Glycosyl thioimidates in a highly convergent one-pot strategy for oligosaccharide synthesis

Article abstract of DOI:10.1016/j.tetasy.2004.11.029

Application of two classes of thioimidoyl derivatives, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) glycosides to selective activation over thioglycosides is described. These results allowed us to synthesize a tetrasaccharide derivative using a leaving group differentiated one-pot strategy in 73% yield over three sequential glycosylation steps.

Full text of DOI:10.1016/j.tetasy.2004.11.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 433–439
Glycosyl thioimidates in a highly convergent one-pot strategy
for oligosaccharide synthesis
Papapida Pornsuriyasak and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri––St. Louis, One University Boulevard,
St. Louis, Missouri, MO 63121, USA
Received 8 November 2004; accepted 16 November 2004
Available online 8 January 2005
Abstract—Application of two classes of thioimidoyl derivatives, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) glycosides to selec-
tive activation over thioglycosides is described. These results allowed us to synthesize a tetrasaccharide derivative using a leaving
group differentiated one-pot strategy in 73% yield over three sequential glycosylation steps.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ing groups in either or in both of the reaction compo-
nents.9,10,12 It is now well known that electron-
withdrawing groups deactivate (disarm) the leaving
group while electron-donating moieties activate (arm)
the leaving group.13 As illustrated in Scheme 1a, this ap-
proach in its conventional mode requires a set of build-
ing blocks with the same type of a leaving group, the
reactivity of which is differentiated by the protecting
group pattern. In this context, the reactivity difference
between similarly protected sugars of different series
has to be also taken into consideration. For example,
the reactivity ratio between per-benzylated S-(p-methyl-
phenyl) glycosides of L-fuco, D-galacto, and D-gluco ser-
ies was found to be 27.1/6.4/1, respectively.10
Recent understanding of the involvement of carbohy-
drate molecules and conjugates in many vital biological
processes1 and, consequently, the appreciation of their
tremendous therapeutic potential2 has stimulated the
development of new methods for the synthesis of this
class of compounds. The main efforts in the field of syn-
thetic carbohydrate chemistry have been focused on the
development of new glycosylation methodologies and
convergent strategies for oligosaccharide synthesis, in
which the number of synthetic and purification steps is
reduced. As a result, many efficient approaches have
been developed both on the solid phase3 and in solu-
tion.4 The most efficient solution-based techniques
include armed–disarmed,5 active–latent,6 orthogonal/
semi-orthogonal,7,8 and one-pot strategies.9,10 Amongst
these, one-pot strategies perhaps offer the shortest path-
way to oligosaccharides, as the sequential glycosylation
reactions are performed in a single flask (pot) and do not
require isolation and purification of the intermediates.
Although many variations of the one-pot strategy have
been developed,11 there are two major concepts these
protocols are based upon.
The second concept is based on selective activation of
one leaving group over another (Scheme 1b).14 Since this
OH
OH
OH
OH
O
O
O
O
LG
LG
O
O
(a)
(b)
OP3
OH
OP2
OH
LG
O
O
OP1
O
O
O
O
LG3
LG2
O
OP
O
OP
The first approach is relying on the chemoselectivity
principle, according to which the reactivity difference be-
tween the glycosyl donor and the glycosyl acceptor is
achieved by varying the electronic properties of protect-
O
LG1
OP
Oligosaccharides
P - protecting group; LG - leaving group
Scheme 1. Two concepts for one-pot oligosaccharide assembly: (a)
chemoselective activation (reactivity is differentiated by protecting
groups) and (b) selective activation (reactivity is differentiated by
leaving groups).
*
Corresponding author. Tel.: +1 314 516 7995; fax: +1 314 516
5342; e-mail: demchenkoa@umsl.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.029

434
P. Pornsuriyasak, A. V. Demchenko / Tetrahedron: Asymmetry 16 (2005) 433–439
Table 1. Chemoselective activation of SBox glycosyl donors over SEt
glycosyl acceptors in the presence of AgOTf
is a leaving group-based concept, one should be flexible
with the protecting groups. Unfortunately, the number
of leaving groups suitable for multi-step sequential selec-
tive activation is limited to too few examples at this
stage.
