Facile synthesis of de-O-sulfated salacinols: Revision of the structure of neosalacinol, a potent α-glucosidase inhibitor

Article abstract of DOI:10.1016/j.bmcl.2009.02.103

Facile synthesis of de-O-sulfated salacinols (3) was developed by employing the coupling reaction of an epoxide, 1,2-anhydro-3,4-di-O-benzyl-d-erythritol (9) with 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epithio-d-arabinitol (10) as the key reaction. The report

Full text of DOI:10.1016/j.bmcl.2009.02.103

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2195–2198
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Facile synthesis of de-O-sulfated salacinols: Revision of the structure
of neosalacinol, a potent a-glucosidase inhibitor
Genzoh Tanabe a, Weijia Xie a, Ai Ogawa a, Changnian Cao b, Toshie Minematsu a,
Masayuki Yoshikawa c, Osamu Muraoka a,
*
a School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
b Chemical Engineering College of Qinghai Universty, Qinghai Xining 810016, China
c Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile synthesis of de-O-sulfated salacinols (3) was developed by employing the coupling reaction of an
Received 15 December 2008
Revised 24 February 2009
Accepted 26 February 2009
Available online 1 March 2009
epoxide, 1,2-anhydro-3,4-di-O-benzyl-
D
-erythritol (9) with 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epithio-
D-arabinitol (10) as the key reaction. The reported structure of a potent
a
-glucosidase inhibitor named
neosalacinol (8), isolated recently from Ayurvedic medicine Salacia oblonga, was proved incorrect, and
revised to be de-O-sulfated salacinol formate (3c) by comparison of the spectroscopic properties with
those of the authentic specimen synthesized. Discrepancies and confusion in the literature concerning
the NMR spectroscopic properties of salacinol (1) have also been clarified.
Keywords:
a-Glucosidase inhibitor
Ó 2009 Elsevier Ltd. All rights reserved.
Salacinol
De-O-sulfated salacinol
Thiosugar
From the roots and stems of Salacia species plants, which have
traditionally been used for the treatment of diabetes in Sri Lanka,
Very recently, Asano group also reported the isolation of highly
potent -glucosidase inhibitor named neosalacinol from Salacia
a
India, and Thailand, the authors had isolated highly potent
a
-glu-
oblonga, and presented a thiosugar sulfonium-alkoxide inner salt
structure (8) for the inhibitor, claiming that our proposed structure
3 was ambiguous, and the further investigation would be needed
(Fig. 2).7
cosidase inhibitors, salacinol (1) and kotalanol (2).1 Their structure
are quite unique, bearing thiosugar sulfonium sulfate inner salt
comprised of 1-deoxy-4-thio-
D-arabinofranosyl cation and 1-
deoxyaldosyl-3-sulfate anion as shown in Figure 1. Their
a
-gluco-
In this Letter, to clarify the structure of this potent inhibitor,
three sulfonium salts (3a, 3b, 3c) have been synthesized via two
routes. Of the three, spectral properties of 3c were in accord with
those reported by Asano and co-workers. The discrepancies and
confusion appeared in the literature7 concerning the NMR spectro-
scopic properties of salacinol (1) have also been clarified.
