Pyrrolizidine alkaloids and diterpenes from Villasenoria orcuttii

Abstracts

The chemical study of Villasenoria orcuttii, the only species of the genus Villasenoria, afforded three acyclic diterpenes, two of them described for the first time. Two pyrrolizidine alkaloids, florosenine and floridanine, among other known compounds were also isolated. The absolute configuration of floridanine was determined by X-ray analysis using anomalous dispersion with Cu Kαradiation, and its¹ H and13 C nuclear magnetic resonance (NMR) data were corrected.

Villasenoria orcuttii; diterpenes; pyrrolizidine alkaloids; absolute configuration

O estudo químico da Villasenoria orcuttii, a única espécie do gênero Villasenoria, levou ao isolamento de três diterpenos acíclicos, dois deles descritos pela primeira vez. Dois alcaloides pirrolizidínicos, florosenina e floridanina, entre outros compostos já conhecidos, também foram isolados. A configuração absoluta da floridanina foi determinada por análise de raios X usando dispersão anômala com radiação Cu Kα e seus dados de ressonância magnética nuclear (RMN) de¹ H e de13 C foram corrigidos.

ARTICLES

Pyrrolizidine alkaloids and diterpenes from Villasenoria orcuttii

Amira Arciniegas^I; Ana L. Pérez-Castorena^I,*; Karina González^I; Marisol Reyes-Lezama^II; José Luis Villaseñor^III; Alfonso Romo de Vivar^I

^IInstituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, D. F., México

^IICentro Conjunto de Investigación en Química Sustentable, Universidad Autónoma del Estado de México-Universidad Nacional Autónoma de México (UAEM-UNAM), Carretera Toluca-Atlacomulco, km 14.5, Toluca 50200, Estado de México, México

^IIIInstituto de Biología, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, D. F., México

ABSTRACT

The chemical study of Villasenoria orcuttii, the only species of the genus Villasenoria, afforded three acyclic diterpenes, two of them described for the first time. Two pyrrolizidine alkaloids, florosenine and floridanine, among other known compounds were also isolated. The absolute configuration of floridanine was determined by X-ray analysis using anomalous dispersion with Cu K_αradiation, and its¹ H and¹³ C nuclear magnetic resonance (NMR) data were corrected.

Keywords: Villasenoria orcuttii, diterpenes, pyrrolizidine alkaloids, absolute configuration

RESUMO

O estudo químico da Villasenoria orcuttii, a única espécie do gênero Villasenoria, levou ao isolamento de três diterpenos acíclicos, dois deles descritos pela primeira vez. Dois alcaloides pirrolizidínicos, florosenina e floridanina, entre outros compostos já conhecidos, também foram isolados. A configuração absoluta da floridanina foi determinada por análise de raios X usando dispersão anômala com radiação Cu K_α e seus dados de ressonância magnética nuclear (RMN) de¹ H e de¹³ C foram corrigidos.

Introduction

Villasenoria orcuttii, the only species of the genus Villasenoria (Asteraceae, Senecioneae), is a shrub that grows in the rainforest of Chiapas, Oaxaca and Southern Veracruz (Mexico) at 100 to 2000 m of elevation. ¹Villasenoria orcuttii (formerly Senecio orcuttii) was initially included into the genus Telanthophora, which together with the genus Pittocaulon is constituted by species segregated from the traditional section Terminales Greenm. of the genus Senecio s.l. ² Further studies evidenced the differences between Senecio (Telanthophora) orcuttii and other species of Senecio, Thelantophora or Pittocaulon and placed it into his own genus: Villasenoria. ¹ To the best of our knowledge, there is no chemical work on the genus Villasenoria. Previous studies on its related genera, Telanthophora, Senecio and Pittocaulon, described the presence, in the three of them, of sesquitepene derivatives mainly of eremophilane and/or oplopane types, while pyrrrolizidine alkaloids (PAs) have been found only in species of Senecio and Pittocaulon. ³ As continuation of our survey on Senecioneae, it is reported the isolation of three acyclic diterpenes from Villasenoria orcuttii: phytane-1,2,3-triol (1), previously obtained as a synthetic product,^4,5 and compounds 2 and 3 which are described for the first time, two PAs: florosenine (4)^6-8 and floridanine (5),^6,9 together with methyl ferulate (6),¹⁰ pterolactame (7),¹¹ tyramine (8)¹² and β-sitosteryl glucoside (Figure 1). Additionally, the absolute configuration of floridanine (5) was determined by X-ray analysis and its¹ H and¹³ C nuclear magnetic resonance (NMR) data were corrected.

