Rapid and efficient synthesis of α(1-2)mannobiosides

Article abstract of DOI:10.1039/c6ob00083e

α(1,2)mannobiosides with different substituents at the reducing end have been synthesized by a common strategy using benzoyls as the permanent protecting groups and an acetyl as the orthogonal protecting group at position C2 of the glycosyl acceptor. The

Full text of DOI:10.1039/c6ob00083e

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Rapid and efficient synthesis of α(1-2)mannobiosides
José J. Reina,*a Antonio Di Maio, a Javier Ramos-Soriano,a Rute C. Figueiredo,b Javier Rojoa
Received 00th January 20xx,
Accepted 00th January 20xx
α(1,2)mannobiosides with different substituents at the reducing end have been synthesized by a common strategy using
benzoyls as permanent protecting groups and an acetyl as orthogonal protecting group at position C2 of the glycosyl
acceptor. The new synthetic strategy has been performed reducing remarkably the number of purification steps, the time
of the synthesis (less than 72 hours) and improving the overall yield at least three times respect to the best procedure
described in the literature at the moment. Additionally, this protecting group strategy is compatible with the presence
of azido groups and the use of the Cu catalyzed azide alkyne cicloaddiction (CuAAC) also called “click chemistry” to
conjugate the α(1-2)mannobiosides to different scaffolds for the preparation of mannosyl multivalent systems.
DOI: 10.1039/x0xx00000x
www.rsc.org/
required to clarify the different biological pathways in which this
receptor is involved. The main carbohydrate ligand recognized by
DC-SIGN is the high mannose glycan, (Man)9(GlcNAc)2, a branched
oligosaccharide containing mannose with α1,2-, α1,3-, α,1,6-, and
Introduction
High-mannose oligosaccharides are ubiquitous biologically β1,4-linkages. (Figure 1) Multiple copies of this glycan are present in
important molecules. They are known to participate in quality
several pathogen glycoproteins and specifically in the gp120
control and intracellular transportation of glycoproteins.1 envelope protein of HIV.
Furthermore, they are present at the surface of many pathogenic
microorganisms as viruses, bacteria, fungi and parasites, and they
are the target of the immune system cells, including macrophages
and dendritic cells.2 The interaction of high- mannose
oligosaccharides with animal lectins are of crucial importance for
the efficient operation of the innate immune system. Examples
include the mannose-binding lectin (MBL), Dendritic Cells Specific
ICAM-3 Grabbing Non-integrin (DC-SIGN), defensins and
macrophages mannose receptors (MR).3 Therefore, the glycan
structures on pathogen glycoproteins present in viral envelopes or
bacterial cell walls help to escape recognition by the immune
system, and the subsequent elimination or neutralization of the
Figure 1. Structure of High-mannose type glycans
pathogen.2 In particular, the group of van Kooyk in 2000
highlighted the relevance of DC-SIGN reporting the role that this
lectin plays in the pathogenesis of HIV-1.4 This virus targets DC-
SIGN, but escapes degradation in lytic compartments, thus using
DCs as a Trojan Horse to invade the host organism.4 In this context,
inhibition of DC-SIGN is currently considered as an interesting new
target for the design of anti-infective agents.5 Information at
molecular level concerning the mechanism by which this receptor
operates is scarce, thus effective modulators of DC-SIGN are also
The total synthesis of Man9 or (Man)9(GlcNAc)2 has been explored
for the past two decades;6 however, the complexity of this kind of
complex glycan structures prevent the accessibility to large
amounts required to address biological studies. Thus synthetic
glycan mimetics can be of great value for interrogating these
relevant biological interactions. The crystal structure of a complex
containing a Fab fragment of the gp120 antibody 2G12 and
(Man)9(GlcNAc)2 was published more than 10 years ago.7 The
resolved structure shows that the Manα1-2Man residues make 85%
of the protein contacts. Additionally, it is known that high density
arrays of unbranched Manα(1,2)Man bind to DC-SIGN almost as
effectively as the entire Man9 oligosaccharide.8 Based on this,
Manα1-2Man can be considered as an interesting fragment to
construct multivalent
systems mimicking
high-mannose
interactions. For this reason, a rapid and straightforward synthesis
of Manα1,2Man disaccharide conveniently functionalized in the
reducing end to facilitate their conjugation to multivalent scaffolds
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is of remarkable interest. The previously described approaches to Then, compounds 5 and 6 were treated with trimethyl orthoacetate
prepare α(1-2) mannobioside derivatives involved many reaction and a catalytic amount of camphorsulphonic acid (CSA) to form the
steps, including the classical protection-deprotection pathway to acetyl orthoester with the hydroxyl groups in positions C2 and C3.
prepare oligosaccharides,
with several purifications of the This orthoester was impossible to isolate due to the partial
intermediate products. These syntheses mean large time consume, hydrolysis of the orthoester functionality during the
high synthetic cost, and rend low overall yield of the final product. A chromatographic purification. The treatment of the orthoester
recent example describes an efficient one-step synthesis of α(1-2) intermediates with 1M HCl implied the partial hydrolysis to obtain
mannobioside using a polymerization-type strategy.9 This approach the hydroxyl groups at position C2 orthogonally protected with an
provides an excellent overall yield only when the linker used in the acetate group and with the hydroxyl groups in C3 and C4
reducting terminus is an alcohol with a particular length and unprotected (7 and 8).12 These compounds were finally benzoylated
substituents implying an important decrease of versatility of the with Bz2O, Et3N and a catalytic amount of 4-dimethylaminopyridine
synthesis. These disadvantages make difficult the current (DMAP) to generate the fully protective mannose derivatives 9 and
application of Manα1,2Man and compromise its use to prepare 10 with an acetyl group as orthogonal protecting group at position
multivalent glycoconjugates with potential anti-infective properties. C2. Finally, selective deprotection of this acetyl group at position C2
using 7% of HCl in methanol afforded mannoses 11 and 12 in good
Here, we present a very rapid, straightforward, versatile and high
yields.13 The use of 7% of HCl in methanol were the best conditions
yield synthesis of Manα1,2Man derivatives with -OMe, 2-azidoethyl
and S-tolyl functionalization in the reducing end. To achieve this
found to achieve the compromise of completing the reaction in less
than 24 hours and avoiding the partial hydrolysis of benzoyl esters
objective, a common orthogonal protection strategy was designed
present in the mannose derivatives. Both intermediates 11 and 12
employing benzoates as permanent protecting groups and
were used as acceptors for the synthesis of the
anacetate as orthogonal protecting group at positon C2 of the
α(1,2)mannobiosides. (Scheme 3)
glycosyl acceptor. The use of this protecting group strategy is
compatible with the presence of azido groups and the use of the
CuAAC (Cu catalyzed azide alkyne cycloaddition) also called “click
chemistry” to conjugate the α(1-2)mannobiosides to different
scaffolds.
Results and discussion
An efficient synthesis of α(1-2)mannobiosides can provide the
required materials to facilitate
a gram scale preparation of
multivalent systems opening the door to explore their biological
applications. The key step for a straightforward synthesis of these
disaccharides is a rapid and efficient strategy to obtain large
amounts of glycosyl donors and acceptors compatibles with the
methodology selected to the multivalent presentation of the final
oligosaccharides. For this aim, we selected as glycosyl donors the
per-acetylated and per-benzoylated mannose trichloroacetimidate
13 and 14 (scheme 3) and as glycosyl acceptors the mannoside
derivatives 11 and 12 (scheme 1). Our strategy starts from the
methyl and 2-azidoethyl mannopyranoside (3 and 4) that were
treated with BzCN at -40ºC and a catalytic amount of Et3N to
selectively protect the C6 hydroxyl group.10 This reaction was
regioselective and the primary alcohols of both mannose
derivatives 3 and 4 were selectively benzoylated with good yield
after chromatographic purification (61% for 5 and 71% for 6), only
small amount (less than 10%) of 2,6- and 3,6-benzoyl derivatives
were observed by TLC and verified by NMR spectroscopy. The
monobenzoylation step could be considered one of the key steps of
this synthetic strategy. The regioselective benzoylation of the
Scheme 1. Synthesis of Mannose derivatives 11 and 12.
This synthetic strategy to prepare mannose acceptors 11 and 12
implied 5 reaction steps and 4 purifications using silica gel flash
chromatography with an overall yield of 42 % in the case of the
OMe derivative 11 and 40% for the 2-azidoethyl derivative 12. In
the literature has been described many different strategies to
afford this kind of intermediates, using 1,2-O-ethylidene-β-D-
mannopyranosides and other approaches like benzyl/acetyl or
benzyl/Fmoc strategies.13-14 All these alternatives mean at least the
same number of reactions and purifications steps with and overall
yield of 25% in the best case.
