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Organic Chemistry International
Volume 2010 (2010), Article ID 603436, 11 pages
http://dx.doi.org/10.1155/2010/603436
Research Article

Study of Catalytic Hydrogenation and Methanol Addition to α-Methylene-γ-Lactone of Eremanthine Derivatives

Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, 23890-970 Seropédica RJ, Brazil

Received 29 September 2010; Accepted 4 November 2010

Academic Editor: Emmanuel Theodorakis

Copyright © 2010 José C. F. Alves. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The sesquiterpene lactones guaia-1(10),11(13)-dieno-4α-hydroxy,9α-acetyl-15-iodine-12,6α-lactone (2), guaia-1(10),4(15),11(13)-trieno-9α-hydroxy-12,6α-lactone (3), (11S)-guaia-4(15),10(14)-dieno-9α-hydroxy-13-methoxy-12,6α-lactone (4), (11S)-guai-1(10)-eno-4α,9α-dihydroxy-13-methoxy-12,6α-lactone (5), and guaia-1(10),11(13)-dieno-4α,9α-dihydroxy-15-iodine-12,6α-lactone (6) were previously obtained starting from the natural product eremanthine (1). In this paper we report the catalytic hydrogenation reactions of allylic derivatives 25 and the methanol addition to α-methylene-γ-lactone of the iodohydrin 6.

1. Introduction

In previous publications [1, 2] we reported the synthesis of allylic derivatives 26 from eremanthine (1) (Figure 1). As an extension to our studies on the chemical transformations of eremanthine, we decided to explore the reactivity of allylic derivatives 25 in catalytic hydrogenation reactions [3, 4] as well as the methanol addition to α-methylene-γ-lactone of the iodohydrin 6. In this paper we present the results of the performed study aiming at to evaluate the reactivity of the mentioned reactions.

603436.fig.001
Figure 1: Eremanthine (1) and its allylic derivatives 2–6.

2. Results and Discussion

Eremanthine (1) is one of the principal sesquiterpene lactones obtained from the extracted oil of the pulverized trunk wood of the Brazilian plants Eremanthus elaeagnus [5] and Vanillosmopsis erythropappa [6, 7] (Eremanthus erythropappus) [8], and, therefore, it was available in sufficient amount to accomplish the sequence of reactions shown in Scheme 1.

603436.sch.001
Scheme 1: Reagents and conditions: (i) H2 (50 psi), 10% Pd-C (0.1 equiv), EtOH (r. t., 5 h); (ii) H2 (40 psi), 10% Pd-C (0.1 equiv), EtOH (r. t., 3 h); (iii) H2 (30 psi), 10% Pd-C (0.1 equiv), EtOH (r. t., 1 h); (iv) H2 (5 psi), 10% Pt-C (0.1 equiv), EtOH (r. t., 30 min); (v) MeONa-MeOH (pH 11, r. t., 7 h); Substance previously described [1]; Substance previously described [2].
2.1. Study of Catalytic Hydrogenation of the Allylic Derivatives 2–5

Catalytic hydrogenation of allylic acetate 2 (Scheme 1) led to hydrogenolysis of the bond C15–I and reduction of double bond C11–C13. The 1H NMR spectrum showed a signal at δ 1.24 (d, J 7.3 Hz, 3H) relative to hydrogens of C-13 methyl group besides a signal at δ 1.28 (s, 3H) assigned for C-15 methyl group, the presence of a double doublet at δ 5.32 (J 2.0 and 4.9 Hz) relative to hydrogen C9-H, a singlet at δ 2.04 relative to hydrogens of methyl at the acetate group, and a doublet at δ 1.73 (J 0.9 Hz) assigned for C-14 methyl group. The stereochemistry of C-13 methyl group was studied by theoretical calculations (molecular mechanic level, MM2) [9] and by NMR-comparison with the sesquiterpene lactones 1619 (Figure 2) reported in the literature [1015]. The theoretical calculations of relative stability of the two stereoisomers, using molecular mechanic tools (MM2 calculation) [16], showed that the C-13 methyl group should be in α position (Scheme 2).

