Total synthesis of the aminopropyl functionalized ganglioside GM 1

Article abstract of DOI:10.1007/s11426-011-4449-x

GM₁ is a common ganglioside pentasaccharide present on mammalian cell surface. It has been shown to play important roles in cellular communications and initiation of β-amyloid aggregation. In order to synthesize GM₁, an efficient synthetic route was developed via a [3+2] strategy. The GM₃ trisaccharide acceptor bearing an azido propyl group at the reducing end was prepared using the traditional acetamide protected sialyl thioglycosyl donor, which gave better stereoselectivity than sialyl donors protected with trichloroacetamide or oxazolidinone. The glycosylation of the axial 4-hydroxyl group of GM₃ by the disaccharide donor was found to be highly dependent on donor protective groups. Donor bearing the more rigid benzylidene group gave low glycosylation yield. Replacing the benzylidene with acetates led to productive coupling and formation of the fully protected GM₁ pentasaccharide. Deprotection of the pentasaccharide produced GM₁ functionalized with the aminopropyl side chain, which will be a valuable probe for biological studies.

Full text of DOI:10.1007/s11426-011-4449-x

SCIENCE CHINA
Chemistry
January 2012 Vol.55 No.1: 31–35
doi: 10.1007/s11426-011-4449-x
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
Total synthesis of the aminopropyl functionalized ganglioside GM1
SUN Bin1,2*, YANG Bo1 & HUANG XueFei1*
1 Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, USA
2 Research Center of Medicinal Chemistry and Chemobiology, Chongqing Technology and Business University, Chongqing 400067, China
Received August 31, 2011; accepted October 11, 2011; published online November 29, 2011
GM1 is a common ganglioside pentasaccharide present on mammalian cell surface. It has been shown to play important roles
in cellular communications and initiation of -amyloid aggregation. In order to synthesize GM1, an efficient synthetic route
was developed via a [3+2] strategy. The GM3 trisaccharide acceptor bearing an azido propyl group at the reducing end was
prepared using the traditional acetamide protected sialyl thioglycosyl donor, which gave better stereoselectivity than sialyl do-
nors protected with trichloroacetamide or oxazolidinone. The glycosylation of the axial 4-hydroxyl group of GM3 by the di-
saccharide donor was found to be highly dependent on donor protective groups. Donor bearing the more rigid benzylidene
group gave low glycosylation yield. Replacing the benzylidene with acetates led to productive coupling and formation of the
fully protected GM1 pentasaccharide. Deprotection of the pentasaccharide produced GM1 functionalized with the aminopropyl
side chain, which will be a valuable probe for biological studies.
carbohydrate, chemical synthesis, gangliosides, GM1
1 Introduction
GM1 (1a), a member of the ganglioside family, is common-
ly present in vertebrate plasma membranes and especially
enriched in nerve tissues [1, 2]. There are many significant
biological functions ascribed to GM1, such as receptor for
pathogen binding [3], cell-growth modulators [4], and neu-
rotrophic factor [5]. Furthermore, GM1 has been proposed
to be a nucleating site for initiating -amyloid aggregation,
which is implicated in the development of Alzheimer’s dis-
eases (AD) [610]. GM1 level showed significant increase
in amyloid positive nerve terminals obtained from the cor-
tex of AD patients [11]. In order to better understand the
roles of GM1 in -amyloid aggregation and AD develop-
ment, sufficient quantity of GM1 is needed. Herein, we re-
port our synthesis of an aminopropyl side chain functional-
ized GM1 derivative (1b), which can be readily used for
bioconjugation.
2 Experimental
2.1 General
All reactions were carried out under nitrogen with anhy-
drous solvents in flame-dried glassware, unless otherwise
noted. All glycosylation reactions were performed in the
presence of molecular sieves, which were flame-dried right
before the reaction under high vacuum. Glycosylation sol-
*Corresponding authors (email: xuefei@chemistry.msu.edu; binsunsh@yahoo.com)
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com www.springerlink.com

