Chemical transformations of eremanthine: synthesis of micheliolide and 1(R),10(R)-dihydromicheliolide

Abstracts

Eremanthine (1), an abundant natural substance, was transformed in four steps into diol 5. Hydrogenolysis of 5 (55 psi of H2, Pd/C, 30 min) furnished 7. Hydrogenation of 5 using a low hydrogen pressure (5 psi) and a short reaction time (15 min) led to a mixture of 6 and 7 (3:1). Compounds 6 and 7 were then transformed respectively to the alpha-methylene-gamma-lactones micheliolide (9) and 1(R),10(R)-dihydromicheliolide (8), after elimination of methanol.

anticancer sesquiterpene lactones; eremanthine; micheliolide

Eremantina (1), uma substância natural abundante, foi transformada em quatro etapas no diol 5. Após hidrogenólise de 5 (55 psi de H2, Pd/C, 30 min) obteve-se 7. Hidrogenação de 5 usando-se uma baixa pressão de hidrogênio (5 psi) e um menor tempo de reação (15 min) forneceu uma mistura de 6 e 7 (3:1). Os compostos 6 e 7 foram, a seguir, transformados nas respectivas alfa-metileno-gama-lactonas miqueliolido (9) e 1(R),10(R)-diidromiqueliolido (8), após eliminação de metanol.

ARTICLE

Chemical transformations of eremanthine. Synthesis of micheliolide and 1(R),10(R)-dihydromicheliolide

José C. F. Alves^*; Edna C. Fantini^†

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

ABSTRACT

Eremanthine (1), an abundant natural substance, was transformed in four steps into diol 5. Hydrogenolysis of 5 (55 psi of H₂, Pd/C, 30 min) furnished 7. Hydrogenation of 5 using a low hydrogen pressure (5 psi) and a short reaction time (15 min) led to a mixture of 6 and 7 (3:1). Compounds 6 and 7 were then transformed respectively to the a-methylene-g-lactones micheliolide (9) and 1(R),10(R)-dihydromicheliolide (8), after elimination of methanol.

Keywords: anticancer sesquiterpene lactones, eremanthine, micheliolide

RESUMO

Eremantina (1), uma substância natural abundante, foi transformada em quatro etapas no diol 5. Após hidrogenólise de 5 (55 psi de H₂, Pd/C, 30 min) obteve-se 7. Hidrogenação de 5 usando-se uma baixa pressão de hidrogênio (5 psi) e um menor tempo de reação (15 min) forneceu uma mistura de 6 e 7 (3:1). Os compostos 6 e 7 foram, a seguir, transformados nas respectivas a-metileno-g-lactonas miqueliolido (9) e 1(R),10(R)-diidromiqueliolido (8), após eliminação de metanol.

Introduction

Sesquiterpene lactone is an important class of naturally occurring substances generally found in Compositae family.¹ Many of these compounds are endowed with an impressively rich spectrum of biological activity² as antileishmanial,³ antifungal,⁴ cytotoxic⁵ and herbicide,⁶ among others.⁷ This diverse bioactivity of sesquiterpene lactones along with their structural complexity makes these compounds important targets for synthetic purposes.⁸ Furthermore, with rare exceptions, their availability from natural sources is very limited. Therefore, it is important to sinthesize these compounds from easily available starting materials.

Eremanthine (1), a sesquiterpene lactone isolated from Brazilian compositae Eremanthus elaeagnus⁹ and Vanillosmopsis erythropappa¹⁰ is an inhibitor against infections caused by cercariae of Schistosoma mansoni. The abundance of this substance turned possible the obtention of others potentially active derivatives, as well as the synthesis of less abundant natural lactones, through chemical modifications of 1.¹¹

Continuing the research programme of chemical transformations of eremanthine (1), this compound was converted to the diol 5,¹² a potential precursor for the synthesis of micheliolide (9), an anticancer sesquiterpene lactone isolated from Michelia compressa¹³ and Michelia champaca.¹⁴

In this paper we report the obtention of diol 5 and its transformation into micheliolide (9) and 1(R),10(R)-dihydromicheliolide (8).

