Oxygenated sesquiterpenoids from a nonpoisonous sardinian chemotype of giant fennel (Ferula communis)

Article abstract of DOI:10.1021/np000468f

The roots of the nonpoisonous chemotype of giant fennel (Ferula communis) from Sardinia afforded a novel cadinanetriol (1), whose structure was established by spectroscopic data and confirmed by synthesis from the E,E-Δ ^1(10),5 germacradiene al

Full text of DOI:10.1021/np000468f

J . Nat. Prod. 2001, 64, 393-395
393
Oxygen a ted Sesqu iter p en oid s fr om a Non p oison ou s Sa r d in ia n Ch em otyp e of
Gia n t F en n el (Fer u la com m u n is)
,
†
†
,‡
§
Giovanni Appendino,* Giancarlo Cravotto, Olov Sterner,* and Mauro Ballero
Dipartimento di Scienza e Tecnologia del Farmaco, Universit a` di Torino, Via Giuria 9, 10125 Torino, Italy,
Department of Organic Chemistry 2, Chemical Center, Lund University, P.O.B. 124, 221 00 Lund, Sweden, and
Dipartimento di Scienze Botaniche, Universit a` di Cagliari, Viale San Ignazio 13, 09123 Cagliari, Italy
Received September 29, 2000
The roots of the nonpoisonous chemotype of giant fennel (Ferula communis) from Sardinia afforded a
novel cadinanetriol (1), whose structure was established by spectroscopic data and confirmed by synthesis
from the E,E-∆ 1
(10),5
germacradiene allohedycariol. A number of known compounds were also identified.
Despite the lack of morphological differences, a broad chemical diversity exists within giant fennel,
underlying the contrasting data on its poisonous properties.
The recognition that a haemorrhagic disease in Canadian
cattle was due to the ingestion of moldy sweet clover raised
considerable interest in the scientific community, eventu-
ally leading to the discovery of the anticoagulant activity
of dicoumarol and to the synthesis of clinically useful
cardiovascular drugs such as Warfarin.1 A similar syn-
drome, named ferulosis, had been known to plague live-
extract from the roots was fractionated by open column
chromatography on silica gel to afford three major con-
6
a,9
stituents, the daucane esters ferutinin (2.1%)
and
jaeskeanadiol benzoate (1.1%) and the sesquiterpene
1
0
alcohol allohedycariol (0.7%).6
a,11
All the other compounds
obtained were present in much lower concentration, and
their isolation required further chromatographic steps,
including HPLC. Four additional jaeskeanadiol esters
(anisate, angelate, ferulate, and veratrate),12 two 1-hy-
droxyjaeskeanadiol esters (diangelate and 1-acetate-5-
2
stock in Sardinia. Despite scientific studies spanning well
over a century, it was only in 1925 that ferulosis was
unambiguously related to the consumption of giant fennel
3
13
(
Ferula communis L., Umbelliferae). The correlation proved
angelate), two siol esters (p-hydroxybenzoate and ani-
sate),6 three sesquiterpene coumarin ethers (isosamar-
a
difficult to establish, since giant fennel occasionally failed
to elicit toxic effects in livestock. As a result, ferulosis was
long considered an infectious disease, an event that might
well have delayed discovery of the anticoagulant activity
of coumarins by several decades.
candine angelate,1 colladonine, and feselol ), and three
3
14
15
1
6
17
phenylpropanoids (2-epielmanticine, methoxylatifolol,
and methoxylatifolone ) as well as the novel cadinane triol
1
7
1 were obtained.
+
To explain the contrasting observations on the toxicity
of giant fennel, the existence of different chemotypes was
The HRMS of 1 showed a [M - H
2
O] peak at 238.1911,
corresponding to the molecular formula C15
15 3
H O . Since the
3
13
postulated as early as 1925. These findings were largely
C NMR spectrum lacked resonances of unsaturated
carbons, 1 was bicyclic. The 13C NMR spectrum showed
three deshielded oxygenated carbons, an oxymethine and
two quaternary centers, and the remaining signals were
assigned to four methyls, four methylenes, and four meth-
ines by DEPT experiments. The 1H NMR spectrum dis-
played signals indicative of an oxygenated sesquiterpene,
key functionalities easily discernible being an oxymeth-
ine proton and four methyls, three of which quaternary.
