Synthesis of β-Glycosyl amides from N-glycosyl dinitrobenzenesulfonamides

Article abstract of DOI:10.1080/07328303.2012.663431

The N-glycosyl-2,4-dinitrobenzenesulfonamides were accessed via benzoyl-protected β-glycosyl azides. The azides were reduced with Adams' catalyst to the corresponding amines. The glycosylamines were sulfonated with 2,4-dinitrobenzenesulfonyl chloride to f

Full text of DOI:10.1080/07328303.2012.663431

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Synthesis of β-Glycosyl Amides from N-
Glycosyl Dinitrobenzenesulfonamides
Vishwanath Gaitonde a & Steven J. Sucheck a
a Department of Chemistry and School for Green Chemistry and
Engineering, The University of Toledo, Toledo, OH, 43606, USA
Version of record first published: 02 Jul 2012.
To cite this article: Vishwanath Gaitonde & Steven J. Sucheck (2012): Synthesis of β-Glycosyl Amides
from N-Glycosyl Dinitrobenzenesulfonamides, Journal of Carbohydrate Chemistry, 31:4-6, 353-370
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Journal of Carbohydrate Chemistry, 31:353–370, 2012
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2012.663431
Synthesis of β-Glycosyl Amides
from N-Glycosyl
Dinitrobenzenesulfonamides
Vishwanath Gaitonde and Steven J. Sucheck
Department of Chemistry and School for Green Chemistry and Engineering, The
University of Toledo, Toledo, OH 43606, USA
The N-glycosyl-2,4-dinitrobenzenesulfonamides were accessed via benzoyl-protected
β-glycosyl azides. The azides were reduced with Adams’ catalyst to the correspond-
ing amines. The glycosylamines were sulfonated with 2,4-dinitrobenzenesulfonyl chlo-
ride to form N-glycosyl-2,4-dinitrobenzenesulfonamides in moderate yields. β-Glycosyl
amides were then prepared in 67% to 81% yields by treatment of the sulfonamides with
thioacetic acid and cesium carbonate. The conversion of the glycosylsulfonamide to the
glycosyl amide proceeded with high stereoselectivity.
Keywords β-Glycosyl amides; 2,4-Dinitrobenzenesulfonamides; Thioacids; Meisen-
heimer complex
INTRODUCTION
Glycosyl amide linkages are found in a variety of natural products. It is
also notable that the glycosyl amide can be activated and used as a glycosyl
donor.[1] A popular strategy for accessing the β-glycosyl amide linkage found
in N-linked glycopeptides is the Lansbury aspartylation, which involves the
direct coupling of a glycosylamine to an activated aspartic acid on a pro-
tected peptide.[2] The intermediate glycosylamines are frequently accessed by
the Kochetkov reaction[3] or by deprotection of a sugar anomeric azide to ac-
cess the amine.[4] Aspartylations have also been performed using less active
esters under microwave-mediated conditions.[5] A limitation of the method
is that the starting glycosylamines are relatively unstable[6] and the hemi-
aminal is prone to mutarotation to give a mixture of anomers, thus making
Received December 21, 2011; accepted January 31, 2012.
Address correspondence to Steven J. Sucheck, Department of Chemistry and School for
Green Chemistry and Engineering, The University of Toledo, 2801 W. Bancroft Street,
Toledo, Ohio 43606, USA. E-mail: steve.sucheck@utoledo.edu
353

V. Gaitonde and S.J. Sucheck
354
stereocontrol difficult.[7] Further, diglycosylamines have also been observed as
by-products of glycosylamine-forming reactions.[8,9] Thus, methods for form-
ing the β-glycosyl amide linkage that do not involve an anomeric amine can
be considered advantageous. Several methods for improving this basic trans-
formation have been explored; however, most are overly complex and have
noted limitations.[10,11] Alternative strategies to access the β-glycosyl amide
include the use of the Staudinger reduction–acylation process,[10,11] starting
from β-glycosyl azides. However, anomerization remains a significant prob-
lem, and mixtures of anomers are often obtained.[12,13] These same azides have
also been used in traceless Staudinger ligations using 2-diphenylphosphanyl-
phenyl alkanoates. The diastereoselectivity of these reactions appears depen-
dent on the sugar-protecting group.[14] Glycosyl azides have also been reported
to react with thioacids to yield the amide,[15] while per-acylated sugars in the
presence of methanesulfonic acid and nitrile form glycosyl amides via a Ritter-
type reaction.[16] Further, β-glycosyl isonitriles and carboxylic acids under the
influence of microwaves react to afford formylated β-glycosyl amides.[17] Thus,
there have been sustained efforts to identify more stereoselective routes to
generate β-glycosyl amides.
2,4-Dinitrobenzenesulfonyl chloride (dNBS-Cl) has been used to protect
primary amines. The resulting 2,4-dinitrobenzenesulfonamides (dNBS) have
in turn been used to synthesize secondary amines and diamines by Fukuyama
et al.[18,19] 2,4-Dintrobenzenesulfonamides were later exploited to generate
amides, thioamides, ureas, and thioureas proceeding through the ipso attack of
various S and O nucleophiles on the sulfonamide to produce the Meisenheimer
complex.[20,21] In the case of a reaction between thioacids and dNBSs, the sul-
fonamide nitrogen ultimately attacks a thioester on the disintegration of the
Meisenheimer complex (Fig. 1). Only recently has this chemistry been taken
up as a possible chemoselective approach to form peptide linkages[22–24] and
neoglycoconjugates.[25] Our lab has reported that a β-glycosyl amide can be
formed from the reaction between 2,4-dinitrobenzenesulfonyl β-N-glycosides
and thioacids.[26] During the course of the study, we found it notable that the
reaction was fast and no α-anomer was isolated. Herein we explore the scope
of that reaction by examining several additional sugar congeners.
O
NO2
O
O
NO2
NO2
O
O
O
R1
R3
Cs2CO3, DMF, rt
S
S
R1
SH
-SO2
S
HS
N
R1
N
R2
R3
+
N
R2
R2
R3
NO2
NO2
NO2
O
Figure 1: Mechanism of amide formation.

