Efficient synthesis of the anticancer β-elemene and other bioactive elemanes from sustainable germacrone

Article abstract of DOI:10.1039/c0ob00467g

Highly efficient preparations of anticancer β-elemene and other bioactive elemanes were carried out using the natural product germacrone as a renewable starting material. The syntheses were achieved in only 3-5 steps with excellent overall yields (43-54%). An enantioselective approach to these molecules is also described

Full text of DOI:10.1039/c0ob00467g

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PAPER
Efficient synthesis of the anticancer b-elemene and other bioactive elemanes
from sustainable germacrone†
Alejandro F. Barrero,* M. Mar Herrador,* Jose´ F. Qu´ılez del Moral, Pilar Arteaga, Niklas Meine,
M. Carmen Pe´rez-Morales and Julieta V. Catala´n
Received 21st July 2010, Accepted 4th November 2010
DOI: 10.1039/c0ob00467g
Highly efficient preparations of anticancer b-elemene and other bioactive elemanes were carried out
using the natural product germacrone as a renewable starting material. The syntheses were achieved in
only 3–5 steps with excellent overall yields (43–54%). An enantioselective approach to these molecules
is also described
the few milligrams available from the total synthesis, and only
after significant effort. In this sense we believe that structure and
Introduction
The sesquiterpenes b-elemene (1) and g-elemene (2) are usually
minor components of the essential oils of numerous plants.1
Compound 1 is a potent antitumor agent2 which has a selective
inhibitory effect on cerebrovascular endothelial cells and has given
excellent results as an antitumor agent in the treatment of brain
tumors and suppresses the growth of brain metastasis from lung
cancer. It induces apoptosis, limits cellular differentiation and
inhibits of neoplastic metastasis proving to be a good candidate
for use in chemotherapy in the treatment of neoplasms in the lung,
colon, stomach, brain etc.3 Some formulations for pharmacolog-
ical uses containing 1 or 1 plus small quantities of 2, have been
patented3 and some more polar derivatives with enhanced activity
have also recently been described,3,4 and are now in application
for clinical studies in the United States.5 8a-Hydroxy-b-elemene
(3) and 8a-acetoxy-b-elemene (4) are sesquiterpenes isolated from
Juniperus species6 featuring antifungal activity against eczema
fungi and also insecticidal activity.7
functionality of germacrone (5), found as the major component in
the oils of Baccharis latifolia10 and Geranium macrorrhizum11 may
well serve as a versatile building block for the efficient preparation
of a wide variety of bioactive molecules.12
In this context, and given the increasing interest of the
aforementioned elemanes, we describe in this paper a convenient
methodology for the semisynthesis of the elemanes 1–4 using 5 as
starting material (Scheme 1).
Concerning the preparation of these four natural elemanes,
several multistep syntheses of 1 and 2 have been reported1a,8 or
patented.4b However, the synthesis of 3 and 4 has still not been
reported, despite the interesting properties attributable to these
compounds.
In the field of the synthesis of potent bioactive natural products,
it should be remarked that the efficiency of synthetic approaches
including the use of renewable starting material is generally far
ahead of the current capabilities of chemical total synthesis. For
instance, tonnes of 10-deacetyl baccatin III are produced by the
needles of Taxus baccata yew tree as a renewable starting material
for the commercial semi-synthesis of taxol,9 in contrast with
Scheme 1 Retrosynthetic analysis for the compounds 1–4.
Results and discussion
The retrosynthetic planning to 1–4 includes as key step a Cope
rearrangement of the germacrane skeleton to provide the elemane
skeleton present in the target molecules as the key step (Scheme 1).
Some years ago, our research group described a Pd-promoted
rearrangement of germacranolides to either elemanolides or
eudesmanolides, depending on the experimental conditions.13
Department of Organic Chemistry, Institute of Biotechnology, University of
Granada, Avda Fuente Nueva, s/n, 18071 Granada, Spain. E-mail: afbarre@
ugr.es, mmar@ugr.es; Fax: +34 958243318; Tel: +34 958243318
† Electronic supplementary information (ESI) available: COSY, HSQC,
HMBC and NOE diff. data of epoxide 13, and NMR spectra of new
intermediates and final products. See DOI: 10.1039/c0ob00467g
1118 | Org. Biomol. Chem., 2011, 9, 1118–1125
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Table 1 Pd(II) catalyzed Cope rearrangement of germacrone (5)
Since compound 8 proved to be unstable, the deconjugation
reaction was repeated under the same conditions but shortening
the reaction time significantly (5 min versus 2.5 h), and then,
the thus-obtained resulting crude reaction was quickly reduced
with LiAlH4. Under these conditions, the desired alcohol 7 was
obtained in 32% yield, together with its isomers 1117 (32%) and 1218
(17%) (Scheme 3). In the 1H NMR spectrum of 7, H-8 appears as a
broad singlet, which determines the b orientation of the hydroxyl
group.
Method
Conditions
Yield of 6 (%)
A
B
C
Toluene, rt, Pd(II) (0.2 equiv), 5 h.
Toluene, reflux, Pd(II) (0.2 equiv), 60 min.
Toluene, reflux, Pd(II) (0.04 equiv), 6.5 h.
82
98
72
Based in this precedent, we started this work by subjecting
germacrone (5), isolated in multigram scale from the essential oil of
Geranium macrorrhizum or Baccharis latifolia, to Pd(II)-catalyzed
Cope rearrangement under different experimental conditions. The
results of this study are summarized in Table 1, method B featuring
the best conditions where the yield obtained of elemenone (6) was
nearly quantitative (98%).14
Once we had elemenone (6) in our hands, the following steps
towards the synthesis of 1 supposed the deconjugation of the a,b-
carbonyl system, and then the reduction of the carbonyl group
to give 7, which after the corresponding deoxygenation would
produce 1 (Scheme 2).
Scheme 3 Deconjugation of 6 with KOBut/Py followed by fast LAH
reduction.
