Synthesis of Thioglycosides with Nitrogen-Containing Heterocyclic Fragments

Article abstract of DOI:10.1134/S1070428018070126

A number of thioglycosides derived from benzoylated glucopyranose and nitrogen-containing heterocyclic thiols have been synthesized in up to 98% yield, and benzoyl protecting groups have been removed from the glycoside with a 3-phenyl-4-oxo-3,4-dihydroqui

Full text of DOI:10.1134/S1070428018070126

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 7, pp. 1041–1044. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © S.V. Pestova, E.S. Izmest’ev, S.A. Rubtsova, A.V. Polukeev, A.V. Kutchin, 2018, published in Zhurnal Organicheskoi Khimii, 2018,
Vol. 54, No. 7, pp. 1036–1039.
Synthesis of Thioglycosides with Nitrogen-Containing
Heterocyclic Fragments
a
a
a
b
a
S. V. Pestova ,* E. S. Izmest’ev , S. A. Rubtsova , A. V. Polukeev , and A. V. Kutchin
a
Institute of Chemistry, Komi Research Center, Ural Branch, Russian Academy of Sciences,
ul. Pervomaiskaya 48, Syktyvkar, 167000 Russia
*
e-mail: pestova-svetlana89@mail.ru
b
Institute of Experimental Medicine, Russian Academy of Medical Sciences,
ul. Akad. Pavlova 12, St. Petersburg, 197376 Russia
Received December 14, 2017
Abstract—A number of thioglycosides derived from benzoylated glucopyranose and nitrogen-containing
heterocyclic thiols have been synthesized in up to 98% yield, and benzoyl protecting groups have been
removed from the glycoside with a 3-phenyl-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl fragment.
DOI: 10.1134/S1070428018070126
Natural and semisynthetic thioglycosides exhibit
a broad spectrum of biological activity, such as anti-
viral, antibacterial, antitumor [1, 2], anti-inflammatory,
and anticoagulant [3]. As a rule, the hydrophobic cell
wall of bacteria is originally stable to a wide range of
antimicrobial agents. Introduction of a hydrophobic
biologically active nitrogen heterocycle into a water-
soluble monosaccharide allows the resulting conjugate
to penetrate through bacterial cell wall and makes it
soluble. Carbohydrate structures are convenient pre-
cursors for selective synthesis of drugs active against
a series of mycobacteria [4], as well as for the prepara-
tion of antitubercular [5] and antifungal agents [4, 6].
small value of the J coupling constant (3.7 Hz)
1
,2
which was similar to that in initial α-glucose 3
(Scheme 1).
By reactions of bromide 1 with thiols 4a–4d in
DMF in the presence of Cs CO –Bu NI we obtained
2
3
4
sulfides 5a–5d (Scheme 2). These reactions were
accompanied by inversion of the configuration of the
anomeric carbon atom, and the coupling constant
J
in sulfides 5a–5d increased to 10.8 Hz. This is con-
1
,2
sistent with the NOESY data which showed disappear-
ance of 1-H/2-H cross peak, indicating opposite orien-
tations of the 1-H and 2-H protons with respect to the
tetrahydropyran ring of the monosaccharide.
We have synthesized thioglycosides based on
α-D-2,3,4,6-tetra-O-benzoylglucopyranosyl bromide 1
and 3-substituted 2-sulfanylquinazolin-4-ones 4a–4c
and 2-sulfanyltetrahydrobenzothienopyrimidin-4-one
Pure thioglycosides 5a–5d were isolated in 43–98%
yield by column chromatography, and the yields of
compounds 5a–5c containing a quinazolinone frag-
ment were higher than the yield of benzothienopyrimi-
dine derivative 5d. Compound 5c with a phenyl sub-
4
d. Bromide 1 was obtained in quantitative yield by
3
reaction of penta-O-benzoyl-α-D-glucopyranose 2 with
HBr in acetic acid. The benzoyloxy group was re-
placed by bromine with retention of the configuration
at the anomeric carbon atom. This followed from the
stituent on N of the quinazoline fragment was isolated
in the highest yield (98%), presumably due to electron-
withdrawing effect of the phenyl group, which en-
hances the activity of the SH group in thiol 4c. A fairly
Scheme 1.
OH
OBz
OBz
BzCl, Py
CHCl , –20°C
6
33% HBr, AcOH
CH Cl , 0°C
O
5
O
O
HO
HO
3
BzO
BzO
2
2
BzO
BzO
2
3
1
OH
OH
OBz
OBz
OBz
Br
3
2
1
1
041

