Stereoselective halogenation of the 16-hydroxymethyl-3-methoxy-13α-estra-1,3,5(10)-trien-17-ols and their solvolytic investigation

Article abstract of DOI:10.1016/S0039-128X(03)00048-5

The primary hydroxy functions of 16α-hydroxymethyl-3-methoxy-13α-estra-1,3,5(10)-trien-17β-ol (3a) and 16β-hydroxymethyl-3-methoxy-13α-estra-1,3,5(10)-trien-17α-ol (4a) were stereoselectively transformed into good leaving groups. On alkaline methanolysis of the 16-halomethyl or 16-tolylsulfonyloxymethyl derivatives, a new D-seco-13α-estrone derivative was obtained in high yield.

Full text of DOI:10.1016/S0039-128X(03)00048-5

Steroids 68 (2003) 451–458
Stereoselective halogenation of the 16-hydroxymethyl-3-methoxy-
13␣-estra-1,3,5(10)-trien-17-ols and their solvolytic investigation
János Wölfling, Erzsébet Mernyák, Péter Forgó, Gyula Schneider∗
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
Received 27 June 2002; received in revised form 22 January 2003; accepted 11 March 2003
Abstract
The primary hydroxy functions of 16␣-hydroxymethyl-3-methoxy-13␣-estra-1,3,5(10)-trien-17␤-ol (3a) and 16␤-hydroxymethyl-3-
methoxy-13␣-estra-1,3,5(10)-trien-17␣-ol (4a) were stereoselectively transformed into good leaving groups. On alkaline methanolysis of
the 16-halomethyl or 16-tolylsulfonyloxymethyl derivatives, a new d-seco-13␣-estrone derivative was obtained in high yield.
© 2003 Elsevier Science Inc. All rights reserved.
Keywords: Steroid; Selective synthesis; d-Secosteroid; 13␣-Estrone
1. Introduction
trans tosylate was converted to the fragmentation product.
Preparation of a d-seco derivative provides a possibility for
the construction of new d-homosteroids and steroid alka-
loids [5].
Natural 13␤-estrone derivatives possess a rigid steroidal
framework, which has oxygen functionalities at positions 3
and 17 separated by well-defined distances. In contrast with
the 13␤-estra steroids, the 13␣-estra compounds possess a
quasi-equatorial 13␣-methyl group and a cis junction of
rings C and D. The special structure of the latter compounds
leads to a different distance between the oxygen functions of
the molecule. This feature of the 13␣ steroids greatly affects
the chemical and biological properties. Recent conforma-
tional investigations proved two kinds of conformations for
the 13␣-estrone derivatives, depending on the substituents
on ring D [1].
We earlier reported that the reduction of 16-hydroxyme-
thylene-3-methoxyestra-1,3,5(10)-trien-17-one with NaBH4
yields two epimeric diols: 16␤-hydroxymethyl-3-methoxy-
estra-1,3,5(10)-trien-17␤-ol and 16␣-hydroxymethyl-3-me-
thoxyestra-1,3,5(10)-trien-17␤-ol, in nearly equal amounts
[2]. The primary hydroxy functions of these diols were trans-
formed into their tosylates. On alkaline methanolysis of the
cis tosylate, a ␤-oxetane condensed to ring D in the ster-
ane skeleton was formed [3]. Oxetane formation takes place
readily when the participating groups are in a favorable steric
configuration [4]. Under similar experimental conditions, the
In contrast with 16-hydroxymethylene-3-methoxyestra-1,
3,5(10)-trien-17-one, the reduction of 16-hydroxymethylene-
3-methoxy-13␣-estra-1,3,5(10)-trien-17-one (2) yields two
trans 16-hydroxymethyl-17-hydroxy epimers (3a, 4a).1
The epimers (3a, 4a) were selectively transformed into
the 16-halomethyl and 16-p-tolylsulfonyloxymethyl deriva-
tives (3b–i, 4b–e). The latter resulted in the desired d-seco
compound in high yield under alkaline conditions, with-
out formation of oxetanes. Fragmentation can occur in all
cases where the nucleophilic group is located distant from
the alcoholate function formed under alkaline conditions
[6]. The fragmentation product 5, containing cis functional
groups, might be of great importance as a starting ma-
terial of ring-closure reactions. We recently reported that
d-homosteroids, including halogens in ring D, can be ob-
tained efficiently from this fragmentation product [7], and
this opens up a route for the preparation of some biologically
important derivatives, especially the 13␣-d-homoestrone
[8]. For assignment of the structures of the new compounds,
various NMR experiments were used.
1
Mernya´k E, Wölfling J, Bunko´czi G, Luo L, Schneider TR,
Schneider G. Stereoselective synthesis of the two trans-(16-hydroxyme-
thyl)-3-methoxy-13␣-estra-1,3,5(10)-trien-17-ol isomers. Coll Czech
Chem Commun, 2003, in press.
∗
Corresponding author. Tel.: +36-62-544276; fax: +36-62-544200.
E-mail address: schneider@chem.u-szeged.hu (G. Schneider).
0039-128X/03/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved.
doi:10.1016/S0039-128X(03)00048-5

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J. Wölfling et al. / Steroids 68 (2003) 451–458
2. Experimental
84.9 (C-17), 112.0 (C-2), 113.3 (C-4), 127.5 (C-1), 133.5
(C-10), 137.9 (C-5), 157.3 (C-3). MS (70 eV); m/z (%):
336 (31, M+ + 2), 334 (100, M+), 212 (8), 186 (28), 173
(16), 147 (13), 121 (6), 91 (6), 57 (11). Continued elution
yielded a mixture of 3b and 4b (503 mg, 50%), and finally
4b (75 mg, 8%) eluted. mp 110–114 ◦C, Rf = 0.15 (ss A);
[␣]2D0 + 53 (c 1) (Found: C, 71.52; H, 8.05%. C20H27ClO2
Melting points (mps) were determined with a Kofler
hot-stage apparatus and are uncorrected. Specific rotations
were measured with a POLAMAT-A (Zeiss-Jena) polarime-
ter in chloroform and are given in units of 10−1 deg cm2/g.