603436.sch.002
Scheme 2
603436.fig.002
Figure 2

In order to determine the probable intermediates and final products from the catalytic hydrogenation reaction of the allylic alcohol 3 we used the data of TLC, 1H NMR, and 13C NMR in combination with the calculations of steric energy performed by molecular mechanics (MM2). For a better understanding of stages involved in the transformation of allylic alcohol 3 into the mixture of isomers 8a and 8c (Scheme 1), we elaborate Scheme 3 containing all intermediates and all probable products from catalytic hydrogenation of compound 3, with the respective steric energies. After the time of hydrogenation (3 h), TLC revealed the total consumption of substrate 3 (Rf 0.33, blue with Ce(SO4)2/H2SO4/heat) [17], the predominance of products with Rf 0.70 (orange) and a minimum amount of intermediates with Rf 0.37 (red) and Rf 0.42 (lilac). The crude product from the reaction was submitted to 1H NMR and 13C NMR and the spectra showed a complex profile. After a detailed spectral analysis, we could assign the signals shown at Table 1 and do some considerations on the probable course of the reaction. The absence at the 1H NMR spectrum of signals relative to methylene from the γ-lactone and the presence of signals with almost imperceptible intensity at δ 5.40–5.30 ppm, characteristic of the two olefinic hydrogens C15–H, confirmed the better reactivity of double bond C11–C13 in relation to C4–C15 on the compound 3. The detection of three signals, at the 13C NMR spectrum (δ 77.64, 77.00 and 73.67 ppm), relative to allylic oxygenated carbons C9–OH suggests that the hydrogenation of double bond C11–C13 on the substrate 3 proceeded, as expected, by a stereoselective manner generating the intermediate 20. However, the hydrogen addition to double bond C4–C15 on that intermediate was processed for both α and β faces generating a more stable substance (compound 22) in mixture with the less stable stereoisomer (compound 23). Thus, those three signals at the 13C NMR spectrum, relative to oxygenated allylic carbons, were attributed to the carbons C9–OH of the intermediates 20, 22 and 23. This result was fundamental to determine the preferential course of the catalytic hydrogenation reaction from the substrate 3, in combination with the assignments for the carbons C-6 at the 13C NMR spectrum. Thus, the seven signals detected at that spectrum (δ 89.98, 89.07, 86.49, 86.28, 85.85, 83.10 and 83.00 ppm) were attributed to the oxygenated carbons C-6 of the intermediates that did not totally react (20, 22, 23, 26 and 27) in mixture with the final products 8a (major) and 8c (minor). The only signals easily assigned at the NMR spectra were those of higher intensity attributed to the major product 8a shown at Table 1. Therefore, with these spectral evidences and analysis of the probable isomers obtained in that reaction through the theoretical calculations from molecular mechanics (MM2) we can affirm that the majority product from the catalytic hydrogenation reaction of allylic alcohol 3 is the isomer 8a. In that transformation process the substrate 3 should preferentially pass for the steps outlined in Scheme 4 to generate the more stable product 8a in mixture with the subproduct 8c.

tab1
Table 1: Selected chemical shifts for the hydrogens and carbons of compounds 20, 22, 23, 26, 27, 8a and 8c.
603436.sch.003
Scheme 3
603436.sch.004
Scheme 4

The analysis of catalytic hydrogenation reaction from allylic alcohol 4 by TLC (50% EtOAc/hexane) after 1 hour of reaction (Scheme 1) revealed the total consumption of substrate 4 (Rf 0.25, blue) and formation of products [Rf 0.66 (brownish)]. The stages proposed for catalytic hydrogenation of the substrate 4 are outlined in Scheme 5. The 1H NMR spectrum of product from catalytic hydrogenation of allylic alcohol 4 showed that the double bond C4–C15 and allylic system were totally hydrogenated, due to absence of characteristic signals of olefinic hydrogens and of the hydrogen attached to carbon C9–OH. The spectral data of the generated product were in agreement with the formation of the lactones 11 and 12 previously described in [2] in a respective proportion of (5 : 1), in mixture with traces of more two lactones characterized as 13 and 14 in previously described [2]. This proportion was measured by the integrals relative to signals at δ 3.75 (t, J 10.0 Hz, C6–H of majority product) and δ 4.01 (t, J 9.6 Hz, C6–H of minority product). The multiplets at δ 4.10 and 4.37 ppm were, respectively, attributed to lactonic hydrogens C6–H of minority products 13 and 14. The stereochemistry of methyl groups C14–H and C15–H on the majority product 11 was determined by experiment of intramolecular Nuclear Overhauser Effect (NOE): irradiation of C15–H methyl group at δ 1.09 showed an enhancement of C5–H sinal (α position) at δ 1.92 (10%) and an enhancement of C14–H signal of methyl group at δ 0.93 (5%), indicating that the methyls C14–H and C15–H are both in α position.