Results and Discussion

Initially, eremanthine (1) was transformed into diol 5 as outlined in Scheme 1 (conditions i - iv).¹²

The a-methylene-g-lactone of eremanthine (1) was protected as methanol adduct 2. The choice was due to the stability of this group and relative facility to be removed.¹⁵ Thus, the reaction of eremanthine (1) with methanol catalysed by sodium methoxide furnished adduct 2 in nearly quantitative yield. Epoxidation of compound 2 with excess of peracetic acid solution in CH₂Cl₂ furnished diepoxide 3¹⁶ and crude product was submitted to ring opening through treatment with glacial acetic acid and equimolar amount of potassium iodide, in reflux of acetone. The use of equimolar amount of KI provided the chemoselective opening of the more reactive 4,15-a-epoxide through the nucleophilic attack of iodide at C₁₅. On the other hand, the protonation of 9,10-a-epoxide contributed for the generation of a cationic intermediary at C₁₀ where elimination of H⁺ at C₁ furnished the compound 4¹⁷ in 66% yield after purification by flash chromatography. Hydrogenolysis of 4 with hydrogen catalysed by palladium on charcoal and mixture of sodium acetate and ethanol gave diol 5.¹² At this point we decided to investigate this reaction more carefully in order to carry out the hydrogenolysis of C₁₅-I and C₉-OH in one step.

The classic literature of Organic Chemistry reports that hydrogenation of allylic alcohol with hydrogen and catalyst, for example palladium on charcoal, proceeds initially with hydrogenolysis of C-OH followed by reduction of double bond C-C.¹⁸ In our case, the hydrogenation of tetrasubstituted double bond C₁-C₁₀ at allylic alcohol 4 seemed to be an unfavourable reaction since tetrasubstituted olefins are more resistent and require higher temperatures and pressures.¹⁹ This resistence is usually a function of increasing substitution and is presumably caused by steric factors.

As we had observed before, the use of 45 psi of hydrogen pressure didn't cause any hydrogenolysis of C₉-OH at 4. We planned to use a higher hydrogen pressure during several hours in order to convert 4 to 6 and an experiment was performed in which we used the highest recommended pressure for the Parr hydrogenation apparatus (condition v – Scheme 1).The reaction course was examined by TLC in regular times of one hour and after 48 h, two spots (Rf 0.29 and 0.6, EtOAc as eluent) were observed. The slow-eluting spot (R_f 0.29) corresponded to diol 5 by comparison with an authentic sample of this compound. On the other hand, the fast-eluting spot (R_f 0.6) seemed to correspond to the target molecule 6 due to its lower polarity. Because of the high polarity of compound 5, we decided to extract the reaction products using two solvents of different polarities (ethyl ether and ethyl acetate) in order to separate the two fractions of R_f 0.29 and 0.6 by extraction. The crude product was partitioned first with ethyl ether and then exhaustively with ethyl acetate. After the usual aqueous work up and evaporation of the solvents, it was obtained two residues which were submitted to TLC. The spot of the ethereal residue corresponded to the product with R_f 0.6 and the residue of ethyl acetate to diol 5 (R_f 0.29). The ratio of diol 5 to product of R_f 0.6 was 5:1 and 96% global yield. In the ¹H NMR spectrum of the ethereal residue was observed the absence of the signals corresponding to H-9 (d 4.22) and H-15 (d 3.60 and d 3.30), present in the spectrum of 4, indicating thus the hydrogenolysis of C₉-OH and C₁₅-I bonds. The triplets at d 3.99 and d 3.79 (H-6 signals) and the singlets at d 3.34 and d 3.32 (H-16 signals) suggested the presence of two lactones (1 : 1 ratio by ¹H NMR). The methyl group attached to sp² carbon (H-14) was observed at d 1.64. With these spectral data we concluded that spot of R_f 0.6 corresponded to two substances, where one of them was the compound 6. A new TLC analysis of the ethereal residue (R_f 0.6) was performed using 35% EtOAc/hexane as eluent (elution repeated three times). After staining, it was observed two spots of very similar R_f. These results suggested that substance 6 had been formed and then transformed in part to another product in the reaction medium, maybe compound 7. However the H-14 doublet of 7 was masked in the ¹H NMR spectrum of this mixture. To confirm the in situ conversion of 6 to 7, we decided to perform the hydrogenolysis reaction using as starting material diol 5 (condition i – Scheme 2) in order to get 7 as a single product.