In order to increase the yield of these two steps, the LiAlH4
reduction was carried out before the work-up of the deconjugation
reaction, however the reduction was slow and the yield of 7 was
only 10%. Gratifyingly, ketone reduction could be carried out
efficiently if KOBut is removed from the crude by Et2O–H2O
partitioning, and the dried ether phase is added to a suspension of
LiAlH4 in ether. Alcohol 7 was thus obtained with an acceptable
yield of 74%. Barton–McCombie deoxygenation19 of 7 yielded
( )-b-elemene (1) (Scheme 2) with a yield of 64%. MS, 1H and 13
C
NMR of our synthetic b-elemene coincide completely with those
Scheme 2 Synthesis of b-elemene (1) from germacrone (5).
of the natural product.8c
Once the synthesis of b-elemene (1) was achieved, we decided
to focus our efforts to the synthesis of its congeners 8a-hydroxy-
b-elemene (3) and 8a-acetoxy-b-elemene (4) (Scheme 4). Thus,
selective epoxidation of the double bond 7,11 of elemenone was
carried out diastereoeselectively with the hydroperoxide anion to
To achieve the desired deconjugation, enone 6 was treated with
different bases. The results obtained (Table 2) showed that no
alteration of the starting material was observed with hard bases
(protonation of the kinetic enolate), and only by using KOBut
in pyridine at reflux15 6 afforded, after 2.5 h, the deconjugated
ketone 8 and by-products 9–10. Compound 9 was the result of a
retroaldolic condensation which also produced acetone,16 whereas
ketone 10 was produced after a Robinson annulation between 6
and the acetone previously formed.
Table 2 Deconjugation of 6 with different bases
Base
Temp. (◦C)
Time (h)
8
9
10
LDA/HMPA
NaH
-78
rt
reflux
24
1a
2.5
—
—
40
—
—
22
—
—
5
KOBut/Py
a Decomposition of 6 was observed after long reaction times.
Scheme 4 Synthesis of 3–4 from 6.
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Table 3 Cope rearrangement of germacrol (15) and its acetate 15a
obtain the a-epoxide 13 with a yield of 65%, together with a
28% of the b-isomer (13b). The nOe effect observed between
H-13 and H-6 and H-14 suggested that the stereochemistry
of epoxy group in 13 is that depicted in Scheme 4. Epoxide
13, was then treated with Zn/AcOH. In this process, the zinc
enolate intermediate evolves to the most stable keto-alcohol,
that is compound 14,20 where the 2-hydroxypropyl moiety is
disposed equatorially. Reduction of 14 with lithium in liquid
ammonia–EtOH led with total stereoselectivity to the most stable
equatorial hydroxyl group, yielding ( )-8a-hydroxy-b-elemol (3)
(71%). The efficiency of this synthesis could be improved by
treating epoxyketone 13 with excess of lithium in liquid ammonia,
a reagent that proved to achieve the required double reduction to
afford 3 in one single step with a 75% yield. This transformation
also permitted the confirmation of the stereochemistry previously
assigned to epoxide 13. Standard acetylation of 3 gave ( )-
8a-acetoxy-b-elemol (4) (97%). The spectroscopic data of both
synthetic products were identical to those of the authentic natural
samples.6
Methoda
Conditionsb
12c
16c
17c
18c
A
B
C
D
E
F
G
H
rt, PdII (0.2 equiv), 15 min
rt, PdII (0.2 equiv), 60 min
rt, PdII (0.05 equiv), 1.5 h
rt, PdII (0.05 equiv), 6 h
19
36
12
31
—
16d
27d
—
—
19
—
15
72
—
14
73
—
5
—
4
19
—
—
18
—
—
—
—
—
72d
45d
—
reflux, PdII (0.2 eq.), 105 min
rt., PdII (0.2 eq.), 15 min
rt., PdII (0.2 equiv), 6 h
reflux, PdII (0.2 equiv), 120 min
Finally, g-elemene (2) was synthesized as depicted in Scheme 5.
This approach included as key step the 1,4 reduction of the diene
intermediate 16, a process which permitted the suitable location for
the tetrasubstituted double bond. Starting again from germacrone,
germacrol (15)21 was obtained almost quantitatively after LiAlH4
reduction.
a Methods A–E used for 15 and methods F–H used for 15a. b All reactions
were realized in toluene. c Isolated yields (%). d Yields (%) calculated after
NMR crude analysis due to the instability of 18
to achieve asymmetrically the key Cope rearrangement of the
germacrane skeleton. In this context, the Pd(II) catalyst known as
COP-Cl (I) (Fig. 1) was the catalyst of choice due to the good yields
and high enantiomeric purities described for the [3.3]-sigmatropic
rearrangement of prochiral allylic imidates into higher value chiral
allylic amides and amines when mediated by this Pd(II) species.22
Unfortunately when germacrone was made to react with COP-
Cl, no alteration of the starting material was observed, even after
increasing the temperature and reaction times. Then, we decided
to prepare enantioselectively a derivative of germacrone, with the
hope the introduced asymmetry would be reflected in the product
of the Pd(II)-catalyzed Cope rearrangement. In this context, and
being sensitive to the advantages of the organocatalysis research
with its potential for savings in cost, time and energy, easier
Scheme 5 Synthesis of g-elemene (2) from 5.
At this point, Pd catalyzed Cope rearrangement of 15 and of its
acetate 15a was studied under different conditions by varying the
temperature, reaction time and the Pd(II) loading (Table 3).
Thus for compound 15, when this transformation was per-
formed at room temperature, compound 12 turned out to be the
major compound, as result of an allylic rearrangement of the C8
hydroxyl group at C11 in addition to the Cope rearrangement.
Fortunately, heating the reaction media led to the target diene
16. Considerable experimentation was needed to find the best
conditions for this transformation (method E, Table 3). In the
case of compound 15a, similar results were obtained, although
at room temperature the major reaction product was acetate 18,
whereas at refluxing toluene the major compound turned out to
be elemene 16. This data indicates that the Cope rearrangement is
previous to the loss of the acetate moiety. Finally, reduction of 16
with sodium in liquid ammonia yielded uneventfully ( )-g-elemene
1
(2). MS, H and 13C NMR of our synthetic coincide completely
with those of the natural product.
Once an efficient methodology to the racemic syntheses of
bioactive elemanes had been established, an enantioselective
approach was envisaged via the use of chiral Pd(II) catalysts
Fig. 1 Catalysts employed in the asymmetric approach to the target
elemenes.
