Direct thiophenylation accompanying orthoester-cleavage of 1,2,4-O-orthoacetyl-3,6-O-(o-xylylene)glucopyranose

Article abstract of DOI:10.1016/j.carres.2014.10.004

The 3,6-O-(o-xylylene) bridge locks the conformation of glucopyranose to an axial-rich form. Although the conformational lock induces complete β-selectivity in a glycosylation reaction, the leaving group of the glycosyl donor is limited to fluorine. On the other hand, the bridge confers the furanose-preferred property to glucose, which makes synthesis of corresponding pyranosyl derivatives that equip various leaving groups difficult. This problem was solved through direct phenylthio glucosidation of 3,6-O-(o-xylylene)-1,2,4-O-orthoacetylglucose accompanying cleavage of the orthoester moiety. This paper describes the process of establishing direct thiophenylation. This process reduced the synthetic steps for the known glucopyranosyl fluoride and will expand application of conformationally locked glycosyl donors.

Full text of DOI:10.1016/j.carres.2014.10.004

Carbohydrate Research 402 (2015) 118–123
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Direct thiophenylation accompanying orthoester-cleavage
of 1,2,4-O-orthoacetyl-3,6-O-(o-xylylene)glucopyranose
⇑
Takuya Uchino, Yusuke Tomabechi, Atsushi Fukumoto, Hidetoshi Yamada
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2014
Received in revised form 8 September 2014
Accepted 10 October 2014
Available online 20 October 2014
The 3,6-O-(o-xylylene) bridge locks the conformation of glucopyranose to an axial-rich form. Although
the conformational lock induces complete b-selectivity in a glycosylation reaction, the leaving group of
the glycosyl donor is limited to fluorine. On the other hand, the bridge confers the furanose-preferred
property to glucose, which makes synthesis of corresponding pyranosyl derivatives that equip various
leaving groups difficult. This problem was solved through direct phenylthio glucosidation of 3,6-O-(o-
xylylene)-1,2,4-O-orthoacetylglucose accompanying cleavage of the orthoester moiety. This paper
describes the process of establishing direct thiophenylation. This process reduced the synthetic steps
for the known glucopyranosyl fluoride and will expand application of conformationally locked glycosyl
donors.
Keywords:
Thiophenylation
Orthoester
o-Xylylene
Axial-rich
Ó 2014 Elsevier Ltd. All rights reserved.
Conformation
Acquisition of varied leaving groups for glycosyl donors is
important in the development of chemical glycosylation reactions.
In the presence of several types of leaving groups, a chemoselective
activation of a leaving group allows the other leaving groups to
remain intact. The survivors behave as protecting groups of carbo-
hydrates during the reaction, and can be activated afterward,
through different methods, to enable elongation of sugar chains.
This strategy is described as orthogonal,1 and has streamlined oli-
gosaccharide synthesis.2–8 Among the variety of leaving groups
used in the orthogonal synthesis, alkyl- and arylthio groups have
been commonly used because these are stable under ubiquitous
activating conditions for a halogen atom and trichloroacetimi-
date,9,10 which are the frequently-used leaving groups of glycosyl
donors. In addition, activation of the alkyl- and arylthio groups is
possible chemoselectively when necessary.
Another important issue that must be considered in the devel-
opment of glycosylation reactions is control of anomeric stereose-
lectivity. For a stereoselective preparation of a 1,2-trans glycosidic
linkage, the neighboring group participation (NGP hereafter) of a 2-
O-acyl protecting group has been proven.11 Recently, it has been
reported that conformational lock of a pyranose ring can be effec-
tive procedures to obtain the stereoselectivity.12–19 In addition,
control of reactivity in glycosylation due to the lock to a conforma-
tion that has more axial substituents has been reported with con-
formational armed–disarmed concept,20 and thus, influence in
glycosylation reactions contributed by the variation of conforma-
tion has attracted attention.21–23 We reported a unique NGP-less
1,2-trans-selective glycosylation employing glycosyl fluoride 1
(Fig. 1a), the conformation of the pyranose ring of which was
locked to an axial-rich form by a 3,6-O-(o-xylylene) bridge.24 First,
preparation of the glycosyl donor 1 required 13 steps (Fig. 1b,
Route A); therefore, the route was inefficient, even in laboratory
synthesis. Later, we improved the synthetic method of the glycosyl
donor (Fig. 1b, Route B),25 where the utilization of conformational-
ly locked orthoester 2 contributed to the formation of the o-xylyl-
ene bridge. In the route, the orthoester group was removed by
unusual thermal glycosylation26,27 with p-methoxyphenol (step 1
in the transformation from 3 to 4). The reason that we could not
rely on the usual method for the removal of the orthoester group,
hydrolysis, was the property of 3,6-O-(o-xylylene)glucose (6) that
preferred the furanose form over the pyranose form (Fig. 1c).
