A 1,2-trans-Selective Glycosyl Donor Bearing Cyclic Protection at the C-2 and C-3 Hydroxy Groups

Article abstract of DOI:10.1002/ejoc.201700671

A new 1,2-trans-selective glycosylation reaction is described. Glucosyl donors protected cyclically at the C-2 and C-3 hydroxy groups as six- (butane diacetal), seven- (tetraisopropyldisiloxanylidene), or eight- (2,3-o-xylylene) membered fused rings were synthesized in a straightforward manner. The glycosylation reactions of the glucosyl donors with various acceptors mainly generated β-glycosides under conventional reaction conditions. The results show that the o-xylylene group is a suitable 1,2-trans-directing group from the points of view of stereoselectivity and chemical stability. A conformational study of the oxocarbenium ion of an o-xylylene-protected glucose derivative by NMR spectroscopy and computational simulation was carried out. The results imply that the oxocarbenium ion mainly adopts a ⁴H₃ conformation owing to the rigid trans-fused ring at C-2 and C-3, while a noncyclically protected derivative might fluctuate between conformations. These results suggest that an eclipsing interaction between the pseudoequatorial xyloxy group at C-2 and the incoming nucleophile hampers 1,2-cis attack.

Full text of DOI:10.1002/ejoc.201700671

A Journal of
Accepted Article
Title: A 1,2-trans-selective glycosyl donor bearing cyclic protection at
the C2 and C3 hydroxyl groups
Authors: Nahoko Yagami, Hideki Tamai, Taro Udagawa, Akiharu Ueki,
Miku Konishi, Akihiro Imamura, Hideharu Ishida, Makoto Kiso,
and Hiromune Ando
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700671
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700671
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10.1002/ejoc.201700671
European Journal of Organic Chemistry
FULL PAPER
A 1,2-trans-selective glycosyl donor bearing cyclic protection at
the C2 and C3 hydroxyl groups
Nahoko Yagami,[a][d] Hideki Tamai,[a][d] Taro Udagawa,[c] Akiharu Ueki,[a][d] Miku Konishi,[a][b][d] Akihiro
Imamura,[a] Hideharu Ishida,*[a][b] Makoto Kiso,[a][d] Hiromune Ando*[a][b][d]
Abstract:
described. Glucosyl donors protected cyclically at the C2 and C3
hydroxyl groups as six- (butanediacetal), seven-
A
new 1,2-trans-selective glycosidation reaction is
by NMR and computational simulation implied that the oxocarbenium
4
ion mainly adopt the H3 conformation owing to the rigid trans-fused
ring at C2 and C3 while non-cyclically protected one might fluctuate
among possible conformations. The results suggested that an
eclipsing interaction between the C2-pseudo-equatorial xyloxy group
and the incoming nucleophile hampered the 1,2-cis-attack.
(tetraisopropyldisiloxanylidene) or eight (2,3-o-xylylene) membered
fused ring were synthesized in a straightforward manner. The
glycosidation reactions of the glucosyl donors with various acceptors
mainly generated β-glycosides under conventional reaction conditions.
The results showed that the o-xylylene-group is suitable as a 1,2-
trans-directing functionality from the perspective of stereoselectivity
and chemical stability. The conformation study on oxocarbenium ion
of an o-xylylene-protected glucose
Keywords: carbohydrates; glycosylation; cyclic protecting
group; stereoselectivity;1,2-trans-glycoside
Introduction
Precise syntheses of glycans are essential for a thorough
understanding of the molecular basis underlying the biological
functions of glycans and for developing glycan-based
therapeutics. There are various methods for assembling diverse
glycan sequences, mainly for stereoselective glycosidation
reactions.1 β (1,2-trans)-Glycosides of D-gluco-type sugars are
abundant in natural glycans; thus, their synthesis has long been
a focus of carbohydrate chemistry. In their stereoselective β-
glycosidation, the neighboring effect of acyl functionalities, the
nitrile solvent effect,2 and the α-coordination of triflate3 have been
widely exploited in independent or synergic ways in the
construction of diverse glycan sequences. However, various
synthetic studies have also uncovered the limited scope of these
approaches. The most widely used neighboring effect-assisted β-
glycosidation is unpredictably accompanied by various side
reactions, such as the formation of the glycosyl orthoester and
migration of the acyl functionality to both the anomeric center and
Fig. 1. 1,2-trans-Glycosidation developed in this study.
the glycosyl acceptor, and the reaction requires orthogonality with
other acyl groups used for tentative protection of other hydroxyl
groups. In addition, the method is not always suitable for
synthesizing molecules that contain ester moieties in their
accessories of hydroxyl groups of sugar residues and aglycones.
Syntheses using the nitrile solvent effect or the α-coordination of
triflate often encounter
a decline of stereoselectivity and
glycosidation yield depending on the reactant structures and
reaction conditions. Therefore, it is still necessary to develop
stereoselective β-glycosidation methods based on different
[a]
Department of Applied Bioorganic Chemistry, Faculty of Applied
Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu
501-1193, Japan, E-mail: ishida@gifu-u.ac.jp (H.I.); hando@gifu-
u.ac.jp (H.A.)
principles of β-selectivity for glycan synthesis.4
Recently,
Demchenko et al. developed a β-selective glycosidation effected
by a 2-O-picolinyl group,5 and furthermore they showcased β-
selective glycosidation via remote picolinyl group mediated
aglycon delivery.6 Meanwhile, several studies have described
conformationally modified glucosyl donors that impart β-
selectivity.7 For furanosyl donor, Lowary et al first demonstrated
that 2,3-o-xylylene-protected arabinosyl donor provided high -
selectivity, the efficay of which was evidenced by the synthesis of
heptasaccharide.8 Our interest was drawn by the Lowary’s
pioneering work and Crich and Jayalath,9 which described a
[b]
[c]
[d]
Center for Highly Advanced Integration of Nano and Life Sciences
(G-CHAIN), Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193,
Japan
Department of Chemistry and Biomolecular Science, Faculty of
Engineering, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193,
Japan
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto
University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501,
Japan
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here].
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10.1002/ejoc.201700671
European Journal of Organic Chemistry
FULL PAPER
cases, the bicyclic donors provided β-glycosides as the major
stereoisomer, with a ratio greater than the α-isomers by a factor
of 1.4 to 11.5. BDA donor 1 needed a higher temperature than
bicyclic donors 2 and 3 to complete the glycosidation reaction.
However, at -40 °C, BDA donor 1 gave good β-selectivity (Entry
1), which was comparable to those of donors 2 and 3 at the same
temperature (Entries 3 and 6). Glycosidation with the TIPDS (2)
and Xyln (3) donors, the β-selectivity was considerably higher at
-80 °C, affording β-glycosides almost exclusively (2: α/β = 1/10.1;
3: α/β = 1/11.5) with high yields (Entries 2 and 5) slightly higher
than that obtained with the corresponding 2,3-O-carbonyl analog
(84%,α/β= 1/9).8 We confirmed by thin layer chromatography that
8 and 9 did not anomerize under the reaction conditions. At higher
temperatures, β-selectivity decreased, which suggested that β-
glycosides were formed under kinetic control. Furthermore, the
results obtained by glycosidations of acyclic donors 4 and 5 at -
80 °C indicated that the β-selectivity of the glucosyl donors (1–3)
was conferred by the 2,3-cyclic protection (Entries 8 and 9)
(Supporting Information Table 1).
