Fast and low-cost purification strategy for oligosaccharide synthesis based on a hop-on/off carrier

Article abstract of DOI:10.1021/acs.orglett.0c00477

A feasible and convenient strategy for oligosaccharide synthesis, which realizes reaction in solution while product purification occurs only by solid-liquid filtration, has been developed. By using a hop-on/off carrier (polytetrafluoroethylene particle), rapid synthesis of tumor-associated antigen Globo-H hexasaccharide has been successfully achieved within 5 steps in 48% overall yield without any intermediate purification by column chromatography. Also, global deprotection, including the cleavage of the tag, proceeded simultaneously only by one-step hydrogenolysis.

Full text of DOI:10.1021/acs.orglett.0c00477

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Letter
Fast and Low-Cost Purification Strategy for Oligosaccharide
Synthesis Based on a Hop-On/Off Carrier
Yingle Feng, Jingjing Wu, Guosong Chen,* and Yonghai Chai*
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ABSTRACT: A feasible and convenient strategy for oligosaccharide synthesis,
which realizes reaction in solution while product purification occurs only by
solid−liquid filtration, has been developed. By using a hop-on/off carrier
(
polytetrafluoroethylene particle), rapid synthesis of tumor-associated antigen
Globo-H hexasaccharide has been successfully achieved within 5 steps in 48%
overall yield without any intermediate purification by column chromatography.
Also, global deprotection, including the cleavage of the tag, proceeded
simultaneously only by one-step hydrogenolysis.
he solid phase method revolutionized the chemical
synthesis of peptides due to the simplicity of product
is applied to oligosaccharides, chemical control on the
glycosylation steps becomes much more crucial and challeng-
ing than solution synthesis due to the difficulties in monitoring
T
purification. It has been estimated that solid phase peptide
synthesis is ∼50-fold less arduous than solution synthesis of
3b
and controlling the heterogeneous reaction.
1
the same target. The solid phase method has allowed peptide
Thus, development of new synthetic techniques in order to
achieve fast and accessible synthesis of oligosaccharides in
laboratories is in great demand. Considering the advantages of
synthesis to be widely accessible to laboratories throughout the
world, which greatly promotes various related investigation,
including peptide-based material science and drug/sensor
development, etc.
4
6a,b
both solid phase synthesis and solution synthesis,
we
envision that the combination of those advantages of both
5
c,c,6g,i
The big dream of carbohydrate chemists is to push the
synthesis of complex oligosaccharides to such a level. However,
because of multiple hydroxyl groups in carbohydrates,
stereoselectivity in glycosylation, and a tedious purification
process, chemical synthesis of oligosaccharides is still very
challenging. The great breakthrough came out when solid
support, similar to that for peptide synthesis, was first proposed
methods
could be achieved if the oligosaccharide
synthetic process is performed in solution phase while product
purification is conducted with the aid of solid support. To this
end, in this paper, we show a novel strategy to achieve fast
oligosaccharide synthesis by employing a convenient solid
carrier. The temporary attachment and detachment of the
targeting oligosaccharide to the solid carrier can be easily
controlled by just changing the solvent. Thus, with the aid of
this “hop-on/off” carrier, the glycosylation reaction can be
achieved in solution and separation of the oligosaccharide can
be easily accessed by filtration, combining the advantages of
both solid phase synthesis and solution synthesis of
oligosaccharides. Moreover, with the optimized chemical
method, the assembly of Globo-H hexasaccharide can be
2
to construct complex oligosaccharides. Later, various
3
4
improvements and a tailor-made synthesizer were achieved.
5
6
Besides the solid support protocol, other strategies have been
developed to simplify the product purification process and
thereby improve the efficiency of oligosaccharide syntheses,
such as one-pot synthesis,
synthesis, ionic-tag-assisted oligosaccharide synthesis,
6a,b
HPLC-assisted oligosaccharide
6
c
6d,e
6f
electrochemical synthesis, hydrophobically assisted switching
6
g
6h
6i
phase synthesis, fluorous-tag and sulfonate-tag assisted
synthesis of oligosaccharides, and so on. However, due to the
requirement of various glycosylation conditions, currently the
oligosaccharide synthesizer could not easily reach the
simplicity level of the peptide synthesizer, which hampers the
accessibility of solid phase synthesis of oligosaccharides in
common laboratories. Moreover, when solid support synthesis
Received: February 6, 2020
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00477
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achieved within 5 steps in 48% overall yield without any
intermediate purification by column chromatography.
