An improved phase transfer catalyzed synthetic method for ononin and rothindin

Article abstract of DOI:10.1081/SCC-100106200

An improved and mild glycosylation reaction was developed and used for the synthesis of ononin and rothindin, two naturally occurring isoflavone glycosides by a modified phase transfer catalyzed process.

Full text of DOI:10.1081/SCC-100106200

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AN IMPROVED PHASE TRANSFER CATALYZED
SYNTHETIC METHOD FOR ONONIN AND ROTHINDIN
a
a
a
b
Yaping Wang , Liangxi Li , Qinglian Wang & Yulin Li
a
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou University , Lanzhou, Gansu, 730000, P. R. China
b
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry,
Lanzhou University , Lanzhou, Gansu, 730000, P. R. China
Published online: 22 Aug 2006.
To cite this article: Yaping Wang , Liangxi Li , Qinglian Wang & Yulin Li (2001) AN IMPROVED PHASE TRANSFER CATALYZED
SYNTHETIC METHOD FOR ONONIN AND ROTHINDIN, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:22, 3423-3427, DOI: 10.1081/SCC-100106200
To link to this article: http://dx.doi.org/10.1081/SCC-100106200
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SYNTHETIC COMMUNICATIONS, 31(22), 3423–3427(2001)
AN IMPROVED PHASE
TRANSFER CATALYZED
SYNTHETIC METHOD FOR
ONONIN AND ROTHINDIN
Yaping Wang, Liangxi Li, Qinglian Wang,
and Yulin Li*
National Laboratory of Applied Organic
Chemistry and Institute of Organic Chemistry,
Lanzhou University, Lanzhou,
Gansu 730000, P. R. China
ABSTRACT
An improved and mild glycosylation reaction was developed
and used for the synthesis of ononin and rothindin, two natu-
rally occurring isoflavone glycosides by a modified phase
transfer catalyzed process.
Isoflavones are a class of compounds mainly occurring in species of the
leguminosae family. Many isoflavones exist naturally as O-glycoside conju-
1
gates. Isoflavonoid glycosides are common dietary phenolics which may be
2
absorbed from the small intestine of humans, and have been reported to
1
exhibit antitumor, antioxidative, antifungal, and antihaemolytic activities.
*
Corresponding author.
3
423
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
3
424
WANG ET AL.
7
-O-Glucoside isoflavones ononin (1a) and rothindin (1b) are natural
0
3
,4,5
products found in numerous sources.
Ononin (1a, 7-O-b-D-gluco-4 -
methoxy-isoflavone) was first isolated from G. Uralensis, which is a prin-
3
6
cipal inhibitor of Epstein–Barr virus early antigen activation in vitro, and
4
possesses antibacterial activity and lowering blood sugar. Rothindin (1b)
was first isolated from Rothia indica Linn which is a copiously branched
5
diffuse annual herb throughout the plains of Indian peninsula.
Previous methods for the synthesis of isoflavone-O-glucosides are
6
low-yielding, e.g. ononin (5–48%). It was reported Zemplen’s 9% KOH
´
6
solution 4 used for the base-catalyzed reaction of a-acetylbromoglucose
with unprotected hydroxyisoflavones in acetone causes significant isoflavone
7
C-ring cleavage (Waltz reported C-ring cleavage using 5% KOH solution )
and anomeric hydrolysis of the a-acetylbromoglucose, but no glycosylation.
The low-yielding of previous methods for glycosylation of isoflavones may
have two reasons: (1) the previous methods using the system of aqueous
6
2
8
NaOH/CH Cl or aqueous KOH/acetone caused C-ring cleavage, deglyco-
2
sylation and gave many by-products; (2) isoflavones hardly dissolved in the
solvent systems.
Herein we introduce a facile and mild glycosylation reaction (as shown
in Scheme 1) for the synthesis of ononin (1a) and rothindin (1b) by using
anhydrous K CO in a solvent mixture of DMF/acetone (3 : 2 v/v) and dode-
2
3
cyltrimethylammonium bromide (DTMAB) as a phase transfer catalyst.
7-O-b-D-Acetyl-glucoside isoflavones 3(a,b) were obtained by glycosylation
of 2 with a-acetylbromoglucose in higher yields (85% for 3a and 80%
for 3b).
We tried to deacetylate 3(a,b) by standard procedure using NaOMe-
6
MeOH, however, we found that the strong basic condition resulted
2 3
Reagents and conditions: i) a-acetylbromoglucose/DMF/acetone/K CO /DTMAB,
reflux, 5h, 80–85%; ii) Zn(OAc) /MeOH, reflux, 7h, 92–96%.
2
Scheme 1.

