1,2,3-Triazoles and related glycoconjugates as new glycosidase inhibitors

Article abstract of DOI:10.1016/j.tet.2005.07.033

A series of saccharidyl-triazoles structurally related to acarbose were prepared and tested as inhibitors of glycosidases. They share in common a 1,4,5-trisubstituted 1,2,3-triazole heterocycle as a functional element able to interact with the active site of the target enzymes. First, it was established that the heterocyclic core exhibits a moderate but highly selective α-glucosidase inhibitory activity. Then, it was confirmed that the inhibitory properties could be modulated by conjugation from one to five carbohydrate residues. The present study includes the regio- and stereocontrolled synthesis of novel non-fused 1,2,3-triazolo- pseudooligosaccharides as well as their evaluation as new glycosidase inhibitors.

Full text of DOI:10.1016/j.tet.2005.07.033

Tetrahedron 61 (2005) 9118–9128
1,2,3-Triazoles and related glycoconjugates as new
glycosidase inhibitors
a
Regis Perion, Vincent Ferrieres, M. Isabel Garcıa-Moreno, Carmen Ortiz Mellet,
a,
b
b
*
´
´
`
´
c
d
Raphael Duval, Jose M. Garcıa Fernandez and Daniel Plusquellec
a
´
´
´
¨
a
´ ´ ´
Ecole Nationale Superieure de Chimie de Rennes, UMR CNRS 6052, Institut de Chimie de Rennes, Avenue du General Leclerc,
35700 Rennes, France
´ ´ ´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Sevilla, 41012 Sevilla, Spain
b
c
´ ` `
Chirosep, Parc d’Activites de la Boissiere, 11 Rue de la Boissiere, 76170 La Frenaye, France
d
´
´
Instituto de Investigaciones Quımicas, CSIC, Americo Vespucio 49, 41092 Sevilla, Spain
Received 3 June 2005; revised 8 July 2005; accepted 11 July 2005
Available online 28 July 2005
Abstract—A series of saccharidyl-triazoles structurally related to acarbose were prepared and tested as inhibitors of glycosidases. They
share in common a 1,4,5-trisubstituted 1,2,3-triazole heterocycle as a functional element able to interact with the active site of the target
enzymes. First, it was established that the heterocyclic core exhibits a moderate but highly selective a-glucosidase inhibitory activity. Then,
it was confirmed that the inhibitory properties could be modulated by conjugation from one to five carbohydrate residues. The present study
includes the regio- and stereocontrolled synthesis of novel non-fused 1,2,3-triazolo-pseudooligosaccharides as well as their evaluation as new
glycosidase inhibitors.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
overall yields. Our research efforts aim at an efficient,
high-yielding synthesis of triazole-containing oligo-
saccharide mimetics, via [3C2] cycloaddition between
azide and acetylene derivatives (‘click reactions’).12
This reaction generally results in the corresponding 1,4-
disubstituted 1,2,3-triazoles in high yields, is particu-
larly well adapted to combinatorial synthetic
strategies13,14 and has already been successfully used
in carbohydrate chemistry for the preparation of
pseudooligosaccharide structures.15
The wide range of physiological and pathological events
involving the rupture or the construction of glycosidic
linkages has spurred an aggressive effort aimed at the
identification of inhibitors of glycosidases and glycosyl
transferases that catalyze these processes.1 On one hand,
such inhibitors represent useful tools to understand the
mechanism of action of these enzymes.2 On the other hand,
they exhibit a high promise as therapeutic agents for the
treatment of ailments as varied as diabetes,3 viral infections4
or cancer metastasis.5
In the present study, we were interested in the evaluation of
the glycosidase inhibitory potential of new 1,4,5-tri-
substituted 1,2,3-triazoles derived from 2-butyn-1,4-diol
derivatives and 4-azido-4-deoxysugars. In a preliminary
screening, the heterocyclic core showed a moderate but
rather specific a-glycosidase competitive inhibitory
activity. The possibility of introducing molecular diversity
with a relatively low synthetic cost offers then a
possibility to explore the effect of different substituents
that might provide aglyconic or satellite interactions
with binding subsites of the enzyme. To probe the
viability of our approach, various saccharidyl-triazole
derivatives have been prepared and assayed against a
panel of glycosidases.
Polysubstituted five-membered azaheterocycles rank among
the most potent glycosidase inhibitors.6 The battery of
structures on record include pyrrolo-,7 imidazolo-,8
triazolo-9 and tetrazolo-glyco-derivatives,10 their biological
activity being dependent on the nature and the
orientation of the functional groups present onto the
ring.2b,11 Most of the syntheses of these compounds,
however, are rather complex and often feature modest
Keywords: Carbohydrates; Triazoles; Glycosylation; Glycosidase
inhibition.
*
Corresponding author. Tel.: C33 223 238 058; fax: C33 223 238 046;
e-mail: vincent.ferrieres@ensc-rennes.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.033

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2. Results and discussion
2.1. Synthesis and properties of non-glycosylated
1,4,5-trisubstituted 1,2,3-triazoles
We have selected 2-butyn-1,4-diol as the dipolarophile
reagent in our synthetic design in order to introduce some
hydrophilicity on the aromatic ring via the hydroxyl groups
and so to offset the high hydrophobicity around the basic
part of the final adducts. Moreover, the hydroxyl functions
are useful anchoring points for further conjunction with
additional saccharide residues in the preparation of
bis(glycosylated) derivatives. In order to check the activity
of the resulting 1,4,5-trisubstituted 1,2,3-triazole core, we
first undertook the synthesis of the trihydroxylated
derivative 4, bearing no saccharidyl residues. For its
preparation, 2-azidoethanol (1) and 2-butyn-1,4-diol were
first heated at 80 8C (Scheme 1). Although the desired
triazole was obtained, it could not be separated from the
starting alkyne neither by selective crystallization nor by
chromatography. Hence, 1 was first benzoylated and the
resulting product 2 was treated with the dipolarophile under
heating to give 3. Further transesterification afforded 4 in
79% yield.
Figure 1. Structure of acarbose.
deoxyglycosides 517 and 6,18 respectively, and 2-butyn-1,4-
diol, under thermal activation followed by hydrogenolysis
of the resulting intermediates 7 and 8 (Scheme 2).
Scheme 2. (a) 2-Butyn-1,4-diol, 120 8C (7: 85%; 8: 85%); (b) H2, Pd/C (9:
93%; 10: 95%).
The synthesis of the saccharidyl derivative 13, which
incorporates the trisaccharide element present in acarbose,
was based on the condensation of the trisaccharidic azide
11, previously prepared in our laboratory19 and the same
acetylenic diol (Scheme 3). The cycloaddition reaction
proceeded smoothly in chlorobenzene and provided the
corresponding triazol adduct 12 in 70% yield. Removal of
the benzyl protecting groups in 12 by classical catalytic
hydrogenation was, however, unsuccessful. Nevertheless,
Scheme 1. (a) BzCl, Et3N, CH2Cl2 (90%); (b) 2-butyn-1,4-diol, 80 8C
(65%); (c) NaOMe, MeOH (79%).
Both triazoles 3 and 4 were tested as inhibitors against
a-glucosidase (baker yeast), isomaltase (yeast), amylo-
glucosidase (Aspergillus niger), b-glucosidase (almonds),
trehalase (pig kidney), a-mannosidase (jack bean),
a-galactosidase (green coffee) and b-glucosidase/b-galacto-
sidase (bovine liver, cytosolic). The benzoylated triazole 3
presented no inhibitory effect for any of the studied
enzymes, even at 2 mM concentration. On the contrary,
the trihydroxylaled derivative 4 exhibited a moderate but
highly selective yeast a-glucosidase competitive inhibition
(inhibition constant, KiZ294 mM). The fact that the triazole
element is able to compete with natural glycosides for the
active site of a-glucosidase, the inhibitory activity being
promoted by hydrophilic substituents at position N-1,
encouraged us to investigate the possibility of introducing
saccharidyl residues to modulate the inhibition properties.