Results and Discussion

Compound2was obtained as colorless oil. Its IR spectrum indicated the presence of hydroxyl (3455 cm^-1) and carbonyl groups (1742 cm^-1). The molecular formula C₂₂H₄₄O₄ was determined by high-resolution electrospray ionization mass spectrometry (HRESIMS). The¹³ C NMR analysis of 2 indicated the presence of three oxygenated carbon atoms and a carbonyl function, besides the signals of three methines, nine methylenes and five methyl groups. The¹ H NMR spectrum exhibited four secondary (δ_H 0.84-0.88), a tertiary (δ_H 1.23) and an acetyl (δ_H 2.12) methyl groups; an oxygenated methylene (δ_H 4.32, dd, J 11.6, 2.8 Hz; 4.09, dd, J 11.6, 8.4 Hz) and an oxygenated methine (δ_H 3.69, dd, J 8.4, 2.8 Hz). 2D NMR spectroscopy allowed the identification of a 3,7,11,15-tetramethylhexadecane skeleton with a vicinal terminal triol, one of them acetylated, indicating that compound 2 was the 1-O-acetyl derivative of the compound 1, as confirmed by the isolation of 2 by the selective acetylation of the compound 1.¹³

Compound 3, isolated as colorless oil, showed the molecular formula C₂₀ (HRESIMS). The NMR spectra were similar to that one from compound 1 with the additional signals of a disubstituted double bond and a hydroxymethine. The long-range (HMBC)¹ H-¹³ C NMR correlation experiment allowed to locate these groups at C-15 and C-14, respectively. As in compound 1, three vicinal hydroxyl groups at C-1, C-2 and C-3 were observed, therefore, the structure of 3 was elucidated as 3,7,11,15-tetramethyl-15-hexadecene-1,2,3,14-tetraol.

The alkaloid 5 was isolated as colorless prisms, mp 199-200 ºC. The molecular formula C₂₁NO₉ was determined by HRFABMS. The EIMS spectrum showed a molecular ion at m/z 441 and the otonecine-type PAs diagnostic fragment ions⁶ at m/z 168 [C₉H₁₄NO₂]⁺, 149 [C₉NO]⁺, 122 [C₇H₈NO]⁺ and 110 [C₆H₈NO]⁺. The presence of the signals of a α,β-unsaturated ketone carbonyl at δ_C 186.9 and of three ester carbonyl atδ_C 174.6, 171.2 and of three ester carbonyl at δ_C 174.6, 171.2 and 169.9 in the 13C NMR spectrum suggested an acetylated macrocyclic diester of otonecine. The proton NMR spectrum of this alkaloid was similar to that of the floridanine,⁹ the main difference was the signal of H-20 assigned by the HMBC and COSY correlations at δ_H 3.72 (q, J 6.5 Hz), which was reported for the floridanine at δ_H 3.03 m. The positions of the signals of H-13 at δ_H 1.47 m, and of H₂-14 at δ_H 1.69 (d, J 14.0 Hz) and δ_H 1.53 (dd, J 14.0, 10.0 Hz) were also different from the reported for these same protons (H-13 at δ_H 1.89 m and H₂-14 at δ_H 2.35 m) in the floridanine. These discrepancies could be due to different positions of the acetoxy group in 5 and in the floridanine. ⁹ In order to clarify these structural differences, an X-ray diffraction experiment (Figure 2) was performed establishing that compound 5 had indeed the structure reported for the floridanine.

