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BI- and Tricyclic Diterpenoids fromHalimium viscosumJesüs M.L. Rodilla a , Dina I. De Mendonça a , M. Isabel G. Ismaela , J. Albertino Figueiredo a , Maria Lücia A. Silva a & ElisabeteLopes aa Departmento de Quimica , Universidade da Beira Interior ,6200, Covilhã, PortugalPublished online: 04 Oct 2006.

To cite this article: Jesüs M.L. Rodilla , Dina I. De Mendonça , M. Isabel G. Ismael , J. AlbertinoFigueiredo , Maria Lücia A. Silva & Elisabete Lopes (2001) BI- and Tricyclic Diterpenoids fromHalimium viscosum , Natural Product Letters, 15:6, 401-409, DOI: 10.1080/10575630108041310

To link to this article: http://dx.doi.org/10.1080/10575630108041310

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BI- AND TRICYCLIC DITERPENOIDS FROM HALIMIUM VISCOSUM

JESUS M.L. RODILLA*, DINA I. DE MENDONCA, M. ISABEL G. ISMAEL, J. ALBERTINO FIGUEIREDO,

MARIA LUCIA A. SILVA and ELISABETE LOPES

Departmento de Quimica, Universidade da Beira Interior, 6200 CovilhB, Portugal

(Received 22 December 2000)

The study of the acid and neutral parts of the n-hexane extract of Halimium viscosum (S. Jolo da Pesqueira, Portugal) has led to the isolation of various known diterpenoids with the ent-hali- mane skeleton. Five new compounds have now been isolated, one with the ent-halimane skele- ton, and four with the valparane skeleton, two of them with the valparane skeleton degraded. The structures of these compounds, determined by spectroscopic methods using 2D experiments ('H-I3C, HMQC and HMBC), were dimethyl l(lO)-halimen-15,18-dioate, dimethyl 3.19-dinor- 15-valparen-2,4-dioate, methyl 16-nor-2,3-secovalpara-3,1 5-dioxo-2-oate, 1,3,5,1 S-valparate- traene and 3R-4a-methoxy- 15-valparen-2-one.

Keywords: Halimium viscosum; Cistaceae; nor-diterpenoids; Acids; ent-halimane; nor-valparenes; Valparenes

INTRODUCTION

A variety of diterpenoid structures and skeleta, many of them described for the first time, have been isolated during the last few years from chemotypes of Halimium viscosum found in the Iberian peninsula, and this has encour- aged the search for other chemotypes. Villarino's chemotype contained only derivatives of em-halimane acids, of which the major component was hali- mic acid (1) having a A'"') double bond and a C-4 carboxyl group [1,2]. The other derivatives resulted from the polyfunctionalization [3j of the side chain or even its degradation [4].

*Corresponding author.

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402 J.M.L. RODILLA et al.

Fregeneda's chemotype, however, contained only ent-halimane acids with a saturated side chain, e.g. hydrohalimic acid (2) [5,6]. The neutral fraction from this chemotype possessed a much greater variety of diterpenoid skeleta than the neutral part from the Villarino chemotype [7,8]. In fact, 3-oxygen- ated labdanes [9,10] such as 7,13E-labdadien-3/?, 15-diol (7) (the major component) were isolated from it as well as other hydroxy-labdanes. Moreover, four different carbon backbones were isolated from the same extract: tormesane, as tormesol (12) [ 1 1,121; tormesolane, as tormesolanone (13) [ 131; fregenedade, as fregenedadiol (14) [I4161 and isofregenedane, as isofregenedadiol (15) [17,18].

From Valparaiso's chemotype were isolated only labdane acids with a carboxyl group at C-17 such as zamoranic acid (8) [19,20], with either a saturated or unsaturated side chain [20]. The neutral part afforded labdanes with and without the oxygenated function at ring A (16) [21] and tricyclic diterpenoids hydroxylated with valparane (17) [7,22-241 and valparolane skeleton (18) [25].

Celorico da Beira's chemotype contained hydroalimic acid derivatives (2, 3) with a free hydroxyl group at C-15 or esterified with acids such as acetic, cinnamic and others [26], and some compounds with an oxygenated function at C-2 (4, 5) [27]. From the neutral part, compound (7) and the corresponding formyl derivatives (9, 10, 11) were isolated, besides tricyclic diterpenoids with the valparane (19) and valparolane (20) skeleta.

In this work we report on the isolation and structural determination of a compound from S. Joiio da Pesqueira Halimium viscosum, which is similar to one isolated from Celorico da Beira's chemotype.

