Synthesis of 7-(N-12-Cytisinylpropoxy)Isoflavones

Article abstract of DOI:10.1007/s10600-020-03222-9

The reactions of cytisine with isoflavone glycidyl ethers were investigated. A series of cytisine–isoflavone conjugates were regioselectively synthesized via opening the oxirane ring by cytisine.

Full text of DOI:10.1007/s10600-020-03222-9

DOI 10.1007/s10600-020-03222-9
Chemistry of Natural Compounds, Vol. 56, No. 6, November, 2020
SYNTHESIS OF 7-(N-12-CYTISINYLPROPOXY)ISOFLAVONES
1*
1
S. P. Bondarenko, O. G. Makarenko,
2
1,3
V. I. Vinogradova, and M. S. Frasinyuk
The reactions of cytisine with isoflavone glycidyl ethers were investigated. A series of cytisine–isoflavone
conjugates were regioselectively synthesized via opening the oxirane ring by cytisine.
Keywords: cytisine, isoflavone, propanolamine, glycidyl ether.
The alkaloid cytisine possesses high affinity for nicotinic acetylcholine receptors (nAChRs), especially the neuronal
α4β2 subtype [1, 2]. Also, cytisine and its derivatives exhibit antidepressant, neuroprotective, nootropic, antiviral, antiparasitic,
insecticidal, and anticancer activity [3].
Cytisine is a promising platform for discovering new compounds with potential therapeutic applications. One of
the key directions of cytisine chemistry is the synthesis of 12-N-alkyl derivatives [4–15]. This structural modification can
expand the spectrum of pharmacological action of cytisine derivatives and produce compounds affecting H-choline receptors
and possessing spasmolytic, hemostatic [6], and antileishmanial properties [9] and antiarrhythmic, analgesic [15], and
antineoplastic activity [16, 17].
The present research was aimed at developing a novel efficient method for conjugation of cytisine and isoflavone
fragments through an alkoxy linker. The potential of this type of cytisine conjugation for designing biologically active molecules
was confirmed by our previous research that found compounds affecting carcinogenesis and revealing their mechanism of
action among cytisine–isoflavone conjugates [17].
The phenolic compounds for conjugation to cytisine that were used to develop the method for synthesizing
7-(N-12-cytisinylpropoxy)isoflavones were 7-O-glycidyl ethers of 4′-chloroisoflavone 1a,b [17]; the natural isoflavones
formononetin (1c), 2-methylformononetin (1d), cladrin (1e), afromosin (1f), cladrastin (1g), pseudobaptigenin (1h); and
isoflavones 1i,j.
The isoflavone glycidyl ethers were synthesized via alkylation of the phenol hydroxyl by epichlorohydrin without
involving the oxirane ring in the reaction in dimethylacetamide (DMA) in the presence of potash by using an excess of
epichlorohydrin [18].
1
O
N
13
OH
O
10
O
O
O
R
1
N
O
O
O
R
1
14
11
16
a
R
R
R
R
3
3
R
2
R
2
4
4
2a-j
1a-j
a: R = R = R = H, R = Cl; b: R = Me, R = R = H, R = Cl; c: R = R = R = H, R = OMe; d: R = Me, R = R = H, R = OMe
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
e: R = R = H, R = R = OMe; f: R = R = H, R = R = OMe; g: R = H, R = R = R = OMe; h: R = R = H, R R = OCH O
1
2
3
4
1
3
2
4
1
2
3
4
1
2
3
4
2
i: R = R = R = H, R = F; j: R = R = H, R R = 3′-OCH CH O-4′
1
2
3
4
1
2
3
4
2
2
+ –
a. Cytisine, MeCN, (C H ) N I
4
9 4
1) National University of Food Technologies, 68 Vladimirskaya St., Kiev, 01601 Ukraine, e-mail:
svitlana.bondarenko@ukr.net; 2) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the
Republic of Uzbekistan, Tashkent; 3) V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy
of Sciences of Ukraine, 1 Murmanskaya St., Kiev, 02094 Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 6,
November–December, 2020, pp. 895–897. Original article submitted March 20, 2020.
