A Review on the Chemistry of Eremanthine : A Sesquiterpene Lactone with Relevant Biological Activity

Eremanthine (1) (Figure 1) is a sesquiterpene lactone abundantly found in the Brazilian Compositae (Asteracea) Eremanthus elaeagnus [1] and Vanillosmopsis erythropappa [2] (Eremanthus erythropappus) [3]. This compound is a target for studies because of its biological properties, structural complexity due to the presence of a flexible seven-membered ring in its skeleton, as well as for the possibility to transform it in other potentially bioactive sesquiterpene lactones. This review is composed by five items which include the isolation, structural classification, biological activity, synthesis, and chemical transformations of eremanthine. The main publications on this sesquiterpenolide from its isolation of natural sources in 1972 to the current days are described in the present review. Special attention is given to the synthetic studies that were developed aiming at the preparation of potentially bioactive sesquiterpene lactones.


Introduction
Eremanthine (1) (Figure 1) is a sesquiterpene lactone abundantly found in the Brazilian Compositae (Asteracea) Eremanthus elaeagnus [1] and Vanillosmopsis erythropappa [2] (Eremanthus erythropappus) [3].This compound is a target for studies because of its biological properties, structural complexity due to the presence of a flexible seven-membered ring in its skeleton, as well as for the possibility to transform it in other potentially bioactive sesquiterpene lactones.
This review is composed by five items which include the isolation, structural classification, biological activity, synthesis, and chemical transformations of eremanthine.The main publications on this sesquiterpenolide from its isolation of natural sources in 1972 to the current days are described in the present review.Special attention is given to the synthetic studies that were developed aiming at the preparation of potentially bioactive sesquiterpene lactones.