After reaction time the TLC revealed that diol 5 had been transformed to a single product of R_f 0.6 (eluent: 3 x 35% EtOAc/hexane). The ¹H NMR spectrum of product indicated hydrogenolysis of the C₉-OH bond besides reduction of double bond C₁-C₁₀ at 5. A doublet at d 0.95 (3H, J 7.2 Hz) was attributed to H-14. One singlet at d 3.32 (3H, H-16) and one triplet at d 3.99 (1H, J 10.3 Hz, H-6) confirmed that 7 was the single product of this reaction. In the ¹³C NMR spectrum was only observed one signal of sp² carbon (d 175.9; C=O) confirming thus the hydrogenation of double bond C₁-C₁₀. The stereochemistry of the stereogenic carbons C₁ and C₁₀ was determined by NOE experiment.²⁰ The trans junction between the five and seven-membered-rings of the hidroazulene system was confirmed by axial-axial coupling constants between H-5 and H-1 (J 11.2 Hz). The fast hydrogenation reaction of tetrasubstituted double bond C₁-C₁₀ was an unexpected result since compound 2, which has a trisubstituted double bond C₉-C₁₀, hydrogenated slowly [H₂ (60 psi); 10% Pd-C (0.1 equiv.); EtOH (r.t. – 4h)].²¹

Our attention was focused, at this stage, to examine the means for effecting only hydrogenolysis of the C₉-OH bond in 5, in order to get compound 6, the immediate precursor of micheliolide (9). After many experiments, we found that the best condition to carry out this reaction was the use of a low hydrogen pressure (5 psi) and a short reaction time (maximum of 15 minutes) (condition ii - Scheme 2). With this condition, the major product obtained was the compound 6, as a mixture with 7 (94% yield, 3:1 ratio by ¹H NMR). The separation of 6 and 7 by column chromatography proved to be troublesome (practically identical R_fs) and to our delight, compound 6 could be crystallized from hexane.

Finally, restoration of a-methylene-g-lactone function of compounds 6 and 7 was achieved using basic conditions.¹⁵ The reactions were quenched with aqueous HCl in order to consume the excess of NaOH and lactonize the hydroxy acids formed in this stage. Micheliolide (9) and 1(R),10(R)-dihydromicheliolide (8) were obtained in 80% and 85% yield, respectively. Micheliolide (9) has already been synthesized before by BF₃-mediated rearrangement of parthenolide.²²

In conclusion, we have developed an efficient and straightforward synthesis (six steps) of micheliolide (9) (31% overall yield) and a new compound 1(R),10(R)-dihydromicheliolide (8) (45% overall yield) from the abundant natural product eremanthine (1), using inexpensive and easily available reagents. We expect that the synthesis outlined herein to be useful for the chemistry of sesquiterpene a-methylene-g-lactones and related systems.

Experimental

Infrared spectra were recorded on a Perkin-Elmer 1420 spectrophotometer using either thin films on NaCl plates (film) or KBr discs (KBr). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AC-200 (¹H : 200 MHz and ¹³C : 50.3 MHz) spectrometer. CDCl₃ was used as the solvent, with Me₄Si (TMS) as internal standard. Coupling constants (J) are reported in Hz. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), dd (doublet of a doublet), dt (double triplet), m (multiplet), bs (broad singlet), bd (broad doublet). ¹³C multiplicities were assigned using a DEPT sequence. Mass spectra were obtained at 70 eV on a VG AutoSpecQ mass spectrometer. Chromatographic purifications were carried out with 230-400 mesh silica gel (flash chromatography). The eluent mixtures, used in the chromatographic separations, were prepared volume to volume (v/v) and are expressed in percentage (%). Thin layer chromatography was performed on aluminium sheets coated with 60 F₂₅₄ silica. The TLC were revealed spraying with 2% Ce(SO₄)₂ in 2 mol L^-1 H₂SO₄ and followed by heating. The melting points were taken on a Kofler apparatus and are uncorrected. Hydrogenations were carried out using a Parr apparatus.

(11S)-Guaia-4(15),9-dieno-13-methoxy-12,6 a-lactone, (2)

A solution of sodium methoxide [sodium (0.040 g, 1.740 mmol) and methanol (7.5 mL)] was added to eremanthine (1) (1.000 g, 4.342 mmol) in methanol (19 mL). The mixture was stirred at room temperature for 24 h. Water (25 mL) was added and resulting mixture was concentrated in vacuo. An aqueous solution of 10% HCl (v/v) was added dropwise to residual mixture until pH 3. The mixture was transferred to a separatory funnel and then extracted with EtOAc (1 x 40 mL).The organic layer was separated and then washed with water (1 x 40 mL). The aqueous phases were extracted with EtOAc (2 x 40 mL) and the combined organic layers were dried (Na₂SO₄), filtered and evaporated to give 2 (1.105 g , 97% yield), as a brown oil. R_f 0.69 (50% EtOAc/hexane). IR (film) n_max / cm^-1 : 2920, 1775, 1660, 1440, 1320, 1180, 1100, 1005, 895. ¹H NMR (CDCl₃): d1.40 – 1.70 (m, 2H); 1.78 (bs, 3H); 1.90 – 2.70 (m, 8H); 3.33 (s, 3H); 3.64 (d, J 4.4 Hz, 2H); 3.93 (t, J 9.6 Hz, 1H); 4.97 (bs, 1H); 5.15 (bs, 1H); 5.47 (bd, J 7.9 Hz, 1H). ¹³C NMR (CDCl₃): d 27.7 (CH₃); 29.2 (CH₂); 29.9 (CH₂); 30.1 (CH₂); 43.6 (CH); 46.9 (CH); 47.9 (CH); 51.7 (CH); 59.0 (CH₃); 68.8 (CH₂); 83.3 (CH); 110.3 (CH₂); 121.3 (CH); 137.7 (C); 150.2 (C); 175.8 (C=O).

