Synthesis of thioglycosides from propargyl glycosides exploiting alkynophilic gold catalyst

Article abstract of DOI:10.1080/07328303.2011.652789

Various thioglycosides were synthesized from stable propargyl glycosides using catalytic quantity of AuBr₃ and various thiol aglycons. The current protocol enables preparation of thioglycosides from propargyl glycosides in an efficient and simp

Full text of DOI:10.1080/07328303.2011.652789

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Synthesis of Thioglycosides from
Propargyl Glycosides Exploiting
Alkynophilic Gold Catalyst
Srinivasa Rao Vidadala a , Shivaji A. Thadke a , Srinivas Hotha a &
Sudhir Kashyap a
a Department of Chemistry , Indian Institute of Science Education &
Research , Pune , 411 021 , India
Published online: 29 Feb 2012.
To cite this article: Srinivasa Rao Vidadala , Shivaji A. Thadke , Srinivas Hotha & Sudhir Kashyap
(2012) Synthesis of Thioglycosides from Propargyl Glycosides Exploiting Alkynophilic Gold Catalyst,
Journal of Carbohydrate Chemistry, 31:3, 241-251, DOI: 10.1080/07328303.2011.652789
To link to this article: http://dx.doi.org/10.1080/07328303.2011.652789
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Journal of Carbohydrate Chemistry, 31:241–251, 2012
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.652789
Synthesis of Thioglycosides
from Propargyl Glycosides
Exploiting Alkynophilic Gold
Catalyst
Srinivasa Rao Vidadala, Shivaji A. Thadke, Srinivas Hotha,
and Sudhir Kashyap
Department of Chemistry, Indian Institute of Science Education & Research,
Pune – 411 021, India
Various thioglycosides were synthesized from stable propargyl glycosides using cat-
alytic quantity of AuBr3 and various thiol aglycons. The current protocol enables prepa-
ration of thioglycosides from propargyl glycosides in an efficient and simple manner.
The reaction is fast, catalytic, and mild. Supplemental materials are available for this
article. Go to the publisher’s online edition of Journal of Carbohydrate Chemistry to
view the free supplemental file.
Keywords Glycosidation; Thioglycoside; Glycoconjugate; Gold catalysis; Oligosaccha-
ride
INTRODUCTION
Oligosaccharides and glycoconjugates play significant roles in various biologi-
cal pathways.[1] Chemical synthesis is the most sought-after technique to get
access to the neoglycoconjugates. The synthesis of glycoconjugates often in-
volves a glycosyl donor that, upon activation using a suitable reagent, gen-
erates an intermediate oxocarbenium ion, which is attacked by an aglycon to
form a glycosidic linkage.[2] Over time, several groups have reported glycosyl
donors that are unique, and the carbohydrate field has exploited those to make
neoglyconconjugates.[3] One of the widely used sets of glycosyl donors utilizes
Received September 7, 2011; accepted December 20, 2011.
Address correspondence to Srinivas Hotha, Department of Chemistry, Indian Insti-
tute of Science Education & Research, Pune – 411 021, India. E-mail: s.hotha@
iiserpune.ac.in; and Sudhir Kashyap, Department of Chemistry, Indian Institute of Sci-
ence Education & Research, Pune – 411 021, India. E-mail: skr.kashyap@gmail.com
241

S.R. Vidadala et al.
242
thioalkyl or thioaryl moiety as the leaving group, which, upon addition of thio-
philic reagent, facilitates the generation of glycosides.[4] Thus, thioglycosides
have become significant for glycochemists as they are stable and can be ac-
tivated when required. Another interesting feature of thioglycosides is that
their glycosidic bond is resistant to enzymatic cleavage and hence they are
considered as promising candidates of carbohydrate-based therapeutics.[5] The
foregoing discussion highlights the general need and significance of the thio-
glycosides.
Traditionally, thioglycosides are synthesized from per-O-acetylated sugars
by the treatment with alkyl/aryl thiols in the presence of Lewis acids.[6] Al-
ternatively, thioglycosides can also be prepared in one pot from unprotected
reducing sugars using S-glycosyl isothiouronium salts.[7] We have recently
identified that propargyl O-glycosides behave as glycosyl donors in the pres-
ence of Au(III) catalysts.[8] In this communication, we wish to report the utility
of propargyl O-glycosides for the synthesis of thioglycosides using AuBr3 as
the catalyst.
