An efficient approach for total synthesis of aminopropyl functionalized ganglioside GM1b

Article abstract of DOI:10.1016/j.tetlet.2012.08.077

A highly efficient protocol for the synthesis of aminopropyl functionalized ganglioside GM1b has been described. The full protected ganglioside GM1b was obtained in 71% yield within 5 h. The key feature of the synthetic approach was the use of sialic acid

Full text of DOI:10.1016/j.tetlet.2012.08.077

Tetrahedron Letters 53 (2012) 5711–5715
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Tetrahedron Letters
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An efficient approach for total synthesis of aminopropyl functionalized
ganglioside GM1b
⇑
Bin Sun , Heyan Jiang
Research Center of Medicinal Chemistry & Chemical Biology, 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:
A highly efficient protocol for the synthesis of aminopropyl functionalized ganglioside GM1b has been
described. The full protected ganglioside GM1b was obtained in 71% yield within 5 h. The key feature
of the synthetic approach was the use of sialic acid donor that was with a C-5 trichloroacetamide moiety
and with a dibenzyl phosphite residue as leaving group at the anomeric carbon. The sialyl donor gave
Received 15 June 2012
Revised 15 August 2012
Accepted 17 August 2012
Available online 23 August 2012
high yields and excellent a-anomeric selectivities with a wide variety of glycosyl acceptors ranging from
C-3 or C-6 hydroxyls of galactoside to C-6 hydroxyl of glucosaminoside by using TMSOTf as catalyst in a
mixture solution of acetonitrile and methylene chloride.
Keywords:
Glycosylation
Synthesis
Ó 2012 Elsevier Ltd. All rights reserved.
Ganglioside GM1b
Sialylation
Pre-activation
Gangliosides, sialic acids containing glycosphingolipids, are a
class of structurally diverse molecules commonly present in the
outer membrane of living cells and are particularly rich in tissues
of central nervous system. They are involved in various biological
processes such as cell differentiation, and cell growth.1 They are
also tumor-associated antigens,2 and important cell-surface recep-
tors, where they inter alia mediate the recruitment of leukocytes to
sites of inflammation.3 Furthermore, gangliosides are efficient
receptors for the adhesion of bacteria and viruses to cells, a prere-
quisite for infection.4 Ganglioside GM1b (Fig. 1, 1a) was first iso-
lated by Yip’s group from rat brain,5 which was described to be
associated with GM1 in extremely minor quantities and was also
associated with some mankind diseases.6 However, the biological
functions of GM1b have not been elucidated because of insufficient
availability of material. Thus, chemical synthesis provides an
attractive opportunity to evaluate its biological functions. Ganglio-
side GM1b had been synthesized previously by several research
groups,7 however, developing a convenient and more efficient
approach for the synthesis of this ganglioside is still significant.
Pre-activation based iterative one-pot oligosaccharides synthesis
method was developed by Huang and his co-workers and they suc-
cessfully assembled numerous complex oligosaccharides.8 Huang’s
strategy granted much more freedom in protective group selection,
enabling it to achieve high-yielding stereospecific glycosylations.
However, this method was seldom used in the synthesis of ganglio-
sides.9 Herein, we describe the total synthesis of aminopropyl
functionalized ganglioside GM1b ( Fig. 1, 1b) by pre-activation
based iterative one-pot method.
As shown in Figure 2, the target compound can be assembled
from the sialylated disaccharide 3, the 2-N-Troc galactoside 4,
and lactose 5. Due to the poor and narrow range of anomeric reac-
tivity values,10 sialic acid thioglycosides cannot be directly used as
donor in one-pot strategy, usually sialylated disaccharides were
used as building blocks in the one-pot synthesis.8c,11 So our first
attention was focused on the synthesis of the sialylated disaccha-
ride. It is well known that owing to the low reactivity and low ste-
reoselectivity, highly efficient a-sialylation is still one of the most
difficult and challenging processes in the chemical synthesis of
oligosaccharides.