Isolation of Eremanthine
The search, here in Brazil, for plant-derived inhibitors against infections by cercariae of Schistosoma mansoni led to the isolation and characterization of eremanthine (1) from the oil of the Compositae Eremanthus elaeagnus and Vanillosmopsis erythropappa in 1972 [1,2].The extraction of crude oil from these vegetable species was made through the classic method of infusion of the pulverized trunk wood in organic solvent, at room temperature, followed by the evaporation stage of the extractor solvent under reduced pressure.Therefore, after evaporation of hexane that was used to extract the oil of Eremanthus elaeagnus and subsequent stage of crystallization of the crude oil with the same solvent, eremanthine (1) was obtained as colorless needles with melting point 73-74 • C and [α] 29  D −59 • (c 1.0 in CHCl 3 ) [1].This value of specific optical rotation was later corrected as it is going to be described soon afterwards in this review.In the case of the hexane concentrated extract obtained from the extraction of the Vanillosmopsis erythropappa oil, eremanthine (1) was obtained after elution over column chromatography of silica gel [2].The physical data of eremanthine obtained from Vanillosmopsis erythropappa were identical to the ones of eremanthine obtained from Eremanthus elaeagnus.The only structural feature not determined in those works published in 1972 was the absolute configuration at the carbon C-1.
It was demonstrated in 1974 that vanillosmin, isolated from Vanillosmopsis erythropappa by a research group in Italy [4], also had the same structure of eremanthine (1).In this case, the oil of that vegetable species was obtained from the acetone concentrated extract of the pulverized trunk wood in infusion, followed by the subsequent stages of treatment with a mixture of MeOH-H 2 O and extraction with petroleum ether.The concentrated oil obtained after these stages was eluted over column chromatography of silica gel impregnated with AgNO 3 to furnish vanillosmin that was crystallized in hexane as long needles with melting point 62-62.5 • C, boiling point 175-180 • C/0.2 mm, and [α] 20 D −110 • .There were elucidated in that work the absolute configurations at C-1 and C-5 as being both R, on the basis of a series of chemical reactions.
The 1,5-cis-fused bicyclo [5.3.0]decaneskeleton for 1 was confirmed by Garcia et al. [5] through the formation of dibromoether 2 when eremanthine (1) was treated with N-bromosuccinimide in dioxane containing 20% of water (Scheme 1).There was demonstrated through threedimensional analysis of 1 that the formation of an ether linkage between the C-4 and C-10 positions was possible only if the five-and seven-membered rings were cis-fused.As the name eremanthine for 1 has historical precedence over vanillosmin the latter name passed no longer to be used.It was demonstrated in that work published by Rabi et al. [5] that the value of specific optical rotation previously calculated [α] 29  D −59 • (c 1.0, CHCl 3 ) [1] was incorrect.A new determination was made and it was obtained [α] 23  D − 111.7 • (c 1.0, CHCl 3 ) being, therefore, in agreement with the value of [α] 20  D −110 • described in [4].In 1985 Lima et al. [6] published a selective method for extraction of α-methylene-γ-lactones from Vanillosmopsis erythropappa.The oil of that vegetable species was obtained by the procedure of infusion of the pulverized trunk wood left in contact with hexane and then in ethanol.After evaporation of the extractor solvents, it was obtained an oil resultant from the hexane extract and another of the ethanol extract.The ethanolic extract furnished a dark oil that was exhaustively extracted with hexane to afford an oil.
The aliquots of each oil were soon afterwards submitted to the separation procedure of α-methylene-γ-lactones from the other chemical substances of the crude extracts.Such procedure used the property of the unsaturated γ-lactones undergo facile 1,4-addition with nucleophilic substances.The sequence of reactions that was used to obtain eremanthine (1) for this procedure is outlined in Scheme 2. For this procedure the crude extract from Vanillosmopsis erythropappa, containing α-methylene-γ-lactones (3) in mixture with other substances, was dissolved in EtOAc and then submitted to reaction with aqueous solution of dimethylamine.The obtained mixture, containing the adducts of dimethylamine (4) together with other substances, was diluted with EtOAc and then washed with water.The separated and concentrated organic layer was submitted to reaction with acetic acid to furnish the acetates 5 in mixture with other substances.The acetates were extracted with water and the aqueous phase was washed with EtOAc, neutralized with saturated solution of sodium carbonate, and then reextracted with EtOAc.The mixture of the adducts of dimethylamine (4) was submitted, soon afterwards, to reaction with MeI to generate a mixture of iodides (6).Saturated solution of sodium carbonate was added and let to react at room temperature for 1 hour to the elimination reaction of the quaternary adducts of trimethylamine.There was obtained, after extraction of the last reaction, an exclusive mixture of α-methyleneγ-lactones (3).Filtration of this mixture of γ-lactones over column chromatography of silica gel, followed by crystallizations, furnished eremanthine (1) as majority product as well as the minority α-methylene-γ-lactones shown in Figure 2.
Due to the importance of bioactive chemical substances present in the crude extract from Vanillosmopsis erythropappa (Eremanthus erythropappus), tree popularly known by the name of candeia, nowadays a plan to conserve this forest species is being developed [7,8].The wood obtained in the forests of candeia is mainly sold for the industries of essential oils [9] that extract the crude oil through the steam distillation process.For that process, the pulverized trunk wood of Eremanthus erythropappus is put inside chemical reactors of high pressure and then it is heated at high temperature with water.The steam generated in the reactors passes, soon afterwards, for industrial condensers where it is cooled and then a mixture of oil and water is collected.The densest substance (water) is removed from the mixture to furnish the concentrated oil of Eremanthus erythropappus which is mainly sold for the industry of cosmetics that uses another important chemical substance found in that oil, the α-bisabolol (20) [10] (Figure 3).The use of the concentrated oil from Eremanthus erythropappus, extracted for the modern industrial method, certainly gives good results for isolation of eremanthine (1).Another recent method to extract the oil from Eremanthus erythropappus, using the supercritical extraction process and phase equilibrium of candeia oil with supercritical carbon dioxide, was reported by de Souza et al. [11].Dehydrocostus lactone (10) Costunolide ( 11) Reynosin ( 12) Santamarin ( 13) Magnolialide ( 14) Arbusculin A (15) 4-epi-Arbusculin A ( 16) Trifloculoside ( 17) Estafiatone ( 18) Eregoyazin (19) α-Cyclocostunolide (7) 4,15-α-Epoxieremanthine (8) 9,10-α-Epoxieremanthine (9)
was determined through the correlation of derivatives from the substance 1 with other lactones that possess known absolute stereochemistry in these positions.The sequences of reactions that were employed by Corbella et al. [4] to synthesize the substances used to determine the absolute stereochemistry of eremanthine are outlined in Schemes 3-8.
As the most guaianolides possess cis fusion in the fiveand seven-membered rings at the hydroazulene system, there was initially attributed the stereochemistry of eremanthine in those centers as shown in the chemical structure 1. Reaction of substance 1 with NaBH 4 generated a single product characterized as the lactone 21 (Scheme 3).Reduction of this substance with hydrogen and soluble Wilkinson's catalyst furnished a product identified as the compound 22. Hydrogenation of 22 in EtOAc with H 2 and Pd resulted in isomerization of the double bond C9-C10 to the tetrasubstituted position C1-C10 to afford the compound 23 as the main product of that reaction.In the following stage, the compound 23 was synthesized starting from O-acetylisophoto-α-santonic lactone (24) (Scheme 4).
Catalytic hydrogenation of lactone 24 furnished the compound 25 of known absolute stereochemistry.Reaction of substance 25 with 1,2-ethanedithiol and BF 3 •OEt 2 furnished thioacetal 26, resultant from the protection of carbonyl group at C-3 position and elimination of acetic acid.
Reductive removal of the thioacetal 26 with Raney-Nickel generated a compound identified as the substance 23, previously obtained from eremanthine (1).
To ensure that the acid treatment of the lactone 25 (Scheme 4) did not affect the configuration of the methyl at C-4, that is more stable in the alpha position than in the beta position, the C-4 epimer of compound 23 was prepared as described in Scheme 5. Alkaline treatment of the lactone 25 generated the compound 27 resultant from the hydrolysis of the acetate and epimerization at C-4 position.Thioacetalization of compound 27 furnished two products: one of them, the compound 28, stayed with the hydroxy group at C-10 and the other, the compound 29, resultant from elimination of water.Desulphurization of the thioacetal 29 generated the lactone 30, whose physical data were different from those of the lactone 23 obtained from eremanthine (1) (Scheme 3).This correlation confirmed the structure proposed for the compound 23 and established the absolute configuration at C-5, C-6, and C-7 positions of eremanthine as shown in the chemical structure 1.
Alkaline hydrolysis of the acetate 24 generated the lactone 33 (Scheme 7) that was submitted to catalytic hydrogenation to furnish the dihydroderivative 34.Treatment of this compound with etanedithiol and BF 3 •OEt 2 , at low temperature, generated the thioacetal 35.This compound was reduced with Raney-Nickel to afford a product whose physical data were identical to those of the hydroxylactone 31 derived from tetrahydroeremanthine (22).
The most abundant product of the oxymercurationdesmercuration reaction on tetrahydroeremanthine (22) was the hydroxy-lactone 32 (Scheme 6), which is the C-10 epimer of substance 31.To ensure that the configuration at C-10 was the only difference between the structures 31 and 32, the product 31 obtained from the conditions described in Scheme 7 was submitted to dehydration with thionyl chloride and pyridine at low temperature (Scheme 8 submitted to subsequent stage of oxymercuration-desmercuration to furnish a compound identical in all its physicochemical properties to the hydroxy-lactone 32.These results demonstrated that the hydrogen at C-1 position of eremanthine (1) has alpha configuration and, consequently, the absolute stereochemistry of this substance is in agreement with the chemical structure shown in Figure 1.
The absolute configuration of eremanthine (1) was also confirmed in an article published in 1999 by Yuuya et al. [12].In that publication the guaianolide 1 was synthesized starting from the natural product α-santonin.

Structural Classification of Eremanthine
Eremanthine (1) belongs to the class of substances denominated guaianolides.These substances possess the basic skeleton of bicyclo[5.3.0]decane,characteristic of the guaiane sesquiterpenes, to which was inserted at positions C-6 and C-7 or C-7 and C-8 a γ-lactonic ring (Figure 4).

