Synthesis and biological evaluation of deoxy salacinols, the role of polar substituents in the side chain on the α-glucosidase inhibitory activity

Article abstract of DOI:10.1016/j.bmc.2005.08.040

Three analogs (5, 6, and 7) lacking polar substituents in the side chain of a naturally occurring α-glucosidase inhibitor, salacinol (1a), were synthesized by the coupling reaction of a thiosugar, 1,4-dideoxy-1,4-epithio-d- arabinitol (3), with cyclic sulfates (8, 9, and 10), and their α-glucosidase inhibitory activities were examined. All these simpler analogs (5, 6, and 7) showed less inhibitory activity compared to 1a, and proved the importance of cooperative role of the polar substituents for the α-glucosidase inhibitory activity. A practical synthetic route to 3 starting from d-xylose is also described.

Full text of DOI:10.1016/j.bmc.2005.08.040

Bioorganic & Medicinal Chemistry 14 (2006) 500–509
Synthesis and biological evaluation of deoxy salacinols, the role
of polar substituents in the side chain on the a-glucosidase
inhibitory activity
Osamu Muraoka,a,* Kazuya Yoshikai,a Hideo Takahashi,a Toshie Minematsu,a
Guangxin Lu,a Genzoh Tanabe,a Tao Wang,b Hisashi Matsudab and
Masayuki Yoshikawab
aSchool of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
bKyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
Received 14 July 2005; revised 13 August 2005; accepted 16 August 2005
Available online 29 September 2005
Abstract—Three analogs (5, 6, and 7) lacking polar substituents in the side chain of a naturally occurring a-glucosidase inhibitor,
salacinol (1a), were synthesized by the coupling reaction of a thiosugar, 1,4-dideoxy-1,4-epithio-D-arabinitol (3), with cyclic sulfates
(8, 9, and 10), and their a-glucosidase inhibitory activities were examined. All these simpler analogs (5, 6, and 7) showed less inhib-
itory activity compared to 1a, and proved the importance of cooperative role of the polar substituents for the a-glucosidase inhib-
itory activity. A practical synthetic route to 3 starting from D-xylose is also described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
opening reaction of a cyclic sulfate (2) with thiosugar (3)
as the key reaction.3 Intensive studies on the structure–ac-
tivity relationship of 1a and its heterocyclic analogs (1b
and 1c) have also been reported,4 and the sulfonium ion
structure has been recognized as one of the essential struc-
tural factors for the potent a-glucosidase inhibitory activ-
ity. Even the S-methylated thiosugar (4) had also been
found to show slight a-glucosidase inhibitory activity,
while the thiosugar 3 itself showed no inhibitory activity
against the enzymes.1b,4b,d
Salacinol (1a) is a potent glycosidase inhibitor isolated
from aqueous extracts of roots and stems of Salacia retic-
ulata WIGHT (known as ÔKotala himbutuÕ in Sinhalese),
which is traditionally used for the treatment of diabetes
in Sri Lanka and the southern region of India. The a-glu-
cosidase inhibitory activities of 1a are potent and have
been revealed to be as strong as those of voglibose and
acarbose, which are widely used clinically these days.1
The structure of 1a established by the X-ray crystallo-
graphic analysis is quite unique, the ring sulfonium ion
being stabilized by the sulfate counteranion by forming
a spirobicyclic-like configuration comprised of 1-deoxy-
4-thioarabinofuranosyl cation and 1-deoxy-L-erythro-
syl-3-sulfate anion, as shown in Scheme 1.1 Due to both
the strong glycosidase inhibitory activity and the intrigu-
ing structure, much attention has been focused on 1a and
related compounds.2 Total synthesis of 1a was accom-
plished by two groups by the use of nucleophilic ring
Thus, as a continuous study on its structure–activity rela-
tionship, three deoxy-analogs of salacinol (5, 6, and 7)
were synthesized by the coupling reaction of 3 with corre-
sponding cyclic sulfates (8, 9, and 10), and their a-glucosi-
dase inhibitory activities were examined. Full details of
the practical synthetic method of 3 previously developed
by the authors5 are also described in the present study.
2. Results and discussion
2.1. Synthesis of thiosugar
Keywords: a-Glucosidase inhibitor; Salacinol; Deoxygenated salacinol;
Thiosugar.
According to the literature,6a,b D-xylose was converted
into 1,2-monoacetonide, 1,2-O-isopropylidene-a-D-
*
Corresponding author. Tel.: +81 6 6721 2332; fax: +81 6 6730
1394; e-mail: muraokai@phar.kindai.ac.jp
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.08.040

O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
501
R2
H
H
CH2OH
O
S
O
O
H
O
O
R1
HO
O
S
S
HO
S
O
O
O
O
3HO
4
-O
X
O
S
O
O
+O-
5
HO
HO
OH
HO
O-
4'
S
R2
HO
X
2'
3'
HO
3
R1
2
1
OH
1'
OH
CH3
S+
OH
HO
2 : R1=α-OR, R2 = CH2OR
8 : R1= H, R2 = H
9 : R1= OR, R2 = H
10 : R1= H, R2 = CH2OR
OH
HO
a : X = S+
b : X = NH+
c : X = Se+
HO
1
5 : R1=H, R2=H
6 : R1=OH, R2=H
7 : R1=H, R2=CH2OH
OH
HO
4
R = protecting groups
Scheme 1.
xylofuranose (11) via diacetonide, 1,2:3,5-di-O-isopro-
pylidene-a-D-xylofuranose (12), in 95% yield. The pri-
mary hydroxyl of 11 was selectively protected by the
tert-butyldimethylsilyl (TBDMS) moiety, and the result-
ing silyl ether, 5-O-tert-butyldimethylsilyl-1,2-O-isopro-
pylidene-a-D-xylofuranose7 (13), was treated with
benzyl (Bn) bromide in the presence of sodium hydride,
to afford the desired benzyl ether, 3-O-benzyl-5-O-tert-
butyldimethylsilyl-1,2-O-isopropylidene-a-D-xylofura-
nose7b (14), in good yield. Simultaneous cyclization was
found to occur when 1,2-O-isopropylidene-5-O-tosyl-a-
D-xylofuranose7c,8 (15), prepared by the treatment of
11 with tosyl chloride, was subjected to benzylation, giv-
ing ca. 1:1.1 mixture of 3,5-anhydro-1,2-O-isopropyli-
dene-a-D-xylofuranose9 (16) and the desired benzyl
derivative, 3-O-benzyl-1,2-O-isopropylidene-5-O-tosyl-
a-D-xylofuranose8,10 (17). Compound 14 was then treat-
ed with 5% methanolic hydrogen chloride, where the
deacetalization was accompanied by methyl glycoside
formation to afford ca. 1:1 anomeric mixture of methyl
3-O-benzyl-a- and b-D-xylofuranoside11 (a- and b-18).
Without separation of these anomers, the mixture was
treated with methanesulfonyl chloride to afford the cor-
responding bismesylates, methyl 3-O-benzyl-2,5-di-O-
mesyl-a- and b-D-xylofuranoside11 (a- and b-19), which
were then treated with sodium sulfide in DMF to give
ca. 1.3:1 anomeric mixture of 2,5-dideoxy-2,5-epithio-
3-O-benzyl-a- and b-D-lyxofuranoside11 (a- and b-20).
Hydrolysis of the mixture with 4 N hydrochloric acid
in THF followed by the reduction of the resulting alde-
hyde (21) with sodium borohydride gave 3-O-benzyl-
1,4-dideoxy-1,4-epithio-D-arabinitol11 (22) in 58%
overall yield from 14. The conversion of 20 to 22 could
be carried out in one-pot by neutralizing the reaction
mixture with sodium hydrogen carbonate prior to the
addition of sodium borohydride. Finally, the Birch
reduction of 22 afforded the desired 3 in 97% yield
(Scheme 2). The overall yield of this sequence via nine
steps from D-xylose was around 53%, thus an efficient
and practical alternative route11 to 3 being developed.
2.2. Synthesis of cyclic sulfates 8, 9, and 10
According to the reported method,12 1,3-propanediol
1,3-cyclic sulfate (8) was prepared in 80% yield by con-
densation of 1,3-propanediol (23) with thionyl chloride,
followed by oxidation of the resulting cyclic sulfoxide
with sodium periodate in the presence of ruthenium
chloride. 2-O-Benzylglycerol 1,3-cyclic sulfate (9) as a
fragment of the deoxymethylated salacinol 6 was synthe-
sized starting from glycerol. Thus, its two primary
hydroxyls were protected by the trityl moiety to afford
bistrityl ether13 (24). Benzylation of 24 followed by de-
tritylation of the benzyloxyl derivative, 2-O-benzyl-1,3-
di-O-tritylglycerol13 (25), by acetic acid at 100 ꢁC gave
2-O-benzylglycerol13 (26) in 68% overall yield from glyc-
erol. The diol 26 was converted into the desired 2-ben-
zyloxy cyclic sulfate 9 in a manner similar to that for
the synthesis of 8 (Scheme 3).
