. D.; Martín, V. S.; Pérez, R.; Tagle, B.; Clardy, J. Rhodolaureol and Rhodolauradiol, Two New Halogenated Tricyclic Sesquiterpenes from a Marine Alga. J. Chem. Soc., Chem. Commun. 1985, 260−261. (283) Martín, J. D.; Caballero, P.; Fernandez, J. J.; Norte, M.; Pérez, R.; Rodriguez, M. L. Metabolites from Laurencia obtusa. Phytochemistry 1989, 28, 3365−3367.

(284) González, A. G.; Martín, J. D.; Martín, V. S.; Norte, M.; Pérez, R. Biomimetic Approach to the Synthesis of Rhodolaureol and Rhodolauradiol. Tetrahedron Lett. 1982, 23, 2395−2398. (285) Díaz-Marrero, A. R.; Brito, I.; de la Rosa, J. M.; Darias, J.; Cueto, M. Gomerones A−C, Halogenated Sesquiterpenoids with a Novel Carbon Skeleton from Laurencia majuscula. Tetrahedron 2008, 64, 10821−10824. (286) Huwyler, N.; Carreira, E. M. Total Synthesis and Stereochemical Revision of the Chlorinated Sesquiterpene (±)-Gomerone C. Angew. Chem., Int. Ed. 2012, 51, 13066−13069. (287) González, A. G.; Martín, J. D.; Martín, V. S.; Pérez, R.; Drexler, S. A.; Clardy, J. Structure of Güimarediol, a New Sesquiterpenoid from the Red Alga Laurencia sp. Chem. Lett. 1984, 13, 1865−1866. (288) Díaz-Marrero, A.-R.; de la Rosa, J. M.; Brito, I.; Darias, J.; Cueto, M. Dactylomelatriol, a Biogenetically Intriguing Omphalane-Derived Marine Sesquiterpene. J. Nat. Prod. 2012, 75, 115−118. (289) Irie, T.; Suzuki, M.; Kurosawa, E.; Masamune, T. Laurinterol and Debromolaurinterol, Constituents from Laurencia intermedia. Tetrahedron Lett. 1966, 7, 1837−1840. (290) Irie, T.; Suzuki, M.; Kurosawa, E.; Masamune, T. Laurinterol, Debromolaurinterol and Isolaurinterol, Constituents of Laurencia intermedia Yamada. Tetrahedron 1970, 26, 3271−3277. (291) Suzuki, M.; Kurosawa, E. Constituents for marine plants. XXXV. Halogenated and non-Halogenated Aromatic sesquiterpenes from the Red Algae Laurencia okamurai Yamada. Bull. Chem. Soc. Jpn. 1979, 52, 3352−3354. (292) Cameron, A. F.; Ferguson, G.; Robertson, J. M. The Crystal Structure and Absolute Stereochemistry of Laurinterol. The Absolute Stereochemistry of Aplysin. Chem. Commun. 1967, 271−272. (293) Irie, T.; Suzuki, M.; Hayakawa, Y. Isolation of Aplysin, Debromoaplysin, and Aplysinol from Laurencia okamurai Yamada. Bull. Chem. Soc. Jpn. 1969, 42, 843−844. (294) Suzuki, M.; Kurosawa, E. New Aromatic Sesquiterpenoids from the Red Alga Laurencia okamurai Yamada. Tetrahedron Lett. 1978, 19, 2503−2506. (295) De Nys, R.; König, G. M.; Wright, A. D.; Sticher, O. Two Metabolites from the Red Alga Laurencia f lexilis. Phytochemistry 1993, 34, 725−728. (296) Ichiba, T.; Higa, T. New Cuparene-Derived Sesquiterpenes with Unprecedented Oxygenation Patterns from the Sea Hare Aplysia dactylomela. J. Org. Chem. 1986, 51, 3364−3366. (297) Shizuri, Y.; Yamada, A.; Yamada, K. Laurequinone, a Cyclolaurane Sesquiterpene from the Red Alga Laurencia nidif ica. Phytochemistry 1984, 23, 2672−2673. (298) Shizuri, Y.; Yamada, K. Laurebiphenyl, a Dimeric Sesquiterpene of the Cyclolaurane-Type from the Red Alga Laurencia nidif ica. Phytochemistry 1985, 24, 1385−1386. (299) Sun, J.; Shi, D.; Ma, M.; Li, S.; Wang, S.; Han, L.; Yang, Y.; Fan, X.; Shi, J.; He, L. Sesquiterpenes from the Red Alga Laurencia tristicha. J. Nat. Prod. 2005, 68, 915−919. (300) Zhang, J.; Ding, L.-P.; Liang, H.; Guo, X.-Y.; Zhang, Q.-Y. Sesquiterpenes from the Red Alga Laurencia tristicha. Biochem. Syst. Ecol. 2015, 60, 116−119. (301) Tsukamoto, S.; Yamashita, Y.; Ohta, T. New Cytotoxic and Antibacterial Compounds Isolated from the Sea Hare, Aplysia kurodai. Mar. Drugs 2005, 3, 22−28. (302) Waraszkiewicz, S. M.; Erickson, K. L. Halogenated Sesquiterpenoids from the Hawaiian Marine Alga Laurencia nidif ica: Nidificene and Nidifidiene. Tetrahedron Lett. 1974, 15, 2003−2006. (303) Ohta, K.; Takagi, M. Halogenated Sesquiterpenes from the Marine Red Alga Marginisporum aberrans. Phytochemistry 1977, 16, 1062−1063. (304) Sims, J. J.; Fenical, W.; Wing, R. M.; Radlick, P. Marine Natural Products. I. Pacifenol, a Rare Sesquiterpene Containing Bromine and Chlorine from the Red Alga. J. Am. Chem. Soc. 1971, 93, 3774−3775. (305) Suzuki, M.; Kawamoto, T.; Vairappan, C. S.; Ishii, T.; Abe, T.; Masuda, M. Halogenated Metabolites from Japanese Laurencia spp. Phytochemistry 2005, 66, 2787−2793. 6155


