Iron(III)-Triflate-Catalyzed Multiple Glycosylations with Peracetylated β-d-Glucosamine

Article abstract of DOI:10.1002/ejoc.201600457

Direct multiple glycosylations of thioaryl and propargyl mannopyranosides with peracetylated β-d-glucosamine have been carried out using catalytic iron(III) triflate as a promoter in the presence of 2,4,6-tri-tert-butylpyrimidine under microwave irradiation. This has led to the one-step formation of various oligosaccharides with mannose at the branching point. Subsequent direct introduction of a linker through copper-catalyzed azide–alkyne cycloaddition with the propargyl branched glycan and final deprotection gave rapid access to N-glycan mimetics.

Full text of DOI:10.1002/ejoc.201600457

DOI: 10.1002/ejoc.201600457
Full Paper
Glycochemistry
Iron(III)-Triflate-Catalyzed Multiple Glycosylations with
Peracetylated ꢀ- -Glucosamine
D
Amandine Xolin,[a] Stéphanie Norsikian,*[a] François-Didier Boyer*[a,b] and
Jean-Marie Beau*[a,c]
Abstract: Direct multiple glycosylations of thioaryl and prop- various oligosaccharides with mannose at the branching point.
argyl mannopyranosides with peracetylated ꢀ-D-glucosamine Subsequent direct introduction of a linker through copper-cata-
have been carried out using catalytic iron(III) triflate as a pro- lyzed azide–alkyne cycloaddition with the propargyl branched
moter in the presence of 2,4,6-tri-tert-butylpyrimidine under mi- glycan and final deprotection gave rapid access to N-glycan
crowave irradiation. This has led to the one-step formation of mimetics.
Introduction
Asparagine-linked oligosaccharides (N-glycans) are commonly
linked to eukaryotic proteins, and give specific properties to
these glycoproteins.[1] The nature of N-linked glycans attached
to a glycoprotein is determined by the type of protein, and
varies across species, leading to numerous different complex
glycan structures (Figure 1). Due to their importance in cell rec-
ognition and communication,[1] the N-glycans or glycoproteins
Figure 1. Core of a complex N-glycan structure with the maximum number
could be useful for therapeutic applications. Libraries of natural
of branches and substitutions. In red: examples of structures targeted in this
work.
N-glycans or N-glycan fragments could be used for analytical
and structural studies, or for developing glycan microarrays as
valuable tools to evaluate the noncovalent interactions be-
tween glycostructures and proteins.[2] The major limitation for
carrying out such studies is the available quantity of well-de-
fined N-glycans. Access to these complex molecules from bio-
logical sources is limited as they are produced in heterogene-
ous form.[3] Organic synthesis, combining chemical and enzy-
matic methods,[4] can be used to produce homogeneous glyc-
ans in larger quantities, and to further allow their incorporation
into proteins that are, in contrast, easily prepared by biological
methods such as recombinant expression and polymerase chain
reaction. Several syntheses of parts of N-glycan mimetics start-
ing from a mannose core have been reported in the literature.[5]
Since 1997, different groups[6] have successfully carried out
total syntheses of highly branched N-glycans starting from a
protected trisaccharidic [Man-ꢀ-(1,4)-GlcNAc-ꢀ-(1,4)-GlcNAc] or
pentasaccharidic {[Man-α-(1,3)- and Man-α-(1,6)]-Man-ꢀ-(1,4)-
GlcNAc-ꢀ-(1,4)-GlcNAc} core (Figure 1). However, these ap-
proaches are long and complex. To build the oligosaccharide
core, these syntheses are often iterative. For the multiple
glycosylations of mannose derivatives by glucosamine units, the
approaches are usually based on the protection of the 2-amino
group of the amino sugar by temporary protecting groups.
These need to be removed after the coupling reactions, and
the amine group has to be transformed into the 2-acetamido
substituent found in the natural products. The glucos-
amine donors used usually carry a participating N-phthalo-
yl,[5a–5e,5h–5j,5l,6a,6b,6d,6e] N-trichloroethoxycarbonyl,[6c,6f] or N-
allyloxycarbonyl group,[5f] and the corresponding oligosacchar-
ides are formed. Moreover, the mannose derivatives used al-
ways have a protected anomeric position, which needs to be
deprotected and activated for further coupling of the oligosac-
charide structure.
[a] Institut de Chimie des Substances Naturelles, CNRS UPR2301, Univ. Paris-
Sud, Université Paris-Saclay,
1 av. de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: stephanie.norsikian@cnrs.fr
francois-didier.boyer@cnrs.fr
jean-marie.beau@cnrs.fr
http://www.icsn.cnrs-gif.fr
[b] Institut Jean-Pierre Bourgin, INRA, AgroParisTech, CNRS, Université Paris-
Saclay,
RD10, 78026 Versailles, France
[c] Laboratoire de Synthèse de Biomolécules, Institut de Chimie Moléculaire et
des Matériaux d'Orsay, Univ. Paris-Sud, CNRS, Université Paris-Saclay,
91405 Orsay, France
On the other hand, it has been reported that the glycosyl-
ation of unprotected α-mannopyranosides[7] mainly gives 6-
linked disaccharides and 3,6-linked trisaccharides, often in mod-
est isolated yields.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600457.
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An efficient and highly selective synthesis of peracetylated ꢀ- branched glycan C in one step; a second α-selective glycosyl-
-N-acetyl glycosides has been reported using rare earth metal ation would directly introduce a linker E at the mannose ano-
D
triflates,[8] or, by our group, using catalytic iron(III) triflate[9] un- meric position to give mimic F. Route B, leading to G, uses
der microwave conditions or using a continuous flow proc- mannose derivative B, with an α-propargyl group already in-
ess.[10] In this paper, we show that under these conditions it is stalled at the anomeric position. After a ꢀ-selective multiple
also possible to carry out the multiple glycosylation of mann- glycosylation step, linker compound E would be introduced di-
osidic derivatives to prepare partial structures similar to those rectly by a copper-catalyzed azide–alkyne cycloaddition (Cu-
found in multiantennary complex-type N-glycans[1,6f] (Figure 1). AAC) reaction.
To the best of our knowledge, a multiple glycosylation step
has never been described using GlcNAc donors directly. We re-
port here the synthesis of N-glycan mimetics F and G from α-
mannose derivatives A and B and the simple, stable, and com-
mercially available peracetyl glucosamine 1ꢀ (Scheme 1).
Results and Discussion
For route A, we chose to use stable thioarylmannosides, which
would later allow a direct coupling of the resulting glycosylated
Route A (X = SMbp) involves two orthogonal glycosylations:
mannose derivatives with linkers, using N-iodosuccinimide (NIS)
first, a multiple glycosylation would allow the formation of ꢀ-
and TfOH as a promoter. We prepared mannose derivative 2[11]
with the non-malodorous 2-methyl-5-tert-butylphenylthio
group (SMbp),[12] which shows sufficient reactivity with NIS/
TfOH activation. Acceptors bearing hydroxyl groups at the 3,6;
2,4; 2,6; and 2,4,6 positions (i.e., alcohols 3–6, respectively) were
easily prepared from 2 in 2–4 steps (24–47 % yield) by known
procedures (see Supporting Information). The optimization of
the ꢀ-glycosylation conditions with iron(III) triflate was first car-
ried out using diol 3 as the acceptor. In the absence of 2,4,6-
tri-tert-butylpyrimidine (TTBP) and the donor, the anomeric thio
group of 3 was activated by treatment with Fe(OTf)3 at 110 °C
in CH2Cl2 under microwave irradiation for 2 h to give 1,6-anhy-
dro derivative 7 in 38 % yield (Table 1, entry 1). In the presence
of TTBP, compound 7 was produced in a very small quantity,
demonstrating that the iron(III)-triflate-catalyzed glycosylation
is viable for this kind of acceptor (Table 1, entry 2). For the
coupling of GlcNAc 1ꢀ to the mannose derivative 5, many pa-
Scheme 1. Approaches to the formation of N-glycan mimetics F and G
(Mbp = 2-methyl-5-tert-butylphenyl. R1, R2, R3, R4 = H or protecting groups).
Table 1. Transformations of mannose derivatives 3 and 5 and disaccharide 9 under the iron-triflate-catalyzed glycosylation conditions.[a]
[a] Conditions: Fe(OTf)3·6.2DMSO (15 mol-%), 110 °C, CH2Cl2, microwave irradiation. [b] Yields are based on the acceptor; TTBP = 2,4,6-tri-tert-butylpyrimidine,
Mbp = 2-methyl-5-tert-butylphenyl.
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rameters were optimized [stoichiometry of reactants, concen- (16–28 %), with complete ꢀ stereoselectivity, as deduced from
tration of acceptor, temperature, amount (mol-%) of iron(III) tri- 1H NMR spectroscopic studies. However, further attachment of
flate — see Supporting Information for the whole optimization]. a linker to these thiomannosides proved problematic. The glyc-
The best glycosylation conditions turned out to be similar to osylation of triethylene glycol (TEG) 16 with 8 was attempted
those we has used previously.[10] The reaction was carried out using NIS/TfOH as a promoter (Table 3). These conditions pro-
using Fe(OTf)3·6.2DMSO (15 mol-%) at 110 °C in CH2Cl2 under vided the expected compound (i.e., 17) in very low yield, de-
microwave irradiation with a reaction time extended to 6 h, spite numerous attempts (< 5 %; Table 3, entry 1). The simpler
and with 2 equiv. of donor 1ꢀ and TTBP per position to be linker 18, with a three-carbon aliphatic chain, was easily glyc-
glycosylated. This led to trisaccharide 8 and disaccharide 9 in osylated with 8 under the same conditions to give 19, which,
20 and 30 % yields, respectively.
surprisingly, was formed as an equimolar mixture of α and ꢀ
anomers (Table 3, entry 2). This lack of selectivity was also ob-
served in the glycosylation of linker 16 with monosaccharide
derivative 20 (α/ꢀ, 59:41) (Table 3, entry 3). Such a low α-select-
ivity has rarely been reported in the syntheses of complex
mannosides bearing a nonparticipating group at the C-2 posi-
tion.[13]
This lack of α-selectivity has been resolved in some simple
instances by changing the reaction conditions[14] or by using
mannoside donors bearing an acetate group at the C-3 posi-
tion,[15] even in branched structures.[5e,6a] In our case, varying
the reaction conditions (solvent, temperature, activator) did not
The transformation of diol 5 into trisaccharide 8 was limited
by the degradation of the donor (i.e., 1ꢀ) during the long reac-
tion time,[10] but also by the instability of the disaccharide prod-
uct (i.e., 9) (Table 1, entry 3). Indeed, when isolated 9 was resub-
mitted to the glycosylation conditions, nearly the same
amounts of compounds 8 and 9 were formed, along with recov-
ered monosaccharide 5 (Table 1, entry 4). When the reaction
time was decreased to 45 min and the quantity of donor 1ꢀ
was decreased to 2 equiv., an efficient regioselective ꢀ-glycosyl-
ation of the 6-OH group took place to produce ꢀ(1→6)-linked
disaccharide 9 in 65 % yield (Table 1, entry 5).