O
OR1
O
OR6
O
R4O
R3O
R1O
R1O
O
AgOTf
SEt
SBox
+
O
SEt
R2O
R2O
1a: R1=R2=Bz
2a:
2b:
2c:
β
-D-Glc, R2=R3=R4=Bz, R6=H
-D-Gal, R2=R3=R4=Bz, R6=H
Disaccharides 3-7
(See Figure 1)
A common feature of both of these approaches is that
they are reactivity based, regardless whether the differ-
ence in reactivity is achieved by the protecting groups
or by the leaving group. Being more reactive under
certain reaction conditions, the glycosyl donor unit is
activated over the less reactive glycosyl acceptor.
Subsequently, the saccharide obtained is then served as
the glycosyl donor under adjusted reaction conditions.
For this purpose, a promoter, suitable for its activation
is added along with the glycosyl acceptor for the next
step.
1b: R1=Ac, R2=Bn
β
α
-D-Man, R2=R3=R6=Bn, R4=H
Entry Donor Acceptor Product Yield (%) a/b Ratio
1
2
3
4
5
1a
1a
1a
1b
1b
2a
2b
2c
2b
2c
3
4
5
6
7
95
99
96
98
92
b Only
b Only
b Only
a Only
a Only
These reactions were no exception in this regard: 1,2-
cis-linked disaccharides 616 and 7 (Fig. 1) were obtained
with complete stereoselectivity in 98% and 92% yield
respectively (entries 4 and 5). It should be noted that
high yields, no by-product formation, and complete ste-
reoselectivity are welcomed traits of any chemical reac-
tion that become increasingly important in one-pot
procedures. In this respect, SBox glycosidations were re-
garded as very promising.
As a part of the program to develop new methods and
strategies for convergent oligosaccharide synthesis, here-
in we report the application of glycosyl thioimidates to a
convergent one-pot procedure. We have already re-
ported the synthesis of two glycosyl donors of this class,
S-benzoxazolyl (SBox)15–17 and S-thiazolyl (STaz, 4,5-
dihydrothiazol-2-yl)18 glycosides, and their evaluation
in stereoselective glycosylations. We demonstrated that
the SBox and STaz derivatives can be glycosidated in
high yields and with excellent stereoselectivity. Unique
activation conditions allow the application of thioimi-
date derivatives in selective activation approaches. For
example, either SBox or STaz derivatives can be selec-
tively activated over S-ethyl or O-pentenyl glycosides
in the presence of AgOTf. We have also demonstrated
that STaz derivatives withstand NIS/TfOH, conven-
tional conditions for S-alkyl/aryl activation.18 The fol-
lowing describes our systematic studies of selective
thioimidoyl activation and its application to convergent
one-pot strategy.
2.2. Selective activation of STaz glycosyl donors over
S-ethyl glycosyl acceptors
Having completed preliminary evaluation of the SBox
glycosides in selective activation processes, we turned
our attention to the investigation of the STaz glycosides.
Also in this case, AgOTf was found to be the promoter
of choice. Per-benzoylated STaz derivatives of the D-glu-
co 8a18 and D-galacto 8b18 series were selected to probe
1,2-trans-glycosidation experiments with S-ethyl glycosyl
acceptors 2a and 2b. These glycosylations proceeded
smoothly and allowed us consistently good results.
Thus, the disaccharide derivatives 3, 4, 9,22 and 1023
(Fig. 1) were obtained in 80–85% yield with complete
1,2-trans-selectivity (Table 2, entries 1–4).
2. Results and discussion
2.1. Selective activation of SBox glycosyl donors over
S-ethyl glycosyl acceptors
Table 2. Chemoselective activation of STaz glycosyl donors over SEt
glycosyl acceptors in the presence of AgOTf
We have already reported that selective activation of the
SBox glycosyl donors over SEt glycosyl acceptors is
achieved in the presence of AgOTf.16,17 To expand these
studies we glycosylated SEt glycosyl acceptors 2a,19
2b,20 and 2c21 with SBox glycosyl donors 1a17 and
1b.16 Complete stereoselectivity was achieved in 1,2-
trans-glycosidations of per-benzoylated SBox glucoside
1a with S-ethyl glycosyl acceptors 2a–c. These experi-
ments are summarized in Table 1 (entries 1–3). Thus,
disaccharide derivatives 3, 4,17 and 517 (Fig. 1) were
obtained in 95%, 99%, and 96% yield, respectively.
