Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols

Article abstract of DOI:10.1016/j.steroids.2016.03.001

Two dimeric steroidal terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols were prepared starting from cholesterol in a five-step synthetic sequence. X-ray crystallography shows that the obtained compounds display novel supramolecular networks in the solid state in which the facial hydrophobicity of the steroidal skeletons plays an important role. Unambiguous NMR characterization of the obtained dimers is also provided.

Full text of DOI:10.1016/j.steroids.2016.03.001

Steroids xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis, NMR and crystal characterization of dimeric terephthalates
derived from epimeric 4,5-seco-cholest-3-yn-5-ols
Carlos Alarcón-Manjarrez a, Rafael Arcos-Ramos b, Marcos Flores Álamo a, Martín A. Iglesias-Arteaga a,
⇑
a Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, D.F., Mexico
b Departamento de Química de Radiaciones y Radioquímica, Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, 04510 México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Two dimeric steroidal terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols were prepared
starting from cholesterol in a five-step synthetic sequence. X-ray crystallography shows that the obtained
compounds display novel supramolecular networks in the solid state in which the facial hydrophobicity
of the steroidal skeletons plays an important role. Unambiguous NMR characterization of the obtained
dimers is also provided.
Received 14 January 2016
Received in revised form 19 February 2016
Accepted 1 March 2016
Available online xxxx
Ó 2016 Elsevier Inc. All rights reserved.
Keywords:
Epimeric 4,5-seco-cholest-3-yn-5-ols
Dimeric steroidal terephthalates
NMR
X-ray diffraction
1. Introduction
Encouraged by this work, and with the aim of exploring new
steroid-based crystalline arrangements and to evaluate the influ-
Steroid dimers have evolved from being mere curiosities iso-
lated from nature [1] or occurring as by-products of different reac-
tions [2] to a developing field in which an increasing number of
linear or cyclic dimers has been isolated from different living
organisms or are designed and synthesized to develop physical
and study, biological or chemical properties [3–6]. In particular,
linear dimers can involve direct or through-spacer connection
between A, B, C or D rings, as well as C-19 or the side chain [6].
To the best of our knowledge, most if not all of the described ster-
oid dimers contain an intact cyclopentaperhydrophenanthrene
steroid skeleton that bear different functionalities.
Although dimeric steroids are known to form well defined crys-
tals, reports on the crystal structure of this kind of compound are
rather scarce compared to those of monomeric steroids. In partic-
ular Vázquez-Tato and coworkers have reported an amphiphilic
head-to-head dimeric amide in which two units of methyl
ence in the crystal packing of both the hydrophobicity of the
nucleus and the configuration of the carbon atom that bears the
linkage, we have prepared dimers derived from epimeric A-seco
steroids with modified hydrophobicity produced by the presence
of an alkyne moiety and the cleavage of ring A.
Herein we report on the synthesis, NMR characterization and
crystal structures of new dimeric steroids in which the monomeric
units of the
a or b epimers of 4,5-seco-cholest-3-yn-5-ol are linked
by a terephthaloyl moiety, a flexible spacer that can act as a C2
axle. In the solid state the obtained compounds produce novel
multidimensional self-assemblies, dominated by interactions that
are able to accommodate the steroid cores exploiting their facial
hydrophobicity.
2. Experimental
3b-amino-7a,12a-dihydroxy-5b-cholanate are linked by an isoph-
Reactions were monitored by TLC on AlugramÒ SIL G/UV254
plates from Macherey–Nagel. Chromatographic 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 and are not corrected. NMR spectra were
recorded in CDCl3 solutions in a Varian Inova 400 spectrometer
using the solvents signal as references. NMR signals assignments
were carried out with the aid of a combination of 1D and 2D
NMR techniques that included 1H, 13C, COSY, Nuclear Overhauser
Effect Spectroscopy (NOESY), Heteronuclear Single Quantum
thaloyl spacer. The crystal structure of the described dimer has the
steroid residues disposed as the branches of a letter V with the
b-faces pointing toward a concave surface that contains ethyl acet-
ate, and the 7a and 12a hydroxyl groups, that dominate the crystal
packing, exposed in the outside shell [7].
⇑
Corresponding author.
E-mail address: martin.iglesias@unam.mx (M.A. Iglesias-Arteaga).
http://dx.doi.org/10.1016/j.steroids.2016.03.001
0039-128X/Ó 2016 Elsevier Inc. All rights reserved.