2.2. Synthesis and properties of saccharidyl-triazoles
The nature of the sugar substituents in the saccharidyl-
triazoles included in this study has been inspired in the
structure of the potent a-glucosidase inhibitor acarbose
(Fig. 1), for which the existence of an oligosaccharide
portion containing quinovosyl (6-deoxyglucosyl) and
maltosyl subunits results in a extremely high enzyme
selectivity.16 The quinovosyl derivatives 9 and 10 were
obtained in 81% overall yield from the known azido-
Scheme 3. (a) 2-Butyn-1,4-diol, chlorobenzene, 130 8C (70%); (b) cyclo-
hexene, MeOH, cat. Pd(OH)2, 90 8C (95%).

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9120
hydrogenolysis could be performed by hydrogen transfer
from cyclohexene in the presence of Pearlman’s catalyst
[palladium(II) hydroxide] at 90 8C, providing the target
fully unprotected conjugate 13 in 95% yield.
chemical structures of these isomeric triazoles were
established on the grounds of NMR data. In the 13C NMR
spectra, the signal corresponding to C-4d is typically
observed at lower field than that for C-5d.22 Moreover,
etherification of a hydroxyl function leads to a large
downfield shift of the a-carbon atom (6–9 ppm) and a less
pronounced high-field shift of the b-carbon atom
(3–4 ppm).23 Comparison of the corresponding 13C NMR
data for the dihydroxymetyl derivative 12 with those for the
monobenzyloxymethylated counterparts 19 and 20, by
combining both types of informations, allowed
unambiguous differentiation between them. Further
glycosylation of acceptor 19 with donor 15 using NIS/
Cu(OTf)2 as promotor proceeded with a moderate 20%
yield but with an excellent diastereocontrol, providing
exclusively the a-anomer 18. A lower diastereoselectivity
was, however, observed in the glycosylation of 20 under
identical reaction conditions. The corresponding dia-
stereomers 17 and 22, characterized by J1e,2e coupling
constant values of 3.6 and 8.0 Hz, respectively, were
obtained in 30% yield as a 1.5:1 mixture. This result may
be ascribed to the greater accessibility, and therefore higher
reactivity, of the hydroxyl group of the hydroxymethyl
substituent at position C-4d as compared with that at
position C-5d in the triazole ring. Finally, removal of the
benzyl protecting groups under hydrogen transfer con-
ditions afforded the target glycomimetics 21, 23 and 24 in
95% yield.
In order to obtain pseudooligosaccharide derivatives
incorporating the 1,2,3-triazole unit in the backbone for
structure–activity studies, the convergent route depicted in
Scheme 4 was explored. The first step implied glycosylation
of the known 4-benzyloxybut-2-yn-1-ol (14)20 using the
perbenzylated thiomaltoside 1521 as the glycosyl donor.
After experimentation, the best compromise between
diastereoselectivity and yield was obtained when the
glycosylation reaction was promoted by N-iodosuccinimide
(NIS) and a catalytic amount of the very mild Lewis acid
copper(II) trifluoromethanesulfonate. These conditions
afforded a 4.6:1 anomeric mixture of 16a and 16b, which
could be chromatographically separated. Subsequent
cycloaddition reaction of the major alkyne 16a and azide
11 gave the isomeric adducts 17 and 18 in 54% yield as an
inseparable 1.2:1 mixture.
In view of the difficulties to obtain the pure pseudo-
oligosaccharides by the above approach, the linear strategy
depicted in Scheme 5 was examined. Click conjugation of
the trisaccharide azide 11 and the asymmetric alkyne 14
afforded the expected regioisomers 19 and 20, which could
be separated by simple silica gel chromatography. The
Scheme 4. (a) NIS, cat. Cu(OTf)2 (61%; 16a/16bZ4.6:1); (b) 11, 110 8C (54%; 17/18Z1.2:1).

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R. Perion et al. / Tetrahedron 61 (2005) 9118–9128
9121
Scheme 5. (a) 14, 130 8C (39%; 19/20Z1.5:1); (b) NIS, cat. Cu(OTf)2 [(18: 20%); (30%, 17/22Z1.5:1)]; (c) cyclohexene, MeOH, cat. Pd(OH)2 (21: 95%; 23:
95%; 24: 95%).
The inhibitory activities of the new saccharidyl-triazoles 9,
10, 13, 21, 23 and 24 against a series of glycosidases are
collected in Table 1. None of the prepared compounds
inhibited invertase, galactosidase, mannosidase and fuco-
sidase, which is in agreement with the configurational
specificity previously observed for the triazole core as well
as with the known specificity of the related pseudo-
oligosaccharide inhibitor acarbose. The total lack of
inhibitory properties for the trisaccharidyl-triazole 13 and
the low a-glucosidase inhibition activities of the higher
pseudooligosaccharides 21, 23, 24 indicated that the
bis(hydroxymethyl)triazole unit is not a functional surrogate
of the natural aminocyclitol moiety (valienamine) present in
acarbose.
The results show that the introduction of glucosyl-type
residues directly linked to the triazole moiety could
modulate the inhibitory properties. Actually, compound 9
turned to be a rather good competitive inhibitor of
a-glucosidase (KiZ73 mM), four-fold more potent as
compared to unglycosylated triazole 4 and twice more
active than acarbose for this particular enzyme. Moreover,
the enzyme specificity of this family of compounds seems to
be strongly dependent upon the nature of the substituents at
the triazole ring. Thus, a change in the anomeric
configuration of the quinovosyl residue, from a (9) to b
(10), totally abolished the biological activity. The specificity
of the pseudooligosaccharides 21, 23, 24 was also
dependent on the linking position of the non-reducing

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9122
Table 1. Glycosidase inhibitory activities (Ki, mM) for triazolo-glycomimetics 9, 10, 13, 21, 23 and 24 in comparison with data for acarbosea
Acarbose
9
10
13
21
23
24
a-Glucosidase (yeast)b
148
n.i.
!20
n.i.
n.i.
73
1925
n.i.
534
597
n.i.c
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
1158
1416
n.i.
n.i.
n.i.
n.i.
Isomaltase (yeast)a
1028
n.i.
n.i.
Amyloglucosidase (A. niger)d
b-Glucosidase (almonds)e
n.i.
n.i.
n.i.
b-Glucosidase/b-Galactosidase (bovine liver)f
n.i.
a The inhibition, when detected, was of the competitive type. None of the compounds 9, 10, 13, 21, 23 and 24 showed inhibitory properties against invertase
(yeast), a-galactosidase (green coffee beans), a-mannosidase (Jack beans), and a-fucosidase (bovine kidney) at their optimal pHs.
b pH 6.8.
c No inhibition detected.
d pH 4.5.
e pH 5.5.
f
pH 7.3.
maltosyl substituent at the triazole core, the C-4d0 linked
derivatives 23 and 24 being weak inhibitors of a-gluco-
sidase while the positional isomer 21 weakly inhibited
isomaltase, instead.
100 MHz for 13C analyses. Chemical shifts are given in
d-units measured from Me4Si, generated from the CHCl3
lock signal at d 7.26. Coupling constants are given in Hz.
Microanalyses were performed by the Service de Micro-
analyse de l’ICSN (Gif sur Yvette, France) and by the
Service de Microanalyse de l’Institut de Chimie de Rennes
(CRMPO, Rennes, France). LSIMS High-resolution mass
spectra were recorded on a MS/MS ZabSpec TOF
Micromass spectrometer at the CRMPO using the fast
atom bombardment technique in positive mode.
