Megastigmane glycosides from the leaves of salacia chinensis

Article abstract of DOI:10.3987/COM-07-11193

Six new megastigmane glycosides, foliasalaciosides A₁ (1), A₂ (2), B₁ (3), B₂ (4), C (5), and D (6), were isolated from the methanolic extract of the leaves of Salacia chinensis (Hippocrateaceae) collected in Th

Full text of DOI:10.3987/COM-07-11193

HETEROCYCLES, Vol. 75, No. 1, 2008
131
HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 131 – 143. © The Japan Institute of Heterocyclic Chemistry
Received, 6th August, 2007, Accepted, 27th September, 2007, Published online, 28th September, 2007. COM-07-11193
MEGASTIGMANE GLYCOSIDES FROM THE LEAVES OF SALACIA
CHINENSIS
Seikou Nakamura, Yi Zhang, Yutana Pongpiriyadacha, Tao Wang,
Hisashi Matsuda, and Masayuki Yoshikawa*
Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412,
Japan, e-mail address: myoshika@mb.kyoto-phu.ac.jp
Abstract – Six new megastigmane glycosides, foliasalaciosides A1 (1), A2 (2), B1
(3), B2 (4), C (5), and D (6), were isolated from the methanolic extract of the
leaves of Salacia chinensis (Hippocrateaceae) collected in Thailand together with
16 known constituents. The absolute stereostructures of 1–6 were elucidated on
the basis of chemical and physicochemical evidence including the application of
the modified Mosher's method.
Salacia chinensis L. (syn. S. prinoides, Hippocrateaceae) is widely distributed in Thailand, Myanmar, and
India. The stems of S. chinensis have been used as a laxative and to relieve muscular pain in Thai
traditional medicine.1 On the other hand, the decoctions of the stems and leaves are given to cure diabetes
mellitus in the Ayurvedic system of Indian traditional medicine.2 Previously, we reported that the extract
from the stems of S. chinensis showed inhibitory activities on rat lens aldose reductase and α-glucosidase
and radical scavenging activity, and the structures of various triterpenes, nor-triterpenes, and
sesquiterpenes were characterized.3–6 However, the chemical constituents as well as the pharmacological
properties of the leaves of S. chinensis have not been characterized. During the course of our serial studies
on the bioactive constituents from Salacia species,7–14 six new megastigmane glycosides,
foliasalaciosides A1 (1), A2 (2), B1 (3), B2 (4), C (5), and D (6), were isolated from the methanolic extract
of the leaves of Salacia chinensis together with 16 known constituents. This paper deals with the isolation
and structure elucidation including the absolute configuration of 1–6.
The leaves of S. chinensis were cut and extracted with methanol under reflux. The methanolic extract was
partitioned into a mixture of ethyl acetate (EtOAc) and water to furnish an EtOAc-soluble portion and an
aqueous layer. The aqueous layer was further extracted with n-butanol (n-BuOH) to give a n-BuOH-
soluble portion. The n-BuOH-soluble portion was subjected to Diaion HP-20 column chromatography
(H2O → MeOH) to give the water- and methanol-eluted fractions. The methanol-eluted fraction was
subjected to normal- and reversed-phase silica gel column chromatographies, and finally HPLC to give
foliasalaciosides A1 (1, 0.0003% from the natural medicine), A2 (2, 0.0003%), B1 (3, 0.0004%), B2 (4,

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HETEROCYCLES, Vol. 75, No. 1, 2008
0.0003%), C (5, 0.0001%), and D (6, 0.0001%), together with 7 known megastigman glycosides,
blumenyl C β-D-glucopyranoside (7, 0.0032%),15 roseoside A (8, 0.0001%),16 dendranthemoside A (9,
0.0004%),17 alangioside A (10, 0.0002%),18 (6S,7E,9R)-6,9-dihydroxy-4,7-megastigmadien-3-one 9-O-α-
L-arabinopyranosyl(1→6)-β-D-glucopyranoside (11, 0.0001%),16 icariside B1 (12, 0.0002%),19 and
citroside B (13, 0.0004%),20 and nine known flavonol glycosides, paeonoside (14, 0.0008%),21
kaempferol 3-O-rutinosyl-7-O-β-D-glucopyranoside (15, 0.0008%),22 kaempferol 3-O-α-L-
rhamnopyranosyl(1→6)-β-D-galactopyranosyl-7-O-β-D-glucopyranoside (16, 0.0017%),23 clitorin (17,
0.0045%),24
kaempferol
3-O-(2,6-α-L-dirhamnopyranosyl-β-D-glucopyranosyl)-7-O-β-D-
glucopyranoside (18, 0.0061%),24 rutin (19, 0.027%),25 quercetin 3-O-rutinosyl-7-O-β-D-glucopyranoside
(20, 0.0016%),26 manghaslin (21, 0.0019%),24 and myricetin 3-O-β-D-rutinoside (22, 0.0015%).27
10
12
11
2
7
9
8
OGlc6 Ara(p)
OGlc6 Ara(f)
1
4
OGlc
OH
6
H
H
H
H
5
O
O
O
3
O
13
OH
OGlc
foliasalacioside B1 (3)
foliasalacioside B2 (4)
foliasalacioside A1 (1)
foliasalacioside A2 (2)
O
OGlc6 Ara(f)
OGlc6 Ara(p)
OGlc
OGlc
OH
H
O
O
O
blumenyl C
-glucopyranoside (7)
foliasalacioside D (6)
β-
D
foliasalacioside C (5)
