Improved enantioselective synthesis of (?)-linderol A: Hindered rotation about aryl?Csp3 bond

Article abstract of DOI:10.1021/jo902567y

An improved enantioselective total synthesis of (?)-linderol A has been achieved via a five-step reaction with a 21% overall yield, starting from phloroacetophenone and (?)-α-phellandrene, two commercially available reagents. In the diastereoselective epoxidation step, the analysis of the two endocyclic epoxide intermediates reveals a hindered sp²?sp ³ rotation, which results in rotational diastereoisomers.

Full text of DOI:10.1021/jo902567y

pubs.acs.org/joc
Improved Enantioselective Synthesis of (-)-Linderol A: Hindered
Rotation about Aryl-Csp3 Bond
Pierre-Olivier Delaye,† Pedro Lameiras,‡ Nelly Kervarec,§ Catherine Mirand,† and
Hatice Berber*,†
†
ꢀ ꢀ
Institut de Chimie Moleculaire de Reims, CNRS UMR 6229, Universite de Reims Champagne-Ardenne,
Faculteꢀde Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims Cedex, France, ‡Institut de Chimie Moleꢀculaire
^
de Reims, CNRS UMR 6229, Moulin de la Housse, Batiment 18, BP 1039, F-51687 Reims Cedex 2, France,
and §Service Commun de RMN-RPE, 6 avenue Victor-Le-Gorgeu, CS 93837, F-29238 Cedex 3, France
hatice.berber@univ-reims.fr
Received December 4, 2009
An improved enantioselective total synthesis of (-)-linderol A has been achieved via a five-step reaction
with a 21% overall yield, starting from phloroacetophenone and (-)-R-phellandrene, two commercially
available reagents. In the diastereoselective epoxidation step, the analysis of the two endocyclic epoxide
intermediates reveals a hindered sp2-sp3 rotation, which results in rotational diastereoisomers.
Introduction
(-)-Linderol A [(-)-1, Figure 1], a monoterpene-substi-
tuted chalcone with four asymmetric carbons at the 6 (R), 5a
(R), 9a (S), and 9 (R) positions, was isolated in 1995 from the
fresh bark of Lindera umbellata (Lauraceae) by Sashida and
co-workers.1 They also reported the potent inhibitory activ-
ity of this natural product on the melanin biosynthesis of
B-16 melanoma cells without causing any cytotoxicity on the
cultured cells.1
Ohta and co-workers were first interested in the total
synthesis of 1 because of structural and biological aspects.
The first-2 and second-generation3 syntheses of (()-1 have
been previously reported by this group (Scheme 1). In the
first-generation synthesis, the critical step of their strategy
was a tandem reaction of the 3-ethoxycarbonylcoumarin
derivative 2 with dimethylsulfoxonium methylide to give the
2-ethoxycarbonylcyclopenta[b]benzofuran-3-ol derivative 3.
The key step of the second-generation synthesis involved a
FIGURE 1. Structure of (-)-linderol A [(-)-1].
stereoconvergent approach to tetrahydrodibenzofuran deriva-
tive 5 from benzo[b]cyclobuta[d]pyran derivative 4 (Scheme 1).
The first synthesis of (-)-1 and (þ)-1 was achieved via optical
resolution of an acetylated intermediate of the total synthesis of
(()-1 (Scheme 1).4 Ohta and co-workers have moreover deter-
mined the absolute configuration of (-)-1, which had not been
previously reported by Sashida and co-workers1 (Figure 1).
Recently, this group has achieved an asymmetric total synthesis
of (-)-1 in 13 steps with 23% overall yield from 5,7-dimethoxy-
coumarin-3-carboxylic acid using the second-generation strat-
egy.5 The two key reactions consist in a diastereoselective [2 þ 2]
(1) Mimaki, Y.; Kameyama, A.; Sashida, Y.; Miyata, Y.; Fujii, A. Chem.
Pharm. Bull. 1995, 43, 893–895.
(2) (a) Yamashita, M.; Ohta, N.; Kawasaki, I.; Ohta, S. Org. Lett. 2001, 3,
1359–1362. (b) Yamashita, M.; Ohta, N.; Shimizu, T.; Matsumoto, K.;
Matuura, Y.; Kawasaki, I.; Tanaka, T.; Maezaki, N.; Ohta, S. J. Org. Chem.
2003, 68, 1216–1224.
(3) (a) Yamashita, M.; Inaba, T.; Shimizu, T.; Kawasaki, I.; Ohta, S.
Synlett 2004, 1897–1900. (b) Yamashita, M.; Inaba, T.; Nagahama, M.;
Shimizu, T.; Kosaka, S.; Kawasaki, I.; Ohta, S. Org. Biomol. Chem. 2005, 3,
2296–2304. (c) Yamashita, M.; Shimizu, T.; Inaba, T.; Takada, A.; Takao, I.;
Kawasaki, I.; Ohta, S. Heterocycles 2005, 65, 1099–109.
(4) Yamashita, M.; Shimizu, T.; Kawasaki, I.; Ohta, S. Tetrahedron:
Asymmetry 2004, 15, 2315–2317.
(5) Yamashita, M.; Yadav, N. D.; Sawaki, T.; Takao, I.; Kawasaki, I.;
Sugimoto, Y.; Miyatake, A.; Murai, K.; Takahara, A.; Kurume, A.; Ohta, S.
J. Org. Chem. 2007, 72, 5697–5703.
DOI: 10.1021/jo902567y
r
Published on Web 03/24/2010
J. Org. Chem. 2010, 75, 2501–2509 2501
2010 American Chemical Society

Delaye et al.
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SCHEME 1
SCHEME 2
photocycloaddition of a coumarin-3-carboxylate bearing a
chiral auxiliary with 3-methyl-1-butene and a subsequent
stereoconvergent transformation of the photoadducts with
the use of dimethylsulfoxonium methylide to afford a tetra-
hydrodibenzofuran derivative.
to increase the diastereoselectivity seeing that the epoxide
10a is the key reagent in the next stereospecific ring closure
step; furthermore the structure of the nonproductive epoxide
100a was not clearly identified because it was never isolated
before.
In parallel, we have reported an efficient short enantiose-
lective total synthesis of (-)-1 via a five-step reaction with a
30% overall yield, starting from 2,6-dihydroxy-4-methoxya-
cetophenone 7 and (-)-R-phellandrene (Scheme 2).6
Herein, we present an improved synthesis of (-)-linderol
A after a detailed study of the asymmetric epoxidation.
