Gold-catalyzed cyclization in the synthesis of antimitotic 2,3-dihydrobenzo[b]oxepine derivatives of colchicine

Article abstract of DOI:10.1007/s11172-019-2689-7

New allocolchicine derivatives bearing 2,3-dihydrobenzo[b]oxepine moiety were synthesized via gold-catalyzed cyclization as a key synthetic step. The obtained 2,3-dihydrobenzo[b]oxepine-containing allocolchicinoids possess cytotoxic activity against HEK293, PANC-1, COL0357, HeLa, and Colon26 cancer cell lines at low micromolar range of concentrations.

Full text of DOI:10.1007/s11172-019-2689-7

Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp. 2205—2215, December, 2019
2205
Gold-catalyzed cyclization in the synthesis of antimitotic
2,3-dihydrobenzo[b]oxepine derivatives of colchicine*
S. Yu. Bukhvalova,a,b A. A. Maleev,b Yu. A. Gracheva,b Yu. V. Voitovich,b S. K. Ignatov,b
E. V. Svirshchevskaya,c and A. Yu. Fedorovb
aG. A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences,
49 ul. Tropinina, 603137 Nizhny Novgorod, Russian Federation.
Fax: +7 (831) 462 7497. E-mail: sv-4.4.1991@rambler.ru
bN. I. Lobachevsky State University of Nizhny Novgorod,
23 prosp. Gagarina, 603950 Nizhny Novgorod, Russian Federation.
Fax: +7 (831) 462 3085. E-mail: afedorovnn@yandex.ru
cM. M. Shemyakin—Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,
16/10 ul. Miklukho-Maklaya, 117997 Moscow, Russian Federation.
Fax: +7 (495) 330 4011. E-mail: esvir@yandex.ru
New allocolchicine derivatives bearing 2,3-dihydrobenzo[b]oxepine moiety were synthesized
via gold-catalyzed cyclization as a key synthetic step. The obtained 2,3-dihydrobenzo[b]oxepine-
containing allocolchicinoids possess cytotoxic activity against HEK293, PANC-1, COLO357,
HeLa, and Colon26 cancer cell lines at low micromolar range of concentrations.
Key words: antitumor agents, colchicine, tubulin, benzo[b]oxepines, gold-catalyzed cyclization.
Scaffolds of natural compounds are the most promis-
ing in the design of new efficient therapeutic molecules.1—3
Thus, colchicine, an alkaloid isolated from plants of
Colchicaceae family, is widely used as an anti-inflammatory
drug for the treatment of acute gouty arthritis, Behcet’s
disease, and familial Mediterranean fever.4—7 Its positive
effect has been reported in the cases of amyloidosis, sclero-
derma, and Sweet’s disease.8 It can potentially be admin-
istered for the treatment of cardiovascular diseases caused
by inflammatory processes9—12 and also chronic infectious,
autoimmune, allergic, and neurodegenerative diseases.13,14
Despite the pronounced antimitotic effect, colchicine has
never been applied in the antitumor clinical practice due
to the high and poorly controlled systemic toxicity at
therapeutic doses.15,16
Nevertheless, the structure of colchicine (1) has been
recognized as one of the keys in the development of
new potentially less toxic cytostatic chemotherapeutic
drugs.17—24 Currently, the only successful approach of
solving the toxicity problem is the synthesis of heterocyclic
allocolchicinoids via the conversion of seven-membered
cycle C into the six-membered ring and the formation of
heterocyclic moiety D.25—28 Compounds of general struc-
ture 2 obtained in our group exhibit cytotoxic activity at
nano- and picomolar concentrations,29—36 demonstrate
a significant decrease in tumor growth rate in vivo without
any pronounced side effects in test animals.30
X = H, Br;
Y = O (substituted furan), NH(Me) (substituted pyrrole);
R = O, OH, NHAc
The present work was aimed to search for the new
colchicine analogs possessing improved antitumor proper-
ties. We have examined a series of derivatives 3a—f bear-
ing a 2,3-dihydrobenzo[b]oxepine moiety that replaces
cycle C in the colchicine structure. Benzo[b]oxepine is
a frequently found motif in natural products such as
pterulone,37,38 ptaeroxylin, radulanins, heliannuols, and
their natural and synthetic analogs.39—46 These compounds
demonstrate a wide range of biological effects, including
anti-inflammatory, anti-diabetic, antiviral, antiprolifera-
tive, antituberculosis, antispermetogenic, and antipsy-
chotic activities.47
* Based on the materials of the 4th Russian Conference on
Medicinal Chemistry with International participation (June 9—14,
2019, Ekaterinburg, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2205—2215, December, 2019.
1066-5285/19/6812-2205 © 2019 Springer Science+Business Media, Inc.

2206 Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
Bukhvalova et al.
a
LYS241
ALA250
LYS352
ASH258
LYS254
THR170
VAL161
SER178
b
LYS254
ALA250
ASN256
LEV245
The performed molecular docking demonstrated that
2,3-dihydrobenzo[b]oxepinoallocolchicines 3 fit well in
the colchicine site of tubulin, while the geometry of bind-
ing to the colchicine site is fundamentally different for
compounds 1 and 3a (X = CO2Me, R1 = Ph, R2 = Bun).
Thus, the molecule containing 2,3-dihydrobenzo[b]ox-
epine moiety turned out to be rotated 90 compared to
colchicine, which provides a new hydrogen bond with
Asn101, Van-der-Waals contacts with Met259, and hy-
drophobic interactions with Tyr224 and Lys254 (Fig. 1).
The number of established interactions allowed us to expect
effective binding of new derivatives to tubulin.
An efficient approach to the formation of 2,3-dihydro-
benzo[b]oxepine rings with high stereoselectivity has been
recently proposed by J. Liu et al.48 The application of
gold-catalyzed cyclization of (o-alkynyl)phenoxyacrylates
with nucleophiles allowed the formation of benzoxepines
under mild conditions. Herein we report a series of new
colchicine derivatives bearing a 2,3-dihydrobenzo[b]ox-
epine moiety and synthesized exploiting the gold-catalyzed
cyclization as a key step of the synthesis.
SER175
THR353
ALA354
Fig. 1. Calculated structures of colchicine (a) and compound 3a
(b) at the tubulin binding site.
colchicine. Colchiceine 4 was then introduced into
a NaOH—I2—NaI system, which led to the oxidative
constriction of seven-membered cycle caused by alkali
and its iodination.
Iodocolchinol 5 isolated in 70% yield was further in-
troduced into the Michael reaction with terminal alkynes
in the presence of base to give vinyl esters 6a,b. To optimize
reaction conditions in the case of methyl propiolate,
various bases (1,4-diazabicyclo[2.2.2]octane (DABCO),
diisopropylethylamine (DIPEA), a mixture of diazabi-
cycloundecene (DBU)—DABCO, and 4-dimethylamino-
pyridine (DMAP)) and solvents (CH2Cl2, THF, toluene,
and DMF) were used (Table 1). A positive result was
achieved only in the case of DABCO taken in the amount
of three equivalents and reaction time increased to three
days. In this case, the target vinyl ether 6a was obtained
Results and Discussion
The synthesis of the series of 2,3-dihydrobenzo[b]-
oxepine derivatives of colchicine was started from the
preparation of iodocolchinol according to the known
procedure.28,30,33 At the first step, colchiceine 4 was ob-
tained from colchicine (1) in 98% yield by the treatment
with 0.1 M hydrochloric acid (Scheme 1). In this case, the
methyl group was removed from the tropolone cycle of

2,3-Benzo[b]oxepine derivatives of colchicine
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
2207
Scheme 1
Scheme 2
Compound 7
X
R
Ph
Pr
Yield (%)
a
b
c
d
CO2Me
CO2Me
CO2Me
CO2Me
90
72
54
65
CH2OAc
(CH2)4Cl
Compound 8
X
R
Ph
Pr
Yield (%)
a
b
c
C(O)Me
C(O)Me
C(O)Me
63
78
65
CH2OAc
X = CO2Me (6a), C(O)Me (6b)
78
76
80
d
e
f
C(O)Me
C(O)Me
C(O)Me
Reagents and conditions: i. 0.1 M HCl, AcOH, 3 h, 100 C;
ii. I2, KI, NaOH, 2 h, 0 C; iii. Alkyne, DABCO, CH2Cl2, 72 h,
25 C.
in the yield close to quantitative (see Table 1, experiment 4),
and product 6b was isolated in 89% yield (see Scheme 1).
It should be noted that compounds 6a,b were obtained
in the form of their (E)-isomers, which was confirmed by
NMR spectroscopy: J values of the protons of the double
bond correspond to the (E)-configuration of vinyl ethers
(see Experimental part).49
At the next step, compounds 6a,b were used in the
Sonogashira cross-coupling reaction with a set of func-
tionalized terminal alkynes (Scheme 2). The reactions
were carried out at 45 C using a Pd(OAc)2—CuI—PPh3
catalytic system (5 : 10 : 15 mol.%).30 Target o-alkynyl-
vinyl ethers 7 and 8 were obtained in 54—90% yields.
The intramolecular cyclization of compounds 7 and 8
with various alcohols catalyzed by gold complexes was
carried out at the last step to afford desired functionalized
2,3-dihydrobenzo[b]oxepines 3a—f. Scheme 3 shows
a proposed mechanism of the cyclization (according to
the literature49). Obviously, at the first step the Au+ com-
Reagents and conditions: i. Pd(OAc)2, CuI, Ph3P, AcOK, MeCN,
16 h, 45 C.
plex is coordinated by the triple bond of substrate 7 (8).
