Modulating lectin inhibition with N-glycosyl-1,2,3-triazole scaffolds

Article abstract of DOI:10.1002/ejoc.201201674

The synthesis of three families of sialyl Lewis^X (sLe ^X) mimetics based on triazole and bis-triazole scaffolds is reported. The flexibility of these mimetics is dictated by the scaffold and gradually increases from flexible to rigid.

Full text of DOI:10.1002/ejoc.201201674

FULL PAPER
DOI: 10.1002/ejoc.201201674
Modulating Lectin Inhibition with N-Glycosyl-1,2,3-triazole Scaffolds
Itxaso Azcune,[a] Eva Balentová,[a] Maialen Sagartzazu-Aizpurua,[a] J. Ignacio Santos,[a]
Jose I. Miranda,[a] Raluca M. Fratila,*[a,b] and Jesus M. Aizpurua*[a]
Keywords: Medicinal chemistry / Click chemistry / Conformation analysis / Glycopeptidomimetics / Lectin inhibitors
The synthesis of three families of sialyl LewisX (sLeX) mi-
metics based on triazole and bis-triazole scaffolds is reported.
The flexibility of these mimetics is dictated by the scaffold
and gradually increases from flexible to rigid. All three fami-
lies were accessible by straightforward synthetic routes and
by taking advantage of the unique features and high yields
of CuI-catalyzed alkyne–azide cycloaddition (CuAAC) reac-
tion. Glycopeptidomimetics 12–15 were submitted to an ex-
tensive evaluation of their binding affinities towards fucose-
specific Ulex Europaeus lectin I by using conformational
analysis (molecular dynamics), docking calculations, and sat-
uration-transfer difference (STD) NMR experiments. The re-
sults reveal that the recognition of the ligands is mostly dic-
tated by the fucose moiety and that semi-rigid ligands are
better sLex mimic candidates because their degree of flexibil-
ity enables the modulation of their conformation to the best-
fitting position.
sation of leukocytes in the inflammatory cascade. The ex-
cessive and/or irregular infiltration of leukocytes is known
to be at the origin of chronic inflammatory diseases such
as rheumatoid arthritis and psoriasis, acute diseases such as
stroke and reperfusion injuries during organ transplan-
tation and surgery, and myocardial infarction.[5] Inhibiting
the selectin–sLeX interaction, which represents the first
event in the adhesion sequence, is an effective therapeutic
approach to these disorders and the design of sLeX mi-
metics as selectin antagonists has become a very active area
of research in biomedicinal chemistry.[5c,6]
The early strategies pursued for the design of sLex mi-
metics involved replacing the monosaccharide moieties by
non-carbohydrate linkers and metabolically labile O-glycos-
idic bonds by more stable backbones while maintaining the
two main pharmacophores: the fucose and the carboxylic
acid group of the sialic acid. For example, the low-molecu-
lar-weight Ser-Glu glycopeptides II (Figure 1) reported by
Wong[7] and Kondo[8] and their co-workers exhibited in-
creased activity and good selectivity against several lectin
receptors. However, from a drug discovery perspective, par-
tially or fully nonpeptidic compounds with reduced biode-
gradability, high oral bioavailability, absence of chiral cen-
ters, and easy availability from simple synthetic procedures
Introduction
Nature exploits the enormous structural diversity of
carbohydrates through a wide range of constructs that play
key roles in many complex biological processes.[1] More
than 50% of the proteins present in humans are glyc-
osylated and are involved in cell–cell recognition events,
neuronal development, and inflammatory processes to
name but a few. Glycosylation also affects protein-folding
and conformation, stabilizes tertiary structures, and en-
hances their proteolytic stability.[1,2] Over the past decade,
much effort has been directed towards the development of
synthetic glycopeptides and -peptidomimetics to achieve a
better understanding of their mechanism of action and to
design more efficient drugs against carbohydrate-based
metabolic disorders.[3]
Lectins are a family of nonenzymatic carbohydrate-bind-
ing proteins that have received considerable attention since
their role in a variety of recognition events was acknowl-
edged.[4] The adhesion of the tetrasaccharide sialyl LewisX
(sLeX) to the carbohydrate recognition domain (CRD) of E
and P selectins regulates the rolling, tethering, and extrava-
[a] Departamento de Química Orgánica-I, Universidad del País are of particular interest. In this direction, minimalistic an-
Vasco UPV/EHU, Joxe Mari Korta R&D Center,
tagonists bearing neither peptidic nor glycosidic moieties
Avda. de Tolosa 72, 20018 San Sebastián, Spain
were recently reported with in vitro activities in the nano-
molar and low micromolar range.[9] In addition, tuning the
flexibility of the peptidomimetic scaffold can be considered
a design variable for modulating the mimetic–lectin interac-
tion. For example, we have previously described the “shape-
modulating linker” design as a useful tool for providing
semi-flexible constructs by connecting their rigid(ified)
Fax: +34-943015383
E-mail: jesusmaria.aizpurua@ehu.es
Homepage: www.ehu.es
[b] MIRA Institute for Biomedical Technology and Technical
Medicine, University of Twente,
P. O. Box 217, 7500 AE Enschede, The Netherlands
E-mail: r.m.fratila@utwente.nl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201674.
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Modulating Lectin Inhibition with N-Glycosyltriazole Scaffolds
Figure 1. Gradually constrained “click” glycopeptide mimetics based on the tetrasaccharide sLex. II: Flexible Ser-Glu glycopeptide pro-
posed by Kondo and co-workers.[8] III–VI: Flexible, semi-rigid, and rigid mimetics based on mono- and bis-triazole scaffolds. PG: protect-
ing group.
parts through rotatable covalent bonds.[10] A hybrid glyco- the natural O-glycosidic bond was replaced by 1,2,3-triazole
peptide-β-lactam mimetic of sLex prepared by using this ap- linkages and the number of epimerizable centers was re-
proach was evaluated against Ulex Europaeus Lectin 1 duced. The “click” synthesis of the three families of sLex
(UEL-1); NMR spectroscopy and molecular dynamics mimetics synthesized in this study is displayed in Figure 1
(MD) studies showed that the binding occurred after a along with the structures of the key intermediates.
“bent-to-extended” conformational change around a tri-
The flexible analogues 6a–c were obtained in good over-
azolylmethylene unit. Herein we report the design and syn- all yields following a straightforward synthetic route
thesis of three new families of glycopeptidomimetics based (Scheme 1). Dipeptides 3a,b were synthesized by the
on 1,2,3-triazole scaffolds as well as the NMR spectro- EEDQ-promoted coupling of Fmoc-l-propargylglycine 1
scopic evaluation of the binding ability of compounds III– and protected α-aminoisobutyrate esters 2a,b. Upon Fmoc
VI (Figure 1) towards UEL-1 lectin. We also provide a ra- group removal with 20% piperidine in DMF and acetyl-
tionale of the effect of different degrees of flexibility on the ation with excess acetic anhydride, alkynyl-dipeptides 4a,b
peptidomimetic–lectin interaction.
were submitted to the CuAAC reaction with per-O-acet-
ylated 1-α-azido-d-mannose and 1-β-azido-l-fucose under
Sharpless conditions.[11]
The synthesis of the semi-rigid glycopeptide bis-triazoles
11 was accomplished starting from the commercially avail-
able 1-trimethylsilyl-1,4-pentadiyne (7) by two consecutive
CuAAC reactions with a glycosyl azide and an α-azido
cycloaddition acid. To avoid problems of thermodynamic stability associ-
Results and Discussion
Synthesis
The
CuI-catalyzed
alkyne–azide
(CuAAC)[11] reaction required to form the triazole unit is ated with the low-molecular-weight azides, the correspond-
remarkably atom-efficient, displays full anomer and config- ing benzyl esters 8, having a higher C/N atom ratio than
urational control, and tolerates both O-protected and free the parent azido-acids, were prepared and used in the click
glycosyl azides.[12] Thus, we envisaged the use of CuAAC to reactions. Benzyl azidoacetate (8a) and benzyl 2-azidoiso-
easily construct scaffolds with tunable mobility and op- butyrate (8b) were obtained in good yields following a
tional chirality that can be employed for the synthesis of modified CuII-catalyzed diazo transfer reaction.[13] The first
sLex analogues. The design of glycopeptidomimetics III–VI CuAAC reaction under Sharpless conditions led to the for-
follows an increasing conformational constraint criterion mation of symmetrically substituted bis-triazoles together
ranging from flexible to rigid. Moreover, to minimize biode- with desilylated products. To investigate the origin of this
gradability and to avoid epimerization at α carbon atoms, failure, the stability of the trimethylsilyl group of the dialk-
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ascorbate were added. Rapid proton/deuterium exchange at
the terminal alkyne was observed; more importantly, no de-
silylated products were identified after 24 h, which indicates
Scheme 1. Synthesis of flexible glycopeptidomimetic precursors 6a–
c. Reagents and conditions: a) EEDQ, CH2Cl2, –10 °C to room
temp., 16 h; b) 20% piperidine in DMF, 30 min, room temp.;
c) Ac2O, K2CO3, room temp.; d) CuSO4·5H2O, Na ascorbate,
tBuOH/H2O/THF, 1:1:1, 16 h, room temp. EEDQ: N-ethoxycarb-
onyl-2-ethoxy-1,2-dihydroquinoline; Fmoc: 9H-fluoren-9-ylmeth-
oxycarbonyl.
yne 7 was tested under slightly basic sodium ascorbate con-
ditions. A CD3OD/D2O solution of compound 7 was pre-
pared in a NMR tube and then CuSO4·5H2O and sodium
Table 1. Synthesis of unsymmetrically substituted bis-triazoles 11.[a]
[a] Reaction conditions: a) CuI, DIPEA, TBTA, MeCN, room
temp., 16 h; b) CsF, MeCN, room temp. to 35 °C, 1–3 h;
c) CuSO4·5H2O, Na ascorbate, tBuOH/H2O, 1:1, 16 h, room temp.
