Synthesis and pharmacological activities of some sesquiterpene quinones and hydroquinones

Article abstract of DOI:10.1016/j.bmc.2009.01.028

Synthesis of protected siphonodictyal C was achieved via drim-7-en-11-al. Some sesquiterpene quinones and hydroquinones were tested for their pharmacological activities in assays in search of antiproliferative, cytotoxic, antiphlogistic, antirheumatic and anti-inflammatory drugs. Wiedendiol B is a ten times stronger cyclooxygenase-2 inhibitor than the reference compound indomethacine. Cyclooxygenase-2 inhibitors are drugs with antiphlogistic and antirheumatic activity.

Full text of DOI:10.1016/j.bmc.2009.01.028

Bioorganic & Medicinal Chemistry 17 (2009) 1422–1427
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and pharmacological activities of some sesquiterpene quinones
and hydroquinones
a
a
b
b
a,*
Thorsten Laube , Andreas Bernet , Hans-Martin Dahse , Ilse D. Jacobsen , Karlheinz Seifert
a
Lehrstuhl für Organische Chemie, NW II, Universität Bayreuth, D-95440 Bayreuth, Germany
Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e.V., Hans-Knöll-Institut, Beutenbergstr. 11 a, D-07745 Jena, Germany
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of protected siphonodictyal C was achieved via drim-7-en-11-al. Some sesquiterpene quinones
and hydroquinones were tested for their pharmacological activities in assays in search of antiprolifera-
tive, cytotoxic, antiphlogistic, antirheumatic and anti-inflammatory drugs. Wiedendiol B is a ten times
stronger cyclooxygenase-2 inhibitor than the reference compound indomethacine. Cyclooxygenase-2
inhibitors are drugs with antiphlogistic and antirheumatic activity.
Received 19 October 2008
Revised 13 January 2009
Accepted 14 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Siphonodictyals
Terpenes
Phenols
Quinones
6
1
. Introduction
earlier. Compounds 17, 18 have been isolated from the East Pacific
brown algae Dictyopteris undulata Okamura and 19, 20 from the
7
Siphonodictyal
C
and further siphonodictyals have been
same species collected in the Gulf of California.
1
obtained from the burrowing sponge Siphonodictyon coralliphagum.
The mucus exudation in the oscular chimney of S. coralliphagum
contains these sesquiterpene hydroquinones which are toxic for
coral polyps. Thus, the overgrowth of the oscular chimneys by coral
polyps is prevented. Additionally, siphonodictyal C inhibits the
growth of Staphylococcus aureus and Bacillus subtilis.
CHO
NaO3SO
OH
OH
Siphonodictyal C has also been isolated from Siphonodictyon sp.
and its structure differs from the one reported by an additional
2
NaO
3
S-group (Fig. 1). This paper describes the synthesis of pro-
tected siphonodictyal C (±)-8. Compound (±)-8, the quinone (±)-5
and 12 structurally similar sesquiterpene quinones and hydroqui-
nones were tested for their antiproliferative, cytotoxic, antiphlogis-
tic, antirheumatic and anti-inflammatory activities.
H
Figure 1. Siphonodytyal C.
Recently, we published the synthesis of spongiaquinone methyl
3
ether ((ꢀ)-10), spongiaquinone (11), hyatellaquinone (12) , wie-
dendiol B ((±)-13) and the sesquiterpene hydroquinone with a
rearranged drimane skeleton (±)-14.4 The sesquiterpene o-benzo-
OMEM
OH
OH
O
Br
Br
quinone (±)-15 and p-benzoquinone (±)-16 with a rearranged dri-
b)
5%
mane skeleton have been synthesized before.5
a)
Our synthesis of zonarol (17), zonarone (18), isozonarol (19),
isozonarone (20) and the building block drim-7-en-11-al (±)-3
for the preparation of the protected siphonodictyal C was reported
7
O
O
9
8%
O
O
O
2
1
*
Corresponding author. Tel.: +49 0921 553396; fax: +49 0921 555358.
E-mail address: karlheinz.seifert@uni-bayreuth.de (K. Seifert).
Scheme 1. Synthesis of 5-bromosesamol MEM-ether (2): (a) Br
(b) NaH, MEMCl, THF, 0 °C, 15 min, room temperature, 45 min.
