Glycosylation of 'basic' alcohols: Methyl 6-(hydroxymethyl)picolinate as a case study

Article abstract of DOI:10.1016/j.carres.2013.02.009

Glycosylation is promoted by acid promoters rendering the reactions with basic acceptors challenging. This report presents an in depth study involving methyl 6-(hydroxymethyl)picolinate as the model acceptor and 22 glycosyl donors to afford the desired glycosides in good yields ranging from 46% to 85%. Several parameters were evaluated, including the protecting groups of the glycosyl donor, the leaving group at the anomeric center, and the promoter. The influence of the pyridine ring was evident with a benzene-based acceptor affording high yields of glycoside (79%) in comparison to the pyridine-based acceptor (46%). The present work provides a general and reliable access to pyridine-containing glycosides.

Full text of DOI:10.1016/j.carres.2013.02.009

Carbohydrate Research 372 (2013) 35–46
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Glycosylation of ‘basic’ alcohols: methyl 6-(hydroxymethyl)picolinate
as a case study
Shuai Wang a, Dominique Lafont a, Jani Rahkila b, Benjamin Picod a, Reko Leino b, Sébastien Vidal a,
⇑
a Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 – Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1,
43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
b Laboratory of Organic Chemistry, Åbo Akademi University, FI-20500 Åbo, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 January 2013
Received in revised form 14 February 2013
Accepted 15 February 2013
Available online 26 February 2013
Glycosylation is promoted by acid promoters rendering the reactions with basic acceptors challenging.
This report presents an in depth study involving methyl 6-(hydroxymethyl)picolinate as the model
acceptor and 22 glycosyl donors to afford the desired glycosides in good yields ranging from 46% to
85%. Several parameters were evaluated, including the protecting groups of the glycosyl donor, the leav-
ing group at the anomeric center, and the promoter. The influence of the pyridine ring was evident with a
benzene-based acceptor affording high yields of glycoside (79%) in comparison to the pyridine-based
Keywords:
acceptor (46%). The present work provides
glycosides.
a
general and reliable access to pyridine-containing
Glycosylation
Pyridine acceptor
Trichloroacetimidate
Carbohydrate
Glycoside
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
pyridine aglycone will find applications for the design of neutral
nucleotide-diphosphate sugar analogues in the search for neutral
inhibitors of glycosyltransferases.14–17 After determining the opti-
mal glycosylation conditions for these glycosides, the ester moiety
will then be conjugated to a 50-aminonucleoside to afford a neutral
NDP-sugar analogue.
Pyridoxine can be glycosylated on the hydroxymethyl groups at
positions 40 or 50, or both, and is better known as vitamin B6. The
40-glucosylated derivative is less stable to hydrolysis in the liver
than its 50-regioisomer. In an initial report, the hydrolysis of the
glycosidic bond of glycosylated derivatives of pyridoxine by glyco-
sidases has been studied (Table 1, entry 1).18 In another series of
experiments, the influence of borate was evaluated in order to ob-
tain a regioselective glucosylation of pyridoxine at the 40- or 50-
positions by microorganisms.19,20 Enzymatic glycosylation could
Carbohydrates are present in nature as monomers (e.g., glucose
is a source of energy) and oligomers (i.e., oligosaccharides) which
are interconnected through glycosidic bonds. Glycosylation1–9 is
therefore one of the most important reactions in carbohydrate
chemistry, challenged by the control of regioselectivity commonly
achieved by protecting group strategies but also by the stereoselec-
tivity of the glycosidic bond created requiring additional strategies
based not only on protecting groups but also on specific reaction
conditions.
Initially, picolinyl ethers have been identified as reactivity-
enhancing replacements for benzyl ethers as exemplified for the
glycosylation at the 4-position of a N-acetylglucosamine acceptor
bearing a picolinyl group at the 3-position.10 More recently, picol-
inyl and picoloyl substituents have been identified as protecting
groups for the stereocontrol of glycosylation.11–13 Nevertheless,
this approach is usually using excess of promoters in order to bal-
ance the intrinsic basicity of the pyridine moiety and then catalyze
the formation of the oxocarbenium intermediate. Surprisingly, a
careful survey of the literature for the glycosylation of glycosyl
acceptors with pyridine-containing acceptors did not afford many
results and most of these were poor in terms of isolated yields of
glycosides and are discussed below. Such glycosides containing a
also be performed using
a- and b-glucosidases (Table 1, entry
2).21,22 Introduction of an additional fluorine atom at the 6-position
of the pyridine ring afforded reporter molecules for the identifica-
tion of genes encoding for b-galactosidase in the search for efficient
molecules for the assessment of location, magnitude, and persis-
tence of gene expression.23 The glycosyl donors used in these re-
ports are natural (oligo)saccharides, sucrose, or dextrins19–22 but
also chemically modified carbohydrates such as p-nitrophenyl18
(PNP) or
a
-bromo23 activated glycosides. Nevertheless, under the
aforementioned conditions using enzymatic or microbial glycosy-
lations, a maximum yield of 40% was achieved. In a similar enzy-
matic approach, the PNP-activated glucose was used as a donor
⇑
Corresponding author. Fax: +33 472 432 752.
E-mail address: sebastien.vidal@univ-lyon1.fr (S. Vidal).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.02.009

36
S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
Table 1
Enzymatic and chemical approaches to the synthesis of glycosylated hydroxymethylpyridine derivatives
Entry
Donor
Glycoside
Method
Yield (%)
32a
Ref.
18
O
OH
4'
O
HO
5'
4
1
2
OH
HO
O
5
OPNP
O
N
Me
1
44b
22
HO
OH
O
Enzymatic
OH
OH
O
HO
HO
HO
HO
O
3
4
5
24
45c
24c
24
25
26
N
HO
OH
OPNP
Br
CO2Me
CN
O
AcO
AcO
N
CO2Me
AcO
O
AcO
AcO
O
N
OMe
OAc
OAc
OAc
O
O
AcO
AcO
AcO
AcO
O
N
Chemical
AcO
OAc
Br
OH
OH
O
O
HO
HO
HO
HO
OH
Br
HO
HO
6
<5d
27
OH
O
O
OH
OH
O
N
HO
a
b
c
Yield reported for galactose derivatives.
The 40-regioisomer was also isolated in a 28:72 mixture with the desired 50-derivative.
Yield calculated over two steps from the data reported through the orthoester intermediate.
Yield calculated from the reported data for the multi-step process.
d
for the glucosylation of a series of aliphatic and benzylic alcohols in
the presence of a glucosidase providing the desired b-D-glucosides
could be transformed into a pyridine moiety through two addi-
tional synthetic steps. The overall process did not afford the de-
sired compounds in good yields (<5%) but represents yet another
possibility for the construction of the pyridine scaffold from a fur-
ane moiety intermediate.
in less than 35% yield (Table 1, entry 3).24 While these synthetic
strategies, inspired by natural enzymes or microorganisms did
not require extensive protecting group chemistry and provided
the desired glycosides in high anomeric stereoselectivities, the
yields obtained remained quite low and did not call for applica-
tions in organic synthesis.
2. Results and discussion
In an organic chemistry approach, a handful of reports have
been identified in the literature in which chemical synthesis has
been applied. The glucuronylation of ciamexon (an immunomodu-
lating agent with application in diabetes) was achieved from the
Methyl 6-(hydroxymethyl)picolinate 2a was chosen as the gly-
cosyl acceptor. After reductive desymmetrization of a diester pre-
cursor,28 the subsequent glycosylation was then investigated
with a large series of glycosyl donors and glycosylation conditions
to address the scope and limitation of such chemical glycosylation
of hydroxymethylpyridine derivative. This general investigation of
the glycosylation of hydroxymethylpyridine was therefore under-
taken based on the literature overview presented above leading
to at least two observations: (1) enzymatic or chemical glycosyla-
tions are possible, but (2) the yields obtained are rather poor. The
chemical glycosylation was studied here with 22 donors and under
43 glycosylation conditions in order to provide a general and useful
methodology for the synthesis of a large series of glycosylated
hydroxymethylpyridine derivatives.
corresponding a-glucuronopyranosyl bromide donor using silver(I)
salt as a promoter leading to the desired glucuronide in 45% yield
(Table 1, entry 4).25 The reaction conditions were quite sensitive
and the use of basic medium (sym-collidine) influenced the reac-
tion affording a large portion of undesired orthoester. This problem
could be overcome by using excess of silver triflate (AgOTf, 3 equiv)
most probably in order to balance the basicity of the pyridine
acceptor. The formation of the orthoester intermediate could not
be prevented in the glycosylation between acetobromoglucose
and 2-vinyl-5-hydroxymethylpyridine derivative using AgOTf as
the promoter26 in a study for the design of peptide functionalizing
agents (Table 1, entry 5). Again, an excess of promoter (1.5 equiv)
was used but led to exclusive formation of the orthoester interme-
diate in 73% yield since the same amount of acceptor was used and
its basicity could therefore not be totally balanced. A subsequent
rearrangement in the presence of trimethylsilyl triflate (TMSOTf)
afforded the desired glycoside in 32% yield corresponding to an
overall yield of only 24% over two steps.
2.1. Galactosyl donors
The first type of glycosylation investigated employed galactosyl
donors in order to address the influence of protecting groups on
the carbohydrate moiety as well as the different leaving groups
at the anomeric position on the outcome of the glycosylation reac-
tion. Galactosylation is usually simpler to be studied in comparison
to glucosylation providing in most cases higher reactivities of the
glycosyl donors, improved yields, and better selectivities.29–31 In
all cases, the promoter was a Lewis acid used in excess in the
Finally, isomaltulose was used as a precursor for a-glucosylated
hydroxymethylpyridine derivatives (Table 1, entry 6).27 Acid dehy-
dration of isomaltulose afforded a glucosylated furfural which