Results and Discussion
Two key reactions have been used, terpenylation7 and a
stereospecific intramolecular epoxide opening with a pheno-
late anion.8 However, our synthesis presents two shortcom-
ings that are the preparation of the starting reagent 2,6-
dihydroxy-4-methoxyacetophenone 7 obtained with poor
yields (20%) from the commercially available phloroaceto-
phenone9 and the low diastereoselectivity of the epoxidation.
Indeed, we have reported the formation of a mixture of two
supposed diastereomeric epoxides 10a and 100a favoring the
desired 10a in a ratio of 72:28 (evaluated by 1H NMR
spectrum). This reaction requires extensive study in order
We started our study by reproducing epoxidation of the
diacetate compound 9a with m-chloroperoxybenzoic acid.
Therefore, the mixture of the two epoxides 10a and 100a
was obtained in good yield (Scheme 3). The separation of
these two supposed diastereoisomers was attempted by
thin-layer chromatography (TLC) and then by column
chromatography on silica gel with different solvents. Un-
fortunately, all our attempts failed (only one spot appeared
in TLC plates).
We then decided to carry out epoxidation of the alkene by
varying the protecting groups in order to check on the
possibility to obtain the mixture of the two epoxides (and
the ratio variation). The dibenzoate product 9b was prepared
in good yield (82%) from 8 by the same procedure as for
acetylation. Surprisingly, epoxidation of 9b gave a mixture of
the two isomers 10b and 100b with a lower selectivity (60:40).
(6) Berber, H.; Delaye, P.-O.; Mirand, C. Synlett 2008, 94–96.
(7) Crombie, L.; Crombie, W. M. L.; Firth, D. F. J. Chem. Soc., Perkin
Trans. 1 1988, 1251–1253.
(8) Uliss, D. B.; Razdan, R. K.; Dalzell, H. C. J. Am. Chem. Soc. 1974, 96,
7372–7374.
(9) Huang, C.; Da, S.; Li, Y.; Li, Y. J. Nat. Prod. 1997, 60, 277–278.
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SCHEME 3
TABLE 1. 1H NMR Data of the Mixtures of Endocyclic Epoxides 10
and 100
C2-H
C3-H
10a and 100a
10b and 100b
10c and 100c
2.80 (s)
2.91 (s)
2.91 (s)
2.91 (s)
2.78 (s)
2.90 (s)
3.06 (d, J = 10.7 Hz)
3.60 (d, J = 10.7 Hz)
3.13 (d, J = 10.6 Hz)
3.67 (d, J = 11.6 Hz)
3.01 (d, J = 10.6 Hz)
3.53 (d, J = 10.9 Hz)
FIGURE 2. Possible structure of rotameric epoxides 10 and 100.
bond rotation about the sp2-sp2 C-C bond is sufficiently
restricted so as to lead to separable conformers.11 Rotation
about the single bond between sp2- and sp3-hybridized
carbon atoms can also be hindered by bulky substituents.11
In general, Ar-Csp3 bonds have very low rotation barriers.11
Nevertheless, there are some examples of compounds with
much higher rotation barriers, such as 9-arylfluorenes, in
which case two rotamers may be isolated.12 Such compounds
usually have bulky ortho-substituents on the aromatic ring,13a
or bulky substituents on the benzylic carbon,13b or both. A
recent study of the bond rotation barriers of 2-aryl perhydro-
pyrrolo[3,4-c]pyrrole-1,3-diones where the rigidity of the rings
and their substituents retard the C-Ar rotation was also
reported.13c
To demonstrate the interconversions between 10 and 100,
compounds 10c and 100c (ratio 68:32) were analyzed by
variable-temperature 1H NMR (Figure 3; see the Supporting
Information for all spectra). As the temperature increased,
the rotation of the pendant aryl ring exchanged the diaster-
eomeric aromatic protons, and the signals broadened and
began to coalesce at 370 K with a three-degree uncertainty.
We applied the Gutowsky-Holm equation11a,b to these
signals to obtain a crude estimate of the rate of the Car-C3
bond rotation, and we found kc = 28.9 s-1. In this case of
exchange of the aromatic uncoupled proton between 10c
(major) and 100c (minor), two unequally populated sites, we
With the monoacetate derivative 9c, epoxidation led to
the mixture of the two epoxides 10c and 100c in a ratio
of 68:32.
With the mixtures of these inseparable isomers (10 and
100) in hand, we attempted the next ring-closure step via
epoxide opening in the presence of 2% sodium hydroxide
in methanol-water (1:1). The hexahydrodibenzofuran
derivatives 11a-c were obtained with good yields without
any byproduct (Scheme 3). The transformation of 10 and
100 to 11 involves an intramolecular trans diaxial cleavage
of the epoxide (via a SN2i mechanism) at its less hindered
site, which fixes the stereochemistry of the furan ring at
C5a and C9a as cis.8 If the major diastereoisomers (10a,
10b, and 10c) of the mixtures are considered as the starting
material for ring-opening, the exact yield for 11a and 11c
is over 100% (108%, 143%, and 148%, respectively),
which is not a realistic outcome. Thus, we concluded that
the mixture of the two epoxides cannot be these diaster-
eoisomers.
1
Furthermore, the H NMR spectra of the mixtures for
10 and 100 were instructive: it showed similar signals
for the C2 proton which appeared as a singlet and for
the C3 proton as a doublet with a large coupling constant
(J ≈ 11 Hz) for the two isomers (Table 1). The stereo-
chemistry of this type of endocyclic epoxides has already
been studied;10 it was shown that these two hydrogen
atoms (on C2 and C3) are therefore in a trans relationship,
and it follows that the epoxide ring and the aryl group
are also trans oriented for the two isomers in each case.
Thus, the proposed structure for isomers 100a-c with the
epoxide ring and the aryl moiety in the same face seemed
incorrect.
had to estimate two rate constants (see the Supporting
-1
0
Information for more details), which are k10f10 =19.6 s
0
and k10 f10 = 41.7 s-1. From these data and the Eyring
-1
equation,11a,b we calculated ΔGq
=82.1 ( 1 kJ mol
3
0
10f10
and ΔGq10 f10 =79.8 ( 1 kJ mol-1. At room temperature
0
3
(298 K), the rate constants were estimated to be 0.031 and
0.079 s-1, and therefore, half-lives of 32.3 and 12.7 s were
deduced. Thus, compounds 10c and 100c are too short-lived to
be atropisomers (lower than 1000 s).11 Nevertheless, these are
two relatively long-lived rotamers which should be separable
From these results, we hypothesized that atropisomerism
was possible around the Car-C3 bond (a sp2-sp3 bond) for
these compounds (10,100a-c) (Figure 2). Atropisomerism
is usually associated with biaryl systems, where a single
(12) Ford, W. T.; Thompson, T. B.; Snoble, K. A. J.; Timko, J. M. J. Am.