2
, THF, 0 °C, 5 min;
0
968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.01.028

T. Laube et al. / Bioorg. Med. Chem. 17 (2009) 1422–1427
1423
MEMO
O
O
O
O
HO
CHO
O
a)
b)
c)
1%
6
9%
9
H
H
H
(±)-3
(±)-4a,b
(±)-5
CHO
3
'
HO
O
MeO
MeO
O
O
O
1
1
O
1
'
O
1
1
2
e)
d)
6%
3
1
7
9
78%
H
H
H
±)-8
4
(
±)-6
(
(±)-7
CHO
HO
OH
OH
H
Scheme 2. Synthesis of protected siphonodityal C (±)-8: (a) 5-lithiumsesamol MEM-ether, THF, ꢀ100 °C, 5 min, ꢀ100 °C–room temperature, 2 h; (b) PTS, THF/H
2
O 10:1,
4
0 °C, 30 min; (c) NaBH
4
, EtOH, room temperature, 30 min; (d) n-Bu
4
NOH, DMS, THF, room temperature; 30 min; (e) TMEDA, n-BuLi, THF, 0 °C, 30 min, DMF, room
temperature, 16 h.
2
2
. Results and discussion
tendency to the rearrangement is probably responsible for the
deprotection of the MEM-group of (±)-4a,b under these reaction
conditions (PTS, THF/H O 10:1, 40 °C, 30 min). The sesamol
2
.1. Synthesis of protected siphonodictyal C
MEM-ether being also present in the reaction mixture could not
The arene part of the diastereomeric benzylic alcohol mixture
±)-4a,b was prepared starting with sesamol which was brominated
with Br in THF to 5-bromosesamol (1). Protection of the hydroxy
be deprotected under these conditions.
(
The reduction of (±)-5 with NaBH
4
in EtOH yielded the phenol
NOH
(±)-6. The free OH-group in (±)-6 was deprotonated with n-Bu
4
2
function of 1 with the MEM-group (MEM = methoxyethoxymethyl)
yielded 5-bromosesamol MEM-ether (2) (Scheme 1) which was
transferred to 5-lithiumsesamol MEM-ether with n-BuLi at ꢀ100 °C.
Drim-7-en-11-al ((±)-3) was coupled with 5-lithiumsesamol
MEM-ether to the benzylic alcohols (±)-4a,b (Scheme 2). Treat-
and the phenolate was methylated with dimethylsulfate (DMS) to
(±)-7. Compound (±)-7 was deprotonated with n-BuLi in o-position
to the methoxy-group and formylated with DMF to (±)-8. The depro-
tection of (±)-8 with different reagents always led to decomposition.
ment of (±)-4a,b with p-toluene sulfonic acid (PTS) in THF/H
2
O
2.2. Pharmacological activities
led to the deprotection of the MEM-group and benzylic dehydra-
tion. Primarily the MEM-group was acid catalyzed removed. The
formed phenol was rearranged in a six membered cyclic transition
state to the alkylidenecyclohexadienone (±)-5 (Scheme 3). This
2.2.1. Antiproliferative and cytotoxic activities
Among the sesquiterpene quinones and hydroquinones alkylid-
enecyclohexadienone (±)-5 shows the highest antiproliferative and
MEMO
HO
O
O
O
O
H
O
O
O
O
HO
H+
-H2O
H
H
H
4a,b
(±)-5
Scheme 3. Possible mechanism of the benzylic dehydration.

1
424
T. Laube et al. / Bioorg. Med. Chem. 17 (2009) 1422–1427
Table 1
Antiproliferative effect (GI50) and cytotoxicity (CC50) of doxorubicin, 5 and 8–16
Compound
L-929
K-562
HeLa
CC50b
(lM/l)
a
a
GI50
(
l
M/l)
GI50
(
lM/l)
Doxorubicin
1.2 ± 0.6
6.2 ± 0.5
1.0 ± 0.6
3.5 ± 0.4
21.1 ± 2.1
6.2 ± 0.6
20.7 ± 1.9
13.4 ± 1.1
8.4 ± 0.7
35.8 ± 3.1
25.6 ± 2.1
26.6 ± 2.2
6.1 ± 0.5
2.0 ± 0.8
7.4 ± 0.6
Sesquit. cyclohexadienone (±)-5
Sesquit. benzaldehyde (±)-8
Sesquit. cyclohexadienone (±)-9
Spongiaquinone methyl ether ((ꢀ)-10)
Spongiaquinone ((±)-11)
Hyatellaquinone ((±)-12)
Wiedendiol B ((±)-13)
Sesquit. hydroquinone (±)-14
Sesquit. o-benzoquinone (±)-15
Sesquit. p-benzoquinone (±)-16
24.0 ± 2.3
12.9 ± 1.1
41.6 ± 4.1
27.1 ± 2.6
20.9 ± 1.9
63.1 ± 5.9
59.9 ± 5.3
73.4 ± 6.9
14.0 ± 1.2
41.4 ± 4.0
20.6 ± 1.9
75.3 ± 6.9
75.1 ± 7.1
72.1 ± 6.9
38.1 ± 3.1
41.3 ± 3.8
61.3 ± 5.9
62.3 ± 5.8
The GI50 and CC50 were determined from the mean dose-response curves (4 parallels per concentration).
