Synthesis and characterization of dimeric steroids based on 5-oxo-4,5-seco-yne units linked by a diyne spacer

Article abstract of DOI:10.24820/ark.5550190.p010.459

New dimeric steroids in which two 5-oxo-4,5-seco-3-yne steroids units are linked by a flexible diyne spacer, were prepared by both Eglinton and Pd-catalyzed coupling of the corresponding monomers. X-Ray crystallography shows that one of the obtained dimers displays a novel supramolecular network in which the facial hydrophobicity of the steroidal skeleton plays an important role. The crystal packing is dominated by interactions that accommodate the steroid cores in a highly crowded packed columnar self-assembly. Unambiguous NMR characterization of the obtained compounds is also provided.

Full text of DOI:10.24820/ark.5550190.p010.459

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Arkivoc 2018, part iv, 13-22
Synthesis and characterization of dimeric steroids based on
5-oxo-4,5-seco-yne units linked by a diyne spacer
Ricardo M. Valdez-García,a Carlos Alarcón-Manjarrez,a Rafael Arcos-Ramos,b
Marcos Flores-Álamo,a and Martín A. Iglesias-Arteaga*a
a Facultad de Química, Universidad Nacional Autónoma de México,
Ciudad Universitaria, 04510 México, D.F., México
b Departamento de Química de Radiaciones y Radioquímica, Instituto de Ciencias Nucleares,
Universidad Nacional Autónoma de México, 04510 México D.F., México
Email: martin.iglesias@unam.mx
Dedicated to Professor Gordon W. Gribble on the occasion of his retirement from Dartmouth College
Received 12-29-2017
Accepted 01-21-2018
Published on line 02-04-2018
Abstract
New dimeric steroids in which two 5-oxo-4,5-seco-3-yne steroids units are linked by a flexible diyne spacer,
were prepared by both Eglinton and Pd-catalyzed coupling of the corresponding monomers. X-Ray
crystallography shows that one of the obtained dimers displays a novel supramolecular network in which the
facial hydrophobicity of the steroidal skeleton plays an important role. The crystal packing is dominated by
interactions that accommodate the steroid cores in a highly crowded packed columnar self-assembly.
Unambiguous NMR characterization of the obtained compounds is also provided.
O
i or ii
O
O
H
i) Method A Cu(CH3COO)2•H2O/pyr/CH3OH reflux
ii) Method B Pd(PPh3)4, O2, CuI, Et3N, RT
Keywords: 5-Oxo-4,5-seco-3-yne steroids, Eglinton alkyne coupling, palladium catalyzed alkyne coupling¸ bis-
4,4-(5-oxo-4,5-seco-3-yne steroids), NMR, X-ray diffraction
DOI: https://doi.org/10.24820/ark.5550190.p010.459
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Introduction
Steroids are a family of lipophilic compounds that are widespread in nature. Their intrinsic biological activity
has kept this kind of compound in the focus of attention for more than a century. The subfamily of steroid
dimers added its first members when a few compounds were isolated from nature1 or occurred as by-products
of various reactions.2 The interesting chemical, biological and physical properties of the rising number of
steroid dimers isolated from living organisms or obtained by synthesis3-7 has prompted intensive activity in
this developing field.
Although dimeric steroids are known to form well-defined crystals, reports on the crystal structure of this
type of compound are rather scarce, compared to those of monomeric steroids. As part of a program on the
development of steroid-based crystalline systems, we have become interested in the preparation of
compounds with flexible structural arrangements. In a previous publication we described the synthesis of
dimeric terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols that display novel supramolecular
networks in the solid state in which the facial hydrophobicity of the steroidal skeletons plays an important
role.8 This prompted us to set up procedures to prepare dimeric steroids in which the steroid cores are joined
by a diyne moiety that acts as a flexible spacer.
1,3-Diynes are considered important building blocks for organic synthesis and material science. This has
prompted the development of a large collection of synthetic methods for the preparation of such
compounds.10,11 In particular, the synthesis of symmetric conjugated diynes can be obtained by several
methods that include the different modifications of the Glaser-Eglinton-Hay oxidative coupling.
