Synergistic Glycosylation as Key to the Chemical Synthesis of an Outer Core Octasaccharide of Helicobacter pylori

Article abstract of DOI:10.1002/chem.201800049

Helicobacter pylori, a widespread gastric bacterial pathogen that infects 90 % of the population in developing countries, causes chronic gastritis, peptic ulcers and gastric cancer. Battling H. pylori infection is a serious challenge due to the increased

Full text of DOI:10.1002/chem.201800049

A Journal of
Accepted Article
Title: Synergistic Glycosylation as Key to the Chemical Synthesis of an
Outer Core Octasaccharide of Helicobacter pylori
Authors: Jian Yin, Xiaopeng Zou, Chunjun Qin, Claney L. Pereira,
Guangzong Tian, Jing Hu, and Peter H. Seeberger
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To be cited as: Chem. Eur. J. 10.1002/chem.201800049
Link to VoR: http://dx.doi.org/10.1002/chem.201800049
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Synergistic Glycosylation as Key to the Chemical Synthesis of an
Outer Core Octasaccharide of Helicobacter pylori
Xiaopeng Zou[a,b], Chunjun Qin[a,b], Claney L. Pereira[b], Guangzong Tian[a,b], Jing Hu[a], Peter H.
Seeberger*[b], and Jian Yin*[a]
Dedicated to the memory of Prof. Dr. Werner G. G. Reutter
Abstract: Helicobacter pylori,
a
widespread gastric bacterial
Lipopolysaccharide (LPS) is a main H. pylori cell wall component
and LPS-associated serotypes have been discovered.[9]
Recently, Monteiro et al. demonstrated the potential of a LPS-
based vaccine against H. pylori, where the conserved core
undecasaccharide[9b,10] 1 (Figure 1) was identified as a promising
antigen for the development of a glycoconjugate vaccine
targeting all strains.[11] Since extraction and purification does not
provide enough pure carbohydrate antigens, synthetic
carbohydrate fragments of H. pylori LPS will enable
immunological investigations.[11d,12]
pathogen that infects 90% of the population in developing countries,
causes chronic gastritis, peptic ulcers and gastric cancer. Battling H.
pylori infection is a serious challenge due to the increased resistance
to antibiotics and the lack of vaccines. The lipopolysaccharide
covering the H. pylori cell-surface outer membrane is an attractive
target for the development of a glycoconjugate vaccine. Here, we
report a [3+5] convergent synthesis of an outer core octasaccharide
of H. pylori employing just three orthogonally protected building
blocks. A synergistic glycosylation strategy enables the creation of
five pivotal 1,2-cis--glucosidic bonds consist of four types of
linkages using just three monomers. This strategy can be expanded
to many 1,2-cis--gluoside-containing oligosaccharides both in
solution and on solid phase.
The bacterial pathogen Helicobacter pylori has coevolved with
humans, and colonizes over half of the world´s population.[1] In
contrast to other Gram-negative bacterial pathogens, H. pylori is
able to sustain the acidic environment of the stomach and
establish chronic infections.[2] H. pylori infections are a major
global health problem, since the pathogen causes not only
chronic gastritis of asymptomatic carriers, but also leads to
gastric and duodenal ulcers, and gastric malignancies. H. pylori
is estimated to be responsible for 5% of all cancer cases and
more than 60% of gastric cancer cases.[3] In 1994, H. pylori was
recognized as a category I human carcinogen by the World
Health Organization.[4] To date, the treatment of H. pylori
infections relies on various combinations of antibiotics that
gradually lose effectiveness due to increased clinical
resistance.[5] No H. pylori vaccines exist even though various
bacterial antigens, including urease, vacuolating cytotoxin A,
cytotoxin-associated antigen, neutrophil-activating protein have
been tested.[5a.6]
Figure 1. Structure of core undecasaccharide 1 of Helicobacter pylori.
The
outer
core
octasaccharide
portion
of
core
undecasaccharide
1
is the key synthetic target. The
retrosynthetic analysis of the outer core octasaccharide 2
bearing an amyl amine linker (Scheme 1) reveals that reliable -
selective glycosylations are essential to install five pivotal 1,2-
cis--glucosidic bonds.[13] Convergent strategies can focus either
on a [4+4] or a [3+5] key coupling. Therefore, three primary
building blocks, glucoside 5 (Scheme 1, A, B, C, G and H),
galactoside 6 (Scheme 1, F) and heptoside 7 (Scheme 1, D and
E) are required in multigram quantities. The selective formation
of five 1,2-cis--glucosidic bonds (-D-Glu) is the most
challenging aspect of the assembly of octasaccharide 2. Many
oligo- and polysaccharides that contain 1,2-cis-O-glycosidic
linkages are biologically important.[14] Numerous successful
methods[15] for the installation of 1,2-cis--glycosides have been
developed but a general method is still elusive.[16]
Protein-saccharide conjugates induce the T-cell mediated
production of antibodies to the corresponding pathogen and
thereby convey immunological memory.[7] Glycoconjugates,
derived by coupling carbohydrate antigens to immunogenic
protein carriers, are safe and efficacious human vaccines.[8]
[a]
X. Zou, C. Qin, G. Tian, Dr. J. Hu, Prof. J. Yin
Key Laboratory of Carbohydrate Chemistry and Biotechnology,
Ministry of Education, School of Biotechnology, Jiangnan University,
Lihu Avenue 1800, Wuxi, Jiangsu province, 214122 (P. R. China)
E-mail: jianyin@jiangnan.edu.cn
[b]
X. Zou, C. Qin, Dr. C. L. Pereira, G. Tian, Prof. P. H. Seeberger
Department of Biomolecular Systems,
Max Planck Institute of Colloids and Interfaces,
Am Mühlenberg 1, 14476 Potsdam (Germany)
E-mail: peter.seeberger@mpikg.mpg.de
Supporting information for this article is given via a link at the end of
the document.