a
5
0% Growth inhibition.
b
Cytotoxic concentration for 50% of the cells exposed.
cytotoxic activity against the cell lines L-929 (murine fibroblasts),
K-562 (human leukaemia) and HeLa (human cervix carcinoma)
ilar and the activities are in the range from good (K-562) to mod-
erate (L-929, HeLa) (Table 1).
(Table 1). The antiproliferative and cytotoxic activity of (±)-5
against L-929, K-562 and HeLa cells is 5.2, 3.5 and 3.7 times lower
in comparison with doxorubicin which is used in cancer therapy
for the treatment of leukaemia, lymphoma, sarcoma and carci-
noma. The antiproliferative and cytotoxic activity was determined
2
.2.2. Anti-inflammatory, antiphlogistic and antirheumatic
activities
Inflammation is a complex process in living organisms, thereby
limiting the availability of cell-free in vitro assays to predict anti-
inflammatory and antiphlogistic activities of natural compounds.
However, interference of natural compounds with some critical
steps in the inflammatory process, such as the activity of key en-
zymes, can be tested in vitro.
8
as described before .
The alkylidenecyclohexedienone (±)-9 (Fig. 2) differs in its
structure from (±)-5 in the position of the double bond in the ses-
quiterpene part ((±)-9, 8,12-double bond, (±)-5, 7,8-double bond)
only but its antiproliferative activity (L-929, K-562) is half time
and the cytotoxicity (HeLa) three times lower in comparison with
3a-Hydroxysteroid dehydrogenase (3a-HSD), one of the key en-
zymes in the inflammatory cascade, is inhibited by the major types
(
±)-5. A similar antiproliferative effect as (±)-9 possesses the ses-
15
of nonsteroidal and steroidal agents. Therefore, inhibition of 3
HSD can be used in an assay in search for anti-inflammatory drugs.
-HSD catalyzes the reduction of 5b-dihydrocortisone under
consumption of NADPH. The NADPH consumption can be deter-
mined photometrically by measuring the decrease of UV/vis
extinction at 340 nm. Indomethacine and ibuprofene are used as
reference compounds.
a-
quiterpene p-benzoquinone (±)-16 with a rearranged drimane
skeleton.
3a
Spongiquinone (11) has been obtained from the sponges Spon-
9
10
gia sp. and Stelospongia conulata. Hyatellaquinone (12) has been
isolated from the alga Peyssonnelia sp. and the marine sponges
Hyatella intestinalis and Spongia sp.9 Spongiaquinone ((±)-11)
11
shows a higher cytostatic/cytotoxic activity against the cell lines
The sesquiterpene quinones (±)-5 and (±)-15 show very good
HMO2 (gastric adenocarcinoma) GI50 3.1
tocellular carcinoma) GI50 3.6 g/ml than hyatellaquinone ((±)-12)
HMO2 GI50 5.3 g/ml, HepG2 GI50 6.0 g/ml. The cytostatic/cyto-
toxic activity against MCF7 (breast carcinoma) of (±)-12 GI50
lg/ml and HepG2 (hepa-
inhibition of 3
pene benzaldehyde (±)-8, spongiaquinone ((±)-11), hyatellaqui-
none ((±)-12), wiedendiol ((±)-13), zonarol ((+)-17)) and
isozonarone ((+)-20)) show good inhibition, compound (±)-14 with
the same hydroquinone part as wiedendiol B ((±)-13) exhibits only
moderate activity (Table 2). The shift of the double bond from the
a-HSD comparable to indomethacine. The sesquiter-
l
l
l
B
2
2
.4
lg/ml is slightly higher than of (±)-11 GI50 2.6
l
g/ml.1
The antiproliferative (L-929, K-562) and cytotoxic (HeLa) activity
of (±)-12 is higher than of (±)-11 (Table 1). Here we found the same
effect as for the alkylidenenecyclohexadienones (±)-5 and (±)-9. The
position of the double bond in the sesquiterpene part of hyatellaqui-
none (8,12) and spongiaquinone (9,11) influences the activity. The
methylation of spongiaquinone (11) to spongiaquinone methyl
ether ((ꢀ)-10) reduces the antiproliferative effect (L-929, K-562)
whereas the cytotoxicity (HeLa) is the same (Table 1).