1
042
PESTOVA et al.
Scheme 2.
OBz
OH
RSH (4a–4d)
N H ·H O
2 4 2
Cs CO , Bu NI, DMF
O
MeOH, CHCl
O
2
3
4
BzO
BzO
3
HO
HO
SR
SR
1
OBz
OH
5
a–5d
6c
m
o
O
O
o
i
p
5'
O
3
CH
"
O
5
8
'
'
5'
8'
1"
4'
4'
Me
2
5'
4'
4'
Me
N
N
m
R =
(a),
2"
(b),
(c),
N
(d).
N
2'
2'
1
'
1'
N
2'
8'
2'
1'
1
'
N
S
9
a'
N
N
8
'
high yield of 5b (75%) can be rationalized in a similar
way, but the electron-withdrawing power of the allyl
group is lower, and (unlike phenyl group) it cannot be
involved in conjugation with the nitrogen lone electron
pair and hence stabilize nitrogen-centered cation. The
ured on a Gallencamp-Sanyo melting point apparatus.
1 13
The H and C NMR spectra were recorded on
a Bruker Avance‑300 spectrometer at 300.17 and
75.48 MHz, respectively; the chemical shifts were
determined relative to the residual proton and carbon
3
presence of an electron-donating methyl group on N
signals of the deuterated solvent (CDCl
3
or DMSO-d ).
6
in thiols 4a and 4d reduces the yield of the corre-
sponding thioglycosides (65 and 43% for 5a and 5d,
respectively). Furthermore, the reactivity of thiol 4d
is likely to be affected by the cyclohexane fragment
which neutralizes electron-withdrawing effect of the
thiophene ring.
We tried to remove benzoyl protecting groups from
the synthesized thioglycosides by the action of hydra-
zine hydrate in methanol–chloroform. However, we
succeeded in deprotecting in this way only compound
Complete signal assignment was done with the aid of
1 1 1 1
two-dimensional homo- ( H– H COSY, H– H
1
13
NOESY) and heteronuclear experiments ( H– C
1
13
HSQC, H– C HMBC). The optical rotations were
measured with a PolAAr 3001 automated digital polar-
imeter (UK). The elemental analyses were obtained
using a EA 1110 automated CHNS-O analyzer. Thin-
layer chromatography was performed on Sorbfil plates
using chloroform–diethyl ether and petroleum ether–
ethyl acetate mixtures at different ratios as eluents
(
gradient elution); spots were visualized by treatment
5
c. Unprotected thioglycoside 6c was formed together
with a solution of phosphomolybdic acid or potassium
permanganate. The products were isolated by column
chromatography on silica gel (0.06–0.2 mm, Alfa
Aesar) using the same solvent systems as for TLC.
with benzohydrazide, and we failed to separate the
products. Attempts to deprotect the other thioglyco-
sides resulted in cleavage of the C–S bond. Pre-
sumably, the stability of thioglycoside 6c is largely
determined by electron-withdrawing properties of the
D-(+)-Glucose (99%, Alfa Aesar) and thiols 4a–4d
(99%, Vekton closed corporation) were commercial
products.
3
phenyl substituent on N of the quinazoline fragment,
which favor increased energy of the C –S bond. The
Ht
use of other basic reagents such as sodium methoxide
Penta-O-benzoyl-α-D-glucopyranose (2) was syn-
[
7], ammonia [8], and triethylamine [9] for removal of
thesized according to the procedure described in [10].
benzoyl protecting groups was unsuccessful.
20
Yield 98%, [α] = +128.0° (c = 0.3, CHCl ),
D
3
2
0
In summary, we have synthesized benzoylated
glucopyranose thioglycosides with N-heterocyclic
fragments on the sulfur atom and successfully removed
benzoyl protecting groups from the one containing
a 3-phenyl-4-oxo-3,4-dihydroquinazolin-2-yl sub-
stituent.
mp 164°C; published data [11]: yield 98%, [α]
=
D
+125.4° (c = 0.3, CHCl ), mp 164–165°C.
3
2
,3,4,6-Tetra-O-benzoyl-α-D-glucopyranozyl
bromide (1) was synthesized as described in [12].
20
Yield 83%, [α] = +120.0° (c = 3.6, CHCl ),
D
3
20
D
mp 125°C; published data [12]: yield 99%, [α]
=
+
119° (c = 3.62, CHCl ), mp 127–128°C.
3
EXPERIMENTAL
Thioglycosides 5a–5d (general procedure). Thiol
The IR spectra were recorded from thin films or
KBr disks on a Shimadzu IR Prestige 21 spectrometer
with Fourier transform. The melting points were meas-
4a–4d, 1.3 mmol, cesium carbonate, 1.3 mmol
(0.42 g), and tetrabutylammonium iodide, 1.3 mmol
(0.48 g), were dissolved in 3 mL of DMF with stirring
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 7 2018

