α:β Selectivity in the synthesis of 3-substituted, 4-methyl umbelliferone glycosides of N-acetyl glucosamine and chitobiose

Article abstract of DOI:10.1016/j.tetasy.2004.11.053

The influence of phenolic acceptor nucleophilicity; for example, 3-substituted, 4-methylumbelliferones, and glycosyl donor electrophilicity; for example, 3- and 4-substituted N-acetylglucosamines, on glycosylation stereochemistry has been evaluated. In a systematic comparison, the stereochemical outcome as well as the reaction yield appeared to be influenced by the 3- and 4-substituents of the donor as well as the 3-substituent of the aryl acceptor. In the context of synthesizing a fluorogenic substrate for oligosaccharyltransferase, an α-glycoside was desired. Although most acceptor-donor pairs led to predominantly or exclusively the β-glycoside, reaction of the most activated (3,4-di-O-benzyl) donor and the least nucleophilic acceptor (3-Br), resulted in a 1:1 ratio of α,β arylglycosides.

Full text of DOI:10.1016/j.tetasy.2004.11.053

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 411–424
a:b Selectivity in the synthesis of 3-substituted, 4-methyl
umbelliferone glycosides of N-acetyl glucosamine and chitobiose
Anjali R. S. Ganguli and James K. Coward*
Departments of Medicinal Chemistry and Chemistry, The University of Michigan, Ann Arbor, MI 48109-1055, USA
Received 8 November 2004;accepted 19 November 2004
Available online 11 January 2005
Abstract—The influence of phenolic acceptor nucleophilicity;for example, 3-substituted, 4-methylumbelliferones, and glycosyl
donor electrophilicity;for example, 3- and 4-substituted N-acetylglucosamines, on glycosylation stereochemistry has been evaluated.
In a systematic comparison, the stereochemical outcome as well as the reaction yield appeared to be influenced by the 3- and 4-sub-
stituents of the donor as well as the 3-substituent of the aryl acceptor. In the context of synthesizing a fluorogenic substrate for
oligosaccharyltransferase, an a-glycoside was desired. Although most acceptor–donor pairs led to predominantly or exclusively
the b-glycoside, reaction of the most activated (3,4-di-O-benzyl) donor and the least nucleophilic acceptor (3-Br), resulted in a
1:1 ratio of a,b arylglycosides.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
chitin polymers.1,8–10 Though this route produces the
desired product efficiently, it is limited to the synthesis
of b-glycosides. The donor used in the OST-catalyzed
reaction contains an a-linked leaving group, requiring
the corresponding fluorescent leaving group also to have
the same a-stereochemistry. Very little precedent exists
for the synthesis of 1,2-cis-phenolic 2-deoxy-2-acetam-
ido glycosides, and the methods currently available
result in very low yields.11–15 This communication
presents the results of studies on the synthesis of 4-
MU glycosides of N-acetyl glucosamine (GlcNAc) as
well as the b-1!3 and b-1!4 GlcNAc disaccharides.
One of the most sensitive methods of monitoring the
progress of enzymatic reactions is by the use of a contin-
uous fluorescent assay. In an effort to develop such an
assay for use in studies of oligosaccharyltransferase
(OST, EC 2.4.2.119) activity, we explored the insertion
of a fluorescent leaving group to replace the naturally
occurring pyrophosphate leaving group of the donor
substrate, 1 (Fig. 1). Currently, glycosides of 4-methyl-
umbelliferone (4-MU, 7-hydroxy-4-methyl coumarin)
are commonly used as fluorogenic substrates to study
a wide variety of glycosidases including chitinase.1–5
Molecular modeling (INSIGHT II) indicated that deriva-
tives of 4-MU, such as 2, containing a 3-polyprenyl sub-
stituent, for example, dolichyl (C95),6 or undecaprenyl
(C55),7 could serve as a neutral, isosteric leaving group
and allow for development of a continuous fluorescence
assay of OST activity.
2. Results
Three key transformations are required for the success-
ful synthesis of chitobiose 4-MU-lipid, 2: (1) formation
of the disaccharide linkage, (2) formation of the a-(4-
MU)-glycoside, and (3) attachment of the lipid to the
umbelliferone ring (Fig. 1). It was initially unclear as
to the order that these bonds should be constructed
for optimal yield and stereoselectivity. Consequently,
we studied the chemistry and reactivity of model com-
pounds in order to design the appropriate synthetic
route. These investigations would indicate whether a
mono- or disaccharide should be used in the glycosyl-
ation reaction and when the lipid substituent at C-3
should be installed on the 4-MU core.
Chitin hydrolyzing enzymes act on b-glycosides, and
consequently the fluorogenic mono-, di-, and even tri-
saccharides have been obtained through an SN2 dis-
placement by the fluorogenic moiety of a readily
accessible a-halo glycoside, derived from hydrolysis of
*
Corresponding author. Tel.: +1 734 936 2843;fax: +1 734 647
4865;e-mail: jkcoward@umich.edu
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.053

412
A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
natural substrate
HO
HO
HO
O
O
HO
HO
O
O
O P
O-
O
P
AcNH
NHAc
O
O
(s)
n
O-
1
proposed chromogenic analogue
HO
n = 13-17
HO
HO
O
O
HO
HO
O
AcNH
O
NHAc
O
O
2
(s)
O
3
4
n
n
O
X
HO
HO
HO
HO
O
AcHN
O
HO
HO
O
Y
NHAc
(s)
LG
n
Figure 1.
Traditionally, the synthesis of any 1,2-cis-glycoside be-
gins by disguising the C-2 participatory group (such as
an amide, ester, carbamate, etc.) as a small, nonpartici-
pating moiety. For amides, the surrogate group is nor-
mally a C-2 azide since this substitution removes steric
hindrance on the a-face, increasing the possibility of
forming the 1,2-cis linkage, and is readily transformed
back into the amide in one step.16 There are two well-
known methods for installing an azide at C-2 on the
pyranose ring;either through azido-nitration of gly-
cals17,18 or via the anhydro sugar19,20 methodology.
The azido-nitration strategy allows for installation of
the azide in one step, however it does not incorporate
a means to discriminate between the C-3 and C-4 posi-
tions and requires extensive protecting group manipula-
tions subsequent to azide installation. In addition, this
method produces only low yields of the desired gluco
product, which is difficult to purify from a mixture of
gluco and manno isomers (Scheme 1).17,18
required for synthesizing a variety of mono- and
disaccharides. There are many additional benefits to
working with anhydro sugars. In particular, these sugars
are known to exhibit enhanced reactivity of the C-4 hy-
droxyl group over their unconstrained counterparts.24
Since the C-4 hydroxyl will serve as the acceptor in for-
mation of the b-1!4 disaccharide linkage of 2, any
improvement in reactivity is highly desirable. Although
the b-1!4 disaccharide, chitobiose, is readily available
via acid hydrolysis of chitin,1,8,9,25,26 use of 1,4-anhydro
sugars derived from isotopically enriched glucal 3b27,28
could permit installation of deuterium at C-1 of the
anhydro sugar, 4b, and lead ultimately to a C-1 deuter-
ated isotopomer of 2. This substitution would enable the
study of a-secondary kinetic isotope effects on glycosyl
transfer reactions (e.g., OST) using isotopically enriched
donor substrates.29
Therefore, we chose the anhydro method over the azido-
nitration method to access the azido sugar donors. The
synthetic route began with a one-step oxidative cycliza-
tion of glucal 3, into 1,6-anhydro-2-deoxy-2-iodo-b-D-
glucopyranose 5, using the method of Leteux and
Incorporation of an azide through the anhydro route
(Scheme 2) is more complicated but orients the pyranose
in a conformation that inherently distinguishes between
the C-3 and C-4 positions;the steric constraints are
much greater on the C-3 hydroxyl due to the acetal
and anhydro rings, as well as the C-6 CH2 group.21–23
The ability to distinguish between these positions re-
duces the number of protecting group manipulations
Veyrieres.19 The 2-iodo substituent is traditionally trans-
`
formed into the 2-azido sugar 4, through a one-pot dis-
placement reaction.20 However, purification of 4 from
the reaction mixture involves a lengthy continuous
extraction. Instead, we adapted a sequential method to
OAc
N3
OAc
OAc
O
OAc
O
CAN, NaN3
O
AcO
O
AcO
AcO
AcO
AcO
AcO
AcO
ONO2
AcO
N3
ONO2
CH3CN
N3
28%
ONO2
19%
29%
Scheme 1.

