Copper-catalyzed 1,3-dipolar cycloaddition reaction of spirosolanederived azide for the preparation of modified solasodine alkaloid

Article abstract of DOI:10.1007/s10593-018-2284-0

[Figure not available: see fulltext.] Modification of the steroidal alkaloid solasodine was performed by introduction of 1,2,3-triazolyl substituents at the С-6 atom of spirosolane ring system. The azidolysis of 5,6α-epoxysolasodine diacetate, formed as the major product during epoxidation of solasodine diacetate by the action of sodium azide in DMF in the presence of ammonium chloride, proceeded through the formation of 6β-azido-5α-hydroxysolasodine diacetate. The newly obtained azide was used in reactions with terminal alkynes in the presence of copper(I) bromide and N,N-diisopropylethylamine in DMF to synthesize the respective (22R,25R)-N,O-diacetyl-6β-[4-aryl-1,2,3-triazol-1-yl]-5α-hydroxyspirosolanes.

Full text of DOI:10.1007/s10593-018-2284-0

DOI 10.1007/s10593-018-2284-0
Chemistry of Heterocyclic Compounds 2018, 54(4), 411–416
Copper-catalyzed 1,3-dipolar cycloaddition reaction of spirosolane-
derived azide for the preparation of modified solasodine alkaloid
Anastasiya O. Finke1,2, Maxim E. Mironov1,2,
Anna B. Skorova1, Elvira E. Shults1,2*
1 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences,
9 Akademika Lavrentieva Ave., Novosibirsk 630090, Russia; e-mail: schultz@nioch.nsc.ru
2 Novosibirsk State University,
1 Pirogova St., Novosibirsk 630090, Russia; e-mail: nfinke@nioch.nsc.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 411–416
Submitted February 20, 2018
Accepted April 26, 2018
O
Me
Me
Me
O
N
Me
Me
Me
Ar
H
Me
Me
N
1. Ac2O, Py
Me
HN
H
O
Me
2. MCPBA
3. NaN3, NH4Cl
H
CH
Me
H
Me
CuACC
O
H
Me
H
O
H
Me
H
H
5
43–78%
H
O
6
H
H
H
5
HO
H
H
N
O
6
O
N
Me
HO
HO
N3
N
Me
O
Ar
Modification of the steroidal alkaloid solasodine was performed by introduction of 1,2,3-triazolyl substituents at the С-6 atom of
spirosolane ring system. The azidolysis of 5,6α-epoxysolasodine diacetate, formed as the major product during epoxidation of solasodine
diacetate by the action of sodium azide in DMF in the presence of ammonium chloride, proceeded through the formation of 6β-azido-
5α-hydroxysolasodine diacetate. The newly obtained azide was used in reactions with terminal alkynes in the presence of copper(I) bro-
mide and N,N-diisopropylethylamine in DMF to synthesize the respective (22R,25R)-N,O-diacetyl-6β-[4-aryl-1,2,3-triazol-1-yl]-
5α-hydroxyspirosolanes.
Keywords: solasodine, steroidal alkaloids, 1,2,3-triazoles, azidolysis, CuААС reaction.
The steroidal alkaloid solasodine (1) is a readily
available metabolite isolated from plants belonging to the
Solanum genus.1 The main source used for industrial
production of this alkaloid is the kangaroo apple Solanum
laciniatum.2 Solasodine has been shown to possess various
types of biological activity, including antimicrobial,3
hepatoprotective,4 analgesic,5 anti-inflammatory,6 antioxi-
dative,7 cytotoxic, and antitumor effects.8 Solasodine
significantly affects the central nervous system,9 resulting
in cognitive enhancement9c and anticonvulsant activity9d in
animal models. For these reasons, there is interest in
performing chemical modifications of solasodine.
Modifications of the hydroxy group at the С-3 position
have been used for the preparation of antitumor agents.10
Transformations of alkaloid 1 into pregnanene- or
pregnanediene-type compounds have also been described.11
Some relatively more complex transformations at the С-2,3
atoms of the А ring in the steroid nucleus produced fused
pyrazole and isoxazole derivatives, as well as converted the
А ring of spirosolane 1 by forming lactone and lactam
moieties.12 The formation of diene motif in the В ring of
the aforementioned alkaloid has been also described.12b In
the current study, we present the synthesis of N,O-diacetyl-
5α-hydroxy-6β-azidosolasodine and its transformations
under the conditions of copper-catalyzed 1,3-dipolar
cycloaddition reaction (CuAAC reaction).
It should be noted that there is also interest in structural
modifications of alkaloid 1 at the С-5,6 atoms, since it is
known that the teratogenic properties of jervanes,
solanidanes, and spirosolanes are linked to the presence of
a double bond between the C-5,6 atoms in the steroid ring
system.13
The initial treatment of solasodine (1) with an excess of
acetic anhydride in refluxing pyridine led to solasodine
0009-3122/18/54(4)-0411©2018 Springer Science+Business Media, LLC
411

Chemistry of Heterocyclic Compounds 2018, 54(4), 411–416
Scheme 1
diacetate 2,14 the epoxidation of which in the presence of
m-chloroperoxybenzoic acid gave a mixture of 5,6α- and
presence of СuBr and N,N-diisopropylethylamine upon
heating to 95°С.
1
5,6β-epoxides 3a,b15 in 3:1 ratio (according to H NMR
As a result of these reactions, (22R,25R)-N,O-diacetyl-
5α-hydroxy-6β-[4-aryl(hetaryl)-1,2,3-triazol-1-yl]spirosolanes
11–16 were obtained in 78, 69, 71, 60, 43, and 52% yields,
respectively. The reaction conditions for the 1,3-dipolar
cycloaddition were selected on the basis of literature data
on reactions between steroidal azido alcohols with terminal
acetylenes,17 which demonstrated the low reactivity of
6β-azido-5α,3β-dihydroxyandrostan-17-one under the com-
monly used conditions of CuAAC reactions,18 using
CuSO4, sodium ascorbate, and aqueous СH2Сl2. According
to the published data,17 the target 1,2,3-triazole fragment
was not formed under these conditions due the steric
influence from the azide group (1,3-diaxial interaction
between the azide functionality at the С-6 atom and the
methyl group at the С-19 atom. An increase of the reaction
temperature led to conformational changes in the steroid
nucleus, associated with a change in the relative orientation
of the azide group at the С-6 atom and the methyl group at
the С-19 atom, as well as removal of the steric strain and
reactivity enhancement. During the interaction of spiro-
spectrum of the reaction mixture) with an overall yield of
79% (Scheme 1). The attempt to separate the epoxides was
not successful, therefore the ring opening step was
performed using the mixture of epoxides.