Despite the complete b-selectivity in the glycosylation reaction
using the o-xylylene bridged glycosyl donor, only glycosyl fluoride
1 has been investigated; none of the variants possessing the other
leaving groups have been developed. Considering usability in
orthogonal synthesis, a synthetic method for the corresponding
thioglycosides must be established. A thioglycoside can be pre-
pared from a glycosyl fluoride,1,28 but application of the transfor-
mation of 1 to 7 would make the synthesis lengthy, and thus
inefficient. Transformation from hemiacetal
5 is similarly
lengthy.29–32 The p-methoxyphenyl (pMP) group can also convert
to an alkyl- or arylthio group,33 but operation of the reported pro-
cedure to 4 was poor, as will be described later. In this study, we
⇑
Corresponding author. Tel.: +81 79 565 8342.
E-mail address: hidetosh@kwansei.ac.jp (H. Yamada).
http://dx.doi.org/10.1016/j.carres.2014.10.004
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

T. Uchino et al. / Carbohydrate Research 402 (2015) 118–123
119
(a)
(b)
(a)
(b)
Scheme 1. Attempts at synthesis of the 3,6-O-(o-xylylene) bridge-possessing
thioglycosides through known methods.
yield of 8 was estimated to be 43% based on the 1H nuclear mag-
netic resonance (NMR) spectra of the crude product after removal
of an acetyl group generated by cleavage of the orthoester. Because
of the low yield and a poignant malodor at the workup operations
due to the use of a large excess of benzenethiol, we decided not to
apply the thermal glycosylation strategy for the transformation.
After the production of many by-products in the thermal thio-
glycosylation, we reconsidered the process of the orthoester cleav-
age (Scheme 2). The orthoester of 3 is cleaved by an acid.
Coordination of the acid with the oxygen atom at the 2-position
(O-2) and O-4 generates oxocarbenium ion intermediates 9 and
11, respectively. The intermediate 9 would only induce 10, which
is the desired thiopyranoside, through the reaction with a thiol.
Reaction of 11 with a thiol provides 10 but an intramolecular
(c)
(d)
Figure 1. Reaction, preparation, and properties of o-xylylene bridged glucose:
Ac = acetyl, Bn = benzyl, BTF = benzotrifluoride, Et = ethyl, MSV = molecular sieves,
Ph = phenyl, pMP = p-methoxyphenyl.
describe investigations for direct conversion from 3,6-O-(o-xylyl-
ene)-1,2,4-O-orthoacetylglucose (3) to the corresponding alkyl-
and arylthioglucosides, the optimized reaction conditions for
phenylthioglucoside 8, and the synthesis of glycosyl fluoride 1
from 8 via 7 which contributes to one-step shortening of the syn-
thesis of 1.
We first attempted the preparation of thioglycoside 7 from pMP
glucoside b-4, (Scheme 1, a) applying the reported method.33
Treatment of b-4 with benzenethiol [3 equiv of b-4] and boron tri-
fluoride diethyl etherate (1.5 equiv of b-4) in dichloromethane
(DCM) under reflux provided 7 in 11% yield as a component of a
complex mixture of products. Operation of the reaction at room
temperature (rt) produced 7 at a 27% yield. During the investiga-
tions, we found that a decreased quantity of benzenethiol from 3
to 1 equiv resulted in a better yield, although it was still 41%.
Therefore, we concluded that the transformation from b-4 to 7
was inadequate, and strived for direct conversion from 3 to 8
(Scheme 1, b).
Our first choice for the direct conversion was thermal glycosyl-
ation similar to the first step in the transformation from 3 to pMP
glucoside 4 in Scheme 1b. Thus, 6 equiv of benzenethiol as both
nucleophile and solvent in the reaction was heated with 3 at
100 °C in the presence of pyridinium p-toluenesulfonate (PPTS)
and molecular sieves (MSV) 5A. The reaction provided the desired
phenylthioglucoside 8 accompanied with many by-products. The
Scheme 2. A possible reaction mechanism for cleavage of orthoester 3: R = an
unspecified alkyl- or aryl group.

120
T. Uchino et al. / Carbohydrate Research 402 (2015) 118–123
Table 2
attack of the O-4 of 11 results in the formation of undesired furan-
oside 14 through 12 and 13. Therefore, the process includes com-
petition between the inter- and intramolecular reactions.
Although an intramolecular reaction is generally faster, the
strained structure of 12 that contains a 2,5,10,14-tetraoxatricy-
clo[9.3.0.03,25] tetradecane skeleton, and stronger nucleophilicity
of the sulfur atom of the thiol than nucleophilicity of O-4 are both
favorable to the formation of 10 in this case. Thus, the transition
state for 12 might be higher than that for 10. Nevertheless, under
the thermal reaction conditions, the pathway to 12 is allowed,
and this might be the reason that the thermal introduction of the
phenylthio group produced complex by-products in the reaction
of Scheme 1b. When a thiol is treated with 3 at lower tempera-
tures, the pathway to 10 might become conspicuous.
