Thioglycosylation of 1,2-cis-glycosyl acetates: A long-standing overlooked issue in preparative carbohydrate chemistry

Article abstract of DOI:10.1016/j.carres.2011.03.033

1,2-cis-Glycosyl acetates with the α-configuration were revealed to be very unreactive towards Lewis acid catalyzed thioglycosylations. Optimal and cost-effective conditions for enabling this direct conversion is absent in the literature. Our studies have

Full text of DOI:10.1016/j.carres.2011.03.033

Carbohydrate Research 346 (2011) 1149–1153
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Thioglycosylation of 1,2-cis-glycosyl acetates: a long-standing overlooked issue
in preparative carbohydrate chemistry
⇑
Ci Xu , Han Liu , Xuechen Li
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2-cis-Glycosyl acetates with the
a-configuration were revealed to be very unreactive towards Lewis
Received 8 February 2011
Received in revised form 14 March 2011
Accepted 23 March 2011
Available online 6 April 2011
acid catalyzed thioglycosylations. Optimal and cost-effective conditions for enabling this direct conver-
sion is absent in the literature. Our studies have shown that elevating the reaction temperature with a
catalytic amount of BF3ÁOEt2 was more effective than changing Lewis acids with higher acidities to
accommodate the low reactivity of
the reaction is also discussed.
a
-glycosyl acetates. The effect of impurities in stored BF3ÁOEt2 on
Dedicated to Professor Ole Hindsgaul for his
60th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Thioglycoside
Lewis-acid catalyzed thioglycosylation
1,2-cis-Glycosyl acetates
Thioglycosides are one of the most important intermediates
that are widely used in preparative carbohydrate chemistry. The
advantages of thioglycoside donors include activation by versatile
reagents, high degree of stability, and ready conversion to other
types of glycosyl donors (e.g., glycosyl halides, lactols, sulfoxides).1
The most preferred and cost-effective method for thioglycoside
preparations is Lewis acid-catalyzed (e.g., BF3ÁOEt, FeCl3, SnCl4)
substitution of the anomeric acetate of peracetylated sugars with
alkyl or aryl thiols, as the starting peracetylated sugars are either
commercially available or can be readily prepared by direct
acetylation of free sugars.2 However, an altered route via glycosyl
halides followed by a thio-mediated SN2 reaction has to be adopted
for some unreactive substrates.3
it has been found that the methyl
a-galactopyranoside hydrolyzes
much faster than the methyl -glucopyranoside, which was pro-
a
posed to derive from relief of steric strain by Edward4 and elec-
tronic effects by Bols.5 However, the yields in the synthesis of
both the thioglucopyranoside (e.g., 2) and thiogalactopyranoside
(e.g., 4) herein were far lower than the reported results under
the same conditions (BF3ÁOEt2, CH2Cl2, room temperature).6 Thus,
the unacceptable yield from the thioglycosylation of 1,2,3,4,6-
penta-O-acetyl-a-D-gluco- and galactopyranoses stimulated our
curiosity. An extensive literature search revealed that the reported
Lewis acid-catalyzed thioglycosylations involving the use of the
per-O-acetylated glycopyranoses with a 1,2-trans configuration
(i.e., 1,2,3,4,6-penta-O-acetyl b-gluco- or galactopyranose), gives
In our recent work towards oligosaccharide synthesis in the
high yields.6–9 Although the higher stability of
a
-anomers is well
preparation of phenyl 2,3,4,6-tetra-O-acetyl-1-thio-b-
D-glucopy-
known as the anomeric effect, such a low reactivity of -glycosyl
a