Synthesis of β-Glycosyl Amides
355
RESULTS AND DISCUSSION
We chose four monosaccharides, D-glucose, D-galactose, D-mannose, and D-
arabinose, and a disaccharide, D-maltose, as a representative set of saccha-
rides to explore the scope of the reaction between 2,4-dinitrobenzenesulfonyl
β-N-glycosides and thioacids. Initially we began by selecting D-glucose and D-
galactose and converted each into the corresponding β-glycosyl azides 1 and
2, respectively.[27] Reduction of glycosyl azides was accomplished using Adams’
catalyst to generate the respective glycosylamines. As free glycosylamines are
prone to anomerization, the reduced glycosylamine was immediately subjected
to sulfonation with dNBS-Cl in pyridine. The resulting per-O-acetylated-β-
glycosyl-2,4-dinitrobenezenesulfonamides 3 and 4 were formed in 24% to 30%
yield (Table 1). Disappointed by the low yields, we attempted to modify the
conditions to improve the yield (Table 2). Pd/C-H2 in methanol and PtO2-H2 in
either ethanol or ethyl acetate were used for the initial reduction steps. Sol-
vents were kept anhydrous, and there appeared to be no difference in the qual-
ity or dryness of the intermediate glycosylamine. The concentration of base
pyridine was varied between neat solvent and 2.0 and 4.0 equivalents, because
we were concerned that high concentrations of base would lead to a competing
deprotection reaction. The dNBS-Cl reagent was also varied between 1.5 and
2.5 equivalents, and the use of catalytic DMAP was explored. No noticeable
Table 1: Preparation of N-2,4-dinitrobenzenesulfonamide from glycosyl azides via
glycosylamines
O2N
O
PtO2, EtOAc
H2, rt, 1.5 h
O
O
O
dNBS-Cl, Py
N2, rt, 2-3 h
H
N
N3
NH2
S
NO2
AcO
AcO
AcO
O
Per-O-acetylated
glycosyl azide
Per-O-acetylated
glycosylamine
Per-O-acetylated
N-dNBS glycoside
Azides
N-dNBS glycosides
Yield
24%
OAc
OAc
O2N
O
O
O
H
AcO
AcO
AcO
AcO
N
N3
S
NO2
AcO
AcO
O
1
3
27–30%
OAc
OAc
O
AcO
AcO
AcO
O2N
O
O
AcO
2
H
N
N3
S
NO2
AcO
AcO
O
4

V. Gaitonde and S.J. Sucheck
356
Table 2: Conditions for reduction/sulfonation of per-O-acetylated glycosyl azide 1
and 2
Entry Compound
Reagents
Solvent
Temperature Time Yielda
a
b
c
1
1
1
Pd/C, H2
MeOH
rt
rt
40 min 24%
3.0 h
dNBS-Cl, (1.5
eq.), N2
Pyridine
PtO2, H2
EtOH
Pyridine
rt
2 h
3.5 h
25%
dNBS-Cl (1.5
eq.), N2
0◦C–rt
PtO2, H2
EtOH
Pyridine (2.0
eq.), CH2Cl
rt
1.5 h
2.5 h
27%
dNBS-Cl (1.5
eq.), N2
0◦C–rt
DMAP (cat.)
PtO2, H2
d
e
f
1
2
2
2
EtOAc
rt
1.5
3.0 h
24%
dNBS-Cl (2.5
eq.), N2
Pyridine (4.0
eq.), CH2Cl
MeOH
0◦C–rt
Pd/C, H2
rt
rt
30 min 24%
3.5 h
dNBS-Cl (1.5
eq.), N2
Pyridine
PtO2, H2
EtOH
Pyridine
rt
1.5 h
3.5 h
30%
dNBS-Cl (1.5
eq.), N2
0◦C–rt
g
PtO2, H2
EtOH
Pyridine (4.0
eq.), CH2Cl
rt
1.5 h
3.0 h
26%
dNBS-Cl (1.5
eq.), N2
0◦C–rt
DMAP (cat.)
PtO2, H2
h
2
EtOAc
Pyridine
rt
1.5 h
2.5 h
28%
dNBS-Cl (2.5
eq.), N2
0◦C–rt
aCombined yields over two-step reaction.
improvement in yield was achieved. Mass spectral analysis of the glycosylsul-
fonamide reaction mixtures suggested liability of acetyl groups under reaction
conditions. ESI-MS showed m/z = 600.08, 558, 516, 474, and 423 M+Na, in-
dicating a progressive loss of acetyl groups with intermediates appearing as
sodium adducts. The apparent sensitivity of the acetyl group led us to examine
other potential routes to access the glycosyl sulfonamides.
Various strategies to access the glycosylsulfonamides 3 and 4 were ex-
plored. Initially the dNBS-Cl was converted to 2,4-dinitrobenzenesulfonamide
(5) in 78% yield by reacting with ammonium carbonate in a mixture of ace-
tone/water (1:1) (Scheme 1). We prepared the 4-methylphenyl 2,3,4,6-tetra-
O-acetyl-β-D-thioglucopyranoside (7) from α/β-D-glucose pentaacetate (6) and
p-thiocresol in the presence of BF3.OEt2.[28,29] Then, we explored the gly-
cosylation of sulfonamide 5 with thioglycoside 7 in the presence of 2,4,6-
tri-tert-butylpyridine (TTBP), N-iodosuccinimide (NIS), and trimethylsilyl
trifluoromethanesulfonate (TMSOTf).[30] To our surprise, this reaction failed.
We attribute the lack of reactivity to the electron-deficient sulfonamide 5,

