molecules

Review Review Linear Triquinane Sesquiterpenoids:Sesquiterpenoids: TheirTheir Isolation,Isolation, Structures, Biological Activities, and Chemical andSynthesis Chemical Synthesis

1 2 1, ID 1, Yi QiuQiu 1, Wen-Jian LanLan 2, Hou-Jin Li 1,** andand Liu-Ping Liu-Ping Chen Chen 1,* * 1 1 SchoolSchool of of Chemistry, Chemistry, Sun Sun Yat-sen Yat-sen Univer University,sity, Guangzhou Guangzhou 510275, 510275, China; China; [email protected] [email protected] 2 2 SchoolSchool of of Pharmaceutical Pharmaceutical Sciences, Sciences, Sun Sun Yat-sen Yat-sen Universi University,ty, Guangzhou Guangzhou 510006, 510006, China; China; [email protected]@mail.sysu.edu.cn ** Correspondence:Correspondence: [email protected] [email protected] (H.-J.L.); (H.-J.L.); [email protected] [email protected] (L.-P.C.); (L.-P.C.); Tel.:Tel.: +86-20-8411-3698 +86-20-8411-3698 (H.-J.L.); (H.-J.L.); +86-20-8411-5559 +86-20-8411-5559 (L.-P.C.) (L.-P.C.)


Received: 22 July 2018; Accepted: 19 Augu Augustst 2018; Published: 21 August 2018


Abstract: LinearLinear triquinane triquinane sesquiterpenoids sesquiterpenoids represent represent an important an important class class of natural of natural products. products. Most Mostof these of compounds these compounds were isolated were isolated from fungi, from sponge fungi,s, sponges, and soft andcorals, soft and corals, many and of them many displayed of them displayeda wide range a wide of biological range of biological activities. activities. On account On of account their structural of their structural diversity diversity and complexity, and complexity, linear lineartriquinane triquinane sesquiterpenoids sesquiterpenoids present present new challenges new challenges for chemical for chemical structure structure identification identification and total and totalsynthesis. synthesis. 118 linear 118 lineartriquinane triquinane sesquiterpenoids sesquiterpenoids were classified were classified into 8 types, into 8 types,named namedtypes I–VIII, types I–VIII,based basedon the on carbon the carbon skeleton skeleton and andthe theposition position of ofcarbon carbon substituents. substituents. Their Their isolation, isolation, structure structure elucidations, biologicalbiological activities, activities, and and chemical chemical synthesis synthesis were were reviewed. reviewed. This paperThis citedpaper 102 cited articles 102 fromarticles 1947 from to 2018.1947 to 2018.

Keywords: linear triquinane sesquiterpenoid; hirsutane; capnellene; isolation; structure; biologicalbiological activity; synthesis

1. Introduction Sesquiterpenoids represent anan importantimportant classclass ofof naturalnatural products.products. Among them,them, linear linear triquinane sesquiterpenoidssesquiterpenoids have have a a basic basic skeleton skeleton 1H 1-cyclopenta[H-cyclopenta[a]pentalenea]pentalene (Figure (Figure1a) [1a)1]. [1]. Since Since the firstthe first linear linear triquinane triquinane sesquiterpenoid, sesquiterpenoid, named named hirsutic hirsutic acid acid C C obtained obtained in in 1947 1947 [[2,3],2,3], moremore thanthan 100 linearlinear triquinanetriquinane sesquiterpenoids sesquiterpenoids have have been been isolated, isolated mainly, mainly from from fungi, fungi, sponges, sponges, and soft and corals. soft Manycorals. compoundsMany compounds displayed displayed a wide range a wide of biological range of activities, biological such activities, as cytotoxic, such antimicrobial,as cytotoxic, andantimicrobial, anti-inflammatory and anti-inflammatory activities [4–7]. Hirsutanesactivities [4 and–7]. capnellenes Hirsutanes are and the capnellenes most common are scaffolds the most of thecommon linear triquinanescaffolds of sesquiterpenoids the linear triquinane (Figure 1sesquiterpenoidsb,c) [ 8]. However, (Figure many compounds 1b,c) [8]. cannotHowever, be simplymany classifiedcompounds into cannot these be two simply types. classified Here, we into categorize these two the types. linear Here, triquinane we categorize sesquiterpenoids the linear triquinane into eight types,sesquiterpenoids types I–VIII, into according eight types, to the types carbon I–VIII, skeleton according and the to position the carbon of carbon skeleton substituents and the position (Figure 2of). Thiscarbon review substituents gives an(Figure overview 2). This about review the gives isolation, an overview structure, about biological the isolation, activities, structure, and biological chemical synthesisactivities, ofand linear chemical triquinane synthesis sesquiterpenoids. of linear triquinane sesquiterpenoids.

13 5 6 8 68 3 14 7 2 10 4 3 9 2 1 1 15 11 1 11 11 12 14 13 12 15 (a) basic scaffold (b) hirsutane scaffold (c) capnellene scaffold

Figure 1. Skeleton of linear triquinanetriquinane sesquiterpenoids.

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FigureFigure 2. StructureStructure types types of of linear linear triquinane sesquiterpenoids.

2. Isolation Isolation and and Structure Structure Elucidation

2.1. Type Type I There are are four four carbon carbon substituents substituents at at C-2, C-2, 3, 3, 10 10,, 10 10 in in type type I compounds I compounds (Figure (Figure 3).3 ).A Atotal total of of76 compounds,76 compounds, constitute constitute the the largest largest classification classification of of linear linear triquinane triquinane sesquiterpenoids. sesquiterpenoids. Hirsutic Hirsutic acid acid CC( (1), was the first first linear triquinane sesquite sesquiterpenoidsrpenoids isolated fr fromom the cultures of Stereum hirsutum inin 1947 1947 [2,3]. [2,3]. The The antibiotic antibiotic coriolin coriolin (2 (),2 ),coriolin coriolin B ( B3), (3 C), ( C4), ( 4and), and hirsutene hirsutene (7) were (7) were purified purified from from the myceliathe mycelia of basidiomycetes of basidiomycetes CoriolusCoriolus consors consors [9–11].[9 –However,11]. However, the initial the initial structures structures of coriolins of coriolins were notwere exactly not exactly right, afterwards right, afterwards their structures their structures and stereochemistry and stereochemistry were revised were by revised the same by theresearch same groupresearch based group on based spectroscopic on spectroscopic analysis, analysis, biogenetic biogenetic consideration consideration and andchemical chemical transformations, transformations, in 1971in 1971 [12]. [12 The]. The revised revised structures structures of ofcoriolins coriolins show showeded that that they they were were hirsutane-type hirsutane-type sesquiterpenes. sesquiterpenes. (−)-Complicatic)-Complicatic acid acid (5 ()5 )was was first first isolated isolated from from the the fungus fungus Stereum Stereum complicatum complicatum in 1973 in 1973 [13]. [13 5-]. Dihydrocoriolin5-Dihydrocoriolin C C(6) ( 6was) was obtained obtained from from CoriolusCoriolus consors consors (ATCC(ATCC 11574) 11574) [14]. [14 ]. Hypnophilin ( (88)) was isolated from mycelial cultures of Pleurotellus hypnophilus (Berk.) Sacc. in 1981 [15[15,16].,16]. Six Six new new hirsutane hirsutane metabolites, metabolites, arthrosporone arthrosporone (9), anhydroarthrosporone (9), anhydroarthrosporone (10), arthrosporol (10), arthrosporol(11), 4-O-acetylarthrosporo (11), 4-O-acetylarthrosporo (12), arthrosporodione (12), arthrosporodione (13), and compound (1314), wereand obtainedcompound from 14 fungus were obtainedUAMH 4262 from by fungus Amouzou UAMH in 1989 4262 [4]. by Incarnal Amouzou (15) wasin 1989 purified [4]. Incarnal from the ( culture15) was fluid purified of Gloeostereum from the cultureincarnatum fluidin 1991of Gloeostereum [17]. In 1992, incarnatum gloeosteretriol in 1991 (16 ),[17]. also namedIn 1992, hirsutanol gloeosteretriol F was obtained(16), also from named the hirsutanolfluid fermentation F was obtained products from of thGloeostereume fluid fermentation incarnatum products[18]. From of Gloeostereum the culture incarnatum extract of the[18]. fungus From theLentinus culture crinitus extract, 1-desoxy-hypnophilin of the fungus Lentinus (17 crinitus), and, hypnophilin1-desoxy-hypnophilin (8) were isolated (17), and as hypnophilin the most active (8) werecompounds. isolated In as addition the most to theseactive ketones, compounds. their corresponding In addition to alcohols these ketones, 6,7-epoxy-4(15)-hirsutene-5-ol their corresponding alcohols(18) and 6,7-epoxy-4(15)-hirsutene-5-ol diol 4 (19) were obtained in 1994 (18 [)19 and]. diol 4 (19) were obtained in 1994 [19]. Chloriolin B B ( 20)) and C ( 21) were purifiedpurified from an unidentifiedunidentified fungus, which was separated fromfrom a marine sponge Jaspis aff. johnstoni [20].[20]. Hirsutanols A–C A–C ( (2222––2424)) and and ent-gloeosteretriol entgloeosteretriol (25) were obtained from from an an unidentified unidentified fungus, fungus, separated from an Indo-Pacific Indo-Pacific sponge Haliclona sp. in 1998, and study study showed that hirsutanol B was an epimer of hirsutanol A [5]. [5]. In In 1998, 1998, from from mycelial mycelial cultures cultures of of the the agaric MacrocystidiaMacrocystidia cucumis cucumis,, cucumis A–D ( 26–29) were were found found together together with with arthrosporone arthrosporone ( 9)[) [21].21]. Hirsutenols Hirsutenols A–C A–C ( (30–32)) were were isolatedisolated in in 2002, 2002, from from the the culture culture broth broth of the mushroom Stereum hirsutum [22].[22]. Connatusins Connatusins A A ( (3333)) and B ( 34) were isolated from the fungus Lentinus connatus BCC 8996, in 2005 [[23].23]. Xeromphalinones A,A, B,B, E, E, F F (35 (35–38–38),), were were isolated isolated from fromXeromphalina Xeromphalinasp. bysp.Liermann by Liermann et al. et in al. 2010. in 2010.At the At same the time,same theytime, isolated they isolated chlorostereone chlorostereone (39) from (39Stereum) from Stereumsp. [24]. sp. In [24]. 2014, In Ma 2014, and Ma co-workers and co- workersfound three found new three sesquiterpenoids new sesquiterpenoids from the myceliafrom the of myceliaStereum of hirsutum Stereum. Since hirsutum they. didSince not they name did these not namecompounds these compounds at that time, at we that called time, them we called compounds them compounds40–42 in proper 40–42 order, in proper successively order, successively [25]. [25]. Li and co-workers have studied Chondrostereum sp., which was separated from the soft coral Sarcophyton tortuosum, from the South China Sea. Their investigations found that the metabolites of Chondrostereum sp., were varied depending on the culture media. By altering the fermentation

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Li and co-workers have studied Chondrostereum sp., which was separated from the soft coral Sarcophyton tortuosum, from the South China Sea. Their investigations found that the metabolites of ChondrostereumMolecules 2018, 23, x sp., were varied depending on the culture media. By altering the fermentation3 of 31 conditions, e.g., carbon and nitrogen source, Chondrostereum sp. can produce highly functionalized conditions, e.g., carbon and nitrogen source, Chondrostereum sp. can produce highly functionalized hirsutanehirsutane type type compounds compounds with with a surprising a surprising chemodiversity chemodiversity [26 [26].]. From From the the PDB PDB (potato (potato dextrose dextrose broth) medium,broth) chondrosterinsmedium, chondrosterins A–D (43– 46A–D)[26 (]43 were–46) isolated,[26] were while isolated, hirsutanol while Ehirsutanol (47)[27], chondrosterinsE (47) [27], L–Ochondrosterins (48–51)[28,29 L–O] were (48 obtained–51) [28,29] from were GPY obtained (glucose-peptone-yeast) from GPY (glucose-peptone-yeast) medium. medium. AimingAiming at findingat finding new new secondary secondary metabolites, metabolites, with with bioactivities bioactivities from from fungi fungi collected collected in thein the region of Tibetregion Plateau, of Tibet a strainPlateau, of aStereum strain of hirsutum Stereum(L515) hirsutum was (L515) isolated was from isolated its fruiting from its body. fruiting Sterhirsutins body. A(52Sterhirsutins) and B (53 A), (52 hirsutic) and B acids(53), hirsutic D (54) acids and ED ((5554),) and were E ( isolated55), were fromisolated this from strain’s this strain’s solid-substrate solid- fermentationsubstrate fermentation culture in 2014 culture [30]. Additionally,in 2014 [30]. Additi in 2015,onally, from in its 2015, ethyl from acetate its extract,ethyl acetate sterhirsutins extract, C–L (56–sterhirsutins65) were obtained C–L (56 [–3165].) were Sterhirsutin obtained L [31]. was Sterhirsutin the first sesquiterpene L was the first coupled sesquiterpene with a xanthinecoupled with moiety. a Antrodinxanthine moiety. D (66) together with coriolin (2), dihydrocoriolin C (6), and chloriolin B (20), were isolatedAntrodin from the D fermentation (66) together of with the basidiomycetecoriolin (2), dihydrocoriolinAntrodiella albocinnamomea C (6), and chloriolinin 2015 B [(3220].), were isolatedScale-up from fermentation the fermenta andtion chemicalof the basidiomycete studies of Antrodiella basidiomycetes albocinnamomeaMarasmiellus in 2015sp. [32]. BCC 22389 led Scale-up fermentation and chemical studies of basidiomycetes Marasmiellus sp. BCC 22389 led to the isolation and characterization of marasmiellins A (67) and B (68) in 2016. Marasmiellins are to the isolation and characterization of marasmiellins A (67) and B (68) in 2016. Marasmiellins are structurally, closely related to coriolins [33]. structurally, closely related to coriolins [33]. Chondrostereum SeparationSeparation of of the the active active principlesprinciples ofof the fermented fermented broth broth of of a afungus fungus Chondrostereum sp. sp. NTOU4196NTOU4196 which which was was isolated isolated from from the marinethe marine red algared Pterocladiellaalga Pterocladiella capillacea capillacea, resulted, resulted in the in isolation the of chondroterpenesisolation of chondroterpenes A–H (69–76 A–H) in 2017(69–76 [34) in]. 2017 [34].

Figure 3. Cont.

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Figure 3. Cont.

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Figure 3. Cont.

