Total Synthesis of the Echinodermatous Ganglioside LLG-3 Possessing the Biological Function of Promoting the Neurite Outgrowth

Article abstract of DOI:10.1021/acs.orglett.0c02692

A total synthesis of echinodermatous ganglioside LLG-3 with neuritogenic activity was accomplished by a convergent strategy. The synthesis of 2-hydroxyethyl 8-O-Me-α-sialoside 2 was started from the phenyl 7,8-di-O-Pico-thiosialoside 5, which can be chemoselectively removed the picoloyl group, and then the methyl group in 8-O-MeNeu5Ac moiety was chemoselectively prepared using TMSCHN2/FeCl3. For preparation of the terminal disialic unit, oxidative amidation was initially utilized by our group to efficiently construct the α(2,11) linkage of 8-O-Me-Neu5Acα(2,11)Neu5Gc. Herein, we also demonstrate that the synthesized ganglioside LLG-3 exhibited the neuritogenic activity toward the primary cortical neurons and that biological activity is superior to that of ganglioside DSG-A.

Full text of DOI:10.1021/acs.orglett.0c02692

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Letter
Total Synthesis of the Echinodermatous Ganglioside LLG‑3
Possessing the Biological Function of Promoting the Neurite
Outgrowth
Yu-Fa Wu, Yow-Fu Tsai,* Yuahn-Sieh Huang,* and Jing-Feng Shih
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ABSTRACT: A total synthesis of echinodermatous ganglioside LLG-3 with neuritogenic activity was accomplished by a convergent
strategy. The synthesis of 2-hydroxyethyl 8-O-Me-α-sialoside 2 was started from the phenyl 7,8-di-O-Pico-thiosialoside 5, which can
be chemoselectively removed the picoloyl group, and then the methyl group in 8-O-MeNeu5Ac moiety was chemoselectively
prepared using TMSCHN2/FeCl3. For preparation of the terminal disialic unit, oxidative amidation was initially utilized by our
group to efficiently construct the α(2,11) linkage of 8-O-Me-Neu5Acα(2,11)Neu5Gc. Herein, we also demonstrate that the
synthesized ganglioside LLG-3 exhibited the neuritogenic activity toward the primary cortical neurons and that biological activity is
superior to that of ganglioside DSG-A.
genesis of a rat pheochromocytoma cell line (PC-12 cells) in
angliosides are sialylated glycosphingolipids and are
Gparticularly found in greater concentration within the the presence of nerve growth factor (NGF). Furthermore, the
brain and nervous system.1 Gangliosides play important roles
activity of neurite outgrowth of DSG-A (40.8%) and LLG-3
(63.1%) was greater than that of GM1 (25.4% and 47.0%,
respectively). Regarding the total synthesis of these two
gangliosides, we have reported the first total synthesis of DSG-
A,8 and the total synthesis of LLG-3 was accomplished by
Kiso’s and Withers’s laboratories,9,10 respectively.
Owing to its significant neuritogenic activity, the synthesis of
LLG-3 and its analogues9a is still attracting attention. For the
synthesis of LLG-3, the construction of the unusual structure
of the 8-O-Me-Neu5Acα(2,11)Neu5Gc moiety with excellent
α-stereoselectivity and yield is a challenge. Because of the
excellent α-stereoselectivity and yield displayed for most
primary hydroxyl acceptors,11 the 7,8-di-O-Pico-thiosialoside
5 was chosen as the glycosyl donor to conquer this challenge.
Another advantage is that the Pico groups can be chemo-
selectively removed to facilitate the establishment of 8-O-Me.
The retrosynthesis of LLG-3 is illustrated in Scheme 1.
During the reaction, the α(2,11) linkage of the 2-hydroxyethyl
in the development and function of the brain and nervous
system, and the type and amount vary significantly during
mammalian development.1d,2 These have roused interest in
exploring treatment using exogenous gangliosides in neuro-
logical disorders; some positive results have been reported.3
Among these results, ganglioside GM1 has been used in
clinical trials for patients with Parkinson’s disease. The results
demonstrate significant reductions in patients’ symptoms and
their behavioral recovery.4 Recently, a costudy between the
authors and Lin’s laboratory demonstrated that the echino-
dermatous ganglioside Hp-s1’s analogue, Hp-s1A, exhibited
the function of protecting amyloid precursor protein (APP)
from amyloidogenic cleavage by β-secretase in vitro, and that
the activity of Hp-s1A possessed greater efficacy than that of
the mammalian ganglioside GM1.5 The positive finding
concerning the biological function of ganglioside Hp-s1A
inspired the authors to undertake further investigations into
the synthesis and biological functions of echinodermatous
gangliosides.
