Pre-activation based stereoselective glycosylations: Stereochemical control by additives and solvent

Article abstract of DOI:10.1007/s11426-010-4186-6

Stereochemical control is an important issue in carbohydrate synthesis. Glycosyl donors with participating acyl protective groups on 2-O have been shown to give 1,2-trans glycosides reliably under the pre-activation based reaction condition. In this work,

Full text of DOI:10.1007/s11426-010-4186-6

SCIENCE CHINA
Chemistry
January 2011 Vol.54 No.1: 66–73
doi: 10.1007/s11426-010-4186-6
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
Pre-activation based stereoselective glycosylations:
Stereochemical control by additives and solvent
WASONGA Gilbert, ZENG YouLin & HUANG XueFei*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, USA
Received May 18, 2010; accepted June 30, 2010
Stereochemical control is an important issue in carbohydrate synthesis. Glycosyl donors with participating acyl protective
groups on 2-O have been shown to give 1,2-trans glycosides reliably under the pre-activation based reaction condition. In this
work, the effects of additives and reaction solvents on stereoselectivity were examined using donors without participating pro-
tective groups on 2-O. While several triflate salt additives did not have major effects, the amount of AgOTf was found to sig-
nificantly impact the reaction outcome. Excess AgOTf led to lower stereochemical control presumably due to its coordination
with the glycosyl triflate intermediate and a more SN1 like reaction pathway. In contrast, the stereoselectivity could be directed
by reaction solvents, with diethyl ether favoring the formation of  glycosides and dichloromethane leading to  isomers. The
trend of stereochemical dependence on reaction solvent was applicable to a variety of building blocks including the selective
formation of -mannosides.
stereoselectivity, pre-activation based glycosylation, additives, solvent effects
clude benzylidene protected mannosyl donor [4, 5] and
1 Introduction
intramolecular aglycon delivery [6, 7] for -mannoside
formation, thioether chiral auxiliary assisted formation of
disarmed -glucosides and galactosides [8]. Despite the
successes in these special cases, in general, anomeric con-
trols still mostly rely on the anomeric effect and/or steric
hindrance, which can vary depending on structures of the
coupling partners and often demand individual analysis [4,
9–14].
Recently, we have developed a pre-activation based one-
pot glycosylation method using thioglycosides, where mul-
tiple sequential glycosylation reactions can be performed
without intermediate purification [15]. This is a powerful
strategy for glyco-assembly, which has been applied to the
constructions of complex oligosaccharides containing both
1,2-cis and 1,2-trans linkages [16, 17]. Using donors bear-
ing participating acyl groups on 2-O position, 1,2-trans
glycoside products can be formed reliably [16, 17]. On the
other hand, the formation of 1,2-cis linkages has not been
systematically evaluated. Herein, we report our results on
During the past two decades, there has been tremendous
growth in the development of novel glycosylation method-
ologies and reagents, resulting in our much improved abili-
ties to form the glycosidic linkages [1, 2]. However, reliable
stereochemical control remains as a major issue in carbohy-
drate synthesis. The glycosidic bond can be linked either in
1,2-cis or 1,2-trans manner. Synthesis of oligosaccharides
containing 1,2-trans glycosidic linkages is typically accom-
plished by the installation of an acyl protective group on
2-O position of the glycosyl donor [1]. Upon donor activa-
tion, neighboring group participation of the 2-O acyl group
will direct the formation of 1,2-trans linkages with a high
degree of stereo-control. By contrast, efficient formation of
1,2-cis glycosidic linkages is a more difficult task [3]. Sev-
eral innovative methods have been developed, which in-
*Corresponding author (email: xuefei@chemistry.msu.edu)
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com
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Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
67
the exploration of various factors impacting stereo-selectivity
2.1 Procedures for pre-activation based glycosylation
using donors without participating neighboring groups on
2-O position.
Method A
Donor (120 mg) was dissolved in Et2O (5 mL) and stirred at
78 °C with freshly activated molecular sieves MS 4 Å
(100 mg) under nitrogen atmosphere for 30 min. AgOTf (1
equiv) dissolved in Et2O (1 mL) was added to the reaction
mixture. After 5 min, p-TolSCl (1 equiv) was added via a
microsyringe. As the reaction temperature was below the
freezing point of p-TolSCl, p-TolSCl should be directly
added to the reaction mixture without touching the flask
wall. The characteristic yellow color of p-TolSCl dissipated
within a few seconds. The donor was completely consumed
after 1 min as confirmed by TLC analysis. Glycosyl accep-
tor (0.9 equiv) dissolved in Et2O (2 mL) was then added
dropwise to the reaction mixture. The reaction was warmed
up to 20 °C over 1 h under N2 at which point, the acceptor
was completely consumed as confirmed by TLC. The reac-
tion was quenched with Et3N then concentrated to dryness.
The residue was diluted with CH2Cl2 (20 mL) and filtrated
over Celite. The Celite was further washed with CH2Cl2
until no organic compound was present in the filtrate as
determined by TLC. The fractions were combined, concen-
trated to dryness and the residue purified by silica gel flash
chromatography.