ORDER
REPRINTS
ONONIN AND ROTHINDIN
3425
in cleavage of the isoflavone’s C-ring, while ZnCl /MeOH system led to
2
significant deglycosylation. Finally, complete deacetylation was achieved
by using anhydrous Zn(OAc) in methanol in good yield.
2
EXPERIMENTAL
Melting points were measured on a XT -100 apparatus and were
4
x
uncorrected. IR spectra were recorded on a Nicolet AVATAR 360 FT-IR
1
13
spectrometer. H-NMR and C-NMR spectra were recorded on a Bruker
AM-400 instrument, using tetramethylsilane as an internal standard, chemi-
cal shifts (d) are measured in ppm and coupling constant J are reported in
Hz. Multiplicity was simplified such as s ¼ singlet, bs ¼ broad singlet,
d ¼ doublet, t ¼ triplet and m ¼ multiplet. Mass spectra were determined
with VG ZAB-HS spectrometer through EI or FAB method. All solvents
were dried by standard procedures.
7
-O-b-D-Acetylglucoside Isoflavones (3a)
In a 25 mL round-bottomed flask, anhydrous K CO (2 g, 6.3 mmol)
2
3
was added to the mixture of DMF (9 mL) and acetone (6 mL), then 2a
80 mg, 0.30 mmol), DTMAB (10 mg) and a-acetylbromoglucose (250 mg,
.60 mmol) were added under stirring, the reaction mixture was refluxed
(
0
for 5 h (monitored by TLC). Then acetone was removed under vacuum,
water (20 mL) was added to the flask. The mixture was extracted with
ethyl acetate (5 Â 10 mL), the organic layer was washed by 20 mL water
and brine, dried over anhydrous MgSO , then removed the solvent to give
4
the residue which was purified by silica gel flash chromatography (ethyl
acetate: petroleum ether 1 : 2 v/v) to give 3a 150 mg, yield: 85%, white
ꢀ
À1
solids, mp.191–193 C; IR: (KBr) cm
2921, 2854, 1742, 1684, 1659,
1
1
8
2
2
5
6
607, 1561, 1439, 1365, 1216, 1026; H-NMR (400 MHz, CDCl ): d ppm
3
.24 (1H, d, J ¼ 9.0 Hz, H-5), 7.9 (1H, s, H-2), 7.50 (2H, dd, J ¼ 8.7,
0
0
,0 Hz, H-2 ,6 ), 7.23 (1H, d, J ¼ 2.3 Hz, H-8), 7.01 (1H, dd, J ¼ 9.0,
0
0
00
.3 Hz, H-6), 6.98 (2H, dd, J ¼ 8.7, 2.0 Hz, H-3 , 5 ), 5.3 (1H, m, H-1 ),
00
00
.23 (1H, m, H-3 ), 5.20 (1H, m, H-2 ), 4.30 (1H, dd, J ¼ 12.0, 2.0 Hz, H-
00
00
00
a), 4.20 (1H, dd, J ¼ 12.0, 2.0 Hz, H-6 b), 3.97(1H, m, H-5 ), 3.94 (1H, m,
00
þ
H-4 ), 3.84 (3H, s, -OCH ), 2.1 (12H, m, -COCH ); EI-MS (m/z): 598 (M ,
3
3
1), 330 (9.2), 295 (1.6), 268 (9.4), 266 (4.7), 252 (1.4), 238 (1.6), 228 (2.1), 168
(
100), 145 (6.1), 127(1 7. 5), 109 (51.3).
Using the above procedure, 7-O-b-D-acetylglucoside isoflavones 3b was
prepared in 80% yield as white solids, mp. 210–213 C; IR: (KBr) cm 2955,
ꢀ
À1

