Application of bis(diphenylphosphino)ethane (DPPE) in Staudinger-type N-glycopyranosyl amide synthesis

Article abstract of DOI:10.1016/j.carres.2006.02.001

Bis(diphenylphosphino)ethane (DPPE) reacts with pyranosyl azides derived from d-glucose and d-glucuronic acid in the presence of acid chlorides to yield the corresponding glycosyl amides. Reaction rates are comparable to those with triphenylphosphine, how

Full text of DOI:10.1016/j.carres.2006.02.001

Carbohydrate Research 341 (2006) 1645–1656
Application of bis(diphenylphosphino)ethane (DPPE) in
Staudinger-type N-glycopyranosyl amide synthesis
David P. Temelkoff,a Craig R. Smith,a Daniel A. Kibler,a Shawn McKee,a Sara J. Duncan,a
Matthias Zeller,a Mo Hunsenb and Peter Norrisa,*
aDepartment of Chemistry, Youngstown State University, 1 University Plaza, Youngstown, OH 44555, USA
bDepartment of Chemistry, Kenyon College, Gambier, OH 43022, USA
Received 10 January 2006; received in revised form 31 January 2006; accepted 2 February 2006
Available online 24 February 2006
Abstract—Bis(diphenylphosphino)ethane (DPPE) reacts with pyranosyl azides derived from D-glucose and D-glucuronic acid in the
presence of acid chlorides to yield the corresponding glycosyl amides. Reaction rates are comparable to those with triphenylphos-
phine, however, the byproduct phosphine oxide is easily removed from reaction mixtures using column chromatography. The simple
and clean workup allows for the formation of collections of related compounds by parallel synthesis, and the method is also appli-
cable to scaled-up reactions. The b-stereochemistry of the glycosyl azide precursor is retained in all cases, which is supported by
X-ray crystallography in several cases.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: N-Glycosyl amide; Staudinger reaction; Phosphine; Phosphine oxide
1. Introduction
these issues by treating a diastereomerically pure azide
precursor with a phosphine and allowing the thus
formed phosphinimine ylide to react with a carboxylic
acid derivative to give the amide product, usually with-
out loss of the integrity of the anomeric stereochemistry.
Unfortunately, many of the phosphines typically
employed in the Staudinger-type methods are either
inconvenient to work with or give oxide byproducts that
are difficult to separate from reaction mixtures.3–6
Recently the ‘Staudinger ligation’ process has come to
the fore and provides an extremely useful method for
conjugating glycosyl azides with peptides to give the nat-
urally occurring b-N-glycosyl amide motif.7–11
Amide bonds are used to conjugate carbohydrates to
other biomolecules, for example, polypeptides in glyco-
proteins and nucleic acids, RNA and DNA. The obvi-
ous importance of this linkage in biology has driven
the search for efficient and stereoselective methodologies
for glycosyl amide synthesis.1 Of major concern in this
endeavor is the control of stereochemistry at the
anomeric carbon of the saccharide and, with a view to
parallel synthesis of novel structures, the development
of methods that allow for rapid workup and isolation
of products.
N-Glycosyl amides may be prepared by coupling a
glycosyl amine with a suitable carboxylic acid derivative;
however, problems associated with this method include
anomeric interconversion and amine decomposition.2
The use of Staudinger-type chemistry avoids many of
Apart from its occurrence in glycoproteins, the glycos-
yl amide functionality has received significant attention
recently, for example, in the synthesis of multivalent
carbohydrate scaffolds,12,13 as well as for their use as
donors in glycosylation reactions.14,15 Amide-linked
glycosyl heterocycles have been reported to possess
interesting biological activity,16–18 therefore the creation
of libraries of these compounds would be useful for
further biological evaluation, as well as for detailed
*
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.2006.02.001

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D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
NMR coupling constants and the X-ray structure of 6
(vide infra). Adding DPPE in toluene solution to a
THF solution of acid chloride and azide gave the best
yield of 6 (92% after workup and column chromatogra-
phy) and using solvents such as THF or CH2Cl2 for dis-
solution of all reagents gave isolated yields of 6 ranging
from 75% to 85%. For library synthesis we relied on
slow, dropwise addition of DPPE in THF.
Scheme 1.
2.2. Structures of the intermediate iminophosphorane
ylide and amide products
structure–activity studies. With a view to the alleviating
problems during workup in glycosyl amide library syn-
thesis we have employed polymer-supported triphenyl-
phosphine in Staudinger-type reactions,19 however, the
rates of reaction are much slower with this reagent than
with triphenylphosphine itself and the greater cost of the
resin-bound phosphine limits its use on scales larger
than 1–2 mmol. The readily available bis(diphenyl-
phosphino)ethane (DPPE, 2, Scheme 1) has been used
as a convenient replacement for triphenylphosphine in
Mitsunobu and Staudinger reactions,20 with rates of
reaction being similar to those observed with PPh3,
and the byproduct bis(phosphineoxide) is easily
removed using simple flash chromatography. Here we
describe the reaction of DPPE (2) with two b-glycosyl
azides (1, R = CH2OAc, CO2CH3) in the presence of
various acid chlorides (3), which affords b-glycosyl
amides exclusively (4, Scheme 1). The amide products
are isolated in very good yields without any contamina-
tion from the phosphine oxide byproduct.
Evolution of gas (N2) upon addition of DPPE was
consistent with the formation of an iminophosphorane
(7, Scheme 2), the usual product of such Staudinger
reactions.23–25 Evidence for the dimeric structure of
7 was garnered by adding DPPE to azide 5 in CDCl3
1
solution and then collecting the H NMR spectrum of
the ylide (Fig. 1). Integration of the clearly resolved sig-
nal for H-5 of the glucopyranose ring (3.42 ppm) and
the broad signal for the [CH2–CH2] group (2.51 ppm)
was found to be 1:2, which strongly supports the struc-
ture for 7 shown in Scheme 2. In the presence of an acid
2. Results and discussion
2.1. Reaction of DPPE with b-D-glucopyranosyl azide 5
Our initial experiments began with b-glucosyl azide 5
(Scheme 2),21,22 which was treated with 0.65 equiv of
DPPE in the presence of p-nitrobenzoyl chloride to give
the b-glucosyl amide 6 with complete retention of con-
Figure 1. Portion of the 1H NMR spectrum of ylide 7 collected in
CDCl3 solution.
1
figuration at the anomeric carbon as judged from H
Scheme 2.

