Specific features of phase transfer catalytic glycosylation of aromatic hydroxy acids

Article abstract of DOI:10.1134/S1068162013030059

Reactions of peracetylated α-D-glucosaminyl chloride with isomeric hydroxybenzoic and 1-hydroxy-2-naphthoic acids in a solid phase transfer system of potassium carbonate-acetonitrile were studied. It was found that the nature of carboxylic acids, lipophilicity of the phase transfer catalyst, and reaction temperatures affected the reaction composition and product yields. The O-β-glycosyl esters of ortho-hydroxyaromatic acids were first found to form anomeric 1,2-cis derivatives in the presence of potassium carbonate. The structures of the synthesized compounds were confirmed by ¹H NMR spectroscopy. As was shown in vivo experiments, the analgesic activities of glycosyl esters of salicylic acid and peracetylated 2-carboxyphenylglucosaminide were comparable with that of aspirin.

Full text of DOI:10.1134/S1068162013030059

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2013, Vol. 39, No. 3, pp. 306–311. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © T.A. Chupakhina, A.A. Astrakhantseva, V.O. Kuryanov, 2013, published in Bioorganicheskaya Khimiya, 2013, Vol. 39, No. 3, pp. 346–352.
Specific Features of Phase Transfer Catalytic Glycosylation
of Aromatic Hydroxy Acids
T. A. Chupakhina, A. A. Astrakhantseva, and V. O. Kuryanov1
Vernadsky Tauric National University, pr. Akademika Vernadskogo 4, Simferopol 95007, Ukraine
Received July 3, 2012; in final form, December 6, 2012
Abstract—Reactions of peracetylated
1ꢀhydroxyꢀ2ꢀnaphthoic acids in a solid phase transfer system of potassium carbonate–acetonitrile were studꢀ
ied. It was found that the nature of carboxylic acids, lipophilicity of the phase transfer catalyst, and reaction
temperatures affected the reaction composition and product yields. The ꢀglycosyl esters of ortho
αꢀDꢀglucosaminyl chloride with isomeric hydroxybenzoic and
Oꢀβ
ꢀ
hydroxyaromatic acids were first found to form anomeric 1,2ꢀcis derivatives in the presence of potassium carꢀ
1
bonate. The structures of the synthesized compounds were confirmed by H NMR spectroscopy. As was
shown in vivo experiments, the analgesic activities of glycosyl esters of salicylic acid and peracetylated 2ꢀcarꢀ
boxyphenylglucosaminide were comparable with that of aspirin.
Keywords: analgesic activity, aromatic hydroxy acids, crown ether, glucosaminides, glycosyl ester, glycosylation,
phase transfer catalysis
DOI: 10.1134/S1068162013030059
1
INTRODUCTION
Since carbohydrate derivatives of salicylic acid and
some other nonsteroid antiꢀinflammatory products
are considered as potential prodrugs nearly lacking
negative side effects related to this group of drugs [11,
17–19], the development of approaches to the syntheꢀ
sis of aromatic hydroxy carboxylic acids varied in the
number of carbohydrate residues and the study of their
biological activity are a topical task.
Selective modifications of polyfunctional aromatic
compounds supporting the molecular design of bioꢀ
logically active compounds with carbohydrate residues
have been extensively reported [1–5]. As was shown in
some publications, aromatic compounds with hydroxy
groups differing in acidity [6, 7] and capacity to
chelating neighboring carbonyl groups [5] have differꢀ
ent potency for glycosylation reactions. It was found
that carbohydrate residues can be regioselectively
introduced at any of the hydroxyl groups by varying
reaction conditions, although in most cases the prepꢀ
aration of glycosides with a definite structure requires
preliminary protection of other nucleophilic centers
potentially capable of being involved in glycosylation
reactions [8, 9].