RESULTS AND DISCUSSION
When an acetonitrile solution of propargyl 2,3,4,6-tetra-O-benzyl mannoside
(1) and thiophenol (A) was treated with AuBr3 at 60◦C for 24 h, 1,2-trans
thioglycoside 2A was obtained in 60% yield (Fig. 1).[9] The stereoselective
formation of 1,2-trans glycosides can be attributed to the anomeric effect
as well as the presence of axially disposed benzyloxy group at C-2. Then,
the scope of the present thioglycoside protocol was judged with a panel of
mercaptans B–F. Worth noting is that all of the reactions were clean, gave
reasonably good yields, and resulted in α-thiomannosides only. For example,
aromatic mercaptans B–D reacted with glycosyl donor 1 to give corresponding
α-thiomannosides 2B–2D. Further, the reaction conditions enabled us to use
aliphatic and furan-containing mercaptans (E and F) as thio-aglycons, which
gave 2E and 2F, respectively.[9]
We then explored the application of this thioglyosidation procedure to the
synthesis of thioglucosides and thiogalactosides. Accordingly, per-O-benzylated
propargyl glucoside (3) and galactoside (5) were treated with the aforemen-
tioned thiols, which were expected to produce thioglycosides 4A–4C, 4F,
6A–6C, and 6F. It is worth mentioning that these glycosyl donors resulted
in the formation of mixtures of α,β-thioglycosides in varied ratios as shown in
Figure 1. Mechanistically, the alkyne moiety of the propargyl glycoside gets
activated by the Au(III), leading to the formation of an oxocarbenium ion,
which was trapped by the thionucleophile in a similar fashion to that of O-
glycosides.[8a]

Synthesis of Thioglycosides
243
OBn
OBn
OBn
OBn
O
O
BnO
BnO
BnO
BnO
SR
2
O
Manno-
1
OBn
O
OBn
AuBr3
RSH
O
BnO
BnO
BnO
BnO
Acetonitrile
O
SR
BnO
BnO
24h, 60oC
Gluco-
3
4
α:β = 4:1)
OBn
O
OBn
BnO
BnO
BnO
O
BnO
Galacto-
RSH:
O
SR
BnO
BnO
5
6
α:β = 4:1)
HS
SH
Cl
SH
SH MeO
O
SH
SH
A
B
D
F
C
E
Aglycone
α:β ratio
S. No. Donor
Product
Yield
A
B
1.
2.
1
1
2A
2B
60
58
1:0
1:0
C
D
E
F
3.
4.
5.
6.
1
1
1
1
2C
2D
2E
2F
60
59
55
64
1:0
1:0
1:0
1:0
A
B
7.
8.
3
3
3
4A
4B
4C
63
68
72
1:1
1:1
C
F
9.
1:1.2
10.
11.
3
5
4F
6A
60
67
1:1
A
1:1.2
5
5
5
B
C
F
12.
13.
14.
6B
6C
6F
80
85
73
1:1.5
1:1
1:1
Figure 1: Synthesis of thioglycosides from propargyl glycosides.

S.R. Vidadala et al.
244
Scheme 1: Synthesis of disaccharides.
In continuation, we have demonstrated that thus prepared thioglycosides
2A and 4A can be utilized to synthesize disaccharide exploiting already re-
ported procedures (Sch. 1). For example, the reactions between glycosyl donors
2A and 4A with glycosyl acceptors 7 and 8 in the presence of NIS/TfOH
afforded disaccharides 9–12 in good yields.[8–10] Furthermore, disaccharide
propargyl glycoside such as 13 was reacted with thiophenol to obtain corre-
sponding thiodisaccharide 14[8f] in a good yield (Sch. 2).
In all the cases we have used nonparticipating protecting groups on the
residue present at the reducing end. The transglycosidation reactions did not
occur when participating groups such as esters were present because of their
strongly disarming nature.[8a,e] Also, it is pertinent to mention that benzyl
ether on the nonreducing residue would activate the interglycosidic bond as
previously observed.[8e]
In summary, we have reported the syntheses of thioglycosides from propar-
gyl glycosides using alkynophilic AuBr3 catalyst. We have also showed that
the resulting thioglycosides can be utilized for the synthesis of disaccharides.
OBz
OBz
OBz
OBz
O
BzO
BzO
O
BzO
BzO
PhSH
AuBr3 (10mol%)
O
O
O
CH3CN, 60oC
36h, 61%
BnO
BnO
O
BnO
BnO
BnO
O
BnO
SPh
13
14
Scheme 2: Synthesis of thiodisaccharides from corresponding propargyl disaccharides.

Synthesis of Thioglycosides
245
We anticipate that swapping of the leaving group would further enhance the
scope of propargyl glycosides as glycosyl donors. Also worth noting is that the
conversion of a stable glycosyl donor, such as propargyl glycoside, to another
stable glycosyl donor, such as thioglycoside, would enable the progression of
the oligosaccharide synthesis without too many synthetic steps.
EXPERIMENTAL
General Methods
Unless otherwise noted, materials were obtained from commercial suppli-
ers and were used without further purification. Unless otherwise reported,
all reactions were performed under argon atmosphere. Removal of solvent in
vacuo refers to distillation using a rotary evaporator attached to an efficient
vacuum pump. Products obtained as solids or syrups were dried under high
vacuum. AuBr3 was purchased from Aldrich. Analytical thin-layer chromatog-
raphy was performed on precoated silica plates (F254, 0.25 mm thickness); com-
pounds were visualized by UV light or by staining with anisaldehyde spray. 1H
1
and 13C NMR spectra were recorded on 200 MHz for H and 50 MHz for 13C
NMR or 400 MHz for 1H and 100 MHz for 13C NMR or 500 MHz for 1H and 125
MHz for 13C NMR spectrometers. Chemical shifts (δH) are quoted in ppm and
are referenced to tetramethylsilane (internal).