roseoside A (8)
O
O
OGlc6 Ara (p)
OGlc
OH
H
OH
OH
OH
HO
GlcO
O
HO
GlcO
OGlc
OH
alangioside A (10)
dendranthemoside A (9)
11
citroside B (
OH
icariside B1 (12)
OH
OH
OH
R2O
O
R2O
O
O
HO
O
OR1
R1
R2
OR1
OGlc6
R1
R2
Glc6-Rha
Glc6-Rha
O
HO
HO
rutin (19):
20:
manghaslin (21): Glc2-Rha
H
Glc
HO
O
paeonoside (14):
Glc
Glc
Glc
Glc
Glc6-Rha
15:
16:
22
Gal6-Rha
H
R6ha
Glc2-Rha
R6ha
clitorin (17):
Glc: β-
Ara(p): α-
Ara(f): α-
Rha: α- -rhamnopyranosy
Gal: β- -galactopyranosyl
D
-glucopyranosyl
-arabinopyrano
-arabinofuranos
H
L
L
18: Glc2-Rha
L
D
R6ha
Glc
Chart 1
Structures of Foliasalaciosides A1 (1), A2 (2), B1 (3), B2 (4), C (5), and D (6)
Foliasalaciosides A1 (1) and A2 (2) were obtained as an amorphous powder with positive optical rotation
28
26
(1: [α]D +24.3°; 2: [α]D +30.9°, both in MeOH), respectively. The IR spectra of 1 and 2 showed
absorption bands assignable to hydroxyl, α,β-unsaturated carbonyl, and ether functions [1: 3420, 1653,
and 1078 cm–1; 2: 3423, 1653, and 1078 cm–1]. The common molecular formula, C19H32O8, of both 1 and
2 were determined from the quasimolecular ion peaks in the positive-ion FAB-MS [m/z 411 (M + Na)+]
and by high-resolution (HR) FAB-MS measurement. Acid hydrolysis of 1 and 2 with 1 M HCl liberated

HETEROCYCLES, Vol. 75, No. 1, 2008
133
D-glucose, which was identified by HPLC analysis
1
using an optical rotation detector.28,29 The H-NMR
13
(CD3OD) and C-NMR (Table 1) spectra of 1 and 2,
which were assigned by various NMR experiment,30
showed signals assignable to aglycon parts {1: δ 1.03,
1.11 (3H each, both s, 12, 11-H3), 1.46, 1.94 (1H each,
both m, 7-H2), 2.01 (1H, m, 6-H), 2.02 (1H, d, J = 17.9
Hz, 2-Hα), 2.55 (1H, d, J = 17.9 Hz, 2-Hβ); 2: δ 1.01,
1.10 (3H each, both s, 12, 11-H3), 1.49, 1.95 (1H each,
both m, 7-H2), 1.94 (1H, m, 6-H), 2.01 (1H, d, J = 17.9
Hz, 2-Hα), 2.56 (1H, d, J = 17.9 Hz, 2-Hβ)}, together
with β-D-glucopyranosyl moieties [1: δ 4.32 (1H, d, J =
8.2 Hz, 1'-H), 2: δ 4.33 (1H, d, J = 8.2 Hz, 1'-H)]. As
shown in Figure 1, the double quantum filter
correlation spectroscopy (DQF COSY) experiment on
1 and 2 indicated the presence of partial structures
written in bold lines, and in the heteronuclear multiple-
bond correlations (HMBC) experiment, long-range
correlations were observed between the following
protons and carbons: (1: 2-H and 3-C; 4-H and 6-C; 7-
H and 1-C; 8-H and 6-C; 10-H and 8, 9-C; 11-H and 1,
2, 6, 12-C; 12-H and 1, 2, 6, 11-C; 13-H and 4, 5, 6, 1'-
C; 1'-H and 13-C; 2: 2-H and 3-C; 4-H and 6, 13-C; 7-H and 1-C; 8-H and 6-C; 9-H and 1'-C; 10-H and 8,
9-C; 11-H and 1, 2, 6, 12-C; 12-H and 1, 2, 6, 11-C; 13-H and 4, 5, 6-C; 1'-H and 9-C). The planar
structures of 1 and 2 were the same as those of glochidionionoside B31 and (6R,9S)-megastigman-4-en-3-
one-9,13-diol 9-O-β-D-glucopyranoside,32 respectively. The relative stereostructures of 1 and 2 except for
the 9-positions were determined by NOESY experiments, in which correlations were observed between
the following proton pairs: 2-Hα and 12-H3; 2-Hβ and 11-H; 6-Hα and 12-H3; 11-H3 and 7-H2. The
absolute stereostructures of the 6-position in 1 and 2 were confirmed by circular dichroic (CD) spectra.15
The CD spectra (MeOH) of 1 and 2 showed Cotton effects at [1: 215 nm (Δε +2.06), 328 nm (Δε +0.27);
2: 216 nm (Δε +4.23), 330 nm (Δε +0.45)], which was very similar to those of blumenyl C β-D-
glucopyranoside (8) [216 nm (Δε +3.74), 333 nm (Δε +0.99)] reported by Buske et al,15 so that the
absolute configuration of the 6-position in 1 and 2 was determined to be R orientation. The absolute
configurations of the 9-position on 1 and 2 were clarified by a modified Mosher's method. Namely,
enzymatic hydrolysis of 1 and 2 with nariginase gave a common aglycon, foliasalaciol A (1a). Next, the
(R)- and (S)-MTPA esters (1b, 1c) were derived from 1a upon reaction with (R)- and (S)-MTPA in the
presence of EDC·HCl and 4-DMAP. The 10-methyl protons of the (S)-MTPA ester (1c) resonated at
lower field than those of the (R)-MTPA ester (1b) [Δδ: positive], while the protons on the 2, 4, 6, 7, 8, 11,
12, and 13-positions of 1c were observed at higher fields compared to those of 1b [Δδ: negative].

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HETEROCYCLES, Vol. 75, No. 1, 2008
Consequently, the absolute configurations of the 9-position in 1 and 2 were elucidated to be R orientation.
On the basis of above-mentioned evidence, the structures of foliasalaciosides A (1) and B (2) were
characterized as shown.33
13
a
b
Table 1. C-NMR Data (125 MHz, CD3OD, CDCl3) for Foliasalaciosides
A1 (1), A2 (2), B1 (3), B2 (4), C (5), and D (6).