The electron-deficient triple bond in complex 9 undergoes
6-endo-dig cyclization to form pentacyclic organometallic
intermediate 10 bearing a substituted cyclopropane moi-
ety. A subsequent nucleophilic attack leads to the expan-
sion of cyclopropyl-containing bicyclic moiety to yield
intermediate 11. The further protonolysis leads to the
formation of target benzoxepine and catalyst regeneration.
We have explored the cyclization of compound 7a
in the presence of freshly prepared gold complexes
(Ph3PAuNTf2, (C6F5)3PAuNTf2, and Ph3PAuSbF6) in
various solvents (1,2-dichloroethane, CH2Cl2, toluene,
and THF) with BunOH as a nucleophile to find optimal
conditions for this reaction. However, neither of attempts
resulted in obtaining the desired benzoxepine structure,
which was obviously due to the instability of gold com-
plexes. An in situ preparation of the catalytic system led
to 3a in 25% yield (Table 2, experiment 1). A subsequent
increase in the product yield was achieved by carrying out
the reaction in the dark (see Table 2, experiments 2—4).
The best yield was observed using SbF6 as an anion, which
could be explained by its lower nucleophilicity.50,51
With found optimal conditions in hand, a set of novel
allocolchicinoids 3a—f possessing a 2,3-dihydrobenzo[b]-
oxepine ring has been prepared with good and moderate
Table 1. Optimization of the Michael reaction conditions
Exp. DABCO
/equiv.
Solvent
Time
/days
Yield of 6a
(%)
1
2
3
4
0.1
0.3
1
THF
1
1
2
3
—
—
~10
95
Toluene
CH2Cl2
CH2Cl2
3

2208 Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
Bukhvalova et al.
Scheme 3
X = CO2Me
Compound 3
R1
Ph
Ph
Ph
R2
Bu
Pri
Et
Yield (%)
Compound 3
R1
Ph
Pr
R2
Me
Bu
Bu
Yield (%)
a
b
c
60
53
40
d
e
f
30
40
22
Cl(CH2)4
yields from compounds 7 in the presence of various alco-
hols. In the case of compounds 8 as starting materials in
this reaction, the desired products could not be obtained.
It should be noted that 2,3-dihydrobenzo[b]oxepino-
allocolchicines 3a—f were formed as mixtures of dia-
stereomers A and B in the ratios of 2 : 1 or 3 : 2, which
differ in the configurations of carboxymethyl and alkoxyl
moieties of the oxepine ring. Separation of these dia-
stereomers by column chromatography failed. Since
compounds of such type can exist in the solution as
Z/E isomers about the amide group and as atropisomers
(colchicinoids possess an axial chirality),29 it was impos-
sible to determine a configuration of the major isomer in
the mixture using a two-dimensional NMR spectroscopy.
According to the proposed mechanism, the major diaste-
reomer should possess the configuration shown in Scheme 3.
Table 2. Optimization of conditions for the gold-catalyzed
cyclization of 7aa in 1,2-dichloroethane
Diastereomers of 3 (A and B)
Exp.
Catalyst (equiv.)
Yield of 3а (%)
Cytotoxicity of the synthesized compounds against
human (HEK293, PANC-1, COLO357, and HeLa) and
mice (Colon26) cancer cell lines was investigated in vitro
using the standard MTT assay (Table 3).52 The lower
overall activity of all the obtained target compounds as
compared to the starting colchicine is presumably related
to a position of the compounds at the tubulin binding site.
1
Ph3PAuCl + AgSbF6 (0.05)
Ph3PAuCl + AgSbF6 (0.05)
Ph3PAuCl + AgNTf2 (0.05)
(C6F5)3PAuCl + AgSbF6 (0.05)
25
60
42
52
2b
3b
4b
а 2 equiv. of BunOH were used for the reaction.
b The reactions were carried out in the dark.

2,3-Benzo[b]oxepine derivatives of colchicine
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
2209
Table 3. Cytotoxic activity (IC50/mol L–1) of compounds 3a—f
DMSO-d6), : 8.63 (d, 1 H, NH, J = 7.3 Hz); 7.32 (d, 1 H,
H(12), J = 11.8 Hz); 7.31 (s, 1 H, H(8)); 7.15 (d, 1 H, H(11),
J = 11.8 Hz); 6.80 (s, 1 H, H(4)); 4.43—4.27 (m, 1 H, H(7));
3.84 (s, 3 H, OMe(1)); 3.78 (s, 3 H, OMe(3)); 3.56 (s, 3 H,
OMe(2)); 2.35—1.89 (m, 4 H, H(5) and H(6)); 1.87 (s, 3 H,
NHC(O)CH3). 13C NMR (101 MHz, DMSO-d6), : 168.7,
153.1, 150.2, 149.9, 140.7, 140.1, 134.7, 128.9, 128.2, 125.7,
125.3, 124.2, 118.2, 107.8, 60.7, 60.7, 55.9, 51.6, 36.9, 29.2, 22.5.
Iodocolchinol 5 was synthesized according to the previously
proposed procedure.28,30,33 The product was isolated as light
beige crystals, yield: 70%, m.p. 237—239 C. 1H NMR (400 MHz,
DMSO-d6), : 10.28 (s, 1 H, ОН); 8.38 (d, 1 H, NH, J = 8.0 Hz);
7.56 (s, 1 H, H(11)); 6.86 (s, 1 H, H(4)); 6.76 (s, 1 H, H(8));
4.40—4.33 (m, 1 H, H(7)); 3.82 (s, 3 H, OMe(1)); 3.77 (s, 3 H,
OMe(3)); 3.48 (s, 3 H, OMe(2)); 2.23—1.87 (m, 4 H, H(5) and
H(6)); 1.87 (s, 3 H, NHC(O)CH3). 13C NMR (101 MHz,
DMSO-d6), : 168.3, 155.6, 152.2, 150.2, 142.4, 140.5, 139.2,
134.8, 126.6, 123.2, 110.1, 108.1, 81.4, 60.6, 60.5, 55.8, 48.2,
37.9, 29.9, 22.6.
Compound
Cells
HEK293 PANC-1 COLO-357 HeLa Colon26
3a
3b
3c
3d
3e
3f
2.76
0.50
0.52
0.54
2.53
0.36
0.005
2.86
1—*
0.65
1—
3.27
0.80
0.031
2.16
0.52
0.62
0.58
3.67
1—
1.97
0.53
0.59
0.50
2.82
2.48
2.00
0.47
0.45
0.14
2.46
2.67
Colchicine
0.004
0.021 0.006
* Not tested.
As was demonstrated by the study of binding geometry,
the bulky benzoxepine moiety does not allow the molecule
to occupy a position similar to that shown for colchicine.
A loss of several hydrogen bonds and hydrophobic interac-
tions may lead to a decrease in the activity of compounds.
In conclusion, we have developed a simple synthetic
approach to new allocolchicine derivatives containing the
2,3-dihydrobenzo[b]oxepine ring, starting from commer-
cially available natural colchicine. The key step of synthe-
sis, formation of 2,3-dihydrobenzo[b]oxepine moiety, was
performed using the gold-catalyzed intramolecular cycli-
zation. The synthesized compounds demonstrated moder-
ate in vitro cytotoxicity towards the human (HEK293,
PANC-1, COLO357, and HeLa) and mouse (Colon26)
cancer cell lines. Research efforts are currently underway
to improve the antimitotic properties of allocolchicinoids
of such type.
Synthesis of compounds 6a,b (general procedure). A mixture
of iodocolchinol 5 and DABCO was dissolved in CH2Cl2 under
an argon atmosphere; the corresponding alkyne was then added
dropwise to the resulting solution. The reaction mixture was
stirred at 40 C for 72 h after that the product was isolated using
silica gel column chromatography, eluent PE—AcOEt—EtOH
(8 : 1 : 1).
N-{3-[(E)-2-Carboxymethylethenyloxy]-2-iodo-6,7-dihydro-
5H-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-yl}acetamide
(6a). Iodocolchinol 5 (500 mg, 1.04 mmol), DABCO (348 mg,
3.12 mmol), and methyl propiolate (102 L, 1.14 mmol) were
used. Product 6a (500 mg, 84%) was isolated as yellow crystals,
m.p. 147—149 C. Found (%): C, 50.99; H, 4.68. C24H26INO7.
Calculated (%): C, 50.81; H, 4.62. 1H NMR (400 MHz,
DMSO-d6), : 8.44 (d, 1 H, NH, J = 8.4 Hz); 7.81 (d, 1 H,
OCH=CH, J = 12.2 Hz); 7.78 (s, 1 H, H(11)); 7.16 (s, 1 H,
H(8)); 6.81 (s, 1 H, H(4)); 5.53 (d, 1 H, OCH=CH, J = 12.2 Hz);
4.55—4.44 (m, 1 H, H(7)); 3.84 (s, 3 H, OCH3(3)); 3.79 (s, 3 H,
OCH3(2)); 3.67 (s, 3 H, C(O)OCH3); 3.54 (s, 3 H, OCH3(1)),
2.20—1.95 (m, 4 H, H(5) and Н(6)); 1.86 (s, 3 H, NHC(O)CH3).
13C NMR (101 MHz, DMSO-d6), : 168.6, 166.4, 159.4, 153.6,
153.0, 150.2, 143.4, 140.5, 140.1, 134.9, 133.1, 122.1, 114.2,
108.3, 101.6, 85.0, 60.8, 60.6, 55.9, 51.2, 48.1, 38.2, 29.8, 22.6.
MS (GC/MS), m/z: 568.1 [М + Н]+. Rt = 9.939 min.
N-{3-[(E)-3-Oxobuten-1-yloxy]-2-iodo-6,7-dihydro-5H-
9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-yl}acetamide (6b).
