Eudesmane Derivatives from Verbesina turbacensis

Article

Eudesmane Derivatives from Verbesina turbacensis

Juan M. Amaro-Luis^*,a, Irama Ramírez^b, Paulino Delgado-Méndez^a and Zacarías D. Jorge^c

^a Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela 5101

^b Instituto de Investigaciones, Facultad de Farmacia, Universidad de Los Andes, Mérida, Venezuela 5101

^c Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, 11510 Cádiz, Spain

Quatro sesquiterpenos do tipo eudesmano foram isolados das partes aéreas de Verbesina turbacensis e foram caracterizados por métodos espectroscópicos incluindo experimentos bidimensionais de RMN.

Four eudesmane sesquiterpene were isolated from the aerial parts of Verbesina turbacensis and were characterised by spectroscopic methods, including 2D NMR experiments.

Keywords: Verbesina turbacensis, Asteraceae, sesquiterpenes, eudesmane

Introduction

Species of the genus Verbesina (Asteraceae, tribe Heliantheae, subtribe Ecliptinae) have produced a range of eudesmane sesquiterpenes with cinnamate or a derived ester group,^1-7 of which, a- and b-verbesinolcoumarates were the first reported examples.^1,8 Several species also afforded elemanolides,^9,10 diterpenes,¹¹ flavonoids,¹² and biological active guanidines as Galegine, the toxic principle of V. enceloides Benth.^13,14

As a continuation of our phytochemical investigation on Venezuelan Compositae,^15-17 in this paper we describe the results of our study of Verbesina turbacensis H.B.K., a previously uninvestigated species, which is widely distributed throughout of Central America from Mexico to Colombia and Venezuela.¹⁸V. turbacensis as well as V. caracasana Fries, a plant which contains the dose-dependent hypotensive agent Caracasanamide,¹⁹ are frequently used in Venezuela as medicinal plants against a variety of diseases.

Results and Discussion

The dried, ground leaves and stems of V. turbacensis were extracted with acetone at room temperature and the obtained extract was purified by standard procedures. Vacuum liquid chromatography separation over silica gel²⁰ of the fractions obtained from a hexane-EtOAc (3:1, v/v) eluate, gave the sesquiterpenes 1, 3, 5 and 9.

Compound 1 was crystallized from acetone as colourless prisms (mp 221-223º C; [a]_D: + 147.2º) and analysed for C₂₄H₃₂O₄ ([M⁺] m/z 384.2189 high resolution EI-MS). Its ¹H NMR spectral data were in close agreement with those reported by Bohlmann and Lonitz ² for the methyl-6b-[cinnamoyloxy]-eudesman-15-oate 2. However the IR, ¹H NMR and ¹³C NMR spectra of compound 1 revealed the presence of a free carboxyl group [IR: 3600-3200 and 1735 cm^-1; d_H 11.45 broad singlet; d_C 181.10 (O=C-O-)], instead of the methyl ester present in 2. In accordance with above assignments, treatment of 1 with CH₂N₂/eter gave 2 and consequently 1 was identified as 6b-[cinnamoyloxy]-eudesman-15-oic acid. Further support to structure 1 was provided by ¹H,¹H-COSY, HMQC and HMBC experiments, which allowed the assignments in Tables 1 and 2. The NOESY spectrum of 1 showed cross peaks between the signal assigned to H-6 and the signals of H-4 and H-7 respectively, suggesting that all three protons were on the same side of the molecule. Assuming an A/B ring fusion (5aH, 10bMe); these results clearly confirm a b-configuration for C-4 carboxyl-, C-6 "trans"-cinnamoyl- and C-7 isopropyl groups.

Compound 3 was obtained as white needles (mp 201-203ºC; [a] _D: +176.72º). Its molecular formula C₂₆H₃₄O₆ ([M⁺] m/z 442.3501, high resolution EI-MS) and its NMR spectral data (Tables 1 and 2) indicated that 3 differed from 1 only by the presence of an extra acetoxy group. [IR: 1.740 cm^-1;d_H 2.06; d_C 21.28 and 170.43]. This group was located in C-1 from the HMBC spectrum, which showed that H-1 (d 4.54, t J 2.5 Hz) was correlated to C-2/C-3 (d 22.73), C-5 (d 43.86), C-10 (d 37.44), C-14 (d 20.53) and C-1" (d 170.43). The a-orientation of acetoxy group already evidenced for the multiplicity of H-1 resonance, also followed from the strong shielding effect on C-3 and C-9 signals, when the chemical shifts of 3 were compared with those of 1 and 2 (Table 2). Thus, 3 was characterised as 1a-acetoxy-6b-[cinnamoyloxy] eudesman-15-oic acid, which had already been reported from Verbesina eggersii Hieron,² but it was isolated as the methyl ester 4. Treatment of 3 with CH₂N₂/eter gave a methyl ester with data identical with those ones of 4. The physical and spectral data of the acid 3 have not been previously published.