ignored in the scientific community, to the point that
4
doubts on the toxicity of giant fennel still lingered on, and
the structure of the major haemorrhagic toxin of the plant,
the prenylated 4-hydroxycoumarin ferulenol, was not
5
reported until 40 years later. In the late 1980s, we showed
that two distinct chemotypes of giant fennel grow in
6
Sardinia and reported the structure elucidation and total
7
synthesis of the major coumarinic toxins of the plant. The
1
study of the nonpoisonous chemotype was hampered by its
scanty distribution and by the lack of diagnostic morpho-
logic elements to differentiate between poisonous and
nonpoisonous plants. A preliminary investigation gave the
phytoestrogen ferutinin and the sesquiterpene alcohol
Severe overlapping in the high-field region of the H NMR
spectrum was overcome by 2D measurements, and scalar
1
1
(COSY) and dipolar (NOESY) H- H correlations, as well
1
13
as one-bond (HMQC) and long-range (HMBC) H- C
correlations, suggested the cadinane structure 1, with the
relative configuration indicated. The triol 1 bears an
obvious biogenetic relationship with allohedycariol, from
which it could be derived by transannular cyclization of a
5,6-epoxide. To support this relationship and establish the
absolute configuration of the isolated product, the conver-
sion of allohedycariol into 1 was investigated.
6
a
allohedycariol () 4S,7S,E,E-germacra-1(10),5-dien-11-ol),
but the shortage of plant material prevented the charac-
terization of further, less abundant constituents.
To get a reliable source of the nonpoisonous chemotype,
over 150 samples of latex obtained from plants growing all
over Sardinia were analyzed.8 This evidenced that the
distribution of the nonpoisonous chemotype is limited to
three enclaves and guided the collection of sufficient plant
material to characterize its constituents. Thus, an acetone
The transannular cyclization of germacradiene mono-
epoxides is a key event in the biosynthesis of sesquiterpe-
noids and has been the subject of a considerable body of
1
8
investigation. Most data available regard compounds of
*
To whom correspondence should be addressed. Tel (G.A.): +39 011
70 7684; (O.S.): +46 4622 28213. Fax (G.A.): + 39 011 670 7687; (O.S.):
46 4622 28213. E-mail (G.A.): appendin@pharm.unito.it; (O.S.):
1(10),4
the ∆
-type, that is, derivatives of germacrene A, and
6
there are few reports on compounds such as allohedycariol,
having the functionalization pattern of germacrene D
+
Olov.Sterner@orgk2.1th.se.
†
Dipartimento di Scienza e Tecnologia del Farmaco.
Department of Organic Chemistry 2.
Dipartimento di Botanica.
1
(10),5
‡
(∆
). Allohedycariol was fairly stable in air, but treat-
§
ment with epoxidizing reagents did trigger an oxidative
1
0.1021/np000468f CCC: $20.00
© 2001 American Chemical Society and American Society of Pharmacognosy
Published on Web 02/08/2001

3
94 J ournal of Natural Products, 2001, Vol. 64, No. 3
Notes
cyclization. Thus, reaction with m-chloroperoxybenzoic acid
MCPBA) in CH Cl gave, after aqueous workup, a mixture
of the powerful phytoestrogen ferutinin,23,24 providing the
opportunity to prepare a variety of analogues to elucidate
the mechanism of its hormonal activity.
(
2
2
containing a product with the same chromatographic
1
behavior as 1. H NMR analysis of the epoxidation mixture
confirmed this finding, and various reagents (MCPBA,
buffered MCPBA, dimethyldioxirane, trifluoromethyldiox-
irane) were tried to optimize the formation of 1. The best
results were observed with MCPBA in buffered THF, which
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Optical rotations
were measured on a Perkin-Elmer 241 polarimeter. IR spectra
were recorded on a Shimadzu DR 8001 spectrophotometer.