Next, we examined the effect of the reaction solvent on the β-
selectivity using glycosyl donor 3 (Supporting Information Table
2). To dissolve the reaction substrates completely in all reaction
media, the glycosidation reactions were performed at 0 °C for
Entries 1 to 4. The selectivity was reproducible in less polar
solvents, such as toluene and CCl4, producing similar results to
CH2Cl2 (Entries 1–3). However, the more polar solvent
propionitrile increased the β-anomer ratio (α/β = 1/5.3) (Entry 4),
although at -80 °C, propionitrile exhibited the opposite effect on
the selectivity, decreasing the β-selectivity (α/β = 1/3.5) compared
with CH2Cl2 (α/β = 1/11.5; Table 1, Entry 5). Furthermore, in
cyclopentyl methyl ether, which is more likely to coordinate at the
β-face of the oxocarbenium ion,15 the ratio of the α-isomer was
increased considerably at -80 °C to give the reversed α/β ratio of
1.2/1. These results implied that the α-coordination of the nitrile
solvent molecule to the oxocarbenium ion generated from donor
3 would be highly restricted at very low temperatures, enhancing
the β-coordination of the nucleophilic solvent molecule and
increasing the generation of the α-glycoside via an SN2-like
pathway.
simple β-selective glycosidation using a 2,3-O-carbonylated
bicyclic glucosyl thioglycoside donor in combination with their
glycosidation promoters to generate an α-triflate intermediate. In
the present study, we explored the potential of bicyclic glucosyl
sugar analogs containing non-acyl cyclic protecting groups at the
C2 and C3 positions as β-selective glycosyl donors, and found
that 2,3-o-xylylene (Xyln)-protected glycosyl donors are useful for
acyl-free β-selective glycosidation (Fig 1).
Results and Discussion
First, we synthesized variations of a 2,3-trans-fused ring at a
thioglucoside donor by using the available non-acyl cyclic
protecting groups, di-tert-butylsilylene (DTBS)10, butanediacetal
(BDA)11, tetraisopropyldisiloxanylidene (TIPDS)12, and Xyln13 (Fig.
2).The BDA-, TIPDS-, and Xyln-protected thioglucoside
derivatives (1–3) were obtained with six-, seven-, and eight-
membered fused rings, respectively, through straightforward
protection-deprotection of the hydroxy groups. The synthetic
procedures for 1–3 are described in Supporting Information
Schemes 1–2. In contrast, the DTBS-protected analog was not
isolable due to its lability.
Fig. 2. Glucosyl donors used in this study.
Table 1. Glycosidation of cyclically protected glucosyl donor
Next, we examined the effect on the stereoselectivity of the
donor’s protecting groups, configuration at C4 and the leaving
group. The TIPDS group was labile under various reaction
conditions while modifying 3. Hence, the Xyln group was used as
the 2,3-cyclic protecting group for further experiments.16 The β-
selectivity of the Xyln-protected donor was affected by the
chemical properties of the protecting groups of C4 and C6
hydroxyl groups (Table 2, Entries 1 to 6). Electron-donating
protecting groups at both hydroxyl groups increased the β-
selectivity, whereas electron-withdrawing acetyl groups at either
or both positions decreased the selectivity to a greater or lesser
extent. For C4-epimer 18, the glycosidation product was also
dominated by the β-anomer with an acceptable anomer ratio (α/β
= 1/5.3), which suggested that this method could be used for β-
galactoside formation. N-Phenyltrifluoroacetimidate17 donor 19
was also β-selectively glycosidated in the presence of a catalytic
amount of Lewis acid (Entries 8 and 9).
Entry
Donor
Temp.
(°C)
-40
-80
-40
0
Time
Product
Yield
(%)
80
α/β
1
2
3
4
5
6
7
8
9
1
2
2
2
3
3
3
4
5
1.0 h
9.0 h
1.0 h
15 min
7.5 h
1.5 h
30 min
24 h
7
8
1/4.6
1/10.1
1/3.8
1/1.4
1/11.5
1/3.8
1/1.7
1/6.1
1/0.72
97
8
99
8
97
-80
-40
0
9
93
9
92
9
87
-80
-80
10
11
81
3.0 h
68
Next, the β-selectivity of bicyclic glucosyl donors 1–3 were
examined by glycosidation with a galactosyl acceptor 6 in the
presence
of
N-iodosuccinimide
(NIS)
and
trifluoromethanesulfonic acid (TfOH)14 in CH2Cl2 (Table 1). In all
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10.1002/ejoc.201700671
European Journal of Organic Chemistry
FULL PAPER
Table 2. Examination of glycosidation of Xyln-protected glycosyl donors 12-17 and 19.
Entry
1[a]
2[a]
3[a]
4[a]
5[a]
6[a]
7[a]
8[b]
9 [c]
Donor
X
R1
MPM
Bn
R2
MPM
TBDPS
Ac
Time (h)
4.5
Product
20
Yield (%)
76
α/β
1/15.7
1/24
12 (Glc)
13 (Glc)
14 (Glc)
15 (Glc)
16 (Glc)
17 (Glc)
18 (Gal)
19 (Glc)
19 (Glc)
SPh (β)
SPh (β)
SPh (β)
SPh (β)
SPh (β)
SPh (β)
SPh (β)
PTFAI (α)
PTFAI (α)
17.0
5.0
21
91
Bn
22
99
1/7.3
1/7.3
1/5.3
1/2.6
1/5.3
1/8.1
1/32.3
TBDPS
Ac
Bn
4.0
23
87
Bn
3.0
24
99
Ac
Ac
21.0
3.0
25
91
Bn
Bn
26
94
Bn
Bn
1.0
9
90
Bn
Bn
4.0
9
81
[a] performed in the presence of NIS (1.5 eq.), TfOH (0.3 – 0.9 eq.) and molecular sieves 4Å.
[b] performed in the presence of TMSOTf (0.05 eq.) and molecular sieves AW 300.
[c] performed in the presence of BF3∙OEt2 (0.1 eq.) and molecular sieves 4Å. PTFAI : N-phenyltrifluoroacetimidate
The best β-selectivity (α/β = 1/32.3) was provided by activation
with BF3·OEt2. In contrast, the 2,3- dibenzylated analog of 19
decreased the anomeric ratio to 1/5.3 (Supporting Information
Scheme 6).
was gained with acceptors (27, 30, 34 and 35) with a suitable
donor-promotor combination (Entries 1, 12, 15 and 16).
To determine the reaction mechanism by which the β-glycoside
was dominant in the glycosidation of the 2,3-Xyln donors, we
investigated the conformation of the oxocarbenium ions formed
from 3 and 4. First, we attempted to determine the conformation
of the oxocarbenium ion of 4516 by following Woerpel’s method,18
but it was unsuccessful because the ions were unstable. Instead,
the conformations of lactone derivatives 45 and 46 were analyzed
by NMR in CD2Cl2 at -80 °C. Fig 4 shows the difference in
coupling constants for H2 and H5 between 45 and 46 (Supporting
Information Fig 1 and Supporting Information Table 3). Based on
the coupling constants, we assumed that Xyln-protected
derivative 45 mainly adopted the 4H3 conformation, whereas the
conformation of 2,3-dibenzylated derivative 46 may fluctuate
among possible conformations. Likewise, it is plausible that the
oxocarbenium ion generated from Xyln-protected donor 3 may
Fig 3. Acceptors used in the glycosidation of 3 and 19.