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Figure 3. Structures of type I compounds. Figure 3. Structures of type I compounds. 2.2. Type II Figure 3. Structures of type I compounds. 2.2. Type II 2.2.There Type IIwere 10 compounds belonging to type II, with four carbon substituents at C-3, 6, 10, 10 (FigureThere 4). were 9 compounds 10 compounds a have belongingcarbonyl group. to type II, with four carbon substituents at C-3, 6, 10, 10 (FigureHirsutanolThere4). 9 compoundswere D 10(77 compounds) was a haveproduced carbonylbelonging from group.theto typeterrestrial II, with fungus four carbon Corious substituents consors, cultured at C-3, under 6, 10, both10 seaHirsutanol(Figure water 4). and 9 Dcompounds deionized (77) was produced awater have carbonylmedia, from ingroup. the 1998 terrestrial [31]. Cucumins fungus Corious E–G (78 consors,–80) werecultured isolated under from both Hirsutanol D (77) was produced from the terrestrial fungus Corious consors, cultured under both seamycelial water and extract deionized of the water agaric media, Macrocystidia in 1998 [31 cucumis]. Cucumins, in 1998 E–G ([21].78–80 From) were the isolated fermentation from mycelial of sea water and deionized water media, in 1998 [31]. Cucumins E–G (78–80) were isolated from extractbasidiomycete of the agaric AntrodiellaMacrocystidia albocinnamomea cucumis, antrodin, in 1998 A [ (2181].) was From obtained, the fermentation in 2015 [32]. Chondrosterins of basidiomycete mycelial extract of the agaric Macrocystidia cucumis, in 1998 [21]. From the fermentation of AntrodiellaE, I–K (82 albocinnamomea–85) were purified, antrodin from the A (81marine) was fungus obtained, Chondrostereum in 2015 [32 ].sp. Chondrosterins [26,28,35]. Cerrenin E, I–K C (8682)– 85) basidiomycete Antrodiella albocinnamomea, antrodin A (81) was obtained, in 2015 [32]. Chondrosterins was obtained from the broth extract of Cerrena sp. A593 [36]. wereE, purified I–K (82– from85) were the purified marine from fungus the Chondrostereummarine fungus Chondrostereumsp. [26,28,35 ].sp. Cerrenin [26,28,35]. C Cerrenin (86) was C obtained(86) from thewas brothobtained extract from oftheCerrena broth extractsp. A593 of Cerrena [36]. sp. A593 [36].

Figure 4. Structures of type II compounds. Figure 4. Structures of type II compounds. Figure 4. Structures of type II compounds.

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2.3.2.3. Type IIIIII InIn typetype IIIIII compounds,compounds, therethere areare fourfour carboncarbon substituentssubstituents inin C-1,C-1, 1,1, 4,4, 99 (Figure(Figure5 ).5). The The most most notablenotable featurefeature ofof thesethese compoundscompounds isis theythey containcontain anan off-ringoff-ring carbon-carboncarbon-carbon doubledouble bondbond atat C-9.C-9.

Figure 5. Structures of type III compounds. Figure 5. Structures of type III compounds.

∆9(12)-capnellene-8β,10α-diol (87), ∆9(12)-capnellene-3β, 8β, 10α-triol (88), ∆9(12)-capnellene- 9(12) β α 9(12) β β α 9(12) 5α,8β∆,10α-triol-capnellene-8 (89), and,10 ∆9(12)-diol-capnellene-2 (87), ∆ ξ,8-capnellene-3β,10α-triol (90,), 8 were, 10 obtained-triol (88 ),from∆ the-capnellene- soft coral α β α 9(12) ξ β α 5Capnella,8 ,10 imbricata-triol (89, by), andSheikh∆ et -capnellene-2al. These compounds,8 ,10 were-triol the (90 ),first were members obtained of a from new thesesquiterpene soft coral Capnellaclass, which imbricata was ,name by Sheikhd capnellane et al. These [37]. compounds∆9(12)-Capnellene-2 were theβ,5 firstα,8β members,10α-tetrol of (91 a), new has sesquiterpene been isolated 9(12) β α β α class,from whichthe alcyonarian was named Capnella capnellane imbricate, [37]. ∆by Kaisin-Capnellene-2 et al. Its structure,5 ,8 ,10 and-tetrol relative (91), configuration has been isolated was fromdetermined the alcyonarian by X-ray Capnelladiffraction imbricate, analysis,by in Kaisin 1979 [38]. et al. In Its 1985, structure Kaisin and and relative co-workers configuration implemented was determinedthe isolation by of X-ray other diffraction eight acetyl analysis,ated capnellenes in 1979 [38 from]. In 1985,acetone Kaisin extraction and co-workers of fresh colonies implemented of C. imbricate. Four of these compounds were named as 3β-acetoxy-∆9(12)-capnellene-8β,10α-diol (92), 5α-

Molecules 2018, 23, 2095 8 of 33 the isolation of other eight acetylated capnellenes from acetone extraction of fresh colonies of C. imbricate. Four of these compounds were named as 3β-acetoxy-∆9(12)-capnellene-8β,10α-diol (92), 5α-acetoxy-∆9(12)-capnellene-8β,10α-diol (93), 3β,14-diacetoxy-∆9(12)-capnellene-8β,10α-diol (94), and 2β,5α-diacetoxy-∆9(12)-capnellene-8β,10α-diol (95)[39]. In 1998, capnellene-8β-ol (96) and 3β-acetoxycapnellene-8β, 10α,14β-triol (97) were isolated from Capnella imbricata, collected from Mayu Island, Molucca Sea, Indonesia, in 1996 [40]. 2α,8β,13-Triacetoxycapnell-9(12)-ene-10α-ol (98), 3α,8β,14-triace-toxycapnell-9(12)-ene-10α-ol (99), 3α,14-diacetoxycapnell-9(12)-ene-8β,10α-diol (100), and 3α,8β-diacetoxycapnell-9(12)-ene-10α-ol (101), were obtained from the soft coral Dendronephthya rubeola, in 2007 [6]. From the acetone/methylene chloride extracts of the Formosan soft coral Capnella imbricate, 8β- acetoxy-∆9(12)-capnellene-10α-ol (102), ∆9(12)-capnellene-10α-ol-8-one (103), ∆9(12)-capnellene-8β,15-diol (104), ∆9(12)-capnellene-8β,10α, 13β-triol (105), ∆9(10)-capnellene-12-ol-8-one (106), 8β,10α-diacetoxy- ∆9(12)-capnellene (107), and 8β-acetoxy-∆9(12)-capnellene (108), were purified in 2008 [7].

2.4. Type IV, V, VI, VII and VIII The number of type IV–VIII compounds (Figure6), is relatively small. It is worth mentioning that type VIII compounds, have one less carbon substituent on the skeleton than other compounds. Type IV: Ceratopicanol (109) was isolated from the fungus Ceratosystis piceae, in 1988. Ceratosystis piceae (Munch) Bakshi, is a sapwood staining ascomycete, occurring on coniferous loga and lumber [41]. Cucumin H (110) was found in 1998, from mycelial cultures of the agaric Macrocystidia cucumis [21]. From fermentation of Antrodiella albocinnamomea, antrodin B (111) was isolated in 2015 [32]. Type V: Antrodin C (112), was obtained from fermentation of Antrodiella albocinnamomea, in 2015 [32]. Cerrenin B (113) was isolated from the broth extract of Cerrena sp. A593, in 2018 [36]. Type VI: Pleurotellic acid (114) and pleurotellol (115) were isolated from mycelial cultures of Pleurotellus hypnophilus (Berk.), in 1986 [15,16]. Type VII: Dichomitol (116), was purified from mycelial solid cultures of Dichomitus squalens, which was a commonly found white-rot basidiomycete fungus, in 2004 [42]. Type VIII: Xeromphalinones C (117) and D (118), were obtained from Xeromphalina sp. by Liermann et al., in 2010 [24]. From the perspective of source, linear triquinane sesquiterpenoids can be isolated from both marine and terrestrial organisms, however, the proportion of terrestrial species is relatively larger. It is worthwhile to note that, there are several highly productive biological species, such as the mushroom Stereum hirsutum, the soft coral Capnella imbricata, and marine fungus Chondrostereum sp. Structurally, there are 76 compounds belonging to type I, accounting for the majority of these 118 compounds, and 22 compounds constitute type III. In fact, it was most common to categorize linear triquinanes, according to their ring scaffold with the hirsutanes and capnellenes. Type I compounds, exactly belong to hirsutanes, while type III belong to capnellenes. As for functional groups, the epoxy bond is easy to form at C-6, 7 positions and the majority of carbonyls are formed at C-4, C-7, and C-9 positions, with a minority of carbonyls formed at C-5. As regards the hydroxyl group, except for C-10, it is possible to form at the other 10 positions. Additionally, Kutateladze and Kuznetsov used the relatively fast parametric/DFT hybrid computational method DU8+, to analyze the reported NMR data for 90+ natural triquinanes in 2017, which resulted in requiring structure correction of 13 compounds, including 10 linear triquinane sesquiterpenoids, noted in this review [43]. However, this review still used the structures from the original literatures, because only the calculations were not convincing enough. Molecules 2018, 23, 2095 9 of 33 Molecules 2018, 23, x 9 of 31

Figure 6. Structures of type VI–VIII compounds. Figure 6. Structures of type VI–VIII compounds.

3. Biological Activity 3. Biological Activity

3.1. Cytotoxicity Cytotoxicity was a kind ofof commoncommon biologicalbiological activityactivity reportedreported forfor linearlinear triquinanetriquinane sesquiterpenoids, usually expressed as inhibitory concentration (IC50), 50% of the effective dose sesquiterpenoids, usually expressed as inhibitory concentration (IC50), 50% of the effective dose (ED50), (ED50), cytotoxic concentration (CC50), lethal concentration (LC50), or growth inhibition (GI50), this cytotoxic concentration (CC50), lethal concentration (LC50), or growth inhibition (GI50), this value emphasizesvalue emphasizes the correction the correction for the for cellthe countcell count at time at time zero) zero) [1]. [1]. Among Among the the 118 118linear linear triquinanetriquinane sesquiterpenoids, manymany compoundscompounds exhibitedexhibited activitiesactivities againstagainst cancercancer cellcell lineslines (Table(Table1 ).1). Coriolin B (3) inhibited human breast cancer cell T-47D and CNS cancer cell line SNB-75, with Coriolin B (3) inhibited human breast cancer cell T-47D and CNS cancer cell line SNB-75, with the the IC50 values of 0.7 and 0.5 μM, respectively [20]. IC50 values of 0.7 and 0.5 µM, respectively [20]. Toxicity assays were carried out with L929 mouse fibroblasts cells. The IC50 values were 2.4 Toxicity assays were carried out with L929 mouse fibroblasts cells. The IC50 values were 2.4 µg/mL μg/mL for 1-desoxy-hypnophilin (17) and 0.9 μg/mL for 6,7-epoxy-4(15)-hirsutene-5-ol (18) [19]. for 1-desoxy-hypnophilin (17) and 0.9 µg/mL for 6,7-epoxy-4(15)-hirsutene-5-ol (18)[19]. Cucumins A–C (26–28) were cytotoxic, with IC100 range from 0.5 to 1 mg/mL for L1210 cells [21]. Cucumins A–C (26–28) were cytotoxic, with IC100 range from 0.5 to 1 mg/mL for L1210 cells [21]. The cytotoxicities (IC50 value) of xeromphalinones A (35), B (36), F (38) and chlorostereone (39) against The cytotoxicities (IC50 value) of xeromphalinones A (35), B (36), F (38) and chlorostereone (39) against Jurkat cells, ranged from 1 to 5 μg/mL (2 to 20 μM). For xeromphalinones C–E (117–118, 37), the IC50 Jurkat cells, ranged from 1 to 5 µg/mL (2 to 20 µM). For xeromphalinones C–E (117–118, 37), the IC50 values were above 50 μg/mL [24]. values were above 50 µg/mL [24]. Compound 40 inhibited the growth of HepG2 cells, with IC50 value of 24.41 ± 1.86 μM [25]. Compound 40 inhibited the growth of HepG2 cells, with IC50 value of 24.41 ± 1.86 µM[25]. Chondrosterin A (43) showed significant cytotoxicity against cancer lines A549, CNE2, and LoVo, Chondrosterin A (43) showed significant cytotoxicity against cancer lines A549, CNE2, and LoVo, with IC50 values of 2.45, 4.95, and 5.47 Μm, respectively, whilst chondrosterins B–E (44–46, 48) were with IC50 values of 2.45, 4.95, and 5.47 Mm, respectively, whilst chondrosterins B–E (44–46, 48) were apparently inactive (IC50 > 200 μM), in the assay developed by Li [26]. Additionally, in Hsiao and co- apparently inactive (IC50 > 200 µM), in the assay developed by Li [26]. Additionally, in Hsiao and workers’ investigation, chondrosterins A (43) and B (44) and chondroterpene H (76), showed potent co-workers’ investigation, chondrosterins A (43) and B (44) and chondroterpene H (76), showed potent cytotoxic activities on BV-2 cells, at a concentration of 20 μM [34]. Chondrosterin J (84) showed potent cytotoxic activities against the cancer cell lines CNE1 and CNE2, with the IC50 values of 1.32 and 0.56 μM, respectively. By comparison, chondrosterin J (84) showed stronger cytotoxic activities than

Molecules 2018, 23, 2095 10 of 33 cytotoxic activities on BV-2 cells, at a concentration of 20 µM[34]. Chondrosterin J (84) showed potent cytotoxic activities against the cancer cell lines CNE1 and CNE2, with the IC50 values of 1.32 and 0.56 µM, respectively. By comparison, chondrosterin J (84) showed stronger cytotoxic activities than chondrosterin A (43) (CNE2: 4.95 µM), hirsutanol A (22) (CNE1:10.08 µM; CNE2: 12.72 µM), and incarnal (15) (CNE1: 34.13 µM; CNE2: 24.87 µM). In contrast, chondrosterin I (83) was inactive (IC50 values > 200 µM) [35]. Yang and co-workers have investigated the molecular mechanisms of the antitumor activity of hirsutanol A, with the result that hirsutanol A inhibited tumor growth, through triggering ROS production and apoptosis [44]. Chondrosterins K–M (85, 48–49) showed cytotoxicities against seven cancer cell lines CNE1, CNE2, HONE1, SUNE1, A549, GLC82, and HL7702, in vitro [28]. Sterhirsutins A–B (52–53) and hirsutic acid D–E (54–55) showed cytotoxicity against K562 and HCT116 cell lines. They exhibited cytotoxicity against K562 cells, with the IC50 values of 12.97, 16.29, 6.93, and 30.52 µg/mL, respectively. For the HCT116 cell line, they showed cytotoxicity with the IC50 values of 10.74, 16.35, 25.43, and 24.17 µg/mL [30]. Sterhirsutins E–G (58–60) and I (62) also showed antiproliferative activity against K562 and HCT116 cancer cells, with IC50 values ranging from 6 to 20 µM.

Table 1. Cytotoxicity of linear triquinane sesquiterpenoids.