It is worth mentioning that, contrary to other azaheterocycle
glycomimetics, the 1,2,3-triazole ring has a low basicity
(pKaZ1.1–1.3)24 and, consequently, the sp2-hybridized
nitrogen atoms will not be protonated at the pH of the
inhibition assays (the optimal for each of the enzymes
considered in this study). Recent results have shown that
sp2-azaheterocyclic glycomimetics may actually behave as
more specific glycosidase inhibitors than the corresponding
basic iminosugars, probably by mimicking the partial
positive charge at the anomeric region in the transition
state of enzymatic glycosidase hydrolysis.25 Though weak,
the activities measured in this study seem to follow this
general trend.
4.2. Materials
The azidodeoxy sugars 5, 6 and 11 were prepared according
to the previously reported procedures.17–19 The glycosidases
a-glucosidase (from yeast), b-glucosidase (from almonds),
b-glucosidase/b-galactosidase (from bovine liver, cyto-
solic), trehalase (from pig kidney), isomaltase (from
yeast), a-galactosidase (from green coffee beans), a-manno-
sidase (from Jack beans), invertase (from yeast), amylo-
glucosidase (from A. Niger) and a-fucosidase (from pig
kidney), used in the inhibition studies, as well as sucrose and
the corresponding o- and p-nitrophenyl glycoside substrates
were purchased from Sigma Chemical Co.
3. Conclusion
In summary, the methodology developed herein provides a
new direction to the development of 1,2,3-triazole-based
pseudooligosaccharidic glycosidase inhibitors that allows
the effective introduction of molecular diversity to modulate
the biological activity. The high efficiency of the proposed
transformation, in combination with the plethora of readily
available azide and acetylene reagents, makes the approach
particularly well suited for combinatorial library schemes,
which should facilitate the identification of more active
compounds. Work in that direction is currently under way in
our laboratories.
4.3. General procedure for inhibition assay
Inhibitory potencies were determined by spectrophotome-
trically measuring the residual hydrolytic activities of the
glycosidases against the respective o- (for b-glucosidase/
b-galactosidase from bovine liver) or p-nitrophenyl a- or
b-D-glycopyranoside in the presence of the corresponding
1,2,3-triazole derivative. Each assay was performed in
phosphate buffer or phosphate-citrate buffer (for a-manno-
sidase and amyloglucosidase) at the optimal pH for each
enzyme. The reactions were initiated by addition of enzyme
to a solution of the substrate in the absence or presence of
various concentrations of inhibitor. After the mixture was
incubated for 10–30 min at 37 or 55 8C (for amylogluco-
sidase) the reaction was quenched by addition of 1 M
Na2CO3. The absorbance of the resulting mixture was
determined at 405 nm. The Ki value and enzyme inhibition
mode were determined from the slope of Lineweaver–Burk
plots and double reciprocal analysis using a Sigma Plot
program (version 4.14, Jandel Scientific).
4. Experimental
4.1. General
Melting points were determined on a Reichert microscope
and are uncorrected. TLC analyses were conducted on
E. Merck 60 F254 Silica Gel non activated plates and
compounds were revealed using a 5% solution of H2SO4 in
EtOH followed by heating. For column chromatography,
Geduran Si 60 (40–63 mm) Silica Gel was used. Optical
rotations were measured on a Perkin-Elmer 341 polarimeter.
1H, 13C, HMQC and COSY NMR spectra were recorded on
4.3.1. 1-(2-O-Benzoxyethyl)-4,5-dihydroxymethyl-1H-1,
2,3-triazole 3. To a solution of 2-azidoethanol 1 (1.00 g,
1
a Bru¨ker ARX 400 spectrometer at 400 MHz for H and

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R. Perion et al. / Tetrahedron 61 (2005) 9118–9128
9123
11.5 mmol) and triethylamine (2.0 mL, 14.2 mmol) in
CH2Cl2 (20 mL), benzoyl chloride (1.6 mL, 13.8 mmol)
was added. After stirring for 4 h at rt, the solution was
successively washed with a 5% HCl aqueous solution, a
saturated aqueous solution of NaHCO3 and water. The
organic layer was then dried (MgSO4) and the solvent
removed under reduced pressure. Chromatographic purifi-
cation (CH2Cl2) gave the desired product 2 (1.98 g, 90%),
which was directly used for the next cycloaddition reaction
without further purification; TLC (EtOAc) Rf 0.7; dH
(CDCl3) 8.08–8.05 (m, 2H, C6H5), 7.59–7.54 (m, 1H,
C6H5), 7.47–7.43 (m, 1H, C6H5), 4.48 (t, 2H, JZ5.1 Hz,
CH2O), 3.59 (t, 2H, CH2N); dC (CHCl3) 166.2 (CO), 133.3,
129.7, 128.5 (C6H5), 63.7 (CH2O), 50.0 (CH2N).
2-Butyn-1,4-diol (56 mg, 0.65 mmol) and azide 6 (50 mg,
0.13 mmol) were heated at 120 8C for 4 h. Column
chromatography (CH2Cl2/MeOH, 19:1) gave 8 (47 mg,
85%) as a white solid; TLC (CH2Cl2/MeOH, 19:1) Rf 0.2;
mp 85 8C; [a]2D0 C43 (c 1.0 in CH2Cl2); dH (CDCl3) 7.30–
6.81 (m, 10H, C6H5), 5.29 (d, 1H, JZ15.6 Hz, OCH2Ph),
5.10–4.08 (m, 6H, OCH2Ph, H-40b, H-50b), 4.95 (d, 1H,
J1a,2aZ9.4 Hz, H-1a), 4.76 (dq, 1H, J4a,5aZ8.9 Hz, J5a,6a
Z
8.5 Hz, H-5a), 4.57 (dd, 1H, J3a,4aZ8.4 Hz, H-4a), 4.55,
(dd, 1H, J2a,3aZ8.9 Hz, H-3a), 4.41 (d, 1H, JZ15.3 Hz,
OCH2Ph), 4.10 (s, 3H, OCH3), 4.08 (dd, 1H, H-2a),
1.97 (d, 3H, H-6a); dC (CDCl3) 136.9 (C-4b), 131.6, 130.6
[Cipso(C6H5)], 129.9 (C-5b), 121.9–122.3 (C6H5), 101.9
(C-1a), 82.5 (C-2a), 82.2 (C-3a), 76.4, 75.2 (OCH2Ph), 71.2
(C-5a), 66.5 (C-4a), 60.1 (OCH3), 58.4 (C-40b), 55.2
(C-50b), 24.7 (C-6a). Found: C, 63.76; H, 6.37; N, 8.91.
C25H31N3O6 requires C, 63.95; H, 6.65; N, 8.94.
Compound 2 (423 mg, 2.2 mmol) and 2-butyn-1,4-diol
(190 mg, 2.2 mmol) were heated at 80 8C for 19 h. After
cooling at rt, EtOAc (2 mL) was added and the mixture
stirred for 10 min. The resulting solid was washed with
EtOAc and finally filtered to give 3 (402 mg, 65%); TLC
(EtOAc) Rf 0.3; dH (CDCl3) 7.95 (d, 2H, JZ7.4 Hz, Ho–
C6H5), 7.58 (t, 1H, JZ7.4 Hz, Hp–C6H5), 7.44 (d, 2H, Hm–
C6H5), 4.91–471 (m, 8H, CH2O, CH2N); dC (CDCl3) 167.4
(CO), 145.9 (C-4), 136.2 (C-5), 134.4, 130.8, 130.6, 129.5
(C6H5), 64.1 (CH2OCO), 55.6 (CH2–C-4), 52.4 (CH2–C-5),
48.6 (CH2CH2–N-1). Found: C, 56.04; H, 5.23; N, 14.92.
C13H15N3O4, requires C, 56.31; H, 5.45; N, 15.15.
