Pre-activation based, highly alpha-selective O-sialylation with N-acetyl-5-N,4-O-carbonyl-protected p-tolyl thiosialoside donor

Article abstract of DOI:10.1016/j.tetlet.2011.09.022

A new method for pre-activation of N-acetyl-5-N,4-O-carbonyl-protected p-tolyl thiosialoside donor with AgOTf and p-toluenesulfenyl chloride followed by coupling with other p-tolyl thioglycosides is reported. Excellent α-sialylation yields were achieved f

Full text of DOI:10.1016/j.tetlet.2011.09.022

Tetrahedron Letters 52 (2011) 6035–6038
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pre-activation based, highly alpha-selective O-sialylation with N-acetyl-5-N,
4-O-carbonyl-protected p-tolyl thiosialoside donor
⇑
Bin Sun , Heyan Jiang
Research Center of Medicinal Chemistry & Chemobiology, Chongqing Technology and Business University, Chongqing 400067, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2011
Revised 17 August 2011
Accepted 6 September 2011
Available online 10 September 2011
A new method for pre-activation of N-acetyl-5-N,4-O-carbonyl-protected p-tolyl thiosialoside donor with
AgOTf and p-toluenesulfenyl chloride followed by coupling with other p-tolyl thioglycosides is reported.
Excellent
isomer.
a-sialylation yields were achieved for these coupling reactions, as high as 91% yield of only a-
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sialic acid
Pre-activation
Thiosialoside
Sialylation
Sialic acid residues are frequently located at the nonreducing
end of glycoconjugates and play important biological roles in many
organisms.1 N-Acetylneuraminic acid is the most common one and
reactivity of donor and acceptor, so it obviates the need for exten-
sive adjustment of armed or disarmed protective groups and signif-
icantly reduces the amount of time needed for preparing building
blocks. However, since the reactivity of thiosialoside is 105 times
less than that of the corresponding thioglycosides of the other sug-
ars,17 up to now, chemistry has not progressed to the level at which
thiosialosides are contemplated as components of pre-activations
is present in a variety of glycosidic linkages, most typically
and
-(2,6) linkages to galactose or galactosamine,2 as well as
-(2,8) or
-(2,9) linkages in polysialic acids.3 The biological signif-
icance of sialoside receptors has driven research for their efficient
synthesis. Significant efforts for improving -sialylation have been
a-(2,3)
a
a
a
a
based iterative one-pot glycan syntheses. In order to assemble a-
made, including the use of anomeric leaving groups,4 the introduc-
tion of an auxiliary group at C-1 and C-3,5 the modification of the
acetamide group at the 5th position of the sialyl donor into
powerful electron-withdrawing groups,6–14 or the optimized com-
binations of the leaving group with positional modification.15 How-
ever, owing to the low reactivity and low stereoselectivity, highly
sialoside-based oligosaccharides by a one-pot method, usually the
sialylated disaccharides have been used as building blocks.18 How-
ever, application of this strategy is limited by the lack of an efficient
and
a-selective sialic acid donor that possesses a leaving group
orthogonal to the thioglycoside. Based on the reactivity based
one-pot method, Crich successfully developed an adamantanyl sial-
yl thioglycoside which could be promoted with NIS/TfOH and re-
acted with phenyl thioglycoside acceptor.19 Up to now, there was
no report about the pre-activation based sialylation. Herein, we re-
port our preliminary observations of pre-activation based and
efficient a-sialylation is still one of the most difficult and challeng-
ing processes in the chemical synthesis of oligosaccharides.
Huang’s group developed a pre-activation based iterative one-
pot synthesis method and successfully assembled numerous classes
of complex oligosaccharides.16 Comparing the traditional reactivity
based one-pot syntheses, Huang’s strategy works regardless of the
highly
a-selective sialylation by using p-tolyl-N-acetyl-5-N,4-O-
carbonyl thiosialoside as donor.
STol
STol
STol
AcO
AcO
TCAHN
AcO
AcO
AcO
AcO
OAc
OAc
O
OAc
O
O
O
CO2CH3
CO2CH3
CO2CH3
N
AcHN
Ac
AcO
AcO
3
O
2
1
⇑
Corresponding author. Tel.: +86 23 62768049; fax: +86 23 62769652.
E-mail address: sunbin@ctbu.edu.cn (B. Sun).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.022

