Synthetic strategies to terpene quinones/hydroquinones.

The cytotoxic and antiproliferative properties of many natural sesquiterpene-quinones and -hydroquinones from sponges offer promising opportunities for the development of new drugs. A review dealing with different strategies for obtaining bioactive terpenyl quinones/hydroquinones is presented. The different synthetic approches for the preparation of the most relevant quinones/hydroquinones are described.

1. Introduction

The chemical substances from plants and animals have been and remain to be an important source of drugs and products used in food products, cosmetics and agriculture, amongst other fields. Natural compounds offer an enormous structural diversity and in some cases, a big biological power and thus it is unlikely that the chemistry of synthesis can replace cellular biochemistry as the source of new compound. These observations, in addition to the enormous biodiversity of the planet (plants, sea and microorganisms), which is in a lot of cases inexplored, point to natural compounds as a promising source of drugs [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45].

Natural products have been a rich source of agents of value to medicine. More than half of the currently available drugs are natural compounds or are related to them, and in the case of cancer this proportion surpasses 60% [4,8]. This situation is accompanied by increasing interest from drug companies and institutions devoted to the search for new drugs [46,47]. Additionally, many new natural compounds of diverse structures have been considered prototypes, leads or heads of series and their later structural modification has afforded compounds with pharmacological activity and extraordinary therapeutic possibilities [11,22,25,26,48].

The research in natural compounds, which is continually expanding and is of enormous interest, explores new compounds coming from different sources, among which the sea could be considered as an almost infinite source of natural resources, some of which have important therapeutic potential [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126]. The discovery of drugs from marine natural products has enjoyed a renaissance in the past few years. Ziconotide (Prialt®; Elan Pharmaceuticals), a peptide originally discovered in a tropicalcone snail, was the first marine-derived compound to be approved in the United States in December 2004 for the treatment of pain [127]. Combination of ziconotide and morphine allows safe and rapid control of oral opioid-refractary malignant pain [128]. In October 2007, trabectedin (Yondelis®; PharmaMar) became the first marine anticancer drug to be approved in the European Union. Trabectedine is an intravenous antineoplastic agent originally derived from tne Caribbean marine tunicate Ecteinascidia turbinata and now produced synthetically [129]. Trabectedine shows variable levels of activity against several types of solid tumor including soft tissue sarcoma, ovarian cancer, breast, melanoma, non small lung cancer, prostate and endometrial cancer [130,131,132]. The drug is especially active in leiomyosarcoma and liposarcoma and is a therapeutic option in the palliative approach to the metastatic uterine leiomyosarcoma patient [133]. Eribulin mesylate (E7389), designed by the Japanese laboratory Eisai (Eisai Research Institute, Andover, MA, USA), shows antitumor properties for the treatment of breast cancer [134]. This is a synthetic analogue of the natural product halichondrin B, isolated from Halichondria okadai (Lissodendoryx sp.), a marine sponge commonly found in Japanese seas; its antitumor activity was discovered in 1986. Eribulin binds to the vinca domain of tubulin and inhibits the polymerization of tubulin and theassembly of microtubules, resulting in the inhibition of mitotic spindle assembly, the induction of cell cycle arrest at G2/M, and, potentially, tumor regression. Eribulin mesylate is now in phase II clinical trials and is active in metastatic or locally advanced breast cancer [135,136,137,138].

Excellent reviews on natural compounds of marine origin have been published [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126] that explore the taxonomy, structural elucidation, role of databases, biosynthetic studies, biomedical potential, synthesis and the technologies necessary for advancing bioactive marine natural product lead compounds into actual pharmaceuticals. Amongst these, the recently published review by Fattorusso et al. [124] particularly stands out.

Among the natural compounds that are receiving an increasing interest we can find the terpenylpurines and the terpenilquinones from marine sources [139,140]. Particularly, the terpenylquinones constitute an interesting group of marine natural product [141,142,143] for which a wide variety of biological activities have been described, including anti-inflamatory, antifungal, anti-HIV and most often antitumor activities [144,145].

The cytotoxic and antiproliferative properties of many natural sesquiterpene quinones and hydroquinones from sponges of the order Dictyoceratida [71,76,140,144] such as avarol 1, avarone 2, illimaquinone 3, nakijiquinone 4 and bolinaquinone 5 (Figure 1), amog others, offer promising opportunities for the development of new antitumor agents [144,145]. This has sparked interest in the chemical composition and cytotoxicity of a large number of marine species that contain metabolites with hybrid structures between terpenes and quinones/hydroquinones [76,140,141,146,147,148,149,150].

Figure 1

Some examples of bioactive terpenequinones/hydroquinones.

Avarol 1 and avarone 2 are the most representative compounds of bioactive terpenequinones. In addition to the above-mentioned pharmacological properties, two monophenyl thioavarol derivatives have recently been described as lacking cytotoxicity, which could point to promising UVB photoprotective agents through the potent inhibition of NF-kappaB activation [151] with a mild antioxidant pharmacological profile. Various formulations with high avarol 1 content have been used for the prevention and treatment of psoriasis, dermatitis, skin cancer, tumors in the gastrointestinal tract, urinary tract and viral infection [152].

It is also important to note the antituberculosis and antimalarial activities of puupehenone 6 [93,153,154], the cardiotonic activity of xestoquinone 7 [155], the antifungal activity of several nakijiquinones 4 [156] and the antiinfective activity of aureol derivatives 9 [157].