ranoside 2 from commercially available 1,2,3,4,6-penta-O-acetyl-
acetates in this routine transformation was still surprising and sel-
dom mentioned.8,9 In a similar O-glycosylation process, the 1,2-cis
isomer was also observed to be inert, even under harsh microwave
irradiation conditions in the presence of FeCl3.10
1,2-trans-Glycosyl acetates can be readily converted into their
corresponding thioglycosides under various Lewis acid-catalyzed
conditions. Nevertheless, from the perspective of fundamental
curiosity and potentially practical value, it is necessary to investi-
gate the issue of the thioglycosylation of 1,2-cis-glycosyl acetates
a
-
D
-glucopyranose 1 and PhSH using BF3ÁOEt2 as the catalyst
(Scheme 1), we obtained an unexpectedly low yield (12%) after
72 h reaction. On the contrary, the BF3ÁOEt2-mediated thioglycosy-
lation of 1,2,3,4,6-penta-O-acetyl-
a-
D-galactopyranose
3
pro-
ceeded much faster (20 h) and in better yield (41%). The
significant reactivity difference between the -glucopyranosyl ace-
tate and the -galactopyranosyl acetate towards Lewis acid-
a
a
catalyzed thioglycosylations is analogous to the reactivity of
non-enzymatic hydrolysis of alkyl glycopyranosides. For example,
with
a-configuration and find an enabling condition. Practically,
the preparation per-O-acetyl-
a
-glycopyranoses is easier and more
cost-effective than their b counterparts. Thermodynamic acetyla-
tion conditions (e.g., pyridine–acetic anhydride) give per-O-acet-
⇑
Corresponding author. Tel.: +852 51829956; fax: +852 28571586.
E-mail address: xuechenl@hku.hk (X. Li).
yl-a-glycopyranoses from free sugars, while the preparation of
These authors contributed equally.
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.03.033

1150
C. Xu et al. / Carbohydrate Research 346 (2011) 1149–1153
OAc
O
F
F
F
F
OAc
AcO B
F
HO B
F
H
H
PhSH 2 eq.
O
AcO
AcO
AcO
AcO
SPh
9
10
BF3•OEt2 3 eq.
AcO
AcO
OAc
r.t. 3 days
12%
Figure 1. Putative Brønsted acids generated in the reaction system.
1
2
OAc
OAc
AcO
AcO
AcO
AcO
PhSH 2 eq.
O
application of the microwave irradiation technology in organic
synthesis,13 these conditions were also tested for both BF3ÁOEt2
and SnCl4 catalyzed reactions. In the case of BF3ÁOEt2 catalysis, only
starting materials were observed, even after 2 h reaction at 50 °C
(entries 9 and 10). On the contrary, thioglycoside 2 can be isolated
in 44% yield when SnCl4 was used (entry 11). Further improving
the yield was quite difficult due to the decomposition of the prod-
uct/starting material probably mediated by the strong acidic com-
O
SPh
BF3•OEt2 3 eq.
AcO
AcO
OAc
r.t. 1 day
41%
3
4
Scheme 1. Thioglycosylation of -anomers of penta-O-acetyl glycopyranoses.
a
per-O-acetyl-b-glycopyranoses requires kinetically controlled
conditions (e.g., Ac2O, NaOAc, 100 °C).11,6g Additionally, there are
cases where the kinetically controlled condition can not be used;
for instance, a tetrachlorophthalimido (TCP)-protected glucosa-
mine cannot survive under such conditions. Herein, we report
our studies on the thioglycosylation of 1,2-cis-glycosyl acetates
plex
9
formed by acetic acid (the byproduct of the
thioglycosylation) and BF3ÁOEt2 (Fig. 1). In the case of the more
reactive 1,2-trans-glycosyl acetates with the b-configuration, side
reactions would be negligible for the rapid main reaction at low
temperature. As evidence for this hypothesis, when 3 equiv acetic
acid was added to the reaction mixture heated at reflux, a 49% yield
of 2 was isolated without the observation of unconsumed 1 (entry
12).
with the
a-configuration.