603436.sch.005
Scheme 5

The transformation of allylic alcohol 5 into compound 9 has been previously described in a satisfactory manner through catalytic hydrogenation (55 psi of H2, 10% Pd-C, EtOH, r. t., 30 min) [1]. In this paper we report the results modifying the hydrogen pressure and the reaction catalyst. Therefore, the substrate 5 was submitted to catalytic hydrogenation with the use of 5 psi of H2, 10% Pt-C as the catalyst and EtOH as the solvent of reaction, accomplished at room temperature (Scheme 1). After 30 minutes, the mixture was submitted to analysis by TLC. The plate of TLC was eluted 3 times with 50% EtOAc/hexane aiming to verify if there was still the intermediate with double bond C1–C10 (Rf 0.44) that is formed after hydrogenolysis of the bond C9–OH, as reported in previous publication [1], and that reveals in solution of ceric sulfate with lilac coloration. We evidenced the presence of just a stain of orange coloration (Rf 0.41), characteristic of the final product 9 from that reaction. The 1H NMR spectrum of the isolated product showed similar spectral characteristics to the ones of compound 9 previously described in [1]. An important datum regarding the synthesis of compound 9 refers to epimeric purity of substrate 5 at C-11 position. It was verified in the stage of isolation of compound 5 that the heating of that substance in EtOAc on the rotatory evaporator generated a very small amount of a product with lightly superior Rf, characteristic of epimer from the substance 5 at C-11 position. This epimer was detected at the 1H NMR spectrum of the substance 5 by a very small singlet at δ 3.28 ppm, relative to methoxyl of the β-oriented group CH2OMe at C-11. In certain occasion we performed an experiment of catalytic hydrogenation with a fraction of 17 mg, obtained from the purification by column chromatography of allylic alcohol 5, which contained an impurity of its epimer at the C-11 position (1 : 1) (Scheme 6). After the time of reaction, the crude product was isolated and then submitted to reaction of methanol elimination by previously described procedure [1]. The 1H NMR spectrum of crude product from that reaction showed signals of the substance 1R,10R-dihydromicheliolide (34), described in previous publication [1], in mixture with the signals of other α-methylene-γ-lactone characterized as 1S,10S-dihydromicheliolide (35), in the proportion of (1 : 1). This result suggests that the addition of hydrogen to double bond C1–C10 on allylic alcohols 5 and 33 is induced by the group CH2OMe attached to C-11 position; in other words, if the group CH2OMe is in α position at C-11, the hydrogen addition to double bond C1–C10 will take place for the β face, as previously described in [1]. On the other hand, if the group CH2OMe is in β position at C-11, the addition of hydrogen will occur for the α face of that double bond. The main chemical shifts of the hydrogens at the 1H NMR spectrum from the crude product of the reaction depicted in Scheme 6 are displayed in Table 2. The substances 34 and 35 are inseparable for column chromatography of silica gel due to their similar Rf.

tab2
Table 2: Selected chemical shifts for the hydrogens of isomers 34 and 35.
603436.sch.006
Scheme 6: Reagents and conditions: (i) H2 (55 psi), 10% Pd-C (0.1 equiv), EtOH (r. t., 30 min); (ii) 4 mol L−1 NaOH (5.5 equiv), DMF (reflux, 2.5 h). The experimental procedures for the sequence of reactions described in this scheme are similar to the ones previously described in [1], using only the isomer 5 as starting material. Substance previously described in [1].
2.2. Evaluation of the Reactivity of Allylic System on the Compounds 2–5 in Catalytic Hydrogenation Reactions

Through the experimental results obtained in the catalytic hydrogenation reactions of allylic derivatives 25 we could compare the reactivity of allylic system in the respective compounds. It was verified that the allylic system of compound 2, constituted by double bond C1–C10 and the bond C9–OAc, was not hydrogenated. In the compound 3 that system was little reactive, unlike the compound 4 in which such system was totally hydrogenated. In the compound 5 that system was strongly reactive, as previously verified with the use of the Pd catalyst [1] and also in the experimental results of this paper, in which Pt was used as catalyst. Starting from these observations, we elaborated the models shown at Figure 3 containing the probable reactive complexes that should be formed among the allylic derivatives 25 and the catalysts used in the mentioned reactions.