Cell Lines Cytotocicity 15 IC = 34.13 µM, 22 IC = 10.08 µM, 48 IC = 33.55 µM, 49 IC = 42.00 µM, 84 IC = 1.32 µM, CNE1 50 50 50 50 50 85 IC50 = 17.66 µM 15 IC = 24.87 µM, 22 IC = 12.72 µM, 43 IC = 4.95µM, 48 IC = 22.50 µM, 49 IC = 44.08 µM, CNE2 50 50 50 50 50 84 IC50 = 0.56 µM, 85 IC50 = 12.03 µM

HONE1 22 IC50 = 17.40 µM, 48 IC50 = 34.60 µM, 49 IC50 = 46.11 µM, 85 IC50 = 22.06 µM

SUNE1 22 IC50 = 3.50 µM, 48 IC50 = 30.40 µM, 49 IC50 = 58.83 µM, 85 IC50 = 16.44 µM

A549 22 IC50 = 11.96 µM, 43 IC50 = 2.45µM, 48 IC50 = 29.67 µM, 49 IC50 = 49.58 µM, 85 IC50 = 23.51 µM

GLC82 22 IC50 = 10.11 µM, 48 IC50 = 37.47 µM, 49 IC50 = 55.90 µM, 85 IC50 = 18.08 µM

HL7702 22 IC50 = 9.76 µM, 48 IC50 = 34.26 µM, 49 IC50 = 56.40 µM, 85 IC50 = 22.14 µM

52 IC50 = 12.97 µg/mL, 53 IC50 = 16.29 µg/mL, 54 IC50 = 6.93 µg/mL, 55 IC50 = 30.52 µg/mL, 87 IC50 = K562 0.7 µM, 96 IC50 = 4.6 µM, 97 IC50 = 24 µM, 98 GI50 = 126.9 ± 3.0 µm/L, 99 GI50 = 126.9 ± 2.0 µm/L, 100 GI50 = 142.0 ± 4.7 µm/L, 101 GI50 = 142.0 ± 4.7 µm/L, Doxorubicin GI50 = 1.0 ± 0.6 µm/L

HCT116 52 IC50 = 10.74 µg/mL, 53 IC50 = 16.35 µg/mL, 54 IC50 = 25.43 µg/mL, 55 IC50 = 24.17 µg/mL

HL-60 87 IC50 = 51 µM, 96 IC50 = 68 µM, 97 IC50 = 713 µM

G402 87 IC50 = 42–51 µM, 96 IC50 > 4500 µM, 97 IC50 = 52 µM

MCF-7 87 IC50 = 93 µM, 96 IC50 > 4500 µM, 97 IC50 = 1029 µM

HT115 87 IC50 = 63 µM, 96 IC50 > 4500 µM

A2780 87 IC50 = 9.7 µM, 96 IC50 = 6.6 µM, 97 IC50 = 32 µM, 98 CC = 126.9 ± 1.8 µm/L, 99 CC = 126.9 ± 2.5µm/L, 100 CC = 142.0 ± 2.7 µm/L, 101 CC = 125.0 HeLa 50 50 50 50 ± 2.0 µm/L, Doxorubicin CC50 = 2.0 ± 0.8 µm/L 17 IC = 2.4 µg/mL, 18 IC = 0.9 µg/mL, 98 GI = 126.9 ± 2.7 µm/L, 99 GI = 126.9 ± 2.9 µm/L, 100 L-929 50 50 50 50 GI50 = 126.4 ± 3.0 µm/L, 101 GI50 = 99.1 ± 1.8 µm/L, Doxorubicin GI50 = 1.2 ± 0.6 µm/L

T-47D 3 IC50 = 0.7 µM

SNB-75 3 IC50 = 0.5 µM

HepG2 40 IC50 = 24.41 ± 1.86 µM

LoVo 43 IC50 = 5.47 µM

Compound 87 was cytotoxic toward human promyelocytic leukemia cell line HL-60, human erythroleukaemia cell line K562, human renal leiomyoblastoma cell line G402, human breast adenocarcinoma cell line MCF-7, human colon-cancer cell line HT 115, and human ovarian cancer cell line A2780, with IC50 values in the range of 0.7–93 µM, and the greatest activity was displayed against Molecules 2018, 23, 2095 11 of 33

K562 at 0.7 µM. Compound 95 showed some selectivity, for the renal leiomyoblastoma and ovarian cancer cell lines. Compound 96 was effective against the K562, as well as HL-60 [40]. Compounds 98–101 showed weak cytotoxic activities against the human cervix carcinoma cell line HeLa, but they also showed weak or moderate antiproliferative effects, against the cell lines K562 and murine fibroblast cell line L-929 [6]. Compounds 87 and 102 exhibited strong activity against HeLa and L-929. Compounds 87, 101, 102 showed similar anti-proliferative activities against K562. The anti-proliferative and cytotoxic activity of compound 84 against L-929 and HeLa cells, is 5.7 and 3.8 times lower than doxorubicin, which was used in the cancer therapy for the treatment of lymphoma, carcinoma, sarcoma, and leukemia [6].

3.2. Antimicrobial Activity Coriolin (2) showed inhibitory effect on the growth of Gram-positive bacteria at 6.25–12.5 mcg/mL, some of Gram-negative bacteria at 50–100 mcg/mL [9]. (−)-Complicatic acid (5) was against a range of Gram-positive and Gram-negative bacteria [42]. Compounds 9–11 displayed weak antifungal activity [4]. Incarnal (15) inhibited the growth of Gram-positive bacteria at 6.25–12.5 µg/mL, while it had no antibacterial activity against Gram-negative bacteria [17]. Compounds 17 had stronger antimicrobial activity than 18 (Table2)[ 19]. Compounds 22 and 25, were found to be anti-microbial (Bacillus subtilus) active [5]. Hirsutenols A–C (30–32) showed moderate antibacterial activity against Escherichia coli [22].

Table 2. Antimicrobial activity of compounds 17 and 18 (MIC50, µg/mL).

Test Organisms 17 18 Bacillus cereus DSM 318 2–5 >100 Staphylococcus aureus ATCC 13709 10–25 >100 Escherichia coli ATCC 9637 >100 >100 Salmonella gallinarum ATCC 9184 50–100 50–100 Mycobacterium smegmatis ATCC 607 25–50 50–100 Candida albicans ATCC 10231 50–100 >100 Candida tropicalis DSM 1346 >100 >100 Rhodotorula glutinis DSM 70398 >100 >100 Aspergillus niger (spores) DSM 737 1–2 25–50 Aspergillus flavus (spores) BD 27 2–5 25–50 Mucor rouxii (spores) DSM 1691 2–5 25–50

3.3. Other Bioactivity Compounds 22, 43–44, 69–70, and 76, inhibited lipopolysaccharide (LPS)-induced NO production in BV-2 microglial cells, at a concentration of 20 µM. Compounds 22 (5–20 µM) and 69, had less effects on cell viability. At the same concentration, 24 and 70–75 had little effect on viabilities. Only 22, with an α-exomethylene carbonyl moiety, was more potent than 24, on inducing cellular toxicity. Compounds 43 and 76, reduced cellular viability, more than 22. Compounds 43, 44 (20 µM), and 76, all decreased the NO levels to the resting condition. These results suggested that cell death, predominantly caused decreasing NO production. However, the decreased NO levels by 22 (5 µM) and 69, were dependent on inhibition of NO production instead of cell death [34] (Tables3 and4). Molecules 2018, 23, 2095 12 of 33

Table 3. Inhibitory effect of compounds 22, 43–44, 69–70 and 76 in LPS-induced NO production in microglial BV-2 cells.

Compounds (20 µM) NO (µM) 22 8 ± 2 43 4 ± 1 44 4 ± 1 69 8 ± 2 70 10 ± 2 76 4 ± 1

Table 4. Effect of compounds 22, 43–44, 69–70, and 76 in LPS-induced NO production in microglial viability.

Viability (%) Compounds 2 µM 5 µM 10 µM 20 µM 22 94 ± 1 87 ± 3 77 ± 8 39 ± 5 43 nt * nt 22 ± 3 12 ± 1 44 nt nt 23 ± 7 11 ± 1 69 93 ± 3 82 ± 5 73 ± 4 67 ± 3 70 95 ± 5 95 ± 4 89 ± 9 69 ± 5 76 47 ± 6 30 ± 5 11 ± 2 11 ± 2 * nt = not tested.

Compound 40 exhibited NO inhibitory effect, on the LPS-induced macrophages, with the IC50 value of 15.44 ± 1.07 µM[25]. Sterhirsutin G (60) showed inhibitory activity on the activation of IFNβ promoter at a dose of 10 µM in HEK293 cells, whereas other compounds exhibited no apparent inhibitory effect on the IFNβ promoter activation, under the same experimental conditions. Furthermore, 60 dramatically reduced the SeV-induced mRNA level of IL6, RANTES, and IFNB1. Compared with 60, sterhirsutin E (58) showed no inhibitory activity on the IFNβ promoter activation. These findings implied that sterhirsutin G, has the ability to inhibit the RLRs-mediated antiviral signaling in cells, and was potent to be a leading compound in the treatment of autoimmune diseases [31]. Sterhirsutin K (64) induced autophagy in HeLa cells, and its autophagy-inducing effect was evaluated via quantification of the number of GFP-LC3 dots in cells. Sterhirsutins A–L (52, 53, 56–65) and hirsutic acids D (54) and E (55), were screened using GFP-LC3 stable HeLa cells. As a result, 64 was found to exhibit strong autophagy-inducing activity at a dose of 50 µM. In comparison with hirsutic acid E (55), sterhirsutin J (63) and K (64) showed cytotoxicity rather than autophagy-inducing effect, on GFP-LC3 stable HeLa cells, at the concentration of 50 µM (inhibition rate = 100%). The double bond between C-6 and C-7 in 55 and 63 increased cytotoxicity, but significantly decreased the autophagy-inducing activity [31]. Compound 86 showed a specific inhibition (77%) of the Myc/Max interaction in yeast, and a lower inhibition of the Tax–CREB interaction (27%) and Myc–Miz-1 interaction (34%). This specific inhibition of Myc–Max interaction, is well associated with its antiproliferative effect against the L-929 cell line [6]. Compounds 87, 102, and 103, significantly reduced the levels of the iNOS protein at concentrations of 10 µM, in comparison with control cells stimulated with LPS. 87 and 102 dramatically reduced the levels of the COX-2 protein at a dose of 10 µM, compared with control cells stimulated with LPS [7]. The anti-inflammatory effects of compounds 87, 96, and 103–109 were tested using LPS-stimulated cells. Stimulation of RAW 264.7 cells with LPS led to up-regulation of the pro-inflammatory iNOS and COX-2 proteins [7]. Molecules 2018, 23, 2095 13 of 33

As a summary, among these 118 compounds, there were 56 compounds showing biological activities. Hirsutanes and capnellenes are major active compounds. They have cytotoxic, antimicrobial, anti-inflammatory activities, and so on. Previous reports revealed that the compounds with a α-methylidene oxo group, such as hypnophilin (8) and desoxyhypnophilin (17), possessed stronger antimicrobial or cytotoxic activities [26]. These structures and bioactivities are a source of inspiration, for synthetic chemists and pharmaceutist, to develop innovative methodologies in the field of medicine chemistry.

4. Chemical Synthesis Linear triquinane sesquiterpenoids, have attracted a lot of interest among synthetic chemists in recent decades, owing to their premium structures and promising biological activities [45]. TheirMolecules skeletal 2018, 23 and, x functional diversities, also pose a considerable synthetic challenge [46]. 13 of 31

4.1. Hirsutane Type In the early 1970s, chemists began to synthesize hirsutane type compounds, in in a a variety variety of of ways. ways. The total synthesis of hirsutic acid C ((11),), waswas achievedachieved viavia thethe suitablysuitably functionalizedfunctionalized skeletonskeleton compound 119 (Figure(Figure7 7).). InIn 1974,1974, HisanobuHisanobu HashimotoHashimoto andand co-workersco-workers reportedreported aa stereospecificstereospecific conversion of 3α-hydroxymethylene ketone (compound 119) to racemic hirsutic acid [47,48]. [47,48]. In In 1978, 1978, Kueh and co-workers co-workers [49] [49 ]reported reported the the synthesis synthesis of ofthe the hirsutane hirsutane carbon carbon skeleton. skeleton. They They found found that thatthe photochemical the photochemical intramolecular intramolecular [2 + 2] cycloaddition [2 + 2] cycloaddition of dicyclopent-l of dicyclopent-l-enylmethanes -enylmethanes (120), followed (120), followedby in situation by in situation of methanol of methanol to the to strained the strained cyclopropane cyclopropane ring ring in inthe the presumed presumed intermediate bicycle[2.1.0]pentanes (121),), ledled toto anan easyeasy synthesissynthesis ofof thethe ringring system.system.

Figure 7. Structures of compounds 119–121..

In 1981, Mehta and co-workers developed a simple expedient synthesis of (+)-hirsutene ((+)-7) In 1981, Mehta and co-workers developed a simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic sequence (Scheme 1). There were three distinctive features in via a novel photo-thermal metathetic sequence (Scheme1). There were three distinctive features this method: (1) the cis-syn-cis-C13-tricyclopentanoid frame (124) was efficiently obtained from in this method: (1) the cis-syn-cis-C -tricyclopentanoid frame (124) was efficiently obtained from cyclopentadiene and 2,5-dimethyl-p-benzoquinone,13 in three high-yielding steps employing only heat cyclopentadiene and 2,5-dimethyl-p-benzoquinone, in three high-yielding steps employing only and light as the reagents; (2) compound 124 with the requisite cis-anti-cis system (125), was in ready heat and light as the reagents; (2) compound 124 with the requisite cis-anti-cis system (125), was in and remarkable thermal equilibration; and (3) generation of abundant functionality on the ready and remarkable thermal equilibration; and (3) generation of abundant functionality on the tricyclopentanoid frame permits the synthesis of the higher oxygenated members of the hirsutane tricyclopentanoid frame permits the synthesis of the higher oxygenated members of the hirsutane type type compounds [50]. compounds [50]. In 1984, Dawson and co-workers reported a simple stereocontrolled sequence to synthesize In 1984, Dawson and co-workers reported a simple stereocontrolled sequence to synthesize hirsutene from dicyclopentadiene which contained ring expansion by ketonization of a hirsutene from dicyclopentadiene which contained ring expansion by ketonization of a cyclopropoxide cyclopropoxide and skeletal rearrangement, through a β-enolate [51]. A primary feature of this and skeletal rearrangement, through a β-enolate [51]. A primary feature of this synthesis, was that the synthesis, was that the stereochemistry at three of the four chiral centers was established essentially stereochemistry at three of the four chiral centers was established essentially at the beginning of the at the beginning of the sequence, and then the β-enolate rearrangement specifically generated the sequence, and then the β-enolate rearrangement specifically generated the correct configuration at the correct configuration at the fourth center, exclusively. fourth center, exclusively. In 1986, Mehta and co-workers [52] developed a simple method for triquinane natural products, In 1986, Mehta and co-workers [52] developed a simple method for triquinane natural products, based on photo-thermal olefin metathesis of readily available Diels-Alder adducts. They also applied based on photo-thermal olefin metathesis of readily available Diels-Alder adducts. They also applied this approach to the total synthesis of (±)-hirsutene ((±)-7) (10 steps, Scheme 2) and (±)-coriolin ((±)-2) this approach to the total synthesis of (±)-hirsutene ((±)-7) (10 steps, Scheme2) and ( ±)-coriolin ((±)-2) (17 steps, Scheme 3). (17 steps, Scheme3). The trimethylsilyl iodide-mediated rearrangement of a bicyclo[4.2.0]octane-2,5-dione to a bicyclo[3.3.0]-oct-1(6)-en-2-one, was achieved by Oda and co-workers, for a short synthesis of (±)- hirsutene ((±)-7) (Scheme 4) [53]. The photochemical reduction of a δ, ε-unsaturated ketone, was a key step to synthesize (±)- hirsutene ((±)-7), reported by Cossy and co-workers (Scheme 5) [54]. Majetich and co-workers achieved a synthesis of (±)-hirsutene ((±)-7), via the intramolecular addition of two functionalized cyclopentane rings, linked by a one-carbon tether (Scheme 6) [55]. In Franck-Neumann and co-workers’ approach to (±)-hirsutene ((±)-7) (Scheme 7), the key strategy was the region and stereospecific cleavage (134→135) of the central bond in the resulting bicyclo[2.1.0]-pentane moiety [56–58]. Sternbach and Ensinger achieved a highly efficient 20-step synthesis of (±)-hirsutene ((±)-7) (Scheme 8) [59]. An intramolecular Diels-Alder reaction of the substituted cyclopentadiene (136), which contains all but two of the carbon atoms found in hirsutene, serves as the key step in this sequence. Castro and co-workers accomplished an enantioselective formal synthesis of hirsutene (7), employing an asymmetric Pauson-Khand bicyclization [60] (Scheme 9).

