Novel synthesis of 5-thio-hexopyranoside: Preparation of 5-thio-D- and L-glucose and 1,6-anhydro-5-thio-L- and D-altrose

Article abstract of DOI:10.1016/S0040-4020(03)00864-0

Asymmetric synthesis of both D- and L-isomers of 5-thioglucose and 1,6-anhydro-5-thioaltrose are described. The key intermediates, L- and D-threose diethylacetal derivatives, were derived by chemical transformation from D-xylose or D-arabinose and by Sharpless asymmetric dihydroxylation from γ-hydroxycrotylaldehyde diethylacetal. They transformed to γ-thiiranyl diethylacetal via trans-2,3-epoxy alcohol in seven steps. Acetic acid-promoted cyclization of γ-thiiranyl diethylacetal gave 5-thiopyranoside. Removal of the protected groups under the acidic conditions afforded 5-thio-D- and L-glucose and 1,6-anhydro-5-thio-L- and D-altrose, respectively.

Full text of DOI:10.1016/S0040-4020(03)00864-0

Tetrahedron 59 (2003) 7011–7022
Novel synthesis of 5-thio-hexopyranoside: preparation of
5-thio-D- and L-glucose and 1,6-anhydro-5-thio-L- and D-altrose
*
Jun’ichi Uenishi and Hirohisa Ohmiya
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 6078412, Japan
Received 28 April 2003; revised 28 May 2003; accepted 29 May 2003
This paper is dedicated to Professor K. C. Nicolaou in honor of his receipt of the 2003 Tetrahedron Prize
Abstract—Asymmetric synthesis of both D- and L-isomers of 5-thioglucose and 1,6-anhydro-5-thioaltrose are described. The key
intermediates, L- and D-threose diethylacetal derivatives, were derived by chemical transformation from D-xylose or D-arabinose and by
Sharpless asymmetric dihydroxylation from g-hydroxycrotylaldehyde diethylacetal. They transformed to g-thiiranyl diethylacetal via trans-
2,3-epoxy alcohol in seven steps. Acetic acid-promoted cyclization of g-thiiranyl diethylacetal gave 5-thiopyranoside. Removal of the
protected groups under the acidic conditions afforded 5-thio-D- and L-glucose and 1,6-anhydro-5-thio-L- and D-altrose, respectively.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Thiosugar in which the ring oxygen atom is replaced with a
sulfur atom in hexopyranose, was first prepared by Adley
and Owen in 1961.1 Since then, it has been developed by
Whistler,2 Hughes,3 Hashimoto,4 and others.5 The biologi-
cal interest in thiosugars has expanded to studies on
diabetes, enzyme inhibitor, anti-viral and anti-tumor
activities.6 No thiosugars have been found in nature except
for 5-thio-D-mannose, which was isolated from a marine
sponge,7 and 5-thio-hexopyranoses have so far been
obtained by transformation of natural sugars. For the
synthesis of 5-thio-D-hexopyranose, sulfur functionality
located on the (R)-chiral center at the 5-position was
introduced by a stereospecific substitution of the 5-hydroxy
group in natural sugar. Namely, the hydroxy group was
substituted by a sulfur group with net retention of the
configuration by double inversion of the original (R)-
hydroxycarbon center. The other chiral hydroxycarbon
centers were used from those present in the original sugar.
For example, 5-thio-D-glucose was derived from D-glu-
cose.8 Therefore, the synthesis of 5-thiopyranose is
depended on the availability and the stereochemistry of
natural sugar sources. Due to a lack of a general and flexible
approach for the synthesis of 5-thio-D-hexopyranose and its
L-isomer, we have started study on their syntheses from an
acyclic precursor, and are planning to construct a library of
optically pure 5-thio-D- and L-hexopyranoses. In this paper,
Keywords: stereoselective synthesis; thiosugar; D- and L-5-thio-
hexopyranoside; asymmetric dihydroxylation.
*
Corresponding author. Tel.: þ81-755954665; fax: þ81-755954763;
Figure 1.
e-mail: juenishi@mb.kyoto-phu.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00864-0

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J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
we report the asymmetric syntheses of D- and L-isomers of
5-thioglucose, D-1 and L-1, and 1,6-anhydro-5-thioaltrose,
D-20 and L-20, in Figure 1.
the presence of pyridine gave 6 in 86% yield. Treatment of 6
with activated zinc powder in a mixture of hot acetic acid
and ethanol gave 4-pentenal (7) in 92% yield. Acetalization
of 7 was performed by treating with triethyl orthoformate in
the presence of BF3 etherate to give 8 in quantitative yield.
Ozonolysis of 8 and successive Horner–Emmons reaction
with sodium triethyl phosphonoacetate gave a,b-unsatu-
rated ester (9) in 61% yield in two steps. Reduction of a,b-
unsaturated ester with DIBAL-H afforded trans allyl alcohol
(10) quantitatively.
2. Results and discussion
2.1. Synthetic plan
Our previous asymmetric synthesis of 2-deoxy-4-thio-D-
ribofuranoside is shown in Scheme 1, in which stereo-
specific conversion of the optically active trans-a-2,3-
epoxy alcohol to 2-deoxy-4-thio-D-ribose was accom-
plished in four steps.9 In this synthesis, it should be noted
that trans-a-2,3-epoxy alcohol gave 4-thio-D- while trans-
b-2,3-epoxy alcohol gave 4-thio-L-furanoside.10 Based on
these results, we have planned for the syntheses of all the
stereoisomers for 5-thio-glucose (1) and altrose (2), the
strategy of which is outlined in Schemes 2 and 3.
The preparation of the corresponding enantiomer 100 started
from D-arabinose. The same four steps from D-arabinose as
those described for the synthesis of 6 afforded 14 in 46%
yield. Reductive opening of the furanose ring for 14 with
zinc powder and acetic acid gave 70 in 92% yield. Exactly
the same reaction sequence from 70 as that described for 10
gave 100 in a similar yield in four steps.
2.3. An approach by asymmetric reaction
This approach is outlined in Scheme 5. Protection of g-
hydroxycrotylaldehyde diethylacetal (15)12 with benzoyl
chloride gave benzoate (16) in 91% yield. Dihydroxylation
of 16 using ADmix-a13 proceeded stereospecifically over
95% e.e. to give b-dihydroxy isomer (17) in 59% yield.
Protection of diol as a tert-butyldimethylsilyl ether and
deprotection of the benzoate ester provided 19 in 87% yield
in two steps. Tetrapropylammonium perruthenate (TPAP)
oxidation gave aldehyde in 94% yield, and the aldehyde was
then subjected to Horner–Emmons reaction to give 9 in
81% yield. Reduction of a,b-unsaturated ester with DIBAL-
H gave 10 as the same reaction described above in Section
2.2.
2.4. Epoxidation and cyclic xanthate formation
The stereochemical course in epoxidation of this allyl
alcohol is a key for dividing a route to D- or L-sugar. As
shown in Scheme 2, a trans-a-2,3-epoxy alcohol will give
5-thio-D-pyranose, while a trans-b-2,3-epoxy alcohol will
give 5-thio-L-pyranose. We have examined a number of
epoxidation conditions for 10.14 Oxidation with mCPBA
gave a 1:1 ratio of inseparable diastereomeric epoxides, 20a
and 20b, in 85–95% yield. Unfortunately, Sharpless
asymmetric epoxidation gave disappointing results due to
a poor reactivity and a formation of unknown products.
VO(acac)2-catalyzed oxidation15 with t-BuOOH gave a
single diastereomer in 70% yield, which was later identified
to be 20b. However, none of the oxidation conditions gave a
satisfactory result in terms of favorable formation of a-2,3-
epoxy alcohol (20a). Pure 20a and 20b were isolated by the
following steps. Namely, after a mixture of 20a and 20b led
to benzyloxycarbonates, they became separable. Hydro-
genolysis of each carbonate afforded pure 20a and 20b in
two steps in 18 and 26% yields, respectively.
Scheme 1.
Enantiomeric trans allyl alcohols have been chosen as
potential precursors for the synthesis. It is expected that both
5-thio-D-glucose (D-1) and 5-thio-L-altrose (L-2) will be
derived from the trans allyl alcohol via the a- and b-2,3-
epoxy alcohols, and that 5-thio-L-glucose (L-1) and 5-thio-
D-altrose (D-2) will be derived from the enantiomeric
isomer of the trans allyl alcohol. As shown in Scheme 3,
these allyl alcohols will be prepared by a two-carbon
extension of L- and D-threose derivatives. The dihydroxy
chiral carbon centers of these threoses may either be brought
from those present in D-xylose and D-arabinose or be
introduced by Sharpless asymmetric dihydroxylation of
trans-alkene.
2.2. An approach from a chiral pool
A 1:1 mixture of 20a and 20b obtained by the mCPBA
oxidation, was treated with carbon disulfide in the presence
of NaH resulting in a ring formation of hydroxy cyclic
xanthate16 to give 21 in 82% yield. After acetylation of the
hydroxy group, diastereomers 22 and 23 became separable
by silica gel column chromatography. A less-polar isomer,
As shown in Scheme 4, the chiral pool approach was started
from D-xylose. Methyl 5-deoxy-5-iodo-D-xylofuranoside
(5)11 can be obtained in 55% yield from D-xylose in the
following three steps; (i) methyl glycosidation in acidic
methanol, (ii) tosylation with TsCl, and (iii) replacement of
the tosylate with NaI. Silylation of 5 with TBDMSOTf in

J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
7013
Scheme 2. Retro-synthetic plan for 5-thio-D- and L-glucose and altrose.
Scheme 3. Precursors in the retro-synthesis for 5-thio-D- and L-glucose and altrose.
Scheme 4. Reagents and conditions; a, HCl (gas), MeOH, rt; b, TsCl, pyrdine, rt; c, NaI, DMF, 1108C; d, TBDMSOTf, pyridine, CH2Cl2, rt; e, Zn, AcOH,
EtOH, reflux; f, CH(OEt)3, BF3 etherate, reflux; g, Ozone, CH2Cl2 then Me2S; h, NaH, EtOOCCH2PO(OEt)2, THF, rt; i, DIBAL-H, CH2Cl2, 2788C.