SYNTHESIS OF THIOGLYCOSIDES
1043
1
in a stream of argon. The solution was stirred for
(O–C–O), 769, 711 (C–S). H NMR spectrum
5
min, 1 mmol (0.66 g) of compound 1 was added, and
(CDCl ), δ, ppm: 4.43–4.58 m (2H, 5-H, 6-H), 4.59–
3
the mixture was refluxed for 12 h. The solvent was
removed under reduced pressure, and the product was
isolated by silica gel column chromatography using
petroleum ether–ethyl acetate (3:2) as eluent.
4.71 m (1H, 6-H), 5.61–5.78 m (2H, 2-H, 4-H), 6.12 t
(1H, 3-H, J = 9.5 Hz), 6.28 d (1H, 1-H, J = 10.5 Hz),
1
3
7.06–8.29 m (29H, H
). C NMR spectrum
2 4
arom
6
(CDCl ), δ , ppm: 63.34 (C ), 69.55 (C ), 69.93 (C ),
3
C
3
5
1
4a′
7
1
1
4.34 (C ), 77.01 (C ), 82.92 (C ), 120.14 (C ),
i 8a′
2
,3,4,6-Tetra-O-benzoyl-1-[(3-methyl-4-oxo-
,4-dihydroquinazolin-2-yl)sulfanyl]-β-D-glucopy-
ranose (5a). Yield 65%, white powder, mp 120°C,
26.14–134.37 (C ), 135.10 (C ), 147.42 (C ),
arom
3
2
′
4′
54.14 (C ), 161.60 (C ), 165.05–166.14 (PhC=O).
2
0
Found, %: C 69.28; H 4.29; N 3.28; S 3.93.
C H N O S. Calculated, %: C 69.22; H 4.36;
[
α] = +83.2° (c = 0.2, CHCl ), R 0.55 (petroleum
D
3
f
–1
4
8
36
2
10
ether–EtOAc, 3:2). IR spectrum, ν, cm : 1730 (C=O),
N 3.36; S 3.85.
1
1
681 (C=S), 1557, 1377, 1271 (C–N), 1089 (C–O),
1
070 (O–C–O), 769, 711 (C–S). H NMR spectrum
2,3,4,6-Tetra-O-benzoyl-1-{(3-methyl-4-oxo-
3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrim-
idin-2-yl)sulfanyl}-β-D-glucopyranose (5d). Yield
(
(
(
CDCl ), δ, ppm: 3.58 s (3H, 3′-CH ), 4.39–4.58 m
3
3
2H, 5-H, 6-H), 4.66 d (1H, 6-H, J = 9.9 Hz), 5.75 t
1H, 2-H, J = 9.49 Hz), 6.43 d (1H, 4-H, J = 10.7 Hz),
2
0
43%, white powder, mp 129°C, [α] = +80.1° (c = 0.3,
D
6
1
.19 t (1H, 3-H, J = 9.35 Hz), 6.43d (1H, 1-H, J =
CHCl ), R 0.50 (petroleum ether–EtOAc, 3:2). IR
3
f
1
3
–1
0.7 Hz), 7.06–8.29 m (24H, H ). C NMR spect-
spectrum, ν, cm : 2938 (C–H), 1732 (C=O), 1678
arom
6
rum (CDCl ), δ , ppm: 30.46 (CH ), 63.42 (C ), 69.59
(C=C), 1524, 1450, 1273 (C–N), 1089 (C–O), 1074
3
C
3
2
4
3
5
1
1
(
C ), 69.66 (C ), 74.31 (C ), 77.10 (C ), 82.64 (C ),
(O–C–O), 732, 712 (C–S). H NMR spectrum
4
a′
8a′
1
19.41 (C ), 126.14–134.37 (C ), 147.02 (C ),
(CDCl ), δ, ppm: 1.77–1.96 m (4H, 6′-H, 7′-H), 2.73 d
arom
3
2
′
4′
1
55.32 (C ), 161.72 (C ), 165.27–166.13 (PhC=O).
(2H, 5′-H, J = 5.50 Hz), 2.90–3.08 m (2H, 8′-H),
Found, %: C 67.15; H 4.38; N 3.70; S 4.09.
C H N O S. Calculated, %: C 67.00; H 4.45;
3.50 s (3H, 3′-CH ), 4.39–4.54 m (2H, 5-H, 6-H),
3
4
3
34
2
10
4.66 d (1H, 6-H, J = 10.2 Hz), 5.75 t (1H, 2-H, J =
9.5 Hz), 5.84 d (1H, 4-H, J = 9.9 Hz), 6.17 t (1H, 3-H,
J = 9.4 Hz), 6.28 d (1H, 1-H, J = 10.5 Hz), 7.22–
N 3.63; S 4.16.
2
,3,4,6-Tetra-O-benzoyl-1-{[4-oxo-3-(prop-
1
3
8
.03 m (20H, Ph). C NMR spectrum (CDCl ), δ ,
3
C
2
-en-1-yl)-3,4-dihydroquinazolin-2-yl]sulfanyl}-
7′ 6′ 5′ 8′
ppm: 22.29 (C ), 22.98 (C ), 25.11 (C ), 25.49 (C ),