It is interesting to note that the benzyloxy group of com-
pound 9 was proved to be axially oriented on the basis
of the X-ray crystallographic analysis as shown in
Figure 1. Small vicinal coupling constants of J 3.0 and
O
O
O
TsO
TsO
e
O
+
O
O
O
O
BnO
O
D-xylose
HO
O
15
16
17
a
d
O
O
O
O
OCH3
HO
TBDMSO
HO
b
c
g
h
O
O
O
O
O
HO
O
RO
O
O
BnO
OH
12
11
13 : R=H
14 : R=Bn
18
f
S
S
S
O
OCH3
O
OHC
HO
MsO
OCH3
j
i
RO
21
OH
RO
22 : R = Bn
3 : R =
OH
BnO
OMs
BnO
19
20
k
H
Scheme 2. Reagents and conditions: (a) acetone, H2SO4, CuSO4, rt; (b) 0.1% aq HCl, rt; (c) TBDMSCl, imidazole, DMF, 0 ꢁC; (d) TsCl, Py., CHCl3,
0 ꢁC–rt; (e) NaH, BnBr, THF, 0 ꢁC; (f) NaH, BnBr, DMF, 0 ꢁC; (g) HCl, MeOH, rt; (h) MsCl, Py., 0 ꢁC–rt; (i) Na2S, DMF, 100 ꢁC; (j) 4 N aq HCl,
THF, then NaBH4, 0 ꢁC–rt; (k) Na, liq. NH3, ꢀ50 ꢁC.

502
O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
O
O
d
S
O
O
a,b
a,b
TrO
TrO
HO
HO
HO
HO
S
OBn
O
OR
R= H
O
O
O
23
26
24:
25:
OBn
O
8
c
9
R = Bn
O
S
O
S
1
f
g
a,b
OTBDMS
O
h
Ph
e
2
O
HO
Ph
O
Ph
OH
OR
OCSCH3
OTBDMS
O
O
3
O
HO
O
OTBDMS
4
OTBDMS
30
29
31
10
27: R= H
28:
R = TBDMS
Scheme 3. Reagents and conditions: (a) SOCl2, Et3N, 0 ꢁC; (b) NaIO4, NaHCO3, RuCl3.H2O, CCl4, CH3CN, H2O, rt; (c) BnCl, KOH, toluene,
reflux; (d) 80% aq AcOH, 100 ꢁC; (e) TBDMSCl, imidazole, DMF, 0 ꢁC; (f) CS2, 5 N aq NaOH, DMSO, 0 ꢁC, then CH3I, 0 ꢁC–rt; (g) H3PO2, Et3N,
EtOH, reflux; (h) H2, Pd–C, EtOH, rt.
4-O-tert-butyldimethylsilyl-2-deoxy-L-erythritol (30) in
80% overall yield from 27. Hydrogenolysis followed by
the cyclic sulfonation of the product, 4-O-tert-butyldi-
methylsilyl-2-deoxy-L-erythritol (31), gave the desired
O-protected cyclic sulfate 10 in 75% yield. The protonat-
ed molecular-ion [M+H]+ peak at m/z 283 in the FAB
mass spectrum and other spectroscopic properties
supported the structure of 10.
2.3. Syntheses of deoxysalacinols (5, 6, and 7)
According to the literature, cyclic sulfates (8, 9, and
10) were treated with
3
in either DMF3a or
1,1,1,3,3,3-hexafluoroisopropanol3b,c (HFIP). Coupling
reaction3 of 8 with thiosugar 3 in HFIP afforded the
corresponding sulfonium sulfate 5 in 61% yield. The
peak at m/z 289 in the FAB mass spectrum run in
the positive mode represented the protonated molecu-
Figure 1. Perspective view of compound 9.
1
lar-ion [M+H]+ of the desired compound 5. In its H
2.5 Hz with respect to the signal at dH 3.65 due to the
C-2 methine proton in its H NMR spectrum showed
1
NMR spectrum, downfield shift owing to sulfonium
ion formation was observed with respect to the signals
due to C-1 methylene (at dH 3.78 and 3.90) and C-4
methine (at dH 3.94) protons. A pair of one-proton
doublet of doublets, which appeared at dH 3.61 and
3.67, due to methylene protons a to the sulfur atom
also supported the sulfonium ion structure. The rela-
tive stereochemistry of the side chain on the sulfur
atom was determined to be in trans relationship to
the hydroxymethyl group at C-4, as shown in
Scheme 4, on the basis of nuclear Overhauser effect
(NOE) experiments. NOE correlations were detected
between the two ring protons a to the sulfur (H-4
and H-1a) and C-10 methylene protons, suggesting
the depicted configuration of the side chain.
that the group is in the same configuration also in
solution state.14
For the synthesis of 4-O-tert-butyldimethylsilyl-2-de-
oxy-L-erythritol 1,3-cyclic sulfate (10), D-glucose was
first converted into 1,3-O-benzylidene-L-erythritol4a
(27). The remaining primary hydroxyl was protected
with tert-butyldimethylsilyl chloride to afford 1,3-
O-benzylidene-4-O-tert-butyldimethylsilyl-L-erythritol
(28), which was then converted into the corresponding
xantate, 1,3-O-benzylidene-2-O-[(S-methylthio)thiocar-
bonyl]-4-O-tert-butyldimethylsilyl-L-erythritol (29), in
the usual manner. Subsequent deoxygenation by the
use of hypophosphorous acid gave 1,3-O-benzylidene-
O
O
O
O
O
O
O
O
O
S
S
S
O-
HO
4
HO
O-
HO
O-
a
a
b
HO
HO
HO
HO
HO
HO
S+
H
S+
8
S+
32
9
3'
1'
H 1
2'
H
Ha
OH
OBn
6
5
O
O
O
O
O
S
S
O-
HO
HO
O
O-
HO
HO
a
HO
HO
10
S+
H
S+
H
c
NOE
H
OH
H
OTBDMS
H
H
33
7
Scheme 4. Reagents and conditions: (a) 3, HFIP, K2CO3, 60 ꢁC or 3, DMF, Na2CO3, 45 ꢁC; (b) H2, Pd–C, AcOH–H2O, rt; (c) 0.1% aq HCl, 40 ꢁC.

O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
503
Table 1. IC50 values (lM) of compounds 1a, 4, 5, 6, and 7 against
disaccharidase
When 9 was subjected to the coupling reaction with 3,
1:1 diastereomeric mixture (32) with respect to the con-
figuration of the benzyloxy moiety at C-20 was obtained
in 45% yield. Hydrogenolysis of the mixture 32 over pal-
ladium on carbon gave the desired deoxymethylated sal-
Compound
Maltase
Sucrase
1a
4
9.6
>1370 (38)
>1390
2.5
445
1
acinol 6 in 60% yield. The mixture displayed similar H
5
>1390 (24)
780
>1260 (29)
NMR spectroscopic properties to those of 1a, signals of
five a-protons to the sulfur being deshielded due to the
formation of the sulfonium ion. Two pairs of signals ap-
peared at dC 50.8 and 51.3 (C-10), and dC 70.2 and 70.3
(C-30) in the 13C NMR spectrum were ascribed to two
carbons around the chiral center at C-20, supporting
the fact that the mixture was composed of two diastereo-
mers of 6.
6
>1320 (24)
>1260
7
Values in parentheses indicate inhibition (%) at 400 lg/ml.
2.4. a-Glucosidase inhibitory activity
The glycosidase inhibitory activity of synthesized com-
pounds 5, 6, and 7 was tested for the intestinal a-glu-
cosidase in vitro15 and compared with that of 1a, as
shown in Table 1. Although maltase and sucrase were
the enzymes effectively inhibited by 1a, 5 showed no
inhibition against both enzymes even at a high concen-
tration of 1.39 mM. Thus, reduction of the two
hydroxyls from 1a caused the significant loss of activ-
ity. The inhibitory activities of 7, deoxygenated at C-20
of 1a, also decreased considerably, indicating that the
hydroxyl with S-configuration at C-20 was essential for
the activity. On the other hand, 6 slightly retained the
inhibitory activity against sucrase, suggesting the supe-
riority of the hydroxyl at C-20 to the hydroxymethyl
group at C-30 in exhibiting the inhibitory activity
against sucrase. These results suggest the importance
of the cooperative role of the polar substituents in
the side chain for the a-glucosidase inhibitory activity.
Thus, all these substituents were found to be necessary
to exhibit the inhibitory activity. Further studies on
the structure–activity relationships of 1a with the po-
tential a-glucosidase inhibitory activity are under
investigation.
