Simple synthesis of glycosylthiols and thioglycosides by rearrangement of O-glycosyl thionocarbamates

Article abstract of DOI:10.1016/j.carres.2014.07.001

The synthesis of thioglycosides has been achieved in a high yielding process employing thionocarbamates prepared from protected reducing sugars and N-alkyl isothiocyanate in the presence of a non-nucleophilic base (K ₂CO₃). In the key step of the synthesis, thionocarbamates were treated with Lewis acid (TMSOTf) to give O,S-rearrangement products that were applied to the synthesis of both anomers of heteroaryl thioglycosides.

Full text of DOI:10.1016/j.carres.2014.07.001

Carbohydrate Research 396 (2014) 37–42
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Simple synthesis of glycosylthiols and thioglycosides
by rearrangement of O-glycosyl thionocarbamates
⇑
R. Komor , A. Kasprzycka, G. Pastuch-Gawołek, W. Szeja
Silesian University of Technology, Faculty of Chemistry, Chair of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Krzywoustego 4, 44-100 Gliwice, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2014
Received in revised form 30 June 2014
Accepted 1 July 2014
Available online 9 July 2014
The synthesis of thioglycosides has been achieved in a high yielding process employing thionocarbamates
prepared from protected reducing sugars and N-alkyl isothiocyanate in the presence of
a non-
nucleophilic base (K2CO3). In the key step of the synthesis, thionocarbamates were treated with Lewis
acid (TMSOTf) to give O,S-rearrangement products that were applied to the synthesis of both anomers
of heteroaryl thioglycosides.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Glycopyranosyl thionocarbamates
O,S-rearrangement
Thioglycosides
Carbohydrate–protein recognition is an important phenomenon
in the biotransformation of natural polysaccharides and has been
demonstrated in recent years as an essential process for the biolog-
ical transfer of information in living organisms.1 Hence, the devel-
opment of complex glycosides as a tool for model studies or even
therapeutic intervention has gained great interest. Investigation
of carbohydrate-protein interaction can be conducted using non-
naturally occurring oligosaccharides. Thiosaccharides, where an
exocyclic oxygen is replaced by a sulfur atom, constitute an
increasingly important group of compounds in glycochemistry,
possessing unique characteristics compared to their oxygen-con-
taining counterparts.2 Thioglycosides have been the subject of sig-
nificant interest as they often exhibit higher stability against
chemical and enzymatic hydrolysis, more potent bioactivities,
and similar conformation in solution in comparison to the corre-
sponding O-glycosides. Furthermore, the resulting thioglycosides
and S-linked conjugates possess increased resistance to degrada-
tion by glycosidases, thus potentiating their use as efficient
building blocks in drug design and therapeutics.
glycoside donors and acceptors in oligosaccharide and neoglyco-
conjugate synthesis.8,9
Due to these properties, thioglycosides, including thiooligosac-
charides and S-glycoconjugates, have frequently been synthetic
targets in carbohydrate chemistry in recent decades.10 The conven-
tional approaches for the synthesis of thioglycosides are realized
by reaction of glycosyl thiols with alkyl or negatively substituted
aryl halides. Corresponding thiols may be prepared by substitution
reaction (SN2) of the starting substrate: glycosyl halide or acetate
with thiourea11 or thioacetate12 together with hydrolysis or de-
S-acetylation of the resulting intermediate. Reductive removal of
the benzyl group from the anomeric thiobenzyl glycoside13 has
also been explored for the preparation of glycosyl thiol derivatives.
Another method for the preparation of glycosyl thiol derivatives
involves reaction of hydrogen sulfide gas with a solution of glyco-
syl halides in hydrogen fluoride.14 Davis et al.15 reported the direct
preparation of glycosyl thiol derivatives upon treatment of the gly-
cosyl hemiacetal derivatives with Lawesson’s reagent in moderate
yields with no stereoselectivity.
They have been highlighted as potent new therapeutic agents,
for example, in antitumoral3 or anti-HIV treatment,4 and in prepa-
ration of glycoconjugates exhibiting some antiviral activity.5
Thioglycosides, including di- and trisaccharides, are potential gly-
cosidase inhibitors for treatment of metabolic diseases.6 Thiodisac-
charides can also serve as useful substrate analogs for studying
enzyme induction.7 These compounds are often used as efficient
The exclusive preparation of a-glycosyl thiol derivatives by the
treatment of a 1,6-anhydro sugar derivative and glycosyl trichloro-
acetimidate derivatives with bis(trimethylsilyl)sulfide [(TMS)2S]
respectively was reported.16 Thioglycosides have also been pre-
pared from glycosyl thiocyanates in reaction with Grignard reagents
at low temperature.17 This method is limited to equatorial thiocya-
nates only having hydroxyl group protected with acetyl or benzoyl
group. There is no straightforward synthetic approach for the simple
preparation of 1-thiosugars and thioglycosides from derivatives of
sugars with alkyl protected group and 1,2-cis configuration.
