Synthesis of amino-acid derivatives of formononetin and cladrin

Article abstract of DOI:10.1007/s10600-012-0313-2

Aminomethylation of natural isoflavones by amino acids was studied. Conditions for selective production of N-(4H-4-oxochromen-8-yl)methyl- substituted amino acids were found.

Full text of DOI:10.1007/s10600-012-0313-2

Chemistry of Natural Compounds, Vol. 48, No. 4, September, 2012 [Russian original No. 4, July–August, 2012]
SYNTHESIS OF AMINO-ACID DERIVATIVES OF
FORMONONETIN AND CLADRIN
1*
1
1
M. S. Frasinyuk, G. P. Mrug, O. D. Fedoryak,
UDC 547.814.5
2
and S. P. Bondarenko
Aminomethylation of natural isoflavones by amino acids was studied. Conditions for selective production of
N-(4H-4-oxochromen-8-yl)methyl-substituted amino acids were found.
Keywords: formononetin, cladrin, amino acid, aminomethylation.
Introducing an amino acid into organic compounds while retaining the amine and carboxylic acid is a promising
pathway for creating physiologically active compounds that enables water-soluble salts of these compounds in both anionic
and cationic forms to be prepared. In this respect the Mannich reaction in addition to reductive amination is an important
method for synthesizing derivatives of natural amino acids and their analogs with retention of the asymmetric centers. However,
depending on the structures of the starting materials and reagents, a decisive factor for performing aminomethylation is the
solution acidity. Thus, catalysis by acids [1–3] and bases [4–9] was used for aminomethylation of phenols involving amino
acids. It is well known that N,N-bis-derivatives of amino acids in addition to the desired mono N-substituted amino acids were
obtained under acid-catalysis conditions [10–13]. Formation of 1,3-benzoxazine derivatives was observed by carrying out the
Mannich reaction in neutral or basic solution [14]. Aminomethylation of 3-formylchromones by amino acids led to their
deformylation [15].
HOOC
N
N
COOH
HO
O
O
R
1
HO
O
R
1
HO
O
O
R
1
R
R
R
R
3
3
3
R
2
R
2
O
R
2
R
4
R
4
4
5a - 7a
1 - 4
5c - 8c
HOOC
COOH
Me
N
COOH
N
N
HO
O
R
1
HO
O
R
1
HO
O
O
R
1
R
R
R
R
R
R
3
3
3
R
2
O
R
2
O
R
2
4
4
4
5b, 7b
5e - 8e
5d- 8d
1, 5a - e: R = R = R = H, R = OMe; 2, 6a, 6c - e: R = R = H, R = R = OMe
1
2
3
4
1
2
3
4
3, 7a - e: R = Me, R = R = H, R = OMe; 4, 8c - e: R = R = H, R = Me, R = OMe
1
2
3
4
1
3
2
4
1) Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Kiev,
Ul. Murmanskaya, 1, Ukraine, e-mail: mfras@i.kiev.ua; 2) National University of Food Technologies, 01601, Kiev,
Ul. Vladimirskaya, 68, Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2012, pp. 514–517.
Original article submitted February 6, 2012.
©
570
0009-3130/12/4804-0570 2012 Springer Science+Business Media, Inc.

Because chemical modification of natural biologically active compounds is a promising pathway to creating new
highly effective low-molecular-weight bioregulators, the goal of our work was to synthesize amino-acid derivatives of
isoflavones. Introducing amino acids into flavonoid molecules, for which special transport mechanisms exist in the body,
improves the permeability of the compounds through the cell membrane. This can enhance the effectiveness of their physiological
action [16]. In addition, increasing the solubility of natural isoflavones and their analogs expands the capability for studying
their biological activity and increases their bioavailability.
In continuation of research on aminomethylation of natural isoflavones such as formononetin (1), 2-methylformononetin
(3), and cladrin (2) in addition to 5-methylformononetin (4), we studied the Mannich reaction involving these compounds and
the N-substituted amino acids L-proline, sarcosine, and piperidinecarboxylic acids.
