New Aloperine–Isoflavone Conjugates

Article abstract of DOI:10.1007/s10600-016-1723-3

The reaction of aloperine with isoflavone glycidyl ethers was investigated. A series of alkaloid–isoflavonoid conjugates were synthesized via regioselective opening of the oxirane ring by aloperine.

Full text of DOI:10.1007/s10600-016-1723-3

DOI 10.1007/s10600-016-1723-3
Chemistry of Natural Compounds, Vol. 52, No. 4, July, 2016
NEW ALOPERINE–ISOFLAVONE CONJUGATES
1*
2
1
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya
The reaction of aloperine with isoflavone glycidyl ethers was investigated. A series of alkaloid–isoflavonoid
conjugates were synthesized via regioselective opening of the oxirane ring by aloperine.
Keywords: aloperine, isoflavone, propanolamine, isoflavone glycidyl ether.
ꢀ-Adrenoblockers play an important role in the treatment of cardiovascular diseases. Their anti-ischemic, anti-
arrhythmic, and antihypertensive properties have been used in clinical medicine for many years. Derivatives of
phenylpropanolamine and phenoxypropanolamine are typical ꢀ-adrenoreceptor blockers [1, 2]. Chromone and flavone
derivatives containing a propanolamine fragment are also known to be capable of blocking ꢀ-adrenoreceptors [3, 4]. Furthermore,
several 7-(3-amino-2-hydroxypropoxy) flavonoid derivatives exhibited antihypertensive [5–7], antihyperglycemic [8], and
antiproliferative [9] activity. Isoflavones containing an aminopropanol fragment showed anti-osteoporosis activity, an estrogen
effect [10], and anticancer activity [11].
In continuation of research on the synthesis of alkaloid–flavonoid conjugates, it seemed interesting to study the
possibility of using a hydroxypropane linker to conjugate 7-hydroxyisoflavones and aloperine, which was isolated as a minor
constituent from seeds and leaves of Sophora alopecuroides L. [12–16].
Modification of this alkaloid was interesting because of its valuable biological properties. Aloperine exhibits anti-
inflammatory, anti-allergic [17, 18], and antiviral activity [19]; inhibits proliferation of HCT116 cancer cells; initiates apoptosis;
and interrupts the cell cycle [20].
The phenols for conjugation with aloperine were the natural isoflavones formononetin 1a [21], 2-methylformononetin
1b [22], cladrin 1c [23], afromorsin 1d [24], cladrastin 1e [23], pseudobaptigenin 1f [25], and their derivatives 1g–j.
Oxiranes are widely used to synthesize phenoxypropanolamines. Their cyclic system can be opened highly
regioselectively by N-nucleophiles. Thus, the most common method for synthesizing phenol glycidyl ethers uses attack of the
phenols at the oxirane ring of 1-chloro-2,3-epoxypropane (epichlorohydrin) to give the chlorohydrin ethers followed by
dehydrochlorination by base to close the epoxide ring [4, 5, 26, 27].
1''
O
OH
1
1
O
8
HO
O
R
1
O
O
R
1
O
R
1
N
3''
4''
a
b
2'
2'
R
R
R
3
4
4
R
R
3
3
R
2
R
2
R
2
5
5
O
O
O
N
R
4
4'
4'
4
4
2a - j
3a - j
1a - j
a: R = R = R = H, R = OMe; b: R = Me, R = R = H, R = OMe; c: R = R = H, R = R = OMe; d: R = R = H, R = R = OMe
1
2
3
4
1
2
3
4
1
2
3
4
1
3
2
4
e: R = H, R = R = R = OMe; f: R = R = H, R R = OCH O; g: R = R = R = H, R = F; h: R = R = R = H, R = Cl
1
2
3
4
1
2
3
4
2
1
2
3
4
1
2
3
4
i: R = Me, R = R = H, R = Cl; j: R = R = H, R R = OCH CH O
1
2
3
4
1
2
3
4
2
2
+ –
a. epichlorohydrin, K CO , DMA, 70°C; b. aloperine, CH CN, (C H ) N I
2
3
3
4 9 4
Scheme 1
1) Taras Shevchenko Kiev National University, 12 Lev Tolstoi St., Kiev, 01033, Ukraine, e-mail:
svitlana.bondarenko@ukr.net; 2) Institute of Bioorganic Chemistry and Petroleum Chemistry, National Academy of Sciences
of Ukraine, 1 Murmanskaya St., Kiev, 02094, Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August,
2016, pp. 532–535. Original article submitted November 26, 2015.