Iodocolchinol 5 (200 mg, 0.41 mmol), DABCO (138 mg,
1.23 mmol), and but-3-yne-2-one (24 L, 0.41 mmol) were used.
Product 6b (220 mg, 95%) was isolated as yellow crystals, m.p.
185—187 C. Found (%): C, 52.17; H, 4.80. C24H26INO6.
Calculated (%): C, 52.28; H, 4.75. 1H NMR (400 MHz,
DMSO-d6), : 8.45 (d, 1 H, NH, J = 8.5 Hz); 7.96 (d, 1 H,
OCH=CH, J = 12.5 Hz); 7.79 (s, 1 H, H(11)); 7.20 (s, 1 H,
H(8)); 6.81 (s, 1 H, H(4)); 5.77 (d, 1 H, OCH=CH, J = 12.5 Hz);
4.51 (dt, 1 Н, Н(7), J = 12.3 and 7.8 Hz); 3.84 (s, 3 H, OCH3(3));
3.79 (s, 3 H, OCH3(2)); 3.55 (s, 3 H, OCH3(1)); 2.24 (s, 3 H,
C(O)CH3); 2.19—1.92 (m, 4 H, H(5) and Н(6)); 1.87 (s, 3 H,
NHC(O)CH3). 13C NMR (101 MHz, DMSO-d6), : 196.6,
168.6, 160.0, 153.7, 153.0, 150.2, 143.3, 140.5, 140.0, 134.9,
132.9, 122.1, 114.3, 112.4, 108.3, 85.0, 60.8, 60.6, 55.9, 48.1,
36.5, 29.9, 27.5, 22.6. MS (GC/MS), m/z: 552.2 [М + Н]+,
Rt = 6.649 min.
Experimental
1Н and 13С NMR spectra were recorded in DMSO-d6 at
25 С on Agilent DD2 400 spectrometer at the operating frequen-
cies of 400 and 101 MHz for 1Н and 13С, respectively. Chemical
shifts () are reported in parts per million (ppm) from Me4Si.
Signals in the proton spectra were assigned using the data re-
ported previously.26—31 The reaction progress was monitored by
analytical HPLC using Agilent Infinity chromatograph (Zorbax
SB-C18 column of 1.8 m (2.150 mm); mobile phase A aque-
ous 0.1% solution of formic acid, and B 0.1% solution of formic
acid in MeCN; flow rate 0.3 mL min–1) equipped with a diode
array UV detector (DAAD) operating at 230 nm. Mass spectra
were recorded on Agilent SQ G6120B mass spectrometer oper-
ating in positive electrospray mode. Combustion analysis was
performed using an Elementar (Vario Micro Cube) apparatus.
Silica gel 60 (70—230 mesh, Alfa Aesar) was used for the column
chromatography. Commercially available reagents (Aldrich, Alfa
Aesar, Acros) were used as received without any further purifica-
tion. The solvents were purified according to standard procedures.
The petroleum ether (PE) refers to the fraction with distillation
range 40—70 C.
Colchiceine 4 was synthesized according to the previously
proposed procedure.28,30,33 The product was isolated as a green-
ish foam, yield: 98%, m.p. 149—151 C. 1H NMR (400 MHz,

2210
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
Bukhvalova et al.
Synthesis of compounds 7a—d and 8a—f (general procedure).
Anhydrous MeCN was poured under an argon atmosphere into
a Schlenk flask containing starting aryl iodide 6a,b, Pd(OAc)2,
CuI, Ph3P, and AcOK; and the corresponding alkyne was then
added to the resulting solution. The reaction mixture was kept
at 45 C for 12 h. The product was isolated using silica gel column
chromatography, eluent PE—AcOEt—EtOH (7 : 1 : 1).
(s, 3 H, C(O)OCH3); 3.48 (s, 3 H, OCH3(1)); 2.26—2.07 (m, 4 H,
H(5) and Н(6)); 2.06 (s, 3 H, CH2OC(O)CH3); 1.89 (s, 3 H,
NHC(O)CH3). 13C NMR (101 MHz, DMSO-d6), : 169.7,
168.6, 166.4, 159.4, 154.5, 152.9, 150.2, 144.2, 140.5, 134.9,
134.5, 131.2, 122.3, 113.8, 110.8, 108.3, 101.5, 89.0, 80.5, 60.7,
60.6, 55.8, 52.2, 51.2, 48.3, 38.3, 29.8, 22.6, 20.4. MS (GC/MS),
m/z: 538.9 [М + Н]+, Rt = 7.762 min.
N-{3-[(E)-2-Carboxymethylethenyloxy]-6,7-dihydro-5H-2-
phenylethynyl-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-yl}-
acetamide (7a). Aryl iodide 6a (150 mg, 0.26 mmol), Pd(OAc)2
(3 mg, 0.013 mmol), CuI (5 mg, 0.026 mmol), Ph3P (11 mg,
0.039 mmol), AcOK (76 mg, 0.78 mmol), and phenylacetylene
(28 L, 0.26 mmol) were used. Product 7a (105 mg, 75%) was
isolated as beige crystals, m.p. 178—180 C. Found (%): C, 70.88;
H, 5.69. C32H31NO7. Calculated (%): C, 70.97; H, 5.77. 1H NMR
(400 MHz, DMSO-d6), : 8.44 (d, 1 H, NH, J = 8.6 Hz); 7.81
(d, 1 H, OCH=CH, J = 12.2 Hz); 7.58 (s, 1 H, H(11)); 7.51
(d, 2 H, Ph, J = 7.6 Hz); 7.38 (t, 3 H, Ph, J = 6.7 Hz); 7.19
(s, 1 H, H(8)); 6.79 (s, 1 H, H(4)); 5.54 (d, 1 H, OCH=CH,
J = 12.2 Hz); 4.65—4.47 (m, 1 H, H(7)); 3.84 (s, 3 H, OCH3(3));
3.79 (s, 3 H, OCH3(2)); 3.67 (s, 3 H, C(O)OCH3); 3.55 (s, 3 H,
OCH3(1)); 2.27—2.02 (m, 4 H, H(5) and Н(6)); 1.89 (s, 3 H,
NHC(O)CH3). 13C NMR (101 MHz, DMSO-d6), : 168.6,
166.4, 159.4, 154.4, 153.6, 153.0, 150.2, 143.4, 140.5, 140.1,
135.0, 133.8, 132.9 (2 C), 128.9 (2 C), 122.1, 120.9, 114.1, 111.4,
108.2, 101.6, 93.0, 84.9, 60.8, 60.6, 55.8, 51.2, 48.2, 38.3, 29.9,
22.6. MS (GC/MS), m/z: 542.3 [М + Н]+, Rt = 7.399 min.
N-{3-[(E)-2-Carboxymethylethenyloxy]-2-propylethynyl-
6,7-dihydro-5H-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-
yl}acetamide (7b). Aryl iodide 6a (150 mg, 0.26 mmol), Pd(OAc)2
(3 mg, 0.013 mmol), CuI (5 mg, 0.026 mmol), Ph3P (11 mg,
0.039 mmol), AcOK (76 mg, 0.78 mmol), and pent-1-yne (26 L,
0.26 mmol) were used. Product 7b (124 mg, 65%) was isolated
as light beige crystals, m.p. 158—160 C. Found (%): C, 68.68;
H, 6.58. C29H33NO7. Calculated (%): C, 68.62; H, 6.55. 1H NMR
(400 MHz, DMSO-d6), : 8.43 (d, 1 H, NH, J = 8.5 Hz); 7.84
(d, 1 H, OCH=CH, J = 12.2 Hz); 7.37 (s, 1 H, H(11)); 7.15
(s, 1 H, H(8)); 6.81 (s, 1 H, H(4)); 5.52 (d, 1 H, OCH=CH,
J = 12.2 Hz); 4.56—4.49 (m, 1 H, H(7)); 3.84 (s, 3 H, OCH3(3));
3.79 (s, 3 H, OCH3(2)); 3.65 (s, 3 H, C(O)OCH3); 3.51 (s, 3 H,
OCH3(1)); 2.41 (t, 2 H, CH2CH2CH3, J = 6.8 Hz); 2.25—2.01
(m, 4 H, H(5) and Н(6)); 1.87 (s, 3 H, NHC(O)CH3); 1.53 (dd,
2 H, CH2CH2CH3, J = 14.3 and 7.1 Hz); 0.97 (t, 3 H, CH2CH2CH3,
J = 7.3 Hz). 13C NMR (101 MHz, DMSO-d6), : 168.6, 166.5,
160.0, 154.3, 152.8, 150.2, 142.7, 140.5, 134.9, 134.2, 131.2,
122.6, 114.1, 112.6, 108.3, 100.8, 95.8, 75.4, 60.7, 60.6, 55.8,
51.2, 48.1, 38.3, 29.8, 22.6, 21.4, 20.8, 13.2. MS (GC/MS), m/z:
508.3 [М + Н]+, Rt = 7.764 min.
N-{3-[(E)-2-Carboxymethylethenyloxy]-2-(4-chlorobutyl)-
ethynyl-6,7-dihydro-5H-9,10,11-trimethoxydibenzo[a,c]cyclo-
heptene-5-yl}acetamide (7d). Aryl iodide 6a (682 mg, 1.18 mmol),
Pd(OAc)2 (13 mg, 0.06 mmol), CuI (23 mg, 0.118 mmol),
Ph3P (46 mg, 0.177 mmol), AcOK (693 mg, 7.08 mmol), and
6-chlorhex-1-yne (150 L, 1.30 mmol) were used. Product 7d
(430 mg, 65%) was isolated as light beige crystals, m.p.
138—140 C. Found (%): C, 67.29; H, 6.50. C31H36ClNO6.
