Synthesis of heteroaromatic N-β-glycosides of N-acetylglucosamine under phase transfer conditions: II. Indolin-2-one glycosaminides

Article abstract of DOI:10.1134/S1068162008060137

Regioselective N-β-glucosamination of various unsubstituted or C4-, C5-, or C6-monosubstituted indolin-2-ones under phase transfer conditions was studied. The regioselectivity was unambiguously proved by ¹H NMR spectroscopy and X-ray analysis. The presence of substituent at C7 of the aromatic ring leads to the formation of either a mixture of isomeric N-β-and O-β-D-glucosaminides, or only oxazoline and/or 2-acetamidoglycal irrespective of the reaction conditions.

Full text of DOI:10.1134/S1068162008060137

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2008, Vol. 34, No. 6, pp. 730–738. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.O. Kur’yanov, T.A. Chupakhina, O.V. Shishkin, S.V. Shishkina, V.Ya. Chirva, 2008, published in Bioorganicheskaya Khimiya, 2008, Vol. 34, No. 6,
pp. 813–821.
Synthesis of Heteroaromatic N-b-Glycosides
of N-Acetylglucosamine under Phase Transfer Conditions: II.1
Indolin-2-one Glycosaminides
V. O. Kur’yanova,2, T. A. Chupakhinaa, O. V. Shishkinb, S. V. Shishkinab, and V. Ya. Chirvaa
a Vernadsky Tauric National University, pr. Akademika Vernadskogo 4, Simferopol, 95007 Ukraine
b Institute for Scintillation Materials, Institute for Single Crystals, National Academy of Sciences of Ukraine,
Kharkov, Ukraine
Received November 16, 2007; in final form, December 19, 2007
Abstract—Regioselective N-β-glucosamination of various unsubstituted or C4-, C5-, or C6-monosubstituted
indolin-2-ones under phase transfer conditions was studied. The regioselectivity was unambiguously proved by
1H NMR spectroscopy and X-ray analysis. The presence of substituent at C7 of the aromatic ring leads to the
formation of either a mixture of isomeric N-β- and O-β-D-glucosaminides, or only oxazoline and/or 2-aceta-
midoglycal irrespective of the reaction conditions.
Key words: amido-imidole tautomers, 15-crown-5, β-elimination, N-β-glucosaminides, phase transfer cataly-
sis, regioselectivity, X-ray analysis
DOI: 10.1134/S1068162008060137
INTRODUCTION
of these studies, we investigated the phase transfer
reaction of α-chloride (I) with the close structural
analogues of these ketals, indolin-2-ones (II)–(XIX),
which are also amido-imidole tautomers [4], and
examined the effect of the structure of compounds
(II)–(XIX) and the glycosylation conditions on the
yields and the composition of the products of the reac-
The reaction of 2-acetamido-3,4,6-tri-é-acetyl-2-
deoxy-α-D-glucosaminyl chloride (I) with benzo-
xazolone-2, 5-methylbenzoxazolone-2, and benzthia-
zolone-2, we had previously investigated under vari-
ous phase transfer conditions, showed these amido-
imidole tautomers to regioselectively form the corre-
sponding N-β-glucosaminides [1–3]3. In continuation tion under study.
( )n
( )n
R1
R1
O
O
OAc
R2
R3
O
R2
R3
O
O
HO
O
AcO
AcO
N
N
H
AcHN
Cl
R1
R4
R4
R1 R2 R3 R4
(I)
(II)–(XIX)
n
R2 R3 R4
n
(II)
1
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
(XI)
2
2
2
2
2
2
2
2
2
H
H
Cl
H
H
H
H
(III)
(IV)
(V)
H
(XII)
H
H
Me
Me
Me
Me
MeO
Br
NO2
Cl
H
H
(XIII)
(XIV)
(XV)
Me
H
H
Me
H
(VI)
(VII)
(VIII)
(IX)
(X)
H
Me Me
(XVI)
(XVII)
Cl
H
H
H
H
Cl
Cl
Cl
H
Cl (XVIII)
H
H
Cl Cl
H
(XIX)
Br
H
Me
1
2
3
For communication I see [1].
Corresponding author; phone:+38 (0652) 32-3885; e-mail: vladimir@tnu.crimea.ua.
Abbreviations: TEBAC, benzyltriethylammonium chloride.
730

SYNTHESIS OF HETEROAROMATIC N-β-GLYCOSIDES
731
RESULTS AND DISCUSSION
[5–14] or described in literature [13, 14]. The ratios of
the substrate, reagents, the base, and the crown ether are
given in the Note to Table 1.