[b] Yield of the isolated pure product. DIPEA: N,N-diisopropyl-
ethylamine; TBTA: tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-
amine.
Figure 2. a) Glycopeptidomimetics selected for conformational
analysis and binding evaluation. b) Molecular dynamics simula-
tions of sLex mimetics 12–15. Dihedral angles are defined as fol-
lows: ψ: 1–2–3–4; φ: 2–3–4–5 (for 12–14); φ: 4–5–6–7 (for 15).
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Modulating Lectin Inhibition with N-Glycosyltriazole Scaffolds
that the desilylation occurred after the formation of the tri- of the rotational freedom around the C3–C4 and C2–C3
azole. Therefore, with the aim of preventing hydrolytic desil- bonds of the methylene bridge. Interestingly, the analogue
ylation, the CuAAC reaction was conducted under anhy- 13 has three clusters of conformers with the two most popu-
drous conditions (Table 1). Addition of TBTA as catalyst lated ones corresponding to an extended (A) and bent (B)
was necessary to reduce the reaction times.[14] Deprotection conformation. In the ROESY spectrum, a cross-peak was
of the trimethylsilyl group with caesium fluoride yielded the identified between the triazole proton and the pro(R)-β-lac-
alkynyltriazoles 10, which were submitted to a second click tam proton, but no correlation was observed between the
reaction under Sharpless aqueous conditions to provide the Aib methyl group and the fucose protons, which indicates
bis-triazoles 11a–d.
that the mimetic 13 adopts a bent conformation in solution.
Finally, fucose-derived peptidomimetics 12–15 (Figure 2, Elimination of the conformational constraint induced by
a) were selected to represent the designed ligands III–VI in the β-lactam ring led to two main conformational clusters
a conformational analysis and evaluation of the lectin bind- for analogue 12 with 80% of the conformers adopting an
ing. Compounds 12 and 14a,b were obtained form the O- extended disposition (A).
protected precursors 6c and 11c,d in practically quantitative
Docking calculation allowed the estimation of the bind-
yields by a two-step deprotection procedure involving Pd- ing energies of the ligands and the prediction of their “best-
catalyzed hydrogenolysis of the benzyl ester protecting fit” orientation to form the more stable complex with the
group and removal of the O-acetyl groups by treatment receptor. Figure 3 shows the binding energy histograms for
with sodium methoxide. β-Lactam mimetic 13 was synthe- the six glycopeptidomimetics evaluated in this study. The
sized as previously reported,[10] whereas rigid analogues greater the energy released, the more stable the complex
15a,b were accessible following the “click–click” strategy and the corresponding conformation is more likely to un-
previously described by our group for the synthesis of non- dergo a binding interaction. Both the semi-rigid and rigid
symmetrical bis(1,2,3-triazoles).[12c]
bis-triazole derivatives 14 and 15 showed highly populated
clusters, whereas the β-lactam analogue 13 showed the
highest dispersion of binding energies. The calculated bind-
ing energies range between –9 and –7.5 kcalmol–1, with the
semi-rigid scaffold 14a being the best ligand (–9 kcalmol–1)
followed by 14b and 13. A superimposition of the ligands
12–15 in the active site of the Ulex Europaeus Lectin I is
Evaluation of the Binding Affinity of Glycopeptidomimetics
12–15
The binding affinities of fucose glycopeptidomimetics displayed in Figure 3 (for pictures of the individual docking
12–15 towards Ulex Europaeus Lectin I (UEL-I) were evalu- of each ligand, see the Supporting Information). The fucose
ated by using a combination of NMR techniques, molecular and carboxylic acid groups of all the sLex mimetics evalu-
dynamic modeling, and docking simulations. In the first in- ated in this study interact with the same sites of the fucose-
stance, a computational conformational analysis of the sLex selective pocket of UEL-I. However, the type of scaffold
mimetics was conducted to identify their most stable con- used induces remarkable differences between the ligands.
formers. The molecular dynamics simulations were carried For example, the pyranose rings of mimetics 12–14 show an
out with NAMD[15] by using the AMBER force field in exact overlap whereas the fucose group of 15 is slightly
vacuo at 298 K for a simulation time of 12 ns. The defini- tilted. The flexibility of the mimetics to accommodate the
tion of the torsion angles φ and ψ, the Ramachandran plots two pharmacophores in the pocket was estimated from the
(φ vs. ψ), and the structures of the main conformers of the distance between the fucose pyranosic oxygen atom and the
glycopeptidomimetics 12–15 are presented in Figure 2 (b). carboxyl carbon atom and it was found to vary from the
ROESY experiments were performed at 400 MHz on aque- shortest for the ligand 13 (6.0 Å, in yellow) to longer values
ous solutions of the same mimetics to compare the consist- for the rigid bitriazoles 15a (10.3 Å, in pink) and 15b
ency of the experimental data with the MD predictions (see (10.1 Å, in red). The acetamide groups of ligands 12 and
the spectra in the Supporting Information). The differences 13 point outwards from the binding pocket and may be
in flexibility between the three families of scaffolds are clear functionalized with hydrophobic appendages to interact
from the Ramachandran representations. Not surprisingly, with the surface of the lectin. According to the fucose/
a single cluster was detected for the rigid mimetics 15 in UEL-I lectin crystal structure, the binding pocket of the
which the bitriazole scaffold is like a rod and the fucose and protein is formed by 11 amino acids, namely Glu-44, Thr-
amino acid moieties, placed at the edges, may turn like the 86, Asp-87, Gly-105, Tyr-106, Thr-113, Asp-127, Asn-134,
sails of a windmill. The anti disposition of the two conju- Phe-135, Trp-136, and Tyr-219.[16] Because Ulex Europaeus
gated triazole rings is stabilized by the aromaticity of the Lectin I is a calcium-dependent protein, a calcium cation in
system, as confirmed by the absence of cross-peaks between close contact or even coordinated to the Asp-127, Asn-134,
the triazole C5 protons in the ROESY spectra of derivatives and Asp-137 residues is also present at the binding site. The
15a and 15b. The insertion of a methylene group between fucose group is situated about 5 Å from the Ca2+ ion and
the triazole units changes drastically the conformational can form hydrogen bonds with Glu-44, Asp-87, Gly-105,
properties of the semi-rigid glycopeptidomimetics 14 with and Asn-134. In addition, the hydrocarbon pyranose ring
respect to their rigid counterparts. Each semi-rigid ana- and the methyl group may undergo hydrophobic interac-
logue shows two main conformational clusters as a result tions with apolar or aromatic amino acid moieties situated
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R. M. Fratila, J. M. Aizpurua et al.
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in close proximity, for example, interactions with the Tyr-
219 and Arg-222 residues were detected by the AutoDock
program.
Figure 3. Top: Binding energy histograms for the sLex mimetics 12–
15. Bottom: Superimposition of the docked conformers of glyco-
peptidomimetics 12–15 in the Ulex Europaeus Lectin I fucose-selec-
tive pocket.
To verify the findings of the molecular dynamics and
docking simulations, saturation-transfer difference (STD)
NMR experiments were carried out. STD NMR enables
the detection of transient binding of small ligands to mac-
romolecular receptors by identifying the changes in the in-
tensities of the resonance signals of the ligand protons in-
1
volved in the interaction with the receptor.[17] The H and
STD NMR spectra of the sLex mimetics 12–15 are pre-
sented in Figure 4. STD effects were observed for all six
analogues, which indicates an efficient interaction with the
UEL-I lectin (see the Supporting Information for details
on the pulse sequence and sample preparation). In general,
fucose exhibits the strongest signals. However, the interac-
tion of the carboxylic acid, considered as the other pharma-
cophore, could not be detected because the NMR experi-
ments were carried out in deuterated water. For the flexible
ligand 12, the most intense signal is displayed by the fucose
methyl protons H6. The other sugar protons show moder-
ate intensities (44–68%) and the STD effect on the triazole,
acetamide, and Aib groups is less than 20%. The closely
related analogue 13, which carries the β-lactam ring, shows
a similar STD pattern with the most intense signals given
by fucose protons H4 and H3. In both ligands, the central
part of their scaffolds (represented in 12 by the methylene
1
Figure 4. STD and H NMR (500 MHz, D2O, 298 K) spectra ac-
quired for glycopeptidomimetics 12–15.
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Modulating Lectin Inhibition with N-Glycosyltriazole Scaffolds
gen in oven- or flame-dried glassware with magnetic stirring. Dry
DMF was purchased from Sigma–Aldrich in Sure-seal™ bottles
and used without further purification. THF and diethyl ether were
purified using PS-MD2 columns. Extra pure dichloromethane,
acetonitrile, hexane, and ethyl acetate were purchased from Schar-
lau. The aqueous solutions used in the click reactions were pre-
pared with H2O previously degassed by nitrogen bubbling for a
period of 30 min. Reaction products were purified by flash
chromatography using silica gel 60 (230–400 mesh). Analytical
TLC was performed on 0.25 mm silica gel 60-F plates. Visualiza-
bridge labeled as H8, and in 13 by the CH2 α protons and
the methylene of the β-lactam, labeled as H8 and H9) do
not take part in the interaction. These results are confirmed
by the docking structures in which the methylene bridges
bulge outside so the ligand can reach the saccharide binding
pocket and the Arg-102 residue. Semi-rigid ligand 14a
shows STD intensities in the range of 65–100% for the sac-
charide moiety, and weak effects for the methylene bridge
protons H8 and the Aib methyl groups (H10–H11). None
of the triazole protons H7 and H9 were found to be in close tion was achieved with UV light and phosphomolybdic acid/ceric
ammonium nitrate/sulfuric acid/water reagent followed by heating.