a
b
a
a
a
a
a
6
1
1a
2
3
4
5
37.3
48.6
202.2
123.2
167.9
47.5
27.5
39.6
68.4
23.7
27.7
28.9
70.8
103.5
75.1
78.1
71.7
78.2
62.8
36.3
47.6
199.7
121.7
167.6
46.0
26.2
38.1
67.6
23.8
27.4
28.7
64.8
37.4
48.6
202.4
121.5
172.5
47.6
27.1
37.8
75.2
20.0
27.8
28.8
65.1
102.1
75.2
78.2
71.8
78.0
62.9
37.4
48.1
202.5
125.3
170.4
52.4
27.0
37.9
75.7
20.1
27.6
29.1
25.1
102.3
75.1
78.0
71.8
76.9
69.4
105.3
72.4
74.2
69.8
66.7
37.4
48.2
202.6
125.4
170.3
52.4
26.9
37.8
75.9
20.1
27.6
29.1
25.1
102.3
75.2
78.1
72.2
76.8
68.2
109.9
83.2
79.0
86.0
63.2
49.4
218.3
37.1
32.6
128.7
138.0
26.1
39.0
76.0
19.94
25.2
25.2
19.89
102.3
75.2
78.1
71.8
76.9
69.4
105.2
72.4
74.2
69.8
66.6
37.7
38.5
35.1
201.7
131.7
168.9
28.1
37.3
76.0
20.0
27.3
27.3
11.8
102.4
75.2
78.1
72.2
76.9
68.2
111.0
83.2
79.0
85.9
63.1
1
2
3
4
5
6
7
8
9
10
11
12
13
1'
2'
3'
4'
5'
6'
1''
2''
3''
4''
5''
Foliasalaciosides B1 (3) and B2 (4) were obtained as an amorphous powder with positive optical rotation
27
26
(3: [α]D +25.2°; 4: [α]D +30.5°, both in MeOH), respectively. The IR spectra of 3 and 4 showed
absorption bands assignable to hydroxyl, α,β-unsaturated carbonyl, and ether functions [3: 3405, 1651,
and 1075 cm–1; 4: 3397, 1655, and 1075 cm–1]. The same molecular formula, C24H40O11, of both 3 and 4
were determined from the positive- and negative-ion FAB-MS [m/z 527 (M + Na)+, m/z 503 (M – H)–]
and by HRFABMS measurements. Acid hydrolysis of 3 and 4 with 1 M HCl liberated D-glucose and L-
1
arabinose, which were identified by HPLC analysis using an optical rotation detector.28,29 The H-NMR
13
(CD3OD) and C-NMR (Table 1) spectra30 of 3 and 4 showed signals due to aglycon parts {3: δ 1.01,
1.09 (3H each, both s, 12, 11-H3), 1.97 (1H, m, 6-H), 1.97 (1H, d, J = 17.2 Hz, 2-Hα), 2.46 (1H, d, J =
17.2 Hz, 2-Hβ); 4: δ 1.01, 1.09 (3H each, both s, 12, 11-H3), 1.97 (1H, d, J = 17.4 Hz, 2-Hα), 1.98 (1H, m,
6-H), 2.47 (1H, d, J = 17.4 Hz, 2-Hβ)}, together with β-D-glucopyranosyl moieties [3: δ 4.31 (d, J = 7.6
Hz, H-1'); 4: δ 4.31 (d, J = 7.6 Hz, H-1')], an α-L-arabinopyranosyl moiety [3: 4.28 (d, J = 6.8 Hz, H-1'')],
and an α-L-arabinofuranosyl moiety [4: δ 4.96 (d, J = 1.5 Hz, H-1'')]. The proton and carbon signals in
1
the H- and 13C-NMR spectra of 3 and 4 were superimposable on those of blumenyl C β-D-
glucopyranoside (7)15 except for the glycoside moiety, while the signals due to the 9-O-diglycosyl moiety

HETEROCYCLES, Vol. 75, No. 1, 2008
135
of 3 and 4 were very similar to those of (6S,7E,9R)-6,9-
dihydroxy-4,7-megastigmadien-3-one 9-O-α-L-
arabinopyranosyl(1→6)-β-D-glucopyranoside (11)16 and
floralginsenoside D,28 respectively. As shown in Figure 2,
the positions of the glycoside linkages in 3 and 4 were
determined by a HMBC experiment, which showed long-
range correlations between the following protons and
carbons: 1'-H and C-9; 1''-H and C-6'. The relative
stereostructures of 3 and 4 except for the 9-position were
determined by a NOESY experiment, in which
correlations were observed between the following proton
pairs: 2-Hα and 12-H3; 2-Hβ and 11-H3; 6-H and 12-H3;
11-H3 and 7-H2. The absolute stereostructures of the 6-
position in 3 and 4 were also confirmed by CD spectra.15
The CD spectra (MeOH) of 3 and 4 showed Cotton effects at [3: 214 nm (Δε +1.92), 335 nm (Δε +0.35);
4: 214 nm (Δε +1.26), 327 nm (Δε +0.19)], so that the absolute configurations of the 6-position in 3 and 4
were determined to be R orientation. Finally, enzymatic hydrolysis of 3 and 4 with nariginase gave a same
aglycon, blumenyl C.33,34 On the basis of above-mentioned evidence, the structures of foliasalaciosides B1
(3) and foliasalaciosides B2 (4) was characterized as shown.
Foliasalaciosides C (5), obtained as an amorphous powder
23
with negative optical rotation ([α]D –20.4° in MeOH),
showed absorption bands at 3379, 1705, 1660, and 1084
cm–1 due to hydroxyl, carbonyl, olefin and ether functions
in the IR spectrum. The molecular formula, C24H40O11,
was determined from the positive- and negative-ion FAB-
MS [m/z 527 (M + Na)+, m/z 503 (M – H)–] and by
HRFABMS measurement. The acid hydrolysis of 5 yielded
1
D-glucose and L-arabinose.28,29 The H-NMR (CD3OD)
13
and C-NMR (Table 1) spectra30 of 5 showed signals due
to an aglycon part {δ 1.16 (6H, s, 11, 12-H3), 1.20 (3H, d,
J = 6.1 Hz, 10-H3), 1.74 (3H, s, 13-H3)}, together with a β-D-glucopyranosyl moiety [δ 4.34 (1H, d, J =
8.0 Hz, 1'-H)] and an α-L-arabinopyranosyl moiety [4.33 (1H, d, J = 6.7 Hz, 1''-H)]. The DQF COSY
experiment on 5 showed correlations as shown in Figure 3. Furthermore, in the HMBC experiment, long-
range correlations were observed between the following protons and carbons: 3-H and 2, 5-C; 4-H and 2,
5, 6-C; 7-H and 1, 5-C; 9-H and 1'-C; 10-H and 8, 9-C; 11-H and 1, 2, 6, 12-C; 12-H and 1, 2, 6, 11-C; 1'-
H and 9-C; 1''-H and 6'-C. The proton and carbon signals of the 9-O-diglycosyl moiety in the 1H- and 13C-
NMR spectra of 5 were very similar to those of 3 and 11.16 Furthermore, the configuration of the 9-
position was characterized by comparison of the 9-, 10-, and 1'-carbon signals of 5 in the 13C NMR
(CD3OD) spectrum with those of synthetic known megastigmane glycosides, (1R/S)-3-[(4R)-4-hydroxy-

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HETEROCYCLES, Vol. 75, No. 1, 2008
2,6,6-trimethylcyclohex-1-enyl]-1-methylpropyl-β-D-glucopyranoside,36 having the same side chain
(butanol O-glycoside moiety) as 5. Namely, It was reported that the 13C NMR signal [δc 76.1 (9-C); 19.8
(10-C); 102.2 (1'-C)] of the synthetic megastigmane having the R-configuration was shifted upfield
relative to that [δc 77.9 (9-C); 21.8 (10-C); 103.9 (1'-C)] of the synthetic megastigmane having the S-
configuration.36 The 9-, 10-, and 1'-carbon signals of 5 were observed at δc 76.0 (9-C), 19.9 (10-C), and
102.3 (1'-C), so that the C-9 configuration of 5 was determined to be R. This evidence led us to formulate
the structure of foliasalaciosides F (5) as shown.