RESULTS AND DISCUSSION
On the continuation of the research of the PT cataꢀ
lytic synthesis of 1ꢀ
cosamine [20–23] we studied the reaction of 2ꢀacetaꢀ
midoꢀ3,4,6ꢀtriꢀ ꢀacetylꢀ2ꢀdeoxyꢀ ꢀglucosaminyl
chloride ( ) with oꢀ, mꢀ, and ꢀbenzoic and
Оꢀderivatives of Nꢀacetyl gluꢀ
О
αꢀD
V
p
1ꢀhydroxyꢀ2ꢀnaphtoic acids. The presence of two
functional groups in the molecules of glycosyl accepꢀ
tors substantially differing in the deprotonating potenꢀ
tial formed the background for the selective involveꢀ
In the synthesis of glycosyl esters of aromatic
hydroxy acids the regioselective introduction of a carꢀ
bohydrate residue at a carboxy group can be achieved
smoothly [10, 11], whereas selective glycosylation of
phenolic hydroxy groups is only possible after prelimꢀ
inary protection of the carboxylic function. Enzymatic
glycosylation of salicylic acid resulted nearly solely in
2ꢀglucosyloxybenzoic acid. In enzymatic reactions of
3ꢀ and 4ꢀhydroxybenzoic acids, both isomeric 3ꢀ and
4ꢀglycosylbenzoic acids and the corresponding glycoꢀ
syl esters were formed [12, 13].
ment of a carboxy function into the reaction with
glucosaminyl chloride ( ) (figure).
αꢀDꢀ
V
Previously, we demonstrated that the maximal conꢀ
version of the glycosyl donor ( ) to glycosyl esters can
be achieved at an equimolar ratio of chloride ( ), carꢀ
V
V
boxylic acid, and anhydrous potassium carbonate in
anhydrous acetonitrile in the presence of catalytic
amounts of 15C5 [24]. This approach resulted in the
Abbreviations: 15C5, 15ꢀcrownꢀ5; PT, phase transfer; [3.3]
DB18C6, [3.3]ꢀdibenzoꢀ18ꢀcrownꢀ6, PTC, phase transfer
catalysis.
glycosyl ester (Ia) in a yield of 69% without
side as a side product (Table 1, method ). In addition
to the target (Ia), the reaction mixture contained
and ꢀacetates (VI and (VII) (TLC control with the
Oꢀglycoꢀ
A
1
βꢀ
Corresponding author: phone: +38 (050) 397ꢀ8777; eꢀmail:
vladimirkuryanov@rambler.ru.
α
)
306

SPECIFIC FEATURES OF PHASE TRANSFER CATALYTIC GLYCOSYLATION
307
COOR'
OR
COOR'
COOR'
OR
COOR'
OR
OR
(
(
(
(
(
(
(
(
I
) R = R' = H
(
(
(
II) R = R' = H
IIa) R = H, R' =
(
(
(
III) R = R' = H
IIIa) R = H, R' =
(
(
(
(
IV) R = R' = H
IVa) R = H, R' =
IVb) R = H, R' = αG
Ia) R = H, R' =
Ib) R = H, R' =
Ic) R = R' =
Id) R = G, R' =
Ie) R = Me, R' = H
If) R = Me, R' =
β
G
G
β
G
β
G
βG
α
IIb) R = R' =
β
G
IIIb) R = R' =
β
G
β
G
IVc) R = R' = βG
α
βG
β
G
Ig) R = βG, R' = H
OAc
OAc
OAc
OAc
OAc
OAc
O
O
O
O
O
O
OAc
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcO
AcHN
AcHN
N
AcHN
AcHN
NHAc
O
Cl
OAc
(V)
(
VI)
(VII
)
α
G
βG
(
VIII
)
Me
The structures of glycosyl donor (
identified side products (VI)–(VIII).
