Synthesis of the marine furanoditerpene (-)-marginatone

Article abstract of DOI:10.1016/j.tet.2005.01.007

A synthesis of the marine labdane furanoditerpene (-)-marginatone 1 has been accomplished by a short sequence of reactions starting from (+)-coronarin E 5. The key step is the stereocontrolled-intramolecular electrophilic cyclisation of the (+)-dihydrocoronarin E 6, to the tetracyclic marginatane skeleton 7, which is subsequently functionalized by allylic oxidation to give 1. As (+)-coronarin E 5 was previously synthesized from (-)-sclareol 10, the herein reported preparation constitutes the first formal total synthesis of (-)-marginatone 1, by which its absolute configuration has been confirmed.

Full text of DOI:10.1016/j.tet.2005.01.007

Tetrahedron 61 (2005) 2003–2010
Synthesis of the marine furanoditerpene (K)-marginatone
*
Maria Kolympadi, Maria Liapis and Valentine Ragoussis
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis Zographou, 157 71 Athens, Greece
Received 6 September 2004; revised 22 November 2004; accepted 5 January 2005
Available online 22 January 2005
Abstract—A synthesis of the marine labdane furanoditerpene (K)-marginatone 1 has been accomplished by a short sequence of reactions
starting from (C)-coronarin E 5. The key step is the stereocontrolled-intramolecular electrophilic cyclisation of the (C)-dihydrocoronarin E
6
, to the tetracyclic marginatane skeleton 7, which is subsequently functionalized by allylic oxidation to give 1. As (C)-coronarin E 5 was
previously synthesized from (K)-sclareol 10, the herein reported preparation constitutes the first formal total synthesis of (K)-marginatone
, by which its absolute configuration has been confirmed.
q 2005 Elsevier Ltd. All rights reserved.
1
1. Introduction
(K)-Marginatone 1 (Fig. 1) is a furanoditerpene, isolated
from the marine sponge Aplysilla glacialis, collected from
1
the west coast of Canada in 1991. This spongian derivative
contains the tetracyclic marginatane skeleton, which was
first encountered in marginatafuran 2, isolated from speci-
mens of the northwestern Pacific common dorid nudibranch
2
Cadlina luteomarginata and also has been found later in a
sponge, belonging to the genus Aplysilla. From the skin
3
extracts of the same dorid nudibranch, another marginatane
metabolite the 20-acetoxy marginatone 3 was isolated.
3
C. luteomarginata, a rich source of terpenoid metabolites, is
a delicate shell less mollusk, feeding mainly on a variety of
3
–5
marine sponges. It sequesters selected metabolites from
sponges in its diet and stores them in glands on its dorsum
and in the skin, where they are used to thwart predators,
since itself lacks any obvious protection. Thus, the
metabolite content of Cadlina luteomarginata depends on
its source and presents geographic variability relative to its
dietary sources. The origin of furanoditerpenes found in this
nudibranch is the dietary sponges of Aplysilla sp.
Figure 1.
The marginatane skeleton has been synthesized previously
6
7
by Sharma and Nishizawa, during their studies on
biomimetic cyclisations of ambliofuran 4. Nevertheless,
the characterisation of the new products and the associated
spectroscopic data were insufficient. Quite recently, Zoretic
obtained a functionalized tricarbocyclic synthon, using a
radical-initiated cyclisation, on which subsequently created
8
the furan-ring of the marginatane skeleton. In the above
syntheses, the marginatane derivatives were obtained in
racemic form. There is no report on a total or formal total
synthesis of an optically active marginatane derivative,
which would provide the decisive confirmation of the
absolute stereochemistry of this class of natural
furanoditerpenes.
Keywords: Furanoditerpenes; Marine natural products; Synthesis; Margin-
atane; Marginatone.
In this paper, we present the synthesis of enantiomerically
pure (K)-marginatone 1. The key intermediate of our
*
Corresponding author. Tel.: C30 210 7274497; fax: C30 210 7274761;
e-mail: ragousi@chem.uoa.gr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.007

2004
M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
synthetic plan is the furanolabdane terpene, (C)-coronarin
E 5, a versatile precursor for the construction of the
tetracyclic marginatane skeleton (outlined in Scheme 1).
Scheme 2. Reagents and conditions: (a) CrO
(
(
3
$Py, CH
b) triphenylphosphonium-3-furylmethyl chloride, n-BuLi, THF, K78 8C
32%).
2 2
Cl (98%);
Scheme 1. Synthesis of (K)-marginatone 1. Reagents and conditions:
(
a) HCOONH
room temperature (46%); (c) t-BuOOH 70%, aq NaOCl 5%, AcOEt, 0 8C,
33%).
4 3 2 2 2
, Pd/C 10%, MeOH reflux (77%); (b) BF $ Et O, CH Cl ,
(
(C)-Coronarin E 5 has been isolated from various
medicinal plants and its absolute stereochemistry was
9
1
elucidated by its synthesis from (K)-sclareol and recently
0
1
1
from (C)-manool, confirming the normal labdane
absolute stereochemistry 5S, 9S and 10S.
Scheme 3. Reagents and conditions: (a) 3-bromofuran, n-BuLi, Et
12aC12b); (b) HMPA, reflux, (76%).
2
O (79%,
(
Partial reduction of the side chain double bond of (C)-
coronarin E 5 to (C)-dihydrocoronarin E 6 and a subsequent
intramolecular electrophilic cyclisation led to the desired
tetracyclic derivative 7 with the marginatane skeleton, on
which an allylic oxidation gave the target molecule (K)-
marginatone 1. By this route, the absolute stereochemistry
of the natural (K)-marginatone was confirmed as to be the
normal marginatane structure 5S,8R,9S,10S.
1
4
available perillene 14, possessing structural similarity
with the upper part of the dihydrocoronarin E 6 (Scheme 4),
was chosen as a model structure.
It must be noted that (K)-dihydrocoronarin E 6 is a marine
natural product, isolated from the marine sponge of genus
1
Cacospongia, collected from the Philipinnes, whose
2
11
absolute configuration was recently elucidated, while
our work was in progress.