Herein we report the synthesis and NMR characterization of bis-4,4-(5-oxo-4,5-seco-3-yne-steroids) by
coupling the corresponding 5-oxo-4,5-seco-3-yne steroid units. An X-ray diffraction analysis of compound 5b
confirmed the proposed structure and provided detailed information about the bond lengths, bond angles and
the conformation that the molecules adopt in the crystal state.
Results and Discussion
The starting alkynones 4a,b were obtained following our previously described sequences that include, as key
steps, the epoxidation of ,-unsaturated ketones and the Eschenmoser-Tanabe fragmentation of a mixture
of diastereomeric epoxides (Scheme 1).8,9,12
OAc
OAc
OH
OAc
i
iii
ii
O
O
O
O
O
3a  epoxide
3a  epoxide
4a
1a
2a
H
iv
iii
ii
O
HO
O
O
O
3b  epoxide
3b  epoxide
4b
1b
2b
H
i) Ac2O, pyr; ii) H2O2, CH2Cl2, MeOH; iii) NH2-NHTs, CH2Cl2, AcOH, iv) Oppenauer oxidation
Scheme 1. Our previously reported synthesis of the 5-oxo-4,5-seco-3-yne steroids 4a and 4b.8,9,12
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The first attempts at dimerization included the conditions of the Hay coupling13 that employs TMEDA as
base and a catalytic amount of CuCl in acetone under an oxygen atmosphere. Although this procedure
produced the desired dimerization, TLC analysis indicated that after 16 hours the amount of starting material
was significant. The more drastic conditions of the Eglinton version14 in which the alkyne and an excess of
cupric acetate are refluxed in methanolic pyridine produced the desired dimers in moderate yields after
chromatographic purification (Scheme 2, and Table 1, Method A).
During the course of a parallel investigation9 we observed that Sonogashira coupling of the alkynone 4a
with o-iodobenzyl alcohol employing Pd(PPh3)4 and CuI in triethylamine produced a significant amount of the
dimer 5a as side product. Exclusion of the oxygen by consecutive purging cycles with Ar under sonication
solved this problem. This prompted us to drive the reaction to the desired dimers by removal of the iodinated
derivative and saturation with oxygen. We were happy to find that treatment of the alkynones 4a,b in such
conditions afforded good yields of the desired dimers 5a,b in reactions with a clean, fast and easy work-up,
followed by chromatographic purification (Scheme 2, and Table 1, Method B).
OAc
15'
16'
17'
AcO
2
3
1
7'
19
6'
5'
10'
14'
8'
12
18
4
10
11
13'
O
9
9'
O
3'
13
i or ii
5
OAc
8
4'
11'
18'
17
16
12'
14
5a
6
O
19'
7
1'
2'
15
4a
H
26'
2
25'
27'
1
19
21
15'
12'
12
13
16'
17'
18
7'
6'
11
3
10
5
23'
22'
14'
8'
20
4
24'
22
23
9
O
i or ii
8
5'
10'
O
3'
17
16
9'
13'
24
25
4'
14
O
20'
11'
6
7
18'
15
5b
21'
19'
27
4b
1'
2'
H
26
i) Method A Cu(OAc)2•H2O/pyr/CH3OH reflux
ii) Method B Pd(PPh3)4, O2, CuI, Et3N, RT
Scheme 2. Synthesis of dimeric steroids 5a,b.
Table 1. Yields of the coupling reactions
5a
5b
Method A (Eglinton)
Method B (Pd catalyzed)
222 mg, 67 %
303 mg, 92 %
259 mg, 68 %
312 mg, 81 %
NMR study allowed unambiguous characterization of the obtained compounds. With the exception of
the 13C signals of C-2, C-3 and C-4, the dimerization does not induce significant changes in the NMR signals of
the neighboring nuclei compared with those of the starting monomer 4 (See Tables 2 and 3). This suggests
that in solution the dimeric compounds adopt a linear conformation in which each steroid core is placed well
away from the other, resembling the conformation observed in solid state (vide infra).