Synthesis of β-Glycosyl Amides
357
which is possibly a very poor nucleophile. In an alternative approach, pentaac-
etate 6 was converted to 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (8),
followed by reacting 8 with 5 in the presence of Cs2CO3 to produce compound
3. Cs2CO3 was deemed a sufficiently strong base, because the pKa of the acidic
sulfonamide NH was estimated to be 8.2 using Chemaxon software. Again, no
desired product was obtained. Peracetate 6 was directly reacted with 5 in the
presence of BF3.OEt2. In this case trace product was obtained according to
mass spectral analysis of the crude reaction mixture; however, the yield was
not synthetically useful. The various attempts are summarized in Scheme 1.
We also accessed the known glucosylamine and treated it with the dNBS-Cl
to access the sulfonamide free of protecting groups. The polar compound was
difficult to handle and purify. Acetylation of this intermediate with acetic an-
hydride in pyridine resulted in an isolable pentaacetate, which contained an
N-acetyl group on the sulfonamide nitrogen (data not shown). It is possible
that acylation using less basic conditions could yield a more direct route to our
desired target.
At this point a less direct approach to access the glycosyl sulfonamides
was considered. Benzoate-protecting groups are reported to be less readily
hydrolyzed in comparison to acetates, and the tendency for benzoate migra-
tion, in contrast to acetates, is not nearly as strong. Therefore, the β-glycosyl
azides 1 and 2 were converted to their benzoyl-protected congeners 12 and 13,
respectively (Table 3). These compounds were further subjected to reduction to
the free amine using Adams’ catalyst to produce intermediate glycosylamines
followed by sulfonation with dNBS-Cl. The desired β-glycosylsulfonamides 17
and 18 were obtained in 44% and 48% yields, respectively. While these yields
are still modest, they represented a significant improvement over the yields
obtained from the acetate-protected sugars. We had also considered that the
improved yield may be a result of increased nucleophilicity of the anomeric
amine when benzoates are present. However, the benzoyl group should be
more withdrawing owing to the sp2 centers of the phenyl ring. Supporting
this notion is experimental evidence in the form of relative reactivity data
comparing per-acetyl and per-benzoyl thioglucosides in model glycosylation
reactions.[31] The data reveal per-benzoyl as slightly more deactivating
that per-acetyl. In addition, pKa studies comparing per-acetylated and per-
benzoylated 1-deoxynojirimycin derivatives show the benzoyl congener (pKa
3.4) to be slightly more electron withdrawing than the acetate (pKa 3.5).[32]
With this data in hand the 2,3,4,6-tetra-O-acetyl-β-D-mannopyranosyl azide
(9), 2,3,4-tetra-O-acetyl-β-D-arabinopyranosyl azide (10), and 2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-
hepta-O-acetyl-β-maltosyl azide (11) were prepared using known procedures
and converted to the corresponding benzoyl-protected glycosyl azides 14, 15,
and 16 in very good yields (Table 3).
With a representative series of β-glycosyl azides, we envisioned converting
each to the corresponding β-glycosyl sulfonamide. These sulfonamides would

V. Gaitonde and S.J. Sucheck
358
NO2
NO2
a.
(NH4)2CO3
acetone, water, rt
1 h, 78%
NO2
NO2
O S O
NH2
O S O
Cl
5
OAc
O
OAc
O
b.
p-thiocresol, BF3.OEt2
CH2Cl, 10 h, rt, 43%
AcO
AcO
AcO
AcO
STol
OAc
AcO
AcO
6
7
5
,
B
F
3
.
O
5, TTBP, NIS,
TMSOTf, CH2Cl2
-CH3CN (1:1)
3A mol. seives
12 h, rt
E
2
t
,
C
e
33% HBr-
AcOH, rt.
2h, 100%
H
n
o
2
C
r
l
°
-
a
c
C
t
H
3
i
o
n
C
N
(
no reaction
1
:
1
)
OAc
O
5, Cs2CO3, DMF, 12 h, rt.
AcO
AcO
3
no reaction
AcO
Br
8
Scheme 1: (a) Synthesis of 2,4-dinitrobenzenesulfonamide (5). (b) Alternative route explored
to access glycosyl sulfonamide 3.
a
c
O
O
b
O
O
N3
N3
N3
NH2
AcO
HO
BzO
BzO
NO2
e
d
H
H
O
S
O
O
N
N
NO2
BzO
BzO
O
O
Scheme 2: Synthetic route to access β-glycosyl amides from per-O-acetylated β-D- glucosyl,
-galactosyl, -arabinosyl, -mannosyl, and -maltosyl azide. Reagents and conditions: (a)
NaOMe, 1 h, rt. (b) BzCl, pyridine, 12–14 h, 0◦C–rt, (87–93% over two steps). (c) PtO2, H2,
EtOAc, 1.5 h, rt. (d) dNBS-Cl, pyridine, DMAP (cat.), 30–60 min, rt, (43–48% over two steps). (e)
Thioacetic acid, Cs2CO3, DMF, 20–30 min, rt, (67–81%).

