The Tetrahydrofuran Motif in Marine Lipids and Terpenes

Heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades. They show promising biological activities, making them potential leads for novel antibiotics, antikinetoplastid drugs, amoebicidal substances, or anticancer drugs. Thus, they have attracted the attention of the synthetics community and numerous approaches to their total syntheses have appeared. Here, we offer the reader an overview of marine-derived terpenoids and related compounds, their isolation, structure determination, and a special focus on their total syntheses and biological profiles.


Introduction
Marine organisms are a source of intriguing and fascinating compounds. These living beings have continuously evolved over time, since they are part of the oldest habitat on earth. Being also the largest ecosystem, the ocean has the potential to offer innumerable compounds with interesting biological activities yet to be discovered [1]. This is supported by the fact that hundreds of new molecules are reported within the scientific community every year [2][3][4].
Usually, the isolation of pure active compounds is a time-consuming and expensive process, due to the need of efficient extraction processes and sequential purification steps. Moreover, large amounts of raw materials have to be collected to finally isolate fairly low quantities of the desired compounds.
Fortunately, the great contribution of chemists in the field of total synthesis and asymmetric catalysis over the last decades has had countless benefits. On one hand, even though nuclear magnetic resonance (NMR) techniques are very powerful tools, in some cases, the characterization of complex molecules can be difficult, leading to misassignments [5]. Fortunately, total synthesis has emerged as a-somewhat-costly but effective tool for the determination of the absolute configuration of marine metabolites. On the other hand, synthesis provides access to sufficient quantities of the desired compounds for further extensive biological studies.
Within the marine-derived metabolites, terpenes represent one of the most significant families. They are a large and diverse group of compounds that usually present valuable pharmacological properties. Various reviews summarize the discovery of a high number of these metabolites in recent years from different sources, namely sponges [6,7], fungi [8][9][10], and corals [11,12], among others [13,14].
Other common structural motifs present in marine drugs are heterocycles. Within them, five-, six-, and seven-membered oxygenated heterocycles are frequently found in such bioactive compounds. The six-membered tetrahydropyrans, the most abundant, are   Table 1. Overview of compounds from this review, their sources, classes, and species (background color code coincides with that of Figure 1).

Marine Source Compound Class Marine Species Compound Name
Lampreys sic examples, as their structure and activity are closely related to the more recently isolated metabolites and help to understand structure-activity relationships. We start with some examples of fatty acids with interesting biological profiles, and then move to the broad family of terpenoid compounds (monoterpenes, sesquiterpenes, diterpenes, triterpenes, and meroterpenoids). At the end, we also highlight other small THF-containing compounds that show interesting biological activities or were recently isolated and, thus, have potential to be shown in the near future. Table 1. Overview of compounds from this review, their sources, classes, and species (background color code coincides with that of Figure 1). New Caledonian Alisiaquinones A-C Alisiaquinol Substituted THF Pachastrissa/Jaspis sp. We want to offer the reader an overview of the most recent tetrahydrofuran-containing terpenoids and related compounds of marine origin, their natural source of isolation, biological properties, and synthetic strategies towards them. We have also included classic examples, as their structure and activity are closely related to the more recently isolated metabolites and help to understand structure-activity relationships. We start with some examples of fatty acids with interesting biological profiles, and then move to the broad family of terpenoid compounds (monoterpenes, sesquiterpenes, diterpenes, triterpenes, and meroterpenoids). At the end, we also highlight other small THF-containing compounds that show interesting biological activities or were recently isolated and, thus, have potential to be shown in the near future.

Lipid Alcohols C19 Lipid Diols
Diastereomeric trans-oxylipids 1, and cis-oxylipid 2 (Figure 3), were isolated in 1980 [21] and 1998 [22], respectively, from the brown alga Notheia anomala. Their structure and relative stereochemistry were assigned by 1D and 2D NMR spectral data and confirmed by single-crystal X-ray analysis. Their absolute configuration was determined by the Horeau method in the case of compound 1, and by the advanced Mosher method for compound 2. Both of them display in vitro antihelmintic activity, inhibiting larval development in parasitic nematodes. The trans-isomer 1 showed LD 50 values against Haemonchus contortus (1.8 ppm) and Trichostrongylus colubriformis (9.9 ppm), comparable to those of the commercial nematocides levamisole and closantel. Synthetic routes for these oxylipids were recently reviewed [18].

C19 Lipid Diols
Diastereomeric trans-oxylipids 1, and cis-oxylipid 2 (Figure 3), were isolated in 1980 [21] and 1998 [22], respectively, from the brown alga Notheia anomala. Their structure and relative stereochemistry were assigned by 1D and 2D NMR spectral data and confirmed by single-crystal X-ray analysis. Their absolute configuration was determined by the Horeau method in the case of compound 1, and by the advanced Mosher method for compound 2. Both of them display in vitro antihelmintic activity, inhibiting larval development in parasitic nematodes. The trans-isomer 1 showed LD50 values against Haemonchus contortus (1.8 ppm) and Trichostrongylus colubriformis (9.9 ppm), comparable to those of the commercial nematocides levamisole and closantel. Synthetic routes for these oxylipids were recently reviewed [18]. An elegant example of the stereodivergent synthesis of both isomers was developed by Kim et al. [23]. They developed an intramolecular amide enolate alkylation, where the C3-hydroxy protecting group selection permits the formation of the desired isomer (Scheme 1). Thus, starting from PMB-protected bromoamide 3, reaction with LiHMDS afforded only the cis-product 4. The preferent formation of the cis-isomer was due to the chelating ability of the PMB group. Therefore, when using a nonchelating group such as TIPS (compound 5), the reaction with KHMDS predominantly yielded the trans-THF 6. Further reaction of 4 and 6 with CH2=CH(CH2)7MgBr and reduction with L-selectride afforded 7 and 8 in good yields (76% and 53% over two steps, respectively). Deprotection of An elegant example of the stereodivergent synthesis of both isomers was developed by Kim et al. [23]. They developed an intramolecular amide enolate alkylation, where the C3-hydroxy protecting group selection permits the formation of the desired isomer (Scheme 1). Thus, starting from PMB-protected bromoamide 3, reaction with LiHMDS afforded only the cis-product 4. The preferent formation of the cis-isomer was due to the chelating ability of the PMB group. Therefore, when using a nonchelating group such as TIPS (compound 5), the reaction with KHMDS predominantly yielded the trans-THF 6. Further reaction of 4 and 6 with CH 2 =CH(CH 2 ) 7 MgBr and reduction with L-selectride afforded 7 and 8 in good yields (76% and 53% over two steps, respectively). Deprotection of 7 with DDQ, and 8 with TBAF, respectively, gave cis-oxylipid 2 in 82% yield and the trans-isomer 1 in 94% yield.

Petromyroxols
In 2015, Li reported the isolation of (+)-and (−)-petromyroxols (9) [24]. They are oxylipids isolated from water conditioned with larval sea lamprey Petromyzon marinus L. Interestingly, these molecules are the first tetrahydrofuran acetogenindiols isolated from a vertebrate animal ( Figure 4). The absolute configuration of each enantiomer was determined by a combination of Mosher ester analysis and comparison with related natural and synthetic products. The (+)-9 shows a potent olfactory response of 0.01 to 1 µM in the sea lamprey, while the (−)-isomer has a softer effect. Synthetic routes towards them were recently reviewed [18].

Petromyroxols
In 2015, Li reported the isolation of (+)-and (−)-petromyroxols (9) [24]. They are oxylipids isolated from water conditioned with larval sea lamprey Petromyzon marinus L. Interestingly, these molecules are the first tetrahydrofuran acetogenindiols isolated from a vertebrate animal ( Figure 4). The absolute configuration of each enantiomer was determined by a combination of Mosher ester analysis and comparison with related natural and synthetic products. The (+)-9 shows a potent olfactory response of 0.01 to 1 μM in the sea lamprey, while the (−)-isomer has a softer effect. Synthetic routes towards them were recently reviewed [18]. A recent example of the synthesis of (+)-9, along with all possible diastereoisomers, was presented in 2020 by Ramana and coworkers [25]. The synthetic route started from the commercial THF compound 10 (Scheme 2). The alkyl chain was installed by reaction

Petromyroxols
In 2015, Li reported the isolation of (+)-and (−)-petromyroxols (9) [24]. They ylipids isolated from water conditioned with larval sea lamprey Petromyzon m Interestingly, these molecules are the first tetrahydrofuran acetogenindiols isolat a vertebrate animal ( Figure 4). The absolute configuration of each enantiomer w mined by a combination of Mosher ester analysis and comparison with related and synthetic products. The (+)-9 shows a potent olfactory response of 0.01 to 1 μ sea lamprey, while the (−)-isomer has a softer effect. Synthetic routes towards th recently reviewed [18]. A recent example of the synthesis of (+)-9, along with all possible diastereo was presented in 2020 by Ramana and coworkers [25]. The synthetic route start the commercial THF compound 10 (Scheme 2). The alkyl chain was installed by A recent example of the synthesis of (+)-9, along with all possible diastereoisomers, was presented in 2020 by Ramana and coworkers [25]. The synthetic route started from the commercial THF compound 10 (Scheme 2). The alkyl chain was installed by reaction with the appropriate cuprate. Subsequent benzyl protection of 11 afforded 12, which after reaction with allyltrimethylsilane, yielded the desired diastereomer (7:2 ratio) of the allylated THF 13. After protection with a para-nitrobenzoate (PNB) group under Mitsunobu conditions, compound 14 was subjected to oxidative olefin cleavage with OsO 4 /NaIO 4 and subsequent Wittig olefination to obtain a-b-unsaturated ester 15. Hydrogenation with Pearlman catalyst (20% Pd(OH) 2 /C) afforded 16 in 89% yield, where the benzyl group, the double bond, and the nitro group were all reduced. Finally, hydrolysis of both ester groups with KOH in methanol afforded the desired (+)-petromyroxol in 77% yield. reaction with allyltrimethylsilane, yielded the desired diastereomer (7:2 ratio) of the allylated THF 13. After protection with a para-nitrobenzoate (PNB) group under Mitsunobu conditions, compound 14 was subjected to oxidative olefin cleavage with OsO4/NaIO4 and subsequent Wittig olefination to obtain a-b-unsaturated ester 15. Hydrogenation with Pearlman catalyst (20% Pd(OH)2/C) afforded 16 in 89% yield, where the benzyl group, the double bond, and the nitro group were all reduced. Finally, hydrolysis of both ester groups with KOH in methanol afforded the desired (+)-petromyroxol in 77% yield. Scheme 2. Synthesis of (+)-petromyroxol by Ramana and coworkers.