V
), substituted benzoic acids (
I
)–(IV), (Ie
,
g), their carbohydrateꢀcontaining derivatives, and
reference compounds), which we previously observed compared with the process in the absence of the cataꢀ
lyst.
in phase transfer reactions [24]. In the absence of the
PT catalyst the total conversion of glucosaminyl chloꢀ
The use of the base excess led to the results shown
ride (
(Table 1, method
twofold reduction of the glucosaminylation time and
V
) was completed in 6 h to give 40% of product (
I)
in Table 1, method . It was found that in addition to
С
В). Thus, the use of 15C5 allowed a
bisderivative (Ic), side compounds (VI), and (VII) and
unspecified products of the carbohydrate destruction,
an increase in the target product (Ia) yield by 20% if the reaction mixture contained a compound that
Table 1. Conditions and results of phase transfer glucosaminylation of aromatic acids with
α
ꢀchloride (
V)
Chloride(
V
), Glycosyl acꢀ Crown ester,
ceptor, mmol 0.2 mmol
Reaction Reaction prodꢀ Side reaction
Method
T
,
°
C
Base, mmol
K CO , 1.10
mmol
time, h
ucts/yield, %
products
A
B
C
22
22
22
1.10
1.10
1.10
(
(
(
I), 1.10
I), 1.10
I), 1.10
15C5
0
15C5
3
6
3
(
(
(
(
(
(
(
(
(
(
Ia)/69
(
(
(
VI), (VII
VI), (VII
VI), (VII
)
)
)
2
3
K CO , 1.10
Ia 40
)/
2
3
K CO , 6.05
Ic)/8,
Id)/7
2
3
D
22
0.87
(
Ia), 0.87
15C5
K CO , 0.87
4
Ic)/14,
(
VI), (VII
)
2
3
Id)/
6
E
F
G
A
22
22
22
22
0.55
0
0
(Ig), 0.55
(Ia), 1.10
(Ia), 1.10
(II), 1.10
15C5
15C5
0
K CO , 0.55
5
2
2
Ic)/58
Ib)/41
Ib)/51
IIa)/49,
(
(
(
(
VI), (VII)
2
3
K CO , 1.10
VI), (VII
VI), (VII
VI), (VII
)
)
)
2
3
K CO , 1.10
2
3
1.10
15C5
K CO , 1.10
30
2
3
(
(
(
IIb)/15
IIIa)/20,
IIIb)/22
H
I
50
22
22
1.10
1.10
1.10
(
(
(
III), 1.10
III), 1.10
IV), 1.10
15C5
K CO , 1.10
6
7
(
(
(
VIII
)
)
2
3
[3.3]DB
18K6
15C5
KHCO , 1.10
(IIIa)/38
VIII
3
A
K CO , 1.10
12
(
IVa)/43,
VI), (VII
)
2
3
(IVc)/7
D
G
A
22
22
22
0.77
0
1.10
(
(
(
IVa), 0.77
IVa), 1.10
Ie), 1.10
15C5
0
15C5
K CO , 3.47
5
>10
3
(IVc)/69
(IVb)/27
(If)/67
(
(
(
VI), (VII
VI), (VII
VI), (VII
)
)
)
2
3
K CO , 1.10
2
3
K CO , 1.10
2 3
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 3
2013

308
CHUPAKHINA et al.