Chemical Reviews

Review

(306) Mao, S.-C.; Guo, Y.-W. A Laurane Sesquiterpene and Rearranged Derivatives from the Chinese Red Alga Laurencia okamurai Yamada. J. Nat. Prod. 2006, 69, 1209−1211. (307) Stallard, M. O.; Faulkner, D. J. Chemical Constituents of the Digestive Gland of the Sea Hare Aplysia californica-I. Importance of Diet. Comp. Biochem. Physiol., Part B 1974, 49, 25−35. (308) Mao, S.-C.; Guo, Y.-W. Cuparene-Derived Sesquiterpenes from the Chinese Red Alga Laurencia okamurai Yamada. Helv. Chim. Acta 2005, 88, 1034−1039. (309) Ji, N.-Y.; Li, X.-M.; Li, K.; Ding, L.-P.; Wang, B.-G. LauraneDerived Sesquiterpenes from the Marine Red Alga Laurencia tristicha (Rhodomelaceae). Nat. Prod. Res. 2008, 22, 715−718. (310) Kladi, M.; Vagias, C.; Papazafiri, P.; Furnari, G.; Serio, D.; Roussis, V. New Sesquiterpenes from the Red Alga Laurencia microcladia. Tetrahedron 2007, 63, 7606−7611. (311) Brito, I.; Cueto, M.; Dorta, E.; Darias, J. Bromocyclococanol, a Halogenated Sesquiterpene with a Novel Carbon Skeleton from the Red Alga Laurencia obtusa. Tetrahedron Lett. 2002, 43, 2551−2553. (312) König, G. M.; Wright, A. D.; Sticher, O.; Angerhofer, C. K.; Pezzuto, J. M. Biological Activities of Selected Marine Natural Products. Planta Med. 1994, 60, 532−537. (313) Kousara, M.; Le Bideau, F.; Ibrahim, R.; Ferry, A.; Venot, P.-V.; Dejean, C.; Raingeaud, J.; Dubois, J.; Retailleau, P.; Dumas, F. Suberosanes as Potential Antitumor Agents: First Enantioselective Total Synthesis of (1S)-Suberosanone and Configurational Assignment of Suberosenol A. Synthesis 2016, 48, 1637−1646. (314) Yang, F.; Gao, Y.-H.; Wu, K.-W.; Deng, R.; Li, D.-D.; Wei, Z.-X.; Jiang, S.; Wu, X.-Q.; Feng, G.-K.; Li, H.-J.; Zhu, X.-F. A Novel Sesquiterpene Hirsutanol A Induces Autophagical Cell Death in Human Hepatocellular Carcinoma Cells by Increasing Reactive Oxygen Species. Chin. J. Cancer 2010, 29, 655−660. (315) Yang, F.; Chen, W.-D.; Deng, R.; Zhang, H.; Tang, J.; Wu, K.-W.; Li, D.-D.; Feng, G.-K.; Lan, W.-J.; Li, H.-J.; Zhu, X.-F. Hirsutanol A, a Novel Sesquiterpene Compound from Fungus Chondrostereum sp., Induces Apoptosis and Inhibits Tumor Growth through MitochondrialIndependent ROS Production: Hirsutanol A Inhibits Tumor Growth through ROS Production. J. Transl. Med. 2013, 11, 32−41. (316) Yang, F.; Chen, W.-D.; Deng, R.; Li, D.-D.; Wu, K.-W.; Feng, G.K.; Li, H.-J.; Zhu, X.-F. Hirsutanol A Induces Apoptosis and Autophagy via Reactive Oxygen Species Accumulation in Breast Cancer MCF-7 Cells. J. Pharmacol. Sci. 2012, 119, 214−220. (317) Bauer, A. W.; Kirby, W. M.; Sherris, J. C.; Truck, M. Antibiotic Susceptibility Testing by a Standardized Single Disk Method. Am. J. Clin. Pathol. 1966, 45, 493−496. (318) Jorgensen, J. H.; Ferraro, M. J. Antimicrobial Susceptibility Testing: General Principles and Contemporary Practices. Clin. Infect. Dis. 1998, 26, 973−980. (319) Sims, J. J.; Donnell, M. S.; Leary, J. V.; Lacy, G. H. Antimicrobial Agents from Marine Algae. Antimicrob. Agents Chemother. 1975, 7, 320− 321. (320) da Silva Machado, F.; Ventura, T. L. B.; de Souza Gestinari, L. M.; Cassano, V.; Resende, J. A. L. C.; Kaiser, C. R.; Lasunskaia, E. B.; Muzitano, M. F.; Soares, A. R. Sesquiterpenes from the Brazilian Red Alga Laurencia dendroidea J. Agardh. Molecules 2014, 19, 3181−3192. (321) Vairappan, C. S.; Suzuki, M.; Abe, T.; Masuda, M. Halogenated Metabolites with Antibacterial Activity from the Okinawan Laurencia Species. Phytochemistry 2001, 58, 517−523. (322) Qi, S. H.; Zhang, S.; Yang, L. H.; Qian, P. Y. Antifouling and Antibacterial Compounds from the Gorgonians Subergorgia suberosa and Scripearia gracillis. Nat. Prod. Res. 2008, 22, 154−166. (323) Wu, B.; Kashiwagi, T.; Kuroda, I.; Chen, X. H.; Tebayashi, S.-I.; Kim, C.-S. Antifeedants against Locusta migratoria from the Japanese Cedar, Cryptomeria japonica II. Biosci., Biotechnol., Biochem. 2008, 72, 611−614. (324) Chen, X. H.; Kim, C.-S.; Kashiwagi, T.; Tebayashi, S.; Horiike, M. Antifeedants against Acusta despesta from the Japanese Cedar, Cryptomeria japonica II. Biosci., Biotechnol., Biochem. 2001, 65, 1434− 1437.