(11S)-4a,15a,9a,10a-Diepoxyguaia-13-methoxy-12,6a -lactone, (3)

Preparation of peracetic acid solution. H₂O₂ (30% - 37 mL) was added to glacial acetic acid (37 mL) and the mixture was stirred for 30 minutes. CH₂Cl₂ (60 mL) was added and the mixture, kept in the dark, was vigorously stirred at room temperature for 24 h. The organic layer was separated and then used in the epoxidation reaction.

Epoxidation of 2. Adduct 2 (1.000 g , 3.811 mmol) was dissolved in a solution of AcO₂H/CH₂Cl₂ (60 mL), prepared as described above. The resulting solution was kept in the dark and stirred at room temperature for 2 days. The solution was washed with water (2 x 40 mL), aqueous 5% NaHCO₃ (2 x 40 mL) and again with water (2 x 40 mL). The organic layer was separated and the aqueous phases were extracted with CH₂Cl₂ (3 x 40 mL). The combined organic layers were dried (Na₂SO₄), filtered under activated charcoal and the solvent removed under reduced pressure to furnish diepoxide 3 as a colourless crystalline residue (1.077 g, 96% yield). R_f 0.29 (50% EtOAc/hexane). IR (KBr) n_max/cm^-1: 2925, 1785, 1450, 1380, 1350, 1310, 1230, 1180, 1100, 1040, 880, 760. ¹H NMR (CDCl₃): d 1.36 (s, 3H); 1.45 – 1.95 (m, 4H); 2.10 – 2.55 (m, 4H); 2.60 2.75 (m, 1H); 2.85 (d, J 4.2 Hz, 1H); 2.90 – 3.05 (m, 1H); 2.97 (d, J 5.2 Hz, 1H); 3.11 (d, J 4.2 Hz, 1H); 3.33 (s, 3H); 3.60 (m, 2H); 3.72 (dd, J 9.7 and 11.3 Hz, 1H). ¹³C NMR (CDCl₃): d 25.4 (CH₃); 26.0 (CH₂); 28.1 (CH₂); 28.8 (CH₂); 39.7 (CH); 44.8 (CH) ; 46.7 (CH); 49.7 (CH₂); 51.6 (CH); 58.9 (CH₃); 61.4 (CH); 62.8 (C); 65.8 (C); 69.0 (CH₂); 81.2 (CH); 175.2 (C=O).

(11S)-Guai-1(10)-eno-4a,9a-dihydroxy-13-methoxy-15 -iodine-12,6a-lactone, (4)

A mixture of diepoxide 3 (1.050 g, 3.567 mmol), acetone (6.3 mL), glacial acetic acid (3.1 mL, 54.151 mmol) and KI (0.652 g, 3.927 mmol) was refluxed for 11 h. It was then allowed to cool, diluted with EtOAc (35 mL) and solution was washed with water (1 x 35 mL), aqueous 5% NaHCO₃ (2 x 35 mL), aqueous 5% Na₂S₂O₃ (1 x 35 mL) and again with water (1 x 35 mL). The organic layer was separated and the aqueous phases were extracted with EtOAc (2 x 35 mL). The combined organic layers were dried (Na₂SO₄), filtered and concentrated to furnish a brownish crystaline residue which was purified by column chromatography (45% EtOAc/hexane) to yield 4 (0.996 g, 66% yield) as yellowish crystals [mp 109 ºC (decomposition)]. R_f 0.11 (50% EtOAc/hexane). IR (KBr) n_max / cm^-1: 3500, 2920, 1780, 1440, 1310, 1210, 1155, 1125, 1040. ¹H NMR (CDCl₃): d 1.40 – 1.60 (m, 1H); 1.60 – 1.90 (m, 3H); 1.79 (bs, 3H); 2.00 – 2.55 (m, 5H); 2.80 – 3.05 (m, 1H); 3.15 – 3.40 (m, 1H); 3.30 (d, J 10.8 Hz, 1H); 3.35 (s, 3H); 3.60 (dd, J 2.2 and 10.8 Hz, 1H); 3.67 (d, J 4.2 Hz, 2H); 3.86 (t, J 10.3 Hz, 1H); 4.22 (m, 1H). ¹³C NMR (CDCl₃): d 15.3 (CH₂); 22.5 (CH₃); 29.6 (CH₂); 33.9 (CH₂); 37.1 (CH₂); 39.8 (CH); 46.2 (CH); 55.3 (CH); 59.1 (CH₃); 68.2 (CH₂); 72.0 (CH); 80.8 (C); 82.6 (CH); 133.5 (C); 133.7 (C); 175.3 (C=O).