General Experimental Procedure for the Thioglycosidation
AuBr3 (10% mol) in acetonitrile was added to a solution of propargyl glyco-
side (1.0 equiv) and thio-aglycone (1.2 equiv) in acetonitrile and heated to 60◦C
for 24 h. The reaction mixture was diluted with water and extracted with ethyl
acetate (3×), and the combined organic layers were concentrated in vacuo to
obtain a crude residue of thioglycoside that was purified by silica gel column
chromatography using ethyl acetate-petroleum ether as the mobile phase.
Phenyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (2A)
[α]D = +10.00 (c, 1.10, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.74 (dd,
25
1H, J = 1.95, 10.80 Hz), 3.77–3.89 (m, 2H), 4.00 (dd, 1H, J = 1.71, 2.97 Hz),
4.07 (t, 1H, J = 4.47 Hz), 4.29 (qd, 2H, J = 1.85 Hz, J = 4.69 Hz), 4.47 (d, 1H,
J = 10.08 Hz), 4.53 (d, 1H, J = 8.98 Hz), 4.60 (s, 2H), 4.67 (dd, 2H, J = 4.70,
11.88 Hz), 4.91 (d, 1H, J = 10.77 Hz), 5.61 (d, 1H, J = 1.46 Hz), 7.17–7.47 (m,
25H); 13C NMR (CDCl3, 50.32 MHz): δ 69.1, 71.8, 72.0, 72.7, 73.2, 74.9, 75.2,
76.1, 80.1, 85.7, 127.4-128.4, 129.0, 129.0, 131.6, 131.6, 134.3, 137.8, 138.1,
138.3, 138.4; Calcd mass for C40H40O5S: 632.81; Found 653.70 (M+ + 23 for
Na).

S.R. Vidadala et al.
246
p-Methoxybenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (2B)
[α]D = +35.55 (c, 0.90, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ
25
3.52–3.77 (m, 5H), 3.78 (s, 3H), 3.84 (d, 1H, J = 2.65 Hz), 4.02 (t, 1H, J =
9.35 Hz), 4.10–4.20 (m, 1H), 4.48–4.56 (m, 4H), 4.60 (s, 1H), 4.65 (t, 1H, J =
2.95 Hz), 4.73 (d, 1H, J = 5.30 Hz), 4.88 (d, 1H, J = 10.87 Hz), 5.27 (s, 1H),
6.82 (d, 2H, J = 8.72 Hz), 7.10–7.38 (m, 22H); 13C NMR (CDCl3, 50.32 MHz):
δ 34.1, 55.2, 69.1, 71.7, 71.9, 72.2, 73.3, 75.0, 75.1, 75.8, 80.4, 80.6, 113.9,
127.4-128.3, 129.7, 130.1, 137.9, 138.1, 138.3, 138.5, 158.6; Calcd mass for
C42H44O6S: 676.86; Found 699.77 (M+ + 23 for Na).
p-Chlorobenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (2C)
[α]D = +40.00 (c, 1.20, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.58–3.72
25
(m, 4H), 3.74–3.84 (m, 2H), 4.02 (d, 1H, J = 8.46 Hz), 4.48 (d, 1H, J = 1.64 Hz),
4.53 (s, 2H), 4.54 (s, 1H), 4.59 (d, 2H, J = 4.92 Hz), 4.63 (s, 1H), 4.66–4.75 (m,
1H), 4.88 (d, 1H, J = 10.74 Hz), 5.18 (d, 1H, J = 1.27 Hz), 7.15–7.39 (m, 24H);
13C NMR (CDCl3, 50.32 MHz): δ 33.9, 69.0, 71.9, 72.0, 72.2, 73.3, 74.9, 75.1,
75.8, 80.3, 80.7, 127.5-128.3, 128.6, 130.3, 132.8, 136.3, 137.8, 138.1, 138.2,
138.3; Calcd mass for C41H41ClO5S: 681.28; Found 704.69 (M+ + 23 for Na).
Ethylbenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (2D)
[α]D = +22.72 (c, 1.10,CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 2.74–2.91
25
(m, 4H), 3.67–3.85 (m, 4H), 3.97–4.17 (m, 2H), 4.47–4.73 (m, 7H), 4.87 (d, 1H,
J = 10.74 Hz), 5.36 (s, 1H), 7.13–7.38 (m, 25H); 13C NMR (CDCl3, 50.32 MHz): δ
32.5, 36.3, 69.1, 71.9, 72.0, 72.0, 73.3, 75.0, 75.1, 76.2, 80.3, 82.3, 126.3, 127.4-
128.5, 138.1, 138.2, 138.3, 138.4, 140.2; Calcd mass for C42H44O5S: 660.86;
Found 683.80 (M+ + 23 for Na).
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (2E)
[α]D = +12.50 (c, 0.80, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 1.20–2.28
25
(m, 3H), 2.59 (t, 2H, J = 7.09 Hz), 3.67–3.86 (m, 4H), 3.98–4.17 (m, 2H), 4.50
(d, 2H, J = 11.88 Hz), 4.57 (s, 2H), 4.60–4.64 (m, 1H), 4.70 (d, 2H, J = 4.57
Hz), 4.88 (d, 1H, J = 10.87 Hz), 5.40 (d, 1H, J = 1.50 Hz), 7.14–7.41 (m, 20H);
13C NMR (CDCl3, 50.32 MHz): δ 14.9, 25.3, 69.1, 71.9, 72.0, 72.0, 73.3, 75.0,
75.1, 76.3, 80.3, 81.8, 127.4-128.3, 138.1, 138.2, 138.3, 138.5; Calcd mass for
C36H40O5S: 584.76; Found 607.88 (M+ + 23 for Na).