Synthesis of β-Glycosyl Amides
359
Table 3: Synthesis of per-O-benzoylated glycosyl azides from per-O-acetylated
glycosyl azides
O
1. NaOMe, MeOH, rt
O
N3
N3
BzO
°
AcO
2. BzCl, Py, 0 C - rt
Peracetate
Perbenzoate
Time in h (Step) Yield
1
(1) 1.5
(2) 14.5
(1) 98%
(2) 93%
OBz
O
BzO
BzO
N3
BzO
12
2
(1) 1.5
(2) 14.0
(1) 98%
(2) 92%
OBz
BzO
O
N3
BzO
BzO
13
(1) 1.0
(2) 15.0
(1) 100%
(2) 89%
OAc
OBz
OAc
O
OBz
O
AcO
AcO
BzO
BzO
N3
N3
N3
N3
9
14
(1) 1.0
(2) 14.0
(1) 100%
(2) 92%
OAc
O
OBz
O
AcO
BzO
AcO
BzO
10
15
(1) 1.5
(2) 14.5
(1) 98%
(2) 87%
OBz
O
OAc
O
OBz
O
OAc
O
BzO
BzO
AcO
AcO
BzO
AcO
O
O
N3
N3
BzO
AcO
BzO
AcO
11
16
then be combined with a thioacid and the yield, reaction time, and propen-
sity for anomerization determined. The overall reaction sequence is shown in
Scheme 2. Thus, β-glycosyl azides 14, 15, and 16 were treated with PtO2-H2
to form the corresponding glycosylamines followed by treatment with dNBS-
Cl in pyridine with catalytic DMAP to form the sulfonamides 19, 20, and 21,

V. Gaitonde and S.J. Sucheck
360
Table 4: Formation of N-dNBS glycoside from per-O-benzoylated glycosyl azide
1. PtO2, EtOAc
O
H
O
H2, rt
N
dNBS
N3
BzO
BzO
2. dNBS-Cl, Py
DMAP, N2, rt
Perbenzoate
N-dNBS glycoside
Time in h (Step)
Yield
12
(1) 1.5
(2) 1.0
(1) 98%
(2) 44%
OBz
O
BzO
17
H
BzO
BzO
N
dNBS
13
14
(1) 1.5
(2) 1.0
(1) 98%
(2) 48%
OBz
BzO
BzO
O
H
N
dNBS
BzO
18
(1) 2.0
(1) 100%
(2) 45%
OBz
OBz
O
(2) 0.75
H
BzO
BzO
N
dNBS
dNBS
19
15
16
(1) 1.0
(2) 0.5
(1) 97%
(2) 45%
OBz
O
H
N
BzO
BzO
20
OBz
O
(1) 1.5
(2) 1.5
(1) 98%
(2) 43%
OBz
O
BzO
BzO
H
BzO
O
N
dNBS
BzO
BzO
21
respectively, in 43% to 45% yields (Table 4). β-Glycosyl sulfonamides 17–21
reacted smoothly with thioacetic acid in the presence of Cs2CO3 to generate
β-glucosyl amides 22–26, respectively, in 67% to 81% yields. Reactions were
complete in 20 to 30 min (Table 5), and the β-anomers appeared to be the ex-
3
3
clusive products. Coupling constants for the JH-1,H-2 and JH-1,NH for 23–26

Synthesis of β-Glycosyl Amides
361
Table 5: Formation of per-O-benzoylated glycosylamides from per-O-benzoylated
glycosyl sulfonamide
O
SH
O
O
H
Cs2CO3, DMF, rt
20-30 mins
H
N
N
dNBS
BzO
BzO
O
N-dNBS glycoside
N-glycosylamide
Yield
67%
17
OBz
O
BzO
22
H
BzO
BzO
N
O
18
68%
OBz
BzO
BzO
O
H
N
BzO
O
23
19
20
81%
73%
OBz
OBz
O
H
BzO
BzO
N
O
O
24
OBz
O
H
N
BzO
BzO
25
21
67%
OBz
O
OBz
BzO
BzO
H
BzO
O
O
N
BzO
BzO
O
26

