Synthesis of N-acetylglucosaminides with coumarin and chromone aglycones

Article abstract of DOI:10.1023/A:1019635914082

β-O-Glycosides of N-acetylglucosamine with substituted 7-hydroxychromones and 7-hydroxycoumarins as the aglycones are synthesized. The phenyl hydroxyls' are O-glycosylated in a solid - liquid system with crown-ether catalysts. The structures of the chromone and coumarin N-acetylglucosaminides and their per-O-acetates are proved by PMR spectroscopy.

Full text of DOI:10.1023/A:1019635914082

Chemistry of Natural Compounds, Vol. 38, No. 2, 2002
SYNTHESIS OF N-ACETYLGLUCOSAMINIDES WITH
COUMARIN AND CHROMONE AGLYCONES
A. E. Zemlyakov,1 V. O. Kur′yanov,1 T. A. Chupakhina,1
V. Ya. Chirva,1 V.V. Ishchenko,2 M. M. Garazd,3
and V. P. Khilya2
UDC 547.455.623'233.1
β
-O-Glycosides of N-acetylglucosamine with substituted 7-hydroxychromones and 7-hydroxycoumarins as
the aglycones are synthesized. The phenyl hydroxyls are O-glycosylated in a solid—liquid system with crown-
ether catalysts. The structures of the chromone and coumarin N-acetylglucosaminides and their per-O-
acetates are proved by PMR spectroscopy.
Key words: glycoside synthesis, 7-hydroxychromone glycosides, 7-hydroxycoumarin glycosides, N-acetylglucosamine
glycosides, crown ether.
Natural and synthetic derivatives of 7-hydroxycoumarin and 7-hydroxychromone exhibit a wide spectrum of biological
activity. The corresponding O-glycosides of neutral sugars are widely distributed in the plant kingdom and also have a variety
of physiological activities [1]. In particular, rutin and its analogs act as vitamins [2] and possess antispasmodic [3], anti-
inflammatory, and anti-allergic activity [4]. Anti-oxidants, cardiostimulants, hypoglycemics, hepatoprotectants [5], and
antibiotics, for example, novobiocin [6] are represented among this class of compounds.
R
3
O
R
3
O
R
4
R
2
R
4
R
2
OAc
OH
O
O
O
O
R
1
O
O
R
1
AcO
AcO
HO
HO
R
5
R
5
NHAc
NHAc
3a - e
2a - e
2a, 3a: R = Me, R
=
=
, R = R = R = H
3 4 5
1
2
O
2b, 3b: R = Me, R
, R = R = R = H
3 4 5
1
2
O
2c, 3c: R = Me, R
=
, R = R = R = H
NO
3 4 5
2
1
2
2d, 3d: R = Me, R
=
, R = R = R = H
3 4 5
Cl
1
2
N
S
Me
2e, 3e: R = H,
R
=
, R = R = H, R = Et
3 5 4
1
2
1) V. I. Vernadskii Tavricheskii National University, 95007, Ukraine, Simferopol′, ul. Yaltinskaya, 4, fax (0652) 23
23 10, e-mail: vladimir@tnu.crimea.ua; 2) Taras Shevchenko Kiev National University, 01033, Ukraine, Kiev, ul.
Vladimirskaya, 60, fax (044) 23 51 273, e-mail: alexish@i.com.ua; 3) Institute of Bioorganic and Petroleum Chemistry,
National Academy of Sciences, Ukraine, 02094, Ukraine, Kiev, ul. Murmanskaya, 1. Translated from Khimiya Prirodnykh
Soedinenii, No. 2, pp. 125-128, March-April, 2002. Original article submitted April 5, 2002.
0009-3130/02/3802-0149$27.00 ©2002 Plenum Publishing Corporation
149