It is important to highlight that the synthetic approach described in
primary alcohol using fully deprotected mannose has not been scheme 1 to obtain the glycosyl acceptors 11 and 12 presents an
important advantage: the conditions of the protection reactions are
all compatible to be carried out sequentially simply by removal of
the reaction solvent and a work up without chromatographic
purification of intermediate products. For these reason, we
afforded the sequence synthesis of 11 and 12 as described in
scheme 2. The preparation of intermediate 11 and 12 were
performed in only 28 hours with a single final chromatographic
done previously. The selective protection of primary alcohols in the
presence of secondary alcohols has been often addressed by the
use of high hindrance protecting groups as tert-butyldiphenylsilyl
ether (TBDPS).11 In our strategy, the use of silylethers is
incompatible with the deprotection conditions of the orthogonal
acetyl group at position C2 of the glycosyl donor.
2 | J. Name., 2012, 00, 1-3
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purification with 72% and 70% overall yields, respectively. This To explore the scope of the methodology described in this work as
consecutive strategy means a 30% increase in the yield over the an straightforward strategy to addressed the preparation of more
step-wise traditional synthetic strategy demonstrating that limiting complex oligosaccharides that present Manα1,2Man units in their
the number of purification steps produces an improvement in the structure, the S-tolyl mannose derivative 21 was prepared following
final overall yield. Additionally, the consecutive strategy also the consecutive synthetic procedure describes for compounds 11
introduces a significant reduction of the total cost and time of the and 12 and starting from the S-tolyl derivative 19. (Scheme 4)
synthesis of these key intermediates to achieve the preparation of Compound 20 was prepared from the S-tolyl derivative 1916 in less
the target molecule, the mannobioside. In fact, we have obtained a than 36 hours with 65% of yield using only one chromatographic
decrease of about 80% of time, allowing the preparation of these purification. Then, applying the methodology describe by Wong and
derivatives in a gram scale very easily in less than two days. co-workers,17 compound 20 was used simultaneously as a glycosyl
Moreover, this versatile approach allows different modifications to donor and acceptor to afford a self-glycosidation with N-Iodo
generate
a large number of mannose monosaccharides, for succinimide (NIS) and triflic acid (TfOH) at -40ºC providing the
example, the benzoyl groups could be substituted by benzyls or dimannoside 21 with 68% of yield. The dimannoside 21 is an
other kind of protecting groups.
excellent synthetic intermediate that could be used as donor or
acceptor to synthesize more complex oligosaccharides.
Scheme 2. Consecutive synthetic procedure to prepare 11 and 12.
At this stage, only the preparation of the glycosyl donors is
necessary to complete the synthesis of the disaccharides. α-1,2-
linked dimannosides 1 and 2 were synthesized with the α linkage
typically controlled by a participating neighboring group in the C2 of
the glycosyl donor. Two different glycosyl donors were selected,
per-acetylated and per-benzoylated trichloroacetimidates 13 and
14 (scheme 3). The disaccharides 15 and 16 were prepared by
reaction of the glycosyl donor 13 with the glycosyl acceptors 11 and
12 using trimethylsilyl triflate (TMSOTf) as promotor at 0 ºC with
moderate yields (46% and 59%, respectively). The moderate yield of
these glycosylations was due to the orthoester formation during the
reaction. In order to avoid this problem and to increase the yield of
the glycosylation step, per-benzoylated mannose 14 was used as
glycosyl donor.15 Using the same conditions (0.2 eq of TMSOTf),
disaccharides 17 and 18 were obtained in good yields (75% and
78%, respectively). Finally, the disaccharides 1 and 2 were prepared
by deprotection of acetyl and benzoyl groups using classical
Zempler conditions (NaOMe/MeOH) to afford the final compounds
1 and 2 in quantitative yields.
Scheme 4. (a) Consecutive synthesis of donor/acceptor 20; (b) Self-glycosidation of 20
to obtain the disaccharide 21.
Conclusions
In summary, we have completed a consecutive synthesis of three
α(1,2)mannobiosides, the methyl derivative 1, the 2-azidoethyl
derivative 2 and the S-tolyl derivative 21. The preparation of these
molecules have been achieved using a common strategy based on
benzoyls as permanent protecting groups and an acetyl as an
orthogonal protecting group at the C2 of the glycosyl acceptor.
Following this strategy, it has been reduced the purification steps
up to only two silica gel column chromatographies for every
disaccharide, minimizing the time spent to perform the synthesis of
these final compounds to less than 72 hours and improving the
overall yield at least three times respect to the best procedure
describe in the literature. This synthetic strategy allows the
preparation of α(1,2)dimannosides in gram scale reducing a lot the
cost of the synthesis. Additionally, the used of the ester strategy
(Benzoyl/acetyl) make the synthesis compatible with the 2-
azidoethyl spacer in the case of compound 2. This is fundamental
for the preparation of glycoconjugates by click chemistry reactions
using multivalent scaffolds. On the basis of this development, we
are preparing multivalent Manα1,2Man conjugates using the
compound 1 as ligand and we are synthetizing more complex
mannose oligosaccharides using the S-tolyl 21 derivative as
synthetic intermediate.
Scheme 3. Synthetic strategies to prepare the α(1,2)mannobiosides 1 and 2.
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3.34 (m, 2H, 2H8). 13C NMR (101 MHz, CDCl3) δ 167.1 (C=OBz),
133.2 (CBz), 129.7 (CHBz), 128.4 (CHBz), 100.0 (C1Man), 71.4 (C3Man or
C5Man), 71.0 (C3Man or C5Man), 70.5 (C2Man), 67.8 (C4Man), 66.5(C7), 64.6
(C6Man), 50.4 (C8). ESI-MS for C15H19N3O7; calcd: 353.1 M+; found:
376.2 [M+Na]+; ESI-HRMS for C15H19N3O7; calcd: 376.1121 [M+Na]+;
found: 376.1113 [M+Na]+.
Experimental
Materials and methods
All chemicals were obtained from Sigma-Aldrich and used without
further purification, unless otherwise noted. H and 13C NMR were
1
Synthesis
of
Methyl-2-O-acetyl-6-O-benzoyl-α-D-
recorded on Bruker Advance DPX 300, and DRX 400 MHz
spectrometers. Chemical shifts are in ppm with respect to
tetramethylsilane (TMS) using the manufacturer indirect
referencing method. 2D experiments (COSY and HSQC) were done
when necessary to assign the oligosaccharide spectra. Mass spectra
were carried out with an Esquire 6000 ESI-Ion Trap from Bruker
Daltonics.
mannopyranoside (7)
To a solution of methyl-6-O-benzoyl-α-D-mannopyranoside (5) (220
mg, 0.74 mmol) and CSA (35 mg, 0.15 mmol) in CH3CN (7 mL) was
added trimethyl orthoacetate (285 ꢀL, 2.22 mmol) and the reaction
was stirred at room temperature 1 hour. After that, the reaction
was quenched with Et3N (100 ꢀL) and the solvent was evaporated.
Then, the residue was dissolved in EtOAc (25 mL) and washed with
HCl 1M (25 mL), the organic phase was dried with anh. MgSO4 and
the solvent was evaporated. Finally, the residue was purified by
flash chromatography on silica gel (CH2Cl2 : MeOH, 50 : 1) to give
compound 7 as a colorless oil (215 mg, 85%). 1H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 7.6 Hz, 2H, 2HBz), 7.62 (t, J = 7.4 Hz, 1H, HBz),
7.48 (t, J = 7.6 Hz, 1H, 2HBz), 5.13 (dd, J = 3.5, 1.6 Hz, 1H, H2Man),
4.81 (dd, J = 12.2, 4.6 Hz, 1H, H6Man), 4.78 (d, J = 1.6 Hz, 1H, H1Man),
4.56 (dd, J = 12.3, 2.1 Hz, 1H, H6Man), 4.08 (dd, J = 9.7, 3.4 Hz, 1H,
H3Man), 3.96 (m, 1H, H5Man), 3.77 (t, J = 9.6 Hz, 1H, H4Man),3.43 (s, 3H,
OCH3), 2.11 (s, 3H, -OCOCH3). 13C NMR (101 MHz, CDCl3) δ 170.7
(C=OAc), 167.3 (C=OBz), 133.4 (CHBz), 129.8 (CHBz), 129.7 (CBz), 128.4
(CHBz), 98.7 (C1Man), 71.8 (C2Man), 70.6 (C5Man), 69.9 (C5Man), 67.9
(C3Man), 63.8 (C6Man), 55.2 (-OCH3), 20.9 (-OCOCH3). ESI-MS for
C16H20O8; calcd: 340.1 M+; found: 363.2 [M+Na]+; ESI-HRMS for
C16H20O8; calcd: 363.1056 [M+Na]+; found: 363.1045 [M+Na]+.