©
0009-3130/16/5204-0615 2016 Springer Science+Business Media New York
615

Isoflavone glycidyl ethers should be synthesized in the absence of strong bases because isoflavone derivatives are
unstable to basic reagents. In our opinion, direct alkylation of the isoflavone phenol hydroxyl by alkylhalide without involving
the oxirane ring in the reaction would be the most effective approach to synthesizing their glycidyl ethers. For this, we studied
the reaction of 7-hydroxyisoflavones with epichlorohydrin in various solvents in the presence of bases. Dimethylacetamide
(DMA) turned out to be the most convenient solvent for using epichlorohydrin as an alkylating agent. High yields of the
glycidyl ethers without side products were obtained by using an excess of epichlorohydrin in the presence of potash. The
proposed conditions for alkylating isoflavone 7-hydroxy groups avoided opening the chromone ring to form
phenoxychlorohydrin and diphenoxypropanol derivatives. They produced high yields of 7-hydroxyisoflavone glycidyl
ethers 2a–j.
The known methods required some adjustment in order to use aloperine as a nucleophile to open the oxirane ring.
7-Hydroxyisoflavone glycidyl ethers 2a–j were reacted with aloperine in MeCN with a catalytic amount of tetrabutylammonium
+ –
iodide [(C H ) N I ]. Classical attack at the least substituted C atom (S 2 mechanism) occurred. These conditions gave high
4
9 4
N
yields of isoflavonoid 7-(3-amino-2-hydroxypropoxy) derivatives 3a–j with an aloperine fragment (Scheme 1).
The structures of the synthesized compounds were elucidated using PMR spectra. Thus, PMR spectra of the aloperine–
isoflavone conjugates lacked peaks characteristic of an oxirane ring and exhibited resonances for an aloperine fragment as
unresolvable multiplets.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck plates (Germany) using
CH Cl –MeOH (100:1, 50:1). PMR spectra were measured on the ꢁ-scale vs. TMS (internal standard) on an M-400 instrument
2
2
(Varian, 400 MHz). Elemental analyses of all compounds agreed with those calculated. Starting natural 7-hydroxyisoflavones
and their analogs 1a–j were synthesized earlier by us [28–30].
General Method for Preparing 7-Hydroxyisoflavone Glycidyl Ethers 2a–j. A solution of 1a–j (10 mmol) in
DMA (20 mL) was treated with potash (5.56 g, 40 mmol) and epichlorohydrin (20 mL) and stirred at 70°C for 5–10 h (end of
reaction determined by TLC). The potash was filtered off. The solvent was evaporated. The solid was crystallized from
i-PrOH.
3-(4-Methoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2a). C H O , yield 78%, mp 139–141ꢂC.
19 16
5
1
2
3
2
3
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.81 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.96 (1H, t, J = 4.8, J = 4.8,
3
2
3
2
Í-3ꢃꢃꢀ), 3.38–3.44 (1H, m, Í-2ꢃꢃ), 3.84 (3H, s, OCH -4ꢃ), 4.02 (1H, dd, J = 11.1, J = 5.9, H-4ꢃꢃꢄ), 4.37 (1H, dd, J = 11.1,
3
3
J = 2.9, H-4ꢃꢃꢀ), 6.89 (1H, d, J = 2.4, H-8), 6.97 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.02 (1H, dd, J = 8.9, 2.4, H-6), 7.50 (2H, d, J = 8.9,
H-2ꢃ, 6ꢃ), 7.92 (1H, s, H-2), 8.22 (1H, d, J = 8.9, H-5).