PMA
Petromyric acids A and B (PMA and PMB) are dehydroxylated tetrahydrofuranyl fatty acids that were isolated from larval washing extracts from the sea lamprey Petromyzon marinus in 2018 [26].  Figure 5). Their chemical structure was elucidated by NMR spectroscopy and confirmed by chemical synthesis and X-ray crystallography. Scheme 2. Synthesis of (+)-petromyroxol by Ramana and coworkers.

PMA
Petromyric acids A and B (PMA and PMB) are dehydroxylated tetrahydrofuranyl fatty acids that were isolated from larval washing extracts from the sea lamprey Petromyzon marinus in 2018 [26]. Sea lampreys are anadromous fishes that migrate, using their olfactory cues to orien tate, from the ocean to freshwater to find a suitable spawning stream. When approaching river mouths, the decision of which stream is optimal to spawn in is taken using thei olfactory system to detect a pheromone emitted from larval sea lampreys. When investi gating larval washing extracts, four fatty acids were identified, but only (+)-17 has proven to be the pheromone that guides lamprey adults. However, its enantiomer, (−)-17, doe not produce the same behavioral effect. Fatty acid analogues have been reported to be pheromones in insects, but this is the first identification in fish. The sea lamprey is a de Sea lampreys are anadromous fishes that migrate, using their olfactory cues to orientate, from the ocean to freshwater to find a suitable spawning stream. When approaching river mouths, the decision of which stream is optimal to spawn in is taken using their olfactory system to detect a pheromone emitted from larval sea lampreys. When investigating larval washing extracts, four fatty acids were identified, but only (+)-17 has proven to be the pheromone that guides lamprey adults. However, its enantiomer, (−)-17, does not produce the same behavioral effect. Fatty acid analogues have been reported to be pheromones in insects, but this is the first identification in fish. The sea lamprey is a destructive invader in the Laurentian Great Lakes, while in Europe, its population has decreased precipitously, so (+)-17 can be used for the control and conservation of their populations.
Although they have a high potential for application, to the best of our knowledge, no total synthesis has been reported so far for these compounds.

Mutafurans
Mutafurans A-G (19)(20)(21)(22)(23)(24)(25) are brominated ene-ynetetrahydrofurans ( Figure 6) that were isolated by Molinski in 2007 from the marine sponge Xextospongia muta [27]. Later, Liu reported the isolation of mutafuran H (26), a brominated ene-tetrahydrofuran isolated from sponge Xextospongia testudinaria within other sterols and brominated compounds [28]. Their structure and absolute configuration were determined by 1D and 2D magnetic resonance, mass spectrometry, and circular dichroism. river mouths, the decision of which stream is optimal to spawn in is taken using their olfactory system to detect a pheromone emitted from larval sea lampreys. When investigating larval washing extracts, four fatty acids were identified, but only (+)-17 has proven to be the pheromone that guides lamprey adults. However, its enantiomer, (−)-17, does not produce the same behavioral effect. Fatty acid analogues have been reported to be pheromones in insects, but this is the first identification in fish. The sea lamprey is a destructive invader in the Laurentian Great Lakes, while in Europe, its population has decreased precipitously, so (+)-17 can be used for the control and conservation of their populations.
Although they have a high potential for application, to the best of our knowledge, no total synthesis has been reported so far for these compounds.

Aspericacids
Aspericacids A (27) and B (28) were isolated in 2020 by Ding and He from the spongeassociated Aspergillus sp. LS78 [29]. Both compounds bear a 2,5-disubstituted tetrahydrofuran ring coupled with an unsaturated fatty acid (Figure 7). Their structure was determined by HRESIMS and 1D and 2D NMR spectroscopy, while their absolute configuration was established relying on electronic circular dichroism (ECD). Compound 27 presents a moderate inhibitory activity against Candida albicans and Cryptococcus neoformans with a MIC value of 50 µg/mL, although 28 has a weaker activity, MIC = 128 µg/mL. No synthetic approach has been reported to date. associated Aspergillus sp. LS78 [29]. Both compounds bear a 2,5-disubstituted tetrahydrofuran ring coupled with an unsaturated fatty acid (Figure 7). Their structure was determined by HRESIMS and 1D and 2D NMR spectroscopy, while their absolute configuration was established relying on electronic circular dichroism (ECD). Compound 27 presents a moderate inhibitory activity against Candida albicans and Cryptococcus neoformans with a MIC value of 50 μg/mL, although 28 has a weaker activity, MIC = 128 μg/mL. No synthetic approach has been reported to date.

Pantofuranoids
Pantofuranoids A-F (29)(30)(31)(32)(33)(34) are monoterpenes that were isolated in 1996 from the Antarctic red alga Pantoneura plocamioides [30]. They are the first monoterpenes found to contain a tetrahydrofuran moiety, and their common framework ( Figure 8) suggests that they all come from the same terpene precursor. In 2006, Toste reported the enantioselective total synthesis of (−)-33, in which the key step is a vanadium-catalyzed sequential resolution/oxidative cyclization [31]. Using an in situ generated vanadium(V)-oxo complex with chiral tridentate Schiff base ligand 35 as catalyst, racemic homoallylic alcohol 36 was readily converted into 2,4-cis-substituted THF 37 (Scheme 3). The observed stereochemistry can be explained through a chair-like Pantofuranoids A-F (29)(30)(31)(32)(33)(34) are monoterpenes that were isolated in 1996 from the Antarctic red alga Pantoneura plocamioides [30]. They are the first monoterpenes found to contain a tetrahydrofuran moiety, and their common framework ( Figure 8) suggests that they all come from the same terpene precursor. furan ring coupled with an unsaturated fatty acid (Figure 7). Their structure was determined by HRESIMS and 1D and 2D NMR spectroscopy, while their absolute configuration was established relying on electronic circular dichroism (ECD). Compound 27 presents a moderate inhibitory activity against Candida albicans and Cryptococcus neoformans with a MIC value of 50 μg/mL, although 28 has a weaker activity, MIC = 128 μg/mL. No synthetic approach has been reported to date.

Pantofuranoids
Pantofuranoids A-F (29)(30)(31)(32)(33)(34) are monoterpenes that were isolated in 1996 from the Antarctic red alga Pantoneura plocamioides [30]. They are the first monoterpenes found to contain a tetrahydrofuran moiety, and their common framework ( Figure 8) suggests that they all come from the same terpene precursor. In 2006, Toste reported the enantioselective total synthesis of (−)-33, in which the key step is a vanadium-catalyzed sequential resolution/oxidative cyclization [31]. Using an in situ generated vanadium(V)-oxo complex with chiral tridentate Schiff base ligand 35 as catalyst, racemic homoallylic alcohol 36 was readily converted into 2,4-cis-substituted THF 37 (Scheme 3). The observed stereochemistry can be explained through a chair-like In 2006, Toste reported the enantioselective total synthesis of (−)-33, in which the key step is a vanadium-catalyzed sequential resolution/oxidative cyclization [31]. Using an in situ generated vanadium(V)-oxo complex with chiral tridentate Schiff base ligand 35 as catalyst, racemic homoallylic alcohol 36 was readily converted into 2,4-cis-substituted THF 37 (Scheme 3). The observed stereochemistry can be explained through a chair-like transition state in which coordination of the pseudo-equatorial ester group to the vanadium complex determines the selectivity of the syn-epoxidation step. Then, compound 37 was further elaborated to (−)-33 in 6 steps and 29% overall yield from 37.
Mar. Drugs 2022, 20, x FOR PEER REVIEW 9 of 35 transition state in which coordination of the pseudo-equatorial ester group to the vanadium complex determines the selectivity of the syn-epoxidation step. Then, compound 37 was further elaborated to (−)-33 in 6 steps and 29% overall yield from 37. Scheme 3. Vanadium-catalyzed synthesis of the tetrahydrofuranyl core of (−)-pantofuranoid E by Toste.

