Ionic-liquid supported rapid synthesis of an: N -glycan core pentasaccharide on a 10 g scale

Article abstract of DOI:10.1039/c8ob01046c

A new and efficient Ionic Liquid-Supported Oligosaccharide Synthesis (ILSOS) strategy for an N-linked core pentasaccharide on a 10 g scale is reported. This new ILSOS includes a new spacer for an IL support, a new tagging strategy, and fast, efficient and orthogonal removal of the ionic-liquid support, producing the N-linked core pentasaccharide with direct applicability potential in a short time, with high yield and on a large gram scale.

Full text of DOI:10.1039/c8ob01046c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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ARTICLE
Ionic-liquid Supported Rapid Synthesis of N-glycan Core
Pentasaccharide in 10g Scale
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Li, Yu Gao, Qing Li and Zhong-Jun Li*
A
new and efficient Ionic Liquid-Supported
DOI: 10.1039/x0xx00000x
Oligosaccharide Synthesis (ILSOS) strategy for
N-linked core pentasaccharide in 10g scale is
reported. This new ILSOS includes new spacer
for IL support, new tagging strategy, fast,
efficient and orthogonal removal of ionic-liquid
support, producing N-linked core pentasaccharide
with direct applicability potential in short time,
high yield and large gram scale.
www.rsc.org/
strategy and centrifugal purification via DCM-iPr2O solvent
system, and successfully synthesized a homolinear α(1→2)
linked nonamannoside using DOX-linker modified IL
support.25 Similar strategy was also utilized in Galan group’s
work,26,27 Beau’s group28 and Itoh’s group.29 Besides, Li’s
group has successfully assembled a homolinear β(1→6)
Introduction
a
The importance of structurally defined oligosaccharides
with specified biological activities is well known.1-4 Great
efforts have been made to acquire these molecules efficiently
and conveniently over the decades. During the preparation
process, the purifications after each protection-deprotection
reaction and/or glycosylation are likely the most laborious
and costly steps5-7. Several strategies have been developed to
simplify such process. Wong and co-workers developed a
computer programmed one pot oligosaccharide synthesis
strategy which avoids the need for protecting group
manipulations between glycosylation couplings.8-10 In
addition, several one pot synthesis strategies, like iterative
one-pot method were developed.11-13 To simplify the
purification after glycosylation coupling, supported synthesis
strategies were investigated, which mainly include solid
phase approach,14-16 fluorous-assisted separation method17-21
and Ionic Liquid Supported Oligosaccharides Synthesis
(ILSOS).22-30
linked hexaglucosamine and
a glycopeptide applying a
PMB-type linker-modified IL support.30 These reports have
confirmed the validity of ILSOS strategy, in which the rapid
glycosylation via active trichloroacetimidates, rational
acceptor-tagged strategy, stable ether-type linker modified IL
support and efficient centrifugal purification in DCM-iPr2O
solvent system were prevailingly adopted.
However, there are still drawbacks of current ILSOS
strategy(Figure 1a): 1)the feasibility in preparation of
commonly existing hetero-branching oligosaccharides instead
of simple homo-linear ones needs to be broadened; 2)the
removal of the IL support was not ideal: The DOX-type
support was removed cumbersomely via long time
hydrogenation,25-27 while the PMB-type support was
detached in acidic condition30 which challenges some
glycosides’ stability;31 3) ILSOS’ ability to assemble
oligosaccharides with direct applicability potential needs to
be improved: Current ILSOS’ deprotection processes leave a
free reductive hydroxyl group, which proceeds through
multiple steps to forms linkage to other molecules/structures
(like microarray and/or glyco-conjugates) for advanced
biological chemical studies,32-34 thus constraining synthesized
oligosaccharides’ further applications; 4) ILSOS’ scalability
needs to be proven: Scaled up ILSOS needs to be investigated
to afford enough amount of target oligosaccharide molecules
for further advanced researches mentioned above.
In recent years, several groups have successfully
developed and applied ILSOS strategy in homo-linear
oligosaccharides assemblies:22 Pathak et al. synthesized
homolinear α(1→6) linked tetra- and octamannoside using
ester-linker IL support via fragment coupling.23,24 Our group
has systematically explored an ILSOS methodology including
trichloroacetimidate glycosylation method, acceptor-tagging
The State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, Beijing 100191, China.
E-mail: zjli@bjmu.edu.cn
† Electronic Supplementary Informaꢀon (ESI) available: selective 1H, 13C NMR
spectra. See DOI: 10.1039/x0xx00000x
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Figure 1. Drawbacks of current ILSOS (
a) and scheme of new ILSOS designation in the synthesis of 1(b).