Chem. Soc. 1975, 97, 95–101.
€
(13) (a) Martin, H. J.; Drescher, M.; Kahlig, H.; Schneider, S.; Mulzer, J.
(10) Mechoulam, R.; Shvo, Y. Tetrahedron 1963, 19, 2073–2078.
(11) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry Of Organic
Compounds; Wiley-Interscience: New York, 1994. (b) Kessler, H. Angew.
Chem., Int. Ed. 1970, 9, 219–235. (c) Wolf, C. Dynamic Stereochemistry of
Chiral Compounds; Royal Society of Chemistry: Cambridge, 2008.
Angew. Chem., Int. Ed. 2001, 40, 3186–3188. (b) Murrison, S.; Glowacki, D.;
Einzinger, C.; Titchmarsh, J.; Bartlett, S.; McKeever-Abbas, B.; Warriner,
S.; Nelson, A. Chem.;Eur. J. 2009, 15, 2185–2189. (c) Damodaran, K.;
Nielsen, S. D.; Geib, S. J.; Zhang, W.; Lu, Y.; Curran, D. P. J. Org. Chem.
2009, 74, 5481–5485.
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FIGURE 4. TLC plates at rt (left) and -10 °C (right) (eluent: 7:3
hexane/EtOAc) for 10,100b (1) and 10,100c (2).
In order to verify this hypothesis, we achieved separation
of 10b,c and 100b,c by TLC (7:3, hexane/EtOAc) at -10 °C
(half-lives of 44.5 and 15.4 min for 10c and 100c, respectively)
by placing the plate in the frozen compartment of a refrig-
erator (Figure 4). Two spots appeared in each case and were
identified as 10 and 100 by UV (at 254 nm) and after staining
with vanillin. As a reference, TLC was performed at room
temperature with the same eluent, and only one spot was
obtained in each case.
To illustrate more explicitly the interconversion, 2D TLCs
were then run on rotamers 10,100c at three different tem-
peratures (Figure 5). At very low temperature (-20 °C), four
spots appeared, in which the two most intense spots (right)
correspond to the major rotamer 10c and the two less intense
spots (left) to the minor rotamer 100c.
These compounds possess four asymmetric centers (C1,
C2, C3 and C4), and a fifth element of chirality (namely an
axis of chirality along the Car-C3 bond) must be present in
order to account for the apparent diastereoisomers seen by
NMR at room temperature and by TLC at very low tem-
perature. This point suggests that 10 and 100 are mixtures of
rotational diastereoisomers (Figure 2).
FIGURE 3. Expansion of the aromatic region of the VT-NMR
spectra of 10,100c in DMSO-d6 at 500 MHz (Δν = 13 Hz).
at low temperature by HPLC. In fact, a baseline separation
of 10c and 100c was attempted by maintaining the tempera-
ture of the HPLC column at 4 °C (eluent: 75/25, hexane/
EtOAc). At this temperature separation failed, and only
one broad peak was obtained on the chromatogram. This
result suggested that the equilibration of the rotamers 10c
and 100c was too fast at 4 °C (half-lives around 6.7 and
2.4 min) to distinguish them. Consequently, according to
our observations and results, the equilibrium should be
slow at a lower temperature.
In order to confirm this conclusion we prepared, accord-
ing to the same synthetic route as for (-)-1, the endocyclic
epoxide 14 with a symmetrical aromatic moiety from phloro-
glucinol in three steps (Scheme 4). As expected, epoxide 14
was isolated as a single isomer. Furthermore, in compound
14, the two o-methoxy groups and the two meta protons
1
appeared at different chemical shifts in the H NMR spec-
trum (in DMSO-d6 at 500 MHz). The corresponding signals
also showed different chemical shifts in the 13C NMR
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FIGURE 5. 2D TLC plates at rt (left), 8 °C and -20 °C (right) (eluent: 7:3 hexane/EtOAc) for 10,100c.
SCHEME 4
spectrum (see the Supporting Information). This meant that
the rotation of the aryl ring was slow enough on the NMR
time scale to make the two o-methoxy groups and the two
meta protons diastereotopic. This rotamer (14) was also
studied by VT-NMR (Figure 6; see the Supporting Informa-
tion for all spectra). When rotamer 14 was heated in DMSO-
d6 at 500 MHz, the two doublets with a small meta coupling
(2.1 Hz) for the diastereotopic aromatic protons broadened
and coalesced at about 368 K (with an uncertainty of 5°) and
emerged at higher temperature as one sharp singlet. The rate
constant kc for these meta coupling protons was about 30 s-1
calculated by application of an alternative equation to the
Gutowsky-Holm equation11a,b (see the Supporting Infor-
mation for more details) and ΔGq = 80.4 ( 1.3 kJ mol-1
.
3
For the o-methoxy protons, the coalescence was observed at
358 K ((5°) and we found kc = 16.2 s-1. The value found for
ΔGq (79.9 ( 1.3 kJ mol-1) is in good agreement with those
obtained from the meta protons.
3
FIGURE 6. Expansion of the aromatic and the methoxy regions
of the VT-NMR spectra of 14 in DMSO-d6 at 500 MHz (Δν = 12.5
and 7.3 Hz, respectively).
Finally, we also observed this interesting phenomenon
with alkenes 9a-c (Scheme 3) where rotation at the Car-C3
bond is restricted but with lower rotation barriers than for
1
epoxides 10 and 100. Indeed, in H NMR spectra, a very
spectra of 9a-c (see the Supporting Information for NMR
spectra). These dynamic effects were assigned to a restricted
sp2-sp3 rotation with a coalescence temperature between 15
and 25 °C.11b,13a,13c Variable-temperature (VT) NMR stu-
dies were already reported for this type of compounds.13a,c
broad signal for the benzylic proton (3-H) and a slightly less-
broad signal for the neighboring alkene proton (2-H) were
found in compounds 9a-c. In addition, the corresponding
signals (C2 and C3) appeared with difficulty in the 13C NMR
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SCHEME 5
As a conclusion, the high rotation barriers (around
80 kJ mol-1) for rotamers 10, 100c, and 14 could therefore
which terpenylation required a stoichiometric quantity of
TsOH. The monoterpenylated derivative 15 was regioselec-
tively converted into its dimethyl ether 16 in good yield in the
presence of dimethyl sulfate and K2CO3. Then the dimethyl
ether 16 was allowed to react with m-chloroperoxybenzoic
acid generating a mixture of two rotameric epoxides (17 and
170) which were directly opened (without purification by
column chromatography) by phenolate anion under basic
conditions leading to the desired hexahydrodibenzofuran
derivative 11c in very good yield (87% for two steps). The
selective demethylation of the methoxy group by treatment
with BBr3 afforded the phenol 11a in 63% yield. Finally the
chalcone chain was introduced by aldol condensation in the
presence of benzaldehyde under alkaline conditions giving
(-)-linderol A with good yield (64%).