A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
413
4).21–23 Treatment of 7 with Ba(OH)2 and BnBr, after
the method first described by van Boeckel et al.,21 effects
stepwise migration of the TBS group from the hydroxyl
at C-4 to that at C-3, followed by benzylation of the C-4
hydroxyl (7!8). Desilylation (TBAF) of 8 provides 9,
containing a free hydroxyl group at C-3. Alternatively,
one can access the 4-hydroxyl regioisomers, 12 or 13,
from the same 4-OTBS molecule using less basic condi-
tions (BnBr, Ag2O (7!10) or Ac2O, pyridine (7!1132)
to prevent migration of the TBS group while protecting
the 3-hydroxyl. Subsequent desilylation with TBAF or
HF–pyridine then generates 12 and 13, respectively,
with a free hydroxyl group at C-4.
H
6
O
6
OH
O
OH
H
(3 steps, 63%)
4
5
1
HO
HO
O
5
1
X
4
3
2
3
X
2
OH
N3
a, X = 1
b, X = 2H
H
3
4
Scheme 2.
4 using known methods to first generate a 1,6:2,3-di-
anhydroglycopyranose, 6,30 and subsequently open the
epoxide with ammonium chloride and sodium azide to
yield 431 (Scheme 3). Though it involved an extra purifi-
cation step, the sequential method was preferable in our
hands because it produced a 2-azido product in higher
yields and purity.
This methodology provides stable, readily available, and
highly reactive glycosyl acceptor precursors to either a
1!3- or 1!4-linked disaccharide (vide infra). Mono-
saccharides 9, 12, and 13 were then either transformed
directly into the monosaccharide donors or elaborated
into disaccharide donor molecules, both of which can
be used to explore the stereochemistry of aryl glycoside
formation.
O
HO
1. (Bu3Sn)2O
2. I2
OH
O
O
HO
HO
CH3CN
70%
H
OH
I
5
3
To synthesize the disaccharides, 2-deoxy-2-(2,2,2-tri-
chloroethanoxycarbonylamino)glucopyranosyl bromide,
14, was chosen as the donor. The 2,2,2-trichloro-
ethanoxycarbonyl (Troc) group has recently gained
popularity in glycosylation reactions because, unlike
the 2-acetamido moiety, it can regioselectively direct
reactions without the formation of a formal dioxocarbe-
nium species.33 This property gives rise to the stereose-
lective formation of b-glycosides in high yields.34 The
Troc group is also favored because it can be easily and
selectively removed under very mild conditions (Zn–
HOAc) that do not affect most other protecting groups
used in carbohydrate chemistry.35 Coupling of the
acceptors with the N-Troc glycosyl bromide 14, pro-
ceeded efficiently using AgOTf as the promoter. Use of
4-O-benzyl 9 or 3-O-benzyl 12 acceptors, produced
1!3-15 and 1!4-16 disaccharides, respectively, in high
NaN3,
DMF, H2O
75%
NaHCO3
DMF, H2O
95%
O
O
NaN3, NH4Cl,
DMF, H2O
O
OH
O
O
OH
95%
OH
N3
6
4
Scheme 3.
As mentioned, one can readily distinguish between the
hydroxyl groups of 4 (C-3 vs C-4) and selectively form
a TBS ether 7, of the more accessible C-4 OH (Scheme
O
O
OTBS
O
OH
O
TBAF
90%
BnBr,
Ba(OH)2
OBn N3
OBn N3
8
9
90%
O
O
OH
O
OH
O
O
O
TBDSCl,
imidazole
OBn
O
OBn
O
BnBr, Ag2O
82 %
TBAF
78%
OH
N3
OTBS N3
82%
OTBS N3
OH
N3
7
4
10
12
Ac2O
pyridine
quant.
O
O
OAc
O
OAc
O
HF-pyridine
70%
OTBS N3
OH
N3
11
13
Scheme 4.

414
A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
O
O
OR
OH
O
O
OH
N3
OBn
N3
12, R = Bn
9
13, R = Ac
OAc
O
AcO
AcO
AgOTf
NH
AgOTf
Troc
Br
OAc
Troc
O
14
OR
O
O
O
O
OAc
O
AcO
AcO
O
NH
AcO
AcO
N3
O
N3
NH
OBn
Troc
15, (90%)
16, R = Bn (88%)
17, R = Ac (70%)
TFA, Ac2O
or
BF3 OEt2, Ac2O
TFA, Ac2O
or
3
BF OEt2, Ac2O
OAc
OAc
OAc
OAc
O
O
O
O
RO
O
AcO
AcO
AcO
AcO
O
RO
N3
NH
NH
OAc
N3
OAc
Troc
Troc
18, R = Bn (TFA, Ac2O; 87%)
20, R= Ac (BF3 OEt2, Ac2O; 83%)
19, R = Bn (TFA, Ac2O; 77% from 16)
21, R = Ac (BF3 OEt2, Ac2O; 85% from 16; 83% from 17)
Scheme 5.
yields (Scheme 5). Use of the 3-O-acetyl acceptor, 13,
resulted in somewhat lower yields of the disaccharide
product, 17, presumably due to the stronger electron-
withdrawing properties of the ester (O-acetyl) versus
ether (O-benzyl) protecting group at C-3;this effect
has considerable precedent in glycosylation reactivity
studies.36–41 After forming the disaccharide bond, the
anhydro ring could be opened by one of two methods.
TFA/Ac2O-mediated reaction (15!18 or 16!19) fur-
nished the disaccharide in high purity and in good yield,
but was quite slow and required 3 days for completion.
In contrast, the alternate method (BF3ÆOEt2, Ac2O) pro-
ceeded much faster, leading to anhydro sugar ring open-
ing in 20 min at 0 °C42 (15!20, 16, or 17!21);however,
partial conversion of the benzyl ether (15 or 16) to the
acetate ester (20 or 21) was observed. Complete removal
of the benzyl protecting group (15!20 or 16!21) re-
quired 15 h at 4 °C then 2 h at rt, but the prolonged
reaction time also caused 5–10% cleavage of the disac-
charide linkage.
O
OAc
OR1
O
O
R2O
TFA, Ac2O
R1O
OAs
N3
OR2
N3
9, R1 = H, R2 = Bn
12, R1 = Bn, R2 = H
22, R1= R2 = Bn
23, R1 = Bn, R2 = Ac
24, R1 = Ac, R2 = Bn
25, R1 = R2 = Bn
Scheme 6.
yl-2-azido-3,4-di-O-benzyl-a,b-D-glucopyranose, 25,20
from the diol precursor, 1,6-anhydro-2-deoxy-2-azido-
glucose 4, via the 3,4-dibenzyl anhydro sugar 2243
followed by TFA/Ac2O ring opening. Protection of the
sugar hydroxyl with electron-donating benzyl ethers
was desired because of the known rate-enhancing effect
of benzyl ethers on the reactivity of glycosyl
donors.37,38,40,44 These monosaccharides were investi-
gated for their ability to form 3-substituted, 4-MU gly-
cosides as potential precursors of 2.
The anhydro monosaccharides 9, 12, and 22 were simi-
larly transformed into the glycosyl acetates (Scheme
6). Starting from 4-O-benzyl-3-hydroxy-2-azido anhy-
dro sugar 9, or 3-O-benzyl-4-hydroxy-2-azido anhydro
sugar 12, TFA/Ac2O-mediated ring opening gave either
the 1,3,6-tri-O-acetyl-4-O-benzyl-2-azido-2-deoxy-a,b-
D-glucopyranose 2350 or 1,4,6-tri-O-acetyl-3-O-benzyl-
2-azido-2-deoxy-a,b-D-glucopyranose 24,20 respectively.
Unlike the slow reaction of the disaccharides, ring open-
ing of the monosaccharides proceeded overnight at
room temperature. One can also access the 1,6-di-O-acet-
In order to determine the optimal glycosylation partners
for the synthesis of various 3-substituted, 4-MU glyco-
sides of GlcNAc-containing disaccharides, three glyco-
syl acceptors, 4-MU 26, as well as the 3-ethyl, 27, and
3-bromo, 28, derivatives, were studied. Since the 4-
MU acceptor is a weak nucleophile (pKa = 7.8),45 it
was anticipated that enhanced reactivity of the glycosyl
donor would be necessary to achieve acceptable yields of
the 4-MU glycoside products. Conversely, a change in

A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
415
OAc
1. HBr, HOAc
OAc
O
2. AgOTf, CH2Cl2
sym-collidine
R2O
R1O
O
O
R2O
R1O
N3
O
O
X
N3
3.
HO
O
O
X
OAc
CH3
CH3
23, R1 = Bn, R2 = Ac
24, R1 = Ac, R2 = Bn
25, R1 = R2 = Bn
26, X = H
29, R1 = Bn, R2 = Ac, X = H
30, R1 = Bn, R2 = Ac, X = Et
31, R1 = Ac, R2 = Bn, X = H
32, R1 = Ac, R2 = Bn, X = Br
33, R1 = R2 = Bn, X = H
34, R1 = R2 = Bn, X = Br
35, R1 = R2 = Bn, X = Et
27, X = Et
28, X = Br
OAc
OAc
36, R1
37, R2
=
=
O
, R2 = Bn
, R1 = Bn,
18, R1
19, R2
=
=
, R2 = Bn,
, R1 = Bn,
O
X = H
X = H
AcO
AcO
AcO
AcO
NH
NH
Troc
Troc
Scheme 7.
Table 1. Effect of donor and acceptor structures on a:b selectivity
Saccharide Phenolic Glycoside a (%) b (%) Yield
nucleophilicity of the acceptor, due to the effect of C-3
substituents on the phenolic pKa,45 could affect the yield
and/or a:b selectivity of the glycosylation reaction. In
fact, this trend was observed within the monosaccharide
series used in the research reported herein. The ethyl
coumarin 27, was synthesized as described by Chakrav-
arti,46 and used as a model system to explore the effects
of an alkyl substituent at C-3 on glycosylation stereose-
lectivity in case attachment of the lipid at C-3 prior to
glycosylation was required. Bromination at C-3 of the
umbelliferone ring system to provide 28 was effected
using NBS.47 The bromo substituent at C-3 on the cou-
marin ring system should allow for lipid attachment
using transmetalation reactions (e.g., Suzuki cross-cou-
pling) subsequent to glycosylation.
donor
acceptor (X) product
(%)
Monosaccharides
23
24
25
23
25
24
25
26 (H)
29
31
33
30
35
32
34
0
0
100
100
83
64
54
77
43
58
64
50
26 (H)
26 (H)
27 (Et)
27 (Et)
28 (Br)
28 (Br)
17
0
100
91
9
44
59
56
41
Disaccharides
18
19
26 (H)
26 (H)
36
37
0
0
100
100
33
34
The ring-open disaccharides, 18–21, and monosacchar-
ides, 23–25 were transformed into the corresponding
1-bromo glycopyranosyl donors in quantitative yield
using HBr/HOAc. Subsequent glycosylation reactions
followed the approach developed by Crich et al. in their
efforts to prepare 1,2-cis-glycosides in the manno ser-
ies,48 namely in situ isomerization of the a-bromide to
the b-triflate, followed by glycosylation with the incom-
ing acceptor (Scheme 7). Unfortunately, this method did
not provide a satisfactory means to the desired 1,2-cis-
glycoside with our system. However, a profound influ-
ence of the protecting groups on the stereochemical out-
come of the glycosylation reaction was observed (Table
1). In the series using 4-MU, 26, as the glycosyl accep-
tor, only donor 25, containing two electron-donating
(benzyl) hydroxyl-protecting groups, produced any of
the desired 1,2-cis linkage. In the cases where even one
of these benzyl groups was replaced with an electron-
withdrawing (acetyl) group (23, 24), no 1,2-cis (a) link-
age was formed. The alkyl-substituted, 3-ethyl-4-MU
acceptor 27, showed slightly better selectivity over the
unsubstituted 4-MU acceptor with the di-O-benzyl
donor 25, although the undesired 1,2-trans product still
predominated. And not surprisingly, acceptor 27
showed the same selectivity as 26 with the mono-O-benz-
ylated donor 23, to give only the 1,2-trans product. In
contrast, when 3-bromo-4-MU 28, was the acceptor, in-
creased amounts of the 1,2-cis linkage was observed
with either the mono- or di-O-benzylated donors, 24
and 25, though neither gave stereoselective formation
of the 1,2-cis product.
These results suggest that decreasing the nucleophilicity
of the phenol acceptor through the incorporation of
electron-withdrawing substituents tends to favor forma-
tion of the desired a-linked product. Overall, substitu-
tions on both the glycosyl donors and acceptors exert
important influences over reaction reactivity and stereo-
selectivity.41,44 These results led to selection of glycosyl
bromide donors derived from the benzylated disacchar-
ides 18 and 19 rather than the less reactive acetylated
versions 20 and 21, to extend the investigation from
monosaccharides to disaccharides. However, as seen
previously with the monosaccharide donors, the
presence of only a single electron-donating group (3-
or 4-OBn) was not sufficient to produce any of the
1,2-cis-glycosylation product. Since the yields and
a-selectivity of the glycosylation reaction were very
poor with the unsubstituted 4-MU acceptor 26, attempts
to couple the disaccharide to 3-ethyl-4-MU 27, or
3-bromo-4-MU 28, were not pursued.