1H and 13C NMR spectra were recorded at 500 and 125 MHz.
Chemical shifts are reported as δ values [ppm] relative to residual
contact with the protein surface, as revealed by the absence
of any STD effect. According to the docking simulation,
the triazole rings are positioned in such a way that the ni-
trogen atoms may be involved in hydrogen-bond formation
and the triazole protons would point outside of the binding
pocket without interacting with the surface. This is in fact
the binding that gives the highest energy release (Figure 3).
However, ligand 14b, which differs from 14a only in the
absence of the two α-methyl groups, shows the triazole pro-
CDCl3 (δH = 7.26 ppm, δC = 77.16 ppm) or [D6]DMSO (δH
=
2.5 ppm, δC = 36.46 ppm) as internal standards. Mass spectra were
recorded under either EI (70 eV) or CI conditions after direct injec-
tion (HRMS) or by GC–MS (column: fused silica gel,
15 mϫ0.25 mm, 0.25 nm phase SPB-5). Melting points were mea-
sured with a Büchi SMP-20 melting point apparatus. IR spectra
were recorded with a Shimadzu IR-435 spectrophotometer and
tons in contact with the surface (STD intensities of 31% samples were prepared in KBr pellets. Optical rotations were mea-
sured with a Perkin–Elmer 243B polarimeter using a sodium lamp
(589 nm, D line) at 25Ϯ0.2 °C. Molecular dynamics simulations
were carried out with the NAMD AMBER-11 force field in vacuo
at 298 K for a simulation time of 12 ns. The most stable conformers
of glycopeptidomimetics 12–15 were docked on the reported struc-
ture of Ulex Europeaus Lectin I (pdb code, 1JXN). Then different
possibilities of arranging the side-chain were used as input geome-
tries for AutoDock 3.0 simulations with the multiple Lamarckian
Genetic Algorithm. Grids of probe atom interaction energies and
electrostatic potentials were generated by the AutoGrid program
available in AutoDock 3.0. Grid spacings of 0.6 and 0.375 Å were
used for the global and local searches, respectively. For each calcu-
lation, 100 docking runs were performed by using a population
of 200 individuals and an energy evaluation number of 3ϫ106.
Saturation transfer difference (STD) experiments were performed
without saturation of the residual HDO signal for molar ratios be-
tween 40:1 of compound/lectin. A train of Gaussian-shaped pulses
of 50 ms each was employed with a total saturation time of the
protein envelope of 2 s and a maximum B1 field strength of 50 Hz.
An off-resonance frequency of δ = 40 ppm and on-resonance fre-
quencies between δ = –1.0 ppm (protein aliphatic signals region)
were applied. In all cases, the line broadening of ligand protons
was monitored.
for H7 and 25% for H9) and shows moderate STD effects
for the methylene bridge (H8, 30%) and the glycine protons
(H10, 27%). Again, the strongest effect was observed for
the fucose protons with intensities between 49 and 100%.
The rigid analogues 15a,b do not possess the ability to mod-
ulate the distance between the two pharmacophores. They
produce very similar STD spectra with low intensities for
the triazole and amino acid protons and moderate-to-high
intensities for the fucose protons.
Conclusions
We have developed three new families of “dipeptide-like”
molecular scaffolds 12–15, characterized by decreasing flex-
ibility and controlled stereochemistry. The utility of these
scaffolds for the preparation of Ser-Glu-type glycopeptido-
mimetics was demonstrated by taking advantage of readily
available azido-glycosides and azido-acids, and the high
yields, orthogonality, and anomeric integrity of the CuAAC
click reaction.
A combined conformational and binding study of fu-
cose-related glycopeptidomimetics 12–15 by molecular dy-
namics, docking, and NMR experiments revealed that the
recognition of the ligands by Ulex Europaeus Lectin I is
dictated mostly by the fucose moiety. Scaffolds with a cer-
tain degree of flexibility proved better than rigid ones at
inducing an effective dual interaction with the lectin be-
cause of the ability to modulate their conformation to the
best-fitting position. Based on these results, we believe that
mono- and bis-triazoles can be useful as scaffolds for con-
structing semi-flexible minimalistic and universal peptido-
mimetics.[18] This aspect is under investigation in our labo-
ratory.
Benzyl Azidoacetate (8a): CuSO4·5H2O (0.013 mmol, 3.2 mg) and
Et3N (2.6 mmol, 0.36 mL) were added to a solution of benzyl glyc-
inate (1.3 mmol, 216 mg) in MeCN (5 mL) at 0 °C, followed by
the dropwise addition of freshly prepared TfN3 (1.57 mmol). The
mixture was allowed to reach ambient temperature overnight, the
solvent was evaporated under reduced pressure, and the crude
product was purified by column chromatography (Hex/EtOAc,
3:1), yield 146 mg (60%). Colorless oil. 1H NMR (500 MHz,
CD3OD): δ = 7.37 (m, 5 H, Ar), 5.23 (s, 2 H, OCH2), 3.91 (s, 2 H,
NCH2) ppm.
Benzyl α-Azidoisobutyrate (8b): CuSO4·5H2O (0.015 mmol, 3.7 mg)
and Et3N (3 mmol, 0.42 mL) were added to a solution of benzyl
α-aminoisobutyrate (1.5 mmol, 290 mg) in MeCN (8 mL) at 0 °C,
followed by the dropwise addition of freshly prepared TfN3
(1.8 mmol). The mixture was allowed to reach ambient temperature
overnight. The solvent was then evaporated under reduced pressure
and the product was purified by column chromatography (Hex/
Experimental Section
General: All commercially available products were used as supplied
unless otherwise stated. All reactions were carried out under nitro-
1
EtOAc, 3:1), yield 175 mg (55%). H NMR (500 MHz, CD3OD):
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δ = 7.38–7.35 (m, 5 H, Ar), 5.22 (s, 2 H, OCH2), 1.49 (s, 6 H,
= 12.3 Hz, 1 H, OCH2Ph), 5.14 (d, J = 12.3 Hz, 1 H, OCH2Ph),
Me) ppm.
4.52–4.48 (m, 1 H, NHCH), 2.72 (ddd, J1 = 17.0, J2 = 5.4, J3
2.6 Hz, 1 H, CHCH2CCH), 2.49 (ddd, J1 = 17.0, J2 = 7.5, J3
2.6 Hz, 1 H, CHCH2CCH), 2.05 (t, 1 H, CCH), 1.98 (s, 3 H, Ac),
1.59 (s, 3 H, Me), 1.57 (s, 3 H, Me) ppm. 13C NMR (125 MHz,
CDCl3): δ = 173.9, 170.3, 169.1, 135.8, 128.6, 128.4, 128.2, 79.7,
71.6, 67.3, 56.9, 51.6, 24.9, 24.7, 23.16, 22.4 ppm.
=
=
Fmoc-Gly(propargyl)-Aib-OMe (3a): EEDQ (1.34 mmol, 331 mg)
was added to
(0.819 mmol,
a
solution of methyl α-aminoisobutyrate
96 mg) and (S) Fmoc-Gly(propargyl)-OH
(0.745 mmol, 250 mg) in CH2Cl2 (20 mL) cooled to –10 °C. The
suspension was allowed to reach ambient temperature overnight.
The reaction mixture was diluted with CH2Cl2, washed with 1 m
HCl solution, and the product purified by column chromatography
(silica gel, EtOAc/hexanes), yield 291.3 mg (90%). White solid; m.p.
(3S)-Ac-Gly{α-[N-(2,3,4,6-tetra-O-acetyl-β-D-mannosyl)-4-triazolyl-
methyl]}-Aib-OMe (6a): Compound 4a (0.082 mmol, 21 mg) and 1-
azido-2,3,4,6-tetra-O-acetyl-α-d-mannose (5a) (0.083 mmol,
31 mg) were dissolved in tBuOH/THF/H2O (6 mL, 1:1:1) under N2
and CuSO4·5H2O (0.02 mmol, 5 mg) and sodium ascorbate
(0.04 mmol, 7 mg) were added. The reaction mixture was stirred
overnight. Then the organic solvents were evaporated under re-
duced pressure and the product was extracted with EtOAc or
CH2Cl2. The organic layer was dried with MgSO4, the solvent was
evaporated, and the crude product purified by flash or column
chromatography (Hex/EtOAc, 1:1), yield 46 mg (90%). White solid;
m.p. 74–75 °C. [α]2D0 = +22.06 (c = 1.01, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.69 (s, 1 H, triazole), 7.18 (s, 1 H, NH),
1
124–125 °C. [α]2D0 = +7.62 (c = 0.8, CH2Cl2). H NMR (500 MHz,
CDCl3): δ = 7.78–7.30 (m, 8 H, Ar), 6.81 (br. s, 1 H, NH), 5.60
(br. s, 1 H, NH), 4.45–4.49 (br. s, 2 H, CH2 Fmoc), 4.35.4.15 (br.
s, 1 H, CH), 4.24 (dd, J = 6.9, J = 6.9 Hz, 1 H, CH2 Fmoc), 3.75
(s, 3 H, OMe), 2.82–2.78 (m, 1 H, CH2), 2.59–2.57 (m, 1 H, CH2),
2.12 (s, 1 H, CCH), 1.59 (s, 3 H, Me), 1.58 (s, 3 H, Me) ppm. 13C
NMR (125 MHz, CDCl3): δ = 174.8, 168.9, 156.0, 143.8, 141.5,
127.9, 127.2, 125.2, 120.2, 79.5, 72.0, 67.4, 57.1, 53.5, 52.9, 47.3,
24.7, 24.7, 22.9 ppm. IR (KBr): ν = 3336, 3309 (NH), 1739, 1684,
˜
1652 (C=O), 1549 cm–1.