7
,8-position in the sesquiterpene part of (±)-5 to the 8,11-position
in (±)-9 reduced the high activity observed in (±)-5 (Table 2).
Another key enzyme in inflammation is cyclooxigenase-2
(
COX2), which mediates the first step in prostaglandine synthesis.
COX2 inhibitors are drugs with antiphlogistic and antirheumatic
activities. Wiedendiol B ((±)-13) and (±)-15 were tested for their
COX2 inhibition. The sesquiterpene o-benzoquinone (±)-15 does
not interact with COX2 whereas wiedendiol B ((±)-13) exhibits a
selective COX2 inhibition with an IC50 value between 0.7 and
16
Wiedendiol B (13) has been isolated from the marine sponge
13
Xestospongia wiedemayeri and inhibits the cholesteryl ester trans-
1
4
fer protein (CETP). This is a plasma neutral glycoprotein which
mediates the net transfer of cholesteryl ester from high density
lipoprotein (HDL) into the low density lipoprotein (LDL). Since
low levels of HDL and high levels of LDL are directly correlated
with increased coronary artery diseases, CETP may play a role in
the pathogenesis of atherosclerosis. The inhibition of CETP by com-
pounds as wiedendiol B (13) may be used for reduction of the risks
of coronary artery disease.
7 lM. COX2 inhibition by wiedendiol B ((±)-13) is ten times stron-
ger than the reference compound indomethacine (data not shown).
Phagocytic cells such as granulocytes, monocytes and macro-
phages form the first line of defense against microbes. Upon attrac-
tion and activation by various inflammatory stimuli such as
chemokines and binding of antigens to specialized receptors, gran-
ulocytes employ a number of mechanisms to attack and destroy
microbes. One of these defense mechanisms is the production of
Wiedendiol B ((±)-13) and the sesquiterpene hydroquinone (±)-
17
reactive oxygen species (ROS). ROS are generated by NADPH oxi-
1
4 differ strongly in their sesquiterpene part but their GI50 and
dase in a process termed ‘respiratory burst’. The NADPH oxidase of
CC50 values for the three cell lines L-929, K-562 and HeLa are sim-
ꢀ
phagocytes catalyzes the conversion of O
2
to O2 which is further

T. Laube et al. / Bioorg. Med. Chem. 17 (2009) 1422–1427
1425
MeO
MeO
MeO
O
O
O
O
O
O
O
O
O
OMe
OH
OH
H
H
H
H
sesquiterpene cyclo-
hexadienone (9)
spongiaquinone methyl
ether (10)
spongiaquinone (11)
hyatellaquinone (12)
MeO
MeO
MeO
OH
MeO
OH
O
O
MeO
O
OH
OH
OH
O
H
wiedendiol B (13)
sesquiterpene hydro-
quinone (14)
sesquiterpene o-benzo-
quinone (15)
sesquiterpene p-benzo
quinone (16)
HO
OH
O
O
HO
OH
O
O
H
H
H
H
zonarol (17)
zonarone (18)
isozonarol (19)
isozonarone (20)
Figure 2. Pharmacologically tested sesquiterpene hydroquinones and sesquiterpene quinones.
converted into H
2
O
2
. Excessive ROS production and release into the
drugs. In our experiments, we stimulated ROS production of gran-
ulocytes by serum-opsonized zymosan (SOZ). The influence of our
compounds on ROS production was determined by measuring ROS
extracellular compartment may be of importance in a number of
inflammatory diseases, including arthritis, atherosclerotic lesions,
and ischaemic tissue injury.1
8,19
The degree of ROS release after
by luminol-dependent chemiluminescence.