416
A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
3. Discussion
could be of great use in the development of continuous
fluorescence assays of previously uninvestigated glyco-
sidases and glycosyltransferases.
To develop an efficient method for synthesizing an aryl
glycoside cis to an amide, a nonparticipating group
was desired at C-2 as a surrogate for the NHAc group
found in 2-deoxy-2-acetamido sugars. An azide is a well
known nonparticipating amide surrogate16 because it
can be easily transformed to an acetamido group. There-
fore, synthesis of the fluorogenic compound 2, began
with formation of 1,6-anhydro-2-deoxy-2-azido-b-D-
glucopyranose 4, from glucal 3, by adapting established
literature procedures. Further elaboration of the anhy-
dro skeleton provided access to a variety of monosac-
charide synthons from which both 1!3 and 1!4
disaccharides were obtained.
4. Experimental
4.1. General methods
All air- and moisture-sensitive reactions were carried out
under nitrogen or argon using oven-dried glassware, and
distilled solvents (MeOH, Et3N, Pr2NH, and CH2Cl2
i
distilled from CaH2, THF distilled from Na–benzophe-
none). All flash column chromatography was carried
out using silica gel (40–60 lm, 230–400 mesh) as the sta-
tionary phase, and thin layer chromatography pre-
formed on Whatman 250 lm silica gel plates. All
NMR spectra were recorded on Bruker AVANCE
Masking the C-2-amide was, however, insufficient for
effecting a stereoselective synthesis of the desired 1,2-
cis linkage between the sugar donor and the fluorescent
4-MU acceptor. The systematic comparison of glycosyl-
ation efficiency performed for a variety of donors and
acceptors in this study has shown that effects of the sub-
stituents on the pyranose donor as well as the electronic
properties of the phenolic acceptor play influential roles
in governing the stereochemical outcome of the glycosyl-
ation reactions (Table 1). These effects have been dis-
cussed previously when comparing efficiencies of
carbohydrate donors and acceptors,36–41,44 and further
emphasize the importance of protecting group strategy
in the design and synthesis of complex carbohydrates.
The highest yield of an a-aryl glycoside was obtained
using the Crich activation method to link the 3-bromo
acceptor 28, with the 3,4-di-O-benzyl donor 25. In this
case, ca. 1:1 a:b mixture of GlcN3-O-(3-Br-4-MU) 34,
was obtained in 50% yield. This route could be useful
for isolating sufficient amounts of 34 to complete the
synthesis of the substrate analogue 2. The C-3 bromide
should provide a useful handle to direct alkylation of
the polyisoprene chain onto the umbelliferone ring to
complete the synthesis. Dasgupta and Masuda49
recently reported the isolation of a 3:2 a:b mixture of
glycosides when coupling 3,4,6-tri-O-acetyl-2-azido-2-
deoxy glucopyranosyl fluoride with 7-O-trimethylsilyl-
4-methylcoumarin (4-MU-OTMS). Taking their data
together with the data presented in this paper, it is evi-
dent that distal substituents as well as the nature of
the leaving group leading to the transient oxocarbenium
ion, at C-1 of the donor, strongly influence the stereo-
chemical outcome of the glycosylation reaction.
1
DRX300 or DRX500 spectrometers. H NMR spectra
were recorded at 300 or 500 MHz and are reported as
follows: chemical shifts in ppm downfield from inter-
nal tetramethylsilate (multiplicity, integrated intensity,
coupling constant in Hz). 13C NMR spectra were
obtained at 75 or 126 MHz and referenced to tetrameth-
ylsilane. 31P NMR spectra were recorded at 121 MHz
with 1% aqueous phosphoric acid as an external
reference. All 13C and 31P NMR spectra are
proton decoupled. MS data for chlorinated and
brominated compounds contain multiple peaks
correlated to the natural abundance ratios of the halo-
gen isotopes. Common reagent chemicals were pur-
chased from commercial sources. The following
carbohydrates were synthesized as described in the
literature;1,6-anhydro-2-deoxy-2-iodo- b-D-glucopyranose
5,19 1,6-anhydro-2-azido-2-deoxy-4-O-(tert-butyl-dimeth-
ylsilyl)-glucopyranose 7,21–23 1,6-anhydro-2-azido-2-
deoxy-4-O-benzyl-3-O-(tert-butyl-dimethylsilyl)-gluco-
pyranose 8,21 1,6-anhydro-2-azido-2-deoxy-4-O-benzyl-
glucopyranose 9,21 1,6-anhydro-3-O-acetyl-2-azido-2-
deoxy-4-O-(tert-butyl-dimethylsilyl)-glucopyranose 11,32
1,6-anhydro-3-O-acetyl-2-azido-2-deoxy-glucopyranose
13,32
oxycarbonylamino)-glycopyranosyl
3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroeth-
bromide
1434
1,6-anhydro-2-azido-2-deoxy-3,4-di-O-benzyl-b-D-gluco-
pyranose 22,20,43 1,3,6-tri-O-acetyl-2-azido-2-deoxy-4-
O-benzyl-b-D-glucopyranose 23,50 1,4,6-tri-O-acetyl-2-
azido-2-deoxy-3-O-benzyl-b-D-glucopyranose 24,20 1,6-
di-O-acetyl-2-azido-2-deoxy-3,4-di-O-benzyl-b-D-gluco-
pyranose 25,20 4-methylumbelliferone 26,46 and 3-ethyl-
4-methylumbelliferone 27.46
In conclusion, a systematic study of aryl glycoside for-
mation within a series of 3-substituted, 4-methyl-umbel-
liferone (4-MU) acceptors, and mono- and disaccharide
donors has led to conditions whereby one can synthesize
aryl glycosides of GlcNAc and chitobiose. The b-glyco-
side of both GlcNAc and chitobiose is favored in the
case of 4-MU acceptors with either H or an alkyl group
at the 3-position. In contrast, a 1:1 mixture of a,b glyco-
sides is obtained with a 3-Br-4-MU acceptor. Due to the
differential protection of the carbohydrate moieties of
the donors, the approach described herein allows for
the synthesis of complex GlcNAc-containing oligosac-
charides possessing a fluorescent leaving group that
4.2. 1,6-Anhydro-2-azido-2-deoxy-b-D-glucopyranose 4
O
OH
O
OH
N3
A heterogeneous solution of 1,6-anhydro-2-deoxy-2-
iodo-b-D-glucopyranose (3.47 g, 12.8 mmol) and
NaHCO3 (2.52 g, 30 mmol) in DMF–H2O (10:1) was
5