Elemental analyses were performed in the analytical labo-
ratory of the University of Szeged. Thin-layer chromatog-
raphy: silica gel 60 F254; layer thickness 0.2 mm (Merck);
solvent system (ss): (A) tert-butyl methyl ether/light
petroleum (20:80 v/v), (B) tert-butyl methyl ether/light
petroleum (40:60 v/v), (C) tert-butyl methyl ether/light
petroleum (60:40 v/v), (D) dichloromethane/light petroleum
(60:40 v/v), (E) dichloromethane; detection with iodine or
UV (365 nm) after spraying with 50% phosphoric acid and
heating at 100–120 ◦C for 10 min. Flash chromatography:
silica gel 60, 40–63 ␮m (Merck). 1H NMR spectra were
recorded with a Bruker DRX-500 instrument at 500 MHz
in CDCl3 solution (if not otherwise given), using Me4Si as
internal standard. 13C NMR spectra were recorded with the
same instrument at 125 MHz under the same conditions.
EI-MS spectra were measured on a Varian MAT 311A.
1
requires C, 71.73; H, 8.13%); H NMR δ (ppm) 0.98 (s,
3H, 18-H3), 2.80 (m, 2H, 6-H2), 3.65 (d, 2H, J = 5.7 Hz,
16␣-H2), 3.76 (s, 3H, 3-OMe), 3.94 (m, 1H, 17␤-H), 6.60
(d, 1H, J = 2.5 Hz, 4-H), 6.71 (dd, 1H, J = 8.6, 2.5 Hz,
2-H), 7.20 (d, 1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm)
23.1 (C-18), 26.6, 28.4, 29.3, 30.5, 33.2, 42.2, 43.1, 44.2,
45.5, 48.6, 49.0, 55.2 (3-OCH3), 76.5 (C-17), 111.8 (C-2),
113.6 (C-4), 126.9 (C-1), 132.2 (C-10), 138.2 (C-5), 157.5
(C-3). MS (70 eV); m/z (%): 336 (30, M+ + 2), 334 (100,
M+), 306 (3), 247 (4), 212 (11), 186 (29), 147 (18), 134
(9), 91 (7), 41 (6).
2.3. 16α-Bromomethyl-3-methoxy-13α-estra-1,3,5(10)-
trien-17β-ol (3c) and 16β-bromomethyl-3-methoxy-
13α-estra-1,3,5(10)-trien-17α-ol (4c)
A 6:1 mixture of 3a and 4a (950 mg, 3 mmol) was dis-
solved in CH2Cl2 (30 ml) and CBr4 (1490 mg, 4.5 mmol)
was added. Ph3P (1572 mg, 6 mmol) was added to the so-
lution during cooling in ice, and the mixture was allowed
to warm to room temperature. The mixture was stirred
overnight and then evaporated to dryness. The residue was
subjected to chromatographic separation on a silica gel col-
umn with tert-butyl methyl ether/light petroleum (20:80),
as eluent. During the separation, 3c (950 mg, 61%) eluted
first as an oil. Rf = 0.20 (ss A); [␣]20 + 66 (c 1) (Found:
C, 63.45; H, 7.03%. C20H27BrO2 rDequires C, 63.33; H,
2.1. 16α-Hydroxymethyl-3-methoxy-13α-estra-1,3,5(10)-
trien-17β-ol (3a) and 16β-hydroxymethyl-3-methoxy-
13α-estra-1,3,5(10)-trien-17α-ol (4a)
Compound 2 (10 g, 32 mmol) was suspended in methanol
(200 ml) and KBH4 (8.6 g, 160 mmol) was added in small
portions at room temperature. The reaction mixture was al-
lowed to stand for 4 h, then poured onto ice (500 g) and acid-
ified with dilute hydrochloric acid to pH 3. The precipitate
that separated out was filtered off, washed until free from
acid and dried; yield: 9.8 g (97%). The mixture obtained
consisted of the diols 3a and 4a in a ratio of 6:1.
1
7.17%); H NMR δ (ppm) 1.07 (s, 3H, 18-H3), 2.77 (m,
2H, 6-H2), 3.49 (m, 2H, 17␣-H, and 16␣-H), 3.56 (dd, 1H,
J = 9.9, 5.9 Hz, 16␣-H), 3.75 (s, 3H, 3-OMe), 6.58 (d, 1H,
J = 2.5 Hz, 4-H), 6.70 (dd, 1H, J = 8.5, 2.5 Hz, 2-H), 7.14
(d, 1H, J = 8.5 Hz, 1-H). 13C NMR δ (ppm) 27.9, 28.9,
29.3 (C-18), 29.5, 30.4, 31.7, 37.5, 38.7, 41.0, 43.9 (C-13),
48.0, 50.4, 55.2 (3-OCH3), 85.7 (C-17), 112.0 (C-2), 113.3
(C-4), 127.5 (C-1), 133.6 (C-10), 137.9 (C-5), 157.3 (C-3).
MS (70 eV); m/z (%): 380 (98), 378 (100, M+), 212 (15),
186 (30), 173 (21), 147 (17), 57 (14). Continued elution
yielded a mixture of 3c and 4c (350 mg, 23%), and finally
4c (30 mg, 2%) eluted. mp 113–115 ◦C, Rf = 0.18 (ss A).
