Bicyclo [6.3.0] Undecane Sesquiterpenoids: Structures, Biological Activities, and Syntheses

Sesquiterpenoids constitute a marvelously varied group of natural products that feature a vast array of molecular architectures. Among them, the unusual bicyclo [6.3.0] undecane sesquiterpenoids are one of the most representative. To date, only approximately 42 naturally occurring compounds with this unique scaffold, which can be classified into seven different groups, have been reported. As the first-found member of each type, dactylol, asteriscanolide, dumortenol, toxicodenane C, and capillosanane S are characteristic of the four methyl groups on the five-eight-membered ring system. Only 11-hydroxyjasionone and sinuketal decorate the core with an isopropyl group. These natural products exhibit a wide range of bioactivities, including antifouling, anti-inflammatory, immune suppression, cytotoxic, antimutagenic, antiplasmodial, and antiviral activities. It was noted that some total syntheses of precapnellane-sesquiterpenoids (dactylol, poitediol, precapnelladiene), asteriscanolide, and 11-hydroxyjasionone have been achieved, because their cyclooctanoid core represents an important target for the development of synthetic strategies to prepare eight-membered ring-containing compounds. This review focuses on these natural sesquiterpenoids and their biological activities and synthesis, and aims to provide a foundation for further research of these interesting compounds.


Precapnellane-Sesquiterpenoid
In 1977, the first bicyclo [6.3.0] undecane sesquiterpenoid, named dactylol (1, Figure 2), was reported in the Caribbean sea hare Aplysia dactylomela by Schmitz's group [9]. Its absolute configuration was derived from the CD data of a substituted cyclopentanone degradation product, which is a chemical conversion compound. In its structure, as the cyclooctanoid core represents an important and challenging target [10] for preparing the eight-membered ring-containing compounds, dactylol, an exemplary member of this class, has been widely synthesized (in total) by synthetic chemists. In order to construct the necessary carbon-carbon bonds, both Paquette's group and Gadwood's group used a [3,3] sigmatropic rearrangement strategy from 1985 to 1987 [10][11][12]. On the other hand, in the Paquette route, a cycooctadiene ring was built from cycloheptane precursors by Friedel-Crafts cyclization, while the Gadwood route featured an anionic oxy-Cope rearrangement. Later, to solve the undesired isomer problem, originatingthe stereoselective functional group transformations, Feldman et al. developed concise and stereoselective novel [6π + 2π] intramolecular photocycloaddition to synthesize dactylol in 1989 and 1990 [13,14]. Then, in 2000, intramolecular 4 + 3 cycloaddition was achieved in the synthesis of dactylol by Harmata's group [15,16]. In 1996, ringclosing metathesis was used to synthesize dactylol by Fürstner et al. [17], and Vanderwal's group further developed this strategy [18]. Molandar's team reported the concise, nonracemic synthesis of dactyol utilizing a novel [3 + 5] annulation approach in 1995 [19].
A chemical examination of the aerial parts of the Asteriscus graveolens subsp. stenophyllus. by León et al. in 2016 resulted in the isolation of asteriscanolidenol (27, Figure 3), a new sesquiterpene lactone of the asteriscanolide type [48]. Unfortunately, this lactone showed no cytotoxicity effects against the HL-60 and MOLT-3 leukemia cell lines.

Dumortane-Sesquiterpenoid
The first dumortane sesquiterpenoid, dumortenol (28, Figure 4), was isolated from the diethyl ether extract of Argentinian liverwort Dumortiera hirsuta by Toyota and coworkers in 1997 [49]. The stereochemical assignments of 28 were clarified by X-ray crystallographic analysis (crystals were obtained from the methanol solution). In 1999, their reinvestigation of a new collection of Argentine D. hirsuta led to the isolation of two new dumortane derivatives (29 and 30), together with nor-dumortane sesquiterpene 31 [50].
lactone of the asteriscanolide type [48]. Unfortunately, this lactone showed no cytotoxicity effects against the HL-60 and MOLT-3 leukemia cell lines.