(325) Wright, A. D.; König, G. M.; Angerhofer, C. K.; Greenidge, P.; Linden, A.; Desqueyroux-Faúndez, R. Antimalarial Activity: The Search for Marine-Derived Natural Products with Selective Antimalarial Activity. J. Nat. Prod. 1996, 59, 710−716. (326) Jean, Y.-H.; Chen, W.-F.; Sung, C.-S.; Duh, C.-Y.; Huang, S.-Y.; Lin, C.-S.; Tai, M.-H.; Tzeng, S.-F.; Wen, Z.-H. Capnellene, a Natural Marine Compound Derived from Soft Coral, Attenuates Chronic Constriction Injury-Induced Neuropathic Pain in Rats. Br. J. Pharmacol. 2009, 158, 713−725. (327) Lin, Y.-C.; Huang, S.-Y.; Jean, Y.-H.; Chen, W.-F.; Sung, C.-S.; Kao, E.-S.; Wang, H.-M.; Chakraborty, C.; Duh, C.-Y.; Wen, Z.-H. Intrathecal Lemnalol, a Natural Marine Compound Obtained from Formosan Soft Coral, Attenuates Nociceptive Responses and the Activity of Spinal Glial Cells in Neuropathic Rats. Behav. Pharmacol. 2011, 22, 739−750. (328) Goldsmith, D. In The Total Synthesis of Natural Products; Pirrung, M. C., Morehead, A. T., Jr., Young, B. G., Goldsmith, D., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2000; Vol. 11 (A Sesquidecade of Sesquiterpenes: Total Synthesis, 1980−1994. Part B: Bicyclic and Tricyclic Sesquiterpenes), pp 275−420. (329) Mehta, G.; Srikrishna, A. Synthesis of Polyquinane Natural Products: An Update. Chem. Rev. 1997, 97, 671−720. (330) Basler, B.; Brandes, S.; Spiegel, A.; Bach, T. Total Syntheses of Kelsoene and Preussin. Top Curr. Chem. 2005, 243, 1−42. (331) Mehta, G.; Srinivas, K. Synthetic Studies Towards Novel Terpenic Natural Products Kelsoene and Poduran: Construction of the Complete 4−5-5-Fused Tricarbocyclic Core. Synlett 1999, 1999, 555− 556. (332) Mehta, G.; Srinivas, K. A Stereoselective Total Synthesis of the Novel Sesquiterpene Kelsoene. Tetrahedron Lett. 1999, 40, 4877−4880. (333) Mehta, G.; Srinivas, K. Enantioselective Total Syntheses of the Novel Tricyclic Sesquiterpene Hydrocarbons (+)-and (−)-Kelsoene. Absolute Configuration of the Natural Product. Tetrahedron Lett. 2001, 42, 2855−2857. (334) Petasis, N. A.; Bzowej, E. I. Titanium-Mediated Carbonyl Olefinations. 1. Methylenations of Carbonyl Compounds with Dimethyltitanocene. J. Am. Chem. Soc. 1990, 112, 6392−6394. (335) Nair, V.; Paul, R. R. Five-Membered Carbocycles. In Stereoselective Multiple Bond-Forming Transformations in Organic Synthesis; Rodriguez, J., Bonne, D., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2015; pp 157−184. (336) Singh, V.; Thomas, B. Recent Developments in General Methodologies for the Synthesis of Linear Triquinanes. Absolute Configuration of the Natural Product. Tetrahedron 1998, 54, 3647− 3692. (337) Lemière, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Generation and Trapping of Cyclopentenylidene Gold Species: Four Pathways to Polycyclic Compounds. J. Am. Chem. Soc. 2009, 131, 2993−3006. (338) Bach, T.; Hehn, J. P. Photochemical Reactions as Key Steps in Natural Product Synthesis. Angew. Chem., Int. Ed. 2011, 50, 1000−1045. (339) Shen, S.-J.; Li, W.-D. Z. Formal Homoiodo Allylsilane Annulations: Dual Total Syntheses of (±)-Hirsutene and (±)-Capnellene. J. Org. Chem. 2013, 78, 7112−7120. (340) Little, R. D.; Carroll, G. L. Intramolecular 1,3-Diyl Trapping Reactions: Total Synthesis of the Marine Natural Product (d,l)-Δ9(12)Capnellene. Tetrahedron Lett. 1981, 22, 4389−4392. (341) Little, R. D.; Masjedizadeh, M. R.; Moeller, K. D.; DanneckerDoerig, I. Factors Affecting Regioselectivity in the Intramolecular Diyl Trapping Reaction. Synlett 1992, 1992, 107−113. (342) Stevens, K. E.; Paquette, L. A. Stereocontrol Total Synthesis of (±)-Δ 9(12)-Capnellene. Tetrahedron Lett. 1981, 22, 4393−4396. (343) Pattenden, G.; Teague, S. J. Total Synthesis of Δ9(12)Capnellene-8α,10α-Diol. Tetrahedron Lett. 1982, 23, 5471−5474. (344) Corey, E. J.; Nicolaou, K. C.; Shibasaki, M.; Machida, Y.; Shiner, C. S. Superoxide as a Synthetically Useful Oxigen Nucleophile. Tetrahedron Lett. 1975, 16, 3183−3186. 6156