In order to achieve highly efficient
a-sialylation, recently, sig-
nificant efforts have been made, including the use of anomeric
leaving groups,12 the introduction of an auxiliary group at C-1
and C-3,13 the modification of the acetamide group at the C-5 posi-
HO
OH
C
OH
D
OH
O
OH
O
CO2H
O
OH
HO
HO
O
E
O
O
AcHN
OH
O
OH
O
NHAc
OH
O
OR
HO
HO
O
OH
A
OH
B
C17H35
C13H27
HN
1a R =
1b
GM1b
NH2
R =
⇑
Corresponding author. Tel.: +86 23 62768059; fax: +86 23 62769652.
E-mail addresses: sunbin@ctbu.edu.cn, binsunsh@yahoo.com (B. Sun).
Figure 1. Structure of ganglioside GM1b.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.077

5712
B. Sun, H. Jiang / Tetrahedron Letters 53 (2012) 5711–5715
1b
)
GM1b (
Ph
Ph
O
O
AcO
O
O
CO2Me
OAc
AcO
AcO
O
O
O
O
O
O
TCAHN
OBn
O
OBn
O
TrocHN
OBz
O
O
N3
2
BnO
BnO
OBn
OBn
Ph
Ph
O
O
OBn
O
OH
AcO
O
O
OBn
O
CO2Me
OAc
AcO
O
O
O
O
O
N3
STol BnO
NHTroc
STol
BnO
O
HO
TCAHN
OBn
OBn
AcO
OBz
4
3
5
Ph
O
AcO
AcO
TCAHN
OP(OBn)2
CO2M2
OAc
O
O
O
STol
HO
AcO
OH
6
7
Figure 2. Retrosynthetic analysis for synthesis of GM1b (1b).
of remaining hydroxy groups.19 The compound 10 was treated
with N-bromosuccinimide in aqueous acetone to convert thiocre-
sol into hydroxyl, and the resulting intermediate was reacted with
dibenzyl N,N-diisopropyl phosphoramidite in the presence of 1H-
tetrazole to produce phosphite sialyl donor 6.25
The sialylation was realized by treating a mixture of donor 6
and thioglycoside accepter 7 with a catalytic amount of TMSOTf
in a mixture solvent of CH3CN and CH2Cl2 (1:1) leading to disac-
charide 11 in 79% yield (Table 1, entry 1), benzoylation of the free
CO2H
OH
CO2Me
HO
AcO
OH
HO
OAc
a,b,c
d,e,f
HO
AcO
O
O
STol
AcHN
AcHN
AcO
9
8
OP(OBn)2
O
CO2Me
AcO
CO2Me
STol
AcO
OAc
AcO
OAc
AcO
g, h
AcO
O
TCAHN
TCAHN
AcO
10
6
Scheme 1. Reagents and conditions: (a) MeOH, IR(H+) resin, rt, overnight, almost
100%; (b) Ac2O, Py, DMAP, 0 °C to rt, over night, 81%; (c) TolSH, BF3ꢀEt2O, 0 °C to rt,
4–5 h, 78%; (d) MsOH, MeOH, 60 °C, 24 h; (e) CCl3CO2Me, Et3N, MeOH, rt, 1 h; (f)
Ac2O, Py, DMAP, 72% for three steps; (g) NBS, acetone, rt, 1.5 h; (h) (BnO)2PNiPr2,
1H-tetrazole, CH2Cl2, 82% for two steps.