Fortunately, single crystals of the mixture were ob-
tained, and structural confirmation including the stereo-
chemistry at the sulfonium center was established on the
basis of the X-ray crystallographic analysis. Both diaste-
reomers were packed to form P212121 type orthorhom-
bic crystals, and stereostructure of one of the
diastereomers was extracted and its ORTEP drawing is
presented in Figure 2. It is noteworthy that the two ionic
centers in the molecule are far apart from each other
(open-chain form), while 1a had been proved to con-
struct the inner salt structure between these two ionic
centers (cyclic form).1
Inhibition mechanisms of salacinol (1a) have been pro-
posed,4d where two ionic centers are shown to be the
binding sites to the enzyme in the open-chain form.
Decreased inhibitory activity of these synthesized
compounds suggests the presence of another factor gov-
erned by the hydroxyls for the salacinol to bind the cor-
responding enzymes.
The reaction of the cyclic sulfates 10 with 3 was also per-
formed to give the coupled product (33) in 20% yield.
Subsequent hydrolysis of 33 with 0.1% aqueous HCl at
40 ꢁC afforded the target compound 7 in 75% yield. Its
MS and NMR spectra supported the desired coupled
structure. The relative stereochemistry of the side chain
on the sulfur was also established on the basis of
NOESY experiments as shown in Scheme 4.
3. Experimental
Mps were determined with a Yanagimoto MP-3S micro-
melting point apparatus, and mps and bps are uncor-
rected. IR spectra were measured on a Shimadzu
IR-435 grating spectrophotometer. NMR spectra were
recorded either on a JEOL JNM-GSX 270 (270 MHz
1H, 67.5 MHz 13C) or
a JEOL JNM-GSX 500
(500 MHz 1H, 125 MHz 13C) spectrometer. Chemical
shifts (d) and coupling constants (J) are given in parts
per million and hertz, respectively. Low-resolution and
high-resolution mass spectra (electron impact) were
recorded either on a Shimadzu QP 1000EX spectrometer
or a JEOL JMS-HX 100 spectrometer. Optical rotations
were determined with a JASCODIP-370 digital polarim-
eter. Column chromatography was effected over Merck
Kieselgel 60 (70–230 mesh). All the organic extracts
were dried over anhydrous magnesium sulfate prior to
evaporation.
3.1. 1,2-O-Isopropylidene-a-D-xylofuranose (11)
According to the literature,6a a mixture of D-xylose
(30 g, 200 mmol), CuSO4 (60 g, 376 mmol), sulfuric acid
Figure 2. Perspective view of compound 6.

504
O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
(3 ml), and acetone (1 l) was stirred at room temperature
for 12 h. After neutralization of the mixture with sodium
carbonate, solid material was removed by filtration, and
the filtrate was evaporated to give 1,2:3,5-di-O-isopro-
pylidene-a-D-xylofuranose (12, 46.5 g), which was used
in the next step without purification.
60% in liquid paraffin, washed with benzene) in THF
(3 ml) at 0 ꢁC. After being stirred at room temperature
for 1.5 h, the mixture was poured into water (50 ml),
and then the resulting mixture was extracted with
CHCl3. The extract was washed with brine and evapo-
1
rated to give a colorless oil (67 mg). H NMR spectrum
of the crude mixture indicated the formation of ca. 1.1:1
mixture of 3,5-anhydro-1,2-O-isopropylidene-a-D-xylo-
furanose9 (16) and 3-O-benzyl-1,2-O-isopropylidene-5-
O-tosyl-a-D-xylofuranose8,10 (17). A signal due to the
quaternary carbon in the acetonide moiety of 17, which
lacked in the literature,10 was observed at dC 112.1 in the
present study.
The crude diacetonide 12 (46.5 g) was hydrolyzed with
0.2% hydrochloric acid (600 ml) by applying the proce-
dure reported.6b The reaction was quenched with sodi-
um hydrogen carbonate after the reaction mixture was
stirred at room temperature for 1.5 h. The precipitates
were removed by filtration, and the filtrate was concen-
trated in vacuo. The residue was triturated with ethyl
acetate, and the ethyl acetate-insoluble solid material
was filtered off. The filtrate was evaporated to give a
pale yellow oil (39.4 g), which on distillation at reduced
pressure (bp 158–160 ꢁC/2 mmHg) gave monoacetonide
11 (36.1 g, 95% from D-xylose) as a pale yellow viscose
When 15 (100 mg, 0.29 mmol) was treated with sodium
hydride (17.4 mg, 0.44 mmol, 60% in liquid paraffin,
washed with benzene) in THF, the bicycle 16 (43 mg,
86%) was obtained as the sole product, bp 80–81 ꢁC/
22
2 mmHg, lit.9b 64 ꢁC/0.1 mmHg, ½aꢁ +13.1 (c 2.5,
D
oil. The oil solidified on keeping in a refrigerator, mp
CHCl3), lit.9a +11.9 (c 0.75, CHCl3), lit.9c +12.7 (c 2.1,
CHCl3). The spectral properties of 16 were in accord
with those reported.9a
20
D
40–41 ꢁC, lit.6b 41–43 ꢁC, lit.6c 42–44 ꢁC, ½aꢁ ꢀ22.4 (c
1.10, CHCl3), lit.6c ꢀ23 (c 0.7, MeOH). The spectral
properties of 11 were in accord with those reported.6c,6d
3.5. Methyl 3-O-benzyl-a- and b-D-xylofuranoside (18)
3.2. 5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-a-
D-xylofuranose (13)
A mixture of 14 (58.8 g, 149 mmol) and 5% methanolic
hydrogen chloride (400 ml) was stirred at room temper-
ature for 3 h. After the reaction was quenched with
sodium hydrogen carbonate, the precipitates were re-
moved by filtration, and the filtrate was evaporated.
The residue was dissolved in ethyl acetate, and ethyl
acetate-insoluble solid material was filtered off. The fil-
trate was evaporated to give a colorless oil (46.2 g),
which was washed with n-hexane to give 18 (37.9 g)
as a ca. 1:1 anomeric mixture of a-18 and b-18. Analyt-
ical samples of both anomers were obtained by means
of column chromatography (hexane–ethyl acetate 3:1).
Yoshimura et al.11a had identified the less polar ano-
mer as the b-isomer (b-18). On the basis of differential
NOE experiments in the present study, their assign-
ment was found to be reversed with respect to these
two anomers. Significant NOE was detected between
the signals of d 4.96 (H-1) and d 4.29 (H-2) of the less
polar isomer, which was thus identified as a-anomer (a-
18). On the other hand, NOE was observed between
the signals d 4.80 (H-1) and d 4.10 (H-3) in the case
of b-18 as shown below.
A mixture of the monoacetonide 11 (33.6 g, 176 mmol),
imidazole (14.6 g, 215 mmol), tert-butyldimethylsilyl
chloride (27 g, 179 mmol), and DMF (200 ml) was stir-
red at 0 ꢁC for 1 h. The mixture was poured into ice
water (800 ml) and extracted with diethyl ether. The ex-
tract was washed with brine and evaporated to give a
colorless oil (54.4 g), which on distillation at reduced
pressure gave silyl ether 13 (52.8 g, 98%) as a colorless
20
D
oil, bp 127–129 ꢁC/0.002 mmHg, ½aꢁ ꢀ5.40 (c 0.83,
CHCl3), lit.7aꢀ9.3 (c 10.0, CHCl3). The spectral proper-
ties of 13 were in accord with those reported.7b,c
3.3. 3-O-Benzyl-5-O-tert-butyldimethylsilyl-1,2-O-iso-
propylidene-a-D-xylofuranose (14)
A solution of 13 (52.8 g, 174 mmol) and benzyl bromide
(21.2 ml, 178 mmol) in DMF (50 ml) was added drop-
wise to
a suspension of sodium hydride (8.3 g,
208 mmol, 60% in liquid paraffin, washed with benzene)
in DMF (150 ml) at 0 ꢁC. After being stirred at 0 ꢁC for
1 h, the mixture was poured into ice water (700 ml) and
extracted with diethyl ether. The extract was washed
with brine and evaporated to give a colorless oil
(70.8 g), which on distillation at reduced pressure gave
OCH3
H
O
O
HO
HO
H
H
H
H
OCH3
H
H
BnO
H
OH
the title compound 14 (66.8 g, 98%) as a colorless oil,
bp 150–152 ꢁC/0.002 mmHg, ½aꢁ
BnO OH
20
D
CHCl3). The spectral properties of 14 were in accord
NOE
ꢀ36.6 (c 0.80,
α-18
β-18
with those reported.7b
3.4. Benzylation of 1,2-O-isopropylidene-5-O-tosyl-a-D-
xylofuranose (15)
The two close signals at dC 77.5 and 77.9 in the 13C
NMR spectrum of a-18 were unambiguously assigned
on the basis of two-dimensional NMR spectroscopic
studies, and the reported assignments11c for signals
due to two methine carbons (C-2 and C-4) were found
interchanged with each other.