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J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
Scheme 5. Reagents and conditions; a, BzCl, pyridine, CH2Cl2, rt; b, ADmix-a, t-BuOH:H2O (1:1), 08C; b0, ADmix-b, t-BuOH:H2O (1:1), 08C; c,
TBDMSOTf, 2,6-lutidine, CH2Cl2, rt; d, DIBAL-H, CH2Cl2, 2788C; e, TPAP, NMO, MS 4A, CH2Cl2, rt; f, NaH, EtOOCCH2PO(OEt)2, THF, rt.
which was obtained in 46% yield, was found later to be 22
affording ethyl 5-thio-D-glucopyranoside. Another polar
isomer, obtained in 39% yield, was 23 affording ethyl 5-
thio-L-altropyranoside. Independently, cyclic xanthate for-
mation of 20a and the following acetylation gave 22 in 74%
yield in two steps. By the same two steps, 20b gave 23 in
72% yield (Scheme 6).
2.5. Synthesis of 5-thioglucose
Thiirane (24) was formed in 94% yield by potassium
carbonate promoted methanolysis of 22. The ring contrac-
tion reaction17 was completed within 3 min at room
temperature chemoselectively without a methanolysis of
the acetate. Acid-promoted ring formation of ethyl 5-thio-
glucopyranoside was carried out by heating of the g-
thiiranyl diethylacetal (24) with a mixture of acetic
anhydride and potassium acetate in acetic acid at 1108C.
Compound 25 was obtained in 54% as a 1:1 ratio of an
anomeric mixture. Deprotection of the two TBDMS groups
with TBAF followed by acetylation with acetic anhydride
gave tetraacetate (26) in 69% yield in two steps. Compound
26 was identified in comparison of its spectroscopic data
with those derived from (þ)-5-thio-D-glucose.18 Thus,
treatment of commercial D-1 in ethanol saturated with
HCl gas, gave ethyl glycoside, which was acetylated with
acetic anhydride in pyridine to give 26 in 53% yield in two
steps. Both materials were clearly identical.
All of the protecting groups of 26, including acetate and
ethyl glycoside, were hydrolyzed by heating in hot aq. HCl
solution. After the acid was removed by the treatment of
basic resin, evaporation of solvents in vacuo furnished the
synthesis of pure 5-thio-D-glucose (D-1) in quantitative
yield. All the spectroscopic and physical data, including mp,
proton NMR, and specific rotation, were identical to those
of the authentic 5-thio-D-glucose.19
Scheme 6. Reagents and conditions; a, ClCOOCH2Ph, iPr2NEt, CH2Cl2, rt,
then chromatographic separation; b, cat. Pd–C (10%), H2, EtOH, rt; c,
NaH, cat. MeOH, CS2, THF, 2308C; d, Ac2O, pyridine, rt.

J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
7015
Scheme 7. Reagents and conditions; a, K2CO3, MeOH, rt, 3 min; b, AcOK, Ac2O, AcOH, 1108C, 4 h; c, (i) TBAF, THF rt, (ii) Ac2O, pyridine, rt; d, aq. HCl
(3.4 M): THF (1:1), reflux; e, HCl gas, EtOH, rt; f, Ac2O, pyridine, rt.
In the same manner, 5-thio-L-glucose (L-1) was obtained
from 100 in eight steps via cyclic xanthate 220. All the
intermediates were in accordance with those for the
synthesis of D-series except a sign of the specific rotations
(Scheme 7).
2.6. Synthesis of 5-thioaltrose
On the other hand, compounds 23 and 230 were attempted to
lead to 5-thio-L-altrose (L-2) and D-altrose (D-2)20 as shown
in Schemes 8 and 9. The reactions are quite similar to those
Scheme 8. Reagents and conditions; a, K2CO3, MeOH, rt, 3 min; b, AcOK, Ac2O, AcOH, 1108C, 4 h; c, (i) TBAF, THF, rt, (ii) Ac2O, pyridine, rt; d, aq. HCl
(3.4 M): THF (1:1), reflux.

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J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
Scheme 9.
for the synthesis for D-1. The thiirane formation of 23
proceeded well to give 27 in 91% yield. Cyclization of 27 to
5-thiopyranoside was carried out in a hot acetic acid in the
presence of potassium acetate and acetic anhydride, to give
28 in 64% yield. Changing the O-silyl protecting group to
acetate furnished the synthesis of ethyl 2,3,4,6-O-tetra-
acetyl-5-thio-L-altropyranoside (29)21 in 78% yield. How-
ever, removal of all the protecting groups under the acidic
conditions gave 1,6-dehydrated 5-thio-L-altrose (L-20) in
73% yield, and unexpectedly, L-2 was not obtained at all.22
Since Hughes reported that 6-hydroxymethyl group locates
at the axial position in methyl 5-thio-b-D-altropyranoside,21
the dehydration between 1,6-dihydroxy groups would take
place quite easily under the acidic conditions. Thus,
thionium cation could be produced from an intermediary
ethyl glycoside (30), and a subsequent attack of 6-hydroxy
group to the thionium cation from an axial direction resulted
the 1,6-anhydro-5-thio-altrose (L-20). In the same reaction
sequences, 1,6-anhydro-5-thio-D-altrose (D-20) was also
obtained from 100 via 230.
packed with silica gel was attached. All experiments were
carried out under an argon atmosphere. THF and ether were
dried over sodium/benzophenone ketyl, and CH2Cl2 was
dried over P2O5, and they were distilled prior to use. The
solvent extracts were dried over MgSO4, and the solutions
were evaporated under reduced pressure.
4.2. Preparation of 9 and 90 from D-xylose and D-
arabinose
4.2.1. Methyl 2,3-bis-O-tert-butyldimethylsilyl-5-deoxy-
5-iodo-D-xylofuranoside (6). To
a CH2Cl2 solution
(40 mL) of methyl 5-deoxy-5-iodo-D-xylofuranoside (5)11
(3.92 g, 14 mmol) and pyridine (9 mL) was dropped
TBDMSOTf (9.46 g, 8 mL, 36 mmol) at 08C and the
mixture was stirred for 1 h at room temperature. Water
was added and the mixture was extracted with EtOAc. The
crude product was purified by silica gel flash chromato-
graphy eluted with 5% EtOAc in hexane to give 6 (6.16 g) in
86% yield as a 2:3 ratio of anomers. Colorless oil. Rf¼0.45
(5% EtOAc in hexane). 1H NMR (300 MHz, CDCl3) d 4.77
(2/5H, d, J¼3.9 Hz), 4.64 (3/5H, s), 4.34–4.22 (1H, m),
4.11 (2/5H, t, J¼4.9 Hz), 4.00–3.84 (8/5H, m), 3.36 (6/5H,
s), 3.29 (9/5H, s), 3.34–3.18 (2H, m), 0.82 (27/5H, s), 0.81
(27/5H, s), 0.80 (18/5H, s), 0.78 (18/5H, s), 0.03 (6/5H, s),
0.02 (12/5H, s), 0.01 (3H, s X2), 0.00 (18/5H, s), 20.07 (9/
5H, s). 13C NMR (75 MHz, CDCl3) d 110.8, 103.6, 83.5,
82.7, 79.1, 78.8, 78.3, 77.6, 56.4, 55.9, 26.3, 26.2, 26.1,
26.1, 18.7, 18.4, 18.3, 18.3, 5.3, 4.8, 22.5, 23.9, 24.0,
24.1(£2), 24.2, 24.3, 24.4. MS (FAB) m/z: 525
(MþNa)þ. HR-MS (FAB) m/z: 525.1324 (Calcd for
C18H39IO4Si2Na: 525.1328).
3. Conclusion
The asymmetric syntheses of 5-thio-D- and L-glucose, and
1,6-anhydro-5-thio-D- and L-altrose were accomplished in
enantiomerically pure forms. Both the chiral pool approach
from D-xylose or D-arabinose and the asymmetric approach
using Sharpless asymmetric dihydroxylation worked effec-
tively. The use of this methodology will enable the synthesis
of other kinds of 5-thio-hexopyranosides, and that will bring
a great contribution to pseudo sugar chemistry in carbo-
hydrate research as well as to molecular recognition study in
cell surface science.
4.2.2. Methyl 2,3-bis-O-tert-butyldimethylsilyl-5-deoxy-
5-iodo-D-arbinofuranoside (14). To a CH2Cl2 solution
(50 mL) of methyl 5-deoxy-5-iodo-D-arabinofuranoside
(13)11 (5.6 g, 20.4 mmol) and pyridine (13.2 mL) was
dropped TBDMSOTf (13.5 g, 11.7 mL, 51.1 mmol) at 08C
and the mixture was stirred for 1 h at room temperature.
Water was added and the mixture was extracted with
EtOAc. The crude product was purified by silica gel flash
chromatography eluted with 5% EtOAc in hexane to give 14
(7.5 g) in 73% yield as a 1:4 ratio of anomers. Colorless oil.
Rf¼0.45 (5% EtOAc in hexane). 1H NMR (300 MHz,
CDCl3) d 4.75 (4/5H, d, J¼1.5 Hz), 4.72 (1/5H, d,
J¼3.7 Hz), 4.06 (1/5H, m), 4.04 (4/5H, dd, J¼3.5,
1.5 Hz), 3.85 (1/5H, m), 3.85 (4/5H, dd, J¼6.1, 3.5 Hz),
3.80–3.71 (1H, m), 3.45 (1/5H, m), 3.44 (3/5H, s), 3.43 (4/
5H, dd, J¼10.6, 4.8 Hz), 3.36 (12/5H, s), 3.25 (4/5H, dd,
J¼10.6, 5.5 Hz), 3.23 (1/5H, m), 0.90 (9H, s), 0.88 (36/5H,
s), 0.84 (9/5H, s), 0.12 (3H, s), 0.11 (3H, s), 0.09 (3H, s),
0.08 (3H, s). 13C NMR (75 MHz, CDCl3) d 109.6, 103.4,
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded at 300 or
400 MHz and at 75 or 100 MHz, respectively. Melting
points were obtained on a melting point apparatus and were
uncorrected. Mass spectra were recorded using electron
impact (EI) ionization at 70 eV. Fast atom bombardment
(FAB) mass spectra were obtained using a glycerol as a
matrix. Silica gel (70–230 mesh) was used for flash
chromatography. Analytical thin-layer chromatography
(TLC) was performed on glass pre-coated with silica gel
(0.25 mm thickness). High performance liquid chromato-
graphy (HPLC) was carried out on a UV spectrophotomeric
detector (254 nm) to which a 20£250 mm size column

