Synthesis of Symmetrical and Hybrid Dimeric Steroids by Double Suzuki-Miyaura Cross Coupling of 4-Bromo-3-oxo Steroids and Benzene-1,4-diboronic Acid

Article abstract of DOI:10.1055/s-0037-1611484

Two symmetrical dimers and one hybrid dimer in which the steroid cores are connected by a 1,4-phenylene moiety were obtained by double Suzuki-Miyaura cross coupling of benzene-1,4-diboronic acid with 4-bromo-4-en-3-oxosteroids derived from cholesterol and diosgenin. Detailed NMR characterization of the obtained dimers is described.

Full text of DOI:10.1055/s-0037-1611484

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
en
Synthesis
M. C. Mayorquín-Torres et al.
Paper
Synthesis of Symmetrical and Hybrid Dimeric Steroids by Double
Suzuki–Miyaura Cross Coupling of 4-Bromo-3-oxo Steroids and
Benzene-1,4-diboronic Acid
O
O
Martha C. Mayorquín-Torres
Gerardo I. Santiago-Sampedro
Marcos Flores-Álamo
from cholesterol
O
O
HO
OH
i
O
O
O
B
B
O
Martín. A. Iglesias-Arteaga*
0
0
0
0-
0
0
0
3-4
7
6
4-7
6
6
4
HO
OH
21 %
33 %
14 %
hybrid
Br
symmetrical
symmetrical
O
from diosgenin
Facultad de Química, Universidad Nacional Autónoma de
México. Ciudad Universitaria, 04510 CDMX, México
martin.iglesias@unam.mx
O
O
O
O
O
O
Br
i) Pd(PPh3)2Cl2/K2CO3, dioxane/H2O reflux
O
Received: 20.02.2019
Accepted after revision: 18.03.2019
Published online: 10.04.2019
synthesized have triggered intense activity in this field.3
The large number of steroid dimers reported to date include
compounds that have shown properties as catalysts, artifi-
4
DOI: 10.1055/s-0037-1611484; Art ID: ss-2019-m0115-op
5
6
cial receptors or molecular umbrellas as well as activity as
Abstract Two symmetrical dimers and one hybrid dimer in which the
steroid cores are connected by a 1,4-phenylene moiety were obtained
by double Suzuki–Miyaura cross coupling of benzene-1,4-diboronic
acid with 4-bromo-4-en-3-oxosteroids derived from cholesterol and di-
osgenin. Detailed NMR characterization of the obtained dimers is de-
scribed.
7
8
sulfatase inhibitors, antimalarials, or cytotoxic and anti-
proliferative agents9 amongst others.3 Recent solid-state
studies revealed that several crystalline steroid dimers act
as molecular rotors.10
As a part of our ongoing program on the study of the
properties of such compounds, we have described the syn-
thesis of several symmetrical and hybrid dimers derived
from cholesterol, diosgenin, testosterone and estradiol in
which the steroid cores are bridged by different structural
fragments.11 In particular, we have recently described di-
meric terephthalates of the 5- and 5-epimers of 4,5-seco-
cholest-3-yn-5-ol as well as dimeric 4,5-seco-3-yn-5-ones,
in which the facial hydrophobicity of the steroidal frame-
works plays an important role in the crystal packing, forc-
ing the dimeric molecules to accommodate the steroid
cores in cisoid or linear conformations.1 We have also de-
Key words cholesterol, diosgenin, 4-bromo-4-en-3-oxosteroids, ben-
zene-1,4-diboronic acid, double Suzuki–Miyaura cross coupling, steroid
dimers, NMR, X-ray diffraction
The subfamily of steroid dimers gained its first mem-
bers when compounds considered as mere curiosities were
isolated from Nature or were found as side products of
some reactions. In the last decades the interesting chemi-
cal, biological, and physical properties of the increasing
number of steroid dimers isolated from living organisms or
1
2
1a,c
i
ii
iii
+
Route A
HO
O
O
O
O
with 3b
O
O
1
2
3a
3b
Br
4
O
O
O
O
O
O
O
O
O
O
i
ii
iii
Route b
+
HO
O
O
O
O
with 7b
O
O
5
6
7a
7b
Br
8
Scheme 1 Synthesis of bromoenones 4 and 8. Reagents and conditions: (i) Oppenauer oxidation; (ii) H O , NaOH, CH Cl , CH OH; fractional crystalliza-
2
2
2
2
3
tion; (iii) 40 % HBr (aq), acetone.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

B
Synthesis
M. C. Mayorquín-Torres et al.
Paper
scribed two crystalline symmetrical dimers derived from
diosgenin that exhibit interesting properties as molecular
rotors with fast dynamic processes in the solid state at
room temperature that are significantly influenced by non-
conventional intermolecular hydrogen bonds, which hinder
the rotation of the phenyl fragment at lower tempera-
HBr (aq) produced bromoenone 4 and the unchanged epox-
ide 3a, which were separated by column chromatography.