The Biogenesis of Sesquiterpene Lactones.
Guaianolides are biogenetically derived from the farnesyl pyrophosphate (37) that passed by cyclization to generate the cyclodecadiene 38.This intermediate undergoes enzymatic oxydations to yield the germacranolide (39), a presumed precursor of the skeleton of guaianolides (Scheme 9) [13].A detailed study on the biogenesis of sesquiterpene lactones was reported by Fischer et al. [14].
The skeletons of sesquiterpene lactones, with lactonic fusion at C-6 and C-7 positions, derived from germacranolides and the respective references were described in the works of Ferreira's M.S. [15] and Fantini's Ph.D. [16].In Scheme 10 are outlined such biogenetical relationships reported in those works.
The biogenetical hypothesis of the guaianolides formation and their transformation into pseudoguaianolides reported by Fischer et al. [14] is outlined in Schemes 11-14.It was formulated that the skeleton of guaianolides is formed by the cyclization of a germacranolide-4,5-epoxide (40) in a chair-like transition state (Scheme 11).The intermediate cisfused guaianolide cation (41) undergoes reaction with water to furnish the guaianolide 42 with cis fusion between the fiveand seven-membered rings that is, with rare exceptions, the stereochemistry found in the most guaianolides.
The biogenesis for the few trans-fused guaianolides found as natural products was proposed to proceed via either the melampolide-4,5-epoxide (43) or germacranolide-4,5-epoxide (44) pathways (Scheme 12).The cyclization of these compounds should furnish the trans-fused guaianolide cation (45) which after reaction with water would result in the formation of the skeleton 46 with trans fusion between the five-and seven-membered rings.
The biogenesis for the pseudoguaianolides-denominated ambrosanolides, with C-10β methyl group and lactonic ring at C-6 and C-7 positions with the C-6 oxygen at β orientation, is outlined in Scheme 13.The cyclization of the germacranolide-4,5-epoxide (47) would give the cation guaianolide (48) which upon double hydride and methyl shift, as indicated by the arrows, gives the ambrosanolide skeleton (49).As all ambrosanolides possess cis lactonic fusion at C-6 and C-7 positions, it was proposed that a C-6-β-oxygen would be assisting the rearrangement step of the carbocation 48 to compound 49.The intramolecular frontside stabilization of the cationic center at C-10 by the C-6 oxygen at β position would allow a C-1 to C-10 hydride shift to occur before the competing step of elimination or nucleophilic attack at C-10 to form a guaianolide.
The biogenesis of the pseudoguaianolides-denominated helenanolides, with C-10α methyl group and lactonic ring at  C-7 and C-8 positions with the C-8 oxygen oriented either α or β, is outlined in Scheme 14. Acid-induced cyclization of the melampolide-4,5-epoxide (43) would give the cation 45 from which by the indicated shifts, the skeleton of the helenanolides (50) would be formed.An alternative route to the helenanolide intermediate ( 45) could involve a germacranolide 4,5-epoxide precursor (44) which would provide the same cyclised skeleton (50) which is formed via the melampolide route.
In 1981 Fischer et al. [17] published an article on the biomimetic transformation of guaianolide into pseudoguaianolide.The conditions studied in that biogenetic type in vitro conversion are outlined in Scheme 15.The reaction of epoxide 51 with BF 3 •OEt 2 furnished the compounds 52 and 53 and not the desired product 54 with pseudoguaianolide skeleton.It was proposed that the minor product (52) resulted from the acid-catalysed opening of the ring epoxide of 51 and the major eudesmanolide 53 from the skeleton rearrangement of that substrate catalysed by BF 3 •OEt 2 .The nonformation of substance 54 starting from the epoxide 51 reinforces the hypothesis that, to occur the rearrangements indicated by the arrows in Scheme 15, there is necessary a precursor guaianolide with a β-oxygenated function at C-6 position.

Stereochemistry of Bicyclo
The hydroazulene system is composed by a fivemembered ring (rigid system) fused with a seven-membered ring (flexible system).Due to the flexibility of the sevenmembered ring at the hydroazulene system, the study of conformational analysis of that system became necessary for a better understanding of stereoelectronic course of the reactions occured with the classes of substances that contain this nucleus in its hydrocarbon skeleton.The conformational analysis of hydroazulenes is also important for the interpretation of spectral data from nuclear magnetic resonance (NMR) of the substances that possess this system.
The study of conformational analysis applied to cyclic systems, including the hydroazulene, was initiated in the decade of 1960 with Hendrickson's works [102][103][104][105][106][107][108][109].Subsequent studies, in that area, were published in the decade   of 1980 by Clercq [110][111][112][113][114][115].Those works were focused on the conformational analysis of the seven-membered ring that commands the geometry of the hydroazulene system.According to the results of those published studies, the sevenmembered ring can present itself in the basic conformations shown in Figures 6-7.
In Figure 6 the subscript used to define a particular form (twist-chair TC, chair C, twist-boat TB, and boat B) indicates the atom sectioned by the symmetry element and the strain energies are given in parenthesis in kilojoules per mol.The same annotation was used in Figure 7, with the symbol ∼C 2 indicating a pseudo-C 2 axis of symmetry.
According to Clercq [110] the chair and boat conformations of cycloheptane are flexible and undergo pseudorotation.The twist forms (TC and TB) with C 2 -axis of symmetry are generally more stable than the chair (C) and boat (B) forms with a C S plan of symmetry.In the case of cycloheptene, the chair form is generally the most stable conformation and the order of relative stability of conformers is the following: C > TB(C 2 ) > TB (∼C 2 ) > B. The method of de Clercq [110,111], for systematic conformational analysis of hydroazulenes, was used in synthetic studies to explain the stereoselectivity of the reactions of sesquiterpene lactones that possess the hydroazulene skeleton in its molecular structure [115].
Nowadays, with the technological progresses, several research groups are using computation programs that were developed to aid in the visualization of the three-dimensional chemical structures of the molecules and to calculate their physical properties.It is possible to perform the conformational analyses of the studied substances, starting from the three-dimensional structures drawn by computation programs.Articles were published on the several modern techniques used to determine the conformations of the hydroazulene system from sesquiterpene lactones, including the analyses of X-ray diffraction, calculations of quantum mechanics, and molecular mechanics in combination with the NMR data [116][117][118][119][120][121][122][123].