Compound 5 was isolated as colourless hexagonal plates (mp185-87º C; [a] _D: +65.89º). On the basis of high resolution EI-MS (m/z 368.2375 [M-H₂O]⁺) and ¹³C-NMR (BB and DEPT) spectral data, the molecular formula of 5 was deduced to be C₂₄H₃₄O₄. These data, as well as 2D-NMR experiments, revealed that 5 is a 6b-[cinnamoyloxy]-eudesmane sesquiterpene similar to 1, with an additional secondary hydroxyl group (d_H 3.10 (-OH) and 3.44 (H-C-O-); d_C 78.84), but in which, the C-15 carboxyl group was replaced by a methyl (d_H 1.14; d_C 17.92) located on a carbon that supports a tertiary hydroxyl group (d_C 75.18). The position of secondary hydroxyl group was clarified by the correlation peaks between C-1/H-3; C-2/H-3; C-4/H-3; C-5/H-3; C-15/H-3; C-3/H-1; C-3/H-2; C-3/H-5 and C-3/H-15 in the HMBC spectrum. On acetylation with Ac₂O/Py, compound 5 gave the monoacetate 6. Treatment of 5 with H₂SO₄ in dry acetone gave the dehydration products 7 and 8, but did not give an acetonide derivative. In spite of this result, the stereochemistry in C-3 was evidenced on the basis of H-3 multiplicity signal and the magnitude of its coupling constants to H-2a (J 3.5 Hz) and H-2b a (J 11.5 Hz), which were in agreement with a b-equatorial oriented hydroxyl group. All the above data were consistent with the structure proposed for 5, and these ones also agree well with the spectroscopic data reported for the 6b-[cinnamoyloxy]-3b, 4a-dihydroxyeudesmane, a sesquiterpene previously isolated from V. persicifolia D.C.⁶ and V. oncophora Rob. et Seat.⁷

Compound 9 (oil, [a] _D: -13.8º, formula molecular C₂₄H₃₄O₄) was also identified as a 6b-[cinnamoyloxy]-eudesmane derivative similar to 5. The ¹H- and ¹³C-NMR data, as well as the carbon connectivity pattern deduced from ¹H,¹H-COSY, HMQC and HMBC experiments, indicated that 9 lacks of the C-3 hydroxyl group and that the C-4 methyl has been replaced by a hydroxymethyl group [d_H 3.35 d (J 11.0 Hz) and 3.75 dd (J 11.0 and J1.3 Hz); d_C 62.73]. The W coupling (J= 1.3 Hz) between H-15_b and H-3a revealed a b-axial orientation of hydoxymethyl group. The physical constants and the EIMS and ¹H-NMR data of 9, were in agreement with those published for the 6b-[cinnamoyloxy]-4a, 15-dihydroxyeudesmane, which has been previously isolated from V. eggersii.⁵ Until now ¹³C-NMR data of 9 have not been reported in the literature.

From a chemotaxonomic aspect the isolated eudesmane sesquiterpenes have to be regarded as typical constituents of Verbesina species, even though similar eudesmane cinnamates has sporadically been isolated from Ambrosia, Brintonia and Solidago species.^21-23 From a biological point of view, it is also important to highlight that many eudesmane derivatives, with structures related to 1-9, have shown antifeedant,²⁴ antibacterial²⁵ or cytotoxic²⁶ properties.

Experimental

General experimental procedures

Melting points were determined with a Fisher-Johns apparatus and they have not been corrected. Optical activities were measured in CHCl₃ on a Rudolph Research Autopol III polarimeter. IR spectra were taken on a Perkin-Elmer FT-1725X spectrophotometer as film or KBr pellets. ¹H, ¹³C and two-dimensional NMR spectra were measured on a Bruker-Avance DRX400 instrument, using CDCl₃ as solvent with TMS as internal standard. EI-MS and HREI-MS were run on a Hewlett-Packard 5930A and on an Autospec VG spectrometer, respectively; direct inlet, 70 eV. TLC was carried out on 0.25 mm layers of silica gel PF 254 (Merck). VCC was performated with silica gel 60 (70-230 mesh.).