S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
37
reaction in order to balance the basicity of the pyridine-based
acceptor. In almost all cases, an excess of glycosyl donor was used
to ensure maximal functionalization of the acceptor. The yields re-
ported are based on at least two experiments providing similar
reproducible results. All reactions were performed in dichloro-
methane unless stated otherwise in the Tables.
attention then turned to trichloroacetimidate donors such as deriv-
ative 1c35,36 as powerful glycosylation agents.5,8,37,38 Boron tri-
fluoride etherate was used as promoter and provided the best
results in this respect. Molecular sieves were used to keep the reac-
tion mixture anhydrous and the initial attempts under these stan-
dard conditions provided improved yields (up to 34%) in
comparison to the previous attempts (Table 2, entries 11 and 12).
Molecular sieves could also be avoided and the reaction outcome
improved to reach 46% yield (Table 2, entry 13). Changing the sol-
vent to acetonitrile (Table 2, entry 14) or using excess of acceptor
(Table 2, entry 15) or larger proportions of donor (Table 2, entry
16) did not improve the yields. Trimethylsilyl trifluoromethanesul-
fonate is also a general promoter used for these glycosylations but
the glycosylation yield was not improved (Table 2, entry 17) and
the main product obtained was the silylated acceptor 2b.
A series of six different galactosyl donors 1a–f were synthesized
and used in the present study (Scheme 1). Peracetylated galactose
1a was the simplest donor tested being readily available commer-
cially without requiring additional synthetic steps for its activation
at the anomeric center. We have previously reported an efficient
synthetic methodology for the glycosylation using silver and tin
salts.32 Nevertheless, in the present work, the same protocol used
for the galactosylation of alcohol 2a28 with the peracetylated donor
1a did not afford the desired galactoside 3a even though a small
amount of the product could be detected by TLC analysis of the
crude mixture (Table 2, entry 7). We then turned to the Koenigs–
Knorr glycosylation system using the galactopyranosyl bromide
donor 1b and insoluble silver salts.5,33 Later, the Helferich modifi-
cation34 used mercury(II) cyanide (Table 2, entry 8) as the pro-
moter for this glycosylation and under these conditions the
reaction afforded the desired glycoside 3a with complete stereose-
lectivity in favor of the expected b-anomer due to anchimeric par-
ticipation of the acetyl group at the 2-position of the saccharide. A
mixture of acetonitrile and dichloromethane was used for maximal
solubility of the reagents. Nevertheless, the poor yield obtained
prompted the evaluation of a more common silver triflate pro-
moter (Table 2, entries 9 and 10) but the excess of either donor
or acceptor did not improve the yield of isolated galactoside. Our
More recently, Schmidt et al.39,40 have introduced the use of
neutral glycosylation conditions with difluoro(phenyl)borane
(PhBF2) as the promoter. Since the basicity of the acceptor appeared
as a major problem in our glycosylation study, this new methodol-
ogy was also evaluated (Table 2, entries 18 and 19) but proved rather
unsuccessfulprovidingpooryieldsevenathighertemperaturesthan
initially required. Although less stable than trichloroacetimidates,
we also turned our attention to N-phenyl-trifluoroacetimidate
donor 1d which was recently shown to provide better yields than
for standard trichloroacetimidates41 but the yield of galactoside 3b
was not improved (Table 2, entry 20).
Acetates are the most common protecting groups in carbohy-
drate chemistry, but benzoates are also used in some cases for sta-
bility issues or even possible detection using UV analysis due to
AcO
AcO
AcO
AcO
OAc
O
OAc
OAc
OAc
1a
1b
O
HO
OMe
N
AcO
AcO
AcO
OAc
Br
O
O
2a
O
AcO
AcO
OAc
O
OMe
See Table 2
N
O
OAc
O
3a
AcO
CCl3
NH
1c
AcO
AcO
OAc
O
AcO
O
O
CF3
NPh
1d
HO
OMe
BzO
BzO
OBz
N
BzO
BzO
OBz
O
O
2a
O
O
OMe
N
See Table 2
BzO
OBz
CCl3
O
1e
1f
3b
NH
HO
N
OMe
BnO
BnO
OBn
BnO
BnO
OBn
O
2a
O
O
S
N
See Table 2
OBn
BnO
O
OMe
N
3c
O
Scheme 1. Galactosylation of methyl 6-(hydroxymethyl)picolinate 2a with galactosyl donors 1a–f.

38
S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
Table 2
Galactosylation of methyl 6-(hydroxymethyl)picolinate 2a with galactosyl donors 1a–f
Entry
Donor
Ratio
Donor:acceptor
Temp Time
Promoter
Yielda (%)
Product
Ratio
a
:b
AcO
AcO
OAc
O
OAc
7
1.5:1
0 °C to rt 16 h
SnCl4 (5 equiv)/CF3CO2Ag (2.5 equiv)
<5b
ꢀ/ꢀ
OAc
1a
OAc
AcO
AcO
3a
b only
3a
b only
3a
8
9
1.5:1
1:1.5
rt 16 h
rt 18 h
Hg(CN)2 (4 equiv)
AgOTf (1.5 equiv)
11c
8
O
AcO
Br
10
2.5:1
rt 26 h
AgOTf (1.5 equiv)
18
1b
b only
AcO
AcO
OAc
O
3a
b only
3a
b only
3a
11
12
1.25:1
1.5:1
ꢀ20 °C 4 h
ꢀ20 °C 16 h
BF3ꢁEt2O (2 equiv) 4 Å MS
BF3ꢁEt2O (2 equiv) 4 Å MS
34
32
AcO
O
CCl3
NH
13
14
1.5:1
1.5:1
ꢀ20 °C 2 h
ꢀ20 °C 2 h
BF3ꢁEt2O (2 equiv)
BF3ꢁEt2O (2 equiv)
46
1c
b only
3a
36d
b only
ꢀ/ꢀ
15
16
1:3
3:1
ꢀ20 °C 2.5 h
ꢀ20 °C 16 h
BF3ꢁEt2O (2 equiv)
BF3ꢁEt2O (3 equiv)
<5b
42
3a
b only
b only
3a
b only
3a
17
18
1.5:1
2:1
ꢀ20 °C 1 h
ꢀ78 °C 3 h
TMSOTf (0.5 equiv) 4 Å MS
PhBF2 (2 equiv)
5e
16
19
1.5:1
ꢀ20 °C 2 h
PhBF2 (2 equiv)
14
b only
AcO
AcO
OAc
O
3a
b only
20
1.5:1
ꢀ20 °C 2 h
BF3ꢁEt2O (2 equiv)
32
AcO
1d
O
O
CF3
NPh
BzO
BzO
OBz
O
3b
b only
3b
b only
21
22
1.3:1
1.3:1
ꢀ20 °C 22 h
ꢀ20 °C 20 h
TMSOTf (2 equiv) 4 Å MS
33
42
BF3ꢁEt2O (3 equiv)
BzO
CCl3
1e
NH
BnO
BnO
OBn
O
3c
a
S
N
23
1:1
50 °C 78 h
MeI (4.5 equiv) 4 Å MS
75
OBn
onlyf
1f
a
b
c
d
e
f
Values are isolated yields.
Product could not be isolated but was detected by TLC.
The glycosylation was performed in CH3CN/CH2Cl2 (1/1, v/v).
The glycosylation was performed in CH3CN.
The main product isolated was methyl 6-(trimethylsilyloxymethyl)picolinate 2b.
Even if the b-anomer was formed during the reaction, it was not isolated by column chromatography.
their aromatic rings. The benzoylated trichloroacetimidate donor
1e42,43 was therefore used under the best conditions obtained
(Table 2, entry 13) although with only 1.3 equiv of donor excess
and prolonged reaction time (Table 2, entries 21 and 22). The yield
obtained was acceptable, but not improved, remaining below 42%.
The reactivity of the donor can be tuned by choosing the appro-
priate protecting groups on the carbohydrate scaffold.44,45 While
ester protected glycosyl donors (e.g., acetates or benzoates) would
be considered as disarmed and lead to poorer reactivity (i.e., longer
reactions and need for stronger promoters) in the glycosylation
reaction, the ether protected donors (e.g., benzyl) are armed and
would provide higher reactivities and better yields for the glycosyl-
ation. The 2-thiopyridyl perbenzylated donor 1f46 was therefore
investigated providing a good yield (75%) of the desired galactoside
3c (Table 2, entry 23) although with opposite stereochemistry at
the anomeric center, the a-anomer being favored in this case
due to the benzyl ether as a non-participating group at the
2-position.
As
a conclusion for the galactosylation of 6-(hydroxy-
methyl)picolinate 2a, the best conditions obtained after investigat-
ing four ester-protected galactosyl donors 1a–d under 16 different
reaction conditions are using the trichloroacetimidate donor with
boron trifluoride etherate as a promoter in excess (1.5 equiv) and
with only 2 h reaction time at low temperature (ꢀ20 °C) to afford
the desired b-anomer. Better yields, albeit with the opposite con-
figuration at the anomeric center, can be obtained with benzylated
armed donors such as 1f.
We then investigated the influence of the pyridine-based accep-
tors in order to address the influence of the basicity of the pyridine
ring under acid-promoted glycosylation conditions (Scheme 2).