The starting material for our synthesis, (C)-coronarin E 5,
was prepared from synthetic (C)-albicanol 8 by a procedure
that could be applied as well to the synthesis of the opposite
1
3
enantiomer, given that (K)-albicanol is available
Scheme 2). Larger quantities of (C)-coronarin E 5 were
also prepared from natural (K)-sclareol 10, by minor
(
Scheme 4. Reagents and conditions: (a) 3-furylmethylmagnesium chloride,
Li CuCl , THF, 0 8C (72%); (b) BF Et O, CH Cl , room temperature
2 4 3 2 2 2
(60%); (c) aq tert-butylhydroperoxide 70%, aq NaOCl 5%, 0 8C (42%).
1
0
modifications of the reported procedures (Scheme 3).
In order to explore the best conditions for the cyclisation
and especially the allylic to the furan oxidation, for which
no reports have been found in the literature, the easily
The formal total synthesis of (K)-marginatone 1, described
herein constitutes the first synthesis of an optically active
marginatane derivative, by which the absolute

M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
2005
2
D
0
9a
stereochemistry of this class of natural marine products is
confirmed.
([a] ZC25.3 (c 0.45, CHCl ) (lit. [a] ZC22.3 (c 0.44,
3
D
CHCl )).
3
Sequentially to our synthetic plan, selective reduction of the
conjugate to the furan ring double bond of (C)-coronarin E
5 was attempted (Scheme 1). Classical hydrogenation with
H2 and 10% Pd/C or 5% Pd/C as catalyst at room
temperature, proved no regioselective, because all double
bonds of the molecule, including furan ring, were reduced in
few minutes. A recent reinvestigation on the use of
ammonium formate as an active hydrogen donor for the
selective reduction of the double bond of conjugated
2
. Results and discussion
As point of departure for the synthesis of (K)-marginatone
, (C)-coronarin E 5 was used. We decided to undertake the
synthesis of the starting material 5, as depicted in Scheme 2,
from the synthetic enantiomer (C)-albicanol 8, bearing the
1
(
5S,9S,10S) stereochemistry. The total synthesis of both
1
3
22
enantiomers of 8 has been reported by us. Thus, oxidation
of (C)-albicanol 8 was achieved with pyridinium chloro-
chromate (PCC) in methylene chloride at room temperature
and gave almost quantitatively the unstable (K)-albicanal
carbonyl compounds, prompted us to use this procedure.
Thus, ammonium formate in the presence of Pd/C (10%) as
a catalyst, regioselectively reduced the conjugated double
bond of (C)-coronarin E 5 to (C)-dihydrocoronarin E 6,
without affecting the exocyclic methylene and the vulner-
able furan ring. The above reduction at room temperature
requires large quantities of catalyst and long reaction times
(2 days), and subsequently some full hydrogenation of 5
takes place. However, by refluxing a methanolic solution of
5 and the reduction reagents, with control of the progress of
the reaction by TLC, the reaction was completed in a few
hours, giving pure 6 in 77% yield. The spectral data of the
1
5,16
9
,
which was used in the next step without purification.
Wittig reaction of the aldehyde 9 with the triphenylpho-
sphonium-3-furylmethylide gave (C)-coronarin E 5 as a
gum, in 25% yield after purification by column chromato-
graphy. The spectral data and the optical rotation of the
obtained product were in good agreement with those
1
0a,11
2
0
found in the literature. ([a] C24.2 (c 0.245, CHCl ),
3
D
9
lit. [a] C22.3 (c 0.44, CHCl )).
a
D
3
1
2
product are identical to those quoted in the literature for
the natural product, but the optical rotation measured for 6,
Taking into account the multi-step synthesis of (C)-
albicanol 8 and the low yield of the above Wittig reaction,
the synthesis of (C)-coronarin 5 from natural (K)-sclareol
10, through (K)-g-bicyclohomofarnesal 11, was also
undertaken (Scheme 3). Several syntheses of this versatile
2
D
0
[a] ZC42.6 (c 0.155, CHCl ) was of opposite sign to that
3
1
originally reported by Ireland for the dihydrocoronarin
2
2
0
isolated from a marine sponge, [a] ZK22.0 (c 0.14,
D
CHCl ). The present synthesis starting from (K)-sclareol
3
1
7–19
intermediate 11 have been reported.
chain degradation of (K)-sclareol 10, by a slight modifi-
Oxidative side
10, via (K)-g-bicyclohomofarnesal 11 and (C)-coronarin E
5, confirms that our synthetic furanolabdane derivative (C)-
dihydrocoronarin 6 has the normal labdane absolute
stereochemistry (5S,9S,10S), and that the compound
isolated by Ireland possesses the ent-6 structure
(5R,9R,10R). Antipodal stereochemistry has already been
reported by Mungai for 6, isolated from a terrestrial plant,
but the absence of optical rotation value does not allow a
1
7
cation of the procedure reported by Zahra (7 steps, 52%
from sclareol), which is the most suitable for large scale
preparation, gave the ambergris odorant, (K)-g-bicyclo-
homofarnesal 11. The 8a-OH group of sclareol was
protected as an acetate, which was easily removed under
basic conditions. Optical rotation of compound 11 thus
2
D
0
23
obtained [a] ZK24.5 (c 0.35, CHCl ) was in accordance
with the literature value (lit. [a] ZK25.5 (c 1.07,
firm conclusion for the absolute stereochemistry. It must
3
21
1
8
be noted that earlier studies on labdane diterpenes correlate
positive optical rotation for normal labdane series and
negative optical rotation for those with the ent-labdane
D
CHCl )).
3
2
4
The coupling reaction of 11 with fleshy prepared 3-lithio-
furan led to a mixture of two diastereoisomeric alcohols
structure.
