N-Glycoside neoglycotrimers from 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide

Article abstract of DOI:10.1016/j.carres.2006.04.011

2,3,4,6-Tetra-O-acetyl-β-d-glucopyranosyl azide is available on large scale from d-glucose by means of a three-step sequence involving acetylation, activation as the glycosyl bromide, and stereospecific displacement with azide anion. The azide functionality then serves as a convenient anchor upon which to introduce new functionality, usually with retention of the β-stereochemistry. Here we report the synthesis of an amide-linked N-glycosyl trimer, by employing a Staudinger-aza-Wittig process on the azide, as well as a hybrid N-glycosyl triazole-amide-linked trimer in which the sugars are separated by 1,2,3-triazole heterocycles. Both of these neoglycotrimers are isolated in good yield with high β-selectivity in each case.

Full text of DOI:10.1016/j.carres.2006.04.011

Carbohydrate Research 341 (2006) 1081–1090
N-Glycoside neoglycotrimers from
2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide
David P. Temelkoff, Matthias Zeller and Peter Norris*
Department of Chemistry, Youngstown State University, 1 University Plaza, Youngstown, OH 44555-3663, USA
Received 11 March 2006; received in revised form 6 April 2006; accepted 10 April 2006
Available online 6 May 2006
Abstract—2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl azide is available on large scale from D-glucose by means of a three-step
sequence involving acetylation, activation as the glycosyl bromide, and stereospecific displacement with azide anion. The azide func-
tionality then serves as a convenient anchor upon which to introduce new functionality, usually with retention of the b-stereochem-
istry. Here we report the synthesis of an amide-linked N-glycosyl trimer, by employing a Staudinger–aza-Wittig process on the azide,
as well as a hybrid N-glycosyl triazole–amide-linked trimer in which the sugars are separated by 1,2,3-triazole heterocycles. Both of
these neoglycotrimers are isolated in good yield with high b-selectivity in each case.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Neoglycotrimer; N-Glycoside; Staudinger reaction; Dipolar cycloaddition
1. Introduction
has been complemented by studies into their structure,
particularly their folding properties, for example, by
NMR spectroscopy,5,7,11–13 circular dichroism,10,14 and
most recently by molecular dynamics simulations.15,16
Although these oligomers have great potential,17 both
as practical molecules in medicinal chemistry and from a
theoretical perspective in terms of their folding proper-
ties, the synthesis of diverse collections of related com-
pounds is undoubtedly hindered by the availability of
sugar-derived amino acid precursors, as well as by the
tedious workups and isolation procedures required. A
long term goal of our research is to develop chemistry
that alleviates such problems in workup such that the
synthesis of collections of related oligomeric structures
becomes routine. In this paper, we describe methods
for the synthesis of two related N-glycoside neoglycotri-
mers, 1 and 2, in Figure 1 that are produced from readily
available precursors by classical Staudinger–aza-Wittig
chemistry using bis(diphenylphosphino)ethane (dppe)
as a convenient replacement for triphenylphosphine (to
give 1), and by Cu(I)-catalyzed dipolar cycloaddition
with a sugar-derived alkyne (to give 2). Both methods
produce very clean products and avoid some of the
issues related to oligomer purification.
Since the original suggestion by Fuchs and Lehmann,1
and later Nicolaou,2 that amide-linked carbohydrate
oligomers would be of interest as new materials with
potentially valuable properties, there have been numer-
ous reports on the synthesis and subsequent study of
such molecules. Most of the previous work has centered
on C-glycosidic linkages where, for example, an exo-
cyclic carboxylic acid group is pre-installed at the
anomeric carbon, which is then conjugated to an amino-
deoxy sugar ‘amino acid’ through an amide linkage.3
Extensive work by Fleet and co-workers has led to an
understanding of the intramolecular folding properties
of oligomeric structures constructed from furanose
building blocks.4–7 Sugar-derived acyclic amino acids
containing furan rings have been used to produce novel
oligomers,8 and more recent work by the Fleet group
has led to novel ‘carbohydrate–cyclodextrins’ through
coupling acyclic carbohydrate-based amino acid ana-
logs.9,10 The interest in the synthesis of carbopeptoids
*
Corresponding author. Fax: +1 330 941 1579; e-mail: pnorris@ysu.
edu
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.04.011

1082
D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
Figure 1.
2. Results and discussion
classical bromination method using HBr in AcOH.
