0031-9422/82/122899-05$03.00/O 0 1982Pergamon Press Ltd. zyxwvut Phytochemistry, Vol. 21,No. 12,pp. 2899-2903, 1982. Printedin Great Britain. FURANOHELIANGOLIDES AND FARNESOL FROM CALEA HISPIDA” DERIVATIVES FERDINAND BOHLMANN, RAJINDER K. GUPTA, JASMIN JAKUPOVIC, ROBERT and HAROLD RoBINsoNt M. KINGt Institute for Organic Chemistry, Technical University of Berlin, D-1000 Berlin 12, West Germany; tSmithsonian Department of Botany, Stop No. 166, Washington, DC 20560, U.S.A. Institution, (Revised received 5 March 1982) Key Word Index-Calea hispida ; Compositae; sesquiterpene lactones; furanoheliangolides; substituted sesquiterpene lactone; farnesol derivatives; dihydroxy dehydromenthone. myrtenyl Abstract-From Calea hispida, in addition to known compounds, two new furanoheliangolides, one substituted with a myrtenyl residue, two further farnesol derivatives and a dihydroxy dehydromenthone were isolated. The structures were elucidated by high field ‘H NMR spectroscopy and by comparison of the data with those of similar compounds. The chemotaxonomic situation is discussed briefly. INTRODUCTION Several species of the large genus Calea (tribe Heliantheae) with ca 100 taxa have already been investigated chemically. Most of them afforded sesquiterpene lactones, especially furanoheliangolides [l-8], but also other germacranolides [l, 2,4,9-121 and a few eudesmanolides [4,71 were found. Furthermore, several species gave prenylated p-hydroxyacetophenone derivatives [3,5-7,13,14]. We now have studied the constituents of Calea hispida (DC.) Baker. The results are discussed in this paper. RESULTS AND DISCUSSION The roots of C. hispida afforded the thymol derivatives l-4, the eudesmene derivative 9 [15] and the chromenes 5-8 [ 16-181, while the aerial parts gave germacrene D, caryopyhllene, a-humulene, bicyclogermacrene, 2, 4, the furanoheliangolides 12 [3] and 13 [l], the heliangolide 11 [19], two further heliangolides, the myrtenyl substituted angelate 14 and the hydrated furanoheliangolide 15, the farnesol derivatives 16 and 17 as well as the dihydroxy dehydromenthone 10. The structure of the latter followed from the molecular formula and the ‘H NMR spectral data (see Experimental). Spin decoupling showed that the isopropyl proton was allylic to the olefinic proton. The chemical shift of the latter showed that it must be in a P-position to the keto group. The presence of an unsaturated keto group also was evident from the corresponding IR band (1690 cm-‘). The olefinic proton was further coupled with a proton, which displayed a double doublet at S 4.30. The latter was further coupled with a hydroxy doublet at 8 2.41. *Part 453 in the series “Naturally Occurring Terpene Derivatives”. For Part 452 see Bohlmann, F. and Zdero, C. (1982) Phytochemistry 21, 2263. Accordingly, the sequence A was established. OH , .-fi=Cyo CH Me, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSR A A downfield methyl singlet at 6 1.36 indicated the presence of a tertiary hydroxyl group, while a pair of doublets at 6 2.74 and 2.50 obviously were the signals of a methylene group a to the carbonyl. Thus the structure of 10 was established, but the stereochemistry at C-l could not be determined. Probably 10 was formed by hydroxylation of 1,2,3,4-tetradehydromenthone, an intermediate in the biogenesis of thymol. The diacetate 16 gave no molecular ion in the mass spectrum, similarly chemical ionization produced an ion by loss of acetic acid. The ‘H NMR