Absolute structure of shoreaketone: A rotational isomeric resveratrol tetramer in Dipterocarpaceaeous plants

Article abstract of DOI:10.1016/j.tet.2012.02.036

A rotational isomeric shoreaketone (1), identified as a skeletal member of resveratrol tetramers, was isolated from three species of Dipterocarpaceaeous plants: Shorea uliginosa, Shorea hemsleyana, and Vateria indica. The structure was elucidated by spect

Full text of DOI:10.1016/j.tet.2012.02.036

Tetrahedron 68 (2012) 2950e2960
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Absolute structure of shoreaketone: a rotational isomeric resveratrol tetramer
in Dipterocarpaceaeous plants
,
a
b
c
c
Tetsuro Ito a , Masayoshi Oyama , Hironao Sajiki , Ryuichi Sawa , Yoshikazu Takahashi ,
*
Munekazu Iinuma a
a Laboratory of Pharmacognosy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
b Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
c Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 January 2012
Received in revised form 13 February 2012
Accepted 14 February 2012
Available online 22 February 2012
A rotational isomeric shoreaketone (1), identified as a skeletal member of resveratrol tetramers, was
isolated from three species of Dipterocarpaceaeous plants: Shorea uliginosa, Shorea hemsleyana, and
Vateria indica. The structure was elucidated by spectroscopic analysis including NMR experiments and
their absolute configurations determined based on circular dichroism data. Shoreaketone has 10
asymmetric carbons and a framework of fused heptacyclic ring system including a spiro ring and an a,b-
unsaturated carbonyl group that has not been reported in any other natural product. NMR experiments
using shoreaketone indicate the presence of two conformers due to restricted rotation of a CeC bond in
solution. The complex stereochemistry is due to its skeleton, 10 asymmetric carbons, and a chiral axis.
The conformations of rotational isomeric stilbenoid were studied by variable-temperature NMR, ROESY,
a skeletal conversion. The coexistence of two conformers for shoreaketone (1) was confirmed to be 1a
and 1b, in which the diaryl-dihydrobenzofuran moiety (unit 1B) is extended below or above the plane of
the cyclopentane ring (unit 1A), respectively.
Keywords:
Rotational isomer
Absolute structure
Resveratrol tetramer
Skeletal rearrangement
Dipterocarpaceae
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
complicated stereochemistry that comprise diastereomers, epimers,
and enantiomers makes structural determination difficult. The
Several natural stilbenoids in Dipterocarpaceae and Vitaceae exist
as ‘oligomers’ in which some stilbenoid molecules are coupled with
others at various positions. These oligomeric stilbenoids have been
shown to possess a wide range of physiological and biological prop-
erties, including anticancer,1,2 anti-inflammatory,3 and antiviral ac-
tivities.4,5 The oligomeric stilbenoids in Dipterocarpaceaeous plants
have been our main focus of extensive structural investigation for the
past decade.6e14 The tetramers of a resveratrol (3,5,40-trihydrox-
ystilbene), such as (ꢀ)-hopeaphenol,15 vaticanol B6, and vaticanol C6
are widespread and are present in large quantities in Dipter-
ocarpaceaeous plants. These are of special interest due to the large
number of stereoisomers resulting from many asymmetric carbons
and the various frameworks obtained when a resveratrol is homo-
geneously oligomerized. About 120 stilbenoids of this type have been
isolated from the Dipterocarpaceae family. Although a detailed
structural determination based on NMR spectra is required as a part
of ongoing chemical investigations, the difficulties caused by the
complex stereostructure of stilbenoids causes hindered rotation of
some benzene rings and adds to spectral complexity. Based on the
stereostructures of epimeric and diastereomeric derivatives, CHe
p
and/or OHe
p
interaction has also been proposed.8
In the present study, the structural characterization of shor-
eaketone (1) isolated from three Dipterocarpaceaeous plants is
described because 1 appears to be different from other resveratrol
tetramers with respect to its skeleton and NMR spectral complex-
ity.11 The heterocyclic ring in 1 is unique and has not been recorded
in any other natural product and contains a dense array of func-
tionality and stereochemistry. Shoreaketone (1) is the first rota-
tional isomeric stilbenoid with an arkylearyl axis. The isomerism is
caused by a slow rotation about the axis due to steric hindrance.
They therefore occur as two configurationally stable rotational
isomers of 1a and 1b.
The NMR spectra of shoreaketone (1) exhibit multiplicity due
to rotational isomerism at ambient temperatures (Supplementary
data). Changes in the ratio of two conformers and in various sol-
vents at the variable-temperature (VT) NMR and the cross peaks
by a conformational exchange observed in NOESYexperiments can
be attributed to rotational isomerism. Complete and unequivocal
* Corresponding author. Tel.: þ81 58 230 8100; fax: þ81 58 230 8105; e-mail
address: teito@gifu-pu.ac.jp (T. Ito).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.036

T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
2951
assignment of proton and carbon resonances of the two rotational
2. Results and discussion
2.1. Isolation
isomers was demonstrated through structural analysis. The rota-
tional state of rotamers could be defined using NOESY experi-
ments that show the presence or absence of correlation between
H-8c and H-14c. It was then possible to differentiate the two
rotamers. The conformations are supported by the anisotropy that
is explained by the different chemical shifts of H-2b and H-14c in
the two rotamers.
An acid-catalyzed rearrangement of 1 resulted in formation of
a mono alkyl ether of the known resveratrol tetramer, (þ)-iso-
hopeaphenol (2). It was found that 1 undergoes stereoselective
rearrangement to form a monomethyl ether (2a) in excellent yield
and high stereoselectivity when treated with methanolic tri-
fluoromethane sulfonic acid or H2SO4. This skeletal transformation
results in a stereodefined approach toward two heterocyclic ring
systems in 1. The work reported here is directed toward the iso-
lation, structural elucidation, and rotational isomeric properties of
shoreaketone (1).
An acetone extract (60 g) of dried and ground bark (1.2 kg) of
Shorea uliginosa was subjected to column chromatography on silica
gel (EtOAc/CHCl3/MeOH/H2O gradient system) to provide 57 frac-
tions. Further purification of combined fractions from the eighth to
14th fraction [EtOAc/CHCl3/MeOH/H2O (160:80:11:2)] by repeated
vacuum liquid chromatography (VLC) [EtOAc/CHCl3/MeOH/H2O
(80:40:11:2)] achieved the isolation of 1 (450 mg). Stem barks of
Shorea hemsleyana and Vateria indica were similarly examined to
isolate 1 (120 mg and 25 mg, respectively).
2.2. Planar structure of shoreaketone
Shoreaketone (1) is the first example of an atropisomeric stil-
benoid isolated naturally. The structure and the brief spectral data,
including the 1H and 13C NMR spectral data at rt have been men-
tioned in our previous communication.11 The structure is composed
of four resveratrol units (AeD; resveratrol A unit: i.e., between rings
A1 and A2 via atoms C-7a and C-8a). A detailed elucidation was
carried out as follows.
RO
2a
4a
A1
1a
OR
O
12b
B2
7a
8a
10b
The molecular formula was established as C56H42O12 from the
HRESIMS data [m/z 929.2610 [MþNa]þ; 929.2574 calcd for
C56H42O12Na] together with the NMR spectral data, indicating 36ꢁ
of unsaturation. The UV and IR spectra indicated the presence of
12c
9c
C2
OR
RO
9a
10a
9b
10c
8d
A2
H
8b
O
12a
7d
8c
7c
1c
7b
H
9d
aromatic rings [lmax (log
spectrum indicated the presence of an
3
) 285 (4.14) nm; nmax 1598 cmꢀ1]. The IR
-unsaturated carbonyl
H
1d 2d
D1
4d
O
1b
B1
2c
D2
10d
RO
2b
a,b
group (1743 cmꢀ1) and ether groups (1153 and 1173 cmꢀ1). Meth-
ylation of 1 yielded an octamethyl ether (HRESIMS: m/z 1041.3821
[MþNa]þ) and acetylation resulted in an octaacetate (HRESIMS : m/
z 1265.3389 [MþNa]þ), respectively, suggesting that 1 bears eight
phenolic hydroxyl groups. Considering the molecular formula, an-
other four oxygen functions were allotted for a carbonyl group and
three ether linkages. A formation of hydrazone further supports the
existence of the carbonyl group.
C1
12d
4b
OR
OR
4c
OR
O
1a: R = H
1c: R = CH3
1e: R = COCH3
Extended Rotamer
OR
RO
In the 1H NMR spectrum, signals due to an aromatic ring and
hydroxyl groups became broadened and doubled at rt in acetone-
d6.11 Duplication of signals in the 1H and 13C NMR spectra suggested
the existence of two conformers. The relative proportions of the
two forms in various conditions are listed in Table 1. Reducing the
temperature resulted in some alterations in the spectral features
and a varied ratio of 1a and 1b. When the spectrum was measured
at rt in acetone-d6 the ratio was 1 (1a):0.58 (1b), which changed to
1 (1a):0.74 (1b) at ꢀ20 ꢁC. The 1H NMR spectra measured in DMSO-
d6 showed a turnover ratio of 1a and 1b and temperature increase
also showed alterations in the spectral features and the ratio of 1a
and 1b (Fig. S1), indicating that solvent viscosity also controls the
interconversion rate constants. This alteration strongly suggested
that isomerization occurs in the solution depending on solvent
(polarity and viscosity) and temperature. The methyl ether also
displayed signal duplications in the 1H NMR spectrum. The ob-
served peaks are assignable to the structures of 1c and 1d. The
conformers appeared as an equilibrium mixture in the ratio of 1
(1c):0.25 (1d). The acetate (1e) displayed no duplication of signals
due to isomerism. The 1H NMR spectrum of the deacetylated
product was superimposed to that of 1, which displayed signal
duplications. The 1H and 13C NMR spectra of the hydrazone, which
appeared as an equilibrium mixture of four conformers, were too
complicated to assign.
OR
O
RO
OR
RO
O
H
H
H
O
OR
OR
O
1b: R = H
1d: R = CH3
Compact Rotamer
12c
O
1d
R1O
OR1
OR1
D1
4d
12b
B2
C2
7d
8d
O
10c
1a 7a
9c
A1
R1O
4a
9d
10d
7c
8c
10b
8a
9b
D2
12d
OR1
H
1c
8b
7b
9a
A2
12a
H
10a
R1O
R1O
C1
4c
1b
OR1
B1
R1O
4b
As observed by Haslam et al. for the representative rotational
isomeric compound catechin-(4a-8)-catechin,16 the proton spectra
of 1 predominantly showed one rotamer when the spectra were
recorded in a high ratio of deuterium oxide (D2O) in acetone-d6.