A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
417
O
heated to 120 °C. After 4 h, the reaction mixture was
OBn
O
cooled, concentrated (in vacuo) and subjected to chro-
matography (SiO2, EtOAc containing 0–10% MeOH)
to yield 1,6:2,3-di-anhydro-b-D-glucopyranose 6, in
quantitative yield (1.84 g, 12.8 mmol). 1H NMR
(CDCl3): d 3.13 (d, 1H, H-2, J2,1 = 3.3 Hz), 3.47 (dd,
1H, H-4, J4,3 = 2.7 Hz, J4,5 = 2.7 Hz), 3.68 (m, 2H, H-
3, H-6), 3.93 (d, 1H, H-6, J6,6 = 5.7 Hz), 4.44 (m, 1H,
H-5), 5.3 (d, 1H, OH, J = 6.3 Hz), 5.7 (d, 1H, H-1b,
J1b,2 = 2.7 Hz,). 13C NMR (CDCl3): d 49.5, 54.1, 65.6,
66.8, 75.9, 100.5. The di-anhydro sugar 6 (1.84 g,
12.8 mmol) was heated to reflux temperature in a 10:1
MeOH–H2O solution containing NaN3 (8.33 g,
128 mmol), and NH4Cl (5.14 g, 96 mmol). After 1H
NMR showed complete conversion to the azide 4
(4.5 days), the solution was cooled and concentrated
(in vacuo). Column chromatography yielded pure prod-
uct 4, as a reddish semi-solid (2.2 g, 92%). IR (cmÀ1):
OH
N3
ture. After 1.5 h, the reaction was concentrated (in
vacuo). Column chromatography (SiO2, 1.5:1 hexanes–
EtOAc–2% MeOH) yielded pure product 12 (40 mg,
1
78%) as a colorless oil. H NMR (CDCl3): d 3.52 (s,
1H, H-2), 3.67 (s, 1H, H-3), 3.81 (dd, 1H, H-6,
J6,5 = 7.6 Hz, J6,6 = 5.4 Hz), 3.90 (m, 2H, H-4, OH),
4.25 (dd, 1H, H-6, J6,5 = 1.4 Hz, J6,6 = 5.8 Hz), 4.64–
4.5 (m, 3H, H-5, CH2Ph), 5.51 (s, 1H, H-1b), 7.35 (m,
5H, Ph–H). 13C NMR (CDCl3): d 59.9, 65.5, 69.2,
72.9, 76.7, 78.4, 100.5, 128.1, 128.5, 129.0, 137.6. MS
(CI) m/z (%) 295.0 (100.0, (M+NH4)+). HRMS (CI)
calcd for C13O4N4H14 (M+NH4)+ 295.1406. Found
295.1400.
1
3428.1, 2113, 1263, 1050. H NMR (CDCl3): d 3.02 (s,
1H, H-2), 3.41 (s, 1H, H-4), 3.55 (m, 2H, H-3, H-6),
3.93 (d, 1H, H-6, J6,5 = 6.9 Hz), 4.43 (m, 1H, H-5),
5.28 (d, 1H, OH, J = 3.6 Hz), 5.38 (s, 1H, H-1b), 5.41
(d, 1H, OH, J = 4.2 Hz). 13C NMR (DMSO): d 100.7,
77.2, 72.4, 71.5, 65.8, 62.9.
4.5. 1,6-Anhydro-2-azido-4-O-benzyl-3-O-(3,4,6-tri-O-
acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-
b-D-glucopyranosyl)-2-deoxy-b-D-glucopyranose 15
4.3. 1,6-Anhydro-2-azido-2-deoxy-3-O-benzyl-4-O-(tert-
butyl-dimethylsilyl)-b-D-glucopyranose 10
OAc
O
O
AcO
AcO
O
O
NH
O
O
Cl3C
OBn
O
OBn
N3
O
OTBS
N
3
A solution of 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichlo-
roethoxycarbonylamino)-a-D-glucopyranosyl bromide
14 (0.35 g, 0.63 mmol), 1,6-anhydro-2-azido-2-deoxy-4-
O-benzyl-b-D-glucopyranose, 9 (0.125 g, 0.45 mmol)
Benzyl bromide (32 lL, 0.30 mmol) was added to a solu-
tion of 7, (75 mg, 0.25 mmol) and Ag2O (92 mg,
0.4 mmol) in DMF (2 mL) and stirred at room temper-
ature. After 15 h, the reaction mixture was filtered
through Celite (1:1 hexanes–EtOAc) diluted with
20 mL of 1:1 hexanes–EtOAc and 20 mL water and stir-
red vigorously for 45 min. The aqueous layer was re-
extracted with hexanes–EtOAc;and the pooled organic
layers were washed with water, satd aq NaHCO3, and
brine, then dried (Na2SO4), filtered, and concentrated
(in vacuo). Column chromatography (SiO2, 20:1 hex-
anes–EtOAc) afforded pure 10 (80 mg, 82%) as a color-
less oil. 1H NMR (CDCl3): d 0.16 (s, 6H, 2CH3), 0.93 (s,
9H, t-Bu–CH3), 3.13 (s, 1H, H-2), 3.67–3.77 (m, 3H, H-
3, H-6, H-4), 4.06 (d, 1H, H-6, J6,6 = 7.5 Hz), 4.47 (m,
1H, H-5), 4.7 (s, 2H, CH2Ph), 5.51 (s, 1H, H-1b) 7.30
(m, 5H, Ph–H). 13C NMR (CDCl3): d À4.5, À4.4,
26.1, 59.2, 65.5, 70.9, 72.7, 77.6, 79.6, 101.1, 128.2,
128.5, 128.9, 137.7. MS (ESI) m/z (%) 414.2 (100.0,
(M+Na)+). HRMS (ESI) calcd for C19O4N3H30SiNa
(M+Na)+ 414.1825. Found 414.1831.
˚
and 3 A molecular sieves (0.05 g) in freshly distilled
CH2Cl2 (8 mL) was stirred at room temperature for
15 min, then cooled to 0 °C. After 30 min, AgOTf
(0.231 g, 0.90 mmol) was added and the solution
warmed slowly to room temperature. After 15 h, the
reaction was filtered through Celite (CH2Cl2), washed
with water, satd aq NaHCO3, and brine, then dried
(Na2SO4), filtered, and concentrated (in vacuo) to ob-
tain the crude product. Column chromatography
(SiO2, 2:1 hexanes–EtOAc) afforded pure product, 15
1
(0.320 g, 90%) as a colorless oil. H NMR (CDCl3): d
2.01–2.04 (s, 9H, 3CH3), 3.10 (s, 1H, H-2), 3.56 (s, 1H,
H-3), 3.62–3.71 (m, 3H, H-4, H-50, H-20), 4.0 (m, 2H,
H-6, H-5), 4.12 (dd, 1H, H-60, J6 ,6 = 12.3 Hz,
0
0
J6 ,5 = 1.9 Hz), 4.23 (dd, 1H, H-60, J6 ,6 = 12.4 Hz,
0
0
0
0
0
J6 ,5 = 5 Hz), 4.62–4.83 (m, 6H, CH2Ph, TrocCH2,
0
H-10b, H-6), 5.07 (dd, 1H, H-40, J4 ,3 = 9.7 Hz,
0
0
J4 ,5 = 9.7 Hz), 5.20 (m, 2H, H-30, NH), 5.51 (s, 1H,
H-1b), 7.33–7.42 (m, 5H, Ph–H). 13C NMR (CDCl3):
d 21.0, 21.1, 21.5, 53.9, 56.6, 60.9, 62.3, 65.4, 68.7,
71.7, 72.5, 74.7, 75.0, 77.6, 95.7, 100.5, 128.3, 128.5,
128.9, 137.8, 157.9, 169.8, 171.1, 170.9, 171.1. MS
(ESI) m/z (%) 761.1 (94.43, (M+Na)+), 763.1 (100.0),
765.1 (33.92), 767.1 (6.60). HRMS (ESI) calcd
for C28H33Cl3N4O13Na (M+Na)+ 761.1007. Found
761.1011.
0
0
4.4. 1,6-Anhydro-2-azido-2-deoxy-3-O-benzyl-b-D-gluco-
pyranose 12
TBAF (1 M in THF, 0.23 mL, 0.23 mmol) was added
dropwise to a 0 °C solution of 10 (76 mg, 0.195 mmol)
in THF (2 mL), and slowly warmed to room tempera-