On the basis of the analysis described above, we examined the
cleavage of orthoester at various temperatures (Table 1). In the
examination, we used benzenethiol, trimethylsilyl (TMS) trifluoro-
methanesulfonate (triflate or OTf), and MSV 5A as the nucleophile,
the activator, and the additive, respectively, in DCM. After the
cleavage reaction, treatment of each crude product with sodium
methoxide in methanol removed the remained acetyl group. The
results clarified that the yield of 8 increased at a lower reaction
temperature. The peak of the yield appeared when the temperature
Search for appropriate thiols in direct thioglycosylation of 3
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
C2H5
n-C12H25
C6H5
C6H4-o-CH3
C6H4-p-CH3
C6H4-p-NO2
15
16
8
17
18
19
5
24
88 (82)b
29
29
N.D.
a
NMR yield of each b-isomer.
Isolated yield.
b
yields were calculated on the basis of the ratio of 1H NMR signal-
areas between crude reaction-product and an internal standard
that was non-deuterated acetone. The molar amount of acetone
was identical to that of the starting material 3. In order to obtain
correct yields, signals definitely derived from the desired product
of each entry should be recognized among the multiple signals of
the crude products. For this purpose, we isolated compounds 8
and 15–18 in pure form after the 1H NMR observation of each
crude product and confirmed the spectral data.
With benzenethiol, we explored the activator and reaction sol-
vents to determine the reaction conditions listed in Table 2, entry
3, in which the use of TMSOTf and DCM as the activator and sol-
vent, respectively, was optimal. As the activator, TMSOTf, tert-
butyldimethylsilyl triflate, PPTS, boron trifluoride diethyl etherate,
bismuth(III) bromide, and hafnium(IV) triflate34 were attempted in
DCM as the reaction solvent. However, they were all less effective
than TMSOTf. Fixing TMSOTf as the activator, the use of acetoni-
trile, diethyl ether, N,N-dimethylformamide (DMF), pyridine, tetra-
hydrofuran (THF), and toluene were compared as reaction solvents.
This examination showed that the yield and stereoselectivity of the
cleaving reaction were highly dependent on the solvent, and the
yield of 8 was highest in DCM. For details of these results, see
Table S1 of the Supplementary data. The limitation of the method
in the use of other thiols, activators, and solvents may involve the
competition between intermediates 9 and 11 (Scheme 2). How-
ever, the formation of many by-products in the cases obtained les-
ser yield prevented accurate analysis for the limitation.
was À40 °C (Table 1, entry 2); at the temperature, the
a/b-ratio
was also most biased to b.
With the gratifying outcome at À40 °C (Table 1, entry 2), we
then examined the employment of the other thiols to find that only
benzenethiol was useful for the cleavage of orthoester (Table 2). In
the examination, we fixed the solvent, the activator, and the addi-
tive at DCM, TMSOTf, and MSV 5A, respectively. The yields were
obtained after removal of the acetyl group, the cleaved orthoester.
The examination demonstrated that the reactions with ethanethiol
and 1-dodecanethiol provided products as a complex mixture,
hence the yields of the desired alkylthioglucosides 15 and 16 were
low (Table 2, entries 1 and 2). The result listed in Table 2, entry 3 is
a transcription of Table 1, entry 2, in which the chromatogram of
thin layer chromatography (TLC) used for tracing the reaction
was simple. On the other hand, the treatments with 2-methylben-
zenethiol and 4-methylbenzenethiol produced a complex mixture
containing desired thioglucosides 17 and 18 in 29% yields, respec-
tively (Table 2, entries 4 and 5). In addition, the attempt at using 4-
nitrobenzenthiol gave a complicated mixture that did not allow
isolation of the desired product 19 (Table 2, entry 6). The NMR
Table 1
Examination of reaction temperature for cleavage of orthoester in 3
For each reaction in this paper so far, we handled 50 mg of 3 to
find the optimal reaction conditions (Table 2, entry 3). We next
applied the reaction conditions for a gram-scale synthesis of 8.
Thus, treatment of 3.5 g of 3 under the optimal conditions afforded
b-8 in a 70% yield (Scheme 3). From the experiment, we discovered
that b-8 could be purified by recrystallization from a mixture of
CHCl3 and n-hexane after removal of unreacted benzenethiol
through short column chromatography. The obtained 70% yield
after the recrystallization illustrated great practicality in labora-
tory synthesis.