32
Sun B, et al. Sci China Chem January (2012) Vol.55 No.1
vents were dried using a solvent purification system and
used directly without further drying. Chemicals used were
of reagent grade as supplied except where noted. Analytical
thin-layer chromatography 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
2.3 Deprotected GM1 (1b)
The mixture of 2 (231 mg, 0.1 mmol), 1 M NaOH (2 mL, 2
mmol), and THF (15 mL) was stirred at 50 °C overnight and
then concentrated to dryness. The resulting residue was di-
luted with CH2Cl2 (100 mL), and the organic phase was
washed by H2O and then dried over Na2SO4, filtered, and
concentrated to dryness. The resulting residue was dissolved
in a mixture of methanol (20 mL) and triethylamine (0.14
mL, 1 mmol). Acetic anhydride (0.094 mL, 1 mmol) was
added dropwise, and the mixture was stirred at room tem-
perature for 4 h. The reaction was quenched by adding a
few drops of H2O and then diluted with EtOAc (100 mL).
The organic phase was washed with a saturated aqueous
solution of NaHCO3 and H2O, dried over Na2SO4, filtered,
and concentrated to dryness. Silica gel column chromatog-
raphy (hexanes:EtOAc = 2:1) afforded the N-acetylated
product as a white solid. The mixture of the N-acetylated
product, 1 M PMe3 in THF (0.2 mL, 0.056 mmol), 0.1 M
NaOH (2 mL, 0.5 mmol), and THF (12 mL) was stirred at
60 °C under N2 overnight. The mixture was concentrated,
and the resulting residue was diluted with CH2Cl2 (150 mL).
The organic phase was washed with H2O and then dried
over Na2SO4, filtered, and concentrated to dryness. The
resulting residue was purified by quickly passing through a
short silica gel column (CH2Cl2:MeOH = 10:1). The mix-
ture of the obtained solid and Pd(OH)2 in MeOH/H2O (10
mL:3 mL) was stirred under H2 at room temperature over-
night and then filtered. The filtrate was concentrated to
dryness under vacuum. The aqueous phase was further
washed with CH2Cl2 (5 mL × 3) and EtOAc (5 mL × 3), and
the aqueous phase was dried under vacuum to afford 1b
(acetate salt) as a white solid (68.6 mg, 65% for four steps).
1H NMR (500 MHz, D2O) δ 4.71 (d, 1 H, J = 8.5 Hz),
4.504.43 (m, 3 H), 4.124.05 (m, 3 H), 4.01-3.89 (m, 3 H),
3.85 (d, 1 H, J = 3.5 Hz), 3.81 (dd, 1 H, J = 13.0, 4.0 Hz),
3.793.65 (m, 14 H), 3.653.50 (m, 7 H), 3.463.41 (m, 2
H), 3.323.23 (m, 2 H), 3.07 (t, 2 H, J = 6.6 Hz), 2.60 (dd, 1
H, J = 12.5, 4.0 Hz), 1.97 (s, 3 H), 1.94 (s, 3 H), 1.94 (t, 1 H,
J = 12 Hz), 1.901.84 (m, 2 H). 13C NMR (125 MHz, D2O)
δ 181.6, 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, 23.4, 22.7, 22.2. HRMS:
[M+Na]+ C40H69N3NaO29 calcd 1078.3914, obsd 1078.3942.
1
1
constant assignments are based on H NMR and H-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).
2.2 Synthesis of fully protected GM1 pentasaccharide 2
The mixture of donor 3 (216 mg, 0.2 mmol), acceptor 4
(809 mg, 0.6 mmol) and freshly activated MS 4 Å (600 mg)
in dry CH2Cl2 (6 mL) was stirred for 30 min at room tem-
o
perature, and cooled down to 70 C followed by the addi-
tion of AgOTf (154 mg, 0.6 mmol) in anhydrous acetoni-
trile (0.1 mL). After 5 min, p-TolSCl (29 L, 0.2 mmol)
was added via a microsyringe directly to the solution with-
out touching the wall of the reaction flask. The orange color
of p-TolSCl dissipated within a minute. The reaction mix-
ture was stirred for 1.5 h until the temperature reached
o
20 C and triethylamine (30 L) was added. The mixture
was diluted with CH2Cl2 (50 mL) and filtered through celite.
The filtrate was concentrated and purified by flash column
chromatography (hexanes:EtOAc = 3:2) to give fully pro-
tected GM1 2 (267.6 mg, 58%). 1H NMR (500 MHz, CDCl3)
δ 7.95 (s, 2 H), 7.546.99 (m, 45 H), 5.525.46 (t, 1 H),
5.44 (d, J = 7.0 Hz, 1 H), 5.39 (d, J = 3.0 Hz, 1 H),
5.255.20 (m, 2 H), 5.16 (d, J = 10 Hz, 2 H), 5.055.00 (m,
1 H), 4.94 ( d, J = 10 Hz, 2 H), 4.4.76 (m, 3 H),
4.754.65 (m, 3 H), 4.634.52 (m, 4 H), 4.514.37 (m, 5 H),
4.364.30 (m, 2 H), 4.264.08 (m, 2 H), 4.053.76 (m, 11
H), 3.723.55 (m, 8 H), 3.543.47 (t, 2 H), 3.453.39 (m, 2
H), 3.383.36 (m, 5 H), 2.111.97 (m, 8 H), 1.96 (s, 6H),
1.89 (s, 3 H), 1.88 (s, 3 H), 1.871.70 (m, 5 H); 13C NMR
(125 MHz, CDCl3) δ 170.9, 170.5, 170.47, 170.2, 168.7,
165.3, 162.2, 139.11, 139.1, 139.0, 138.9, 138.8, 138.5,
138.0, 133.2, 130.5, 130.1, 129.3, 128.6, 128.57, 128.5,
128.49, 128.4, 128.36, 128.2, 128.15, 127.8, 127.77, 127.7,
127.6, 127.5, 126.6, 126.5, 103.7, 102.7, 100.9, 100.6,
100.5, 83.1, 82.5, 81.9, 80.3, 76.8, 76.0, 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, 67.7, 67.6, 67.2, 66.7, 66.4, 62.4, 53.1,
51.8, 48.6, 29.9, 25.5, 21.7, 21.0, 20.9, 20.8. ESI-MS:
[M+Na]+ C117H132Cl3N5NaO37 calcd 2326.8, obsd 2327.0.
3 Results and discussion
Although synthesis of ganglioside GM1 and its derivatives
had previously been accomplished by several laboratories
[1217], it is still a challenging task. The main difficulty
lies in the construction of the bifurcating branches onto the
reducing end lactoside. As the sialic acid and the galactose
(Gal)-galactosamine (GalN) disaccharide are linked to