Nevertheless, during such separation, we observed exten-
sive decomposition of bromoenone 4, which, in our hands,
proved to be light-sensitive on silica gel. To avoid long ma-
nipulation of 4, we found it more convenient to perform
this step with the pure -epoxide 3b, which can be ob-
tained in pure state by fractional crystallization of the
3a/3b mixture in hexane, and cleanly produced bromoe-
none 4 that was sufficiently pure for the next step (Scheme
1, Route A). Similar treatment of diosgenin, including sepa-
ration of the -epoxide 7b from the diastereomeric 7a/7b
mixture by fractional crystallization in hexane/ethyl ace-
tate, led to bromoenone 8 (Scheme 1, Route B).
10c
tures.
The results described above prompted us to set up pro-
cedures for the synthesis of dimers, in which the steroid
cores are connected by a 1,4-phenylene moiety. Herein, we
describe the synthesis of steroid dimers employing a double
Suzuki–Miyaura cross coupling of benzene-1,4-diboronic
acid with 4-bromo-4-en-3-oxosteroids derived from cho-
lesterol and diosgenin. Detailed NMR characterization of
the obtained dimers and synthetic intermediates is de-
scribed. X-ray crystal structures of several synthetic inter-
mediates are also provided.
Treatment of a mixture of benzene-1,4-diboronic acid
and 4-bromo-4-en-3-oxosteroids 4 or 8 with Pd(PPh ) Cl
3
2
2
and K CO3 in refluxing dioxane/H O afforded the corre-
2
2
Oppenauer oxidation of cholesterol (1) afforded the ,-
unsaturated ketone 2 that, on treatment with H O /NaOH,
sponding symmetric dimers 9 or 10 (Scheme 2). When a
1:1 mixture of 4 and 8 was submitted to the same treat-
ment, the hybrid dimer 11 (14%) was obtained along with
the symmetric partners 9 (21%) and 10 (33%) (Scheme 3;
2
2
produced a mixture of diastereomeric epoxides 3a and 3b.12
Treatment of the mixture of epoxides 3a and 3b with 40%
21
O
25
2
1
22
2
4
27
26
2
0
25
26
18
O
18 20
22
27
2
3
12
12
23
2
4
1
7
17
11
19
13
14
11
13
O
1
9
1
6
1
9
1
9
16
O
2
15
2
14
15
10
8
1
0
8
3
3
i
6
7
6
7
5
5
O
4
i
O
4
O
ipso
9, 80%
CH phenyl
10, 53%
CH phenyl
O
ipso
4
CH phenyl
CH phenyl
CH phenyl
CH phenyl
Br
8
Br
CH phenyl
CH phenyl
HO
HO
OH
OH
ipso
HO
HO
OH
OH
ipso
B
B
6'
6'
4'
O
B
B
4'
5
'
O
7'
7'
5'
3
'
3'
1
5'
10'
19'
15'
10'
1
4'
9'
2'
14'
8
1
'
8
'
9'
2'
1'
16'
1
6'
1'
1
7' 13'
O
17' 13'
19'
2
6'
11'
11'
2'
24'
12'
2
5'
23'
20'
22'
23'
20'
1
1
21'
8'
22'
8'
2
7'
27'
24'
26'
O
2
5'
21'
Scheme 2 Synthesis of symmetrical steroids dimers 9 and 10. Reagents and conditions: i) Pd(PPh ) Cl , K CO , dioxane, H O reflux.
3
2
2
2
3
2
2
1
22
6
24
27
21
20
O
26
25
25
2
0
25
26
21
18 20
O
2
6
1
8
2
3
18
22
27
22
27
1
2
1
7
12
23
24
2
12
23
1
1
1
7
24
1
9
13
14
1
1
17
13
O
11
1
19
13
14
O
1
9
19
1
9
16
1
9
16
2
15
10
8
14
2
15
1
0
8
10
15
3
8
HO
HO
OH
OH
6
7
3
5
7
3
4
O
4
5
7
i
5
O
B
B
O
4
O
ipso
9, 21%*
CH phenyl
6
10, 33%*
6
11, 14%*
ipso
4
CH phenyl
CH phenyl
ipso-a
Br
CH phenyl
CH phenyl
CH phenyl
CH phenyl-a
CH phenyl-b
CH phenyl-a
CH phenyl
O
CH phenyl
CH phenyl -b
ipso
6'
ipso
ipso-b
4'
4
'
O
5'
6'
4'
7'
O
6'
7'
O
3
'
7'
5'
10'
O
5'
3'
10'
19'
3'
1
5'
1
4'
9'
2'
10'
8'
15'
14'
9'
1
2'
15'
1
'
8'
17' 13'
12'
14'
9'
2'
16'
16'
1'
8'
17' 13'
12'
1
7' 13'
1'
26'
11'
O
19'
16'
1'
26'
25'
19'
O
12'
11'
23'
20'
22'
24'
25'
23'
1
21'
8'
2
2'
20'
18'
23'
Br
8
27'
20'
22'
18'
21'
27'
24'
2
6'
O
25'
21'
27'
24'
Scheme 3 Random cross coupling. Reagents and conditions: i) Pd(PPh ) Cl , K CO , dioxane, H O reflux. * Yields are referenced to benzene-1,4-di-
3
2
2
2
3
2
boronic acid.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