S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
39
Me3SiO
OMe
OMe
N
AcO
AcO
OAc
O
2b
O
O
O
OMe
OMe
See Table 3
N
OAc
O
O
3a
3d
HO
N
AcO
AcO
OAc
AcO
AcO
OAc
O
O
2c
O
See Table 3
CCl3
O
See Table 3
N
O
AcO
1c
OAc
O
NH
HO
OMe
AcO
AcO
OAc
O
O
2d
O
OMe
See Table 3
OAc
3e
O
Scheme 2. Influence of the pyridine-based acceptor on the galactosylation reaction.
In the first attempt the silylated acceptor 2b was reintroduced
for galactosylation with the best donor identified in the previous
experiments, namely the trichloroacetimidate 1c. The acidic pro-
moter can trigger the cleavage of the trimethylsilyl group allowing
the glycosylation to proceed with the alcohol function newly gen-
erated.47–50 Nevertheless, only a very small amount of the desired
galactoside 3a (<5%) could be observed by TLC (but not isolated)
although the donor 1c was totally consumed while the silylated
acceptor 2b was largely unreacted (Table 3, entry 24). A common
method for masking the basicity of a pyridine ring is the oxidation
to the N-oxide derivative such as in 2c.51 Excess of promoter
should not be required under these conditions and while an excess
of glycosyl donor 1c was used, only very limited amounts of the de-
sired galactoside 3d could be isolated (Table 3, entry 25).
Finally, the influence of the nitrogen atom of the pyridine ring
could be clearly demonstrated by studying the galactosylation of
the methyl 3-hydroxymethylbenzoate acceptor 2d.52 When the
reaction was performed under the best conditions determined ear-
lier, a similar yield of 44% was obtained (Table 3, entry 26). Inter-
estingly, we could isolate and identify the acetylated acceptor,
namely methyl 3-acetoxymethylbenzoate, in 37% yield. Therefore,
using a threefold excess of acceptor provided a very good yield of
79% (Table 3, entry 27). While this last result appeared promising,
similar conditions and more specifically, the use of excess of donor
did not improve the yield when the pyridine-based acceptor 2a
was used (Table 2, entry 15)
2.2. N-Acetylglucosaminyl donors
After assessing the parameters influencing the glycosylation
reaction in the galactose series, we then studied the same reaction
for other donors 1g–m in the N-acetylglucosamine (GlcNAc) ser-
ies53–55 (Scheme 3).
The isoxazoline donor 1g56 is commonly employed for glycosyl-
ation in the GlcNAc series (also referred as GlcNAcylation). Even
though two different promoters were used, only moderate yields
could be obtained (Table 4, entries 28 and 29). The influence of
the protecting group at the 2-position of GlcNAc donors is largely
influencing the outcome of the reaction in terms of yields and
stereocontrol. Carbamates, such as donors 1h–k, are usually
invoked for their good stereocontrol in favor of b-anomers through
anchimeric participation while 2-azido-2-deoxy-derivatives 1l–m
would lead to
a-anomers. The 2,2,2-trichloroethyl-carbamate
(Troc) protecting group associated with an anomeric acetate leav-
ing group in donor 1h57,58 improved slightly the yield of GlcNAcy-
lation (Table 4, entry 30) to 25%. Much better results were then
obtained with the more sophisticated donor 1i59 bearing a trichlo-
roacetimidate as leaving group and more specifically under
Table 3
Influence of the pyridine-based acceptors 2b–d with the galactosyl donor 1c
Entry
Acceptor
Ratio
Donor:acceptor
Temp
Time
Promoter
Yielda (%)
Product
Ratio
a
:b
Me3SiO
HO
OMe
b
24
25
N
1.5:1
ꢀ20 °C 3 h
ꢀ20 °C 3 h
TMSOTf (1 equiv) 4 Å MS
ꢀ/ꢀ
3a
O
2b
OMe
3dc
32:68
N
2.25:1
BF3ꢁEt2O (0.6 equiv)
7
O
O
O
2c
3e
b only
3e
b only
26
27
1.5:1
1:3
ꢀ20 °C 2 h
ꢀ20 °C 1 h
BF3ꢁEt2O (0.2 equiv)
BF3ꢁEt2O (0.2 equiv)
44d
79
HO
OMe
2d
a
b
c
Values are isolated yields.
Product was not isolated but identified by TLC in a very small proportion.
Product was isolated as an inseparable mixture of hydroxylated donor, unreacted acceptor, a- and b-anomers. Yield was calculated excluding the unreacted 2c and 1c
based on 1H NMR data.
d
Acetylated acceptor (methyl 6-acetoxymethylbenzoate) was also isolated in 37% yield. This observation was not made for other glycosylation conditions.

40
S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
HO
OMe
OAc
N
OAc
O
O
AcO
AcO
2a
O
AcO
AcO
O
OMe
N
See Table 4
N
NHAc
O
1g
O
3f
Me
OAc
O
AcO
AcO
OAc
NHT roc
OAc
HO
OMe
AcO
OAc
N
O
1h
O
2a
See Table 4
AcO
AcO
O
OMe
N
O
NHTroc
O
3g
AcO
TrocHN
O
CCl3
NH
1i
OAc
O
AcO
OAc
NHAlloc
OAc
HO
OMe
AcO
OAc
N
2a
1j
O
O
AcO
AcO
O
OMe
N
See Table 4
O
NHAlloc
AcO
AcO
O
3h
AllocHN
1k
O
CCl3
NH
OAc
O
AcO
AcO
OAc
OAc
HO
OMe
N
2a
O
AcO
AcO
O
N3
1l
N3
OAc
See Table 4
O
OMe
3i
O
N
AcO
AcO
O
N
3O
CCl3
NH
1m
Scheme 3. Glycosylation of methyl 6-(hydroxymethyl)picolinate 2a with donors 1g–m.
activation with boron trifluoride etherate as a promoter (Table 4,
entries 31 and 32) leading to an isolated yield of 66%. The
introduction of an allyl-carbamate (Alloc) in donors 1j–k60,61 did
not provide better yields (Table 4, entries 33 and 34).
The GlcNAcylation was performed using seven different donors
with various protecting groups at the 2-position and under a total
of eleven synthetic methodologies. The best conditions found in
this series involved the use 2-azido-2-deoxy derivatives to obtain
The azido functionality is a general precursor of N-acetyl moie-
ties and its use in GlcNAcylation has two consequences. The azido
group is a non-participating group and, therefore, the glycoside ob-
the a-anomer while the Troc carbamate was preferred for prepara-
tion of the b-anomer.
tained is usually the
a-anomer, although some discrepancies can
2.3. Other glycosyl donors
be observed according to specific glycosylation conditions. The
need for the 2-acetamido substituent requires a subsequent reduc-
tion/acetylation process which must be included in the synthetic
strategy in terms of steps but also in terms of stability to further
elaboration of the target molecule. Nevertheless, these types of
2-azido-2-deoxy donors are quite useful and the peracetylated do-
nor 1l62–64 was used but provided only moderate yields (Table 4,
entries 35 and 36). Interestingly, a transfer of acetyl group was ob-
served from the glycosyl donor 1l to the acceptor 2a affording the
methyl 6-(acetoxymethyl)picolinate in 53% isolated yield (Table 4,
entries 35). This result explains in part the poor yields obtained
under these conditions since a good proportion of the acceptor
was trapped by this acetyl transfer, along with some decomposi-
tion of the donor losing one acetate protecting group. The 2-azi-
do-2-deoxy-glucopyranosyl trichloroacetimidate donor 1m65 was
treated with TMSOTf as a promoter but only small amounts of
the desired glycoside could be detected (Table 4, entry 37). A very
good yield of 82% could then finally be obtained using boron
trifluoride etherate as the promoter (Table 4, entry 38) but with
a partial erosion of stereoselectivity.
In order to broaden the scope of this glycosylation methodology
of pyridine-based acceptors, the reaction was studied with several
other glycosyl donors of monosaccharides (glucose, mannose, fu-
cose, and rhamnose) and one disaccharide (lactose). The reactions
were performed in dichloromethane usually involving a slight ex-
cess of the glycosyl donor in order to ensure maximal conversion of
the acceptor to the desired glycoside (Scheme 4).
2.3.1. Glucose
Glucosyl donors were evaluated as acetylated or benzoylated
trichloroacetimidates 1n66 and 1o67 respectively, and the yields
obtained were good (Table 5, entries 39 and 40) as previously ob-
served in the galactose series (Table 2, entry 13) with a slightly bet-
ter yield observed in the glucose series which was somewhat
unexpected. An improved yield of 85% was obtained as expected
when the more reactive armed benzylated donor 1p68 was used
although the promoter was changed to TMSOTf (Table 5, entries
41 and 42). The more sophisticated donor 1q69 can be used to
adjust the reactivity due to the bicyclic system involving the

