Synthesis and elucidation of absolute stereochemistry of salaprinol, another thiosugar sulfonium sulfate from the ayurvedic traditional medicine Salacia prinoides

Article abstract of DOI:10.1016/j.tet.2008.08.010

Synthesis and elucidation of absolute stereochemistry of salaprinol (3) isolated from the root and stems of Salacia prinoides, which has been used for the treatment of diabetes in India, Sri Lanka, and Southeast Asia countries, is described. Compound 3 an

Full text of DOI:10.1016/j.tet.2008.08.010

Tetrahedron 64 (2008) 10080–10086
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and elucidation of absolute stereochemistry of salaprinol, another
thiosugar sulfonium sulfate from the ayurvedic traditional medicine
Salacia prinoides
Genzoh Tanabe a, Mika Sakano a, Toshie Minematsu a, Hisashi Matusda b,
,
Masayuki Yoshikawa b, Osamu Muraoka a
*
a School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
b 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:
Received 15 July 2008
Received in revised form 4 August 2008
Accepted 6 August 2008
Available online 9 August 2008
Synthesis and elucidation of absolute stereochemistry of salaprinol (3) isolated from the root and stems
of Salacia prinoides, which has been used for the treatment of diabetes in India, Sri Lanka, and Southeast
Asia countries, is described. Compound 3 and its 20-epimer, epi-salaprinol (epi-3) were synthesized via
the coupling reaction of a cyclic sulfate, 2-O-benzylglycerol 1,3-cyclic sulfate (5), with a thiosugar, 1,4-
dideoxy-1,4-epithio-
the side chain of 3 was elucidated by the X-ray crystallographic analysis.
Ó 2008 Published by Elsevier Ltd.
D-arabinitol (6), as the key reaction, and S configuration of the asymmetric center in
Keywords:
Salaprionol
epi-Salaprinol
a
-Glucosidase inhibitor
Sulfonium sulfate
Salacia prinoides
1. Introduction
the methanolic extract of roots and stems of Indian S. prinoides,
which are also used for the treatment of diabetes.7
In the course of our studies on the antidiabetogenic compounds
In our previous SAR studies,5e the authors have briefly com-
mented the synthesis of the diastereomeric mixture of 3 and its 20-
epimer (epi-3). Careful reexamination on the synthesis enabled us
to isolate each isomer as single crystals. In this paper we describe
full details of the synthesis of 3 and epi-3, and unambiguous elu-
cidation of the absolute stereostructure of both isomers on the basis
of the single crystal X-ray analysis.
from natural medicines,1 we have isolated two potent
a-glucosi-
dase inhibitors, salacinol (1) and kotalanol (2), with unique thio-
sugar sulfonium sulfate inner salt structure from the roots, stems,
and leaves of Salacia reticulata,2 Salacia oblonga,3 and Salacia chi-
nensis,4 which have traditionally been used for the treatment of
diabetes in Sri Lanka, India, and Thailand. Their a-glucosidase in-
hibitory activities are potent, and have been revealed to be as high
as those of voglibose and acarbose, which are widely used clinically
these days. Owing to both the high inhibitory activity and the in-
triguing structure, much attention has been focused on 1 and re-
lated compounds, intensive studies on the structure–activity
relationships (SAR) on 1 and heterocyclic analogs having been
reported.5 In addition, clinical evaluation6 of the safety of the ex-
tract has also been intensively carried out with a view to develop
the Salacia extract as an effective functional foods for slight degree
of diabetics. In our continuous studies on exploring the active
constituents in Salacia species, we recently isolated two new thio-
sugar derivatives named salaprinol (3) and ponkoranol (4) from
2. Synthesis of salaprinol (3) and epi-salaprinol (epi-3)
Firstly, glycerol (7) was derived into 2-O-benzylglycerol8 (8).
When 7 was treated with trityl chloride according to the literature,8
formation of considerable amount of 1,2,3-tri-O-tritylglycerol9 (9)
was observed. Furthermore, undesirable acetylation forming
mono- and diacetates10a,b,11 (10 and 11) was found to occur on
detritylation to 8. Thus, the reaction condition of these two steps
were modified and optimized in this study. Thus, selective trityla-
tion of the primary hydroxyl of 7 was performed when the reaction
was conducted in pyridine at room temperature, to give 1,3-di-O-
tritylglycerol8 (12) predominantly (12/9¼ca. 20:1), although pro-
longed reaction time was required (24 h). The carbinol moiety of 12
was then protected with benzyl bromide in the presence of sodium
* Corresponding author. Tel.: þ81 6 6721 2332; fax: þ81 6 6721 2505.
E-mail address: muraoka@phar.kindai.ac.jp (O. Muraoka).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.08.010

G. Tanabe et al. / Tetrahedron 64 (2008) 10080–10086
10081
OH
OH OH
OH OH OH
OH
OH
OH
-
S+ OSO3
S+
OH
S+
OH
-
HO
-
OSO3
HO
OSO3
HO
OH
HO
OH
HO
OH
HO
salacinol (1)
ponkoranol (4)
kotalanol (2)
OH
2'
OH
OBn
3'
1'
2'
S
5
-
S+ OSO3
-
S+ OSO3
OH
HO
+
1
+
HO
HO
O
O
S
3
OH
HO
O
O
OH
HO
HO
5
6
salaprinol (3)
epi-salaprinol (epi-3)
Scheme 1.
hydride to give 2-O-benzyl-1,3-di-O-tritylglycerol8 (13) in good
yield. Hydrolysis of 13 was successfully performed by refluxing
a mixture of 10% sulfuric acid and 1,4-dioxane to give 8 in 95% yield.