[␣]2D0 + 26 (c 1) (Found: C, 63.17; H, 7.38%. C20H27BrO2
2.2. 16α-Chloromethyl-3-methoxy-13α-estra-1,3,5(10)-
trien-17β-ol (3b) and 16β-chloromethyl-3-methoxy-
13α-estra-1,3,5(10)-trien-17α-ol (4b)
A 6:1 mixture of 3a and 4a (950 mg, 3 mmol) was sus-
pended in CCl4 (20 ml) and Ph3P (0.8 g, 3 mmol) was
added. After a 36 h reflux, the solvent was evaporated. The
residue obtained was subjected to chromatographic separa-
tion on a silica gel column with tert-butyl methyl ether/light
petroleum (20:80) as eluent. 3b (200 mg, 20%) eluted first
as an oil. Rf = 0.20 (ss A); [␣]2D0 + 85 (c 1) (Found: C,
71.78; H, 8.21%. C20H27ClO2 requires C, 71.73; H, 8.13%);
1H NMR δ (ppm) 1.08 (s, 3H, 18-H3), 2.78 (m, 2H, 6-H2),
3.55 (d, 1H, J = 7.3 Hz, 17␣-H), 3.63 (dd, 1H, J = 10.7,
6.4 Hz); and 3.68 (dd, 1H, J = 10.7, 5.9 Hz): 16␣-H2, 3.76
(s, 3H, 3-OMe), 6.58 (d, 1H, J = 2.4 Hz, 4-H), 6.70 (dd,
1H, J = 8.5, 2.4 Hz, 2-H), 7.15 (d, 1H, J = 8.5 Hz, 1-H).
13C NMR δ (ppm) 27.9, 28.8, 29.2 (C-18), 29.4, 30.3, 30.4,
38.7, 41.0, 43.7 (C-13), 48.0, 48.1, 50.3, 55.2 (3-OCH3),
1
requires C, 63.33; H, 7.17%); H NMR δ (ppm) 0.97 (s,
3H, 18-H3), 2.79 (m, 2H, 6-H2), 3.54 (m, 2H, 16␣-H2),
3.75 (s, 3H, 3-OMe), 3.89 (d, 1H, J = 7.9 Hz, 17␤-H), 6.59
(d, 1H, J = 2.5 Hz, 4-H), 6.69 (dd, 1H, J = 8.6, 2.5 Hz,
2-H), 7.22 (d, 1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm)
23.2 (C-18), 26.6, 28.4, 30.5, 30.7, 33.2, 38.9, 42.2, 43.3,
44.4 (C-13), 45.4, 48.5, 55.2 (3-OCH3), 77.6 (C-17), 111.9
(C-2), 113.7 (C-4), 127.0 (C-1), 132.2 (C-10), 138.2 (C-5),
157.6 (C-3).

J. Wölfling et al. / Steroids 68 (2003) 451–458
453
2.4. 16α-Iodomethyl-3-methoxy-13α-estra-1,3,5(10)-
trien-17β-ol (3d) and 16β-iodomethyl-3-methoxy-
13α-estra-1,3,5(10)-trien-17α-ol (4d)
3H, Ts-Me), 2.75 (m, 2H, 6-H2), 3.47 (m, 1H, 17␣-H), 3.75
(s, 3H, 3-OMe), 4.10 (m, 2H, 16␣-H2), 6.57 (d, 1H, J =
2.4 Hz, 4-H), 6.69 (dd, 1H, J = 8.6, 2.4 Hz, 2-H), 7.13 (d,
1H, J = 8.6 Hz, 1-H), 7.33 (d, 1H, J = 8.2 Hz, 3ꢀ,5ꢀ-H),
7.78 (d, 1H, J = 8.2 Hz, 2ꢀ,6ꢀ-H). 13C NMR δ (ppm) 21.6
(Ts-CH3), 27.8, 28.8, 28.9, 29.0 (C-18), 29.1, 30.3, 38.5,
40.8, 43.5 (C-13), 45.2, 50.2, 55.2 (3-OCH3), 72.6 (C-16␣),
83.5 (C-17), 112.0 (C-2), 113.2 (C-4), 127.5 (C-1), 127.9
(2C, C-2ꢀ,6ꢀ), 129.8 (2C, C-3ꢀ,5ꢀ), 133.1 (C-1ꢀ), 133.5 (C-10),
137.8 (C-5), 144.8 (C-4ꢀ), 157.2 (C-3). MS (70 eV); m/z
(%): 470 (100%) [M+], 316 (22), 298 (43), 213 (17), 186
(29), 147 (22), 91 (27). Continued elution yielded a mix-
ture of 3e and 4e (200 mg, 14%), and finally 4e (52 mg, 4%)
eluted. Mp 129–131 ◦C, Rf = 0.16 (ss B); [␣]20 − 5 (c 1)
(Found: C, 68.81; H, 7.35%. C27H34O5S requirDes C, 68.91;
Ph3P (1572 mg, 6 mmol), imidazole (408 mg, 6 mmol),
iodine (760 mg, 6 mmol), and a 6:1 mixture of 3a and 4a
(950 mg, 3 mmol) were added to dichloromethane (30 ml).
The mixture was stirred at room temperature for 24 h, then
poured into water and extracted with dichloromethane. The
dichloromethane solution was washed with water, dried
(Na2SO4), and evaporated to dryness. The residue obtained
was subjected to chromatographic separation on a silica
gel column with tert-butyl methyl ether/light petroleum
(20:80) as eluent. 3d (794 mg, 62%) eluted first as an oil.
Rf = 0.23 (ss A); [␣]2D0 + 73 (c 1) (Found: C, 56.22; H,
1
1
H, 7.28%); H NMR δ (ppm) 0.93 (s, 3H, 18-H3), 2.37 (s,
6.47%. C20H27IO2 requires C, 56.35; H, 6.38%); H NMR
3H, Ts-Me), 2.81 (m, 2H, 6-H2), 3.77 (s, 3H, 3-OMe), 3.79
(m, 1H, 17␤-H), 4.11 (m, 2H, 16␣-H2), 6.59 (d, 1H, J =
2.5 Hz, 4-H), 6.71 (dd, 1H, J = 8.6, 2.5 Hz, 2-H), 7.18 (d,
1H, J = 8.6 Hz, 1-H), 7.23 (d, 1H, J = 8.2 Hz, 3ꢀ,5ꢀ-H),
7.73 (d, 1H, J = 8.2 Hz, 2ꢀ,6ꢀ-H). 13C NMR δ (ppm) 21.5
(Ts-CH3), 22.8 (C-18), 26.5, 27.6, 28.2, 30.4, 33.0, 42.2,
42.8, 42.9, 43.9 (C-13), 48.6, 55.2 (3-OCH3), 72.8 (C-16␣),
75.2 (C-17), 111.7 (C-2), 113.6 (C-4), 126.9 (C-1), 127.8
(2C, C-2ꢀ,6ꢀ), 129.9 (2C, C-3ꢀ,5ꢀ), 132.1 (C-10), 133.1 (C-1ꢀ),
138.2 (C-5), 144.8 (C-4ꢀ), 157.5 (C-3).