Calculated (%): C, 67.20; H, 6.55. 1H NMR (400 MHz,
DMSO-d6), : 8.46 (d, 1 H, NH, J = 8.4 Hz); 7.87 (d, 1 H,
OCH=CH, J = 12.2 Hz); 7.41 (s, 1 H, H(11)); 7.19 (s, 1 H,
H(8)); 6.82 (s, 1 H, H(4)); 5.56 (d, 1 H, OCH=CH, J = 12.2 Hz);
4.61—4.51 (m, 1 H, H(7)); 3.86 (s, 3 H, OCH3(3)); 3.81 (s, 3 H,
OCH3(2)); 3.68 (s, 3 H, C(O)OCH3); 3.68—3.56 (m, 2 Н,
CH2CH2CH2CH2Cl); 3.54 (s, 3 H, OCH3(1)); 2.44—2.01 (m,
4 H, H(5) and Н(6)); 1.90 (s, 3 H, NHC(O)CH3); 1.88—1.84
(m, 4 H, CH2CH2CH2CH2Cl); 1.66 (dd, 2 H, CH2CH2CH2CH2Cl,
J = 14.6 and 7.1 Hz). 13C NMR (101 MHz, DMSO-d6), : 168.6,
166.5, 160.0, 154.4, 152.9, 150.2, 142.8, 140.5, 134.9, 134.2,
131.3, 122.6, 114.0, 112.5, 108.2, 100.8, 95.4, 75.6, 60.7, 60.6,
55.8, 51.1, 48.2, 44.8, 38.4, 31.2, 25.3, 25.2, 22.6, 18.2. MS
(GC/MS), m/z: 556.3 [М]+, Rt = 7.761 min.
N-{3-[(E)-3-Oxobuten-1-yloxy]-6,7-dihydro-5H-2-phenyl-
ethynyl-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-yl}acet-
amide (8a). Aryl iodide 6b (200 mg, 0.36 mmol), Pd(OAc)2 (4 mg,
0.018 mmol), CuI (7 mg, 0.036 mmol), Ph3P (14 mg, 0.054 mmol),
AcOK (106 mg, 1.08 mmol), and phenylacetylene (24 L,
0.41 mmol) were used. Product 8a (155 mg, 81%) was isolated
as light beige crystals, m.p. 208—210 C. Found (%): C, 73.09;
H, 5.90. C32H31NO6. Calculated (%): C, 73.13; H, 5.94.
1H NMR (400 MHz, DMSO-d6), : 8.48 (d, 1 H, NH, J = 8.5 Hz);
8.10 (d, 1 H, OCH=CH, J = 12.5 Hz); 7.54 (s, 1 H, H(11));
7.53—7.48 (m, 2 H, Ph); 7.45—7.40 (m, 3 H, Ph); 7.27 (s, 1 H,
H(8)); 6.83 (s, 1 H, H(4)); 5.87 (d, 1 H, OCH=CH, J = 12.5 Hz);
4.60 (dd, 1 H, H(7), J = 9.3 Hz, J = 5.9 Hz); 3.85 (s, 3 H,
OCH3(3)); 3.80 (s, 3 H, OCH3(2)); 3.54 (s, 3 H, OCH3(1)); 2.21
(s, 3 H, C(O)CH3); 2.17—1.92 (m, 4 H, H(5) and Н(6)); 1.90
(s, 3 H, NHC(O)CH3). 13C NMR (101 MHz, DMSO-d6), :
196.7, 168.7, 160.7, 154.5, 152.9, 150.3, 143.8, 140.6, 134.9,
134.2, 131.3, 131.2 (2 C), 129.1, 128.8 (2 C), 122.5, 122.1, 114.3,
112.1, 111.8, 108.3, 94.2, 84.4, 60.8, 60.6, 55.9, 48.3, 38.4, 29.9,
27.3, 22.7. MS (GC/MS), m/z: 526.3 [М + Н]+, Rt = 7.167 min.
N-{3-[(E)-3-Oxobuten-1-yloxy]-6,7-dihydro-5H-2-propyl-
ethynyl-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-yl}acet-
amide (8b). Aryl iodide 6b (200 mg, 0.36 mmol), Pd(OAc)2 (4 mg,
0.018 mmol), CuI (7 mg, 0.036 mmol), Ph3P (14 mg, 0.054 mmol),
AcOK (106 mg, 1.08 mmol), and pent-1-yne (24 L, 0.41 mmol)
were used. Product 8b (140 mg, 78%) was isolated as light beige
crystals, m.p. 135—137 C. Found (%): C, 70.79; H, 6.70.
C29H33NO6. Calculated (%): C, 70.86; H, 6.77. 1H NMR
(400 MHz, DMSO-d6), : 8.42 (d, 1 H, NH, J = 8.4 Hz); 7.99
(d, 1 H, OCH=CH, J = 12.5 Hz); 7.37 (s, 1 H, H(11)); 7.17
(s, 1 H, H(8)); 6.81 (s, 1 H, H(4)); 5.74 (d, 1 H, OCH=CH,
J = 12.5 Hz); 4.54 (dd, 1 Н, Н(7), J = 12.2 and 5.1 Hz); 3.84
N-{3-[(E)-2-Carboxymethylethenyloxy]-2-acetoxyethynyl-
6,7-dihydro-5H-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-
yl}acetamide (7c). Aryl iodide 6a (100 mg, 0.17 mmol), Pd(OAc)2
(2 mg, 0.009 mmol), CuI (3 mg, 0.017 mmol), Ph3P (7 mg,
0.026 mmol), AcOK (51 mg, 0.52 mmol), and propargyl acetate
(17 L, 0.17 mmol) were used. Product 7c (50 mg, 54%) was
isolated as light beige crystals, m.p. 167—169 C. Found (%):
C, 64.89; H, 6.73. C29H31NO9. Calculated (%): C, 64.80; H, 5.81.
1H NMR (400 MHz, DMSO-d6), : 8.46 (d, 1 H, NH, J = 8.3 Hz);
7.84 (d, 1 H, OCH=CH, J = 11.5 Hz); 7.43 (s, 1 H, H(11)); 7.19
(s, 1 H, H(8)); 6.82 (s, 1 H, H(4)); 5.58 (d, 1 H, OCH=CH,
J = 12.2 Hz); 4.93 (s, 2 H, CH2OC(O)CH3); 4.57—4.50 (m, 1 H,
H(7)), 3.84 (s, 3 H, OCH3(3)), 3.79 (s, 3 H, OCH3(2)), 3.67

2,3-Benzo[b]oxepine derivatives of colchicine
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
2211
(s, 3 H, OCH3(3)); 3.79 (s, 3 H, OCH3(2)); 3.51 (s, 3 H,
OCH3(1)); 2.41 (t, 2 H, CH2CH2CH3, J = 6.9 Hz); 2.21 (s, 3 H,
C(O)CH3); 2.20—1.93 (m, 4 H, H(5) and Н(6)); 1.87 (s, 3 H,
NHC(O)CH3); 1.53 (dd, 2 H, CH2CH2CH3, J = 14.3 Hz,
J = 7.1 Hz); 0.97 (t, 3 H, CH2CH2CH3, J = 7.4 Hz). 13C NMR
(101 MHz, DMSO-d6), : 196.5, 168.6, 160.9, 154.4, 152.8,
150.2, 142.7, 140.5, 134.9, 134.2, 131.2, 122.6, 114.3, 112.7,
111.8, 108.3, 95.8, 75.5, 60.7, 60.6, 55.8, 48.1, 38.4, 29.9, 27.2,
22.6, 21.5, 20.8, 13.2. MS (GC/MS), m/z: 492.3 [М + Н]+,
Rt = 6.929 min.
(s, 1 H, H(11)); 7.20 (s, 1 H, H(8)); 6.82 (s, 1 H, H(4)); 5.70 (d,
1 H, OCH=CH, J = 12.5 Hz); 5.47 (s, 1 H, ОН); 4.62—4.50
(m, 1 H, Н(7)); 3.84 (s, 3 H, OCH3(3)); 3.79 (s, 3 H, OCH3(2));
3.50 (s, 3 H, OCH3(1)); 2.21 (s, 3 H, C(O)CH3); 2.19—1.92
(m, 4 H, H(5) and Н(6)); 1.88 (s, 3 H, NHC(O)CH3); 1.82 (d, 2 Н,
CyH, J = 7.2 Hz); 1.60 (d, 2 Н, CyH, J = 2.0 Hz); 1.48 (dd,
6 Н, CyH, J = 18.2 and 9.6 Hz). 13C NMR (101 MHz,
DMSO-d6), : 196.5, 168.6, 161.0, 154.2, 152.9, 150.2, 143.1,
140.5, 134.9, 134.1, 131.3, 122.5, 114.5, 112.4, 111.8, 108.3,
99.9, 77.6, 67.3, 60.8, 60.6, 55.8, 48.1, 38.4, 30.9, 29.8, 27.1
(2 C), 24.9, 22.8 (2 C), 22.7. MS (GC/MS), m/z: 547.7 [М]+,
Rt = 7.133 min.
N-{3-[(E)-3-Oxobuten-1-yloxy]-2-[(1-acetoxy)ethynyl]-
6,7-dihydro-5H-9,10,11-trimethoxydibenzo[a,c]cyclohepten-5-
yl}acetamide (8c). Aryl iodide 6b (200 mg, 0.36 mmol), Pd(OAc)2
(4 mg, 0.018 mmol), CuI (7 mg, 0.036 mmol), Ph3P (14 mg,
0.054 mmol), AcOK (106 mg, 1.08 mmol), and propargyl acetate
(36 L, 0.41 mmol) were used. Product 8c (124 mg, 65%) was
isolated as light beige crystals, m.p. 168—170 C. Found (%):
C, 66.89; H, 6.08. C29H31NO8. Calculated (%): C, 66.78; H, 5.99.
