Synthesis of aminomethyl derivatives of sophoricoside

Article abstract of DOI:10.1007/s10600-012-0151-2

Aminomethylation of the natural isoflavonoid sophoricoside (genistein-4-O-β-D-glucoside) was studied. It was shown that the most convenient method for performing the aminomethylation was the use of aminals. 6,8-bis-Substituted derivatives of sophoricoside

Full text of DOI:10.1007/s10600-012-0151-2

Chemistry of Natural Compounds, Vol. 48, No. 1, March, 2012 [Russian original No. 1, January-February, 2012]
SYNTHESIS OF AMINOMETHYL DERIVATIVES OF SOPHORICOSIDE
1
2*
3
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya
UDC 547.814.5
Aminomethylation of the natural isoflavonoid sophoricoside (genistein-4-O-ꢀ-D-glucoside) was studied. It
was shown that the most convenient method for performing the aminomethylation was the use of aminals.
6,8-bis-Substituted derivatives of sophoricoside were synthesized.
Keywords: isoflavone, sophoricoside, electrophilic substitution, aminomethylation, aminal.
Heightened interest in the study of natural flavonoids and their various modifications is due to the important role of
these compounds in metabolic processes of plants and animals, their broad range of physiological activity, and their low
toxicity.
In continuation of research on the modification of natural compounds, we decided to study sophoricoside (genistein-
4-O-ꢀ-D-glucoside) (1), which occurs in Sophora japonica [1–5], Piptanthus nepalensis [6], and Lupinus albus [7].
Sophoricoside is known to exhibit anti-inflammatory [8], antioxidant [5, 9], and anticancer [4, 10] activity and to inhibit the
activity of cyclooxygenase [8] and aldehyde reductase [11].
A promising pathway for modifying natural phenolic compounds and their analogs is aminomethylation because
Mannich bases of flavones and isoflavones regulate the activity of the central nervous system and respiratory pathways;
exhibit high anticonvulsant, anti-allergic, and analgesic activity [12, 13]; and act as CDK1/Cyclin B inhibitors [14].
Therefore, we selected aminomethylation for modification of sophoricoside extracted from fruit of S. japonica using
the published method [15]. Considering the presence of the labile glycoside bond in sophoricoside and the mechanism of the
Mannich reaction [16], the reaction was carried out using the aminal method that was applied successfully to several flavonoids
[17].
R
N
1
O
8
R
R
HO
N
O
HO
N
N
OH
O
OH
O
HO
O
OH
OH
1'
6
4
HO
OH
Dioxane, 100ꢁÑ, 3 - 5 h
4''
4'
OH
O
OH
O
OH
1''
O
R
6''
1
2a - d
X
N
X
X
N
N
HO
O
OH
Dioxane, 100ꢁÑ, 3 - 5 h
HO
O
OH
OH
2a: R = H, 2b: R = Me-2
2c: R = Me-3, 2d: R = Me-4
3a: X = bond; 3b: X = N-Me
N
X
OH
O
O
3c: X = N-CH CH OH; 3d: X = O
3a - d
2
2
1) National University of Food Technology, 01601, Kiev, Ul. Vladimirskaya, 68, Ukraine; 2) Institute of Bioorganic
Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Kiev, Ukraine, e-mail: mfras@i.kiev.ua;
3) Taras Shevchenko Kiev National University, 01033, Kiev, Ul. Vladimirskaya, 64, Ukraine. Translated from Khimiya
Prirodnykh Soedinenii, No. 1, January–February, 2012, pp. 29–31. Original article submitted July 9, 2011.
©
26
0009-3130/12/4801-0026 2012 Springer Science+Business Media, Inc.