Sesquiterpenequinones represent a substance class with increasing pharmacological interest [140]. New developments and new discoveries in the field of terpenequinones continually occur. Recently, neopetrosiquinones A 10 and B 11 (Figure 2), sesquiterpene benzoquinones have been isolated from the deep-water sponge Neopetrosia cf. proxima, of the Petrosiidae family [158]. Neopetrosiquinones A 10 and B 11 inhibit the in vitro proliferation of the DLD-1 human colorectal adenocarcinoma cell line with IC50 values of 3.7 and 9.8 μM, respectively, and the PANC-1 human pancreatic carcinoma cell line with IC50 values of 6.1 and 13.8 μM, respectively. Neopetrosiquinone A also inhibited the in vitro proliferation of the AsPC-1 human pancreatic carcinoma cell line with an IC50 value of 6.1 μM. The compounds are structurally related to known terpene quinine xestoquinone 7. This research is part of the program to identify novel marine natural products with therapeutic properties from a library of extracts of the Harbor Branch Oceanographic Institute (HBOI) [158].

Figure 2

Neopetrosiquinones A 10 and B 11.

Regarding the mechanism of action of terpenylquinones, the accumulated data about the biological activity of quinone moieties suggest redox processes and/or Michael-type addition-elimination reactions [144]. Their cytotoxicity has been explained in terms of their ability to undergo redox cycling and the generation of reactive oxygen species, which would damage tumor cells [159,160,161]. NADH/NAD+ dehydrogenase reduction of the several terpenylnaphthoquinones increases the rate of oxygen consumption, such rates being higher for quinones with more positive redox potentials. In this process, reactive oxygen species are formed in small amounts, which also correlate with the quinine redox potential. Semiquinone derivatives of these quinones are generated under anaerobic conditions and in the presence of NADH/NAD+ dehydrogenase. Since this enzymatic system is found in mitochondria, a possible pathway in the cytotoxic activity of these terpenylnaphthoquinones could be by interference with or the inhibition of mitochondrial respiration, as reported for other naphthoquinone derivatives, in addition to free radical degradation [162,163]. The results obtained with avarol 1 and avarone 2 supported the mechanism of antitumor action via the reactive oxygen radicals [164,165] but there were also indications of the relevance of arylation of biomolecules, such as proteins [144,166,167].

Regarding such terpenequinone structures, many studies have been published addressing the isolation, structural elucidation, activity and mechanisms of action of the compounds [140,143,144,146,147,160]. We present in this review a compilation of the different synthetic approches for the preparation of the most relevant compounds.

2. Synthetic Approches Terpenylquinone/Hydroquinone

The synthesis of marine natural products has been widely researched and published in excellent reviews [3,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183], and is of particular interest in the case of compounds that have some kind of biological or therapeutic activity. The two major obstacles to advancing a natural product lead into drug development are compound supply and adequate structural elucidation. One must not underestimate how much material may be needed. Even the most straightforward courses of pre-clinical studies require hundreds of grams of highly consistent well-characterized product, which represents a major hurdle for natural products derived from non-renewable sources [3]. Therefore, it is of interest to consider the relative role of chemical synthesis in the structure elucidation. Moreover, in the case of revision of relative and absolute configuration, total synthesis is a proven partner for natural product structure elucidation for marine, as well as terrestrial species [169]. Structural misassignments continue to be made even for recently reported marine natural products, and thus, it seems that the increasingly high-field magnets and sensitive probes do not necessarily attenuate the rate of structural misassignments. Rather, they permit the attempted structure elucidation of increasingly limited quantities of minor components from natural products extracts, as well as larger molecules of greater structural complexity. Therefore, total synthesis of natural products will surely continue to be central to the confirmation of the structure of natural products, as well as providing material for biological testing towards pharmaceutical development, and investigations of biosynthetic pathways [169]. Advances in total synthesis, especially function-oriented syntheses, biosynthetic technologies and genomic research offer new strategies for the medicinal chemical optimization of biologically active secondary metabolites as sources of novel drug leads [3].

In the case of biologically active terpenoquinones, the limited quantities components from the natural sources and the structural complexity are the main problems in continuining the clinical studies. Most of these terpenoquinones are characterised by possessing a quinone fragment attached to a terpenoid, which usually includes a decaline core, mostly with a drimane or rearranged drimane skeleton. Most sesquiterpenequinone/hydroquinones have been isolated from sponges, although some of them have been described from brown algae [74] and fungi [184]. The initial extract of the natural material usually consists of a complex mixture after fractionation. It may contain small quantities of bioactive substances, often as a mixture with structurally related molecules. The initial concentration of an interesting compound may be too low to be effectively tested in some biological and pharmacological assays. Thus, compounds have become attractive to carry out its total synthesis and obtaining of derivatives to improve the biological properties of natural compounds. Consequently, the development of these marine natural products is highly desirable and worthwhile from the viewpoint of medicinal chemistry and pharmaceuticals.

In the present paper, the most interesting strategies addressed in the total synthesis of sesquiterpenilquinones by terpenic structure coupling to an aromatic ring have been reviewed. In general, the strategies employed in the total synthesis of sesquiterpenilquinones, are as follows:

➢ Diels-Alder cycloaddition reaction.

➢ Coupling of the aldehydes with lithiated hydroquinone ether.

➢ Radical decarboxylation and quinone addition reaction

➢ Grignard reagent conjugated addition to α,β-unsaturated carbonyl group.

➢ Reductive alkylation of enones.

➢ Cross-coupling reaction.

➢ Furan polyene cationic cyclization.

In addition, the application of cell culture for the production of bioactive compounds from sponges is a promising way to utilize the bioactive potential of marine terpenoquinones sources.

3. Diels-Alder Cycloaddition Reaction

The Diels-Alder cycloaddition reaction continues to fuel the imaginations of synthetic chemists engaged in the assembly of complex molecular structures, in particular biologically significant natural products and provide rich opportunities for the rapid and selective generation of molecular complexity [185].