3
be explained by the rigidity of the endocyclic epoxide and the
presence of the ortho-substituents on the aromatic ring.
Epoxidation is accordingly completely diastereoselective
in term of asymmetric centers. In view of this, we wish to
revise the reported6 “mixture of the two diastereomeric
epoxides” which turned out to be a mixture of two rotational
diastereoisomers.
The last point that required improvement is the prepara-
tion of the starting reagent 2,6-dihydroxy-4-methoxyaceto-
phenone 7 which was obtained with a poor yield (∼20%) by
para-methylation of the commercially available phloroace-
tophenone, due to the low regioselectivity of the reaction.9
Considering this fact the overall yield of our described
synthesis was only 6% over six steps. After several attempts
to optimize the reaction yield, we decided to recast the
synthesis by slightly modifying our approach (Scheme 5).
In the first key step, the terpenylation was directly con-
ducted with phloroacetophenone, an easily available com-
mercial reagent (instead of 7). The obtained monoter-
penylated derivative 15 was regioselectively dimethylated
(step ii). Then, the asymmetric epoxidation of the dimethyl
ether 16 was followed by stereospecific intramolecular ep-
oxide ring-opening with the phenolate anion to give the
hexahydrodibenzofuran ring 11c (step iii). Finally, the acet-
yl-adjacent methyl ether was regioselectively cleaved, the
subsequent introduction of the chalcone chain led to the
target natural product (-)-1 (steps iv and v). We planned an
improved synthesis of (-)-1 according to this route
(Scheme 5).
Conclusion
We have accomplished a concise and improved enantio-
selective total synthesis of (-)-linderol A after only five steps
and from cheap commercial reagents in 21% overall yield.
We have also shown that in the epoxidation step, the reaction
is diastereoselective and allows to obtain a mixture of two
rotameric diastereoisomers.
Experimental Section
2-Acetyl-4-((1R,6R)-6-isopropyl-3-methylcyclohex-2-enyl)-5-
methoxy-1,3-phenylene Diacetate (9a). Ac2O (3 mL) was added
to a solution of 8 (180 mg, 0.57 mmol) in pyridine (2 mL) at rt
under a N2 atmosphere, and the whole was stirred at 70 °C
overnight. The reaction mixture was evaporated under reduced
pressure, and then the residue was purified by silica gel column
Terpenylation of the phloroacetophenone using (-)-R-
phellandrene in the presence of a catalytic amount of TsOH
(0.2 equiv) gave the monoterpenylated compound 15 in 71%
yield. Surprisingly, phloroacetophenone was more reactive
than its corresponding para-methylated derivative 7 for
chromatography (8:2 petroleum ether/EtOAc) to give 9a (210
1
mg, 91%) as a colorless oil: [R]23 þ14 (c 0.44, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 6.56 (s, 1H), 5.09 (s, 1H), 3.80 (m,
4H), 2.40 (s, 3H), 2.31 (s, 3H), 2.12 (s, 3H), 2.03 (m, 2H), 1.90 (m,
1H), 1.78 (dt, J = 12.9 Hz, J = 2.3 Hz, 1H), 1.63 (s, 3H), 1.36 (m,
2506 J. Org. Chem. Vol. 75, No. 8, 2010

Delaye et al.
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2H), 0.86 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 198.4 (C), 169.2 (C), 168.5 (C), 160.1
(C), 147.4 (C), 147.1 (C), 132.9 (C), 124.9 (CH), 124.3 (C), 121.1
(C), 102.6 (CH), 55.9 (CH3), 42.5 (CH), 36.0 (CH), 30.8 (CH3),
30.6 (CH2), 28.0 (CH), 23.4 (CH3), 22.3 (CH2), 21.5 (CH3), 21.1
(CH3), 20.8 (CH3), 15.9 (CH3); MS (EI) m/z (rel intensity) 402
(Mþ, 0.1), 359 (52), 317 (99), 290 (22), 248 (100), 233 (30);
HRMS (EI) m/z calcd for C23H30O6 402.2042, found 402.2041.
2-Acetyl-4-((1R,6R)-6-isopropyl-3-methylcyclohex-2-enyl)-5-
methoxy-1,3-phenylene Dibenzoate (9b). BzCl (0.12 mL, 1 mmol)
was added to a solution of 8 (123 mg, 0.4 mmol) in pyridine
(2 mL) at rt under a N2 atmosphere, and the whole was stirred at
70 °C overnight. The reaction mixture was evaporated under
reduced pressure, and then the residue was purified by silica
gel column chromatography (98:2 CH2Cl2/ EtOAc) to give 9b
(170 mg, 82%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
8.25-8.06 (m, 4H), 7.87-7.42 (m, 6H), 6.72 (s, 1H), 5.12 (s, 1H),
3.96 (br s, 1H), 3.84 (s, 3H), 2.40 (s, 3H), 2.00-1.00 (m, 9H), 0.89
(d, J = 6.9Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H);13C NMR (75MHz,
CDCl3) δ 198.3 (C), 165.0 (C), 164.5 (C), 160.2 (C), 147.7 (C),
147.3 (C), 134.5 (CH), 134.0 (CH), 133.5 (CH), 133.4 (C), 130.5
(CH), 130.3 (CH), 130.26 (CH), 129.0 (2C), 128.9 (CH), 128.8
(CH), 128.3 (CH), 125.7 (C), 124.8 (C), 124.5 (CH), 102.9 (CH),
56.0 (CH3), 43.1 (CH), 36.2 (CH), 31.1 (CH3), 30.3 (CH2), 28.1
(CH), 23.1 (CH3), 22.3 (CH2), 21.7 (CH3), 16.0 (CH3); MS (EI)
m/z (rel intensity) 526 (Mþ, 0.3), 422 (99), 421 (100), 379 (98), 351
(90), 122 (64), 106 (66), 105 (100); HRMS (EI) m/z calcd for
C33H34O6 526.2355, found 526.2337.
(CH), 23.0 (CH3), 22.8 (CH3), 21.6 (CH3), 21.4 (CH3), 21.3
(CH3), 21.1 (CH3), 21.08 (CH3), 20.8 (CH3), 17.9 (CH2), 17.4
(CH2), 15.8 (CH3), 15.7 (CH3); MS (EI) m/z (rel intensity) 418
(Mþ, 0.06), 204 (49), 149 (66), 113 (100); HRMS (EI) m/z calcd
for C23H30O7 418.1992, found 418.1964.