Please cite this article in press as: C. Alarcón-Manjarrez et al., Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric
4,5-seco-cholest-3-yn-5-ols, Steroids (2016), http://dx.doi.org/10.1016/j.steroids.2016.03.001

2
C. Alarcón-Manjarrez et al. / Steroids xxx (2016) xxx–xxx
Correlation (HSQC) and Heteronuclear Multiple Bond Correlation
(HMBC) All 2D NMR spectra were recorded using the standard
pulse sequences and parameters recommended by the manufac-
turer and were processed employing the MestreNova NMR pro-
cessing program [See http://mestrelab.com/]. Single-crystal X-ray
diffraction of the dimeric terephthalates corroborated the obtained
structures [8].
2.1.2. 4,5-Epoxy-5a-cholestan-3-one (3a)
Mp. 120.5–121.5 (from isopropanol) Lit. 123–124 °C [10]. 1H
NMR (400 MHz, CDCl3) d ppm: 3.03 (s, 1H, H-4b), 2.39 (ddd,
J = 19.6, 7.2, 1.2 Hz, 1H, H-2a), 2.24 (dd, J = 7.2, 4.3 Hz, 1H, H-2b),
1.05 (s, 3H H-19), 0.91 (d, J = 6.5 Hz, 3H, H-21), 0.87 (d, J = 1.9 Hz,
3H, H-26), 0.86 (d, J = 1.9 Hz, 3H, H-27), 0.69 (s, 3H, H-18). 13C
NMR (100.52 MHz) d ppm: 29.1 C-1, 33.1 C-2, 207.2 C-3, 62.9 C-
4, 70.3 C-5, 29.8 C-6, 29.0 C-7, 35.4 C-8, 50.7 C-9, 36.7 C-10, 21.4
C-11, 39.7 C-12, 42.5 C-13, 55.6 C-14, 23.8 C-15, 28.2 C-16, 56.2
C-17, 12.0 C-18, 16.5 C-19, 35.8 C-20, 18.7 C-21, 36.1 C-22, 24.2
C-23, 39.5 C-24, 28.0 C-25, 22.8 C-26, 22.6 C-27.
Reactions were monitored by TLC on AlugramÒ SIL G/UV254
plates from Macherey–Nagel. Chromatographic 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 and are not corrected. NMR spectra were
recorded in CDCl3 solutions in a Varian Inova 400 spectrometer
using the solvents signal as references. NMR signals assignments
were carried out with the aid of a combination of 1D and 2D
NMR techniques that included 1H, 13C, COSY, Nuclear Overhauser
Effect Spectroscopy (NOESY), Heteronuclear Single Quantum Cor-
relation (HSQC) and Heteronuclear Multiple Bond Correlation
(HMBC) All 2D NMR spectra were recorded using the standard
pulse sequences and parameters recommended by the manufac-
turer and were processed employing the MestreNova NMR pro-
cessing program [See http://mestrelab.com/]. Single-crystal X-ray
diffraction of the dimeric terephthalates corroborated the obtained
structures [8].
2.1.3. 4,5-Epoxy-5b-cholestan-3-one (3b)
