Directing/protecting groups mediate highly regioselective glycosylation of monoprotected acceptors

Article abstract of DOI:10.1016/j.tet.2011.07.026

A directing/protecting group designed for regioselective functionalization of partially-protected glucopyrannosides has been successfully used to prepare disaccharides in high yields. Most importantly, it has been demonstrated that highly regioselective a

Full text of DOI:10.1016/j.tet.2011.07.026

Tetrahedron 67 (2011) 8411e8420
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Directing/protecting groups mediate highly regioselective glycosylation of
monoprotected acceptors
,b,
Janice Lawandi a, Sylvain Rocheleau a, Nicolas Moitessier a
*
a
ꢀ
ꢀ
Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montreal, Quebec H3A 2K6, Canada
Groupe SUCRES, Unite Mixte 7565 CNRS, Universite Henri Poincare-Nancy 1, B.P. 239, F-54506 Nancy-Vandoeuvre, France
b
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2011
Received in revised form 8 July 2011
Accepted 11 July 2011
Available online 16 August 2011
A directing/protecting group designed for regioselective functionalization of partially-protected gluco-
pyrannosides has been successfully used to prepare disaccharides in high yields. Most importantly, it has
been demonstrated that highly regioselective and stereoselective glycosylation can be achieved when
disarmed donors are employed. This study demonstrates the ability of directing/protecting group to
induce regioselective glycosylation of carbohydrates and opens the field to the design of other DPGs for
other monosaccharides.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Regioselective glycosylation
Directing protecting group
Hydrogen bond acceptor
Disaccharide
1. Introduction
HO
(a)
O
HO
HO
Carbohydrate derivatives, carbohydrate-based peptidomi-
metics, carbohydrate mimics, and oligosaccharides are gaining in
popularity not only as a means of targeting and delivering thera-
peutics efficiently, but also as drugs and vaccines.1e8 However, their
challenging synthesis hinders many groups from exploring their
true potential. One major issue is that synthetic routes utilizing
carbohydrates require numerous, wasteful steps of hydroxyl pro-
tection and deprotection. In lieu of these steps, researchers de-
veloped various strategies to perform simple, selective reactions on
carbohydrates,9,10 including enzymatic,11 and catalytic processes.12
In fact, open glycosylation has been seen as a promising but chal-
lenging strategy for effective preparation of oligosaccharides.13,14
In the early seventies, efforts were directed by Ferrier15,16 to-
ward the glycosylation of partially or non-protected donors with
simple alcohols. Years later, Hanessian reacted designed un-
protected glycosyl donors with simple alcohols17 or with sugar
acceptors (Fig. 1a).18 Similar efforts have also been reported more
recently by Schmidt for unprotected glycosylation.19 Despite these
successful study cases, only a few research groups have dealt with
the regioselective glycosylation with partially or non-protected
acceptors. Aoyama regioselectively glycosylated a fucose unit us-
ing arylboronic acid as a transient activating group13 (Fig. 1b), an
approach further investigated by Kaji.20
O
O
AgOTf
(HO)3
O
O
(HO)3
(RO)3
O
O
R'
MOP
(RO)3
O
R'
MOP-based donor
acceptor
partially protected
disaccharide
(b)
OMe
OMe
O
B O
Me
O
-
OH
Me
HO
O
O
B
OH
O
Et4N+
HO
Et4NI
O
fucoside acceptor
OMe
OH
RO
Me
O
O
RO
(RO)
3
O
O
HO
O
O
R'
donor
(RO)3
partially protected
disaccharide
* Corresponding author. Tel.: þ1 514 398 8543; fax: þ1 514 398 3797; e-mail
Fig. 1. Selected methods for glycosylation with partially or non-protected donors or
acceptors.
address: nicolas.moitessier@mcgill.ca (N. Moitessier).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.026

8412
J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
Wang and Kong disclosed the glycosylation of partially or non-
Tol
Tol
PG O
O
protected mannose21e24 and glucose25 acceptors with high regio-
selectivity. Open glycosylation (glycosylation with non-protected
acceptors) mediated by stannylene activation was also reported.14
In the mid-90s, Vasella has shown that regioselectivity of the
glycosylation with glycosylidene carbenes or trichloroacetimidate
as donors can be controlled by their relative acidity and nucleo-
philicity, respectively.26 The relative reactivity of the secondary
hydroxyl groups of monosaccharides can also be modulated by
intra- or intermolecular hydrogen bonds.27e29 Recently, there have
been a few new innovative approaches aiming at regioselective
manipulation of carbohydrate hydroxyl groups through the control
of the surrounding hydrogen bond pattern.30 Yoshida’s seminal
work on the relative reactivity of secondary hydroxyl groups
revealed the role and potential of the H-bonds in the control of the
relative reactivities of the carbohydrate hydroxyl groups.31 Kawa-
bata et al. followed up on this work with the regioselective acyla-
O
R
O
O
O
OH
OH
N
OH
HO
OMe
OH
1a. PG = H
1b, PG = CPh3
O
OMe
OH
1g. R = OMe
HO
OMe
OH
X
1h. R = H
1i. R = NO2
1c, PG = Si(Ph)2t-Bu
1d. PG = Si(Me)2t-Bu
1e. PG = COCH3
1f. PG = COPh
R
O
O
R
1l. X = N
1m. X = CH
DPG O
OH
N
OOct
O
Tol
Tol
OH
HO
1j, R=(O)
1k, R=Tol
OMe
OH
HO
DPG=
OH
N
2
DPG
O
HO
DPG O
N
O
OH
O
tion of 6-O-protected octyl
b-D
-glucopyranosides using DMAP.32
OH
OH
OMe
OH
The hydrogen bond network has also been proposed to explain
HO
OMe
the regioselectivity observed with other reactions.33
3
4
An efficient open glycosylation strategyda procedure allowing
regiocontrolled glycosylation without recourse to protection/
deprotection stepsdimplies the modulation of the rates of glyco-
sylation reactions. Such a strategy would represent an expeditious
approach to form a given oligosaccharide or libraries of oligosac-
charides (for a report on random glycosylation of unprotected N-
acetyl glucosamine, see Ref. 34). We reasoned that a protecting
group at position 6dthe easiest to installdwould greatly facilitate
our investigations.
Based on these premises, we have designed a hydrogen-bonding
protecting group referred to as a directing/protecting group (DPG)
that we predicted to hydrogen bond with the hydroxyl groups of
glucopyranosides.29 In the past, Crich and Dudkin have shown that
hydrogen-bonding protecting groups influence the rate of glyco-
sylation reaction.35 In the present work, we demonstrate that gly-
cosyl donors can glycosylate DPG-protected glucosyl acceptors
regioselectively. By means of NMR spectroscopy and various ac-
ceptors (1e4), we have further investigated the mechanism leading
to the observed regioselectivity.
BnO
BnO
BzlO
O
OBn
O
NH
NH
OBzl
O
CCl3
BzlO
O
OBzl
CCl3
OBn
5
6
HO
HO
O
BnO
BnO
OH
HO
HO
O
BnO
BnO
O
OH
HO
OMe
O
O
OBn
O
O
OBn
O
OMe
OH
OBn
O
BnO
OMe
OH
BnO
OBn
OBn
OBn
8a: α configuration
8b: β configuration
9a: α configuration
9b: β configuration
7a: α configuration
7b: β configuration
Fig. 2. Selected monoprotected glycosyl acceptors (1e4) and glycosyl donors (5, 6) and
possible regio/stereoisomeric disaccharides (7a,be9a,b).
products (7a/b, 8a/b, 9a/b) were prepared individually from 1a in
5e6 steps, using traditional protection/deprotection strategies
(Schemes 1 and 2).
2. Influence of protecting groups on regioselectivity
2.1. Preparation and reaction of monoprotected
glucopyranosides
The synthesis began with the differentiation of the two hydroxyl
groups of 1g (Scheme 1). Monoacetylation of diol 1g with acetic
anhydride led to chromatographically separable regioisomers 11
and 12.36 Glycosylation of donor 537 with both alcohols was next
carried out. Optimization at this stage eventually led to the use of
Schmidt trichloroacetimidate method38,39 and catalytic trime-
thylsilyl triflate (TMSOTf) as an activator providing separable di-
saccharides 13a and 13b and non-separable disaccharides 14a and
At the outset of this research program, we assessed how dif-
ferent protecting groups at position 6 of monoprotected methyl
-glucopyranoside acceptors influenced the regioselectivity of
glycosylation reactions. A set of monoprotected methyl -gluco-
pyranoside acceptors (1bem) were prepared from methyl
a-
D
a-D
a-D-
glucopyranoside 1a following previously described synthetic ap-
proaches (Fig. 2).29 We then reacted each of these partially-
protected glycosyl acceptors with 1 equiv of glycosyl donor (5) in
the presence of TMSOTf. The reactions yielded the six possible
isomers 7a/b, 8a/b, and 9a/b after deprotection (Fig. 2 and Table 1).
Quick filtration allowed us to isolate the six expected disaccharides
in combined yields of 30e55%. Careful analysis of the reaction
mixtures confirmed that little to no trisaccharidedresulting from
di-glycosylation of the acceptorsdwas formed and that conver-
sions and isolated yields were equivalent. At this stage, regiose-
lectivity and not yield was investigated.
Table 1
Initial investigations: regioselectivity versus PG via Scheme 3
Entry
Compd
7a/7ba (%)
8a/8ba (%)
9a/9ba (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
39 (1:1.1)
39 (1.0:1)
40 (1.3:1)
24 (1.6:1)
27 (1.5:1)
41 (1.4:1)
45 (1.8:1)
45 (2.2:1)
35 (1.1:1)
40 (1:1.1)
65 (1.6:1)
45 (1:1)
53 (1:4.2)
57 (1:1.4)
56 (1.1:1)
60 (1:1.2)
69 (1:1.2)
59 (1:1.6)
55 (1:7.9)
55 (1:2.1)
53 (1:1.2)
56 (1:1.4)
33 (1.6:1)
51 (2.2:1)
8
4
4
16
4
d
d
d
12
4
9
1j
1k
1l
10
11
12
2.2. Preparation of the 6 possible isomers
2
4
1m
a
In order to evaluate the regioselectivity and stereoselectivity of
these glycosylation reactions, the six possible disaccharide
HPLC analysis of the mixtures after filtration on a silica gel pad, a:b ratios are
given in brackets.

J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
8413
addition, the ratios of model mixtures of known composition of 7a,b,
8a,b, and 9a,b were accurately reproduced on chromatograms with
an accuracy of 0.5%. However, even if the isomers 7a, 7b, 8a, and 8b
were separated, the epimers 9a and 9b came out with identical re-
tention times on silica gel or reversed phase HPLC columns.