2 Experimental
All reactions were carried out under nitrogen with anhy-
drous solvents in flame-dried glassware. All glycosylation
reactions were performed in the presence of molecular
sieves, which were flame dried right before the reaction
under high vacuum. Glycosylation solvents were dried us-
ing a solvent purification system and used directly without
further drying. Chemicals used were of reagent grade as
supplied except where noted. Analytical thin-layer chroma-
tography was performed using silica gel 60 F254 glass plate.
Compound spots were visualized by UV light (254 nm) and
by staining with a yellow solution containing Ce(NH4)2(NO3)6
(0.5 g) and (NH4)6Mo7O24·4H2O (24.0 g) in 6% H2SO4 (500
mL). Flash Column chromatography was performed on sil-
ica gel 60 (230–400 Mesh). NMR spectra were referenced
using Me4Si (0 ppm), residual CHCl3 ( 1H NMR 7.24 ppm,
13C NMR 77.0 ppm). Peak and coupling constant assign-
ments are based on 1H NMR, 1H-1H gCOSY and (or) 1H-13C
1
gHMQC and H-13C gHMBC experiments. All optical rota-
tions were measured at 25 °C using the sodium D line. ESI
mass spectra were recorded in the positive ion mode. High-
resolution mass spectra were recorded on a Micromass
electrospray. Figure 1 shows the structures of compounds
1–18.
Method B
Donor (120 mg) was dissolved in CH2Cl2 (5 mL) and stirred
at 78 °C with freshly activated molecular sieves MS 4 Å
(100 mg) under nitrogen atmosphere for 30 min. AgOTf
Figure 1 Structures of 1–18.

68
Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
(1 equiv) dissolved in acetonitrile/CH2Cl2 (v:v=1:4, 0.5 mL)
was added to the reaction mixture. After 5 min, p-TolSCl (1
equiv) was added via a microsyringe. As the reaction tem-
perature was below the freezing point of p-TolSCl, p-TolSCl
should be directed added to the reaction mixture without
touching the flask wall. The characteristic yellow color of
p-TolSCl dissipated within a few seconds. The donor was
completely consumed after 5 min as confirmed by TLC
analysis. Glycosyl acceptor (0.9 equiv) dissolved in CH2Cl2
(1 mL) was then added dropwise to the reaction mixture.
The reaction was warmed up to 20 °C over 1 h under N2 at
which point, the acceptor was completely consumed as con-
firmed by TLC. The reaction was quenched with Et3N then
concentrated to dryness. This was followed by dilution with
CH2Cl2 (20 mL) and filtration over Celite. The Celite was
further washed with CH2Cl2 until no organic compounds
was present in the filtrate. The fractions were combined
then concentrated to dryness. The residue was purified by
silica gel flash chromatography.
138.74, 139.24, 165.32, 165.39, 166.00; HRMS C68H64NaO13S
[M + Na+] calcd 1143.3965 found 1143.3999.
p-Tolyl 2,3,4-tri-O-benzyl-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzyl-1-thio--D-glucopyranoside (5)
Using method A of general procedure for glycosylation,
donor 1 reacted with acceptor 4 to give desired product 5 in
80% yield (/ 5.7:1) after column purification (hexanes/
ethyl acetate/CH2Cl2, 5.5:1:0.5). 1H NMR (400 MHz, CDCl3)
  anomer 2.23 (s, 3H), 3.27 (t, 1H, J3 =9.2 Hz), 3.42–3.92
(m, 10 H), 4.01 (t, 1H, J3 = 9.2 Hz), 4.47 (d, 1H, J3 = 12.0
Hz), 4.52 (d, 1H, J3 = 11.2 Hz), 4.58 (d, 1H, J3 = 9.6 Hz),
4.63 (d, 1H, J3 = 10.0 Hz), 4.64 (d, 1H, J3 = 12.0 Hz), 4.68
(d, 1H, J3 = 11.2 Hz), 4.76–4.95 (m, 8 H), 5.00 (d, 1H, J3 =
10.8 Hz), 5.04 (d, 1H, J3 = 3.2 Hz), 7.06–7.12 (m, 2H),
7.13–7.52 (m, 37H);  anomer 2.30 (s, 3H, SPhCH3),
3.46–3.56 (m, 4H), 3.63–3.70 (m,3H), 3.73–3.81 (m, 3H),
4.24 (dd, 1H, J3 = 1.8 Hz, 11.2 Hz,), 4.47 (d, 1H, J3 = 7.6
Hz), 4.57–4.67 (m, 4H, CH2Ph), 4.70 (d, 1H, J3 = 9.8 Hz),
4.75–5.02 (m, 10H, CH2Ph), 7.06–7.52 (m, 39H, aromatic);
13C NMR (100 MHz, CDCl3)   anomer 21.32, 68.79,
70.47, 72.70, 73.67, 75.18, 75.21, 75.71, 75.89, 75.92,
77.85, 77.93, 79.01, 80.42, 81.37, 82.03, 86.93, 88.73,
97.62, 127.78, 127.90, 127.93, 128.00, 128.08, 128.15,
128.23, 128.50, 128.59, 128.61, 128.65, 128.66, 128.71,
130.03, 133.15, 138.03, 138.26, 138.35, 128.45, 138.70,
138.75, 138.81, 139.14;  anomer 29.98, 60.65, 68.87,
69.18, 73.79, 75.08, 75.16, 75.63, 75.98, 76.00, 77.49,
78.13, 78.25, 79.12, 81.06, 82.48, 84.97, 86.99, 87.90,
100.05, 127.74, 127.84, 128.03, 128.20, 128.36, 128.44,
128.54, 129.94, 130.24, 130.27, 132.39, 137.66, 138.29,
138.60, 138.86. HRMS C68H70NaO10S [M + Na+] calcd.