J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
7017
84.1, 82.7, 82.5, 81.8, 80.0, 79.6, 55.6, 55.1, 25.8, 25.8,
25.7, 25.6, 18.2 (£2), 17.8, 17.8, 8.8, 7.1, 24.0, 24.1, 24.2,
24.3, 24.3, 24.4, 24.6, 24.9. MS (FAB) m/z: 525
(MþNa)þ. HR-MS (FAB) m/z: 525.1334 (Calcd for
C18H39IO4Si2Na: 525.1329).
temperature. Then the mixture was diluted with EtOAc
and washed with water, brine. The residual oil was purified
by chromatography on silica gel eluted by 20% EtOAc in
hexane to give crude aldehyde, which was used directly for
the next reaction. To a solution of sodium salt of triethyl
phosphonoacetate prepared by NaH (60% in mineral oil,
551 mg, 13.8 mmol) and triethyl phosphonoacetate
(3.3 mL, 16.5 mmol) at 08C in THF, was added the aldehyde
in THF (6 mL) and the mixture was stirred for 15 min at
room temperature. Sat. ammonium chloride was added and
extracted with EtOAc. The residue of the extract was
purified by flash chromatography on silica gel to give 9
(1.8 g) in 61% yield. Colorless oil. Rf¼0.53 (10% EtOAc in
4.2.3. (2R,3S)-2,3-Bis(tert-butyldimethylsilyloxy)-4-pen-
tenal (7) and its enantiomer (70). A suspension of activated
zinc powder (2.0 g, 30.1 mmol) and 6 (5.05 g, 10 mmol) in
ethanol (25 mL) and acetic acid (5.1 mL, 85.4 mmol) was
heated at 1108C for 30 min with stirring. After cooling, solid
was removed by filtration and extracted with ether and
washed with sodium bicarbonate. The extract was washed
with water and brine. The crude product was purified by
flash chromatography on silica gel eluted with 50% CH2Cl2
in hexane. Compound 7 (3.2 g) was obtained in 92% yield.
Colorless oil. Rf¼0.45 (5% EtOAc in hexane). [a]D23¼247
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) d 9.64 (1H, s),
6.0 (1H, ddd, J¼17.3, 10.4, 5.0 Hz), 5.29 (1H, dt, J¼17.3,
1.7 Hz), 5.05 (1H, dt, J¼10.4, 1.7 Hz), 4.37 (1H, tt, J¼5.0,
1.5 Hz), 3.99 (1H, dd, J¼5.0, 1.2 Hz), 0.91 (9H, s), 0.90
(9H, s), 0.07 (6H, s), 0.05 (6H, s). 13C NMR (75 MHz,
CDCl3) d 202.8, 136.4, 116.2, 80.2, 74.9, 25.7 (£2), 18.4,
18.1, 24.5, 24.6, 25.0, 25.1. IR (film) cm21: 1739. MS
(CI) m/z: 345 (Mþ1, 18). HR-MS (CI) m/z: 345.2286 (Calcd
for C17H37O3Si2: 345.2281).
1
hexane). [a]D22¼212 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3) d 7.05 (1H, dd, J¼15.7, 5.0 Hz), 5.93 (1H, dd,
J¼15.7, 1.7 Hz), 4.38–4.35 (2H, m), 4.15 (2H, ddd,
J¼14.3, 7.1, 2.4 Hz), 3.69–3.38 (5H, m), 1.25 (3H, t,
J¼7.0 Hz), 1.16 (3H, t, J¼7.0 Hz), 1.13 (3H, t, J¼7.0 Hz),
0.88 (9H, s), 0.86 (9H, s), 0.05 (3H, s), 0.02 (3H, s), 0.00
(3H, s), 20.01 (3H, s). 13C NMR (75 MHz, CDCl3) d 166.9,
149.7, 120.8, 102.3, 76.7, 73.6, 64.1, 63.0, 60.6, 26.3, 26.2,
18.6, 18.5, 15.7, 15.5, 14.7, 23.7, 23.8, 24.3, 24.5. IR
(CHCl3) cm21: 1724. MS (FAB) m/z: 513 (MþNa)þ. HR-
MS (FAB) m/z: 513.3048 (Calcd for C24H50O6Si2Na:
513.3044). Compound 90 was also prepared from 80 by the
same method described for 9.
The enantiomer 70 was obtained in 92% yield from
arabinoside 14 (6.0 g) by the same experimental operation
described for 7. The physical and spectroscopic data are
exactly the same except a positive sign in specific rotation.
4.2.6. (E,4S,5R)-4,5-Bis(tert-butyldimethylsilyloxy)-6,6-
diethoxy-2-hexenol (10). To a stirred solution of 9 (1.7 g,
3.5 mmol) in CH2Cl2 was dropped DIBAL-H (7.4 mL in
0.93 M hexane solution, 7.0 mmol) at 2788C and the
reaction was continued for 30 min at the same temperature.
Sat. NH4Cl was added and the mixture was vigorously
stirred for 10 min. Solid was filtered through celite pad and
the filtrate was extracted with ether. The crude product was
purified by silica gel flash chromatography eluted with 20%
EtOAc in hexane to give 10 (1.54 g) in quantitative yield.
Colorless oil. Rf¼0.45 (20% EtOAc in hexane). [a]D21¼29
(c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) d 5.84 (1H, dd,
J¼15.8, 5.8 Hz), 5.75 (1H, dt, J¼15.8, 4.6 Hz), 4.40 (1H, d,
J¼6.1 Hz), 4.30 (1H, m), 4.12 (2H, d, J¼4.6 Hz), 3.72–
3.40 (5H, m), 1.18 (3H, t, J¼7.0 Hz), 1.17 (3H, t,
J¼7.0 Hz), 0.87 (18H, s), 0.06 (3H, s), 0.02 (3H, s), 0.00
(6H, s). 13C NMR (75 MHz, CDCl3) d 133.0, 129.2, 102.3,
76.7, 73.7, 63.5, 63.3, 62.5, 25.9, 25.8, 18.2, 18.0, 15.3,
15.2, 23.8, 24.0, 24.5, 24.8. IR (film) cm21: 3413. MS
(FAB) m/z: 471 (MþNa)þ. HR-MS (FAB) m/z: 471.2933
(Calcd for C22H48O5Si2Na: 471.2928). Compound 100 was
also prepared from 90 by the same method described for 10.
4.2.4. (2R,3S)-2,3-Bis(tert-butyldimethylsilyloxy)-4-pen-
tenal diethylacetal (8) and its enantiomer (80). To a
mixture of 7 (3.2 g, 9.3 mmol) and triethyl orthoformate
(46 mL) was added dropwise borontrifluoride etherate
(1.32 g, 9.3 mmol) on an ice bath. The mixture was refluxed
for 30 min. Saturated NaHCO3 solution was added to the
mixture and extracted with EtOAc. The residual oil of the
extract was purified by flash chromatography on silica gel
eluted with 50% CH2Cl2 in hexane to give 8 (3.8 g) in
quantitative yield. Colorless oil. Rf¼0.65 (CH2Cl2).
1
[a]D22¼217 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) d
5.9 (1H, ddd, J¼17.2, 10.5, 6.6 Hz), 5.14 (1H, dt, J¼17.2,
1.5 Hz), 5.05 (1H, dt, J¼10.5, 1.5 Hz), 4.38 (1H, d,
J¼6.2 Hz), 4.21 (1H, dt, J¼6.6, 1.3 Hz), 3.70–3.40 (5H,
m), 1.17 (3H, t, J¼7.0 Hz), 1.16 (3H, t, J¼7.0 Hz), 0.86
(18H, s), 0.04 (3H, s), 0.01 (3H, s), 0.00 (3H, s), 20.01 (3H,
s). 13C NMR (75 MHz, CDCl3) d 139.5, 114.8, 102.5, 76.8,
75.0, 63.4, 62.5, 25.9, 25.8, 18.3 (£2), 15.4, 15.2, 23.9,
24.4 (£2), 24.8. MS (FAB) m/z: 441 (MþNa)þ. HR-MS
(FAB) m/z: 441.2828 (Calcd for C21H46O4Si2Na:
441.2824). Compound 80 was also prepared in 80% yield
from 70 (3.8 g) by the same method described for 8. The
physical and spectroscopic data are exactly the same except
a positive sign in specific rotation.
4.3. Preparation of 9 by asymmetric dihydroxylation
approach
4.3.1. (E)-4-Benzoyloxy-2-butenal diethylacetal (16). To
a CH2Cl2 solution (40 mL) of 15 (2.0 g, 12.5 mmol) and
pyridine (2 g, 25 mmol) was added benzoyl chloride at 08C.
The mixture was stirred for 30 min at room temperature,
poured into water, and extracted with EtOAc. The extract
was washed with water, brine. The residue was purified by
flash chromatography on silica gel eluted with 20% EtOAc
in hexane to give 16 (3.0 g) in 91% yield. Colorless oil.
Rf¼0.56 (20% EtOAc in hexane). 1H NMR (300 MHz,
C6D6) d 8.20–8.14 (2H, m), 7.22–7.05 (3H, m), 6.03 (1H,
4.2.5. Ethyl (E,4S,5R)-4,5-bis(tert-butyldimethylsily-
loxy)-6,6-diethoxy-2-hexenoate (9). Ozone was bubbled
into a solution of 8 (2.5 g, 6 mmol) in CH2Cl2 (17 mL) at
2788C. After the reaction was completed, which was
monitored by TLC, dimethyl sulfide (0.5 mL) was added
and the mixture was allowed to warm up to room

