Modulation of the relative reactivities of carbohydrate secondary hydroxyl groups. Modification of the hydrogen bond network

Article abstract of DOI:10.1016/S0040-4039(03)00141-2

An approach towards the control of the relative regioselectivity of the secondary hydroxyl groups is presented. Original protecting groups, which are capable of specific intramolecular hydrogen bonds and are likely to modulate the partial charges of the o

Full text of DOI:10.1016/S0040-4039(03)00141-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1731–1735
Modulation of the relative reactivities of carbohydrate secondary
hydroxyl groups. Modification of the hydrogen bond network
Nicolas Moitessier* and Yves Chapleur
Groupe SUCRES, Unite´ Mixte 7565 CNRS, Universite´ Henri Poincare´-Nancy 1, B.P. 239, F-54506 Nancy-Vandoeuvre, France
Received 31 October 2002; revised 14 January 2003; accepted 15 January 2003
Abstract—An approach towards the control of the relative regioselectivity of the secondary hydroxyl groups is presented. Original
protecting groups, which are capable of specific intramolecular hydrogen bonds and are likely to modulate the partial charges of
the oxygen atoms, have been developed. Qualitative NMR experiments confirmed the existence of the expected hydrogen bonds
and shed light on the perturbation of the cooperative intramolecular hydrogen bond network. Further reactivity studies are
presented and confirm the potential of protecting group-mediated regioselective functionalization of carbohydrates. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
In this communication, we describe a new alternative
approach to the control of the relative reactivities of
carbohydrate secondary hydroxyl groups. In this pre-
liminary work, we took advantage of designed protect-
ing groups at position 6 and explored the effect of
intramolecular interactions modulating the nucle-
ophilicity of the oxygen atoms.
The number of therapeutic targets is expected to
increase dramatically due to the completion of the
human genome project. In order to screen libraries of
oligosaccharides, which are potential ligands of target
proteins such as lectins, one strategy is to develop
suitable methods for combinatorial or parallel synthesis
of such polymeric molecules. Indeed, the poor availabil-
ity of naturally occurring oligosaccharides has to be
balanced by synthetic approaches. This calls for
efficient and regioselective coupling methods, which still
require suitably protected synthons and therefore neces-
sitate synthetic efforts for their preparation. In an
attempt to decrease the number of tedious protection/
deprotection transformations, one can take advantage
of selective enzymes. However, this approach is
restricted to particular substrates, since enzymes do not
recognize some of the modified sugars.
2. Design and synthesis of hydrogen bond acceptor
protecting groups
Recent papers shed light on the intramolecular network
that controls the relative reactivity of the glucose
hydroxyl groups (Fig. 1).5,6
With this in mind, we set out to explore the role of
protecting groups at position 6 that would beneficially
interact with positions 3 and 4. Hopefully, this would
result in a modification of the electronic distribution
and consequently of the intrinsic reactivity of the inter-
acting hydroxyl groups.
Open glycosylation is therefore regarded as a promising
alternative. However, only a few studies, which are
directed toward non protected (or partially protected)
donor and acceptor coupling, have been reported.1,2 To
achieve regioselective glycosylation, the relative reactiv-
ities of the free hydroxyl groups of the acceptors must
be controlled. The use of Lewis acids (boron, tin) was
envisioned and successfully used in the preparation of
particular disaccharides.3,4
Figure 1. Glucose intramolecular H bond network in chloro-
* Corresponding author. Tel.: +33-383-68-4776; fax: +33-383-68-4780;
e-mail: nicolas.moitessier@persmail.uhp-nancy.fr
form as proposed by Yoshida5 and Davies.6
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00141-2