Foliasalaciosides G (6), obtained as an amorphous powder with negative optical rotation ([α]D26 –17.7° in
MeOH), showed absorption bands at 3339, 1653, and 1074 cm–1 due to hydroxyl, α,β-unsaturated
carbonyl, and ether functions in the IR spectrum. The molecular formula, C24H40O11, was determined
from the positive- and negative-ion FAB-MS [m/z 527 (M + Na)+, m/z 503 (M – H)–] and by HRFABMS
1
measurement. The acid hydrolysis of 6 yielded D-glucose and L-arabinose.28,29 The H-NMR (CD3OD)
13
and C-NMR (Table 1) spectra30 of 6 showed signals due to an aglycon part [δ 1.20 (6H, s, 11, 12-H3),
1.22 (3H, d, J = 6.1 Hz, 10-H3), 1.76 (3H, s, 13-H3)], together with a β-D-glucopyranosyl moiety [δ 4.34
(1H, d, J = 7.6 Hz, 1'-H)] and an α-L-arabinofuranosyl moiety [4.98 (1H, d, J = 1.4 Hz, 1''-H)]. The
proton and carbon signals of the aglycon part of 6 in the 1H- and 13C-NMR spectra were superimposable
on those of plataninoside F,36 whereas the signals due to the 9-O-diglycosyl moiety of 6 were very similar
to those of 4 and floralginsenoside D.28 The structure of 6 was characterized by means of DQF COSY and
HMBC experiments (Figure 3). The position of the glycosides linkage were determined by a HMBC
experiment, which showed long-range correlation between 1'-H and 9-C; 1''-H and 6'-C. Furthermore, the
configuration of the 9-position of 6 was characterized by comparison of the 13C-NMR data.36 Namely, the
9-, 10-, and 1'-carbon signals of 6 were observed at δc 76.0 (9-C), 20.0 (10-C), and 102.4 (1'-C), so that
the 9-C configuration was determined to be R and the total structure of foliasalaciosides G (6) was
characterized as shown.
EXPERIMENTAL
The following instruments were used to obtain physical data: specific rotations, Horiba SEPA-300 digital
polarimeter (l = 5 cm); CD spectra, JASCO J-720WI spectrometer; UV spectra, Shimadzu UV-1600
spectrometer; IR spectra, Shimadzu FTIR-8100 spectrometer; 1H NMR spectra, JEOL JNM-LA500 (500
MHz) spectrometer; 13C NMR spectra, JEOL JNM-LA500 (125 MHz) spectrometer with
tetramethylsilane as an internal standard; EIMS and HREIMS, JEOL JMS-GCMATE mass spectrometer;
FABMS and HRFABMS, JEOL JMS-SX 102A mass spectrometer; HPLC detector, Shimadzu RID-6A
refractive index and SPD-10A UV-VIS detectors. HPLC column, Cosmosil 5C18-MS-II (Nacalai Tesque
Inc., 250 × 4.6 mm i.d.) and (250 × 20 mm i.d.) columns were used for analytical and preparative
purposes, respectively.
The following experimental conditions were used for chromatography: normal-phase silica gel column
chromatography, silica gel BW-200 (Fuji Silysia Chemical, Ltd., 150–350 mesh); reversed-phase silica
gel column chromatography, Chromatorex ODS DM1020T (Fuji Silysia Chemical, Ltd., 100–200 mesh);
Diaion HP-20 column chromatography (Nippon Rensui); TLC, pre-coated TLC plates with silica gel

HETEROCYCLES, Vol. 75, No. 1, 2008
137
60F254 (Merck, 0.25 mm) (normal-phase) and silica gel RP-18 F254S (Merck, 0.25 mm) (reversed-phase);
detection was achieved by spraying with 1% Ce(SO4) 2–10% aqueous H2SO4, followed by heating.
Plant Material
The dried leaves of S. chinensis were collected at Thailand in 2006 and identified by one of authors
(Rajamangala University of Technology Srivijaya, Pongpiriyadacha Y.). A voucher of the plant is on file
in our laboratory (2006. Thai-06).
Extraction and Isolation
The dried leaves of S. chinensis Linn. (5.8 kg) were finely cut and extracted 3 times with methanol
(MeOH) under reflux for 3 h. Evaporation of the solvent under reduced pressure provided a methanolic
extract (756 g, 13.0%). The MeOH extract (712 g) was partitioned into an EtOAc–H2O (1:1, v/v) mixture
to furnish an EtOAc-soluble fraction (222 g, 4.1%) and an aqueous phase. The aqueous phase was further
extracted with n-BuOH to give a n-BuOH-soluble fraction (130 g, 2.4%) and a H2O-soluble fraction (361
g, 6.6%).