Afterward, the fluorous-tagged product can be detached by
elution with conventional organic solvent to continue the next
coupling or deprotection steps. In short, this strategy has both
advantages of solution-phase reaction and solid-phase synthesis
of oligosaccharides: (a) The homogeneous reaction can be
monitored by traditional methods such as TLC, NMR, and
MS; (b) The purification process is very simple and rapid,
avoiding the use of fluorous solvent and tedious transfer
process; (c) PTFE particles are cheap and stable under general
conditions in carbohydrate synthesis, which makes the particles
easily recyclable to save cost.
In this “hop-on/off” carrier design, the linkage between the
solid support and the oligosaccharide could not be the
previous covalent linkages that were used for peptide synthesis
and solid support oligosaccharide synthesis. The linkage
provided by the “hop-on/off” carrier should be fully reversible.
Considering the ease of procedure in laboratories and, more
importantly, the reversibility of the linkage, we utilized the
fluorous−fluorous interaction, which can be easily tuned by
changing solvent. The crucial aspect to achieve this design of
“
hop-on/off” carrier, is the employment of the inert and
To screen the appropriate solvent and the ratio of water for
the separation of fluorous oligosaccharides from nonfluorous
compounds, the behavior of fluorous-tagged lactose 3 (Figure
2) in mixture solvent was first investigated and acetone was
commercial available polytetrafluoroethylene particle (PTFE
particle, 100 μm), which is well-known in material science. It is
worth mentioning that, since the fluorous technique was first
introduced by Horvath and Rabai, the fluorous tagging
́ ́
7
7a
strategy (including fluorous liquid−liquid extractions (F-LLE)
and fluorous solid-phase extraction (F-SPE)) has been widely
used in the synthesis of small molecules and separation of
7
b
6h,8
peptides and oligosaccharides.
However, PTFE has not
been employed in any fluorous tagging strategy to our
knowledge and it is much cheaper and easier to access than
the perfluorinated solvent used in F-LLE and fluorous-
modified silica gel used in F-SPE.
Thus, the design of this “hop-on/off” carrier based on the
PTFE bead can be explained in Figure 1. To interact with the
Figure 2. Compared spectra of nonfluorous and fluorous components
separated by PTFE.
preferentially used in the evaluation. It was found that obvious
turbidity appeared when the ratio of water was increased to
2
8%, indicating strong fluorous−fluorous interaction drove the
molecules together. Thus, under this condition, once the PTFE
particles are added, their large surface area leads to the
anchoring of the fluorous-tagged oligosaccharide to their
surface, which supports separation of the latter from
nonfluorous compounds.
Figure 1. General procedure for PTFE-assisted synthesis of
oligosaccharides.
To prove this separation efficiency assisted by PTFE, the
purification of reaction mixtures between fluorous tag 1 and
lactose building block 2 was tested. Just as in the process in
Figure 1, after 1.5 h, TLC analysis showed the complete
consumption of fluorous tag 1; PTFE powder (100 μm,
roughly 5−10 times the mass of starting materials ) was
added to the reaction mixtures, and the solvent was completely
removed under reduced pressure. Then, a mixed solvent of
acetone and water (v/v = 7/3) was added, followed by stirring
at room temperature for 10−20 min. The resulting mixtures
were filtrated through a sand core funnel and washed with
9
PTFE bead, a recyclable benzyl-type fluorous tag 1 was
employed. As shown in Figure 1, after each coupling or
deprotection reaction proceeded in a traditional solution-phase
manner, inert and commercial available polytetrafluoro-
ethylene particles (PTFE particles, 100 μm) were added into
reaction mixtures. The fluorous−fluorous interaction in the
7c
presence of polar solvent (e.g., acetone/H O) leads to
2
attachment of fluorous-tagged oligosaccharides on the PTFE
particle surface. Therefore, the nonfluorous components that
remain in the solution phase could be readily separated from
fluorous-tagged oligosaccharides only by simple filtration.
additional acetone/H O to thoroughly remove nonfluorous
2
components that remain in solution. Finally, the crude product
B
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1
10h
of 3 was collected by washing with acetone. TLC plate and H
participating group TCA (trichloroacetyl)
and acetyl,
NMR spectra (Figure 2) showed that byproduct and reagents
respectively. To guarantee the 1,2-cis-glycoylation, the 2-O-
position of 9 was protected with nonparticipating Bn (benzyl)
group. After successful assembly of hexasaccharide 4, all of the
protecting groups including the fluorous tag, benzyl,
benzylidene, and chlorine will be globally removed only by
one-step hydrogenolysis.