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N. Moitessier, Y. Chapleur / Tetrahedron Letters 44 (2003) 1731–1735
Thus, novel hydrogen bond acceptor protecting groups
were designed with the help of molecular modeling. For
instance, a phenyl group in 1a was substituted for a
precisely positioned pyridyl ring that would hydrogen
bond with the 4-OH (1b). The expected stability of this
protecting group in acidic medium (protonation of the
pyridyl group favored over cleavage of the ether bond)
was balanced by the introduction of electrodonating
groups, which further stabilize the corresponding ter-
tiary carbocation (1c). A second pyridyl group was next
added and linked to the trityl-like protecting group by
means of a selected spacer (1e). This extra heterocycle
should participate in a second hydrogen bond as sug-
gested by molecular modeling studies. For comparison
purpose, 1a and 1d were also prepared.
and 5b were converted into the conjugated olefins 6a
and 6b (83 and 76%). These unsaturated intermediates
were isolated and then further reduced by catalytic
hydrogenation to afford the advanced intermediates 7a
and 7b in fairly good yields (94 and 72%). These
alcohols were transformed into the chlorinated reagents
8a and 8b by treatment with a mixture of acetyl chlo-
ride and thionyl chloride. Conversion of 7a and 7b into
their hydrochloride counterpart was a prerequisite for
an efficient chlorination. These activated trityl-like moi-
eties were reacted in situ with methyl a-D-glucopyran-
oside in pyridine to afford the target compounds 1d and
1e.
Scheme 1. Reagents and conditions: (a) TolMgBr (0.9 equiv.),
THF, rt then TolMgBr (1.1 equiv.), −78°C, 45%; (b) toluene,
t-BuLi, THF, −78°C then 3, HMPT, 35% (along with 30% of
3); (c) 2-picoline, n-BuLi, THF, −78°C then 3, HMPT, 83%;
(d) LiAlH4, THF, 0°C, 70%; (e) H2, 10% Pd/C, EtOH/THF,
60%; (f) NaHMDS, THF, −78°C, then PhNTf2, −50°C, 83%
(6a), 76% (6b); (g) H2, 10% Pd/C, EtOH/THF, 94% (7a), 72%
(7b); (h) HCl, H2O, reflux then SOCl2, AcCl; (i) pyridine,
Figure 2. Selected protecting groups.
The synthesis of 1d and 1e, outlined in Scheme 1, began
with the selective disubstitution of symmetric pyridine
diester 2. This desymmetrization was achieved under
optimized temperature conditions with a reasonable
yield. The appropriate lithio derivatives were next
added onto the remaining ester moiety. Surprisingly,
although 4a adopted the keto form, the presence of
nitrogen on the ring favored the enol form over the
keto form in 4b. As a consequence, monoaddition of
2-lithio picoline onto 3 was accomplished with a good
yield (83%) while the yield for the reaction of lithio
toluene with 3 gave no selectivity (35% mono addition,
35% diaddition, 30% starting material). Reductions of
the ketone carbonyl of 4a and of the enol double bond
of 4b were accomplished by hydride-mediated reduction
and catalytic hydrogenation respectively yielding the
diols 5a and 5b. Dehydration of these alcohols was next
achieved by triflation and in situ elimination. Thus, on
treatment with a base and PhNTf2 (milder that triflic
anhydride which induced partial decomposition), 5a
methyl a-D-glucopyranoside, 50% (1d, two steps), 63% (1e,
two steps, along with 7b 23%). Tol: p-tolyl.
3. Solution conformation
In order to prove that the pyridyl ring acts as suggested
by the modeling, extensive NMR solution conforma-
tion studies were carried out. The hydroxy resonance is
highly sensitive to his implication in hydrogen bonding.
Besides, adjacent ring proton resonance is an additional
indication that would infer the existence of hydrogen
bonds. Fortunately, unambiguous assignments of all
the peaks were made possible by COSY experiments.
1H NMR analysis in both DMSO-d6 and CDCl3 indi-
cated the presence of the expected specific interaction
(Table 1). A closer look to the data revealed that