1101.4587 found 1101.4531.
2.2 Characterization of anomeric stereochemistry
The stereochemistry of the newly formed glycosidic link-
3
1
ages are determined by JH1,H2 through H NMR and/or
1JC1,H1 through gHMQC 2-D NMR (without 1H decoupling).
Smaller coupling constants of JH1,H2 (around 3 Hz) indicate
 linkages and larger coupling constants JH1,H2 (7.2 Hz or
3
3
larger) indicate  linkages for glucosides and galactosides.
1
This can be further confirmed by JC1,H1 (~170 Hz) for 
1
linkages and JC1,H1 (~160 Hz) for  linkages for all glyco-
sidic linkages [32].
p-Tolyl 2,3,4-tri-O-benzyl-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzoyl-1-thio--D-glucopyranoside (3)
Methyl 2,3,4-tri-O-benzyl-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzyl--D-glucopyranoside (7)
Using method A of general procedure for glycosylation,
donor 1 reacted with acceptor 2 to give desired product 3 in
69% yield (/ 6:1) after column purification (hexanes/
ethyl acetate 3:1). 1H NMR (600 MHz, CDCl3)  anomer 
2.15 (s, 3H), 3.48 (dd, 1H, J3 = 1.8, 10.8 Hz), 3.54 (dd, 1H,
J3 =3.0, 9.6 Hz), 3.62 (dd, 1H, J3 =1.8, 10.2 Hz), 3.66 (t, 1H,
J3 = 9.6 Hz), 3.71 (dd, 1H, J3 = 3.0, 10.8 Hz), 3.89 (dd, 1H,
J3 = 7.8, 10.8 Hz), 3.93–3.98 (m, 2H), 4.05–4.12 (m, 1H),
4.43 (d, 1H, J3 = 12.0 Hz), 4.50 (d, 1H, J3 = 10.8 Hz), 4.58
(d, 1H, J3 = 12.0 Hz), 4.60 (d, 1H, J3 =12.0 Hz), 4.65 (d, 1H,
J3 = 3.6 Hz), 4.75 (d, 1H, J3 = 12.0 Hz), 4.79 (d, 1H, J3 =
10.8 Hz), 4.81 (d, 1H, J3 = 10.8 Hz), 4.92 (d, 1H, J3 = 10.8
Hz), 5.40 (t, 1H, J3 = 10.2 Hz), 5.42 (t, 1H, J3 = 10.2 Hz),
5.83 (t, 1H, J3 = 9.0 Hz), 6.98–7.02 (m, 2H), 7.10–7.98 (m,
37 H); 13C NMR (100.5 MHz, CDCl3)  21.31, 67.52, 68.63,
69.88, 70.42, 70.89, 73.62, 73.70, 74.64, 75.23, 75.98,
77.54, 77.96, 80.40, 82.23, 87.34, 97.54, 127.69, 127.78,
127.85, 128.02, 128.06, 128.12, 128.35, 128.44, 128.49,
128.62, 128.63, 128.67, 129.12, 129.58, 129.97, 130.13,
133.39, 133.49, 133.70, 133.93, 138.22, 138.48, 138.68,
Using method B of general procedure for glycosylation,
donor 1 reacted with acceptor 6 to give the desired product
7 in 79% yield (/ 1:9) after column purification (hexanes/
1
ethyl acetate 3:1). Comparison of H NMR spectra with
literature values [33] confirmed the identity of compound 7.
1H NMR (500 MHz, CDCl3) 3.36 (s, 3H, OCH3), 3.44–3.47
(m, 2H), 3.51–3.71(m, 14H), 3.74 (d, 1H, J3 = 1.5 Hz), 3.76
(d, 1H, J3 = 2 Hz), 3.84–3.87 (m, 1H), 4.0–4.04 (m, 2H),
4.22 (dd, 1H, J3 = 2, 11 Hz), 4.39 (d, 1H, J3 = 8 Hz),
4.50–4.85 (m, 18H), 4.92–4.95 (m, 1H), 4.98–5.02 (m, 3H),
7.14–7.38 (m, 64H, aromatic), 7.81–7.86 (m, 6H, aromatic).
p-Tolyl 2,3,4-tri-O-benzyl-1-thio--D-glucopyranosyl-(1→4)-
2,3-di-O-benzoyl-6-O-benzyl-1-thio--D-galatcopyranoside
(9)
Using method A of general procedure for glycosylation,
donor 1 reacted with acceptor 8 to give desired product (9)
in 60 % yield as  isomer after column purification (hexanes/

Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
69
1
13C NMR (125 MHz, CDCl3),  19.4, 21.3, 24.9, 26.86, 26.9,
29.9, 36.9, 63.1, 69.6, 69.9, 72.4, 72.6, 73.6, 74.8, 75.1, 75.6,
75.7, 75.8, 77.0, 77.3, 77.46, 77.5, 77.9, 78.0, 79.0, 80.3,
81.4, 81.7, 86.9, 89.0 (JC-1,H-1 = 170.04 Hz, C-1c), 97.5
(JC-1,H-1 =170.72 Hz, C-1b), 101.5 (JC-1,H-1 =161.68 Hz, C-1a),
127.5, 127.56, 127.6, 127.7, 127.8,127.83, 127.89, 127.92,
128.03, 128.06, 128.1, 128.43, 128.49, 128.53, 128.54,
128.58, 128.6, 128.65, 128.7, 129.2, 129.5, 129.58, 129.86,
129.89, 129.9, , 130.0,130.1, 130.5, 133.1, 133.2, 133.22,
133.28, 133.3, 133.4, 135.8, 135.9, 138.0, 138.4, 138.5, 138.7,
138.8, 138.9, 139.2, 165.16, 165.26, 166.19; HRMS C104-
H108NO18SSi [M+NH4]+ calcd 1718.7135, found 1718.7137.