Chemical Reviews

Review

(345) Ladlow, M.; Pattenden, G.; Teague, S. J. Synthesis of Δ9(12)Capnellene-8β,10α-Diol from Soft Coral Capnella Imbricata. Tetrahedron Lett. 1986, 27, 3279−3280. (346) Meyers, A. I.; Bienz, S. Asymmetric Total Synthesis of (+)-Δ 9(12) -Capnellene. J. Org. Chem. 1990, 55, 791−798. (347) Curran, D. P.; Chen, M. H. Radical-Initiated Polyolefinic Cyclisations in Condensed Cyclopentanoid Synthesis. Total Synthesis of (±)-Δ 9(12)-Capnellene. Tetrahedron Lett. 1985, 26, 4991−4994. (348) Sonawane, H. R.; Naik, V. G.; Bellur, N. S.; Shah, V. G.; Purohit, P. C.; Kumar, M. U.; Kulltarni, D. G.; Ahuja, J. R. Photoinduced Vinylcyclopropane-Cyclopentene Rearrangement: A Methodology for Chiral Bicyclo[3.2.0] heptenes. Formal Syntheses of (±)-Grandisol and Naturally Occurring (+)-Δ 9(12)-Capnellene Antipode. Tetrahedron 1991, 47, 8259−8276. (349) Sonawane, H. R.; Nanjundiah, B. S.; Shah, V. G.; Kulkarni, D. G.; Ahuja, J. R. Synthesis of Naturally Occurring (+)-Δ9(12)-Capnellene and its Antipode: An Application of the Photo-Induced VinylcyclopropaneCyclopentene Rearrangement. Tetrahedron Lett. 1991, 32, 1107−1108. (350) Piers, E.; Karunaratne, V. Organotin-Based Bifunctional Reagents: 4-Chloro-2-Lithio-1-Butene and Related Substances. Methylenecyclopentane Annulations. Total Synthesis of (±)-Δ9(12)-Capnellene. Tetrahedron 1989, 45, 1089−1104. (351) Asaoka, M.; Obuchi, K.; Takei, H. An Enantioselective Route to (−)-Δ 9(12)-Capnellene Employing Silyl Group Directed Stereo Control. Tetrahedron 1994, 50, 655−660. (352) Asaoka, M.; Hayashibe, S.; Sonoda, S.; Takei, H. Synthesis and Utilisation of Optically Active 2-Substituted 4-(Trimethylsilyl)cyclopentanone: Synthesis of (−)-Massoialactone and (+)-β-Cuparenone. Tetrahedron Lett. 1990, 31, 4761−4764. (353) Tanaka, K.; Ogasawara, K. Stereocontrolled Synthesis of Natural (−)-Δ9(12)-Capnellene from a (−)-Oxodicyclopentadiene. Chem. Commun. 1996, 1839−1840. (354) Ohshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. Asymmetric Heck Reaction-Carbanion Capture Process. Catalytic Asymmetric Total Synthesis of (−)-Δ9(12)-Capnellene. J. Am. Chem. Soc. 1996, 118, 7108−7116. (355) Iwata, C.; Takemoto, Y.; Doi, M.; Imanishi, T. Stereoselective Total Synthesis of (±)-Subergorgic Acid, a New Type of Angular Triquinane Sesquiterpene. J. Org. Chem. 1988, 53, 1623−1628. (356) Wender, P. A.; DeLong, M. A. Synthetic Studies on Arene-Olefin Cycloadditions. XII. Total Synthesis of (±)-Subergorgic Acid. Tetrahedron Lett. 1990, 31, 5429−5432. (357) Paquette, L. A.; Meister, P. G.; Friedrich, D.; Sauer, D. R. Enantioselective Total Synthesis of (−)-Subergorgic Acid. J. Am. Chem. Soc. 1993, 115, 49−56. (358) Chen, E. Y. Total Synthesis of (±)-Cycloeudesmol and (±)-Epicycloeudesmol. J. Org. Chem. 1984, 49, 3245−3250. (359) Ando, M.; Wada, K.; Takase, K. The Total Synthesis of (±)-Cycloeudesmol. Tetrahedron Lett. 1985, 26, 235−238. (360) Piers, E.; Britton, R. W.; de Waal, W. α-Cubebene and βCubebene. Synthetic Proof of Gross Structure. Tetrahedron Lett. 1969, 10, 1251−1253. (361) Tanaka, A.; Uda, H.; Yoshikoshi, A. Total Synthesis of αCubebene, β-Cubebene and Cubebol. J. Chem. Soc. D 1969, 0, 308−308. (362) Torii, S.; Okamoto, T. The Synthesis of Cubebol from (−)-Carvone by Introducing the Electrochemical Acetoxylation Reaction. Bull. Chem. Soc. Jpn. 1976, 49, 771−774. (363) Fürstner, A.; Hannen, P. Platinum- and Gold-Catalyzed Rearrangement Reactions of Propargyl Acetates: Total Syntheses of (−)-α-Cubebene, (−)-Cubebol, Sesquicarene and Related Terpenes. Chem. - Eur. J. 2006, 12, 3006−3019. (364) Fehr, C.; Galindo, J. Synthesis of (−)-Cubebol by Face-Selective Platinum-, Gold-, or Copper-Catalyzed Cycloisomerization: Evidence for Chirality Transfer. Angew. Chem., Int. Ed. 2006, 45, 2901−2904. (365) Fehr, C.; Winter, B.; Magpantay, I. Synthesis of (−)-Cubebol by Face-Selective Platinum-, Gold-, or Copper-Catalyzed Cycloisomerization: Evidence of Chirality Transfer and Mechanistic Insights. Chem. Eur. J. 2009, 15, 9773−9784.

