α-Selective Glycosylation of 3,6- O - O -Xylylene-Bridged Glucosyl Fluoride

Article abstract of DOI:10.1055/s-0036-1590927

A 1,2- cis -(α)-selective glycosylation has been developed. An ortho -xylylene group bridged between 3-O and 6-O of d -glucosyl fluoride, which straddles the β-face of the pyranose ring, hinders the ?-approach of glycosyl acceptors from that face. The det

Full text of DOI:10.1055/s-0036-1590927

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–M
paper
A
en
A. Motoyama et al.
Paper
Synthesis
α-Selective Glycosylation of 3,6-O-o-Xylylene-Bridged Glucosyl
Fluoride
Atsushi Motoyama
Tomoki Arai
Kazutada Ikeuchi
Kazuya Aki
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Shinnosuke Wakamori
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Hidetoshi Yamada*
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School of Science and Technology, Kwansei Gakuin University,
2-1 Gakuen, Sanda 669-1337, Japan
hidetosh@kwansei.ac.jp
Received: 10.08.2017
Accepted after revision: 12.09.2017
Published online: 09.10.2017
workers reported more aggressive methods for controlling
the direction of the participation exploiting protecting
groups bearing an asymmetric carbon (a-2).9 The second
method (b) is intramolecular aglycon delivery.10 In this
method, an aglycon is first installed to a hanger (Q in the
structure) on an oxygen of the glycosyl donor, where the
oxygen orients to a desired face of the pyranose ring, and
then migrates with retention of the face to the anomeric
position. For the hanger, atoms such as Si,11 C,10b,12 and B,13
and molecular clamps14 are applied. The third method (c)
involves the dragging of a glycosyl acceptor by hydrogen
bonding. Demchenko and co-workers have reported a re-
markable dragging effect of the nitrogen atom of pyridine,
as illustrated in Figure 1, c.15 The fourth method (d) relies
simply on steric hindrance of the approach of the glycosyl
acceptor,16 on which we report herein.
Previously, we reported a complete 1,2-trans-(β)-selec-
tive glycosylation reaction without NGP by adopting 3,6-O-
o-xylylene-bridged glycosyl fluoride 1 (Figure 1, e).17 This
reaction consists of glycosylation and isomerization cycles,
catalyzed respectively by SnB(C6F5)4Cl and HB(C6F5)4, both
generated in situ. The 1,2-trans-selectivity arises thermo-
dynamically in the isomerization cycle because of the steric
repulsion between α-O-1 and O-2. Here, both the oxygens
orient axially to the α-face of the pyranose due to the re-
stricted conformation resulting from the o-xylylene bridge.
On the other hand, the drawn scheme for 1, in which the
bridge covers the β-face of the pyranose ring, is expected to
induce 1,2-cis-(α)-selectivity if its actual structure is as
drawn. Here, we report the development of a 1,2-cis-(α)-
selective glycosylation using 1.
DOI: 10.1055/s-0036-1590927; Art ID: ss-2017-f0519-op
Abstract A 1,2-cis-(α)-selective glycosylation has been developed. An
ortho-xylylene group bridged between 3-O and 6-O of D-glucosyl fluo-
ride, which straddles the β-face of the pyranose ring, hinders the
approach of glycosyl acceptors from that face. The determination of the
three-dimensional structure of the bridged glucosyl fluoride, the opti-
mization process of the reaction conditions oriented toward kinetic
control to realize the high α-selectivity, and the scope of the reaction
are described.
Key words glycosylation, 1,2-cis-selectivity, kinetic control, confor-
mation, o-xylylene bridge
The structures of aldopyranosides can be divided into
four types on the basis of the orientation of O-2 (axial or
equatorial) and the relative configuration between C-1 and
C-2 (trans or cis) (Figure 1).1 Thus, the classes correspond to
(i) axially oriented O-2 and 1,2-trans type (ax-O2/trans) as
α-D-mannosides, (ii) equatorially oriented O-2 and 1,2-
trans type (eq-O2/trans) as β-D-glucosides, (iii) ax-O2/cis as
β-D-mannosides, and (iv) eq-O2/cis as α-D-glucosides (Fig-
ure 1). Among the four, the synthesis of 1,2-trans-glyco-
sides (types i and ii) is reliable because of the inherent
preference for ax-O2/trans-glycosides2 and the existence of
the neighboring group participation (NGP) method for
eq-O2/trans-glycosides.3 In contrast, the synthesis of 1,2-
cis-glycosides (types iii and iv) is difficult. Although classic
methods achieve 1,2-cis-selectivity, the origin of the selec-
tivity is often unclear.4 Therefore, chemists have tested a
variety of working hypotheses.5
Among the hypotheses, successful methods for the in-
duction of eq-O2/cis stereoselectivity can be roughly classi-
fied into four categories (Figure 1, a–d). The first method (a)
utilizes facial selective intramolecular participation of a
protecting group,6–8 similar to NGP. Recently, Boons and co-
We first determined the three-dimensional structure of
1 on the basis of NMR studies and chemical calculation. In
the NMR studies, the correlation between H-1 and H-5 in
the NOESY spectrum indicated the axial orientation of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

B
A. Motoyama et al.
Paper
Synthesis
Classification of aldopyranosides
OH
O
OH
O
O
O
OR
OR
1
(OH)n
(OH)n
2
(OH)n
(OH)n
OH
HO
OR
OR
(i)
(iii)
ax-O2/cis
(iv)
(ii)
ax-O2/trans
eq-O2/cis
eq-O2/trans
a-1
R
a-2
O
NGP
O
HOR
+
O
O
O
+
O
O
O
O
O
+
O
O
S
O
O
Ph
H
H
H
H
Ph
O
R
O
HOR
O
O
O
c
b
d
O
X
+
O
O
BULKY
O
+
Substituent
O
O
O
+
OR
O
H
OR
O
O
O
H
H
O
N
Q
O
HOR
e
SnCl2
+
AgB(C6F5)4
O
O
O
SnB(C6F5)4Cl
ROH
O
O
O
O
HB(C6F5)4
O
O
OR
β-only
OBn
Figure 2 Conformational representation of 1 (a) and the oxocarbeni-
um ion intermediate derived from 1 (b). (a) Left: Observed long-range
coupling (blue arrow) and selected NOESY correlations (red arrows).
† The most reasonable value is listed between solutions given by the
modified Karplus equation. Right: Composite view of calculated con-
formers: the color strength reflects the Boltzmann distributions of each
conformer. § Weighted average based on the Boltzmann distribution of
conformers. (b) Composite view of calculated conformers: the color
strength reflects the Boltzmann distributions of each conformer
isomerization
cycle
glycosylation
cycle
F
OR
BnO
BnO
BnO
OBn
BnO
1
Figure 1 Classification of aldopyranosides, neighboring group
participation (NGP), (a–d) methods for induction of eq-O2/stereoselec-
tivity [(a) facial selective intramolecular participation, (b) intramolecular
aglycon delivery, (c) dragging of glycosyl acceptors, (d) use of steric hin-
drance], and (e) completely β-selective glycosylation by adopting 3,6-O-
o-xylylene-bridged glucosyl fluoride 1
3
these protons (Figure 2, a, left). JH–H values provided dihe-
(Figure 2, b). In Figure 2, the top 10 stable conformers are
displayed. The potential energy range of the conformers is
within 8.56 kJ/mol.
dral angles of the adjacent C–H bonds on the pyranose
ring.18 A molecular model assembled on the basis of the an-
1
4
gles had a S3 pyranose ring. A JH–H coupling between H-2
and H-4 (0.7 Hz) supported the ring conformation.
To obtain high α-selectivity exploiting the steric hin-
drance over the β-face, kinetic reaction conditions are re-
quired because the corresponding glucosides converge to
the β-isomer under thermodynamic conditions (Figure 1, e
and Table 1, entry 1).17 Thus, we surveyed the α/β ratio of
the glycosylation reaction of 1 with cyclohexylmethanol (2)
under several reported conditions for the activation of gly-
cosyl fluorides (Table 1, entries 2–7).20 Among them, the
use of AgClO4 and AgOTf provided more of the α-isomer
than the β-isomer (entries 4–7). For the second survey of
the reagents, the adoption of various Lewis acids with
AgClO4 was tested (Table 1, entries 8–15).20a,f,g In these tests,
the reactions were started at –25 °C. When the reaction
was quite slow at –25 °C, the temperature was raised. The
results indicated that various Lewis acids activated 1 with
α-selectivity. Among the Lewis acids tested, Cp2ZrCl2 (entry
10) gave the best α-selectivity; therefore, on the basis of
this condition, the optimization of the reaction was contin-
ued.
The model illustrated in Figure 2, a, right was rendered
computationally using Spartan 14 software. In the calcula-
tion, a molecular force field calculation was used to obtain
the distribution of conformers, and then each conformer
within 16.75 kJ/mol from the most stable one was opti-
mized applying the DFT calculation at the B3LYP/6-31G*
level in vacuo.19 Figure 2 displays the top eight stable con-
formers after the DFT calculations. The potential energy
range of the eight is within 7.75 kJ/mol, which suggests the
existence of a rigid 3,6-O-o-xylylene-bridged pyranose and
flexible benzyl groups. The calculated dihedral angles were
reasonably consistent with those derived from the NMR
studies. Hence, the o-xylylene moiety stands upright to the
β-face of the pyranose ring and might become a steric hin-
drance for the approach of an alcohol. Similar calculation of
the corresponding oxocarbenium ion intermediate indicat-
ed that the bridge could be steric hindrance over the β-face
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

C
A. Motoyama et al.
Paper
Synthesis
Table 1 Reagent Survey
Table 2 Solvent Selection
solvent
1
+
2
3
Cp2ZrCl2, AgClO4
MS 4A
O
O
O
O
reagents
HO
O
O
Entry
Solvent
Temp
Yield (%)
α/β Ratio
+
F
O
MS 4A
1
2
pyridine
DMF
–25 °C
trace
0
–
Et2O
BnO
BnO
OBn
OBn
3
1
2
0
–
Entry Reagents
Temp
rt
Yield (%)
α/β Ratio
3
toluene
benzene
DCM
rt
83
96
69
52
87
58
37
81
20
1:>99
40:60
46:54
41:59
56:44
94:6
90:10
90:10
36:64
1a,b
2
SnCl2, AgB(C6F5)4
96
70
88
83
85
82
94
50
25
89
91
78
63
79
47
1:>99
1:>99
31:69
58:42
62:38
60:40
73:27
74:26
77:23
89:11
61:39
70:30
88:12
69:31
80:20
4
rt
5
rt
TMSOTf
–25 °C
–25 °C
rt
6
MeCN
DME
rt
3
BF3·OEt2
4b
5
SnCl2, AgClO4
SnCl2, AgClO4
SnCl2, AgOTf
Cp2ZrCl2, AgClO4
Sc(OTf)3, AgClO4
Cp2TiCl2, AgClO4
Cp2ZrCl2, AgClO4
7
–25 °C
–25 °C
–25 °C
–25 °C
–25 °C to rt
8
i-Pr2O
t-BuOMe
CPME
rt
9
6
rt
10
11
7
rt
Me2S
8
–25 °C
–25 °C to rt
–25 °C
–25 °C
–25 °C to rt
–25 °C to rt
–25 °C to rt
–25 °C
9
10
when Et2O was used, but the yield was decreased. The reac-
tion in Me2S gave 3 in poor yield and the selectivity moved
to slightly β (Table 2, entry 11). Hence, Et2O was adopted for
the subsequent investigations.