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leaving groups had only little effect on the diastereoselectivity of
the glycosylation. Glycosyl trichloroacetimidates (Schmidt
donor)[19] and thioglycosides,[20] are the most popular
glycosylating agents. Recently, the Yu donor has evolved as an
effective and alternative glycosylating agent;[21] (3) Reaction
temperature: is an important factor to select a proper glycosyl
donor. While Schmidt glycosylation proceeds at low temperature,
Yu donors are generally activated under mild condition,[21] which
well meets the required reaction temperature for Bz-capped C6
hydroxyl group to drive the remote anchimeric assistance;[17,22]
(4) Solvents system: diethyl ether (Et2O) ensures better 
selectivity as does the additive thiophene.[15c,16] A combination of
solvents and additive (DCM/Et2O/thiophene) was considered to
improve the selectivity. Taking the four aspects, leaving group,
protecting group at 6-position, as well reaction temperature and
solvents laid out in detail above into account, the building blocks
for the synergistic glycosylation strategy were designed (Figure
2). Next, this strategy was tested using the designated Yu donor
5 for the assembly of oligosaccharides.
Orthogonally protected Yu donor 5, together with four glycosyl
acceptors 7D, 8, 9 and 10 (synthesis details see Supporting
Information) were utilized to test the formation of four different
types of 1,2-cis--glucosidic bonds (Scheme 2) present in
octasaccharide 2 (Scheme 1, 8 for 1→6 bond between A and B;
9 for 1→3 bond between G and H; 10 for 1→4 bond between F
and G; 7D for 1→2 bond between C and D). After careful
optimization of the glycosylations, the assembly of all
disaccharides (Figure 5) involving donor 5 (1.0 equiv.) and
acceptors 7D, 8, 9 and 10 (1.2–1.5 equiv.) were successfully
promoted by using catalytic TMSOTf (0.15 equiv.) in the
presence of a solvent mixture (DCM/Et2O=1/2) at 0 °C - RT. The
addition of ten equivalents thiophene enhanced the 
Scheme 1. Retrosynthetic analysis of octasaccharide 2.
Figure 2. Synergistic glycosylation by using a versatile Yu donor for high selectivity in the presence of DCM/Et2O/thiophene at 0 °C - RT.
selectivity.[16,23] Three disaccharides 11 (3JH1/H2 = 3.5 Hz), 12
Here, we report a synergistic glycosylation strategy (Figure 2),
which relies on an integrated design centered on an orthogonally
protected glycosyl trifluroacetimidate (Yu donor) 5. Several
aspects of glycoside formation were taken into consideration: (1)
Protecting groups: remote participation by placement of
benzoate esters (Bz) on the C3 and/or C6 hydroxyl groups
results in higher selectivities during the construction of 1,2-cis--
glucosidic bonds.[17] The C2-hydroxyl is protected with a benzyl
ether (Bn) as a non-participating group. In anticipation of chain
elongation, naphthalene ether (Nap) was placed for orthogonal
protection of the C3-hydroxyl; (2) Leaving group: aside from
occasional SN-2 like inversion transformations, most
glycosylation reactions proceeded via an SN-1 displacement
mechanism.[16,18] Accordingly, the orientation of the anomeric
(3JH1/H2 = 3.6 Hz) and 14 (3JH1/H2 = 3.6 Hz) were synthesized in
good yields (53-75%) as exclusively 1,2-cis--glucosidic
disaccharides were obtained. The union of donor 5 and acceptor
10 (synthesis details see Supporting Information) yielded only 28%
of target disaccharide 13 (3JH1/H2 = 3.5 Hz) due to the
intermolecular migration of the ethylthio functional group from
acceptor to donor.[24] To avoid this undesired migration, 1-O-TBS
glycoside 6 (synthesis details see Supporting Information) was
employed for the synthesis, and exclusively -linked
disaccharide 15 (3JH1/H2 = 3.8 Hz) was obtained in 72% yield.
According to these disaccharides models, the synergistic
glycosylation strategy enabled the selective formation of four
types of 1,2-cis--glucosidic bonds present in octasaccharide 2.
