Effects of CoCl2 on the regioselective tosylation of oligosaccharides

Article abstract of DOI:10.1016/j.molstruc.2021.130609

The tosyl functional group is commonly used in carbohydrate chemistry as a nucleofuge. Tosylation of the primary hydroxyls of carbohydrates are generally performed after orthogonal protection/deprotection reactions. However, it can be done regioselectivel

Full text of DOI:10.1016/j.molstruc.2021.130609

Journal of Molecular Structure 1241 (2021) 130609
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Effects of CoCl2 on the regioselective tosylation of oligosaccharides
Jamal El-Abid, Vincent Moreau, José Kovensky∗∗, Vincent Chagnault∗
Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources (LG2A), UMR 7378 CNRS, Université de Picardie Jules Verne, 33 rue Saint Leu, F-80039
Amiens Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The tosyl functional group is commonly used in carbohydrate chemistry as a nucleofuge. Tosylation of
the primary hydroxyls of carbohydrates are generally performed after orthogonal protection/deprotection
reactions. However, it can be done regioselectively from unprotected sugars. Several examples have been
described in the literature starting from free monosaccharides. Yields are generally good but may vary ac-
cording to the nature of the sugar. Starting from free oligosaccharides, the regioselectivity and the yields
generally drop significantly. The use of catalysts, such as DMAP or NEt3, improves the conversion but
to the detriment of the regioselectivity. In our current work, we developed a tosylation reaction of the
primary positions of several oligosaccharides with improved regioselectivity, using cobalt II chloride in
catalytic amounts. Adaptability of this methodology has been tested on cellobiose, maltose, lactose, su-
crose and maltotriose.
Received 22 March 2021
Revised 23 April 2021
Accepted 30 April 2021
Available online 8 May 2021
Keywords:
Regioselective reaction
Glycochemistry
Cobalt catalyzed tosylation
Tosylation of oligosaccharides
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
oligosaccharides, are rarely described in literature. In 1982, Gero
ꢀ
ꢀ
et al. reported the synthesis of 6,6 -di-O-tosyl-D-maltose and 6,6 -
di-O-tosyl-D-lactose using 3.5 equiv. of TsCl in pyridine at room
temperature [5]. After acetylation, the authors obtained the ex-
pected products in 40% yield for both maltose and lactose deriva-
tives (purification performed by HPLC). More recently, Oscarson
et al. describe the preparation of 1’,6,6’-tri-O-tosylsucrose and 6,6’-
di-O-tosyltrehalose in 19% and 16% yields respectively [3]. It ap-
pears that the regioselective tosylation of oligosaccharides is more
difficult than that of monosaccharides. In order to improve the re-
search currently in progress in our laboratory, we report here a
new methodology to obtain better regioselectivity in the tosylation
reaction using anhydrous CoCl2 as a catalyst.
In carbohydrate chemistry, tosylation reactions are popular as
they are very useful for the preparation of high added value pre-
cursors. The introduction of a tosyl functional group is usually
achieved by the reaction of a carbohydrate containing a free hy-
droxyl group with TsCl in pyridine [1]. Depending on the reactivity
of the substrate, the reaction conditions can be adapted by select-
ing the appropriate temperature and stirring time. Catalysts such
as DMAP or triethylamine have been used to reduce the reaction
times [1,2]. However, when several hydroxyl functions are acces-
sible, this procedure may result in complex mixtures of tosylated
products [1,3].
In literature, some examples show the regioselective tosyla-
tion of monosaccharides on primary positions starting from unpro-
tected substrates.
2. Results/Discussion
In a first attempt, we reproduced the classical conditions, de-
scribed by Gero et al., using D-maltose 1 as substrate [5]. Sev-
eral experimental conditions were evaluated, including TsCl equiv-
alents, temperature and stirring time. All these results are summa-
rized in Table 1.
In 2017, Chen et al. described the preparation of tosylated
monosaccharides (Scheme 1) [4]. After 12 hours of reaction at
room temperature, the products were obtained in 62-78 yields. It
is important to note that secondary and anomeric positions are not
tosylated. On the other hand, similar conditions, applied to free
The first attempts (Entry 1) were carried out by slowly adding
4 equiv. of TsCl in a solution of maltose in dry pyridine at 0°C.
The mixture was then gradually warmed up to room temperature.
The reactions were monitored by TLC, mass spectrometry and 1D
NMR, between 2 and 24 hours of stirring. It is evident that, de-
spite the use of an excess of TsCl (Entry 1), the conversion remains
∗
Corresponding author.