Comparable glycosylation yields were achieved in glyco-
sidations of 1b with acceptors 2b and 2c.
O
OR1
O
OR6
O
R4O
R3O
R1O
R1O
AgOTf
O
SEt
STaz
+
O
R1O
SEt
R2O
8a: D-Glc, R1=Bz
8b: D-Gal, R1=Bz
8c: D-Glc, R1=Bn
8d: D-Gal, R1=Bn
2a: D-Glc, R2=R3=R4=Bz, R6=H
2b: D-Gal, R2=R3=R4=Bz, R6=H
2d: D-Glc, R2=Bn,R3=H,
R4,R6= >CHPh
Disaccharides
3,4,9-15
(See Figure 1)
Entry Donor Acceptor Product Yield (%) a/b Ratio
1
2
3
4
5
6
7
8
9
8a
8a
8b
8b
8c
8c
8c
8d
8d
2a
2b
2a
2b
2a
2b
2d
2a
2b
3
80
82
81
85
90
86
93
98
99
b Only
b Only
b Only
b Only
2.5:1
4
9
10
11
12
13
14
15
2:1
5.0:1
Glycosyl donor 1b bearing a nonparticipating benzyl
ether group at C-2, is known to provide excellent stereo-
control even in methylene chloride, a solvent, which
does not normally promote 1,2-cis-stereoselectivity.16
1.8:1
1.4:1

P. Pornsuriyasak, A. V. Demchenko / Tetrahedron: Asymmetry 16 (2005) 433–439
435
Per-benzylated STaz glycosides 8c18 and 8d18 were em-
ployed in 1,2-cis-glycosylations of the SEt moiety-con-
taining glycosyl acceptors 2a,b, and 2d.21 In all cases
high yields were achieved, thus, disaccharides 11,19
12,8 13,18 14, and 15 (Fig. 1) were obtained as anomeric
mixtures in 86–99% yield (Table 2, entries 5–9). Previ-
ously, we demonstrated that the selectivity of 1,2-cis-gly-
cosidation of STaz glycosides can be significantly
improved by the use of partially acetylated glycosyl do-
nors18 or by performing the reaction in a participating
solvent system, such as toluene–dioxane.18,24 It should
be noted that the stereoselectivity achieved with the sec-
ondary glycosyl acceptor 2d was significantly higher (a/b
5.0:1) than that achieved with primary glycosyl accep-
tors 2a or 2b (typically around 2:1).
Table 3. Chemoselective activation of SEt and SPh glycosyl donors
over STaz glycosyl acceptors in the presence of NIS/catalytic TfOH
O
OR2
O
OR6
O
R2O
R2O
NIS/TfOH
R4O
O
+
SR1
STaz
R3O
O
R2O
R2O
STaz
2e: D-Glc, R1=Et,R2=Bz
2f: D-Glc, R1=Et,R2=Bn
2g: D-Gal, R1=Et,R2=Bn
16a: D-Glc, R1=Ph,R2=Bn
16b: D-Gal, R1=Ph,R2=Bn
8e: R2=R3=R4=Bz, R6=H
8f: R2=Bn,R3=H,
Disaccharides 17-21
(See Figure 1)
R4,R6= >CHPh
8g: R2=R4=R6=Bn, R3=H
Entry Donor Acceptor Product Yield (%) a/b Ratio
1
2
3
4
5
6
7
2e
2f
8e
8f
8g
8e
8f
8e
8f
17
18
19
20
21
20
21
81
85
80
98
40
75
48
b Only
1.2:1
2.1:1
1.2:1
2.7:1
1.4:1
1.1:1
2f
2f
2g
2.3. Selective activation of S-ethyl and S-phenyl
glycosyl donors over STaz glycosyl acceptors
16a
16b
Most commonly, SBox glycosides allow marginally bet-
ter results in comparable glycosylation reactions, which
is assumed to be due to their higher reactivity in com-
parison to that of STaz glycosides (see, for example, en-
tries 1 and 2 in Tables 1 and 2). Thus, we have recently
demonstrated that STaz glycosides are significantly
more stable than SBox glycosides under a variety of
reaction conditions, ranging from the use of strong acids
to the use of strong inorganic bases.18 Remarkably, the