Stoichiometric glycosylation of ketals (II)–(XIX)
with α-chloride (I) (Schemes 1 and 2) was carried out
under various phase transfer conditions used previously
( )n
OAc
OAc
O
O
OAc
R1
O
O
O
AcO
AcO
AcO
AcO
+ (II)–(VIII), (X), (XI)
+
O
AcO
AcO
N
R2
N
AcHN
O
Cl
NHAc
R3
(I)
(XX)–(XXVIII)
(XXIX)
n
R1
R2
R3
(XX)
1
2
2
2
2
2
2
2
2
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
Cl
(XXI)
H
(XXII)
(XXIII)
(XXIV)
(XXV)
(XXVI)
(XXVII)
(XXVIII)
Me
MeO
Br
NO2
Cl
H
H
Scheme 1. The synthetic scheme for N-β-glucosaminides (XX)–(XXVIII).
R2
R1
R3
R4
OAc
O
O
OAc
R1
O
O
O
O
AcO
AcO
OAc
O
+ (IX), (XVI)–(XIX)
+
O
AcO
AcO
N
N
R2
AcHN
Cl
O
AcO
AcO
NHAc
(I)
R3
R4
NHAc
(XXXV)–(XXXIX)
R4
AcO
(XXX)–(XXXIV)
AcO
AcO
O
R1
R2
R3
(XXX), (XXXV)
H
Cl
H
H
H
H
H
H
H
Cl
H
Cl
Cl
Cl
Cl
Me
(XXXI), (XXXVI)
H
AcHN
(XL)
(XXXII), (XXXVII)
(XXXIII), (XXXVIII)
(XXXIV), (XXXIX)
Cl
H
Br
Scheme 2. The synthetic scheme for the mixture of N-β- and O-β-glucosaminides (XXX)–(XXXIV) and (XXXV)–(XXXIX);
structure of 2-acetamidoglycal (XL).
The experimental data obtained (Table 1) allowed us data [4], just the oxo form of indolin-2-ones is the pre-
to maintain reasonably that the direction of the reac- vailing form usually participating in the chemical trans-
tion, the yield, and the composition of the product mix- formations. Thus, it should be logical to expect that the
ture were dictated by the position and the nature of the formation of N-glycosides will also be the main direc-
substituents in the carbocyclic ring of indolin-2-ones tion of the reaction under discussion.
(II)–(XIX).
In was found that the absence of the substituents in
As in the cases described earlier in [1–3, 11, 12], the the aromatic ring (compounds (II) and (III)) or the
tautomerism of the starting heterocycle (see figure) presence of the substituent only at C5 of the indoline
made possible the formation of the two products, O-β- system resulted in the formation of presumably N-β-
and/or N-β-glucosaminides. According to the literature glucosaminides (XX)–(XXVI) (Scheme 1). As in the
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

732
KUR’YANOV et al.
Table 1. Reaction time, yields, and the products of glycosylation of (II)–(XIX)
Glycosyl acceptor
(reagent)
Reaction
Reaction
time**, h
Yield of the glycoside or the
mixture of glycosides, %
Reaction products
(XX), (XXIX)
(XXI), (XXIX)
(XXIX)
(XXII), (XXIX)
–
conditions*
(II)
(III)
(III)
(IV)
(IV)
(IV)
(IV)
(IV)
(IV)
(IV)
(V)
(VI)
(VII)
(VII)
(VIII)
(IX)
(IX)
(IX)
A
A
G
A
B
C
D
E
F
G
A
A
A
B
A
A
B
C
D
A
A
A
B
F
5
5
20
23
5
–
5
16
>8
5
–
7
(XXII), (XXIX)
(XXII), (XXIX)
(XXII), (XXIX)
(XXII), (XXIX)
(XXIX)
(XXIII), (XXIX)
(XXIV), (XXIX)
(XXV), (XXIX)
3
7
9
11
7
14
5
–
3
6
4
29
6
40
9
40
(XXV), (XXIX)
4
26
(XXVI), (XXIX)
(XXX), (XXXV)
(XXX), (XXXV)
(XXX), (XXXV)
(XXX), (XXXV)
(XXVII), (XXIX)
(XXVIII), (XXIX)
(XXIX), (XL)
(XXIX)
(XXIX), (XL)
(XXIX)
(XXIX), (XL)
3
76***
63***
84***
76***
18
7
2.5
0.5
10
10
4
(IX)
(X)
(XI)
12
(XII)
(XII)
(XII)
(XII)
(XIII)
(XIII)
(XIII)
(XIII)
(XIV)
(XV)
(XVI)
(XVII)
(XVIII)
(XVIII)
(XVIII)
(XVIII)
(XVIII)
(XVIII)
(XVIII)
(XIX)
–
10
7
–
–
G
A
B
F
5
–
4
–
11
8
–
(XXIX)
(XXIX), (XL)
(XXIX)
(XXIX), (XL)
–
G
A
A
A
A
A
B
C
D
E
F
3
–
4.5
5
–
–
(XXIX), (XL)
2
68***
64***
63***
52***
45***
30***
43***
64***
24***
16***
(XXXI), (XXXVI)
(XXXII), (XXXVII)
(XXXIII), (XXXVIII), (XXIX)
(XXXIII), (XXXVIII), (XXIX)
(XXXIII), (XXXVIII), (XXIX)
(XXXIII), (XXXVIII), (XXIX)
(XXXIII), (XXXVIII), (XXIX)
(XXXIII), (XXXVIII), (XXIX)
(XXXIII), (XXXVIII), (XXIX)
(XXXIV), (XXXIX), (XXIX)
2
2
3
1
0.75
4
2
G
A
5
6.5
Notes: *The ratio of chloride (I)–acceptor–K CO –crown ether; temperature, t; and the solvent are given. A, 1 : 1 : 4.5 : 0.2, 20–22°C,
2
3
CH CN; B, 1 : 1 : 4.5, 20–22°C, CH CN; C, 1 : 1 : 4.5 : 0.2, 50°C, CH CN; D, 1 : 1 : 4.5 : 0.2, 80°C, CH CN; E, 1 : 1 : 1,
3
3
3
2
3
3
3
CH CN; F, 1 : 1 : 4.5 : 0.2, 42°C, CH Cl ; G, chloride (I)–reagent–saturated aqueous K CO –TEBAC, CHCl .