ORDER
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3
426
WANG ET AL.
1
896, 1754, 1645, 1621, 1490, 1439, 1371, 1239, 1038, 909, 731; H-NMR
2
(
7
400 MHz, CDCl ): d ppm 8.24 (1H, d, J ¼ 8 Hz, H-5), 7.93 (1H, s, H-2),
3
0
0
.09 (1H, d, J ¼ 1.0 Hz, H-2 ), 7.06 (1H, d, J ¼ 2.0 Hz, H-6 ), 7.03 (1H, d,
J ¼ 6.0 Hz, H-8), 6.97(1H, dd, J ¼ 8.6, 2.0 Hz, H-6), 6.87(1H, J ¼ 8.0 Hz, H-
0
00 00
), 6.0 (2H, s, -OCH O-), 5.3 (1H, m, H-1 ), 5.23 (1H, m, H-3 ), 5.20 (1H,
2
5
00
00
m, H-2 ), 4.30 (1H, dd, J ¼ 12.0, 2.0 Hz, H-6 a), 4.20 (1H, dd, J ¼ 12.0,
00 00 00
2
.0 Hz, H-6 b), 3.97(1H, m, H-5 ), 3.94 (1H, m, H-4 ), 2.1 (12H, m,
1
3
CH CO-); C-NMR (100 MHz, CDCl ): d ppm 175.5 (C-4), 170.4, 170.1,
3
3
0
1
1
4
69.3, 169.2 (-CO-), 169.2 (C-7), 157.3 (C-8a), 152.4 (C-2), 147.8 (C-3 ),
0
0
0
47.8 (C-4 ), 28.2 (C-5), 125.3 (C-3), 125.3 (C-1 ), 122.3 (C-6 ), 120.2 (C-
0
0
00
a), 115.3 (C-6), 109.7(C-2 ), 108.4 (C-5 ), 104.3 (C-8), 104.2 (C-1 ), 101.2 (-
00
00
00
00
00
OCH O-), 77.3 (C-5 ), 76.8 (C-3 ), 71.0 (C-2 ), 68.2 (C-4 ), 62.0 (C-6 ), 20.6
2
þ
(
(
-CH ); EI-MS (m/z): 612 (M , 3), 170 (9), 69 (100), 145 (11), 139 (9), 129
3
21), 115 (3), 109 (71), 97 (8), 85 (5), 81 (7), 69 (4), 43 (87).
Ononin (1a)
In a 5 mL round-bottomed flask, 3a (65 mg, 0.109 mmol) was dissolved
in methanol (2 mL), anhydrous zinc acetate (23 mg, 0.126 mmol) was added
to the stirring solution. The mixture was refluxed for 7h (monitored by
TLC). After cooled down at RT the mixture was filtered by cation exchange
resin, the solvent was evaporated under vacuum. The residue was purified by
silica gel flash chromatography (CHCl : MeOH 12 : 1 v/v) to get the product
3
ꢀ
À1
1
2
a 45 mg, yield: 96%, white solids, mp. 203–205 C; IR: (KBr) cm 3404,
1
924, 2853, 1629, 1570, 1513, 1444, 1252, 1194, 1074, 1017, 819; H-NMR
(
400 MHz, DMSO-d ): d ppm 8.43 (1H, s. H-2), 8.06 (1H, d, J ¼ 9.0 Hz,
6
0 0
H-5), 7.53 (2H, dd, J ¼ 8.7, 2.0 Hz, H-2 , 6 ), 7.23 (1H, d, J ¼ 2.3 Hz, H-8),
0
0
7
5
5
-
3
.14 (1H, dd, J ¼ 9.0, 2.3 Hz, H-6), 6.98 (2H, dd, J ¼ 8.7, 2.0 Hz, H-3 , 5 ),
00 00 00
.41 (1H, d, 2 -OH), 5.10–5.13 (1H, m, 3 -OH), 5.06–5.09 (1H, m, 4 -OH),
0
0
00
.06 (1H, d, J ¼ 5.2 Hz, H-1 ), 4.58–4.61 (1H, m, 6 -OH), 3.78 (3H, s,
00 00 00
OCH ), 3.69–3.70 (1H, m, H-5 , 6 a), 3.43–3.48 (1H, m, H-6 b),
3
00
00
00
13
.28–3.32 (1H, m, H-2 , 3 ), 3.16–3.20 (1H, m, H-4 );
C-NMR
0
(
100 MHz, DMSO-d ): d ppm 174.6 (C-4), 161.4 (C-7), 159 (C-4 ), 157.0
6
0
0
0
(
1
(
C-8a), 153.5 (C-2), 130.0 (C-2 , 6 ), 127.0 (C-5), 124.0 (C-3), 123.3 (C-1 ),
0 0 00
18.4 (C-4a), 115.6 (C-6), 113.6 (C-3 , 5 ), 103.4 (C-8), 100 (C-1 ), 77.2
C-5) , 76.4 (C-3 ), 73.1 (C-2 ), 69.6 (C-4 ), 60.6 (C-6 ), 55.1 (-OCH );
00
00
00
00
00
3
þ
FAB-MS (m/z): 430 [M ].
Using the above procedure, rothindin 1b was obtained in 92% yield as
white solids, mp. 213–215 C; IR: (KBr) cm 3430, 2926, 1623, 1501, 1439,
1
1
ꢀ
À1
248, 1074, 1014, 920, 810; H-NMR (400 MHz, DMSO-d ): d ppm 8.45
6
0
(
1H, s, H-2), 8.05 (1H, d, J ¼ 9.0 Hz, H-5), 7.24 (1H, d, J ¼ 2.0 Hz, H-2 ),

