Linear Triquinane Sesquiterpenoids: Their Isolation, Structures, Biological Activities, and Chemical Synthesis

Linear triquinane sesquiterpenoids represent an important class of natural products. Most of these compounds were isolated from fungi, sponges, and soft corals, and many of them displayed a wide range of biological activities. On account of their structural diversity and complexity, linear triquinane sesquiterpenoids present new challenges for chemical structure identification and total synthesis. 118 linear triquinane sesquiterpenoids were classified into 8 types, named types I–VIII, based on the carbon skeleton and the position of carbon substituents. Their isolation, structure elucidations, biological activities, and chemical synthesis were reviewed. This paper cited 102 articles from 1947 to 2018.


Introduction
Sesquiterpenoids represent an important class of natural products. Among them, linear triquinane sesquiterpenoids have a basic skeleton 1H-cyclopenta[a]pentalene ( Figure 1a) [1]. Since the first linear triquinane sesquiterpenoid, named hirsutic acid C obtained in 1947 [2,3], more than 100 linear triquinane sesquiterpenoids have been isolated, mainly from fungi, sponges, and soft corals. Many compounds displayed a wide range of biological activities, such as cytotoxic, antimicrobial, and anti-inflammatory activities [4][5][6][7]. Hirsutanes and capnellenes are the most common scaffolds of the linear triquinane sesquiterpenoids (Figure 1b,c) [8]. However, many compounds cannot be simply classified into these two types. Here, we categorize the linear triquinane sesquiterpenoids into eight types, types I-VIII, according to the carbon skeleton and the position of carbon substituents (Figure 2). This review gives an overview about the isolation, structure, biological activities, and chemical synthesis of linear triquinane sesquiterpenoids.
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
Aiming at finding new secondary metabolites, with bioactivities from fungi collected in the region of Tibet Plateau, a strain of Stereum hirsutum (L515) was isolated from its fruiting body. Sterhirsutins A (52) and B (53), hirsutic acids D (54) and E (55), were isolated from this strain's solidsubstrate fermentation culture in 2014 [30]. Additionally, in 2015, from its ethyl acetate extract, sterhirsutins C-L (56-65) were obtained [31]. Sterhirsutin L was the first sesquiterpene coupled with a xanthine moiety.
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 structurally, closely related to coriolins [33].

Type II
There were 10 compounds belonging to type II, with four carbon substituents at C-3, 6, 10, 10 ( Figure 4). 9 compounds a have carbonyl group.

Type II
There were 10 compounds belonging to type II, with four carbon substituents at C-3, 6, 10, 10 ( Figure 4). 9 compounds a have carbonyl group.

Type II
There were 10 compounds belonging to type II, with four carbon substituents at C-3, 6, 10, 10 ( Figure 4). 9 compounds a have carbonyl group.

Type III
In type III compounds, there are four carbon substituents in C-1, 1, 4, 9 ( Figure 5). The most notable feature of these compounds is they contain an off-ring carbon-carbon double bond at C-9.

Type IV, V, VI, VII and VIII
The number of type IV-VIII compounds ( Figure 6), is relatively small. It is worth mentioning that type VIII compounds, have one less carbon substituent on the skeleton than other compounds.
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, x 9 of 31 Figure 6. Structures of type VI-VIII compounds.

Cytotoxicity
Cytotoxicity was a kind of common biological activity reported for linear triquinane sesquiterpenoids, usually expressed as inhibitory concentration (IC50), 50% of the effective dose (ED50), cytotoxic concentration (CC50), lethal concentration (LC50), or growth inhibition (GI50), this value emphasizes the correction for the cell count at time zero) [1]. Among the 118 linear triquinane sesquiterpenoids, many compounds exhibited activities against cancer cell lines (Table 1).

Cytotoxicity
Cytotoxicity was a kind of common biological activity reported for linear triquinane sesquiterpenoids, usually expressed as inhibitory concentration (IC 50 ), 50% of the effective dose (ED 50 ), cytotoxic concentration (CC 50 ), lethal concentration (LC 50 ), or growth inhibition (GI 50) , this value emphasizes the correction for the cell count at time zero) [1]. Among the 118 linear triquinane sesquiterpenoids, many compounds exhibited activities against cancer cell lines (Table 1).
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].

Other Bioactivity
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].
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].
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.

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]. Their skeletal and functional diversities, also pose a considerable synthetic challenge [46].

Hirsutane Type
In the early 1970s, chemists began to synthesize hirsutane type compounds, in a variety of ways. The total synthesis of hirsutic acid C (1), was achieved via the suitably functionalized skeleton compound 119 (Figure 7). In 1974, Hisanobu Hashimoto and co-workers reported a stereospecific conversion of 3α-hydroxymethylene ketone (compound 119) to racemic hirsutic acid [47,48]. In 1978, Kueh and co-workers [49] reported the synthesis of the hirsutane carbon skeleton. They found that the photochemical intramolecular [2 + 2] cycloaddition of dicyclopent-l-enylmethanes (120), followed by in situation of methanol to the strained cyclopropane ring in the presumed intermediate bicycle[2.1.0]pentanes (121), led to an easy synthesis of the ring system.