As a bonus of the establishment of the direct production of
phenylthioglucoside 8 from 3, we were able to shorten the route
for synthesizing glycosyl fluoride 1 (Fig. 1a). In our previous
report,25 we described the reduction in the number of preparation
steps of 1 from 13 to 9 (Fig. 1b). The present work removed one
more step (Scheme 4). Thus, after dibenzylation of 8 producing 7,
treatment of 7 with N,N-diethylaminosulfur trifluoride and N-bro-
Entry
Temperature (°C)
Time (h)
Yielda (%)
a
/b ratiob
1
2
3
4
5
6
À50
À40
À30
À20
0
48
10
4
1.5
0.75
0.5
84
5/95
3/97
5/95
7/93
12/88
22/78
88 (82)c
79
76
44
14
23
a
b
c
NMR yield.
Determined by 1H NMR.
Isolated yield.

T. Uchino et al. / Carbohydrate Research 402 (2015) 118–123
121
ethanol or a solution of 10% phosphomolybdic acid in ethanol, fol-
lowed by heating at ca. 200 °C. Column chromatography (CC) was
performed on Merck silica gel 60 (63–200 or 40–63
l
m) and Kanto
Chemical silica gel 60 N (Spherical, neutral, 40–50 or 63–210
l
m).
The melting points were uncorrected. Optical rotations were
determined with a 100 mm cell at 589 nm. Infrared (IR) spectra
were recorded with a spectrophotometer equipped with an atten-
uated total reflectance sampling unit, and the major absorbance
bands are reported in wavenumbers (cmÀ1). High-resolution (HR)
MS were obtained for electrospray ionization (ESI). The data are
reported in units of mass to charge.
Scheme 3. Gram-scale synthesis of 8.
NMR spectra were recorded at 400 and 100 MHz for 1H and 13
C
NMR, respectively, and with either tetramethylsilane or residual
proton of deuterated solvent as internal reference in the indicated
solvent in each parenthesis. The 1H NMR data are indicated by a
chemical shift (d), with the multiplicity, the coupling constants,
and the integration in parentheses. The multiplicities are abbrevi-
ated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet; and br, broad. The 13C NMR data are reported as the
chemical shift (d). When the number of the carbon was more than
one, the number was added in the parentheses.
Scheme 4. Synthesis of glycosyl fluoride 1 from thioglucoside b-8.
1.2. Experimental procedures
1.2.1. Typical procedure for preparation of phenyl 2,4-di-O-
mosuccinimide (NBS) in DCM at À15 °C for 30 min,35 1 was
benzyl-1-thio-3,6-O-(o-xylylene)-b-
from pMP glucoside b-4 (Scheme 1a)
mixture of 4-methoxyphenyl glucoside b-4 (60.0 mg,
mol) and PhSH (12.8 mg, 117 mol) in DCM (2 mL) was stir-
red for 5 min at rt. To the mixture was added BF3ÁEt2O (7.5 mg
53 mol). The mixture was stirred for 2 h at rt. Addition of satu-
D-glucopyranoside (b-7)
obtained in a 95% yield as a mixture of anomers (a/b = 18/82).
In conclusion, we have established an efficient synthetic
method of 3,6-O-(o-xylylene) bridged thioglycoside 8 from ortho-
acetylglucose 3. The key point for this direct conversion was the
choice of the low reaction temperature, which prevented side reac-
tions including the formation of the corresponding furanoside 14.
For thiol, the reaction solvent, and activator, the adoption of ben-
zenethiol, DCM, and TMSOTf, respectively, was optimal. Direct
and efficient conversion of the phenylthioglucoside b-7, that was
dibenzylated b-8, to the corresponding fluoride 1 was also possible,
which reduced the previous number of synthetic steps for 1 by one.
The successful preparation of the thioglucoside possessing the 3,6-
O-(o-xylylene) bridge would expand the application of the con-
formationally locked carbohydrates to orthogonal synthesis pro-
viding oligosaccharides.
A
106
l
l
l
rated (satd) aqueous (aq) NaHCO3 (2 mL) quenched the reaction.