418
A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
4.6. 1,6-Anhydro-2-deoxy-2-azido-3-O-benzyl-4-O-(3,4,6-
tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl-
amino)-b-D-glucopyranosyl)-b-D-glucopyranose 16
with water, satd aq NaHCO3, and brine, then dried
(Na2SO4), filtered, and concentrated (in vacuo). Column
chromatography (SiO2, 1:1 hexanes–EtOAc) yielded
pure 17 (0.410 g, 70%) as a clear colorless oil. 1H
NMR (CDCl3): d 2.04–2.1 (m, 12H, 4CH3), 3.19 (s,
1H, H-2), 3.49 (m, 1H, H-20), 3.67 (s, 1H, H-4), 3.79–
3.87 (m, 2H, H-50, H-6), 4.03 (d, 1H, H-6,
J6,6 = 7.6 Hz), 4.25 (m, 2H, H-60, H-60), 4.65 (m, 2H,
1/2 TrocCH2, H-5), 4.87 (d, 1H, 1/2 TrocCH2,
O
OBn
OAc
O
O
AcO
O
N3
AcO
NH
O
O
J = 12.0 Hz), 5.08 (dd, 1H, H-40, J4 ,3 = 9.4 Hz,
Cl3C
H
0
0
0
0
J4 ,5 = 9.0 Hz) 5.36 (d, 1H, NH, JNH,H2 = 8.1 Hz), 5.48
(s, 1H, H-1), 5.58 (dd, 1H, H-30, J3 ,4 = 9.8,
0
0
J3 ,2 = 9.2 Hz). 13C NMR (CDCl3): d 21.1, 21.1, 21.4,
23.1, 56.9, 59.0, 62.3, 65.3, 69.2, 70.7, 71.5, 72.5, 74.4,
74.8, 75.7, 95.8, 99.67, 100.6, 154.3, 169.8, 169.9,
170.7, 171.1. MS (ESI) m/z (%) 713.0 (99.30,
(M+Na)+), 715.0 (99.90), 717.0 (35.61), 719.0 (5.38).
HRMS (ESI) calcd for C23O14N4H29Cl3Na (M+Na)+
713.0644. Found 713.0645.
A solution of the 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-
trichloroethoxycarbonylamino)-a-D-glucopyranosyl bro-
mide 14 (106 mg, 0.191 mmol), 1,6-anhydro-2-de-oxy-
0
0
2-azido-3-O-benzyl-b-D-glucopyranose,
12 (35 mg,
˚
0.127 mmol), and 3 A molecular sieves (35 mg) in freshly
distilled CH2Cl2 (3 mL) was stirred at room temperature
for 15 min, then cooled to 0 °C. After 30 min, AgOTf
(75 mg, 0.29 mmol) was added and the solution warmed
slowly to room temperature. After 15 h, the reaction was
filtered through Celite (CH2Cl2), washed with water,
satd aq NaHCO3, and brine, then dried (Na2SO4), fil-
tered, and concentrated (in vacuo). Column chromato-
graphy (SiO2, 1:1 hexanes–EtOAc) yielded pure 16
(0.410 g, 88%) as a clear colorless oil. 1H NMR
(CDCl3): d 2.02 (m, 9H, 3CH3), 3.17 (s, 1H, H-2), 3.39
(m, 1H, H-20), 3.71-3.83 (m, 4H, H-3, H-4, H-50, H-6),
4.09 (m, 2H, H-6, H-60), 4.19 (m, 1H, H-60,
4.8. 1,6-Di-O-acetyl-2-azido-4-O-benzyl-3-O-(3,4,6-tri-O-
acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-
b-D-glucopyranosyl)-2-deoxy-a,b-D-glucopyranose 18
OAc
OAc
O
O
BnO
O
AcO
AcO
N3
NH
OAc
O
Cl3C
0
J6 ,5 = 4.4 Hz, J6 ,6 = 12.8 Hz), 4.56–4.79 (m, 5H, H-5,
0
0
0
O
TrocCH2, CH2Ph), 5.04 (dd, 1H, H-40, J4 ,3 = 9.6 Hz,
0
0
J4 ,3 = 9.7 Hz), 5.18 (d, 1H, H-10b, J1 ,2 = 8.0 Hz), 5.48
(s, 1H, H-1), 5.55 (m, 2H, H-30, NH) 7.33–7.42 (m,
5H, Ph–H). 13C NMR (CDCl3): d 21.1, 56.9, 59.4,
62.3, 65.3, 69.2, 71.4, 72.3, 72.7, 74.1, 74.8, 75.6, 77.3,
95.8, 98.9, 101.0, 128.0, 128.5, 129.0, 137.7, 154.4,
169.9, 170.78, 171.0. MS (ESI) m/z (%) 761.1 (94.87,
(M+Na)+), 763.1 (100.0), 765.1 (35.90), 767.1 (5.22).
HRMS (ESI) calcd for C28O13N4H33Cl3Na (M+Na)+
761.1007. Found 761.1006.
0
0
0
0
Trifluoroacetic acid (63 mg, 0.55 mmol) was added to a
solution of disaccharide 15 (0.10 g, 0.14 mmol) in acetic
anhydride (0.429 g, 4.2 mmol), and stirred at room tem-
perature. After 3 days, the reaction was concentrated (in
vacuo), and the residual acid removed by multiple tritur-
ations with toluene. Column chromatography (SiO2, 2:1
hexanes–EtOAc) afforded pure product, 18 (0.103 g,
1
87%) as a light yellow semi-solid. H NMR (CDCl3): d
2.10–2.21 (m, 15H, 5 CH3), 3.56 (m, 1H, H-20), 3.75
(m, 1H, H-50), 3.89 (m, 2H, H-2, H-5), 4.07–4.34 (m,
5H, H-6, H-6, H-60, H-4, H-3), 4.55 (dd, 1H, H-60,
4.7. 1,6-Anhydro-3-O-acetyl-2-azido-2-deoxy-4-O-(3,4,6-
tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl-
amino)-b-D-glucopyranosyl)-b-D-glucopyranose 17
0
0
0
0
J6 ,6 = 12.4 Hz, J6 ,5 = 4.0 Hz), 4.80 (m, 3H, 1/2 CH2Ph,
0
TrocCH2), 4.92 (d, 1H, H-10b, J1 ,2 = 8.3 Hz), 5.05 (d,
0
1H, 1/2 CH2Ph, J = 10.5 Hz), 5.16 (dd, 1H, H-40,
J4 ,3 = 9.74 Hz, J4 ,5 = 9.7 Hz), 5.27 (dd, 1H, H-30,
0
0
0
0
O
OAc
0
0
0
0
J3 ,4 = 10.02 Hz, J3 ,2 = 9.2 Hz) 5.48 (d, 1H, NH,
JNH,H2 = 9.2 Hz), 5.75 (d, 1H, H-1b, J1,2 = 8.7 Hz),
6.27 (d, 1H, H-1a, J1,2 = 3.5 Hz), 7.3 (m, 5H, Ph–H).
13C NMR (CDCl3): d 21.0, 21.2, 21.4, 21.4, 21.5, 23.0,
62.2, 62.2, 63.2, 65.2, 68.7, 71.2, 72.3, 72.5, 74.9, 75.5,
78.9, 90.5, 95.7, 100.5, 128.6, 128.7, 128.8, 137.8,
154.9, 169.1, 170.9, 171.0, 171.2. MS (ESI) m/z (%)
863.2 (98.27, (M+Na)+), 865.2 (100.0), 867.2 (39.11),
869.2 (6.63). HRMS (ESI) calcd for C32O16N4H39Cl3Na
(M+Na)+ 831.1324. Found 831.1327.
OAc
O
O
AcO
AcO
O
N3
NH
O
O
Cl3C
H
A solution of the 3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-tri-
chloroethoxycarbonylamino)-a-D-glucopyranosyl bro-
mide 14 (0.65 g, 1.19 mmol), 1,6-anhydro-2-deoxy-2-
azido-3-O-acetyl-b-D-glucopyranose,
13
(0.195 g,
˚
0.78 mmol) and 3 A molecular sieves (0.05 g) in freshly
distilled CH2Cl2 (25 mL) was stirred at room tempera-
ture for 15 min, then cooled to 0 °C. After 30 min,
AgOTf (0.442 g, 1.72 mmol) was added and the solution
warmed slowly to room temperature. After 15 h, the
reaction was filtered through Celite (CH2Cl2), washed
4.9. 1,6-Di-O-acetyl-2-azido-3-O-benzyl-4-O-(3,4,6-tri-O-
acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-
b-D-glucopyranosyl)-2-deoxy-a,b-D-glucopyranose 19
Trifluoroacetic acid (20 lL, 0.264 mmol) was added to a
solution of disaccharide 16 (48 mg, 0.07 mmol) in acetic

A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
419
(M+Na)+), 817.1 (100.0), 819.1 (35.81), 821.1 (5.66%).
HRMS (ESI) calcd for C27H35Cl3N4O17Na (M+Na)+
815.0960. Found 815.0975.
OAc
OAc
O
AcO
AcO
O
O
BnO
NH
N3
O
OAc
Cl3C
4.11. 1,3,6-Tri-O-acetyl-2-azido-2-deoxy-4-O-(3,4,6-tri-
O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl-
amino)-b-D-glucopyranosyl)-a,b-D-glucopyranose 21
O
anhydride (0.373 mL, 3.95 mmol), and stirred at room
temperature. After 3 days, the reaction was concen-
trated (in vacuo), and the residual acid removed by mul-
tiple triturations with toluene. Column chromatography
(SiO2, 2:3 hexanes–EtOAc) afforded pure product, 19
(42 mg, 77%) as a light yellow semi-solid. 1H NMR
(CDCl3): d 1.95–2.17 (m, 15H, 5CH3), 3.54 (m, 3H, H-
20, H-50, H-3), 3.87 (m, 4H, H-4, H-5, H-2, H-60), 4.19
(m, 2H, H-6, H-60), 4.47 (dd, 1H, H-6, J6,6 = 12.0 Hz),
4.60–4.86 (m, 4H, NH, TrocCH2, H-10b), 4.98–5.12
(m, 4H, CH2Ph, H-40, H-30) 6.21 (d, 1H, H-1b,
J1,2 = 8.1 Hz), 6.21 (d, 1H, H-1a, J1,2 = 3.5 Hz), 7.27–
7.34 (m, 5H, Ph–H). 13C NMR (CDCl3): d 20.9, 21.29,
57.2, 60.7, 62.2, 62.4, 62.8, 71.4, 72.4, 74.9, 75.5, 78.9,
90.5, 95.9, 101.6, 127.6, 127.7, 128.1, 128.7, 178.8,
138.5, 154.7, 169.0, 169.7, 170.8, 170.9, 171.4. MS
(ESI) m/z (%) 863.1 (96.77, (M + Na)+), 865.1 (100.0),
867.1 (37.20), 869.1 (5.73). HRMS (ESI) calcd for
C32O16N4H39Cl3Na (M+Na)+ 863.1324. Found
863.1339.
OAc
OAc
O
AcO
AcO
O
O
AcO
NH
N3
O
OAc
Cl3C
O
From 16: BF3ÆOEt2 (22 lL, 0.18 mmol) was added to a
0 °C solution of 1,6-anhydro-2-azido-2-deoxy-3-O-benz-
yl-4-O-(3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroeth-
oxy-carbonylamino)-b-D-glucopyranosyl)-2-deoxy-b-D-
glucopyranose 16 (26 mg, 0.04 mmol) in Ac2O (0.4 mL).
After 14.5 h, the solution was warmed to room tempera-
ture. After 2 h, the reaction was quenched with Et3N
(0.4 mL), diluted with toluene (5 mL), and concentrated
(in vacuo). Chromatography (preparative TLC, 3:2
hexanes–EtOAc) yielded pure 21 (25 mg, 85%) as a
yellowish oil. Spectral data were identical to those
given below for 21 derived from 17.
From 17: BF3ÆOEt2 (84 lL, 0.724 mmol) was added to a
0 °C solution of 1,6-anhydro-2-azido-2-deoxy-3-O-acet-
yl-4-O-(3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroeth-
oxycarbonylamino)-b-D-glucopyranosyl)-2-deoxy-b-D-
glucopyranose 17 (98 mg, 0.145 mmol) in Ac2O
(1.3 mL). After 30 min, the reaction was quenched with
Et3N (0.8 mL), diluted with toluene (5 mL), and concen-
trated (in vacuo). Chromatography (SiO2, 1:1 hexanes–
EtOAc) yielded pure 21 (62 mg, 83%) as a yellowish oil.
1H NMR (CDCl3): d 1.98–2.17 (m, 18 H, 6 CH3), 3.53
(m, 2H, H-20, H-2), 3.67 (m, 1H, H-50), 3.81 (dd, 1H,
H-4, J4,3 = 9.5 Hz, J4,5 = 9.6 Hz), 4.03 (dd, 1H, H-60,
4.10. 1,4,6-Tri-O-acetyl-2-azido-2-deoxy-3-O-(3,4,6-tri-
O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonyl-
amino)-b-D-glucopyranosyl)-a,b-D-glucopyranose 20
OAc
OAc
O
O
AcO
AcO
AcO
O
N3
NH
OAc
O
Cl3C
O
BF3ÆOEt2 (0.345 mL, 2.99 mmol) was added to a 0 °C of
1,6-anhydro-2-azido-4-O-benzyl-3-O-(3,4,6-tri-O-acetyl-
2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-b-D-
glucopyranosyl)-2-deoxy-b-D-glucopyranose 15 (440
mg, 0.597 mmol) in Ac2O (0.5 mL), and stirred at 0 °C
for 14.5 h. The solution was warmed to room tempera-
ture, stirred for an additional 2 h, then quenched with
Et3N (0.4 mL), diluted with toluene (3 mL), and concen-
trated (in vacuo). Column chromatography (SiO2, 1:1
hexanes–EtOAc) yielded pure product 20 (390 mg,
0
J6 ,6 = 12.3 Hz), 4.26 (s, 2H, H-6, H-6), 4.40 (dd, 1H,
0
H-60, J6 ,6 = 12.2 Hz, J6 ,5 = 3.6 Hz), 4.66–4.74 (m,
0
0
0
0
3H, TrocCH2, H-10b), 5.03 (dd, 1H, H-40, J4 ,3 = 9.7 Hz,
0
0
J4 ,5 = 9.5 Hz), 5.30 (dd, 1H, H-30, J3 ,4 = 9.6 Hz,
0
0
0
0
0
0
J3 ,2 = 8.9 Hz), 5.42 (dd, 1H, H-3, J3,4 = 9.6 Hz,
J3,2 = 9.5 Hz), 5.55 (d, 1H, H-1b, J1,2 = 8.5 Hz), 5.72
(d, 1H, NH, JNH,H2 = 8.4 Hz), 6.22 (d, 1H, H-1a,
J1,2 = 3.4 Hz). 13C NMR (CDCl3): d 20.9, 21.1, 21.1,
21.3, 21.4, 56.9, 60.9, 62.2, 62.2, 68.7, 70.5, 70.9, 71.9,
72.3, 74.9, 75.6, 90.3, 95.8, 100.7, 154.4, 169.8, 170.3,
170.5, 170.8, 171.9, 171.3. MS (ESI) m/z (%) 815.1
(95.53, (M+Na)+), 817.1 (99.91), 819.1 (34.48), 821.1
(5.34). HRMS (ESI) calcd for C27O17N4H35Cl3Na
(M+Na)+ 815.0960. Found 815.0975.
1
83%) as a yellowish oil. H NMR (CDCl3): d 2.04–2.1
(m, 15H, 5CH3), 2.2 (s, 3H, CH3), 3.54 (m, 1H, H-20),
3.67 (m, 1H, H-2), 3.76 (m, 1H, H-50), 3.97 (dd, 1H,
H-3, J3,4 = J3,2 = 8.2 Hz), 4.10–4.02 (m, 4H, H-4, H-6,
H-5, H-60), 4.25 (dd, 1H, H-6, J6,6 = 12.3 Hz,
J6,5 = 3.6 Hz), 4.44 (dd, 1H, H-60, J6 ,6 = 12.5 Hz,
0
0
4.12. 7-Triisopropylsilyloxy-4-methylcoumarin
0
0
J6 ,5 = 3.7 Hz), 4.73 (m, 2H, TrocCH2),0 4.92 (d, 1H,
H-10b, J1 ,2 = 8.4 Hz), 5.1 (m, 3H, H-4 , H-1b), 5.28
TiPSO
O
O
0
0
(d, 1H, NH, JNH,H2 = 8.2 Hz), 5.42 (dd, 1H, H-30,
0
0
0
0
J3 ,4 = J3 ,2 = 9.6 Hz), 6.34 (d, 1H, H-1a, J1,2
=
3.5 Hz). 13C NMR (CDCl3): d 20.9, 21.0, 21.1, 21.3,
57.1, 62.7, 62.1, 63.1, 67.7, 68.6, 70.3, 71.9, 72.1, 74.9,
90.3, 95.7, 96.5, 100.7, 154.3, 168.9, 169.7, 169.8,
170.7, 170.8, 171.0. MS (ESI) m/z (%) 815.1 (97.12,
7-Hydroxy-4-methylcoumarin 26 (2 g, 11.4 mmol) in
THF (80 mL) was added dropwise to a 0 °C solution of
sodium hydride (0.38 g, 12.4 mmol) in THF (5 mL).

