Assembly of homolinear α(1→2)-linked nonamannoside on ionic liquid support

Article abstract of DOI:10.1021/jo2006126

An improved method for the synthesis of large and complex oligosaccharides on ionic liquid (IL) support was developed. A strategy to attach the acceptor on IL using a more stable ether linker was used to prevent undesirable decomposition and side products

Full text of DOI:10.1021/jo2006126

ARTICLE
pubs.acs.org/joc
Assembly of Homolinear r(1f2)-Linked Nonamannoside on
Ionic Liquid Support
Qing Ma, Sheng Sun, Xiang-Bao Meng, Qing Li, Shu-Chun Li, and Zhong-Jun Li*
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100191, P. R. China
S Supporting Information
b
ABSTRACT: An improved method for the synthesis of large
and complex oligosaccharides on ionic liquid (IL) support was
developed. A strategy to attach the acceptor on IL using a more
stable ether linker was used to prevent undesirable decomposi-
tion and side products. A “dissolutionꢀevaporationꢀprecipita-
tion” purification procedure was also developed by combining
the advantages of precipitation and solidꢀliquid extraction to
reduce mechanical loss and purification time. This approach was
successfully used for the rapid assembly of ionic liquid sup-
ported homolinear R(1f2)-linked nonamannoside in 25.2%
overall yield within 28.5 h.
exploited for the synthesis of oligosaccharides.5c,10,23 In view of one-
pot synthesis, this method has also developed into a strategy known
as the fluorous assisted one-pot assembly of oligosaccharides.11
Ionic liquids have been extensively studied because of their
fascinating and intriguing properties,12 such as their use as
solvents and reaction supports.13 An attractive feature of IL
supports is that their solubility can be altered readily by modify-
ing the structure of cation or anion. This property suggests the
possibility of using ionic liquids as soluble supports for organic
synthesis. The compounds attached on IL are expected to retain
their reactivity under homogeneous reaction conditions. Several
groups have successfully demonstrated the feasibility of ionic
liquid supported synthesis of peptides, nucleotides, and other
types of organic molecules.14ꢀ16
More recently, several groups utilized ionic liquid supports as
phase-separation tags in the synthesis of oligosachharides.17,18
Although successful in the synthesis of disaccharides and trisac-
charides, its application in the synthesis of more complex
oligosaccharides still remains to be explored. Only recently,
Pathak et al. synthesized homolinear R(1f6)-linked tetra- and
octamannoside using this method via fragment coupling.19,20
The following three key aspects of IL support may limit its
application. First, the attachment strategy: whether ionic liquids
should be tagged on glycosyl donors or acceptors has to be
determined by the synthetic manipulation; Second, stability of
linker: even trace decomposition of the unstable linker in the
process may cause accumulative effects and thus limit the yield.
1. INTRODUCTION
The study of carbohydrates has been widely valued in many
different areas of chemistry and biology since they possess a
variety of unique functionalities and structures.1 Chemical synth-
esis of pure and structurally complex oligosaccharides is still a
challenge because of the selective protection and deprotection of
multiple hydroxyl groups. Moreover, traditional synthesis re-
quires purification by chromatography after each glycosylation
step, which is not only time-consuming but also costly.2
Extensive efforts were made to improve the synthesis of oligo-
saccharides. Wong and co-workers developed a programmable one-
potoligosaccharide synthesis procedure to enhance the efficiency
of synthesis by eliminating the need for protecting groups
between coupling steps.3 An iterative one-pot method for the
synthesis of oligosaccharides with fewer protective group manip-
ulations has been investigated.4 The simplification of the pur-
ification step is also important for the improvement of the
synthesis. The solid-phase approach is attractive mainly because
of its simple purification process, which allows convenient
product isolation and automation.5ꢀ7 Despite its success, solid-
phase synthesis has limitations because of the heterogeneous
reaction conditions. An alternative polymer-supported liquid-
phase strategy that maintains the homogeneous reaction condi-
tions was developed to overcome some of the limitations of solid-
phase synthesis.8 However, several limitations of polymer-sup-
ported synthesis including low loading capacity and limited
solubility of the glycosyl donors during the reaction process
hamper its wider use, and there is still a need to improve the
method.9 Fluorous-assisted separations methodology using fluorous
support and fluorous biphasic systems has also been recently
Received: March 24, 2011
Published: June 08, 2011
r
2011 American Chemical Society
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Figure 1. Oligosaccharide synthetic strategy using IL support: (a) pathway with donor attached to IL support; (b) pathway with acceptor attached to IL
support.
Third, purification technique: the existing purification technique
is either through precipitation or solidꢀliquid extraction, which
resulted in mechanical loss; optimization is likely necessary.
Based on these analyses, we believe further optimization of ionic
liquid supported synthesis is still necessary for its successful
application in the synthesis of complex oligosaccharides.