STaz glycosides are even more stable than similarly pro-
tected S-ethyl and S-phenyl glycosides. Comparative
experiments were performed in the presence of acidic
thiophilic reagents, for example, N-iodosuccinimide/cat-
alytic TfOH, commonly used for thioglycoside hydroly-
sis.25 It has been clearly demonstrated that the STaz
moiety is entirely stable under these reaction conditions,
while either SEt or SPh glycosides were hydrolyzed in
the matter of minutes.18
this case was the hemiacetal, a product of the competing
hydrolysis. Quite possibly, this side reaction could be
suppressed by varying the solvent or by using a milder
promoter, such as iodonium(dicollidine)perchlorate
and/or by lowering the reaction temperature. These re-
sults, along with aforementioned STaz activation over
SEt glycosides imply a fully orthogonal character of
the two classes of leaving groups. Very comparable re-
sults were achieved with SPh glycosyl donors 16a and
16b.
2.4. Thioimidate-based one-pot glycosylation strategy
Based on the results of selective activations, we assumed
that it should be possible to perform the following acti-
vation sequence. Presumably, the most reactive SBox
moiety has to be activated first over SEt, subsequently,
SEt is then activated over STaz (SBox+SEt+STaz acti-
vation sequence). To execute this one-pot sequence
along with the anticipated pathway, we chose the fol-
lowing building blocks: SBox glycosyl donor 1a to be
glycosidated at the first step with S-ethyl glycosyl accep-
tor 2b. This should result in a disaccharide derivative 4,
the SEt moiety of which will be activated over the STaz
moiety of the second step acceptor 8e (Scheme 2). The
resulting trisaccharide 22 could be then glycosidated
with 6-OH glycosyl acceptor 2333 bearing a stable O-
methyl moiety at the anomeric center to afford a linear
tetrasaccharide 24. The promoters of choice would be:
AgOTf for the activation of the SBox, NIS/catalytic
TfOH for the activation of S-ethyl, and, finally, more
AgOTf should be added for the activation of STaz
moiety of 22.
Based on these observations, we anticipated that it
might be possible to activate SEt or SPh glycosyl donors
over STaz glycosides. To prove this, we synthesized a
number of building blocks, S-alkyl/aryl glycosyl donors
2e,26 2f,27 2g,28 16a,29 and 16b30 and STaz glycosyl
acceptors 8e,31 8f,18 and 8g.31 Reactions with conven-
tional thioglycosides rarely proceed quantitatively due
to a number of side processes commonly taking place
along with glycosylation, the most important of which
is hydrolysis.32 To suppress those, the reactions were ini-
tiated at ꢀ20ꢁC and then were allowed to gradually
warm up to room temperature. As a result of these
precautions, glycosidations of the S-ethyl glycosyl
donors of the D-gluco series 2e and 2f proceeded very
well. While per-benzoylated donor 2e allowed 1,2-
trans-linked disaccharide 1731 (Fig. 1) with complete