Plant material

Verbesina turbacensis H.B.K. was collected at La Hechicera, Municipio Autónomo Libertador (Mérida, Venezuela) in November. A voucher specimen (JMA 1511) was deposited in the MERF Herbarium (Faculty of Pharmacy, ULA).

Extraction and isolation of the constituents

Leaves and stems of V. turbacensis (ca 7.5 kg) were air-dried, ground and exhaustively extracted with acetone at room temperature for 1 week. The dissolution obtained was concentrated in vacuo to afford a dark brown residue (450 g), which was preadsorbed on silica gel and subjected to VCC over silica gel,²⁰ using hexane with increasing amounts of EtOAc as eluent. Fractions of 1 L were collected and combined based upon TLC monitoring. From fractions eluted with hexane-EtOAc (7:3, v/v), stigmasterol (55 mg) was purified by crystallisation and identified by mp, IR, ¹H NMR and TLC comparison. Fractions eluted with hexane-EtOAc (3:2, v/v) were purified by repeated flash chromatography or preparative TLC yielding four compounds, which were obtained in the following sequence: 1 (2.83 g), 3 (870 mg), 5 (6.25 g) and 9 (35 mg).

6b-[cinnamoyloxy]-eudesman-15-oic acid (1)

Colourless prisms (Me₂CO), mp 221-223º C (lit.² mp 193º C); [a]_D: + 147.2º (c, 0.43 CHCl₃).; IR n_max/ cm^-1 3600-3200, 2950, 1735, 1690, 1665, 1220, 1180, 790, 700 (KBr); UV (MeOH) l_max: 275 nm; HR-EIMS, [m/z, (% rel. int.)]: 384.2189 (M⁺, calcd. for C₂₄H₃₂O₄: 384.2300) (4.32); LR-EIMS [m/z, (% rel. int.)]: 384 [M⁺] (4.35), 366 [M⁺-H₂O](3.80), 356 [M⁺-CO](2.89), 338 [M⁺-HCOOH](46.48), 253 [M⁺-PhCH=CHCO](9.07), 236 [M⁺-PhCH=CHCOOH](39.60), 235 (48.34), 221 [M⁺-PhCH=CHCOOH-CH₃] (7.74), 193 [M⁺-PhCH=CHCOOH-C₃H₇ ](54.51), 190 (30.48), 175 (22.15), 148 (20.83), 147 (20.88), 131 [PhCH=CHCO]⁺ (100), 103 [PhCH=CH]⁺ (22.45), 91 (8.59), 77 (9.62).

Methyl-6b-[cinnamoyloxy]-eudesman-15-oate (2)

Compound 1 (320 mg) was treated with excess ethereal CH₂N₂ and solution was left standing overnight in a refrigerator at 4°. Evaporation of ether yielded the methyl ester 2 (325 mg): White needles (EtOAc), mp 109-111º C; [a]_D: + 45.1º (c, 0.32 CHCl₃); IR n_max/ cm^-1 1723, 1700, 1667, 1211, 1018, 859, 727 (KBr); HR-EIMS [m/z, (% rel. int.)]: 398.2808 (M⁺, calcd. for C₂₅H₃₄O₄: 398.2497) (1.52); LR-EIMS [m/z, (% rel. int.)]: 398 [M⁺] (1.54), 370 (0.53), 338 [M⁺-HCOOCH₃](9.89), 293 (1.23), 267 [M⁺-PhCH=CHCO](6.66), 250 [M⁺-PhCH=CHCOOH](5.89), 235 [M⁺-PhCH=CHCOOH-CH₃] (20.88), 207 [M⁺-PhCH=CHCOOH-C₃H₇ ](9.11), 190 [M⁺-PhCH=CHCOOH- HCOOCH₃](16.47), 175 (4.01), 131 [PhCH=CHCO]⁺ (100), 103 (20.36), 91 (4.58), 77 (7.98), 55 (6.43).

1a-Acetoxy-6b-[cinnamoyloxy]-eudesman-15-oic (3)

