Study of the Inversion Reaction of the Lactonic Fusion on Eremanthine Derivatives

As α-metileno-γ-lactonas 4(15)-diidroeremantina (8), 4(15),9(10)-tetraidroeremantina (9), isoeremantina (10), acetato alílico Δ (11), 1(R),10(R)-diidromiqueliolido (12) e 4α-hidróxi acetato alílico Δ (13) foram sintetizadas a partir do produto natural abundante eremantina (1). Essas substâncias foram submetidas à reação de hidrólise com KOH aquoso e os sais carboxílicos dessas lactonas tiveram suas hidroxilas ativadas na posição C-6, pela formação dos respectivos mesilatos (MsCl, Et 3 N, THF ou DMSO) para deslocamento nucleofílico efetuado pelo grupo carboxilato. A utilidade dessa metodologia foi investigada para a obtenção de guaianolidos com fusão lactônica cis na posição C6-C7 e para sintetizar um precursor para estudo posterior da transformação biomimética de guaianolidos em pseudoguaianolidos.


Introduction
Sesquiterpene lactones, with their several skeletons, constitute a great class of natural products generally found in Compositae family. Among these sesquiterpenolides, two groups of substances have received considerable attention in what refers to isolation and synthesis, due to their biological properties and varied structural patterns. These substances are the guaianolides and their biogenetical derivatives, the pseudoguaianolides. 1 Guaianolides have the skeleton of bicyclo [5.3.0]decane, characteristic of sesquiterpenes denominated guaianes, to which was inserted at positions C-6 and C-7 or C-7 and C-8 a γ-lactonic ring containing in C-11 a methyl group or a vinylic methylene and at positions C-4 and C-10 methyl groups or vinylic methylenes. As examples of guaianolides we can cite eremanthine (1), a schistosomicidal substance isolated from Brazilian compositae Eremanthus elaeagnus and Vanillosmopsis erythropappa, 2 and gaillardin (2) 3 ( Figure 1).
Pseudoguaianolides also have the skeleton of bicyclo [5.3.0]decane to which is associated a γ-lactonic ring. They usually have a β-methyl group at C-5 position and are classified as ambrosanolides and helenanolides according to the stereochemistry of methyl group at C-10; in other words, ambrosanolides have β-methyl and helenanolides an α-methyl in this position. Damsin (3) 4 and carpesiolin (4) 5 are ambrosanolides and helenalin (5) 6 and aromatin (6) 7 are helenanolides examples (Figure 2).

Strategies for the syntheses of eremanthine derivatives
Previous studies on the lactonic fusion inversion of eremanthine (1) led to the synthesis of 6-epi-eremanthine (7) (see Figure 3) that was shown unstable. Such instability was attributed to conformational effects of hydroazulene system 9 that resulted in a high tension at the lactonic ring, evidenced through its infrared spectral data. 10,11 Due to the instability of synthesized 6-epi-eremanthine, it was intended to evaluate the reactivity of eremanthine derivatives in the reaction of lactonic fusion inversion, in order to obtain more stable epimers.
For this study of stereochemical inversion on the C-6 position, it was idealized to synthesize substances derived from 1 differing in the unsaturation degree as well as in the positions of double bonds at the hydroazulene system. Such procedure would result in the formation of substances, that we denominated as models, with different conformations and steric interactions among their functional groups, due to the flexibility of the system in study. Therefore, the models 8-13 ( Figure 3) were selected to be submitted to conditions of lactonic fusion inversion.