Like for aminomethylation of the natural isoflavones biochanin A, the 3ꢂ-O-methyl ether of pratensein, and their
derivatives [18], the action on genistein-4-O-glucoside of one equivalent of aminal in refluxing dioxane formed a complicated
product mixture. Changing the reaction conditions (solvent, temperature, reaction time) did not cause the electrophilic
substitution in the benzopyrone ring to become regioselective. Increasing the amount of aminal to two equivalents produced
6,8-bis-aminomethyl derivatives of sophoricoside. This indicated that the C atoms in the 6- and 8-positions of the chromone
ring had practically identical reactivities toward electrophilic reagents.
The structures of the synthesized Mannich bases were proved using NMR spectroscopy. Formation of C-6 and C-8
bis-aminomethyl derivatives of sophoricoside was confirmed by the disappearance in PMR spectra of resonances for H-6 and
H-8 and the appearance of resonances for two methylenes and amines.
Proof of the substitution of the C-6 and C-8 protons was the change of position of the resonances for these atoms in
C NMR spectra. Thus, instead of characteristic resonances of tertiary C atoms at 94–98 ppm, resonances of quaternary C
13
atoms were observed at 100–103 ppm. Also, resonances of the amines had chemical shifts differing by 0.2–0.6 ppm because
of the slight non-equivalence of the aminomethyl moieties in the 6- and 8-positions of the chromone ring.
Thus, we synthesized 6,8-bis-aminomethyl derivatives of sophoricoside. Variation of the amine component (secondary
amine) enabled promising biologically active compounds to be prepared. Introducing aminomethyls into sophoricoside increased
its solubility and expanded the capability for studying the physiological activity of this isoflavone.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck
(Germany) plates. The eluent was a mixture of CHCl and MeOH (95:5 and 9:1). PMR spectra were measured in DMSO-d
3
6
13
relative to TMS (internal standard) on a VXR-300 instrument (Varian, 300 MHz) on the ꢃ-scale; C NMR spectra, in
DMSO-d (internal standard) on a Mercury 400 instrument (Varian, 400 MHz). Melting points were determined on a Buchi
6
B-535 instrument. Elemental analyses of all compounds agreed with those calculated.
General Method for Synthesizing 2a–d and 3a–d. A hot solution of sophoricoside (2 mmol) in dioxane (10 mL)
was treated with the appropriate aminal (4.4 mmol), refluxed for 3–5 h, and cooled (TLC monitoring). The solvent was
evaporated in vacuo. The solid was ground with Et O, dried, and crystallized from i-PrOH:hexane.
2
4-[5,7-Dihydroxy-4-oxo-6,8-bis(piperidin-1-ylmethyl)-4H-chromen-3-yl]phenyl-ꢀ-D-glucopyranoside (2a). Yield
71%, C H N O , mp 150–151°C.
33 42
2 10
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.28–1.60, 2.52–2.68 (12H, 8H, 2m, piperidine protons), 3.12–
3.50 (6H, m, H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ), 3.67 (2H, s, CH -8), 3.75 (2H, s, CH -6), 4.90 (1H, d, J = 7.0, H-1ꢄ), 7.08 (2H, d, J = 8.8,
6
3
3
2
2
3
H-3ꢂ, 5ꢂ), 7.49 (2H, d, J = 8.8, H-2ꢂ, 6ꢂ), 8.38 (1H, s, H-2).
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 23.2, 23.7, 25.0, 25.4, 52.7, 53.3; 50.4 (CH -8), 51.7
6
2
(CH -6), 60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.8 (C-8), 102.4 (C-6), 103.9 (C-4a),
2
116.0 (C-3ꢂ, 5ꢂ), 121.4 (C-3), 124.5 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 153.8 (C-2), 155.0 (C-8a), 157.2 (C-7), 158.5 (C-5), 167.7 (C-4ꢂ),
179.9 (C-4).
4-{5,7-Dihydroxy-6,8-bis[(2-methylpiperidin-1-yl)methyl]-4-oxo-4H-chomen-3-yl}phenyl-ꢀ-D-glucopyranoside
(2b). Yield 67%, C H N O , mp 148–149°C.
35 46
2 10
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 0.80–1.81, 2.65–2.91 (18H, 6H, 2m, piperidine protons), 3.15–
6
3
3
3.54 (6H, m, H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ), 3.67 (2H, m, CH -8), 4.05 (2H, m, CH -6), 4.91 (1H, d, J = 7.2, H-1ꢄ), 7.08 (2H, d, J = 8.0,
H-3ꢂ, 5ꢂ), 7.50 (2H, d, J = 8.0, H-2ꢂ, 6ꢂ), 8.37 (1H, s, H-2).
2
2
3
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 19.6, 19.8, 23.3, 23.8, 25.2, 25.5, 31.0, 31.2, 53.4, 53.8,
6
60.8, 61.9; 51.2 (CH -8), 51.4 (CH -6), 60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.8
2
2
(C-8), 102.3 (C-6), 104.0 (C-4a), 116.0 (C-3ꢂ, 5ꢂ), 121.4 (C-3), 124.4 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 153.8 (C-2), 155.0 (C-8a), 157.2
(C-7), 158.5 (C-5), 167.6 (C-4ꢂ), 179.9 (C-4).
4-{5,7-Dihydroxy-6,8-bis[(3-methylpiperidin-1-yl)methyl]-4-oxo-4H-chromen-3-yl}phenyl-ꢀ-D-glucopyranoside
(2c). Yield 56%, C H N O , mp 148–150°C.
35 46
2 10
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 0.92, 1.65–2.00, 2.63–3.08 (6H, 10H, 4H, 3m, piperidine
6
protons), 3.16–3.51 (10H, m, H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ and 4H of piperidines), 4.38 (2H, m, CH -8), 4.49 (2H, m, CH -6), 4.98 (1H,
2
2
3
3
3
d, J = 7.1, H-1ꢄ), 7.18 (2H, d, J = 8.0, H-3ꢂ, 5ꢂ), 7.54 (2H, d, J = 8.0, H-2ꢂ, 6ꢂ), 8.54 (1H, s, H-2).
27