Unfortunately, this led to a complex mixture of prod-
ucts from which the expected a-bromide could not be
isolated. Turning our attention to alternative methods
for the introduction of an azide group at C-1 of the
glucopyranuronosyl ring, we employed trimethylsilyl-
azide (TMSN3) and SnCl4, which has been shown to give
mainly the a-anomer when an amide group is present at
C-6.21 Participation of the amide group in 6 could be
reasonably expected and this was confirmed when an
inseparable mixture of anomers of 7 was isolated in
ꢀ5:1 a/b ratio. The signal for H-1 of the major isomer
appears at 5.70 ppm with a J1,2 coupling of 4.4 Hz,
which is in close agreement with previously reported
analogs.21
The anomeric azides (7a/b) could not be cleanly sepa-
rated and were used as a mixture for the second round
of Staudinger–aza-Wittig chemistry. Thus, reacting
7a/b with acid chloride 5 in the presence of dppe
(Scheme 2) again proceeded smoothly and the major
amide product (1, 53% yield) was isolated by flash chro-
matography, again without any trace of phosphine
oxide impurity. The mass spectrum of this material con-
firmed that it was indeed a trimer (HRMS calculated
for C40H52N2O27: 1015.2655 [+Na], found: 1015.2618
[+Na]); however, analysis of the 1H NMR spectrum
suggested the b-stereochemistry for the newly formed
amide linkage at C-1 of the middle glucopyranuronosyl
ring, that is, compound 1 in Scheme 2. The H-1 signal
for simple b-analogs of 1 typically appears around
5.4 ppm,20 while the corresponding proton in the a-iso-
mers is usually found in the 5.8–5.9 ppm region.22,23 The
protons at C-1 of the glucopyranose and C-1 of the mid-
dle glucopyranuronosyl rings are part of a complex set
of signals that overlap in the region 4.9–5.4 ppm, which
matches the previously reported b-analogs and not the
a-isomers. Additionally, the N–H/H-1 coupling con-
stants of 9.5 and 9.3 Hz, obtained from the N–H signals
at 7.14 and 7.32 ppm, respectively, are consistent with
the b-stereochemistry at both anomeric positions; the
corresponding coupling constants in the a-isomers are
typically around 7 Hz. Isolation of 1 as the b-anomer
infers that the a-phosphinimine intermediate formed
from the major a-isomer of azide 7 must be undergoing
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl azide (4) is
available in three steps from D-glucose (3) as a highly
crystalline solid on multigram scale by the sequence
shown in Scheme 1.18 The precursor bromide is exclu-
sively the a-anomer, which leads to isolation of only
the b-azide after stereospecific displacement by azide;
the X-ray crystal structure of 4 has recently been
reported.19
Whereas the use of triphenylphosphine is often prob-
lematic when applied to sugars, we have found that
bis(diphenylphosphino)ethane (dppe) serves as a useful
replacement as the byproduct bis(phosphineoxide) is
very polar and does not streak on silica gel as is often
the case with Ph3P@O.20 Application of dppe to
amide-linked oligomer synthesis could therefore offer
advantages over other methods of amide coupling,
because in all examples using glycosyl azide precursors
the b-configuration of the azide is retained in the amide
product.20 In the present context, reacting azide 4 with
glucopyranuronoyl chloride 5, in the presence of dppe,
resulted in a single amide product (6, Scheme 2) isolated
in 72% yield after an aqueous workup and column chro-
matography. There is no contamination from the phos-
phine oxide byproduct. Evidence for the retention of b-
1
stereochemistry in 6 comes from its H NMR spectrum
in which the 1H triplet at 5.29 ppm (assigned from a
COSY experiment) with J = 9.4 Hz is consistent with
H-1 of the glucopyranosyl ring being aligned anti to
both the exocyclic N–H and C-2–H bonds. This orienta-
tion about C-1 of the glucopyranose ring is in close
agreement with other examples of glucosyl amides
formed by this method.20
To convert 6 into a glycosyl azide suitable for synthe-
sis of the desired trimer (1), we first investigated the
OAc
O
OH
O
1. Ac2O, pyridine
AcO
AcO
HO
HO
N3
2. HBr, AcOH
3. NaN3, DMF
OH
OAc
OH
3
4
Scheme 1.

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
1083
O
Cl
OAc
O
O
AcO
OAc
OAc
O
AcO
H
N
AcO
AcO
OAc
O
5
AcO
AcO
N3
OAc
AcO
O
dppe, THF
OAc
OAc
AcO
4
6
OAc
OAc
H
N
O
AcO
AcO
O
TMSN3, SnCl4
CH2Cl2
OAc
AcO
O
AcO
N3
7α/β
OAc
OAc
O
O
Cl
H
N
AcO
AcO
O
O
AcO
OAc
AcO
OAc
AcO
OAc
H
N
5
O
O
AcO
dppe, THF
OAc
AcO
O
1
OAc
AcO
OAc
Scheme 2.
ring-opening–ring-closing epimerization to give the cor-
responding b-ylide, which then reacts with the acid chlo-
ride 5 to give the isolated product. Such phosphinimine
epimerizations have been reported by others.22
in Scheme 3. The X-ray crystal structure of 9 is shown
in Figure 2 with the crystallographic data compiled in
Table 1 and selected bond lengths and angles being
shown in Table 2. As would be expected, the pyranosyl
ring in 9 is clearly in the 4C1 conformation and the
terminal alkyne is accessible to the azide partner as is
required for cycloaddition to occur.
The reaction of azide 4 and alkyne 9 was accom-
plished using the copper sulfate/ascorbic acid catalyst
system,30 and we were gratified to find that the t-butyl
alcohol/water solvent system worked well with these
compounds; although the materials never completely
dissolve, there is obviously enough dissolution to allow
the reaction to occur. The triazole product (10) was
isolated by either directly filtering the precipitate from
the cooled reaction mixture or, in an attempt to improve
overall yield, by extraction from the aqueous reaction
mixture. In either case, pure material was obtained that
gave the expected mass spectral data (mass calculated
for C31H40N4O19: 795.2184 [+Na], found: 795.2203
[+Na]). The presence of a triazole heterocycle was
While glycosyl phosphinimines may be capable of
anomeric interconversion, dipolar cycloaddition reac-
tions between the precursor glycosyl azides and alkynes
are known to result in retention of the anomeric stereo-
chemistry in the glycosyl 1,2,3-triazole products. We
have used this reaction to advantage in numerous
systems to produce collections of triazole-linked carbo-
hybrids.24,25 Interest in the use of this chemistry for
conjugating biologically important molecules together
has grown recently and has been included in the ‘click
chemistry’ paradigm described by Sharpless and
co-workers.26 Because the cycloaddition reaction is com-
pletely atom economical and generates no waste, this
chemistry offers a convenient way to produce novel
sugar-based oligomers.27 Additionally, several catalytic
systems have been developed recently that result in the
formation of only the 1,4-disubstituted triazole isomer,28,29
some of which allow for the chemistry to be performed
in water or aqueous alcohol mixtures.30 This method
thus offers the possibility of catalytic ‘green’ chemistry
conditions with complete control over the stereo- and
regiochemical identity of the products.