2.3. Regioselectivity of the glycosylation reaction
These six individually-prepared disaccharides were used as
HPLC references to identify the disaccharides produced in each
reaction. As expected, we observed that glycosylation with the
bulky armed donor 5 occurred preferentially at position 3 over
position 2 with all the traditional protecting groups investigated in
this work (Table 1, entries 1e8, Scheme 3). Furthermore, for the
reaction of 5 with the bulky TBDPS or trityl group-containing de-
rivatives 1b and 1c, we observed low levels (4e8%) of 4-O-glyco-
sylated products 9a and 9b. On the other hand, the small acetylated
derivative 1e gave larger amounts of 9a/b (16%, entry 4).
P
G
H
O
O
O
,
. 5
1
TM Tf 0°
SO
C
,
,
O
H
l
C
2C 2
H
O
(
)
H
O 2
Bn
B
O
Me
O
2. Deprotection
O
H
Me
O
O
O
H
O
Bn
O
n
O
7
,
8 9
,
n
B
O
Scheme 1. (a) Ac2O (1.1 equiv), DMAP, K2CO3, CH2Cl2, 47% (11), 40% (12); (b) 2,3,4,6-
tetra-O-benzyl glucopyranosyl trichloroacetimidate 5, TMSOTf, 4 A MS, CH2Cl2, 0 ꢀC,
84% (13a/13b¼2:1), 72% (14a/14b¼2:1); (c) preparative HPLC separation; (d) AcOH/
THF/H2O, 1:1:1, 40 ꢀC; (e) MeONa, MeOH, 90% (7a), 93% (7b), 93% (8aþ8b).
ꢁ
Scheme 3. Regioselectivity in the glycosylation.
14b, respectively (Scheme 1). Both anomers 13a and 13b were se-
quentially deprotected by hydrolysis in acidic medium followed by
The higher regioselectivity observed using electron-
withdrawing esters (7a/b:8a/b: 1:2.5e2.55, entries 4 and 5) over
that observed using ethers (1:1.35, entry 1) and silyl ethers (1:1.40
to 1.45, entries 2 and 3) was rationalized by electronic effects.
Electronic effects were further investigated using benzylidene
protecting groups ranging from electron-poor to electron-rich
(entries 6e8). This study revealed that the electronic effects of
this series of protecting groups are not strong enough to provide
a tool for regioselective transformations.
ꢀ
Zemplen deacetylation to give target compounds 7a and 7b in good
yields. Similarly, compounds 14a and 14b were hydrolyzed then
methanolized affording the corresponding separable mixture of
anomers 8a and 8b.
The last two reference compounds 9a and 9b were prepared
from readily available triacetylated glucopyranoside 16.40 As illus-
trated on Scheme 2, peracetylation of triol 1c was achieved on
treatment with acetic anhydride in presence of DMAP yielding the
fully protected saccharide 15. Triacetylated compound 15 was
subsequently reacted with a fluoride source to generate 16 after
acetyl migration as reported by Passancatelli et al.41 Both glyco-
sylation partners (5 and 16) were next reacted to give the in-
separable mixture of disaccharides 17a and 17b. These two fully
protected compounds were methanolized into the target di-
saccharides 9a and 9b, which unfortunately remained inseparable
When comparing the outcome of the glycosylation reactions
with 1b and 1k differing only by the presence of a nitrogen atom,
we were also pleased to observe the influence of the pyridyl ring of
1, which altered the ratio of 4-O-glycosylated products 9a and 9b
(entries 1 and 10). Although the same amount of 4-O regioisomers
9a/b were observed with the pyridyl-containing glucopyrannoside
1k and TBDPS-containing glucopyrannoside 1c, we believe that the
reduced levels of 9a/9b observed with 1 was due to the effect of the
intramolecular hydrogen bond while the low level of 9a/9b ob-
served with 1c is due to the steric effects induced by this bulky
protecting group, which is known to adopt conformations very
different to ethers.42 Even more gratifying was the reversal of se-
lectivity observed when moving from 1k (7/8: 1:1.4, entry 10) to 1l
(7/8: 2.0:1, entry 11). We previously showed that position 3 was the
most reactive,29 and yet we observed glycosylation predominantly
at position 2. Although the substitution of a phenyl ring in 1b to
a pyridyl ring in 1k did not significantly affect the rate of the Lewis
acid mediated glycosylation reactions, introduction of the second
pyridyl ring in 1l significantly did. Although one could rationalize
this loss of reactivity by a reaction between TMSOTf and the ter-
minal pyridyl group, a similar trend was previously observed with
the acetylation reaction carried out in basic media with 1b, 1k, and
1l.29 Hence this poor reactivity cannot be only attributed to the
formation of trimethylsilylpyridinium salts (see below).
Scheme 2. (a) Ac2O (10 equiv), DMAP, Et3N, CH2Cl2, 100%; (b) TBAF, THF, 0 ꢀC then rt,
84%; (c) 5, TMSOTf, 4 A MS, CH2Cl2, 0 ꢀC, 79%; (d) MeONa, MeOH, 91%.
ꢁ
even after extensive chromatographic work.
Analytical HPLC conditions were found where 2, 3, and 4-
glycosylated isomers were clearly identified on chromatograms. In
In order to further assess the role of the terminal pyridyl ring of
1l, the terminal phenyl analogue 1m was reacted under the same

8414
J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
conditions. Once the hydrogen bond between the protecting group
and position 3 was removed, the regioselectivity of the glycosyla-
tion reverted to a level closer to that of the reaction of the simpler,
mono-pyridyl-protected acceptor (entries 10 and 12 vs 11). This
observation confirmed the critical role of the nitrogen of the ter-
minal pyridyl group of 1l, which provides bulk and blocks position
3 from being glycosylated.
3. Optimization for practical applications
At this stage, DPGs were shown to influence the regioselectivity of
the investigated reaction, however not with practical levels of regio-
selectivity. Optimization of the reaction conditions (Lewis acid,
temperature, addition time, and amount of donors) significantly
increased the efficiency of this method in terms of yields and regio-
selectivities (Table 2, entry 1). Unlike other reported methods, our
strategy significantly favors glycosylation of position 2 over positions
3 and 4. However, we failed to increase the stereoselectivity to prac-
tical levels. To address this issue, we turned our attention to the
disarmed glycosyl donor 6. Our set of reference disaccharides 7a/b,
8a/b, 9a/b was no longer valid. Fortunately, products formed with the
new donor yielded significantly clearer NMR spectra, no longer clut-
tered with the benzylic protons, which prevented any possible 2D
NMR analysis of the products. Thus, rather thanpreparing another set
of reference compounds, we were able to perform extensive 2D NMR
experiments (COSY, HSQC, and HMBC) of each product in order to
determine the position of the glycosidic linkage formed and stereo-
chemistry of the anomeric center.
Scheme 4. Glycosylation of DPG-functionalized acceptors.
network positions the DPG close to the 3-OH and 4-OH, increasing
the steric hindrance at these positions while increasing their nu-
cleophilicity. Armed donors (5) are reactive enough to glycosylate
the three hydroxyl groups and steric factors will induce regiose-
lective glycosylation at position 2. In contrast, poorly reactive donors
(6) are not reactive enough to react with non-activated position 2
and proceeds through regioselective glycosylation at position 3.
Table 2
Regioselectivity and stereoselectivity
Entry
1
Reactants
T (ꢀC)
ꢁ50
2-Oa (%)
3-Oa (%)
SMa (%)
8
1le5
61 (1:1.8)
18a,b
11 (1:1.9)
19a,b
2
3
4
5
6
7
1ce6
1le6
1le6
2e6
3e6
3e6
ꢁ50
ꢁ50
þ5
18 (0:1), 20
<5%
<5%
<5%
<5%
Complex
mixtureb
<5%
20 (0:1), 21
80% (0:1), 22
90% (0:1), 22
87% (0:1), 23
<5%
62
<5%
<5%
<5%
>90%
ꢁ50
ꢁ50
5
8
9
4e6
4e6
ꢁ50
<5%
>90%
5
Complex
mixtureb
a
a
:
b
ratios are given in brackets.
b
Several products were observed in the reaction mixtures.
Our investigation started with the widely used TBDPS protecting
group and confirmed the expected stereoselectivity obtained with
the disarmed donor. However, even at low temperature and low
conversions, no regioselectivity was observed (Table 2, entry 2)
revealing the challenge we were facing. We were very pleased to
observe reproducible, high levels of regioselectivity (glycosylation
at position 3 almost exclusively) and stereoselectivity (
b-anomer
formed), low levels of polyglycosylation (very little trisaccharide
was observed) and high yields (yields of 90% and 87%, entries 4 and
5, respectively) with the anomers 1l and 2.
Although the proposed strategy was successful in producing
a single isomer out of the six possible, we were puzzled with the
reversal of regioselectivity observed when moving from the armed
donor 5 to the disarmed donor 6 (Scheme 4).
4. Mechanistic study
Fig. 3. Proposed alternative mechanisms.
4.1. Two possible mechanisms
As an alternative mechanism, silylation of 3-OH by internal
delivery of a TMS group by the terminal pyridyl ring of the DPG
blocks this position. This last mechanism is supported by
Two mechanisms were proposed to explain this reversal of
regioselectivity (Fig. 3). In a first mechanism, the hydrogen bond

J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
8415
previously reported carbohydrate silylation using trimethylsi-
lylpyridinium triflate.43 This fairly labile protecting group would
then come off at the deprotection stage and/or during work up. The
internal delivery at position 3 is most likely faster than the in-
termolecular delivery at position 2. Although the 3-O-silylated
regioisomer is majoritarily formed (kinetic product), equilibrium
either by intramolecular or intermolecular migration would lead to
the more stable 2-O-silylated regioisomer (thermodynamic
isomer).
The DPG described herein has been specifically designed for
glucopyrannosides and is not expected to induce the same levels of
selectivity with the mannopyranoside and galactopyrannoside 3
and 4. Recently, a TBDPS-protected mannose derivative has been
shown to be highly selective for glycosylation at position 3 and
poorly reactive at position 2 (axial hydroxyl group).44 In the present
work, the additional postulated hydrogen bond between O-H2 and
O-3 blocks position 3 (Fig. 6), making this acceptor most likely
unreactive. In fact, we observed the expected low conversions and
poor regioselectivities with the mannose derivative 3 (Table 2,
entries 6 and 7). Similarly, the DPG specifically designed for glucose
provided low regioselectivities with the galactose derivative 4
(Table 2, entries 8 and 9). This data provides additional evidences
for the role of hydrogen bonds in the DPG-mediated regioselective
glycosylation of glucopyranosides.
4.2. Mechanism #2
To investigate this second mechanism, an NMR spectroscopy
study was carried out. A reversible formation of trimethylsilylpyr-
idinium salts primarily with the terminal pyridyl group was ob-
served by alternative addition of TMSOTf and 1l in CDCl3. However,
this study also revealed that no silylation of the hydroxyl groups
took place after 4 h (Fig. 4) and rules out the second mechanism. In
addition, during the glycosylation experiments described in Tables
1 and 2, TMSOTf was added over time keeping its levels sub-
stoichiometric and leaving hydrogen-bonded 1l free to react.
