Benzothieno and benzofurano annelated estranes

Article abstract of DOI:10.1016/j.steroids.2005.06.001

The preparation of estrone derived benzothieno- and benzofurano fused steroids is described. Keystep is an intramolecular thienyl(/furyl)-ene-yne cyclization of 16-ethynyl-17-heterarylestra-1,3,5(10),16-tetraenes. The cyclization was carried out under Pt as well as under Ru catalysis.

Full text of DOI:10.1016/j.steroids.2005.06.001

Steroids 70 (2005) 856–866
Benzothieno and benzofurano annelated estranes
Masataka Watanabea, Shuntaro Matakab, Thies Thiemannb,∗
a
Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Japan
b
Institute of Materials Chemistry and Engineering, Kyushu University, 6-1, Kasuga-koh-en,
Kasuga-shi, Fukuoka 816-8580, Japan
Received 11 April 2005; received in revised form 24 May 2005; accepted 2 June 2005
Available online 19 July 2005
Abstract
The preparation of estrone derived benzothieno- and benzofurano fused steroids is described. Keystep is an intramolecular thienyl(/furyl)-
ene-yne cyclization of 16-ethynyl-17-heterarylestra-1,3,5(10),16-tetraenes. The cyclization was carried out under Pt as well as under Ru
catalysis.
© 2005 Elsevier Inc. All rights reserved.
Keywords: Synthesis; Estranes; Fused steroids; Heteroaryl-ene-ynes; Diene-ynes; Cyclization
1. Introduction
reactions of tricyclic secosteroids [7,8]. Ring annelations
at C-16,C-17 in steroids in the non-estrane series, were
obtained through intermolecular Diels Alder reactions using
the steroid as the ene component [9,10], through a combina-
tion of Heck reaction and triene cyclization [11–13]. From
our previous experience, however, intermolecular reactions
with estra-1,3,5(10),16-tetraenes, in which two bonds are
formed, often proceed sluggishly. Thus, the 16,17-olefinic
moiety often needs to be activated, especially in cycload-
dition reactions. Combinations of Heck reactions with an
intramolecular cyclization often suffer from low yields as the
temperatures needed for the Heck reaction often induce the
cyclization as follow-up reactions, but often without allowing
for a completion of the second reaction. Furthermore, partial
double bond migration within the newly formed ring system
under the reaction conditions often leads to a number of
isomeric by-products. In the following, the authors present a
novel ring annelation procedure for steroids, which relies on a
Suzuki reaction, but potentially can be expanded to other C–C
bond forming reactions, in combination with the generally
little known heteroaryl-ene-yne cyclization, closely related
to the diene-yne cyclization, as the key step of the synthesis.
Here, this procedure is used for the preparation of a number
of novel 16,17-benzofurano- and benzothieno-annelated
estranes.
Recently, a number of ring annelated estranes have been
synthesized. They include compounds with a heterocyclic as
well as compounds with a carbocyclic E-ring, where the ring
annelation has been fused to positions 16,17. Some of these
pentacyclic molecules such as cyclopentano- and cyclohex-
ano annelated 3,17␤-estradiols, had a good binding affinity to
the human estradiol or progesterone receptors and have been
advanced as inhibitors of osteoporosis [1]. Ring annelation
has been used to link bioactive molecules to estranes such as
in the case of the synthesis of estrarubincin, which is a hybrid
of estrane and anthraquinone [2]. Moreover, 16,17-ring
annelated estranes have been used as key intermediates in
the synthesis of natural occurring pentacyclic triterpenoids
such as of alnusenone [3]. The routes to these ring annelated
steroids have been many-fold and include Robinson annela-
tion [4,5] for cyclohexeno-estranes and the intermolecular
Diels Alder reaction with the steroid as diene [2] and, in
the case of pyrazolo- and oxazoloestranes, intermolecular
1,3-dipolar cycloaddition reactions of estra-1,3,5(10),16-
tetraenes [6] and intramolecular 1,3-dipolar cycloaddition
∗
Corresponding author. Tel.: +81 92 583 7812; fax: +81 92 583 7894.
E-mail address: thies@cm.kyushu-u.ac.jp (T. Thiemann).
0039-128X/$ – see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2005.06.001