Furoplocamioids
Furoplocamioids A-C 38-40 ( Figure 9) are monoterpenes that were isolated in 2001 from the red marine alga Plocamium cartilagineum [32]. They bear an unusual polyhalogenated tetrahydrofuranyl ring. Their structural similarity to pantofuranoids suggests a close relationship between the species that produce them. This is an interesting fact, since Scheme 3. Vanadium-catalyzed synthesis of the tetrahydrofuranyl core of (−)-pantofuranoid E by Toste.

Furoplocamioids
Furoplocamioids A-C 38-40 ( Figure 9) are monoterpenes that were isolated in 2001 from the red marine alga Plocamium cartilagineum [32]. They bear an unusual polyhalogenated tetrahydrofuranyl ring. Their structural similarity to pantofuranoids suggests a close relationship between the species that produce them. This is an interesting fact, since Plocamium cartilagineum and Pantoneura plocamioides are classified in different orders, Gigartinales and Ceramiales. Therefore, a taxonomic revision could be required. Later, the Darias group determined the C7 relative stereochemistry by comparison with the NMR spectra of similar reported terpenes [33]. González-Coloma and coworkers found that 38 and 40 show antifeedant effects against Leptinotarsa decemlineata. It was shown that 40 was also an efficient aphid repellent (against Mizuspersicae and Ropalosiphumpadi) and selective insect cell toxicant. In addition, both compounds showed low mammalian toxicity and phytotoxic effects [34]. Scheme 3. Vanadium-catalyzed synthesis of the tetrahydrofuranyl core of (−)-pantofuranoid E by Toste.

Furoplocamioids
Furoplocamioids A-C 38-40 ( Figure 9) are monoterpenes that were isolated in 2001 from the red marine alga Plocamium cartilagineum [32]. They bear an unusual polyhalogenated tetrahydrofuranyl ring. Their structural similarity to pantofuranoids suggests a close relationship between the species that produce them. This is an interesting fact, since Plocamium cartilagineum and Pantoneura plocamioides are classified in different orders, Gigartinales and Ceramiales. Therefore, a taxonomic revision could be required. Later, the Darias group determined the C7 relative stereochemistry by comparison with the NMR spectra of similar reported terpenes [33]. González-Coloma and coworkers found that 38 and 40 show antifeedant effects against Leptinotarsa decemlineata. It was shown that 40 was also an efficient aphid repellent (against Mizuspersicae and Ropalosiphumpadi) and selective insect cell toxicant. In addition, both compounds showed low mammalian toxicity and phytotoxic effects [34].
The first total synthesis of (+)-41 was reported in 2014 by Brimble and coworkers, who used as key steps to introduce the five stereogenic centers a Julia-Kocienski coupling, a Shi epoxidation, and a catalytic epoxide-opening reaction [39]. The same year, the first total synthesis of (+)-42 was achieved by Capon and Stark using a similar approach [36]. In 2016, Brimble and Furkert reviewed the isolation and synthesis of this family of compounds [40].
The first total synthesis of (+)-41 was reported in 2014 by Brimble and coworkers, who used as key steps to introduce the five stereogenic centers a Julia-Kocienski coupling, a Shi epoxidation, and a catalytic epoxide-opening reaction [39]. The same year, the first total synthesis of (+)-42 was achieved by Capon and Stark using a similar approach [36]. In 2016, Brimble and Furkert reviewed the isolation and synthesis of this family of compounds [40].

Kumausallene and Kumausyne
(−)-Kumausallene (46) was isolated in 1983 from the marine red alga Laurencia nipponica Yamada [43]. This compound belongs to a family of non-isoprenoid sesquiterpenes that contain a 2,6-dioxa-bicyclo [3.3.0]octane core with an exo-cyclic bromoallene ( Figure  11). In 1993, the first total synthesis of (±)-46 was reported by Overman, who chose a hex-  In 1993, the first total synthesis of (±)-46 was reported by Overman, who chose a hexahydrobenzofuranone 47 (obtained by a Prins cyclization-pinacol rearrangement from 48) as the key intermediate for the construction of the bis-tetrahydrofuran unit (Scheme 5). Further transformation of 47 into bicyclic lactone 49 (within three further steps) and final methanolisis and tandem cyclization of the corresponding hydroxyester provided, in good yield, the desired dioxabicyclo [3.3.0]octane 50 [44]. In 1993, the first total synthesis of (±)-46 was reported by Overman, who chose a hexahydrobenzofuranone 47 (obtained by a Prins cyclization-pinacol rearrangement from 48) as the key intermediate for the construction of the bis-tetrahydrofuran unit (Scheme 5). Further transformation of 47 into bicyclic lactone 49 (within three further steps) and final methanolisis and tandem cyclization of the corresponding hydroxyester provided, in good yield, the desired dioxabicyclo [3.3.0]octane 50 [44]. In 2011, a synthetic approach for (−)-46 by Tang employed a desymmetrization strategy for the formation of the 2,5-cis-substituted THF ring [45]. C2-symmetric diol 51 is desymmetrized by a palladium-catalyzed cascade reaction to form lactone 52 in 87% yield (Scheme 6). The total synthesis comprised just 12 steps from commercial acetylacetone. In In 2011, a synthetic approach for (−)-46 by Tang employed a desymmetrization strategy for the formation of the 2,5-cis-substituted THF ring [45]. C 2 -symmetric diol 51 is desymmetrized by a palladium-catalyzed cascade reaction to form lactone 52 in 87% yield (Scheme 6). The total synthesis comprised just 12 steps from commercial acetylacetone. In 2015, Ramana et al. published a different formal total synthesis of (−)-46 based on a chiral pool approach [46]. (+)-Trans-Kumausyne (53) ( Figure 12) is a halogenated non-isoprenoid sesquiterpene isolated in 1983 from red alga Laurencia nipponica Yamada [47]. Its first total synthesis was achieved in 1991 by Overman and coworkers [48]. A review covering the synthetic approaches towards kumausallene and kumausyne, and other natural products containing a 2,3,5-trisubstituted tetrahydrofuran moiety, was published by Fernandes in 2020 [18].  Figure 13) is a diterpene isolated in 2016 by Baker from the Antarctic Dendroceratid sponge Dendrilla membranosa [49]. It presents fourfold selectivity against a biofilm phase of methicillin-resistant Staphylococcus aureus (IC50 of 33.2μM), compared to the planktonic phase (with the higher MIC of 132.9 μM). This interesting property Scheme 6. Synthesis of the tetrahydrofuranyl ring of (−)-46 through desymmetrization by Tang.

Darwinolide
(+)-Darwinolide (54) (Figure 13) is a diterpene isolated in 2016 by Baker from the Antarctic Dendroceratid sponge Dendrilla membranosa [49]. It presents fourfold selectivity against a biofilm phase of methicillin-resistant Staphylococcus aureus (IC50 of 33.2μM), compared to the planktonic phase (with the higher MIC of 132.9 μM). This interesting property and its low mammalian cytotoxicity (IC50 of 73.4 mM) against a J774 macrophage cell line turn darwinolide into a possible scaffold for antibiofilm-specific antibiotics. Additionally, it was found to have modest activity (11.2 μM) against L. donovani-infected macrophages [50].  Its total synthesis was reported in 2019 by Christmann [51]. The required tetrahydrofuranyl ring is installed starting from the commercially available anhydride 55, which is converted to the 2,5-dimethoxylated tetrahydrofuran 56 in four steps. A sequence of oxidation (with o-iodoxybenzoic acid), saponification, and Criegee oxidation with Pb(OAc) 4 is then used to convert 56 into 57 in 61% yield over three steps (Scheme 7). A further 14 linear steps are needed to complete the total synthesis of 54, with an overall yield of 1.4%.
Mar. Drugs 2022, 20, x FOR PEER REVIEW 13 of 35 Its total synthesis was reported in 2019 by Christmann [51]. The required tetrahydrofuranyl ring is installed starting from the commercially available anhydride 55, which is converted to the 2,5-dimethoxylated tetrahydrofuran 56 in four steps. A sequence of oxidation (with o-iodoxybenzoic acid), saponification, and Criegee oxidation with Pb(OAc)4 is then used to convert 56 into 57 in 61% yield over three steps (Scheme 7). A further 14 linear steps are needed to complete the total synthesis of 54, with an overall yield of 1.4%.

Uprolides
Cembranolides are a family of compounds related to cembrene, which is a 14-membered macrocyclic diterpene with multiple (E)-double bonds. Among them, uprolides are a subfamily of compounds named after the University of Puerto Rico. Uprolides A-G were isolated in 1995 by Rodríguez and coworkers from the Caribbean gorgonian Eunicea Mammosa and their structure was assigned by spectroscopic methods and chemical interconversion [52,53]. They are the first natural cembranolides from a Caribbean gorgonian that bear a double bond at C6 or C8. While uprolides A-C show an epoxy moiety, up-

Uprolides
Cembranolides are a family of compounds related to cembrene, which is a 14-membered macrocyclic diterpene with multiple (E)-double bonds. Among them, uprolides are a subfamily of compounds named after the University of Puerto Rico. Uprolides A-G were isolated in 1995 by Rodríguez and coworkers from the Caribbean gorgonian Eunicea Mammosa and their structure was assigned by spectroscopic methods and chemical interconversion [52,53]. They are the first natural cembranolides from a Caribbean gorgonian that bear a double bond at C6 or C8. While uprolides A-C show an epoxy moiety, uprolides D-G seemed to contain a tetrahydrofuran moiety instead. Uprolides D (58), D acetate (59), D diacetate (60), and E acetate (61)  In 2007, a synthetic approach to obtain the macrocyclic core of 58 was proposed by Ramana [58]. The formation of the macrocyclic core is produced by ring-closing metathesis (RCAM) using a Grubbs' first-generation catalyst. The RCAM of acetate 62 produces 13-membered macrocyclic 63 in 67% yield (Scheme 8). The macrocyclic core of uprolide E could not be synthesized using the same methodology. Marshall developed a synthetic route for C1/C14 bis-epimer of 58 in which the macrocyclization is produced by an intramolecuar Barbier reaction [59]. Some years later, other members of the uprolide family, which lack the tetrahydrofuran ring, have been isolated from the gorgonian octocoral Eunicea succinea [60].