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
1647
Figure 2. X-ray structure of N-glucosyl amide 6 showing 50% probability ellipsoids.
˚
Table 2. Selected bond lengths (A) and bond angles (ꢁ) for amide 6
chloride an aza-Wittig reaction ensues (Scheme 2),
giving an imidoyl chloride (8), which is subsequently
hydrolyzed to give the amide product. Amide 6 is readily
purified by flash column chromatography and then
recrystallized from ethanol.
Bond lengths
C-1–C-2
C-2–C-3
C-3–C-4
C-4–C-5
1.517(3)
1.521(3)
1.520(3)
1.537(3)
C-5–C-6
C-1–N-1
C-5–O-1
C-1–O-1
1.516(3)
1.430(3)
1.428(3)
1.434(3)
The structure of glucopyranosyl amide 6 was assigned
1
initially from its H, 13C NMR, and mass spectra (m/e
Bond angles
N-1–C-1–O-1
N-1–C-1–C-2
C-1–C-2–C-3
C-2–C-3–C-4
107.30(19)
110.8(2)
110.2(2)
C-3–C-4–C-5
C-4–C-5–C-6
O-1–C-5–C-6
N-1–C-15–O-10
111.21(19)
109.4(2)
106.8(2)
124.5(2)
calculated for M++Na: 519.1227, found: 519.1227)
and then supported by its single crystal X-ray structure
(Fig. 2, Tables 1 and 2). The 1H NMR spectrum reveals
111.31(19)
Table 1. Crystallographic data for N-glucopyranosyl amide 6
the amide N–H signal as a doublet at 7.30 ppm
(J = 8.8 Hz) and the signal corresponding to H-1 of
the pyranose ring as a triplet (assigned from a COSY
experiment) that overlaps with the H-2 signal at
Empirical formula
Formula weight
Crystal size (mm)
Crystal system
Z
C21H26N2O13
514.44
0.39 · 0.15 · 0.15
Orthorhombic
4
1
5.4 ppm. Neither the H nor 13C NMR spectra show
Space group
P212121
any traces of the (polar) bis-phosphine oxide byproduct.
The solid state structure of 6 (Fig. 2) clearly shows the
N–H amide proton and the C-1 glucopyranosyl ring
proton to be aligned in an anti fashion. We were inter-
ested in correlating this structure with the solution state
conformation, which would have obvious ramifications
for the spatial presentation of the amide aglycon. The
observed C-1–N-1 coupling constant of 8.8 Hz could
be reconciled with either syn or anti alignments around
this bond, however, a NOESY experiment revealed
interaction between the amide proton and H-2 of the
˚
a (A)
6.4411(3), a = 90ꢁ
17.5338(9), b = 90ꢁ
21.0656(10), c = 90ꢁ
2379.1(2)
1.436
1080
0.121
100(2)
0.71073
Block, colorless
˚
b (A)
˚
c (A)
3
˚
V (A )
Density (calculated) (Mg/m3)
F(000)
Absorption coefficient (mmꢀ1
Temperature (K)
)
˚
Wavelength (A)
Crystal shape, color
h range for data collection
Limiting indices
1.51–28.28ꢁ
ꢀ8 6 h 6 8, ꢀ23 6 k 6 23,
ꢀ27 6 l 6 28
25,550
Reflections collected
Independent reflections
Completeness to h = 28.28ꢁ
Absorption correction
Refinement method
5914 (R(int) = 0.0296)
100.0%
Multi-scan
Full-matrix least-squares
on F2
Data/restraints/parameters
Goodness-of-fit on F2
5914/0/374
1.228
Final R indices [I > 2r(I)]
R indices (all data)
Absolute structure parameter
R1 = 0.0457, wR2 = 0.1075
R1 = 0.0462, wR2 = 0.1079
0.8(7)
0.341 and ꢀ0.286
ꢀ3
˚
Largest diff. peak and hole (eA
)
Figure 3. Observed interactions in the NOESY spectrum of 6.

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D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
Table 3. Structures and yields of b-D-glucopyranosyl amides formed
from azide 5
Table 3 (continued)
Compound
Yield (%)
67
Compound
Yield (%)
82
60
71
74
Table 4. Structures and yields of b-D-glucopyranuronosyl amides
formed from azide 9
Compound
Yield (%)
77
72
98
58
70
80
60
59
75
64
75
70
71
50
56

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
Table 5. Crystallographic data for N-glucopyranosyl amide 16
1649
glucopyranose ring (as well as between H-1, H-3, and
H-5 of the sugar ring) (Fig. 3). The solution conforma-
tion about the C-1–N-1 bond in amide 6 is therefore anti
and is similar to that observed in the solid state
(Fig. 2).26 Both the NMR and X-ray studies reveal that
the b-stereochemistry of the azide starting material (5) is
retained in the amide product and that epimerization is
not a significant competing process under the reaction
conditions.27
Empirical formula
Formula weight
Crystal size (mm)
Crystal system
Z
C
457.44
0.44 · 0.39 · 0.36
Monoclinic
4
19H23NO10
S
Space group
C2
˚
a (A)
16.247(3), a = 90ꢁ
14.105(3), b = 124.950(3)ꢁ
11.182(2), c = 90ꢁ
2100.4(7)
1.447
960
0.211
100(2)
0.71073
Block, colorless
˚
b (A)
˚
c (A)
3
˚
V (A )
Density (calculated) (Mg/m3)
F(000)
2.3. Parallel synthesis of N-glycosyl amides
Absorption coefficient (mmꢀ1
Temperature (K)
)
Once the reaction conditions had been optimized for
amide 6, we expanded the synthesis to include the
b-glucuronosyl azide 928,29 and studied the reactions of
5 and 9 with a variety of acid chlorides and DPPE
(Tables 3 and 4). Using a simple parallel synthesizer
we were able to run multiple reactions in series and,
after an aqueous workup, the amides were isolated by
flash column chromatography. In all cases the b-glycos-
yl amides were isolated in good yields in >95% purity
(NMR) without any contamination from the bis-phos-
phine oxide byproduct.
All of the N-glycopyranosyl amides formed here gave
satisfactory NMR spectral and mass spectral data in
accordance with their assigned structures and further
support for the b-selectivity was obtained from the
X-ray crystal structure of the thiophene derivative 16
(Fig. 4, Tables 5 and 6). The anti conformation about
the C-1–N-1 bond can clearly be seen, as can the reten-
tion of the chair conformation within the pyranose ring.
˚
Wavelength (A)
Crystal shape, color
h range for data collection
Limiting indices
2.10–30.50ꢁ
ꢀ22 6 h 6 23,ꢀ20 6 k 6 20,
ꢀ15 6 l 6 15
Reflections collected
12,648
Independent reflections
Completeness to h = 30.50ꢁ
Absorption correction
Refinement method
6292 (R(int) = 0.0157)
99.9%
Multi-scan
Full-matrix least-squares
on F2
6292/1/284
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole (eA
1.034
R1 = 0.0322, wR2 = 0.0848
R1 = 0.0326, wR2 = 0.0852
ꢀ0.01(4)
ꢀ3
˚
)
0.413 and ꢀ0.292
and 4) were notably slower than in other cases. Indeed,
in the case of azide 5, working the reaction up after 1 h
did not afford amide 15 but a compound considered to
be the imidoyl chloride 30 (Scheme 3), which is the puta-
tive intermediate formed during the aza-Wittig portion
of the conversion of azide 5 to the amide. This com-
pound was stable to column chromatography, crystal-
lized upon isolation (68% yield), and was amenable to
2.4. Mechanism of amide formation
While most of the glycosyl amides in Tables 3 and 4
were formed readily, albeit at different rates, the reac-
tions to give the furan derivatives 15 and 25 (Tables 3
Figure 4. X-ray structure of N-glycosyl amide 16 showing 50% probability ellipsoids.