To develop a more efficient methodology for IL supported
synthesis of complex oligosaccharides, homolinear R(1f2)-linked
oligomannoside was chosen as our target structure, because
D-mannose oligomers are present in nature and are essential sub-
structures in many biologically relevant glycoconjugates.21 More-
over, oligomannan synthesis has been reported using several
different methodologies,22 including solution- and solid-phase
synthesis,8c as well as fluorous-23 and ionic liquid-tagged syn-
thesis.19,20 Specifically, the homolinear R(1f2) oligomannans
were previously synthesized in the solution phase24 and by a
solid-phase approach.25
As illustrated in Figure 1b, ionic liquid supported acceptors
were used for the synthesis of the R(1f2)-linked oligomanno-
side. An oligosaccharide attached on IL was prepared by coupling
IL-supported glycosyl acceptor with glycosyl donors in an appro-
priate solvent such as CH2Cl2. Highly pure IL-tagged product
was generated after washing with aqueous solution and phase
separation with a solvent in which the IL-tagged oligosaccharide
is not soluble (e.g., diethyl ether). The reagents as well as unreacted
donor glycoside and other side products were removed during
the process.
Additionally, in any support-assisted synthesis, high reaction
yield is necessary because unreacted species will be carried to the
next step. We could use excess donors and more reactive leaving
groups to increase the reaction yield.
2.2. Synthesis of a New DOX Linker Modified Ionic Liquid
Support. In previous works, ionic liquids and glycosyl donors
were conjugated via an acetyl linker, which is relatively unstable
under both acid and alkali conditions. Consequently, accumula-
tion of the side products produced by the decomposition of the
linker led to lower yield and purity. We designed and synthesized
an IL support using R,R0-dioxyxylyl diether (DOX) as the linker.8c
Unlike acetyl linker, it has several advantages: it is more stable
under most reaction conditions and readily removable by hydro-
genolysis; it can be bound via an ether or O-glycosidic linkage;
and it is easily prepared from commercially available R,R0-
dibromo-p-xylene.
In the present work, we developed a glycosyl acceptor tagging
strategy, employed a stable ether linker, and used a new puri-
fication technique to improve IL supported synthesis of complex
oligosaccharides, which allowed the rapid assembly of a homo-
linear R(1f2)-linked nonamannoside without chromatographic
purification.
2. RESULTS AND DISCUSSION
The R,R0-dibromo-p-xylene was first treated with NaOAc to
produce 4-(bromomethyl)benzyl alcohol acetate 2 (Scheme 1).
Following reaction with N-methylimidazole and KPF6, the
acetylated IL support 3 was formed via simple phase separation.
The linker-modified IL support 4 was obtained after deacetyla-
tion with NaOMe. The structure of 4 was confirmed by NMR
and MS spectra.
2.3. Selection of the glycosyl Acceptor Donor and Opti-
mization of the Coupling Condition. After the synthesis of the
linker modified ionic liquid support, a glycosyl donor can be
attached to it. 3,4,6-Tri-O-benzyl-2-O-acetyl-R-D-mannose tri-
chloroacetimidate 5 was selected as the donor because it can be
prepared easily from D-mannose and it has been widely used in
2.1. Development of an Acceptor Attachment Strategy.
Most published methods attached the glycosyl donors to the
ionic liquid supports18ꢀ20 as illustrated in Figure 1a. Because the
glycosyl donors are the reactive agents, many side products like
anomer-to-anomer coupling products, donor rearrangement
products, and other side products remained on the IL support
and could not be removed in the purification process, which
decreased the purity. Alternatively, acceptors could be attached
on the ionic liquid supports to avoid the contamination by side
products. Indeed, acceptors attached on the ionic liquid supports
were tried in the early research,17 but not widely used since then.
Therefore, we decided to revisit this attachment strategy.
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Scheme 1. Synthesis of Linker-Modified IL Support
Table 1. Optimization of the Glycosylation Conditions
entry
donor (equiv)
solvent
temp (°C)
time (h)
TLCa
ratio of 6-10b (%)
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
4.0
3.0
2.0
1.5
CH3CN
CH3CN
CH3CN
0
ꢀ40
50
0
0.5
4.0
2.0
0.5
0.5
0.5
0.5
0.5
complete
complete
complete
complete
complete
complete
complete
incomplete
21
43
c
c
c
c
c
c
CH3CN:CH2Cl2 (1:10)
CH3CN:CH2Cl2 (1:10)
CH3CN:CH2Cl2 (1:10)
CH3CN:CH2Cl2 (1:10)
CH3CN: CH2Cl2 (1:10)
0
0
0
0
a Analyzed by TLC: “complete” represents no ionic liquid support remaining, “incomplete” represents IL support remaining. Rf value of ionic liquid
b
0
2
support is 0.27 (CH Cl2/CH3OH 10:1) and Rf value of the product is 0.43 (CH2Cl2/CH3OH 10:1). The structure of compound 6-1 was deduced
based on 1H NMR and 13C NMR spectra of the mixture, which are included in the Supporting Information. The ratio was determined by 1H NMR. c The
signal of ortho ester 6-10 was not detected by both 1H NMR and 13C NMR.
the synthesis of R(1f2)-linked mannoside.26 Glycosyl acceptor
5 is highly reactive because of the arm-effect, and the 2-O-acetyl
ensures R-stereospecific reaction through the neighboring group
participation. Moreover, as a temporary protection group, the
acetyl group can be removed easily and rapidly.