HRMS (EI, 70 eV) were taken on a VG 7070 EQ spectrometer.
gave the cadinane triol 1 as the major reaction product
1
(
24% yield), identical ( H NMR, MS, [R]
D
) to the natural
1
13
H and C NMR spectra were taken on a Bruker DRX-500
product. The eudesmane diol 2 and the epoxyalcohol 3 were
spectrometer (500 and 125 MHz, respectively). Silica gel 60
(70-230 mesh, Merck) was used for open-column chromatog-
raphy (CC). A Waters Microporasil column (0.8 × 30 cm) was
used for HPLC, with detection by a Waters differential
refractometer 340. Known compounds were identified by
also obtained (14 and 8%, respectively). The reaction of
allohedycariol with MCPBA in nonbuffered CH Cl gave
2 2
as major reaction product the eudesmane diol 2 (23%),
accompanied by substantial amounts of the epoxyalcohol
1
3
(18%), the diols 4,5 (15%), the cadinane 1 (14%), and the
comparison of their spectroscopic data ( H NMR, MS) with the
published values (see references in the main text).
epoxydiol 6 (10%). None of the eudesmane derivatives
obtained in the epoxidation studies were present in the
plant extract (HPLC and NMR analysis), and their struc-
ture elucidation was accomplished using the same basic
NMR experiments detailed for 1. The formation of eudes-
mane drivatives 2-6 is mechanistically detailed in the
Supporting Information and affords chemical precedent for
a novel biogenetic pathway linking eudesmanes and ger-
macranes. Since the formation of 1 from allohedycariol
required chemical manipulation and gave also compounds
not present in the plant extract, it is reasonable to assume
that 1 is a true natural product and not an artifact of
isolation and/or purification procedures.
P la n t Ma ter ia l. Ferula communis L. was collected in
Seneghe (Oristano, Sardinia) in March 2000 and was identified
by M.B. A voucher specimen (612b) is deposited at the
Dipartimento di Scienze Botaniche, Universit a` di Cagliari.
Extr a ction a n d Isola tion . The dried powdered root (208
g) was extracted with acetone (3 × 1 L) to give 19.5 g (9.4%)
of a yellowish oil. The latter was chromatographed on silica
gel (150 g) using a hexane-EtOAc gradient system (from 95:5
to 6:4). Altogether, 515 fractions (ca. 15 mL each) were
collected. These were combined into nine primary fractions (A-
I). Fractions B (1.4 g, 0.7%), C (2.2 g, 1.1%), and E (3.8 g) were
pure compounds, identified as allohedycariol, jasekanadiol
benzoate, and ferutinin, respectively. Fraction A was made up
essentially by triglycerides and was not further investigated.
Fraction D (0.6 g) was purified by HPLC (hexanes-EtOAc,
8
:2) to afford the phenylpropanoids methoxylatifolone (21 mg)
and 2-epielmanticine (65 mg). Fraction F was further purified
by CC (hexanes-EtOAc, 9:1) to afford ferutinin (0.4 g, overall
yield 4.2 g, 2.1%) and a mixture further separated by HPLC
(
hexanes-EtOAc, 7:3) to afford siol angelate (3.8 mg), siol
anisate (8 mg), methoxylatifolol (21 mg), jaeskeanadiol ferulate
8 mg), jaeskeanadiol veratrate (7 mg), and jaeskanadiol
angelate (2 mg). Franction G (210 mg) was purified by HPLC
hexanes-EtOAc, 7:3) to afford 1-hydroxyjaeskanadiol diange-
(
(
late (8 mg), 1-hydroxyjaeskanadiol 1-acetate-5-angelate (3 mg),
and compound 1 (81 mg). No pure chemical entity could be
obtained from fraction H, while fraction I afforded, after
purification by HPLC (hexanes-EtOAc, 6:4), the coumarins
isosamarcandine angelate (8.6 mg), feselol (30 mg), and
colladonine (25 mg).