Azidolysis of epoxides 3а,b by the action of NaN3 was
achieved in DMF medium in the presence of NH4Cl by
following a previously published procedure.16a It is known
that the presence of ammonium salt facilitates the
nucleophilic substitution reaction by azide ion through
coordination at the oxygen atom and weakening of the
binding orbital in the oxygen–carbon bond of the epoxide
group.16b As a result of this reaction followed by silica gel
column chromatography, a new compound – 6β-azido-
N,O-diacetyl-5α-hydroxysolasodine 4 was isolated in 64%
yield (Scheme 1). The interaction of azide 4 with terminal
alkynes (phenylacetylene (5), p-tolylacetylene (6),
4-methoxyphenylacetylene (7), 5-ethynyl-1,2,3-trimethoxy-
benzene (8), 4-fluorophenylacetylene (9), and 2-ethynyl-
pyridine (10)) was achieved in DMF medium in the
412

Chemistry of Heterocyclic Compounds 2018, 54(4), 411–416
solane azide 4 with arylacetylenes 9 and 10 in the presence
spectrometer, vaporizer temperature 200–250°С, EI
ionization (70 eV). The specific rotation values were
measured on a PolAAr 3005 polarimeter and were
expressed in (deg·ml)/(g·dm), with concentration in g per
100 ml of solution. Melting points were determined on a
Stuart SMP30 hot stage apparatus. The reaction progress
was controlled by TLC on Silufol UV-254 plates using
CHCl3 and 10:1 CHCl3–EtOH mixture as eluents, with
visualization in iodine chamber and under UV light. The
reaction products were isolated by column chromatography
using silica gel from Acros (0.035–0.240 mm).
of СuBr catalyst and N,N-diisopropylethylamine as a base,
the yields of the CuAAC reaction deteriorated, and also the
corresponding homocoupling products – 1,1'-buta-1,3-diyn-
1,4-diylbis(4-fluorobenzene)19 and 2,2'-buta-1,3-diyn-1,4-diyl-
dipyridine19 were isolated in 18 and 22% yields,
respectively.
The composition and structure of the synthesized
1
compounds were confirmed from data of IR, Н and 13С
1
NMR spectroscopy, and mass spectrometry. Н and 13C
NMR spectra of the synthesized compounds featured the
characteristic signal set of spirosolane system and the
substituent that was present. 1H NMR spectrum of
epoxides 3a,b contained signals of the 6-CH proton at
2.85 ppm (doublet, J = 4.3 Hz) for the α-isomer and at
3.04 ppm (singlet) for the β-isomer. The relative amounts
of isomeric epoxides 3a and 3b in the mixture were
determined from the ratio of the integrated intensities of the
aforementioned signals. The 6-CH proton of azide 4 gave a
signal at 3.36 ppm in the form of a broadened singlet,
pointing to its equatorial orientation and corresponding to
the stereoelectronic requirements of trans-diaxial
configuration of azide and hydroxy groups in azido
alcohols that are obtained by epoxide ring opening.16a The
presence of an azide substituent was also confirmed from
IR spectral data (a strong absorption band at 2096 cm–1,
corresponding to the stretching vibrations of azide group).
The reagents used in this work – sodium azide,
phenylacetylene (5), p-tolylacetylene (6), 4-methoxy-
phenylacetylene (7), 4-fluorophenylacetylene (9), 2-ethynyl-
pyridine (10), 3-chloroperoxybenzoic acid (50–55%),
СuBr, and N,N-diisopropylethylamine were purchased
from Alfa Aesar. The solvents (CHCl3, DMF, pyridine)
were purified according to standard procedures. DMF was
additionally distilled under argon flow immediately before
use. Solasodine (1) was obtained from diosgenin,22 mp 199–
25
201°С (EtOH), [α]D –98.5 (с 0.41, MeOH). Compounds
2,14 3a,b,15 and 1,2,3-trimethoxy-5-ethynylbenzene (8)23
were synthesized according to previously published
procedures.
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2-azido-2a-hydroxy-5',6a,8a,9-tetramethylocta-
decahydrospiro[naphtho[2',1':4,5]indeno[2,1-b]furan-
10,2'-piperidin]-4-yl acetate (N,O-diacetyl-6β-azido-
5α-hydroxysolasodine) (4). NaN3 (114 mg, 1.75 mmol) and
NH4Cl (47 mg, 0.88 mmol) were added to a solution
containing a mixture of solasodine diacetate α- and
β-epoxides 3a,b (451 mg, 0.88 mmol) in DMF (7 ml). The
reaction mixture was stirred while heating to 90°С for 44 h,
then poured onto a Petri dish for evaporation of DMF
under ambient conditions. The residue was dissolved in
CHCl3 (30 ml), the solution was washed with saturated
NaCl solution (3×15 ml), the organic extracts were
combined and dried over anhydrous MgSO4. The drying
agent was removed by filtration, the solvent was
evaporated at reduced pressure, the residue was separated
by silica gel column chromatography (eluent petroleum
ether – EtOAc, gradient from 100:1 to 10:1). The fraction
containing the azide was recrystallized from 5:1 petroleum
ether – EtOAc mixture. Yield 312 mg (64%), colorless fine
1
The 1,2,3-triazole ring proton in H NMR spectra of
compounds 11–16 appeared as a singlet in the region of
7.74–8.19 ppm. The carbon atoms of this heterocycle gave
13C NMR signals at 120.1–120.8 ppm (the С-5 atom was
observed as a doublet in spectra acquired in JMOD
experiment) and 145.8–147.1 ppm (singlet of the С-4
atom). These data confirmed the formation of 1,4-disub-
stituted 1H-1,2,3-triazoles as a result of СuAAС reaction.20
Thus, we report the first modification of steroidal
alkaloid solasodine involving the introduction of a
heterocyclic substituent at the С-6 position. We propose a
method for the preparation of a new group of solasodine
derivatives, in which the spirosolane nucleus and aromatic
(heteroaromatic) system are connected through a linker
with potential biological activity – a 1Н-1,2,3-triazole ring.