S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
41
Table 4
Glycosylation in the GlcNAc series with methyl 6-(hydroxymethyl)picolinate 2a
Entry
Donor
Ratio
Donor:acceptor
Temp Time
Promoter
Yielda (%)
Product
Ratio
a
:b
OAc
O
3f
b only
3f
b only
28
29
1.1:1
1.5:1
60 °C 5.5 h
20 °C 22 h
CSA (1.2 equiv) 4 Å MS
17
20
AcO
AcO
BF3ꢁEt2O (3 equiv) 4 Å MS
N
O
1g
Me
OAc
O
3g
b only
AcO
AcO
OAc
30
1.1:1
ꢀ20 °C 22 h
TMSOTf (3 equiv)
25
NHTroc
1h
OAc
3g
b only
3g
b only
31
32
1.6:1
1.1:1
ꢀ2 °C 4.5 h
ꢀ20 °C 3 h
TMSOTf (2 equiv)
48
66
O
AcO
AcO
BF3ꢁEt2O (2 equiv)
TrocHN
O
CCl3
NH
1i
OAc
O
3h
b only
AcO
AcO
OAc
33
34
1.5:1
1.1:1
ꢀ20 °C, 3.5 h rt, 15.5 h
TMSOTf (3 equiv)
27
48
NHAlloc
1j
OAc
O
AcO
AcO
3hb
b only
ꢀ20 °C 17 h
BF3ꢁEt2O (3 equiv)
AllocHN
1k
O
CCl3
NH
OAc
35
36
1.5:1
1.5:1
ꢀ20 °C, 2.5 h rt, 16 h
ꢀ20 °C, 2.5 h rt, 16 h
TMSOTf (4 equiv)
BF3ꢁEt2O (4 equiv)
<5
35
3ic
3i
O
AcO
onlyd
OAc
n
a
AcO
N3
1l
OAc
O
3i
a
37
38
1.5:1
1.5:1
ꢀ20 °C 2 h
ꢀ20 °C, 2 h rt, 16 h
TMSOTf (2 equiv)
17
82
onlyd
AcO
AcO
BF3ꢁEt2O (4 equiv)
3i
N3
72:28
O
CCl3
NH
1m
a
Values are isolated yields.
b
Product was isolated as a mixture of b-anomer 3h and 0.3 equiv unreacted acceptor 2a and could not be separated due to similar polarity. Yield was calculated excluding
the unreacted acceptor 2a based on 1H NMR data.
c
Product could not be isolated but detected by TLC. A byproduct identified as methyl 6-(acetoxymethyl)picolinate was isolated in 53% yield.
Even if the b-anomer was formed during the reaction, it was not isolated by column chromatography.
d
benzylidene ring. Thus, donor 1q was reacted with 1-benzenesulfi-
nyl piperidine (BSP) and triflic anhydride as the activating agents
in the presence of 2,4,6-tri-tert-butylpyrimidine (TTBP) used as a
base.70 The reaction afforded in high yield (89%) the corresponding
orthoester 3m resulting from the attack of the nucleophilic alcohol
moiety of acceptor 2a on the resonating carbocation of the acti-
vated donor 1q (Table 5, entry 43).
2.3.3. Fucose and rhamnose
Glycosylation using 6-deoxyhexoses such as
L-fucose and
L-rhamnose is also of prime importance due to the relevant biolog-
ical implications of such carbohydrates in cancer and bacterial
infections.76,77 The peracetylated fucosyl trichloroacetimidate do-
nor 1t78 was therefore reacted under the best conditions elabo-
rated in the galactose series leading to a moderate isolated yield
of 39% of fucoside 3p (Table 5, entry 48). Similarly, the perbenzoy-
lated rhamnosyl trichloroacetimidate donor 1u79 afforded the de-
sired rhamnoside 3q in 66% isolated yield using TMSOTf as a
promoter (Table 5, entry 49).
2.3.2. Mannose
Mannosylation is a challenging reaction, especially the forma-
tion of 1,2-cis mannosides with b-configuration at the anomeric
center.2,71,72 The benzoylated trichloroacetimidate mannosyl
donor 1r73 afforded the desired
a-mannoside 3n in good yield
2.3.4. Lactose
(Table 5, entries 44 and 45). When a bicyclic and more reactive
armed donor 1s74 was used, the b-mannoside 3o was isolated in
68% yield (Table 5, entry 46) and with an optimal isolated of 80%
when using a slight excess of acceptor 2a although with a poorer
stereoselectivity (Table 5, entry 47). The configurations at the ano-
meric carbon of mannosides 3n and 3o were clearly identified from
the 1J coupling constants measured between the anomeric carbon
(C-1) and the anomeric proton (H-1) with values above 170 Hz as
Finally, the perbenzoylated lactosyl trichloroacetimidate donor
1v80 was reacted with the acceptor 2a using boron trifluoride
etherate as a promoter and afforded the desired lactoside 3r in
51% isolated yield (Table 5, entry 50).
Glycosylation of a pyridine-based acceptor has been investi-
gated for a series of 22 glycosyl donors derived from glucose,
galactose, mannose, fucose, rhamnose, and lactose and using a
large number of activating groups at the anomeric center (e.g., ace-
tate, bromide, tricholoracetimidate, and thiophenyl) and with a
complete set of activating conditions and numerous promoters.
expected for
a-mannosides versus values below 160 Hz for
b-mannosides.75

42
S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
OAc
OAc
O
AcO
AcO
O
AcO
AcO
O
OMe
OMe
AcO
1n
OBz
N
N
OAc
O
O
CCl3
NH
O
O
3j
OBz
O
BzO
BzO
O
BzO
BzO
O
BzO
1o
OBz
CCl3
NH
3k
OBn
OBn
O
BnO
BnO
O
BnO
BnO
OAc
BnO
OBn
O
OMe
1p
3l
N
HO
OMe
N
O
Ph
Ph
O
O
O
O
O
2a
O
O
SPh
AcO
Av
See Table 5
O
OAc
O
O
3m
1q
Me
OBz
OMe
N
OBz
O
BzO
BzO
BzO
O
BzO
BzO
BzO
O
O
CCl3
NH
1r
O
OMe
3n
N
O
O
OBn
O
Ph
OBn
O
O
O
Ph
O
O
BnO
1s
O
OMe
BnO
N
SPh
O
3o
NH
O
CCl3
Me
N
O
Me
O
O
OMe
OMe
OAc
OAc
OAc
1t
OAc
AcO
AcO
3p
NH
O
N
O
CCl3
O
Me
O
Me
BzO
O
BzO
OBz
OBz
OBz
OBz
3q
1u
BzO
BzO
OBz
OBz
BzO
BzO
OBz
OBz
O
O
O
O
O
O
O
OMe
BzO
BzO
N
BzO
OBz
1v
OBz
O
CCl3
NH
OBz
3r
O
Scheme 4. Glycosylation of methyl 6-(hydroxymethyl)picolinate 2a with mono- and disaccharidic glycosyl donors 1n–v.
The pyridine moiety was demonstrated to have a negative influ-
ence on the reaction since glycosylation with a ‘benzene-based’ do-
nor 2d afforded high yields in comparison to the pyridine donor 2a.
Therefore, the basicity of the pyridine ring could be identified as a
limitation to the outcome of the glycosylation reaction. The best
conditions for the glycosylation of the model donor methyl 6-
(hydroxymethyl)picolinate 2a could therefore be identified for
each type of glycosyl donor and provided isolated yields of glyco-
sides from 46% to 85%.
or nanotechnology. A main preoccupation for chemists is the
design of powerful and reliable glycosylation methodologies which
are still required in order to better control the stereoselectivity of
this reaction. Nevertheless, another main feature of glycosylation
reaction is the fact that the reaction is catalyzed by acid promoters
being Lewis or Brønsted acids. We have identified the glycosylation
of pyridine-based donors as challenging. Only very few earlier
studies have been reported, mainly focusing on biochemical
approaches and the chemical syntheses were always quite poor
in terms of yields.
Since glycosylation is usually an acid-promoted reaction,
pyridine-containing acceptors are therefore competing with the
acid promoter due to the intrinsic basicity of the pyridine moiety.
In order to achieve good glycosylation yields, the promoter was
3. Conclusion
The realm of glycomics is now a challenging domain of science
at the interface of chemistry, biology, medical sciences, and physics