Mp. 118 °C (from hexane–ethyl acetate) Lit. 118–119 °C [10]. 1H
NMR (400 MHz, CDCl3) d 2.96 (s, 1H, H-4
a), 2.28 (ddd, J = 19.4, 5.9,
2.2 Hz, 1H, H-2 ), 2.14 (dd, J = 13.4, 6.5 Hz, 1H, H-2b), 1.14 (s, 3H,
a
H-19), 0.89 (d, J = 6.5 Hz, 3H, H-21), 0.86 (d, J = 1.8 Hz, 3H, H-26),
0.85 (d, J = 1.8 Hz, 3H, H-27), 0.68 (s, 3H, H-18). 13C NMR
(100.52 MHz) d ppm: 26.1C-1, 32.6 C-2, 206.9 C-3, 62.7 C-4, 70.5
C-5, 29.9 C-6, 30.4 C-7, 35.0 C-8, 46.4 C-9, 37.2 C-10, 21.5 C-11,
39.4 C-12, 42.6 C-13, 55.8 C-14, 23.8 C-15, 28.1 C-16, 56.1 C-17,
12.0 C-18, 19.0 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.
2.1.4. 4,5-Secocholest-3-yn-5-one (4)
p-Toluenesulfonyl hydrazide (1.024 g, 5.5 mmol, 1.1 eq) was
slowly added over 20 min to a solution of a mixture of the diaster-
eomeric epoxides 3a and 3b (2.0 g, 5.0 mmol) in CH2Cl2/AcOH 1:1
(60 mL) and the mixture was stirred for 2.5 h and poured into sat-
urated NaCl solution (180 mL). The organic layer was separated
and the aqueous phase was extracted with ethyl acetate
(3 ꢀ 50 mL). The combined organic layers were washed with water
(4 ꢀ 50 mL), 10% aqueous NaHCO3 al (6 ꢀ 50 mL), water
(2 ꢀ 20 mL), brine (20 mL); dried (anh. Na2SO4) and evaporated.
The obtained syrup was purified on a column packed with silica
gel employing hexane/ethyl acetate 10/1 as eluent, to afford the
alkynone 4 (1.53 g, 79.3%) as a transparent oil. Lit. oil [11]. 1H
NMR (CDCl3, 400 MHz): d (ppm) 2.51 (td, J = 14.5, 6.4 Hz, 1H, H-6
2.1. Cholest-4-en-3-one (2)
Cholesterol (1) (28.0 g, 72.41 mmol) and cyclohexanone
(60 mL) were dissolved in toluene (480 mL) and 60 mL of the sol-
vent were distilled off. Aluminum isopropoxide (4.5 g, 22 mmol)
was added and the mixture was refluxed for 1.5 h, poured into a
solution of sodium tartrate (30 g in 600 mL of water), stirred for
20 min and filtered. The organic layer was washed with water
(3 ꢀ 100 mL), dried (anh. Na2SO4) and evaporated. The obtained
oil was crystallized from methanol to afford the
a,b-unsaturated
ketone 2 (23.9 g, 85.8%). Mp. 79.5–80.5 (from methanol) Lit. 78–
79 °C [9]. 1H NMR (400 MHz, Chloroform-d) (d ppm): 5.71 (s, 1H,
H-4), 2.42–2.36 (m, 2H, H-2), 1.17 (s, 3H, H-19), 0.90 (d,
J = 6.5 Hz, 3H, H-21), 0.86 (d, J = 1.9 Hz, 3H, H-26), 0.84 (d,
J = 1.9 Hz, 3H, H-27), 0.69 (s, 3H, H-18). 13C NMR (CDCl3,
100 MHz) d(ppm): 35.6 C-1, 34.0 C-2, 199.6 C-3, 123.7 C-4, 171.6
C-5, 32.9 C-6, 32.0 C-7, 35.6 C-8, 53.8 C-9, 38.6 C-10, 21.0 C-11,
39.6 C-12, 42.3 C-13, 55.8 C-14, 23.8 C-15, 28.1 C-16, 56.0 C-17,
11.9 C-18, 17.4 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.
b), 2.25 (ddd, J = 14.5, 4.5, 2.3 Hz, 1H, H-6a), 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) d (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.
2.1.1. 4,5-Epoxy-5a-cholestan-3-one (3a) and 4,5-epoxy-5b-
cholestan-3-one (3b)
2.1.5. 4,5-Secocholest-3-yn-5a-ol (5a) and 4,5-secocholest-3-yn-5b-ol
Methanol (100 mL) 10% p/v NaOH solution (5.6 mL) and 30%
(5b)
H2O2 (11.2 mL) were added in this order to a solution of the
a
,b-
NaBH4 (0.727 g, 19.22 mmol) was slowly added to a solution of
4 (3.697 g, 9.61 mmol) in methanol (75 mL) and the mixture was
stirred for 30 min. Acetone (10 mL) was added and half of the sol-
vent was evaporated in vacuum Ethyl acetate (200 mL) was added
and the mixture was washed with brine (2 ꢀ 50 mL), dried (anh.
Na2SO4) and evaporated in vacuum to afford a mixture of the alky-
nols 5a and 5b (dr 1/1.9, determined by relative integration of the
H-5 NMR signals in each compound). Chromatographic separation
on a column packed with silica gel employing hexane/ethyl acetate
12/1 as eluent afforded each epimeric alkynol.
unsaturated ketone 1 (7.28 g, 20 mmol) in CH2Cl2 (100 mL) and
the resulting mixture was stirred for 72 h at room temperature.