Molecules 2018, 23, 2095 14 of 33

The trimethylsilyl iodide-mediated rearrangement of a bicyclo[4.2.0]octane-2,5-dione to a bicyclo[3.3.0]-oct-1(6)-en-2-one, was achieved by Oda and co-workers, for a short synthesis of (±)-hirsutene ((±)-7) (Scheme4)[53]. The photochemical reduction of a δ, ε-unsaturated ketone, was a key step to synthesize (±)-hirsutene ((±)-7), reported by Cossy and co-workers (Scheme5)[54]. Majetich and co-workers achieved a synthesis of (±)-hirsutene ((±)-7), via the intramolecular addition of two functionalized cyclopentane rings, linked by a one-carbon tether (Scheme6)[55]. In Franck-Neumann and co-workers’ approach to (±)-hirsutene ((±)-7) (Scheme7), the key strategy was the region and stereospecific cleavage (134→135) of the central bond in the resulting bicyclo[2.1.0]-pentane moiety [56–58]. Sternbach and Ensinger achieved a highly efficient 20-step synthesis of (±)-hirsutene ((±)-7) (Scheme8)[ 59]. An intramolecular Diels-Alder reaction of the substituted cyclopentadiene (136), which contains all but two of the carbon atoms found in hirsutene, serves as the key step in this sequence. Castro and co-workers accomplished an enantioselective formal synthesis of hirsutene (7), employing an asymmetric Pauson-Khand bicyclization [60] (Scheme9). Paquette and co-workers have achieved a total synthesis of (±)-hirsutene ((±)-7) in 9 steps and in 14% overall yield via a twofold cycloadditive scheme, utilizing an iodine catalyzed rearrangement of the methylenetricyclo[6.3.0.03,6]undecane derivative (138) into the norketone (139), a commonly used precursor of hirsutene (7)[61] (Scheme 10). In the formal synthesis of (±)-hirsutene ((±)-7), by Sarkar and co-workers [62–65] (Scheme 11), two key cyclopentannulation protocols, leading to the diquinane 141, were an efficient intramolecular ene reaction (140→141) and a titanium catalyzed epoxy-allylsilane cyclization (142→143). Then, 143 was further transformed to the 144, via the classical aldol condensation. Keith and co-workers [66] achieved a highly efficient total synthesis of (±)-hirsutene ((±)-7), by using dilithiomethane equivalent in a novel one-flask [2 + 1 + 2] cyclopentannulation reaction (Scheme 12). Toyota and co-workers developed a new, highly diastereocontrolled approach, for the synthesis of hirsutene (7), in which the key step utilized an acid catalyzed intramolecular conjugate addition (145→146), and a Pd2+-promoted highly stereocontrolled cyclization (147→148)[67] (Scheme 13). An efficient stereocontrolled synthesis of (±)-endo-hirsutene (149) was achieved, in which the key steps included intramolecular Diels-Alder, Paterno-Buchi reactions, and a reductive fragmentation [68]. (±)-Endo-hirsutene (149), earlier converted to (±)-hirsutene ((±)-7), was furnished from the deoxygenation of triquinane 154 (Scheme 14). Wang and Yu described a rhodium-catalyzed [5+2+1] cycloaddition of ene-vinylcyclopropanes and CO, and applied this method to synthesize (±)-hirsutene ((±)-7) (Scheme 15), (+)-hirsutene ((+)-7) (Scheme 16), 1-desoxyhypnophilin (155) (Scheme 17), and hirsutic acid C (1) (Scheme 18)[69]. A facile synthesis of the hirsutane framework was reported in 2002 [58]. This method was via a novel [6 + 2] cycloaddition of fulvenes with alkenes, as shown in Scheme 19. In 2002, Geng and co-workers presented a direct 10-step route from a squarate ester to hypnophilin (8)[70]. The access route involved a combination of chlorination, reduction, dehydration, and oxidation maneuvers in the proper sequence (Scheme 20). The first application of the squarate ester cascade to natural products synthesis, was realized by Paquette and Geng, in 2002 [71]. Only 10 laboratory steps were needed to achieve the conversion of diisopropyl squarate to hypnophilin (8) (Scheme 21). A penultimate precursor to 8, has previously been transformed to 2 (Scheme 22), thereby achieving a formal synthesis of racemic 2. A rather different strategy was employed to synthesize ceratopicanol (109) (Scheme 23). In 2013, Bon and co-workers accomplished the formal total syntheses of (−)-hypnophilin ((−)-8) and (−)-coriolin ((−)-2)[72]. In particular, they reported the synthesis of compound 159, an advanced intermediate related with previously reported syntheses of both compounds (−)-8 and Molecules 2018, 23, 2095 15 of 33

(−)-2. They attempted to prepare its methylated congener 160, and the generation of the isomeric tetracyclic system 161, representing a late-stage precursor to (−)-2 (Scheme 24). Bon and co-workers showed great interest in the synthesis of the linear triquinane sesquiterpenoids. In 2010, they reported a chemoenzymatic total synthesis of (+)-connatusin B ((+)-34) from toluene [73]. In this synthesis, the starting material employed the cis-1,2-dihydrocatechol (167), which was acquired in enantiomerically pure via the enzymatic dihydroxylation of toluene. Diels-Alder cycloaddition and oxa-di-π-methane rearrangement reactions, represented the key steps in the reaction sequence, leading to the cyclopropane ring-fused linear triquinane (172). Reductive cleavage of the three-membered ring within this framework and types of functional group interconversions, then provided (+)-connatusin B ((+)-34) (Scheme 25). In 2011, the researchers applied this work to the synthesis of (−)-connatusin A ((−)-33). Notably, the final step of this sequence required cleaving the acetate residue within compound 177, to reveal the corresponding alcohol, and they could not secure good yields of the final product. Eventually, after considerable experimentation, they found that the use of acidified DOWEX-50WX-100 resin in 5:1 v/v methanol at 65 ◦C for 18 h, showed the most effective result and provided a crystalline sample of (−)-connatusin A ((−)-33) in 84% yield (SchemeMolecules 2018 26)[, 2374, x]. 15 of 31

Molecules 2018, 23, x 15 of 31 Molecules 2018, 23, x 15 of 31

Scheme 1. The simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic Scheme 1. The simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal Schemesequence.metathetic 1. The sequence. simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic Scheme 1. The simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic sequence. sequence.

Scheme 2. The total synthesis of (±)-hirsutene ((±)-7). SchemeScheme 2.2. TheThe totaltotal synthesissynthesis ofof ((±)-hirsutene±)-hirsutene ((±)- ((±)-77).). H H Scheme 2. The Htotal synthesisH of (±)-hirsutene ((±)-7).H H H H H H H H H H H O O (±)-2 H H H O O O OH O OH (±)-2 (±)-2 128H O 130H O 131H O H O H OH H OH 128 130 OH 131 O 128 O Scheme 3. The total 130 synthesis of (±)-coriolin ((±)- 1312). OH 128 130 131 Scheme 3. The total synthesis of (±)-coriolin ((±)-2). SchemeScheme 3. 3.The Thetotal totalsynthesis synthesis of of ( ±(±)-coriolin)-coriolin ((((±)-±)-22).).

Scheme 4. The short synthesis of (±)-7.

Scheme 4. The short synthesis of (±)-7. SchemeScheme 4.4. TheThe shortshort synthesissynthesis ofof ((±)-±)-77..

Scheme 5. The synthesis of (±)-7 utilizing photochemical reduction.

Scheme 5. The synthesis of (±)-7 utilizing photochemical reduction. Scheme 5. The synthesis of (±)-7 utilizing photochemical reduction.

Scheme 6. The synthesis of (±)-7 via the intramolecular addition.

Scheme 6. The synthesis of (±)-7 via the intramolecular addition. Scheme 6. The synthesis of (±)-7 via the intramolecular addition.

Scheme 7. The synthesis of (±)-7 via the region and stereospecific cleavage.

Scheme 7. The synthesis of (±)-7 via the region and stereospecific cleavage. Scheme 7. The synthesis of (±)-7 via the region and stereospecific cleavage.

Molecules 2018, 23, x 15 of 31 Molecules 2018, 23, x 15 of 31 Molecules 2018, 23, x 15 of 31

Scheme 1. The simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic Scheme 1. The simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic sequence. Schemesequence. 1. The simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel photo-thermal metathetic sequence.

Scheme 2. The total synthesis of (±)-hirsutene ((±)-7). Scheme 2. The total synthesis of (±)-hirsutene ((±)-7). Scheme 2. The total synthesis of (±)-hirsutene ((±)-7). H H H H H H H H H H H H H H H O O (±)-2 H O H O H (±)-2 O H O O H OH O H OH (±)-2 O 128H O 130H OH 131H OH O 128 O 130 OH 131 OH 128 130 131 Scheme 3. The total synthesis of (±)-coriolin ((±)-2). Scheme 3. The total synthesis of (±)-coriolin ((±)-2). Scheme 3. The total synthesis of (±)-coriolin ((±)-2).

Molecules 2018, 23, 2095 16 of 33 Scheme 4. The short synthesis of (±)-7. Scheme 4. The short synthesis of (±)-7. Scheme 4. The short synthesis of (±)-7.

Scheme 5. The synthesis of (±)-7 utilizing photochemical reduction. SchemeScheme 5.5. TheThe synthesissynthesis ofof ((±)-±)-77 utilizingutilizing photochemical photochemical reduction. reduction. Scheme 5. The synthesis of (±)-7 utilizing photochemical reduction.

Scheme 6. The synthesis of (±)-7 via the intramolecular addition. Scheme 6. The synthesis of (±)-± 7 via the intramolecular addition. SchemeScheme 6.6. The synthesis ofof ((±)-)-77 viavia the the intramolecular intramolecular addition. addition.

Scheme 7. The synthesis of (±)-7 via the region and stereospecific cleavage. Scheme 7. The synthesis of (±)-7 via the region and stereospecific cleavage. Scheme 7. The synthesis of (±)-± 7 via the region and stereospecific cleavage. Molecules 2018, 23, x Scheme 7. The synthesis of ( )-7 via the region and stereospecific cleavage. 16 of 31 Molecules 2018, 23, x 16 of 31 Molecules 2018, 23, x 16 of 31

Scheme 8. The highly efficient synthesis of (±)-7. SchemeScheme 8.8. TheThe highlyhighly efficientefficient synthesissynthesis ofof ((±)-±)-7.. Scheme 8. The highly efficient synthesis of (±)-7.

Scheme 9. The enantioselective formal synthesis of hirsutene (7). Scheme 9. The enantioselective formal synthesis of hirsutene (7). SchemeScheme 9. 9. TheThe enantioselective enantioselective formal formal synthesis synthesis of of hirsutene hirsutene (7 (7).).

Scheme 10. The total synthesis of (±)-7 via a twofold cycloaddition. Scheme 10. The total synthesis of (±)-7 via a twofold cycloaddition. SchemeScheme 10. 10. TheThe total total synthesis synthesis of of (±)- (±7)- 7viavia a atwofold twofold cycloaddition. cycloaddition. TMS TMS TMS O TMS H TMS H TMS H H O TMS H TMS H TMS H H H HO H H H H H H (±)-7 H H OH (±)-7 O (±)-7 OH H COOEt H COOEt H O OH H COOEt H COOEt H O H H H H 140COOEt H 141COOEt H 142 H 143 H H 144H 140 141 142 H 143 H 144 140 141 142 143 144 Scheme 11. The formal synthesis of (±)-7 via an intramolecular ene reaction and a titanium catalyzed Scheme 11. The formal synthesis of (±)-7 via an intramolecular ene reaction and a titanium catalyzed Schemeepoxy-allylsilane 11. The formal cyclization. synthesis of (±)-7 via an intramolecular ene reaction and a titanium catalyzed epoxy-allylsilane cyclization. epoxy-allylsilane cyclization.

Scheme 12. The total synthesis of (±)-7 via a novel one-flask [2+1+2] cyclopentannulation reaction. Scheme 12. The total synthesis of (±)-7 via a novel one-flask [2+1+2] cyclopentannulation reaction. Scheme 12. The total synthesis of (±)-7 via a novel one-flask [2+1+2] cyclopentannulation reaction.

Scheme 13. The synthesis of 7 utilizing an acid catalyzed intramolecular conjugate addition and a Scheme 13. The synthesis of 7 utilizing an acid catalyzed intramolecular conjugate addition and a SchemePd2+-promoted 13. The highlysynthesis stereocontrolled of 7 utilizing cyclization.an acid catalyzed intramolecular conjugate addition and a Pd2+-promoted highly stereocontrolled cyclization. Pd2+-promoted highly stereocontrolled cyclization.

Molecules 2018, 23, x 16 of 31 Molecules 2018, 23, x 16 of 31 Molecules 2018, 23, x 16 of 31

Scheme 8. The highly efficient synthesis of (±)-7. Scheme 8. The highly efficient synthesis of (±)-7. Scheme 8. The highly efficient synthesis of (±)-7.

Scheme 9. The enantioselective formal synthesis of hirsutene (7). Scheme 9. The enantioselective formal synthesis of hirsutene (7). Scheme 9. The enantioselective formal synthesis of hirsutene (7).

Molecules 2018, 23, 2095 17 of 33

Scheme 10. The total synthesis of (±)-7 via a twofold cycloaddition. Scheme 10. The total synthesis of (±)-7 via a twofold cycloaddition. Scheme 10. The total synthesis of (±)-7 via a twofold cycloaddition. TMS TMS TMS O TMS H TMS H TMS H H O TMS H TMS H TMS H H H H O H H H H H H (±)-7 H H OH (±)-7 O (±)-7 COOEt H COOEt H O OH H H COOEt H COOEt H O H H OH H H 140COOEt H 141COOEt H 142 H 143 H H 144 H 140 141 142 H 143 H 144 140 141 142 143 144 Scheme 11.11. The formal synthesis ofof ((±)-±)-77 viavia an an intramolecular intramolecular ene reac reactiontion and a titanium catalyzed Scheme 11. The formal synthesis of (±)-7 via an intramolecular ene reaction and a titanium catalyzed Schemeepoxy-allylsilane 11. The formal cyclization.cyclization. synthesis of (±)-7 via an intramolecular ene reaction and a titanium catalyzed epoxy-allylsilane cyclization. epoxy-allylsilane cyclization.