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Table 2. Selected 1H NMR signals of the starting alkynones 4a,b and the obtained dimers 5a,b* (δ, ppm)
4a12
2.12
1.92
2.51
2.25
1.08
4b8
5a
2.15
-
2.50
2.27
1.07
5b
2.16
-
2.50
2.25
1.07

+0.04
-
-0.01
+0.01
-0.01
-
4
5
2.16
-
2.50
2.26
1.07
5
4
H-2
H-4
H-6 ax
H-6 eq.
H-19
2.12
1.92
2.51
2.25
1.08
2.12
1.92
2.51
2.25
1.08
= mean value, * Since the dimers 5a,b are C2 symmetrical, the chemical shifts of protons are identical for
both halves
Table 3. Selected 13C NMR signals of the starting alkynones 4a,b and the obtained dimers 5a,b* (δ, ppm)
4a12
33.5
13.7
84.9
68.1
214.1
37.9
30.5
34.6
47.3
50.7
20.5
4b8
33.6
13.7
85.1
67.9
214.7
38.2
31.2
34.8
47.4
50.7
20.6
4
33.6
13.7
85.0
68.0
214.4
38.1
30.9
34.7
47.4
50.7
20.6
5a
5b
33.3
14.6
77.9
65.3
214.7
38.2
31.2
34.9
47.5
50.7
20.5

5
5-
4
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-19
33.3
14.5
77.8
65.3
214.1
37.9
30.5
34.6
47.4
50.7
20.5
33.3
14.6
77.9
65.3
214.4
38.1
30.9
34.8
47.5
50.7
20.5
-0.3
+0.9
-7.2
-2.7
0.0
-0.1
0.0
0.0
+0.1
0.0
-0.1
= mean value, * Since the dimers 5a,b are C2 symmetrical, the chemical shifts of carbon atoms are identical
for both halves
Crystal structure discussion
While all attempts at production of monocrystals of compounds 5a suitable for X-ray diffraction were
unsuccessful, crystallization of compound 5b from ethyl acetate-acetone afforded monocrystals suitable for
such studies.
The molecular structure of 4,4’-bis(4,5-secocholest-3-yn-5,5’-dione) (5b) was solved in the monoclinic
space group C2 and Z = 2. The asymmetric unit contains only half of the dimeric molecule and the other half is
generated by a 2-fold rotation axis perpendicular to the alkyne moiety which deviates slightly from linearity
(175.6°), in accordance with similar steroidal dimeric structures15,16 as shown in Figure 1. Additionally, the
planes of both steroidal cores adopt an orthogonal position with respect to the dialkyne axis.
The dimeric molecules of compound 5b are packed in parallel layers propagated by C(2)-H(2)···Ocarbonyl
[2.63Å] and C(19)-H(19)···Ocarbonyl [2.64Å] interactions between neighboring molecules along the
crystallographic bc plane. This particular arrangement favors the interaction between the hydrophobic faces of
adjacent steroidal dimers generating a multidimensional highly crowded packed columnar self-assembly (see
Figure 2).
The absolute configuration of compound 5b can be assumed without risk, as that known for the starting
material considering that the synthetic transformations carried out do not affect the absolute configuration of
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the chiral centres in the naturally occurring steroid framework. Crystal data and experimental details of the
structure determination of compound 5b are listed in Table 4.17
Figure 1. ORTEP perspective of compound 5b with thermal ellipsoids drawn at 50% probability level for all
atoms other than hydrogen, with their corresponding unit cell viewed along the crystallographic c axis.
Figure 2. Crystal packing of compound 5b.