Synthesis of sulfonium salt (3c) by the coupling reaction of epoxide
(9) and thiosugar (10): According to the protocol for the prepara-
tion of b-hydroxylated sulfonium compound,8 a mixture of epox-
ide9 9 and thiosugar3b,10 10 was treated with tetrafluoroboric
sidase inhibitory activities are potent, and have been revealed to be
as high as those of voglibose and acarbose, which are widely used
clinically these days.1 De-O-sulfated analogs (3 and 4), which were
readily derived from 1 and 2, respectively, were also found to be as
potent as the original sulfates (1 and 2).2 Because of the intriguing
structure and high a-glucosidase inhibitory activities, much atten-
tion has been focused on them, and intensive studies on the struc-
ture–activity relationships (SAR) have been reported.3 Thereafter,
the authors also isolated related thiosugar analogs, ponkolanol
(5) and salaprinol (6) from the same species of plant,2b and abso-
lute stereochemistry of 6 was successfully determined on the basis
of the single crystal X-ray crystallographic analysis.4 Meanwhile,
Ozaki and co-workers reported the isolation of 13-memberd sulf-
oxide (7) as a more potent constituent from Salacia reticulata, men-
acid dimethyl ether complex (HBF4ꢀMe2O) at ꢁ60 °C. Preferred
facial attack of the thiosugar to the epoxide 9 was observed, giving
predominantly the corresponding -isomer of the sulfonium tetra-
fluoloborate11
-11d) along with a small amount of its b-isomer
(b-11d) in 90% yield ( /b = ca. 9:1). These two diastereomers were
a-
a
(a
a
tioning that the compound was responsible for the
a
-glucosidase
successfully separated over silica gel column chromatography, and
the relative stereochemistry of the side chain of the major com-
pound was confirmed to be in anti relationship to the benzyloxym-
ethyl moiety at C-4 on the basis of nuclear Overhauser effect
spectroscopy (NOESY) experiments as shown in Scheme 1. Its
FAB-MS spectrum run in the positive and negative modes showed
activity of the plants.5 Later, the structure was revised, and the
compound was proved to be kotalanol de-O-sulfate (4)6 (Fig. 1).
* Corresponding author. Tel.: +81 6 6721 2332; fax: +81 6 6721 2505.
E-mail address: muraoka@phar.kindai.ac.jp (O. Muraoka).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.103

2196
G. Tanabe et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2195–2198
OH OH OH
OH OH OH
OH
OH
OH
OH
3'
5'
7'
1'
2'
4'
6'
OH
-
OH
X-
S+ OH
S+
S+ OSO3
S+ OH
OH
OH
4
3
-
1
5
X-
HO
HO
OSO3
HO
HO
lit.2b
lit.2a
2
OH
HO
OH
HO
-
OH
salacinol (1)
OH
HO
HO
3
OH
4
kotalanol (2)
OH
a : X = CH3OSO3
OH OH
HO
S
OH
OH
b : X = Cl
c : X = HCO2
OH
O
S+ OSO3
S+
OH
HO
-
OSO3
HO
HO
HO
OH
OH
OH
HO
OH
HO
ponkoranol (5)
salaprinol (6)
7
Figure 1. Thiosugar sulfonium sulfate inner salts 1, 2, 5 and 6 and related de-O-sulfated analogs 3 and 4.
peaks at m/z 705 and m/z 87 corresponding to [MꢁBF4]+ and [BF4]ꢁ
OH
ions, respectively. The major isomer a-11d was then treated with
OH
ion exchange resin IRA-400J (Clꢁ form) to give the corresponding
chloride ( -11b) in 95% yield.
The chloride -11b was subjected to hydrogenolysis with palla-
S+ O-
HO
a
a
OH
HO
dium on carbon in 80% aq acetic acid to give the corresponding
chloride 3b in 90% yield. Its FAB-MS spectrum run in the positive
mode showed a peak at m/z 255, and the compound was positive
to the Beilstein test. The 13C NMR spectrum of 3b showed nine
peaks reasonably related to the nine carbons of this sulfonium cat-
ion part.
neosalacinol (8)
Figure 2. Proposed structure of neosalacinol (8).
OBn
The chloride 3b was then treated with an ion exchange resin
Dowex 1-X2 (HCO2 form) to give the corresponding formate
OH
OH
4'
ꢁ
OBn
1'
H2C
O
X-
OBn
+
OBn
NOE
BnO
(3c) in good yield. Its FAB-MS spectrum run in the positive mode
showed, as well as 3b, the peak at m/z 255. In its 13C NMR spectrum
measured in D2O, a signal corresponding to HCO2ꢁ moiety was ob-
served at dC 173.7 in addition to the nine peaks of the cation moi-
9
a
S+
OBn
X-
OBn
H
S+
+
4
BnO
3
S
BnO
b : X = Cl
BnO
OBn
β-11
BnO
OBn
α-11
ety. In its 1H NMR spectrum, one-proton singlet due to HCO2 was
c : X = HCO2
d : X = BF4
ꢁ
OBn
BnO
clearly detected at dH 8.46 as shown in Figure 3 and the IR spec-
trum showed strong absorption at 1597 cmꢁ1 typical for the car-
boxylate moiety. On the basis of these evidences, the presence of
the formate anion in the molecule has been approved (Scheme 1).