To accommodate the low activity of
a
-glycosyl-acetates, we
first tried to use other Lewis acids with higher acidity than
BF3ÁOEt2 in a model reaction with 1.12 As summarized in Table 1,
SiCl4 and BBr3 gave no, or only a trace amount, of the desired prod-
uct at room temperature (entries 2 and 3), and extensive decompo-
sition of 1 was observed when BBr3 with very high Lewis acidity
was used. When SnCl4 was used, 43% yield of 2 was obtained (entry
4). Next, considering the existence of the unconsumed starting
material after a prolonged reaction time with BF3ÁOEt2 and SnCl4
at room temperature, we investigated the effect of temperature
on the reaction outcome. Heating the reaction mixture at reflux
in CH2Cl2, for 20 h did increase the yield to 62% and 69% in the
cases of BF3ÁOEt2 and SnCl4 as catalysts, respectively (entries 5
and 7). When 0.5 equiv BF3ÁOEt2 was used, the yield was main-
tained (entry 6). In the case of SnCl4 catalysis, when the tempera-
ture was further increased to 60 °C in 1,2-dichloroethane, only a
trace amount of the desired product was observed together with
a complex mixture of side products (entry 8). Considering the wide
With the encouraging result for the glucose derivative, the
thioglycosylation of 1,2,3,4,6-penta-O-acetyl-a-D-galactopyranose
3 was optimized in a similar way (Table 2). The best result was
obtained at room temperature under the catalysis of 3 equiv
BF3ÁOEt2 (entry 2) after a prolonged reaction period (48 h), while
higher temperature and using more active SnCl4 catalyst gave low-
er yields due to the decomposition of the product (entries 3–5).
Delightfully, when the reaction mixture was heated at reflux with
a catalytic amount of BF3ÁOEt2, a higher yield (73%) was obtained in
a short period of time (12 h) (entries 6 and 7).
The difficult thioglycosylation of 1,3,4,6-tetra-O-acetyl-2-
deoxy-2-N-TCP-a-D-glucopyranose 5 had been observed by Fra-
ser-Reid and co-workers.14 The synthesis of the 2-deoxy-2-N-
TCP-1,3,4,6-tetra-acetyl glucopyranose in a b form is not trivial,
as the direct acetylation of a in situ generated N-TCP-glucosamine
under the kinetic acetylation condition (Ac2O, NaOAc, 100 °C)
damages the TCP group. Thus, an indirect three-step process
was devised to overcome this obstacle, wherein the readily ob-
tained N-TCP-protected
a-glycosyl acetate was first converted to
the b-acetate counterpart via the glycosyl bromide. The
Table 1
Thioglycosylations of 1,2,3,4,6-penta-O-acetyl-a
-D-glucopyranosea
OAc
OAc
PhSH 2 eq.
Catalyst
O
O
AcO
AcO
Table 2
AcO
AcO
SPh
Thioglycosylations of 1,2,3,4,6-penta-O-acetyl-
a
-D-galactopyranosea
AcO
AcO
OAc
OAc
AcO
OAc
AcO
1
2
PhSH 2 eq.