), (IIb), (IIIb), (IVc)
Table 2. 1H NMR spectral data of bisderivatives (Ic
,
d
CS (ppm), multiplicity, and SSCC (JHH, Hz)
Protons
(Id)
(Ic)
(IIb
)
(
IIIb
)
(IVc)
H1 (
J
)
5.59d (8.4),
6.17d (3.2)
5.53d (8.8),
5.92d (8.8)
5.49d (8.4),
5.83d (8.8)
5.43d (9.2),
5.86d (8.8)
5.13d (8.4),
5.90d (8.8)
1,2
H2 (
H3 (
J
J
)
)
4.18m
4.11m
4.18m
4.06m, 4.23m
4.15m
2,3
5.28dd (2H)
(9.6)
5.28dd (9.6),
5.25dd (9.6)
5.21dd (9.6),
5.23dd (9.2)
5.25dd (10.4),
5.27dd (10.4)
4.95dd (9.6),
5.27dd (10.0)
3,4
H4 (
J
)
4.97dd (9.6),
5.04dd (10.0)
4.93dd (10.0),
4.96dd (9.6)
4.93dd (9.6),
4.95dd (9.6)
4.94dd (10.0),
4.97dd (9.2)
4.81dd (8.8),
5.20dd (9.6)
4,5
H5
4.18m
4.11m
4.03m
4.15m, 4.34m
4.23m, 4.01m
1.79s, 1.80s
3.63ddd
(2.0; 5.0),
4.06m
(J
;
J
)
5,6a 5,6b
H6 (Jqem
)
4.18m
4.11m
4.03m
3.78dd,
4.23dd (12.0),
4.12m (2H)
NHAc
OAc
1.72s, 1.81s
1.76s, 1.78s
1.73s, 1.77s
1.86s, 1.88s
1.96s (9H),
1.99s, 2.01s,
2.02s
1.97s,1.98s,
2.00s, 2.02s,
2.01s (6H)
1.96s, 1.97s,
1.99s,
2.01s (9H)
1.97s, 1.99s,
2.00s (6H),
2.01s, 2.02s
1.95s, 1.96s,
1.98s, 1.99s,
2.02s, 2.04s
NH (
J
)
8.00d (8.0),
8.01d (8.4)
7.95d (8.0),
8.06d (9.6)
8.03d (9.2),
8.08d (9.2)
8.10d (9.2),
8.14d (9.2)
8.28d (8.0),
8.36d (9.2)
NH,2
CH
7.22t,
7.39d,
7.64dd,
7.89d
7.13t,
7.28d,
7.59dd,
7.73d
7.15d (2H),
7.90d (2H)
7.32dd,
7.51d,
7.52s,
7.64d
7.54d, 7.60dd,
7.66dd,
7.89d,
arom
7.95d,
8.10d
Note: The working frequency of 400 MHz; DMSOꢀ
d as a solvent.
6
could not pertain to any of the known products of the
ꢀchloride ( ) conversion under PTC conditions hydrate destruction were formed. In the absence of the
according to the TLC analysis (Figure) [22, 24, 25]. PT catalyst the process was also completed in 2 h to
Due to the presence of two doublets of anomeric proꢀ give 51% ꢀanomer (Ib) (Table 1, method ). Similar
tons at 6.17 and 5.59 ppm and 3.2 Hz and 8.4 Hz procedures with compound (Ic) failed to give the
respectively (Table 2), the structure of this compound product (Id). The use of an alternative approach, the
was unambiguously defined as bisderivative (Id) with synthesis of compound (Ic) from ꢀcarboxyphenylꢀ
the ꢀconfiguration of the glycosyl ester and ꢀconfigꢀ ꢀglucosaminide (Ig) (Table 1, method ), resulted in
uration of the glycosyl bonds (Figure). The formation the only product (Ic) with the ꢀconfiguration of the
(VI), (VII), and some unspecified products of carboꢀ
α
V
α
G
J
o
βꢀ
α
β
D
E
β
of derivative (Id) may be explained by anomerization anomeric center in both carbohydrate residues (Table 2).
of the glycosyl ester (Ia) in the process of synthesis.