603436.fig.003
Figure 3

For allylic acetate 2 we elaborate the reactive complex 2a, whose complexation of the catalyst (Pd) should preferentially occur with the sp2 oxygen of acetate group that possess high electronic density, and not with the sp3 oxygen of the bond that would be hydrogenolysed (C9–OAc). The formation of that complex with the sp2 oxygen of C=O and the bond C1-C10 should disfavor the hydrogenolysis of the bond C9-OAc turning it to no reactive, as observed in experimental results. The absence of product formed by the catalytic hydrogenation reaction of double bond C1–C10 can be related to the difficulty to hydrogenate a tetrasubstituted double bond. For the compounds 35 we elaborate the models of reactive complexes 3a5a in which the catalyst is complexed with the respective double bonds and the oxygens of their allylic systems. Those reactive π-allyl complexes [18] should favor the hydrogenolysis of the bond C9-OH and hydrogenation of the respective double bonds. The low reactivity experimentally observed with the allylic alcohol 3 can be related to the difficulty to hydrogenate a tetrasubstituted double bond. In the case of allylic alcohol 4, the high reactivity experimentally observed can be related to the facility to hydrogenate a disubstituted double bond. Concerning allylic alcohol 5, the extreme facility to hydrogenate the tetrasubstituted double bond by using the Pd catalyst, as previously described in [1], or the Pt catalyst used in the experiment described in this paper can be related to additional complexation of the catalyst that should occur between the oxygen of the hydroxy group at C-4 position and the oxygen of carboxy group of the lactonic ring at C-6 [19]. That additional complexation of the catalyst with the oxygens at C-4 and C-6 should favor the polarization of tetrasubstituted double bond C1–C10, turning it extremely reactive with the reagent H2 adsorbed onto the surface of catalyst in the form of a pair of radical anions H..H [20].

It is important to mention in this point that, in previous catalytic hydrogenation experiment of allylic alcohol 10 [1], the allylic system was not hydrogenated when NaOAc was added to reactional mixture to minimize the action of strong acid (HI) formed during hydrogenolysis of the bond C15-I. In this case, the formation of product from hydrogenation of allylic system was insignificant, even if high hydrogen pressure was used during a long period of time [1]. For this exception, in which the allylic system was not hydrogenated, we elaborate the reactive complex 10a (Figure 3). In this case, the complexation of the catalyst (Pd) should preferentially occur with the acetate anion and not with the solvent of reaction (EtOH). This type of complex should turn the catalyst less reactive to make the hydrogenolysis of the bond C9–OH and hydrogenation of tetrasubstituted double bond C1–C10. This kind of competition between solvent and ligand to form complexes with metals used as catalysts in hydrogenation reactions, as well as the decrease of the catalytic activity resultant from the alteration of electron density around the central atom of those complexes, was discussed in review articles [3, 4].

2.3. Study of Methanol Addition to α-Methylene-γ-Lactone of the Iodohydrin 6

It has been previously shown that MeOH can be additioned satisfactorily to α-methylene-γ-lactone of eremanthine (1) using solution of MeONa/MeOH, prepared from MeOH and Na [1]. This conjugate addition reaction was performed in nearly quantitative yield and now we wish to report the result of this reaction accomplished with the iodohydrin 6. It was verified through analysis by TLC (50% EtOAc/hexane) from the reaction of iodohydrin 6 with a solution of MeONa in MeOH, after 7 h (Scheme 1), the consumption of substrate 6 (Rf 0.16, blue) and formation of product [Rf 0.08 (blue)]. The 1H NMR spectrum of the isolated product was in agreement with the formation of dimethoxylated compound 15, resultant from methanol addition to α-methylene-γ-lactone and nucleophilic substitution at C-15 position. The presence of doublets with very small intensity at δ 6.19 and 5.48 ppm, relative to olefinic hydrogens C13-H, confirmed that the nucleophilic substitution at the C-15 position proceeded in a faster way than the methanol addition to α-methylene-γ-lactone. The singlets with same intensity at δ 3.36 and 3.34 ppm were attributed to the 6 hydrogens of two methoxyl groups. The stereochemistry at C-11 position on the product 15 was determined through the coupling constants of the signal of hydrogen C11-H (δ 2.42); an axial-axial interaction was verified between C11-H and C7-H (J 12.3 Hz) and two equatorial-equatorial interactions between C11-H and the hydrogens C13-H (J 4.8 and 4.2 Hz).