(11S)-Guai-1(10)-eno-4a,9a-dihydroxy-13-methoxy -12,6a-lactone, (5)

A mixture of compound 4 (0.300 g, 0.710 mmol), ethanol (9.0 mL), NaOAc (0.290 g, 3.535 mmol) and 10% Pd-C (0.075 g, 0.070 mmol) was shaken with hydrogen (45 psi) in a Parr apparatus for 3 h at room temperature. The reaction was filtered, water (20 mL) was added and the mixture was concentrated in vacuo. The residual product was diluted with EtOAc (20 mL) and then washed with water (20 mL), aqueous 5% NaHCO₃ (20 mL), aqueous 5% Na₂S₂O₃ (20 mL) and again with water (20 mL). The organic layer was separated and the aqueous phases were vigorously extracted with EtOAc (5 x 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and evaporated. Purification of the crystalline residue by silica gel column chromatography using 80% EtOAc/hexane gave diol 5 (0.187 g, 89% yield) as colourless crystals [mp 142-144 ºC]. R_f 0.03 (50% EtOAc/hexane). IR (KBr) n_max / cm^-1: 3500, 2930, 1760, 1445, 1200, 1140, 990. ¹H NMR (CDCl₃): d 1.25 (s, 3H); 1.40 – 1.60 (m, 2H); 1.65 – 1.90 (m, 4H); 1.78 (bs, 3H); 2.05 – 2.35 (m, 2H); 2.44 (dt, J 4.2 and 14.4 Hz, 1H); 2.75 – 3.00 (m, 2H); 3.35 (s, 3H); 3.67 (d, J 4.2 Hz, 2H); 3.85 (t, J 10.3 Hz, 1H); 4.21 (m, 1H). ¹³C NMR (CDCl₃): d 22.3 (CH₃); 22.4 (CH₃); 30.0 (CH₂); 34.0 (CH₂); 37.8 (CH₂); 39.5 (CH); 46.3 (CH); 57.0 (CH); 59.0 (CH₃); 68.3 (CH₂); 72.0 (CH); 80.0 (C); 83.4 (CH); 132.8 (C); 134.6 (C); 175.6 (C=O).

(1R,10R,11S)-Guaia-4a-hydroxy-13-methoxy-12,6 a-lactone, (7)

Diol 5 (0.100 g, 0.337 mmol), ethanol (3.0 mL) and 10% Pd-C (0.036 g, 0.034 mmol) were shaken with hydrogen (55 psi) in a Parr apparatus for 30 min at room temperature. The mixture was filtered and evaporated to furnish a residual product, which was then filtered on silica gel (80% EtOAc/hexane). After evaporation under reduced pressure compound 7 (0.093 g, 98% yield) was obtained as colourless crystals [mp 84-85 ºC]. R_f 0.41 (50% EtOAc/hexane). IR (KBr) n_max / cm^-1: 3480, 2930, 1780, 1460, 1410, 1345, 1195, 1100, 1000. ¹H NMR (CDCl₃): d 0.80 – 1.10 (m, 2H); 0.95 (d, J 7.2 Hz, 3H); 1.15 – 1.35 (m, 2H); 1.32 (s, 3H); 1.35 – 1.85 (m, 4H); 1.85 – 2.10 (m, 2H); 1.94 (dd, J 10.3 and 11.2 Hz, 1H); 2.16 (bs, 1H, OH, D₂O exchange); 2.25 – 2.50 (m, 2H); 3.32 (s, 3H); 3.64 (m, 2H); 3.99 (t, J 10.3 Hz, 1H). ¹³C NMR (CDCl₃): d 13.3 (CH₃); 24.4 (CH₂); 24.8 (CH₃); 26.0 (CH₂); 31.5 (CH₂); 31.9 (CH); 38.8 (CH₂); 43.7 (CH); 46.4 (CH); 48.4 (CH); 55.3 (CH); 59.2 (CH₃); 68.6 (CH₂); 80.0 (C); 83.9 (CH); 175.9 (C=O). m/z (%): 282 (M⁺, 2%); 264 (100); 232 (25); 219 (14); 205 (22); 192 (51); 178 (80); 161 (42); 149 (52); 133 (40); 120 (82); 105 (50); 93 (55); 79 (60); 71 (72); 55 (86).