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experimental procedures and reduction in chemical waste, we
decided to explore the asymmetric epoxidation of the enone
present in germacrone via iminium catalysis, using either the
diarylprolinol ether derivative II23 or and the diamine salt III24
in the presence of H2O2. Unfortunately, no satisfactory results
were obtained when these epoxidation were tested under different
experimental conditions, with the starting material remaining
unaltered in most of cases.
Experimental
General details
IR spectra were recorded on a Mattson Satellite FTIR spectrom-
eter. NMR spectra were performed with a Varian Direct-Drive
400 (1H 400 MHz/13C 100 MHz) and 500 (1H 500 MHz/13C
125 MHz) spectrometers. High-resolution MS were determined
on an Autospec-Q VG-Analytical (FISONS) mass spectrometer.
HPLC with RI detection was used. Semi-preparative HPLC
separations were carried out on a column (5 mm silica, 10 ¥
250 mm) at a flow rate of 2.0 cm3 min-1 in an Agilent Series 1100
instrument. All air- and water-sensitive reactions were performed
in flasks flame-dried under a positive flow of argon and conducted
under an argon atmosphere. The solvents used were purified
according to standard literature techniques and stored under
argon.
We next shifted our efforts to check the enantioselective
reduction of germacrone to germacrol25 using the chiral 2-methyl-
CBS-oxazaborolidine catalyst IV. When performing this reaction
under usually reported experimental conditions,26 it was observed
that low transformations were obtained by using the 1 equiv of IV
and 1.2 equiv of borane and only a 15% of germacrol27 together
with a 72% of starting material were obtained. When the quantities
of IV and borane were increased up to 3 and 3.6 equiv respectively,
moderate yields of germacrol were produced (52%, together with
30% of starting germacrone). When the acetate derivative of the
thus-obtained germacrol was heated at reflux for 2 h with 0.2 equiv
of Pd(II) (Method H, Table 3), 72% of 16, together with 19%
of 1728 were obtained. Treatment of tetraene 16 with sodium
in liquid ammonia afforded (+)-g-elemene (2), which showed an
optical rotation value of +3.5◦. Comparison of this datum with
that of the natural product29 permitted us to establish that our
synthetic (+)-2 showed an enantiomeric excess of 75% (Scheme 6).
It was thus proved that an enantioselective version of our
protocol for the asymmetric preparation of bioactive elemenes is
viable.
Isolation of germacrone (5) from essential oil of Geranium
macrorrhizum
The essential oil (5 g) was chromatographed over silica gel column
(hexane/t-butylmethylether, 98 : 2) to obtain 530 (2.7 g, 54%) as a
crystalline solid. Crystals mp 53–54 ◦C (from hexane).
Cope rearrangement of germacrone (5). Preparation of elemenone
(6)
Germacrone (5, 105 mg, 0.48 mmol) and PdCl2(PhCN)2 (37 mg,
0.2 equiv) were dissolved in dry toluene (6 cm3), under argon.
The solution was heated at reflux under stirring for 60 min. After
cooling at room temperature, the mixture was filtered through
silica gel and the layer was washed with t-butylmethylether.
The solvent was concentrated in vacuo yielding a crude product
which was chromatographed over a silica gel column (hexane : t-
butylmethylether, 95 : 5) to obtain 6 (86 mg, 98%).14
Elemenone (6). dC(125 MHz; CDCl3; Me4Si) 19.1 (CH3, C-14),
22.6 (CH3, C-15), 23.4 (CH3, C-13) 24.8 (CH3, C-14), 32.0 (CH2,
C-6), 41.9 (C, C-10), 50.7.3 (CH, C-5), 54.1 (CH2, C-9), 111.3
(CH2, C-2), 113.0 (CH2, C-3), 130.8 (C, C-7), 144.0 (C, C-11),
146.4 (C, C-4), 146.8 (CH, C-1), and 202.7 (C, C-8).
Scheme 6 Enantioselective approach to (+)-g-elemene (2).
Deconjugation of 6 with KOBut/Py. Preparation of compound 7
Method A. KOBut (78 mg, 0.66 mmol) was added to a solution
of 6 (97 mg, 0.44 mmol) in pyridine (2.5 cm3). The mixture was
heated at reflux under stirring for 2.5 h. After cooling at room
temperature, the mixture was diluted with t-butylmethylether and
washed with 2 N HCl solution, saturated aqueous NaHCO3
solution and brine, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo yielding a crude product which was chro-
matographed over a silica gel column (hexane : t-butylmethylether,
95 : 5) to obtain 8 (39 mg, 40%), 9 (17 mg, 22%)16 and 10 (6 mg,
5%).
Conclusions
In this work the natural product germacrone (5), obtained from the
essential oils of Baccharis latifolia or Geranium macrorrhizum, is
used for first time as a starting material in the synthesis of bioactive
elemanes. Thus, the racemic synthesis of antitumor b-elemene
(1) and g-elemene (2) and that of the antifungal 8a-hydroxy-
b-elemene (3) and 8a-acetoxy-b-elemene (4) has been achieved
by a process entailing just a few steps (3–5) and featuring high
overall yields (43–53%.). These results show that semisyntheses
using an easily available renewable starting material constitute
a advantageous alternative to total syntheses in the preparation
of products of interest. Moreover, this method can be easily
adapted for asymmetric synthesis, via CBS asymmetric reduction
of germacrone to chiral germacrol.
(6S,7S)-3,4,5,6,7,8-Hexahydro-4,4,7-trimethyl-6-isopropenyl-7-
vinylnaphthalen-2(1H)-one
n
(10). Yellow
syrup.