3. Conclusions

In summary, we could verify the reactivity and stereoselectivity on studied addition reactions through the results obtained in this work. The catalytic hydrogenation of α-methylene-γ-lactone from allylic acetate 2 proceeded by a stereoselective manner with simultaneous hydrogenolysis of the bond C15-I resulting in the synthesis of the new eremanthine derivative 7. The absence of hydrogenolysis reaction on allylic system of acetate 2 in opposition to total hydrogenation of the mentioned system on allylic alcohol 5 suggests the use of acetate as protective group for allylic alcohols in similar guaianolides during catalytic hydrogenation reactions. After a detailed spectral analysis in combination with theoretical calculations of molecular mechanics (MM2), we propose the stages involved in the catalytic hydrogenation reaction of allylic alcohol 3 with formation of the final products 8a (major) and 8c (minor). The lactone 11 was obtained from allylic alcohol 4, with high stereoselectivity in relation to previous experiment [2] in which the methanol adduct of eremanthine was used as substrate. The unequivocal attribution of the stereochemistry of methyl groups C14–H and C15-H of 11 was determined through experiment of intramolecular Nuclear Overhauser Effect (NOE). The synthesis of compound 9 in softer conditions of hydrogen pressure (5 psi) than the ones previously used (55 psi) [1], suggests the use of Pt–C as preferential catalyst for that reaction. It was verified that the hydrogen addition to double bond C1–C10 on allylic alcohol 5 is induced by the group CH2OMe attached to carbon C-11. This was confirmed when the reaction was accomplished with a mixture of allylic alcohol 5 and its epimer at C-11 position (33). The product from that reaction, after methanol elimination, generated a mixture characterized as 1R,10R-dihydromicheliolide (34), previously described in [1], and the new eremanthine derivative 1S,10S-dihydromicheliolide (35). For the stage of catalytic hydrogenation from allylic alcohols 35, we propose the formation of π-allyl complexes as reactive intermediates of those reactions. The high reactivity of tetrasubstituted double bond C1–C10 on allylic alcohol 5 was attributed to additional complexation of the catalyst at the oxygenated positions C-4 and C-6, turning that tetrasubstituted double bond highly polarized. The comparison of the high reactivity from allylic alcohol 5 in relation to the low reactivity on allylic system of compound 10 reported in previous publication [1] in which NaOAc was used in the reaction mixture led us to deduce that the acetate anion displaces EtOH from the complex initially formed with the catalyst. The addition of a ligand to reaction mixture, containing an electron-withdrawing group (AcO–), should alter the electronic density around the central atom of the complex turning the catalyst less reactive. The methanol addition to α-methylene-γ-lactone of iodohydrin 6 resulted in the formation of a single product characterized as the new eremanthine derivative 15.

4. Experimental

NMR spectra were recorded on a Bruker AC-200 (1H: 200 MHz and 13C: 50.3 MHz) spectrometer. CDCl3 was used as the solvent and TMS as internal standard. Coupling constants (J) are reported in Hertz (Hz). Multiplicities are indicated as s (singlet), bs (broad singlet), d (doublet), t (triplet), m (multiplet), dd (double doublet), and ddd (doublet of a double doublet). Assignment of the hydrogens for the substance 15 was made with base on the Homonuclear Correlation Spectra 1H × 1H − COS Y. The spectrum of intramolecular Nuclear Overhauser Effect (NOE) was obtained by spectral difference, subtracting the spectrum registered with irradiation in the frequencies of absorption of the hydrogen atoms from that obtained with irradiation in region free of absorption. Thin layer chromatography was performed on aluminium sheets coated with 60 F254 silica. Visualization of the substances on the plates of TLC was accomplished spraying them with 2% Ce(SO4)2 in 2 mol L−1 H2SO4 and subsequent heating. Purifications and isolations for column chromatography were performed with silica gel (230–400 mesh). The eluent mixtures, used in the chromatographic separations, were prepared volume to volume (v/v) and are expressed in percentage (%). The values of Rf from the studied substances were measured to evaluate the polarity differences, at TLC, of the obtained compounds. Solvents and reagents were dried and purified by the usual methods [21]. Hydrogenations were carried out using a Parr apparatus.