TABLE 1. PMR Spectra of 2a-j*
Atom
Com-
H-1
(J1,2
H-2
(J2,3
H-3
(J3,4
H-4
(J4,5
H-5
H-6
(Jgem
NH
pound
NAc, OAc
R1
R2
R3
R4
R5
)
)
)
)
(J5,6A; J5,6B
)
)
(JNH,2)
2a 5.58d 4.09ddd 5.26dd 4.96dd 4.27ddd
(8.5) (10) (9.5) (9.5) (2.5; 5.5) 4.23dd (12) 2.03s, 2.06s
2b 5.56d 4.09ddd 5.26dd 4.96dd 4.26ddd 4.17dd,
(8.5) (10) (9.5) (9.5) (2.5; 5.5) 4.22dd (12) 2.03s, 2.05s (8.5)
4.19dd, 1.81s, 1.97s, 8.12d 2.27s
7.30m,
7.43m
7.99d 7.09dd 7.29d
(8)
1.80s, 1.97s 8.11d 2.28s 2.14m, 4.18t, 7.97d 6.86dd 7.27d
6.90s, 7.01d,
7.08d
2c
5.58d 4.09ddd 5.24dd 4.96dd 4.30ddd
(8.5) (10) (9.5) (9.5) (2.5; 5)
2d 5.57d 4.08dd 5.24dd 4.95dd 4.30ddd
(8.5) (10) (9.5) (9.5) (2; 5)
4.11dd, 1.80s, 1.97s, 8.17d 2.30s 7.63d, 8.30d 8.00d 7.10dd 7.34d
4.20dd(12) 2.02s, 2.05s
(9)
4.11dd, 1.79s, 1.96s, 8.16d 2.27s 7.33d, 7.50d 7.98d 7.08dd 7.31d
4.20dd
(12.5)
4.18dd
2.02s, 2.05s (9.5)
2e
5.03d 4.39ddd 5.24dd 5.10dd 3.68ddd
(8.5) (10) (9.5) (9.5)
5.58d 4.07ddd 5.24dd 4.95dd 4.30ddd
(8.5) (10) (9.5) (9.5) (2; 5)
2g 5.47d 4.18ddd 5.24dd 4.98dd 4.35ddd
(8.5) (10) (9.5) (9.5) (2; 5)
5.24 4.32ddd 5.36dd 5.17dd 3.85ddd
(8.5) (10) (9.5) (9.5) (2.5; 5.5) 4.24dd (12) (6H), 2.06s (8.5)
5.36d 4.20ddd 5.37dd 5.13dd 3.95ddd 4.16dd 1.96s, 2.05s, 6.14d 1.79m,
2.05s, 2.06s, 6.24d 7.07s 2.52s, 8.96s 7.82s 1.15t, 6.82s
(2.5; 5) 4.22dd (12) 2.07s, 2.09s
(8)
2.56q
2f
4.10dd
1.79s, 1.96s, 8.17d 2.37s
7.02dd,
7.11dd
7.95d 7.09dd 7.36d
4.20dd (12) 2.02s, 2.05s (8.5)
4.14dd
4.23dd (12) 2.02s, 2.05s
4.15dd 2.01s, 2.04c 6.07d 6.16s 7.29 - 7.48m 7.19d 6.84d 2.28s
1.79s, 1.98s, 8.17d 8.66s 1.17d, 2.84m 7.84s 1.10t, 7.40s
(9) 6.89d, 7.15d 2.59m
2h
2i
7.36d 6.86dd 6.86d
7.98d 7.08dd 7.25d
(8.5)
(10)
(9.5)
(9.5)
(2.5; 5) 4.29dd (12) 2.07s, 2.09s (8.5) 2.47m,
2.66m
2j
5.56d 4.08ddd 5.25dd 4.97dd 4.31ddd
(8) (10) (9.5) (9.5) (2; 5)
4.11dd
4.22dd
(12.5)
1.80s, 1.98s, 8.15d 2.47s,
2.03s, 2.04s (9) 8.96s
7.44d
______
*Working frequency 400 MHz; for 2a, -b, -e, -h, and -i, 300 MHz. Solvent DMSO-d6; for 2e, -h, and -i, CDCl3.
Adding carbohydrates to the coumarin or chromone structures substantially changes the hydrophilic—lipophilic
balance. Therefore, transport in biological systems is affected. We determined the influence of the carbohydrate component
on the biological activity of modified 7-hydroxycoumarins and chromones by synthesizing the corresponding N-
acetylglucosaminides. The glycosylation of 7-hydroxycoumarin and -chromone derivatives by glycosyl donors based on only
neutral sugars has been described [7].
We developed a method for preparing arylglycosides of N-acetylglucosamine under phase-transfer catalysis conditions
in a solid—liquid system [8] and used it to glycosylate hydroxyl derivatives of coumarin and chromone. The reaction between
equivalent amounts of phenolic compounds, anhydrous K CO , and glycosyl donor, -glucosaminyl chloride peracetate (1), was
2
3
carried out at room temperature in acetonitrile in the presence of 15-crown-5 (20 mol %). The reaction was usually complete
in 24 h. Glycosides 2a-j were isolated by crystallization in 63-84% yields. Signals for protons of the aglycone and carbohydrate
were unambiguously identified in the PMR spectra (Table 1). In particular, the presence in the spectra of doublets for the
anomeric protons at 5.03-5.58 ppm and spin—spin coupling constants 8-8.5 Hz is consistent with formation of a 1,2-trans-
glycoside bond.
De-acetylation of the peracetates (2a-j) by a modified Zemplen method produced the desired N-acetylglucosaminides
(3a-j). The chromone and coumarin algycones were not opened under the synthetic conditions. This was confirmed by PMR
spectroscopy (Table 2).
150