4.3.5. 4,5-Dihydroxymethyl-1-(methyl 4,6-dideoxy-a-D-
glucopyranosid-4-yl)-1H-1,2,3-triazole 9. A suspension of
compound 7 (45 mg, 0.09 mmol) in dry MeOH (1 mL) and
Pd/C (30 mg) was stirred for 4 h under H2 at atmospheric
pressure, then filtered over a bed of Celite. The resulting
filtrate was dried (MgSO4) and concentrated. Chromato-
graphic purification (9:1 CH2Cl2/MeOH) afforded 9 (25 mg,
93%) as a white foam; TLC (CH2Cl2/MeOH, 9:1) Rf 0.3;
[a]2D0 C208 (c 0.8 in CH2Cl2); dH (CD3OD) 4.84–4.73 (m,
2H, H-40b), 4.78 (d, 1H, J1a,2aZ3.7 Hz, H-1a), 4.69 (s, 2H,
H-50b), 4.60–4.56 (m, 1H, H-5a), 4.22–4.17 (m, 2H, H-3a,
H-4a), 3.56 (dd, 1H, J2a,3aZ9.0 Hz, H-2a), 3.46 (s, 3H,
OCH3), 0.97 (d, 3H, J5a,6aZ6.2 Hz, H-6a); dC (CD3OD)
137.8 (C-4b), 130.5 (C-5b), 101.8 (C-1a), 74.8 (C-3a), 73.6
(C-2a), 67.5 (C-4a, C-5a), 56.2 (OCH3), 56.1 (C-40b), 52.5
(C-50b), 18.0 (C-6a). Found: C, 45.54; H, 6.53; N, 14.35.
C11H19N3O6 requires C, 45.67; H, 6.62; N, 14.52.
4.3.2. 1-(2-Hydroxyethyl)-4,5-dihydroxymethyl-1H-1,2,
3-triazole 4. Debenzoylation of triazole 3 (70 mg,
0.25 mmol) was achieved in a 0.1 M solution of sodium
methylate in methanol (2 mL) for 2 h. The reaction media was
neutralized with an acidic resin (IR 120, HC-form), filtered,
concentrated and subjected to chromatographic purification
(EtOAc and then 7:3 EtOAc/MeOH) to give 4 (39 mg, 89%);
TLC(EtOAc) Rf 0.1;dH (CD3OD)4.75(s, 2H, CH2–C-5), 4.65
(s, 2H, CH2–C-4), 4.50(t, 2H, JZ5.4 Hz, CH2CH2–N-1), 3.91
(t, 2H, CH2CH2–N-1); dC (CD3OD) 145.8 (C-4), 136.6 (C-5),
61.9 (CH2CH2–N-1), 55.7 (CH2–C-4), 52.4 (CH2–C-5), 51.9
(CH2CH2–N-1). Found: C, 41.71; H, 6.34; N, 24.08.
C6H11N3O3, requires C, 41.62; H, 6.40; N, 24.27.
4.3.6. 4,5-Dihydroxymethyl-1-(methyl 4,6-dideoxy-b-D-
glucopyranosid-4-yl)-1H-1,2,3-triazole 10. Compound 10
(20 mg, 95% yield) was obtained from 8 (34 mg,
0.07 mmol) following the procedure above described for
the preparation of 9 and isolated a white foam; TLC
(CH2Cl2/MeOH, 4:1) Rf 0.3; [a]2D0 K8 (c 0.8 in CH2Cl2); dH
(CD3OD) 4.84–4.72 (m, 4H, H-40b, H-50b), 4.45 (d, 1H,
4.3.3. 4,5-Dihydroxymethyl-1-(methyl 2,3-di-O-benzyl-4,
6-dideoxy-a-D-glucopyranosid-4-yl)-1H-1,2,3-triazole 7.
2-Butyn-1,4-diol (56 mg, 0.65 mmol) and azide 5 (50 mg,
0.13 mmol) were heated at 120 8C for 4 h. Purification by
flash chromatography (CH2Cl2/MeOH, 19:1) afforded 7
(47 mg, 85%) as a white solid; TLC (light petroleum/ethyl
actetate, 1:2) Rf 0.2; mp 98 8C; [a]2D0 C72 (c 1.0 in CH2Cl2);
dH (CDCl3) 7.32–6.80 (m, 10H, C6H5), 5.20–4.89 (m, 7H,
OCH2Ph, H-40b, H-50b), 5.03 (d, 1H, J1a,2aZ4.3 Hz, H-1a),
4.96 (dq, 1H, J5a,6aZ8.6 Hz, J4a,5aZ9.0 Hz, H-5a), 4.78
(dd, 1H, J3a,4aZ9.0 Hz, H-4a), 4.40 (d, 1H, JZ14.0 Hz,
OCH2Ph), 4.39 (dd, 1H, J2a,3aZ9.0 Hz, H-3a), 4.16 (dd, 1H,
H-2a), 3.98 (s, 3H, OCH3), 1.91 (d, 3H, H-6a); dC (CDCl3)
136.3 (C-4b), 130.8, 130.3 [Cipso(C6H5)], 129.3 (C-5b),
122.6–122.1 (C6H5), 95.8 (C-1a), 80.2 (C-3a), 79.5 (C-2a),
76.0, 73.7 (OCH2Ph), 66.8 (C-5a), 66.3 (C-4a), 58.1 (OCH3,
C-40b), 54.8 (C-50b), 24.2 (C-6a). Found: C, 63.92; H, 6.51;
N, 8.91. C25H31N3O6 requires C, 63.95; H, 6.65; N, 8.94.
J1a,2aZ7.9 Hz, H-1a), 4.38 (dq, 1H, J4a,5aZ9.7 Hz, J5a,6a
Z
6.1 Hz, H-5a), 4.28 (dd, 1H, J3a,4aZ9.4 Hz, H-4a), 4.05 (dd,
1H, J2a,3aZ9.0 Hz, H-3a), 3.69 (s, 3H, OCH3), 3.39 (dd, 1H,
H-2a), 0.99 (d, 1H, H-6a); dC (CD3OD) 145.6 (C-4b), 138.2
(C-5b), 105.8 (C-1a), 76.5 (C-3a), 76.3 (C-2a), 72.0 (C-5a),
67.3 (C-4a), 57.7 (OCH3), 56.0 (C-40b), 52.5 (C-50b), 18.0
(C-6a). Found: C, 45.55; H, 6.50; N, 14.51. C11H19N3O6
requires C, 45.67; H, 6.62; N, 14.52.
4.3.7. 1-[Benzyl 2,3-di-O-benzyl-4,6-dideoxy-a-D-gluco-
pyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-
syl-(1/4)-2,3,6-tri-O-benzyl-b-D-glucopyranosid-4c-
yl]-4,5-dihydroxymethyl-1H-1,2,3-triazole 12. A solution
of the trisaccharidic azide 11 (100 mg, 0.08 mmol) and
2-butyn-1,4-diol (35 mg, 0.40 mmol) in chlorobenzene
(1 mL) was heated at 130 8C for 24 h. The solvent was
then removed under reduced pressure and the resulting
crude oil was purified by column chromatography (light
petroleum/EtOAc, 2:3) to give the desired adduct 12
(82 mg, 70%) as a colourless oil; TLC (light petroleum/
4.3.4. 4,5-Dihydroxymethyl-1-(methyl 2,3-di-O-benzyl-4,
6-dideoxy-b-D-glucopyranosid-4-yl)-1H-1,2,3-triazole 8.