Supporting evidences of the rotational isomerism were obtained by
2: R1 = R2 = H
OR2
2a: R1 = H, R2 = CH3
2b: R1 = H, R2 = C2H5
2c: R1 = R2 =CH3

2952
T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
Table 1
Table 2
Relative proportions of two conformers 1a and 1b under various solvent and temp
1H NMR spectral data at ꢀ20 ꢁC (600 MHz, CD3COCD3) of 1
conditionsa
No. (1H)
1a
1b
Solvent
Ratio (v/v)
Temp
1a
1b
H-2a,6a
H-3a,5a
H-7a
7.49 (2H, d, 8.8)
6.85 (2H, d, 8.8)
5.84 (1H, d, 10.4)
5.170 (1H, br d, 10.4)
6.15 (1H, d, 2.0)
7.46 (2H, d, 8.8)
6.85 (2H, d, 8.8)
5.85 (1H, d, 10.4)
5.174 (1H, br d, 10.4)
6.04 (1H, d, 2.0)
b
b
c
Acetone-d6
ꢀ20
25
ꢀ60
ꢀ40
ꢀ20
0
10
20
30
40
50
25
40
55
70
85
ꢀ20
0
25
50
25
25
25
25
25
25
25
25
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.74
0.58
0.58
0.60
0.72
0.70
0.68
0.63
0.58
0.56
0.50
3.38
2.98
2.65
2.49
1.56
0.39
0.39
0.34
0.23
0.58
0.64
0.65
0.62
0.57
0.51
0.35
0.13
H-8a
c
H-12a
H-14a
H-2b
c
6.44 (1H, br s)
4.76 (1H, m)
6.38 (1H, br s)
3.85 (1H, m)
c
c
H-3b(
H-3b(
H-5b
H-6b
H-7b
H-8b
a
)
2.68 (1H, dd, 17.0, 3.0)
3.14 (1H, dd, 17.0, 1.2)
5.44 (1H, d, 10.1)
6.45 (1H, dd, 10.1, 2.2)
3.92 (1H, d, 11.2)
3.69 (1H, t, 11.2)
6.10 (1H, d, 1.8)
2.35 (1H, dd, 17.2, 3.4)
2.21 (1H, dd, 17.2, 1.4)
5.30 (1H, d, 10.1)
6.35 (1H, dd, 10.1, 2.2)
3.83 (1H, d, 10.8)
3.60 (1H, t, 10.8)
6.12 (1H, d, 1.8)
c
b)
c
c
c
b
b
b
b
b
b
b
b
b
d
d
d
d
d
d
d
d
DMSO-d6
H-12b
H-14b
H-2c
H-3c
H-5c
H-6c
H-7c
H-8c
H-12c
H-14c
6.08 (1H, d, 1.8)
6.00 (1H, d, 1.8)
7.26 (1H, br d, 8.3)
6.73 (1H, br d, 8.3)
6.46 (1H, br d, 8.3)
6.76 (1H, br d, 8.3)
3.26 (1H, d, 9.2)
3.57 (1H, dd, 11.2, 9.2)
6.19 (1H, d, 2.0)
6.77 (1H, d, 2.0)
6.68 (2H, d, 8.8)
6.70 (2H, d, 8.8)
4.90 (1H, d, 4.6)
3.24 (1H, d, 4.6)
5.90 (1H, d, 2.0)
6.02 (1H, t, 2.0)
5.90 (1H, d, 2.0)
8.74 (1H, br s, OH-13a)
8.79 (1H, br s, OH-13b)
8.59 (1H, br s, OH-4d)
7.95 (1H, br s, OH-11d)
7.95 (1H, br s, OH-13d)
7.38 (1H, br d, 8.3)
6.76 (1H, br d, 8.3)
6.47 (1H, br d, 8.3)
6.41 (1H, br d, 8.3)
3.15 (1H, d, 10.8)
3.51 (1H, t, 10.8)
6.30 (1H, d, 2.2)
5.73 (1H, d, 2.2)
7.19 (2H, d, 8.8)
6.68 (2H, d, 8.8)
5.20 (1H, d, 2.0)
4.61 (1H, d, 2.0)
5.90 (1H, br s)
6.40 (1H, t, 2.0)
6.51 (1H, br s)
8.68 (1H, br s, OH-13a)
8.36 (1H, br s, OH-13b)
8.64 (1H, br s, OH-13c)
8.82 (1H, br s, OH-11d)
8.97 (1H, br s, OH-13d)
Methanol-d4
Acetone-d6-D2O
10:0
9:1
4:1
7:3
3:2
1:1
2:3
1:4
H-2d,6d
H-3d,5d
H-7d
H-8d
H-10d
H-12d
H-14d
OH
a
The ratio of the two conformers was evaluated by the integral values of H-5b.
b
c
600 MHz.
300 MHz.
400 MHz.
d
1a and 1b represent major and minor conformers at ꢀ20 ꢁC, respectively. Un-
altering the relative proportions of 1a and 1b in acetone-d6 con-
taining different portions of D2O in acetone-d6. Addition of small
amounts of D2O (up to 10%) resulted in a slight decrease in the
population of 1a. Further addition of D2O resulted in a gradual in-
cline in the proportion of 1a with corresponding decrease in the
signals due to 1b (Table 1). When 1 was in 80% D2O, 1a occupied
87% of the population. These results reinforce the rotational
isomerism of 1.
assigned OH signals: 8.60, 8.60, 8.69, 8.72, 8.89, 8.90 (br s).
Table 3
13C NMR spectral data at ꢀ20 ꢁC (150 MHz, CD3COCD3) of 1
No. (13C)
1a
1b
C-1a
131.38
131.28
Assignments of the 1H and 13C NMR spectra of 1a and 1b in
acetone-d6 are shown in a previous communication (measured at rt
(Figs. S12 and S13))11 and Tables 2 and 3 (measured at ꢀ20 ꢁC (Figs.
S5 and S6)). These assignments were developed primarily using
1He1H COSY and 1He13C HSQC as well as 1He13C HMBC experi-
ments (Fig. 1 and Table 4). The protocol used for assignment under
different conditions was similar; hence only selected examples are
described in detail here. In the 1H NMR spectrum in acetone-d6 at
ꢀ20 ꢁC, some aromatic and hydroxyl protons displayed sharpened
signals. NMR data at ꢀ20 ꢁC were applied to the following struc-
tural analysis. The major conformer in acetone (extended rotamer)
(1a) was first analyzed to determine the structure of 1. The primary
discussion is based on first-order consideration.
C-2a,6a
C-3a,5a
C-4a
C-7a
C-8a
130.12
129.94
116.03a
116.03a
158.43/158.32*
87.59
50.20
142.40
113.93
158.51/158.41*
87.56
50.29
142.18
113.61
C-9a
C-10a
C-11a
C-12a
C-13a
C-14a
C-1b
C-2b
C-3b
C-4b
C-5b
154.76
154.94
101.55/101.46b,
157.62/157.52*
105.83/105.74*
46.35
*
101.55/101.46b
157.45/157.35*
105.73/105.63*
45.76
75.95
39.72
196.19
128.97
75.63
39.63
196.24
128.77
The 1H NMR spectrum shows two sets of ortho coupled aro-
matic signals from two p-hydroxyphenyl group (H-2a,6a/H-3a,5a
and H-2d,6d/H-3d,5d: rings A1 and D1). The spectrum also showed
eight signals for meta coupled aromatic protons due to four
resorcinol-type aromatic rings (H-12a/H-14a, H-12b/H-14b, H-
12c/H-14c, and H-10d,14d/H-12d: rings A2eD2) and four aliphatic
methine sequence functionalities (H-7b/H-8b/H-8c/H-7c) were
also observed in the spectrum. Benzylic proton signals charac-
teristic of a diaryl-dihydrobenzofuran moiety were observed at dH
5.84 (H-7a)/5.170 (H-8a) and dH 4.90 (H-7d)/3.24 (H-8d) in the 1H
NMR spectrum of 1 and showed one-bond correlations with the
13C NMR resonances at dC 87.59 (C-7a)/50.20 (C-8a) and dC 94.18
C-6b
C-7b
C-8b
C-9b
C-10b
C-11b
C-12b
C-13b
C-14b
C-1c
154.21
47.72
49.42
138.74
117.82
160.03
97.05/96.95*
157.14/157.05*
109.60/109.49*
132.10
130.8703
116.4479
157.05/156.96*
154.67
48.01
47.29
139.47
117.56
160.24
96.47/96.38*
158.52/158.42*
109.35/109.27*
131.62
130.4315
116.2762
156.64
C-2c
C-3c
C-4c

T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
2953
Table 3 (continued )
Table 4
HMBC data of 1a
No. (13C)
1a
1b
No. (1H)
No. (13C)
C-5c
C-6c
C-7c
C-8c
115.4273
131.00
63.31
57.39
143.88
120.28
162.20
96.01/95.93
160.06/159.95*
105.59/105.51*
133.01
128.64
115.82
157.93/157.82*
94.18
54.90
115.0839
132.2725
56.99
62.65
141.52
116.51
164.42
96.32/96.24*
158.8/158.72*
113.36/113.25*
134.20
127.72
115.95
158.05/157.94*
93.99
56.99
H-2a
H-3a
H-5a
H-6a
H-7a
H-8a
H-12a
H-14a
H-2b
H-3b(
H-3b(
H-5b
H-6b
H-7b
H-8b
C-4a, C-6a, C-7a
C-1a, C-4a, C-5a
C-1a, C-3a, C-4a
C-2a, C-4a, C-7a
C-9c
C-10c
C-11c
C-12c
C-13c
C-14c
C-1d
C-2d,6d
C-3d,5d
C-4d
C-1a, C-2a, C-6a, C-8a, C-9a
C-1a, C-7a, C-9a, C-10a, C-14a, C-9b, C-10b, C-11b
C-10a, C-11a, C-13a, C-14a
C-8a, C-10a, C-12a, C-13a
C-4b, C-6b, C-7b, C-1c
a
)
C-1b, C-2b, C-4b, C-5b
b)
C-4b, C-11ad
C-1b, C-3b
C-1b, C-2b, C-4b, C-7b
C-7d
C-8d
C-9a, C-10a, C-11a, C-1b, C-2b, C-6b, C-8b, C-9b
C-9a, C-7b, C-9b,d C-10b,d C-8c, C-9c
C-10b, C-11b, C-13b, C-14b
C-8b, C-10b, C-12b, C-13b
C-1c, C-6c, C-4c, C-7c
C-1c, C-4c, C-5c
C-1c, C-3c, C-4c
C-1c, C-2c, C-4c, C-7c
C-9d
146.67
148.99
H-12b
H-14b
H-2c
H-3c
H-5c
C-10d
C-11d
C-12d
C-13d
C-14d
107.03/106.95c,*
106.21/106.12*
160.48/160.36*
102.23/102.13*
160.56/160.47*
107.08/106.99*
159.09/158.99d,
101.95/101.87*
159.09/158.99d,
*
*
107.03/106.95c,*
H-6c
H-7c
H-8c
C-1b, C-2b, C-6b, C-1c, C-8c, C-9c
C-8b, C-9b, C-7c, C-9c, C-10c, C-14c
C-10c, C-11c, C-13c, C-14c
C-8c, C-10c, C-12c, C-13c
C-4d, C-6d, C-7d
C-1d, C-4d, C-5d
C-1d, C-3d, C-4d
C-2d, C-4d, C-7d
1a and 1b represent major and minor conformers at ꢀ20 ꢁC, respectively.