δ (ppm) 1.10 (s, 3H, 18-H3), 2.79 (m, 2H, 6-H2), 3.26 (dd,
1H, J = 9.4, 7.1 Hz, 16␣-H), 3.42 (m, 2H, 16␣-H, and
17␣-H), 3.78 (s, 3H, 3-OMe), 6.60 (d, 1H, J = 2.4 Hz,
4-H), 6.72 (dd, 1H, J = 8.6, J = 2.4 Hz, 2-H), 7.16 (d, 1H,
J = 8.6 Hz, 1-H). 13C NMR δ (ppm) 12.0 (C-16␣), 27.8,
28.9, 29.3 (C-18), 29.4, 30.4, 33.8, 38.5, 41.1, 44.1 (C-13),
47.8, 50.2, 55.3 (3-OCH3), 86.9 (C-17), 112.1 (C-2), 113.3
(C-4), 127.6 (C-1), 133.6 (C-10), 137.9 (C-5), 157.3 (C-3).
Continued elution yielded a mixture of 3d and 4d (370 mg,
29%), and finally 4d (51 mg, 4%) eluted. Mp 98–100 ◦C,
Rf = 0.18 (ss A); [␣]2D0 + 35 (c 1) (Found: C, 56.48; H,
1
6.43%. C20H27IO2 requires C, 56.35; H, 6.38%); H NMR
2.6. 16α-Halomethyl- and 16α-toluene-
p-sulfonyloxymethyl-3-methoxy-13␣-estra-
1,3,5(10)-trien-17␤-acetates (3f–i)
δ (ppm) 0.98 (s, 3H, 18-H3), 2.80 (m, 2H, 6-H2), 3.29 (dd,
1H, J = 9.6, 7.0 Hz), and 3.39 (dd, 1H, J = 9.6, 6.1 Hz):
16␣-H2, 3.77 (m, 4H, 17␤-H and 3-OMe), 6.61 (d, 1H,
J = 2.7 Hz, 4-H), 6.71 (dd, 1H, J = 8.8, 2.7 Hz, 2-H),
7.22 (d, 1H, J = 8.8 Hz, 1-H). 13C NMR δ (ppm) 14.4
(C-16␣), 23.3 (C-18), 26.6, 28.2, 30.4, 32.5, 33.2, 42.0,
43.3, 44.4 (C-13), 45.2, 48.0, 55.1 (3-OCH3), 78.8 (C-17),
111.7 (C-2), 113.5 (C-4), 126.9 (C-1), 132.1 (C-10), 138.1
(C-5), 157.3 (C-3). MS (70 eV); m/z (%): 426 (100, M+),
281 (4), 212 (7), 186 (8), 173 (13), 147 (15).
2.6.1. General procedure
Compound 3b (170 mg, 0.5 mmol), 3c (190 mg, 0.5 mmol),
3d (215 mg, 0.5 mmol), or 3e (235 mg, 0.5 mmol) was
dissolved in anhydrous pyridine (2 ml), and a solution of
two equivalents of acetic anhydride in pyridine (1 ml) was
added. The reaction mixture was stirred overnight, then
poured onto a mixture of sulfuric acid (1 ml) and ice (10 g)
and extracted with chloroform. The chloroform phase was
evaporated to dryness. Products 3f and 3g were crystallized
from light petroleum and 3i from acetone/light petroleum.
Product 3j remained an oil.
2.5. 16α-Toluene-p-sulfonyloxymethyl-3-methoxy-13α-
estra-1,3,5(10)-trien-17β-ol (3e) and 16β-toluene-
p-sulfonyloxymethyl-3-methoxy-13α-estra-
1,3,5(10)-trien-17α-ol (4e)
3f (155 mg, 81%) mp 75–77 ◦C, Rf = 0.19 (ss D); [␣]2D0+
51 (c 1) (Found: C, 70.26; H, 7.65%. C22H29ClO3 requires
C, 70.11; H, 7.76%); 1H NMR δ (ppm) 1.09 (s, 3H, 18-H3),
2.00 (s, 3H, Ac-Me), 2.82 (m, 2H, 6-H2), 3.58 (dd, 1H, J =
10.7, 7.5 Hz) and 3.73 (dd, 1H, J = 10.7, 5.4 Hz): 16␣-H2,
3.77 (s, 3H, 3-OMe), 4.75 (d, 1H, J = 5.4 Hz, 17␣-H), 6.62
(d, 1H, J = 2.5 Hz, 4-H), 6.72 (dd, 1H, J = 8.6, 2.5 Hz,
2-H), 7.19 (d, 1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm) 21.2
(Ac-CH3), 28.4, 29.0, 29.9 (C-18), 30.4, 30.9, 33.0, 40.6,
40.7, 44.2 (C-13), 47.9, 48.0, 51.8, 55.1 (3-OCH3), 85.1
(C-17), 111.9 (C-2), 113.4 (C-4), 127.2 (C-1), 132.7 (C-10),
138.1 (C-5), 157.4 (C-3), 170.7 (Ac-CO). MS (70 eV); m/z
(%): 378 (33, M+ + 2), 376 (100, M+), 186 (18), 147 (11),
91 (5), 43 (20).
A 6:1 mixture of 3a and 4a (950 mg, 3 mmol) was dis-
solved in anhydrous pyridine (4.5 ml) and a solution of
p-toluenesulfonyl chloride (855 mg, 4.5 mmol) in anhydrous
pyridine (4.5 ml) was added dropwise with cooling in ice.