Catalyst
O
O
Entry Catalyst
Condition
Yieldb (%)
SPh
AcO
AcO
1
2
3
4
5
6
7
8
9
BF3ÁOEt2
SiCl4
BBr3
SnCl4
BF3ÁOEt2
CH2Cl2, 20 °C, 72 h
CH2Cl2, 20 °C, 20 h
CH2Cl2, 20 °C, 20 h
CH2Cl2, 20 °C, 20 h
CH2Cl2, reflux, 20 h
12
0
Trace
43
62
62
69
Trace
Trace
Trace
44
AcO
AcO
OAc
3
4
Entry
Catalyst
Condition
Yieldb (%)
1
2
3
4
5
6
7
BF3ÁOEt2
CH2Cl2, 20 °C, 20 h
CH2Cl2, 20 °C, 48 h
CH2Cl2, reflux, 20 h
CH2Cl2, 20 °C, 20 h
CH2Cl2, reflux, 20 h
CH2Cl2, reflux, 12 h
CH2Cl2, reflux, 12 h
41
73
60
43
34
73
73
BF3ÁOEt2 (0.5 equiv) CH2Cl2, reflux, 12 h
BF3ÁOEt2
SnCl4
SnCl4
BF3ÁOEt2
BF3ÁOEt2
SnCl4
BF3ÁOEt2
CH2Cl2, reflux, 20 h
BF3ÁOEt2
CH2ClCH2Cl, 60 °C, 20 h
CH2Cl2, MW, 50 °C, 1 h
CH2Cl2, MW, 50 °C, 2 h
CH2Cl2, MW, 50 °C, 1 h
SnCl4
SnCl4
10
11
12
BF3ÁOEt2 (0.5 equiv)
BF3ÁOEt2 (0.25 equiv)
CH2Cl2, AcOH 3 equiv, reflux, 20 h 49
a
a
The reaction was conducted at 0.5 mmol scale in 4 mL solvent. For BF3ÁOEt2
The reaction was conducted at 0.5 mmol scale in 4 mL solvent. For BF3ÁOEt2
(freshly distilled before use) catalyzed reaction, the catalyst loading was 3 equiv,
while 0.7 equiv was used for SnCl4 catalysis.
(freshly distilled before use) catalyzed reaction, the catalyst loading was 3 equiv,
while 0.7 equiv was used for SnCl4 catalysis.
b
b
Isolated yield.
Isolated yield.

C. Xu et al. / Carbohydrate Research 346 (2011) 1149–1153
1151
OAc
O
OAc
O
OAc
68%
TiCl4
r.t.
O
AcO
AcO
AcO
AcO
OAc
AcO
AcO
SR
X
FeCl3,
or TiCl4,
TCPN
TCPN
TCPN
OAc
OAc
O
or BF3•OEt2
50%
2 steps
r.t.
AcO
AcO
TCPN
Br
Scheme 2. Thioglycosylation of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-N-TCP-
a-
D
-glucopyranose in the literature.14
thioglycosylation of the b anomer proceeded smoothly to afford
the TCP-protected thioglycoside 6 (68%) using TiCl4 (Scheme 2)
as the Lewis acid.14 In such a strategy, a corrosive HBr–HOAc mix-
ture and expensive silver reagent were involved, and the overall
yield was low (34%) and not cost-effective. Thus, a more conve-
nient and efficient process towards 6 is still required.
OAc
OAc
O
PhSH 2 eq.
BF3•OEt2 2 eq.
O
AcO
AcO
AcO
AcO
SPh
ClCH2CH2Cl
AcHN
AcHN
OAc
50 oC
r.t.
40%
trace
7
8
As described for the thioglycosylation of the aforementioned
a-glycosyl acetates, we tried the thioglycosylation of 1,3,4,6-tet-
ra-O-acetyl-2-deoxy-2-N-TCP- -glucopyranose at elevated
a
-
D
5
Scheme 3. Thioglycosylations of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-
glucopyranose.
temperatures (Table 3). To our surprise, the TCP-protected thiogly-
coside could be obtained in 57% yield after heating at reflux in
CH2Cl2, for 20 h. After careful optimization, up to a 76% yield of
the product can be obtained when the reaction is carried out at
50 °C in 1,2-dichloroethane under the catalysis of BF3ÁOEt2 (entry
4). According to TLC, the starting material was fully consumed after
4.5 h, and the formation of some side products with lower Rf than 6
can be observed, which was attributed to partial deacetylation.