The scope of the multiple ꢀ-glycosylation was then evalu- improve the α-selectivity. Moreover, an attempted protecting
ated using acceptors 2–4 and 6 to allow the formation of tri-, group interconversion from 3-O-benzyl trisaccharide manno-
tetra-, or pentasaccharides 12, 14, 15, and 10 (Table 2). All the side 8 to the corresponding 3-O-acetyl trisaccharide mannoside
oligosaccharides were obtained with yields in the same range failed due to the presence of the thio group, which impeded
Table 2. Iron-triflate-catalyzed multiple glycosylations of thiomannosides 2–4, 6 with donor (D) 1ꢀ.[a]
[a] Conditions: Fe(OTf)3·6.2DMSO (15 mol-%), 110 °C, CH2Cl2, microwave irradiation. [b] Yields are based on the acceptor; TTBP = 2,4,6-tri-tert-butylpyrimidine,
Mbp = 2-methyl-5-tert-butylphenyl.
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Table 3. Glycosylation with mannoside donors 8 and 20.[a]
[a] Conditions: NIS (2.2 equiv.), TfOH (35 mol-%), CH2Cl2, –20 °C to room temp. [b] Yields are based on the acceptor.
an easy O-benzyl deprotection (e.g., H2, cat. Pd/C or FeCl3).
Monosaccharide mannose acceptors bearing an ester group
(acetate or benzoate) at the C-3 position were prepared, but
they were unstable during multiple glycosylation attempts us-
ing our iron(III) triflate conditions (results not shown).
An alternative method, involving anomerization of the ꢀ-
mannoside derivatives was studied, using Fe(OTf)3 (70 mol-%)
under microwave irradiation. At 90 °C, this selectively produced
α-monosaccharide 21 (Scheme 2). In contrast, no anomeriza-
tion was detected at 90 °C with trisaccharidic mannoside 19. A
modest improvement in the α/ꢀ ratio (from 50:50 to 71:29) was
obtained at 110 °C, but this resuled in significant degradation,
and 19 was recovered in less than 20 % yield (Scheme 2).
The alternative route B was then developed (Scheme 1), in
which the α-mannosylation preceded the multiple ꢀ-GlcNAc-
ylation. Linker 16 was introduced onto the branched oligosac-
charide through a CuAAC reaction.[16] The acceptors, propargyl
Scheme 2. Anomerization of monosaccharidic mannopyranose 21 and trisac-
charidic mannopyranose 19 with iron(III) triflate; MW = microwave.
α-
bearing hydroxyl groups at the 2,4,6 positions, were easily pre-
pared from penta-O-acetyl- -mannopyranose in four steps by
D
-mannopyranoside 22 and α-
D
-mannopyranosyl azide 23,
D
known procedures (see Supporting Information). α-Azido-
mannose 23 was rapidly degraded under the iron(III) triflate
glycosylation conditions in the presence of donor 1ꢀ, without
giving the oligosaccharides. However, acceptor 22 was glycosyl-
ated with the GlcNAc donor to give branched tetrasaccharide
24 in 18 % yield (Scheme 3). To the best of our knowledge, a
threefold glycosylation of this kind leading to a tribranched mo-
tif has only been described once before, using a N-phthaloyl
glycosyl fluoride as a donor.[6a] The CuAAc reaction between
derivative 25 in 83 % yield. Final hydrogenolysis of the O-benzyl
group and and removal of the acetates gave deprotected
branched tetrasaccharide 26 in high overall yield (91 %), which
demonstrates that this approach can be used to produce
branched oligosaccharide mimetics.
Conclusions
linker azide 17 and tetrasaccharide alkyne 24 was carried out We have shown that the direct and multiple ꢀ-GlcNAc-ylation
in a water/dichloromethane mixture to smoothly give triazole of mannose derivatives with a peracetylated ꢀ- -GlcNAc donor
D
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mimic. This compound could be selectively extended by reac-
tion using appropriate glycosyltransferases[6f,17] to give more
complex N-glycan mimetics.
Experimental Section
Materials and Methods: All reagents and chemicals were pur-
chased from commercial suppliers, and were used without further
purification. Non-aqueous reactions were generally run under an
inert atmosphere (argon), using standard techniques for manipulat-
ing air-sensitive compounds. All the glassware was stored in the
oven before use. Anhydrous solvents were obtained by filtration
through drying columns. Dichloromethane and chloroform were
stabilized with amylene. Molecular sieves (4 Å) were used as a pow-
der, and were activated overnight at 250 °C under reduced pressure
in a kugelrohr apparatus. Microwave irradiation experiments were
carried out in an Anton Paar Monowave 300 instrument with inter-
nal fiberoptic or IR temperature control. The vials used were Pyrex,
and were sealed with Teflon-coated septa. The homogeneity and
efficient magnetic stirring of the reaction were controlled with a
camera directly focused on the reaction vial. Flash chromatography
was carried out with an Isco Combiflash Companion instrument
using 50 μm silica columns. Preparative thin-layer chromatography
was carried out on silica gel 60 F254 0.5 mm 20 × 20 cm plates,
which were visualized under UV light (254 nm). Semi-preparative
HPLC was carried out using a Waters 600 instrument, combined
with a 2424 evaporating light-scattering detector (ELSD), a 2996
photodiode-array detector (PDA), a 2767 sample manager, and a
Waters Sunfire C18, 150 mm × 19 mm, 5 μm column. Semi-prepara-
tive HPLC was also carried out using an Interchim puriFlash® 4250
instrument, combined with a fraction collector with integrated
ELSD, a PDA, and a Phenomenex Luna C18, 250 × 21.2 mm, 5 μm
column. In each case, formic acid (1:1000 v/v) was added to the
eluent used for purification. Deuterated chloroform used for NMR
spectroscopic analysis was usually neutralized by the addition of
anhydrous granular K2CO3. 1H NMR spectra were recorded with a
Bruker 300 or 500 MHz instrument. 13C NMR spectra were recorded
with the same instruments at 75 or 125 MHz. Chemical shifts (δ)
are expressed in parts per million, and chloroform was used as an
Scheme 3. Synthesis of N-glycan mimic 26 (MW = microwave. TTBP = 2,4,6-
tri-tert-butylpyrimidine).
1
internal standard (δ = 7.26 ppm for residual chloroform in H NMR
spectra, and δ = 77.4 ppm for deuterated chloroform in 13C NMR
spectra). For 1H NMR spectra, data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadru-
plet, m = multiplet, br. s = broad singlet, dt = doublet of triplets),
coupling constant [Hz] and integration. Spectra were assigned using
DEPT 135, 1H,1H-COSY, 1H,13C-HSQC and HMBC experiments. Low-
resolution mass spectra were obtained with a Waters Acquity UPLC
system using electrospray ionization (ESI), combined with a photo-
diode-array detector (PDA), an evaporating light-scattering detector
(ELSD) and a tandem quadrupole detector (TQD). High-resolution
catalyzed by iron(III) triflate provides well-defined oligosacchar-
ides in one step. These oligosaccharides represent the natural
mannose branching points found in N-glycans, as well as the
nonnatural 2,3,4,6-branched structure. This approach avoids the
multistep protection/deprotection sequence usually used with
the 2-amino group in classical ꢀ-glucosamine glycosylation to
install the natural 2-acetamido substituent. Moreover, the donor
used is commercially available, and the choice of anomeric mass spectra were obtained with a Waters Acquity UPLC (by direct
injection or with a BEH C18 2.1 × 50 mm, 1.7 μm column) combined
with a diode-array detector (DAD) and a Waters LCT Premier XE
mass instrument [electrospray ionization with a time-of-flight (ToF)
analyzer]. IR spectra were recorded with a Perkin–Elmer Spectrum
100 FTIR spectrometer, and data are given in wavenumbers (cm–1).
Melting points were determined with a Büchi B-540 apparatus. Opti-
cal rotations were determined with an Anton Paar MCP 300
polarimeter with a cell length of 1 dm; data are reported as follows:
[α]Dtemperature (in 10–1 deg cm2/g), concentration (c = = in g/100 mL)
and solvent. The anomeric configuration (α or ꢀ) of mannosides
group of the mannose derivatives allows a direct further activa-
tion, unlike previous syntheses. To the best of our knowledge,
this is the shortest synthetic pathway to motifs of this kind.
Much longer sequences (five to seven steps) have previously
been reported, using non-commercially available donors, with
overall yields generally comparable to our direct multiple glyco-
sylations. Our glycosylation conditions are compatible with the
presence of a thiol/propargyl group at the anomeric position of
the mannoside acceptor. The CuI-catalyzed click coupling of a
linker was particularly efficient, leading to a triantennary glycan was determined by 1H and 13C NMR spectroscopy, according to
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the chemical shifts described in the literature.[18] The α/ꢀ ratio was
determined using UPLC-MS-UV or by the integration of 1H NMR
spectra.
crude product was purified by chromatography on silica gel (hept-
ane/EtOAc, 6:4 to 0:1) to give pure monosaccharide 5 (9.5 mg,
27 %), pure trisaccharide 8 (4 mg, 5 %), and pure disaccharide 9
(37 mg, 65 %) as a white amorphous solid.
The preparation and characterization details of intermediate com-
pounds 3–7, 19–23 are included in the Supporting Information.
