Linear Triquinane Sesquiterpenoids: Their Isolation, Structures ... - MDPI

molecules Review Review

Linear Triquinane Triquinane Sesquiterpenoids: Sesquiterpenoids: Their Their Isolation, Isolation, Linear Structures, Biological Activities, and Chemical and Chemical Synthesis Synthesis 1 2 1, ID 1,* 1, * Liu-Ping Chen Yi Yi Qiu Qiu 1, Wen-Jian Wen-Jian Lan Lan 2, Hou-Jin Li 1,** andand Liu-Ping Chen 1

SchoolofofChemistry, Chemistry,Sun SunYat-sen Yat-senUniversity, University, Guangzhou Guangzhou 510275, 510275, China; China; [email protected] [email protected] School School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; [email protected] [email protected] ** Correspondence: Correspondence:[email protected] [email protected](H.-J.L.); (H.-J.L.);[email protected] [email protected](L.-P.C.); (L.-P.C.); Tel.: +86-20-8411-3698 (H.-J.L.); +86-20-8411-5559 (L.-P.C.) Tel.: +86-20-8411-3698 (H.-J.L.); +86-20-8411-5559 (L.-P.C.) 1

2

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

represent an important classclass of natural products. Most Abstract: Linear Lineartriquinane triquinanesesquiterpenoids sesquiterpenoids represent an important of natural products. of these were isolated from fungi, and soft and corals, and manyand of them displayed Most of compounds these compounds were isolated fromsponges, fungi, sponges, soft corals, many of them a wide range of biological activities.activities. On account their structural diversity and complexity, linear displayed a wide range of biological On of account of their structural diversity and complexity, triquinane sesquiterpenoids present new challenges for chemical structure identification and linear triquinane sesquiterpenoids present new challenges for chemical structure identificationtotal and synthesis. 118 linear triquinane sesquiterpenoids were classified into 8 types, namednamed types I–VIII, total synthesis. 118 linear triquinane sesquiterpenoids were classified into 8 types, types based based on theon carbon skeleton and and the the position of of carbon substituents. I–VIII, the carbon skeleton position carbon substituents.Their Theirisolation, isolation, structure elucidations, biological biologicalactivities, activities, and chemical synthesis reviewed. This cited paper102 cited 102 elucidations, and chemical synthesis werewere reviewed. This paper articles articles from 1947 to 2018. from 1947 to 2018. Keywords: linear triquinane sesquiterpenoid; hirsutane; capnellene; isolation; structure; biological activity; synthesis

1. Introduction Sesquiterpenoids represent an an important important class class of of natural natural products. products. Among them, them, linear linear triquinane 1H-cyclopenta[a]pentalene (Figure 1a) 1a) [1]. [1]. Since the triquinane sesquiterpenoids sesquiterpenoidshave havea abasic basicskeleton skeleton 1H-cyclopenta[a]pentalene (Figure Since first linear triquinane sesquiterpenoid, named hirsutic acid the first linear triquinane sesquiterpenoid, named hirsutic acidC Cobtained obtainedinin1947 1947[2,3], [2,3], more more than 100 have been isolated, mainly fromfrom fungi,fungi, sponges, and soft corals. 100 linear lineartriquinane triquinanesesquiterpenoids sesquiterpenoids have been isolated, mainly sponges, and soft Many displayeddisplayed a wide range of biological such as cytotoxic, corals.compounds Many compounds a wide range ofactivities, biological activities, such antimicrobial, as cytotoxic, and anti-inflammatory activities [4–7]. Hirsutanes and capnellenes the capnellenes most common of antimicrobial, and anti-inflammatory activities [4–7]. Hirsutanesareand arescaffolds the most the linear triquinane sesquiterpenoids (Figure 1b,c) [8]. However, (Figure many compounds be simply common scaffolds of the linear triquinane sesquiterpenoids 1b,c) [8]. cannot However, many classified into thesebe two types.classified Here, weinto categorize the linear triquinane sesquiterpenoids into eight compounds cannot simply these two types. Here, we categorize the linear triquinane types, types I–VIII,into according to thetypes carbon skeleton and thetoposition of carbon substituents (Figure 2). sesquiterpenoids eight types, I–VIII, according the carbon skeleton and the position of This review gives an overview about thegives isolation, structure, biological activities, and biological chemical carbon substituents (Figure 2). This review an overview about the isolation, structure, synthesis linear triquinane sesquiterpenoids. activities, of and chemical synthesis of linear triquinane sesquiterpenoids.

6 4

6

8 2

1

3 11

(a) basic scaf f old

13

5

8 2 1

12

10 11

14 15

(b) hirsutane scaf fold

13 3

7 9 12

11 1 14

15

(c) capnellene scaf f old

Figure 1. 1. Skeleton of linear linear triquinane triquinane sesquiterpenoids. sesquiterpenoids. Figure Skeleton of Molecules 2018, 23, x; doi: Molecules 2018, 23, 2095; doi:10.3390/molecules23092095

www.mdpi.com/journal/molecules www.mdpi.com/journal/molecules

Molecules 2018, 23, 2095 Molecules 2018, 23, x

2 of 33 2 of 31

Figure Figure 2. 2. Structure Structure types types of of linear linear triquinane triquinane sesquiterpenoids. sesquiterpenoids.

2. 2. Isolation Isolation and and Structure Structure Elucidation Elucidation 2.1. 2.1. Type Type II There I compounds (Figure 3).3). A total of 76 There are are four four carbon carbonsubstituents substituentsatatC-2, C-2,3,3,10, 10,1010inintype type I compounds (Figure A total of compounds, constitute thethe largest classification 76 compounds, constitute largest classificationofoflinear lineartriquinane triquinanesesquiterpenoids. sesquiterpenoids. Hirsutic Hirsutic acid acid C linear triquinane triquinane sesquiterpenoids C (1), (1), was was the the first first linear sesquiterpenoids isolated isolated from from the the cultures cultures of of Stereum Stereum hirsutum hirsutum in 1947 [2,3]. The antibiotic coriolin (2), coriolin B (3), C (4), and hirsutene (7) were purified fromfrom the in 1947 [2,3]. The antibiotic coriolin (2), coriolin B (3), C (4), and hirsutene (7) were purified mycelia of basidiomycetes Coriolus consors [9–11]. However, the initial structures of coriolins were the mycelia of basidiomycetes Coriolus consors [9–11]. However, the initial structures of coriolins not exactly right, afterwards their structures and stereochemistry were revised by the same research were not exactly right, afterwards their structures and stereochemistry were revised by the same group based spectroscopic analysis, biogenetic consideration and and chemical transformations, in research grouponbased on spectroscopic analysis, biogenetic consideration chemical transformations, 1971 [12]. The revised structures ofof coriolins in 1971 [12]. The revised structures coriolinsshowed showedthat thatthey theywere werehirsutane-type hirsutane-typesesquiterpenes. sesquiterpenes. (−)-Complicatic fungus Stereum complicatum in 1973 [13].[13]. 5(−)-Complicaticacid acid(5) (5)was wasfirst firstisolated isolatedfrom fromthethe fungus Stereum complicatum in 1973 Dihydrocoriolin CC (6)(6) was obtained from Coriolus consors (ATCC 5-Dihydrocoriolin was obtained from Coriolus consors (ATCC11574) 11574)[14]. [14]. Hypnophilin (8) was isolated from mycelial cultures of Pleurotellus hypnophilus (Berk.) Sacc. Hypnophilin (8) was isolated from mycelial cultures of Pleurotellus hypnophilus (Berk.) Sacc. in in 1981 [15,16]. Six new hirsutane metabolites, arthrosporone (9), anhydroarthrosporone (10), 1981 [15,16]. Six new hirsutane metabolites, arthrosporone (9), anhydroarthrosporone (10), arthrosporol arthrosporol (11), 4-O-acetylarthrosporo (12), arthrosporodione (13), and obtained compound 14fungus were (11), 4-O-acetylarthrosporo (12), arthrosporodione (13), and compound 14 were from obtained from fungus UAMH 4262 by Amouzou in 1989 [4]. Incarnal (15) was purified from the UAMH 4262 by Amouzou in 1989 [4]. Incarnal (15) was purified from the culture fluid of Gloeostereum culture fluid of Gloeostereum incarnatum in 1991 [17]. In 1992, gloeosteretriol (16), also named incarnatum in 1991 [17]. In 1992, gloeosteretriol (16), also named hirsutanol F was obtained from the hirsutanol F was obtained from fluid fermentation products of Gloeostereum [18].fungus From fluid fermentation products of the Gloeostereum incarnatum [18]. From the culture incarnatum extract of the the culture extract of the fungus Lentinus crinitus, 1-desoxy-hypnophilin (17), and hypnophilin (8) Lentinus crinitus, 1-desoxy-hypnophilin (17), and hypnophilin (8) were isolated as the most active were isolatedInas the most activeketones, compounds. In addition to these ketones, their corresponding compounds. addition to these their corresponding alcohols 6,7-epoxy-4(15)-hirsutene-5-ol alcohols 6,7-epoxy-4(15)-hirsutene-5-ol (18) and diol 4 (19) were obtained in 1994 [19]. (18) and diol 4 (19) were obtained in 1994 [19]. Chloriolin B (20) and C (21) were purified from an unidentified fungus, which separated Chloriolin B (20) and C (21) were purified from an unidentified fungus, which was was separated from from aa marine marine sponge sponge Jaspis Jaspis aff. aff. johnstoni johnstoni [20]. [20]. Hirsutanols A–C (22–24) and ent-gloeosteretriol (25) were Hirsutanols A–C (22–24) and entgloeosteretriol (25) were obtained obtained from from an an unidentified unidentified fungus, fungus, separated from an Indo-Pacific sponge Haliclona sp. in 1998, and study showed that separated from an Indo-Pacific sponge Haliclona sp. in 1998, and study showed that hirsutanol hirsutanol B B was was an an epimer epimer of of hirsutanol hirsutanol A A [5]. [5]. In In 1998, 1998, from from mycelial mycelial cultures cultures of of the the agaric agaric Macrocystidia Macrocystidia cucumis, cucumis, cucumis cucumis A–D A–D (26–29) (26–29) were were found found together together with with arthrosporone arthrosporone (9) (9) [21]. [21]. Hirsutenols Hirsutenols A–C A–C (30–32) (30–32) were were isolated isolated in in 2002, 2002, from from the the culture culture broth broth of of the the mushroom mushroom Stereum Stereum hirsutum hirsutum [22]. [22]. Connatusins Connatusins A A (33) (33) and B (34) were isolated from the fungus Lentinus connatus BCC 8996, in 2005 [23]. and B (34) were isolated from the fungus Lentinus connatus BCC 8996, in 2005 [23]. Xeromphalinones A,B,B,E,E,F F(35–38), (35–38), were isolated from Xeromphalina sp.Liermann by Liermann in Xeromphalinones A, were isolated from Xeromphalina sp. by et al.etinal. 2010. 2010. the time, same they time,isolated they isolated chlorostereone (39)Stereum from Stereum 2014, and coAt theAt same chlorostereone (39) from sp. [24].sp. In [24]. 2014,In Ma and Ma co-workers workers found three new sesquiterpenoids from the mycelia of Stereum hirsutum. Since they didthese not found three new sesquiterpenoids from the mycelia of Stereum hirsutum. Since they did not name name these compounds at that time, we called them compounds 40–42 in proper order, successively compounds at that time, we called them compounds 40–42 in proper 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