5. Conclusion
We have established a novel strategy for modulation of the
relative reactivity in glycosylation reactions of the 2-, 3-, and 4-
OH’s, consistent with the experimentally observed hydrogen
Fig. 4. NMR spectra of 1l with various amount of TMSOTfd0.0 equiv (a), 0.5 equiv (b), 1.0 equiv (c), 1.5 equiv (d). Addition of 1l to (c) leads to (b) and vice-versa. No significant
changes in the spectra were observed after 4 h.
4.3. Mechanism #1-modulating the hydrogen bond network
bonds. Our designed directing/protecting group, which can be se-
lectively installed at position 6, can direct glycosylation with dis-
armed glycosyl donors to position 3 with great levels of regio- and
stereoselectivity and high yields. To our knowledge, this is the first
report on the stereo- and regioselective synthesis of Glu-Glu using
monoprotected acceptors offering an alternative to the traditional
approaches of orthogonal protection. This study also demonstrated
that DPGs can be used in different ways, as they enhanced not only
the nucleophilicity of hydroxyl groups (i.e., increasing selectivity by
directing glycosylation with disarmed donors to position 3) but also
the steric hindrance around selected hydroxyls (i.e., increasing se-
lectivity by directing glycosylation with armed donors to position
2). Further design and synthesis are underway to better explore this
concept and more specifically to apply it to other carbohydrate
acceptors such as galactose and mannose.
To further elucidate the role of hydrogen bonds in the regiose-
lectivity of this reaction and probe the first mechanism (Fig. 3), the
derivatives 2, 3, and 4 were prepared and their induced hydrogen
bond network investigated by NMR following a method reported
previously (Fig. 5).29 In
a
nutshell, hydroxyl protons when
hydrogen-bonded to a pyridyl ring are significantly shifted down-
field (d in the range of 7 ppm) and broad in CDCl3. This makes their
observation and identification on 1H NMR spectra difficult. Using
various mixtures of CDCl3 and DMSO-d6 these proton peaks were
shifted and sharpened and extrapolation can be used to evaluate
their chemical shift in neat CDCl3.
Based on this data, we proposed hydrogen bond networks
shown in Fig. 6. First, both glucopyranosides 1l and 2 adopted the
same hydrogen bond network and their reactivity and regiose-
lectivity in the glycosylation were expected to be highly similar.
Although the mannopyrannoside derivative 3 adopted a network
similar to 1l, the postulated hydrogen bond between O-3 and HO-2
shuts down the reactivity of O-3. In contrast, the NMR spectroscopy
investigation of the galactopyranoside derivative 4 did not show
any pyridyl-hydroxyl group interaction.
6. Experimental section
6.1. General methods
Solvents were distilled and dried by standard methods; THF and
ether, from Na/benzophenone; and CH2Cl2 from P2O5. All

8416
J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
a PerkineElmer 141 polarimeter in a 1 dm cell at 20 ꢀC. FTIR spectra
were recorded on a Perkin Elmer Spectrum 1000 on NaCl windows
or KBr pellets or a PerkineElmer Spectrum One FT-IR. 1H and 13C
NMR spectra were recorded on Bruker AC 250 or DRX 400 spec-
trometers (250 and 400 MHz, respectively) or on Varian mercury
400 MHz, 300 MHz or Unity 500 spectrometers. Chemical shifts are
reported in parts per million using the residual of chloroform as
internal standard (7.27 ppm for 1H and 77.0 ppm for 13C, re-
spectively). Mass spectra were recorded on a Trio 1000 Thermo
Quest spectrometer in the electron impact mode, a Platform
Micromass in the electrospray mode, a Kratos MS25 RFA Double
focusing mass spectrometer in electron impact Peak matching
(70 eV) mode or on a IonSpec 7.0 t FTMS by electrospray ionization.
Elemental analyses were obtained on
a PerkineElmer 240C
microanalyser. Analytical thin-layer chromatography was per-
formed on Merck 60 F254 pre-coated silica gel plates or on Silicycle
60 F254 pre-coated silica gel plates. Visualization was performed by
UV or by development using KMnO4, H2SO4/MeOH or Mo/Ce so-
lutions. Preparative chromatography was performed on silica gel 60
(230e40 mesh ASTM) at increased pressure. Analytic reverse phase
HPLC was performed on two C18 columns: Kromasyl C18 10
from A.I.T. Chromato (Le Mesnil le Roi, France) and Platinum C18
10
m, from Alltech (Laarne, Belgium). A flow rate of 1.0 mL minꢁ1
mm,
m
was used with a mobile phase of CH3CN/H2O (gradient A: 50%e70%
within 45 min, gradient B: 70e90% within 40 min). UV detection
was monitored at 254 nm.
6.2. Preparation of the monoprotected glucopyrannosides
1bem
Fig. 5. 1H NMR chemical shift of hydroxyl groups. Top panel: glucopyrannoside 2.
Bottom: mannopyrannoside 3. When the chemical shift was not ascertained (peaks
hidden within the carbohydrate peaks or too broad), values are missing. For gal-
actopyrannoside 4, the OH peaks were all in the 2.5e5 ppm region indicating no strong
hydrogen bonds.
Synthesis of these compounds has been reported previously.29
6.3. Preparation of the reference compounds
6.3.1. Methyl 2/3-O-acetyl-4,6-O-(p-methoxybenzylidene)-a-D-glu-
copyranoside (11/12). To a suspension of 1g29 (2.15 g, 6.9 mmol)
and K2CO3 (4.4 g, 32 mmol) in CH2Cl2 (400 mL) were added acetic
anhydride (0.78 mL, 8.3 mmol) and DMAP (77 mg, 1.4 mmol). After
stirring for 5 h, the reaction mixture was concentrated and the
resulting mono- and diacetylated compounds were separated (sil-
ica gel, H/EA, 4:1 then 3:2) to afford isomers 11 (1.15 mg, 47%, white
crystals) and 12 (991 mg, 40%, white powder) along with the
diacetylated compound (344 mg, 12%).
20
Data for 11: Rf¼0.24 (H/EA, 1:1); [
a
]
þ92.8 (c 0.9, CHCl3); mp
D
175 ꢀC; IR (neat/NaCl) 3474, 1741 cmꢁ1
;
1H NMR (250 MHz, CDCl3)
d
7.39 (d, 2H, J¼8.9 Hz), 6.88 (d, 2H, J¼8.9 Hz), 5.45 (s, 1H), 5.22 (dd,
1H, J¼9.5, 9.5 Hz), 4.80 (d,1H, J¼3.5 Hz), 4.29 (dd,1H, J¼3.5, 9.5 Hz),
3.87 (m, 1H), 3.81 (s, 3H), 3.75 (dd, 1H, J¼9.5, 9.5 Hz), 3.65 (m, 1H),
3.56 (dd, 1H, J¼9.5, 9.5 Hz), 3.47 (s, 3H), 2.29 (d, 1H, J¼11.0 Hz), 2.12
(s, 3H); 13C NMR (65 MHz, CDCl3)
d 170.9, 159.9, 129.4, 127.4, 113.4,
101.3, 100.0, 78.5, 72.1, 71.6, 68.6, 62.6, 55.4, 55.1, 20.9.
20
Data for 12: Rf¼0.34 (H/EA, 1:1); [
a]
þ93.6 (c 0.8, CHCl3); mp
D
123 ꢀC; IR (neat/NaCl) 3480, 1741 cmꢁ1; 1H NMR (250 MHz, CDCl3)
d
7.43 (d, 2H, J¼8.9 Hz), 6.90 (d, 2H, J¼8.9 Hz), 5.51 (s, 1H), 4.96 (d,
1H, J¼4.5 Hz), 4.81 (dd, 1H, J¼4.5, 9.5 Hz), 4.29 (dd, 1H, J¼3.5,
9.5 Hz), 4.18 (ddd, 1H, J¼2.0, 9.5, 9.5 Hz), 3.82 (m, 1H), 3.81 (s, 3H),
3.75 (dd, 1H, J¼9.5, 9.5 Hz), 3.54 (dd, 1H, J¼9.5, 9.5 Hz), 3.41 (s, 3H),
2.57 (br s, 1H), 2.17 (s, 3H); 13C NMR (65 MHz, CDCl3)
d 170.6, 159.9,
129.3, 127.4, 113.4, 101.6, 97.2, 81.0, 73.3, 68.5, 68.1, 61.8, 55.1, 55.0,
20.6.
Fig. 6. Hydrogen bond network of DPG-protected gluco-, galacto- and
mannopyrannosides.
6.3.2. Methyl 3-O-acetyl-2-O-(20,30,40,60-tetra-O-benzyl-
a-D
-gluco-
commercially available reagents were used without further purifi-
cation. 4 A molecular sieves were dried at 100 C prior to use.
pyranosyl)-4,6-O-(p-methoxybenzylidene)-a/b-D-glucopyranoside
(13a/13b). To a solution of pyranoside 1129 (307 mg, 0.87 mmol),
glucopyranosyl trichloroacetimidate 5 (652 mg, 0.95 mmol) and
ꢀ
ꢁ
€
Melting points are uncorrected and recorded with a Buchi capillary
ꢁ
tube melting-point apparatus. Optical rotations were measured on
4 A MS in dry CH2Cl2 (25 mL) was added a freshly prepared 0.1 M

J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
8417
solution of TMSOTf in CH2Cl2. The resulting mixture was stirred for
1 h at 0 ꢀC then quenched with a drop of Et3N, diluted with CH2Cl2,
washed with 1 M NaHCO3 and brine, dried over MgSO4, and con-
centrated in vacuo. The isomers were separated by chromatography
(H/EA, 4:1) to afford regioisomers 13a (425 mg, 56%, colorless oil)
CDCl3)
d
7.32 (m, 18H, Ph), 7.18 (m, 2H, Ph), 5.00 (d, 1H, J¼11.0 Hz,
0
0
0
CH2Ph), 4.92 (d, 1H, J1 e2 ¼4.5 Hz, H-1 ), 4.86 (d, 1H, J¼10.5 Hz,
CH2Ph), 4.85 (d, 1H, CH2Ph), 4.84 (d, 1H, J1e2¼3.5 Hz, H-1), 4.78 (d,
1H, J¼12.0 Hz, CH2Ph), 4.65 (d, 1H, CH2Ph), 4.58 (d, 1H, J¼11.5 Hz,
CH2Ph), 4.51 (d, 1H, CH2Ph), 4.48 (d, 1H, CH2Ph), 4.12 (ddd, 1H,
0
0
0
0
and 13b (215 mg, 28%, white crystals).