A mixture of 157c,8 (100 mg, 0.29 mmol), prepared by
tosylation of monoacetonide 11, and benzyl bromide
(37ll, 0.31 mmol) in THF (2 ml) was added dropwise
to a suspension of sodium hydride (17.4 mg, 0.44 mmol,

O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
505
20
a-18: colorless oil. Bp 97–98 ꢁC/0.025 mmHg, ½aꢁ +65.3
3.7. 2,5-Dideoxy-2,5-epithio-3-O-benzyl-a- and b-D-lyxo-
furanoside (20)
D
(c 0.78, CHCl3). IR (CHCl3): 3549, 1119, 1047 cmꢀ1
.
13C
NMR (CDCl3) d: 55.5 (OCH3), 62.1 (C-5), 72.0
(OCH2Ph), 77.5 (C-4), 77.9 (C-2), 84.3 (C-3), 101.4 (C-
1), 127.7/127.9/128.5 (d, arom.), 137.4 (s, arom.).
A mixture of the crude dimesylate 19 (64.0 g), sodium
sulfide nonahydrate (52.3 g, 218 mmol), and DMF
(400 ml) was heated at 100 ꢁC for 4 h. After being
cooled, the mixture was poured into ice water (2 l)
and extracted with diethyl ether. The extract was
washed with brine and evaporated to give ca. 1.3:1
anomeric mixture of a- and b-20 (36.2 g) as a pale
brown oil, which was used in the next step without
purification.
20
D
b-18: colorless oil. Bp 97–99 ꢁC/0.025 mmHg, ½aꢁ
ꢀ48.3 (c 0.60, CHCl3). IR (CHCl3): 3423, 1107,
1049 cmꢀ1 13C NMR (CDCl3) d: 55.8 (OCH3), 62.2
.
(C-5), 72.6 (OCH2Ph), 79.9 (C-2), 80.4 (C-4), 84.3 (C-
3), 109.3 (C-1), 127.8/128.1/128.6 (d, arom.), 137.5 (s,
arom.).
3.6. Methyl 3-O-benzyl-2,5-di-O-mesyl-a- and b-D-xylo-
furanoside (19)
On the other hand, pure a-19 and b-19 obtained above
were converted to the corresponding bicycles a-20 and
b-20, respectively. The H NMR spectroscopic proper-
1
Mesyl chloride (23.8 ml, 309 mmol) was added dropwise
to a solution of the crude mixture of 18 (37.9 g) in pyr-
idine (100 ml) at 0 ꢁC. After being stirred at room tem-
perature for 2 h, the reaction mixture was poured into
ice water (100 ml) and extracted with CHCl3. The ex-
tract was washed with brine and evaporated to give an
anomeric mixture of 19 as a pale yellow oil (64.0 g),
which was used in the next step without purification.
The ratio of a- and b-anomers in the mixture was deter-
ties of a-20 were consistently in accordance with those
of b-20 in the literature.11a The structure of both isomers
was unambiguously confirmed on the basis of differen-
tial NOE experiments in the present study.
H
H
H
H
H
H
S
S
OCH3
H
H
O
O
OCH3
H
H
H
H
OBn
OBn
α-20
1
NOE
mined to be ca. 1:1 on the basis of the H NMR spec-
β-20
trum. As the mixture was found hardly separable,
analytical samples of a-19 and b-19 were derived from
pure a-18 and b-18, respectively.
a-20: colorless needles. Mp 51–52 ꢁC (hexane–acetone),
20
a-19: colorless oil. ½aꢁ +61.5 (c 1.30, CHCl3), bp
.
1207, 1178, 1133, 1072 cmꢀ1 1H NMR (CDCl3) d:
22
D
½aꢁ +25.6 (c 1.20, CHCl3). IR (CHCl3): 1147, 1082,
D
180 ꢁC/1.5 mmHg (decomp.). IR (CHCl3): 1362, 1225,
1016 cmꢀ1
.
13C NMR (CDCl3) d: 34.9 (C-5), 48.6 (C-
2), 55.0 (OCH3), 72.1 (OCH2Ph), 76.1 (C-4), 79.8 (C-
3), 109.7 (C-1), 127.8/128.0/128.5 (d, arom.), 137.5 (s,
arom.).
2.99 (3H, s, OSO2CH3), 3.06 (3H, s, OSO2CH3), 3.45
(3H, s, OCH3), 4.32 (1H, dd, J = 10.5, 6.0 Hz, H-5a),
4.40 (1H, dd, J = 10.5, 2.5 Hz, H-5b), 4.42–4.46 (2H,
m, H-3, H-4), 4.57 (1H, d, J = 11.5 Hz, OCHHPh),
4.73 (1H, d, J = 11.5 Hz, OCHHPh), 4.97 (1H, dd,
J = 5.0, 4.5 Hz, H-2), 5.13 (1H, d, J = 4.5 Hz, H-1),
7.30–7.40 (5H, m, arom.). 13C NMR (CDCl3) d: 37.5/
38.7 (OSO2CH3), 55.8 (OCH3), 68.2 (C-5), 73.0
(OCH2Ph), 74.2 (C-4), 79.5 (C-3), 81.7 (C-2), 100.2 (C-
1), 128.0/128.3/128.6 (d, arom.), 136.6 (s, arom.). MS
m/z (%): 410 (M+, 2), 209 (46), 185 (17), 165 (60), 129
(17), 99 (50), 81 (100). HRMS m/z: 410.0717
(C15H22O9S2 requires 410.0705).
20
b-20: colorless oil. Bp 103–104 ꢁC/2 mmHg, ½aꢁ ꢀ32.5
D
(c 0.40, CHCl3). IR (CHCl3): 1126, 1099, 1024 cmꢀ1
.
13C NMR (CDCl3) d: 35.1 (C-5), 50.5 (C-2), 56.5
(OCH3), 71.7 (OCH2Ph), 78.2 (C-4), 80.0 (C-3), 106.3
(C-1), 127.9/128.1/128.5 (d, arom.), 137.2 (s, arom.).
3.8. 3-O-Benzyl-1,4-dideoxy-1,4-epithio-D-arabinitol (22)
The crude mixture of 20 obtained above (36.2 g) was dis-
solved in THF (300 ml) and was treated with 4 N hydro-
chloric acid (450 ml) at room temperature for 1 h. The
reaction was quenched with sodium hydrogen carbon-
ate, and NaBH4 (6.5 g, 172 mmol) was added in small
portions with vigorous stirring at 0 ꢁC, and the resulting
mixture was stirred at room temperature for 1 h. The
precipitates were filtered off, and the filtrate was extract-
ed with CHCl3. The extract was washed with brine and
evaporated to give a pale brown oil (32.6 g), which on
column chromatography (hexane–acetone, 3:1) gave 22
(20.7 g, 58% from 14) as a pale yellow oil. The 1H
NMR spectroscopic properties of 22 were in accord with
those reported.11a
20
b-19: colorless oil. ½aꢁ ꢀ42.3 (c 1.20, CHCl3), bp
D
180 ꢁC/1.5 mmHg (decomp.). IR (CHCl3): 1362, 1225,
1207, 1178, 1115, 1072 cmꢀ1 1H NMR (CDCl3) d:
.
3.00 (3H, s, OSO2CH3), 3.04 (3H, s, OSO2CH3), 3.45
(3H, s, OCH3), 4.31 (1H, dd, J = 6.0, 2.0 Hz, H-3),
4.41 (2H, d-like, J = 6.0 Hz, H-5a, H-5b), 4.56 (1H,
dt, J = 6.0, 6.0 Hz, H-4), 4.57 (1H, d, J = 11.5 Hz,
OCHHPh), 4.76 (1H, d, J = 11.5 Hz, OCHHPh), 5.04
(1H, br s-like, H-2), 5.05 (1H, s, H-1), 7.31–7.40 (5H,
m, arom.). 13C NMR (CDCl3) d: 37.5/38.4 (OSO2CH3),
55.8 (OCH3), 69.0 (C-5), 72.7 (OCH2Ph), 78.7 (C-4),
80.7 (C-3), 84.3 (C-2), 107.0 (C-1), 128.3/128.55/
128.63 (d, arom.), 136.5 (s, arom). MS m/z (%): 410
(M+, 0.2), 209 (34), 187 (12), 165 (37), 99 (31), 81
(100). HRMS m/z: 410.0687 (C15H22O9S2 requires
410.0705).
20
22: colorless oil. Bp 127–128 ꢁC (3 mmHg), ½aꢁ +20.0
D
(c 2.95, MeOH). IR (CHCl3): 3370, 1070 cmꢀ1
.
13C
NMR (CDCl3) d: 38.2 (C-1), 53.5 (C-4), 63.1 (C-5),

506
O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
72.0 (OCH2Ph), 76.5 (C-2), 89.0 (C-3), 127.7/127.9/128.5
(d, arom.), 137.7 (s, arom.).
tol (29, 6.82 g) as a pale yellow oil, which was used in the
next step without purification.