4.1. General Procedure for the Catalytic Hydrogenation Reactions of Allylic Derivatives 2–5

A general procedure is described for the catalytic hydrogenation reaction of allylic acetate 2. A mixture of compound 2 (0.020 g, 0.046 mmol), EtOH (1.5 mL) and 10% Pd-C (0.005 g, 0.0046 mmol) at room temperature, was shaken with hydrogen (50 psi) in a Parr apparatus during 5 h. The consumption of substrate was accompanied by reduction of hydrogen pressure on the reaction middle and TLC. After the reaction time the mixture was filtered, H2O (15 mL) was added, and then concentrated in vacuum. The concentrated mixture was extracted with EtOAc (  mL) and then the organic extract was washed with aqueous 5% NaHCO3 (  mL), aqueous 5% Na2S2O3 (  mL), and again with H2O (  mL). The organic layer was separated, and the aqueous phases were extracted with EtOAc (  mL). The organic extracts were dried with Na2SO4, filtered, and concentrated in vacuum. Crude product was filtered over column chromatography of silica gel eluted with 50% EtOAc/hexane. It was obtained allylic acetate 7 (0.012 g, 85%) as a colourless oil. Rf 0.25 (lilac) (50% EtOAc/hexane). 1H NMR (CDCl3, partial assignment): δ 5.32 (dd, J 2.0 and 4.9 Hz, 1H, H-9), 3.87 (dd, J 10.2 and 10.5 Hz, 1H, H-6), 2.81 (m, 1H, H-5), 2.70–1.00 {21H [2.04 (s, OCOCH3), 1.73 (d, J 0.9 Hz, H-14), 1.28 (s, H-15), 1.24 (d, J 7.3 Hz, H-13)]}.

4.2. Catalytic Hydrogenation Reaction of Allylic Alcohol 3

The reaction was executed following general procedure, using 3 (0.020 g, 0.081 mmol), EtOH (2.0 mL), 10% Pd-C (0.009 g, 0.0081 mmol), and hydrogen (40 psi). After the time of reaction (3 h), the mixture was filtered and concentrated in vacuum. It was obtained a colourless oil (0.018 g, 96%) containing a majority product characterized as the compound 8a in mixture with other minority substances, characterized as intermediates of reaction that not totally react (20, 22, 23, 26 and 27) and the minority product 8c. Characteristic of the majority product 8a: Rf 0.70 (orange) (50% EtOAc/hexane). Characteristics of the minority substances: 20 [Rf 0.37 (red)], 22 and 23 [Rf 0.42 (lilac)], 26, 27 and 8c [Rf 0.70 (orange)] (50% EtOAc/hexane). The partial assignment for the hydrogens and carbons of the intermediates and final products from this reaction is displayed at the Table 1.

4.3. Catalytic Hydrogenation Reaction of Allylic Alcohol 4

The reaction was executed following general procedure, using 4 (0.100 g, 0.359 mmol), EtOH (4.0 mL), 10% Pd-C (0.038 g, 0.036 mmol), and hydrogen (30 psi). After the time of reaction (1 h) the mixture was filtered and concentrated in vacuum. It was obtained a colourless oil (0.095 g, 100%) characterized as the compound 11 and the subproduct 12 (5 : 1), in mixture with traces of the lactones 13 and 14. Characteristics of the majority product 11 :  Rf 0.66 (brownish) (50% EtOAc/hexane); 1H NMR (CDCl3, partial assignment) : δ 3.75 (t, J 10.0 Hz, 1H, H-6), 3.62 (m, 2H, H-13), 3.34 (s, 3H, OCH3), 2.50–2.15 (m, 2H, H-7 and H-11), 2.10–0.80 {18H [1.92 (m, H-5), 1.09 (d, J 6.5 Hz, H-15), 0.93 (d, J 7.2 Hz, H-14)]}. Characteristics of subproduct 12: Rf 0.66 (brownish) (50% EtOAc/hexane); 1H NMR (CDCl3, partial assignment): δ 4.01 (t, J 9.6 Hz, 1H, H-6). Characteristics of the minority lactones 13 and 14: Rf 0.66 (brownish) (50% EtOAc/hexane); 1H NMR (CDCl3, partial assignment): δ 4.10 (m, 1H, H-6 of 13) and δ 4.37 (m, 1H, H-6 of 14).