After extraction, the organic layer was successively washed with
satd aq NaHCO3, H2O, and brine. After the general drying proce-
dure, the crude product was purified by CC (2 g of SiO2, n-hex-
ane/EtOAc = 9:1) to afford b-7 (24.1 mg, 41%) as
a
colorless
15
amorphous solid [
a]
D
+15.9 (c 2.82, CHCl3); IR 3059, 3028, 2869,
1108, 1027, 738, 694 cm–1
;
1H NMR (CDCl3, 20.1 °C) d 7.46–7.26
(m, 13H), 7.24–7.10 (m, 6H), 5.58 (d, J = 9.9 Hz, 1H), 5.08 (d,
J = 10.1 Hz, 1H), 4.95 (d, J = 9.2 Hz, 1H), 4.80 (d, J = 11.9 Hz, 1H),
4.69 (d, J = 11.9 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.50 (d,
J = 11.9 Hz, 1H), 4.44 (dd, J = 1.4, 1.4 Hz, 1H), 4.31 (d, J = 9.9 Hz,
1H), 4.24 (d, J = 10.1 Hz, 1H), 4.17 (dd, J = 3.4, 3.0 Hz, 1H), 3.93
(dd, J = 3.0, 1.4 Hz, 1H), 3.84 (d, J = 13.7 Hz, 1H), 3.75 (dd, J = 13.7,
3.4 Hz, 1H), 3.69 (dd, J = 9.2, 1.4 Hz, 1H); 13C NMR (CDCl3,
20.1 °C) d 138.2, 137.8, 137.0, 136.4, 134.8, 130.8–126.7 (19C, ele-
ven peaks were observed), 85.1, 84.5, 81.5, 74.7, 74.5, 73.2, 71.8,
70.6, 70.4, 70.2; ESIHRMS (m/z) calculated (calcd) for C34H34O5SNa
[M+Na]+ 577.2025, found 577.2032.
1. Experimental
1.1. General methods
Commercially available reagents were used without further
purification except for NBS that was recrystallized from H2O and
dried prior to use. Moisture and air sensitive reactions were per-
formed in glassware equipped with rubber septa (or a septum)
under the positive pressure of argon or nitrogen. When necessary,
the glassware was dried under reduced pressure by heating with a
heat-gun and solvents were distilled prior to use. MSV were dried
under reduced pressure by heating with a heat-gun before use. The
reaction mixture was magnetically stirred. Concentration was per-
formed under reduced pressure.
The reactions were monitored by TLC and mass spectra (MS).
Ethyl acetate (EtOAc) was used as the organic layer in extraction.
Anhydrous MgSO4 or Na2SO4 were used to dry organic layers after
extraction, and it was removed by filtration through a cotton pad.
The filtrate was concentrated and subjected to further purification
protocols if necessary. This sequence was represented as ‘the gen-
eral drying procedure’ in the following experimental methods.
TLC was performed on Merck precoated silica gel 60 F-254
plates. Spots were visualized by exposure to ultraviolet (UV) light,
or by immersion into a solution of 2% anisaldehyde, 5% H2SO4 in
1.2.2. Thermal thioglycosylation of 8 (Scheme 1b)
A mixture of MSV 5A (33 mg), PPTS (4.5 mg, 18
lmol), PhSH
(108 mg, 978 mol), and 3 (50.0 mg, 163 mol) was stirred for
l
l
4 h at 100 °C. Addition of satd aq NaHCO3 (2 mL) quenched the
reaction. The mixture was filtered through a cotton-Celite pad to
remove MSV 5A. After extraction of the aq filtrate, the organic layer
was successively washed with satd aq NaHCO3, H2O, and brine.
After the general drying procedure, a mixture of the crude product
and NaOMe (26.4 mg, 490 lmol) in MeOH (3.26 mL) was stirred for
1 h at rt. After addition of 1 M hydrochloric acid (2 mL), the reac-
tion mixture was extracted. The organic layer was successively
washed with 1 M hydrochloric acid, H2O, and brine. After the gen-
eral drying procedure, a crude product (66.9 mg) was obtained as a
yellow solid. 1H NMR spectrum of the crude product showed that
yields of phenyl 1-thio-3,6-O-(o-xylylene)-a-D-glucopyranoside
(a-8) and b-8 were 13% and 30%, respectively. A part of b-8 was

122
T. Uchino et al. / Carbohydrate Research 402 (2015) 118–123
separated by recrystallization from a mixture of CHCl3 and n-hex-
ane. Pure -8 was obtained by HPLC (column, RMC-Pack R&D SIL,
D-SIL-5-A, 250 mm  20 mm; eluent, n-hexane/EtOAc = 3:1; flow
rate, 13.0 mL/min; detection, UV 254 nm; retention time, 50 min)
followed by recrystallization from a mixture of CHCl3 and n-
Entry 6: In a reaction similar to that described for Table 1, entry
1, the reaction temperature and time for the first step of this pro-
cedure were changed to 23 °C and 0.5 h, respectively, to provide a
crude product containing 8. The NMR yield of 8 was 14% (a/b = 22/
78).
a
hexane.