S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
43
Table 5
Glycosylation of methyl 6-(hydroxymethyl)picolinate 2a with mono- and disaccharidic glycosyl donors 1n–v
Entry
Donor
Ratio
Donor:acceptor
Temp
Time
Promoter
Yielda (%)
Product
Ratio
a
:b
OAc
O
AcO
AcO
3j
b only
39
40
1.5:1
1.3:1
ꢀ20 °C 22 h
BF3ꢁEt2O (3 equiv)
53
61
AcO
O
O
CCl3
NH
1n
OBz
O
BzO
BzO
3kb
b only
ꢀ20 °C 22.5 h
TMSOTf (2 equiv) 4 Å MS
BzO
1o
CCl3
NH
OBn
O
3l
a
3l
a
41
42
1.3:1
1.3:1
ꢀ20 °C 20.5 h
ꢀ20 °C 22.5 h
BF3ꢁEt2O (4 equiv)
TMSOTf (2 equiv)
60
85
only
only
BnO
BnO
OAc
OBn
1p
Ph
O
BSP (1.2 equiv)
TTBP (1.5 equiv)
Tf2O (1.3 equiv)
1-octene (2 equiv)
O
O
SPh
43
1:1.15
ꢀ60 °C 0.5 h ꢀ78°C 3 h
89
3m
3nc
AcO
OAc
1q
OBz
O
BzO
BzO
BzO
44
45
1.3:1
1.3:1
ꢀ20 °C 22.5 h
ꢀ20 °C 22.5 h
BF3ꢁEt2O (2 equiv)
TMSOTf (2 equiv)
48
22
a
only
3nc
a
only
O
CCl3
NH
1r
3od
OBn
O
TMSOTf (2 equiv)
NIS (1.56 equiv)
BSP (1.2 equiv)
TTBP (1.5 equiv)
Tf2O (1.3 equiv)
1-octene (2 equiv)
O
Ph
46
47
1.3:1
ꢀ40 °C 5.5 h
ꢀ60 °C 0.5 h ꢀ78°C 3 h
68
80
O
b onlye
3of
BnO
1:1.15
19:81
SPh
1s
NH
O
CCl3
3p
48
49
50
1.5:1
1.3:1
1:1
ꢀ20 °C 2 h
ꢀ20 °C 4 h
ꢀ20 °C 4 h
BF3ꢁEt2O (2 equiv) CH2Cl2
TMSOTf (0.8 equiv)
BF3ꢁEt2O (2 equiv)
39
66
51
Me
O
b only
OAc
1t
OAc
AcO
NH
O
CCl3
3q
Me
O
a
only
BzO
1u
OBz
OBz
BzO
BzO
OBz
OBz
O
O
O
3r
b only
BzO
BzO
OBz
O
CCl3
NH
1v
a
Values are isolated yields.
b
Product was isolated as a mixture of b-anomer 3k and 0.2 equiv unreacted acceptor 2a and could not be separated due to similar polarity. Yield was calculated excluding
the unreacted acceptor 2a based on 1H NMR data.
c
1
Configuration at the a-anomeric center was confirmed by the JC-1,H-1 = 172.4 Hz value.
d
e
f
1
Configuration at the b-anomeric center was confirmed by the JC-1,H-1 = 155.5 Hz value.
Even if the -anomer was formed during the reaction, it was not isolated by column chromatography.
Configuration at the
a
1
a-anomeric center was confirmed by the JC-1,H-1 = 171.5 Hz value.
systematically used in excess (>1.1 equiv). Some very good results
could then be obtained for the glycosylation of methyl 6-
(hydroxymethyl)picolinate chosen as a model substrate for the
present study. A detailed and in depth study was therefore per-
formed in order to determine the influence of the glycosyl donor
being galactose, glucose, or mannose but also the nature of the
leaving group at the anomeric carbon such as halogens or trichlo-
roacetimidates. A series of 22 glycosyl donors were tested and a
reliable and efficient glycosylation could in all cases be obtained
for each type of glycosylation. The present study provides a gen-
eral and reliable access to ‘pyridine’-containing glycosides. The
best conditions for b-galactosylation were obtained using an
acetylated trichloroacetimidate donor in the presence of boron
trifluoride etherate, while a-galactosylation involved a benzylated
2-thiopyridyl donor. The 2-trichloroethoxycarbamate protecting
group was identified as optimal for the b-glycosylation of
N-acetylglucosamine. b-Glucosylation was readily achieved from
the benzoylated trichloroacetimidate donor while
a-glucosides
were obtained from the benzylated 1-O-acetyl donor. b-Mannosy-
lation was achieved using the benzylated thiophenyl 4,6-O-ben-
zylidene-
perform than
a
-
D
-mannopyranoside donor and proved easier to
-mannosylation.
a