The glycosidation of the thioglycoside donor 3 with simple
alcohols (27-29), glycosyl acceptors (30-34) and tertiary hydroxyl
group of 1-adamantanol 35 provided -glycosides as the major
product in all cases (Fig 3 and Table 3, Entries 1-9). The results
of the thioglycoside 3 indicated the match-mismatch between the
donor and acceptor, as has been widely observed in
stereoselective glycosidation reactions that are independent of
4
mainly adopt the H3 conformation owing to the rigid trans-fused
ring at C2 and C3. The computational study of the oxocarbenium
4
ion of 45 also supported H3 conformation (A) as the minimum
energy conformation (Data are dedcribed in Supporting
Information Table 2). Therefore, there might be an eclipsing
interaction between the C2-pseudo-equatorial xyloxy group and
the incoming nucleophile, thereby disfavoring the 1,2-cis-attack.
This mechanism would also account for the impaired β-selectivity
in EtCN-CH2Cl2 and the reversed stereoselectivity in CPME-
CH2Cl2 at -80 °C (Table 2, Entries 5 and 6).
neighboring
participation
effect.
Likewise,
N-
phenyltrifluoroacetimidate donor 19 preferentially produced β-
glycosides with moderate to excellent stereoselectivity (Entries
10-17). It was also revealed by 19 that glycosylation promotor
strongly affected the stereoselectivity of products. Taken together
with the results of the thioglylcoside donor 3, excellent selectivity
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10.1002/ejoc.201700671
European Journal of Organic Chemistry
FULL PAPER
Table 3. Glycosidation of 3 and 19.
Entry
1
Donor
3
Acceptor
27
Promotor
Time
4.0 h
Product
36
Yield (%)
83
α/β
1/19
a
a
a
a
a
a
a
a
a
b
c
b
c
b
c
b
c
2
3
28
30 min
20 min
1.0 h
37
98
1/7.3
1/6.7
1/4.6
1/4.3
1/13.3
1/9.0
1/2.3
1/15.7
1/9.0
1/24
3
3
29
38
97
4
3
30
39
88
5
3
31
2.0 h
40
83
6
3
32
5.5 h
41
71
7
3
33
20 min
5.5 h
42
60
8
3
34
43
70
9
3
35
1.0 h
44
76
10
11
12
13
14
15
16
17
19
19
19
19
19
19
19
19
27
5.0 h
36
98
27
7.0 h
36
95
30
30 min
30 min
5.0 min
3.0 h
39
91
1/24
30
39
55
1/3.5
1/2.7
1/5.3
1/9.0
1/3.2
34
43
72
34
43
59
35
10 min
2.5 h
44
85
35
44
89
Conclusions
We have demonstrated that a 2,3-trans-fused ring in a glucosyl
donor
served
as
a
stereo-directing
factor
for
imparting β-selectivity.
A
detailed examination of the
glycosidation reaction of Xyln-bearing donors revealed the
importance of the structural factors of reactants, including
stereoelectronic factors, in exerting the β-selectivity. Our method
can be used as an alternative for β -glycosidation with the most
widely used leaving group-promotor systems. Moreover, our
method would streamline the syntheses of glycans or
glycoconjugate-bearing acyl moieties, such as partially
acetylated glycans and glycoglycerolipids.
Experimental Section
General procedures: All chemicals were purchased from commercial
suppliers and used without further purification, unless otherwise noted.
Molecular sieves were purchased from Wako Chemicals Inc. and pre-dried
Fig 4. Conformational study of oxocarbenium ion generated from 2,3-Xyln
glucosyl donor. Structure A drawn in stick model indicates the optimized structure
obtained by DFT calculations (B3LYP/ 6-311G(d)).
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10.1002/ejoc.201700671
European Journal of Organic Chemistry
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give phenyl 4,6-O-benzylidene-2,3-O-(1,1,3,3-tetraisopropyldisiloxanylide
ne)-1-thio-β-D-glucopyranoside (5.00 g, quant.); [α]D -16.0 ° (c 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.58-7.18 (m, 10 H, 2 Ph), 5.57 (s, 1 H,
>CHPh), 4.71 (d, 1 H, J1,2 = 9.5 Hz, H-1), 4.36 (dd, 1 H, J5,6a = 5.0 Hz, Jgem
at 300 °C for 2 h in a muffle furnace, and dried in a flask at 300 °C for 12
h in vacuo prior to use. Dry solvents for reaction media (CH2Cl2, toluene,
THF, CH3CN, DMF, pyridine) were purchased from Kanto Chemical Co.
Inc. (Tokyo, Japan) and used without purification. Other solvents as
reaction media were dried over molecular sieves and used without further
purification. TLC analysis was performed on Merck TLC plates (silica gel
60F254 on glass). Compounds were visualized either by exposure to UV
light (254 nm) or by soak in 10 % H2SO4 solution in EtOH or 20 %
phosphomolybdic acid solution in EtOH, followed by heating. Silica gel (80
mesh and 300 mesh; Fuji Silysia Co.,(Aichi, Japan) was used for flash
column chromatography. The quantity of silica gel was usually 100 to 200
times the weight of the crude sample to be charged. Sephadex (Pharmacia
LH-20) was used for size exclusion chromatography. Solvent systems for
chromatography were specified as v/v ratios. Evaporation and
concentration were conducted in vacuo. 1H and 13C NMR spectra were
recorded with Bruker Avance III 500 spectrometers. Chemical shifts in 1H
NMR spectra are expressed in ppm (δ) relative to the Me4Si signal,
adjusted to δ 0.00 ppm. Data are presented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double
doublet, td = triple doublet, m = multiplet and/or multiple resonances),
integration, coupling constant in hertz (Hz), and position of the
corresponding proton. COSY methods were used to confirm the NMR peak
assignments. High-resolution mass spectrometry (HRMS) was performed
with a Bruker Daltonics micrOTOF (ESI-TOF) mass spectrometer. Specific
rotations were determined with a Horiba SEPA-300 high-sensitivity
polarimeter.
= 10.5 Hz, H-6a), 3.89 (t, 1 H, J2,3 = J3,4 = 9.5 Hz, H-3), 3.79 (t, 1 H, J5,6b
=
10.5 Hz, H-6b), 3.72 (t, 1 H, H-2), 3.59 (t, 1 H, J4,5 = 9.5 Hz, H-4), 3.44 (td,
1 H, H-5), 1.18-0.86 (m, 28 H, 4 iPr); 13C NMR (125 Hz, CDCl3) δ 137.5,
134.2, 131.7, 128.9, 128.7, 128.1, 128.1, 127.5, 125.9, 101.0, 89.8, 80.3,
77.8, 76.5, 70.6, 68.7, 17.5, 17.4, 17.2, 17.2, 17.2, 17.1, 17.0, 12.9, 12.8,
12.3; HRMS (ESI) m/z: found [M+Na]+ 625.2244, C31H46O6SSi2 calcd for
[M+Na]+ 625.2246.