(
1S,4S,5R,6S,7S,10S)-5,10,11-Ca d in a n etr iol (1): white
2
5
crystals (petroleum ether), mp 51 °C; [R]
D
2 2
+6 (CH Cl , c 0.8);
-
1
1
IR (KBr) νmax 3432, 1460, 1375, 1184, 1040, 1011 cm
; H
NMR (CDCl ) δ 2.88 (1H, dd, J ) 10, 10 Hz, H-5), 1.81 (1H,
3
ddd, J ) 13.1, 3, 3 Hz, H-9R), 1.77 (1H, m, H-2â), 1.76 (1H, m,
H-3R), 1.63 (1H, dddd, J ) 12.6, 4, 4, 4 Hz, H-8â), 1.52 (1H,
ddd, J ) 13, 13, 4 Hz, H-9â), 1.44 (1H, m, H-7), 1.40 (1H, m,
H-4), 1.36 (1H, m, H-1), 1.32 (3H, s, H-12), 1.20 (1H, m, H-8R),
1
.17 (3H, s, H-14), 1.09 (1H, m, H-2R), 1.08 (3H, s, H-13), 0.98
(
3H, d, J ) 6.4 Hz, H-15), 0.98 (1H, m, H-6), 0.95 (1H, m, H-3â);
1
3
C NMR (CDCl
3
) 85.0 (d, C-5), 81.7 (d, C-11), 73.1 (s, C-10),
5
2.9 (d, C-7), 51.2 (d, C-6), 48.2 (d, C-1), 43.3 (t, C-9), 38.1 (d,
The results of this study demonstrate that, despite the
lack of morphological differences, a broad chemical diver-
sity occurs within giant fennel, even in an insular environ-
ment where infraspecific diversity tends to be low.19 Apart
from the occurrence of the same phenylpropanes and siol
esters, the only other chemical trait shared by the two
chemotypes of F. communis growing in Sardinia is the
C-4), 33.3 (t, C-3), 29.0 (q, C-12), 25.0 (q, C-13), 25.0 (t, C-2),
23.7 (t, C-8), 21.7 (q, C-14), 18.8 (q, C-15); HREIMS m/z
238.1911 [M - H
+
2
O] (4) (calcd for C15
H
28
O
3
2
- H O, 238.1933).
Ep oxid a tion of a lloh ed yca r iol: (a) In buffered THF: to
a solution of allohedycariol (550 mg, 2.49 mmol) in THF (10
mL) were added solid NaHCO (250 mg, 3 mmol) and 85%
3
MCPBA (506 mg, corresponding to 2.49 mmol, 1 molar equiv).
After 5 min the reaction was worked up by partitioning
between EtOAc and 5% aqueous Na
2
0
accumulation of ent-sesquiterpenes (aristolanes and ger-
macranes, respectively), a rare feature in higher plants.
Daucane esters are widespread in plants from the genus
2
CO
3
(50 mL each). The
SO ), and
organic phase was washed with brine, dried (Na
2
4
evaporated. The semisolid residue was purified by CC (20 g
silica gel, hexanes-EtOAc gradient (from 9:1 to 7:3)) to give,
in order of elution, 3 (47 mg, 8%), 1 (153 mg, 24%), and 2 (84
2
1
Ferula, but the accumulation of sizable amounts of
specific esters is rare.22 In this context, the nonpoisonous
chemotype of giant fennel from Sardinia is a viable source
2 2
mg, 14%). (b) In nonbuffered CH Cl : to a solution of allo-

Notes
J ournal of Natural Products, 2001, Vol. 64, No. 3 395
hedycariol (200 mg, 0.90 mmol) in dry CH
2
Cl
2
(5 mL) was
s, H-13), 1.06 (1H, m, H-3â), 1.04 (1H, m, H-9â), 1.03 (3H, d,
J ) 6.7 Hz, H-15), 0.94 (1H, d, J ) 12.7 Hz, H-5), 0.79 (3H, s,
added 85% MCPBA (182 mg, corresponding to 0.90 mmol).
After stirring at room temperature for 5 min, the reaction was
worked up as described above. The crude residue was purified
by CC (silica gel, 10 g hexane-EtOAc gradient, from 8:2 to
H-14); 13C NMR (CDCl
) δ 77.1 (d, C-1), 70.0 (s, C-11), 64.7 (s,
3
C-7), 56.1 (d, C-6), 50.7 (d, C-5), 36.9 (s, C-10), 33.8 (t, C-3),
30.5 (t, C-9), 29.9 (t, C-2), 28.8 (d, C-4), 26.0 (q, C-13), 25.1 (q,
6
:4) to give, in order of elution, 3 (38 mg, 18%), 1 (32 mg, 14%),
C-12), 20.1 (t, C-8), 19.1 (q, C-15), 10.9 (q, C-14); HREIMS m/z
+
a mixture of 4 and 5 (ca. 1:1, 32 mg, 15%), 6 (23 mg, 10%),
and 2 (50 mg, 23%). 4 and 5 could be further separated by
HPLC (hexanes-EtOAc, 5:5).
254.1876 [M] (5) (calcd for C15
H
26
O
3
, 254.1882).
Ack n ow led gm en t. We are grateful to Mrs. Giada Bellone
for her help throughout this investigation. This work was
supported by EU (Contract ERB FAIR CT 1781) and MURST
(Fondi 40%, Progetto Chimica dei Composti Organici di
Interesse Biologico).