The n-BuOH-soluble fraction (100 g) was subjected to Diaion HP-20 column chromatography (1.5 kg,
H2O → MeOH → acetone) to give H2O-eluted fraction (49.8 g, 1.2%), MeOH-eluted fraction (39.2 g,
0.93%) and acetone-eluted fraction (11.0 g, 0.26%), respectively. The MeOH-eluted fraction (39.2 g) was
subjected to ordinary-phase silica gel column chromatography {480 g, CHCl3–MeOH (10:1, v/v)
→ CHCl3–MeOH–H2O [(10:3:1, v/vv, lower layer) → (7:3:1, v/vv, lower layer) → (6:4:1, v/vv, lower
layer)] → MeOH} to give ten fractions [Fr. 1 (0.5 g), Fr. 2 (0.6 g), Fr. 3 (1.3 g), Fr. 4 (7.3 g), Fr. 5 (3.0 g),
Fr. 6 (6.7 g), Fr. 7 (1.6 g), Fr. 8 (2.4 g), Fr. 9 (9.3 g), Fr. 10 (3.5 g)]. Fraction 3 (1.3 g) was subjected to
reversed-phase silica gel column chromatography [480 g, MeOH–H2O (10:90 → 20:80 → 30:70 → 40:60
→ 50:50 → 60:40 → 100: 0, v/v)] to give five fractions [Fr. 3-1 (121 mg), Fr. 3-2 (111 mg), Fr. 3-3 (389
mg), Fr. 3-4 (131 mg), Fr. 3-5 (450 mg)]. Fraction 3-3 (389 mg) was separated by HPLC [MeOH–H2O
(40:60, v/v)] and finally purified with HPLC [MeCN–MeOH–H2O (15:8:77, v/v/v)] to furnish blumenyl
C β-D-glucopyranoside (7, 71.5 mg). Fraction 3-4 (131 mg) was subjected to HPLC [MeOH–H2O (40:60,
v/v)] and purified by HPLC [MeCN–MeOH–H2O (15:8:77, v/v/v)] to give blumenyl C β-D-
glucopyranoside (7, 17.2 mg). Fraction 4 (7.3 g) was subjected to reversed-phase silica gel column
chromatography [220g, MeOH–H2O (0:100 → 10:90 → 20:80 → 30:70 → 40:60 → 60:40 → 100: 0,
v/v) → CHCl3] to give ten fractions [Fr. 4-1 (783 mg), Fr. 4-2 (821 mg), Fr. 4-3 (1.12 g), Fr. 4-4 (577
mg), Fr. 4-5 (288 mg), Fr. 4-6 (652 mg), Fr. 4-7 (1.30 g), Fr. 4-8 (413 mg), Fr. 4-9 (253 mg), Fr. 4-10
(760 mg)]. Fraction 4-6 (652 mg) was separated by HPLC [MeOH–H2O (30:70, v/v)] to furnish ten
fractions [Fr. 4-6-1 (7.2 mg), Fr. 4-6-2 (15.6 mg), Fr. 4-6-3 (17.8 mg), Fr. 4-6-4 (18.6 mg), Fr. 4-6-5 (51.2
mg), Fr. 4-6-6 (20.5 mg), Fr. 4-6-7 (30.6 mg), Fr. 4-6-8 (35.8 mg), Fr. 4-6-9 (18.0 mg), Fr. 4-6-10 (44.6
mg)]. Fr. 4-6-8 (35.8 mg) was finally purified by HPLC [MeCN–MeOH–H2O (12:8:80, v/v/v)] to give
foliasalacioside A1 (1, 13.9 mg), foliasalacioside A2 (2, 11.1 mg), and icariside B1 (12, 6.2 mg). Fraction
4-7 (1.30 g) was separated by HPLC [MeOH–H2O (40:60, v/v)] and [MeCN–MeOH–H2O (15:8:77,
v/v/v)] to furnish foliasalacioside B1 (3, 17.3 mg), foliasalacioside B2 (4, 11.9 mg), foliasalacioside D (6,

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HETEROCYCLES, Vol. 75, No. 1, 2008
5.8 mg), blumenyl C β-D-glucopyranoside (7, 48.1 mg), roseoside A (8, 3.6 mg), dendranthemoside A (9,
2.2 mg), and citroside B (13, 10.0 mg). Fraction 4-8 (413 mg) was subjected to HPLC [MeOH–H2O
(40:60, v/v)] to afford nine fractions [Fr. 4-8-1 (11.9 mg), Fr. 4-8-2 (22.2 mg), Fr. 4-8-3 (47.6 mg), Fr. 4-
8-4 (16.2 mg), Fr. 4-8-5 (14.2 mg), Fr. 4-8-6 (11.4 mg), Fr. 4-8-7 (14.6 mg), Fr. 4-8-8 (16.8 mg), Fr. 4-8-
9 (16.2 mg)]. Fr. 4-8-7 (14.6 mg) was further purified by HPLC [MeCN–MeOH–H2O (15:8:77, v/v/v)] to
give foliasalacioside C (5, 3.8 mg). Fraction 5 (3.0 g) was subjected to reversed-phase silica gel column
chromatography [90 g, MeOH–H2O (10:90 → 20:80 → 30:70 → 40:60 → 50:50 → 100: 0, v/v) ] to
afford seven fractions [Fr. 5-0 (812 mg), Fr. 5-1 (196 mg), Fr. 5-2 (212 mg), Fr. 5-3 (224 mg), Fr. 5-4
(158 mg), Fr. 5-5 (400 mg), Fr. 5-6 (624 mg)]. Fraction 5-3 (224 mg) was purified by HPLC [MeOH–
H2O (26:74, v/v)] and [MeCN–MeOH–H2O (10:8:82, v/v/v)] to furnish dendranthemoside A (9, 13.7 mg)
and alangioside A (10, 7.1 mg). Fraction 6 (6.7 g) was subjected to reversed-phase silica gel column
chromatography [220 g, MeOH–H2O (10:90 → 20:80 → 30:70 → 40:60 → 50:50 → 60:40 → 100:0,
v/v) → CHCl3] to give eleven fractions [Fr. 6-1 (809 mg), Fr. 6-2 (859 mg), Fr. 6-3 (118 mg), Fr. 6-4
(103 mg), Fr. 6-5 (480 mg), Fr. 6-6 (300 mg), Fr. 6-7 (250 mg), Fr. 6-8 (1.28 g), Fr. 6-9 (239 mg), Fr. 6-
10 (335 mg), Fr. 6-11 (1.25 g)]. Fraction 6-2 (859 mg) was separated by HPLC [MeOH–H2O (25:75,
v/v)] to afford thirteen fractions [Fr. 6-2-1 (18.2 mg), Fr. 6-2-2 (28.5 mg), Fr. 6-2-3 (36.3 mg), Fr. 6-2-4
(16.7 mg), Fr. 6-2-5 (42.5 mg), Fr. 6-2-6 (32.1 mg), Fr. 6-2-7 (38.9 mg), Fr. 6-2-8 (70.6 mg), Fr. 6-2-9
(37.5 mg), Fr. 6-2-10 (58.3 mg), Fr. 6-2-11 (21.2 mg), Fr. 6-2-12 (24.6 mg), Fr. 6-2-13 (18.9 mg)].