Received: August 12, 2020
Ganglioside DSG-A (9-O-Me-NeuAcα(2,6)Glcβ(1,1)-ce-
ramide) and LLG-3 (8-O-Me-NeuAcα(2,11)NeuGcα(2,3)-
Galβ(1,4)Glcβ(1,1)ceramide, 1), which are bioactive metab-
olites found in the sea urchin Diadema setosum and the starfish
Linckia laevigata,6,7 respectively, promote excellent neurito-
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© XXXX American Chemical Society
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A

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Scheme 1. Retrosynthesis of the Ganglioside LLG-3 (1)
Table 1. Optimized Conditions for Methylation of Diol 7
a
entry
Lewis acid
temp (°C) time (h) yield (%) BRSM (%)
b
1
2
3
4
5
6
7
8
9
Bu2SnO
70
0
12
3
0
−
Bi(OTf)3
Zn(OTf)2
Cu(OTf)2
MgCl2
33
38
13
0
68
74
99
−
98
84
99
−
rt
rt
rt
rt
rt
rt
0
11
11
11
13
14
10
2.5
ZnCl2
AlCl3
FeCl3
FeCl3
7
62
79
84
8-O-Me-5Ac-α-neuraminoside 2 and 5-NH2-Neuα(2,3)Gal
disaccharide 3 was constructed by means of oxidative
amidation12 followed by the glycosylation of the observed
trisaccharide with Glc-Cer 4. The 7,8-di-O-Pico-thiosialoside 5
was used as a starting material for the synthesis of 2-
hydroxyethyl 8-O-Me-α-sialoside 2.
a
b
BRSM = based on recovered starting material. MeOH was used as
solvent.
Scheme 3. Construction of the Protected Phytoceramide 16
The glycosylation of the sialyl donor 5 with 2-benzylox-
yethanol acceptor was promoted by NIS/TfOH in anhydrous
CH2Cl2 employing powdered 3 Å molecular sieves at −40 °C
to provide 2-benzyloxyethyl neuraminoside 6 as a single α-
stereoisomer in 95% yield (Scheme 2). To achieve 8-O-methyl
Scheme 2. Synthesis of N-Acetylneuraminic Acid Derivative
2
genation condition to afford primary alkanol 12 in 99% yield.
Oxidation of compound 12 was finished with 2-Iodoxybenzoic
acid (IBX) and Pinnick reaction,16 and the resulting carboxylic
acid 13 moiety was connected with NHS using coupling
reagent EDCI to furnish succinimidyl benzoyloxyester 14,
which was subjected to amidation with the corresponding
aminoalcohol 158 to observe phytoceramide 16 with 83%
overall yield in four steps.
After completing the preparation of the above-mentioned
building blocks, we first created the terminal 4-OHGlc-
PhytoCer 4 (Scheme 4). The phytoceramide 16 was coupled
to the synthesized 4-TBSglucoside 17 (Scheme S3)9 to afford
the Glc-PhytoCer 18 in 98% yield as a single β-stereoisomer.
The desilylation of the silylated 18 was treated with tetra-n-
butylammonium fluoride (TBAF) to provide the Glc-
PhytoCer 19 with 4-free hydroxyglucose moiety in 91%
yield. To favor the production of LLG-3, the isopropylidenyl
modification of neuraminic acid, 4,9-di-O-Bz-7,8-di-O-Picosia-
loside 6 was treated with Cu(OAc)2 in MeOH at room
temperature to chemoselectively remove the Pico protecting
groups to afford 7,8-dihydroxysialoside 7 in 97% yield.13 The
selective 8-O-methylation of 7,8-diol 7 was conducted using
trimethylsilyldiazomethane (TMSCHN2) in the presence of
various Lewis acids (such as Bu2SnO, Zn(OTf)2, Cu(OTf)2,
MgCl2, and FeCl3, Table 1) at different temperatures (70 °C,
room temperature, and 0 °C).14 7-OH-8-O-Me-Neu5Ac 8 was
observed in high yield (84%) in the presence of FeCl3 at 0 °C.