Scheme 12. The total synthesis of (±)-7 via a novel one-flask [2+1+2] cyclopentannulation reaction. Scheme 12. The total synthesis of (±)-7 via a novel one-flask [2+1+2] cyclopentannulation reaction. SchemeScheme 12.12. TheThe totaltotal synthesissynthesis ofof ((±)-±)-77 viavia a a novel novel one-flask one-flask [2+1+2] [2+1+2] cyclopentannulation cyclopentannulation reaction. reaction.

Scheme 13. The synthesis of 7 utilizing an acid catalyzed intramolecular conjugate addition and a Scheme2+ 13. The synthesis of 7 utilizing an acid catalyzed intramolecular conjugate addition and a SchemePd -promoted 13. The highly synthesis stereocontrolled of 7 utilizing cyclization. an acid catalyzed intramolecular conjugate addition and a SchemePd2+-promoted 13. The highly synthesis stereocontrolled of 7 utilizing cyclization. an acid catalyzed intramolecular conjugate addition and a Pd2+-promoted-promoted highly highly stereocontrolled stereocontrolled cyclization. cyclization. MoleculesMolecules 2018 2018, ,23 23, ,x x 1717 ofof 3131

OO HH HH HH HH

O O HH HH OH OH OO OO 150 151 152 153 154 149 150 151 152 153 154 149

SchemeScheme 14. 14. The TheThe stereocontrolled stereocontrolled stereocontrolled synthesis synthesis of of (±)-endo-hirsutene (±)-endo-hirsutene (±)-endo-hirsutene ( (149149 (149)) via )via via intramolecular intramolecular intramolecular Diels-Alder, Diels-Alder, Diels-Alder, Paterno-BuchiPaterno-Buchi reactions reactions and and a a reductive reductive fragmentation. fragmentation.

OO HH OHOH HH OO COCO22MeMe [Rh(CO)[Rh(CO)22Cl]Cl]22 (7 (7 mol mol %) %) 1 atm CO/N (1:4,V/V) 1 atm CO/N22 (1:4,V/V) (±)-(±)-77 1,4-dioxane1,4-dioxane (0.025M), (0.025M), 80 80 °C °C 62%62% HH OTBSOTBS OO HH OO SchemeScheme 15. 15. The The synthesis synthesis of of (±)- (±)-77. . Scheme 15. The synthesis of (±)-7.

OO OO H [Rh(CO)[Rh(CO)22Cl]Cl]22 (5 (5 mol mol %) %) HH H 11 atm atm CO/N CO/N22 (1:4,V/V) (1:4,V/V) (+)-(+)-77 1,4-dioxane1,4-dioxane (0.05M), (0.05M), 90 90 °C °C 65%65% HH HH OO SchemeScheme 16. 16. The The synthesis synthesis of of (+)-hirsutene (+)-hirsutene ((+)- ((+)-77).).

HH OHOH HH OHOH HH HH OO (COCl) ,DMSO HH (COCl)22,DMSO OO OO HH HH HH HH HH 155 OO 155 SchemeScheme 17. 17. The The synthesis synthesis of of 1-desoxyhypnophilin 1-desoxyhypnophilin ( (155155).).

HH OHOH

MeOMeO22CC

[Rh(CO)[Rh(CO)22Cl]Cl]22 (10 (10 mol mol %) %) HH OHOH MeOMeO22CC HH 1atm1atm CO/N CO/N(1:4,(1:4, V/V) V/V) 22 156156 OO 1,4-dioxane1,4-dioxane (0.02M), (0.02M), 80°C 80°C MeOMeO22CC thenthen HCl, HCl, MeOH/H MeOH/HOO 22 H OH H OTBSOTBS 65%,65%, 154/155=1.5:1 154/155=1.5:1 H OH H 158158 HH MeOMeO22CC HH MeOMeO22CC 11 OO OO 157157 HH

SchemeScheme 18. 18. The The synthesis synthesis of of hirs hirsuticutic acid acid C C ( (11).).

SchemeScheme 19. 19. The The facile facile synthesis synthesis of of the the hirsutane hirsutane framework. framework.

Molecules 2018, 23, x 17 of 31 Molecules 2018, 23, x 17 of 31 Molecules 2018, 23, x 17 of 31 Molecules 2018, 23, x 17 of 31 O H H H H O H H H H O H H H H O H H H H O H H O H H OH O O OH O H H O O O H H 150 OH O 151 O 152 153 154 149 150 OH 151 152 153 154 149 150 O 151 O 152 153 154 149 150 151 152 153 154 149 Scheme 14. The stereocontrolled synthesis of (±)-endo-hirsutene (149) via intramolecular Diels-Alder, Scheme 14. The stereocontrolled synthesis of (±)-endo-hirsutene (149) via intramolecular Diels-Alder, SchemePaterno-Buchi 14. The reactions stereocontrolled and a reductive synthesis fragmentation. of (±)-endo-hirsutene (149) via intramolecular Diels-Alder, SchemePaterno-Buchi 14. The reactions stereocontrolled and a reductive synthesis fragmentation. of (±)-endo-hirsutene (149) via intramolecular Diels-Alder, Paterno-Buchi reactions and a reductive fragmentation. Paterno-Buchi reactions and a reductive fragmentation. O O O H OH H OH H O O CO2Me [Rh(CO)2Cl]2 (7 mol %) H OH H O CO2Me [Rh(CO) Cl] (7 mol %) O CO2Me 1 atm CO/N2 2 2(1:4,V/V) H OH H 1[Rh(CO) atm CO/N2Cl] 2(1:4,V/V) (7 mol %) H O CO2Me(±)-7 1,4-dioxane[Rh(CO) Cl] (0.025M),2 (7 mol %)80 °C (±)-7 1 atm CO/N2 2 2(1:4,V/V) (±)-7 1,4-dioxane1 atm CO/N (0.025M),62% (1:4,V/V) 80 °C H OTBS1,4-dioxane (0.025M),62%2 80 °C H O H (±)-7 OTBS1,4-dioxane (0.025M),62% 80 °C H O H O OTBS O H O Molecules 2018, 23, 2095 62% H O 18 of 33 OTBS Scheme 15. The synthesisO of (±)-7. H Scheme 15. The synthesis of (±)-7. O Scheme 15. The synthesis of (±)-7. Scheme 15. The synthesisO of (±)-7. O O O [Rh(CO)2Cl]2 (5 mol %) H H O [Rh(CO) Cl] (5 mol %) H O H 1 atm CO/N2 2 2(1:4,V/V) H O 1[Rh(CO) atm CO/N2Cl] 2(1:4,V/V) (5 mol %) H O [Rh(CO) Cl]2 (5 mol %) H (+)-7 1,4-dioxane1 atm CO/N2 (0.05M),2 2(1:4,V/V) 90 °C H (+)-7 1,4-dioxane1 atm CO/N (0.05M),65%2 (1:4,V/V) 90 °C (+)-7 1,4-dioxane (0.05M),65% 90 °C (+)-7 1,4-dioxane (0.05M), 90 °C H H 65% H H O 65% H H O H H O Scheme 16. The synthesis of (+)-hirsutene ((+)-7). SchemeScheme 16.16. TheThe synthesissynthesis ofof (+)-hirsutene(+)-hirsutene ((+)-7). O Scheme 16. The synthesis of (+)-hirsutene ((+)-7). H OH SchemeH 16.OH The synthesis of (+)-hirsuteneH ((+)-7). H O H OH H OH H H O H OH H OH H H O H (COCl)2,DMSO H OH H OH (COCl) ,DMSO H H O H 2 O O H (COCl)2,DMSO H H O H O H H HH (COCl)2,DMSO O O H O H H H155 H H O H155 O H O H H H O H H H155 Scheme 17. The synthesis of 1-desoxyhypnophilin (155). 155 O Scheme 17. The synthesis of 1-desoxyhypnophilin (155). Scheme 17. The synthesis of 1-desoxyhypnophilin ( 155). Scheme 17. The synthesis of 1-desoxyhypnophilinH OH (155). H OH H OH MeO2C H OH MeO2C [Rh(CO)2Cl]2 (10 mol %) MeO C H OH MeO2C 2 H [Rh(CO)2Cl]2 (10 mol %) MeO C H OH MeO2C 1atm CO/N2 (1:4, V/V) 2 H MeO C [Rh(CO)2Cl]2 (10 mol %) 156 O H OH 2 [Rh(CO)1atm CO/NCl]2 (1:4,(10 mol V/V) %) H O MeO C 1atm CO/N2 22 (1:4, V/V) 156 MeO2C H OH 2 1,4-dioxane (0.02M), 80°C 156H O MeO C 1atm1,4-dioxane CO/N2 (0.02M),(1:4, V/V) 80°C 2 then HCl, MeOH/H2O O MeO C 1,4-dioxanethen HCl, (0.02M), MeOH/H 80°CO H156 OH 2 H OTBS1,4-dioxanethen65%, HCl, 154/155=1.5:1 (0.02M), MeOH/H 80°C2O H OH MeO2C H OTBS 65%, 154/155=1.5:12 H OH H158 OTBS then65%, HCl, 154/155=1.5:1 MeOH/H2O 158 OTBS H 65%, 154/155=1.5:1 MeO2C H OH H158 H MeO2C H MeO2C 158 MeO C H MeO2C H 1 2 H O MeO2C 1 H MeO C O 1 157 O 2 H O H157 O MeO2C H O 1 157 O H O 157 H Scheme 18. The synthesis of hirsutic acid C (1). Scheme 18. The synthesis of hirsutic acid C (1). Scheme 18. The synthesis of hirsutic acid C (1). Scheme 18. The synthesis of hirs hirsuticutic acid C (1).

Scheme 19. The facile synthesis of the hirsutane framework. Scheme 19. The facile synthesis of the hirsutane framework. Scheme 19. The facile synthesis of the hirsutane framework. Scheme 19. The facile synthesis of the hirsutane framework. Molecules 2018, 23, x Scheme 19. The facile synthesis of the hirsutane framework. 18 of 31

Scheme 20. The synthesis of hypnophilin (8) via a combination of chlorination, reduction, Scheme 20. The synthesis of hypnophilin (8) via a combination of chlorination, reduction, dehydration anddehydration oxidation and maneuvers. oxidation maneuvers.

O H H H i-PrO O

i-PrO i-PrO O 8 H i-PrO O OH H i-PrO O OMOM OH OH Scheme 21. The conversion of diisopropyl squarate to 8.

Scheme 22. The formal synthesis of racemic coriolin (2).

H O H i-PrO O O

i-PrO 109 i-PrO i-PrO O OH i-PrO Scheme 23. The synthesis of ceratopicanol (109).

Scheme 24. The synthesis of compound 159, an advanced intermediate of both compounds (−)-8 and (−)-2 and the synthesis of the isomeric tetracyclic system 161, a late-stage precursor to (−)-2.

Scheme 25. The synthesis of (+)-connatusin B ((+)-34) via reductive cleavage of the three-membered ring within this framework and kinds of functional group interconversions.

Molecules 2018, 23, x 18 of 31 Molecules 2018, 23, x 18 of 31 Molecules 2018, 23, x 18 of 31 Molecules 2018, 23, x 18 of 31 Molecules 2018, 23, x 18 of 31

MoleculesScheme2018, 2320., 2095 The synthesis of hypnophilin (8) via a combination of chlorination, reduction,19 of 33 Scheme 20. The synthesis of hypnophilin (8) via a combination of chlorination, reduction, Schemedehydration 20. andThe ox synthesisidation maneuvers. of hypnophilin (8) via a combination of chlorination, reduction, dehydrationScheme 20. andThe ox synthesisidation maneuvers. of hypnophilin (8) via a combination of chlorination, reduction, Schemedehydration 20. andThe ox synthesisidation maneuvers. of hypnophilin (8) via a combination of chlorination, reduction, dehydration and oxidationO maneuvers.H H H dehydrationi-PrO O and oxidationO maneuvers.H H H i-PrO O O H H H i-PrO O O H H H 8 i-PrO H i-PrO O H i-PrO O i-PrOO H O H 8 i-PrO O OH i-PrO H i-PrO O i-PrOi-PrO OH O i-PrO H OMOM O H OH 8 i-PrO O i-PrOi-PrO O OH O H OH 8 i-PrO O OH i-PrO H OMOM 8 i-PrOi-PrO OH O OH i-PrO H OMOM O H OH i-PrO O i-PrO OH H OH i-PrO O SchemeOH 21.O The conversion of diisopropylH OMOM squarate to 8. i-PrOScheme 21.O The conversion OH of diisopropylOMOM squarate to 8. OH Scheme 21. The conversionOH of diisopropyl squarate to 8. Scheme 21. The conversion of diisopropyl squarate to 8. Scheme 21. The conversion of diisopropyl squarate to 8.

Scheme 22. The formal synthesis of racemic coriolin (2). Scheme 22. The formal synthesis of racemic coriolin (2). Scheme 22. The formal synthesis of racemic coriolin (2).). SchemeO 22. The formalH synthesis of racemic coriolin (2). Scheme 22. The formalH synthesis of racemicO coriolin (2H). i-PrO O O H i-PrO O O H O H O H i-PrO O i-PrO O H 109 O H i-PrO O i-PrO O i-PrO OH O H 109 i-PrOi-PrO O i-PrOi-PrO i-PrO 109 i-PrO O OH i-PrOi-PrO OH i-PrO 109 i-PrO O i-PrOi-PrO i-PrO 109 i-PrO O Scheme 23.OH The synthesis of ceratopicanoli-PrO (109). i-PrO O Schemei-PrO 23.OH The synthesis of ceratopicanol (109). Schemei-PrO 23. The synthesis of ceratopicanol (109). Scheme 23. The synthesis of ceratopicanol (109109).). Scheme 23. The synthesis of ceratopicanol (109).

Scheme 24. The synthesis of compound 159, an advanced intermediate of both compounds (−)-8 and Scheme 24. The synthesis of compound 159, an advanced intermediate of both compounds (−)-8 and Scheme(−)-2 and 24. the The synthesis synthesis of theof compound isomeric tetracyclic 159, an advanced system 161 intermediate, a late-stage of precursor both compounds to (−)-2 . (−)-8 and (Scheme−)-2 and 24. the The synthesis synthesis of the of compoundisomeric tetracyclic 159, an advanced system 161 intermediate, a late-stage of precursor both compounds to (−)-2. (−)-8 and Scheme(−)-2 and 24. the The synthesis synthesis of the of compound isomeric tetracyclic 159,, anan advancedadvanced system 161 intermediateintermediate, a late-stage ofof precursor bothboth compoundscompounds to (−)-2. ( (−−)-8 and (−−)-2 and the synthesis of the isomeric tetracyclic system 161, a late-stage precursor to (−)-2. (−)-)-22 andand the the synthesis synthesis of of the the isomeric isomeric tetracyclic tetracyclic system system 161161,, a a late-stage late-stage precursor precursor to to ( (−)-)-22. .

Scheme 25. The synthesis of (+)-connatusin B ((+)-34) via reductive cleavage of the three-membered Scheme 25. The synthesis of (+)-connatusin B ((+)-34) via reductive cleavage of the three-membered Schemering within 25. thisThe frameworksynthesis of and (+)-connatusin kinds of functional B ((+)-34 group) via reductiveinterconversions. cleavage of the three-membered ringScheme within 25. thisThe framework synthesis of and (+)-connatusin kinds of functional B ((+)-34 group) via reductiveinterconversions. cleavage of the three-membered Schemering within 25. thisThe frameworksynthesis of and (+)-connatusin kinds of functional B ((+)-34 group) via reductiveinterconversions. cleavage of the three-membered Schemering within 25. thisThe framework synthesis of and (+)-connatusin kinds of functional B ((+)-34 group) via reductiveinterconversions. cleavage of the three-membered ring within this framework and kinds of functional group interconversions. ring within this framework and kinds of functional group interconversions.

