An efficient synthesis of (+)-aureol via boron trifluoride etherate-promoted rearrangement of (+)-arenarol

Article abstract of DOI:10.1016/S0040-4039(02)01627-1

A novel marine natural product, (+)-aureol (1), was efficiently synthesized starting from the cis-fused decalin derivative 4. The synthetic method features boron trifluoride etherate-promoted rearrangement/cyclization reaction of (+)-arenarol (2) to form

Full text of DOI:10.1016/S0040-4039(02)01627-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6929–6932
An efficient synthesis of (+)-aureol via boron trifluoride
etherate-promoted rearrangement of (+)-arenarol
Masahiko Nakamura,† Akiyuki Suzuki,‡ Mari Nakatani, Takamasa Fuchikami, Munenori Inoue and
Tadashi Katoh*
Sagami Chemical Research Center, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
Received 1 July 2002; revised 29 July 2002; accepted 2 August 2002
Abstract—A novel marine natural product, (+)-aureol (1), was efficiently synthesized starting from the cis-fused decalin derivative
4. The synthetic method features boron trifluoride etherate-promoted rearrangement/cyclization reaction of (+)-arenarol (2) to
form (+)-aureol (1) with complete stereoselectivity in high yield. (+)-Arenarol (2) was prepared in an alternative and more efficient
manner employing salcomine oxidation protocol. © 2002 Elsevier Science Ltd. All rights reserved.
Over the past two decades a number of clerodane
diterpenoids and related compounds have been isolated
from marine algae and sponges.1 Several of these
marine natural products were reported to possess inter-
esting biological properties such as antimicrobial,
antiviral, and cytotoxic activities.1 Aureol (1, Fig. 1)
was originally isolated from the marine sponge,
Smenospongia aurea, by Faulkner et al. in 1980, and its
structure and stereochemistry including the absolute
configuration were determined by X-ray diffraction
analysis of the brominated O-acetyl derivative of 1 to
have a novel tetracyclic benzo[d]xanthen skeleton
(ABCD ring system).2 Recently, 1 was found to exhibit
selective cytotoxicity against the A549 human non-
small cell lung cancer cells3 and anti-influenza A virus
activity.4 Its unique structural features and promising
biological profiles as well as the limited supplies5 from
natural resources, make 1 an attractive target for total
synthesis. However, to the best of our knowledge, the
total synthesis of 1 has not been disclosed to date.
OH
OH
OH
D
It is envisioned that aureol (1) might be produced
biogenetically by acid-promoted rearrangement of are-
narol (2), which was initially isolated from the marine
sponge, Dysidea arenaria, by Schmitz et al.6 in 1984.
This type of acid-promoted rearrangement has been
successfully applied to reveal the absolute stereochem-
istry of marine sesquiterpene quinones and
hydroquinones.7,8 So far, to our knowledge, two exam-
ples of acid-promoted rearrangement of 2 have been
recorded in the literature; however, the important syn-
thetic chemical issues of stereocontrol and efficiency
were not considered. Thus, Schmitz et al.9 reported for
the first time that treatment of 2 with p-toluenesulfonic
acid in benzene at room temperature overnight, fol-
lowed by at reflux for 30 min, resulted in the formation
of compound 3, a stereoisomer of 1 possessing the
trans-fused decalin system, in approximately 60% yield.
On the other hand, Capon et al.7a described that reac-
tion of 2 in the same acid solution at reflux for 30 min
provided a 25% yield of 1 together with a mixture of
unidentified products.
HO
H
Me
Me
Me
O
O
C
Me
Me
Me
A
B
Me
H
Me
H
Me
Me
Me
arenarol (2)
aureol (1)
3
Figure 1. Structures of aureol (1), arenarol (2), and related
compound 3.
Keywords: aureol; arenarol; marine natural product; rearrangement;
domino reaction.
* Corresponding author. Tel.:+81-467-76-9295; fax: +81-467-77-4114;
e-mail: takatoh@alles.or.jp
† Graduate student from the Department of Electronic Chemistry,
Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502,
Japan.
‡ Undergraduate student from the Department of Chemistry,
Kitasato University, Kitasato, Sagamihara, Kanagawa 228-0829,
Japan.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01627-1