Phenyl 4-O-benzyl-2,3-O-(1,1,3,3-tetraisopropyldisiloxanylidene)-1-
thio-β-D-glucopyranoside: Dichlorophenylborane (650 µL, 4.40 mmol)
and triethylsilane (680 µL, 4.40 mmol) were added to a suspension of
phenyl 4,6-O-benzylidene-2,3-O-(1,1,3,3-tetraisopropyldisiloxanyliden
e)-1-thio-β-D-glucopyranoside (1.00 g, 1.70 mmol) and molecular sieves
4Å (1.00 g) in CH2Cl2 (16.0 mL) under argon atmosphere. The mixture was
stirred for 5.5 h at -80 °C as the progress of the reaction was monitored by
TLC (EtOAc/n-Hexane = 1/3). The reaction mixture was quenched with
Et3N and MeOH, filtered through a pad of Celite and the filtered residue
was washed with CHCl3. The combined filtrate and washings were washed
with sat. NaHCO3 aq., H2O and brine, dried (Na2SO4) and concentrated.
The resulting residue was purified by silica gel column chromatography
(EtOAc/n-Hexane
tetraisopropyldisiloxanylidene)-1-thio-β-D-glucopyranoside
quant.); [α]D -11.5° (c 0.07, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.47-7.23
(m, 10 H, 2 Ph), 4.95, (d, 1 H, Jgem = 11.5 Hz, PhCH2), 4.65 (d, 1 H, J1,2
=
1/7) to give phenyl 4-O-benzyl-2,3-O-(1,1,3,3-
(1.00 g,
=
Phenyl 4,6-di-O-benzyl-2,3-O-(2’,3’-dimethoxybutane-2’,3’-diyl)-β-D-
glucopyranoside (1): Butane-2,3-dione (79.0 μL, 890 μmol), BF3∙OEt2
added under argon atmosphere to a solution of phenyl 4,6-di-O-benzyl-β-
D-glucopyranoside (53.7 mg, 119 μmol) in MeOH (600 μL). The mixture
was stirred for 42 h at room temperature as the progress of the reaction
was monitored by TLC (EtOAc/Toluene = 1/10). Next, the reaction mixture
was concentrated. The resulting residue was purified by silica gel column
chromatography (EtOAc/n-Hexane = 1/10 → 1/3) to give 1 (64.4 mg, 84%);
[α]D -92.2 ° (c 0.09, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.56-7.19 (m, 15
H, 3 Ph), 4.92 (d, 1 H, Jgem = 11.0 Hz, PhCH2), 4.74 (d, 1 H, J1,2 = 9.5 Hz,
H-1), 4.58 (d, 1 H, Jgem = 12.0 Hz, PhCH2), 4.57 (d, 1 H, PhCH2), 4.51 (d,
1 H, PhCH2), 3.92 (t, 1 H, J2,3 = J3,4 = 9.5 Hz, H-3), 3.78-3.68 (m, 4 H, H-
2, H-4, H-6a, H-6b), 3.53 (m, 1 H, H-5), 3.29 (s, 3 H, OCH3), 3.20 (s, 3 H,
OCH3), 1.35-1.34 (2s, 6 H, 2 CH3); 13C NMR (125 Hz, CDCl3) δ 138.4,
138.3, 133.5, 131.6, 128.7, 128.3, 128.3, 128.0, 127.7, 127.6, 127.5, 127.2,
100.1, 99.5, 84.8, 79.5, 77.6, 75.5, 75.0, 74.6, 73.4, 69.1, 68.0, 48.1, 47.9,
17.8, 17.6; HRMS (ESI) m/z: found [M+Na]+ 589.2230, C31H38O7S calcd
for [M+Na]+ 589.2230.
9.5 Hz, H-1), 4.64 (d, 1 H, PhCH2), 3.87 (t, 1H, J2,3 = J3,4 = 8.5 Hz, H-3),
3.80 (ddd, 1H, J5,6a = 3.0 Hz, Jgem = 10.0 Hz, J6a,OH = 7.0 Hz, H-6a), 3.66
(dd, 1 H, H-2), 3.61 (m, 1 H, H-6b), 3.49 (t, 1 H, J4,5 = 8.5 Hz, H-4), 3.37-
3.33 (m, 1 H, H-5), 1.78 (t, 1 H, J6b,OH = 7.0 Hz, OH), 1.17-0.97 (m, 28 H,
4iPr); 13C NMR (125 Hz, CDCl3) δ 138.0, 134.3, 131.4, 128.9, 128.5, 128.3,
127.9, 127.3, 88.4, 82.2, 78.9, 77.7, 75.8, 75.4, 62.4, 17.6, 17.5, 17.5, 17.5,
17.3, 17.2, 17.2, 12.9, 12.8, 12.3; HRMS (ESI) m/z: found [M+Na]+
672.2602, C32H48O7SSi2 calcd for [M+Na]+ 672.2602.
Phenyl
4,6-di-O-benzyl-2,3-O-(1,1,3,3-
(2):
tetraisopropyldisiloxanylidene)-1-thio-β-D-glucopyranoside
Benzyl bromide (344 μL, 2.90 mmol) and sodium hydride (60.4 mg, 868
μmol) were added to a solution of phenyl 4-O-benzyl-2,3-O-(1,1,3,3-
tetraisopropyldisiloxanylidene)-1-thio-β-D-glucopyranoside (350 mg, 579
μmol) in DMF (2.90 mL) at -20 °C under argon atmosphere. The mixture
was stirred for 4.0 h at -20 °C as the progress of the reaction was
monitored by TLC (EtOAc/n-Hexane = 1/3). The reaction mixture was
quenched with MeOH, co-evaporated with toluene and diluted with EtOAc.