2
2
3
** Until the complete conversion of substrate (I).
*** The total yield of N-β- and O-β-glucosaminides.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

SYNTHESIS OF HETEROAROMATIC N-β-GLYCOSIDES
733
C 25
C l1
C 9
O 10
C 8
C 24
O 11
C 23
C 5
C 7
C 10
O 1
C 11
O 3
C 6
O 9
C 21
C 1
C 14
N 1
C 12
C 13
O 2
O 5
C 4
C 22
O 8
C 2
C 15
O 4
C 3
O 6
C 16
C 17
N 2
C 19
O 7
C 18
C 20
The molecular structure of N-β-glycoside (XXVI).
case of glucosaminylation of benzazoles [1], the forma- protons H3 (with δ = 5.10 and 5.32 ppm and coupling
tion of significant amount of oxazoline (XXIX) was constants = 9.9 and 9.6 Hz[a1], respectively) and H4
noted (TLC, comparison with the notorious reference). (with δ = 4.94 and 5.19 ppm and coupling constants =
9.6 and 9.9 Hz[a2]). The signals of protons H2, H5, H6,
The structures of the resulting glucosaminides
OAc and NAc moieties, aliphatic, and aromatic protons
were also doubled.
(XX)–(XXVI) were established by 1H NMR spectros-
copy (Table 2).
The results obtained throw doubt on the rightness of
The chemical shifts of the signals of backbone pro-
the previous conclusion concerning the structure of
tons (δ 5.58–5.63 ppm), their interposition, and also
(XX)–(XXVIII) as N-β-glycosides. Thus, we carried
the values of coupling constants for the anomeric pro-
out the X-ray study of the crystals of glycoside (XXVI)
ton (8.8–10.4 Hz, Table 2) are close to those previously
(Tables 3–5, figure) that unambiguously proved its
obtained for N-β-glucosaminides [1–3, 11]. This fact
structure as N-β-glucosaminide. The tetrahydropyran
allowed us to refer compounds (XX)–(XXVI) synthe-
ring was in the chair conformation (the folding param-
sized to N-β-derivatives.
eters were: S = 1.20, Θ = 3.5°, Ψ = 9.9° [15]). All sub-
The study of the effect of the substituent localization
in the aromatic ring of indolin-2-ones on the reaction
route using the reaction of chloride (I) with four iso-
meric monochloro derivatives (VIII)–(XI) demon-
strated that in the case of glycosylation of 4-, 5- and 6-
chloroindolin-2-ones (X), (VIII), and (XI) the process
occurred in the same way as for glycosyl acceptors
(II)–(VII). This was also proved by 1H NMR spectros-
copy data for glycosides (XXVI)–(XXVIII) (Table 2).
stituents in the ring are in the equatorial position. The
pentamerous pyrroline ring was in the envelope confor-
mation, whereas the m-dioxane ring spiro-joint with it
was in the chair conformation (the folding parameters
were: S = 1.12, Θ = 1.9°, Ψ = 16.9°).
1
The comparison of H NMR spectra of glycosides
(XX)–(XXV), (XXVII), and (XXVIII) with that of
(XXVI) with the structure established showed that they
are N-β-glucosaminides as was expected.
As opposed to three isomers under study, 7-chlor-
oindolin-2-one (IX) was found to react smoothly with
chloride (I) without generation of side products (Table
1). However, the chromatographically homogenous
(TLC) product isolated by column chromatography
appeared to be the mixture of two compounds, presum-
Thus, glucosaminylation of indolin-2-ones without
substituents in the aromatic ring or bearing the substit-
uent only at C4, C5 or C6 of the aromatic ring resulted
in the regioselective formation of the corresponding
N-β-glycosides (XX)–(XXVIII) under the phase trans-
fer conditions. Therefore, the second product generated
upon glycosylation of (IX) and (XVI)–(XVIII) is the
é-β-isomer.