Molecules 2018, 23, 2095 20 of 33 Molecules 2018, 23, x 19 of 31 Molecules 2018, 23, x 19 of 31

Scheme 26. The synthesis of (−)-connatusin A ((−)-33). SchemeScheme 26.26. TheThe synthesissynthesis ofof ((−−)-connatusin)-connatusin A (( −)-)-3333).). 4.2. Capnellene Type 4.2. Capnellene Capnellene Type Capnellene is one of the most popular targets for synthesis, mainly owing to its molecular Capnellene is one of the most popular targets for synthesis, mainly owing to its molecular architecture, exocyclic olefinic linkage, disposition of methyl groups, and its role in the defense architecture, exocyclic olefinic olefinic linkage, dispositio dispositionn of of methyl methyl groups, groups, and and its its role role in the defense mechanism and biosynthesis of oxygenated capnellenes [75], especially (±)-∆9(12)-capnellene (178), mechanism and biosynthesisbiosynthesis ofof oxygenatedoxygenated capnellenescapnellenes [75[75],], especially especially ( ±(±)-)-∆∆9(12)9(12)-capnellene-capnellene ( (178178),), ∆9(12)-capnellene (179), (−)-∆9(12)-capnellene (180), and (+)-∆9(12)-capnellene (181) (Figure 8). The first ∆9(12)9(12)-capnellene-capnellene ( (179179),), ( (−−)-)-∆∆9(12)9(12)-capnellene-capnellene (180 (180), ),and and (+)- (+)-∆∆9(12)9(12)-capnellene-capnellene (181 (181) )(Figure (Figure 8).8). The firstfirst total synthesis of (±)-∆9(12)-capnellene (178), was reported in 1981 [76]. total synthesis of (±)- (±)-∆∆9(12)9(12)-capnellene-capnellene (178 (178), ),was was reported reported in in 1981 1981 [76]. [76 ].

Figure 8. Structures of compounds 178–181. Figure 8. StructuresStructures of compounds 178–181. Stille and Grubbs [77] realized the synthesis of (±)-∆9(12)-capnellene (178) by using titanium Stille and Grubbs [77] realized the synthesis of (±)-∆9(12)-capnellene (178) by using titanium reagentsStille (Scheme and Grubbs 27). Stille [77] realizedand co-worke the synthesisrs [78] achieved of (±)-∆ 9(12)the-capnellene total synthesis (178 )of by 178, using through titanium the reagents (Scheme 27). Stille and co-workers [78] achieved the total synthesis of 178, through the reagentsrearrangement (Scheme of 27bicyclo[2.2.1]heptane). Stille and co-workers ring [sy78stems] achieved by titanocene the total synthesisalkylidene of complexes178, through to rearrangement of bicyclo[2.2.1]heptane ring systems by titanocene alkylidene complexes to thebicyclo[3.2.0]heptane rearrangement of enol bicyclo[2.2.1]heptane ethers (Scheme 28). ring A new systems synthetic by titanocenestrategy for alkylidene(±)-∆9(12)-capnellene complexes (178 to) bicyclo[3.2.0]heptane enol ethers (Scheme 28). A new synthetic strategy for (±)-∆9(12)-capnellene (178) bicyclo[3.2.0]heptaneand (±)-∆9(12)-capnellene-8 enolβ,10 ethersα-diol (Scheme (182), was 28). presented A new synthetic in 1992 [79]. strategy This strategy for (±)- ∆was9(12) presented-capnellene as and (±)-∆9(12)-capnellene-8β,10α-diol (182), was presented in 1992 [79]. This strategy was presented as (a178 model) and study (±)-∆ in9(12) the-capnellene-8 synthesis ofβ ,10theα -diolpentalanic (182), trimethylketone, was presented in which 1992 [has79]. been This used strategy as a waskey a model study in the synthesis of the pentalanic trimethylketone, which has been used as a key presentedintermediate as ain model the total study synthesis in the synthesis of both 178 of theand pentalanic 182 (Scheme trimethylketone, 29). which has been used as intermediate in the total synthesis of both 178 and 182 (Scheme 29). a keyIt intermediate was worth inmentioning the total synthesis that although of both palladium178 and 182 catalyzed(Scheme zipper 29). mode cyclization, using It was worth mentioning that although palladium catalyzed zipper mode cyclization, using HeckIt reaction was worth conditions mentioning had thatcaused although widespread palladium concern catalyzed for the zipper construction mode cyclization, of polycyclic using system, Heck Heck reaction conditions had caused widespread concern for the construction of polycyclic system, reactionthis methodology conditions was had not caused suitable widespread for the required concern cis for-anti the-cis constructionstereochemistry ofpolycyclic of the capnellane system, this methodology was not suitable for the required cis-anti-cis stereochemistry of the capnellane thissystem methodology [61]. However, was notin suitable1994 Genevieve for the requiredBalme achievedcis-anti-cis thestereochemistry total synthesis of of the 178, capnellane using a system [61]. However, in 1994 Genevieve Balme achieved the total synthesis of 178, using a systempalladium-catalyzed [61]. However, bis-cyclization in 1994 Genevieve step [80]. Balme Functionalized achieved the totaldiquinanes synthesis were of 178easily, using and a palladium-catalyzed bis-cyclization step [80]. Functionalized diquinanes were easily and palladium-catalyzedstereoselectively gained bis-cyclization from a new step palladium [80]. Functionalized catalyzed cyclisation diquinanes 183 were→186 easily (Scheme and stereoselectively 30). Applying stereoselectively gained from a new palladium catalyzed cyclisation 183→186 (Scheme 30). Applying gainedthe intramolecular from a new palladiumversion of catalyzedthis strategy, cyclisation a triquina183→ne186 should(Scheme be directly 30). Applying obtained the in intramolecular a single step, the intramolecular version of this strategy, a triquinane should be directly obtained in a single step, versionby construction of this strategy, of the two a triquinane outer rings should around be directlythe central obtained ring (Scheme in a single 31). step, by construction of the by construction of the two outer rings around the central ring (Scheme 31). two outerIn 1997, rings Singh around and the co-workers central ring [81] (Scheme developed 31). a novel synthesis of capnellene from p-cresol and In 1997, Singh and co-workers [81] developed a novel synthesis of capnellene from p-cresol and cyclopentadiene,In 1997, Singh the and key co-workerssteps of the [synthesis81] developed were ainverse novel demand synthesis Diels-Alder of capnellene reaction from and p-cresol oxa- cyclopentadiene, the key steps of the synthesis were inverse demand Diels-Alder reaction and oxa- anddi-π-methane cyclopentadiene, rearrangement the key [74]. steps Th ofey the also synthesis developed were a inverse novel and demand efficient Diels-Alder total synthesis reaction of and178 di-π-methane rearrangement [74]. They also developed a novel and efficient total synthesis of 178 oxa-di-from p-cresolπ-methane employing rearrangement π4s + [ 74π].2s Theycycloaddition also developed of spiroepoxycyclohexa-2,4-dienone a novel and efficient total synthesis and from p-cresol employing π4s + π2s cycloaddition of spiroepoxycyclohexa-2,4-dienone and ofphotochemical178 from p-cresol 1,2-acyl employing shift, as keyπ4s features+ π2s cycloaddition (Scheme 32). of spiroepoxycyclohexa-2,4-dienone and photochemical 1,2-acyl shift, as key features (Scheme 32). photochemicalIn 2009, Nguyen 1,2-acyl and shift, co-workers as key features [82] presente (Schemed a 32 general). route to a formal synthesis of 178. This In 2009, Nguyen and co-workers [82] presented a general route to a formal synthesis of 178. This cascadeIn 2009,strategy, Nguyen combined and co-workers an intramolecular [82] presented Diels-Alder a general reaction route tandem to a formal metathesis synthesis protocol of 178 to. cascade strategy, combined an intramolecular Diels-Alder reaction tandem metathesis protocol to Thisproduce cascade the linear strategy, cis- combinedanti-cis-tricyclo[6.3.0.0 an intramolecular2,6]undecane Diels-Alder skeleton reaction directly tandem (Scheme metathesis 33). protocol to produce the linear cis-anti-cis-tricyclo[6.3.0.02,6]undecane skeleton directly (Scheme 33). produceIn 2009, the linearHsu andcis- antico-workers-cis-tricyclo[6.3.0.0 [83] developed2,6]undecane an efficient skeleton and short directly route (Scheme from 2-methoxyphenols 33). In 2009, Hsu and co-workers [83] developed an efficient and short route from 2-methoxyphenols to polyfunctionalized linear triquinanes, which was characterized by the photochemistry of to polyfunctionalized linear triquinanes, which was characterized by the photochemistry of tricyclo[5.2.2.02,6]undeca-4,10-dien-8-ones. They successfully applied this methodology to the total tricyclo[5.2.2.02,6]undeca-4,10-dien-8-ones. They successfully applied this methodology to the total

Molecules 2018, 23, 2095 21 of 33

In 2009, Hsu and co-workers [83] developed an efficient and short route from 2-methoxyphenols to polyfunctionalized linear triquinanes, which was characterized by the photochemistry of tricyclo[5.2.2.02,6]undeca-4,10-dien-8-ones. They successfully applied this methodology to the total synthesis of 178, in nine steps, with 20% overall yield by using the strategy of masked o-benzoquinone chemistry (Scheme 34). In 2013, Shen and Li [84] achieved dual total syntheses of (±)-hirsutene ((±)-7) and (±)-capnellene (178), via a formal [3 + 2] annulation strategy. In this synthesis, the key bifunctional synthons were the cyclic homoiodo allylsilanes, which were readily prepared from the corresponding cyclopropanated cyclopentenones (Scheme 35). In 1983, a total synthesis of ∆9(12)-capnellene (179) was described by Little and co-workers [85]. They used an intramolecular 1,3-diyl trapping reaction as a primary strategy, to achieve this objective. That ketone 188 corresponded to the desired cis, anti, cis ring-fused product and was confirmed unambiguously by converting it to 179 with a simple Wittig reaction (Scheme 36). In 1984, a stereocontrolled total synthesis of 179, in 8 steps, from bicyclic enone (189) in 8.3% overall yield was reported (Scheme 37)[86]. Crisp and co-workers [87] developed a method for palladium-catalyzed carbonylative coupling of vinyl triflates with organostannanes, and this methodology was applied to the total synthesis of the 179. The approach to 179 was based on two intermediates, 190 and 191, which were envisioned as arising from a carbonylative coupling of a vinyl triflate with vinylstannane (Scheme 38). New type of fulvenes undergo cycloadditions regioselectively to produce synthetically useful tricyclopentanoids, and a formal synthesis of 179 was reported by Ying Wang and co-workwers (Scheme 39)[88]. A direct stereocontrolled route to construct cyclopentanones with substituents up to three contiguous chiral centres, had been achieved in 1998 [89], and this approach was applied in the formal synthesis of 179 (Scheme 40). In 2009, Lemiere found that cyclopentenylidene gold complexes could be easily formed from vinyl allenes, through a Nazarovlike mechanism. At the same time, polycyclic frameworks may be converted from such carbenes in four different ways [90]: Electrophilic cyclopropanation, C-H insertion, C-C migration, or proton shift. They have studied the selectivity of these different pathways and used their findings to synthesize 179 (Scheme 41). A formal asymmetric synthesis of (−)-capnellene (180) was achieved in 1991, based on the photoinduced vinyl-cyclopropane−cyclopentene rearrangement of the bicyclic alcohol 193, which was obtained from (+)-3-carene (192) (Scheme 42)[91,92]. In 1994, Asaoka and co-workers [93] achieved a formal synthesis of 180 by employing silyl group directed stereo control, starting from (−)-2-methyl-4-trimetylsilyl-2-cyclopenten-l-one (194) (Scheme 43). They also noted that compound 194, could be an advanced intermediate in the synthesis of more complex triquinanes. In 1996, Tanaka and Ogasawara reported [94] the first stereocontrolled synthesis of 180, starting from (−)-oxodicyclopentadiene (195). This synthesis was based on the structure and high functionality of the starting material, which resulted in the stereoselective construction of the requisite stereogenic centres on the triquinane framework easily (Scheme 44). The first asymmetric Heck reaction-carbanion capture process was accomplished in 1996, by Ohshima et al. [95]. They achieved the first catalytic asymmetric total synthesis of 180, in 19 steps, and in 20% overall yield, by using 196 as an asymmetric building block (Scheme 45). The first asymmetric total synthesis of the unnatural enantiomer of (+)-∆9(12)-capnellene (181) was achieved by Meyers and Bienz, on the basis of the chiral nonracemic bicyclic lactam 197 derived from inexpensive (S)-valinol and levulinic acid (Scheme 46)[96]. The first total syntheses of ∆9(12)-capnellene-8β,10α-diol (87) and ∆9(12)-capnellene-3β,8β, 10α-troil (88), was achieved by Shibasaki and co-workers [97] (Scheme 47). Molecules 2018, 23, 2095 22 of 33

Kagechika and Shibasaki [98] accomplished a catalytic asymmetric synthesis of the key intermediates 198 and 199, for the capnellenols by an asymmetric Heck reaction, followed by an anion capture process. Furthermore, an improved synthetic route to (+)-capnellenols was developed, which led to the synthesis of ∆9(12)-capnellene-8β,10α-diol (87) and ∆9(12)-capnellene-3β,8β,10α-troil

(MoleculesMolecules88) (Scheme 20182018,, 23 2348,, x).x 2121 ofof 3131 Molecules 2018,, 23,, xx 21 of 31

9(12) SchemeScheme 27.27. TheThe synthesissynthesis ofof ± (±)-(±)-∆∆9(12)9(12)-capnellene-capnellene ((178178)) byby usingusing titaniumtitanium reagents.reagents. SchemeScheme 27. 27.The The synthesis synthesis of of ( (±)-)-∆9(12)9(12)-capnellene-capnellene (178 (178) )by by using using titanium titanium reagents. reagents.

O COOEt O O O TsOTsO COOEt H O HH O HH O TsO COOEt HO H O H H OO H H OO O 178178 O 178 HH HH HH H H H

SchemeScheme 28.28. TheThe totaltotal synthesissynthesis ofof 178178 throughthrough thethe rearrangementrearrangement ofof bicyclo[2.2.1]heptanebicyclo[2.2.1]heptane ringring Scheme 28. The total synthesis of 178 throughthrough thethe rearrangementrearrangement ofof bicyclo[2.2.1]heptanebicyclo[2.2.1]heptane ringring Schemesystems.systems. 28. The total synthesis of 178 through the rearrangement of bicyclo[2.2.1]heptane ring systems. systems.

SchemeScheme 29.29. TheThe totaltotal synthesissynthesis ofof bothboth 178178 andand 182182.. Scheme 29. The total synthesis of both 178 andand 182..