Biological Activity of Eremanthine
Researchers verified that animals of laboratory (mice) were protected against infections caused by cercariae of Schistosoma mansoni, when the essential oils from Eremanthus elaeagnus and Vanillosmopsis erythropappa were applied on the skin of those guinea-pigs.That protective action was mainly attributed to the substance eremanthine (1), an abundant component found in those oils [1,2].The biological activity of eremanthine was attributed to the presence of an α-methylene-γ-lactone in its molecular structure [1].That functional group was indicated as the main responsible for the biological activity in sesquiterpene lactones, due to its ability to react with the biological nucleophiles in a conjugate fashion [124][125][126][127][128][129][130].The pharmacological results from the protective action of Eremanthus elaeagnus and Vanillosmopsis erythropappa oils were reported by Baker et al. [2].

Synthesis of Eremanthine
The synthesis of sesquiterpene lactones with their varied skeletons is composed by two crucial stages, which are the construction of the basic skeleton and the formation of the α-methylene-γ-lactone.In the following subitems some considerations are done about the construction of the hydroazulene skeleton characteristic of the guaiane [131] and pseudoguaiane sesquiterpenoids, the formation of the α-methylene-γ-lactone, besides the strategy and stages of the synthesis of eremanthine (1).

Basic Strategies to Construction of the Hydroazule Skeleton.
The construction of the hydroazulene skeleton, reported by Heathcock et al. [132], involves four basic strategies which are shown in Scheme 16 with the respective substances that were synthesized.The synthesis of confertin (60) [133] was accomplished by the strategy A, in which the construction of the hydroazulene skeleton (55) was planned starting from a hydronaphthalene precursor (56) through a rearrangement reaction.The damsim (61) [134] could be obtained by the strategy B, whose construction of the hydroazulene skeleton was planned starting from a cyclopentane precursor (57) on which the cycloheptane ring was inserted.In the synthesis of deoxydamsim (62) [135] the construction of the hydroazulene skeleton was planned by the strategy C, using a precursor derived from the cyclodecane (58), through a transannular rearrangement reaction.Finally in strategy D, used to the synthesis of dehydrocostus lactone (10) [136], the construction of the hydroazulene skeleton was planned starting from a cycloheptane derivative (59) on which the cyclopentane ring was inserted.The most recent literature on the synthesis of sesquiterpenoids reports the preparation of a chiron derived from cycloheptenone as a building block to the synthesis of guaiane sesquiterpene natural products [137] as well as the synthetic approaches to bicyclo[5.3.0]decanesesquiterpenes [138].

Synthesis of the α-Methylene-γ-Lactone
Moiety.The α-methylene-γ-lactone is an important structural subunit found in several natural products with relevant biological activity.Due to the importance of this functional group, several researchers dedicated to the study of this structural moiety, with prominence to the various synthetic methods reported in literature [139][140][141][142][143].

Strategy to the Synthesis of Eremanthine.
The enantioselective synthesis of eremanthine (1), developed by Yuuya et al. [12], employs the chiron approach strategy with the use of a chiral natural product as starting material on which chemical transformations are performed to reach the synthesis of the target molecule.There was used the strategy A shown in Scheme 16 to the construction of the hydroazulene skeleton of eremanthine (1) Scheme 20: Synthesis of dehydrocostus lactone (10).
was planned to be synthesized via the cationic intermediate 63, that could be generated from the mesylate 64 through solvolytic rearrangement.The mesylate 64 could be obtained from α-santonin (65).derivatives as well as the preparation of less abundant naturally occurring lactones.As a result of this research program, several works of M.S. and Ph.D. degrees were accomplished using eremanthine (1) as object of study [15,16,[144][145][146][147][148][149][150].In the following subitems are described the syntheses of several eremanthine derivatives published in the period of 1972 to the current days.

The First Chemical Transformations of Eremanthine.
The first chemical transformations performed with eremanthine (1) were published in 1972 by Vichnewski and Gilbert [1] and are depicted in Scheme 19.
Dehydrogenation of eremanthine (1) with palladium by heating in nujol gave chamazulene (78), and the selective epoxidation of 1 yielded the epoxide 9. Treatment of compound 9 with excess of BF 3 -etherate furnished a product that was initially characterized as the ketone 79 [1].Reinvestigation of this reaction by Garcia et al. [5] showed this structural assignment to be incorrect and the structure of the aldehyde 81, resultant from a rearrangement, could be demonstrated by physical methods.Catalytic hydrogenation of eremanthine (1) resulted in the generation of a mixture of the isomers 80. Reduction of 1 with NaBH 4 furnished a mixture of 3 products characterized as the compounds 82, 83, and 84.

Chemical Transformations of Eremanthine for the Synthesis of Other Natural Guaianolides.
In 1977 Mac ¸aira et al. [151] published an article on the selective chemical modifications performed with eremanthine, aiming at the syntheses of other guaianolides of natural occurrence.As result of the chemical modifications performed with the substrate 1, there were obtained the synthetic derivatives depicted in Scheme 20 besides the natural product dehydrocostus lactone (10), a guaianolide initially isolated from Saussurea lappa [152].
The isomerization of exocyclic double bond at fivemembered ring of eremanthine (1) was achieved treating this compound with excess of BF 3 •OEt 2 .In these conditions isoeremanthine (85) could be obtained in yields ranging from 65 to 80%, according to scale of the substrate, quantity of BF 3 •OEt 2 , and reaction time.To ensure that the isomerization of 1 to 85 did not result in change of the configuration at C-1 and C-5, isoeremanthine (85) was treated with NBS in a mixture of dioxane-H 2 O.The formation of the dibromoether 86 did confirm the cis fusion at the five-and seven-membered rings of isoeremanthine.The aldehyde 87 could be obtained selectively, without isomerization of exocyclic double bond at five-membered ring, by treating epoxide 9 with equimolar amount of BF 3 •OEt 2 .When epoxide 9 was treated with concentrated HCl in THF, the chlorohydrins 88 and 89 were isolated in a respective proportion of (6 : 5).Treatment of compound 88 with a mixture of thionyl chloride and pyridine, at low temperature, gave allylic chloride 90.Dechlorination of 90 in acid medium with zinc and MeOH furnished a compound identified as dehydrocostus lactone (10).The isomerization of exocyclic double bond at five-membered ring of 10 was achieved through the reaction of this compound with BF 3 •OEt 2 , at the same conditions used to convert eremanthine (1) into isoeremanthine (85).In those conditions isodehydrocostus lactone (91) was obtained.