The reaction mixture was allowed to stand for 24 h and then
poured into a mixture of sulfuric acid (3 ml) and ice (150 g).
The precipitate was filtered off and was subjected to chro-
matographic separation on a silica gel column with tert-butyl
methyl ether/light petroleum (20:80), as eluent. 3e (984 mg,
70%) eluted first as an oil. Rf = 0.19 (ss B); [␣]20+57 (c 1).
(Found: C, 69.03; H, 7.21%. C27H34O5S requirDes C, 68.91;
1
H, 7.28%); H NMR δ (ppm) 1.02 (s, 3H, 18-H3), 2.44 (s,

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J. Wölfling et al. / Steroids 68 (2003) 451–458
3g (185 mg, 86%) mp 73–76 ◦C, Rf = 0.25 (ss D); [␣]2D0+
tracted with dichloromethane, and the dichloromethane solu-
tion was washed with water, dried (Na2SO4) and evaporated.
The residue was subjected to chromatographic separation on
a silica gel column with dichloromethane as eluent. Product
5 eluted first as an oil. Rf = 0.39 (ss D); [␣]20 + 68 (c 1)
(Found: C, 80.38; H, 8.85%. C20H26O2 requiDres C, 80.50;
H, 8.78%); 1H NMR (C6D6, δ [ppm]): 0.91 (s, 3H, 18-H3),
1.02 (m, 1H, 14-H), 1.07 and 1.82 (2× m, 2× 1H, 12-H2),
1.09 and 2.00 (2× m, 2× 1H, 7-H2), 1.27 and 2.00 (2× m,
2× 1H, 11-H2), 1.58 (m, 1H, 8-H), 2.11 (m, 1H, 9-H), 2.19
and 2.27 (2× m, 2× 1H, 15-H2), 2.66 (m, 2H, 6-H2), 3.42
(s, 3H, 3-OMe), 4.92 and 4.95 (2× m, 2× 1H, 16␣-H2),
5.69 (m, 1H, 16-H), 6.66 (d, 1H, J = 2.6 Hz, 4-H), 6.79 (dd,
1H, J = 8.6, 2.6 Hz, 2-H), 7.07 (d, 1H, J = 8.6 Hz, 1-H),
9.48 (s, 1H, formyl-H). 13C NMR (C6D6, δ [ppm]): 23.5
(C-18), 28.2 (C-11), 28.3 (C-7), 30.9 (C-6), 34.1 (C-15),
36.9 (C-12), 42.9 (C-8), 44.0 (C-9), 49.9 (C-14), 50.4 (C-13),
55.2 (3-OCH3), 112.6 (C-2), 114.2 (C-4), 115.3 (C-16␣),
127.2 (C-1), 132.6 (C-10), 138.3 (C-5), 140.3 (C-16), 158.8
(C-3), 205.9 (C-formyl). MS (70 eV); m/z (%): 298 (100,
M+), 213 (42), 173 (22), 147 (21), 115 (9), 91 (10). Con-
tinued elution yielded 6. mp 85–88 ◦C, Rf = 0.31 (ss A);
[␣]2D0 + 71 (c 1) (Found: C, 80.63; H, 8.86%. C20H26O2 re-
62 (c 1) (Found: C, 62.85; H, 7.04%. C22H29BrO3 requires
C, 62.71; H, 6.94%); 1H NMR δ (ppm) 1.10 (s, 3H, 18-Me),
2.01 (s, 3H, Ac-Me), 2.82 (m, 2H, 6-H2), 3.43 (dd, 1H, J =
9.7, 8.1 Hz) and 3.64 (dd, 1H, J = 9.8, 5.4 Hz): 16␣-H2,
3.77 (s, 3H, 3-OMe), 4.72 (d, 1H, J = 5.4 Hz, 17␣-H), 6.62
(d, 1H, J = 2.6 Hz, 4-H), 6.72 (dd, 1H, J = 8.6, 2.6 Hz,
2-H), 7.19 (d, 1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm)
21.3 (Ac-CH3), 28.4, 29.0, 30.0 (C-18), 30.4, 32.2, 33.1,
36.8, 40.6, 40.7, 44.4 (C-13), 47.9, 51.8, 55.2 (3-OCH3),
85.8 (C-17), 111.9 (C-2), 113.4 (C-4), 127.2 (C-1), 132.6
(C-10), 138.1 (C-5), 157.4 (C-3), 170.8 (Ac-CO).
3h (195 mg, 84%) oil, Rf = 0.23 (ss C); [␣]2D0 + 51 (c 1)
(Found: C, 56.62; H, 6.08%. C22H29IO3 requires C, 56.42;
1
H, 6.24%); H NMR δ (ppm) 1.11 (s, 3H, 18-H3), 2.01 (s,
3H, Ac-Me), 2.82 (m, 2H, 6-H2), 3.20 (t, 1H, J = 8.9 Hz)
and 3.45 (dd, 1H, J = 9.6, 5.5 Hz): 16␣-H2, 3.77 (s, 3H,
3-OMe), 4.65 (d, 1H, J = 5.5 Hz, 17␣-H), 6.62 (d, 1H, J =
2.6 Hz, 4-H), 6.72 (dd, 1H, J = 8.6, 2.6 Hz, 2-H), 7.18 (d,
1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm) 10.4 (C-16␣), 21.3
(Ac-CH3), 28.4, 28.9, 30.1 (C-18), 30.4, 33.0, 34.4, 40.6,
40.7, 44.8 (C-13), 48.0, 51.8, 55.2 (3-OCH3), 86.7 (C-17),
111.9 (C-2), 113.4 (C-4), 127.2 (C-1), 132.7 (C-10), 138.1
(C-5), 157.4 (C-3), 170.8 (Ac-CO). MS (70 eV); m/z (%):
468 (100, M+), 281 (7), 186 (13), 173 (18), 147 (17), 86
(10), 43 (23).