Consequently, the ¹H and ¹³C NMR data (obtained by means of 2D NMR spectroscopy) should correct those from the literature. ⁹ The absolute stereochemistry of the floridanine (5) (7R, 12R, 13R, 15S and 20R) was determined by the anomalous dispersion method with Cu K_α radiation, used in the X-ray experiment, which afforded an absolute structure parameter of 0.08 (4).

Conclusions

The presence of pyrrolidizine alkaloids is in agreement with the chemistry of many genera of the tribe Senecioneae, but the absence of sesquiterpenes as well as the presence of acyclic diterpenes establish a clear chemotaxonomic difference between Villasenoria and its related genera Telanthophora, Senecio and Pittocaulon and support its position in a new genus.

Experimental

General experimental procedures

Melting points were determined on a Fisher-Jones melting point apparatus and are uncorrected. Optical rotations were determined on a Perkin-Elmer 343 polarimeter. Circular dichroism was obtained on a Jasco J-720 spectropolarimeter. UV and IR spectra were recorded on a spectrophotometer Shimadzu UV 16U and a Bruker Tensor 27 spectrometer, respectively. 1D and 2D NMR spectra were obtained on a Bruker Avance III 400 MHz or on a Varian-Unity Inova 500 MHz spectrometer with tetramethylsilane (TMS) as internal standard. Electron ionization mass spectrometry (EIMS) analyses were determined on a Bruker Daltonics Analysis 3.2 mass spectrometer. HRESIMS analyses were performed on a Bruker MicrOTOF II mass spectrometer with a mass resolution of 16.500 FWHM (full width at half maximum), mass interval 50-20.000 m/z and speed of 40 Hz. Fast atom bombardment mass spectrometry (FABMS) analyses were obtained on a JEOL JMS-SX102A mass spectrometer operated with an acceleration voltage of 10 kV, and the samples were desorbed from a nitrobenzyl alcohol matrix using 6 kV xenon atoms. HRFABMS analyses were performed at a 10,000 resolution using electric field scans and polyethylene glycol ions (Fluka 200 and 300) as the reference material. Column chromatography was carried out under vacuum on silica gel G-60 (Merck, Darmstadt, Germany). Analytical thin layer chromatography (TLC) was carried out on silica gel 60-G F₂₅₄ or RP-18W/UV₂₅₄ (Macherey-Nagel, Germany) and preparative TLC on silica gel G-200 F₂₅₄, layer thickness of 2.0 mm, or RP-18W/UV₂₅₄, layer thickness of 1.0 mm.

Plant material

Villasenoria orcuttii (Greenm. ) B. L. Clark was collected in San Miguel Soyaltepec, Tuxtepec, Oaxaca, México, in January 2009. A voucher specimen was deposited at the Herbarium del Instituto de Biología, UNAM, México (MEXU 1256447).