4.4. Catalytic Hydrogenation Reaction of Allylic Alcohol 5

The reaction was executed following general procedure, using 5 (0.006 g, 0.020 mmol), EtOH (0.5 mL), 10% Pt-C (0.004 g, 0.002 mmol) and hydrogen (5 psi). After the time of reaction (30 min), the mixture was filtered and concentrated in vacuum. It was obtained a colourless oil (0.006 g, 100%) characterized as the compound 9 previously described in [1]. Rf 0.41 (orange) (50% EtOAc/hexane). 1H NMR (CDCl3, partial assignment): δ 3.99 (t, J 10.3 Hz, 1H, H-6), 3.64 (m, 2H, H-13), 3.32 (s, 3H, OCH3), 2.50–2.25 (m, 2H, H-7 and H-11), 2.25–0.80 {18H [1.94 (dd, J 10.3 and 11.2 Hz, H-5), 1.32 (s, H-15), 0.95 (d, J 7.2 Hz, H-14)]}.

4.5. Reaction of Methanol Addition to α-Methylene-γ-Lactone of Iodohydrin 6
4.5.1. Preparation of NaOMe Solution

To a round bottom flask with MeOH (10 mL), at room temperature, sodium was added slowly until the solution reaches pH 11.

4.5.2. Reaction of Iodohydrin 6 with NaOMe Solution

Iodohydrin 6 (0.023 g, 0.059 mmol) was dissolved in the solution of NaOMe (2.0 mL) recently prepared as described in the previous item 4.5.1. The mixture was left under magnetic stirring and room temperature for 7 h. Aqueous 10% (v/v) HCl was added dropwise until pH 3, diluted with H2O (15 mL), and then concentrated in vacuum. The concentrated mixture was transferred to a separatory funnel and then extracted with EtOAc (  mL). The organic extracts were dried with Na2SO4, filtered, and concentrated in vacuum. It was obtained the allylic alcohol 15 as a yellowish oil (0.016 g, 83%). Rf 0.08 (blue) (50% EtOAc/hexane). 1H NMR (CDCl3, partial assignment): δ 4.21 (m, 1H, H-9), 3.86 (t, J 10.6 Hz, 1H, H-6), 3.67 (d, J 4.3 Hz, 2H, H-13), 3.43 (m, 2H, H-15), 3.36 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.10–2.70 (m, 2H, H-5 and H-7), 2.70–1.40 {12H [2.42 (ddd, J 4.2, 4.8 and 12.3 Hz, H-11), 1.79 (bs, H-14)]}.

Acknowledgments

José C. F. Alves thanks FAPERJ and CNPq for the concession of the fellowships to develop the project “Chemical transformations of natural substances. I-Studies with eremanthine.” Professor Dr. Edna C. Fantini (in memoriam) for the supervision and the department of Chemistry (UFRRJ) for the NMR spectra.