J4e5¼10.0, J5 e6 ¼02.0, 5.5 Hz, H-5), 4.06 (dd, 1H, J2 e3 ¼9.5,
20
0
0
Data for 13a: Rf¼0.43 (H/EA, 7:3); [
a
]
þ48.5 (c 1.1, CHCl3); IR
J3 e4 ¼9.5 Hz, H-3 ), 3.88 (dd, 1H, J2e3¼9.5, J3e4¼9.5 Hz, H-3), 3.82
(m, 2H, H-60, H-60), 3.72e3.64 (m, 3H, H-5, H-6, H-6), 3.60 (dd, 1H,
H-20), 3.56 (dd, 1H, H-40), 3.47 (dd, 1H, J4e5¼9.5 Hz, H-4), 3.45 (dd,
1H, H-2), 3.42 (s, 3H, OMe), 2.94 (br s, 1H, OH), 2.28 (br s, 1H, OH),
D
(neat/NaCl) 1755 cmꢁ1
;
1H NMR (250 MHz, CDCl3)
d 7.40 (d, 2H,
J¼8.9 Hz), 7.32 (m, 20H), 6.88 (d, 2H, J¼8.9 Hz), 5.62 (dd, 1H, J¼9.5,
9.5 Hz), 5.43 (s, 1H), 4.96 (d, 1H, J¼11.5 Hz), 4.91 (d, 1H, J¼3.5 Hz),
4.86 (d, 1H, J¼3.5 Hz), 4.84 (d, 1H, J¼11.5 Hz), 4.82 (2d, 2H,
J¼11.5 Hz), 4.65 (d, 1H, J¼11.5 Hz), 4.59 (d, 1H, J¼11.5 Hz), 4.46 (2d,
2H, J¼11.5 Hz), 4.28 (dd, 1H, J¼4.5, 9.5 Hz), 3.96 (dd, 1H, J¼9.5,
9.5 Hz), 3.92 (m, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.79 (dd, 1H, J¼3.5,
9.5 Hz), 3.74e3.60 (m, 3H), 3.53 (dd, 1H, J¼9.5, 9.5 Hz), 3.54 (dd, 1H,
J¼3.5, 9.5 Hz), 3.51 (dd, 1H, J¼9.5, 9.5 Hz), 3.43 (s, 3H), 2.02 (s, 3H);
1.97 (br s, 1H, OH); 13C NMR (65 MHz, CDCl3)
d 138.6, 137.9, 137.8,
137.5 (Ph), 128.2e127.3 (Ph), 97.0 (C-1), 94.8 (C-10), 81.4 (C-30), 79.1
(C-20), 77.4 (C-4), 76.8 (C-40), 75.3, 74.9, 73.1, 72.5 (CH2Ph), 72.0 (C-
3), 70.7 (C-50), 70.0 (C-2), 69.7 (C-5), 68.1 (C-60), 61.3 (C-6), 54.8
(OMe); LRMS (EIþ, m/z, %): 625 (5) (MꢁBnþ), 522 (7), 431 (12), 325
(17), 281 (26), 253 (100), 181 (100); Anal. calcd for C41H48O11: C,
68.70; H, 6.75; found: C, 68.90; H, 6.78.
13C NMR (65 MHz, CDCl3)
d 169.4, 159.9, 138.6, 138.3, 138.2, 137.7,
129.4, 128.3e127.3, 113.4, 101.3, 97.5, 95.8, 81.4, 79.3, 79.2, 77.2,
75.4, 74.7, 74.6, 73.2, 72.9, 70.6, 69.8, 68.7, 68.1, 62.2, 55.1, 55.0, 20.9.
6.3.5. Methyl 2-O-(20,30,40,60-tetra-O-benzyl-
-glucopyranoside (7b). Following the same procedure as for di-
saccharide 7a, disaccharide 13b (250 mg, 0.285 mmol) led to di-
b-D-glucopyranosyl)-a-
20
Data for 13b: Rf¼0.30 (H/EA, 7:3); [
a
]
þ35.7 (c 0.7, CHCl3); IR
D
D
(neat/NaCl) 1755 cmꢁ1
;
1H NMR (250 MHz, CDCl3)
d
7.40 (d, 2H,
J¼8.9 Hz), 7.32 (m, 18H), 7.19 (m, 2H), 6.88 (d, 2H, J¼8.9 Hz), 5.65
(dd, 1H, J¼9.5, 9.5 Hz), 5.45 (s, 1H), 5.07 (d, 1H, J¼3.5 Hz), 4.94 (d,
1H, J¼11.5 Hz), 4.92 (d, 1H, J¼11.5 Hz), 4.82 (d, 1H, J¼11.5 Hz), 4.78
(d, 1H, J¼11.5 Hz), 4.70 (d, 1H, J¼11.5 Hz), 4.57 (d, 1H, J¼11.5 Hz),
4.52 (2d, 2H, J¼11.5 Hz), 4.50 (d, 1H, J¼7.5 Hz), 4.30 (dd, 1H, J¼4.5,
10.0 Hz), 3.95 (dd, 1H, J¼4.5, 10.0, 10.0 Hz), 3.82 (dd, 1H, J¼3.5,
9.5 Hz), 3.81 (s, 3H), 3.75e3.58 (m, 4H), 3.58e3.45 (m, 3H), 3.43 (m,
saccharide 7b (195 mg, 93%, white powder).
20
Rf¼0.52 (EA); tR¼24.6 min (gradient A); [
a
]
þ54.7 (c 0.8,
7.32
D
CHCl3); IR (neat/NaCl) 3422 cmꢁ1; 1H NMR (250 MHz, CDCl3)
d
(m, 18H, Ph), 7.17 (m, 2H, Ph), 4.93 (d, 1H, J¼11.0 Hz, CH2Ph), 4.92 (d,
1H, J1e2¼4.0 Hz, H-1), 4.92 (d, 1H, J¼10.5 Hz, CH2Ph), 4.86 (2d, 2H,
0
0
CH2Ph), 4.83 (d, 1H, J¼10.5 Hz, CH2Ph), 4.70 (d, 1H, J1 e2 ¼8.0 Hz, H-
10), 4.59 (d, 1H, J¼12.0 Hz, CH2Ph), 4.57 (d, 1H, CH2Ph), 4.52 (d, 1H,
CH2Ph), 3.91 (dd, 1H, J2e3¼8.5, J3e4¼8.5 Hz, H-3), 3.87 (dd, 1H,
J5e6¼3.5, J6e6¼11.5 Hz, H-6), 3.80 (dd, 1H, J5e6¼4.5 Hz, H-6),
3.73e3.61 (m, 4H, H-30, H-50, H-60, H-60), 3.61e3.49 (m, 5H, H-2, H-
20, H-4, H-40, H-5), 3.39 (s, 3H, OMe), 3.21 (br s, 1H, OH), 2.71 (br s,
1H), 3.45 (s, 3H), 1.79 (s, 3H); 13C NMR (65 MHz, CDCl3)
d 169.8,
159.9, 138.4, 138.3, 137.82, 137.79, 129.4, 128.3e127.2, 113.4, 105.0,
101.2, 100.3, 84.5, 81.4, 79.7, 78.6, 77.5, 75.5, 74.9, 74.6, 74.3, 73.3,
70.1, 69.0, 68.8, 62.1, 55.3, 55.1, 20.6.
1H, OH), 2.09 (br s, 1H, OH); 13C NMR (65 MHz, CDCl3)
d 138.3,
6.3.3. Methyl 2-O-acetyl-3-O-(20,30,40,60-tetra-O-benzyl-
pyranosyl)-4,6-O-(p-methoxybenzylidene)- -glucopyranoside
a/
b-
D-gluco-
138.0, 137.9, 137.8 (Ph), 128.4e127.6 (Ph), 103.8 (C-10), 99.5 (C-1),
84.8 (C-30), 82.0 (C-20), 80.9 (C-4), 77.9 (C-40), 75.6, 75.1, 74.9, 73.4
(CH2Ph), 74.6 (C-2), 72.4 (C-3), 70.5, 70.4 (C-5, C-50), 69.0 (C-60), 62.1
(C-6), 55.2 (OMe); LRMS (EIþ, m/z, %): 625 (7) (MꢁBnþ), 593 (5), 522
(7), 431 (49), 325 (55), 313 (61), 253 (75), 181 (78), 91 (100); Anal.
calcd for C41H48O11: C, 68.70; H, 6.75; found: C, 68.75; H, 6.77.
a-D
(14a/14b). Following the same procedure as for compounds 13a
and 13b, glucopyranoside 12 (415 mg, 1.17 mmol) and 5 (882 mg,
1.29 mmol) led to an inseparable mixture of regioisomers 14a and
14b (740 mg, 72% 14a/14b¼2:1).
Rf¼0.40 (H/EA, 7:3); IR (neat/NaCl) 1754 cmꢁ1
;
1H NMR (1:1
7.38e7.23 (m, 38ꢂ0.5H), 7.20e7.08 (m,
mixture, 250 MHz, CDCl3)
d
6.3.6. Methyl 3-O-(20,30,40,60-tetra-O-benzyl-
-glucopyranoside (8a). Following the same procedure as for 7a,
a-D-glucopyranosyl)-a-
5ꢂ0.5H), 7.00 (m, 0.5H), 6.86 (d, 2ꢂ0.5H, J¼8.9 Hz), 6.76 (d, 2ꢂ0.5H,
J¼8.9 Hz), 5.58 (d, 0.5H, J¼3.0 Hz), 5.48 (s, 0.5H), 5.48 (s, 0.5H), 5.00
(d, 1H, J¼3.0 Hz), 4.99 (d, 1H, J¼3.0 Hz), 4.95 (m, 4ꢂ0.5H),
4.88e4.32 (m, 17ꢂ0.5H), 4.27 (dd, 0.5H, J¼5.0, 10.0 Hz), 4.26 (dd,
0.5H, J¼5.0,10.0 Hz), 4.05 (m, 0.5H), 3.94e3.82 (m, 4ꢂ0.5H), 3.82 (s,
3ꢂ0.5H), 3.81e3.70 (m, 5ꢂ0.5H), 3.71 (s, 3ꢂ0.5H), 3.69e3.55 (m,
5ꢂ0.5H), 3.52e3.43 (m, 2ꢂ0.5H), 3.42 (s, 3ꢂ0.5H), 3.41 (s, 3ꢂ0.5H),
3.27 (m, 0.5H), 2.05 (s, 3H), 1.97 (s, 3H); 13C NMR (65 MHz, CDCl3)
D
the mixture 14a/14b (309 mg, 0.352 mmol) was deprotected into
the separable compounds (HPLC, H/EA, 3:1) 8a (160 mg, 62%, col-
orless oil) and 8b (79 mg, 31%, colorless oil).