6036
B. Sun, H. Jiang / Tetrahedron Letters 52 (2011) 6035–6038
Table 1
Sialylation results of different sialyl thioglycosides
1) p-TolSCl (1 eq)
2)
OH
OR
O
BzO
BzO
BzO
O
BzO
STol
OBz
1(2,3) + AgOTf (3eq)
4
STol
CH2Cl2/Et2O(or CH3CN)
-75 °C to 0 °C
OBz
5 6 7
( , )
CO2CH3
CO2CH3
AcO
AcO
AcO
Ac
CO2CH3
AcO
AcO
ACTHN
OAc
AcO
OAc
O
OAc
O
AcO
O
O
5
6
R =
R =
AcHN
N
7
R =
AcO
O
Entry
Donor
Condition
Acceptor
Product
Yield (%)
a/b
1
2
3
4
5
1 (0.1 mmol)
1 (0.1 mmol)
1 (0.1 mmol)
2 (0.1 mmol)
3 (0.1 mmol)
A
B
C
C
C
4 (0.075 mmol)
4 (0.075 mmol)
4 (0.075 mmol)
4 (0.075 mmol)
4 (0.075 mmol)
5
5
5
6
7
87
91
91
83
33
5:1a
10:1a
a
Only
1:1b
a
Only
A: Compound 1 was dissolved in CH2Cl2 (5 mL), AgOTf was dissolved in Et2O (1 mL), 4 was dissolved in CH2Cl2 (2 mL). B: Compound 1 was dissolved in CH2Cl2 (5 mL), AgOTf
was dissolved in CH3CN (0.1 mL), 4 was dissolved in CH2Cl2 (2 mL). C: Compound 1 was dissolved in CH2Cl2 (5 mL), AgOTf was dissolved in CH3CN (1 mL), 4 was dissolved in
CH2Cl2 (2 mL).
a
Determined by 1H NMR on the crude reaction mixture.
Isolated product.
b
Crich and his co-workers found that N-acetyl-5-N,4-O-carbonyl thi-
osialoside donors can lead to highly -selective sialylation and that
donor 2 and donor 3 and found that donor 2 provided good sialy-
lation yields (83%), but no selectivity ( /b = 1/1) and donor 3 led to
good -selectivity ( only), but compared to donor 1 and 2, the
a
a
the oxazolidinone group can be easily cleaved under mild condi-
tions leaving the acetamide intact.14 Thus, initially we examined
the pre-activation of p-tolyl thiosialoside donor 1 by AgOTf/p-TolSCl
in CH2Cl2/CH3CN (or CH2Cl2/Et2O) at À75 °C, followed by coupling
a
a
yield was very low (33%), most of donor 3 being converted to the
eliminated product.9b
In Table 1, the ratio of donor:acceptor is 1:0.75, donor 1 gave an
excellent a-sialylation result, but TLC and column chromatography
with p-Tol-2,3,4-tri-O-benzoyl-1-thio-b-D-galacopyranoside (4)
and were able to achieve a sialylation product in good yield and
with high -selectivity (Table 1).
The solvent to dissolve AgOTf directly affects the
sialylation. When using 1 mL of Et2O to dissolve AgOTf, the ratio of
:b isomer of the product is 5:1, and when using 1 mL of acetoni-
trile only isomer was obtained. The reason for this result was
mostly due to the fact that acetonitrile reacts with activated sialic
donor 1 (oxonium ion) to form nitrilium cations and to stabilize
oxonium ion against collapse to eliminated glycal byproducts be-
fore adding the acceptor.4g,20 On the other hand, nitrilium cations
also can explain the stereoselectivities of sialylation in acetonitrile
solvents.4g,21 In addition, we also investigated the reactivity of
indicated that a small amount of donor 1 was converted to glycal.
In order to improve the sialylation efficiency, the ratio of donor to
acceptor was changed with the results shown in Table 2.
a
a
-selectivity of
The results of Table 2 indicate that when the ratio of donor to
acceptor was increased from 0.75 to 0.9, the sialylation yield (based
on the quantity of 4) was not changed (ca. 91%), and when the ratio
was increased to 0.95, the sialylation yield decreased to 87%, TLC also
showed that there was a small amount of acceptor left unreacted.
Hence, we prefer 0.9 as the best ratio for donor 1 to acceptor 4.
Encouraged by the results of donor 1 coupling with acceptor 4,
under the reaction conditions (3 equiv of AgOTf, 1 equiv of p-TolSCl,
ratio of donor to acceptor 1:0.9, CH2Cl2/CH3CN, under N2, at À75 °C
a
a
Table 2
The relationship of elimination product and the ratio of donor and acceptor
1)
2)
p
-TolSCl (1 eq)
OH
O
BzO
BzO
STol
AcO
CO2CH3
O
AcO
AcO
OAc
OAc
O
STol
AcO
OBz
O
4
O
CO2CH3
+ AgOTf (3 eq)
N
N
Ac
CH2Cl2/CH3CN
-75oC to 0oC
Ac
O
BzO
O
O
O
BzO
STol
OBz
1
5
Entry
1 (mmol)
4 (mmol)
Yieldd (%)
a/b
Glycal
1
2
3
4
5
0.1
0.1
0.1
0.1
0.1
0.075
0.08
0.085
0.09
91
92
90
91
87
a
a
a
a
a
Only
Yesa
Yesa
Yesb
No
Only
Only
Only
Only
0.095
Noc
a
b
c
Isolated product.
TLC indicated.
TLC indicated small part of 4 left.
d
Based on the quantity of acceptor.