(
nonfluorous part, line 4, dark blue spectrum) produced in the
coupling reaction were almost removed from the reaction
mixtures, and crude product (line 3, soft blue spectrum) with
high purity was obtained by comparison with β configuration
(
line 2, green spectrum) and α configuration (line 1, red
spectrum) of compound 3. The ratio of β to α (3-β/3-α = 2/
Initially, trichloroacetyl (TCA) and phthalimide (Phth)
protected acceptor 12 and 12-p were respectively attempted in
the glycosylation with 13, and only minor product was afforded
(Scheme 2). However, when azido-containing acceptor 12-
1
1
) configuration can be readily confirmed by the H NMR
spectra. It should be noted that additional postprocessing, i.e.
washing with Na S O aqueous, was avoided after glycosyla-
2
2
3
tion in the presence of NIS (N-iodosuccinimide), since the
excess of NIS and the nonfluorous byproducts can be
Scheme 2. Preparation of Disaccharide 7
simultaneously removed by washing with acetone/H O.
2
Therefore, the workup and purification for oligosaccharide
syntheses were simplified and time consumption on the
postprocessing procedure (including purification) can be
largely shortened to only 0.5−1 h. Feasible and convenient
glycosylation by combining the advantages of traditional
liquid-phase reaction and solid-phase reaction was well
demonstrated by this strategy.
1
0g
n
was used, glycosylation of 12-n with 13 was smoothly
12
To evaluate the applicability of the above protocol, tumor-
associated carbohydrate antigen Globo-H with a complex
structure which is overexpressed on tumor cells (such as breast,
colon, lung, ovary, prostate tumors) was selected as a synthetic
target. Although state-of-the-art technologies have been
promoted by trifilic acid using the inverse procedure, and the
disaccharide 7-n was achieved in 68% yield.
With 7-n in hand, the azide group was reduced with PPh
3
13
and then protected with TCA followed by deaceylation to
give compound 8 (Scheme 3). However, pretest studies on
10
applied in literature to synthesize Globo-H, a new route
suitable for our purification strategy was designed with
consideration of easy access of building blocks and least
number of deprotection steps. Retrosynthetic analysis (Scheme
Scheme 3. Preparation of Trisaccharide 17
1
) shows that the protected hexasaccharide 4 can be prepared
Scheme 1. Retrosynthetic Analysis of Globo-H
glycosylation between 8 and 9 showed that there was almost
no reaction and disaccharide 8 was recovered in CH Cl while
2
2
the glycosylation was complete but complex mixtures were
14
afforded in toluene. The problem regarding the synthesis of
trisaccharide 17 was solved by switching the reaction sequence
(
See Scheme 3). Thus, deacetytlation of 7-n led to 14, which
by successive coupling of 6 with 7 and 9. The construction of
was coupled with fucose building block 9 smoothly in toluene
in the presence of TfOH to provide the desired trisaccharide
15 with α configuration as the main product (54% yield).
Finally, the azide was reduced by Staudinger reduction
followed by protection with TCA to provide compound 17
in 73% yield in two steps (Scheme 3).
1
,2-cis-glycosidic linkages of 10 and 11 will be ensured by
9,11
remote anchimeric assistance
of acyl groups at O-3 in the
thioglycosides 11. To stereoselectively construct 1,2-trans-
glycoside of 6 and 7 as well as 12 and 13, the 2-N-position of
1
2 and 2-O-position of 13 were protected with the
C
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After successful preparation of compound 17, PTFE
particle-assisted synthesis of Globo-H was carried out
according to the procedure in Scheme 4. First, the coupling
phase synthesis and solid phase separation, which means that
TLC monitor and regular purification are available for
oligosaccharide synthesis. These advantages have been
supported by fast and high-yield synthesis of complex
oligosaccharide Globo-H. Considering the routine synthesis
procedure and separation steps during this process, and the
low cost of PTFE beads, this strategy makes the oligosacchar-
ide synthesis accessible by general laboratories in chemistry
and material science with routine equipment. With the aid of
solution synthesis and TLC monitoring, the regioselectivity,
stereoselectivity, and efficiency of coupling reactions can be
optimized, which are critical to the rapid syntheses of
oligosaccharides. Moreover, by combination of our strategy
with enzymatic glycosylation, it is possible to expand the
library of oligosaccharides. And finally we expect the general
access to oligosaccharides could greatly promote the develop-
ment of related research in drug discovery and material
science.