2-Acetyl-4-((1S,2S,3R,6R)-3-isopropyl-6-methyl-7-oxabicyclo-
[4.1.0]heptan-2-yl)-5-methoxy-1,3-phenylene Dibenzoate (10,100b):
55%, dr 60/40; TLC (7:3 hexane/EtOAc) at rt Rf 0.36, at -10 °C
Rf 0.40 and 0.31; 1H NMR (300 MHz, CDCl3) δ8.18(m, 4H), 7.67
(m, 2H), 7.52 (m, 4H), 6.79 (s, 0.6H), 6.73 (s, 0.4H), 3.90 (s, 1.8H),
3.88 (s, 1.2H), 3.67 (d, J = 11.6 Hz, 0.4H), 3.13 (d, J = 10.6 Hz,
0.6H), 2.91 (s, 1H), 2.41 (s, 1.8H), 2.39 (s, 1.2H), 2.04-0.69 (m,
13.2H), 0.60 (d, J = 6.8 Hz, 1.8H); 13C NMR (75 MHz, CDCl3) δ
198.2 (C), 198.1 (C), 165.2 (C), 164.7 (C), 164.5 (C), 164.4 (C),
160.0 (C), 159.6 (C), 148.1 (C), 147.9 (C), 147.6 (C), 147.2 (C),
134.1 (2CH), 134.0 (2CH), 130.4 (4CH), 130.3 (4CH), 129.1 (2C),
128.84 (2CH), 128.8 (2CH), 128.7 (2CH), 128.66 (2CH), 128.5
(2C), 123.6 (C), 123.5 (C), 121.3 (C), 121.1 (C), 104.1 (CH), 102.9
(CH), 64.25 (CH), 64.22 (CH), 58.7 (C), 58.6 (C), 56.1 (CH3), 56.0
(CH3), 43.0 (CH), 41.9 (CH), 36.4 (CH), 35.5 (CH), 31.2 (CH3),
31.1 (CH3), 30.3 (CH2), 29.7 (CH2), 28.1 (CH), 22.9 (CH3), 22.5
(CH3), 21.6 (CH3), 21.5 (CH3), 18.0 (CH2), 17.4 (CH2), 16.2
(CH3), 15.8 (CH3); MS (EI) m/z (rel intensity) 542 (Mþ, 1), 350
(66), 315 (36), 105 (100); HRMS (EI) m/z calcd for C33H34O7
542.2305, found 542.2297.
2-Acetyl-6-((1S,2S,3R,6R)-3-isopropyl-6-methyl-7-oxabicyclo-
[4.1.0]heptan-2-yl)-3,5-dimethoxyphenyl Acetate (10,100c): 97%,
dr 68/32; TLC (7:3 hexane/EtOAc) at rtRf 0.22, at -10 °C Rf 0.25
and 0.16; 1H NMR (300 MHz, CDCl3) δ 6.39 (s, 0.67H), 6.37 (s,
0.33H), 3.90 (s, 0.99H), 3.89 (s, 2.01H), 3.88 (s, 2.01H), 3.87 (s,
0.99H), 3.53 (d, J = 10.9 Hz, 0.33H), 3.01 (d, J = 10.6 Hz,
0.67H), 2.90 (s, 0.33H), 2.78 (s, 0.67H), 2.48 (s, 2.01H), 2.47 (s,
0.99H), 2.26 (s, 3H), 2.17-1.95 (m, 1H), 1.80-1.10 (m, 7H),
1.01-0.80 (m, 1H), 0.74 (d, J = 6.8 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 200.6 (C), 200.3 (C), 169.4 (C), 169.1 (C), 160.6 (C),
160.2 (C), 157.9 (C), 157.6 (C), 147.8 (C), 147.2 (C), 117.5 (C),
117.3 (C), 116.3 (C), 116.1 (C), 93.2 (CH), 92.1 (CH), 64.7 (CH),
64.6 (CH), 58.6 (C), 58.4 (C), 55.7 (CH3), 55.6 (CH3), 42.9 (CH),
42.1 (CH), 35.7 (CH), 34.7 (CH), 31.7 (CH3), 31.6 (CH3), 30.8
(CH2), 30.3 (CH2), 27.8 (CH), 27.78 (CH), 23.0 (CH3), 22.8
(CH3), 21.5 (CH3), 21.3 (CH3), 20.9 (CH3), 20.8 (CH3), 17.9
(CH2), 17.4 (CH2), 15.8 (CH3), 15.7 (CH3); MS (EI) m/z (rel
intensity) 390 (Mþ, 12), 209 (47), 156 (89), 139 (100), 111 (44);
HRMS (EI) m/z calcd for C22H30O6 390.2042, found 390.1986.
General Procedure for the Synthesis of 11a and 11c. The
mixture of rotameric epoxides 10,100a-c was treated at rt with
2% NaOH solution in MeOH/H2O (1:1). The solution was
stirred at rt for 2 h and then neutralized with 10% HCl. The
mixture was extracted with CH2Cl2, and the organic layer was
washed with water and dried over MgSO4. The solvent was then
removed under reduced pressure, and the residue was purified
by silica gel column chromatography to give 11a (from 10,100a,
b) or 11c (from 10,100c).
2-Acetyl-6-((1R,6R)-6-isopropyl-3-methylcyclohex-2-enyl)-3,5-
dimethoxyphenyl Acetate (9c). Ac2O (0.75 mL) was added to a
solution of 16 (43 mg, 0.13 mmol) in pyridine (0.5 mL) at rt under
a N2 atmosphere, and the whole was stirred at 90 °C overnight.
The reaction mixture was evaporated under reduced pressure,
and then the residue was purified by silica gel column chroma-
tography (9:1 petroleum ether/EtOAc) to give 9c (46 mg, 94%) as
1
a colorless oil: H NMR (500 MHz, DMSO-d6) δ 6.66 (s, 1H),
4.93 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.72 (br s, 1H), 2.32 (s, 3H),
2.12-1.63 (m, 7H),1.59 (s, 3H), 1.32 (m, 1H), 1.23 (dq, J =
12.4 Hz, J = 5.2 Hz, 1H), 0.79 (d, J = 7.0 Hz, 3H), 0.75 (d, J =
6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 199.3 (C), 169.0
(C), 160.6 (C), 157.1 (C), 147.1 (C), 132.1 (C), 125.5 (CH), 117.6
(C), 117.0 (C), 94.0 (CH), 56.4 (CH3), 56.3 (CH3), 42.4 (CH), 35.4
(CH), 31.7 (CH3), 30.3 (CH2), 27.9 (CH), 23.5 (CH3), 22.4 (CH2),
21.6 (CH3), 20.8 (CH3), 16.2 (CH3); MS (EI) m/z (rel intensity)
374 (Mþ, 2), 331 (76), 262 (100); HRMS (EI) m/z calcd for
C22H30O5 374.2093, found 374.2051.
