The crystal structure of 3-epismilagenin acetate and 23-oxo-3-epismilagenin acetate

Article abstract of DOI:10.1007/s10870-011-0126-3

The crystal structure together with unambiguous assignation of ¹H and ¹³C NMR signals of 3-epismilagenin acetate 4 and 23-oxo-3-epismilagenin acetate 5 are described. Compound 4, crystallized as orthorhombic system a = 10.535(1) A, b = 13.775 (1) A, c = 18.347 (1) A, α = β = γ = 90°; with space group P2 ₁ 2 ₁ 2 ₁ ; while compound 5 crystallized as a monoclinic system a = 10.380(1) A, b = 7.327(1) A, c = 17.881(1) A, α = γ = 90°, β = 99.56(1)°, with a space group P2 ₁ . The presence a carbonyl group at C(23) in compound 5 produces a significant deviation from the chair conformation observed in compound 4. The effects of the side chain modifications on the puckering parameters derived from are discussed.

Full text of DOI:10.1007/s10870-011-0126-3

J Chem Crystallogr (2011) 41:1476–1482
DOI 10.1007/s10870-011-0126-3
ORIGINAL PAPER
The Crystal Structure of 3-Epismilagenin Acetate
and 23-Oxo-3-epismilagenin Acetate
•
Mariana Macıas-Alonso Nuria Esturau-Escofet
•
´
´
•
•
´
Marcos Flores-Alamo Martın A. Iglesias-Arteaga
Rafael Moreno-Esparza
Received: 12 October 2010 / Accepted: 7 May 2011 / Published online: 8 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The crystal structure together with unambigu-
1
regarded as 1,6-dioxaspiro[4.5]decane derivatives. This
ous assignation of H and 13C NMR signals of 3-epismi-
kind of compounds have been subject of much research due
its intrinsic biological activity [22–27] or their usefulness
as staring materials for the synthesis of different bioactive
compounds as sexual and adrenocortical hormones [1],
ecdysteroids [28] plant growth stimulators [29–35] and
cytotoxic steroids [36–41], among many others.
lagenin acetate 4 and 23-oxo-3-epismilagenin acetate 5 are
described. Compound 4, crystallized as orthorhombic sys-
˚
tem a = 10.535(1) A, b = 13.775 (1) A, c = 18.347
˚
˚
(1) A, a = b = c = 90°; with space group P212121; while
compound 5 crystallized as a monoclinic system a =
˚
˚
˚
10.380(1) A, b = 7.327(1) A, c = 17.881(1) A, a = c =
90°, b = 99.56(1)°, with a space group P21. The presence a
carbonyl group at C(23) in compound 5 produces a sig-
nificant deviation from the chair conformation observed in
compound 4. The effects of the side chain modifications on
the puckering parameters derived from are discussed.
As a part of our project to explore the reactivity and
applications of steroid bearing spiroketals side chains, we
have focused our attention on different steroid sapogenins
bearing intact or functionalized side chains that serve as
starting materials for the synthesis of bioactive compounds.
Consequently we need the detailed characterization of
several compounds that are being employed as starting
materials for different chemical transformations. Here in
Keywords Steroids Á Spirostanes Á 23-Oxospirostan Á
NMR Á X-ray structure Á Puckering parameters Á Ring
conformation
1
we report on the assignments of all H and 13C chemical
shifts of 3-epismilagenin acetate 4 and 23-oxo-3-epismi-
lagenin acetate 5. The structures of compounds 4 and 5 as
well as the configuration of all present chiral centers were
confirmed with the aid of X-ray studies.
Introduction
Steroids bearing different oxygenated spiroketal side
chains are wide spread in both the natural and synthetic
domains. Steroid sapogenins, which particular reactivity
have produced a large variety of interesting reactions and
rearrangements [1–21] are characterized by the presence of
a 16b,22:22,26-diepoxy moiety in side chain and can be
Experimental
General
Reactions were monitored by TLC on ALUGRAMÒ SIL
G/UV254 plates from MACHEREY–NAGEL. Chromato-
graphic 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 equipment and
are uncorrected. Mass spectra were registered in a thermo-
electron spectrometer model DFS (double focus sector).