20
activation of phagocytes can be modulated by compounds or
Zonarol ((+)-17)), zonarone ((+)-18)), isozonarol ((+)-19))
show a very good, isozonarone ((+)-20)) a good and the quinones
(
±)-9, (±)-11, (±)-12 and (±)-16 a moderate inhibition of ROS re-
Table 2
3
a-Hydroxysteroid dehydrogenase (3
a
-HSD) activitya
lease of ganulocytes (Table 3). The additional methoxy and hy-
droxy group in the quinone part of hyatellaquinone ((±)-12) in
comparison with zonarone ((+)-18) strongly reduces the activity
Compound
Category
Sesquit. cyclohexadienone (±)-5
Sesquit. benzaldehyde (±)-8
Sesquit. cyclohexadienone (±)-9
Spongiaquinone methyl ether ((ꢀ)-10)
Spongiaquinone ((±)-11)
Hyatellaquinone ((±)-12)
Wiedendiol B ((±)-13)
Sesquit. hydroquinone (±)-14
Sesquit. o-benzoquinone (±)-15
Sesquit. p-benzoquinone (±)-16
Zonarol ((+)-17))
3
2
1
1
2
2
2
1
3
1
2
2
(Table 3).
3
3
. Experimental
.1. General
MPLC: Labomatic Laboprep-MPLC unit MD-50/80/100. Flash chro-
matography (FC): silica gel Si 60 (40-63 l; Merck). TLC: Merck pre-
coated plates silica gel 60 F254, detection by 5% molybdophosphoric
Isozonarone ((+)-20)
acid in EtOH (Aldrich Chemicals Ltd.). NMR: Bruker AC-300; d in
(
3) High activity, comparable to indomethacine; (2) good activity; (1) moderate
activity.
3
ppm, J in Hertz; CDCl as solvent and internal standard. MS: Finn-
a
In vitro assay for the search of nonsteroidal inhibitors of the 3a-HSD.
igan MAT 8500, 70 eV; in m/z (rel.%).

1
426
T. Laube et al. / Bioorg. Med. Chem. 17 (2009) 1422–1427
Table 3
crude product was purified by flash chromatography on silica gel
Modulation of ROS productiona
(
R
hexane/EtOAc 6:1) to yield 2 (1.15 g, 75%) as light brownish oil.
+Å
Compound
Category
f
: 0.68 (hexane/EtOAc 4:1). MS m/z (%): 306 (8, M ), 304 (8,
+Å
M ), 218 (13), 216 (13), 150 (13), 89 (86), 59 (100). HRMS: calcd
Sesquit. cyclohexadienone (±)-9
Spongiaquinone ((±)-11)
Hyatellaquinone ((±)-12)
Sesquit. p-benzoquinone (±)-16
Zonarol ((+)-17))
Zonarone ((+)-18))
Isozonarol ((+)-19)
Isozonarone ((+)-20)
1
1
1
1
3
3
3
2
1
for C11
6.91 (s, 1H, H-6), 6.78 (s, 1H, H-3), 5.88 (s, 2H, Ar–O–CH
.16 (s, 2H, O–CH –O), 3.87 (m, 2H, O–CH –CH ), 3.55 (m, 2H,
CH –CH –O), 3.33 (s, 3H, CH O).
13
H O
5
Br 303.9946. Found 303.9946. H NMR (CDCl
3
): d
2
–O–Ar),
5
2
2
2
2
2
3
0
0
0
3.2.3. 6-(11 -Hydroxy-7 -drimen-11 -yl)-3,4-
methylendioxyphenol MEM-ether ((±)-4a,b)
(
3) High activity; (2) good activity; (1) moderate activity.
a
To
4.0 mmol) in 40 ml of THF was added at ꢀ100 °C n-BuLi (3 ml,
.8 mmol, 1.6 M in cyclohexane). After 5 min a solution of drim-
a solution of 5-bromosesamol MEM-ether (2, 1.22 g,
In vitro chemiluminiscence assay detecting inhibition of ROS production in
SOZ-stimulated granulocytes.
4
3
.2. Preparation, physical and spectroscopic data of the
7-en-11-al ((±)-3, 386 mg, 1.75 mmol) in 5 ml of THF was added
and the reaction mixture was warmed up to room temperature
during 2 h. For workup saturated NH Cl-solution was added and
4
compounds
3
.2.1. 5-Bromosesamol (1)
A solution of sesamol (1.38 g, 10.0 mmol) in 60 ml of THF was
the reaction mixture was extracted 3 times with t-butyl methyl
ether. The combined organic phases were filtered through silica
gel/Na SO and the solvent was removed under vacuum. Flash
2 4
chromatography on silica gel (hexane/EtOAc 9:1) gave the diaste-
reomeric mixture of benzyl alcohols (±)-4a,b which was not fur-
ther purified and characterized.
cooled to 0 °C and Br
for 5 min at 0 °C saturated Na
tion mixture was extracted three times with t-butyl methyl ether.