V. Gaitonde and S.J. Sucheck
362
were in the range of 9.0 to 9.6 Hz, with the H-1 signals all appearing as appar-
3
3
ent triplets. The coupling constants for JH-1,H-2 and JH-1,NH in the known β-
glycosyl amides, such as 1-acetamido-1-deoxy-2,3,4,6-tetraacetyl-β-D-glucose,
are also in the range of 9.0 Hz, with H-1 appearing as an apparent triplet.[33]
On the other hand, the coupling pattern of H-1 in α-glycosyl amides usually ap-
pears as a doublet of doublets in compounds with H-2 in the axial position.[34]
In conclusion, we have shown that
a variety of β-glycosyl-2,4-
dinitrobenzenesulfonamides can be accessed in moderate yields from the
benzoyl-protected β-glycosyl azides. Some mutarotation of the glycosylamine
during the conversion from per-O-acetylated glycosyl azide compounds
to glycosyl-2,4-dinitrobenzenesulfonamides (∼5–10%) was usually observed.
While considerable effort was required to manipulate the starting sugars into
the β-glycosyl-sulfonamides, it is likely that more direct routes to these in-
termediates can be developed, which would improve the utility of the strat-
egy. The electron-deficient sulfonamides reacted with thioacetic acid, rapidly,
in good yield, and in high stereoselectively. Furthermore, it is likely that
the β-glycosyl-2,4-dinitrobenzenesulfonamides behave similarly to N-alkyl 2,4-
dinitrobenzenesulfonamides, which suggests they could be used to access sec-
ondary glycosylamides, thioamides, ureas, thioureas, and potentially even
guanidinium derivatives. Examples of these reactions would further expand
the usefulness of glycosyl-2,4-dinitrobenzenesulfonamides.
EXPERIMENTAL
General Methods
The starting sugars D-glucose, D-galactose, D-mannose, D-arabinose, and D-
maltose and other fine chemicals were purchased from Acros Organics. Boron
trifluoride diethyl etherate was from Sigma-Aldrich. The chemicals were used
without further purification. All solvents were obtained from Fisher Scientific
Co. Dichloromethane was dried and distilled following the standard proce-
dures, while pyridine, dimethyl, sulfoxide, and dimethylformamide were stored
´
˚
over 4 A molecular sieves. Silica (230–400 mesh) for flash column chromatog-
raphy was obtained from Sorbent Technologies; precoated plates for thin-layer
chromatography (TLC) were from E. Merck. TLCs (Silica Gel 60, F254) were vi-
sualized under UV light by charring (5% H2SO4–MeOH) or by use of a ninhy-
drin solution. Flash column chromatography was performed on 230–400 mesh
1
silica gel using solvents as received. H NMR spectra were recorded either on
a Varian VXRS 400 MHz or an INOVA 600 MHz spectrometer in CDCl3 using
residual CHCl3 as an internal reference. 13C NMR spectra were recorded at
1
100 or 150 MHz in CDCl3 using the triplet centered at δ 77.0. H-1H gCOSY

Synthesis of β-Glycosyl Amides
363
was performed on a 600 MHz spectrometer. High-resolution mass spectrome-
try (HRMS) was performed on an ESI-TOF mass spectrometer for m/z < 1000;
for m/z > 1000 MALDI-TOF data was obtained.
General Procedures
Synthesis of 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl azide (12), 2,3,4,
6-tetra-O-benzoyl-β-D-galactopyranosyl azide (13), 2,3,4,6-tetra-
O-benzoyl-β-D-mannopyranosyl azide (14), 2,3,4-tri-O-benzoyl-β-D-
arabinopyranosyl azide (15), and 2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-hepta-O-benzoyl-β-
maltosyl azide (16)
The starting materials 2,3,4,6-tetra-O-acetyl-β-D-glucosyl azide,[27]
2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl azide,[27] 2,3,4-tri-O-acetyl-β-D-
arabinopyranosyl azide,[27] and 2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-hepta-O-acetyl-β-maltosyl
azide[27] were all prepared from a known literature procedure. The 2,3,4,6-
tetra-O-acetyl-β-D-mannopyranosyl azide could not be prepared in our hands
using reference 27; however, we could access the known compound starting
from the glycosyl chloride followed by displacement with tetrabutylammonium
azide.[35] Once in hand, 2.0 g of the respective per-O-acetylated-β-glycosyl
azides was dissolved in 15 mL anhydrous methanol in a round-bottom flask
and stirred until complete dissolution under nitrogen atmosphere. A cat-
alytic amount of sodium metal (ca. 25 mg) was added to the flask and the
solution was allowed to stir for about 1 h. The completion of the reaction
was monitored using TLC. On completion the solution was neutralized with
Amberlite IR 120 H resin. The resin was filtered and rinsed with additional
methanol followed by concentration of the filtrate to dryness on a rotary
evaporator under reduced pressure. The products were dried under high
vacuum and used in the next step without further purification. The polyols
were dissolved in 10 mL of anhydrous pyridine under N2 atmosphere and
cooled to 0◦C. Benzoyl chloride (1.5 equiv. per OH) was added dropwise
to the stirred solution. After addition of benzoyl chloride was complete, the
reaction mixtures were brought to rt and stirred for a time respective to
each compound (Table 3). Completion of the reactions was monitored by TLC.
After completion, 2 to 3 mL methanol was added to quench residual benzoyl
chloride. The solutions were diluted with toluene, evaporated to dryness, and
purified by flash column chromatography on silica gel using 20% ethyl acetate
in toluene as an eluent. The 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl azide
(12),[36,37] 2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl azide (13),[38] and
2,3,4,6-tetra-O-benzoyl-β-D-mannopyranosyl azide (14)[37] are reported.