Intricatetraol
Intricatetraol (64) is a halogenated triterpenoid with a C2 symmetry that was isolated in 1993 from the red alga Laurencia intricata ( Figure 15). Suzuki and coworkers observed that a crude fraction of the extract showed cytotoxic activity against P388 leukemia cells with an IC50 value of 12.5 μg/mL. Nevertheless, pure intricatetraol was no longer active after chromatography. At first, its stereostructure was proposed as being based on its hypothetical biogenesis [61]. In 2006, Morimoto confirmed this assignment by synthesizing a degradation product of intricatetraol through a two-directional synthesis [62].  Later structural revisions determined the presence of a tetrahydropyran ring, instead of the previously proposed tetrahydrofuran, in uprolides F diacetate and G acetate, hypotheses that were confirmed by asymmetric total synthesis of these natural products [54][55][56][57].
In 2007, a synthetic approach to obtain the macrocyclic core of 58 was proposed by Ramana [58]. The formation of the macrocyclic core is produced by ring-closing metathesis (RCAM) using a Grubbs' first-generation catalyst. The RCAM of acetate 62 produces 13-membered macrocyclic 63 in 67% yield (Scheme 8). The macrocyclic core of uprolide E could not be synthesized using the same methodology. In 2007, a synthetic approach to obtain the macrocyclic core of 58 was proposed by Ramana [58]. The formation of the macrocyclic core is produced by ring-closing metathesis (RCAM) using a Grubbs' first-generation catalyst. The RCAM of acetate 62 produces 13-membered macrocyclic 63 in 67% yield (Scheme 8). The macrocyclic core of uprolide E could not be synthesized using the same methodology. Marshall developed a synthetic route for C1/C14 bis-epimer of 58 in which the macrocyclization is produced by an intramolecuar Barbier reaction [59]. Some years later, other members of the uprolide family, which lack the tetrahydrofuran ring, have been isolated from the gorgonian octocoral Eunicea succinea [60].

Intricatetraol
Intricatetraol (64) is a halogenated triterpenoid with a C2 symmetry that was isolated in 1993 from the red alga Laurencia intricata ( Figure 15). Suzuki and coworkers observed that a crude fraction of the extract showed cytotoxic activity against P388 leukemia cells with an IC50 value of 12.5 μg/mL. Nevertheless, pure intricatetraol was no longer active after chromatography. At first, its stereostructure was proposed as being based on its hypothetical biogenesis [61]. In 2006, Morimoto confirmed this assignment by synthesizing a degradation product of intricatetraol through a two-directional synthesis [62]. Marshall developed a synthetic route for C1/C14 bis-epimer of 58 in which the macrocyclization is produced by an intramolecuar Barbier reaction [59]. Some years later, other members of the uprolide family, which lack the tetrahydrofuran ring, have been isolated from the gorgonian octocoral Eunicea succinea [60].

Intricatetraol
Intricatetraol (64) is a halogenated triterpenoid with a C 2 symmetry that was isolated in 1993 from the red alga Laurencia intricata ( Figure 15). Suzuki and coworkers observed that a crude fraction of the extract showed cytotoxic activity against P388 leukemia cells with an IC 50 value of 12.5 µg/mL. Nevertheless, pure intricatetraol was no longer active after chromatography. At first, its stereostructure was proposed as being based on its hypothetical biogenesis [61]. In 2006, Morimoto confirmed this assignment by synthesizing a degradation product of intricatetraol through a two-directional synthesis [62].
Intricatetraol (64) is a halogenated triterpenoid with a C2 symmetry that was isolated in 1993 from the red alga Laurencia intricata (Figure 15). Suzuki and coworkers observed that a crude fraction of the extract showed cytotoxic activity against P388 leukemia cells with an IC50 value of 12.5 μg/mL. Nevertheless, pure intricatetraol was no longer active after chromatography. At first, its stereostructure was proposed as being based on its hypothetical biogenesis [61]. In 2006, Morimoto confirmed this assignment by synthesizing a degradation product of intricatetraol through a two-directional synthesis [62]. One year later, Morimoto completed the asymmetric total synthesis of (+)-64 and, thus, determined its absolute configuration [63]. The tetrahydrofuran ring 65 was stereospecifically constructed by treatment of diepoxyalcohol 66 with lithium hydroxide aqueous solution. A further 10 steps (with an accumulated yield of 30%) were needed to obtain One year later, Morimoto completed the asymmetric total synthesis of (+)-64 and, thus, determined its absolute configuration [63].

Omaezakianol
Omaezakianol (69) (Figure 16) is a squalene-derived triterpene polyether that was isolated in 2008 from the red alga Laurencia omaezakiana by Morimoto and coworkers [64]. The same group rapidly reported its first asymmetric total synthesis and, therefore, stablished its absolute configuration [65]. Key steps were olefin cross-metathesis and an epoxide-opening cascade. In 2010, Corey reported a short total synthesis via a biomimetic epoxide-initiated cationic cascade reaction [66]. Compound 70 was treated with camphorsulfonic acid (CSA) to induce the epoxide-opening cascade cyclization, producing 71. Reduction of 71, with sodium in acetone under reflux, formed the terminal double bond with opening of the THF ring, affording 69 in 76% yield (Scheme 10). Thus, the synthesis was accomplished in Scheme 9. Synthesis of (+)-intricatetraol ((+)-64).

Omaezakianol
Omaezakianol (69) (Figure 16) is a squalene-derived triterpene polyether that was isolated in 2008 from the red alga Laurencia omaezakiana by Morimoto and coworkers [64]. The same group rapidly reported its first asymmetric total synthesis and, therefore, stablished its absolute configuration [65]. Key steps were olefin cross-metathesis and an epoxide-opening cascade.

Omaezakianol
Omaezakianol (69) (Figure 16) is a squalene-derived triterpene poly isolated in 2008 from the red alga Laurencia omaezakiana by Morimoto and c The same group rapidly reported its first asymmetric total synthesis and, t lished its absolute configuration [65]. Key steps were olefin cross-metathesi ide-opening cascade. In 2010, Corey reported a short total synthesis via a biomimetic epoxid ionic cascade reaction [66]. Compound 70 was treated with camphorsulfo to induce the epoxide-opening cascade cyclization, producing 71. Reduct In 2010, Corey reported a short total synthesis via a biomimetic epoxide-initiated cationic cascade reaction [66]. Compound 70 was treated with camphorsulfonic acid (CSA) to induce the epoxide-opening cascade cyclization, producing 71. Reduction of 71, with sodium in acetone under reflux, formed the terminal double bond with opening of the THF ring, affording 69 in 76% yield (Scheme 10). Thus, the synthesis was accomplished in just six steps from squalene.

Longilenes
Longilenes are triterpene polyethers that were first isolated from the wood of Eurycoma longifolia in the form of (−)-longilene peroxide ((−)-73) [68,69]. In 2001, Morimoto accomplished its total synthesis [70] and determined its absolute configuration. The same author also developed a biomimetic synthesis of the C9-C16 fragment of oxasqualenoids in an enantioselective manner [71]. This chiral building block could be used as an advanced intermediate for the synthesis of different polyethers, such as teurilene, longilene peroxide, or glabrescol.

Longilenes
Longilenes are triterpene polyethers that were first isolated from the wood of Eurycoma longifolia in the form of (−)-longilene peroxide ((−)-73) [68,69]. In 2001, Morimoto accomplished its total synthesis [70] and determined its absolute configuration. The same author also developed a biomimetic synthesis of the C9-C16 fragment of oxasqualenoids in an enantioselective manner [71]. This chiral building block could be used as an advanced intermediate for the synthesis of different polyethers, such as teurilene, longilene peroxide, or glabrescol.

Longilenes
Longilenes are triterpene polyethers that were first isolated from the wood of Eurycoma longifolia in the form of (−)-longilene peroxide ((−)-73) [68,69]. In 2001, Morimoto accomplished its total synthesis [70] and determined its absolute configuration. The same author also developed a biomimetic synthesis of the C9-C16 fragment of oxasqualenoids in an enantioselective manner [71]. This chiral building block could be used as an advanced intermediate for the synthesis of different polyethers, such as teurilene, longilene peroxide, or glabrescol.

Laurokanols and Yucatecone
In 2021, laurokanols A-E (76-80) and yucatecone (81) (Figure 18), polyether triterpenes, were isolated from the red alga Laurencia viridis [73]. Laurokanols have an unprecedented tricyclic core with an [6,6]-spiroketal system. Yucatecone is the first compound of this series with an R configuration at the C14 position. A biogenetic model, supported by DFT calculations, was then postulated for the biogenesis of yucatecone.