The interaction of equimolar amounts of
The substantial impact of side reactions led to low
yields of compounds (Ic) and (Id) (8 and 7% respecꢀ base in anhydrous acetonitrile in the presence of 20
tively) (Table 1, method ). An insignificant increase mol % 15C5 for 30 min resulted in 49 and 15% of
in the yield of product (Ic) to 14% was achieved by the monoꢀ and bisderivatives (IIa) and (IIb), respectively
reaction of the glycosyl ester (Ia) with ꢀchloride ( (Table 1, method ). It is noteworthy that our attempt
in the presence of the equimolar amount of potassium of the regioselective preparation of the glycosyl ester
carbonate. The yield of isomer (Id) remained nearly IIa) failed. Also, we failed to synthesize the glycosyl
unchanged at 6% (Table 1). Thus, the formation of the ester of ꢀhydroxybenzoic acid (IIIa) under these conꢀ
ꢀanomer (Id) was a result of anomerization of the ditions and could only observe small destruction of
glycosyl ester (Ia) but not the pseudodisaccharide (Ic chloride ( ). Derivatives (IIIa) and (IIIb) were
(figure). To confirm this hypothesis, a mixture of glycoꢀ obtained in yields of 20 and 22% when the reaction
syl ester (Ia), potassium carbonate, and 15C5 (20 mol %) temperatures were increased to 50 . This increase
was stirred in anhydrous acetonitrile (Table 1, method also supported the formation of oxazoline (VIII) (TLC
) until anomerization of ester (Ia) was completed control, the comparison with the reference compound)
(2 h, TLC, 1H NMR spectroscopy, Table 3). The yield and some unidentified carbohydrate destruction prodꢀ
of the ꢀanomer (Ib) was 41%. In addition, acetates ucts (Table 1, method ). The regioselective synthesis
mꢀhydroxybenzoic acid (II), chloride (V), and the
С
α
V)
А
(
p
α
)
V
°С
F
α
H
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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SPECIFIC FEATURES OF PHASE TRANSFER CATALYTIC GLYCOSYLATION
Table 3. 1H NMR spectral data of glycosyl esters (Ia
309
, b, f), (IIa), (IIIa), (IVa, b)
CS (ppm), multiplicity, and SSCC (JHH, Hz)
Protons
(Ia)*
(
Ib)
(If)
(IIa
)
(
IIIa
)
(
IVa)
(IVb)
H1 (
H2 (
H3 (
H4 (
H5
J
J
J
J
)
)
)
)
5.92d
(8.4)
6.25d
(3.2)
5.86d
(8.4)
5.90d
(8.8)
5.81d (8.8)
4.19m
5.97d
(8.4)
6.37d (3.2)
1,2
2,3
3,4
4,5
4.12m
4.37ddd
(9.8)
4.11ddd
(8.8)
4.15ddd
(9.6)
4.25ddd
(8.8)
4.44ddd
(10.2)
5.27dd
(10.2)
5.35dd
(8.8)
5.23dd
(9.6)
5.23dd
(9.6)
5.22dd
(9.6)
5.29dd
(8.8)
5.40dd
(10.8)
4.97dd
(10.2)
5.06dd
(9.2)
4.95dd
(9.6)
4.96dd
(10.0)
4.94dd
(10.0)
4.99dd
(10.0)
5.10dd
(9.2)
4.12m
4.28ddd
(2.4; 4.0)
4.03m
4.12m
4.01m
4.11ddd
(2.0; 4.0)
4.31ddd
(2.0; 4.0)
(J
;
J
)
5,6a 5,6b
H6 (
J
)
4.12m
4.02dd,
4.21dd
(12.4)
4.03m
4.03dd,
4.23dd
(12.0)
4.01m
4.01dd,
4.04dd
(12.4)
4.03dd,
4.23dd
(12.0)
gem
NHAc
OAc
1.75s
1.79s
1.76s
1.74s
1.73s
1.76s
1.79s
1.96s,
2.00s
(6H)
1.97s,
2.00s,
2.01s
1.96s,
2.00s,
2.02s
1.96s,
2.01s
(6H)
1.96s,
2.00s
(2H)
2.00s,
2.01s,
2.02s
1.99s,
2.00s,
2.02s
NH (
J
)
8.09d,
(9.3)
8.20d
(8.4)
8.03d
(9.6)
8.07d,
(9.2)
8.02d
(9.6)
8.32d
(8.0)
8.34d (8.4)
NH,2
CH
6.96dd,
7.01d,
7.55dd,
7.68d
7.01d,
7.55m,
7.94d,
7.96d
7.02dd,
7.15d,
7.58dd,
7.67d
7.37s,
6.84d (2H), 7.41d,
7.56d,
7.64dd,
7.75 dd,
7.97d,
7.99d,
8.34d
arom
7.33d (2H), 7.78d (2H)
7.07dd
7.59dd,
7.69dd,
7.70d,
7.88d,
8.03d
OH
10.19s
–
10.40s
–
–
9.97s
–
10.46s
–
11.50s
–
11.56s
–
–OCH
3.83s
3
* The working frequency of 300 MHz; for the other compounds, 400 MHz.