C
Synthesis
M. C. Mayorquín-Torres et al.
Paper
1
Table 1 Selected H NMR Signals of Steroid Dimers 9–11
9a
10a
11
Cholestane part
Spirostane part
H-Phenyl
H-2 ax.
6.98 s
2.57 ddd
N.A.
6.96 s
2.56 ddd
4.40 m
6.97 s
2.56 ddd
H-16
N.A.
0.71 s
1.27 s
N.A.
4.40 ddd
H-18
0.72 s
1.28 s
N.A.
0.83 s
0.83 s
H-19
1.29 s
1.29 s
1.87 p
H-20
1.87 p
H-21
0.92 d
0.87 d
0.86 d
0.97 d
0.91 d
0.86 d
0.86 d
0.97 d
H-26
3.47 eq. ddd; 3.36 ax. dd
0.78 d
3.47 eq. ddd; 3.36 ax. dd
0.78 d
H-27
a
Since 9 and 10 are C
2
symmetrical, the chemical shifts are identical for both halves.
1
1
yields relative to benzene-1,4-diboronic acid). The relative
amounts obtained of the products 9, 10 and 11 from the
H– H COSY, NOESY, HSQC and HMBC. Table 1 and Table 2
1
13
show selected H and C signals of the obtained dimers 9–
11.
‘
random cross-coupling’ is as yet unexplained; the fact that
the mixed product 11 is the least rather than the most
abundant is, to us, unexpected.
In summary, we have set up procedures for double
Suzuki–Miyaura cross couplings of 4-bromo-3-oxo steroids
with benzene 1,4-diboronic acid that allow the synthesis of
symmetrical and hybrid steroid dimers in which the cores
are connected by a 1,4-phenylene moiety.
Table 2 Selected 13C NMR Signals of Steroid Dimers 9–11
9a
10a
11
C-1
35.1
34.3
35.1
34.2
35.1
34.2
Reactions were monitored by TLC on ALUGRAM® SIL G/UV254 plates
from Macherey–Nagel. Chromatographic plates were sprayed with a
C-2
C-3
198.0
135.1
166.8
29.3
197.7
135.2
166.1
29.2
197.8, 197.9
135.2. 135.0
166.1, 166.6
29.2, 29.3
32.6, 32.5
35.0, 35.4
54.6
1% solution of vanillin in 50% HClO and heated until color developed.
4
Melting points were measured with a Melt-Temp II apparatus. NMR
spectra were recorded in CDCl3 solutions with a Varian INOVA 400
C-4
C-5
1
spectrometer using the solvent signals 7.26 ppm for H and 77.00
13
C-6
ppm for C as references. All NMR spectra were recorded using the
standard pulse sequences and parameters recommended by the man-
ufacturer and were processed by employing MestreNova (http://me-
C-7
32.5
32.6
C-8
35.4
35.1
1
13
strelab.com/). Copies of the H and C NMR spectra are given in the
Supporting Information. Mass spectra were registered in a Thermo-
Electron spectrometer model DFS (Double Focus Sector). HRMS (APCI)
spectra were registered with a Perkin Elmer AxION-2 TOF MS spec-
trometer. X-ray measurements were performed with an Oxford Dif-
fraction Atlas (Gemini) diffractometer.
C-9
C-10
54.6
54.6
39.2
39.2
39.2
C-18
12.0
16.4
12.0 C-18′
16.4 C-18
C-19
17.8
17.9
17.8
C-ipso
135.1
129.6
135.1
129.6
135.0, 135.2
129.6, 129.5
CCDC 1897512 (4), CCDC 1897513 (7b) and CCDC 1897514 (8) con-
tain the supplementary crystallographic data for this paper. The data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
CH phenyl
Since 9 and 10 are C
a
2
symmetrical, the chemical shifts are identical for
both halves.