spectrum, however, showed (Table 1) that a diacetate was present. A three-fold doublet at 8 4.49 indicated an additional hydroxyl group. Spin decoupling showed that the corresponding proton was coupled with an olefinic proton, which displayed a broadened double quartet at 8 5.19. Further couplings with two pairs of double doublets at 8 2.45 and 2.24 showed that the allylic hydroxyl group was at C-S or C-9 of a farnesol with an acetoxyl group at C-15. The position of the latter followed from the chemical shifts of the olefinic protons and methyl groups. Spin decoupling further indicated that the broadened triplet at 6 5.06 showed allylic couplings with two olefinic methyls. Accordingly, the hydroxyl group was at C-5. In addition 17 showed no molecular ion in the mass spectrum even under CI conditions where, however, F. BOHL.MANN et al. 2900 A I R'H 2 t?=iBu 2’ ’ A 3 4 R-H R=iBu R zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML 5 6 7 8 R H OH H OH R’ H H OH OH 12 13 H OH R’ OH 0 H OH 0 15 OH 14 OAc OAc 16 an ion formed by loss of water and acetic acid could be detected. The presence in 17 of the end group of 16 with acetoxyl groups at C-l and C-15 and a hydroxyl group at C-5 clearly followed from the ‘H NMR spectral data (Table 1) as the corresponding signals were nearly identical with those of 16. An additional hydroxyl and an exomethylene group was revealed in the ‘H NMR spectrum by a broadened triplet at 6 4.04 and a pair of narrowly split double quartets at 6 4.94 and 4.84. The position of the second hydroxyl followed from the chemical shifts of the methylene protons. The relative configuration at C-5 and C-10, however, could not be determined. The structure of 14 followed from the molecular formula (GOHj80,), the fragmentation pattern in the mass spectrum and from the ‘H NMR spectrum (Table 2), which was close to that of a similarly modified furanoheliangolide isolated from C&a morii and C. pilosa [3]. The H-9 signals, however, were replaced by a broadened double doublet at S 4.21. 17 Accordingly, a 9-hydroxyl group was present. Consequently, most signals were similar to those of 12[3]. Spin decoupling allowed the assignment of all signals, thus confirming the structure of 14 as S/3 - myrtenyl- 8 - 0 9cV - hydroxy - 4,5 - dihydroatripliciolide angelate. The stereochemistry of 14 at C-4, C-S and C-8 was obviously the same as that of the myrtenyl derivative from C. pilosa [3]. Accordingly, the H-4 signal showed no allylic coupling with H-2 and J+,, and J,, were nearly equal. Inspection of a model showed that this was more likely with a 5o-proton. 14 is the third example of a heliangolide combined with a monoterpene[3,7]. The ‘H NMR spectrum of 15 was again in part similar to that of zyxwvutsrqponmlkjihgfedcbaZYXWVU 12. However, that the situation at C-4 and C-5 was changed was obvious as the olefinic methyl signal was replaced by a doublet at fi 1.29. Spin decoupling showed that the corresponding methyl group was coupled with a proton, which gave rise to a broadened double quartet. The latter was Furanoheliangolides and farnesol derivatives from Calea hispida Table 1. ‘H NMR spectral data of compounds 16 and 17 (400MHz, CDC13, TMS as int. standard) 2901 Table 2. ‘H NMR spectral data of compounds 14 and 15 (400 MHz, CDCII, TMS as int. standard) 16 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 17 14 15 H-l H-l’ H-2 H-4 H-4’ H-S H-6 H-8 H-9 H-9’ I H-10 H-12 H-13 H-13’ H-14 H-15 H-15’ OAc 4.68 br dd 4.64 br dd 5.73 