of the glycosyl ester (IIIa) was performed in the presꢀ in dry acetonitrile in the presence of potassium carꢀ
ence of [3.3]DB18C6, a higher lypophilic macrocyclic bonate (Table 1, method
) provided 27% of ester
IVb). Its formation was proved by H NMR spectral
data (Table 4). The conversion of ester (IVa) to the
G
1
(
ester, and potassium hydrocarbonate. Under these
conditions the substrate ( ) was converted to the prodꢀ
uct (IIIa) in a yield of 38% and oxazoline (VIII) (Table
1, method ). It was found that in the reactions of
chloride ( ) with either metaꢀ or paraꢀhydroxybenzoic
acids (II) or (III) the anomerzation of the correspondꢀ
ing glycosyl esters (IIa) or (IIIa) did not take place.
V
α
ꢀanomer (IVb) was incomplete.
J
The anomerization was only observed for acids (I)
V
and (IV) with the orthoꢀlocation of functional groups,
which supported the involvement of the proton of the
phenolic hydroxy group in the anomerization process.
This was confirmed experimentally using the prelimiꢀ
nary prepared glycosyl ester of 2ꢀmethoxybenzoic acid
If), whose stirring in acetonitrile in the presence of
potassium carbonate did not result in anomerization.
No regioselective formation of glycosyl esters was
observed in the reaction of chloride (
1ꢀhydroxyꢀ2ꢀnaphtoic acid (IV), whose functional
groups are located similarly to that of salicylic acid (
(Table 1, method ). Together with glucopyranose
IVa), the bisderivative (IVc) was formed (43 and 7%
V) and
(
I)
А
The structures of the synthesized compounds (Ia
–
1
(
d
,
f
), (IIa
spectroscopy (Tables 2 and 3). A characteristic feature
of the 1H NMR spectra of glycosyl esters (Ia
), (IIa),
IIIa), and (IVa ) was the presence of a phenolic
, b)–(IVa, b) were confirmed by H NMR
respectively). The yield of the derivative (IVc) was
increased to 69% when the glycosyl ester (IVa) was
,
b
used as a glycosyl acceptor (Table 1, method
formation of a bisderivative with the ꢀconfiguration
of the glycosyl ester bond was observed under these
conditions (method ) even in the presence of the
base excess. However, keeping the glycosyl ester (IVa
D). No
(
, b
α
hydroxy group singlet at 9.97–11.50 ppm and a signifꢀ
icant downfield shift of the anomeric proton doublet
.81–6.25 ppm), which agrees well with the previꢀ
ous data [24]. Values of J1,2 in glycosyl esters (Ia)–(IVa
D
(
δ
5
)
)
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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310
CHUPAKHINA et al.
)–(IVa
Compound
Table 4. Physicochemical constants of compounds (Ia
–
d
,
f
–c)
[
α
]
[α]
546
546
Compound
Ia
mp, °C
mp, °C
(c
1.0; CHCl )
(c 1.0; CHCl )
3
3
(
)
140–142
155–157
130–134
209–211
amorph.
160–161
–50
+231
–38
°
°
°
(
IIb
IIIa
IIIb
IVa
IVb
IVc
)
192–193
172–174
193–194
148–149
amorph.