General Procedure for the Synthesis of Rotameric Epoxides
10,100a-c. m-CPBA (1.2 to 1.5 equiv) was added to a solution of
9a-c in CH2Cl2 at rt under a N2 atmosphere, and the whole was
stirred for 2 h. The reaction mixture was treated with saturated
K2CO3 and extracted with CH2Cl2. The organic layer was
washed, dried, and evaporated. The residue was purified by
silica gel column chromatography to give rotameric epoxides
10,100a-c.
1-((5aR,6R,9R,9aS)-3,6-Dihydroxy-9-isopropyl-1-methoxy-6-
methyl-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-4-yl)ethanone
(11a): 76% from 10,100a and 86% from 10,100b, pale yellow
solid; mp 155-158 °C; [R]22D -84.5 (c 0.83, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 13.18 (s, 1H), 6.02 (s, 1H), 4.16 (dd, J =
5.5 and 1.3 Hz, 1H), 3.81 (s, 3H), 3.11 (dd, J = 11.1 and 5.5 Hz,
1H), 2.60 (s, 3H), 1.95-1.60 (m, 3H), 1.55 (br s, 1H), 1.49 (s,
3H), 1.40 (m, 2H), 1.10 (m, 1H), 0.90 (d, J = 6.9 Hz, 3H), 0.83
(d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 201.8 (C),
165.0 (C), 162.0 (C), 161.8 (C), 113.1 (C), 102.9 (C), 92.5 (CH),
92.3 (CH), 69.3 (C), 55.4 (CH3), 46.5 (CH), 39.6 (CH), 35.2
(CH2), 31.1 (CH3), 28.2 (CH3), 27.1 (CH), 21.7 (CH3), 17.1
(CH2), 15.4 (CH3); IR (KBr) 3442, 2958, 2930, 1619, 1362,
1293, 1208, 1149, 1054 cm-1; MS (EI) m/z (rel intensity) 334
(Mþ, 28), 249 (100), 207 (30); HRMS (EI) m/z calcd for
2-Acetyl-4-((1S,2S,3R,6R)-3-isopropyl-6-methyl-7-oxabicyclo-
[4.1.0]heptan-2-yl)-5-methoxy-1,3-phenylene Diacetate (10,100a):
90%, dr 72/28; 1H NMR (300 MHz, CDCl3) δ 6.62 (s, 0.72H),
6.58 (s, 0.28H), 3.85 (s, 2.16H), 3.84 (s, 0.84H), 3.60 (d, J = 10.7
Hz, 0.28H), 3.06 (d, J = 10.7 Hz, 0.72H), 2.91 (s, 0.28H), 2.80 (s,
0.72H), 2.43 (s, 2.16H), 2.42 (s, 0.84H), 2.33 (s, 0.84H), 2.31 (s,
2.16H), 2.28 (s, 2.16H), 2.26 (s, 0.84H), 2.19-1.99 (m, 1H),
1.82-1.46 (m, 3H), 1.43-1.18 (m, 4H), 0.98-0.68 (m, 7H); 13
C
NMR (75 MHz, CDCl3) δ 198.5 (C), 198.2 (C), 169.1 (C), 168.7
(C), 168.5 (C), 168.3 (C), 159.8 (C), 159.5 (C), 147.8 (C), 147.6
(C), 147.2 (C), 146.8 (C), 123.0 (C), 122.9 (C), 120.4 (C), 120.2
(C), 103.7 (CH), 102.5 (CH), 64.2 (CH), 64.1 (CH), 58.6 (C), 58.3
(C), 55.9 (CH3), 55.8 (CH3), 43.0 (CH), 41.8 (CH), 36.2 (CH),
35.0 (CH), 30.9 (CH3), 30.8 (CH3), 30.2 (CH2), 29.6 (CH2), 27.9
J. Org. Chem. Vol. 75, No. 8, 2010 2507

Delaye et al.
JOCArticle
C19H26O5 334.1780, found 334.1779. Anal. Calcd for C19H26-
O5: C, 68.24; H, 7.84. Found: C, 68.46; H, 7.68.
(CH), 90.2 (CH), 66.1 (CH), 58.7 (C), 55.5 (CH3), 55.3 (CH3), 55.1
(CH3), 42.8 (CH), 34.0 (CH), 30.7 (CH2), 28.0 (CH), 23.1 (CH3),
21.5 (CH3), 17.9 (CH2), 15.9 (CH3); IR (NaCl) 2944, 2840, 1605,
1-((5aR,6R,9R,9aS)-6-Hydroxy-9-isopropyl-1,3-dimethoxy-6-
methyl-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-4-yl)ethanone
1586, 1456, 1418, 1220, 1201, 1187, 1149, 1123, 1106, 1038 cm-1
;
(11c): 99%, pale yellow solid; mp 53-55 °C; [R]22 -72.5 (c
MS (EI) m/z (rel intensity) 320 (Mþ, 51), 302 (32), 300 (30), 259
(77), 181 (100), 168 (92); HRMS (EI) m/z calcd for C19H28O4
320.1988, found 320.1990. Anal. Calcd for C19H28O4: C, 71.22; H,
8.81. Found: C, 70.86; H, 8.58.
D
0.63, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.02 (s, 1H), 4.10
(d, J = 5.3 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.12 (dd, J = 11.1
and 5.3 Hz, 1H), 2.51 (s, 3H), 1.89 (m, 1H), 1.74 (m, 2H), 1.57
(br s, 1H), 1.46 (s, 3H), 1.41 (m, 2H), 1.11 (m, 1H), 0.90 (d, J =
6.9 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 197.7 (C), 160.7 (C), 159.8 (C), 158.3 (C), 114.7 (C),
108.8 (C), 91.7 (CH), 88.5 (CH), 69.5 (C), 56.2 (CH3), 55.3
(CH3), 46.2 (CH), 39.7 (CH), 35.1 (CH2), 32.5 (CH3), 28.1
(CH3), 27.1 (CH), 21.7 (CH3), 17.2 (CH2), 15.4 (CH3); IR (KBr)
3432, 2958, 2920, 2849, 1605, 1459, 1262, 1102 cm-1; MS (EI)
m/z (rel intensity) 348 (Mþ, 38), 263 (68), 222 (50), 221 (100),
205 (36), 149 (36); HRMS (EI) m/z calcd for C20H28O5
348.1937, found 348.1937.