The mixture was neutralized with 10% aqueous acetic acid solu-
tion; 10% aqueous Na2SO3 solution (40 mL) was added and the
resulting mixture was stirred for 10 min. Evaporation of the
organic solvent in vacuum produced a solid that was filtered off
and washed with water to afford the mixture of the epoxides 3a
and 3b (4.89 g). The mother liquor was extracted with ethyl acet-
ate (3 ꢀ 150 mL) and the organic layer was washed with water
(4 ꢀ 150 mL), and brine (80 mL), dried (anh. Na2SO4) and evapo-
rated to afford an additional amount (0.96 g) of the mixture of 3a
and 3b. Total yield 5.85 g (73%). Recrystallization from hexane/
ethyl acetate 9/1 afforded an analytical sample of the epoxide 3b,
while chromatographic separation employing hexane/ethyl acetate
9/1 as eluent afforded an analytical sample of 3a.
2.1.6. 4,5-Secocholest-3-yn-5a-ol (5a)
Yield 1.138 g (30.7%) Mp 98.0–99.2 °C (from methanol) Lit. 90–
91 °C [12] 1H NMR (CDCl3, 400 MHz): d (ppm) 3.60 (dd, J = 2.9,
2.9 Hz, 1H, H-5b), 2.23 (qddt, J = 14.9, 8.8, 5.8, 2.7 Hz, 2H, H-2),
1.97 (s, 1H, H-4), 0.89 (d, J = 6.5 Hz, 3H, H-21), 0.87 (d, J = 1.9 Hz,
Please cite this article in press as: C. Alarcón-Manjarrez et al., Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric
4,5-seco-cholest-3-yn-5-ols, Steroids (2016), http://dx.doi.org/10.1016/j.steroids.2016.03.001

C. Alarcón-Manjarrez et al. / Steroids xxx (2016) xxx–xxx
3
Table 1
Crystal data and structure refinement for compounds 6a and 6b.
Parameters
6a
6b
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
C
62H94O4
C62H94O4
903.37
130 (2)
1.54184
Monoclinic
C2
31.850(4)
7.6776(5)
15.245(2)
903.37
130 (2)
0.71073
Tetragonal
P43212
11.9790(2)
11.9790(2)
41.0932(10)
90.0
b (Å)
c (Å)
a
(°)
90.0
b (°)
90.0
90.0
5896.7 (2)
4
1.018
119.586 (18)
90.0
3241.8 (8)
2
0.925
0.423
c
(°)
Volume (Å3)
Z
Density (mg/m3)
Absorption coefficient (mmꢁ1
F(000)
)
0.061
1992
996
Crystal size (mm3)
h range for data collection
Index ranges
0.24 ꢀ 0.26 ꢀ 0.44
3.427–25.679
ꢁ14 6 h 6 14
ꢁ14 6 k 6 14
ꢁ49 6 l 6 48
49,486
0.025 ꢀ 0.32 ꢀ 0.54
5.559–73.705
ꢁ39 6 h 6 38
ꢁ6 6 k 6 9
ꢁ18 6 l 6 18
12,230
Reflections collected
Independent reflections
Completeness to h = 25.242°
Refinement method
5596 [R(int) = 0.0486]
99.6%
4724 [R(int) = 0.0630]
99.8%
Full-matrix least-squares on F2
5596/0/293
1.082
Full-matrix least-squares on F2
4724/1/303
0.999
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
R1 = 0.0624, wR2 = 0.1575
R1 = 0.0665, wR2 = 0.1608
ꢁ0.8(5)
R1 = 0.0602, wR2 = 0.1486
R1 = 0.0938, wR2 = 0.1799
ꢁ0.7(5)
Absolute structure parameter
Largest diff. peak and hole (e Åꢁ3
)
0.255 and ꢁ0.294
0.181 and ꢁ0.253
i
ii
HO
O
O
O
1
2
3a α epoxide
3b β epoxide
dr 3a/3b : 1/3.92
iii
iv
HO
HO
O
+
5a
5b
4
H
H
H
dr 5a/5b : 1 / 1.91
i) Oppenahuer oxidaꢀon, ii) H2O2/NaOH/CH3Cl2/CH3OH rt, iii) TsNHNH2/CH2Cl2/CH3COOH, vi) NaBH4/MeOH
Scheme 1. Synthesis of the epimeric alkynols 5a and 5b.