General Procedure for Microwave-Assisted Glycosylation: Per-
acetylated N-acetyl- -glucosamine 1ꢀ (2 equiv. per position to be
D
glycosylated), TTBP (2 equiv. per position to glycosylate), and
Fe(OTf)3·6.2DMSO (15 mol-%) were added to the acceptor (1 equiv.)
in an oven-dried, argon-purged microwave vial (4 mL filling vol-
ume), equipped with a magnetic stirrer bar. Everything was flushed
under argon and dry CH2Cl2 was added (acceptor concentration:
0.052–0.134
M). The vial was sealed, and the reaction mixture was
heated at 110 °C under microwave irradiation for 45 min to 8 h
(1 min ramp time from room temperature to 110 °C, and 3–8 h hold
time at 110 °C, stirring set at 800 rpm). The reaction mixture was
diluted with CH2Cl2, and poured into saturated aqueous NaHCO3.
The organic layer was separated, the aqueous layer was extracted
with CH2Cl2 (4 ×), and the combined organic layers were washed
with brine, dried with Na2SO4, filtered, and concentrated under re-
duced pressure. The crude product was prepurified by chromatog-
raphy on silica gel, and purified by silica preparative thin-layer chro-
matography, C18 reverse-phase chromatography, or C18 reverse-
phase preparative HPLC.
Data for trisaccharide 8 (for atom numbering see the graphic
1
above): [α]2D0: +28.8 (c = 0.5, CHCl3). H NMR (500 MHz, CDCl3): δ =
7.54 (d, J = 1.5 Hz, 1 H, SMbp), 7.44–7.31 (m, 10 H, Ph), 7.16 (dd,
J = 8.0, J = 1.5 Hz, 1 H, SMbp), 7.09 (d, J = 8.0 Hz, 1 H, SMbp), 5.88
(t, JB3,B2 = JB3,B4 = 10.0 Hz, 1 H, B3-H), 5.70 (s, 1 H, A1-H), 5.46 (d,
JB1,B2 = 8.0 Hz, 1 H, B1-H), 5.17–5.11 (m, 1 H, C-NH), 5.01 (t, JB4,B3
=
JB4,B5 = 10.0 Hz, 1 H, B4-H), 4.97 (t, JC4,C3 = JC4,C5 = 10.0 Hz, 1 H, C4-
H), 4.93 (d, J = 12.5 Hz, 1 H, CH2Ph), 4.88 (dd, JC3,C5 = 10.5, JC3,C4
=
10.0 Hz, 1 H, C3-H), 4.84 (d, J = 11.0 Hz, 1 H, CH2Ph), 4.71 (d, J =
12.5 Hz, 1 H, CH2Ph), 4.51 (d, J = 11.0 Hz, 1 H, CH2Ph), 4.40–4.39 (m,
1 H, A2-H), 4.23 (dd, JB6,B6′ = 12.0, JB6,B5 = 5.0 Hz, 1 H, B6-H), 4.18
(dd, JC6,C6′ = 12.5, JC6,C5 = 4.5 Hz, 1 H, C6-H), 4.13 (dd, JB6′,B6 = 12.0,
JB6′,B5 = 2.0 Hz, 1 H, B6'-H), 4.06 (dd, JC6′,C6 = 12.5, JC6′,C5 = 2.5 Hz,
(2-Methyl-5-tert-butylphenyl) 2,6-Di-O-(2-acetamido-3,4,6-tri-
O-acetyl-2-deoxy-ꢀ-
-mannopyranoside (8) and (2-Methyl-5-tert-butylphenyl) (2-
Acetamido-3,4,6-tri-O-acetyl-2-deoxy-ꢀ- -glucopyranosyl)-
(1→6)-3,4-di-O-benzyl-1-thio-α- -mannopyranoside (9)
D-glucopyranosyl)-3,4-di-O-benzyl-1-thio-α-
1 H, C6'-H), 4.05–4.02 (m, 1 H, A5-H), 3.99 (dd, JA3,A4 = 9.0, JA3,A2
=
D
3.0 Hz, 1 H, A3-H), 3.98–3.92 (m, 1 H, C2-H), 3.92 (dd, JA6,A6′ = 10.5,
JA6,A5 = 1.5 Hz, 1 H, A6-H), 3.86 (t, JA4,A3 = JA4,A5 = 9.5 Hz, 1 H, A4-
D
D
H), 3.83 (d, JC1,C2 = 8.5 Hz, 1 H, C1-H), 3.81 (ddd, JB5,B4 = 10.0, JB5,B6
=
Procedure to Prepare Trisaccharide 8 from Monosaccharide 5:
Compounds 8 and 9 were obtained using donor 1ꢀ (200 mg,
0.514 mmol, 4 equiv.), TTBP (130 mg, 0.523 mmol, 4 equiv.),
Fe(OTf)3·6.2DMSO (19 mg, 0.019 mmol, 15 mol-%), and acceptor 5
(70 mg, 0.134 mmol, 1 equiv.) in dry CH2Cl2 (1 mL), according to
the general procedure (110 °C under microwave irradiation, 6 h).
After work-up, the crude product was prepurified by chromatogra-
phy on silica gel (heptane/EtOAc, 5:5 to 0:1) to give pure monosac-
charide 5 (5 mg, 7 %), and a mixture of disaccharide 9 and trisac-
charide 8. This mixture was purified by silica preparative thin-layer
chromatography (heptane/EtOAc, 2:8) to give pure trisaccharide 8
(32 mg, 20 %) as a white amorphous solid, and pure disaccharide 9
(34 mg, 30 %) as a white amorphous solid.
5.0, JB5,B6′ = 2.0 Hz, 1 H, B5-H), 3.62 (dd, JA6′,A6 = 10.5, JA6′,A5 = 1.5 Hz,
1 H, A6'-H), 3.49 (ddd, JC5,C4 = 10.0, JC5,C6 = 4.5, JC5,C6′ = 2.5 Hz, 1 H,
C5-H), 3.19–3.14 (m, 1 H, B2-H), 2.32 (s, 3 H, ArCH3), 2.04 (s, 6 H, 2
COCH3), 2.03 (s, 3 H, COCH3), 2.02 (s, 3 H, COCH3), 2.01 (s, 3 H,
COCH3), 1.98 (s, 3 H, COCH3), 1.95 (s, 3 H, COCH3), 1.90 (s, 3 H,
COCH3), 1.31 [s, 9 H, ArC(CH3)3] ppm. 13C NMR (125 MHz, CDCl3):
δ = 172.9 (C, COCH3), 171.3 (C, COCH3), 171.2 (C, COCH3), 171.0 (C,
COCH3), 171.0 (C, COCH3), 170.4 (C, OCOCH3), 170.3 (C, OCOCH3),
169.7 (C, OCOCH3), 150.3 (C, SMbp), 139.8 (C, Ph), 138.5 (C, Ph),
135.1 (C, SMbp), 133.1 (C, SMbp), 130.3 (CH, SMbp), 129.1 (2 CH,
Ph), 128.8 (2 CH, Ph), 128.7 (2 CH, Ph), 128.7 (2 CH, Ph), 128.7 (CH,
Ph), 128.2 (CH, Ph), 127.4 (CH, SMbp), 124.4 (CH, SMbp), 102.3 (CH,
C-C1), 97.1 (CH, C-B1), 83.5 (CH, C-A1), 79.2 (CH, C-A3), 74.8 (CH, C-
A2), 73.8 (CH2, CH2Ph), 72.3 (2 CH, C-A4 or C-C3 or C-C5 or C-B5),
72.2 (CH, C-A4 or C-C3 or C-C5 or C-B5), 72.1 (CH, C-A4 or C-C3 or
C-C5 or C-B5), 71.6 (CH, C-A5), 71.4 (CH, C-B3), 70.5 (CH2, CH2Ph),
70.2 (CH, C-B4), 69.0 (CH, C-C4), 68.4 (CH2, C-A6), 63.0 (CH2, C-B6),
62.5 (CH2, C-C6), 57.0 (CH, C-B2), 54.1 (CH, C-C2), 35.0 [C, ArC(CH3)3],
31.8 [3 CH3, ArC(CH3)3], 24.0 (CH3, COCH3), 23.7 (CH3, COCH3), 21.2
(CH3, COCH3), 21.1 (CH3, COCH3), 21.1 (CH3, COCH3), 21.0 (2 CH3,
Procedure to Prepare Trisaccharide 8 from Disaccharide 9: Com-
pound 8 was obtained using donor 1ꢀ (40 mg, 0.104 mmol,
2 equiv.), TTBP (26 mg, 0.104 mmol, 2 equiv.), Fe(OTf)3·6.2DMSO
(8 mg, 0.008 mmol, 15 mol-%), and disaccharide 9 (44 mg,
0.052 mmol, 1 equiv.) in dry CH2Cl2 (1 mL), according to the general
procedure (110 °C under microwave irradiation, 6 h). After work-up,
the crude product was prepurified by chromatography on silica gel
(heptane/EtOAc, 5:5 to 0:1) to give pure monosaccharide 5 (2 mg,
6 %), and a mixture of disaccharide 9 and trisaccharide 8. This mix-
ture was purified by silica preparative thin-layer chromatography
(heptane/EtOAc, 2:8) to give pure trisaccharide 8 (10 mg, 17 %) as
a white amorphous solid, and pure disaccharide 9 (16 mg, 37 %) as
a white amorphous solid.
COCH ), 21.0 (CH , COCH ), 20.4 (CH , ArCH ) ppm. IR: ν = 3275 (N–
˜
3
3
3
3
3
H), 3083 (=C–H), 2962 and 2872 (C–H), 1745 (C=O), 1675 (NH–C=O)
cm–1. HRMS (ESI): calcd. for C59H76N2NaO21S [M + Na]+ 1203.4559;
found 1203.4552.