Fraction 6-2-12 (24.6 mg) was purified by HPLC [MeCN–MeOH–H2O (7:7:86, v/v/v)] to furnish
(6S,7E,9R)-6,9-dihydroxy-4,7-megastigmadien-3-one
9-O-α-L-arabinopyranosyl(1→6)-β-D-
glucopyranoside (11, 4.3 mg) and citroside B (13, 5.5 mg). Fraction 7 (1.6 g) was subjected to reversed-
phase silica gel column chromatography [50 g, MeOH–H2O (20:80 → 30:70 → 40:60 → 50:50 → 100:0,
v/v) ] to afford three fractions [Fr. 7-1 (529 mg), Fr. 7-2 (570 mg), Fr. 7-3 (321 mg)]. Fraction 7-2 was
identified as rutin (19, 570 mg). Fraction 8 (2.4 g) was subjected to reversed-phase silica gel column
chromatography [100 g, MeOH–H2O (20:80 → 30:70 → 40:60 → 50:50 → 100:0, v/v) ] to give four
fractions [Fr. 8-1 (562 mg), Fr. 8-2 (445 mg), Fr. 8-3 (284 mg), Fr. 8-4 (463 mg)]. Fraction 8-2 was
identified as rutin (19, 445 mg), fraction 8-3 (284 mg) was purified by HPLC [MeOH–H2O (45:55, v/v)]
to give rutin (19, 7.6 mg). Fraction 9 (9.3 g) was subjected to reversed-phase silica gel column
chromatography [50 g, MeOH–H2O (20:80 → 30:70 → 40:60 → 50:50 → 60:40 →100:0, v/v) ] to
afford eleven fractions [Fr. 9-1 (1.19 g), Fr. 9-2 (322 mg), Fr. 9-3 (230 mg), Fr. 9-4 (295 mg), Fr. 9-5
(511 mg), Fr. 9-6 (954 mg), Fr. 9-7 (189 mg), Fr. 9-8 (1.30 g), Fr. 9-9 (484 mg), Fr. 9-10 (981 mg), Fr. 9-
11 (1.66 g)]. Fraction 9-4 (295 mg) was separated by HPLC [MeOH–H2O (24:76, v/v)] to furnish
kaempferol 3-O-(2,6-α-L-dirhamnopyranosyl-β-D-glucopyranosyl)-7-O-β-D-glucopyranoside (18, 138
mg). Fraction 9-5 (511 mg) was subjected to HPLC [MeOH–H2O (24:76, v/v)] to give paeonoside (14,
32.5 mg), kaempferol 3-O-rutinosyl-7-O-β-D-glucopyranoside (15, 18.2 mg), kaempferol 3-O-α-L-
rhamnopyranosyl(1→6)-β-D-galatopyranosyl-7-O-β-D-glucopyranoside (16, 71.6 mg), kaempferol 3-O-
(2,6-α-L-dirhamnopyranosyl-β-D-glucopyranosyl)-7-O-β-D-glucopyranoside (18, 118.1 mg), and
quercetin 3-O-rutinosyl-7-O-β-D-glucopyranoside (20, 69.2 mg). Fraction 9-8 (1.30 g) was separated by
HPLC [MeOH–H2O (24:76, v/v)] and finally purified by HPLC [MeOH–H2O–MeCN (13:8:79, v/v/v)] to

HETEROCYCLES, Vol. 75, No. 1, 2008
139
furnish kaempferol 3-O-rutinoside 7-O-β-D-glucopyranoside (15, 17.1 mg), clitorin (17, 188 mg),
manghalin (21, 80.3 mg), and myricetin 3-O-β-D-rutinoside (22, 63.0 mg). Fraction 9-9 (484 mg) was
purified by HPLC [MeOH–H2O (40:60, v/v)] to give rutin (19, 65.8 mg).
1
13
The known compounds were identified by comparison of their physical data ([α]D, H-NMR, C-NMR,
MS] with reported values.
Foliasalacioside A1 (1): An amorphous powder, [α]D28 +24.3° (c 0.65, MeOH). High-resolution positive-
ion FAB-MS: Calcd for C19H32O8Na (M+Na)+: 411.1995. Found: 411.1990. CD [MeOH, nm (Δε)]: 215
(+2.06), 328 (+0.27). UV [MeOH, nm (log ε)]: 238 (4.20). IR (KBr): 3420, 2932, 1653, 1489, 1387, 1078,
1036 cm-1. 1H-NMR (CD3OD, 500 MHz) δ: 1.03, 1.11 (3H each, both s, 12, 11-H3), 1.16 (3H, d, J = 6.2
Hz, 10-H3), 1.46, 1.94 (1H each, both m, 7-H2), 1.53 (2H, m, 8-H2), 2.01 (1H, m, 6-H), 2.02 (1H, d, J =
17.9 Hz, 2-Hα), 2.55 (1H, d, J = 17.9 Hz, 2-Hβ), 3.71 (1H, m, 9-H), 4.32 (1H, d, J = 8.2 Hz, 1'-H), 4.38,
4.54 (1H each,both dd, J = 1.4, 16.5 Hz, 13-H2), 6.16 (1H, br s, 4-H). 13C-NMR (125 MHz, CD3OD) δc:
given in Table 1. Positive-ion FAB-MS: m/z 411 (M+Na)+.
Foliasalacioside A2 (2): An amorphous powder, [α]D26 +30.9° (c 0.55, MeOH). High-resolution positive-
ion FAB-MS: Calcd for C19H32O8Na (M+Na)+: 411.1995. Found: 411.1990. CD [MeOH, nm (Δε)]: 216
(+4.23), 330 (+0.45). UV [MeOH, nm (log ε)]: 239 (4.09). IR (KBr): 3423, 2932, 1653, 1489, 1387, 1078,
1034 cm-1. ; 1H-NMR (CD3OD, 500 MHz) δ: 1.01, 1.10 (3H each, both s, 12, 11-H3), 1.18 (3H, d, J = 6.2
Hz, 10-H3), 1.49, 1.95 (1H each, both m, 7-H2), 1.62 (2H, m, 8-H2), 1.94 (1H, m, 6-H), 2.01 (1H, d, J =
17.9 Hz, 2-Hα), 2.56 (1H, d, J = 17.9 Hz, 2-Hβ), 3.88 (1H, m, 9-H), 4.18 (1H, dd, J = 2.0, 17.8 Hz, 13-
13
H ), 4.36 (1H, dd, J = 1.4, 17.8 Hz, 13-Hb), 4.33 (1H, d, J = 8.3 Hz, 1'-H), 6.04 (1H, br s, 4-H). C-
NMR (125 MHz, CD3OD) δc: given in Table 1. Positive-ion FAB-MS: m/z 411 (M+Na)+.