Correspondingly (Figure 1b), we designed and investigated
a new ILSOS in the 1) successful rapid assembly of a complex
The fully protected and tagged target pentasaccharide was
designed as , which was prepared by assembling the
branching mannosyl moiety , the medium disaccharide block
and the tagged unit . Donor was prepared according to
previous report (Detailed preparation process seen in
supporting information).40 Disaccharide
, as the key building
block containing a -mannoside, was prepared conventionally
via a new route in large scale. Tagged unit was the key
2
hetero-branched pentasaccharide
1, which is the core
3
structure of N-glycans of great biological importance.35-39 2)
To avoid the cumbersome or challenging removal of IL
support, a new spacer-modified IL support was designed,
which was efficiently removed after the assembly process.
3)To prepare target molecules with direct applicability
potential, a non-reductive site (the 6-OH on reducing end unit)
was tagged with IL support, allowing the reductive hydroxyl
group being conjugated to a linker with a protected ending
amino group, which was released and could directly form an
amide bond with other molecules after global deprotection. 4)
4
5
3
4
β
5
block to develop a new ILSOS strategy which mainly included
a new methoxyphenyl(MP-)41-45 type spacer modified IL
support and new tagging strategy on the 6-OH of the
reductive end unit.
Multigram scale assembly of 1 by ILSOS was practiced to
investigate the scalability of ILSOS.
Large scale preparation of disaccharide block 4
Among the many reports of synthesizing N-glycans or its
core pentasaccharide, the construction of β-mannoside was
Results and discussion
always
β-mannosylation
a
key point.46-50 Among commonly adopted
Retrosynthetic analysis:
methods,
direct
construction
of
β-mannoside from 4,6-benzylidened mannosyl donor
requires strict conditions (low temperature, extra unhydrous
conditions) and chemical equivalence of relatively expensive
steric bases like TTBP or TTDMP.51-54 Such reaction conditions
would be costly and difficult to control especially in large
scale preparation; Mannosyl halide method involves large
amount of heavy metal salts;55 And the intramolecular
aglycon delivery (IAD) strategy requires a regioselective
oxidation of the protecting group on 2’-OH,56,57 which was
not suitable in our case.
However, the 2’-OH inversion strategy58-61 has shown its
advantages in preparing building blocks containing
β-mannoside as it involves environment-friendly reagents,
exhibits excellent tolerance with various protection groups
and proceeds in mild conditions, thus being adopted for large
scale preparation of disaccharide
4 to meet the requirements
of scalability investigation of ILSOS. Herein, a highly stable,
efficient, convenient and economical route was designed and
practiced to prepare disaccharide
preparation trial (Figure 3
4 in about 20g scale in one
)
Figure 2. Retrosynthetic analysis of TM and synthesis design.
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of the new ILSOS. The new ILSOS was established in a “catch
and release” mode (Figure ): tagging process to synthesize
unit (“Catch” step) and efficient removal of the new IL
4
5
support (“Release” step).
Phenol 17 (detailed preparation process seen in supporting
information) and the 6-OH on 16 (detailed preparation
process seen in supporting information) was condensed by a
Mitsunobu reaction58, giving ether 18 in 76% yield. Then 18
was substituted by 1-methyl imidazole to complete the
“Catch” step, giving supported
yield. Such substitution reaction was amenable to large scale
synthesis, and unit was prepared in 5g scale for the
following exploration. model detachment reaction
(“Release” step) of
by CAN41-45 was completed within 5min
5 in 95% ILSOS separation
5
A
5
to recover 16 in 95% chromatography yield, which was much
faster compared with previously reported detaching
processes.25-27 By far, the new ILSOS strategy was
fundamentally established.
Figure 3. Large scale preparation of disaccharide 4.
1) i) NapBr, NaH(60%), DMF; ii) TsOH, 75% MeCNa.q., reflux; iii)
Ac
DCM; ii) TMSOTf, DCM, 98%; 3) i) MeONa, MeOH, DMF; ii)
PhCH(OMe) , TsOH, DMF, 93% in 2 steps; 4) Ac O, DMSO, then
NaBH , MeOH, DCM, 90%, 10:11=30:70; 5) Tf O, Pyr, DCM, then
NaNO , DMF, 48%, 2g scale; 6) BnBr, NaH(60%), DMF, 93%;
7)DDQ, DCM, MeOH, 89% ; 8)BH3.THF, Bu BOTf, DCM, 84%; 9)
Ac O, Pyr, quant.; 10)CAN, 80% MeCNa.q., 95%.
Commercial 1,2;5,6-Di-O-isopropylidene-
was converted into in 90% yield over four continuous
steps by only one final flash column chromatography.