∗∗
Co-corresponding author.
E-mail
addresses:
jose.kovensky@u-picardie.fr
(J.
Kovensky),
vincent.chagnault@u-picardie.fr (V. Chagnault).
https://doi.org/10.1016/j.molstruc.2021.130609
0022-2860/© 2021 Elsevier B.V. All rights reserved.

J. El-Abid, V. Moreau, J. Kovensky et al.
Journal of Molecular Structure 1241 (2021) 130609
These results suggested that the color indicator, i.e. CoCl2, was
at the origin of the higher regioselectivity of the tosylation. Know-
ing that cobalt (II) chloride has been described in previous works
for the catalysis of regioselective acetylations and also in tosylation
reactions of some aliphatic and aromatic alcohols with TsOH, fur-
ther reactions were carried out using anhydrous CoCl2 [9–11]. Af-
ter optimization of the conditions, 4 equiv. of NEt3 and 0.6 equiv.
of CoCl2, in anhydrous pyridine, led to the total conversion and we
obtained 75% of compound 2 after only 2 hours at room temper-
ature (Entry 5). Monotosylated and polytosylated derivatives were
only observed in trace amounts by NMR. Encouraged by these re-
sults, we extended this methodology to other disaccharides as well
as to maltotriose (Table 2).
Scheme 1. Some examples of monotosylation on monosaccharide from Chen
et al. [4]
All the products described in the table above were obtained
after purification on silica gel chromatography without prior
peracetylation. In all cases, mass spectrometry analyses of the reac-
tion mixture clearly indicate a significant decrease in the amount
of polytosylation products when using CoCl2. The tosylation reac-
tion appears to be more selective for primary positions. Starting
from lactose 3, the reaction has to be stirred only 15 min. to avoid
further tosylations. Sucrose 5 has also been tested, which led to
the formation of 1’,6,6’-tri-O-tosylsucrose 6 and 1’,2,6,6’-tetra-O-
tosylsucrose 7 in 41 % and 34 % yields respectively. The position
of the fourth tosyl functional group has been identified using 13C
NMR spectroscopy which indicates a deshielding effect on carbon
C2 from compound 6 to compound 7 (72.2 to 79.2 ppm). This ob-
servation has been confirmed by 1H NMR analyses. In the case of
cellobiose, our experimental conditions did not lead to the forma-
tion of the expected product, but to a complex mixture that we
failed to analyze the nature. In contrast, the reaction of methyl-
cellobioside 8 was more efficient. We thus obtained the product 9
in 66% yield after 30 min of stirring. In some cases, the anomeric
position may be involved in the formation of side products that
have not been identified. Finally, we decided to try the tosyla-
tion of maltotriose 10, a trisaccharide. Using 1.75 equiv. per OH
of both TsCl and Et3N in the presence of CoCl2, we observed the
formation of the desired compound 11 in 50% yield after purifi-
cation. This compound has never been described in the litera-
ture and may be of importance for the preparation of molecules
of higher added value, such as those described in our previous
work [12].
limited and unreacted maltose was still present in a significant
amount.
In addition to an incomplete conversion, the reaction mixture
contains monotosylated maltose and polytosylated derivatives. The
desired compound 2, was obtained as a minor product in a mixture
of several polytosylated derivatives, making its purification ineffec-
tive on silica gel, even after peracetylation. Therefore, under these
classical conditions, the yields previously reported could not be
achieved. To improve the conversions of our next trials, we drew
inspiration from the literature. Recently, Krause et al. observed a
significant improvement of the ditosylation reaction on β-azido-D-
maltoside using ZnBr2 [6]. However, using free maltose 1 as sub-
strate, no difference was noted in comparison with entry 1. Only
the addition of triethylamine to the medium (Entry 2) increased
our conversions. Using 4 equiv. of anhydrous NEt3, no traces of free
maltose were detected after 2 hours of reaction. Thereafter, the 24-
hour reaction monitoring showed no significant changes. Despite
the complexity of the mixture, we were able to perform a purifica-
tion of the ditosylated derivative 2 on silica gel, bringing the yield
to 23%. It is interesting to note that reducing the temperature to
8°C did not sufficiently reduce the presence of polytosylated com-
pounds [2,7].
In view of the difficulties of purification, and the low yields
of product 2, we decided to carry out a final optimization by
adapting the conditions described by Tatsuta et al. in 1967 [8].