(366) Hodgson, D. M.; Salik, S.; Fox, D. J. Stereocontrolled Syntheses of (−)-Cubebol and (−)-10-Epicubebol Involving Intramolecular Cyclopropanation of α-Lithiated Epoxides. J. Org. Chem. 2010, 75, 2157−2168. (367) Piers, E.; Britton, R. W.; De Waal, W. Total Synthesis of (±)-Aristolone. Can. J. Chem. 1969, 47, 831−840. (368) Rücker, G.; Kretzschmar, U. 9-Aristolen-1α-ol und 1.2.9.10Tetradehydro-Aristolan, Neue Sesquiterpene mit einem AristolanGerüst. Justus Liebigs Ann. Chem. 1971, 748, 214−217. (369) Sugimura, T.; Futagawa, T.; Tai, A. Synthetic Approach to (+)-Africanol. Chem. Lett. 1990, 19, 2295−2298. (370) Shirahama, H.; Hayano, K.; Kanemoto, Y.; Misumi, S.; Ohtsuka, T.; Hashiba, N.; Furusaki, A.; Murata, S.; Noyori, R.; Matsumoto, T. Conformationally Selective Transannular Cyclizations of Humulene 9,10-Epoxide. Synthesis of the Two Skeletally Different Cyclohumulanoids: DL-Bicyclohumulenone and DL-Africanol. Tetrahedron Lett. 1980, 21, 4835−4838. (371) Paquette, L. A.; Ham, W. H. Total Synthesis of the Marine Sesquiterpenes Dactylol and Africanol. De Novo Construction of a Cyclooctanoid Natural Product from Cycloheptane Precursors. J. Am. Chem. Soc. 1987, 109, 3025−3036. (372) Fan, W.; White, J. B. Total Synthesis of (±)-Africanol and (±)-Isoafricanol. J. Org. Chem. 1993, 58, 3557−3562. (373) Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Mo-Catalyzed Asymmetric Olefin Metathesis in Target-Oriented Synthesis: Enantioselective Synthesis of (+)-Africanol. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5805−5809. (374) Büchi, G.; Hofheinz, W.; Paukstelis, J. V. The Synthesis of (−)-Aromadendrene and Related Sesquiterpenes. J. Am. Chem. Soc. 1969, 91, 6473−6478. (375) Birch, A. J.; Lahey, F. N. The Structure of Aromadendrene. Aust. J. Chem. 1953, 6, 379−384. (376) Tanaka, T.; Funakoshi, Y.; Uenaka, K.; Maeda, K.; Mikamiyama, H.; Takemoto, Y.; Maezaki, N.; Iwata, C. Synthetic Studies on Aromadendrane-Type Compounds. I. Stereoselective Construction of Aromadendrane- and Alloaromadendrane-Type Skeletons. Chem. Pharm. Bull. 1994, 42, 300−305. (377) Tanaka, T.; Maeda, K.; Mikamiyama, H.; Funakoshi, Y.; Uenaka, K.; Iwata, C. Synthetic Studies on Aromadendrane-Type Compounds. II. Stereoselective Total Synthesis of (+)-Aromadendrene and (−)-Alloaromadendrene. Tetrahedron 1996, 52, 4257−4268. (378) Finefield, J. M.; Sherman, D. H.; Kreitman, M.; Williams, R. M. Enantiomeric Natural Products: Occurrence and Biogenesis. Angew. Chem., Int. Ed. 2012, 51, 4802−4836. (379) Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Cycle-Specific Organocascade Catalysis: Application to Olefin Hydroamination, Hydro-Oxidation, and Amino-Oxidation, and to Natural Product Synthesis. Angew. Chem., Int. Ed. 2009, 48, 4349−4353. (380) Carreras, J.; Livendahl, M.; McGonigal, P. R.; Echavarren, A. M. Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)-Epiglobulol and (−)-4β,7α- and (−)-4α,7α-Aromadendranediols. Angew. Chem., Int. Ed. 2014, 53, 4896−4899. (381) van Lier, F. P.; Hesp, T. G. M.; van der Linde, L. M.; van der Weerdt, A. J. A. First Preparation of (+)-Spathulenol. Regio- and Stereoselective Oxidation of (+)-Aromzadendrene with Ozone. Tetrahedron Lett. 1985, 26, 2109−2110. (382) Tran, D. N.; Cramer, N. Biomimetic Synthesis of (+)-Ledene, (+)-Viridiflorol, (−)-Palustrol, (+)-Spathulenol, and Psiguadial A, C, and D via the Platform Terpene (+)-Bicyclogermacrene. Chem. - Eur. J. 2014, 20, 10654−10660. (383) Isayama, S.; Mukaiyama, T. A New Method for Preparation of Alcohols from Olefins with Molecular Oxygen and Phenylsilane by the Use of Bis(acetylacetonato)cobalt(II). Chem. Lett. 1989, 18, 1071− 1074. (384) Collins, P. A.; Wege, D. The Total Synthesis of Sinularene, a Sesquiterpene Hydrocarbon from the Soft Coral Sinularia Mayi. Aust. J. Chem. 1979, 32, 1819−1826. (385) Oppolzer, W.; Strauss, H. F.; Simmons, D. P. Stereoselective Total Synthesis of (±)-Sinularene and of (±)-5-Epi-Sinularene via 6157