The solution was washed with H2O and brine, dried (Na2SO4) and
concentrated. The resulting residue was purified by silica gel column
chromatography (EtOAc/n-Hexane = 1/30) to give 2 (320 mg, 79%); [α]D -
16.5 ° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.68-7.18 (m, 15 H, 3
Ph), 4.93 (d, 1 H, Jgem = 11.0 Hz, PhCH2), 4.61 (d, 1 H, J1,2 = 9.5 Hz, H-1),
4.57 (d, 1 H, PhCH2,), 4.59 (d, 1 H, Jgem = 12.5 Hz, PhCH2), 4.50 (d, 1 H,
PhCH2), 3.84 (t, 1 H, J2,3 = J3,4 = 9.0 Hz, H-3), 3.74-3.69 (m, 2 H, H-2, H-
5), 3.64 (dd, J5,6a = 4.5 Hz, Jgem = 10.5 Hz, H-6a), 3.54 (t, 1 H, J4,5 = 9.0
Phenyl 4,6-O-benzylidene-2,3-O-(1,1,3,3- tetraisopropyldisiloxanylide
ne)-1-thio-β-D-glucopyranoside:
1,3-Dichloro-1,1,3,3-
tetraisopropyldisiloxane (7.70 mL, 25.0 mmol) and imidazole (3.40 g, 50.0
mmol) were added to a solution of phenyl 4,6-O-benzylidene-β-D-
glucopyranoside (3.00 g, 8.30 mmol) in DMF (83.0 mL) under argon
atmosphere. The mixture was stirred for 30 min at 50 °C as the progress
of the reaction was monitored by TLC (EtOAc/n-Hexane = 1/3). The
reaction mixture was neutralized with sat. NaHCO3 aq. in the ice bath and
extracted with EtOAc. The organic phase was washed with H2O and brine,
dried (Na2SO4) and concentrated. The resulting residue was purified by
i
Hz, H-4), 3.47 (dd, 1 H, J5,6b = 5.0 Hz, H-6b), 1.15-0.98 (m, 28 H, 4 Pr);
13C NMR (125 Hz, CDCl3) δ 138.3, 138.2, 134.9, 131.3, 128.8, 128.3,
silica gel column chromatography (EtOAc/n-Hexane
=
1/15) to
128.1, 127.7, 127.7, 127.5, 127.0, 88.5, 82.3, 80.0, 78.8, 77.6, 75.7, 75.4,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700671
European Journal of Organic Chemistry
FULL PAPER
73.4, 69.2, 30.9, 17.6, 17.5, 17.5, 17.3, 17.3, 17.3, 17.2, 12.9, 12.8, 12.3,
12.3; HRMS (ESI) m/z: found [M+Na]+ 717.3075, C32H48O7SSi2 calcd for
[M+Na]+ 717.3072.
for 2.0 h at -20 °C as the progress of the reaction was monitored by TLC
(EtOAc/n-Hexane = 1/3). The reaction mixture was quenched with MeOH,
co-evaporated with toluene and diluted with EtOAc. The solution was
washed with H2O and brine, dried (Na2SO4) and concentrated. The
resulting residue was purified by silica gel column chromatography
(EtOAc/Toluene = 1/10) to give 3 (395 mg, quant.); [α]D +22.1 ° (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.73-7.11 (m, 19 H, 3 Ar), 5.17 (d, 1
H, Jgem = 13.5 Hz, ArCH2), 5.09 (s, 2 H, 2 ArCH2), 4.92 (d, 1 H, Jgem = 11.0
Hz, ArCH2), 4.90 (d, 1 H, ArCH2), 4.59 (d, 1 H, J1,2 = 10.0 Hz, H-1), 4.56
(d, 2 H, Jgem = 15.5 Hz, 2 ArCH2), 4.50 (d, 1 H, ArCH2), 3.76 (d, 1 H, Jgem
= 10.5 Hz, H-6a), 3.70 (t, 1 H, J2,3 = J 3,4 = 8.5 Hz, H-3), 3.66 (dd, 1 H, J5,6b
= 4.5 Hz, H-6b), 3.51 (t, 1 H, J4,5 = 8.5 Hz, H-4), 3.47 (m, 1 H, H-5), 3.40
(t, 1 H, H-2); 13C NMR (125 Hz, CDCl3) δ 138.3, 138.2, 134.9, 131.3, 128.8,
128.3, 128.1, 127.7, 127.7, 127.5, 127.0, 88.5, 82.3, 78.8, 77.9, 75.6, 75.4,
73.4, 69.2, 30.9, 17.6, 17.5, 17.5, 17.3, 17.3, 17.2, 17.2, 12.9, 12.8, 12.3,
12.3; HRMS (ESI) m/z: found [M+Na]+ 577.2016, C34H34O5S calcd for
[M+Na]+ 577.2019.
Phenyl
4,6-O-benzylidene-2,3-O-(o-xylylene)-1-thio-β-D-
glucopyranoside: Sodium hydride (2.60 g, 64.0 mmol) was added to a
solution of phenyl 4,6-O-benzylidene-β-D-glucopyranoside (5.00 g, 12.8
mmol) in DMF (256 mL) in the ice bath under argon atmosphere. The
mixture was stirred for 30 min. To the mixture was added α-α’-dibromo-o-
xylene (3.80 g, 14.1 mmol), and the stirring was continued for 11.5 h at
room temperature as the progress of the reaction was monitored by TLC
(EtOAc/n-Hexane = 1/3). Next, the reaction mixture was quenched with
MeOH, co-evaporated with toluene and diluted with EtOAc. The solution
was washed with H2O and brine, dried (Na2SO4) and concentrated. The
resulting residue was purified by silica gel column chromatography
(Chloroform/Toluene = 1/1) to give phenyl 4,6-O-benzylidene-2,3-O-(o-
xylylene)-1-thio-β-D-glucopyranoside (5.00 g, 84%); [α]D +6.5 ° (c 0.1,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.55-7.12 (m, 14 H, 3 Ar), 5.51 (s, 1
H, >CHPh), 5.18 (d, 1 H, Jgem = 13.5 Hz, ArCH2), 5.15 (d, 1 H, Jgem = 9.5
[4,6-Di-O-benzyl-2,3-O-(2’,3’-dimethoxybutane-2’,3’-diyl)-D-
Hz, ArCH2), 5.12 (d, 1 H, ArCH2), 4.89 (d, 1 H, ArCH2), 4.71 (d, 1 H, J1,2
=
glucopyranosyl]-(1
→
6)-1,2:3,4-di-O-isopropylidene-α-D-
9.5 Hz, H-1), 4.34 (dd, 1 H, J5,6a = 4.5 Hz, Jgem = 10.5 Hz, H-6a), 3.82 (t, 1
H, J2,3 = J3,4 = 9.0 Hz, H-3), 3.73 (t, 1 H, J5,6b = 10.5 Hz, H-6b), 3.53 (t, 1 H,
J4,5 = 9.0 Hz, H-4), 3.50-3.46 (m, 2 H, H-2, H-5); 13C NMR (125 Hz, CDCl3)
δ 139.0, 137.1, 136.6, 136.4, 132.9, 132.3, 131.3, 129.1, 129.1, 129.0,
128.3, 128.1, 127.9, 127.2, 126.4, 120.9, 101.8, 87.7, 81.4, 79.4, 79.3,
79.3, 73.5, 73.0, 72.4, 70.3, 68.6; HRMS (ESI) m/z: found [M+Na]+
485.1391, C27H26O5S calcd for [M+Na]+ 485.1393.