References

  1. J. C. F. Alves and E. C. Fantini, “Chemical transformations of eremanthine. Synthesis of micheliolide and 1(R),10(R)-dihydromicheliolide,” Journal of the Brazilian Chemical Society, vol. 16, no. 4, pp. 749–755, 2005. View at Google Scholar
  2. J. C. F. Alves and E. C. Fantini, “Study of the inversion reaction of the lactonic fusion on eremanthine derivatives,” Journal of the Brazilian Chemical Society, vol. 18, no. 3, pp. 643–664, 2007. View at Google Scholar · View at Scopus
  3. R. A. W. Johnstone, A. H. Wilby, and I. D. Entwistle, “Heterogeneous catalytic transfer hydrogenation and its relation to other methods for reduction of organic compounds,” Chemical Reviews, vol. 85, no. 2, pp. 129–170, 1985. View at Google Scholar · View at Scopus
  4. G. Brieger and T. J. Nestrick, “Catalytic transfer hydrogenation,” Chemical Reviews, vol. 74, no. 5, pp. 567–580, 1974. View at Google Scholar · View at Scopus
  5. W. Vichnewski and B. Gilbert, “Schistosomicidal sesquiterpene lactone from Eremanthus elaeagnus,” Phytochemistry, vol. 11, no. 8, pp. 2563–2566, 1972. View at Google Scholar · View at Scopus
  6. P. M. Baker, C. C. Fortes, E. G. Fortes et al., “Chemoprophylactic agents in schistosomiasis: eremanthine, costunolide, α-cyclocostunolide and bisabolol,” Journal of Pharmacy and Pharmacology, vol. 24, no. 11, pp. 853–857, 1972. View at Google Scholar · View at Scopus
  7. P. D. D. B. Lima, M. Garcia, and J. A. Rabi, “Selective extraction of α-methylene-γ-lactones. Reinvestigation of Vanillosmopsis erythropappa,” Journal of Natural Products, vol. 48, no. 6, pp. 986–988, 1985. View at Google Scholar · View at Scopus
  8. M. S. Silvério, O. V. Sousa, G. Del-Vechio-Vieira, M. A. Miranda, F. C. Matheus, and M. A. C. Kaplan, “Pharmacological properties of the ethanol extract from Eremanthus erythropappus (DC.) McLeisch (Asteraceae),” Brazilian Journal of Pharmacognosy, vol. 18, no. 3, pp. 430–435, 2008. View at Publisher · View at Google Scholar
  9. K. Gundertofte, T. Liljefors, P. O. Norrby, and I. Pettersson, “A comparison of conformational energies calculated by several molecular mechanics methods,” Journal of Computational Chemistry, vol. 17, no. 4, pp. 429–449, 1996. View at Google Scholar · View at Scopus
  10. N. H. Fischer, Y. F. Wu-Shih, G. Chiari, F. R. Fronczek, and S. F. Watkins, “Molecular structure of a cis-decalin-type eudesmanolide and its formation from a guaianolide-1(10)-epoxide,” Journal of Natural Products, vol. 44, no. 1, pp. 104–110, 1981. View at Google Scholar · View at Scopus
  11. T. R. Govindachari, B. S. Joshi, and V. N. Kamat, “Structure of parthenolide,” Tetrahedron, vol. 21, no. 6, pp. 1509–1519, 1965. View at Google Scholar · View at Scopus
  12. T. R. Govindachari, B. S. Joshi, and V. N. Kamat, “Revised structure of parthenolide,” Tetrahedron Letters, vol. 5, no. 52, pp. 3927–3933, 1964. View at Google Scholar · View at Scopus
  13. A. Corbrella, P. Gariboldi, G. Jommi, F. Orsini, and G. Ferrari, “Structure and absolute stereochemistry of vanillosmin, a guaianolide from Vanillosmopsis erythropappa,” Phytochemistry, vol. 13, no. 2, pp. 459–465, 1974. View at Google Scholar · View at Scopus
  14. Z. Hassan, H. Hussain, V. U. Ahmad et al., “Absolute configuration of 1β,10β-epoxydesacetoxymatricarin isolated from Carthamus oxycantha by means of TDDFT CD calculations,” Tetrahedron Asymmetry, vol. 18, no. 24, pp. 2905–2909, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. F. Bitam, M. L. Ciavatta, E. Manzo, A. Dibi, and M. Gavagnin, “Chemical characterisation of the terpenoid constituents of the Algerian plant Launaea arborescens,” Phytochemistry, vol. 69, no. 17, pp. 2984–2992, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. The calculations were performed using MM2 program from Cambridge Soft Corporation, minimizing energy to minimum RMS gradient of 0.100, CS Chem3D Ultra 7.0, Molecular Modeling and Analysis, Cambridge Soft Corporation, Cambridge, UK, 2001.
  17. Eremanthine and its derivatives reveal on TLC with varied colors using solution of 2% Ce(SO4)2 in 2 mol L-1 H2SO4 and subsequent heating.
  18. K. J. Szabó, “Nature of the interaction between β-substituents and the allyl moiety in (η3-allyl)palladium complexes,” Chemical Society Reviews, vol. 30, no. 2, pp. 136–143, 2001. View at Publisher · View at Google Scholar · View at Scopus
  19. E. C. Fantini, J. L. P. Ferreira, and J. A. Rabi, “Metal ion promoted methanolysis of sesquiterpene lactones leading to O6,15-cycloguaiane methyl esters,” Journal of Chemical Research (Synopses), no. 8, pp. 298–299, 1986. View at Google Scholar
  20. P. Sykes, A Guidebook to Mechanism in Organic Chemistry, Longman Scientific & Technical, Harlow, UK, 6th edition, 1986.
  21. D. D. Perrin, W. L. F. Armarego, and D. R. Perrin, Purification of Laboratory Chemicals, Pergamon Press, New York, NY, USA, 2nd edition, 1980.