N. Moitessier, Y. Chapleur / Tetrahedron Letters 44 (2003) 1731–1735
Table 1. Chemical shift dependence of glycoside protons
1733
Proton
1a
1b
1a
1b
1c
1d
1e
DMSO
DMSO
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
H-1
H-2
H-3
H-4
H-5
H-6
H-6%
OMe
OH-2
OH-3
OH-4
4.61
3.22
3.46
2.95
3.61
3.04
3.37
3.39
4.74
4.78
4.82
4.61
3.23
3.46
3.00
3.61
3.06
3.37
3.40
4.74
4.79
4.90
4.79
3.55
3.74
3.53
3.70
3.41
3.70
3.43
2.10
2.53
2.62
4.76
3.63
3.86
4.06
3.70
3.13
3.70
3.33
2.20
2.95
–
4.76
3.61
3.86
4.04
3.70
3.13
3.70
3.33
2.21
2.97
–
4.74
3.65
3.87
3.85
3.97
3.21
3.41
3.35
2.18
2.86
6.72
4.71
3.65
3.94
3.85
3.85
3.27
3.27
3.35
2.30
4.72
–
although 1a and 1b spectra are roughly identical in
DMSO-d6, several significant variations in the chemical
shifts could be measured in CDCl3. For instance, the
H-4 and H-3 ring proton signals shifted downfield
(DlH-4(1c–1a)=0.51 ppm; DlH-3(1c–1a)=0.12 ppm).
Similarly, the modified patterns for the H-6 and OMe
signals as well as the optical rotation values (Fig. 2)
strongly support a large conformational change. The
coupling constant values were also useful for the deter-
mination of the geometry and therefore of the confor-
mation adopted in chloroform.7,8 All these data are
consistent with the models proposed on Figure 3.
still exists although the chemical shift variations were
less marked (DlH-4(1d–1a)=0.32 ppm, DlH-4(1e–1a)=
0.32 ppm). When comparing 1d to 1e, H-3 shifted
downfield by l=0.07 ppm. The H-2 signal was dis-
placed downfield from 1a to 1b by 0.08 ppm and
remained roughly unchanged for 1d and 1e.
These observations were attributed to a reorganization
of the hydroxy hydrogen bonding as illustrated in
Figure 3b. Initially, OH-3 weakly hydrogen bonded
with O-2 (1a). Owing to the intramolecular hydrogen
bond with the pyridyl ring, OH-4 polarization
increased. Consequently, OH-3 favored an interaction
with O-4 over O-2 inducing an increase in O-2 partial
charge. The extra pyridyl ring of 1e hydrogen bonded
with OH-3 whereas the phenyl counterpart 1d cannot.
Again, the significant variations of recorded optical
rotation values corroborated the proposed models.
4. Relative reactivities
Our primary concern was the control of the relative
reactivities of the secondary hydroxyl groups. In this
context, is this established cooperative hydrogen bond-
ing relevant to the hydroxy relative reactivities? To
answer this question, the regioselectivity of the acetyla-
tion with these five triols was investigated. Solvents of
different polarity and hydrogen bond properties were
used to evaluate the role of the hydrogen bonding. It is
worth noting that THF and dichloromethane are usual
solvents for most of the glycosylation procedures and
that we plan to extend this approach to open
glycosylation.
Figure 3. Proposed conformations on the basis of NMR
spectroscopic data and by NMR restrained molecular model-
ing. g and t stand for gauche and trans.
The well-known higher reactivity of the 3-OH was
observed whatever the protecting group (Table 2) while
the reactivities for the other two-hydroxyl groups were
similar in THF. As the solvent hydrophobicity
increased, the amount of 9 and 11 decreased in favor of
10 (from 1:4.8:1.2 in THF to 1:11.7:1.9 in CHCl3). The
reactivity of the three positions was modified when the
designed protecting groups acted as a hydrogen bond
acceptor (in chloroform and dichloromethane). In this
context, the proposed hydrogen bonding (Fig. 3b)
released (O-2 not hydrogen bonded) and activated
The existence of the hydrogen bond in 1b being estab-
lished, the protecting group was further elaborated
leading to 1e. 1d Was concomitantly used as a model
for non-intramolecular hydrogen bonded OH-3.
Analysis of the 1H spectra of chloroform solutions of 1e
and its analogue 1d compared to those of 1a, 1b and 1c
showed that the previously observed hydrogen bond

