Glycosylation of 5-phenyl-1,3,4-oxadiazole-2-thiol with α-D-glucopyranosyl chloride under phase transfer conditions

Article abstract of DOI:10.1134/S1068162006050098

5-Phenyl-1,3,4-oxadiazole-2-thiol is glycosylated easily and in high yields with 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride in the presence of catalytic amounts of aliphatic and aromatic crown ethers under phase transfer (solid-organic solvent) conditions. The reaction rate and the ratio of the resulting N-and S-regioisomers depend on the catalyst nature. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S1068162006050098

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2006, Vol. 32, No. 5, pp. 468–471. © Pleiades Publishing, Inc., 2006.
Original Russian Text © V.O. Kur’yanov, S.A. Kotlar, U.S. Priskoka, T.A. Chupakhina, V.Ya. Chirva, 2006, published in Bioorganicheskaya Khimiya, 2006, Vol. 32, No. 5,
pp. 520–523.
Glycosylation of 5-Phenyl-1,3,4-oxadiazole-2-thiol
with a-D-Glucopyranosyl Chloride
under Phase Transfer Conditions
V. O. Kur’yanov , S. A. Kotlar , U. S. Priskoka , T. A. Chupakhina , and V. Ya. Chirva
a, 1
b
a
a
a
a
Vernadsky Tauric National University, pr. Vernadskogo 4, Simferopol, Autonomous Republic of Crimea, 95007 Ukraine
b
Bogatsky Physicochemical Institute, National Academy of Sciences of Ukraine, Chernomorskaya doroga 86,
Odessa, 270080 Ukraine
Abstract—5-Phenyl-1,3,4-oxadiazole-2-thiol is glycosylated easily and in high yields with 2-acetamido-3,4,6-
tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride in the presence of catalytic amounts of aliphatic and aro-
matic crown ethers under phase transfer (solid–organic solvent) conditions. The reaction rate and the ratio of
the resulting N- and S-regioisomers depend on the catalyst nature.
Key words: crown ethers, glucosaminides, N- and S-glycosylation, phase transfer catalysis, 5-phenyl-1,3,4-
oxadiazole-2-thiol
DOI: 10.1134/S1068162006050098
INTRODUCTION
identification of reaction products were achieved by
TLC (through a comparison with reference substances,
We have found [1] that the phase transfer glycosyla-
1
whose synthesis is given in [1], and H NMR spectros-
tion of thiol–thione tautomeric pair of 5-phenyl-1,3,4-
oxadiazole-2-thiol (I) with 2-acetamido-3,4,6-tri-O-
acetyl-2-deoxy-α-D-glucopyranosyl chloride (II)
results in a mixture of the corresponding N- and S-β-D-
copy). The TLC analysis was done at 0.5-h intervals up
to the complete conversion of chloride (II) (i.e., the dis-
appearance of the corresponding spot on chromato-
gram). The yields of products (III) and (IV), which
were isolated in pure state by column chromatography,
were satisfactorily reproduced in control experiments,
with deviations being no more than 5%. The glycosyla-
tion results are given in the table.
2
glucosaminides (III) and (IV) (scheme). We continued
these investigations and studied the effect of the nature
of phase transfer catalysts (some aliphatic, benzo-,
dibenzo-, and tetrabenzo-CEs) on the rate and yield of
the glycosylation reaction and also the ratio of the
resulting regioisomers (III) and (IV) under conditions
of the reaction series.