420
A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
After addition was complete, stirring continued at 0 °C
for 5 min, then the solution was warmed to room temper-
ature, and TiPS–chloride (0.132 mL, 0.688 mmol) was
added. After 15 h, the reaction mixture was condensed
(in vacuo) diluted up CHCl3, washed with H2O, brine,
dried (Na2SO4), and concentrated (in vacuo). The
crude mixture was then passed through a plug of
silica using 5:1 hexanes–EtOAc as the eluant and
concentrated to obtain pure product (2.96 g, 82%) as a
white solid. Mp 63-65 °C. 1H NMR (CDCl3): d 1.11
(m, 18H, TiPS–CH3), 1.28 (m, 3H, TiPS–CH), 2.41 (s,
3H, CH3), 6.16 (s, 1H, H-3), 6.85 (m, 2H, H-6, H-8),
7.46 (d, 1H, H-5 J5,6 = 8.8 Hz). 13C NMR (CDCl3): d
12.9, 12.9, 18.5, 18.7, 18.9, 107.5, 112.4, 114.8, 117.5,
126.3, 127.6, 154.1, 155.3, 159.6, 160.9. MS (ESI) m/z
(%) 333.2 (100.0, (M+H)+). HRMS (ESI) calcd for
C19O3H29Si (M+H)+ 333.1886. Found 333.1877.
AcOH (0.5 mL) at room temperature. After 3.5 h, the
reaction mixture was diluted with CH2Cl2, washed with
satd aq NaHCO3, and brine, dried (Na2SO4), filtered,
and concentrated (in vacuo) to obtain the a-bromide. Sil-
ver triflate (0.14 mmol) was added to a solution (À78 °C)
of the a-bromide (70 lmol) in CH2Cl2 (1.5 mL) contain-
˚
ing 3 A molecular sieves, and sym-collidine (13 lL,
0.1 mmol) under Ar, in the dark. After stirring 5 min at
À78 °C, the umbelliferone acceptor (0.14 mmol) was
added, and the mixture warmed to room temperature.
After 16 h, the mixture was filtered through Celite,
washed with satd aq NaHCO3, and brine, dried
(Na2SO4), filtered, and concentrated in vacuo.
4.15. 4-Methylumbelliferyl 2-azido-4,6-di-O-acetyl-3-O-
benzyl-2-deoxy-b-D-glucopyranose 29
OAc
4.13. 3-Bromo-7-hydroxy-4-methylcoumarin 28
O
AcO
O
O
O
H
BnO
N3
HO
O
O
Br
CH3
1,4,6-Tri-O-acetyl-2-deoxy-2-azido-3-O-benzyl-a-D-glu-
copyranose 23 (30 mg, 70 lmol) was coupled with
4-methylumbelliferone 26 (0.14 mmol) following the
general procedure outlined above. Column chromato-
graphy (SiO2, 1.5:1 hexanes–EtOAc) yielded pure 29,
(23 mg, 64%, 100% b) as light yellow semi-solid. 1H
NMR (CDCl3): d 1.77 (s, 3H, CH3), 2.14 (s, 3H,
CH3), 2.43 (s, 3H, CH3) 3.53 (dd, 1H, H-3,
J3,4 = 9.53 Hz, J3,2 = 10.41 Hz), 3.75 (m, 1H, H-5),
3.82 (dd, 1H, H-2, J2,1 = 8.4 Hz, J2,3 = 9.6 Hz), 4.13
(dd, 1H, H-6, J6,6 = 11.9 Hz, J6,5 = 2.0 Hz), 4.27 (dd,
1H, H-6, J6,6 = 12.4 Hz, J6,5 = 6.2 Hz), 4.72 (d, 1H, 1/2
CH2Ph, J = 11.4), 4.88 (d, 1H, 1/2 CH2Ph, J = 11.4),
4.95 (d, 1H, H-1b, J1,2 = 8.1 Hz), 5.12 (dd, 1H, H-4,
J4,3 = 9.8 Hz, J4,5 = 9.5 Hz), 6.21 (s, 1H, H-3c), 7.03
(m, 2H, H-8c, H-6c), 7.31–7.36 (m, 5H, Ph–H), 7.56
(d, 1H, H-5c, J5c,6c = 8.4 Hz). 13C NMR (CDCl3): d
19.1, 21.2, 62.4, 65.9, 69.8, 73.1, 75.7, 80.4, 100.2,
104.2, 113.6, 114.6, 115.9, 126.2, 128.5, 128.6, 128.9,
137.7, 152.7, 155.3, 159.6, 161.2, 166.8, 169.9, 171.1.
MS (ESI) m/z (%) 560.2 (100.0, (M+Na)+). HRMS
(ESI) calcd for C27O9N3H27Na (M+Na)+ 560.1645.
Found 560.1647.
A solution of NBS (0.89 g, 5 mmol) in 10 mL acetonitrile
was added to a solution of 4-methyl-7-triisopropylsilan-
oxycoumarin (1.67 g, 5 mmol) in acetonitrile (20 mL) at
room temperature. After 26 h, the solvent was removed
(in vacuo) the residue was dissolved up in CH2Cl2 and
extracted with water, satd aq NaHCO3, and brine, dried
(Na2SO4), filtered, and concentrated (in vacuo). Column
chromatography (silica gel, 20:1 hexanes–EtOAc) yielded
pure 3-bromo-7-triisopropylsilanoxy-4-methylcoumarin
1
as a white solid (2.04 g, 99% yield). Mp 104–105 °C. H
NMR (CDCl3): d 1.11 (d, 18H, TiPS–CH3), 1.28 (m,
3H, TiPS–CH), 2.40 (s, 3H, CH3), 6.86 (m, 2H, H-6, H-
8), 7.53 (d, 1H, H-5, J5,6 = 8.7 Hz). 13C NMR (CDCl3):
d 13.0, 18.2, 19.9, 107.8, 110.2, 114.3, 118.2, 126.4,
151.6, 157.8, 157.9, 160.2. MS (ESI) m/z (%) 411.1
(92.51, (M+H)+), 413.1 (100.0). HRMS (ESI) calcd for
C19O3H28SiBr (M+H)+ 411.0991. Found 411.1014.
To a solution of 3-bromo-7-triisopropylsilanoxy-4-methyl-
coumarin (380 mg, 0.92 mmol) in EtOH (15 mL) was
added 2 M HCl (3 mL), and the resulting solution was
then heated at reflux temperature. After 4 h, the solution
was poured onto ice and the precipitated product was iso-
lated by filtration and washed with cold water to give 28
1
4.16. 3-Ethyl-4-methylumbelliferyl 2-azido-4,6-di-O-acet-
yl-3-O-benzyl-2-deoxy-b-D-glucopyranose 30
(225 mg, 96%) as a white powder. Mp 205–209 °C. H
NMR (DMSO): d 2.49 (s, 3H, CH3), 6.75 (d, 1H, H-8,
J8.6 = 2.4 Hz), 6.84 (dd, H, H-6, J6,5 = 8.9 Hz,
J6,8 = 2.5 Hz), 7.72 (d, 1H, H-5, J5,6 = 8.8 Hz) 10.71 (br
s, 1H, OH). 13C NMR (CDCl3): d 20.2, 102.9, 109.2,
112.7, 114.4, 128.3, 152.9, 154.0, 157.9, 162.3. MS (EI)
m/z (%) 253.8 (M+, 100%), 255.8 (M+, 96.7%). HRMS
(EI) calcd for C10O3H7Br (M+) 253.9579. Found 253.9587.
OAc
O
AcO
BnO
O
O
O
N3
Et
CH3
4.14. General procedure for 4-methylumbelliferyl
glycosylation
1,4,6-Tri-O-acetyl-2-deoxy-2-azido-3-O-benzyl-a-D-glu-
copyranose 23 (30 mg, 70 lmol) was coupled with 3-
ethyl-4-methylumbelliferone 27, following the general
A 30% solution of HBr in AcOH (47 lL, 0.35 mmol) was
added to a solution of the saccharide (0.11 mmol) in