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R. Perion et al. / Tetrahedron 61 (2005) 9118–9128
9124
EtOAc, 1:1) Rf 0.3; [a]2D0 C208 (c 0.8 in CH2Cl2); dH
(CDCl3) 7.40–7.06 (m, 43H, C6H5), 6.82–6.78 (m, 2H,
C6H5), 5.83 (d, 1H, J1c,2cZ3.3 Hz, H-1c), 5.61 (d, 1H,
J1b,2bZ3.3 Hz, H-1b), 5.03–4.91 (m, 4H, OCH2Ph), 4.82–
4.44 (m, 17H, OCH2Ph, H-40d, H-50d), 4.78–4.70 (m, 1H,
H-5c), 4.54 (d, 1H, J1a,2aZ7.6 Hz, H-1a), 4.39 (dd, 1H,
J1b,2bZ3.6 Hz, H-1b), 5.00 (d, 1H, J1b,2bZ3.6 Hz, H-1a),
4.98 (d, 1H, JZ11.2 Hz, OCH2Ph), 4.81 (d, 1H, JZ
10.7 Hz, OCH2Ph), 4.77–3.30 (m, 31H, H carbohydrate,
CH2Ph, CH2CCCH2); dC (CDCl3) 138.9, 138.8, 138.5,
138.2, 138.0, 137.9, 137.8, 137.3 [8C, Cipso(C6H5)], 128.5,
128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 127.2, 126.8, 126.7 (C6H5), 96.7
(C-1b), 94.9 (C-1a), 82.7, 82.1 (C-3a, C-3b), 82.0, 81.8
(CH2CCCH2), 79.7 (C-2), 79.4 (C-2b), 77.6 (C-4b), 75.6,
75.0, 74.5, 73.5, 73.4, 73.3, 73.2 (CH2Ph), 73.0 (C-4a), 71.9,
71.7 (CH2Ph), 71.0 (C-5b), 70.2 (C-5a), 68.8, 68.1 (C-6a,
C-6b), 57.4, 54.7 (CH2CCCH2). Found: C, 77.66; H, 6.65.
C72H74O11 requires C, 77.53; H, 6.69. Compound 16b: TLC
(light petroleum/EtOAc, 4:1) Rf 0.20; dH (CDCl3) 7.35–7.09
(m, 40H, C6H5), 5.67 (d, 1H, J1b,2bZ3.6 Hz, H-1b), 4.98–
4.72 (m, 6H, OCH2Ph), 4.65 (d, 1H, J1a,2aZ7.6 Hz, H-1a),
4.61–4.19 (m, 14H, OCH2Ph), 4.07 (t, 1H, JZ8.9 Hz,
H-4a), 3.89 (t, 1H, JZ9.7 Hz, H-3b), 3.82–3.57 (m, 8H,
H-2a, H-3a, H-5a, H-4b, H-5b, H-6), 3.48 (dd, 1H, H-2b),
3.41 (br d, 1H, JZ9.9 Hz, H-6); dC (CDCl3) 138.9, 138.8,
138.5, 138.2, 138.0, 137.9, 137.8, 137.3 [8C, Cipso(C6H5)],
128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7,
127.6, 127.5, 127.4, 127.3, 127.2, 126.8, 126.7 (C6H5),
101.3 (C-1a), 96.8 (C-1b), 84.8 (C-3a), 82.8 (C-2a or C-2b),
82.0 (CH2CCCH2), 81.9 (C-3b), 79.4 (C-2a or C-2b), 77.7
(C-4b), 75.6, 75.1 (CH2Ph), 74.6 (C-5a, CH2Ph), 74.1, 73.5,
73.4, 73.3 (CH2Ph), 72.6 (C-4a), 71.7 (CH2Ph), 71.1 (C-5b),
69.1, 68.2 (C-6a, C-6b), 57.4, 56.2 (CH2CCCH2). Found: C,
77.46; H, 6.55. C72H74O11 requires C, 77.53; H, 6.69.
J2c,3cZ9.4 Hz, J3c,4cZ9.9 Hz, H-3c), 4.22 (dd, 1H, J3b,4b
Z
9.1 Hz, J4b,5bZ8.9 Hz, H-4b), 4.14–4.05 (m, 2H, H-4a,
H-3b), 4.05–3.95 (m, 2H, H-60a, H-5b), 3.92 (dd, 1H, H-4c),
3.88–3.84 (m, 1H, H-6a), 3.83–3.76 (m, 2H, H-3a, H-6b),
3.79 (d, 1H, JZ10.0 Hz, OCH2Ph), 3.65–3.62 (m, 5H,
H-2a, H-5a, H-2b, H-60b, H-2c), 0.82 (d, 3H, J5c,6cZ6.4 Hz,
H-6c); dC (CDCl3) 144.0 (C-4d), 138.7–137.2 [9C,
Cipso(C6H5)], 135.9 (C-5d), 128.4–126.5 (45C, C6H5), 102.4
(C-1a), 95.8 (C-1c), 96.4 (C-1b), 84.6 (C-3a), 82.0 (C-3b),
81.9 (C-2a), 80.2 (C-2c), 79.7 (C-3c), 79.4 (C-2b), 75.7
(OCH2Ph), 74.7 (C-5a), 74.6, 73.9 (OCH2Ph), 73.3 (C-4a),
72.9, 72.7, 71.0 (OCH2Ph), 71.2 (C-4b), 70.5 (C-5b), 68.8
(C-6a), 68.2 (C-6b), 66.2 (C-5c), 64.9 (C-4c), 55.5 (C-40d),
51.8 (C-50d), 17.3 (C-6c). Found: C, 72.66; H, 6.65; N, 3.05.
C85H91N3O16 requires C, 72.37; H, 6.50; N, 2.98.
4.3.8. 1-[4,6-Dideoxy-a-D-glucopyranosyl-(1/4)-a-D-
glucopyranosyl-(1/4)-D-glucopyranos-4c-yl]-4,5-di-
hydroxymethyl-1H-1,2,3-triazole 13. A solution of 12
(190 mg, 0.13 mmol) in a 1:1 mixture of cyclohexene/
MeOH (4 mL) was heated under reflux in the presence of
Pd(OH)2 (200 mg) for 12 h. After removal of the catalyst by
filtration over a bed of Celite, chromatographic purification
(EtOAc/MeOH/water, 7:2:1/5:3:2) yielded 13 as a white
foam; TLC (EtOAc/MeOH/water, 5:3:2) Rf 0.2; [a]2D0 C145
(c 1.0 in H2O); dH (D2O) 5.48 (d, 1H, J1c,2cZ3.3 Hz, H-1c),
5.39 (d, 1H, J1b,2bZ3.6 Hz, H-1b a-anomer), 5.20 (d, 1H,
J1a,2aZ3.8 Hz, H-1a), 4.80–4.70 (m, 2H, H-50d), 4.71 (s,
2H, H-40d), 4.63 (d, 1H, J1a,2aZ7.6 Hz, H-1a b-anomer),
4.60–4.54 (m, 1H, H-5c), 4.32–4.27 (m, 2H, H -3c, H-4c),
4.3.10. 1-[Benzyl 2,3-di-O-benzyl-4,6-dideoxy-a-D-gluco-
pyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-
syl-(1/4)-2,3,6-tri-O-benzyl-b-D-glucopyranosid-4c-
yl]-4-benzyloxymethyl-5-hydroxymethyl-1H-1,2,3-tri-
azole and 1-[benzyl 2,3-di-O-benzyl-4,6-dideoxy-a-D-
glucopyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-gluco-
pyranosyl-(1/4)-2,3,6-tri-O-benzyl-b-D-glucopyrano-
sid-4c-yl]-5-benzyloxymethyl-4-hydroxymethyl-1H-1,2,
3-triazole 19 and 20. Heat-promoted 1,3-dipolar cyclo-
addition between azide 11 (1.00 g, 0.75 mmol) and alkyne
14 (530 mg, 3.00 mmol) for 4 h, following the procedure
above described for the preparation of 12, and subsequent
purification of the crude product by column chromato-
graphy (7:3 light petroleum/EtOAc) afforded 19 (270 mg,
24%) and 20 (170 mg, 15%) as colourless oils. Compound
19: TLC (light petroleum/EtOAc, 2:1) Rf 0.3; [a]2D0 C30 (c
1.0 in CHCl3); dH (CDCl3) 7.40–7.06 (m, 48H, C6H5), 6.82–
6.78 (m, 2H, C6H5), 5.83 (d, 1H, J1c,2cZ3.6 Hz, H-1c), 5.61
(d, 1H, J1b,2bZ3.3 Hz, H-1b), 5.03–4.92 (m, 4H, OCH2Ph),
4.82–4.45 (m, 19H, OCH2Ph, H-40d, H-50d), 4.56 (d, 1H,
J1a,2aZ6 Hz, H-1a), 4.75–4.70 (m, 1H, H-5c), 4.44 (dd, 1H,
J2c,3cZ9.9 Hz, J3c,4cZ11.7 Hz, H-3c), 4.22 (dd, 1H,
J3b,4bZ9.2 Hz, J4b,5bZ9.2 Hz, H-4b), 4.12–4.06 (m, 2H,
H-4a, H-3b), 4.06–3.98 (m, 2H, H-60a, H-5b), 3.99–3.92 (m,
4.00–3.52 (m, 12H, H carbohydrate), 3.62 (dd, 1H, J2a,3a
Z
9.7 Hz, H-2a a-anomer), 3.25 (dd, 1H, J2a,3aZ8.4 Hz, H-2a
b-anomer), 0.96 (d, 3H, JZ6.1 Hz, H-6c); dC (D2O) 144.5
(C-4d), 136.7 (C-5d), 100.2 (C-1c), 99.8 (C-1b), 96.1 (C-1a
b-anomer), 92.2 (C-1a a-anomer), 77.4, 77.3, 77.1, 76.5,
74.9, 73.7, 73.6, 71.9, 71.8, 71.6, 70.2 (C carbohydrate),
74.3 (C-2a b-anomer), 72.5 (C-2a a-anomer), 71.4 (C-3c),
67.70 (C-5c), 65.3 (C-4c), 60.8, 60.7 (C-6a, C-6b), 54.0
(C-4 d), 50.8 (C-50d), 16.4 (C-6c). Found: C, 41.05; H, 6.37;
N, 6.20. C22H37N3O16$2.5 H2O requires C, 40.99; H, 6.57;
N, 6.52.