Thus, the yield of 8 from 7 was improved to ca. 90% from 50%
reported.8 Finally, the diol 8 was converted into the desired 2-
benzyloxy cyclic sulfate 5 according to the conditions reported
previously by the authors (Scheme 1).5e
observed at lower field than those of 3 as shown in Figure 1 and
Table 1. Coupling patterns of all the proton signals of both 3 and epi-
3 were unambiguously resolved in the present study by the use of
a 700 MHz 1H NMR spectrometer (Table 1). 1H NMR and 13C NMR
spectroscopic properties of 3 were completely in accord with those
of authentic salaprinol isolated from S. prinoides (Tables 1 and 2).7
The cyclic sulfate (5) was subjected to the coupling reaction with
a thiosugar5e (6) in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at 65–
70 ꢀC. When the reaction was carried out in relatively large scale
(4 mmol), one of the epimers (14) deposited fortunately in the re-
action mixture and pure 14 was obtained in 16% yield after re-
crystallization. In addition, careful column chromatography of the
condensed filtrate afforded a fraction composed of ca.10:1 epimeric
mixture of 15 and 14, although these two epimers were hardly
separable by TLC analysis. 1H and 13C NMR spectroscopic properties
of 14 and 15 were quite similar with each other. Downfield shift with
respect to the signals due to C-1 methylene (14: dC 50.8, 15: dC 51.5),
C-4 methine (14: dC 73.4, 15: dC 73.6), and C-10 methylene (14: dC
49.6, 15: dC 49.9) carbons supported their sulfonium ion structure.
Hydrogenolysis of 14 with palladium on carbon in 80% aqueous
acetic acid gave epi-salaprinol (epi-3) in good yield. The ca. 10:1
mixture of 15 and 14 was also hydrogenated to give a mixture of 3
and epi-3, and exclusive crystallization of the major product (3)
from the mixture was successfully conducted by the use of meth-
anol as the solvent, affording pure 3 as colorless crystals (Scheme
2). Although their 13C NMR spectroscopic properties were quite
similar with each other, discrimination of each isomer was possible
3. X-ray crystallographic analysis of salaprinol (3)
and epi-salaprinol (epi-3)
Single crystals of 3 were obtained as colorless prisms from a
methanol solution, and the stereochemistry of both the sulfonium
center and C-20 were established on the basis of the X-ray crystal-
lographic analysis. Compound 3 was found to be packed to form
P212121 type orthorhombic crystals, and the sulfonium and C-20 was
proved to be both in S configuration as shown in Figure 2. On the
other hand, single crystals of epi-salaprinol (epi-3) were obtained
from an aqueous methanol solution as colorless prisms, and were
found to be P21 type monoclinic crystals. The absolute stereochem-
istry of the epimeric center (C-20) was proved to be R configuration.
Unlike salacinol (1), which forms characteristic spirobicyclic-like
inner salt structure, both compounds were found to be packed to
form salts intermolecularly between the sulfonium cation and sul-
fate anion at the solid state, as shown in the packing diagram (Fig. 3).
In summary, salaprinol (3), another sulfonium sulfate from the
Salacia species, and its epimer (epi-3) were synthesized by the
coupling reaction of a cyclic sulfate (5) and a thiosugar (6). Each of
the epimers was successfully recrystallized to give single crystals.
Absolute stereochemistry of both epimers was unambiguously
elucidated by the X-ray crystallographic analysis. These two twitter
on the basis of 1H NMR spectra, some signals due to
a-protons to
the sulfonium center (H-4, H-1a, H-10a, H-10b) of epi-3 being
OH
OBn
-
S+ OSO3
-
S+ OSO3
f
HO
HO
OH
HO
OH
HO
OBn
OBn
14
epi-salaprinol (epi-3)
OH
OR
a
c
e
d
+
OR1 OR2
O
O
O
S
OH OH
OTr OTr
OH
OBn
O
9 : R = Tr
12 : R = H
13 : R = Bn
8 : R1 = R2 = H
5
7
10 : R1 = H, R2 = Ac
11 : R1 = R2 = Ac
-
-
S+ OSO3
S+ OSO3
f
b
HO
HO
OH
HO
salaprinol (3)
OH
HO
15
Scheme 2. Reagents and conditions: (a) TrCl, py, rt; (b) BnBr, NaH, DMF, 0 ꢀC to rt or BnCl, KOH, toluene, reflux; (c) 10% aq H2SO4, 1,4-dioxane, reflux; (d) (1) SOCl2, Et3N, CH2Cl2, 0 ꢀC,
then (2) NaIO4, RuCl3, NaHCO3, CCl4, CH3CN, H2O, 0 ꢀC to rt; (e) thiosugar 6, K2CO3, HFIP, 65–70 ꢀC; (f) H2, Pd–C, 80% AcOH, 50 ꢀC.