3H, H-26), 0.85 (d, J = 2.4 Hz, 3H, H-27), 0.85 (s, 3H, H-19), 0.65
(s, 3H, H-18). 13C NMR (CDCl3, 100 MHz) d (ppm) 37.2 C-1, 12.7
C-2, 86.0 C-3, 68.0 C-4, 71.7 C-5, 24.9 C-6, 28.2 C-7, 35.3 C-8,
45.6 C-9, 39.0 C-10, 21.1 C-11, 40.0 C-12, 42.5 C-13, 55.9 C-14,
23.9 C-15, 28.0 C-16, 56.3 C-17, 12.0 C-18, 17.7 C-19, 35.8 C-20,
18.6 C-21, 36.1 C-22, 24.2 C-23, 39.5 C-24, 28.2 C-25, 22.6 C-26,
22.8 C-27.
2.16–2.10 (m, 2H, H-2), 1.95 (s, 1H, H-4), 0.89 (d, J = 6.6 Hz, 3H,
H-21), 0.86 (d, J = 1.9 Hz, 3H, H-26), 0.84 (d, J = 1.8 Hz, 3H, H-27),
0.82 (s, 3H, H-19), 0.63 (s, 3H, H-18) 13C NMR (CDCl3, 100 MHz) d
(ppm) 34.1 C-1, 11.9 C-2, 85.5 C-3, 68.0 C-4, 72.8 C-5, 30.1 C-6,
29.8 C-7, 34.6 C-8, 45.7 C-9, 40.6 C-10, 21.1 C-11, 39.7 C-12, 42.4
C-13, 56.1 C-14, 23.8 C-15, 28.0 C-16, 56.2 C-17, 11.9 C-18, 14.7
C-19, 35.7 C-20, 18.6 C-21, 36.1 C-22, 24.2 C-23, 39.5 C-24, 28.2
C-25, 22.5 C-26, 22.9 C-27.
2.1.7. 4,5-Secocholest-3-yn-5b-ol (5b)
Yield 2.196 g, (59.1%). (oil). Lit. 62 °C [12]. 1H NMR(CDCl3,
2.1.7.1. General procedure for the synthesis of symmetrical dimers.
400 MHz):
d
(ppm) 3.47 (dd, J = 11.6, 4.3 Hz, 1H, H-5
a
),
The corresponding alkynol 5a or 5b (386.6 mg, 1.0 mmol) was
Please cite this article in press as: C. Alarcón-Manjarrez et al., Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric
4,5-seco-cholest-3-yn-5-ols, Steroids (2016), http://dx.doi.org/10.1016/j.steroids.2016.03.001

4
C. Alarcón-Manjarrez et al. / Steroids xxx (2016) xxx–xxx
H
4´
3´
26
1´
25
2´
axial
19
27
11´
8´
21´
12
6a
9´
15
18
20´
17´
16
17
20
23
22
5´
7
10´
O
O
24
14
6
22´
13
13´
8
14´
6´
24´
i
O
O
axial
2
10
5
7´
23´
16´
9
15´
HO
21
12
axial
5a
11
19
27´
25´
1
H
26´
H
3
4
H
6b
equatorial
O
O
i
O
O
HO
equatorial
equatorial
5b
H
i) terephthaloyl chloride (0.5 eq.) Et3N, DMAP, toluene, reflux.
H
Scheme 2. Synthesis of dimers 6a and 6b.