br t 2.45 dd 2.24 dd 4.49 ddd 5.19 br dq 2.07 m 5.62 d H-2 5.63 d H-4 2.82 br dq 3.36 br dq dd H-5 4.44 br dd 2.98 ddt 5.75 br t 4.51 dd H-6 4.40 dd 2.44 dd 3.55 m H-7 2.24 dd 3.73 m 5.04 br d H-8 5.04 br d 4.52 br ddd 4.21 br dd H-9 4.16 br dd 5.23 br dq H-13 6.41 d 6.33 d 2.07 m H-13’ 5.81 d 5.74 d 2.00 m 2.02 m 1.50 s H-14 1.48 s 1.64 m 1.21 d H-15 1.29 d 5.06 br t 4.04 br t H-2 5.31 br s 1.67 br zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA s 1.72 br s H-5; 0.99 d 4.94 dq 1.60brs H-5; 2.35 dt 4.85 dq H-3’,7’ 2.05 m 1.68brs 1.68 brs H-9’ 0.82 s 4.61brd 4.62 br d H-10’ 1.27 s 4.54 br d 4.55 br d OAng 6.15 qq 6.16 qq 2.09 s 2.09 s 1.94 dq 1.94 dq 2.06 s 2.06 s 1.81 dq 1.81 dq J (Hz): 1,l’ = 4,4’ = 15,15’ = 14; 1,2 = 7; J (Hz): Compound 14: 2,4 = 1.5; 4,5 = 5; 1,2’ = 6; 4,5 = 8; 4’,5 = 4; 5,6 = 8; 6,14 = 1; 4,15=7; 5,6=6,7=5; 5,7’=6; 7,8-2; 9,lO = 7; lo,12 = lo,13 - 1 (compound 17: 7,13 = 3; 7,13’ = 2.5; 8,9 = 6; 9,0H = 5; 9,lO = 6.5; lo,13 = 10,13’- 1.5). 4’,5’ = 5’,6’ = 5; 5;,5i = 9; compound 15: 2,4=1.5; 4,5=4,15=7; 5,6=9; 6,7=4; 7,8 - 2; 7,13 = 3; 7,13’ = 2.5; 8,9 = 5; 9,0H = 4; OAng: 3,4 = 7; 3,s = 4,5 = 1.5. 4.70 br dd 4.65 br Table 3. Distribution of typical constituents C. cuneifozia DC. [14] C. hispida (DC.) Baker C. hymenolepis Baker[7] C. morii H. Rob.[3] C. oxylepis Baker [6] C. pilosa Baker[3] C. pinnatifida Baker [l 11 C. reticulata Gardn. [IS] C. rotundifolia (Less) Baker[4] C. teucrijofia (Gardn.) Baker[5] C. urticifolia (Miiller) DC. [ 1,2, 11, 121 C. zacatechichi Schlecht.[l, 9-111 C. species [5] * Eudesmene 9. tIsocostic acid. $ Ichthyotherol. + + + in Calea species , + + + + + ? + + (+I* + + + + (+)* + + + + + + + + + + + + + + + t (:)t + F. BOHLMANN 2902 further coupled with a narrowly split doublet at 6 5.63 and a broadened double doublet at 4.44. As the latter was coupled with H-7, whose identity followed from spin decoupling, sequence H-4-H-7 was established. While the missing allylic coupling of H-4 again required a 4&methyl, the changed couplings of H-5 supported a SP-proton if a model was considered, though the flexibility in such a ring system does not allow a definite assignment. The constituents of this Calea species again show that furanoheliangolides and related germacranolides are typical for this genus (see Table 3). The only exceptions so far are C. cuneifolia, which only was investigated for compounds like S-8[14] and C. reticulata [15]. However, prenylated p-hydroxyacetophenone and thymol derivatives are widespread in this genus. Only two species have so far afforded eudesmanolides, while three others contain eudesmene derivatives. Farnesyl derivatives, so far isolated from three species, also may be of interest. The placement of Calea in the Neurolaeninae [Robinson, H., unpublished] is supported by the presence of similar germacranolides in Neurolaena [20], which also contains several thymol derivatives. Furanoheliangolides, and related lactones, however, are also reported from several other genera, which belong to the tribes Heliantheae (Helianthus, Tithonia, Zexmenia, Viguiera, Eriophy llum, Eupatorieae Bejaranoa, Podanthus, (Eupatorium, Disy naphia, Bahia and Liatris, Conocliniopsis, Leptocarpha), Trichogonia, Isocarpha and Hartwrightia) and Vernonieae (Eremanthus, Chresta, Piptolepis, Alcantara and Lychnophora). As in other cases, therefore, only the combination of different types of constituents can be regarded as characteristic for a genus. EXPERIMENTAL The air-dried