O
HO
AcO
O
1. (COCl)2, DMF, CH2Cl2
HN
AcO
O
OAc
O
2.
, pyridine
AcO
For the construction of neoglycooligomers, we
required a suitable alkyne partner to react with b-gluco-
syl azide 4 and produced amide-linked alkyne 9, from
protected glucuronic acid 8,21 by the sequence shown
H2N
OAc
AcO
OAc
OAc
8
9
Scheme 3.

1084
D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
support for this assignment comes from the X-ray
crystal structure of the related azide 12 (Scheme 4,
X-ray structure shown in Fig. 3), the synthesis of which
is described below.
To introduce an azide at C-1 of the glucopyranuron-
osyl ring for a second cycloaddition, we treated 10 with
HBr in acetic acid, which resulted in smooth formation
of the corresponding glycosyl bromide, 11 (Scheme 4).
The doublet at 6.44 ppm, with J1,2 = 4 Hz, clearly indi-
cates that the a-bromide had been formed. Displace-
ment with NaN3 proved to be straightforward and
glycosyl azide 12 was isolated in good yield as a crystal-
line solid, the structure of which was solved by X-ray
diffraction (Fig. 3, Tables 3 and 4). Isolation of only
the b-anomer of 12 (1H NMR: H-1 at 4.77 ppm,
J1,2 = 8.8 Hz) after stereospecific SN2 reaction with
azide anion indicates that the precursor was in fact the
a-bromide (11). Analysis of the crystal structure of 12
(Fig. 3) confirms not only the b-stereochemistry of the
newly formed glycosyl azide but also that the earlier
cycloaddition, that is, 4 to 10 (Scheme 4), was indeed
completely regioselective resulting in the formation of
the 1,4-disubstituted 1,2,3-triazole and that the b-stereo-
chemistry of the precursor glycosyl azide (4) had been
retained during the dipolar cycloaddition step.
Figure 2. X-ray structure of alkyne 9 showing 50% probability
ellipsoids.
Table 1. Crystallographic data for amide-linked alkyne 9
Empirical formula
Formula weight
Crystal size (mm)
Crystal system
Space group
C17H21N1O10
399.35
0.42 · 0.24 · 0.187
Orthorhombic
P212121
2379.1(2)
1.301
840
0.109
The second iteration of the dipolar cycloaddition
chemistry, this time involving azide 12 and alkyne 9,
proved problematic in that the conditions applied previ-
ously (copper sulfate/ascorbic acid in aqueous alcohol)
did not give appreciable amounts of triazole product,
which was most likely due to the insolubility of azide
12 (even at reflux) in the solvents used (aqueous t-butyl
alcohol, aqueous ethanol). We therefore switched our
3
˚
V (A )
Density (calculated) (Mg/m3)
F(000)
Absorption coefficient (mmꢁ1
Temperature (K)
)
100(2)
0.71073
˚
Wavelength (A)
Crystal shape, color
h Range for data collection
Limiting indices
Block, colorless
1.56–28.28ꢁ
ꢁ7 6 h 6 7, ꢁ23 6 k 6 23,
ꢁ26 6 l 6 26
21061
2899 (R(int) = 0.0324)
100.0%
Multi-scan
attention to organic solvents and the Cu(PPh3)3Br cata-
29
´
lyst described by Santoyo-Gonzalez and co-workers.
Gratifyingly, this provided the trimeric compound 2
in 54% yield as a solid that gave mass spectral data
in agreement with its structure; mass calculated for
C46H58N8O27: 1177.3309 (+Na), found: 1177.3302
(+Na). Again the cycloaddition proved to be regioselec-
tive as the 1,4-disubstituted isomer was formed exclu-
Reflections collected
Independent reflections
Completeness to h = 28.28ꢁ
Absorption correction
Refinement method
Full-matrix least-squares
on F2
2899/0/257
1
sively (singlets at 8.18 and 8.24 ppm in the H NMR
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
1.065
spectrum of 2 collected in DMSO-d6). The b-orientation
R1 = 0.0335, wR2 = 0.0894
R1 = 0.0347, wR2 = 0.0906
0.273 and ꢁ0.192
of the new triazole ring about the anomeric carbon is
1
also deduced from the H NMR spectrum of 2 with
ꢁ3
˚
Largest diff. peak and hole (e · A
)
the signal for H-1 of the two pyranuronosyl rings show-
ing at 6.37 and 6.42 ppm with J1,2 being 9.0 and 8.8 Hz,
respectively.