IR
max(film)/cm-1 2963, 2926, 2876, 1714, 1667, 1455, 1416,
1374, 1304, 1260, 1076, 1035, 911, 895 and 803; dH(500 MHz;
CDCl3; Me4Si) 0.99 (3 H, s, 15-H)a, 1.02 (3 H, s, 14-H)a, 1.08 (3
H, s, 13-H)a, 1.66–1.80 (3 H, m, 5b-H, 8a-H, 8b-H), 1.75 (3 H,
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s, 16-H), 2.02–2.21 (4 H, m, 3a-H, 3b-H, 5a-H, 6a-H), 2.36 (1
H, d, J 13.3, 1a-H), 2.42 (1 H, d, J 13.3, 1b-H), 4.73 (1 H, s,
11a-H), 4.85 (1 H, s, 11b-H), 4.93 (1 H, d, J 10.6, 10a-H), 4.94
(1 H, d, J 17.2, 10b-H) and 5.80 (1 H, dd, J 10.6 and 17.2, 9-H)
(aSignals with the same letter are exchangeable); dC(125 MHz;
CDCl3; Me4Si) 19.4 (CH3, C-16), 24.8 (CH3, C-15)a, 27.2 (CH3,
C-13)a, 27.5 (CH3, C-14)a, 28.4 (CH2, C-5), 38.7 (C, C-4), 39.3
(CH, C-7), 43.1 (CH2, C-8), 45.1 (CH2, C-1), 49.3 (CH, C-6),
55.1 (CH2, C-3), 110.8 (CH2, C-10), 112.4 (CH2, C-11), 123.2
(C, C-4a), 135.2 (C, C-8a), 147.7 (C, C-12), 147.8 (CH, C-9) and
210.5 (C, C-2) (aSignals with the same letter are exchangeable);
m/z (HRMS(FAB)) 281.1881 (M + Na. C18H26ONa requires
281.1882)
(5S,10S)-Elema-1,4,7-trien-11-ol (12). Colorless syrup. IR
n
max(film)/cm-1 3381, 3081, 2971, 2905, 2833, 1637, 1455, 1435,
1373, 1136, 1035, 1002, 908, 890 and 816; dH(500 MHz; CDCl3;
Me4Si) 0.97 (3 H, s, 14-H), 1.32 (3 H, s, 12-H)a, 1.34 (3 H, s, 13-H)a,
1.74 (3 H, s, 15-H), 1.86 (1 H, dd, J 4.0 and 17.3, 9a-H), 2.13-2.32
(4 H, m, 5a-H, 2 H-6, 9b-H), 4.73 (1 H, bs, 3a-H), 4.84 (1 H, bs,
3b-H), 4.92 (1 H, d, J 10.7, 2a-H), 4.95 (1H, d, J 17.5, 2b-H), 5.70
(1 H, m, 8-H), 5.81 (1H, dd, J 10.7 and 17.5, 1-H) (aSignals with
the same letter are exchangeable); dC(100 MHz; CDCl3; Me4Si)
19.1 (CH3, C-15), 24.7 (CH3, C-14), 28.3 (CH2, C-6), 29.2 (2 CH3,
C-12, C-13), 38.2 (C, C-10), 38.6 (CH2, C-9), 49.2 (CH, C-5), 73.0
(C, C-11), 110.6 (CH2, C-3), 112.3 (CH2, C-2), 117.3 (CH, C-8),
143.0 (C, C-7), 147.9 (C, C-4) and 148.4 (CH, C-1).
Method C. KOBut (250 mg, 2.12 mmol) was added to a
solution of 6 (303 mg, 1.416 mmol) in dry pyridine (6 cm3) under
argon and the mixture was refluxed for 5 min. After cooling at 0 ◦C
it was diluted with dry Et2O (10 cm3) and was rapidly washed with
water, dried over anhydrous Na2SO4 and filtered. This solution
was added to a suspension of LiAlH4 (566 mg, 14.16 mmol) in
dry Et2O, under argon and vigorous stirring. After 5 min at room
temperature, the reaction was stopped by successive addition of
water (2 drops), 6 N NaOH solution (2 drops) and water (6 drops).
The mixture was worked up as usual to give a crude product, which
was chromatographed over silica gel column to give 7 (hexane/t-
butylmethylether, 70 : 30, 225 mg, 74%).
Method B. This method is similar to the method A but
the reaction time was 5 min. LiAlH4 (93 mg) was added to
a cold (-10 ◦C) solution of the crude product (411 mg) in
dry THF (15 cm3) under argon and vigorous stirring. After
10 min the reaction was stopped by successive addition of water
(2 drops), 6 N NaOH solution (2 drops) and water (6 drops).
The mixture was worked up as usual to give a crude product
which was chromatographed over silica gel column (hexane : t-
butylmethylether, 70 : 30) to obtain alcohols 7 (325 mg, 32%), 11
(322 mg, 32%) and 12 (171 mg, 17%).18
(5S,7R,8R,10S)-Elema-1,3,11-trien-8-ol (7). Colorless syrup.
IR nmax(film)/cm-1 3551, 3479, 3083, 2966, 2926, 2870, 1712, 1642,
1446, 1376, 1260, 1151, 1059, 1027, 1005 and 964; dH(500 MHz;
CDCl3; Me4Si) 1.12 (3 H, s, 14-H), 1.29 (1 H, m, 6a-H), 1.41 (1
H, br s, OH), 1.53 (1 H, dd, J 3.2 and 14.5, 9a-H), 1.67 (3 H,
br s, 13-H), 1.73 (3 H, br s, 15-H), 1.73 (1 H, dd, J 2.9 and 14.4,
9b-H), 1.95–2.07 (3 H, m, 5a-H, 7a-H, 6b-H), 3.96 (1 H, br s,
8a-H), 4.58 (1 H, br s, 3a-H), 4.77 (1 H, br s, 3b-H), 4.80 (1 H, br
s, 12a-H), 4.83 (1 H, dd, J 1.1 and 17.8, 2a-H), 4.84 (1 H, dd, J 1.1
and 10.5, 2b-H), 4.93 (1 H, br s, 12b-H) and 5.72 (1 H, dd, J 10.4
and 17.8, 1-H) (aSignals with the same letter are exchangeable);
dC(125 MHz; CDCl3; Me4Si) 19.5 (CH3, C-14), 22.8 (CH3, C-13),
24.8 (CH3, C-15), 26.2 (CH2, C-6), 39.9 (C, C-10), 44.7 (CH2, C-
9), 49.7 (CH, C-7), 53.3 (CH, C-5), 66.6 (CH, C-8), 110.5 (CH2,
C-2), 111.9 (CH2, C-12), 112.7 (CH2, C-3), 146.9 (C, C-4), 147.5
(C, C-11) and 150.7 (CH, C-1); m/z (HRMS(FAB)) 243.1727 (M
+ Na. C15H24ONa requires 243.1725).