Laurokanols and Yucatecone
In 2021, laurokanols A-E (76-80) and yucatecone (81) (Figure 18), polyether triterpenes, were isolated from the red alga Laurencia viridis [73]. Laurokanols have an unprecedented tricyclic core with an [6,6]-spiroketal system. Yucatecone is the first compound of this series with an R configuration at the C14 position. A biogenetic model, supported by DFT calculations, was then postulated for the biogenesis of yucatecone.

Laurokanols and Yucatecone
In 2021, laurokanols A-E (76-80) and yucatecone (81) (Figure 18), polyether triterpenes, were isolated from the red alga Laurencia viridis [73]. Laurokanols have an unprecedented tricyclic core with an [6,6]-spiroketal system. Yucatecone is the first compound of this series with an R configuration at the C14 position. A biogenetic model, supported by DFT calculations, was then postulated for the biogenesis of yucatecone.

Thyrsenol
Thyrsenol A (82) and B (83) (Figure 19) are polyether squalene derivatives that were isolated by Norte and coworkers in 1997 from the red alga Laurencia viridis [74]. Although both compounds show high activity against murine lymphoid neoplasm P-388 cells, compound 83 induced significantly higher inhibitory effects [75]. Other related compounds, such as thyrsiferol derivatives and dehydrovenustatriol, were found to be even more active. Therefore, it was postulated that the presence of a flexible chain around C14 to C19, and its configuration, are of particular importance for the bioactivity of these compounds. Later, Fernández and coworkers also found 83 to have protein phosphatase PP2A inhibitory activity [76]. The activity was comparable to that of dehydrothyrsiferol and thysiferyl-23-acetate, concluding that a hydroxyl group at C15 or C16 is a key factor for their intrinsic activity. In 2011, the isolation of other derivatives has been reported [77].

Thyrsenol
Thyrsenol A (82) and B (83) (Figure 19) are polyether squalene derivatives that were isolated by Norte and coworkers in 1997 from the red alga Laurencia viridis [74]. Although both compounds show high activity against murine lymphoid neoplasm P-388 cells, compound 83 induced significantly higher inhibitory effects [75]. Other related compounds, such as thyrsiferol derivatives and dehydrovenustatriol, were found to be even more active. Therefore, it was postulated that the presence of a flexible chain around C14 to C19, and its configuration, are of particular importance for the bioactivity of these compounds. Later, Fernández and coworkers also found 83 to have protein phosphatase PP2A inhibitory activity [76]. The activity was comparable to that of dehydrothyrsiferol and thysiferyl-23-acetate, concluding that a hydroxyl group at C15 or C16 is a key factor for their intrinsic activity. In 2011, the isolation of other derivatives has been reported [77].  [78]. In 2015, saiyacenol C (86), and two hydroxylated derivatives 87 and 88, were isolated from the same alga [79]. Although saiyacenols showed no activity toward a range of bacteria and fungal strains, compounds 85 and 86 avoid Navicula cf. salinicola and Cylindrotheca sp. growth, while compounds 87 and 88 were also active against germination of Gayralia oxysperma.   [78]. In 2015, saiyacenol C (86), and two hydroxylated derivatives 87 and 88, were isolated from the same alga [79]. Although saiyacenols showed no activity toward a range of bacteria and fungal strains, compounds 85 and 86 avoid Navicula cf. salinicola and Cylindrotheca sp. growth, while compounds 87 and 88 were also active against germination of Gayralia oxysperma.

Thyrsenol
Thyrsenol A (82) and B (83) (Figure 19) are polyether squalene derivatives that were isolated by Norte and coworkers in 1997 from the red alga Laurencia viridis [74]. Although both compounds show high activity against murine lymphoid neoplasm P-388 cells, compound 83 induced significantly higher inhibitory effects [75]. Other related compounds, such as thyrsiferol derivatives and dehydrovenustatriol, were found to be even more active. Therefore, it was postulated that the presence of a flexible chain around C14 to C19, and its configuration, are of particular importance for the bioactivity of these compounds. Later, Fernández and coworkers also found 83 to have protein phosphatase PP2A inhibitory activity [76]. The activity was comparable to that of dehydrothyrsiferol and thysiferyl-23-acetate, concluding that a hydroxyl group at C15 or C16 is a key factor for their intrinsic activity. In 2011, the isolation of other derivatives has been reported [77].   More recently, Piñero and Fernández evaluated a range of natural and semisynthetic terpenoid polyethers against protozoan parasites of the Trypanosoma and Leishmania genera [80]. Both 84 and 85 have anti-protozoal activity against Leishmania amazonensis (IC 50 = 12.96 and 10.32 µM, respectively). Interestingly, saiyacenol A 84 was also effective against the highly resistant Trypanosoma cruzi (IC 50 = 13.75 ± 2.28 µM). The semisynthetic 28-iodosaiyacenol B showed a high value (IC 50 = 5.40 ± 0.13 µM) against Leishmania amazonensis and no toxicity to murine macrophage J774.A1. This turns it into a possible scaffold for antikinetoplastid drugs, as the data are comparable to those of the reference drug miltefosine (IC 50 = 6.48).
Very recently, Nishikawa and Morimoto reported the asymmetric total synthesis of saiyacenol A, along with that of the related Aplysiol B [81]. In their research, an epoxideopening cascade was used to form both THF rings in the same step (Scheme 12). Thus, from advanced precursor 89, treatment with CSA provoked two sequential 5-exo openings to form the oxygenated rings in bis-tetrahydrofuran 90. The last step consisted of crossmethathesis with the ruthenium catalyst 91 and later bromoetherification with BDSB. Preliminary cytotoxicity was tested against P388, HT-29, and HeLa tumor cell lines, showing values of 5.4, 85, and >100 µM, respectively.

Teurilene
Teurilene (92) (Figure 21) is a triterpene polyether that was isolated in 1985 from the red alga Laurencia obtusa by Kurosawa and coworkers [82]. It has three linked 2,5-disubstituted THF rings and, even though it has eight stereogenic centres, it is an achiral compound due to its meso-symmetry (Cs). Compound 92 has a remarkable cytotoxic activity against KB cells (IC50 = 7.0 μg mL −1 ) [69]. Synthetic approaches and routes up to 2014 are commented on in a previous review [83].

Teurilene
Teurilene (92) (Figure 21) is a triterpene polyether that was isolated in 1985 from the red alga Laurencia obtusa by Kurosawa and coworkers [82]. It has three linked 2,5-disubstituted THF rings and, even though it has eight stereogenic centres, it is an achiral compound due to its meso-symmetry (C s ). Compound 92 has a remarkable cytotoxic activity against KB cells (IC 50 = 7.0 µg mL −1 ) [69]. Synthetic approaches and routes up to 2014 are commented on in a previous review [83].  ) against Leishmania amazonensis and no toxicity to murine macrophage J774.A1. This turns it into a possible scaffold for antikinetoplastid drugs, as the data are comparable to those of the reference drug miltefosine (IC50 = 6.48). Very recently, Nishikawa and Morimoto reported the asymmetric total synthesis of saiyacenol A, along with that of the related Aplysiol B [81]. In their research, an epoxideopening cascade was used to form both THF rings in the same step (Scheme 12). Thus, from advanced precursor 89, treatment with CSA provoked two sequential 5-exo openings to form the oxygenated rings in bis-tetrahydrofuran 90. The last step consisted of crossmethathesis with the ruthenium catalyst 91 and later bromoetherification with BDSB. Preliminary cytotoxicity was tested against P388, HT-29, and HeLa tumor cell lines, showing values of 5.4, 85, and >100 μM, respectively.

Teurilene
Teurilene (92) (Figure 21) is a triterpene polyether that was isolated in 1985 from the red alga Laurencia obtusa by Kurosawa and coworkers [82]. It has three linked 2,5-disubstituted THF rings and, even though it has eight stereogenic centres, it is an achiral compound due to its meso-symmetry (Cs). Compound 92 has a remarkable cytotoxic activity against KB cells (IC50 = 7.0 μg mL −1 ) [69]. Synthetic approaches and routes up to 2014 are commented on in a previous review [83].

Thyrsiferol
Thyrsiferol (93) is a polyoxygenated triterpenoid ether that was isolated in 1978 from the red alga Laurencia thyrsifera [84]. Its absolute stereochemistry (Figure 22) was determined in 1986 when venustatriol was isolated, since the latter could be crystallized and characterized by X-ray diffraction [85]. During the next two decades, a plethora of thyrsiferol derivatives have been isolated. Their biological profiles (cytotoxic, anti-viral, anti-tumor) have attracted much attention and several syntheses were published and reviewed in 2008 [86].

Thyrsiferol
Thyrsiferol (93) is a polyoxygenated triterpenoid ether that was isolated in 1978 from the red alga Laurencia thyrsifera [84]. Its absolute stereochemistry (Figure 22) was determined in 1986 when venustatriol was isolated, since the latter could be crystallized and characterized by X-ray diffraction [85]. During the next two decades, a plethora of thyrsiferol derivatives have been isolated. Their biological profiles (cytotoxic, anti-viral, antitumor) have attracted much attention and several syntheses were published and reviewed in 2008 [86]. Thyrsiferol has later been found to inhibit hypoxia-induced hypoxia-inducible factor-1 (HIF-1) activation in T47D human breast tumor cells, as well as to inhibit a mitochondrial ETC complex I and show tumor cell line-selective time-dependent inhibition of cell viability/proliferation [77]. In addition, Piñero and Fernández recently reported it to be active against Acanthamoeba castellanii trophozoites (IC50 = 13.97 μM). Its derivative, 22-hydroxydehydrotyrsiferol, was similarly active (IC50 = 17.00 μM) and both were not toxic against murine macrophages, which makes them potential leads for the discovery of novel amoebicidal substances [87].