2-Furfuryl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (2F)
[α]D = +32.00 (c, 1.00, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.62–4.26
25
(m, 7H), 4.48–4.74 (m, 6H), 4.85–4.98 (m, 2H), 5.39 (s, 1H), 6.16 (d, 1H, J =
2.93 Hz), 6.28 (dd, 1H, J = 1.89, 3.16 Hz), 7.14–7.33 (m, 22H); 13C NMR
(CDCl3, 50.32 MHz): δ 26.7, 69.3, 71.8, 71.9, 72.4, 73.3, 74.9, 75.1, 75.8, 81.1,

Synthesis of Thioglycosides
247
81.3, 107.9, 110.4, 127.4–128.3, 137.9, 138.1, 138.4, 138.4, 142.3, 150.8; Calcd
mass for C39H40O5S: 636.80; Found 659.71 (M+ + 23 for Na).
p-Methoxybenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α/β-D-glucopyranoside (4B)
1H NMR (CDCl3, 200.13 MHz): δ 3.54–3.79 (m, 12H), 3.77 (s, 3H), 3.78 (s,
3H), 3.86 (d, 1H, J = 3.16 Hz), 3.95 (s, 1H), 4.24 (d, 2H, J = 9.47 Hz), 4.44
(s,1H), 4.46–4.57 (m, 5H), 4.59 (s, 2H), 4.61 (s,1H), 4.65–4.67 (m, 1H), 4.71 (d,
1H, J = 3.28 Hz), 4.75–4.81 (m, 3H), 4.85 (t, 2H, J = 2.84 Hz) 4.93 (d, 1H, J =
10.86 Hz), 5.20 (d, 1H, J = 5.05 Hz), 6.80 (d, 2H, J = 8.85 Hz), 6.83 (d, 2H, J =
8.71 Hz), 7.11–7.38 (m, 44H); 13C NMR (CDCl3, 50.32 MHz): δ 32.7, 33.7, 55.2,
55.3, 68.5, 69.1, 70.7, 71.8, 73.4, 73.4, 75.0, 75.0, 75.3, 75.7, 75.7, 77.4, 78.0,
78.9, 79.0, 81.6, 81.9, 82.8, 83.0, 86.6, 113.8, 113.9, 127.5-128.4, 129.4, 129.9,
130.2, 130.3, 137.6, 137.9, 138.0 138.1, 138.2, 138.4, 138.5, 138.6, 158.5, 158.6;
Calcd mass for C42H44O6S: 676.86; Found 699.80 (M+ + 23 for Na).
p-Chlorobenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α/β-D-glucopyranoide (4C)
1H NMR (CDCl3, 200.13 MHz): δ 3.49–3.50 (m, 1H), 3.54–3.57 (m, 2H), 3.59
(d, 1H, J = 3.24 Hz), 3.62 (s, 1H), 3.65 (s, 2H), 3.69–3.72 (m, 1H), 3.75 (d, 1H,
J = 3.86 Hz), 3.79 (d, 1H, J = 2.11 Hz), 3.83 (d, 1H, J = 2.89 Hz), 3.94–4.24
(m, 3H), 4.43 (s, 1H), 4.50 (s, 4H), 4.56–4.59 (m, 3H), 4.65 (d, 1H, J = 4.70 Hz),
4.71–4.75 (m, 2H), 4.78 (d, 2H, J = 2.80 Hz), 4.81 (d, 2H, J = 2.37 Hz), 4.85 (s,
2H), 4.90 (s, 1H), 4.96 (d, 1H, J = 2.41 Hz), 5.13 (d, 1H, J = 5.07 Hz), 7.11–7.36
(m, 48H); 13C NMR (CDCl3, 50.32 MHz): δ 32.5, 33.6, 68.4, 69.1, 70.7, 70.7,
72.2, 73.4, 73.4, 75.0, 75.1, 75.4, 75.7, 75.7, 77.4, 77.9, 78.9, 82.0, 82.7, 83.0,
86.6, 127.6-128.6, 128.6, 130.4, 130.5, 132.7, 132.8, 136.2, 136.4, 137.5, 137.7,
137.8, 138.0, 138.1, 138.2, 138.3, 138.6; Calcd mass for C41H41ClO5S: 681.28;
Found 704.79 (M+ + 23 for Na).