hydroxyl group of 11 gave disaccharide 3. The
a configuration was
assigned by the three bond coupling constant between C1 and H3ax
(3JC1-H3ax = 5.8 Hz) of the sialic acid.10 This sialylation reaction for
other acceptors was also examined next. A variety of acceptors
including carbohydrate hydroxyl groups of galactose and glucosa-
mine were sialylated in excellent a-selectivity and good sialylation
tion of the sialyl donor into powerful electron-withdrawing
groups, such as N,N-diacetyl,14 azido,15 N-TFA,16 N-Troc,17
N-Fmoc,18 N-trichloroacetyl,19 N-phthalimide,20 5-N,4-O-car-
bonyl21 and N-acetyl 5-N,4-O-carbonyl,22 or the optimized combi-
nations of the leaving group with positional modification.23 Here
we designed sialyl donor 6 bearing the 5-N-trichloroacetyl (TCA)
moiety, as NH-TCA can be converted into acetamide under a vari-
ety of reaction conditions including hydrogenolysis, radical reduc-
tion, and basic cleavage followed by acetylation.24 The phosphite
aglycon leaving group was chosen due to the possibility for its
selective activation over a thioglycoside, on the other hand, the
phosphite donor can be activated by a catalytic amount of TMSOTf
yields (Table 1). Acid labile benzylidene and isopropylidene groups
were stable under the reaction condition. This selective activation
protocol is attractive as the resulting sialylated thioglycoside
product can be used as a donor for further glycosylation without
additional aglycon leaving group adjustment.
After achieving the sialylated disaccharide, we assessed the for-
mation of the second building block 4. To prepare compound 4, the
amino group of galactosamine hydrochloride 18 was protected by
the trichloroethoxocarbonyl (Troc) group followed by peracetyla-
tion to give 19 (Scheme 2). The anomeric acetate in 19 was
replaced with p-toluenethiol as promoted by boron trifluoride
diethyl etherate to yield thioglycoside 20. Zemplen reaction using
sodium methoxide to remove all acetyl groups in 20 followed by
benzylidenation of the newly liberated 4,6-hydroxyl groups led
to the compound 4.9
Next, our attention was focused on the preparation of lactose
acceptor 5. It is well known that the 40-OH lactose derivatives
showed a very low reactivity as glycosyl accepters.26 As benzyl
ethers are able to enhance the reactivity of neighboring hydroxyl
groups in glycosylation reactions, we selected benzyl group as pro-
tection group for lactose unit 5. The synthetic route of lactose
acceptor was depicted in Scheme 3. Heating a mixture of lactose
and usually lead to predominant formation of the
glycosylation.
a-product during
The synthesis of sialic acid donor 6 was described in Scheme 1.
Treatment of 8 with acidified MeOH gave sialic acid methyl ester,
which followed by acetylation of acetyl anhydride in pyridine
and then treatment with p-toluenethiol by the promotion of boron
trifluoride diethyl etherate gave thiosialoside 9. The thiosialoside
10 was synthesized by removal of all acetyl groups from N-acetyl
thiosialoside 9 under acidic condition, followed by selective acety-
lation of amino group with methyl trichloroacetate and acetylation

B. Sun, H. Jiang / Tetrahedron Letters 53 (2012) 5711–5715
5713
Table 1
Sialylation results using sialyl donor 6
OAc
OAc
OAc
CO2Me
OR
OP(OBn)2
CO2Me
cat, TMSOTf,
AcO
OAc
AcO
TCAHN
CH3CN/CH2Cl2
O
O
+
ROH
3A MS,-40oC
TCAHN
AcO
AcO
6
11, 15-17
Entry
1
Acceptor
Product
Yield (%)
a
a
/b
3JC1-H3ax(Hz)
Ph
O
Ph
O
OAc
7
MeO2C
O
O
AcO
OAc
79
89
75
only
5.8
4.8
6.0
O
O
O
HO
BzO
BzO
STol
STol
O
11
STol
TCAHN
AcO
OH
OH
OAc
OAc
OH
O
CO2Me
AcO
STol
O
O
2
3
a
only
TCAHN
O
12
OBz
AcO
BzO
OBz
15
BzO
CO2Me
O
OH
O
OAc
OAc
AcO
HO
OBn
O
BnO
20:1a
33:1a
TCAHN
13
NPhth
AcO
HO
O
BnO
OBn
16
OAc
OAc
NPhth
O
OH
O
CO2Me
AcO
O
O
O
TCAHN
O
4
92
6.2
O
AcO
17
O
14
O
O
O
O
a
Anomeric ratios were determined by 1H NMR analysis.