1
indicated from the H NMR spectrum with a singlet
appearing at 7.82 ppm, which is typical for a proton at
H-5 of a 4-substituted 1,2,3-triazole ring attached at
C-1 of a pyranose ring.25 The question of whether the
anomeric identity of the precursor b-azide had been
retained in the glycosyl triazole product is answered by
considering the 1H doublet at 5.85 ppm. The coupling
constant J1,2 = 9.0 Hz is only reconcilable with the
b-stereochemistry shown for 10 in Scheme 4. Additional
In conclusion, we have developed routes to two types of
amide-linked neoglycotrimers. The first route produces a
carbopeptoid-like trimer that relies on efficient Stau-
dinger–aza-Wittig chemistry using bis(diphenylphosph-
ino)ethane (dppe) as the phosphine to avoid the workup
problems associated with other phosphines. The second
pathway uses the regioselective Cu(I)-catalyzed dipolar
cycloaddition between glycosyl azides and a glucopyran-

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
1085
˚
Table 2. Selected bond lengths (A) and bond angles (ꢁ) for amide-
linked alkyne 9
using a 5% H2SO4 in EtOH solution with subsequent
burning. NMR spectra were recorded on a Varian Gem-
ini 2000 system at 400 MHz for H and 100 MHz for
1
Bond lengths
13C. In the reported spectra, ‘glc’ refers to signals for
protons in the glucopyranose ring(s) and ‘glcU’ refers
to protons in the glucuronosyl ring(s). Low resolution
mass spectra (LRMS) were collected using a Bruker Es-
quire-HP 1100 instrument at YSU and high resolution
spectra (HRMS) were collected on a Micromass LCT
instrument at The Ohio State University Campus Chem-
ical Instrumentation Center. Optical rotations were
determined on a Perkin–Elmer 343 automatic polari-
meter as solutions in CH2Cl2 or DMF. Diffraction data
for compounds 9 and 12 were collected on a Bruker AXS
SMART APEX CCD diffractometer at 100(2) K using
monochromatic Mo Ka radiation with omega scan tech-
nique using the SMART software.31 The unit cell was
refined and the data were integrated using SAINT+.32 The
structures were solved by direct methods and refined
by full matrix least squares against F2 with all reflections
using SHELXTL.33 Refinement of an extinction coefficient
was found to be insignificant. All nonhydrogen atoms
were refined anisotropically. Hydrogen atoms were
placed in calculated positions and refined with an isotro-
pic displacement parameter 1.5 (CH3) or 1.2 times (all
C-1–C-2
C-2–C-3
C-3–C-4
C-4–C-5
1.518(19)
1.521(19)
1.512(19)
1.541(19)
C-5–C-6
C-6–N-1
C-6–O-10
N-1–C-15
1.524(2)
1.3363(19)
1.2251(18)
1.455(2)
Bond angles
O-1–C-1–O-2
C-2–C-1–O-2
C-1–O-1–C-5
O-1–C-5–C-6
104.33(11)
110.58(11)
113.39(10)
108.36(11)
C-5–C-6–O-10
C-5–C-6–N-1
N-1–C-15–C-16
C-6–N-1–C-15
120.42(13)
115.65(13)
112.58(14)
177.0(2)
uronosyl-derived alkyne to produce a triazole-linked tri-
mer with retention of stereochemistry at each anomeric
center. We are currently studying the intramolecular fold-
ing interactions of the deprotected, that is, polyhydroxyl-
ated, derivatives of these compounds.
3. Experimental
3.1. General methods
Reactions were monitored by TLC using pre-coated alu-
minum-backed plates and compounds were visualized
O
OAc
HN
N
N
N
O
O
AcO
AcO
AcO
OAc
AcO
OAc
OAc
OAc
9
O
HN
AcO
O
AcO
AcO
H
N3
O
CuSO4, ascorbic acid
OAc
OAc
H2O, t-BuOH, 60 o
C
AcO
10
4
OAc
OAc
O
OAc
O
N
N
N
N
N
N
AcO
AcO
AcO
AcO
OAc
OAc
HN
AcO
O
O
HN
AcO
O
H
H
HBr, HOAc
NaN3, DMF
O
N3
AcO
AcO
12
11
OAc
AcO
Br
OAc
O
N
N
N
AcO
AcO
O
HN
AcO
OAc
HN
AcO
O
O
H
OAc
N
N
N
AcO
O
OAc
AcO
9
2
OAc
HN
AcO
O
H
Cu(PPh3)3Br, i-Pr2NEt
ClCH2CH2Cl, 60 o
O
C
OAc
AcO
OAc
Scheme 4.

1086
D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
Figure 3. X-ray structure of azide 12 showing 50% probability ellipsoids.
Table 3. Crystallographic data for azide 12
˚
Table 4. Selected bond lengths (A) and bond angles (ꢁ) for azide 12
Empirical formula
Formula weight
Crystal size (mm)
Crystal system
Space group
C
755.66
0.52 · 0.27 · 0.05
Monoclinic
P21
15.837(4) A, b = 94.613(5)ꢁ
1759.6(8)
1.426
792
29H37N7O17
Bond lengths
C-1–N-1
C-1–O-1
C-1–C-2
N-4–C-13
1.465(2)
1.417(2)
1.518(3)
1.451(2)
C-13–C-14
N-7–C-16
C-16–C-17
C-16–O-9
1.496(3)
1.444(2)
1.527(3)
1.410(2)
˚
˚
b (A)
Bond angles
3
˚
V (A )
C-1–N-1–N-2
C-2–C-1–N-1
N-4–C-13–C-14
C-13–C-14–C-15
114.66(18)
106.21(16)
113.71(16)
130.52(17)
C-14–N-5–N-6
N-5–N-6–N-7
N-6–N-7–C-16
N-7–C-16–C-17
109.09(17)
106.67(16)
119.49(15)
112.12(15)
Density (calculated) (Mg/m3)
F(000)
Absorption coefficient (mmꢁ1
)
0.119
100(2)
Temperature (K)
˚
Wavelength (A)
0.71073
Crystal shape, color
h Range for data collection
Limiting indices
Plate, colorless
1.90–30.50ꢁ
ꢁ14 6 h 6 14,
ꢁ22 6 k 6 22,
ꢁ14 6 l 6 15
21023
5518 (R(int) = 0.0332)
99.3%
Multi-scan
www.ccdc.cam.ac.uk/data_request/cif, by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting the
Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 (0)1223
336033.