Fmoc-Gly(propargyl)-Aib-OBn (3b): EEDQ (0.89 mmol, 221 mg) 6.92 (d, J = 7.3 Hz, 1 H), 5.97 (s, overlapped 2 H, mannose 1-H,
was added to a solution of benzyl α-aminoisobutyrate (0.96 mmol, 2-H), 5.84 (d, J = 9.0 Hz, 1 H, mannose 3-H), 5.36 (dd, J1 = 9.1,
187 mg) and Fmoc-Gly(propargyl)-OH (0.745 mmol, 250 mg) in J2 = 9.1 Hz, 1 H, mannose 4-H), 4.74 (dd, J1 = 12.5, J2 = 6.0 Hz,
CH2Cl2 (20 mL) cooled to –10 °C. The suspension was allowed to
reach ambient temperature overnight. The reaction mixture was
then diluted with CH2Cl2, washed with 1 m HCl solution, and the
product purified by column chromatography (silica gel, EtOAc/hex-
1 H, CH), 4.35 (dd, J1 = 12.5, J2 = 5.2 Hz, 1 H, mannose 6Ј-H),
4.05 (dd, J1 = 12.5, J2 = 1.8 Hz, 1 H, mannose 6-H), 3.86–3.83 (m,
1 H, mannose 5-H), 3.68 (s, 3 H, OMe), 3.30 (dd, J1 = 15.0, J2 =
4.7 Hz, 1 H, CH2), 3.10 (dd, J1 = 14.9, J2 = 6.1 Hz, 1 H, CH2),
anes), yield 311 mg (82%). Colorless oil. 1H NMR (500 MHz, 2.17 (s, 3 H, Ac), 2.08 (s, 3 H, Ac), 2.05 (s, 3 H, Ac), 2.04 (s, 3 H,
CDCl3): δ = 7.78–7.30 (m, 8 H, Ar), 6.83 (br. s, 1 H, NH), 5.60 Ac), 2.03 (s, 3 H, Ac), 1.46 (s, 6 H, Me Aib) ppm. 13C NMR
(br. s, 1 H, NH), 5.17 (s, 2 H, CH2Ph), 4.46–4.21 (m, 4 H, CHCH2 (125 MHz, CDCl3): δ = 174.6, 170.7, 170.6, 169.9, 169.7, 169.7,
Fmoc, CH), 2.75–2.73 (m, 1 H, CHCH2C), 2.54–2.51 (m, 1 H,
169.5, 144.5, 123.3, 83.9, 72.3, 69.0, 68.3, 66.2, 61.7, 56.6, 52.7,
CHCH2C), 2.06 (br. s, 1 H, CCH), 1.60 (s, 3 H, Me), 1.59 (s, 3 H, 52.5, 27.7, 24.9, 24.8, 23.4, 20.8, 20.8, 20.7 ppm. IR (KBr): ν =
˜
Me) ppm.
3279, 2955, 2925, 1750, 1652, 1546, 1436, 1226 cm–1. CID-MS/MS
[ESI(+)]: MS+1: m/z (%) = 628; MS2(628) = 628.1 (100), 511 (37),
331 (17). HRMS: calcd. for C26H37N5O13 628.2466 [M + 1]+; found
628.2470. MS (TOF CI): m/z (%) = 331.1 (100), 169.0 (82), 628.2
(41), 484.2 (41), 511.2 (35), 483.2 (26).
Ac-Gly(propargyl)-Aib-OMe (4a): Compound 3a (0.65 mmol,
281 mg) was treated with 20% piperidine in DMF (10 mL) at ambi-
ent temperature for 30 min. Then the solvent and excess piperidine
were evaporated under reduced pressure. The crude white solid was
treated with Ac2O (10 mL) at ambient temperature for 20 min. The
excess of reagent was evaporated under reduced pressure and the
resulting crude product was purified by preparative TLC (CH2Cl2);
the product remained on the base line, yield 148 mg (90%). White
solid; m.p. 110 °C. [α]2D0 = +2.63 (c = 0.34, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.00 (br. s, 1 H, NH), 6.44 (br. s, 1 H, NH),
4.57–4.53 (m, 1 H, CH), 3.73 (s, 3 H, OMe), 2.77–2.72 (m, 1 H,
CH2), 2.60–2.55 (m, 1 H, CH2), 2.09 (d, J = 2.4 Hz, 1 H, CH), 2.03
(s, 3 H, Ac), 1.56 (s, 3 H, Me), 1.55 (s, 3 H, Me) ppm. 13C NMR
(125 MHz, CDCl3): δ = 174.7, 170.3, 169.1, 79.7, 71.75, 57.0, 52.8,
(3S)-Ac-Gly{α-[N-(2,3,4-tri-O-acetyl-β-L-fucosyl)-4-triazolyl-
methyl]}-Aib-OMe (6b): Compound 4a (0.136 mmol, 34 mg) and
peracetylated l-fucose β-azide (5b) (0.202 mmol, 64 mg) were dis-
solved in tBuOH/THF/H2 O (6 mL, 1:1:1) under N2 and
CuSO4·5H2O (0.028 mmol, 7 mg) and sodium ascorbate
(0.05 mmol, 11 mg) were added. The reaction mixture was stirred
overnight. Then the organic solvents were evaporated under re-
duced pressure and the product was extracted with EtOAc or
CH2Cl2. The organic layer was dried with MgSO4, the solvent was
evaporated, and the crude product purified by flash or column
chromatography (Hex/EtOAc, 1:1), yield 69 mg (89%). White solid;
m.p. 119–120 °C. [α]2D0 = +15.50 (c = 0.71, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.75 (s, 1 H, triazole), 7.18 (s, 1 H, NH),
6.79 (d, J = 7.2 Hz, 1 H, NH), 5.74 (d, J = 9.2 Hz, 1 H, fucose 1-
H), 5.45 (dd, J1 = 9.7, J2 = 9.7 Hz, 1 H, fucose 2-H), 5.37 (d, J =
2.6 Hz, 1 H, fucose 4-H), 5.23 (dd, J1 = 10.2, J2 = 3.0 Hz, 1 H,
fucose 3-H), 4.67 (dd, J1 = 11.6, J2 = 6.0 Hz, 1 H, CH), 4.12–4.08
(m, 1 H, fucose 5-H), 3.69 (s, 3 H, OMe), 3.29 (dd, J1 = 14.9, J2 =
4.4 Hz, 1 H, CH2), 3.07 (dd, J1 = 14.9, J2 = 6.0 Hz, 1 H, CH2),
2.23 (s, 3 H, Ac), 2.06 (s, 3 H, Ac), 2.00 (s, 3 H, Ac), 1.89 (s, 3 H,
Ac), 1.48 (s, 3 H, Me), 1.47 (s, 3 H, Me), 1.23 (d, J = 6.3 Hz, 3 H,
Me Fuc) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.7, 170.5,
170.4, 169.9, 169.8, 169.4, 144.0, 121.3, 86.4, 72.7, 71.2, 70.0, 68.3,
60.4, 56.5, 52.6, 52.5, 28.0, 24.7, 24.7, 23.2, 20.6, 20.6, 20.3,
51.7, 24.8, 24.7, 23.3, 22.5 ppm. IR (KBr): ν = 3322, 3296, 3266
˜
(NH), 1751, 1738, 1636 (CO), 1558, 1525 cm–1. CID-MS/MS
(ESI(+)): MS+1: m/z (%) = 255; MS2(255) = 117.9 (100), 57.6 (31).
HRMS: calcd. for C12H18N2O4 255.1345 [M + 1]+; found 255.1357.
MS (TOF CI): m/z (%) = 118.1 (100), 111.1 (59), 223.1 (50), 110.1
(36), 138.1 (30), 237.1 (24).
Ac-Gly(propargyl)-Aib-OBn (4b): Compound 3b (0.73 mmol,
374 mg) was treated with 20% piperidine in DMF (10 mL) at ambi-
ent temperature for 30 min. Then the solvent and excess piperidine
were evaporated under reduced pressure and the crude was purified
by flash chromatography. The amine was treated with Ac2O at
room temperature for 30 min. The product was purified by column
chromatography (Hex/EtOAc, 3:1), yield 147 mg (60%). Colorless
oil. 1H NMR (500 MHz, CDCl3): δ = 7.38–7.32 (m, 5 H, Ph), 6.92
(br. s, 1 H, AcNH), 6.25 (d, J = 6.8 Hz, 1 H, NHAib), 5.18 (d, J
16.1 ppm. IR (KBr): ν = 3288 (NH), 1751, 1653 (C=O), 1539 cm–1.
˜
2440
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2434–2444

Modulating Lectin Inhibition with N-Glycosyltriazole Scaffolds
(3S)-Ac-Gly{α-[N-(2,3,4-tri-O-acetyl-β- -fucosyl)-4-triazolyl-
L
13C NMR (125 MHz, CDCl3): δ = 166.2, 144.7, 134.6, 129.0, 128.9,
methyl]}-Aib-OBn (6c): Compound 4b (0.303 mmol, 100 mg) and
per-O-acetylated l-fucose β-azide (5b; 0.32 mmol, 110 mg) were
dissolved in tBuOH/THF/H2O (9 mL, 1:1:1) under N2 and
CuSO4·5H2O (0.06 mmol, 15 mg) and sodium ascorbate
(0.12 mmol, 26 mg) were added. The reaction mixture was stirred
overnight. Then the organic solvents were evaporated under re-
duced pressure and the product was extracted with EtOAc or
CH2Cl2. The organic layer was dried with MgSO4, the solvent was
evaporated, and the crude product purified by column chromatog-
raphy (Hex/EtOAc, 1:1), yield 166 mg (85%). White solid; m.p.