2-Furfuryl 2,3,4,6-tetra-O-benzyl-1-thio-α/β-D-glucopyranoside (4F)
1H NMR (CDCl3, 200.13 MHz): δ 3.57–3.66 (m, 5H), 3.69–3.77 (m, 3H),
3.76–3.85 (m, 4H), 4.00 (d, 1H, J = 9.64 Hz), 4.19–4.20 (m,2H), 4.44 (s, 2H),
4.49 (s, 1H), 4.50 (s, 1H), 4.55–4.62 (m, 3H), 4.64–4.66 (m, 1H), 4.72 (s, 1H),
4.76 (d, 1H, J = 4.18 Hz), 4.81 (s, 2H), 4.84–4.86 (m, 2H), 4.87 (d, 1H, J = 1.63
Hz), 4.90 (d, 1H, J = 1.37 Hz), 4.96 (d, 1H, J = 1.75 Hz), 5.42 (d, 1H, J = 4.33
Hz), 5.62–5.63 (m, 1H), 6.02 (d, 1H, J = 1.80 Hz), 6.21 (t, 1H, J = 3.78 Hz), 6.27
(dd, 1H, J = 1.90, 3.27 Hz), 6.30 (dd, 1H, J = 1.85, 3.21 Hz), 7.11–7.36 (m, 44H);
13C NMR (CDCl3, 50.32 MHz): δ 25.5, 26.3, 68.3, 68.4, 70.6, 70.7, 70.8, 71.8,
73.3, 73.4, 75.0, 75.1, 75.7, 77.5, 77.9, 79.0, 79.6, 81.9, 82.6, 82.7, 86.6, 95.8,
107.7, 107.7, 110.4, 110.4, 125.5-128.4, 137.6, 137.8, 137.8, 138.0, 138.1, 138.2,
138.6, 138.7, 142.1, 142.1, 151.2, 151.2; Calcd mass for C39H40O5S: 636.80;
Found 659.89 (M+ + 23 for Na).

S.R. Vidadala et al.
248
p-Methoxybenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-galactopyranoside (6Bα)
[α]D = +55.95 (c, 1.10, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.46–3.54
25
(m, 2H), 3.60 (d, 1H, J = 4.16 Hz), 3.63 (d, 1H, J = 4.41 Hz), 3.76 (s, 3H),
3.78–3.79 (m, 1H), 3.86 (d, 2H, J = 9.20 Hz), 3.92 (d, 1H, J = 2.27 Hz), 4.24 (d,
1H, J = 9.63 Hz), 4.46 (d, 2H, J = 3.68 Hz), 4.60 (d, 1H, J = 11.61 Hz), 4.69
(s, 2H), 4.74 (d, 2H, J = 3.54 Hz), 4.94 (d, 1H, J = 11.61 Hz), 6.74 (d, 1H, J
= 1.99 Hz), 6.78 (d, 1H, J = 2.19 Hz), 7.21–7.33 (m, 22H); 13C NMR (CDCl3,
50.32 MHz): δ 32.3, 55.2, 69.2, 69.8, 71.9, 73.3, 73.4, 74.7, 74.9, 75.8, 79.7, 81.9,
113.7, 113.8, 127.4-128.3, 129.9, 130.0, 130.2, 138.0, 138.0, 138.5, 138.7, 158.5;
Calcd mass for C42H44O6S: 676.86; Found 699.92 (M+ + 23 for Na).
p-Methoxybenzyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside (6Bβ)
25
1
[α]D = –19.29 (c, 1.00, CHCl3); H NMR (CDCl3, 200.13 MHz): δ 3.52 (d,
1H, J = 6.30 Hz), 3.64 (d, 1H, J = 9.19 Hz), 3.70 (m, 1H), 3.75 (s, 1H), 3.77 (s,
3H), 3.78 (s, 1H), 3.83–3.92 (m, 1H), 4.21 (dd, 1H, J = 5.63, 9.80 Hz), 4.28–4.39
(m, 2H), 4.40 (d, 1H, J = 1.13 Hz), 4.45 (d, 1H, J = 4.52 Hz), 4.53 (d, 1H, J =
3.40 Hz), 4.62 (d, 1H, J = 9.77 Hz), 4.70 (d, 1H, J = 2.50 Hz), 4.82 (d, 1H, J =
11.82 Hz), 4.91 (d, 1H, J = 11.43 Hz), 5.25 (d, 1H, J = 5.67 Hz), 6.78 (d, 1H,
J = 1.80 Hz), 6.81 (d, 1H, J = 2.08 Hz), 7.21–7.36 (m, 22H); 13C NMR (CDCl3,
50.32 MHz): δ 33.4, 55.2, 68.9, 72.8, 73.5, 73.7, 74.5, 75.6, 77.2, 78.3, 83.5, 84.0,
113.8, 127.5-128.4, 129.8, 130.2, 137.8, 138.2, 138.3, 138.6, 158.5; Calcd mass
for C42H44O6S: 676.86; Found 699.57 (M+ + 23 for Na).
p-Chlorobenzyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-galactopyranoside (6Cα)
[α]D = +84.93 (c, 1.00, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.46 (d,
25
2H, J = 6.42 Hz), 3.59 (d, 1H, J = 4.88 Hz), 3.66 (d, 1H, J = 3.40 Hz), 3.72–3.75
(m, 1H), 3.79–3.81 (m, 1H), 3.87–3.91 (m, 1H), 4.17–4.41 (m, 3H), 4.43 (d, 2H,
J = 3.55 Hz), 4.52 (s, 2H), 4.74 (ABq, 2H, J = 11.85 Hz), 4.92 (d, 1H, J = 11.51
Hz), 7.22–7.35 (m, 24H); 13C NMR (CDCl3, 50.32 MHz): δ 32.1, 69.2, 69.9, 72.3,
73.4, 73.4, 74.7, 74.8, 75.8, 79.6, 81.9, 127.4-128.5, 130.5, 132.5, 136.7, 136.7,
137.9, 138.4, 138.6; Calcd mass for C41H41O5S: 681.28; Found 704.77 (M+ + 23
for Na).