Chemical Reviews

Review

Intramolecular Type-I-“Magnesium-Ene” Reaction. Tetrahedron Lett. 1982, 23, 4673−4676. (386) Kingston, J. F.; Ser, N. A.; Gallacher, G.; Fallis, A. Studies in Marine Organic Chemistry: Marine Natural Products from Invertebrates Found in Newfoundland Waters and Approaches to the Total Synthesis of Sinularene and 12-Acetoxysinularene. Mar. Chem. 1983, 12, 147−157. (387) Antczak, K.; Kingston, J. F.; Fallis, A. G. Stereoselective Total Syntheses of (±)-Sinularene and (±)-5-Epi-Sinularene: A General Intramolecular Diels-Alder Approach to Tricyclic Sesquiterpenes. Can. J. Chem. 1985, 63, 993−995. (388) Piers, E.; Jung, G. L. Thermal Rearrangement of Functionalized 6-Exo-(1-Alkenyl) Bicyclo[3.1. 0]Hex-2-Enes. A Total Synthesis of (±)-Sinularene. Can. J. Chem. 1985, 63, 996−998. (389) Antczak, K.; Kingston, J. F.; Fallis, A. G.; Hanson, A. W. A General Intramolecular Diels-Alder Approach to Tricyclic Sesquiterpenes: Stereoselective Total Syntheses of (±)-Sinularene and (±)-5Epi-Sinularene. Can. J. Chem. 1987, 65, 114−123. (390) Piers, E.; Jung, G. L. Preparation and Thermal Rearrangement of 2-(tert-Butyldimethylsiloxy)-5-Methyl-6-Exo-[(Z)-3-Methyl-1-Butenyl]-4-Exo-Vinylbicyclo[3.1.0]hex-2-Ene. A Total Synthesis of (±)-Sinularene. Can. J. Chem. 1987, 65, 1668−1675. (391) Corey, E. J.; Watt, D. S. A Total Synthesis of (±)-α- and (±)-βCopaenes and Ylangenes. J. Am. Chem. Soc. 1973, 95, 2303−2311. (392) Snider, B. B.; Kulkarni, Y. S. Simple Synthesis of (±)-copaene, (±)-β-Ylangene and Lemnalol. Tetrahedron Lett. 1985, 26, 5675−5676. (393) Kulkarni, Y. S.; Niwa, M.; Ron, E.; Snider, B. B. Synthesis of Terpenes Containing the Bicyclo [3.1.1] Heptane Ring System by the Intramolecular [2 + 2] Cycloaddition Reaction of Vinylketenes with Alkenes. Preparation of Chrysanthenone, β-Pinene, β-Cis-Bergamotene, β-Trans-Bergamotene, β-Copaene, and β-Ylangene and Lemnalol. J. Org. Chem. 1987, 52, 1568−1576. (394) Srikrishna, A.; Gharpure, S. J. Enantiospecific Total Synthesis of (−)-4-Thiocyanato neopupukeanane. J. Org. Chem. 2001, 66, 4379− 4385. (395) Srikrishna, A.; Gharpure, S. J. Enantiospecific Synthesis of (−)-4Thiocyanatoneopupukeanane. Arkivoc 2002, 7, 52−62. (396) Srikrishna, A.; Gharpure, S. J. Enantiospecific First Total Synthesis of (−)-4-Thiocyanato neopupukeanane. Tetrahedron Lett. 1999, 40, 1035−1038. (397) Srikrishna, A.; Gharpure, S. J. Enantiospecific Total Synthesis of Both Enantiomers of 2-Thiocyanatoneopupukeanane from (R)Carvone. J. Chem. Soc., Perkin Trans. 1 2000, 3191−3193. (398) Corey, E. J.; Behforouz, M.; Ishiguro, M. Total Synthesis of the Racemate of the Sesquiterpenoid Marine Allomone 9-Isocyanopupukeanane. J. Am. Chem. Soc. 1979, 101, 1608−1609. (399) Yamamoto, H.; Sham, H. L. M. Total Synthesis of (±)-9Isocyanopupukeanane. J. Am. Chem. Soc. 1979, 101, 1609−1611. (400) Ho, T.-L.; Jana, G. H. Total Synthesis of 9-Isocyanoneopupukeanane. J. Org. Chem. 1999, 64, 8965−8967. (401) Hsieh, S. L.; Chiu, C.-T.; Chang, N.-C. A Formal Total Synthesis of (±)-9-Isocyanopupukeanane. J. Org. Chem. 1989, 54, 3820−3823. (402) Srikrishna, A.; Satyanarayana, G. A Formal Total Synthesis of (±)-9-Isocyanoneopupukeanane. Tetrahedron 2005, 61, 8855−8859. (403) Ho, T.-L.; Kung, L.-R.; Chein, R.-J. Total Synthesis of (±)-2Isocyanoallopupukeanane. J. Org. Chem. 2000, 65, 5774−5779. (404) Ho, T.-L.; Kung, L.-R. Stereoselective Synthesis of 2Isocyanoallopupukeanane. Org. Lett. 1999, 1, 1051−1052. (405) Piers, E.; Isenring, H.-P. Total Synthesis of (+)-Cis- and (+)-Trans-Sativenediol. Synth. Commun. 1976, 6, 221−226. (406) Piers, E.; Isenring, H.-P. Total Synthesis of Ylango Sesquiterpenoids:(+)-Cis-and (+)-Trans-Sativenediol, (+)-Helminthosporal, (+)-Helminthosporol, Prehelminthosporal, Prehelminthosporal Diethyl Acetal, (+)-Victoxinine, (+)-Isosativenediol. Can. J. Chem. 1977, 55, 1039−1044. (407) McMurry, J. E.; Silvestri, M. G. Total Synthesis of (±)-CisSativenediol. J. Org. Chem. 1976, 41, 3953−3955.