Synthetic procedures
Synthesis of Methyl-6-O-benzoyl-α-D-mannopyranoside (5)
To a solution of Methyl-α-D-mannopyranoside (3) (300 mg, 1.55
mmol) in DMF (10 mL) at -40 ºC were added dropwise a solution of
BzCN 1M in DMF (2 mL) and a catalytic amount of Et3N and the
reaction was stirred for 2 hours. After that, MeOH (4 mL) was added
to quench the excess of BzCN and the reaction was warmed up to
room temperature. Then, the solvent was evaporated and the
residue was purified by flash chromatography on silica gel (CH2Cl2 :
MeOH, 40 : 1) to give compound 5 as a colorless oil (280 mg, 61%).
1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.4, 1.3 Hz, 2H, 2HBz), 7.60
(tt, J = 7.6, 1.3 Hz, 1H, 1HBz), 7.47 (dd, J = 8.4, 1.3 Hz, 2H, 2HBz), 4.82
(dd, J = 12.2, 4.8 Hz, 1H, H6Man), 4.79 (d, J = 1.5 Hz, 1H, H1Man), 4.54
(dd, J = 12.1, 2.2 Hz, 1H, H6Man), 3.99 (dd, J = 3.4, 1.6 Hz, 1H, H2Man),
3.89 (dd, J = 9.1, 3.3 Hz, 1H, H3Man), 3.87 – 3.83 (m, 1H, H5Man), 3.73
(t, J = 9.5 Hz, 1H, H4Man), 3.42 (s, 3H, -OCH3). 13C NMR (101 MHz,
CDCl3) δ 167.2 (C=OBz), 133.2 (CHBz), 129.7 (CHBz), 128.4 (CHBz),
100.9 (C1Man), 71.6 (C5Man), 70.6 (C3Man), 70.5 (C2Man), 67.9 (C4Man),
64.6 (C6Man), 54.9 (OCH3). ESI-MS for C14H18O7; calcd: 298.1 M+;
found: 321.2 [M+Na]+; ESI-HRMS for C14H18O7; calcd: 321.0950
[M+Na]+; found: 321.0943 [M+Na]+.
Synthesis
of
2-Azidoethyl-2-O-acetyl-6-O-benzoyl-α-D-
mannopyranoside (8)
To a solution of 2-Azidoethyl-6-O-benzoyl-α-D-mannopyranoside
(6) (80 mg, 0.23 mmol) and CSA (5 mg, 0.02 mmol) in CH3CN (4 mL)
was added trimethyl orthoacetate (86 mL, 0.68 mmol) and the
reaction was stirred at room temperature 1 hour. After that, the
reaction was quenched with Et3N (50 ꢀL) and the solvent was
evaporated. Then, the residue was dissolved in EtOAc (25 mL) and
washed with HCl 1M (25 mL), the organic phase was dried with anh.
MgSO4 and the solvent was evaporated. Finally, the residue was
purified by flash chromatography on silica gel (CH2Cl2 : MeOH, 100 :
3) to give compound 8 as a colorless oil (63 mg, 70%). 1H NMR (400
MHz, CDCl3) δ 8.10 (dd, J = 8.3, 1.4 Hz, 2H, 2HBz), 7.61 (t, J = 7.2 Hz,
1H, HBz), 7.47 (t, J = 7.6 Hz, 1H, 2HBz), 5.16 (dd, J = 3.5, 1.6 Hz, 1H,
H2Man), 4.91 (d, J = 1.6 Hz, 1H, H1Man), 4.78 (dd, J = 12.1, 4.7 Hz, 1H,
H6Man), 4.59 (dd, J = 12.2, 2.2 Hz, 1H, H6Man), 4.12 (dd, J = 9.5, 3.5 Hz,
1H, H3Man), 3.96 (ddd, J = 9.9, 4.7, 2.2 Hz, 1H, H5Man), 3.91 (ddd, J =
10.6, 7.0, 3.6 Hz, 1H, H7), 3.82 (t, J = 9.7 Hz, 1H, H4Man), 3.66 (ddd, J =
10.5, 6.0, 3.4 Hz, 1H, H7), 3.44 (qdd, J = 13.3, 6.5, 3.5 Hz, 2H, 2H8),
2.11 (s, 3H, -OCOCH3). 13C NMR (101 MHz, CDCl3) δ 170.8 (C=OAc),
167.1 (C=OBz), 133.4 (CHBz), 129.8 (CHBz), 129.7 (CBz), 128.5 (CHBz),
97.8 (C1Man), , 76.7 (C2Man), 71.7 (C2Man), 71.1 (C5Man), 69.6 (C3Man),
Synthesis of 2-Azidoethyl-6-O-benzoyl-α-D-mannopyranoside (6)
To a solution of 2-Azidoethyl-α-D-mannopyranose (4) (100 mg, 0.40
mmol) in DMF (4 mL) at -40 ºC were added a solution of BzCN 1M in
DMF (480 ꢀL) and a catalytic amount of Et3N and the reaction was
stirred for 2 hours. After that, MeOH (1 mL) was added to quench
the excess of BzCN and the reaction was warmed up to room
temperature. Then, the solvent was evaporated and the residue
was purified by flash chromatography on silica gel (CH2Cl2 : MeOH,
20 : 1) to give compound 6 as a colorless oil (99 mg, 71%). 1H NMR
(400 MHz, CDCl3) δ 8.06 (d, J = 8.2 Hz, 2H, 2HBz), 7.58 (t, J = 7.8 Hz,
HBz), 7.44 (t, J = 7.7 Hz, 2HBz), 4.91(d, J = 1.6 Hz, 1H, H1Man) 4.75
(ddd, J = 12.2, 5.8, 2.9 Hz, 1H, H6Man), 4.58 (dt, J = 12.2, 1.8 Hz, 1H,
H6Man), 4.04 (dd, J = 3.4, 1.6 Hz, 1H, H2Man), 3.97-3.84 (m, 3H, H3Man
+
H5Man + H7) 3.80 (t, J = 9.4 Hz, 1H, H4Man), 3.67-3.59 (m, 1H, H7), 3.45-
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67.7 (C4Man), 66.8 (C7), 63.8 (C6Man), 50.5 (C8), 20.9 (-OCOCH3). ESI- (C=OBz), 133.4 (CHBz), 133.2 (CHBz), 133.0 (CHBz), 129.8 (CHBz), 129.7
MS for C17H21N3O8; calcd: 395.1 M+; found: 418.2 [M+Na]+; ESI- (CBz), 129.7 (CHBz), 129.6 (CHBz), 129.6 (CHBz), 129.5 (CBz), 129.0 (CBz),
HRMS for C17H21N3O8; calcd: 418.1226 [M+Na]+; found: 418.1219 128.8 (CHBz), 128.4 (CHBz), 128.3 (CHBz), 128.2 (CHBz), 97.5 (C1Man),
[M+Na]+.
69.7 (C2Man), 69.5 (C4Man), 69.1 (C5Man), 67.1 (C7), 66.8 (C3Man), 63.1
(C6Man), 50.3 (C8), 20.7 (-OCOCH3). ESI-MS for C31H29N3O10; calcd:
603.2 M+; found: 626.2 [M+Na]+; ESI-HRMS for C31H29N3O10; calcd:
626.1751 [M+Na]+; found: 626.1740 [M+Na]+.
Synthesis
of
Methyl-2-O-acetyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (9)
To a solution of Methyl-6-O-benzoyl-α-D-mannopyranoside (7) (177
mg, 0.52 mmol) in CH2Cl2 (10 mL) was subsequently added, Bz2O
(350 mg, 1.56 mmol), Et3N (220 ꢀL, 1.56 mmol) and 4-
Dimethylaminopyridine (4-DMAP) (7 mg, 0.01 mmol) and the
reaction was stirred at room temperature for 1 hour. Then, the
solvent was evaporated and the residue dissolved in EtOAc (25 mL).