The synthesis of substance 8 was idealized through the chemoselective reduction of double bond C4-C15 at the eremanthine methoxy derivative (14), with hydrogen and catalyst, followed by restoration of α-methylene-γ-   645 Alves and Fantini Vol. 18, No. 3, 2007 lactone for methanol elimination. 12 The synthesis of substance 9 was planned in the same conditions employed in the conversion of 14 in 8 using, in this case, more drastic conditions of hydrogen pressure during the stage of catalytic hydrogenation, since trisubstituted double bond (C9-C10) is less reactive than disubstituted double bond (C4-C15). Isoeremanthine (10) was previously synthesized from isomerization of double bond C4-C15 of eremanthine (1) to C3-C4 position and it would be obtained by the same procedure. 13 For the synthesis of allylic acetate 11 we planned to obtain it through an elimination step of iodohydrins 18-19, previously described, 14 by metal in acid medium to generate the respective products 16 and 11. 15 In the case of allylic alcohol 16, it would be made an additional stage of protection at the hydroxy group in C-9 position through an acetylation reaction for obtention of compound 11. Alternatively, substance 11 would be obtained starting from iodohydrin 20, 8 by the same procedure used in the conversion of 18 in 16, followed by stage of methanol elimination commonly used with eremanthine derivatives 12 and subsequent acetylation of hydroxy group at C-9 position. Substance 12, previously synthesized from diol 21, 8 would be obtained by the same procedures. Substance 13 would be obtained by simple reaction of methanol elimination accomplished on compound 21, previously described, 8 followed by acetylation of hydroxy group at C-9 position.

Results and Discussion
The syntheses of models 8-13 were performed according to conditions described in Scheme 1.
Initially, eremanthine methoxy derivative (14), obtained from previously described procedure, 8 was submitted to hydrogenation reaction catalyzed by palladium on charcoal using a hydrogen pressure of 40 psi at the conditions i described in Scheme 1. After the time of reaction, a product was isolated and then submitted to 1 H NMR. The spectrum indicated that we obtained a mixture of epimers at C-4 position, in the proportion of 1:1, due to the presence of singlets with same intensity at δ 3.34 and 3.33 ppm relative to hydrogens of methoxy groups, as well as the doublets of methyl groups C15-H at δ 1.13 (J 6.6 Hz) and 0.94 (J 6.2 Hz). In the step ii, we submitted the mixture of intermediate epimers, resultant of hydrogenation of 14, to stage of methanol elimination for restoration of α-methylene-γ-lactone. Crude product was purified by column chromatography to give a 1:1 mixture of epimers 8a and 8b, identified by 1 H NMR.
For the synthesis of model 9 it was used the conditions iii-iv described in Scheme 1. The crude product obtained in these two steps was purified by column chromatography and then submitted to 1 H NMR. The spectrum revealed that we obtained a mixture of 3 substances in a proportion of 2:5:3, measured by  energies (Table 1), by using MM2 program, 16 for the probable products (23a-d) obtained after stage of catalytic hydrogenation, we can deduce that the products of this reaction in crescent order of steric energy are the substances 23a-c, that submitted to subsequent stage of methanol elimination give as final products the respective diastereoisomers 9a-c. According to proportion of the three products verified at the 1 H NMR spectrum, we can do the following suppositions: as the substances 22a and 22b are generated in same amounts and being considered that formation of compound 23d is disfavored due to steric effects of two bulky methyl groups both in axial β-position (C14-H and C15-H), we can conclude that compound 22b just generates a diastereoisomer, the compound 23c (50% of the mixture). Compound 22a, for its time, will be responsible for the formation of the other 50% of the mixture. In this case as product 23a, with the bulky methyl groups C14-H and C15-H in equatorial α-position, presents less steric interactions than product 23b that has the bulky methyl group C14-H in axial β-position and C15-H in equatorial α-position, we can expect that 23a are in a larger proportion in the mixture than compound 23b (30% versus 20%). These substances when are submitted to stage of methanol elimination give their respective α-methylene-γ-lactones 9c, 9a and 9b in a respective proportion of 5:3:2.
For the synthesis of model 10, previously described, 13 we used conditions v (Scheme 1). After the time of reaction, a product was isolated and then identified as isoeremanthine (10) by spectroscopy methods. This substance was obtained with high purity, evidenced at the TLC and at their NMR spectra not needing, therefore, of additional purification.