OAc
O
OH
O
OAc
OAc
OH
OAc
O
OH
OH
O
OH
O
OAc
O
a
d
a, b, c
O
O
OAc
AcO
OAc
OH
HO
OH
AcO
AcO
HO
HO
OAc
OH
OAc
NHTroc
19
OH
NH3Cl
18
22
21
Ph
OAc
OAc
OAc
O
O
b
c, d, e
O
OAc
O
O
O
Cl
OAc
O
AcO
AcO
O
e, f
OAc
OAc
AcO
STol
HO
STol
23
Ph
NHTroc
20
NHTroc
4
O
OBn
O
OH
O
OH OBn
O
BnO
O
f, g
O
O
O
Scheme 2. Reagents and conditions: (a) NaOMe, MeOH; (b) trichloroethyl chloro-
formate, Et3N, rt, 2 h; (c) Ac2O, Py, DMAP, 0 °C to rt, overnight, 92% for three steps;
(d) toluenethiol, BFꢀEt2O, CH2Cl2, 0 °C to rt, 4–5 h, 75%; (e) NaOMe, MeOH, ꢁ20 °C;
(f) PhCH(OMe)2, CSA, THF, 73% for two steps.
OR
OR
BnO
OBn
HO
HO
OH
OBn
OH
R =
5
24
N3
Scheme 3. Reagents and conditions: (a) NaOAc, Ac2O, 120 °C, 3 h, 62%; (b) 3-
chloropropan-1-ol, BF3ꢀEt2O, CH2Cl2, 0 °C to rt, 5 h, 75%; (c) NaN3, DMF, 90 °C,
overnight; (d) NaOMe, MeOH; (e) PhCH(OMe)2, CSA, THF, ref. 3 h, 75% for 2 steps; (f)
NaH, BnBr, anhydrous DMF, rt, overnight, 85%; (g) 2 M NaCNBH3-HCl, THF, rt, 75%.
21, acetyl anhydride, and anhydrous sodium acetate afforded
peracetyllactose 22, which underwent boron trifluoride diethyl
etherate promoted glycosylation with 3-chloropropan-1-ol to pro-
vide the desired b-lactoside 23. SN2 displacement of the chloride
with sodium azide followed by Zemplen deacetylation and regiose-
lective benzylidenation produced lactoside 24. The remaining
hydroxyl groups were benzylated with sodium hydride and benzyl
bromide in anhydrous DMF, followed by selective cleavage of
benzaldehyde acetal with a solution of sodium cyanoborohydride
and hydrogen chloride in dry THF to afford lactose acceptor 5.8b,26
With all the building blocks in hand, we assemble the full pro-
tected GM1b using pre-activation based one-pot protocol (Scheme
4). Pre-activation of disaccharide 3 by AgOTf/p-TolSCl, was rapidly
achieved at ꢁ78 °C. The thioglycosyl acceptor 4 was added to the
reaction mixture at the same temperature. The reaction tempera-
ture was raised to ꢁ20 °C, and the acceptor 4 was completely
consumed as judged by TLC analysis. The reaction temperature
was cooled back down to ꢁ78 °C, followed by the addition of
AgOTf, p-TolSCl, the lactose acceptor 5, and warmed up to room
temperature. The full protected GM1b pentasaccharide 227 was
obtained in 71% yield from the three component one-pot reactions
within 5 h. The a-linkage between sialic acid and the galactose was
conformed in the sialylation step. The b linkage for the rest of the
glycosidic bonds was supported by the one bond coupling con-
stants between the respective anomeric carbon and proton
(162 Hz, 157 Hz, 160 Hz, 160 Hz).
The deprotection of pentasaccharide 2 began with the removal
of Troc, trichloroacetyl, acetyl and ester protecting groups using
1 M NaOH in THF overnight (Scheme 4). The newly liberated amino
group was selectively acetylated in the presence of multiple hydro-
xyl groups by acetic anhydride and triethylamine in methanol.