⇑
Corresponding author. Tel.: +48 32 237 17 59.
E-mail address: rkomor@polsl.pl (R. Komor).
http://dx.doi.org/10.1016/j.carres.2014.07.001
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

38
R. Komor et al. / Carbohydrate Research 396 (2014) 37–42
Although a number of reports18 have appeared in the literature
column chromatography. These compounds are stable, and can
be stored without degradation for a long time. However, when dis-
solved in CDCl3 they undergo a cis–trans isomerization25 which
complicates spectral interpretation. Full description of the major
rotamers’ NMR spectra and the representative signals for the minor
rotamers’ were given in the experimental section.
Many reports illustrate the intramolecular rearrangement of
various derivatives to afford thiolcarbamates. An example is the
thiono–thiol rearrangement, known as the Newman–Kwart rear-
rangement (NKR)—a valuable technique for converting phenols to
thiophenols via their N-phenyl thionocarbamates.26 The NKR pro-
ceeds via O- to S-migration, which has a high activation energy
and requires temperatures of 200–300 °C. This methodology has
been improved upon and microwave technology has proven to
be exceptionally convenient in a laboratory setting for rapid NKR
reaction.27 Transition-metal species containing elements such as
palladium,28 nickel,29 and rhodium28b have also been employed
to promote rearrangement and formation of the product.
Having synthesized the thionocarbamates 3 and 4, we turned
our attention to the evaluation of the rearrangement reaction. In
these derivatives, thiono–thiol rearrangement under NKR condi-
tions led to the complex mixture of products. However, in the pres-
ence of acid the rate of this reaction is increased significantly.
Since glucosyl thionocarbamate 3 is well soluble in most
organic solvents, the initial screening of the reaction conditions
was conducted in toluene or a toluene/acetonitrile mixture.
Our method provides a means of obtaining N-methyl thiolcar-
bamates in a short time in the presence of acids at room tempera-
ture. Table 1 summarizes the synthetic data for the glycosyl
N-methyl thiolcarbamates that were prepared. The progress of
the conversion is easily followed using NMR spectroscopy by
observing the upfield shift for protons, the N-methyl in S-glycosyl
and O-glycosyl derivatives. When the N-alkyl group was methyl,
the transformation was 93% complete after 5 min. The experiments
show that the use of trimethylsilyl triflate and boron trifluoride
(Lewis acids) may allow isomerization in good yields but not a very
high stereoselectivity.
The glycosyl N-methyl thiolcarbamates were applied to the syn-
thesis of glycosyl thiols. The alcoholysis made it possible to obtain
the glycosylthiols, which could be used for heteroaryl thioglyco-
side preparation. The transformation of glycosyl N-methyl thiolcar-
bamates to the corresponding glycosylthiols was carried out at
room temperature in acetone solution by treatment with methyl
alcohol in the presence of potassium carbonate. Under these
conditions the desired glycosylthiols were obtained in high yields,
as confirmed by 1H NMR analysis of the crude reaction mixture.
for the preparation of glycosyl thiol derivatives, most of the reac-
tion conditions suffer from several shortcomings, which include
longer reaction time, multiple steps, unsatisfactory yield, forma-
tion of isomeric mixtures, use of expensive reagents [e.g., (TMS)2S],
use of hazardous gases (e.g., H2S), use of appropriately functional-
ized substrates, etc. Hence, there is a strong need for the effective
preparation of glycosyl thiol derivatives. We have already reported
the synthesis of O-glycosyl thionocarbamates and evaluated them
in stereoselective glycosylation. N-Alkyl thiolcarbamates (S-alkyl
thiourethanes) are an important class of compounds that have
received considerable attention in the literature due to their
numerous biological effects including fungicidal,19 bactericidal,20
and antiviral.21 Therefore, we focused on the synthesis of complex
biologically active thioglycoside derivatives and developed a sim-
ple way to activate the anomeric hydroxyl group.22 Study of the
reaction mechanism leads to the conclusion that the crucial step
is activation of thionocarbamate in reaction with an electrophile,
and the formation of a carbonium ion following nucleophilic sub-
stitution at the anomeric carbon atom. Taking this into account,
one can expect that the electrophilic activation of glycosyl thionoc-
arbamates should lead to a relatively stable carboxonium ion. One
can expect that in the absence of a nucleophile the rearrangement
or elimination of glycosyl thionocarbamates can take place. In this
context, we envisioned that rearrangement of O-glycosyl thionoc-
arbamates obtained in the reaction of protected reducing sugars
with N-alkyl isothiocyanates could furnish the desired glycosyl
thiol derivatives in one-step reaction conditions.
The synthesis of many N-alkyl thiolcarbamates and N-alkyl
thionocarbamates has received considerable attention in the liter-
ature (for comprehensive reviews see Ref. 23). It was likewise
desirable to acquire a library of thiolcarbamates and thionocarba-
mates through the use of commercially available reagents in a
straightforward, high yielding process, employing less toxic mate-
rials and preferably nongaseous reagents. Scheme 1 represents the
synthetic route starting from protected D-gluco- (1) and D-galacto-
pyranose (2) to generate glycosyl thiols and/or thioglycosides.