3.9. 1,4-Dideoxy-1,4-epithio-D-arabinitol (3)
Under argon, a solution of the crude xantate (29, 6.62 g)
in ethanol (40 ml) was added dropwise to a mixture of
50% aqueous hypophosphorous acid (5.3 ml,
48.2 mmol), triethylamine (14 ml, 101 mmol), azoisobu-
tyronitrile (525 mg, 3.2 mmol), and ethanol (40 ml), and
the resulting mixture was heated under reflux for 2 h.
The mixture was poured into aqueous sodium hydrogen
carbonate (400 ml) and extracted with ethyl acetate. The
extract was washed with brine, and evaporated to give a
pale brown oil (5.21 g), which on column chromatogra-
phy (hexane–acetone, 25:1) gave title compound 30
(3.35 g, 80% from 27) as a colorless oil, bp 180–181 ꢁC
According to the literature,11d a solution of 22 (5.3 g,
22.1 mmol) in THF (50 ml) was treated with a solution
of sodium (2.4 g, 104 mg-atom) in liquid ammonia (ca.
100 ml) at ꢀ50 ꢁC for 1 h. After addition of methanol
(30 ml) to the mixture, ammonia was gradually removed
by increasing the temperature of the mixture, and the
resulting mixture was acidified with conc. hydrochloric
acid to pH 5. The resulting precipitates were filtered
off and washed with methanol. The combined filtrate
and washings were evaporated to give a pale yellow oil
(3.6 g), which on column chromatography (CHCl3–
(1 mmHg). IR (CHCl3): 1215, 1107 cmꢀ1 1H NMR
.
t
EtOH, 10:1) gave 3 (3.2 g, 97%) as a pale yellow oil,
(CDCl3) d: 0.07 [6H, s, Si(CH3)2 Bu], 0.89 [9H, s, Si-
Me2C(CH3)3], 1.64 (1H, dddd, J = 12.0, 3.0, 3.0,
1.5 Hz, H-2a), 1.81 (1H, dddd, J = 12.0, 12.0, 11.0,
5.0 Hz, H-2b), 3.62 (1H, dd, J = 10.5, 6.0 Hz, H-4a),
3.81 (1H, dd, J = 10.5, 5.5 Hz, H-4b), 3.95 (1H, dddd,
J = 11.0, 6.0, 5.5, 3.0 Hz, H-3), 3.98 (1H, ddd, J =
12.0, 12.0, 3.0 Hz, H-1a), 4.30 (1H, ddd, J = 12.0, 5.0,
1.5 Hz, H-1b), 5.52 (1H, s, PhCH), 7.30–7.51 (5H, m,
20
D
The spectral properties of 3 were in accord with those
½aꢁ +41.9 (c 0.82, MeOH), lit.11d +40.2 (c 1.28, MeOH).
reported.11d
3.10. 1,3-O-Benzylidene-4-O-tert-butyldimethylsilyl-L-
erythritol (28)
arom). 13C NMR (CDCl3) d:ꢀ5.4/ꢀ5.3 [Si(CH3)2 Bu],
t
A
mixture of 1,3-O-benzylidene-L-erythritol4a (27,
3.41 g, 16.2 mmol), tert-butyldimethylsilyl chloride
(3.18 g, 21.0 mmol), imidazole (1.55 g, 22.8 mmol), and
DMF (30 ml) was stirred at 0 ꢁC for 1 h. The mixture
was poured into ice water (100 ml) and extracted with
diethyl ether. The extract was washed with brine and
evaporated to give 28 (6.0 g) as a colorless oil, which
was used in the next step without purification. Analyti-
18.3 [SiMe2C(CH3)3], 25.9 [SiMe2C(CH3)3], 28.3 (C-2),
66.2, 67.0 (C-1, C-4), 77.6 (C-3), 101.2 (PhCH), 123.5/
126.1/128.7 (d, arom.), 138.6 (s, arom.). MS m/z (%):
t
251 (M+ꢀ Bu, 0.1), 143 (40), 117 (62), 91 (65), 73
(100), 59 (45). FABMS m/z: 309 [M+H]+ (pos). FAB-
HRMS m/z: 309.1893 (C17H29O3Si requires 309.1887).
cal sample of 28 was obtained as a colorless oil by means
22
of column chromatography (CHCl3–EtOH 20:1), ½aꢁ
3.12. 4-O-tert-Butyldimethylsilyl-2-deoxy-L-erythritol
(31)
D
+5.7 (c 2.0, CHCl3). IR (CHCl3): 3503, 1107,
1
t-
1088 cmꢀ1. H NMR (CDCl3) d: 0.13 [6H, s, Si(CH3)2
A suspension of 10% palladium-on-carbon (2.0 g) in eth-
anol (25 ml) was pre-equilibrated with hydrogen. To the
suspension was added a solution of compound 30 (2.3 g,
7.47 mmol) in ethanol (25 ml), and the mixture was
hydrogenated at 50 ꢁC under atmospheric pressure until
the uptake of hydrogen ceased. The catalyst was filtered
off, and the filtrate was evaporated to give a colorless oil
(1.64 g), which on column chromatography (CHCl3–
Bu], 0.92 [9H, s, SiMe2C(CH3)3], 3.63 (1H, dd, J = 11.0,
10.0 Hz, H-1a), 3.73 (1H, ddd, J = 8.5, 8.5, 4.5 Hz, H-3),
3.85 (1H, dd, J = 10.0, 8.5 Hz, H-4a), 3.90 (1H, ddd,
J = 10.0, 8.5, 5.0 Hz, H-2), 4.04 (1H, dd, J = 10.0,
4.5 Hz, H-4b), 4.32 (1H, dd, J = 11.0, 5.0 Hz, H-1b),
5.50 (1H, s, PhCH), 7.32–7.50 (5H, m, arom.). 13C
t
NMR (CDCl3) d: ꢀ5.62/ꢀ5.57 [Si(CH3)2 Bu], 18.2 [Si-
Me2C(CH3)3], 25.8 [SiMe2C(CH3)3], 66.2 (C-4), 66.4
(C-2), 70.6 (C-1), 79.1 (C-3), 101.1 (PhCH), 126.1/
128.2/129.0 (d, arom.), 137.5 (s, arom.). MS m/z (%):
324 (M+, 0.4), 161 (36), 143 (23), 131 (78), 117 (96), 91
(100), 75 (88), 59 (58). HRMS m/z: 324.1760
(C17H28O4Si requires 324.1757).
EtOH, 30:1) gave title compound 31 (1.33 g, 81%) as a
24
D
1
colorless oil, bp 152 ꢁC/7 mmHg (decomp.). ½aꢁ +17.9
(c 1.4, MeOH). IR (neat): 3356, 1253, 1072 cmꢀ1. H
t
NMR (CD3OD) d: 0.08 [6H, s, Si(CH3)2 Bu], 0.91 [9H,
s, SiMe2C(CH3)3], 1.58 (1H, ddt, J = 14.0, 9.0, 6.0 Hz,
H-2a), 1.78 (1H, dtd, J = 14.0, 7.0, 4.0 Hz, H-2b), 3.53
(1H, dd, J = 10.0, 5.0 Hz, H-4a), 3.58 (1H, dd,
J = 10.0, 5.0 Hz, H-4b), 3.69 (2H, dd, J = 7.0, 6.0 Hz,
H-1), 3.73 (1H, dddd, J = 9.0, 5.0, 5.0, 4.0 Hz, H-3).
3.11. 1,3-O-Benzylidene-4-O-tert-butyldimethylsilyl-2-de-
oxy-L-erythritol (30)
13C NMR (CDCl3) d:ꢀ5.3/ꢀ5.2 [Si(CH3)2 Bu], 19.2 [Si-
t
A mixture of the crude silyl ether (28, 5.18 g), 5 N aque-
ous sodium hydroxide (3.5 ml), and dimethylsulfoxide
(20 ml) was stirred at 0 ꢁC for 15 min. To the mixture
was added dropwise methyl iodide (2.0 ml, 32.1 mmol)
at 0 ꢁC, and the resulting mixture was stirred at that
temperature for 10 min. The reaction mixture was dilut-
ed with ethyl acetate (40 ml), and the resulting mixture
was washed with water. The organic phase was evapo-
rated to give 1,3-O-benzylidene-2-O-[(S-methyl-
thio)thiocarbonyl]-4-O-tert-butyldimethylsilyl-L-erythri-
Me2C(CH3)3], 26.4 [SiMe2C(CH3)3], 37.1 (C-2), 60.0 (C-
1), 68.7 (C-4), 70.6 (C-3). MS m/z (%): 149 (17), 91 (35),
75 (80), 57 (100). FABMS m/z: 221 [M+H]+ (pos). FAB-
HRMS m/z: 221.1559 (C10H25O3Si requires 221.1573).