Preparation of 3c via methanolysis of salacinol (1): We had al-
ready reported that the acid catalyzed methanolysis of salacinol
b, c
10
d
3b
3c
Scheme 1. Reagents and conditions: (a) HBF4ꢀ(CH3)2O, CH2Cl2, ꢁ60 °C; (b) IRA-400 J
(Clꢁ form), MeOH–H2O, rt; (c) H2, Pd–C, 80% AcOH, 50–60 °C; (d) Dowex 1-X2
(HCO2 form), H2O.
ꢁ
Figure 3. 1H NMR spectrum of 3c in D2O (TSP as an internal standard).

G. Tanabe et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2195–2198
2197
Asano and co-workers reported 1H NMR spectroscopic proper-
ties of 8 measured in D2O.7 Comparison of their data with those
of 3c in D2O obtained in the present study12 did not correlate with
each other. On the other hand, they mentioned in the experimental
section the use of C5D5N and C5D5N–D2O (5:1) as the solvents for
NMR measurements. Surprisingly enough, the NMR spectral prop-
erties of 3c in C5D5N–D2O (5:1) showed perfect correlations with
those reported with respect to all the signals with deviations of
0.10–0.12 and 0.4 ppm for 1H and 13C signals, respectively, as
OH
OH
X-
a or b
S+ OH
salacinol (1)
HO
OH
HO
3
a : X = CH3OSO3
c
c : X = HCO2
ꢁ
shown in Table 1. In this solvent, signal due to HCO2 appeared
Scheme 2. Reagents and conditions: (a) 5% HCl in MeOH, refluxlit.7; (b) 5% HCl in
at dH 9.36 as a broad signal as shown in Table 1, and 13C NMR peak
due to HCO2ꢁ was hardly observed. As for the MS properties, Asano
and co-workers assigned the peak at m/z 225 to the quasimolecular
ion peak [M+H]+. It is more reasonable to identify this peak as the
sulfonium ion itself [M]+ of 3c. Thus, the structure of the compound
they isolated has been unambiguously identified as formate of sal-
MeOH, 45 °Clit.2a; (c) Dowex 1-X2 (HCO2 form), H2O.
ꢁ
(1) readily took place at 45 °C,2a giving the thiosugar-sulfonium
methyl sulfate (3a) in 86% yield. In this study, the procedure by
Asano and co-workers7 has been reexamined. Thus, 1 was first
heated under reflux in methanol containing 5% hydrogen chloride
to give the corresponding methyl sulfate (3a) in 88% yield. The
FAB-MS spectrum of 3a run in the positive and negative modes
showed peaks at m/z 255 and m/z 111, corresponding to
[MꢁCH3OSO3]+ ion and [CH3OSO3]ꢁ ion, respectively. In the 1H
ꢁ
acinol de-O-sulfate (3c). The anion HCO2 would be originated
from the ion exchange resin during the isolation process.
In addition to this, we should comment here that 1H and 13C
NMR spectral data of salacinol (1) in D2O reported in the same lit-
erature7 must be revised as those measured in pridine-d5.1c The
data of 1 in D2O were collected in the present study, and are pre-
sented in Table 2.
and 13C NMR spectra, peaks due to the CH3OSO3 anion were ob-
ꢁ
served clearly at dH 3.68 and dc 55.2, respectively. The methyl sul-
fate 3a was then treated with an ion exchange resin Dowex 1-X2
(HCO2 form) to give the corresponding formate (3c) in good yield.
The NMR and MS spectroscopic properties of 3c thus obtained
were completely in accord with those of the specimen synthesized
above (Scheme 2).