We then carried out experiments to optimize the coupling
condition to ensure high reaction yield (Table 1). Generally, the
IL-conjugated donor 5 and the acceptor 4 were dissolved in dry
solvent, and 0.5 equiv of TMSOTf was added as a promoter of
the assembling reaction. The crude product was obtained by
washing with saturated aq NaHCO3 and brine to remove all the
water-soluble impurities. Further purification of the product was
carried out by concentrating the product into syrup, which was
dissolved in CH2Cl2 and precipitated with diethyl ether. The
white precipitate was immediately separated from the solvent by
centrifugation to afford the product.
Because ionic liquid 4 cannot be dissolved in CH2Cl2, CH3CN
was used as the solvent initially. However, an ortho ester side
product such as 6-10 was produced, which cannot be eliminated
in further phase separation. As a kinetically controlled product,
the formation of 6-10 increased with the decrease of reaction
temperature. Moreover, we found that when solvent was
switched from CH3CN to a mixture of CH3CN and CH2Cl2
(1:10), generation of ortho ester was prevented. Fortunately,
because ionic liquid modified with oligosaccharides is soluble
in CH2Cl2, the formation of ortho ester in the assembly of
oligosaccharides was avoided by selecting CH2Cl2 as the
solvent.
The amount of donors was also optimized to attain cost-
effective and complete glycosylation. The reaction process was
already highly efficient when only 2.0 equiv of donor was added
according to TLC analysis.
Finally, following the optimized condition in entry 7, highly
pure IL-supported monosaccharide 6-1 was prepared. The
structure was confirmed by its NMR spectrum, and the NMR
spectrum also showed it was highly pure. This was further
supported by the MS analysis.
On the basis of careful optimization, the final glycosylation
condition is as follows: 2.0 equiv of trichloroacetimidate donor
with 0.5 equiv of TMSOTf as promoter in dry CH2Cl2 at 0 °C for
0.5 h with stirring. The same post-treatment and precipitation
purification technique were used in the next steps. Because of the
potential difference in nucleophilicities of the benzyl alcohol
acceptor and the secondary axial alcohol acceptor, caution should
be raised that the optimized reaction conditions may not be
optimal for the elongation with saccharide acceptors. In our
experiments, the elongation went smoothly under the optimized
conditions.
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Scheme 2. Attempted Assembly of r(1f2)-Linked Mannoside Using Precipitation Purification
Figure 2. Novel purification technique for IL-supported oligosaccharide synthesis.
2.4. Attempted Assembly of r(1f2)-Linked Oligomanno-
side Using Precipitation Purification. After the attachment of a
sugar to the IL support, the IL-supported monosaccharide 6-1
was deacetylated by treatment with NaOMe. The mixture was
concentrated in vacuo, dissolved in CH2Cl2, and filtered. The
acceptor 7-1 was obtained after evaporating solvent, which was
sufficiently pure for further reactions.
Glycosyl trichloroacetimidates served as donors in two
consecutive glycosylation reactions to furnish R(1f2)-
linked trimannoside (Scheme 2), whose structure was con-
firmed by NMR spectrum and MS analysis. However, when
this approach was employed to assemble the tetrasaccharide,
even though the coupling was still highly efficient according
to spectroscopic analysis, only 35% of the product was
recovered.
2.5. Development of a New Purification Procedure. The
low recovery in the synthesis of tetrasaccharide motivated us to
develop a new purification procedure. The existing purification
procedure for IL-supported synthesis includes either precipita-
tion or solidꢀliquid extraction. In the precipitation method, the
low recovery is probably attributed to the less role played by the
IL moiety when larger oligosaccharides are attached to it, thus
increasing the solubility of the ILꢀoligosacchride conjugate.12b
The decreased influence of IL on the solubility of the ILꢀ
oligosacchride causes greater loss of product in synthesis of larger
oligosaccharides due to the gradually increased solubility. To
avoid the increased solubility of ionic liquid tagged oligosacchar-
ides in solvents like CH2Cl2, we tried solidꢀliquid extraction.
The crude products were washed with diethyl ether directly
without polar solvent. However, because of the extremely
high viscosity of ionic liquid species and thus poor impurity
dissolution kinetics, products were still not pure after stir-
ring for 48 h at room temperature in a large volume of
diethyl ether.
