D-secoestrone derivatives. V1:0 3-Methoxy-17-oxo-17-phenyl-16,17-secoestra-1,3,5(10)-triene-16-nitrile and 17-hydroxy-3-methoxy-17-phenyl-16,17-secoestra-1,3,5(10)-triene-16-nitrile

Article abstract of DOI:10.1107/S0108270101018182

The conformations of two secoestrone derivatives, C₂₅H₂₇NO₂ and C₂₅H₂₉NO₂ were determined. The compounds exhibited different conformations in the solid state, which was responsible for the

Full text of DOI:10.1107/S0108270101018182

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
With the aim of further investigations into the in¯uence of
C17 substituents on biological activity, the two new title 16,17-
secoestrone derivatives, (I) and (II), were prepared. Since the
starting materials were synthesized from natural oestrone, the
absolute stereochemistry of which is known (Fieser & Fieser,
1967), the X-ray structures of (I) and (II) are described for the
appropriate enantiomer.
ISSN 0108-2701
D-Secoestrone derivatives. V1.
3-Methoxy-17-oxo-17-phenyl-16,17-
secoestra-1,3,5(10)-triene-16-nitrile
and 17-hydroxy-3-methoxy-17-
phenyl-16,17-secoestra-1,3,5(10)-
triene-16-nitrile
a
a
Âa
Ï
Â
Dusan Lazar, * Slobodanka Stankovic, Vjera Pejanovic
and Christiane Courseilleb
a
Â
Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 4, 21000 Novi
Sad, Yugoslavia, and bLaboratoire de Cristallographie et de Physique Cristalline,
Â
Â
Faculte des Sciences, Universite de Bordeaux I, Bordeaux, France
Correspondence e-mail: dlazar@im.ns.ac.yu
Perspective views of the molecules of (I) and (II) are shown
in Figs. 1 and 2. During the anisotropic re®nement, it became
evident from the displacement parameters of compound (I)
that the phenyl ring is disordered; the phenyl-ring atoms exibit
large thermal displacements which are almost parallel with the
plane containing them. The model that describes this disorder
has at least two phenyl rings, denoted A and B. Since the
phenyl-ring plane practically coincides with the plane
containing the C13ÐC17 and C17ÐC20 bonds, as seen from
the C13ÐC17ÐC20A/BÐC25A/B torsion angles (Table 1),
these thermal displacements cause deformation of the C13Ð
C17ÐC20A/B angles (Table 1), which is signi®cant for
conformer A.
Received 6 July 2001
Accepted 25 October 2001
Online 16 January 2002
The two title 16,17-secoestrone derivatives, 3-methoxy-17-oxo-
17-phenyl-16,17-secoestra-1,3,5(10)-triene-16-nitrile, C25H27-
NO2, (I) (17-oxo substituent), and 17-hydroxy-3-methoxy-17-
phenyl-16,17-secoestra-1,3,5(10)-triene-16-nitrile, C25H29NO2,
(II) (17-hydroxy substituent), have quite different conforma-
tions in the solid state. These conformational differences can
be minimized by molecular mechanics calculations. Thus, the
remarkable difference in the biological activity of the two
compounds, e.g. the strong oestrogenic characteristics of (I)
and the moderate antioestrogenic action of (II), must be
caused by the difference in substitution at C17. In (II), the
molecules are linked by OÐHÁ Á ÁN hydrogen bonds, forming
spirals along the b direction.