Data for disaccharide 9: [α]2D0: +103.4 (c = 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.52 (d, J = 2.0 Hz, 1 H, SMbp), 7.41–7.31 (m,
10 H, Ph), 7.23 (d, J = 8.0, J = 2.0 Hz, 1 H, SMbp), 7.14 (d, J = 8.0 Hz,
Procedure to Selectively Prepare Disaccharide 9: Compound 9
was obtained using donor 1ꢀ (50 mg, 0.128 mmol, 2 equiv.), TTBP
(32 mg, 0.128 mmol, 2 equiv.), Fe(OTf )3·6.2DMSO (10 mg,
0.010 mmol, 15 mol-%), and acceptor 5 (35 mg, 0.067 mmol,
1 equiv.) in dry CH2Cl2 (1 mL), according to the general procedure
(110 °C under microwave irradiation, 45 min). After work-up, the
1 H, SMbp), 5.53 (d, JA1,A2 = 1.5 Hz, 1 H, A1-H), 5.35 (d, JNH,B2
8.0 Hz, 1 H, NH), 5.22 (t, JB3,B2 = JB3,B4 = 10.0 Hz, 1 H, B3-H), 5.00 (t,
B4,B3 = JB4,B5 = 10.0 Hz, 1 H, B4-H), 4.87 (d, J = 11.5 Hz, 1 H, CH2Ph),
=
J
4.75 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.69 (d, J = 11.5 Hz, 1 H, CH2Ph),
4.66 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.55 (d, JB1,B2 = 8.5 Hz, 1 H, B1-H),
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Full Paper
4.29 (dd, JA2,A3 = 3.0, JA2,A1 = 1.5 Hz, 1 H, A2-H), 4.23 (ddd, JA5,A4
=
83.1 (CH, C-A1), 73.8 (CH, C-B5 or C-C3), 73.8 (CH, C-B5 or C-C3),
10.0, JA5,A6′ = 3.5, JA5,A6 = 2.0 Hz, 1 H, A5-H), 4.18 (dd, JB6,B6′ = 12.5, 73.2, 73.2, 72.5, 71.9, 71.9 (7 CH, C-A2, C-A5, C-C5, C-E3, C-E5, C-D3,
JB6,B5 = 4.5 Hz, 1 H, B6-H), 4.09 (dd, JB6′,B6 = 12.5, JB6′,B5 = 2.5 Hz, 1
H, B6'-H), 4.02 (dd, JA6,A6′ = 11.0, JA6,A5 = 2.0 Hz, 1 H, A6-H), 3.96
(dd, JA3,A4 = 9.0, JA3,A2 = 3.0 Hz, 1 H, A3-H), 3.82 (dd, JA6′,A6 = 11.0,
JA6′,A5 = 3.5 Hz, 1 H, A6'-H), 3.82–3.74 (m, 2 H, A4-H and B2-H), 3.58
(ddd, JB5,B4 = 10.0, JB5,B6 = 4.5, JB5,B6′ = 2.5 Hz, 1 H, B5-H), 2.86 (br.
and C-D5), 71.2 (CH2, C-A6), 70.7 (CH, C-B3), 69.8 (CH, C-A4 or C-B4),
69.8 (CH, C-A4 or C-B4), 69.4 (CH, C-A3), 69.1 (CH, C-D4 or C-E4),
69.0 (CH, C-D4 or C-E4), 68.7 (CH, C-C4), 63.0 (CH2, GlcNAc-C6), 62.6
(2 CH2, 2 GlcNAc-C6), 62.2 (CH2, GlcNAc-C6), 57.6 (CH, C-B2), 54.9
(CH, C-D2), 53.9 (CH, C-E2), 53.6 (CH, C-C2), 35.0 [C, ArC(CH3)3], 31.8
s, 1 H, OH), 2.37 (s, 3 H, ArCH3), 2.02 (s, 3 H, OCOCH3), 2.01 (s, 3 H, [3 CH3, ArC(CH3)3], 24.2 (CH3, COCH3), 24.1 (CH3, COCH3), 24.0 (CH3,
OCOCH3), 2.00 (s, 3 H, OCOCH3), 1.81 (s, 3 H, NHCOCH3), 1.30 [s, 9
H, ArC(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 171.2 (C,
OCOCH3), 171.1 (C, OCOCH3), 170.9 (C, NHCOCH3), 169.7 (C,
OCOCH3), 150.3 (C, SMbp), 138.7 (C, Ph), 138.1 (C, Ph), 137.2 (C,
COCH3), 23.6 (CH3, COCH3), 21.5 (CH3, COCH3), 21.2 (2 CH3, COCH3),
21.2 (CH3, COCH3), 21.1 (CH3, COCH3), 21.0 (3 CH3, COCH3), 21.0 (2
CH3, COCH3), 21.0 (2 CH3, COCH3), 20.3 (CH3, ArCH3) ppm. IR: ν =
˜
3377, 3290 (N–H), 3083 (=C–H), 2960, 2932, and 2855 (C–H), 1747
SMbp), 132.7 (C, SMbp), 130.5 (CH, SMbp), 130.0 (CH, SMbp), 129.0 (C=O), 1671 (NH–C=O) cm–1. HRMS (ESI): calcd. for C73H103N4O37
S
(2 CH, Ph), 128.9 (2 CH, Ph), 128.5 (2 CH, Ph), 128.4 (CH, Ph), 128.4
(3 CH, Ph), 125.6 (CH, SMbp), 100.9 (CH, C-B1), 87.9 (CH, C-A1), 80.6
(CH, C-A3), 75.1 (CH2, CH2Ph), 73.9 (CH, C-A4), 72.8 (CH, C-A5), 72.5
(CH, C-B3), 72.2 (CH2, CH2Ph), 72.2 (CH, C-B5), 70.3 (CH, C-A2), 69.0
(CH, C-B4), 67.5 (CH2, C-A6), 62.5 (CH2, C-B6), 55.2 (CH, C-B2), 34.9
[C, ArC(CH3)3], 31.7 [3 CH3, ArC(CH3)3], 23.7 (CH3, COCH3), 21.1 (CH3,
COCH3), 21.1 (CH3, COCH3), 21.0 (CH3, COCH3), 20.7 (CH3, ArCH3)
[M + H]+ 1659.6022; found 1659.6094.
(2-Methyl-5-tert-butylphenyl) 3,6-Di-O-(2-acetamido-3,4,6-tri-
O-acetyl-2-deoxy-ꢀ- -glucopyranosyl)-2,4-di-O-benzyl-1-thio-α-
-mannopyranoside (12) and (2-Methyl-5-tert-butylphenyl) (2-
Acetamido-3,4,6-tri-O-acetyl-2-deoxy-ꢀ- -glucopyranosyl)-
(1→6)-2,4-di-O-benzyl-1-thio-α- -mannopyranoside (11): Com-
pounds 12 and 11 were obtained using donor 1ꢀ (100 mg,
0.258 mmol, 4 equiv.), TTBP (65 mg, 0.258 mmol, 4 equiv.),
Fe(OTf)3·6.2DMSO (10 mg, 0.010 mmol, 15 mol-%), and acceptor 3
(35 mg, 0.067 mmol, 1 equiv.) in dry CH2Cl2 (1 mL), according to
the general procedure (110 °C under microwave irradiation, 6 h).
After work-up, the crude product was prepurified by chromatogra-
phy on silica gel (heptane/EtOAc, 6:4 to 0:1) to give pure monosac-
charide 3 (2 mg, 6 %), and a mixture of disaccharide 11 and trisac-
charide 12. This mixture was purified by C18 reverse-phase chroma-
tography (water/CH3CN, 6:4 to 3:7) to give pure trisaccharide 12
(22 mg, 28 %) as a white amorphous solid, and pure disaccharide
11 (17 mg, 29 %) as a pale yellow amorphous solid.
D
D
D
D
ppm. IR: ν = 3496 (O–H), 3282 (N–H), 3071 and 3024 (=C–H), 2959
˜
and 2869 (C–H), 1747 (C=O), 1661 (NH–C=O) cm–1. HRMS (ESI):
calcd. for C45H57NNaO13S [M + Na]+ 874.3448; found 874.3475.
(2-Methyl-5-tert-butylphenyl) 2,3,4,6-Tetra-O-(2-acetamido-
3,4,6-tri-O-acetyl-2-deoxy-ꢀ-D-glucopyranosyl)-1-thio-α-D-
mannopyranoside (10): Compound 10 was obtained using donor
1ꢀ (203 mg, 0.520 mmol, 8 equiv.), TTBP (129 mg, 0.520 mmol,
8 equiv.), Fe(OTf)3·6.2DMSO (10 mg, 0.010 mmol, 15 mol-%), and
acceptor 2 (23 mg, 0.065 mmol, 1 equiv.) in dry CH2Cl2 (1 mL),
according to the general procedure (110 °C under microwave irradi-
ation, 8 h). After work-up, the crude product was prepurified by
chromatography on silica gel (100 % EtOAc, then CH2Cl2/MeOH, 9:1)
and purified by C18 reverse-phase preparative HPLC using the Sun-
Data for trisaccharide 12: [α]2D0: +25.8 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.53 (d, J = 1.5 Hz, 1 H, SMbp), 7.42–7.32 (m,
fire column (water/acetonitrile, 65:35 for 2 min, then 65:35 to 5:5 10 H, Ph), 7.23 (dd, J = 8.0, J = 1.5 Hz, 1 H, SMbp), 7.16 (d, J =
over 8 min, then 5:5 for 15 min, then 5:5 to 3:7 over 10 min) to give 8.0 Hz, 1 H, SMbp), 5.39 (d, JA1,A2 = 3.5 Hz, 1 H, A1-H), 5.37–5.34 (m,
pure pentasaccharide 10 (20 mg, 19 %) as a white amorphous solid.