(
1R,4R,5R,7R,10R)-Eu d esm a n e-1,11-d iol (2): white pow-
2
5
der (petroleum ether), mp 63 °C; [R]
D
+21 (CH
2
Cl
2
1
, c 0.8);
-1
IR (KBr) νmax 3431, 1456, 1389, 1163, 1034, 926 cm ; H NMR
(
)
CDCl
3
) δ 3.34 (1H, dd, J ) 4.8, 11.1 Hz, H-1), 1.96 (1H, dd, J
6.9, 12.3 Hz, H-9R), 1.73 (1H, m, H-3R), 1.67 (1H, m, H-2â),
1
1
0
.52 (1H, m, H-4), 1.46 (1H, m, H-2R), 1.40 (2H, m, H-8R,â),
.21 (3H, s, H-12), 1.20 (2H, m, H-6R,â), 1.16 (3H, s, H-13),
.98 (1H, m, H-9â), 0.97 (3H, d, J ) 6.4 Hz, H-15), 0.96 (3H,
Su p p or tin g In for m a tion Ava ila ble: Discussion of the mecha-
nistic rationale for the formation of the cadinane 1 and the eudesmanes
2-6 from the epoxidation of allohedycariol. This material is available
free of charge via the Internet at http://pubs.acs.org.
s, H-14), 0.90 (1H, dd, J ) 4, 4 Hz, H-7), 0.86 (1H, m, H-3â),
.50 (1H, dd, J ) 4.9, 11.7 Hz, H-5); 13C NMR (CDCl
) δ 77.7
d, C-1), 69.9 (s, C-11), 60.7 (d, C-5), 57.8 (s, C-10), 51.6 (d,
C-7), 43.3 (t, C-9), 34.6 (t, C-3), 30.8 (t, C-2), 29.4 (d, C-4), 29.0
q, C-12), 28.4 (q, C-13), 24.4 (t, C-6), 21.7 (t, C-8), 20.3 (q,
0
(
3
Refer en ces a n d Notes
(1) Shofield, F. S. Can. Vet. Rec. 1922, 3, 74-76. For an account of the
discovery of dicoumarol, see: Sneader W. Drug Prototypes and their
Exploitation; Wiley: Chichester, 1996; pp 245-246.
(
+
C-15), 14.2 (q, C-14); HREIMS m/z 240.2101 [M] (5) (calcd
for C15 , 240.2089).
4S,5S,6R,7R,10R)-Eu desm a-5-en -11-ol epoxide (3): white
(
2) For a review, see: Appendino, G. The Toxins of Ferula communis.
In Virtual Activity, Real Pharmacology; Verotta, L., Ed.; Research
Signpost: Trivandrum; 1997; pp 1-15.
28 2
H O
(
2
5
(3) Altara, I. La Nuova Veterinaria 1925, 31, 194-198.
(
crystals (petroleum ether), mp 103-106 °C; [R]
D
2
+38 (CH -
4) A case of human poisoning from F. communis has recently been
reported in Morocco: Lamnehoa, Y.; Harry, P.; Michau, C.; Fareta,
R.; Merad, R. Presse Med. 1998, 27, 1579.
Cl , c 0.54); IR (KBr) νmax 3314, 1464, 1369, 1186, 1125, 935
2
-
1 1
cm ; H NMR (CDCl
3
) δ 3.27 (1H, s, H-6), 2.06 (1H, ddq, J )
1
1
1
1
2.6, 6.6, 3.8 Hz, H-4), 1.94 (1H, dd, J ) 11.5, 7.8 Hz, H-7),
(5) Carboni, S.; Malaguzzi, V.; Marsili, A. Tetrahedron Lett. 1964, 2783-
786.
6) (a) Valle, M. G.; Appendino, G.; Nano, G. M.; Picci, V. Phytochemistry
2
.57 (1H, m, H-2â), 1.56 (1H, m, H-3R), 1.54 (1H, m, H-9â),
.46 (1H, m, H-1â), 1.43 (1H, m, H-8â), 1.33 (1H, m, H-1R),
.32 (1H, m, H-3â), 1.25 (1H, m, H-8R), 1.26 (3H, s, H-12), 1.22
(
(
1
987, 26, 253-256. (b) Appendino, G.; Tagliapietra, S.; Nano, G. M.;
Picci, V. Phytochemistry 1988, 27, 944-946. (c) Appendino, G.;
Tagliapietra, S.; Gariboldi, P.; Nano, G. M.; Picci, V. Phytochemistry
1988, 27, 3619-3624.