Reflections collected
Independent reflections
Completeness to h = 30.50ꢁ
Absorption correction
Refinement method
3.2. 1,2,3,4-Tetra-O-acetyl-b-D-glucopyranuronoyl
chloride (5)
Full-matrix least-squares
on F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
5518/1/485
1.082
R1 = 0.0430, wR2 = 0.1053
R1 = 0.0455, wR2 = 0.1070
0.415 and ꢁ0.222
This is a modification of the method reported by Tosin
and Murphy for a related compound.21 A solution of
1,2,3,4-tetra-O-acetyl-b-D-glucopyranuronic acid (8)21
(2.0 g, 5.52 mmol) in CH2Cl2 (0.02 g/mL) was cooled
to 0 ꢁC and oxalyl chloride (0.96 mL, 11.04 mmol) was
added. DMF (2.5 mL) was slowly added to the stirring
solution and evolution of gas was observed. The pale
yellow solution was allowed to stir for 30 min at 0 ꢁC
and then for 2 h at rt. The solution was evaporated to
leave a purple chalky solid (2.04 g, 97%), which was
ꢁ3
˚
Largest diff. peak and hole (e · A
)
others) that of the adjacent carbon or nitrogen atom.
CCDC-299743 (9) and CCDC-299744 (12) contain the
Supplementary crystallographic data for this paper.
These data can be obtained free of charge via

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
1087
stored in a desiccator under vacuum: mp 120–123 ꢁC;
stirred vigorously for 30 min. After separation, the
aqueous layer was extracted with CH2Cl2 (2 · 25 mL)
and the combined extracts were washed with water
(2 · 50 mL), dried over anhydrous MgSO4, filtered,
and reduced to an off-white foam. Flash column chro-
matography (4:5, hexanes/EtOAc) gave the product as
a colorless foam (0.23 g, 64%), which was a mixture of
a/b isomers (5:1) by 1H NMR: for the major (a-) isomer
(CDCl3): d 2.02 (s, 3H, COCH3), 2.04 (s, 6H,
2 · COCH3), 2.05 (s, 3H, COCH3), 2.08 (s, 3H,
COCH3), 2.12 (s, 3H, COCH3), 2.15 (s, 3H, COCH3),
3.80 (ddd, 1H, J = 2.1, 4.3, 10.2 Hz, H-5glc), 4.08 (dd,
1H, J = 2.0, 12.4 Hz, H-6glc), 4.30 (dd, 1H, J = 4.4,
1
[a]D +6.4 (c 1.0, CH2Cl2); H NMR (CDCl3): d 2.05
(s, 3H, COCH3), 2.07 (s, 3H, COCH3), 2.08 (s, 3H,
COCH3), 2.15 (s, 3H, COCH3), 4.46 (d, 1H,
J = 8.6 Hz, H-5), 5.12 (dd, 1H, J = 6.3, 8.1 Hz, H-2),
5.28 (dd, 1H, J = 8.2, 8.8 Hz, H-3), 5.41 (t, 1H,
J = 8.7 Hz, H-4), 5.89 (d, 1H, J = 6.4 Hz, H-1); 13C
NMR (CDCl3): d 20.5, 20.6 (2 · C), 20.8, 67.6, 69.7,
70.7, 78.7, 90.9, 168.2, 168.8 (2 · C), 169.4, 169.5.
3.3. N-(2,3,4.6-Tetra-O-acetyl-b-D-glucopyranosyl)-
1,2,3,4-tetra-O-acetyl-b-D-glucopyranuronamide (6)
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl azide (4, 0.747 g,
2.0 mmol), acid chloride 5 (1.218 g, 3.2 mmol), and dppe
(0.518 g, 1.3 mmol) were mixed in dry THF (0.1 g/mL)
at rt. After disappearance of the intermediate ylide
was confirmed by TLC, satd NaHCO3 (3 mL) was
added and the mixture was allowed to stir vigorously
overnight. Following removal of the solvent under vac-
uum, the crude product was extracted into CHCl3
(3 · 20 mL) and the combined extracts were washed
with water (20 mL). After drying over anhydrous
MgSO4 and evaporating, the crude product was purified
by flash column chromatography (1:2, hexanes/EtOAc)
to yield 6 as a colorless crystalline solid (0.99 g, 72%):
mp 185–188 ꢁC; [a]D +4.7 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.026 (s, 6H, 3 · COCH3), 2.029 (s, 3H,
COCH3), 2.050 (s, 3H, COCH3), 2.052 (s, 3H, COCH3),
2.09 (s, 3H, COCH3), 2.15 (s, 3H, COCH3), 2.19 (s, 3H,
COCH3), 3.79 (ddd, 1H, J = 2.1, 4.4, 10.1 Hz, H-5glc),
4.04 (d, 1H, J = 10.1 Hz, H-5glcU), 4.05 (dd, 1H,
J = 1.9, 12.5 Hz, H-6glc), 4.31 (dd, 1H, J = 4.5,
12.5 Hz, H-60glc), 4.95 (t, 1H, J = 9.61 Hz), 5.00 (dd,
1H, J = 9.6, 10.0 Hz, H-4glcU), 5.06 (t, 1H, J =
9.79 Hz), 5.10–5.16 (m, 2H), 5.29 (t, 1H, J = 9.43 Hz),
5.31 (t, 1H, J = 9.52 Hz, H-2glc), 5.75 (d, 1H, J =
8.24 Hz, H-1glcU), 7.13 (d, 1H, J = 9.34 Hz, N–H); 13C
NMR (CDCl3): d 20.56 (2 · C), 20.59 (3 · C), 20.66,
20.73, 20.8, 61.5, 67.8, 68.5, 69.9, 70.1, 71.8, 72.5, 72.5,
73.6, 77.6, 90.9, 166.3, 168.5, 168.9, 169.2 (2 · C),
169.4, 169.5, 170.3, 171.0. LRMS calcd for
[C28H37NO19+Na]+: 714.186. Found: 714.2. ESIMS
m/z calcd for [C28H37NO19+Na]+: 714.1857. Found:
714.1808.