44
S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
The glycosides prepared here will next be conjugated with
4.3. (6-Methoxycarbonylpyrid-2-yl)methyl 2,3,4,6-tetra-O-
benzyl- -galactopyranoside (3c)
5-aminonucleoside for the design of neutral glycosyltransferase
inhibitors. Their pyridine moiety will be considered as a chelating
agent for binding to the cation involved in most of the enzymatic
reactions catalyzed by such enzymes while their neutral character
should allow them to penetrate cells and find applications for
in vivo studies. This strategy is now under investigation in our
laboratory and the results will be reported in due course.
a-D
To
a dried round bottom flask containing 1f (618 mg,
0.896 mmol, 1 equiv), 2a (164 mg, 0.896 mmol, 1 equiv) in CH2Cl2
(1 mL) was added methyl iodide (0.18 mL, 3 equiv). Then, the reac-
tion mixture was stirred at 50 °C in the presence of 4 Å MS. After
22 h, another portion of methyl iodide (0.09 mL, 1.5 equiv) was
added. After another 55 h, the reaction mixture was filtered
through celite, washed with CH2Cl2 and evaporated to dryness.
The residue was purified by silica gel column chromatography
(PE/EtOAc, 4:1 to 3:1) to afford 3c as a white foam (506 mg,
4. Experimental section
75%). Rf = 0.24 (PE/EtOAc = 3:1); ½a D20
ꢂ
+46.0 (CH2Cl2, c 0.2); 1H
4.1. Materials and methods
NMR (400 MHz, CDCl3) d (ppm) = 8.01 (d, J = 7.4 Hz, 1H, HPyr),
7.79 (d, J = 7.7 Hz, 1H, HPyr), 7.71 (t, J = 7.7 Hz, 1H, HPyr), 7.44–
7.27 (m, 20H, HAr), 4.99–4.73 (m, 7H, H1, 4 ꢃ OCH2a, 2 ꢃ OCH2b),
4.67 (d, J = 11.9 Hz, 1H, OCH2b), 4.59 (d, J = 11.4 Hz, 1H, OCH2b),
4.46 and 4.39 (2d, AB system, J = 11.7 Hz, 2H, OCH2a, OCH2b), 4.13
(dd, J = 10.3, 3.1 Hz, 1H, H2), 4.05 (m, 3H, H3, H4, H5), 3.99 (s, 3H,
OMe), 3.62–3.55 (m, 1H, H6a), 3.48 (dd, J = 9.1, 5.5 Hz, 1H, H6b);
All reagents were obtained from commercial sources and used
without further purification. Dichloromethane and acetonitrile
were distilled over CaH2. All reactions were performed under an
argon atmosphere. Thin-layer chromatography (TLC) was carried
out on aluminum sheets coated with silica gel 60 F254 (Merck).
TLC plates were inspected by UV light (k = 254 nm) and developed
by treatment with a mixture of 10% H2SO4 in EtOH/H2O (1:1 v/v)
followed by heating. Silica gel column chromatography was
13C NMR (100 MHz, CDCl3)
d (ppm) = 165.9 (CO2Me), 159.2,
147.3, 138.84, 138.79 (CPyrH), 138.7, 138.0, 137.8, 128.6, 128.51,
128.49, 128.36, 128.27, 128.05, 128.00, 127.9, 127.8, 127.69,
127.65, 127.60, 124.9 (CPyrH), 124.0 (CPyrH), 98.0 (C1), 79.2 (C3 or
C4 or C5), 76.7 (C2), 75.0 (s, 2C, C3 or C4 or C5, OCH2), 73.9
(OCH2), 73.7 (OCH2), 73.1 (OCH2), 70.0 (OCH2), 69.8 (C3 or C4 or
C5), 68.7 (C6), 53.1 (OMe); HRMS m/z: Calcd for C42H44NO8,
[M+H]+ 690.3061, found 690.3052.
performed with silica gel Si 60 (40–63 lm). NMR spectra were
recorded at 293 K, unless otherwise stated, using a Bruker 400
or 500 MHz spectrometers. Chemical shifts are referenced relative
to deuterated solvent residual peaks. The following abbreviations
are used to explain the observed multiplicities: s, singlet; d,
doublet; t, triplet; q, quadruplet; m, multiplet and bs, broad sin-
glet. Complete signal assignments were based on 1D and 2D NMR
(COSY, HSQC, and HMBC correlations). High resolution (HR-
ESI-QToF) mass spectra were recorded using a Bruker MicroToF-
Q II XL spectrometer. Optical rotation was measured using a
Perkin Elmer polarimeter at 20 °C and values are given in
4.4. (6-Methoxycarbonylpyrid-2-yl)methyl 3,4,6-tri-O-acetyl-2-
deoxy-2-trichloroethoxycarbonylamino-b-D-glucopyranoside
(3g)
10ꢀ1 deg cm2 gꢀ1
.
BF3ꢁEt2O (38
lL, 0.3 mmol, 1 equiv) was added dropwise into a
stirred solution of 2a (50 mg, 0.30 mmol, 1 equiv) and 1i
A selection of the best glycosylation conditions is reported
below while the complete set of experimental procedures for
Tables 2–5 and complete characterization of new compounds and
copies of the 1H and 13C NMR data is reported in the Supporting
Information of this manuscript.
(206 mg, 0.33 mmol, 1.1 equiv) in freshly distilled CH2Cl2 (3 mL)
at ꢀ20 °C under argon. After 2 h, additional BF3ꢁEt2O (38
lL,
0.3 mmol, 1 equiv) was added into the reaction. After another
1 h, Et3N (0.2 mL) was injected into the reaction mixture at
ꢀ20 °C to quench the reaction. Then, the solvent was evaporated
and the residue was purified by silica gel column chromatography
(PE/EtOAc, 9:1 to 1:1) to afford 3g as a white foam (124 mg, 66%).
4.2. (6-Methoxycarbonylpyrid-2-yl)methyl 2,3,4,6-tetra-
O-acetyl-b-
D-galactopyranoside (3a)
Rf = 0.32 (PE/EtOAc = 1:1); ½a D20
ꢂ
ꢀ10.2 (CH2Cl2, c 1.2); 1H NMR
BF3ꢁEt2O (62
l
L, 0.488 mmol, 2 equiv) was added dropwise to a
(400 MHz, CDCl3) d (ppm) = 8.03 (d, J = 7.4 Hz, 1H, Hpyr), 7.82 (t,
stirred solution of 2a (41 mg, 0.244 mmol, 1 equiv) and 1c
(169 mg, 0.366 mmol, 1.5 equiv) in freshly distilled CH2Cl2 (3 mL)
at ꢀ20 °C. The reaction mixture was stirred at ꢀ20 °C for 2 h.
Et3N (0.2 mL) was injected to quench the reaction. The reaction
mixture was concentrated and the residue was purified by silica
gel column chromatography (PE/EtOAc, 9:1 to 3:2) to afford 3a
J = 7.8 Hz, 1H,
Hpyr), 7.47 (d, J = 7.8 Hz, 1H, Hpyr), 6.34 (d,
J = 9.1 Hz, 1H, NH), 5.25–5.19 (m, 1H, H3), 5.12 (t, J = 9.6 Hz, 1H,
H4), 5.06–5.03 (m, 2H, H1, OCH2a), 4.92 (d, J = 15.0 Hz, 1H, OCH2b),
4.63 (2d, AB system, J = 12.1 Hz, 2H, CH2CCl3), 4.26 (dd, J = 12.3,
4.9 Hz, 1H, H6a), 4.15–4.12 (m, 1H, H6b), 4.02 (s, 3H, OMe), 3.94
(m, 1H, H2), 3.72 (ddd, J = 9.8, 4.7, 2.2 Hz, 1H, H5), 2.03 (s, 3H,
COCH3), 2.03 (s, 3H, COCH3), 2.02 (s, 3H, COCH3); 13C NMR
(100 MHz, CDCl3) d (ppm) = 170.9 (C@O), 170.8 (C@O), 169.5
(C@O), 165.5 (Cpyr), 156.0 (C@O), 154.9 (C@O), 147.2 (Cpyr), 137.9
(CpyrH), 124.6 (CpyrH), 124.2 (CpyrH), 101.5 (C1), 95.6 (CCl3), 74.5
(CH2CCl3), 72.9 (C3), 72.3 (C5), 70.3 (OCH2), 68.5 (C4), 62.2 (C6),
56.3 (C2), 53.2 (OMe), 20.9 (COCH3), 20.8 (COCH3), 20.7 (COCH3);
HRMS m/z: Calcd for C23H28Cl3N2O12, [M+H]+ 629.0702, found
629.0697.
as a white foam (56 mg, 46%). Rf = 0.26 (PE/EtOAc = 1:2); ½a D20
ꢂ
ꢀ14.0 (CH2Cl2, c 0.5); 1H NMR (400 MHz, CDCl3) d (ppm) =
8.04 (d, J = 7.7 Hz, 1H, HPyr), 7.86 (t, J = 7.8 Hz, 1H, HPyr), 7.65
(d, J = 7.6 Hz, 1H, HPyr), 5.41 (d, J = 3.3 Hz, 1H, H4), 5.34 (dd,
J = 10.5, 7.9 Hz, 1H, H2), 5.15 (d, J = 13.9 Hz, 1H, OCH2a), 5.04 (dd,
J = 10.4, 3.4 Hz, 1H, H3), 4.86 (d, J = 13.7 Hz, 1H, OCH2b), 4.65
(d, J = 7.9 Hz, 1H, H1), 4.16–4.12 (m, 2H, H6a, H6b), 4.00 (s, 3H,
OMe), 3.95 (t, J = 6.4 Hz, 1H, H5), 2.16 (s, 3H, COCH3), 2.05 (s, 6H,
2 ꢃ COCH3), 1.99 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) d
(ppm) = 170.6 (C@O), 170.4 (C@O), 170.2 (C@O), 169.7 (C@O),
165.7 (CO2Me), 158.3 (CPyr), 147.2 (CPyr), 138.0 (CPyrH), 124.6
(CPyrH), 124.2 (CPyrH), 101.2 (C1), 71.8 (OCH2), 71.1 (C5), 70.9 (C3),
69.0 (C2), 67.2 (C4), 61.6 (C6), 53.2 (OMe), 20.9 (COCH3), 20.8
(COCH3), 20.8 (COCH3), 20.7 (COCH3); HRMS m/z: Calcd for
4.5. (6-Methoxycarbonylpyrid-2-yl)methyl 2,3,4,6-tetra-O-
benzoyl-b-D-glucopyranoside (3k)
The trichloroacetimidate 1o (87 mg, 0.117 mmol, 1.3 equiv) was
dissolved in freshly distilled CH2Cl2 (5 mL) under argon in the pres-
C
22H28NO12, [M+H]+ 498.1606, found 498.1604.