(3H, s, H-13), 1.09 (3H, s, H-14), 0.97 (1H, ddd, J ) 13.0, 4, 4
13
Hz, H-9R), 0.68 (3H, d, J ) 6.7 Hz, H-15); C NMR (CDCl
2.6 (s, C-11), 67.3 (s, C-5), 56.9 (d, C-6), 45.6 (d, C-7), 37.4 (t,
C-1), 34.0 (t, C-9), 33.7 (s, C-10), 33.0 (t, C-3), 29.8 (d, C-4),
8.7 (q, C-12), 25.4 (q, C-13), 21.7 (t, C-2), 20.7 (q, C-14), 19.0
3
) δ
7) Appendino, G.; Cravotto, G.; Nano, G. M.; Palmisano, G. Synth.
Commun. 1992, 22, 2205-2212. (b) Appendino, G.; Cravotto, G.;
Toma, L.; Annunziata, R.; Palmisano, G. J . Org. Chem. 1994, 59,
5556-5564. (c) Appendino, G.; Cravotto, G.; Palmisano, G.; Annun-
ziata, R. Tetrahedron 1998, 54, 10819-10826.
8) Appendino, G.; Ballero, M., Poli, F. Manuscript in preparation.
9) Saidkhodzhaev, A. I.; Nikonov, G. K. Khim. Prir. Soedin. 1973, 26-
30.
7
2
+
(
t, C-8), 14.5 (q, C-15); HREIMS m/z 238.1920 [M] (5) (calcd
for C15 , 238.1933).
1R,4S,5S,10R)-Eu desm a-6-en -1,11-diol (4): colorless gum;
H NMR (CDCl ) δ 5.72 (1H, s, H-6), 3.29 (1H, dd, J ) 10, 3
(
(
26 2
H O
(
1
(10) Saidkhodzhaev, A. I.; Nikonov, G. K. Khim. Prir. Soedin. 1978, 105-
06.
11) For
3
1
Hz, H-1), 2.12 (2H, m, H-8R,â), 1.98 (1H, ddd, J ) 11, 6, 2 Hz,
H-9â), 1.74 (1H, m, H-3â), 1.72 (1H, m, H-2R), 1.62 (1H, m,
H-2â), 1.41 (1H, m, H-5), 1.36 (1H, m, H-4), 1.33 (3H, s, H-12),
1
0
(
(
a total synthesis, see: Zhabinskii, V. N.; Minnaard, A. J .;
Wijnberg, J . B. P. A.; de Groot, A. J . Org. Chem. 1996, 61, 4022-
4027.
12) Miski, M.; Mabry, T. J . Phytochemistry 1985, 24, 1735-1741.
(13) Appendino, G.; J akupovic, J .; Alloatti, S.; Ballero, M. Phytochemistry
.32 (3H, s, H-13), 1.25 (1H, m, H-9R), 1.06 (1H, m, H-3R),
13
3
.93 (3H, d, J ) 6.5, H-15), 0.77 (3H, s, H-14); C NMR (CDCl )
1
997, 45, 1639-1643.
δ 142.9 (s, C-7), 118.6 (s, C-6), 78.1 (d, C-1), 73.0 (s, C-11),
8.9 (d, C-5), 37.4 (s, C-10), 34.2 (t, C-3), 33.6 (t, C-9), 30.1 (t,
C-2), 29.2 (q, C-12), 29.3 (d, C-4), 29.0 (q, C-13), 21.6 (t, C-8),
9.3 (q, C-15), 10.1 (q, C-14); HREIMS m/z 238.1941 [M]+ (2)
calcd for C15 , 238.1933).
1R,4S,7S,10R)-Eu desm a-5-en -1,11-diol (5): colorless gum;
H NMR (CDCl ) δ 5.45 (1H, d, J ) 1.5 Hz, H-6), 3.25 (1H, dd,
(
14) Pinar, M.; Rodr ´ı guez, B. Phytochemistry 1977, 16, 1987-1989.
4
(15) Kir’yalov, N. P.; Bukreeva, T. V. Khim. Prir. Soedin. 1972, 643-646.
(
(
16) Minski, M.; J akupovic, J . Phytochemistry 1990, 29, 1995-1998.