R R RI & 1 A"' CHzOH R!=Ra= H 7 Me OH OH 1 C H a H Rs-Ra=H I) COOH OH H A" 3 CHIOMe R,-R,= H 9 Me W H O OH 4 CHGH R&=O 10 Ms OH WHO S CHiOH RI= OK R2= H 11 Me W H O WHO 6 COOMe RI=R.=H 16 CH~OH H H A ~ ~ , I ~ R O H I1 C&OH 18,2!3-01ide

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BI- AND TRICYCLIC DITERPENOIDS 403

12 18 A2; 20 ZpOAc 11 A2 ; 19 3pOH ; 24 20x0 3a,4aepoxi ; 25 A', A', As

RESULTS AND DISCUSSION

The acid fraction of the n-hexane extract of Halimium viscosum (S. Jo50 da Pesqueira) was separated according to the procedure described in the experi- mental section. The major product was hydrohalimic acid which was puri- fied as its methyl ester 2 with the hydroxyl group C-15 free, unlike that in the Celorico da Beira chemotype which had C-15 esterified with acetic, cinnamic or a fatty acid. As minor components also three new methyl esters, 6, 22 and 23 and the known compounds, 3, 4 and 5 were isolated.

By mass spectrometry, compound 6 presented the molecular ion (Mt m/z 364) corresponding to the molecular formula CZ2H3604. The 'H and 13C NMR spectra were very similar to 2 relative to the position of the methyl groups, except for the lack of signals of the hydroxymethylene group at C-15 and the presence of one more methoxycarbonyl group. This led to the conclusion that this compound was an unsaturated dimethyl ester whose structure is dimethyl l(lO-ent-halimen-15,18-dioate.

Compound 22 is a dimethyl ester whose 'H NMR spectrum presented the following signals: MeOOC-CH2- (6 3.65, 3H, s and 2.18, 2H, s), MeOOC- CH2-CH(6 2.36, 2H, d, J=6.0Hz), Me-C(=CHZ) (6 1.74, 3H, s; 4.78 and 4.80, 2H, s each) and two methyl groups Me-C (6 0.81 and 0.96, 3H, s each). The comparison of the multiplicity and the chemical shift of the sig- nals in the 13C NMR spectrum with the spectra of compounds with a valpar- ane skeleton previously isolated (17, 19) [27,28] confirmed the presence of a B and C ring, two methyl singlets and an isopropenyl group. The mass spectrum presented a molecular ion (Mf at m/z 336) in agreement with the formula CZ0H3204 corresponding to a bicyclic system with two double bonds and two methoxycarbonyl groups. The fragments at mjz 73 and

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404 J.M.L. RODILLA et al.

74 indicated the loss of two MeOO-CH2-, characteristic of the McLafferty rearrangement, leading to the corresponding fragment m/z 189. The loss of 42 units gave the base peak, according to Scheme 1.

The correlations observed in the 'H-I3C long-range coupling (Table I), especially those of the methylene groups 1 and 5 , the methyne group 6 and the methyl group 18, confirmed that compound 22 has the structure of dimethyl 3,19-dinor- 1 S-valparen-2,4-dioate.

25 336

22

m+ 3%

1-74

1-73

161

119

Scheme 1

Compound 23 is a diketoester (IR cm-I: 1728, 1713). The 'H NMR spec- trum showed clearly the following groups: MeOOC-CH2-C (6 3.62, 3H, s and 2.23, 2H, s), Me-CO-CH-(6 2.14, 3H, s and 2.62, 1 H, ddd, J , = 8.1, J2= 8.1 and J3 =4.2 Hz) and Me-CO-CH2 (6 2.12, 3H, s and 2.50, 2H, m). The I3C NMR spectrum presented signals for twenty carbon atoms: five methyl groups (one of them Me0 and other two Me-CO-), seven methy- lene groups, three methyne groups and five quaternary carbons, three of them C=O, one as an ester (6 172.4) and two as ketones (6 208.9 and 212.1). The mass spectrum presented a molecular ion M+ at rn/z 336, corre- sponding to the formula C20H3204, which with the characteristic loss of a methyl ester (MeOOC-CH2), two methylketones Me-CO-CH2- and Me-CO- afforded the m/z 161 fragment.

Table I shows the correlations observed in the 2D experiments (HMQC, HMBC). The more important correlations are: H-1 with C-2, 6, 10, 20 and H-6 with C-S,7, 11 and 18, which confirmed the valparane skeleton with the breaking of C-2-C-3 bond and oxidation of both atoms. It is also possible to verify the presence of acetyl group on C-14 instead of the isopropenyl group. This compound can be identified as methyl 16-nor-2,3-secovalpara-3,15- dioxo-2-oate.