1
quires C, 80.50; H, 8.78%); H NMR δ (ppm) 0.94 (s, 3H,
18-H3), 2.78 (m, 2H, 6-H2), 3.75 (s, 3H, 3-OMe), 3.94 (s,
1H, 17␣-H), 5.06 and 5.18 (2× s, 2× 1H, 16␣-H2), 6.58 (d,
1H, J = 2.6 Hz, 4-H), 6.70 (dd, 1H, J = 8.6, 2.6 Hz, 2-H),
7.19 (d, 1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm) 28.9, 29.3,
29.7 (C-18), 30.5, 32.4, 34.1, 40.7, 42.5, 43.9 (C-13), 50.6,
55.2 (3-OCH3), 84.1 (C-17), 110.1 (C-16␣), 111.8 (C-2),
113.5 (C-4), 127.3 (C-1), 133.1 (C-10), 138.2 (C-5), 155.8
(C-16), 157.3 (C-3). MS (70 eV); m/z (%): 298 (100, M+),
227 (37), 186 (7), 173 (11), 147 (10), 91 (3), 43 (4). Finally
eluted 8. Oil, Rf = 0.38 (ss B); [␣]2D0 +102 (c 1) (Found: C,
76.21; H, 9.27%. C21H30O3 requires C, 76.33; H, 9.15%);
1H NMR δ (ppm) 1.08 (s, 3H, 18-H3), 2.74 (m, 2H, 6-H2),
3.34 (s, 3H, 16␣-OMe), 3.39 (t, 1H, J = 8.0 Hz, 16␣-H),
3.50 (m, 2H, 16␣-H, and 17␣-H), 3.74 (s, 3H, 3-OMe), 6.56
(d, 1H, J = 2.7 Hz, 4-H), 6.69 (dd, 1H, J = 8.6, 2.7 Hz,
2-H), 7.13 (d, 1H, J = 8.6 Hz, 1-H). 13C NMR δ (ppm)
27.6, 28.2, 28.9 (C-18), 29.0, 29.4, 30.4, 38.0, 41.1, 43.6
(C-13), 45.0, 50.3, 55.2 (3-OCH3), 59.1 (16␣-OCH3), 77.0
(C-16␣), 86.3 (C-17), 112.1 (C-2), 113.2 (C-4), 127.7 (C-1),
134.1 (C-10), 137.9 (C-5), 157.2 (C-3) (Table 1).
3i (222 mg, 87%) mp 124–125 ◦C, Rf = 0.15 (ss E);
[␣]2D0 + 17 (c 1) (Found: C, 68.12; H, 7.17%. C29H36O6S
1
requires C, 67.94; H, 7.08%); H NMR δ (ppm) 1.00 (s,
3H, 18-H3), 1.96 (s, 3H, Ac-Me), 2.45 (s, 3H, Ts-Me), 2.81
(m, 2H, 6-H2), 3.78 (s, 3H, 3-OMe), 4.07 (dd, 1H, J = 9.7,
7.3 Hz) and 4.17 (dd, 1H, J = 9.7, 5.4 Hz): 16␣-H2, 4.60
(d, 1H, J = 5.4 Hz, 17␣-H), 6.62 (d, 1H, J = 2.8 Hz, 4-H),
6.72 (dd, 1H, J = 8.6, 2.8 Hz, 2-H), 7.18 (d, 1H, J = 8.6 Hz,
1-H), 7.35 (d, 2H, J = 8.0 Hz, 3ꢀ,5ꢀ-H), 7.79 (dd, 2H, J =
6.6, 1.7 Hz, 2ꢀ,6ꢀ-H). 13C NMR δ (ppm) 21.2 (Ac-CH3), 21.6
(Ts-CH3), 28.4, 29.0, 29.7, 29.8 (C-18), 30.4, 32.9, 40.4,
40.6, 44.0 (C-13), 45.2, 51.7, 55.2 (3-OCH3), 72.3 (C-16␣),
83.9 (C-17), 111.9 (C-2), 113.4 (C-4), 127.2 (C-1), 127.9
(2C, C-2ꢀ,6ꢀ), 129.8 (2C, C-3ꢀ,5ꢀ), 132.6 (C-10), 133.0 (C-1ꢀ),
138.1 (C-5), 144.7 (C-4ꢀ), 157.4 (C-3), 170.7 (Ac-CO). MS
(70 eV); m/z (%): 512 (100, M+), 452 (6), 280 (11), 186
(16), 173 (13), 91 (8), 43 (8).
2.7. 3-Methoxy-16,17-seco-13α-estra-1,3,5(10),
16-tetraen-17-al (5), 3-methoxy-16-methylene-
13α-estra-1,3,5(10)-trien-17β-ol (6) and
3-methoxy-16α-methoxymethyl-13α-estra-
1,3,5(10)-trien-17β-ol (8)
Table 1
Yields of the products (5, 6, 8) formed by alkaline solvolysis of the differ-
ent 16-halomethyl- or 16-tosyloxymethyl-17-hydroxy compounds (3b–e)
Starting material
Products (%)
2.7.1. General procedure
5
6
8
Compound 3b, 3c, 3d, or 3e (1 mmol) was dissolved
in methanol (15 ml) and heated under reflux with KOH
(280 mg, 5 mmol) for 3 h. The reaction mixture was next
poured into water and neutralized with 10% hydrochloric
acid, and the precipitate was filtered off. The mixture was ex-
3b
3c
3d
3e
65
71
79
73
12
11
10
11
6
6
5
6

J. Wölfling et al. / Steroids 68 (2003) 451–458
455
2.7.2. 3-Methoxy-16-methylene-13α-estra-1,3,5(10)-
trien-17α-ol (7)
with the analogous reaction of the normal estrone series,
we selectively obtained the two trans diols (3a and 4a) in
a ratio of 6:1.1 Reduction of the 17-ketones of the 13␤
steroids normally leads to 17␤-hydroxy derivatives [9–11]
(with a few exceptions [12–14]). This is why the reduction
of 16-hydroxymethylene-17-ketone in the normal series
leads to two epimeric diols, both containing 17␤-hydroxy
groups and with opposite configurations at C-16. Reduc-
tion of the 17-ketones of the 13␣-estrone series results in
two epimeric diols in different amounts, depending on the
reaction conditions [15]. Therefore, on the reduction of
16-hydroxymethylene-3-methoxy-13␣-estra-1,3,5(10)-trien-
17-one (2), we expected the formation of more than two
isomers. Surprisingly, we selectively obtained only two
diastereomers: the trans diols. The main isomer was the
16␣-hydroxymethyl-17␤-hydroxy compound (3a). The rea-
son for the predominant formation of this isomer may be
that the relatively large hydroxymethyl group prefers to take
up a quasi-equatorial position, and the smaller 17-hydroxy
group is quasi-axial.