Mamanuthaquinone 12 is a cytotoxic metabolite collected in the Fiji islands from Fasciospongia sp. [186]. In the first total synthesis of (±)-mamanuthaquinone 12 (Scheme 1) [187] an exothermic Diels-Alder reaction have been used as main reaction, giving the decalin system that already contains the aromatic moiety. The Diels-Alder reaction proceeded via an exo transition state, favored by the steric hindrance between the aromatic ring of 13 and a methyl of the cyclohexene 14. This exo approach mode reached the desired stereochemistry for mamanuthaquinone 12. With the configuration of the three stereocenters established, the cycloadduct 15 was treated with LiAlH4 yielding the reduction of the ketone and the demethylation of one methoxyl in the ortho position: diastereomers 16a,b. The acetylated derivative 17a,b which Li/NH3 gave deoxygenation at C-15 and was acetylated in alcohol C-21 leading to 19. Finally, oxidation with CAN, followed by saponification of the acetate at C-21 yielded (±)-mamanutaquinone 12.

Scheme 1

Synthesis of (±)-mamanuthaquinone 12.

Starting from natural terpenes, various approaches to terpenoquinones analogues have been reported. The terpene contributes the decalin part that attaches via Diels-Alder cycloaddition to commercial quinones. Thus, some diterpenylquinones/hydroquinones have been prepared through a Diels-Alder cycloaddition between myrceocommunic acid 20 and p-benzoquinone 21 or naphthoquinone 22 [149,159,188] (Scheme 2). The natural labdane acid used as starting material was isolated from berries of Juniperus oxycedrus. In order to optimise the synthesis of cycloadduct, two Diels-Alder procedures were considered, one in ethereal solution using BF3·Et2O as a catalyst and the other under Mw irradiation in the absence of solvent. Although the Mw irradiation has the advantage of shortening reaction time, this procedure needs an excess of quinone that impeeds the purification of the final product. Several derivatives of cycloadducts 23 and 29 were evaluated in vitro for determinig their cytotoxicity against the human cell lines HT-29 (colon carcinoma), A-549 (lung carcinoma) and MEL-28 (malignant melanoma). Some of them were cytotoxic with IC50 values under the μM level.

Scheme 2

Diels-Alder cycloaddition between myrceocummunic acid and p-benzoquinone/naphthoquinone.

Puupehenones belong to an important class of marine terpenequinone metabolites from Hyrtios sp. and other marine sponges [189,190,191,192], which are constructed from drimane and polyphenolic moieties. Puupehenones exhibit a wide variety of biological activity including angiogenesis inhibition [193]. The Diels Alder cycloaddition approach has been used to synthesize puupehenone related metabolites [194,195]. Utilizing this, the potent angiogenesis inhibitor 8-epipuupehedione 33 was synthesized from sclareol oxide 30, via ent-chromazonarol 32 (Scheme 3); in this case, the methodologie used prevents the obtention of the 8-epimer which is formed when the electrophilic cyclization methodology is utilized [196,197]. Microwave-assisted Diels-Alder reaction of 1,3,3-trimethyl-2-vinyl-1-cyclohexene 34 with chromones 35 (Scheme 4) is an expeditious approach to analogues of the puupehenone group 36 of marine diterpenoids [198].

Scheme 3

Diels-Alder cyclooaddition approach to puupehenone-related metabolites.

Scheme 4

Microwave-assisted Diels-Alder reaction of 1,3,3-trimethyl-2-vinyl-1-cyclohexene with chromones.

The marine (−)-cyclozonarone 37 has been isolated from the Pacific brown algae Dictyopteris undulata and possesses a potent feeding-deterrent activity towards young abalones [199]. The total synthesis was achieved starting from albicanol 38 (Scheme 5) [200]. Elimination of water led to drima-(8,12)(9,11)-diene 39, which reacted in the key step of the synthesis, a Diels-Alder reaction, with benzoquinone. Further oxidation led to 37.

Scheme 5

Synthesis of (−)-cyclozonarone 37.

The Diels-Alder cycloaddition between two polygodial-derived dienes 41 and 43 and simple quinones 42 and 22 yield substituted naphthaquinones 40 and anthraquinones 44, some of them with in vitro trypanocide activity (Scheme 6) [201].

Scheme 6

Diels-Alder reaction between polygodial-derived dienes and simple quinones.

Halenaquinone 8, a pentacyclic polyketide isolated from Xestospongia sp. [202], has been synthesized both through a strategy based on an intramolecular inverse-electron-demand Diels-Alder reaction and an intramolecular Heck cyclization [203,204].

4. Coupling of the Aldehydes with Lithiated Hydroquinone Ethers

This strategy is an efficient and general way of accessing drimane-type sequiterpenequinones. The strategy consists on the coupling of an aldehyde as terpene precursor and a lithium anion which carries the quinone structure. The five marine natural products yahazunol 45, zonarone 46, zonarol 47, isozonarone 48 and isozonarol 49 have been synthesised starting from (+)-albicanic acid (+)-51 [205,206]. Yahazunol 45, zonarone 46 and zonarol 47 have been obtained from the East Pacific brown algae Dictyopteris undulata Okamura. Isozonarone 48 and isozonarol 49 have been isolated from the same species collected in the Gulf of California [207]. These compound present fungitoxic, anti-inflammatory activities and locks the MCF-7 cells initially in the mitose phase (G2/M-phase) and induce apoptosis, also blocks the synthesis phase with replication of DNA (S-phase) [72,142,207,208].

The synthesis of the marine natural products zonarone 46 and isozonarone 48 was achieved via (+)-albicanic acid 51, a sesquiterpene of the drimane type (Scheme 7). Coupling of the appropiate drimane-synthon with lithiated hydroquinone ethers led to sesquiterpene arenes, which were further modified to the target molecules. Stereoselective epoxidation followed by regioselective opening of the oxirane ring yielded yahazunol [205,206]. The key step of the synthesis (Scheme 8) was the coupling of the sesquiterpene part with the lithiated arene unit. The starting quiral aldehydes (+)-albicanal ((+)-52) and (−)-drim-7-en-11-al (−)-50 were obtained from (+)-albicanic acid (+)-51. This chiral synthon was prepared starting from β-ionone via a known route [209]. The di-THP-ether of hydroquine was lithiated with sec-butyllithium and added (+)-albicanal 52, respectively (−)-drim-7-en-11-al 50, to formed lithium organyl. The reaction afforded the benzyl alcohol 54a,b and 56a,b, as coupling products as mixture of diastereoisomers. Removal of the hydroxyl group led to the deoxygenated species zonarol-di-THP-ether 55 and isozonarol-di-THP-ether 57, respectively. Desprotection in presence of oxalic acid [205] gave zonarol 47 and isozonarol 49. Optimized oxidation of zonarol and isozonarol with cerium (IV) ammonium nitrate (CAN) yielded the sesquiterpenequinone zonarone 46 and isozonarone 48.