Molecular mechanics calculations (MMC) using PC-
MODEL (Serena Software, 1989) were also performed to
de®ne the conformation of the molecules in terms of energy
minima. It was found that the molecule of (I) with an unsplit
Comment
Within the framework of a broader project aimed at obtaining
potential antioestrogens, a series of new 16,17-secoestrone
Â
derivatives has been reported by Petrovic et al. (1990). While
studying the structure±activity relationships of these deriva-
Â
tives (Stankovic, Petrovic et al., 1992; Stankovic, Stefanovic
et al., 1992; Stankovic et al., 1994), we observed that the
Â
Â
Â
Â
substituent at C17 has a remarkable in¯uence on the biolog-
ical properties of the synthesized compounds. Thus, to a large
extent,
3-methoxy-17-hydroxy-17-methyl-16,17-secoestra-
1,3,5(10)-triene-16-nitrile retained oestrogenic characteristics,
while the corresponding 17-benzyl derivative showed a
complete loss of oestrogenic activity, exhibiting a moderate
Figure 1
A perspective view of (I) with the atomic labelling scheme. Displacement
ellipsoids are shown at the 30% probability level and H atoms are drawn
as spheres of arbitrary radii. The disordered phenyl ring is represented by
two subgroups, C20A±C25A and C20B±C25B. The site-occupancy factor
of subgroup A is 0.287 (6) and that of subgroup B 0.713 (6).
Ï
 Â
antioestrogenic action (Medic-Mijacevic, 1992).
1
Â
Part IV: Stankovic et al. (1998).
Acta Cryst. (2002). C58, o63±o65
DOI: 10.1107/S0108270101018182
# 2002 International Union of Crystallography o63

organic compounds
In compound (II), there is a short intramolecular contact of
Ê
1.96 A between H17 and H151, which is much shorter than the
Ê
van der Waals sum of 2.4 A. However, the corresponding
Ê
value of 2.04 A in the energy-minimized structure suggests
that this shortness is simply a consequence of the minimum
energy conformation of the molecule.
Also in compound (II), there is an OÐHÁ Á ÁN hydrogen
bond (Table 3). In (I), there are only van der Waals separa-
tions between molecules. The non-bonded intramolecular
O1Á Á ÁO2 distances, which could be responsible for biological
Ê
activity, are shorter than the corresponding distance of 10.9 A
found in oestradiol (Fullerton, 1977; Duax et al., 1977).
Figure 2
A perspective view of (II) with the atomic labelling scheme. Displace-
ment ellipsoids are shown at the 30% probability level and H atoms are
drawn as spheres of arbitrary radii.
Experimental
The starting material was 3-methoxy-1,3,5(10)-triene-16,17-dione 16-
oxime, (1), which was prepared from oestrone using the procedure of
phenyl ring has an energy minimum conformation with respect
to the molecule with disordered phenyl rings, so this model
was used for MMC in the ring-conformation and molecular-
energy analysis.
Â
Â
Miljkovic & Petrovic (1977). Addition of phenyllithium to the C17
carbonyl function of (1) led to the formation of 3-methoxy-17ꢀ-
phenyl-17ꢁ-hydroxyestra-1,3,5(10)-triene-16-one oxime, (2), in a
69.64% yield. The action of p-toluenesulfonyl chloride on (2) in dry
pyridine resulted in a Beckmann fragmentation reaction and the
formation of the 16,17-seco derivative, (I), in high yield. Finally,
sodium borohydride reduction of (I) afforded (II) as the sole product.
Ring puckering parameters (Cremer & Pople, 1975) and
asymmetry parameters (Duax et al., 1976) de®ne the ring
conformations for both (I) and (II). Steroid ring B exhibits a
7ꢀ,8ꢁ-half chair conformation (3H4) in both molecules, which
is slightly distorted towards a 7ꢀ-envelope (3E) after MMC.
Steroid ring C has an almost ideal 8ꢁ,12ꢀ-chair conformation
in (I), but it is signi®cantly distorted in (II). After MMC, the
conformation of ring C in (I) also became signi®cantly
distorted and similar to (II). The orientation of the phenyl
ring, de®ned by the C14ÐC13ÐC17ÐC20 and C13ÐC17Ð
C20ÐC25 torsion angles, was also changed, by about 26 and
75ꢁ, respectively. Rotation of the phenyl ring about the
C17ÐC20 bond in the rigid-rotor approximation con®rmed
that, in the crystalline state, molecule (I) is in a shallow
minimum, signi®cantly removed from the absolute minimum.