Staudinger reduction of the azide group and subsequent catalytic
hydrogenation over Pearlman’s catalyst gave the fully deprotected
GM1b analog 1b28 in 64% overall yield for all deprotection steps.

5714
B. Sun, H. Jiang / Tetrahedron Letters 53 (2012) 5711–5715
Ph
O
O
O
HO
STol
4
NHTroc
a
b
OBn
O
OH
OBn
O
Ph
O
O(CH2)3N3
BnO
O
BnO
OAc
MeO2C
O
OBn
OBn
AcO
OAc
O
5
O
O
STol
Ph
TCAHN
AcO
OBz
3
Ph
O
O
O
OAc
MeO2C
O
AcO
OAc
O
O
O
OBn
O
O
O
OBn
O
TCAHN
AcO
OBz
O
TrocHN
O
O(CH2)3N3
BnO
BnO
2
OBn
OBn
c, d, e, f
OH
HO2C
O
OH
OH
OH
O
OH
O
HO
OH
HO
OH
O
O
O
OH
O
O
AcHN
OH
AcHN
O
O(CH2)3NH2
HO
HO
OH
1b
OH
Scheme 4. Reagents and conditions: (a) (i) AgOTf, p-TolSCl, ꢁ78 °C, (ii) 4, TTBP, ꢁ78 °C to ꢁ20 °C; (b) AgOTf, p-TolSCl, ꢁ78 °C, (iii) 5, ꢁ78 °C to rt, 71% for two steps; (c) 1 M
NaOH, THF, 50 °C, overnight; (d) Ac2O, Et3N, MeOH, 4–5 h; (e) PMe3, 0.1 M NaOH, THF, 60 °C, overnight; (f) Pd(OH)2/C, H2, MeOH, H2O, 24 h, 64%.
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In conclusion, we have demonstrated the application of the
sialylation reagent with trichloroacetyl (TCA) modification of the
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And also, an efficient and stereo-controlled total synthesis of ami-
nopropyl functionalized GM1b was achieved by pre-activation
one-pot protocol. The full protected GM1b was obtained in 71%
yield within 5 h. With the aminopropyl side chain, this kind of
GM1b analog can be readily conjugated to liposomes and proteins.
This will be very useful for further investigation of its biological
properties.
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Acknowledgements
This work was supported by the Chongqing Municipal Commis-
sion of Education (KJ110704), Chongqing Technology & Business
University (2010-56-01), Natural Science Foundation Project of
CQ CSTC 2010BB5083 and Chongqing Innovative Research Team
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6038.
J = 9.5 Hz),5.54–5.42 (m, 3H), 5.39 (s, 1H), 5.26 (d, 1H, J = 9.5 Hz), 5.12 (d, 1H,
J = 7.5 Hz), 4.99–4.92 (m, 3H), 4.87–4.72 (m, 5H), 4.67–4.56 (m, 3H), 4.55–4.51
(m, 2H), 4.46–4.26 (m, 9H), 4.21–4.07 (m, 7H), 4.00–3.93 (m, 2H), 3.91–3.86(m,
1H), 3.77–3.53 (m, 8H), 3.49 (t, 1H), 3.46 (s, 3H), 3.41–3.23 (m, 7H), 2.68 (dd,
1H, J = 4.5, 12.8 Hz), 2.25 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.94 (s, 3H), 1.92–
1.85 (m, 2H). 13C NMR (125 MHz, CDCl3) d 170.9, 170.5, 170.47, 170.2, 168.7,
165.3, 162.2, 154.5, 139.11, 139.10, 139.04, 139.03, 139.0, 138.97, 138.96,
138.94, 138.93, 138.6, 138.54, 138.52, 138.5, 138.47, 138.4, 138.0, 133.2, 130.5,
130.1, 129.3, 128.6, 128.57, 128.52, 128.5, 128.43, 128.4, 128.36, 128.2, 128.15,
128.14, 128.1, 127.8, 127.77, 127.7, 127.6, 127.5, 126.6, 103.8, 102.7, 100.9,
100.6, 100.5, 97.0, 96.4, 92.2, 83,1, 82.5, 81.9, 80.3, 76.8, 76.2, 75.6, 75.5, 75.45,
75.4, 74.0, 73.4, 73.3, 73.1, 73.0, 72.9, 72.3, 71.8, 70.2, 69.4, 69.1, 68.5, 68.4,
67.7, 67.6, 67.2, 66.8, 66.7, 66.5, 62.4, 54.7, 53.1, 51.8, 48.6, 38.9, 29.5, 21.7,
21.0, 20.9, 20.8. HRMS: [M+Na]+ C113H121Cl6N5NaO35 calcd for 2340.5871, obsd
2340.5837.
