Short access to the aromadendrane family: Highly efficient stereocontrolled total synthesis of (±)-cyclocolorenone and (±)-α-gurjunene

Article abstract of DOI:10.1002/ejoc.200900253

(±)-Cyclocolorenone (2), an aromadendrane, was prepared stereoselectively; in seven steps in 10.8-12.5% overall yield from, the commercially available tropylium. cation via key intermediate 6, which was used as a general and. efficient precursor to bicycl

Full text of DOI:10.1002/ejoc.200900253

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900253
Short Access to the Aromadendrane Family: Highly Efficient Stereocontrolled
Total Synthesis of (؎)-Cyclocolorenone and (؎)-α-Gurjunene
Mihaela Calancea,[a] Sébastien Carret,[a] and Jean-Pierre Deprés*[a]
Keywords: Total synthesis / Sesquiterpenes / Isomerization / Hydrogenation / Cyclopropanation
(Ϯ)-Cyclocolorenone (2), an aromadendrane, was prepared
stereoselectively in seven steps in 10.8–12.5% overall yield
from the commercially available tropylium cation via key in-
termediate 6, which was used as a general and efficient pre-
cursor to bicyclo[5.3.0]decane sesquiterpenes. (Ϯ)-α-Gurju-
nene (3) was obtained through the efficient deoxygenation
of (Ϯ)-2, constituting therefore the first total synthesis of this
natural product in eight steps from the tropylium cation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The first reported member of the aromadendrane family,
(+)-aromadendrene [(+)-1], which inspired the name of this
new group of tricyclic compounds, was isolated by Smith
over one century ago by distillation of Eucalyptus Globulus
essential oil.[1] These sesquiterpenes possessing the bicy-
clo[5.3.0]decane skeleton represent more than 100 natural
compounds.[2] The presence of a gem-dimethylcyclopropane
ring fused to an hydroazulene ring system at the C-6,7 posi-
tion is characteristic of this family (representative examples
are shown in Figure 1). Although the biological properties
of aromadendranes need further study[3] one of them, (–)-
macrocarpal A, has shown antibacterial[3b] activity.
(–)-Cyclocolorenone [(–)-2] was first isolated in 1958
from Pseudowintera Colorata[4] and more recently from
Magnolia grandiflora bark.[5] Cutler and co-workers[3d] re-
vealed that [(–)-2] has phytotoxic, antibacterial, antiviral,
and antifungal activities. In 1974, Matsuo and co-
workers,[6] and more recently Asakawa and co-workers,[7]
isolated (+)-cyclocolorenone [(+)-2], which belongs to the
ent-aromadendrane family. The latter compound has never
been assayed for its biological activity. (–)-α-Gurjunene
[(–)-3] was first isolated in 1958 from Dipterocarpus Dyeri
(gurjun balsam resin),[8a] the structure of which was deter-
mined in 1963[8c] and confirmed, two years later, through a
rational correlation with cyclocolorenone by Ourisson and
co-workers.[8e] Later, (–)-3 was isolated in 1973 from Lan-
Figure 1. Selected members of aromadendranes.
sium Anamalayanum,[8f] then in 1978 from Helichrysum spe-
cies,[8g] and finally in 1987 from Balsamum Tolutanum.[8h]
As for all most-abundant aromadendrenes, the enantio-
meric form (ent-aromadendrene) (+)-gurjunene [(+)-3] was
isolated in 1978 from Porella species.[8i] Only a few ap-
proaches of this intriguing family of compounds have been
reported. One of them uses the photochemical rearrange-
ment outlined by Barton,[9] and another one is based on
the thermolysis of an allylidenecyclopropane.[10] Nicholas
and co-workers more recently applied their cyclopentannul-
ation reaction to this class of compounds and synthesized
(Ϯ)-cyclocolorenone (2) over 10 steps in 8.9% overall yield
from tropone.[11] On our side, we developed an efficient
strategy for the construction of hydroazulenone 6 (key in-
termediate) through a highly selective [2+2] cycloaddition
of dichloroketene followed by a regioselective ring expan-
sion with diazomethane and HCl elimination.[12a] This op-
ens access to different natural sesquiterpenes[12] (Scheme 1).
[a] Department de Chimie Moléculaire (SERCO)UMR-5250,
ICMG FR-2607, CNRS, Bât. C,
301 rue de la Chimie, B. P. 53, 38041 Grenoble CEDEX 9,
France
Fax: +33-4-76514982
E-mail: Jean-Pierre.Depres@ujf-grenoble.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900253.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3134–3137