V. Gaitonde and S.J. Sucheck
364
Synthesis of N-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-2,4-
dinitrobenzenesulfonamide (17), N-(2,3,4,6-tetra-O-benzoyl-β-
D-galactopyranosyl)-2,4-dinitrobenzenesulfonamide (18), N-(2,3,4,6-tetra-
O-benzoyl-β-D-mannopyranosyl)-2,4-dinitrobenzenesulfonamide (19),
N-(2,3,4-tri-O-benzoyl-β-D-arabinopyranosyl)-2,4-
dinitrobenzenesulfonamide (20), and
N-(2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-hepta-O-benzyl-β-maltosyl)-2,4-
dinitrobenzenesulfonamide (21)
Per-O-benzoylated-β-glycosyl azide, 1.5 g, was dissolved in 10 mL of an-
hydrous ethyl acetate and transferred to a reaction flask containing platinum
oxide (0.17 equiv.). The solution was placed under 1 atm of H2 atmosphere
and allowed to stir according to the respective times shown in Table 4. Com-
pletion of the reaction was monitored by TLC. The reaction was worked up
by filtering through a bed of Celite 545 in a sintered glass funnel. The fil-
trate was concentrated by rotatory evaporation under reduced pressure. The
concentrated glycosyl amines were used in the sulfonation without further
purification. Crude per-O-benzoylated-β-glycosylamine was dissolved in 15 mL
of anhydrous pyridine with a catalytic amount of DMAP under an N2 atmo-
sphere. 2,4-Dinitrobenzenesulfonyl chloride (1.5 equiv.) was added to the solu-
tion and the reaction was allowed to stir for the respective time as shown in
Table 4. Completion of the reaction was monitored with TLC. The reaction was
worked up by diluting with 50 mL of ice-cold water and followed by extraction
with 3 × 50 mL portions of ethyl acetate. The organic layers were combined and
washed successively with saturated NaHCO3 and brine. It was dried over an-
hydrous Na2SO4. The solution was concentrated by rotatory evaporation under
reduced pressure. The products were purified by flash column chromatography
using silica gel using 25% acetone in hexanes as an eluent.
Synthesis of N-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl) acetamide (22),
N-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl) acetamide (23),
N-(2,3,4,6-tetra-O-benzoyl-β-D-mannopyranosyl) acetamide (24),
N-(2,3,4-tri-O-benzoyl-β-D-arabinopyranosyl) acetamide (25), and
N-(2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-hepta-O-benzoyl-β-maltosyl) acetamide (26)
To a suspension of cesium carbonate (2 equiv.) in 10 mL of anhydrous
DMF was added thioacetic acid (2 equiv.). The mixture was stirred for 10 min
at rt under N2 atmosphere before addition of 300 mg of N-glycosyl 2,4-
dinitrobenzenesulfonamide. The resulting solution was further stirred for the
time given in Table 5. Completion of the reaction was monitored by TLC.
After completion, the reaction was worked up by diluting with EtOAc and
washing the organic layer with saturated aqueous NH4Cl followed by brine.
The organic layer was dried over anhydrous Na2SO4 and concentrated under

Synthesis of β-Glycosyl Amides
365
reduced pressure by rotatory evaporator. The product was purified by flash
column chromatography on silica gel using 30% acetone in hexanes as an elu-
ent. The physical data for N-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl) ac-
etamide (22) matches the previously reported data.[15]
Spectral Data
1H NMR and 13C NMR spectra for known compounds matched the data
reported in the cited references. Data for new compounds are reported below.
2,3,4-Tri-O-benzoyl-β-D-arabinopyranosyl azide (15)
Colorless solid. 1H NMR (600 MHz, CDCl3): δ 8.14–7.27 (m, 15H, aromatic),
5.74 (m, 1H, H-4), 5.72 (s, 1H, H-3), 5.64 (dd, 1H, J = 3.6 Hz, 9.6 Hz, H-2), 4.97
(d, 1H, J = 6.0 Hz, H-1), 4.42 (dd, 1H, J = 3.0 Hz, 13.2 Hz, H-5), 4.03 (d, 1H,
J = 13.2 Hz, H-5ꢁ). 13C NMR (100 MHz, CDCl3): δ 165.7–165.38 (3C, carbonyl),
133.9–128.61 (18C, aromatic), 88.28 (1C, C-1), 70.9–65.59 (4C, ring carbon).
HRMS: m/z [M+Na]+ calcd for C26H21N3O7Na is 510.1277, found 510.1290.
2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-Hepta-O-benzoyl-β-maltosyl azide (16)
Colorless solid. 1H NMR (600 MHz, CDCl3): δ 8.11–7.16 (m, 35H, aromatic),
6.08 (t, 1H, J = 9.9 Hz, H-3ꢁ), 5.78 (t, 1H, J = 9.3 Hz, H-3), 5.75 (d, 1H, J =
4.2 Hz, H-1’), 5.66 (t, 1H, J = 9.9 Hz, H-4ꢁ), 5.27 (dd, 1H, J = 8.7 Hz, 9.3 Hz,
H-2), 5.24 (dd, 1H, J = 3.9Hz, 10.5 Hz, H-2ꢁ), 4.94 (dd, 1H, J = 2.1 Hz, 12.3 Hz,
H-6b), 4.91 (d, 1H, J = 8.4 Hz, H-1), 4.77 (dd, 1H, J = 3.9 Hz, 12.3 Hz, H-6a),
4.51 (t, 1H, J = 9.3 Hz, H-4), 4.45 (m, 1H, H-5ꢁ), 4.40 (dd, 1H, J = 3.0 Hz,
12.0 Hz, H-6ꢁa), 4.27 (dd, 1H, J = 3.6 Hz, 12.0 Hz, H-6ꢁb), 4.18 (m, 1H, H-5). 13
C
NMR (100 MHz, CDCl3): δ 166.31–165.09 (7C, carbonyl), 133.75–125.48 (42C,
aromatic), 96.67 (1C, C-1’), 88.06 (1C, C-1), 75.15–62.65 (10C, ring carbon).
MALDI: m/z [M+Na]+ calcd for C61H49N3O17 is 1095.31, found 1118.341.
N-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-2,4-
dinitrobenzenesulfonamide (17)
1
Yellow solid. H NMR (600 MHz, CDCl3): δ 8.40–7.23 (m, 23H, aromatic),
6.02 (t, 1H, J = 9.6 Hz, H-3), 5.64 (t, 1H, J = 9.9 Hz, H-4), 5.46 (t, 1H, J =
9.3 Hz, H-2), 5.29 (d, 1H, J = 9.0 Hz, H-1), 4.48 (d, 1H, J = 9.6 Hz, H-6ꢁ),
4.23–4.19 (m, 2H, H-5, H-6). 13C NMR (100 MHz, CDCl3): δ 166.23–165.21 (4C,
carbonyl), 149.76–120.81 (30C, aromatic), 83.81 (1C, C-1), 74.24–62.10 (5C,
ring carbon). HRMS: m/z [M+Na]+ calcd for C40H31N3O15SNa is 848.1374,
found 848.1343.