12.6 Hz, H-60 ), 4.37 (d, 1H, J = 10.3 Hz, H-5glcU),
glc
4.86–4.95 (m, 2H), 5.06 (t, 1H, J = 9.8 Hz), 5.17 (t,
1H, J = 9.4 Hz), 5.33 (t, 1H, J = 9.6 Hz), 5.42 (t, 1H,
J = 9.9 Hz), 5.70 (d, 1H, J = 4.4 Hz, H-1glcU), 7.12 (d,
1H, J = 9.3 Hz, N–H).
3.5. Amide-linked trimer 1
The a/b mixture of azides (7, 0.690 g, 1.023 mmol), acid
chloride 5 (0.623 g, 1.637 mmol), and dppe (0.245 g,
0.614 mmol) were mixed in dry THF (0.1 g/mL) at rt.
When disappearance of the intermediate ylide was con-
firmed by TLC, satd NaHCO3 (3 mL) was added and
the mixture was allowed to stir vigorously overnight.
Workup as for 4 gave a syrup that was purified by flash
column chromatography (1:3, hexanes/EtOAc) to yield
the title compound as a colorless solid (0.546 g, 53%):
mp 178–180 ꢁC; [a]D +5.2 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.03 (s, 9H, 3 · COCH3), 2.04 (s, 3H,
COCH3), 2.05 (s, 3H, COCH3), 2.06 (s, 6H,
2 · COCH3), 2.09 (s, 3H, COCH3), 2.14 (s, 3H,
COCH3), 2.15 (s, 3H, COCH3), 2.21 (s, 3H, COCH3),
3.76 (m, 1H, H-5glc), 3.97 (d, 1H, J = 10.1 Hz, H-5glcU),
4.05 (dd, 1H, J = 1.7, 12.5 Hz, H-6glc), 4.09 (d, 1H,
J = 10.1 Hz, H-5glcU), 4.29 (dd, 1H, J = 4.6, 12.4 Hz,
H-60glc), 4.88–5.08 (m, 5H), 5.12–5.18 (m, 3H), 5.28–
5.37 (m, 3H), 5.79 (d, 1H, J = 8.1 Hz, H-1glcU), 7.14
(d, 1H, J = 9.5 Hz, N–H), 7.32 (d, 1H, J = 9.3 Hz,
N–H); 13C NMR (CDCl3): d 20.48 (3 · C), 20.53
(3 · C), 20.63 (2 · C), 20.69 (2 · C), 20.74, 61.3, 61.8,
68.3, 68.7, 70.2, 70.3, 70.6, 71.9, 72.1, 72.9 (2 · C),
73.9 (2 · C), 77.81, 77.87, 91.3, 166.7, 166.8, 168.8,
169.2, 169.4, 169.5, 169.6 (2 · C), 169.7, 170.6, 171.2
(2 · C), 171.3; ESIMS m/z calcd for [C40H52N2O27+
Na]+: 1015.2655. Found: 1015.2618.
3.4. N-(2,3,4.6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-
azidodeoxy-2,3,4-tri-O-acetyl-a/b-D-glucopyranuron-
amides (7a/b)
3.6. N-(Prop-2-ynyl)-1,2,3,4-tetra-O-acetyl-b-D-gluco-
pyranuronamide (9)
Amide 6 (0.368 g, 0.53 mmol) was dissolved in dry
CH2Cl2 (4 mL) under N2. TMSN3 (0.174 mL, 1.33
mmol) and SnCl4 (0.03 mL, 0.265 mmol) were added
successively and the mixture was allowed to stir at rt
for 15 h. The reaction mixture was diluted with CH2Cl2
(25 mL) and satd NaHCO3 (25 mL) and the suspension
Oxalyl chloride (0.48 mL, 5.52 mmol) was added to a
solution of carboxylic acid 821 (1.0 g, 2.76 mmol) in
dry CH2Cl2 (0.02 g/mL) held at 0 ꢁC. With stirring,
DMF (1.2 mL) was added slowly and evolution of gas

1088
D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
was observed. The pale yellow solution was allowed to
stir for 30 min at 0 ꢁC and then 2 h at rt. Evaporation
afforded a purple solid (5), which was immediately dis-
solved in dry CH2Cl2 (20 mL), and to this was added
a solution of propargyl amine (0.19 mL, 3.04 mmol)
and pyridine (0.67 mL, 8.28 mmol) in CH2Cl2 (5 mL).