With the aim of preparing a d-secosteroid of the 13␣-
estrone series, the primary hydroxy groups of 3a and
4a were converted into good leaving groups, since the
␣,␥-halohydrins and ␣,␥-diol monosulfonates contain ap-
propriate nucleophilic groups for Grob fragmentation.
When the mixture of 3a and 4a obtained by reduction of the
16-hydroxymethylene-17-keto compound (2) was treated
with toluene-p-sulfonyl chloride in pyridine, it yielded the
desired derivatives (3e, 4e) in an overall yield of 88%, but
disadvantageous disubstitution (3j) was also observed. In
order to avoid the formation of any by-products, and par-
ticularly disubstituted derivatives, we decided to investigate
other kinds of nucleophilic substitution reactions.
According to the general procedure, alkaline solvolysis of
the mixture of isomers (3b–e and 4b–e) yielded the above
products (5, 6, 8) in nearly the same yields, and one addi-
tional by-product (7), formed from the minor isomers. Due
to its small amount, the latter compound was not fully char-
acterized, but the 1H NMR spectrum was recorded. Oil:
Rf = 0.28 (ss A); (Found: C, 80.42; H, 8.93%. C20H26O2
requires C, 80.50; H, 8.78%); 1H NMR δ (ppm) 0.83 (s, 3H,
18-H3), 2.79 (m, 2H, 6-H2), 3.76 (s, 3H, 3-OMe), 4.42 (s,
1H, 17␤-H), 5.06 and 5.16 (2× s, 2× 1H, 16␣-H2), 6.60 (d,
1H, J = 2.6 Hz, 4-H), 6.71 (dd, 1H, J = 8.6, 2.6 Hz, 2-H),
7.23 (d, 1H, J = 8.6 Hz, 1-H).
2.7.3. Preparation and alkaline solvolysis of
16α-p-tolylsulfonyloxymethyl-17β-tetrahydropyranyl
acetal (3k)
Compound 3e (471 mg, 1 mmol) was dissolved in
dichloromethane (10 ml), and 3,4-dihydropyran (0.27 ml,
3 mmol) and a catalytic amount of p-toluenesulfonyl chlo-
ride was added. The reaction mixture was stirred for 1 h
at room temperature, then diluted with water, neutralized
with morpholine, extracted with dichloromethane, dried
(Na2SO4) and evaporated. The oil obtained was a mixture of
the two epimers on C-1ꢀꢀ in a ratio of 3:2, in 90% (500 mg)
yield. The 1H NMR data on the two epimers are as follows.
1H NMR δ (ppm) 0.95 (s, 3H, 18-H3), 2.43 (s, 3H,
Ts-H3), 2.77 (m, 2H, 6-H2), 3.26 (m, 2H, 3ꢀꢀ-H2), 3.63
(m, 1H, 17␣-H), 3.75 (s, 3H, 3-OMe), 4.10 and 4.25 (2×
m, 2× 1H, 16␣-H2), 4.40 (s, 1H, 1ꢀꢀ-H), 6.59 (d, 1H,
J = 2.4 Hz, 4-H), 6.68 (dd, 1H, J = 8.6, 2.4 Hz, 2-H),
7.16 (d, 1H, J = 8.6 Hz, 1-H), 7.33 (m, 2H, 3ꢀ,5ꢀ-H), 7.80
(m, 2H, 2ꢀ,6ꢀ-H).
Appel reaction is a convenient method for halogenation
of primary and secondary alcohols [16–19]. A mixture of
3a and 4a was used as the starting material of this re-
action. There were two reasons why this procedure was
used. Firstly, halogenated compounds can be separated by
flash chromatography on silica gel (in order to verify their
structures) more easily than 3a and 4a. Secondly, it is not
necessary to separate the isomers for the fragmentation
process, because both compounds result in the same frag-
mentation product in high yield. Reaction of the 6:1 mixture
of 3a and 4a with CCl4 and Ph3P in CH2Cl2 furnished two
isomeric products (3b, 4b), in the same ratio as in the case
of the starting material, in an overall yield of 78%. Similar
compounds (3c, 4c) were formed in the reaction of 3a and
4a with CBr4 and Ph3P in CH2Cl2, but the yield was higher
(86%). During these two reactions, we also observed the
formation of by-products, which seemed to be the dihalo-
genated steroids. The latter derivatives could not be isolated
in pure form because of their instability and since they could
not be distinguished from the excess of Ph3P by flash chro-
matography on silica gel. The preparation of 16-iodomethyl
derivatives (3d, 4d) proved to be the most efficient method,
because no by-products were obtained and the yield was
1H NMR δ (ppm) 0.91 (s, 3H, 18-H3), 2.43 (s, 3H, Ts-H3),
2.77 (m, 2H, 6-H2), 3.47 (m, 2H, 3ꢀꢀ-H2), 3.75 (s, 3H,
3-OMe), 3.81 (m, 1H, 17␣-H), 4.05 (m, 2H, 16␣-H2), 4.48
(s, 1H, 1ꢀꢀ-H), 6.59 (d, 1H, J = 2.4 Hz, 4-H), 6.68 (dd, 1H,
J = 8.6 Hz, J = 2.4 Hz, 2-H), 7.16 (d, 1H, J = 8.6 Hz,
1-H), 7.33 (m, 2H, 3ꢀ,5ꢀ-H), 7.80 (m, 2H, 2ꢀ,6ꢀ-H).