Molecules 2018, 23, 2095

3 of 33

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 Molecules 2018, 23, x 3 of 31 of Chondrostereum sp., were varied depending on the culture media. By altering the fermentation 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 hirsutane typetype compounds with a surprising chemodiversity [26]. From thethe PDB (potato dextrose broth) hirsutane compounds with a surprising chemodiversity [26]. From PDB (potato dextrose medium, A–D (43–46) [26] were isolated, hirsutanol (47) [27], chondrosterins broth) chondrosterins medium, chondrosterins A–D (43–46) [26] werewhile isolated, while Ehirsutanol E (47) [27], L–Ochondrosterins (48–51) [28,29] were obtained from GPY (glucose-peptone-yeast) medium. L–O (48–51) [28,29] were obtained from GPY (glucose-peptone-yeast) medium. Aiming at finding newnew secondary metabolites, with bioactivities from fungi collected in the region Aiming at finding secondary metabolites, with bioactivities from fungi collected in the of Tibet Plateau, of aStereum hirsutum was(L515) isolated its fruiting body. Sterhirsutins region of Tibeta strain Plateau, strain of Stereum(L515) hirsutum wasfrom isolated from its fruiting body. Sterhirsutins A (52) and Bacids (53), hirsutic (54) and E (55), were from isolated from this strain’s solidA (52) and B (53), hirsutic D (54) acids and ED (55), were isolated this strain’s solid-substrate substrate fermentation culture in 2014 [30]. Additionally, in 2015, from its ethyl acetate extract, fermentation culture in 2014 [30]. Additionally, in 2015, from its ethyl acetate extract, sterhirsutins C–L sterhirsutins C–L (56–65) obtainedL[31]. L was the first sesquiterpene coupled with (56–65) were obtained [31]. were Sterhirsutin wasSterhirsutin the first sesquiterpene coupled with a xanthine moiety. a Antrodin xanthine moiety. D (66) together with coriolin (2), dihydrocoriolin C (6), and chloriolin B (20), were (66) togetherofwith coriolin (2), dihydrocoriolin C (6), and chloriolin (20), were isolatedAntrodin from the D fermentation the basidiomycete Antrodiella albocinnamomea in 2015B[32]. isolated from the fermentation of the basidiomycete Antrodiella albocinnamomea in 2015 [32]. Scale-up fermentation and chemical studies of basidiomycetes Marasmiellus sp. 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]. Separation of ofthe fermentedbroth brothofofa afungus fungus Chondrostereum Separation theactive activeprinciples principles of of the the fermented Chondrostereum sp. sp. NTOU4196 which waswas isolated fromfrom the marine red alga capillacea, resulted in theinisolation NTOU4196 which isolated the marine red Pterocladiella alga Pterocladiella capillacea, resulted the of chondroterpenes A–H (69–76) in 2017 [34]. isolation of chondroterpenes A–H (69–76) in 2017 [34].

Figure 3. Cont.

Molecules 2018, 23, 2095

4 of 33

Molecules 2018, 23, x

4 of 31

Figure 3. Cont.

Molecules 2018, 23, 2095

5 of 33


5 of 31

Figure 3. Cont.

Molecules 2018, 23, 2095

6 of 33


6 of 31


6 of 31

Figure 3. Structures of type I compounds.


2.2. Type II

2.2. Type II


10 compounds belonging to type II, with four carbon substituents at C-3, 6, 10, 10 2.2.There Type IIwere There were 10 compounds to type II, with four carbon substituents at C-3, 6, 10, (Figure 4). 9 compounds a have belonging carbonyl group. There were 10 compounds belonging to type II, with four carbon at C-3,under 6, 10, both 10 10 (Figure 4). 9 compounds have carbonyl group. Hirsutanol D (77) wasa produced from the terrestrial fungus Corioussubstituents consors, cultured (Figure 4). 9 compounds a have carbonyl group. Hirsutanol D deionized (77) was produced fromin the1998 terrestrial fungus Corious consors, cultured under both sea water and water media, [31]. Cucumins E–G (78–80) were isolated from D (77)water was produced from the terrestrial fungus Corious consors, cultured under both sea mycelial water Hirsutanol andextract deionized media, in 1998 [31]. Cucumins E–G (78–80) were isolated from mycelial of the agaric Macrocystidia cucumis, in 1998 [21]. From the fermentation of sea water and deionized water media, in 1998 [31]. Cucumins E–G (78–80) were isolated from extract of the agaric Macrocystidia cucumis,antrodin in 1998A[21]. From the fermentation of basidiomycete basidiomycete Antrodiella albocinnamomea, (81) was obtained, in 2015 [32]. Chondrosterins mycelial extract of the agaric Macrocystidia cucumis, in 1998 [21]. From the fermentation of E, I–K (82–85) were purified from the marine Chondrostereum [26,28,35]. Cerrenin C (82–85) (86) Antrodiella albocinnamomea, antrodin A (81) wasfungus obtained, in 2015 [32].sp. Chondrosterins E, I–K basidiomycete Antrodiella albocinnamomea, antrodin A (81) was obtained, in 2015 [32]. Chondrosterins was obtained from themarine broth extract of Chondrostereum Cerrena sp. A593 sp. [36].[26,28,35]. Cerrenin C (86) was obtained were purified from the fungus E, I–K (82–85) were purified from the marine fungus Chondrostereum sp. [26,28,35]. Cerrenin C (86) from the extract sp. A593 [36]. sp. A593 [36]. wasbroth obtained from of theCerrena broth extract of Cerrena

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

Figure 4. Structures of type II compounds.


7 of 33 7 of 31

2.3. 2.3. Type Type III III In In type type III III compounds, compounds, there there are are four four carbon carbon substituents substituents in in C-1, C-1, 1, 1, 4, 4, 99 (Figure (Figure 5). 5). The The most most notable feature of these compounds is they contain an off-ring carbon-carbon double bond at C-9. notable feature of these compounds is they contain an off-ring carbon-carbon double bond at 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)-capnellene9(12) -capnellene-8β,10α-diol (87), ∆9(12) -capnellene-3β, 8β, 10α-triol (88), ∆9(12) -capnellene∆ 5α,8β,10α-triol (89), and ∆9(12)-capnellene-2ξ,8β,10α-triol (90), were obtained from the soft coral 5α,8β,10α-triol (89), ∆9(12) (90), were obtained soft coral Capnella imbricata, by and Sheikh et -capnellene-2ξ,8β,10α-triol al. These compounds were the first members of afrom new the sesquiterpene Capnella imbricata, by Sheikh et al. These were the first members of(91), a new class, which was named capnellane [37].compounds ∆9(12)-Capnellene-2β,5α,8β,10α-tetrol hassesquiterpene been isolated 9(12) -Capnellene-2β,5α,8β,10α-tetrol (91), has been isolated class, which was named capnellane [37]. ∆ from the alcyonarian Capnella imbricate, by Kaisin et al. Its structure and relative configuration was from the alcyonarian imbricate, byinKaisin et al.InIts1985, structure configuration was determined by X-ray Capnella diffraction analysis, 1979 [38]. Kaisinand andrelative co-workers implemented determined analysis, in 1979 [38]. In 1985, Kaisin and co-workers implemented the isolationbyofX-ray otherdiffraction 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-

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, 8βacetoxy-∆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 (Figure 6), 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.


9 of 33 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 3.1. Cytotoxicity was was aa kind kind of of common common biological biological activity activity reported reported for for linear linear triquinane triquinane Cytotoxicity sesquiterpenoids, usually expressed as inhibitory concentration (IC 50), 50% of the effective dose sesquiterpenoids, usually expressed as inhibitory concentration (IC50 ), 50% of the effective dose (ED50 ), (ED50), cytotoxic concentration 50), lethal concentration (LC50), or growth inhibition (GI50), this cytotoxic concentration (CC50 ), (CC lethal concentration (LC50 ), or growth inhibition (GI50) , this value value emphasizes the correction forcell the count cell count at time zero) Amongthe the118 118linear linear triquinane triquinane emphasizes the correction for the at time zero) [1].[1]. Among sesquiterpenoids, many compounds exhibited activities against cancer cell lines (Table 1). sesquiterpenoids, many compounds exhibited activities against cancer cell lines (Table 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 coapparently 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

CNE1

15 IC50 = 34.13 µM, 22 IC50 = 10.08 µM, 48 IC50 = 33.55 µM, 49 IC50 = 42.00 µM, 84 IC50 = 1.32 µM, 85 IC50 = 17.66 µM

CNE2

15 IC50 = 24.87 µM, 22 IC50 = 12.72 µM, 43 IC50 = 4.95µM, 48 IC50 = 22.50 µM, 49 IC50 = 44.08 µM, 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


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


HL7702


K562 HCT116

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 = 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 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,

HeLa

98 CC50 = 126.9 ± 1.8 µm/L, 99 CC50 = 126.9 ± 2.5µm/L, 100 CC50 = 142.0 ± 2.7 µm/L, 101 CC50 = 125.0 ± 2.0 µm/L, Doxorubicin CC50 = 2.0 ± 0.8 µm/L

L-929

17 IC50 = 2.4 µg/mL, 18 IC50 = 0.9 µg/mL, 98 GI50 = 126.9 ± 2.7 µm/L, 99 GI50 = 126.9 ± 2.9 µm/L, 100 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 (Table 2) [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 Staphylococcus aureus ATCC 13709 Escherichia coli ATCC 9637 Salmonella gallinarum ATCC 9184 Mycobacterium smegmatis ATCC 607 Candida albicans ATCC 10231 Candida tropicalis DSM 1346 Rhodotorula glutinis DSM 70398 Aspergillus niger (spores) DSM 737 Aspergillus flavus (spores) BD 27 Mucor rouxii (spores) DSM 1691

2–5 10–25 >100 50–100 25–50 50–100 >100 >100 1–2 2–5 2–5

>100 >100 >100 50–100 50–100 >100 >100 >100 25–50 25–50 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] (Tables 3 and 4).

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 43 44 69 70 76

8±2 4±1 4±1 8±2 10 ± 2 4±1

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

Compounds 22 43 44 69 70 76

2 µM

5 µM

10 µM

20 µM

94 ± 1 nt * nt 93 ± 3 95 ± 5 47 ± 6

87 ± 3 nt nt 82 ± 5 95 ± 4 30 ± 5

77 ± 8 22 ± 3 23 ± 7 73 ± 4 89 ± 9 11 ± 2

39 ± 5 12 ± 1 11 ± 1 67 ± 3 69 ± 5 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]. Molecules 2018, 23,and x functional diversities, also pose a considerable synthetic challenge [46]. 13 of 31 Their skeletal 4.1. Hirsutane Type Type In the early 1970s, chemists began to synthesize hirsutane type compounds, in a variety variety of of ways. ways. The total synthesis of hirsutic acid C (1), (1), was was achieved achieved via via the the suitably suitably functionalized functionalized skeleton skeleton compound 119 (Figure 7). 7). In 1974, Hisanobu Hashimoto and co-workers reported a stereospecific stereospecific conversion of 3α-hydroxymethylene ketone (compound 119) to racemic hirsutic acid [47,48]. In 1978, Kueh and and co-workers co-workers[49] [49]reported reportedthe thesynthesis synthesisofof hirsutane carbon skeleton. found thethe hirsutane carbon skeleton. TheyThey found that that the photochemical intramolecular [2 + 2] cycloaddition of dicyclopent-l-enylmethanes (120), the photochemical intramolecular [2 + 2] cycloaddition of dicyclopent-l -enylmethanes (120), followed followed by in situation of methanol the strained cyclopropane ring thepresumed presumed intermediate by in situation of methanol to thetostrained cyclopropane ring in inthe bicycle[2.1.0]pentanes (121), led to to an an easy easy synthesis synthesis of of the the ring ring system. system.