Precipitation of an off-white solid was observed and
the mixture was allowed to stir overnight and then
poured into ice water (50 mL) and extracted with
CH2Cl2 (3 · 25 mL). The combined extracts were
washed with 5% H2SO4 (3 · 15 mL), then water
(15 mL), dried with anhydrous MgSO4, filtered, and re-
duced to a cream-colored solid, which was recrystallized
from CH3OH to give colorless crystals (0.91 g, 83%): mp
166–167 ꢁC; [a]D +3.7 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.03 (s, 3H, COCH3), 2.05 (s, 3H, COCH3),
2.08 (s, 3H, COCH3), 2.16 (s, 3H, COCH3), 2.27 (t, 1H,
J = 2.6 Hz, C„C–H), 4.11 (d, 1H, J = 9.7 Hz, H-5),
3.99, (ddd, 1H, J = 2.6, 5.3, 17.6 Hz, C„C–CH), 4.06
(ddd, 1H, J = 2.7, 5.5, 17.6 Hz, C„C–CH), 5.12 (dd,
1H, J = 8.0, 8.9 Hz, H-2), 5.22 (t, 1H, J = 9.5 Hz, H-
3), 5.31 (t, 1H, J = 9.2 Hz, H-4), 5.77 (d, 1H, 7.9 Hz,
H-1), 6.50 (t, 1H, J = 5.2 Hz, N–H); 13C NMR (CDCl3):
d 20.6 (2 · C), 20.7, 20.8, 28.9, 68.6, 70.0, 71.7, 72.0,
72.7, 74.0, 91.1, 165.4, 168.5, 168.9, 169.3, 169.5; ESIMS
m/z calcd for [C17H21NO10+Na]+: 422.1063. Found:
422.1063.
70.2, 71.8, 72.6, 72.8, 75.0, 85.6, 91.1, 121.1, 144.7,
165.8, 168.5 (2 · C), 169.0, 169.1, 169.5 (2 · C), 169.7,
170.27; ESIMS m/z calcd for [C31H40N4O19+Na]+:
795.2184. Found: 795.2203.
3.8. Triazole-linked glycosyl bromide 11
Amide 10 (0.750 g, 0.97 mmol) was dissolved in 33%
HBr/AcOH (8 mL) and the brown solution was allowed
to stir at rt for 2 h when TLC (5% CH3OH in toluene)
showed consumption of starting material. The reaction
mixture was diluted with CHCl3 (50 mL) and neutral-
ized by slow addition of satd NaHCO3. The mixture
was extracted with CHCl3 (3 · 30 mL) and the extracts
were washed with water (100 mL), dried over MgSO4,
filtered, and reduced to a hygroscopic tan foam
(0.71 g, 92%): [a]D +71.2 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 1.88 (s, 3H, COCH3), 2.03 (s, 3H, COCH3),
2.04 (s, 3H, COCH3), 2.07 (s, 3H, COCH3), 2.08 (s, 3H,
COCH3), 2.09 (s, 3H, COCH3), 2.10 (s, 3H, COCH3),
4.02 (ddd, 1H, J = 2.4, 4.9, 10.2 Hz, H-5glc), 4.16 (dd,
1H, J = 2.0, 12.6 Hz, H-6glc), 4.31 (dd, 1H, J = 4.9,
12.6 Hz, H-60glc), 4.47 (dd, 1H, J = 5.6, 15.3 Hz, C„C–
CH), 4.51 (d, 1H, J = 10.3 Hz, H-5glcU), 4.59 (dd, 1H,
J = 6.0, 15.4 Hz, C„C–CH), 4.83 (dd, 1H, J = 4.1,
10.0 Hz, H-2glcU), 5.21 (dd, 1H, J = 9.5, 10.3 Hz), 5.26
(m, 1H), 5.40 (m, 2H), 5.61 (t, 1H, J = 9.8 Hz), 5.89
(m, 1H, H-1glc), 6.64 (d, 1H, J = 4.0 Hz, H-1glcU), 7.16
(t, 1H, J = 5.7 Hz, N–H), 7.82 (s, 1H, triazole-H); 13C
NMR (CDCl3): d 20.2, 20.5 (2 · C), 20.6 (2 · C), 20.7
(2 · C), 34.4, 61.4, 67.5, 68.3, 69.2, 70.3 (2 · C), 72.4,
72.5, 77.2, 84.9, 85.4, 121.4, 144.4, 165.8, 168.4, 169.0,
169.1 (2 · C), 169.5, 169.6, 170.2.
3.7. Triazole-linked amide 10
Azide 4 (0.747 g, 2 mmol), alkyne 9 (0.798 g, 2 mmol),
ascorbic acid (0.141 g, 0.8 mmol), and CuSO4 (0.100 g,
0.4 mmol) were mixed in water (20 mL) and stirred vig-
orously while being heated at 60 ꢁC until the reaction
was determined complete by TLC. After cooling to rt,
cold water was added, and the resulting precipitate
was filtered on a glass frit. To obtain the best yield,
the reaction mixture was extracted with CH2Cl2, the
extracts were dried over anhydrous MgSO4, filtered,
and reduced to give the product as an off-white solid
(1.59 g, 91%): mp 221–224 ꢁC; [a]D ꢁ9.4 (c 1.0, CH2Cl2);
1H NMR (CDCl3): d 1.88 (s, 3H, COCH3), 2.02 (s, 3H,
COCH3), 2.03 (s, 3H, COCH3), 2.04 (s, 3H, COCH3),
2.07 (s, 3H, COCH3), 2.10 (s, 3H, COCH3), 2.13 (s,
3H, COCH3), 3.98 (m, 1H, H-5glc), 4.10 (d, 1H,
J = 9.7 Hz, H-5glcU), 4.16 (m, 1H, H-6glc), 4.30 (dd,
1H, J = 4.9, 12.5 Hz, H-60glc), 4.46 (dd, 1H, J = 5.7,