ethyl acetate 3:1). Comparison of H NMR with literature
values [15] confirmed the identity of compound 9. 1H NMR
(600 MHz, CDCl3) 2.14 (s, 3H SPhCH3), 2.88 (dd, 1H,
J3 = 1.8, 11.4 Hz), 3.13 (dd, 1H, J 3 =1.8, 10.8 Hz), 3.49 (dd,
1H, J3 = 3.0, 9.6 Hz), 3.65(t, 1H, J3 = 9.6 Hz), 3.76 (m, 1H),
3.74–3.77. (m, 1H), 3.89–3.96 (m, 4H), 4.04 (d, 1H, J3 =12
Hz, CH2Ph), 4.34–4.41 (m, 5H), 4.61 (d, 1H, J3 = 11.4 Hz,
CH2Ph), 4.74–4.92 (m, 6H), 5.29 (dd, 1H, J3 =3.0, 10.2 Hz),
5.65 (t, 1H, J3 = 10.2 Hz), 6.99–7.00 (m, 2H, aromatic),
7.10–7.14 (m, 4H, aromatic), 7.20–7.19 (m, 29H, aromatic),
7.89–7.94 (m, 4H, aromatic).
p-Tolyl 2,3-di-O-benzyl-4,6-di-O-benzoyl-D-glucopyranosyl-
(1→6)-2,3,4-tri-O-benzoyl-1-thio--D-glucopyranoside (11)
Methyl 2,3,4-tri-O-benzoyl-6-O-tert-butyldiphenylsilyl--D-
glucopyranosyl-(1→6)-2,3,4-tri-O-benzyl--D-glucopyranosyl-
(1→6)-2,3,4-tri-O-benzyl--D-glucopyronoside (14)
Compound 14 was synthesized from donor 12 and acceptor
6 in 76% yield as  isomer using method B of general pro-
cedure and purified by flash column chromatography (hexanes/
ethyl acetate/CH2Cl2, 4:1:0.5). []D20 + 12 (c = 0.2, CH2Cl2);
Using method A of general procedure for glycosylation,
donor 10 reacted with acceptor 2 to give the desired product
11 in 69% yield (/ 6:1 as determined from SPhCH3
singlet and H-3 ratios) after column purification (hexanes/
1
ethyl acetate 3:1). []D20 + 33 (c = 1.0, CH2Cl2); H NMR
(600 MHz, CDCl3)  2.18 (s, 3H, SPhCH3, ), 2.27(s,
SPhCH3 ), 3.56 (m, 1H), 3.72 (dd, 1H, J3 = 3.6, 9.6 Hz),
3.95–4.00 (m, 1H), 4.14–4.24 (m, 3H), 4.32–4.36 (m, 1H),
4.42 (dd, 1H, J3 = 2.4, 12 Hz), 4.64–4.68 (m, 2H), 4.74 (d,
1H, J3 = 3 Hz, H-1), 4.81 (d, 1H, J3 = 12 Hz, CH2Ph), 4.89
(d, 1H, J3 = 12 Hz, CH2Ph), 4.99 (d, 1H, J3 = 9.6 Hz, H-1),
5.38–5.45 (m, 3H), 5.84 (t, 1H, J3 = 12 Hz), 7.07–7.56 (m,
32H, aromatic), 7.77–8.04 (m, 11H, aromatic). 13C NMR
(150 MHz, CDCl3),  21.07, 62.99,66.76, 68.01, 69.42, 70.54,
70.76, 73.62, 74.41, 75.69, 76.79, 77.0, 77.21, 79.42, 79.98,
87.07 (JC-1,H-1 =159.07 Hz, C-1a), 97.01 (JC-1,H-1 =169.76 Hz,
C-1b) 114.77, 127.49, 127.79, 127.98, 128.13, 128.2, 128.26,
128.32, 128.37, 128.47, 128.52, 128.81, 128.89, 129.31,
129.54, 129.74, 129.78, 129.82, 129.83, 129.87, 132.44,
132.94,133.1,133.2, 133.3, 133.5, 138.06, 138.17, 138.2,
165.02, 165.08, 165.31, 165.77, 166.04. HRMS C68H60NaO15S
[M + Na]+ calcd 1171.3551 found 1171.3600.