ꢀ
The authors obtained 45% of peracetyl-6,6 -di-O-tosyl-D-maltose
using Drierite®. After adding Drierite® in our conditions, we no-
ticed a drastic decrease in the formation of polytosylated prod-
ucts by mass spectrometry. Using triethylamine, in the presence of
blue Drierite® (Entry 3), we obtained 53% of compound 2 (major
product) after purification on silica gel. Surprisingly, using white
Drierite® without color indicator (Entry 4), the reaction led to a
complex mixture.
Based on all the tests performed, we hypothesize that Co II
chelates the secondary hydroxyl groups, limiting their substitu-
tion. Further researches are currently being carried out in our
laboratory to establish the precise role of cobalt salts in these
reactions.
Table 1
Regioselective tosylation of D-maltose 1.
Entry
Time
Additive
Compound 2
1
2
3
4
5
2
2
2
2
̵
̵
̵
̵
>24 h
>24 h
>24 h
>24 h
̵
Complex mixture
23%
NEt3
NEt3 + blue Drierite®a
53%
NEt3 + white Drierite®d
Complex mixture
75%
c
2 h
NEt3 + CoCl2
Reaction conditions: Using D-maltose, 4 equiv. of TsCl were used in dry pyridine at room tempera-
ture. 4 equiv. of NEt3 were used for entries 2, 3, 4, and 5.
a
Drierite® (anhydrous calcium sulfate containing 97% CaSO4 and 3% CoCl2 as color indicator)
d
Drierite® without color indicator
f
0.6 equiv. of CoCl2 (0.3 equiv. per OH)
2

J. El-Abid, V. Moreau, J. Kovensky et al.
Journal of Molecular Structure 1241 (2021) 130609
Table 2
Regioselective tosylation on oligosaccharides.
Reaction conditions: Oligosaccharides were diluted in dry pyridine and anhydrous CoCl2 (0.3 equiv. per primary OH) was added. The
reaction mixture was cooled to 0°C before the addition of TsCl (2 equiv. per OH for maltose and 1.75 equiv. per OH for the others)
and Et3N (same quantity as for TsCl). Then temperature was gradually increased to RT and the reaction stirred for the time indicated
a
in the table above. Preparation of compounds 6, 7 and 9 has been described in literature but not fully characterized.
3. Conclusion
We developed a regioselective tosylation of primary positions
COSY, HSQC, HMBC spectra. TLC were performed on Silica F254
and detection by UV light at 254 nm or by charring with cerium
molybdate reagent. Column chromatography was performed on Sil-
ica Gel 60 (230 mesh). High-resolution electrospray mass spec-
tra in the positive ion mode were obtained on a Q-TOF Ultima
Global hybrid quadrupole/time-of-flight instrument, equipped with
a pneumatically assisted electrospray (Z-spray) ion source and an
additional sprayer (Lock Spray) for the reference compound. The
source and desolvation temperatures were kept at 80 and 150°C,
respectively. Nitrogen was used as the drying and nebulizing gas at
flow rates of 350 and 50 L/h, respectively. The capillary voltage was
3.5 kV, the cone voltage 100 V and the RF lens1 energy was opti-
mized for each sample (40 V). For collision-induced dissociation
(CID) experiments, argon was used as collision gas at an indicated
analyser pressure of 5.10−5 Torr and the collision energy was opti-
mized for each parent ion (50-110 V). Lock mass correction, using
appropriate cluster ions of sodium iodide (NaI)nNa+, was applied
for accurate mass measurements. The mass range was typically 50-
2050 Da and spectra were recorded at 2 s/scan in the profile mode
at a resolution of 10000 (FWMH).
of di-and trisaccharides by using CoCl2 in catalytic amounts with
triethylamine, and pyridine as solvent. This addition minimizes the
formation of polytosylated products and improves the yields of se-
lective tosylated compounds.
4. Financial support
We thank the Ministère français de lʼEnseignement supérieur,
de la Recherche et de lʼInnovation for the financial support.
5. Experimental Section
All reagent-grade chemicals were obtained from commercial
suppliers and were used as received. Cobalt (II) chloride purum
p.a., anhydrous (98.0%) was purchased from Sigma-Aldrich (CAS
# 7646-79-9), and was used as received without further purifica-
tion process. Characterizations of known compounds were in ac-
cordance with literature. Optical rotations were recorded in MeOH
solution. FTIR spectra were obtained using ATR and are reported
5.1. Synthesis of 6,6’-di-O-tosyl-D-maltose (2)
in cm−1 1H NMR (400 and 600 MHz) and 13C NMR (101 and 151
.