10082
G. Tanabe et al. / Tetrahedron 64 (2008) 10080–10086
Figure 1. 1H NMR spectra (700 MHz) of salaprinol (3) and epi-salaprinol (epi-3).
Table 1
1H NMR data for compounds 3 and epi-3 in CD3OD
Salaprinol (500 MHz)7
3 (700 MHz)
epi-3 (700 MHz)
H-1a
H-1b
H-2
H-3
H-4
H-5a
H-5b
H-10a
H-10b
H-20
H-30a
H-30b
3.85 (dd, J¼12.4, 3.5)
3.88 (dd, J¼12.4, 2.0)
4.63 (ddd-like)
4.38 (br s-like)
4.04 (dd-like)
3.93 (dd, J¼13.0, 11.0)
4.05 (dd, J¼13.0, 5.5)
3.71 (dd, J¼13.0, 8.2)
3.84 (dd, J¼13.0, 3.4)
4.35 (m)
3.84 (dd, J¼12.6, 3.4)
3.81 (dd, J¼12.6, 2.0)
3.86 (dd, J¼12.6, 2.2)
3.86 (dd, J¼12.6, 3.4)
4.61 (dt-like, J¼ca. 3.4, 2.2)
4.37 (br dd-like, J¼ca. 2.2, 1.2)
4.02 (br dd like, J¼ca. 11.2, 5.4)
3.92 (dd, J¼13.5, 11.2)
4.62 (dt-like, J¼ca. 3.4, 2.0)
4.41 (br dd-like, J¼ca. 2.0, 2.0)
4.09 (br dd-like, J¼ca. 8.6, 5.8)
3.96 (dd, J¼11.6, 8.6)
4.03 (dd, J¼13.5, 5.4)
4.03 (dd, J¼11.6, 5.8)
3.70 (dd, J¼13.2, 8.2)
3.74 (dd, J¼13.2, 7.7)
3.83 (dd, J¼13.2, 3.4)
3.78 (dd, J¼13.2, 3.8)
4.34 (dddd, J¼8.2, 6.6, 4.6, 3.4)
3.98 (dd, J¼10.9, 6.6)
4.33 (dddd, J¼7.7, 6.4, 4.7, 3.8)
3.98 (dd, J¼10.9, 6.4)
4.00 (dd, J¼11.0, 6.2)
4.11 (dd, J¼11.0, 4.8)
4.09 (dd, J¼10.9, 4.6)
4.10 (dd, J¼10.9, 4.7)
Table 2
13C NMR data for compounds 3 and epi-3 in CD3OD
were recorded on a JEOL JMS-HX 100 spectrometer. Optical rota-
tions were determined with a JASCODIP-370 digital polarimeter.
Column chromatography was effected over Fuji Silysia Chemical
silica gel BW-200. All the organic extracts were dried over anhy-
drous sodium sulfate prior to evaporation.
C-1
C-2
C-3
C-4
C-5
C-10
C-20 C-30
Salaprinol (125 MHz)7 51.7
3 (125 MHz)
epi-3 (125 MHz)
79.4 79.6 73.7 60.9 51.3
79.4 79.6 73.7 60.9 51.4
67.4 70.4
67.3 70.3
51.7
50.76 79.4 79.8 73.4 60.9 50.84 67.3 70.2
4.2. 3.1.2-O-Benzyl-1,3-tri-O-tritylglycerol (13)
ionic analogs were found not to form the spirobicyclic-like inner
salt structure as salacinol.
4.2.1. Method A
According to the method reported,8 a mixture of glycerol (7,
3.3 g, 35.9 mmol), trityl chloride (25 g, 89.6 mmol), and pyridine
(30 ml) was heated at 100 ꢀC for 1 h. After being cooled, the re-
action mixture was poured into ice-cooled water (150 ml) and
extracted with ethyl acetate. The extract was subsequently washed
by water and brine. After removal of the ethyl acetate in vacuo, the
remaining pyridine was co-evaporated with n-hexane to give a ca.
3.3:1 mixture of 1,3-di-O-tritylglycerol8 (12) and 1,2,3-tri-O-trityl-
glycerol9 (9) as a colorless solid (25.7 g). When glycerol (7, 1.0 g,
10.9 mmol) was treated with trityl chloride (7.4 g, 26.5 mmol) in
pyridine (20 ml) at 50 ꢀC, a ca. 10:1 mixture of 12 and 9 was
obtained.
4. Experimental
4.1. General
Melting points were determined on a Yanagimoto MP-3S
micromelting point apparatus, and mps and bps are uncorrected. IR
spectra were measured on either a Shimadzu IR-435 grating spec-
trophotometer or a Shimadzu FTIR-8600PC spectrophotometer.