(11S)-Guai-1(10)-eno-4a-hydroxy-13-methoxy-12,6 a-lactone, (6)

Diol 5 (0.050 g, 0.168 mmol), ethanol (1.5 mL), 10% Pd-C (0.018 g, 0.017 mmol) and hydrogen (5 psi) were shaken in a Parr apparatus at room temperature for 15 minutes. The mixture was filtered and concentrated in vacuo. Hexane (10 mL) was added to the crude product (0.045 g) and the mixture was heated to boil. The resulting cloudy solution was carefully separated from insoluble residual oil with a pipette and then transferred to a round-botton flask which was allowed at room temperature. After 24 h, it was observed crystalline agglomerates inside the solution. The liquid phase was separated and crystals were washed with hexane and then dried under reduced pressure. Compound 6 (0.020 g, 42% yield) was obtained as colourless crystals [mp 108-109 ºC]. R_f 0.44 (50% EtOAc/hexane). IR (KBr) n_max / cm^-1: 3590, 2940, 1775, 1445, 1385, 1205, 1180, 1110, 990. ¹H NMR (CDCl₃): d 1.15 – 1.40 (m, 1H); 1.26 (s, 3H); 1.64 (d, J 1.5 Hz, 3H); 1.65 1.85 (m, 2H); 1.85 – 2.05 (m, 1H); 2.05 – 2.25 (m, 5H); 2.25 – 2.40 (m, 1H); 2.40 (dt, J 4.0 and 12.0 Hz, 1H); 2.64 (bd, J 10.1 Hz, 1H); 3.34 (s, 3H); 3.67 (m, 2H); 3.79 (t, J 10.1 Hz, 1H). ¹³C NMR (CDCl₃): d 22.5 (CH₃); 23.5 (CH₃); 26.8 (CH₂); 29.7 (CH₂); 34.9 (CH₂); 38.1 (CH₂); 47.7 (CH); 48.5 (CH); 57.8 (CH); 58.9 (CH₃); 68.1 (CH₂); 80.0 (C); 83.8 (CH); 131.0 (C); 131.5 (C); 175.4 (C=O). m/z (%): 280 (M⁺, 22%); 262 (36); 230 (24); 222 (20); 204 (14); 190 (31); 177 (42); 159 (60); 146 (51); 131 (43); 118 (100); 105 (63); 91 (64); 79 (38); 67 (22); 55 (52).

Micheliolide, (9)

A solution of compound 6 (0.020 g, 0.071 mmol) in DMF (0.5 mL) and aqueous 4 mol L^-1 NaOH (0.10 mL, 0.400 mmol) was refluxed for 3 h. After allowed to cool at room temperature, aqueous 10% HCl (v/v) was added dropwise until pH 3. EtOAc (20 mL) was added and solution was washed with H₂O (2 x 20 mL). The organic layer was separated and the aqueous phases were extracted with EtOAc (2 x 20 mL). The organic phases were dried (Na₂SO₄), filtered and then exhaustively evaporated under reduced pressure. The residual product was filtered on silica gel (CHCl₃) and concentrated to furnish 9 (0.014 g, 80% yield) as colourless crystals.²³ mp lit.²²:142-145 ºC; mp 131-133 ºC. R_f 0.50 (50% EtOAc/hexane). IR (KBr) n_max / cm^-1: 3550, 2930, 1765, 1670, 1450, 1410, 1375, 1260, 1155, 990, 950. ¹H NMR (CDCl₃): d 1.15 – 1.45 (m, 1H); 1.28 (s, 3H); 1.66 (bs, 3H); 1.70 – 1.95 (m, 2H); 2.00 – 2.50 (m, 6H); 2.55 – 2.80 (m, 2H); 3.79 (t, J 10.0 Hz, 1H); 5.48 (d, J 3.3 Hz, 1H); 6.19 (d, J 3.3 Hz, 1H). ¹³C NMR (CDCl₃): d 22.7 (CH₃); 23.9 (CH₃); 25.7 (CH₂); 30.0 (CH₂); 34.9 (CH₂); 38.2 (CH₂); 49.5 (CH); 58.6 (CH); 80.2 (C); 84.4 (CH); 119.5 (CH₂); 130.8 (C); 131.8 (C); 138.7 (C); 169.7 (C=O). m/z (%): 248 (M⁺, 23%); 230 (41); 215 (26); 202 (30); 190 (100); 175 (28); 159 (25); 145 (64); 131 (32); 119 (33); 105 (50); 91 (44); 79 (27); 67 (17); 53 (45).