p-Chlorobenzyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside (6Cβ)
[α]D = –19.56 (c, 0.90, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.43–3.51
25
(m, 2H), 3.54–3.62 (m, 2H), 3.74–3.83 (m, 2H), 3.88 (s, 1H), 3.80–3.95 (m, 1H),
4.21 (d, 1H, J = 9.61 Hz), 4.45 (d, 2H, J = 3.42 Hz), 4.60 (d, 1H, J = 11.45 Hz),
4.69 (s, 2H), 4.73 (s, 2H), 4.94 (d, 1H, J = 11.45 Hz), 7.14–7.38 (m, 24H); 13C
NMR (CDCl3, 50.32 MHz): δ 32.2, 68.9, 72.7, 73.5, 73.6, 74.5, 75.6, 77.2, 78.1,
83.3, 84.0, 127.5-128.5, 130.5, 132.6, 136.6, 137.7, 138.1, 138.2, 138.5; Calcd
mass for C41H41O5S: 681.28; Found 704.07 (M+ + 23 for Na).

Synthesis of Thioglycosides
249
2-Furfuryl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-galactopyranoside (6F)
1H NMR (CDCl3, 200.13 MHz): δ 3.50–3.62 (m, 5H), 3.66 (s, 1H), 3.68–3.75
(m, 1H), 3.78–3.82 (m, 2H), 3.85–3.87 (m, 1H), 3.91–3.96 (m, 3H), 4.01–4.09 (m,
1H), 4.14–4.38 (m, 4H), 4.41–4.45 (m, 3H), 4.48–4.65 (m, 4H), 4.70 (s, 2H), 4.74
(d, 1H, J = 2.52 Hz), 4.79 (s, 1H), 4.91 (d, 1H, J = 2.65 Hz), 4.97 (d, 1H, J =
2.90 Hz), 5.46 (d, 1H, J = 5.56), 6.15 (d, 2H, J = 3.25 Hz), 6.23 (dd, 1H, J =
1.89, 3.16 Hz), 6.28 (dd, 1H, J = 1.76, 3.15 Hz), 7.12–7.35 (m, 44H); 13C NMR
(CDCl3, 50.32 MHz): δ 25.1, 25.6, 68.7, 69.0, 70.0, 72.0, 72.7, 73.3, 73.4, 73.5,
73.6, 74.5, 74.7, 74.9, 75.6, 75.8, 77.2, 78.1, 79.6, 82.7, 83.7, 84.0, 107.7, 107.8,
110.3, 110.4, 127.4-128.4, 137.8, 138.0, 138.0, 138.1, 138.3, 138.5, 138.6, 138.7,
142.0, 142.0, 151.2, 151.3; Calcd mass for C39H40O6S: 636.80; Found 659.96
(M+ + 23 for Na).
Phenyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-galactopyranoside (6Aα)
[α]D = +9.15 (c, 1.00, CHCl3); 1H NMR (CDCl3, 200.13 MHz): δ 3.57–3.68
25
(m, 4H), 3.91 (d, 1H, J = 9.47 Hz), 3.98 (d, 1H, J = 2.27 Hz), 4.44 (d, 2H, J =
3.41 Hz), 4.56–4.70 (m, 3H), 4.72 (s, 2H), 4.76 (d, 1H, J = 3.41 Hz), 4.97 (d, 1H,
J = 11.50 Hz), 7.15–7.59 (m, 25H); 13C NMR (CDCl3, 50.32 MHz): δ 68.7, 72.7,
73.5, 73.5, 74.4, 75.6, 77.2, 84.1, 87.7, 127.0, 127.4–128.4, 128.8, 131.4, 134.1,
137.9, 138.2, 138.2, 138.7; Calcd mass for C40H40O5S: 632.81; Found 655.03
(M+ + 23 for Na).
Phenyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside (6Aβ)
25
1
[α]D = +89.7 (c, 1.20, CHCl3); H NMR (CDCl3, 200.13 MHz): δ 3.52 (d,
1H, J = 4.45 Hz), 3.54 (1H, J = 4.20 Hz), 3.82 (dd, 1H, J = 2.85, 10.05 Hz), 4.00
(d, 1H, J = 1.77 Hz), 4.33–4.50 (m, 4H), 4.59 (d, 1H, J = 11.51 Hz), 4.67–4.77
(m, 3H), 4.82–4.99 (m, 2H), 5.72 (d, 1H, J = 5.43 Hz), 7.19–7.51 (m, 25H); 13C
NMR (CDCl3, 50.32 MHz): δ 68.8, 70.3, 72.6, 73.3, 73.4, 74.8, 75.0, 79.4, 87.5,
126.9, 127.5-128.3, 128.8, 131.6, 134.6, 137.9, 138.0, 138.5, 138.6; Calcd mass
for C40H40O5S: 632.81; Found 656.05 (M+ + 23 for Na).