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Table 4. Crystal data and structure refinement for the dimeric steroid 5b
Parameters
Empirical formula
Formula weight
Value
C54H86O2
767.22
Temperature
Wavelength
Crystal system
Space group
130(2) K
1.54184 Å
Monoclinic
C 2
Unit cell dimensions
Volume
a = 20.6034(19) Å, b = 7.4289(6) Å, c = 15.9737(14) Å, = 101.557(9) °
2395.4(4) Å3
2
Z
Density (calculated)
Absorption coefficient
F(000)
1.064 Mg/m3
0.461 mm-1
852
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 67.684°
Refinement method
Data / restraints / parameters
0.410 x 0.170 x 0.030 mm3
4.381 to 74.132°
-24<=h<=25, -9<=k<=5, -19<=l<=19
8086
3267 [R(int) = 0.0566]
100.0 %
Full-matrix least-squares on F2
3267 / 1 / 258
2
1.066
Goodness-of-fit on F
Final R indices [I>2sigma(I)]
R indices (all data)
Absolute structure parameter
Extinction coefficient
R1 = 0.0505, wR2 = 0.1202
R1 = 0.0734, wR2 = 0.1388
0.1(6)
n/a
Largest diff. peak and hole
0.186 and –0.195 e.Å-3
Conclusions
We have developed straightforward procedures that allow the synthesis of dimers constituted of two units of
a 5-oxo-4,5-seco-3-yne steroid derived from the naturally occurring compounds testosterone (1a), and
cholesterol (1b). Although both procedures afforded the desired compounds, the palladium-catalyzed
homocoupling emerged as more convenient than the Eglinton procedure due to its more environmental
friendly conditions, higher yields and easier work-up of the reaction mixture.
Crystallographic studies showed that the flexible diyne spacer of dimer 5b favors a crystal packing
dominated by interactions that are capable of accommodationg the steroid cores in a highly crowded packed
columnar self-assembly. Further studies to explore the solid-state properties and synthetic applications of
dimers derived from the obtained compounds are in development.
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Experimental Section
General. Reactions were monitored by TLC on ALUGRAM SIL G/UV254 plates from MACHEREY-NAGEL. TLC
plates were sprayed with a 1% solution of vanillin in 50% HClO4 and heated until color developed. Melting
points were measured on a Melt-Temp II apparatus. NMR spectra were recorded in CDCl3 solutions in a Varian
INOVA 400 spectrometer using the solvent signal as reference. NMR signals assignments were carried out with
1
the aid of combined 1D and 2D NMR techniques that included H, 13C, COSY, Nuclear Overhauser Effect
Spectroscopy (NOESY), Heteronuclear Single Quantum Correlation (HSQC) and Heteronuclear Multiple Bond
Correlation (HMBC). High resolution mass spectra were registered in a Jeol, AccuTOF JMS-T100LC
spectrometer. The starting alkynones 4a and 4b were obtained following our previously described protocols
(vide supra Scheme 1).8,9,12 Previously obtained physical and NMR data for 4a and 4b are provided for
comparison purposes.
1
17-Acetoxy-4,5-epoxy-5-androstan-3-one (4a).12 Mp 140–142 °C (from EtOAc) H NMR (400 MHz, CDCl3)
ppm: 4.59 (dd, J 9.2, 7.8 Hz, 1H, H-17), 2.51 (ddd, J 14.5, 6.3, 6.3 Hz, 1H, H-6 ax.), 2.26 (ddd, J 14.7, 4.5, 2.4
Hz, 1H, H-6 eq.), 1.91 (m, 1H, H-4), 2.03 (s, 3H, CH3 acetyl), 1.07 (s, 3H, H-19), 0.84 (s, 3H, H-18). 13C NMR
(CDCl3 100 MHz) ppm: 33.5 C-1, 13.7 C-2, 84.9 C-3, 68.1 C-4, 214.1 C-5, 37.9 C-6, 30.5 C-7, 34.6 C-8, 47.3 C-9,