4,5-Epoxy-5-cholestan-3-one (3a) and 4,5-Epoxy-5-cholestan-3-
one (3b)
Although all attempts at crystallization produced amor-
phous solids that were unsuitable for X-ray diffraction ex-
periments, we decide to run a detailed NMR characteriza-
tion of the obtained dimers that provides useful reference
data for additional experiments that are projected. NMR
signal assignment was carried out with the aid of a combi-
MeOH (100 mL), 10% NaOH solution (5.6 mL) and 30% H O (11.2 mL)
2
2
were sequentially added to a solution of the ,-unsaturated ketone
11a
2
(7.2800 g, 20 mmol) in CH Cl (100 mL) and the resulting mixture
2 2
was stirred for 72 h at r.t. The mixture was neutralized with 10%
aqueous acetic acid solution, 10% aqueous Na SO solution (40 mL)
was added and the resulting mixture was stirred for 10 min. Evapora-
tion of the organic solvent under reduced pressure produced a solid
that was filtered off and washed with water to afford the mixture of
2
3
1
13
nation of 1D and 2D NMR techniques that included H, C,
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

D
Synthesis
M. C. Mayorquín-Torres et al.
Paper
epoxides 3a and 3b (4.89 g). The mother liquor was extracted with
(25R)-Spirost-4-en-3-one (6)
EtOAc (3 × 150 mL) and the organic layer was washed with water
Diosgenin (5) (9.95 g, 24 mmol) and cyclohexanone (20 mL) were dis-
solved in toluene (160 mL) and 10 mL of the solvent was distilled off.
Aluminum isopropoxide (1.47 g,) was added and the mixture was
heated at reflux for 3 h, poured into a solution of sodium tartrate (10
g in 200 mL of water), stirred for 20 min and filtered. The organic lay-
er was washed with water (3 × 50 mL), dried (anhyd Na SO ) and
(
4 × 150 mL), and brine (80 mL), dried (anhyd. Na SO ) and evaporat-
2 4
ed to afford an additional amount (960 mg) of the mixture of 3a and
b. Total yield: 5.85 g (73%) (dr 3a/3b, 1:3.92).12 Fractional recrystalli-
zation from hexane afforded epoxide 3b.
3
2
4
4
,5-Epoxy-5-cholestan-3-one (3b)
evaporated. Chromatographic purification afforded the desired ,-
unsaturated ketone 2.
Mp 118.0 °C (from hexane–EtOAc); Lit. 118.0–119.0 °C.12
1
Yield: 8.63 g (20.95 mmol, 87%); mp 189.1–190.6 °C (from EtOAc/hex-
ane) [Lit. 186–188 °C].
H NMR (400 MHz, CDCl ):  = 2.96 (s, 1 H, H-4), 2.28 (ddd, J = 19.4,
3
10c
5
3
2
.9, 2.2 Hz, 1 H, H-2), 2.14 (dd, J = 13.4, 6.5 Hz, 1 H, H-2), 1.14 (s,
H, H-19), 0.89 (d, J = 6.5 Hz, 3 H, H-21), 0.86 (d, J = 1.8 Hz, 3 H, H-
6), 0.85 (d, J = 1.8 Hz, 3 H, H-27), 0.68 (s, 3 H, H-18).
1
H NMR (CDCl , 400 MHz):  = 5.70 (d, J = 1.8 Hz, 1 H), 4.38 (ddd, J =
3
8.8, 7.5, 6.3 Hz, 1 H), 3.45 (ddd, J = 11.4, 4.9, 2.0 Hz, 1 H), 3.34 (t, J =
10.9 Hz, 1 H), 1.18 (s, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.80 (s, 3 H), 0.77
13C NMR (100.52 MHz):  = 26.1 (C-1), 32.6 (C-2), 206.9 (C-3), 62.7 (C-
(d, J = 6.3 Hz, 3 H).
4
2
1
3
2
), 70.5 (C-5), 29.9 (C-6), 30.4 (C-7), 35.0 (C-8), 46.4 (C-9), 37.2 (C-10),
1.5 (C-11), 39.4 (C-12), 42.6 (C-13), 55.8 (C-14), 23.8 (C-15), 28.1 (C-
6), 56.1 (C-17), 12.0 (C-18), 19.0 (C-19), 35.7 (C-20), 18.6 (C-21),
6.1 (C-22), 24.2 (C-23), 39.5 (C-24), 28.0 (C-25), 22.8 (C-26), 22.5 (C-
7).