Sun B, et al. Sci China Chem January (2012) Vol.55 No.1
33
neighboring hydroxyl groups, the installation of one branch
can pose serious steric hindrance for introduction of the
other. We decided to attach the sialic acid first as sialyl do-
nors are known to have lower anomeric reactivities than
common pyranosyl donors due to the presence of the elec-
tron withdrawing carbonyl group at the anomeric center [18,
19] (Figure 1). Based on this consideration, the key step of
our synthesis will be the coupling of the GalE-GalND disac-
charide fragment 3 with a selectively protected sialyllactose
block 4 (GM3 chain).
To synthesize the GM3 trisaccharide, the lactosyl diol 8
bearing multiple benzyl ethers as the protective groups was
selected as the acceptor, which should have good nucleo-
philicity due to the electron donating nature of the multiple
benzyl ether groups present. The synthesis of lactose ac-
ceptor 8 began with the commercially available lactose 9
(Scheme 1). Acetylation of 9 in the presence of sodium ac-
etate and acetic anhydride gave the per-acetylated lactose 10,
which underwent BF3·Et2O promoted glycosylation with
3-chloropropan-1-ol to provide the desired β-lactoside 11
[20]. SN2 displacement of the chloride with sodium azide
followed by Zemplen deacetylation and regioselective iso-
propylidene formation produced lactoside 14. Global pro-
tection of the free hydroxyl groups as benzyl ethers and acid
mediated isopropylidene removal led to the desired lactosyl
diol acceptor 8 [21] in 85% yield for the two steps.
tive group including TCA and oxazolidinone on the 5-N
position significantly enhanced the reaction yield and stere-
oselectivity [22, 23]. Thus, we investigated three sialyl do-
nors 16 [24], 17 [24] and 18 [25] with their 5-N-acetyl
group substituted with more electron withdrawing protec-
tive groups. As shown in Scheme 2, donor 16 gave excellent
stereoselectivity, albeit with a low yield (Scheme 2(a)).
Changing the anomeric leaving group from STol in 16 to
trifluoroacetimidate (donor 17) did not improve the situa-
tion much (Scheme 2(b)). On the other hand, the usage of
the oxazolidinone protected sialyl donor 18 gave 76% yield
Sialylation of the lactosyl disaccharide 8 was tested next.
Besides the aforementioned low reactivity of sialyl donor,
another difficulty in sialylation is stereochemical control as
the naturally existing sialyl linkage is the thermodynami-
cally less favored  linkage [19]. Recently, it was discov-
ered that the installation of an electron withdrawing protec-
Scheme 1 Synthesis of the lactosyl acceptor 8.
Figure 1 Retrosynthetic analysis for synthesis of GM1 1b.
Scheme 2 Synthesis of GM3 trisaccharide acceptor.