1 H, C-NH), 5.27–5.22 (m, 1 H, B-NH), 5.14 (t, JC3,C2 = JC3,C4 = 9.5 Hz,
1
[α]2D0: –10.2 (c = 0.6, CHCl3). H NMR (CDCl3, 500 MHz): δ = 7.55 (d, 1 H, C3-H), 5.09 (t, JB3,B2 = JB3,B4 = 9.5 Hz, 1 H, B3-H), 5.02 (t, JB4,B3
=
JNH,B2 = 6.5 Hz, 1 H, B-NH), 7.52 (d, J = 2.0 Hz, 1 H, SMbp), 7.17 (dd,
J = 8.0, J = 2.0 Hz, 1 H, SMbp), 7.08 (d, J = 8.0 Hz, 1 H, SMbp), 6.83
(d, JNH,E2 = 10.0 Hz, 1 H, E-NH), 6.26 (d, JNH,C2 = 10.0 Hz, 1 H, C-NH),
6.06 (d, JNH,D2 = 8.5 Hz, 1 H, D-NH), 5.97 (t, JB3,B2 = JB3,B4 = 10.0 Hz,
1 H, B3-H), 5.71 (s, 1 H, A1-H), 5.61 (d, JB1,B2 = 8.0 Hz, 1 H, B1-H),
5.30 (t, JE3,E2 = JE3,E4 = 10.0 Hz, 1 H, E3-H), 5.22–5.17 (m, 2 H, C3-H
JB4,B5 = 9.5 Hz, 1 H, B4-H), 4.99 (t, JC4,C3 = JC4,C5 = 9.5 Hz, 1 H, C4-
H), 4.82 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.69 (d, J = 11.5 Hz, 1 H, CH2Ph),
4.59 (d, JB1,B2 = 8.5 Hz, 1 H, B1-H), 4.55 (d, J = 12.0 Hz, 1 H, CH2Ph),
4.53 (d, JC1,C2 = 8.5 Hz, 1 H, C1-H), 4.44 (d, J = 11.5 Hz, 1 H, CH2Ph),
4.21–4.16 (m, 3 H, A3-H, B6-H, C6-H), 4.14–4.11 (m, 1 H, A5-H), 4.07
(dd, J6′,6 = 12.0, J6′,5 = 2.0 Hz, 1 H, B6′-H or C6′-H), 4.04 (dd, J6′,6
12.0, J6′,5 = 2.5 Hz, 1 H, C6′-H or B6′-H), 3.99 (t, JA2,A1 = JA2,A3
=
=
and C4-H), 5.09–5.05 (m, 3 H, D3-H, E4-H and D4-H), 4.92 (d, JD1,D2
=
8.0 Hz, 1 H, D1-H), 4.86 (t, JB4,B3 = JB4,B5 = 10.0 Hz, 1 H, B4-H), 4.62
(d, JC1,C2 = 8.5 Hz, 1 H, C1-H), 4.58–4.52 (m, 2 H, A3-H, GlcNAc-6-H),
4.55 (d, JE1,E2 = 8.5 Hz, 1 H, E1-H), 4.44 (dd, J = 12.5, J = 5.0 Hz, 1
H, GlcNAc-6-H), 4.38–4.26 (m, 6 H, A2-H, A4-H, A5-H, C2-H, GlcNAc-
6'-H, GlcNAc-6-H), 4.21–4.06 (m, 5 H, D2-H, E2-H, GlcNAc-6'-H,
GlcNAc-6'-H, GlcNAc-6-H), 4.01 (d, J = 12.0 Hz, 1 H, GlcNAc-6'-H),
3.95 (m, 1 H, A6-H), 3.82–3.77 (m, 5 H, A6'-H, B5-H, C5-H, D5-H, E5-
3.5 Hz, 1 H, A2-H), 3.93 (dd, JA6,A6′ = 11.5, JA6,A5 = 1.5 Hz, 1 H, A6-
H), 3.89–3.69 (m, 4 H, A4-H, A6′-H, B2-H, C2-H), 3.59–3.54 (m, 2 H,
B5-H and C5-H), 2.37 (s, 3 H, ArCH3), 2.03 (s, 9 H, 3 OCOCH3), 2.01
(s, 3 H, OCOCH3), 2.00 (s, 3 H, OCOCH3), 1.99 (s, 3 H, OCOCH3), 1.78
(s, 3 H, NHCOCH3), 1.71 (s, 3 H, NHCOCH3), 1.29 [s, 9 H, ArC(CH3)3]
ppm. 13C NMR (75 MHz, CDCl3): δ = 171.2 (C, OCOCH3), 171.1 (C,
OCOCH3), 171.0 (C, OCOCH3), 170.9 (C, OCOCH3), 170.6 (C,
H), 2.86 (ddd, JB2,B3 = 10.0, JB2,B1 = 8.0, JB2,NH = 6.5 Hz, 1 H, B2-H), NHCOCH3), 170.5 (C, NHCOCH3), 169.8 (C, OCOCH3), 169.8 (C,
2.28 (s, 3 H, ArCH3), 2.17 (s, 6 H, 2 COCH3), 2.13 (s, 3 H, COCH3), 2.08
(s, 3 H, COCH3), 2.06–2.05 (m, 9 H, 3 COCH3), 2.03–2.00 (m, 15 H, 5
COCH3), 1.98 (s, 3 H, COCH3), 1.94 (s, 3 H, COCH3), 1.92 (s, 3 H,
COCH3), 1.83 (s, 3 H, COCH3), 1.32 [s, 9 H, ArC(CH3)3] ppm. 13C NMR
OCOCH3), 150.3 (C, SMbp), 138.8 (C, Ph), 138.1 (C, Ph), 137.0 (C,
SMbp), 132.7 (C, SMbp), 130.6 (CH, SMbp), 129.9 (CH, SMbp), 129.1
(2 CH, Ph), 128.9 (2 CH, Ph), 128.9 (3 CH, Ph), 128.4 (2 CH, Ph), 128.3
(CH, Ph), 125.6 (CH, SMbp), 101.0 (CH, C-C1), 99.3 (CH, C-B1), 84.9
(CDCl3, 125 MHz): δ = 173.9 (C, COCH3), 172.4 (C, COCH3), 171.8 (C, (CH, C-A1), 77.0 (CH, C-A3), 76.2 (CH, C-A2), 74.3 (CH, C-A4), 73.6
COCH3), 171.5 (C, COCH3), 171.2 (C, COCH3), 171.1 (C, COCH3), 170.9
(C, COCH3), 170.9 (C, COCH3), 170.8 (C, COCH3), 170.6 (C, COCH3),
170.2 (C, COCH3), 170.1 (C, COCH3), 170.0 (C, COCH3), 169.9 (2 C,
COCH3), 169.8 (C, COCH3), 150.8 (C, SMbp), 134.6 (C, SMbp), 132.4
(CH2, CH2Ph), 73.4 (CH, C-A5), 72.7 (CH, C-B3 or C-C3), 72.6 (CH2,
CH2Ph), 72.6 (CH, C-B3 or C-C3), 72.4 (CH, C-B5 or C-C5), 72.0 (CH,
C-B5 or C-C5), 69.0 (CH, C-C4), 68.8 (CH, C-B4), 68.1 (CH2, C-A6), 62.5
(CH2, C-B6 or C-C6), 62.4 (CH2, C-B6 or C-C6), 55.2 (CH, C-B2), 55.0
(C, SMbp), 130.4 (CH, SMbp), 127.3 (CH, SMbp), 124.8 (CH, SMbp), (CH, C-C2), 34.9 [C, ArC(CH3)3], 31.7 [3 CH3, ArC(CH3)3], 23.6 (2 CH3,
104.9 (CH, C-E1), 97.4 (CH, C-D1), 96.2 (CH, C-C1), 96.0 (CH, C-B1),
NHCOCH3), 21.1 (CH3, OCOCH3), 21.1 (CH3, OCOCH3), 21.1 (CH3,
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Full Paper
OCOCH3), 21.0 (CH3, OCOCH3), 21.0 (CH3, OCOCH3), 21.0 (CH3, H), 4.78 (d, J = 11.0 Hz, 1 H, CH2Ph), 4.72–4.66 (m, 2 H, CH2Ph), 4.70
OCOCH3), 20.8 (CH3, ArCH3) ppm. IR: ν = 3289 (N–H), 3089 (=C–H),
(d, JC1,C2 = 8.0 Hz, 1 H, C1-H), 4.42 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.32
(m, 1 H, A2-H), 4.19–4.12 (m, 4 H, A4-H, A5-H, C6-H and B6-H), 4.09
˜
2960, 2929, and 2881 (C–H), 1749 (C=O), 1663 (NH–C=O) cm–1
.
HRMS (ESI): calcd. for C59H76N2NaO21S [M + Na]+ 1203.4559; found (dd, JB6,B6′ = 12.0, JB6,B5 = 2.0 Hz, 1 H, B6′-H), 4.01–3.96 (m, 2 H, A3-
1203.4596.