*Each signals was observed in duplicate in the intensity ratio 1:0.7e1:0.2. The values
on the left side of the slash represent large signals.
H-12c
H-14c
H-2d
H-3d
H-5d
H-6d
H-7d
H-8d
H-10d
H-12d
H-14d
OH-13a
OH-13b
OH-13cb
OH-4dc
OH-11d
OH-13d
aed
Overlapping.
A
COSY in 1a (at rt)
C-10c,e C-11c, C-1d, C-2d, C-6d, C-8d, C-9d
C-10c, C-1d, C-7d, C-9d, C-10d, C-14d
C-7d, C-11d, C-12d, C-14d
C-10d, C-11d, C-13d, C-14d
C-7d, C-10d, C-12d, C-13d
C-12a, C-13a, C-14a
C-12b, C-13b, C-14b
C-12c, C-13c, C-14c
C-3d, C-4d, C-5d
C-10d, C-11d, C-12d
HMBC in 1a (at rt and -2
3a
2
HMBC in 1a (at -
HO
2a
4a
A1
1a
11b
OH
O
7a
HO
B2
9b
8a
10b
14b
14a
14c
HO
9a
C2
A2
9c
10a
11c
O
7d
10c
2d
D1
C-12d, C-13d, C-14d
8b
11a
7b
a
In acetone-d6 at 600 MHz. Correlations were observed both at rt and ꢀ20 ꢁC, and
8c
7c
1d
O
4d
8d
both in 1a and 1b, unless noted otherwise.
OH
b
Correlations for 1b.
Correlations for 1a.
Weak correlations.
Not observed at ꢀ20 ꢁC.
9d
c
d
10d
D2
1c
2c
e
OH
C1
3c
12d
HO
4c
OH
HO
were scarcely observed because of extreme signal broadening in
DMSO-d6 and acetone-d6. When the temperature was raised to
85 ꢁC in DMSO-d6, the equivalent protons of H-2c,6c (dH 6.90 (br
s)) and H-3c,5c (dH 6.54 (br d)) appeared as two atom-integrated
signals (Fig. S1). Under this condition, ring C1 rotated almost
freely. When the temperature was lowered in acetone-d6, the four
protons H-2c, H-6c, H-3c, and H-5c were observed as separated,
broad signals at 0ꢁ (data not shown), and became a broad doublet
at ꢀ20ꢁ. At such low temperatures, steric hindrance prevents ring
C1 from rotating freely, i.e., these protons are located in different
chemical environments. Similar phenomena have been reported
in some related stilbene oligomers of vaticanols G and H,7 and
vateriaphenol A.10
C
B
A2
8b
6b
(O)
7b
11a
8c
7c
1b
B1
2b
O
1b
H(a)
3b
6b
5b
2b
3b
B1
4b
H(a)
H(b)
H(b)
4b
5b
O
O
Fig. 1. Selected 2D-NMR correlations for the partial structures AeC of shoreaketone (1).
In the 1He13C HMBC spectrum, significant correlations were
observed between H-7a/C-2a,6a, H-8a/C-14a, H-8a/C-11b, H-7b/C-
11a, H-14b/C-8b, H-8c/C-14c, H-7d/C-2d,6d, H-8d/C-10d,14d, and
H-8d/C-10c, which support the connections between C-1a/C-7a, C-
8a/C-9a, C-8a/C-10b, C-10a/C-7b, C-8b/C-9b, C-8c/C-9c, C-1d/C-7d,
C-8d/C-9d, and C-10c/C-8d, respectively (Fig. 1, partial structure A).
An additional cross peak observed for H-7d/C-11c supports the
presence of an ether linkage, C-11ceOeC-7d, which is part of
(C-7d)/54.90 (C-8d), respectively, in the 1He13C HSQC spectrum,
thereby indicating the presence of two diaryl-dihydrobenzofuran
units in the molecule. In the 1H NMR spectra of 1 measured under
different conditions, complicated signal patterns were observed
for H-2c, H-3c, H-5c, and H-6c due to different degrees of immo-
bilization of ring C1 by steric hindrance. At rt, the four H-atoms
a
dihydrobenzofuran moiety (C-7deC-8deC-10ceC-11ceO).

2954
T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
Although no long-range correlation with H-7a/C-11b was observed,
the presence of another dihydrobenzofuran moiety (C-7aeC-8aeC-
10beC-11beO) was deduced after considering the carbon chemical
shift and the molecular skeleton. Based on the cross peaks observed
for H-2c/C-7c and H-6c/C-7c in the 1He13C HMBC spectrum at
ꢀ20 ꢁC (A), the position of ring C1 was deduced to be C-7c. The
remaining ring system and the connectivity in the molecule were
determined as follows. Considering the molecular formula, the
remaining unit in the molecule corresponds to C6H5O. The 1H NMR
spectrum also exhibited a set of mutually coupled aliphatic protons
(a)
HO
H
14a
2a
O
7a
8a
OH
OH
A1
B2
A2
HO
14c
14b
H
H
8b
C2
7b
H
H
8c
O
H
O
2b
8d
H
1b
OH
D1
H
7c
at dH 4.76 (H-2b), dH 2.68 (H-3b(a)), and dH 3.14 (H-3b(b)) and
7d
B1
10d
exhibited one-bond connectivities in the 1He13C HSQC spectrum
with the 13C NMR signals at dC 75.95 (C-2b), dC 39.72 (C-3b), and dC
39.72 (C-3b), respectively. Another two signals in the 1H NMR
spectrum, at dH 5.44 (H-5b) and dH 6.45 (H-6b), which correlated
with the 13C NMR resonances at dC 128.97 (C-5b) and dC 154.21 (C-
6b), respectively, were assigned for cis-olefinic protons. In the 13C
NMR spectrum, quaternary signals assigned to an aliphatic carbon
H
2c
2d
H
H
6b
3b
D2
H
HO
OH
C1
H
O
OH
unit 1A
unit 1B
at dC 46.35 (C-1b) and an a,b-unsaturated carbonyl carbon at dC
(b)
196.19 (C-4b) were also observed. These data suggested that the
ring formed a cyclohex-2-enone ring (partial structure B: ring B1),
which was confirmed by the 1He13C HMBC correlations between
HO
10d
HO
OH
O
H-6b/C-4b, H-5b/C-3b(a), H-2b/C-4b, H-3b(a)/C-1b, and H-5b/C-
D2
1b. The important correlations of 1He13C HMBC measurement for
OH
B2
OH
the fused cyclic system of ring B1 were as follows; H-7b/C-2b, H-7c/
OH
14b
9d
C-6b, and H-3b(
b)/C-11a (weak correlation: 4J) for the connection
H
8d
H
of CeC bonds and an ether linkage, C-1b/C-7b, C-1b/C-7c, and C-
11aeOeC-2b in this order (partial structure C). Based on these re-
sults, the planar structure of 1 was confirmed.
8b
8c
B1
7c
H
H
HO
O
O
2b
O
H
C2
14c
unit 1A
2.3. Relative structure of shoreaketone
unit 1B
HO
The stereostructure was determined from the results of the
ROESYexperiment [Fig. 2 (selected) and Table 5 (total)] and skeletal
conversion. The trans orientations of H-7a/H-8a and H-7d/H-8d on
the dihydrobenzofuran rings were confirmed by the distinctive
ROEs between H-7a/H-14a, H-8a/H-2a,6a, H-14a/H-2a,6a, H-7d/H-
10d,14d, H-2d,6d/H-10d,14d, and H-8d/H-2d,6d. The strong one (H-
14a/H-2a,6a) and the large coupling constant (H-7a/H-8a:
J¼10.4 Hz) supported the trans diequatorial orientation of two ar-
omatic rings (rings A1 and A2) and trans diaxial orientation of H-7a/
H-8a,1 namely, asymmetric carbon (C-8a) form the flap of the en-
velope conformation. Significant ROEs between H-14c/H-8b and H-
14c/H-7c indicated that ring C2, H-8b, and H-7c were of syn ori-
entation on a cyclopentane ring (C-1b/C-7b/C-8b/C-8c/C-7c). The
syn orientation of H-7b and ring C1 was deduced based on the cross
peaks observed for H-2c/C-7b in the spectrum at ꢀ20 ꢁC. The large
coupling constant values of H-7b/H-8b (J¼11.2 Hz), H-8b/H-8c
(J¼11.2 Hz), and H-7c/H-8c (J¼9.2 Hz) also supported the trans
stereo relationship of four methine sequences, H-7b/H-8b/H-8c/H-
7c. In addition, the syn orientation of the CeC bond (C-1b/C-6b), H-
7b, and H-8a was supported by ROEs between H-7b/H-6b and H-
7b/H-8a. Distinct ROEs of H-2b/H-7c and H-2b/H-8b indicated H-2b
1a
(c)
HO
O
OH
B2
OH
14b
H
8b
8c
B1
2b
7c
H
H
OH
14c
HO
O
O
H
H
8d
D2
OH
C2
HO
10d
O
unit 1A
HO
1b
unit 1B
Fig. 2. Stereostructure and selected ROESY correlations (indicated by lines). ROEs
observed for 1a and 1b (a), 1a (b), and 1b (c).
to be in b-orientation. Based on the results, the relative configu-
ration of eight asymmetric carbons (C-7a, C-8a, C-1b, C-2b, C-7b, C-
8b, C-7c, C-8c) in unit 1A were determined as rel-R, R, R, R, S, R, R, R,
respectively. The configurations of C-7d and C-8d in unit 1B were
determined as follows. A strong ROE was observed between H-14b/
H-10d,14d, which indicated that the rings B2 and D2 were co-facial.
Therefore, the orientation of C-7d and C-8d was determined to be
rel-R. When the difference in the conformation of the cyclohex-2-
enone ring (ring B1) was considered, a boat and a chair conforma-
tion were indicated. It was found that the chair conformation of the
2.4. Skeletal conversion of shoreaketone
A skeletal rearrangement of stilbenoids offers important in-
formation for determination of a stereostructure. Takaya et al.
determined the absolute stereostructures of resveratrol dimers
((þ)-ampelopsin A, (þ)-ampelopsin B, (þ)-ampelopsin D,
(þ)-ampelopsin F) and tetramers ((þ)-hopeaphenol, (ꢀ)-iso-
hopeaphenol, (þ)-vitisin A and (þ)-vitisin D) isolated from Vita-
ceaeous plants by acid- and peroxidase-catalyzed reactions of
ring system satisfied ROE (H-3b(b)/H-7c). The relative configura-
tion and conformation of 1 were then established.

T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
2955
Table 5
BCl3, 2 was obtained. In the case of 2, two identical dimers
(hemsleyanol A’s12) are coupled through a CeC bond of C(8b)e
C(8c). Half signals of the total atom numbers can be observed in
ROESY data of 1a
No. (1H)
1 and 1b
1
1
the 1H and 13C NMR spectrum. The [
a]D value implied that 2 is not
H-2a,6a
H-7a
H-8a
H-12a
H-14a
H-7a, H-8a, H-14a
H-2a,6a, H-14a
H-2a,6a, H-14a,b H-7b
OH-13ac
a meso form. From these evidences, the identity of configurations
in two dihydrobenzofuran rings has been demonstrated, and the
structural elucidation of 1 described above was further reinforced
(Scheme 1).