1H NMR (500 MHz, CDCl3) 1.00 (s, 9H, (CH3)3CSi), 3.33
(d, 1H, J3 = 8.5 Hz), 3.35 (s, 3H, OCH3), 3.39–3.41 (m, 2H),
3.43–3.49 (m, 2H), 3.52–3.56 (m, 2H), 3.61–3.65 (m, 1H),
3.70–3.72 (m, 1H), 3.76–3.79 (m, 1H), 3.83–3.85 (m, 2H),
3.96 (t, 1H, J3 = 9.5 Hz), 4.00 (dd, 1H, J3 = 1.8, 10.8 Hz),
4.17 (d, 1H, J3 = 7.5 Hz, H-1b), 4.20 (dd, 1H J3 = 1.8, 11.4
Hz), 4.39 (d, 1H, J3 = 11 Hz, CH2Ph), 4.44 (d, 1H, J3 = 11
Hz, CH2Ph), 4 59 (d, 1H, J3 = 11 Hz, CH2Ph), 4.61 (d, 1H,
J3 = 6 Hz, H-1a), 4.64 (d, 1H, J3 = 11 Hz, CH2Ph), 4.67 (d,
1H, J3 = 11 Hz, CH2Ph), 4.71 (d, 1H, J3 = 11 Hz, CH2Ph),
4.75–4.77 (m, 2H, CH2Ph), 4.82 (d, 1H, J3 =11 Hz, CH2Ph),
4.85 (d, 1H, J3 = 8Hz, H-1c), 4.91 (d, 1H, J3 = 11 Hz,
CH2Ph), 4.95 (d, 1H, J3 = 11 Hz, CH2Ph), 5.50–5.53 (m, 1H,
H-2c), 5.61 (t, 1H, J3 =9.5 Hz, H-4c), 5.78 (t, 1H, J3 =9.5 Hz,
H-3c), 7.08–7.40 (m, 49H aromatic), 7.49–7.52 (m, 1H,
aromatic), 7.66–7.68 (m, 2H, aromatic), 7.79–7.81 (m, 2H,
aromatic), 7.81–7.86 (m, 6H, aromatic); 13C NMR (125
MHz, CDCl3),  19.4, 26.9, 55.65, 55.7, 63.1, 68.1, 69.5,
69.9, 72.4, 73.5, 73.6, 74.9, 75.08, 75.1, 75.4, 75.77, 75.8,
77.0, 77.3, 77.46, 77.5, 77.9, 78.0, 79.95, 82.1, 82.2, 85.0,
98.4 (JC-1,H-1 = 168.69 Hz, C-1a), 101.7 (JC-1,H-1 = 159.14 Hz,
C-1c), 103.7 (JC-1,H-1 = 159.32 Hz, C-1b), 127.68, 127.71,
127.74, 127.8, 127.9, 128.0, 128.13, 128.16, 128.38, 128.49,
128.53, 128.54, 128.56, 128.58, 128.61, 128.7, 129.2, 129.5,
129.7, 129.84, 129.88, 129.96, 130.0, 133.2, 133.31, 133.34,
133.4, 135.7, 135.9, 138.3, 138.4, 138.7, 138.8, 139.2,
165.20, 165.24, 166.1; HRMS C98H104NO19SSi [M + NH4]+
calcd 1626.6972, found 1626.6976.
p-Tolyl 2,3,4-tri-O-benzoyl-6-O-tert-butyldiphenylsilyl--D-
glucopyranosyl-(1→6)-2,3,4-tri-O-benzyl--D-glucopyranosyl-
(1→6)-2,3,4-tri-O-benzyl-1-thio--D-glucopyronoside (13)
Using method A of general procedure for glycosylation,
donor 13 reacted with acceptor 4 to give the desired product
13 in 70 % yield exclusively as -isomer after column puri-
fication (hexanes/ethyl acetate/CH2Cl2, 6:1:0.5). []D20 + 22
1
(c = 0.35, CH2Cl2); H NMR (600 MHz, CDCl3) 1.00 (s,
9H, (CH3)3CSi), 2.19 (s, 3H, SPhCH3), 3.18 (t, 1H, J3 =9.6
Hz), 3.27–3.37 (m, 1H), 3.40–3.44 (m, 2H), 3.56–3.63 (m,
2H), 3.69–3.72 (m, 2H), 3.76–3.88 (m, 5H), 4.17 (d, 1H,
J3 = 9 Hz), 4.26 (d, 1H, J3 = 11.4 Hz), 4.45 (d, 1H, J3 =11.4
Hz), 4.50 (d, 1H, J3 = 9 Hz, H1c), 4.56 (d, 1H, J3 =10.8 Hz),
4.59–4.64 (m, 4H), 4.70 (d, 1H, J = 8.4 Hz, H-1a), 4.71–4.90
(m, 5H), 5.01 (d, 1H, J3 = 3.6 Hz, H-1b), 5.54–5.58 (m, 2H),
5.81 (t, 1H, J3 = 10.2 Hz), 6.96–7.65 (m, 49H, aromatic),
7.67–7.71 (m, 2H, aromatic), 7.81–7.89 (m, 7H, aromatic);
p-Tolyl 2,3,4-tri-O-benzoyl-6-O-tert-butyldiphenylsilyl--D-
glucopyranosyl-(1→6)-2,3,4-tri-O-benzyl--D-glucopyranosyl-
(1→4)-2,3-di-O-benzoyl-6-O-benzyl-1-thio--D-galactopyr-
anoside (15)
Using method A of general procedure for glycosylation,

70
Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
donor 12 reacted with acceptor 8 to give the desired product
15 in 74% yield exclusively as  isomer after column puri-
fication (hexanes/ethyl acetate/CH2Cl2, 6:1:0.5). []D20 +41
Methyl 2,3,4-tri-O-benzyl--D-mannopyranosyl-(1→6)-2,3,4-
tri-O-benzyl-1-methyl--D-glucopyranoside (18)
Using method A of general procedure for glycosylation,
donor 16 reacted with acceptor 6 to give the desired product
18 in 79% yield after column purification (hexanes/ethyl
acetate 3:1). / = 1:3 as determined by integration of OCH3
peaks and JC1-H1 coupling constants. Comparison with lit-
erature data confirmed its identity [34]. 1H NMR (600 MHz,
CDCl3)  3.30 (s,OCH3-), 3.31 (s, 3H, OCH3-), 3.36–3.46
(m, 6H), 3.48 (dd, 1H, J3 =3.6, 9.6 Hz), 3.59–3.87 (m, 10H),
3.96–4.02 (m, 2H), 4.11 (s, 1H), 4.13 (d, 1H, J3 = 10 Hz,
H-1), 4.19–4.71 (m, 15H), 4.76–4.88 (m, 8H), 4.91(d, 1H,
J3 = 12 Hz), 4.46 (d, 1H, J3 =3 Hz, H-1), 4.51 (d, 1H, J3 =12
Hz), 7.06–7.40 (m, 49H, aromatic).