Deoxygenation of 7. Preparation of b-elemene (1)
A solution of 7 (94 mg, 0.43 mmol) and carbon disulfide (154 mL,
4.0 equiv) in THF (5 cm3) was added to suspension of sodium
hydride (86 mg, 1.2 equiv, 60% dispersion) in THF (3 cm3) at
0
◦C. The mixture was stirred at room temperature for 90 min
and iodomethane (214 mL, 8.0 equiv) was added at 0 ◦C.
The mixture was stirred at room temperature for 3 h, diluted
with t-butylmethylether, and carefully poured into water. After
extraction with t-butylmethylether, the combined organic phases
were washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. A solution of tri-n-butyltin hydride
(198 mL, 2 equiv) and AIBN (3 mg, 0.1 equiv) in dry and strictly
deoxygenated toluene (8 cm3) was added dropwise (10 cm3 h-1)
to a solution of crude product in dry and strictly deoxygenated
toluene (8 cm3), under argon and heated at reflux. 15 min after the
addition had finished, the solvent was concentrated in vacuo and
the crude product was chromatographed over silica gel column
(hexane) to obtain 1 (56 mg, 64%).8c
(5S,10R)-Elema-1,3,7(11)-trien-8b-ol (11). Colorless syrup.
IR nmax(film)/cm-1 3334, 3080, 2965, 2917, 2727, 1636, 1447, 1373,
1261, 1098, 1051, 1018, 905, 889 and 802; dH(400 MHz; CDCl3;
Me4Si) 0.92 (3 H, s, 14-H), 1.56 (1 H, br s, OH), 1.67 (1 H, dd, J 3.9
and 14.6, 9a-H), 1.69 (3 H, s, 12-H)a, 1.72 (3 H, s, 15-H), 1.79 (3 H,
s, 13-H)a, 1.87 (1 H, dd, J 3.8 and 14.6, 9b-H), 2.31 (1 H, dd, J 7.9
and 14.9, 6a-H), 2.43–2.50 (1 H, m, H-6b), 2.52 (1 H, dd, J 4.6 and
7.8, 5-H), 4.69 (1 H, br s, 3a-H), 4.74 (1 H, t, J 3.8, 8-H), 4.79 (1 H,
br s, 3b-H), 4.96 (1 H, d, J 10.8, 2a-H), 5.04 (1 H, d, J 17.6, 2b-H)
and 6.26 (1 H, dd, J 10.8 and 17.6, 1-H) (aSignals with the same
letter are exchangeable); dC(100 MHz; CDCl3; Me4Si) 20.2 (CH3,
C-12)a, 20.7 (CH3, C-13)a, 23.9 (CH3, C-14), 25.1 (CH3, C-15), 28.1
(CH2, C-6), 38.1 (C, C-10), 43.7 (CH2, C-9), 48.1 (CH, C-5), 67.5
(CH, C-8), 110.1 (CH2, C-2), 112.1 (CH2, C-3), 128.7 (C, C-11),
131.5 (C, C-7), 148.2 (C, C-4) and 151.1 (CH, C-1) (aSignals with
the same letter are exchangeable); m/z (HRMS(FAB)) 243.1726
(M + Na. C15H24ONa requires 243.1725).
b-Elemene (1). Colorless syrup. IR nmax(film)/cm-1 2955, 2925,
2855, 1643, 1454, 1375, 1260, 1093, 1025, 948, 908 and 809;
dH(500 MHz; CDCl3; Me4Si) 0.94 (3 H, s, 14-H), 1.14–1.60 (6
H, m, 6-H, 8-H, 9-H), 1.64 (3 H, s, 13-H), 1.68 (3 H, s, 15-H),
1.84–1.98 (2 H, m, 5a-H, 7a-H), 4.52 (1 H, br s, 3a-H), 4.63 (1 H,
br s, 3b-H), 4.65 (1 H, br s, 12a-H), 4.75 (1 H, br s, 12b-H), 4.83 (1
H, d, J 10.9, 2a-H), 4.84 (1 H, d, J 17.5, 2b-H) and 5.76 (1 H, dd,
J 10.9, 17.5, 1-H) (aSignals with the same letter are exchangeable);
dC(125 MHz; CDCl3; Me4Si) 16.9 (CH3, C-14), 21.2 (CH3, C-13),
24.9 (CH3, C-15), 27.0 (CH2, C-8), 33.1 (CH2, C-6), 40.0 (C, C-
10), 40.1 (CH2, C-9), 45.9 (CH, C-7), 53.0 (CH, C-5), 108.4 (CH2,
C-12), 110.0 (CH2, C-2), 112.3 (CH2, C-3), 148.0 (C, C-4), 150.5
(CH, C-1) and 150.6 (C, C-11).
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Epoxidation of elemenone (6) with H2O2/OH-
12-H, 13-H), 1.76 (3 H, s, 15-H), 1.92 (1 H, q, J 13.1, 6b-H),
1.98–2.04 (1 H, m, 6a-H), 2.08 (1 H, d, J 12.9, 9a-H), 2.45–2.52
(3 H, m, 5a-H, 7a-H, 9b-H), 3.82 (1 H, br s, OH), 4.69 (1 H,
br s, 3a-H), 4.90 (1 H, d, J 17.4, 2a-H), 4.93 (1 H, br s, 3b-H),
4.97 (1 H, d, J 10.7, 2b-H) and 5.82 (1 H, dd, J 10.7 and 17.4,
1-H); dC(125 MHz; CDCl3; Me4Si) 17.5 (CH3, C-15), 25.1 (CH3,
C-14), 25.8 (CH3, C-12)a, 28.8 (CH3, C-13)a, 31.0 (CH2, C-6),
45.0 (C, C-10), 52.1 (CH, C-5), 55.2 (CH2, C-9), 59.1 (CH, C-7),
71.4 (C, C-11), 111.5 (CH2, C-3), 113.8 (CH2, C-2), 145.5 (C, C-
4), 146.6 (CH, C-1) and 214.2 (C, C-8) (aSignals with the same
letter are exchangeable); m/z (HRMS(FAB)) 237.1856 (M + Na
C15H25O2Na requires 237.1854).