Compound 13. [α]D = +18.5(c, 1.0, CHCl3); 1H NMR (CDCl3, 200.13
25
MHz): δ 2.47 (t, 1H, J = 2.3 Hz), 3.55 (t, 1H, J = 9.1 Hz), 3.63 (dd, 1H, J = 3.7,
9.7 Hz), 3.75–3.95 (m, 3H), 4.05 (t, 1H, J = 9.2 Hz), 4.25–4.51 (m, 2H), 4.38 (s,
2H), 4.58–4.89 (m, 3H), 4.75 (s, 2H), 4.95–5.16 (m, 4H), 5.73 (dd, 1H, J = 1.7,
3.1 Hz), 5.87 (dd, 1H, J = 3.1, 10.0 Hz), 6.09 (t, 1H, J = 10.0 Hz), 7.20–7.65
(m, 27H), 7.76–8.15 (m, 8H); 13C NMR (CDCl3, 50.32 MHz): δ 54.6, 62.6, 66.6,
66.7, 68.8, 69.9, 70.1, 70.5, 73.0, 75.0, 75.0, 75.7, 77.5, 78.8, 79.6, 81.9, 94.9,
97.7, 127.6–129.8, 133.0, 133.1, 133.4, 133.4, 137.9, 138.1, 138.6, 165.2, 165.4,
165.4, 166.1; HRMS (MALDI-TOF) Calcd for C64H58O15Na, 1089.3673; Found,
1089.3609.
Compound 14. 1H NMR (CDCl3, 200.13 MHz): δ 3.53–3.63 (m, 2H),
3.79–4.10 (m, 6H), 4.22–4.40 (m, 6H), 4.48–4.84 (m, 10H), 4.91–5.20 (m, 6H),

S.R. Vidadala et al.
250
5.68–5.74 (m, 2H), 5.83–5.92 (m, 3H), 6.05–6.10 (m, 3H), 6.29 (t, 1H, J = 10.1
Hz), 6.62 (d, 1H, J = 1.8 Hz), 7.20–7.70 (m, 64H), 7.81–8.21 (m, 16H); 13C NMR
(CDCl3, 50.32 MHz): δ 62.3, 62.7, 66.1, 66.6, 66.8, 69.0 (2C), 69.4, 69.9, 70.0
(2C), 70.2, 70.5 (2C), 71.0 (2C), 71.1 (2C), 73.3 (2C), 75.0, 75.1, 75.2, 75.7, 77.2,
77.6, 80.0, 81.9, 91.3, 95.4, 119.5 (2C), 127.5–130.2 (80C), 133.0–133.1 (6C),
138.0–138.7 (8C), 163.8, 165.1, 165.3 (2C), 165.4, 165.7, 166.0, 166.1; HRMS
(MALDI-TOF) Calcd for C67H60O14SNa, 1143.3601; Found, 1143.3655.
ACKNOWLEDGMENTS
SH thanks the Swarnajayanti Fellowship from DST, New Delhi. SRV, SAT, and
SK acknowledge fellowship from CSIR-New Delhi.
REFERENCES
1. (a) Varki, A. Biological roles of oligosaccharides: all of the theories are correct.
Glycobiology 1993, 3, 97–130; (b) Bertozzi, C.R.; Kiessling, L.L. Chemical glycobiology.
Science, 2001, 291, 2357–2364; (c) Dwek, R.A. Glycobiology: towards understanding the
functions of sugars. Chem. Rev. 1996, 96, 683–720.
2. Toshima, K.; Tatsuta, K. Recent progress in O-glycosylation methods and its ap-
plication to natural products synthesis. Chem. Rev. 1993, 93, 1503–1531.
3. (a) Tamborrini, M.; Werz, D.B.; Frey, J.; Pluschke, G.; Seeberger, P.H. Anti-
carbohydrate antibodies for the detection of anthrax spores. Angew. Chem. Int. Ed.
2006, 45, 6581–6582; (b) Ragupathi, G.; Koide, F.; Livingston, P.O.; Cho, Y.S.; Endo, A.;
Wan, Q.; Spassova, M.K.; Keding, S.J.; Allen, J.; Ouerfelli, O.; Wilson, R.M.; Danishef-
sky, S.J. Preparation and evaluation of unimolecular pentavalent and hexavalent anti-
genic constructs targeting prostate and breast cancer: a synthetic route to anticancer
vaccine. J. Am. Chem. Soc. 2006, 128, 2715–2725.
4. (a) Schmidt, R.R.; Kinzy, W. Anomeric oxygen activation for glycoside synthesis:
the trichloroacetimidate method. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123;
(b) Garegg, P.J. Thioglycosides as glycosyl donors in oligosaccharide synthesis. Adv.
Carbohydr. Chem. Biochem. 1997, 52, 179–205; (c) Nguyen, H.M.; Chen, Y.; Duron,
S.G.; Gin, D.Y. Sulfide-mediated dehydrative glycosylation. J. Am. Chem. Soc. 2001,
123, 8766–8772; (d) Plante, O.J.; Palmacci, E.R.; Seeberger, P.H. Development of an au-
tomated oligosaccharide synthesizer. Adv. Carbohydr. Chem. Biochem. 2003, 58, 35–54.