©
1040
0009-3130/20/5606-1040 2020 Springer Science+Business Media, LLC

The reactions of cytisine glycidyl ethers were studied to prepare new vicinal aminoalcohol derivatives and to diversify
the cytisine derivatives. Known methods for aminolysis of epoxides had to be slightly adapted to use cytisine as the nucleophile
for opening the oxirane ring. Studies of the effects of temperature, solvent nature, and ratio of starting compounds on the
course of the reaction enabled development of the optimal conditions for synthesizing the vicinal aminoalcohol derivatives
with isoflavone fragments and cytisine. The glycidyl ethers of 7-hydroxyisoflavones reacted with cytisine to give satisfactory
+ –
yields in MeCN in the presence of catalytic amounts of Bu NI [(C H ) N I ] in a 1:1:1 ratio.
4
4 9 4
The oxirane ring opened regiospecifically under the proposed conditions through the action of cytisine at the least
substituted C atom according to NMR spectral data. Thus, PMR spectra of the cytisine–isoflavone conjugates lacked
characteristic resonances of the oxirane ring and exhibited resonances for the cytisine fragment. The synthesized compounds
13
were mixtures of epimers in a 1:1 ratio. PMR and C NMR spectra showed doubled resonances for the cytisine and aminoalcohol
fragments and for the chromone core atoms positioned close to the alcohol fragment. This feature prevented observation of
13
the spin–spin fine structure in PMR spectra. Resonances of C atoms in C NMR spectra appeared as two closely positioned
singlets (chemical shifts of the second peak are given in parentheses in the Experimental part), which was also confirmed by
HSQC and HMBC spectra of 2a,b.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck plates (Germany) using
13
CH Cl –MeOH mixtures (100:1, 50:1) as eluents. PMR and C NMR spectra were recorded in CDCl on the δ-scale vs.
2
2
3
TMS (internal standard) on Varian M400 (400 and 100 MHz, respectively) and Bruker 500 instruments (500 and 125 MHz).
GC-MS used an Agilent 1100 Series liquid-chromatograph–mass-spectrometer system equipped with an Agilent LC/MSD SL
diode-array and mass-selective detector and chemical ionization at atmospheric pressure (APCI). Analyses of all compounds
agreed with those calculated. Glycidyl ethers of 7-hydroxyisoflavones 1a–j were synthesized as before [18].
General Method for Synthesizing 2a–j. A solution of glycidyl ether 1a–j (1 mmol) in MeCN (20 mL) was treated
with cytisine (0.21 g, 1.1 mmol) and Bu NI (10 mg) and stirred under reflux for 10–12 h (end of reaction determined by TLC).
4
The precipitate that formed upon cooling was filtered off and crystallized from EtOH.
(1S,5R)-3-(3-{[3-(4-Chlorophenyl)-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-hexahydro-8H-
1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2a). C H ClN O , yield 405 mg (78%), mp 180–182°Ñ. APCI MS: 519.2
29 27
2 5
+
1
[M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl
3
fragment: 1.59–1.86 (2H, m, CH -8), 2.24–2.70 (6H, m, H-9, 11à, 13à, 14, OH), 2.71–3.02 (3H, m, H-7, 11b, 13b), 3.63–4.06
2
(5H, m, H-10, 15, 16), 5.75–5.91 (1H, m, Í-5), 6.27 (1H, d, J = 9.0, Í-3), 7.02–7.12 (1H, m, H-4), protons of the isoflavone
fragment: 6.57–6.66 (1H, m, H-8), 6.74–6.83 (1H, m, H-6), 7.25 (2H, d, J = 8.4, H-3′, 5′) (2H, m), 7.35 (2H, d, J = 8.4, H-2′, 6′),
13
7.80 (1H, s, H-2), 7.95–8.06 (1H, m, H-5). C NMR spectrum (100 MHz, CDCl , δ, ppm): 25.7, 27.9 (28.2), 35.6 (35.3), 50.0
3
(49.9), 59.3 (59.7), 60.0 (59.9), 62.0 (61.5), 66.1 (65.9), 70.4 (70.3), 100.9 (100.8), 104.7 (104.6), 115.0, 116.9, 118.4 (118.4), 124.2,
127.7, 128.6, 130.2, 130.3, 134.1, 138.8 (138.8), 150.8 (150.6), 152.6 (152.6), 157.8 (157.8), 163.0, 163.3 (163.0), 175.3.