1650
D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
˚
Table 6. Selected bond lengths (A) and bond angles (ꢁ) for amide 16
After stirring at rt for 5 h the imidoyl chloride was con-
sumed and the workup yielded a syrupy product in 95%
yield that proved to be the 5-substituted glycosyl tetra-
zole 34 (Scheme 4). The formation of 34 may be
explained by nucleophilic attack of azide at the imidoyl
carbonyl, to produce tetrahedral intermediate 32, which
then undergoes a 5-endo-trig cyclization to give 33,
which in turn loses chloride to afford the aromatic tetra-
zole product. Synthesis of 1,5-disubstituted tetrazoles by
combining imidoyl chlorides with sodium azide is
known from the literature,30 however, 34 appears to
be the first example of this type of compound involving
a carbohydrate.
Bond lengths
C-1–C-2
C-2–C-3
C-3–C-4
C-4–C-5
1.5236(15)
1.5286(15)
1.5288(15)
1.5248(15)
C-5–C-6
C-1–N-1
C-5–O-1
C-1–O-1
1.5102(15)
1.4322(14)
1.4366(13)
1.4403(12)
Bond angles
N-1–C-1–O-1
N-1–C-1–C-2
C-1–C-2–C-3
C-2–C-3–C-4
108.14(8)
C-3–C-4–C-5
C-4–C-5–C-6
O-1–C-5–C-6
N-1–C-7–O-2
108.10(8)
109.4(2)
108.09(9)
122.50(10)
110.04(9)
113.88(9)
112.16(8)
analysis by NMR and mass spectrometry, data that
agreed with the structure assigned to 30 (m/z for
M++Na calculated; 482.0830, found; 482.0835). The
low rate of hydrolysis of this material is likely explained
by stabilization of the imidoyl carbonyl by donation of
electron density from the furan ring (resonance structure
31 in Scheme 3). Even under basic conditions the chlo-
ride was sluggish in converting to the amide; in fact
deacetylation of the sugar protecting groups became a
competitive process.
3. Conclusions
We have shown that using bis(diphenylphosphino)-
ethane (DPPE) in place of PPh3 in the Staudinger-type
synthesis of glucosyl and glucuronosyl amides removes
some of the drawbacks associated with the removal of
triphenylphoshine oxide from reaction mixtures. The
polar bis-phosphine oxide is readily separated from
amide products, which allows for the convenient synthe-
sis of collections of related glycosyl amides. The evi-
dence gained from NMR and X-ray crystallography
While spectroscopic evidence pointed to the imidoyl
chloride 30 we wished to prove this chemically and thus
treated this material with NaN3 in DMF in an effort to
displace the chloride ion with a powerful nucleophile.
Scheme 3.
Scheme 4.

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
1651
shows that the amides adopt an anti conformation about
the C-1–N-1 bond, and that the b-configuration of the
azide precursor is retained in the amide product. Isola-
tion of the imidoyl chloride intermediate (30) from reac-
tion with 2-furoyl chloride provides an indication of the
mechanism operating in the Staudinger–aza-Wittig se-
quence, and the formation of a 5-substituted glucosyl
tetrazole (34) from this imidoyl chloride opens an ave-
nue for further exploration.
(0.1 g/mL) was added dropwise at rt. The mixture was
allowed to stir until TLC showed reaction to be com-
plete (disappearance of the intermediate ylide). A satu-
rated NaHCO3 solution (2 mL) was added and the
mixture stirred vigorously for 3 h. The organic solvent
was removed under reduced pressure and the residue
was partitioned between CHCl3 (20 mL) and water
(20 mL). The aqueous layer was extracted with further
portions of CHCl3 (2 · 20 mL) and the combined
organic extracts were washed with water (20 mL), dried
over MgSO4, filtered, and concentrated under reduced
pressure. The product was isolated by flash column
chromatography using the appropriate eluent.
4. Experimental
4.1. General methods
4.3. 4-Nitro-N-(2,3,4,6-tetra-O-acetyl-b-D-glucopyran-
osyl)benzamide (6)
Reactions were monitored by TLC using pre-coated alu-
minum-backed plates and compounds were visualized
using a 5% H2SO4 in EtOH solution with subsequent
burning. All samples described here were recrystallized
from EtOH and are homogeneous by TLC. NMR spec-
tra were recorded on a Varian Gemini 2000 system at
Colorless solid (0.405 g, 82%) isolated from flash
column chromatography using 1:1 hexane/EtOAc: mp
199–201 ꢁC, lit.5 168–170 ꢁC; [a]D ꢀ29.6 (c 1.0, CH2Cl2),
lit.5 ꢀ16.5; 1H NMR (CDCl3)
d 2.06 (s, 6H,
1
400 MHz for H and 100 MHz for 13C. Low resolution
2 · COCH3), 2.07 (s, 3H, COCH3), 2.09 (s, 3H,
COCH3), 3.93 (ddd, 1H, J = 2.1, 4.2, 10.1 Hz, H-5),
4.12 (dd, 1H, J = 2.1, 12.5 Hz, H-6), 4.33 (dd, 1H,
J = 4.3, 12.5 Hz, H-60), 5.05 (t, 1H, J = 9.6 Hz, H-3),
5.12 (t, 1H, J = 9.8 Hz, H-4), 5.42 (2 · t, overlap-
ping, 2H, J = 9.5, 9.2 Hz, H-1, H-2), 7.29 (d, 1H,
J = 8.8 Hz, N–H), 7.95 (d, 2H, J = 9.2 Hz, Ar–H),
8.32 (d, 2H, J = 8.8 Hz, Ar–H); 13C NMR (CDCl3)
d 20.7 (2 · C), 20.81, 20.84, 61.6, 68.1, 70.9, 72.3,
73.7, 79.0, 123.8 (2 · C), 128.4 (2 · C), 138.0, 149.9,
164.9, 169.3, 169.6, 170.3, 171.5; ESIMS calcd for
C21H24N2O12: 519.1227 (+Na), found: 519.1227
(+Na). The X-ray crystal structure of this compound
is discussed in the text.
mass spectra (LRMS) were collected using a Bruker
Esquire-HP 1100 instrument at YSU and high resolu-
tion spectra (ESIMS) were collected on a Micromass
LCT instrument at The Ohio State University Campus
Chemical Instrumentation Center. Optical rotations
were determined on a Perkin–Elmer 343 automatic
polarimeter as solutions in CH2Cl2. Diffraction data of
compounds 6 and 16 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
determined using SAINT+.32 The structure was 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 non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were placed in calcu-
lated positions and refined with an isotropic displace-
ment parameter 1.5 (CH3) or 1.2 times (all others) that
of the adjacent carbon or nitrogen atom. CCDC-
294740 (6) and CCDC-294741 (16) contain the supple-
mentary crystallographic data for this paper. These data
can be obtained free of charge via 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.
4.4. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-
benzamide (10)
Colorless solid (0.406 g, 60%) isolated from flash column
chromatography using 1:1 hexane/EtOAc: mp 190–
1
192 ꢁC; [a]D ꢀ14.5 (c 1.0, CH2Cl2); H NMR (CDCl3):
d 2.05 (s, 3H, COCH3), 2.06 (s, 6H, 2 · COCH3), 2.08
(s, 3H, COCH3), 3.92 (ddd, 1H, J = 2.1, 4.2, 10.2 Hz,
H-5), 4.10 (dd, 1H, J = 2.1, 12.5 Hz, H-6), 4.36 (dd,
1H, J = 4.2, 12.6 Hz, H-60), 5.08 (t, 1H, J = 9.6 Hz,
H-3), 5.12 (t, 1H, J = 9.7 Hz, H-4), 5.40 (t, 1H,
J = 9.5 Hz, H-2), 5.46 (t, 1H, J = 9.3 Hz, H-1), 7.14 (d,
1H, J = 9.2 Hz, N–H), 7.43–7.47 (m, 2H, Ar–H), 7.53
(m, 1H, Ar–H), 7.76–7.78 (m, 2H, Ar–H); 13C NMR
(CDCl3): d 20.7 (2 · C), 20.8 (2 · C), 61.6, 68.1, 70.7,
72.5, 73.5, 78.8, 127.0, 128.6 (3 · C), 132.2, 132.5,
166.8, 169.3, 169.6, 170.4, 171.2; ESIMS calcd for
C21H25NO10: 474.1376 (+Na), found: 474.1337 (+Na).
This data is in agreement with a sample of 10 produced
previously by a different method.12
4.2. General procedure for glucosyl and glucuronosyl
amide synthesis
The azide (5 or 9, 1.0 mmol) and acid chloride
(2.0 mmol) were dissolved in dry THF (0.1 g/mL) and
bis(diphenylphosphino)ethane (2, 0.65 mmol) in THF