Syntheses of Eregoyazin and Eregoyazidin.
In order to confirm the structures of eregoyazin (19) and eregoyazidin (95), two guaianolides isolated from Eremanthus goyazensis by Vichnewski et al. [153], the syntheses of these compounds were accomplished according to the sequence of reactions depicted in Scheme 21 [153,154].The reaction of isoeremanthine (85) with one equivalent of bromine at −70   afforded mainly the α-epoxide 93.Exposure of this epoxide to methanolic zinc resulted in debromination to furnish compound 94.Treatment of 94 with BF 3 •OEt 2 afforded a substance identical in all aspects with eregoyazin (19).Further reduction of 19 with zinc in hot glacial acetic acid yielded eregoyazidin (95).

Reaction of Eremanthine and Isoeremanthine with Bromine.
The search for a selective method to protect the most nucleophilic 9,10-double bond of eremanthine (1) led to the investigation of eletrophilic addition of bromine to this compound and also to isoeremanthine (85).The conditions that were employed by Garcia et al. [157] to study this addition reaction are described in Schemes 24-27.When eremanthine (1) was allowed to react with one equivalent of bromine at kinetic conditions, an equimolar mixture of tetrabromide 104 and 1 could be detected by 1 H NMR spectroscopy (Scheme 24).Addition of two equivalents of bromine to eremanthine (1) resulted in the exclusive formation of tetrabromide 104.Reaction of this compound with zinc in methanol regenerated eremanthine (1) in quantitative yield.When   A complex mixture of products was obtained when isoeremanthine (85)    the rearrangements preconized by the biogenesis hypothesis of the ambrosanolides (Scheme 13). 13C NMR Spectroscopy on Eremanthine Derivatives.In 1981 da Silva et al. [158] published an article with the chemical shifts assigned to the carbons of naturally occurring guaianolides eremanthine (1), dehydrocostus lactone (10), eregoyazin (19), eregoyazidin (95), and other semisynthetic lactones derived from eremanthine (1).A detailed discussion correlating the data of 13 C NMR with the probable conformations at the seven-membered ring of the investigated guaianolides is presented in the article.
as allylic chloride 134.On the other hand, the reaction of 133 with triphenylphosphine and CCl 4 gave a mixture of desired product 135 accompanied by another compound identified as the conjugate diene 136.Dechlorination of 135 with zinc and AcOH in refluxing MeOH furnished a mixture of two products with the same R f of authentic samples of the methanol adducts of eremanthine (121) and dehydrocostus lactone (137).

Study on the Chemical Reactivity of Eremanthine:
The α-Methylene-γ-Lactone Moiety.With the objective of extending the study on the chemical transformations of eremanthine (1) to the lactonic ring, Fantini [16] developed her Ph.D. thesis focusing the α-methylene-γ-lactone of that substance and of its synthetic derivatives.The syntheses of compounds used in that study are outlined in Schemes 32-35.
The search for a protective group of α-methylene-γlactones resistant in certain reaction conditions, for example, catalytic hydrogenation, led to the synthesis of methanol adduct of eremanthine (121).It was verified that in basic conditions (aqueous NaOH, DMF, reflux), the α-methyleneγ-lactone could be regenerated in high yields [159].The use of methoxyl as protective group for the α-methylene-γlactone of eremanthine (1) was accomplished with success during the synthesis of diol 141 (Scheme 32) [16].The reaction of eremanthine (1) with a solution of MeONa in methanol gave the adduct 121.Treatment of this compound with a solution of peracetic acid in chloroform yielded diepoxide 138.The cleavage of oxiranic rings of 138 with KI and acetic acid in refluxing acetone furnished iodohydrin 139.Catalytic hydrogenation of 139 with hydrogen, Pd-C, and sodium acetate in EtOH yielded diol 140.This substance was submitted to subsequent step of treatment with an aqueous solution of NaOH in refluxing DMF to give, after aqueous acid work up, the α-methylene-γ-lactone 141 as the main product of this reaction.
The inversion of configuration at C-6 position of eremanthine (1), aiming at the synthesis of 6-epi-eremanthine (142), was studied by the two sequences of reactions depicted in Scheme 33 [16,160].In the route A, the inversion of configuration at C-6 position of 1 was planned by the method of oxidation-reduction of secondary hydroxy group in this position.The reduction of carboxy group of the lactonic ring at methanol adduct 121 with NaBH 4 in ethanol gave diol 143.In the next step, this compound was submitted to protection of primary hydroxyl with (Ph) 3 CCl and pyridine in CH 2 Cl 2 to furnish compound 144.The oxidation of secondary hydroxyl at 144 was performed with pyridinium dichromate in DMF to afford the ketone 145.Treatment of 145 with sodium borohydride in DMF furnished an unstable product of difficult purification.With this unsatisfactory result, the synthesis of 142 was studied by the route B. The inversion of configuration at C-6 of eremanthine (1) was achieved by displacement of intermediate mesylate generated in this position to afford a mixture of 1 and the unstable 6-epi-eremanthine (142) (43 : 57, 1 H NMR). The instability of 142 was attributed to steric effects at the hydroazule system.After the synthesis of triene 128, obtained in mixture with oxacycloguaiane methyl ester 129 (Scheme 30), there was initiated a study aiming at to optimize the formation of compound 129 [15,16,161,162].As a result of this study, the furanic derivatives 129, 146, and 147 were obtained (Schemes [34][35].There is a discussion evaluating the structures of reactive eremanthine derivatives (111, 124, 125, and 127) in comparison with other inert compounds obtained from eremanthine (1) as well as the reactive species responsible for the methanolysis of the lactonic ring in that reaction as reported in an article published in 1986 by Fantini et al. [163].
The reaction of iodohydrin 111 with zinc in refluxing methanol (Scheme 30) showed that furanic derivative 129 was formed after the triene 128.It was also verified that triene 128 did not generate the compound 129.Starting from these observations, it was presumed that the reactive species responsible for the formation of compound 129 was a by-product from the reaction of iodohydrin 111 with zinc (IZnOH) [16].As an attempt to simulate the reactional system of iodohydrin 111 with zinc in methanol, there was developed a reagent that in fact converted directly the substrate 111 into oxacycloguaiane 129.This reagent was the filtrate of a mixture containing MeI, zinc, and methanol left in contact for 16 h at room temperature [15].When iodohydrin 111 was submitted to reaction with this reagent under reflux during 48 h, the oxacycloguaiane 129 was obtained as a single product (Scheme 34).When iodohydrin 124 was submitted to similar conditions, the compound 147 was obtained after 72 h of reaction (Scheme 35) [15].In the following stage this reaction was performed with ZnI 2 .When iodohydrins 111, and 127 were allowed to react with ZnI 2 in methanol at room temperature, the respective furanic derivatives 129 and 146 were obtained (Scheme 34).It was also verified that the addition of zinc to reactional mixture accelerated the formation of these compounds.When the iodohydrins 111, 127 and epoxide 125 were allowed to react with a mixture of ZnI 2 , zinc, and methanol at room temperature for 40 h, there was verified the total conversion of these substrates to respective products 129 and 146 (Scheme 34).