2 N NaOH solution (3 cm3) and 30% H2O2 (9.1 cm3) were
successively added to a solution of 6 (1031 mg, 4.73 mmol) in
◦
MeOH (150 cm3) at -45 C. The mixture was vigorously stirred
for 7 h and was then kept at room temperature for 2 h. The mixture
was diluted with t-butylmethylether (150 cm3), washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated in vacuo
to afford a crude product, which was chromatographed over silica
gel column to obtain the epoxides 13 (hexane/t-butylmethylether,
90 : 10, 719 mg, 65%) and 19 (hexane/t-butylmethylether, 80 : 20,
314 mg, 28%).
(5S,7R,10S)-7,11-Epoxyelema-1,3-dien-8-one (13). Colorless
syrup. IR nmax(film)/cm-1 3084, 3001, 2966, 2927, 2732, 1722,
1641, 1453, 1433, 1377, 1273, 1123, 1063, 1002, 914 and 809;
dH(500 MHz; CDCl3; Me4Si) 1.08 (3 H, s, 14-H), 1.27 (3 H, s, 12-
H), 1.35 (3 H, s, 13-H), 1.83 (3 H, s, 15-H), 2.10 (2 H, d, J 6.1, 6-H),
2.47 (1 H, t, J 6.2, 5a-H), 2.49 (1 H, d, J 14.5, 9a-H), 2.70 (1 H, d,
J 14.5, 9b-H), 4.76 (1 H, br s, 3a-H), 5.00 (1 H, br s, 3b-H), 5.03
(1 H, d, J 17.5, 2a-H), 5.04 (1 H, d, J 10.7, 2b-H) and 5.80 (1 H,
dd, J 10.7 and 17.4, 1-H); dC(125 MHz; CDCl3; Me4Si) 20.1 (CH3,
C-12)a, 21.0 (CH3, C-13)a, 23.0 (CH3, C-14), 26.0 (CH3, C-15),
32.2 (CH2, C-6), 43.9 (C, C-10), 49.4 (CH, C-5), 50.9 (CH2, C-9),
65.9 (C, C-11), 68.3 (C, C-7), 113.3 (CH2, C-3), 113.4 (CH2, C-2),
145.9 (C, C-4), 146.5 (CH, C-1) and 206.7 (C, C-8) (aSignals with
the same letter are exchangeable); m/z (HRMS(FAB)) 257.1519
(M + Na C15H22O2Na requires 257.1517).
Preparation of 8a-hydroxyelemol (3). Method A
A solution of 14 (440 mg, 1.86 mmol) in a (1 : 1) mixture of
diethylether : absolute ethanol (40 cm3) and lithium (17 mg) were
successively added to a cold (-35 ◦C) stirred liquid ammonia
(120 cm3) under argon. After 10 min, the mixture was kept at room
temperature and the excess of ammonia evaporated. The residue
obtained was extracted with t-butylmethylether, concentrated
in vacuo and the crude product was chromatographed over silica
gel column (hexane : t-butylmethylether, 50 : 50) to obtain 36a,31
(315 mg, 71%).
8a-Hydroxyelemol (3). White solid, mp 108 ◦C (from hexane–
t-butylmethylether). IR nmax(film)/cm-1 3300, 3082, 2971, 2939,
2873, 1640, 1464, 1443, 1377, 1276, 1169, 1050, 1030, 968, 907
and 893; dH(500 MHz; CDCl3; Me4Si) 0.94 (3 H, s, 14-H), 1.18
(3 H, s, 12-H), 1.23 (3 H, s, 13-H), 1.28 (1 H, q, J 13.2, 6b-H),
1.43–1.48 (3 H, m, 6a-H, 7a-H, 9a-H), 1.63 (1 H, dd, J 4.3, 12.5,
9b-H), 1.64 (3 H, s, 15-H), 1.96 (1 H, dd, J 3.1, 12.8, 5a-H), 3.26
(2 H, br s, 2 OH), 3.92 (1 H, dt, J 4.3, 10.0, 8b-H), 4.52 (1 H, br
s, 3a-H), 4.77 (1 H, br s, 3b-H), 4.85 (1 H, dd, J 1.1, 10.7, 2a-H),
4.86 (1 H, dd, J 1.1, 17.7, 2b-H) and 5.72 (1 H, dd, J 10.7, 17.7,
1-H); dC(125 MHz; CDCl3; Me4Si) 18.0 (CH3, C-14), 24.1 (CH3,
C-12), 24.9 (CH3, C-15), 29.4 (CH2, C-6), 30.2 (CH3, C-13), 41.2
(C, C-10), 48.5 (CH2, C-9), 52.5 (CH, C-7), 54.3 (CH, C-5), 69.4
(CH, C-8), 75.3 (C, C-11), 110.7 (CH2, C-3), 112.7 (CH2, C-2),
146.8 (CH, C-4) and 149.0 (C, C-1).
(5S,7S,10S)-7,11-Epoxyelema-1,3-dien-8-one (13b). Colorless
syrup. IR nmax(film)/cm-1 3087, 2961, 2925, 1719, 1641, 1451, 1376,
1275, 1117, 1059, 923, 912, 889, 820 and 750; dH(500 MHz; CDCl3;
Me4Si) 1.08 (3 H, s, 14-H), 1.22 (3 H, s, 12-H), 1.43 (3 H, s, 13-H),
1.76 (3 H, s, 15-H), 1.79 (1 H, dd, J 3.3 and 14.2, 6a-H), 2.31 (1
H, d, J 13.5, 9a-H), 2.38 (1 H, d, J 13.7, 9b-H), 2.39 (1 H, t, J
14.0, 6b-H), 2.53 (1 H, dd, J 3.3 and 13.8, 5a-H), 4.71 (1 H, br
s, 3a-H), 4.94 (1 H, d, J 17.3, 2a-H), 4.95 (1 H, t, J 1.4, 3b-H),
5.01 (1 H, d, J 10.7, 2b-H), and 5.84 (1 H, dd, J 10.7 and 17.3,
1-H); dC(125 MHz; CDCl3; Me4Si) 17.6 (CH3, C-14), 19.7 (CH3,
C-13), 19.8 (CH3, C-12), 24.7 (CH3, C-15), 32.4 (CH2, C-6), 44.1
(C, C-10), 51.6 (CH, C-5), 55.2 (CH2, C-9), 63.8 (C, C-11), 69.9
(C, C-7), 111.9 (CH2, C-2), 114.3 (CH2, C-3), 145.5 (C, C-4), 146.2
(CH, C-1) and 205.8 (C, C-8); m/z (HRMS(FAB)) 257.1515 (M +
Na C15H22O2Na requires 257.1517).