1
(c = 0.55, CH2Cl2); H NMR (500 MHz, CDCl3) 0.94 (s,
9H, (CH3)3CSi), 2.10 (s, 3H, SPhCH3), 3.29 (dd, 1H, J3 =3,
10.2 Hz), 3.35–3.42 (m, 2H), 3.46–3.50 (m, 1H), 3.66–3.70
(m, 1H), 3.73–3.74 (m, 2H), 3.82–3.91 (m, 4H), 4.17 (d, 1H,
J3 = 11.5 Hz), 4.22 (d, 1H, J3 = 8 Hz, H-1c), 4.28–4.38 (m,
4H), 4.48 (d, 1H, J3 = 12 Hz, CH2Ph), 4.66 (d, 1H, J3 =10.2
Hz), 4.67 (d, 1H, J3 = 9 Hz), 4.80 (d, 1H, J3 = 11 Hz), 4.82
(d, 1H, J3 = 10 Hz, H-1a), 4.90 (d, 1H, J3 = 3.5 Hz, H-1b),
5.34–5.43 (m, 2H), 5.50–5.69 (m, 3H), 6.95–7.03 (m, 4H,
aromatic), 7.06–7.40 (m, 41H, aromatic), 7.44–7.51 (m, 4H
aromatic), 7.64–7.65 (m, 2H, aromatic), 7.77–7.79 (m, 3H,
aromatic), 7.82–7.85 (m, 4H, aromatic), 7.87–7.89 (m, 2H,
aromatic); 13C NMR (125 MHz, CDCl3),  29.9, 26.9, 21.3
19.3, 21.3, 26.9, 29.9, 63.1, 67.8, 68.17, 68.2, 69.5, 70.5,
72.2, 73.5, 73.6, 74.1, 74.34, 74.39, 75.0, 75.34, 77.0, 77.3,
77.5, 78.5, 80.3, 81.6, 86.3 (JC-1,H-1 = 170.04 Hz, C-1b),
98.97 (JC-1,H-1 = 163.06 Hz, C-1c), 101.7 (JC-1,H-1 =159.71Hz,
C-1a), 127.55, 127.57, 127.64, 127.83, 127.84, 127.95,
127.97, 128.0, 128.02, 128.04, 128.40, 128.45, 128.48,
128.53, 128.57, 128.60, 128.64, 128.7, 129.24, 129.38,
129.6, 129.63, 129.8, 129.84, 129.88, 129.95, 129.99, 130.3,
133.0, 133.2, 133.24, 133.3, 133.34, 133.37, 133.4,
135.8,138.06, 138.1,138.7, 139.0, 139.2, 165.1, 165.2,
165.9, 166.2; HRMS C104H104NO20SSi [M + NH4]+ calcd
1746.6636 found 1746.6638.
3 Results
Our investigation started from the per-benzylated glucoside
1. As ethereal solvents can enhance  selectivity [19–23],
we first performed the glycosylation in diethyl ether. Donor
1 dissolved in diethyl ether was pre-activated by 1 equiv of
p-TolSOTf, formed in situ through the stoichiometric reac-
tion of p-TolSCl [15] with AgOTf. 3 equiv of AgOTf was
typically added as a standard protocol [16, 17, 24]. Upon
the rapid complete activation of 1 within 1 min as judged by
TLC, acceptor 2 was added, which led to the formation of
disaccharide 3 with close to equal amounts of  and  ano-
mers (: = 1.1:1) in 67% total yield (Table 1, entry 1).
While 10 equiv of AgOTf produced more  anomer (: =
1:1.5) (Table 1, entry 2), interestingly, decreasing the
amount of AgOTf to 1.1 equiv significantly improved 
selectivity (: = 6:1) (Table 1, entry 3). The  selectivity
could be further enhanced by performing the reaction under
a more dilute condition. Increasing the volume of diethyl
ether by 10 folds under otherwise identical conditions pro-
duced disaccharide 3 in a 10:1  ratio (Table 1, entry 4).