1
ably glycosides (XXX) and (XXXV), according to H
NMR spectroscopy data. This was proved by doubling
of the signals of all protons in the 1H NMR spectrum.
In particular, the doublet of the anomeric proton with
δ = 5.70 ppm (J1,2 = 10.2 Hz) conformed to N-β-glu-
cosaminides [1–3] in the values of the chemical shift
and the coupling constant, whereas the doublet with a
It should be noted that among approaches (A–G)
used, the best results for glycosylation of (II)–(VIII),
(X), and (XI) were obtained by method Ä.
During the further investigations, the essential influ-
chemical shift equal to 6.15 ppm (J1,2 = 9.6 Hz) evi- ence of the nature of the substituent at C7 of indolin-2-
dently refered to the isomeric é-β-glucosaminide. The ones on the direction of the reaction with chloride (I)
spectrum contained the doubled signals of backbone was revealed. Thus, 7-methylindolin-2-one (XII) did
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

734
KUR’YANOV et al.
Table 2. Chemical shifts (ppm), multiplicity of signals, and coupling constant, Hz (in parentheses) in the 1H NMR spectra
of (XX)–(XXVIII)
(XX)*
(XXI)
(XXII)*
(XXVI)
(XXIII) (XXIV)*
(XXV)
(XXVII) (XXVIII)
H1 (J1,2)
H2 (J2,3)
H3 (J3,4)
H4 (J4,5)
5.58d
5.63d
5.59d
(9.6)
5.58d
5.59d
(10.0)
5.58d
(9.9)
5.63d
5.61d
(10.0)
5.61d
(8.8)
(9.9)
(10.4)
4.54m
(10.0)
4.53m
(9.6)
4.59m
4.53m
4.52m
4.53m
4.57m
4.55ddd
(9.6)
4.53m
5.31dd
(9.6)
5.32dd
(9.6)
5.30dd
(9.2)
5.30dd
(9.6)
5.31dd
(9.6)
5.30dd
(9.6)
5.33dd
(10.0)
5.33dd
(10.0)
5.32br. s
5.17dd
(10.8)
5.18dd
(9.6)
5.16dd
(9.0)
5.19dd
(8.4)
5.16dd
(9.6)
5.19dd
(9.3)
5.25dd
(9.6)
5.22 (9.2) 5.32br. s
H5
(J5,6a; J5,6b
4.11m
4.13m
4.11m
4.12m
4.09ddd
(2.0; 5.0)
4.11m
4.16m
4.15m
4.17m
)
H6a,b (Jgem
)
4.11m
1.61s
4.13m
1.60s
4.11m
1.60s
4.12m
1.60s
4.13m
1.60s
4.11m
1.60s
4.16m
1.60s
4.15m
1.64s
4.17m
1.63s
NAc
OAc
1.92s,
2.01s,
2.03s
1.91s,
2.01s,
2.03s
1.91s,
2.01s,
2.03s
1.91s,
2.01s,
2.04s
1.91s,
2.01s,
2.03s
1.92s,
2.01s,
2.04s
1.92s,
2.01s,
2.05s
1.93s,
2.03s,
2.05s
1.95s,
2.03s,
2.07s
NH (JNH,2
)
7.98d (9.6) 7.98d (9.2) 7.97d (9.0) 8.00d (9.2) 7.95d (9.6) 8.00d (9.3) 8.07d (9.6) 8.03d (9.2) 8.03d (9.6)
–(CH2)3–
4.48m,
4.34m
1.65m,
2.17m,
3.91m,
4.71m
1.65d,
2.15m,
3.91m,
4.71m
1.65d,
2.17m,
3.94m,
4.68m
1.65m,
2.17m,
3.91m,
4.72m
1.67m,
2.18m,
3.93m,
4.68m
1.70m,
2.26m,
3.98m,
4.69m
1.66m,
2.24m,
3.96m,
4.76m
1.69m,
2.18m,
3.93m,
4.71m
R'
–
–
2.27s
–
3.74s
–
–
–
–
CHarom
7.11m,
7.35d,
7.43m
7.08m,
7.36m
7.17m,
7.22m
7.37br. s, 6.92m,
7.44br. s 7.27m
7.39d,
7.48d,
7.57d
7.71d,
8.08s,
8.32d
7.11d,
7.39m
7.16d,
7.38d,
7.48s
Note: * The working frequency is 300 MHz.
not form the corresponding glucosaminide (Table 1).