NMR spectra were recorded on a JEOL AL 400 (400 MHz 1H,
100 MHz 13C), a JEOL JNM-ECA 500 (500 MHz 1H, 125 MHz 13C),
a JEOL JNM-ECA 600 (600 MHz 1H, 150 MHz 13C) or a JEOL JNM-ECA
700 (700 MHz 1H, 175 MHz 13C) spectrometer. Chemical shifts (
and coupling constants (J) are given in parts per million and hertz,
respectively. Low-resolution and high-resolution mass spectra
d)
A suspension of a ca. 3.3:1 mixture of 12 and 9 (25.6 g), benzyl
chloride (20 ml, 174 mmol), and crushed potassium hydroxide
(18 g, 321 mmol) in toluene (100 ml) was heated under reflux for

G. Tanabe et al. / Tetrahedron 64 (2008) 10080–10086
10083
Figure 2. Perspective views of salacinol (1), salaprinol (3), and epi-salaprinol (epi-3).
1 h. After being cooled, the reaction mixture was washed sub-
sequently with water and brine. Removal of the solvent left an
orange oil (33.1 g), which on column chromatography (CHCl3–n-
hexane, 1:2/1:1) gave 2-O-benzyl-1,3-di-O-tritylglycerol8 (13,
16.8 g, 70% from 7) and 9 (6.2 g, 21% from 7).
gave a ca. 20:1 mixture of 12 and 9 as a colorless solid (9.0 g), which
was used in the next step without purification.
The solid (9.0 g) was added in small portions to a mixture of
benzyl bromide (2.7 ml, 22.7 mmol) and sodium hydride (1.0 g,
25 mmol, 60% in mineral oil) in DMF (40 ml) with vigorous stirring
at 0 ꢀC, and the resulting mixture was stirred at 0 ꢀC for 1.5 h. The
mixture was allowed to warm to room temperature and was stirred
for another 2 h. The reaction mixture was poured into ice-water
(150 ml), and the deposited brown solid was filtered and washed
with water to give a brown solid (10.3 g), which on column
4.2.2. Method B
A mixture of glycerol (7, 1.0 g, 10.9 mmol), trityl chloride (7.4 g,
26.5 mmol), and pyridine (20 ml) was stirred at room temperature
for 24 h. Work-up in a manner similar to that used in method A
Figure 3. Packing diagrams of salaprinol (3) and epi-salaprinol (epi-3).

10084
G. Tanabe et al. / Tetrahedron 64 (2008) 10080–10086
chromatography (CHCl3–n-hexane, 1:2/1:1) gave 13 (6.7 g, 93%
from 7) and 9 (230 mg, 5% from 7).
4.4. Preparation of diol 8 from glycerol (7) without isolation
of the intermediates 12 and 13
4.2.2.1. Compound 13. Colorless needles, mp 155–158 ꢀC (from
Following the method B described above for the preparation of
13, a mixture of 7 (2.05 g, 22.3 mmol), trityl chloride (15.0 g,
53.8 mmol), and pyridine (40 ml) was stirred at room temperature
for 24 h. Work-up gave a ca. 20:1 mixture of 12 and 9 (17.5 g), which
was treated with benzyl bromide (7.5 ml, 63.2 mmol) in DMF
(100 ml) in the presence of sodium hydride (2.5 g, 62.5 mmol, 60%
in mineral oil). After being stirred at room temperature for 2 h, the
reaction mixture was poured into ice-cooled water (300 ml), and
the separated paste-like material was taken up in ethyl acetate. The
organic layer was washed successively with water and brine, and
evaporated to give a brown oil (22.6 g), which on trituration with
hot methanol gave a pale yellow solid (17.3 g). The solid (17.3 g) was
then heated under reflux in a mixture of 10% sulfuric acid (30 ml)
and 1,4-dioxane (90 ml) for 2 h. The reaction mixture was diluted
with water (500 ml) and the resulting mixture was neutralized
with sodium hydrogen carbonate. The deposited trityl alcohol
(13.8 g) was filtered and washed with water. The combined filtrate
and the washings were then washed with diethyl ether, and the
organic layer was reextracted with water. All the aqueous layers
were combined and saturated with sodium chloride, then extracted
with ethyl acetate. The extracts were evaporated to give a brown oil
(4.28 g), which on distillation at reduced pressure gave 8 (3.63 g,
90% from 7) as a colorless oil, which solidified when seeded with
the authentic sample 8 obtained by the above experimental section.
EtOH–AcOEt), lit.8 solid (no mp). 1H NMR (400 MHz, CDCl3)
d: 3.27
(2H, dd, J¼9.6, 5.6 Hz, H-1a and H-3a), 3.32 (2H, dd, J¼9.6, 4.8 Hz,
H-1b and H-3b), 3.74 (1H, tt, J¼5.6, 4.8 Hz, H-2), 4.60 (2H, s, PhCH2),
7.18–7.42 (35H, m, arom.). 13C NMR (100 MHz, CDCl3)
d: 63.4 (C-1
and C-3), 72.1 (PhCH2), 77.7 (C-2), 86.6 (Ph3C), 126.8/127.4/127.6/
127.7/128.3/128.7 (d, arom.), 138.7/144.1 (s, arom.).