SchemeScheme 30.30. TheThe synthesissynthesis ofof 186186 fromfrom aa newnew palladiumpalladium catalyzedcatalyzed cyclisation.cyclisation. Scheme 30. TheThe synthesis synthesis of 186 fromfrom a a new new palladium palladium catalyzed catalyzed cyclisation. cyclisation.

SchemeScheme 31.31. TheThe totaltotal synthesissynthesis ofof 178178 usingusing aa palladium-catalyzedpalladium-catalyzed bis-cyclizationbis-cyclization step.step. Scheme 31. The total synthesis of 178 using a palladium-catalyzed bis-cyclizationbis-cyclization step.step.

Molecules 2018, 23, x 21 of 31

Scheme 27. The synthesis of (±)-∆9(12)-capnellene (178) by using titanium reagents.

COOEt O TsO H O H O H O O 178

H H H

Scheme 28. The total synthesis of 178 through the rearrangement of bicyclo[2.2.1]heptane ring systems.

Scheme 29. The total synthesis of both 178 and 182.

Molecules 2018, 23, 2095 23 of 33 Scheme 30. The synthesis of 186 from a new palladium catalyzed cyclisation.

Scheme 31. The total synthesis of 178 using a palladium-catalyzed bis-cyclization step. MoleculesScheme 2018, 23, x 31. The total synthesis of 178 using a palladium-catalyzed bis-cyclization step.22 of 31

Molecules 2018, 23, x 22 of 31 Molecules 2018, 23, x 22 of 31 Molecules 2018, 23, x 22 of 31

Scheme 32. The total synthesis of 178 from p-cresol employing π4s + π2s cycloaddition. Scheme 32. The total synthesis of 178 from p-cresol employing π4s + π2s cycloaddition.

Scheme 32. The total synthesis of 178 from p-cresol employing π4s + π2s cycloaddition. Scheme 32. The total synthesis of 178 from p-cresol employing π4s + π2s cycloaddition. Scheme 32. The total synthesis of 178 from p-cresol employing π4s + π2s cycloaddition.

Scheme 33. The formal synthesis of 178 via an intramolecular Diels-Alder reaction tandem metathesis protocol. Scheme 33. The formal synthesis of 178 via an intramolecular Diels-Alder reaction tandem metathesis Scheme 33. The formal synthesis of 178 via an intramolecular Diels-Alder reaction tandem Schemeprotocol. 33. The formal synthesis of 178 via an intramolecular Diels-Alder reaction tandem metathesis metathesisprotocol.Scheme protocol. 33. The formal synthesis of 178 via an intramolecular Diels-Alder reaction tandem metathesis protocol. 178 O 178 O O O 178 O Scheme 34. The total synthesis of 178 by using the strategy of masked o-benzoquinone178 chemistry. O O O O O Scheme 34. The totalO synthesis of 178 by using the strategy of maskedO o-benzoquinone chemistry. Scheme 34. The total synthesis of 178 by using the strategy of masked o-benzoquinone chemistry. Scheme 34. The total synthesis of 178 by using the strategy of masked o-benzoquinone chemistry. Scheme 34. The total synthesis of 178 by using the strategy of masked o-benzoquinone chemistry.

Scheme 35. The total syntheses of (±)-7 and 178 via a formal [3 + 2] annulation strategy.

Scheme 35. The total syntheses of (±)-7 and 178 via a formal [3 + 2] annulation strategy. Scheme 35. The total syntheses of (±)-7 and 178 via a formal [3H + 2] annulation strategy. Scheme 35. The total syntheses of (±)-7 and 178 via a formal [3 + 2] annulation strategy. SchemeHO 35. The total syntheses of (±)-7 and 178 via a formalH [3 + 2] annulation strategy. H 179 HO O N H H HO N O 179 179 HO O 187 N H188 O N N O H 179 Scheme 36.O The total synthesis of ∆9(12)-capnellene187N N (179) by using anO intramoleculH188 ar 1, 3-diyl trapping 187N O reaction as a primary strategy. 188 Scheme 36. The total synthesis of ∆9(12)-capnellene187 (179) by using an intramolecul188 ar 1, 3-diyl trapping 9(12) Schemereaction 36.as a The primary total synthesisstrategy. of ∆ -capnellene (179) by using an intramolecular 1, 3-diyl trapping reactionScheme 36.as a The primary total synthesisstrategy. of ∆9(12)-capnellene (179) by using an intramolecular 1, 3-diyl trapping reaction as a primary strategy.

Molecules 2018, 23, x 22 of 31

Scheme 32. The total synthesis of 178 from p-cresol employing π4s + π2s cycloaddition.

Scheme 33. The formal synthesis of 178 via an intramolecular Diels-Alder reaction tandem metathesis protocol.

178 O O O Scheme 34. The total synthesis of 178 by using the strategy of masked o-benzoquinone chemistry.

Molecules 2018, 23, 2095 24 of 33 Scheme 35. The total syntheses of (±)-7 and 178 via a formal [3 + 2] annulation strategy.

H

HO 179 O N H N O 187 188

Scheme 36. TheThe total synthesis of ∆9(12)-capnellene-capnellene (179 (179) )by by using using an an intramolecul intramolecularar 1, 1, 3-diyl 3-diyl trapping trapping Moleculesreactionreaction 2018, as 23 ,a x primary strategy. 23 of 31 Molecules 2018, 23, x 23 of 31 MoleculesMolecules 2018 2018, ,23 23, ,x x 2323 ofof 3131 O O O O O O O O O OO OO H O O O OO H O O H O O HH 179 H OO 179 HH 189 H 179179 189 H H 189189 HH H HH SchemeScheme 37.37. TheThe stereocontrolledstereocontrolled totaltotal synthesissynthesis ofof 179179.. Scheme 37. The stereocontrolled total synthesis of 179. SchemeScheme 37. 37. The The stereocontrolled stereocontrolled total total synthesis synthesis of of 179 179. . O O O O O H O OO OO H OO HH 179 SiMe 179 3 SiMe3 179179 190 SiMe 191 SiMe3 SiMe3 190 SiMe33 191 SiMeSiMe3 190190 191 3 Scheme 38. The total synthesis of 179 via palladium-catalyzed191 carbonylative coupling of vinyl triflates Scheme 38. The total synthesis of 179 via palladium-catalyzed carbonylative coupling of vinyl triflates SchemewithScheme organostannanes. 38. 38. The TheThe total totaltotal synthesis synthesissynthesis of ofof 179 179179 via via palladium-catalyzed palladium-catalyzed carbonylative carbonylativecarbonylative coupling coupling of of vinyl vinyl triflates triflatestriflates with organostannanes. withwith organostannanes. organostannanes. EtO2C O EtO C O H EtOEtO2CC OO H OHC O 22 H OHC O H OHCOHC O 179 O O 179 O 179179 OO H H HH Scheme 39. The formal synthesis of 179 by using new type of fulvenes undergo cycloadditions Scheme 39. The formal synthesis of 179 by using new type of fulvenes undergo cycloadditions Schemeregioselectively.Scheme 39.39. TheThe Theformalformal formal synthesissynthesis synthesis ofof 179179 by ofby usingusing179 by newnew using typetype ofof new fulvenesfulvenes type undergoundergo of fulvenes cycloadditionscycloadditions undergo regioselectively. cycloadditionsregioselectively.regioselectively. regioselectively. PhH2C PhH C OH 2 O O PhHPhH22CC OEt OH O O OEt O OHOH OO O OEtOEt OO O O O O O O OH 179 OO O O 179 H CO2Me OO OO OH H 179179 CO Me H OHOH H CO2Me H H HH CO22Me HH HH Scheme 40. The formal synthesis of 179 via the construction of cyclopentanones with substituents up Scheme 40. The formal synthesis of 179 via the construction of cyclopentanones with substituents up SchemetoScheme three contiguous40. 40. The The formal formal chiral synthesis synthesis centres. of of 179 179 via via the the construction construction of of cyclopentano cyclopentanonesnes with with substituents substituents up up Schemeto three contiguous 40. The formal chiral synthesis centres. of 179 via the construction of cyclopentanones with substituents up to three contiguous chiral centres. toto three three contiguous contiguous chiral chiral centres. centres.

OH O OH OH O OH O OHOH O OHOH O O OO TBSO TBSO O TBSO H H TBSO H H O H H TBSOTBSO TBSOTBSO H H O H H H H O H H HH HH H H HH HH 179 179 179179 H H H H O H OH H HH HH OH HH O OH OO Scheme 41.OH The synthesis of 179. Scheme 41. The synthesis of 179. SchemeScheme 41. 41. The The synthesis synthesis of of 179 179. . HO O HO HO O HOHO HO O OO HOHO O OO 180 180 180180 H H H 192 193 H H H 192 193 HH HH HH 192192 Scheme193193 42. The formal asymmetric synthesis of (−)-capnellene (180). Scheme 42. The formal asymmetric synthesis of (−)-capnellene (180). SchemeScheme 42. 42. The The formal formal asymmetric asymmetric synthesis synthesis of of ( (−−)-capnellene)-capnellene ( (180180).).

Molecules 2018, 23, x 23 of 31 Molecules 2018, 23, x 23 of 31 O O O O O O O O O H O O H H O 179 H 179 189 H 189 H H H Scheme 37. The stereocontrolled total synthesis of 179. Scheme 37. The stereocontrolled total synthesis of 179.

O O O O O H O H 179 179 SiMe3 SiMe 190 SiMe 3 3 191 SiMe3 190 191 Scheme 38. The total synthesis of 179 via palladium-catalyzed carbonylative coupling of vinyl triflates Scheme 38. The total synthesis of 179 via palladium-catalyzed carbonylative coupling of vinyl triflates with organostannanes. with organostannanes.

EtO2C O EtO2C O H OHC H OHC O O 179 O 179 O H H Scheme 39. The formal synthesis of 179 by using new type of fulvenes undergo cycloadditions Scheme 39. The formal synthesis of 179 by using new type of fulvenes undergo cycloadditions regioselectively. regioselectively.

PhH2C PhH2C OH O OEt O OH O O OEt O O O O O 179 O O OH O OH 179 H CO2Me H H H CO2Me H H MoleculesScheme2018, 2340., 2095The formal synthesis of 179 via the construction of cyclopentanones with substituents up25 of 33 Scheme 40. The formal synthesis of 179 via the construction of cyclopentanones with substituents up to three contiguous chiral centres. to three contiguous chiral centres.

OH OH OH O OH O O O

TBSO TBSO O TBSO H H TBSO H H O H H H H H H H H 179 179 H H H H H O OH H O OH Scheme 41. The synthesis of 179. Scheme 41. The synthesis of 179. HO O HO HO O O HO O 180 180 H H H 192 193 H H H 192 193 Scheme 42. The formal asymmetric synthesis of (−)-capnellene (180). Scheme 42. The formal asymmetric synthesis of (−)-capnellene (180). Molecules 2018, 23, x Scheme 42. − 180 24 of 31 Molecules 2018, 23, x The formal asymmetric synthesis of ( )-capnellene ( ). 24 of 31

Scheme 43. The formal synthesis of 180 by employing silyl group directed stereo control. SchemeScheme 43.43. TheThe formalformal synthesissynthesis ofof 180180 byby employingemploying silylsilyl groupgroup directeddirected stereostereo control.control.

HO OO H HO H H H H H HH

OO HO H HO H H O OTs H HH H 195 O OTs H BzOH2C 195 BzOH2C OCS2Me H OCS2Me H HH HH HH 180180 H H H H H H H H H HH H BzOH2C HO I BzOH2C HO I Scheme 44. The stereocontrolled synthesis of 180 based on the structure and high functionality of the SchemeScheme 44.44. The stereocontrolled synthesis of 180 based on the structure and high functionality ofof thethe starting material. startingstarting material.material.

OBz OBz CO Et OBz OBz EtO2C CO2 Et EtO2C 2 H H H H H OTBOPSOTBOPS H OTBOPS H H OTBOPS II

H HH H HO 196196 HO HH HH

180180 H H H HH H H H HO SeC6H4(2-NO2) HO SeC6H4(2-NO2) SchemeScheme 45.45. TheThe firstfirst catalyticcatalytic asymmetricasymmetric totaltotal synthesissynthesis ofof 180180 byby usingusing 196196 asas anan asymmetricasymmetric buildingbuilding block.block.

OO O O OO OO H O O N OO H N MeO2C MeO2C O 197 O CO2Me 197 CO2Me Br OHOH Br H HH H 181181

9(12) SchemeScheme 46.46. TheThe firstfirst asymmetricasymmetric totaltotal synthesissynthesis ofof thethe unnaturalunnatural enantiomerenantiomer ofof (+)-(+)-∆∆9(12)-capnellene-capnellene (181(181).).

Molecules 2018, 23, x 24 of 31 Molecules 2018, 23, x 24 of 31

Scheme 43. The formal synthesis of 180 by employing silyl group directed stereo control. Scheme 43. The formal synthesis of 180 by employing silyl group directed stereo control. HO O O H H HO H H H H H H O H HO O HO H H H 195H O OTs BzOH C H 2 H H 195 O OTs BzOH C OCS2Me H H 2 H OCS2Me H H H H H 180 180 H H H H H H H H H H BzOH2C H H HO I BzOH2C HO I MoleculesScheme2018, 23 44., 2095 The stereocontrolled synthesis of 180 based on the structure and high functionality of the26 of 33 startingScheme material. 44. The stereocontrolled synthesis of 180 based on the structure and high functionality of the starting material. OBz OBz CO Et EtO2C 2 OBz OBz EtO C CO2Et H2 OTBOPS H H H OTBOPS I H OTBOPS H H H OTBOPS I

H H 196 HO H H 196 H H HO H H 180 180 H H H H H H H HO H SeC6H4(2-NO2) HO SeC6H4(2-NO2) Scheme 45. The first catalytic asymmetric total synthesis of 180 by using 196 as an asymmetric Scheme 45. The first catalytic asymmetric total synthesis of 180 by using 196 as an asymmetric buildingScheme block.45. The first catalytic asymmetric total synthesis of 180 by using 196 as an asymmetric building block. building block.