MHz) spectra were recorded in MeOD . The proton and carbon sig-
nal assignments were determined from decoupling experiments,
To a solution of D-maltose monohydrate 1 (3.15 g, 8.75 mmol)
in dry pyridine (50 mL), anhydrous cobalt (II) chloride (0.6 equiv.,
3

J. El-Abid, V. Moreau, J. Kovensky et al.
Journal of Molecular Structure 1241 (2021) 130609
0.68 g, 5.25 mmol) was added and the reaction mixture was
cooled to 0°C. Then p-toluenesulfonyl chloride (4 equiv., 6.66 g,
35.07 mmol) and anhydrous triethylamine (4 equiv., 4.88 mL, 35.07
mmol) were slowly added and the reaction mixture stirred at room
temperature for 120 min. The reaction was then quenched using
methanol (150 mL). After stirring for 5 min., the mixture was con-
centrated to dryness in vacuo and purified over silica gel column
chromatography (gradient from cyclohexane/EtOAc (2/3; v/v) to
EtOAc/Methanol (8/2; v/v). The desired product 2 was isolated as a
white solid containing the two anomers (4.25 g, 75%, α/β: 65/35).
Rf (EtOAc/Methanol, 7/3, v/v) 0.5; 1H NMR (600 MHz, Methanol-
d4) δ 7.81 – 7.76 (m, CH-Ar, 6.9H), 7.41-7.44 (m, CH-Ar, 7.8H), 4.98
(d, J = 3.7 Hz, H1α, 1H), 4.94 (d, J = 3.8 Hz, H1’β, 0.6H), 4.91
(d, J = 3.8 Hz, H1’α, 1.1H), 4.43 (d, J = 7.8 Hz, H1β, 0.6H), 4.35
– 4.08 (m, H6α, H6β, H6’α, H6’β, 7.1H), 3.93-3.96 (m, H5α, 1H),
3.82 (t, J = 9.3 Hz, H3α, 1.1H), 3.81-3.64 (m, 1.78H, H5’α, H5’β,
1.8H), 3.56-3.51(m, H5β, H3β, H3’α, H3’β, 3.2H), 3.34 – 3.24 (m,
H2α, H4’α, H4β, H4’β, H4α, H2’α, H2’β, 7.8H), 3.12 (dd, J = 9.5,
7.7 Hz, H2β, 0.6H), 2.46 (s, CH3, 7.34H), 2.45 (s, CH3, 2.7H). 13C
NMR (151 MHz, Methanol-d4) δ 146.5 (C-Ar), 146.4 (C-Ar), 134.3
(C-Ar), 134.3 (C-Ar), 134.1 (C-Ar), 131.1 (CH-Ar), 131.0 (CH-Ar), 131.0
(CH-Ar), 130.9 (CH-Ar), 129.1 (CH-Ar), 129.1 (CH-Ar), 129.0 (CH-Ar),
129.0 (CH-Ar), 102.8 (C1’β; C1’α), 98.0(C1β), 93.6 (C1α), 81.9, 81.5,
77.5, 75.4, 74.8, 74.7, 74.3, 73.8, 73.6, 73.0, 72.2, 72.2, 70.5, 70.2
(C2, C3, C5, C2’, C4’), 70.8, 70.4, 70.3 (C6α, C6β, C6’α, C6’β), 69.1
(C5α), 21.6 (CH3). IR (ATR) ν = 3437, 2937, 1598, 1450, 1354, 1174,
1055, 1018, 931, 813 cm−1; HRMS (CI, NH3): MNa+, found 673.1251.
C26H34O15NaS2 requires 673.1237.