Indolin-2-ones monosubstituted at C7 resulted
The reaction mixture was found to contain oxazoline either in the mixture of N-β- and é-β-glucosaminides
(XXIX) and 2-acetamidoglycal (XL) (TLC, the com- [in the case of 7-chloro derivative (IX)], or could not be
1
parison with the reference compound [16], H NMR glycosylated at all [7-methylindolin-2-one (XII)]. In
spectroscopy data).
this case, substrate (I) was converted either to oxazo-
line (XXIX), or to the mixture of oxazoline (XXIX)
and 2-acetamido glycal (XL).
The route of the reaction of glycosyl donor (I) with
monosubstituted derivatives (IV)–(XII) was dictated
by the two structural specialties of glycosyl acceptors,
namely, the localization and the nature of the substitu-
ents in the indoline ring.
The analysis of the nature of substituents at C5 in
indolin-2-ones (II)–(VIII) demonstrated the yield of
the glycoside to be the maximum (40%) in the case of
Thus, unsubstituted indolin-2-ones (II) and (III) 5-nitro derivative (VII). The comparison of the yields
and monosubstituted derivatives bearing the substituent of glycosides (XXII)–(XXVI) allowed us to claim that
at C4, C5 or C6, (IV)–(VIII), (X), and (XI), were trans- the more extend the electron donor properties of the
formed to N-β-glucosaminides.
substituents at N5 appeared, the lower were the yields
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

SYNTHESIS OF HETEROAROMATIC N-β-GLYCOSIDES
735
Table 3. Coordinates (×104, Å) and equivalent isotropic ca-
loric parameters (U × 103, Å2) of atoms in the structure of
(XXVI)*
of the target glycosides [from 26 and 29% for 5-chloro
and 5-bromo derivatives (VIII) and (VI) to 16 and 6%
for 5-methyl- and 5-methoxyindolin-2-ones (IV) and
(V), respectively]. In the case of 4- and 6-chloro deriv-
atives (X) and (XI), the yields were low, 18 and 12%,
respectively.
It was found that the reaction of chloride (I) with
dichloro-substituted derivatives (XVI)–(XVIII) pro-
ceeded similarly to glycosylation of 7-chloro derivative
(IX) (Table 1). According to the 1H NMR spectroscopy
data, the mixture of the two glycosides, (XXXI) and
(XXXVI), (XXXII) and (XXXVII), or (XXXIII) and
(XXXVIII), was generated in all three cases. The val-
ues of the chemical shifts, integral intensities, and cou-
pling constants of the protons are close to those
obtained for the products of glycosylation of 7-chlor-
oindolin-2-one (IX). The formation of the only side
product, oxazoline (XXIX), should be noted.
The comparison of glycosylation conditions carried
out using (XVIII) as an example showed that the for-
mation of the mixture of glycosides (XXXIII) and
(XXXVIII) was observed in all cases irrespective of
the nature of the two phase system, temperature and the
presence of the catalyst. Thus, in the case of 7-chloro-
substituted indolin-2-ones the composition of the reac-
tion products was dictated by the presence of the chlo-
rine atom at C7 of the indoline backbone. The position
of the second chlorine atom did non play the important
role in the specification of the glycosylation route.
x
y
z
Ueq
Cl1
N1
N2
O1
O2
O3
O4
O5
O6
O7
O8
O9
O10
O11
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
5791(1)
10500(2)
10629(2)
10282(2)
12641(2)
11218(1)
10925(1)
8741(2)
2961(1)
588(1)
1069(1)
446(1)
36(1)?
20(1)
22(1)
21(1)
29(1)
21(1)
21(1)
30(1)
21(1)
31(1)
20(1)
36(1)
23(1)
48(1)
19(1)
18(1)
18(1)
19(1)
19(1)
18(1)
23(1)
24(1)
21(1)
20(1)
16(1)
17(1)
20(1)
26(1)
28(1)
27(1)
21(1)
30(1)
21(1)
31(1)
24(1)
32(1)
23(1)
26(1)
32(1)
–1383(1)
–277(1)
999(1)
1132(1)
–563(1)
677(1)
3007(1)
1726(1)
–940(1)
–3110(1)
–3964(1)
–2971(1)
–3685(1)
–671(1)
–2208(1)
–371(2)
–1292(2)
–2256(2)
–2107(2)
–1148(2)
1032(2)
744(2)
1053(1)
1862(1)
1646(1)
318(1)
9676(1)
11540(2)
10443(1)
8457(2)
544(1)
–1063(1)
–1076(1)
–1777(1)
–2273(1)
104(1)
8958(2)
8639(2)
10750(2)
10115(2)
10392(2)
9975(2)
460(1)
43(1)
–678(1)
–961(1)
564(1)
10637(2)
9264(2)
We failed to separate the mixture of isomeric glyco-
sides either by column chromatography, or by HPLC.