One can see that the use of CEs (V)–(XVII) in the
phase transfer–potassium carbonate–acetonitrile sys-
tem increases the rate of glycosylation reaction 1.5- to
fourfold and the total yield of target glucosaminides, by
RESULTS AND DISCUSSION
1
8–42% in comparison with the experiments when no
The glycosylation was carried out by the procedure
we had earlier suggested [1–4] in the medium of anhy-
drous acetonitrile (25°C) at the stoichiometric ratio of
I), glycosyl donor (II), and a base, anhydrous finely
ground K CO . In all the cases, 20 mol % of a phase
catalyst were used: 15-crown-5 (V), benzo-15-crown-5
VI), 18-crown-6 (VII), benzo-18-crown-6 (VIII), iso-
meric [3.3]-, [2.4]-, or [1.5]dibenzo-18-crown-6 (IX)–
XI), thia[1.5]dibenzo-18-crown-6 (XII), di-tert-butyl-
3.3]dibenzo-18-crown-6 (XIII), biphenyl-20-crown-6
XIV), [3.4]dibenzo-21-crown-7 (XV), [4.4]dibenzo-
4-crown-8 (XVI), or tetrabenzo-24-crown-8 (XVII).
Monitoring of the composition of reaction mixtures and
catalysts were used. A side product, 2-methyl-(3,4,6-
tri-O-acetyl-1,2-dideoxy-α-D-glucopyrano)-[1,2-d]-2-
oxazoline (XVIII), was identified in the reaction mix-
tures in all the experiments using a reference com-
pound, synthesized as described in [1, 5]; it is common
for similar conversions (cf., e.g., [1, 2]).
(
2
3
(
OAc
(
[
(
O
AcO
AcO
2
N
O
1
Corresponding author; phone: (0652) 23-3885;
e-mail: vladimir@tnu.crimea.ua.
2
Abbreviations: CE, crown ether.
(XVIII)
4
68

GLYCOSYLATION OF 5-PHENYL-1,3,4-OXADIAZOLE-2-THIOL
469
SH
S
N
HN
N
N
O
O
N
N
OAc
O
OAc
OAc
S
O
O
AcO
AcO
O
O
S
AcO
AcO
AcO
AcO
N
N
+
+
AcHN
NHAc
NHAc
Cl
(
I)
(II)
(III)
(IV)
Scheme of glycosylation of aglycone (I) with chloride (II).
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
(
V)
(VI)
(VII)
(VIII)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
O
O
O
O
(
IX)
(X)
(XI)
(XII)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
(
XIII)
(XIV)
(XV)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
(
XVI)
(XVII)
Crown ethers used as catalysts.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 32 No. 5 2006

4
70
KUR’YANOV et al.
Yields and ratios of glycosylation products, S- and N-β-D-
glucosaminides (IV) and (III)
S-Isomer dominates for the catalysts (XII), (XIII),
XV), and (XVI); the ratios are 1.7–2.0/1 (table). In the
(
series of hexadentate isomeric dibenzo-CEs (IX)–(XI),
the selectivity drops along with a decrease in the dis-
tance between benzene rings in macrocycle; it is small
for the related biphenyl macrocycle (XIV). Let us stress
that the substitution of only one atom within the frag-
ment Ar–X–Ar in the molecule of macrocycle, namely,
sulfur for oxygen in diphenyloxide CE (X) to get diphe-
nylsulfide CE (XII) leads to a sharp increase in the
selectivity (table).
No full conversion of (II) has been observed in the
absence of CEs even for 12 h, and the total yield of
products (IV) and (III) at the ratio of 1.3/1 was no more
than 50%.