Synthesis of the Trienes 128 and 130.
Besides the reactions of her Ph.D. thesis [16], described in the previous subitem (6.9), Fantini developed the synthesis of the trienes 128 and 130 starting from the respective iodohydrins 111 and 127 as a Researcher Professor of the Department of Chemistry at the Rural Federal University of Rio de Janeiro (UFRRJ).The optimized conditions of those reactions were reported in a congress abstract [164] and are depicted in Scheme 36.

Study of the Inversion Reaction of the Lactonic Fusion on Eremanthine Derivatives and Synthesis of Micheliolide.
The last studies with eremanthine (1) were performed by Alves [150].These studies were developed aiming at the syntheses of substrates derived from the lactone 1 with different structural features to be used in the next stage of inversion of the lactonic fusion employing the conditions depicted in Scheme 33 (route B), aiming to get epimers more stable than 6-epi-eremanthine (142) previously synthesized [16,160].That study of inversion of the lactonic fusion was also planned to obtain a substance with the necessary structural requirements for an eventual investigation of the biomimetic transformation of guaianolide into pseudogua-ianolide, discussed in the text of this review at the subitems 3.1 (Scheme 13) and 6.6 (Scheme 28).There was also studied the synthesis of micheliolide, a naturally occurring substance initially isolated from Michelia compressa with relevant biological activity [165].In the following subitems are described the sequences of reactions that were developed aiming to attain these objectives [150,[166][167][168][169][170] as well as the results of the study from the reactions of catalytic hydrogenation and methanol addition to α-methylene-γ-lactone of eremanthine derivatives [171].

Study on the Synthesis of Micheliolide.
The synthesis of micheliolide (155) was studied by the sequences of reactions depicted in Schemes 37 and 38.Initial attempts to deoxygenate the C-9 position of acetate 148 and iodohydrin 139 with concomitant hydrogenolysis of the bond C15-I in these compounds were unsuccessful [150].When the allylic acetate 148 was submitted to photolysis conditions in a solution of HMPA and water, using the procedure reported by Deshayes et al. [172], an untreatable mixture of products was obtained instead of the desired compound 149 (Scheme 37).On the other hand, treatment of iodohydrin 139 with MsCl and Et 3 N in dichloromethane, by the procedure of Crossland and Servis [173], generated a mixture of conjugate dienes 151 and 152 instead of the intermediate mesylate at C-9 position (150), which would be used in the next step of hydrogenolysis with NaBH 3 CN in HMPA by the procedure of Hutchins et al. [174], aiming to obtain the target molecule 149.The author is disregarding in this review the preliminary results reported before about this reaction [166].On that occasion this reaction was described in the following way: treatment of 139 with MsCl/Et 3 N/CH 2 Cl 2 (r.e [168,169] d [170] f  [148] and 126 [15].With those unsatisfactory results, the synthesis of compound 149 was attempted by catalytic hydrogenation of iodohydrin 139 with NaOAc in EtOH, using a longer reaction time and a higher hydrogen pressure than those commonly used to get diol 140 (Scheme 32).In those reaction conditions (60 psi of hydrogen, r. t., 48 h), the desired compound 149 was obtained as the minor product in mixture with diol 140 and compound 153 (Scheme 37) [168,169].
In the next stage, the hydrogenolysis reaction aiming at the synthesis of compound 149 was performed with the substrate 140 (Scheme 38), using the hydrogenolysis conditions of allylic alcohols reported by House [176, page 23].When diol 140 in EtOH was submitted to hydrogenation (55 psi of hydrogen) with Pd-C, a compound identified as 153 was obtained as a result of hydrogenolysis of the bond C9-OH and hydrogenation of tetrasubstituted double bond C1-C10.Attempt to perform only hydrogenolysis of the bond C9-OH on diol 140 without reduction of double bond C1-C10 was carried out using a less reactive catalyst (PdS-C) than Pd-C in EtOH under low hydrogen pressure (5 psi).After the reaction time (1.5 h, r. t.), the substrate 140 was recovered in mixture with 149 and 153 in a respective proportion of (4 : 3 : 3) [150].Hydrogenation of allylic alcohol 140 using a low hydrogen pressure (5 psi) during a short reaction time (15 min) generated the target compound 149 as the main product of this reaction in mixture with the lactone 153 in a respective proportion of (8 : 1), according to 1 H NMR spectrum of crude product from that reaction.The probable causes from the low reactivity of allylic alcohol 139 in catalytic hydrogenation reaction with NaOAc, in opposition to the high reactivity of the similar allylic alcohol 140 without the use of NaOAc, were reported in a recently published work [171].Elimination of methanol on the compounds 149 and 153 generated the respective α-methylene-γ-lactones micheliolide (155) and 1R,10R-dihydromicheliolide (154) (Scheme 38).