Thionocarbamates were readily prepared according to the pre-
viously described method from selectively protected sugar and
N-alkyl isothiocyanate in the presence of a non-nucleophilic base
with excellent yields as a mixture of
thionocarbamate derivatives of 2,3,4,6-tetra-O-benzyl-
anose (1) and -galactopyranose (2) were obtained in the reaction
a
- and b-esters.24 The starting
-glucopyr-
D
D
with N-methyl isothiocyanate in the presence of a base—potassium
carbonate (K2CO3). This method provided the desired products 3
and 4 as mixtures of the
a- and b-esters which were purified by
BnO
R1
BnO
R1
S
BnO
R1
O
O
O
O
a
b
OBn
OBn
OBn
O
NHCH3
OH
S
NHCH3
R2
R2
R2
OBn
OBn
OBn
1
2
or
3
4
or
5
6
or
BnO
R1
BnO
R1
O
O
d
c
OBn
OBn
SH
S
NO2
N
R2
R2
OBn
OBn
10
7
8
or
9
or
1,3,5,7,9: R1=H, R2=OBn
2,4,6,8,10: R1=OBn, R2=H
Scheme 1. Synthetic route to generate heteroaryl 1-thioglycosides. Reagents and conditions: (a) S@C@N–CH3, K2CO3, toluene, ultrasonic bath, 50 °C, 8 h; (b) TMSOTf, toluene,
rt, 5 min; (c) 1 M MeONa, THF/MeOH (1:1), then Amberlyst 15 (H+), 1 h; (d) 2-chloro-5-nitropyridine, K2CO3, acetone, rt.

R. Komor et al. / Carbohydrate Research 396 (2014) 37–42
39
Table 1
suspension was sonicated for 5 min. Then methyl isothiocyanate
was added (660 mg, 9 mmol) and the mixture was sonicated for
another 8 h at 50 °C. K2CO3 was filtered off and the filtrate was
washed with brine, dried over MgSO4, and evaporated to give a
light yellow syrup.
Rearrangement of O-glycosyl N-alkyl thionocarbamates.
Entry
Substrate
Catalyst
Solvent
Product
yield(%);
(a/b)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
4
4
4
TMSOTf
TMSOTf
BF3 Et2O
TsOH
MSA
MSA
TMSOTf
TMSOTf
BF3ꢀEt2O
Toluene
93; (5.4:1)
74; (1:1.2)
72; (1:3.2)
57; (11:1)
67; (3.9:1)
62; (9.2:1)
66; (1.1:1)
44; (1:1.4)
76; (1:1.1)
Toluene/acetonitrile: 1:1
Toluene/acetonitrile: 1:1
Toluene/acetonitrile: 1:1
Toluene
Toluene/acetonitrile: 1:1
Toluene
1.2.1. 2,3,4,6-Tetra-O-benzyl-1-O-[N-methyl thionocarbamoyl]-
D
-glucopyranose (3)
The 3 b mixture was purified by column chromatography with
hexane–EtOAc (6:1) elution system to give a colorless thick syrup
a
(1.07 g,
a:b 4:1, 94%).
Toluene/acetonitrile: 1:1
Toluene
1.2.1.1.
3a
.
1H NMR (CDCl3, 400 MHz):
d 2.90 (d, 3H,
J = 5.2 Hz, CH3, minor rotamer); 3.11 (d, 3H, J = 4.9 Hz, CH3, major
rotamer); 3.64–3.98 (m, 6H, H-2, H-3, H-4, H-5, H-6a, H-6b);
4.46, 4.62 (qAB, 2H, J = 12.0 Hz, CH2Ph); 4.64, 4.78 (qAB, 2H,
J = 11.4 Hz, CH2Ph); 4.51, 4.84 (qAB, 2H, J = 10.6 Hz, CH2Ph); 4.80,
4.96 (qAB, 2H, J = 10.8 Hz, CH2Ph); 6.48 (q, 1H, J = 4.7 Hz, NH, major
rotamer); 6.71 (q, 1H, J = 4.7 Hz, NH, minor rotamer); 6.97 (d, 1H,
Table 2
Obtained glycosylthiol and heteroaryl thioglycosides
Entry
Substrate
Product
Yield(%); (a/b)
1
2
3
4
5
7
5
6
7
9
9
58; (4:1)
64; (4:1)
80; (3.9:1)
77; (1.4:1)
J = 3.6 Hz, H-1
a, major rotamer); 7.01 (d, 1H, J = 3.5 Hz, H-1a,
minor rotamer); 7.10–7.37 (m, 20H, H-Ph).