Experimental
26
IR spectra were recorded on a Bruker Vector 22 FTIR
spectrometer in KВr pellets. 1H and 13С NMR spectra were
acquired on Bruker Avance 400 (400 and 100 MHz,
respectively, compounds 12–14) and Bruker Avance 600
(600 and 150 MHz, respectively, compounds 4, 11, 15, 16)
spectrometers in CDCl3, using TMS as internal standard.
The structures of the obtained compounds were elucidated
crystalline powder, mp 220–223°С (EtOAc), [α]D –91.2
(с 0.23, CHCl3). IR spectrum, ν, cm–1: 609, 665, 692, 717,
755, 804, 856, 871, 923, 966, 1002, 1031, 1068, 1135,
1160, 1178, 1245, 1321, 1363, 1380, 1405, 1432, 1454,
1631, 1731, 2096, 3411. 1H NMR spectrum, δ, ppm
(J, Hz): 0.90 (3H, s, 18-СH3); 0.93 (3H, d, J = 7.0,
27-СH3); 1.07 (3H, d, J = 6.6, 21-СH3); 1.15 (3H, s,
19-СH3); 1.16–1.23 (3H, m, 12,24-CН2, 14-CН); 1.31–1.47
(5H, m, 1,11,15-CН2, 9-CН); 1.56–1.61 (3H, m, 1,2,23-CН2);
1.67–1.85 (8H, m, 2,4,7,12,23-CН2, 8,17-CН); 1.92–2.01
(3H, m, 15,24-CН2, 25-CН); 2.03 (3H, s, OCOCH3); 2.12
(2H, m, 4-СH2, 5-OH); 2.19 (3H, s, NCOCH3); 2.84–2.87
(1H, m, 26-CН2); 3.03–3.09 (1H, m, 20-CН); 3.36 (1H, br. s,
6-CН); 3.98–4.04 (1H, m, 26-CН2); 4.16 (1H, ddd, J = 8.8,
J = 7.4, J = 6.6, 16-CН); 5.09–5.14 (1H, m, 3-СH).
1
1
using Н and 13С NMR spectra, two-dimensional Н–1Н
NMR experiments (COSY, NOESY, mixing time 1 s, pulse
delay 2 s), as well as two-dimensional heteronuclear NMR
experiments (1H–13C COLOC, H–13C HMBC), relying on
1
literature data for solasodine (1).21 The multiplicity of 13С
NMR signals was determined from spectra acquired in the
J-modulation (JMOD) mode. High-resolution mass spectra
were recorded on a Thermo Scientific DFS mass
413

Chemistry of Heterocyclic Compounds 2018, 54(4), 411–416
13C NMR spectrum, δ, ppm: 16.4 (19,21-CH3); 16.6
5'-CH). 13C NMR spectrum, δ, ppm: 15.7 (C-19); 16.3
(C-21); 16.8 (C-18); 18.5 (C-27); 21.0 (С-11); 21.5
(OCOCH3); 24.0 (С-23); 24.3 (С-24); 25.2 (NCOCH3);
26.5 (С-2); 28.0 (С-25); 30.6 (С-7); 31.6 (C-8); 31.8
(С-15); 32.5 (С-1); 38.4 (С-20); 38.5 (С-4); 38.8 (С-10);
40.3 (С-13); 41.5 (С-12); 45.5 (С-9); 48.9 (С-26); 55.3
(С-14); 62.1 (С-17); 65.3 (С-6); 70.7 (С-3); 76.1 (С-5);
78.8 (С-16); 101.2 (С-22); 120.7 (С-5'), 125.6 (С-2'',6'');
128.2 (С-4''); 128.9 (С-3'',5''); 130.4 (С-1''); 146.7 (C-4');
171.1 (OCOCH3); 171.2 (NCOCH3). Mass spectrum, m/z
(Irel, %): 659 (41), 658 (100), 504 (30), 163 (31), 149 (29),
146 (58), 114 (41), 109 (26), 91 (28), 43 (32). Found, m/z:
658.4089 [M]+. C39H54N4O5. Calculated, m/z: 658.4084.
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2a-hydroxy-5',6a,8a,9-tetramethyl-2-[4-(4-methyl-
phenyl)-1H-1,2,3-triazol-1-yl]octadecahydrospiro[naphtho-
[2',1':4,5]indeno[2,1-b]furan-10,2'-piperidin]-4-yl acetate
((22R,25R)-N,O-diacetyl-5α-hydroxy-6β-[4-(4-methyl-
phenyl)-1,2,3-triazol-1-yl]spirosolane) (12). Yield 167 mg
(18-CH3); 18.4 (27-CH3); 20.8 (С-11); 21.4 (OCOCH3);
23.7 (С-23); 24.4 (С-24); 25.2 (NCOCH3); 26.5 (С-2); 28.0
(С-25); 30.0 (С-8); 31.1 (С-7); 31.9 (С-15); 32.0 (С-1);
37.4 (С-4); 38.4 (С-20); 38.8 (С-10); 40.1 (С-12); 41.3
(С-13); 45.2 (С-9); 49.0 (С-26); 54.8 (С-14); 62.2 (С-17);
66.6 (С-6); 70.6 (С-3); 75.6 (С-5); 78.7 (С-16); 101.1
(С-22); 170.9 (OCOCH3); 171.0 (NCOCH3). Mass spectrum,
m/z (Irel, %): 556 (52), 542 (35), 541 (100), 498 (36), 487
(45), 180 (30), 156 (49), 155 (81), 114 (36), 43 (30).