stereoselectivity in 81% yield (Table 3, entry 1), 1,2-cis-
glycosidations of 2f with acceptors 8e–g were nonstereo-
selective. As a result, disaccharides 18,18 19,31 and 2031
(Fig. 1) were obtained in 80–98% yield with a/b-stereose-
lectivity ranging from 1.2:1 to 2.1:1 (Table 3, entries 2–
4). Unfortunately, we were not able to control the gly-
cosidation of a more reactive D-galacto derivative 2g
at this temperature. Thus, reaction of 2g with 8f afforded
21 (Fig. 1) in only 40% yield. The major by-product in
Having selected the building blocks and the promoters
suitable with their sequential glycosylations, we were
set to perform the synthesis, which was executed as fol-
lows. A mixture of SBox glycoside 1a (1.1 equiv), ethyl-
˚
thio glycoside 2b (1.0 equiv) and molecular sieves 3 A in
1,2-dichloroethane was treated with AgOTf (2.2 equiv)
at room temperature. As anticipated, the reaction was
complete in less than 10min, at this stage only the
product 4 could be seen by TLC. Subsequently, STaz

436
P. Pornsuriyasak, A. V. Demchenko / Tetrahedron: Asymmetry 16 (2005) 433–439
OBz
O
OBz
O
OH
O
BzO
BzO
BzO
BzO
O
O
BnO
BnO
OBz
O
BzO
BzO
BzO
BzO
BnO
O
O
23
OMe
BzO
BzO
O
BzO
O
BzO
O
OBz
O
BzO
BzO
BzO
BzO
O
O
O
BzO
BzO
BzO
BzO
SBox
SEt
STaz
BzO
BzO
BzO
O
BzO
1a
BzO
BzO
BzO
8e
23
2b
O
BnO
4
22
BnO
24
BnO
OMe
AgOTf
AgOTf
NIS/TfOH
73% over-all
Scheme 2. One-pot synthesis of 24 from building blocks 1a, 2b, 8e, and 23.
OBn
OBz
O
OBz
O
OAc
BzO
OBn
O
BzO
BzO
BzO
BzO
AcO
AcO
O
BzO
BzO
O
O
O
BnO
5
O
BzO
BnO
BzO
BzO
BzO
BzO
BzO
O
OBz
O
O
SEt
BzO
SEt
SEt
O
BzO
BzO
4
SEt
BzO
3
BzO
6
OBz
BzO
BzO
OBn
BzO
OBz
O
OAc
O
O
O
BnO
BnO
O
AcO
AcO
OBn
O
O
BzO
BzO
OBn
O
BzO
BnO
BzO
BzO
BzO
BzO
O
BnO
O
O
O
SEt
BzO
BnO
SEt
BzO
SEt
BzO
SEt
10
BzO
BzO
9
7
11
BnO
BnO
OBn
O
OBn
O
OBn
BnO
BnO
BnO
Ph
O
O
O
BnO
BnO
O
O
O
BnO
SEt
BnO
O
O
SEt
O
BnO
BzO
BnO
BnO
BzO
BnO
BnO
O
BzO
BzO
O
BzO
O
SEt
BzO
SEt
BzO
13
BzO
BzO
12
15
14
OBz
O
OBn
O
BzO
BzO
Ph
O
O
O
OBn
O
BnO
BnO
BnO
O
O
O
BnO
O
BnO
BnO
STaz
BzO
BzO
STaz
BnO
O
BnO
BnO
BnO
STaz
BzO
18
BzO
19
17
OBn
OBn
O
BnO
BnO
BnO
BnO
Ph
O
O
O
O
O
BnO
BzO
O
STaz
O
BnO
BnO
STaz
BzO
BzO
20
21
Figure 1. Structures of disaccharide derivatives 3–7, 9–15, 17–21.
acceptor 8e (0.9 equiv) and promoter NIS/TfOH (2.2/
0.22 equiv) were added to the reaction mixture, which
was left stirring for 30 min, when the TLC showed the
disappearance of the starting material. Only one spot
corresponding to 22 could be detected at this stage. To
complete the sequence, acceptor 23 (1 equiv) along with
another portion of AgOTf (2.2 equiv) was added to the
reaction mixture. As a result, the desired tetrasaccharide
24 was obtained in 73% isolated yield over three steps.
as it, together with NIS remaining from the second acti-
vation step, could serve as an activator for the STaz
functionality. However, this activation approach has
proven to be somewhat less efficient.