galactopyranose (7): Molecular sieves 4 Å (20.0 mg) were added to a
solution of 1 (25.0 mg, 44.2 μmol) and 6 (14.8 mg, 66.2 μmol) in CH2Cl2
(0.40 μL) under argon atmosphere. The suspension was stirred at ambient
temperature for 30 min and cooled to -40 °C. To the suspension were
added NIS (14.8 mg, 66.2 μmol) and TfOH (1.20 μL, 13.2 μmol), and then
the reaction mixture was stirred for 1 h at -40 °C as the progress of the
reaction was monitored by TLC (EtOAc/Toluene = 1/5). Then, the reaction
mixture was neutralized with Et3N, filtered through a pad of Celite, and the
filtered residue was washed with CHCl3. The combined filtrate and
washings were washed with sat. Na2S2O3 aq., H2O and brine, dried
(Na2SO4) and concentrated. The resulting residue was purified by silica
gel column chromatography (EtOAc/Toluene = 1/10) to give 7 as β-
glycoside (18.2 mg, 66%) and α-glycoside (2.6 mg, 14%); β-form [α]D
+13.3 ° (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.34-7.21 (m, 10 H, 2
Ph), 5.50 (d, 1 H, J1,2 = 5.0 Hz, H-1Gal), 4.90 (d, Jgem = 11.0 Hz, 1 H, PhCH2),
4.60 (d, Jgem = 12.0 Hz, 1 H, PhCH2), 4.55 (dd, 1 H, J2,3 = 2.0 Hz, J3,4 = 8.0
Hz, H-3Gal), 4.53 (d, 1 H, PhCH2), 4.52 (d, 1 H, PhCH2), 4.51 (d, 1 H, J1,2
= 8.0 Hz, H-1Glc), 4.32 (dd, 1 H, J4,5 = 1.5 Hz, H-4Gal), 4.27 (dd, 1 H, H-2Gal),
4.05-4.01 (m, 2 H, H-6aGal, H-6bGal), 3.87 (t, 1 H, J2,3 = J3,4 = 10.0 Hz, H-
3Glc), 3.71 (dd, 1 H, J5,6a = 5.0 Hz, J5.6b = 9.5 Hz, H-5Gal), 3.71-3.68 (m, 2
H, H-6aGlc, H-6bGlc), 3.67 (t, 1 H, J4,5 = 10.0 Hz, H-4Glc), 3.57 (dd, 1 H, H-
2Glc), 3.48 (m, 1 H, H-5Glc), 3.29 (s, 3 H, OCH3), 3.28 (s, 3 H, OCH3), 1.41-
1.26 (m, 24 H, 6 CH3); 13C NMR (125 Hz, CDCl3) δ 138.4, 138.3, 128.3,
128.0, 127.8, 127.7, 127.5, 109.1, 108.5, 100.8, 99.4, 96.3, 75.6, 74.8,
74.8, 73.7, 73.4, 71.1, 70.7, 70.6, 69.4, 69.0, 68.9, 68.6, 67.2, 47.8, 26.0,
26.0, 25.0, 24.4, 17.8, 17.6; HRMS (ESI) m/z: found [M+Na]+ 739.3302,
C38H52O13 calcd for [M+Na]+ 739.3300; α-form [α]D -47.7 ° (c 0.2, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.34-7.05 (m, 10 H, 2 Ph), 5.48 (d, 1 H, J1,2
Phenyl
4-O-benzyl-2,3-O-(o-xylylene)-1-thio-β-D-glucopyranoside:
Dichlorophenylborane (334 µL, 2.58 mmol) and triethylsilane (265 µL, 2.58
mmol) were added to a suspension of phenyl 4,6-O-benzylidene-2,3-O-(o-
xylylene)-1-thio-β-D-glucopyranoside (350 mg, 760 µmol) and molecular
sieves 4Å (350 mg) in CH2Cl2 (7.20 mL) under argon atmosphere. The
mixture was stirred for 1.0 h at -80 °C as the progress of the reaction was
monitored by TLC (EtOAc/n-Hexane = 1/3). The reaction mixture was
quenched with Et3N and MeOH, filtered through a pad of Celite and the
filtered residue was washed with CHCl3. The combined filtrate and
washings were washed with sat. NaHCO3 aq., H2O and brine, dried
(Na2SO4) and concentrated. The resulting residue was purified by silica
gel column chromatography (EtOAc/n-Hexane = 1/7) to give phenyl 4-O-
benzyl-2,3-O-(o-xylylene)-1-thio-β-D-glucopyranoside (323 mg, 92%); [α]D
+50.3 ° (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37-7.12 (m, 14 H, 3
Ar), 5.18 (d, 1 H, Jgem = 13.0 Hz, ArCH2), 5.11 (s, 1 H, ArCH2), 5.10 (s, 1
H, ArCH2), 4.94 (d, 1 H, Jgem = 11.0 Hz, ArCH2), 4.85 (d, 1 H, ArCH2), 4.66
(d, 1 H, ArCH2), 4.63 (d, 1H, J1,2 = 9.5 Hz, H-1), 3.83 (m, 1 H, H-6a), 3.72
(t, 1 H, J2,3 = J3,4 = 8.5 Hz, H-3), 3.62 (m, 1 H, H-6b), 3.45 (t, 1 H, J4,5 = 8.5
Hz, H-4), 3.37-3.36 (m, 2 H, H-2, H-5), 1.84 (t, 1 H, J6a,OH = J6b,OH = 5.0 Hz,
OH); 13C NMR (125 Hz, CDCl3) δ 138.3, 136.8, 136.6, 133.1, 131.9, 130.7,
129.3, 129.0, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 86.6, 86.0,
79.6, 79.0, 76.7, 75.0, 73.1, 73.0, 62.4; HRMS (ESI) m/z: found [M+Na]+
487.1554, C34H34O5S calcd for [M+Na]+ 487.1550.
= 5.0 Hz, H-1Gal), 4.93 (d, 1 H, J1,2 = 4.0 Hz, H-1Glc), 4.90 (d, 1 H, Jgem
=
11.0 Hz, PhCH2), 4.64 (d, 1 H, Jgem = 12.0 Hz, 1 H, PhCH2), 4.57 (dd, 1 H,
J2,3 = 2.0 Hz, J3,4 = 8.0 Hz, H-3Gal), 4.49 (d, 1 H, PhCH2), 4.45 (d, 1 H,
PhCH2), 4.31 (dd, 1 H, J4,5 = 1.5 Hz, H-4Gal), 4.26 (dd, 1 H, H-2Gal), 4.18 (t,
1 H, J2,3 = J3,4 = 10.0 Hz, H-3Glc), 4.05 (m, 1 H, H-5Gal), 4.64 (m, 1 H, H-
6aGal), 3.84-3.74 (m, 5 H, H-2Glc, H-4Glc, H-5Glc, H-6aGlc, H-6bGal), 3.63 (dd,
1 H, J5,6b = 2.0 Hz, Jgem = 10.5 Hz, H-6bGlc), 3.27 (s, 3 H, OCH3), 3.25 (s,
3 H, OCH3), 1.46-1.21 (m, 24 H, 6 CH3); 13C NMR (125 Hz, CDCl3) δ 128.3,
Phenyl
glucopyranoside (3): Sodium hydride (42.8 mg, 1.07 mmol) was added
to solution of phenyl 4-O-benzyl-2,3-O-(o-xylylene)-1-thio-β-D-
4,6-di-O-benzyl-2,3-O-(o-xylylene)-1-thio-β-D-
a
glucopyranoside (331 mg, 713 µmol) in DMF (3.60 mL) at -20 °C under
argon atmosphere. The mixture was stirred for 30 min at -20 °C, and
benzyl bromide (423 μL 3.56 mmol) was added. The stirring was continued
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700671
European Journal of Organic Chemistry
FULL PAPER
128.2, 127.9, 127.8, 127.6, 127.5, 109.1, 108.6, 99.3, 97.9, 96.2, 75.0,
74.7, 70.8, 70.6, 70.4, 68.4, 68.3, 47.8, 29.7, 26.0, 25.0, 24.3, 22.7, 18.0,
17.6; HRMS (ESI) m/z: found [M+Na]+ 739.3303, C38H52O13 calcd for
[M+Na]+ 739.3300.
the reaction mixture was stirred for 7.5 h at -80 °C as the progress of the
reaction was monitored by TLC (EtOAc/Toluene = 1/5). Then, the reaction
mixture was neutralized with Et3N, filtered through a pad of Celite, and the
filtered residue was washed with CHCl3. The combined filtrate and
washings were washed with sat. Na2S2O3 aq., H2O and brine, dried
(Na2SO4) and concentrated. The resulting residue was purified by silica
gel column chromatography (EtOAc/n-Hexane = 1/5) to give 9 as β-
glycoside (106 mg, 86%) and α-glycoside (9.3 mg, 7%).