Figure 7. 7. Structures of compounds compounds 119–121. 119–121. Figure Structures of

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 (Scheme 1). 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-C13 -tricyclopentanoid frame (124) was efficiently obtained from cyclopentadiene and 2,5-dimethyl-p-benzoquinone, 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, Scheme 2) and (±)-coriolin ((±)-2) (17 steps, Scheme 3). (17 steps, Scheme 3). 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

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) (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). 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 (Scheme 26) 23, [74]. Molecules 2018, x 15 of 31 Molecules 2018, 23, x Molecules 2018, 23, x

15 of 31 15 of 31

Scheme simple expedient synthesis of (+)-hirsutene ((+)-7) via a novel metathetic Scheme 1.1.The The simple expedient synthesis of (+)-hirsutene ((+)-7) viaphoto-thermal a novel photo-thermal sequence. metathetic sequence. 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. sequence.

Scheme 2. The total synthesis of (±)-hirsutene ((±)-7). H

H

H H

H H

O O O

H

O 128 H HO 128 O 128

Scheme ±)-hirsutene ((±)-7). ((±)-7). Scheme 2. 2. The The total total synthesis synthesis of of ((±)-hirsutene Scheme 2. The Htotal synthesis of (±)-hirsutene ((±)-7).H H O

H H

H H H

O

H H H

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

Scheme 3. 3. The total total synthesis of of (±)-coriolin Scheme )-coriolin ((±)-2). (( ±)-2). Scheme 3.The The totalsynthesis synthesis of(± (±)-coriolin ((±)-2).

Scheme 4. The short synthesis of (±)-7. Scheme 4. The short synthesis of (±)-7. Scheme4. 4. The The short short synthesis synthesis of of ((±)-7. Scheme ±)-7.

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.

(±)- 2 (±)- 2 (±)- 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 The synthesisof of (±)-7 utilizing photochemical reduction. Scheme ±)-7 utilizing utilizing photochemical photochemical reduction. reduction. Scheme 5. 5. The synthesis synthesis of ((±)-7 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 ±)-7 via via the the intramolecular intramolecular addition. addition. Scheme 6. 6. The The synthesis synthesis of of ((±)-7

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.

Molecules 2018, 23, x Molecules 2018, 23, x

16 of 31 16 of 31 16 of 31

Scheme 8. The highly efficient synthesis of (±)-7. Scheme ±)-7. Scheme8. 8. The The highly highly efficient efficientsynthesis synthesisof of((±)-7. Scheme 8. The highly efficient synthesis of (±)-7.

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

Scheme 10. The total synthesis of (±)-7 via a twofold cycloaddition. Scheme10. 10. The The total total synthesis synthesis of of ((±)-7 via twofold cycloaddition. Scheme ±)-7via viaa aatwofold twofoldcycloaddition. cycloaddition. Scheme 10. The total synthesis of (±)-7 TMS TMS TMS COOEt COOEt 140 COOEt 140 140

H H H

TMS TMS TMS

H COOEt H COOEt H 141 COOEt 141 141

H H H H H H 142 142 142

TMS TMS TMS

O O O

H H H H H H

OH OH OH H H H143 H H 143 H 143

O H H O H HO H H

H H H H H 144 H 144 144

(±)-7 (±)-7 (±)-7

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.

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

TMS TMS TMS

H H H

TMS TMS TMS

H H H

H H H H H H

O O O

O H H O H H O H H

OH OH OH

(±)-7 (±)-7 (±)-7

H H H COOEt COOEt H H H H H H COOEt COOEt H 140COOEt H143 H H 142 H 141COOEt H 144 H 140 141 142 144 H143 H 14011. The formal synthesis 141 142an intramolecular 143 ene reaction and a titanium 144 Scheme of (±)-7 via catalyzed

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. epoxy-allylsilane cyclization. Scheme 11. The formal 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 ±)-7 via via aa novel novel one-flask one-flask [2+1+2] [2+1+2]cyclopentannulation cyclopentannulationreaction. reaction. Scheme 12. 12. The The total total synthesis synthesis of of ((±)-7

Scheme 13. The synthesis of 7 utilizing an acid catalyzed intramolecular conjugate addition and a Scheme 13. Thehighly synthesis of 7 utilizingcyclization. an acid catalyzed intramolecular conjugate addition and a stereocontrolled Pd2+-promoted Scheme 13. The synthesis of utilizing an an acid acid catalyzed catalyzed intramolecular intramolecular conjugate Scheme 13. Thehighly synthesis of 77 utilizing conjugate addition addition and and aa stereocontrolled cyclization. Pd2+-promoted 2+ 2+ -promoted highly stereocontrolled cyclization. Pd Pd -promoted highly stereocontrolled cyclization.

Molecules Molecules2018, 2018,23, 23,xx

17 17 of of 31 31

OO HH OO OH OH 150 150

HH

HH

HH

HH

HH

154 154

149 149

OO

OO 151 151

152 152

153 153

Scheme14. 14.The Thestereocontrolled stereocontrolledsynthesis synthesisof of(±)-endo-hirsutene (±)-endo-hirsutene(149) (149)via viaintramolecular intramolecularDiels-Alder, Diels-Alder, Scheme Scheme 14. The stereocontrolled synthesis of (±)-endo-hirsutene (149) via intramolecular Diels-Alder, Paterno-Buchi reactions and a reductive fragmentation. Paterno-Buchi Paterno-Buchireactions reactionsand andaareductive reductivefragmentation. fragmentation.

O O OH OH

HH [Rh(CO) [Rh(CO)22Cl] Cl]22(7 (7mol mol%) %) 11atm (1:4,V/V) atmCO/N CO/N22(1:4,V/V)

CO CO22Me Me (±)-7 (±)-7

1,4-dioxane 1,4-dioxane(0.025M), (0.025M),80 80°C °C

OTBS OTBS

O O

HH

HH

62% 62%

HH

O O

O O

Scheme Scheme15. 15.The Thesynthesis synthesisof of(±)-7. (±)-7. Scheme 15. The synthesis of (±)-7. [Rh(CO) [Rh(CO)22Cl] Cl]22(5 (5mol mol%) %) 11atm (1:4,V/V) atmCO/N CO/N22(1:4,V/V) 1,4-dioxane 1,4-dioxane(0.05M), (0.05M),90 90°C °C 65% 65%

HH

O O

HH

O O (+)-7 (+)-7

HH

Scheme Scheme16. 16.The Thesynthesis synthesisof of(+)-hirsutene (+)-hirsutene((+)-7). ((+)-7).

HH

O O

[Rh(CO)2Cl] 2 (7 mol %) [Rh(CO) (7 mol %) 2Cl] 1[Rh(CO) atm CO/N 2 2(1:4,V/V) (7 mol %) 2Cl] 1 atm CO/N 2 2(1:4,V/V) [Rh(CO) Cl] (7 mol %) 1,4-dioxane (0.025M), 80 °C 1 atm CO/N 2 2 2(1:4,V/V) 1,4-dioxane (0.025M), 62% (1:4,V/V)80 °C 1 atm CO/N 2 80 °C OTBS1,4-dioxane (0.025M), 62% OTBS1,4-dioxane (0.025M), 62% 80 °C Molecules 2018, 23,OTBS 2095 62%

H H H H

OH OH OH OH

H H H H

H O H H O O H OTBS Scheme 15. The synthesisOof (±)-7. Scheme 15. The synthesis of (±)-7. Scheme 15. The synthesis of (±)-7. Scheme 15. The synthesis of (±)-7. O O [Rh(CO) 2Cl]2 (5 mol %) H O (5 mol %) H 2Cl] 1[Rh(CO) atm CO/N 2 2(1:4,V/V) O (5 mol %) H 2Cl] 1[Rh(CO) atm CO/N 22(1:4,V/V) (5 mol H 1[Rh(CO) atm CO/N 2Cl] 1,4-dioxane (0.05M), 90%) °C 2 2(1:4,V/V) 1,4-dioxane (0.05M), 90 °C 1 atm CO/N 2 (1:4,V/V) 65% 1,4-dioxane (0.05M), 90 °C 65% 1,4-dioxane (0.05M), 90 °C 65% 65%

H H H H H H H H

MeO C MeO2C MeO22C MeO2C

H H H H

H H H H H H H H

H H H H

Scheme 16. The The synthesis of of (+)-hirsutene ((+)-7). ((+)-7). Scheme Scheme 16. 16. The synthesis synthesis of (+)-hirsutene (+)-hirsutene ((+)-7). Scheme 16. The synthesis of (+)-hirsutene ((+)-7). Scheme 16. ((+)-7). H H OHThe synthesis of (+)-hirsutene OH H H OH OH H H OH OH (COCl)2,DMSO H (COCl) H H OH H OH 2,DMSO O H (COCl)2,DMSO H O H H H (COCl)2,DMSO H O H H O H O H H O H H O H Scheme 17. The synthesis of 1-desoxyhypnophilin (155). O Scheme 17. 17. The synthesis of of 1-desoxyhypnophilin 1-desoxyhypnophilin (155). (155). Scheme The synthesis synthesis Scheme 17. The of 1-desoxyhypnophilin (155). Scheme 17. The synthesis of 1-desoxyhypnophilin H OH (155). H OH H OH H OH MeO2 C MeO C [Rh(CO)2Cl]2 (10 mol %) MeO22C H [Rh(CO)2Cl]2 (10 mol %) MeO2 C 1 atm CO/N (1:4,mol V/V) H 2 (10 [Rh(CO) %) O 2Cl]2 (1:4, 156 1 atm CO/N V/V) H 2 O [Rh(CO) (10 mol %) 156 2Cl]22(0.02M), 11,4-dioxane atm CO/N (1:4, V/V) 80°C H O 156 (0.02M), 80°C 11,4-dioxane atm CO/N (1:4, V/V) O then HCl,2(0.02M), MeOH/H 2O 156 OH 1,4-dioxane 80°C H then HCl, MeOH/H O 2 65%, 154/155=1.5:1 OTBS1,4-dioxane (0.02M), 80°C H OH then HCl, MeOH/H O 2 154/155=1.5:1 OTBS 65%, H OH HCl, MeOH/H2O 65%, 154/155=1.5:1 OTBS then H OH MeO 2C H OTBS H 65%, 154/155=1.5:1 MeO C MeO 22C H H H MeO2 C 1MeO 2C H O MeO2 C 1 H O 157 O MeO2 C 1 O 157 O H H MeO2 C 1 O 157 O H O 157 H H Scheme 18. The synthesis of hirsutic acid C (1). Scheme 18. The synthesis of hirsutic acid C (1). Scheme The C (1). Scheme 18. 18. The synthesis synthesis of of hirsutic hirsutic acid acid Scheme 18. The synthesis of hirsutic acid C C (1). (1).


O O CO2Me O CO Me O CO22Me O CO2Me(±)-7 (±)-7 (±)-7 (±)-7 O O 18 of 33 O O

O O O O

(+)-7 (+)-7 (+)-7 (+)-7

O O O O H H H H

O O O O

O O O O

H H155 H155 H155 155

H H H H

MeO C MeO 2C MeO 22C MeO 2C

OH OH OH OH

H H158 H158 H 158 158

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. 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 dehydration oxidation maneuvers. and oxidationand maneuvers. i-PrO

i-PrO i-PrO

O

H

O

O

i-PrO

OH

i-PrO O

H

H

OH

O H

OMOM

Scheme 21. The conversion of diisopropyl squarate to 8.