1-(2,4,6-Trihydroxy-3-((1R,6R)-6-isopropyl-3-methylcyclohex-
2-enyl)phenyl)ethanone (15). A solution of 20,40,60-trihydroxyace-
tophenonemonohydrate(500 mg, 2.69 mmol) intoluene/CH3CN
(5 mL/10 mL) was added dropwise to a suspension of (-)-R-
phellandrene (1 mL, 879 mg, 6.45 mmol) and TsOH (110 mg, 0.58
mmol) in dry toluene (23 mL) at rt under a N2 atmosphere. The
whole was stirred for 1 h. After neutralization with saturated
NaHCO3, the mixture was extracted with EtOAc. The combined
extracts were washed, dried, and evaporated. The residue was
chromatographed (96:4 CH2Cl2/ EtOAc) to give 15 (583 mg,
71%) as a pale yellow solid: mp 69-71 °C; [R]23D þ11.6 (c 0.61,
2-((1R,6R)-6-Isopropyl-3-methylcyclohex-2-enyl)benzene-1,3,5-
triol (12). A solution of phloroglucinol dihydrate (250 mg, 1.54
mmol) in CH3CN/benzene (5 mL/5 mL) was added dropwise to a
suspension of (-)-R-phellandrene (0.7 mL, 420 mg, 4.34 mmol)
and dried TsOH (90 mg, 0.47 mmol) in dry benzene under ice
cooling and a N2 atmosphere. The whole was stirred for 2 h. After
neutralization with saturated NaHCO3, the mixture was extracted
with EtOAc. The combined extracts were washed, dried, and
evaporated. The residue was chromatographed (95:5 CH2Cl2/
EtOAc) to give 12 (214 mg, 53%): [R]25D þ35.9 (c 1.31, CHCl3);
1H NMR (300 MHz, CD3OD) δ 5.81 (s, 2H), 5.28 (s, 1H), 3.73 (br
d, J = 9.0 Hz, 1H), 2.20-1.94 (m, 2H), 1.88 (m,1H), 1.75 (m, 1H),
1.68 (s, 3H), 1.56 (m, 1H), 1.32 (m, 1H), 0.82 (m, 6H); 13C NMR
(75 MHz, CD3OD) δ 158.4 (C), 157.2 (C), 135.6 (C), 127.9 (CH),
110.3 (2C), 95.9 (2CH), 44.0 (CH), 36.7 (CH), 31.9 (CH2), 29.2
(CH), 24.0 (CH2), 23.7 (CH3), 22.0 (CH3), 16.8 (CH3); IR (KBr)
3432, 2949, 2930, 2863, 1619, 1456, 1225, 1137 cm-1; MS (EI) m/z
(rel intensity) 262 (Mþ, 46), 192 (87), 177 (100); HRMS (EI) m/z
calcd for C16H22O3 262.1569, found 262.1568.
1
CHCl3); H NMR (300 MHz, CD3OD) δ 5.84 (s, 1H), 5.17 (s,
1H), 3.76 (br d, J = 9.1 Hz, 1H), 2.60 (s, 3H), 2.18-1.90 (m, 3H),
1.71 (m, 1H), 1.62 (s, 3H), 1.50 (m, 1H), 1.30 (m, 1H), 0.82 (d, J =
7.0 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 204.6 (C), 165.5 (C), 164.8 (C), 162.1 (C), 134.3 (C),
127.4 (CH), 110.3 (C), 105.5 (C), 95.2 (CH), 43.0 (CH), 36.4
(CH), 33.0 (CH3), 31.9 (CH2), 29.5 (CH), 24.1 (CH2), 23.7 (CH3),
22.0 (CH3), 16.9 (CH3); IR (KBr) 3413, 2953, 2925, 2863, 1617,
1440, 1362, 1295, 1269, 1246 cm-1; MS (EI) m/z (rel intensity) 304
(Mþ, 23), 234 (35), 219 (100), 181 (24), 153 (25); HRMS (EI) m/z
calcd for C18H24O4 304.1675, found 304.1675. Anal. Calcd for
C18H24O4: C, 71.03; H, 7.95. Found: C, 70.93; H, 7.85.
1-(2-Hydroxy-3-((1R,6R)-6-isopropyl-3-methylcyclohex-2-enyl)-
4,6-dimethoxyphenyl)ethanone (16). A suspension of 15 (619 mg,
2.04 mmol), Me2SO4 (641 mg, 5.09 mmol), and anhydrous
K2CO3 (560 mg, 4.06 mmol) in Me2CO (20 mL) was stirred under
reflux for 4 h. The reaction mixture was filtered and evaporated
under reduced pressure to give a residue that was purified by
column chromatography (98:2 petroleum ether/EtOAc) to yield
2-((1R,6R)-6-Isopropyl-3-methylcyclohex-2-enyl)-1,3,5-tri-
methoxybenzene (13). A suspension of 12 (107 mg, 0.41 mmol),
Me2SO4 (0.15 mL, 206 mg, 1.63 mmol), and anhydrous K2CO3
(198 mg, 1.43 mmol) in Me2CO (5 mL) was stirred under reflux
for 6 h. The reaction mixture was filtered and evaporated under
reduced pressure to give a residue that was purified by silica gel
column chromatography (70:30 petroleum ether/CH2Cl2) to
16 (588 mg, 87%) as a pale yellow solid: mp 76-79 °C; [R]25
D
þ126.1 (c 1.06, CHCl3); 1H NMR (300 MHz, CDCl3) δ 13.91 (s,
1H), 5.87 (s, 1H), 5.10 (s, 1H), 3.90-3.64 (m, 7H), 2.53 (s, 3H),
2.15-1.80 (m, 3H), 1.68 (m, 1H), 1.59 (s, 3H), 1.29 (m, 2H), 0.75
(d, J = 6.9 Hz, 3H), 0.70 (d, J = 6.9Hz, 3H);13C NMR (75MHz,
CDCl3) δ 203.4 (C), 164.7 (C), 164.3 (C), 161.7 (C), 132.0 (C),
125.9 (CH), 112.7 (C), 105.9 (C), 86.0 (CH), 55.4 (CH3), 55.2
(CH3), 41.3 (CH), 35.3 (CH), 33.2 (CH3), 30.7 (CH2), 28.5 (CH),
23.4 (CH3), 22.5 (CH2), 21.6 (CH3), 16.2 (CH3); IR (KBr) 3437,
2949, 2920, 2365, 1615, 1418, 1274, 1217, 1118, 1092 cm-1; MS
(EI) m/z (rel intensity) 332 (Mþ, 26), 262 (100), 247 (70); HRMS
(EI) m/z calcd for C20H28O4 332.1988, found 332.1992. Anal.
Calcd for C20H28O4: C, 72.26; H, 8.49. Found: C, 72.35; H, 8.54.