In summary, we developed the facile synthesis of highly potent
ꢁ
a-glucosidase inhibitors 3 by employing the coupling reaction of
epoxide 9 with thiosugar 10 as the key reaction. Reexamination
and careful comparison of the 1H and 13C NMR spectroscopic
properties of the isolated inhibitor 8 with those of de-O-sulfated
Table 1
1H and 13C NMR data of neosalacinol (8) reported and de-O-sulfated salacinol formate (3c) synthesized in the present study (d in ppm and J in Hz)
Compound 8 in D2Olit.7 TSP as an internal standard
Compound 3c in pyridine-d5/D2O (5:1) TMS as an external standard
Deviations of the
chemical shifts
(500 MHz and 125 MHz)
(500 MHz and 125 MHz)
dH
H-1a,1b 4.21 (br d)
dC
dH
dC
D
dH
DdC
50.9
78.1
78.3
72.5
59.9
4.33 (d-like, J = 2.9)
5.18 (ddd-like, J = 2.9, 2.9, 2.6)
4.98 (dd-like, J = 2.6, 1.7)
4.70 (br dd-like, J = 9.7, 5.4)
4.42 (dd, J = 12.0, 9.7)
4.50 (dd, J = 12.0, 5.4)
4.38 (dd, J = 13.2, 8.9)
4.52 (dd, J = 13.2, 3.4)
4.80 (ddd, J = 8.9, 6.6, 3.4)
4.31 (m)
51.3
78.5
78.7
72.9
60.3
0.12
0.12
0.11
0.10
0.12
0.12
0.11
0.10
0.12
0.12
0.12
0.12
0.4
0.4
0.4
0.4
0.4
H-2
5.06 (br ddd)
H-3
H-4
4.87 (dd, J = 2.5, 1.6)
4.60 (br ddd)
H-5a
H-5b
H-10a
H-10b
H-20
4.30 (dd, J = 11.9, 9.6)
4.38 (dd, J = 11.9, 5.5)
4.27 (dd, J = 13.0, 8.7)
4.42 (dd, J = 13.0, 3.4)
4.68 (ddd, J = 8.7, 6.2, 3.4)
4.19 (ddd, J = 6.2, 5.0, 4.4)
4.10 (dd, J = 11.2, 5.0)
4.16 (dd, J = 11.2, 4.4)
51.1
51.5
0.4
68.4
74.5
63.0
68.8
74.9
63.4
0.4
0.4
0.4
H-30
H-40a
H-40bꢁ
HCO2
4.22 (dd, J = 11.5, 5.0)
4.28 (dd, J = 11.5, 4.0)
9.36 (br s,)
173.7a
a
Datum in D2O. The signal was hardly detected in pyridine–D2O (5:1).
Table 2
1H and 13C NMR data of salacinol (1) in pyridine-d5 and in D2O (d in ppm and J in Hz)
Reportedlit.1c (500 MHz and 125 MHz) in pyridine-d5;
Reportedlit.7 (500 MHz and 125 MHz) in D2O; an
internal standard: TSP
Observed (500 MHz and 125 MHz) in D2O; an
external standard: DSS
an internal standard: TMS
dH
H-1a,1b 4.33 (br s)
dC
dH
dC
dH
dC
50.7
78.5
79.0
72.6
60.2
4.32 (br d)
5.12 (s)
5.12 (s)
4.70 (br t)
4.53 (dd, J = 11.9, 7.3)
4.55 (dd, J = 11.9, 6.4)
4.63 (dd, J = 12.8, 4.1)
4.80 (dd, J = 12.8, 4.6)
5.01 (br dt)
5.27 (dt, J = 7.7, 3.7)
4.38 (dd, J = 11.9, 3.7)
4.62 (dd, J = 11.9, 3.7)
50.5
78.4
79.2
72.4
60.2
3.90 (d-like, J = 4.0)
4.75 (ddd, J = 4.0, 4.0, 3.5)
4.45 (dd., J = 3.5, 2.9)
50.5
79.5
80.3
72.7