Following coupling of and to give disaccharide was
almost quantitative. proceeded a continuous de-acetylation
2O, Pyr; iv)H2NC3H6NMe2, THF, 90% in 4 steps; 2) i) CNCCl3, DBU,
2
2
4
2
2
2
2
α
-D-glucofuranose
6
7
7
8
9
Figure 4. Establishment of the new ILSOS.
1) Ph3P, DIAD, THF, reflux, 76%; 2) Me-Im, KPF6, MeCN, reflux,
9
95%; 3) CAN, 80% MeCNa.q., 5min, 95%.
and benzylidenation to give 10 in 93% yield. For the key
inversion of 10 to 11 with the inversion of 2’-OH,
“oxidation-reduction” method58-61 and SN2 inversion62 were
tried and compared. The SN2 replacement method showed
low yield and limited scalability (48%, 2g scale at most in our
trial). The oxidation-reduction method gave high yield (90% in
2 steps), but the stereo-outcome of reduction by NaBH4 in a
Rapid assembly of target pentasaccharide via new ILSOS
After large scale preparation of disaccharide block
successful establishment of the new ILSOS final assembly of
the target pentasaccharide was carried out Table ).
Disaccharide donor was converted to a trichloroacetimidate
intermediate and used in coupling acceptor (about 4g scale),
giving a supported trisaccharide 19 in 96% yield (about 6g
scale). Acetyl groups were removed by MeONa in
4
and
(
1
co-solvent of MeOH/DCM was moderate (10
:
11=30:70).54
4
Because substrate 10 could be recovered and recycled, such
5
an oxidation-reduction method was finally adopted. The
followed benzylation (giving 12 in 93%), oxidative Nap-
deprotection (giving 13 in 89%)63,
a
64
and regioselective
ring-opening65, 66 of benzylidene 13 all went smoothly to give
intermediate 14. Then 14 was converted into after two
co-solvent of MeOH and DCM (3h), giving a trisaccharide
acceptor 20 quantitatively for the next coupling. Mannosyl
4
donor
(about 6g scale) smoothly to give the fully protected and
tagged pentasaccharide with high yield (98%, 10g scale). In
3 was treated with CNCCl3/DBU, and coupled with 23
efficient manipulations. In this route, all steps proceeded in
mild conditions and were repeatable. The required reagents
were commercially available at low cost. Finally, about 20g
2
both glycosylation couplings, TfOH was a better promoter
than TMSOTf in avoiding the formation of TMS-byproduct of
acceptors,60,61 which was certified in the sugar chain
desired disaccharide
4 was prepared in one preparation trial
with an overall yield of 34% apart from recycling 10
.
extending coupling of
5 promoted by TMSOTf (For NMR
results comparison, see Figure S1-S4).
After successful assembly of pentasaccharide 2, IL support
Establishment of a new ILSOS strategy—tagging unit 5
Disaccharide was the key block for the synthesis of target
pentasaccharide, and unit was the key for the development
was removed orthogonally by previously experimented
4
5
oxidation method, giving an un-tagged pentasaccharide 21 in
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72% chromatography yield. Reason of such relative low
recovery of release process was analyzed in the following
HPLC analysis paragraph. Compound 21 proceeded through a
would accumulate along with the assembly process. Because
ILSOS is
a rapid synthesis method which excludes
conventional chromatographic purification, the results of its
easily practiced precipitation-centrifugation separation
process, i.e. the purity of separated supported oligomers
requires to be measured by precise method. As a precise
purity analysis method, HPLC analysis was applied. Results
reported four-step global deprotection process to give the
in 70% yield69,
70
unprotected target pentasaccharide
1
.
Besides, abundantly assembled 21 can also be directly used in
the preparation of other N-glycan derivatives.71-73
were shown in Figure 5
:
Table 1.Rapid synthesis of target pentasaccharide
Several apparent tendencies were observed in the HPLC
result above:
a): Purity of supported oligomers indeed decreased as the
increase of supported sugar units (from 1 unit to 5 units),
which was the most intuitive conclusion from these spectra.