Scheme 7

Retrosynthesis of yahazunol 45 and isozonarone 48.

Scheme 8

Total synthesis of zonarol 47, isozonarol 49, zonarone 46 and isozonarone 48.

The synthesis of the marine sesquiterpene quinones (+)-hyatellaquinone 58 and spongiaquinone 60 was respectively achieved starting from the sesquiterpene aldehydes (+)-albicanal 52 and (−)-albicanal 61 (Scheme 9) [210,211]. The sesquiterpene quinone hyatellaquinone has been isolated from the alga Peyssonnelia sp. and the marine sponges Hyatella intestinalis [212] and Spongia sp. [211]. Spongiaquinone 60 has been obtained from the sponges Spongia sp. [211] and Stelospongia conulata [213]. These terpenequinone were attractive candidates for pharmacological testing as antitumor, HIV-1 reverse transcriptase inhibitor and immunomodulatory activities [72,142,208].

Scheme 9

Retrosynthesis of hyatellaquinone 58 and spongiaquinone 60.

The synthesis of (+)-hyatellaquinone 58 was achieved starting from the sesquiterpene aldehyde (+)-albicanal 52 (Scheme 10) [210]. Coupling of (+)-albicanal 52 with 2,3,5,6-tetramethoxyphenyllithium 63 led to the aryl-sesquiterpene system 59, which was modified to the target molecule. Furthermore, the first total synthesis of spongiaquinone 60 was carried out starting from (−)-albicanal 61 (Scheme 11) [211] in a reaction sequence encompassing a stereoselective C=C bond hydrogenation and a one-pot AcOH elimination/demethylation reaction.

Scheme 10

Synthesi of (+)-hyatellaquinone 58.

Scheme 11

Synthesis of (−)-spongiaquinone 60.

Siphonodictyal C 69, isolated from sponge Siphonodictyon sp. [214,215], was tested for its pharmacological activities in assays in search of antiproliferative, cytotoxic, antiphlogistic, antirheumatic and anti-inflammatory drugs [70,208]. Synthesis of siphonodictyal C 69 was achieved via drim-7-en-11-al 70 by coupling with 5-lithium sesamol MEM-ether to the benzylic alcohols (±)-71a,b (Scheme 12) [206,208]. Treatment of (±)-71a,b with p-toluene sulfonic acid (PTS) in THF/H2O led to the deprotection of the MEM-group and benzylic dehydration. The formed phenol was rearranged in a six membered cyclic transition state to the alkylidenecyclohexadienone which by reduction with NaBH4 in EtOH yielded the phenol that was deprotonated with n-Bu4NOH and the phenolate was methylated with dimethylsulfate (DMS), deprotonated with n-BuLi in o-position to the methoxy-group and formylated with DMF to (±)-72. The deprotection of (±)-72 with different reagents always led to decomposition.

Scheme 12

Synthesis of protected siphonodictyal C 69 via drim-7-en-11-al 70.

In addition, aureol 9 and their analogues were synthesized by coupling of the aldehydes with lithiated hydroquinone ethers using, in this case, a cis-decaline as starting material [216,217]. Aureol was isolated from the Caribbean sponges Smenospongia aurea [218] and Verongula gigantea [219]. Aureol 9 has been shown to exhibit selective cytotoxicity against A-549 human non-small cell lung cancer cells and antiinfluenza-A virus activity [67,220]. As shown in Scheme 13, the synthesis commenced with the crucial coupling reaction of the cis-fused aldehyde [221,222] previously prepared from the enantiomerically pure (−)-Wieland-Miescher ketone 73 analogue (Figure 3) [223,224] with commercially available 2-bromoanisole.

Scheme 13

Synthesis of (+)-arearone 80, (+)-arenarol 81 and (+)-aureol 9 staning from cis-fused decalin.

Figure 3

Wieland-Miescher Ketone 73.

Thus, the aryllithium generated in situ by treatment of 2-bromoanisole with n-butyllithium in THF was allowed to react with 74 providing an excellent yield of the desired coupling product 75. Simultaneous removal of both the benzylic hydroxyl group and the ethylene acetal moiety in 75 was achieved effectively by initial formation of the corresponding trifluoroacetate 76 followed by reaction under the conditions for hydrogenolysis, wich led to the production of the carbonyl group 77. Subsequent methylenation of the sterically hindered carbony group in 77 was achieved by employing the Takai procedure [225]. Thus, treatment of 77 with a mixture of dibromoethane, zinc powder and titanium (IV) chloride in THF furnished the exo-olefinic compound 78. The methylenation of 77 with Wittig reagent, Peterson’s reagent or Tebbe reagent gave none of desired product 78. Next, deprotection of the methyl ether protecting group of exo-olefin by treatment with lithium n-butylthiolate in hexamethyl-phosphoramide afforded the liberated phenolic compound 79. The pivotal conversion of the phenolic derivative to arenarone 80 was effected by reaction of 79 with molecular oxygen in the presence of salcomine in DMF. Subsequent reduction of the quinone system in arenarone 80 using sodium hydrosulfite gave arenarol 81. By treating of arenarol with BF3·Et2O, the desired acid-promoted rearrangement/cyclation reaction was found to proceed, producing aureole 9 with a good stereoselectively in excellent yield [221,222].