For the synthesis of model 11, previously described, 15 we employed conditions vi-ix as outlined in Scheme 1. Epoxidation of eremanthine (1) with diluted solution of peracetic acid in chloroform, in conditions vi, generated a product identified as diepoxide 15. This substance was previously obtained in the same conditions described in Scheme 1 using dichloromethane as the solvent of reaction. 17 Opening of oxiranic rings of crude product 15, in acid medium, with equimolar amount of KI and reflux of acetone (step vii) generated a product that was purified by column cromatography and then identified as iodohydrin 18. Acetylation of substance 18 at the conditions viii yielded acetate 19. When the substances 18 and 19 were submitted to elimination conditions by metal in acid medium (step ix) it was obtained the respective trienes 16 and 11 in almost quantitative yield. These substances were obtained with high purity evidenced at the TLC and at their NMR spectra no needing, therefore, of additional purification. Soon afterwards the hydroxy group at C-9 position of compound 16 was protected to give allylic acetate 11 (step viii). This protection stage of allylic alcohol 16 was accomplished in order to avoid elimination reaction when exposed to MsCl/Et 3 N during step of lactonic inversion, since previous attempts of obtaining the mesylate at C-9 position derived from allylic alcohol 20, gave elimination products with formation of conjugate dienes. 18 When this same elimination reaction by metal in acid medium (step ix) was accomplished on iodohydrin 20, for our surprise we obtained substance 24 instead of the expected product 25. After analysis of three-dimensional structures of the molecules involved in these processes of chemical transformations, by using MM2 program, 16 we verified that substances 25 and 16 have different conformations at the hydroazulene system (Scheme 3).
Cycloheptene ring, that commands the geometry of hydroazulene system, is in the chair form at substance 16, with a plane of symmetry passing through the C-7 position (C 7 ) while substance 25 has the seven-membered ring in twist-boat conformation with a pseudo-C 2 axis passing through the C-8 position (TB 8 ). 9 Conformations of the seven-membered ring of substances 16 and 25, obtained in the MM2 program 16 are shown at the Figure 4.
Starting from these observations, we concluded that substance 25 is initially generated as expected and then it should react with zinc species (I-Zn-OH) 11 obtained as subproducts of iodohydrin elimination, to give allylic alcohol 24. In the case of allylic alcohol 16, the subsequent isomerization reaction of double bond C1-C10 to C10-C14 position, catalysed by I-Zn-OH, should not occurs due to probable steric effects of conformation at this molecule that do not favor complexation of I-Zn-OH with the oxygen of hydroxy group at C-9 position and C-10 sp 2 carbon which concentrates a high electronic density. The free-radical mechanism depicted in Scheme 4 was proposed to reaction of reactive intermediate 25 with I-Zn-OH. In this case, the stereochemistry at C-1 position would be defined by stability of the final product, in other words, the radical B would react with the radical H . to generate the more stable isomer (24). This kind of zinc species complexation, between two sterically related functional groups, was previously proposed to reactions of iodohydrin 18 with zinc in acid medium and methanol as the solvent, in the generation of O 6,15 -cycloguaianes derived from eremanthine. 11,14 The structure of substance 24 was confirmed by comparison of its 1 H NMR, IR and R f data with the ones of this substance, previously obtained by opening of epoxide 9,10-α-epoxy-eremanthine in acid medium, followed by a protection stage of α-methylene-γ-lactone with methanol and sodium carbonate. 17 Moreover, analysing three-dimensional structures of compounds 24 and (24)-1-epi, obtained by MM2 program, 16 we can verify differences at these isomers that would implicate in different values of chemical shifts at the signals of hydrogens of two substances, mainly at the signal of C6-H (see Figure 5). At the isomer 24 this hydrogen is located at shielding area of double bond C10-C14 located in βposition. In the isomer (24)-1-epi this shielding effect should be attenuated, due to the change of conformation that puts double bond C10-C14 in α-position, opposed to hydrogen C6-H. These additional data of molecular modeling contributed to confirm the stereochemistry at C-1 position of substance 24, since we had obtained the isomer (24)-1-epi its 1 H NMR data would be substantially different from those in reference 17.