To be more detailed, decreased purity of supported
oligomers mainly attributed to the accumulation of large
polar impurities which occupied shorter retention time (apart
from the column’s death volume which shared a common
negative peak and the peaks around) compared with
supported oligomer’s peak in each spectrum. Such large polar
impurities were likely inferred as inorganic salts and/or
supported byproducts since each supported oligomer is a
large polar organic salt essentially. Besides, such impurity
accumulation assumption provided a likely explanation of the
1): CNCCl3, DBU, DCM, 91%; 2): TfOH, DCM, 96%; 3)MeONa,
MeOH/DCM, 99%; 4): CNCCl3, DBU, DCM, 96%; 5):TfOH, DCM,
98%; 6): CAN, 80% MeCNa.q., 10min, 72%; 7): i)H2NC2H4NH2,
EtOH, reflux; ii) Ac2O, Pyr; iii) MeONa, MeOH/ DMF; iv) Pd(OH)2,
MeOH, 70%.
n
1
3
operationsa product
timeb
40
90+40
180
90+40
10+180
670
recovery purityc scale
B
A then B
C
A then B
D
5
95%
96%
>99%
98%
99%
95%
90%
80%
/
>5g
>7g
>6g
10g
>6g
19
20
2
5
21
72%
total
64.4%
a
A:glycosylation. B: purification. C: removal of acetyl group. D:
detachment of IL support. Typical time of glycosylation is about
Figure 5. HPLC analysis of the assembly process via new ILSOS
Generally, higher proportion of MeCN in solvent gradient and
longer analysis time were required in supported oligomers
occupying more sugar units. General HPLC conditions seen in
Experimental section. Detailed gradients and retention for
b
90min (60min of preparation and 30min of coupling); Typical time of
centrifugal purification is 40min. The time of removing acetyl
protection groups is about 3h. The time of detaching IL support is
10min and typical flash chromatography time is about 3h. purity
was roughly estimated deducted from baseline inequality and
column’s death volume.
c
each compound: 1) for compound
5, isocratic elution
(MeCN:H2O(0.1% TFA) = 75:25), retention time(RT) 4.757min;
2) for compound 19, gradient elution (MeCN:H2O (0.1% TFA) =
90:10~100:0 (0-10min), 100:0 (10-15min)), RT 5.619min; 3) for
compound 20, gradient elution (MeCN:H2O (0.1% TFA) =
HPLC analysis of the new ILSOS
85:15~95:5 (0-15min)), RT 6.638min; 4) for compound
2,
In our ILSOS exploration, we assumed that inseparable
byproducts like large polar inorganics, supported byproducts
gradient elution(MeCN:H2O (0.1% TFA) = 95:15~100:0 (0-5min),
100:0 (5-20min)), RT 9.910min.
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relatively low recovery of 21 released from
2
. The purity of
2
chromatography was performed employing silica gel
(300-400 mesh). 1H NMR and 13C NMR spectra were recorded
on Advance spectrometers. Chemical shifts (in ppm) were
referenced with tetramethylsilane (δ = 0 ppm) for 1H NMR
and CDCl3 (δ = 77.00 ppm) for 13C NMR in deuterated
chloroform. High-resolution mass spectrometry was
performed on FTICR mass spectrometer.
was already decreased due to impurity accumulation, so the
actual release process was likely more efficiently practiced
than the apparent moderate detachment (72% recovery).
b): Baseline inequality phenomena were commonly
observed not only in the HPLC spectra of the new ILSOS,
which was also observed in our other unpublished ILSOS
works. Based on the analysis of a), such inequality was likely
caused by the systematically accumulated large polar
impurities, for baseline inequality was more obviously
recorded in larger supported oligomer’s spectra. At least,
there was a strong positive correlation between impurity
accumulation and baseline inequality, which could be a
possible mechanism explanation of HPLC results. Besides,
ionic liquid support itself as an organic salt could possibly
contribute to such baseline inequality in part.
General ILSOS separation procedure
After filtration and concentration of the reaction mixture,
the residue was dissolved in small volume of CH2Cl2 (about
2mL/g), followed by addition of 5-10 equiv. volume of
isopropyl ether in shaking until no more visible precipitate
was generated, which indicated the full precipitation of each
oligomer. After centrifugation (3000 r/min, 10 min, 3 times),
the precipitate was collected and became a sticky syrup.
General HPLC condition:
c): Based on the analysis above, the purity of each
oligomer just couldn’t be regularly precisely calculated by
HPLC because of the uncertainty between baseline inequality
and suspicious signal peaks, as well as the exaggerated
response factor difference between supported oligomers and
impurities, especially the inorganic impurities which acquired
few or none aromatic rings. So only a rough purity estimation
could be proceeded on the deduction from baseline
inequality, column’s death column etc. Rough estimated
purity of each oligomer was listed in Table 1, and final purity
HPLC analyses were performed on an Agilent 1260 infinite
analyzer with an Agilent ZORBRAX SB-C18 column (5μm,
4.6×250mm), detection wavelength of 220nm, mobile phase
of MeCN/H2O (0.1% TFA) and a constant flow rate of
1mL/min.