M. Watanabe et al. / Steroids 70 (2005) 856–866
857
2. Experimental
(86), 160 (55); HRMS found: 368.2347 calcd. for C24H32O3:
368.2347; anal. calcd. for C24H32O3: C 78.22, H 8.75; found:
C 78.07 H 8.76.
Starting material estrone (1) (Wako Pure Chemical Indus-
tries Ltd.) was used as purchased. 3-O-Methylestrone (2a)
(KOH, MeI, DMSO [14]), 3-O-benzylestrone (2b) (BnBr,
NaH, dry DMF [15]), 16-hydroxymethylene-3-O-methyl-
estrone (3a), 16-hydroxymethylene-3-O-benzylestrone (3b)
(HCO2Et, NaOMe, dry benzene [16]) and 17-bromo-16-
formyl-estra-1,3,5(10),16-tetraen-3-ol (9) [17] were syn-
thesized by procedures anaologous to ones found in the
literature. Bis(␩6-p-cymene-dichlororuthenium) was synthe-
sized according to the literature [18]. Ruthenium(III)chloride
(Kishida), phellandrene (TCI) and NH4PF6 (Aldrich) were
used as purchased. Anhydrous THF (stabilizer-free,
KANTO) and anhydrous diethyl ether (KANTO) were used
as purchased. Benzene, dichloromethane and dimethylfor-
mamide were dried over CaH2. Ethyl formate was distilled
over phosphorous pentoxide. Melting points were measured
on a Yanaco microscopic hotstage and are uncorrected. IR
spectra were measured with JASCO IR-700 and Nippon
2.2. 3-Benzyloxy-16-tert-butoxymethylene-
estra-1,3,5(10)-trien-17-one (4b)
Hydroxymethylene ketone 3b (10.0 g, 25.8 mmol) was
reacted with p-TsOH–H2O (245 mg, 1.29 mmol) and tert-
BuOH (18 mL, 190 mmol) in benzene (100 mL) according to
general procedure A. Column chromatography of the crude
material on silica gel (hexane:ether:CH2Cl2 = 2:1:1) gave 4b
as colorless prisms (9.31 g, 81%); mp: 163–165 ◦C; IR(KBr):
3062, 3029, 2976, 2936, 2858, 1711, 1636, 1604, 1500, 1454,
1371, 1310, 1285, 1263, 1234, 1161, 1126, 1089, 1055, 1036,
993, 960, 914, 885, 860, 841, 820, 732, 693, 650 cm−1
;
1H NMR (270MHz, CDCl3): δH 0.92(s, 3H, CH3, C-18),
1.27–1.63 (m, 15H), 1.97–2.11 (m, 3H), 2.27–2.39 (m, 2H),
2.66 (dd, 1H, J 14.9 Hz, J 5.9 Hz), 2.87–2.92 (m, 2H), 5.03
4
(s, 2H, PhCH2O), 6.73 (d, 1H, J 2.5 Hz, C-4), 6.78 (dd,
Denshi JIR-AQ2OM machines. H and 13C NMR spectra
1H, 3J 8.4 Hz, 4J 2.5 Hz, C-2), 7.20 (d, 1H, 3J 8.4 Hz, C-1),
7.26–7.53 (m, 6H); 13C NMR (100 MHz, CDCl3): δC 14.7,
24.7, 26.0, 26.8, 28.3, 29.7, 31.6, 37.9, 44.1, 48.7, 48.9, 70.0,
79.6, 112.3, 114.9, 115.5, 126.3, 127.4, 127.8, 128.5, 132.7,
137.3, 137.9, 148.4, 156.8, 210.4; MS (FAB, 3-nitrobenzyl
alcohol): m/z (%) 445 (MH+, 27), 444 (M+, 17), 443 (M+ − 1,
5); HRMS found: 445.2740 calcd. for C30H37O3: 445.2743;
anal. calcd. for C30H36O3: C 81.04, H 8.16; found: C 81.10
H 8.12.
1
were recorded with a JEOL EX-270 (1H at 270 MHz and
13C at 67.8 MHz) and JEOL Lambda 400 spectrometer
(1H at 395 MHz and 13C at 99.45 MHz). The chemical
shifts are relative to TMS (solvent CDCl3, unless otherwise
noted). Mass spectra were measured with a JMS-01-SG-2
spectrometer [electron impact mode (EI), 70 eV or fast atom