2-Methyl-3-(4-methoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2b). C H O , yield 51%,
20 18
2
5
1
3
mp 102–104ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.30 (3H, s, CH -2), 2.81 (1H, dd, J = 4.8, J = 2.6,
3
3
2
3
2
Í-3ꢃꢃꢄ), 2.97 (1H, t, J = 4.8, J = 4.8, Í-3ꢃꢃꢀ), 3.38–3.44 (1H, m, Í-2ꢃꢃ), 3.84 (3H, s, OCH -4ꢃ), 4.02 (1H, dd, J = 11.1,
J = 5.9, H-4ꢃꢃꢄ), 4.37 (1H, dd, J = 11.1, J = 2.8, H-4ꢃꢃꢀ), 6.87 (1H, d, J = 2.4, H-8), 6.95–7.00 (3H, m, H-6, 3ꢃ, 5ꢃ), 7.18–7.23
3
3
2
3
(2H, J = 8.9, H-2ꢃ, 6ꢃ), 8.14 (1H, d, J = 8.9, H-5).
3-(3,4-Dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2c). C H O , yield 75%, mp 151–153ꢂC.
20 18
6
1
2
3
2
3
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.82 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.97 (1H, t, J = 4.8, J = 4.8,
3
2
3
Í-3ꢃꢃꢀ), 3.38–3.42 (1H, m, Í-2ꢃꢃ), 3.92 (3H, s, OCH -3ꢃ), 3.94 (3H, s, OCH -4ꢃ), 4.04 (1H, dd, J = 11.1, J = 5.9, H-4ꢃꢃꢄ),
4.39 (1H, dd, J = 11.1, J = 2.8, H-4ꢃꢃꢀ), 6.90 (1H, d, J = 2.4, H-8), 6.93 (1H, d, J = 8.3, H-5ꢃ), 7.00–7.05 (2H, m, H-6, 6ꢃ), 7.21
(1H, d, J = 2.0, H-2ꢃ), 7.96 (1H, s, Í-2), 8.23 (1H, d, J = 8.9, H-5).
3
3
2
3
3
6-Methoxy-3-(4-methoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2d). C H O , yield 68%,
20 18
6
1
2
3
mp 153–154ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.83 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.98 (1H, t,
J = 4.8, J = 4.8, Í-3ꢃꢃꢀ), 3.43–3.50 (1H, m, Í-2ꢃꢃ), 3.85 (3H, s, OCH -4ꢃ), 3.99 (3H, s, OCH -6), 4.10 (1H, dd, J = 11.4,
J = 5.8, H-4ꢃꢃꢄ), 4.43 (1H, dd, J = 11.4, J = 3.0, H-4ꢃꢃꢀ), 6.95–7.00 (3H, m, H-6, 3ꢃ, 5ꢃ), 7.51 (2H, d, J = 8.8, H-2ꢃ, 6ꢃ), 7.64
3
2
3
3
2
3
3
2
3
(1H, s, H-2), 7.94 (1H, s, H-5).
3-(3,4-Dimethoxyphenyl)-6-methoxy-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2e). C H O , yield 85%,
21 20
7
1
2
3
mp 159–161ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.82 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.97 (1H, t,
J = 4.8, J = 4.8, Í-3ꢃꢃꢀ), 3.42–3.49 (1H, m, Í-2ꢃꢃ), 3.91 (3Í, s, OCH -3ꢃ), 3.93 (3H, s, OCH -4ꢃ), 3.98 (3Í, s, OCH -6), 4.09
3
2
3
3
3
3
616

2
3
2
3
(1H, dd, J = 11.5, J = 5.9, H-4ꢃꢃꢄ), 4.43 (1H, dd, J = 11.5, J = 3.0, H-4ꢃꢃꢀ), 6.93 (1H, d, J = 8.3, H-5ꢃ), 6.97 (1H, s, H-8), 7.04
3
4
(1H, dd, J = 8.3, J = 2.0, H-6ꢃ), 7.24 (1H, d, J = 2.0, H-2ꢃ), 7.64 (1H, s, Í-2), 7.97 (1H, s, H-5).
3-(1,3-Benzodioxol-5-yl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2f). C H O , yield 87%, mp 150–152ꢂC.