were added. After stirring for 30 min., the reaction mixture was
quenched using methanol, concentrated to dryness in vacuo and
dissolved in DCM. The solution was washed three times with wa-
ter, dried over sodium sulfate, filtered and concentrated. A purifi-
cation over silica gel column chromatography (gradient from cy-
clohexane/EtOAc (1/1, v/v) to EtOAc/Methanol (9/1, v/v) led to the
desired product 6, isolated as a white solid (0.48 g, 41 %). Com-
pound 6: Rf (EtOAc/Methanol, 9/1, v/v) 0.63; 1H NMR (600 MHz,
Methanol-d4) δ 7.86 – 7.73 (m, CH-Ar, 6H), 7.52 – 7.38 (m, CH-
Ar, 6H), 4.65 (d, J = 3.9 Hz, H1, 1H), 4.32 – 4.28 (m, H6, 2H),
4.17 – 4.12 (m, H6’, 1H), 4.05 (d, J = 11.4 Hz, H3’, 1H), 3.99 (dd,
J = 9.5, 6.7 Hz, H1’, 1H), 3.88 (d, J = 8.9 Hz, H5, 1H), 3.81 (t,
J = 8.7 Hz, H4’, 1H), 3.69 (td, J = 8.8, 1.9 Hz, H5’, 1H), 3.51 (dd,
J = 9.8, 8.9 Hz, H3, 1H), 3.13 (dd, J = 9.8, 3.9 Hz, H2, 1H), 3.02
(dd, J = 9.8, 8.8 Hz, H4, 1H), 2.53 – 2.46 (m, CH3, 9H); 13C NMR
(151 MHz, Methanol-d4) δ 146.6 - 134.0 (C-Ar), 131.1 - 129.0 (CH-
Ar), 103.0 (C2’), 92.7 (C1), 80.80 (C5’), 77.1 (C3’), 74.8 (C4’), 74.3
(C3), 72.8 (C6), 72.2 (C2), 71.8 (C5), 71.52 (C4), 71.1 (C6’), 68.3
(C1’), 21.6, 21.6, 21.6 (CH3); IR (ATR) ν = 2532, 1598, 1450, 1355,
1174, 974, 813 cm−1; [α]D20 +56.2 (c 0.5, MeOH); HRMS (CI, NH3)
MNa+: found 827.1334. C33H40O17 NaS3 requires 827.1325; 1’,2,6,6’-
tetra-O-tosylsucrose 7 were also isolated during this process as a
white solid (0.48 g, 34 %). Rf (EtOAc/Methanol, 9/1, v/v) 0.77; 1H
NMR (600 MHz, Methanol-d4) δ 7.93 – 7.86 (m, CH-Ar, 6H), 7.70
(d, J = 8.4 Hz, CH-Ar, 2H), 7.56 – 7.39 (m, CH-Ar, 8H), 4.91 (d,
J = 3.7 Hz, H1, 1H), 4.32 (dd, J = 10.4, 1.7 Hz, H6, 1H), 4.28
– 4.18 (m, H6, H6’, 2H), 4.14 – 4.07 (m, H1’, H6’, 2H), 4.00 –
3.76 (m, H2, H5, H1’, H5’, H4’, H3’, 6H), 3.66 (dd, J = 9.8, 8.8
Hz, H3, 1H), 3.01 (dd, J = 10.0, 8.8 Hz, H4, 1H), 2.55 – 2.47 (m,
CH3, 12H); 13C NMR (151 MHz, Methanol-d4) δ 146.8 - 133.7 (C-
Ar), 131.2 - 129.0 (CH-Ar), 103.2 (C2’), 90.5 (C1’), 80.8 (C5’), 79.2
(C2), 76.7 (C3’), 74.5(C4’), 72.6 (C6’), 71.6 (C5), 71.4 (C4), 71.2 (C3),
70.8 (C6), 68.0 (C1’), 21.8, 21.7, 21.7 (CH3); IR (ATR) ν = 3522,
1597, 1357, 1174, 1097, 975, 813 cm−1; [α]D20 +48.6 (c 0.5, MeOH);
HRMS (CI, NH3) MNH4+: found 976.1860. C40H50NO19 S4 requires
976.1860.