The initial formation of reactive intermediate 25 in the generation of product 24, described in Scheme 3, was confirmed in an experiment in which the reaction depicted in Scheme 1 (step ix) was interrupted after 10 minutes from its beginning. The TLC of crude product obtained in this reaction revealed the presence of two substances, with practically identical R f . This mixture was submitted to 1 H    Table 2. The synthesis of substance 12 was described in a recent article about chemical transformations of eremanthine (1). 8 When diol 21 was submitted to step ii of methanol elimination depicted in Scheme 1, it was obtained a mixture of two products with practically identical R f in a proportion of 3:1, measured by integrals relative to the signals of C13-H of the two products at 1 H NMR spectrum. Major product corresponded to diol 17 previously described 11 and minor product was later characterized as epimer 27, for occasion of the lactonic inversion reaction of substance 17 protected in the form of its allylic acetate 13, by comparison of 1 H NMR spectra obtained by the two procedures. Soon afterwards the mixture of epimers 17 and 27 was submitted to protection stage viii (Scheme 1) of hydroxy groups at C-9 position. The major product of this reaction was separated by column chromatography and then identified as allylic acetate 13 for spectroscopy Alves and Fantini Vol. 18, No. 3, 2007 methods. This epimeric mixture, obtained at the stage of methanol elimination, was only verified with substance 21 containing double bond at the C1-C10 position of hydroazulene system. This facility to generate product with inversion of configuration at the C-6 position of diol 17 was verified for occasion of the study of lactonic fusion inversion on eremanthine derivatives.
After the preparation of models 8-13 we started the study of the lactonic fusion inversion on these compounds.

Reactions of the lactonic fusion inversion on eremanthine derivatives
The study of the transformation of eremanthine derivatives with trans lactonic fusion into substances with cis lactonic fusion was accomplished by stereochemical inversion on the alkoxy carbon of the lactonic ring. There are three classic methods to make the configuration inversion on secondary hydroxy groups: the first of them is the traditional method of oxidation-reduction, 19 in which a hydroxy group is oxidized in a first stage to a ketonic carbonyl group, for in the following stage to be stereoselectively reduced by hydride, to give in the end a hydroxy group with opposite stereochemistry to that of initial secondary alcohol. The inversion of configuration of secondary hydroxy groups can also be made through Mitsunobu's reaction, 20 in which occurs the activation of hydroxy group in a first stage by formation of an alkoxyphosphonium, for soon afterwards to occur the nucleophylic displacement of this activated leaving group. In the last case, we can cite the method of hydroxy activation by formation of correspondent mesylate, in which the inversion of configuration occurs by nucleophylic displacement of mesylate leaving group. 21 For the study of stereochemical inversion on alkoxy carbon of the lactones derived from eremanthine (1), we opted for the use of intramolecular displacement of mesylate, since this reaction was previously well described during the stereochemical inversion on the alkoxy carbon of a γlactone with hydroazulene skeleton 22 and during the synthesis of 6-epi-eremanthine. 10,11 Attempts to make inversion of configuration on alkoxy carbon of a γ-lactone with hydroazulene skeleton by displacement of alkoxyphosphonium 22 or by oxidation-reduction on C6-OH of an eremanthine derivative 10,11 were unsuccessful.