B. Sun, H. Jiang / Tetrahedron Letters 52 (2011) 6035–6038
6037
to 0 °C, ethyl acetate/hexane for column chromatography), we fo-
cused our attention on donor 1 reacting with other thioglycoside
acceptors (8–13). In all cases, except 12, isolated yields of the sialy-
lation products ranged from good to excellent. In the case of accep-
tor 12, the mass spectrum of the reaction mixture indicated a peak
for sialylated disaccharide but the product could not be isolated
purely. The stereoselectivity in all cases was very good, only a-link-
age products were found. Regioselective sialylation of galactopy-
ranoside 2,3-diols, 3,4-diols, and 2,6-diols analogous 8, 11, 10,
configurations were assigned using empirical rules.22 The most use-
ful characteristic parameters to unequivocally assign configura-
tion were the chemical shift of H-3eq (d = 2.72–2.98 ppm), JH-7, H-8
(7.0–7.5 Hz), and d{H-9a–H-9b} (0.1–0.45 ppm). On the other
hand, the
a
D
a
configuration was also assigned by 3J (C-1, H-3eq) cou-
pling constants17 (Table 3). The 2?3, 2?6, and 2?9 linkages were
determined by the correlation of gHMBC between the signal of H-3,
H-6 of galactose unit or H-9 of sialic acid acceptor, and the signal of
C-2 of the sialic acid donor.
and 14 was observed with the formation of
products, and with sialic acid 8,9-diol analog 13,
uct was obtained.
a
-2,3 and
a
-2,6 linkage
In conclusion, regardless of huge difference between the reac-
tivity of sialyl p-tolyl thioglycoside and other p-tolyl thioglycosides
(except of 13, the reactivity of other p-tolyl thioglycoside is 105
times higher than that of sialyl p-tolyl thioglycoside), N-acetyl-5-
N-4-O-carbonyl protected p-tolyl thiosialoside donor can be
a-2,9 linked prod-
The structures of sialylated disaccharides 5, 6, 7, and 14–18 were
confirmed by 1H and gCOSY NMR experiments, and the anomeric
Table 3
Sialylation results of donor 1 coupled with different acceptors
1) p-TolSCl (1 eq)
STol
CO2CH3
O
OR
AcO
AcO
AcO
AcO
2) ROH (0.9 eq)
CH2Cl2/CH3CN
OAc
O
OAc
O
O
CO2CH3
+
AgOTf (3 eq)
CO2CH3
N
N
-75oC to 0oC
Ac
Ac
1
5 14 18
,
-
O
O
Entry
Acceptor
BzO
Product
Yield (%)
3J(C-1, H-3eq) (Hz)
a
/b
OH
O
AcO
AcO
OAc
O
4
STol
O
BzO
BzO
N
O
Ac
5
1
91
6.2
a
Only
OBz
O
O
BzO
STol
OBz
Ph
Ph
O
O
O
8
CH O2C
OAc 3
O
14
O
AcO
AcO
2
O
81
78
5.5
a
a
Only
Only
O
STol
STol
STol
STol
HO
N
N
O
Ac
O
OH
OH
O
Ph
Ph
O
O
O
9
15
CH O2C
OAc 3
O
AcO
AcO
3
4
O
O
6.0
6.3
O
HO
O
Ac
O
NHTroc
NHTroc
O
OH
CO2CH3
AcO
O
O
10
OAc
O
AcO
O
O
STol
N
O
O
16
Ac
89
85
a
a
Only
Only
OH
O
O
O
STol
OH
OH OBz
O
CH O2C
OBz
O
HO
17
STol
AcO
AcO
OAc3
11
STol
O
O
5
6
7
6.2
HO
N
Ac
O
OBz
OBz
O
OAc
OBn
O
OH
12
STol
CO2Me
OH
OBn
AcO
Ac
OAc
O
a
a
O
HO
O
/
/
/
N
STol
OAc
OBn
O
OBn
O
STol
CO2CH
O
HO
AcHN
AcO
AcO
3HO
AcHN
OAc
AcO
OAc
O
STol
18
CO2CH3
HO
O
O
CO2C
O
N
82
6.0
a
Only
Ac
13
AcO
O
a
No pure product isolated, based on MS spectrum indication we draw structure of disaccharide, we cannot calculate yield and selectivity.