To improve the purification process of ionic liquid tagged
oligosaccharides, we designed a novel purification procedure that
consisted of mixed-solvent dissolution, evaporation, precipita-
tion, and centrifugation steps (Figure 2). In this strategy, the
reaction mixture was first dissolved in a mixed solvent of dichlo-
romethane and isopropyl ether. Subsequently, the solvent was
removed partially by rotary evaporation in vacuo. Dichloromethane
was evaporated before isopropyl ether because its boiling point is
lower. With the evaporation of polar solvent dichloromethane,
ionic liquid tagged oligosaccharides precipitated gradually. After
the complete removal of CH2Cl2, the white precipitates in
isopropyl ether were collected by centrifugation to yield the pro-
duct. This “dissolutionꢀevaporationꢀprecipitation” purification
procedure is equivalent to the precipitation procedure in non-
polar solvent, but the new evaporationꢀprecipitation procedure
showed higher recovery than the traditional precipitation proce-
dure. Compared with the solidꢀliquid extraction method, this
method avoided slow impurity dissolution kinetics; it was shown
to be quite efficient.
We used the optimized coupling conditions, and this new
purification technique to synthesize homolinear R(1f2)-linked
nonamannoside. The reaction was conducted under the opti-
mized coupling conditions: 2.0 equiv of trichloroacetimidate
donor with 0.5 equiv TMSOTf as promoter in dry CH2Cl2
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Scheme 3. IL-Supported Assembly of Homolinear r(1f2)-Linked Nonamannosidea
a Key: (a) Glycosylation: TMSOTf (0.5 equiv), CH2Cl2, molecular sieves (4 Å), 0 °C, Ar, 30 min. (b) Purification. (c) Removal of acetyl group: NaOMe,
MeOH, 1 h. (d) Hydrogenation: H2 (4 atm), Pb(OH)2, MeOH/EtOAc, 4 d.
stirred at 0 °C for 0.5 h. After the glycosylation was complete, the
solution was concentrated in vacuo to a syrup, dissolved in
CH2Cl2, and washed with satd aq NaHCO3 and brine. For
further purification, the crude product was concentrated into a
syrup, dissolved in CH2Cl2, and added with isopropyl ether.
Thereafter, solvent was removed partially by rotary evaporation
in vacuo, until the remaining solution was about double the
original CH2Cl2 volume; a white precipitate appeared, and it was
immediately collected by centrifugation (Figure 2). The purifica-
tion procedure produced highly pure IL-supported species.
2.6. Rapid Assembly of Nonamannoside Using the New
Purification Procedure. Following the pathway illustrated in
Scheme 3, R(1f2)-linked nonamannoside 7ꢀ9 was synthesized
with glycosyl trichloroacetimidates 5 as donors in consecutive
glycosylation reactions. The structure of 7ꢀ9 was supported by
1H and 13C NMR spectra and further confirmed by MALDI-
TOF-MS analysis, which showed a m/z at 4132.1 [M ꢀ PF6]+.
Details of each step are listed in Table 2. Nonamer 7ꢀ9 was
prepared in average yields of 80ꢀ90% per step. The short
reaction times, about 3 h per monomer addition, allowed for
the synthesis of 7ꢀ9 in 25.2% overall yield within 28.5 h.
Comparing with the manual solid supported synthesis of a
structurally similar heptamannoside in 14 days and 9% overall,25
our method is faster and higher yielding. Our method is similar to
the automated solid-phase synthesis method for oligosaccharides
in terms of reaction time and yield.6a Moreover, the 2 equiv
excess of glycosyl donors used in our method is much less than
that in automated solid-phase synthesis, which used a 10ꢀ20
equiv excess of donors.
The target nonamannoside 1 was eventually achieved follow-
ing catalytic hydrogenation and simple purification. The final
structure confirmation of nonamannoside 1 was obtained by its
1H and 13C NMR spectra, as well as MALDI-TOF-MS analysis,
which showed a molecular ion m/z peak at 1498.4 [M + Na]+.
In summary, we have developed an acceptor-tagged support-
ing strategy mainly to eliminate undesirable side products. A
more stable ether linker was employed to decrease the accumu-
lative decomposition, and we designed a new purification
technique to minimize the loss of product. With this method,
we achieved the efficient synthesis of a nanosacharide on IL
support without chromatographic purification. Our method for
the efficient synthesis of large oligosaccharides on IL support
could be a very useful technique to produce oligosaccharides on a
large scale. Currently, other complex oligosaccharides are being
synthesized using this technique in our laboratory.
3. EXPERIMENTAL SECTION
Synthesis of 4-(Bromomethyl)benzyl Alcohol Acetate (2).
A mixture of R,R0-dibromo-p-xylene (10.0 g, 37.9 mmol) and AcONa
(6.21 g, 75.8 mmol) in dried MeCN (300 mL) was stirred at reflux for 16
h. The residue obtained by evaporation was dissolved in Et2O, washed
with saturated aq NaCl solution, and dried (MgSO4). After concentra-
tion, column chromatographic purification yielded 2 (2.12 g, 23.0%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 4H), 5.10 (s, 2H),
4.49 (s, 2H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.0, 137.9,
136.2, 129.2, 128.6, 65.6, 32.8, 20.8.