H-2a,6a, H-7a,
H-8a,b OH-13ac
H-2b
H-3b(
a
), H-3b(
a
),
H-14c
H-14c
H-8d,b H-10db
H-8b, H-7c
H-2b
H-3b(
H-3b(
H-6b
H-7b
H-8b
a
)
CF3SO3H (cat)
b)
H-2b, H-7c
H-7b
2a
shoreaketone (1)
MeOH, N2, rt, 72 h
H-8a, H-6b
H-2b, H-14b
OH-13bc
CH3I
H-8d
CF3SO3H (cat)
EtOH, N2, rt, 72 h
H-12b
H-14b
acetone
H-8b, H-8c, OH-13bc
H-14c, H-10d,
H-14d
H-3d,5d, H-8d
H-2c
H-3c
H-7c
H-7cc
BCl3
2b
H-7c,c H-8cc
H-2c,c H-3c,c
H-14c
2
2c
2c
H-2b, H-3b(
b
)
H-10d
H-14c
CH2Cl2
H-8c
H-14b
H-3c,c H-8d,
H-10d, H-14d
CH3I
H-12c
H-14c
OH-13cc
2
H-2b, H-8b,
H-14b, H-7c
H-10d, H-14d
OH-4dc
H-10d
H-8c
H-8c, OH-13cc
acetone
Scheme 1. Skeletal conversion and functional derivation of 1.
H-2d,6d
H-3d,5d
H-7d
H-8d
H-10d
H-7d, H-8d
H-14b
On the basis of these facts, the formation of isohopeaphenol (2)
in the reaction of shoreaketone (1) with trifluoromethane sulfonic
acid can be reasonably explained by virtue of a formation of
a methoxydiene intermediate (E) via hemiketal (D). The sub-
sequent intramolecular cyclization induced by the nucleophilic
H-2d,6d, H-14d
H-2d,6d, H-10d, H-14d
H-2bb, H-8b, H-14b
H-2b,b H-7c
H-8d, OH-11dc
H-14b, H-8c,
H-2d,6d, H-7d
H-12d
H-14d
OH-11d,c OH-13dc
H-7d, H-8d, OH-13dc
H-14b, H-8c,
H-2d,6d
attack of the
p-electron of an electron-rich resorcinol ring to the
OH-13a
OH-13b
OH-13c
OH-4d
OH-11d
OH-13d
H-12a,c H-14ac
H-12b,c H-14bc
benzylic position (C-7c) (F) and the re-aromatization of the resor-
cinol ring (G) leads to 2a as the ultimate product (Scheme 2). The
neighboring stereo relation of C-10d/C-7c and SN2 reaction explains
the high regio- and stereoselective skeletal transformation.
H-12c, H-14cc
H-3d,5dc
H-10d,c H-12dc
H-12d,c H-14dc
a
In acetone-d6 at 600 MHz. Correlations were observed both at rt and ꢀ20 ꢁC,
2.5. Absolute structure of shoreaketone
unless noted otherwise.
b
Weak correlations.
Correlations at ꢀ20 ꢁC.
c
The absolute configuration of two 1,2-diaryl-dihydrobenzofuran
chiral centers of (ꢀ)-isohopeaphenol have been determined by
Takaya et al.18 On the basis of the absolute configuration of
(þ)-isohopeaphenol (2)13 and the transformation reaction mecha-
nisms of shoreaketone (1) shown above, the absolute configura-
tions of 1 were clearly determined.
(þ)-
3
rearrangement of
1
(þ)-isohopeaphenol (2)13,19,20 in high stereo peculiarity. Tri-
fluoromethane sulfonic acid or sulfuric acid is used as an acidic
additive. When a mixture of shoreaketone (1) with each acid in
dry MeOH was kept at rt for 18 h and the resulting mixtures
purified by preparative TLC, monomethyl ether (2a) was obtained
in almost quantitative yield. Monoethyl ether (2b) was also ob-
tained when the mixture of 2 was reacted with trifluoromethane
sulfonic acid in EtOH. The structures of products were confirmed
by combined analyses of its 1H,1H-COSY, 1H,13C-HMBC, 13C,1H-
COSY, and 1H,1H-NOESY spectra. The detailed structural elucida-
tion of 2a is described in Supplementary data. On the other hand,
(þ)-isohopeaphenol (2) and (ꢀ)-hopeaphenol15 were unchanged
even when each compound was treated under more aggressive
conditions (trifluoromethane sulfonic acid in CH3NO2). This re-
action proceeded by cleavages of a CeC bond and an ether bond of
the skeleton, and produced another CeC bond. This rearrange-
ment maintains the stereostructure related to the 1,6,7,11b-tet-
rahydro-4,8,10-trihydroxy-benzo[6,7]cyclohepta[1,2,3-cd]benzo-
furan skeleton in unit 1A. When 2a was treated with CH3I,
a permethyl ether 2c was obtained. The 1H NMR spectrum and
2.6. Rotational conformation analysis by NMR study
Shoreaketone (1) showed conformational change in solution,
and two sets of conformers (1a and 1b) appeared in the NMR
spectra. To clarify their conformational properties, the direction of
the 2,3-diaryl-dihydrobenzofuran ring (1B) in each conformer was
determined by ROE correlations (Fig. 2). ROE correlations were
observed between H-14c/H-7c and H-14c/H-8b in 1a and H-14c/H-
8c in 1b. Conversely, no correlations were noted between H-14c/H-
8c in 1a and between H-14c/H-7c and H-14c/H-8b in 1b. These
results suggested that the bond C-9ceC-14c is situated in syn to H-
7c and H-8b in 1a and in syn to H-8c in 1b. Supporting ROE evi-
dences in each conformer are correlations between H-14b/H-
10d,14d, H-14b/H-14c, H-8c/H-8d, and H-8c/H-10d,14d in 1a and H-
14b/H-2d,6d, H-14b/H-8d, and H-7c/H-10d,14d in 1b. These results
strongly indicated that rotational isomerism is due to restricted
rotation of the CeC bond (C-8c/C-9c).
An important feature of the rotational isomerism in the free
phenol 1 was the ‘rotational conformation exchange’ first noted in
the NOESY experiment of 1 when recorded in acetone-d6 at rt. This
[a] value of the product (2c) was superimposed on those pre-
D
pared from (þ)-isohopeaphenol (2). When 2a was treated with

2956
T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
HO
H
O
OH
HO
H2SO4
H
OH
H
O
H2O
H
O
HO
O
O
O
O
H O S CF3
O
CH3
O
H
H
-
O
HSO4
H
H
H3C
H
O
CH3
OH
D
HO
HO
H
O
O
OH
OH
HO
HO
H
H
OH
OH
H
H
HO
O
+H+
H
O
O
H
H
OH
OCH3
OCH3
OH
F
E
HO
HO
O
O
OH
HO
OH
HO
HO
HO
_
H+
H
H
OH
OH
O
O
H
H
H
OH
OH
OCH3
HO
OCH3
HO
O
OH
HO
OH
H+
2a
G
Scheme 2. A plausible mechanism for the transformation of shoreaketone (1) to methyl ether of (þ)-isohopeaphenol (2a).
unusual NOE phenomenon was first reported by Hatano et al. in
two conformers of procyanidin dimers.18 The spectrum showed
that strong cross peaks represents conformational exchange in
which correlations between the same protons in each of the two
rotameric isomers dominate the spectrum. This effect was explored
further in differential NOE experiments, which clearly showed that
despite sharp signals for each of the two rotamers, the effect of
irradiation of a proton in one rotamer was translated to the same
proton in the other rotamer, indicating that there is rotational in-
terchange between two conformers in the timescale of this ex-
periment. The cross peaks attributable to conformational exchange,
for example, was observed between H-14c of 1a and H-14c of 1b in
the NOESY spectrum (Fig. S2). The translated irradiation was ob-
served when H-14c of 1a was irradiated, H-14c of 1b was enhanced,
and vice versa, in the differential NOE spectrum. The observation of
irradiation transfer requires sufficient difference in chemical shift
at respective resolutions. In the case of 1, the chemical shift of H-
14c, H-7d, and H-8d in each rotamer is sufficiently separated in the
1H NMR spectrum, which visualizes the cross peaks in the NOESY
spectrum and the irradiation transfers in the differential NOE
spectrum.
The extended rotamer conformation (1a), in which the CeC
bond of C-9c/C-14c was directed to the -side of the reference
plane, was predominant in 1 in organic solvents. In 1a, the units 1A
and 1B lie horizontally and the molecule is in an extended form.
The compact rotamer conformation (1b), in which the CeC bond of
C-9c/C-14c was facing the a-side of the reference plane, was in-
ferior in 1. The units 1A and 1B lie vertically and the molecule is in
a compact form in 1b (Fig. 3).
b
2.7. Chemical shift properties of rotational conformers
The chemical shifts of the particular protons and carbons were
markedly different between 1a and 1b. This could be explained by
the anisotropic shielding/deshielding effects of the aromatic rings.
The important matters observed in the 1H NMR spectrum in ace-
tone-d6 at ꢀ20 ꢁC are as follows (Fig. 3). In 1a, H-8d was observed at
dH 3.24, whereas that of 1b was at 4.61. A similar behavior of proton
signals was also observed for H-7d (dH 4.90 for 1a; 5.20 for 1b) and
H-2d,6d (dH 6.68 for 1a; 7.19 for 1b). These data and the configu-
ration of 1a and 1b described above explain reasonably well the
anisotropy effect of ring C1 on these protons. The anisotropic effect

T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
2957
Fig. 3. Stereostructure and shielding of protons by anisotropy in 1a and 1b. Energy-minimized conformations of the two rotamers were generated using the MMFF94 force field
(MM2 type). Factors of anisotropy are given in parentheses.
by ring C1 was altered to H-14c in 1b. Namely, H-14c of 1b was
observed at dH 5.73, while that of 1a was at 6.77. The other aniso-
tropic effects in 1b were caused by ring D2, which resulted in up-
Chemical Industries Ltd., Japan) for enantiomeric separation by
HPLC.
field shift of H-2b (dH 3.85 for 1b; 4.76 for 1a) and H-3b (dH 2.35 (
a),
4.2. Plant material
2.21 ( ) for 1b; 2.68 ( ), 3.14 (
b
a
b
) for 1a). In the 13C NMR spectrum in
acetone-d6, the chemical shifts assigned to C-7c and C-8c are quite
different between 1a and 1b, which appeared at dH 63.31 (C-7c) for
1a, 57.39 (C-7c) for 1b, 56.99 (C-8c) for 1a, and 62.65 (C-8c) for 1b.
The reason for this difference is still unclear.
Stem barks of S. uliginosa (Foxw) and S. hemsleyana were col-
lected in India in October 1997. The stem bark of V. indica was
collected in India in June 2004. Voucher specimens DP-004 (S.
uliginosa), DP-003 (S. hemsleyana), and DP-031 (V. indica) have been
deposited at Gifu Pharmaceutical University, Gifu, Japan.