Hirsutane Type
In the early 1970s, chemists began to synthesize hirsutane type compounds, in a variety of ways. The total synthesis of hirsutic acid C (1), was achieved via the suitably functionalized skeleton compound 119 (Figure 7). In 1974, Hisanobu Hashimoto and co-workers reported a stereospecific conversion of 3α-hydroxymethylene ketone (compound 119) to racemic hirsutic acid [47,48]. In 1978, Kueh and co-workers [49] reported the synthesis of the hirsutane carbon skeleton. They found that the photochemical intramolecular [2 + 2] cycloaddition of dicyclopent-l -enylmethanes (120), followed by in situation of methanol to the strained cyclopropane ring in the presumed intermediate bicycle  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 this method: (1) the cis-syn-cis-C13-tricyclopentanoid frame (124) was efficiently obtained from cyclopentadiene and 2,5-dimethyl-p-benzoquinone, in three high-yielding steps employing only heat and light as the reagents; (2) compound 124 with the requisite cis-anti-cis system (125), was in 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 type compounds [50].
In 1984, Dawson and co-workers reported a simple stereocontrolled sequence to synthesize hirsutene from dicyclopentadiene which contained ring expansion by ketonization of a cyclopropoxide and skeletal rearrangement, through a β-enolate [51]. A primary feature of this synthesis, was that the stereochemistry at three of the four chiral centers was established essentially at the beginning of the sequence, and then the β-enolate rearrangement specifically generated the correct configuration at the fourth center, exclusively.
Majetich and co-workers achieved a synthesis of (±)-hirsutene ((±)-7), via the intramolecular 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 this method: (1) the cis-syn-cis-C 13 -tricyclopentanoid frame (124) was efficiently obtained from cyclopentadiene and 2,5-dimethyl-p-benzoquinone, in three high-yielding steps employing only heat and light as the reagents; (2) compound 124 with the requisite cis-anti-cis system (125), was in 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 type compounds [50].
In 1984, Dawson and co-workers reported a simple stereocontrolled sequence to synthesize hirsutene from dicyclopentadiene which contained ring expansion by ketonization of a cyclopropoxide and skeletal rearrangement, through a β-enolate [51]. A primary feature of this synthesis, was that the stereochemistry at three of the four chiral centers was established essentially at the beginning of the sequence, and then the β-enolate rearrangement specifically generated the correct configuration at the fourth center, exclusively.
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).
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 (Scheme 26) [74].

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

Scheme 10.
The total synthesis of (±)-7 via a twofold cycloaddition. 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 epoxy-allylsilane cyclization.
Scheme 13. The synthesis of 7 utilizing an acid catalyzed intramolecular conjugate addition and a Pd 2+ -promoted highly stereocontrolled cyclization.
It was worth mentioning that although palladium catalyzed zipper mode cyclization, using Heck reaction conditions had caused widespread concern for the construction of polycyclic system, this methodology was not suitable for the required cis-anti-cis stereochemistry of the capnellane system [61]. However, in 1994 Genevieve Balme achieved the total synthesis of 178, using a palladium-catalyzed bis-cyclization step [80]. Functionalized diquinanes were easily and stereoselectively gained from a new palladium catalyzed cyclisation 183→186 (Scheme 30). Applying the intramolecular version of this strategy, a triquinane should be directly obtained in a single step, by construction of the two outer rings around the central ring (Scheme 31).
It was worth mentioning that although palladium catalyzed zipper mode cyclization, using Heck reaction conditions had caused widespread concern for the construction of polycyclic system, this methodology was not suitable for the required cis-anti-cis stereochemistry of the capnellane system [61]. However, in 1994 Genevieve Balme achieved the total synthesis of 178, using a palladium-catalyzed bis-cyclization step [80]. Functionalized diquinanes were easily and stereoselectively gained from a new palladium catalyzed cyclisation 183→186 (Scheme 30). Applying the intramolecular version of this strategy, a triquinane should be directly obtained in a single step, by construction of the two outer rings around the central ring (Scheme 31).
It was worth mentioning that although palladium catalyzed zipper mode cyclization, using Heck reaction conditions had caused widespread concern for the construction of polycyclic system, this methodology was not suitable for the required cis-anti-cis stereochemistry of the capnellane system [61]. However, in 1994 Genevieve Balme achieved the total synthesis of 178, using a palladium-catalyzed bis-cyclization step [80]. Functionalized diquinanes were easily and stereoselectively gained from a new palladium catalyzed cyclisation 183→186 (Scheme 30). Applying the intramolecular version of this strategy, a triquinane should be directly obtained in a single step, by construction of the two outer rings around the central ring (Scheme 31).
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).
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).
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).