The orientation of atom O2 was also changed by about 10ꢁ,
going from synperiplanar to synclinal in relation to atom C14.
Since the conformations of the molecules became similar after
MMC (Fig. 3), the difference in biological activity can be
interpreted as being due to the different substituents at C17, as
well as the fact that, in (II), a new chiral centre has been
introduced.
Compound (I)
Crystal data
3
C25H27NO2
Dx = 1.207 Mg m
Cu Kꢀ radiation
Cell parameters from 25
re¯ections
Mr = 373.48
Monoclinic, P21
a = 8.1540 (10) A
Ê
Ê
b = 8.602 (3) A
ꢂ = 10±20ꢁ
ꢃ = 0.59 mm
T = 293 (2) K
1
Ê
c = 15.005 (4) A
ꢁ = 102.47 (2)ꢁ
V = 1027.6 (5) A
Z = 2
3
Ê
Prism, colourless
0.45 Â 0.08 Â 0.03 mm
Data collection
Enraf±Nonius CAD-4
diffractometer
!/ꢂ scans
1616 measured re¯ections
1616 independent re¯ections
978 re¯ections with I > 2ꢄ(I)
ꢂmax = 59.9ꢁ
h = 9 ! 8
k = 0 ! 9
l = 0 ! 16
3 standard re¯ections
frequency: 180 min
intensity decay: none
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.061
wR(F2) = 0.150
S = 1.18
1616 re¯ections
w = 1/[ꢄ2(Fo2) + (0.0443P)2
+ 0.3945P]
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max = 0.007
3
Ê
Áꢅmax = 0.11 e A
3
Ê
0.14 e A
251 parameters
H-atom parameters constrained
Áꢅmin
=
Table 1
Selected interatomic distance (A, ) for (I).
ꢁ
Ê
O1Á Á ÁO2
10.368 (1)
137 (2)
11 (3)
C20AÐC17ÐC13
C13ÐC17ÐC20AÐC25A
C13ÐC17ÐC20B
118.4 (10)
8.6 (13)
Figure 3
The superimposed ®t for the energy minimized molecular structures of (I)
(solid lines) and (II) (dashed lines).
C13ÐC17ÐC20BÐC25B
ꢀ
Ï
o64 Dusan Lazar et al.
C25H27NO2 and C25H29NO2
Acta Cryst. (2002). C58, o63±o65

organic compounds
Table 2
Selected interatomic distance (A) for (II).
1.2Ueq or 1.3Ueq of the parent atoms, or 1.5Ueq for the methyl-H
atoms. Re®nement of the Flack (1983) parameter was not successful
for either compound.
Ê
O1Á Á ÁO2
10.119 (2)
For both compounds, data collection: CAD-4 Software (Enraf±
Nonius, 1989); cell re®nement: CAD-4 Software; data reduction:
CAD-4 Software; program(s) used to solve structure: SHELXS86
(Sheldrick, 1990); program(s) used to re®ne structure: SHELXL97
(Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976);
Table 3
Hydrogen-bonding geometry (A, ) for (II).
ꢁ
Ê
Â
software used to prepare material for publication: CSU (Vickovic,
1988).
DÐHÁ Á ÁA
O2ÐH1O2Á Á ÁNi
Symmetry code: (i) x; y 12; 2 z.
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
0.82
2.01
2.829 (3)
171
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: AV1086). Services for accessing these data are
described at the back of the journal.
Compound (II)
Crystal data
References
3
C25H29NO2
Mr = 375.49
Monoclinic, P21
Dx = 1.196 Mg m
Cu Kꢀ radiation
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354±1358.
Duax, W. L., Weeks, C. M. & Rohrer, D. C. (1976). Topics in Stereochemistry,
Vol. 9, edited by E. L. Eliel & N. Allinger, pp. 271±383. New York: John
Wiley.