NMR spectra were recorded in CDCl3 solution in a Varian
INOVA 400 spectrometer using the solvent signal
´
´
M. Macıas-Alonso Á N. Esturau-Escofet Á M. Flores-Alamo Á
M. A. Iglesias-Arteaga Á R. Moreno-Esparza (&)
´
Facultad de Quımica, Edificio B, Universidad Nacional
Autonoma de Mexico, Av. Universidad 3000, Coyoacan,
´
´
´
Mexico, DF 04510, Mexico
e-mail: moresp@servidor.unam.mx
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J Chem Crystallogr (2011) 41:1476–1482
1477
7.26 ppm for 1H and 77.00 ppm for 13C as references.
NMR signals assignments were made with the aid of DEPT
and a combination of 2D homonuclear (1H–1H) and het-
eronuclear (1H–13C) correlation techniques, which inclu-
ded 1H–1H COSY, 1H–1H nuclear overhauser effect
(NOESY), Total correlation spectroscopy (TOCSY), het-
eronuclear single quantum correlation (HSQC) and heter-
onuclear multiple bond correlation (HMBC). All 2D NMR
spectra were recorded using the standard pulse sequences
and parameters recommended by the manufacturer.
Table 2 13C chemical shifts of compounds 4 and 5
C (Number)
4
5
C (Number)
4
5 (D ppm)
1
35.0 35.0 16
26.6 26.6 17
74.3 74.2 18
32.2 32.2 19
41.8 41.8 20
26.9 26.9 21
26.6 26.5 22
35.4 35.4 23
40.5 40.5 24
34.7 34.7 25
20.6 20.5 26
40.2 40.0 27
80.9 83.4 (?2.5)
62.3 61.8 (-0.5)
16.4 16.1 (-0.3)
23.3 23.3
2
3
4
5
41.6 34.7 (-6.9)
14.5 14.4 (-0.1)
6
7
109.2 109.8 (?0.6)
31.4 201.8 (?170.4)
28.8 45.2 (?16.4)
30.3 35.8 (?5.5)
66.8 65.6 (-1.2)
17.1 17.1 (0)
8
Synthesis, Characterization and Spectroscopy
9
10
11
12
13
14
15
(25R)-5b-spirostan-3a-ol acetate, namely 3-epi-smilagenin
acetate (4) Ac2O (20 mL) and a few crystals of DMAP were
added to a solution of 3 in pyridine (40 mL) and the mixture
was stirred overnight and poured into a mixture of ice and
10% HCl (300 mL). The produced solid was filtered off and
dissolved in ethyl acetate (200 mL). The organic layer was
washed with 10% HCl (2 9 70 mL), 10% CuSO4 aqueous
solution (2 9 70 mL) and water (2 9 100 mL), dried (anh.
Na2SO4) and evaporated to afford the acetylated compound 4
(3.6 g, 7.85 mmol, 98.7%). M.p 162–163 °C from acetone
40.6 41.1 CH3COO-3 170.6 170.5
56.3 56.4 CH3COO-3
21.4 21.4
31.8 31.7
D ppm associated to the changes in the side chain are given in
parentheses and were calculated using the previous compound as
reference
19.7 mmol) was added over 20 min. The additions of
BF3ÁEt2O and NaNO2 were repeated, the reaction mixture
was poured into ice-water (1 L). The separated solid was
filtered off and, washed with water (4 L), dissolved in
CH2Cl2 (200 mL), dried (anh. Na2SO4) and evaporated.
The produced residue was dissolved in the minimum
amount of 1/1 hexane/benzene mixture applied to a chro-
matographic column packed with Al2O3 (Brockmann
activity III), and eluted with 10/1 hexane/ethyl acetate
1
(see Tables 1 and 2 for H and 13C NMR signals). MS
(70 eV): 458 M?, 380, 365, 329, 284, 256, 255, 254, 239,
161, 147, 139. HRMS (70 eV): observed 458.3391 required
for C29H46O4458.3396.
(25R)-3a-acetoxy-5b-spirostan-23-one, namely 23-oxo-
3-epi-smilagenin acetate (5) BF3ÁEt2O (8 mL, 64.8 mmol)
was added to a solution of 4 (8 g, 17.44 mmol) in glacial
acetic acid (200 mL). To the stirred mixture NaNO2 (1.4 g,
Table 1 1H chemical shifts of steroid sapogenins 4 and 5
H
4
5
H
4
5
1a
1.80
1.80
1.02
1.38
1.67
4.71 (m)
1.80
1.53
1.44
1.23
1.85
1.07
1.38
1.57
1.40
1.38
1.23
1.13
12b
1.70
1.74
1b
2a
1.01
14a
1.19 (m)
1.15
1.40
15a
1.97 (m)
1.98 (m)
2b
3b
4a
1.67
15b
1.20 (m)
1.27
4.71 (m)
1.81 (m)
1.53
16a
4.38 (m)
4.59 (m)
17a
1.75
1.74
4b
5b
6a
18 (CH3)
19 (CH3)
20b
0.74 (s)
0.74 (s)
1.44
0.93 (s)
0.93 (s)
1.24
1.85
2.86 (m)
6b
7a
1.85
21 (CH3)
23 a
0.95 (d, J = 6.9)
0.92 (d, J = 7.0)