3. Conclusions
4.3. Extraction and isolation
We determined the absolute structure of shoreaketone (1), i.e.,
the first occurrence of rotational isomerism among stilbenoids. Our
findings demonstrate complex chemical and dynamic behavior in 1.
From detailed spectral data analysis to examine the mutual effect of
the hindered rotation around the chiral axis, we demonstrated the
presence of two rotamers. Using edited ROESY, NOESY, and differ-
ential NOE experiments, we propose that both rotamers exhibit
rotational conformation exchanges. The formation of the dimeric
dimer molecule, (þ)-isohopeaphenol (2) solves the stereochemical
aspect of 1. The present study signifies a new dimension in the
ongoing research in this field by exploring this type of complex
system bearing a 2,3-diaryl-dihydrobenzofuran ring.
Dried and ground stem bark (1.2 kg) of S. uliginosa was extracted
successively with acetone (4 Lꢂ24 hꢂ3), MeOH (4 Lꢂ24 hꢂ3), and
70% MeOH (4 Lꢂ24 hꢂ2) at rt. The extract was concentrated to
yield respective residues; 62 g (acetone), 82 g (MeOH), and 43 g
(70% MeOH). The acetone extract (60 g) was subjected to column
chromatography on silica gel eluted with a mixture of EtOAc/CHCl3/
MeOH/H2O increasing in the polarity to give 57 fractions (Fr. 1e57).
Fractions were combined by indication of the Gibbs test on TLC. The
combined fractions of fractions 8 to 14 [EtOAc/CHCl3/MeOH/H2O
(160:80:11:2), 1.2 g] were purified by VLC [EtOAc/CHCl3/MeOH/H2O
(80:40:11:2)] to produce 1 (450 mg). The experimental procedure
for stem bark of S. hemsleyana12 and V. indica20 has been described
in a previous report. Each of these two sources provided 1 (120 mg
from S. hemsleyana and 25 mg from V. indica).
4. Experimental
4.1. General
4.3.1. Shoreaketone (1; 1a,b). A yellow amorphous solid; solid; mp
The following instruments were used: a JASCO P-1020 polar-
imeter for optical rotations; a Shimadzu UV-3100 spectrophotom-
eter (in MeOH solution) for UV spectroscopy; a JASCO J-820
spectrometer (in MeOH solution) for CD spectroscopy; a JEOL JNM
256e258 ꢁC (decomp.); ½a 2D5
ꢃ
ꢀ225 (c 0.1, MeOH); CD (c 22.1
mM,
MeOH) nm (
D
3
): 237 (ꢀ96.9), 261 (ꢀ11.3), 272 (ꢀ19.2), 299 (þ4.9)
(Fig. S5); UV (MeOH) lmax (log ): 285 (4.14), 292sh (4.08) nm; IR n
3
(KBr disk): 3400, 2920, 2851, 1743, 1660, 1616, 1598, 1516, 1453,
1340,1244,1173,1153, 1022, 999, 834 cmꢀ1; Positive ion ESIMS m/z:
929 [MþNa]þ; Positive ion HRESIMS m/z: 929.2610 [MþNa]þ (calcd
929.2574 for C56H42O12Na); Negative ion FABMS m/z: 905 [MꢀH]ꢀ;
The 1H and 13C NMR spectral data at rt: see literature; The 1H and
13C NMR spectral data at ꢀ20 ꢁC: Tables 2 and 3, respectively;
HMBC and NOESY* correlations: Tables 4 and 5, respectively. *Se-
lected correlations are designated in the literature11 and Fig. 1.
ECA-600, AL-400, EX-400, and LA-300 spectrometer for 1H and 13
C
NMR spectroscopy (chemical shift values in 1H NMR spectra were
presented asÔ values with TMS as the internal standard); JEOL-
JMS-T100 LC mass spectrometer mass spectrometer for ESIMS;
and JEOL JMS-DX-300 instrument for FABMS. The following ad-
sorbents were used for purification: Merck Kieselgel 60 F254
(0.25 mm) for analytical TLC; Merck Kieselgel 60, Fuji Silysia
Chemical Chromatorex, and Waters Sep-Pak C18 cartridges for
column chromatography; a Capcell Pak C18 column (UG120,
250ꢂ10 mm i.d., SHISEIDO, Japan) for preparative HPLC; and
CHIRALPAK IB and OJ-RH columns (each 150ꢂ4.6 mm i.d., Daicel
4.3.2. Methylation of 1. Shoreaketone (1) (20 mg) was reacted with
K2CO3 (200 mg) and MeI (20 mg) in dry acetone under reflux for
5 h. The reaction mixture was treated in the usual manner and the

2958
T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
crude product (24 mg) obtained was purified by preparative TLC (n-
hexane/EtOAc 1:1) to afford permethyl ether (1c,d) (20 mg).
were not identified because they were obscured by neighboring
peaks. H-2c, H-3c, H-5c, and H-6c were not identified (*Masked
by neighboring peaks and J-values were not clear. Assignments
were obtained from 1He1H COSY and 13Ce1H COSY correlations).
4.3.3. Shoreaketone permethyl ether (1c,d). A pale yellow solid;
½
a 2D5
ꢃ
ꢀ280 (c 0.1, CHCl3); UV (CHCl3) lmax (log
3
): 285 (4.19), 292sh
(4.12) nm; Positive ion ESIMS m/z: 1041 [MþNa]þ; Positive ion
HRESIMS m/z: 1041.3821 [MþNa]þ (calcd 1041.3820 for
4.3.4. Acetylation of 1. Shoreaketone (1) (30 mg) was dissolved in
a mixture of pyridine (2.0 mL) and Ac2O (0.2 mL). The reaction
mixture was kept at rt for 24 h. The solution was treated with the
usual manner and the resulting crude product (35 mg) was purified
by prep. TLC with n-hexane/EtOAc 1:1 to afford peracetate (1e)
(32 mg).
C64H58O12Na); 1H NMR for 1c [400 MHz, acetone-d6]
d: 7.61 (2H,
d, J¼8.8 Hz, H-2a,6a), 7.03 (2H, d, J¼8.8 Hz, H-3a,5a), 6.03 (1H, d,
J¼9.8 Hz, H-7a), 5.13 (1H, d, J¼9.8 Hz, H-8a), 6.28 (1H, d, J¼2.0 Hz,
H-12a), 6.57 (1H, br s, H-14a), 4.93 (1H, br s, H-2b), 2.71(1H, dd,
J¼15.1, 2.2 Hz, H-3b(
a
)), 3.10 (1H, dd, J¼15.1, 0.9 Hz, H-3b(
b)), 5.45
(1H, d, J¼10.2 Hz, H-5b), 6.62 (1H, dd, J¼10.2, 2.4 Hz, H-6b), 3.91
(1H, H-7b)*, 3.68 (1H, H-8b)*, 6.06 (1H, d, J¼2.0 Hz, H-12b), 5.73
(1H, d, J¼2.0 Hz, H-14b), 3.46 (1H, d, J¼10.4 Hz, H-7c), 3.89 (1H,
H-8c)*, 6.37 (1H, d, J¼2.0 Hz, H-12c), 6.93 (1H, d, J¼2.0 Hz, H-14c),
6.67 (2H, d, J¼8.8 Hz, H-2d,6d), 6.72 (2H, d, J¼8.8 Hz, H-3d,5d),
5.31 (1H, d, J¼3.4 Hz, H-7d), 3.54 (1H, d, J¼3.4 Hz, H-8d), 6.21 (1H,
d, J¼2.0 Hz, H-10d), 6.13 (1H, t, J¼2.0 Hz, H-12d), 6.21 (1H, d,
J¼2.0 Hz, H-14d), 3.82 (3H, s, OMe-4a), 3.70 (3H, s, OMe-13a),
3.32 (3H, s, OMe-13b), 3.64 (3H, s, OMe-4c), 3.85 (3H, s, OMe-
13c), 3.78 (3H, s, OMe-4d), 3.70 (3H, s, OMe-11d), 3.70 (3H, s,
OMe-13d). H-2c, H-3c, H-5c, and H-6c were not identified
(*Masked by neighboring peaks and J-values were not clear. As-
signments were obtained from 1He1H COSY and 13Ce1H COSY
4.3.5. Shoreaketone peracetate (1e). A pale yellow solid; ½a D25
ꢀ192
ꢃ
(c 0.1, CHCl3); UV (CHCl3) lmax (log ): 281 (4.01), 288sh (4.00) nm;
3
Positive ion ESIMS m/z: 1265 [MþNa]þ; Positive ion HRESIMS m/z:
1265.3389 [MþNa]þ (calcd 1265.3414 for C72H58O20Na); 1H NMR
[400 MHz, CDCl3]