2
0
1
0a,11
1
2a and 12b
in a ratio of 1:2.5 (Scheme 3), in 78%
The first trial for the cyclisation of 6 mediated by SnCl in
4
overall yield. The above alcohols were readily separated by
column chromatography over silica gel. Only 12a could be
obtained in crystalline form from hexane. Diastereoisomeric
pure alcohols 12 or their mixture could be used indifferently
to the next step, because dehydration removes the center of
asymmetry.
benzene at room temperature or at reflux, as it is described
for the cyclisation of ambliofuran, failed to give distinct
7
products. Since the above multi-stage synthesis afforded a
very small quantity of 6, we have chosen a structural model
for the study of the cyclisation and the subsequent allylic
oxidation step. The easily available synthetic perillene 14
1
4
(
Scheme 4), demonstrating a similar structure to the upper
It was reported that dehydration of 12a and 12b with 2,6-
lutidine in the presence of a sulfonyl chloride gave (C)-
part of dihydrocoronarin E 6, was the ideal choice. Perillene
14 was conveniently prepared by coupling the prenyl acetate
13 with the 3-furylmethyl magnesium chloride in the
1
0a,11
coronarin E 5 in high yield (70%).
above reported conditions gave (C)-coronarin E 5 in yields
20%. This dehydration proceeded much better by
In our hands, the
2
5
presence of Li CuCl as the catalyst. This reaction
2
4
%
gave significant amounts of unreacted prenyl acetate, but
no g-substitution product was detected.
2
1
refluxing the alcohols 12 in HMPA. Indeed, by this
procedure one major product was obtained, which after
purification by column chromatography on silica gel gave
pure (C)-coronarin E 5 in 76% yield. The obtained 5
exhibited spectral properties and optical rotation similar to
The cyclisation of perillene 14, was studied by three
reagents under various conditions. The results are summar-
ized in Table 1. SnCl in refluxing benzene or at room
4
9
those reported for the product isolated from natural sources
temperature gave a complex hydrocarbon mixture, from

2006
M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
Table 1. Model cyclisation of perillene 14
a
Reagent
Ratio reagent/substrate
Solvent
Temperature (8C)
Yield (%)
SnCl
SnCl
SnCl
4
4
4
2.0
2.0
0.15
0.2
0.3
C
C
CH
CH
CH
6
H
H
6
Reflux
—
—
18
48
60
6
6
K10 8C–room temperature
K40 8C–room temperature
Reflux
2
2
2
Cl
2
2
2
p-TsOH$H
$Et
2
O
Cl
Cl
BF
3
2
O
Room temperature
a
Substrate concentration in all attempts was 0.04 M.
which no interesting compounds have been isolated. Only a
small amount of the tetrahydrobenzofuran derivative 15 was
obtained using SnCl in anhydrous methylene chloride at
4
conditions on the model system, afforded (K)-marginatone
1 in 33% yield. The spectroscopic data of the synthetic
product were identical to those reported for the natural
1
low temperature. Use of p-TsOH$H O in refluxing meth-
2
product, isolated from the marine sponge A. glacialis.
Optical rotation of the synthetic compound was found to be
ylene chloride gave similar results to those reported by
Czeskis for the cyclisation of perillene. The best results
2
6
20
D
[a] ZK26.0 (c 0.365, CHCl ), which is in good
3
were obtained by the use of BF $Et O as catalyst, in
3
anhydrous methylene chloride at room temperature, afford-
ing the tetrahydrobenzofuran 15 in 60% yield.
accordance with the rotation of the natural (K)-marginatone
2
1 20
(lit. [a] ZK16.0 (c 0.4, CHCl )).
D
3
The first approach for the oxidation of derivative 15, was
achieved using common reagents employed for allylic
oxidation, bearing in mind that the furan ring could undergo
oxidation as well. Attempts with chromium (VI) com-
3. Conclusion
In conclusion, the first formal total synthesis of the natural
(K)-marginatone 1, from the naturally occurring (C)-
coronarin E 5, has been described. The essential electro-
philic cyclisation of dihydrocoronarin 6 and the new
oxidation of the methylene in the 3-position of the furan
ring, were initially investigated in the model compound
perillene 14 and in the corresponding tetrahydrobenzofuran
derivative 15, respectively. The reported synthesis of (K)-
marginatone 1 establishes its absolute stereochemistry to be
2
7a
pounds, such as Na CrO
2
in acetic acid or acetic
4
2
7b
anhydride, and CrO –pyridine complex
completely
destroyed the furan ring. Two milder oxidations with
3
2
m-chloroperoxybenzoic acid and air, and with KMnO4
8
2
9
on a solid support of CuSO $5H O led also to products
4
2
without the furan unit. Finally, the desired allylic oxidation
was conveniently achieved, using aqueous tertbutylhydro-
3
0
peroxide and aqueous NaOCl at 0 8C. Under these
conditions the furan ring was not affected and the
benzofuranone 16 was isolated in good yield (42%). No
extensive study was made to improve the yield of the above
oxidation. As far as we know, this is the first example of an
oxidation at the a-alkyl position of a furan derivative.
(5S,8R,9S,10S).
4
. Experimental
Returning to our initial plan and using the protocol that gave
the best results for the cyclisation of perillene, (C)-
dihydrocoronarin E 6 was treated with BF $Et O in
4
.1. General
3
2
All reagents are commercially available and used us
supplied. Solvents for synthesis were distilled and dried
before use. (C)-Albicanol 8 was prepared according to the
literature. (K)-Sclareol 10 was a gift from Vioryl S. A.
Athens, Greece. Melting points were determined on a B u¨ chi
anhydrous CH Cl at room temperature to afford (K)-
2
2
marginata-13,15-diene 7 in 46% yield. It should be noted
that the cyclisation of dihydrocoronarin E 6 is regio-
controlled, giving the 2,3-substituted furan and no trace of
1
3
3
,4-substituted furan derivatives, with the spongian skeleton
Fig. 1) have been detected. This fact is explained by the
pronounced nucleophilicity of the C2-position in the furan
510 apparatus and are uncorrected. Optical rotations were
measured with a Perkin-Elmer 343 digital polarimeter and
(
K1
2
K1
3
1
[
a] values are given in 10 deg cm g . IR spectra were
D
ring. Similar results have been obtained in the cyclisation
of dendrolasin to give pallescensin A.