1(R),10(R) – Dihydromicheliolide, (8)

A solution of compound 7 (0.020 g, 0.070 mmol) in DMF (0.5 mL) and aqueous 4 mol L^-1 NaOH (0.10 mL, 0.400 mmol) was refluxed for 2.5 h. After allowed to cool at room temperature, aqueous 10% HCl (v/v) was added dropwise until pH 3. EtOAc (20 mL) was added and solution was washed with H₂O (2 x 20 mL). The organic layer was separated and the aqueous phases were extracted with EtOAc (2 x 20 mL). The organic phases were dried (Na₂SO₄), filtered and then exhaustively evaporated under reduced pressure. The residual product was filtered on silica gel (CHCl₃) and concentrated to furnish 8 (0.015 g, 85% yield) as colourless oil. R_f 0.50 (50% EtOAc/hexane). IR (film) n_max / cm^-1: 3440, 2940, 1765, 1660, 1470, 1380, 1150, 1000. ¹H NMR (CDCl₃): d 0.80 – 1.05 (m, 2H); 0.96 (d, J 7.2 Hz, 3H); 1.15 – 1.47 (m, 2H); 1.34 (s, 3H); 1.50 – 2.50 (m, 8H); 2.75 – 3.00 (m, 1H); 4.02 (t, J 10.2 Hz, 1H); 5.41 (d, J 3.5 Hz, 1H); 6.13 (d, J 3.5 Hz , 1H). ¹³C NMR (CDCl₃): d 12.5 (CH₃); 23.0 (CH₂); 25.0 (CH₃); 26.0 (CH₂); 31.0 (CH₂); 31.9 (CH); 38.7 (CH₂); 45.5 (CH); 47.5 (CH); 56.3 (CH); 80.0 (C); 83.2 (CH); 119.3 (CH₂); 140.4 (C); 169.9 (C=O).

Acknowledgments

J. C. F. A. thanks FAPERJ and CNPq for the fellowships, Dequim - UFRRJ for running the ¹H NMR, ¹³C NMR and IR spectra and NPPN - UFRJ for mass spectra. The author also thanks the referees for helpful suggestions about English grammar and the JBCS editorial staff for patience and understanding.

References

1. Fraga, B. M.; Nat. Prod. Rep. 1998, 15, 73; Ibid. 1999, 16, 21; Ibid 1999, 16, 711; Ibid. 2000, 17, 483; Ibid. 2001, 18, 650; Ibid. 2002 , 19, 650; Ibid. 2003, 20, 392; Ibid. 2004, 21, 669.

2. Schmidt, T. J.; Current Org. Chem. 1999, 3, 577.

3. Satake, M.; Fuchino, H.; Koide, T.; Takahashi, M.; Sekita, S.; Jpn Patent PCT Int. Appl. WO 01 58,888 2001 (CA 2001, 135: 180895 h).

4. Vajs, V.; Todorovic, N.; Ristic, M.; Tesevic, V.; Todorovic, B.; Janackovic, P.; Marin, P.; Milosavljevic, S.; Phytochemistry 1999, 52, 383.

5. Harimaya, K.; Inayama, S.; Heterocycles 1990, 30 (2, Spec. Issue), 993; Appendino, G.; Gariboldi, P.; Menichini, F.; Fitoterapia 1991, 62, 275.

6. Macias, F. A.; Galindo, J. C. G.; Molinillo, J. M. G.; Castellano, D.; Velasco, R. F.; Chinchilla, D.; Pestic. Sci. 1999, 55, 662.

7. Fischer, N. H.; Lu, T.; Cantrell, C. L.; Acosta, J. C.; Quijano, L.; Franzblau, S. G.; Phytochemistry 1998, 49, 559; Macias, F. A.; Galindo, J. C. G.; Massanet, G. M.; Phytochemistry 1992, 31, 1969; Giordano, O. S.; Pestchanker, M. J.; Guerreiro, E.; Saad, J. R.; Enriz, R. D.; Rodriguez, A. M.; Jauregui, E. A.; Gusman, J.; Maria, A. O. M.; Wendel, G. H.; J. Med. Chem. 1992, 35, 2452; Baker, P. M.; Fortes, C. C.; Fortes, E. C.; Gazzinelli, G.; Gilbert, B.; Lopes, J. N. C.; Pellegrino, J.; Tomassini, T. C. B.; Wichinewski, W.; J. Pharm. Pharmac. 1972, 24, 853.