From the neutral part, besides 7 and 21 [26], five valparane derivatives 17, 19, 24, 25 and 26 have been isolated, two of them (25 and 26) identified for the first time. Compound 25 is a tetraene derivative whose mass spectrum possessed the molecular ion m/z 268 which corresponds to the molecular

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BI- AND TRICYCLIC DITERPENOIDS 405

formula C20H2X, a tricyclic diterpene with four double bonds. The I3C NMR showed the signals of the eight sp2 carbon atoms: one methylene group, four methyne groups and three quaternary carbon atoms (sp2) indicating that 25 is a tricyclic diterpene with four double bonds. The 'H NMR signals from an isopropenyl group MeC(=CH2) (6 1.72, 3H, s; 4.93 and 4.84, 2H, s each), and three methyl groups, and the base peak (m/z 132) of the mass spectrum (Scheme 1) confirmed that the structure of 25 is a valparane skeleton with three double bonds in ring A. The I3C NMR signals of the carbon atoms of rings B and C and of the isopropenyl group are comparable with those of the other valparanic compounds (17, 19, 24) [27,28]. The 'H-13C correlations (Table I) observed for H-1, H-2, H-4, H-19 and H-20 fixed the position of the double bonds, and thus compound 25 was assigned as 1,3,5,16-~alparatetraene.

The mass spectrum of compound 26 showed a molecular ion m/z 318 corresponding to the molecular formula C21H3402. The other spectroscopic data suggested that 26 contained a ketone and one double bond. The 'H NMR showed two methyl groups as singlets and one isopropenyl group. COSY experiments indicated the presence of a set of signals corresponding to: C-CH2-CO-CH(0Me)- (Table I) belonging to the ring A of the valpar- ane skeleton. The 13C NMR chemical shifts of the remaining signals corre- sponding to rings B and C as in similar compounds. By the HC correlation experiments (Table I) it was confirmed that the carbonyl group is in position 2 and correlates with a CH;, group (8 3.36, lH, d, J = 6.8 Hz and 1.99, lH, d, J = 6.8 Hz) in position 1 and a methoxy group linked to C-4.

The nOe effect in 26 between H-4 and Me-19 showed the stereochemical configuration cis, and the nOe effect between H-1 and Me-19 fixed the con- formation of ring A. The Me0 group is in disposition a, owing to the fact

TABLE I Correlations for compounds 22, 23, 25 and 26 in 2D experiment (CDC13)

22 23 25 26 HMBC HMBC HMBC HMBC

H- 1 H-2 H-4 H-5 H-6 H-9 H-14 H-16 H-17 H-18 H-20

11,20 H- 1 1 H-4 5 , 6 H-6 4, 6, 7, 11 H-8 4, 5 H-14 7, 8, 11 H-17 16 H-18 14, 17 H-19 14, 16 H-20 6, 7, 8, 12 OCH3 1, 6, 10, 11

2, 6, 10, 20 H-1 3 H-2 1, 5, 7, 11, 18 H-4 7, 14, 18 H-5 8, 9, 13, 15 H-14 14, 15 H-16 7, 8, 12 H-17 3, 4 H-18 1, 6, 10, 11 H-19 2 H-20

3, 10, 11 3, 4, 11, 19 5 , 6, 19 3, 4, 7, 11 15, 16 14, 17 14, 15, 16 6, 7, 8, 12 3, 4 1, 6, 10, 11

H- 1 H-4 H-18 H-14 H-16 H-17 H-18 H-19

OCH3 H-20

2, 3, 6, 10, 11, 20 3, 6, 19, OCH3 2, 4, 19 8, 15 14, 17 14, 15, 16 6, 7, 8, 12 2, 3, 4 1, 6, 10, 11 4

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406 J.M.L. RODILLA ei al.

that H-4 forms a dihedral angle near 90" with Hb-5, explaining the signal for H-4 as a dd because J l = J2=9.9Hz. From this data, the structure 3R-4a-methoxy-15-vaIparen-2-one could be assigned to compound 26.

EXPERIMENTAL

Spectral Analysis

NMR: 400 or 250MHz for 'H and 100.1 or 62.9MHz for I3C. Chemical shifts are given in 6 (ppm) and are referenced to the residual CHC13, 7.26ppm for the 'H and 77.0 for I3C respectively. EI MS: VG, 70eV and GC-MS Shimadzu QP 5000.