3
2
registered on a Perkin–Elmer 7200 spectrophotometer in
% CCl solutions. NMR spectra were recorded on a Varian
Mercury spectrometer at 200 MHz for H and at 80 MHz for
5
4
1
The H NMR spectrum of 7 is in complete agreement with a
marginatane skeleton, having a 2,3-disubstituted furan ring
1
1
3
C, using CDCl
reported in ppm relative to residual chloroform, d
77.0, respectively. Mass spectra were obtained on a
as solvent. Chemical shifts values are
3
1
,2
and the trans-anti-trans structure. The construction of the
tetracyclic marginatane skeleton, with high stereoselectivity
of the trans-anti-trans fused ABC ring system, can be
explained by a synchronous intramolecular electrophilic
cyclisation, during which the more favorable approach of
the furan ring to the C8 carbon atom from the less hindered
a-face of the molecule, creates the axial C8 methyl group
with the b-configuration.
H
7.27 and
d
C
Hewlett–Packard 5890–5970 GC–MS system. Column
chromatography was carried out using Merck silica gel 60
(0.063–0.2 mm). Dry-column flash chromatography was
carried out using Merck silica gel 60 (!0.063 mm). Thin
layer chromatography (TLC) was performed on 0.25 mm
Merck DC Alufolien Kieselgel 60 (F254) and it was
visualised by UV light or spraying with methanolic solution
of H SO (8%) or alkaline KMnO .
Finally, allylic oxidation of 7, under the previously tested
2
4
4

M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
2007
4
.2. Synthesis of (C)-coronarin E from (C)-albicanol
.2.1. (1S,4aS,8aS)-1-Naphthalenecarboxaldehyde,deca-
4.3. Synthesis of (C)-coronarin E from (K)-sclareol
4
4.3.1. (1S,4aS,8aS)-1-Naphthaleneacetaldehyde, deca-
hydro-5,5,8a-trimethyl-2-methylene [(K)-g-bicyclo-
homofarnesal] (11). Following the described procedure
hydro-5,5,8a-trimethyl-2-methylene [(K)-albicanal] (9).
Pyridinium chlorochromate (0.645 g, 3 mmol) was stirred
for 15 min in CH Cl (15 mL). A solution of (C)-albicanol
1
7
(K)-sclareol 10 (15.4 g, 0.05 mol) was degraded to the title
compound 11 (4.0 g, 32%) which was obtained as colorless
2
2
8
(0.220 g, 1.0 mmol) in CH Cl (5 mL) was slowly added
2 2
2
D
0
18
21
D
at room temperature. Stirring was continued at room
temperature until the starting material was disappeared on
TLC. Diethyl ether (25 mL) was added and the reaction
mixture was stirred at room temperature for 15 min. The
supernatant solution was filtered through a short silica gel
column and the solvent was evaporated under reduced
pressure at room temperature, to give 9 (0.210 g, 95%) as
oil: [a] ZK24.5 (c 0.350, CHCl ) [lit. [a] ZK25.5 (c
3
K1
1.07, CHCl )]; IR nmax/cm 3086, 2935, 1727, 1643, 901,
3
1
887; H NMR d 0.72 (3H, s), 0.83 (3H, s), 0.91 (3H, s), 1.77
(1H, m), 2.10 (1H, td, JZ4.9, 12.4 Hz), 2.32–2.51 (4H,m),
4.40 (1H, s), 4.83 (1H, s), 9.64 (1H, dd, JZ1.4, 2.6 Hz);
NMR d 14.5, 19.2, 21.7, 23.8, 33.5, 37.4, 38.8, 39.3, 39.8,
1
3
C
41.9, 50.9, 55.2, 108.0, 148.5, 203.5.
2
0
a colorless oil, homogeneous in TLC; [a] ZK64.5
D
16
20
(
c 1.12, CHCl ); [lit. [a] ZK67.3 (c 1.83, CHCl )]; IR
4.3.2. (5S,9S,10S)-15,16-Epoxy-12-hydroxy-labda-8(17)-
13(16),14-triene (12). A solution of n-BuLi 1.6 M in
hexane (2.0 mL, 3.2 mmol) was added dropwise into a
stirred solution of 3-bromofuran (0.380 g, 2.69 mmol) in
3
D
3
K1
1
nmax/cm 3080, 2950, 1720, 1640, 890; H NMR d 0.80
3H, s), 0.83 (3H, s), 1.08 (3H, s), 1.15 (2H, m), 1.50 (1H,
m), 1.62 (1H, m), 2.04 (1H, m), 2.38 (2H, m), 4.42 (1H, s),
(
4
.84 (1H, s), 9.80 (1H, d, JZ4.0 Hz).
anhydrous Et O (15 mL) at K78 8C under argon atmo-
2
sphere. After 15 min, to the solution of 3-lithiofuran thus
obtained, a solution of 11 (0.50 g, 2.13 mmol) in anhydrous
Et O (15 mL) was added slowly. Stirring was continued for
2
4
1
.2.2. [(5S,9S,10S)-11(E)]-15,16-Epoxy-8(17),11,13(16),
4-labdatetraene [(C)-coronarin E] (5).
4
chloride. A solution of 3-furylmethyl chloride (2.40 g,
2
.2.2.1. (a) 3-Furylmethyltriphenylphosphonium
additional 2 h at -78 8C. Then, the reaction was quenched
with saturated aqueous NH Cl (20 mL) and the mixture was
4
3
4 mmol), prepared from 3-furylmethanol, and triphenyl-
3
allowed to reach room temperature. The organic phase was
separated and the aqueous phase was extracted with Et O
phosphine (6.30 g, 24 mmol) in benzene (30 mL) was
refluxed for 48 h. Filtration of the white precipitate and
washing by diethylether (2!50 mL) gave the 3-furyl-
methyltriphenylphosphonium chloride (3.90 g, 43%) as a
2
(3!15 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na SO and concentrated
2
4
under reduced pressure. The residue was purified by column
chromatography to afford the two diastereoisomeric
alcohols, 12a (elution with petroleum ether–diethyl ether
6:1; 0.150 g, 23%) and 12b (elution with petroleum ether–
diethyl ether 4:1; 0.36 g, 56%). Alcohol 12a was crystal-
lized from n-hexane to give white needles: mp 70–71 8C;
3
4
white crystalline solid; mp 282–284 8C dec. [lit. 283–
87 8C dec.]. More of the salt can be obtained by adding into
2
the filtrate additional triphenyl phosphine (3.15 g, 12 mmol)
and refluxing for another 48 h.