S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
45
ence of 4 Å MS. Then, the mixture was cooled down to ꢀ20 °C.
TMSOTf (3.3
2a (15 mg, 0.090 mmol, 1 equiv) dissolved in 1.5 mL of freshly dis-
4.7. (6-Methoxycarbonylpyrid-2-yl)methyl 2,3-di-O-benzyl-4,6-
O-benzylidene-b- -mannopyranoside (3o)
l
L, 0.018 mmol, 0.2 equiv) was added at ꢀ20 °C, then
D
tilled CH2Cl2 was added. The reaction mixture was stirred at
To a solution of 1s (126 mg, 1.3 equiv) and 2a (30 mg, 1 equiv)
in 10 mL freshly distilled CH2Cl2 at ꢀ40 °C was added NIS
ꢀ20 °C for 30 min. Another 3.3
lL of TMSOTf (0.2 equiv) was
added. After 1 h, another portion of TMSOTf (3.3
lL, 0.018 mmol,
(63 mg, 1.56 equiv) and TMSOTf (6.5 lL, 0.2 equiv). The reaction
0.2 equiv) was added. After 2.5 h, TMSOTf (6.6
0.4 equiv) was added. Then, after 2 h, another 1 equiv of TMSOTf
l
L, 0.039 mmol,
was stirred for a total of 5.5 h, and the addition of TMSOTf was
according to the following: 6.5 L (0.2 equiv) after 1 h, 19.5
(0.2 equiv) after 2 h, and finally another 33 L (1 equiv) after 3 h,
l
lL
(16.5 L) was added and the reaction mixture was stirred at
l
l
ꢀ20 °C for another 16 h. Et3N (0.2 mL) was injected at ꢀ20 °C to
quench the reaction. The reaction mixture was filtered and washed
with CH2Cl2. The solvent was evaporated, then, the residue was
purified by silica gel column chromatography (PE/EtOAc, 9:1 to
7:3) to afford 3k as a white foam (41 mg, 61%). Rf = 0.29 (PE/
EtOAc = 2:1); 1H NMR (400 MHz, CDCl3) d (ppm) = 7.98–7.15 (m,
23H, HAr), 5.85 (t, J = 9.7 Hz, 1H, H3), 5.69–5.55 (m, 2H, H2, H4),
5.07 (d, J = 14.3 Hz, 1H, OCH2a), 4.94 (d, J = 7.8 Hz, 1H, H1), 4.87
(d, J = 14.3 Hz, 1H, OCH2b), 4.55 (dd, J = 12.2, 2.9 Hz, 1H, H6a),
4.41 (dd, J = 12.2, 5.2 Hz, 1H, H6b), 4.16–4.08 (m, 1H, H5), 3.90
(s, 3H, OMe); 13C NMR (100 MHz, CDCl3) d (ppm) = 166.2, 165.9,
165.6, 165.3, 165.2, 158.3, 147.0, 137.7, 133.6, 133.5, 133.4,
133.3, 129.92, 129.91, 129.86, 129.6, 129.2, 128.82, 128.79,
128.53, 128.51, 128.4, 124.9, 124.1, 101.2 (C1), 72.9, 72.5, 72.2,
72.0, 69.6, 63.1, 53.1; HRMS m/z: Calcd for C42H36NO12, [M+H]+
746.2232, found 746.2221.
for a total of 2 equiv. After 2.5 h the reaction was complete, the
reaction was quenched by adding satd aq NaHCO3 (10 mL). The
reaction mixture was diluted with CH2Cl2 (50 mL), warmed to
room temperature and washed with satd aq NaHCO3 (2 ꢃ 50 mL).
The aqueous layers were combined and extracted with CH2Cl2
(2 ꢃ 50 mL), after which the combined organic layers were washed
with brine (50 mL), dried (Na2SO4) and concentrated. The crude
product was purified by column chromatography (PE/EtOAc, 2:1)
to yield 3o as a slightly yellow amorphous solid (73 mg, 68%).
Rf = 0.38 (hexane/EtOAc = 1:1); ½a D20
ꢂ
ꢀ111.1 (CH2Cl2, c 1.8); 1H
NMR (400 MHz, CDCl3) d (ppm) = 8.00 (dd, J = 7.7 Hz, 1.0 Hz, 1H,
HPyr), 7.79 (dd, J = 7.8 Hz, 7.7 Hz, 1H, HPyr), 7.56 (dd, J = 7.8 Hz,
1.0 Hz, 1H, HPyr), 7.50–7.20 (m, 15 H, HAr), 5.58 (s, 1H, 4,6-OCHPh),
5.10(d, J = 13.9 Hz, 1H, OCH2Pyr), 4.97 (d, J = 12.2 Hz, 1H, OCH2Ph),
4.90 (d, J = 12.2 Hz, 1H, OCH2Ph), 4.82 (d, J = 13.9 Hz, 1H, OCH2Pyr),
4.70 (d, J = 12.4 Hz, 1H, OCH2Ph), 4.59 (d, J = 12.4 Hz, 1H, OCH2Ph),
4.58 (s, 1H, H1), 4.24 (dd, J = 10.5 Hz, 4.8 Hz, 1H, H6a), 4.21 (dd,
J = 9.9 Hz, 9.3 Hz, 1H, H4), 4.00 (d, J = 3.0 Hz, 1H, H2), 3.95 (s, 3H,
OCH3), 3.88 (dd, J = 10.5 Hz, 10.1 Hz, 1H, H6b), 3.60 (dd, J = 9.9 Hz,
3.0 Hz, 1H, H3), 3.32 (ddd, J = 10.1 Hz, 9.3 Hz, 4.8 Hz, 1H, H5). 13C
NMR (100 MHz, CDCl3) d (ppm) = 165.6 (CO2Me), 158.6 (CPyr),
4.6. (6-Methoxycarbonylpyrid-2-yl)methyl 2,3,4,6-tetra-
O-benzyl-a-D-glucopyranoside (3l)
To a solution of 1p (136 mg, 1.3 equiv) and 2a (30 mg, 1 equiv)
in 10 mL freshly distilled CH2Cl2 at ꢀ20 °C was added TMSOTf
147.2 (CPyr), 137.8 (CPyr), 138.4, 138.3, 137.6, 128.9, 128.7, 127.7,
1
127.6, 126.1, 124.7 (CPyr), 124.0 (CPyr), 101.8 (C1, JC-1,
H-
(6.5 lL, 0.2 equiv). The reaction was stirred for a total of 22.5 h,
1 = 155.5 Hz), 101.5 (4,6-OCHPh), 78.7 (C4), 78.0 (C3), 76.1 (C2),
75.0 (OCH2Ph), 72.6 (OCH2Ph), 72.0 (OCH2Pyr), 68.2 (C6), 67.7
(C5), 53.0(OCH3); HRMS m/z: Calcd for C35H36NO8 [M+H]+
598.2441, found 598.2432; C35H35NO8Na [M+Na]+ 620.2260, found
620.2264; C35H35NO8K [M+K]+ 636.2000, found 636.2042.
and the addition of TMSOTf was according to the following:
6.5 L (0.2 equiv) after 0.5 h, 19.5 L (0.6 equiv) after 2 h, 33
(1 equiv) after 3.5 h, and finally another 33 L (1 equiv) after 6 h
l
l
lL
l
for a total of 2 equiv. After 16.5 h the reaction was complete, the
reaction mixture was diluted with CH2Cl2 (25 mL) and washed
with satd aq NaHCO3 (2 ꢃ 25 mL). The aqueous layers were
combined and extracted with CH2Cl2 (2 ꢃ 25 mL) after which the
combined organic layers were washed with brine (30 mL), dried
(Na2SO4) and concentrated. The crude product was purified by
column chromatography (PE/EtOAc, 2:1) to yield 3l as a colorless
Acknowledgments
The authors thank the Université Claude Bernard Lyon 1, the
CNRS and the Academy of Finland (research Grant #252371) for
financial support. S.W. thanks the Ministère de la Recherche for a
PhD stipend. Dr. F. Albrieux, C. Duchamp, and N. Henriques are
gratefully acknowledged for mass spectrometry analyses and Dr.
Filip Ekhom (Glykos Finland Ltd) for helpful discussions. COST Ac-
tion CM-1102 is gratefully acknowledged for STSM funding to J.R.
oil (105 mg, 85%). Rf = 0.31 (PE/EtOAc = 2:1); ½a D20
ꢂ
+18.2 (CH2Cl2,
c 3.6); 1H NMR (400 MHz, CDCl3) d (ppm) = 8.05 (dd, J = 7.7 Hz,
1.1 Hz, 1H, HPyr), 7.82 (dd, J = 7.9 Hz, 1.1 Hz, 1H, HPyr), 7.79
(dd, J = 7.9 Hz, 7.7 Hz, 1H, HPyr), 7.45–7.10 (m, 20 H, HAr), 5.05
(d, J = 10.9 Hz, 1H, OCH2Ph), 4.98 (d, J = 3.6 Hz, 1H, H1), 4.96
(d, J = 14.5 Hz, 1H, OCH2aPyr), 4.90 (d, J = 10.9 Hz, 1H, OCH2Ph),
Supplementary data
4.84 (d, J = 11.9 Hz, 1H, OCH2Ph), 4.80 (d,
J =14.5 Hz, 1H,
OCH2bPyr), 4.67 (d, J = 10.7 Hz, 1H, OCH2Ph), 4.64 (d, J = 12.1 Hz,
1H, OCH2Ph), 4.52 (d, J =10.7 Hz, 1H, OCH2Ph), 4.52 (d, J=
11.9 Hz, 1H, OCH2Ph), 4.49 (d, J = 12.1 Hz, 1H, OCH2Ph), 4.11
(dd, J = 9.7 Hz, 9.0 Hz, 1H, H3), 4.01 (s, 3H, OCH3), 3.86 (ddd,
J = 10.1 Hz, 3.1 Hz, 2.0 Hz, 1H, H5), 3.77 (dd, J = 10.7 Hz, 3.1 Hz,
1H, H6a), 3.77 (dd, J = 10.1 Hz, 9.0 Hz, 1H, H4), 3.68 (dd, J =
9.7 Hz, 3.6 Hz, 1H, H2), 3.64 (dd, J = 10.7 Hz, 2.0 Hz, 1H, H6b);
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2013.
02.009.
References
1. Codee, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft, H. S.; van der
Marel, G. A. Chem. Soc. Rev. 2005, 34, 769–782.
13C NMR (100 MHz, CDCl3)
d (ppm) = 165.7 (CO2Me), 158.8
(CPyr), 147.3 (CPyr), 137.6 (CPyr), 138.8, 138.2, 137.7, 138.8,
128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 124.7 (CPyr),
124.0 (CPyr), 97.2 (C1), 82.1 (C3), 80.1 (C2), 77.6 (C4), 75.8
(OCH2Ph), 75.2 (OCH2Ph), 73.6 (s, 2C, OCH2Ph, OCH2Ph), 70.8
(C5), 69.8 (OCH2Pyr), 68.3 (C6), 53.0 (OCH3); HRMS m/z: Calcd
for C42H44NO8 [M+H]+ 690.3061, found 690.3047; C42H43NO8Na
[M+Na]+ 712.2861, found 712.2881; C42H43 NO8K [M+K]+
728.2620, found 728.2615.
2. Crich, D. Acc. Chem. Res. 2010, 43, 1144–1153.
3. Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137–2160.
4. Demchenko, A. V. Synlett 2003, 1225–1240.
5. Fügedi, P. Glycosylation Methods. In The Organic Chemistry of Sugars; Levy, D. E.,
Fügedi, P., Eds.; Taylor & Francis: New York, 2006; pp 89–180.
6. Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007.
7. Jensen, K. J. J. Chem. Soc., Perkin Trans. 1 2002, 2219–2233.
8. Schmidt, R. R.; Kinzy, W.; Derek, H. Anomeric-Oxygen Activation for Glycoside
Synthesis: The Trichloroacetimidate Method. In Advances in Carbohydrate
Chemistry and Biochemistry; Academic Press: New York, 1994; pp 21–123.