Found, m/z: 556.3619 [M]+. C31H48N4O5. Calculated, m/z:
556.3623.
Preparation of (22R,25R)-N,O-diacetyl-5α-hydroxy-
6β-[4-aryl-1,2,3-triazol-1-yl]spirosolanes 11–16 (General
method). CuBr (10 mg, 0.07 mmol) and N,N-diiso-
propylethylamine (371 mg, 2.88 mmol) were added to a
solution of azido alcohol 4 (200 mg, 0.36 mmol) and the
appropriate terminal acetylene 5–10 (0.43 mmol) in DMF
(10 ml). The reaction mixture was stirred with heating to
95°С for 48 h under argon flow, cooled, and poured onto a
Petri dish for evaporation under ambient conditions. The
residue was treated with CHCl3 (20 ml), washed with
saturated aqueous NaCl solution (3×15 ml), the organic
extracts were combined and dried over anhydrous MgSO4.
The drying agent was filtered off and the solvent was
removed by evaporation at reduced pressure using water
aspirator. The oily residue was dissolved in a minimum
amount of CHCl3 and separated by silica gel column
chromatography (eluent CHCl3–EtOH, gradient from 100:1
to 10:1). The reaction products were isolated in the
following sequence: compounds 11–16 (using 50:1 СHСl3–
MeOH as eluent), then compounds 5–8, 10 (trace amounts)
or compound 9 (20 mg) and the homocoupling products (in
the reactions of compound 4 with alkynes 9, 10) – 1,4-bis-
(4-fluorophenyl)buta-1,3-diyne19 and 1,4-di(pyridin-2-yl)-
buta-1,3-diyne.19
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2a-hydroxy-5',6a,8a,9-tetramethyl-2-(4-phenyl-
1H-1,2,3-triazol-1-yl)octadecahydrospiro[naphtho[2',1':4,5]-
indeno[2,1-b]furan-10,2'-piperidin]-4-yl acetate ((22R,25R)-
N,O-diacetyl-5α-hydroxy-6β-(4-phenyl-1,2,3-triazol-1-yl)-
spirosolane) (11). Yield 184 mg (78%), yellow amorphous
powder, [α]D27 –73.6 (c 0.23, CHCl3). IR spectrum, ν, cm–1:
609, 678, 694, 723, 763, 802, 838, 865, 923, 966, 985,
1033, 1072, 1137, 1243, 1321, 1365, 1382, 1402, 1432,
1454, 1500, 1633, 1731, 2873, 2900, 2950, 3062, 3428.
1H NMR spectrum, δ, ppm (J, Hz): 0.75 (3H, s, 19-СH3);
0.94 (3H, d, J = 7.0, 27-СH3); 1.00 (3H, s, 18-СH3); 1.09
(3H, d, J = 6.6, 21-СH3); 1.21–1.50 (6H, m, 1,7,11,12,24-CН2,
14-CН); 1.53–1.63 (3H, m, 9-CН, 15,23-CН2); 1.69 (1H, td,
J = 11.0, J = 3.7, 1-CH2); 1.76–1.83 (4H, m, 2,12,23-CН2);
1.93–2.03 (5H, m, 4,11,15,23-CН2, 25-CН); 2.04 (3H, s,
OCOCH3); 2.14 (1H, dd, J = 12.8, J = 4.8, 4-CН2); 2.20–
2.25 (2H, m, 7,24-CН2); 2.23 (3H, s, NCOCH3); 2.50–2.56
(1H, m, 8-CH); 2.80–2.88 (2H, m, 26-CН2, 5-OH); 3.02–
3.09 (1H, m, 20-CH); 4.04–4.10 (1H, m, 26-CH2); 4.21
(1H, ddd, J = 8.6, J = 7.4, J = 6.4, 16-СН); 4.37 (1H, br. s,
6-СH); 5.16–5.21 (1H, m, 3-CH); 7.31–7.47 (3H, m,
3'',4'',5''-СН); 7.80–7.86 (2H, m, 2'',6''-CH); 7.86 (1H, s,
25
(69%), yellow amorphous powder, [α]D –77.4 (c 0.24,
CHCl3). IR spectrum, ν, cm–1: 609, 661, 727, 755, 796,
821, 877, 923, 966, 1033, 1072, 1137, 1164, 1245, 1322,
1365, 1380, 1400, 1452, 1498, 1580, 1610, 1635, 1654,
1
1731, 2873, 2950, 3065, 3398. H NMR spectrum, δ, ppm
(J, Hz): 0.74 (3H, s, 19-CH3); 0.93 (3H, d, J = 6.4, 27-CH3);
0.99 (3H, s, 18-CH3); 1.08 (3H, d, J = 6.6, 21-СH3); 1.21–1.80
(14H, m, 1,2,7,11,12,15,23,24-CН2, 9,14,17-CН); 1.91–2.00
(5H, m, 4,11,15,23-CН2, 25-CH); 2.03 (3H, s, OCOCH3);
2.10–2.16 (1H, m, 4-CН2); 2.19–2.24 (2H, m, 7,24-CН2);
2.21 (3H, s, NCOCH3); 2.38 (3H, s, CH3); 2.50–2.56 (1H,
m, 8-CH); 2.80–2.88 (2H, m, 26-CH2, 5-OH); 3.05–3.10
(1H, m, 20-CH); 4.02–4.06 (1H, m, 26-CH2); 4.20 (1H,
ddd, J = 8.8, J = 7.3, J = 6.6, 16-CH); 4.36 (1H, br. s,
6-CH); 5.16–5.22 (1H, m, 3-CH); 7.23 (2H, d, J = 7.8,
3'',5''-CH); 7.73 (2H, d, J = 7.8, 2'',6''-CH); 7.80 (1H, s,
5'-CH). 13C NMR spectrum, δ, ppm: 15.7 (19-CH3); 16.3
(21-CH3); 16.7 (18-CH3); 18.5 (27-CH3); 21.0 (С-11); 21.3
(CH3 Ar); 21.5 (OCOCH3); 24.0 (С-23); 24.2 (С-24); 25.2
(NCOCH3); 26.4 (С-2); 27.9 (С-25); 30.6 (С-7); 31.5
(C-8); 31.8 (С-15); 32.5 (С-1); 38.3 (С-20); 38.4 (С-4);
38.8 (С-10); 40.2 (С-13); 41.5 (С-12); 45.4 (С-9); 48.8
(С-26); 55.3 (С-14); 62.0 (С-17); 65.1 (С-6); 70.7 (С-3);
76.1 (С-5); 78.8 (С-16); 101.2 (С-22); 120.4 (С-5'); 125.5
(С-2'',6''); 127.5 (С-4''); 129.5 (С-3'',5''); 138.0 (С-1'');
146.7 (C-4'); 171.0 (OCOCH3); 171.2 (NCOCH3). Mass
spectrum, m/z (Irel, %): 672 (78), 657 (26), 388 (94), 178
(56), 160 (63), 135 (96), 114 (43), 72 (44), 44 (79), 43
(100). Found, m/z: 672.4245 [M]+. C40H56N4O5. Calculated,
m/z: 672.4248.