10
13C NMR (CDCl3, 100 MHz): d 30.12 (CH3, minor rotamer); 31.82
(CH3, major rotamer); 68.11 (C-6); 73.55 (C-5); 72.95, 73.15, 75.24,
75.61 (CH2Ph); 76.93 (C-4); 78.84 (C-2); 81.93 (C-3); 94.79 (C-1,
major rotamer); 96.62 (C-1, minor rotamer); 127.62, 127.67,
127.75, 127.90, 127.94, 127.98 128.08, 128.18, 128.32, 128.35,
128.38, 128.47 (C-Ph); 137.39, 137.90, 138.09 138.62 (C-Ph);
189.25 (C@S, minor rotamer); 189.50 (C@S, major rotamer).
ESI-MS: 636.7 [M+Na]+.
The glycosylthiols are unstable during purification using chroma-
tography on silica gel. Thus, only glucosylthiol 7 was isolated
before transformation to corresponding thioglycoside in order to
confirm the thiol structure. In the next experiments, glycosylthiols
were transformed to stable thioglycosides without separation by
chromatography (Table 2). Treatment of the reaction mixture with
2-chloro-5-nitropyridine led to the formation of heteroaryl thio-
glycosides, which are stable substrates for reactions such as nitro
group reduction in aglycon (performed in acidic conditions) or
benzyl group removal. The glycosides were purified by column
chromatography and the purified products were fully
characterized.
1.2.1.2. 3b.
1H NMR (CDCl3, 400 MHz):
d 2.78 (d, 3H,
J = 5.2 Hz, CH3, minor rotamer); 3.00 (d, 3H, J = 4.9 Hz, CH3, major
rotamer); 3.56–3.83 (m, 6H, H-2, H-3, H-4, H-5, H-6a, H-6b);
4.44, 4.57 (qAB, 2H, J = 12.0 Hz, CH2Ph); 4.51, 4.74 (qAB, 2H,
J = 11.2 Hz, CH2Ph); 4.70, 4.80 (qAB, 2H, J = 11.3 Hz, CH2Ph); 4.81,
In conclusion, a straightforward approach for the preparation of
both anomers of heteroaryl thioglycoside derivatives from the pro-
tecting reducing sugars is presented. Such derivatives are stable
glycosyl acceptors22a and can be used as substrates in the synthesis
of glycoconjugates—potential glycosyltransferase inhibitors.22c
4.89 (qAB, 2H, J = 10.9 Hz, CH2Ph); 6.17 (d, 1H, J = 7.9 Hz, H-1
a,
major rotamer); 6.23 (d, 1H, J = 7.3 Hz, H-1 , minor rotamer);
a
6.33 (q, 1H, J = 4.7 Hz, NH, major rotamer); 6.75 (q, 1H, J = 5.0 Hz,
NH, minor rotamer); 7.11–7.36 (m, 20H, H-Ph).
13C NMR (CDCl3, 100 MHz): d 29.94 (CH3, minor rotamer);
31.81 (CH3, major rotamer); 68.15 (C-6); 75.00 (C-5); 73.41,
74.79, 74.84, 75.65 (CH2Ph); 77.24 (C-4); 81.08 (C-2); 84.79
(C-3); 98.22 (C-1, major rotamer); 99.55 (C-1, minor rotamer);
127.58, 127.63, 127.67, 127.75, 127.87, 127.93 127.98, 128.15,
128.26, 128.29, 128.31, 128.34, 128.36 (C-Ph); 137.82, 138.06,
138.26 138.37 (C-Ph); 189.01 (C@S, major rotamer); 189.13
(C@S, minor rotamer).
1. Experimental section
1.1. General information
NMR spectra were recorded with an Agilent spectrometer
400 MHz using TMS as an internal standard and CDCl3 as a solvent.
NMR solvent was purchased from ACROS Organics (Geel, Belgium).
Chemical shifts (d) are expressed in ppm and coupling constants (J)
in Hz. Optical rotations were measured with a JASCO 2000 polar-
imeter using a sodium lamp (589.3 nm) at room temperature. Mass
spectra were recorded with a 4000 QTRAP ABSciex mass spectrom-
eter using electrospray-ionization (ESI) technique. Reactions were
monitored by TLC on precoated plates of silica gel 60 F254 (Merck).
TLC plates were inspected under UV light (k = 254 nm) or charring
after spraying with 10% sulfuric acid in ethanol. Crude products
were purified using column chromatography performed on Silica
Gel 60 (70–230 mesh, Fluka) developed with hexane/EtOAc solvent
systems. Organic solvents were evaporated on a rotary evaporator
under diminished pressure at 40 °C.
ESI-MS: 636.7 [M+Na]+.
1.2.2. 2,3,4,6-Tetra-O-benzyl-1-O-[N-methyl thionocarbamoyl]-
D
-galactopyranose (4)
The 4 b mixture was purified by column chromatography with
hexane–EtOAc (6:1) elution system to give a colorless thick syrup
a
(1.09 g,
a:b 1.1:1, 96%).
1.2.2.1.