7018
J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
dt, J¼15.6, 5.5 Hz), 5.90 (1H, dd, J¼15.6, 4.2 Hz), 4.91
(1H, d, J¼4.2 Hz), 4.70 (2H, d, J¼5.5 Hz), 3.60 (2H, dq,
J¼9.5, 7.1 Hz), 3.40 (2H, dq, J¼9.5, 7.1 Hz), 1.16 (6H, t,
J¼7.1 Hz). 13C NMR (75 MHz, C6D6) d 165.8, 132.8,
131.8, 130.7, 129.9, 128.5, 127.9, 100.3, 64.3, 60.6 (£2),
15.4 (£2). IR (film) cm21: 1720. MS (FAB) m/z: 287
(MþNa)þ. HR-MS (FAB) m/z: 287.1265 (Calcd for
C15H20O4Na: 287.1260).
with ether. The crude product was purified by flash
chromatography on silica gel eluted with 10% EtOAc in
hexane to give 19 (282 mg) in 92% yield. Colorless oil.
Rf¼0.45 (10% EtOAc in hexane). [a]D21¼211 (c 1.23,
CHCl3). 1H NMR (300 MHz, C6D6) d 4.67 (1H, d,
J¼4.9 Hz), 3.99 (1H, td, J¼5.5, 3.1 Hz), 3.93 (1H, dd,
J¼4.9, 3.1 Hz), 3.77 (2H, t, J¼5.5 Hz), 3.64 (1H, dq, J¼9.1,
7.0 Hz), 3.53–3.40 (3H, m), 1.75 (1H, m), 1.12 (3H,
t, J¼7.0 Hz), 1.11 (3H, t, J¼7.0 Hz), 1.04 (9H, s), 1.00
(9H, s), 0.24 (3H, s), 0.19 (3H, s), 0.15 (3H, s), 0.14 (3H, s).
13C NMR (75 MHz, C6D6) d 102.0, 74.7, 74.0, 63.9, 63.1,
61.8, 26.2, 26.1, 18.6, 18.4, 15.5, 15.3, 23.8, 24.1, 24.5,
24.6. IR (film) cm21: 3465. MS (FAB) m/z: 445 (MþNa)þ.
HR-MS (FAB) m/z: 445.2778 (Calcd for C20H46O5Si2Na:
445.2775).
4.3.2. 4-O-Benzoyl-L-threose diethylacetal (17). ADmix-
a (3.16 g) was added to a solution of t-BuOH (8 mL) and
water (8 mL) and the mixture was stirred for 5 min at room
temperature and for additional 10 min at 08C. Then, a
solution of 16 (600 mg, 226 mmol) in a mixed solvent of t-
BuOH (4 mL), water (4 mL) and THF (6 mL) was added
into the former mixture, and the whole mixture was stirred
for 12 h at 08C. Then, powdered Na2SO3 was added and the
mixture was extracted with EtOAc for 3 times. The crude
product was purified by flash chromatography on silica gel
eluted with 50% EtOAc in hexane to give 17 (402 mg) in
59% yield. Colorless oil. Rf¼0.45 (40% EtOAc in hexane).
4.3.5. Preparation of 9 from 19. A mixture of 19 (300 mg,
0.71 mmol), N-methylmorpholine N-oxide (124 mg,
1.1 mmol) and molecular sieves 4A (50 mg) was stirred in
CH2Cl2 (7 mL) for 10 min. To this suspension TPAP
(12 mg) was added and the mixture was stirred for 1 h at
room temperature. The mixture was directly charged on
silica gel eluted with CH2Cl2 to give aldehyde (280 mg) in
94% yield. Colorless oil. Rf¼0.6 (10% EtOAc in hexane).
1
[a]D24¼5 (c 1.25, CHCl3). H NMR (300 MHz, C6D6) d
8.16–8.12 (2H, m), 7.16–6.90 (3H, m), 4.64 (1H, dd,
J¼12.0, 7.0 Hz), 4.50 (1H, d, J¼5.9 Hz), 4.54 (1H, dd,
J¼12.0, 5.5 Hz), 4.35 (1H, m), 3.67 (1H, d, J¼5.9 Hz),
3.55–3.45 (2H, m), 3.48–3.15 (2H, m), 2.74 (1H, brs), 2.54
(1H, brs), 0.98 (6H, s, J¼7.0 Hz). 13C NMR (75 MHz,
C6D6) d 166.4, 132.8, 131.5, 130.0, 128.4, 103.5, 71.3, 68.8,
66.5, 64.5, 63.2, 15.4 (£2). IR (film) cm21: 3458, 1720. MS
(FAB) m/z: 321 (MþNa)þ. HR-MS (FAB) m/z: 321.1310
(Calcd for C15H22O6Na: 321.0306).
[a]D22¼217 (c 1.4, CHCl3). H NMR (300 MHz, CDCl3) d
1
9.61 (1H, s), 4.39 (1H, t, J¼7.1 Hz), 3.99 (1H, d, J¼3.8 Hz),
3.88 (1H, d, J¼3.8 Hz), 3.65–3.36 (4H, m), 1.10 (3H, t,
J¼7.0 Hz), 1.06 (3H, t, J¼7.1 Hz), 0.82 (9H, s), 0.77 (9H,
s), 20.05 (6H, s), 20.04 (3H, s), 0.00 (3H, s). 13C NMR
(75 MHz, CDCl3) d 202.8, 101.3, 78.6, 75.2, 63.7, 62.9,
25.8, 25.7, 18.2 (£2), 15.3, 15.0, 24.2, 24.4, 25.0, 25.2.
IR (film) cm21: 1736. MS (FAB) m/z: 443 (MþNa)þ. HR-
MS (FAB) m/z: 443.2628 (Calcd for C20H44O5Si2Na:
443.2625). This aldehyde was treated with sodium salt of
triethyl phosphonoacetate as described for the synthesis of 9
from 8. Yield of 9 from 19 was 76% in two steps.
4.3.3. 4-O-Benzoyl-2,3-bis-O-(tert-butyldimethylsilyl)-L-
threose diethylacetal (18). To a stirred solution of 17
(228 mg, 0.76 mmol) and 2,6-lutidine (0.72 mL, 6.1 mmol)
in CH2Cl2 (7.6 mL) was added TBDMSOTf (0.61 g,
2.3 mmol) at room temperature. The mixture was stirred
for 30 min and quenched with water. The mixture was
extracted with EtOAc and washed with water and brine. The
crude product was purified by silica gel flash chromatog-
raphy eluted with 10% EtOAc in hexane to give 18
(384 mg) in 95% yield. Colorless oil. Rf¼0.50 (10% EtOAc
in hexane). [a]2D2¼221 (c 0.65, CHCl3). 1H NMR
(300 MHz, C6D6) d 8.21–8.16 (2H, m), 7.15–7.00 (3H,
m), 4.72 (1H, dd, J¼11.0, 7.0 Hz), 4.70 (1H, d, J¼5.7 Hz),
4.64 (1H, dd, J¼11.0, 5.3 Hz), 4.43 (1H, ddd, J¼7.0, 5.3,
2.6 Hz), 4.00 (1H, dd, J¼5.7, 2.6 Hz), 3.64 (1H, dq, J¼9.4,
7.0 Hz), 3.68–3.60 (3H, m), 1.14 (3H, t, J¼7.0 Hz), 1.10
(3H, t, J¼7.0 Hz), 1.06 (9H, s), 0.99 (9H, s), 0.25 (3H, s),
0.20 (3H, s), 0.18 (3H, s), 0.17 (3H, s). 13C NMR (75 MHz,
C6D6) d 166.2, 132.8, 130.9, 129.8, 128.5, 101.8, 74.0, 71.7,
66.5, 63.4, 61.2, 26.2, 26.0, 18.6, 18.3, 15.6, 15.3, 23.6,
24.1, 24.6, 24.7. IR (film) cm21: 1716. MS (FAB) m/z:
549 (MþNa)þ. HR-MS (FAB) m/z: 549.3038 (Calcd for
C27H50O6Si2Na: 549.3032).
4.3.6. Epoxidation of 10. With mCPBA. To a solution of 10
(0.66 g, 1.5 mmol) in CH2Cl2 (5 mL) was added mCPBA
(507 mg, 3 mmol) at room temperature by several portions.
After it was stirred for 1 h, the mixture was diluted with
EtOAc, washed with Na2S2O3, NaHCO3, water, and brine.
The residual oil was purified by flash chromatography on
silica gel eluted with 15% EtOAc in hexane to give a
mixture of 20a and 20b (650 mg) in 95% yield.
With VO(acac)2. To a mixture of 10 (230 mg, 0.51 mmol)
and VO(acac)2 (6.8 mg, 26 mmol) in CH2Cl2 (2.5 mL) was
added TBHP (2.91 M solution in CH2Cl2 0.53 mL,
1.55 mmol) at room temperature and stirred for 1 h at
room temperature. An excess of dimethyl sulfide (0.2 mL)
was added and solvent was removed. The crude product was
purified by flash chromatography on silica gel eluted with
15% EtOAc in hexane to give 20b (166 mg) as a single
diastereomer in 70% yield.
4.3.4. 2,3-Bis-O-(tert-butyldimethylsilyl)-L-threose
diethylacetal (19). DIBAL-H (0.93 M in hexane solution,
1.88 mL) was dropped to 18 (384 mg, 0.73 mmol) in
CH2Cl2 (7.4 mL) at 2788C and the mixture was stirred
for 30 min at the same temperature. Sat. NH4Cl was added
and the mixture was vigorously agitated. The precipitate
was filtered through celite pad and the filtrate was extracted
Isolation of pure 20a and 20b. A mixture of 20a and 20b
(300 mg, 0.6 mmol) and diisopropylethylamine (166 mg,
1.3 mmol) in CH2Cl2 (3 mL) was added benzyl chlorocar-
bonate (132 mg, 1.3 mmol) at 08C. The mixture was stirred
for 24 h at room temperature. Sat. NaHCO3 was added and
the mixture was extracted with EtOAc. The extract was
washed with water and brine. The crude product was