Selected synthetic processes and compound data
5-aminopentyl
mannopyranosyl-(1→6)]-β-
deoxy-2-acetimido-β- -glucopyranosyl-(1→4)-2-deoxy-2-
- glucopyranoside (1) The global deprotection
was proceeded via 4 conventional steps: 1) To
α-D-mannopyranosyl-(1→3)-[α-D-
D
-mannopyranosyl-(1→4)-2-
D
of supported 2 was about 80%.
acetimido-β-
D
By far, the overall yield, consumed time, assembly scale
and estimated purity of core pentasaccharide 21 were
summarized in Table 1. Released 21 was prepared in 670min
with an overall 64.4% yield, a final purity of about 80% (for
of 21 to give
1
a solution of 21 (500 mg, 0.2 mmol, 1.0 equiv.) in EtOH (10
mL) was added ethylenediamine (337 µL, 5.06 mmol, 25.0
equiv.). The reaction was refluxed at 100 °C for 12h. After
cooled down to RT, the solution was neutralized by adding
AcOH, and concentrated; 2) Residue from 1) was dissolved in
pyridine (10 ml), followed by adding Ac2O (5 ml) and a
catalytic amount of DMAP. The mixture was stirred o.n..
MeOH was added to quench acetylation. The solution was
concentrated. Residue was dissolved in DCM, washed with
1N HCla.q, sat. NaHCO3a.q. and brine sequentially. Organic
layer was collected, dried over Na2SO4, concentrated and
purified via flash column chromatography on silica gel
(PE:EA=1:2), giving a light yellow syrup; 3) the syrup from 2)
was dissolved in MeOH/DMF (v/v=1:1, 10mL), followed by
adding MeONa (0.1 M in MeOH), adjusting solution’s pH
supported oligomer 2), and in about 10g scale, conclusively.
Conclusion
In summary, we have developed a new ILSOS strategy to
assemble an N-glycan core pentasaccharide of direct
applicability potential based on our previously established
ILSOS method. Apart from the advantages of efficiency and
rapidness, the new ILSOS allows the efficient and orthogonal
removal of IL support and large scale preparation of complex
hetero-branching oligosaccharides. The combination of this
new ILSOS with orthogonal protection strategy74 could find
application in constructing structurally complex sugar
molecules like N-glycans in a more efficient way and on a
larger scale.
between 8~10. The reaction was kept at 60 °C for 12h with
TLC (PE:EA = 1:4) showing a single spot on the plate. 1N HCla.q.
was added to neutralize MeONa and the solution was
concentrated, re-dissolved in DCM, filtered and concentrated;
4) Residue from 3) was co-evaporated with toluene three
times, dissolved in MeOH, mixed with Pd(OH)2/C, and
hydrogenated under 4 atm of H2 for 16h at RT. The mixture
was filtered. Filtrate was concentrate and purified by
Experimental section
General experimental methods
All chemicals were purchased as reagent grade and used
without further purification, unless otherwise noted.
Dichloromethane was distilled over calcium hydride.
Analytical TLC was performed on silica Gel 60 F254 pre-coated
on glass plates, with detection by fluorescence and/or by
staining with 5% concentrated sulfuric acid in EtOH. Column
size-exclusion chromatography (Sephadex LH-20) with dH2O
1
to give a white solid as
1
(136 mg, 70%). H NMR, 13C NMR
and MS results were in accordance with previous report, see
reference (DOI: 10.1002/chem.201001295).75
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N-Benzyl-N’-benzyloxycarbonyl-5-aminopentyl
2-O-acetyl-3,4,6-O-tri-benzyl-α- -mannopyranosyl-(1→3)-[2
-O-acetyl-3,4,6-O-tri-benzyl-α- -mannopyranosyl-(1→6)-]-2,
4-O-di-benzyl-β- -mannopyranosyl-(1→4)-3,6-O-di-benzyl-2
-deoxy-2-phthalimido-β- -glucopyranosyl-(1→4)-3-O-benzyl
separation Procedure, giving a yellowish syrup as 5 (5.39 g,
1
D
95%). H NMR (400 MHz, CDCl3) δ: 8.46 (s, 1H), 7.71-7.57 (m,
4H), 7.35-7.20 (m, 10H), 7.18 (s, 1H), 7.14 (d, 1H),7.09 (s, 1H),
7.06-7.02 (m, 2H), 6.98-6.92 (m, 3H), 6.84 (d, 2H), 6.75 (d,
2H),5.13 (d, 1H), 5.09 (s, 2H),4.73 (d, 1H), 4.53 (d, 1H),
4.31-4.28 (m, 4H), 4.27-4.21 (m, 2H), 4.20-4.08 (m, 2H), 3.89
(t, 2H), 3.83 (d, 1H), 3.80 (s, 3H), 3.77-3.71 (m, 2H), 3.68 (s,
1H), 3.30 (s, 1H), 2.90-2.81 (m, 2H), 2.31-2.21 (m, 2H),
1.37-1.19 (m, 4H), 1.02-0.88 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ: 153.39, 152.71, 138.24, 136.32, 134.04, 128.64,
128.35, 128.01, 127.87, 127.65, 127.39, 123.59, 122.65,
116.04, 115.51, 98.55, 79.32, 77.35, 74.64, 74.29, 72.69,
67.19, 64.48, 55.74, 47.36, 36.33, 29.56, 23.10. HRMS m/z
calcd. 923.4226 [M-PF6]+ for C54H59N4O10, found 923.4207.