4a
.
1H NMR (CDCl3, 400 MHz):
d 2.71 (d, 3H,
J = 5.1 Hz, CH3, minor rotamer); 3.11 (d, 3H, J = 4.9 Hz, CH3, major
rotamer); 3.54 (dd, 1H, J = 5.3 Hz, J = 9.1 Hz, H-6a); 3.59–3.65 (m,
1H, H-6b); 3.90 (dd, 1H, J = 2.8 Hz, J = 10.1 Hz, H-3); 3.93–3.98
(m, 1H, H-5); 4.05 (d, 1H, J = 2.1 Hz, H-4); 4.23 (dd, 1H, J = 3.9 Hz,
J = 10.1 Hz, H-2); 4.38, 4.44 (qAB, 2H, J = 11.6 Hz, CH2Ph); 4.67,
4.77 (qAB, 2H, J = 11.3 Hz, CH2Ph); 4.72, 4.81 (qAB, 2H,
J = 11.8 Hz, CH2Ph); 4.58, 4.95 (qAB, 2H, J = 11.4 Hz, CH2Ph); 6.53
(q, 1H, J = 4.6 Hz, NH, major rotamer); 6.81 (q, 1H, J = 4.7 Hz, NH,
1.2. General procedure for preparation of N-methyl O-glycosyl
thionocarbamate 3 and 4
To a solution of sugar 1 (1.00 g, 1.85 mmol) in toluene (40 mL)
anhydrous K2CO3 was added (2.66 g; 18.5 mmol). The resulting
minor rotamer); 6.97 (d, 1H, J = 3.7 Hz, H-1a); 7.20–7.41 (m, 20H,
H-Ph).

40
R. Komor et al. / Carbohydrate Research 396 (2014) 37–42
13C NMR (CDCl3, 100 MHz): d 29.74 (CH3, minor rotamer); 31.72
1.3.2.1.
J = 4.6 Hz, CH3b); 2.70 (d, 3H, J = 4.7 Hz, CH3
J = 5.8, Hz, J = 9.6 Hz, H-6a ); 3.52–3.69 (m, 6H, H-3
3b, H-4b, H-6ab, H-6bb); 3.90 (br s, 1H, H-4 ); 4.13 (br t, 1H,
J = 6.2 Hz, H-5 ); 4.35 (dd, 1H, J = 5.3 Hz, J = 9.8 Hz, H-2 ); 4.39–
4.97 (m, 17H, CH2Ph, H-1b); 6.11 (q, 1H, J = 4.5 Hz, NH ); 6.19 (d,
); 6.36 (q, 1H, J = 4.5 Hz, NHb); 7.19–7.41 (m,
6
a
b.
1H NMR (CDCl3, 400 MHz):
d
2.48 (d, 3H,
); 3.46 (dd, 1H,
, H-6b , H-
(CH3, major rotamer); 68.27 (C-6); 74.51 (C-4); 72.98, 73.35, 73.56,
74.83 (CH2Ph); 71.84 (C-5); 75.52 (C-2); 78.84 (C-3); 95.60 (C-1,
major rotamer); 97.39 (C-1, minor rotamer);127.30, 127.49,
127.50, 127.52, 127.55, 127.59 127.74, 127.96, 128.27, 128.18,
128.20, 128.32, 128.33, 128.37, 128.40 (C-Ph); 137.76, 137.78,
138.53 138.61 (C-Ph); 189.18 (C@S, minor rotamer); 189.76
(C@S, major rotamer).
a
a
a
a
a
a
a
a
1H, J = 5.3 Hz, H-1
a
40H, H-Ph).
ESI-MS: 636.6 [M+Na]+.
13C NMR (CDCl3, 100 MHz): d 27.31 (CH3b); 27.71 (CH3
(C-6b); 68.80 (C-6a); 72.09 (C-5a
a
); 68.14
); 72.48, 72.82, 73.48, 73.53,
73.54, 74.77, 74.93; 75.86 (CH2Ph); 73.62 (C-4b); 74.56 (C-4 );
75.53 (C-2 ); 77.53 (C-5b); 77.72 (C-2b); 79.50 (C-3 ); 83.53 (C-
1b); 83.82 (C-1 and C3b); 127.51, 127.57, 127.70, 127.78,
1.2.2.2. 4b.