J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
7019
purified by flash chromatography on silica gel eluted with
5% EtOAc in hexane to give a mixture of diastereomer
(298 mg) and some recovery of the starting material. The
mixture was separated by HPLC; column 20 £ 500 mm,
silica gel, eluent; 7% EtOAc in hexane, 15 mL/min. The
carbonate derived from 20a appeared at 9.9 min was
isolated in 28% yield, and that from 20b appeared at
8.5 min in 37% yield. Hydrogenolysis of the each benzyl
carbonate (0.4 mmol) was conducted in EtOH (4 mL) in the
presence of 10% Pd on charcoal (13 mg) under hydrogen
gave 20a in 64% yield and 20b in 71% yield, respectively.
20a Colorless oil. Rf¼0.45 (20% EtOAc in hexane).
(MþNa)þ. HR-MS (FAB) m/z: 563.2322 (Calcd for
C23H48O6Si2S2Na: 563.2328). 21b Colorless oil. Rf¼0.65
(20% EtOAc in hexane). [a]D21¼22 (c 0.5, CHCl3). 1H
NMR (300 MHz, C6D6) d 4.80 (1H, dd, J¼9.9, 5.8 Hz), 4.53
(1H, d, J¼3.0 Hz), 4.34 (1H, dd, J¼9.9, 6.8 Hz), 4.06 (1H,
d, J¼0.9 Hz), 4.06 (1H, m), 3.90 (1H, m), 3.87 (1H, dd,
J¼3.7, 3.0 Hz), 3.71 (1H, dd, J¼5.8, 3.7 Hz), 3.54 (1H, dq,
J¼9.0, 7.0 Hz), 3.37 (1H, dq, J¼9.0, 7.0 Hz), 3.34 (1H, dq,
J¼9.0, 7.0 Hz), 3.22 (1H, dq, J¼9.0, 7.0 Hz), 1.04 (3H, t,
J¼7.0 Hz), 1.03 (3H, t, J¼7.0 Hz), 0.98 (9H, s), 0.90 (9H,
s), 0.18 (3H, s), 0.13 (3H, s), 0.03 (3H, s), 0.01 (3H, s). 13C
NMR (75 MHz, CDCl3) d 212.0, 101.4, 79.4, 76.5, 75.3,
74.8, 63.9, 63.4, 53.1, 26.0 (£2), 18.4, 18.1, 15.4, 15.2,
24.2, 24.4, 24.5, 24.7. IR (film) cm21: 3466. MS (FAB)
m/z: 563 (MþNa)þ. HR-MS (FAB) m/z: 563.2333 (Calcd
for C23H48O6Si2S2Na: 563.2328).
1
[a]D22¼214 (c 0.8, CHCl3). H NMR (300 MHz, C6D6) d
4.65 (1H, d, J¼4.9 Hz), 3.78 (1H, dd, J¼3.3, 2.9 Hz), 3.65–
3.28 (8H, m), 2.90 (1H, m), 1.50 (1H, m), 1.15–1.05 (6H,
m), 1.08 (9H, s), 1.02 (9H, s), 0.40 (3H, s), 0.24 (3H, s), 0.22
(3H, s), 0.10 (3H, s). 13C NMR (75 MHz, C6D6) d 102.3,
77.0, 75.9, 63.5, 62.9, 61.8, 58.1, 56.6, 26.2, 26.1, 18.5,
4.4.2. Acetylation of a mixture of 21a and 21b. To a
mixture of 21a and 21b (130 mg, 0.24 mmol) in pyridine
(1 mL) was added acetic anhydride (0.07 mL, 0.72 mmol) at
08C. The mixture was stirred for 1 h and poured in water.
The mixture was extracted with EtOAc and washed with
water and brine. The crude product was purified by flash
chromatography on silica gel eluted with 5% EtOAc in
hexane to give a mixture of 22 and 23 as a 1:1 ratio. They
were partially separable by flash column chromatography
and completely separable by HPLC. HPLC separation was
performed by the use of silica gel column; 20 mm£250 mm,
eluent; 5% EtOAc in hexane. Less polar isomer appeared at
8.9 min was found to be 22 derived from 20a, and polar
isomer to be 23 appeared at 15.7 min derived from 20b. The
yields were 46% for 22 and 39% for 23.
18.4, 15.5, 15.3, 23.7, 23.8, 24.7, 25.0. IR (film) cm21
:
3466. MS (FAB) m/z: 487 (MþNa)þ. HR-MS (FAB) m/z:
487.2892 (Calcd for C22H48O6Si2Na: 482.2888). 20b
Colorless oil. Rf¼0.45 (20% EtOAc in hexane). [a]D20¼29
(c 0.65, CHCl3). 1H NMR (300 MHz, C6D6) d 4.70 (1H, d,
J¼5.3 Hz), 4.04 (1H, dd, J¼5.3, 2.6 Hz), 3.92 (1H, dd,
J¼4.8, 2.6 Hz), 3.72–3.31 (7H, m), 3.10 (1H, m), 1.55 (1H,
m), 1.13 (3H, t, J¼7.1 Hz), 1.08 (3H, t, J¼7.1 Hz), 1.06
(9H, s), 0.99 (9H, s), 0.26 (3H, s), 0.24 (3H, s), 0.13 (6H, s).
13C NMR (75 MHz, C6D6) d 101.2, 75.0, 72.6, 62.4, 61.9,
61.2, 57.6, 55.9, 26.1, 25.9, 18.5, 18.4, 15.4, 15.3, 23.8,
24.0, 24.7, 25.0. IR (film) cm21: 3465. MS (FAB) m/z:
487 (MþNa)þ. HR-MS (FAB) m/z: 487.2892 (Calcd for
C22H48O6Si2Na: 482.2888).
4.4. Synthesis of 5-thio-hexopyranoside
Compound 22. Colorless oil. Rf¼0.45 (10% EtOAc in
hexane). [a]D21¼235 (c 2.95, CHCl3). 1H NMR (300 MHz,
CDCl3) d 5.60 (1H, d, J¼9.4 Hz), 5.16 (1H, dm, J¼7.2 Hz),
4.80 (1H, dd, J¼9.9, 2.5 Hz), 4.51 (1H, s), 4.50 (1H, dd,
J¼9.9, 7.2 Hz), 3.80 (1H, d, J¼3.8 Hz), 3.67 (1H, dd,
J¼9.4, 3.8 Hz), 3.49 (1H, dq, J¼9.0, 7.0 Hz), 3.30 (2H, q,
J¼7.0 Hz), 3.07 (1H, dq, J¼9.0, 7.0 Hz), 1.96 (3H, s), 1.00
(3H, t, J¼7.0 Hz), 0.98 (3H, t, J¼7.0 Hz), 0.89 (9H, s), 0.88
(9H, s), 0.14 (3H, s), 0.01 (6H, s), 20.01 (3H, s). 13C NMR
(75 MHz, CDCl3) d 211.7, 169.6, 100.9, 78.3, 76.4, 74.5,
73.7, 65.1, 63.9, 51.2, 26.0, 25.7, 20.9, 18.4, 17.9, 15.4,
15.3, 24.4, 24.6, 24.7, 24.9. IR (film) cm21: 1747. MS
(FAB) m/z: 605 (MþNa)þ. HR-MS (FAB) m/z: 605.2430
(Calcd for C25H50O7Si2S2Na: 605.2435).
4.4.1. Transformation of trans-2,3-epoxy alcohol to cyclic
xanthate 21. To a stirred suspension of NaH (103 mg, 60%
in mineral oil, 2.6 mmol) in CS2 (4 mL) and THF (3 mL)
was added a THF (2 mL) solution of 20a and 20b (600 mg,
1.3 mmol) at 2308C. A small amount of methanol
(0.03 mL) was then dropped, and the reaction mixture was
warmed up to 08C during 15 min. Then, the mixture was re-
cooled down to 2308C, and powder of silica gel (ca. 2 g)
was added by several portions. The reaction mixture was
stirred for 5 min at the same temperature and diluted with
ether (30 mL). The whole was passed through silica gel
column and silica gel was washed with ether. The ethereal
filtrates were combined and condensed. The residual oil was
purified by flash chromatography on silica gel eluted with
5% EtOAc in hexane to give 21 (572 mg) in 82% yield.
Independently, the same reaction of 20a gave 21a and that
of 20b gave 21b, respectively. These physical and spectro-
scopic data are following: 21a Colorless oil. Rf¼0.65 (20%
EtOAc in hexane). [a]D21¼2 (c 0.4, CHCl3). 1H NMR
(300 MHz, C6D6) d 4.97 (1H, dd, J¼9.9, 5.0 Hz), 4.65 (1H,
d, J¼4.0 Hz), 4.24 (1H, d, J¼4.0 Hz), 4.16–4.07 (2H, m),
3.84–3.71 (3H, m), 3.60 (1H, dq, J¼9.0, 7.1 Hz), 3.53–3.42
(2H, m), 3.28 (1H, dq, J¼9.0, 7.1 Hz), 1.04 (3H, t,
J¼7.1 Hz), 1.01 (3H, t, J¼7.1 Hz), 0.99 (9H, s), 0.89 (9H,
s), 0.15 (3H, s), 0.14 (3H, s), 0.04 (3H, s), 20.02 (3H, s). 13C
NMR (75 MHz, CDCl3) d 209.8, 79.8, 75.4, 74.1, 69.6,
63.2, 63.1, 53.3 (£2), 26.0, 25.9, 18.2, 18.1, 15.3 (£2), 23.7,
24.4, 24.6 (£2). IR (film) cm21: 3376. MS (FAB) m/z: 563
Compound 23. Colorless crystals, mp 95–978C. Rf¼0.42
1
(10% EtOAc in hexane). [a]D24¼21 (c 0.55, CDCl3). H
NMR (300 MHz, C6D6) d 5.76 (1H, dd, J¼3.2, 2.4 Hz), 4.92
(1H, dd, J¼9.9, 4.2 Hz), 4.62 (1H, ddd, J¼7.3, 4.2, 3.2 Hz),
4.44 (1H, d, J¼2.8 Hz), 4.34 (1H, dd, J¼9.9, 7.3 Hz), 4.01
(1H, dd, J¼4.6, 2.4 Hz), 3.74 (1H, dd, J¼4.6 and 2.8 Hz),
3.59 (1H, dq, J¼9.0, 7.0 Hz), 3.75 (1H, dq, J¼9.0, 7.0 Hz),
3.74 (1H, dq, J¼9.0, 7.0 Hz), 3.25 (1H, dq, J¼9.0, 7.0 Hz),
1.72 (3H, s), 1.05 (3H, t, J¼7.0 Hz), 1.04 (3H, t, J¼7.0 Hz),
1.01 (9H, s), 0.88 (9H, s), 0.16 (3H, s), 0.15 (3H, s), 0.04
(3H, s), 0.02 (3H, s). 13C NMR (75 MHz, C6D6) d 211.4,
169.0, 101.7, 78.8, 76.1, 75.5, 73.3, 63.7, 62.8, 51.4, 26.1,
26.0, 20.4, 18.5, 18.2, 15.5, 15.4, 24.2, 24.3, 24.5, 24.6.
IR (KBr) cm21: 1749. MS (FAB) m/z: 605 (MþNa)þ. HR-
MS (FAB) m/z: 605.2438 (Calcd for C25H50O7Si2S2Na:

7020
J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
605.2435). Anal. Calcd for C25H50O7Si2S2: C, 51.51; H,
8.64. Found: C, 51.19; H, 8.83.
flash chromatography on silica gel eluted with 30% EtOAc in
hexane. Compound26(9.6 mg)wasobtainedin69%yieldasa
1:1 ratio of a- and b-anomers.
4.4.3. (2R,3R,4S,5S)-4-Acetoxy-2,3-bis-(tert-butyldi-
methylsilyloxy)-5,6-epithiohexanal diethylacetal (24). A
methanol (0.5 mL) solution of 22 (52 mg, 0.089 mmol) was
stirred in the presence of anhydrous K2CO3 (50 mg) for 3 min.
The mixture was diluted with ether and washed with water and
brine. The crude product was purified by flash chromatog-
raphy on silica gel eluted with 5% EtOAc in hexane to give 24
(44 mg) in 94% yield. 24. Colorless oil. Rf¼0.5 (10% EtOAc
in hexane). [a]D21¼217 (c 0.55, CHCl3). 1H NMR (300 MHz,
CDCl3) d 5.60 (1H, dd, J¼6.3, 4.6 Hz), 4.73 (1H, d,
J¼2.8 Hz), 4.00 (1H, s), 3.99 (1H, dt, J¼10.0, 3.7 Hz),
3.75–3.62 (2H, m), 3.55–3.35 (3H, m), 3.42 (1H, d,
J¼5.4 Hz), 2.19 (1H, d, J¼6.3 Hz), 1.83 (3H, s), 1.17 (3H, t,
J¼7.0 Hz), 1.10 (3H, t, J¼7.0 Hz), 1.00 (9H, s), 0.99 (9H, s),
0.23 (3H, s), 0.19 (3H, s), 0.16 (3H, s), 0.12 (3H, s). 13C NMR
(75 MHz, CDCl3) d 169.3, 101.3, 75.9, 75.7, 73.7, 63.2, 63.1,
33.6, 26.1, 26.0, 21.3, 20.9, 18.5, 18.3, 15.5, 15.4, 24.0, 24.2,
24.4, 24.5. IR (film) cm21: 1744. MS (FAB) m/z: 545
(MþNa)þ. HR-MS (FAB) m/z: 545.2770 (Calcd for C24H50-
O6Si2SNa: 545.2764).
Preparation from D-1. A solution (þ)-5-thio-D-glucose (D-
1) (20 mg, 0.1 mmol) in ethanol (0.1 mL) was added 0.5 mL
of ethanol saturated with HCl gas, and the mixture was
stirred for 7 h at room temperature. An excess of silver
carbonate was added and it was further stirred for 2 h.
Precipitates were filtered and the filtrate was condensed.
The crude product was dissolved in pyridine (0.4 mL), and
acetic anhydride (0.15 mL, 1.6 mmol) was added. The
mixture was stirred for 12 h and water and EtOAc were
added. The organic layer was washed with water and brine.
The residue was purified by flash chromatography on silica
gel. Elution with 30% EtOAc gave 26 (21 mg) in 53% yield
as a 10:1 ratio of a- and b anomers. The a-anomer (26a)
was partially isolated by the column chromatography.
Compound 26a. Colorless oil. Rf¼0.55 (40% EtOAc in
1
hexane). [a]D22¼279 (c 0.12, CHCl3). H NMR (300 MHz,
CDCl3) d 5.43 (1H, t, J¼9.5 Hz), 5.22 (1H, dd, J¼10.1,
9.5 Hz), 5.06 (1H, dd, J¼10.1, 2.9 Hz), 4.7 (1H, d,
J¼2.9 Hz), 4.32 (1H, dd, J¼12.0, 4.5 Hz), 3.98 (1H, dd,
J¼12.0, 3.2 Hz), 3.79 (1H, dq, J¼9.5, 7.0 Hz), 3.42–3.30
(2H, m), 2.00 (3H, s), 1.98 (3H, s), 1.95 (3H, s), 1.93 (3H, s),
1.16 (3H, t, J¼7.0 Hz). 13C NMR (75 MHz, CDCl3) d
170.6, 170.2, 169.8, 169.6, 79.0, 74.8, 72.2, 70.9, 64.6, 61.3,
38.3, 20.8, 20.7, 20.6, 20.5, 14.6. IR (film) cm21: 1747. MS
(FAB) m/z: 415 (MþNa)þ. HR-MS (FAB) m/z: 415.1046
(Calcd for C16H24O9SNa: 415.1039). 26b. Colorless oil.
Rf¼0.55 (40% EtOAc in hexane). 1H NMR (300 MHz,
CDCl3) d 5.22 (1H, dd, J¼10.0, 9.5 Hz), 5.00 (1H, dd,
J¼9.5, 9.2 Hz), 4.52 (1H, d, J¼8.8 Hz), 4.20 (1H, dd,
J¼11.5, 5.5 Hz), 4.07 (1H, dd, J¼11.5, 4.0 Hz), 3.78 (1H,
m), 3.47 (1H, dq, J¼9.5, 7.0 Hz), 3.42–3.30 (1H, m), 3.08
(1H, ddd, J¼10.0, 5.5, 4.4 Hz), 2.00 (3H, s), 1.97 (3H, s),
1.95 (3H, s), 1.93 (3H, s), 1.12 (3H, t, J¼7.0 Hz). 13C NMR
(75 MHz, CDCl3) d 170.5, 169.8, 169.5, 169.4, 81.3, 74.7,
73.0, 71.7, 66.6, 62.1, 40.1, 20.7, 20.6, 20.6, 20.5, 14.9. IR
(film) cm21: 1747. MS (FAB) m/z: 415 (MþNa)þ. HR-MS
(FAB) m/z: 415.1046 (Calcd for C16H24O9SNa: 415.1039).
4.4.4. Ethyl 4,6-di-O-acetyl-2,3-bis-O-(tert-butyldi-
methylsilyl)-5-thio-D-glucopyranoside (25). A mixture of
24 (21.6 mg, 0.041 mmol), potassium acetate (224 mg,
2.2 mmol) and acetic anhydride (0.02 mL, 0.1 mmol) in
acetic acid (1 mL) was heated in oil bath at 1108C for 4 h.
After cooling, water was added and the mixture was
extracted with ether. Ethereal extract was washed with
water and brine. The crude product was purified by flash
chromatography on silica gel eluted with 5% EtOAc in
hexane to give 25 (12 mg) in 54% yield as a 1:1 ratio of
anomers. Colorless oil. Rf¼0.40 (10% EtOAc in hexane).
1H NMR (300 MHz, CDCl3) d 5.52 (1/2H, dd, J¼10.2,
8.7 Hz), 5.48 (1/2H, t, J¼5.1 Hz), 4.62 (1/2H, d, J¼7.7 Hz),
4.49 (1/2H, dd, J¼11.9, 4.6 Hz), 4.40 (1/2H, dd, J¼13.8,
2.4 Hz), 4.19 (1/2H, t, J¼8.8 Hz), 4.10 (1/2H, t, J¼3.3 Hz),
4.08–3.50 (5/2H, m), 3.90 (1/2H, dq, J¼9.0, 7.0 Hz), 3.74
(1/2H, dq, J¼9.0, 7.0 Hz), 3.34 (1/2H, dt, J¼10.6, 4.4 Hz),
3.26 (1/2H, m), 3.10 (1/2H, dq, J¼9.0, 7.0 Hz), 3.04 (1/2H,
dq, J¼9.0, 7.0 Hz), 1.85 (3/2H, s), 1.78 (3/2H, s), 1.76 (3/
2H, s), 1.73 (3/2H, s), 1.10–1.00 (3H, m), 1.01 (9/2H, s),
1.00 (9/2H, s), 0.97 (9H, s), 0.20 (3/2H, s), 0.19 (3H, s), 0.10
(3H, s), 0.08 (3/2H, s), 0.04 (3/2H, s), 20.04 (3/2H, s). 13C
NMR (75 MHz, CDCl3) d 170.1, 169.8, 169.6, 169.3, 85.0,
83.4, 78.6, 75.0, 73.9, 73.2, 72.9, 70.4, 66.0, 64.8, 64.3,
62.3, 40.8, 39.8, 26.3, 26.2, 25.9, 25.8, 21.2, 20.9, 20.4,
20.3, 18.4, 18.2, 18.1, 18.0, 15.0, 14.8, 22.2, 22.9, 24.1.
24.2, 24.4, 24.5, 24.6, 24.8. IR (film) cm21: 1748. MS
(FAB) m/z: 559 (MþNa)þ. HR-MS (FAB) m/z: 559.2552
(Calcd for C24H48O7Si2SNa: 559.2557).
4.4.6. Preparation of 5-thio-D-glucose (D-1). A solution of
26 (10 mg, 25 mmol) in 3.4 M HCl (0.5 mL) and THF
(0.6 mL)washeatedatrefluxingtemperaturefor3 h.Then, the
mixture was passed through IRA-400 eluted with 50%
aqueous methanol. The eluents were combined and evapor-
ated to give D-1 (5 mg) as a white solid. Mp 135–138 8C.
Rf¼0.35 (30% MeOH in CHCl3). [a]D21¼188 (c 1.0, H2O).
4.4.7. (2R,3R,4R,5R)-4-Acetoxy-2,3-bis-(tert-butyldi-
methylsilyloxy)-5,6-epithiohexanal diethylacetal (27).
The ring contraction of 23 (86 mg, 0.15 mmol) was
performed by the same reaction manner described for the
synthesis of 24. Compound 27 was obtained in 91% yield.
Colorless oil. Rf¼0.47 (10% EtOAc in hexane). [a]D21¼221
(c 1.07, CHCl3). 1H NMR (300 MHz, C6D6) d 5.40 (1H, dd,
J¼5.9, 3.7 Hz), 4.61 (1H, d, J¼4.4 Hz), 4.00 (1H, dd,
J¼4.0, 3.7 Hz), 4.05 (1H, dd, J¼4.4, 4.0 Hz), 3.63 (1H, dq,
J¼9.0, 7.0 Hz), 3.68–3.28 (4H, m), 2.39 (1H, d, J¼5.5 Hz),
2.13 (1H, d, J¼6.6 Hz), 1.73 (3H, s), 1.14 (3H, t, J¼7.0 Hz),
1.12 (3H, t, J¼7.0 Hz), 1.09 (9H, s), 1.01 (9H, s), 0.27 (6H,
4.4.5. Ethyl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyrano-
side (26). Preparation form 25. A mixture of 25 (19 mg,
0.04 mmol) in THF (0.4 mL) and tetrabutylammonium
fluoride (1 M THF solution, 0.14 mL, 0.14 mmol) was stirred
for 1 h at room temperature. Then, solvent was removed. The
crude product was dissolved in pyridine (0.4 mL) and acetic
anhydride (16 mL, 0.16 mmol) was added at 08C. The mixture
was stirred for 2 h at room temperature, diluted with EtOAc,
washed with water, and brine. The residue was purified by