The combined organic layers were washed with saturated NaCl-
2
(0.51 ml, 10 mmol) was added. After stirring
CO -solution was added and the reac-
2
3
solution and filtered through silica gel/Na
2
SO
: 0.57 (hexane/EtOAc
:1). MS m/z (%): 218 (12, M ), 216 (12, M ), 91 (100). HRMS: calcd
4
. Removing the sol-
0
0
vent yielded 1 (2.13 g, 98%) as brownish oil. R
f
3.2.4. 6-(7 -Drimen-11 -yliden)-3,4-methylendioxy-2,4-
cyclohexadienone ((±)-5)
+
?
+?
4
for C
1
7
H
O
5 3
Br 215.9422. Found 215.9422. H NMR (CDCl
3
): d 6.90 (s,
To the mixture of diastereomeric benzyl alcohols (±)-4a,b in
50 ml of THF/H
100 mg). After heating at 40 °C for 30 min saturated Na
1
H, H-6), 6.74 (s, 1H, H-3), 5.89 (s, 2H, O–CH
2
–O).
2
O
10:1 was added p-toluene sulfonic acid
CO -solu-
(
2
3
3
.2.2. 5-Bromosesamol MEM-ether (2)
tion was added. The reaction mixture was extracted three times
with t-butyl methyl ether, the combined organic phases were fil-
To a solution of 1 (1.53 g, 5.0 mmol) in 60 ml of THF was added
at 0 °C NaH (370 mg, 10 mmol, 65% in mineral oil). After stirring for
0 min MEM-chloride (1.2 ml, 10.2 mmol) was added. The reaction
mixture was left for 15 min at 0 °C and for 45 min at room temper-
ature. Saturated NH Cl-solution was added and three times ex-
tered through silica gel/Na
vacuum. Further purification was carried out by MPLC (LiChro-
spher RP-8, 15 m; MeCN/H O 85:15) to yield (±)-5 (411 mg, 69%
over 2 steps) as yellow crystals. R : 0.68 (hexane/EtOAc 4:1). Mp
2 4
SO and the solvent evaporated under
1
l
2
4
f
ꢀ
1
tracted with t-butyl methyl ether. The combined organic phases
were washed with saturated NaCl-solution, filtered through silica
gel/Na
2
150–152 °C (MeCN/H O). IR (cm ): 2928, 1648, 1612, 1430,
+
Å
1358, 890. MS m/z (%): 340 (40, M ), 325 (16), 217 (100), 201
2
SO
4
and the solvent was evaporated under vacuum. The
(43), 189 (47), 151 (24), 115 (8), 105 (8), 91 (7), 55 (20), 41 (28).
Table 4
1
H and 13C NMR data of compounds (±)-5–(±)-8 in CDCl
3
, coupling constants J in Hertz
Pos.