ORDER
REPRINTS
ONONIN AND ROTHINDIN
3427
0
7
7
-
5
6
.14 (1H, dd, J ¼ 8.1, 2.0 Hz, H-6 ), 7.07 (1H, dd, J ¼ 9.0, 2.0 Hz, H-6),
0
.07 (1H, d, J ¼ 2.0 Hz, H-8), 6.97(1H, d, J ¼ 8.1 Hz, H-5 ), 6.04 (2H, s,
0
0
00
OCH O-), 5.44–5.46 (1H, m, 2 -OH), 5.15 (1H, d, J ¼ 5.0 Hz, H-1 ),
2
0
0
0
0
.14–5.16 (1H, m, 3 -OH), 5.07–5.11 (1H, m, 4 -OH), 4.60–4.63 (1H, m,
-OH), 3.70–3.73 (1H, m, H-6 b), 3.45–3.47(2H, m, H-5 , 6 a), 3.30–3.32
00
00
00
00
00
00
00
13
(
2H, m, H-2 , 3 ), 3.17–3.25 (1H, m, H-4 );
C-NMR (100 MHz,
DMSO-d ): d ppm 174.5 (C-4), 165.1 (C-7), 157.0 (C-8a), 154 (C-2), 147.0
6
0
0
0
0
(
(
1
(
C-3 ), 147.0 (C-4 ), 127.0 (C-5), 126.9 (C-3), 125.5 (C-1 ), 122.4 (C-6 ), 118.4
0 0 00
C-4a), 115.6 (C-6), 109.3 (C-2 ), 108.1 (C-5 ), 103.4 (C-8), 101.0 (C-1 ),
00 00 00 00
00.0 (-OCH O-), 77.2 (C-5 ), 76.5 (C-3 ), 73.1 (C-2 ), 69.6 (C-4 ), 60.6
2
00
þ
C-6 ); FAB-MS (m/z): 444[M ].
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¨ ¨ ¨
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¨
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hala, K. The Phase Transfer Catalysed
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Received in Japan October 6, 2000

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