19 14
6
1
2
3
2
3
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.81 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.97 (1H, t, J = 4.8, J = 4.8,
3
2
3
2
3
Í-3ꢃꢃb), 3.37–3.46 (1H, m, Í-2ꢃꢃ), 4.02 (1H, dd, J = 11.1, J = 5.9, H-4ꢃꢃꢄ), 4.38 (1H, dd, J = 11.1, J = 2.8, H-4ꢃꢃꢀ), 5.99 (2H, s,
3ꢃ, 4ꢃ-OCH O), 6.87 (1H, d, J = 8.0, H-5ꢃ), 6.89 (1H, d, J = 2.4, H-8), 6.97 (1H, dd, J = 8.0, J = 1.7, H-6ꢃ), 7.02 (1H, dd, J = 8.9,
J = 2.4, H-6), 7.09 (1H, d, J = 1.7, H-2ꢃ), 7.91 (1H, s, Í-2), 8.21 (1H, d, J = 8.9, H-5).
3
4
3
2
4
4
7-(Oxiran-2-ylmethoxy)-3-(4-fluorophenyl)-4H-chromen-4-one (2g). C H FO , yield 76%, mp 155–157ꢂC.
18 13
4
1
2
3
2
3
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.81 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.96 (1H, t, J = 4.8, J = 4.8,
3
2
3
2
3
Í-3ꢃꢃꢀ), 3.39–3.45 (1H, m, Í-2ꢃꢃ), 4.03 (1H, dd, J = 11.1, J = 6.0, H-4ꢃꢃꢄ), 4.39 (1H, dd, J = 11.1, J = 2.8, H-4ꢃꢃꢀ), 6.90 (1H,
d, J = 2.4, H-8), 7.04 (1H, dd, J = 8.9, J = 2.4, H-6), 7.13 (2H, t, J
3
4
3
3
3
= 8.9, J = 8.9, H-3ꢃ, 5ꢃ), 7.53 (2H, dd, J
= 8.9,
H,H
H,F
H,H
4
3
J
= 5.5, H-2ꢃ, 6ꢃ), 7.94 (1H, s, H-2), 8.22 (1H, d, J = 8.9, H-5).
H,F
7-(Oxiran-2-ylmethoxy)-3-(4-chlorophenyl)-4H-chromen-4-one (2h). C H ClO , yield 73%, mp 164–166ꢂC.
18 13
4
1
2
3
2
3
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.81 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.97 (1H, t, J = 4.8, J = 4.8,
3
2
3
2
3
Í-3ꢃꢃꢀ), 3.38–3.45 (1H, m, Í-2ꢃꢃ), 4.03 (1H, dd, J = 11.1, J = 5.9, H-4ꢃꢃꢄ), 4.39 (1H, dd, J = 11.1, J = 2.8, H-4ꢃꢃꢀ), 6.91 (1H,
d, J = 2.4, H-8), 7.04 (1H, dd, J = 8.9, J = 2.4, H-6), 7.40 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.51 (2H, d, J = 8.9, H-2ꢃ, 6ꢃ), 7.95 (1H,
s, H-2), 8.22 (1H, d, J = 8.9, H-5).
3
4
2-Methyl-7-(oxiran-2-ylmethoxy)-3-(4-chlorophenyl)-4H-chromen-4-one (2i). C H ClO , yield 70%, mp 160–
19 15
2
4
3
1
162ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.29 (3H, s, ÑÍ -2), 2.81 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.95
3
3
2
3
2
3
2
(1H, t, J = 4.8, J = 4.8, Í-3ꢃꢃꢀ), 3.38 –3.44 (1H, m, Í-2ꢃꢃ), 4.03 (1H, dd, J = 11.1, J = 5.9, H-4ꢃꢃꢄ), 4.38 (1H, dd, J = 11.1,
J = 2.8, H-4ꢃꢃꢀ), 6.88 (1H, d, J = 2.4, H-8), 6.99 (1H, dd, J = 8.9, J = 2.4, H-6), 7.23 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.41 (2H, d,
3
4
3
4
J = 8.9, H-2ꢃ, 6ꢃ), 8.13 (1H, d, J = 8.9, H-5).