Rhabdastins
The first members of this family, Rhabdastins A-G, were first isolated in 2010 by Iwagawa from the sponge Rhabdastrella globostellata [88]. They belong to the group ofisomalabaricane triterpenes. In 2021, the tetrahydrofuran-containing rhabdastins H (94) and I (95) (Figure 23) were isolated from the sponge Rhabdastrella sp. [89]. They are the first marine isomalabaricanes that present a tetrahydrofuran unit in their structure. Both compounds show antiproliferative effect against K562 (IC50 11.7 and 9.8 μM, respectively) and Molt4 (IC50 16.5 and 11.0 μM) leukemic cells.

Alisiaquinones and Alisiaquinol
Alisiaquinones A-C (96-98) and alisiaquinol (99) (Figure 24) are meroterpenes that were isolated in 2008 from a New Caledonian deep-water sponge [90]. They display mild antimalarial activity, but the high level of toxicity (100% and 80% mortality, respectively) Thyrsiferol has later been found to inhibit hypoxia-induced hypoxia-inducible factor-1 (HIF-1) activation in T47D human breast tumor cells, as well as to inhibit a mitochondrial ETC complex I and show tumor cell line-selective time-dependent inhibition of cell viability/proliferation [77]. In addition, Piñero and Fernández recently reported it to be active against Acanthamoeba castellanii trophozoites (IC 50 = 13.97 µM). Its derivative, 22-hydroxydehydrotyrsiferol, was similarly active (IC 50 = 17.00 µM) and both were not toxic against murine macrophages, which makes them potential leads for the discovery of novel amoebicidal substances [87].

Rhabdastins
The first members of this family, Rhabdastins A-G, were first isolated in 2010 by Iwagawa from the sponge Rhabdastrella globostellata [88]. They belong to the group ofisomalabaricane triterpenes. In 2021, the tetrahydrofuran-containing rhabdastins H (94) and I (95) (Figure 23) were isolated from the sponge Rhabdastrella sp. [89]. They are the first marine isomalabaricanes that present a tetrahydrofuran unit in their structure. Both compounds show antiproliferative effect against K562 (IC 50 11.7 and 9.8 µM, respectively) and Molt4 (IC 50 16.5 and 11.0 µM) leukemic cells.

Thyrsiferol
Thyrsiferol (93) is a polyoxygenated triterpenoid ether that was isolated in 1978 from the red alga Laurencia thyrsifera [84]. Its absolute stereochemistry (Figure 22) was determined in 1986 when venustatriol was isolated, since the latter could be crystallized and characterized by X-ray diffraction [85]. During the next two decades, a plethora of thyrsiferol derivatives have been isolated. Their biological profiles (cytotoxic, anti-viral, antitumor) have attracted much attention and several syntheses were published and reviewed in 2008 [86]. Thyrsiferol has later been found to inhibit hypoxia-induced hypoxia-inducible factor-1 (HIF-1) activation in T47D human breast tumor cells, as well as to inhibit a mitochondrial ETC complex I and show tumor cell line-selective time-dependent inhibition of cell viability/proliferation [77]. In addition, Piñero and Fernández recently reported it to be active against Acanthamoeba castellanii trophozoites (IC50 = 13.97 μM). Its derivative, 22-hydroxydehydrotyrsiferol, was similarly active (IC50 = 17.00 μM) and both were not toxic against murine macrophages, which makes them potential leads for the discovery of novel amoebicidal substances [87].

Rhabdastins
The first members of this family, Rhabdastins A-G, were first isolated in 2010 by Iwagawa from the sponge Rhabdastrella globostellata [88]. They belong to the group ofisomalabaricane triterpenes. In 2021, the tetrahydrofuran-containing rhabdastins H (94) and I (95) (Figure 23) were isolated from the sponge Rhabdastrella sp. [89]. They are the first marine isomalabaricanes that present a tetrahydrofuran unit in their structure. Both compounds show antiproliferative effect against K562 (IC50 11.7 and 9.8 μM, respectively) and Molt4 (IC50 16.5 and 11.0 μM) leukemic cells.

Alisiaquinones and Alisiaquinol
Alisiaquinones A-C (96-98) and alisiaquinol (99) (Figure 24) are meroterpenes that were isolated in 2008 from a New Caledonian deep-water sponge [90]. They display mild antimalarial activity, but the high level of toxicity (100% and 80% mortality, respectively) shown in in vivo assays limited their interest as antimalarial agents. Nevertheless, their structure can be an inspiration for the development of related structures towards novel antimalarial drugs.
Mar. Drugs 2022, 20, x FOR PEER REVIEW 21 of 35 shown in in vivo assays limited their interest as antimalarial agents. Nevertheless, their structure can be an inspiration for the development of related structures towards novel antimalarial drugs.

Tricycloalterfurenes
Tricycloalterfurenes A-D (100-103) were isolated in 2017 from the culture extract of an Alternaria alternata strain (k21-1) isolated from the surface of the marine red alga Lomentaria hakodatensis [91]. These meroterpenes present activity against three phytoplankton (Chattonella marina, Heterosigma akashiwo, and Prorocentrum donghaiense) and one marine zooplankton (Artemia salina). The higher activity of tricycloalterfurene A (64, 37, 46%, respectively, against the phytoplankton species) indicates that hydroxylation at C2 or C3 negatively influences the activity against these organisms. Later, Oh and Shin reported the isolation, from a marine-derived Stemphylium sp. fungus, of tricycloalterfurenes E-G (104-106) [92]. Very recently, Fraga proposed some structural revisions [93]. Regarding tricycloalterfurenes A-C, the correct configuration of the hydroxyl group would be 4R (Figure 25), comparing the NMR data with that of guignardone T [94]. With respect to trycicloalterfurene D, the correct configuration was proposed to be 6-β-OH (6R), also by NMR data comparison to similar systems [95]. To date, no synthetic approaches have been reported.

Tricycloalterfurenes
Tricycloalterfurenes A-D (100-103) were isolated in 2017 from the culture extract of an Alternaria alternata strain (k21-1) isolated from the surface of the marine red alga Lomentaria hakodatensis [91]. These meroterpenes present activity against three phytoplankton (Chattonella marina, Heterosigma akashiwo, and Prorocentrum donghaiense) and one marine zooplankton (Artemia salina). The higher activity of tricycloalterfurene A (64, 37, 46%, respectively, against the phytoplankton species) indicates that hydroxylation at C2 or C3 negatively influences the activity against these organisms. Later, Oh and Shin reported the isolation, from a marine-derived Stemphylium sp. fungus, of tricycloalterfurenes E-G (104-106) [92]. Very recently, Fraga proposed some structural revisions [93]. Regarding tricycloalterfurenes A-C, the correct configuration of the hydroxyl group would be 4R (Figure 25), comparing the NMR data with that of guignardone T [94]. With respect to trycicloalterfurene D, the correct configuration was proposed to be 6-β-OH (6R), also by NMR data comparison to similar systems [95]. To date, no synthetic approaches have been reported.

Marinoterpins
Marinoterpins A-C (107-109) (Figure 26) are linear merosesterterpenoids that were recently isolated (2021) by Winter and Fenical from the marine-derived actinomycete bacteria Streptomyces sp. AJS-327 and CNQ-253 [96]. Due to their similarity to the aurachin family of compounds, a marinoterpin biosynthetic cluster (mrt) was identified. Thus, a biosynthetic route for the 3-geranylfarnesyl-2-methylquinoline core was proposed, although the reactions that lead to the tetrahydrofuran rings as well as the N-oxidation still remain unknown.

Pachastrissamine (Jaspine B)
Pachastrissamine (110) was first isolated by Higa and coworkers from a marine sponge of the genus Pachastrissa [97]. A year later, Debitus reported its isolation from another sponge Jaspis sp. and, thus, named the compound jaspine B [98]. Other related compounds were also isolated, including jaspine A (111) (Figure 27). Pachastrissamine is a sphingolipid-in particular, a derivative from anhydrophytosphingosine. Its biological activity and synthetic endeavors until 2016 were summarized by Martinková in a minireview [99].  Pachastrissamine (110) was first isolated by Higa and coworkers from a marine sponge of the genus Pachastrissa [97]. A year later, Debitus reported its isolation from another sponge Jaspis sp. and, thus, named the compound jaspine B [98]. Other related compounds were also isolated, including jaspine A (111) (Figure 27). Pachastrissamine is a sphingolipid-in particular, a derivative from anhydrophytosphingosine. Its biological activity and synthetic endeavors until 2016 were summarized by Martinková in a mini-review [99].

Pachastrissamine (Jaspine B)
Pachastrissamine (110) was first isolated by Higa and coworkers from a marine sponge of the genus Pachastrissa [97]. A year later, Debitus reported its isolation from another sponge Jaspis sp. and, thus, named the compound jaspine B [98]. Other related compounds were also isolated, including jaspine A (111) (Figure 27). Pachastrissamine is a sphingolipid-in particular, a derivative from anhydrophytosphingosine. Its biological activity and synthetic endeavors until 2016 were summarized by Martinková in a minireview [99].