The total synthesis of the (+)-puupehenone 6 was achieved in 10 steps (Scheme 14) by the arenol oxidative activation route [153] starting from commercially available (+)-sclareolide 86. The key feature of this synthesis is the construction of the heterocycle via an intramolecular attack of the terpenoid-derived C-8 oxygen function onto an oxidatively activated 1,2-dihydroxyphenyl unit. The sequiterpene moiety of puupehenone 6 features a normal drimane skeleton annelated to a shikimate-derived hydroxyquinone unit. The drimane precursor (+)-sclarolide 86 already possesses the correct chirality for three of the four (+)-puupehenone 6 stereogenic centers. It can be purchased from commercial sources or convenientelly prepared from labdane 85 [226]. The nucleophilic character of the terpenoid 8-oxygen will serve to mediate the desired heterocyclization by attacking an oxidatively activated 1,2-dihydroxyphenyl unit. The shikimate unit 84 was elaborated from catechol 83 through bromination and benzylation to give bromide. Coupling of this bromide with aldehyde 87 obtained from (+)-sclarolide 86, was achieved via a standard halogen-metal exange protocol. A subsequent hydrogenolysis under standard conditions allowed removal of both benzyl protective groups, and the benzylic C-15 hydroxyl group that was unveiled at the previous coupling reaction, to afford the catechol 88 in good yield. The remarkable deprotection-deoxygenation step set the stage for the key oxidative activation of the catechol unit toward intramolecular attack by the drimane 8-oxygen. This activation relied on the use of [bis(trifluoroacetoxy)iodo]benzene (BTI), that as other iodine reagents, constitute today a convenient alternative to the use of toxic heavy metal-based reagents for activating arenols toward oxidative nucleophilic substitution reaction [227,228].

Scheme 14

Enantiospecific synthesis of (+)-puupehenone 6. The arenol oxidative activation route.

The synthesis of peyssonol A 90 is a special case of fusion between a cis-decalin and the aryl ring [229]. Peissonol A was isolated from the Red Sea marine alga Peyssonnelia sp. that has been shown to act as an allosteric inhibitor of the reverse transcriptases of Human Immunodeficiency Virus [212,230]. This compound is the only known natural product possessing a cis-decalin framework likely arising from a halonium-induced cation-π cyclization. As indicated in Scheme 15, the retrosynthetic analysis suggested that the late-stage disconnection on the pendant aryl ring projecting a nucleophilic addition onto the aldehyde 92 to effect its incorporation, might afford the most efficient means to reach a suitable polyene cyclization precursor.

Scheme 15

Retrosynthetic analysis of peyssonol A 90.

5. Radical Decarboxylation and Quinone Addition Reaction

The application of the Barton’s radical decarboxylation reaction, in which the generated radicals are trapped by a quinone trap, gives rise to addition products in good to excellent yields. This addition reaction is characterized by good chemoselectivity, taking place only at conjugated and unsubstituted double bonds, and regioselectivity, being strongly influenced by the resonance effect of heteroatoms located on the quinone ring. The synthetic value of this reaction was demonstrated by the synthesis of selected members of a family of quinone sesquiterpenes. Both symmetric and unsymmetric quinones can be used as radical traps and provide facile access to heteroatom-substituted quinone sesquiterpenes. The versatility of our strategy was further expanded by developing reaction conditions that allow subsequent oxygenation of the quinone adducts, providing access to complementary oxygenated structures [231].

Essential to this strategy is a radical addition reaction that permits the attachment of a fully substituted bicyclic core 97 to a variably substituted p-quinone 98 (Scheme 16). The addition product 96 can be further functionalized, giving access to natural products with a high degree of oxygenation at the quinone unit. The quinone addition reaction is characterized by excellent chemoselectivity, taking place only at conjugated and unsubstituted double bonds, and regioselectivity, being strongly influenced by the resonance effect of heteroatoms located on the quinone ring. These features were successfully applied to the synthesis of avarol 1, avarone 2, ilimaquinone 3 and smenospongidine 116, thereby demonstrating the synthetic value of this method [231].

Scheme 16

Strategic bond disconnections of quinone sesquiterpenes.

Avarol 1 and its quinone derivative avarone 2 are secondary metabolites isolated from the marine sponge Dysidea avara [232,233]. Both compounds were first discovered as anti-leukaemia agents in vitro and in vivo, and later it was found that they had an in vitro inhibitory capacity against HIV-1. Controlled clinical studies revealed, however, that it was not efficient in the clinical treatment of patients with AIDS. Additionally, the potent T-lymphotropic cytostatic activity shown by avarol 1, and its low toxicity in mice, its ability to cross the blood-brain barrier and its ability to stimulate the synthesis of interferon make both these compounds optimum candidates for transformations aimed at improving their cytostatic and antiviral activity [234,235,236,237,238].

The synthetic approach toward the core fragment of avarol and avarone (Scheme 17) began with enantimerically enriched enone 73 (Figure 3), which was readily available through a L-phenylalanine-mediated asymmetric Robinson annulation [239]. The selective protection of the more basic C4 carbonyl group followed by reductive alkylation of the enone functionality with allyl bromide afforded ketone 99. Conversion of ketone 99 to silyl ether 100 was accomplished via a sequence of three steps including ozonolysis of the terminal double bond, reduction of the resulting aldehyde, and selective silylation of the primary alcohol. The C8 ketone functionality that also suffered reduction during the above procedure was subsequently restored upon treatment with Dess-Martin periodinane [240]. Functionalization of C8 stereocenter was achieved by Wittig olefination, followed by a Pd-catalyzed hydrogenation of the resulting exocyclic methylene unit, furnishing alcohol 102. Acid-catalyzed deprotection of the C4 ketal of 102 gave rise to ketone 103, which a second Witting methylenation provided the exocyclic alkene 104. The exocyclic double bond of 104 was isomerized to produce de most substituted alkene 105, wich after a two-step oxidation involoving Dess-Martin periodinane and sodium chlorite, produced the desired carboxylic acid 106. The stage was now set for the attachment of the aromatic residue on the decalin ring. This was accomplished by DCC-induced esterification of 106 with commercially available 2-mercaptopyridine-N-oxide 108, which furnished the photolabile ester 108. Light-induced decarboxylation of ester 108 in the presence of benzoquinone 21 produced the substituted quinone 110. At this point, brief treatment of 110 with Raney nickel produced synthetic avarol 1 in 84% yield. Consequently, avarone 2 was produced from 1 via heterogeneous oxidation with MnO2.