It was found that the reaction of chloride (I) with
dimethylindolin-2-ones (XIII)–(XV) did not give the
glycosylation products, resulting in oxazoline (XXIX)
and 2-acetamido glycal (XL) (TLC, the comparison
with reference compounds).
8067(2)
306(1)
6993(2)
1347(2)
2192(2)
2480(2)
1883(2)
2001(2)
1160(2)
3197(2)
2930(2)
1843(2)
–1110(2)
–1025(2)
–3937(2)
–4789(2)
–3707(2)
–4514(2)
–902(2)
–1379(2)
–984(2)
483(1)
7135(2)
892(1)
8341(2)
1151(1)
981(1)
However, interaction of α-D-glucosaminyl chloride C11
9398(2)
(I) with 5-bromo-7-methyl-3,3-trimethylenedioxyin-
C12
10802(2)
11482(2)
12560(2)
12730(2)
12233(2)
9913(2)
1179(1)
739(1)
dolin-2-one (XIX) (Scheme 2) allowed us to establish
C13
that this glycosyl acceptor resulted in the mixture of
two products, (XXXIV) and (XXXIX), according to
the 1H NMR spectroscopy data (Table 1). Obviously, in
the case of the methyl group at N7 of glycosyl accep-
tors (XIII)–(XV) and (XIX), the route of the reaction
was dictated by the nature of the substituent at C5.
Thus, the presence of the methyl group displaying the
+I-effect (the positive induction effect) resulted in the
two side processes, intramolecular substitution yielding
C14
C15
C16
C17
C18
C19
1260(1)
1989(1)
2123(1)
1677(1)
2319(1)
535(1)
10678(3)
10368(2)
9479(3)
oxazoline (XXIX) or elimination of hydrogen chloride C20
750(2)
because of the attack of the base (the deprotonated form
C21
9577(2)
–1240(1)
–1656(1)
–1682(1)
–2104(1)
–2232(1)
of glycosyl acceptors) for the hydrogen atom at C2 in
C22
10211(3)
10315(2)
8220(2)
glycosyl donor (I) and the formation of unsaturated
derivative (XL). Introduction of the electronegative
C23
C24
C25
4
bromine atom (–I > +M) at N5 of the indoline ring
resulted in glycosylation to isomeric é-β- and N-β-glu-
6888(3)
4
The negative induction effect exceeds the positive mesomeric
effect.
Note: * The error for determination of coordinates and caloric
parameters is given in parentheses.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

736
KUR’YANOV et al.
1
Table 4. The bond lengths (Å) in the structure of (XXVI)*
mat-A polarimeter (λ = 546 nm) at 20–22°ë. The H
NMR spectra (δ, ppm; coupling constant, Hz) were
measured on Varian VXR-300 (300 IHz) and Varian
Mercury-400 (400 IHz) spectrometers in DMSO-d6
using Me4Si as the internal standard.
The crystals of (XXVI) are rhombic, C25H29N2O11ël,
at –173°ë a = 10.255(1), b = 12.976(1), c = 19.985(1) Å,
V = 2659.2(3) Å3, Mr = 568.95, Z = 4, the spatial group
P212121, dcalc = 1.421 g/cm3, µ(MoKα) = 0.208 mm–1,
F(000) = 1192. The parameters of the elementary cell
and the intensity of 14227 reflections (6090 indepen-
dent, Rint = 0.039) were measured on an Xcalibur-3 dif-
fractometer (MoKα, NND-detector, graphite mono-
chromator, ω-scanning, 2θmax = 55°).
The structure was decoded by the direct method
using the SHELXTL software complex [17]. The posi-
tions of hydrogen atoms were revealed from the differ-
ence synthesis of electron density and were isotropi-
cally defined. The structure was specified from the
squares of the structural amplitudes by the full matrix
method of minimum squares in the anisotropic approx-
imation for nonhydrogen atoms up to wR2 = 0.078 from
6073 reflections (R1 = 0.043 from 5017 reflections with
F > 4σ(F), S = 1.029).