Method B. This method is similar to method A, but the
starting material was 13 (97 mg, 0.41 mmol). 8a-hydroxyelemol
(3) was obtained with a yield of 75% (74 mg).
Reduction of 13 with Zn/AcOH
Acetylation of 3. Preparation of 8a-acetoxyelemol (4)
Glacial acetic acid (13.25 cm3) and zinc dust (1.3 g, 9 equiv)
were added to a solution of 13 (514 mg, 2.20 mmol) in THF
(13.25 cm3). The mixture was heated at 50 ◦C and vigorously stirred
for 5 h. It was then diluted with t-butylmethylether (100 cm3),
washed with saturated NaHCO3 solution and brine, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo yielding
a crude product, which was chromatographed over a silica gel
column (hexane : t-butylmethylether, 80 : 20) to obtain 14 (483 mg,
94%).
Acetic anhydride (2 cm3) and 4-dimethylaminopyridine (5 mg)
were added to solution of 3 (27 mg, 11.34 mmol) in pyridine
(2 cm3). The mixture was kept at room temperature for 15 h
and then was worked up as usual to give a crude product
which was chromatographed over silica gel column (hexane : t-
butylmethylether, 60 : 40) to obtain 46 (31 mg, 97%).
8a-Acetoxyelemol (4). Colorless syrup. IR nmax(film)/cm-1
3451, 3082, 2971, 2936, 2875, 1731, 1639, 1465, 1443, 1376, 1246,
1165, 1128, 1025, 968, 910 and 895; dH(500 MHz; CDCl3; Me4Si)
1.01 (3 H, s, 14-H), 1.13 (3 H, s, 12-H)a, 1.14 (3 H, s, 13-H)a, 1.41
(1 H, q, J 12.8, 6b-H), 1.64 (3 H, br s, 15-H), 1.64–1.75 (4 H, m,
6a-H, 7a-H, 9a-H), 1.71 (1 H, dd, J 4.0, 12.5, 9b-H), 1.97 (1 H,
dd, J 3.2, 13.1, 5a-H), 1.99 (3 H, s, OCOCH3), 4.54 (1 H, br s,
(5S,7R,10S)-11-Hydroxyelema-1,3-dien-8-one (14). Colorless
syrup. IR nmax(film)/cm-1 3525, 3082, 2968, 2878, 1696, 1640,
1445, 1377, 1278, 1210, 1155, 1060, 1026, 1003, 913 and 897;
dH(500 MHz; CDCl3; Me4Si) 0.96 (3 H, s, 14-H), 1.24 (6 H, s,
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3a-H), 4.79 (1 H, t, J 1.5, 3b-H), 4.84 (1 H, d, J 17.4, 2a-H-), 4.86
(1 H, d, J 10.7, 2b-H), 5.01 (1 H, dt, J 4.2, 11.0, 8b-H) and 5.70 (1
H, dd, J 10.7, 17.4, 1-H); dC(125 MHz; CDCl3; Me4Si) 17.7 (CH3,
C-14), 21.9 (CH3, CH3CO), 24.8 (CH3, C-15), 26.4 (CH3, C-12),
28.7 (CH3, C-13), 29.3 (CH2, C-6), 41.3 (C, C-10), 45.0 (CH2, C-
9), 52.3 (CH, C-5)a, 52.4 (CH, C-7)a, 72.9 (C, C-11)b, 73.0 (CH,
C-8)b, 111.0 (CH2, C-3), 113.0 (CH2, C-2), 146.4 (C, C-4), 148.5
(CH, C-1) and 169.9 (C, CH3CO) (aSignals with the same letter
are exchangeable).
obtained mixture was subjected to HPLC (hexane) to yield 2
(768 mg, 76%).
c-Elemene (2). Colorless syrup, HPLC (hexane, Rt = 8.7 min).
IR nmax(film)/cm-1 3081, 2966, 2917, 2855, 1637, 1450, 1373, 1260,
1096, 1004, 908 and 889; dH(500 MHz; CDCl3; Me4Si) 1.06 (3 H,
s, 14-H), 1.40–1.44 (2 H, m, 9-H), 1.66 (3 H, s, 12-H)a, 1.67 (3 H, s,
13-H)a, 1.72 (3 H, s, 15-H)a, 1.90–1.99 (1 H, m, 8b-H), 1.96 (1 H,
dd, J 3.4 and 12.8, 5a-H), 2.08 (1 H, t, J 13.5, 6b-H), 2.43 (1 H,
dq, J 2.0 and 13.9, 6a-H), 2.50 (1 H, dsextuplet, J 2.0 and 14.2,
8a-H), 4.63 (1 H, br s, 3a-H), 4.83 (1 H, d, J 1.6, 3b-H), 4.89 (1
H, dd, J 1.3 and 10.8, 2a-H), 4.91 (1 H, dd, J 1.2 and 17.6, 2b-H)
and 5.79 (1H, dd, J 10.8 and 17.6, 1-H) (aSignals with the same
letter are exchangeable); dC(125 MHz; CDCl3; Me4Si) 17.1 (CH3,
C-15)a, 20.1 (CH3, C-13)a, 20.2 (CH3, C-12)a, 24.9 (CH3, C-14),
25.6 (CH2, C-8), 31.5 (CH2, C-6), 40.1 (C, C-10), 40.2 (CH2, C-9),
53.2 (CH, C-5), 110.1 (CH2, C-2), 112.0 (CH2, C-3), 121.1 (CH3,
C-7), 131.1 (C, C-11), 148.1 (C, C-4) and 150.1 (CH, C-1) (aSignals
with the same letter are exchangeable).