White needles (EtOAc), mp 201-203ºC; [a]_D: +176.72º (c, 0.55 CHCl₃).; IR n_max/ cm^-1 3500-3250, 2950, 1740,1735, 1700, 1650, 1280, 1180, 750, 690 (KBr); UV (MeOH) l_max: 275 nm; HR-EIMS [m/z, (% rel. int.)]: 442.3501 (M⁺, calcd. for C₂₆H₃₄O₆: 442.2355) (0.56); LR-EIMS [m/z, (% rel. int.)]: 442 [M⁺] (0.60), 424 [M⁺-H₂O](2.52), 414 [M⁺-CO](2.76), 396 [M⁺-HCOOH](6.06), 364 [M⁺-H₂O-AcOH] (1.83), 336 [M⁺-HCOOH-AcOH](13.85), 311 [M⁺-PhCH=CHCO](2.73), 294 [M⁺-PhCH=CHCOOH](3.30), 293 (9.27), 251 [M⁺-PhCH=CHCOOH-C₃H₇ ](1.08), 234 [M⁺-PhCH=CHCOOH-AcOH](29.97), 233 (12.03), 219 [M⁺-PhCH=CHCOOH-AcOH-CH₃](6.93), 191[M⁺-PhCH=CHCOOH-AcOH-C₃H ₇] (22.41), 148 (6.34), 147 (16.02), 145 (18.71), 131 [PhCH=CHCO]⁺ (100), 103 [PhCH=CH]⁺ (22.10), 91 (7.45), 77 (8.37).

Methyl-1a-acetoxy-6b-[cinnamoyloxy]-eudesman-15 -oate (4)

Compound 3 (200 mg) was methylated following the procedure above indicated. The methyl ester 4 (195 mg) was obtained as white needles (hexane), mp 172-75ºC; [a]_D: +68.25º (c, 0.18 CHCl₃).; IR n_max/ cm^-1 1735, 1730, 1715, 1635, 1280, 1243, 1018, 750 (KBr); HR-EIMS [m/z, (% rel. int.)]: 456.2491 (M⁺, calcd. for C₂₇H₃₆O₆: 456.2511) (0.86); LR-EIMS [m/z, (% rel. int.)]: 456 [M⁺] (0.70), 428 (0.67), 396 [M⁺-AcOH](7.67), 350 (7.85), 336 [M⁺-AcOH-HCOOCH₃] (7.81), 325 [M⁺-PhCH=CHCO](6.47), 308 [M⁺-PhCH=CHCOOH](3.22), 293 [M⁺-PhCH=CHCOOH-CH₃](25.06), 248 [M⁺-PhCH=CHCOOH-AcOH](23.33), 233 (14.08), 205 [M⁺-PhCH=CHCOOH-AcOH-C₃H ₇] (27.26), 188 (13.56), 147 (15.38), 145 (40.11), 131 [PhCH=CHCO]⁺ (100), 103 (37.60), 91 (7.28), 77 (15.09), 55 (18.08).

6b-[cinnamoyloxy]-3b, 4a-dihydroxyeudesmane (5)

Colourless hexagonal plates (EtOAc), mp 185-87º C; [a] _D: +65.89º (c, 0.39 CHCl₃); IR n_max/ cm^-1 3430, 2950, 1730, 1647, 1200, 1100, 700 (KBr); UV (MeOH) l_max: 280 nm; HR-EIMS [m/z, (% rel. int.)]: 368.2375 ([M-H₂O]⁺, calcd. for C₂₄H₃₂O₃: 368.2351) (2.82); LR-EIMS [m/z, (% rel. int.)]: 368 [M⁺-H₂O](2.79), 350 [M⁺-2H₂O] (0.79), 307 [M⁺-2H₂O-C₃H₇ ](1.49), 238 [M⁺-PhCH=CHCOOH](48.76), 220 [M⁺-PhCH=CHCOOH-H₂O](20.72), 205 [M⁺-PhCH=CHCOOH-H₂O-CH₃ ](7.86), 202 [M⁺-PhCH=CHCOOH-2H₂O] (8.91),195 [M⁺-PhCH=CHCOOH-C₃H₇ ] (20.61), 177 [M⁺-PhCH=CHCOOH-H₂O-C₃ H₇] (38.20), 159 [M⁺-PhCH=CHCOOH-2H₂O-C₃ H₇] (10.45), 149 (12.68), 137 (20.14), 131 [PhCH=CHCO]⁺ (100), 121 (10.14), 103 [PhCH=CH]⁺ (27.84), 95 (11.68), 91 (10.75), 81 (18.10), 77 (11.79).