17) De Pasqual Teresa, J .; Villaseco, M. A.; Hern a´ ndez, J . M.; Mor a´ n, J .
R.; Urones, J . G.; Grande, M. Planta Med. 1986, 458-462.
1
(
H
26
O
2
(18) Appendino, G.; J akupovic, J .; Cravotto, G.; Biavatti-Weber, M.
Tetrahedron 1997, 53, 4681-4692.
(
1
(19) J osephson, J . J . Environ. Sci. Technol. 2000, 34, 130A-135A.
3
(
20) Carboni, S.; Da Settimo, A.; Malaguzzi, V.; Marsili, A.; Pacini, P. L.
J ) 11.6, 4.4 Hz, H-1), 2.17 (1H, m, H-4), 2.10 (1H, m, H-7),
Tetrahedron Lett. 1965, 3017-3021.
1
1
1
.94 (1H, ddd, J ) 12.6, 3.7, 2.1 Hz, H-9R), 1.75 (1H, m, H-3â),
.74 (1H, m, H-2â), 1.72 (1H, m, H-8â), 1.66 (1H, m, H-2R),
.36 (1H, m, H-9â), 1.27 (1H, m, H-8R), 1.24 (3H, s, H-12), 1.18
(21) Gonz a´ lez, A. G.; Bermejo Barrera, J . B. In Progress in the Chemistry
of Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E.,
Steglich, W., Tamm, Ch., Eds.; Springer: New York, 1995; Vol. 64,
pp 1-92
(
1
(
3
3H, s, H-13), 1.04 (3H, s, H-14), 1.02 (3H, d, J ) 6.5, H-15),
.00 (1H, m, H-3R); 13C NMR (CDCl
) δ 147.2 (s, C-5), 119.6
d, C-6), 80.2 (d, C-1), 73.0 (s, C-11), 47.8 (d, C-7), 40.3 (s, C-10),
6.6 (t, C-9), 33.3 (t, C-3), 32.3 (d, C-4), 30.5 (t, C-2), 27.9 (q,
C-12), 25.7 (q, C-13), 20.3 (t, C-8), 18.4 (q, C-15), 17.8 (q, C-14);
(
22) We have observed that large amounts of ferutinin and jaeskeanadiol
benzoate, the major constituents of the nonpoisonous chemotype of
giant fennel from Sardinia, occur in F. hermonis Boiss., a plant that
made headline news for its alleged aphrodisiac properties and is
advertized as a plant alternative to Viagra (for a CNN report, see:
http://europe.cnn.com/HEALTH/9808/12/natural.viagra/).
3
+
HREIMS m/z 238.1946 [M] (2) (calcd for C15
H
26
O
2
, 238.1933).
(23) Singh, M. M.; Agnihotri, A.; Garg, S. N.; Agarwal, S. K.; Gupta, D.
N.; Keshri, G.; Kamboj, V. P. Planta Med. 1988, 54, 492-494. (b)
Zamaraeva, M. V.; Hagelgans, A. I.; Lubnina, L. V.; Abramov, A. Y.;
Ahmedhodjaeva, H. S.; Saidhodjaev, A. I.; Glazyrina, N. G.; Sala-
khutdinov, B. A. Cell. Mol. Biol. Lett. 1999, 4, 189-201.
(24) For a historical account of the use of plants from the genus Ferula
as antifertility agents, see: Riddle, J . M. Eve’s Herbs; Harvard
University Press: Cambridge, 1997; pp 44-46.
(
1R,4S,5S,6R,7S,10R)-Eu d esm a -6-en -1,11-d iol ep oxid e
2
5
(
(
6): white crystals (petroleum ether), mp 59 °C; [R]
D
+28
CH Cl , c 0.2); IR (KBr) νmax 3420, 1450, 1360, 1192, 1106,
2
2
-
1 1
9
3
35 cm ; H NMR (CDCl
3
) δ 3.19 (1H, dd, J ) 10, 4 Hz, H-1),
.14 (1H, s, H-6), 1.93 (1H, m, H-8â), 1.80 (1H, m, H-8R), 1.80
(
(
1H, m, H-9R), 1.78 (1H, m, H-3R), 1.73 (1H, m, H-2â), 1.58
1H, m, H-2R), 1.45 (1H, m, H-4), 1.31 (3H, s, H-12), 1.28 (3H,
NP000468F