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D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
4.5. 4-Fluoro-N-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)benzamide (11)
148.5 (2 · CH3), 162.6, 169.6 (2 · C), 170.5, 171.1;
ESIMS calcd for C21H23N3O14: 564.1078 (+Na), found:
564.1074 (+Na).
Colorless solid (0.331 g, 71%) isolated from flash
column chromatography using 1:1 hexane/EtOAc: mp
149–152 ꢁC; [a]D ꢀ17.8 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.05 (s, 9H, 3 · COCH3), 2.08 (s, 3H,
COCH3), 3.91 (ddd, 1H, J = 2.1, 4.2, 10.2 Hz, H-5),
4.11 (dd, 1H, J = 2.0, 12.6 Hz, H-6), 4.36 (dd, 1H,
J = 4.2, 12.6 Hz, H-60), 5.05 (t, 1H, J = 9.7 Hz, H-2),
5.12 (t, 1H, J = 9.7 Hz, H-3), 5.40 (t, 1H, J = 9.6 Hz,
H-4), 5.41 (t, 1H, J = 9.3 Hz, H-1), 7.03 (d, 1H,
J = 9.0 Hz, N–H), 7.11–7.15 (m, 2H, Ar–H), 7.76–7.80
(m, 2H, Ar–H); 13C NMR (CDCl3): d 20.6 (2 · C),
20.8 (2 · C), 61.6, 68.1, 70.8, 72.5, 73.5, 78.8, 115.7
(2 · C, d, J = 22.1 Hz), 128.7 (d, J = 3.1 Hz), 129.54
(2 · C, d, J = 9.2 Hz), 164.9 (d, J = 252.5 Hz), 165.8,
169.3, 169.5, 170.3, 171.2; LRMS calcd for
C21H24FNO10: 492.128 (+Na), found: 492.2 (+Na).
4.8. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-4-tri-
fluoromethylbenzamide (14)
Colorless solid (0.364 g, 70%) isolated from flash
column chromatography using 1:1 hexane/EtOAc: mp
189–190 ꢁC; [a]D ꢀ15.7 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.06 (s, 9H, 3 · COCH3), 2.08 (s, 3H,
COCH3), 3.93 (ddd, 1H, J = 2.1, 4.2, 10.2 Hz, H-5),
4.12 (dd, 1H, J = 2.0, 12.6 Hz, H-6), 4.36 (dd, 1H,
J = 4.3, 12.5 Hz, H-60), 5.07 (t, 1H, J = 9.6 Hz, H-2),
5.12 (t, 1H, J = 9.8 Hz, H-3), 5.42 (t, 1H, J = 9.5 Hz,
H-4), 5.45 (t, 1H, J = 9.3 Hz, H-1), 7.29 (d, 1H,
J = 8.8 Hz, N–H), 7.72 (d, 2H, J = 8.4 Hz, Ar–H),
7.89 (d, 2H, J = 8.1 Hz, Ar–H); 13C NMR (CDCl3): d
20.6 (2 · C), 20.8 (2 · C), 61.6, 68.1, 70.8, 72.4, 73.6,
78.9, 123.3 (q, J = 271.9 Hz), 125.6 (2 · C, q,
J = 3.1 Hz), 127.6, 133.9 (2 · C, q, J = 32.8 Hz), 135.8,
165.6, 169.3, 169.5, 170.3, 171.3; LRMS calcd for
C22H24F3NO10: 542.125 (+Na), found: 542.2 (+Na).
4.6. 2,3,4,5,6-Pentafluoro-N-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)benzamide (12)
Colorless solid (0.418 g, 77%) isolated from flash
column chromatography using 7:4 hexane/EtOAc: mp
129–132 ꢁC; [a]D +4.7 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.04 (s, 3H, COCH3), 2.05 (s, 3H, COCH3),
2.09 (s, 3H, COCH3), 2.10 (s, 3H, COCH3), 3.90 (ddd,
1H, J = 2.1, 4.3, 10.2 Hz, H-5), 4.12 (dd, 1H, J = 2.2,
12.5 Hz, H-6), 4.36 (dd, 1H, J = 4.5, 12.5 Hz, H-60),
5.02 (t, 1H, J = 9.6 Hz, H-3), 5.10 (t, 1H, J = 9.7 Hz,
H-4), 5.36 (t, 1H, J = 9.5 Hz, H-2), 5.39 (t, 1H,
J = 9.3 Hz, H-1), 6.95 (d, 1H, J = 9.2 Hz, N–H); 13C
NMR (CDCl3): d 20.6, 20.7 (2 · C), 20.8, 61.5, 68.0,
70.2, 72.4, 73.9, 78.4, 110.2, 137.4 (2 · C, d,
J = 256.4 Hz), 142.5 (d, J = 258.6 Hz), 143.9 (2 · C, d,
J = 248.7 Hz), 157.6, 169.3, 169.6, 170.4, 170.8; ESIMS
calcd for C21H20F5NO10: 564.0905 (+Na), found:
564.0915 (+Na).
4.9. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)furan-
2-carboxamide (15)
Colorless solid (0.26 g, 59%) isolated from flash column
chromatography using 4:5 hexane/EtOAc: mp 160–
1
163 ꢁC; [a]D ꢀ17.7 (c 1.0, CH2Cl2); H NMR (CDCl3):
d 2.03 (s, 3H, COCH3), 2.04 (s, 3H, COCH3), 2.05 (s,
3H, COCH3), 2.08 (s, 3H, COCH3), 3.90 (ddd, 1H,
J = 2.1, 4.3, 10.2 Hz, H-5), 4.10 (dd, 1H, J = 2.1,
12.5 Hz, H-6), 4.38 (dd, 1H, J = 4.3, 12.5 Hz, H-60),
5.08 (t, 1H, J = 9.6 Hz, H-3), 5.12 (t, 1H, J = 9.7 Hz,
H-4), 5.38, 5.43 (2t overlapping, 2H, J = 9.9, 9.5 Hz,
H-1, H-2), 6.52 (dd, 1H, J = 1.8, 3.5 Hz, Ar–H), 7.16
(d, 1H, J = 9.3 Hz, N–H), 7.18 (d, 1H, J = 3.5 Hz,
Ar–H), 7.50 (d, 1H, J = 1.8 Hz, Ar–H); 13C NMR
(CDCl3): d 20.6 (2 · C), 20.7, 20.8, 61.5, 68.0, 70.3,
72.6, 73.4, 77.9, 112.2, 115.8, 144.7, 146.3, 157.8,
169.3, 169.6, 170.3, 170.6; ESIMS calcd for
C19H23NO11: 464.1169 (+Na), found: 464.1169 (+Na).
4.7. 3,5-Dinitro-N-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)benzamide (13)
Colorless solid (0.283 g, 58%) isolated from flash
column chromatography using 5:4 hexane/EtOAc: mp
149–152 ꢁC; [a]D ꢀ36.8 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.07 (s, 6H, 2 · COCH3), 2.08 (s, 3H,
COCH3), 2.09 (s, 3H, COCH3), 3.94 (ddd, 1H,
J = 2.2, 4.5, 10.2 Hz, H-5), 4.14 (dd, 1H, J = 2.1,
12.5 Hz, H-6), 4.34 (dd, 1H, J = 4.4, 12.6 Hz, H-60),
5.07 (t, 1H, J = 9.6 Hz, H-2), 5.14 (t, 1H, J = 9.8 Hz,
H-3), 5.43 (t, 1H, J = 9.6 Hz, H-4), 5.45 (t, 1H,
J = 9.52 Hz, H-1), 7.64 (d, 1H, J = 8.6 Hz, N–H), 8.98
(d, 2H, J = 2.2 Hz, Ar–H), 9.21 (t, 1H, J = 2.0 Hz,
Ar–H); 13C NMR (CDCl3): d 20.6, 20.7, 20.8 (2 · C),
61.9, 68.2, 70.9, 72.5, 73.8, 78.8, 121.6, 127.5, 136.1,
4.10. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)thio-
phene-2-carboxamide (16)
Colorless solid (0.342 g, 75%) isolated from flash
column chromatography using 3:2 hexane/EtOAc: mp
170–171 ꢁC; [a]D ꢀ32.2 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.04 (s, 3H, COCH3), 2.05 (2s overlapping,
6H, COCH3), 2.09 (s, 3H, COCH3), 3.90 (ddd, 1H,
J = 2.1, 4.3, 10.2 Hz, H-5), 4.11 (dd, 1H, J = 2.1,
12.5 Hz, H-6), 4.36 (dd, 1H, J = 4.3, 12.5 Hz, H-60),
5.04 (t, 1H, J = 9.6 Hz, H-3), 5.11 (t, 1H, J = 9.8 Hz,