5.2. Synthesis of 6,6’-di-O-tosyl-D-lactose (4)
Compound 4 was prepared as described for compound 2 start-
ing from D-lactose monohydrate 3 (0.52 g, 1.46 mmol) in dry pyri-
dine (15 ml), 0.6 equiv. of anhydrous cobalt chloride (0.11 g, 0.87
mmol), 3.5 equiv. of both tosylchloride (0.97 g, 5.13 mmol) and an-
hydrous triethylamine (0.71 ml, 5.13 mmol). After 15 min. of stir-
ring, the reaction mixture was treated as described previously. The
mixture was purified over silica gel column chromatography (gra-
dient from cyclohexane/EtOAc (1/1, v/v) to EtOAc/Methanol (8/2:
v/v). The desired product 4 was isolated as a white solid containing
the two anomers (0.51 g, 54 %, α/β: 60/40). Rf (EtOAc/Methanol,
7/3, v/v) 0.6; 1H NMR (400 MHz, Methanol-d4) δ 7.92 – 7.76 (m,
CH-Ar, 9.6H), 7.51 – 7.39 (m, CH-Ar, 9.9H), 5.01 (d, J = 3.8 Hz, H1α,
1H), 4.50 – 4.43 (m, H1β, 1.5H), 4.42 – 4.00 (m, H6α, H6β, H6’α,
H6’β, H1’α, H1’β, H5α, 10.8H), 3.82 – 3.71 (m, H5’α, H5’β, H3’α,
H3’β, 5.1H), 3.68 – 3.58 (m, H5β, 0.8H), 3.52 – 3.44 (m, H3α, H3β,
H2’α, H2’β, 3.1H), 3.43 – 3.31 (m, H4α, H4β, H2α, H4’α, H4’β,
11.9H), 3.18 (t, J = 8.4 Hz, H2β, 0.7H), 2.46 (s, CH3, 8.3H). 13C NMR
(101 MHz, Methanol-d4) δ 146.7 (C-Ar), 146.4 (C-Ar), 146.3 (C-Ar),
134.5 (C-Ar), 134.3 (C-Ar), 133.9 (C-Ar), 133.9 (C-Ar), 131.2 (CH-Ar),
131.0 (CH-Ar), 131.0 (CH-Ar), 130.9 (CH-Ar), 129.2 (CH-Ar), 129.2
(CH-Ar), 129.1 (CH-Ar), 104.4, 104.3 (C1’), 97.9, 93.5 (C1), 80.3, 79.8
(C4), 75.8, 75.6, 74.1, 73.9, 73.9, 73.5, 73.1, 72.6, 71.8, 71.7, 69.6, 68.8
(C2, C3, C5, C2’, C3’, C4’, C5’), 70.5, 70.1, 70.1 (C6, C6’), 21.6 (CH3);
5.4. Synthesis of Methyl-6,6’-di-O-tosyl-β-cellobioside (9)
Compound 9 was prepared as described previously, starting
from compound 8 (2 g, 5.61 mmol) in dry pyridine (60ml), 0.6
equiv. of anhydrous cobalt II chloride (0.43 g, 3.36 mmol), 3.5
equiv. of both tosylchloride (3.73 g, 19 mmol) and anhydrous tri-
ethylamine (2.73 ml, 19 mmol). After stirring for 30 min, the re-
action mixture was treated as described previously. The mixture
was purified over silica gel column chromatography (gradient from
pure EtOAc to EtOAc/Methanol (9/1, v/v). The desired product 9
was isolated as a white solid (2.44 g, 66%). Rf (EtOAc/Methanol,
7/3, v/v) 0.65; 1H NMR (400 MHz, Methanol-d4) δ 7.97 – 7.81 (m,
CH-Ar, 4H), 7.56 – 7.41 (m, CH-Ar, 4H), 4.54 – 4.34 (m, H6, H6’,
3H), 4.31 (d, J = 7.9 Hz, H1’, 1H), 4.23 – 4.14 (m, H1, H6, H6’,
2H), 3.71 – 3.14 (m, H2, H3, H4, H5, H2’, H3’, H4’, H5’, OCH3,
11H), 2.51 (s, Ar-CH3, 6H); 13C NMR (101 MHz, Methanol-d4) δ
146.6 (C-Ar), 146.4 (C-Ar), 134.2 (C-Ar), 134.0 (C-Ar), 131.15 (CH-
Ar), 131.04 (CH-Ar), 129.12 (CH-Ar), 129.09 (CH-Ar), 129.05 (CH-
Ar), 104.8 (C1’), 103.7 (C1), 79.8, 77.3, 75.4, 75.1, 74.4, 74.2, 73.3,
70.8 (C2, C3, C4, C5, C2’, C3’, C4’, C5’), 70.3 (C6, C6’), 70.0 (C6,
C6’), 57.2 (OCH3), 21.6 (CH3); [α]2D0 = -4.00 (c 0.5, MeOH); IR
IR (ATR) ν = 3437, 2924, 1612, 1355, 1174, 1070, 1022, 825 cm−1
;
HRMS (CI, NH3) MNH4+, found 668.1683. C26H34NO15S2 requires
668.1686.
(ATR) ν = 2989, 2519, 1355, 1174, 1053, 975, 929, 815, 790 cm−1
.
5.3. Synthesis of 1’,6,6’-tri-O-tosylsucrose (6)
+
HRMS (CI, NH3): MNH4 found, 682.1839. C27H40NO15S2 requires
682.1842.