The previously proposed method for aminomethylation of isoflavones in aqueous alcohol [17–20] turned out in our
instance to be unsuitable because of the low solubility of isoflavonoids 1–4. Also, prolonged heating of the reaction mixture
facilitated the formation of 8-ethoxymethyl derivatives of the isoflavones as before [18]. This reduced the yields and hindered
purification of the target amino-acid derivatives.
We proposed an aminomethylation method using anhydrous EtOH and paraformaldehyde in the presence of a catalytic
amount of 4-N,N-dimethylaminopyridine (DMAP) for the synthesis of Mannich bases of the isoflavones that contained amino
acids. Under these conditions, regioselective aminomethylation of the 7-hydroxyisoflavones occurred with formation of their
8-aminomethyl derivatives in high yields and purities.
The structures of 5–8 were confirmed by PMR spectroscopy. Thus, PMR spectra of these compounds contained
resonances for isoflavone and amino-acid protons. The resonance of the chromone CH -8 protons of N-substituted nipecotinic
2
acid 5c, 6c, 7c, and 8c; isonipecotinic acid 5d, 6d, 7d, and 8d; and sarcosine 5e, 6e, 7e, and 8e was observed as a 2H singlet at
3.90–4.18 ppm. Peaks for the CH -8 protons in spectra of derivatives of L-proline 5a and 5b and of D,L-pipecolic acid 7a and
2
7b appeared as a diastereotopic pair of doublets at 4.00–4.18 ppm with SSCC 14.0–14.3 Hz because of the closely situated
asymmetric center.
Thus, we synthesized a series of amino-acid derivatives of formononetin, cladrin, and their analogs. The presence of
basic and acidic groups in them expands the capability of studying their biological activity. The method for aminomethylation
of isoflavones that was developed by us can be used to synthesize amino-acid derivatives of other natural compounds.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck plates (Germany) with elution by
CHCl :MeOH (9:1, 95:5). PMR spectra were measured in DMSO-d with TMS internal standard on the ꢀ-scale on a Mercury
3
6
M 400 instrument (Varian, 400 MHz). Elemental analyses of all compounds agreed with those calculated.
General Method for Preparing Amino-acid Derivatives of 7-Hydroxyisoflavones 5–8. A solution of
7-hydroxyisoflavone (1–4, 2 mmol) in anhydrous EtOH (10 mL) was refluxed; treated with the appropriate amino acid
(2.4 mmol), paraformaldehyde (2.4 mmol calculated as formaldehyde), and DMAP (5 mg); refluxed for 2–8 h (end of reaction
determined by TLC); cooled; and filtered to remove the precipitate. The solid was crystallized from EtOH.
1-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-L-proline (5a). Yield 46%, C H NO ,
22 21
6
mp 200–202°C.
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.65–1.97, 2.14–2.30, 2.52–2.65, 2.98–3.11, 3.39–3.54 (3H,
6
2
3
1H, 1H, 1H, 1H, 5m, proline protons), 3.80 (3H, s, 4ꢁ-OCH ), 4.16, 4.21 (2H, 2d, J = 14.0, CH -8), 6.94 (1H, d, J = 9.2,
3
2
3
3
3
H-6), 6.98 (2H, d, J = 8.2, H-3ꢁ, H-5ꢁ), 7.52 (2H, d, J = 8.2, H-2ꢁ, H-6ꢁ), 7.95 (1H, d, J = 9.2, H-5), 8.29 (1H, s, H-2).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-2-carboxylic Acid (5b). Yield
89%, C H NO , mp 220–222°C.
23 23
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.28–2.12, 2.69–3.34 (6H, 3H, 2m, pipecolic acid protons),
6
2
3
3
3.79 (3H, s, 4ꢁ-OCH ), 4.00, 4.10 (2H, 2d, J = 14.3, CH -8), 6.89 (1H, d, J = 9.2, H-6), 6.98 (2H, d, J = 8.2, H-3ꢁ, H-5ꢁ), 7.51
3
2
3
3
(2H, d, J = 8.2, H-2ꢁ, H-6ꢁ), 7.92 (1H, d, J = 9.2, H-5), 7.31 (1H, s, H-2).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic Acid (5c). Yield
95%, C H NO , mp 215–216°C.