A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
OAc
421
procedure outlined above. Column chromatography
(SiO2, 8:1 CHCl3–EtOAc) yielded pure 30 (9 mg, 43%,
100% b) as a faint yellow semi-solid. 1H NMR (CDCl3):
d 1.15 (t, 3H, CH3, J = 7.5 Hz), 1.97 (s, 3H, CH3), 2.12
(s, 3H, CH3), 2.39 (s, 3H, CH3), 2.67 (q, 2H, CH2,
J = 7.5 Hz), 3.54 (dd, 1H, H-3, J3,2 = 9.6 Hz,
J3,4 = 9.5), 3.73 (m, 1H, H-5), 3.81 (dd, 1H, H-2,
J2,3 = 9.7 Hz, J2,1 = 8.2 Hz), 4.11 (dd, 1H, H-6,
J6,5 = 2.3 Hz, J6,6 = 12.2 Hz), 4.25 (dd, 1H, H-6,
J6,5 = 6.2 Hz, J6,6 = 12.4 Hz), 4.67 (d, 1H, 1/2 CH2Ph,
J = 11.4 Hz), 4.86 (d, 1H, 1/2 CH2Ph, J = 11.4 Hz),
4.86 (d, 1H, H-1b, J1,2 = 8.2 Hz), 5.10 (dd, 1H, H-4,
J4,5 = 9.9 Hz, J4,3 = 9.4 Hz), 6.97–6.99 (m, 2H, H-8c,
H-6c), 7.30–7.38 (m, 5H, Ph–H), 7.53 (d, 1H, H-5c,
J5c,6c = 8.6 Hz). 13C NMR (CDCl3): d 13.5, 15.0, 21.1,
21.2, 21.3, 62.4, 65.9, 73.1, 75.7, 80.4, 100.4, 104.0,
114.4, 116.8, 125.9, 126.7, 128.4, 128.5, 137.8, 153.7,
158.6, 161.9, 169.8, 171.1. MS (ESI) m/z (%) 588.2
(100.0, (M+Na)+). HRMS (ESI) calcd for C29O9N3H31Na
(M+Na)+ 588.1958. Found 588.1961.
O
BnO
AcO
O
O
O
N3
Br
CH3
b-Anomer: 1H NMR (CDCl3): d 1.9–1.8 (m, 6H, 2
CH3), 3.75–3.5 (m, 3H, H-4, H-5, H-2), 4.3–4.2 (m,
2H, H-6, H-6), 4.6 (m, 2H, CH2Ph), 5.01 (d, 1H, H-
1b, J = 8.6 Hz), 5.24 (dd, 1H, H-3, J3,4 = 3,2 = 7.6 Hz),
7.0 (m, 2H, H-8c, H-6c), 7.2 (m, 5H, Ph–H), 7.5 (d,
1H, H-5c, J5c,6c = 8.9 Hz).
1
a-Anomer: H NMR (CDCl3): d 2.10 (s, 3H, 1CH3),
2.61 (s, 3H, CH3), 3.39 (dd, 1H, H-2, J2,1 = 3.4 Hz,
J2,3 = 10.7 Hz), 3.72 (dd, 1H, H-4, J4,3 = 9.3 Hz,
J4,5 = 9.9 Hz), 4.00 (m, 1H, H-5), 4.27 (m, 2H, H-6, H-
6), 4.62 (q, 2H, CH2Ph, J = 11.2 Hz), 5.67 (dd, 1H, H-
1a, J1,2 = 3.4 Hz,), 5.78 (dd, 1H, H-3, J3,4 = 9.0 Hz,
J3,2 = 10.7 Hz), 7.10 (dd, 1H, H-6c, J6c,5c = 8.8 Hz,
J6c,8c = 2.4 Hz) 7.17 (d, 1H, H-8c, J8c,6c = 2.4 Hz),
7.26–7.39 (m, 10H, Ph–H), 7.63 (d, 1H, H-5c,
J5c,6c = 8.9 Hz). 13C NMR (CDCl3): d 19.9, 21.2, 63.4,
62.6, 70.5, 72.3, 75.3, 76.1, 80.6, 97.4, 104.5, 114.5,
115.8, 126.7, 128.4, 128.7, 129.01, 137.3, 151.1, 153.6,
157.3, 158.9, 170.2, 170.8. MS (ESI) m/z (%) 638.0
(87.56, (M+Na)+), 640.0 (100.0). HRMS (ESI) calcd
for C27O9N3H26BrNa (M+Na)+ 638.0750. Found
638.0764.
4.17. 4-Methylumbelliferyl 2-azido-3,6-di-O-acetyl-4-O-
benzyl-2-deoxy-b-D-glucopyranose 31
OAc
O
BnO
AcO
O
O
O
H
N3
CH3
1,3,6-Tri-O-acetyl-2-deoxy-2-azido-4-O-benzyl-a-D-glu-
copyranose, 24 (12 mg, 30 lmol) was coupled with 4-
methylumbelliferone 26 (12 mg, 0.07 mmol) following
the general procedure outlined above. Column chroma-
tography (SiO2, 1:2 hexanes–EtOAc) yielded pure 31,
(23 mg, 54%, 100% b) as an off-white semi-solid. 1H
NMR: d 2.12 (s, 6H, 2CH3), 2.43 (s, 3H, CH3) 3.63
(dd, 1H, H-4, J4,3 = 9.48 Hz, J4,5 = 9.33 Hz), 3.72–3.81
(m, 2H, H-2, H-5), 4.27 (dd, 1H, H-6, J6,6 = 11.1 Hz,
J6,5 = 5.6 Hz), 4.40 (m, 1H, H-6, J6,6 = 10.4 Hz,
J6,5 = 1.2 Hz), 4.60 (m, 2H, CH2Ph), 5.02 (d, 1H, H-
1b, J1,2 = 8.0 Hz), 5.20 (dd, 1H, H-3, J3,4 = 9.8 Hz,
J3,2 = 9.6 Hz), 6.22 (s, 1H, H-3c), 6.98–7.03 (m, 2H, H-
8c, H-6c), 7.28–7.38 (m, 5H, Ph–H), 7.55 (d, 1H, H-5c,
J5c,6c = 8.5 Hz). 13C NMR (CDCl3): d 19.1, 21.2, 62.4,
65.9, 69.8, 73.0, 75.7, 80.4, 100.2, 104.2, 113.6, 114.6,
115.9, 126.2, 128.5, 128.6, 128.9, 137.7, 152.7, 155.23,
159.6, 161.2, 166.8, 169.9, 171.1. MS (ESI) m/z (%)
560.4 (100.0, (M+Na)+). HRMS (ESI) calcd for
C27O9N3H27Na (M+Na)+ 560.1645. Found 560.1648.
4.19. 4-Methylumbelliferyl 2-azido-6-O-acetyl-3,4-di-O-
benzyl-2-deoxy-a,b-D-glucopyranose 33
OAc
O
BnO
BnO
O
N3
O
O
H
CH3
1,6-Di-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-a-D-
glucopyranose 25 (38 mg, 80 lmol) was coupled to
4-methylumbelliferone 26 (0.16 mmol), following the
general procedure outlined above. Column chromato-
graphy (SiO2, 1:1 hexanes–EtOAc) separated the
a- and b-anomers and afforded pure 33 (35 mg, 77%,
a:b = 17:83) as an off-white semi-solid.
4.18. 3-Bromo-4-methylumbelliferyl 2-azido-3,6-di-O-
acetyl-4-O-benzyl-2-deoxy-a,b-D-glucopyranose 32
1,3,6-Tri-O-acetyl-2-deoxy-2-azido-4-O-benzyl-a-D-glu-
copyranose 24 (21 mg, 50 lmol) was coupled to 3-bro-
mo-4-methylumbelliferone 28 (0.1 mmol) following the
general procedure outlined above. Column chromato-
graphy (SiO2, 8:1 CHCl3–EtOAc) separated the a- and
b-anomers and yielded 32 (19 mg, 64%, a:b = 44:56) as
a yellowish semi-solid.
b-Anomer: 1H NMR (CDCl3): d 2.08 (s, 3H, CH3), 2.40
(s, 3H, CH3), 3.18 (m, 1H, H-5) 3.24–3.33 (m, 2H, H-3,
H-4), 3.55 (dd, 1H, H-2, J2,1 = 8.7 Hz, J2,3 = 9.3 Hz),
4.10 (dd, 1H, H-6, J6,5 = 6.4 Hz, J6,6 = 11.9 Hz), 4.31–
4.35 (m, 2H, H-6, 1/2 CH2), 4.52 (d, 1H, H-1b,
J1,2 = 8.1 Hz), 4.65–4.78 (m, 2H, CH2Ph), 4.85 (d, 1H,
1/2 CH2, J = 11.1 Hz), 6.18 (s, 1H, H3c), 7.01 (m, 2H,