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2a-hydroxy-2-[4-(4-methoxyphenyl)-1H-
1,2,3-triazol-1-yl]-5',6a,8a,9-tetramethyloctadecahydro-
spiro[naphtho[2',1':4,5]indeno[2,1-b]furan-10,2'-piperi-
din]-4-yl acetate ((22R,25R)-N,O-diacetyl-5α-hydroxy-6β-
[4-(4-methoxyphenyl)-1,2,3-triazol-1-yl]spirosolane)
(13). Yield 176 mg (71%), yellowish amorphous powder,
25
[α]D –46.6 (c 0.34, CHCl3). IR spectrum, ν, cm–1: 613,
663, 755, 796, 836, 867, 923, 968, 985, 1033, 1072, 1108,
1137, 1176, 1247, 1286, 1303, 1322, 1365, 1380, 1454,
414

Chemistry of Heterocyclic Compounds 2018, 54(4), 411–416
1498, 1520, 1584, 1633, 1731, 2873, 2950, 3050, 3428.
138.2 (С-3'',5''); 146.5 (C-4'); 153.7 (C-4''); 171.1
(OCOCH3); 171.2 (NCOCH3). Mass spectrum, m/z (Irel, %):
748 (10), 513 (90), 453 (65), 435 (58), 264 (57), 235 (100),
220 (55), 163 (58), 114 (79), 109 (53). Found, m/z:
748.4415 [M]+. C42H60N4O8. Calculated, m/z: 748.4406.
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2-[4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl]-
2a-hydroxy-5',6a,8a,9-tetramethyloctadecahydrospiro-
[naphtho-[2',1':4,5]indeno[2,1-b]furan-10,2'-piperidin]-
4-yl acetate ((22R,25R)-N,O-diacetyl-5α-hydroxy-6β-[4-
(4-fluorophenyl)-1,2,3-triazol-1-yl]spirosolane) (15). Yield
1H NMR spectrum, δ, ppm (J, Hz): 0.76 (3H, s, 19-CH3);
0.94 (3H, d, J = 6.4, 27-CH3); 1.00 (3H, s, 18-CH3); 1.09
(3H, d,
J
=
6.6, 21-СH3); 1.21–1.62 (9H, m,
1,7,11,12,15,23,24-CН2, 9,14-CН); 1.69 (1H, td, J = 14.1,
J = 3.4, 1-CH2); 1.75–1.82 (4H, m, 2,12-CН2, 17-CН); 1.93–
2.02 (5H, m, 4,11,15,23-CН2, 25-CH); 2.04 (3H, s,
OCOCH3); 2.11 (1H, dd, J = 12.4, J = 4.0, 4-CН2); 2.18–
2.24 (2H, m, 7,24-CН2); 2.23 (3H, s, NCOCH3); 2.50–2.56
(1H, m, 8-CH); 2.78–2.89 (2H, m, 26-CH2, 5-OH), 3.05–
3.10 (1H, m, 20-CH); 3.85 (3H, s, OCH3); 4.02–4.06 (1H,
m, 26-CH2); 4.20 (1H, ddd, J = 8.6, J = 7.1, J = 6.6,
16-CH); 4.33 (1H, br. s, 6-CH); 5.14–5.21 (1H, m, 3-CH);
6.97 (2H, d, J = 8.6, 3'',5''-CH); 7.74 (1H, s, 5'-CH); 7.78
(2H, d, J = 8.6, 2'',6''-CH). 13C NMR spectrum, δ, ppm:
15.7 (C-19); 16.4 (C-21); 16.8 (C-18); 18.5 (C-27); 21.1
(С-11); 21.4 (OCOCH3); 24.1 (С-23); 24.4 (С-24); 25.2
(NCOCH3); 26.5 (С-2); 28.0 (С-25); 30.7 (С-7); 31.6 (C-8);
31.9 (С-15); 32.6 (С-1); 38.5 (С-4,20); 38.9 (С-10); 40.3
(С-13); 41.5 (С-12); 45.6 (С-9); 49.0 (С-26); 55.3 (С-14);
55.4 (OCH3); 62.2 (С-17); 65.2 (С-6); 70.7 (С-3); 76.2 (С-5);
78.9 (С-16); 101.2 (С-22); 114.3 (С-2'',6''); 120.1 (С-5');
123.2 (С-1''), 127.0 (С-3'',5''); 146.5 (C-4'), 159.6 (C-4'');
171.0 (OCOCH3); 171.1 (NCOCH3). Mass spectrum, m/z
(Irel, %): 688 (31), 556 (79), 176 (55), 175 (57), 163 (76),
162 (62), 149 (59), 132 (66), 114 (100), 43 (92). Found, m/z:
688.4197 [M]+. C40H56N4O6. Calculated, m/z: 688.4194.