To study the lactonic fusion inversion on eremanthine derivatives, we used the reaction conditions outlined at Scheme 5 and previously described for the synthesis of 6epi-eremanthine. 10,11 Therefore, the models 8-13 were submitted to reaction conditions depicted in Scheme 5, in which at the stage i starting materials (A) were treated with aqueous solution of potassium hydroxide to generate the correspondent carboxylates (B). At stage ii, we proceeded to evaporation of water and then dryness of residual product in high vacuum. At stage iii dried carboxylates (B) were submitted to treatment with trietylamine and mesyl chloride, conditions wherein sulfene is generated. This reactive species should react with carboxylates in a reversible way to give intermediates such as C, while the reaction of sulfene with the hydroxy group at C-6 should be unreversible to generate intermediates as D. 22 Soon afterwards, the intramolecular nucleophilic substitution (SNi) should occurs at the intermediates D to give the compounds E with cis lactonic fusion, along with any mesylates D that did not react. At stage iv it was used aqueous solution of sodium hydroxide to hydrolize any mixed anhydrides (C) as well as the mesylates at C-6 (D) that did not suffer nucleophilic displacement by carboxylates. At stage v aqueous solution of hydrochloric acid was added until pH 3 to convert the carboxylates into respective hydroxy-acids in order to lactonize them giving, in the end, epimeric mixtures at C-6 (A + E). Crude products of the reactions depicted at Scheme 5 were extracted with organic solvent and then submitted to 1 H NMR. The proportion of epimeric products obtained in these reactions was measured by the integrals relative to the signals of C13-H. A common characteristic observed at 1 H NMR spectra of products with cis lactonic fusion is related to position of the signals relative to these hydrogens. It was verified at spectra of epimeric mixtures of models 8-13 that all products with cis lactonic fusion presented the signals of C13-H located in higher values of chemical shifts in relation to the ones of substances with trans lactonic fusion. In the cases in which starting materials, with trans lactonic fusion, had double bond at C1-C10 or C9-C10 positions, a deshielding effect was verified at the hydrogen C6-H of their epimers evidenced at the respective 1 H NMR spectra. This deshielding effect observed at the C6-H signals of products with cis lactonic fusion was attributed to position change of these hydrogens that passed from the axial position at products with trans lactonic fusion (located at shielding area, on the electronic cloud of double bonds C1-C10 or C9-C10) to equatorial position, no more on the respective electronic clouds. The cis fusion at the products of lactonic inversion was verified by equatorial-equatorial coupling constants at the C6-H signals. Products of lactonic fusion inversion of models 8-13 are depicted in Table 3 and chemical shifts of the main hydrogens at starting materials and products of inversion reactions are in Table 4.
Initially, some experiments were accomplished with isoeremanthine (10), varying concentrations and times of reaction, in order to verify the ideal conditions for the  Table 3. Alves and Fantini Vol. 18, No. 3, 2007 reaction of lactonic fusion inversion. The choice of substance 10 to study the optimization of this reaction was due to the easy access from eremanthine (1) in just a step. In one of the experiments in which the lactonic inversion reaction was executed with 0.1 mol L -1 solution, it was obtained 6-epi-isoeremanthine (36) in mixture with a subproduct identified by 1 H NMR as the dymer 44. The proportion of these two substances was 5:1 in favor of 6epi-isoeremanthine (36). Substance 44 resulted from an intermolecular reaction of nucleophilic substitution between two molecules of carboxylate 42, as speculative mechanism outlined in Scheme 6. The main chemical shifts for the hydrogens of dymer 44 observed in its 1 H NMR spectrum are shown in Table 5. As the hydroazulene system has different conformations, we display in Table 6 conformational diagrams of the seven-membered rings that command the geometry of this system in study, for the models 8-13 and their respective products of lactonic fusion inversion, obtained with the MM2 program. 16 In Table  7 are depicted the torsion angles for these substances obtained in the MOPAC program. 16 The sevenmembered rings presented in Table 6 were analyzed in the form of two different models: the cycloheptane and cycloheptene. These models can present themselves in the basic conformations such as chair (C), twist-chair (TC), boat (B) and twist-boat (TB). 9 The substance 11 (Exp. 4 - Table 3) was totally unstable to conditions of lactonic fusion inversion. After the end of reaction, it was verified the formation of an insoluble organic pellicle at surface of solution, with aspect of a polymeric product. This supposed polymeric product was removed from the reaction middle by filtration and resulting mixture was extracted with organic solvent. It was obtained a product with moderate yield (46%) that was submitted to 1 H NMR. At the spectrum were observed the singlets of acetate group and C14-H at δ 2.01 and 1.69 ppm, respectively. With the enlargement of spectrum signals between δ 6.50 and 3.50 ppm it was possible to visualize and to attribute by attempts the signals of C15-H and C9-H to the multiplets at δ 5.30 -4.80 ppm and the methylenes of γ-lactone to the superposed doublets at δ 6.30 -6.10 and δ 5.60 -5.35 ppm. A broad doublet at δ 4.19 ppm with coupling constant of 5.5 Hz suggested the presence of a γ-lactone with cis fusion. After experiment to obtain the 1 H NMR spectrum, it was made a TLC in which was detected decomposition of the material submitted to NMR, due to the presence of several stains on the plate.