23. (a) Liang, F.-F.; Chen, L.; Xing, G.-W. Synlett 2009, 425–428; (b) Crich, D.; Wu, B.
Org. Lett. 2008, 10, 4033–4035; (c) Yu, C.-S.; Niikura, K.; Lin, C.-C.; Wong, C.-H.
Angew. Chem., Int. Ed. 2001, 113, 2984–2987; (d) Wang, Y.; Ye, X.-S. Tetrahedron
Lett. 2009, 50, 3823–3826.
24. (a) Donohoe, T. J.; Logan, J. G.; Laffan, D. D. P. Org. Lett. 2003, 5, 4995–4998; (b)
Sherman, A. A.; Yudina, O. N.; Mironov, Y. V.; Sukhova, E. V.; Shashkov, A. S.;
Menshov, V. M.; Nifantieva, N. E. Carbohydr. Res. 2001, 336, 13–46; (c) Bélot, F.;
Jacquinet, J.-C. Carbohydr. Res. 2000, 325, 93–106.
28. Compound 1b: 1H NMR (500 MHz, D2O) d 4.71 (d, 1H, J = 8.5 Hz), 4.50–4.43 (m,
3H), 4.12–4.05 (m, 3H), 4.01–4.39 (m, 3H), 3.85 (d, 1H, J = 3.5 Hz), 3.83–3.79
(dd, 1H, J = 13, 4 Hz), 3.79–3.65 (m, 14H), 3.65–3.50 (m, 7H), 3.46–3.41 (m, 2H),
3.32–3.23 (m, 2H), 3.10–3.04 (t, 2H), 2.63–2.57 (dd, 1H, J = 12.5, 4.0 Hz), 1.97
(s, 3H), 1.94 (s, 3H), 1.96–1.92 (t, 1H), 1.90–1.84 (m, 2H). 13C NMR (125 MHz,
D2O) d 175.1, 174.9, 174.2, 104.8, 102.7, 102.6, 102.2, 101.8, 80.5, 78.7, 77.2,
75.0, 74.9, 74.5, 74.2, 73.2, 72.8, 72.6, 72.4, 70.8, 68.8, 68.7, 68.1, 68.0, 63.0,
61.2, 61.1, 60.8, 60.2, 51.7, 51.3, 37.7, 27.1, 22.7, 22.2. HRMS: [M+Na]+
C40H69N3NaO29 calcd 1078.3914, obsd 1078.3942.
25. Bhattacharya, S. K.; Danishefsky, S. J. J. Org. Chem. 2000, 65, 144–151.
26. Sun, B.; Pukin, A. V.; Visser, G. M.; Zuilhof, H. Tetrahedron Lett. 2006, 47, 7371–
7374.
27. Compound 2: 1H NMR (500 MHz, CDCl3) d 8.10–8.07 (m, 2H), 7.58–7.49 (m, 4H),
7.39–7.19 (m, 30H), 7.08–7.02 (m, 3H), 6.63 (d, 1H, J = 9.5 Hz), 6.42 (d, 1H,