(1S,5R)-3-(3-{[3-(4-Chlorophenyl)-2-methyl-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-
hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2b). C H ClN O , yield 394 mg (74%), mp 165–167°Ñ.
30 29
2 5
+
1
APCI MS: 533.0 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-
3
hydroxypropyl fragment: 1.73–1.96 (2H, m, H-8), 2.37–2.80 (6H, m, H-9, 11à, 13à, 14, OH), 2.82–3.10 (3H, m, H-7, 11b, 13b),
3.63–4.18 (5H, m, H-10, 15, 16), 5.87–6.03 (1H, m, Í-5), 6.32–6.45 (1H, m, Í-3), 7.18–7.23 (1H, m, H-4), protons of the
isoflavone fragment: 2.27 (3H, s, CH -2), 6.66–6.78 (1H, m, H-8), 6.81–6.89 (1H, m, H-6), 7.19 (2H, d, J = 8.6, H-3′, 5′)
3
13
(2H, m), 7.37 (2H, d, J = 8.6, H-2′, 6′), 8.00–8.11 (1H, m, H-5). C NMR spectrum (100 MHz, CDCl , δ, ppm): 19.6,
3
25.9, 28.0 (28.3), 35.7 (35.4), 50.1 (50.2), 59.5 (60.1), 60.0, 62.1 (61.7), 66.3 (66.0), 70.4, 100.8 (100.8), 104.7 (104.8),
114.6, 117.0, 117.5, 122.4, 127.7, 128.7, 131.7, 132.0, 133.8, 138.9 (138.9), 151.0 (150.7), 157.5, 162.9 (163.0), 163.0,
163.4 (163.5), 176.1.
(1S,5R)-3-(2-Hydroxy-3-{[3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}propyl)-1,2,3,4,5,6-hexahydro-8H-
1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2c). C H N O , yield 324 mg (63%), mp 169–171°Ñ. APCI MS: 515.2
30 30
2 6
+
1
[M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl fragment:
3
1.74–1.98 (2H, m, H-8), 2.38–2.70 (6H, m, H-9, 11à, 13à, 14, OH), 2.85–3.14 (3H, m, H-7, 11b, 13b), 3.84–4.18 (5H, m, H-10, 15, 16),
5.94–6.01 (1H, m, Í-5), 6.40–6.47 (1H, m, Í-3), 7.19–7.27 (1H, m, H-4), protons of the isoflavone fragment: 3.84 (3H, s, 4′-OCH ),
3
1041

6.72–6.78 (1H, m, H-8), 6.89–6.94 (1H, m, H-6), 6.97 (2H, d, J = 8.7, H-3′, 5′), 7.50 (2H, d, J = 8.7, H-2′, 6′), 7.93 (1H, s,
H-2), 8.17 (1H, d, J = 8.9, H-5).