3.13. Preparation of cyclic sulfates (8, 9, and 10)
According to the literature,12,3a a mixture of 1,3-propan-
diol (23, 613 mg, 8.06 mmol), triethyl amine (2.79 ml,
20.2 mol), and dichloromethane (10 ml) was treated with

O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
507
a solution of thionyl chloride (0.84 ml, 9.69 mmol) in
dichloromethane (5 ml) at 0 ꢁC for 10 min. Work-up
gave a pale brown oil (983 mg), which was used in the
next oxidation without purification.
2.0 mmol), and DMF (300 ll) was stirred at 45 ꢁC for
60 h. The reaction mixture was diluted with methanol
(10 ml), and the solid material was filtered off. The fil-
trate was concentrated in vacuo, and the residue was
triturated with diethyl ether to give a pale brown oil
(326 mg), which on column chromatography (AcOEt–
MeOH–H2O, 20:4:1) gave 1,4-dideoxy-1,4-(S)-[3-(sulfo-
oxy)propyl]episulfoniumylidene-D-arabinitol inner salt
(5, 38 mg, 20%) as a colorless oil.
In the presence of sodium hydrogen carbonate (1.49 g
17.7 mmol), the oil (983 mg) was treated with ruthenium
(VIII) oxide12,3a generated in situ from sodium metape-
riotate (3.62 g, 16.9 mmol) and ruthenium (III) chloride
n-hydrate (90 mg), in a mixture of carbon tetrachloride
(8 ml), acetonitrile (8 ml), and water (8 ml) at room tem-
perature for 30 min. The reaction mixture was diluted
with diethyl ether (100 ml) and washed successively with
aqueous sodium thiosulfate–sodium hydrogen carbon-
ate and brine, and evaporated to give a pale yellow oil
(1.11 g), which on column chromatography (benzene–
acetone, 10:1) gave 1,3-propanediol 1,3-cyclic sulfate
(8, 890 mg, 80%) as colorless needles, mp 58.5–59.5 ꢁC,
lit.12d 60 ꢁC. The spectral properties of 8 were in accord
with those reported.12e
Method B. A mixture of 8 (104 mg, 0.75 mmol), 3 (75 mg,
0.67 mmol), potassium carbonate (28 mg, 0.2 mmol),
and HFIP (1.2 ml) was stirred at 60 ꢁC for 60 h. After
removal of the solvent, the residue was triturated with
diethyl ether to give a pale yellow oil (212 mg), which
on column chromatography (AcOEt–MeOH–H2O,
20:4:1) gave 5 (88 mg, 61%) as a colorless oil.
5: colorless oil. ½aꢁ24 +0.4 (c 1.4, MeOH). IR (neat): 3514,
D
1651, 1285, 1177, 1098 cmꢀ1
.
1H NMR (CD3OD) d:
2.24–2.34 (2H, m, H-20), 3.61 (1H, ddd, J = 12.9, 6.9,
6.3 Hz, H-10a), 3.67 (1H, ddd, J = 12.9, 7.5, 7.5 Hz, H-
10b), 3.78 (1H, dd, J = 12.6, 3.4 Hz, H-1a), 3.88 (1H, t-
like, J = 10.9 Hz, H-5a), 3.90 (1H, d-like, J = 12.6 Hz,
H-1b), 3.94 (1H, dd, J = 10.9, 4.0 Hz, H-4), 4.06 (1H,
dd, J = 10.9, 4.0 Hz, H-5b), 4.18 (2H, t, J = 5.8 Hz, H-
30), 4.37 (1H, br s, H-3), 4.64 (1H, br s, H-2). 13C
NMR (CD3OD) d: 27.1 (C-20), 44.1 (C-10), 49.3 (C-1),
60.9 (C-5), 66.4 (C-30), 73.7 (C-4), 79.3 (C-2), 79.6 (C-
3). FABMS m/z: 289 [M+H]+ (pos.). FABHRMS m/z:
289.0429 (C8H17O7S2 requires 289.0416).
Following the method described above, diols 2613 (1.3 g,
7.14 mmol) and 31 (760 mg, 3.45 mmol) were converted
to 2-O-benzylglycerol 1,3-cyclic sulfate (9, 1.52 g, 87%)
and 4-O-tert-butyldimethylsilyl-2-deoxy-L-erythritol
1,3-cyclic sulfate (10, 730 mg, 75%), respectively.
9: colorless needles. Mp 75–77 ꢁC (hexane–diethyl
ether). IR (KBr): 1400, 1200 1011 cmꢀ1 1H NMR
.
(CDCl3) d: 3.65 (1H, tt, J = 3.0, 2.5 Hz, H-2), 4.65
(2H, dd, J = 12.0, 3.0 Hz, H-1a), 4.67 (2H, s, OCH2Ph),
4.78 (2H, dd, J = 12.0, 2.5 Hz, H-1b), 7.31-7.43 (5H, m,
arom.). 13C NMR (CDCl3) d: 66.4 (C-2), 71.3
(OCH2Ph), 74.4 (C-1), 127.8/128.5/128.8 (d, arom.),
136.3 (s, arom.). MS m/z (%): 244 (M+, 5), 149 (42),
122 (14), 105 (100), 91 (98), 77 (42), 65 (38). HRMS
m/z: 244.0400 (C10H12O5S requires 244.0406).
Following the method A, a mixture of 9 (342 mg,
1.4 mmol), 3 (142 mg, 0.93 mmol), sodium carbonate
(297 mg, 2.8 mmol), and DMF (300 ll) was stirred at
45 ꢁC for 60 h. Work-up gave a pale brown oil
(745 mg), which on column chromatography (AcOEt–
MeOH–H2O, 20:4:1) gave 1,4-dideoxy-1,4-(S)-[2-ben-
zyloxy-3-(sulfooxy)propyl]episulfoniumylidene-D-ara-
24
10: colorless needles. Mp 34–35 ꢁC. ½aꢁ +8.7 (c 1.0,
D
CHCl3). IR (KBr): 1339, 1253, 1142, 1022 cmꢀ1
.
1H
binitol inner salt (32, 92 mg, 25%) as
diastereomeric mixture.
a
1:1
t
NMR (CDCl3) d: 0.09 [6H, s, Si(CH3)2 Bu], 0.90 [9H,
s, SiMe2C(CH3)3], 1.86 (1H, dddd, J = 15.0, 2.0, 2.0,
1.5 Hz, H-2a), 2.31 (1H, dddd, J = 15.0, 13.0, 12.0,
5.5 Hz, H-2b), 3.79 (1H, dd, J = 11.5, 4.5 Hz, H-4a),
3.82 (1H, dd, J = 11.5, 4.5 Hz, H-4b), 4.61 (1H, ddd,
J = 11.0, 5.5, 1.5 Hz, H-1a), 4.81 (1H, ddd, J = 13.0,
11.0, 2.0 Hz, H-1b), 4.91 (1H, dtd, J = 12.0, 4.5,
2.0 Hz, H-3). 13C NMR (CDCl3) d: ꢀ5.5/ꢀ5.4
Following the method B, a mixture of 9 (366 mg,
1.5 mmol), 3 (150 mg, 1.0 mmol), potassium carbonate
(69 mg, 0.5 mmol), and HFIP (1.5 ml) was stirred at
65 ꢁC for 60 h. Work-up gave a pale yellow oil
(685 mg), which on column chromatography (AcOEt–
MeOH–H2O, 20:4:1) gave 32 (179 mg, 45%) as a 1:1 dia-
stereomeric mixture.
t
[Si(CH3)2 Bu], 18.2 [SiMe2C(CH3)3], 25.6 (C-2), 25.7 [Si-
Me2C(CH3)3], 64.0 (C-4), 71.9 (C-1), 85.0 (C-3). MS m/z
t
(%): 225 (M+ꢀ Bu, 5), 145 (17), 81 (44), 69 (100), 99
32: colorless prisms. Mp 161–164.5 ꢁC (from MeOH–
(31). FABMS m/z: 283 [M+H]+ (pos.). FABHRMS
m/z: 283.1028 (C10H23O5SiS requires 283.1035).
Et2O). IR (KBr): 3435, 1269, 1196, 1011 cmꢀ1 1H
.
NMR (CD3OD) d: 3.55 (0.5H, br dd, J = 12.6, 2.3 Hz,
H-1a), 3.75 (0.5H, dd, J = 12.6, 3.7 Hz, H-1b), 3.76–
4.03 (4.5H, m, H-1a*, H-1b*, H-10a, H-10a*, H-10b,
H-10b*, H-4, H-4*, H-5a, H-5a*, H-5b, H-5b*), 4.17–
4.23 (2.5H, m, H-30a, H-30a*, H-30b, H-30b*, H-20),
4.25–4.29 (0.5H, m, H-20*), 4.34 (0.5H, br s, H-3),
4.37 (0.5H, br s, H-3*), 4.55–4.59 (1H, m, H-2, H-2*),
4.63 (0.5H, d, J = 11.2 Hz, OCHHPh), 4.64 (0.5H, d,
J = 11.5 Hz, OCHHPh), 4.72 (0.5H, d, J = 11.5 Hz,
OCHHPh), 4.79 (0.5H, d, J = 11.2 Hz, OCHHPh),
7.23–7.45 (10H, m, arom.). 13C NMR (CD3OD) d:
3.14. Coupling reaction between cyclic sulfates (8, 9, and
10) and thiosugar 3
According to the literature, cyclic sulfates (8, 9, and 10)
were treated with 3 in either DMF3a or 1,1,1,3,3,3-hexa-
fluoroisopropanol3b,3c (HFIP).