174–176
–25
–44
–33
+8
+181
–58
°
(
Ib
)
(
)
°
(
Ic
)
(
)
°
(
Id
If
IIa
)
–34
–21
–63
°
(
)
°
(
)
°
(
)
°
(
)
°
(
)
°
were observed in a range of 8.4–8.8 ppm, which is Mercuryꢀ400 (400 MHz) spectrometers with Me4Si as
common for ꢀglucosaminides. For glycosyl esters an internal standard and DMSOꢀd6 as a solvent.
Ib) and (IVb) the
Оꢀβ
(
J value of 3.2 Hz can be explained by
15ꢀCrownꢀ5 was purchased from Merck (Gerꢀ
many), [3.3]DB18C6 of at least 98% purity, from
Bogatskii Physicochemical Institute, National Acadꢀ
a 1,2ꢀcis diaxial localization of carbohydrate protons.
The absence of the resonance of the phenolic hydroxy
group and duplication of the resonances of carbohyꢀ
drate backbone protons relative to aglycon resonances
emy of Science of Ukraine, Odessa,
cosamine, from Acros (Belgium), and
zoic acids ( )–(III) and 1ꢀhydroxynaphtoic acid (IV),
Nꢀacetylgluꢀ
oꢀ, mꢀ, pꢀbenꢀ
was characteristic for bisderivatives
and
IVc). In the 1H NMR spectra of derivatives (Ic
IIb), (IIIb), and (IVc) the value of the anomeric proꢀ
ton doublet of 8.4–8.8 Hz evidenced the ꢀconfiguraꢀ
(Ic, d), (IIb), (IIIb)
I
(
),
from Reachim (Russia).
(
J
Acetonitrile was refluxed with phosphorus oxide
(V), fractioned, refluxed with freshly calcined potasꢀ
sium carbonate, distilled, and the distillate was fracꢀ
tionated using a Vigreux column. Dry K2CO3 was
obtained by calcination for 5h at 340–360°С followed
β
tion of glycosyl and glycoside bonds. Chemical shifts
of the resonances of carbohydrate backbone protons
and aglycon resonances of monoꢀ and biscarbohydrate
derivatives corresponded to those found in previous
studies [20–25].
by grinding and fractionating with 140
μ
m sieves. The
fraction with the particle size of 140
used in PT reactions.
μm and less was
With the goal of the assessing the impact of
Nꢀ
acetylglucosamine residues in the molecule of salicylic
acid on the analgesic activity we compared derivatives
2ꢀAcetamidoꢀ3,4,6ꢀtriꢀ
cosaminyl chloride ( ) and 2ꢀcarboxyphenylꢀ2ꢀacetaꢀ
midoꢀ3,4,6ꢀtriꢀ ꢀacetylꢀ2ꢀdeoxyꢀ ꢀglucopyranoꢀ
Oꢀacetylꢀ2ꢀdeoxyꢀαꢀDꢀgluꢀ
V
(
Ia) and (Iс) with aspirin as a reference in the test for
О
βꢀD
the pain threshold [26] on white outbred male rats. We
showed that the analgesic activities of these comꢀ
pounds were comparable with that of aspirin. The
results of these experiments will be published later.
side (Ig) were prepared as described in [28] and [29],
respectively.
A general procedure of glucosaminylation. A mixꢀ
ture of
acids (
α
ꢀchloride (1.10 mmol), hydroxyaromatic
(
V
)
I)–(IV) or (Ie, g) (1.10 mmol), compounds
EXPERIMENTAL
(1.10 mmol) or a base (6.02 mmol or 1.10 mmol), and
crown ether (0.22 mmol) in anhydrous acetonitrile
(12 mL) was stirred at 20–22°С or 50°С up to a full
conversion of the glycosyl donor (TLC, system A)
(Table 1). The solid phase was removed by filtration,
the residue was washed on the filter with acetonitrile
Melting points were measured on a PTP device in
open glass capillaries at a heating rate of 4°C/min.