13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 19.7, 19.9, 25.3, 25.6, 31.1, 31.2, 32.6, 32.9, 53.3, 53.8,
6
60.9, 61.8; 51.1 (CH -8), 51.3 (CH -6), 60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.8
2
2
(C-8), 102.3 (C-6), 104.0 (C-4a), 116.0 (C-3ꢂ, 5ꢂ), 121.4 (C-3), 124.4 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 153.8 (C-2), 155.0 (C-8a), 157.2
(C-7), 158.5 (C-5), 167.6 (C-4ꢂ), 180.0 (C-4).
4-{5,7-Dihydroxy-6,8-bis[(4-methylpiperidin-1-yl)methyl]-4-oxo-4H-chromen-3-yl}phenyl-ꢀ-D-glucopyranoside
(2d). Yield 70%, C H N O , mp 179–180°C.
35 46
2 10
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 0.90, 1.04–1.71, 2.07–2.34, 2.84–3.01 (6H, 10H, 4H, 4H, 4m,
6
3
piperidine protons), 3.13–3.53 (6H, m, H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ), 3.72 (2H, s, CH -8), 3.79 (2H, s, CH -6), 4.91 (1H, d, J = 7.1,
H-1ꢄ), 7.10 (2H, d, J = 8.5, H-3ꢂ, 5ꢂ), 7.49 (2H, d, J = 8.5, H-2ꢂ, 6ꢂ), 8.38 (1H, s, H-2).
2
2
3
3
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 21.5, 21.7, 29.6, 30.0, 33.2, 33.7, 52.1, 52.7; 50.0
6
(CH -8), 51.3 (CH -6), 60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.8 (C-8), 102.3 (C-6),
2
2
104.0 (C-4a), 116.0 (C-3ꢂ, 5ꢂ), 121.4 (C-3), 124.4 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 153.8 (C-2), 155.0 (C-8a), 157.2 (C-7), 158.5 (C-5),
167.6 (C-42), 179.9 (C-4).
4-{5,7-Dihydroxy-4-oxo-6,8-bis[(pyrrolidin-1-yl)methyl]-4H-chromen-3-yl}phenyl-ꢀ-D-glucopyranoside (3a).
Yield 45%, C H N O , mp >250°C (dec).
31 38
2 10
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.85–1.97, 2.65–2.99 (8H, 4H, 2m, pyrrolidine protons), 3.10–
6
3
3.50 (10H, m, H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ and 4H of pyrrolidines), 3.70 (2H, m, CH -8), 3.96 (2H, m, CH -6), 4.90 (1H, d, J = 8.0,
H-1ꢄ), 7.08 (2H, d, J = 8.5, H-3ꢂ, 5ꢂ), 7.47 (2H, d, J = 8.5, H-2ꢂ, 6ꢂ), 8.27 (1H, s, H-2).
2
2
3
3
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 23.6 (CH ), 23.7 (CH ), 53.6 (CH ), 54.0 (CH ); glucose:
6
2
2
2
2
60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ); aglycon: 49.7 (CH -8), 50.9 (CH -6), 100.7
2
2
(C-8), 103.2 (C-6), 104.2 (C-4a), 116.0 (C-3ꢂ, 5ꢂ), 121.6 (C-3), 124.3 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 154.2 (C-2), 154.7 (C-8a), 157.3
(C-7), 158.5 (C-5), 165.5 (C-4ꢂ), 180.1 (C-4).
4-{5,7-Dihydroxy-6,8-bis[(4-methylpiperazin-1-yl)methyl]-4-oxo-4H-chromen-3-yl}phenyl-ꢀ-D-
glucopyranoside (3b). Yield 68%, C H N O , mp 165–166°C.
33 44
4 10