61.7
H-2
5.10 (br s)
H-3
5.12 (dd-like)
H-4
4.69 (t-like)
4.10 (ddd, J = 7.8, 4.9, 2.9)
3.96 (dd, J = 10.9, 7.8)
4.13 (dd, J = 10.9, 4.9)
3.84 (dd, J = 13.6, 8.3)
4.00(dd, J = 13.6, 3.2)
4.41 (ddd, J = - 8.3, 7.5, 3.2)
4.36 (ddd, J = 7.5, 3.2, 3.2)
3.87 (dd, J = 12.6, 3.2)
3.97 (dd, J = 12.6, 3.2)
H-5a
H-5b
H-10a
H-10b
H-20
4.51 (dd, J = 11.6, 8.0)
4.54 (dd, J = 11.6, 6.8)
4.62 (dd, J = 13.1, 4.2)
4.76 (dd, J = 13.1, 4.9)
4.99 (ddd, J = 7.6, 4.9, 4.2)
5.25 (ddd, J = 7.6, 3.9, 3.7)
4.37 (dd, J = 11.6, 3.9)
4.60 (dd, J = 11.6, 3.7)
52.6
52.8
52.4
67.6
79.4
62.2
67.6
79.3
62.3
68.3
82.6
62.2
H-30
H-40a
H-40b

2198
G. Tanabe et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2195–2198
7. Minami, Y.; Kuriyama, C.; Ikeda, K.; Kato, A.; Takebayashi, K.; Adachi, I.; Fleet,
W. J. G.; Kettawan, A.; Okamoto, T.; Asano, N. Bioorg. Med. Chem. 2008, 16, 2734.
8. (a) Cimetiere, B.; Jacob, L.; Julia, M. Tetrahedron Lett. 1986, 27, 6329; (b)
Cimetiere, B.; Jacob, L.; Julia, M. Bull. Soc. Chim. Fr. 1991, 128, 926; (c) Okuma,
K.; Nakamura, S.; Ohta, H. Heterocycles 1987, 26, 2343.
salacinol (3c) concluded that the compound isolated by Asano
group was formate of de-O-sulfated salacinol (3c). The authors re-
cently detected de-O-sulfated salacinol (3) and de-O-sulfated
kotalanol (4) in the cold water extract by means of LC–MS analysis.
Further studies on the evaluation of extracts involving the contri-
bution of these de-O-sulfates (3 and 4) are in progress.
9. Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu,
D. C.-J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598.
10. Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001, 66, 2312.
11. Compound
a
-11d: Colorless oil. ½a D23
ꢂ
+4.25 (c 2.43, CHCl3). IR (neat) 3503, 1496,
1452, 1400, 1362, 1211, 1087 cmꢁ1
.
1H NMR (500 MHz, CDCl3) d 3.62 (1H, dd,
Acknowledgements
J = 10.6, 3.5 Hz, H-40a), 3.67 (2H, d-like, J = 3.2 Hz, H-1a, H-1b), 3.68–3.73 (3H,
m, H-40b, H-5a and H-5b), 3.74–3.77 (1H, m, H-30), 3.78 (1H, dd, J = 13.2, 6.9 Hz,
H-1a0), 3.85 (1H, dd, J = 13.2, 3.8 Hz, H-1b0), 4.05 (1H, br-t like, J = ca. 7.6 Hz, H-
4), 4.14 (1H, br s, OH), 4.19 (1H, br t-like, J = ca. 1.5 Hz, H-3), 4.29/4.36 (each
1H, d, J = 11.8 Hz, PhCH2), 4.31–4.36 (2H, m, H-2, H-20), 4.43–4.53 (6H, m,
PhCH2), 4.58/4.64 (each 1H, d, J = 11.2 Hz, PhCH2), 7.08–7.35 (25H, m, arom.).