22
Data for
a
-8 mp 164.1–165.7 °C; [
a
]
À30.9 (c 0.27, CHCl3); IR
1.2.4. Examinations listed in Table 2
D
3382, 3060, 3008, 2935, 2878, 1088, 1011, 755 cmÀ1
;
1H NMR
Entry 1: To a stirred mixture of MSV 5A (978 mg), 3 (100 mg,
326 mol), and C2H5SH (28.3 mg, 456 mol) in DCM (3.3 mL)
was added TMSOTf (72.5 mg, 326
mol) at À40 °C. The mixture
(CDCl3, 22.5 °C) d 7.47–7.45 (m, 2H), 7.35–7.20 (m, 7H), 5.39 (d,
J = 1.4 Hz, 1H), 5.00 (d, J = 13.3 Hz, 1H), 4.88 (d, J = 10.3 Hz, 1H),
4.62 (d, J = 10.3 Hz, 1H), 4.56 (d, J = 13.3 Hz, 1H), 4.31 (br dd,
J = 9.9, 7.1 Hz, 1H), 4.23 (br s, 1H), 4.15 (dd, J = 9.9, 9.6 Hz, 1H),
4.00 (ddd, J = 6.6, 6.6, 1.4 Hz, 1H), 3.97 (br d, J = 6.6 Hz, 1H), 3.92
(dd, J = 9.6, 7.1 Hz, 1H), 3.61 (d, J = 6.6 Hz, 1H), 3.13 (d, J = 7.1 Hz,
1H); 13C NMR (CDCl3, 23.0 °C) d 137.3, 135.7, 134.6, 131.4, 131.0
(2C), 130.2, 129.3, 129.1, 128.5, 127.3, 81.9, 78.5, 74.7, 74.2, 71.5,
70.6, 68.1, 63.6; ESIHRMS (m/z) calcd for C20H22O5SNa [M+Na]+
l
l
l
was stirred for 13 h at À40 °C. After addition of satd aq NaHCO3
(2 mL), the mixture was filtered through a cotton-Celite pad to
remove MSV 5A. After extraction of the aq filtrate, the organic
layer was successively washed with satd aq NaHCO3, H2O, and
brine. The general drying procedure gave a crude product. A
mixture of the crude product and NaOMe (52.8 mg, 978 lmol)
in MeOH (6.6 mL) was stirred for 1 h at rt. Amberlite IR 120
(H+) ion exchange resin was added until the pH of the mixture
was neutral. After filtration of the mixture through a cotton
pad, the filtrate was concentrated to give a crude product con-
397.1086, found 397.1080.
25
Data for b-8 mp 102.8–104.9 °C; [
a]
À73.2 (c 0.50, CHCl3); IR
D
3384, 2870, 1109, 1078, 1052, 1024, 958, 740 cmÀ1; 1H NMR (CD3-
OD, 25.1 °C) d 7.50–7.47 (m, 2H), 7.29–7.14 (m, 7H), 5.56 (d,
J = 9.9 Hz, 1H), 5.22 (d, J = 10.3 Hz, 1H), 4.84 (d, J = 8.7 Hz, 1H),
4.71 (br s, 1H), 4.40 (d, J = 10.3 Hz, 1H), 4.31 (d, J = 9.9 Hz, 1H),
4.03 (br d, J = 3.2 Hz, 1H), 3.87 (dd, J = 13.7, 3.2 Hz, 1H), 3.81 (br
d, J = 13.7 Hz, 1H), 3.80 (br s, 1H), 3.69 (dd, J = 8.7, 0.7 Hz, 1H);
13C NMR (CD3OD, 25.4 °C) d 138.5, 138.3, 136.3, 131.8 (2C),
130.3, 129.8 (2C), 129.5, 128.7, 128.6, 128.1, 88.0, 87.7, 81.4,
75.7, 75.1, 71.5, 71.4, 64.6; ESIHRMS (m/z) calcd for C20H22O5SNa
[M+Na]+ 397.1086, found 397.1102.
taining ethyl 1-thio-3,6-O-(o-xylylene)-D-glucopyranoside (15).
The NMR yield of b-15 was 5%. CC (5 g of SiO2, n-hexane/
24
EtOAc = 5:1 to 2:1) separated a part of b-15 in pure form [
+16.4 (c 0.225, CHCl3); IR 3380, 2928, 2870, 1114, 1023,
962 cmÀ1 1H NMR (CDCl3, 20 °C) d 7.21–7.11 (m, 4H), 5.56 (d,
a]
D
;
J = 10.0 Hz, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.79 (br s, 1H), 4.49
(d, J = 8.4 Hz, 1H), 4.42 (d, J = 10.4 Hz, 1H), 4.33 (d, J = 10.0 Hz,
1H), 4.06 (br d, J = 2.4 Hz, 1H), 3.90 (dd, J = 13.8, 3.0 Hz, 1H),
3.86–3.80 (m, 3H), 2.75–2.64 (m, 3H), 2.53 (br s, 1H), 1.29 (t,
J = 7.6 Hz, 3H); 13C NMR (CDCl3, 20 °C) d 137.0, 136.3, 129.5,
128.7, 127.9, 127.8, 86.9, 84.8, 78.5, 75.0, 74.5, 71.0, 70.5, 64.8,
1.2.3. Examinations listed in Table 1
Entry 1: To a stirred mixture of MSV 5A (489 mg), 3 (50.0 mg,
25.0, 15.2; ESIHRMS (m/z) calcd for C
16H22O5SNa [M+Na]+
163
lmol), and PhSH (25.2 mg, 229
lmol) in DCM (1.6 mL) was
349.1086, found 349.1086.