23 23
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.41–1.96, 2.26–2.40, 2.68–2.80, 2.91–3.02, 3.33–3.53 (5H,
6
3
1H, 1H, 1H, 1H, 5m, nipecotinic acid protons), 3.80 (3H, s, 4ꢁ-OCH ), 3.98 (2H, s, CH -8), 6.90 (1H, d, J = 8.9, H-6), 6.98
(2H, d, J = 8.9, H-3ꢁ, H-5ꢁ), 7.52 (2H, d, J = 8.5, H-2ꢁ, H-6ꢁ), 7.93 (1H, d, J = 8.9, H-6), 8.29 (1H, s, H-2).
3
2
3
3
3
571

1-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-4-carboxylic Acid (5d). Yield
86%, C H NO , mp 160–162°C.
23 23
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.50–1.66, 1.81–1.91, 2.23–2.35, 2.85–2.95 (2H, 2H, 3H, 2H,
4m, isonipecotinic acid protons), 3.78 (3H, s, 4ꢁ-OCH ), 3.95 (2H, s, CH -8), 6.89 (1H, d, J = 9.2, H-6), 6.98 (2H, d, J = 8.5,
6
3
3
3
2
3
3
H-3ꢁ, H-5ꢁ), 7.49 (2H, d, J = 8.5, H-2ꢁ, H-6ꢁ), 7.90 (1H, d, J = 9.2, H-5), 8.34 (1H, s, H-2).
N-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-N-methylglycine (5e). Yield 94%,
C H NO , mp 225–226°C.
20 19
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.39 (3H, s, NCH ), 3.38 (2H, s, NCH ), 3.81 (3H, s, 4ꢁ-OCH ),
6
3
2
3
3
3
3
4.01 (2H, s, CH -8), 6.92 (1H, d, J = 9.2, H-6), 6.98 (2H, d, J = 8.5, H-3ꢁ, H-5ꢁ), 7.52 (2H, d, J = 8.5, H-2ꢁ, H-6ꢁ), 7.95 (1H,
2
3
d, J = 9.2, H-5), 8.27 (1H, s, H-2).
1-{[7-Hydroxy-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-L-proline (6a). Yield 46%,
C H NO , mp 216–217°C.
23 23
7
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.66–1.97, 2.13–2.22, 2.52–2.62, 2.99–3.10, 3.43–3.55 (3H,
6
3
1H, 1H, 1H, 1H, 5m, proline protons), 3.79 (6H, s, 3ꢁ-OCH , 4ꢁ-OCH ), 4.18 (2H, s, CH -8), 6.95 (1H, d, J = 8.9, H-6), 7.00
(1H, d, J = 8.2, H-5ꢁ), 7.15 (1H, dd, J = 8.2, J = 1.4, H-6ꢁ), 7.21 (1H, d, J = 1.4, H-2ꢁ), 7.96 (1H, d, J = 8.9, H-5), 8.33 (1H,
3
3
2
3
3
4
4
3
s, H-2).
1-{[7-Hydroxy-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic Acid (6c).
Yield 92%, C H NO , mp 227–229°C.
24 25
7
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.43–1.95, 2.27–2.42, 2.51–2.59, 2.70–2.80, 2.93–3.02 (5H,
6
3
1H, 1H, 1H, 1H, 5m, nipecotinic acid protons), 3.80 (6H, s, 3ꢁ-OCH , 4ꢁ-OCH ), 3.99 (2H, s, CH -8), 6.90 (1H, d, J = 8.5,
H-6), 7.00 (1H, d, J = 8.2, H-5ꢁ), 7.15 (1H, dd, J = 8.2, J = 1.4, H-6ꢁ), 7.23 (1H, d, J = 1.4, H-2ꢁ), 7.94 (1H, d, J = 8.5,
H-6), 8.32 (1H, s, H-2).