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 2.20–2.70 (22H, m, piperazine protons), 3.13–3.50 (6H, m,
6
3
3
H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ), 3.74 (2H, m, CH -8), 3.80 (2H, m, CH -6), 4.91 (1H, d, J = 7.2, H-1ꢄ), 7.09 (2H, d, J = 8.4, H-3ꢂ, 5ꢂ),
7.50 (2H, d, J = 8.4, H-2ꢂ, 6ꢂ), 8.40 (1H, s, H-2).
2
2
3
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 45.7, 51.7, 51.8, 54.3, 54.4; 49.7 (CH -8), 50.9 (CH -6),
6
2
2
60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.7 (C-8), 103.2 (C-6), 104.3 (C-4a), 116.0
(C-3ꢂ, 5ꢂ), 121.6 (C-3), 124.3 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 154.1 (C-2), 154.7 (C-8a), 157.3 (C-7), 158.5 (C-5), 165.5 (C-4ꢂ), 180.2
(C-4).
4-(5,7-Dihydroxy-6,8-bis{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-4-oxo-4H-chromen-3-yl)phenyl-ꢀ-D-
glucopyranoside (3c). Yield 53%, C H N O , mp 148–150°C.
35 48
4 12
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 2.20–2.70 (20H, m, piperazine protons), 3.13–3.81 (14H, m,
6
3
3
H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ and 4H of piperazines, CH -8 and CH -6), 4.91 (1H, d, J = 6.7, H-1ꢄ), 7.08 (2H, d, J = 8.4, H-3ꢂ, 5ꢂ), 7.49
2
2
3
(2H, d, J = 8.4, H-2ꢂ, 6ꢂ), 8.42 (1H, s, H-2).
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 52.6 (CH ), 52.8 (CH ), 53.0 (CH ), 57.8, 57.9 (CH ),
6
2
2
2
2
59.2 (CH ); 49.8 (CH -8), 50.9 (CH -6), 60.7 (C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.7
2
2
2
(C-8), 103.2 (C-6), 104.3 (C-4a), 116.0 (C-3ꢂ, 5ꢂ), 121.6 (C-3), 124.3 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 154.1 (C-2), 154.7 (C-8a), 157.3
(C-7), 158.4 (C-5), 165.5 (C-4ꢂ), 180.0 (C-4).
4-[5,7-Dihydroxy-6,8-bis(morpholin-1-ylmethyl)-4-oxo-4H-chromen-3-yl]phenyl-ꢀ-D-glucopyranoside (3d).
Yield 78%, C H N O , mp 239–240°C.
31 38
2 12
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 2.40–2.63 (8H, m, morpholine protons), 3.05–3.84 (18H, m,
6
3
3
H-2ꢄ, 3ꢄ, 4ꢄ, 5ꢄ, 6ꢄ and 8H of morpholines, CH -8 and CH -6), 4.92 (1H, d, J = 7.2, H-1ꢄ), 7.10 (2H, d, J = 8.8, H-3ꢂ, 5ꢂ), 7.50
2
2
3
(2H, d, J = 8.8, H-2ꢂ, 6ꢂ), 8.46 (1H, s, H-2).
13
C NMR spectrum (100 MHz, DMSO-d , ꢃ, ppm): amine: 52.4, 52.7, 65.0, 65.1; 50.2 (CH -8), 51.2 (CH -6), 60.7
6
2
2
(C-6ꢄ), 69.7 (C-4ꢄ), 73.2 (C-2ꢄ), 76.6 (C-5ꢄ), 77.1 (C-3ꢄ), 100.3 (C-1ꢄ), 100.3 (C-8), 103.5 (C-6), 104.2 (C-4a), 116.0 (C-3ꢂ,
5ꢂ), 121.7 (C-3), 124.2 (C-1ꢂ), 130.1 (C-2ꢂ, 6ꢂ), 154.3 (C-2), 154.4 (C-8a), 157.3 (C-7), 158.8 (C-5), 164.8 (C-4ꢂ), 180.3 (C-4).
28

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