(±)-5
(±)-6
(±)-7
(±)-8
dc
d
H
d
C
d
H
d
C
d
H
d
C
d
H
1
2
3
4
5
6
7
8
9
40.9
18.6
42.3
33.2
49.8
23.7
123.0
131.7
54.4
38.4
149.5
22.5
33.3
21.8
1.19 1.36
1.32 1.38
1.03 1.20
—
39.6
18.9
42.2
33.0
50.3
23.7
122.4
135.1
54.4
36.9
26.1
22.2
33.3
22.0
13.7
121.6
147.2
98.1
145.4
141.4
109.0
100.8
1.07 1.88
1.42 1.54
1.16 1.40
39.6
19.0
42.3
33.1
50.3
23.8
122.0
135.9
54.6
36.9
26.1
22.2
33.3
22.0
13.9
124.6
151.8
94.6
145.4
140.9
109.3
100.8
56.3
1.07 1.88
1.44 1.53
1.18 1.40
39.7
18.9
42.2
33.0
50.2
23.7
123.1
134.9
54.9
36.8
25.5
22.2
33.2
21.9
14.0
129.8
153.3
114.3
146.1
144.8
114.2
102.8
63.6
1.07 1.89
1.48 1.58
1.18 1.43
1.25
1.28
1.88 1.93
5.36 br s
1.25
1.88 1.93
5.38 br s
1.24
1.87 1.92
5.36 br s
1.85 2.06
5.55 br s
—
2.92 d (12.9)
—
7.07 d (12.9)
1.42 s
0.84 s
0.86 s
0.94 s
—
2.25
2.25
2.21
1
1
1
1
1
1
1
2
3
4
5
6
0
1
2
3
4
2.51 d (6.1)
1.47 s
0.86 s
0.89 s
0.86 s
2.48 dd (15.3, 2.5) 2.64 dd (15.3, 9.2)
2.53 dd (15.3, 2.5) 2.63 dd (15.3, 9.2)
1.43 s
0.86 s
0.89 s
0.86 s
1.41 s
0.85 s
0.87 s
0.88 s
5
15.0
0
133.5
184.2
101.7
162.0
145.2
98.0
0
0
0
0
0
—
5.87 s
—
6.32 s
6.47 s
—
6.36 s
5.84 br s
6.68 s
5.85 br s
6.73 s
5.86 br s
3.74 s
6.95 s
6.06 s
3.77 s
10.24 s
OCH
OMe
CHO
2
O
101.7
188.5
Trivial numbering, see Scheme 2.

T. Laube et al. / Bioorg. Med. Chem. 17 (2009) 1422–1427
1427
HRMS: calcd for C22
NMR: Table 4.
H
28
O
3
340.2038. Found 340.2040. 1H and 13
C
lenediamine (TMEDA, 0.15 ml, 0.95 mmol) and n-BuLi (0.6 ml,
0.95 mmol) the reaction mixture was stirred for 30 min at 0 °C.
DMF (0.5 ml, 6.31 mmol) was dropped to the reaction mixture and
the stirring was continued for 16 h at room temperature. For workup
0
0
3
.2.5. 6-(7 -Drimen-11 -yl)-3,4-methylendioxyphenol ((±)-6)
To a solution of (±)-5 (240 mg, 0.70 mmol) in 25 ml of EtOH
NaBH (60 mg, 1.59 mmol) was added and the suspension was stir-
red for 30 min at room temperature. After addition of 2 N HCl
10 ml) the reaction mixture was three times extracted with t-bu-
tyl methyl ether. The combined organic phases were filtered
through silica gel/Na SO and the solvent was removed under vac-
saturated NH
three times with t-butyl methyl ether. The combined organic phases
were filtered through silica gel/Na SO and the solvent was removed
under vacuum. After flash chromatography on silica gel (hexane/
EtOAc 12:1) (±)-8 (189 mg, 78%) was obtained as colourless oil. R
4
Cl-solution was added and the mixture extracted
4
2
4
(
f
:
ꢀ1
2
4
0.66 (hexane/EtOAc 6:1). IR (cm ): 2925, 1620, 1540, 1495, 1450,
+Å
uum. The crude product was purified by flash chromatography on
1150, 1120, 1075, 920. MS m/z (%): 384 (11, M ), 193 (100), 121
(7), 109 (20), 69 (9), 41 (10). HRMS: calcd for C24 384.2301.
silica gel (hexane/EtOAc 7:1) to give (±)-6 (218 mg, 91%) as colour-
32 4
H O
ꢀ
1
1
13
less oil. R
f
: 0.39 (hexane/EtOAc 4:1). IR (cm ): 3390, 2925, 1611,
Found 384.2301. H and C NMR: Table 4.
+Å
1
1
6
500, 1448, 1180, 1110, 1075, 910, 730. MS m/z (%): 342 (9, M ),
89 (8), 151 (100), 109 (34), 107 (16), 105 (15), 95 (19), 91 (19),
9 (22), 55 (24), 41 (30). HRMS: calcd for C22 342.2195.
References and notes
30 3
H O
1
13
Found 342.2195. H and C NMR: Table 4.
1.
Sullivan, B. W.; Faulkner, D. J.; Matsumoto, G. K.; Cun-heng, H.; Clardy, J. J. Org.
Chem. 1986, 51, 4568.
0
0
3
.2.6. 6-(7 -Drimen-11 -yl)-3,4-methylendioxyanisol ((±)-7)
2. Mukku, V. J. R. V.; Edrada, R. A.; Schmitz, F. J.; Shanks, M. C.; Chaudhuri, B.;
Fabbro, D. J. Nat. Prod. 2003, 66, 686.