Compound 6 was prepared as described previously, starting
from powdered sucrose 5 (0.5 g, 1.46 mmol) in dry pyridine (15
ml). If needed, this solution can be heated for 15 min. at 60°C until
complete dissolution. Then 0.9 equiv. of anhydrous cobalt II chlo-
ride (0.17 g, 1.31 mmol) and 5.25 equiv. of both tosylchloride(1,5
g, 7,66 mmol) and anhydrous triethylamine(0,98 ml, 7.66 mmol)
5.5. Synthesis of 6,6’,6’’-tri-O-tosyl-D-maltotriose (11)
The trisaccharide 11 was prepared as described before, starting
from maltotriose 10 (0.5 g, 0.99 mmol) in dry pyridine (10ml), 0.9
4

J. El-Abid, V. Moreau, J. Kovensky et al.
Journal of Molecular Structure 1241 (2021) 130609
equiv. of anhydrous cobalt II chloride (0.115 g, 0.89 mmol), 5.25
equiv. of both tosylchloride (1.88 g, 5.20 mmol) and anhydrous tri-
ethylamine (0.83 ml, 5.20 mmol). After stirring for 60 min., the re-
action mixture was quenched with methanol, concentrated to dry-
ness in vacuo and dissolved into DCM. The solution was washed
three times with water, dried over sodium sulfate, filtered and
concentrated. A purification over silica gel column chromatogra-
phy (gradient from cyclohexane/EtOAc (1/1, v/v) to EtOAc/Methanol
(9/1, v/v) led to the desired product 11 as a white solid (0.48 g, 50
%, α/β: 70/30). Rf: 0.6 (EtOAc:Methanol; 9:1; v:v). 1H NMR (600
MHz, Methanol-d4) δ 7.88 – 7.79 (m, CH-Ar, 10H), 7.49 – 7.42 (m,
CH-Ar, 10.3H), 5.03 (d, J = 3.7 Hz, H1α, 1H), 4.98 (dd, J = 23.2, 3.7
Hz, H1’α, H1’β, H1’’α, H1’’β, 3.1H), 4.51 – 4.16 (m, H1β, H6α, H6β,
H6’α, H6’β, H6’’α, H6’’β, 9.4H), 4.03 – 3.96 (m, H5α, 1H), 3.92 –
3.54 (m, H5β, H5’α, H5’β, H5’’α, H5’’β, H3’α, H3’β, H3’’α, H3’’β,
8.2H), 3.47 – 3.28 (m, H4’α, H4’β, H4’’α, H4’’β, H4α, H4β, H2α,
H2β, H2’α, H2’β, H2’’α, H2’’β, 10.7H), 3.17 (dd, J = 9.5, 7.8 Hz,
H2β, 0.53H), 2.50 (s, CH3, 5.3H), 2.48 (d, J = 2.6 Hz, CH3, 9H); 13C
NMR (151 MHz, Methanol-d4) δ 146.5 (C-Ar), 146.4 (C-Ar), 146.4
(C-Ar), 146.3 (C-Ar), 134.4 (C-Ar), 134.3 (C-Ar), 134.2 (C-Ar), 134.2
(C-Ar), 134.1 (C-Ar), 131.1 (CH-Ar), 131.0 (CH-Ar), 131.0 (CH-Ar),
131.0 (CH-Ar), 131.0 (CH-Ar), 129.1 (CH-Ar), 129.1 (CH-Ar), 129.0
(CH-Ar), 129.0 (CH-Ar), 102.7-102.3 (C1’, C1’’), 97.9, 93.6 (C1), 81.7,
81.1, 80.1 (C4, C4’), 77.4, 75.4, 74.7, 74.4, 74.4, 74.2, 73.7, 73.6, 73.3,
73.1, 73.0, 72.2, 72.1, 70.8, 70.5 (C2, C3, C5, C2’, C3’, C5’, C2’’, C3’’,
C4’’, C5’’), 70.75, 70.47, 70.41, 70.31 (C6, C6’, C6’’), 69.0 (C5), 21.6
(CH3); IR (ATR) ν = 3369, 2935, 1577, 1354, 1174, 1018, 1001, 931,
815 cm−1; HRMS (CI, NH3) MNa+: found 989.1871. C39H50O22NaS3
requires 989.1854.
Declaration of Competing Interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing in-
terests:
Jamal EL-ABID reports financial support was provided by Min-
istere francais de l’Enseignement superieur, de la Recherche et de
l’Innovation.