75 °C (decomp.). [α]2D0 = +8.31 (c = 1.0, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.71 (s, 1 H, triazole), 7.34–7.24 (m, 5 H,
Ph), 6.69 (d, J = 7.3 Hz, 1 H, NH), 5.71 (d, J = 9.2 Hz, 1 H, fucose
1-H), 5.42 (dd, J1 = 10.0, J2 = 9.9 Hz, 1 H, fucose 2-H), 5.35 (d, J
= 3.0 Hz, 1 H, fucose 4-H), 5.21 (dd, J1 = 10.3, J2 = 3.3 Hz, 1 H,
fucose 3-H), 5.11 (d, J = 12.6 Hz, 1 H, OCH2Ph), 5.08 (d, J =
12.6 Hz, 1 H, OCH2Ph), 4.62 (q, J = 6.2 Hz, 1 H, fucose 5-H), 4.07
(dd, J = 6.2 Hz, 1 H, CH), 3.23 (dd, J1 = 15.0, J2 = 4.6 Hz, 1 H,
CH2), 3.01 (dd, J1 = 15.0, J2 = 6.1 Hz, 1 H, CH2), 2.20 (s, 3 H,
Ac), 1.98 (s, 3 H, Ac), 1.97 (s, 3 H, Ac), 1.86 (s, 3 H, Ac), 1.48 (s,
6 H, Me Aib), 1.20 (d, J = 6.3 Hz, 3 H, Me Fuc) ppm. 13C NMR
(125 MHz, CDCl3): δ = 174.0, 170.5, 170.5, 169.9, 169.7, 169.4,
143.9, 135.7, 128.5, 128.3, 128.1, 121.3, 86.3, 72.6, 71.1, 69.9, 68.2,
67.1, 56.5, 52.4, 27.8, 24.7, 24.5, 23.1, 20.6, 20.5, 20.3, 16.0 ppm.
128.7, 123.4, 102.2, 87.0, 68.2, 51.1, 17.9, 0.1 ppm. IR (KBr): ν
˜
= 2180, 1751 (C=O), 1197 cm–1. HRMS: calcd. for C17H21N3O2Si
328.1481 [M + 1]+; found 328.1486. MS (TOF CI): m/z = 328.1,
327.1, 312.1, 329.1.
1-[2-(Benzyloxycarbonyl)-2-propyl]-4-[3-(trimethylsilyl)prop-2-ynyl]-
1H-1,3,3-triazole (9b): CuI (0.16 mmol, 31 mg) and DIPEA
(4.1 mmol, 0.70 mL) were added to a solution of 1-trimethylsilyl-
1,3-pentadiyne (0.98 mmol, 0.17 mL), benzyl α-azidoisobutyrate
(8b; 0.82 mmol, 179 mg), and TBTA (8.2 μmol, 4.3 mg) in acetoni-
trile under N2. The mixture was stirred at ambient temperature
overnight. After completion, the solvent was evaporated under re-
duced pressure and the product was purified by flash chromatog-
raphy, yield 140 mg (40 %). Colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 7.67 (br. s, 1 H, triazole), 7.35–7.23 (m, 5 H, Ph), 5.16
(s, 2 H, CH2Ph), 3.73 (s, 2 H, CH2C), 1.96 (s, 6 H, Me), 0.18 (s, 9
H, SiMe3) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.1, 143.5,
135.0, 128.6, 128.5, 127.9, 127.9, 120.5, 102.5, 86.5, 67.8, 64.5, 25.6,
17.8, 0.0 ppm. IR (KBr): ν = 3290, 2957, 2179, 1745 (C=O), 1498,
˜
1456, 1272, 1153 cm–1. HRMS: calcd. for C19H25N3O2Si 356.1794
[M + 1]+; found 356.1808. MS (TOF CI): m/z = 356.2, 178.1, 192.1,
355.2, 357.2.
1-(2,3,4-Tri-O-acetyl-β-L-fucosyl)-4-[3-(trimethylsilyl)prop-2-ynyl]-
1H-1,2,3-triazole (9c): CuI (0.28 mmol, 54 mg) and DIPEA
(6.9 mmol, 1.2 mL) were added to a solution of 1-trimethylsilyl-
1,3-pentadiyne (1.73 mmol, 0.3 mL), 1-azido-2,3,4-tri-O-acetyl-β-
l-fucose (1.42 mmol, 450 mg), and TBTA (14.2 μmol, 7.5 mg) in
acetonitrile under N2. The mixture was stirred at ambient tempera-
ture overnight. After completion, the solvent was evaporated under
reduced pressure and the product was purified by flash chromatog-
raphy, yield 589.0 mg (92%). Colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 7.73 (s, 1 H, triazole), 5.79 (d, J = 9.3 Hz, 1 H, fucose
1-H), 5.57 (dd, J = 9.7 Hz, 1 H, fucose 2-H), 5.39 (d, J = 2.8 Hz,
1 H, fucose 4-H), 5.23 (dd, J = 10.2, J = 2.8 Hz, 1 H, fucose 3-H),
4.13 (q, J = 6.2 Hz, 1 H, fucose 5-H), 3.73 (s, 2 H, CH2), 2.23 (s,
3 H, Ac), 2.01 (s, 3 H, Ac), 1.89 (s, 3 H, Ac), 1.29 (d, J = 6.2 Hz, 3
H, Me), 0.19 (s, 9 H, SiMe3) ppm. HRMS: calcd. for C20H29N3O7Si
452.1853 [M + 1]+; found 452.1838. MS (TOF CI): m/z = 273.1,
153.1, 111.0, 451.2, 436.1, 452.2, 179.1, 213.1.
IR: ν = 3276, 2986, 2939, 1741 (C=O), 1648 (C=O), 1541,
˜
1214 cm–1.
(3S)-Ac-Gly{α-[N-(β-
L-fucosyl)-4-triazolylmethyl]}-Aib-OH
(12):
Compound 6c (0.076 mmol, 49 mg) was dissolved in MeOH
(3 mL), Pd/C (5 mg, 10% in mass) was added, and the suspension
was stirred for 30 min under H2. The suspension was filtered
through a pad of Celite and the solvent was evaporated under re-
duced pressure. Then the debenzylated product was dissolved in
dry MeOH (3 mL) cooled to 0 °C and NaOMe (0.30 mmol,
0.6 mL, 0.5 n in MeOH) was added. The solution was stirred for
20 min at the same temperature. Then the solution was neutralized
by the addition of Dowex resin and the mixture was filtered
through a pad of Celite. The solvent was evaporated under reduced
pressure, yield quantitative. White solid; m.p. 133 °C (decomp.)
[α]2D0 = –8.3 (c = 0.18, MeOH). 1H NMR (500 MHz, CD3OD): δ =
8.00 (s, 1 H, triazole), 5.48 (d, J = 9.1 Hz, 1 H, fucose 1-H), 4.64
(dd, J1 = 7.3, J2 = 6.5 Hz, 1 H, CH), 4.07 (dd, J1 = 9.3, J2 = 9.3 Hz,
1 H, fucose 2-H), 3.94 (q, J = 6.3 Hz, 1 H, fucose 5-H), 3.75 (d, J
= 2.8 Hz, 1 H, fucose 4-H), 3.68 (dd, J1 = 9.5, J2 = 3.1 Hz, 1 H,
fucose 3-H), 3.21 (dd, J1 = 14.8, J2 = 6.1 Hz, 1 H, CH2), 3.06 (dd,
J1 = 14.8, J2 = 7.8 Hz, 1 H, CH2), 1.96 (s, 3 H, Ac), 1.48 (s, 3 H,
Me), 1.45 (s, 3 H, Me), 1.28 (d, J = 6.5 Hz, 3 H, Me Fuc) ppm.
13C NMR (100 MHz, CD3OD): δ = 179.2, 173.2, 171.7, 144.6,
123.4, 90.1, 75.4, 75.2, 72.9, 71.1, 54.5, 29.1, 25.2, 24.9, 22.5,
1-Benzyloxycarbonylmethyl-4-propargyl-1H-1,2,3-triazole (10a):
Compound 9a (0.313 mmol, 102.4 mg) was dissolved in acetonitrile
(5 mL) and CsF (0.47 mmol, 71 mg) was added. The mixture was
stirred at ambient temperature for 2–4 h. The solvent was evapo-
rated, the salts were dissolved in water, and the product was ex-
tracted with EtOAc. The product was purified by column
chromatography (silica gel, Hex/EtOAc, 1:1), yield 45 mg (57%).
White solid; m.p. 118–120 °C. 1H NMR (500 MHz, CDCl3): δ =
7.65 (s, 1 H, triazole), 7.39–7.33 (m, 5 H, Ph), 5.24 (s, 2 H,
COCH2), 5.18 (s, 2 H, CH2Ph), 3.73 (d, J = 1.7 Hz, 2 H, CH2C),
2.13 (br. s, 1 H, CH) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.2,
144.2, 134.6, 128.9, 128.8, 128.6, 123.2, 80.0, 70.2, 68.1, 51.0,
16.8 ppm. IR (KBr): ν = 3274, 3143, 2984, 2922, 1617, 1557,
˜
1429 cm–1. CID-MS/MS [ESI(+)]: calcd. for C17H27N5O8 429.1860
[M + 1]+; found 430.27.
16.3 ppm. IR (KBr): ν = 3280, 1749 (C=O), 1457, 1387 cm–1
.
˜
1-Benzyloxycarbonylmethyl-4-[3-(trimethylsilyl)prop-2-ynyl]-1H-
1,2,3-triazole (9a): CuI (0.15 mmol, 30 mg) and DIPEA
(3.95 mmol, 0.69 mL) were added to a solution of 1-trimethylsilyl-
1,3-pentadiyne (1.18 mmol, 0.204 mL) and benzyl azidoacetate (8a;
0.79 mmol, 152 mg) in acetonitrile under N2. The mixture was
stirred at ambient temperature overnight. After completion, the
solvent was evaporated under reduced pressure and the product
HRMS: calcd. for C14H13N3O2 256.1086 [M + 1]+; found 256.1088.