3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (2j). C H O , yield 83%,
20 16
6
1
2
3
mp 146–148ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.81 (1H, dd, J = 4.8, J = 2.6, Í-3ꢃꢃꢄ), 2.96 (1H, t,
J = 4.8, J = 4.8, Í-3ꢃꢃꢀ), 3.38–3.44 (1H, m, Í-2ꢃꢃ), 4.02 (1H, dd, J = 11.1, J = 5.9, H-4ꢃꢃꢄ), 4.28 (4H, s, 3ꢃ, 4ꢃ-OCH ÑÍ O),
4.37 (1H, dd, J = 11.1, J = 2.8, H-4ꢃꢃꢀ), 6.88 (1H, d, J = 2.5, H-8), 6.92 (1H, d, J = 8.3, H-5ꢃ), 7.00–7.05 (2H, m, H-6, 6ꢃ), 7.10
(1H, d, J = 2.1, H-2ꢃ), 7.90 (1H, s, Í-2), 8.21 (1H, d, J = 8.9, H-5).
3
2
3
2
3
2
2
2
3
General Method for Preparing 3a–j. A solution of 2a–j (1 mmol) in MeCN (20 mL) was treated with aloperine
+ –
(0.25 g, 1.1 mmol) and (C H ) N I (10 mg), stirred, refluxed for 10–15 h (end of reaction determined by TLC), and cooled.
4
9 4
The resulting precipitate was filtered off and crystallized from i-PrOH.
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1
1(6aH)-yl]propoxy}-3-(4-methoxyphenyl)-4H-chromen-4-one (3a). C H N O , yield 68%, mp 161–163ꢂC. Í NMR
34 40
2 5
spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.17–1.94, 1.96–2.47, 2.56–2.90, 2.96–3.23, 5.51–5.66 (12H, 7Í, 4Í, 2Í, 1Í,
3
5m, aloperine protons and NCH CH(OH)CH O-7), 3.85 (3H, s, OCH -4ꢃ), 4.00–4.24 (3H, m, NCH CH(OH)CH O-7), 6.88
2
2
3
2
2
3
4
(1H, d, J = 2.4, H-8), 6.97 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.02 (1H, dd, J = 8.9, J = 2.4, H-6), 7.50 (2H, d, J = 8.9, H-2ꢃ, 6ꢃ), 7.92
(1H, s, H-2), 8.22 (1H, d, J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1(6aH)-yl]propoxy}-2-methyl-3-(4-methoxyphenyl)-4H-chromen-4-one (3b). C H N O , yield 69%, mp 93–95ꢂC.
35 42
2 5
1
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.19–1.93, 1.95–2.48, 2.60–2.90, 2.95–3.22, 5.51–5.65 (12H, 10Í, 4Í, 2Í,
3
1Í, 5m, aloperine protons, CH -2 and NCH CH(OH)CH O-7), 3.85 (3H, s, OCH -4ꢃ), 3.98–4.24 (3H, m, NCH CH(OH)CH O-7),
3
2
2
3
2
2
3
4
6.86 (1H, dd, J = 8.9, J = 2.4, H-6), 6.93–7.01 (3H, m, H-8, 3ꢃ, 5ꢃ), 7.21 (2H, d, J = 8.9, H-2ꢃ, 6ꢃ), 8.13 (1H, d, J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1
1(6aH)-yl]propoxy}-3-(3,4-dimethoxyphenyl)-4H-chromen-4-one (3c). C H N O , yield 82%, mp 94–96ꢂC. Í NMR
35 42
2 6
spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.20–1.92, 1.95–2.46, 2.58–2.89, 2.95–3.21, 5.51–5.63 (12H, 7Í, 4Í, 2Í, 1Í,
3
5m, aloperine protons and NCH CH(OH)CH O-7), 3.91, 3.93 (each 3H, s, OCH -3ꢃ, 4ꢃ), 4.00–4.26 (3H, m,
2
2
3
NCH CH(OH)CH O-7), 6.81–6.96 (2Í, m, Í-8, 5ꢃ), 6.99–7.09 (2Í, m, Í-6, 6ꢃ), 7.18–7.23 (1Í, m, Í-2ꢃ), 7.95 (1H, s, Í-2),
2
2
8.21 (1H, d, J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1(6aH)-yl]propoxy}-6-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (3d). C H N O , yield 84%, mp 103–105ꢂC.