3. Conclusions
In conclusion, we investigated selective activation of two
classes of thioimidoyl derivatives, S-benzoxazolyl
(SBox) and S-thiazolyl (STaz) glycosides over S-ethyl
glycosides. In addition, we demonstrated that S-ethyl
A possible alternative to this strategy would be the use
of a stoichiometric amount of TfOH in the last step,

P. Pornsuriyasak, A. V. Demchenko / Tetrahedron: Asymmetry 16 (2005) 433–439
437
and S-phenyl glycosides can be selectively activated over
STaz glycosides. These results clearly demonstrate the
versatility of glycosyl thioimidates and their high poten-
tial in the glycoside and, consequently, oligosaccharide
synthesis. The selective activation conditions were ap-
plied to the one-pot synthesis of a linear tetrasaccharide
derivative in 73% yield over three sequential glycosyla-
tion steps. This was achieved by the stepwise activation
of SBox over S-ethyl, S-ethyl over STaz, and, finally
STaz over stable glycosyl acceptor (OMe). It is antici-
pated that the strategy outlined here can be applied in
the syntheses of many oligosaccharides and glycoconju-
gates for subsequent biological studies and potential
therapeutic applications.
respectively. Analytical data for 3: Rf = 0.65 (ethyl ace-
27
1
tate–hexane, 1/1, v/v); ½aꢁ ¼ þ17:0 (c 0.9, CHCl3); H
D
NMR data: d 7.26–8.00 (m, 35H), 5.88 (dd, 1H,
J = 9.6 Hz), 5.82 (dd, 1H, J = 9.5 Hz), 5.63 (dd, 1H,
J = 9.7 Hz), 5.52 (dd, 1H, J = 7.8, J = 9.7 Hz), 5.40
(dd, 1H, J = 9.7 Hz), 5.33 (dd, 1H, J = 9.7 Hz), 5.00
(d, 1H, J = 7.8 Hz), 4.67 (d, 1H, J = 10.0 Hz), 4.62
(dd, 1H, J = 3.0, J = 12.1 Hz), 4.42 (dd, 1H, J = 5.0,
J = 12.1 Hz), 3.80–4.16 (m, 4H), 2.55 (m, 2H), 1.10 (t,
3H) ppm; 13C NMR data: d, 166.27, 165.99, 165.89,
165.60, 165.37, 165.34, 165.32, 133.68, 133.64, 133.43,
133.36, 130.09, 130.05, 129.97, 129.90, 129.77, 129.48,
129.42, 129.08, 129.02, 128.99, 128.93, 128.64, 128.61,
128.54, 128.49, 128.45, 101.46, 83.65, 78.31, 74.26,
73.10, 72.51, 72.08, 70.80, 69.93, 69.77, 68.79, 63.12,
24.28, 14.96 ppm; HR-FAB MS [M+Na]+ calcd for
C63H54O17SNa 1137.2979, found 1137.2985.
4. Experimental
4.1. General
Ethyl 4-O-(3,4,6-tri-O-acetyl-2-O-benzyl-a-D-glucopyr-
anosyl)-2,3,6-tri-O-benzyl-1-thio-a-D-mannopyranoside 7
was obtained from 1b and 2c in 92% yield. Analytical
data for 7: Rf = 0.55 (acetone–toluene, 1:4, v/v);
Column chromatography was performed on silica gel 60
(EM Science, 70–230 mesh), reactions were monitored
by TLC on Kieselgel 60 F254 (EM Science). The com-
pounds were detected by examination under UV light
and by charring with 10% sulfuric acid in methanol. Sol-
vents were removed under reduced pressure at >40 ꢁC.
CH2Cl2 and (ClCH2)2 were distilled from CaH2 directly
25
D
1
½aꢁ ¼ þ72:8 (c 1.0, CHCl3); H NMR data: d 7.03–
7.33 (m, 20H), 5.68 (d, 1H, J = 3.7 Hz), 5.35 (d, 1H,
J = 1.6 Hz), 5.26 (dd, 1H, J = 9.8 Hz), 4.81 (dd, 1H,
J = 9.8 Hz), 4.29–4.65 (m, 8H), 4.14 (m, 2H), 4.03 (dd,
1H, J = 3.6 Hz, J = 12.3 Hz), 3.75–3.94 (m, 4H), 3.54–
3.70 (m, 2H), 3.36 (dd, 1H, J = 3.7 Hz, J = 10.1 Hz),
2.65 (m, 2H), 1.99, 1.99, 1.93 (3s, 9H), 1.30 (t, 3H)
ppm; 13C NMR data: d, 170.81, 170.33, 169.96,
138.57, 138.40, 138.23, 137.89, 128.63, 128.57, 128.50,
127.94, 127.91, 127.80, 127.72, 127.23, 97.80, 81.93,
80.78, 77.46, 76.08, 73.66, 72.39, 72.25, 71.81, 71.72,
70.91, 69.69, 68.63, 67.92, 61.99, 25.67, 15.24 ppm;
HR-FAB MS [M+Na]+ calcd for C48H56O13SNa
895.3339, found 895.3354.