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M. Nakamura et al. / Tetrahedron Letters 43 (2002) 6929–6932
In view of the foregoing facts, development of an
efficient and reliable method for obtaining aureol (1) in
high yield is strongly desirable and useful from a phar-
maceutical point of view. We have now found that
arenarol (2) undergoes a very facile acid-promoted rear-
rangement in the presence of boron trifluoride etherate
at low temperature, which exclusively provided 1 with
complete stereoselectivity in an almost quantitative
yield. In this communication, we report our preliminary
results concerning the enantioselective total synthesis of
1, which features a biogenetic-type rearrangement (2“
1, Schemes 2 and 3) as the pivotal step. Recently, we
have reported the enantioselective total synthesis of 2
starting from the cis-fused decalin derivative 4 (10%
overall yield from 4 over six steps);10 an outline of the
synthetic route is depicted in Scheme 1. In this synthe-
sis, 1-bromo-2,5-dimethoxybenzene (5) was employed
as an aromatic synthon, and oxidative cleavage of the
two methyl ether protecting groups in the intermediate
6 to deliver the corresponding quinone 7 (arenarone)
was carried out by employing ceric ammonium nitrate
(CAN); however, the reaction was not clean and the
yield of 7 was observed to be poor (ꢀ33%).11 In order
to circumvent the problematic CAN oxidation step, we
sought a potential alternative synthetic method for 2.
Herein, we also disclose an improved synthetic route to
2 (36% overall yield from 4 over seven steps) which
involves salcomine [N,N%-bis(salicylidene)ethylene-
diiminocobalt(II)]12 oxidation of the phenolic com-
pound 12 as the strategic step (12“7, Scheme 2).
MeO
H
MeO
H
Me
Me
a
c
X
Me
4
Me
O
Me
Me
O
X
8 : X = OH
9 : X = OCOCF3
10 : X = O
11 : X = CH2
b
d
O
HO
O
H
g
e
Me
f
Me
H
Me
Me
Me
Me
12
arenarone (7)
OH
OH
HO
H
h
Me
Me
Me
O
Me
H
Me
Me
Me
aureol (1)
arenarol (2)
As shown in Scheme 2, we initially pursued the synthe-
sis of the anisole derivative 11 by employing a reaction
sequence analogous to that reported previously.10,12a
Thus, the aryllithium generated in situ by treatment of
2-bromoanisole with n-butyllithium was allowed to
react with the known cis-fused decalin 4,10,12a affording
the coupling product 8, mp 188–189°C, [h]2D0 −11.1° (c
1.01, CHCl3), in 93% yield as the sole product; the
stereochemistry at the benzylic carbon was not deter-
Scheme 2. Synthesis of aureol (1) starting from the cis-fused
decalin 4. Reagents and conditions: (a) 2-bromoanisole, n-
BuLi, THF, −78°C; 4, −78°C, 93%; (b) (CF3CO)2O, pyridine,
0°C, 91%; (c) H2, 10% Pd–C, MeOH, rt, 90%; (d) CH2Br2,
Zn, TiCl4, THF, rt, 82%; (e) n-BuSLi, HMPA, 100°C, 84%;
(f) O2, salcomine, DMF, rt, 91%; (g) Na2S2O4, THF–H2O, rt,
76%; (h) BF3·Et2O, CH2Cl2, −40°C, 97%.
mined. Removal of both the benzylic hydroxy group
and ethylene acetal function in 8 was achieved by initial
formation of the corresponding trifluoroacetate 9, [h]D20
+19.3° (c 1.05, CHCl3), followed by treatment under the
conditions for hydrogenolysis, providing the ketone 10,
mp 84–86°C, [h]2D0 +50.6° (c 1.00, CHCl3), in 82% yield
for the two steps. Subsequent olefination of the car-
bonyl group in 10 was carried out by the Takai
procedure13 to furnish the exo-olefin 11, mp 63–64°C,
[h]2D0 +53.3° (c 1.03, CHCl3), in 82% yield.
OMe
Me
CHO
H
OMe
MeO
H
Me
Me
+
Me
MeO
O
Me
Br
O
Me
4
5
6
OH
O
The next task was deprotection of the methyl ether
protecting group in 11 to obtain the phenolic com-
pound 12, a key substrate for the following critical
salcomine oxidation event. Since the exo-olefin moiety
present in this type of decalin system is known to be
labile under acidic conditions,14 demethylation of 11
was performed by the use of a non-acidic alkylthiolate
reagent. Thus, treatment of 11 with lithium n-
butylthiolate15 (10 equiv.) in hexamethylphosphoramide
(HMPA) at 100°C for 2 h, led to the formation of 12,
[h]2D0 +49.7° (c 1.02, CHCl3), in 84% yield.
CAN
MeCN-H2O, rt
Na2S2O4
HO
H
O
THF-H2O, rt
Me
Me
H
Me
Me
33%
75%
Me
Me
arenarone (7)
Scheme 1. Previous synthetic route to arenarol (2).
arenarol (2)