15.2 Hz, C„C–CH), 4.59 (dd, 1H, J = 6.2, 15.6 Hz,
C„C–CH), 5.10 (t, 1H, J = 8.7 Hz, H-2glcU), 5.19 (t,
1H, J = 9.6 Hz, H-4glcU), 5.26 (t, 1H, J = 9.5 Hz, H-
3.9. Triazole-linked azide 12
Bromide 11 (0.68 g, 0.86 mmol) was dissolved in dry
DMF (8 mL), sodium azide (0.25 g, 3.85 mmol) was
added, and the orange solution was allowed to stir at
rt for 6 h. The solvent was removed, the crude mixture
was partitioned between water (50 mL) and CH2Cl2
(50 mL), and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (2 · 50 mL) and the
combined extracts were washed with water (3 ·
150 mL), dried over anhydrous MgSO4, filtered, and
reduced to a colorless solid that was recrystallized from
EtOH (0.53 g, 82%): mp 193 ꢁC (decomp.); [a]D ꢁ19.7 (c
1.0, CH2Cl2); 1H NMR (CDCl3): d 1.87 (s, 3H,
COCH3), 2.02 (s, 3H, COCH3), 2.03 (s, 3H, COCH3),
2.07 (s, 3H, COCH3), 2.08 (s, 3H, COCH3), 2.09
(s, 6H, 2 · COCH3), 4.04 (ddd, 1H, J = 2.4, 4.9,
10.1 Hz, H-5glc), 4.09 (d, 1H, J = 9.9 Hz, H-5glcU), 4.17
(dd, 1H, J = 2.1, 12.5 Hz, H-6glc), 4.31 (dd, 1H,
J = 4.9, 12.6 Hz, H-60glc), 4.50 (dd, 1H, J = 5.9,
15.4 Hz, C„C–CH), 4.61 (dd, 1H, J = 6.0, 15.5 Hz,
C„C–CH,), 4.77 (d, 1H, J = 8.8 Hz, H-1glcU), 4.94
4
glc), 5.31 (t, 1H, J = 9.3 Hz, H-3glcU), 5.41 (t, 1H,
J = 9.3 Hz, H-3glc), 5.47 (t, 1H, J = 9.3 Hz, H-2glc),
5.75 (d, 1H, J = 8.1 Hz, H-1glcU), 5.85 (d, 1H,
J = 9.0 Hz, H-1glc), 6.89 (t, 1H, J = 6.0 Hz, N–H),
7.82 (s, 1H, triazole-H); 13C NMR (CDCl3): d 20.3,
20.6 (4 · C), 20.8 (3 · C), 34.6, 61.5, 67.5, 68.7, 70.0,

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1081–1090
1089
(t, 1H, J = 9.2 Hz), 5.17 (t, 1H, J = 9.7 Hz), 5.25
Supplementary data
(m, 2H), 5.43 (t, 1H, J = 9.4 Hz), 5.48 (t, 1H,
J = 9.3 Hz), 5.90 (d, 1H, J = 9.0 Hz, H-1glc), 7.23
(t, 1H, J = 6.0 Hz, N–H), 7.87 (s, triazole-H, 1H); 13C
NMR (CDCl3): d 20.3, 20.6 (4 · C), 20.7, 20.8, 34.7,
61.6, 67.6, 68.9, 70.3, 70.4, 71.7, 72.7, 74.2, 75.0, 85.6,
87.9, 121.1, 144.7, 165.8, 168.5, 168.9, 169.1, 169.4,
169.6, 169.7, 170.2; ESIMS m/z calcd for
[C29H37N7O17+Na]+: 778.2144. Found: 778.2158. The
X-ray crystal structure of 12 is discussed in the text.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2006.04.011.
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1
DMF); H NMR (DMSO-d6): d 1.83 (s, 3H, COCH3),
1.85 (s, 3H, COCH3), 1.95 (s, 3H, COCH3), 2.00 (s,
6H, COCH3), 2.02 (s, 6H, COCH3), 2.057 (s, 3H,
COCH3), 2.062 (s, 3H, COCH3), 2.08 (s, 3H, COCH3),
2.12 (s, 3H, COCH3), 4.10 (m, 1H), 4.18 (m, 1H),
4.26–4.43 (m, 6H), 4.55 (d, 1H, J = 9.9 Hz), 5.03 (dd,
1H, J = 8.5, 9.6 Hz), 5.16 (t, 1H, J = 9.7 Hz), 5.21 (t,
1H, J = 9.7 Hz), 5.37 (t, 1H, J = 9.5 Hz), 5.50 (t, 1H,
J = 9.6 Hz), 5.57–5.68 (m, 4H), 6.02 (d, 1H,
J = 8.2 Hz), 6.37 (d, 1H, J = 9.0 Hz), 6.42 (d, 1H,
J = 8.8 Hz), 8.18 (s, 1H, triazole-H), 8.24 (s, 1H, tri-
azole-H), 8.76–8.81 (m, 2H, 2 · N–H); 13C NMR
(CDCl3): d 19.7 (2 · C), 20.1 (6 · C), 20.2, 20.3
(2 · C), 34.0 (2 · C), 61.6, 67.6, 68.8, 69.0, 69.8
(2 · C), 70.1, 71.5, 72.0, 72.3, 72.9, 73.3, 74.6, 83.7,
83.8, 90.8, 122.1, 122.3, 144.6, 144.7, 165.5, 165.7,
168.4 (2 · C), 168.7, 168.90, 168.94; 169.1, 169.3,
169.4, 169.5, 169.6, 170.0; ESIMS m/z calcd for
[C46H58N8O27+Na]+: 1177.3309. Found: 1177.3302.
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}
P.N. thanks the National Institutes of Health
(R15-AI053112-01) for sponsorship and Professor
Mo Hunsen of Kenyon College for help with some
of the spectra. The X-ray diffractometer used in this
work was purchased using funds from the NSF
(NSF-0087210), the Ohio Board of Regents (CAP-491)
and YSU.
´
}
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