Study of the Inversion Reaction of the Lactonic Fusion on
Eremanthine Derivatives.The inversion of configuration at C-6 position on eremanthine derivatives was studied with the substrates 85, 130, 154, and 156-158 shown in Scheme 39.These substances were prepared from eremanthine (1) by simple standard procedures and were described in recent articles [168][169][170].After exposure of these substrates to reaction conditions of inversion of the lactonic fusion, epimeric mixtures at C-6 were obtained in different proportions (Scheme 39).The variations in the proportions of products with cis lactonic fusion obtained in that work were attributed to steric effects at the hydroazulene system.A detailed discussion on the probable causes of variation in the proportions of products with cis lactonic fusion displayed in Scheme 39 was reported in a recent article and in its supplementary information [170].The author would like to make a correction on the major product of the inversion reaction of lactonic fusion of the allylic acetate 156 (Scheme 39) previsously described in a congress abstract [167].The major product obtained in that reaction is the allylic acetate 163 and not the allylic alcohol 162 as it was written in an equivocal way in that abstract [167].
An intriguing result was obtained in the reaction of diol 140 with aqueous NaOH in refluxing DMF (Scheme 40).The product of this reaction was identified by 1 H NMR as a mixture of epimers 141 and 162 (3 : 1).After acetylation of this mixture with Ac 2 O and pyridine, the major product 156 was separated and then used in reaction of inversion of the lactonic fusion (Scheme 39) [170].The author would like to explain that the allylic acetate 156 was obtained for the first time in his works of scientific initiation [166] and M.S. [150] and not as it was previously described in an equivocal way [167].It was reported in the congress abstract [167] that the substance 156 had been obtained in a work of Ph.D. [16], but the compound obtained in that thesis [16] was the diol 141 (Scheme 32).Reinvestigation of the methanol elimination on diol 140 using MeCN as the solvent of reaction resulted in generation of the epimeric mixture 141 and 162.The major product of that reaction was the epimer 162 with cis lactonic fusion obtained in a proportion of (6 : 5) ( 1 H NMR) in relation to compound 141 (Scheme 40) [170].The allylic alcohol 162 and its correspondent allylic acetate 163 possess the necessary structural requirements to unchain the rearrangements preconized by the hypothesis of the biotransformation of guaianolide into pseudoguaianolide (ambrosanolide) reported by Fischer et al. [14].
It was verified at the step of inversion of the lactonic fusion on isoeremanthine (85) that the use of concentrated solutions of that substrate in THF generated 6-epiisoeremanthine (159) in mixture with a minor product identified by 1 H NMR as the compound 166 (5 : 1) (Scheme 41) [170].The allylic alcohol 133, was obtained when iodohydrin 139 was treated with zinc and acetic acid in refluxing EtOH (Scheme 42).The speculative mechanism of this reaction was published in a recent article [170].

Study of Catalytic Hydrogenation and Methanol Addition to α-Methylene-γ-Lactone of Eremanthine Derivatives.
Besides the sequences of reactions described in the previous subitem (6.11), Alves [171] also studied the reactivity of allylic derivatives 127, 128, 133, and 140 in catalytic hydrogenation reactions as well as the methanol addition to α-methylene-γ-lactone of iodohydrin 111 (Scheme 43).Catalytic hydrogenation of iodohydrin acetate 127 in EtOH with hydrogen and Pd-C yielded a single product identified by 1 H NMR as the allylic acetate 167.On the other hand, catalytic hydrogenation of allylic alcohol 128 in EtOH with hydrogen and Pd-C furnished a complex mixture of substances.After a meticulous analysis of the 1 H NMR and 13 C NMR spectra, in combination with the calculations of molecular modeling, it was verified that the mixture obtained in the reaction was composed by intermediates that did not totally react and two products were resultant from hydrogenation of the reactive functions of the substrate 128, characterized as the isomers 168 (major) and 169 (minor).Hydrogenation of allylic alcohol 133 afforded a mixture of products characterized by 1 H NMR as the compounds 170 and 171 (5 : 1) in mixture with traces of the lactones 172 and 173.The stereochemistry of methyl groups C-14 and C-15 at the major product 170 was determined by NOE experiment.The catalytic hydrogenation reaction of allylic alcohol 140 using the catalyst Pt-C and low hydrogen pressure generated the compound 153 in quantitative yield.The treatment of iodohydrin 111 with a solution of NaOMe in methanol at room temperature furnished a single product characterized by 1 H NMR as the dimethoxylated compound 174, as result of methanol addition to α-methylene-γ-lactone and nucleophilic substitution at C-15.
The catalytic hydrogenation of allylic alcohol 140 in mixture with its epimer at C-11 position (175), followed by the step of methanol elimination, generated a mixture of compounds 154 and 176 (Scheme 44).This result suggests that the addition of hydrogen to double bond C1-C10 on this mixture of allylic alcohols is induced by the group CH 2 OMe at C-11 position.A detailed discussion on the reactivity of allylic derivatives from eremanthine shown in Schemes 43-44, in catalytic hydrogenation reaction, was presented in a recently published work including analysis of molecular modeling with the use of molecular mechanic tools (MM2 calculation) [171].