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2a-hydroxy-5',6a,8a,9-tetramethyl-2-[4-(3,4,5-
trimethoxyphenyl)-1H-1,2,3-triazol-1-yl]octadecahydro-
spiro[naphtho[2',1':4,5]indeno[2,1-b]furan-10,2'-piperidin]-
4-yl acetate ((22R,25R)-N,O-diacetyl-5α-hydroxy-6β-[4-
(3,4,5-trimethoxyphenyl)-1,2,3-triazol-1-yl]spirosolane)
(14). Yield 161 mg (60%), yellowish amorphous powder,
24
104 mg (43%), yellowish amorphous powder, [α]D –65.1
(c 0.25, CHCl3). IR spectrum, ν, cm–1: 611, 663, 696, 757,
813, 840, 865, 923, 966, 1033, 1072, 1137, 1157, 1243,
1322, 1365, 1380, 1400, 1452, 1496, 1582, 1610, 1655,
1
1731, 2873, 2900, 2950, 3045, 3432. H NMR spectrum,
δ, ppm (J, Hz): 0.74 (3H, s, 19-CH3); 0.93 (3H, d, J = 6.8,
27-CH3); 1.00 (3H, s, 18-CH3); 1.08 (3H, d, J = 6.8,
21-СH3); 1.21–1.49 (6H, m, 1,7,11,12,24-CН2, 14-CН);
1.53–1.62 (3H, m, 9-CН, 15,23-CН2); 1.68 (1H, td,
J = 13.0, J = 3.4, 1-CH2); 1.76–1.83 (4H, m, 2,12-CН2,
17-CН); 1.91–2.02 (5H, m, 4,11,15,23-CН2, 25-CH); 2.04
(3H, s, OCOCH3); 2.14 (1H, dd, J = 12.4, J = 4.2 , 4-CН2);
2.08–2.16 (2H, m, 7-CН2, 24-CН2); 2.21 (3H, s, NCOCH3);
2.52–2.60 (1H, m, 8-CH); 2.78–2.89 (2H, m, 26-CH2,
5-OH); 3.08–3.12 (1H, m, 20-CH); 4.00–4.06 (1H, m,
26-CH2); 4.20 (1H, ddd, J = 8.4, J = 7.2, J = 6.6, 16-CH);
4.36 (1H, br. s, 6-CH); 5.18–5.25 (1H, m, 3-CH); 7.13 (2H,
d, J = 8.4, 3'',5''-CH); 7.82 (2H, dd, JHH = 8.4, JHF = 5.5,
2'',6''-CH); 7.81 (1H, s, 5'-CH). 13C NMR spectrum, δ, ppm
(J, Hz): 15.9 (C-19); 16.3 (C-21); 16.8 (C-18); 18.5 (C-27);
21.0 (С-11); 21.5 (OCOCH3); 24.0 (С-23); 24.3 (С-24);
25.2 (NCOCH3); 26.5 (С-2); 27.9 (С-25); 30.6 (С-7); 31.5
(С-8); 31.8 (С-12); 32.5 (С-1); 38.3 (С-20); 38.4 (С-4);
38.8 (С-10); 40.3 (С-13); 41.5 (С-15); 45.5 (С-9); 49.0
(С-26); 55.3 (С-14); 62.1 (С-17); 65.3 (С-6); 70.7 (С-3);
76.1 (С-5); 78.8 (С-16); 101.2 (С-22); 115.9 (С-3'',5'');
120.5 (С-5'); 126.6 (С-1''); 127.4 (С-2'',6''); 145.8 (C-4');
162.6 (JCF = 241.2, С-4''); 171.0 (OCOCH3); 171.1
(NCOCH3). Mass spectrum, m/z (Irel, %): 677 (53), 676
(100), 453 (27), 264 (77), 213 (47), 164 (98), 163 (61), 162
(48), 126 (29), 114 (61). Found, m/z: 676.3995 [M]+.
C39H53FN4O5. Calculated, m/z: 676.3999.
24
[α]D –60.1 (c 0.25, CHCl3). IR spectrum, ν, cm–1: 609,
623, 665, 681, 756, 800, 856, 924, 966, 1009, 1034, 1068,
1088, 1107, 1128, 1178, 1242, 1363, 1381, 1410, 1429,
1460, 1498, 1589, 1655, 1732, 2873, 2943, 3138, 3425.
1H NMR spectrum, δ, ppm (J, Hz): 0.79 (3H, s, 19-CH3);
0.93 (3H, d, J = 6.5, 27-CH3); 0.99 (3H, s, 18-CH3); 1.09
(3H, d,
J
=
6.8, 21-СH3); 1.21–1.61 (9H, m,
1,7,11,12,15,23,24-CН2, 9,14-CН); 1.67 (1H, td, J = 14.2,
J = 3.2, 1-CH2); 1.75–1.87 (4H, m, 2,12-CН2, 17-CН); 1.93–
2.02 (5H, m, 4,11,15,23-CН2, 25-CH); 2.04 (3H, s,
OCOCH3); 2.10 (1H, dd, J = 12.1, J = 4.2, 4-CН2); 2.08–2.16
(2H, m, 7,24-CН2); 2.23 (3H, s, NCOCH3); 2.52–2.60 (1H,
m, 8-CH); 2.78–2.89 (2H, m, 26-CH2, 5-OH); 3.02–3.08
(1H, m, 20-CH); 3.85 (3H, s, OCH3); 3.95 (6H, 2OCH3);
4.05–4.09 (1H, m, 26-CH2); 4.20 (1H, ddd, J = 8.4, J = 7.0,
J = 6.6, 16-CH); 4.30 (1H, br. s, 6-CH); 5.14–5.21 (1H, m,
3-CH); 7.09 (2H, s, 2'',6''-CH); 7.76 (1H, s, 5'-CH). 13C NMR
spectrum, δ, ppm: 15.7 (C-19); 16.3 (C-21); 16.7 (C-18);
18.5 (C-27); 21.0 (С-11); 21.5 (OCOCH3); 24.0 (С-23);
24.3 (С-24); 25.2 (NCOCH3); 26.4 (С-2); 27.9 (С-25); 30.8
(С-7); 31.5 (C-8); 31.8 (С-15); 32.5 (С-1); 38.3 (С-4); 38.6
(С-20); 38.8 (С-10); 40.24 (С-13); 41.5 (С-12); 45.5 (С-9);
48.8 (С-26); 55.3 (С-14); 56.4 (OCH3); 61.0 (2OCH3); 62.1
(С-17); 65.5 (С-6); 70.7 (С-3); 76.1 (С-5); 78.8 (С-16);
101.2 (С-22); 103.0 (С-2'',6''); 120.8 (С-5'); 126.0 (С-1'');
(2R,2aR,4S,5'R,6aR,6bS,8aS,8bR,9S,10R,11aS,12aS,12bS)-
1'-Acetyl-2a-hydroxy-5',6a,8a,9-tetramethyl-2-[4-(pyri-
din-2-yl)-1H-1,2,3-triazol-1-yl]octadecahydrospiro[naphtho-
[2',1':4,5]indeno[2,1-b]furan-10,2'-piperidin]-4-yl acetate
((22R,25R)-N,O-diacetyl-5α-hydroxy-6β-[4-(pyridin-2-yl)-
1,2,3-triazol-1-yl]spirosolane) (16). Yield 123 mg (52%),
brownish amorphous powder, [α]D25 –44.2 (c 0.29, CHCl3).