Duax, W. L., Weeks, C. M., Rohrer, D. C. & Grif®n, J. F. (1977). Proceedings of
the Vth International Congress of Endocrinology, edited by V. H. T. James,
Vol. 2, pp. 565±569. Amsterdam: Excerpta Medica.
Enraf±Nonius (1989). CAD-4 Software. Version 5.0. Enraf±Nonius, Delft, The
Netherlands.
Fieser, L. F. & Fieser, M. (1967). Steroids, pp. 507±511. New York: Reinhold.
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Lippincot.
Johnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National
Laboratory, Tennessee, USA.
Cell parameters from 25
re¯ections
Ê
a = 9.8063 (5) A
ꢂ = 22.0±30.5ꢁ
ꢃ = 0.58 mm
T = 293 (2) K
Ê
b = 6.697 (1) A
1
Ê
c = 16.201 (1) A
ꢁ = 101.455 (5)ꢁ
3
Ê
V = 1042.8 (2) A
Z = 2
Prism, colourless
0.38 Â 0.18 Â 0.15 mm
Data collection
Enraf±Nonius CAD-4
diffractometer
!/ꢂ scans
2305 measured re¯ections
2305 independent re¯ections
2134 re¯ections with I > 2ꢄ(I)
ꢂmax = 74ꢁ
h = 12 ! 11
k = 0 ! 8
l = 0 ! 20
3 standard re¯ections
frequency: 120 min
intensity decay: none
Â
Ï
Medic-Mijacevic, Lj. (1992). PhD Thesis, University of Novi Sad, Yugoslavia.
Miljkovic, D. & Petrovic, J. (1977). J. Org. Chem. 42, 2101±2102.
Â
Re®nement
Â
Â
Â
Â
 Â
Petrovic, J. A., Pejanovic, V. M., Miljkovic, D. A. & Hranisavljevic, J. T. (1990).
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.039
wR(F2) = 0.100
S = 0.96
2305 re¯ections
w = 1/[ꢄ2(Fo2) + (0.0520P)2
+ 0.2489P]
Steroids, 55, 276±278.
Serena Software (1989). PCMODEL. Version 4.0. Serena Software,
Bloomington, Indiana, USA.
Sheldrick, G. M. (1990). Acta Cryst. A46, 467±473.
È
Sheldrick, G. M. (1997). SHELXL97. University of Gottingen, Germany.
Stankovic, S., Lazar, D., Pejanovic, V., Petrovic, J. & Courseille, C. (1998). Acta
where P = (Fo2 + 2Fc2)/3
(Á/ꢄ)max < 0.001
3
Ê
Áꢅmax = 0.12 e A
3
Ê
0.19 e A
257 parameters
H-atom parameters constrained
Áꢅmin
=
Â
Â
Â
Cryst. C54, 1158±1160.
The crystals of (I) were very thin and their diffracting power very
low, so the data collection was stopped at ꢂ = 59.93ꢁ. For this reason,
the calculated sin(ꢂmax)/wavelength (0.561) is less than the required
value of 0.575, and the required ratio of re¯ections to parameters of 8
has not been satis®ed either (6.11). The H atoms were generated and
re®ned as riding, with isotropic displacement parameters ®xed at
Â
Â
Â
Â
Ï
Stankovic, S., Petrovic, J., Miljkovic, D., Pejanovic, V., Kovacevic, R.,
Stefanovic, A. & Bruvo, M. (1992). Acta Cryst. C48, 1248±1252.
Â
Â
Â
Â
Â
 Â
Stankovic, S., Petrovic, J., Miljkovic, D., Pejanovic, V., Stefanovic, A. & Bruvo,
M. (1994). Acta Cryst. C50, 1745±1747.
Â
Â
Stankovic, S., Stefanovic, A., Bruvo, M. & Altomare, A. (1992). Acta Cryst.
C48, 2082±2085.
Â
Vickovic, I. (1988). CSU. University of Zagreb, Croatia.
ꢀ
Ï
Acta Cryst. (2002). C58, o63±o65
Dusan Lazar et al.
C25H27NO2 and C25H29NO2 o65