1734
N. Moitessier, Y. Chapleur / Tetrahedron Letters 44 (2003) 1731–1735
(OH-3 hydrogen bonded with O-4) the 2-OH and 3-OH.
Concomitantly, the amount of 4-OAc regio-isomers
produced decreased significantly (oxygen atom not
hydrogen bonded in 1a, bonded in 1b) in favor of the
2-OAc regioisomer. This expected deactivation resulted
in a reversal of the relative reactivities of the positions
2 and 4 between 1a and 1b (from 1:4.6:1.1 in THF to
1:4:0.4 in CHCl3). In addition, this new network remark-
ably deactivated the whole carbohydrate since conver-
sions dropped down to 10% for 1b, 1c and 1d and even
to almost 0% with 1e where two pyridyl rings are
presumed to hydrogen bond. In contrast to the trityl
group of 1a, part of the partial charge of the hydroxyl
groups is transferred to the protecting group. In this
context, donor groups should be more appropriate and
are presently considered.
5. Conclusions
In the search for novel regioselective functionalization or
glycosylation of free carbohydrates, we proposed herein
a strategy relying on the control of the relative reactivities
of the hydroxy groups. As a proof of concept, the
effectiveness of this methodology was demonstrated in a
systematic regioselectivity study using acetylation as a
model reaction. These particularly protected glucopyran-
osides have demonstrated somewhat enhanced, though
still modest, selectivity.
A first monopyridyl protecting group was designed that
H-bonded with the 4-OH decreasing its reactivity. Less
conclusive were the data for 1e relative to those for 1b.
Since the ratios were identical, we cannot conclude to a
positive effect. Further work is now underway to extend
this study to a large panel of usual and designed
protecting groups and to evaluate the potential of this
strategy in open glycosylation.
These encouraging results were further validated with the
ratios measured for the acetylation of 1c, 1d and 1e.
Again, dichloromethane was the best solvent in terms of
regioselectivity and intrinsic reactivity. So far, we cannot
decide between steric or electronic effects and both.
When considering the loss of reactivity that comes with
the increasing number of hydrogen bonds, one can
conclude to an electronic effect. However, the presence
of the pyridyl ring close to the western part of the sugar
ring can also explain the decrease of the amount of 11.
Acknowledgements
We thank Dr. Philippe Gros (Nancy, France) for helpful
discussions on pyridine chemistry.
Table 2. Regioselectivity versus protecting groups
Compd
Solvent
9a (%)
10 (%)
11 (%)
Ratio
1a
THF
14
13
7
68
74
80
69
79
74
73
83
71
78
81
93
76
83
NRc
18
13
13
16
5
7
12
6
7
5
5
B3
11
1:4.8:1.2
1:5.5:1.0
1:11.8:1.0
1:4.6:1.1
1:5.0:0.34
1:3.9:0.40
1:4.8:0.8
1:7.2:0.5
1:3.2:0.35
1:4.5:0.30
1:5.8:0.38
1:13.2:B0.1
1:5.8:0.84
1:7.2:0.66
–
CH2Cl2
CHCl3
THF
CH2Cl2
CHCl3
THF
CH2Cl2
CHCl3
THF
CH2Cl2
CHCl3
THF
CH2Cl2
CHCl3
1b
1c
1d
1e
15
16
19
15
11
22
17
14
7
b
b
b
13
11
6
c
c
a Based on 1H NMR of the crude mixture ( 2%).
b Reacted for 6 h, 10% conversion (estimated 5%).
c No reaction: reacted for 24 h, <5% conversion.

N. Moitessier, Y. Chapleur / Tetrahedron Letters 44 (2003) 1731–1735
1735
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