4.2.2.2. Compound 9. Colorless moss-like solid, mp 197–199 ꢀC,
lit.9a,b 196–197 ꢀC. 1H NMR (400 MHz, CDCl3)
d
: 2.99 (2H, dd, J¼9.6,
4.4 Hz, H-1a and H-3a), 3.19 (2H, dd, J¼9.6, 6.0 Hz, H-1b and H-3b),
3.70 (1H, tt, J¼6.0, 4.4 Hz, H-2), 7.08–7.34 (45H, m, arom.). 13C NMR
(100 MHz, CDCl3) d: 63.4 (C-1 and C-3), 72.7 (C-2), 86.3/86.8 (Ph3C),
126.6/126.8/127.5/127.6/128.9/129.0 (d, arom.), 144.2/144.8 (s,
arom.).
4.3. Detritylation of 2-O-benzyl-1,3-di-O-tritylglycerol (13)
4.3.1. Method A
According to the method reported,8 13 (1.0 g, 1.5 mmol) was
treated in refluxing 80% aqueous acetic acid (5 ml) for 1 h to give
a ca. 4.7:1 mixture of 2-O-benzylglycerol8,10 (8) and 2-O-benzyl-
glycerol 1-acetate10a,b,11 (10) contaminated with a trace amount of
2-O-benzylglycerol 1,3-diacetate10a (11) as a colorless oil (396 mg).
The crude oil was heated under reflux in a mixture of 10% hydro-
chloric acid (1 ml) and methanol (3 ml) for 1 h. Removal of the
solvent in vacuo left a colorless oil (366 mg), which on column
chromatography (CHCl3/CHCl3–MeOH, 30:1) gave 8 (232 mg, 85%
from 13) as a colorless oil. Analytical sample of the side product 10
was obtained by means of column chromatography (CHCl3/
CHCl3–MeOH, 30:1) of a small portion of the crude hydrolyzed
products from 13.
4.5. 2-O-Benzylglycerol 1,3-cyclic sulfate (5)
A
solution of freshly distilled thionyl chloride (1.04 ml,
14.3 mmol) in dichloromethane (50 ml) was added dropwise to
a stirred mixture of 8 (2.0 g, 11 mmol), triethyl amine (4.6 ml,
33.2 mol), and dichloromethane (60 ml) at 0 ꢀC. After being stirred
at 0 ꢀC for 10 min, the mixture was poured into ice-cooled and
vigorously stirred aqueous sodium hydrogen carbonate (100 ml),
and extracted with dichloromethane. The extract was washed with
brine and evaporated to give a pale yellow oil (2.53 g), which was
used in the next step without purification.
To a well stirred mixture of the oil (2.53 g), sodium hydrogen
carbonate (3.3 g, 39.2 mmol), carbon tetrachloride (60 ml), aceto-
nitrile (60 ml), and water (60 ml) was added dropwise a brown
mixture of sodium metaperiodate (7.05 g, 32.9 mmol), ruthenium
chloride n-hydrate (100 mg), and water (60 ml) at 0 ꢀC. After being
stirred at room temperature for 30 min, the reaction was quenched
by the addition of aqueous sodium thiosulfate-sodium hydrogen
carbonate (50 ml). The resulting purple mixture was filtered and
the filtrate was extracted with diethyl ether. The extract was
washed with brine and evaporated to give a colorless solid (2.66 g),
which on column chromatography (n-hexane–acetone, 5:1) gave
the title compound (5, 2.5 g, 93%) as colorless solid. The spectral
properties of 5 were in accord with those reported.5e
4.3.2. Method B
A mixture of 13 (11.6 g, 17.4 mmol), 10% aqueous sulfuric acid
(15 ml), and 1,4-dioxane (40 ml) was heated under reflux for 3 h.
After being cooled, the reaction mixture was diluted with water and
the resulting mixture was neutralized with sodium hydrogen car-
bonate. The deposited trityl alcohol (9.1 g) was filtered and washed
with water. The combined filtrate and the washings were saturated
with sodium chloride, and the resulting mixture was extracted with
ethyl acetate. Removal of the solvent left practically pure 8 (2.93 g,
92%) as a colorless oil, which on distillation at reduced pressure gave
8 (2.9 g, 91%). The oil solidified on standing at room temperature.
4.3.2.1. Compound 8. Mp 34–36 ꢀC, lit.8 35–36 ꢀC, lit.10d 35–37 ꢀC;
bp 150–152 ꢀC/0.1 mmHg, lit.10b 180 ꢀC/3 mmHg, lit.10d 149 ꢀC/
0.2 mmHg. 1H NMR (400 MHz, CDCl3)
d: 2.10 (2H, br s, OH), 3.60
(1H, tt, J¼4.8, 4.4 Hz, H-2), 3.72 (2H, dd, J¼11.6, 4.8 Hz, H-1a and H-
3a), 3.79 (2H, dd, J¼11.6, 4.4 Hz, H-1b and H-3b), 4.66 (2H, s,
PhCH2), 7.23–7.40 (5H, m, arom.). 13C NMR (100 MHz, CDCl3)
d
: 62.1
4.6. Coupling reaction between cyclic sulfate 5
and thiosugar 6
(C-1 and C-3), 79.1 (C-2), 71.9 (PhCH2), 127.8/127.9/128.5 (d, arom.),
137.9 (s, arom.).