Cl1–C9
N1–C6
1.737(2)
1.412(3)
1.361(3)
1.422(2)
1.214(3)
1.458(3)
1.447(3)
1.358(3)
1.203(3)
1.442(2)
1.358(3)
1.207(3)
1.529(3)
1.527(3)
1.382(3)
1.397(3)
1.392(3)
1.501(3)
1.507(3)
1.508(3)
1.487(3)
N1–C13
N1–C1
1.381(3)
1.442(3)
1.448(3)
1.429(2)
1.397(2)
1.416(2)
1.224(3)
1.439(2)
1.352(3)
1.195(3)
1.436(3)
1.535(3)
1.515(3)
1.513(3)
1.390(3)
1.376(3)
1.374(3)
1.565(3)
1.524(4)
1.496(3)
1.481(4)
N2–C17
O1–C1
N2–C2
O1–C5
O2–C13
O3–C14
O4–C16
O6–C19
O7–C19
O8–C4
O3–C12
O4–C12
O5–C17
O6–C3
O8–C21
O9–C21
O10–C23
C1–C2
O10–C24
O11–C24
C2–C3
C3–C4
C4–C5
C5–C23
C6–C11
C8–C9
TLC was carried out on Sorbfil-AFV-UV (Sorb-
polimer, Russia) plates. The spots were visualized by
treating with 2% sulfuric acid in 1-butanol followed by
heating to 200–300°ë. Benzene–ethanol, 10 : 1, was
used as the developing system. The compounds were
separated by column chromatography on Silica gel 60
(0.063–0.200 mm, Merck, Germany), elution with ben-
C6–C7
C7–C8
C9–C10
C11–C12
C14–C15
C17–C18
C21–C22
C10–C11
C12–C13
C15–C16
C19–C20
C24–C25
zene
15 : 1 benzene–2-propanol. The elemental
analysis data correspond to the values calculated.
Indolin-2-ones (II)–(XIX) were synthesized as
described in [18]. The reference oxazoline (XXIX) was
synthesized according to Lemieux [16]. α-D-Glu-
cosaminyl chloride was obtained as described in [19].
Triethylbenzylammonium chloride (99%, Aldrich) and
15-crown-5 (98%, Merck) were also used in this study.
Note: * The error for determination of bond length is given in
parentheses.
Acetonitrile was refluxed over phosphorus(V)
oxide, rectified, refluxed over freshly calcined potash,
and distilled using a Vigreux column. Dichloromethane
was distilled from phosphorus(V) oxide, refluxed over
freshly calcined potassium carbonate to remove acidic
impurities, and distilled. Anhydrous K2CO3 was pre-
pared by calcination for 5 h at 340–360°ë.
cosaminides along with intramolecular substitution.
Thus, the electron characteristics of the substituent at of
C5 indolin-2-ones played a crucial role in the route of
the process in the case of 5,7-disubstituted glycosyl
acceptors.
Glycosides (XX)–(XXVIII) were synthesized by
method Ä. The target compounds were isolated by col-
umn chromatography.
Thus, we have for the first time carried out glu-
cosaminylation of indolin-2-one derivatives (II)–
(XIX), clarified the factors dictating the route of glyco-
sylation, and demonstrated the composition of the reac-
1-N-(2-Acetamido-3,4,6-tri-é-acetyl-2-deoxy-b-D-
tion products to primarily depend on the presence, the glucopyranosyl)-2-oxo-3,3-ethylenedioxyindoline (XX)
nature, and the localization of substituents in the aro- was obtained by glycosylation of 2-oxo-3,3-ethylene-
matic carbocyclic ring of indolin-2-ones.
dioxyindoline (II) (0.20 g, 1.37 mmol) with chloride (I)
(0.50 g, 1.37 mmol); yield 0.14 g (20%); mp 155°ë
(decomp.); [α]546 –29° (Ò 1.0; ëçël3).
EXPERIMENTAL
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glu-
Melting points were taken on a PTP-1 instrument. copyranosyl)-3,3-trimethylenedioxyindolin-2-one (XXI)
The values of optical rotation were measured on a Pola- was obtained by the reaction of chloride (I) (0.50 g,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

SYNTHESIS OF HETEROAROMATIC N-β-GLYCOSIDES
Table 5. The valent angles in the structure o (XXVI)*
737
1.37 mmol) with indolin-2-one (III) (0.20 g, 1.37 mmol);
yield 0.12 g (18%); mp 234–237°C; [α]546 = –60.4°
Angle
grad
Angle
grad
(c = 1.0, CHCl3).
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
C13–N1–C6
111.4(2) C13–N1–C1
126.2(2) C17–N2–C2
111.6(2) C12–O3–C14
113.8(2) C19–O6–C3
122.3(2)
121.7(2)
113.3(2)
117.7(2)
glucopyranosyl)-5-methyl-3,3-trimethylenedioxyin-
dolin-2-one (XXII) was synthesized from substrate (I) C6–N1–C1
(0.50 g, 1.37 mmol) and ketal (IV) (0.30 g, 1.37 mmol);
C1–O1–C5
yield 0.08 g (11%); mp 178–180°C; [α]546 = –7.3°
(c = 1.0, CHCl3).
C12–O4–C16
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
C21–O8–C4
118.0(2) C24–O10–C23 117.5(2)
glucopyranosyl)-3,3-trimethylenedioxy-5-chloroin-
dolin-2-one (XXIV) was prepared from α-chloride (I)
(0.50 g, 1.37 mmol) and compound (VI) (0.25 g,
1.37 mmol); yield 0.20 g (26%); mp 114°C (decomp.);
[α]546 = –81.2° (c = 1.0, CHCl3).