According to the general procedure, alkaline solvolysis of
the C-1ꢀꢀ epimers yielded a mixture which was not separated
by column chromatography, but was hydrolyzed with dilute
hydrochloric acid. After the hydrolysis an oil remained a 1:1
mixture of 6 and 8.
3. Results and discussion
Epi-estrone 3-methyl ether can easily be obtained in
one step from the readily available estrone 3-methyl ether.
Claisen condensation of 1 with ethyl formate and sodium
methylate leads to the 16-hydroxymethylene-3-methoxy-
13␣-estra-1,3,5(10)-trien-17-one (2). Treatment of 2 with
KBH4 in methanol yielded two diastereomeric diols (3a,
4a) in an overall yield of 97% (Scheme 1). In contrast

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J. Wölfling et al. / Steroids 68 (2003) 451–458
Scheme 1. Selective hydroxymethylation of 3-methoxy-13␣-estra-1,3,5(10)-trien-17-one (1) and transformation of the primary hydroxy functions of the
diols (3a, 4a) to good leaving groups (3b–e, 4b–e).
almost 95%. If we compare the nucleophilic properties of
the halogen groups, and the yields of the substitution reac-
tions, it can be stated that the iodo derivatives are the most
appropriate starting materials for the fragmentation process.
In order to confirm the structures of the halohydrins,
1H, and 13C NMR measurements (including J-MOD exper-
5 as the main product in high yield (65–79%). In all
cases, fragmentation was accompanied by an elimina-
tion reaction: nearly 10% of 16-methylene-3-methoxy-
13␣-estra-1,3,5(10)-trien-17␤-ol (6) was formed. A second
type of by-product (16␣-methoxymethyl-17␤-hydroxy
derivative (8)) could be observed in yield of 5–6%, due
to the substitution of the leaving group by the methanol
solvent (Scheme 2). The formation of the by-products can
readily be explained, since fragmentation reactions are
sometimes accompanied by side-reactions, such as elim-
ination or substitution [20]. Since the 16-halomethyl or
16-p-tolylsulfonyloxymethyl group is located well away
from the C-17 hydroxy function, cyclization was not ex-
pected, though nucleophilic exchange or elimination re-
actions were not hindered. Since the steric conditions for
heterolytic fragmentation exist, this latter takes place as the
main process. Fragmentation proceeds in the manner ob-
served for ␣,␥-halohydrins [21]. Fragmentation can occur
in all cases where the nucleofugal group is located distant
from the alcoholate function formed in the alkaline medium,
and therefore cyclization cannot take place.
1
iments) were made. When the similar H NMR spectra are
compared, we can assume that the singlet of the 18-methyl
hydrogens appears at different chemical shifts, depending
on whether it is a 17␣- or 17␤-substituted compound. In
the spectra of the latter derivatives, this singlet is approx-
imately 0.10–0.20 ppm upfield from that in the spectra of
17␣ derivatives, and is usually above 1.00 ppm.
Since the main halogenated compounds occurred as oils,
in contrast with the minor derivatives, they were acetylated
(3f, 3g, 3h) in order to convert them to solid form. Only 3h
remained as an oil after acetylation.
Alkaline solvolysis was performed on the following
16-halomethyl and 16-monotosyloxymethyl compounds:
3b–d, 3e. All reactions, which were carried out with KOH
in methanol under reflux for 3 h furnished the d-secosteroid

J. Wölfling et al. / Steroids 68 (2003) 451–458
457
Scheme 2. Alkaline solvolysis of 16-halomethyl- (3b–d, 4b–d) and 16-tolylsulfonyloxymethyl-17-hydroxy (3e, 4e) or 16␣-tolylsulfonyloxymethyl-17␤-
tetrahydropyranyl (3k) 13␣-estrone 3-methyl ether derivatives.
The solvolytic reactions were carried out using the 16␣,
17␤/16␤, 17␣ diastereomeric mixture as starting materials,
too. These reactions resulted in the same d-secoaldehyde
(5) as above and the same type of by-products (6, 7, 8).
This refers to the fact, that the fragmentation reactions
of the 16␤,17␣-diastereomers (4b–e) result in only one
by-product, which is formed by elimination (7). Conse-
quently, in order to obtain the d-secosteroid (5) it is not
necessary to separate the two trans isomers of the 16-halo-
or tosyloxymethyl-derivatives. This makes our fragmenta-
tion process simple and efficient.
can be assigned to the vinyl protons. NOESY experiments
proved the configurations of C-17 in 6 and 7 and of both
C-17 and C-16 in 8. In the case of 6, a cross-peak can be
observed between the signals of 18-Me and 17-H, which
confirms that 6 contains a 17␤-hydroxy function.
The ring-opening reactions of 16-halomethyl and
16-tosyloxymethyl derivatives via a simple pathway led to
the cis fragmentation product (5) in high yield. This syn-
thesis route provides a possibility for the preparation of
various kinds of novel ring-closed steroids, including new
heterocyclic compounds.
We also investigated the alkaline solvolysis of the
17-tetrahydropyranyl acetal (3k). The reaction of the main
16-tolylsulfonyloxymethyl-17-hydroxy derivative (3e) with
3,4-dihydropyran yielded two C-1ꢀꢀ epimers in a ratio of
3:2. Without separation, the mixture of the latter isomers
was subjected to alkaline solvolysis. The d-secosteroid (5)
was not formed in this reaction. After acidic hydrolysis
of the protecting group, we obtained 6 and 8 in nearly
equal amounts. The formation of 6 and 8 can be ex-
plained by the elimination or by the SN2 exchange of the
16␣-p-tolylsulfonyloxy group. This proves that the alcoho-
late function in the trans position relative to the nucleophilic
group is necessary for the fragmentation process.
Acknowledgments
The authors thank the Hungarian Scientific Research Fund
(OTKA T042673) and the Hungarian Ministry of Education
(FKFP 0110/2000) for financial support and Mrs. Györgyi
Udvarnoki (University of Göttingen, Germany) for the mass
spectra.
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