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
1653
H-4), 5.38 (t, 1H, J = 9.3 Hz, H-2), 5.39 (t, 1H,
J = 9.5 Hz, H-1), 6.94 (d, 1H, J = 9.0 Hz, N–H), 7.09
(dd, 1H, J = 3.8, 5.0 Hz, Ar–H), 7.49 (dd, 1H, J = 1.1,
3.9 Hz, Ar–H), 7.55 (dd, 1H, J = 1.1, 5.1 Hz, Ar–H);
13C NMR (CDCl3): d 20.7 (2 · C), 20.8 (2 · C), 61.6,
68.1, 70.6, 72.5, 73.5, 78.8, 127.2, 129.0, 131.5, 137.3,
161.4, 169.3, 169.6, 170.4, 171.3; ESIMS calcd for
C19H23NO10S: 480.0940 (+Na), found: 480.0936
(+Na). Only mass spectral data for this compound has
been reported previously.18
165–168 ꢁC, lit.6 138–140 ꢁC; [a]D +16.5 (c 1.0,
CH2Cl2), lit.6 +38.0 (c 0.21, CHCl3); 1H NMR
(CDCl3): d 2.05 (s, 3H, COCH3), 2.06 (s, 3H, COCH3),
2.09 (s, 3H, COCH3), 2.10 (s, 3H, COCH3), 3.95
(ddd, 1H, J = 2.1, 4.2, 10.1 Hz, H-5), 4.16 (dd,
1H, J = 2.1, 12.5 Hz, H-6), 4.37 (dd, 1H, J = 4.3,
12.5 Hz, H-60), 5.06 (t, 1H, J = 9.6 Hz, H-2),
5.13 (t, 1H, J = 9.7 Hz, H-3), 5.41 (t, 1H, J = 9.5 Hz,
H-4), 5.58 (t, 1H, J = 9.4 Hz, H-1), 6.83 (d, 1H,
J = 9.7 Hz, N–H), 7.45 (dd, 1H, J = 7.1, 8.1 Hz,
Ar–H), 7.51–7.58 (m, 2H, Ar–H), 7.86–7.89 (m, 1H,
Ar–H), 7.95 (d, 1H, J = 8.2 Hz, Ar–H,), 8.32–8.35
(m, 1H, Ar–H). 13C NMR (CDCl3): d 20.7 (2 · C),
20.78, 20.83, 61.7, 68.2, 70.7, 72.8, 73.7, 78.4, 124.4,
125.0, 125.1, 126.4, 127.2, 128.2, 129.9, 131.5, 132.1,
133.5, 169.0, 169.3, 169.6, 170.4, 170.7; LRMS
calcd for C25H27NO10: 524.153 (+Na), found: 524.2
(+Na).
4.11. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-
butyramide (17)
Colorless solid (0.273 g, 64%) isolated from flash col-
umn chromatography using 3:2 hexane/EtOAc: mp
114–117 ꢁC; [a]D +12.9 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 0.92 (t, 3H, J = 7.42 Hz, Hc), 1.58 (m, 2H,
Hb), 2.10 (m, 2H, Ha), 2.03 (s, 3H, COCH3), 2.04 (s,
3H, COCH3), 2.05 (s, 3H, COCH3), 2.09 (s, 3H,
COCH3), 3.85 (ddd, 1H, J = 2.1, 4.3, 10.2 Hz, H-5),
4.08 (dd, 1H, J = 2.1, 12.5 Hz, H-6), 4.33 (dd, 1H,
J = 4.3, 12.5 Hz, H-60), 4.94 (t, 1H, J = 9.6 Hz, H-2),
5.07 (t, 1H, J = 9.7 Hz, H-4), 5.30 (t, 1H, J = 9.7 Hz,
H-1), 5.32 (t, 1H, J = 9.6 Hz, H-3), 6.44 (d, 1H,
J = 9.3 Hz, N–H); 13C NMR (CDCl3): d 13.6, 18.6,
20.59 (2 · C), 20.64, 20.7, 38.4, 61.6, 68.0, 70.4, 72.6,
73.4, 77.9, 169.2, 169.5, 170.3, 170.5, 172.9; ESIMS
calcd for C18H27NO10: 440.1533 (+Na), found:
440.1541 (+Na).
4.14. 4-Bromo-N-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)benzamide (20)
Colorless solid (0.36 g, 67%) isolated from flash column
chromatography using 1:1 hexane/EtOAc: mp 179–
1
180 ꢁC; [a]D ꢀ2.6 (c 1.0, CH2Cl2); H NMR (CDCl3):
d 2.05 (s, 3H, COCH3), 2.06 (s, 6H, 2 · COCH3),
2.08 (s, 3H, COCH3), 3.91 (ddd, 1H, J = 2.0, 4.1,
10.1 Hz, H-5), 4.11 (dd, 1H, J = 2.1, 12.5 Hz, H-6),
4.36 (dd, 1H, J = 4.2, 12.6 Hz, H-60), 5.04 (t, 1H,
J = 9.6 Hz, H-2), 5.12 (dd, 1H, J = 9.7 Hz, H-3), 5.40
(t, 1H, J = 9.6 Hz, H-4), 5.41 (t, 1H, J = 9.3 Hz, H-
1), 7.04 (d, 1H, J = 9.0 Hz, N–H), 7.58–7.64 (m, 4H,
Ar–H); 13C NMR (CDCl3): d 20.6 (2 · C), 20.7
(2 · C), 61.5, 68.1, 70.7, 72.4, 73.5, 78.8, 127.1, 128.6,
131.4, 131.7, 165.9, 169.3, 169.5, 170.2, 171.1; LRMS
calcd for C21H24BrNO10: 552.048 (+Na), found: 552.2
(+Na).
4.12. 3-Methyl-N-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)butanamide (18)
Colorless solid (0.303 g, 71%) isolated from flash col-
umn chromatography using 1:2 hexane/EtOAc: mp
137–139 ꢁC; [a]D +11.8 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 0.91 (d, 3H, J = 6.2 Hz, Hc), 0.94 (d, 3H,
J = 6.2 Hz, Hc), 1.96–2.15 (m, 3H, Ha, Hb), 2.03 (s,
3H, COCH3), 2.04 (s, 6H, 2 · COCH3), 2.08 (s, 3H,
COCH3), 3.83 (ddd, 1H, J = 2.1, 4.4, 10.1 Hz, H-5),
4.07 (dd, 1H, J = 2.1, 12.5 Hz, H-6), 4.33 (dd, 1H,
J = 4.4, 12.5 Hz, H-60), 4.93 (t, 1H, J = 9.6 Hz, H-3),
5.07 (t, 1H, J = 9.8 Hz, H-4), 5.28 (t, 1H, J = 9.5 Hz,
H-2), 5.31 (t, 1H, J = 9.5 Hz, H-1), 6.22 (d, 1H,
J = 9.3 Hz, N–H); 13C NMR (CDCl3): d 20.6 (2 · C),
20.7, 20.8, 22.2, 22.3, 26.0, 45.9, 61.6, 68.1, 70.4, 72.6,
73.4, 77.9, 169.2, 169.5, 170.3, 170.6, 172.5; ESIMS
calcd for C19H29NO10: 454.1689 (+Na), found:
454.1691 (+Na).
4.15. 4-Cyano-N-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)benzamide (21)
Colorless solid (0.352 g, 74%) isolated from flash col-
umn chromatography using 1:1 hexane/EtOAc: mp
105–107 ꢁC; [a]D ꢀ22.3 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.06 (s, 9H, 3 · COCH3), 2.08 (s, 3H,
COCH3), 3.92 (ddd, 1H, J = 2.1, 4.3, 10.1 Hz, H-5),
4.12 (dd, 1H, J = 4.3, 12.5 Hz, H-6), 4.35 (dd, 1H,
J = 2.1, 12.5 Hz, H-60), 5.04 (t, 1H, J = 9.6 Hz, H-2),
5.12 (t, 1H, J = 9.8 Hz, H-3), 5.41 (2 · t, overlapping,
2H, J = 9.2, 9.5 Hz, H-1, H-4), 7.27 (d, 1H,
J = 8.4 Hz, N–H), 7.76 (m, 2H, Ar–H), 7.86 (m, 2H,
Ar–H); 13C NMR (CDCl3): d 21.9 (2 · C), 22.0, 22.1,
62.7, 69.2, 72.0, 73.5, 74.8, 80.1, 117.1, 118.9, 129.0,
133.7, 137.6, 166.4, 170.6, 170.9, 171.6, 172.9; LRMS
calcd for C22H24N2O10: 499.133 (+Na), found: 499.2
(+Na).
4.13. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-
naphthamide (19)
Colorless solid (0.25 g, 50%) isolated from flash
column chromatography using 1:1 hexane/EtOAc: mp