35 42
2 6
1
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.18–1.91, 1.96–2.45, 2.58–2.89, 2.97–3.18, 5.52–5.62 (12H, 7Í, 4Í,
3
617

2Í, 1Í, 5m, aloperine protons and NCH CH(OH)CH O-7), 3.85, 3.97 (each 3H, s, OCH -4ꢃ, 6), 3.98–4.31 (3H, m,
2
2
3
NCH CH(OH)CH O-7), 6.92 (1H, s, H-8), 6.97 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.51 (2H, d, J = 8.9, H-2ꢃ, 6ꢃ), 7.62 (1H, s, H-2), 7.94
2
2
(1H, s, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1(6aH)-yl]propoxy}-3-(3,4-dimethoxyphenyl)-6-methoxy-4H-chromen-4-one (3e). C H N O , yield 75%, mp 102–104ꢂC.
36 44
2 7
1
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.19–1.91, 1.94–2.45, 2.56– 2.89, 2.95–3.19, 5.50–5.62 (12H, 7Í, 4Í,
3
2Í, 1Í, 5m, aloperine protons and NCH CH(OH)CH O-7), 3.91, 3.93, 3.97 (each 3H, s, OCH -3ꢃ, 4ꢃ, 6), 4.02–4.30 (3H, m,
2
2
3
3
4
NCH CH(OH)CH O-7), 6.91 (1H, d, J = 8.3, H-5ꢃ), 6.94 (1H, s, H-8), 7.05 (1H, dd, J = 8.3, J = 2.0, H-6ꢃ), 7.25 (1H, d, J = 2.0,
2
2
H-2ꢃ), 7.62 (1H, s, Í-2), 7.97 (1H, s, H-5).
3-(1,3-Benzodioxol-5-yl)-7-{2-hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-
methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-1(6aH)-yl]propoxy}-4H-chromen-4-one (3f). C H N O , yield 77%, mp 170–172ꢂC.
34 38
2 6
1
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.20–1.93, 1.98–2.46, 2.58–2.90, 2.96–3.21, 5.50–5.64 (12H, 7Í, 4Í, 2Í,
3
1Í, 5m, aloperine protons and NCH CH(OH)CH O-7), 4.00–4.24 (3H, m, NCH CH(OH)CH O-7), 6.00 (2H, s, 3ꢃ, 4ꢃ-OCH O),
2
2
2
2
2
6.85–6.91 (2Í, m, Í-8, 5ꢃ), 6.96–7.06 (2Í, m, Í-6, 6ꢃ), 7.11 (1H, d, J = 1.7, H-2ꢃ), 7.92 (1H, s, Í-2), 8.21 (1H, d, J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1
1(6aH)-yl]propoxy}-3-(4-fluorophenyl)-4H-chromen-4-one (3g). C H FN O , yield 73%, mp 177–179ꢂC. Í NMR
33 37
2 4
spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.18–1.92, 1.96–2.45, 2.58–2.90, 2.96–3.20, 5.50–5.64 (12H, 7Í, 4Í, 2Í, 1Í,
3
5m, aloperine protons and NCH CH(OH)CH O-7), 4.00–4.25 (3H, m, NCH CH(OH)CH O-7), 6.89 (1H, d, J = 2.4, H-8),
2
2
2
2
3
4
3
3
3
4
7.04 (1H, dd, J = 8.9, J = 2.4, H-6), 7.13 (2H, t, J
= 8.9, J
= 8.9, H-3ꢃ, 5ꢃ), 7.54 (2H, dd, J
= 8.9, J
= 5.5,
H,H
H,F
H,H
H,F
H-2ꢃ, 6ꢃ), 7.94 (1H, s, H-2), 8.21 (1H, d, J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1
1(6aH)-yl]propoxy}-3-(4-chlorophenyl)-4H-chromen-4-one (3h). C H ClN O , yield 52%, mp 157–159ꢂC. Í NMR
33 37
2 4
spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.19–1.90, 1.94–2.45, 2.56–2.90, 2.93–3.20, 5.50–5.64 (12H, 7Í, 4Í, 2Í, 1Í,
3
5m, aloperine protons and NCH CH(OH)CH O-7), 4.00–4.26 (3H, m, NCH CH(OH)CH O-7), 6.89 (1H, d, J = 2.4, H-8),
2
2
2
2
3
4
7.05 (1H, dd, J = 8.9, J = 2.4, H-6), 7.40 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.51 (2H, d, J = 8.9, H-2ꢃ, 6ꢃ), 7.59 (1Í, s, Í-2), 8.21 (1H,
d, J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1(6aH)-yl]propoxy}-2-methyl-3-(4-chlorophenyl)-4H-chromen-4-one (3i). C H ClN O , yield 68%, mp 89–91ꢂC.