d
: 7.52 (2H, d, J¼8.8 Hz, H-2a,6a), 7.18 (2H, d,
J¼8.8 Hz, H-3a,5a), 6.17 (1H, d, J¼8.3 Hz, H-7a), 4.89 (1H, d,
J¼8.3 Hz, H-8a), 6.54 (1H, d, J¼2.0 Hz, H-12a), 6.73 (1H, br s, H-14a),
4.59 (1H, br s, H-2b), 2.87(1H, dd, J¼15.1, 2.2 Hz, H-3b(
a)), 2.80 (1H,
dd, J¼15.1, 0.9 Hz, H-3b( )), 5.68 (1H, d, J¼10.0 Hz, H-5b), 6.52 (1H,
b
dd, J¼10.0, 2.4 Hz, H-6b), 3.75 (1H, d, J¼11.4 Hz, H-7b), 3.37 (1H, t,
J¼11.4 Hz, H-8b), 6.41 (1H, d, J¼2.2 Hz, H-12b), 5.90 (1H, d,
J¼2.2 Hz, H-14b), 3.12 (1H, d, J¼9.7 Hz, H-7c), 3.43 (1H, dd, J¼11.4,
9.7 Hz, H-8c), 6.56 (1H, d, J¼2.0 Hz, H-12c), 6.75 (1H, d, J¼2.0 Hz, H-
14c), 6.86 (2H, d, J¼8.8 Hz, H-2d,6d), 6.95 (2H, d, J¼8.8 Hz, H-
3d,5d), 5.39 (1H, d, J¼6.4 Hz, H-7d), 3.29 (1H, d, J¼6.4 Hz, H-8d),
6.60 (1H, d, J¼2.2 Hz, H-10d), 6.37 (1H, t, J¼2.2 Hz, H-12d), 6.60 (1H,
d, J¼2.2 Hz, H-14d), 2.18 (9H, s, OAc), 2.24 (3H, s, OAc), 2.25 (3H, s,
OAc), 2.27 (3H, s, OAc), 2.29 (3H, s, OAc), 2.32 (3H, s, OAc); 13C NMR
correlations); 13C NMR for 1c [100 MHz, acetone-d6]
d: 134.1 (C-
1a), 129.6 (C-2a,6a), 114.8 (C-3a,5a), 161.1 (C-4a), 86.9 (C-7a), 51.4
(C-8a), 143.2 (C-9a), 114.6 (C-10a), 155.5 (C-11a), 99.9 (C-12a),
160.6 (C-13a), 105.6 (C-14a), 46.1 (C-1b), 76.8 (C-2b), 40.4 (C-3b),
195.9 (C-4b), 129.7 (C-5b), 154.1 (C-6b), 48.6 (C-7b), 50.4 (C-8b),
137.7 (C-9b), 118.1 (C-10b), 160.4 (C-11b), 95.6 (C-12b), 160.8 (C-
13b), 106.7 (C-14b), 132.8 (C-1c), 159.8 (C-4c), 63.6 (C-7c), 57.6 (C-
8c), 142.8 (C-9c), 124.3 (C-10c), 161.7 (C-11c), 95.1 (C-12c), 163.1
(C-13c), 105.5 (C-14c), 134.8 (C-1d), 128 (C-2d,6d), 115.2 (C-3d,5d),
160.6 (C-4d), 93.9 (C-7d), 55.7 (C-8d), 147.2 (C-9d), 106.4 (C-10d),
162 (C-11d), 99.1 (C-12d), 162 (C-13d), 106.4 (C-14d), 55.9 (OMe-
4a), 55.7 (OMe-13a), 54.8 (OMe-13b), 55.5 (OMe-4c), 56.2 (OMe-
13c), 55.6 (OMe-4d), 55.7 (OMe-11d), 55.7 (OMe-13d). C-2c, C-3c,
C-5c, and C-6c were not identified; COLOC correlations for 1c: C-
1a/H-3a,5a, C-1a/H-8a, C-2a,6a/H-7a, C-4a/H-2a,6a, C-4a/OMe-4a,
C-8a/H-14a, C-9a/H-7a, C-9a/H-8a, C-9a/H-7b, C-10a/H-12a, C-
10a/H-14a, C-10a/H-7b, C-11a/H-12a, C-11a/H-7b, C-12a/H-14a, C-
13a/H-12a, C-13a/H-14a, C-13a/OMe-13a, C-14a/H-12a, C-1b/H-
[100 MHz, CDCl3] d: 138.8 (C-1a), 126.7 (C-2a,6a), 121.8 (C-3a,5a),
150.47 (C-4a), 84 (C-7a), 50.8 (C-8a), 141.3 (C-9a), 117.8 (C-10a),
153.8 (C-11a), 108.9 (C-12a), 150.1 (C-13a), 109.7 (C-14a), 44 (C-1b),
75.7 (C-2b), 38.5 (C-3b), 195 (C-4b), 129.7 (C-5b), 151.5 (C-6b), 46.5
(C-7b), 49 (C-8b), 135.2 (C-9b), 121.9 (C-10b), 158.7 (C-11b), 102.5
(C-12b), 150.9 (C-13b), 114.3 (C-14b), 136 (C-1c), 130.5 (C-2c), 121.3
(C-3c), 149.9 (C-4c), 121.3 (C-5c), 130.5 (C-6c), 62.7 (C-7c), 56 (C-8c),
139.7 (C-9c), 126.78 (C-10c), 160.3 (C-11c), 102.7 (C-12c), 152.5 (C-
13c), 112.2 (C-14c), 137.5 (C-1d), 126.81 (C-2d,6d), 121.7 (C-3d,5d),
150.52 (C-4d), 92.3 (C-7d), 55.5 (C-8d), 143.3 (C-9d), 119.3 (C-10d),
150.7 (C-11d), 113.1 (C-12d), 150.7 (C-13d), 119.3 (C-14d), 168.4 (C]
OeOAc), 168.96 (C]OeOAc), 168.98 (C]OeOAc), 169.11 (C]
OeOAc), 169.11 (C]OeOAc), 169.15 (C]OeOAc), 169.17 (C]
OeOAc), 169.24 (C]OeOAc), 21.0 (MeeOAc); COLOC correlations
for 1e: C-8a/H-14a, C-9a/H-7a, C-9a/H-8a, C-9a/H-7b, C-10a/H-12a,
C-10a/H-14a, C-10a/H-7b, C-11a/H-12a, C-11a/H-7b, C-12a/H-14a,
C-13a/H-12a, C-13a/H-14a, C-14a/H-12a, C-1b/H-3b(a), C-1b/H-5b,
C-1b/H-7b, C-1b/H-7c, C-2b/H-3b(a), C-2b/H-6b, C-2b/H-7b, C-2b/
H-7c, C-4b/H-2b, C-4b/H-3b(a), C-4b/H-3b(b), C-4b/H-6b, C-5b/H-
3b(a), C-6b/H-2b, C-6b/H-7b, C-7b/H-6b, C-7b/H-8b, C-8b/H-7b, C-
8b/H-14b, C-9b/H-7b, C-9b/H-8b, C-10b/H-8a, C-10b/H-12b, C-10b/
H-14b, C-11b/H-12b, C-12b/H-14b, C-13b/H-12b, C-13b/H-14b, C-
14b/H-12b, C-14b/H-8b, C-1c/H-7c, C-7c/C-8c, C-8c/C-8b, C-8c/C-
14c, C-9c/H-8b, C-9c/H-7c, C-9c/H-8c, C-9c/H-8d, C-10c/H-12c, C-
10c/H-14c, C-10c/H-8d, C-11c/H-12c, C-12c/H-14c, C-13c/H-12c, C-
13c/H-14c, C-14c/H-8c, C-14c/H-12c, C-1d/H-3d,5d, C-1d/H-7d, C-
1d/H-8d, C-2d,6d/H-7d, C-4d/H-2d,6d, C-7d/H-8d, C-8d/H-10d, C-
8d/H-14d, C-9d/H-7d, C-9d/H-8d, C-10d/H-8d, C-10d/H-12d, C-
10d/H-14d, C-11d/H-12d, C-12d/H-10d, C-12d/H-14d, C-13d/H-12d,
C-14d/H-8d, C-14d/H-10d, C-14d/H-12d; NOESY correlations: H-
2a,6a/H-7a, H-2a,6a/H-8a, H-2a,6a/H-14a, H-7a/H-2a,6a, H-7a/H-
14a, H-8a/H-2a,6a, H-8a/H-7b, H-14a/H-2a,6a, H-14a/H-7a, H-2b/
H-3b(a), H-2b/H-3b(b), H-2b/H-7c, H-3b(a)/H-2b, H-3b(b)/H-2b, H-
6b/H-7b, H-7b/H-8a, H-7b/H-6b, H-8b/H-7c, H-8b/H-14c, H-14b/H-
14c, H-14b/H-10d,14d, H-7c/H-2b, H-7c/H-8b, H-7c/H-14c, H-14c/
H-14b, H-14c/H-8b, H-14c/H-7c, H-2d,6d/H-7d, H-2d,6d/H-8d, H-
3b(
6b, C-2b/H-7b, C-2b/H-7c, C-4b/H-2b, C-4b/H-3b(
3b( ), C-4b/H-6b, C-5b/H-3b( ), C-6b/H-2b, C-6b/H-7b, C-7b/H-
a
), C-1b/H-5b, C-1b/H-7b, C-1b/H-7c, C-2b/H-3b(
a
), C-2b/H-
a
), C-4b/H-
b
a
6b, C-7b/H-8b, C-8b/H-7b, C-8b/H-14b, C-9b/H-7b, C-9b/H-8b, C-
10b/H-8a, C-10b/H-12b, C-10b/H-14b, C-11b/H-12b, C-12b/H-14b,
C-13b/H-12b, C-13b/H-14b, C-13b/OMe-13b, C-14b/H-12b, C-14b/
H-8b, C-1c/H-7c, C-4c/OMe-4c, C-7c/C-8c, C-8c/C-8b, C-8c/C-14c,
C-9c/H-8b, C-9c/H-7c, C-9c/H-8c, C-9c/H-8d, C-10c/H-12c, C-10c/
H-14c, C-10c/H-8d, C-11c/H-12c, C-12c/H-14c, C-13c/H-12c, C-
13c/H-14c, C-13c/OMe-13c, C-14c/H-8c, C-14c/H-12c, C-1d/H-
3d,5d, C-1d/H-7d, C-1d/H-8d, C-2d,6d/H-7d, C-4d/H-2d,6d, C-4d/
OMe-4d, C-7d/H-8d, C-8d/H-10d, C-8d/H-14d, C-9d/H-7d, C-9d/
H-8d, C-10d/H-8d, C-10d/H-12d, C-10d/H-14d, C-11d/H-12d, C-
11d/OMe-11d, C-12d/H-10d, C-12d/H-14d, C-13d/H-12d, C-13d/
OMe-13d, C-14d/H-8d, C-14d/H-10d, C-14d/H-12d; 1H NMR for
1d [400 MHz, acetone-d6]
d
: 7.60 (2H, d, J¼8.8 Hz, H-2a,6a), 6.93
(2H, d, J¼8.8 Hz, H-3a,5a), 6.04 (1H, d, J¼9.8 Hz, H-7a), 5.13 (1H, d,
J¼9.8 Hz, H-8a), 3.91 (1H, H-2b), 2.32 (1H, br d, J¼15.2 Hz, H-
3b(
a
)), 2.14 (1H, br d, J¼15.2 Hz, H-3b(
b)), 5.32 (1H, H-5b), 6.40
(1H, H-6b)*, 6.04 (1H, H-12b)*, 5.89 (1H, d, J¼2.0 Hz, H-14b), 7.33
(2H, d, J¼8.8 Hz, H-2d,6d), 6.78 (2H, d, J¼8.8 Hz, H-3d,5d), 5.40
(1H, d, J¼2.0 Hz, H-7d), 5.00 (1H, d, J¼2.0 Hz, H-8d). H-12a, H-14a,
H-7b, H-8b H-7c, H-8c, H-12c, H-14c, H-10d, H-12d, and H-14d

T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
2959
7d/H-2d,6d, H-7d/H-10d,14d, H-8d/H-2d,6d, H-8d/H-10d,14d, H-
10d,14d/H-14b, H-10d,14d/H-7d, H-10d,14d/H-8d.