11
12
13
14
15
Cp2Zr(OTf)2, AgClO4
Cp2HfCl2, AgClO4
Tb(OTf)3, AgClO4
Er(OTf)3, AgClO4
Yb(OTf)3, AgClO4
We then obtained information regarding a change of the
silver salt counteranion (Table 3). The reaction with AgBF4
(entry 1) produced 3 in a highly β-selective manner, indi-
cating that this combination of the reagents induced ano-
meric isomerization. Adoption of AgB(C6H5)4 gave a 1:1
mixture of the anomers (entry 2). This result is in contrast
to that obtained by the use of AgBF4, although both are sil-
ver borates. Similarly, AgSbF6 provided a 1:1 mixture (entry
3). Only a trace of the ion signal for 3 was detected in mass
spectra in the reactions with Ag2CO3 and Ag2SO4 (entries 4
a Molecular sieves 5A were used.
b Benzotrifluoride (BTF) was used as the solvent.
The optimization using Cp2ZrCl2 and AgClO4 as the acti-
vator of 1 began with an investigation of the reaction sol-
vent (Table 2). Among them, entries 1–6 are the results
when the type of solvent was varied; in entries 7–11, vari-
ous (thio)ethers were used. Thus, in pyridine or DMF, the
reaction was quite slow (Table 2, entries 1 and 2). The use of
toluene induced complete β-selectivity (entry 3). In con-
trast, the reaction in benzene was slightly β-selective (entry
4). Similar moderate β-selectivity was observed when DCM
or acetonitrile was the solvent (entries 5 and 6). Therefore,
none of the tested solvents provided better α-selectivity
than Et2O at room temperature (α/β = 73:27; Table 1, entry
7). The use of other ethers was also investigated. DME did
not induce remarkable α-selectivity (Table 2, entry 7). Re-
actions in i-Pr2O, t-BuOMe, and cyclopentyl methyl ether
(CPME) provided α-selectivity better than α/β = 9:1 (Table
2, entries 8–10), which in turn were better than Et2O at
–25 °C (Table 1, entry 10). However, the melting point of
i-Pr2O is –60 °C, which would limit further investigations at
varied reaction temperature. The use of t-BuOMe resulted
in poor yield (37% yield with 38% recovery of the starting
material 1) because of poor solubility of 1 in the solvent.
When CPME was used, the stereoselectivity was similar to
Table 3 Variation of the Silver Salt Anion
AgX
1
+
2
3
Cp2ZrCl2
Et2O, MS 4A
Entry
AgX
Temp
Yield (%)
α/β Ratio
1
2
3
4
5
6
7
8
AgBF4
–25 °C
87
2:98
49:51
50:50
–
AgB(C6F5)4
AgSbF6
rt
70
–25 to 0 °C
–25 °C to rt
–25 °C to rt
rt
73
Ag2CO3
Ag2SO4
trace
trace
90
–
AgOTf
65:35
78:22
79:21
AgOCOCF3
AgNO3
–25 to 0 °C
–25 °C to rt
58
70
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

D
A. Motoyama et al.
Paper
Synthesis
and 5). AgOTf, AgOCOCF3, and AgNO3 induced α-selectivity
(entries 6–8), but the selectivities were lower than that
with AgClO4 (Table 1, entry 10). Collectively, the use of AgClO4
had advantages.
To investigate the effect of molecular sieves (MS) (Table
4), the use of MS 3A, 5A, or 13X was tested (entries 1–4),
but all results were less selective than when MS 4A was em-
ployed. Additionally, the reaction was carried out without
molecular sieves for comparison, and complete β-selectivity
was obtained (entry 5), which demonstrates the occurrence
of anomeric isomerization. Thus, molecular sieves might
act as an acid scavenger.
Changing the amounts of the reagents was ineffective.
Thus, doubling (5.0 and 10.0 equiv for Cp2ZrCl2 and AgClO4,
respectively) provided 3 quantitatively with a 96:4 α/β
ratio, a result which was close enough to the optimized one
(Table 5, entry 5) where 2.5 and 5.0 equivalents of Cp2ZrCl2
and AgClO4, respectively, were used. When both the re-
agents were decreased to 1.5 equivalents, the reaction de-
celerated drastically.
The effect of the o-xylylene group in obtaining the α-
selectivity was confirmed by using the glucosyl fluoride 4
with a (Z)-2-butenylene group21 bridged between the 3-O
and 6-O (Scheme 1). Compound 4 was synthesized from
1,2,4-O-orthoacetyl-D-glucose (5). Thus, double etherifica-
tion of 5 with (Z)-1,4-dichloro-2-butene furnished 6 in 34%
yield. Thermal cleavage of the orthoester in 6 associated
with the introduction of a 4-methoxyphenyloxy group to
the anomeric position followed by MS 4A mediated metha-
nolysis of the acetyl group,22 which arises from the ortho-
ester, yielded diol 7 as the β-isomer. Benzylation of 7 gave 8.
Oxidative removal of the 4-methoxyphenyl group from 8
with Ce(SO4)2 followed by fluorination of the anomeric
position of 9 with (diethylamino)sulfur trifluoride (DAST)
afforded 4 as a mixture of diastereomers (α/β = 7:93). The
predominance of the β-isomer was determined on the basis
of the NOE correlation between H-1 and H-5 of the major
Table 4 Effect of Molecular Sieves
MS
1
+
2
3
Cp2ZrCl2, AgClO4
Et2O, –25 °C
Entry
MS
Yield (%)
α/β Ratio
1
3A
58
89
28
64
80
86:14
89:11
78:22
87:13
1:>99
2a
3
4A
5A
4
13X
none
5
1
isomer in C6D6. The pyranose ring of β-4 was S3 form, the
a Copy of Table 1, entry 10.
conformation of which was determined on the basis of the
3JH–H values observed for hydrogens on the pyranose ring.
The glycosylation reaction of 4 with cyclohexylmethanol
(2) produced the corresponding glucoside 10 with 24:76
α/β-selectivity at –20 °C. Although the optimal temperature
was –60 °C with 1, no reaction occurred with 4 even when
the temperature was –40 °C. The moderate β-selectivity
clearly demonstrates that the o-xylylene group has a key
role in hindering the β-face of the pyranose. The pyranose
rings of α- and β-10 were 1C4 and 1S3 form, respectively, the
conformation of which were determined on the basis of the
3JH–H values with information derived by chemical calcula-
tions. As additional information, β-10 is unstable on silica
gel, the details of which are described in the Supporting In-
formation, Section 4.4.
Finally, the effect of the reaction temperature was inves-
tigated (Table 5). The peak of the α-selectivity (α/β = 97:3)
was obtained when the temperature was –60 °C (entry 5).
At –78 °C, both the reaction rate and the α-selectivity de-
creased (entry 6). Therefore, the optimized reaction condi-
tions were concluded to be as follows: 1 (1.0 equiv), 2 (1.2
equiv), Cp2ZrCl2 (2.5 equiv), AgClO4 (5.0 equiv), and MS 4A
(3.0 g/mmol) in Et2O at –60 °C.
Table 5 Effect of Temperature
Temp
1
+
2
3
Cp2ZrCl2, AgClO4
MS 4A, Et2O
Table 6 summarizes the scope of the glycosyl acceptor.
The optimized reaction conditions (Table 5, entry 5) were
applied to each glycosyl acceptor listed. The reaction at 6-
OH of a glucose derivative (Table 6, entry 1) provided the
corresponding disaccharide 11 in 76% yield with a >97:3
α/β ratio. The α-selectivity was similar to that observed in
the reaction with 2. Entries 2 to 5 show the results of the
reactions with secondary alcohols. In the reactions with
each enantiomer of menthol (entries 2 and 3), a difference
in stereoselectivity was observed. Thus, the reaction with
(+)-menthol proceeded with higher α-selectivity (entry 2,
α/β = 89:11) than the reaction with the (–)-isomer (entry 3,
α/β = 72:28). The matching and mismatching effect of the
Entry
Temp
Yield (%)
α/β Ratio
1a
2
rt
94
82
89
91
93
25
73:27
73:27
89:11
94:6
0 °C
–25 °C
–50 °C
–60 °C
–78 °C
3b
4
5
97:3
6
84:16
a Copy of Table 1, entry 7.
b Copy of Table 1, entry 10.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

E
A. Motoyama et al.
Paper
Synthesis
Table 6 Scope of the α-Selective Glycosylation
a
OH
O
O
NaH
HO
O
p-HO-C6H4-OMe
100 °C, 11.5 h;
O
Cl
Cl
ROH
Cp2ZrCl2 (2.5 equiv)
AgClO4 (5.0 equiv)
MS 4A (3.0 g/mmol)
toluene, DMF
80 °C, 4 h;
rt, 11.5 h
34%
O
O O
MS 4A, MeOH
reflux, 20 h
39%
O
O
O
O
O
O
1
CH3
CH3
5
6
OR
Et2O, –60 °C
BnO
OBn
O
11–16
O
O
O
NaH, BnBr
O
O
O
O
Entry ROH
Time
(h)
Yielda (%),
Glucoside
DMF
70 °C, 2.5 h
100%
α/β ratiob
BnO
HO
OBn
OH
OMe
OMe
7
8
OH
O
BnO
BnO
1
24
76,c >97:3
11
O
O
O
O
α/β = 7:93
BnO
O
DAST
Ce(SO4)2
OMe
5
O
F
THF, 0 °C, 0.5 h
88%
MeCN, H2O, rt
74%
1
OH
OBn
H
H
BnO
BnO
BnO
2
3
2
2
86, 89:11
86, 72:28
12
13
9
HO
HO
NOESY
β-isomer: 1S3
4
b
O
O
2, Cp2ZrCl2, AgClO4
α/β = 24:76
MS 4A
O
4
O
Et2O, –20 °C, 7 h
H
BnO
H
H
4
2
77,d 79:21
14
OBn
10
α-isomer:1
β-isomer:1
H
C4
S3
HO
H
Scheme 1 (a) Synthesis of 4 equipped with a (Z)-2-butenylene group.
(b) Glycosylation reaction of 4
OBn
O
HO
5
6
24
24
12, >99:1
66,e 86:14
15
16
BnO
BnO
OMe
enantiomers could explain the difference.23 The α/β ratio
(79:21) of 14 provided by the reaction with β-cholestanol
(entry 4) was between the results of entries 2 and 3. The
hydroxy group at the 4-position of a glucose derivative
(entry 5) reacted with a low isolated yield (12%) of 15, while
the α-selectivity was perfect. The reaction with a tertiary
alcohol, 1-adamantanol, proceeded in a moderately α-
selective manner to give 16 (entry 6, α/β = 86:14).
HO
a Isolated yield of the anomeric mixture.
b Determined by 1H NMR spectroscopy, after isolation of the glucoside as the
anomeric mixture.
c 2% of 1 was unreacted.
d 12% of 1 was unreacted.
e 32% of 1 was unreacted.