8 H

OH


18 of 31

Scheme 20. The synthesis of hypnophilin (8) via a combination of chlorination, reduction, Molecules 2018, 23, 2095 19 of 33 Scheme 20. The synthesis of hypnophilin (8) via a combination of chlorination, reduction, dehydration Scheme 20. and Theoxidation synthesismaneuvers. of hypnophilin (8) via a combination of chlorination, reduction, dehydration Scheme 20. and Theoxidation synthesismaneuvers. of hypnophilin (8) via a combination of chlorination, reduction, dehydration and oxidation maneuvers. Scheme 20. The synthesis of hypnophilin (8) via a combination of chlorination,H reduction, dehydration and oxidation maneuvers. H H O H dehydration maneuvers. H H O i-PrO O and oxidation H H H O i-PrO O H H H O 8 i-PrO O O i-PrO i-PrO H H H O 8 i-PrO O O H i-PrO OH i-PrO H 8 i-PrO O O H OH i-PrOi-PrO OH O i-PrO H OMOM i-PrO O 8 OH i-PrO O H OH i-PrOi-PrO OH O H OMOM i-PrO O 8 O OH i-PrO H OH i-PrOi-PrO OH O H OMOM i-PrO O OH H OH i-PrO Scheme of diisopropyl squarate to 8. OH 21.OThe conversion H OMOM i-PrO O Scheme The conversion conversion of squarate OH OH i-PrO Scheme 21. 21.OThe of diisopropyl diisopropyl squarate to to 8. 8. OMOM OH Scheme 21. The conversion of diisopropyl squarate to 8. Scheme 21. The conversion of diisopropyl squarate to 8. Scheme 21. The conversion of diisopropyl squarate to 8.

i-PrO i-PrO i-PrO i-PrO i-PrO i-PrO i-PrO i-PrO i-PrO

O O O O O O O O O

Scheme 22. The formal synthesis of racemic coriolin (2). Scheme 22. The formal synthesis of racemic coriolin (2). Scheme Scheme 22. 22. The formal synthesis of racemic coriolin (2). H synthesis of racemic coriolin (2). SchemeO22. The formal H O coriolin (2). SchemeO22. The formal H synthesis of racemic H O H O H O H i-PrO O H O H i-PrO i-PrO O H OH O i-PrO i-PrO i-PrO OH i-PrO i-PrOi-PrO O H i-PrO i-PrO i-PrO 23. OH Scheme The synthesis of ceratopicanol (109). i-PrO i-PrO 23. OH Scheme The synthesis of ceratopicanol (109). i-PrO 23. The synthesis of ceratopicanol (109). Scheme Scheme Scheme 23. 23. The The synthesis synthesis of of ceratopicanol ceratopicanol (109). (109). Scheme 23. The synthesis of ceratopicanol (109).

109 109 109 109 109

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 (−)-2 and24. theThe synthesis of the isomeric tetracyclic system 161, a late-stageofprecursor to (−)-2. (−)-8 and Scheme synthesis of compound 159, an advanced intermediate both compounds (−)-2 and24. theThe synthesis of the isomeric tetracyclic system 161, a late-stageofprecursor to (−)-2. (−)-8 and Scheme synthesis of compound 159, an advanced intermediate both compounds Scheme The synthesis of 159, intermediate of both −)-8 and and (−)-2 and24. theThe synthesis of the isomeric tetracyclic system 161, a late-stage to (−)-2.((−)-8 Scheme 24. synthesis of compound compound 159, an an advanced advanced intermediate ofprecursor bothcompounds compounds (−)-2 and the synthesis of the isomeric tetracyclic system 161, late-stage precursor to (−)-2. ((−)-2 −)-2and andthe thesynthesis synthesisof ofthe theisomeric isomeric tetracyclic tetracyclic system system 161, 161, aaa late-stage late-stage precursor precursor to to (−)-2. (−)-2.

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 ring within kinds of functional group interconversions. Scheme 25. this The framework synthesis ofand (+)-connatusin B ((+)-34) via reductive cleavage of the three-membered ring within kinds of functional group interconversions. Scheme 25. this Theframework synthesis ofand (+)-connatusin B ((+)-34) via reductive cleavage of the three-membered ring within kinds of functional group interconversions. Scheme 25. this The framework synthesis ofand (+)-connatusin B ((+)-34) via reductive cleavage of the three-membered Scheme 25. The synthesis of (+)-connatusin B ((+)-34) via reductive cleavage ring within this framework and kinds of functional group interconversions. 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 Molecules 2018, 23, x Molecules 2018, 23, x

20 of 33 19 of 31 19 of 31

Scheme 26. The synthesis of (−)-connatusin A ((−)-33). Scheme −)-connatusin A A ((−)-33). ((−)-33). Scheme26. 26.The Thesynthesis synthesisof of((−)-connatusin

4.2. Capnellene Type Capnellene Type 4.2. Capnellene 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 Capnellene architecture, exocyclic olefinic linkage, disposition of methyl groups, and its role in the defense architecture, exocyclic exocyclic olefinic olefinic linkage, linkage, disposition disposition of of methyl methyl groups, groups, and and its its9(12) role in the defense architecture, role mechanism and biosynthesis of oxygenated capnellenes [75], especially (±)-∆9(12) -capnellene (178), 9(12) mechanism and biosynthesis of oxygenated especially )-∆ -capnellene -capnellene (178), (178), mechanism biosynthesis oxygenated capnellenes capnellenes[75], [75], especially(± (±)-∆ 9(12)of 9(12)-capnellene ∆9(12) -capnellene (179), (−)-∆ -capnellene (180), and (+)-∆ (181) (Figure The first 9(12) -capnellene (179), (−)-∆ 9(12) -capnellene (180), and (+)-∆ 9(12) -capnellene (181) (Figure8). ∆9(12) 8). The The first first ∆ -capnellene (179), 9(12) (−)-∆9(12) -capnellene (180), and (+)-∆9(12) -capnellene (181) (Figure 8). total synthesis of (±)-∆ 9(12) -capnellene (178), was reported in 1981 [76]. total synthesis of (±)-∆ (±)-∆9(12)-capnellene -capnellene (178), was reported in 1981 [76]. (178), was reported in 1981 [76].

Figure 8. Structures of compounds 178–181. Figure Figure 8. 8. Structures Structures of of compounds compounds 178–181. 178–181.

Stille and Grubbs [77] realized the synthesis of (±)-∆9(12)-capnellene (178) by using titanium 9(12)-capnellene (178) by using titanium Stille and Grubbs [77] realized the synthesis of (±)-∆9(12) reagents 27). Stille and co-workers [78] achieved total synthesis through the Stille(Scheme and Grubbs [77] realized the synthesis of (±)-∆ the-capnellene (178)ofby178, using titanium reagents (Scheme 27). Stille and co-workers [78] achieved the total synthesis of 178, through the rearrangement of bicyclo[2.2.1]heptane ring systems by titanocene alkylidene complexes to reagents (Scheme 27). Stille and co-workers [78] achieved the total synthesis of 178, through rearrangement of bicyclo[2.2.1]heptane ring systems by titanocene alkylidene complexes to 9(12) bicyclo[3.2.0]heptane ethers (Scheme 28).ring A new synthetic strategy foralkylidene (±)-∆ -capnellene (178) the rearrangement ofenol bicyclo[2.2.1]heptane systems by titanocene complexes to bicyclo[3.2.0]heptane enol ethers (Scheme 28). A new synthetic strategy for (±)-∆9(12)-capnellene (178) 9(12)-capnellene-8β,10α-diol 9(12) and (±)-∆ (182), was presented in 1992 [79]. This strategy was presented as bicyclo[3.2.0]heptane enol ethers (Scheme 28). A new synthetic strategy for (±)-∆ -capnellene and (±)-∆9(12)-capnellene-8β,10α-diol (182), was presented in 1992 [79]. This strategy was presented as 9(12) a model study in the synthesis of the pentalanic trimethylketone, which has been used as a key (178) and (±)-∆ -capnellene-8β,10α-diol (182), was presented in 1992 [79]. This strategy was a model study in the synthesis of the pentalanic trimethylketone, which has been used as a key intermediate the total synthesis of both 178 andpentalanic 182 (Scheme 29). presented as ainmodel study in the synthesis of the trimethylketone, which has been used as intermediate in the total synthesis of both 178 and 182 (Scheme 29). It was worth mentioning that although palladium catalyzed zipper mode cyclization, using a key intermediate in the total synthesis of both 178 and 182 (Scheme 29). It was worth mentioning that although palladium catalyzed zipper mode cyclization, using HeckItreaction conditions had that caused widespread concern for the construction of polycyclic system, was worth mentioning although palladium catalyzed zipper mode cyclization, using Heck Heck reaction conditions had caused widespread concern for the construction of polycyclic system, this methodology suitable for the required stereochemistry of the capnellane reaction conditionswas hadnot caused widespread concerncis-anti-cis 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 suitable 1994 Genevieve Balme achieved total synthesisofofthe 178, using a this methodology was not for the required cis-anti-cisthe stereochemistry capnellane system [61]. However, in 1994 Genevieve Balme achieved the total synthesis of 178, using a palladium-catalyzed bis-cyclization step [80]. diquinanes were easily and system [61]. However, in 1994 Genevieve BalmeFunctionalized 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 palladium-catalyzed bis-cyclization step [80]. Functionalized diquinanes were easily and stereoselectively stereoselectively gained from a new palladium catalyzed cyclisation 183→186 (Scheme 30). Applying the intramolecular version of catalyzed this strategy, a triquinane should be directly obtained a single step, gained from a new palladium cyclisation 183→186 (Scheme 30). Applying theinintramolecular 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). version of this strategy, a triquinane should be directly obtained in a single step, by construction of the by construction of the two outer rings around the central ring (Scheme 31). In 1997, Singh and co-workers [81] developed a novel synthesis of capnellene from p-cresol and two outer rings around the central ring (Scheme 31). In 1997, Singh and co-workers [81] developed a novel synthesis of capnellene from p-cresol and cyclopentadiene, theand keyco-workers steps of the[81] synthesis were ainverse reaction oxaIn 1997, Singh developed novel demand synthesisDiels-Alder of capnellene from and p-cresol cyclopentadiene, the key steps of the synthesis were inverse demand Diels-Alder reaction and oxadi-π-methane rearrangement developed novel and efficient total synthesis of and 178 and cyclopentadiene, the key [74]. stepsThey of thealso synthesis wereainverse demand Diels-Alder reaction di-π-methane rearrangement [74]. developed a novel and efficient total synthesis of 178 4s +They 2s also from p-cresol employing π π cycloaddition of spiroepoxycyclohexa-2,4-dienone and oxa-di-π-methane rearrangement [74]. They also developed a novel and efficient total synthesis from p-cresol employing π4s + 4s π2s 2s cycloaddition of spiroepoxycyclohexa-2,4-dienone and photochemical 1,2-acyl shift, as key (Scheme 32). of spiroepoxycyclohexa-2,4-dienone and of 178 from p-cresol employing π features + π cycloaddition photochemical 1,2-acyl shift, as key features (Scheme 32). In 2009, Nguyen and co-workers [82] presented general route to a formal synthesis of 178. This photochemical 1,2-acyl shift, as key features (Schemea32). In 2009, Nguyen and co-workers [82] presented a general route to a formal synthesis of 178. This cascade strategy, combined an intramolecular Diels-Alder reaction tandem metathesis protocol to In 2009, Nguyen and co-workers [82] presented a general route to a formal synthesis of 178. cascade strategy, combined an intramolecular Diels-Alder reaction tandem metathesis protocol to 2,6 produce the linear cis-anti-cis-tricyclo[6.3.0.0 ]undecane skeleton directly (Scheme 33). protocol to This cascade strategy, combined an intramolecular Diels-Alder reaction tandem metathesis 2,6]undecane skeleton directly (Scheme 33). produce the linear cis-anti-cis-tricyclo[6.3.0.02,6 In 2009, Hsu and co-workers [83] developed an efficient and short route from 2-methoxyphenols produce the linear cis-anti-cis-tricyclo[6.3.0.0 ]undecane skeleton directly (Scheme 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 (88) (Scheme 48). Molecules 2018, xx 21 Molecules 2018,23, 23, 21 of of 31 31 Molecules 2018, 23, x

21 of 31

9(12) 9(12)-capnellene (178) Scheme (±)-∆ by using titanium reagents. 9(12) Scheme 27. 27. The The synthesis synthesis of of± (±)-∆ (178) by using titanium reagents. Scheme )-∆9(12) -capnellene(178) (178)by byusing usingtitanium titaniumreagents. reagents. 9(12) -capnellene Scheme27. 27.The Thesynthesis synthesisof of((±)-∆ -capnellene

O O O

TsO TsO TsO O O O

COOEt COOEt COOEt

O H HO HO O O O H H H

H H H

O O O

H H H 178 178 178

H H H

H H H

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

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

Scheme Scheme 30. 30. The The synthesis synthesis of of 186 186 from from aa new new palladium palladium catalyzed catalyzed cyclisation. cyclisation. Scheme Scheme 30. 30. The The synthesis synthesis of of 186 186 from from aa new new palladium palladium catalyzed catalyzed cyclisation. cyclisation.