13C NMR (125 MHz, CDCl3) d 48.1 (C-1), 50.8 (C-10), 66.0 (C-4), 66.7 (C-5), 68.5
(C-20), 68.7 (C-40), 71.7/72.0/72.9/73.4/73.5 (PhCH2), 79.5 (C-30), 82.3 (C-3) 82.5
(C-2), 127.8/127.88/127.90/128.0/128.1/128.2/128.3/128.36/128.40/128.43/
128.47/128.51/128.6/128.7 (d, arom.), 135.9/136.1/136.8/137.5/137.6 (s,
arom.). FAB-MS m/z 705 [MꢁBF4]+ (pos.), 87 [BF4]ꢁ (neg.). HR-FAB-MS m/z
705.3220 (C44H49O6S requires 705.3250), 87.0027 (BF4 requires 87.0030).
12. A mixture of salacinol (1, 50 mg, 0.15 mmol) and 5% methanolic hydrogen
chloride (5 ml) was heated under reflux for 1 h. After removal of the solvent,
the residue (60 mg) was purified on column chromatography (AcOEt/MeOH/
This work was supported by ‘High-Tech Research Center’ Pro-
ject for Private Uni: matching fund subsidy from MEXT (Ministry
of Education, Culture, Sports. Science and Technology), 2007–2011.
References and notes
1. (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara, J.;
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Murakami, T.; Yashiro, K.; Matsuda, H. Chem. Pharm. Bull. 1998, 46, 1339; (c)
Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka, O. Bioorg. Med.
Chem. 2002, 10, 1547.
2. (a) Tanabe, G.; Yoshikai, K.; Hatanaka, T.; Yamamoto, M.; Shao, Y.; Minematsu,
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Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551; (d) Choubdar, N.; Sim,
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cited therein.
ꢁ
H2O, 20:4:1) to give the methyl sulfate 3a (48 mg, 88%). Dowex 1-X2 (HCO2
form, 1 g) was well washed with H2O. An aqueous solution of 3a (10 ml) was
treated with the half volume (ca. 500 mg) of the resin to give 3c (32 mg, 82%)
as an oil. Another half of the resin was washed with H2O (10 ml), and the
washings was concentrated in vacuo. The residue showed no signals due to
HCO2 moiety in its 1H NMR spectrum in D2O. Compound 3c: IR (neat) 3360,
ꢁ
1597, 1388, 1350, 1249, 1219, 1069, 1022 cmꢁ1 1H NMR (700 MHz, D2O,
.
internal standard: TSP) d 3.66 (dd-like, J = 11.4, 5.6 Hz, H-40a), 3.75 (ddd, J = 6.8,
5.6, 3.6 Hz, H-30), 3.78 (dd, J = 11.4, 3.6 Hz, H-40b), 3.79 (dd, J = 13.2, 9.4 Hz, H-
10a), 3.90 (dd, J = 13.2, 3.8 Hz, H-1a), 3.91 (dd, J = 13.2, 3.0 Hz, H-10b), 3.95 (dd,
J = 13.2, 3.2 Hz, H-1b), 3.96 (dd, J = 12.0, 9.2 Hz, H-5a), 4.11 (ddd, J = 9.2, 4.8,
2.6 Hz, H-4), 4.15 (dd, J = 12.0, 4.8 Hz, H-5b), 4.17 (ddd, J = 9.4, 6.8, 3.0 Hz, H-
20), 4.47 (dd-like, J = 3.2, 2.6 Hz, H-3), 4.77 (ddd-like, J = 3.8, 3.2, 3.2 Hz, H-2),
8.46 (1H, s, HCO2). 13C NMR (175 MHz, D2O, internal standard: TSP) d 51.0 (C-
1), 52.3 (C-10), 61.9 (C-5), 64.7 (C-40), 70.3 (C-20), 72.7 (C-4), 76.2 (C-30), 79.7 (C-
2), 80.3 (C-3), 173.7 (HCO2ꢁ). The spectral properties of 3c in pyridine-d5/D2O
(5:1) are presented in Table 1.
4. Tanabe, G.; Sakano, M.; Minematsu, T.; Matusda, H.; Yoshikawa, M.; Muraoka,
O. Tetrahedron 2008, 64, 10080–10086.
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6. Muraoka, O.; Xie, W.; Tanabe, G.; Amer, F. A. M.; Minematsu, T.; Yoshikawa, M.
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