Scheme 17

Total synthesis of avarol 1 and avarone 2 via radical decarboxyation and quinone addition reaction.

One of the synthetic strategies to ilimaquinone 3 and smenospongidine 116 is also based on a radical decarboxylation and quinone addition methodology (Scheme 18) [231,241]. These terpenoquinones were colleted from Hippospongia sp. [224,242,243]. The cytotoxicity against the NCI-H460, HepG2, SF-268, MCF-7, HeLa, and HL-60 human tumour cell lines, the inhibitory effects on the maturation of starfish oocytes, and cell cycle arrest in the HepG2 cell line were evaluated [242].

Scheme 18

Total synthesis of ilimaquinone and smenospongidine.

The chemical structures of ilimaquinone 3 and smenospongidine 116 differ from those of avarone-like molecules at the position of unsaturation of the decalin core and the additional oxygenation at the C21 center of the quinone ring. The application of radical decarboxylation and quinone addition methodology produces quinone 113 from reaction of thiohydroxamic acid derivative with benzoquinone 21. Functionalization of 113 to ilimaquinone 3 is achieved by exploiting the electronic effects of the residual thiopyridyl group. Finally, exposure of 3 to phenylethylamine under basic conditions afforded synthetic smenospongidine 116.

Ent-halimic acid 117 is used as starting material for the synthesis of aureole (−)-9, neomammanuthaquinone 120, smenoqualone 121, and cyclosmenospongine 122. The Barton decarboxylation in presence of benzoquinone is the key reaction in this synthesis (Scheme 19) [244].

Scheme 19

Retrosynthetic analysis of some sesquiterpenequinones/hydroquinones from ent-halimic acid.

6. Grignard Reagent Conjugated Addition to α,β-Unsaturated Carbonyl Group

The total synthesis of (±)-zonarol 47, (±)-isozonarol 49 [205,206] and (−)-yahazunol 45 [207,208] also were achieved by Grignard reagent (1,4) conjugated addition to α,β-unsaturated carbonyl group (Scheme 20 and Scheme 21) [245].

Scheme 20

Synthesis of yahazunol 45 by Grignard reagent conjugated 1,4-addition to enone 12-nordrim-9-dn-8-one.

Scheme 21

Synthesis of (±)-zonarol 47 and (±)-isozonarol 49 by Grigard reagent conjugated 1,4-addition.

The synthesis of yahazunol 45 started from (+)-11-hydroxy-12-nordriman-8-one 123 which was transformed with p-toluene sulfonic acid by elimination of water to enone (+)-124. The cuprate catalyzed conjugated 1,4-addition of 2,4-dibenzyloxyphenylmagnesium bromide to (+)-12-nordrim-9-en-8-one (+)-124 yielded the enolate anion which was trappe with acetic anhydride. Treatment of the resulting enolacetate (−)-125 with potassium hydroxide in methanol afforded the ketone (+)-126. Wittig reaction of (+)-126 with PH3PCH2 gave (+)-zonarol dibenzyl ether (+)-127. Epoxidation in position 8–12 gave the oxirane ring which was opened with LiAlH4 to (+)-yahazunol dibenzyl ether. Debenzylation of (+)-10 with H2 and Pd/C yielded (−)-yahazunol 45 (Scheme 20) [245].

In the synthesis of (±)-zonarol 47 and (±)-isozonarol 49 (Scheme 21), the terpene ketone 128, was prepared following a sequence of reactions [246] from the racemic mixture of the Wieland-Miescher ketone 73 (Figure 3). This ketone and its analogs are of great interest as starting materials to terpenequinones by asymmetric synthesis [223,224,239]. After preparing the Grignard reagent 129, which provides the hydroquinone moiety, it was reacted with the α,β-unsaturated ketone 128, and Ac2O, yielding the enol acetate obtained by conjugate addition. Treatment of the enol acetate with KOH gave ketone 130, which established the stereochemistry of the molecule. From compound 130, (±)-zonarol 47 and (±)-isozonarol 49, were obtained by two different ways. Wittig reaction, followed by demethylation, zonarol racemate 6 was obtained. By 1,2-addition of organolithium to the ketone 130, (±)-isozonarol 49 was obtained through a tertiary alcohol, which by dehydration gave a mixture of compounds 131 and 132. Finally, the demethylation of the methoxy group by treatment with lithium butanetiolate and HMPA led to (±)-zonarol 47 and (±)-isozonarol 49.

7. Reductive Alkylation of Enones

This strategy to connect the unit to a terpene quinone is based on the alkylation in the reaction medium during metal reduction of a conjugated double bond. Lithium with a solvent proton reduces the double bond through electron transfer giving an enolate. Thus, alkyl halide reaction generates the desired alkylated ketone. In all cases, the α,β-unsaturated ketone that is coupled to the quinone has the (S)-(+)-Wieland-Miescher diketone 73 as the starting material.

The synthesis of (+)-avarone 2, (+)-avarol 1, (−)-neoavarone, 134 (−)-neovarol 133 and (+)-aureol 9 is a good example of reductive alkylation of enones with bromides (Scheme 22) [247]. Thus, the enone 139 with bromide 140, and applying previously described protocols from the literature [156,239,248,249,250,251] gave the exo-olefin 138. The endo-olefin 136 should be accessible from 138 by isomerization at the C4 olefinic double bond.