Synthesis of 3-[4-(Acetoxymethyl)benzyl]-1-methylimi-
dazolium Hexafluorophosphate (3). Compound 2 (2.0 g, 8.2
mmol) was dissolved in dry CH3CN (30 mL) under argon, and to it
were added N-methylimidazole (1.31 mL, 16.4 mmol) and KPF6 (1.5 g,
8.2 mmol). The reaction was refluxed overnight at 80 °C with stirring,
and TLC showed complete conversion. The reaction mixture was cooled
to room temperature, filtered, and concentrated under vacuum. The
residue was dissolved in CH3CN (1 mL) and precipitated with diethyl
ether (10 mL) to obtain acetylated IL support 3 (2.82 g, 87.0%) as a
1
colorless oil: H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.78
(s, 1H), 7.71 (s, 1H), 7.42 (m, 4H), 5.41 (s, 2H), 5.08 (s, 2H), 3.85
(s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.7, 137.3,
137.1, 135.0, 129.0, 128.9, 124.5, 122.8, 65.4, 52.0, 36.3, 21.1; ESI-MS
m/z calcd 245.1 [M ꢀ PF6]+, found 245.1 [M ꢀ PF6]+; HRMS m/z
calcd 245.12845 [M ꢀ PF6]+ for C14H17N2O2, found 245.12805.
Synthesis of 3-[4-(Hydroxymethyl)benzyl]-1-methylimi-
dazolium Hexafluorophosphate (4). The acetylated IL support
3 (1.5 g, 3.8 mmol) was dissolved in MeOH (20 mL), a solution of
NaOMe (0.1 M in MeOH) was added, and the mixture was stirred for 1
h. The mixture was concentrated in vacuo, dissolved in CH3CN, and
filtered. After concentration, the IL support 4 (1.32 g, 98.7%) was
1
obtained as a colorless oil: H NMR (400 MHz, DMSO-d6) δ 9.11
(s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.29 (d, 4H), 5.31 (s, 2H), 4.43
(s, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 143.7, 137.0,
133.5, 128.6, 127.4, 124.4, 122.7, 62.9, 52.2, 36.3.
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Table 2. IL Supported Assembly of Homolinear r(1f2)-
easily by a second round of evaporationꢀprecipitation separation
following the purification protocol, and the products were nearly
quantitatively recovered after the second purification. Both the 13C
NMR spectra before and after the second purification were attached in
the Supporting Information for each compound.
General Procedure D: Removal of Acetate Protecting
Groups. To a solution of 6-n in methanol (1 g/100 mL) was added
saturated sodium methoxide solution in methanol (1 mL). After the
solution was stirred at room temperature for 45 min, when TLC showed
complete consumption of the compound 6-n, the solution was neu-
tralized with concentrated HCl and evaporated in vacuo. The residue
was dissolved in CH2Cl2 and filtered. The filtrate solution was concen-
trated to give the target compound 7-n.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-
acetyl-3,4,6-tri-O-benzyl-R-D-mannopyranoside (6-1). Acceptor 4
(150 mg, 0.431 mmol), donor 5 (550 mg, 0.862 mmol), and promoter
TMSOTf (39 μL, 0.22 mmol) were used to synthesize IL-supported
monosaccharide 6-1 (305 mg, 85.6%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 9.14 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.35ꢀ7.12
(m, 21H), 5.35 (s, 2H), 5.23 (s, 1H), 4.87 (s, 1H), 4.70ꢀ4.43 (m, 8H),
3.79 (s, 4H), 3.63 (m, 4H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.2, 138.8, 138.3, 137.1, 134.8, 128.7, 128.1, 127.9, 122.8, 96.9, 72.8,
71.7, 71.2, 69.2, 68.5, 68.3, 52.1, 36.3, 21.3; ESI-MS m/z calcd 677.3
[M ꢀ PF6]+, found 677.3 [M ꢀ PF6]+; HRMS m/z calcd 677.32213
[M ꢀ PF6]+ for C41H45N2O7, found 677.32075.
Linked Nonamannoside
n
operationb
product
timea (min)
recovery (%)
1
2
3
4
5
6
7
8
9
A and B
C
6-1
7-1
6-2
7-2
6-3
7-3
6-4
7-4
6-5
7-5
6-6
7-6
6-7
7-7
6-8
7-8
6-9
7-9
60 + 30 + 40
85.6
>99
86.8
>99
88.1
>99
81.7
>99
89.6
>99
88.5
>99
92.0
>99
85.0
>99
80.1
>99
25.2
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
A and B
C
60 + 30 + 40
60
total
1710
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-
acetyl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-
benzyl-R-D-mannopyranoside (6-2). Acceptor 7-1 (200 mg, 0.256
mmol), donor 5 (330 mg, 0.512 mmol), and promoter TMSOTf
(23 μL, 0.13 mmol) were used to prepare IL-supported disaccharide
6ꢀ2 (280 mg, 86.8%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 9.03 (s, 1H), 7.30ꢀ7.06 (m, 36H), 5.30 (s, 2H), 5.26 (s, 1H), 5.08
(s, 1H), 4.99 (s, 1H), 4.86 (dd, 2H), 4.70ꢀ4.30 (m, 12H), 4.04
(s, 1H), 3.98ꢀ3.71 (m, 12H), 2.13 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 138.2, 136.6, 129.1, 128.4, 128.3, 128.0, 127.8,
127.5, 121.7, 99.6, 98.3, 78.1, 75.1, 73.4, 71.9, 68.7, 53.5, 53.2, 36.3,
21.1; ESI-MS m/z calcd 1109.5 [M ꢀ PF6]+, found 1109.3 [M ꢀ
a The time includes the preparation time before glycosylation (60 min),
the time of glycosylation (30 min), and the time of purification (40 min).