Data for 8a: Rf¼0.59 (EA); tR¼27.2 min (gradient A); [
a
]
20 þ80.6
D
(c 0.5, CHCl3); IR (neat/NaCl) 3447 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.32 (m, 18H, Ph), 7.15 (m, 2H, Ph), 4.94 (d, 1H, J¼11.0 Hz, CH2Ph),
0
0
0
4.91 (d, 1H, CH2Ph), 4.91 (d, 1H, J1 e2 ¼4.5 Hz, H-1 ), 4.84 (d, 1H,
J¼11.0 Hz, CH2Ph), 4.83 (d, 1H, J¼10.5 Hz, CH2Ph), 4.83 (d, 1H,
J1e2¼3.5 Hz, H-1), 4.71 (d, 1H, CH2Ph), 4.58 (d, 1H, J¼12.0 Hz,
CH2Ph), 4.51 (d, 1H, CH2Ph), 4.50 (d, 1H, CH2Ph), 4.10 (m, 1H, H-3),
4.03 (dd, 1H, J2e3¼9.5, J3e4¼9.5 Hz, H-30), 3.89 (dd, 1H, J5e6¼3.5,
J6e6¼11.5 Hz, H-6), 3.81 (dd, 1H, J5e6¼4.5 Hz, H-6), 3.73 (m, 1H, H-
5), 3.70e3.62 (m, 3H, H-50, H-60, H-60), 3.62e3.49 (m, 4H, H-2, H-20,
H-4, H-40) 3.46 (s, 3H, OMe), 3.22 (br s, 1H, OH), 2.11 (br s, 1H, OH),
d
170.1, 169.9, 160.1, 159.8, 138.6e137.6, 129.6, 129.3, 128.1e127.2,
113.5, 113.2, 102.9, 101.8, 101.3, 97.3, 97.1, 95.7, 84.5, 82.4, 82.0, 81.1,
79.7, 78.4, 77.5, 77.1, 75.3, 75.2, 74.6, 74.5, 73.6, 73.3, 73.2, 71.9, 70.9,
70.3, 70.1, 68.7, 68.6, 68.5, 68.3, 62.3, 61.7, 55.0, 54.8, 20.7, 20.6.
6.3.4. Methyl 2-O-(20,30,40,60-tetra-O-benzyl-
-glucopyranoside (7a). A solution of 13a (550 mg, 0.63 mmol) in
a-D-glucopyranosyl)-a-
D
an equimolar mixture of AcOH/THF/H2O (60 mL) was stirred at
50 ꢀC for 3 h then concentrated in vacuo. Flash purification by
chromatography (H/A, 4:1 then 1:4) afforded the diol, pure enough
for the next step. Thus, the residue was dissolved in MeOH then
a catalytic amount of freshly prepared MeONa/MeOH solution was
added. After stirring for 3 h, the mixture was concentrated and
purified by chromatography (CH2Cl2/MeOH, 19:1) to afford di-
1.70 (br s, 1H, OH); 13C NMR (65 MHz, CDCl3)
d 138.3, 137.7, 137.4,
137.1 (Ph), 128.6e127.6 (Ph), 99.7, 99.5 (C-1, C-10), 86.9 (C-3), 82.3
(C-30), 79.3 (C-20), 77.8 (C-40), 75.6, 74.9, 74.0, 73.4 (CH2Ph), 71.0,
70.7, 70.5, 70.1 (C-2, C-4, C-5, C-50), 68.3 (C-60), 62.4 (C-6), 55.2
(OMe); LRMS (EIþ, m/z, %): 625 (3) (MꢁBnþ), 522 (3), 431 (55), 325
(65), 313 (49), 91 (100); Anal. calcd for C41H48O11: C, 68.70; H, 6.75;
found: C, 68.65; H, 6.77.
saccharide 7a (416 mg, 90%, white crystals).
Data for 8b: Rf¼0.70 (EA); tR¼31.9 min (gradient A); [
a
]
20 þ68.3
D
20
Rf¼0.48 (EA); tR¼24.2 min (gradient A); [
a
]
þ95.1 (c 0.7,
(c 1.0, CHCl3); IR (neat/NaCl) 3429 cmꢁ1; 1H NMR (400 MHz, CDCl3)
D
CHCl3); mp 156 ꢀC; IR (neat/NaCl) 3441 cmꢁ1
;
1H NMR (400 MHz,
d
7.34 (m, 18H, Ph), 7.18 (m, 2H, Ph), 5.06 (d, 1H, J¼11.0 Hz, CH2Ph),

8418
J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
4.94 (d, 1H, J¼11.0 Hz, CH2Ph), 4.83 (2d, 2H, J¼11.0 Hz, CH2Ph), 4.80
reacting 5 with 1e, 1f, or 1j were stirred in a MeONa/MeOH solution
for 5 h. Standard workup and filtration on a silica gel pad (eluent
hexanes/EtOAc 1:1 then 0:1) led to the isolated disaccharides 7a,
7b, 8a, 8b, 9a, and 9b described above.
0
0
0
(d,1H, J1 e2 ¼4.0 Hz, H-1 ), 4.78 (d,1H, CH2Ph), 4.58e4.48 (m, 4H, H-
1, CH2Ph), 3.99 (dd, 1H, J5e6¼4.0, J6e6¼11.5 Hz, H-6), 3.80 (dd, 1H,
0
0
J5e6¼5.0 Hz, H-6), 3.700 (2dd, 2H, J2e3¼9.0, J3e4¼9.0, J2 e3 ¼9.00,
0
0
J3 e4 ¼9.0 Hz, H-3, H-3 ), 3.68e3.60 (m, 3H, H-2, H-5, H-5 ),
3.60e3.51 (m, 5H, H-20, H-4, H-40, H-60, H-60), 3.44 (s, 3H, OMe), 2.33
(br s, 1H, OH), 2.15 (br s, 1H, OH), 1.77 (br s, 1H, OH); 13C NMR
6.4.3. Glycosylation-optimized procedure. To
a solution of 1l
(0.50 mmol) in dry CH2Cl2 (50 mL) was added a freshly prepared
solution of TMSOTf (2 mL, 0.1 M in CH2Cl2) and a freshly prepared
(65 MHz, CDCl3)
d 138.3, 138.0, 137.7, 137.5 (Ph), 128.4e127.7 (Ph),
104.2 (C-10), 99.0 (C-1), 86.9 (C-3), 84.6 (C-30), 81.9 (C-20), 77.7, 74.3
(C-4, C-40), 75.7, 75.1, 73.5 (CH2Ph), 71.1, 69.6 (C-2, C-5, C-50), 68.8
(C-60), 62.9 (C-6), 55.1 (OMe); LRMS (EIþ, m/z, %): 625 (3) (MꢁBnþ),
593 (2), 522 (3), 431 (30), 325 (35), 281 (65), 253 (100), 181 (96);
Anal. calcd for C41H48O11: C, 68.70; H, 6.75; found: C, 68.70; H, 6.72.
solution of glucopyranosyl trichloroacetimidate
5
(2 mL,
0.50 mmol, 0.25 M) at ꢁ50 ꢀC. The resulting mixture was stirred for
1 h. This protocol was repeated two to three times (TMSOTf,
2ꢂ2 mL, trichloroacetimidate 5, 2ꢂ2 mL). After stirring for a further
3 h at ꢁ50 ꢀC, the reaction was quenched with a drop of Et3N. The
resulting mixture was diluted with CH2Cl2, washed with 1 M
NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo.
The residue was filtered on a silica gel pad and analyzed by HPLC
and further purified by chromatography (H/EA, gradient from 2:3 to
0:5) to afford 18a (120 mg, 22%), 18b (214 mg, 39%), together with
another two regioisomers (21 mg, 4% and 39 mg, 7%).
6.3.7. Methyl 2,3,6-tri-O-acetyl-4-O-(20,30,40,60-tetra-O-benzyl-
glucopyranosyl)- -glucopyranoside (17a/17b). Following the
a-D-
a/b-D
same procedure as for disaccharides 13a and 13b, coupling of
compounds 16 (351 mg, 1.10 mmol) made following reported pro-
cedures41 and 5 (1.5 g, 2.19 mmol) led to an inseparable mixture of
disaccharides 17a and 17b (730 mg, 79% 17a/17b¼2.4:1).
Rf¼0.61 (H/EA, 7:3); IR (neat/NaCl) 1745 cmꢁ1
;
1H NMR
6.4.4. Methyl 2-O-(20,30,40,60-tetra-O-benzyl-
O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tolylmethyl-a-D
a-
D-glucopyranosyl)-6-
(400 MHz, CDCl3)
d
7.32 (m, 18H), 7.14 (m, 2H), 5.61 (dd, 0.7H, J¼9.5,
-glucopyr-
9.5 Hz), 5.45 (m, 0.3H), 4.95e4.24 (m, 13H), 3.98e3.41 (m, 8H), 3.40
anoside (18a). Rf¼0.57 (CH2Cl2/MeOH, 9:1); tR¼33.2 min (gradient
20
(s, 3H), 2.11 (s, 3H), 2.04 (s, 3H), 2.03 (s, 0.9H), 1.95 (s, 2.1H); 13C
B); IR (neat/NaCl) 3409 cmꢁ1; [
(250 MHz, CDCl3)
a
]
D
þ56.2 (c 0.8, CHCl3); 1H NMR
NMR (65 MHz, CDCl3)
d
170.2, 170.1, 169.7, 138.5e137.5,
d
8.45 (d, 1H, J¼4.5 Hz), 7.54e6.92 (m, 34H),
128.3e127.3, 102.8, 98.9, 96.3, 84.5, 82.3, 81.1, 80.0, 77.2, 76.4, 75.5,
75.4, 75.3, 75.0, 74.7, 74.5, 73.5, 73.3, 73.0, 71.4, 70.9, 70.6, 70.5, 69.4,
68.7, 68.3, 68.0, 62.6, 61.7, 55.1, 55.0, 20.7, 20.7, 20.5.
6.40e5.80 (br s, 1H (OH)), 5.02 (d, 1H, J¼11.0 Hz), 4.95 (d, 1H,
J¼3.5 Hz), 4.85 (2d, 2H, J¼11.0 Hz), 4.79 (d, 1H, J¼3.5 Hz), 4.77 (d,
1H, J¼11.0 Hz), 4.72 (d, 1H, J¼11.0 Hz), 4.62 (d, 1H, J¼11.0 Hz), 4.52
(d, 1H, J¼11.0 Hz), 4.43 (d, 1H, J¼11.0 Hz), 4.27 (d, 1H, J¼10.0 Hz),
4.13 (dd, 1H, J¼9.5, 9.5 Hz), 4.08 (m, 1H), 3.90e3.53 (m, 9H), 3.42 (s,
3H), 3.44e3.06 (m, 4H), 2.36 (s, 3H), 2.34 (s, 3H); 13C NMR (65 MHz,
6.3.8. Methyl 4-O-(20,30,40,60-tetra-O-benzyl-
-glucopyranoside (9a/9b). A solution of disaccharides 17a and
a-D-glucopyranosyl)-a/
b-D
17b (710 mg, 0.84 mmol) in MeOH (10 mL) was treated with a cat-
alytic amount of freshly prepared solution of MeONa/MeOH. After
stirring for 3 h and concentration, the residue was purified by
chromatography (CH2Cl2/MeOH, 19:1) to afford disaccharides 9a/
9b (545 mg, 91%, 9a/9b¼2.4:1).