1.08
1.67
–
7b
8b
9a
1.36
23 b
1.59
–
1.57
24 Pro-S (ax.)
24 Pro-R (eq.)
25
1.62
2.42 (m)
1.42
1.45 (m)
2.47 (dd, J = 10.7, 10.7)
2.27 (m)
11a
11b
12a
1.38
1.61 (m)
1.24 (m)
1.17
26 Pro-S (eq.)
26 Pro-R (ax.)
3.46 (ddd, J = 10.7, 4.4, 1.6)
3.36 (dd, J = 10.9, 10.9)
3.57 (ddd, J = 11.2, 4.6, 1.4)
3.77 (dd, J = 11.3, 11.3)
123

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J Chem Crystallogr (2011) 41:1476–1482
mixture. The collected fractions were evaporated to afford
chromatography in Al2O3 (Brockman Activity III) afforded
the ketone 5 (4.5 g, 9.52 mmol, 54.6%). M.p 184–186 °C
the ketone 5 (Scheme 1).
1
from ethyl acetate/hexane (see Tables 1 and 2 for H and
13C NMR signals). MS (FAB): 473 MH?, 444, 389, 329,
255. HRMS (FAB) observed 473.3260 required for
C29H45O5473.3267.
Crystallographic Studies
The absolute configuration of the studied compound 5 was
considered and corroborated as that from the starting
material 4. Both studied compounds contain the steroid
ABCD fused framework with the axial methyl groups
attached to C(10) and C(13). All compounds show cis A/B,
trans B/C and trans C/D ring junctions. Compounds 4 and 5
bear the 16b,22:22,26-diepoxy moiety characteristic of the
spirostanic side chain. Puckering parameters for com-
pounds 4, and 5, were calculated as described by Cremer
and Pople [45] (Table 3).
Crystallography
Suitable crystals for X-ray diffraction studies were
obtained from the analytical samples as follows: crystals of
4 on cooling from a warm acetone solution; crystals of 5 on
overnight cooling from a warm ethyl acetate solution.
Compound 5 crystallized as a monoclinic system with a
space group P21; while compound 4, crystallized as
orthorhombic systems with space group P212121. X-ray
diffraction measurements were performed on an oxford
diffraction atlas (Gemini) diffractometer with Mo Ka
In compound 4 the equatorial acetoxy group bonded to
C(3) is arranged in such a way that the carbonyl O atom is
close to eclipse the axial H atom attached to C(3) and does
not disturb A ring, which presents a conformation very
similar to a chair. B ring assumes an almost perfect chair
conformation while C ring assumes a perfect chair con-
formation. D ring can be described as cyclopentane twisted
on C(13)–C(14). E Ring is an envelope in O(3)-exo with
absolute L configuration. The tetrahydrofuran E ring is cis-
fused to the cyclopentane D ring. Finally F ring assumes a
conformation very similar to a chair, (see Table 4; Fig. 1).
The crystal structure of compound 4 is shown in Fig. 2,
with the ellipsoid drawn at the 50% of probability [46].
The molecules in the unit cell of 4 show no classic
hydrogen bonds and all are linked via short contacts at
C–HÁÁÁO hydrogen bonds, C(18)–H(18B)ÁÁÁO(3) (2.56
HÁÁÁO, 3.267(3) CÁÁÁO). The packing of the crystal is
assumed to be dictated by van der Waals interactions and
intermolecular C–HÁÁÁO hydrogen bonds. In Fig. 3 two
view of the cell packing of this compound is shown. Where
it can be observed less symmetrical arrangement than in 5.
In compound 5, the equatorial acetoxy group bonded to
C(3) is arranged in such a way that the carbonylic oxygen
nearly eclipses the axial H atom attached to C(3) and does
not disturb A ring, which present a chair conformation.