4.3.9. 4-Benzyloxy-2-butynyl 2,3,4,6-tetra-O-benzyl-a-D-
glucopyranosyl-(1/4)-2,3,6-tri-O-benzyl-a- and b-D-
glucopyranoside 16a and 16b. To a solution of maltosyl
donor 1516 (100 mg, 0.10 mmol) and 4-benzyloxybut-2-yn-
1-ol 14 (35 mg, 0.20 mmol) in CH2Cl2 (1 mL) were
successively added NIS (222 mg, 0.10 mmol) and
Cu(OTf)2 (7 mg, 0.02 mmol). The reaction was stirred at
rt for 10 min before neutralization by adding a few drops of
Et3N. The reaction media was then diluted with Et2O and
successively washed with an aqueous solution of sodium
thiosulfate and water. After drying (MgSO4) and removal of
the solvents, flash chromatography (light petroleum/EtOAc,
4:1) gave 16a (55 mg, 50%) and 16b (12 mg, 11%).
Compound 16a: TLC (light petroleum/EtOAc, 4:1) Rf
0.24; dH (CDCl3) 7.28–6.99 (m, 40H, C6H5), 5.65 (d, 1H,
0
1H, H-4c), 3.88 (dd, 1H, J5a,6aZ4.1 Hz, J6a,6a Z11.2 Hz,
H-6a), 3.85–3.78 (m, 2H, H-3a, H-6b), 3.81 (d, 1H, JZ
10.0 Hz, OCH2Ph), 3.66–3.54 (m, 4H, H-2a, H-5a, H-2b,
H-60b), 3.53 (dd, 1H, H-2c), 0.82 (d, 3H, J5c,6cZ6.1 Hz,
H-6c); dC (CDCl3) 141.4 (C-4d), 138.8, 138.4, 138.3, 138.2,
137.7, 137.5, 137.4, 137.1, 136.4 [10C, Cipso(C6H5)], 136.3
(C-5d), 129.0, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 127.6, 127.5, 127.4, 127.3, 127.2,
126.7, 126.6 (50C, C6H5), 102.4 (C-1a), 95.9 (C-1c), 96.4

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R. Perion et al. / Tetrahedron 61 (2005) 9118–9128
9125
(C-1b), 84.7 (C-3a), 82.0 (C-2a, C-3b), 80.2 (C-2c), 79.7
(C-3c), 79.4 (C-2b), 75.8, 74.7 (OCH2Ph), 74.6 (C-5a), 74.0,
73.9, 73.4 (OCH2Ph), 73.3 (C-4a), 72.8, 72.7 (OCH2Ph),
71.2 (C-4b), 71.0 (OCH2Ph), 70.5 (C-5b), 68.8 (C-6a), 68.2
(C-6b), 66.2 (C-5c), 65.0 (C-4c), 63.5 (C-40d), 52.2 (C-50d),
17.4 (C-6c). Found: C, 73.57; H, 6.46; N, 2.80.
C92H97N3O16 requires C, 73.63; H, 6.51; N, 2.80.
Compound 20: TLC (light petroleum/EtOAc, 2:1) Rf 0.2;
[a]2D0 47 (c 1.0 in CHCl3); dH (CDCl3) 7.40–7.04 (m, 48H,
72.9, 72.8, 72.4, 72.0, 71.3, 71.0, 70.6, 70.1, 69.0, 68.8,
68.2, 66.6, 65.9, 65.0 (28C carbohydrate, 34 OCH2Ph), 59.7
(C-40d), 58.3 (C-50d), 17.4 (C-6c). Found: C, 75.25; H, 6.59;
N, 1.79. C153H159N3O26 requires C, 74.83; H, 6.52; N, 1.71.
4.3.12. 1-[Benzyl 2,3-di-O-benzyl-4,6-dideoxy-a-D-gluco-
pyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-
syl-(1/4)-2,3,6-tri-O-benzyl-b-D-glucopyranosid-4c-
yl]-5-benzyloxymethyl-4-[2,3,4,6-tetra-O-benzyl-a-D-
glucopyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-gluco-
pyranosyloxymethyl]-1H-1,2,3-triazole and 1-[benzyl 2,
3-di-O-benzyl-4,6-dideoxy-a-D-glucopyranosyl-(1/4)-
2,3,6-tri-O-benzyl-a-D-glucopyranosyl-(1/4)-2,3,6-tri-
O-benzyl-b-D-glucopyranosid-4c-yl]-5-benzyloxy-
methyl-4-[2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl-
(1/4)-2,3,6-tri-O-benzyl-b-D-glucopyranosyloxy-
methyl]-1H-1,2,3-triazole 17 and 22. NIS (45 mg,
0.20 mmol) and Cu(OTf)2 (10 mg, 0.03 mmol) were
successively added to a solution of donor 15 (203 mg,
0.20 mmol) and acceptor 20 (200 mg, 0.13 mmol) in
CH2Cl2 (2 mL) at rt. After stirring for 30 min and quenching
with Et3N (10 mL), the reaction mixture was diluted with
Et2O (25 mL), washed with a 20% aqueous solution of
sodium thiosulfate (2!10 mL) and water (2!10 mL),
dried (MgSO4), and the solvent removed under reduced
pressure. The resulting crude oil was purified by column
chromatography (light petroleum/EtOAc, 4:1) to give 17
(60 mg, 18%) and 22 (40 mg, 12%) as colourless oils.