In summary, we have developed a highly α-selective re-
action using the o-xylylene group as the steric hindrance
for the approach of glycosyl acceptors. The o-xylylene group
bridging the 3-O and 6-O of the glucopyranosyl ring stands
upright to the β-face of the pyranose ring, as the computer
calculations and the NMR studies suggest, and generates
the steric hindrance. The optimization process could be un-
derstood as the search for discovering the kinetic reaction
conditions that inhibit isomerization of the resulting α-
glycosides to the β-isomers. The 3,6-O-o-xylylene bridge
generates steric hindrance over the β-face, while the bridge
locks the conformation of the pyranose ring to orient the 2-O
of the glucose axially, which causes steric hindrance at the
α-face. Because of the steric hindrance at both faces, selec-
tivity was achieved by control that diminishes reactivity as
a whole, which presumably is the reason for the stagnant
chemical yields in the reactions with sterically hindered al-
cohols.
All commercially available reagents were used without further purifi-
cation. Reactions were performed under a positive pressure of N2, un-
less otherwise noted. When necessary, glassware was dried under re-
duced pressure by heating with a heat gun. Reaction mixtures were
magnetically stirred. Concentration was performed under reduced
pressure. The reactions were monitored by TLC and mass spectrome-
try. Anhydrous MgSO4 was used to dry organic layers after extraction
and was removed by filtration through a cotton pad. The filtrate was
concentrated and subjected to further purification protocols if neces-
sary. This sequence is represented as ‘the general drying procedure’ in
the experimental section. TLC was performed on Merck precoated sil-
ica gel 60 F-254 plates. Spots were visualized by exposure to UV light,
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A. Motoyama et al.
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Synthesis
or by immersion into a solution of 2% anisaldehyde, 5% H2SO4 in EtOH,
followed by heating at ca. 200 °C. Column chromatography (CC) was
performed on Merck silica gel 60 (0.063–0.200 or 0.040–0.063 mm)
or Kanto Chemical silica gel 60 N (spherical, neutral, 40–50 or 63–210
μm). Melting points were determined using a Yanagimoto micro
melting point apparatus and are uncorrected. Optical rotations were
determined using a JASCO DIP-370 polarimeter with a 100-mm cell at
589 nm. For IR spectra, the major absorbance bands are reported in
wavenumbers (cm–1). HRMS data were obtained on a JEOL JMS-
T100LC spectrometer. NMR spectra were recorded on JEOL JNM-ECX-
400 or JNM-ECX-500 spectrometers at 400 or 500 MHz for 1H NMR
and 100 or 126 MHz for 13C NMR, respectively, with either TMS or re-
sidual proton of the deuterated solvent as internal reference in the in-
dicated solvent. The 1H NMR data are indicated by chemical shifts (δ),
with the multiplicity (standard abbreviations), the coupling con-
stants, and the number of protons in parentheses. The 13C NMR data
are reported as the chemical shifts (δ) with the hydrogen multiplicity
in parentheses (s, C; d, CH; t, CH2; q, CH3) obtained from the DEPT
spectra. When the number of carbons was more than one, the num-
ber has been added in parentheses.
Table 1, Entry 5
In a reaction similar to that of Table 1, entry 4, use of Et2O (1.3 mL),
instead of BTF, gave a crude product. The reaction time was 1.5 h. CC
(hexane/EtOAc, 10:1 to 6:1) of the crude product provided 3 (30.8 mg,
85% yield, α/β = 62:38).
Table 1, Entry 6
In a reaction similar to that of Table 1, entry 4, use of AgOTf (19.9 mg,
77.5 μmol) and Et2O (1.3 mL), instead of AgClO4 and BTF, respectively,
provided a crude product. The reaction time was 1.5 h. CC (hex-
ane/EtOAc, 10:1 to 6:1) of the crude product provided 3 (29.7 mg, 82%
yield, α/β = 60:40).
Table 1, Entry 7
In a reaction similar to that of Table 1, entry 4, use of Cp2ZrCl2 (47.4
mg, 162 μmol), instead of SnCl2, AgClO4 (67.0 mg, 323 μmol), and Et2O
(1.3 mL), instead of BTF, gave a crude product. The reaction time was
1.5 h. CC (hexane/EtOAc, 10:1 to 5:1) of the crude product provided 3
(34 mg, 94% yield, α/β = 73:27).
Cyclohexylmethyl 2,4-Di-O-benzyl-3,6-O-o-xylylene-D-glucopyran-
Table 1, Entry 8
oside (3)
A mixture of 1 (23.8 mg, 51 μmol), 2 (9.0 mg, 79 μmol), Sc(OTf)3 (66.2
mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and MS 4A (161 mg) in
Et2O (1.0 mL) was stirred at –25 °C for 6 h. After addition of saturated
aq NaHCO3 (5 mL), the mixture was filtered through a cotton–Celite
pad. The pad was washed with Et2O. The Et2O layer of the filtrate was
separated, and the aqueous layer was extracted with Et2O. The com-
bined Et2O layer was washed with brine. After the general drying pro-
cedure, the ratio of α-3/β-3/unreacted 1 in the crude product was
40:14:46 on the basis of the integral of the anomeric signals in the 1H
NMR spectrum. Purification by CC (2 g of silica gel; hexane/Et2O, 9:1
to 17:2) provided a mixture of α- and β-3 (14.4 mg, 50% yield) as a
colorless syrup. On the basis of the isolated amount of 3, the amount
of unreacted 1 was calculated to be 10.2 mg (43%).
Table 1, Entry 1
Prepared according to a literature procedure.17
Table 1, Entry 2
A mixture of glucosyl fluoride 1 (24.5 mg, 52.7 μmol), cyclohexyl-
methanol (2; 6.9 mg, 60 μmol), TMSOTf (24 mg, 130 μmol), and MS
4A (161 mg) in Et2O (1.0 mL) was stirred at –25 °C for 18 h. After addi-
tion of saturated aq NaHCO3 (5 mL), the mixture was filtered through
a cotton–Celite pad. The pad was washed with Et2O. The Et2O layer of
the filtrate was separated, and the aqueous layer was extracted with
Et2O. The combined Et2O layer was washed with brine. After the
general drying procedure, 1H NMR spectroscopy of the crude product
detected only β-3 as the glycosylated product. Purification by CC (2 g
of silica gel; hexane/Et2O, 10:1 to 8:1) provided β-3 (20.6 mg, 70%
yield).
Table 1, Entry 9
In a reaction similar to that described in the previous procedure, use
of 1 (29.5 mg, 64 μmol), Cp2TiCl2 (40 mg, 160 μmol), and AgClO4 (67
mg, 320 μmol) gave a crude product. The reaction temperature was
–25 °C for the first 3 h, and then rt for the subsequent 15 h. The ratio
of α-3/β-3/unreacted 1 in the crude product was 20:6:74. CC (hex-
ane/Et2O, 10:1 to 4:1) of the crude product provided a mixture of α-3,
β-3, and 1 (29.6 mg). On the basis of the isolated amount, the respec-
tive amounts of 3 and 1 were calculated to be 8.8 mg (25% yield) and
20.8 mg (71% unreacted).
Table 1, Entry 3
In a reaction similar to that of Table 1, entry 2, use of 1 (23.8 mg, 51.2
μmol) and BF3·OEt2 (10 mg, 65 μmol), instead of TMSOTf, provided a
crude product. The reaction time was 2 h. In the crude product, the
ratio of α-3/β-3/unreacted 1 was 31:69:<1 on the basis of the integral
of the anomeric signals in the 1H NMR spectrum. CC (hexane/Et2O,
10:1 to 4:1) of the crude product gave a mixture of α- and β-3 (25.2
mg, 88% yield).
Table 1, Entry 10
In a reaction similar to that of Table 1, entry 8, use of 1 (30.0 mg, 65
μmol), Cp2ZrCl2 (47 mg, 160 μmol), AgClO4 (67 mg, 320 μmol), and MS
4A (194 mg) gave a crude product. The ratio of α-3/β-3/unreacted 1 in
the crude product was 89:11:<1. CC (hexane/Et2O, 10:1 to 9:1) of the
crude product provided a mixture of α- and β-3 (32.1 mg, 89% yield).
Table 1, Entry 4
A mixture of 1 (30.0 mg, 64.6 μmol), 2 (8.8 mg, 78 μmol), SnCl2 (14.7
mg, 77.5 μmol), AgClO4 (16.1 mg, 77.5 μmol), and MS 4A (97 mg) in
BTF (1.3 mL) was stirred for 12 h at rt. After addition of saturated aq
NaHCO3 (5 mL), the mixture was filtered through a cotton–Celite pad.
The pad was washed with EtOAc. The EtOAc layer of the filtrate was
separated, and the aqueous layer was extracted with EtOAc. The com-
bined EtOAc layer was successively washed with H2O and brine. After
the general drying procedure, purification by CC (hexane/EtOAc, 10:1
to 4:1) provided a mixture of α- and β-3 (30.1 mg, 83% yield, α/β =
58:42).
Table 1, Entry 11
In a reaction similar to that of Table 1, entry 8, use of 1 (30.0 mg, 65
μmol), Cp2Zr(OTf)2 (99 mg, 160 μmol), AgClO4 (67 mg, 320 μmol), and
MS 4A (194 mg) gave a crude product. The reaction time was 30 min.
The ratio of α-3/β-3/unreacted 1 in the crude product was 61:39:<1.
CC (hexane/Et2O, 10:1 to 4:1) of the crude product provided a mixture
of α- and β-3 (32.8 mg, 91% yield).
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A. Motoyama et al.
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Table 1, Entry 12
crude product. The reaction temperature and time were rt and 2 h,
respectively. CC (hexane/EtOAc, 10:1 to 6:1) of the crude product pro-
vided 3 (30.0 mg, 83% yield, α/β = 1:>99).
In a reaction similar to that of Table 1, entry 8, use of 1 (28.5 mg, 61
μmol), Cp2HfCl2 (63 mg, 170 μmol), AgClO4 (67 mg, 320 μmol), and
MS 4A (194 mg) gave a crude product. The reaction time was 18 h.
The reaction temperature was –25 °C for the first 3 h, and then rt for
the subsequent 15 h. The ratio of α-3/β-3/unreacted 1 in the crude
product was 70:30:<1. CC (hexane/Et2O, 10:1 to 4:1) of the crude
product provided a mixture of α- and β-3 (26.6 mg, 78% yield).
Table 2, Entry 4
In a reaction similar to that of Table 2, entry 3, use of benzene, instead
of toluene, provided a crude product. The reaction temperature and
time were rt and 1.5 h, respectively. CC (hexane/EtOAc, 10:1 to 5:1) of
the crude product provided 3 (34.8 mg, 96% yield, α/β = 40:60).