34 39
2 4
1
Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.22–1.92, 1.95–2.44, 2.57–2.87, 2.91–3.22, 5.43–5.64 (12H, 10Í, 4Í,
3
2Í, 1Í, 5m, aloperine protons, ÑÍ -2 and NCH CH(OH)CH O-7), 3.98–4.26 (3H, m, NCH CH(OH)CH O-7), 6.87 (1H, d,
3
2
2
2
2
3
4
J = 2.4, H-8), 6.99 (1H, dd, J = 8.9, J = 2.4, H-6), 7.32 (2H, d, J = 8.9, H-3ꢃ, 5ꢃ), 7.41 (2H, d, J = 8.9, H-2ꢃ, 6ꢃ), 8.12 (1H, d,
J = 8.9, H-5).
7-{2-Hydroxy-3-[(6S,6aR,13aS)-3,4,6,7,8,9,10,12,13,13a-decahydro-2H-6,13-methanopyrido[1,2-a:3ꢃ,2ꢃ-e]azocin-
1(6aH)-yl]propoxy}-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-4H-chromen-4-one (3j). C H N O , yield 77%,
35 40
2
6
1
mp 138–140ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.20–1.92, 1.97–2.44, 2.58–2.88, 2.96–3.18, 5.51–5.63
3
(12H, 7Í, 4Í, 2Í, 1Í, 5m, aloperine protons and NCH CH(OH)CH O-7), 4.00–4.24 (3H, m, NCH CH(OH)CH O-7), 4.29 (4H, s,
2
2
2
2
OÑÍ CH O-3ꢃ, 4ꢃ), 6.85–6.94 (2Í, m, Í-8, 5ꢃ), 6.99–7.06 (2Í, m, Í-6, 6ꢃ), 7.11 (1H, d, J = 1.7, H-2ꢃ), 7.90 (1H, s, Í-2), 8.21
2
2
(1H, d, J = 8.9, H-5).
REFERENCES
1.
2.
3.
4.
5.
S. D. Yuzhakov, Pharm. Chem. J., 14, 149 (1980).
S. D. Yuzhakov, R. G. Glushkov, and M. D. Mashkovskii, Pharm. Chem. J., 25, 283 (1991).
P. Da Re, P. Valenti, A. Borraccini, and G. P. Primofiore, J. Med. Chem., 15, 198 (1972).
P. Da Re, G. P. Primofiore, and A. Bertelli, J. Med. Chem., 15, 868 (1972).
E. S. C. Wu, T. E. Cole, T. A. Davidson, J. C. Blosser, A. R. Borrelli, C. R. Kinsolving, T. E. Milgate, and R. B. Parker,
J. Med. Chem., 30, 788 (1987).
6.
E. S. C. Wu, T. E. Cole, T. A. Davidson, M. A. Dailey, K. G. Doring, M. Fedorchuk, J. T. Loch, T. L. Thomas,
and J. C. Blosser, J. Med. Chem., 32, 183 (1989).
618

7.
8.
E. S. C. Wu, J. T. Loch, B. H. Toder, A. R. Borrelli, D. Gawlak, L. A. Radov, and N. P. Gensmantel, J. Med. Chem.,
35, 3519 (1992).