J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
7021
s), 0.20 (3H, s), 0.15 (3H, s). 13C NMR (75 MHz, C6D6) d
169.1, 102.6, 76.8, 74.7, 74.2, 63.4, 62.0, 32.2, 26.4, 26.2,
22.0, 20.6, 18.7, 18.5, 15.6, 15.3, 23.9, 24.1, 24.2, 24.3.
IR (neat) cm21: 1742. MS (FAB) m/z: 545 (MþNa)þ. HR-
MS (FAB) m/z: 545.2772 (Calcd for C24H50O6Si2SNa:
545.2764).
Cooperative Research administered by the Japan Private
School Promotion Foundation.
References
4.4.8. Ethyl 4,6-di-O-acetyl-2,3-bis-O-(tert-butyldi-
methylsilyl)-5-thio-L-altropyranoside (28). The synthesis
of 28 was performed from 27 (70 mg, 0.13 mmol) by the
same reaction manner described for the synthesis of 25.
Compound 28 was obtained in 64% yield as a 10:1 ratio of
a- and b-anomers. Colorless oil. Rf¼0.37 (10% EtOAc in
hexane). [a]D22¼7 (c 2.23, CHCl3). Only a spectrum of a-
anomer was indicated in 1H NMR and 13C NMR. 1H NMR
(400 MHz, CDCl3) d 5.39 (1H, dd, J¼9.9, 1.8 Hz), 4.96
(1H, brs), 4.27 (1H, dd, J¼11.5, 6.0 Hz), 4.10 (1H, dd,
J¼11.5, 4.2 Hz), 3.98 (2H, brs), 3.79 (1H, dq, J¼9.0,
7.0 Hz), 3.55–3.42 (2H, m), 2.06 (3H, s), 2.05 (3H, s), 1.19
(3H, t, J¼7.0 Hz), 0.94 (9H, s), 0.90 (9H, s), 0.09 (3H, s),
0.08 (3H, s), 0.05 (6H, s). 13C NMR (75 MHz, CDCl3) d
170.8, 169.9, 89.4, 74.3, 71.7, 66.2, 65.6, 63.4, 32.8, 25.7
(£2), 21.3, 20.7, 18.2, 18.0, 15.0, 24.3, 24.9 (£3). IR (neat)
cm21: 1748. MS (FAB) m/z: 559 (MþNa)þ. HR-MS (FAB)
m/z: 559.2563 (Calcd for C24H48O7Si2SNa: 559.2557).
1. Adley, T. J.; Owen, L. N. Proc. Chem. Soc. 1961, 418.
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Asymmetry of Carbohydrates; Harmon, R. E., Ed.; Marcel
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Biochemistry 1968, 7, 4479–4483. (b) Whistler, R. L.; Lake,
W. C. Biochem. J. 1972, 130, 919–925. (c) Hellman, B.;
Lernmark, A.; Sehlin, J. B.; Taljedal, J. B.; Whistler, R. L.
Biochem. Pharmacol. 1973, 22, 29–35. (d) Zysk, J.; Bushway,
A. A.; Whistler, R. L.; Carlton, W. W. J. Reprod. Fertil. 1975,
45, 69–72. (e) Kim, J. H.; Kim, S. H.; Hahn, E. W.; Song,
C. W. Science 1978, 200, 206–207. (f) Hashimoto, H.;
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1987, 1200–1201.
4.4.9. Ethyl 2,3,4,6-tetra-O-acetyl-5-thio-L-altropyrano-
side (29). The synthesis of 29 was performed from 28
(44.6 mg, 0.083 mmol) by the same reaction manner
described for the synthesis of 26. Compound 29 was
obtained in 78% yield as a 10:1 anomeric ratio. Colorless
oil. Rf¼0.50 (40% EtOAc in hexane). [a]D22¼171 (c 0.54,
CHCl3). Only a spectrum of a-anomer was indicated in 1H
1
NMR and 13C NMR. H NMR (400 MHz, CDCl3) d 5.67
(1H, t, J¼3.1 Hz), 5.55 (1H, dd, J¼10.8, 3.0 Hz), 5.45 (1H,
dd, J¼10.8, 3.1 Hz), 4.76 (1H, dd, J¼3.0, 1.5 Hz), 4.43 (2H,
m), 3.88 (1H, dq, J¼9.0, 7.0 Hz), 3.38 (1H, dq, J¼9.0,
7.0 Hz), 3.11 (1H, dddd, J¼8.8, 7.1, 3.1, 1.5 Hz), 2.15 (3H,
s), 2.09 (3H, s), 2.07 (3H, s), 2.01 (3H, s), 1.21 (3H, t,
J¼7.0 Hz). 13C NMR (75 MHz, CDCl3) d 170.5, 170.4,
170.2, 169.7, 80.7, 70.9, 69.8, 65.2, 64.7, 64.5, 42.8, 21.0,
20.9, 20.8, 20.7, 14.4. IR (film) cm21: 1742. MS (FAB) m/z:
415 (MþNa)þ. HR-MS (FAB) m/z: 415.1046 (Calcd for
C16H24O9SNa: 415.1039).
8. Synthesis of 5-thio-D-glucose, (a) Feather, M. S.; Whistler,
R. L. Tetrahedron Lett. 1962, 667–668. (b) Chiu, C.-W.;
Whistler, R. L. J. Org. Chem. 1973, 38, 832–834. (c) Driguez,
H.; Henrissat, B. Tetrahedron Lett. 1981, 22, 5061–5062. (d)
Yuasa, H.; Tamura, J.; Hashimoto, H. J. Chem. Soc., Perkin
Trans. 1 1990, 2763–2769.
4.4.10. Removal of the protective groups for 29.
Deproection of acetates and ethyl glycoside of 29
(21.6 mg) was carried out by the same reaction manner
described for the synthesis of D-1. After purification by
silica gel column chromatography eluted with 20%
methanol in CHCl3, L-20 (7.2 mg) was obtained in 73%
yield as a white solid. Colorless crystals, mp 138–1438C.
Rf¼0.47 (20% MeOH in CHCl3). [a]D24¼95 (c 0.25, MeOH).
1H NMR (300 MHz, D2O) d 5.35 (1H, s), 4.23 (1H, t,
J¼4.8 Hz), 4.14 (1H, d, J¼9.5 Hz), 3.99 (1H, t, J¼4.5 Hz),
3.91 (1H, dd, J¼9.5, 4.5 Hz), 3.64 (1H, m), 3.55 (1H, dd,
J¼8.6, 4.8 Hz). 13C NMR (75 MHz, D2O) d 86.6, 77.0,
73.0, 72.6, 70.8, 52.5.
9. Uenishi, J.; Motoyama, M.; Nishiyama, Y.; Wakabayashi, S.
J. Chem. Soc., Chem. Commun. 1991, 1421–1422.
10. Uenishi, J.; Motoyama, M.; Takahashi, K. Tetrahedron:
Asymmetry 1994, 5, 101–110.
11. Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc. 2000, 122,
8444–8452.
12. Rees, M. S.; van Kuijk, F. J. G. M. Synth. Commun. 1993, 23,
757–763.
13. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; 2nd ed., Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp 357–398.
14. Epoxidation with mCPBA in similar system for 4,5-disilyloxy-
allyl alcohol was reported by Saito et al. in which b-epoxide
(corresponding to 20b in this case) was formed preferentially
Saito, S.; Itoh, H.; Ono, Y.; Nishioka, K.; Moriwake, T.
Tetrahedron: Asymmetry 1993, 4, 5–8.
Acknowledgements
15. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136–6137.
This work was financially supported by a Special Grant for