1H NMR (400 MHz, DMSO-d6), : 8.46 (d, 1 H, NH,
J = 8.2 Hz); 8.00 (d, 1 H, OCH=CH, J = 12.5 Hz); 7.43 (s, 1 H,
H(11)); 7.22 (s, 1 H, H(8)); 6.82 (s, 1 H, H(4)); 5.79 (d, 1 H,
OCH=CH, J = 12.5 Hz); 4.93 (s, 2 H, CH2OC(O)CH3);
4.60—4.51 (m, 1 H, Н(7)); 3.84 (s, 3 H, OCH3(3)); 3.79 (s, 3 H,
OCH3(2)); 3.51 (s, 3 H, OCH3(1)); 2.22 (s, 3 H, C(O)CH3);
2.21—2.09 (m, 4 H, H(5) and Н(6)); 2.05 (s, 3 H, CH2OC(O)
CH3); 1.88 (с, 3 H, NHC(O)CH3). 13C NMR (101 MHz,
DMSO-d6), : 196.7, 169.7, 168.6, 160.4, 154.6, 152.9, 150.2,
144.1, 140.5, 134.9, 134.5, 131.2, 122.4, 114.1, 112.4, 110.9,
108.3, 89.1, 80.6, 60.8, 60.6, 55.9, 52.2, 48.2, 38.3, 29.8, 27.3,
22.7, 20.4. MS (GC/MS), m/z: 521.5 [М]+, Rt = 7.689 min.
N-{3-[(E)-3-Oxobuten-1-yloxy]-2-[(1-hydroxycyclopentyl)-
ethynyl]-6,7-dihydro-5H-9,10,11-trimethoxydibenzo[a,c]cyclo-
hepten-5-yl}acetamide (8d). Aryl iodide 6b (200 mg, 0.36 mmol),
Pd(OAc)2 (4 mg, 0.018 mmol), CuI (7 mg, 0.036 mmol), Ph3P
(14 mg, 0.054 mmol), AcOK (106 mg, 1.08 mmol), and 1-ethynyl-
cyclopentanol (40 mg, 0.41 mmol) were used. Product 8d
(108 mg, 57%) was isolated as light beige crystals, m.p.
151—153 C. Found (%): C, 69.70; H, 6.70. C31H35NO7.
Calculated (%): C, 69.78; H, 6.61. 1H NMR (400 MHz,
DMSO-d6), : 8.42 (d, 1 H, NH, J = 8.5 Hz); 7.98 (d, 1 H,
OCH=CH, J = 12.5 Hz); 7.38 (s, 1 H, H(11)); 7.19 (s, 1 H,
H(8)); 6.82 (s, 1 H, H(4)); 5.74 (d, 1 H, OCH=CH, J = 12.5 Hz);
5.36 (s, 1 H, ОН); 4.60—4.51 (m, 1 H, Н(7)); 3.84 (s, 3 H,
OCH3(3)); 3.79 (s, 3 H, OCH3(2)); 3.50 (s, 3 H, OCH3(1)); 2.20
(s, 3 H, C(O)CH3); 2.18—1.89 (m, 4 H, H(5) and Н(6)); 1.88
(s, 3 H, NHC(O)CH3); 1.86—1.60 (m, 8 H, CyP). 13C NMR
(101 MHz, DMSO-d6), : 196.6, 168.6, 161.1, 154.3, 152.8,
150.2, 143.1, 140.5, 134.9, 134.1, 131.3, 122.5, 114.5, 112.3,
111.8, 108.3, 100.3, 76.2, 72.9, 60.8, 60.6, 55.8, 48.1, 41.9, 41.8,
38.4, 29.8, 27.2, 23.0 (2 C), 22.7. MS (GC/MS), m/z: 534.5
[М + Н]+, Rt = 6.987 min.
N-{3-[(E)-3-Oxobuten-1-yloxy]-6,7-dihydro-5H-2-[-pyr-
idin-2-ylethynyl]-9,10,11-trimethoxydibenzo[a,c]cyclohepten-
5-yl}acetamide (8f). Aryl iodide 6b (200 mg, 0.36 mmol),
Pd(OAc)2 (4 mg, 0.018 mmol), CuI (7 mg, 0.036 mmol), Ph3P
(14 mg, 0.054 mmol), AcOK (106 mg, 1.08 mmol), and 1-ethy-
nylpyridine (36 L, 0.41 mmol) were used. Product 8f (124 mg,
65%) was isolated as light beige crystals, m.p. 169—171 C.
Found (%): C, 70.83; H, 5.81. C31H30N2O6. Calculated (%):
C, 70.71; H, 5.74. 1H NMR (400 MHz, DMSO-d6), : 8.61
(d, 1 H, Py, J = 4.6 Hz); 8.48 (d, 1 H, NH, J = 8.3 Hz); 8.11
(d, 1 H, OCH=CH, J = 12.5 Hz); 7.85 (dd, 1 H, Py, J = 8.7 Hz,
J = 7.7 Hz); 7.64—7.55 (m, 1 Н, Py); 7.59 (s, 1 H, H(11)); 7.42
(dd, 1 H, Py, J = 6.7 Hz, J = 5.7 Hz); 7.28 (s, 1 H, H(8)); 6.84
(s, 1 H, H(4)); 5.88 (d, 1 H, OCH=CH, J = 12.5 Hz); 4.64—4.53
(m, 1 H, Н(7)); 3.85 (s, 3 H, OCH3(3)); 3.80 (s, 3 H, OCH3(2));
3.55 (s, 3 H, OCH3(1)); 2.23 (s, 3 H, C(O)CH3); 2.20—1.93
(m, 4 H, H(5) and Н(6)); 1.90 (s, 3 H, NHC(O)CH3). 13C NMR
(101 MHz, DMSO-d6), : 196.7, 168.7, 160.3, 154.7, 153.0,
150.3, 144.6, 142.0, 140.6, 136.9 (2 С), 134.9, 134.6, 131.3, 127.3,
123.7, 122.4, 114.1, 112.5, 110.8, 108.3, 93.5, 83.4, 60.8, 60.6,
55.9, 48.3, 38.3, 29.8, 27.4, 22.7. MS (GC/MS), m/z: 526.8 [М]+,
Rt = 7.532 min.
Synthesis of compounds 3a—f (general procedure). Starting
compound 7 (or 8) was placed in a Schlenk flask equipped with
a stirrer and dissolved in 1,2-dichloroethane (1.5 mL) under an
inert atmosphere. The resulting system was isolated from the
daylight by a foil. A solution of corresponding alcohol in 1,2-di-
chloroethane (0.5 mL) and a mixture of Ph3PAuCl and Ag[SbF6]
in 1,2-dichloroethane (1 mL) were then added. The reaction
mixture was stirred at ~20 C in the dark for 24 h. The product
was isolated using column chromatography on silica gel, eluent
PE—AcOEt—EtOH (9 : 1 : 1).
Methyl (7S,10S,11R,14aR)-7-acetamido-10-butoxy-6,7,10,11-
tetrahydro-5H-1,2,3-trimethoxy-12-phenylbenzo[6´,7´]cyclo-
hepta[1´,2´:4,5]benzo[1,2-b]oxepine-11-carboxylate (3a). Com-
pound 7a (40 mg, 0.074 mmol), n-butanol (11 mg, 0.148 mmol),
Ph3PAuCl (2 mg, 0.004 mmol), and Ag[SbF6] (2 mg, 0.004 mmol)
were used. Product 3a (27 mg, 60%) was isolated as a mixture of
two diastereomers A and B in the ratio of 2 : 1, light yellow
crystals, m.p. 169—171 C. Found (%): C, 70.37; H, 6.62.
C36H41NO8. Calculated (%): C, 70.23; H, 6.71. Diastereomer A.
1H NMR (400 MHz, DMSO-d6), : 8.40 (d, 1 H, NH, J = 8.5 Hz);
7.48 (d, 2 Н, Ph, J = 7.6 Hz); 7.36 (t, 3 Н, Ph, J = 6.7 Hz); 7.28
(s, 1 H, H(11)); 7.01 (s, 1 H, H(8)); 6.92 (s, 1 H, —СН=С<);
6.78 (s, 1 H, H(4)); 5.66 (d, 1 H, CH–OBu, J = 4.6 Hz);
4.57—4.51 (m, 1 H, H(7)); 4.47 (d, 1 Н, CHC(O)OCH3,
J = 4.3 Hz); 3.84 (s, 3 H, OCH3(3)); 3.79 (s, 3 H, OCH3(2));
3.71—3.64 (m, 2 Н, OCH2CH2CH2CH3); 3.59 (s, 3 H, C(O)
OCH3); 3.56 (s, 3 H, OCH3(1)); 2.20—2.00 (m, 4 H, H(5) and
N-{3-[(E)-3-Oxobuten-1-yloxy]-2-[(1-hydroxycyclohexyl)-
ethynyl]-6,7-dihydro-5H-9,10,11-trimethoxydibenzo[a,c]cyclo-
hepten-5-yl}acetamide (8e). Aryl iodide 6b (200 mg, 0.36 mmol),
Pd(OAc)2 (4 mg, 0.018 mmol), CuI (7 mg, 0.036 mmol), Ph3P
(14 mg, 0.054 mmol), AcOK (106 mg, 1.08 mmol), and 1-ethynyl-
cyclohexanol (45 mg, 0.41 mmol) were used. Product 8e (124 mg,
65%) was isolated as light beige crystals, m.p. 153—155 C.