5. (a) Comber, R.N.; Friedrich, J.D.; Dunshee, D.A.; Petty, S.L.; Secrist III, J.A. α-
(1→2)-, α-(1→3)-, and α-(1→6)-Linked thioglycosidic disaccharides: syntheses and anti-
HIV testing of thiojibiose octaacetate, thionigerose, and thioisomaltose. Carbohydr. Res.
1994, 262, 245–255; (b) Sulzenbacher, G.; Driguez, H.; Henrissat, B.; Schulein, M.;
Davies, G.J. Structure of the Fusarium oxysporum endoglucanase I with a nonhydrolyz-
able substrate analogue: substrate distorsion gives rise to the preferred axial orienta-
tion for the leaving group. Biochem. 1996, 35, 15280–15287; (c) Kiefel, M.J.; Beisner,
B.; Bennett, S.; Holmes, I.D.; von Itzstein, M. Synthesis and biological evaluation of N-
acetylneuraminic acid-based rotavirus inhibitors. J. Med. Chem. 1996, 39, 1314–1320;
(d) Parsiegla, G.; Reverbel-Leroy, C.; Tardif, C.; Belaich, J.P.; Driguex, H.; Haser, R.
Crystal structure of the cellulose Ce148F in complex with inhibitors and substrate give
insights into its processive action. Biochem. 2000, 39, 11238–11246.
6. (a) Pozsgay, V.; Jennings, H.J. A new, stereoselective synthesis of methyl 1,2-trans-
1-thioglycosides. Tetrahedron Lett. 1987, 28, 1375–1376; (b) Nambiar, S.; Daeuble,

Synthesis of Thioglycosides
251
J.F.; Doyle, R.J.; Taylor, K.G. Facile synthesis of silylated thioglycosides. Tetrahedron
Lett. 1989, 30, 2179–2182; (c) Olsson, L.; Kelberlau, S.; Jia, Z.J.; Bert, F.-R. Access to
tetrachlorophthalimide-protected ethyl 2-amino-2-deoxy-1-thio-β-D-glucopyranosides.
Carbohydr. Res. 1998, 314, 273–276; (d) Tai, C.-A.; Kulkarni, S.S.; Hung, S.-C. Facile
Cu(OTf)2- catalyzed preparation of per-O-acetylated hexopyranoses with stoichiometric
acetic anhydride and sequential one-pot anomeric substitution to thioglycosides under
solvent-free conditions. J. Org. Chem. 2003, 68, 8719–8722.
7. (a) Agnihotri, G.; Tiwari, P.; Misra, A.K. One –pot synthesis of per-O-
acetylated thioglycosides from unprotected reducing sugars. Carbohydr. Res. 2005, 340,
1393–1396; (b) Tiwari, P.; Agnihotri, G.; Misra, A.K. Modified one-pot protocol for the
preparation of thioglycosides from unprotected aldoses via S-glycosyl isothiouronium
salts. J. Carbohydr. Chem. 2005, 24, 723–732.
8. (a) Hotha, S.; Kashyap, S. Propargyl glycosides as stable glycosyl donors:
anomeric activation and glycoside syntheses. J. Am. Chem. Soc. 2006, 128, 9620–9621;
(b) Sureshkumar, G.; Hotha, S. Propargyl 1,2-orthoesters as glycosyl donors: stereose-
lective synthesis of 1,2-trans glycosides and disaccharides. Tetrahedron Lett. 2007, 48,
6564; (c) Kashyap, S.; Hotha, S.; Vidadala, S.R. Synthesis of C-2 methylene glucosides
from C-2-propargyloxymethyl glucals exploiting the alkynophillicity of AuCl3. Tetrahe-
dron Lett. 2007, 48, 8960–8962; (d) Vidadala, S.R.; Thadke, S.A.; Hotha, S. Orthogonal
activation of propargyl and n-pentenyl glycosides and 1,2-orthoesters. J. Org. Chem.
2009, 74, 9233–9236; (e) Gold-catalyzed glycosidations: unusual cleavage of the inter-
glycosidic bond while studying the armed/disarmed effect of propargyl glycosides. Tetra-
hedron Lett. 2010, 51, 5269–5272; (f) Vidadala, S.R.; Hotha, S. Methyl glycosides are
identified as glycosyl donors for the synthesis of glycosides, disaccharides and oligosac-
charides. Chem. Commun. 2009, 2505–2507.
9. See supplementary material available online.
10. (a) Liu, B.; Roy, R. Synthesis of clustered xenotransplantation antagonists using
palladium-catalyzed cross-coupling of prop-2-ynyl-α-D-galatopyranosides. J. Chem. Soc.
Perkin Trans. 1 2001, 773–779; (b) Uriel, C.; Agocs, T.; Gomez, Lopez, J.C.; Fraser-Reid,
B. Relevance of the glycosyl donor to the regioselectivity of glycosylation of primary-
secondary diol acceptors and application of these ideas to in situ three-component dou-
ble differential glycosidation. Org. Lett. 2005, 7, 4899–4902.