1H NMR (CDCl3, 400 MHz):
d
2.78 (d, 3H,
a
J = 5.2 Hz, CH3, minor rotamer); 3.01 (d, 3H, J = 4.9 Hz, CH3, major
rotamer); 3.55–3.61 (m, 2H, H-6a H-6b); 3.66 (dd, 1H, J = 2.9 Hz,
J = 9.7 Hz, H-3); 3.72 (m, 1H, H-5); 3.95–4.03 (m, 2H, H-2, H-4);
4.38, 4.46 (qAB, 2H, J = 11.6 Hz, CH2Ph); 4.72 (s, 2H, CH2Ph); 4.69,
4.80 (qAB, 2H, J = 11.5 Hz, CH2Ph); 6.12 (d, 1H, J = 8.0 Hz, H-1b,
major rotamer); 6.15 (d, 1H, J = 8.0 Hz, H-1b, minor rotamer);
6.19 (q, 1H, J = 4.8 Hz, NH); 6.66 (q, 1H, J = 5.0 Hz, NH, minor rot-
amer); 7.20–7.38 (m, 20H, H-Ph).
a
a
a
127.83, 127.92, 127.96, 128.05, 128.21, 128.27, 128.28, 128.32,
128.34, 128.37, 128.41, 128.47 (C-Ph); 137.56, 137.70, 137.73,
137.84, 138.05, 138.20, 138.27, 138.44 (C-Ph); 165.51 (C@Ob);
165.90 (C@Oa).
ESI-MS: 636.7 [M+Na]+.
13C NMR (CDCl3, 100 MHz): d 29.98 (CH3, minor rotamer); 31.77
(CH3, major rotamer); 68.01 (C-6); 73.29 (C-4); 73.81 (C-5); 73.02,
73.45, 74.66, 75.06 (CH2Ph); 78.26 (C-2); 82.36 (C-3); 98.61 (C-1,
major rotamer); 99.98 (C-1, minor rotamer); 127.57, 127.75,
127.96, 128.15, 128.17, 128.18, 128.21, 128.37 (C-Ph); 137.79,
138.24, 138.51, 138.58 (C-Ph); 189.25 (C@S, major rotamer);
189.34 (C@S, minor rotamer).
1.4. 2,3,4,6-Tetra-O-benzyl-1-thio-D-glucose (7)
To a solution of 5ab (370 mg; 604
lmol) in 8 mL of THF/MeOH
(1:1) 1 M MeONa (300
l
L, 300 mol) was added. The resulting
l
mixture was stirred for 1 h and neutralized with Amberlyst 15
(H+). After filtration the solvent was evaporated to give a thick
syrup. Purification on a silica gel column (hexane/ethyl acetate;
ESI-MS: 636.7 [M+Na]+.
20:1) gave the pure product 7 (197 mg, a:b 4:1, 58%).
1.3. General procedure for preparation of glycosyl N-methyl
thiolcarbamates 5 and 6
1.4.1. 7
1H NMR (CDCl3, 400 MHz): d 1.89 (d, 1H, J = 4.6 Hz, SH
(d, 1H, J = 7.8 Hz, SHb); 3.34–3.40 (m, 1H, H-2b); 3.45–3.50 (m,
1H, H-5b); 3.60–3.89 (m, 8H, H-3 , H-4 , H6b , H-3b, H-4b, H-
5b, H-6ab, H-6bb); 4.18–4.23 (m, 1H, H-5 ); 4.45–4.96 (m, 17H,
ab
a); 2.31
To a solution of 3 (1 g; 1.6 mmol) in toluene (40 mL), TMSOTf
a
a
a
(980
lL, 0.54 mmol) in toluene (5 mL) was added. The resulting
a
mixture was stirred for 5 min and diluted with toluene (25 mL),
washed with saturated NaHCO3, dried over MgSO4, and
evaporated.
CH2Ph, H-1b); 5.74 (ddꢁt, 1H, J = 5.0 Hz, H-1
a); 7.10–7.40 (m,
40H, H-Ph).
13C NMR (CDCl3, 100 MHz): d 68.29 (C-6
a
); 68.67 (C-6b); 73.47
); 71.15, 72.30, 73.49, 75.01, 75.05, 75.65 (CH2Ph); 77.24
); 77.69 (C-2b); 78.84, 79.16 (C-2 , C-3 ); 79.40 (C-4b);
); 84.69 (C-3b); 86.40 (C-1b); 127.69,
(C-5
(C-4
a
a
1.3.1. 2,3,4,6-Tetra-O-benzyl-1-thio–[N-methyl
a
a
thiolcarbamoyl]-
The 5 b mixture was purified by column chromatography with
hexane–EtOAc (4:1) elution system to give a colorless thick syrup
D-glucopyranose (5)
79.76 (C-5b); 81.77 (C-1
a
a
127.80, 127.90, 128.01, 128.26, 128.35, 128.41 (C-Ph); 137.55,
137.74, 137.89, 138.13, 138.34, 138.55, 138.57 (C-Ph).
ESI-MS: 555.7 [MꢂH]ꢂ.
(960 mg,
a:b 4:1, 96%).
1.3.1.1.
5
a
b.