V. Gaitonde and S.J. Sucheck
366
N-(2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl)-2,4-
dinitrobenzenesulfonamide (18)
1
Yellow solid. H NMR (600 MHz, CDCl3): δ 8.38–7.21 (m, 23H, aromatic),
6.89 (d, 1H, J = 9.6 Hz, NH), 6.00 (d, 1H, J = 3.6 Hz, H-4), 5.79 (dd, 1H, J =
3.0 Hz, 10.2 Hz, H-3), 5.72 (t, 1H, J = 9.6 Hz, H-2), 5.27 (d, 1H, J = 9.0 Hz, H-
1), 4.46 (m, 1H, H-5), 4.28 (dd, 1H, J = 2.7 Hz, 9.3 Hz, H-6), 4.12 (dd, 1H, J =
7.2 Hz, 14.4 Hz, H-6ꢁ). 13C NMR (100 MHz, CDCl3): δ 166.22–165.48 (4C, car-
bonyl), 149.60–120.77 (30C, aromatic), 84.03 (1C, C-1), 73.63–60.62 (5C, ring
carbon). HRMS: m/z [M+Na]+ calcd for C40H31N3O15SNa is 848.1374, found
848.1349.
N-(2,3,4,6-Tetra-O-benzoyl-β-D-mannopyranosyl)-2,4-
dinitrobenzenesulfonamide (19)
1
Yellow solid. H NMR (600 MHz, CDCl3): δ 8.57–7.27 (m, 23H, aromatic),
6.85 (d, 1H, J = 9.6 Hz, NH), 5.98 (s, 1H, H-2), 5.94 (t, 1H, J = 10.2 Hz, H-4),
5.67 (t, 1H, J = 10.2 Hz, H-3), 5.53 (d, 1H, J = 10.2 Hz, H-1), 4.43 (d, 1H, J =
12.0 Hz, H-6), 4.08 (d, 1H, J = 8.4 Hz, H-5), 3.99 (d, 1H, J = 11.4 Hz, H-6ꢁ).
13C NMR (100 MHz, CDCl3): δ 165.57–165.31 (4C, carbonyl), 150.13–121.28
(30C, aromatic), 81.46 (1C, C-1), 74.10–61.21 (5C, ring carbon). HRMS: m/z
[M+Na]+ calcd for C40H31N3O15SNa is 848.1374, found 848.1364.
N-(2,3,4-Tri-O-benzoyl-β-D-arabinopyranosyl)-2,4-
dinitrobenzenesulfonamide (20)
1
Pale yellow solid. H NMR (600 MHz, CDCl3): δ 8.40–7.25 (m, 18H, aro-
matic), 6.98 (s, 1H, NH), 5.72 (s, 1H, H-3), 5.71 (s, 1H, H-2), 5.68 (s, 1H, H-4),
5.10 (d, 1H, J = 6.6 Hz, H-1), 4.18 (d, 1H, J = 13.8 Hz, H-5), 3.95 (d, 1H, J
= 13.8 Hz, H-5ꢁ). 13C NMR (100 MHz, CDCl3): δ 165.9–165.54 (3C, carbonyl),
149.7–120.85 (24C, aromatic), 84.34 (1C, C-1), 71.02–66.34 (4C, ring carbon).
HRMS: m/z [M+Na]+ calcd for C32H25N3O13SNa is 714.1006, found 714.1006.
N-(2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-Hepta-O-benzoyl-β-maltosyl)-2,4-dinitrobenzenesulfonamide
(21)
1
Yellow solid. H NMR (600 MHz, CDCl3): δ 8.37–7.17 (m, 38H, aromatic),
6.85 (s, 1H, NH), 6.06 (t, 1H, J = 10.2 Hz, H-3ꢁ), 5.86 (t, 1H, J = 9.3 Hz, H-
3), 5.76 (d, 1H, J = 3.6 Hz, H-1’), 5.65 (t, 1H, J = 9.9 Hz, H-4ꢁ), 5.24 (d, 1H,
J = 3.6 Hz, H-2ꢁ), 5.23 (d, 1H, J = 4.2 Hz, H-2), 5.19 (d, 1H, J = 6.6 Hz, H-
1), 4.71 (d, 1H, J = 10.8 Hz, H-6a), 4.49 (dd, 1H, J = 3.3 Hz, 12.3 Hz, H-6b),
4.45 (dd, 1H, J = 3.0 Hz, 12.0 Hz, H-6ꢁb), 4.39 (m, 2H, H-5ꢁ, H-4), 4.27 (dd, 1H,
J = 3.6 Hz, 12.0 Hz, H-6ꢁa), 4.07 (m, 1H, H-5). 13C NMR (100 MHz, CDCl3): δ
166.29–164.97 (7C, carbonyl), 149.77–120.82 (48C, aromatic), 96.76 (1C, C-1’),
83.43 (1C, C-1), 74.89–62.34 (10C, ring carbons). MALDI: m/z [M+Na]+ calcd
for C67H53N3O23SNa is 1322.269, found 1322.237.