11d)(n), 102.2 (C-12d)(o), 156.56 (C-13d)(d), 106.9 (C-14d)(p), 54.8
(OMe-4b). (a)e(h): interchangeable. (i)ꢀ(u): overlapping; HMBC
correlations: H-2a,6a/C-4a, H-2a,6a/C-7a, H-3a,5a/C-1a, H-3a,5a/C-
4a, H-7a/C-1a, H-7a/C-2a,6a, H-7a/C-8a, H-7a/C-9a, H-8a/C-1a, H-8a/
C-7a, H-8a/C-9a, H-8a/C-10a, H-8a/C-14a, H-8a/C-9b, H-8a/C-10b, H-
8a/C-11b, H-12a/C-10a, H-12a/C-11a, H-12a/C-13a, H-12a/C-14a, H-
14a/C-8a, H-14a/C-10a, H-14a/C-12a, H-14a/C-13a, H-2b,6b/C-4b, H-
2b,6b/C-7b, H-3b,5b/C-1b, H-3b,5b/C-4b, H-7b/C-9a, H-7b/C-10a, H-
7b/C-11a, H-7b/C-1b, H-7b/C-2b,6b, H-7b/C-8b, H-7b/C-9b, H-7b/C-
8c, H-8b/C-10a, H-8b/C-1b, H-8b/C-7b, H-8b/C-9b, H-8b/C-10b, H-
8b/C-14b, H-8b/C-7c, H-8b/C-9c, H-12b/C-10b, H-12b/C-11b, H-12b/
C-13b, H-12b/C-14b, H-14b/C-8b, H-14b/C-10b, H-14b/C-12b, H-14b/
C-13b, H-2c,6c/C-4c, H-2c,6c/C-7c, H-3c,5c/C-1c, H-3c,5c/C-4c, H-7c/
C-8b, H-7c/C-9d, H-7c/C-10d, H-7c/C-11d, H-7c/C-1c, H-7c/C-2c,6c,
H-7c/C-8c, H-7c/C-9c, H-8c/C-7b, H-8c/C-9b, H-8c/C-10d, H-8c/C-1c,
H-8c/C-7c, H-8c/C-9c, H-8c/C-10c, H-8c/C-14c, H-12c/C-10c, H-12c/
C-11c, H-12c/C-13c, H-12c/C-14c, H-14c/C-8c, H-14c/C-10c, H-14c/C-
12c, H-14c/C-13c, H-2d,6d/C-4d, H-2d,6d/C-7d, H-3d,5d/C-1d, H-
3d,5d/C-4d, H-7d/C-1d, H-7d/C-2d,6d, H-7d/C-8d, H-7d/C-9d, H-8d/
C-1d, H-8d/C-7d, H-8d/C-9d, H-8d/C-10d, H-8d/C-14d, H-8d/C-9c,
H-8d/C-10c, H-8d/C-11c, H-12d/C-10d, H-12d/C-11d, H-12d/C-13d,
H-12d/C-14d, H-14d/C-8d, H-14d/C-10d, H-14d/C-12d, H-14d/C-13d,
OH-4a/C-3a,5a, OH-4a/C-4a, OH-11a/C-10a, OH-11a/C-11a, OH-13a/
C-12a, OH-13a/C-13a, OH-13a/C-14a, OH-13b/C-12b, OH-13b/C-13b,
OH-13b/C-14b, OH-4c/C-3c,5c, OH-4c/C-4c, OH-13c/C-12c, OH-13c/
C-13c, OH-13c/C-14c, OH-4d/C-3d,5d, OH-4d/C-4d, OH-11d/C-10d,
OH-11d/C-11d, OH-13d/C-12d, OH-13d/C-13d, OH-13d/C-14d, OMe-
4b/C-4b; NOESY correlations: H-2a,6a/H-7a, H-2a,6a/H-8a, H-
2a,6a/H-14a, H-3a,5a/OH-4a, H-3a,5a/OH-13a, H-3a,5a/OH-11d, H-
7a/H-2a,6a, H-7a/H-14a, H-8a/H-2a,6a, H-8a/H-14a, H-8a/H-2c,6c,
H-8a/H-8c, H-8a/H-14c, H-12a/OH-11a, H-12a/OH-13a, H-14a/H-
2a,6a, H-14a/H-7a, H-14a/H-8a, H-14a/OH-13a, H-2b,6b/H-7b, H-
2b,6b/H-8b, H-2b,6b/H-14b, H-2b,6b/H-8d, H-3b,5b/OMe-4b, H-7b/
H-2b,6b, H-7b/H-8b, H-8b/H-2b,6b, H-8b/H-7b, H-8b/H-14b, H-8b/
H-8d, H-12b/OH-13b, H-14b/H-2b,6b, H-14b/H-8b, H-14b/H-8d, H-
14b/OH-13b, H-2c,6c/H-7c, H-2c,6c/H-8c, H-2c,6c/H-14c, H-2c,6c/H-
8a, H-3c,5c/OH-4c, H-3c,5c/OH-4d, H-7c/H-2c,6c, H-7c/H-8c, H-8c/
H-2c,6c, H-8c/H-7c, H-8c/H-14c, H-8c/H-8a, H-12c/OH-13c, H-14c/
H-8a, H-14c/H-2c,6c, H-14c/H-8c, H-14c/OH-13c, H-2d,6d/H-7d, H-
2d,6d/H-8d, H-2d,6d/H-14d, H-3d,5d/OH-11a, H-3d,5d/OH-13d, H-
7d/H-2d,6d, H-7d/H-14d, H-8d/H-2b,6b, H-8d/H-8b, H-8d/H-14b, H-
8d/H-2d,6d, H-8d/H-14d, H-12d/OH-11d, H-12d/OH-13d, H-14d/H-
2d,6d, H-14d/H-7d, H-14d/H-8d, H-14d/OH-13d, OH-4a/H-3a,5a,
OH-11a/H-12a, OH-11a/H-3d,5d, OH-13a/H-3a,5a, OH-13a/H-12a,
OH-13a/H-14a, OH-13b/H-12b, OH-13b/H-14b, OH-4c/H-3c,5c, OH-
13c/H-12c, OH-13c/H-14c, OH-4d/H-3c,5c, OH-11d/H-3a,5a, OH-11d/
H-12d, OH-13d/H-3d,5d, OH-13d/H-12d, OH-13d/H-14d, OMe-4b/H-
3b,5b.
4.3.6. Deacetylation of 1e. Shoreaketone peracetate (1e) (5 mg)
was kept at 80 ꢁC for 4 h with 2 M NaOH (10 mL) and MeOH
(10 mL). The reaction mixture was neutralized with H2SO4 and
extracted with EtOAc. The resulting solid was purified with PTLC
[EtOAc/CHCl3/MeOH/H2O 80:40:11:2] to afford 1 (4 mg).
4.3.7. Preparation of hydrazone of 1. 2-Chloro-4.6-dinitrophenyl
hydrazine (35 mg) was added in 2 drops of sulfuric acid and 10 mL
of EtOH, and heated on a boiling water bath until hydrazine was
dissolved. After cooling, 1 (100 mg) in 2 mL of EtOH and 1 mL of
water was added to the solution. After 24 h, the solution was pu-
rified by column chromatography on silica gel with CHCl3/MeOH
(10:1) as an eluent to obtain phenylhydrazone derivative. An or-
ange solid; Positive ion ESIMS m/z: 1143 [MþNa]þ; Positive ion
HRESIMS m/z: 1143.2466 [MþNa]þ (calcd 1143.2462 for
C62H45O15N4ClNa).
4.3.8. Acidic conversion of shoreaketone (1). A mixture of shor-
eaketone (1) (5 mg) and trifluoromethane sulfonic acid (2.0 mL) in
MeOH (1.0 mL) was stirred under an atmosphere of nitrogen at rt
for 18 h. The reaction mixture was diluted by water (10 mL) and
extracted with ethyl acetate (10 mLꢂ2). The extract was dried over
anhydrous sodium sulfate. After solvent evaporation, the residue
was subjected to prep. TLC (EtOAc/CHCl3/MeOH/H2O 80:40:11:2) to
give 2a (4.8 mg). A reaction in EtOH gave 2b (1 mg).
4.3.9. Demethylation of 2a. To a solution of dry CH2Cl2 (30 mL)
containing 2a (2 mg) BCl3 was added (0.5 mL) at ꢀ25 ꢁC. The re-
action mixture was left at rt for 6 h and evaporated under reduced
pressure. The residue was purified by prep. TLC (EtOAc/CHCl3/
MeOH/H2O 80:40:11:2) to give 2 (1.6 mg).
4.3.10. (þ)-Isohopeaphenol monomethyl ether (2a). A pale yellow
solid; ½a 2D5
ꢃ
þ214 (c 0.1, MeOH); CD (c 21.7
mM, MeOH) nm (D 3 ): 241
(ꢀ51.1), 263 (þ19.2), 274 (þ16.5), 288 (þ29.3) (Fig. S5); Positive ion
ESIMS m/z: 943 [MþNa]þ; Positive ion HRESIMS m/z: 943.2712
[MþNa]þ (calcd 943.2725 for C57H44O12Na); 1H NMR [400 MHz,
acetone-d6]
d
: 7.54 (2H, d, J¼8.8 Hz, H-2a,6a)(a), 7.00 (2H, d, J¼8.8 Hz,
H-3a,5a)(b), 8.00 (1H, br s, OH-4a)(J), 5.65 (1H, d, J¼10.2 Hz, H-7a)(k)
,
5.45 (1H, br d, J¼10.2 Hz, H-8a)(l), 8.65 (1H, br s, OH-11a)(c), 6.38 (1H,
d, J¼2.2 Hz, H-12a)(d), 8.14 (1H, br s, OH-13a)(e), 6.31 (1H, d, J¼2.2 Hz,
H-14a)(f), 6.48 (2H, d, J¼8.6 Hz, H-2b,6b), 6.43 (2H, d, J¼8.6 Hz, H-
3b,5b), 5.19 (1H, br s Hz, H-7b), 3.47 (1H, br s Hz, H-8b)(g), 5.85 (1H, d,
J¼2.2 Hz, H-12b)(h), 7.71 (1H, br s, OH-13b)(i), 5.51 (1H, d, J¼2.2 Hz,
H-14b)(m), 6.40 (2H, d, J¼8.6 Hz, H-2c,6c), 6.35 (2H, d, J¼8.6 Hz, H-
3c,5c), 7.76 (1H, br s, OH-4c), 5.17 (1H, br s Hz, H-7c), 3.47 (1H, br s
Hz, H-8c)(g), 5.85 (1H, d, J¼2.2 Hz, H-12c)(h), 7.71 (1H, br s, OH-13c)(i)
,
,
4.3.11. (þ)-Isohopeaphenol monoethyl ether (2b). A pale yellow
solid; Positive ion ESIMS m/z: 957 [MþNa]þ; Positive ion HRESIMS
m/z: 957.2870 [MþNa]þ (calcd 957.2881 for C58H46O12Na); 1H NMR
5.52 (1H, d, J¼2.2 Hz, H-14c)(m), 7.54 (2H, d, J¼8.8 Hz, H-2d,6d)(a)
7.00 (2H, d, J¼8.8 Hz, H-3d,5d)(b), 7.96 (1H, br s, OH-4d)(J), 5.66 (1H,
d, J¼10.2 Hz, H-7d)(k), 5.44 (1H, br d, J¼10.2 Hz, H-8d)(l), 8.65 (1H, br
s, OH-11d)(c), 6.38 (1H, d, J¼2.2 Hz, H-12d)(d), 6.31 (1H, d, J¼2.2 Hz,
H-14d)(f), 3.58 (3H, s, OMe-4b). (a)e(i): overlapping. (j)e(m): in-
[400 MHz, acetone-d6]
d
: 7.54 (2H, d, J¼8.8 Hz, H-2a,6a)[a], 7.00 (2H,
d, J¼8.8 Hz, H-3a,5a)[b], 8.00 (1H, br s, OH-4a)[J], 5.65 (1H, d,