Table 1, Entry 13
In a reaction similar to that of Table 1, entry 8, use of 1 (24.8 mg, 53
μmol), Tb(OTf)3 (81.5 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and
MS 4A (161 mg) gave a crude product. The reaction temperature was
–25 °C for the first 3 h, and then rt for the subsequent 21 h. The ratio
of α-3/β-3/unreacted 1 in the crude product was 66:9:25. CC (hex-
ane/Et2O, 10:1 to 4:1) of the crude product provided a mixture of α-3,
β-3, and 1 (24.0 mg). On the basis of the isolated amount, the respec-
tive amounts of 3 and 1 were calculated to be 18.8 mg (63% yield) and
5.2 mg (21% unreacted).
Table 2, Entry 5
In a reaction similar to that of Table 2, entry 1, use of 1 (29.5 mg, 63.5
μmol), 2 (8.7 mg, 76 μmol), Cp2ZrCl2 (93.0 mg, 318 μmol), AgClO4
(65.9 mg, 318 μmol), and MS 4A (95 mg) in DCM (1.2 mL) gave a crude
product. The reaction temperature and time were rt and 1.5 h, re-
spectively. CC (hexane/EtOAc, 10:1 to 8:1) of the crude product pro-
vided 3 (24.6 mg, 69% yield, α/β = 46:54).
Table 2, Entry 6
In a reaction similar to that of Table 2, entry 3, use of MeCN, instead of
benzene, provided a crude product. The reaction temperature and
time was rt and 1.5 h, respectively. CC (hexane/EtOAc, 10:1 to 6:1) of
the crude product provided 3 (18.6 mg, 52% yield, α/β = 41:59).
Table 1, Entry 14
In a reaction similar to that of Table 1, entry 8, use of 1 (22.0 mg, 47
μmol), Er(OTf)3 (83 mg, 130 μmol), AgClO4 (55.8 mg, 269 μmol), and
MS 4A (161 mg) gave a crude product. The reaction temperature was
–25 °C for the first 3 h, and then rt for the subsequent 21 h. The ratio
of α-3/β-3/unreacted 1 in the crude product was 69:31:<1. CC (hex-
ane/Et2O, 10:1 to 4:1) of the crude product provided a mixture of α-
and β-3 (20.8 mg, 79% yield).
Table 2, Entry 7
A mixture of 1 (22.4 mg, 48.2 μmol), 2 (6.9 mg, 65 μmol), Cp2ZrCl2
(39.3 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and MS 4A (161
mg) in DME (1.0 mL) was stirred for 30 min at –25 °C. The ratio of
α-3/β-3/unreacted 1 in the crude product was 56:44:<1. CC (hex-
ane/Et2O, 10:1 to 9:1) of the crude product provided a mixture of α-
and β-3 (23.4 mg, 87% yield).
Table 1, Entry 15
In a reaction similar to that of Table 1, entry 8, use of 1 (24.6 mg, 53
μmol), Yb(OTf)3 (83.4 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol),
and MS 4A (161 mg) gave a crude product. The reaction time was 3 h.
The ratio of α-3/β-3/unreacted 1 in the crude product was 39:10:51.
CC (hexane/Et2O, 10:1 to 4:1) of the crude product provided a mixture
of α-3, β-3, and 1 (26.0 mg). On the basis of the isolated amount, the
respective amounts of 3 and 1 were calculated to be 13.9 mg (47%
yield) and 12.1 mg (49% unreacted).
Table 2, Entry 8
In a reaction similar to that of Table 2, entry 7, use of 1 (24.9 mg, 54.0
μmol) and i-Pr2O, instead of DME, gave a crude product. The reaction
time was 40 min. The ratio of α-3/β-3/unreacted 1 in the crude prod-
uct was 76:5:19. CC (hexane/Et2O, 10:1 to 4:1) of the crude product
provided a mixture of α-3, β-3, and 1 (20.8 mg). On the basis of the
isolated amount, the respective amounts of 3 and 1 were calculated to
be 17.4 mg (58% yield) and 3.4 mg (14% unreacted).
Table 2, Entry 1
A mixture of 1 (30.9 mg, 66.5 μmol), 2 (8.8 mg, 77.5 μmol), Cp2ZrCl2
(47.4 mg, 162 μmol), AgClO4 (67.0 mg, 323 μmol), and MS 4A (194
mg) in pyridine (1.0 mL) was stirred for 21 h at –25 °C. After addition
of saturated aq NaHCO3 (5 mL), the mixture was filtered through a
cotton–Celite pad. The pad was washed with EtOAc. The EtOAc layer
of the filtrate was separated, and the aqueous layer was extracted
with EtOAc. The combined EtOAc layer was successively washed with
H2O and brine. Most of the crude product was unreacted 1; only a
trace amount of α-3 was in the crude product.
Table 2, Entry 9
In a reaction similar to that of Table 2, entry 7, use of 1 (25.1 mg, 55.0
μmol), 2 (9.1 mg, 80 μmol), Cp2ZrCl2 (48.5 mg, 166 μmol), AgClO4
(68.7 mg, 332 μmol), and MS 4A (199 mg) in t-BuOMe (1.2 mL), in-
stead of DME, gave a crude product (20.3 mg). The reaction time and
temperature were 18 h and –25 °C, respectively. The ratio of α-3/β-
3/unreacted 1 in the crude product was 44:5:51. On the basis of the
ratio, the respective amounts of 3 and 1 were calculated to be 10.9 mg
(37% yield) and 9.4 mg (38% unreacted).
Table 2, Entry 2
A mixture of 1 (31.9 mg, 68.7 μmol), 2 (8.8 mg, 78 μmol), Cp2ZrCl2
(47.4 mg, 162 μmol), AgClO4 (67.0 mg, 323 μmol), and MS 4A (194
mg) in DMF (1.0 mL) was stirred for 24 h at 0 °C. No reaction occurred.
Table 2, Entry 10
In a reaction similar to that of Table 2, entry 7, use of 1 (23.4 mg, 50.4
μmol) and CPME, instead of DME, gave a crude product. The reaction
time was 1.5 h. CC (hexane/Et2O, 10:1 to 4:1) of the crude product
provided a mixture of α- and β-3 (22.7 mg, 81% yield, α/β = 90:10).
Table 2, Entry 3
In a reaction similar to that of Table 2, entry 1, use of 1 (30.0 mg, 64.6
μmol), 2 (8.8 mg, 77.5 μmol), Cp2ZrCl2 (94.4 mg, 323 μmol), AgClO4
(67.0 mg, 323 μmol), and MS 4A (97 mg) in toluene (1.2 mL) gave a
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Table 2, Entry 11
Table 3, Entry 7
In a reaction similar to that of Table 2, entry 7, use of 1 (23.6 mg, 50.8
μmol) and Me2S, instead of DME, gave a crude product. The reaction
time and temperature were 3 h and –25 °C to rt, respectively. The ra-
tio of α-3/β-3/unreacted 1 in the crude product was 8:14:78. CC (hex-
ane/Et2O, 10:1 to 4:1) of the crude product provided a mixture of α-3,
β-3, and 1 (26.9 mg). On the basis of the isolated amount, the respec-
tive amounts of 3 and 1 were calculated to be 6.8 mg (20% yield) and
20.1 mg (85% unreacted).
In a reaction similar to that of Table 3, entry 1, use of 1 (22.4 mg, 48.2
μmol) and AgOCOCF3 (59.4 mg, 269 μmol), instead of AgBF4, gave a
crude product. The reaction temperature was –25 °C for the first 4 h,
and then 0 °C for the subsequent 9 h. The ratio of α-3/β-3/unreacted 1
in the crude product was 61:17:22. CC (hexane/Et2O, 8:1 to 15:2) of
the crude product provided a mixture of α-3, β-3, and 1 (19.4 mg). On
the basis of the isolated amount, the respective amounts of 3 and 1
were calculated to be 15.7 mg (58% yield) and 3.7 mg (17% unreacted).
Table 3, Entry 1
Table 3, Entry 8
A mixture of 1 (24.9 mg, 53.6 μmol), 2 (6.9 mg, 65 μmol), Cp2ZrCl2
(39.3 mg, 135 μmol), AgBF4 (52.4 mg, 269 μmol), and MS 4A (161 mg)
in Et2O (1.0 mL) was stirred for 24 h at –25 °C. After addition of satu-
rated aq NaHCO3, the mixture was filtered through a cotton–Celite
pad. The pad was washed with Et2O. The Et2O layer of the filtrate was
separated, and the aqueous layer was extracted with Et2O. The com-
bined Et2O layer was successively washed with saturated aq NaHCO3,
H2O, and brine. After the general drying procedure, CC (2 g of silica
gel; hexane/Et2O, 9:1 to 4:1) of the crude product provided a mixture
of α- and β-3 (26.0 mg, 87% yield, α/β = 2:98).
In a reaction similar to that of Table 3, entry 1, use of 1 (23.7 mg, 51.0
μmol) and AgNO3 (45.7 mg, 269 μmol), instead of AgBF4, gave a crude
product. The reaction temperature was –25 °C for the first 4 h, 0 °C for
the subsequent 9 h, and then rt for the final 12 h. The ratio of α-3/β-
3/unreacted 1 in the crude product was 77:21:2. CC (hexane/Et2O, 8:1
to 15:2) of the crude product provided a mixture of α-3, β-3, and 1
(20.2 mg). On the basis of the isolated amount, the respective
amounts of 3 and 1 were calculated to be 19.9 mg (70% yield) and 0.3
mg (1% unreacted).
Table 4, Entry 1
Table 3, Entry 2
A mixture of 1 (23.2 mg, 49.9 μmol), 2 (6.9 mg, 65 μmol), Cp2ZrCl2
(39.3 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and MS 3A (161
mg) in Et2O (1.0 mL) was stirred for 15 min at –25 °C. After addition of
saturated aq NaHCO3, the mixture was filtered through a cotton–
Celite pad. The pad was washed with Et2O. The Et2O layer of the fil-
trate was separated, and the aqueous layer was extracted with Et2O.
The combined Et2O layer was successively washed with saturated aq
NaHCO3, H2O, and brine. After the general drying procedure, the ratio
of α-3/β-3/unreacted 1 in the crude product was 67:11:22. CC (2 g of
silica gel; hexane/Et2O, 9:1 to 4:1) of the crude product provided a
mixture of α-3, β-3, and 1 (20.0 mg). On the basis of the isolated
amount, the respective amounts of 3 and 1 were calculated to be 16.2
mg (58% yield) and 3.8 mg (16% unreacted).
In a reaction similar to that of Table 3, entry 1, use of 1 (25.0 mg, 53.8
μmol) and AgB(C6F5)4 (50.8 mg, 64.6 μmol), instead of AgBF4, gave a
crude product. The reaction temperature and time were rt and 1.5 h,
respectively. CC (hexane/Et2O, 10:1 to 9:1) of the crude product pro-
vided a mixture of α- and β-3 (21.0 mg, 70% yield, α/β = 49:51).
Table 3, Entry 3
In a reaction similar to that of Table 3, entry 1, use of 1 (22.9 mg, 49.3
μmol) and AgSbF6 (92.4 mg, 269 μmol), instead of AgBF4, gave a crude
product. The reaction temperature was –25 °C for the first 4 h, and
then 0 °C for the subsequent 1.5 h. The ratio of α-3/β-3/unreacted 1 in
the crude product was 50:50:<1. CC (hexane/Et2O, 9:1 to 17:2) of the
crude product provided a mixture of α- and β-3 (20.1 mg, 73% yield).