Dumortane-Sesquiterpenoid
The first dumortane sesquiterpenoid, dumortenol (28, Figure 4), was isolated from the diethyl ether extract of Argentinian liverwort Dumortiera hirsuta by Toyota and coworkers in 1997 [49]. The stereochemical assignments of 28 were clarified by X-ray crystallographic analysis (crystals were obtained from the methanol solution). In 1999, their reinvestigation of a new collection of Argentine D. hirsuta led to the isolation of two new dumortane derivatives (29 and 30), together with nordumortane sesquiterpene 31 [50]. Compound 28 was also obtained from soft coral Sinularia capillosa by Duh's group in 2010, which is the first report of this type of sesquiterpenoid in a marine organism [51]. In 2014, chemical examination of the same soft coral species was carried out by Lin's group and resulted in the isolation of two dumortane analogues, capillosananes W and X (32 and 33, Figure 4) [52]. The absolute configuration of 32 was determined via the CD data of the in situ complex of the tertiary alcohol with Rh2(OCOCF3)4 by applying the bulkiness rule; 33 was assumed to be the same as 32 from biogenetic consideration. Bioactive assays indicated that compound 32 has anti-inflammatory effects with an inhibitory rate of 34% (at 10 μM, the positive control NK007 with inhibitory rates of 46% at 100 nM).

Toxicodenane-Sesquiterpenoid
In 2013, toxicodenanes C (35, Figure 5) was obtained from the dried resin of Toxicodendron vernicifluum by Cheng's group [54]. This compound showed significantly inhibitory effects with a dose-and time-dependent relationship on fibronectin, collagen IV, and IL-6 in high-glucose-induced mesangial cells, which means that it has potential in treating diabetic nephropathy. Compound 28 was also obtained from soft coral Sinularia capillosa by Duh's group in 2010, which is the first report of this type of sesquiterpenoid in a marine organism [51]. In 2014, chemical examination of the same soft coral species was carried out by Lin's group and resulted in the isolation of two dumortane analogues, capillosananes W and X (32 and 33, Figure 4) [52]. The absolute configuration of 32 was determined via the CD data of the in situ complex of the tertiary alcohol with Rh 2 (OCOCF 3 ) 4 by applying the bulkiness rule; 33 was assumed to be the same as 32 from biogenetic consideration. Bioactive assays indicated that compound 32 has anti-inflammatory effects with an inhibitory rate of 34% (at 10 µM, the positive control NK007 with inhibitory rates of 46% at 100 nM).

Toxicodenane-Sesquiterpenoid
In 2013, toxicodenanes C (35, Figure 5) was obtained from the dried resin of Toxicodendron vernicifluum by Cheng's group [54]. This compound showed significantly inhibitory effects with a dose-and time-dependent relationship on fibronectin, collagen IV, and IL-6 in high-glucose-induced mesangial cells, which means that it has potential in treating diabetic nephropathy.

Capillosane-Sesquiterpenoid
One year later, Lin's group reported capillosananes S and T (36 and 37, Figure 5) from the soft coral S. capillosa [52]. The absolute configuration of compound 36 was determined by the octant rule for cyclopentenones and further supported by the ECD method; compound 37 was only determined by the octant rule. Unfortunately, these compounds were not active in cytotoxic (HCT-8, HePG2, BGC-823, A549, SKOV3) and pathogenetic microorganism assays.

Capillosane-Sesquiterpenoid
One year later, Lin's group reported capillosananes S and T (36 and 37, Figure 5) from the soft coral S. capillosa [52]. The absolute configuration of compound 36 was determined by the octant rule for cyclopentenones and further supported by the ECD method; compound 37 was only determined by the octant rule. Unfortunately, these compounds were not active in cytotoxic (HCT-8, HePG2, BGC-823, A549, SKOV3) and pathogenetic microorganism assays.

Isopropyl Type Bicyclo [6.3.0] Undecane Sesquiterpenoids
Isopropyl type bicyclo [6.3.0] undecane sesquiterpenoids are rare in nature. By the end of August 2019, only 5 isopropyl type bicyclo [6.3.0] undecane sesquiterpenoids (far fewer than the four methyl type) have been reported. This may be due to the difficulty for diverse biogenic pathways to form a 5-8 fused ring in nature. As shown in Scheme 1, the plausible biosynthetic pathways of bicyclo [6.3.0] undecane sesquiterpenoids were proposed. The carbon skeletons of the four methyl type bicyclo [6.3.0] sesquiterpenoids can be carried out by cyclization reaction and Wagner-Meerwein rearrangements from the farnesyl diphosphate (FPP) [54,55]. However, an unexpected cycloheptane to cyclooctane ring expansion process [56], a key step, may determine the occurrence rate of isopropyl type bicyclo [6.3.0] undecane sesquiterpenoids.
In the following year, Rustaiyan and coworkers isolated a new jasionane type sesquiterpene lactone tehranolide (39, Figure 6) from the aerial parts of Artemisia diffusa [58]. As there is an endoperoxide pharmacophore like the antimalarial agent artemisinin in the molecule, some bioactivity test works on compound 39 [59][60][61][62][63][64][65] and the fractions containing it [66,67] have been done by Iranian scientists. In summary, tehranolide (39) has a variety of biological activities, including modulating the immune response by reducing regulatory T cell [59,60], inhibiting proliferation of MCF-7, HeLa, and K562 cells [61][62][63], against chemical mutagens in Salmonella strains [63], and inhibiting the growth of Plasmodium falciparum [64,65].  Figure  6) [68]. The absolute configuration of compound 40 was determined by single-crystal X-ray diffraction with Cu Kα radiation, and the absolute configuration of compound 41 was the same as compound 40 based on biogenetic consideration and comparing its optical rotation with 40. Compound 40 showed a moderate inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells.