Compound (±)-6 (625 mg, 1.82 mmol) was dissolved in 20 ml of
3
4
.
.
Bernet, A.; Schröder, J.; Seifert, K. Helv. Chim. Acta 2003, 86, 2009.
Bernet, A.; Seifert, K. Helv. Chim. Acta 2006, 89, 784.
methanolic n-Bu
4
NOH-solution and the solvent was removed under
O) SO (1.2 ml,
3.2 mmol) was dropped and the reaction mixture was stirred for
0 min at room temperature. For workup NH -solution (10 ml,
5%) was added and the stirring continued for 15 min. Three times
vacuum. To the residue in 12 ml of THF (CH
3
2
2
5. A. Bernet, Dissertation, University of Bayreuth, 2006.
6
7
.
.
Laube, T.; Schröder, J.; Stehle, R.; Seifert, K. Tetrahedron 2002, 58, 4299.
Fenical, W.; Sims, J. J.; Squatrito, D.; Wing, R. M.; Radlick, P. J. Org. Chem. 1973,
1
3
2
3
3
8, 2383.
8. Dahse, H.-M.; Schlegel, B.; Gräfe, U. Pharmazie 2001, 56, 489.
Capon, R. J.; Groves, D. R.; Urban, S.; Watson, R. G. Aust. J. Chem. 1993, 46, 1245.
9.
extraction with t-butyl methyl ether gave the organic phases which
were combined, filtered through silica gel/Na SO and evaporated in
vacuum. Purification with flash chromatography on silica gel (hex-
ane/EtOAc 12:1) yielded (±)-7 (623 mg, 96%) as colourless oil. R
10. Kazlauskas, R.; Murphy, P. T.; Warren, R. G.; Wells, R. J.; Blount, J. F. Aust. J.
2
4
Chem. 1978, 31, 2685.
11. Talpir, R.; Rudi, A.; Kashman, Y.; Loya, Y.; Hizi, A. Tetrahedron 1994, 50, 4179.
2. Laube, T.; Beil, W.; Seifert, K. Tetrahedron 2005, 61, 1141.
1
f
:
ꢀ1
13. Coval, S. J.; Conover, M. A.; Mierzwa, R.; King, A.; Puar, M. S.; Phife, D. W.; Pai, J.-
K.; Burrier, R. E.; Ahn, H.-S.; Boykow, G. C.; Patel, M.; Pomponi, S. A. Bioorg. Med.
Chem. Lett. 1995, 5, 605.
0
1
.74 (hexane/EtOAc 4:1). IR (cm ): 2920, 1615, 1490, 1455, 1165,
125, 1070, 925. MS m/z (%): 356 (3, M ), 232 (2), 217 (3), 201 (2),
+
?
1
65 (100), 135 (21), 91 (24), 77 (42), 55 (36), 41 (63). HRMS: calcd
14. Chackalamannil, S.; Xia, Y.; Wang, Y.; Tsai, H.; Czarniecki, M.; Wang, S.;
Clemmons, A.; Ahn, H.-S.; Boykow, G. C. Bioorg. Med. Chem. Lett. 1995, 5, 2005.
1
13
for C23
H
32
O
3
356.2351. Found 356.2353. H and C NMR: Table 4.
1
1
5. Penning, T. M. J. Pharm. Sci. 1985, 74, 651.
6. Mutschler, E. Lehrbuch der Pharmakologie und Toxikologie; Wissenschaftliche
Verlagsgesellschaft: Stuttgart, 1991; pp 176–183.
0
0
3
.2.7. 5-(7 -Drimen-11 -yl)-2,3-methylendioxy-6-
1
1
1
7. Hurst, N. P. Ann. Rheum. Dis. 1987, 46, 265.
8. Babior, B. M. J. Clin. Invest. 1984, 73, 599.
9. Morel, F.; Doussiere, J.; Vignais, P. V. Eur. J. Biochem. 1991, 201, 523.
methoxybenzaldehyd ((±)-8)
Compound (±)-7 (225 mg, 0.63 mmol) was dissolved in 30 ml of
0
0
THF and cooled to 0 °C. After addition of N,N,N ,N -tetremethylethy-
20. Yu, P.-W.; Czuprynski, C. J. Veterinary Immunol. Immunopathol. 1996, 50, 29.