Table 4, Entry 2
See Table 1, entry 10.
Table 3, Entry 4
In a reaction similar to that of Table 3, entry 1, 1 (22.0 mg, 47.4 μmol)
and Ag2CO3 (74.2 mg, 269 μmol), instead of AgBF4, were used. The re-
action temperature was –25 °C for the first 4 h, 0 °C for the subse-
quent 9 h, and then rt for the final 24 h. Most of the crude product
was unreacted 1; only a trace amount of 3 was in the crude product.
Table 4, Entry 3
In a reaction similar to that of Table 4, entry 1, use of 1 (25.5 mg, 54.9
μmol) and MS 5A, instead of MS 3A, gave a crude product. The ratio of
α-3/β-3/unreacted 1 in the crude product was 25:7:68. CC (hex-
ane/Et2O, 9:1 to 4:1) of the crude product provided a mixture of α-3,
β-3, and 1 (24.0 mg). On the basis of the isolated amount, the respec-
tive amounts of 3 and 1 were calculated to be 8.7 mg (28% yield) and
15.3 mg (60% unreacted).
Table 3, Entry 5
In a reaction similar to that of Table 3, entry 1, 1 (25.6 mg, 53.8 μmol)
and Ag2SO4 (83.9 mg, 269 μmol), instead of AgBF4, were used. The re-
action temperature was –25 °C for the first 4 h, 0 °C for the subse-
quent 9 h, and then rt for the final 24 h. Most of the crude product
was unreacted 1; only a trace amount of 3 was in the crude product.
Table 4, Entry 4
In a reaction similar to that of Table 4, entry 1, use of 1 (24.9 mg, 53.6
μmol) and MS 13X, instead of MS 3A, gave a crude product. The ratio
of α-3/β-3/unreacted 1 in the crude product was 67:10:23. CC (hex-
ane/Et2O, 9:1 to 4:1) of the crude product provided a mixture of α-3,
β-3, and 1 (24.0 mg). On the basis of the isolated amount, the respec-
tive amounts of 3 and 1 were calculated to be 19.2 mg (64% yield) and
4.8 mg (19% unreacted).
Table 3, Entry 6
In a reaction similar to that of Table 3, entry 1, use of 1 (24.3 mg, 52.3
μmol), MS 4A (81 mg), and AgOTf (69.1 mg, 269 μmol), instead of
AgBF4, gave a crude product. The reaction temperature and time were
rt and 1.5 h, respectively. CC (hexane/Et2O, 10:1 to 9:1) of the crude
product provided a mixture of α- and β-3 (26.3 mg, 90% yield, α/β =
65:35).
Table 4, Entry 5
In a reaction similar to that of Table 4, entry 1, but without the molec-
ular sieves, use of 1 (25.3 mg, 54.5 μmol) provided a crude product
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(24.4 mg), in which the ratio of α-3/β-3/unreacted 1 was <1:99:<1;
thus, the yield of β-3 was 80%.
IR (ATR): 2897, 2860, 1740, 1404, 1321, 1121, 1078, 1055, 1015, 974,
887 cm–1
.
1H NMR (500 MHz, CDCl3, 24 °C): δ = 5.84–5.75 (m, 2 H), 5.77 (d, J =
5.0 Hz, 1 H), 4.66 (dd, J = 4.4, 2.1 Hz, 1 H), 4.60 (dd, J = 4.1, 2.1 Hz, 1 H),
4.53 (m, 1 H), 4.44 (m, 1 H), 4.42 (d, J = 5.0 Hz, 1 H), 4.08 (dd, J = 12.4,
4.6 Hz, 1 H), 3.97 (dd, J = 11.1, 5.5 Hz, 1 H), 3.91 (dd, J = 4.4, 2.1 Hz, 1
H), 3.74 (dd, J = 13.5, 4.1 Hz, 1 H), 3.74 (dd, J = 13.5, 2.1 Hz, 1 H), 1.65
(s, 3 H).
13C NMR (125 MHz, CDCl3, 23 °C): δ = 130.7 (d), 128.1 (d), 119.4 (s),
97.8 (d), 78.6 (d), 73.9 (d), 81.7 (d), 70.0 (d), 69.3 (t), 69.0 (t), 66.3 (t),
20.5 (q).
Table 5, Entry 1
See Table 1, entry 7.
Table 5, Entry 2
A mixture of 1 (29.8 mg, 64.2 μmol), 2 (8.8 mg, 78 μmol), Cp2ZrCl2
(47.4 mg, 162 μmol), AgClO4 (67.0 mg, 323 μmol), and MS 4A (194
mg) in Et2O (1.0 mL) was stirred for 30 min at 0 °C. After addition of
saturated aq NaHCO3 (5 mL), the mixture was filtered through a cot-
ton–Celite pad. The pad was washed with Et2O. The Et2O layer of the
filtrate was separated, and the aqueous layer was extracted with Et2O.
The combined Et2O layer was successively washed with saturated aq
NaHCO3, H2O, and brine. After the general drying procedure, CC (2 g of
silica gel; hexane/Et2O, 9:1 to 4:1) of the crude product provided a
mixture of α- and β-3 (29.5 mg, 82% yield, α/β = 73:27).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H16NaO6: 279.08446;
found: 279.08492.
4-Methoxyphenyl 3,6-O-[(Z)-2-Butenylene]-β-D-glucopyranoside
(7)
A mixture of orthoester 6 (275 mg, 1.07 mmol) and 4-methoxyphenol
(1.33 g, 10.7 mmol) was stirred at 100 °C for 11.5 h, then cooled to rt.
MeOH (10.7 mL) and MS 4A (1.6 g) were added, and the mixture was
stirred for 20 h at reflux. After cooling to rt, the mixture was filtered
through a cotton–Celite pad. The concentrated filtrate was purified by
CC (10 g of silica gel; hexane/EtOAc, 5:1 to 1:2). The separated, de-
sired product was crystallized (CHCl3 and hexane) to give 4-methoxy-
phenyl glucoside 7 (134 mg, 39% yield, dr 98:2) as a colorless solid;
mp 143–145 °C; [α]D24 +79.1 (c 1.03, CHCl3).
Table 5, Entry 3
See Table 1, entry 10.
Table 5, Entry 4
In a reaction similar to that of Table 5, entry 1, use of 1 (29.0 mg, 62.4
μmol) at –50 °C gave a crude product. The reaction time was 14 h. CC
(hexane/Et2O, 9:1 to 4:1) of the crude product provided a mixture of
α- and β-3 (31.6 mg, 91% yield, α/β = 94:6).
IR (ATR): 3600–3160, 2866, 1510, 1215, 1109, 1059, 1036, 970, 826,
748 cm–1
.
1H NMR (500 MHz, CDCl3, 24 °C): δ = 6.97 (d, J = 9.2 Hz, 2 H), 6.81 (d, J
= 9.2 Hz, 2 H), 5.85 (m, 1 H), 5.64 (m, 1 H), 5.31 (d, J = 3.4 Hz, 1 H), 4.75
(br s, 1 H), 4.50 (dd, J = 10.3, 6.3 Hz, 1 H), 4.31–4.17 (m, 4 H), 4.03 (br
d, J = 3.4 Hz, 1 H), 3.98 (dd, J = 10.3, 6.3 Hz, 1 H), 3.81 (br s, 1 H), 3.77
(s, 3 H), 3.68 (dd, J = 10.3, 5.7 Hz, 1 H), 3.61 (br s, 1 H), 3.15 (br s, 1 H).
13C NMR (125 MHz, CDCl3, 24 °C): δ = 154.9 (s), 151.1 (s), 131.4 (d),
127.2 (d), 117.8 (d, 2 C), 114.7 (d, 2 C), 101.1 (d), 79.1 (d), 75.6 (d), 72.4
(d), 69.3 (t), 69.2 (t), 64.0 (t), 63.2 (d), 55.8 (q).
Table 5, Entry 5
In a reaction similar to that of Table 5, entry 1, use of 1 (31.5 mg, 67.8
μmol) at –60 °C gave a crude product. The reaction time was 20 h. The
ratio of α-3/β-3/unreacted 1 in the crude product was 92:3:5. CC
(hexane/Et2O, 10:1 to 4:1) of the crude product provided a mixture of
α-3, β-3, and 1 (36.7 mg). On the basis of the isolated amount, the re-
spective amounts of 3 and 1 were calculated to be 35.2 mg (93% yield)
and 1.5 mg (5% unreacted).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H22NaO7: 361.1263;
found: 361.1265.
Table 5, Entry 6
In a reaction similar to that of Table 5, entry 1, use of 1 (25.0 mg, 53.8
μmol) at –78 °C gave a crude product. The reaction time was 54 h. The
ratio of α-3/β-3/unreacted 1 in the crude product was 26:5:69. CC
(hexane/Et2O, 10:1 to 8:1) of the crude product provided a mixture of
α-3, β-3, and 1 (21.5 mg). On the basis of the isolated amount, the re-
spective amounts of 3 and 1 were calculated to be 7.5 mg (25% yield)
and 14 mg (56% unreacted).
4-Methoxyphenyl 2,4-Di-O-benzyl-3,6-O-[(Z)-2-butenylene]-β-D-
glucopyranoside (8)
A mixture of diol 7 (127 mg, 374 μmol) and NaH (60% in mineral oil,
60 mg; 36 mg as NaH, 1.5 mmol) in DMF (3.7 mL) was added BnBr
(259 mg, 1.50 mmol) at 0 °C. The mixture was stirred for 2.5 h at
70 °C, then cooled to rt. H2O was added to quench the reaction. The
aqueous mixture was extracted with EtOAc. The organic layer was
successively washed with 1 M HCl and brine. After the general drying
procedure, the concentrated extract was purified by CC (3 g of silica
gel; hexane/EtOAc, 9:1 to 5:1) to give dibenzylated 8 (194 mg, 100%
yield) as a colorless syrup; [α]D23 +28.5 (c 0.2, CHCl3).
3,6-O-[(Z)-2-Butenylene]-1,2,4-O-orthoacetyl-D-glucopyranose (6)
To a stirred mixture of NaH (60% in mineral oil, 607 mg; 364 mg as
NaH, 15.2 mmol) in toluene (253 mL) at 80 °C were added a solution
of diol 5 (516 mg, 2.53 mmol) in DMF (50.6 mL) and a solution of (Z)-
1,4-dichloro-2-butene (348 mg, 2.78 mmol) in toluene (50.6 mL), re-
spectively, using syringe pumps (rate of addition: each 0.25 mL/min).
After the end of the additions, the mixture was stirred for 11.5 h at rt.
The mixture was cooled to 0 °C and H2O was added to quench the re-
action. The aqueous mixture was extracted with EtOAc. The organic
layer was successively washed with H2O and brine. After the general
drying procedure, the concentrated extract was purified by CC (26 g
of silica gel; hexane/EtOAc, 1:0 to 7:1) to give (Z)-butenylene-bridged
IR (ATR): 2880, 2859, 1520, 1456, 1217, 1109, 1040, 739, 698 cm–1
.