Method A. A mixture of 8 (138 mg, 1.0 mmol), 3
(100 mg, 0.67 mmol), sodium carbonate (212 mg,

508
O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
49.6/50.2 (C-10), 50.7/52.1 (C-1), 60.8/60.9 (C-5), 67.1/
67.3 (C-30), 73.0/73.2 (OCH2Ph), 73.8/73.9 (C-4), 73.9/
74.5 (C-20), 79.3/79.5 (C-2), 79.6/80.0 (C-3), 129.3/
129.4/129.55/129.59/129.7/129.8 (d, arom.), 138.5/138.7
(s, arom.). FABMS m/z: 395 [M+H]+ (pos). FABHRMS
m/z: 395.0829 (C15H23O8S2 requires 395.0835).
ed solid was removed by filtration, and the filtrate was
neutralized with ion exchange resin (IRA-67). After
removal of the resin by filtration, the filtrate was concen-
trated in vacuo. The residue (20 mg) was purified on col-
umn chromatography (AcOEt–MeOH–H2O 20:4:1) to
24
D
1.2, MeOH). IR (neat): 3360, 1651, 1215, 1065, 1042,
give 7 (16 mg, 75%) as a colorless oil, ½aꢁ +11.9 (c
1
Following the method A, a mixture of 10 (231 mg,
0.82 mmol), 3 (82 mg, 0.55 mmol), sodium carbonate
(174 mg, 2.8 mmol), and DMF (200 ll) was stirred at
45 ꢁC for 60 h. Work-up gave a pale brown oil
(313 mg), which on column chromatography (CHCl3–
MeOH 7:1) gave 1,4-dideoxy-1,4-(S)-[(3S)-4-tert-butyl-
dimethylsiloxy-3-(sulfooxy)butyl]episulfoniumylidene-
D-arabinitol inner salt (33, 47 mg, 20%) as a colorless oil.
1018 cmꢀ1. H NMR (CD3OD) d: 2.23–2.27 (1H, m,
H-20), 3.63 (1H, dt, J = 12.9, 6.3 Hz, H-10a), 3.71 (1H,
dd, J = 12.9, 4.0 Hz, H-40a), 3.72–3.77 (1H, m, H-10b),
3.75 (1H, dd, J = 12.9, 4.9 Hz, H-40b), 3.78 (1H, dd,
J = 12.3, 3.2 Hz, H-1a), 3.85 (1H, d-like, J = 12.3, H-
1b), 3.86 (1H, t-like, J = 9.8 Hz, H-5a), 3.90 (1H, br
dd, J = 9.8, 3.2 Hz, H-4), 4.04 (1H, dd, J = 9.8, 3.2 Hz,
H-5b), 4.34 (1H, br s, H-3), 4.47–4.53 (1H, m, H-30),
4.63 (1H, br s, H-2). 13C NMR (CD3OD) d: 28.8 (C-
20), 43.5 (C-10), 49.3 (C-1), 60.9 (C-5), 64.5 (C-40), 73.9
(C-4), 77.5 (C-30), 79.2 (C-2), 79.5 (C-3). FABMS m/z:
319 [M+H]+ (pos.). FABHRMS m/z: 319.0540
(C9H19O8S2 requires 319.0522).
25
33: colorless oil. ½aꢁ +19.3 (c 0.81, MeOH). IR (neat):
D
3412, 1651, 1215, 1061 cmꢀ1
.
1H NMR (CD3OD) d:
t
0.10 [6H, s, Si(CH3)2 Bu], 0.91 [9H, s, SiMe2C(CH3)3],
2.18–2.34 (2H, m, H-20), 3.63 (1H, ddd, J = 12.1, 6.0,
5.6 Hz, H-10a), 3.70–3.91 (7H, m, H-1a, H-1b, H-4, H-
5a, H-10b, H-40a, H-40b), 4.02–4.08 (1H, m, H-5b),
4.34 (1H, br s, H-3), 4.45–4.49 (1H, m, H-30), 4.62
(1H, br s, H-2). 13C NMR (CD3OD) d: ꢀ6.6/ꢀ6.5
3.17. X-ray crystallographic analysis
Data of both compounds 6 and 9 were taken on a Rigaku
AFC5R diffractometer with graphite-monochromated
t
[Si(CH3)2 Bu], 17.9 [SiMe2C(CH3)3], 25.1 [Si-
Me2C(CH3)3], 27.8 (C-20), 42.2 (C-10), 48.2 (C-1), 59.6
(C-5), 64.3 (C-40), 72.8 (C-4), 75.6 (C-30), 77.9 (C-2),
78.2 (C-3). FABMS m/z: 431 [MꢀH]ꢀ (neg.). FAB-
HRMS m/z: 431.1222 (C15H31O8SiS2 requires 431.1230).
Mo-Ka radiation (k = 0.71069 A). The structures of 6
˚
and 9 were solved by direct methods with SAPI9116
and SIR97,17 respectively. Full-matrix least-squares
refinement was employed with anisotropic thermal
parameters for all non-hydrogen atoms. All calculations
were performed using the teXsan18 crystallographic soft-
ware package of Molecular Structure Corporation. OR-
TEP drawings of compounds 6 and 9 are shown in
Figures 2 and 1, respectively. The data of 6 and 9 have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number
CCDC 265901 and CCDC 265900, respectively.
3.15. 1,4-Dideoxy-1,4-(S)-[2-hydroxy-3-(sulfooxy)pro-
pyl]episulfoniumylidene-D-arabinitol Inner Salt (6)
A solution of 32 (60 mg, 0.15 mmol) in a 20% aqueous
acetic acid (2 ml) was hydrogenated in a manner similar
to that used for hydrogenation of compound 30. Work-
up gave a colorless oil (98 mg), which on column chro-
matography (AcOEt–MeOH–H2O, 20:4:1) gave
6
(28 mg, 60%) as a colorless solid, mp 148–151 ꢁC (from
MeOH–Et2O). IR (KBr): 3464, 3360, 1258, 1204, 1061,
3.17.1. Crystal data for sulfonium sulfate 6. Orthorhom-
bic, space group P212121, a = 9.719(5), b = 18.056(6),
3
1030, 1011 cmꢀ1
.
1H NMR (CD3OD) d: 3.70 (0.5H,
c = 6.872(4) A,
V = 1205.9(7) A ,
Z = 4,
l(Mo-
˚
˚
dd, J = 13.2, 8.3 Hz, H-10a), 3.73 (0.5H, dd, J = 13.2,
7.8 Hz, H-10a*), 3.79 (0.5H, dd, J = 13.2, 4.1 Hz, H-
10b), 3.83 (0.5H, dd, J = 13.2, 3.8 Hz, H-10b*), 3.83–
3.88 (2H, m, H-1a, H-1a*, H-1b, H-1b*), 3.92 (0.5H,
dd, J = 13.5, 11.2 Hz, H-5a), 3.96 (0.5H, dd, J = 11.8,
8.6 Hz, H-5a*), 3.96–4.05 (3H, m, H-30a, H-30a*, H-
5b, H-5b*, H-4, H-4*), 4.09 (0.5H, dd, J = 10.9,
2.6 Hz, H-30b), 4.11 (0.5H, dd, J = 13.7, 2.6 Hz, H-
30b*), 4.31–4.35 (1H, m, H-20, H-20*), 4.37 (0.5H, dd,
J = 2.6, 1.2 Hz, H-3), 4.41 (0.5H, dd, J = 2.0, 1.7 Hz,
H-3*), 4.60–4.63 (1H, m, H-2, H-2*). 13C NMR
(CD3OD) d: 50.7/51.7 (C-1), 50.8/51.3 (C-10), 60.9 (C-
5), 67.3 (C-20), 70.2/70.3 (C-30), 73.3/73.7 (C-4), 79.4
(C-2), 79.5/79.8 (C-3). FABMS m/z: 305 [M+H]+
(pos.). FABHRMS m/z: 305.0342 (C8H17O8S2 requires
305.0364).