27
Foliasalacioside B1 (3): An amorphous powder, [α]D +25.2° (c 0.80, MeOH). High-resolution positive-
ion FAB-MS: Calcd for C24H40O11Na (M+Na)+: 527.2468. Found: 527.2461. CD [MeOH, nm (Δε)]:214
(+1.92), 335 (+0.35). UV [MeOH, nm (log ε)]: 241 (3.98). IR (KBr): 3405, 2934, 1651, 1379, 1075, 1009
1
cm-1. H-NMR (CD3OD, 500 MHz) δ: 1.01, 1.09 (3H each, both s, 12, 11-H3), 1.18 (3H, d, J = 6.2 Hz,
10-H3), 1.48, 1.98 (1H each, both m, 7-H2), 1.62 (2H, m, 8-H2), 1.97 (1H, m, 6-H), 1.97 (1H, d, J = 17.2
Hz, 2-Hα), 2.46 (1H, d, J = 17.2 Hz, 2-Hβ), 2.05 (3H, s, 13-H3), 3.85 (1H, m, 9-H), 4.28 (1H, d, J = 6.8
13
Hz, 1''-H), 4.31 (1H, d, J = 8.2 Hz, 1'-H), 5.80 (1H, s, 4-H). C-NMR (125 MHz, CD3OD) δc: given in
Table 1. Positive-ion FAB-MS: m/z 527 (M+Na)+. Negative-ion FAB-MS: m/z 503 (M–H)–.
26
Foliasalacioside B2 (4): An amorphous powder, [α]D +30.5° (c 0.60, MeOH). High-resolution positive-
ion FAB-MS: Calcd for C24H40O11Na (M+Na)+: 527.2468. Found: 527.2473. CD [MeOH, nm (Δε)]: 214
(+1.26), 327 (+0.19). UV [MeOH, nm (log ε)]: 240 (3.92). IR (KBr): 3397, 2930, 1655, 1379, 1075, 1040
1
cm-1. H-NMR (CD3OD, 500 MHz) δ: 1.01, 1.09 (3H each, both s, 12, 11-H3), 1.18 (3H, d, J = 6.1 Hz,
10-H3), 1.41, 1.96 (1H each, both m, 7-H2), 1.61 (2H, m, 8-H2), 1.97 (1H, d, J = 17.4 Hz, 2-Hα), 2.47 (1H,
d, J = 17.4 Hz, 2-Hβ), 1.98 (1H, m, 6-H), 2.05 (3H, s, 13-H3), 3.83 (1H, m, 9-H), 4.31 (1H, d, J = 7.1 Hz,
1'-H), 4.96 (1H, d, J = 1.5 Hz, 1''-H), 5.81 (1H, s, 4-H). 13C-NMR (125 MHz, CD3OD) δc: given in Table
1. Positive-ion FAB-MS: m/z 527 (M+Na)+. Negative-ion FAB-MS: m/z 503 (M–H) –.
23
Foliasalacioside C (5): An amorphous powder, [α]D –20.4° (c 0.24, MeOH). High-resolution positive-

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HETEROCYCLES, Vol. 75, No. 1, 2008
ion FAB-MS: Calcd for C24H40O11Na (M+Na)+: 527.2468. Found: 527.2470. IR (KBr): 3379, 2928, 1705,
1660, 1456, 1379, 1084, 1044 cm-1. 1H-NMR (CD3OD, 500 MHz) δ: 1.16 (6H, s, 11, 12-H3), 1.20 (3H, d,
J = 6.1 Hz, 10-H3), 1.61 (2H, m, 8-H2), 1.74 (3H, s, 13-H3), 2.09, 2.31 (1H each, both m, 7-H2), 2.34 (2H,
t, J = 6.7 Hz, 4-H2), 2.52 (2H, t, J = 6.7 Hz, 3-H2), 3.90 (1H, m, H-9), 4.33 (1H, d, J = 6.7 Hz, 1''-H), 4.34
(1H, d, J = 8.0 Hz, 1'-H). 13C-NMR (125 MHz, CD3OD) δc: given in Table 1. Positive-ion FAB-MS: m/z
527 (M+Na)+. Negative-ion FAB-MS: m/z 503 (M–H)–.
26
Foliasalacioside D (6): An amorphous powder, [α]D –17.7° (c 0.29, MeOH). High-resolution positive-
ion FAB-MS: Calcd for C24H40O11Na (M+Na)+: 527.2468. Found: 527.2474. UV [MeOH, nm (log ε)]:
1
247 (3.86). IR (KBr): 3339, 2928, 1653, 1074, 1036 cm-1. H-NMR (CD3OD, 500 MHz) δ: 1.20 (6H, s,
11, 12-H3), 1.22 (3H, d, J = 6.1 Hz, 10-H3), 1.65 (2H, m, 8-H2), 1.76 (3H, s, 13-H3), 1.81 (2H, t, J = 6.8
Hz, 2-H2), 2.31, 2.54 (1H each, both m, 7-H2), 2.44 (2H, t, J = 6.8 Hz, 3-H2), 3.93 (1H, m, 9-H), 4.34 (1H,
13
d, J = 7.6 Hz, 1'-H), 4.98 (1H, d, J = 1.4 Hz, 1''-H). C-NMR (125 MHz, CD3OD) δc: given in Table 1.
Positive-ion FAB-MS: m/z 527 (M+Na)+. Negative-ion FAB-MS: m/z 503 (M–H)–.