Extraction and isolation

Dried and ground aerial parts (276 g) and roots (116 g) of V. orcuttii were separately and successively extracted with hexane and methanol. Solvents were removed under reduced pressure to obtain the respective extracts. The methanolic extracts were partitioned with EtOAc-H₂O. The aqueous extracts, which gave positive test with the Dragendorff alkaloid reagent, were treated with Zn/aq.H₂SO₄¹⁴ to give the alkaloidal residues. The hexanic extract of roots (820 mg) was fractionated by vacuum column chromatography (VCC) using hexane-EtOAc mixtures in increasing gradient of polarity. Fractions eluted with hexane-EtOAc 19:1 (65 mg) were purified by flash column chromatography (FCC) (hexane-acetone 19:1) to obtain compound 2 (25 mg). Fractions eluted with hexane-EtOAc 9:1 afforded phytane-1,2,3-triol^4,5 (1, colorless oil, 361 mg). The hexanic extract of aerial parts (2.9 g) was submitted to VCC using hexane-acetone mixtures as gradient elution system to afford fractions A-C eluted with hexane-acetone 49:1, 19:1 and 9:1 mixtures, respectively. Fraction A (268 mg) was purified by FCC eluted with CH₂Cl₂ to obtain a mixture of β-sitosterol-stigmasterol (38 mg). Fractions B (150 mg) produced by FCC eluted with hexane-acetone 19:1 compound 2 (24 mg). Fraction C (550 mg) by two successive FCC eluted with hexane-acetone 9:1 and CH₂Cl₂, respectively, afforded 250 mg of compound 1. The ethyl acetate extract of the aerial parts (3.0 g) was purified by VCC eluting with hexane-EtOAc mixtures in gradient of increasing polarity to afford compound 1 (15 mg) from the hexane-EtOAc 9:1 mixtures, and from fractions eluted with hexane-EtOAc 4:1, a mixture (45 mg) which by preparative TLC (hexane-acetone 4:1) produced methyl ferulate¹⁰ (6, white needles, mp 66-67 ºC, 10 mg). The ethyl acetate extract of roots (1.5 g) purified by the same way as extract of aerial parts afforded 20 mg of 1, from the hexane-EtOAc 9:1 mixtures, and from fractions eluted with hexane-EtOAc 7:3, a mixture (95 mg) which was purified by RPTLC (reversed-phase TLC) (MeOH-H₂O 3:2 × 4) followed of FCC (hexane-acetone 7:3) to produce compound 3 (25 mg). The alkaloidal extract of roots (480 mg) was purified by VCC (CH₂Cl₂-MeOH in increasing gradient of polarity) to afford, from CH₂Cl₂-MeOH 98:2 mixtures, pterolactame¹¹ (7, colorless needles, mp 55-56 ºC, 32 mg) and tyramine¹² (8, white crystals, mp 160-162 ºC, 98 mg), fraction E from CH₂Cl₂-MeOH 95:5, and fraction F from CH₂Cl₂-MeOH 9:1 eluates. Fraction E (65 mg) was submitted to FCC (CH₂Cl₂-MeOH 95:5) followed by a preparative TLC (CH₂Cl₂-MeOH-NH₄OH 95:4.9:0.1 × 2) to afford florosenine^6-8 (4, mp 99-101 ºC, + 30.5, c 0.2, CHCl₃, 5 mg). Fraction F (102 mg) afforded after two successive FCC (CH₂Cl₂-MeOH 9:1) and a preparative TLC (CH₂Cl₂-MeOH-NH₄OH 95:4.9:0.1 × 3) floridanine (5, 12 mg). ^6,9 The alkaloidal extract of aerial parts (450 mg) was worked up as described for the root alkaloidal extract to afford 4 (3.5 mg), 5 (10 mg), 7 (17 mg) and 8 (35 mg).

Selective acetylation of phytane-1,2,3-triol (1)

Compound 1 (0.28 mmol), acetylchloride (0.28 mmol) and iPr₂EtN (0.56 mmol) in CH₂Cl₂ (2 mL) were stirred at -70 ^oC for 3 h and then 1 h at room temperature. ¹³ The reaction mixture was washed with HCl (5%) and NaHCO₃ to obtain 87 mg of a mixture which was purified by FCC (hexane-acetone 85:15) to obtain 35 mg (34 %) of compound 2.