Ka) = 4.73 cmꢀ1, F(000) = 640, Dc = 1.676 g/cm3, crys-
tal dimensions: 0.06 · 0.22 · 0.30 mm. A total of 1629
reflections (1609 unique) were collected using the x–2h
scan technique to a maximum 2h value of 55ꢁ, and
1400 reflections with I > 2r(I) were used in the structure
determination. Final R and Rw values were 0.054 and
0.073, respectively. The maximum and minꢀimuꢀm3 peaks
˚
in theꢀ difference map were 0.39 e A
and
ꢀ0.30 e Aꢀ3, respectively.
˚
3.17.2. Crystal data for cyclic sulfate 9. Monoclinic,
˚
space group P21, a = 9.306(3) A, b = 12.839(2) A,
˚
3
˚
˚
c = 9.956(2) A, b = 101.58(2)ꢁ, V = 1165.4(5) A , Z = 4,
l(Mo-Ka) = 2.8 cmꢀ1, F(000) = 512, Dc = 1.392 g/cm3,
crystal dimensions: 0.12 · 0.14 · 0.30 mm. A total of
2740 reflections (2582 unique) were collected using the
x–2h scan technique to a maximum 2h value of 55ꢁ,
and 1860 reflections with I > 2r(I) were used in the
structure determination. Final R and Rw values were
0.057 and 0.091, respectively. The maximum andꢀmini-
3.16. 1,4-Dideoxy-1,4-(S)-[(3S)-4-hydroxy-3-(sulfooxy)-
butyl]episulfoniumylidene-D-arabinitol Inner Salt (7)
ꢀ3
˚
A solution of 33 (29 mg, 0.07 mmol) and 0.1% hydro-
chloric acid (1 ml) was stirred at 40 ꢁC for 4 h. Deposit-
mum peaksꢀin the difference map were 0.56 e A
and ꢀ0.75 e Aꢀ3, respectively.
˚

O. Muraoka et al. / Bioorg. Med. Chem. 14 (2006) 500–509
509
2002, JP 2002179673. Chem. Abstr. 2002, 137, 63418; (h)
Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson,
B.; Pinto, B. M. J. Am. Chem. Soc. 2004, 126, 12458; (i)
Gallienne, E.; Benazza, M.; Demailly, G.; Bolte, J.;
Lemaire, M. Tetrahedron 2005, 61, 4557; (j) Kuntz, D.
A.; Ghavami, A.; Johnston, B. D.; Pinto, B. M.; Rose, D.
R. Tetrahedron: Asymmetry 2005, 16, 25; (k) Liu, H.;
Pinto, B. M. J. Org. Chem. 2005, 70, 753.
3.18. Enzyme inhibition assays
Rat small intestinal brush border membrane vesicles
were prepared and their suspension in 0.1 M maleate
buffer (pH 6.0) was used as small intestinal a-glucosidase
of maltase and sucrase. Test compound was dissolved in
dimethylsulfoxide DMSO, and the resulting solution was
diluted with 0.1 M maleate buffer to prepare the test
compound solution (concentration of DMSO: 10%).
The substrate solution in the maleate buffer (maltose:
74 mM, sucrose: 74 mM, 100 ll), test compound solu-
tion (50 ll), and the enzyme solution (50 ll) were mixed
and incubated at 37 ꢁC for 30 min. After incubation, the
solution was mixed with water (0.8 ml) and was immedi-
ately heated by boiling water for 2 min to stop the reac-
tion. Glucose concentration was then determined by the
glucose-oxidase method. Final concentration of DMSO
in test solution was 2.5% and no influence of DMSO
was detected on the inhibitory activity.
5. Presented at 14th French–Japanese Symposium on Medic-
inal and Fine Chemistry (FJS-99) held in September 1999
at La Baule France.
6. (a) Levene, P. A.; Raymond, A. L. J. Biol. Chem. 1933,
102, 317; (b) Svanberg, O.; Sjo¨berg, K. Ber. Chem. Ges.
1923, 56, 863; (c) Hasegawa, A.; Kiso, M. Carbohydr. Res.
1980, 79, 265; (d) Xie, M.; Berges, D. A.; Robins, M. J. J.
Org. Chem. 1996, 61, 5178.
7. (a) Rarr, I. B.; Horenstein, S. A. J. Org. Chem. 1997, 62,
7489; (b) Bearder, J. R.; Dewis, M. L.; Whiting, D. A.
J. Chem. Soc., Perkin Trans. 1 1995, 227; (c) Lu, Y.; Just,
G. Tetrahedron 2001, 57, 1677.
8. Young, R. C.; Kent, P. W.; Dwek, R. A. Tetrahedron
1970, 26, 3983.
9. (a) Cooke, N. G.; Jones, D. A.; Whiting, A. Tetrahedron
1992, 48, 9553; (b) Paulsen, H.; Budzis, M. Chem. Ber.
1974, 107, 1998; (c) Whistler, R. L.; Luttenegger, T. J.;
Rowell, R. M. J. Org. Chem. 1968, 33, 396.
10. Hori, M.; Nakatsubo, F. Carbohydr. Res. 1998, 309, 281.
11. (a) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.;
Watanabe, M.; Miura, S.; Sakata, S.; Sasaki, T.; Matsuda,
A. J. Org. Chem. 1997, 62, 3140; (b) Yoshimura, Y.;
Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata,
S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 882; (c)
Liptak, A.; Neszmelyi, A.; Kovac, P.; Hirsch, J. Tetrahe-
dron 1981, 37, 2379; (d) Yuasa, H.; Kajimoto, T.; Wong,
H. C. Tetrahedron Lett. 1994, 35, 8243.
Acknowledgments
This study was supported in part by a Grant-in-Aid for
Scientific Research from the Japan Society of the Pro-
motion of Science. The authors also thank Pharmaceu-
tical Research and Technology Institute of Kinki
University for financial support.
References and notes
12. (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110,
7358; (b) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett.
1989, 30, 566–658; (c) Lohray, B. B. Synthesis 1992, 1035;
(d) Lowe, G.; Thatcher, G. R. J.; Turner, J. C. G.; Waller,
A.; Watkin, D. J. J. Am. Chem. Soc. 1988, 110, 8512; (e)
Guijarro, D.; Guillena, G.; Mancheno, B.; Yus, M.
Tetrahedron 1994, 50, 3427.
1. (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsu-
da, H.; Yamahara, J.; Tanabe, G.; Muraoka, O. Tetrahe-
dron Lett. 1997, 38, 8367; (b) Yoshikawa, M.; Morikawa,
T.; Matsuda, H.; Tanabe, G.; Muraoka, O. Bioorg. Med.
Chem. 2002, 10, 1547.
2. Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H.
Chem. Pharm. Bull. 1998, 46, 1339.
3. (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) Ghavami,
A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.;
Snider, B. B.; Pinto, B. M. Synlett 2003, 1259.
13. Hronowski, L. J. J.; Szarek, W. A.; Hay, G. W.; Krebs,
A.; Depew, W. T. Carbohydr. Res. 1989, 190, 203.
14. The axial preference of the alkoxy group in the chair-type
six-membered ring molecules was reported: (a) Nagao, Y.;
Goto, M.; Ochiai, M.; Shiro, M. Chem. Lett. 1990, 1503;
(b) Nagao, Y.; Goto, M.; Kida, K.; Shiro, M. Heterocy-
cles 1995, 41, 419; (c) Leurquin, F.; Ozturk, T.; Pilkington,
M.; Wallis, J. D. J. Chem. Soc., Perkin. Trans. 1 1997,
3173.
15. a-Glucosidase inhibitory activities of 4, 5, 6, and 7 were
measured according to the method described in the
literature.1
16. Fan, H.-F. Structure Analysis Programs with Intelligent
Control; Rigaku Corporation: Tokyo, Japan, 1991.
17. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, C.;
Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115.
4. (a) Muraoka, O.; Ying, S.; Yoshikai, K.; Matsuura, Y.;
Yamada, E.; Minematsu, T.; Tanabe, G.; Matsuda, H.;
Yoshikawa, M. Chem. Pharm. Bull. 2001, 49, 1503; (b)
Yuasa, H.; Takada, J.; Hashimoto, H. Bioorg. Med.
Chem. Lett. 2001, 11, 1137; (c) Ghavami, A.; Johnston, B.
D.; Jensen, M. T.; Svensson, B.; Pinto, B. M. J. Am.
Chem. Soc. 2001, 123, 6268; (d) Yuasa, H.; Izumi, M.;
Hashimoto, H. Yuki Gosei Kagaku Kyokaishi 2002, 60,
774; Chem. Abstr. 2002, 138, 122763; (e) Johnston, B. D.;
Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto, B. M. J.
Am. Chem. Soc. 2002, 124, 8245; (f) Ghavami, A.;
Johnston, B. D.; Maddess, M. D.; Chinapoo, S. M.;
Jensen, M. T.; Svensson, B.; Pinto, B. M. Can. J. Chem.
2002, 80, 937; (g) Hashimoto, H.; Yuasa, H.; Takada, J.
18. Crystal Structure Analysis Package, Molecular Structure
Corporation, 1985 and 1999.