(1S,5R)-3-(2-Hydroxy-3-{[3-(4-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-7-yl]oxy}propyl)-1,2,3,4,5,6-
hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2d). C H N O , yield 328 mg (62%), mp 223–225°Ñ. APCI
31 32
2 6
+
1
MS: 529.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl
3
fragment: 1.79–2.00 (2H, m, H-8), 2.40–2.77 (6H, m, H-9, 11à, 13à, 14, OH), 2.87–3.14 (3H, m, H-7, 11b, 13b), 3.85–4.18 (5H, m,
H-10, 15, 16), 5.93–6.04 (1H, m, Í-5), 6.41–6.46 (1H, m, Í-3), 7.22–7.26 (1H, m, H-4), protons of the isoflavone fragment: 2.31 (3H,
s, CH -2), 3.84 (3H, s, 4′-OCH ), 6.69–6.77 (1H, m, H-8), 6.84–6.92 (1H, m, H-6), 6.97 (2H, d, J = 8.3, H-3′, 5′), 7.21 (2H, d, J = 8.3,
3
3
H-2′, 6′), 8.09 (1H, d, J = 8.8, H-5).
(1S,5R)-3-(3-{[3-(3,4-Dimethoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-hexahydro-
8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2e). C H N O , yield 414 mg (76%), mp 190–192°Ñ. APCI MS: 545.1
31 32
2 7
+
1
[M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl
3
fragment: 1.78–1.99 (2H, m, H-8), 2.44–2.71 (6H, m, H-9, 11à, 13à, 14, OH), 2.85–3.14 (3H, m, H-7, 11b, 13b), 3.81–4.21
(5H, m, H-10, 15, 16), 5.90–6.04 (1H, m, Í-5), 6.43 (1H, d, J = 9.1, Í-3), 7.22–7.26 (1H, m, H-4), protons of the isoflavone
fragment: 3.92 (3H, s, 3′-OCH ), 3.93 (3H, s, 4′-OCH ), 6.74–6.79 (1H, m, H-8), 6.90–6.96 (2H, m, H-5′, 6′), 7.06 (1H, dd,
3
3
J = 8.3, 2.0, H-6), 7.21 (1H, d, J = 2.0, H-2′), 7.93–8.00 (1H, m, H-2), 8.13–8.24 (1H, m, H-5).
(1S,5R)-3-(2-Hydroxy-3-{[6-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}propyl)-1,2,3,4,5,6-
hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2f). C H N O , yield 261 mg (48%), mp 115–117°Ñ. APCI
31 32
2 7
+
1
MS: 545.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl
3
fragment: 1.81–2.01 (2H, m, H-8), 2.37–2.73 (6H, m, H-9, 11à, 13à, 14, OH), 2.90–3.20 (3H, m, H-7, 11b, 13b), 3.78–4.21 (5H, m,
H-10, 15, 16), 5.94–5.99 (1H, m, Í-5), 6.40 –6.45 (1H, m, Í-3), 7.18–7.26 (1H, m, H-4), protons of the isoflavone fragment: 3.85, 3.94
(3H each, s, 6, 4′-OCH ), 6.76–6.80 (1H, m, H-8), 6.98 (2H, d, J = 8.8, H-3′, 5′), 7.52 (2H, d, J = 8.8, H-2′, 6′), 7.59–7.61 (1H, m,
3
H-2), 7.93–8.00 (1H, m, H-5).
(1S,5R)-3-(3-{[3-(3,4-Dimethoxyphenyl)-6-methoxy-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-
hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2g). C H N O , yield 264 mg (46%), mp 121–123°Ñ.
32 34
2 8
+
1
APCI MS: 575.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-
3
hydroxypropyl fragment: 1.74–2.06 (2H, m, H-8), 2.38–2.70 (6H, m, H-9, 11à, 13à, 14, OH), 2.84–3.12 (3H, m, H-7, 11b, 13b),
3.76–4.17 (5H, m, H-10, 15, 16), 5.92–6.00 (1H, m, Í-5), 6.38–6.46 (1H, m, Í-3), 7.17–7.22 (1H, m, H-4), protons of the
isoflavone fragment: 3.91, 3.92, 3.93 (3H, each, s, 6, 3′, 4′-OCH ), 6.71–6.78 (1H, m, H-8), 6.93 (1H, d, J = 8.3, H-5′), 7.06 (1H, dd,
3
J = 8.3, 1.8, H-6′), 7.22–7.26 (1H, m, H-2′), 7.55–7.62 (1H, m, H-2), 7.95–8.02 (1H, m, H-5).