The solution was washed with HCl 1M (25 mL), sat. NaHCO3 (25 mL)
and water (25 mL), the organic phase was dried over anh. MgSO4
and the solvent was evaporated. Finally, the residue was purified by
flash chromatography on silica gel (Hexane : EtOAc, 2 : 1) to give
compound 9 as a colorless oil (255 mg, 90%). 1H NMR (400 MHz,
CDCl3) δ 8.08 (d, J = 7.5, 2H, 2HBz), 7.97 (d, J = 7.5 Hz, 1H, 2HBz), 7.91
(d, J = 7.5, 2H, 2HBz), 7.60-7.29 (m, 9H, 9HBz), 5.92 (t, J = 10.0 Hz, 1H,
H4Man), 5.81 (dd, J = 10.0, 3.2 Hz, 1H, H3Man), 5.52 (dd, J = 3.2, 1.6 Hz,
1H, H2Man), 4.88 (d, J = 1.6 Hz, 1H, H1Man), 4.65 (dd, J = 12.2, 3.0 Hz,
1H, H6Man), 4.52 (dd, J = 12.0, 5.2 Hz, 1H, H6Man), 4.41 -4.37 (m, 1H,
H5Man), 3.53 (s, 3H, -OCH3), 2.17 (s, 3H, -OCOCH3). 13C NMR (75
MHz, CDCl3) δ 169.9 (C=OAc), 166.2 (C=OBz), 165.6 (C=OBz), 165.4
(C=OBz), 133.5 (C=OBz), 133.2(CHBz), 133.1 (CHBz), 129.8 (CHBz), 129.7
(CHBz), 129.2 (CBz), 129.0, (CHBz) 128.5 (CHBz), 128.4 (CHBz), 98.6
(C1Man), 69.9 (C2Man), 69.8 (C3Man), 68.7 (C5Man), 67.1 (C4Man), 63.4
(C6Man), 50.5 (-OCH3), 20.8 (-OCOCH3). ESI-MS for C30H28O10; calcd:
548.2 M+; found: 571.3 [M+Na]+; ESI-HRMS for C30H28O10; calcd:
571.1780 [M+Na]+; found: 571.1771 [M+Na]+.
Synthesis of Methyl-3,4,6-tri-O-benzoyl-α-D-mannopyranoside
(11)
To
a
solution of Methyl-2-O-acetyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (9) (244 mg, 0.445 mmol) in CH3CN (5 mL) was
added a solution of HCl 7 % in MeOH (10 mL) and the reaction was
stirred at room temperature for 24 hours. Then, the solvent was
evaporated and the residue dissolved in EtOAc (25 mL). The
solution was washed with a solution of sat. NaHCO3 (2 x 50 mL) and
water (50 mL). The organic phase was dried over anh. MgSO4 and
the solvent was evaporated to obtain compound 11 as a colorless
oil (200 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 6.9 Hz,
1H, 2HBz), 8.00 (d, J = 8.3, 1.6 Hz, 1H, 2HBz), 7.97 (d, J = 8.3, 1.6 Hz,
1H, 2HBz), 7.63-7.47 (m, 2H, 3 HBz), 7.48-7.34 (m, 6H, 6HBz), 5.96 (t, J
= 10.0 Hz, 1H, , H4Man), 5.70 (dd, J = 10.0, 3.1 Hz, 1H, H3Man), 4.92 (d,
J = 1.8 Hz, 1H, H1Man), 4.63 (dd, J = 12.0, 3.0 Hz, 1H, H6Man), 4.52 (dd,
J = 12.0, 5.5 Hz, 1H, , H6Man), 4.42-4.33 (m, 1H, H2Man + H5Man), 3.54
(s, 3H, -OCH3), 2.26 (d, J = 4.7 Hz, 1H, -OH). 13C NMR (101 MHz,
CDCl3) δ 166.2 (C=OBz), 165.6 (C=OBz), 165.5 (C=OBz), 133.4 (CHBz) ,
133.3 (CHBz), 133.1 (CHBz), 129.8 (CHBz), 129.8 (CHBz), 129.7 (CHBz),
129.2 (CHBz), 129.1 (CHBz), 128.4 (CHBz), 128.4 (CHBz), 128.3 (CHBz),
100.7 (C1Man), 72.6 (C3Man), 69.41 (C2Man or C5Man), 68.6 (C2Man or
C5Man), 67.0 (C4Man), 63.6 (C6Man), 55.38 (C-OCH3). ESI-MS for C28H26O9;
calcd: 506.2 M+; found: 529.3 [M+Na]+; ESI-HRMS for C28H26O9;
calcd: 529.1469 [M+Na]+; found: 529.1452 [M+Na]+.
Synthesis of 2-Azidoethyl-2-O-acetyl-3,4,6-tri-O-benzoyl-α-D-
Synthesis of 2-Azidoethyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (10)
mannopyranoside (12)
To a solution of 2-Azidoethyl-6-O-benzoyl-α-D-mannopyranoside
(8) (60 mg, 0.15 mmol) in CH2Cl2 (4 mL) was subsequently added
Bz2O (138 mg, 0.61 mmol), Et3N (85 ꢀL, 0.61 mmol) and 4-DMAP (3
mg, 0.02 mmol) and the reaction was stirred at room temperature
for 1 hour. Then, the solvent was evaporated and the residue
dissolved in EtOAc (20 mL). The solution was washed with HCl 1M
(20 mL), sat. NaHCO3 (20 mL) and water, the organic phase was
dried over anh. MgSO4 and the solvent was evaporated. Finally, the
residue was purified by flash chromatography on silica gel (Hexane :
EtOAc, 2 : 1) to give compound 10 as a colorless oil (81 mg, 90%).
1H NMR (300 MHz, CDCl3) δ 8.08 (d, J = 7.5, 2H, 2HBz), 7.97 (dd, J =
8.3, 1.4 Hz, 1H, 2HBz), 7.9 2 (d, J = 7.5, 2H, 2HBz), 7.69-7.31 (m, 9H,
9HBz), 5.96 (t, J = 9.9 Hz, 1H, H4Man), 5.83 (dd, J = 10.1, 3.3 Hz, 1H,
H3Man), 5.52 (dd, J = 3.3, 1.8 Hz, 1H, H2Man), 5.02 (d, J = 2.0 Hz, 1H,
H1Man), 4.65 (dd, J = 12.0, 2.4 Hz, 1H, H6Man), 4.60 -4.39 (m, 2H, H5Man
+ H6Man), 3.99 (ddd, J = 10.7, 7.2, 3.6 Hz, 1H, H7), 3.75 (ddd, J = 10.2,
5.9, 3.5 Hz, 1H, H7), 3.58 (ddd, J = 9.8, 6.5, 2.9 Hz, 1H, H8), 3.47(ddd,
J = 9.8, 6.5, 2.9 Hz, 1H, H8), 2.14 (s, 3H, -OCOCH3). 13C NMR (75
MHz, CDCl3) δ 169.8 (C=OAc), 166.0 (C=OBz), 165.4 (C=OBz), 165.3
To a solution of 2-Azidoethyl-2-O-acetyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (10) (64 mg, mmol) in CH3CN (1 mL) was added a
solution of HCl 7 % in MeOH (2 mL) and the reaction was stirred at
room temperature for 24 hours. Then the solvent was evaporated
and the residue dissolved in EtOAc (25 mL). The solution was
washed with a solution of sat. NaHCO3 (2 x 25 mL) and water (25
mL). The organic phase was dried over anh. MgSO4 and the solvent
was evaporated to obtain compound 12 as a colorless oil (49 mg,
90%). 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 6.9 Hz, 1H, 2HBz), 7.97
(d, J = 7.0 Hz, 2H, 2HBz), 7.94 (d, J = 7.0 Hz, 2H, 2HBz), 5.98 (t, J = 10.0
Hz, 1H, H4Man), 5.71 (dd, J = 10.0, 3.1 Hz, 1H, H3Man), 5.04 (d, J = 1.9
Hz, 1H, H1Man), 4.60 (dd, J = 12.0, 3.1 Hz, 1H, H6Man), 4.52 (dd, J =
12.0, 5.2 Hz, 1H, H6Man), 4.47-4.33 (m, 2H, H2Man + H4Man), 4.00 (ddd,
J = 10.4, 6.2, 3.9 Hz, 1H, H7), 3.74 (ddd, J = 10.4, 6.0, 3.7 Hz, 1H, H7),
3.61-3.39 (m, 2H, H8). 13C NMR (75 MHz, CDCl3) δ 166.6 (C=OBz),
166.0 (C=OBz), 133.7 (CHBz), 133.4 (CHBz), 130.2 (CHBz), 130.1 (CHBz),
130.0 (CHBz), 129.5 (CBz), 129.4 (CBz), 128.8 (CHBz), 128.8 (CHBz),
128.7 (CHBz), 100.2 (C1Man), 72.8 (C3Man), 69.5 (C2Man or C5Man), 69.4
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C6OB00083E
ARTICLE
Journal Name
(C2Man or C5Man), 67.4 (C4Man or C7), 67.3 (C4Man or C7), 63.9 (C6Man), trimethyl orthoacetate (2.60 mL, 21.63 mmol) and the reaction was
50.8 (C8). ESI-MS for C29H27N3O9; calcd: 561.2 M+; found: 583.2 stirred at room temperature 1 hour. After that, the reaction was
[M+Na]+; ESI-HRMS for C29H27N3O9; calcd: 584.1645 [M+Na]+; quenched with Et3N (1 mL) and the solvent was evaporated. Then,
found: 583.1636 [M+Na]+.
the residue was dissolved in EtOAc (200 mL) and washed with HCl
1M (200 mL), the organic phase was dried with anh. MgSO4 and the
solvent was evaporated. To the resulting mixture containing 2-
Azidoethyl 2-O-acetyl-6-O-benzoyl-α-D-mannopyranoside (8) in
CH2Cl2 (100 mL) was subsequently added, Bz2O (6.5 g, 28.92 mmol),
Et3N (4 mL, 28.92 mmol) and 4-DMAP (104 mg, 0.80 mmol) and the
reaction was stirred at room temperature for 1 hour. Then, the
solvent was evaporated and the residue pure with EtOAc (200 mL).