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D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
4.16. N-(Methyl 2,3,4-tetra-O-acetyl-b-D-glucuronosyl)-
4-nitro-benzamide (22)
4.19. N-(Methyl 2,3,4-tetra-O-acetyl-b-D-glucuronosyl)-
furan-2-carboxamide (25)
Colorless solid (0.347 g, 72%) isolated from flash col-
umn chromatography using 1:1 hexane/EtOAc: mp
105–107 ꢁC; [a]D ꢀ49.7 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.05 (s, 6H, 2 · COCH3), 2.06 (s, 3H,
COCH3), 3.72 (s, 3H, –OCH3), 4.25 (d, 1H,
J = 9.9 Hz, H-5), 5.05 (t, 1H, J = 9.6 Hz, H-4), 5.16 (t,
1H, J = 9.7 Hz, H-2), 5.37 (t, 1H, J = 9.8 Hz, H-3),
5.47 (t, 1H, J = 9.1 Hz, H-1), 7.39 (d, 1H, J = 9.0 Hz,
N–H), 7.93 (d, 2H, J = 8.6 Hz, Ar–H), 8.30 (d, 2H,
J = 8.4 Hz, Ar–H); 13C NMR (CDCl3): d 21.6, 21.7,
21.8, 54.0, 70.5, 71.6, 72.9, 74.5, 79.4, 124.7 (2 · C),
129.8 (2 · C), 139.1, 150.8, 166.6, 168.1, 170.5, 170.7,
171.8; ESIMS calcd for C20H22N2O12: 505.1070
(+Na), found: 505.1056 (+Na).
Colorless solid (0.256 g, 60%) isolated from flash col-
umn chromatography using 1:1 hexane/EtOAc: mp
137–140 ꢁC; [a]D +36.0 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 1.99 (s, 3H, COCH3), 2.00 (s, 3H, COCH3),
2.02 (s, 3H, COCH3), 3.69 (s, 3H, –OCH3), 4.20 (d, 1H,
J = 10.1 Hz, H-5), 5.09 (t, 1H, J = 9.7 Hz, H-4), 5.14 (t,
1H, J = 9.7 Hz, H-2), 5.43 (t, 1H, J = 9.5 Hz, H-3), 5.60
(t, 1H, J = 9.6 Hz, H-1), 7.26 (d, 1H, J = 10.4 Hz, N–
H), 7.43 (m, 1H, Ar–H), 7.52 (m, 1H, Ar–H), 7.63 (m,
1H, Ar–H); 13C NMR (CDCl3): d 21.7, 21.8, 22.0,
54.2, 70.8, 71.1, 72.9, 74.9, 78.8, 113.3, 129.5, 133.0,
146.5, 159.1, 168.1, 170.5, 170.6, 171.7; LRMS calcd
for C18H21NO11: 427.1, found: 428.1 (+H+).
4.20. N-(Methyl 2,3,4-tetra-O-acetyl-b-D-glucuronosyl)-
2,3,4,5,6-pentafluorobenzamide (26)
4.17. N-(Methyl 2,3,4-tetra-O-acetyl-b-D-glucuronosyl)-
benzamide (23)
Colorless solid (0.395 g, 75%) isolated from flash column
chromatography using 2:1 hexane/EtOAc: mp 175–
178 ꢁC; [a]D +42.6 (c 1.0, CH2Cl2); H NMR (CDCl3):
Colorless solid (0.428 g, 98%) isolated from flash col-
umn chromatography using 2:1 hexane/EtOAc: mp
193–195 ꢁC; [a]D ꢀ19.1 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.04 (s, 3H, COCH3), 2.05 (s, 3H, COCH3),
2.06 (s, 3H, COCH3), 3.72 (s, 3H, –OCH3), 4.24 (d, 1H,
J = 10.1 Hz, H-5), 5.10 (t, 1H, J = 9.6 Hz, H-4), 5.18 (t,
1H, J = 10.1 Hz, H-2), 5.47 (t, 1H, J = 9.6 Hz, H-3),
5.48 (t, 1H, J = 9.2 Hz, H-1), 7.15 (d, 1H, J = 9.2 Hz,
N–H), 7.44 (t, 2H, J = 6.6 Hz, Ar–H), 7.53 (t, 1H,
J = 7.1 Hz, Ar–H), 7.75 (d, 2H, J = 6.8 Hz, Ar–H);
13C NMR (CDCl3): d 21.7, 21.8, 21.9, 54.0, 70.8, 71.7,
73.0, 74.9, 79.6, 128.3 (2 · C), 129.7 (2 · C), 133.4,
133.7, 168.1, 168.2, 170.4, 170.7, 172.1; ESIMS calcd
for C20H23NO10: 460.1220 (+Na), found: 460.1221
(+Na). The deacetylated derivative of this compound
has been reported.18
1
d 2.02 (s, 3H, COCH3), 2.03 (s, 3H, COCH3), 2.05 (s,
3H, COCH3), 3.71 (s, 3H, –OCH3), 4.21 (d, 1H,
J = 10.1 Hz, H-5), 5.09 (t, 1H, J = 9.5 Hz, H-4), 5.13 (t,
1H, J = 9.8 Hz, H-2), 5.41 (t, 1H, J = 9.5 Hz, H-3), 5.46
(t, 1H, J = 9.3 Hz, H-1), 7.26 (d, 1H, J = 9.2 Hz, N–H);
13C NMR (CDCl3): d 21.7, 21.8, 21.9, 54.1, 70.6, 71.8,
73.3, 74.1, 78.3, 113.0, 138.4 (d, 2 · C, J = 251 Hz),
143.1 (d, J = 251 Hz), 144.5 (d, 2 · C, J = 251 Hz),
158.6, 168.6, 170.2, 170.7, 170.8; ESIMS calcd for
C20H18F5NO10: 550.0749 (+Na), found: 550.0737 (+Na).
4.21. N-(Methyl 2,3,4-tetra-O-acetyl-b-D-glucuronosyl)-
butyramide (27)
Colorless solid (0.282 g, 70%) isolated from flash column
chromatography using 1:1 hexane/EtOAc: mp 81–83 ꢁC;
[a]D +24.1 (c 1.0, CH2Cl2); 1H NMR (CDCl3): d 0.84 (t,
3H, J = 7.3 Hz, Hc), 1.56 (sextet, 2H, J = 3.7 Hz, Hb),
1.97 (s, 3H, COCH3), 1.98 (s, 6H, 2 · COCH3), 2.10 (t,
2H, J = 8.0 Hz, Ha), 3.66 (s, 3H, –OCH3), 4.14 (d, 1H,
J = 10.1 Hz, H-5), 4.92 (t, 1H, J = 9.6 Hz, H-4), 5.08
(t, 1H, J = 9.8 Hz, H-2), 5.29 (t, 1H, J = 8.5 Hz, H-3),
5.34 (t, 1H, J = 9.5 Hz, H-1), 6.59 (d, 1H, J = 9.5 Hz,
N–H); 13C NMR (CDCl3): d 14.8, 19.8, 21.7, 21.8,
21.9, 54.1, 70.6, 71.4, 73.0, 74.8, 77.9, 168.1, 170.4,
170.6, 171.6, 174.4; ESIMS calcd for C17H25NO10:
426.1376 (+Na), found: 426.1365 (+Na).
4.18. 4-Fluoro-N-(methyl 2,3,4-tetra-O-acetyl-b-D-
glucuronosyl)benzamide (24)
Colorless solid (0.364 g, 80%) isolated from flash col-
umn chromatography using 1:1 hexane/EtOAc: mp
116–119 ꢁC; [a]D ꢀ31.3 (c 1.0, CH2Cl2); 1H NMR
(CDCl3): d 2.00 (s, 3H, COCH3), 2.03 (s, 6H,
2 · COCH3), 3.66 (s, 3H, –OCH3), 4.24 (d, 1H,
J = 10.1 Hz, H-5), 5.09 (t, 1H, J = 9.5 Hz, H-4), 5.12
(t, 1H, J = 9.5 Hz, H-2), 5.46 (t, 1H, J = 9.5 Hz, H-3),
5.50 (t, 1H, J = 9.2 Hz, H-1), 7.06 (dd, 2H, J = 8.5,
8.5 Hz, Ar–H), 7.40 (d, 1H, J = 9.2 Hz, N–H), 7.76
(dd, 2H, J = 8.5, 4.7 Hz, Ar–H); 13C NMR (CDCl3): d
21.7, 21.8, 21.9, 54.0, 70.8, 71.7, 73.0, 74.8, 79.6, 116.6
(d, 2 · C, J = 22.1 Hz), 129.9, 130.9 (d, 2 · C,
J = 9.2 Hz), 164.8, 166.1 (d, J = 252.5 Hz), 167.3,
168.2, 170.9, 172.6; ESIMS calcd for C20H22FNO10:
478.1125 (+Na), found: 478.1133 (+Na).
4.22. N-(Methyl 2,3,4-tetra-O-acetyl-b-D-glucuronosyl)-
3-methylbutanamide (28)
Colorless solid (0.234 g, 56%) isolated from flash col-
umn chromatography using 1:1 hexane/EtOAc: mp