After acetylation of 7-OH-Neu5Ac 8 with Ac2O at 40 °C,
subsequent debenzylation of the produced 2-benzyloxyethyl 7-
O-Ac-sialoside 9 product (97% yield) was accomplished under
hydrogenolysis condition to give the 2-hydroxyethyl 8-O-Me-
sialoside 2 in 94% yield.
Scheme 4. Synthesis of the 4-OHGlc-PhytoCer 4
Synthesis of the required phytoceramide was commenced
using synthesized enediol 10 (Scheme 3), which was treated
with Grubbs second-generation catalyst and 1-docosene to
facilitate the intermolecular olefin metathesis reaction produc-
ing the desired alkene 11 as a ca. 9.8:1 mixture of E- and Z-
stereoisomers (99% yield).15 Debenzylation and hydrogena-
tion of 1-benzyloxy-alkene 11 was performed under hydro-
B
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group in 19 was converted into acetyl group via sequential
transformations to observe the 4-OHGlc-PhytoCer 4 in 82%
yield over four steps.
Table 2. Optimized Conditions for Oxidative Amidation
Scheme 5 displays the construction of the inner amino-
disaccharide 3. The 4-OHGal 21 was synthesized by following
Scheme 5. Synthesis of the Amino-Disaccharide 3
yield
entry
1
conditions
(%)
(a) IBX, ACN, MS-3 Å, reflux, 2 h
33
(b) 3, NaClO2, NaH2PO4, 2-methyl-2-butene, toluene, 40
°C, 3 h
2
3
Bobbitt’s Salt, 2,6-lutidine, MS-3 Å, CH2Cl2, rt, 1 h, then 3,
0
rt, 4 h
(a) Bobbitt’s Salt, pyrazole, 2,6-lutidine, CH2Cl2, rt, 2 h
(b) 3, Et3N, CH2Cl2, 40 °C, 17 h
68
4
(a) Bobbitt’s Salt, pyrazole, 2,6-lutidine, CH2Cl2, rt, 2 h
(b) 3, Et3N, THF, 40 °C, 3.5 h
82
a previously described methodology (Scheme S4) with some
modification,17 and the sialylation of the acceptor 21 with the
sialyl donor 2018 was performed using TMSOTf as the
promoter to form the disaccharide 22 as a ca. 20:1 mixture of
α- and β-epimers in 77% yield. Decarbonylation of the
separated oxazolidone 22α was treated with TBAF at 30 °C to
obtain 5-NH2Neuα(2, 3)Gal 3, which was used in the next
step reaction without further purification.
20
́
according to Zemplen’s method to furnish the target
ganglioside LLG-3 (1) in 73% yield in three steps.
After finishing the total synthesis of the ganglioside LLG-3,
the effect of the synthesized LLG-3, DSG-A, and the
commercial GM1 on neurite outgrowth in primary cortical
neurons was also inspected. The cultured cortical neurons were
treated with 35 μM of LLG-3, DSG-A, and GM1 for 24 h, and
then subjected to immunofluorescence staining using an anti-
MAP2 antibody. The result (Figure 1) revealed that LLG-3,
but not DSG-A or GM1, significantly expanded the average
total length of the neurites per cell by 1.45-fold relative to the
control group.
Progression to the final step in the fabrication of ganglioside
LLG-3 is shown in Scheme 6. The manufacture of the terminal
Scheme 6. Completion of the Total Synthesis of the
Ganglioside LLG-3 (1)
trisaccharide 23 was completed by oxidative amidation of
hydroxyethyl sialoside 2 with an amine unit 3 in the presence
of a Bobbitt’s salt oxidant in 82% yield from 3 in three steps
(Table 2).19 The IBX oxidant was also used in this amidation,
and the yield of the disialic 23 produced was very poor (33%).