2
D
0
11
20
D
4
.2.2.2. (b) Wittig reaction. A solution of n-BuLi 1.6 M
[a]
ZC45.9 (c 0.49, CHCl
3
) [lit [a]
)]; IR nmax/cm 3623, 3081, 2946, 1641, 891, 874;
3
ZC19.0 (c 1.0,
K1
in hexane (0.7 mL, 1.1 mmol) was added dropwise into a
stirred suspension of the above phosphonium salt (0.416 g,
CHCl
1
H NMR d 0.69 (3H, s), 0.82 (3H, s), 0.89 (3H, s), 2.06 (1H,
td, JZ5.2, 12.8 Hz), 2.43 (1H, ddd, JZ2.5, 3.9, 12.7 Hz),
4.48 (1H, d, JZ1.6 Hz), 4.69 (1H, m) 4.88 (1H, d, JZ
1.4 Hz), 6.42 (1H, dd, JZ1.2, 2.6 Hz), 7.39 (2H, d, JZ
1
.1 mmol) in anhydrous THF (10 mL) at K78 8C, under
nitrogen. The resulting brown-red mixture was stirred for
0 min at the same temperature and then a solution of 9
0.210 g, 0.95 mmol) in anhydrous THF (5 mL) was added
dropwise. The reaction mixture was stirred for an additional
h at K78 8C, brought to 0–4 8C and left overnight in the
2
(
1
3
1.8 Hz); C NMR d, 14.6, 19.3, 21.6, 24.3, 32.6, 33.3, 33.5,
38.2, 39.0, 39.2, 42.0, 52.3, 55.3, 65.2, 106.4, 108.5, 130.2,
138.4, 143.2, 149.0.
1
refrigerator. The total was poured into water (15 mL) and
extracted with diethyl ether (3!20 mL). The combined
extracts were washed with brine, dried over anhydrous
Na SO and concentrated under reduced pressure. The
2
0
The alcohol 12b was obtained as a colorless oil: [a] Z
D
1
1
) [lit [a]
20
C8.5 (c 0.495, CHCl
CHCl )]; IR nmax/cm
3
Z C13.0 (c 1.2,
3619, 3082, 2932, 2870, 1641,
894, 874; H NMR d 0.69 (3H, s), 0.78 (3H, s), 0.83 (3H, s),
2.37 (1H, ddd, JZ2.4, 4.0, 12.6 Hz), 4.68 (1H, m), 4.71
(1H, d, JZ1.4 Hz), 4.88 (1H, d, JZ1.4 Hz), 6.41 (1H, dd,
3
D
K1
2
4
1
residue was purified by column chromatography on silica
gel (elution with petroleum ether 40–60 8C) and the major
product (C)-coronarin E 5 was obtained as a gum
2
0
13
homogeneous on TLC (86 mg, 32%); [a] ZC24.2 (c
JZ0.8, 1.8 Hz), 7.32 (1H, br s), 7.38 (1H, br s); C NMR d
D
9
a
11
0
[
2
.245, CHCl ) [lit. [a] ZC22.3 (c 0.44, CHCl ); lit.
14.5, 19.2, 21.6, 24.2, 31.8, 33.4, 33.4, 38.1, 38.7, 39.4,
41.9, 52.8, 55.2, 65.9, 106.6, 108.2, 128.7, 139.6, 143.3,
148.8.
3
D
3
2
D
4
K1
a] ZC25.0 (c 1.7, CHCl )]; IR nmax/cm 3083, 2962,
3
1
930, 1641, 969, 893, 872; H NMR d 0.86 (6H, s), 0.90
(
4
3H, s), 2.12 (1H, td, JZ4.4, 13.2 Hz), 2.40–2.48 (2H, m),
.54 (1H, d, JZ1.8 Hz), 4.77 (1H, d, JZ1.8 Hz), 5.99 (1H,
dd, JZ9.6, 15.8 Hz), 6.21 (1H, d, JZ15.8 Hz), 6.56 (1H, br
4.3.3. [(5S,9S,10S)-11(E)]-15,16-Epoxy-8(17),11,13(16),
14-labdatetraene [(C)-coronarin E] (5). A solution of a
mixture of 12a and 12b (0.450 g, 1.49 mmol) in HMPA
(27 mL) was refluxed for 5 h. Then, the reaction mixture
was allowed to reach room temperature, poured into water
1
3
s), 7.37 (2H, br s); C NMR d 15.0, 19.1, 22.0, 23.4, 33.6,
3
1
2
3.6, 36.8, 39.1, 40.8, 42.3, 54.8, 61.5, 107.6, 108.0, 121.7,
C
24.5, 128.3, 139.6, 143.3, 150.2; MS m/z 284 (M , 80%),
69 (6), 199 (4), 160 (17), 147 (100), 95 (27), 91 (32), 81
and extracted with Et O (4!20 mL). The combined organic
2
(
64).
extracts were washed with brine, dried over anhydrous

2008
M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
Na SO and concentrated under reduced pressure. The
2
and perillene 14 (0.88 g, 72% based on the consumed
acetate) as a colorless oil; IR nmax/cm 2972, 2921, 2859,
4
K1
residue was purified by column chromatography (elution
with petroleum ether) to afford the (C)-coronarin E 5
1
1673, 1027, 873, 719; H NMR d 1.60 (3H, s), 1.70 (3H, s),
2
0
(
CHCl ). All spectroscopic data are identical to the
0.320 g, 76%) as a white gum: [a] ZC25.5 (c 0.45,
2.24 (2H, q, JZ7.3 Hz), 2.46 (2H, t, JZ7.5 Hz), 5.16 (1H,
tq, JZ1.5, 6.9 Hz), 6.29 (1H, s), 7.22 (1H, br s), 7.35 (1H, br
s); C NMR d 25.0, 25.7, 28.5, 111.0, 123.8, 124.9, 132.1,
D
3
1
3
previously obtained compound from (K)-albicanal 9.
1
38.8, 142.5.