Sinulane-Sesquiterpenoid
In 2018, Li's team found the first example of marine-originated isopropyl type bicyclo [6.3.0.] undecane sesquiterpenoid sinuketal (42, Figure 6) from soft coral Sinularia sp. [56]. Its relative and absolute configurations were determined on the basis of the NOESY spectrum in combination with a conformational analysis, density functional theory-NMR, and the TDDFT/ECD method. Compared with the similar analogue compound 39, the positions of the methyl and isopropyl groups of compound 42 were quite different. The biological activity tests showed that 42 displayed antiviral activities (against influenza A viruses H1N1 and PR8, with IC50 values of 172 and 443 μM, respectively), weak cytotoxic activities (toward Jurkat, MDA-MB-231, and U2OS cell lines), mild in vitro antimalarial activity (against Plasmodium falciparum 3D7), as well as mild inhibitory acetylcholinesterase activity.

Conclusions
Bicyclo [6.3.0] undecane sesquiterpenoids are relatively rare in nature. From 1977 to 2018, only approximately 42 compounds with this unique scaffold were reported in terrestrial plants of the genera Asteriscus, Lippia, Cynanchum, Dumortiera, Toxicodendron, Jasonia, and Artemisia, marine organisms of the genera Aplysia, Laurencia, Capnella, Sinularia, and Phyllodesmium, and a mutant bacteria of Tubercularia sp. Their absolute configurations were determined by X-ray diffraction, Mosher's method, CD rules, ECD calculaion, biogenetic consideration, and chemical conversion methods. They can be classified into seven different types. Structurally, precapnellane, asteriscane, dumortane, toxicodenane, and capillosane feature four methyl groups on the 5-8 ring moiety, while jasionane and sinulane decorate the core with an isopropyl group. How the isopropyl type bicyclo [6.3.0] undecane sesquiterpenoids were formed remains a mystery, though this question may be resolved by a biosynthesis study. Because of the broad bioactivities and synthetic challenges of the  Figure 6) [68]. The absolute configuration of compound 40 was determined by single-crystal X-ray diffraction with Cu Kα radiation, and the absolute configuration of compound 41 was the same as compound 40 based on biogenetic consideration and comparing its optical rotation with 40. Compound 40 showed a moderate inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells.

Sinulane-Sesquiterpenoid
In 2018, Li's team found the first example of marine-originated isopropyl type bicyclo [6.3.0.] undecane sesquiterpenoid sinuketal (42, Figure 6) from soft coral Sinularia sp. [56]. Its relative and absolute configurations were determined on the basis of the NOESY spectrum in combination with a conformational analysis, density functional theory-NMR, and the TDDFT/ECD method. Compared with the similar analogue compound 39, the positions of the methyl and isopropyl groups of compound 42 were quite different. The biological activity tests showed that 42 displayed antiviral activities (against influenza A viruses H1N1 and PR8, with IC 50 values of 172 and 443 µM, respectively), weak cytotoxic activities (toward Jurkat, MDA-MB-231, and U2OS cell lines), mild in vitro antimalarial activity (against Plasmodium falciparum 3D7), as well as mild inhibitory acetylcholinesterase activity.

Conclusions
Bicyclo [6.3.0] undecane sesquiterpenoids are relatively rare in nature. From 1977 to 2018, only approximately 42 compounds with this unique scaffold were reported in terrestrial plants of the genera Asteriscus, Lippia, Cynanchum, Dumortiera, Toxicodendron, Jasonia, and Artemisia, marine organisms of the genera Aplysia, Laurencia, Capnella, Sinularia, and Phyllodesmium, and a mutant bacteria of Tubercularia sp. Their absolute configurations were determined by X-ray diffraction, Mosher's method, CD rules, ECD calculaion, biogenetic consideration, and chemical conversion methods. They can be classified into seven different types. Structurally, precapnellane, asteriscane, dumortane, toxicodenane, and capillosane feature four methyl groups on the 5-8 ring moiety, while jasionane and sinulane decorate the