Total Synthesis of (Ϯ)-Cyclocolorenone and (Ϯ)-α-Gurjunene
Attempts to epimerize 6 to 7 with KOH/MeOH[13] led to
a complex mixture of products and partial degradation.
The best yield of isolated 7 (48%) was obtained (Table 1,
Entry 1) in a 1:1 mixture of toluene/ethanol at 100 °C in
the presence of RhCl3(H2O)n catalyst[14] (70% yield con-
sidering the recovery and recycling of unreacted 6). Under
these conditions, only trace amounts of C-8,9 double-bond
migration product 11 were observed, whereas 11 was the
major product (55%) in a 5:1 mixture of toluene/ethanol
(Table 1, Entry 4).
Scheme 1. Synthesis of key intermediate 6 (three steps with 50%
overall yield from the tropylium cation, ref.[12c,12d]).
Results and Discussion
Table 1. Epimerization at the C-1 position of β-trienone 6 and mi-
Herein, we propose a new total synthesis of (Ϯ)-cycloco-
lorenone [(+/–)-2] and the first total synthesis of (Ϯ)-gurju-
nene [(+/–)-3] via [(+/–)-2]. Our approach realizes an ef-
ficient, versatile, and stereocontrolled access to the aromad-
endrane family. Our retrosynthetic analysis of cyclocolo-
renone [(+/–)-2] begins with epimerization at the C-1 posi-
tion of key intermediate 6 (Scheme 2, pathway 1). Molecu-
lar models suggested that the relative configuration of C-1
controls that of C-7 upon conjugate addition. Indeed, en-
ergy minimizations on β-trienone 6 revealed partial decon-
jugation of the last double bond at C-8,9 as a consequence
of a dihedral angle of 15° of the latter double bond with
that at C-6,7.[12a] Similarly, a dihedral angle of 12° was cal-
culated for C-6,7,8,9 of 7. Selective hydrogenation of 7 was
thus expected to occur at C-8,9, and conjugate additions
preferentially at C-7. Two retrosynthetic pathways, ex-
ploiting these chemical features, were envisaged to synthe-
size (Ϯ)-cyclocolorenone [(+/–)-2] (Scheme 2).
gration of the C-8,9 double bond.
Entry
Toluene/alcohol β-Trienone 6 α-Trienone 7
Trienone 11
[%][a]
[%][a]
[%][a]
1
2
3
4
5
6
7
1:1 (EtOH)
0:1 (EtOH)
3:1 (EtOH)
5:1 (EtOH)
10:1 (EtOH)
1:1 (MeOH)
4:1 (MeOH)
40
60
30
17
33
50
60
60
40
40
28
33
50
40
Traces[b]
0
30
55
34
0
0
[a] Determined by NMR spectroscopy. [b] Ͻ5%.
Our next goal was to introduce the gem-dimethylcyclo-
propane at the C-6,7 positions. Simmons-Smith[15a,15b] cy-
clopropanation, including also that of Furukawa,[15c] and
reaction with 2-diazopropane[15d] applied to substrate 6 did
not give the desired tricyclic skeleton. Our attention was
turned then to a Michael addition/intramolecular substitu-
tion sequence of the sulfur ylide. Applying the conditions
outlined by Corey[16] (LDA, CH2Cl2/DME, –78Ǟ–50 °C)
to 7 led only to products of degradation. We reasoned that
this failure was due to the ability of 7 to be readily enolized.
By screening[17] various bases, solvents, temperature condi-
tions, and Lewis acids,[18] we found that NaHMDS in THF
at –110 °C in the presence of Sc(OTf)3 gave the best results.
The desired cyclopropane product 8 was isolated in 40%
yield. No regio- or stereoisomers could be detected by
NMR spectroscopic analysis of the crude reaction mix-
ture.[19] Quantitative hydrogenation with 10% Pd/C fol-
lowed by Suzuki–Miyaura coupling afforded natural (Ϯ)-
cyclocolorenone [(+/–)-2] in 71% yield (Scheme 3).
In parallel, we examined the second retrosynthetic path-
way of Scheme 2. Assuming that partial deconjugation in
trienone 6 would make its catalytic hydrogenation at C-8,9
selective, we explored various reaction conditions (Table 2).
The best results in terms of yield and reproducibility
were obtained with 5% Pd/Al2O3 as catalyst, with ethyl ace-
tate as solvent, and by controlling the amount of H2 (sy-
ringe addition) as a function of the reaction progress (1H
NMR spectroscopy). We thus obtained 3:1 to 4:1 mixtures
Scheme 2. Retrosynthetic analysis.
Eur. J. Org. Chem. 2009, 3134–3137
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3135