The time for removal of acetyl protecting groups is about 1 h. b A:
glycosylation. B: purification. C: removal of acetyl group.
General Procedure a: Coupling Reaction Using Trichlor-
oacetimidates and TMSOTf. IL support 4 and trichloroacetimidate
5 were coevaporated three times with toluene (3 ꢁ 5 mL) and dried
under vacuum. After crushed 4 Å molecular sieves (0.5 g) were added,
the mixture was dissolved in dry CH2Cl2 or 10:1 CH2Cl2/CH3CN (only
for IL-supported monosaccharide synthesis), and then the solution was
cooled to 0 °C. After the mixture was stirred for 10 min, a solution of 0.5
equiv of TMSOTf in dry CH2Cl2 was added, and after 30 min, when
TLC showed complete consumption of acceptor, the reaction was
quenched at the same temperature by the addition of Et3N.
General Procedure B: Purification by Precipitation. After
filtration and concentration of the reaction mixture, the residue was
dissolved in CH2Cl2, quickly washed with saturated aqueous NaHCO3
solution and saturated aq NaCl solution, and dried over anhydrous
Na2SO4. After evaporation in vacuo to a syrup, the residue was diluted in
CH2Cl2 (1 mL/g), and 10 equiv volume of diethyl ether was added. Each
oligomer was precipitated out of solution as a white precipitate. After
centrifugation (3000 r/min, 10 min), the precipitate was collected and
became sticky oil.
General Procedure C: Purification by the Novel Tech-
nique. After filtration and concentration of the reaction mixture, the
residue was dissolved in CH2Cl2, quickly washed saturated aqueous
NaHCO3 solution and saturated aq NaCl solution, and dried over
anhydrous Na2SO4. After evaporation in vacuo, the residue was dis-
solved in CH2Cl2 (5 mL/g), and then 4 equiv volume of isopropyl ether
was added. The solvent was removed partially by rotary evaporation in
vacuo until the residual solution was about two equivalent volume of the
initially added CH2Cl2. Each oligomer was precipitated out of solution
as a white precipitate. After centrifugation (3000 r/min, 10 min), the
precipitate was collected and became a sticky oil.
PF6]+; HRMS m/z calcd 1109.51580 [M ꢀ PF6]+ for C68H73N2O12
,
found 1109.51611.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-Acet-
yl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-
R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyrano-
side (6-3). Acceptor 7ꢀ2 (200 mg, 0.165 mmol), donor 5 (210 mg,
0.330 mmol), and promoter TMSOTf (15 μL, 0.082 mmol) were used
to prepare IL-supported trisaccharide 6-3 (245 mg, 88.1%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.32ꢀ6.98 (m, 51H),
5.53 (d, 1H), 5.18 (d, 2H), 5.04 (s, 1H), 5.01 (s, 1H), 4.98 (s, 1H), 4.82
(m, 2H), 4.67ꢀ4.24 (m, 18H), 4.09ꢀ3.71 (m, 20H), 2.11 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.1, 139.2, 138.9, 138.8, 138.5, 138.4,
138.3, 138.2, 138.0, 137.8, 137.7, 137.4, 131.9, 129.1, 129.0, 128.9, 128.8,
128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5,
127.2, 123.3, 121.7, 121.6, 121.5, 100.7, 99.4, 98.4, 80.2, 79.9, 79.5, 79.3,
77.4, 77.2, 77.0, 76.7, 75.6, 75.2, 75.1, 75.0, 74.8, 74.4, 74.3, 73.3, 73.1,
72.6, 72.2, 72.1, 71.9, 71.8, 71.5, 71.1, 69.8, 69.7, 69.3, 69.1, 68.9, 68.7,
68.4, 68.3, 53.2, 36.4, 29.7, 22.9, 21.1; ESI-MS m/z calcd 1541.7 [M ꢀ
PF6]+, found 1541.9 [M ꢀ PF6]+; HRMS m/z calcd 1541.70948 [M ꢀ
PF6]+ for C95H101N2O17, found 1541.70776.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-Acetyl-
3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-man-
nopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-
3,4,6-tri-O-benzyl-R-D-mannopyranoside (6-4). Acceptor 7-3 (200 mg,
0.122 mmol), donor 5 (155 mg, 0.243 mmol), and promoter TMSOTf
(11μL, 0.061 mmol) were used to prepare IL-supported tetrasaccharide 6-4
(210 mg, 81.7%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.16