Found (%): C, 70.28; H, 6.89. C32H37NO7. Calculated (%): C,
70.18; H, 6.81. 1H NMR (400 MHz, DMSO-d6), : 8.43 (d, 1 H,
NH, J = 8.4 Hz); 8.00 (d, 1 H, OCH=CH, J = 12.5 Hz); 7.38

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
Bukhvalova et al.
Н(6)); 1.88 (s, 3 H, NHC(O)CH3); 1.39—1.30 (m, 2 H,
OCH2CH2CH2CH3); 1.06—0.96 (m, 2 H, OCH2CH2CH2CH3);
0.67 (t, 3 Н, OCH2CH2CH2CH3, J = 7.4 Hz). 13C NMR
(101 MHz, DMSO-d6), : 169.4, 168.4, 152.4, 151.0, 150.3,
142.1, 140.6, 134.7, 134.4, 132.4, 129.6, 128.4 (2 C), 127.2, 126.2
(2 C), 124.5, 124.4, 123.7, 115.3, 108.1, 97.9, 68.1, 60.8, 60.5
(2 C), 55.8, 52.2, 47.8, 38.4, 30.8, 29.9, 22.6, 18.5, 13.4.
Diastereomer В. 1H NMR (400 MHz, DMSO-d6), : 8.36 (d, 1 H,
NH, J = 8.9 Hz); 7.48 (d, 2 Н, Ph, J = 7.6 Hz); 7.36 (t, 3 Н, Ph,
J = 6.7 Hz); 7.29 (s, 1 H, H(11)); 7.01 (s, 1 H, H(8)); 6.86 (s, 1 H,
—СН=С<); 6.80 (s, 1 H, H(4)); 5.61 (d, 1 H, CH—OBu,
J = 5.2 Hz); 4.57—4.51 (m, 1 H, H(7)); 4.47 (d, 1 Н, CHC(O)
OCH3, J = 4.3 Hz); 3.84 (s, 3 H, OCH3(3)); 3.78 (s, 3 H,
OCH3(2)); 3.71—3.64 (m, 2 Н, OCH2CH2CH2CH3); 3.51
(s, 3 H, C(O)OCH3); 3.46 (s, 3 H, OCH3(1)); 2.20—2.00 (m, 4 H,
H(5) and Н(6)); 1.88 (s, 3 H, NHC(O)CH3); 1.39—1.30 (m, 2 H,
OCH2CH2CH2CH3); 1.06—0.96 (m, 2 H, OCH2CH2CH2CH3);
0.71 (t, 3 Н, OCH2CH2CH2CH3, J = 7.4 Hz). 13C NMR
(101 MHz, DMSO-d6), : 169.3, 168.2, 152.3, 151.2, 150.4,
142.0, 140.5, 134.8, 134.1, 132.8, 129.6, 128.5, 128.3 (2 C), 127.2,
126.2 (2 C), 124.6, 124.2, 123.7, 115.2, 108.1, 98.9, 68.3, 60.8,
60.6, 60.5, 55.8, 52.0, 47.9, 38.4, 30.8, 30.1, 22.6, 18.5, 13.4. MS
(GC/MS), m/z: 638.7 [М + Na]+, Rt = 7.663 min.
Methyl (7S,10S,11R,14аR)-7-acetamido-10-isopropyloxy-
6,7,10,11-tetrahydro-5H-1,2,3-trimethoxy-12-phenylbenzo-
[6´,7´]cyclohepta[1´,2´:4,5]benzo[1,2-b]oxepine-11-carboxylate
(3b). Compound 7a (100 mg, 0.184 mmol), propan-2-ol (22 mg,
0.37 mmol), Ph3PAuCl (5 mg, 0.009 mmol), and Ag[SbF6] (3 mg,
0.009 mmol) were used. Product 3b (60 mg, 53%) was isolated
as a mixture of two diastereomers A and B in the ratio of 2 : 1,
light yellow crystals, m.p. 173—175 C. Found (%): C, 69.99;
H, 6.42. C35H39NO8. Calculated (%): C, 69.87; H, 6.53.
Diastereomer А. 1H NMR (400 MHz, DMSO-d6), : 8.42 (d, 1 H,
NH, J = 8.8 Hz); 7.48 (d, 2 Н, Ph, J = 8.0 Hz); 7.36 (t, 3 H, Ph,
J = 7.6 Hz); 7.27 (s, 1 H, H(11)); 7.01 (s, 1 H, H(8)); 6.88 (s, 1 H,
—СН=С<); 6.78 (s, 1 H, H(4)); 5.67 (d, 1 H, CH—OPri,
J = 5.0 Hz); 4.55—4.50 (m, 1 H, H(7)); 4.42 (d, 1 Н, CHC(O)-
OCH3, J = 5.1 Hz); 4.04—3.96 (m, 1 Н, CH(CH3)2); 3.83 (s, 3 H,
OCH3(3)); 3.80 (s, 3 H, OCH3(2)); 3.60 (s, 3 H, C(O)OCH3);
3.53 (s, 3 H, OCH3(1)); 2.23—1.98 (m, 4 H, H(5) and Н(6));
1.88 (s, 3 H, NHC(O)CH3); 1.09 (t, 3 Н, CH(CH3)2, J = 6.0 Hz);
0.96 (t, 3 H, CH(CH3)2, J = 6.0 Hz). 13C NMR (101 MHz,
DMSO-d6), : 169.4, 168.4, 152.4, 151.5, 150.3, 142.0, 141.8,
140.6, 134.7, 134.3, 132.7, 129.4, 128.6, 128.3 (2 C), 127.2, 126.2
(2 C), 124.5, 123.7, 115.2, 108.1, 97.4, 70.8, 60.8, 60.5, 55.8,
52.1, 47.9, 38.5, 30.1, 22.6 (2 C), 21.4. Diastereomer В. 1H NMR
(400 MHz, DMSO-d6), : 8.39 (d, 1 H, NH, J = 8.8 Hz); 7.48
(d, 2 Н, Ph, J = 8.0 Hz); 7.36 (t, 3 H, Ph, J = 7.6 Hz); 7.29
(s, 1 H, H(11)); 7.99 (s, 1 H, H(8)); 6.84 (s, 1 H, —СН=С<);
6.80 (s, 1 H, H(4)); 5.66 (d, 1 H, CH—OPri, J = 5.0 Hz);
4.55—4.50 (m, 1 H, H(7)); 4.41 (d, 1 Н, CHC(O)OCH3,
J = 5.1 Hz); 4.04—3.96 (m, 1 Н, CH(CH3)2); 3.84 (s, 3 H,
OCH3(3)); 3.78 (s, 3 H, OCH3(2)); 3.67 (s, 3 H, C(O)OCH3);
3.54 (s, 3 H, OCH3(1)); 2.23—1.98 (m, 4 H, H(5) and Н(6));
1.88 (s, 3 H, NHC(O)CH3); 1.09 (t, 3 Н, CH(CH3)2, J = 6.0 Hz);
0.97 (t, 3 H, CH(CH3)2, J = 6.0 Hz). 13C NMR (101 MHz,
DMSO-d6), : 169.3, 168.3, 152.3, 151.6, 150.4, 141.9, 141.6,
140.5, 134.8, 133.9, 133.0, 129.5, 128.6, 128.3 (2 C), 127.2, 126.3
(2 С), 124.4, 123.7, 115.2, 108.1, 98.1, 70.5, 60.8, 60.5, 55.9,
51.9, 48.0, 38.3, 29.8, 22.7, 22.6, 21.3. MS (GC/MS), m/z: 624.3
[М + Na]+, Rt = 7.207 min.
Methyl (7S,10S,11R,14аR)-7-acetamido-10-ethoxy-6,7,10,11-
tetrahydro-5H-1,2,3-trimethoxy-12-phenyl-benzo[6´,7´]cyclo-
hepta[1´,2´:4,5]benzo[1,2-b]oxepine-11-carboxylate (3c). Com-
pound 7a (40 mg, 0.074 mmol), ethanol (11 mg, 0.148 mmol),
Ph3PAuCl (2 mg, 0.004 mmol), and Ag[SbF6] (2 mg, 0.004 mmol)
were used. Product 3c (17 mg, 40%) was isolated as a mixture of
two diastereomers A and B in the ratio of 2 : 1, light yellow
crystals, m.p. 175—177 C. Found (%): C, 69.64; H, 6.29.
C34H37NO8. Calculated (%): C, 69.49; H, 6.35. Diastereomer А.
1H NMR (400 MHz, DMSO-d6), : 8.45 (d, 1 H, NH, J = 8.4 Hz);
7.48 (d, 2 Н, Ph, J = 7.6 Hz); 7.36 (t, 3 Н, Ph, J = 6.7 Hz); 7.27
(s, 1 H, H(11)); 7.03 (s, 1 H, H(8)); 6.90 (s, 1 H, —СН=С<);
6.78 (s, 1 H, H(4)); 5.65 (d, 1 H, CH—OEt, J = 4.6 Hz);
4.58—4.50 (m, 1 H, H(7)); 4.46 (d, 1 Н, CHC(O)OCH3,
J = 5.0 Hz); 3.83 (s, 3 H, OCH3(3)); 3.79 (s, 3 H, OCH3(2));
3.70—3.61 (m, 2 Н, OCH2CH3); 3.59 (s, 3 H, C(O)OCH3); 3.54
(s, 3 H, OCH3(1)); 2.20—2.01 (m, 4 H, H(5) and Н(6)); 1.89
(s, 3 H, NHC(O)CH3); 1.01 (t, 3 Н, OCH2CH3, J = 7.0 Hz).