MS (TOF CI): m/z = 256.1.
1-[2-(Benzyloxycarbonyl)-2-propyl]-4-propargyl-1H-1,2,3-triazole
(10b): Compound 9b (0.32 mmol, 113 mg) was dissolved in acetoni-
trile (7 mL) and CsF (0.47 mmol, 73 mg) was added. The mixture
was stirred at ambient temperature for 2–4 h. The solvent was evap-
orated, the salts were dissolved in water, and the product was ex-
was purified by flash chromatography, yield 214 mg (83%). White
1
solid; m.p. 124–125 °C. H NMR (500 MHz, CDCl3): δ = 7.63 (s, tracted with EtOAc. The product was purified by column
1 H, triazole), 7.39–7.34 (m, 5 H, Ph), 5.24 (s, 2 H, COCH2), 5.18
(s, 2 H, CH2Ph), 3.78 (s, 2 H, CH2C), 0.18 (s, 9 H, SiMe3) ppm.
chromatography (silica gel, Hex/EtOAc, 1:1), yield 86 mg (90%).
Colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.63 (s, 1 H, tri-
Eur. J. Org. Chem. 2013, 2434–2444
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2441

R. M. Fratila, J. M. Aizpurua et al.
FULL PAPER
azole), 7.37–7.25 (m, 5 H, Ph), 5.19 (s, 2 H, CH2Ph), 3.74 (s, 2 H, tBuOH/THF under nitrogen. The homogeneous solution (tBuOH/
CH2C), 2.15 (s, 1 H, CH), 1.97 (s, 6 H, Me) ppm. 13C NMR
THF/H2O, 1:1:1) was stirred overnight. Then the organic solvents
(125 MHz, CDCl3): δ = 171.2, 143.3, 135.1, 128.7, 128.6, 128.0, were evaporated under reduced pressure and the crude was ex-
120.6, 80.3, 70.1, 67.9, 64.6, 25.8, 16.4 ppm. IR (KBr): ν = 3289,
tracted with EtOAc. The organic layer was dried with MgSO4 and
˜
3150, 2995, 1741 (C=O), 1456, 1273, 1151 cm–1. HRMS: calcd. for
the product was purified by column chromatography, yield 85.2 mg
C16H17N3O2 284.1399 [M + 1]+; found 284.1398. MS (TOF CI): (75%). Colorless oil. [α]2D0 = +36.03 (c = 0.63, CH2Cl2). H NMR
1
m/z (%) = 284.1 (100), 91.0 (31), 120.1 (11).
(500 MHz, CDCl3): δ = 7.64 (s, 1 H, triazole), 7.60 (s, 1 H, triazole),
7.34–7.22 (m, 5 H, Ar), 5.95–5.92 (m, 3 H, mannose 1-H, 2-H, 3-
H), 5.36 (dd, J = 9.0, J = 9.0 Hz, 1 H, mannose 4-H), 5.16 (s, 2 H,
CH2Ph), 4.34 (dd, J = 2.4, J = 5.4 Hz, 1 H, mannose 6Ј-H), 4.24
(s, 2 H, CH2), 4.05 (dd, J = 12.4, J = 2.5 Hz, 1 H, mannose 6-H),
3.90–3.86 (m, 1 H, mannose 5-H), 2.17 (s, 3 H, Ac), 2.07 (s, 3 H,
Ac), 2.05 (s, 3 H, Ac), 2.04 (s, 3 H, Ac), 1.96 (s, 6 H, Me) ppm.
13C NMR (125 MHz, CDCl3): δ = 171.3, 170.6, 169.7, 169.4, 146.2,
144.3, 135.2, 128.8, 128.6, 128.0, 122.4, 120.9, 83.7, 72.2, 69.0, 68.5,
1-(2,3,4-Tri-O-acetyl-β- -fucosyl)-4-propargyl-1H-1,2,3-triazole
L
(10c): Compound 9c (1.17 mmol, 530 mg) was dissolved in acetoni-
trile (15 mL) and CsF (1.75 mmol, 266 mg) was added. The mixture
was stirred at ambient temperature for 2–4 h. The solvent was evap-
orated, the salts were dissolved in water, and the product was ex-
tracted with EtOAc. The product was purified by column
chromatography, yield 444 mg (quant.). White solid; m.p. 48–50 °C.
1
[α]2D0 = +31.39 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ
67.9, 66.3, 61.8, 25.8, 22.9, 20.8, 20.7 ppm. IR (KBr): ν = 1750
˜
= 7.78 (s, 1 H, triazole), 5.79 (d, J = 9.3 Hz, 1 H, fucose 1-H), 5.53
(dd, J1 = 9.9, J2 = 9.5 Hz, 1 H, fucose 2-H), 5.39 (d, J = 2.4 Hz, 1
H, fucose 4-H), 5.24 (dd, J1 = 10.2, J2 = 3.3 Hz, 1 H, fucose 3-H),
4.10 (q, J = 6.2 Hz, 1 H, fucose 5-H), 3.71 (s, 2 H, CH2), 2.25 (s,
3 H, Ac), 2.01 (s, 3 H, Ac), 1.89 (s, 3 H, Ac), 1.27 (d, J = 6.3 Hz,
3 H, Me Fuc) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.5, 169.9,
169.3, 144.3, 120.1, 86.6, 79.8, 72.9, 71.4, 70.3, 70.1, 68.2, 20.8,
(C=O), 1225 cm–1. CID-MS/MS [ESI(+)]: MS+1: m/z (%) = 657;
MS2(657) = 108.9 (100), 169.1 (48), 126.9 (47).
1-[2-(Benzyloxycarbonyl)-2-propyl]-1Ј-(2,3,4-tri-O-acetyl-β-L-fucos-
yl)-4,4Ј-methylenebis(1H-1,2,3-triazole) (11c): A deoxygenated
aqueous solution of sodium ascorbate (0.263 mmol, 34 mg) and
CuSO4·5H2O (53 μmol, 10 mg) was added to a solution of 10b
(0.263 mmol, 100 mg), 1-azido-2,3,4-tri-O-acetyl-β-l-fucose
(0.342 mmol, 75 mg), and TBTA (2.6 μmol, 1.5 mg) in tBuOH/
THF under nitrogen. The homogeneous solution (tBuOH/THF/
H2O, 1:1:1) was stirred overnight. Then the organic solvents were
evaporated under reduced pressure and the crude was extracted
with EtOAc. The organic layer was dried with MgSO4 and the
product purified by column chromatography, yield 110 mg (70%).
Colorless oil. [α]2D0 = +0.219 (c = 1.11, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.79 (s, 1 H, triazole), 7.51 (s, 1 H, triazole),
7.34–7.22 (m, 5 H, Ar), 5.77 (d, J = 9.2 Hz, 1 H, fucose 1-H), 5.47
(dd, J1 = 9.7, J2 = 9.7 Hz, 1 H, fucose 2-H), 5.39 (d, J = 2.6 Hz, 1
H, fucose 4-H), 5.23 (dd, J1 = 10.3, J2 = 3.3 Hz, 1 H, fucose 3-H),
5.14 (s, 2 H, CH2Ph), 4.26 (d, J = 16.7 Hz, 1 H, CH2), 4.20 (d, J
= 16.7 Hz, 1 H, CH2), 4.12–4.08 (m, 1 H, 5-H), 2.23 (s, 3 H, Ac),
2.01 (s, 3 H, Ac), 1.93 (s, 6 H, Me), 1.86 (s, 3 H, Ac) ppm. 13C
NMR (125 MHz, CD3OD): δ = 171.2, 170.4, 169.8, 169.2, 145.6,
145.0, 135.1, 128.6, 128.4, 127.9, 120.8, 120.5, 86.5, 72.7, 71.2, 69.9,
68.4, 67.7, 64.4, 25.6, 25.6, 22.9, 20.6, 20.5, 20.3, 16.1 ppm. IR
20.6, 20.4, 16.5, 16.2 ppm. IR (KBr): ν = 3283, 1752 (C=O) cm–1.
˜
CID-MS/MS [ESI(+)]: MS+1: m/z (%) = 380; MS2(380) = 273.1
(100), 152.9 (74), 213.0 (40). HRMS: calcd. for C17H21N3O7
380.1458 [M + 1]+; found 380.1460. MS (TOF CI): m/z (%) = 273.1
(100), 153.1 (75), 111.0 (39), 213.1 (32), 171.1 (30). C17H21N3O7
(379.37): calcd. C 53.82, H 5.58, N 11.08; found C 55.14, H 5.47,
N 10.44.