3
3
2
3
3
4
4
3
1-{[7-Hydroxy-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-4-carboxylic Acid (6d).
Yield 86%, C H NO , mp 170–172°C.
24 25
7
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.48–1.97, 2.23–2.42, 2.83–3.08 (5H, 2H, 2H, 3m, isonipecotinic
6
3
3
acid protons), 3.80 (6H, s, 3ꢁ-OCH , 4ꢁ-OCH ), 3.98 (2H, s, CH -8), 6.88 (1H, d, J = 9.2, H-6), 6.99 (1H, d, J = 9.2, H-5ꢁ),
3
3
2
3
4
4
3
7.15 (1H, dd, J = 9.2, J = 2.4, H-6ꢁ), 7.23 (1H, d, J = 2.4, H-2ꢁ), 7.93 (1H, d, J = 9.2, H-5), 8.30 (1H, s, H-2).
N-{[7-Hydroxy-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-N-methylglycine (6e). Yield 95%,
C H NO , mp 214–215°C.
21 21
7
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.39 (3H, s, NCH ), 3.39 (2H, s, NCH ), 3.80 (6H, s, 3ꢁ-OCH ,
6
3
2
3
3
3
3
4
4ꢁ-OCH ), 4.08 (2H, s, CH -8), 6.92 (1H, d, J = 8.5, H-6), 7.00 (1H, d, J = 8.5, H-5ꢁ), 7.15 (1H, dd, J = 8.5, J = 2.4, H-6ꢁ),
3
2
4
3
7.22 (1H, d, J = 2.4, H-2ꢁ), 7.95 (1H, d, J = 8.5, H-5), 8.33 (1H, s, H-2).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-8-yl]methyl}-L-proline (7a). Yield 81%,
C H NO , mp 194–195°C.
23 23
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.68–2.00, 2.13–2.23, 2.56–2.68, 3.01–3.11, 3.43–3.55 (3H,
6
2
1H, 1H, 1H, 1H, 5m, proline protons), 2.28 (3H, s, 2-CH ), 3.81 (3H, s, 4ꢁ-OCH ), 4.17, 4.22 (2H, 2d, J = 14.0, CH -8), 6.90
3
3
2
3
3
3
3
(1H, d, J = 8.5, H-6), 6.98 (2H, d, J = 9.2, H-3ꢁ, H-5ꢁ), 7.19 (2H, d, J = 9.2, H-2ꢁ, H-6ꢁ), 7.85 (1H, d, J = 8.5, H-5).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-8-yl]methyl}piperidine-2-carboxylic Acid
(7b). Yield 96%, C H NO , mp 242–253°C.
24 25
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.28–2.11, 2.68–3.37 (6H, 3H, 2m, pipecolic acid protons),
6
2
3
2.25 (3H, s, 2-CH ), 3.81 (3H, s, 4ꢁ-OCH ), 4.00, 4.08 (2H, 2d, J = 14.3, CH -8), 6.84 (1H, d, J = 8.5, H-6), 6.97 (2H, d,
J = 8.5, H-3ꢁ, H-5ꢁ), 7.18 (2H, d, J = 8.5, H-2ꢁ, H-6ꢁ), 7.82 (1H, d, J = 8.5, H-5).
3
3
2
3
3
3
1-{[7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic Acid
(7c). Yield 75%, C H NO , mp 159–161°C.
24 25
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.36–1.87, 2.28–2.38, 2.65–2.81, 2.88–3.02 (6H, 1H, 1H, 1H,
6
3
4m, nipecotinic acid protons), 2.25 (3H, s, 2-CH ), 3.78 (3H, s, 4ꢁ-OCH ), 3.96 (2H, s, CH -8), 6.86 (1H, d, J = 8.9, H-6),
3
3
2
3
3
3
6.97 (2H, d, J = 8.5, H-3ꢁ, H-5ꢁ), 7.18 (2H, d, J = 8.5, H-2ꢁ, H-6ꢁ), 7.81 (1H, d, J = 8.9, H-5).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-8-yl]methyl}piperidine-4-carboxylic Acid
(7d). Yield 57%, C H NO , mp 182–184°C.