D
D
D
-2-deoxy-2-phthalimido-6-{4-[3-(1-
Methylimdazoliumhexafluorophospho)propyloxy]phenyl}-β-
D
-glucopyranoside (2) a) Donor
equiv.) was dissolved in dry DCM (50 mL) in ice bath,
by adding CNCCl3 (6 mL) and DBU (0.6 mL). The
3 (6.30g, 12.79mmol, 3.50
followed
reaction was
stirred for 15min, directly concentrated and
purified via a short column on silica gel (PE:EA=5:1), giving a
yellow syrup (7.8 g, 96%), which was dried in vacuo for
next coupling; b) Acceptor 20 (6.88g, 3.65mmol, 1.0 equiv.)
was dried in vacuo, mixed with prepared intermediate in a),
and dissolved in dry DCM (40 mL) in ice bath. After stirred
for 10min, TfOH (32µL, 0.36mmol, 0.1 equiv.) was slowly
added. The reaction was kept for 30min with TLC
(DCM:MeOH=10:1) showing the absence of 20. The reaction
HPLC isocratic elution: MeCN:H2O (0.1% TFA)
(0-15min); purity: 99%.
=
75:25
N-Benzyl-N’-benzyloxycarbonyl-5-aminopentyl
3,6-O-di-
acetyl-2,4-O-dibenzyl-β-
D
-mannopyranosyl-(1→4)-3,6-O-di-
-glucopyranosyl-(1→4)-3-
benzyl-2-deoxy-2-phthalimido-β-
D
by adding Et3N, and
was warmed to RT, neutralized
General ILSOS separation
Purified
O-benzyl-2-deoxy-2-phthalimido-6-O-{4-[3-(1-
via
syrup as
Procedure, giving a yellowish
(10.15 g, 98%). 1H NMR (400 MHz, CDCl3) δ: 8.68 (s,
Methylimdazoliumhexafluorophospho)propyloxy]phenyl}-β-
2
D-glucopyranoside (19) a) Donor 4 (5.41g, 5.88 mmol, 1.6
1H), 7.76-7.46 (m, 7H), 7.45-7.00 (m, 68H), 7.00-6.55 (m, 15H),
5.49 (s, 1H), 5.31 (s, 1H), 5.21 (s, 1H), 5.17-5.03 (m, 3H),
5.00-4.72 (m, 8H), 4.70-4.24 (m, 23H), 4.20 (d, 2H), 4.15 (d,
2H), 4.10 (s, 1H), 4.05 (s, 3H), 4.00-3.72 (m, 18H), 3.72-3.52
(m, 10H), 3.48 (d, 4H), 3.36 (d, 1H), 3.31 (s, 1H), 3.13 (s, 6H),
2.93-2.76 (m, 2H), 2.27 (s, 2H), 2.09 (s, 3H), 1.83 (s, 3H),
1.26-1.15 (m, 4H), 0.88 (s, 2H). 13C NMR (100 MHz, CDCl3) δ:
170.09, 169.84, 153.01, 152.52, 138.79, 138.63, 138.59,
138.52, 138.32, 138.04, 138.02, 137.89, 137.85, 137.82,
137.79, 137.73, 136.85, 136.81, 136.78, 136.61, 136.59,
133.91, 133.81, 133.67, 131.56, 131.16, 129.80, 128.66,
128.53, 128.45, 128.38, 128.30, 128.27, 128.25, 128.21,
128.10, 127.94, 127.89, 127.80, 127.75, 127.67, 127.59,
127.48, 127.34, 126.96, 123.49, 123.35, 123.14, 122.62,
122.15, 118.97, 116.03, 115.13, 101.95, 99.65, 98.29, 98.15,
97.56, 81.06, 79.58, 78.13, 77.91, 77.69, 77.35, 75.03, 74.99,
74.72, 74.68, 74.52, 74.23, 74.17, 74.06, 73.65, 73.50, 73.33,
73.21, 72.40, 71.87, 71.22, 69.12, 68.72, 68.69, 68.36, 68.16,
67.05, 66.48, 64.26, 60.44, 56.52, 55.71, 52.43, 50.36, 47.29,
47.02, 46.03, 36.38, 29.61, 28.82, 27.55, 27.16, 22.92, 21.06,
20.79, 14.25, 8.74, 7.31. HRMS m/z calcd. 2685.1460 [M-PF6]+
for C160H166N5O33, found 2685.1705. HPLC gradient elution:
MeCN:H2O (0.1% TFA)= 95:5~100:0 (0-5min), 100:0 (5-20min);
purity: 80%.