1-Benzyloxycarbonylmethyl-1Ј-(2,3,4,6-tetra-O-acetyl-a-D-mann-
osyl)-4,4Ј-methylenebis(1H-1,2,3-triazole) (11a): A deoxygenated
aqueous solution of sodium ascorbate (0.05 mmol, 10 mg) and
CuSO4·5H2O (25 μmol, 6 mg) was added to a solution of 10a
(0.125 mmol, 32 mg), 1-azido-2,3,4,6-tetra-O-acetyl-α-d-mannose
(0.125 mmol, 47 mg), and TBTA (1.2 μmol, 0.6 mg) in tBuOH/
THF under nitrogen,. The homogeneous solution (tBuOH/THF/
H2O, 1:1:1) was stirred overnight. Then the organic solvents were
evaporated under reduced pressure and the crude was extracted
with EtOAc. The organic layer was dried with MgSO4 and the
product was purified by column chromatography, yield 74 mg
(95%). White solid; m.p. 59–61 °C. [α]2D0 = +36.3 (c = 0.91,
CH2Cl2). 1H NMR (500 MHz, CD3OD): δ = 7.65 (s, 1 H, triazole),
7.63 (s, 1 H, triazole), 5.96–5.90 (m, overlapped 3 H, mannose 1-
H, 2-H, 3-H), 5.36 (dd, J1 = 9.0, J2 = 9.0 Hz, 1 H, mannose 4-H),
5.23 (s, 2 H, COCH2), 5.17 (s, 2 H, CH2Ph), 4.34 (dd, J1 = 12.4,
J2 = 5.3 Hz, 1 H, mannose 6-H), 4.27 (s, 2 H, CH2), 4.05 (dd, J1
= 12.5, J2 = 1.5 Hz, 1 H, mannose 6-H), 3.88–3.86 (m, 1 H, mann-
ose 5-H), 2.17 (s, 3 H, Ac), 2.07 (s, 3 H, Ac), 2.05 (s, 3 H, Ac), 2.04
(s, 3 H, Ac) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.6, 169.7,
169.4, 166.3, 146.0, 145.1, 134.7, 128.9, 128.8, 128.6, 123.5, 122.4,
83.7, 72.1, 69.0, 68.4, 68.1, 66.3, 61.7, 50.9, 22.8, 20.8, 20.7,
(KBr): ν = 1747 (C=O), 1369, 1242, 1220 cm–1. CID-MS/MS
˜
[ESI(+)]: MS+1: m/z (%) = 599.1; MS2(599.1) = 110.8 (100), 153.0
(66), 82.7 (17). C28H34N6O9 (598.61): calcd. C 56.18, H 5.72, N
14.04; found C 55.94, H 5.35, N 13.48.
1-(Benzyloxycarbonylmethyl)-1Ј-(2,3,4-tri-O-acetyl-β-L-fucosyl)-
4,4Ј-methylenebis(1H-1,2,3-triazole) (11d): To a solution of 10c
(0.263 mmol, 100 mg), benzyl azidoacetate (0.342 mmol, 65.4 mg)
and TBTA (2.6 μmol, 1.4 mg) in tBuOH/THF under nitrogen at-
mosphere, a deoxygenated aqueous solutions of sodium ascorbate
(0.263 mmol, 34 mg) and CuSO4·5H2O (52 μmol, 10 mg) was
added. The homogeneous solution (tBuOH/THF/H2O, 1:1:1) was
stirred overnight. Then the organic solvents were evaporated under
reduced pressure and the crude was extracted with EtOAc. The
organic layer was dried with MgSO4 and the product was purified
by column chromatography, yield 134 mg (90%). White solid; m.p.
173–176 °C. [α]2D0 = +0.12 (c = 0.93, CH2Cl2). 1H NMR (500 MHz,
CD3OD): δ = 7.74 (s, 1 H, triazole), 7.55 (s, 1 H, triazole), 7.35–
7.29 (m, 5 H, Ph), 5.76 (d, J = 9.2 Hz, 1 H, fucose 1-H), 5.46 (dd,
20.6 ppm. IR (KBr): ν = 1750 (C=O), 1369, 1222, 1049 cm–1. CID-
˜
MS/MS [ESI(+)]: MS+1: m/z (%) = 629; MS2(629) = 629.0 (100),
169.0 (24), 299.1 (14). HRMS: calcd. for C28H32N6O11 629.2207
[M + 1]+; found 629.2218. MS (TOF CI): m/z (%) = 331.1 (54),
629.2 (52), 169.0 (45), 108.1 (31), 111.0 (23).
1-[2-(Benzyloxycarbonyl)-2-propyl]-1Ј-(2,3,4,6-tetra-O-acetyl-α-D-
mannosyl)-4,4Ј-methylenebis(1H-1,2,3-triazole) (11b): A deoxy- J = 9.9, J = 9.4 Hz, 1 H, fucose 2-H), 5.35–5.35 (m, 1 H, fucose
genated aqueous solution of sodium ascorbate (0.176 mmol,
22 mg) and CuSO4·5H2O (35 μmol, 7 mg) was added to a solution
4-H), 5.22 (dd, J = 10.3, J = 3.1 Hz, 1 H, fucose 3-H), 5.19 (s, 2
H, COCH2), 5.14 (s, 2 H, CH2Ph), 4.21 (s, 2 H, CH2), 4.07 (dd, J
of 10b (0.176 mmol, 77 mg), 1-azido-2,3,4,6-tetra-O-acetyl-α-d- = 12.5, J = 6.1 Hz, 1 H, 5-H), 2.20 (s, 3 H, Ac), 1.97 (s, 3 H, Ac),
mannose (0.264 mmol, 58 mg), and TBTA (1.8 μmol, 0.9 mg) in
1.84 (s, 3 H, Ac), 1.22 (d, J = 6.3 Hz, 3 H, Me) ppm. 13C NMR
2442
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2434–2444

Modulating Lectin Inhibition with N-Glycosyltriazole Scaffolds
(125 MHz, CDCl3): δ = 170.5, 169.9, 169.2, 166.3, 145.7, 145.5, reduced pressure, yield quantitative. White solid; m.p. 153 °C (de-
134.7, 128.5, 123.4, 120.5, 86.4, 77.2, 72.7, 70.0, 68.0, 50.9, 23.0,
20.7, 20.6, 20.3, 16.1 ppm. IR (KBr): ν = 1751 (C=O), 1369, 1231, CD3OD): δ = 8.53 (s, 1 H, triazole), 8.44 (s, 1 H, triazole), 5.60 (d,
comp.). [α]2D0 = –1.38 (c = 0.14, MeOH). 1H NMR (500 MHz,
˜
1219 cm–1. CID-MS/MS [ESI(+)]: MS+1: m/z (%) = 571.0;
MS2(571.0) = 110.8 (100), 153.0 (35), 82.7 (14). C26H30N6O9 fucose 2-H), 3.99 (q, J = 6.4 Hz, 1 H, fucose 5-H), 3.78 (d, J =
J = 9.2 Hz, 1 H, fucose 1-H), 4.16 (dd, J1 = 9.4, J2 = 9.2 Hz, 1 H,
(570.56): calcd. C 54.73, H 5.30, N 14.73; found C 55.01, H 5.22,
N 15.13.
2.7 Hz, 1 H, fucose 4-H), 3.72 (dd, J1 = 9.4, J2 = 3.1 Hz, 1 H,
fucose 3-H), 1.97 (s, 6 H, Me), 1.32 (d, J = 6.4 Hz, 1 H, Me fuc-
ose) ppm. 13C NMR (125 MHz, CD3OD): δ = 175.6, 140.8, 139.8,
122.1, 121.4, 90.3, 75.5, 75.4, 73.0, 71.2, 67.2, 26.4, 16.8 ppm. IR
1-(2-Carboxy-2-propyl)-1Ј-(β-L-fucosyl)bis(1H-1,2,3-triazol-4-yl)meth-
ane (14a): Compound 11c (0.1 mmol, 60 mg) was dissolved in
MeOH (10 mL), Pd/C (6 mg) was added, and the suspension was
stirred for 1 h under H2. The suspension was filtered through a pad
of Celite and the solvent was evaporated under reduced pressure.
Then the debenzylated product was dissolved in dry MeOH (3 mL)
cooled to 0 °C and NaOMe (0.4 mmol, 0.9 mL, 0.5 n in MeOH)
was added. The solution was stirred for 1 h at ambient temperature.
Then the solution was neutralized by the addition of Dowex resin
and the mixture was filtered through a pad of Celite. The solvent
was evaporated under reduced pressure, yield quantitative. White
solid; m.p. 138 °C (decomp.). [α]2D0 = –13.5 (c = 0.2, MeOH). 1H
NMR (500 MHz, CD3OD): δ = 8.01 (s, 1 H, triazole), 7.95 (s, 1 H,
triazole), 5.49 (d, J = 9.1 Hz, 1 H, fucose 1-H), 4.19 (s, 2 H, CH2),
4.05 (dd, J1 = 9.3, J2 = 9.3 Hz, 1 H, fucose 2-H), 3.94 (q, J =
6.3 Hz, 1 H, fucose 5-H), 3.74 (d, J = 2.9 Hz, 1 H, fucose 4-H),
3.67 (dd, J1 = 9.5, J2 = 3.2 Hz, 1 H, fucose 3-H), 1.90 (s, 6 H,
Me), 1.28 (d, J = 6.5 Hz, 3 H, Me Fuc) ppm. 13C NMR (100 MHz,
CD3OD): δ = 175.5, 146.5, 145.3, 123.1, 122.7, 90.3, 75.4, 74.3,
(KBr): ν = 3284, 3139, 2984, 2921, 1722, 1610, 1458, 1388 cm–1.
˜
CID-MS/MS [ESI(+)]: calcd. for C14H20N6O6 368.1444 [M + 1]+;
found 369.18.
1-(Carboxymethyl)-1Ј-(β-L-fucosyl)-4,4Ј-bi-1H-1,2,3-triazole (15b):
The corresponding 4,4Ј-bis-1,2,3-triazole (0.077 mmol, 43 mg) was
dissolved in MeOH (3 mL), Pd/C (4 mg) was added, and the sus-
pension was stirred for 1 h under H2. The suspension was filtered
through a pad of Celite and the solvent was evaporated under re-
duced pressure. Then the debenzylated product was dissolved in
dry MeOH (3 mL) cooled to 0 °C and NaOMe (0.308 mmol,
0.62 mL, 0.5 n in MeOH) was added. The solution was stirred for
1 h at ambient temperature. Then the solution was neutralized by
the addition of Dowex resin and the mixture was filtered through
a pad of Celite. The solvent was evaporated under reduced pressure,
yield quantitative. White solid; m.p. 124 °C (decomp.). [α]2D0 = –8.0
1
(c = 0.12, MeOH). H NMR (500 MHz, CDCl3): δ = 8.51 (s, 1 H,
triazole), 8.30 (s, 1 H, triazole), 5.59 (d, J = 9.1 Hz, 1 H, fucose 1-
H), 5.59 (s, 2 H, CH2), 4.16 (dd, J1 = 9.3, J2 = 9.3 Hz, 1 H, fucose
2-H), 3.99 (q, J = 6.4 Hz, 1 H, fucose 5-H), 3.77 (d, J = 2.7 Hz, 1
H, fucose 4-H), 3.71 (dd, J1 = 9.5, J2 = 3.3 Hz, 1 H, fucose 3-H),
1.32 (d, J = 6.4 Hz, 1 H, Me) ppm. 13C NMR (125 MHz, CD3OD):
δ = 172.5, 140.9, 140.1, 124.3, 121.3, 90.3, 75.5, 75.4, 73.1, 71.2,
73.0, 71.2, 63.7, 26.3, 23.1, 16.7 ppm. IR (KBr): ν = 3316, 3143,
˜
2984, 2921, 2851, 1721, 1603, 1458 cm–1. CID-MS/MS [ESI(+)]:
calcd. for C15H22N6O6 382.1601 [M + 1]+; found 383.23.