4
[
.4. (5S,9S,10S)-15,16-epoxy-8(17),13(16),14-labdatriene
(C)-dihydrocoronarin E] (6)
4.5.2. 7,7-Dimethyl-4,5,6,7-tetrahydro-1-benzofuran
15). To a stirred solution of 14 (0.60 g, 4.00 mmol) in
anhydrous CH Cl (100 mL), a solution of BF $Et O
(
To a stirred solution of (C)-coronarin E 5 (0.240 g,
2
2
3
2
0
1
.84 mmol) in MeOH (17 mL), a small amount of catalyst
0% Pd/C (15 mg) was added, followed by ammonium
(0.08 mL, 0.65 mmol) in anhydrous CH Cl (3 mL) was
2 2
added dropwise at room temperature under argon atmo-
sphere. After 1 h, additional BF $Et O (0.08 mL,
formate (0.100 g, 1.59 mmol) and the reaction mixture was
refluxed. Control of the progress of the reaction by TLC was
performed every 30 min. After every control, the same
quantity (0.100 g 1.59 mmol) of ammonium formate was
added. The reaction was completed in 5 h, when 0.74 g
ammonium formate (11.8 mmol) have been added in total.
The mixture was allowed to reach room temperature and
filtered through a pad of celite. The filtrate was concentrated
under reduced pressure and the residue was dissolved in
3
2
0.65 mmol) in anhydrous CH Cl (3 mL) was added to the
2
2
bright red reaction mixture which was stirred 2 h more at
room temperature. The total was poured into cold H O
2
(50 mL), the organic phase was separated and the aqueous
phase was extracted with CH Cl (3!20 mL). The
2
2
combined organic extracts were washed with aqueous
NaHCO3 5%, followed by brine, dried over anhydrous
Na SO and concentrated under reduced pressure. The
2
4
Et O (25 mL). The ether solution was washed with brine,
2
dried over anhydrous Na SO4 and concentrated under
2
reduced pressure. The residue was purified by column
chromatography (elution with petroleum ether) to afford
residue was purified by dry-column flash chromatography
(elution with petroleum ether) to afford the tetrahydro-
benzofuran 15 as a colorless oil (0.36 g, 60%); IR
2
6
K1
nmax/cm
697; H NMR d 1.25 (6H, s), 1.59–1.83 (4H, m), 2.41
2967, 2934, 2853, 1503, 1457, 1160, 892,
1
(
[
C)-dihydrocoronarin E 6 (0.184 g, 77%) as a colorless oil:
20
11
24
a] ZC42.6 (c 0.155, CHCl ) [lit. [a] ZC23.0 (c 2.00,
(2H, t, JZ6.1 Hz), 6.16 (1H, d, JZ2.2 Hz), 7.24 (1H, d,
D
3
D
K1
1
3084, 2930, 1641, 891, 873; H
13
CHCl )]; IR nmax/cm
JZ2.0 Hz); C NMR d 20.5, 22.7, 27.7, 30.3, 39.4,
110.1, 115.0, 140.0, 157.4; MS m/z 150 (M , 21%),
3
C
NMR d 0.70 (3H, s), 0.82 (3H, s), 0.88 (3H, s), 2.00 (1H, td,
JZ5.1, 12.8 Hz), 2.25 (1H, m), 2.42–2.58 (2H, m), 4.58
135 (100), 117 (9), 107 (8), 91 (28), 79 (26), 77 (16),
55 (14).
(
1H, s), 4.88 (1H, s), 6.28 (1H, s), 7.21 (1H, s), 7.36 (1H, t,
1
3
JZ1.7 Hz); C NMR d 14.5, 19.4, 21.7, 23.6, 24.1, 24.4,
3
1
3.6, 33.6, 38.3, 39.0, 39.6, 42.1, 55.4, 56.0, 106.2, 111.0,
25.4, 138.6, 142.6, 148.5.
4.5.3. 7,7-Dimethyl-6,7-dihydro-1-benzofuran-4(5H)-one
(16). To a vigorously stirred solution of 15 (80 mg,
0
.53 mmol) in ethyl acetate (2 mL) and aqueous tert-butyl
4.5. Synthesis of the 7,7-dimethyl-6,7-dihydro-1-
benzofuran-4(5H)-one (16)
hydroperoxide 70% (0.4 mL, 2.9 mmol), small drops of
aqueous NaOCl 4–5% (commercial bleach, 2 mL) were
added slowly, at 0 8C during 45 min. Then, aqueous
4
.5.1. 3-(4-Methyl-3-pentenyl)furan [perillene] (14). To a
NaHSO
at room temperature for 30 min. Then the organic phase was
separated and the aqueous phase was extracted with Et
(3!5 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na SO and concentrated
3
10% (5 mL) was added and the total was stirred
stirred suspension of magnesium (3.00 g, 123 mmol) and
anhydrous THF (20 mL), a crystal of iodine and 2 drops of
1
initiate the reaction. Then, a solution of 3-chloromethyl-
furan (2.91 g, 29 mmol) in anhydrous THF (30 mL) was
added dropwise at a rate to keep the reaction mixture at
O
2
,2-dibromoethane were added under argon atmosphere, to
2
4
3
3
under reduced pressure. The residue was purified by dry-
column flash chromatography (elution with petroleum
ether–diethyl ether 1:1) to afford 16 (36 mg, 42%) as a
30–35 8C. After the addition, stirring was continued for
1.5 h at room temperature, and then left to decant for 30 min
K1
colorless oil; IR nmax/cm 2973, 2933, 2862, 1683, 1160,
1
without stirring. The supernatant solution of 3-furylmethyl-
magnesium chloride thus obtained, was added in 2 min, via
syringe, to a stirred solution of 3-methyl-2-butenyl acetate
(1.98 g, 15.4 mmol) in anhydrous THF (15 mL) at 0 8C
under argon atmosphere in the presence of Li CuCl
1126, 909, 697; H NMR d 1.38 (6H, s), 2.00 (2H, dd, JZ
5.9, 6.9 Hz), 2.58 (2H, dd, JZ6.1, 7.1 Hz), 6.63 (1H, d, JZ
1
3
1.8 Hz), 7.32 (1H, d, JZ1.8 Hz); C NMR d 25.9, 26.3,
35.4, 37.9, 106.3, 118.8, 142.5, 172.9, 194.6; MS m/z 164
(M , 46%), 149 (100), 136 (16), 121 (51), 108 (43), 93 (25),
25
C
2
4
(
17 mL 0.1 M in anhydrous THF, 1.7 mmol). The total was
91 (25), 77 (32). Anal. Calcd for C10
7.37. Found: C, 72.94; H, 7.23.
H O : C, 73.15; H,
12 2
stirred at the same temperature for 1 h and left at room
temperature overnight. Then, it was poured into saturated
aqueous NH Cl (40 mL). The organic phase was separated
4.6. (5S,8R,9S,10S)-Marginata-13,15-diene (7)
4
and the aqueous phase was extracted with Et O (3!30 mL).