D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
1655
67–70 ꢁC; [a]D +6.0 (c 1.0, CH2Cl2); 1H NMR (CDCl3):
d 0.90 (d, 6H, J = 11.2 Hz, Hc), 0.97 (d, 2H, J = 6.6 Hz,
Ha), 2.02 (s, 9H, 3 · COCH3), 2.08 (m, 1H, Hb), 3.71 (s,
3H, –OCH3), 4.15 (d, 1H, J = 9.8 Hz, H-5), 4.94 (t, 1H,
J = 9.6 Hz, H-4), 5.12 (t, 1H, J = 10.1 Hz, H-2), 5.31 (t,
1H, J = 9.5 Hz, H-3), 5.37 (t, 1H, J = 9.5 Hz, H-1), 6.39
(d, 1H, J = 9.3 Hz, N–H); 13C NMR (CDCl3): d 21.7,
21.8 (2 · C), 23.4 (2 · C), 27.1, 47.0, 54.1, 70.8, 71.3,
73.1, 74.9, 78.8, 168.1, 170.4, 170.6, 171.7, 173.9; ESIMS
calcd for C18H27NO10: 440.1533 (+Na), found: 440.1545
(+Na).
12.6 Hz, H-6), 4.26 (dd, 1H, J = 5.1, 12.6 Hz, H-60),
5.31 (t, 1H, J = 9.8 Hz, H-3), 5.45 (t, 1H, J = 9.4 Hz,
H-4), 6.01 (t, 1H, J = 9.4 Hz, H-2), 6.22 (d, 1H,
J = 9.3 Hz, H-1), 6.70 (dd, 1H, J = 1.7, 3.6 Hz, Ar–H),
7.40 (d, 1H, J = 3.6 Hz, Ar–H), 7.75 (d, 1H,
J = 1.7 Hz, Ar–H); 13C NMR (CDCl3): d 20.3, 20.6
(2 · C), 20.7, 61.5, 67.5, 69.4, 73.1, 74.9, 83.6, 112.5,
116.1, 138.8, 145.9, 146.9, 168.1, 168.9, 170.0, 170.1;
ESIMS calcd for C19H22N4O10: 489.1234 (+Na), found:
489.1245 (+Na).
4.23. N-(Chloro(furan-2-yl)methylene)(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)amine (30)
Acknowledgments
Sara Duncan and Shawn McKee were participants in
the National Science Foundation (NSF) sponsored
Research Experience for Undergraduates program at
YSU (NSF-0097682, 2001-2003). P.N. thanks the
National Institutes of Health (R15-AI053112-01) for
sponsorship and 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.
DPPE (0.518 g, 1.3 mmol) in dry THF (0.1 g/mL) was
added dropwise to a solution of azide 5 (0.747 g,
2.0 mmol) and 2-furoyl chloride (0.396 mL, 4.0 mmol)
at rt. After stirring for 1 h the solvent was removed under
reduced pressure and the residue dissolved in CHCl3
(70 mL) and washed with a satd aq NaHCO3 solution
(20 mL), water (20 mL), and the organic layer dried
(MgSO4), filtered and concentrated to leave a pale yellow
syrup that was subjected to flash column chromatogra-
phy using 1:1 hexane/EtOAc. The imidoyl chloride was
isolated as a colorless solid (0.626 g, 68%): mp 120–
Supplementary data
1
122 ꢁC; [a]D ꢀ36.4 (c 1.0, CH2Cl2); H NMR (CDCl3):
d 1.97 (s, 3H, COCH3), 2.03 (s, 3H, COCH3), 2.06 (s,
3H, COCH3), 2.09 (s, 3H, COCH3), 3.91 (ddd, 1H,
J = 2.4, 4.8, 10.0 Hz, H-5), 4.19 (dd, 1H, J = 2.3,
12.4 Hz, H-6), 4.28 (dd, 1H, J = 4.9, 12.4 Hz, H-60),
5.18–5.38 (m, 4H, H-1, H-2, H-3, H-4), 6.53 (dd, 1H,
J = 1.7, 3.6 Hz, Ar–H), 7.18 (d, 1H, J = 3.6 Hz, Ar–
H), 7.61 (d, 1H, J = 1.7 Hz, Ar–H); 13C NMR (CDCl3):
d 20.6, 20.7 (2 · C), 20.8, 62.0, 68.2, 71.8, 73.1, 73.6, 89.1,
112.2, 118.8, 136.5, 147.0, 147.2, 168.8, 169.1, 170.0,
170.4; ESIMS calcd For C19H22ClNO10: 482.0830
(+Na), found: 482.0835 (+Na).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2006.02.001.
References
1. Davis, B. G. Chem. Rev. 2002, 102, 579–602.
2. Knauer, S.; Kranke, B.; Krause, L.; Kunz, H. Curr. Org.
Chem. 2004, 8, 1739–1761.
3. Maunier, V.; Boullanger, P.; Lafont, D. J. Carbohydr.
Chem. 1997, 16, 231–235.
4. Boullanger, P.; Maunier, V.; Lafont, D. Carbohydr. Res.
4.24. 5-(Furan-2-yl)-1-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)-1H-tetrazole (34)
2000, 324, 97–106.
}
´
}
5. Kovacs, L.; Osz, E.; Domokos, V.; Holzer, W.; Gyorgy-
´
deak, Z. Tetrahedron 2001, 57, 4609–4621.
´
6. Gyo¨ergydeak, Z.; Hadady, Z.; Felfo¨ldi, N.; Krakomper-
Sodium azide (0.30 g, 4.61 mmol) and imidoyl chloride
30 (0.53 g, 1.15 mmol) were stirred at rt in dry DMF
(3 mL) for 5 h. The solvent was removed under reduced
pressure and the residue was partitioned between water
(10 mL) and CH2Cl2 (10 mL). The aqueous layer was
further extracted with CH2Cl2 (3 · 10 mL) and the com-
bined extracts were washed with water (10 mL), dried
over MgSO4, and concentrated to a syrup that was then
purified by flash column chromatography using 1:2 hex-
ane/EtOAc. Tetrazole 34 was isolated as a colorless syr-
´
´
ger, A.; Nagy, V.; Toth, M.; Brunyanszki, A.; Docsa, T.;
Gergely, P.; Somsak, L. Bioorg. Med. Chem. 2004, 12,
4861–4870.
´
7. Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007–2010.
8. Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett.
2000, 2, 2141–2143.
9. He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org.
Lett. 2004, 6, 4479–4482.
10. Bianchi, A.; Russo, A.; Bernardi, A. Tetrahedron: Asym-
metry 2005, 16, 381–385.
11. Lin, F. L.; Hoyt, H. M.; Van Halbeek, H.; Bergman, R.
G.; Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686–
2695.
1
up (0.51 g, 95%): [a]D ꢀ15.1 (c 1.0, CH2Cl2); H NMR
(CDCl3): d 1.86 (s, 3H, COCH3), 2.04 (s, 3H, COCH3),
2.06 (s, 3H, COCH3), 2.08 (s, 3H, COCH3), 4.08 (ddd,
1H, J = 2.5, 5.1, 10.1, H-5), 4.17 (dd, 1H, J = 2.4,
12. Murphy, P. V.; Bradley, H.; Tosin, M.; Pitt, N.; Fitzpa-
trick, G. M.; Glass, W. K. J. Org. Chem. 2003, 68, 5692–
5704.