added TMSOTf (36.3 mg, 163
l
mol) at À50 °C. The mixture was
Entry 2: In a reaction similar to that described for Table 2, entry
1, the use of 1-dodecanethiol (92.4 mg, 456 mol) provided a crude
product containing dodecyl 1-thio-3,6-O-(o-xylylene)- -glucopy-
stirred for 48 h at À50 °C. After addition of satd aq NaHCO3
(2 mL), the reaction mixture was filtered through a cotton-Celite
pad to remove MSV 5A. After extraction of the aq filtrate, the
organic layer was successively washed with satd aq NaHCO3,
H2O, and brine. The general drying procedure gave a crude product.
l
D
ranoside (16). The NMR yield of b-16 was 24%. CC (5 g of SiO2, n-
hexane/EtOAc = 5:1 to 2:1) separated a part of b-16 in pure form
23
[a]
+2.03 (c 1.0, CHCl3); IR 3395, 2923, 2853, 1118, 964,
D
A mixture of the crude product and NaOMe (26.4 mg, 490
l
mol) in
751 cmÀ1 1H NMR (CDCl3, 20 °C) d 7.21–7.11 (m, 4H), 5.55 (d,
;
MeOH (3.3 mL) was stirred for 1 h at rt. After addition of 1 M
hydrochloric acid (2 mL), the aq mixture was extracted. The
organic layer was successively washed with 1 M hydrochloric acid,
H2O, and brine. The general drying procedure gave a crude product.
1H NMR spectrum of the crude product showed that the yields of
J = 10.0 Hz, 1H), 5.20 (d, J = 10.0 Hz, 1H), 4.75 (br s, 1H), 4.45 (d,
J = 8.0 Hz, 1H), 4.41 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 10.0 Hz, 1H),
4.03 (br d, J = 2.4 Hz, 1H), 3.88 (dd, J = 13.4, 3.0 Hz, 1H), 3.84–
3.78 (m, 3H), 2.83 (d, J = 7.6 Hz, 1H), 2.74 (d, J = 5.6 Hz, 1H),
2.68–2.64 (m, 2H), 1.66–1.58 (m, 2H), 1.36–1.20 (m, 18H), 0.88
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 20 °C) d 140.0, 136.3, 129.4,
128.7, 127.9, 127.8, 86.9, 85.0, 78.5, 75.0, 74.6, 71.0, 70.5, 64.7,
32.0, 31.0, 30.1, 29.8, 29.7, 29.7, 29.6, 29.5, 29.3, 29.0, 22.8, 14.2;
ESIHRMS (m/z) calcd for C26H42O5SNa [M+Na]+ 489.2651, found
489.2644.
a-8 and b-8 were 4% and 80%, respectively; the anomeric ratio
was /b = 5/95.
a
Entry 2: In a reaction similar to that described for Table 1, entry
1, the reaction temperature and time for the first step of this pro-
cedure were changed to À40 °C and 10 h, respectively, to provide a
crude product containing 8. The NMR yield of 8 was 88% (
a/b = 3/
Entry 4: In a reaction similar to that described for Table 2, entry
97). Purification by CC (2 g of SiO2, n-hexane/EtOAc = 5:1 to 2:1)
afforded b-8 (50.1 mg, 82%) as a white powder.
1, the use of 2-methylbenzenethiol (56.6 mg, 456
crude product containing o-tolyl 1-thio-3,6-O-(o-xylylene)-
lmol) provided a
D-
Entry 3: In a reaction similar to that described for Table 1, entry 1,
the reaction temperature and time for the first step of this procedure
were changed to À30 °C and 4 h, respectively, to provide a crude
glucopyranoside (17). The NMR yield of b-17 was 29%. CC (5 g of
SiO2, n-hexane/EtOAc = 5:1 to 2:1) separated a part of b-17 in pure
25
form [
a]
À20 (c 0.16, CHCl3); IR 3395, 3017, 2924, 2857, 1112,
D
product containing 8. The NMR yield of 8 was 79% (
a
/b = 5/95).