Other Type
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 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 (+)-ceratopicanol (109) (Scheme 50). This method has been used to form many compounds of the triquinane class.
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 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). This method started from (R)-limonene employing two different cyclopentannulation methodologies, which were to confirm the structure, as well as establish the absolute configuration of the natural product.
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 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 system, through simple reaction sequences [46]

Other Type
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 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 (+)ceratopicanol (109) (Scheme 50). This method has been used to form many compounds of the triquinane class.
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 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). This method started from (R)-limonene employing two different cyclopentannulation methodologies, which were to confirm the structure, as well as establish the absolute configuration of the natural product.
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 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 system, through simple reaction sequences [46] (Scheme 53). Scheme 51. The first total synthesis of cucumin E (78) by using an ynolate-initiated tandem reaction for the construction of the cyclopentenone unit.

Conclusions
From 1947 to July 2018, more than 100 linear triquinane sesquiterpenoids have been isolated, and most of them were isolated from fungi, sponges, and soft corals, among which the mushroom stereum hirsutum, the soft coral capnella imbricata, and marine fungus chondrostereum sp. were typical sources. It is important to note in particular, that Li and co-workers have obtained 19 linear triquinane sesquiterpenoids including chondrosterins A-E, I-O, hirsutanols A, C, E, F, incarnal, arthrosporone, and anhydroarthrosporone, from the marine-derived fungus Chondrostereum sp. Furthermore, the production of secondary metabolites often correlated with a specific stage of morphological differentiation [102]. It indicated that in addition to looking for new sources to produce linear triquinane sesquiterpenoids, we can also find ways to isolate linear triquinane sesquiterpenoids with multiple structural types from one "talented" organism. Many of these compounds displayed a variety of biological activities, such as cytotoxicity, anti-microbial, and anti-inflammatory activities. Given their structural diversity and complexity, and significant biological activities, linear triquinane sesquiterpenoids attracted great interest from synthetic chemists. Among the 8 skeletal types, type I and III are the most popular ones, a number of efficient synthesis methods have been developed to construct the unique skeleton of linear triquinane sesquiterpenoids.

Conclusions
From 1947 to July 2018, more than 100 linear triquinane sesquiterpenoids have been isolated, and most of them were isolated from fungi, sponges, and soft corals, among which the mushroom stereum hirsutum, the soft coral capnella imbricata, and marine fungus chondrostereum sp. were typical sources. It is important to note in particular, that Li and co-workers have obtained 19 linear triquinane sesquiterpenoids including chondrosterins A-E, I-O, hirsutanols A, C, E, F, incarnal, arthrosporone, and anhydroarthrosporone, from the marine-derived fungus Chondrostereum sp. Furthermore, the production of secondary metabolites often correlated with a specific stage of morphological differentiation [102]. It indicated that in addition to looking for new sources to produce linear triquinane sesquiterpenoids, we can also find ways to isolate linear triquinane sesquiterpenoids with multiple structural types from one "talented" organism. Many of these compounds displayed a variety of biological activities, such as cytotoxicity, anti-microbial, and anti-inflammatory activities. Given their structural diversity and complexity, and significant biological activities, linear triquinane sesquiterpenoids attracted great interest from synthetic chemists. Among the 8 skeletal types, type I and III are the most popular ones, a number of efficient synthesis methods have been developed to construct the unique skeleton of linear triquinane sesquiterpenoids. Scheme 53. The first total synthesis of pleurotellic acid (115) and pleurotellol (114).

Conclusions
From 1947 to July 2018, more than 100 linear triquinane sesquiterpenoids have been isolated, and most of them were isolated from fungi, sponges, and soft corals, among which the mushroom stereum hirsutum, the soft coral capnella imbricata, and marine fungus chondrostereum sp. were typical sources. It is important to note in particular, that Li and co-workers have obtained 19 linear triquinane sesquiterpenoids including chondrosterins A-E, I-O, hirsutanols A, C, E, F, incarnal, arthrosporone, and anhydroarthrosporone, from the marine-derived fungus Chondrostereum sp. Furthermore, the production of secondary metabolites often correlated with a specific stage of morphological differentiation [102]. It indicated that in addition to looking for new sources to produce linear triquinane sesquiterpenoids, we can also find ways to isolate linear triquinane sesquiterpenoids with multiple structural types from one "talented" organism. Many of these compounds displayed a variety of biological activities, such as cytotoxicity, anti-microbial, and anti-inflammatory activities. Given their structural diversity and complexity, and significant biological activities, linear triquinane sesquiterpenoids attracted great interest from synthetic chemists. Among the 8 skeletal types, type I and III are the most popular ones, a number of efficient synthesis methods have been developed to construct the unique skeleton of linear triquinane sesquiterpenoids.