1656
D. P. Temelkoff et al. / Carbohydrate Research 341 (2006) 1645–1656
13. Tosin, M.; Gouin, S. G.; Murphy, P. V. Org. Lett. 2005, 7,
211–214.
24. Braese, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–5240.
14. Pleuss, N.; Kunz, H. Synthesis 2005, 122–130.
15. Pleuss, N.; Kunz, H. Angew. Chem., Int. Ed. 2003, 42,
25. Kohn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004,
43, 3106–3116.
3174–3176.
26. For detailed discussion of N-glycosyl amide structure in
solid state and solution see: Avalos, M.; Babiano, R.;
Carretero, M. J.; Cintas, P.; Higes, F. J.; Jimenez, J. L.;
Palacios, J. C. Tetrahedron 1998, 54, 615–628.
}
´
´
´
´
16. Somsak, L.; Kovacs, L.; Toth, M.; Osz, E.; Szilagyi, L.;
}
´
´
Gyoergydeak, Z.; Dinya, Z.; Docsa, T.; Toth, B.; Gergely,
P. J. Med. Chem. 2001, 44, 2843–2848.
17. Murphy, P. V.; Pitt, N.; O’Brien, A.; Enright, P. M.;
Dunne, A.; Wilson, S. J.; Duane, R. M.; O’Boyle, K. M.
Bioorg. Med. Chem. Lett. 2002, 12, 3287–3290.
18. Pitt, N.; Duane, R. M.; O’Brien, A.; Bradley, H.; Wilson,
S. J.; O’Boyle, K. M.; Murphy, P. V. Carbohydr. Res.
2004, 339, 1873–1887.
19. Root, Y. Y.; Bailor, M. S.; Norris, P. Synth. Commun.
2004, 34, 2499–2506.
20. O’Neil, I. A.; Thompson, S.; Murray, C. L.; Kalindjian, S.
B. Tetrahedron Lett. 1998, 39, 7787–7790.
21. Tropper, F. D.; Andersson, F. O.; Braun, S.; Roy, R.
Synthesis 1992, 7, 618–620.
22. For the X-ray crystal structure of 5 see: Temelkoff, D. P.;
Norris, P.; Zeller, M. Acta Crystallogr. Sect. E: Struct.
Rep. Online 2004, E60, 1975–1976.
27. For an example of ylide epimerization see: Damkaci, F.;
DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408–4409.
´
28. Gyo¨ergydeak, Z.; Thiem, J. Carbohydr. Res. 1995, 268,
85–92, and references cited therein.
29. For the X-ray crystal structure of 9 see: Smith, C. R.;
Norris, P.; Zeller, M. Acta Crystallogr. Sect. E: Struct.
Rep. Online 2005, E61, 736–737.
30. Artamonova, T. V.; Zhivich, A. B.; Dubinskii, M. Y.;
Koldobskii, G. I. Synthesis 1996, 1428–1430.
31. SMART, Software for the CCD Detector System, version
5.630; Bruker AXS, Inc.: Madison, WI, 2002.
32. SAINT+, Data Processing Software for the CCD Detector
System, version 6.45; Bruker AXS, Inc.: Madison, WI,
2003.
33. SHELXTL, Software Package for the Refinement of Crystal
Structures, version 6.10; Bruker AXS, Inc.: Madison, WI,
2000.
23. Gololobov, Yu. G.; Kasukhin, L. F. Tetrahedron 1992, 48,
1353–1406.