1051, 1025, 748 cm–1 1H NMR (CDCl3, 20 °C) d 7.49–7.45 (m,
;
Entry 4: In a reaction similar to that described for Table 1, entry 1,
the reaction temperature and time for the first step of this procedure
were changed to À20 °C and 1.5 h, respectively, to provide a crude
1H), 7.24–7.09 (m, 7H), 5.62 (d, J = 10.4 Hz, 1H), 5.24 (d,
J = 10.0 Hz, 1H), 4.84 (br s, 1H), 4.78 (d, J = 8.4 Hz, 1H), 4.44 (d,
J = 10.0 Hz, 1H), 4.35 (d, J = 10.4 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H),
3.96–3.85 (m, 3H), 3.88 (br s, 1H), 2.63 (d, J = 8.0 Hz, 1H), 2.40 (s,
3H), 2.38 (d, J = 5.6 Hz, 1H); 13C NMR (CDCl3, 20 °C) d 138.6,
137.0, 136.2, 134.2, 130.2, 129.4, 129.1, 128.7, 127.9, 127.8,
127.1, 126.6, 86.7, 86.5, 78.5, 75.0, 74.4, 71.1, 70.4, 64.9, 20.8; ESI-
HRMS (m/z) calcd for C21H24O5SNa [M+Na]+ 411.1242, found
411.1238.
product containing 8. The NMR yield of 8 was 76% (a/b = 7/93).
Entry 5: In a reaction similar to that described for Table 1, entry
1, the reaction temperature and time for the first step of this pro-
cedure were changed to 0 °C and 0.75 h, respectively, to provide a
crude product containing 8. The NMR yield of 8 was 44% (a/b = 12/
88).

T. Uchino et al. / Carbohydrate Research 402 (2015) 118–123
123
Entry 5: In a reaction similar to that described for Table 2, entry
1, the use of 4-methylbenzenethiol (56.6 mg, 456 mol) provided a
crude product containing p-tolyl 1-thio-3,6-O-(o-xylylene)-
as a mixture of anomers (
a
/b = 18/82). The 1H and 13C NMR spec-
l
tral data were identical to those of the reported data.24
D
-
glucopyranoside (18). The NMR yield of b-18 was 29%. CC (5 g of
Acknowledgments
SiO2, n-hexane/EtOAc = 5:1 to 2:1) separated a part of b-18 in pure
22
form: [
a]
À33.5 (c 0.88, CHCl3); IR 3396, 3018, 2923, 2870, 1118,
We thank Mr. Hajime Yamamoto for his support in several
experiments. The ministry of education, culture, sports, science
and technology-supported program for the strategic research foun-
dation at private universities (S1311046), Mizutani foundation for
glycoscience, and mutual aid corporation-supported science
research promotion fund partly supported this work.
D
1026, 754 cmÀ1 1H NMR (CDCl3, 20 °C) d 7.37 (d, J = 7.6 Hz, 2H),
;
7.23–7.17 (m, 2H), 7.15–7.09 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H),
5.57 (d, J = 10.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.73–4.67 (m,
2H), 4.36 (d, J = 10.4 Hz, 1H), 4.35 (d, J = 10.0 Hz, 1H), 4.01 (br s,
1H), 3.85 (br d, J = 0.8 Hz, 2H), 3.85–3.81 (br m, 1H), 3.76 (br d,
J = 2.8 Hz, 1H), 3.01 (d, J = 8.0 Hz, 1H), 2.87 (d, J = 4.8 Hz, 1H),
2.27 (s, 3H); 13C NMR (CDCl3, 20 °C) d 137.6, 137.0, 136.3, 131.5
(2C), 130.7, 129.7 (2C), 129.4, 128.8, 127.9, 127.8, 87.6, 86.6,
78.6, 75.0, 74.2, 71.0, 70.4, 64.7, 21.2; ESIHRMS (m/z) calcd for C21-
H24O5SNa [M+Na]+ 411.1242, found 411.1249.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.
10.004.
Entry 6: In a reaction similar to that described for Table 2, entry
1, the use of 4-nitrobenzenthiol (71.0 mg, 456 lmol) provided a
crude product. The reaction time was 24 h for the first step of this
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1.2.6. 2,4-Di-O-benzyl-3,6-O-(o-xylylene)-D-glucopyranosyl
fluoride (1)
To a solution of thioglycoside b-7 (16.0 mg, 28.8
(500 L) was added Et2NSF3 (7.3 mg, 45
mol) at À15 °C, and the
mixture was stirred for 2 min. To this mixture was added NBS
(7.0 mg, 39
lmol) in DCM
l
l
lmol) at À15 °C, and the mixture was stirred for
30 min at the same temperature. EtOAc (15 mL) was added to
the mixture to dilute, and the mixture was poured into satd aq
NaHCO3 (10 mL) on ice. The organic layer was separated and suc-
cessively washed with satd aq NaHCO3, H2O, and brine. After the
general drying procedure, the resulting crude product was purified
by CC (2 g of SiO2, n-hexane/EtOAc = 9:1) to afford 1 (12.7 mg, 95%)