The solution was washed with HCl 1M (250 mL), sat. NaHCO3 (250
mL) and water (250 mL), the organic phase was dried over anh.
MgSO4 and the solvent was evaporated. Finally, to the residue
containing the 2-Azidoethyl 2-O-acetyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (10) in CH3CN (40 mL) was added a solution of
HCl 7 % in MeOH (200 mL) and the reaction was stirred at room
temperature for 24 hours. Then the solvent was evaporated and the
residue dissolved in EtOAc (250 mL). The solution was washed with
a solution of sat. NaHCO3 (2 x 500 mL) and water (500 mL). The
organic phase was dried over anh. MgSO4 and the solvent was
evaporated. The residue was purified by flash chromatography on
silica gel (Hexane : EtOAc, 3 : 1) to obtain compound 12 as a
transparent oil (2.84 g, 70%).
Consecutive
synthesis
of
Methyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (11)
To a solution of Methyl α-D-mannopyranose (3) (1.5 g, 7.72 mmol)
in DMF (80 mL) at -40 ºC were added dropwise a solution of BzCN
(1.21 g, 9.26 mmol) in DMF (20 mL) and a catalytic amount of Et3N
and the reaction was stirred for 2 hours. After that, MeOH (40 mL)
was added to quench the excess of BzCN and the reaction was
warmed until room temperature. Then, the solvent was
evaporated. After being dissolved in CH3CN (80 mL), to the resulting
mixture containing the Methyl 6-O-benzoyl-α-D-mannopyranoside
(5) were added CSA (361 mg, 1.55 mmol) and trimethyl
orthoacetate (2.95 mL, 23.16 mmol) and the reaction was stirred at
room temperature 1 hour. After that, the reaction was quenched
with Et3N (1.5 mL) and the solvent was evaporated. Then, the
residue was dissolved in EtOAc (200 mL) and washed with HCl 1M
(200 mL), the organic phase was dried with anh. MgSO4 and the
solvent was evaporated. To the resulting mixture containing 2-
Methyl 2-O-acetyl-6-O-benzoyl-α-D-mannopyranoside (7) in CH2Cl2
(100 mL) was subsequently added, Bz2O (7.0 g, 30.88 mmol), Et3N
(4.3 mL, 30.88 mmol) and 4-DMAP (104 mg, 0.80 mmol) and the
reaction was stirred at room temperature for 1 hour. Then, the
solvent was evaporated and the residue dissolved EtOAc (200 mL).
The solution was washed with HCl 1M (250 mL), sat. NaHCO3 (250
Synthesis
of
Methyl
O-(2,3,4,6-tetra-O-acetyl-α-D-
mannopyranosyl)-(1→2)-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (15)
mL) and water (250 mL), the organic phase was dried over anh. A mixture of the acceptor 11 (150 mg, 0.296 mmol) and the donor
MgSO4 and the solvent was evaporated. Finally, to the residue 13 (219 mg, 0.445 mmol) was co-evaporated from toluene three
times. Powdered and activated 4 Å molecular sieves were added,
and the mixture was kept under vacuum for few hours and then
dissolved in CH2Cl2 (10 mL). The mixture was cooled to -0 ºC for 15
containing
the
Methyl
2-O-acetyl-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (9) in CH3CN (40 mL) was added a solution of HCl
7 % in MeOH (200 mL) and the reaction was stirred at room
temperature for 24 hours. Then the solvent was evaporated and the min, followed by the addition of TMSOTf (13 ꢀL, mmol, 0.059
residue dissolved in EtOAc (250 mL). The solution was washed with mmol), and stirred for 30 min at 0 ºC. The reaction was quenched
a solution sat. NaHCO3 (2 x 500 mL) and water (500 mL). The by the addition of Et3N, filtered over a pad of celite and dried under
organic phase was dried over anh. MgSO4 and the solvent was vacuum. The crude was purified by flash column chromatography
evaporated. The residue was purified by flash chromatography on on silica gel (CH2Cl2-MeOH, 100:1) to obtain 15 as an white solid
silica gel (Hexane : EtOAc, 3 : 1) to obtain compound 11 as a (114 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 8.15-8.07 (m, 4H, 4HBz),
colorless oil (2.81 g, 72%).
8.04 (d, J = 7.0 Hz, 2H, 2HBz), 8.02 (d, J = 7.0 Hz, 2H, 2HBz), 8.00-7.95
(m, 4H, 4HBz), 7.90 (d, J = 6.9 Hz, 2H, 2HBz), 7.65-7.30 (m, 21H,
21HBz), 6.12-6.05 (m, 2H, H3ManB + H4ManB), 6.02 (t, J = 9.9 Hz, 1H,
H4ManA), 5.94 (dd, J = 2.3, 1.8 Hz, 1H, H2ManB), 5.91 (dd, J = 9.9, 3.2
Hz, 1H, H3ManA), 5.29 (d, J = 1.8 Hz, 1H, H1ManB), 5.09 (d, J = 1.8 Hz,
1H, H1ManA), 4.73-4.64 (m, 3H, H5ManB + H6ManB + H6ManA), 4.60 (dd, J =
12.2, 5.5 Hz, 1H, H6ManA), 4.50 (dd, J = 12.0, 5.3 Hz, 1H, H6ManB), 4.41
(dd, J = 2.6, 1.8 Hz, H2ManA), 4.41-4.35(m, 1H, H5ManA), 3.42 (s, 3H, -
OMe). 13C NMR (101 MHz, CDCl3) δ 166.4 (C=OBz), 166.1 (C=OBz),
165.6 (C=OBz), 165.3 (C=OBz), 165.0 (C=OBz), 165.0 (C=OBz), 133.5
(CHBz), 133.4 (CHBz), 133.3 (CHBz), 133.3 (CHBz), 133.1 (CHBz), 133.0
(CHBz), 130.0 (CHBz), 130.0 (CHBz), 129.9 (CHBz), 129.8 (CHBz), 129.8
(CHBz), 129.7 (CHBz), 129.2 (CBz), 129.1 (CBz), 128.9 (CBz), 128.8 (CBz),
128.5 (CHBz), 128.5 (CHBz), 128.4 (CHBz), 128.4 (CHBz), 128.3 (CHBz),
Consecutive synthesis of 2-Azidoethyl-3,4,6-tri-O-benzoyl-α
-D-mannopyranoside (12)
To a solution of 2-Azidoethyl-α-D-mannose (4) (1.8 g, 7.23 mmol) in
DMF (80 mL) at -40 ºC were added dropwise a solution of BzCN
(1.14 g, 8.68 mmol) in DMF (20 mL) and a catalytic amount of Et3N
and the reaction was stirred for 2 hours. After that, MeOH (40 mL)
was added to quench the excess of BzCN and the reaction was
warmed until room temperature. Then, the solvent was
evaporated. After being dissolved in CH3CN (80 mL), to the resulting
mixture
containing
the
2-Azidoethyl-6-O-benzoyl-α-D-
mannopyranoside (6) were added CSA (335 mg, 1.45 mmol) and
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00083E
Journal Name
ARTICLE
99.6 (C1ManA), 99.6 (C1ManB), 76.9 (C2ManA), 70.8, 70.1, 69.8, 69.7, crude was purified by flash column chromatography on silica gel
68.8, 67.6, 67.0, 63.8 (C6ManA), 63.1 (C6ManB), 55.2(C-OCH3). ESI-MS for (CH2Cl2-MeOH, 100:1) to obtain 17 as an white solid (97 mg, 75 %).
C42H44O18; calcd: 836.2 M+; found: 859.3 [M+Na]+; ESI-HRMS for 1H NMR (400 MHz, CDCl3) δ 8.15-8.07 (m, 4H, 4HBz), 8.04 (d, J = 7.0
C42H44O18; calcd: 859.2425 [M+Na]+; found: 859.2413 [M+Na]+.