2
The combined organic extracts were washed with brine,
dried over anhydrous Na SO and concentrated under
To a stirred solution of (K)-dihydrocoronarin E 6 (0.150 g,
0.52 mmol) in anhydrous CH Cl (20 mL) a solution of
2
4
2
2
reduced pressure. The residue was purified by column
chromatography (elution with petroleum ether) to afford
unchanged 3-methyl-2-butenyl acetate (0.94 g, 7.3 mmol)
BF $Et O (0.01 mL, 0.08 mmol) in anhydrous CH Cl
3 2 2 2
(1 mL) was added dropwise at room temperature under
argon atmosphere. After 1 h, additional BF $Et O
3
2

M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
2009
(
0.01 mL, 0.08 mmol) in anhydrous CH Cl (1 mL) was
2
References and notes
2
added to the bright red reaction mixture and stirring was
continued for 3 h. The reaction was monitored by the
disappearance of the olefinic protons of 6 in the H NMR
1. Tischler, M.; Andersen, R. J.; Choudhary, M. I.; Clardy J. Org.
Chem. 1991, 56, 42–47.
1
spectrum. Then, the total was poured into cold H O
2
2. Gustafson, K.; Andersen, R. J.; Cun-heng, H.; Clardy, J.
Tetrahedron Lett. 1985, 26, 2521–2524.
(
phase was extracted with CH Cl (3!5 mL). The combined
20 mL), the organic phase was separated and the aqueous
2
2
3. Dumdei, E. J.; Kunabek, J.; Coleman, J. E.; Pika, J.; Andersen,
R. J.; Steiner, J. R.; Clardy, J. Can. J. Chem. 1997, 75,
773–789.
organic extracts were washed with aqueous NaHCO 5%,
3
followed by brine, dried over anhydrous Na SO and
2
4
concentrated under reduced pressure. The residue was
purified by dry column flash chromatography (elution with
petroleum ether) to afford (K)-marginata-13,15-diene 7
4. Tischler, M.; Andersen, R. J. Tetrahedron Lett. 1989, 30,
5717–5720.
5. (a) Hellou, J.; Andersen, R. J.; Rafii, S.; Arnold, E.; Clardy, J.
Tetrahedron Lett. 1981, 22, 4173–4176. (b) Thompson, J. E.;
Walker, R. P.; Wratten, S. J.; Faulkner, D. J. Tetrahedron
1982, 38, 1865–1873. (c) Hellou, J.; Andersen, R. J.;
Thompson, J. E. Tetrahedron 1982, 38, 1875–1879.
6. Pandey, U. C.; Sarmah, P.; Sharma, R. P. Tetrahedron 1984,
40, 3739–3748.
2
0
as a colorless oil (69 mg, 46%); [a] ZK40.0 (c 0.365,
D
K1
1
2935, 2870, 2852, 1264, 874; H
CHCl ); IR nmax/cm
3
NMR d 0.86 (3H, s), 0.88 (3H, s), 0.92 (3H, s), 1.21 (3H,
s), 2.20–2.54 (6H, m), 6.11 (1H, d, JZ1.8 Hz), 7.19 (1H,
1
3
d, JZ1.8 Hz); C NMR d 16.4, 18.3, 18.5, 19.1, 21.3,
2
1
2
2.5, 22.9, 33.3, 33.4, 37.1, 39.8, 42.2, 56.8, 56.9, 109.9,
13.5, 140.0, 159.9; MS m/z 286 (M , 24%), 271 (100),
01 (6), 147 (61), 137 (56), 105 (14), 95 (22), 81 (23).
C
7. (a) Nishizawa, M.; Yamada, H.; Hayashi, Y. Tetrahedron Lett.
1986, 27, 187–190. (b) Nishizawa, M.; Yamada, H.; Hayashi,
Y. J. Org. Chem. 1987, 52, 4878–4884.
Anal. Calcd for C H O: C, 83.86; H, 10.55. Found: C,
2
0 30
8
3.69; H, 10.38.
8. Zoretic, P. A.; Shen, Z.; Wang, M. Tetrahedron Lett. 1995, 36,
2
925–2928.
9
. (a) Itokawa, H.; Morita, H.; Takeya, K.; Motidome, M. Chem.
Pharm. Bull. 1988, 36, 2682–2684. (b) Singh, S.; Gray, A. I.;
Skelton, B. W.; Waterman, P. G.; White, A. H. Aust. J. Chem.
4.7. (5S,8R,9S,10S)-Marginata-13,15-diene-12-one [(K)-
marginatone] (1)
1
991, 44, 1789–1793. (c) Sirat, H. M.; Masri, D.; Rahman,
To a vigorously stirred solution of 7 (43 mg, 0.15 mmol) in
ethyl acetate (1 mL) and aqueous tert-butyl hydroperoxide
A. A. Phytochemistry 1994, 36, 699–701. (d) Sy, L. K.;
Brown, G. D. J. Nat. Prod. 1997, 60, 904–908.
7
4
0
0% (0.12 mL, 0.87 mmol), small drops of aqueous NaOCl
–5% (commercial bleach, 0.8 mL) were added slowly at
8C during 15 min. Then, aqueous NaHSO 10% (2 mL)
1
0. (a) Jung, M.; Ko, I.; Lee, S. J. Nat. Prod. 1998, 61, 1394–1396.
b) Jung, M.; Lee, S.; Choi, S. J.; Youn, B. H.; Kim, S. K.
(
3
Bioorg. Med. Chem. Lett. 1998, 8, 3295–3298. (c) M u¨ ller, M.;
Schr o¨ der, J.; Magg, C.; Seifert, K. Tetrahedron Lett. 1998, 39,
was added to the reaction mixture and stirring was
continued at room temperature for 30 min. Then, the
organic phase was separated and the aqueous phase was
4
655–4656.