M. Calancea, S. Carret, J.-P. Deprés
SHORT COMMUNICATION
Scheme 3. Synthesis of (Ϯ)-cyclocolorenone [(+/–)-2] by pathway 1.
Reagents and conditions: (a) A (1.5 equiv.), NaHMDS
(1.65 equiv.), Sc(OTf)3 (cat), THF, –78Ǟ10 °C, 40%; (b) H2, 10%
Pd/C, EtOAc, quantitative; (c) MeB(OH)2 (3 equiv.), Pd(OAc)2
(0.2 equiv.), dpdb (0.4 equiv.), K3PO4 (2 equiv.), toluene, 100 °C,
24 h, 71%. HMDS = 1,1,1,3,3,3-hexamethydisilylazide, dpdb = di-
cyclohexylphosphanyl-2Ј,6Ј-dimethoxybiphenyl.
Scheme 4. Synthesis of (Ϯ)-cyclocolorenone [(+/–)-2] by pathway 2
and its conversion into (Ϯ)-α-gurjunene [(+/–)-3]. Reagents and
conditions: (a) 5% Pd/Al2O3 (cat.), H2 (1.0–1.5 equiv.), EtOAc, 65–
75%; (b) A (2 equiv.) NaHMDS (2 equiv.), Sc(OTf)3 (cat), THF,
–110Ǟ10 °C, 65%; (c) MeB(OH)2 (3 equiv.), Pd(OAc)2 (0.2 equiv.),
dpdb (0.4 equiv.), K3PO4 (2 equiv.), toluene, 100 °C, 20 h, 75%;
(d) AlCl3 (27 equiv.) LiAlH4 (6 equiv.), THF, –20 °C, 90%. HMDS
Table 2. Selective hydrogenation of the C-8,9 double bond in β-
trienone 6.[20]
=
1,1,1,3,3,3-hexamethydisilylazide, dpdb = dicyclohexylphos-
phanyl-2Ј,6Ј-dimethoxybiphenyl.
Conclusions
Entry Hydrogenation conditions
12[a]
13[a]
1
2
3
4
5
6
7
8
H2, 5% Pd/BaSO4, EtOAc
0
2–5
3–4
3
1
2
1
1
1
2
1
1
1
1
In conclusion, we have developed a highly efficient total
synthesis of (Ϯ)-cyclocolorenone [(+/–)-2] that requires only
seven steps (10.8–12.5% overall yield) from the tropylium
cation. The method exploited the rapid regio- and stereose-
lective construction of the aromadendrane core that relies
upon stereocontrol at the C-1 position of α-trienone 7. (Ϯ)-
α-Gurjunene [(Ϯ)-3] was obtained through the efficient de-
oxygenation of aromadendrane [(Ϯ)-2], constituting there-
fore the first total synthesis of this natural product in eight
steps and with 9.7–11.3% overall yield from the tropylium
cation. Complementary studies are undergoing in our
group to generalize this strategy to other members of this
family of natural compounds. More particularly, we plan to
open a route to (Ϯ)-1(10)-4(5)-aromadendradiene[8h,24] (4)
and (Ϯ)-aromadendra-1(10),4-dien-15-al-3-one[25] (5) (Fig-
ure 1) thanks to the formation of product 11 from 6
through migration of the C-8,9 double bond to the C-1,10
positions (Table 1).
H2, Pd/CaCO3 (5% Pb), EtOAc[20a]
H2, 5% Pd/Al2O3, EtOAc[20b]
[20c]
Et3SiH, TFA, 50 °C, CH2Cl2
TsNHNH2, NaOAc, ∆, DME/H2O[20d]
H2, (Ph3P)3RhCl, toluene[20e,20f]
Et3SiH, (Ph3P)3RhCl, 50 °C, toluene[20g]
Na2S2O4, Adogen464, NaHCO3, C6H6/H2O[20h]
1
0
[a] Ratio 12/13 determined by NMR spectroscopy.
of 12/13 (Table 2, Entry 3). These latter compounds were
readily separated by column chromatography on silica gel.
Dienone 12 was isolated in 65–75% yield and contained
trace amounts of isomerized trienone 11.[21]
α-Dienone 9 was then engaged in the cyclopropanation
reaction by using the optimized conditions, and we were
pleased to obtain tricyclic compound 10 in 65% yield (95%
conversion and complete regio- and stereoselectivity). This
higher conversion relative to that obtained for the conver-
sion of 7 into 8 (Scheme 3) can be attributed to the slight
difference in pKa values corresponding to the side reaction
of enolization. Finally, methylation of 10 by applying the
Suzuki–Miyaura cross-coupling reaction provided the tar-
get (Ϯ)-cyclocolorenone [(+/–)-2] (m.p. 40 °C).[22] The
NMR spectroscopic data of (Ϯ)-2 were identical to those
reported in the literature[9a] for the natural product. A final
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for 2, 3,
1
7–11; copies of the H and 13C NMR spectra for 2, 3, 7–11.
Acknowledgments
This work was supported by the University Joseph Fourier and the
CNRS (UMR-5250, ICMG FR-2607) for a fellowship award to
M. C. We thank Prof. Pierre Vogel for his assistance with the manu-
script and for his interest in this research and Dr. Andrew E.
Greene for his interest in our work.
[23]
one-step deoxygenation of (Ϯ)-2 with LiAlH4/AlCl3 per-
mitted the isolation of (Ϯ)-α-gurjunene [(+/–)-3] in 90%
yield (Scheme 4). The structure of (Ϯ)-3 was deduced from
its IR, NMR and LRMS data and was confirmed by show-
ing identical physical constants and spectra to those of (–)-
α-gurjunene [(–)-3] isolated (by distillation) from Diptero-
carpus Dyeri (gurjun balsam resin)[8c] and later from dif-
ferent species.[8f,8g,8h]
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Total Synthesis of (Ϯ)-Cyclocolorenone and (Ϯ)-α-Gurjunene
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Received: March 9, 2009
Published Online: May 14, 2009
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