Scheme 22

Synthetic plan for (+)-avarone 2, (+)-avarol 1, (−)-neoavarone 134, (−)-neovarol 133 and (+)-aureol 9 by enones reductive alkylation.

The synthesis of the decalin derivative 138 (Scheme 23), a common key intermediate for the synthesis of (+)-avarone 2, (+)-avarol 1, (−)-neoavarone 134, (−)-neovarol 133 and (+)-aureol 9, started with the reductive alkylation of enantiomerically pure enone 139 with 2-methoxybromide 140. Thus, treatment of enone 139 with lithium metal in liquid ammonia followed by reaction of the intermediary lithium enolate with bromide 140 provided the expected coupling product 141 as a simple diastereomer. Subsequent methylenation of the sterically hindered carbonyl group in 141 was achieved by employing a combination of Ph3P+CH3Br- and t-BuOK furnishing the exo-olefin. To establish the C8 sterogenic center, the ethylene acetal moiety was first removed by acid treatment and the resulting ketone 142 was subjected to hydrogenation, which afforded the product 143 and its C8 epimer 144 after separation by coumn chromatography on silica gel. Finally, compound 144 was efficiently converted to the desired key intermediate 138 by Wittig methylenation [247].

Scheme 23

Synthesys of key intermediate 138.

The Scheme 24 shows the synthesis of avarol 1 and avarone 2 from key intermediate 138. Isomerization of the exo-olefin moiety in 138 to endo-olefinic double bond was efficienthly achieved by treatment with RhCl3·3H2O. The endo-olefin 145 was then converted to avarone 2 and avarol 1 via phenol 146. To construct the quinone system directly, phenol 146 was allowed to react with molecular oxygen in the presence of salcomine, producing (+)-avarone 2. Subsequent treatment of avarone 2 with NaBH4 in THF/H2O resulted in the quinol avarol 1 [247].

Scheme 24

Synthesis of avarol 1 and avarone 2 reductive alkylation of enones.

Ilimaquinone 3 [224,242] and nakijiquinones 4, 163–165 [252,253,254,255,256,257] have also been synthesized using this strategy. In the synthesis of (−)-ilimaquinone 3 (Scheme 25) [250,251], compound 147 was treated with Li/NH3 giving the lithium enolate and subsequent treatment with benzyl halide 148 led to the α-alkylation product 149. The configuration of the remaining stereocenter (C-8) was established with a Wittig reaction followed by hydrogenation to yield compound 151 and its diastereomers (3:1). The oxidation of alcohol at C-4 and subsequent formation of the olefin led to 153. Finally, treatment with CAN and Pd (0) in basic medium, yielded (−)-ilimaquinone 3.

Scheme 25

Synthesis of ilimaquinone 3 by reductive alkylation of enones.

The reductive alkylation as strategy for building sesquiterpenilquinones has also been used in the synthesis of nakijiquinones [156,252]. From extracts of sponges from the family Spongiidae, collected in Okinawa several nakijiquinones were isolated. Nakijikinones are terpenequinones with an amino acid on the benzoquinone ring [253,254,255,256,257]. The HER2/Neu receptor tyrosine kinase is hugely overexpressed in about 30% of primary breast, ovary, and gastric carcinomas. Nakijiquinones are the only naturally occurring inhibitors of this important oncogene, and structural analogues of nakijiquinones may display inhibitory properties against another tyrosine kinase receptor involved in cell signaling and proliferation [156]. The synthetic route (Scheme 26), was optimized to obtain nakijiquinone C, using as intermediate the isospongiaquinone 162 and later the strategy was extended to obtain nakijiquinones A–D 4, 163–165.

Scheme 26

Synthesis of isospongiaquinone and nakijiquinone A–D 4, 163–165 by reductive alkylation of enones.

8. Cross-Coupling Reaction

This strategy consists on the application of a (dppf)NiCl2-mediated neopentyl coupling in natural product synthesis and emphasizes the attractive combination of hydroxyl-directed hydrogenation to control stereochemistry followed by a neopentyl coupling to elaborate the carbon skeleton. Retrosynthetic analysis as summarized in Scheme 27 readily dissects arenarol to a neopentyl iodide 166 and 2,4-dimethoxyphenylmagnesium bromide [258]. The neopentyl iodide turn could be derived from the corresponding alcohol 167, assuming that the hydroxyl group could be employed to control the stereochemistry of reduction at an adjacent exocyclic olefin, or the diene alcohol 169, if the hydroxyl group could be employed to fix both adjacent stereocenters. Either olefin could be viewed as a derivative of the decalin 168, depending on the sequence employed to accomplish methylation, introduction of the exocyclic olefin, and for compound 168, reduction of the endocyclic olefin. The synthesis of arenarol, based on this approach, includes both directed introduction of two key stereogenic centers and a (dppf)NiCl2-mediated coupling at a neopentyl center.

Scheme 27

Retrosynthetic analysis of arenarol 81.

Arenarol 81, isolated from Dysidea sp. and Fenestraspongia sp. [259,260] is a cis-decalin the synthesis of which calls for stereocontrol at two tertiary and two quaternary carbons. These compounds showed cytotoxic activity when assayed against P-388 leukaemia cells, with ED50 = 17.5 μg/mL for arenarol 81 and ED50 = 1.7 μg/mL for arenarone 80 [259]. Arenarol 81 showed DPPH radical scavenging activity with an IC50 value of 19 μM [260]. The Grignard reagent needed for preparation of arenarol 81, (2,5-dimethoxyphenyl)magnesium bromide 129, has been shown to undergo a cross-coupling reaction with neopentyl iodide in the presence of (dppf)NiCl2 and Zn2 dioxane forming the desired coupling product 171. Conversion of 171 to the target compounds required cleavage of the methyl protecting groups. Treatment of compound 171 with ceric ammonium nitrate (CAN) resulted in oxidation to the natural product arenarone 80. Mild reduction of arenarone 80 with Na2S2O4 gave the final target arenarol 81 (Scheme 28).