Thus, the crude product was treated with acetic anhydride and
pyridine, and the isolated yield was improved to 80%. When
0.5 equiv of BF3ÁOEt2 was used, the reaction was rather slow. When
SnCl4 was involved at the optimized temperature, only inseparable
mixtures of side products with trace amount of the desired were
observed (entry 5). Furthermore, we extended our studies on the
thioglycosylation of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-
directly used without pre-distillation, better yields within shorter
reaction time were obtained for the thioglycosylation of -glycosyl
a
acetates of glucose and galactose at room temperature, in contrast
to using freshly distilled BF3ÁOEt2 under the same conditions. How-
ever, the yield was decreased at higher temperature. For instance,
58% of thiogalactopyranoside 4 was obtained at room temperature
with full consumption of the starting material 3 (Table 4, entry 4),
while the freshly distilled BF3ÁOEt2 only partially consumed the
starting material to give 41% yield of the desired product (Table
2, entry 1) within the same reaction time. We postulated that puta-
tive Brønsted acid 10 (Fig. 1) may be formed in water-contami-
nated BF3ÁOEt2, and this species helps to accelerate the reaction
but also decomposes some products. To test this hypothesis, we
intentionally added 1 equiv of H2O to the reaction mixture of 1
with distilled BF3ÁOEt2 to mimic the contaminated BF3ÁOEt2. As ex-
pected, a similar 16% yield was obtained at room temperature in
20 h. In addition, the formation of side products can be observed
when the isolated thioglycosylation product 2 was treated with
3 equiv BF3ÁOEt2 and 1 equiv of H2O. The quality of the BF3ÁOEt2
made no difference on the reaction of the N-TCP-protected
a-D-glucopyranose 7. At room temperature, the thioglycosylation
with BF3ÁOEt2 gave only a trace amount of thioglycoside 8 after
20 h, while 40% yield of the desired product was isolated when
the reaction was carried out at 50 °C in 1,2-dichloroethane for
40 h (Scheme 3). The reaction with SnCl4 gave only decomposed
products at 50 °C in 1,2-dichloroethane.
During our investigations, an interesting phenomenon was ob-
served. When BF3ÁOEt2 that had been stored for a long time was
Table 3
Thioglycosylations of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-N-TCP-
a
-D-glucopyranosea
Table 4
a
Thioglycosylations of 1,2-cis glycosyl acetates using un-distilled BF3ÁOEt2
OAc
OAc
OAc
OAc
O
R2
R2
PhSH 2 eq.
Catalyst
O
O
AcO
AcO
AcO
AcO
SPh
PhSH 2 eq.
O
R1
AcO
R1
AcO
SPh
TCPN
TCPN
OAc
BF3•OEt2 3 eq.
AcO
AcO
OAc
5
6
R1 = OAc, R2 = H
R1 = H, R2 = OAc
Entry
Catalyst
Condition
Yieldb (%)
1
3
2
4
1
2
3
4
5
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
SnCl4
CH2Cl2, reflux, 20 h
57
CH2ClCH2Cl , reflux, 20 h
CH2ClCH2Cl, 50 °C, 20 h
CH2ClCH2Cl, 50 °C, 4.5 h
CH2ClCH2Cl, reflux, 20 h
43d
Entry
Substrate
Conditions
Yieldb (%)
55
76 (80)c
Trace
1
2
3
4
5
1
1
1
3
3
CH2Cl2, 20 °C, 20 h
CH2Cl2, reflux, 20 h
CH2Cl2, MW, 50 °C, 1 h
CH2Cl2, 20 °C, 20 h
CH2Cl2, reflux, 20 h
23
47c
31
a
The reaction was conducted at 0.3 mmol scale in 4 mL solvent. For BF3ÁOEt
58c
44c
(freshly distilled before use) catalyzed reaction, the catalyst loading was 2 equiv,
while 0.7 equiv was used for SnCl4 catalysis.
b
a
Isolated yield.
The reaction was conducted at 0.5 mmol scale in 4 mL solvent under the
catalysis of 3 equiv BF3ÁOEt2 (without distillation).
c
The yield in parenthesis was obtained after being treated with acetic anhydride
b
and pyridine.
Isolated yield.
d
c
Decomposed product was observed.