Extvaction and Isolation

Aerial parts of Halimium viscosum (1.6 kg) collected in S . Jog0 da Pesqueira (Braganga, Portugal) were dried and extracted with n-hexane in a Soxhlet apparatus for 24 h. The extract (160.4 g) was dewaxed with MeOH (1 1.1 g) and then extracted with 4% NaOH (110.1 g). The neutral fraction weighed 39.2 g.

A sample of the acid part (5.0g) was esterified with CHzNz and the methyl esters were subjected to CC on silica-gel with n-hexane and n-hexanelAcOEt mixtures giving six fractions (I-VI). CC of fraction I on silica-gel have 3 (159mg) and 6 (140mg). CC of fraction I1 afforded 22 (86mg). CC of fraction I11 on silica-gel gave 2 (2.840g), CC of fraction IV gave 23 (60mg). CC of fraction V on silica-gel gave 4 (220mg) and CC of fraction VI gave 5 ( 1 70 mg).

The neutral part of n-hexane extract (39.2g) was hydrolysed with 6% KOHlMeOH at room temperature. The neutral part obtained by hydrolysis was extracted with ether (35.4g), and then subject to CC on silica-gel with n-hexane and n-hexanelAcOEt mixtures giving four fractions. CC of fraction I afforded 24 (60 mg) and 25 (40 mg), and CC of fraction I1 afforded 26 (22 mg). From the most polar fractions (I11 and IV), the well known: 15- hydroxy-7-labden-3-one, [29] the major compound 38,15-dihydroxy-7-lab- dene [6,9] and a trio1 labdane 8( 17)-labden-3B,7a,l5-triol [6] were obtained.

Dimethyl 1 (lO)-halimen-15,18-dioate (6) Colourless oil, IR $,': cm-' : 2935, 2874, 1730, 1462, 1382, 1258, 1116. 'H NMR 6 (ppm): H-1, 5.30,

3H, d, J=6.9Hz; H-17, 0.93, 3H, d, J=6.6Hz; H-19, 1.10, 3H, s; H-20, lH, t, J=4.5Hz; H-5, 2.60, IH, dd, J1=12.0Hz, J2=3.5Hz; H-16, 0.78,

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BI- AND TRICYCLIC DITERPENOIDS 407

0.86, 3H, s; 15-C00CH3, 3.66, 3H, s and 18-COOCH3, 3.64, 3H, s. I3C NMR S (ppm): C-1, 119.5; C-2, 22.7; C-3, 30.5; C-4, 44.9; C-5, 38.3; C-6, 22.9; C-7, 28.4; C-8, 38.3; C-9, 42.7; C-10, 141.4; C-11, 36.6; C-12, 30.6; C-13, 31.1; C-14, 41.6; C-15, 173.9; C-16, 19.9; C-17, 15.6; C-18, 178.6; C-19, 20.0; C-20, 22.5; 1 5 - 0 m 3 , 51.7 and 18-OCH3, 51.3. EI MS, 70eV, m/z (rel. int.): 364 [M+], 333, 305, 273, 235, 175, 161, 147, 133, 119, 105, 91, 79, 69.

Dimethyl 3,19-dinor-l5-valparen-2,4-dioate (22) Colourless oil. IR u;Ecm-l: 2950, 2934, 1730, 1625, 1439, 760. 'H NMR 6 (ppm): H-1, 2.18, 2H, s; H-5, 2.36, 2H, d, J=6.0Hz; H-6, - 1.82, m; H-14, 2.70, lH, q, J=7.8Hz; H-16, 4.78 and 4.80, lH, s, each; H-17, 1.74, 3H, s; H-18, 0.81, 3H, s; H-20, 0.96, 3H, s; 2-C00CH3, 3.65, 3H, s and 4-C00CH3, 3.63, 3H, s. l3C NMR S (ppm): C-1, 47.7; C-2, 174.7; C-4, 172.3; C-5, 32.4; C-6, 52.7; C-7, 41.8; C-8, 54.3; (2-9, 21.4; C-10, 40.1; (2-11, 37.8; C-12, 40.0; (2-13, 27.1; C-14, 46.0; C-15, 148.0; C-16, 110.5; C-17, 25.0; C-18, 16.0; C-20, 21.3; 2-COOCH3, 51.2 and 4-C00CH3, 51.6. EI MS, 70eV, m/z (rel. int.): 336 [M+], 304, 289, 260, 247, 235, 220, 206, 194, 189, 180, 175, 161, 147, 133, 121, 105, 93, 79, 67, 55.