13C NMR (101 MHz, DMSO-d6), : 169.4, 168.4, 152.4, 151.3,
150.3, 142.0, 141.8, 140.6, 134.7, 134.4, 132.6, 129.5, 128.5,
128.4 (2 C), 127.2, 126.2 (2 C), 124.2, 123.7, 115.2, 108.1,
98.4, 64.2, 60.8, 60.5, 55.8, 52.2, 47.9, 38.5, 30.1, 22.7, 14.7.
Diastereomer B. 1H NMR (400 MHz, DMSO-d6), : 8.43 (d, 1 H,
NH, J = 8.4 Hz); 7.48 (d, 2 Н, Ph, J = 7.6 Hz); 7.36 (t, 3 Н, Ph,
J = 6.7 Hz); 7.26 (s, 1 H, H(11)); 7.03 (s, 1 H, H(8)); 6.86 (s, 1 H,
—СН=С<); 6.80 (s, 1 H, H(4)), 5.61 (d, 1 H, CH—OEt,
J = 5.3 Hz); 4.58—4.50 (m, 1 H, H(7)); 4.47 (d, 1 Н, CHC(O)
OCH3, J = 5.0 Hz); 3.83 (s, 3 H, OCH3(3)); 3.78 (s, 3 H,
OCH3(2)); 3.70—3.61 (m, 2 Н, OCH2CH3); 3.59 (s, 3 H,
C(O)OCH3); 3.50 (s, 3 H, OCH3(1)); 2.20—2.01 (m, 4 H, H(5)
and Н(6)); 1.89 (s, 3 H, NHC(O)CH3); 1.03 (t, 3 Н, OCH2CH3,
J = 7.0 Hz). 13C NMR (101 MHz, DMSO-d6), : 169.3, 168.4,
152.4, 151.4, 150.4, 141.9, 141.6, 140.5, 134.8, 134.1, 132.9,
129.5, 128.5, 128.3 (2 C), 127.3, 126.3 (2 C), 124.2, 123.6, 115.2,
108.1, 99.2, 69.8, 60.6, 60.3, 56.0, 52.0, 47.9, 38.4, 30.2, 22.7,
15.1. MS (GC/MS), m/z: 610.8 [М + Na]+, Rt = 7. 291 min.
Methyl (7S,10S,11R,14аR)-7-acetamido-6,7,10,11-tetra-
hydro-5H-10-methoxy-1,2,3-trimethoxy-12-phenylbenzo[6´,7´]-
cyclohepta[1´,2´:4,5]benzo[1,2-b]oxepine-11-carboxylate (3d).
Compound 7a (40 mg, 0.074 mmol), methanol (11 mg,
0.148 mmol), Ph3PAuCl (2 mg, 0.004 mmol), and Ag[SbF6]
(2 mg, 0.004 mmol) were used. Product 3d (32 mg, 30%) was
isolated as a mixture of two diastereomers A and B in the ratio
of 2 : 1, light yellow crystals, m.p. 189—191 C. Found (%):
C, 69.24; H, 6.21. C33H35NO8. Calculated (%): C, 69.10; H, 6.15.
Diastereomer А. 1H NMR (400 MHz, DMSO-d6), : 8.42 (d, 1 H,
NH, J = 8.6 Hz); 7.47 (d, 2 Н, Ph, J = 7.3 Hz); 7.38—7.34 (m,
3 H, Ph); 7.28 (s, 1 H, H(11)); 7.05 (s, 1 H, H(8)); 6.91 (s, 1 H,
—СН=С<); 6.79 (s, 1 H, H(4)); 5.60 (d, 1 H, CH—OMe,
J = 4.7 Hz); 4.58—4.52 (m, 1 H, H(7)); 4.47 (d, 1 Н, CHC(O)-
OCH3, J = 4.7 Hz); 3.84 (s, 3 H, OCH3(3)); 3.79 (s, 3 H,
OCH3(2)); 3.57 (s, 3 H, C(O)OCH3); 3.56 (s, 3 H, OCH3(1));
3.40 (s, 3 H, CH—OMe); 2.22—2.02 (m, 4 H, H(5) and Н(6));
1.89 (s, 3 H, NHC(O)CH3). 13C NMR (101 MHz, DMSO-d6),
: 169.4, 168.4, 152.4, 151.0, 150.3, 142.1, 141.7, 140.6, 134.7,
134.4, 132.4, 129.6, 128.5, 128.4 (2 C), 127.2, 126.2 (2 C), 124.6,
124.2, 115.3, 108.1, 97.9, 60.8, 60.5, 55.8, 55.7, 52.2, 51.2,
47.8, 38.6, 30.8, 22.6. Diastereomer В. 1H NMR (400 MHz,
DMSO-d6), : 8.39 (d, 1 H, NH, J = 8.4 Hz); 7.47 (d, 2 Н, Ph,
J = 7.3 Hz); 7.38—7.34 (m, 3 H, Ph); 7.30 (s, 1 H, H(11)); 7.05
(s, 1 H, H(8)); 6.87 (s, 1 H, —СН=С<); 6.76 (s, 1 H, H(4));

2,3-Benzo[b]oxepine derivatives of colchicine
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
2213
5.57 (d, 1 H, CH—OMe, J = 4.9 Hz); 4.58—4.52 (m, 1 H, H(7));
4.50 (d, 1 Н, CHC(O)OCH3, J = 4.9 Hz); 3.82 (s, 3 H, OCH3(3));
3.78 (s, 3 H, OCH3(2)); 3.53 (s, 3 H, C(O)OCH3); 3.48 (s, 3 H,
OCH3(1)); 3.40 (s, 3 H, CH—OMe); 2.22—2.02 (m, 4 H, H(5)
and Н(6)); 1.87 (s, 3 H, NHC(O)CH3). 13C NMR (101 MHz,
DMSO-d6), : 169.3, 168.2, 152.3, 151.2, 150.4, 142.0, 141.6,
140.5, 134.8, 134.1, 132.8, 129.1, 128.4, 128.3 (2 C), 127.2, 126.3
(2 C), 124.4, 123.7, 115.2, 108.1, 98.9, 60.6, 60.5, 55.8, 55.7,
52.0, 51.3, 47.8, 38.6, 30.8, 22.6. MS (GC/MS), m/z: 596.3
[М + Na]+, Rt = 7.454 min.
8.37 (d, 1 H, NH, J = 8.3 Hz); 7.15 (s, 1 H, H(8)); 6.96 (s, 1 H,
H(11)); 6.77 (s, 1 H, H(4)); 6.40 (s, 1 H, —СН=С<); 5.39 (d,
1 H, CH—OBu, J = 5.7 Hz); 4.54—4.47 (m, 1 H, H(7)); 3.83
(s, 3 H, OCH3(3)); 3.78 (s, 3 H, OCH3(2)); 3.72—3.69 (m, 1 Н,
CHC(O)OCH3); 3.66 (s, 3 H, C(O)OCH3); 3.62—3.57 (m, 2 H,
CH2CH2CH2CH2Cl); 3.55 (s, 3 H, OCH3(1)); 3.54—3.47
(m, 2 Н, OCH2CH2CH2CH3); 2.20—2.12 (m, 4 H, H(5) and
Н(6)); 2.08—1.98 (m, 2 H, CH=C—CH2CH2CH2CH2Cl); 1.86
(s, 3 H, NHC(O)CH3); 1.76—1.69 (m, 2 H, CH2CH2CH2CH2Cl);
1.61—1.52 (m, 2 H, CH2CH2CH2CH2Cl); 1.19—1.09 (m, 2 H,
OCH2CH2CH2CH3); 1.08—0.98 (m, 2 H, OCH2CH2CH2CH3);
0.72 (t, 3 Н, OCH2CH2CH2CH3, J = 7.4 Hz). 13C NMR
(101 MHz, DMSO-d6), : 169.5, 168.4, 158.6, 152.3, 151.2,
150.3, 140.8, 140.5, 136.7, 134.7, 133.1, 128.5, 126.7, 124.7,
123.7, 115.2, 108.1, 99.0, 68.0, 60.7, 60.5, 55.8, 52.1 (2 C), 47.8,
45.1, 38.4, 31.4, 31.3, 30.8, 30.0, 24.6, 22.6, 18.5, 13.4. Dia-
stereomer B. 1H NMR (400 MHz, DMSO-d6), : 8.43 (d, 1 H,
NH, J = 8.1 Hz); 7.14 (s, 1 H, H(8)); 6.97 (s, 1 H, H(11)); 6.78
(s, 1 H, H(4)); 6.36 (s, 1 H, —СН=С<); 5.43 (d, 1 H, CH—OBu,
J = 5.1 Hz); 4.54—4.47 (m, 1 H, H(7)); 3.83 (s, 3 H, OCH3(3));
3.78 (s, 3 H, OCH3(2)); 3.72—3.69 (m, 1 Н, CHC(O)OCH3);
3.65 (s, 3 H, C(O)OCH3); 3.62—3.57 (m, 2 H, CH2CH2-
CH2CH2Cl); 3.55 (s, 3 H, OCH3(1)); 3.54—3.47 (m, 2 Н,
OCH2CH2CH2CH3); 2.20—2.12 (m, 4 H, H(5) and Н(6));
2.08—1.98 (m, 2 H, CH=C—CH2CH2CH2CH2Cl); 1.86 (s, 3 H,
NHC(O)CH3); 1.76—1.69 (m, 2 H, CH2CH2CH2CH2Cl);
1.61—1.52 (m, 2 H, CH2CH2CH2CH2Cl); 1.19—1.09 (m, 2 H,
OCH2CH2CH2CH3); 1.08—0.98 (m, 2 H, OCH2CH2CH2CH3);
0.75 (t, 3 Н, OCH2CH2CH2CH3, J = 7.4 Hz). 13C NMR
(101 MHz, DMSO-d6), : 169.6, 168.4, 158.6, 152.3, 151.3,
150.4, 140.9, 140.5, 136.7, 134.8, 133.1, 128.7, 126.8, 124.8,
123.8, 115.2, 108.2, 99.0, 68.1, 60.6, 60.5, 55.8, 52.1, 52.0, 47.8,
45.2, 38.5, 31.5, 31.3, 30.8, 30.1, 24.7, 22.6, 18.5, 13.5. MS
(GC/MS), m/z: 653.1 [М + Na]+, Rt = 7.347 min.