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, x31.

The total synthesis of 178 using a palladium-catalyzed bis-cyclization step. 22 of 31


22 of 31 22 of 31


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

O

178

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

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.

Scheme HO 35. The total syntheses of (±)-7 and 178 via a formalH[3 + 2] annulation strategy. 179 H HO O N HH 179 O HO N 179 H188 HO O 187 N O H 179 NN O N N (179) by using anOintramolecular 187 H188 Scheme 36.OThe total synthesis of ∆9(12)-capnellene 1, 3-diyl trapping O 188 N 187 reaction as a primary strategy.

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 187

N

O

H 188

9(12) Scheme of ∆ Scheme 36. 36. The The total total synthesis synthesis of ∆9(12)-capnellene -capnellene(179) (179)by byusing usingan anintramolecular intramolecular 1, 1, 3-diyl 3-diyl trapping trapping reaction as a primary strategy. reaction as a primary strategy. Molecules 2018, 23, x 23 of 31

Molecules 2018, 23, x Molecules Molecules2018, 2018,23, 23,xx

O O OO

O O OO

O O OO H H HH

23 of 31 23 23 of of 31 31

O O OO

O H O H OO HH

O 179 O OO 179 179 189 H 179 H 189 H 189 H H 189 H HH Scheme 37. 37. The The stereocontrolled stereocontrolled total total synthesis synthesis of of 179. 179. Scheme Scheme 37. The stereocontrolled total synthesis of 179. Scheme Scheme37. 37.The Thestereocontrolled stereocontrolledtotal totalsynthesis synthesisof of179. 179. O O O H O O O OO OO H OO HH 179 179 SiMe3 SiMe3 179 179 190 SiMe3 191 SiMe3 SiMe SiMe33 190 SiMe 191 SiMe33 190 191 190 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 of vinyl vinyl triflates triflates Scheme 38. The total synthesis of 179 via palladium-catalyzed carbonylative coupling with organostannanes. Scheme 38. The total synthesis of 179 via palladium-catalyzed carbonylative Scheme 38. The total synthesis of 179 via palladium-catalyzed carbonylativecoupling couplingof ofvinyl vinyltriflates triflates with organostannanes. with with organostannanes. withorganostannanes. organostannanes.

OHC OHC OHC OHC

O O O O O O O O

O O H O OH HH

EtO2C EtO2C EtO EtO22CC

179 179 179 179

H H HH

Scheme 39. The formal synthesis of 179 by using new type of fulvenes undergo cycloadditions Scheme 39. The The formal synthesis of 179 by using newusing type of fulvenes undergo cycloadditions regioselectively. Scheme 39. The formal synthesis of 179 by new type undergo of fulvenes undergo Scheme synthesis of new fulvenes cycloadditions Scheme 39. 39. The formal formal synthesis of 179 179 by by using using new type type of of fulvenes undergo cycloadditions regioselectively. cycloadditions regioselectively. regioselectively. regioselectively.

O O OO

PhH2C PhH2C PhH PhH22CC OEt OEt OEt OEt O O OO H CO2Me CO2Me H CO Me HH CO22Me

O O OO

OH OH OH OH

O O OO O O OO

O O OO

OH OH OH OH

H H H H HH H Scheme 40. The formal synthesis of 179 via the construction of H cyclopentanones with substituents up

Scheme 40. The formal synthesis of 179 via the construction of cyclopentanones with substituents up to three contiguous chiral centres.of Scheme 40. synthesis Scheme 40.The Theformal formal synthesis of179 179via viathe theconstruction constructionof ofcyclopentanones cyclopentanoneswith withsubstituents substituentsup up Scheme 40. The formal synthesis to three contiguous chiral centres.of 179 via the construction of cyclopentanones with substituents up to three contiguous chiral centres. tothree threecontiguous contiguouschiral chiralcentres. centres. to

O O O O TBSO TBSO H H TBSO TBSO H H HH HH H H O HH O O O

OH OH OH OH TBSO TBSO H H TBSO TBSO H H HH HH

OH OH OH OH

O O O O O O H H O OH H HH HH

H H H OH H HH OH HH OH OHThe synthesis of 179. Scheme 41.

Scheme 41. The synthesis of 179. Scheme 41. The synthesis of 179.

179 179 179 179

179 179 179 179

OEt OEt

O O

OH

O

O O CO2Me CO2Me

H H

O O

O O

O

OH OH

H H

179 179

H H

Molecules 2018, 23, 25 of 33 Scheme 40.2095 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 to three contiguous chiral centres. to three contiguous chiral centres.

OH OH

O O

OH OH

O O

TBSO TBSO H H H H

TBSO TBSO H H H H

O O H H H H

H H OH OH

H H O O

179 179

H H

Scheme 41. 41. The synthesis synthesis of 179. 179. Scheme Scheme 41. The The synthesis of of 179.

HO HO

192 192

HO HO

H H

193 193


O O

O O

180 180 H H

H H

Scheme 42. The formal asymmetric synthesis of (−)-capnellene (180). Scheme 42. The formal asymmetric synthesis of (−)-capnellene (180). Scheme 42. The formal asymmetric synthesis of (−)-capnellene (180).

24 of 31 24 of 31

Scheme 43. 43. The formal formal synthesis of of 180 by by employing silyl silyl group directed stereo control. Scheme Scheme 43. The The formal synthesis synthesis of 180 180 by employing employing silyl group group directed stereo control.

H H O O

H H 195 195 H H

H H

H H

H H

HO HO

OTs OTs

O O OCS OCS22Me Me

H H

H H

H H

O O

HO HO

BzOH BzOH22C C

H H HH

H H 180 180

H H HH BzOH BzOH22C C

H H HH

H H HH

HO HO

II

Scheme Scheme 44. 44. The The stereocontrolled stereocontrolled synthesis synthesis of of 180 180 based based on on the the structure structure and and high high functionality functionality of of the the Scheme 44. stereocontrolled synthesis of 180 based on structure and high functionality of the starting material. starting material. material. starting

CO Et EtO EtO22C C CO22Et H OTBOPS H OTBOPS

196 196

H H

OBz OBz

OBz OBz H H

OTBOPS OTBOPS

H H

H H

II

HO HO

H H 180 180

H H HH

H H

H

HH BzOH 2C H H BzOH 2C

HH HH

HO HO

I I

180 180

HH HH

Scheme 44.2095 The stereocontrolled synthesis of 180 based on the structure and high functionality of the26 of 33 Molecules 2018, 23, Schemematerial. 44. The stereocontrolled synthesis of 180 based on the structure and high functionality of the starting starting material.

EtO2C CO2Et EtO2C CO2Et H OTBOPS H OTBOPS

196 196

OBz OBz

OBz OBz H H

OTBOPS OTBOPS

H H

H H

H H

I I

HH HH

HO HO

H H 180 180

HH HH HH SeC 6H 4(2-NO 2) HH HO SeC H (2-NO ) HO 6 4 2 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 Scheme block. 45. The first catalytic asymmetric total synthesis of 180 by using 196 as an asymmetric building building block. building block.

O O

O O

O O

N N O 197 O 197

O O

H MeO2C H MeO2C CO2Me CO2Me Br Br H H

OH OH

H H

O O

O O

181 181

Scheme 46. The first asymmetric total synthesis of the unnatural enantiomer of (+)-∆9(12)-capnellene 9(12)-capnellene Scheme46. 46. Thefirst first asymmetric total synthesis of unnatural the unnatural enantiomer of9(12) (+)-∆ (181). Scheme asymmetric total synthesis of the enantiomer of (+)-∆ -capnellene (181). Molecules 2018, 23, The x 25 of 31 (181). Molecules 2018, 23, x 25 of 31

O O

H H

OTMS OTMS

EtO 2C EtO 2C H H

O O

87 87

H H

H H H H HO H HO OH OH H

O O

H H

H H EtO2 C EtO2 C H H

O O

O O 88 88

H H

MPMO MPMO H H

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

O O

O O

H OAc H H OAc H

H H

O O

198 198

EtO 2C EtO 2C H H

199 199

O O

87 87

H H

88 88

Scheme 48. The synthesis of 87 and 88. Scheme 48. 48. The The synthesis synthesis of Scheme of 87 87 and and 88. 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

O

O

O H

198 Molecules 2018, 23, 2095

199

Scheme 48. The synthesis of 87 and 88.

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 In 1996, Baralotto and co-workers [99]which proposed (±)-ceratopicanol ((±)-109), employing seven steps, in thea total key synthesis one wasof racemic an intramolecular meta (( ± )-109), employing seven steps, in which the key one was an intramolecular meta photocycloaddition photocycloaddition of the phenylpentene derivative 200, which constituted a typical holosynthon of the phenylpentene 200,co-workers which constituted a typical holosynthon (Scheme 49). In 1996, (Scheme 49). In 1996,derivative Clive and [100] also reported a method to synthesize (+)Clive and co-workers [100] also reported a method to synthesize (+)-ceratopicanol (109) (Scheme ceratopicanol (109) (Scheme 50). This method has been used to form many compounds of 50). the This method has been used to form many compounds of the triquinane class. triquinane class. The first total (78) was was achieved achieved in in 2002, 2002, which which used used an an ynolate-initiated ynolate-initiated The first total synthesis synthesis of of cucumin cucumin E E (78) tandem reaction for the construction of the cyclopentenone unit (Scheme 51). This strategy proved the tandem reaction for the construction of the cyclopentenone unit (Scheme 51). This strategy proved feasibility of a short access to triquinane sesquiterpenoids [45]. the feasibility of a short access to triquinane sesquiterpenoids [45]. The −)-cucumin H H ((−)-110) ((−)-110)was wasreported reportedin in2003 2003[101] [101] (Scheme (Scheme 52). 52). The first first total total synthesis synthesis of of the the ((−)-cucumin This method started from (R)-limonene employing two different cyclopentannulation methodologies, This method started from (R)-limonene employing two different cyclopentannulation which were to which confirm theto structure, well as as establish the absolute configuration of the methodologies, were confirm theasstructure, well as establish the absolute configuration natural product. of the natural product. Furthermore pleurotellic acid (115) and and pleurotellol pleurotellol (114) Furthermore in in 2003, 2003, the the first first total total synthesis synthesis of of pleurotellic acid (115) (114) was was achieved. One notable notable feature feature of of this this synthesis, synthesis, was was that that it it followed achieved. One followed an an adaptation adaptation of of the the versatile versatile photo-thermal The other other feature feature was photo-thermal metathesis-based metathesis-based approach approach to to triquinane triquinane sesquiterpenoids. sesquiterpenoids. The was the 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, system, through through simple simple reaction reaction sequences sequences [46] [46] (Scheme (Scheme 53). 53).