1
1
1. Villamizar, J.; Fuentes, J.; Salazar, F.; Tropper, E.; Alonso, R.
J. Nat. Prod. 2003, 66, 1623–1627.
2. Tasdemir, D.; Concepci o´ n, G. P.; Mangalindan, G. C.; Harper,
M. K.; Hajdu, E.; Ireland, C. M. Tetrahedron 2000, 56,
extracted with Et O (3!2 mL). The combined organic
2
extracts were washed with brine, dried over anhydrous
Na SO and concentrated under reduced pressure. The
2
4
residue was purified by dry column flash chromatography
elution with petroleum ether–diethyl ether 1:1) to
9
025–9030.
(
1
3. Ragoussis, V.; Liapis, M.; Ragoussis, N. J. Chem. Soc. Perkin
Trans. 1 1987, 987–992.
afford 1 (15 mg, 33%) as a white solid which was
recrystallized from n-hexane to give white shiny
2
0
14. (a) Tanis, S. P. Tetrahedron Lett. 1982, 23, 3115–3118. (b)
Nishizawa, A.; Honda, G.; Tabata, M. Phytochemistry 1990,
29, 2873–2875. (c) Bock, I.; Bornowski, H.; Ranft, A.; Theis,
H. Tetrahedron 1990, 46, 1199–1210.
crystals. Mp 167–168 8C; [a] ZK26.0 (c 0.365,
D
1
20
D
CHCl ) [lit. [a] ZK16.0 (c 0.4, CHCl )]; IR nmax/
3
K1
3
1
2930, 2858, 1681, 1047, 717; H NMR d 0.86
cm
(
(
3H, s), 0.89 (3H, s), 0.99 (3H, s), 1.29 (3H, s), 1.90
1H, dd, JZ4.9, 11.5 Hz), 2.26–2.60 (3H, m), 6.60 (1H,
1
5. Laube, T.; Schroder, J.; Stehle, R.; Seifert, K. Tetrahedron
2002, 58, 4299–4309.
6. Poigny, S.; Huor, T.; Guyot, M.; Samadi, M. J. Org. Chem.
1
3
d, JZ2.2 Hz), 7.26 (1H, d, JZ2.0 Hz); C NMR d
1
1
6.0, 17.9, 18.2, 20.5, 21.3 33.2, 35.3, 35.5, 37.4, 39.3,
1.8, 56.0, 56.5, 106.2, 118.2, 142.2, 176.0, 195.2; MS
1999, 64, 9318–9320.
17. Zahra, J. P.; Chauvet, F.; Coste-Mani e` re, I.; Martres, P.;
Perfetti, P.; Waegell, B. Bull. Soc. Chim. Fr. 1997, 134,
4
m/z 300 (M , 53%), 285 (27), 258 (26), 176 (32), 163
C
(
1
90), 161 (87), 149 (77), 147 (100), 137 (62), 135 (53),
09 (56), 91 (76), 81 (54), 79 (49), 77 (56), 69 (70).
Anal. Calcd for C H O : C, 79.95; H, 9.39. Found: C,
1
001–1024.
8. Nozawa, M.; Ono, E.; Akita, H. Heterocycles 2000, 53,
811–1819.
1
1
2
0 28 2
1
7
9.81; H, 9.55.
9. (a) De la Torre, M. C.; Garc ´ı a, I.; Sierra, M. A. Tetrahedron
Lett. 2002, 43, 6351–6353. (b) Kinoshita, M.; Ohtsuka, M.;
Nakamura, D.; Akita, H. Chem. Pharm. Bull. 2002, 50,
930–934.
Acknowledgements
2
0. Fukuyama, Y.; Kawashima, Y.; Miwa, T.; Tokoroyama, T.
Synthesis 1974, 443–444.
We thank the University of Athens for the financial support
of this work from the Special Account for Research Grants.
M. K. thanks the Greek State Scholarship Foundation for a
postgraduate studentship.
21. San Feliciano, A.; Barrero, A. F.; Miguel del Corra, J. M.
Tetrahedron 1985, 41, 671–680.
22. (a) Ranu, B. C.; Sarkar, A. Tetrahedron Lett. 1994, 35,

2
010
M. Kolympadi et al. / Tetrahedron 61 (2005) 2003–2010
649–8650. (b) Paryzek, Z.; Koenig, H.; Tabaczka, B. 28. Ma, D.; Xia, C.; Tian, H. Tetrahedron Lett. 1999, 40,
Synthesis 2003, 2023–2025.
8
8915–8917.
2
2
2
2
2
3. Zdero, C.; Bohlmann, F.; Mungai, G. M. Phytochemistry 1991,
29. Noureldin, N. A.; Zhao, D.; Lee, D. G. J. Org. Chem. 1997, 62,
8767–8772.
30, 3297–3303.
4. Waridel, P.; Wolfender, J. L.; Lachavanne, J. B.; Hostettmann,
K. Phytochemistry 2003, 64, 1309–1317.
5. B a¨ ckvall, J. E.; Sell e´ n, M.; Grant, B. J. Am. Chem. Soc. 1990,
30. Marwah, P.; Lardy, H. A.; Marwah, A. K. US 6,274,746 B1,
August 14, 2001.
3
3
1. Ram, R. N.; Charles, I. Chem. Commun. 1999, 2267–2268.
2. Nasipuri, D.; Das, G. J. Chem. Soc. Perkin Trans. 1 1979,
112, 6615–6621.
6. Cheskis, B. A.; Baeckstr o¨ m, P.; Moiseenkov, A. M.; Norin, T.
Bull. Acad. Sci. USSR Div. Chem. Sci. 1989, 38, 131–134.
7. (a) Marshall, C. W.; Ray, R. E.; Laos, I.; Riegel, B. J. Am.
Chem. Soc. 1957, 79, 6308–6313. (b) Masterson, S. P.; Miller,
T. A.; Nassim, B. E. Steroids 2003, 68, 253–256.
2
776–2778.
3. Sherman, E.; Amstutz, E. D. J. Am. Chem. Soc. 1950, 72,
195–2199.
4. Matsumoto, T.; Usui, S. Chem. Lett. 1978, 105–108.
3
3
2