While B ring assumes a perfect chair conformation, C ring
is very similar to a chair. D ring can be described as
cyclopentane twisted on C(13)–C(14). Finally E ring
˚
radiation k = 0.71073 A. Data collection routine and data
reduction were carried out with the CrysAlisPro, Oxford
Diffraction Ltd., Oxford Diffraction [42]. The structures of
all molecules were solved using SIR2004 [43] and refined
using SHELXL-97 [44]. All non-hydrogen atoms were
refined anisotropically and the hydrogen atoms were found
in difference Fourier maps, placed at geometrically calcu-
lated positions and refined using the riding model. The
obtained bond lengths and angles of each compound are
normal and are available from the electronic supporting
information (CIF file) for the structure. Crystallographic
data have been deposited at the Cambridge Crystallo-
graphic Data Center as supplementary material numbers
CCDC 773327 4, CCDC 773329 5. Copies 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.
Results and Discussion
3-Epismilagenin acetate 4 was obtained by acetylation of
3-epismilagenin 3 following the standard Ac2O/pyridine
procedure. Treatment of 3-epismilagenin acetate 4 with
NaNO2 and BF3ÁEt2O in acetic acid followed by column
25
21
O
O
26
O
27
F
F
F
20
E
18
23
12
22
24
17
E
E
11
9
O
C 13
C
O
19
O
O
D
D
D
C
1
16
8
14
2
15
A
B
A
10 B
A
B
5
i
ii, iii
7
3
HO
H3CCOO
H3CCOO
4
6
H
H
H
i) Ac2O/pyr, RT, overnigth; ii) BF3.Et2O/NaNO2/H3CCOOH; iii) Al2O3
Scheme 1 Synthetic approach, carbon numbering and ring designation of studied compounds
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J Chem Crystallogr (2011) 41:1476–1482
1479
Table 3 Crystal data and structure refinement for 4 and 5
Identification code
4
5
Empirical formula
Formula weight
Temperature (K)
C29H46O4
458.66
C29H44O5
472.64
298(2)
293(2)
˚
Wavelength (A)
0.71073
0.71073
Monoclinic
P21
Crystal system
Space group
Orthorhombic
P212121
˚
˚
Unit cell dimensions
a = 10.5350(4) (A), a = 90°
a = 10.3800(5) (A), a = 90°
˚
˚
b = 13.7750(6) (A), b = 90°
b = 7.3270(3) (A), b = 99.56(1)°
˚
˚
c = 18.3470(7) (A), c = 90°
2662.51(18)
c = 17.8810(8) (A), c = 90°
1341.02(10)
3
˚
Volume (A )
Z
4
2
Density (calculated) (Mg/m3)
Absorption coefficient (/mm)
Diffractometer/scan
1.144
1.171
0.074
0.078
Oxford diffraction atlas (Gemini)
Oxford diffraction atlas (Gemini)
˚
Radiation/wavelength (A)
Mo Ka/0.71073
Mo Ka/0.71073
516
F(000)
1008
h range for data collection (°)
Index ranges
3.16–26.06
3.29–26.05
-12 B h B 13, -17 B k B 16, -17 B l B 22
-12 B h B 12, -9 B k B 6, -22 B l B 18
Reflections collected
9313
7025
Independent reflections
Completeness to theta = 26.06°, 26.05°
Refinement method
2960 [R(int) = 0.0310]
99.7%
Full-matrix least-squares on F2
2857 [R(int) = 0.0242]
99.8%
Full-matrix least-squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
2960/0/304
2857/1/312
0.972
0.962
R1 = 0.0363, wR2 = 0.0876
R1 = 0.0503, wR2 = 0.0920
-0.006(13)
R1 = 0.0358, wR2 = 0.0837
R1 = 0.0495, wR2 = 0.0869
-0.006(13)
Absolute structure parameter
Extinction coefficient
0.0104(13)
None
3
Largest diff. peak and hole (e/A )
˚
0.137 and -0.110
0.125 and -0.147
Table 4 Calculated puckering parameters for compound 4
˚
Q (A)
Ring
h (°)
u (°)
Order and direction of the calculation
A
B
C
F
0.552(2)
0.563(2)
0.564(2)
0.533(2)
177.0(2)
3.5(2)
213(5)
271(3)
226(5)
170(2)
From C(1) to C(10), counterclockwise
From C(5) to C(10), counterclockwise
From C(8) to C(14), clockwise
3.0(2)
171.5 (2)
From O(4) to C(26), clockwise
˚
Q(2) (A)
Ring
u (°)
Order and direction of the calculation
D
E
0.488(2)
0.368(2)
197.9(2)
182.1(3)
From C(13) to C(17), counterclockwise
In this order; O(3), C(22) C(20), C(17), C(16)
presents an envelope O(3)-exo with absolute L configura-
tion. The tetrahydrofuranic E ring is cis-fused to the
cyclopentane D ring. The F ring assumes a conformation
close to a chair that is somewhat distorted due to the
presence of carbonyl function at C(23) (see Table 5). The
crystal structure of compound 5 is shown in Fig. 4, with the
ellipsoid drawn at the 50% of probability [46].