A. K. Verma, H. Singh, M. Satyanarayana, S. P. Srivastava, P. Tiwari, A. B. Singh, A. K. Dwivedi, S. K. Singh,
M. Srivastava, C. Nath, R. Raghubir, A. K. Srivastava, and R. Pratap, J. Med. Chem., 55, 4551 (2012).
H. Chen, A. A. Mrazek, X. Wang, C. Ding, Y. Ding, L. J. Porro, H. Liu, C. Chao, M. R. Hellmich, and J. Zhou,
Bioorg. Med. Chem., 22, 3393 (2014).
9.
10.
C.-H. Tseng, Y.-L. Chen, C.-M. Lu, C.-K. Wang, Y.-T. Tsai, R.-W. Lin, C.-F. Chen, Y.-F. Chang, G.-J. Wang, M.-L. Ho,
and C.-C. Tzeng, Eur. J. Med. Chem., 44, 3621 (2009).
11.
12.
13.
D. Zhou, W. Tuo, H. Hu, J. Xu, H. Chen, Z. Rao, Y. Xiao, X. Hu, and P. Liu, Eur. J. Med. Chem., 64, 432 (2013).
A. Orechoff, N. Proskurnina, and R. Konowalowa, Chem. Ber., 68, 431 (1935).
T. E. Monakhova, O. N. Tolkachev, V. S. Kabanov, M. E. Perelꢃson, and N. F. Proskurnina, Chem. Nat. Compd.,
10, 477 (1974).
14.
O. N. Tolkachev, T. E. Monakhova, V. I. Sheichenko, V. S. Kabanov, O. G. Fesenko, and N. F. Proskurnina, Chem. Nat.
Compd., 11, 29 (1975).
15.
16.
17.
S. Kuchkarov, Yu. K. Kushmuradov, and Kh. A. Aslanov, Chem. Nat. Compd., 13, 250 (1977).
S. Kuchkarov and Yu. K. Kushmuradov, Chem. Nat. Compd., 15, 364 (1979).
C. C. Zhou, H. B. Gao, X. B. Sun, H. B. Shi, W. Liu, H. N. Yuan, and Z. X. Wang, Zhongguo Yaoli Xuebao,
10, 360 (1989).
18.
19.
20.
21.
22.
X.-Y. Yuan, W. Liu, P. Zhang, R.-Y. Wang, and J.-Y. Guo, Eur. J. Pharmacol., 629, 147 (2010).
Z. Dang, K. Jung, L. Zhu, W. Lai, H. Xie, K.-H. Lee, L. Huang, and C.-H. Chen, Med. Chem. Lett., 5, 942 (2014).
L. Zhang. Y. Zheng, H. Deng, L. Liang, and J. Peng, Int. J. Mol. Med., 33, 1613 (2014).
E. T. Bailey and C. M. Francis, Aust. J. Agric. Res., 22, 731 (1971).
R. Maurya, D. K. Yadav, G. Singh, B. Bhargavan, P. S. Narayana Murthy, M. Sahai, and M. M. Singh, Bioorg. Med.
Chem. Lett., 19, 610 (2009).
23.
24.
25.
M. Shamma and L. D. Stiver, Tetrahedron, 25, 3887 (1969).
P. Lebreton, K. R. Markham, W. T. Swift, B. Oung, and T. J. Mabry, Phytochemistry, 6, 1675 (1967).
Y. Shirataki, S. Yoshida, Y. Sugita, I. Yokoe, M. Komatsu, M. Ohyama, T. Tanaka, and M. Iinuma, Phytochemistry,
44, 715 (1997).
26.
A. F. Crowther, D. J. Gilman, B. J. McLoughlin, L. H. Smith, R. W. Turner, and T. M. Wood, J. Med. Chem.,
12, 638 (1969).
27.
28.
29.
30.
A. F. Crowther and L. H. Smith, J. Med. Chem., 11, 1009 (1968).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Chem. Nat. Compd., 39, 265 (2003).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Chem. Nat. Compd., 39, 340 (2003).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Chem. Nat. Compd., 39, 344 (2003).
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