(408) Yanagiya, M.; Kaneko, K.; Kaji, T. New Synthesis of DLSativene, DL-Copacamphene, DL-Cis-Sativenediol and DL-Helminthosporal. Tetrahedron Lett. 1979, 20, 1761−1764. (409) Wenkert, E.; Bookser, B. C.; Arrhenius, T. S. Total Syntheses of (±)-α- and (±)-β-Copaene and Formal Total Syntheses of (±)-Sativene, (±)-Cis-Sativenediol, and (±)-Helminthosporal. J. Am. Chem. Soc. 1992, 114, 644−654. (410) Sigrist, R.; Rey, M.; Dreiding, A. S. 89. Kurze Totalsynthesen von (±)-Sativen und (±)-cis−Sativendiol. Helv. Chim. Acta 1988, 71, 788− 807. (411) Halsall, T. G.; Theobald, D. W.; Walshaw, K. B. Studies in the Synthesis of Terpenes. Part VIII. The Absolute Configuration of Elemol. J. Chem. Soc. 1964, 1029−1037. (412) Piers, E.; Geraghty, M. B.; Kido, F.; Soucy, M. Stereoselective Total Synthesis of Sesquiterpenoids: (−)-Ylangocamphor, (−)-Ylangoborneol and (−)-Ylangoisoborneol. Synth. Commun. 1973, 3, 39−43. (413) Piers, E.; Britton, R. W.; Geraghty, M. B.; Keziere, R. J.; Kido, F. Stereoselective Total Synthesis of Copa and Ylango Sesquiterpenoids: (+)-Copacamphor, (+)-Copaborneol,(+)-Copaisoborneol, (−)-Ylangocamphor, (−)-Ylangoborneol and (−)-Ylangoisoborneol. Can. J. Chem. 1975, 53, 2838−2848. (414) Piers, E.; Geraghty, M. B.; Soucy, M. Stereoselective Total Synthesis of Sesquiterpenoids: (+)-Sativene and (+)-Cyclosativene. Synth. Commun. 1973, 3, 401−405. (415) Piers, E.; Isenring, H.-P. Total Synthesis of Ylango Sesquiterpenoids: (+)-Cis- and (+)-Trans-Sativenediol, (+)-Helminthosporal, (+)-Helminthosporol, Prehelminthosporal, Prehelminthosporal Diethyl Acetal, (+)-Victoxinine, (+)-Isosativenediol. Can. J. Chem. 1977, 55, 1039−1044. (416) Fehr, C.; Galindo, J. Syntheses of the Enantiomers of γCyclogeranic Acid, γ-Cyclocitral, and γ-Damascone: Enantioselective Protonation of Enolates. Helv. Chim. Acta 1995, 78, 539−552. (417) Klobus, M.; Zhu, L.; Coates, R. M. Solvolytic Rearrangement of Silphin-2α-yl Methanesulfonate to α-Terrecyclene: a Probable Biogenetic Relationship Between Silphinene and Quadrone. J. Org. Chem. 1992, 57, 4327−4329. (418) Coates, R. M.; Ho, J. Z.; Klobus, M.; Zhu, L. Carbocationic Rearrangements of Silphinane Derivatives. J. Org. Chem. 1998, 63, 9166−9176. (419) Wender, P. A.; Ternansky, R. J. Synthetic Studies on AreneOlefin Cycloadditions-VII: a Three-Step Total Synthesis of (±)-Silphinene. Tetrahedron Lett. 1985, 26, 2625−2628. (420) Lee, H.-Y.; Kim, B. G. A Facile Construction of the Quadranoid Skeleton: Application to the Total Synthesis of (±)-Suberosenone. Org. Lett. 2000, 2, 1951−1953. (421) Kousara, M.; Ferry, A.; Le Bideau, F.; Serré, K. L.; Chataigner, I.; Morvan, E.; Dubois, J.; Chéron, M.; Dumas, F. First Enantioselective Total Synthesis and Configurational Assignments of Suberosenone and Suberosanone as Potential Antitumor Agents. Chem. Commun. 2015, 51, 3458−3461. (422) Froborg, J.; Magnusson, G. Fungal Extractives. 12. Construction of the Vellerane Skeleton with Total Syntheses of Racemic Velleral, Vellerolactone, and Pyrovellerolactone. Revised Structuresl. J. Am. Chem. Soc. 1978, 100, 6728−6733. (423) Presset, M.; Coquerel, Y.; Rodriguez, J. Microwave-Assisted Wolff Rearrangement of Cyclic 2-Diazo-1,3-Diketones: An EcoCompatible Route to α-Carbonylated Cycloalkanones. J. Org. Chem. 2009, 74, 415−418. (424) Presset, M.; Mailhol, D.; Coquerel, Y.; Rodriguez, J. DiazoTransfer Reactions to 1,3-Dicarbonyl Compounds with Tosyl Azide. Synthesis 2011, 2011, 2549−2552. (425) Ren, Y.; Presset, M.; Godemert, J.; Vanthuyne, N.; Naubron, J.V.; Giorgi, M.; Rodriguez, J.; Coquerel, Y. A Switchable Dual Organocatalytic System and the Enantioselective Total Synthesis of the Quadrane Sesquiterpene Suberosanone. Chem. Commun. 2016, 52, 6565−6568. (426) Roberts, B. W.; Poonian, M. S.; Welch, S. C. A Total Synthesis of Culmorin. J. Am. Chem. Soc. 1969, 91, 3400−3401. 6158