1H NMR (CDCl3, 400 MHz):
d
2.69 (d, 3H,
); 3.53–3-77 (m,
, H-3b, H-2b, H-4b, H-5b, H-6b, H-
, H-5 ); 4.43–4.60 (m, 9H, CH2Ph);
1.5. (5-Nitro-2-pyridyl) 2,3,4,6-tetra-O-benzyl-1-thio-D-
glucopyranoside (9)
J = 4.6 Hz, CH3b); 2.83 (d, 1.5H, J = 4.6 Hz, CH3
8H, H-3 , H-4 , H-6a , H-6b
6bb); 3.87–3.97 (m, 2H, H-2
a
a
a
a
a
a
a
To a solution of 7 mol) in dry acetone (5 mL)
ab (150 mg; 270
l
4.72–5.03 (m, 15H, CH2Ph, H-1b); 5.73 (q, 0.5H, J = 4.9 Hz, NH
6.18 (q, 1H, J = 3.9 Hz, NHb); 6.24 (d, 0.5H, J = 5.3 Hz, H-1
7.11–7.37 (m, 30H, H-Ph).
a
a
);
);
2-chloro-5-nitropyridine (47 mg, 297 lmol) and anhydrous K2CO3
(180 mg, 1.28 mmol) were added. The resulting suspension was
stirred for 2 h at room temperature. K2CO3 was filtered off and
the filtrate was evaporated.
13C NMR (CDCl3, 100 MHz): d 27.75 (CH3b); 27.97 (CH3
a
);
68.50 (C-6
75.07, 75.21, 75.49, 75.68, 75.82 (CH2Ph); 76.97 (C-4
79.04 (C-4b, C-5b); 78.64 (C-2 ); 80.86 (C-2b); 83.03 (C-3
83.31 (C-3b); 83.69 (C-1 ); 86.48 (C-1b); 127.63, 127.73,
a
); 68.74 (C-6b); 73.40 (C-5
a
); 72.24, 73.53, 73.57,
); 77.55,
);
The 9
solvent system (94 mg, 51%). White powder; mp 138.2–139.1 °C,
188.9 (c 1.0, CHCl3); The filtrate contained <1% 9 and 13%
9b (determined by NMR spectra).
a was purified by crystallization from hexane–EtOAc (2:1)
a
a
a
½
a 2D2
ꢃ
a
a
127.79, 127.84, 127.93, 127.96, 128.02, 128.09, 128.35, 128.38,
128.39, 128.41, 128.43, 128.44 (C-Ph); 137.41, 137.66, 137.78,
1.5.1. 9
a
137.81, 137.87, 138.03, 138.27, 138.53 (C-Ph); 165.27 (C@O
a
);
1H NMR (CDCl3, 400 MHz): d 3.58 (dd, 1H, J = 2.0 Hz, J = 11 Hz,
H-6a); 3.69–3.74 (m, 2H, H-4, H-6b); 3.80 (t, 1H, J = 9.2 Hz, H-3);
3.99–4.04 (m, 2H, H-2, H-5); 4.40, 4.53 (qAB, 2H, J = 12.0 Hz, CH2-
Ph); 4.50, 4.84 (qAB, 2H, J = 10.7 Hz, CH2Ph); 4.68, 4.72 (qAB, 2H,
J = 11.7 Hz, CH2Ph); 4.81, 4.98 (qAB, 2H, J = 10.8 Hz, CH2Ph); 6.66
165.38 (C@Ob).
ESI-MS: 636.7 [M+Na]+.
1.3.2. 2,3,4,6-Tetra-O-benzyl-1-thio-[N-methyl thiolcarbamoyl]-
-galactopyranose (6)
The 6 b mixture was purified by column chromatography with
hexane–EtOAc (4:1) elution system to give a colorless thick syrup
(920 mg, :b 1.4:1, 92%).
D
(d, 1H, J = 5.5 Hz, H-1a); 7.13–7.40 (m, 20H, H-Ph, H-3pyr); 8.20
a
(dd, 1H, J = 2.7 Hz, J = 9.0 Hz, H-4pyr); 9.22 (d, 1H, J = 2.7 Hz, H-6pyr).
13C NMR (CDCl3, 100 MHz): d 68.33 (C-6); 72.81, 73.34, 75.19,
75.73 (CH2Ph); 73.27 (C-5); 77.00 (C-4); 78.94 (C-2); 82.90 (C-3),
a

R. Komor et al. / Carbohydrate Research 396 (2014) 37–42
41
83.40 (C-1); 122.60 (C-3pyr); 127.69, 127.71, 127.76, 127.85,
127.94, 127.96, 127.99, 128.30, 128.39, 128.42 (C-Ph); 130.90 (C-
The 10b was purified by crystallization from hexane–EtOAc
(2:1) solvent system (810 mg, 32%). White powder; mp 109.1–
4pyr); 137.31, 137.72, 138.00, 138.43 (C-Ph); 141.56 (C-5pyr);
111.1 °C, ½a 2D2
ꢃ
ꢂ14.7 (c 1.0, CHCl3).
144.90 (C-6pyr); 165.65 (C-2pyr).
ESI-MS: 701.7 [M+Na]+.
1.6.1.2. 10b.