Acid Hydrolysis of 1–6
Solutions of 1, 2 (each 0.5 mg) and 3–6 (each 1.0 mg) in 1 M HCl (1.0 mL) were heated under reflux for
3 h. After cooling, each reaction mixture was neutralized with Amberlite IRA-400 (OH– form) and
filtrated, and the solution was partitioned with EtOAc to give two layers. The aqueous layer was
evaporated and then subjected to HPLC analysis using Kaseisorb LC NH2-60-5 column (4.6 mm × 250
mm i.d., Tokyo Kasei Co., Ltd., Tokyo, Japan) and an optical rotation detector (Shodex OR-2, Showa
Denko Co., Ltd., Tokyo, Japan). D-Glucose (from 1–6) and L-arabinose (from 3–6) were confirmed by
comparison of the retention times with the authentic samples (Wako Pure Chemicals Ltd., Osaka, Japan)
[mobile phase: MeCN–H2O (85:15, v/v), flow rate: 0.8 mL/min, tR: 10.2 min (L-arabinose, positive
optical rotation); tR: 12.8 min (D-glucose, positive optical rotation)].
Enzymatic Hydrolysis of 1 and 2 with β-Glucosidase
Solutions of 1 and 2 (12.6, 3.8 mg, respectively) in H2O (1.0 mL) were treated with β-glucosidase (16.0,
6.1 mg, respectively) and the solution was stirred at 37 °C for 20 h. Work-up of the reaction mixture as
described above to furnish foliasalaciol A (1a, 5.7 mg, 77.7% from 1 and 2.0 mg, 90.5% from 2).
27
Foliasalaciol A (1a): Colorless oil; [α]D +69.2° (c 0.25, MeOH); High-resolution positive-ion EI-MS:
Calcd for C13H22O3: 226.1569. Found: 226.1564. IR (film) 3415, 2965, 2932, 2874, 1651, 1372, 1121 cm-
1; 1H-NMR (CDCl3, 500 MHz) δ: 1.02, 1.09 (3H each, both s, 12, 11-H3), 1.21 (3H, d, J = 6.1 Hz, 10-H3),
1.54, 1.87 (1H each, both m, 7-H2), 1.51 (2H, m, 8-H2), 2.08, 2.47 (1H each, both d, J = 17.5 Hz, 2-H2),
1.96 (1H, m, 6-H), 3.82 (1H, m, 9-H), 4.25 (1H, dd, J = 1.5, 16.8 Hz, 13-Ha), 4.35 (1H, dd, J = 1.4, 16.8
Hz, 13-Hb), 6.08 (1H, br s, 4-H); 13C-NMR (125 MHz, CD3OD) δc: given in Table 1. Positive-ion FAB-
MS: m/z 527 (M+Na)+. Negative-ion FAB-MS: m/z 503 (M–H)–.13C NMR data, see Table 1; Positive-ion
EI-MS (%): m/z 226 (M+, 9), 209 (14), 208 (66), 193 (16), 179 (42), 135 (89), 109 (100).
Preparation of the (R)-MTPA Ester and (S)-MTPA Esters from Foliasalaciol A (1a)

HETEROCYCLES, Vol. 75, No. 1, 2008
141
A solution of 1a (2.9 mg) in dry CHCl3 (1.0 mL) was reacted with (R)-2-methoxy-2-
trifluoromethylphenylacetic acid [(R)-MTPA, 40.7 mg] in the presence of 1-ethyl-3-(3-
dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl, 44.0 mg) and 4-dimethylaminopyridine
(4-DMAP, 15.5 mg), and the resulting mixture was stirred at room temperature for 10 h. The reaction
mixture was poured into ice-water and extracted with EtOAc. The EtOAc extract was washed
successively with 5% HCl, NaHCO3-saturated H2O and brine and dried over Na2SO4 and filtered.
Removal of the solvent from the filtrate under reduced pressure. The residue was subjected to normal-
phase silica gel column chromatography [500 mg, n-hexane-EtOAc (10: 1 →3:1 →1:1) to furnish 1b (2.9
mg, 34.3%). Using a similar procedure, (S)-MTPA ester [1c, 2.9 mg, 45.2%] was obtained from 1a (2.2
mg) with (S)-MTPA (30.9 mg), EDC·HCl (38.2 mg) and 4-DMAP (12.0 mg).
1
Compound 1b. Colorless oil; H-NMR (CDCl3, 500 MHz) δ: 0.95, 0.98 (3H each, both s, 12, 11-H3),
1.28 (3H, d, J = 6.4 Hz, 10-H3), 1.39, 1.75 (1H each, both m, 7-H2), 1.70 (2H m, 8-H2), 1.80 (1H, m, 6-H),
2.04, 2.30 (1H each, both d, J = 17.4 Hz, 2-H2), 3.48, 3.54 (3H each, both s, -OCH3), 4.78, 4.89 (1H each,
both br d, J = ca. 16, 13-H2), 5.04 (1H, m, 9-H), 5.88 (1H, s, 4-H), 7.40 (3H, m, Ph-H), 7.43 (3H m, Ph-
H), 7.50 (4H, m, Ph-H).
1
Compound 1c. Colorless oil; H-NMR (CDCl3, 500 MHz) δ: 0.88 (6H, s, 12, 11-H3), 1.35 (3H, d, J =
6.4 Hz, 10-H3), 1.27, 1.58 (1H each, both m, 7-H2), 1.64 (2H m, 8-H2), 1.71 (1H, dd, m, 6-H), 1.98, 2.19
(1H each, both d, J = 17.4 Hz, 2-H2), 3.55, 3.57 (3H each, both s, -OCH3), 4.70 (1H, dd, J = 1.2, 15.0 Hz,
13-Ha), 4.83 (1H, dd, J = 1.6, 15.0 Hz, 13-Hb), 5.04 (1H, m, 9-H), 5.85 (1H, s, 4-H), 7.38 (3H, m, Ph-H),
7.43 (3H m, Ph-H), 7.50 (4H, m, Ph-H).
Enzymatic Hydrolysis of 3 and 4 with Nariginase
Solutions of 3 and 4 (5.5, 5.1 mg, respectively) in 0.2 M acetate buffer (pH 3.8) (1.0 mL) were treated
with nariginase (10.5 and 12.2 mg, respectively) and the solution was stirred at 40 °C for 4 day. After
cooling, the reaction mixture was extracted with EtOAc. The EtOAc solvent was removed under reduced
pressure and the residue was purified by HPLC [MeOH-H2O (50:50, v/v)] to give blumenyl C (1.3 mg,
54.9% from 3 and 2.0 mg, 91.3% from 4).
ACKNOWLEDGMENTS
Part of this work was supported by the 21st COE program and Academic Frontier Project from the
Ministry of Education, Culture, Sports, Science and Technology of Japan.
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