Hz, 2H, 2HBz), 8.02 (d, J = 7.0 Hz, 2H, 2HBz) δ 8.00-7.95 (m, 4H, 4HBz),
7.90 (d, J = 6.9 Hz, 2H, 2HBz), 7.65-7.30 (m, 21H, 21HBz), 6.12-6.05
(m, 2H, H3ManB + H4ManB), 6.02 (t, J = 9.9 Hz, 1H, H4ManA), 5.94 (dd, J =
2.3, 1.8 Hz, 1H, H2ManB), 5.91 (dd, J = 9.9, 3.2 Hz, 1H, H3ManA), 5.29 (d,
J = 1.8 Hz, 1H, H1ManB), 5.09 (d, J = 1.8 Hz, 1H, H1ManA), 4.73-4.64 (m,
3H, H5ManB + H6ManB + H6ManA), 4.60 (dd, J = 12.2, 5.5 Hz, 1H, H6ManA),
4.50 (dd, J = 12.0, 5.3 Hz, 1H, H6ManB), 4.41 (dd, J = 2.6, 1.8 Hz,
H2ManA), 4.41-4.35(m, 1H, H5ManA), 3.42 (s, 3H, -OMe). 13C NMR (101
MHz, CDCl3) δ 166.4 (C=OBz), 166.1 (C=OBz), 165.6 (C=OBz), 165.3
(C=OBz), 165.0 (C=OBz), 165.0 (C=OBz), 133.5 (CHBz), 133.4 (CHBz),
133.3 (CHBz), 133.3 (CHBz), 133.1 (CHBz), 133.0 (CHBz), 130.0 (CHBz),
130.0 (CHBz), 129.9 (CHBz), 129.8 (CHBz), 129.8 (CHBz), 129.7 (CHBz),
129.2 (CBz), 129.1 (CBz), 128.9 (CBz), 128.8 (CBz), 128.5 (CHBz), 128.5
(CHBz), 128.4 (CHBz), 128.4 (CHBz), 128.3 (CHBz), 99.6 (C1ManA), 99.6
(C1ManB), 76.9 (C2ManA), 70.8, 70.1, 69.8, 69.7, 68.8, 67.6, 67.0, 63.8
(C6ManA), 63.1 (C6ManB), 55.2 (C-OCH3). ESI-MS for C62H52O18; calcd:
1084.3 M+; found: 1107.3 [M+Na]+; ESI-HRMS for C62H52O18; calcd:
1107.3051 [M+Na]+; found: 1107.3039 [M+Na]+.
Synthesis of 2-Azidoethyl O-(2,3,4,6-tetra-O-acetyl-α-D-
mannopyranosyl)-(1→2)-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (16)
A mixture of the acceptor 12 (120 mg, 0.214 mmol) and the donor
13 (158 mg, 0.321 mmol) was co-evaporated from toluene three
times. Powdered and activated 4 Å molecular sieves were added,
and the mixture was kept under vacuum for few hours and then
dissolved in CH2Cl2 (8 mL). The mixture was cooled to 0 ºC for 15
min, followed by the addition of TMSOTf (8,5 ꢀL, mmol, 0.040
mmol), and stirred for 30 min at 0 ºC. The reaction was quenched
by the addition of Et3N, filtered over a pad of celite and dried under
vacuum. The crude was purified by flash column chromatography
on silica gel (CH2Cl2-MeOH, 100:1) to obtain 16 as a white solid (112
mg, 59%). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.1 Hz, 2H, 2HBz),
7.98 (d, J = 7.1 Hz, 2H, 2HBz), 7.95 (d, J = 7.0 Hz, 2H, 2HBz), 7.68-6.99
(m, 9H, 9HBz), 5.94 (t, J = 9.9 Hz, 1H, H4ManA), 5.84 (dd, J = 9.9, 3.2 Hz,
1H, H4ManA), 5.49-5.43 (m, 2H, H2ManB + H3ManB), 5.26 (t, J = 9.5 Hz, 1H,
H4ManB), 5.15 (d, J = 1.9 Hz, 1H, H1ManA), 4.98 (d, J = 1.5 Hz, 1H,
H1ManB), 4.63 (dd, J = 12.2, 3.0 Hz, 1H, H6ManA), 4.52 (dd, J = 12.1, 5.4
Hz, 1H, H6ManA), 4.41 (ddd, J = 10.1, 5.4, 2.9 Hz, 1H, H5ManA), 4.34 (dd,
J = 3.2, 1.9 Hz, 1H, H2ManA), 4.25 (dd, J = 11.9, 5.4 Hz, 1H, H6ManB),
4.17 (ddd, J = 12.1, 7.4, 3.3 Hz, 1H, H5ManB), 4.11 (dd, J = 11.9, 2.5 Hz,
1H, H6ManB), 4.01 (dt, J = 10.3, 4.7 Hz, 1H, H7), 3.82-3.72 (m, 1H, H7),
3.54 (t, J = 5.0 Hz, 2H, H8), 2.10 (s, 3H, -OCOCH3), 2.06 (s, 3H, -
OCOCH3), 2.04 (s, 3H, -OCOCH3), 2.01 (s, 3H, -OCOCH3). 13C NMR
Synthesis
of
2-Azidoethyl
O-(2,3,4,6-tetra-O-benzoyl-α-D-
mannopyranosyl)-(1→2)-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (18)
A mixture of the acceptor 12 (250 mg, 0.440 mmol) and the donor
14 (494 mg, 0.670 mmol) was co-evaporated from toluene three
times. Powdered and activated 4 Å molecular sieves were added,
and the mixture was kept under vacuum for few hours and then
dissolved in CH2Cl2 (12 mL). The mixture was cooled to 0 ºC for 15
(101 MHz, CDCl3) δ 170.51 (C=OAc), 169.80 (C=OAc), 169.48 (C=OAc), min, followed by the addition of TMSOTf (20 ꢀL, mmol, 0.088
169.42 (C=OAc), 166.22 (C=OBz), 165.50 (C=OBz), 165.19 (C=OBz), mmol), and stirred for 30 min at 0 ºC. The reaction was quenched
133.43 (CHBz), 133.32 (CHBz), 133.02 (CHBz), 129.92 (CHBz), 129.86 by the addition of Et3N, filtered over a pad of celite and dried under
(CHBz), 129.70 (CHBz), 128.97 (CBz), 128.82 (CBz), 128.55 (CHBz), vacuum. The crude was purified by flash column chromatography
128.47 (CHBz), 128.36 (CHBz), 99.46 (C1ManB), 98.65 (C1ManA), 76.50 on silica gel (CH2Cl2-MeOH, 100:1) to obtain 18 as an white solid
(C2ManA), 70.62 (C3ManA), 69.30 (C2ManB), 69.2 (C5ManB), 69.1 (C5ManA), (396 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.3 Hz, 2H,
68.8 (C3ManB), 67.2 (C7), 67.1 (C4ManA), 66.3 (C4ManB), 63.6 (C6ManA), 2HBz), 8.09 (d, J = 7.3 Hz, 2H, 2HBz), 8.06 (d, J = 7.3 Hz, 2H, 2HBz) δ
62.6 (C6ManB), 50.4 (C8), 20.70 (-OCOCH3), 20.67 (-OCOCH3). ESI-MS 8.03-7.95 (m, 6H, 4HBz), 7.91 (d, J = 7.6 Hz, 2H, 2HBz), 7.65-7.29 (m,
for C43H45N3O18; calcd: 891.3 M+; found: 914.3 [M+Na]+; ESI-HRMS 21H, 21HBz), 6.15-6.02 (m, 3H, H4ManA +H3ManB + H4ManB), 5.97-5.90
for C43H45N3O18
[M+Na]+.
;
calcd: 914.2596 [M+Na]+; found: 914.2590 (m, 2H, H2ManB+ H3ManA), 5.31 (d, J = 1.8 Hz, 1H, H1ManB), 5.24 (d, J =
1.8 Hz, 1H, H1ManA), 4.74-4.60 (m, 3H, H5ManB + H6ManB + H6ManA), 4.53
(dd, J = 12.0, 4.9 Hz, 1H, H6ManA), 4.49 (m, 2H, H2ManA + H6ManB), 3.91
Synthesis
of
Methyl
O-(2,3,4,6-tetra-O-benzoyl-α-D-
(ddd, J = 10.5, 6.7, 3.8 Hz 1H, H7), 3.59 (ddd, J = 10.2, 6.0, 3.5 Hz 1H,
H7), 3.52-3.37 (m, 2H, H8) 13C NMR (101 MHz, CDCl3) δ 166.3
(C=OBz), 166.1 (C=OBz), 165.6 (C=OBz), 165.3 (C=OBz), 165.1 (C=OBz),
164.9 (C=OBz), 133.5 (CHBz), 133.4 (CHBz), 133.3 (CHBz), 133.3 (CHBz),
133.1 (CHBz), 133.1 (CHBz), 130.0 (CHBz), 130.0 (CHBz), 129.9 (CHBz),
129.8 (CHBz), 129.8 (CHBz), 129.7 (CHBz), 129.2 (CBz), 129.0 (CBz),
128.8 (CBz), 128.6 (CBz), 128.5 (CHBz), 128.5 (CHBz), 128.4 (CHBz),
128.4 (CHBz), 128.3 (CHBz), 99.7 (C1ManA), 98.7 (C1ManB), 76.9 (C2ManA),
70.6, 70.1, 69.8, 69.7, 69.2, 67.5, 67.0, 66.9, 63.7 (C6ManA), 63.1
(C6ManB), 50.3(C8). ESI-MS for C63H53N3O18; calcd: 1139.3 M+; found:
mannopyranosyl)-(1→2)-3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (17)
A mixture of the acceptor 11 (60 mg, 0.119 mmol) and the donor 14
(105 mg, 0.142 mmol) was co-evaporated from toluene three times.