46
S. Wang et al. / Carbohydrate Research 372 (2013) 35–46
9. Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934.
50. Ziegler, T.; Seidl, U. J. Carbohydr. Chem. 1991, 10, 813–831.
51. Keizers, P. H. J.; Saragliadis, A.; Hiruma, Y.; Overhand, M.; Ubbink, M. J. Am.
Chem. Soc. 2008, 130, 14802–14812.
52. Breschi, M. C.; Calderone, V.; Digiacomo, M.; Macchia, M.; Martelli, A.;
Martinotti, E.; Minutolo, F.; Rapposelli, S.; Rossello, A.; Testai, L.; Balsamo, A.
J. Med. Chem. 2006, 49, 2628–2639.
53. Banoub, J.; Boullanger, P.; Lafont, D. Chem. Rev. 1992, 92, 1167–1195.
54. Bongat, A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342, 374–406.
55. Enugala, R.; Carvalho, L. C. R.; Dias Pires, M. J.; Marques, M. M. B. Chem. Asian J.
2012, 7, 2482–2501.
10. Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819–6825.
11. Smoot, J. T.; Demchenko, A. V. J. Org. Chem. 2008, 73, 8838–8850.
12. Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem., Int. Ed. 2005, 44,
7123–7126.
13. Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc. 2012, 134, 20097–20102.
14. Jiang, J.; Lazarus, M. B.; Pasquina, L.; Sliz, P.; Walker, S. Nat. Chem. Biol. 2012, 8,
72–77.
15. Jorgensen, R.; Grimm, L. L.; Sindhuwinata, N.; Peters, T.; Palcic, M. M. Angew.
Chem., Int. Ed. 2012, 51, 4171–4175.
16. Schaefer, K.; Albers, J.; Sindhuwinata, N.; Peters, T.; Meyer, B. ChemBioChem
2012, 13, 443–450.
17. Vembaiyan, K.; Pearcey, J. A.; Bhasin, M.; Lowary, T. L.; Zou, W. Bioorg. Med.
Chem. 2011, 19, 58–66.
56. Matta, K. L.; Bahl, O. P. Carbohydr. Res. 1972, 21, 460–464.
57. Boullanger, P.; Jouineau, M.; Bouammali, B.; Lafont, D.; Descotes, G. Carbohydr.
Res. 1990, 202, 151–164.
58. Paulsen, H.; Krogmann, C. Liebigs Ann. Chem. 1989, 1203–1213.
59. Paulsen, H.; Helpap, B. Carbohydr. Res. 1992, 216, 289–313.
60. Boullanger, P.; Banoub, J.; Descotes, G. Can. J. Chem. 1987, 65, 1343–1348.
61. Vargas-Berenguel, A.; Meldal, M.; Paulsen, H.; Bock, K. J. Chem. Soc., Perkin
Trans. 1 1994, 2615–2619.
ˇ
ˇ
18. Weignerová, L.; Suzuki, Y.; Hunková, Z.; Sedmera, P.; Havlícek, V.; Marek, R.;
ˇ
Kren, V. Collect. Czech. Chem. Commun. 1999, 64, 1325–1334.
19. Asano, Y.; Wada, K. Biosci. Biotechnol. Biochem. 2003, 67, 499–507.
20. Wada, K.; Asano, Y. Appl. Environ. Microbiol. 2003, 69, 7058–7062.
21. Charles, R. E.; Divakar, S. Biosci. Biotechnol. Biochem. 2009, 73, 233–236.
22. Tramice, A.; Giordano, A.; Andreotti, G.; Mollo, E.; Trincone, A. Mar. Biotechnol.
2006, 8, 448–452.
62. Compound 1l was prepared from commercially available 2-azido-2-deoxy-D-
glucose in refluxing acetic anhydride in the presence of sodium acetate.
63. Orgueira, H. A.; Bartolozzi, A.; Schell, P.; Litjens, R. E. J. N.; Palmacci, E. R.;
Seeberger, P. H. Chem. Eur. J. 2003, 9, 140–169.
23. Yu, J.; Mason, R. P. J. Med. Chem. 2006, 49, 1991–1999.
24. Kurashima, K.; Fujii, M.; Ida, Y.; Akita, H. Chem. Pharm. Bull. 2004, 52, 270–275.
25. Schultz, M.; Zörkler, G. Liebigs Ann. Chem. 1989, 1989, 393–395.
26. Watts, A. G.; Kantner, T.; MacKenzie, A. B. Vinylpyridines as Functionalizing
Reagents for Polypeptides, WO2010070300A2, 2010.
27. Müller, C.; Diehl, V.; Lichtenthaler, F. W. Tetrahedron 1998, 54, 10703–10712.
28. Zeng, X.; Coquière, D.; Alenda, A.; Garrier, E.; Prangé, T.; Li, Y.; Reinaud, O.;
Jabin, I. Chem. Eur. J. 2006, 12, 6393–6402.
64. Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. Helv. Chim. Acta 1991, 74,
2073–2077.
65. Arungundram, S.; Al-Mafraji, K.; Asong, J.; Leach, F. E., III; Amster, I. J.; Venot,
A.; Turnbull, J. E.; Boons, G.-J. J. Am. Chem. Soc. 2009, 131, 17394–17405.
66. Schmidt, R. R.; Michel, J.; Roos, M. Liebigs Ann. Chem. 1984, 1343–1357.
67. Ivanova, I. A.; Ross, A. J.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc., Perkin
Trans. 1 1999, 1743–1754.
29. Bülow, A.; Meyer, T.; Olszewski, T. K.; Bols, M. Eur. J. Org. Chem. 2004, 323–329.
30. Lahmann, M.; Oscarson, S. Can. J. Chem. 2002, 80, 889–893.
31. Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am.
Chem. Soc. 1999, 121, 734–753.
32. Xue, J. L.; Cecioni, S.; He, L.; Vidal, S.; Praly, J.-P. Carbohydr. Res. 2009, 344,
1646–1653.
68. Vaghefi, M. M.; Bernacki, R. J.; Dalley, N. K.; Wilson, B. E.; Robins, R. K. J. Med.
Chem. 1987, 30, 1383–1391.
69. Larsen, K.; Olsen, C. E.; Motawia, M. S. Carbohydr. Res. 2003, 338, 199–202.
70. Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–9020.
71. Cai, F.; Wu, B.; Crich, D.; Horton, D. Stereocontrolled Synthesis of Mannans and
Rhamnans. In Advances in Carbohydrate Chemistry and Biochemistry; Academic
Press: New York, 2009; pp 251–309.
33. Koenigs, W.; Knorr, E. Ber. Chem. 1901, 34, 957–981.
34. Helferich, B.; Zirner, J. Chem. Ber. 1962, 95, 2604–2611.
35. Koeman, A. W.; Meissner, J. W. G.; van Ritter, H. R. P.; Kamerling, J. P.;
Vliegenthart, J. F. G. J. Carbohydr. Chem. 1994, 13, 1–25.
72. Crich, D. Chemistry of Glycosyl triflates: Synthesis of b-Mannopyranosides. In
Glycochemistry: Principles, Synthesis and Applications; Wang, P. G., Bertozzi, C. R.,
Eds.; Marcel Dekker: New York, 2001; pp 53–75.
36. Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1983, 1249–1256.
37. Milat, M.-L.; Zollo, P. A.; Sinaÿ, P. Carbohydr. Res. 1982, 100, 263–271.
38. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. 1980, 19, 731–732.
39. Kumar, A.; Kumar, V.; Dere, R. T.; Schmidt, R. R. Org. Lett. 2011, 13, 3612–3615.
40. Kumar, A.; Schmidt, R. R. Eur. J. Org. Chem. 2012, 2715–2719.
41. Thomas, M.; Gesson, J.-P.; Papot, S. J. Org. Chem. 2007, 72, 4262–4264.
42. Du, Y.; Zhang, M.; Yang, F.; Gu, G. J. Chem. Soc., Perkin Trans. 1 2001, 3122–3127.
43. Rio, S.; Beau, J.-M.; Jacquinet, J.-C. Carbohydr. Res. 1991, 219, 71–90.
44. Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem. 1990, 55,
6068–6070.
45. Premathilake, H. D.; Demchenko, A. V. Top. Curr. Chem. 2011, 301, 189–221.
46. Mereyala, H. B.; Reddy, G. V. Tetrahedron 1991, 47, 6435–6448.
47. Kreuzer, M.; Thiem, J. Carbohydr. Res. 1986, 149, 347–361.
48. Kunz, H.; Sager, W. Helv. Chim. Acta 1985, 68, 283–287.
49. Ziegler, T. J. Prakt. Chem. 1998, 340, 204–213.
73. Heng, L.; Ning, J.; Kong, F. J. Carbohydr. Chem. 2001, 20, 285–296.
74. Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348.
75. Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293–297.
76. Nizet, V.; Esko, J. D. Bacterial and Viral Infections. In Essentials of Glycobiology
(2nd ed.); Varki, A., Cummings, R. D., Esko, J. D., Freeze, H. H., Stanley, P.,
Bertozzi, C. R., Hart, G. W., Etzler, M. E., Eds.; Cold Spring Harbor Laboratory
Press: Cold Spring Harbor, NY, 2009.
77. Varki, A.; Kannagi, R.; Toole, B. P. Glycosylation Changes in Cancer. In Essentials
of Glycobiology (2nd ed.); Varki, A., Cummings, R. D., Esko, J. D., Freeze, H. H.,
Stanley, P., Bertozzi, C. R., Hart, G. W., Etzler, M. E., Eds.; Cold Spring Harbor
Laboratory Press: Cold Spring Harbor, NY, 2009.
78. Schmidt, R. R.; Wegmann, B.; Jung, K.-H. Liebigs Ann. Chem. 1991, 121–124.
79. Ziegler, T.; Bien, F.; Jurisch, C. Tetrahedron: Asymmetry 1998, 9, 765–780.
80. Barrientos, Á. G.; de la Fuente, J. M.; Rojas, T. C.; Fernández, A.; Penadés, S.
Chem. Eur. J. 2003, 9, 1909–1921.