H and C2-H), 3.90 (dd, JC6,C6′ = 12.0, JC6,C5 = 2.0 Hz, 1 H, C6′-H), 3.73
(dd, JA6,A6′ = 10.5, JA6,A5 = 2.5 Hz, 1 H, A6-H), 3.68 (ddd, JB5,B4 = 10.0,
JB5,B6′ = 4.5, JB5,B6 = 2.0 Hz, 1 H, B5-H), 3.57–3.55 (dd, JA6′,A6 = 10.5,
JA6′,A5 = 1.5 Hz, 1 H, A6′-H), 3.47–3.43 (m, 1 H, B2-H), 3.38–3.36 (m,
1 H, C5-H), 2.35 (s, 3 H, ArCH3), 2.01 (s, 3 H, COCH3), 2.00 (s, 3 H,
COCH3), 2.00 (s, 3 H, COCH3), 1.99 (s, 6 H, 2 COCH3), 1.93 (s, 3 H,
COCH3), 1.74 (s, 3 H, COCH3), 1.64 (s, 3 H, COCH3), 1.29 [s, 9 H,
ArC(CH3)3] ppm. 13C NMR (150 MHz, CDCl3): δ = 171.2 (C, COCH3),
171.2 (C, COCH3), 171.1 (C, COCH3), 171.0 (C, COCH3), 170.7 (C,
COCH3), 170.5 (C, COCH3), 170.0 (C, COCH3), 169.7 (C, COCH3), 150.2
(C, SMbp), 138.7 (C, Ph), 138.5 (C, Ph), 136.3 (C, SMbp), 133.1 (C,
SMbp), 130.4 (CH, SMbp), 129.1, 129.0, 128.9 (7 CH, Ph and SMbp),
128.5 (CH, Ph), 128.5 (CH, Ph), 128.4 (CH, Ph), 128.4 (CH, Ph), 125.1
(CH, SMbp), 101.1 (CH, C-C1), 98.5 (CH, C-B1), 85.4 (CH, C-A1), 77.7
(CH, C-A3), 75.6 (2 CH, C-A2 and C-A4), 73.9 (CH2, CH2Ph), 73.5 (CH,
C-C3), 72.4 (CH, C-A5), 72.3 (CH2, CH2Ph), 72.2 (CH, C-B5), 72.1 (CH,
C-C5), 71.7 (CH, C-B3), 69.2 (CH2, C-A6), 69.2 (CH, C-B4), 68.5 (CH, C-
C4), 62.5 (CH2, C-B6), 62.2 (CH2, C-C6), 56.1 (CH, C-B2), 54.9 (CH, C-
C2), 34.9 [C, ArC(CH3)3], 31.7 [3 CH3, ArC(CH3)3], 23.6 (CH3, COCH3),
23.6 (CH3, COCH3), 21.1 (CH3, COCH3), 21.1 (CH3, COCH3), 21.0 (2
CH3, COCH3), 21.0 (CH3, COCH3), 21.0 (CH3, COCH3), 20.6 (CH3,
Data for disaccharide 11: [α]2D0: +59.7 (c = 0.8, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.50 (d, J = 2.0 Hz, 1 H, SMbp), 7.41–7.31 (m,
10 H, Ph), 7.24 (dd, J = 8.0, J = 2.0 Hz, 1 H, SMbp), 7.15 (d, J =
8.0 Hz, 1 H, SMbp), 5.53 (d, JA1,A2 = 1.5 Hz, 1 H, A1-H), 5.30 (dd,
JB3,B2 = 10.5, JB3,B4 = 9.5 Hz, 1 H, B3-H), 5.20 (d, JNH,B2 = 8.5 Hz, 1 H,
NH), 5.01 (t, JB4,B3 = JB4,B5 = 9.5 Hz, 1 H, B4-H), 4.91 (d, J = 11.5 Hz,
1 H, CH2Ph), 4.73 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.72 (d, JB1,B2 = 8.0 Hz,
1 H, B1-H), 4.65 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.52 (d, J = 12.0 Hz, 1
H, CH2Ph), 4.21–4.18 (m, 2 H, B6-H and A5-H), 4.09–4.04 (m, 3 H,
B6′-H, A3-H and A6-H), 3.98 (dd, JA2,A3 = 5.0, JA2,A1 = 1.5 Hz, 1 H,
A2-H), 3.85 (dd, JA6′,A6 = 11.5, JA6′,A5 = 4.5 Hz, 1 H, A6′-H), 3.71–3.67
(m, 1 H, B2-H), 3.64 (t, JA4,A3 = JA4,A5 = 9.0 Hz, 1 H, A4-H), 3.59 (ddd,
JB5,B4 = 9.5, JB5,B6′ = 4.5, JB5,B6 = 2.0 Hz, 1 H, B5-H), 2.39 (d, JOH,B3
=
9.0 Hz, 1 H, OH), 2.36 (s, 3 H, ArCH3), 2.03 (s, 3 H, OCOCH3), 2.01 (s,
3 H, OCOCH3), 2.00 (s, 3 H, OCOCH3), 1.70 (s, 3 H, NHCOCH3), 1.30
[s, 9 H, ArC(CH3)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 171.1 (C,
OCOCH3), 170.9 (C, OCOCH3), 170.5 (C, NHCOCH3), 169.8 (C,
OCOCH3), 150.3 (C, SMbp), 138.8 (C, Ph), 137.6 (C, Ph), 137.5 (C,
SMbp), 132.8 (C, SMbp), 130.6 (CH, SMbp), 130.4 (CH, SMbp), 129.1
(2 CH, Ph), 128.9 (2 CH, Ph), 128.7 (CH, Ph), 128.6 (2 CH, Ph), 128.3
(3 CH, Ph), 125.7 (CH, SMbp), 100.6 (CH, C-B1), 85.5 (CH, C-A1), 80.1
(CH, C-A2), 76.7 (CH, C-A4), 74.9 (CH2, CH2Ph), 72.9 (CH2, CH2Ph),
72.8 (CH, C-A5), 72.6 (CH, C-B3 or C-A3), 72.6 (CH, C-B3 or C-A3),
72.1 (CH, C-B5), 69.1 (CH, C-B4), 68.1 (CH2, C-A6), 62.6 (CH2, C-B6),
55.5 (CH, C-B2), 34.9 [C, ArC(CH3)3], 31.8 [3 CH3, ArC(CH3)3], 23.6
(CH3, NHCOCH3), 21.1 (CH3, OCOCH3), 21.1 (CH3, OCOCH3), 21.0 (CH3,
ArCH3) ppm. IR: ν = 3297 (N–H), 3072 (=C–H), 2964, 2922, and 2867
˜
(C–H), 1749 (C=O), 1666 (NH–C=O) cm–1. HRMS (ESI): calcd.
for C59H77N2O21S [M + H]+ 1181.4740; found 1181.4745.
Data for disaccharide 13: [α]2D0: +86.3 (c = 0.1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.53 (d, J = 2.0 Hz, 1 H, SMbp), 7.47–7.28 (m,
10 H, Ph), 7.19 (dd, J = 8.0, J = 2.0 Hz, 1 H, SMbp), 7.12 (d, J =
8.0 Hz, 1 H, SMbp), 5.55 (d, JA1,A2 = 1.0 Hz, 1 H, A1-H), 5.02 (t, JB4,B3
=
OCOCH3), 20.8 (CH3, ArCH3) ppm. IR: ν = 3466 and 3288 (O–H and
˜
JB4,B5 = 9.5 Hz, 1 H, B4-H), 4.92 (m, 1 H, B3-H), 4.92 (d, J = 12.0 Hz,
1 H, CH2Ph), 4.84 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.75 (d, JNH,B2 = 9.0 Hz,
1 H, NH), 4.67 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.52 (d, JB1,B2 = 8.5 Hz, 1
H, B1-H), 4.35 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.24–4.13 (m, 4 H, A2-H,
N–H), 3065 and 3030 (=C–H), 2958, 2926, and 2855 (C–H), 1749 (C=
O), 1663 (NH–C=O) cm–1. HRMS (ESI): calcd. for C45H58NO13S [M +
H]+ 852.3629; found 852.3638.
(2-Methyl-5-tert-butylphenyl) 2,4-di-O-(2-Acetamido-3,4,6-tri-
A4-H, A5-H, B6-H), 3.99–3.90 (m, 2 H, B2-H, B6′-H), 3.82 (dd, JA3,A4
=
O-acetyl-2-deoxy-ꢀ-
-mannopyranoside (14) and (2-Methyl-5-tert-butylphenyl) (2-
Acetamido-3,4,6-tri-O-acetyl-2-deoxy-ꢀ- -glucopyranosyl)-
(1→4)-3,6-di-O-benzyl-1-thio-α- -mannopyranoside (13): Com-
D-glucopyranosyl)-3,6-di-O-benzyl-1-thio-α-
8.0, JA3,A2 = 3.0 Hz, 1 H, A3-H), 3.70 (dd, JA6,A6′ = 10.5, JA6,A5 = 2.5 Hz,
1 H, A6-H), 3.52–3.45 (m, 2 H, B5-H and A6′-H), 2.75 (br. s, 1 H, OH),
2.34 (s, 3 H, ArCH3), 2.02 (s, 3 H, OCOCH3), 2.00 (s, 3 H, OCOCH3),
1.95 (s, 3 H, OCOCH3), 1.71 (s, 3 H, NHCOCH3), 1.29 [s, 9 H, ArC(CH3)3]
ppm. 13C NMR (75 MHz, CDCl3): δ = 171.1 (C, OCOCH3), 171.1 (C,
OCOCH3), 170.3 (C, NHCOCH3), 169.7 (C, OCOCH3), 150.1 (C, SMbp),
138.7 (C, Ph), 138.3 (C, Ph), 136.5 (C, SMbp), 133.0 (C, SMbp), 130.4
(CH, SMbp), 129.4 and 129.3 (4 CH, Ph and SMbp), 129.1 (CH, Ph),
129.1 (CH, Ph), 128.8 (2 CH, Ph), 128.1 (CH, Ph), 127.6 (2 CH, Ph),
124.9 (CH, SMbp), 101.3 (CH, C-B1), 86.8 (CH, C-A1), 78.5 (CH, C-A3),
75.6 (CH, C-A4), 74.3 (CH2, CH2Ph), 73.4 (CH2, CH2Ph), 73.4 (CH, C-
B3), 72.1 and 71.9 (2 CH, C-A5 and C-B5), 71.5 (CH, C-A2), 68.8 (CH,
C-B4), 68.5 (CH2, C-A6), 62.3 (CH2, C-B6), 54.8 (CH, C-B2), 34.9 [C,
ArC(CH3)3], 31.7 [3 CH3, ArC(CH3)3], 23.5 (CH3, NHCOCH3), 21.0 (3
D
D
D
pounds 14 and 13 were obtained using donor 1ꢀ (100 mg,
0.258 mmol, 4 equiv.), TTBP (65 mg, 0.258 mmol, 4 equiv.),
Fe(OTf)3·6.2DMSO (10 mg, 0.010 mmol, 15 mol-%), and acceptor 4
(35 mg, 0.067 mmol, 1 equiv.) in dry CH2Cl2 (1 mL), according to
the general procedure (110 °C under microwave irradiation, 6 h).
After work-up, the crude product was prepurified by chromatogra-
phy on silica gel (heptane/EtOAc, 6:4 to 0:1) to give pure monosac-
charide 4 (12 mg, 34 %), crude trisaccharide 14, and a mixture of
disaccharides. The crude trisaccharide was purified by C18 reverse-
phase preparative HPLC using the Luna column (water/acetonitrile,
35:65 over 30 min) to give pure trisaccharide 14 (14 mg, 18 %). The
mixture of disaccharides was purified by silica preparative thin-layer
chromatography (toluene/acetone, 7:3, twice) to give pure disac-
charide 13 (14 mg, 24 %).
CH3, OCOCH3), 20.5 (CH3, ArCH3) ppm. IR: ν = 3327 (O–H and N–H),
˜
3062 and 3027 (=C–H), 2960, 2932, and 2869 (C–H), 1748 (C=O),
1664 (NH–C=O). HRMS (ESI): calcd. for C45H58NO13S [M + H]+
852.3629; found 852.3627.