References
[1] D.T. Whitaker, K.S. Whitaker, C.R. Johnson, J. Haas, p -Toluenesulfonyl Chloride,
Encycl. Reagents Org. Synth., John Wiley & Sons, Ltd, Chichester, UK, 2006,
doi:10.1002/047084289X.rt136.pub2.
[2] Y. Yoshida, Y. Sakakura, N. Aso, S. Okada, Y. Tanabe, Practical and effi-
cient methods for sulfonylation of alcohols using Ts(Ms)Cl/Et3N and catalytic
•
Me3H HCl as combined base: Promising alternative to traditional pyridine,
Tetrahedron 55 (1999) 2183–2192, doi:10.1016/S0040-4020(99)00002-2.
[3] S. Oscarson, J.V. Fahy, I. Gitlin, W. Raymond, Dithiolsaccharide mucolytic agents
and uses thereof., WO2020055916A1, 2020.
[4] Y. Zhu, X. Chen, Expanding the scope of metabolic glycan labeling in Arabidop-
sis thaliana, ChemBioChem 18 (2017) 1286–1296, doi:10.1002/cbic.201700069.
[5] N. Rolland, G. Vass, J. Cleophax, A.-M. Sepulchre, S.D. Gero, A. Cier, Synthèse to-
tale d’α-disaccharidyles de tridésoxy-2,5,6-streptamine apparentés aux amino-
sides à partir du maltose et du lactose, Helv. Chim. Acta. 65 (1982) 1627–1636,
doi:10.1002/hlca.19820650536.
[6] A. Wiegand, V. Wiese, B. Glowacki, L. Iovkova, R. Schirrmacher, K. Jurkschat,
N. Krause, GlucoSiFA and LactoSiFA: New types of carbohydrate-tagged silicon-
based fluoride acceptors for 18F-Positron Emission Tomography (PET), Synthe-
sis (Stuttg). 51 (2019) 1196–1206, doi:10.1055/s-0037-1611656.
[7] M. Yamagami, H. Kamitakahara, A. Yoshinaga, T. Takano, Thermo-reversible
supramolecular hydrogels of trehalose-type diblock methylcellulose analogues,
Carbohydr. Polym. 183 (2018) 110–122, doi:10.1016/j.carbpol.2017.12.006.
[8] S. Umezawa, T. Tsuchiya, S. Nakada, K. Tatsuta, Studies of Aminosugars. XIV.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Syntheses of 6,6 -Diamino-6,6 -dideoxymaltosylamine, 1 ,6,6 -Triamino-,1 ,6,6 -
ꢀ
ꢀ
trideoxysucrose and 6,6 -Diamino-6,6 -dideoxytrehalose, Bull. Chem. Soc. Jpn.
40 (1967) 395–401, doi:10.1246/bcsj.40.395.
CRediT authorship contribution statement
[9] J. Iqbal, R.R. Srivastava, Cobalt(II) chloride catalyzed acylation of alcohols with
acetic anhydride: scope and mechanism, J. Org. Chem. 57 (1992) 2001–2007,
doi:10.1021/jo00033a020.
Jamal El-Abid: Investigation, Experimental work, Characteriza-
tion of compounds, Writing - review & editing.
[10] S. Velusamy, S. Borpuzari, T. Punniyamurthy, Cobalt(II)-catalyzed direct acety-
lation of alcohols with acetic acid, Tetrahedron 61 (2005) 2011–2015, doi:10.
1016/j.tet.2005.01.006.
Vincent Chagnault: Conceptualization, Methodology, Writing -
review & editing, Writing - original draft, Formulation of hypothe-
sis, Design of analytical experiments, Supervised this work.
José Kovensky: Conceptualization, Methodology, Writing - re-
view & editing, Project administration.
[11] S. Velusamy, J.S. Kiran Kumar, T. Punniyamurthy, Cobalt(II) catalyzed tosylation
of alcohols with p-toluenesulfonic acid, Tetrahedron Lett 45 (2004) 203–205,
doi:10.1016/j.tetlet.2003.10.106.
[12] D.S.-E. Koffi Teki, A. Bil, V. Moreau, V. Chagnault, B. Fanté, A. Adjou, J. Kovensky,
Synthesis of multivalent S -glycoside analogs of a heparan sulfate sequence,
Org. Chem. Front. 6 (2019) 2718–2725, doi:10.1039/C9QO00581A.
Vincent Moreau: Writing - review & editing.
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