50.7 C-10, 21.0 C-11, 36.2 C-12, 42.5 C-13, 50.2 C-14, 23.5 C-15, 27.4 C-16, 82.3 C-17, 12.0 C-18, 20.5 C-19,
21.1 CH3 acetyl, 171.1 C=O acetyl.
1
4,5-secocholest-3-yn-5-one (4b).8 Transparent oil. H NMR (CDCl3, 400 MHz): δ ppm: 2.51 (td, J 14.5, 6.4 Hz,
1H, H-6ax.), 2.25 (ddd, J 14.5, 4.5, 2.3 Hz, 1H, H-6eq.), 1.92 (t, J 2.4 Hz, 1H, H-4), 2.12 (m, 2H, H-2) 1.08 (s, 3H,
H-19), 0.91 (d, J 6.5 Hz, 3H, H-21), 0.87 (d, J 1.8 Hz, 3H, H-26), 0.85 (d, J 1.8 Hz, 3H, H-27), 0.72 (s, 3H, H-18). 13C
NMR (CDCl3, 100 MHz) δ ppm: 33.6 C-1, 13.7 C-2, 85.1 C-3, 67.9 C-4, 214.7 C-5, 38.2 C-6, 31.2 C-7, 34.8 C-8,
47.4 C-9, 50.7 C-10, 21.5 C-11, 39.3 C-12, 42.5 C-13, 55.8 C-14, 23.8 C-15, 28.1 C-16, 56.0 C-17, 12.0 C-18, 20.6
C-19, 35.7 C-20, 18.6 C-21, 36.1 C-22, 24.2 C-23, 39.5 C-24, 28.0 C-25, 22.8 C-26, 22.5 C-27.
Method A (Eglinton coupling): A solution of the alkynone 4a, 4b (1 mmol) and Cu(OAc)2•H2O (280 mg, 1.40
mmol) in CH3OH/pyridine (10 mL, 1:1) was refluxed for 6 h. The mixture was cooled to 0 °C and poured
carefully into chilled concentrated HCl (4 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was
washed with H2O (3 x 20 mL), 10% aq. CuSO4, H2O (2 x 30 mL), dried (Na2SO4) and evaporated to produce an
oil that was purified in a column packed with silica gel (15 g) employing hexane-EtOAc 15/1 as eluent to afford
the desired dimeric compound (See Table 1 for yields).
Method B (Pd catalyzed coupling): A mixture of the alkynone (1 mmol), Pd(PPh3)4 (9.6 mg, 0.0083 mmol) and
CuI (3.2 mg, 0.0166 mmol in Et3N (3 mL) was stirred at rt for 2 h under an oxygen atmosphere. EtOAc (50 mL)
was added and the mixture was washed with H2O (5 × 20 mL) dried (anh. Na2SO4) and evaporated. The
residue produced was purified in a chromatographic column packed with silica gel (15 g) that was eluted with
→
hexane/EtOAc mixture (10/0 10/3) to afford the desired dimer (See Table 1 for yields).
1
4,4´-Bis-(4,5-secoandrost-3-yn-5-one) (5a). Oil. NMR H (CDCl3, 400 MHz) δ (ppm): 4.59 (dd, J 9.2, 7.7 Hz, 2H,
H-17, H-17'), 2.50 (ddd, J 15.0, 14.5, 6.3 Hz, 2H, H-6 ax. H-6'ax.), 2.27 (ddd, J 15.0, 4.6, 2.4 Hz, 1H, H-6 eq. H-
6'eq.), 2.15 (m, 4H, H-2 H-2'), 2.04 (s, 6H 2x CH3 acetyl), 1.07 (s, 6H, H-19 H-19'), 0.84 (s, 6H, H-18 H-18') 13C
NMR (CDCl3, 100.53 MHz) δ (ppm): 33.3 C-1 C-1', 14.5 C-2 C-2', 77.8 C-3 C-3', 65.3 C-4 C-4', 214.1 C-5 C-5', 37.9
C-6 C-6', 30.5 C-7 C-7', 34.6 C-8 C-8', 47.4 C-9 C-9', 50.7 C-10 C-10', 21.1 C-11 C-11', 36.22 C-12 C-12', 42.5 C-13
C-13', 50.1 C-14 C-14', 23.5 C-15 C-15', 27.4 C-16 C-16', 82.4 C-17 C-17', 12.1 C-18 C-18', 20.5 C-19 C-19' 171.0
2 x C=O acetyl, 21.1 2 x CH3 acetyl. HRMS (FAB) Estimated for C42H59O6 (MH+) 659.4312, observed 659.4312.