A suspension of the cyclic sulfate 5 (1.47 g, 6.0 mmol), a thio-
4.3.2.2. Compound 10. Colorless oil. The closed signals due to two
methylene carbons C-1 and C-3 were unambiguously assigned on
the basis of two dimensional NMR studies. 1H NMR (500 MHz,
sugar7
6 (602 mg, 4.0 mmol), potassium carbonate (277 mg,
2 mmol), and HFIP (3 ml) was stirred at 65–70 ꢀC. Potassium car-
bonate was dissolved in HFIP within 2 h, and the resulting solution
was heated at 65–70 ꢀC for another 70 h. In the course of the re-
action, precipitates were gradually formed in the reaction mixture,
and the precipitates were filtered and washed with a mixture of
ethyl acetate and methanol (10:1, v/v) to give a colorless solid
(482 mg), which on recrystallization from aqueous methanol
gave 1,4-dideoxy-1,4-{(S)-[(2R)-2-benzyloxy-3-(sulfooxy)propyl]-
CDCl3) d: 2.02 (1H, br s, OH), 2.08 (3H, s CH3C]O), 3.61–3.67 (1H, br
m, H-3a), 3.69–3.75 (2H, br m, H-2 and H-3b), 4.23 (2H, d, J¼4.9 Hz,
H-1a and H-1b), 4.61/4.71 (each d, J¼11.7 Hz) 7.27–7.39 (5H, m,
arom.). 13C NMR (125 MHz, CDCl3)
d: 20.8 (O]CCH3), 62.0 (C-3),
62.9 (C-1), 72.2 (PhCH2), 77.6 (C-2), 127.9/128.0/128.5 (d, arom.),
137.8 (s, arom.), 171.0 (O]CCH3).

G. Tanabe et al. / Tetrahedron 64 (2008) 10080–10086
10085
episulfoniumylidene}-D-arabinitol inner salt (14, 258 mg, 16%) as
4.9. X-ray crystallographic analysis
colorless prisms. The combined filtrate and the washings were
evaporated to give a colorless paste (2.88 g), which on column
Data of both compounds 3 and epi-3 were taken on Rigaku
chromatography (AcOEt–MeOH–H2O, 20:2:1) gave
mixture of 1,4-dideoxy-1,4-{(S)-[(2S)-2-benzyloxy-3-(sulfooxy)-
propyl]-episulfoniumylidene}- -arabinitol inner salt (15) and its
a
ca. 10:1
RAXIS RAPID imaging plate area detector with graphite mono-
chromated Mo K
a
radiation (
l¼0.71075 Å). The structures of 3 and
D
epi-3 were solved by direct methods with SIR97 and SHELX97, re-
spectively. Full-matrix least-squares refinement was employed
with anisotropic thermal parameters for all non-hydrogen atoms.
All calculations were performed using the CrystalStructure 3.8
crystal structure analysis package, Rigaku and Rigaku/MSC. ORTEP
drawings of compounds 3 and epi-3 are shown in Figure 2. The data
of 3 and epi-3 have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC
683290 and CCDC 683289, respectively.
epimer 14 (103 mg, 6.5%), a ca. 6:1 mixture of 15 and 14 (216 mg,
14%), and a ca. 1.4:1 mixture of 15 and 14 (102 mg, 6.5%).
Compound 14: colorless prisms, mp 178.5–180 ꢀC (from aq
23
MeOH), [
a
]
ꢁ71.4 (c 0.52, H2O). IR (Nujol): 3344, 1461, 1377, 1273,
D
1192, 1123, 1088, 1057, 1011 cmꢁ1. 1H NMR (600 MHz, pyridine-d5)
d
: 4.08 (dd, J¼12.5, 2.2 Hz, H-1a), 4.25 (dd, J¼12.5, 3.9 Hz, H-1b),
4.44 (dd, J¼13.2, 4.3 Hz, H-10a), 4.48 (dd, J¼11.6, 7.9 Hz, H-5a), 4.51
(dd, J¼11.6, 6.0 Hz, H-5b), 4.55 (dd, J¼13.2, 5.8 Hz, H-10b), 4.61
(dddd, J¼6.9, 5.8, 4.3, 4.0 Hz, H-20), 4.65/4.77 (each 1H, d, J¼11.7 Hz,
PhCH2), 4.71 (dd, J¼11.5, 6.9 Hz, H-30a), 4.75–4.78 (m, H-4), 4.84
(dd, J¼11.5, 4.0 Hz, H-30b), 5.01 (br s-like, H-3), 5.10 (br m, H-2),
7.21–7.29 (3H, m, arom.), 7.36–7.39 (2H, m, arom.), 7.60–7.84 (1H, br
s, OH), 8.29/8.39 (each 1H, s, OH). 13C NMR (150 MHz, pyridine-d5)
Crystal data for salaprinol (3). Orthorhombic, space group P212121,
a¼6.8882(4), b¼9.6565(7), c¼18.1174(4) Å, V¼1205.10(14) Å3, Z¼4,
m
(Mo K
a
)¼4.73 cmꢁ1, F(000)¼640, Dc¼1.677 g/cm3, crystal di-
mensions: 0.20ꢂ0.20ꢂ0.10 mm. A total of 11,878 reflections (2758
unique) were collected at a temperature of 23 ꢀC to a maximum
d
: 49.6 (C-10), 50.8 (C-1), 60.2 (C-5), 65.6 (C-30), 71.9 (OCH2Ph), 73.4
2q
value of 55ꢀ. Final R and Rw values were 0.040 and 0.115,
(C-4), 74.0 (C-20), 79.0 (C-2), 79.4 (C-3), 128.3/128.5/128.8 (d,
arom.), 138.0 (s, arom.).
respectively. The maximum and minimum peaks in the difference
map were 0.40 eꢁ Åꢁ3 and ꢁ0.22 eꢁ
Å
ꢁ3, respectively.