M. Nakamura et al. / Tetrahedron Letters 43 (2002) 6929–6932
6931
similar acid-catalyzed rearrangement.7a The reaction
process would involve three possible tertiary carboca-
tion intermediates such as I, II, and III. Initial coordi-
nation–activation between the Lewis acid and the
exo-olefin functionality in 2 would lead to the interme-
diate I, which then would furnish the intermediate II
via migration of the C-5 methyl group to the C-4
carbocation center. The intermediate II would undergo
a 1,2-hydride shift from the C-10 position to the C-5
center at the a-face of the molecule to furnish the
intermediate III, in which the C-10 carbocation center
would be trapped by the inner phenolic hydroxy group
to provide the requisite cyclized product 1 after pro-
tonolysis of the CꢀBF3 bond. We believe that the
sequence of this domino-type rearrangement/cyclization
reaction would proceed under kinetically controlled
conditions.16
Having obtained the phenolic compound 12 in an
efficient way, our next effort was devoted to the critical
construction of the quinone system to produce are-
narone (7). Toward this end, 12 was reacted with
molecular oxygen (O2 balloon) in the presence of
salcomine12 (1.0 equiv.) in N,N-dimethylformamide
(DMF) at room temperature for 2 h, which successfully
gave rise to the corresponding quinone 7 (arenarone),
[h]D20 +32.0° (c 0.21, CHCl3) [lit.,10 [h]2D0 +31.8° (c 0.21,
CHCl3)], in 91% yield. Subsequent reaction of 7 with
sodium hydrosulfite afforded the subtarget arenarol (2),
[h]2D0 +17.1° (c 0.10, CHCl3) [lit.,6 [h]D +19° (c 0.1,
CHCl3)], in 76% yield.
With an improved process for the synthesis of arenarol
(2) developed, we next focused our attention on the
crucial acid-promoted rearrangement of 2 to complete
the synthesis of the targeted aureol (1). After several
experiments, to our delight, the desired acid-promoted
rearrangement was found to proceed effectively by
treating 2 with boron trifluoride etherate (1.0 equiv.) in
dichloromethane at −40°C for 3 h, which led to the
formation of aureol (1), mp 141–142°C [lit.,2 mp 144–
145°C], [h]2D0 +65.6° (c 0.20, CCl4) [lit.,2 [h]D +65° (c 2.0,
In summary, we have succeeded in developing a facile
and efficient synthetic pathway to (+)-aureol (1) starting
from the known cis-fused decalin derivative 4. The
explored synthetic method features a highly stereocon-
trolled Lewis acid-promoted rearrangement/cyclization
reaction of (+)-arenarol (2) as the key step. In addition,
we have achieved an alternative and more efficient
synthesis of (+)-arenarol (2) by means of salcomine
oxidation methodology. Further applications of the
rearrangement/cyclization strategy to the synthesis of
biologically significant natural products that possess a
tetracyclic benzo[d]xanthen skeleton containing a cis-
fused decalin system are currently under investigation
and will be reported in due course.
1
CCl4)], in 97% yield. The IR, H and 13C NMR, and
MS spectra of the synthetic material 1 were identical
with those reported2 for natural aureol (1). It is note-
worthy that no isomeric products (e.g. trans-fused
decalin isomer 3, Fig. 1) were obtained in this rear-
rangement/cyclization reaction.
The remarkable stereocontrolled rearrangement/cycliza-
tion reaction of 2 leading to 1 can be rationalized by
the mechanistic route shown in Scheme 3, which is
essentially based on the proposed mechanism for a
Acknowledgements
OH
We are grateful to Professor H. Miyaoka and Dr. H.
Mitome, Tokyo University of Pharmacy and Life Sci-
ence, for valuable discussions.
OH
HO
BF3·Et2O
Me
Me
O
1
4
H
Me
Me
9
2
3
10
8
7
5
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F3B
Me
H
Me
Me
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