CDCl3) d 161.9, 160.9, 160.3, 149.0, 140.8, 140.0, 138.9, 138.4, 137.9,
137.1,136.9,136.6,136.4,129.3,128.8,128.5,128.3,127.9,127.7,127.6,
123.2, 121.8, 121.2, 121.1, 97.5, 95.6, 86.9, 81.8, 79.6, 77.7, 77.2, 75.5,
74.9, 73.5, 73.4, 72.8, 71.4, 70.1, 69.6, 68.4, 66.1, 55.0, 38.7, 38.0, 21.0.
Rf¼0.48 (EA); tR¼28.1 min (gradient A); IR (neat/NaCl)
6.4.5. Methyl 2-O-(20,30,40,60-tetra-O-benzyl-
O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tolylmethyl-b-D
a-
D
-glucopyranosyl)-6-
3412 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.33 (m, 18H), 7.14 (m, 2H),
-glucopyr-
5.02e4.71 (m, 6H), 4.61e4.40 (m, 4H), 4.07e3.43 (m, 12H), 3.42 (s,
anoside (18b). Rf¼0.66 (CH2Cl2/MeOH, 9:1); tR¼35.4 min (gradient
3H), 2.37 (m, 1H), 2.20 (d, 1H, J¼8.0 Hz); 13C NMR (65 MHz, CDCl3)
B); IR (neat/NaCl) 3400 cmꢁ1; [
1H NMR (250 MHz, CDCl3)
a]
20 þ52.3 (c 0.5, CHCl3); mp 74 ꢀC;
D
d
138.1e136.8, 128.4e127.6, 102.9, 100.2, 99.0, 84.4, 81.9, 81.7, 80.2,
d
8.41 (d, 1H, J¼3.5 Hz), 7.54e6.98 (m,
80.0, 78.8, 77.7, 77.5, 75.5, 75.4, 75.1, 74.8, 74.2, 73.9, 73.8, 73.3, 73.2,
72.0, 71.7, 71.2, 70.2, 70.0, 68.4, 61.0, 60.6, 55.2, 55.0; LRMS (EIþ, m/z,
%): 625 (2) (MꢁBnþ), 522 (2), 431 (33), 325 (20), 281 (30), 253 (93),
181 (100); Anal. calcd for C41H48O11: C, 68.70; H, 6.75; found: C,
68.77; H, 6.77.
34H), 5.28 (d, 1H, J¼11.0 Hz), 4.96 (d, 1H, J¼11.0 Hz), 4.93 (d, 1H,
J¼3.5 Hz), 4.83 (2d, 2H, J¼11.0 Hz), 4.80 (d, 1H, J¼11.0 Hz), 4.70 (d,
1H, J¼7.5 Hz), 4.58 (d,1H, J¼11.0 Hz), 4.55 (d,1H, J¼11.0 Hz), 4.50 (d,
1H, J¼11.0 Hz), 4.32e4.10 (br s, 1H, OH), 4.19 (dd, 1H, J¼9.0, 9.0 Hz),
3.89 (m, 2H), 3.75e3.53 (m, 8H), 3.58 (m, 1H), 3.45 (s, 3H),
3.47e3.05 (m, 4H), 2.37 (s, 3H), 2.34 (s, 3H); 13C NMR (65 MHz,
6.4. Preparation and glycosylation of monoprotected
acceptors
CDCl3) d 161.8, 160.7, 160.4, 149.3, 141.1, 139.6, 138.9, 138.7, 138.1,
137.4, 136.9, 136.8, 136.5, 129.5, 128.5, 128.4, 128.3, 128.0, 127.9,
127.6, 127.5, 123.1, 122.3, 121.3, 121.2, 105.3, 99.8, 87.0, 84.7, 81.9,
81.8, 77.7, 75.6, 75.0, 74.6, 74.5, 74.3, 73.4, 71.6, 69.3, 69.2, 66.7, 55.3,
39.1, 38.2, 21.0.
6.4.1. Glycosylation-general procedure (Table 1). To a solution of
1bem29 (0.25 mmol) and glucopyranosyl trichloroacetimidate 5
(0.25 mmol) in dry CH2Cl2 (25 mL) was added a freshly prepared
0.1 M solution of TMSOTf. The resulting mixture was stirred for 1 h
then quenched with a drop of Et3N, diluted with CH2Cl2, washed
with 1 M NaHCO3 and brine, dried over MgSO4, and concentrated in
vacuo. For the systematic glycosylation reactions, the residue was
deprotected without further purification (Table 1).
6.4.6. Octyl 2,3,4-tri-O-acetyl-6-O-[6-(2-pyridinylethyl)-pyridin-2-
yl]-di-p-tolylmethyl-
b-
D-glucopyranoside (2a). Following the same
procedure as for the preparation of 1l, octyl-b-D-glucopyranoside
(3.50 g, 12.0 mmol) and (6-(2-(pyridin-2-yl)ethyl)pyridin-2-yl)di-
p-tolylmethanol (1.10 g, 2.79 mmol) led to 2. Acetylation was car-
ried out to facilitate its purification. Thus a solution of acetic an-
hydride (6.5 mL, excess) in pyridine (30 mL) in CH2Cl2 was added to
the crude mixture. After stirring for 16 h, the solution was con-
centrated to provide, after flash chromatography (H/EA, 4:1 then
3:2), 2a (1.03 g, 46%).
6.4.2. Deprotection. Disaccharides made by reacting 5 with either
1b, 1k, 1l or 1m were stirred in a mixture of TFA/CH2Cl2 (1:1, 10 mL)
for 5 h. Disaccharides made by reacting 5 with 1c or 1d were
reacted with TBAF (0.75 mL of a 1 M solution in THF, 0.75 mmol)
and AcOH (0.05 mL, 1.0 mmol) in THF (10 mL). Disaccharides made
by reacting 5 with 1g, 1h or 1i were heated at 40 ꢀC in a mixture of
AcOH/H2O/THF (1:1:1, 20 mL) for 3 h. Disaccharides made by
Rf¼0.5 (H/EA, 1:1); IR (neat): 2927, 2856, 1755 cmꢁ1; [
a
]
20 þ25.5
D
(c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.49 (br d, 1H, J¼4 Hz),
7.63 (d, 1H, J¼8 Hz), 7.49 (t, 1H, J¼8 Hz), 7.43e7.37 (m, 3H), 7.28 (s,

J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
8419
1H), 7.06 (3d, 5H J¼7 Hz), 6.85 (d, 1H, J¼7.5 Hz), 6.77 (d, 1H,
J¼7.5 Hz), 5.24 (t, 1H, J¼9.5 Hz), 5.15 (t, 1H, J¼9.5 Hz), 5.06 (t, 1H,
J¼8 Hz), 4.50 (d, 1H, J¼8 Hz), 3.95e3.89 (ddd, 1H, J¼6.5, 9.5 Hz),
3.57e3.51 (m, 2H), 3.33 (dd, 1H, J¼2, 11 Hz), 3.12e3.07 (m, 5H), 2.31
(s, 6H), 2.05 (s, 3H), 2.00 (s, 3H), 1.76 (s, 3H), 1.67e1.57 (m, 2H),
1.34e1.26 (m, 10H), 0.89e0.85 (t, 3H, J¼7 Hz); 13C NMR (75 MHz,
J¼2.5 Hz), 4.60 (br s, 1H), 3.98 (dd, 1H, J¼6.5, 8 Hz), 3.92 (br s, 2H),
3.47 (t, 1H, 8.5 Hz), 3.33 (s, 3H), 3.31e3.14 (m, 4H), 3.10 (dd, 1H,
J¼5.5, 8 Hz), 2.37 (s, 3H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3)
161.72, 160.92, 160.19, 149.18, 142.05, 138.89, 137.53, 136.73, 136.69,
136.44, 130.08, 128.53, 128.44, 128.02, 123.10, 121.89, 121.40, 121.17,
99.99, 86.96, 70.39, 70.17, 69.26, 69.16, 63.26, 55.35, 38.62, 37.93,
21.09, 21.02; HRMS (EIþ) calcd for [C34H38N2O6þH]þ: 571.28026.
Found: 571.28003.
CDCl3)
d 170.62, 169.56, 169.08, 162.92, 161.59, 159.44, 149.07,
140.63, 140.16, 136.54, 136.51, 136.27, 129.49, 129.39, 128.19, 128.14,
123.27, 121.01, 120.73, 118.82, 100.91, 86.63, 73.40, 73.37, 71.68,
69.96, 68.79, 62.21, 37.64, 37.31, 31.94, 29.63, 29.43, 26.08, 22.78,
21.17, 20.85, 20.57, 14.23; HRMS (EIþ) calcd for [C47H59N2O9þH]þ:
795.42151. Found: 795.42232.
6.5. General procedure
To a solution of the acceptor (0.50 mmol) in dry CH2Cl2 (50 mL)
was added a freshly prepared solution of TMSOTf (2 mL, 0.1 M) and
a freshly prepared solution of glucopyranosyl trichloroacetimidate
5 (2 mL, 0.50 mmol, 0.25 M) at ꢁ50 ꢀC. The resulting mixture was
stirred for 1 h. This protocol was repeated two to three times
(TMSOTf, 2ꢂ2 mL, trichloroacetimidate 8, 2ꢂ2 mL). After stirring
for a further 3 h at ꢁ50 ꢀC, the reaction was quenched with a drop
of Et3N. The resulting mixture was diluted with CH2Cl2, washed
with 1 M NaHCO3 and brine, dried over MgSO4, and concentrated in
vacuo. The crude mixture was next treated with TBAF in THF to
cleave any silyl ethers formed. The solution was concentrated and
the residue was purified by column chromatography (H/EA, gradi-
ent from 7:3 to 1:1) to afford the corresponding products.
6.4.7. Octyl
ylmethyl-
6-O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tol-
-glucopyranoside (2). A solution of 2a (1.03 g,
b
-
D
1.30 mmol) in MeOH (80 mL) was stirred in presence of MeONa
(280 mg, 5.2 mmol) for 2 h. The solution was neutralized with
IR120H resin, filtered and concentrated to provide pure 2 (light
yellow foam, 760 mg, 88%).