(1S,5R)-3-(3-{[3-(1,3-Benzodioxol-5-yl)-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-hexahydro-
8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2h). C H N O , yield 275 mg (52%), mp 228–230°Ñ. APCI MS: 529.2
30 28
2 7
+
1
[M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz):protons of the 3-(12-cytisinyl)-2-hydroxypropyl fragment:
3
1.78–2.00 (2H, m, H-8), 2.41–2.74 (6H, m, H-9, 11à, 13à, 14, OH), 2.86–3.18 (3H, m, H-7, 11b, 13b), 3.80–4.23 (5H, m, H-10, 15, 16),
5.95–5.99 (1H, m, Í-5), 6.43 (1H, d, J = 9.0, Í-3), 7.20–7.26 (1H, m, H-4), protons of the isoflavone fragment: 5.99 (2H, s, OCH O),
2
6.74–6.79 (1H, m, H-8), 6.87 (1H, d, J = 8.0, H-7′), 6.90–6.95 (1H, m, H-6), 6.98 (1H, d, J = 8.0, H-6′), 7.10 (1H, s, H-4′), 7.92 (1H, s,
H-2), 8.17 (1H, d, J = 8.9, H-5).
(1S,5R)-3-(3-{[3-(4-Fluorophenyl)-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-hexahydro-8H-
1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2i). C H FN O , yield 437 mg (87%), mp 164–166°Ñ. APCI MS: 503.2
29 27
2 5
+
1
[M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl
3
fragment: 1.81–1.99 (2H, m, H-8), 2.40–2.76 (6H, m, H-9, 11à, 13à, 14, OH), 2.86–3.12 (3H, m, H-7, 11b, 13b), 3.78–4.21
(5H, m, H-10, 15, 16), 5.93–6.03 (1H, m, Í-5), 6.40–6.46 (1H, m, Í-3), 7.21–7.26 (1H, m, H-4), protons of the isoflavone
fragment: 6.72–6.80 (1H, m, H-8), 6.90–6.96 (1H, m, H-6), 7.12 (2H, t, J = 8.7, H-3′, 5′), 7.54 (2H, dd, J = 8.8, 5.4, H-2′, 6′), 7.94
(1H, s, H-2), 8.17 (1H, d, J = 8.9, H-5).
(1S,5R)-3-(3-{[3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-oxo-4H-chromen-7-yl]oxy}-2-hydroxypropyl)-1,2,3,4,5,6-
hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2j). C H N O , yield 396 mg (73%), mp 217–219°Ñ. APCI
31 30
2 7
+
1
MS: 543.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): protons of the 3-(12-cytisinyl)-2-hydroxypropyl
3
fragment: 1.77–2.03 (2H, m, H-8), 2.42–2.71 (6H, m, H-9, 11à, 13à, 14, OH), 2.85–3.13 (3H, m, H-7, 11b, 13b), 3.79–4.21 (5H, m,
H-10, 15, 16), 5.93–6.03 (1H, m, Í-5), 6.44 (1H, d, J = 9.1, Í-3), 7.21–7.27 (1H, m, H-4), protons of the isoflavone fragment: 4.25–4.36
(4H, m, H-2, 3), 6.76 (1H, d, J = 2.1, H-8), 6.90–6.95 (2H, m, H-7′, 8′), 7.03 (1H, dd, J = 8.3, 2.0, H-6), 7.11 (1H, d, J = 2.0, H-5′), 7.92
(1H, s, H-2), 8.18 (1H, d, J = 9.0, H-5).
1042

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