No starting material left.

1152
C. Xu et al. / Carbohydrate Research 346 (2011) 1149–1153
derivative, probably due to the stability of thioglycosides of 2-ami-
no sugars.
(m, 3H), 7.43–7.46 (m, 2H). 13C NMR (100 MHz, CDCl3): d = 20.6,
20.6, 20.7, 20.8, 61.9, 68.1, 68.5, 70.4, 70.7, 84.9, 127.8, 129.1,
131.8, 132.4, 169.6, 169.87, 169.9, 170.6. MS (EI, 70 eV): 440
(M+). All NMR data were in accordance with literature results.6
The Lewis acid-catalyzed thioglycosylation is the most common
way to prepare thioglycosides in carbohydrate synthesis. A wealth
of reported methods have adopted the corresponding per-O-acety-
lated glycopyranoses having a 1,2-trans-configuration as the start-
ing material, while the thioglycosylation of 1,2-cis-glycosyl
1.3. Phenyl 2,3,4,6-tetra-O-acetyl-1-thio-b-D-galactopyranoside
(4)
acetates with the
looked or avoided issue in preparative carbohydrate chemistry.
The challenge associated with the low reactivity of -glycosyl ace-
tates towards the Lewis acid-catalyzed thioglycosylation was re-
vealed here and simple solution was found. Our studies
showed the significant difference between -glycosyl acetate of
glucose and galactose towards BF3ÁOEt2 catalyzed thioglycosyla-
tion. In addition, the elevation of the reaction temperature with a
catalytic amount of BF3ÁOEt2 is demonstrated to be more effective
than changing the Lewis acids to one with higher acidities to
a-configuration has been a long standing over-
1H NMR (400 MHz, CDCl3): d = 1.98 (s, 3H), 2.05 (s, 3H), 2.10 (s,
3H), 2.13 (s, 3H), 3.94 (t, J = 7.1 Hz, 1H), 4.12 (dd, J1 = 6.2 Hz,
J2 = 11.3 Hz, 1H), 4.20 (dd, J1 = 7.0 Hz, J2 = 11.3 Hz, 1H), 4.72 (d,
J = 10.0 Hz, 1H), 5.05 (dd, J1 = 3.3 Hz, J2 = 9.9 Hz, 1H), 5.25 (t,
J = 10.0 Hz, 1H), 5.42 (dd, J1 = 0.9 Hz, J2 = 3.3 Hz, 1H), 7.31–7.33
(m, 3H), 7.51–7.53 (m, 2H). 13C NMR (100 MHz, CDCl3): d = 20.4,
20.50, 20.53, 20.7, 61.5, 67.1, 71.8, 74.2, 76.7, 86.4, 128.0, 128.6,
132.3, 132.4, 169.3, 169.9, 170.0, 170.2. MS (EI, 70 eV): 440 (M+).
All NMR data were in accordance with literature results.6
a
a
a
accommodate the low reactivity of
tates. An otherwise tedious preparation of phenyl 3,4,6-tri-O-acet-
yl-2-deoxy-2-N-TCP-1-thio- -glucopyranoside was simplified by
the direct BF3ÁOEt2 mediated thioglycosylation of 3,4,6-tri-O-acet-
yl-2-deoxy-2-N-TCP- -glucopyranose. Furthermore, we identi-
a-glucosyl and galactosyl ace-
1.4. General procedure for the thioglycosylation of glucosamine
derivatives
a
-D
a
-D
To a round bottom flask, the carbohydrate substrate (185 mg for
fied that water-contaminated BF3ÁOEt2 has both accelerating and
deteriorating effects on the thioglycosylation reaction. The proce-
dure reported here would benefit the preparation of thioglycosides
of glucose, galactose and N-TCP-protected glucosamine in a feasi-
ble and cost-effective manner.