For compound 6-3 and 6-7, some additional signals at around δ 92
ppm were detected in their 13C NMR spectra, which were potentially
derived from residual donors. These additional signals were removed
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The Journal of Organic Chemistry
ARTICLE
(s, 1H), 7.60ꢀ7.00 (m, 70H), 5.63 (d, 1H), 5.28 (m, 2H), 5.39ꢀ4.10 (m,
30H), 4.09ꢀ3.54 (m, 26H), 2.18 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.2, 138.5, 129.1, 128.5, 128.2, 127.9, 127.7, 127.5, 121.7, 101.3, 100.7,
99.5, 98.5, 75.2, 74.4, 72.2, 71.3, 68.4, 53.5, 53.1, 36.3, 21.2; ESI-MS m/z
calcd 1974.9 [M ꢀ PF6]+, found 1974.2 [M ꢀ PF6]+; HRMS m/z
1974.90705 [M ꢀ PF6]+ calcd for C122H129N2O22, found 1974.90449.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-Acet-
yl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-
R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyrano-
syl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-
benzyl-R-D-mannopyranoside (6-5). Acceptor 7-4 (180 mg, 0.0870
mmol), donor 5 (110 mg, 0.173 mmol), and promoter TMSOTf (8.0 μL,
0.043 mmol) were used to prepare IL-supported pentasaccharide 6ꢀ5
(198 mg, 89.6%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.21
(s, 1H), 7.70ꢀ6.98 (m, 81H), 5.75 (m, 1H), 5.50ꢀ3.55 (m, 72H), 2.26
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 138.5, 138.4, 138.3,
136.5, 128.0, 127.6, 121.8, 101.5, 100.9, 99.5, 98.6, 97.2, 80.2, 74.7, 73.4,
72.2, 69.9, 68.4, 53.6, 53.1, 36.3, 23.1; MALDI-TOF-MS m/z calcd
2406.1 [M ꢀ PF6]+, found 2405.1 [M ꢀ PF6]+; HRMS m/z calcd
2406.09682 [M ꢀ PF6]+ for C149H157N2O27, found 2406.09692.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-Acet-
yl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-
R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyrano-
syl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-
benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-manno-
pyranoside (6-6). Acceptor 7-5 (180 mg, 0.0720 mmol), donor 5 (91.0
mg, 0.143 mmol), and promoter TMSOTf (7.0 μL, 0.036 mmol) were
used to prepare IL-supported hexasaccharide 6-6 (190 mg, 88.5%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 7.57ꢀ6.88
(m, 98H), 5.72 (m, 1H,), 5.30ꢀ3.19 (m, 84H), 2.20 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.2, 138.6, 129.1, 128.6, 128.3, 128.1, 127.8,
127.4, 121.7, 101.6, 101.5, 100.9, 99.5, 98.5, 74.6, 73.4, 72.0, 69.4, 68.3,
53.1, 36.3, 23.0, 21.2; MALDI-TOF-MS m/z calcd 2838.3 [M ꢀ PF6]+,
found 2838.2 [M ꢀ PF6]+; HRMS m/z calcd 2838.29050 [M ꢀ PF6]+
for C176H185N2O32, found 2838.28284.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-
Acetyl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-be-
nzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyr-
anosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-
tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-ma-
nnopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranoside (6-7).
Acceptor 7-6 (180 mg, 0.0610 mmol), donor 5 (80.0 mg, 0.122 mmol),
and promoter TMSOTf (6.0 μL, 0.031 mmol) were used to prepare IL-
supported heptasaccharide 6ꢀ7 (192 mg, 92.0%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 7.47ꢀ6.85 (m, 116H), 5.61
(m, 1H,), 5.33ꢀ3.49 (m, 99H), 2.11 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 139.3, 139.2, 139.0, 138.6, 138.4, 138.2, 137.0, 132.0,
129.0, 128.9, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5,
127.4, 126.4, 126.1, 123.5, 121.6, 101.5, 101.4, 101.0, 100.8, 99.5, 98.5,
80.1, 79.2, 77.4, 77.2, 77.1, 76.9, 76.8, 76.3, 75.2, 75.1, 74.8, 73.3,
72.4, 72.2, 72.0, 71.9, 69.8, 69.4, 68.8, 68.4, 53.1, 36.4, 22.9, 21.2;
MALDI-TOF-MS m/z calcd 3270.5 [M ꢀ PF6]+, found 3270.7
[M ꢀ PF6]+; HRMS m/z calcd 3270.48417 [M ꢀ PF6]+ for
C203H213N2O37, found 3272.45480.