[4,6-Di-O-benzyl-2,3-O-(1,1,3,3-tetraisopropyldisiloxanylidene)-D-
glucopyranosyl]-(1→6)-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (8): Molecular sieves 4 Å (70.0 mg) were added to a
solution of 2 (100 mg, 144 μmol) and 6 (37.4 mg, 144 μmol) in CH2Cl2
(1.40 mL) under argon atmosphere. The suspension was stirred at ambient
temperature for 30 min and cooled to -80 °C. To the suspension were
added NIS (48.6 mg, 240 μmol) and TfOH (3.80 μL, 43.2 μmol), and then
the reaction mixture was stirred for 9 h at -80 °C as the progress of the
reaction was monitored by TLC (EtOAc/Toluene = 1/5). Then, the reaction
mixture was neutralized with Et3N, filtered through a pad of Celite, and the
filtered residue was washed with CHCl3. The combined filtrate and
washings were washed with sat. Na2S2O3 aq., H2O and brine, dried
(Na2SO4) and concentrated. The resulting residue was purified by silica
gel column chromatography (EtOAc/Toluene = 1/30) to give 8 as β-
Glycosidation of 19 : Molecular sieves AW 300 (35.0 mg) were added to a
solution of 19 (45.3 mg, 71.5 μmol) and 6 (18.6 mg, 71.5 μmol) in CH2Cl2
(0.70 mL) under argon atmosphere. The suspension was stirred at ambient
temperature for 5 min and cooled to -80 °C. To the suspension were added
TMSOTf (0.60 μL, 3.60 μmol), and then the reaction mixture was stirred
for 1.0 h at -80 °C as the progress of the reaction was monitored by TLC
(EtOAc/Toluene = 1/5). Then, the reaction mixture was neutralized with
Et3N, filtered through a pad of Celite, and the filtered residue was washed
with CHCl3. The combined filtrate and washings were washed with H2O
and brine, dried (Na2SO4) and concentrated. The resulting residue was
purified by silica gel column chromatography (EtOAc/n-Hexane = 1/5) to
give 9 as β-glycoside (39.5 mg, 80%) and α-glycoside (4.88 mg, 10%); β-
form [α]D +5.26 ° (c 0.08, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.33-7.07
(m, 14 H, 3 Ar), 5.56 (d, 1 H, J1,2 = 5.0 Hz, H-1Gal), 5.23 (d, 1 H, Jgem = 13.0
Hz, ArCH2), 5.10 (d, 1 H, Jgem = 15.0 Hz, ArCH2), 5.05 (d, 1 H, ArCH2),
4.91 (d, 1 H, Jgem = 11.0 Hz, ArCH2), 4.81 (d, 1 H, ArCH2), 4.60 (dd, 1 H,
J2,3 = 2.0 Hz, J3,4 = 8.0 Hz, H-3Gal), 4.57 (d, 1 H, Jgem = 12.0 Hz, ArCH2),
4.54 (d, 1 H, ArCH2), 4.50 (d, 1 H, ArCH2), 4.42 (d, 1 H, J1,2 = 8.0 Hz, H-
1Glc), 4.31 (dd, 1 H, H-2Gal), 4.29 (dd, 1 H, J4,5 = 1.5 Hz, H-4Gal), 4.08-4.04
(m, 2 H, H-5Gal, H-6aGal), 3.78 (dd, 1 H, J5,6b = 8.0 Hz, Jgem = 12.5 Hz, H-
6bGal), 3.72-3.67 (m, 2 H, H-3Glc, H-6aGlc), 3.64 (dd, 1 H, J5,6b = 4.5 Hz, Jgem
= 11.0 Hz, H-6bGlc), 3.49 (t, 1 H, J3,4 = J4,5 = 8.0 Hz, H-4Glc), 3.41 (m, 1 H,
glycoside (106 mg, 88%) and α-glycoside (11.0 mg, 9%).; β-form [α]D
-
20.8 ° (c 0.1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.35-7.18 (m, 10 H, 2
Ph), 5.49 (d, 1 H, J1,2 = 5.0 Hz, H-1Gal), 4.91 (d, 1 H, Jgem = 11.0 Hz, PhCH2),
4.58 (d, 1 H, Jgem = 12.0 Hz, PhCH2), 4.56 (d, 1 H, PhCH2), 4.55 (s, 1 H,
PhCH2), 4.54 (m, 1 H, H-3Gal), 4.32 (dd, 1 H, J3,4 = 8.0 Hz, J4,5 = 1.5 Hz, H-
4Gal), 4.29 (d, 1 H, J1,2 = 7.5 Hz, H-1Glc), 4.27 (dd, 1 H, J2,3 = 2.5 Hz, H-
2Gal), 4.09 (dd, J5,6a = 6.5 Hz, Jgem = 10.5 Hz, H-6aGal), 3.98 (td, 1 H, J5,6b
= 6.5 Hz, H-5Gal), 3.82 (t, J2,3 = J3,4 = 8.5 Hz, H-3Glc), 3.72-3.67 (m, 2 H, H-
6aGlc, H-6bGal), 3.65 (dd, 1 H, J5,6b = 4.5 Hz, Jgem = 11.0 Hz, H-6bGlc), 3.53
(dd, 1 H, H-2Glc), 3.51 (t, 1 H, J4,5 = 8.5 Hz, H-4Glc), 3.42 (m, 1 H, H-5Glc),
1.54-1.26 (4 s, 12 H, 4 CH3), 1.10-0.94 (m, 28 H, 4 iPr); 13C NMR (125 Hz,
CDCl3) δ 138.3, 138.3, 128.3, 128.3, 128.1, 127.9, 127.7, 127.6, 109.0,
108.4, 103.3, 96.4, 81.2, 78.1, 76.5, 75.3, 74.5, 73.5, 70.9, 70.7, 70.6, 68.9,
68.6, 66.4, 26.1, 26.0, 25.0, 24.3, 17.5, 17.4, 17.4, 17.4, 17.3, 17.3, 17.3,
17.3, 13.0, 12.8, 12.6, 12.2; HRMS (ESI) m/z: found [M+Na]+ 867.4141,
C44H68O12Si2 calcd for [M+Na]+ 867.4142; α-form [α]D +73.3 ° (c 0.03,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.35-7.15 (m, 10 H, 2 Ph), 5.48 (d, 1
H, J1,2 = 5.0 Hz, H-1Gal), 4.91 (d, 1 H, Jgem = 11.0 Hz, PhCH2), 4.90 (d, 1 H,
J1,2 = 4.5 Hz, H-1Glc), 4.61 (d, 1 H, Jgem = 12.0 Hz, PhCH2), 4.56 (dd, 1 H,
J2,3 = 2.5 Hz, J3,4 = 8.0 Hz, H-3Gal), 4.49 (d, 1 H, PhCH2), 4.48 (d, 1 H,
PhCH2), 4.34 (dd, 1 H, J4,5 = 2.0 Hz, H-4Gal), 4.28 (dd,1 H, H-2Gal), 4.12 (t,