5, and 117 mg for 7, 0.3 mmol, 1.0 equiv), dry ClCH2CH2Cl (4 mL),
and thiophenol (61 lL, 0.6 mmol, 2.0 equiv) were added sequen-
tially under argon. The mixture was stirred at room temperature
for 20 min, and then cooled to 0 °C in an ice water bath. To this
mixture was added BF3ÁOEt2 (74
lL, 0.6 mmol, 2.0 equiv), and the
reaction was stirred at 50 °C (4.5 h for 5, 40 h for 7). When the
reaction finished, the mixture was diluted with CH2Cl2 and
quenched with saturated NaHCO3 (aq). The organic layer was
washed with 1 N NaOH (aq) and brine, dried over anhydrous
Na2SO4, and concentrated under vacuum. For substrate 5, the res-
idue was dissolved into pyridine (2 mL), and excess amount of
Ac2O (1 mL) was added. The mixture was stirred at room temper-
ature over night, and diluted with CH2Cl2. The organic layer was
washed thoroughly with 1 N HCl (aq) to remove the pyridine,
and then washed with brine. After being dried over anhydrous
Na2SO4, the solvent was removed under vacuum. The desired prod-
uct was obtained through silica gel flash chromatography using
hexane–EtOAc (3:1 v/v for product 6, 1:2 v/v for product 8) as
the eluent.
1. Experimental section
1.1. General procedure for the thioglycosylation of
penta-O-acetyl- -glucopyranose and -1,2,3,4,6-penta-O-
acetyl- -galactopyranose
a-1,2,3,4,6-
a
-D
a
a-D
To a round bottom flask, the sugar pentaacetate (195 mg,
0.5 mmol, 1.0 equiv), dry CH2Cl2 (4 mL), and thiophenol (102 L,
1.0 mmol, 2.0 equiv) were added sequentially under argon. The
mixture was stirred at room temperature for 20 min, and then
cooled to 0 °C in an ice water bath. To this mixture was added
l
BF3ÁOEt2 (31
lL, 0.25 mmol, 0.50 equiv) or SnCl4 (82 lL, 0.7 equiv),
and the reaction was stirred under reflux for 12–20 h, as listed in
the tables. When the reaction was finished, the mixture was di-
luted with CH2Cl2 and quenched by the addition of saturated NaH-
CO3 (aq). The organic layer was washed with saturated NaHCO3
(aq) and brine, dried over anhydrous Na2SO4, and concentrated un-
der vacuum. The desired product was obtained through silica gel
flash chromatography using hexane–EtOAc (3:1, v/v) as eluent.
1.5. Phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-N-
tetrachlorophthalimido-1-thio-b-D-glucopyranoside (6)
1H NMR (400 MHz, CDCl3): d = 1.88 (s, 3H), 2.03 (s, 3H), 2.11 (s,
3H), 3.87 (ddd, J1 = 2.3 Hz, J2 = 5.1 Hz, J3 = 10.2 Hz, 1H), 4.20 (dd,
J1 = 2.3 Hz, J2 = 10.0 Hz, 1H), 4.29 (dd, J1 = 5.1 Hz, J2 = 12.3 Hz, 1H),
4.35 (t, J = 10.4 Hz, 1H), 5.15 (dd, J1 = 9.2 Hz, J2 = 10.1 Hz, 1H),
5.67 (d, J = 10.5 Hz, 1H), 5.72 (dd, J1 = 9.2 Hz, J2 = 10.0 Hz, 1H),