2.1.8. Bis-(4,5-secocholest-3-yn-5a-yl)terephthalate (6a)
Yield 261 mg, (0.289 mmol, 57.8%). Mp. 133–134.5 °C (from
ethyl acetate). 1H NMR (400 MHz, Chloroform-d) d 8.13 (s, 4H
Ar-H), 4.96 (t, J = 2.7 Hz, 2H, H-5, H-50), 1.84 (t, J = 2.6 Hz, 2H,
H-4, H-40), 1.02 (s, 6H, H-19, H-190), 0.94 (d, J = 6.5 Hz, 6H, H-21,
H-210), 0.89 (d, J = 1.7 Hz, 6H, H-26, H-260), 0.87 (d, J = 1.7 Hz, 6H,
H-27, H-270), 0.71 (s, 6H, H-18, H-180). 13C NMR (100.52 MHz) d
ppm: 37.4 C-1 C-10, 12.8 C-2 C-20, 68.0 C-3 C-30, 85.0 C-4 C-40,
76.1 C-5 C-50, 25.6 C-6 C-60, 25.6 C-7 C-70, 35.2 C-8 C-80, 47.1 C-9
C-90, 38.8 C-10 C-100, 21.4 C-11 C-110, 40.0 C-12 C-120, 42.6 C-13
C-130, 56.1 C-14 C-140, 23.8 C-15 C-150, 28.2 C-16 C-160, 56.3
C-17 C-170, 12.1 C-18 C-180, 17.5 C-19 C-190, 35.8 C-20 C-200,
18.7 C-21 C-210, 36.2 C-22 C-220, 24.2 C-23 C-230, 39.5 C-24
C-240, 28.0 C-25 C-250, 22.6 C-26 C-260, 22.8 C-27 C-270, 129.6
4 ꢀ C-Ar, 134.5 2 ꢀ C-ipso, 164.9 2 ꢀ C@O.
Table 2
Selected 1H NMR signals of the alkynols 5a/5b and the corresponding dimeric
terephthalates 6a/6b (d, ppm).
5a
6a
D
(d6a ꢁ d5a
)
5b
6b
D
(d6b ꢁ d5b
)
H-2
H-4
H-5
H-19
2.23
1.97
3.60
0.85
2.10
1.84
4.96
1.02
ꢁ0.13
ꢁ0.13
+1.36
+0.17
2.13
1.95
3.47
0.82
2.13
1.84
4.93
1.08
0
ꢁ0.11
+1.46
+0.26
Table 3
Selected 13C NMR signals of the alkynols 5a/5b and the corresponding dimeric
terephthalates 6a/6b (d, ppm).
5a
6a
D
(d6a ꢁ d5a
)
5b
6b
D
(d6b ꢁ d5b
)