13C NMR (100.52 MHz):  = 33.6 (C-1), 33.9 (C-2), 199.4 (C-3), 123.9,
(C-4), 171.1 (C-5), 32.7 (C-6), 32.1 (C-7), 34.1 (C-8), 53.7 (C-9), 38.6
(C-10), 20.7 (C-11), 39.6 (C-12), 40.3 (C-13), 55.6 (C-14), 31.6 (C-15),
80.7 (C-16), 61.9 (C-17), 16.3 (C-18), 17.33 (C-19), 41.6 (C-20), 14.5
(C-21), 109.2 (C-22), 31.3 (C-23), 28.7 (C-24), 30.2 (C-25), 67.0 (C-26),
4-Bromo-cholest-4-en-3-one (4)
17.1 (C-27).
A suspension of 4,5-epoxy-5-cholest-3-one (3b) (1.202 g, 3 mmol)
in acetone (40 mL) was gently warmed until dissolution and cooled to
r.t. Aqueous HBr (40%, 1.2 mL) was added dropwise and the mixture
was stirred for 2 h and diluted with water (75 mL). The mixture was
extracted with EtOAc (3 × 100 mL), washed with water (3 × 100 mL),
dried (anhyd. Na SO ) and evaporated to give 4-bromocholest-4-en-
(25R)-4,5-Epoxy-5-spirostan-3-one (7a) and (25R)-4,5-Epoxy-5-
spirostan-3-one (7b)
MeOH (100 mL), 10% p/v NaOH solution (5.6 mL) and 30% H O (11.2
2
2
mL) were added sequentially to a solution of the ,-unsaturated ke-
tone 2 (8.2522 g, 20.0 mmol) in CH Cl (100 mL) and the resulting
2
4
2
2
3
-one.
mixture was stirred for 72 h at r.t. Water was added and the solvent
was evaporated until a copious precipitate was produced. The solid
was filtered, washed with water and dried in the filter. Crystallization
from hexane EtOAc afforded a 1:3.02 mixture of the epimeric epox-
ides (7a) and (7b) (total yield: 6.46 g, 75%). Fractional recrystalliza-
tion from hexane/EtOAc afforded epoxide 7b.
Yield: 1.2946 g (93%); mp 114.0–116.1 °C (from EtOAc) [Lit.13 115–
116 °C].
1
H NMR (400 MHz, CDCl ):  = 3.25 (ddd, J = 14.9, 4.1, 2.6 Hz, 1 H, H-6
3
10c
equiv), 2.72–2.47 (m, 2 H, H-2), 2.24 (ddd, J = 14.9, 13.9, 5.2 Hz, 1 H,
H-6 ax.), 2.08–1.94 (m, 2 H, H-1eq. and H-12eq.), 1.73 (td, J = 13.6,
(25R)-4,5-Epoxy-5-spirostan-3-one (7b)
5.3 Hz, 1 H, H-1ax.), 1.22 (s, 3 H, H-19), 0.90 (d, J = 6.5 Hz, 3 H, H-21),
0.86 (d, J = 1.9 Hz, 3 H, H-26), 0.85 (d, J = 1.9 Hz, 3 H, H-25), 0.70 (s,
3 H, H-18).
Mp 199.7–201.3 °C (from EtOAc).
1
H NMR (400 MHz, CDCl ):  = 4.39 (ddd, J = 8.6, 7.5, 6.3 Hz, 1 H, H-
3
13
C NMR (CDCl , 100.53 MHz):  = 34.5 (C-1), 34.0 (C-2), 190.8 (C-3),
16), 3.46 (ddd, J = 10.9, 4.6, 2.0 Hz, 1 H, H-26 eq.), 3.35 (t, J = 10.9 Hz,
1 H, H-26 ax.), 2.96 (s, 1 H, H-4), 1.15 (s, 3 H, H-19), 0.95 (d, J =
7.0 Hz, 3 H, H-21), 0.79 (s, 3 H, H-18), 0.78 (d, J = 7.5 Hz, 3 H, H-27).
13
3
121.7 (C-4), 168.4 (C-5), 32.9 (C-6), 31.3 (C-7), 35.2 (C-8), 54.0 (C-9),
42.5 (C-10), 21.2 (C-11), 39.6 (C-12), 42.4 (C-13), 55.8 (C-14), 23.8 (C-
15), 28.2 (C-16), 56.0 (C-17), 11.9 (C-18), 17.8 (C-19), 35.7 (C-20),
18.6 (C-21), 36.1 (C-22), 24.1 (C-23), 39.5 (C-24), 28.0 (C-25), 22.5 (C-
26), 22.8 (C-27).
C NMR (CDCl , 100.53 MHz):  = 26.1 (C-1), 32.5 (C-2), 206.7 (C-3),
3
6
3
2.6 (C-4), 70.2 (C-5), 29.7 (C-6), 30.5 (C-7), 34.7 (C-8), 46.5 (C-9),
7.2 (C-10), 21.3 (C-11), 39.7 (C-12), 40.6 (C-13), 55.6 (C-14), 31.7 (C-
An X-ray crystal structure (CCDC 1897512) for the compound was ob-
tained (Figure 1).