Synthesis of β-Glycosyl Amides
367
N-(2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl) acetamide (23)
1
Pale yellow solid. H NMR (600 MHz, CDCl3): δ 8.08–7.23 (m, 20H, aro-
matic), 6.65 (d, 1H, J = 8.4 Hz, NH), 6.05 (m, 1H, H-4), 5.81 (dd, 1H, J = 3.3 Hz,
9.9 Hz, H-3), 5.65 (t, 1H, J = 9.9 Hz, H-2), 5.60 (t, 1H, J = 9.0 Hz, H-1), 4.63 (dd,
1H, J = 6.6 Hz, 10.8 Hz, H-6), 4.48 (t, 1H, J = 13.2 Hz, H-5), 4.39 (dd, 1H, J =
6.9 Hz, 11.1 Hz, H-6ꢁ), 1.99 (s, 1H, -CH3). 13C NMR (100 MHz, CDCl3): δ 170.59
(1C, amide carbonyl), 167.26–165.54 (4C, carbonyl), 134.10–128.50 (m, 24C,
aromatic), 79.09 (1C, C-1), 73.12–62.07 (5C, ring carbon), 23.64 (1C, -CH3).
HRMS: m/z [M+Na]+ calcd for C36H31NO10Na is 660.1846, found 660.1862.
N-(2,3,4,6-Tetra-O-benzoyl-β-D-mannopyranosyl) acetamide (24)
1
Pale yellow solid. H NMR (600 MHz, CDCl3): δ 8.14–7.24 (m, 20H, aro-
matic), 6.42 (d, 1H, J = 9.6 Hz, NH), 6.08 (t, 1H, J = 10.2 Hz, H-4), 5.86
(d, 1H, J = 9.6 Hz, H-1), 5.85 (d, 1H, J = 2.4 Hz, H-2), 5.68 (dd, 1H, J =
3.0 Hz, 10.2 Hz, H-3), 4.72 (dd, 1H, J = 2.1 Hz, 12.3 Hz, H-6ꢁ), 4.47 (dd,
1H, J = 3.9 Hz, 12.3 Hz, H-6), 4.26 (m, 1H, H-5), 1.99 (s, 1H, CH3). 13C
NMR (100 MHz, CDCl3): δ 169.59 (1C, amide carbonyl), 166.27–165.46 (4C,
carbonyl), 134.11–128.49 (m, 24C, aromatic), 76.59 (1C, C-1), 74.28–62.86 (5C,
ring carbon), 23.54 (1C, CH3). HRMS: m/z [M+Na]+ calcd for C36H31NO10Na
is 660.1846, found 660.1829.
N-(2,3,4-Tri-O-benzoyl-β-D-arabinopyranosyl) acetamide (25)
1
Pale yellow solid. H NMR (600 MHz, CDCl3): δ 8.09–7.26 (m, 15H, aro-
matic), 6.75 (d, 1H, J = 9.6 Hz, NH), 5.77 (d, 1H, J = 3.6 Hz, H-3), 5.75 (s,
1H, H-4), 5.68 (t, 1H, J = 9.3 Hz, H-2), 5.47 (t, 1H, J = 9.0 Hz, H-1), 4.27
(d, 1H, J = 13.2 Hz, H-5equatorial), 4.05 (d, 1H, J = 13.8 Hz, H-5axial), 1.98
(s, 1H, CH3). 13C NMR (100 MHz, CDCl3): δ 170.76 (1C, amide carbonyl),
167.2–165.5 (3C, carbonyl), 134.01–128.51 (18C, aromatic), 79.38 (1C, C-1),
71.5–66.4 (4C, ring carbon), 23.7 (1C, -CH3). HRMS: m/z [M+Na]+ calcd for
C28H25NO8Na is 526.1478, found 526.1495.
N-(2,3,6,2ꢁ,3ꢁ,4ꢁ,6ꢁ-Hepta-O-benzoyl-β-maltosyl) acetamide (26)
1
Yellow solid. H NMR (600 MHz, CDCl3): δ 8.10–7.18 (m, 35H, aromatic),
6.49 (d, 1H, J = 9.0 Hz, NH), 6.07 (t, 1H, J = 10.2 Hz, H-3ꢁ), 5.91 (t, 1H, J =
9.3 Hz, H-3), 5.75 (d, 1H, J = 3.0 Hz, H-1’), 5.66 (t, 1H, J = 9.6 Hz, H-4ꢁ),
5.52 (t, 1H, J = 9.3 Hz, H-1), 5.25 (dd, 1H, J = 3.0 Hz, 10.2 Hz, H-2ꢁ), 5.18
(t, 1H, J = 9.6 Hz, H-2), 4.88 (d, 1H, J = 12.0 Hz, H-6a), 4.75 (d, 1H, J =
9.6 Hz, H-6b), 4.50 (t, 1H, J = 9.3 Hz, H-4), 4.38 (m, 2H, H-5ꢁ, H-6ꢁb), 4.20 (m,
2H, H-5, H-6ꢁa). 13C NMR (100 MHz, CDCl3): δ 170.54–164.95 (7C, carbonyl),
133.96–128.23 (42C, aromatic), 96.51 (1C, C-1’), 78.48 (1C, C-1), 75.09–62.53
(10C, ring carbon). MALDI: m/z [M+Na]+ calcd for C63H53NO18 is 1111.33,
found 1134.305.

V. Gaitonde and S.J. Sucheck
368
ACKNOWLEDGMENTS
This work was supported in part by a grant to SJS by the National Institutes
of Health (GM094734).
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