˚
˚
prior to application. Molecular sieves (3 A or 4 A), used
for reactions, were crushed and activated in vacuo at
390 ꢁC during 8 h in the first instance and then for 2–
3 h at 390 ꢁC directly prior to application. AgOTf (Ac-
ros) was co-evaporated with toluene (3 · 10 mL) and
dried in vacuo for 2–3 h directly prior to application.
Optical rotations were measured at ÔJasco P-1020Õ polar-
imeter. 1H NMR spectra were recorded at 300 MHz, 13
C
NMR spectra were recorded at 75 MHz (Bruker
Avance). HRMS determinations were made with the
use of JEOL MStation (JMS-700) mass spectrometer.
Ethyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-a/
b-D-galactopyranosyl)-1-thio-b-D-glucopyranoside
14
4.2. General AgOTf-promoted glycosylation procedure
for selective activation of STaz and SBox glycosyl donors
was obtained from 8d and 2a in 98% yield (a/b 1.8/1).
Analytical data for a-14: Rf = 0.40 (ethyl acetate-hex-
1
ane, 3/7, v/v); selected H NMR data: d 4.80 (d, 1H,
A mixture of the glycosyl donor (0.05 mmol), glycosyl
acceptor (0.045 mmol), and freshly activated molecular
J = 3.9 Hz), 4.73 (d, 1H, J = 10.1), 4.47 (d, 1H,
J = 7.6 Hz) ppm; selected 13C NMR data: d, 104.11,
98.19, 83.78 ppm; HR-FAB MS [M+Na]+ calcd for
C63H62O13SNa 1081.3809, found 1081.3820.
˚
sieves (3 A, 90 mg) in CH2Cl2 or (ClCH2)2 (0.5 mL)
was stirred under argon for 1 h. AgOTf (0.10 mmol)
was added. The reaction mixture was then stirred for
10–30 min at rt. Upon completion, the reaction mixture
was diluted with CH2Cl2, the solid was filtered-off and
the residue was washed with CH2Cl2. The combined fil-
trate (30 mL) was washed with 20% aq NaHCO3
(15 mL) and water (3 · 10 mL), the organic phase was
separated, dried with MgSO4, and concentrated in
vacuo. The residue was purified by column chromatogra-
phy on silica gel (acetone/toluene gradient elution) to
allow the corresponding disaccharide. Anomeric ratios
(if applicable) were determined by comparison of the
integral intensities of relevant signals in 1H NMR
spectra.
Ethyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-a/
b-D-galactopyranosyl)-1-thio-b-D-galactopyranoside 15
was obtained from 8d and 2b in 99% yield (a/b 1.4:1).
Analytical data for a-15: Rf = 0.40 (ethyl acetate–hex-
1
ane, 3/7, v/v); selected H NMR data: d 4.79 (d, 1H,
J = 3.7 Hz), 4.72 (d, 1H, J = 9.6 Hz), 4.38 (d, 1H,
J = 7.5 Hz) ppm; selected 13C NMR data: d, 104.12,
98.80, 84.14 ppm; HR-FAB MS [M+Na]+ see data for
compound 14.