O O O O O O O H O O N O O MeO C H N O 2 MeO2C O 197 CO2Me O CO Me 197 OH Br2 H OH H Br H H 181 181

Scheme 46. The first asymmetric total synthesis of the unnatural enantiomer of (+)-∆9(12)-capnellene Scheme 46. The first asymmetric total synthesis of the unnatural enantiomer of 9(12)(+)-∆9(12)-capnellene MoleculesScheme(181 2018). ,46. 23, Thex first asymmetric total synthesis of the unnatural enantiomer of (+)-∆ -capnellene (18125). of 31 Molecules(181 2018). , 23, x 25 of 31

EtO2C O O H O EtO2C O O H O H H 87 H 87 OTMS H H OTMS H H H H H EtO2C O HO H O EtO2C O H HO OH O H OH H H H 88 H 88 MPMO H MPMO H H OH OH 9(12) 9(12) Scheme 47. The first total syntheses of 9(12)∆ -capnellene-8β,10α-diol (87) and ∆9(12)-capnellene-3β,8β, SchemeScheme 47. 47.The The first first total total syntheses syntheses of of∆ ∆9(12)-capnellene-8-capnellene-8ββ,10,10αα-diol-diol ((8787)) andand ∆∆9(12)-capnellene-3-capnellene-3ββ,8,8ββ, , 10α-troil (88). 1010αα-troil-troil ( 88(88).). EtO C EtO2C 87 O H OAc H O H 2 O 87 O H OAcH H O H O H O O O O O O H H 198 199 198 199 88 88 Scheme 48. The synthesis of 87 and 88. SchemeScheme 48.48. The synthesis of 87 and 88.. 4.3. Other Type 4.3. Other Type In 1996, Baralotto and co-workers [99] proposed a total synthesis of racemic (±)-ceratopicanol In 1996, Baralotto and co-workers [99] proposed a total synthesis of racemic (±)-ceratopicanol ((±)-109), employing seven steps, in which the key one was an intramolecular meta ((±)-109), employing seven steps, in which the key one was an intramolecular meta photocycloaddition of the phenylpentene derivative 200, which constituted a typical holosynthon photocycloaddition of the phenylpentene derivative 200, which constituted a typical holosynthon (Scheme 49). In 1996, Clive and co-workers [100] also reported a method to synthesize (+)- (Scheme 49). In 1996, Clive and co-workers [100] also reported a method to synthesize (+)- ceratopicanol (109) (Scheme 50). This method has been used to form many compounds of the ceratopicanol (109) (Scheme 50). This method has been used to form many compounds of the triquinane class. triquinane class. The first total synthesis of cucumin E (78) was achieved in 2002, which used an ynolate-initiated The first total synthesis of cucumin E (78) was achieved in 2002, which used an ynolate-initiated tandem reaction for the construction of the cyclopentenone unit (Scheme 51). This strategy proved tandem reaction for the construction of the cyclopentenone unit (Scheme 51). This strategy proved the feasibility of a short access to triquinane sesquiterpenoids [45]. the feasibility of a short access to triquinane sesquiterpenoids [45]. The first total synthesis of the (−)-cucumin H ((−)-110) was reported in 2003 [101] (Scheme 52). The first total synthesis of the (−)-cucumin H ((−)-110) was reported in 2003 [101] (Scheme 52). This method started from (R)-limonene employing two different cyclopentannulation This method started from (R)-limonene employing two different cyclopentannulation methodologies, which were to confirm the structure, as well as establish the absolute configuration methodologies, which were to confirm the structure, as well as establish the absolute configuration of the natural product. of the natural product. Furthermore in 2003, the first total synthesis of pleurotellic acid (115) and pleurotellol (114) was Furthermore in 2003, the first total synthesis of pleurotellic acid (115) and pleurotellol (114) was achieved. One notable feature of this synthesis, was that it followed an adaptation of the versatile achieved. One notable feature of this synthesis, was that it followed an adaptation of the versatile photo-thermal metathesis-based approach to triquinane sesquiterpenoids. The other feature was the photo-thermal metathesis-based approach to triquinane sesquiterpenoids. The other feature was the installation of the sensitive functionalization pattern in the two five-membered rings of the triquinane installation of the sensitive functionalization pattern in the two five-membered rings of the triquinane system, through simple reaction sequences [46] (Scheme 53). system, through simple reaction sequences [46] (Scheme 53).

Scheme 49. The total synthesis of racemic (±)-ceratopicanol ((±)-109) via intramolecular meta Scheme 49. The total synthesis of racemic (±)-ceratopicanol ((±)-109) via intramolecular meta photocycloaddition. photocycloaddition.

Molecules 2018, 23, x 25 of 31

EtO2C O O H O H 87 H OTMS H H H

EtO2C O HO O H OH H H 88 H MPMO H OH Scheme 47. The first total syntheses of ∆9(12)-capnellene-8β,10α-diol (87) and ∆9(12)-capnellene-3β,8β, 10α-troil (88).

EtO2C 87 O H OAc H O H O H O O O H 198 199 88

Molecules 2018, 23, 2095 Scheme 48. The synthesis of 87 and 88. 27 of 33

4.3. Other Type 4.3. Other Type In 1996, Baralotto and co-workers [99] proposed a total synthesis of racemic (±)-ceratopicanol ((±)-109In 1996,), employing Baralotto andseven co-workers steps, in [99 ]which proposed the a totalkey synthesisone was of racemican intramolecular (±)-ceratopicanol meta ((photocycloaddition±)-109), employing of seven the steps,phenylpentene in which thederivative key one was200, anwhich intramolecular constituted meta a typical photocycloaddition holosynthon of(Scheme the phenylpentene 49). In 1996, derivative Clive and200 co-workers, which constituted [100] also a typical reported holosynthon a method (Scheme to synthesize 49). In 1996, (+)- Cliveceratopicanol and co-workers (109) (Scheme [100] also 50). reported This method a method has to been synthesize used (+)-ceratopicanolto form many compounds (109) (Scheme of 50the). Thistriquinane method class. has been used to form many compounds of the triquinane class. The first first total synthesis of cucumin E ( 78) was achieved in 2002, which used an ynolate-initiated tandem reactionreaction forfor the the construction construction of of the the cyclopentenone cyclopentenone unit unit (Scheme (Scheme 51 ).51). This This strategy strategy proved proved the feasibilitythe feasibility of a of short a short access access to triquinane to triquinane sesquiterpenoids sesquiterpenoids [45]. [45]. The firstfirst total synthesissynthesis ofof thethe ((−−)-cucumin)-cucumin H H (( −)-)-110110) )was was reported reported in in 2003 2003 [101] [101] (Scheme (Scheme 52).52). This methodmethod started started from (R)-limonenefrom (R)-limonene employing em twoploying different two cyclopentannulation different cyclopentannulation methodologies, whichmethodologies, were to which confirm were the to structure,confirm the as structure, well as as establish well as establish the absolute the absolute configuration configuration of the naturalof the natural product. product. Furthermore in 2003, the firstfirst total synthesis of pleurotellic acid ( 115) and pleurotellol (114) was achieved. One One notable notable feature feature of this synthesis, was that it followed an adaptation of the versatile photo-thermal metathesis-based approach to triquinanetriquinane sesquiterpenoids. The other feature was the installation of the sensitive functionalization pattern in the two five-membered five-membered rings of the triquinane triquinane system, through simple reaction sequencessequences [[46]46] (Scheme(Scheme 5353).).

Scheme 49. The total synthesis of racemic (±)-ceratopicanol ((±)-109) via intramolecular meta Scheme 49. The total synthesis of racemic (±)-ceratopicanol ((±)-109) via intramolecular photocycloaddition. Moleculesmeta 2018 photocycloaddition., 23, x 26 of 31 Molecules 2018, 23, x 26 of 31

Scheme 50. The synthesis of 109. Scheme 50. The synthesis of 109..

Scheme 51. The first total synthesis of cucumin E (78) by using an ynolate-initiated tandem reaction Scheme 51. The first total synthesis of cucumin E (78) by using an ynolate-initiated tandem reaction Schemefor the construction 51. The first of total the synthesiscyclopentenone of cucumin unit. E (78) by using an ynolate-initiated tandem reaction for the construction of the cyclopentenone unit. for the construction of the cyclopentenone unit.

Scheme 52. The first total synthesis of the (−)-cucumin H ((−)-110). Scheme 52. The first total synthesis of the (−)-cucumin H ((−)-110).

Scheme 53. The first total synthesis of pleurotellic acid (115) and pleurotellol (114). Scheme 53. The first total synthesis of pleurotellic acid (115) and pleurotellol (114). 5. Conclusions 5. Conclusions From 1947 to July 2018, more than 100 linear triquinane sesquiterpenoids have been isolated, and mostFrom of1947 them to wereJuly 2018, isolated more from than fungi, 100 linearsponges, triquinane and soft sesquiterpenoids corals, among which have thebeen mushroom isolated, andstereum most hirsutum of them, the were soft isolated coral capnella from fungi, imbricata, sponges, and marine and soft fungus corals, chondrostereum among which sp the. were mushroom typical stereumsources. hirsutum It is important, the soft to notecoral in capnella particular, imbricata, that Li and and marine co-workers fungus have chondrostereum obtained 19 linearsp. were triquinane typical sources.sesquiterpenoids It is important including to note chondrosterins in particular, thatA–E, Li I–O, and hirsutanols co-workers A, have C, E,obtained F, incarnal, 19 linear arthrosporone, triquinane sesquiterpenoidsand anhydroarthrosporone, including chondrosterins from the marine-derived A–E, I–O, hirsutanols fungus Chondrostereum A, C, E, F, incarnal, sp. Furthermore, arthrosporone, the andproduction anhydroarthrosporone, of secondary metabolites from the marine-derived often correlated fungus with Chondrostereum a specific stage sp. ofFurthermore, morphological the productiondifferentiation of [102].secondary It indicated metabolites that inoften addition correl atedto looking with afor specific new sources stage ofto producemorphological linear differentiationtriquinane sesquiterpenoids, [102]. It indicated we can that also in find addition ways toto isolate looking linear for triquinanenew sources sesquiterpenoids to produce linear with triquinanemultiple structural sesquiterpenoids, types from we canone also“talented” find ways organism. to isolate Many linear of triquinane these compounds sesquiterpenoids displayed with a multiplevariety of structural biological types activities, from such one as“talented” cytotoxici organism.ty, anti-microbial, Many of and these anti-inflammatory compounds displayed activities. a varietyGiven their of biological structural activities, diversity such and complexity,as cytotoxici andty, anti-microbial, significant biological and anti-inflammatory activities, linear triquinane activities. Givensesquiterpenoids their structural attracted diversity great and interest complexity, from synt andhetic significant chemists. biological Among activities, the 8 skeletal linear types, triquinane type I sesquiterpenoidsand III are the most attracted popular great ones, interest a number from of synt efficienthetic chemists. synthesis Among methods the have 8 skeletal been developedtypes, type to I andconstruct III are the the unique most popular skeleton ones, of linear a number triquinane of efficient sesquiterpenoids. synthesis methods have been developed to construct the unique skeleton of linear triquinane sesquiterpenoids.

Molecules 2018, 23, x 26 of 31 Molecules 2018, 23, x 26 of 31

Scheme 50. The synthesis of 109. Scheme 50. The synthesis of 109.

MoleculesScheme2018, 2351., 2095The first total synthesis of cucumin E (78) by using an ynolate-initiated tandem reaction28 of 33 Scheme 51. The first total synthesis of cucumin E (78) by using an ynolate-initiated tandem reaction for the construction of the cyclopentenone unit. for the construction of the cyclopentenone unit.

Scheme 52. The first total synthesis of the (−)-cucumin H ((−)-110). SchemeScheme 52. 52.The The firstfirst total total synthesis synthesis of of the the ( −(−)-cucumin)-cucumin HH ((((−)-)-110110).).

Scheme 53. The first total synthesis of pleurotellic acid (115) and pleurotellol (114). Scheme 53. The first total synthesis of pleurotellic acid (115) and pleurotellol (114). Scheme 53. The first total synthesis of pleurotellic acid (115) and pleurotellol (114). 5. Conclusions 5. Conclusions 5. Conclusions From 1947 to July 2018, more than 100 linear triquinane sesquiterpenoids have been isolated, From 1947 to July 2018, more than 100 linear triquinane sesquiterpenoids have been isolated, and mostFrom of 1947 them to were July 2018,isolated more from than fungi, 100 linearsponges, triquinane and soft sesquiterpenoidscorals, among which have the been mushroom isolated, and most of them were isolated from fungi, sponges, and soft corals, among which the mushroom andstereum most hirsutum of them, the were soft isolated coral capnella from fungi, imbricata, sponges, and marine and soft fungus corals, chondrostereum among which sp the. were mushroom typical stereum hirsutum, the soft coral capnella imbricata, and marine fungus chondrostereum sp. were typical stereumsources. hirsutum It is important, the soft to note coral incapnella particular, imbricata, that Liand and marine co-workers fungus havechondrostereum obtained 19 linearsp. were triquinane typical sources. It is important to note in particular, that Li and co-workers have obtained 19 linear triquinane sources.sesquiterpenoids It is important including to note chondrosterins in particular, A–E, that Li I–O, and hirsutanols co-workers A, have C, E, obtained F, incarnal, 19 linear arthrosporone, triquinane sesquiterpenoids including chondrosterins A–E, I–O, hirsutanols A, C, E, F, incarnal, arthrosporone, sesquiterpenoidsand anhydroarthrosporone, including chondrosterinsfrom the marine-derived A–E, I–O, hirsutanols fungus Chondrostereum A, C, E, F, incarnal, sp. Furthermore, arthrosporone, the and anhydroarthrosporone, from the marine-derived fungus Chondrostereum sp. Furthermore, the andproduction anhydroarthrosporone, of secondary metabolites from the marine-derivedoften correlated funguswith aChondrostereum specific stage sp.of morphological Furthermore, production of secondary metabolites often correlated with a specific stage of morphological thedifferentiation production [102]. of secondary It indicated metabolites that in addition often correlated to looking with for a specificnew sources stage to of produce morphological linear differentiation [102]. It indicated that in addition to looking for new sources to produce linear differentiationtriquinane sesquiterpenoids, [102]. It indicated we can that also infind addition ways to to isolate looking linear for triquinane new sources sesquiterpenoids to produce linear with triquinane sesquiterpenoids, we can also find ways to isolate linear triquinane sesquiterpenoids with triquinanemultiple structural sesquiterpenoids, types from we one can “talented” also find waysorganism. to isolate Many linear of these triquinane compounds sesquiterpenoids displayed a multiple structural types from one “talented” organism. Many of these compounds displayed a withvariety multiple of biological structural activities, types fromsuch oneas cytotoxici “talented”ty, organism. anti-microbial, Many and of these anti-inflammatory compounds displayed activities. a variety of biological activities, such as cytotoxicity, anti-microbial, and anti-inflammatory activities. varietyGiven their of biological structural activities, diversity suchand complexity, as cytotoxicity, and anti-microbial,significant biological and anti-inflammatory activities, linear triquinane activities. Given their structural diversity and complexity, and significant biological activities, linear triquinane Givensesquiterpenoids their structural attracted diversity great and interest complexity, from synt andhetic significant chemists. biological Among activities,the 8 skeletal linear types, triquinane type I sesquiterpenoids attracted great interest from synthetic chemists. Among the 8 skeletal types, type I sesquiterpenoidsand III are the most attracted popular great ones, interest a number from of synthetic efficient chemists.synthesis Amongmethods the have 8 skeletal been developed types, type to I and III are the most popular ones, a number of efficient synthesis methods have been developed to andconstruct III are the the unique mostpopular skeleton ones, of linear a number triquinane of efficient sesquiterpenoids. synthesis methods have been developed to construct the unique skeleton of linear triquinane sesquiterpenoids. construct the unique skeleton oflinear triquinane sesquiterpenoids.

Author Contributions: Y.Q., W.-J.L. and H.-J.L. reviewed the literatures and wrote the paper. L.-P.C. supervised the writing and revised the paper. All authors approved the final version of the manuscript. Funding: This work was funded by National Natural Science Foundation of China (No. 81872795), Guangdong Natural Science Foundation (No. 2018A030313157), Guangdong Provincial Science and Technology Research Program (Nos. 2015A020216007 and 2016A020222004), National Science and Technology Major Project for New Drug Innovation and Development (No. 2017ZX09305010), and the Fundamental Research Funds for the Central Universities (No. 15ykpy05). Conflicts of Interest: The authors declare no conflict of interest.

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