Cope rearrangement of germacrol (15)
Germacrol (15, 150 mg, 0.67 mmol) and PdCl2(PhCN)2 (52 mg,
0.14 mmol, 0.2 equiv) were dissolved in dry toluene (9 cm3),
under argon. The solution was heated at reflux under stirring
for 105 min. After cooling at room temperature, the mixture
was filtered through silica gel and the layer was washed with
a 3 : 1 mixture of hexane : t-butylmethylether. The solvent was
concentrated in vacuo yielding a crude product which was
chromatographed over 20% AgNO3-silica gel column to obtain
the hydrocarbons 16 (hexane : t-butylmethylether, 90 : 10, 99 mg,
72%) and (5S,10R)-elema-1,3,7(11),8-tetraene (17)28 (hexane : t-
butylmethyl ether, 95 : 5, 26 mg, 19%).
Reduction of 5 with (S)-2-methyl-CBS-oxazaborolidine (IV)
A solution of 5 (80 mg, 0.37 mmol) in anhydrous THF (1.80 cm3)
was added slowly (1–2 h) over an ice-cooled solution of IV (1
M in toluene, 1.10 cm3) and borane:THF complex (1 M in THF,
1.32 cm3), under argon. The mixture was vigorously stirred at
When this reaction is carried out at room temperature for
15 min, a mixture of 12 and 18 in an approximate ratio of 1 : 4.5,
respectively (NMR crude analysis).
0
◦C for 2 h. After water was added and was extracted with t-
butylmethylether. The organic phase was washed with 2 N NaOH
solution, 2 N HCl solution, saturated aqueous NaHCO3 solution
and brine, dried over anhydrous Na2SO4, filtered and concentrated
in vacuo yielding a crude product which was chromatographed over
silica gel column (hexane : t-butylmethylether, 4 : 1) to obtain of 15
(42 mg, 52%) and recovering 24 mg of starting material.
(5S,10R)-Elema-1,3,7(11)-trien-8b-yl
acetate
(18).
dH(400 MHz; CDCl3; Me4Si) 1.18 (3 H, s), 1.58 (1 H, dd, J
3.5 and 14.2), 1.68–1.80 (3 H, m), 1.70 (3 H, s), 1.73 (3 H, s), 1.77
(3 H, s), 1.97 (1 H, t, J 7.1), 2.02 (3 H, s), 2.39 (1 H, d, J 7.8), 4.67
(1 H, br s), 4.86–4.91 (3 H, m), 5.72 (1 H, d, J 10.5 and 17.6) and
5.88 (1 H, t, J 3.2).
(+)-(5S,10S)-Elema-1,3,7,11(12)-tetraene (16). [a]D +4.1 (c 1,
CHCl3).
(5S,10S)-Elema-1,3,7,11(12)-tetraene (16). Colorless syrup.
IR nmax(film)/cm-1 3081, 2967, 2901, 1638, 1608, 1437, 1372, 1000,
884 and 816; dH(400 MHz; CDCl3; Me4Si) 0.98 (3 H, s, 14-H),
1.75 (3 H, s, 15-H), 1.90 (3 H, s, 13-H), 2.20–2.35 (5 H, m, 5-H,
6-H, 9-H), 4.74 (1 H, br s, 3a-H), 4.85 (2 H, br s, 3b-H, 12a-H),
4.90 (1 H, d, J 10.5, 2a-H), 4.92 (1 H, d, J 17.5, 2b-H), 4.95 (1
H, br s, 12b-H), 5.80 (1 H, m, 8-H), 5.85 (1 H, dd, J 10.5 and
17.5, 1-H); dC(100 MHz; CDCl3; Me4Si) 18.5 (CH3, C-15)a, 20.6
(CH3, C-13)a, 24.7 (CH3, C-14), 29.2 (CH2, C-6), 38.2 (C, C-10),
39.6 (CH2, C-9), 49.1 (CH, C-5), 109.9 (CH2, C-3), 110.4 (CH2,
C-2), 112.2 (CH2, C-12), 122.9 (CH, C-8), 135.7 (C, C-7), 143.1
(C, C-11), 147.7 (C, C-4) and 148.1 (CH, C-1) (aSignals with the
same letter are exchangeable).
(+)-c-Elemene (2). [a]D +3.5 (c 1, CHCl3), in literature [a]D
+3.93 (c 1, CHCl3).29
Acknowledgements
This research was supported by the Proyecto de Excelencia P08-
FQM-3596 of the Consejer´ıa de Innovacio´n, Ciencia y Empresa,
Junta de Andaluc´ıa, the Program CYTED (Project IV. 12) and the
Spanish Ministry of Science and Technology (Project BQU 2002-
03211). Thanks go to the Alban Programme (predoctoral grant
to J. C, scholarship N. E04D041998AC), Lcda. Ingrid Loayza,
Universidad Mayor de San Simo´n, Cochabamba, Bolivia for the
gift of the germacrone (1) and Dr Luc´ıa Silva, Universidad de
Covilha, Biera Interior, Portugal for help in the optimization of
the deconjugation reaction.
Reduction of 16 with Na/liq NH3. Preparation of c-elemene (2)
A solution of 16 (1000 mg, 4.95 mmol) in dry THF (80 cm3) was
added to a cold (-78 ◦C) stirred solution of sodium (494 mg,
21.48 mmol) in liquid ammonia (50 cm3). The mixture was stirred
for 25 min, then treated with t-BuOH (10 cm3) and allowed to stir
for an additional 5 min. The excess of ammonia was then removed
at room temperature. The residue was dissolved in hexane (50 cm3)
and the organic layer was washed with water and brine, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo yielding a
crude product, which was chromatographed over 20% AgNO3-
silica gel column (hexane : t-butylmethylether, 80 : 20), and the
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enones with exocyclic double bonds has not been extensively studied,26
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the thus-obtained germacrol with those of the natural compounds.
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