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δH-1 = 5.68 ppm) in 61% yield (= 15/1). Subsequent
transformations completed the synthesis of trisaccharide
trifluroacetimidate 3 in high yield (Scheme 3).
The synthesis of pentasaccharide fragment 4 commenced
by coupling Yu donor 5 with heptosyl acceptor 7D, to form
exclusively the -linked disaccharide 14 (Scheme 2).
Subsequent removal of the temporary benzoyl protecting group
was realized by sodium methoxide to afford 18 (Scheme 4). The
second and third couplings were achieved employing the
synergistic glycosylation strategy, to afford trisaccharide 19
(3JH1/H2 = 3.6 Hz, δH-1 = 5.00 ppm) and tetrasaccharide 21 (3JH1/H2
= 3.6 Hz, δH-1 = 5.13 ppm) in good yields. Finally, heptosyl
acceptor 7E was added to the solution of tetrasaccharide
promoted by triflic acid[26] to give pentasaccharide 22 in 73%
yield. The selective deprotection of acetyl (Ac) protecting group
of 22 using 10% acetyl chloride,[27] prevented the cleavage of
benzoyl protecting groups, to yield pentasaccharide acceptor 4
(Scheme 4). The two saccharide fragments 3 and 4 containing
five 1,2-cis--glucosidic linkages were efficiently prepared
through a synergistic glycosylation strategy in good yields with
very high selectivities (only  in four cases and /= 15/1 in
one case). Union of saccharides 3 and 4 to furnish target
octasaccharide 2 was investigated next.
Scheme 2. Model synthesis of 1,2-cis--glucosidic disaccharides 11-15
through synergistic glycosylation strategy.
The remaining primary glycosylating building block 7E
(synthesis details see Supporting Information) was synthesized
by glycosylation of an amyl amine linker with 7D. With all
required glycosides 5, 6 and 7 in hand, the assembly of
octasaccharide 2 commenced (Scheme 1). Initially, a [4+4]
convergent entry where the final coupling was tried between two
heptosides 7D and 7E was evaluated. However, only traces of
octasaccharide were detected while tetrasaccharide acceptor
was mainly recovered (Scheme 1) because steric hindrance in
7E impeded the completion of the planned coupling. Therefore,
the union of 3 and 4 following a [3+5] entry (Scheme 1) was
selected for octasaccharide assembly because the free C7-
hydroxyl group in 7E is better accessible than the free hydroxyl
group at the C2-postion of 7E.
Scheme 3. Synthesis of trisaccharide fragment 3 containing two 1,2-cis--
glucosidic linkages (1→3 and 1→4 bonds).
Scheme 4. Synthesis of pentasaccharide fragment 4 containing three 1,2-cis-
-glucosidic linkages (one 1→2 and two 1→6 bonds).
Trisaccharide 3, containing two 1,2-cis--glucosidic linkages,
was synthesized stepwise from the reducing to the non-reducing
end (Scheme 3). The orthogonally protected Yu donor 5,
activated by using catalytic TMSOTf, reacted with galactosyl
acceptor 6 to access disaccharide 15 in 72% yield ( exclusively)
(Scheme 2). The Nap protecting group was removed smoothly
with the help of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)[25] to give disaccharide acceptor 16. The second
glycosylation using 5 afforded trisaccharide 17 (3JH1/H2 = 3.5 Hz,
A convergent [3+5] synthesis strategy (Scheme 5) was used
for the final coupling of trisaccharide Yu donor
3 with
pentasaccharide acceptor 4 catalyzed by TMSOTf to afford the
fully protected octasaccharide 23 in good yield. Subsequent
removal of all acyl protecting groups and global deprotection
furnished the target octasaccharide 2 in 63% yields over two
steps after final purification (Scheme 5).
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In conclusion, the first chemical synthesis of the outer core
octasaccharide of H. pylori is described.
A synergistic
glycosylation strategy based on orthogonally protected Yu
donors enabled the selective formation of five 1,2-cis--
glucosidic linkages present in octasaccharide 2 in good yields
and with very high selectivities. The synthetic octasaccharide 2
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Acknowledgements
We are grateful for financial support from National Natural
Science Foundation of China (21302068), the Max Planck
Society International Partner Group Program, the High-end
Foreign Experts Recruitment Program, the Thousand Talents
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P.H.S. thanks the Max-Planck Society for generous financial
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: helicobacter pylori•synergistic glycosylation•1,2-cis-
-glucosides•oligosaccharides•glycosylation
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Constructing Glycans of the
Stomach. H. pylori infects more than
half of the world's population. A
synergistic glycosylation strategy was
developed to construct the
lipopolysaccharide of the pathogen as
a first step towards developing a
glycoconjugate vaccine.
X. Zou, C. Qin, C. L. Pereira, G. Tian, J.
Hu, P. H. Seeberger*, and J. Yin*
Page No. – Page No.
Synergistic Glycosylation as key to
the Chemical Synthesis of an Outer
Core Octasaccharide of Helicobacter
pylori
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