3a j*
TABLE 2. PMR Spectra of
-
Atom
R1
Com-
pound
H-1(J1,2
)
OH
NAc
NH (JNH,2
)
R2
R3
R4
R5
3a
3b
5.20d (8)
4.69t,
5.17m
1.82s
7.88d (9)
7.87d (9)
2.27s
7.30m,
7.45m
2.13m, 4.16t,
4.18t, 6.90d,
7.02m
7.96d
7.04dd
7.18d
5.20d (8) 4.68t, 5.15d
5.18d
1.82s
2.28s
7.95d
6.85dd
7.16d
3c
3d
3e
3f
5.22d (8.5) 4.67t, 5.16d,
5.19d
5.21d (8.5) 4.67t, 5.14d,
5.18d
5.10d (8.5) 4.75t, 5.16d,
5.24d
5.21d (9) 4.66t, 5.16d,
5.19d
1.82s
1.82s
1.82s
1.82s
1.82s
1.83s
1.81s
1.82s
7.87d (9)
7.86d (9)
7.88d (9.5)
7.87d (9)
7.87d (9.5)
7.85d (9)
7.84d (8.5)
7.87d (9)
2.31s
2.27s
7.35s
2.38s
8.64s
6.29s
7.62d, 8.30d
7.97d
7.96d
7.95s
7.94d
7.81s
7.23d
7.63d
7.95d
7.06dd
7.04dd
7.20d
7.17d
7.33s
7.22d
7.30d
2.19s
6.98
7.33d, 7.50d
2.44s, 9.21s
1.13t, 2.62m
7.05dd
7.01dd,
7.11dd
1.17d, 2.84m,
6.88d, 7.15d
7.53m, 7.57m
3g
3h
3i
5.08d (8) 4.72t, 5.16d,
5.23d
1.10t, 2.59m
7.12d
4.94d (8)
4.63br t,
5.18m
5.10d (9) 4.69t, 5.13d,
5.17d
5.19d (9) 4.68t, 5.16d,
5.19d
1.74m,
2.41m, 2.77m
2.46s, 8.95
6.93dd
3j
7.42s
7.03dd
7.12d
______
*Working frequency 400 MHz, solvent DMSO-d6.
R
3
R
2
R
3
R
2
R
4
R
1
R
4
R
1
OAc
OH
O
O
O
O
O
O
O
O
AcO
AcO
HO
HO
R
5
R
5
NHAc
NHAc
2f - j
3f - j
2f, 3f: R = Me, R
=
=
=
, R = R = R = H
F
3 4 5
O
O
1
2
2
2
2g, 3g: R = H, R
, R = R = H, R = Et
3 5 4
1
2h, 3h: R = H, R
, R = R = H, R = Me
3 4 5
1
2i, 3i: R R = -(CH ) -,
R = R = R = H
3 4 5
2 4
1
2
N
S
Me
2j, 3j: R =
,
R
= R = R = R = H
2 3 4 5
1
2a
b
We previously used glycosides ( and - ) to prepare the corresponding glycoside derivatives of N-acetylmuramoyl-L-
alanyl-D-isoglutamine [9].
151