As selectivity was obtained, it would be desirable that
from the same glycosyl donor and acceptor, simple changes
of the reaction condition can lead to a switch to products.
Following formation of p-TolSOTf, the thioglycosyl donor
is first converted to a disulfonium ion (Figure 2), which can
evolve into other intermediates such as glycosyl triflate.
Crich and coworkers have reported that with benzylidene
protected thio-glycosides including glucosides without 2-O
acyl groups, the glycosyl triflates were the predominant
intermediates following pre-activation as observed by low
temperature NMR studies [25, 26]. Similarly, in our low
temperature NMR studies, we did not observe the presence
of the glycosyl disulfonium ion [27], suggesting transient
nature of this species. As the most likely intermediate is the
glycosyl triflate and the stereochemical outcome in glyco-
side formation is dependent upon the balance between glycosyl
p-Tolyl 2,3,4-tri-O-benzyl--D-mannopyranosyl-(1→6)-2,3,4-
tri-O-benzoyl-1-thio--D-glucopyranoside (17)
Using method A of general procedure for glycosylation,
donor 16 reacted with acceptor 4 to give the desired product
17 in 61% yield after column purification (hexanes/ethyl
1
acetate/CH2Cl2, 5.5:1:0.5). []D20 +27 (c = 0.15, CH2Cl2); H
NMR (600 MHz, CDCl3) 2.20 (s, 3H, SPhCH3), 3.36–3.46
(m, 3H), 3.65–3.69 (m, 2H), 3.71–3.74 (m, 2H), 3.77–3.80
(m, 1H), 3.84–3.89 (m, 3H), 4.04 (t, 1H, J3 = 9.6 Hz),
4.47–4.53 (m, 3H), 4.58 (dd, 1H, J3 = 1.8, 10.2 Hz),
4.61–4.62 (m, 2H), 4.66 (d, 1H, J3 = 12 Hz), 4.73–4.84 (m,
5H), 4.89–4.95 (m, 3H), 5.05(s, 1H), 7.01–7.03 (m, 2H,
aromatic), 7.14–7.20 (m, 2H, aromatic), 7.23–7.35 (m, 29H,
aromatic), 7.41–7.43 (m, 6H, aromatic); 13C NMR (125
MHz, CDCl3),  21.3, 29.9, 66.6, 69.4, 72.2, 72.6, 73.5,
74.8, 75.1, 75.23, 75.3, 75.7, 76.1, 77.0, 77.3, 77.5, 77.8,
78.6, 79.9, 81.3, 86.9, 88.3 (JC-1,H-1 = 169.9 Hz, C-1b), 98.8
(JC-1,H-1 = 157.7 Hz, C-1a), 127.96, 127.63, 127.78, 127.81,
127.88, 127.9, 127.93, 127.95, 127.99, 128.01, 128.04,
128.05, 128.43, 128.45, 128.48, 128.49, 128.57, 128.60,
128.63, 128.64, 128.67, 128.69, 128.7, 129.89, 129.96,
130.1, 131.96, 133.1, 138.1, 138.27, 138.59, 138.62, 138.67,
138.95; HRMS C68H74NO10S [M + NH4]+ calcd 1096.5033
found 1096.5031.

Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
71
Table 1 Evaluation of stereoselectivity using donors with no 2-O acyl groups
Entry
1
Donor
1
Acceptor
AgOTf
3
Reaction condition
Pdt
3
Yield % )
67 (1.1:1)
66 (1:1.5)
69 (6:1)
2
2
2
2
2
2
4
4
6
6
8
2
2
4
4
6
6
6
8
4
6
6
a
2
1
10
a
3
3
1
1.1
1.1
3
a
3
4
1
a*
b
b
a
3
55 (10:1)
92 (1:1.8)
90 (1:8)
5
1
3
6
1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
3
7
1
5
80 (5.7:1)
71 (1:1.7)
86 (2:1)
8
1
b
a
5
9
1
7
10
11
12
13
14
15
16
17
18
19
20
21
22
1
b
a
7
79 (1:9.4)
69 (only)
69 (6:1)
1
9
10
10
12
12
12
12
12
12
16
16
16
a
11
11
13
13
14
14
14
15
17
18
18
b
a
56 (1:1.2)
70 (only)
90 (1:1.2)
65 (2:1)
b
a
b
b**
a
92 (only)
90 (only)
74 (only
61 (only)
58 (2:1)
a
a
b
71 (1:3)
a) Reaction was performed in diethyl ether (donor concentration was 50 mM). b) Reaction was performed in dichloromethane (donor concentration was 50
mM). * Donor concentration is 5 mM. ** Toluene (5% of final volume) was added to the reaction to dissolve AgOTf.
Figure 2 Proposed mechanism of the effects of solvents and excess AgOTf on stereoselectivity.

72
Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
triflates and the oxacarbenium ion [28], we envision that
addition of exogenous triflate ion could potentially shift the
equilibrium towards glycosyl triflate. This would favor the
formation of the glycoside product through a SN2 like
reaction pathway, which could be supported by our obser-
vation that excess AgOTf led to more  products (Table 1,
entry 2). To test this hypothesis, we explored the effects of
triflate salts on stereoselectivity. The reaction between 1 and
2 was performed with 1.1 equiv of AgOTf in the presence of
up to 10 equiv of triflate salts including NaOTf, Hf(OTf)4
and the more organic solvent soluble tetrabutylammonium
triflate. However, none of these salts affected the stereose-
lectivity, which ruled out that the additional triflate anion
could significantly influence the reaction pathway.