15), 80.5 (C-16), 62.0 (C-17), 16.4 (C-18), 19.0 (C-19), 41.6 (C-20), 14.4
(C-21), 109.2 (C-22), 31.3 (C-23), 28.8 (C-24), 30.2 (C-25), 66.8 (C-26),
17.1 (C-27).
An X-ray crystal structure (CCDC 1897513) for the compound was ob-
tained (Figure 2).
Figure 1 Crystal structure of bromoketone 4 with the thermal ellip-
14
soids drawn at 30% probability
Figure 2 Crystal structure of the epoxide 7b with the thermal ellip-
soids drawn at 30% probability14
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

E
Synthesis
M. C. Mayorquín-Torres et al.
Paper
(
25R)-4-Bromo-spirost-4-en-3-one (8)
When the epoxide 7b (1.286 g, 3 mmol) was treated with 40% HBr
aq) as described for the synthesis of 4, bromoenone 8 was produced.
Benzene-1,4-di(4-yl-(25R)-spirost-4-en-3-one) (10)
The procedure described above employing 4-bromoenone 8 (589.8
mg, 1.2 mmol), benzene-1,4-diboronic acid (82.8 mg, 0.5 mmol),
(
Yield: 1.4612 g (99%); mp 180.4–182.1 °C (from hexane/EtOAc) [Lit.15
K
2
CO
3
(120 mg), Pd(PPh ) Cl (16 mg, 0.02 mmol) and dioxane/H O
3
2
2
2
(3:1, 10 mL), afforded the symmetric dimer 10 after purification in a
225.0–225.5 °C].
chromatographic column packed with silica gel and eluted with CH2-
Cl /EtOAc 15:1.
1
H NMR (400 MHz, CDCl ):  = 4.40 (ddd, J = 8.5, 7.5, 6.4 Hz, 1 H, H-
3
2
1
6), 3.46 (ddd, J = 10.9, 4.6, 2.0 Hz, 1 H, H-26 eq.), 3.35 (dd, J = 10.9,
0.9 Hz, 1 H, H-26 ax.), 3.26 (ddd, J = 14.9, 4.1, 2.6 Hz, 1 H, H-6 eq.),
.68–2.47 (m, 2 H, H-2), 2.26 (ddd, J = 14.8, 13.9, 5.2 Hz, 1 H, H-6 ax.),
.23 (s, 3 H, H-19), 0.96 (d, J = 7.0 Hz, 3 H, H-21), 0.81 (s, 3 H, H-18),
.78 (d, J = 6.3 Hz, 3 H, H-27).
Yield: 289 mg (0.32 mmol, 53%); mp 335.9–337.4 °C (from CH Cl /ac-
etone).
1
2
1
0
2
2
1
H NMR (400 MHz, CDCl ):  = 6.96 (s, 4 H, H-Ph), 4.40 (m, 2 H, H-16
3
and H-16′), 3.47 (ddd, J = 11.3, 1.9, 1.9 Hz, 2 H, H-26 eq. and H-26
eq.′), 3.36 (dd, J = 10.9, 10.9 Hz, 2 H, H-26 ax. and H-26 ax.′), 2.56
13
C NMR (CDCl , 100.53 MHz):  = 34.5 (C-1), 33.9 (C-2), 190.6 (C-3),
3
(ddd, J = 16.3, 14.3, 4.8 Hz, 2 H), 2.51–2.42 (m, 4 H), 1.87 (p, J = 6.9 Hz,
121.9 (C- 4), 167.9 (C-5), 32.8 (C-6), 31.3 (C-7), 34.8 (C-8), 53.9 (C-9),
42.5 (C-10), 21.0 (C-11), 39.6 (C-12), 40.3 (C-13), 55.5 (C-14), 31.6 (C-
15), 80.6 (C-16), 61.9 (C-17), 16.3 (C-18), 17.9 (C-19), 41.6 (C-20),
14.4 (C-21), 109.2 (C-22), 31.4 (C-23), 28.8 (C-24), 30.2 (C-25), 66.8
1 H, H-20 and H-20′), 1.29 (s, 6 H, H-19 and H-19′), 0.97 (d, J =
6.9 Hz, 6 H, H-21 and H-21′), 0.83 (s, 6 H, H-18′), 0.78 (d, J = 6.3 Hz,
6 H, H-27′).
13
(C-26), 17.1 (C-27).