EXPERIMENTAL
1
Melting points were determined on a PTP apparatus; optical rotation, at 20-22°C on a Polamat-A polarimeter. H NMR
spectra were obtained on Varian VXR-300 (300 MHz) and Varian Mercury 400 (400 MHz) spectrometers with TMS internal
standard. Chemical shifts are given in ppm using the δ scale. TLC was performed on Sorbfil-AFV-UV plates (Sorbpolimer,
Russia) with development by H SO in ethanol (5%) with heating to 200-300°C and UV light (254 nm). Solvent systems used
2
4
CHCl —propan-2-ol (15:1, 1; 3:1, 2).
3
The synthesis of substituted 7-hydroxycoumarins and 7-hydroxychromones has been published [10-13].
General Glycosylation Method. A solution of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosylchloride
(1, 1.7 g, 4.65 mmole) [11] in acetonitrile (30 mL) was treated with 2-methyl-7-hydroxyisoflavone (1.17 g, 4.65 mmole), finely
ground anhydrous K CO (640 mg, 4.65 mmole), and 15-crown-5 (185 µL, 0.93 mmole). The reaction mixture was stirred at
2
3
room temperature until the glycosyl donor completely disappeared (TLC monitoring using system 1). The solvent was
evaporated. The solid was dissolved in CHCl (100 mL) and washed with KOH (1 N, 2×20 mL) and water (3×30 mL). The
3
organic layer was separated, dried over anhydrous Na SO , and evaporated. Crystallization of the solid from isopropanol
2
4
produced:
2-methyl-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)isoflavone (2a), yield 66%, mp 194-
196°C, [α]546 +2° (c 1.0, methylenechloride);
2-methyl-3′,4′-trimethylenedioxy-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)isoflavone
(2b), yield 76%, mp 233-235°C (dec.), [α]546 +10° (c 1.0, methylenechloride);
2-methyl-4′-nitro-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)isoflavone (2c), yield 65%,
mp 249-250°C, [α]546 -8° (c 1.0, methylenechloride);
2-methyl-4′-chloro-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)isoflavone (2d), yield 84%,
mp 241-242°C, [α]546 -19° (c 1.0, methylenechloride);
3-(4-methylthiazolyl-2)-6-ethyl-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)chromone (2e),
yield 63%, mp 257-258°C, [α]546 -27° (c 1.0, methylenechloride);
2-methyl-3-(4′-fluorophenoxy)-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)chromone (2f),
yield 73%, mp 229-230°C, [α]546 -17° (c 1.0, methylenechloride);
3-(4′-isopropylphenoxy)-6-ethyl-7-(2-acetamido-3,4,6-tri-O-acetyl-2-dexoy-β-D-glucopyranosyloxy)chromone (2g),
yield 72%, mp 209-210°C, [α]546 -29° (c 0.95, CHCl );
3
4-phenyl-8-methyl-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)coumarin (2h), yield 80%,
mp 221-222°C, [α]546 -62° (c 1.0, methylenechloride);
7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)-3,4-tetramethylenecoumarin (2i), yield 67%,
mp 206-209°C, [α]546 -31° (c 1.0, methylenechloride);
3-(4-methylthiazolyl-2)-7-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)coumarin (2j), yield
70%, mp 250-251°C, [α]546 -11° (c 0.75, CHCl —isopropan-2-ol, 3:1).
3
General Deacetylation Method. A solution or suspension of acetate (2a, 1.7 g, 2.9 mmole) in a mixture (50 mL) of
dry methanol and dichloromethane (1:1) was treated with NaOMe (0.1 N, 0.5 mL) in methanol. The precipitate that formed
after 12 h (TLC monitoring using system 2) was filtered off and washed with cold methanol. The mother liquor was neutralized
+
using KU-2 cation exchanger (H ). The resin was filtered off. The filtrate was evaporated and treated with ether to produce
an additional portion of crystals. This method produced:
2-methyl-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)isoflavone (3a), yield 86%, mp 163-165°C, [α]546 -10°
(c 1.0, DMF);
2-methyl-3′,4′-trimethylenedioxy-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)isoflavone (3b), yield 90%, mp
148-150°C, [α]546 -15° (c 1.0, DMF);
2-methyl-4′-nitro-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)isoflavone (3c), yield 89%, mp 232-234°C,
[α]546 -13° (c 1.0, DMF);
2-methyl-4′-chloro-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)isoflavone (3d), yield 86%, mp 243-244°C,
[α]546 -8° (c 1.0, DMF);
3-(4-methylthiazolyl-2)-6-ethyl-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)chromone (3e), yield 95%, mp
201°C (dec.), [α]546 -42° (c 1.0, DMF);
152

2-methyl-3-(4′-fluorophenoxy)-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)chromone (3f), yield 82%, mp 271-
272°C, [α]546 -21° (c 1.0, DMF);
3-(4′-isopropylphenoxy)-6-ethyl-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)chromone (3g), yield 87%, mp
221-222°C, [α]546 -48° (c 1.0, DMF);
4-phenyl-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)-8-methylcoumarin (3h), yield 97%, mp 203-204°C,
[α]546 -63° (c 1.0, DMF);
7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)-3,4-tetramethylenecoumarin (3i), yield 92%, mp 195-196.5°C,
[α]546 -10° (c 1.0, DMF);
3-(4-methylthiazolyl-2)-7-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)coumarin (3j), yield 94%, mp 187-188°C,
[α]546 -8° (c 1.0, DMF).
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