Crystal data for epi-salaprinol (epi-3). Monoclinic, space group
Data for 15 extracted from 1H and 13C NMR spectra of ca. 10:1
mixture of 15 and 14: 1H NMR (700 MHz, pyridine-d5)
d: 4.29 (2H,
P21, a¼8.9887(14), b¼6.9476(10), c¼9.9149(13) Å,
b
¼91.543(4)ꢀ,
F(000)¼320,
d-like J¼2.8 Hz, H-1a and H-1b), 4.39 (dd, J¼13.2, 7.1 Hz, H-10a),
4.41 (dd, J¼11.6, 9.5 Hz, H-5a), 4.47 (dd, J¼11.6, 5.4 Hz, H-5b), 4.57
(dd, J¼13.2, 2.9 Hz, H-10b), 4.67–4.72 (m, H-20), 4.70–4.73 (m, H-
30a), 4.74/4.85 (each 1H, d, J¼11.2 Hz, PhCH2), 4.80 (br dd, J¼9.5,
5.4 Hz, H-4), 4.84 (dd, J¼13.8, 6.2 Hz, H-30b), 4.95 (br dd-like, J¼ca.
2.8 Hz, H-3), 5.11 (br td-like, J¼ca., 2.8, 2.8 Hz, H-2), 7.19–7.29 (3H,
m, arom.), 7.39–7.42 (2H, m, arom.), 7.77/8.19/8.27 (each 1H, br s,
V¼618.96(15) Å3, Z¼2,
m(Mo
K
a
)¼4.604 cmꢁ1
,
Dc¼1.633 g/cm3, crystal dimensions: 0.35ꢂ0.32ꢂ0.20 mm. A total
of 5957 reflections (2661 unique) were collected at a temperature
q
of 23 ꢀC to a maximum 2 value of 55ꢀ. Final R and Rw values were
0.040 and 0.093, respectively. The maximum and minimum peaks
in the difference map were 0.44 eꢁ Åꢁ3 and ꢁ0.37 eꢁ Åꢁ3
,
respectively.
OH). 13C NMR (175 MHz, pyridine-d5) : 49.9 (C-10), 51.5 (C-1), 60.2
d
(C-5), 66.3 (C-30), 72.2 (OCH2Ph), 73.6 (C-4), 74.4 (C-20), 78.7 (C-2),
79.2 (C-3), 128.1/128.5/128.8 (d, arom.), 138.2 (s, arom.).
Acknowledgements
This work was supported by a Grant-in Aid for Scientific
Research from ‘High-Tech Research Center’ Project for Private
Universities: matching fund subsidy from MEXT (Ministry of Edu-
cation, Culture, Sports, Science and Technology), 2007–2011 and
also supported by a grant-in aid for scientific research by the Japan
society for the promotion of science (JSPS).
4.7. Salaprinol (3)
A suspension of 10% palladium on carbon (50 mg) in 80%
aqueous acetic acid (1 ml) was pre-equilibrated with hydrogen. To
the suspension was added a solution of a ca. 10:1 mixture of 15 and
14 (36 mg, 0.09 mmol) in 80% aqueous acetic acid (2 ml), and the
mixture was hydrogenated at room temperature under atmo-
spheric pressure until the uptake of hydrogen ceased. The catalyst
was filtered and washed with a mixture of methanol and water. The
combined filtrate and the washings were evaporated to give a col-
orless viscous oil (31 mg), which on column chromatography
(CHCl3–MeOH–H2O, 10:5:1) gave a solid (23.8 mg, 86%). The solid
References and notes
1. (a) Yoshikawa, M.; Xu, F.; Morikawa, T.; Pongpiriyadacha, Y.; Nakamura, S.;
Asao, Y.; Kumahara, A.; Matsuda, H. Chem. Pharm. Bull. 2007, 55, 308; (b)
Yoshikawa, M.; Nakamura, S.; Ozaki, K.; Kumahara, A.; Morikawa, T.; Matsuda,
H. J. Nat. Prod. 2007, 70, 210; (c) Yoshikawa, M.; Wang, T.; Morikawa, T.; Xie, H.;
Matsuda, H. Chem. Pharm. Bull. 2007, 55, 1308; (d) Zhang, H.; Matsuda, H.;
Kumahara, A.; Ito, Y.; Nakamura, S.; Yoshikawa, M. Bioorg. Med. Chem. Lett. 2007,
17, 4972; (e) Matsuda, H.; Yoshikawa, M.; Morikawa, T.; Tanabe, G.; Muraoka, O.
J. Trad. Med. 2005, 22, 145; (f) Yoshikawa, M.; Nishida, N.; Shimoda, H.; Takada,
M.; Kawahara, Y.; Matsuda, H. Yakugaku Zasshi 2001, 121, 371.