The carboxylic salt 41 was not much soluble in the solvent THF that we chose to study the reaction of lactonic fusion inversion on the models presented in Table 3. Due to this property we performed the Experiment 6 ( Table  3), in which the reaction was executed with DMSO. The reduction in the yield of crude product at this reaction was attributed to losses in the partition phase due to the high polarity of the used solvent (DMSO). Moreover, it was verified a reduction in the conversion rate to epimeric product 27. The 1 H NMR spectrum of crude product from Experiment 6 was identical to that previously obtained in the stage of methanol elimination on diol 21 (see Scheme 1 -step ii), from where it was confirmed that the subproduct obtained in that reaction was the epimer 27. At the Experiment 7 (Table 3) this reaction was performed with THF and we obtained the epimer 28, with cis lactonic fusion, in a double proportion of that obtained at the Exp. 6. Surprisingly, the acetate protection group stayed intact at the product 28 [δ 2.00 (s, 3H, -OCOCH 3 ) and 5.09 (m, 1H, C9-H) -1 H NMR], suggesting that hydrolysis of this protection group in the solvent THF occurs in a slower rate than the one of the acetate at the substance 13.
After verification that the configuration inversion on C-6 position of substance 17 could be done directly, starting from diol 21 at the stage of methanol elimination, we decided to investigate this reaction with more details. Initially, we planned to substitute DMF commonly employed at the reactions of methanol elimination on eremanthine derivatives, for a polar aprotic solvent of lower ebullition point, the acetonitrile. Such procedure was idealized in order to facilitate the isolation of product since the use of DMF, with high ebullition point, turned more difficult the purification process of the elimination products. The starting material initially used on the methanol elimination with the new solvent (CH 3 CN) was the methoxy derivative 14, due to the easy access from eremanthine (1) in just a stage. The reaction was executed at the conditions described in Scheme 7. After the time of reaction, crude product was extracted and it was verified by TLC total regeneration of eremanthine (1) with excellent yield and chromatography purity. With this satisfactory result, we performed the elimination reaction with diol 21 (Scheme 8). After the time of reaction, crude product was extracted and then submitted to 1 H NMR. The spectrum showed the

Stereochemical considerations
From the results described in Table 3 for the reactions of lactonic fusion inversion of models 8-13, we can deduce that intramolecular nucleophilic substitution, responsible for configuration inversion on C-6 position of the γ-lactones in study depends on geometric factors, intrinsic to molecular structure of each substance, that favor the attack of carboxylate to carbon containing the mesylate leaving group. Besides the favorable geometry of reactive substrate to attack by carboxylate, it should also be considered the stability of final product with cis lactonic fusion as well as the conformational interconversions, whose transitions from a particular form to another one generally involve high energies. 23 Therefore, the low proportions of products with cis lactonic fusion obtained in the Exp. 2, 3 and 5 (Table 3) were attributed to conformational effects in the hydroazulene system that turned the C-6 position of substrates disfavored to attack by carboxylate, as well as to the changes of conformation in the system, passing from stableer conformations in the substrates to conformers with higher steric energies at products with cis lactonic fusion, according to theoretical calculations obtained with MM2 program. 16 Due to the few steric interactions observed in the model 11 (Exp. 4 - Table 3), the probable successive intermolecular reactions by attack of carboxylate to C-6 position at the reactive intermediate mesylate, resulted in the formation of supposed polymeric subproducts obtained in this reaction. The good conversion rate to product with cis lactonic fusion, obtained by the model 8 (Exp. 1 - Table 3) was attributed to favorable geometry of the carboxylates to attack the C-6 positions of reactive intermediates containing the mesylate leaving groups, as well as the generation of products (32a-b) with less steric interactions than the substrates (8a-b). The best result obtained by the model 13 (Exp. 7 - Table 3) was attributed to favorable geometry of the system for the reaction of lactonic inversion and for not having conformational interconversion in the seven-membered ring, during the transformation process of the substrate (13) into product with cis lactonic fusion (28) (see Table 6).