1-(Carboxymethyl)-1Ј-(β-L-fucosyl)bis(1H-1,2,3-triazol-4-yl)meth-
ane (14b): Compound 11d (0.44 mmol, 252 mg) was dissolved in
MeOH (20 mL), Pd/C (25 mg) was added, and the suspension was
stirred for 1 h under H2. The suspension was filtered through a pad
of Celite and the solvent was evaporated under reduced pressure.
Then the debenzylated product was dissolved in dry MeOH (3 mL)
cooled to 0 °C and NaOMe (1.76 mmol, 3.5 mL, 0.5 n in MeOH)
was added. The solution was stirred for 1 h at room temperature.
Then the solution was neutralized by the addition of Dowex resin
and the mixture was filtered through a pad of Celite. The solvent
was evaporated under reduced pressure, yield quantitative. White
solid; m.p. 97 °C (decomp.) [α]2D0 = –18.9 (c = 0.19, MeOH). 1H
NMR (500 MHz, CD3OD): δ = 8.02 (s, 1 H, triazole), 7.82 (s, 1 H,
triazole), 5.48 (d, J = 9.1 Hz, 1 H, fucose 1-H), 5.10 (s, 2 H, CH2),
4.20 (s, 2 H, CH2), 4.05 (dd, J1 = 9.3, J2 = 9.3 Hz, 1 H, fucose 2-
H), 3.93 (q, J = 6.3 Hz, 1 H, fucose 5-H), 3.73 (d, J = 2.9 Hz, 1
H, fucose 4-H), 3.67 (dd, J1 = 9.5, J2 = 3.2 Hz, 1 H, fucose 3-H),
1.28 (d, J = 6.4 Hz, 3 H, Me) ppm. 13C NMR (100 MHz, CD3OD):
δ = 172.4, 146.6, 145.7, 125.4, 122.8, 90.2, 75.3, 75.2, 73.0, 71.1,
54.6, 19.76 ppm. IR (KBr): ν = 3273, 3139, 2985, 2922, 1612,
˜
1385 cm–1. CID-MS/MS [ESI(+)]: calcd. for C12H16N6O6 340.1131
[M + 1]+; found 341.21.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of compounds 4a,b, 10a,b, 12, 11a–
d, 14a,b, and 15a,b, individual docking images for ligands 12–15,
ROESY spectra of compounds 12–15, and details of STD-NMR
experiments.
Acknowledgments
We thank the Spanish Ministerio de Ciencia y Competitividad
(MEC) (project number CTQ2010-21625-C02-01) and the Gobi-
erno Vasco (ETORTEK-nanoIKER IE-11/304) for financial sup-
port, and SGIker UPV/EHU for NMR facilities. Grants from the
Gobierno Vasco to I. A. and M. S.-A. are acknowledged.
54.0, 23.1, 16.7 ppm. IR (KBr): ν = 3269, 3138, 2985, 2923, 1724,
˜
1613, 1556, 1386 cm–1. CID-MS/MS [ESI(+)]: calcd. for
C13H18N6O6 354.1288 [M + 1]+; found 355.19.
[1] D. P. Gamblin, E. M. Scanlan, B. G. Davis, Chem. Rev. 2008,
109, 131–163.
[2] C.-H. Wong, J. Org. Chem. 2005, 70, 4219–4225.
[3] a) F. Schweizer, Angew. Chem. 2002, 114, 240; Angew. Chem.
Int. Ed. 2002, 41, 230–253; b) A. W. Gruner, E. Locardi, E.
Lohof, H. Kessler, Chem. Rev. 2002, 102, 491–514; c) L. Ci-
polla, F. Peri, Mini-Rev. Med. Chem. 2011, 11, 39–54.
[4] a) H. Lis, N. Sharon, Chem. Rev. 1998, 98, 637–674; b) E. E.
Simanek, G. J. McGarvey, J. A. Jablonowski, C.-H. Wong,
Chem. Rev. 1998, 98, 833–862; c) H.-J. Gabius, H.-C. Siebert,
S. André, J. Jiménez-Barbero, H. Rüdiger, ChemBioChem 2004,
5, 740–764.
1-(2-Carboxy-2-propyl)-1Ј-(β-L-fucosyl)-4,4Ј-bi-1H-1,2,3-triazole
(15a): The corresponding 4,4Ј-bis-1,2,3-triazole (0.143 mmol,
84 mg) was dissolved in MeOH (5 mL), Pd/C (8 mg) was added,
and the suspension was stirred for 1 h under H2. The suspension
was filtered through a pad of Celite and the solvent was evaporated
under reduced pressure. Then the debenzylated product was dis-
solved in dry MeOH (5 mL) cooled to 0 °C and NaOMe
(0.57 mmol, 1.14 mL, 0.5 n in MeOH) was added. The solution
was stirred for 1 h at ambient temperature. Then the solution was
neutralized by the addition of Dowex resin and the mixture was
filtered through a pad of Celite. The solvent was evaporated under
[5] a) R. McEver, Glycoconjugate J. 1997, 14, 585–591; b) G. Lopa-
schuk, Am. Heart J. 2000, 139, s115–s119; c) N. Kaila, B. E.
Thomas IV, Med. Res. Rev. 2002, 22, 566–601.
Eur. J. Org. Chem. 2013, 2434–2444
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2443

R. M. Fratila, J. M. Aizpurua et al.
FULL PAPER
[6] a) P. Sears, C.-H. Wong, Angew. Chem. 1999, 111, 2446; Angew.
Chem. Int. Ed. 1999, 38, 2300–2324; b) B. Ernst, J. L. Magnani,
Nat. Mater. Nat. Rev. Drug Discovery 2009, 8, 661–677.
[7] C.-H. Wong, F. Moris-Varas, S.-C. Hung, T. G. Marron, C.-C.
Lin, K. W. Gong, G. Weitz-Schmidt, J. Am. Chem. Soc. 1997,
119, 8152–8158.
Rutjes, Org. Lett. 2004, 6, 3123–3126; b) S. Dedola, S. A. Ne-
pogodiev, R. A. Field, Org. Biomol. Chem. 2007, 5, 1006–1017;
c) J. M. Aizpurua, I. Azcune, R. M. Fratila, E. Balentova, M.
Sagartzazu-Aizpurua, J. I. Miranda, Org. Lett. 2010, 12, 1584–
1587.
[13] J. T. Lundquist, J. C. Pelletier, Org. Lett. 2002, 4, 3219–3221.
[14] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett.
2004, 6, 2853–2855.
[8] T. Tsukida, H. Moriyama, K. Kurokawa, T. Achiha, Y. Inoue,
H. Kondo, J. Med. Chem. 1998, 41, 4279–4287.
[9] a) H. K. Ulbrich, A. Luxenburger, P. Prech, E. E. Eriksson, O.
Soehnlein, P. Rotzius, L. Lindbom, G. Dannhardt, J. Med.
Chem. 2006, 49, 5988–5999; b) R. Kranich, A. S. Busemann,
D. Bock, S. Schroeter-Maas, D. Beyer, B. Heinemann, M.
Meyer, K. Schierhorn, R. Zahlten, G. Wolff, E. M. Aydt, J.
Med. Chem. 2007, 50, 1101–1115.
[15] J. C. Phillips, R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid,
E. Villa, C. Chipot, R. D. Skeel, L. Kalé, K. Schulten, J. Com-
put. Chem. 2005, 26, 1781–1802.
[16] G. F. Audette, D. J. Olson, A. R. Ross, J. W. Quail, L. T. Delba-
ere, Can. J. Chem. 2002, 80, 1010–1021.
[17] a) M. Mayer, B. Meyer, Angew. Chem. 1999, 111, 1902; Angew.
Chem. Int. Ed. 1999, 38, 1784–1788; b) M. Mayer, B. Meyer, J.
Am. Chem. Soc. 2001, 123, 6108–6117.
[10] C. Palomo, J. M. Aizpurua, E. Balentová, I. Azcune, J. I. San-
tos, J. Jiménez-Barbero, J. Cancada, J. I. Miranda, Org. Lett.
˜
2008, 10, 2227–2230.
[18] a) E. Ko, J. Liu, L. M. Perez, G. Lu, A. Schaefer, K. Burgess,
J. Am. Chem. Soc. 2010, 133, 462–477; b) E. Ko, J. Liu, K.
Burgess, Chem. Soc. Rev. 2011, 40, 4411–4421.
[11] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001,
113, 2056; Angew. Chem. Int. Ed. 2001, 40, 2004–2021.
[12] a) B. H. M. Kuijpers, S. Groothuys, A. R. Keereweer,
P. J. L. M. Quaedflieg, R. H. Blaauw, F. L. van Delft, F. P. J. T.
Received: December 11, 2012
Published Online: March 6, 2013
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