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1
4,4´-Bis-(4,5-secocholest-3-yn-5-one) (5b). Mp. 132-135 °C (from EtOAc-Me2CO). NMR H (CDCl3, 400 MHz) δ
(ppm): 2.50 (td, J 14.4, 6.3 Hz, 2H, H-6 ax. H-6´ax.), 2.25 (m, 2H, H-6eq. H-6´eq.), 2.16 (m, 4H, H-2 H-2´), 1.07
(s, 6H, H-19 H-19´), 0.91 (d, J 6.5 Hz, 6H, H-21 H-21´), 0.87 (d, J 1.9 Hz, 6H, H-26 H-26´), 0.85 (d, J 1.9 Hz, 6H,
H-27 H-27´), 0.72 (s, 6H, H-18 H-18´) 13C NMR (CDCl3, 100.53 MHz) δ (ppm): 33.3 C-1 C-1´, 14.6 C-2 C-2´, 77.9 C-
3 C-3´, 65.3 C-4 C-4´, 214.7 C-5 C-5´, 38.2 C-6 C-6´, 31.2 C-7 C-7´, 34.9 C-8 C-8´, 47.5 C-9 C-9´, 50.7 C-10 C-10´,
21.6 C-11 C-11´, 39.3 C-12 C-12´, 42.5 C-13 C-13´, 56.1 C-14 C-14´, 23.9 C-15 C-15´, 28.1 C-16 C-16´, 55.8 C-17
C-17´, 12.0 C-18 C-18´, 20.5 C-19 C-19´, 35.7 C-20 C-20´, 18.6 C-21 C-21´, 36.1 C-22 C-22´, 24.2 C-23 C-23´, 39.5
C-24 C-24´, 28.0 C-25 C-25´, 22.6 C-26 C-26´, 22.8 C-27 C-27´. HRMS Estimated for C54H87O2 (MH+) 767.6706,
observed 767.6688.
X-ray crystallography. A monocrystal of the dimer 5b grown by slow evaporation from an EtOAc-Me2CO
solution was mounted on a glass fiber in the goniometer head with a crystal-to-detector distance of 55.00 mm
and crystallographic data were collected at 130 K with an Oxford Diffraction Gemini "A" diffractometer (CuK
=
1.54184 Å, monochromator: graphite) with a CCD area detector. The collected data set consisted of 19 runs of
1126 frames of intensity (1° in ). The double pass method of scanning was used to exclude any noise. The
collected frames were integrated by using an orientation matrix determined from the narrow frame scans.
CrysAlisPro and CrysAlis RED software packages18 were used for data collection and integration. Analysis of the
integrated data did not reveal any decay. Final cell parameters were determined by a global refinement of
1699 (4.318 <  < 72.464°). Collected data were corrected for absorption effects by analytical numeric
absorption19 using a multifaceted crystal model based on expressions upon the Laue symmetry with
equivalent reflections. Structure solution and refinement were carried with the programs SHELXS-2014 and
SHELXL-2014 respectively.20 WinGX and ORTEP softwares21 were used to prepare material for publication. Full-
matrix least-squares refinement was carried out by minimizing (Fo2 - Fc2)2. All nonhydrogen atoms were
anisotropically refined. Hydrogen atoms attached to carbons were placed in geometrically idealized positions
and refined as riding on their parent atoms, with C–H = 0.98 – 1.00 Å with Uiso (H) = 1.2Ueq(C) for methylene
and methyne groups, and Uiso (H) = 1.5 Ueq(C) for methyl groups.
Acknowledgements
The authors acknowledge the financial support provided by Dirección General de Asuntos del Personal
Académico (Project DGAPA-IN211714) and the Faculty of Chemistry (PAIP-5000- 9063). Thanks are due to
CONACYT-Mexico for the scholarship granted to C.A.-M. and to DGAPA-ICN for a postdoctoral fellowship
granted to R.A.-R. We want to express our gratitude to Rosa I. del Villar Morales (USAI-UNAM) for recording
NMR spectra and to Dr. Carlos Cobas from Mestrelab for assistance with the MestreNova NMR processing
program. We thank Professor John Boulton for correcting the manuscript.
Supplementary Material
1H and 13C NMR spectra of the dimeric steroids 5a and 5b.
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