11c. m-CPBA (295 mg, 1.72 mmol) was added to a solution of
16 (457 mg, 1.38 mmol) in CH2Cl2 (17 mL) at rt under a N2
atmosphere, and the whole was stirred for 1 h. NaOH (2% in
MeOH-H2O 1:1, 17 mL) was added to the reaction mixture.
The solution was stirred at rt for 30 min and then neutralized
with 10% HCl. The mixture was extracted with CH2Cl2, and the
organic layer was washed with H2O and dried over MgSO4. The
solvent was then removed under reduced pressure, and the
residue was purified by silica gel column chromatography (6:4
petroleum ether/EtOAc) to give 11c (420 mg, 87%) as a pale
yellow solid.
yield 13 (96 mg, 77%) as a colorless oil: [R]25 þ125.9 (c 1.08,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.12 (s, 2H), 5.12 (s, 1H),
3.80 (m, 4H), 3.72 (s, 6H), 2.20-1.89 (m, 3H), 1.72 (m, 1H), 1.64
(s, 3H), 1.49-1.23 (m, 2H), 0.80 (d, J = 7.0 Hz, 3H), 0.75 (d, J =
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.8 (C), 159.1 (C),
131.4 (C), 126.4 (CH), 114.8 (2C), 91.5 (2CH), 55.9 (2CH3), 55.1
(CH3), 42.1 (CH), 35.6 (CH), 31.0 (CH2), 28.4 (CH), 23.4 (CH3),
23.1 (CH2), 21.6 (CH3), 16.1 (CH3); IR (NaCl) 2949, 2930, 2830,
1603, 1589, 1463, 1452, 1220, 1201, 1154, 1118 cm-1; MS (EI) m/z
(rel intensity) 304 (Mþ, 24), 234 (100), 203 (57); HRMS (EI) m/z
calcd for C19H28O3 304.2038, found 304.2042.
(1R,4R,5S,6S)-4-Isopropyl-1-methyl-5-(2,4,6-trimethoxyphenyl)-
oxabicyclo[4.1.0]heptane (14). m-CPBA (105 mg, 0.61 mmol) was
added to a solution of 13 (140 mg, 0.46 mmol) in CH2Cl2 (5 mL) at
rt under a N2 atmosphere, and the whole was stirred for 1.5 h. The
reaction mixture was treated with saturated K2CO3, extracted with
CH2Cl2. The organic layer was washed, dried, and evaporated. The
residue was chromatographed (70:30 petroleum ether/EtOAc) to
give 14 (113 mg, 77%) as a colorless oil: [R]25 þ34.2 (c 0.91,
11a. BBr3 (1 M in CH2Cl2, 1.2 mL, 1.2 mmol) was added
dropwise to a solution of 11c (280 mg, 0.8 mmol) in CH2Cl2
(5 mL) under ice cooling and a N2 atmosphere. The whole was
stirred for 10 min at 0 °C. After the addition of H2O, the reaction
mixture was stirred for 30 min at rt and then extracted with CH2Cl2.
The combined extracts were washed, dried, and evaporated.
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.12 (s, 2H), 3.81 (s, 3H),
3.78 (s, 3H), 3.77 (s, 3H), 3.44 (d, J = 10.8 Hz, 1H), 2.82 (s, 1H),
2.04 (dt, J = 13.9 and 3.2 Hz, 1H), 1.73 (m, 1H), 1.51-1.12 (m,
7H), 0.77 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.5 (C), 159.0 (C), 158.8 (C), 112.9 (C), 91.0
2508 J. Org. Chem. Vol. 75, No. 8, 2010

Delaye et al.
JOCArticle
The residue was chromatographed (75:25 petroleum ether/
EtOAc) to give 11a (168 mg, 63%) as a pale yellow solid.
(E)-1-((5aR,6R,9R,9aS)-3,6-Dihydroxy-9-isopropyl-1-methoxy-
6-methyl-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-4-yl)-3-phenyl-
prop-2-en-1-one ((-)-1). NaOH (56 mg, 1.4 mmol) and benzalde-
hyde (60 mg, 0.57 mmol) was added to a solution of 11a (95 mg,
0.28 mmol) in MeOH (4 mL) at rt under a N2 atmosphere.
The mixture was stirred for 3 h at 80 °C, neutralized with HCl
(1 N), and extracted with CH2Cl2. The combined extracts were
washed, dried, and evaporated. The residue was chromatographed
(98:2 CH2Cl2/ EtOAc) to give (-)-1 (76 mg, 64%) as a yellow
powder: mp 179-181 °C; [R]22 -35.6 (c 0.88, CHCl3); [R]26
-25.9 (c 0.68, CHCl3); H NMR (300 MHz, CDCl3) δ 13.96
(s, 1H), 8.09 (d, J = 15.6 Hz, 1H), 7.86 (d, J=15.6 Hz, 1H), 7.61
(m, 2H), 7.39 (m, 3H), 6.09 (s, 1H), 4.24 (dd, J=5.4 and 0.9 Hz,
1H), 3.83 (s, 3H), 3.13 (dd, J=11.1 and 5.5 Hz, 1H), 1.81 (m,
3H), 1.62 (s, 3H), 1.45 (m, 3H), 1.12 (m, 1H), 0.90 (d, J = 6.8 Hz,
3H), 0.84 (d, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
191.0 (C), 166.7 (C), 162.1 (C), 161.5 (C), 143.4 (CH), 135.3 (C),
130.3 (CH), 128.9 (2CH), 128.4 (2CH), 125.8 (CH), 113.3 (C),
103.3 (C), 93.0 (CH), 92.3 (CH), 69.3 (C), 55.4 (CH3), 46.5 (CH),
39.5 (CH), 35.4 (CH2), 28.3 (CH), 27.1 (CH3), 21.7 (CH3), 17.2
(CH2), 15.4 (CH3); IR (KBr) 3449, 2953, 1631, 1586, 1345, 1236,
1206, 1142 cm-1; MS (EI) m/z (rel intensity) 422 (Mþ, 47), 337
(100), 295 (26); HRMS (EI) m/z calcd for C26H30O5 422.2093,
found 422.2103.
Acknowledgment. We thank Dr. Y. S. Wong and Prof.
F. Chuburu for helpful discussions, A. Martinez, C. Petermann,
and P. Sigaut for spectroscopic recordings (NMR and MS,
respectively), S. Lanthony for microanalysis and HPLC techni-
cal assistance, and the Centre National de la Recherche Scien-
tifique (CNRS) for financial support.
D
D
1
Supporting Information Available: 1H and 13C NMR
spectra of compounds 9a-c, mixtures of 10,100a-c, 11a-c,
12-16, and (-)-1 and VT 1H NMR spectra of 10,100c and 14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 8, 2010 2509