Compound 2

Colorless oil; [α]²⁵_D + 5.0 (c 0.11, CHCl₃); IR (CHCl₃) ν_max/cm^-1 3455, 1742; ¹H NMR (400 MHz, CDCl₃)δ 4.32 (dd, 1H, J 11.6, 2.8 Hz, H1a), 4.09 (dd, 1H, J 11.6, 8.4 Hz, H1b), 3.69 (dd, 1H, J 8.4, 2.8 Hz, H2), 1.06-1.32 (m, 21H, H4 to H15), 2.12 (s, 3H, CH₃CO), 1.23 (s, 3H, H17), 0.84-0.88 (m, 12H, H16, H18, H19, H20); ¹³C NMR (100 MHz, CDCl₃)δ 171.4 (CH₃CO), 75.7 (C2), 73.6 (C3), 65.9 (C1), 39.4, 37.7, 37.6, 37.4, 37.3, 37.2, 24.8, 24.5, 20.7 (C4 to C6, C8 to C10, C12 to C14), 32.8, 32.7, 27.7 (C15, C11, C7), 23.5 (C17), 22.7, 22.6, 19.7, 18.6 (C16 and C18 to C20), 20.9 (CH₃CO); HRESIMS m/z 395.3146 [M + Na]⁺ (C₂₂H₄₄NaO₄ requires 395.3132).

Compound 3

Colorless oil; [α]²⁵_D + 11.0 (c 0.21, CHCl₃); IR (CHCl₃) ν_max/cm^-1 3433, 1603, 1460;¹ H NMR (500 MHz, CDCl₃) δ 4.93 (br quint, 1H, J 1.0 Hz, H16a), 4.84 (br quint, 1H, J 1.5 Hz, H16b), 4.03 (br dd, 1H, J 11.0, 6.0 Hz, H14), 3.78 (d, 2H, J 5.0 Hz, H1), 3.49 (br t, 1H, J 5.0 Hz, H2), 1.72 (s, 3H, H20), 1.23 (s, 3H, H17), 1.05-1.60 (m, 18H, H4 to H13), 0.86* (d, 3H, J 6.5 Hz, H18), 0.87* ( d, 3H, J 6.5 Hz, H19), *interchangeable signals;¹³ C NMR (125 MHz, CDCl₃) δ 147.5 (C15), 111.2 (C16), 76.5 (C14), 76.1 (C2), 74.7 (C3), 63.9 (C1), 38.4, 37.5, 37.2, 37.1, 32.3, 24.3, 24.2, 20.9 (C4 to C6, C8 to C10, C12, C13), 32.7, 32.5 (C11, C7), 23.7 (C17), 20.9 (C18 and C19) 17.5 (C20); HRESIMS m/z 367.2832 [M + Na]⁺ (C₂₀NaO₄requires 367.2819).(C₂₀H₄₀NaO₄ requires 367.2819).

Floridanine (5)

Colorless prism from hexane-EtOAc, mp 199200 ºC; + 68.0 (c 0.10, CHCl₃); IR (CHCl₃) ν_max/cm^-1 3691, 3518, 1735, 1602; CD (c 4.5 × 10^-5 mol L^-1, EtOH) Δε_{209 nm} + 18.6; ¹H NMR (500 MHz, CDCl₃)δ 6.09 ( -br t, 1H, J 2.0 Hz, H2), 5.15 (d, 1H, J 11.0 Hz, H9a), 4.98 (t, 1H, J 2.5 Hz, H7), 4.44 (br d, 1H, J 11.0 Hz, H9b), 3.72 (q, 1H, J 6.5 Hz, H20), 3.46 (br d, 1H, J 17.5 Hz, H3a), 3.32 (br d, 1H, J 17.5 Hz, H3b), 2.90 (m, 1H, H5a), 2.85 (m, 1H, H5b), 2.60 (dddd, 1H, J 14.0, 12.0, 7.5, 2.5 Hz, H6a), 2.31 (br t, 1H, J 14.0 Hz, H6b), 2.08 (s, 6H, H22, CH₃CO), 1.69 (d, 1H, J 14.0 Hz, H14a), 1.64 (s, 3H, H18), 1.53 (dd, 1H, J 14.0, 10.0 Hz, H14b), 1.47 (m, 1H, H13), 1.24 (d, 3H, J 6.5 Hz, H21), 1.19 (d, 3H, J 6.5 Hz, H19);¹³ C NMR (125 MHz, CDCl₃)δ 186.9 (C8), 174.6 (C16), 171.2 (C11), 169.9 (CH₃CO), 136.8 (C2), 133.9 (C1), 83.9 (C12), 81.9 (C15), 79.1 (C7), 72.7 (C20), 64.2 (C9), 59.5 (C3), 53.7 (C5), 40.3 (C22), 39.7 (C13), 36.3 (C6), 35.8 (C14), 21.6 (C18), 21.4 (CH₃CO), 17.1 (C21), 14.6 (C19); EIMS m/z 441 [M]⁺ (30), 397 [C₂₀H₃₁NO₇]⁺ (30), 354 [C₁₈H₂₈NO₆]⁺ (90), 168 [C₉H₁₄NO₂]⁺ (100), 149 [C₉H₁₁NO]⁺ (65), 122 [C₇H₈NO]+ (50), 110 [C₆H₈NO]+ (48); HRFABMS m/z 442.2080 [M + H]+ (C₂₁H₃₂NO₉ requires 442.2077).