24 25
6
572

PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.48–1.68, 1.79–1.94, 2.27–2.37, 2.85–2.98 (2H, 2H, 3H, 2H,
6
3
4m, isonipecotinic acid protons), 2.24 (3H, s, 2-CH ), 3.78 (3H, s, 4ꢁ-OCH ), 3.97 (2H, s, CH -8), 6.84 (1H, d, J = 8.9, H-6),
3
3
2
3
3
3
6.97 (2H, d, J = 8.9, H-3ꢁ, H-5ꢁ), 7.18 (2H, d, J = 8.9, H-2ꢁ, H-6ꢁ), 7.81 (1H, d, J = 8.9, H-5).
N-{[7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-8-yl]methyl}-N-methylglycine (7e). Yield
92%, C H NO , mp 219–220°C.
21 21
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.26 (3H, s, 2-CH ), 2.50 (3H, s, NCH ), 3.38 (2H, s, NCH ),
6
3
3
2
3
3
3
3.81 (3H, s, 4ꢁ-OCH ), 4.08 (2H, s, CH -8), 6.88 (1H, d, J = 8.9, H-6), 6.98 (2H, d, J = 8.2, H-3ꢁ, H-5ꢁ), 7.19 (2H, d, J = 8.2,
3
2
3
H-2ꢁ, H-6ꢁ), 7.84 (1H, d, J = 8.9, H-6).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-5-methyl-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic Acid
(8c). Yield 91%, C H NO , mp 222–224°C.
24 25
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.41–1.88, 2.21–2.37, 2.71–2.81, 2.89–3.02 (6H, 1H, 1H, 1H,
6
4m, nipecotinic acid protons), 2.70 (3H, s, 5-CH ), 3.80 (3H, s, 4ꢁ-OCH ), 3.93 (2H, s, CH -8), 6.64 (1H, s, H-6), 6.96 (2H, d,
3
3
2
3
3
J = 8.5, H-3ꢁ, H-5ꢁ), 7.46 (2H, d, J = 8.5, H-2ꢁ, H-6ꢁ), 8.16 (1H, s, H-2).
1-{[7-Hydroxy-3-(4-methoxyphenyl)-5-methyl-4-oxo-4H-chromen-8-yl]methyl}piperidine-4-carboxylic Acid
(8d). Yield 82%, C H NO , mp 223–225°C.
24 25
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 1.50–1.64, 1.81–1.90, 2.19–2.36, 2.85–2.95 (2H, 2H, 3H, 2H,
6
4m, isonipecotinic acid protons), 2.67 (3H, s, 5-CH ), 3.77 (3H, s, 4ꢁ-OCH ), 3.90 (2H, s, CH -8), 6.64 (1H, s, H-6), 6.96 (2H,
3
3
2
3
3
d, J = 8.9, H-3ꢁ, H-5ꢁ), 7.44 (2H, d, J = 8.9, H-2ꢁ, H-6ꢁ), 7.22 (1H, s, H-2).
N-{[7-Hydroxy-3-(4-methoxyphenyl)-5-methyl-4-oxo-4H-chromen-8-yl]methyl}-N-methylglycine (8e). Yield
85%, C H NO , mp 223–225°C.
21 21
6
PMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.34 (3H, s, NCH ), 2.68 (3H, s, 5-CH ), 3.37 (2H, s, NCH ),
6
3
3
2
3
3
3.77 (3H, s, 4ꢁ-OCH ), 4.02 (2H, s, CH -8), 6.67 (1H, s, H-6), 6.96 (2H, d, J = 8.9, H-3ꢁ, H-5ꢁ), 7.44 (2H, d, J = 8.9, H-2ꢁ,
3
2
H-6ꢁ), 8.22 (1H, s, H-2).
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