equiv.) was dissolved in dry DCM (30mL) in ice bath, followed
by adding CNCCl3 (3 mL) and DBU (0.2 mL). The reaction was
kept for 30min with TLC (PE:EA=2:1) showing the absence of
4. The reaction was directly concentrated and purified via a
short column on silica gel (PE:EA=3:1), giving a yellow syrup
(5.71g, 91%), which was dried in vacuo for next coupling; b)
Acceptor
5 (4.0 g, 3.74 mmol, 1.0 equiv.) was dried in vacuo,
mixed with previously prepared intermediate in a) and
dissolved in dry DCM (50mL) in ice bath. After stirred for
10min, TfOH (34 µL, 0.37 mmol, 0.1 equiv.) was slowly added.
The reaction was kept for 30min with TLC (PE:EA =10:1)
showing the absence of 5. The reaction was neutralized by
adding Et3N and concentrated. Residue was purified via
General ILSOS separation Procedure, giving a yellowish syrup
1
as 19 (7.21 g, 96%). H NMR (400 MHz, CDCl3) δ: 8.65 (s, 1H),
7.79-7.59 (m, 4H), 7.49 (m, 4H), 7.40-7.16 (m, 30H), 7.14-7.02
(m, 3H), 6.96 (d, 2H), 6.86-6.63 (m, 13H), 5.26 (d, 1H), 5.07 (s,
2H), 4.95 (d, 1H), 4.87 (d, 2H), 4.81 (d, 1H), 4.75 (dd, 1H),
4.70-4.60 (m, 3H), 4.52 (dt, 5H), 4.33 (dd, 6H), 4.25-3.98 (m,
10H), 3.96-3.71 (m, 9H), 3.83 (s, 3H), 3.67-3.52 (m, 2H), 3.48
(dd, 1H), 3.37-3.33 (m, 2H), 3.15 (td, 4H), 2.91-2.74 (m, 1H),
2.35-2.22 (m, 2H), 1.93 (s, 3H), 1.84 (s, 3H), 1.27-1.21 (m, 4H),
0.88 (s, 2H). 13C NMR (100 MHz, CDCl3) δ: 170.85, 170.23,
153.06, 152.60, 138.92, 138.67, 138.54, 137.97, 137.88,
137.84, 136.52, 134.00, 133.73, 131.62, 128.65, 128.56,
128.52, 128.37, 127.98, 127.92, 127.84, 127.78, 127.62,
127.31, 126.97, 123.52, 122.63, 116.00, 115.24, 101.03, 98.23,
97.62, 79.24, 77.35, 76.11, 76.00, 74.87, 74.76, 74.70, 74.64,
74.57, 73.73, 73.40, 73.27, 73.16, 68.41, 68.25, 64.37, 63.23,
56.53, 55.78, 52.47, 47.31, 47.04, 36.33, 29.63, 28.87, 21.02,
20.73, 8.75, 7.28. HRMS m/z calcd 1820.7586 [M-PF6]+ for
N-Benzyl-N’-benzyloxycarbonyl-5-aminopentyl 3-O-benzyl-2
-deoxy-2-phthalimido-6-O-{4-[3-(1-
Methylimdazoliumhexafluorophospho)propyloxy]phenyl}-β-
D
-glucopyranoside (5) To a solution of 18 (4.89 g, 5.31 mmol,
1.0 equiv.) in MeCN (50 mL) was added 1-Methylimidazole
(1.27 mL, 15.93 mmol, 3.0 equiv.) and KPF6(1.17 g, 6.37 mmol,
1.2 equiv.). The reaction was refluxed o.n. with TLC
(PE:EA=1:1) showing the absence of 18. After cooling down,
the reaction was concentrated, re-dissolved in DCM, filtered
and concentrated. Residue was purified via General ILSOS
C106H110N5O23, found 1820.7593. HPLC gradient elution:
MeCN:H2O (0.1% TFA)
(10-15min); purity: 95%.