Conclusions
The results obtained in this work have demonstrated that allylic acetate 13 emerged as a promising substance for subsequent preparation of its epimer 28 in a multigram scale. Compound 28 was obtained with a good conversion rate starting from substrate 13 and it was stable in the reaction conditions of lactonic inversion. Moreover we  Although this mixture of epimeric allylic alcohols has presented separation problems for column chromatography of silica gel, due to the high polarity and proximity of their R f , their correspondent allylic acetates 13 and 28 were easily separated. Allylic acetate 28, with cis lactonic fusion, has the necessary structural requirements to unchain the rearrangements preconized by the hypothesis of pseudoguaianolides biogenesis, 24 in other words, α-hydroxy group at C-4, oxygen at β-position at C-6 and a potential cationic center at C-1. These results allow us to idealize the possibility of obtaining the substance 28 for one of the two epimerization methods developed in this work, for an eventual study of biomimetic transformation of guaianolides into pseudoguaianolides.

Experimental
Infrared spectra (IR) were recorded on a Perkin-Elmer 1420 spectrophotometer, using either thin films on NaCl plates (film) or KBr discs. NMR spectra were recorded on a Hx 1 H-COSY. Multiplicities of the signals of carbon-13 were obtained using a DEPT sequence. Low resolution mass spectrum of allylic alcohol 16 was obtained at 70 eV, for electrons impact, on a VG AutoSpecQ spectrometer. Thin layer chromatography was performed on aluminium sheets coated with 60 F 254 silica. Visualization of the substances on the plates of TLC was accomplished under lamp of ultraviolet light (UV) and/or for contact of the plates with silica gel impregnated with iodine and/or spraying with 2% Ce(SO 4 ) 2 in 2 mol L -1 H 2 SO 4 and subsequent heating. Purifications and isolations by column chromatography were performed with silica gel (230-400 mesh). Solvents and reagents were dried and purified by the usual methods. 25 Hydrogenations were carried out using a Parr apparatus. Melting points were taken on a Kofler apparatus and are uncorrected. The values of steric energies and the three-dimensional structures of substances presented in this paper were obtained by using MM2 and MOPAC programs, minimizing energy to minimun RMS gradient of 0.100 and displaying each iteration. 16

General procedure for the reactions of lactonic fusion inversion of substances 8-13
A common procedure is described for the reaction of lactonic fusion inversion of substance 8. To a botton round flask containing the substance 8 (0.013 g, 0.056 mmol) an aqueous solution of 4% KOH (0.36 mL, 0.258 mmol) was added and it was left under magnetic stirring at the temperature and time indicated in Table 3 (Exp. 1). After total solubilization of the substrate, TLC revealed consumption of starting material. The mixture was concentrated under reduced pressure and then dried in high vacuum. The carboxylic salt was dissolved in THF (0.56 mL) and then put in a bath of ice at the temperature of 0 °C under magnetic stirring. Et 3 N (0.055 mL, 0.392 mmol) and MsCl (0.026 mL, 0.336 mmol) were added to solution and after 1 h the bath of ice was removed and mixture was left at room temperature for 3 h. Soon afterwards, an aqueous solution of 0.2 mol L -1 NaOH (0.90 mL, 0.179 mmol) was added and the mixture was put in a bath at the temperature of 50 °C for 1 h. The mixture was allowed to cool at room temperature and an aqueous 10% (v/v) HCl was added dropwise until pH 3. It was diluted with EtOAc (20 mL) and then washed with H 2 O (2 × 20 mL). The organic layer was separated and the aqueous phases were extracted with EtOAc (1 × 20 mL). The organic phases were dried with Na 2 SO 4 , filtered and concentrated in vacuum. It was obtained: crude product (0.012 g, 92%). 1 H NMR (CDCl 3 ): partial assignment for the substance 32 (see Table 4).