8. Ando, M.; Yuki Gozei Kagaku Kyokaishi 1992, 50, 858 (CA 1992, 117 : 251566 t); Kuroda, C.; Inoue, S.; Kato, S.; Satoh, J. Y.; J. Chem. Res. (S) 1993, 2, 62; Asaoka, M.; Ohkubo, T.; Itahama, H.; Kosaka, T.; Takei, H.; Tetrahedron 1995, 51, 3115; Rubinger, M. M. M.; Mann, J.; J. Chem. Res. (S) 1999, 7, 454; Yuuya, S.; Hagiwara, H.; Suzuki, T.; Ando, M.; Yamada, A.; Suda, K.; Kataoka, T.; Nagai, K.; J. Nat. Prod. 1999, 62, 22.

9. Vichnewski, W.; Gilbert, B.; Phytochemistry 1972, 11, 2563.

10. Corbella, A.; Gariboldi, P.; Jommi, G.; Ferrari, G.; Phytochemistry 1974, 13, 459; Lima, P. D. D. B.; M.Sc. Dissertation, NPPN, Universidade Federal do Rio de Janeiro, Brazil, 1983.

11. Maçaira, L. A.; Garcia, M.; Rabi, J. A.; J. Org. Chem. 1977, 42, 4207; Rabi, J. A.; Garcia, M.; Maçaira, L. A.; Machado, F. W. L.; An. Acad. Bras. Cienc. 1977, 49, 563; Garcia, M.; Machado, F. W. L.; Maçaira, L. A.; Rabi, J. A.; Tetrahedron Lett. 1980, 21, 777; Silva, A. J. R.; Garcia, M.; Baker, P. M.; Rabi, J. A.; Org. Magn. Res. 1981, 16, 230; Fantini, E. C.; Ferreira, J. L. P.; Rabi, J. A.; J. Chem. Res. (S) 1986, 298.

12. Fantini, E. C.; PhD Thesis, Universidade Federal do Rio de Janeiro, Brazil, 1985.

13. Ogura, M.; Cordell, G. A.; Farnsworth, N. R.; Phytochemistry 1978, 17, 957.

14. Sethi, V. K.; Thappa, R. K.; Dhar, K. L.; Atal, C. K.; Planta Med. 1984, 50, 364.

15. Fantini, E. C.; Rabi, J. A.; Cienc. Cult. 1983, 35 (7 Supl.), 403 (49-D.2.3).

16. Diepoxide 3 was prepared according to the procedure described for the synthesis of 9,10-a-4,15-a-diepoxy-eremanthine by : Ferreira, J. L. P.; M.Sc. Dissertation, NPPN, Universidade Federal do Rio de Janeiro, Brazil, 1985.

17. Compound 4 was prepared using the same procedure described for the ring opening of epoxide 9,10-a-4,15-a-diepoxy-eremanthine by : Fantini, E. C.; Ferreira, J. L. P.; Rabi, J. A.; J. Chem. Res. (S) 1986, 298.

18. House, H. O.; Modern Synthetic Reactions, 2^nd ed., W. A. Benjamin, INC.: Menlo Park, California, 1972, p. 23.

19. March, J.; Advanced Organic Chemistry, 3^th ed., John Wiley & Sons: New York, 1985, p. 693.

20. The stereochemistry of methyl group at C-10 was established by NOE experiment. Irradiation of C-14 methyl group at d 0.95 showed an enhancement of H-7 signal at d 2.35 (3%) and an enhancement of H-5 signal at d 1.94 (8%), indicating that methyl is in a-position.

21. Alves, J. C. F.; M.Sc. Dissertation, Universidade Federal Rural do Rio de Janeiro, Brazil, 1993.

22. Acosta, J. C.; Fischer, N. H.; Vargas, D.; J. Nat. Prod. 1993, 56, 90.

23. Crystallography data of micheliolide were reported by: Acosta, J. C.; Fronczek, F. R.; Fischer, N. H.; Acta Cryst. 1991, C 47, 2702.

Received: January 7, 2004

Published on the web: May 18, 2005

†

Deceased in 1993.

Publication Dates

• Publication in this collection
  25 Aug 2005
• Date of issue
  Aug 2005

History

• Accepted
  18 May 2005
• Received
  07 Jan 2004