Scheme 28

Synthesis of arenarone 80 and arenatol 81 by cross-coupling reaction.

9. Furylation of Quinones

This procedure consists on furylation of quinones and hydroquinones through oxidative coupling and Michael addition reactions. Thus, the oxidative coupling reaction of (+) euryfuran with 1,4-quinones in acetic acid yielded euryfuryl-1,4-quinones with leishmanicidal activity. The influence of the solvent to promote the Michael addition and the regioselectivity of the reaction with unsymmetrical quinones are important feactures that can be useful for the synthesis of new bioactive members of the euryfurylquinones series [261] (Scheme 29). The Michael reaction of (+) euryfuran 172 with activated monosubstituted 1,4-benzoquinones 22 provides a regiospecific access to antiprotozoal active euryfuran derivatives 173 containinig a quinone or hydroquinone fragment bond to the 12 position [262]. Access to furylnaphthoquinones from unactivated quinones requires acid-induced conditions. However, oxidative coupling reactions of activate quinones proceed under neutral conditions. Most of the furyl-1,4-quinones exhibited good antiproliferative activity against MCF-7, NCI-H460 and SF-268 cancer cell lines [145].

Scheme 29

Furylation of quinones.

10. Furan Polyene Cationic Cyclization

This strategy is a diversity-oriented synthesis that follows a biomimetic route [263] to marine natural products like liphagal 1, the first member of a new of new liphagane type of meroterpenoid carbon skeleton. Liphagal 180 isolated from the methanol extract of the sponge Aka coralliphaga, collected from reefs in Prince Rupert Bay, Portsmouth, Dominica [264] exhibited impressive biological activity including inhibitory activity against PI3K a (phosphoinositide-3-kinase α) and cytotoxic to LoVo and CaCo human colon, and MDA-468 human breast tumor cell lines [264,265,266].

Liphagal 180 has a tetracyclic skeleton, harboring a trans-fused 6,7-bicarbocyclic core with three stereogenic centers. The retrosynthetic strategy toward liphagal (Scheme 30) was based on the proposed biogenetic pathway and hinged on a key C–C bond disconnection that mandated connecting a preformed benzofuran precursor 178 with a readily available monoterpenoid 177 to establish the crucial C-C bond and access the framework 8. Further elaboration of 176 into 175 was envisaged to set up the furan polyene cationic cyclization cascade en route to the target.The key furan precursor 178 was to be ascessed from a readily available aromatic precursor 179.

Scheme 30

Synthesis of meroterpenoid natural product (±)-liphagal 180 Retrosynthetic analysis by furan polyene cationic cyclization.

11. Application of Cell Culture for the Production of Bioactive Compounds from Sponges

Sponges [phylum Porifera] are a rich source of biologically active and pharmacologically valuable compounds with a high potential to become effective drugs for therapeutic use. However, until now, only a few compounds have been introduced into clinics because of the limited amounts of starting material available for extraction. To overcome this serious problem in line with the rules for a sustainable use of marine resources, the following routes can be pursued; first, chemical synthesis, second, cultivation of sponges in the sea (mariculture), third, growth of sponge specimens in a bioreactor, and fourth, cultivation of sponge cells in vitro in a bioreactor [267].

Recently, it was demonstrated that the in vitro culture of primmorph from the marine sponge Dysidea avara produces avarol 1. Single cells apparently do not have the potency to produce this secondary metabolite, but the primmorph model is a suitable system for the synthesis of bioactive compounds in vitro [268,269]. In addition, it has also been suggested that some of the bioactive secondary metabolites isolated from sponges are produced by functional enzyme clusters, which originated from the sponges and their associated microorganisms. In order to exploit the bioactive potential of both the sponge and the “symbionts”, a 3D-aggregate primmorph culture system was studied, and it was proved that avarol/avarone is produced by the sponge Dysidea avara. Another promising way to utilize the bioactive potential of the microorganisms is the cloning and heterologous expression of enzymes involved in secondary metabolism [270].

In situ sponge aquaculture is nowadays one of the most reliable methods to supply pharmaceutical companies with sufficient quantities of the target compound. Its use in addition to immortalization of sponge cells by transfection with genomic DNA appears to be a promising way, since recent studies underscore the applicability of this technique for sponges [270].

12. Summary

Sesquiterpenequinones represent a substance class with increasing pharmacological interest. The initial concentration of an interesting compound may be too low to be effectively tested in some biological and pharmacological assays. Thus, the total synthesis of terpenequinones has become attractive in order to obtain the required amounts of compounds natural product analogues with optimized biological properties. Consequently, the development of these marine natural products is highly desirable and worthwhile from the viewpoint of medicinal chemistry and pharmaceuticals. Therefore, total synthesis of natural products will surely continue to be central to confirmation of natural product structure assignment, as well as providing material for biological testing towards pharmaceutical development, and investigations of biosynthetic pathways.

The main routes to synthesize terpenequinones/hydroquinones include Diels-Alder cycloaddition reaction, coupling of the aldehydes with lithiated hydroquinone ether, radical decarboxylation and quinone addition reaction, Grignard reagent conjugated addition to α,β-unsaturated carbonyl group, reductive alkylation, cross-coupling reaction, furylation of quinones and furan polyene cationic cyclization. In addition, the application of cell culture for the production of bioactive compound from sponge is a promising way to utilize the bioactive potential of marine terpenoquinones sources.

Advances in total synthesis, especially function-oriented synthesis, biosynthetic technologies, primmorph models and genomic research offer new strategies for the medicinal chemical optimization of biologically active terpenequinones/hydroquinones.