Data for trisaccharide 14: [α]2D5: +21.3 (c = 0.3, CHCl3). 1H NMR (2-Methyl-5-tert-butylphenyl) 2,4,6-Tri-O-(2-acetamido-3,4,6-tri-
(600 MHz, CDCl3): δ = 7.54 (d, J = 2.0 Hz, 1 H, SMbp), 7.44–7.31 (m,
10 H, Ph), 7.20 (dd, J = 8.0, J = 2.0 Hz, 1 H, SMbp), 7.12 (d, J =
8.0 Hz, 1 H, SMbp), 5.54 (t, JB3,B2 = JB3,B4 = 10.0 Hz, 1 H, B3-H), 5.41
(d, JA1,A2 = 2.0 Hz, 1 H, A1-H), 5.36 (d, JNH,B2 = 7.5 Hz, 1 H, B-NH),
5.25 (d, JNH,C2 = 9.0 Hz, 1 H, C-NH), 5.07 (d, JB1,B2 = 7.5 Hz, 1 H, B1-
O-acetyl-2-deoxy-ꢀ-D-glucopyranosyl)-3-O-benzyl-1-thio-α-D-
mannopyranoside (15): Compound 15 was obtained using donor
1ꢀ (157 mg, 0.402 mmol, 6 equiv.), TTBP (100 mg, 0.402 mmol,
6 equiv.), Fe(OTf)3·6.2DMSO (10 mg, 0.010 mmol, 15 mol-%), and
acceptor 6 (29 mg, 0.067 mmol, 1 equiv.) in dry CH2Cl2 (1 mL),
according to the general procedure (110 °C under microwave irradi-
ation, 6 h). After work-up, the crude product was prepurified by
H), 5.05 (dd, JC4,C3 = JC4,C5 = 10.0 Hz, 1 H, C4-H), 5.01 (dd, JB4,B3
=
JB4,B5 = 10.0 Hz, 1 H, B4-H), 4.93 (t, JC3,C2 = JC3,C4 = 10.0 Hz, 1 H, C3-
Eur. J. Org. Chem. 0000, 0–0
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8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
chromatography on silica gel (100 % EtOAc, then CH2Cl2/MeOH,
9:1), and purified by C18 reverse-phase preparative HPLC using the
Sunfire column (water/acetonitrile, 72:28 for 10 min, then 72:28 to
J
C1,C2 = 8.0 Hz, 1 H, C1-H), 4.39–4.38 (m, 1 H, A2-H), 4.32 (dd, JD6,D6′ =
12.5, JD6,D5 = 4.5 Hz, 1 H, D6-H), 4.26 (t, JA4,A3 = JA4,A5 = 10.5 Hz, 1
H, A4-H), 4.18–4.09 (m, 7 H, B6-H, B6′-H, C6-H, D6′-H, CHHPh,
45:55 over 1 min, then 45:55 for 19 min) to give pure tetrasacchar- CH2C≡ CH), 4.04–3.99 (m, 4 H, A3-H, A6-H, C6′-H and D2-H), 3.93 (m,
ide 15 (15 mg, 16 %) as a white amorphous solid. [α]D20: –6.0 (c = 1 H, C2-H), 3.83–3.79 (m, 2 H, A5-H and B5-H), 3.74 (ddd, JD5,D4
=
1
0.4, CHCl3). H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 2.0 Hz, 1 H,
SMbp), 7.45–7.36 (m, 6 H, Ph and B-NH), 7.16 (dd, J = 8.0, J = 2.0 Hz,
1 H, SMbp), 7.08 (d, J = 8.0 Hz, 1 H, SMbp), 6.96 (d, JNH,D2 = 10.0 Hz,
1 H, D-NH), 5.94 (t, JB3,B2 = JB3,B4 = 10.0 Hz, 1 H, B3-H), 5.69 (s, 1 H,
A1-H), 5.56 (d, JB1,B2 = 8.0 Hz, 1 H, B1-H), 5.40–5.38 (m, 1 H, C-NH),
10.0, JD5,D6 = 4.5, JD5,D6′ = 2.0 Hz, 1 H, D5-H), 3.68 (dd, JA6′,A6 = 12.5,
JA6′,A5 = 2.0 Hz, 1 H, A6′-H), 3.42 (ddd, JC5,C4 = 10.0, J = 4.5, J =
2.5 Hz, 1 H, C5-H), 3.18–3.13 (m, 1 H, B2-H), 2.48 (t, J = 2.0 Hz, 1 H,
CH2C≡ CH), 2.08 (s, 3 H, COCH3), 2.07 (s, 3 H, COCH3), 2.05 (s, 3 H,
COCH3), 2.04 (s, 3 H, COCH3), 2.03 (s, 3 H, COCH3), 2.01 (s, 3 H,
COCH3), 2.00 (s, 3 H, COCH3), 1.99 (s, 3 H, COCH3), 1.97 (s, 3 H,
COCH3), 1.91 (s, 3 H, COCH3), 1.90 (s, 3 H, COCH3), 1.62 (s, 3 H,
COCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.7 (C, COCH3),
172.0 (C, COCH3), 171.7 (C, COCH3), 171.4 (C, COCH3), 171.1 (C,
COCH3), 170.8 (C, COCH3), 170.8 (C, COCH3), 170.6 (C, COCH3), 170.5
(C, COCH3), 170.2 (C, COCH3), 169.9 (C, COCH3), 169.8 (C, COCH3),
138.5 (C, Ph), 129.0 (2 CH, Ph), 128.9 (2 CH, Ph), 128.6 (CH, Ph), 104.3
(CH, C-D1), 97.9 (CH, C-C1), 97.0 (CH, C-A1), 96.6 (CH, C-B1), 79.2 (C,
CH2C≡ CH), 75.5 (C, CH2C≡ CH), 73.0 (CH, C-D3), 72.5 (CH, C-C3), 72.2
(CH, C-A5 or C-B5 or C-C5 or C-D5), 72.0 (CH, C-A5 or C-B5 or C-C5
or C-D5), 71.9 (CH, C-A5 or C-B5 or C-C5 or C-D5), 71.9 (CH, C-A5 or
C-B5 or C-C5 or C-D5), 71.7 (CH, C-A3), 71.3 (CH, C-A2), 71.2 (CH, C-
A4 or C-B3), 71.1 (CH, C-A4 or C-B3), 71.0 (CH2, C-A6), 70.3 (CH, C-
B4), 69.2 (CH, C-C4 or C-D4), 68.9 (CH2, CH2Ph), 68.6 (CH, C-C4 or C-
D4), 62.7 (2 CH2, C-B6 and C-D6), 62.4 (CH2, C-C6), 57.1 (CH, C-B2),
55.6 (CH2, CH2C≡ CH), 55.1 (CH, C-C2), 54.4 (CH, C-D2), 23.9 (CH3,
COCH3), 23.9 (CH3, COCH3), 23.7 (CH3, COCH3), 21.2 (CH3, COCH3),
21.2 (CH3, COCH3), 21.1 (CH3, COCH3), 21.1 (CH3, COCH3), 21.1 (CH3,
5.29 (t, JD2,D1 = JD2,D3 = 10.0 Hz, 1 H, D3-H), 5.06 (t, JD4,D3 = JD4,D5
10.0 Hz, 1 H, D4-H), 5.03–5.00 (m, 2 H, B4-H and C4-H), 4.93 (t,
C3,C2 = JC3,C4 = 10.0 Hz, 1 H, C3-H), 4.80 (d, J = 10.0 Hz, 1 H, CH2Ph),
=
J
4.63 (d, JA2,A3 = 3.0 Hz, 1 H, A2-H), 4.54 (d, JD1,D2 = 8.5 Hz, 1 H, D1-
H), 4.41 (t, JA4,A3 = JA4,A5 = 10.5 Hz, 1 H, A4-H), 4.40–4.36 (m, 1 H,
D6-H), 4.38 (d, JC1,C2 = 8.0 Hz, 1 H, C1-H), 4.31 (m, 1 H, A5-H), 4.24
(d, J = 10.0 Hz, 1 H, CH2Ph), 4.18–4.05 (m, 6 H, D2-H, B6-H, B6′-H,
D6′-H, C6-H and C6′-H), 4.02 (dd, JA3,A4 = 10.5, JA3,A2 = 3.0 Hz, 1 H,
A3-H), 4.00–3.95 (m, 2 H, A6-H and C2-H), 3.81–3.73 (m, 3 H, A6′-H,
B5-H, D5-H), 3.50 (ddd, JC5,C4 = 9.0, JC5,C6 = 6.5, JC5,C6′ = 2.5 Hz, 1 H,
C5-H), 3.08–3.03 (m, 1 H, B2-H), 2.31 (s, 3 H, ArCH3), 2.09 (s, 3 H,
COCH3), 2.06 (s, 3 H, COCH3), 2.05 (s, 3 H, COCH3), 2.04 (s, 3 H,
COCH3), 2.00 (s, 6 H, 2 COCH3), 1.99 (s, 3 H, COCH3), 1.95 (s, 6 H, 2
COCH3), 1.92 (s, 3 H, COCH3), 1.91 (s, 3 H, COCH3), 1.59 (s, 3 H,
COCH3), 1.32 [s, 9 H, ArC(CH3)3] ppm. 13C NMR (125 MHz, CDCl3):
δ = 173.5 (C, COCH3), 171.9 (C, COCH3), 171.9 (C, COCH3), 171.5 (C,
COCH3), 171.2 (C, COCH3), 170.9 (C, COCH3), 170.8 (C, COCH3), 170.7
(C, COCH3), 170.4 (C, COCH3), 170.3 (C, COCH3), 169.9 (C, COCH3),
169.8 (C, COCH3), 150.7 (C, SMbp), 138.2 (C, Ph), 134.5 (C, SMbp), COCH3), 21.0 (2 CH3, COCH3), 21.0 (CH3, COCH3), 21.0 (CH3, COCH3)
133.3 (C, SMbp), 130.3 (CH, SMbp), 129.4 (2 CH, Ph), 129.1 (2 CH, ppm. IR: ν = 3284 (N–H and ≡ C–H), 3080 (=C–H), 2935 and 2860
˜
Ph), 128.9 (CH, Ph), 127.1 (CH, SMbp), 124.5 (CH, SMbp), 104.8 (CH,
C-D1), 97.7 (CH, C-C1), 95.7 (CH, C-B1), 83.7 (CH, C-A1), 73.6 (CH, C-
A2), 73.3 (CH, C-D3), 72.8 (CH, C-A5), 72.4, 72.3, 72.2, 71.8, and 71.8
(5 CH, C-A3, C-C3, C-B5, C-D5 and C-C5), 71.5 (CH2, C-A6), 71.1 (CH,
C-A4), 71.1 (CH, C-B3), 70.3 (CH, C-B4 or C-C4), 69.1 (CH, C-D4), 69.0
(CH2, CH2Ph), 68.6 (CH, C-B4 or C-C4), 62.7 (CH2, C-D6 or C-C6 or C-
B6), 62.6 (2 CH2, C-D6 or C-C6 or C-B6), 57.4 (CH, C-B2), 55.1 (CH, C-
C2), 54.1 (CH, C-D2), 35.0 [C, ArC(CH3)3], 31.8 [3 CH3, ArC(CH3)3],
23.9 (CH3, COCH3), 23.7 (CH3, COCH3), 23.6 (CH3, COCH3), 21.4 (CH3,
COCH3), 21.2 (2 CH3, COCH3), 21.1 (2 CH3, COCH3), 21.1 (CH3,
COCH3), 21.0 (CH3, COCH3), 21.0 (2 CH3, COCH3), 20.3 (CH3, ArCH3)
(C–H), 1748 (C=O), 1667 (NH–C=O) cm–1. HRMS (ESI): calcd.
for C58H78N3O30 [M + H]+ 1296.4670; found 1296.4719.