The two molecules in the unit cell of 5 show no classic
hydrogen bonds and they are linked via short contacts at:
˚
˚
C(8)–H(8)ÁÁÁO(5) (2.686 A HÁÁÁO, 3.606(2) A CÁÁÁO) and
123

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J Chem Crystallogr (2011) 41:1476–1482
Fig. 1 Some naturally
occurring steroid sapogenins
Fig. 2 Crystal structure of
compound 4 with the thermal
ellipsoids drawn at the 50%
of probability
˚
C(11)–H(11B)ÁÁÁC(24) (2.870 A HÁÁÁC, 3.635(2) CÁÁÁC).
Each molecule has four of these short contacts and the
crystal grows along the b axe. The packing of the crystal is
assumed to be dictated by van der Waals interactions and
intermolecular C–HÁÁÁO hydrogen bonds. In Fig. 5 the cell
packing of this compound is shown.
In order to establish quantitative differences among the
studied compounds, a least-squares overlay analysis of the
structures by pairs is performed. Table 6 shows the results
of least-squares overlay analysis obtained with the program
Mercury [47]. From the obtained data it is clear that, as
expected, the modifications introduced in the side chain do
not produce significant conformational changes in the
Fig. 3 View of the intermolecular interactions in compound 4
Table 5 Calculated puckering parameters for compound 5
˚
Q (A)
Ring
h (°)
u (°)
Order and direction of the calculation
A
B
C
F
0.550(2)
0.564(2)
0.570(2)
0.551(2)
175.9(2)
0.0(2)
234(3)
264(7)
259(3)
188(1)
From C(1) to C(10), counterclockwise
From C(5) to C(10), counterclockwise
From C(8) to C(14), clockwise
3.1(2)
176.7(2)
From O(4) to C(26), clockwise
˚
Q(2) (A)
Ring
u (°)
Order and direction of the calculation
D
E
0.474(2)
0.373(2)
201(1)
110(4)
From C(13) to C(17), counterclockwise
In this order; O(3), C(22), C(20), C(17), C(16)
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J Chem Crystallogr (2011) 41:1476–1482
1481
Fig. 4 Crystal structure of
compound 5 with the thermal
ellipsoids drawn at the 50% of
probability
Table 7 Puckering descriptors of compound 4 and 5 obtained using
the PLATON program
Rings
4
5
A
B
C
D
E
F
Very similar to a C-form
Very similar to a C-form
C-form
Very similar to a C-form
C-form
Very similar to a C-form
Twisted on C(13)–C(14)
Envelope O(3)-exo
Close to a C-form
Twisted on C(13)–C(14)
Envelope O(3)-exo
Very similar to a C-form
steroid framework at least qualitatively, (notice that the
observed deviation in rings A to D are less than 0.016).
While a small deviation is observed when E ring of
compounds 4 and 5 are compared, introduction of the
carbonyl group at C(23) in compound 5, that implies the
introduction of a sp [2] atom in the F ring results on a
significant deviation from the chair conformation observed
in compound 4 (compare the puckering parameters of 4
and 5). Table 7 shows the puckering descriptors as defined
by Cremer and Pople [45] and calculated using the PLA-
TON program [48, 49]. The minor differences observed
amongst rings A to D across all compounds may be
attributed to the different intermolecular interactions that
are, of course, influenced by the changes introduced in the
side chain.
Fig. 5 View of the intermolecular interactions in compound 5
Table 6 Least-squares overlay analysis of the rings, performed by
each pair of structures
Rings
5 vs 4
A
B
C
D
E
F
0.0143
0.0105
0.0095
0.0158
0.0203
0.0322
´
Acknowledgments The authors thank to the Direccion General de
Asuntos del Personal Academico (DGAPA-UNAM) for financial
´
support via project IN204008-3 and to CONACyT for scholarship
´
granted to Mariana Macıas-Alonso. Thanks are due to Georgina
Duarte Lisci (USAI-UNAM) for registering Mass spectra.
123

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