C NMR (CDCl , 100.53 MHz):  = 35.1 (C-1 C-1′), 34.2 (C-2 C-2′),
3
1
3
97.7 (C-3 C-3′), 135.2 (C-4 C-4′), 166.1 (C-5 C-5′), 29.2 (C-6 C-6′),
2.6 (C-7 C-7′), 35.1 (C-8 C-8′), 54.6 (C-9 C-9′), 39.2 (C-10 C-10′), 20.9
An X-ray crystal structure (CCDC 1897514) for the compound was ob-
tained (Figure 3).
(C-11 C-11′), 39.8 (C-12 C-12′), 40.4 (C-13 C-13′), 55.8 (C-14 C-14′),
31.4 (C-15 C-15′), 80.7 (C-16 C-16′), 62.0 (C-17 C-17′), 16.4 (C-18 C-
18′), 17.9 (C-19 C-19′), 41.6 (C-20 C-20′), 14.4 (C-21 C-21′), 109.2 (C-
22 C-22′), 31.7 (C-23 C-23′), 28.8 (C-24 C-24′), 30.3 (C-25 C-25′), 66.9
(C-26 C-26′), 17.1 (C-27 C-27′), Phenyl ring: 135.1 (ipso), 129.6 (CH
phenyl).
HRMS (APCI): m/z [MH+] calcd for C60H83O : 899.6190; found:
6
899.6157.
Figure 3 Crystal structure of bromoketone 8 with the thermal ellip-
14
soids drawn at 30% probability
Benzene-1-(4-yl-(25R)-spirost-4-en-3-one)-4-(4-yl-cholest-4-en-
-one) (11)
3
Benzene-1,4-di(4-yl-cholest-4-en-3-one) (9)
A mixture of the bromoenones 4 (463.5 mg, 1 mmol) and 8 (491.51
mg, 1.0 mmol), benzene-1,4-diboronic acid (165.8 mg, 1.0 mmol),
K CO (240 mg) and Pd(PPh ) Cl (32 mg, 0.04 mmol), dioxane/H O
A mixture of bromoenone 4 (927.08 mg, 2.0 mmol), benzene-1,4-di-
boronic acid (165.8 mg, 1.0 mmol), K CO (240 mg) and Pd(PPh ) Cl
2
3
3
2
2
2
3
3
2
2
2
(
32 mg, 0.04 mmol) was heated at reflux in dioxane/H O (20 mL, 3:1)
(40 mL, 3:1) was treated as described above to afford a mixture of the
symmetric dimers 9 and 10 together with the hybrid partner 11. Sep-
aration in a chromatographic column packed with silica gel and elut-
ed with hexane/EtOAc 8:1 afforded 9 (178.6 mg, 0.212 mmol, 21%), 10
(284.3 mg, 0.326 mmol, 33%) identical as described above, and the de-
sired hybrid dimer 11 (128 mg, 0.142 mmol, 14%).
2
for 6 hours under argon atmosphere. After dilution with EtOAc (60
mL), water (40 mL) was added and the organic layer was separated.
The aqueous layer was extracted with EtOAc (3 × 30 mL). The com-
bined organic layers were washed with water (3 × 30 mL), brine
(3 × 30 mL), dried with Na SO and evaporated. The produced solid
2 4
was purified in a chromatographic column packed with silica gel us-
ing hexanes/ethyl acetate (8:1) mixture for elution, to afford the sym-
metric dimer 9.
Mp 233.7–234.9 °C (from CH Cl /acetone).
2
2
1
H NMR (400 MHz, CDCl ):  = 4.40 (ddd, J = 8.1, 7.7, 6.5 Hz, 1 H, H-
3
1
1
6), 3.47 (ddd, J = 11.0, 4.5, 2.0 Hz, 1 H, H-26 eq.), 3.36 (dd, J = 10.9,
0.9 Hz, 1 H, H-26 ax.), 2.56 (ddd, J = 16.3, 14.3, 4.8 Hz, 2 H, H-2 ax.
Yield: 670.9 mg (0.795 mmol, 80%); mp 175.9–177.0 °C (from hex-
ane/EtOAc).
and H-2′ ax.), 2.50–2.41 (m, 4 H), 1.87 (m, 1 H, H-20), 1.29 (s, 3 H, H-
19), 1.27 (s, 3 H, H-19′), 0.97 (d, J = 6.8 Hz, 3 H, H-21), 0.91 (d, J =
6.5 Hz, 3 H, H-21′), 0.86 (d, J = 6.7 Hz, 6 H, H-26′ and H-27′), 0.83 (s,
3 H, H-18), 0.78 (d, J = 6.3 Hz, 3 H, H-27), 0.71 (s, 3 H, H-18′), Phenyl
ring: 6.97 (s, 4 H, CH phenyl).