2.1.9. Bis-(4,5-secocholest-3-yn-5b-yl)terephthalate (6b)
C-1
C-2
C-3
C-4
C-5
C-6
C-9
C-19
37.2
12.7
86.0
68.0
71.7
24.9
45.6
17.7
37.4
12.8
85.0
68.0
76.1
25.6
47.1
17.5
+0.2
34.1
11.9
85.5
68.0
72.8
30.1
45.7
14.7
34.8
12.0
84.7
68.0
76.4
26.8
46.0
16.0
+0.7
+0.1
ꢁ1.0
0
+4.4
+0.7
+1.5
ꢁ0.2
+0.1
ꢁ0.8
0
+3.6
ꢁ3.3
+0.3
+1.3
Yield 230 mg, (0.254 mmol, 51.0%). Mp. 177.5–179 °C (from
ethyl acetate). 1H NMR (400 MHz, Chloroform-d) d ppm: 8.10
(s, 4H Ar-H), 4.93 (dd, J = 11.4, 4.5 Hz, 2H, H-5, H-50), 1.84 (t,
J = 2.5 Hz, 2H, H-4, H-40), 1.08 (s, 6H, H-19, H-190), 0.91 (d,
J = 6.5 Hz, 6H, H-21, H-210), 0.88 (d, J = 1.9 Hz, 6H, H-26, H-260),
0.86 (d, J = 1.9 Hz, 6H, H-27, H-270), 0.68 (s, 6H, H-18, H-180). 13C
NMR (100.52 MHz) d ppm: 34.8 C-1 C-10, 12.0 C-2 C-20, 68.0 C-3
C-30, 84.7 C-4 C-40, 76.4 C-5 C-50, 26.8 C-6 C-60, 29.4 C-7 C-70,
34.6 C-8 C-80, 46.0 C-9 C-90, 40.0 C-10 C-100, 20.9 C-11 C-110, 39.6
C-12 C-120, 42.5 C-13 C-130, 56.1 C-14 C-140, 23.8 C-15 C-150,
28.2 C-16 C-160, 56.1 C-17 C-170, 12.0 C-18 C-180, 16.0 C-19
C-190, 35.7 C-20 C-200, 18.7 C-21 C-210, 36.1 C-22 C-220, 24.2
C-23 C-230, 39.5 C-24 C-240, 28.0 C-25 C-250, 22.6 C-26 C-260,
22.8 C-27 C-270, 129.5 4 ꢀ C-Ar, 134.4 2 ꢀ C-ipso, 165.1 2 ꢀ C@O.
dissolved in toluene (30 mL) and 15 mL were distilled off. DMAP
(42 mg), Et3N (0.26 mL) and terephthaloyl chloride (120 mg,
0.59 mmol) were added and the solution was refluxed under argon
for 5 h. Further amounts of the reagents [DMAP (10.5 mg) Et3N
(0.07 mL) and terephthaloyl chloride (30 mg)] were added and
the solution was refluxed for 28 h. Ethyl acetate (50 mL) was added
and the mixture was washed with saturated NaHCO3 solution
(2 ꢀ 15 mL), water (3 ꢀ 15 mL), and brine (15 mL), dried (Na2SO4)
and evaporated. The residue was purified on a column packed with
silica gel using hexane/ethyl acetate 30/:1 as eluent to afford the
desired compound.
3. X-ray crystallography
Suitable crystals of 6a and 6b grown on slow evaporation of
ethyl acetate solutions were mounted on a glass fiber under
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5
Fig. 1. (A) ORTEP-plot for compound 6a with their corresponding unit cell. Thermal ellipsoids are drawn at 50% probability level for all atoms other than hydrogen. (B) Unit
cell viewed along the crystallographic b axis.
Fig. 2. Crystal packing of 6a showing the multilayered self-assembly extended along the crystallographic bc plane.
Fig. 3. (A) ORTEP-plot for compound 6b with their corresponding unit cell. Thermal ellipsoids are drawn at 50% probability level for all atoms other than hydrogen. (B) Unit
cell viewed along the crystallographic b axis.
cryogenic system and crystallographic data were collected with an
Oxford Diffraction Gemini ‘‘A” diffractometer with a CCD area
detector, using graphite-monochromatized radiation at 130 K. Unit
cell parameters were determined with a set of three runs of 15
global refinement. The collected data were corrected for absor-
bance by using analytical numeric absorption correction using a
multifaceted crystal model based on expressions upon the Laue
symmetry using equivalent reflections [14]. Structure solution
and refinement were carried out with the SHELXS-2014 and
SHELXL-2014 packages [15]; WinGX v2014.1 software was used
to prepare material for publication [16].
Full-matrix least-squares refinement was carried out by mini-
mizing (Fo2 ꢁ Fc2)2. All nonhydrogen atoms were refined
anisotropically. Hydrogen atoms attached to carbon atoms were
placed in geometrically idealized positions and refined as riding
on their parent atoms, with C–H = 0.95–1.00 Å with Uiso(H)
= 1.2 Ueq(C) for methylene, methyne and aromatic groups, and
Uiso(H) = 1.5 Ueq(C) for methyl group. The absolute configuration
frames (1° in
19/1339 runs/frames of intensity (1° in
x
). The collected data set consisted of 6/478 and
) for 6a and 6b respec-
x
tively, and a crystal-to-detector distance of 55.00 mm. The double
pass method of scanning was used to exclude noise. The collected
frames were integrated by using an orientation matrix determined
from the narrow frame scans.
CrysAlisPro and CrysAlis RED software packages were used for
data collection and integration [13]. The collected frames were
integrated by using an orientation matrix determined from the
narrow frame scans. Final cell constants were determined by a
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4,5-seco-cholest-3-yn-5-ols, Steroids (2016), http://dx.doi.org/10.1016/j.steroids.2016.03.001

6
C. Alarcón-Manjarrez et al. / Steroids xxx (2016) xxx–xxx
Fig. 4. Crystal packing of 6b showing the displaced multilayered self-assembly. Pictures are viewed along the crystallographic (A) b and (B) c axis.
of the studied compounds can be assumed without risk, as that
known for the starting material (1) considering that the synthetic
transformations carried out do not affect the chirality in the natu-
rally occurring steroid framework. Crystal data and experimental
details of the structure determination are listed in Table 1.
ORTEP-3 for Windows [16] and Mercury [17] programs were used
to prepare artwork representations.