Powdered and activated 4 Å molecular sieves were added, and the
mixture was kept under vacuum for few hours and then dissolved in
CH2Cl2 (5 mL). The mixture was cooled to 0 ºC for 15 min, followed
by the addition of TMSOTf (4,5 ꢀL, mmol, 0.024 mmol), and stirred
for 30 min at 0 ºC. The reaction was quenched by the addition of
Et3N, filtered over a pad of celite and dried under vacuum. The
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DOI: 10.1039/C6OB00083E
ARTICLE
Journal Name
1162.5 [M+Na]+; ESI-HRMS for C63H53N3O18
[M+Na]+; found: 1139.3212 [M+Na]+
;
calcd: 1162.3222 1H NMR (400 MHz, D2O) δ 5.08 (d, J = 1.8 Hz, 1H, H1ManB), 4.95 (d, J
= 1.9 Hz, 1H, H1ManA), 3.99 (dd, J = 3.4, 1.8 Hz, 1H, H2ManB), 3.92 (dd, J
= 3.3, 1.8 Hz, 1H, H2ManA), 3.89-3.74 (m, 4H, H3ManA + H3ManB + H6ManA
H4ManA+ H7), 3.73-3.50 (m, 7H, H4ManB + H5ManA + H5ManB + H6ManA
+
+
Synthesis
of
Methyl
α-D-mannopyranosyl)-(1→2)-α-D-
mannopyranoside (1)
2H6ManB+ H7), 3.49-3.35 (m, 2H, H8); 13C NMR (101 MHz, D2O) δ
102.3 (C1ManB),, 98.2 (C6ManA),, 78.6 (C2ManB), 73.3 (C5ManB), 72.9
(C5ManA), 70.3 (C3ManB), 70.0 (C3ManA),, 69.9 (C2ManB),, 66.9 (C4ManB),,
66.9 (C4ManA), 66.4 (C7), 61.1(C6ManA), 60.9 (C6ManB), 50.2 (C8); ESI-
MS for C14H25N3O11; calcd: 411.1 M+; found: 434.2 [M+Na]+; ]+; ESI-
HRMS for C14H25O11N3; calcd: 434.1381 [M+Na]+; found: 434.1372
[M+Na]+.
From 15. To a solution of 15 (100 mg, 0.119 mmol) in dry methanol,
under nitrogen at room temperature, was added a 1M solution of
sodium methoxide in MeOH (2 equiv.) and the reaction was stirred
for 1 hour. Then, the reaction mixture was neutralized with
Amberlite IRA 120-H+ resin. The resin was filtered off and the
filtrate was concentrated under reduce pressure. The crude was
diluted in H2O (10 mL) washed with CH2Cl2 (10 mL) and the aqueous
phase was lyophilized to obtain 1 as a white solid (42 mg, quant.)
Consecutive synthesis of S-Tolyl 3,4,6-tri-O-benzoyl-α-D-
mannopyranoside (20)
To a solution of S-Tolyl α-D-mannopyranose (19)14 (1.5 g, 5.24
mmol) in DMF (50 mL) at -40 ºC were added dropwise a solution of
BzCN (0.9 g, 8.68 mmol) in DMF (20 mL) and a catalytic amount of
Et3N and the reaction was stirred for 2 hours. After that, MeOH (30
mL) was added to quench the excess of BzCN and the reaction was
warmed up to room temperature. Then, the solvent was
evaporated. After being dissolved in CH3CN (50 mL), to the resulting
mixture containing the 6-O-benzoyl derivative were added CSA
(364 mg, 1.57 mmol) and trimethyl orthoacetate (2.0 mL, 15.7
mmol) and the reaction was stirred at room temperature 1 hour.
After that, the reaction was quenched with Et3N (1 mL) and the
solvent was evaporated. Then, the residue was dissolved in EtOAc
(200 mL) and washed with HCl 1M (200 mL), the organic phase was
dried with anh. MgSO4 and the solvent was evaporated. To the
resulting mixture containing 2-O-acetyl-6-O-benzoyl derivative in
CH2Cl2 (60 mL) was subsequently added, Bz2O (4.75 g, 20.96 mmol),
Et3N (3 mL, 20.96 mmol) and 4-DMAP (104 mg, 0.80 mmol) and the
reaction was stirred at room temperature for 1 hour. Then, the
solvent was evaporated and the residue pure with EtOAc (150 mL).
The solution was washed with HCl 1M (200 mL), sat. NaHCO3 (200
mL) and water (200 mL), the organic phase was dried over anh.
MgSO4 and the solvent was evaporated. Finally, to the residue
containing the 2-O-acetyl-3,4,6-tri-O-benzoyl derivative in CH3CN
(40 mL) was added a solution of HCl 7 % in MeOH (150 mL) and the
reaction was stirred at room temperature for 24 hours. Then the
solvent was evaporated and the residue dissolved in EtOAc (200
mL). The solution was washed with a solution of sat. NaHCO3 (2 x
300 mL) and water (300 mL). The organic phase was dried over anh.
MgSO4 and the solvent was evaporated. The residue was purified by
flash chromatography on silica gel (Hexane : EtOAc, 4 : 1) to obtain
compound 20 as a white solid (2.04 g, 65%). 1H NMR (400 MHz,
CDCl3) δ 8.04-7.99 (m, 6H, 6HBz), 7.62-7.52 (m, 3H, 3HBz), 7.50-7.37
(m, , 8H, 6HBz + 2HTolyl), 5.98 (t, J = 10.0 Hz, 1H, , H4Man), 5.69 (dd, J =
9.9, 3.0 Hz, 1H, H3Man), 5.64 (d, J = 1.6 Hz, 1H, H1Man), 4.98 (ddd, J =
9.6, 6.0, 3.0 Hz, 1H, H5Man), 4.65-4.55 (m, 3H, H2Man + 2H6Man), 2.54
(s, 3H, CH3Tolyl), 13C NMR (101 MHz, CDCl3) δ 166.2 (C=OBz), 165.6
(C=OBz),138.1(CTolyl) 133.5 (CHBz) , 133.4 (CHBz), 133.0 (CHBz), 132.3
(CHTolyl), 130.0 (CHTolyl), 129.9 (CHBz), 129.8 (CHBz), 129.7 (CHBz)
129.1 (CHBz), 129.0 (CHBz), 129. (CTol) 128.5 (CHBz), 128.4 (CHBz),
From 17. To a solution of 17 (90 mg, 0.081) in dry methanol, under
nitrogen at room temperature, was added a 1M solution of sodium
methoxide in MeOH (2 equiv.) and the reaction was stirred for 1
hour. Then, the reaction mixture was neutralized with Amberlite
IRA 120-H+ resin. The resin was filtered off and the filtrate was
concentrated under reduce pressure. The crude was diluted in H2O
(10 mL) washed with CH2Cl2 (10 mL) and the aqueous phase was
lyophilized to obtain 1 as a white solid (29 mg, quant.)
1H NMR (400 MHz, D2O) δ 4.95 (d, J = 1.8 Hz, 1H, H1ManB), 4.92 (d, J
= 2.0 Hz, 1H, H1ManB), 3.99 (dd, J = 3.3, 1.8 Hz, 1H, H2ManB), 3.88 (dd, J
= 3.3, 1.8 Hz, 1H, H2ManA), 3,85-375 (m, 4H, H3ManA + H3ManB + H6ManA
H4ManA), 3.74-3.50 (m, 6H, H4ManB + H5ManA + H5ManB + H6ManA
+
+
2H6ManB), 3,33 (s, 3H, -OMe); 13C NMR (101 MHz, D2O) δ 102.3
(C1ManB),, 99.3 (C6ManA),, 78.5 (C2ManB), 73.2 (C5ManB), 72.5 (C5ManA),
70.3 (C3ManB),, 70.3 (C3ManA),, 69.9 (C2ManB),, 66.9 (C4ManB),, 66.8
(C4ManA), 61.1(C6ManA), 60.9 (C6ManB),
54.8 (C-OCH3); ESI-MS for
C13H24O11; calcd: 356.1 M+; found: 379.2 [M+Na]+; ESI-HRMS for
C13H24O11; calcd: 379.1211 [M+Na]+; found: 379.1204 [M+Na]+.