IR spectrum, ν, cm–1: 619, 665, 692, 752, 784, 836, 867,
921, 966, 1033, 1072, 1153, 1245, 1321, 1365, 1380, 1405,
1436, 1471, 1550, 1571, 1604, 1635, 1731, 2873, 2937,
2950, 3056, 3419. 1H NMR spectrum, δ, ppm (J, Hz): 0.77
(3H, s, 19-CH3); 0.93 (3H, d, J = 6.6, 27-CH3); 0.99 (3H, s,
18-CH3); 1.10 (3H, d, J = 6.6, 21-СH3); 1.19–1.46 (6H, m,
1,7,11,12,24-CН2, 14-CН); 1.55–1.63 (3H, m, 9-CН,
15,23-CН2); 1.69 (1H, td, J = 12.7, J = 2.8, 1-CH2); 1.75–1.82
(4H, m, 2,12-CН2, 17-CН); 1.91–1.99 (5H, m, 4,11,15,23-CН2,
415

Chemistry of Heterocyclic Compounds 2018, 54(4), 411–416
Vaishnav, D.; Ranpariya, V.; Sheth, N.; Parmar, S. Eur. J.
25-CH); 2.03 (3H, s, OCOCH3); 2.16 (1H, dd, J = 12.6,
J = 4.0, 4-CН2); 2.16–2.24 (2H, m, 7,24-CН2); 2.24 (3H, s,
NCOCH3); 2.54–2.62 (1H, m, 8-CH); 2.78–2.89 (2H, m,
26-CH2, 5-OH); 2.98–3.06 (1H, m, 20-CH); 4.06–4.12 (1H,
m, 26-CH2); 4.20 (1H, ddd, J = 8.2, J = 7.3, J = 6.8,
16-CH); 4.38 (1H, br. s, 6-CH); 5.16–5.22 (1H, m, 3-CH);
7.25 (1H, d, J = 6.5, 6''-CH); 7.80 (1H, dd, J = 7.2, J = 6.8,
4''-CH); 8.19 (1H, s, 5'-CH); 8.23 (1H, dd, J = 7.2, J = 6.5,
Pharmacol. 2014, 725, 40. (c) Munari, C. C.; de Oliveira, P. F.;
Campos, J. C. L.; Martins, S. de P. L.; Da Costa, J. C.;
Bastos, J. K.; Tavares, D. C. J. Nat. Med. 2014, 68, 236.
(d) Cham, B. E. Int. J. Clin. Med. 2017, 8, 692.
9. (a) Seyfulla, K. I. Farmakol. i Toksikol. 1965, 28, 657. (b)
Lecanu, L.; Hashim, A. I.; McCourty, A.; Giscos-Douriez, I.;
Dinca, I.; Yao, W.; Vicini, S.; Szabo, G.; Erdélyi, F.;
Greeson, J.; Papadopoulos, V. Neuroscience 2011, 183, 251.
(c) Chauhan, K.; Sheth, N.; Ranpariya, V.; Parmar, S. Pharm.
Biol. 2011, 49, 194. (d) Desai, A. B; Kagathara, V. G.; Joshi, H.;
Rangani, A. T.; Mungra, H. Int. J. PharmTech Res. 2011, 3,
732.
10. (a) Zha, X. M.; Zhang, F. R.; Shan, J. Q.; Zhang, Y. H.; Liu, J. O.;
Sun, H.-B. Chin. Chem. Lett. 2010, 21, 1087. (b) Cui, C. Z.;
Wen, X. S.; Cui, M.; Gao, J.; Sun, B.; Lou, H. X. Drug
Discoveries Ther. 2012, 6, 9.
11. (a) Li, H.; Liu, H.-M.; Ge, W.; Huang, L.; Shan, L. Steroids
2005, 70, 970. (b) Jastrzebska, I.; Morzycki, J. W. Steroids
2017, 127, 13.
12. (a) Irismetov, M. R.; Kharlamova, T. V.; Dzhiembaev, B. Zh.;
Praliev, K. D. Izv. Min. Obr. Nauki Resp. Kaz., Ser. Khim.
2000, 4, 82. (b) Irismetov M. P. Dissertation of Doctor of
Chemical Sciences; Almaty, 1993.
13. (a) Friedman, M.; Rayburn, J. R.; Bantle, J. A. Food Chem.
Toxicol. 1991, 29, 537. (b) Jiang, Q.-W.; Chen, M.-W.;
Cheng, K.-J.; Yu, P.-Z.; Wei, X.; Shi, Z. Med. Res. Rev. 2016,
36, 119.
14. Briggs, L. H.; O'Shea, T. J. Chem. Soc. 1952, 1654.
15. (a) Tolstikov, G. A.; Yur'ev, V. P.; Gailyunas, I. A.;
Dzhemilev, U. M. J. Gen. Chem. USSR 1974, 44, 205. [Zh.
Obsch. Khim. 1974, 44, 215.] (b) Cambie, R. C.; Potter, G. J.;
Read, R. W.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem.
1981, 34, 599.