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

26 of 31

Scheme 50. The synthesis of 109. Scheme Scheme 50. 50. The The synthesis synthesis of of 109. 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 for the construction thesynthesis cyclopentenone unit. E Scheme 51. The firstof total of cucumin (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 51.2095 The first total synthesis of cucumin E (78) by using an ynolate-initiated tandem reaction Molecules 2018, 23, 28 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.

Scheme52. 52. Thefirst first totalsynthesis synthesis of the((−)-cucumin H (( ((−)-110). Scheme )-cucumin H −)-110). Scheme 52.The The firsttotal total synthesisofofthe 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). 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 most them isolated from fungi, sponges, and softsesquiterpenoids corals, among which mushroom Fromof 1947 to were July 2018, more than 100 linear triquinane havethe been isolated, and most of them were isolated from fungi, sponges, and soft corals, among which the mushroom stereum hirsutum, softisolated coral capnella imbricata, and marine fungus typical and most of themthe were from fungi, sponges, and soft corals,chondrostereum among whichsp. thewere mushroom stereum hirsutum, the soft coral capnella imbricata, and marine fungus chondrostereum sp. were typical sources.hirsutum, It is important to note particular, that Liand andmarine co-workers have obtained 19 linear triquinane stereum the soft coralincapnella imbricata, 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 I–O, C, E, F, incarnal, arthrosporone, sources. It is important to note in particular, A–E, that Li andhirsutanols co-workersA, 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 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 correlatedfungus with aChondrostereum specific stage sp. of morphological and anhydroarthrosporone, from the marine-derived Furthermore, production of secondary metabolites often correlated with a specific stage of morphological differentiation It indicated that in addition to looking new sources linear the production [102]. of secondary metabolites often correlated withfor a specific stage to of produce morphological differentiation [102]. It indicated that in addition to looking for new sources to produce linear triquinane sesquiterpenoids, we canthat alsoin find ways totoisolate linear sesquiterpenoids with differentiation [102]. It indicated addition looking fortriquinane new sources to produce linear triquinane sesquiterpenoids, we can also find ways to isolate linear triquinane sesquiterpenoids with multiple structural types from organism. Manylinear of these compounds displayed a triquinane sesquiterpenoids, weone can“talented” also find ways to isolate triquinane sesquiterpenoids multiple structural types from one “talented” organism. Many of these compounds displayed a variety of biological activities, such one as cytotoxicity, anti-microbial, anti-inflammatory activities.a with multiple structural types from “talented” organism. Manyand of these compounds displayed variety of biological activities, such as cytotoxicity, anti-microbial, and anti-inflammatory activities. Given their structuralactivities, diversitysuch and complexity, andanti-microbial, significant biological activities, linear triquinane variety of biological as cytotoxicity, 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 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 efficientchemists. synthesisAmong methods have been developed sesquiterpenoids attracted great interest fromof synthetic the 8 skeletal types, typetoI and III are the most popular ones, a number of efficient synthesis methods have been developed to construct skeletonones, of linear triquinane sesquiterpenoids. and III arethe theunique most popular a number of efficient synthesis methods have been developed to construct the unique skeleton of linear triquinane sesquiterpenoids. construct the unique skeleton of linear 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.

References 1. 2. 3. 4.

Le, B.F.; Kousara, M.; Chen, L.; Wei, L.; Dumas, F. Tricyclic sesquiterpenes from marine origin. Chem. Rev. 2017, 117, 6110–6159. [CrossRef] Comer, F.W.; Mocapra, F.; Qureshi, I.H.; Scott, A.I. The structure and chemistry of hirsutic acid. Tetrahedron 1967, 23, 4761–4768. [CrossRef] Heatley, N.G.; Jennings, M.A.; Florey, H.W. Antibiotics from Stereum hirsutum. Brit. J. Exp. Pathol. 1947, 28, 35–46. Amouzou, E.; Ayer, W.A.; Browne, L.M. Antifungal sesquiterpenoids from an arthroconidial fungus. J. Nat. Prod. 1989, 52, 1042–1054. [CrossRef]

Molecules 2018, 23, 2095

5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

16.

17. 18.

19. 20.

21. 22. 23.

24.

25.

29 of 33

Wang, G.-Y.-S.; Abrell, L.M.; Avelar, A.; Borgeson, B.M.; Crews, P. New hirsutane based sesquiterpenes from salt water cultures of a marine sponge-derived fungus and the terrestrial fungus Coriolus consors. Tetrahedron 1998, 54, 7335–7342. Grote, D.; Hanel, F.; Dahse, H.M.; Seifert, K. Capnellenes from the soft coral Dendronephthya rubeola. Chem. Biodivers. 2007, 4, 1683–1693. [CrossRef] [PubMed] Chang, C.H.; Wen, Z.H.; Wang, S.K.; Duh, C.Y. Capnellenes from the formosan soft coral Capnella imbricate. J. Nat. Prod. 2008, 71, 619–621. [CrossRef] [PubMed] Helaly, S.E.; Richter, C.; Thongbai, B.; Hyde, K.D.; Stadler, M. Lentinulactam, a hirsutane sesquiterpene with an unprecedented lactam modification. Tetrahedron Lett. 2016, 57, 5911–5913. [CrossRef] Takeuchi, T.; Iinuma, H.; Iwanaga, J.; Takahashi, S.; Takita, T.; Umezaw, H. Coriolin, a new basidiomycetes antibiotic. J. Antibiot. 1969, 22, 215–217. [CrossRef] [PubMed] Takahashi, S.; Iinuma, H.; Takita, T.; Maeda, K.; Umezawa, H. The structures of coriolin B and C. Tetrahedron Lett. 1970, 11, 1637–1639. [CrossRef] Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Isolation, structure and synthesis of hirsutene, a precursor hydrocarbon of coriolin biosynthesis. Tetrahedron Lett. 1976, 17, 195–198. [CrossRef] Takahashi, S.; Naganawa, H.; Iinuma, H.; Takita, T.; Maeda, K.; Umezawa, H. Revised structure and stereochemistry of coriolins. Tetrahedron Lett. 1971, 12, 1955–1958. [CrossRef] Mellows, G.; Mantle, P.G.; Feline, T.C.; William, D. Sesquiterpenoid metabolites from Stereum complicatun. J. Phytochemistry 1973, 12, 2717–2720. [CrossRef] Tanabe, M.; Suzuki, K.T. Biosynthetic studies with carbon-13: The FT-13 C NMR spectra of the sesquiterpenoid coriolins. Tetrahedron Lett. 1974, 15, 2271–2274. [CrossRef] Kupka, J.; Anke, T.; Giannetti, B.M.; Steglich, W. Antibiotics from basidiomycetes XIV. * Isolation and biological characterization of hypnophilin, pleurotellol, and pleurotellic acid from Pleurotellus hypnophilus (Berk.) Sacc. Arch. Microbiol. 1981, 130, 223–227. [CrossRef] Giannetti, B.M.; Steffan, B.; Steglich, W. Antibiotics from basidiomycetes. Part 24.1: Antibiotics with a rearranged hirsutane skeleton from Pleurotellus Hypnophilus (agaricales). Tetrahedron 1986, 42, 3587–3593. [CrossRef] Takazawa, H.; Kashino, S. Incarnal, a new antibacterial sesquiterpene from basidiomycetes. Chem. Pham. Bull. 1991, 39, 555–557. [CrossRef] [PubMed] Gao, J.; Yue, D.C.; Cheng, K.D.; Wang, S.C.; Yu, K.B.; Zheng, Q.T.; Yang, J.S. Gloeosteretriol, a new sesquiterpene from the fermentation products of Gloeostereum incarnatum S. Ito et Imai. Acta Pharm. Sin. 1992, 27, 33–36. [CrossRef] Abate, D.; Abraham, W.R. Antimicrobial metabolites from Lentinus crinitus. J. Antibiot. 1994, 47, 1348–1350. [CrossRef] [PubMed] Cheng, X.C.; Varoglu, M.; Abrell, L.; Lobkovsky, E.; Clardy, J. Chloriolins A–C, chlorinated sesquiterpenes produced by fungal cultures separated from a juspis marine sponge. J. Org. Chem. 1994, 59, 6344–6348. [CrossRef] Hellwig, V.; Dasenbrock, J.; Schumann, S.; Steglich, W.; Leonhardt, K.; Anke, T. New triquinane-type sesquiterpenoids from Macrocystidia cucumis (Basidiomycetes). Eur. J. Org. Chem. 1998, 73–79. [CrossRef] Yun, B.S.; Lee, I.K.; Cho, Y.; Cho, S.M.; Yoo, I.D. New tricyclic sesquiterpenes from the fermentation broth of Stereum hirsutum. J. Nat. Prod. 2002, 65, 786–788. [CrossRef] [PubMed] Rukachaisirikul, V.; Tansakul, C.; Saithong, S.; Pakawatchai, C.; Isaka, M.; Suvannakad, R. Hirsutane sesquiterpenes from the fungus Lentinus connatus BCC 8996. J. Nat. Prod. 2005, 68, 1674–1676. [CrossRef] [PubMed] Liermann, J.C.; Schuffler, A.; Wollinsky, B.; Birnbacher, J.; Kolshorn, H.; Anke, T.; Opatz, T. Hirsutane-type sesquiterpenes with uncommon modifications from three basidiomycetes. J. Org. Chem. 2010, 75, 2955–2961. [CrossRef] [PubMed] Ma, K.; Bao, L.; Han, J.J.; Yang, X.L.; Zhao, F.; Li, S.F.; Song, F.H.; Liu, M.M.; Liu, H.W. New benzoate derivatives and hirsutane type sesquiterpenoids with antimicrobial activity and cytotoxicity from the solid-state fermented rice by the medicinal mushroom Stereum hirsutum. Food Chem. 2014, 143, 239–245. [CrossRef] [PubMed]

Molecules 2018, 23, 2095

26.

27. 28.

29. 30.

31.

32.

33.

34.

35.

36.

37.

38.

39. 40. 41. 42. 43.

44.