J¼10.2 Hz, H-7a)[k], 5.45 (1H, br d, J¼10.2 Hz, H-8a)[l], 8.60 (1H, br s,
terchangeable; 13C NMR for 2a [100 MHz, acetone-d6]
d: 133.54 (C-
OH-11a)[c], 6.38 (1H, d, J¼2.2 Hz, H-12a)[d], 8.11 (1H, br s, OH-13a)[e]
,
1a)(a), 130.5 (C-2a,6a)(i), 116.3 (C-3a,5a)(j), 158.3 (C-4a)(k), 93.3 (C-
6.31 (1H, d, J¼2.2 Hz, H-14a)[f], 6.48 (2H, d, J¼8.6 Hz, H-2b,6b), 6.43
(2H, d, J¼8.6 Hz, H-3b,5b), 5.19 (1H, br s Hz, H-7b), 3.47 (1H, br s Hz,
7a)(l), 53.53 (C-8a)(b), 140.5 (C-9a)(m), 117.9 (C-10a)(c), 158.2 (C-11a)(n)
,
102.2 (C-12a)(o),156.59 (C-13a)(d),106.9 (C-14a)(p),138.5 (C-1b),129.6
H-8b)[g], 5.85 (1H, d, J¼2.2 Hz, H-12b)[h], 7.66 (1H, br s, OH-13b)[i]
,
(C-2b,6b)(q), 112.9 (C-3b,5b), 157.5 (C-4b), 52.5 (C-8b)(e), 141.3 (C-
5.51 (1H, d, J¼2.2 Hz, H-14b)[m], 6.40 (2H, d, J¼8.6 Hz, H-2c,6c), 6.35
(2H, d, J¼8.6 Hz, H-3c,5c), 7.70 (1H, br s, OH-4c), 5.17 (1H, br s Hz, H-
7c), 3.47 (1H, br s Hz, H-8c)[g], 5.85 (1H, d, J¼2.2 Hz, H-12c)[h], 7.66
(1H, br s, OH-13c)[i], 5.52 (1H, d, J¼2.2 Hz, H-14c)[m], 7.54 (2H, d,
J¼8.8 Hz, H-2d,6d)[a], 7.00 (2H, d, J¼8.8 Hz, H-3d,5d)[b], 8.00 (1H, br
s, OH-4d)[J], 5.66 (1H, d, J¼10.2 Hz, H-7d)[k], 5.44 (1H, br d,
J¼10.2 Hz, H-8d)[l], 8.60 (1H, br s, OH-11d)[c], 6.38 (1H, d, J¼2.2 Hz,
9b)(f), 116.7 (C-10b)(s), 160.2 (C-11b)(t), 95.1 (C-12b)(g), 158 (C-13b)(u)
,
109.4 (C-14b)(h), 137.1 (C-1c), 129.6 (C-2c,6c)(q), 114.4 (C-3c,5c), 154.9
(C-4c), 43.3 (C-7c)(r), 52.4 (C-8c)(e), 141.4 (C-9c)(f), 116.7 (C-10c)(s)
,
160.2 (C-11c)(t), 95 (C-12c)(g), 158 (C-13c)(u), 109.3 (C-14c)(h), 133.49
(C-1d)(a), 130.5 (C-2d,6d)(i), 116.3 (C-3d,5d)(j), 158.3 (C-4d)(k), 93.3 (C-
7d)(l), 53.45 (C-8d)(b), 140.5 (C-9d)(m), 117.8 (C-10d)(c), 158.2 (C-

2960
T. Ito et al. / Tetrahedron 68 (2012) 2950e2960
H-12d)[d], 6.31 (1H, d, J¼2.2 Hz, H-14d)[f], 1.23 (3H, t, J¼7.0 Hz, CH3
in OEt-4b), 3.81 (2H, q, J¼7.0 Hz, CH2 in OEt-4b). [a]e[i]: over-
lapping. [j]e[m]: interchangeable.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.02.036. This data includes MOL file and
InChiKeys of the most important compounds described in this
article.
4.3.12. Methylation of 2 and 2a. (þ)-Isohopeaphenol (2) (4 mg),
previously isolated from the stem bark of V. indica,1,2 was reacted
with K2CO3 (200 mg) and MeI (10 mg) in dry acetone under reflux
for 6 h. The reaction mixture was treated in the usual manner and
the crude product (5 mg) obtained was purified by prep. TLC (n-
hexane/EtOAc 1:1) to provide permethyl ether (2c) (4 mg). Mono-
methyl ether of (þ)-isohopeaphenol (2a) (2 mg) was treated in the
same manner as 2 to afford 2c (2 mg).
References and notes
1. Seo, E.-K.; Chai, H.; Constant, H. L.; Santisuk, T.; Reutrakul, V.; Beecher, C. W. W.;
Farnsworth, N. R.; Cordell, G. A.; Pezzuto, J. M.; Kinghorn, A. D. J. Org. Chem.
1999, 64, 6976e6983.
2. Hui, M. G.; Chen, X.; Xiao, T. W.; Bo, H.; Ren, X. T. Eur. J. Org. Chem. 2006,
5551e5554.
3. Tabata, Y.; Takano, K.; Ito, T.; Iinuma, M.; Yoshimoto, T.; Miura, H.; Kitao, Y.;
Ogawa, S.; Hori, O. Am. J. Physiol. Cell. Physiol. 2007, 293, C411eC418.
4. Zhang, H. J.; Tan, G. T.; Hoang, V. D.; Hung, N. V.; Cuong, N. M.; Soejarto, D. D.;
Pezzuto, J. M.; Fong, H. H. J. Nat. Prod. 2003, 66, 263e268.
5. Dai, J. R.; Hallock, Y. F.; Cardellina, J. H., II; Boyd, M. R. J. Nat. Prod. 1998, 61,
351e353.
4.3.13. (þ)-Isohopeaphenol permethyl ether (2c). A pale yellow
solid; ½a 2D5
þ312 (c 0.05, CHCl3); Positive ion ESIMS m/z: 1069
ꢃ
[MþNa]þ; Positive ion HRESIMS m/z: 1069.4126 [MþNa]þ (calcd
6. Tanaka, T.; Ito, T.; Nakaya, K.; Iinuma, M.; Riswan, S. Phytochemistry 2000, 54,
63e69.
1069.4133 for C66H62O12Na); 1H NMR for 2a [400 MHz, acetone-d6]
7. Ito, T.; Tanaka, T.; Nakaya, K. i.; Iinuma, M.; Takahashi, Y.; Naganawa, H.;
Ohyama, M.; Nakanishi, Y.; Bastow, K. F.; Lee, K. H. Tetrahedron 2001, 57,
7309e7321.
8. Ito, T.; Tanaka, T.; Iinuma, M.; Iliya, I.; Nakaya, K. i.; Ali, Z.; Takahashi, Y.; Sawa,
R.; Shirataki, Y.; Murata, J. Tetrahedron 2003, 59, 5347e5363.
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Darnaedi, D. J. Nat. Prod. 2004, 67, 932e937.
10. Ito, T.; Tanaka, T.; Iinuma, M.; Nakaya, K. i.; Takahashi, Y.; Sawa, R.; Naganawa,
H.; Chelladurai, V. Tetrahedron 2003, 59, 1255e1264.
11. Ito, T.; Furusawa, M.; Iliya, I.; Tanaka, T.; Nakaya, K. i.; Sawa, R.; Kubota, Y.;
Takahashi, Y.; Riswan, S.; Iinuma, M. Tetrahedron Lett. 2005, 46, 3111e3114.
12. Ito, T.; Tanaka, T.; Ido, Y.; Nakaya, K. I.; Iinuma, M.; Riswan, S. Chem. Pharm. Bull.
2000, 48, 1001e1005.
13. Ito, T.; Abe, N.; Oyama, M.; Iinuma, M. Helv. Chim. Acta 2008, 91, 1989e1998.
14. Ito, T.; Abe, N.; Oyama, M.; Iinuma, M. Tetrahedron Lett. 2009, 50, 2516e2520.
15. Coggon, P.; Janes, N. F.; King, F. E.; King, T. J.; Molyneux, R. J.; Morgan, J. W. W.;
Sellars, K. J. Chem. Soc. 1965, 406e409.
16. Fletcher, A. C.; Porter, L. J.; Haslam, E.; Gupta, R. K. J. Chem. Soc., Perkin Trans. 1
1977, 1628e1637.
d
: 7.70 (2H, d, J¼8.8 Hz, H-2a,6a), 7.17 (2H, d, J¼8.8 Hz, H-3a,5a),
5.73 (1H, d, J¼10.5 Hz, H-7a), 5.52 (1H, br d, J¼10.5 Hz, H-8a), 6.55
(1H, d, J¼2.4 Hz, H-12a), 6.36 (1H, d, J¼2.4 Hz, H-14a), 6.41 (2H, d,
J¼8.6 Hz, H-2b,6b), 6.39 (2H, d, J¼8.6 Hz, H-3b,5b), 5.04 (1H, br s, H-
7b), 3.48 (1H, br s, H-8b), 5.98 (1H, d, J¼2.2 Hz, H-12b), 5.54 (1H, d,
J¼2.2 Hz, H-14b), 6.41 (2H, d, J¼8.6 Hz, H-2c,6c), 6.39 (2H, d,
J¼8.6 Hz, H-3c,5c), 5.04 (1H, br s, H-7c), 3.48 (1H, br s, H-8c), 5.98
(1H, d, J¼2.2 Hz, H-12c), 5.54 (1H, d, J¼2.2 Hz, H-14c), 7.70 (2H, d,
J¼8.8 Hz, H-2d,6d), 7.17 (2H, d, J¼8.8 Hz, H-3d,5d), 5.73 (1H, d,
J¼10.5 Hz, H-7d), 5.52 (1H, br d, J¼10.5 Hz, H-8d), 6.55 (1H, d,
J¼2.4 Hz, H-12d), 6.36 (1H, d, J¼2.4 Hz, H-14d), 3.48 (3H, s, OMe),
3.48 (3H, s, OMe), 3.58 (3H, s, OMe), 3.58 (3H, s, OMe), 3.63 (3H, s,
OMe), 3.63 (3H, s, OMe), 3.69 (3H, s, OMe), 3.69 (3H, s, OMe), 3.91
(3H, s, OMe), 3.91 (3H, s, OMe).
17. Takaya, Y.; Yan, K. X.; Terashima, K.; Ito, J.; Niwa, M. Tetrahedron 2002, 58,
7259e7265.
Supplementary data
18. Takaya, Y.; Yan, K. X.; Terashima, K.; He, Y. H.; Niwa, M. Tetrahedron 2002, 58,
9265e9271.
19. Ito, J.; Niwa, M.; Oshima, Y. Heterocycles 1997, 45, 1809e1813.
20. Ito, T.; Ali, Z.; Iliya, I.; Furusawa, M.; Tanaka, T.; Nakaya, K.; Takahashi, Y.; Sawa,
R.; Murata, J.; Darnaedi, D.; Iinuma, M. Helv. Chim. Acta 2005, 88, 23e34.
1D NMR spectra (1H, 13C, and DEPT spectra) and 2D NMR spectra
(1He1H COSY, 1He1H ROESY, 1He13C HSQC, 1He13C HMBC) for 1 at
ꢀ20 ꢁC in acetone-d6. 1D NMR spectra for derivatives of 1.