3b-Acetoxy-6b-[cinnamoyloxy]-4 a-hydroxyeudesmane (6)

Compound 5 (340 mg) was dissolved in pyridine (5 ml) and treated with Ac₂O (10 ml) at room temperature overnight. Ice was added to the reaction mixture and immediately was extracted with EtOAc. The EtOAc layer was dried on MgSO₄ and evaporated to yield the acetate 6 (295 mg): Colourless oil; [a] _D: +24.5º (c, 0.20 CHCl₃); n_max/ cm^-1 3515, 1712, 1633, 1264, 1076, 700 (nujol); HR-EIMS [m/z, (% rel. int.)]: 428.2556 ([M⁺], calcd. for C₂₆H₃₆O₅: 428.2562) (0.32); LR-EIMS [m/z, (% rel. int.)]: 428 [M⁺](0.18), 410 [M⁺-H₂O] (0.15), 368 [M⁺-AcOH] (2.34), 350 (0.91), 280 [M⁺-PhCH=CHCOOH](5.27), 262 [M⁺-PhCH=CHCOOH-H₂O](12.94), 238 (7.15), 220 [M⁺-PhCH=CHCOOH-AcOH](33.98), 202 (32.72), 187 (9.00), 177 (26.21), 159 (22.73), 148 (9.75), 137 (14.34), 131 [PhCH=CHCO]⁺ (100), 107 (10.41), 103 [PhCH=CH]⁺ (46.61), 91 (12.67), 77 (25.52), 69 (11.37), 55 (14.84).

Treatment of compound 5 with H₂SO₄/Me₂CO

Compound 5 (210 mg) was dissolved in dry acetone (20 ml) and a few drops of H₂SO₄ were added. The solution was stirred for 24 h. at room temperature, neutralized with 10% aq. HCO₃Na and extracted with EtAcO. The EtAcO layer was dried on Na₂SO₄ and concentrated "in vacuo" yielding an oily residue, which after chromatography gave 7 (95 mg) and 8 (45 mg).

6b-[cinnamoyloxy]-3b-hydroxyeudesm-4,15-ene (7): mp140-42º C; IR n_max/cm^-1 3510, 1735, 1630, 1255 1085, 890, 710 (KBr); HR-EIMS [m/z, (% rel. int.)]: 368.22321 ([M⁺], calcd. for C₂₄H₃₂O₃: 368.2351) (3.72); LR-EIMS [m/z, (% rel. int.)]: 368 [M⁺](4.07), 350 [M⁺-H₂O] (2.25), 307 [M⁺-H₂O-C₃H₇ ] (4.69), 220 [M⁺-PhCH=CHCOOH](15.87), 202 [M⁺-PhCH=CHCOOH-H₂O](41.31), 187 (9.39), 177 [M⁺-PhCH=CHCOOH- C₃H₇](15.25), 159 (44.99), 145 (6.37), 131 [PhCH=CHCO]⁺ (100), 103 [PhCH=CH]⁺ (38.03), 91 (13.29), 77 (20.43), 67 (6.63), 55 (9.46).

6b-[cinnamoyloxy]-3-oxo-4bH-eudesmane (8): Colourless oil; IR n_max/cm^-1 1732, 1715, 1633, 1220, 740, 710 (nujol).

6b-[cinnamoyloxy]-4a,15-dihydroxyeudesmane (9)

Colourless oil; [a]_D: -13.8º (c, 0.25 CHCl₃).; IR n_max/cm^-1 3590, 2960, 1720, 1642, 1130, 710 (nujol); UV (MeOH) l_max: 278 nm; HR-EIMS [m/z, (% rel. int.)]: 368.2369 ([M-H₂O] ⁺, calcd. for C₂₄H₃₂O₃: 368.2351) (7.98); LR-EIMS [m/z, (% rel. int.)]: 368 [M⁺-H₂O](8.45), 355 [M⁺-CH₂OH] (11.23), 337 [M⁺-H₂O-CH₂OH] (2.81), 325 [M⁺-H₂O-C₃H₇ ] (1.37), 294 (0.42), 238 [M⁺-PhCH=CHCOOH](12.35), 220 [M⁺-PhCH=CHCOOH-H₂O](32.18), 207 [M⁺-PhCH=CHCOOH-CH₂OH](73.18), 205 (7.53), 195 [M⁺-PhCH=CHCOOH-C₃H₇ ] (19.15), 189 (27.16), 177 [M⁺-PhCH=CHCOOH-H₂O-C₃ H₇] (32.71), 146 (11.36), 131 [PhCH=CHCO]⁺ (100), 103 [PhCH=CH]⁺ (38.15), 91 (12.41), 77 (11.10).

Acknowledgements

We are grateful to CDCHT-ULA (Grant Fa-185-96C) for financial support. Thanks are also due to Ing. For. Juan Carmona (MERF Herbarium, Facultad de Farmacia, ULA) for identification of plant material.

References

Received: October 10, 2001

Published on the web: May 9, 2002

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Publication Dates

• Publication in this collection
  01 July 2002
• Date of issue
  June 2002

History

• Received
  10 Oct 2001
• Accepted
  09 May 2002