7.28–7.30 (m, 3H), 7.40–7.42 (m, 2H). 13C NMR (100 MHz, CDCl3):
d = 20.4, 20.6, 20.7, 54.3, 62.1, 68.3, 71.6, 75.9, 82.3, 126.7, 127.0,
128.5, 129.0, 130.0, 130.4, 133.2, 134.6, 134.8, 162.1, 163.2,
169.3, 170.5, 170.6. MS (EI, 70 eV): 663 (M+). The NMR data were
in accordance with literature result.14
1.2. Phenyl 2,3,4,6-tetra-O-acetyl-1-thio-b-D-glucopyranoside
(2)
1H NMR (400 MHz, CDCl3): d = 2.00 (s, 3H), 2.02 (s, 3H), 2.086 (s,
3H), 2.093 (s, 3H), 3.73 (ddd, J1 = 2.6 Hz, J2 = 5.0 Hz, J3 = 10.1 Hz,
1H), 4.18 (dd, J1 = 2.6 Hz, J2 = 12.3 Hz, 1H), 4.23 (dd, J1 = 5.0 Hz,
J2 = 12.3 Hz, 1H), 4.71 (d, J = 10.1 Hz, 1H), 4.98 (dd, J1 = 9.3 Hz,
J2 = 10.0 Hz, 1H), 5.05 (t, J = 9.8 Hz, 1H), 5.23 (t, J = 9.3 Hz, 1H),
7.32–7.33 (m, 3H), 7.49–7.51 (m, 2H). 13C NMR (100 MHz, CDCl3):
d = 20.4, 20.4, 20.6, 20.6, 61.9, 68.0, 69.7, 73.7, 75.6, 85.4, 128.2,
128.8, 131.4, 132.9, 169.1, 169.2, 170.0, 170.4. MS (EI, 70 eV): 440
(M+). A small amount (<5%) of phenyl 2,3,4,6-tetra-O-acetyl-1-
1.6. Phenyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-1-thio-b-D-
glucopyranoside (8)
1H NMR (400 MHz, CDCl3): d = 1.98 (s, 3H), 2.00 (s, 3H), 2.02 (s,
3H), 2.07 (s, 3H), 3.74–3.76 (m, 1H), 4.05 (q, J = 9.9 Hz, 1H), 4.15–
4.24 (m, 2H), 4.88 (d, J = 10.4 Hz), 5.05 (t, J = 9.8 Hz, 1H), 5.25 (t,
J = 9.6 Hz, 1H), 5.96 (br, 1H), 7.29 (s, 3H), 7.49–7.50 (m, 2H). 13C
NMR (100 MHz, CDCl3): d = 20.5, 20.6, 20.7, 23.2, 53.2, 62.3, 68.4,
73.6, 75.6, 86.5, 128.0, 128.9, 132.3, 132.5, 169.3, 170.1, 170.6,
thio-a-D
-glucopyranoside was observed. 1H NMR (400 MHz,
CDCl3): d = 2.03 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.11 (s, 3H), 4.04
(dd, J1 = 2.2 Hz, J2 = 12.3 Hz, 1H), 4.28 (dd, J1 = 5.1 Hz, J2 = 12.3 Hz,
1H), 4.57 (ddd, J1 = 2.2 Hz, J2 = 5.1 Hz, J3 = 10.3 Hz, 1H), 5.06–5.13
(m, 2H), 5.45 (t, J = 10.0 Hz, 1H), 5.92 (d, J = 5.7 Hz, 1H), 7.29–7.31

C. Xu et al. / Carbohydrate Research 346 (2011) 1149–1153
1153
171.0. MS (ESI): 462.2 [M+Na]+. The NMR data were in accordance
with literature result.15
(c) Fukunaga, K.; Yoshida, M.; Nakajima, F.; Uematsu, R.; Hara, M.; Inoue, S.;
Kondo, H.; Nishimura, S.-I. Bioorg. Med. Chem. Lett. 2003, 13, 813–815; (d)
Cheng, M. S.; Wang, Q. L.; Tian, Q.; Song, H. Y.; Liu, Y. X.; Li, Q.; Xu, X.; Miao, H.
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Acknowledgement
We thank the University of Hong Kong for the financial support
and a seed funding support (HKU200912159008).
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Kahn, S. H., O’Neil, R. A., Eds.; Harwood Academic Publishers: Amsterdam,
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