To facilitate final deprotection with high efficiency, the
isopropylidene and benzylidene functionalities in 23 were
first converted into acetyl-protecting groups, and Glc-PhytoCer
4 was glycosylated with the resulting trisaccharide 24 (in 75%
yield over two steps), promoted by NIS/TfOH in CH2Cl2 at
−30 °C, to afford the protected LLG-3 25 with high yield
(83%) and excellent stereoselectivity (β only). Finally, the
protected structure 25 was subjected to a sequence of
deprotections, which included demethylation of methyl ester
with LiCl, debenzylation using H2/Pd(OH)2, and deacylation
Figure 1. Effect of ganglioside GM1, DSG-A and LLG-3 on neurite
outgrowth in primary cortical neurons. (A−D) Cultured cortical
neurons were treated with or without 35 μM of GM1, DSG-A, and
LLG-3 for 24 h, respectively, and then subjected to immunofluor-
escence staining with anti-MAP2 antibody. (E) Quantitation of
neurite outgrowth. The total neurite lengths are shown as mean SD,
n = 3 experiments with 200−300 cells per eexperiments with 200-300
cells per experiment, **P < 0.01 vs control. Bar = 30 μM.
C
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In conclusion, we have accomplished the total synthesis of
ganglioside LLG-3. The assembly of the linkage between
(2,11) of 8-O-Me-Neu5Acα(2,11)Neu5Gc was efficiently
performed by means of oxidative amidation of 2-hydroxyethyl
8-O-Mesialoside 2 with amine unit 3. To the best of our
knowledge, the oxidative amidation was also actively
functioning to construct the Neu5Acα(2,11)Neu5Gc struc-
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was achieved from the phenyl 7,8-di-O-Pico-thiosialoside 5,
along with the chemoselective removal of the picoloyl group
and the selective 8-O-methylation of 7,8-diol 7 that was
achieved by using TMSCHN2/FeCl3. Furthermore, we also
demonstrated that the neuritogenic activity of the synthesized
ganglioside LLG-3 toward primary cortical neurons is superior
to that of the ganglioside DSG-A. From these exciting results,
the exploration of the synthesis and neuritogenic activity of the
LLG-3 analogues will be advanced to improve the efficacious
drug treatment of diseases associated with neurological
disorders. The corresponding results will be reported in due
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02692.
Detailed experimental procedures for the preparation
and characterization of all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Yow-Fu Tsai − Department of Chemistry, Chung Yuan
Christian University, Taoyuan City 32023, Taiwan;
orcid.org/0000-0002-8175-8408; Email: tsaiyofu@
cycu.edu.tw
Yuahn-Sieh Huang − Department of Biology and Anatomy,
National Defense Medical Center, Taipei City 11490, Taiwan;
orcid.org/0000-0003-3527-6421; Email: anatoman2001@
yahoo.com.tw
(7) (a) Inagaki, M.; Miyamoto, T.; Isobe, R.; Higuchi, R.
Biologically Active Glycosides from Asteroidea, 43. Isolation and
Structure of a New Neuritogenic-Active Ganglioside Molecular
Species from the Starfish Linckia laevigata. Chem. Pharm. Bull. 2005,
53, 1551−1554. (b) Inagaki, M.; Isobe, R.; Higuchi, R. Isolation and
Structure of a New Ganglioside Molecular Species. Eur. J. Org. Chem.
1999, 1999, 771−774.
(8) Wu, Y.-F.; Tsai, Y.-F.; Guo, J. R.; Yu, C.-P.; Yu, H.-M.; Liao, C.-
C. First Total Synthesis of Ganglioside DSG-A Possessing
Neuritogenic Activity. Org. Biomol. Chem. 2014, 12, 9345−9349.
(9) (a) Yamagishi, M.; Hosoda-Yabe, R.; Tamai, H.; Konishi, M.;
Imamura, A.; Ishida, H.; Yabe, T.; Ando, H.; Kiso, M. Structure-
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Ganglioside LLG-3 Isolated from the Starfish Linckia laevigata.
Angew. Chem., Int. Ed. 2011, 50, 2330−2333.
(10) Rich, J. R.; Withers, S. G. A Chemoenzymatic Total Synthesis
of the Neurogenic Starfish Ganglioside LLG-3 Using an Engineered
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(c) Gunanathan, C.; Ben-David, Y.; Milstein, D. Direct Synthesis of
Authors
Yu-Fa Wu − Department of Chemistry, Chung Yuan Christian
University, Taoyuan City 32023, Taiwan
Jing-Feng Shih − Department of Chemistry, Chung Yuan
Christian University, Taoyuan City 32023, Taiwan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02692
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
Ministry of Science and Technology, Taiwan (MOST 108-
2113-M-033-009, and MOST 109-2623-E-033-001-D).
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