Methyl (7S,10S,11R,14аR)-7-acetamido-10-butoxy-6,7,10,11-
tetrahydro-5H-1,2,3-trimethoxy-12-propyl-benzo[6´,7´]cyclo-
hepta[1´,2´:4,5]benzo[1,2-b]oxepine-11-carboxylate (3e). Com-
pound 7b (100 mg, 0.197 mmol), n-butanol (29 mg, 0.394 mmol),
Ph3PAuCl (5 mg, 0.010 mmol), and Ag[SbF6] (4 mg, 0.010 mmol)
were used. Product 3e (46 mg, 40%) was isolated as a mixture of
two diastereomers A and B in the ratio of 2 : 1, light yellow
crystals, m.p. 181—183 C. Found (%): C, 68.25; H, 7.52.
C
33H43NO8. Calculated (%): C, 68.14; H, 7.45. Diastereomer А.
1H NMR (400 MHz, DMSO-d6), : 8.36 (d, 1 H, NH, J = 8.5 Hz);
7.14 (s, 1 H, H(8)); 6.96 (s, 1 H, H(11)); 6.77 (s, 1 H, H(4));
6.36 (s, 1 H, —СН=С<); 5.39 (d, 1 H, CH—OBu, J = 5.2 Hz);
4.52—4.48 (m, 1 H, H(7)); 3.83 (s, 3 H, OCH3(3)); 3.78 (s, 3 H,
OCH3(2)); 3.71—3.69 (m, 1 Н, CHC(O)OCH3); 3.65 (s, 3 H,
C(O)OCH3); 3.55 (s, 3 H, OCH3(1)); 3.20—3.14 (m, 2 Н,
OCH2CH2CH2CH3); 2.17—2.10 (m, 4 H, H(5) and Н(6));
2.08—2.00 (m, 2 H, CH=C—CH2CH2CH3); 1.86 (s, 3 H,
NHC(O)CH3); 1.55—1.48 (m, 2 H, OCH2CH2CH2CH3);
1.47—1.42 (m, 2 H, CH=C—CH2CH2CH3); 1.41—1.32 (m, 2 H,
OCH2CH2CH2CH3); 0.86 (t, 3 Н, CH=C—CH2CH2CH3,
J = 7.7 Hz); 0.74 (t, 3 Н, OCH2CH2CH2CH3, J = 7.4 Hz).
13C NMR (101 MHz, DMSO-d6), : 169.7, 168.5, 159.0, 152.4,
151.3, 150.3, 140.8, 140.6, 136.7, 134.8, 133.5, 128.6, 126.7,
124.8, 123.8, 115.2, 108.1, 99.6, 68.0, 60.8, 60.5, 56.2, 55.9, 52.1,
47.8, 40.3, 38.5, 30.8, 30.0, 22.6, 20.8, 18.5, 13.5 (2 C).
Diastereomer В. 1H NMR (400 MHz, DMSO-d6), : 8.43 (d, 1 H,
NH, J = 8.5 Hz); 7.15 (s, 1 H, H(8)); 6.97 (s, 1 H, H(11)); 6.78
(s, 1 H, H(4)); 6.36 (s, 1 H, —СН=С<); 5.36 (d, 1 H, CH—OBu,
J = 6.1 Hz); 4.52—4.48 (m, 1 H, H(7)); 3.83 (s, 3 H, OCH3(3));
3.79 (s, 3 H, OCH3(2)); 3.78—3.73 (m, 1 Н, CHC(O)OCH3);
3.64 (s, 3 H, C(O)OCH3); 3.55 (s, 3 H, OCH3(1)); 3.28—3.22
(m, 2 Н, OCH2CH2CH2CH3); 2.17—2.10 (m, 4 H, H(5) and
Н(6)); 2.08—2.00 (m, 2 H, CH=C—CH2CH2CH3); 1.86 (s, 3 H,
NHC(O)CH3); 1.55—1.48 (m, 2 H, OCH2CH2CH2CH3);
1.47—1.42 (m, 2 H, CH=C—CH2CH2CH3); 1.41—1.32 (m, 2 H,
OCH2CH2CH2CH3); 0.89 (t, 3 Н, CH=C—CH2CH2CH3,
Analysis of cytotoxicity in vitro. Cytotoxic effect of the allo-
colchicinoids was estimated by a standard 3-(4,5-dimethylthi-
azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma) test.
Human cell lines of pancreatic carcinoma (metastases) COLO-357,
pancreatic duct carcinomas PANC-1, embryonic kidney cells
HEK293, cervical cancer cells HeLa, and cells of mouse colon
adenocarcinoma Colon26 were used. The cells were cultivated
in RPMI-1640 (PANC-1, COLO-357, HeLa, and Colon26) or
DMEM (HEK293) medium. Fetal bovine serum (FBS) (8%),
L-glutamine (300 g mL–1), ampicillin/streptomycin (50 g mL–1),
and 2-mercaptoethanol (5•10–5 mol L–1) were added to
the media. The cells were cultivated in a CO2-filled incubator
at 37 C. To this end, the cells were introduced into a flat-bot-
tomed 96-well plate (50 thousands per well), wherein the pre-
parations were titrated in advance. The plates were incubat-
ed in a CO2-filled incubator for 72 h, and before the last 4 h,
MTT (250 g mL–1) was added. The supernatants were re-
moved at the end of incubation, and DMSO (100 L)
was added into the wells in order to dissolve formazan. The
plates were analyzed on a Titertek plate reader at the wavelength
of 540 nm. The inhibition index (II) was calculated according to
the formula
J = 7.7 Hz); 0.76 (t, 3 Н, OCH2CH2CH2CH3, J = 7.3 Hz). 13
C
NMR (101 MHz, DMSO-d6), : 169.7, 168.5, 159.0, 152.4,
151.5, 150.4, 140.8, 140.6, 136.7, 134.8, 133.8, 128.8, 126.7,
125.0, 123.8, 115.2, 108.2, 99.6, 68.1, 60.8, 60.6, 56.2, 55.9, 52.0,
47.9, 40.3, 38.5, 30.8, 30.1, 22.7, 21.0, 18.6, 13.4 (2 C). MS
(GC/MS), m/z: 604.5 [М + Na]+, Rt = 7.120 min.
Methyl (7S,10S,11R,14аR)-7-acetamido-10-butoxy-12-(4-
chlorobutyl)-6,7,10,11-tetrahydro-5H-1,2,3-trimethoxybenzo-
[6´,7´]cyclohepta[1´,2´:4,5]benzo[1,2-b]oxepine-11-carboxylate
(3f). Compound 7d (96 mg, 0.184 mmol), n-butanol (22 mg,
0.370 mmol), Ph3PAuCl (5 mg, 0.009 mmol), and Ag[SbF6]
(3 mg, 0.009 mmol) were used. Product 3f (30 mg, 22%) was
isolated as a mixture of two diastereomers A and B in the ratio
of 3 : 2, light yellow crystals, m.p. 168—170 C. Found (%):
C, 64.97; H, 7.14. C34H44ClNO8. Calculated (%): C, 64.80;
H, 7.04. Diastereomer А. 1H NMR (400 MHz, DMSO-d6), :
II = 1 – ODexp/ODcontr
,
wherein ODexp and ODcontr are the optical density of experimen-
tal and control solution, respectively. IC50 values were determined
as a half of the inhibition index.

2214
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 12, December, 2019
Bukhvalova et al.
Docking was performed using Autodock 4.253 and AutoGrid
20. J. Kurek, P. Kwaśniewska-Sip, K. Myszkowski, G. Cofta,
M. Murias, P. Barczyński, B. Jasiewicz, R. Kurczab, Med.
Chem. Comm., 2018, 9, 1708.
21. I. Spasevska, A. Ayoub, P. Winter, J. Preto, S. Wong, C. Id,
J. A. Tuszynski, Int. J. Mol. Sci., 2017, 18, 1676.
22. E. S. Shchegravina, D. S. Tretiakova, A. S. Alekseeva, T. R.
Galimzyanov, Y. N. Utkin, Y. A. Ermakov, E. V. Svir-
shchevskaya, V. V. Negrebetsky, N. Yu. Karpechenko, V. P.
Chernikov, N. R. Onishchenko, E. L. Vodovozova, A. Yu.
Fedorov, I. A. Boldyrev, Bioconjugate Chem., 2019, 30, 1098.
23. N. S. Sitnikov, A. Yu. Fedorov, Russ. Chem. Rev., 2013,
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programs. A MGLTools 1.5.6 shell was used during the work
with the program. Each the docking experiment was performed
using a LGA genetic algorithm (200 conformations, 25 000 000
calculations per each). The - and -subunits of stathmin-like
domain 1SA0.pdb54 were taken as the starting protein. The
geometry of colchicinoid molecules was optimized using the
Gaussian 0355 program according to the density functional
method B3LYP/6-31G(d,p).
This work was financially supported by the Russian
Science Foundation (Project No. 19-13-00158).
24. A. I. Konovalov, I. S. Antipin, V. A. Burilov, T. I. Madzhidov,
A. R. Kurbangalieva, A. V. Nemtarev, S. E. Solovieva, I. I.
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Received August 5, 2019;
in revised form September 29, 2019;
accepted October 9, 2019