422
A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
H6c, H8c), 7.29–7.41 (m, 10H, Ph–H), 7.53 (d, 1H, H-5c,
J5c,6c = 8.8 Hz).
OAc
O
BnO
BnO
a-Anomer: 1H NMR (CDCl3): d 2.10 (s, 3H, CH3), 2.42
(s, 3H, CH3), 3.05 (dd, 1H, H-2, J2,1 = 3.4 Hz,
J2,3 = 10.4 Hz), 3.27 (m, 1H, H-4), 3.40 (dd, 1H, H-3,
J3,4 = 9.2 Hz, J3,2 = 9.7 Hz), 3.92 (m, 1H, H-5), 4.20–
4.28 (m, 2H, H-6, H-6), 4.45 (d, 2H, CH2Ph,
J = 11.0 Hz), 4.65–4.78 (m, 2H, CH2Ph), 5.61 (d, 1H,
H-1a, J1,2 = 3.4 Hz), 6.18 (s, 1H, H-3c), 7.01 (m, 2H,
H-6c, H-8c), 7.29–7.41 (m, 10H, Ph–H), 7.53 (d, 1H,
H-5c, J5c,6c = 8.8 Hz). 13C NMR (CDCl3): d 18.0, 20.7,
62.9, 66.4, 73.9, 75.2, 75.78, 77.8, 83.1, 99.9, 104.3,
113.8, 114.12, 115.6, 125.9, 128.0, 128.4, 128.9, 138.3,
138.6, 151.3, 155.7, 159.7, 159.9, 170.1, 171.2. MS
(ESI) m/z (%) 608.2 (100.0, (M+Na)+). HRMS (ESI)
calcd for C32O8N3H31Na (M+Na)+ 608.2009. Found
608.2014.
O
N3
O
O
Et
CH3
a:b = 1:10), as an off-white semi-solid. 1H NMR
(CDCl3): d 1.17 (t, 3H, CH3, J = 7.4 Hz), 2.08 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 2.67 (q, 2H, CH2,
J = 7.5 Hz), 3.59 (m, 2H, H-3, H-4), 3.67 (m, 1H, H-
5), 3.74 (dd, 1H, H-2, J2,3 = 9.2 Hz, J2,1 = 8.4 Hz), 4.23
(dd, 1H, H-6, J6,5 = 5.8 Hz, J6,6 = 12.0 Hz), 4.35 (dd,
1H, H-6, J6,5 = 2.1 Hz, J6,6 = 12.0 Hz), 4.61 (d, 1H, 1/2
CH2, J = 10.7 Hz) 4.84–4.90 (m, 3H, CH2, H1b), 5.59
(d, 1H, H1a), 6.97 (m, 2H, H-8c, H-6c), 7.28–7.42 (m,
10H, Ph–H), 7.52 (d, 1H, H-5c, J5c,6c = 9.5 Hz). 13C
NMR (CDCl3): d 13.5, 14.9, 21.2, 21.3, 63.1, 66.3,
74.0, 75.6, 76.2, 83.3, 100.4, 104.2, 114.9, 116.7, 125.9,
126.6, 128.4, 128.5, 128.5, 128.6, 128.6, 128.9, 129.0,
137.6, 137.9, 145.8, 153.7, 158.7, 161.9, 171.1. MS
(ESI) m/z (%) 636.3 (99.84, (M+Na)+). HRMS (ESI)
calcd for C34O8N3H35Na (M+Na)+ 636.2322. Found
636.2329.
4.20. 3-Bromo-4-methylumbelliferyl 2-azido-6-O-acetyl-
3,4-O-benzyl-2-deoxy-ab-D-glucopyranose 34
OAc
O
BnO
BnO
O
N3
O
O
4.22. 4-Methylumbelliferyl 6-O-acetyl-2-azido-4-O-benz-
yl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxy-
carbonylamino)-b-D-glucopyranosyl)-2-deoxy-b-D-gluco-
pyranose 36
Br
CH3
1,6-Di-O-acetyl-2-deoxy-2-azido-3,4-di-O-benzyl-a-D-
glucopyranose 25 (5 mg, 10 lmol) was coupled to 3-bro-
mo-4-methylumbelliferone 28 (20 lmol) following the
general procedure outlined above. Column chromato-
graphy (SiO2, 2:1 hexanes–EtOAc) yielded pure 34, an
inseparable mixture of a- and b-anomers (4 mg, 50%,
a:b = 59:41), as a yellowish, semi-solid. 1H NMR
(CDCl3): d 2.08 (s, 3H, CH3), 2.67 (s, 3H, CH3),
3.56–3.81 (m, 6H, H-4b, H-3b, H-2b, H-4a, H-3a, H-
2a), 3.98 (m, 1H, H-5a), 4.29 (m, 4H, H-5b, H-6b, H-
6a, H-6a), 4.67 (d, 2H, CH2Ph, J = 10.5 Hz), 5.07–4.95
(m, 7H, 3CH2Ph, H-1b), 5.68 (d, 1H, H-1a,
J1a,2 = 3.3), 7.07–7.19 (m, 4H, H-6c, H-8c), 7.32–
7.48 (m, 20H, Ph–H), 7.66 (d, 2H, H-5c, J5c,6c = 8.8 Hz).
13C NMR (CDCl3): d 19.9, 21.2, 62.7, 63.4, 70.8,
75.7, 76.12, 80.6, 97.1, 104.8, 111.5, 114.6, 115.6,
126.7, 128.4, 128.5, 129.0, 137.6, 137.8, 151.1,
153.6, 157.4, 159.1, 170.9. MS (ESI) m/z (%) 686.1
(100.0, (M+Na)+), 688.1 (99.78). HRMS (ESI) calcd
for C32O8N3H30BrNa (M+Na)+ 686.1114. Found
686.1117.
OAc
OAc
O
O
BnO
O
AcO
AcO
O
O
O
N3
NH
O
Cl3C
O
1,6-Di-O-acetyl-2-azido-4-O-benzyl-3-O-(3,4,6-tri-O-acet-
yl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-b-D-
glucopyranosyl)-2-deoxy-a-D-glucopyranose 18 (64 mg,
76 lmol) was coupled to 4-methylumbelliferone 26
(0.14 mmol) following the general procedure outlined
above. Column chromatography (SiO2, 8:1 CHCl3–
EtOAc) yielded pure product 36 (25 mg, 33%, 100% b)
1
as an off-white semi-solid. H NMR (CDCl3): d 1.8–
1.9 (m, 12H, 4CH3), 2.10 (s, 3H, CH3), 3.4–3.5 (m,
3H, H-5, H-50, H-2), 3.75–3.80 (m, 2H, H-3, H-2),
3.94 (m, 1H, H-20), 4.14 (d, 1H, H-60, J = 12.5 Hz),
4.4–4.3 (m, 3H, H-6, H-6, H-60), 4.57 (d, 1H, 1/2 CH2Ph,
J = 11.0 Hz), 4.71 (d, 1H, H-1b, J = 7.5 Hz), 4.83 (dd,
2H, TrocCH2, J = 12.1 Hz), 5.07 (d, 1H, H-10b,
J = 8.3 Hz), 5.17 (d, 1H, 1/2 CH2Ph, J = 10.5 Hz), 5.27
(d, 1H, NH, J = 8.8 Hz), 5.34 (dd, 1H, H-40,
4.21. 3-Ethyl-4-methylumbelliferyl 2-azido-6-O-acetyl-
3,4-O-benzyl-2-deoxy-a,b-D-glucopyranose 35
J4 ,3 = 9.3 Hz, J4 ,5 = 9.0 Hz), 5.56 (dd, H-30,
0
0
0
0
1,6-Di-O-acetyl-2-deoxy-2-azido-3,4-di-O-benzyl-a-D-
glucopyranose 25 (23 mg, 50 lmol) was coupled to 3-
ethyl-4-methylumbelliferone 27 (0.09 mmol) following
the general procedure outlined above. Column chroma-
tography (SiO2, 2:1 hexanes–EtOAc) yielded pure 35, an
inseparable mixture of a- and b-anomers (18 mg, 58%,
0
0
0
0
J3 ,4 = 9.8 Hz, J3 ,2 = 10.1 Hz), 5.9 (s, 1H, H-3c), 6.9
(s, 1H, H-8c), 7.0 (s, 1H, H-6c), 7.2 (m, 5h, Ph–H), 7.5
(d, 1H, H-5c). 13C NMR (CDCl3): d 18.0, 20.34, 20.5,
20.6, 30.4, 62.2, 63.0, 63.3, 66.2, 66.2, 69.2, 72.4, 72.7,
73.9, 74.9, 75.8, 83.9, 91.4, 96.8, 102.5, 104.8, 112.8,

A. R. S. Ganguli, J. K. Coward / Tetrahedron: Asymmetry 16 (2005) 411–424
423
114.0, 115.7, 125.9, 128.0, 128.2, 128.7, 130.6, 138.67,
References
151.4, 154.6, 155.7, 159.4, 160.0, 169.4, 170.2, 170.5.
MS (ESI) m/z (%) 979.2 (100.0, (M+Na)+), 981.2
(97.97), 983.2 (42.18), 985.2 (8.10). HRMS (ESI) calcd
for C40O17N4H43Cl3Na (M+Na)+ 979.1586. Found
979.1595.
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BnO
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1.84 (m, 12H, 4CH3), 2.11 (s, 3H, CH3), 3.39 (m, 2H,
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1
(dd, 1H, H-60, J6 ,6 = 12.0 Hz), 4.29 (m, 2H, H-6, H-
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J = 11.7 Hz), 5.34 (d, 1H, H-40, J4 ,3 = 9.6 Hz,
0
0
J4 ,5 = 9.3 Hz), 5.41 (dd, 1H, H-30, J3 ,2 = 9.9 Hz,
0
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0
0
J3 ,4 = 9.8 Hz), 5.95 (s, 1H, H-3c), 6.90–7.11 (m, 2H,
H-6c, H-8c), 7.27–7.43 (m, 5H, Ph–H), 7.62 (d, 1H, H-
5c, J5c,6c = 7.4 Hz). 13C NMR (CDCl3): d 18.0, 20.4,
20.5, 20.8, 30.4, 57.5, 61.7, 63.1, 66.5, 68.9, 72.4, 72.5,
73.5, 75.0, 75.3, 78.0, 81.5, 96.4, 99.9, 102.8, 104.3,
113.8, 114.2, 115.6, 125.5, 127.5, 128.0, 128.2, 130.7,
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170.3, 170.7. MS (ESI) m/z (%) 979.1 (99.73,
(M+Na)+), 981.1 (100.0), 983.1 (41.95), 985.2 (5.85).
HRMS (ESI) calcd for C40O17N4H43Cl3Na (M+Na)+
979.1586. Found 979.1590.
`
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