Lactonic fusion inversion of substance 9 (Exp. 2 - Table 3) The reaction was executed following general procedure, using 9 (0.016 g, 0.068 mmol) and aqueous solution of 4% KOH (0.44 mL, 0.313 mmol). The dry carboxylic salt was dissolved in THF (0.68 mL) and it was added to resulting solution Et 3 N (0.066 mL, 0.476 mmol) and MsCl (0.032 mL, 0.408 mmol). After the time of reaction, aqueous solution of 0.2 mol L -1 NaOH (1.09 mL, 0.218 mmol) was added and the mixture was warmed in a bath at 50 °C for 1 h. The mixture was neutralized with 10% (v/v) HCl until pH 3 and then extracted with EtOAc. It was obtained: crude product (0.015 g, 94%). 1 H NMR (CDCl 3 ): partial assignment for the substance 34 (see Table 4).
Lactonic fusion inversion of substance 10 (Exp. 3 - Table 3) The reaction was executed following general procedure, using 10 (0.012 g, 0.052 mmol) and aqueous solution of 4% KOH (0.34 mL, 0.239 mmol). The dry carboxylic salt was dissolved in THF (2.40 mL) and it was added to resulting solution Et 3 N (0.051 mL, 0.364 mmol) and MsCl (0.024 mL, 0.312 mmol). After the time of reaction, aqueous solution of 0.2 mol L -1 NaOH (0.83 mL, 0.166 mmol) was added and the mixture was warmed in a bath at 50 °C for 1 h. The mixture was neutralized with 10% (v/v) HCl until pH 3 and then extracted with EtOAc. It was obtained: crude product (0.011 g, 92%). Due to difference of polarity between the two substances of this mixture, we proceeded to purification by column chromatography of silica gel (20% EtOAc / hexane) and it was separated a fraction as a colourless oil, identified as 6-epi-isoeremanthine (36). R f 0.69 (50% EtOAc / hexane). IR (film) ν max / cm -1 : 3050, 2920, 2850, 1765, 1660, 1610, 1460, 1380, 1270, 1155, 820. 1 Table 3) The reaction was executed following general procedure, using 11 (0.011 g, 0.038 mmol) and aqueous solution of 4% KOH (0.25 mL, 0.175 mmol). The dry carboxylic salt was dissolved in THF (0.87 mL) and it was added to resulting solution Et 3 N (0.037 mL, 0.266 mmol) and MsCl (0.017 mL, 0.228 mmol). After the time of reaction, aqueous solution of 0.2 mol L -1 NaOH (0.61 mL, 0.122 mmol) was added and the mixture was warmed in a bath at 50 °C for 1 h. The mixture was neutralized with 10% (v/v) HCl until pH 3, filtered to remove a supposed insoluble polymeric material and then extracted