Compound 17: TLC (hexane/Et2O, 3:2) Rf 0.2; [a]2D0 C49 (c
1.4 in CHCl3); dH (CDCl3) 7.40–7.04 (m, 83H, C6H5), 6.81–
6.78 (m, 2H, C6H5), 5.81 (d, 1H, J1c,2cZ3.0 Hz, H-1c), 5.69
(d, 1H, J1f,2fZ3.6 Hz, H-1f), 5.60 (d, 1H, J1b,2bZ3.3 Hz,
H-1b), 5.00 (d, 1H, J1e,2eZ3.6 Hz, H-1e), 5.01–3.38 (m,
34H OCH2Ph, 28H carbohydrate, H-40d, H-50d), 4.55 (d,
1H, J1a,2aZ7.6 Hz, H-1a), 0.80 (d, 3H, J5c,6cZ5.8 Hz,
H-6c); dC (CDCl3) 141.9 (C-4d), 138.9, 138.8, 138.5, 138.4,
138.3, 138.2, 138.0, 137.9, 137.8, 137.7, 137.5, 137.2 [17C,
Cipso(C6H5)], 134.2 (C-5d), 128.5, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4,
127.3, 127.2, 127.1, 126.8, 126.7, 126.6 (85C, C6H5), 102.4
(C-1a), 96.9 (C-1f), 96.6 (C-1b), 96.1 (C-1c), 95.2 (C-1e),
84.7, 82.0, 81.9, 80.2, 79.9, 79.8, 79.4, 77.6, 75.6, 75.0,
74.7, 74.2, 74.0, 73.7, 73.5, 73.3, 73.2, 73.1, 72.9, 72.8,
72.4, 72.0, 71.3, 71.0, 70.5, 70.1, 69.0, 68.8, 68.1, 66.6,
65.9, 65.0 (28C carbohydrate, 34 OCH2Ph), 59.7 (C-40d),
58.3 (C-50d), 17.4 (C-6c); m/z (ESMS) 2477.1124 ([MC
Na]C. C153H159N3O26Na requires 2477.1110). Compound
22: TLC (hexane/Et2O, 3:2) Rf 0.1; [a]2D0 C35 (c 1.4 in
CHCl3); dH (CDCl3) 7.40–7.04 (m, 83H, C6H5), 6.81–6.78
(m, 2H, C6H5), 5.80 (d, 1H, J1c,2cZ3.6 Hz, H-1c), 5.68 (d,
1H, J1f,2fZ3.6 Hz, H-1f), 5.59 (d, 1H, J1b,2bZ3.6 Hz,
H-1b), 5.08–3.38 (m, 34H OCH2Ph, 28H carbohydrate,
H-40d, H-50d), 4.56 (d, 1H, J1e,2eZ8.0 Hz, H-1e), 4.55 (d,
1H, J1a,2aZ7.6 Hz, H-1a), 0.80 (d, 3H, J5c,6cZ6.1, Hz,
H-6c); dC (CDCl3) 142.0 (C-4d), 138.9, 138.8, 138.4, 138.3,
138.2, 138.1, 137.9, 137.8, 137.7, 137.5, 137.0 [17C,
Cipso(C6H5)], 134.0 (C-5d), 128.5, 128.4, 128.3, 127.8,
127.6, 127.3, 127.1, 126.7, 126.6 (85C, C6H5), 102.6 (C-1e),
102.4 (C-1a), 96.8 (C-1f), 96.6 (C-1b), 96.1 (C-1c), 84.7,
82.0, 80.0, 79.8, 79.5, 79.3, 77.7, 75.6, 75.4, 75.1, 74.7,
74.6, 74.5, 74.0, 73.4, 73.3, 72.9, 72.8, 72.4, 72.2, 71.2,
71.0, 70.5, 68.8, 68.1, 606.5, 65.9, 65.0 (28C carbohydrate,
34 OCH2Ph), 61.6 (C-4 d), 58.4 (C-50d), 17.3 (C-6c); m/z
C6H5), 6.82–6.78 (m, 2H, C6H5), 5.83 (d, 1H, J1c,2c
Z
3.6 Hz, H-1c), 5.61 (d, 1H, J1b,2bZ3.6 Hz, H-1b), 5.02–4.92
(m, 4H, OCH2Ph), 4.82–4.35 (m, 19H, OCH2Ph, H-40d,
H-50d), 4.55 (d, 1H, J1a,2aZ7.6 Hz, H-1a), 4.75–4.67 (m,
1H, H-5c), 4.37 (dd, 1H, JZ10.9 Hz, H-3c), 4.22 (dd, 1H,
J3b,4bZ9.4 Hz, J4b,5bZ9.4 Hz, H-4b), 4.12–4.06 (m, 2H,
H-4a, H-3b), 4.04–3.94 (m, 2H, H-60a, H-5b), 4.00–3.95 (m,
0
1H, H-4c), 3.86 (dd, 1H, J5a,6aZ4.2 Hz, J6a,6 aZ10.7 Hz,
H-6a), 3.83–3.76 (m, 2H, H-3a, H-6b), 3.78 (d, 1H, JZ
10.0 Hz, OCH2Ph), 3.65–3.55 (m, 4H, H-2a, H-5a, H-2b,
H-60b), 3.46 (dd, 1H, H-2c), 0.82 (3H, J5c,6cZ6.1 Hz,
H-6c); dC (CDCl3) 145.2 (C-4d), 138.9, 138.8, 138.4, 138.3,
138.2, 137.9, 137.8, 137.7, 137.5, 136.8 [10C, Cipso(C6H5)],
132.8 (C-5d), 127.8, 127.7, 127.6, 127.5, 127.3, 126.8,
126.6 (50C, C6H5), 102.4 (C-1a), 97.0 (C-1c), 96.5 (C-1b),
84.6 (C-3a), 82.0 (C-2a, C-3b), 80.6 (C-2c), 80.1 (C-3c),
79.4 (C-2b), 75.6, 74.7 (OCH2Ph), 74.6 (C-5a), 73.9
(OCH2Ph), 73.5 (C-4a), 73.3, 72.9, 72.7, 72.4 (OCH2Ph),
71.2 (C-4b), 71.0 (OCH2Ph), 70.5 (C-5b), 68.8 (C-6a), 68.2
(C-6b), 66.4 (C-5c), 65.1 (C-4c), 58.8 (C-50d), 56.0 (C-40d),
17.4 (C-6c). Found: C, 73.96; H, 6.55; N, 2.93.
C92H97N3O16 requires C, 73.63; H, 6.51; N, 2.80.
4.3.11. 1-[Benzyl 2,3-di-O-benzyl-4,6-dideoxy-a-D-gluco-
pyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-
syl-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranosid-4c-
yl]-4-benzyloxymethyl-5-[2,3,4,6-tetra-O-benzyl-a-D-
glucopyranosyl-(1/4)-2,3,6-tri-O-benzyl-a-D-gluco-
pyranosyloxymethyl]-1H-1,2,3-triazole 18. To a solution
of donor 15 (176 mg, 0.17 mmol) and acceptor 19 (130 mg,
0.087 mmol) in toluene (1 mL) at rt were successively
added NIS (39 mg, 0.173 mmol) and Cu(OTf)2 (6.3 mg,
0.017 mmol). After stirring for 30 min, the reaction was
quenched by adding Et3N (10 mL) and diluted with Et2O
(25 mL). The mixture was then washed with a 20% aqueous
solution of sodium thiosulfate (2!10 mL) and water (2!