O1–C1–N1
108.1(2) O1–C1–C2
112.2(2) N2–C2–C3
109.8(2) C3–C2–C1
108.5(2) O6–C3–C2
111.2(2) O8–C4–C3
106.7(2) C3–C4–C5
108.0(2) O1–C5–C4
115.3(2) C7–C6–C11
128.6(2) C11–C6–N1
117.0(2) C9–C8–C7
121.9(2) C8–C9–Cl1
118.4(2) C11–C10–C9
111.0(2)
111.8(2)
107.8(2)
109.1(2)
108.3(2)
109.3(2)
109.0(2)
121.7(2)
109.6(2)
120.9(2)
119.6(2)
117.2(2)
N1–C1–C2
N2–C2–C1
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl)-5-methoxy-3,3-trimethylenedioxy-
indolin-2-one (XXIII) was synthesized from substrate
(I) (0.50 g, 1.37 mmol) and ketal (V) (0.30 g,
1.37 mmol); yield 0.047 g (6%) as amorphous sub-
stance; [α]546 = –2° (c = 1.0, CHCl3).
O6–C3–C4
C4–C3–C2
O8–C4–C5
O1–C5–C23
C23–C5–C4
C7–C6–N1
1-N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl)-5-bromo-3,3-trimethylenedioxyindo-
lin-2-one (XXV) was obtained by glycosylation of com-
pound (VII) (0.40 g, 1.37 mmol) with chloride (I)
(0.50 g, 1.37 mmol); yield 0.29 g (29%); mp 231–
235°C; [α]546 = –52° (c = 1.0, CHCl3).
C6–C7–C8
C8–C9–C10
C10–C9–Cl1
C10–C11–C6
C6–C11–C12
O3–C12–C11
O3–C12–C13
C11–C12–C13
O2–C13–C12
O3–C14–C15
O4–C16–C15
O5–C17–C18
O7–C19–O6
O6–C19–C20
O9–C21–C22
O10–C23–C5
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glu-
copyranosyl)-5-nitro-3,3-trimethylenedioxyindolin-2-
one (XXVI) was obtained from substrate (I) (0.50 g,
1.37 mmol) and ketal (VIII) (0.34 g, 1.37 mmol); yield
0.318 g (40%); mp 270–272°C; [α]546 = –19° (c = 1.0,
CHCl3).
121.2(2) C10–C11–C12 129.3(2)
109.5(2) O3–C12–O4
109.9(2) O4–C12–C11
114.5(2) O4–C12–C13
102.0(2) O2–C13–N1
127.8(2) N1–C13–C12
112.4(2)
108.3(2)
109.1(2)
125.4(2)
106.7(2)
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl)-3,3-trimethylenedioxy-4-chloroin-
dolin-2-one (XXVII) was obtained from α-chloride (I)
(0.50 g, 1.37 mmol) and compound (XI) (0.25 g,
1.37 mmol); yield 0.14 g (18%); mp 244–245°C
(decomp.); [α]546 = –67° (c 1.0, CHCl3).
110.2(2) C14–C15–C16 110.1(2)
N-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranosyl)-3,3-trimethylenedioxy-6-chloroin-
dolin-2-one (XXVIII) was obtained from α-chloride
(I) (0.50 g, 1.37 mmol) and compound (XII) (0.25 g,
1.37 mmol); yield 0.09 g (12%); mp 212–214°C
(decomp.); [α]546 –79° (c 1.0, CHCl3).
110.1(2) O5–C17–N2
122.8(2) N2–C17–C18
123.4(2) O7–C19–C20
110.9(2) O9–C21–O8
126.3(2) O8–C21–C22
122.4(2)
114.8(2)
125.7(2)
122.8(2)
110.9(2)
2-Acetamido-3,4,6-tri-O-acetyl-1,2-dideoxy-D-ara-
bino-hex-1-enopyranose (XL) was isolated by column
chromatography as colorless syrup, [α]546 = –46°
(c = 1.0, CHCl3);1H NMR (400 MHz, DMSO-d6): 1.85
(3 H, s, NAc), 1.98, 2.01, and 2.03 (9 H, 3s, 3OAc),
4.15 (1 H, m, I5), 4.34 (2 H, m, H6a, H6b), 5.08 (1 H,
dd, J4,3 6, J4,5 6, H4), 5.34 (1 H, d, J3,4 6, H3), 7.11 (1 H,
s, H1), 8.80 (1 H, s, NH). Lit. [20]: colorless syrup, [α]D
–24.6° (Ò 0.5, CHCl3).
112.4(2) O11–C24–O10 122.6(2)
O11–C24–C25 126.1(2) O10–C24–C25 111.3(2)
Note: * The error for determination of angle value is given in
parentheses.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 34 No. 6 2008

738
KUR’YANOV et al.
Khim., 2004, vol. 30, pp. 334–336; Rus. J. Bioorg.
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