34
Sun B, et al. Sci China Chem January (2012) Vol.55 No.1
presence of the benzylidene ring on the GalN conforma-
tionally rigidifies the ring [29], thus hindering conforma-
tional changes in the pyranosyl ring and lowering the reac-
tivity of the activated donor towards the sterically hindered
GM3 acceptor. To overcome this difficulty, the benzylidene
group was removed from disaccharide 24 and the free hy-
droxyl groups were acetylated (disaccharide 3). Gratifyingly,
glycosylation of donor 3 with GM3 trisaccharide 4 pro-
ceeded to give the fully protected GM1 pentasaccharide 2 in
58% yield (70% based on acceptor consumed) (Scheme
4(b)), with the correct molecular weight of 2327.0 [M+Na]+
given by mass spectrometry. NMR spectra of compound 2
showed broad peaks, which was presumably due to the
presence of multiple conformations at room temperature.
The deprotection of pentasaccharide 2 began with the
removal of the Troc, acyl and ester protecting groups using
1 M NaOH in THF overnight (Scheme 4(c)). The newly
liberated amine was selectively acetylated in the presence of
multiple hydroxyl groups by acetic anhydride in methanol.
Staudinger reduction of the azide group and subsequent
catalytic hydrogenation over Pearlman’s catalyst gave the
fully deprotected GM1 analog 1b in 65% overall yield for
all deprotection steps. The α linkage between sialic acid and
the lactose unit was confirmed by the NMR coupling con-
stant between C1 and H3ax of sialic acid (3J(C1,H3ax) = 5.7 Hz)
[27]. The linkages for the rest of the glycosidic bonds
were supported by the one bond coupling constants between
the respective anomeric carbon and proton (163.5 Hz, 162
Hz, 162 Hz, 164 Hz) [27]. Correlations of the anomeric
carbon of the GalND unit (102.6 ppm) with H4 of GalB (4.06
ppm) and the anomeric carbon of the sialic acid unit (101.8
ppm) with H3 of GalB (4.08 ppm) were found in HMBC
NMR spectrum, thus confirming the regiochemistry of 1b.
of the trisaccharide as a 2:1 mixture of : anomers, which
were difficult to separate (Scheme 2(c)). Instead of further
optimizing the glycosylation reactions using these donors,
we examined the 5-N-acetamide donor 7[24], as it was sim-
pler to prepare than donors 1618. Interestingly, donor 7
gave 60% yield and exclusive  selectivity in coupling with
the lactose acceptor 8 (Scheme 2(d)).
After establishing a viable route to GM3, we assessed the
formation of the second branch. The Gal-GalN disaccharide
building block 3 was accessed by the reaction of galactosyl
donor 5 [26] and galactosaminyl acceptor 6 [27]. To prepare
compound 6, the amino group of GalN 21 was protected by
the trichloroethoxocarbonyl (Troc) group followed by
peracetylation to give 22 (Scheme 3(a)). The anomeric ace-
tate in 22 was replaced with p-toluenethiol as promoted by
BF3·Et2O to yield compound thioglycoside 23. Zemplen
reaction using sodium methoxide to remove all the acetyl
groups in 23 followed by benzylidenation of the newly lib-
erated 4,6-hydroxyl groups led to the galactosylaminyl ac-
ceptor 6. It was important to maintain low temperature for
this reaction to avoid the possible side reaction of Troc with
sodium methoxide. As both 5 and 6 are thioglycosides, the
glycosylation of 6 by 5 was performed under the
pre-activation condition [28] to avoid the activation of the
acceptor or the product. Treatment of donor 5 with
AgOTf/p-TolSCl [27] at 78 C in the presence of a steri-
cally hindered base tri-tbutylpyrimidine (TTBP) [27] cleanly
activated the donor within a few minutes. Addition of ac-
ceptor 6 to the activated donor solution led to the formation
of disaccharide 24 in 66% yield (Scheme 3(b)).
The union of the Gal-GalN disaccharide 24 and GM3 tri-
saccharide 4 was then explored, which failed to produce the
desired GM1 pentasaccharide. We hypothesized this was
because upon donor activation, the Troc moiety in donor 24
participates in stabilizing the oxacarbenium ion through the
formation of a five membered oxazoline ring (Scheme 4(a)).
In order to accommodate this, the pyranosyl ring of GalN
needs to undergo conformational changes. However, the
Scheme 4 (a) Formation of the 5-membered oxazoline ring by activated
donor 24 was presumably difficult due to the presence of the rigid benzyl-
idene ring, thus lowering the reactivity of activated 24 towards acceptor 4.
(b) Formation of the fully protected GM1 pentasaccharide 2. (c) Deprotec-
tion of pentasaccharide 2.
Scheme 3 Synthesis of (a) the galactosaminyl acceptor 6; and (b)
Gal-GalN disaccharides 24 and 3.

Sun B, et al. Sci China Chem January (2012) Vol.55 No.1
35
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In conclusion, a stereo- and regio-controlled total synthesis
of aminopropyl functionalized GM1 was achieved. Com-
pared to previous synthesis, our method only employed a
single type of glycosyl donors, i.e., thioglycosides, which
simplified overall building block design. With the ami-
nopropyl side chain, our GM1 analog can be readily conju-
gated to liposomes and nanoparticles. This will be very
useful for deciphering the role of GM1 ganglioside in the
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