Next, we tested the reactions in a variety of solvents in-
cluding dichloromethane, cyclopentyl methyl ether, THF,
toluene, toluene/1,4-dioxane [23] and acetonitrile. THF,
toluene, toluene/1,4-dioxane and acetonitrile did not lead to
productive coupling. Cyclopentyl methyl ether has been
reported to improve cis selectivity [19]. However, in our
reaction, it gave similar results as diethyl ether. Interestingly,
a selectivity shift was observed when the reaction between 1
and 2 was performed in dichloromethane with 3 equiv of
AgOTf, which gave disaccharide 3 with 92% total yield
with the anomer becoming the major product (: =1:1.8)
(Table 1, entry 5). Decreasing the amount of AgOTf to 1.1
eq greatly enhanced the selectivity (: = 1:8) (Table 1,
entry 6). Therefore, the stereochemical outcome of the reac-
tion can be controlled by simply switching the reaction sol-
vent, with diethyl ether favoring glycoside and dichloro-
methane generating more product.
With the stereoselective reaction conditions in hand, we
examined their generality. Pre-activation of donor 1 in di-
ethyl ether by 1 equiv of p-TolSCl and 1.1 equiv of AgOTf
followed by addition of the electron rich glucoside acceptor
4 gave disaccharide 5 in 90% yield with the  anomer as the
major isomer (: = 5.7:1) (Table 1, entry 7). Exchanging
the reaction solvent to dichloromethane produced the 
isomer as the major product (: = 1:1.7) (Table 1, entry 8).
The same trend held for a variety of building blocks, in-
cluding glucoside acceptor 6 without the STol aglycon, ga-
lactoside acceptor 8 with a secondary hydroxyl group, elec-
tron poor glucosyl donor 10 and disaccharide donor 12 (Ta-
ble 1, entries 7–19). -Mannoside formation is a challeng-
ing problem for carbohydrate synthesis. The excellent
methodology developed by Crich and coworkers for stereo-
selective -mannoside formation required the installation of
a benzylidene moiety on the mannosyl donor [4]. It is
noteworthy that under the selective reaction condition, the
per-benzylated electron rich mannosyl donor 16 without the
benzylidene glycosylated glucoside 6 in dichloromethane
forming -mannoside 18 as the major product (Table 1,
entry 22).
4 Discussion
As the glycosyl triflate is a likely intermediate formed after
pre-activation, when the reaction is performed in diethyl
ether, it is possible that it goes through a double inversion
mechanism (Figure 2, pathway a). The diethyl ether can act
as a nucleophile, displacing the triflate in an SN2 like fash-
ion from the -face. Subsequent SN2 like displacement of
the ether molecule by the nucleophilic acceptor can lead to
 glycoside as the major product. Under a dilute condition,
the larger amount of diethyl ether can participate more ef-
fectively thus resulting in higher  selectivity. In the pres-
ence of excess AgOTf, it is most likely that AgOTf coordi-
nates with the oxygen atom of the triflate, leading to its ac-
tivation and glycosylation through a more SN1 like pathway
(Figure 1, pathway b). This would result in the formation of
anomeric mixtures.
When the glycosylation is performed in dichloromethane,
due to the low solubility of AgOTf in dichloromethane, a
solution of AgOTf in acetonitrile was added to the reaction.
Although the amount of acetonitrile is small (2% of the final
solvent volume for the reaction), it is possible that the
selectivity observed is a result of acetonitrile participating
from the  face due to the known nitrile effect [29–31]. To
test this possibility, we replaced acetonitrile with toluene in
reaction of 13 with 6. The  linked disaccharide was the
only product isolated (Table 1, entry 18), which suggests
that acetonitrile does not play a significant role in deter-
mining the stereochemical outcome of the reaction. The 
selectivity observed with dichloromethane as the reaction
medium is thus likely due to the non-nucleophilic and non-
polar nature of the solvent. The reaction goes through a
more SN2 like pathway with the acceptor directly displacing
the -glycosyl triflate leading to  glycosides (Figure 1,
pathway c).
In conclusion, glycosyl donors with participating acyl
protective groups on 2-O have been shown previously to
give 1,2-trans glycosides reliably under the pre-activation
based reaction condition. In this work, we discovered that
the stereoselectivity of the pre-activation based glycosyla-
tion using donors without participating protective group on
2-O can be controlled by the reaction solvent, with diethyl
ether favoring the formation of  glycosides and dichloro-
methane leading to  isomers. Besides its role in generating
the promoter p-TolSOTf, AgOTf can also exert significant
impact on stereoselectivity presumably due to coordination
with the glycosyl triflate intermediate. The stereochemical
dependence can be applied to a variety of building blocks
including the formation of -mannosides. Other factors in-
cluding donor and acceptor structures and protective groups
also affect the outcome. A general strategy that can be ap-
plied to a wide range of building blocks for on demand
stereospecific glycosylation requires further development

Wasonga G, et al. Sci China Chem January (2011) Vol.54 No.1
73
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