(R)-5-[(1R,2R)-1-ethyl-2-(4-oxocyclohexyl)butyl]oxepan-2-one, an enantiopure 'pseudosteroid'

Article abstract of DOI:10.1515/znb-2006-0122

The title compound C₁₈H₃₀O₃ represents an optically pure member of a class of 'pseudosteroids', i.e. perhydrostilbene derivatives which mimic steroidal androgens (in the way like hexestrols or stilbestrols serve to substit

Full text of DOI:10.1515/znb-2006-0122

Note
111
(R)-5-[(1R,2R)-1-Ethyl-2-
(4-oxocyclohexyl)butyl]oxepan-2-one,
an Enantiopure ‘Pseudosteroid’
Brigitte Kluessa, Wolfgang Kreisera, Tony Sukria,
Wolfgang Pollb, and Hartmut Wunderlichb
a Fachbereich Chemie Universita¨t Dortmund,
Otto-Hahn-Str. 6, D-44227 Dortmund
b
Institut fu¨r Anorganische Chemie und Strukturchemie,
Universita¨t Du¨sseldorf, Universita¨tsstr. 1,
D-40225 Du¨sseldorf
Reprint requests to Dr. H. Wunderlich.
E-mail: hartmut.wunderlich@uni-duesseldorf.de
Z. Naturforsch. 61b, 111 – 112 (2006);
received September 20, 2005
The title compound C18H30O3 represents an optically pure
member of a class of ‘pseudosteroids’, i. e. perhydrostilbene
derivatives which mimic steroidal androgens (in the way like
hexestrols or stilbestrols serve to substitute natural estro-
gens). The molecule 2 is characterized by three consecutive
chiral centers leading to eight possible stereoisomers includ-
ing four diastereomers. All enantiomers have been separated
and their biological profile has been determined. As the re-
sult of the crystal structure presented here the two symmetry
independent molecules display the configuration R,R,R at the
centers of chirality.
Key words: Pseudosteroid, Perhydrostilbenes,
Androgenic Activity, Crystal Structure
Fig. 1. The crystal structure of C18H30O3 (2) showing 25%
probability displacement ellipsoids. Only one of two symme-
try independent molecules in the unit cell is shown. For the
atom numbering of the second molecule the first digit has to
be increased by 2. H atoms were calculated and are displayed
Results and Discussion
Since 1943 several investigations have been under-
taken to synthezise nonsteroidal compounds with an-
drogenic activity [1] – in analogy to the estrogens.
First of all the perhydro derivatives meso-1 and rac-
1 were examined. They lack any biological activity.
Later on a successful resolution of rac-1 by means
of the crystalline amine bisulfite adduct with L-(-)-α-
phenylethylamine led to the pure 3R,4R antipode [2].
A third chiral center was introduced by statistical
Baeyer-Villiger oxidation on 3R,4R-1. The mixture of
diastereomers 2 formed in 46% yield had to be sub-
mitted to several thin layer purifications until the more
˚
as circles with a radius of 0.1 A.
melting one showed [α]578 = +26◦◦, the lower melt-
ing one [α]578 = −37◦ (T = 25 C). The question
arose which one corresponded to the R and S con-
figuration, respectively, at the newly introduced cen-
ter C-5. The answer is given by the crystal structure
presented here. The low melting isomer 2 crystallizes
in the monoclinic space group P21 with a = 8.310(3),
◦
˚
b = 11.956(2), c = 9.214(2) A, and β = 111.57(2) ,
Dm = 1.14 Mg m−3, Z = 2, but its structure could not
be solved. Therefore, the structure of the higher melt-
ing crystals had to be determined [3, 4] which contains
two symmetry independent molecules per asymmet-
ric unit (space group P212121, Z = 8). One of these
is displayed in Fig. 1. The (1R,2R,5R)-configuration
◦
polar needles (m. p. 129– 130 C) could be separated
from rocky crystals (m. p. 99– 100 C).
The enantiopure diastereomeric lactones 2a, b dis-
played inverse signs of optical rotations. The higher
◦
c
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112
Note
Table 1. Crystal data and structure refinement of
(1R,2R,5R)-2.
– although well defined – disclosed a biological activ-
ity of about 25% of androsterone.