Sinularones
Sinularones A-I were isolated in 2012 from the marine soft coral Sinularia sp. [102]. Their structures were elucidated by IR, MS, CD, 1D, and 2D NMR. Among them, sinularones E (117) and F (118) contain a tetrahydrofuran moiety ( Figure 30). Their first total synthesis, based on a hydrogenative metathesis of enynes, was reported in 2020 by Fürstner and coworkers [103]. The required 2,5-cis-tetrahydrofuran derivative 119 was readily obtained by hydrogenation (over Rh/Al2O3) of commercial furane 120. Three further steps were needed to obtain silyl ether 121, which in the presence of ruthenium catalyst 122 and H2 undergoes a hydrogenative metathesis. Later deprotection with TBAF produces 117 with 65% yield over both steps. Sinularone F (118) synthesis utilizes the same strategy (Scheme 13).

Sinularones
Sinularones A-I were isolated in 2012 from the marine soft coral Sinularia sp. [102]. Their structures were elucidated by IR, MS, CD, 1D, and 2D NMR. Among them, sinularones E (117) and F (118) contain a tetrahydrofuran moiety ( Figure 30). Their first total synthesis, based on a hydrogenative metathesis of enynes, was reported in 2020 by Fürstner and coworkers [103]. The required 2,5-cis-tetrahydrofuran derivative 119 was readily obtained by hydrogenation (over Rh/Al2O3) of commercial furane 120. Three further steps were needed to obtain silyl ether 121, which in the presence of ruthenium catalyst 122 and H2 undergoes a hydrogenative metathesis. Later deprotection with TBAF produces 117 with 65% yield over both steps. Sinularone F (118) synthesis utilizes the same strategy (Scheme 13).

Sinularones
Sinularones A-I were isolated in 2012 from the marine soft coral Sinularia sp. [102]. Their structures were elucidated by IR, MS, CD, 1D, and 2D NMR. Among them, sinularones E (117) and F (118) contain a tetrahydrofuran moiety ( Figure 30). Their first total synthesis, based on a hydrogenative metathesis of enynes, was reported in 2020 by Fürstner and coworkers [103]. The required 2,5-cis-tetrahydrofuran derivative 119 was readily obtained by hydrogenation (over Rh/Al2O3) of commercial furane 120. Three further steps were needed to obtain silyl ether 121, which in the presence of ruthenium catalyst 122 and H2 undergoes a hydrogenative metathesis. Later deprotection with TBAF produces 117 with 65% yield over both steps. Sinularone F (118) synthesis utilizes the same strategy (Scheme 13). Their first total synthesis, based on a hydrogenative metathesis of enynes, was reported in 2020 by Fürstner and coworkers [103]. The required 2,5-cis-tetrahydrofuran derivative 119 was readily obtained by hydrogenation (over Rh/Al 2 O 3 ) of commercial furane 120. Three further steps were needed to obtain silyl ether 121, which in the presence of ruthenium catalyst 122 and H 2 undergoes a hydrogenative metathesis. Later deprotection with TBAF produces 117 with 65% yield over both steps. Sinularone F (118) synthesis utilizes the same strategy (Scheme 13).  [104]. Its structure and relative stereochemistry were determined by NMR studies. It displays low cytotoxic activity against leukemia, ovarian, and colon cells, but its response to renal, CNS, and breast cancer cell lines was very promising (of the range of GI50 = 1.63-2.44·10 −7 M). In 2006, Jennings and coworkers achieved the first total synthesis of its enantiomer (-)-123 and, thus, determined its absolute stereochemistry [105]. Its activity towards the mentioned cancer cell lines attracted the attention of synthetic chemists; different synthetic approaches for (+)-123 appeared in the next few years [106]. Taylor employed a known tetrahydrofuran-2,3,4-triol derivative as the starting material for the synthesis (in three further steps) of the desired (−)-123 and its 3′-epi-derivative [107]. Srihari also achieved the synthesis of (−)-123, (+)-123, and its 6′-epi-derivative starting from commercial D-(−)-ribose [108,109]. Krause performed a modular synthesis of (+)-123 in 10 steps, with an overall yield of 6,4% [110]. The key tetrahydrofuran with the appropriate four stereocenters 124 was prepared in four linear steps from a known enyne. Thus, Sharpless epoxidation and benzylation of (E)-hex-2-en-4-yn-1-ol provided propargyl epoxide 125 in 47% yield over two steps. A copper hydride-catalyzed reduction of 125, followed by a gold-catalyzed cycloisomerization, furnished the key dihydrofuranyl intermediate 126, with two of the required stereogenic centers. Final Sharpless dihydroxylation of 126 afforded 124 as a satisfactory 78:22 mixture of diastereoisomers. The desired natural product was obtained in a further four steps (Scheme 14).  [104]. Its structure and relative stereochemistry were determined by NMR studies. It displays low cytotoxic activity against leukemia, ovarian, and colon cells, but its response to renal, CNS, and breast cancer cell lines was very promising (of the range of GI 50 = 1.63-2.44·10 −7 M). In 2006, Jennings and coworkers achieved the first total synthesis of its enantiomer (-)-123 and, thus, determined its absolute stereochemistry [105].  [104]. Its structure and relative stereochemistry were determined by NMR studies. It displays low cytotoxic activity against leukemia, ovarian, and colon cells, but its response to renal, CNS, and breast cancer cell lines was very promising (of the range of GI50 = 1.63-2.44·10 −7 M). In 2006, Jennings and coworkers achieved the first total synthesis of its enantiomer (-)-123 and, thus, determined its absolute stereochemistry [105]. Its activity towards the mentioned cancer cell lines attracted the attention of synthetic chemists; different synthetic approaches for (+)-123 appeared in the next few years [106]. Taylor employed a known tetrahydrofuran-2,3,4-triol derivative as the starting material for the synthesis (in three further steps) of the desired (−)-123 and its 3′-epi-derivative [107]. Srihari also achieved the synthesis of (−)-123, (+)-123, and its 6′-epi-derivative starting from commercial D-(−)-ribose [108,109]. Krause performed a modular synthesis of (+)-123 in 10 steps, with an overall yield of 6,4% [110]. The key tetrahydrofuran with the appropriate four stereocenters 124 was prepared in four linear steps from a known enyne. Thus, Sharpless epoxidation and benzylation of (E)-hex-2-en-4-yn-1-ol provided propargyl epoxide 125 in 47% yield over two steps. A copper hydride-catalyzed reduction of 125, followed by a gold-catalyzed cycloisomerization, furnished the key dihydrofuranyl intermediate 126, with two of the required stereogenic centers. Final Sharpless dihydroxylation of 126 afforded 124 as a satisfactory 78:22 mixture of diastereoisomers. The desired natural product was obtained in a further four steps (Scheme 14). Its activity towards the mentioned cancer cell lines attracted the attention of synthetic chemists; different synthetic approaches for (+)-123 appeared in the next few years [106]. Taylor employed a known tetrahydrofuran-2,3,4-triol derivative as the starting material for the synthesis (in three further steps) of the desired (−)-123 and its 3 -epi-derivative [107]. Srihari also achieved the synthesis of (−)-123, (+)-123, and its 6 -epi-derivative starting from commercial D-(−)-ribose [108,109]. Krause performed a modular synthesis of (+)-123 in 10 steps, with an overall yield of 6,4% [110]. The key tetrahydrofuran with the appropriate four stereocenters 124 was prepared in four linear steps from a known enyne. Thus, Sharpless epoxidation and benzylation of (E)-hex-2-en-4-yn-1-ol provided propargyl epoxide 125 in 47% yield over two steps. A copper hydride-catalyzed reduction of 125, followed by a gold-catalyzed cycloisomerization, furnished the key dihydrofuranyl intermediate 126, with two of the required stereogenic centers. Final Sharpless dihydroxylation of 126 afforded 124 as a satisfactory 78:22 mixture of diastereoisomers. The desired natural product was obtained in a further four steps (Scheme 14). A recent example of the total synthesis of (+)-123 was reported by Cordero-Vargas [111]. In this approach, the tetrahydrofuranyl key intermediate 127, bearing the four precise sterocenters, was obtained from commercial L-ribono-1,4-lactone in six steps. The key step in this process is the stereocontrolled nucleophilic addition to five-membered oxocarbenium ions directed by the protecting groups. Thus, TBS-protected lactone 128, obtained in four conventional steps from L-ribono-1,4-lactone, undergoes acetylide addition; a subsequent Lewis acid promoted oxocarbenium ion formation. The following stereoselective hydride attack provides tetrahydrofuran 127 as a single diastereomer in 60% yield. The final synthesis of (+)-123 is achieved in a further four steps with 31% yield over them (Scheme 15).
Later on, Qin developed a direct cross-coupling between terminal alkynes and glycosyl acetates, which was applied to the formal synthesis of (+)-123 and analogues [112]. More recently, Wang and coworkers reported another formal synthesis of (+)-123 [113]. They developed a chromium-catalyzed enantioconvergent allenylation of aldehydes to synthesize α-allenols from racemic propargyl halides. Starting from silylated propargyl bromide 129 and benzyloxyacetaldehyde, allenol 130 can be accessed through the developed procedure. The chromium catalyst was formed in situ by the addition of chromium chloride and the oxazoline ligand (R,S)-131. Manganese acted as a reducing agent, and Scheme 14. Modular synthesis of (+)-varitriol ((+)-123) by Krause.
A recent example of the total synthesis of (+)-123 was reported by Cordero-Vargas [111]. In this approach, the tetrahydrofuranyl key intermediate 127, bearing the four precise sterocenters, was obtained from commercial L-ribono-1,4-lactone in six steps. The key step in this process is the stereocontrolled nucleophilic addition to five-membered oxocarbenium ions directed by the protecting groups. Thus, TBS-protected lactone 128, obtained in four conventional steps from L-ribono-1,4-lactone, undergoes acetylide addition; a subsequent Lewis acid promoted oxocarbenium ion formation. The following stereoselective hydride attack provides tetrahydrofuran 127 as a single diastereomer in 60% yield. The final synthesis of (+)-123 is achieved in a further four steps with 31% yield over them (Scheme 15). A recent example of the total synthesis of (+)-123 was reported by Cordero-Vargas [111]. In this approach, the tetrahydrofuranyl key intermediate 127, bearing the four precise sterocenters, was obtained from commercial L-ribono-1,4-lactone in six steps. The key step in this process is the stereocontrolled nucleophilic addition to five-membered oxocarbenium ions directed by the protecting groups. Thus, TBS-protected lactone 128, obtained in four conventional steps from L-ribono-1,4-lactone, undergoes acetylide addition; a subsequent Lewis acid promoted oxocarbenium ion formation. The following stereoselective hydride attack provides tetrahydrofuran 127 as a single diastereomer in 60% yield. The final synthesis of (+)-123 is achieved in a further four steps with 31% yield over them (Scheme 15).
Later on, Qin developed a direct cross-coupling between terminal alkynes and glycosyl acetates, which was applied to the formal synthesis of (+)-123 and analogues [112]. More recently, Wang and coworkers reported another formal synthesis of (+)-123 [113]. They developed a chromium-catalyzed enantioconvergent allenylation of aldehydes to synthesize α-allenols from racemic propargyl halides. Starting from silylated propargyl bromide 129 and benzyloxyacetaldehyde, allenol 130 can be accessed through the developed procedure. The chromium catalyst was formed in situ by the addition of chromium chloride and the oxazoline ligand (R,S)-131. Manganese acted as a reducing agent, and Cp2ZrCl2 as a dissociation reagent. Then, removal of the silyl group with Scheme 15. Protecting group-directed nucleophilic addition for the synthesis of (+)-varitriol (123).
Later on, Qin developed a direct cross-coupling between terminal alkynes and glycosyl acetates, which was applied to the formal synthesis of (+)-123 and analogues [112]. More recently, Wang and coworkers reported another formal synthesis of (+)-123 [113]. They developed a chromium-catalyzed enantioconvergent allenylation of aldehydes to synthesize α-allenols from racemic propargyl halides. Starting from silylated propargyl bromide 129 and benzyloxyacetaldehyde, allenol 130 can be accessed through the developed procedure. The chromium catalyst was formed in situ by the addition of chromium chloride and the oxazoline ligand (R,S)-131. Manganese acted as a reducing agent, and Cp 2 ZrCl 2 as a dissociation reagent. Then, removal of the silyl group with tetrabutylammonium fluoride gave advanced intermediate 132 in 82% yield, thus accomplishing the formal synthesis of the desired (+)-123 (Scheme 16).