Rf¼0.30 (DCM/MeOH, 9:1); IR (DCM solution): 3380, 2925, 2856,
1451 cmꢁ1; [
d
a
]
þ11.9 (c 0.16, CHCl3); 1H NMR (400 MHz, CDCl3)
20
D
8.65 (br s, 1H), 7.63, (br s, 1H), 7.59e7.52 (m, 2H), 7.39 (d, 2H,
J¼7.5 Hz), 7.28 (s, 1H), 7.21 (d, 3H, J¼8 Hz), 7.14 (d, 3H, J¼8 Hz), 7.08
(d, 3H, J¼8 Hz), 4.31 (d, 1H, J¼8 Hz), 3.82e3.74 (m, 3H), 3.62e3.59
(m, 1H), 3.49e3.39 (m, 2H), 3.37e3.33 (t, 1H, J¼8 Hz), 3. 28e3.26
(m, 1H), 3.20e3.18 (m, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 1.60e1.53 (m,
2H), 1.28e1.23 (m, 10H), 0.87e0.84 (t, 3H, J¼7 Hz); 13C NMR
6.5.1. Methyl 2-O-(20,30,40,60-tetra-O-benzoyl-
(6-O-tert-butyldiphenylsilyl)- -glucopyranoside (20) and methyl 3-
O-(20,30,40,60-tetra-O-benzoyl-
-glucopyranosyl)-6-O-(tert-butyldi-
phenylsilyl)- -glucopyranoside (21). Following the general gly-
b-D-glucopyranosyl)-
a-D
b-D
(75 MHz, CDCl3)
d
161.82, 160.63, 160.59, 149.43, 142.05, 138.23,
138.14, 137.25, 137.07, 136.90, 130.41, 128.76, 127.87, 123.41,122.80,
121.70, 121.67, 103.00, 87.24, 75.55, 75.21, 74.33, 73.93, 70.34, 67.86,
39.47, 38.58, 31.92, 29.67, 29.50, 29.31, 26.04, 22.77, 21.26, 21.18,
14.24; HRMS (EIþ) calcd for [C41H52N2O6þH]þ: 669.38981. Found:
669.39095.
a-D
cosylation procedure, 1c (1 equiv) was reacted with 6 (1 equiv)
yielding both 20 and 21 (18%: 20%, 20/21).
Data for 20: Rf¼0.2 (H/EA, 7:3); IR (CHCl3) 3494, 1724 cmꢁ1
;
20
[a
]
þ43.4 (c 0.17, CHCl3); 1H NMR (500 MHz, CDCl3)
d 8.06 (d,
D
J¼8.2 Hz, 2H), 7.97 (d, J¼7.1 Hz, 2H), 7.93 (d, J¼7.3 Hz, 2H), 7.83 (d,
J¼5.8 Hz, 2H), 7.71e7.65 (m, 5H), 7.55e7.49 (m, 4H), 7.45e7.33 (m,
17H), 7.30 (dd, J¼8.3 Hz, 16.5, 4H), 5.95 (t, J¼9.6 Hz, 1H), 5.67 (t,
J¼9.7 Hz, 1H), 5.58 (dd, J¼7.9, 9.8 Hz, 1H), 5.25 (d, J¼7.9 Hz, 1H),
5.05 (d, J¼7.9 Hz, 0.3H), 4.77 (d, J¼3.2 Hz, 2H), 4.73 (dd, J¼3.3,
15.1 Hz, 1H), 4.43 (dd, J¼5.8, 12.2 Hz, 1H), 4.40e4.34 (m, J¼12.4 Hz,
0.4H), 4.23e4.18 (m, J¼6.5 Hz, 0.2H), 4.07 (t, J¼6.8 Hz, 0.2H), 3.93
(dd, J¼7.1, 16.3 Hz, 1H), 3.85 (t, J¼4.8 Hz, 2H), 3.76e3.69 (m,
J¼9.1 Hz, 0.5H), 3.66e3.61 (m, 1H), 3.58e3.54 (m, 2H), 3.39 (s,
6.4.8. Methyl
ylmethyl-
6-O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tol-
-mannopyranoside (3). Following the same procedure
a-D
as for the preparation of 1l, methyl-a-D-mannopyranoside (3.10 g,
16.0 mmol) and (6-(2-(pyridin-2-yl)ethyl)pyridin-2-yl)di-p-tol-
ylmethanol (1.60 g, 4.06 mmol) led, after purification by flash
chromatography (CH2Cl2/MeOH, gradient 98:2 to 9:1), to 3 (brown
foam, 1.80 g, 85%).
Rf¼0.35 (DCM/MeOH, 9/1); IR (CDCl3 solution): 3372 (broad),
20
2924, 1451 cmꢁ1; [
a
]
þ104.4 (c 0.10, CHCl3); 1H NMR (400 MHz,
0.8H), 3.27 (s, 3H),1.04 (s,11H); 13C NMR (126 MHz, CDCl3)
d 166.29,
D
CDCl3)
d
8.59e8.58 (d, 1H, J¼3.5 Hz), 8.06 (br s, 1H), 7.61e7.55 (m,
166.24, 165.91, 165.82, 165.55, 165.35, 165.33, 135.81, 135.80, 135.75,
133.83, 133.74, 133.72, 133.68, 133.61, 133.54, 133.44, 133.38, 133.27,
133.26, 130.13, 130.03, 130.00, 129.95, 129.91,129.90,129.88, 129.68,
129.67, 129.47, 129.39, 129.15, 128.86, 128.80, 128.66, 128.61, 128.60,
128.46, 128.41, 127.85, 127.84, 127.71, 102.77, 101.39, 99.27, 98.86,
87.86, 81.24, 72.88, 72.76, 72.64, 72.32, 72.28, 72.21, 71.83, 71.66,
71.01, 70.64, 69.53, 68.66, 64.33, 63.42, 63.07, 55.21, 55.00, 36.77,
26.94, 26.92, 24.82, 19.46, 19.37; HRMS (ESIþ) calcd for
2H), 7.43e7.41 (d, 2H, J¼8 Hz), 7.30e7.28 (d, 1H, J¼8 Hz), 7.23e7.21
(d, 2H, J¼8 Hz), 7.18e7.12 (m, 4H), 7.08e7.06 (d, 3H, J¼7.5 Hz), 4.68
(d, 1H, J¼1 Hz), 4.09e4.07 (m, 2H,), 4.02 (s, 1H), 3.87e3.82 (m, 1H),
3.43e3.39 (t,1H, J¼9 Hz), 3.30 (s, 3H), 3.29e3.20 (m, 2H), 3.15e3.09
(m, 2H), 3.07e3.00 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d 161.99, 160.65, 160.52, 149.29, 142.46, 138.13,
137.88, 137.26, 137.21, 136.76, 130.66, 128.77, 127.62, 123.46, 122.91,
121.74, 121.65, 100.83, 87.43, 72.50, 70.62, 70.05, 69.64, 68.59,
55.25, 39.54, 38.65, 21.25, 21.16; HRMS (EIþ) calcd for
[C34H38N2O6þH]þ: 571.28026. Found: 571.28081.
[C57H58O15SiþNa]þ: 1033.34372. Found: 1033.34419.
20
Data for 21: Rf¼0.3 (H/EA, 7:3); IR (CHCl3) 3494,1724 cmꢁ1; [
a]
D
þ54.7 (c 0.12, CHCl3); 1H NMR (500 MHz, CDCl3)
8.08 (d, J¼7.9 Hz,
d
2H), 7.98 (d, J¼7.8 Hz, 2H), 7.93 (d, J¼7.7 Hz, 2H), 7.83 (d, J¼7.8 Hz,
2H), 7.70 (t, J¼7.3 Hz, 4H), 7.51 (dt, J¼6.7, 9.4 Hz, 3H), 7.47e7.27 (m,
19H), 5.93 (t, J¼9.6 Hz, 1.1H), 5.64 (t, J¼9.7 Hz, 1H), 5.61e5.54 (m,
1.2H), 5.35e5.30 (m, 0.2H), 5.25 (d, J¼7.8 Hz, 0.2H), 5.05 (d,
J¼7.9 Hz, 1H), 4.78 (d, J¼12.2 Hz, 1.2H), 4.72 (d, J¼3.8 Hz, 1H),
4.67e4.63 (m, 0.2H), 4.50e4.41 (m, 0.4H), 4.38 (dd, J¼6.7, 12.1 Hz,
1H), 4.26e4.19 (m, 1.2H), 4.14e4.04 (m, 0.2H), 3.96 (d, J¼10.7 Hz,
1H), 3.93e3.89 (m, 0.2H), 3.85 (dd, J¼5.5, 10.8 Hz, 1.2H), 3.72 (dd,
J¼8.0, 17.1 Hz, 2H), 3.68e3.63 (m, J¼5.4 Hz, 1.2H), 3.59e3.53 (m,
J¼9.0 Hz, 2H), 3.39 (s, 3H), 3.27 (s, 0.5H), 2.82 (s, 0.2H), 2.64 (s,
0.2H), 1.92 (d, 0.7H), 1.05 (s, 10H); 13C NMR (126 MHz, CDCl3)
6.4.9. Methyl
ylmethyl- -galactopyranoside (4). Following the same procedure
as for the preparation of 1l, methyl- -galactopyranoside (3.10 g,
16.0 mmol) and (6-(2-(pyridin-2-yl)ethyl)pyridin-2-yl)di-p-tol-
ylmethanol (1.60 g, 4.06 mmol) led, after purification by flash
chromatography (gradient 98:2 to 9:1), to 4 (brown foam, 330 mg,
14%).
6-O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tol-
a-D
a-D
Rf¼0.35 (DCM/MeOH, 9/1); IR (CDCl3 solution): 3361 (broad),
20
2924, 1451 cmꢁ1; [
a
]
þ99.9 (c 0.15, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
8.65 (br s,1H), 7.58 (br s,1H), 7.50 (t,1H, J¼7.5 Hz), 7.18 (dd,
2H, J¼8, 21 Hz), 7.08 (d, J¼8 Hz), 7.03 (d, 1H, J¼7.5 Hz), 4.79 (d, 1H,
d 166.37, 166.29, 166.24, 165.96, 165.91, 165.82, 165.55, 165.40,

8420
J. Lawandi et al. / Tetrahedron 67 (2011) 8411e8420
165.35, 165.33, 136.01, 135.81, 135.80, 135.75, 135.64, 133.83, 133.74,
133.72, 133.68, 133.61, 133.58, 133.55, 133.45, 133.38, 133.26, 130.22,
130.13, 130.03, 130.00, 129.96, 129.89, 129.83, 129.68, 129.67, 129.47,
129.39, 129.30, 129.16, 129.10, 129.05, 128.86, 128.81, 128.68, 128.67,
128.61, 128.60, 128.54, 128.52, 128.46, 128.41, 128.16, 127.86, 127.84,
127.71, 102.78, 101.39, 99.27, 98.86, 90.62, 87.86, 81.24, 77.41, 72.88,
72.77, 72.64, 72.35, 72.32, 72.28, 72.21, 71.82, 71.67, 71.01, 70.63,
70.23, 69.59, 69.52, 68.66, 67.97, 64.33, 63.42, 63.05, 55.21, 55.00,
36.77, 27.06, 26.92, 24.82, 19.47, 19.37; HRMS (ESIþ) calcd for
[C57H58O15SiþNa]þ: 1033.34372. Found: 1033.34436.