30 of 33

Li, H.J.; Xie, Y.L.; Xie, Z.L.; Chen, Y.; Lam, C.K.; Lan, W.J. Chondrosterins A–E, triquinane-type sesquiterpenoids from soft coral-associated fungus Chondrostereum sp. Mar. Drugs 2012, 10, 627–638. [CrossRef] [PubMed] Li, H.J.; Lan, W.J.; Lam, C.K.; Yang, F.; Zhu, X.F. Hirsutane sesquiterpenoids from the marine-derived fungus Chondrostereum sp. Chem. Biodivers. 2011, 8, 317–324. [CrossRef] [PubMed] Huang, L.; Lan, W.J.; Deng, R.; Feng, G.K.; Xu, Q.Y.; Hu, Z.Y.; Zhu, X.F.; Li, H.J. Additional new cytotoxic triquinane-type sesquiterpenoids chondrosterins K–M from the marine fungus Chondrostereum sp. Mar. Drugs 2016, 14, 157. [CrossRef] [PubMed] Huang, L.; Lan, W.J.; Li, H.J. Two new hirsutane-type sesquiterpenoids chondrosterins N and O from the marine fungus Chondrostereum sp. Nat. Prod. Res. 2018, 32, 1578–1582. [CrossRef] [PubMed] Qi, Q.Y.; Bao, L.; Ren, J.W.; Han, J.J.; Zhang, Z.Y.; Li, Y.; Yao, Y.J.; Cao, R.; Liu, H.W. Sterhirsutins A and B, two new heterodimeric sesquiterpenes with a new skeleton from the culture of Stereum hirsutum collected in Tibet plateau. Org. Lett. 2014, 16, 5092–5095. [CrossRef] [PubMed] Qi, Q.Y.; Ren, J.W.; Sun, L.W.; He, L.W.; Bao, L.; Yue, W.; Sun, Q.M.; Yao, Y.J.; Yin, W.B.; Liu, H.W. Stucturally diverse sesquiterpenes produced by a Chinese Tibet fungus Stereum hirsutum and their cytotoxic and immunosuppressant activities. Org. Lett. 2015, 17, 3098–3101. [CrossRef] [PubMed] Chen, Z.M.; Chen, H.P.; Wang, F.; Li, Z.H.; Feng, T.; Liu, J.K. New triquinane and gymnomitrane sesquiterpenes from fermentation of the basidiomycete Antrodiella albocinnamomea. Fitoterapia 2015, 102, 61–66. [CrossRef] [PubMed] Isaka, M.; Palasarn, S.; Sappan, M.; Supothina, S.; Boonpratuang, T. Hirsutane sesquiterpenes from cultures of the basidiomycete Marasmiellus sp. BCC 22389. Nat. Prod. Bioprospect. 2016, 6, 257–260. [CrossRef] [PubMed] Hsiao, G.; Chi, W.C.; Pang, K.L.; Chen, J.J.; Kuo, Y.H.; Wang, Y.K.; Cha, H.J.; Chou, S.C.; Lee, T.H. Hirsutane-type sesquiterpenes with inhibitory activity of microglial nitric oxide production from the red alga-derived fungus Chondrostereum sp. NTOU4196. J. Nat. Prod. 2017, 80, 1615–1622. [CrossRef] [PubMed] Li, H.J.; Jiang, W.H.; Liang, W.L.; Huang, J.X.; Mo, Y.F.; Ding, Y.Q.; Lam, C.K.; Qian, X.J.; Zhu, X.F.; Lan, W.J. Induced marine fungus Chondrostereum sp. as a means of producing new sesquiterpenoids chondrosterins I and J by using glycerol as the carbon source. Mar. Drugs 2014, 12, 167–175. [CrossRef] [PubMed] Liu, H.X.; Tan, H.B.; Chen, K.; Chen, Y.C.; Li, S.N.; Li, H.H.; Zhang, W.M. Cerrenins A-C, cerapicane and isohirsutane sesquiterpenoids from the endophytic fungus Cerrena sp. Fitoterapia 2018, 129, 173–178. [CrossRef] [PubMed] Sheikh, Y.M.; Singy, G.; Kaisin, M.; Eggert, H.; Djerassi, C. Terpenoids—LXXI: Chemical studies of marine invertebrates—XIV. Four representatives of a novel sesquiterpene class—The capnellane skeleton. Tetrahedron 1976, 32, 1171–1178. [CrossRef] Kaisin, M.; Tursch, B.; Declercq, J.P.; Germain, G.; Meerssche, M.V. Chemical studies of marine invertebrates. xl. ∆9(12) -capnellene-2β,5α,8β, 10α-tetrol, a new sesquiterpene alcohol from the soft coral Capnella imbricate. Bull. Soc. Chim. Belg. 1979, 88, 253–258. [CrossRef] Kaisin, M.; Braekman, J.C.; Daloze, D.; Tursch, B. Novel acetoxycapnellenes from the alcyonacean capnella imbricate. Tetrahedron 1985, 41, 1067–1072. [CrossRef] Morris, L.A.; Jaspars, M.; Adamson, K.; Woods, S.; Wallace, H.M. The capnellenes revisited: New structures and new biological activity. Tetrahedron 1998, 54, 12953–12958. [CrossRef] Hanssen, H.P.; Abranam, W.R. Sesquiterpene alcohols with novel skeletons from the fungus Ceratocystis piceae (ascomycotina). Tetrahedron 1988, 44, 2175–2180. [CrossRef] Huang, Z.L.; Dan, Y.; Huang, Y.C.; Lin, L.D.; Li, T.H.; Ye, W.H.; Wei, X.Y. Sesquiterpenes from the mycelial cultures of Dichomitus squalens. J. Nat. Prod. 2004, 67, 2121–2123. [CrossRef] [PubMed] Kutateladze, A.G.; Kuznetsov, D.M. Triquinanes and related sesquiterpenes revisited computationally: Structure corrections of hirsutanols B and D, hirsutenol E, cucumin B, antrodins C–E, chondroterpenes A and H, chondrosterins C and E, dichrocephone A, and pethybrene. J. Org. Chem. 2017, 82, 10795–10802. [CrossRef] [PubMed] Yang, F.; Chen, W.D.; Deng, R.; Zhang, H.; Tang, J.; Wu, K.W.; Li, D.D.; Feng, G.K.; Lan, W.J.; Li, H.J.; Zhu, X.F. Hirsutanol A, a novel sesquiterpene compound from fungus Chondrostereum sp., induces apoptosis and inhibits tumor growth through mitochondrial-independent ROS production: Hirsutanol A inhibits tumor growth through ROS production. J. Transl. Med. 2013, 11, 32. [CrossRef] [PubMed]

Molecules 2018, 23, 2095

45. 46. 47. 48. 49.

50. 51. 52.

53. 54. 55. 56.

57. 58.

59. 60.

61. 62. 63.

64.

65. 66.

31 of 33

Shindo, M.; Sato, Y.; Shishido, K. An ynolate-initiated tandem process giving cyclopentenones: Total synthesis of cucumin E. Tetrahedron Lett. 2002, 43, 5039–5041. [CrossRef] Mehta, G.; Murthy, A.S.K. The first total synthesis of the novel triquinane natural products pleurotellol and pleurotellic acid. Tetrahedron Lett. 2003, 44, 5243–5246. [CrossRef] Sakan, F.; Hashimoto, H.; Ichihara, A.; Shirahama, H.; Matsumoto, T. A synthesis of the hirsutane skeleton. Tetrahedron Lett. 1971, 12, 3703–3706. [CrossRef] Hashimoto, H.; Tsuzuki, K.; Sakan, F.; Shirahama, H.; Matsumoto, T. Total synthesis of dl-hirsutic acid. Tetrahedron Lett. 1974, 15, 3745–3748. [CrossRef] Kueh, J.S.H.; Mellor, M.; Pattenden, G. Photocyclisations of dicyclopent-1-enyl methanes to tricyclo[6.3.0.02,6 ]undecanes: A synthesis of the hirsutane carbon skeleton. J. Chem. Soc. Chem. Commun. 1978, 1, 5–6. [CrossRef] Mehta, G.; Reddy, A.V. Olefin metathesis in polycyclic frames. A total synthesis of hirsutene. J. Chem. Soc. Chem. Commun 1981, 15, 756–757. [CrossRef] Dawson, B.A.; Ghosh, A.K.; Jurlina, J.L.; Ragauskas, A.J.; Stothers, J.B. A synthesis of hirsutene: A simple route via β-enolization. Can. J. Chem. 1984, 62, 2521–2525. [CrossRef] Coverdhan, M.; Murthy, A.N.; Reddy, D.S.; Reddy, A.V. A general approach to linearly fused triquinane natural products. Total syntheses of (±)-hirsutene, (±)-coriolin, and (±)-capnellene. J. Am. Chem. Soc. 1986, 108, 3443–3452. [CrossRef] Iyoda, M.; Kushida, T.; Kitami, S.; Oda, M. An extremely short synthesis of hirsutene. J. Chem. Soc. Chem. Commun. 1986, 1049–1050. [CrossRef] Cossy, J.; Belotti, D.; Pete, J.P. Photoreductive cyclization: Application to the total synthesis of (±) Hirsutene. Tetrahedron Lett. 1987, 28, 4547–4550. [CrossRef] Majetich, G.; Defauw, J. Intramolecular additions of allylsilanes in triquinane synthesis. Studies directed toward the total synthesis of (±)-hirsutene. Tetrahedron 1988, 44, 3833–3849. [CrossRef] Franck-Neumann, M.; Miesch, M.; Lacroix, E.; Metz, B.; Kern, J.M. Access to the Linear Triquinane Skeleton via Bicyclo (2.1. 0) pentane Intermediates. Total Synthesis of the Triquinane Hirsutene. Tetrahedron 1992, 48, 1911–1926. [CrossRef] Franck-Neumann, M.; Miesch, M.; Lacroix, E. Total synthesis of the natural linear triquinane (±)-hirsutene from a cyclopropene compound. Tetrahedron Lett. 1989, 30, 3529–3532. [CrossRef] Hong, B.C.; Shr, Y.J.; Wu, J.L.; Gupta, A.K.; Lin, K.J. Novel [6 + 2] cycloaddition of fulvenes with alkenes: A facile synthesis of the anislactone and hirsutane framework. Org. Lett. 2002, 4, 2249–2252. [CrossRef] [PubMed] Sternbach, D.D.; Ensinger, C.L. Synthesis of polyquinanes. 3. Total synthesis of (±)-hirsutene: The intramolecular Diels-Alder approach. J. Org. Chem. 1990, 55, 2725–2736. [CrossRef] Castro, J.; Sorensen, H.; Riera, A.; Morin, C.; Moyano, A.; Greene, A.E. Asymmetric approach to Pauson-Khand bicyclization. Enantioselective formal synthesis of hirsutene. J. Am. Chem. Soc. 1990, 112, 9388–9389. [CrossRef] Paquette, L.A.; Moriarty, K.J.; Chang, S.C. Sequential annulation in molecular construction. A short, stereocontrolled synthesis of (+)-hirsutene. Israel J. Chem. 1991, 31, 195–198. [CrossRef] Sarkar, T.K.; Ghosh, S.K.; Subba Rao, P.S.V.; Mamdapur, V.R. Cyclopentanoid allylsilanes in synthesis: A stereoselective synthesis of (+)-hirsutene. Tetrahedron Lett. 1990, 31, 3465–3466. [CrossRef] Sarkar, T.K.; Ghosh, S.K.; Subba Rao, P.S.V.; Satapathi, T.K. Cyclopentanoid allysilanes in synthesis: Generation via intramolecular ene reaction of activated 1,6-dienes and application to the synthesis of functionalized diquinanes. Tetrahedron Lett. 1990, 31, 3461–3464. [CrossRef] Sarkar, T.K.; Ghosh, S.K.; Subba Rao, P.S.V.; Satapathi, T.K.; Mamdapur, V.R. Cyclopentanoid allylsilanes in synthesis of di- and triquinanes. A stereoselective synthesis of (±)-hirsutene. Tetrahedron 1992, 48, 6897–6908. [CrossRef] Mehta, G.; Srikrishna, A. Synthesis of polyquinane natural products: An update. Chem. Rev. 1997, 97, 671–719. [CrossRef] [PubMed] Ramig, K.; Kuzemko, M.A.; McNamara, K.; Cohen, T. Use of a dilithiomethane equivalent in a novel one-flask [2+1+2] cyclopentannulation reaction: A highly efficient total synthesis of (±)-hirsutene. J. Org. Chem. 1992, 57, 1969–1970. [CrossRef]

Molecules 2018, 23, 2095

67. 68. 69.

70. 71. 72.

73. 74.

75. 76. 77. 78.

79. 80. 81. 82.

83.

84. 85.

86. 87.

88.