Total yields
Time
of reaction
of 100%
(IV)/(III)
Catalyst ClogP
products
substrate product ratio
conversion, h
(
IV) and
(
III), %
(
(
(
(
(
(
(
(
(
(
(
(
(
V)
−0.99
1.35
−1.18
1.15
3.49
3.61
3.40
3.68
7.14
2.91
3.42
3.10
7.58
–
3 ± 0.5
8 ± 0.5
5 ± 0.5
5 ± 0.5
5.5 ± 0.5
5 ± 0.5
4 ± 0.5
5 ± 0.5
5 ± 0.5
5 ± 0.5
6 ± 0.5
6.5 ± 0.5
5 ± 0.5
12*
1/1
1.5/1
2.1/1
1.3/1
1.6/1
1.4/1
1.2/1
1.9/1
2/1
87
84
88
84
70
91
84
74
92
86
90
76
67
49
VI)
VII)
VIII)
IX)
X)
XI)
Note that no clearly expressed relation between the
dentateness and lipophylicity of the CEs studied from
one hand and their activity or selectivity in the phase
transfer reaction under study from the other hand is
observed. Also note that, owing to the impossibility of
isolation of pure oxazoline (XVIII) under the condition
of experiment, the effect (or the absence of effect) of
the studied phase transfer catalysts on the formation
rate and yields of (XVIII) could not revealed. At the
same time, a prolonged stirring of chloride (II), K CO ,
XII)
XIII)
XIV)
XV)
XVI)
XVII)
–
1.3/1
1.7/1
1.7/1
1.5/1
1.3/1
2
3
*
Incomplete conversion of (II).
and CE (V) taken in stoichiometric amounts does not
lead to the formation of oxazoline (VIII).
Thus, the use of CE of a certain structure (topology)
can help regulate (within some limits) the rate and
selectivity of the phase transfer reaction of the glycosy-
lation of tautomeric pair (I) with chloride (II). Obvi-
ously, the revealing the factors that control the process
selectivity found would require an expansion of the set
of the tautomeric pairs, glycosyl donors, bases, and
phase transfer catalysts.
The heterocycle (XVIII) is unstable and is decom-
posed under the conditions of column chromatography,
which does not permit its isolation and establishment of
yield.
The shortest time of complete conversion of (II)
3 h) and a high (87%) total yield of N- and S-glyco-
sides were found for the pentadentate aliphatic CE (V),
and the longest time (8 h, however, at the same total
yield of products), for its monobenzo analogue (VI).
(
EXPERIMENTAL
The other hexa-, hepta-, and octadentate CEs under
study constitute a family of catalysts for which the full
conversion of (II) occurs for 4–6.5 h; i.e., the rate
changes insignificantly. The total yields of N- and
S-glycosides (III) and (IV) are 67–92%; it is maximal
Melting points were determined on a PTP-1 device,
and optical rotation at 20–220°ë, on a Polamat-A pola-
1
rimeter at λ 546 nm. H NMR spectra were obtained on
a Varian VXR-300 (300 MHz) instrument for solutions
in DMSO-d with tetramethylsilane as internal stan-
6
(ëlogP 7.14, table) for di-tert-butyl derivative (XIII).
dard. TLC was carried out on precoated plates Sorbfil-
AFB-UV (Sorbpolymer, Russia). Substance spots were
detected by spraying the plates with 2% sulfuric acid
solution in n-butanol followed by heating at 200–
At the same time, a more lipophylic unsubstituted tet-
rabenzo-CE (XVII) is markedly ranked below (XIII) in
respect of selectivity of product formation and their
total yield at the equal time of process.
3
00°ë. Ethyl acetate–chloroform–ethanol (15 : 1 : 1)
and benzene–ethanol (10 : 1) solvent systems were
used. Kieselgel 60 (0.063–0.200 mm, Merck) was used
for the separation of substances by column chromatog-
raphy. The results of elemental analysis of the com-
pounds synthesized corresponded to the calculated val-
The selectivity of the glycosylation process was
found to be substantially different and depending on the
CE structure. The dominant formation of S-glycoside
(
IV) is always observed except for 15-membered CE
V). In this case (table), the N- and S-glycosides are
(
formed in equal quantities, but the ratio (IV)/(III) is ues. The values of lipophylicity (ClogP) of the CEs
already 1.5/1 for the benzo analogue (VI). This ration studied were calculated using the program Chem-
sharply grows for the 18-membered aliphatic macrocy- DrawUltra 9.0 trial version (http://scistore.cambridgesoft.