4.3. General NIS/TfOH-promoted glycosylation proce-
dure for the selective activation of SEt and SPh glycosyl
donors
Ethyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzoyl-b-
D-glucopyranosyl)-1-thio-b-D-glucopyranoside 3 was ob-
tained from 1a and 2a or 8a and 2a in 95% or 80% yield,
A mixture the glycosyl donor (0.05 mmol), glycosyl
acceptor (0.045 mmol), and freshly activated molecular

438
P. Pornsuriyasak, A. V. Demchenko / Tetrahedron: Asymmetry 16 (2005) 433–439
˚
sieves (4 A, 90 mg) in (ClCH2)2 (0.5 mL) was stirred for
1 h under argon. The reaction mixture was cooled to
ꢀ20 ꢁC, NIS (0.10 mmol) and TfOH (0.01 mmol) were
added and the reaction mixture was stirred for 5 min
to 16 h at ꢀ20 ꢁC to rt. Upon completion, the solid
was filtered-off and washed with CH2Cl2. The combined
filtrate (30 mL) was washed with 20% aq Na2S2O3
(15 mL) water (3 · 10 mL), the organic phase was sepa-
rated, dried with MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography
on silica gel (acetone/toluene gradient elution) to allow
the corresponding disaccharide.
J = 3.2 Hz), 4.44–4.51 (m, 3H), 4.42 (d, 1H,
J = 11.4 Hz), 4.29 (dd, 1H, J = 4.4, J = 11.8 Hz), 4.22
(d, 1H, J = 11.4 Hz), 3.97–4.11 (m, 5H), 3.75–3.90 (m,
4H), 3.44–3.56 (m, 2H), 3.30–3.38 (m, 5H) ppm; 13C
NMR data: d, 166.20, 165.95, 165.57, 165.51, 165.33,
165.24, 165.05, 140.26, 139.12, 138.66, 138.39, 138.08,
133.60, 133.46, 133.33, 133.25, 130.11, 130.00, 129.92,
129.81, 129.24, 129.01, 128.73, 128.64, 128.55, 128.48,
128.43, 128.31, 128.08, 128.01, 127.47, 125.50, 125.07,
124.25, 119.08, 101.82, 101.12, 101.12, 98.27, 82.02,
80.02, 77.43, 75.59, 74.58, 74.31, 73.61, 73.61, 73.01,
73.01, 72.47, 72.14, 71.98, 71.59, 70.23, 70.13, 70.01,
69.63, 69.63, 68.68, 67.76, 67.59, 63.07 ppm; HR-FAB
MS [M+Na]+ calcd for C116H102O31Na 2013.6303,
found 2013.6287.
4,5-Dihydrothiazol-2-yl 2-O-benzyl-3-O-(2,3,4,6-tetra-O-
benzyl-a/b-D-galactopyranosyl)-4,6-O-benzylidene-1-thio-
b-D-glucopyranoside 21 was obtained from 2g and 8f in
40% yield (a/b 2.7:1) or from 16b and 8f in 48% yield
(a/b 1.1:1). Analytical data for a-21: Rf = 0.65 (ethyl
acetate–hexane, 1:1, v/v); selected 1H NMR data:
7.05–7.27 (m, 30H) 5.62 (d, 1H, J = 3.5 Hz), 5.36 (s,
1H), 5.28 (d, 1H, J = 10.0 Hz), 4.40–4.81 (m, 10H),
4.01–4.19 (m, 6H), 3.57–3.90 (m, 5H), 3.15–3.53 (m,
5H) ppm; selected 13C NMR data: d, 163.14, 139.12,
138.66, 138.54, 137.50, 128.60, 128.47, 128.43, 128.39,
128.34, 128.03, 127.76, 127.73, 127.67, 127.61, 127.53,
126.43, 101.94, 96.9, 85.43, 82.37, 79.73, 78.15, 77.44,
76.00, 75.59, 75.08, 73.29, 73.03, 72.15, 70.29, 69.14,
68.83, 64.55, 58.10, 35.37, 29.92 ppm; HR-FAB MS
[M+H]+ calcd for C57H60O10S2 982.3659, found
982.3649.
Acknowledgements
The authors thank the University of Missouri––St.
Louis for financial support and NSF for grants to pur-
chase the NMR spectrometer (CHE-9974801) and the
mass spectrometer (CHE-9708640) used in this work.
We also thank Dr. R. Winter and Mr. J. Kramer for
HRMS determinations.
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˚
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