16. (a) Cimarelli, C.; Fratoni, D.; Palmieri, G. Tetrahedron:
Asymmetry 2009, 20, 2234. (b) Chini, M.; Crotti, P.; Macchia, F.
Tetrahedron Lett. 1990, 31, 5641.
17. Feher, K.; Balogh, J.; Csók, Z.; Kegl, T.; Kollar, L.; Skoda-
Foldes, R. Steroids 2012, 77, 738.
13
5''-CH); 7.82 (1H, d, J = 6.8, 3''-CH). C NMR spectrum,
δ, ppm: 15.7 (C-19); 16.4 (C-21); 16.8 (C-18); 18.4 (C-27);
21.1 (С-11); 21.5 (OCOCH3); 24.0 (С-23); 24.4 (С-24);
25.2 (NCOCH3); 26.5 (С-2); 28.0 (С-25); 30.7 (С-7); 31.5
(C-8); 31.8 (С-15); 32.6 (С-1); 38.3 (С-20); 38.3 (С-4);
38.8 (С-10); 40.3 (С-13); 41.5 (С-12); 45.5 (С-9); 48.7
(С-26); 55.4 (С-14); 62.1 (С-17); 65.5 (С-6); 70.7 (С-3);
76.0 (С-5); 78.9 (С-16); 101.2 (С-22); 120.3 (С-5'); 122.9
(С-6''); 123.4 (С-4''); 137.1 (С-5''); 147.1 (C-4'); 149.2
(С-3''); 150.1 (С-1''); 172.0 (OCOCH3); 171.2 (NCOCH3).
Mass spectrum, m/z (Irel, %): 659 (7), 513 (12), 265 (16),
264 (100), 236 (16), 192 (11), 57 (11), 43 (59), 41 (15), 39
(14). Found, m/z: 659.4041 [M]+. C38H53N5O5. Calculated,
m/z: 659.4046.
The work was performed with financial support from the
Russian Science Foundation (project 17-73-10274) and
Russian Foundation for Basic Research (grant 18-03-
01012).
The authors would like to express their gratitude to the
Collective use Chemical research center of the Siberian
Branch of the Russian Academy of Sciences for the
assistance with spectral and analytical studies.
References
1. (a) Indrayanto, G.; Cholies, N.; Wahyudi Planta Med. 1985,
51, 470. (b) Eltayeb, E. A.; Al-Ansari, A. L.; Roddick, J. G.
Phytochemistry 1997, 46, 489. (c) Lee, M.-H.; Cheng, J.-J.;
Lin, C.-Y., Chen Y.-J.; Lu M.-K. Process Biochem. 2007, 42, 899.
2. Chandler, S.; Dodds, J. Plant Cell Rep. 1983, 2, 69. (b) Amir, M.;
Kumar, S. J. Sci. Ind. Res. 2004, 63, 116.
3. Chataing, B; Concepción, J. L.; Lobatón, R.; Usubillaga, A.
Planta Med. 1998, 64, 31.
4. Lin, C.-N.; Chung, M.-I.; Gan, K.-H. Planta Med. 1988, 54, 222.
5. Pandurangan, A.; Khosa, R. L.; Hemalatha, S. J. Asian Nat.
Prod. Res. 2010, 12, 691.
18. (a) Lipeeva, A. V.; Shults, E. E.; Makhneva, E. A.; Shakirov, M. M.;
Tolstikov, G. A. Chem. Heterocycl. Compd. 2013, 49, 551.
[Khim. Geterotsikl. Soedin. 2013, 591.] (b) Mukusheva, G. K.;
Lipeeva, A. V.; Zanimkhanova, P. Z.; Shults, E. E.;
Gatilov, Yu. V.; Shakirov, M. M.; Adekenov, S. M. Chem.
Heterocycl. Compd. 2015, 51, 146. [Khim. Geterotsikl. Soedin.
2015, 51, 146.] (c) Lipeeva, A. V.; Shults, E. E Chem.
Heterocycl. Compd. 2017, 53, 1302. [Khim. Geterotsikl. Soedin.
2017, 53, 1302.]
19. (а) Wang, P.; Liu, X.; Zhang, S. Chin. J. Chem. 2013, 31, 187.
(b) Kamata, K.; Yamaguchi, S.; Kotani, M.; Yamaguchi, K.;
Mizuno, N. Angew. Chem., Int. Ed. 2008, 47, 2407.
20. Creary, X.; Anderson, A.; Brophy, C.; Crowell, F.; Funk, Z.
J. Org. Chem. 2012, 77, 8756.
6. (a) Emmanuel, S.; Ignacimuthu, S.; Perumalsamy, R.;
Amalraj, T. Fitoterapia 2006, 77, 611. (b) Chiu, F.-L.; Lin, J.-K.
FEBS Lett. 2008, 582, 2407.
7. (a) Lin, C.-N.; Lu, C.-M.; Cheng, M.-K.; Gan, K.-H.; Won, S.-J.
J. Nat. Prod. 1990, 53, 513. (b) Shen, K.-H.; Hung, J.-H.;
Chang, C.-W.; Weng, Y.-T.; Wu, M.-J.; Chen, P.-S. Chem.–
Biol. Interact. 2017, 268, 129. (с) Xu, X.-H.; Zhang, L.-L.;
Wu, G.-S.; Chen, X.; Li, T.; Chen, X.; Wang, Y.-T.; Lu, J.-J.
Planta Med. 2017, 83, 254.
21. Patel, A.V.; Blunden, G.; Crabb, T. A. Phytochemistry 1994,
35, 125.
22. Wu, J.-J.; Shi, Y.; Tian, W.-S. Tetrahedron Lett. 2015, 56, 1215.
23. Odlo, K.; Hentzen, J.; dit Chabert, J. F.; Ducki, S.; Gani, O. A.;
Sylte, I.; Skrede, M.; Flörenes, V. A.; Hansen, T. V. Bioorg.
Med. Chem. 2008, 16, 4829.
8. (a) Koduru, S.; Grierson, D. S.; van de Venter, M.; Afolayan, A. J.
Pharm. Biol. 2007, 45, 613. (b) Sharma, T.; Airao, V.; Panara, N.;
416