Empirical formula
Formular weight
C18H30O3
294.42
Experimental Section
Crystal system; space group
orthorhombic; P2 2121
1
˚
a = 9.048(2) A
According to a published procedure [7] the (-)-(3R,4R)-
diketone 1 was treated with 13% acetic peracid over night at
40 ◦C, leading to 40% starting material, 12% dilactone, and
46% crude product 2. To our knowledge this means the first
application of a statistical Baeyer-Villiger reaction. Full ex-
perimental details are given in [5]. Boiling of the high melt-
ing diastereomer in ethanol with sulfuric acid transformed it
into the corresponding hydroxy ester. Very short treatment of
this material with CrO3 in acetone [8] resulted in the appro-
priate ester acid with 92% yield. The carboxylic acid func-
tion by introduction of excess diazomethane was transformed
into a diester, followed by protection of the remaining ke-
tone function by means of ethyleneglycol. Now the stage was
set for Dieckmann cyclisation. Subsequent ester decarboxy-
lation (heating in pyridine for 5 h), and deprotection led to
the dihydro derivative of 3.
˚
b = 15.799(3) A
˚
c = 24.331(5) A
3
˚
V = 3478.1(12) A
Formular units per cell, Z
Calculated density, Dx
Crystal size
Absorption coefficient, µ(Cu-Kα )
F(000)
8
1.125 Mg m3
0.15×0.25×0.50 mm3
0.586 mm−1
1296
◦
Θ Range for data collection
Range for hkl
3.34 to 57.53◦
0 – 9, 0 – 17, 0 – 26
2694
2357
7.1
Independent reflections
Reflections with I > 2σ(I)
Data:parameter ratio
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R Indices (all data)
1.023
R1 = 0.0442; wR2 = 0.1171
R1 = 0.0502; wR2 = 0.1224
3
˚
Largest diff. peak and hole
0.210 and −0.136 e/A
Crystallographic data of 2 are presented in Table 1. The
intensities of the reflections have been measured at room
temperature with a diffractometer Syntex P21 using mono-
chromatized Cu-Kα radiation and an ω-scan. The structure
has been solved by direct methods [3] and refined in the
usual way [4]. All H atoms have been added in calculated
positions and were included in the refinement in a riding
mode. Positional and atomic displacement parameters have
been deposited with the Cambridge Crystallographic Data
Centre, CCDC-281176. Copies of the data can be obtained
free of charge on application to The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: +44 1223
336-033; e-mail for inquiry: data request@ccdc.cam.ac.uk
can be attributed to this structure, since the (3R,4R)
antipode of 1 served as starting material [5, 6]. The
geometry of the two symmetry independent molecules
of the asymmetric unit does not deviate significantly
from averaged values. The rings are connected equa-
torially and reveal a chair conformation. Three weak
hydrogen bonds of the type C-H...O with distances
˚
C...O between 3.322(5) and 3.484(5) A and angles
at the H atom in the range of 147 to 164◦ connect
the molecules. Later on 2 was transformed for phys-
iological assays into the target molecule 3 containing
four contiguous chiral centers, but the separation of
the diastereomers failed. This diastereomeric mixture 3 or www.ccdc.cam.ac.uk/data request/cif).
[5] B. Kluess, PhD Thesis, TU Braunschweig, Germany
[1] H. H. Inhoffen, W. Kreiser, N.-J. Myung, Liebigs Ann.
Chem. 739, 108 (1970).
(1973).
[6] T. Sukri, PhD Thesis, TU Braunschweig, Germany
(1973).
[7] P. S. Starcher, B. J. Phillips, J. Am. Chem. Soc. 80,
4079 (1958).
[2] H. H. Inhoffen, D. Kopp, S. Maric, J. Bekurdts, R. Se-
limoglu, Tetrahedron Lett. 11, 999 (1970).
[3] G. M. Sheldrick, SHELXTL-Plus Release 4.21/V,
Siemens Analytical X-ray Instruments Inc., Madison,
Wisconsin, USA (1990).
[8] H. Kiliani, Ber. Dtsch. Chem. Ges. 46, 667 (1913).
[4] G. M. Sheldrick, SHELXL-97, Program for Crystal
Structure Refinement, University of Go¨ttingen, Ger-
many (1997).
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