6038
B. Sun, H. Jiang / Tetrahedron Letters 52 (2011) 6035–6038
pre-activated by the promoter of AgOTf/p-TolSCl in the solvent of
CH2Cl2/CH3CN and coupled with other p-tolyl thioglycosides with
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Experimental section
General experimental procedures: All reactions were carried
out under nitrogen with anhydrous solvents in flame-dried glass-
ware, unless otherwise noted. All the 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 using a solvent purification system and used
directly without further drying. Chemicals used were reagent
grade as supplied except where noted. Analytical thin-layer chro-
matography was performed using Silica Gel 60 F254 glass plates;
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 silica gel 60 (230–400 Mesh).
NMR spectra were referenced using Me4Si (0 ppm), residual CHCl3
(1H NMR 7.26 ppm, 13C NMR 77.0 ppm). Peak and coupling con-
stant assignments are based on 1H NMR and 1H–1H gCOSY. High-
resolution mass spectra were recorded on a Q-TOF Ultima API
LC-MS instrument with Waters 2795 Separation Module (Waters
Corporation, Milford, MA). All optical rotations were measured at
20 °C using the sodium D line.
The pre-activation based sialylation of Table 3 was carried out as
follows under N2: The reaction mixture of p-tolyl thiosialoside do-
nor (0.1 mmol) and freshly activated molecular sieves (3 Å, 500 mg)
in anhydrous CH2Cl2 (5 mL) was stirred for 30 min at room temper-
ature, then cooled to À75 °C, a solution of AgOTf (0.3 mmol) in ace-
tonitrile (1 mL) was added directly to the solution without touching
the wall of reaction flask. After 5 min at À75 °C, p-TolSCl (0.1 mmol)
was added via a syringe. The mixture was stirred for 10–15 min un-
til the yellow color disappeared and the donor was completely con-
sumed as judged by TLC. A solution of thioglycoside acceptor
(0.09 mmol) in anhydrous CH2Cl2 (2 mL) was added slowly to the
pre-activated donor. The reaction mixture was stirred for 90 min
while the temperature was raised from À75 °C to 0 °C and was
quenched with triethylamine (0.2 mL). The mixture was diluted
with CH2Cl2 (50 mL) and filtered over Celite. The filtrate was con-
centrated and purified by flash column chromatography (hexane,
ethyl acetate) to afford the desired product.
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Acknowledgments
This work was supported by Chongqing Technology & Business
University (2010-56-01), Natural Science Foundation Project of CQ
CSTC 2010BB5083 and Chongqing Innovative Research Team
Development Program in University (No. KJTD201020).