1 H, J2,3 = J3,4 = 9.0 Hz, H-3Glc), 3.94 (td, 1 H, J5,6a = 6.0 Hz, J5,6b = 8.5 Hz,
H-5Glc), 3.36 (t, 1 H, J2,3 = 8.0 Hz, H-2Glc), 1.55-1.32 (4 s, 12 H, 4 CH3); 13
C
NMR (125 Hz, CDCl3) δ 138.6, 138.3, 137.5, 136.8, 131.6, 128.6, 128.4,
128.3, 128.1, 127.9, 127.8, 127.6, 127.5, 109.3, 108.6, 102.9, 96.4, 84.2,
80.8, 77.8, 76.9, 74.8, 74.5, 73.5, 73.0, 72.5, 71.4, 70.8, 70.6, 69.3, 69.0,
67.7, 26.2, 26.0, 25.1, 24.5; HRMS (ESI) m/z: found [M+Na]+ 727.3089,
C40H48O11 calcd for [M+Na]+ 727.3089; α-form; [α]D +47.1 ° (c 0.1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.34-7.10 (m, 14 H, 3 Ar), 5.47 (d, 1 H, J1,2
5.0 Hz, H-1Gal), 5.15 (d, 1 H, Jgem = 13.5 Hz, ArCH2), 5.03 (d, 1 H, Jgem
=
=
14.5 Hz, ArCH2), 5.00 (d, 1 H, J1,2 = 4.0 Hz, H-1Glc), 4.98 (d, 1 H, ArCH2),
4.96 (d, 1 H, ArCH2), 4.90 (d, 1 H, Jgem = 11.0 Hz, ArCH2), 4.61 (d, 1 H,
Jgem = 12.5 Hz, ArCH2), 4.56 (dd, 1 H, J2,3 = 2.0 Hz, J3,4 = 8.0 Hz, H-3Gal),
4.53 (d, 1 H, ArCH2), 4.45 (d, 1 H, ArCH2), 4.27-4.20 (m, 2 H, H-2Gal, H-
4Gal), 4.01-3.98 (m, 2 H, H-5Gal, H-6aGal), 3.88 (dt, 1 H, J5,6a = 2.0 Hz, Jgem
= 7.5 Hz, H-6aGlc), 3.81-3.73 (m, 3 H, H-3Glc, H-4Glc, H-6bGal), 3.66-3.73 (m,
2 H, H-5Glc, H-6bGlc), 3.56 (dd, 1 H, J2,3 = 9.5 Hz, H-2Glc), 1.45-1.35 (4 s,
12 H, 4 CH3); 13C NMR (125 Hz, CDCl3) δ 138.7, 138.1, 137.2, 136.9,
129.7, 129.2, 128.2, 128.2, 127.8, 127.8, 127.6, 127.5, 127.5, 109.1, 108.5,
98.1, 96.2, 82.3, 80.4, 74.7, 73.6, 73.4, 73.3, 71.0, 70.7, 70.6, 70.0, 68.5,
67.1, 66.5, 29.7, 26.1, 26.0, 25.0, 24.4; HRMS (ESI) m/z: found [M+Na]+
727.3093, C40H48O11 calcd for [M+Na]+ 727.3089.
H-5Gal), 3.80 (m, 1 H, H-5Glc), 3.76-3.68 (m, 4 H, H-2Glc, H-6aGlc, H-6aGal
,
H-6bGal), 3.63 (dd, 1 H, J5,6b = 2.0 Hz, Jgem = 10.5 Hz, H-6bGlc), 3.58 (t, 1 H,
J4,5 = 9.0 Hz, H-4Glc) 151-1.29 (4 s, 12 H, 4 CH3), 1.43-0.91 (m, 28 H, 4
iPr); 13C NMR (125 Hz, CDCl3) δ 138.3, 128.3, 128.3, 128.1, 127.9, 127.6,
127.5, 109.0, 108.4, 103.3, 96.3, 81.2, 78.1, 77.6, 76.5, 75.2, 74.5, 73.5,
70.9, 70.7, 70.6, 68.9, 68.6, 66.4, 26.1, 26.0, 25.0, 24.3, 17.5, 17.4, 17.4,
17.3, 17.3, 17.3, 17.3, 17.2, 13.0, 12.8, 12.2; HRMS (ESI) m/z: found
[M+Na]+ 867.4147, C44H68O12Si2 calcd for [M+Na]+ 867.4142.
[4,6-Di-O-benzyl-2,3-O-(o-xylylene)-D-glucopyranosyl]-(1→6)-1,2:3,4-
di-O-isopropylidene-α-D-galactopyranose (9)
Glycosidation of 3: Molecular sieves 4 Å (90.0 mg) were added to a
solution of 3 (100 mg, 182 μmol) and 6 (46.8 mg, 182 μmol) in CH2Cl2
(1.80 mL) under argon atmosphere. The suspension was stirred at ambient
temperature for 30 min and cooled to -80 °C. To the suspension were
added NIS (60.7 mg, 274 μmol) and TfOH (4.40 μL, 55.0 μmol), and then
Computational detail: All DFT calculations were carried out with
GAUSSIAN 09 program package19. We use B3LYP hybrid exchange-
correlation functional20 and 6-311G(d) electronic basis set for calculations.
Solvent effects (Solvent = CH2Cl2) were included using the polarizable
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10.1002/ejoc.201700671
European Journal of Organic Chemistry
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continuum model (PCM),21 The initial structure of oxocarbenium ion
intermediate was built with the aid of GaussView 5 visualization software
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the optimized structure, and confirmed that the optimized structure has no
imaginary frequencies.
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The iCeMS is supported by World Premier International
Research Center Initiative (WPI), Ministry of Education,
CultureSports, Science, and Technology (MEXT), Japan. This
work was financially supported in part by JSPS KAKENHI Grant
Number 15H04495 (H.A.) and No. 26110704 (H.A.).
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FULL PAPER
Glycosylation
N. Yagami, H. Tamai, T. Udagawa, A.
Ueki, M. Konishi, A. Imamura, H. Ishida,*
M. Kiso, H. Ando,*
A 1,2-trans-selective glycosyl donor
bearing cyclic protection at the C2
and C3 hydroxyl groups
A new 1,2-trans-selective glycosidation reaction is described. Glucosyl donors
protected cyclically at the C2 and C3 hydroxyl groups mainly generated -glycosides
under conventional glycosidation conditions. The results showed that the o-xylylene-
group is suitable as a 1,2-trans-directing functionality.
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