β-D-glucopyranose (5b). Yield 75%, white powder,
6
2
4
2
0
25.49 (CH ), 63.24 (C ), 69.48 (C ), 69.76 (C ), 74.20
3 5 1 4a′
3
mp 181°C, [α] = +80.1° (c = 0.3, CHCl ), R 0.40
D
3
f
–1
(C ), 76.95 (C ), 82.63 (C ), 119.07 (C ), 128.08–
(
petroleum ether–EtOAc, 3:2). IR spectrum, ν, cm :
m 4b′ o
1
28.50 (C ), 128.70 (C ), 129.74–129.69 (C ), 131.31
8a′ i p 2′
1
732 (C=O), 1686 (C=C), 1553, 1273 (C–N), 1090
1
(C ), 132.20–133.64 (C , C ), 152.78 (C ), 158.34
10′ 4′
(
C–O), 1072 (O–C–O), 770, 712 (C–S). H NMR spec-
(
C ), 161.51 (C ), 165.26–166.11 (PhC=O). Found,
: C 65.09; H 4.56; N 3.32; S 7.69. C H N O S .
trum (CDCl ), δ, ppm: 4.44–4.81 m (5H, 1″-H, 5-H,
3
%
4
5
38
2
10 2
6
3
6
1
-H), 5.08 d (1H, 3″-H, J = 10.2 Hz), 5.16 d (1H,
″-H, J = 17.3 Hz), 5.69–5.89 m (3H, 2-H, 2″-H, 4-H),
.18 t (1H, 3-H, J = 9.4 Hz), 6.37 d (1H, 1-H, J =
Calculated, %: C 65.05; H 4.61; N 3.37; S 7.72.
1-[(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
sulfanyl]-β-D-glucopyranose (6c) was synthesized
according to the procedure reported in [13]. Yield 83%
1
3
0.7 Hz), 7.10–8.29 m (24H, H ). C NMR spec-
arom
1
″
6
trum (CDCl ), δ , ppm: 46.28 (C ), 63.39 (C ), 69.64
3
C
2
4
3
5
1
1
1
(
C ), 69.80 (C ), 74.25 (C ), 77.07 (C ), 83.05 (C ),
(according to the H NMR data). H NMR spectrum
3
″
4a′
2″
1
1
1
18.95 (C ), 119.62 (C ), 126.22–134.48 (C , C ),
(DMSO-d ), δ, ppm: 3.40–3.79 m (6H, 2-H, 3-H, 4-H,
arom
6
8
a′
2′
4′
47.07 (C ), 153.17 (C ), 161.28 (C ), 165.27–
5-H, 6-H), 4.49–4.72 m (1H, 1-H), 7.43–7.92 m (9H,
1
3
66.13 (PhC=O). Found, %: C 67.75; H 4.59; N 3.92;
H
). C NMR spectrum (DMSO-d ), δ , ppm: 61.10
arom
6
C
6
2 4 3 5
S 3.96. C H N O S. Calculated, %: C 67.83; H 4.55;
(C ), 70.00 (C ), 71.82 (C ), 79.08 (C ), 82.07 (C ),
4
5
36
2
10
1
4a′
N 3.82; S 4.02.
,3,4,6-Tetra-O-benzoyl-1-[(4-oxo-3-phenyl-3,4-
dihydroquinazolin-2-yl)sulfanyl]-β-D-glucopyra-
85.34 (C ), 120.10 (C ), 126.53–131.51 (C
),
arom
7
′
i′
8a′
2′
1
1
35.40 (C ), 136.23 (C ), 147.70 (C ), 155.91 (C ),
2
4
′
62.55 (C ).
2
0
nose (5c). Yield 98%, white powder, mp 120°C, [α] =
The authors thank the staff of the Laboratory of
D
+
83.2° (c = 0.2, CHCl ), R 0.55 (petroleum ether–
Physicochemical Methods (Institute of Chemistry,
Komi Research Center, Ural Branch, Russian
Academy of Sciences), E.N. Zainullina and S.P. Kuz-
3
f
–1
EtOAc, 3:2). IR spectrum, ν, cm : 1730 (C=O), 1681
(
C=C), 1557, 1377, 1271 (C–N), 1089 (C–O), 1070
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 7 2018

1
044
PESTOVA et al.
netsov for recording the NMR spectra, E.U. Ipatova
for recording the IR spectra, and S.L. Smoleva for
performing elemental analysis.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-33-00771 mol_a) using the facilities of the
Chemistry Joint Center (Institute of Chemistry, Komi
Research Center, Ural Branch, Russian Academy of
Sciences).
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