= 90:10~100:0 (0-10min), 100:0
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DOI: 10.1039/C8OB01046C
Journal Name COMMUNICATION
N-Benzyl-N’-benzyloxycarbonyl-5-aminopentyl2,4-O-di-
169.86, 138.88, 138.76, 138.71, 138.64, 138.43, 138.14,
138.08, 137.99, 137.91, 133.81, 133.79, 133.69, 133.67,
133.65, 133.63, 131.92, 131.65, 131.58, 128.69, 128.58,
128.52, 128.49, 128.45, 128.33, 128.30, 128.26, 128.19,
128.07, 128.00, 127.92, 127.89, 127.82, 127.74, 127.59,
127.48, 127.45, 127.20, 127.00, 126.90, 123.45, 123.33,
123.32, 123.27, 123.20, 123.14, 101.99, 99.81, 98.38, 98.28,
97.58, 81.41, 79.72, 78.20, 77.95, 77.81, 77.35, 76.98, 76.42,
76.11, 75.11, 75.01, 74.91, 74.69, 74.60, 74.47, 74.31, 74.17,
73.62, 73.41, 73.22, 72.39, 71.97, 71.90, 71.31, 69.43, 69.25,
68.81, 68.25, 67.17, 66.57, 61.01, 56.54, 55.84, 28.93, 22.99,
21.14, 20.84. HRMS m/z calcd 2488.0619 [M+NH4]+ for
C147H155N4O32, found 2488.0689.
benzyl-β-
2-phthalimido-β-
y-2-phthalimido-6-O-{4-[3-(1-Methylimdazoliumhexafluorop
hospho)propyloxy] phenyl}-β- -glucopyranoside (20) To a
D
-mannopyranosyl-(1→4)-3,6-O-di-benzyl-2-deoxy-
D
-glucopyranosyl-(1→4)-3-O-benzyl-2-deox
D
solution of 19 (6.67g, 3.39mmol, 1.0 equiv.) in MeOH/DCM
(v/v=2:1, 60 mL) was added MeONa (0.1 M in MeOH),
adjusting solution’s pH between 8~10. The reaction was kept
for 3h with TLC (DCM:MeOH=10:1) showing the completion
of de-acetylation. 1N HCla.q. was added to neutralize MeONa.
The solution was concentrated, re-dissolved in DCM, filtered
and concentrated, giving a yellow syrup as 20 (6.88 g, quant.).
1H NMR (400 MHz, CDCl3) δ: 8.62 (s, 1H), 7.80 (d, 1H), 7.68
(dd, 3H), 7.53 (s, 4H), 7.39-7.14 (m, 28H), 7.13-7.03 (m, 2H),
6.98 (d, 2H), 6.89 (s, 5H), 6.75 (dt, 6H), 5.28 (d, 1H), 5.07 (s,
1H), 4.99-4.92 (m, 1H), 4.92-4.85 (m, 2H), 4.80 (d, 1H), 4.62 (d,
1H), 4.58-4.44 (m, 5H), 4.36-4.26 (m, 4H), 4.26-4.14 (m, 4H),
4.08 (d, 2H), 4.02-3.97 (m, 1H), 3.90 (s, 2H), 3.87-3.71 (m, 7H),
3.68 (d, 2H), 3.60 (d, 3H), 3.48 (dd, 2H), 3.39 (dd, 3H), 3.12
(dd, 4H), 2.88-2.75 (m, 2H), 2.25 (s, 2H), 1.30-1.11 (m, 4H),
0.95-0.80 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 152.99,
152.61, 138.64, 138.43, 138.33, 138.29, 137.64, 136.50,
134.28, 134.22, 133.75, 131.58, 131.57, 128.70, 128.64,
128.57, 128.49, 128.29, 128.13, 128.08, 128.04, 128.01,
127.94, 127.93, 127.87, 127.81, 127.77, 127.65, 127.30,
127.17, 127.08, 126.98, 123.56, 123.22, 122.61, 115.94,
115.25, 101.25, 98.24, 97.56, 78.88, 78.43, 77.35, 76.58,
75.30, 74.75, 74.70, 74.60, 74.25, 73.69, 73.48, 68.04, 67.09,
64.35, 62.35, 56.42, 55.76, 52.48, 52.45, 52.42, 47.30, 46.86,
36.40, 30.38, 29.63, 28.85, 22.96, 8.75, 7.32. HRMS m/z calcd
1736.7375 [M-PF6]+ for C102H106N5O21, found 1736.7381. HPLC
Acknowledgements
This work was financially supported by the national Basic
Research Program of China (973 program, No.2012CB822101),
the National Key Technology R&D Program “New Drug
Innovation” of China (No.2012zx09502001-001) and NSFC
(No.21232002), and the State Key Laboratory of Natural and
Biomimetic Drugs.
Notes and references
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2
3
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Hetero-branched N-glycan core pentasaccharide was rapidly assembled on new ionic liquid
support in 10g scale.