Conclusions
This review about the chemistry of eremanthine (1) has demonstrated the usefulness of the chiron approach to the syntheses of other sesquiterpene lactones derived from 1, by the use of a building block with well-established stereocenters as starting material.From the described synthetic studies it was possible to know the reactivity of several functional groups at the compound 1 as well as in other derivatives obtained from 1.Although the chemistry of eremanthine and its derivatives has been quite explored, there is still opportunity for new discoveries and syntheses of new substances by using this natural sesquiterpenoid as starting material.

Scheme 16 :
Scheme 16: Basic strategies to construction of the hydroazulene skeleton.
with equimolar amount of m-chloroperbenzoic acid resulted in almost exclusive formation of epoxide 98 which upon reaction with HCl in THF gave a mixture of chlorohydrins 99 and 100 (3 : 7).Epoxidation of 99 led to a nearly equimolar

Scheme 29 :
Scheme 29: Syntheses of eremanthine derivatives to the study of13 C NMR spectroscopy.
of reactions developed in that study is depicted in Scheme 28.Epoxidation of eremanthine (1) gave the diepoxide 109 which was submitted to reaction with KI and acetic acid to furnish a mixture of epoxide 110 and allylic alcohol 111.Catalytic hydrogenation of these compounds gave, respectively, the epoxide 112 and diol 113.Treatment of compound 112 with HClO 4 resulted in the formation of diol 113 instead of the pseudoguaianolide 114.Reaction of diol 113 with the acids BF 3 •OEt 2 or p-TsOH furnished a mixture of dienes 115 and 116 instead of the desired compound 117 with pseudoguaianolide skeleton.The nonformation of the substances 114 and 117 with pseudoguaianolide skeleton reinforces, once again, the hypothesis that the formation of those compounds with lactonic fusion at the C-6 and C-7 positions need a β-oxygenated function at the C-6 position of the precursor guaianolide for the occurrence of

Scheme 37 :
Scheme 37: Initial attempts to the synthesis of compound 149.

Scheme 40 :Scheme 41 :
Scheme 40: Inversion of configuration at C-6 position of the diol 141 occurred at the step of methanol elimination on adduct 140.
Sequence of reactions used for the selective isolation of α-methylene-γ-lactones from Vanillosmopsis erythropappa.

1 86 9 85 88 89 90 87 10 91
, whose retrosynthetic analysis is presented in Scheme 17.In this strategy, the compound 1 (65)hesis of Eremanthine.The steps that were employed by Yuuya et al.[12]to obtain eremanthine (1) starting from α-santonin(65), by the strategy outlined in Scheme 17, are depicted in Scheme 18.The starting material used for the synthesis of key intermediate 64 was the α, βunsaturated ketone 66, which was prepared from α-santonin (65) in six steps with an overall yield of 59% (Scheme 18).Ketalization of 66 and subsequent isomerization of double bond at C-2 by heating in ethylene glycol and TsOH gave Solvolytic rearrangement of 64 with a solution of KOAc in AcOH provided a mixture of tetra-, tri-, and disubstituted olefins 72, 21, and 73 in a respective proportion of (2 : 1 : 2.4).After separation of crude product from the reaction by preparative HPLC, a fraction with a mixture (1 : 1.6 : 4) of 72, 21, and 73 was submitted to the following step of phenylselenylation with LDA and diphenyl diselenide to afford epimeric mixtures at C-11 of phenylseleno lactones 74 and 75 along with the lactone 76.
the ketal 67 as the main product of that reaction.The acidic hydrolysis of compound 67 gave the ketone 68, which was submitted to subsequent step of dehydrogenation with DDQ and TsOH to furnish the exo-dienone 69 as the major product.Treatment of this compound with zinc amalgam in refluxing AcOH gave γ, δ-unsaturated ketone 70.Selective reduction of the C-1 carbonyl group of 70 with LiAl(t-BuO) 3 H furnished the desired β-alcohol 71 as the major product of that reaction.Mesylation of 71 with MsCl and pyridine gave the mesylate 64.
was submitted to reaction with one [148]alent of bromine at kinetic conditions (Schemes26- 27).A detailed discussion on the probable mechanisms for these reactions of bromine addition is presented in the article published in 1980[157].6.6.Biomimetic Transformations of Eremanthine.Chemical transformations of eremanthine (1) were studied by Rodrigues[148]aiming to obtain subsidies for the biogenetic hypothesis of pseudoguaianolides formation.The sequence Scheme 34: Methanolysis of the iodohydrins 111 and 127 and epoxide 125.
[172]e 44: Synthesis of the compound 176 in mixture with the lactone 154: (a) (i) H 2 , Pd-C, EtOH; (ii) NaOH-H 2 O, DMF.is instantly converted to the final products of elimination(151 and 152).Therefore, the subsequent and unnecessary step of reduction with NaBH 3 CN was not performed on that occasion of his academic formation (M.S.).It is important to emphasize in this point that the strategy aiming to deoxygenate the C-9 position of allylic acetate 148 and allylic mesylate 150 was unsuccessful due to the following reasons.In the case of the photolysis reaction, the method described by Deshayes et al.[172]is applied to nonactivated carboxylic esters.Evidently the allylic acetate at the substrate 148 is an activated moiety but the chemistry is an experimental science and the author, in that time, should test this reaction with the substance 148 to confirm experimentally the data of literature and know how to execute the reaction in a photochemical reactor.In the case of the attempt to isolate the allylic mesylate 150, this was impossible because electron- [150]3 CN/HMPA (r.t.) furnished dienes (Δ 1,2 , Δ 9,10 ) ( 1 H NMR 200 MHz, CDCl 3 , 5.85, m, 1H, C2-H)[166].On that time, in which that abstract was written with the results from scientific initiation of the author, his supervisor described the 1 H NMR data of only one elimination product (compound 151).For the occasion of the M.S., the author obtained the 1 H NMR spectrum of the crude product from the mesylation reaction described in Scheme 37 and he detected the presence of the conjugate dienes 151 and 152 (1 : 1)[150], concluding that the mesylate 150 is formed and it