1H NMR (500 MHz, CDCl3, 23 °C): δ = 7.39–7.37 (m, 2 H), 7.34–7.27
(m, 8 H), 7.38 (dd, J = 7.7, 1.7 Hz, 2 H), 6.93 (d, J = 9.2 Hz, 2 H), 6.81 (d,
J = 9.2 Hz, 2 H), 5.79–5.71 (m, 2 H), 5.25 (d, J = 6.6 Hz, 1 H), 4.80 (d, J =
12.0 Hz, 1 H), 4.72 (d, J = 12.0 Hz, 1 H), 4.70 (br d, J = 10.3 Hz, 1 H),
4.66 (d, J = 12.0 Hz, 1 H), 4.51 (d, J = 12.0 Hz, 1 H), 4.35 (m, 1 H), 4.30
(dd, 12.3, 2.9 Hz, 1 H), 4.17 (br d, J = 4.0 Hz, 1 H), 3.98 (dd, J = 12.3, 4.8
Hz, 1 H), 3.91–3.87 (m, 2 H), 3.83 (d, J = 3.4 Hz, 1 H), 3.77 (s, 3 H), 3.76
(dd, J = 13.2, 4.0 Hz, 1 H), 3.69 (dd, J = 13.2, 1.2 Hz, 1 H).
25
6 (220 mg, 34% yield) as a colorless powder; mp 76.8–78.0 °C; [α]D
–36 (c 0.65, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

J
A. Motoyama et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3, 24 °C): δ = 155.1 (s), 151.4 (s), 138.6 (s),
138.0 (s), 129.7 (d), 129.7 (d), 128.5 (d, 2 C), 128.3 (d, 2 C), 127.9 (d),
127.8 (d, 6 C), 127.8 (d, 2 C), 127.6 (d), 117.9 (d), 114.6 (d), 101.1 (d),
82.6 (d), 82.1 (d), 75.5 (d), 72.8 (t), 71.8 (t), 70.3 (d), 70.0 (t), 68.2 (t),
65.4 (t), 55.8 (q).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C31H34NaO7: 541.2202;
found: 541.2205.
Cyclohexylmethyl 2,4-Di-O-benzyl-3,6-O-[(Z)-2-butenylene]-D-
glucopyranoside (10)
To a mixture of AgClO4 (29.4 mg, 142 μmol), Cp2ZrCl2 (45.2 mg, 155
μmol), and MS 4A (56.0 mg) in Et2O (0.5 mL) was added cyclohexyl-
methanol (2; 8.2 mg, 72 μmol) at rt. After the reaction mixture was
stirred for 0.5 h at rt, to the mixture was added dropwise a solution of
glucosyl fluoride 4 (20.3 mg, 49.0 μmol) in Et2O (1.0 mL) at –20 °C.
The mixture was stirred for 7 h at –20 °C. Saturated aq NaHCO3 was
added at –20 °C to quench the reaction. After warming to rt, the mix-
ture was filtered through a cotton–Celite pad. The filtrate was ex-
tracted with EtOAc. The organic layer was successively washed with
saturated aq NaHCO3 and brine. After the general drying procedure,
the crude product of this reaction was obtained (28 mg), the 1H NMR
spectrum of which indicated that the anomeric ratio of the obtained
glucoside 10 was α/β = 24:76. The crude product was purified by pre-
parative TLC (hexane/EtOAc, 8:1) to give β-10 (2.4 mg, 10% yield) as a
colorless syrup and an unpurified mixture which included α-10. The
mixture was further purified by preparative TLC (toluene/EtOAc, 8:1)
to give α-10 (7.0 mg, 28% yield) as a colorless syrup. The ratio of α-10
and β-10 at this stage was α/β = 74:26 on the basis of each isolated
amount. For the reason for this inversion of the α/β ratio, see the Sup-
porting Information, Section 4.4.
2,4-Di-O-benzyl-3,6-O-[(Z)-2-butenylene]-D-glucopyranose (9)
A mixture of 4-methoxyphenyl glucoside 8 (194 mg, 374 μmol) and
Ce(SO4)2 (621 mg, 1.87 mmol) in a mixture of MeCN (4.7 mL) and H2O
(0.7 mL) was stirred for 3 h at rt. Then, the mixture was filtered
through a cotton–Celite pad. After addition of 10% aq Na2S2O3 to the
filtrate, the aqueous mixture was extracted with EtOAc. The organic
layer was successively washed with 10% aq Na2S2O3, H2O, and brine.
After concentration, the mixture was diluted to a solution of MeCN
(3.1 mL) and H2O (1.5 mL). To this was added Ce(SO4)2 (370 mg, 1.11
mmol). The mixture was stirred for 6 h at rt. To the mixture, further
Ce(SO4)2 (290 mg, 873 μmol) was added. The mixture was stirred for
2.5 h at rt. Again, to the mixture was added Ce(SO4)2 (370 mg, 1.11
mmol). The mixture was stirred at 40 °C for 2 h. Then, the mixture
was filtered through a cotton–Celite pad. To the filtrate, 10% aq
Na2S2O3 was added. The aqueous mixture was extracted with EtOAc.
The organic layer was successively washed with 10% aq Na2S2O3, H2O,
and brine. After the general drying procedure, the crude product was
purified by CC (5 g of silica gel; hexane/EtOAc, 5:1 to 2:1) to give 9
(115 mg, 74% yield) as a mixture of anomers.
Data for α-10:
[α]D25 +40.3 (c 0.35, CHCl3).
IR (ATR): 2922, 2852, 1454, 1111, 1045, 735, 696 cm–1
.
1H NMR (500 MHz, CDCl3, 24 °C): δ = 7.40 (d, J = 7.5 Hz, 2 H), 7.37 (d,
J = 7.5 Hz, 2 H), 7.32–7.23 (m, 6 H), 5.73 (ddd, J = 11.5, 6.9, 6.3 Hz, 1
H), 5.58 (ddd, J = 11.5, 4.6, 1.2 Hz, 1 H), 4.95 (d, J = 3.4 Hz, 1 H), 4.84 (d,
J = 12.6 Hz, 1 H), 4.66 (d, J = 12.6 Hz, 1 H), 4.64 (d, J = 12.6 Hz, 1 H),
4.60 (d, J = 12.6 Hz, 1 H), 4.32 (dd, J = 6.9, 6.3 Hz, 1 H), 4.25–4.18 (m, 4
H), 3.95 (dd, J = 9.7, 6.9 Hz, 1 H), 3.89 (m, 1 H), 3.85 (dd, J = 10.9, 6.9
Hz, 1 H), 3.68–3.61 (m, 3 H), 3.17 (dd, J = 9.2, 6.9 Hz, 1 H), 1.80–1.60
(m, 6 H), 1.30–1.10 (m, 3 H), 1.00–0.89 (m, 2 H).
13C NMR (126 MHz, CDCl3, 24 °C): δ = 139.2 (s), 138.8 (s), 131.2 (d),
128.3 (d, 2 C), 128.3 (d, 2 C), 128.1 (d), 127.9 (d, 2 C), 127.9 (d, 2 C),
127.5 (d), 127.4 (d), 95.6 (d), 75.6 (d), 75.2 (t), 74.9 (d), 74.5 (d), 73.2
(t), 71.8 (t), 69.1 (d), 68.8 (t), 68.7 (t), 62.9 (t), 38.2 (d), 30.3 (t), 30.2
(t), 26.7 (t), 26.0 (t), 26.0 (t).
2,4-Di-O-benzyl-3,6-O-[(Z)-2-butenylene]-D-glucopyranosyl
Fluoride (4)
A mixture of pyranose 9 (115 mg, 278 μmol) and DAST (134 mg, 833
μmol) in THF (2.8 mL) was stirred for 30 min at 0 °C. MeOH (1 mL) was
added to quench the reaction; to this was further added saturated aq
NaHCO3. The aqueous mixture was extracted with EtOAc. The organic
layer was successively washed with saturated aq NaHCO3, H2O, and
brine. After the general drying procedure, the crude product was pu-
rified by CC (5 g of silica gel; hexane/EtOAc, 7:1 to 5:1) to give 4 (102
23
mg, 88% yield, α/β = 7:93) as a colorless syrup; [α]D +106 (c 0.9,
CHCl3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C31H40NaO6: 531.2723;
found: 531.2704.
IR (ATR): 3030, 2664, 1456, 1107, 1090, 1028, 737, 698 cm–1
.
1H NMR (500 MHz, CDCl3, 24 °C): δ = 7.38–7.28 (m, 10 H), 5.75 (m, 1
H), 5.68 (m, 1 H), 5.60 (dd, J = 53.3, 4.0 Hz, 1 H), 4.74 (d, J = 12.0 Hz, 1
H), 4.66 (d, J = 12.0 Hz, 1 H), 4.61 (d, J = 12.0 Hz, 1 H), 4.55 (d, J = 12.0
Hz, 1 H), 4.41 (ddd, J = 13.2, 4.0, 2.3 Hz, 1 H), 4.34 (m, 1 H), 4.32–4.26
(m, 2 H), 4.10 (dd, J = 13.2, 5.2 Hz, 1 H), 3.91 (dd, J = 12.0, 4.6 Hz, 1 H),
3.90 (dd, J = 11.7, 6.3 Hz, 1 H), 3.81 (br s, 1 H), 3.76 (dd, J = 12.0, 5.2 Hz,
1 H), 3.72 (dd, J = 18.0, 4.0 Hz, 1 H).
1H NMR (500 MHz, C6D6, 23.6 °C): δ = 7.25 (d, J = 7.5 Hz, 4 H), 7.19–
7.06 (m, 6 H), 5.81 (dd, J = 53.8, 4.6 Hz, 1 H), 5.55 (m, 1 H), 5.43 (m, 1
H), 4.51 (d, J = 11.5 Hz, 1 H), 4.42 (d, J = 11.5 Hz, 1 H), 4.39 (m, 1 H),
4.28 (d, J = 11.5 Hz, 1 H), 4.25–4.19 (m, 2 H), 4.17 (d, J = 11.5 Hz, 1 H),
4.11 (dd, J = 4.6, 4.6 Hz, 1 H), 3.93 (dd, J = 18.9, 4.6 Hz, 1 H), 3.86 (dd, J
= 13.2, 5.2 Hz, 1 H), 3.83 (dd, J = 11.7, 4.6 Hz, 1 H), 3.79 (br s, 1 H), 3.63
(dd, J = 11.2, 6.3 Hz, 1 H), 3.57 (dd, J = 11.7, 4.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3, 24 °C): δ = 138.0 (s), 137.9 (s), 130.7 (d),
128.6 (d, 2 C), 128.5 (d, 2 C), 128.2 (d), 128.0 (d), 127.9 (d, 4 C), 127.9
(d), 109.2 (d, J = 216 Hz), 80.2 (d, J = 29 Hz), 79.9 (d), 74.0 (d, J = 6 Hz),
72.7 (t), 72.0 (t), 69.8 (t), 69.0 (d), 68.8 (t), 64.6 (t).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C24H27FNaO5: 437.1740;
found: 437.1735.
Data for β-10:
[α]D24 +42.5 (c 0.12, CHCl3).
IR (ATR): 2920, 2852, 1454, 1112, 1037, 735, 698 cm–1
.