plant material, collected in N.E. Brazil (voucher RMK 8434, deposited in the U.S. National Herbarium, Washington) was extracted with EtzO-petrol (1: 2), and the resulting extracts were separated by CC (SiOz) and further by repeated TLC (SiOz). Known compounds were identified by their high field ‘H NMR spectra, which were compared with those of authentic material, and by their &-values on TLC. Crystalline compounds were further compared by mmp’s. The roots (2Og) afforded 10mg 1, lOmg2, lOmg3, 10mg4,5mg5,5mg6,20mg7,10mg8 and 10 mg 9, while the aerial parts (120g) gave 100 mg germacrene D, 100 mg caryophyllene, 50 mg a-humulene, 20mg bicyclogermacrene, IOmg 2, 10mg 4, 50 mg 5, 20mg 6, 20mg 9, 2mg 10 (TLC: ChH;H6-CHXlrEt20, lO:lO:l, several times), 150 mg 11, 300mg 12, 50 mg 13, 5 mg 14 (EtzO-petrol, 1:1, several times), 2 mg 15 (EtlO, several times), 2 mg 16 (EtIO-petrol, 9: 1. several times) and 2 mg 17 (C~H~-CH~Cl2-EtzO, 10 : IO: 1, several times). l,2 - Dihy droxy - 3,4 - dehydromenthone (10). Colourless oil, IR P$,:$cm-‘: 3500 br (OH), 1690 (C=CCO); MS m/z (rel. int.): 166.099 [M-HzO]+ (17) (CIOH140& 151 [166Me]+ (ll), 149 [166-OH]’ (lo), 126 (100) [M-C3H60]+ (100) (RDA), 111 [126-Me]+ (20), 83 [CsH,O]’ (31); ‘H NMR (CDCll, 400MHz): 6 4.30 (dd, H-2), 6.41 (dd, H-3), 2.74 (d, H-6), 2.50 (d, H-6’), 1.36 (s, H-7), 2.89 (dqq, H-S), 1.04 (d, H-9), 1.01 (d, H-lo), 2.41 (d, OH) [J (Hz): 2,3 = 4; 2,0H = 8; 3,8 = 1; 6,6’= 16; 8,9 = 8,lO = 71; et al. [(Y];~ = ’ 5~ - 589 578 546436 nm ICHC13; c 0.1) ~ +10+14+18+24 M yrtenyl - 9n - hydroxy - 4,5 - dihy droatripliciolide - Colourless gum, JR v%!?cm-‘: 3600 (OH), 1780 (y-lactone), 1720 (C=CCO*R), 1600 (C=COR); MS m/z (rel. int.): 510.262 [Ml’ (I) (C,oH~oi), 492 [M HzO]’ (O.l), 410 [M-RCOzH]+ (l), 392 [410 -H?O]+ (0.3), 382 [410-CO]+ (0.4), 375 [M-C,oH,s]+ (2.5), 135 [C,oH,d+ (12), 83 [C4H,CO]+ (loo), 55 [83 -CO]+ (40); 8 - 0 - angelate [a]‘c= (14). 589 578 +42 +37 546 436nm +34 - 143 (CHCI,; c o.4J. .5p,9a - Dihy droxy - 4,5 - atripliciolide - 8 - 0 - angelate (15). Colourless gum, IR Y:$ cm-‘: 3600 (OH), 1780 (y-lactone), 1720 (C=CCO*R), 1600 (C=COR); MS m/z (rel. int.): 392.147 [Ml+ (6) (CtOH2408),374 [M - H201’ (0.2), 364 [M -CO]+ (11, 293 [M - OCOR]’ (0.5), 292 [M - RCO,H]+ (0.2), 265 [293CO]+ (2), 247 [265-H,O]+ (0.2), 83 [C,H,CO]+ (lOO), 55 [83- CO ]+ (67); [a];40 = 589 f8 578 546 +lO +12 nm (CHCI?: c 0.1) 15 - Acetoxy - 5 - hydroxyfarnesyl acetate (16). Colourless gum, IR Y:$ cm-‘: 3520 (bra-OH), 1745, 1245 (OAc); MS m/z (rel. int.): 135 [CloHls]+ (16), 69 [C~HU]’ (100); CI (isobutane): 279 [M + zyxwvutsrqponmlkjihgfedcbaZYXWVUT 1 - HOAc)’ (3), 261 1279- H?O]’ (78). 219 [261- ketene]+ (30), 201 [261- HOAc]’ (70), 75 (100); [a]~= - 4” (CHClx; c = 0.1). 15 - Acetoxy - 5,10 - dihy droxy - 12,13 - dehydro - lo,11 dihy drofarnesy l acetate (17). Colourless gum, IR ~t%$cm -I: 3500 br (OH), 1760, 1245 (OAc); MS ml; (rel. int.) (CI, isobutane): 277 [M+ 1 -HzO, HOAc]+ (78), 217 [277HOAc]- (loo), 199 [217-HzO]+ (30); [a]~= -7” (CHCl3; c 0.1). Acknowledgements-We thank Drs. Scott A. Mori and P. Alvim, Herbario Centro de Pesquisas do Cacau at Itabanu, Bahia, Brazil, for their help during plant collection and the Deutsche Forschungsgemeinschaft for financial support. REFERENCES 1. Herz, W. and Kumar, N. (1980) Phytochemistry 19, 593. 2. Bohlmann, F. and Jakupovic, J. (1979) Phytochemistry 18, 119. 3. Bohlmann, F., Fritz, U., King, R. 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