7022
J. Uenishi, H. Ohmiya / Tetrahedron 59 (2003) 7011–7022
16. Uenishi, J.; Motoyama, M.; Nishiyama, Y.; Hirota, Y.; Kubo,
Y. Heteroatom Chem. 1994, 5, 51–60, We have found that a
catalytic amount of methanol was very effective for the
initiation of this reaction and ‘silica gel quenching work up’
was essential for high chemical yields.
20. Synthesis of 5-thio-D-altrose, (a) Hughes, N. A. J. Chem. Soc.,
Chem. Commun. 1979, 319–320. (b) Hughes, N. A. Carbo-
hydr. Res. 2000, 326, 323–325.
21. This compound was obtained as a 10:1 ratio of a- and b-
anomers. The 1H NMR spectrum were in good accordance
with methyl 2,3,4,6-O-tetraacetyl-5-thio-b-D-altrose reported
by Hughes, see: Al-Masoudi, N. A. L.; Hughes, N. A.
Carbohydr. Res. 1986, 148, 39–49.
22. Since compounds D-20 and L-20 are quite stable in acidic
conditions, their hydrolysis leading to D-20 and L-20 have not
been successful.
17. Uenishi, J.; Motoyama, M.; Kubo, Y. Heteroatom Chem.
1994, 5, 529–532.
18. 5-Thio-D-glucose is commercially available from Aldrich Co.
Ltd.
19. Lambert, J. B.; Wharry, S. M. J. Org. Chem., 1981, 46,
3193–3196.