1H NMR (500 MHz, CDCl3, 24 °C): δ = 7.39–7.26 (m, 10 H), 5.78–5.68
(m, 2 H), 4.77 (d, J = 12.0 Hz, 1 H), 4.71 (m, 1 H), 4.66 (d, J = 12.0 Hz, 1
H), 4.65 (d, J = 6.3 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.45 (d, J = 12.0
Hz, 1 H), 4.28–4.24 (m, 2 H), 4.02 (br d, J = 3.4 Hz, 1 H), 3.94 (dd, J =
12.3, 5.2 Hz, 1 H), 3.87 (dd, J = 10.9, 6.3 Hz, 1 H), 3.74 (br d, J = 2.9 Hz,
1 H), 3.71 (dd, J = 12.6, 3.4 Hz, 1 H), 3.69 (dd, J = 9.5, 3.4 Hz, 1 H), 3.66
(d, J = 12.6 Hz, 1 H), 3.61 (d, J = 6.3 Hz, 1 H), 3.23 (dd, J = 9.5, 6.9 Hz, 1
H), 1.82–1.56 (m, 6 H), 1.25–1.10 (m, 3 H), 0.98–0.83 (m, 2 H).
13C NMR (126 MHz, CDCl3, 24 °C): δ = 139.0 (s), 138.2 (s), 129.9 (d),
129.7 (d), 128.5 (d, 2 C), 128.4 (d, 2 C), 127.9 (d, 2 C), 127.9 (d), 127.8
(d, 2 C), 127.5 (d), 102.8 (d), 82.8 (d), 82.5 (d), 75.7 (d), 75.3 (t), 72.7
(t), 71.9 (t), 70.5 (d), 70.3 (t), 68.1 (t), 65.4 (t), 38.2 (d), 30.3 (t), 30.0
(t), 26.8 (t), 26.0 (t), 26.0 (t).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C31H40NaO6: 531.2723;
found: 531.2722.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

K
A. Motoyama et al.
Paper
Synthesis
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,4-di-O-benzyl-3,6-O-o-xylylene-
α-D-glucopyranosyl)-α-D-glucopyranoside (α-11; Table 6, Entry 1)
13C NMR (100 MHz, CDCl3, 22 °C): δ = 138.9 (s), 138.6 (s), 137.2 (s),
136.9 (s), 130.0 (d), 129.4 (d), 128.3 (d, 2 C), 128.2 (d, 2 C), 128.1 (d),
128.0 (d, 2 C), 127.9 (d), 127.8 (d, 2 C), 127.5 (d), 127.5 (d), 91.7 (d),
75.9 (d), 75.7 (d), 75.5 (d), 75.2 (d), 74.0 (t), 72.1 (t), 71.8 (t), 71.0 (t),
70.2 (d), 69.0 (t), 48.0 (d), 40.0 (t), 34.6 (t), 31.6 (d), 24.3 (d), 22.9 (t),
22.5 (q), 21.2 (q), 15.4 (q).
A mixture of 1 (25.3 mg, 54.5 μmol), methyl 2,3,4-tri-O-benzyl-α-D-
glucopyranoside (30.0 mg, 64.6 μmol), Cp2ZrCl2 (39.3 mg, 135 μmol),
AgClO4 (55.8 mg, 269 μmol), and MS 4A (161 mg) in Et2O (1.0 mL) was
stirred for 24 h at –60 °C. After addition of saturated aq NaHCO3 (5
mL), the mixture was filtered through a cotton–Celite pad. The pad
was washed with Et2O. The Et2O layer of the filtrate was separated,
and the aqueous layer was extracted with Et2O. The combined organic
layer was washed with brine. After the general drying procedure, the
ratio of α-11/β-11/unreacted 1 in the crude product was 95:<3:2. Pu-
rification by CC (2 g of silica gel; hexane/Et2O, 10:1 to 4:1) provided
almost pure α-11 (37.5 mg, 76% yield), a part of which (15.0 mg) was
isolated in pure form as a colorless syrup to obtain the following spec-
troscopic data.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C38H48NaO6: 623.3349;
found: 623.3345.
(–)-Menthyl 2,4-Di-O-benzyl-3,6-O-o-xylylene-α-D-glucopyrano-
side (α-13; Table 6, Entry 3)
A mixture of 1 (27.4 mg, 59.0 μmol), (–)-menthol (10.1 mg, 64.6
μmol), Cp2ZrCl2 (39.3 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and
MS 4A (161 mg) in Et2O (1.0 mL) was stirred for 2 h at –60 °C. The
workup procedure was similar to that for the synthesis of 11. The ra-
tio of α-13/β-13/unreacted 1 in the crude product was 72:28:<1. Pu-
rification by CC (2 g of silica gel; hexane/Et2O, 10:1 to 8:1) provided a
mixture of α- and β-13 (30.5 mg, 86% yield), of which a part of α-13
(19.2 mg) was isolated in pure form as a colorless syrup to obtain the
following spectroscopic data.
[α]D23 +207 (c 0.75, CHCl3).
IR (ATR): 3030, 2924, 1455, 1110, 1029, 749, 698 cm–1
.
1H NMR (400 MHz, CDCl3, 21 °C): δ = 7.41–7.39 (m, 2 H), 7.34–7.28
(m, 8 H), 7.24–7.07 (m, 19 H), 5.26 (d, J = 10.5 Hz, 1 H), 5.15 (d, J = 5.5
Hz, 1 H), 4.98 (d, J = 10.5 Hz, 1 H), 4.90 (d, J = 11.0 Hz, 1 H), 4.87 (d, J =
11.7 Hz, 1 H), 4.75 (d, J = 11.0 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.66
(d, J = 12.1 Hz, 1 H), 4.60 (d, J = 11.4 Hz, 1 H), 4.57 (d, J = 11.7 Hz, 1 H),
4.52 (d, J = 11.7 Hz, 1 H), 4.51 (d, J = 12.1 Hz, 1 H), 4.47 (d, J = 3.4 Hz, 1
H), 4.41 (d, J = 10.5 Hz, 1 H), 4.38 (d, J = 11.7 Hz, 1 H), 4.36 (d, J = 10.5
Hz, 1 H), 4.19 (br s, 1 H), 4.09 (br s, 1 H), 4.08 (m, 1 H), 4.02 (br s, 1 H),
3.92–3.87 (m, 2 H), 3.73 (dd, J = 12.8, 2.1 Hz, 1 H), 3.70–3.65 (m, 2 H),
3.63 (br d, J = 11.4 Hz, 1 H), 3.58 (dd, J = 12.8, 3.9 Hz, 1 H), 3.28 (s, 3 H),
3.25 (dd, J = 11.4, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3, 22 °C): δ = 139.2 (s), 139.1 (s), 139.0 (s),
138.4 (s), 138.3 (s), 137.0 (s), 136.8 (s), 130.0 (d), 129.4 (d), 128.5–
127.4 (overlapped 27 doublets), 98.2 (d), 96.4 (d), 82.1 (d), 80.2 (d),
77.7 (d), 76.0 (d), 76.0 (d), 75.5 (t), 74.8 (t), 74.2 (t), 73.9 (d), 73.5 (t),
72.1 (t), 71.7 (t), 70.6 (t), 70.2 (d), 69.9 (d), 69.6 (t), 67.5 (t), 55.2 (q).
[α]D21 +29.3 (c 1.26, CHCl3).
IR (ATR): 2952, 2923, 2868, 1454, 1112, 1029, 750, 697 cm–1
.
1H NMR (400 MHz, CDCl3, 21 °C): δ = 7.32–7.30 (m, 2 H), 7.26–7.12
(m, 11 H), 7.06 (m, 1 H), 5.03 (d, J = 5.0 Hz, 1 H), 5.01 (d, J = 12.6 Hz, 1
H), 4.71 (d, J = 11.2 Hz, 1 H), 4.67 (d, J = 12.4 Hz, 1 H), 4.61 (d, J = 12.4
Hz, 1 H), 4.48 (d, J = 12.4 Hz, 1 H), 4.42 (d, J = 11.2 Hz, 1 H), 4.34 (d, J =
12.6 Hz, 1 H), 4.33 (d, J = 12.4 Hz, 1 H), 4.15 (dd, J = 3.8, 3.8 Hz, 1 H),
3.93 (dd, J = 2.5, 2.5 Hz, 1 H), 3.88 (br s, 1 H), 3.78–3.74 (m, 2 H), 3.54
(dd, J = 12.1, 4.4 Hz, 1 H), 3.23 (td, J = 10.7, 4.3 Hz, 1 H), 2.29 (qqd, J =
6.9, 6.9, 2.5 Hz, 1 H), 2.06 (d, J = 12.2 Hz, 1 H), 1.56–1.50 (m, 2 H),
1.36–1.18 (m, 2 H), 1.06 (ddd, J = 6.1, 6.1, 6.1 Hz, 1 H), 0.92–0.73 (m, 8
H), 0.60 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3, 21 °C): δ = 138.8 (s), 138.7 (s), 137.5 (s),
136.9 (s), 130.2 (d), 129.9 (d), 128.3 (d), 128.3 (d, 2 C), 128.2 (d, 2 C),
128.1 (d), 127.9 (d, 2 C), 127.7 (d, 2 C), 127.4 (d, 2 C), 96.9 (d), 81.0 (d),
76.0 (d), 75.7 (d), 75.4 (d), 73.9 (t), 72.3 (t), 71.5 (t), 71.0 (d), 70.9 (t),
68.7 (t), 48.7 (d), 42.9 (t), 34.4 (t), 31.9 (d), 24.9 (d), 23.0 (t), 22.5 (q),
21.4 (q), 16.0 (q).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C56H60NaO11: 931.4033;
found: 931.4030.
(+)-Menthyl 2,4-Di-O-benzyl-3,6-O-o-xylylene-α-D-glucopyrano-
side (α-12; Table 6, Entry 2)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C38H48NaO6: 623.3349;
found: 623.3332.
A mixture of 1 (26.6 mg, 57.2 μmol), (+)-menthol (10.1 mg, 64.6
μmol), Cp2ZrCl2 (39.3 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and
MS 4A (161 mg) in Et2O (1.0 mL) was stirred for 2 h at –60 °C. The
workup procedure was similar to that for the synthesis of 11. The ra-
tio of α-12/β-12/unreacted 1 in the crude product was 89:11:<1. Pu-
rification by CC (2 g of silica gel; hexane/Et2O, 10:1 to 19:2) provided
a mixture of α- and β-12 (29.6 mg, 86% yield), of which a part of α-12
(16.5 mg) was isolated in pure form as a white amorphous solid to ob-
tain the following spectroscopic data.
Dihydrocholesteryl 2,4-Di-O-benzyl-3,6-O-o-xylylene-α-D-gluco-
pyranoside (α-14; Table 6, Entry 4)
A mixture of 1 (25.1 mg, 53.8 μmol), dihydrocholesterol (25.1 mg,
64.6 μmol), Cp2ZrCl2 (39.3 mg, 135 μmol), AgClO4 (55.8 mg, 269
μmol), and MS 4A (161 mg) in Et2O (1.0 mL) was stirred for 2 h at
–60 °C. The workup procedure was similar to that for the synthesis of
11. After the general drying procedure, the ratio of α-14/β-14/unre-
acted 1 in the crude product was 70:18:12, as determined from the 1H
NMR spectrum. Purification by CC (2 g of silica gel; hexane/Et2O, 10:1
to 17:2) provided a mixture of α- and β-14 (34.7 mg, 77% yield), of
which a part of α-14 (11.0 mg) was isolated in pure form as a white
powder to obtain the following spectroscopic data.