Chemical Reviews

Review

(427) Takasu, K.; Mizutani, S.; Noguchi, M.; Makita, K.; Ihara, M. Stereocontrolled Total Synthesis of (±)-Culmorin via the Intramolecular Double Michael Addition. Org. Lett. 1999, 1, 391−394. (428) Takasu, K.; Mizutani, S.; Noguchi, M.; Makita, K.; Ihara, M. Total Synthesis of (±)-Culmorin and (±)-Longiborneol: An Efficient Construction of Tricyclo[6.3.0.0 3,9]Undecan-10-One by Intramolecular Double Michael Addition. J. Org. Chem. 2000, 65, 4112−4119. (429) Reddy, R. T.; Nayak, U. R. A Synthesis of Culmorin from Longifolene via 8,11-Dibromo-Longibornane. Synth. Commun. 1985, 15, 543−547. (430) Srikrishna, A.; Krishnan, K. Total Syntheses of (±)-Cyclolaurene, (±)-Epicyclolaurene and (±)-β-Cuparenone. Tetrahedron 1992, 48, 3429−3436. (431) Takahashi, H.; Tonoi, Y.; Matsumoto, K.; Minami, H.; Fukuyama, Y. Total synthesis of (−)-Laurequinone. Chem. Lett. 1998, 27, 485−486. (432) The current state of knowledge of the membership of kingdoms, phyla, classes, orders and species is available online: World Register of Marine Species (WoRMS) database: http://www.marinespecies.org/ aphia.php?p=browser (accessed Feb 21, 2017). (433) Mayer, AM. M. S. Marine pharmaceuticals: the clinical pipeline; http://marinepharmacology.midwestern.edu/clinPipeline.htm (accessed July 15, 2016). (434) The Marine Pharmacology and Pharmaceuticals Pipeline in 2015, Mayer, A. M.; Nguyen, M.; Newman, D. J.; Glaser, K. B. FASEB J. 2016, 30, Suppl. 932.7. (435) Gomes, N. G. M.; Dasari, R.; Chandra, S.; Kiss, R.; Kornienko, A. Marine Invertebrate Metabolites with Anticancer Activities: Solutions to the “Supply Problem. Mar. Drugs 2016, 14, 98. (436) Martins, A.; Vieira, H.; Gaspar, H.; Santos, S. Marketed Marine Natural Products in the Pharmaceutical and Cosmeceutical Industries: Tips for Success. Mar. Drugs 2014, 12, 1066−1101.

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