The helicoidal arrangements are self-assembled by hydrogen-
bonding interactions between C(19)–H(19)ꢂ ꢂ ꢂO(2) [2.514 Å] pro-
ducing
a multilayered two-dimensional arrangement which
increases along the crystallographic bc plane (Fig. 2). It is notewor-
thy that the alkyne hydrogens do not participate in the crystal
packing due to their close-packed environment; these groups are
located inside the cavities created by the steroidal fragments. In
addition, compound 6a present disorder in the side chain over
two sites with occupancies 0.50:0.50 (C22 C23 C24 C25 C26 C27
and C22A C23A C24A C25A C26A C27A).
4. Results and discussion
In contrast with 6a, the steroidal dimer 6b crystallized in the
monoclinic space group C2 with Z = 2. The equatorial orientation
of the alcohols moieties attached to C-5 forces the steroidal skele-
tons to a linear conformation in 6b as shown in Fig. 3A. One
hydrophobic face of a steroid fragment interacts with the same
face of a neighbor molecule; the other face is involved in hydro-
gen-bonding interactions with the terephthalate ring (Fig. 3B).
The steroidal dimers are connected by hydrogen-bonding inter-
actions between C(4)–H(4)ꢂ ꢂ ꢂO(2) [2.468 Å] forming a one-dimen-
sional monolayer which increases along the crystallographic b axis.
These monolayers are self-assembled by hydrogen-bonding
C(17)–H(17)ꢂ ꢂ ꢂO(20) [2.706 Å] interactions producing a 3D dis-
placed multilayered arrangement (Fig. 4A).
Oppenauer oxidation of cholesterol (1) led to the
a,b-unsatu-
rated ketone 2, which was converted into a mixture of the epoxides
3a and 3b by treatment with H2O2 in basic medium. Eschenmoser-
Tanabe fragmentation of the mixture of epoxides led to the alky-
none 4 that on reduction with NaBH4 in methanol produced the
epimeric alkynols 5a and 5b (Scheme 1).
Treatment of alkynol 5a with terephthaloyl chloride, DMAP and
triethylamine in dry refluxing toluene, afforded the symmetrical
dimer 6a in 57.8% yield. Similar treatment of 5b produced 6b in
50.9% (Scheme 2).
In addition to the expected deshielding in the 1H and 13C signals
of the carbynol atoms, the formation of dimers 5a and 5b produced
varying effects in the resonance of the neighboring nuclei (Tables 2
and 3). These effects may be associated with the stereoelectronic
compression exerted by the bulky terephthalate and its inherent
magnetic anisotropy.
6. Conclusions
The obtained dimeric steroidal terephthalates 6a–b display
novel supramolecular networks due to their structural flexibility.
The facial hydrophobicity of the steroidal skeletons plays an
important role in the crystal packing in which the dimeric mole-
cules are forced to accommodate these fragments only with a
few hydrogen-bonding interactions, that result in a cisoid confor-
mation for 6a and a linear conformation for 6b.
5. X-ray crystallography discussion
Comparison of steroidal dimers in the crystals 6a and 6b
revealed that the major difference is found in the conformation
of the steroidal fragments with respect to the terephthalate ring.
In this sense, the facial hydrophobicity of the steroidal skeleton
plays an important role in the supramolecular self-assembly of
the corresponding steroidal dimers 6a and 6b.
Acknowledgements
In the case of compound 6a, which crystallized in a tetragonal
P43212 space group with Z = 4 (Fig. 1A), the plausible hydrogen-
bonding interactions are not enough to accommodate the
hydrophobic steroid fragments; thus they adopt a cisoid conforma-
tion [18] in which several Van der Waals interactions stacked the
steroidal dimers in a helicoidal arrangement as shown in Fig. 1B.
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
Please cite this article in press as: C. Alarcón-Manjarrez et al., Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric
4,5-seco-cholest-3-yn-5-ols, Steroids (2016), http://dx.doi.org/10.1016/j.steroids.2016.03.001

C. Alarcón-Manjarrez et al. / Steroids xxx (2016) xxx–xxx
7
and CCDC 1447418 (6b). Copy of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. E-mail: deposit@
ccdc.cam.ac.uk.
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
A. Boulton for correcting the manuscript.
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[11] S.K. Pradhan, V.M. GiriJavallabhan, Novel A-nor sterols: synthesis and
stereochemistry, Steroids 13 (1969) 11–20.
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Please cite this article in press as: C. Alarcón-Manjarrez et al., Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric
4,5-seco-cholest-3-yn-5-ols, Steroids (2016), http://dx.doi.org/10.1016/j.steroids.2016.03.001