32 of 33

Toyota, M.; Nishikawa, Y.; Motoki, K.; Yoshida, N.; Fukumoto, K. Pd2+ -promoted cyclization in linear triquinane synthesis total synthesis of (±)-hirsutene. Tetrahedron Lett. 1993, 34, 6099–6102. [CrossRef] Rawal, V.H.; Fabre, A.; Iwasa, S. Photocyclization-fragmentation route to linear triquinanes: Stereocontrolled synthesis of (±)-endo-hirsutene. Tetrahedron Lett. 1995, 36, 6851–6854. [CrossRef] Wang, Y.; Yu, Z.X. Rhodium-catalyzed [5 + 2 +1] cycloaddition of ene–vinylcyclopropanes and CO: Reaction design, development, application in natural product synthesis, and inspiration for developing new reactions for synthesis of eight-membered carbocycles. Acc. Chem. Res. 2015, 48, 2288–2296. [CrossRef] [PubMed] Geng, F.; Liu, J.; Paquette, L.A. Three-component coupling via the squarate ester cascade as a concise route to the bioactive triquinane sesquiterpene hypnophilin. Org. Lett. 2002, 4, 71–73. [CrossRef] [PubMed] Paquette, L.A.; Geng, F. Applications of the squarate ester cascade to the expeditious synthesis of hypnophilin, coriolin, and ceratopicanol. J. Am. Chem. Soc. 2002, 124, 9199–9203. [CrossRef] [PubMed] Bon, D.J.Y.D.; Banwell, M.G.; Ward, J.S.; Willis, A.C. From toluene to triquinanes: Formal total syntheses of the sesquiterpenoid natural products (−)-hypnophilin and (−)-coriolin. Tetrahedron 2013, 69, 1363–1368. [CrossRef] Bon, D.J.Y.D.; Banwell, M.G.; Willis, A.C. A chemoenzymatic total synthesis of the hirsutene-type sesquiterpene (+)-connatusin B from toluene. Tetrahedron 2010, 66, 7807–7814. [CrossRef] Bon, D.J.Y.D.; Banwell, M.G.; Cade, I.A.; Willis, A.C. The total synthesis of (−)-connatusin A, a hirsutane-type sesquiterpene isolated from the fungus Lentinus connatus BCC8996. Tetrahedron 2011, 67, 8348–8352. [CrossRef] Singh, V.; Prathap, S.; Porinehu, M. A novel, stereospecific total synthesis of (±)-∆9(12) -capnellene from p-Cresol. Tetrahedron Lett. 1997, 38, 2911–2914. [CrossRef] Stevens, K.E.; Paquette, L.A. Stereocontrolled total synthesis of (±)-∆9(12) -capnellene. Tetrahedron Lett. 1981, 22, 4393–4396. [CrossRef] Stille, J.R.; Grubbs, R.H. Synthesis of (±)-∆9(12) -capnellene using titanium reagents. J. Am. Chem. Soc. 1986, 108, 855–856. [CrossRef] Stille, J.R.; Santarsiero, B.D.; Grubbs, R.H. Rearrangement of bicyclo[2.2.1]heptane ring systems by Titanocene alkylidene complexes to bicyclo[3.2.0]heptane enol ethers. Total synthesis of (±)-∆9(12) -capnellene. J. Org. Chem. 1990, 55, 843–862. [CrossRef] Augusto, G.; Giovanni, F.; Paolo, B. Bicyclo[3.3.1]nonane approach to triquinanes. Formal synthesis of (±)-∆9(12) -capnellen and (±)-∆9(12) -capnellen-8β-10α-diol. Tetrahedron 1992, 48, 4459–4464. Balme, G.; Bouyssi, D. Total synthesis of the triquinane marine sesquiterpene (±)-∆9(12) -capnellene using a palladium-catalyzed bis-cyclization step. Tetrahedron 1994, 50, 403–414. [CrossRef] Singh, V.; Prathap, S.; Porinchu, M. Aromatics to triquinanes: P-cresol to (±)-∆9(12) -capnellene. J. Org. Chem. 1998, 63, 4011–4017. [CrossRef] Nguyen, N.N.M.; Leclere, M.; Stogaitis, N.; Fallis, A.G. Triquinanes: A “One-Pot” IMDA-Tandem metathesis cascade strategy: Ring-Closing Metathesis (RCM) dominates norbornene ROM! Org. Lett. 2010, 12, 1684–1687. [CrossRef] [PubMed] Hsu, D.S.; Chou, Y.Y.; Tung, Y.S.; Liao, C.C. Photochemistry of tricyclo[5.2.2.02,6 ]undeca-4,10-dien-8-ones: An efficient general route to substituted linear triquinanes from 2-methoxyphenols. Total synthesis of (±)-∆9(12) -capnellene. Chem.-Eur. J. 2010, 16, 3121–3131. [CrossRef] [PubMed] Shen, S.J.; Li, W.D.Z. Formal homoiodo allylsilane annulations: Dual total syntheses of (±)-hirsutene and (±)-capnellene. J. Org. Chem. 2013, 78, 7112–7120. [CrossRef] [PubMed] Little, R.D.; Carroll, G.L.; Petersen, J.L. Total synthesis of the marine natural product ∆9(12) -capnellene. Reversal of regiochemistry in the intramolecular 1,3-diyl trapping reaction. J. Am. Chem. Soc. 1983, 105, 928–932. [CrossRef] Paquette, L.A.; Stevens, K. Stereocontrolled total synthesis of the triquinane marine sesquiterpene ∆9(12) -capnellene. Can J. Chem. 1984, 62, 2415–2419. [CrossRef] Crisp, G.T.; Scott, W.J.; Stille, J.K. Palladium-catalyzed carbonylative coupling of vinyl triflates with organostannanes. A total synthesis of (±)-∆9(12) -capnellene. J. Am. Chem. Soc. 1984, 106, 7500–7506. [CrossRef] Wang, Y.; Mukherjee, D.; Birney, D.; Houk, K.N. Synthesis and reactions of ester-substituted fulvenes. A new route to ∆9(12) -capnellene. J. Org. Chem. 1990, 55, 4504–4506. [CrossRef]

Molecules 2018, 23, 2095

33 of 33

89.

Samajdar, S.; Patra, D.; Ghosh, S. Stereocontrolled approach to highly substituted cyclopentanones. Application in a formal synthesis of ∆9(12) -capnellene. Tetrahedron 1998, 54, 1789–1800. [CrossRef] 90. Lemiere, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A.L.; Fensterbank, L.; Malacria, M. Generation and trapping of cyclopentenylidene gold species: Four pathways to polycyclic compounds. J. Am. Chem. Soc. 2009, 131, 2993–3006. [CrossRef] [PubMed] 91. Sonawane, H.R.; Nanjundiah, B.S.; Shah, V.G.; Kulkarni, D.G.; Ahuja, J.R. Synthesis of naturally occurring (+)-∆9(12) -capnellene and its antipode: An application of the photo-induced vinylcyclopropane-cyclopentene rearrangement. Tetrahedron Lett. 1991, 1991. 32, 1107–1108. [CrossRef] 92. Sonawane, H.R.; Naik, V.G.; Bellur, N.S.; Shah, V.G.; Purohit, P.C.; Kumar, M.U.; Kulltarni, D.G.; Ahuja, J.R. Photoinduced vinylcyclopropane-cyclopentene rearrangement: A methodology for chiral bicyclo[3.2.0]heptenes. Formal syntheses of (±)-grandisol and naturally occurring (+)-∆9(12) -capnellene antipode. Tetrahedron 1991, 47, 8259–8276. [CrossRef] 93. Asaoka, M.; Obuchi, K.; Takei, H. An Enantioselective route to (−)-∆9(12) -capnellene employing silyl group directed stereo control. Tetrahedron 1994, 50, 655–660. [CrossRef] 94. Tanaka, K.; Ogasawara, K. Stereocontrolled synthesis of natural (−)-∆9(12) -capnellene from a (−)-oxodicyclopentadiene. Chem. Commun. 1996, 15, 1839–1840. [CrossRef] 95. Ohshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. Asymmetric heck reaction-carbanion capture process. Catalytic asymmetric total synthesis of (−)-∆9(12) -capnellene. J. Am. Chem. Soc. 1996, 118, 7108–7116. [CrossRef] 96. Meyers, A.I.; Bienz, S. Asymmetric total synthesis of (+)-∆9(12) -capnellene. J. Org. Chem. 1990, 55, 791–798. [CrossRef] 97. Shibasaki, M.; Mase, T.; Ikegami, S. The first total syntheses of ∆9(12) -capnellene-8β,10α-diol and ∆9(12) -capnellene-3β,8β,10α-triol. J. Am. Chem. Soc. 1986, 108, 2090–2091. [CrossRef] 98. Kagechika, K.; Shibasaki, M. Asymmetric heck reaction: A catalytic asymmetric synthesis of the key intermediate for ∆9(12) -capnellene-3β,8β,10α-triol and ∆9(12) -capnellene-3β,8β,10α,14-tetrol. J. Org. Chem. 1991, 56, 4093–4094. [CrossRef] 99. Baralotto, C.; Chanon, M.; Julliard, M. Total synthesis of the tricyclic sesquiterpene (±)-ceratopicanol. An illustration of the holosynthon concept. J. Org. Chem. 1996, 61, 3576–3577. [CrossRef] [PubMed] 100. Clive, D.L.J.; Magnuson, S.R.; Manning, H.W.; Mayhew, D.L. Cyclopentannulation by an iterative process of sequential claisen rearrangement and enyne radical closure: Routes to triquinane and propellane systems and use in the synthesis of (±)-ceratopicanol. J. Org. Chem. 1996, 61, 2095–2108. [CrossRef] 101. Srikrishna, A.; Dethe, D.H. Enantiospecific first total synthesis and assignment of absolute configuration of the sesquiterpene (−)-cucumin H. Org. Lett. 2003, 5, 2295–2298. [CrossRef] [PubMed] 102. Keller, N.P.; Turner, G.; Bennett, J.W. Fungal secondary metabolism from biochemistry to genomics. Nat. Rev. Microbiol. 2005, 3, 937–947. [CrossRef] [PubMed] © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Linear Triquinane Sesquiterpenoids: Their Isolation, Structures ... - MDPI

Linear Triquinane Sesquiterpenoids: Their Isolation, Structures ... - MDPI

Suggest Documents

Allelochemical, Eudesmane-Type Sesquiterpenoids from Inula ... - MDPI

Nitrogen-Containing Diterpenoids, Sesquiterpenoids, and Nor ... - MDPI

Marine Peroxy Sesquiterpenoids Induce Apoptosis by ... - MDPI

Sesquiterpenoids from Farfugium japonicum and Their ... - Springer Link

Sesquiterpenoids from Farfugium japonicum and Their ... - Springer Link

Model Dispersal Isolation Linear Logarithmic Exponential R2 p ... - MDPI

From Linear Industrial Structures to Living Systems: A Design ... - MDPI

Linear Stability Prediction of Vortex Structures on High ... - MDPI

Sesquiterpenoids from Chinese Agarwood Induced by Artificial ... - MDPI

Lipids and Their Structures

Coherent Vortical Structures and Their Relation to Hot/Cold ... - MDPI

Linear and Branched PEIs (Polyethylenimines) and Their ... - MDPI

Four New Sesquiterpenoids from the Roots of Diarthron ... - MDPI

Synthesis of furanoeremophilane sesquiterpenoids

Spherically Symmetric Non Linear Structures

Oxygenated Ylangene-Derived Sesquiterpenoids ... - BioMedSearch

Probabilistic Relational Structures and Their

LINEAR TRANSFORMATIONS AND THEIR REPRESENTING ...

Two New Daucane Sesquiterpenoids from

''Smart'' Base Isolation Systems - Smart Structures Technology ...

New Bergamotane Sesquiterpenoids from the

Analysis of Linear Structures With Non Linear Dampers - ORBi

Circular RNAs: Isolation, characterization and their

Modeling Planar Fluxgate Structures - MDPI