14.25, 14.21; HRMS (ESIþ) calcd for [C75H78N2O15þH]þ: 1247.54750.
Found: 1247.54653.
Acknowledgements
We thank the Canadian Foundation for Innovation for financial
support through the New Opportunities Fund program, NSERC,
FQRNT, CIHR, AstraZeneca, AB Science and ViroChem Pharma for
financial support.
6.5.2. Methyl 3-O-(20,30,40,60-tetra-O-benzoyl-
6-O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tolylmethyl-
b-
D
-glucopyranosyl)-
References and notes
a-D
-gluco-
pyranoside (21). Following the general glycosylation procedure, 1l
1. Murphy, P. V. Eur. J. Org. Chem. 2007, 4177.
2. Risseeuw, M. D. P.; Overhand, M.; Fleet, G. W. J.; Simone, M. I. Tetrahedron:
Asymmetry 2007, 18, 2001.
3. Timmer, M. S. M.; Verhelst, S. H. L.; Grotenbreg, G. M.; Overhand, M.; Over-
kleeft, H. S. Pure Appl. Chem. 2005, 77, 1173.
4. Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491.
5. Martin, O. R.; Compain, P. Curr. Top. Med. Chem. 2003, 471 3-Special Issue.
6. Mulard, L. Ann. Pharm. Fr. 2007, 65, p. 14.
7. Wang, L. X., Ed.; ACS Symposium Series 932; American Chemical Society:
Washington, DC, 2006; p. 133.
8. Astronomo, R. D.; Burton, D. R. Nat. Rev. Drug Discovery 2010, 9, 308.
9. Kawabata, T. Yuki Gosei Kagaku Kyokaishi/J. Synth. Org. Chem. 2007, 65, 1081.
10. Francais, A.; Urban, D.; Beau, J. M. Angew. Chem., Int. Ed. 2007, 46, 8662.
11. Filice, M.; Palomo, J. M.; Bonomi, P.; Bavaro, T.; Fernandez-Lafuente, R.; Guisan,
J. M.; Terreni, M. Tetrahedron 2008, 64, 9286.
was reacted with 6 yielding only 22 (80% yield).
20
Rf¼0.3 (H/EA, 4:6); IR (CHCl3): 3489, 1730 cmꢁ1; [
a
]
þ59.8 (c
D
0.11, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.50 (d, J¼4.8 Hz, 1H), 7.99
(dd, J¼7.3, 12.3 Hz, 5H), 7.92 (d, J¼7.3 Hz, 3H), 7.83 (d, J¼7.3 Hz, 2H),
7.59e7.17 (m, 28H), 7.05 (t, J¼8.5 Hz, 6H), 6.84 (t, J¼8.3 Hz, 2H), 5.91
(t, J¼9.7 Hz, 1H), 5.65e5.52 (m, 2H), 5.11 (d, J¼8.0 Hz, 1H), 4.75 (dd,
J¼3.3, 8.7 Hz, 2H), 4.35 (dd, J¼6.5, 12.2 Hz, 1H), 4.18 (ddd, J¼2.7, 6.4,
9.4 Hz, 1H), 4.04 (s, 1H), 3.76 (dd, J¼7.0, 10.9 Hz, 2H), 3.71e3.57 (m,
2H), 3.43 (s, 3H), 3.33 (dd, J¼5.8, 10.1 Hz, 1H), 3.13 (s, 4H), 2.32 (s,
6H), 2.00 (d, J¼7.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 166.26,
165.83, 165.55, 165.34, 163.10, 161.63, 159.63, 149.20, 141.09, 140.82,
136.55, 136.50, 136.22, 133.71, 133.51, 133.43, 133.27, 130.04, 129.96,
129.89, 129.51, 129.36, 129.27, 129.19, 128.82, 128.70, 128.59, 128.45,
128.40, 128.27, 123.28, 121.04, 120.77, 119.36, 102.52, 87.25, 86.59,
72.80, 72.29, 71.08, 70.94, 69.54, 69.30, 37.62, 21.19; HRMS (ESIþ)
calcd for [C68H64N2O15þH]þ: 1149.43795. Found: 1149.43769.
12. Ueda, Y.; Muramatsu, W.; Mishiro, K.; Furuta, T.; Kawabata, T. J. Org. Chem. 2009,
74, 8802.
13. Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999, 121, 2315.
14. Kaji, E.; Shibayama, K.; In, K. Tetrahedron Lett. 2003, 44, 4881.
15. Ferrier, R. J.; Hay, R. W.; Vethaviyasar, N. Carbohydr. Res. 1973, 27, 55.
16. Van Cleve, J. W. Carbohydr. Res. 1979, 70, 161.
17. Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980, 80, C17.
18. Hanessian, S.; Lou, B. Chem. Rev. 2000, 100, 4443.
19. Cinget, F.; Schmidr, R. R. Synlett 1993, 168.
20. Kaji, E.; Nishino, T.; Ishige, K.; Ohya, Y.; Shirai, Y. Tetrahedron Lett. 2010, 51, 1570.
21. Wang, W.; Kong, F. J. Org. Chem. 1998, 63, 5744.
6.5.3. Octyl 3-O-(20,30,40,60-tetra-O-benzoyl-
O-[6-(2-pyridinylethyl)-pyridin-2-yl]-di-p-tolylmethyl-
b
-D
-glucopyranosyl)-6-
b-D-glucopyr-
22. Wang, W.; Kong, F. J. Org. Chem. 1999, 64, 5091.
23. Wang, W.; Kong, F. Angew. Chem., Int. Ed. 1999, 38, 1247.
24. Zhu, Y.; Kong, F. Carbohydr. Res. 2001, 332, 1.
25. Zeng, Y.; Kong, F. Carbohydr. Res. 2003, 338, 843.
26. Muddasani, P. R.; Bozo, E.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1994, 77, 257.
27. Moitessier, N.; Chapleur, Y. Tetrahedron Lett. 2003, 44, 1731.
28. Vicente, V.; Martin, J.; Jimenez-Barbero, J.; Chiara, J. L.; Vicent, C. Chem.dEur. J.
2004, 10, 4240.
29. Moitessier, N.; Englebienne, P.; Chapleur, Y. Tetrahedron 2005, 61, 6839.
30. Gray, I. J.; Kluger, R. Carbohydr. Res. 2007, 342, 1998.
31. Kurahashi, T.; Mizutani, T.; Yoshida, J. I. J. Chem. Soc., Perkin Trans. 1 1999, 465.
32. Muramatsu, W.; Kawabata, T. Tetrahedron Lett. 2007, 48, 5031.
33. Coste, G.; Gerber-Lemaire, S. Eur. J. Org. Chem. 2006, 3903.
34. Ding, Y.; Labbe, J.; Kanie, O.; Hindsgaul, O. Bioorg. Med. Chem. 1996, 4, 683.
35. Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819.
36. Lu, X. A.; Chou, C. H.; Wang, C. C.; Hung, S. C. Synlett 2003, 1364.
37. Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 1249.
38. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
39. Schmidt, R. R.; Castro-Palomino, J. C.; Retz, O. Pure Appl. Chem. 1999, 71, 729.
40. Hanessian, S.; Kagotani, M. Carbohydr. Res. 1990, 202, 67.
41. Graziani, A.; Passacantilli, P.; Piancatelli, G.; Tani, S. Tetrahedron Lett. 2001, 42,
3857.
anoside (23). Following the general glycosylation procedure, 2 was
reacted with 6 yielding 23 (87% yield).
20
Rf¼0.3 (H/EA, 1:1); IR (CHCl3) 3494, 1730 cmꢁ1; [
a
]
D
þ21.0 (c
0.12, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.49 (d, J¼4.5 Hz, 1H),
8.28e8.23 (m, 1H), 7.98 (t, J¼8.1 Hz, 6H), 7.93e7.85 (m, 5H), 7.82 (d,
J¼7.4 Hz, 3H), 7.57 (d, J¼7.9 Hz, 2H), 7.50 (d, J¼7.2 Hz, 4H), 7.42 (d,
J¼3.0 Hz, 7H), 7.40e7.28 (m, 18H), 7.22 (t, J¼7.7 Hz, 3H), 7.05 (d,
J¼7.9 Hz, 7H), 6.84 (t, J¼8.3 Hz, 2H), 5.91 (t, J¼9.7 Hz, 1H),
5.63e5.52 (m, 2H), 5.10 (d, J¼8.0 Hz, 1H), 4.73 (d, J¼10.1 Hz, 1H),
4.37e4.29 (m, 2H), 4.21 (d, J¼7.9 Hz, 2H), 4.18e4.13 (m, 1H), 4.07 (s,
1H), 3.87 (d, J¼9.6 Hz, 1H), 3.64 (d, J¼9.5 Hz, 1H), 3.55e3.50 (m,
2H), 3.48e3.38 (m, 5H), 3.34e3.30 (m, 1H), 3.12 (s, 6H), 2.29 (s, 9H),
1.63e1.57 (m, 5H), 1.28e1.22 (m, 14H), 0.85 (d, J¼6.8 Hz, 6H); 13C
NMR (75 MHz, CDCl3)
d 171.26, 166.24, 165.82, 165.38, 165.32,
163.07, 161.59, 159.61, 149.16, 141.00, 140.81, 136.50, 136.48, 136.22,
133.67, 133.39, 133.24, 130.00, 129.93, 129.86, 129.47, 129.37, 129.31,
128.82, 128.70,128.56, 128.51,128.42,128.38,128.23, 123.29,121.03,
120.75, 119.43, 102.53, 102.49, 88.36, 86.50, 86.35, 75.18, 72.99,
72.72, 72.08, 69.99, 69.61, 64.10, 63.05, 60.51, 37.65, 37.58, 34.78,
31.90, 31.71, 29.82, 29.73, 29.48, 29.35, 26.15, 22.78, 21.18, 14.32,
42. Marzabadi, C. H.; Anderson, J. E.; Gonzalez-Outeirino, J.; Gaffney, P. R. J.; White,
C. G. H.; Tocher, D. A.; Todaro, L. J. J. Am. Chem. Soc. 2003, 125, 15163.
43. Olah, G. A.; Klumpp, D. A. Synthesis 1997, 744.
44. Cmoch, P.; Pakulski, Z. Tetrahedron: Asymmetry 2008, 19, 1493.