cle (VII) (up to 2.1/1), but decreases to 1.3/1 for benzo com/software/product.cfm?pid=4010). Oxazoline (XVIII)
analogue (VIII).
was obtained by the procedure in [5]. Chloride (II) was
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 32 No. 5 2006

GLYCOSYLATION OF 5-PHENYL-1,3,4-OXADIAZOLE-2-THIOL
471
synthesized as described in [6]. Crown ethers mp 245–246°ë (decomp.), [α] –19° (Ò 1.0, chloro-
5
46
1
(
Bogatsky Physicochemical Institute of the National form); H NMR (δ, ppm, J, Hz): 1.83 (3 H, s, NHAc),
Academy of Sciences of Ukraine, Odessa) contained 1.95, 1.99 (9 H, s, 3 OAc), 4.00, 4.16 (2 H, 2 dd, J
gem
no less than 98.0–99.0% of the main substance (accord- 12.0, H ), 4.11 (1 H, m, J 2.1, J 5.1, H5), 4.11 (1
6
a,b
5,6a
5,6b
1
ing to GLC, HPLC, TLC, and H NMR spectroscopy). H, m, H2), 4.92 (1 H, dd, J4,5 9.6, H4), 5.23 (1 H, dd, J3,4
9
.3, H3), 5.57 (1 H, d, J 10.5, H1), 7.65 (5 H, m,
Glycosylation procedure. 5-Phenyl-1,3,4-oxadiaz-
ole-2-thiol (I) (0.244 g, 1.37 mmol), finely ground
anhydrous potassium carbonate (0.189 g, 1.37 mmol),
and CE (0.274 mol) were added to a solution of
1,2
CHarom), 8.27 (1 H, d, J
9.3, NH); Lit. [1]: mp 244–
NH,2
2
45°ë (decomp.); [α] –18° (Ò 1.0, chloroform).
546
2
-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopy-
ranosyl chloride (II) [6] in anhydrous acetonitrile
60 ml). The reaction mixture was stirred at thermostat-
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(
ting (25°ë) until the complete conversion of glycosyl
donor (TLC monitoring). The solid phase was filtered
off, and the filtrate was evaporated to dryness at
reduced pressure. The products were isolated by col-
umn chromatography using a gradient from benzene to
2
3
1
5 : 1 benzene–isopropanol.
-N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl)-5-phenyl-1,3,4-oxadiazole-2(3H)-
thione (III); mp 256–259°ë (decomp.), [α] –38° (Ò
3
5
46
1
1
.0, chloroform); H NMR (δ, ppm, J, Hz): 1.67 (3 H,
s, NHAc), 1.96, 2.01 (9 H, 2 s, 3 OAc), 4.07, 4.26 (2 H,
dd, Jgem 12.0, H6 ), 4.20 (1 H, ddd, J 2.1, J 5.1,
4
2
a,b
5,6a
5,6b
H5), 4.36 (1 H, ddd, J 9.6, H2), 4.99 (1 H, dd, J 9.6,
2
,3
4,5
H4), 5.48 (1 H, dd, J 9.7, H3), 6.08 (1 H, d, J 9.6,
H1), 7.65, 7.91 (5 H, m, d, CH
8
3
3
,4
1,2
5
. Lemieux, R.U. and Driguez, H., J. Am. Chem. Soc.,
), 8.05 (1 H, d, J
arom.
NH,2
1975, vol. 97, p. 4069.
.4, NH). Lit. [1]: mp 257–260°ë (decomp.); [α]546
9° (Ò 1.0, chloroform).
–
6
. Horton, D., Methods in Carbohydrate Chemistry, vol. 6,
Whistler, R.L. and Bemiller, J.N., Eds., New York: Aca-
demic, 1972. Translated under the title Metody issledo-
vaniya uglevodov, Moscow: Mir, 1975.
2
-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosylthio)-5-phenyl-1,3,4-oxadiazole (IV);
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 32 No. 5 2006