Optical rotation was measured on a PolamatꢀA polaꢀ
rimeter at 20–22°С
.
The analysis of compositions of the reaction mixꢀ
tures, the purity of the synthesized compounds as well
as the reaction monitoring were performed by TLC on
SorbfilꢀAFVꢀUV plates (Sorbpolymer, Russia). The
chromatograms were developed in 40 : 1 chloroform–
ethanol (A), and 15 : 1 chloroform–ethanol (B) sysꢀ
tems. The compounds were detected with 5% sulfuric
acid in propanꢀ2ꢀol at 200–300°С or by UV irradiaꢀ
tion at a wavelength of 254 nm. The compounds were
isolated by column chromatography on Kieselgel 60
(0.063–0.200 mm).
(
2
×
5
mL), and the solvent was evaporated in vacuum.
The reaction products (Ia IIa ), (IIIa ),
and (IVa ) were obtained by column chromatography in
a gradient manner using the following systems: 100 : 1
toluene–propanꢀ2ꢀol 30 : 1 toluene–propanꢀ2ꢀol
,
c–d,
f
),
(
,
b
, b
,
c
→
→
100 : 1 chloroform–propanꢀ2ꢀol
roform–propanꢀ2ꢀol.
1 → and 25 : 1 chloꢀ
A general procedure of anomerizarion. A mixture of
glycosyl ester (Ia) or IVa (0.55 mmol), anhydrous
potassium carbonate (0.55 mmol), 15C5 (0.22 mmol)
or without it in anhydrous acetonitrile (12 mL) was
(
)
1H NMR spectra (ppm,
δ
scale,
J, Hz) were stirred at 20–22°С or 50°C up to a full conversion of
recorded on Varian VXRꢀ300 (300 MHz) and Varian the starting ester (TLC, system A). The reaction prodꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 3
2013

SPECIFIC FEATURES OF PHASE TRANSFER CATALYTIC GLYCOSYLATION
311
14. Strachan, R.G., Ruyle, W.V., Shen, T.Y., and Hirꢀ
schmann, R., J. Org. Chem., 1966, vol. 31, pp. 507–509.
15. Hennig, J., Malamy, J., Grynkiewicz, G., Indulski, J.,
ucts (Ib) and (IVb) were isolated as described above for
glucosaminylation reactions (Table 1).
A general procedure of glycosylation. A mixture of
and Klessig, D.F., Plant J., 1993, vol. 4, pp. 593–600.
glycosyl ester (Ia ꢀglucopyranoside
)
,
(
IVa), or
β
ꢀ
D
(Ig)
16. Xue, L., Sun, G., and Gao, J., Huaxuefongbao = Chemꢀ
istry, 1994, no. 1, pp. 30–32. (Ros. Chem. Zh., 1994,
24E18).
(0.87 mmol), ꢀchloride (V) (0.87 mmol), anhydrous
α
potassium carbonate (0.87 mmol), and 15C5 (0.17 mmol)
in anhydrous acetonitrile (10 mL) was stirred up to a
full conversion of the glycosyl donor (TLC, system B)
(Table 1). The reaction products (Ic, d) and (IVc) were
isolated as described above for glucosaminylation
reactions (Table 1).
17. Hanessian, S., Mascitti, V., Lu, P.ꢀP., and Ishida, H.,
Synthesis, 2002, no. 14, pp. 1959–1968.
18. Samczewska, G. and Borowiecka, J., Acta Poloniae
Pharm. Drug Res., 1999, vol. 56, pp. 361–366.
19. Grynkiewicz, G., Szeja, W., and Boryski, J., Acta Poloꢀ
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Kotlyar, S.A., Kamalov, G.L., and Chirva, V.Ya., Russ.
J. Bioorg. Chem., 2001, vol. 27, pp. 385–389.
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Translated by E. Shirokova
Z. Naturforsc., 2004, vol. 59c, pp. 684–692.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 3
2013