Tetrasaccharide 25: A copper(II) sulfate pentahydrate solution
in degassed water; 30 μL, 0.6 μmol, 5 mol-%) and a sodium
ascorbate solution (0.04
(0.02
M
M
in degassed water; 30 μL, 1.2 μmol,
10 mol-%) were added a to a mixture of tetrasaccharide 24 (15 mg,
11.6 μmol, 1 equiv.) and 2-[2-(2-azidoethoxy)ethoxy]ethanol 16
(3.05 mg, 17.4 μmol, 1.5 equiv.) in degassed CH2Cl2 (60 μL) under
argon. The mixture was stirred for 3 d at room temperature under
argon. The reaction mixture was diluted with CH2Cl2 (5 mL) and
water (5 mL), the organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were dried with Na2SO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by size-exclusion
chromatography (Sephadex LH-20) using MeOH, to give pure tetra-
ppm. IR: ν = 3281 (N–H), 3089 and 3062 (=C–H), 2961, 2926, and
˜
2856 (C–H), 1749 (C=O), 1669 (NH–C=O) cm–1. HRMS (ESI): calcd.
for C66H90N3O29S [M + H]+ 1420.5381; found 1420.5332.
Propargyl 2,4,6-Tri-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-
ꢀ-
D
-glucopyranosyl)-3-O-benzyl-α-
D
-mannopyranoside (24):
saccharide 25 (14 mg, 83 %) as a white amorphous solid.
1
Compound 24 was obtained using donor 1ꢀ (157 mg, 0.402 mmol, [α]2D0: –9.9 (c = = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.01 (s,
6 equiv.), TTBP (100 mg, 0.402 mmol, 6 equiv.), Fe(OTf)3·6.2DMSO
1 H, 9-H), 7.45 (d, JNH,B2 = 6.0 Hz, 1 H, B-NH), 7.39–7.30 (m, 5 H, Ph),
(10 mg, 0.010 mmol, 15 mol-%), and acceptor 22 (22 mg, 7.03 (d, JNH,D2 = 9.0 Hz, 1 H, D-NH), 5.82 (t, JB3,B2 = JB3,B4 = 10.0 Hz,
0.067 mmol, 1 equiv.) in dry CH2Cl2 (1 mL), according to the general 1 H, B3-H), 5.54–5.47 (m, 1 H, C-NH), 5.31 (t, JD3,D2 = JD3,D4 = 10.0 Hz,
procedure (110 °C under microwave irradiation, 3 h). After work-up,
the crude product was prepurified by chromatography on silica gel
(heptane/EtOAc, 3:7 to 0:1, then CH2Cl2/MeOH, 9:1), and purified by
C18 reverse-phase preparative HPLC using the Luna column (water/
acetonitrile, 6:4 for 2 min, then 6:4 to 45:55 over 30 min) to give
pure tetrasaccharide 24 (16 mg, 18 %) as a pale yellow amorphous
1 H, D3-H), 5.26 (d, JB1,B2 = 8.0 Hz, 1 H, B1-H), 5.04 (t, JD4,D3 = JD4,D5 =
10.0 Hz, 1 H, D4-H), 5.04 (t, JC4,C3 = JC4,C5 = 10.0 Hz, 1 H, C4-H), 4.97
(t, JB4,B3 = JB4,B5 = 10.0 Hz, 1 H, B4-H), 4.93 (s, 1 H, A1-H), 4.92 (t,
JC3,C2 = JC3,C4 = 10.0 Hz, 1 H, C3-H), 4.74 (d, J = 10.5 Hz, 1 H, CH2Ph),
4.70 (d, J7,7′ = 12.5 Hz, 1 H, 7-H), 4.63 (d, J7′,7 = 12.5 Hz, 1 H, 7′-H),
4.63–4.56 (m, 2 H, CH2TEG), 4.57 (d, JD1,D2 = 7.5 Hz, 1 H, D1-H), 4.40
solid. [α]2D0: –12.3 (c = 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): δ = (d, JC1,C2 = 8.0 Hz, 1 H, C1-H), 4.34–4.31 (m, 2 H, A2-H and D6-H),
7.47 (d, JNH,B2 = 6.5 Hz, 1 H, B-NH), 7.41–7.32 (m, 5 H, Ph), 7.05 (d,
JNH,D2 = 8.5 Hz, 1 H, D-NH), 5.90 (t, JB3,B2 = JB3,B4 = 10.0 Hz, 1 H, B3-
H), 5.60–5.54 (m, 1 H, C-NH), 5.39 (d, JB1,B2 = 7.5 Hz, 1 H, B1-H), 5.33
(t, JD3,D2 = JD3,D4 = 10.0 Hz, 1 H, D3-H), 5.06–4.99 (m, 3 H, B4-H, C4-
H, D4-H), 4.96–4.90 (m, 1 H, C3-H), 4.93 (s, 1 H, A1-H), 4.79 (d, J =
10.0 Hz, 1 H, CHHPh), 4.58 (d, JD1,D2 = 8.0 Hz, 1 H, D1-H), 4.42 (d,
4.23 (t, JA4,A3 = JA4,A5 = 10.0 Hz, 1 H, A4-H), 4.21–4.18 (m, 1 H, C6-
H), 4.15–4.01 (m, 7 H, A3-H, D6′-H, D2-H, B6-H, B6′-H, C6′-H, CH2Ph),
3.97 (m, 1 H, A6-H), 3.96–3.89 (m, 3 H, C2-H, CH2TEG), 3.81 (m, 1 H,
A5-H), 3.77–3.72 (m, 4 H, D5-H, B5-H and CH2TEG), 3.69–3.64 (m, 5
H, A6′-H, 2 CH2TEG), 3.59 (t, JH15,H14 = 4.5 Hz, 2 H, CH2TEG), 3.44 (ddd,
JC4,C5 = 10.0, JC5,C6 = 4.5, JC5,C6′ = 2.5 Hz, 1 H, C5-H), 3.14–3.10 (m,
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1 H, B2-H), 2.08 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3), 2.04 (s, 3 H,
COCH3), 2.04 (s, 3 H, COCH3), 2.02 (s, 3 H, COCH3), 2.01 (s, 3 H,
COCH3), 2.00 (s, 3 H, COCH3), 1.99 (s, 3 H, COCH3), 1.99 (s, 3 H,
COCH3), 1.92 (s, 3 H, COCH3), 1.89 (s, 3 H, COCH3), 1.58 (s, 3 H,
COCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.9 (C, NHCOCH3),
172.1 (C, NHCOCH3), 171.7 (C, COCH3), 171.4 (C, COCH3), 171.1 (C,
COCH3), 170.9 (2 C, COCH3), 170.6 (C, COCH3), 170.5 (C, COCH3),
170.2 (C, COCH3), 169.9 (C, COCH3), 169.8 (C, COCH3), 143.5 (C, C-8),
138.6 (C, Ph), 129.0 (4 CH, Ph), 128.6 (CH, Ph), 125.4 (CH, C-9), 104.4
(CH, C-D1), 97.9 (CH, C-C1), 96.6 (CH, C-B1), 96.3 (CH, C-A1), 73.0
(CH, C-D3), 73.0 (CH2, CH2TEG), 72.5 (CH, C-C3), 72.2 (CH, C-B5 or C-
D5), 72.0 (CH, C-B5 or C-C5 or C-D5), 71.9 (CH, C-B5 or C-C5 or C-
D5), 71.8 (CH, C-A2 or C-A3 or C-A5), 71.8 (CH, C-A2 or C-A3 or C-
A5), 71.7 (CH, C-A2 or C-A3 or C-A5), 71.3 (CH, C-A4), 71.2 (CH, C-
B3), 71.1 (CH2, C-A6), 70.9 (CH2, CH2TEG), 70.6 (CH2, CH2TEG), 70.3 (CH,
C-B4), 69.7 (CH2, CH2TEG), 69.3 (CH, C-D4), 68.9 (CH2, CH2Ph), 68.5
(CH, C-C4), 62.7 (2 CH2, C-D6 and C-B6), 62.2 (CH2, C-C6), 61.9 (CH2,
CH2TEG), 60.5 (CH2, C-7), 57.1 (CH, C-B2), 55.1 (CH, C-C2), 54.4 (CH,
C-D2), 50.5 (CH2, CH2TEG), 23.9 (CH3, COCH3), 23.8 (CH3, COCH3), 23.6
(CH3, COCH3), 21.2 (CH3, COCH3), 21.2 (CH3, COCH3), 21.2 (CH3,
COCH3), 21.1 (2 CH3, COCH3), 21.0 (2 CH3, COCH3), 21.0 (CH3,
COCH3), 23.5 (CH3, COCH3) ppm. IR: ν = 3283 (N–H), 3104 (=C–H),
˜
2919, 2875, and 2852 (C–H), 1646 (NH–C=O) cm–1. HRMS (ESI): calcd.
for C39H67N6O24 [M + H]+ 1003.4207; found 1003.4244.
Acknowledgments
The authors thank Rosemary Beau for her comments on the
manuscript, and Pauline Aubert for technical assistance. The au-
thors are grateful to the Institut de Chimie des Substances Na-
turelles for the financial support for this study. The CHARM3AT
Labex program is acknowledged for its support. The Institut
Jean-Pierre Bourgin benefits from support by the Labex Saclay
Plant Sciences-SPS (ANR-10-LABX-0040-SPS).
Keywords: Homogeneous catalysis · Microwave chemistry ·
Glycosylation · Carbohydrates · Oligosaccharides
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1
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3.83 (m, 2 H, A3-H, GlcNAc-6-H), 3.71 (dd, J6′,6 = 12.0, J6′,5 = 6.0 Hz,
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Published Online: ■
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Glycochemistry
A. Xolin, S. Norsikian,*
F.-D. Boyer,* J.-M. Beau* ............... 1–12
Iron(III)-Triflate-Catalyzed Multiple
Glycosylations with Peracetylated ꢀ-
D
-Glucosamine
One-pot multiple glycosylations of give a direct and rapid access to N-
mannopyranosides with commercially glycan mimetics.
available peracetylated glucosamine
DOI: 10.1002/ejoc.201600457
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