Crystal data of 5

C₂₁H₃₁NO₉∙0.8 (CH₂Cl₂), MW = 509.43, T = 100(2) K, λ = 1.54178 Å, orthorhombic, space group P2(1)2(1)2(1). Unit cell dimensions α= 8.6486(2) Å, b = 12.2669(2) Å, c= 24.8567(5) Å,α = 90º, β = 90º, γ = 90º, V = 2637.08(9)ų, Z = 4, density (calculated) = 1.283 Mg m^-3, absorption coefficient = 2.257 mm^-1, F(000) = 1078, crystal size: 0.29 × 0.18 × 0.16 mm³, theta range for data collection: 4.02 to 66.74º, index ranges: -10 < h < 10, -14 < k < 14, -29 < l < 29, reflections collected: 37883, independent reflections: 4661 [R(int) = 0.0217], completeness to theta = 66.74º 99.6%, absorption correction = semi-empirical from equivalents, max. and min. transmission = 0.7141 and 0.5636, refinement method = full-matrix least-squares on F², data / restraints / parameters 4661 / 664 / 532, goodness-of-fit on F² = 1.057, final R indices [I > 2sigma(I)], R₁ = 0.0495, wR₂ = 0.1466, R indices (all data), R₁ = 0.0505, wR₂ = 0.1486; absolute structure parameter = 0.08(4); largest diffraction peak and hole = 0.569 and -0.195 e Å^-3, respectively; single crystals of 5 were mounted at 100 K on nylon loops and the data were collected on a Bruker APEX DUO diffractometer equipped with an Apex II CCD detector using Incoatec IµS with multilayer optic, Cu K_α radiation. Frames were collected by omega scans and integrated using SAINT software package. Semi-empirical absorption correction (SADABS) was applied. The structure was solved by direct methods (SHELXS programs), and refined by the full-matrix least-squares on F² with SHELXL-97¹⁵ using the SHELXLE GUI. ¹⁶ All non-hydrogen atoms were refined anisotropically. The disordered was refined using the following geometry and U_ij restraints and constraints implemented in the SHELXL-97 program: SIMU, DELU, SAME and DFIX. Crystallographic data for the structure of 5 were deposited in the Cambridge Crystallographic Data Center (deposition No. CCDC 930369).

Supplementary Information

¹H and ¹³C NMR spectra of compounds 1 and 4,¹H and ¹³C NMR and 2D NMR experiments of compounds 2, 3 and 5, HRESIMS of compounds 2 and 3, and crystal refinement data of 5 are available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgements

We are indebted to Beatriz Quiróz, Ma. de los Angeles Peña, Elizabeth Huerta, Isabel Chávez, Héctor Ríos, Rubén Gaviño, Rocío Patiño, Javier Pérez, Luis Velasco, Carmen Márquez and Lizbeth Triana for technical assistance.

Submitted: February 19, 2013

Published online: June 21, 2013

Supplementary Information

The supplementary material is available in pdf: [Supplementary material]

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Publication Dates

• Publication in this collection
  31 July 2013
• Date of issue
  July 2013

History

• Received
  19 Feb 2013
• Accepted
  21 June 2013