Scheme 4. Preparation of Globo-H Assisted by PTFE
between compound 1 and 2 proceeded and the product was
purified by the previously established procedure (Figure 1).
Although there was a high ratio of 3-α in the crude product,
aiming at free Globo-H with the reducing end, the crude
product 3 separated from PTFE beads with acetone was
collected and used immediately in the next step without further
purification. After removal of acetyl in 3 (neutralized with
Dowex 50WX8 ion-exchange resin or purified by PTFE),
glycosylation with 11 was carried out. It is demonstrated that
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00477.
Experimental procedures, characterization data, and
NMR spectra (PDF)
9
,11
AUTHOR INFORMATION
Corresponding Authors
remote anchimeric assistance
of acyl groups at O-3 in the
■
thioglycosides 11 leads to high efficiency and stereoselectivity
of the glycosylation. Afterward, the same operation with PTFE
Yonghai Chai − Key Laboratory of Applied Surface and Colloid
Chemistry, Ministry of Education and School of Chemistry and
Chemical Engineering, Shaanxi Normal University, Xi’an,
Shaanxi 710119, P. R. China; orcid.org/0000-0003-3157-
1
was used to purify the product. As apparent from H NMR
spectrum (Figure S17), the nonfluorous components that
eluted with actone/H O (7/3, v/v) were almost completely
2
removed, and the purity of the fluorous phase compound
1
79X; Email: ychai@snnu.edu.cn
detached with acetone was quite high compared with the pure
Guosong Chen − The State Key Laboratory of Molecular
Engineering of Polymers, Department of Macromolecular
Science, Fudan University, Shanghai 200433, China;
orcid.org/0000-0001-7089-911X; Email: guosong@
fudan.edu.cn
1
H NMR spectrum of compound 5. After treatment with
MeONa/MeOH to remove acetyl again, the final glycosylation
of 6 with trisaccharide 17 was carried out. The pretest study
demonstrated that when TMSOTf was used to catalyze the
reaction, only minor product was afforded. To our delight, the
desired β-anomer of compound 4 was provided in 91% yield
with TfOH instead of TMSOTf. To confirm the configuration
of 4, the heteronuclear J-resolved spectroscopy (JRES) of
Authors
Yingle Feng − Key Laboratory of Applied Surface and Colloid
Chemistry, Ministry of Education and School of Chemistry and
Chemical Engineering, Shaanxi Normal University, Xi’an,
Shaanxi 710119, P. R. China; The State Key Laboratory of
Molecular Engineering of Polymers, Department of
Macromolecular Science, Fudan University, Shanghai 200433,
China
Jingjing Wu − Key Laboratory of Applied Surface and Colloid
Chemistry, Ministry of Education and School of Chemistry and
Chemical Engineering, Shaanxi Normal University, Xi’an,
Shaanxi 710119, P. R. China
compound 6 was measured (Figure S15). The two 170 Hz
1
values of the J
coupling constant imply the existence of
C1−H1
the two α configurations in compound 6. Under the optimal
conditions, the synthesis of Globo-H assisted by PTFE was
conducted. As expected, both MALDI-TOF mass spectrometry
1
(
Figure S19) and H NMR (Figure S18) demonstrated that
the protected Globo-H 4 with high purity was provided only
by separation with PTFE assistance. According to these results,
the hydrolyzed product of compound 17 was almost
completely removed in the process of washing with acetone/
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00477
H O. The crude product was purified by silica gel column
2
chromatography, and the protected Globo-H was obtained in
4
8% overall yield in 5 steps. The efficiency is higher than the
10h
Notes
solid-phase synthesis (30% total yield) and comparable with
multicomponent one-pot synthesis (47% total yield)
10g
The authors declare no competing financial interest.
of
Globo-H. Finally, global deprotection under a hydrogen
atmosphere gave Globo-H as a target compound.
In summary, we have developed a polytetrafluoroethylene
particle (PTFE)-assisted strategy for oligosaccharides syn-
thesis. This new strategy employs the advantages of solution
1
5
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21072122, 21472119, 91956127),
the Science and Technology Program of Shaanxi Province,
D
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Letter
China (2018ZDXM-GY-152), and the Ministry of Science and
Technology (No. 2012ZX09502-001-001). All of the financial
support is gratefully acknowledged.
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