Conclusions
Terpenes and related compounds represent an important family of marine-derived metabolites. The great number of studies focused on their biological activities and total synthesis remark their importance. We have summarized the most active compounds for a variety of bioactivities (see Table 2). Trans-oxylipid has shown nematocidal properties against Haemonchus contortus (LD50 = 1.8 ppm) and Trichostrongyllus colubriformis (LD50 = 9.9 ppm). These values, comparable to the commercial levamisole and closantel, make this compound an interesting scaffold for the development of antihelmintic substances. Though not related to drug development, we want to remark the biological interest of (+)-PMA. Its potent olfactory response in sea lampreys makes it very valuable for the control and conservation of lamprey populations. Efforts should be made in developing a total synthesis for this compound, as none has been reported to date. Mutafuran D has antifungal activity, showing a moderate value of MIC = 4 mg/mL against Cryptococcus neoformans var. grubii. Although not an impressive value, further studies could shed light on the structure-activity relationship of this brominated ene-yne tetrahydrofuran derivative. Furoplocamioid C could serve as a lead for novel biopesticides, as it has shown a potent antifeedant effect against Leptinotarsa decemlineata, with an EC50 of 19.1 nmol/cm 2 , Myzus Persicae (EC50 of 3.7 nmol/cm 2 ), and Ropalosiphum Padi (EC50 of 1.6 nmol/cm 2 ) but it has low mammalian toxicity and phytotoxic effects. With respect to antibacterial activity, heranopyrrole D has shown very good values against Staphylococcus aureus ATCC 25923 (IC50 = 1.8 mM), Staphylococcus epidermidis ATCC 12228 (IC50 = 0.9 mM), and Bacillus subtilis ATCC 6633 (IC50 = 1.8 mM); thus, the nitropyrrole moiety should be further studied to determine whether it plays an important role in its antibacterial behavior. On the other hand, though (+)-darwinolide shows a more moderate value against Staphylococcus aureus (IC50 = 33.2 μM), its selectivity towards the biofilm phase and its low toxicity makes it a very good lead for the development of antibiofilm-specific antibiotics.

Conclusions
Terpenes and related compounds represent an important family of marine-derived metabolites. The great number of studies focused on their biological activities and total synthesis remark their importance. We have summarized the most active compounds for a variety of bioactivities (see Table 2). Trans-oxylipid has shown nematocidal properties against Haemonchus contortus (LD 50 = 1.8 ppm) and Trichostrongyllus colubriformis (LD 50 = 9.9 ppm). These values, comparable to the commercial levamisole and closantel, make this compound an interesting scaffold for the development of antihelmintic substances. Though not related to drug development, we want to remark the biological interest of (+)-PMA. Its potent olfactory response in sea lampreys makes it very valuable for the control and conservation of lamprey populations. Efforts should be made in developing a total synthesis for this compound, as none has been reported to date. Mutafuran D has antifungal activity, showing a moderate value of MIC = 4 mg/mL against Cryptococcus neoformans var. grubii. Although not an impressive value, further studies could shed light on the structure-activity relationship of this brominated ene-yne tetrahydrofuran derivative. Furoplocamioid C could serve as a lead for novel biopesticides, as it has shown a potent antifeedant effect against Leptinotarsa decemlineata, with an EC 50 of 19.1 nmol/cm 2 , Myzus Persicae (EC 50 of 3.7 nmol/cm 2 ), and Ropalosiphum Padi (EC 50 of 1.6 nmol/cm 2 ) but it has low mammalian toxicity and phytotoxic effects. With respect to antibacterial activity, heranopyrrole D has shown very good values against Staphylococcus aureus ATCC 25923 (IC 50 = 1.8 mM), Staphylococcus epidermidis ATCC 12228 (IC 50 = 0.9 mM), and Bacillus subtilis ATCC 6633 (IC 50 = 1.8 mM); thus, the nitropyrrole moiety should be further studied to determine whether it plays an important role in its antibacterial behavior. On the other hand, though (+)-darwinolide shows a more moderate value against Staphylococcus aureus (IC 50 = 33.2 µM), its selectivity towards the biofilm phase and its low toxicity makes it a very good lead for the development of antibiofilm-specific antibiotics.
Regarding antitumoral applications, there are several compounds that have shown very promising activities. Uprolide D acetate has cytotoxic activity against different tumor cell lines: HeLa cells (IC 50  Although some efforts have already been made and different total syntheses reported, we believe that further studies should point to the synthesis of analogs and the study of structure-activity relationships in this simple scaffold. Regarding antiprotozoal activity, saiyacenol B shows a good IC 50 of 10.3 mM against Leishmania amazonensis. Interestingly it was surpassed by its synthetic counterpart, 28-iodosaiyacenol B, with a value of IC 50 = 5.4 mM pointing to an interesting effect of this 28-iodosubstitution. Alisiaquinone C presents antimalarial activity in vitro against the chloroquineresistant strains MC29 CQR (IC 50 = 0.08 mM) and B1 CQR (IC 50 = 0.21 mM), and the chloroquine-sensitive strain F32 CQS (IC 50 = 0.15 mM). Though it presents a high toxicity, similar structures that preserve antimalarial activity and have reduced toxicity values could be developed. A possible lead for anti-inflammatory development is myrothecol: it shows antioxidant activity with an EC 50 = 1.2 mg/mL (S isomer) and EC 50 = 1.4 mg/mL (R isomer), inhibits nitric oxide formation, and displays anti-inflammatory activity. It is also a small molecule and, thus, its synthesis will require lower effort.
In conclusion, the tetrahydrofuran moiety is a common motif found in a variety of such compounds, which has meant a particular emphasis of researchers on the development of new methodologies for the synthesis of such derivatives. In this context, total synthesis is a powerful tool to have access to these natural products. Firstly, it is an invaluable means for the determination of the structure and total configuration of natural compounds since, in some cases, the available NMR methods are insufficient in definitively determining the structures of biologically relevant substances. Secondly, since extracting and purifying compounds from natural sources are difficult and time-consuming processes, total synthesis has emerged as a suitable solution for the production of larger amounts of compounds, thus bringing possibilities for further biological studies, the discovery of novel drug candidates, and the expansion of the medicinal chemistry frontiers.