1H NMR (CDCl3, 400 MHz): d 3.60–3.61 (m, 2H,
H-6a, H-6b); 3.70 (dd, 1H, J = 2.7 Hz, J = 9.1 Hz, H-3); 3.75 (t, 1H,
J = 6.7 Hz, H-5); 4.03–4.11 (m, 2H, H-4, H-2); 4.47, 4.42 (qAB, 2H,
J = 11.6 Hz, CH2Ph), 4.75, 4.80 (qAB, 2H, J = 11.5 Hz, CH2Ph); 4.76,
4.82 (qAB, 2H, J = 10.5 Hz, CH2Ph), 4.61, 4.97 (qAB, 2H,
J = 11.1 Hz, CH2Ph); 5.34 (d, 1H, J = 10.0 Hz, H-1b); 7.22–7.38 (m,
20H, H-Ph); 7.49 (dd, J = 8.9 Hz, J = 0.6 Hz, H-3pyr); 7.92 (dd, 1H,
J = 2.7 Hz, J = 8.9 Hz, H-4pyr); 9.16 (dd, 1H, J = 0.6 Hz, J = 2.7 Hz,
H-6pyr).
1.5.2. 9b
1H NMR (CDCl3, 400 MHz): d 3.64–3.84 (m, 6H, H-2, H-3, H-4,
H-5, H-6a, H-6b); 4.46, 4.53 (qAB, 2H, J = 11.4 Hz, CH2Ph); 4.50,
4.58 (qAB, 2H, J = 10.7 Hz, CH2Ph); 4.80, 4.83 (qAB, 2H,
J = 11.7 Hz, CH2Ph); 4.89, 4.93 (qAB, 2H, J = 11.0 Hz, CH2Ph); 5.55
(d, 1H, J = 10 Hz, H-1b); 7.12–7.35 (m, 20H, H-Ph); 7.38 (d, 1H,
J = 0.5 Hz, J = 8.9 Hz, H-3pyr); 8.13 (dd, 1H, J = 2.7 Hz, J = 8.8 Hz,
H-4pyr); 9.20 (d, 1H, J = 2.7 Hz, H-6pyr).
13C NMR (CDCl3, 100 MHz): d 68.46 (C-6); 73.46 (C-4); 72.74,
73.58, 74.73, 75.76 (CH2Ph); 76.71 (C-2); 77.73 (C-5); 83.40
(C-1); 84.17 (C-3); 122.30 (C-3pyr); 127.58, 127.81, 127.80,
127.85, 127.91, 127.92 128.20, 128.26, 128.27, 128.29, 128.30,
128.34, 128.48, 128.49 (C-Ph); 130.91 (C-4pyr); 137.66, 137.68,
138.00 138.38 (C-Ph); 141.41 (C-5pyr); 144.80 (C-6pyr); 166.25
(C-2pyr).
13C NMR (CDCl3, 100 MHz): d 68.75 (C-6); 73.41, 75.05, 75.58,
75.80 (CH2Ph); 77.72 (C-4); 79.41, 80.48 (C-2, C-5); 82.99 (C-3),
86.78 (C-1); 121.96 (C-3pyr); 127.69, 127.74, 127.96, 128.08,
128.33, 128.37, 128.45 (C-Ph); 131.00 (C-4pyr); 137.46, 137.89,
137.91, 138.24 (C-Ph); 141.56 (C-5pyr); 144.90 (C-6pyr); 165.83
(C-2pyr).
ESI-MS: 701.7 [M+Na]+.
ESI-MS: 701.7 [M+Na]+.
1.6. ‘One-pot’ synthesis procedure of (5-nitro-2-pyridyl) 2,3,4,6-
Acknowledgments
tetra-O-benzyl-1-thioglycopyranosides 9 and 10
Research studies were part-financed by the European Union
within the European Regional Development Fund (POIG.01.01.02-
14-102/09). Roman Komor received a scholarship under the Project
DoktoRIS—Scholarship Program for Innovative Silesia.
To a solution of sugar 1 or 2 (2 g, 3.7 mmol) in toluene
(100 mL), anhydrous K2CO3 was added (5.1 g; 37 mmol). The
resulting suspension was sonicated for 5 min. Then methyl isothi-
ocyanate was added (1.35 g, 18.5 mmol) and the mixture was
sonicated for another 8 h at 50 °C. K2CO3 was filtered off and
Supplementary data
TMSOTf (230 lL, 120 lmol) in toluene (5 mL) was added. The
resulting mixture was stirred for 5 min and diluted with toluene
(100 mL), washed with saturated NaHCO3, dried over MgSO4, and
evaporated to give a thick syrup. The syrup was dissolved in ace-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.
07.001. These data include MOL files and InChiKeys of the most
important compounds described in this article.
tone (50 mL) and methanol (500 lL), 2-chloro-5-nitropyridine
(1.16 g, 7.40 mmol), and anhydrous K2CO3 (1.04 g, 7.40 mmol)
were added. The resulting suspension was sonicated for 4 h at
room temperature. K2CO3 was filtered off and the filtrate was
evaporated.
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