1
H NMR (400 MHz, CDCl ):  = 6.98 (s, 4 H, phenyl), 2.57 (ddd, J = 16.3,
3
1
6
4.3, 4.8 Hz, 2 H, H-2 ax. and H-2 ax.′ ), 2.51–2.41 (m, 4 H), 1.28 (s,
H, H-19 and H-19′), 0.92 (d, J = 6.4 Hz, 6 H, H-21 and H-21′), 0.87 (d,
J = 6.6 Hz, 6 H, H-26 and H-26′), 0.86 (d, J = 6.6 Hz, 6 H, H-27 and H-
2
7′), 0.72 (s, 6 H, H-18 and H-18′).
13
C NMR (CDCl , 100.53 MHz):  = 35.1 (C-1), 34.2 (C-2), 197.8 (C-3),
3
13
C NMR (CDCl , 100.53 MHz):  = 35.1 (C-1 C-1′), 34.3 (C-2 C-2′),
135.2 (C-4), 166.1 (C-5), 29.2 (C-6), 32.6 (C-7), 35.0 (C-8), 54.6 (C-9),
39.2 (C-10), 20.9 (C-11), 39.8 (C-12), 40.4 (C-13), 55.8 (C-14), 31.4 (C-
15), 80.7 (C-16), 62.0 (C-17), 16.4 (C-18), 17.9 (C-19), 41.6 (C-20),
14.5 (C-21), 109.2 (C-22), 31.6 (C-23), 28.8 (C-24), 30.3 (C-25), 66.8
(C-26), 17.1 (C-27). Cholestane part: 35.1 (C-1′), 34.2 (C-2′), 197.9 (C-
3′), 135.0 (C-4′), 166.6 (C-5′), 29.3 (C-6′), 32.5 (C-7′), 35.4 (C-8′), 54.6
(C-9′), 39.2 (C-10′), 21.1 (C-11′), 39.8 (C-12′), 42.4 (C-13′), 56.0 (C-
14′), 23.8 (C-15′), 28.2 (C-16′), 56.1 (C-17′), 12.0 (C-18′), 17.8 (C-19′),
35.7 (C-20′), 18.6 (C-21′), 36.1 (C-22′), 24.1 (C-23′), 39.5 (C-24′), 28.0
(C-25′), 22.5 (C-26′), 22.8 (C-27′). Phenyl ring: 135.0 (ipso-a), 129.6
3
1
3
98.0 (C-3 C-3′), 135.1 (C-4 C-4′), 166.8 (C-5 C-5′), 29.3 (C-6 C-6′),
2.5 (C-7 C-7′), 35.4 (C-8 C-8′), 54.6 (C-9 C-9′), 39.2 (C-10 C-10′), 21.1
(C-1 C-11′), 39.8 (C-12 C-12′), 42.4 (C-13 C-13′), 56.0 (C-14 C-14′),
2
1
3.8 (C-15 C-15′), 28.2 (C-16 C-16′), 56.1 (C-17 C-17′), 12.0 (C-18 C-
8′), 17.8 (C-19 C-19′), 35.8 (C-20 C-20′), 18.6 (C-21 C-21′), 36.1 (C-22
C-22′), 24.1 (C-23 C-23′), 39.5 (C-24 C-24′), 28.0 (C-25 C-25′), 22.5 (C-
6 C-26′), 22.8 (C-27 C-27′), Phenyl ring: 135.1 (ipso), 129.6 (CH-phe-
2
nyl).
HRMS (APCI): m/z [MH+] calcd for C60H91O : 843.7019; found:
2
(CH phenyl-a), 135.2 (ipso-b), 129.5 (CH phenyl-b).
843.6971.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

F
Synthesis
M. C. Mayorquín-Torres et al.
Paper
HRMS (APCI): m/z [MH+] calcd for C60H87O : 871.6604; found:
(5) (a) Joachimiak, R.; Paryzek, Z. J. Inclusion Phenom. Macrocyclic
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1
Funding Information
Financial support was provided by Consejo Nacional de Ciencia y Tec-
nología (Scholarship # 294665 granted to M.C.M.T.), the Facultad de
Química-UNAM (PAIP-5000-9063), and the Dirección General de
Asuntos del Personal Académico, Universidad Nacional Autónoma de
(7) Fournier, D.; Poirier, D. Bioorg. Med. Chem. Lett. 2009, 19, 693.
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México (DGAPA-IN212417).
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9) Iglesias-Arteaga, M. A.; Morzycki, J. W. In The Alkaloids: Chemis-
try and Biology, Vol. 72; Knölker, H.-J., Ed.; Academic Press:
London, 2013.
Supporting Information
(
10) (a) Czajkowska-Szczykowska, D.; Rodríguez-Molina, B.;
Magaña-Vergara, N. E.; Santillan, R.; Morzycki, J. W.; Garcia-
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611484.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F