Methyl 16-n0r-2,3-~e~0valpara-3,15-dioxo-2-oate (23) Colourless oil, IR ,,film max cm-': 2929, 2873, 1728, 1713, 1457, 1359, 1201, 1164. 'H NMR 6 (ppm): H-1, 2.23, 2H, s; H-4, 2.50, 2H, m; H-14, 2.62, lH, ddd, J1 = 8.1,

s; H-20, 1-00, 3H, s, and 2-COOCH3 3.62, 3H, s. 13C NMR S (ppm): C-1, J 2 ~ 8 . 1 , J3=4.2Hz; H-17, 2.14, 3H, S; H-18, 0.80, 3H, S; H-19, 2.12, 3H,

47.7; C-2, 172.4; C-3, 208.9; C-4, 45.1; C-5, 20.9; C-6, 54.2; C-7, 46.1; C- 8, 53.8; C-9, 21.3; C-10, 39.0; (2-11, 38.4; C-12, 40.7; (2-13, 25.6; C-14, 53.1; C-15, 212.1; C-17, 30.0; C-18, 15.3; C-19, 30.1; C-20, 21.5 and 2-COOCH3, 51.2. EI MS, 70eV, mjz (rel. int.): 336 [Mf], 304, 289, 262, 245, 207, 191, 175, 161, 149, 133, 119, 105, 91, 79, 67, 55.

1,3,5,15- Vdparatetraene (25) Colourless oil, [aID - +30.5"(CHCl,; c0.33); IR vzEcm-': 3079, 1643, 1455, 1374, 887, 839. 'H NMR S (ppm): H-1, 5.27, lH, d, J=10.0Hz; H-2, 5.90, lH, m; H-4, 6.31, lH, d, J = 6.8Hz; H-5, lH, m, H-14, 2.62, lH, m; H-16, 4.93 and 4.84, lH, s each; H-17, 1.72, 3H, s; H-18, 1.21, 3H, s; H-19, 2.03, 3H, s; and H-20, 0.58, 3H, s. l3C NMR 6 (ppm): C-1, 131.1; C-2, 115.1, C-3, 135.3; C-4, 127.3;

24.2 -

(2-5, 126.2; C-6, 152.6; C-7, 48.7; C-8, 49.3; C-9, 18.6; C-10, 35.0; C-11, 38.6; C-12, 40.4; C-13, 28.7; C-14, 45.7; C-15, 147.3; C-16, 110.8; C-17, 25.1; C-18, 21.6; C-19, 23.9; and C-20, 20.6. EI MS, 70eV, m/z (rel. int.): 268 [M+], 266, 223, 169, 157, 132, 117, 105, 91, 77, 67, 41.

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408 J.M.L. RODILLA er al.

3R-4a-Methoxy-lS-valparen-2-one (26) Colourless oil, [a]g.' = -40.0' (CHC13;c0.05); IR u::crn-': 3081, 2940, 1694, 1646, 1458, 1387, 1288, 1197, 1097, 891. 'H NMR 6 (ppm): H-1, 2.36 and 1.99, lH, d, J=6.8Hz each; H-4, 3.09, IH, t, J=9.9Hz; H-8, 2.35, lH, m; H-14, 2.70, lH, m; H-16, 4.82 and 4.79, lH, s each; H-17, 1.75, 3H, s; H-18, 0.74, 3H, s; H- 19, 1.24, 3H, d, J=5.5Hz; H-20, 0.88, 3H, s; and -OCH3, 3.37, 3H, s. 13C NMR 6 (ppm): C-1, 58.0; C-2, 213.1; C-3, 55.0; C-4, 85.7; C-5, 31.6; C-6, 59.4; C-7, 46.7; C-8, 54.8; C-9, 21.6; C-10, 44.0; C-11, 38.0; C-12, 41.1; C-13, 26.8; C-14, 46.2; C-15, 147.8; C-16, 110.5; C-17, 25.0; C-18, 16.3; C-19, 16.7; C-20, 20.9; and O m 3 , 56.7. El MS, 70eV, mi-. (rel. int.): 318 [M+], 287, 276, 246, 194, 189, 175, 162, 147, 135, 133, 123, 121, 107, 106, 95, 93, 91, 82, 80, 79, 78, 69, 67, 55.

Acknowledgements

The authors are grateful to the Departamento de Quimica Organica and Servicio General de Resonancia MagnCtica Nuclear, Facultad de Ciencias Quimicas, Universidad de Salamanca. This work is partially supported by the Program INTERREG 11, no 05/REG 11/6/96.

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