10 mL). The combined organic layers were dried (MgSO4),
concentrated and the residue was purified by column
chromatography (light petroleum/EtOAc, 4:1) to give 18
(42 mg, 20%) as a colourless oil; TLC (light petroleum/
EtOAc, 7:3) Rf 0.3; [a]2D0 C55 (c 1.0 in CHCl3); dH (CDCl3)
7.40–7.04 (m, 83H, C6H5), 6.81–6.78 (m, 2H, C6H5), 5.81
(d, 1H, JZ3.3 Hz, H-1c), 5.65 (d, 1H, JZ3.6 Hz, H-1f),
5.59 (d, 1H, JZ3.3 Hz, H-1b), 5.00 (d, 1H, JZ3.6 Hz,
H-1e), 5.00–3.38 (m, 34H OCH2Ph, 28H carbohydrate,
H-40d, H-50d), 4.55 (d, 1H, JZ7.6 Hz, H-1a), 0.80 (d, 3H,
JZ6.1 Hz, H-6c); dC (CDCl3) 141.9 (C-4d), 138.9, 138.8,
138.5, 138.4, 138.3, 138.2, 138.1, 138.0, 137.9, 137.8,
137.5, 137.2 [17C, Cipso(C6H5)], 134.2 (C-5d), 128.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 127.2, 127.1, 126.9, 126.8, 126.6 (85C,
C6H5), 102.4 (C-1a), 96.9 (C-1f), 96.6 (C-1b), 96.1 (C-1c),
95.2 (C-1e), 84.7, 82.0, 81.9, 80.2, 79.9, 79.8, 79.5, 79.4,
77.7, 75.6, 75.0, 74.7, 74.2, 74.0, 73.7, 73.5, 73.3, 73.1,

´
R. Perion et al. / Tetrahedron 61 (2005) 9118–9128
9126
(ESMS) 2477.1126 [MCNa]C. C153H159N3O26Na requires
2477.1110.
the preparation of 13; [a]2D0 C111 (c 0.8 in H2O); TLC
(EtOAc/MeOH/water, 5:3:2) Rf 0.2; dH (D2O) 5.48 (d, 1H,
J1c,2cZ3.6 Hz, H-1c), 5.39 (d, 1H, J1b,2bZ3.8 Hz, H-1b),
5.34 (d, 1H, J1f,2fZ3.6 Hz, H-1f), 5.19 (d, 1H, J1a,2a
Z
4.3.13. 1-[4,6-Dideoxy-a-D-glucopyranosyl-(1/4)-a-D-
glucopyranosyl-(1/4)-D-glucopyranos-4c-yl]-4-hydro-
xymethyl-5-[a-D-glucopyranosyl-(1/4)-a-D-glucopyra-
nosyloxymethyl]-1H-1,2,3-triazole 21. Pseudohexa-
saccharide 21 (35 mg, 95%) was obtained from 18
(100 mg, 0.04 mmol), following the procedure above
described for the preparation of 13, as a white foam; [a]D20
C227 (c 1.5 in H2O); TLC (EtOAc/MeOH/water, 5:3:2) Rf
0.2; dH (D2O) 5.48 (d, 1H, J1c,2cZ3.3 Hz, H-1c), 5.38 (d,
1H, J1b,2bZ3.6 Hz, H-1b), 5.32 (d, 1H, J1f,2fZ3.6 Hz,
H-1f), 5.19 (d, 1H, J1a,2aZ3.6 Hz, H-1a a-anomer), 5.05 (d,
1H, J1e,2eZ3.3 Hz, H-1e), 4.97 (d, 1H, JZ12.2 Hz, H-50d),
4.74 (d, 1H, H-50d0), 4.65 (s, 2H, H-40d), 4.63–4.54 (m, 1H,
H-5c), 4.62 (d, 1H, J1a,2aZ8.1 Hz, H-1a b-anomer), 4.33 (t,
3.8 Hz, H-1a a-anomer), 5.00 (d, 1H, J1e,2eZ3.6 Hz, H-1e),
4.86–4.70 (m, 2H, H-40d), 4.76 (s, 2H, H-50d), 4.62 (d, 1H,
J1a,2aZ7.8 Hz, H-1a b-anomer), 4.60–4.56 (m, 1H, H-5c),
4.30–4.25 (m, 2H, H-3c, H-4c), 3.97–3.50 (m, 24H, H
carbohydrate, H-2a a-anomer), 3.36 (dd, 1H, J3f,4fZJ4f,5f
Z
9.5 Hz, H-4f), 3.20 (dd, 1H, J2a,3aZ9.4 Hz, H-2a
b-anomer), 0.96 (d, 3H, JZ6.1 Hz, H-6c); dC (D2O) 141.9
(C-4d), 137.6 (C-5d), 100.2 (C-1c), 99.9 (C-1f), 99.8
(C-1b), 98.2 (C-1e), 96.1 (C-1a b-anomer), 92.2 (C-1a
a-anomer), 77.8, 77.6, 77.3, 77.0, 75.4, 74.3 (C-2
b-anomer), 74.2, 74.1, 73.7, 73.0, 72.5, 72.4, 72.3, 72.1,
71.9, 71.8, 70.7, 70.1 (C carbohydrate), 71.3 (C-3c), 67.7
(C-5c), 65.4 (C-4c), 61.0–60.6 (C-6a, C-6b, C-6e, C-6f),
60.1 (C-40d), 50.9 (C-50d), 16.5 (C-6c); m/z (ESMS)
946.3150 ([MCNa]C). C34H57N3O26Na requires 946.3128.
1H, J2c,3cZJ3c,4cZ9.7 Hz, H-3c), 4.26 (dd, 1H, J4c,5c
Z
9.9 Hz, H-4c), 4.00–3.48 (m, 24H, H carbohydrate, H-2a
a-anomer), 3.37 (t, 1H, J3f,4fZJ4f,5fZ9.7 Hz, H-4f), 3.24
(dd, 1H J2a,3aZ8.9 Hz, H-2a b-anomer), 0.97 (d, 3H, JZ
6.1 Hz, H-6c); dC (D2O) 144.0 (C-4d), 133.9 (C-5d), 100.2
(C-1c), 100.1 (C-1f), 99.8 (C-1b), 98.4 (C-1e), 96.1 (C-1a
b-anomer), 92.2 (C-1a a-anomer), 81.7, 81.5, 77.8, 77.6,
77.3, 76.6, 75.8, 75.1, 74.8, 74.7, 74.3 (C-2a b-anomer),
73.9, 73.8, 73.3, 73.0, 70.2 (C carbohydrate), 71.4 (C-3c),
69.6 (C-4f), 67.7 (C-5c), 65.6 (C-4c), 60.9–60.6 (C-6a,
C-6b, C-6e, C-6f), 56.5 (C-50d), 54.1 (C-40d), 16.4 (C-6c).
Found: C, 39.87; H, 6.24. C34H57N3O26$5.5 H2O requires C,
39.92; H, 6.70.
Acknowledgements
The authors are grateful to the Agence Nationale de la
Recherche et de la Technologie (ANRT) for a grant to R.P.
and to Martine Lefeuvre (UMR CNRS 6052, ENSCR,
France) for recording all the NMR spectra. M.I.G.-M.,
´
C.O.M. and J.M.G.F. thank the Ministerio de Educcion y
Ciencia of Spain for financial support (contracts no.
BQU2003-00937 and CTQ2004-05854/BQU).
4.3.14. 1-[4,6-Dideoxy-a-D-glucopyranosyl-(1/4)-a-D-
glucopyranosyl-(1/4)-D-glucopyranos-4c-yl]-5-[a-D-
glucopyranosyl-(1/4)-b-D-glucopyranosyloxymethyl]-
4-hydroxymethyl-1H-1,2,3-triazole 23. Compound 23
(12 mg, 95%) was obtained from 22 (35 mg, 0.01 mmol)
as a white foam following the procedure above described for
the preparation of 13. m/z (ESMS) 946.3128 ([MCNa]C).
C34H57N3O26Na requires 946.3128; [a]2D0 C8 (c 0.1 in
H2O); TLC (EtOAc/MeOH/water, 5:3:2) Rf 0.2; dH (D2O)
References and notes
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5.48 (d, 1H, J1c,2cZ3.6 Hz, H-1c), 5.39 (d, 1H, J1b,2b
Z
3.8 Hz, H-1b), 5.36 (d, 1H, J1f,2fZ3.8 Hz, H-1f), 5.19 (d,
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¨
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