[α]D21 +122 (c 0.83, CHCl3).
IR (ATR): 2952, 2926, 2869, 1455, 1114, 1035, 750, 697 cm–1
.
1H NMR (400 MHz, CDCl3, 21 °C): δ = 7.35–7.33 (m, 2 H), 7.26–7.21
(m, 6 H), 7.18–7.10 (m, 5 H), 7.04 (m, 1 H), 5.21 (d, J = 10.5 Hz, 1 H),
5.17 (d, J = 6.0 Hz, 1 H), 4.85 (d, J = 10.8 Hz, 1 H), 4.68 (d, J = 12.1 Hz, 1
H), 4.56 (d, J = 12.4 Hz, 1 H), 4.54 (d, J = 12.4 Hz, 1 H), 4.36 (d, J = 10.8
Hz, 1 H), 4.35 (d, J = 12.1 Hz, 1 H), 4.23 (d, J = 10.5 Hz, 1 H), 4.10 (br s,
1 H), 4.07 (br s, 1 H), 3.89 (dd, J = 2.3, 2.3 Hz, 1 H), 3.79 (br d, J = 6.0 Hz,
1 H), 3.66 (dd, J = 12.7, 2.0 Hz, 1 H), 3.47–3.40 (m, 2 H), 2.52 (qqd, J =
7.1, 7.1, 2.5 Hz, 1 H), 2.00 (br d, J = 11.7 Hz, 1 H), 1.58–1.55 (m, 2 H),
1.32–1.26 (m, 2 H), 0.92–0.85 (m, 6 H), 0.72 (d, J = 7.1 Hz, 3 H), 0.63 (d,
J = 7.1 Hz, 3 H).
[α]D24 +62.5 (c 0.55, CHCl3).
IR (ATR): 2930, 2906, 2866, 1455, 1113, 1028, 750 cm–1
.
1H NMR (400 MHz, CDCl3, 21 °C): δ = 7.42–7.40 (m, 2 H), 7.37–7.27
(m, 7 H), 7.24–7.16 (m, 4 H), 7.12 (m, 1 H), 5.19 (d, J = 10.8 Hz, 1 H),
5.16 (d, J = 5.5 Hz, 1 H), 4.88 (d, J = 10.8 Hz, 1 H), 4.79 (d, J = 12.6 Hz, 1
H), 4.63 (d, J = 12.6 Hz, 2 H), 4.48 (d, J = 12.6 Hz, 1 H), 4.40 (d, J = 10.8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

L
A. Motoyama et al.
Paper
Synthesis
Hz, 1 H), 4.35 (d, J = 10.8 Hz, 1 H), 4.18 (br s, 1 H), 4.13 (br s, 1 H), 3.92
(br s, 1 H), 3.79–3.75 (m, 2 H), 3.62–3.54 (m, 2 H), 1.99–0.94 (m, 30
H), 0.90 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6 Hz,
3 H), 0.82 (s, 3 H), 0.65 (s, 3 H), 0.60 (m, 1 H).
13C NMR (100 MHz, CDCl3, 22 °C): δ = 139.0 (s), 138.8 (s), 137.1 (s),
137.0 (s), 130.1 (d), 129.5 (d), 128.4 (d, 2 C), 128.3 (d, 2 C), 128.2 (d),
128.0 (d), 128.0 (d), 128.0 (d), 128.0 (d), 128.0 (d), 127.6 (d), 127.5 (d),
93.3 (d), 76.8 (d), 75.9 (d), 75.6 (d), 75.4 (d), 74.1 (t), 72.2 (t), 71.8 (t),
70.8 (t), 69.8 (d), 69.3 (t), 56.6 (d), 56.4 (d), 54.5 (d), 45.3 (d), 42.7 (s),
40.2 (t), 39.7 (t), 37.1 (t), 36.3 (t), 35.9 (d), 35.9 (s), 35.9 (t), 35.6 (d),
32.3 (t), 28.9 (t), 28.4 (t), 28.2 (d), 27.6 (t), 24.4 (t), 24.0 (t), 23.0 (q),
22.7 (q), 21.4 (t), 18.8 (q), 12.5 (q), 12.2 (q).
1H NMR (400 MHz, CDCl3, 21 °C): δ = 7.43–7.41 (m, 2 H), 7.34–7.15
(m, 12 H), 5.41 (d, J = 4.6 Hz, 1 H), 5.05 (d, J = 11.0 Hz, 1 H), 4.83 (d, J =
12.6 Hz, 1 H), 4.80 (d, J = 11.0 Hz, 1 H), 4.66 (d, J = 12.6 Hz, 1 H), 4.54
(d, J = 12.6 Hz, 1 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.47 (d, J = 11.0 Hz, 1 H),
4.44 (d, J = 12.6 Hz, 1 H), 4.27 (dd, J = 4.5, 4.5 Hz, 1 H), 3.97 (br s, 2 H),
3.86 (dd, J = 12.1, 4.3 Hz, 1 H), 3.73–3.65 (m, 2 H), 2.14 (br s, 3 H), 1.90
(br d, J = 11.4 Hz, 3 H), 1.87 (br d, J = 11.4 Hz, 3 H), 1.63 (br s, 6 H).
13C NMR (100 MHz, CDCl3, 21 °C): δ = 139.2 (s), 138.9 (s), 137.2 (s),
137.2 (s), 130.4 (d), 129.7 (d), 128.2 (d), 128.2 (d), 128.2 (d), 128.2 (d),
127.8 (d), 127.8 (d), 127.8 (d), 127.8 (d), 127.8 (d), 127.8 (d), 127.4 (d),
127.3 (d), 88.0 (d), 76.5 (d), 75.7 (d), 75.4 (d), 74.3 (s), 74.2 (t), 72.4 (t),
71.5 (t), 71.0 (t), 70.0 (d), 69.7 (t), 42.6 (t, 3 C), 36.5 (t, 3 C), 30.8 (d, 3
C).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C55H76NaO6: 855.5540;
found: 855.5552.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C38H44NaO6: 619.3036;
found: 619.3048.
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-o-xylylene-
α-D-glucopyranosyl)-α-D-glucopyranoside (α-15; Table 6, Entry 5)
Funding Information
A mixture of 1 (31.5 mg, 67.8 μmol), methyl 2,3,6-tri-O-benzyl-α-D-
glucopyranoside (25.2 mg, 54.2 μmol), Cp2ZrCl2 (49.5 mg, 170 μmol),
AgClO4 (70.3 mg, 339 μmol), and MS 4A (203 mg) in Et2O (1.0 mL) was
stirred for 24 h at –60 °C. The workup procedure was similar to that
for the synthesis of 11. In the crude product, β-15 was not detected.
Purification by CC (2 g of silica gel; hexane/Et2O, 9:1 to 31:4) provided
α-15 (5.8 mg, 12% yield) as a colorless syrup.
MEXT supported the program for the Strategic Research Foundation
at Private Universities (S1311046) and JSPS KAKENHI (Grant Num-
bers JP15K13650, JP16H01163 in Middle Molecular Strategy, and
JP16KT0061) partly supported this work.
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IR (ATR): 3029, 2903, 1454, 1097, 1044, 750, 698 cm–1
Supporting Information
.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590927.
1H NMR (400 MHz, CDCl3, 21 °C): δ = 7.41–7.38 (m, 4 H), 7.34–7.28
(m, 11 H), 7.21–7.17 (m, 10 H), 7.14–7.10 (m, 3 H), 6.98 (m, 1 H), 5.32
(d, J = 9.9 Hz, 1 H), 5.17 (d, J = 11.7 Hz, 1 H), 5.07 (d, J = 10.1 Hz, 1 H),
4.87 (d, J = 6.9 Hz, 1 H), 4.78 (d, J = 12.2 Hz, 1 H), 4.75 (d, J = 11.7 Hz, 2
H), 4.69 (d, J = 11.7 Hz, 1 H), 4.64 (d, J = 12.2 Hz, 1 H), 4.58 (d, J = 3.7
Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.43 (d, J = 11.9 Hz, 1 H), 4.39 (d, J =
11.7 Hz, 1 H), 4.33 (br s, 1 H), 4.29 (d, J = 10.1 Hz, 1 H), 4.25 (d, J = 11.9
Hz, 1 H), 4.05 (br s, 1 H), 3.99 (dd, J = 9.5, 9.5 Hz, 1 H), 3.93 (d, J = 2.5
Hz, 1 H), 3.88 (d, J = 12.2 Hz, 1 H), 3.86 (dd, J = 9.3, 9.3 Hz, 1 H), 3.77 (d,
J = 9.9 Hz, 1 H), 3.69–3.58 (m, 5 H), 3.53 (dd, J = 9.6, 3.7 Hz, 1 H), 3.36
(s, 3 H).
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References
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13C NMR (100 MHz, CDCl3, 22 °C): δ = 140.1 (s), 138.7 (s), 138.6 (s),
138.3 (s), 137.9 (s), 137.2 (s), 136.5 (s), 129.6 (d), 128.4–127.7 (over-
lapped 24 doublets), 127.3 (d), 127.1 (d, 2 C), 126.9 (d), 101.8 (d), 98.5
(d), 83.8 (d), 83.5 (d), 80.7 (d), 78.7 (d), 77.4 (d), 75.1 (t), 75.1 (d), 74.4
(t), 73.8 (t), 72.8 (t), 72.6 (t), 71.8 (t), 70.5 (d), 70.5 (t), 70.4 (t), 70.0
(d), 67.7 (t), 55.4 (q).
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HRMS (ESI-TOF): m/z [M + Na]+ calcd for C56H60NaO11: 931.4033;
found: 931.4015.
1-Adamantanyl 2,4-Di-O-benzyl-3,6-O-o-xylylene-α-D-glucopyran-
oside (α-16; Table 6, Entry 6)
A mixture of 1 (25.3 mg, 54.5 μmol), 1-adamantanol (9.8 mg, 65
μmol), Cp2ZrCl2 (39.3 mg, 135 μmol), AgClO4 (55.8 mg, 269 μmol), and
MS 4A (161 mg) in Et2O (1.0 mL) was stirred for 24 h at –60 °C. The
workup procedure was similar to that for the synthesis of 11. The ra-
tio of α-16/β-16/unreacted 1 in the crude product was 58:10:32. Pu-
rification by CC (2 g of silica gel; hexane/Et2O, 10:1 to 17:2) provided
a mixture of α- and β-16 (21.4 mg, 66% yield), of which a part of α-16
(11.2 mg) was isolated in pure form as a colorless syrup to obtain the
following spectroscopic data.
[α]D22 +43.2 (c 0.56, CHCl3).
IR (ATR): 2917, 2906, 2850, 1110, 1028, 697 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

M
A. Motoyama et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M