Synthesis of 2-Azidoethyl α-D-mannopyranosyl)-(1→2)-α-D-
mannopyranoside (2)
From 16. To a solution of 16 (100 mg, 0.112 mmol) in dry methanol,
under nitrogen at room temperature, was added a 1M solution of
sodium methoxide in MeOH (2 equiv.) and the reaction was stirred
for 1 hour. Then, the reaction mixture was neutralized with
Amberlite IRA 120-H+ resin. The resin was filtered off and the
filtrate was concentrated under reduce pressure. The crude was
diluted in H2O (10 mL) washed with CH2Cl2 (10 mL) and the aqueous
phase was lyophilized to obtain 2 as a white solid (46 mg, quant.)
From 18. To a solution of 18 (390 mg, 0.342 mmol) in dry methanol,
under nitrogen at room temperature, was added a 1M solution of
sodium methoxide in MeOH (2 equiv.) and the reaction was stirred
for 1 hour. Then, the reaction mixture was neutralized with
Amberlite IRA 120-H+ resin. The resin was filtered off and the
filtrate was concentrated under reduce pressure. The crude was
diluted in H2O (10 mL) washed with CH2Cl2 (10 mL) and the aqueous
phase was lyophilized to obtain 2 as a white solid (140 mg, quant.)
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00083E
Journal Name
ARTICLE
Glycoscience (Eds.: B. Fraser-Reid, K. Tatsuta and J. Thiem),
Springer-Verlag, Berlin, Germany, 2008, pp. 135
C. G. Figdor, Y. van Kooyk, G. J. Adema, Nat. Rev. Immunol.,
128.4 (CHBz), 128.3 (CHBz), 88.0 (C1Man), 72.8 (C3Man), 70.7 (C5Man),
69.7 (C2Man), 67.2 (C4Man), 63.5 (C6Man), 21.15 (CH3Tolyl). ESI-MS for
C34H30O8; calcd: 598.2 M+; found: 621.2 [M+Na]+. ESI-HRMS for
C34H30O8S; calcd: 621.1559 [M+Na]+; found: 621.1551 [M+Na]+.
2
3
2002, 2, 77.
(a) R.A. Ezekowitz J. Infect. Dis., 2003, 187, S335; (b) E. van
Liempt, C.M.C. Bank, P.Mehta, J.J. García-Vallejo, Z.S. Kawar,
R. Geyer, R.A. Alvarez, R.D. Cummings, Y. van Kooyk, I. van
Die FEBS Lett., 2006, 580, 6123; (c) T. L. Chang, M. E. Klotman
Synthesis of S-Tolyl O-(3,4,6-tri-O-benzoyl-α-D-mannopyranosyl)-
(1→2)-3,4,6-tri-O-benzoyl-α-D-mannopyranoside (21)
AIDS Res., 2004, 6, 161; (d) E.I. Buzás, B. György, M. Pásztói,
I. Jelinek, A. Falus, H.-J. Gabius Autoimmunity, 2006, 39, 691.
T. B. H. Geijtenbeek, D. S. Kwon, R. Torensma, S. J. Van Vliet,
van G. C. F. Duijnhoven, J. Middel, I. L. M. H. A. Cornelissen,
H. S. L. M. Nottet, V. N. Kewal Ramani, D. R. Littman, C. G.
Figdor, Y. van Kooyk Cell, 2000, 100, 587.
To a solution of compound 20 (200 mg, 0.334 mmol) in anhydrous
CH2Cl2 (3 mL) was added 4 Å molecular sieves and the mixture was
stirred at room temperature for 2h. Then, reaction mixture was
cooled at -40ºC and NIS (53 mg, 0,241 mmol) and TfOH (4.5 mL,
0.017 mmol) were added and the reaction was stirred for 1 hour.
Then was quenched with sat. NaHCO3 (aq). The reaction mixture
was diluted with CH2Cl2 (10 mL) and was filtered over a pad of
celite. The organic layer was washed with sat. Na2S2O3 (aq) (10 mL x
3) and then dried over anhydrous MgSO4. The solvent was removed
under reduced pressure to give colorless oil. The oil was purified by
flash column chromatography on silica gel (4:1 → 2:1 Hexane :
EtOAc) to give the disaccharide 21 as a white solid (243 mg, 68%).
1H NMR (400 MHz, CDCl3) δ 8.07-7.99 (m, 12H, 10HBz), 7.95 (d, J =
4
5
(a) J. J. Reina, A. Bernardi, Mini Rev. Med. Chem., 2012, 12
1434; (b) J. J. Reina, A. Bernardi, M. Clerici, J. Rojo, Fut. Med.
Chem., 2010, , 1141; (c) B. Ernst, J. L. Magnani Nat. Rev.
Drugs Discovery, 2009, , 661; (d) P. Cheshev, A. Bernardi
,
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Chem. Eur. J., 2008, 14, 7434.
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7
8
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Angew. Chem. Int. Ed. 2004, 43, 2562; (b) D. M. Ratner, O. J.
Plante, P. H. Seeberger, Eur. J. Org. Chem., 2002, 826-833; (c)
J. R. Merritt, E. Naisang, B. Fraser-Reid, 1994, 59, 4443.
(a) D. A. Calarese, C. N. Scanlan, M. B. Zwick, S. Deechongkit,
Y. Mimura, R. Kunert, P. Zhu, M. R. Wormald, R. L. Stanfield,
K. H., Roux, J. W. Kelly, P. M. Rudd, R. A. Dwek, H. Katinger,
D. R. Burton, I. A. Wilson, Science, 2003, 300, 2065;
E. W. Adams, D. M. Ratner, H. R., Bokesch, J. B. MacMahon,
B. R. O’Keefe, P. H. Seeberger Chem. Biol., 2004, 11, 875. (b)
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7.1 Hz, 2H, 2HBz), 7.59-7.47 (m, 6H, 6HBz), 7.44-7.32 (m, 14H, 12HBz
+
2HTolyl), 6.98 (d, J = 7.5 Hz, 2H, 2HTolyl), 6.03 (t, J = 9.8 Hz, 1H, H4ManA),
5.97 (t, J = 9.8 Hz, 1H, H4ManB), 5.86 (dd, J = 9.7, 3.1 Hz, 1H, H3Mana),
5.83-5.79 (m, 2H, H1ManA + H3ManB), 5.23 (d, J = 1.9 Hz, 1H, H1ManB),
5.00 (ddd, J = 9.5, 5.9, 3.1 Hz, 1H, H5ManA), 4.73 (dd, J = 3.1, 1.9 Hz,
1H, H2Mana), 4.69-4.41 (m, 6H, H2ManB + H5ManB + 2H6ManB + 2H6ManA),
2.29 (s, 3H, CH3Tolyl). 13C NMR (101 MHz, CDCl3) δ 166.3 (C=OBz),
166.2 (C=OBz), 165.6 (C=OBz), 165.4 (C=OBz), 165.2 (C=OBz), 128.3
(CTolyl), 133.6 (CHBz), 133.4 (CHBz), 133.4 (CHBz), 133.3 (CHBz), 133.0
(CHBz), 132.5 (CHBz), 130.1 (CHBz), 129.9 (CHBz), 129.9 (CHBz), 129.8
(CHBz), 129.8 (CHBz), 129.7 (CHBz), 129.6 (CTolyl), 129.2 (CBz), 129.0
(CBz), 128.8 (CBz), 128.7 (CBz), 128.6 (CHBz), 128.5 (CHBz), 128.4 (CHBz),
128.4 (CHBz), 128.3 (CHBz), 101.4 (C1ManB), 87.1 (C1ManB), 77.2 (C2ManA),
72.1 (C3ManB), 71.7 (C3ManA), 69.8 (C5ManA), 69.4 (C5ManB), 67.6 (C4ManA),
66.8 (C4ManB), 63.7 (C6ManA), 63.4 (C6ManB), 55.2 (CH3Tolyl). ESI-MS for
C61H52O16S; calcd: 1072.3 M+; found: 1095.2 [M+Na]+; . ESI-HRMS
for C61H52O16S; calcd: 1095.2868 [M+Na]+; found: 1095.2860
[M+Na]+.
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Acknowledgements
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This work was supported by Ministerio de Economía
y
Competitividad (MINECO) project CTQ2014-52328-P, co-financed by
European Regional Development Funds (ERDF) and EU H2020-
MSCA-ITN-2014-642870 (Immunoshape). JJR thanks to CSIC for a
JAEdoc contract and JRS thanks MINECO for a FPI fellowship. RCF
acknowledge Fundación Carolina for financial support.
Notes and references
1
(a) Essentials in Glycobiology, (Eds.: A. Varki, T. Cummings, J.
Esko, H. Freeze, G. Hart and J. Marth), Cold Spring Harbor
Laboratory Press, Plainview, 1999; V. Wittman, in
This journal is © The Royal Society of Chemistry 20xx
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