2. (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara, J.;
Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367; (b) Yoshikawa, M.;
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.
was recrystallized from MeOH to give 3 as colorless prisms. Mp
23
159–161 ꢀC, [
a]
þ10.7 (c 0.63, MeOH), lit.7 þ10.3 (c 1.30, MeOH).
D
1H (700 MHz) and 13C (175 MHz) NMR spectroscopic properties
were completely in accord with those reported (500 MHz and
125 MHz),7 and summarized in Tables 1 and 2.
3. Matsuda, H.; Murakami, T.; Yashiro, K.; Yamahara, J.; Yoshikawa, M. Chem.
Pharm. Bull. 1999, 47, 1725.
4. Yoshikawa, M.; Pongpiriyadacha, Y.; Kishi, A.; Kageura, T.; Wang, T.; Morikawa,
T.; Matsuda, H. Yakugaku Zasshi 2003, 123, 871.
4.8. epi-Salaprinol (epi-3)
5. (a) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000, 41, 6615; (b)
Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001, 66, 2312; (c)
Muraoka, O.; Ying, S.; Yoshikai, K.; Matsuura, Y.; Yamada, E.; Minematsu, T.;
Tanabe, G.; Matsuda, H.; Yoshikawa, M. Chem. Pharm. Bull. 2001, 49, 1503; (d)
Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.; Snider, B. B.; Pinto, B.
M. Synlett 2003, 1259; (e) Muraoka, O.; Yoshikai, K.; Takahashi, H.; Minematsu,
T.; Lu, G.; Tanabe, G.; Wang, T.; Matsuda, H.; Yoshikawa, M. Bioorg. Med. Chem.
2006, 14, 500; (f) Tanabe, G.; Yoshikai, K.; Hatanaka, T.; Yamamoto, M.; Shao, Y.;
Minematsu, T.; Muraoka, O.; Wang, T.; Matsuda, H.; Yoshikawa, M. Bioorg. Med.
Chem. 2007, 15, 3926; (g) Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551
and referenced cited therein.
A solution of 14 (100 mg, 0.25 mmol) in 80% aqueous acetic acid
(10 ml) was hydrogenated in a similar manner to that used for
above hydrogenation. Work-up gave a colorless solid (76.9 mg),
which on recrystallization from aqueous methanol gave the title
compound epi-3 (67 mg, 87%) as colorless prisms. Mp 168–170 ꢀC,
23
[
a]
ꢁ59.5 (c 0.56, MeOH). IR (Nujol): 3522, 3402, 3283, 1377, 1246,
D
1207, 1165, 1115, 1072, 1057, 1026, 988 cmꢁ1
.
1H and 13C NMR
spectral data are summarized in Tables 1 and 2.

10086
G. Tanabe et al. / Tetrahedron 64 (2008) 10080–10086
6. (a) Ratnasooriya, W. D.; Jayakody, J. R. A. C.; Premakumara, G. A. S. Braz. J. Med.
Biol. Res. 2003, 36, 931; (b) Wolf, B. W.; Weisbrode, S. E. Food Chem. Toxicol.
2003, 41, 867; (c) Flammang, A. M.; Erexson, G. L.; Mecchi, M. S.; Murli, H. Food
Chem. Toxicol. 2006, 44, 1868; (d) Kitabayashi, H.; Nakamura, C.; Katsuta, K.;
Horii, A.; Momizo, I.; Takano, J.; Yoshikawa, M.; Muraoka, O.; Saito, Y.; Saito, M.;
Koikeda, T. J. Nutr. Food 2007, 10, 23.
9. (a) Verkade, P. E.; van der Lee, J.; Meerburg, W. Recl.Trav.Chim.Pays-Bas1937,56,613;(b)
Hurd, C. D.; Mack, C. O.; Filachione, E. M.; Sowden, J. C. J. Am. Chem. Soc. 1937, 59, 1952.
10. (a) Suemune, H.; Mizuhara, Y.; Akita, H.; Sakai, K. Chem. Pharm. Bull. 1986, 34,
3440; (b) Murata, M.; Terao, Y.; Achiwa, K.; Nishio, T.; Seto, K. Chem. Pharm. Bull.
1989, 37, 2670; (c) Cassel, S.; Debaig, C.; Benvegnu, T.; Chaimbault, P.; Lafosse,
M.; Plusquellec, D.; Rollin, P. Eur. J. Org. Chem. 2001, 875; (d) Ray, W. C., III;
Grinstaff, M. W. Macromolecules 2003, 36, 3557; (e) Wang, Q.; Lo¨ennberg, H.
J. Am. Chem. Soc. 2006, 128, 10716.
7. Yoshikawa, M.; Xu, F.; Nakamura, S.; Wang, T.; Matsuda, H.; Tanabe, G.; Mur-
aoka, O. Heterocycles 2008, 75, 1397.
8. Hronowski, L. J. J.; Szarek, W. A.; Hay, G. W.; Krebs, A.; Depew, W. T. Carbohydr.
Res. 1989, 190, 203.
11. Hronowski, L. J. J.; Szarek, W. A.; Hay, G. W.; Krebs, A.; Depew, W. T. Carbohydr.
Res. 1989, 193, 91.