9.54 (s, 1H), 7.53ꢀ6.84 (m, 124H), 5.66 (m, 1H), 5.41ꢀ3.33 (m,
108H), 2.13 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 139.3,
139.0, 138.6, 138.2, 137.1, 132.0, 129.0, 128.9, 128.7, 128.6, 128.3, 128.0,
127.9, 127.8, 127.5, 127.4, 126.0, 123.4, 121.6, 101.6, 101.4, 101.3, 100.8,
100.8, 99.4, 98.5, 80.1, 79.1, 77.1, 76.8, 76.7, 75.6, 75.2, 75.1, 74.8, 73.3,
72.4, 72.2, 72.0, 71.9, 71.7, 69.9, 69.4, 68.8, 68.4, 53.2, 36.4, 22.9, 21.2;
MALDI-TOF-MS m/z calcd 3702.7 [M ꢀ PF6]+, found 3702.8 [M ꢀ
PF6]+; HRMS m/z calcd 3702.67785 [M ꢀ PF6]+ for C230H241N2O42,
found 3704.69963.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-
Acetyl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-be-
nzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyr-
anosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-
tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-ma-
nnopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-
tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-manno-
pyranoside (6-9). Acceptor 7-8 (151 mg, 0.0400 mmol), donor 5 (51
mg, 0.080 mmol), and promoter TMSOTf (4.0 μL, 0.020 mmol) were
used to prepare IL-supported monosaccharide 6ꢀ9 (136 mg, 80.1%) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.46ꢀ6.82
(m, 147H), 5.60 (m, 1H,), 5.27ꢀ3.25 (m, 128H), 2.17 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.1, 139.3, 139.1, 139.0, 138.7, 138.5,
138.4, 138.2, 137.2, 131.9, 129.0, 128.9, 128.7, 128.6, 128.5, 128.3, 128.1,
127.9, 127.8, 127.6, 127.5, 127.3, 126.0, 123.3, 121.5, 101.7, 101.4, 101.0,
100.9, 99.5, 98.5, 97.2, 80.1, 79.1, 77.4, 77.3, 77.1, 76.8, 75.2, 74.8, 73.3,
72.3, 72.2, 71.9, 71.5, 69.9, 69.4, 68.7, 68.3, 53.2, 36.4, 29.7, 29.4, 22.9,
21.2; MALDI-TOF-MS m/z calcd 4134.9 [M ꢀ PF6]+, found 4132.1
[Mꢀ PF6]+;HRMSm/zcalcd 4134.87152 [M ꢀ PF6]+ for C257H269N2O47,
found 4134.71675.
R-D-Mannopyranosyl-(1f2)-R-D-mannopyranosyl-(1f2)-R-D-
mannopyranosyl-(1f2)-R-D-mannopyranosyl-(1f2)-R-D-mannop-
yranosyl-(1f2)-R-D-mannopyranosyl-(1f2)-R-D-mannopyrano-
syl-(1f2)-R-D-mannopyranosyl-(1f2)-R/β-D-mannopyranoside (1).
The protected nonamannoside 7-9 (135 mg, 0.0318 mmol) was
dissolved in 10% EtOAc/MeOH (10 mL). In the presence of Pb(OH)2
the solution was stirred under 4 atm of H2 for 4 d at room temperature.
The heterogeneous mixture was filtered over Celite, and the solid mass
was washed with a large amount of MeOH. Following concentration of
the mixture in vacuo, the residue was redissolved in H2O, and CH3CN
was added to produce a white precipitate. The nonamannoside 1 (42.0
mg, 89.4%) was obtained as a colorless syrup after removal of the
supernatant by centrifugation: 1H NMR (400 MHz, D2O) δ 5.41
(s, 1H), 5.26 (s, 1H), 5.17 (s, 4H), 5.04 (d, 1H), 4.93 (s, 1H), 4.68
(s, 70H), 4.13 (s, 1H), 3.95 (m, 6H), 3.85ꢀ3.65 (m, 19H), 3.65ꢀ3.45
(m, 27H), 3.42 (m, 2H); 13C NMR (100 MHz, D2O) δ 105.4, 102.1,
100.5, 99.2, 92.4, 78.5, 76.3, 73.2, 72.4, 70.3, 69.7, 66.7, 61.0, 60.9; ESI-
MS m/z calcd 1494.5 [M + Na]+, found 1494.4 [M + Na]+; MALDI-TOF-
MS m/z calcd 1498.5 [M + Na]+, found 1498.4 [M + Na]+.
’ ASSOCIATED CONTENT
S
Supporting Information. General procedures and char-
b
acterization data (1H and 13C NMR spectra). This material is
available free of charge via the Internet at http://pubs.acs.org.
4-[(1-Methylimdazoliumhexafluorophospho)methyl]benzyl 2-O-
Acetyl-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-be-
nzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyr-
anosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-
tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-ma-
nnopyranosyl-(1f2)-3,4,6-tri-O-benzyl-R-D-mannopyranosyl-(1f2)-3,4,6-
tri-O-benzyl-R-D-mannopyranoside (6-8). Acceptor 7-7 (167 mg,
0.0490 mmol), donor 5 (64 mg, 0.098 mmol), and promoter TMSOTf
(5.0 μL, 0.025 mmol) were used to prepare IL-supported octasaccharide
6-8 (162 mg, 85.0%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: zjli@bjmu.edu.cn.
’ ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (No. 20732001) and the State New
5658
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The Journal of Organic Chemistry
ARTICLE
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