bombardment (FAB)]. Column chromatography was carried
out on Wakogel 300.
2.1. 16-tert-Butoxymethylene-3-methoxyestra-
2.3. 16-Formyl-3-methoxy-17-(thien-2ꢀ-yl)-
1,3,5(10)-trien-17-one (4a)—general procedure A
estra-1,3,5(10),16-tetraene (6a)—general procedure B
Hydroxymethylene ketone 3a (14.04 g, 45 mmol) was
added to a solution of p-TsOH–H2O (425 mg, 2.23 mmol)
and tert-BuOH (31 mL, 329 mmol) in benzene (200 mL).
The solution was heated under reflux with the water formed
distilled azeotropically and collected in a Dean–Stark con-
denser. After the reaction was complete, the reaction mix-
ture was diluted with CH2Cl2 (100 mL) and washed with
a conc. aqueous NaHCO3 solution (100 mL) and then with
water (3 × 200 mL). The organic layer was dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue
was subjected to column chromatography on silica gel
(hexane:ether:CH2Cl2 = 2:1:1) to give 4a (11.08 g, 67%) as
colorless prisms, mp: 149–151 ◦C; IR (KBr): 2926, 2853,
1712, 1637, 1574, 1496, 1464, 1425, 1371, 1278, 1256, 1246,
To a solution of 2-bromothiophene (0.77 mL, 8 mmol) in
dry ether (20 mL) was added a solution of n-butyllithium
in pentane (1.6 M, 5 mL) at −78 ◦C under an argon atmo-
sphere. After 1 h at −78 ◦C, the solution was stirred for
30 min at 0 ◦C. Then, the pale yellow solution was cooled
to −78 ◦C, and a solution of 4a (1.47 g, 4 mmol) in THF
(30 mL) was added and the resulting mixture was stirred
at −0 ◦C for 5 h. Then, to the reaction mixture was added
water (5 mL) and p-toluenesulfonic acid (1.52 g, 8 mmol)
and the resulting reaction solution was stirred for 15 h. After
the reaction was complete, the solution was poured into
aqueous sodium bicarbonate solution (40 mL) and extracted
with dichloromethane (3 × 60 mL. The organic phase dried
over MgSO4 and concentrated in vacuo. The residue was
subjected to column chromatography on silica gel (hex-
ane:ether:dichloromethane = 4:1:1) to give 6a (1.22 g, 81%)
as a greenish yellow powder; IR (KBr): 3074, 3032, 2928,
2901, 2846, 1650, 1617, 1573, 1496, 1457, 1431, 1376, 1319,
1279, 1250, 1227, 1168, 1123, 1091, 1017, 864, 939, 816,
787, 754, 735, 714, 698 cm−1; 1H NMR (270 MHz, CDCl3):
δH 1.09 (s, 3H, CH3, C-18), 1.20–2.44 (m, 10H), 2.74–2.96
1201, 1154, 1128, 1101, 1052, 989, 965, 900, 872, 813 cm−1
1H NMR (270 MHz, CDCl3): δH 0.92 (s, 3H, CH3, C-18),
;
3
4
1.32–2.40 (m, 19H), 2.66 (dd, 1H, J 14.7Hz, J 6.1Hz),
2.88–2.93 (m, 2H), 3.78 (s, 3H, OCH3), 6.64 (d, 1H, 4J 2.6Hz,
C-4), 6.72 (dd, 1H, 3J 8.6Hz, 4J 2.6Hz, C-2), 7.21 (d, 1H, 3J
8.6, C-1), 7.54 (s, 1H); 13C NMR (100 MHz, CDCl3): δC
14.7, 24.7, 26.1, 26.8, 28.3, 29.7, 31.6, 37.9, 44.1, 48.7, 48.9,
55.2, 111.5, 113.9, 115.5, 126.3, 132.4, 137.8, 148.4, 157.5,
210.4; MS (70 eV): m/z (%) 368 (M+, 70), 312 (100), 227
4
(m, 3H), 3.78 (s, 3H, OCH3), 6.65 (d, 1H, J 2.5Hz, C-
4), 6.71 (d.d., 1H, 3J 8.4 Hz, 4J 2.6 Hz, C-2), 7.10–7.20

858
M. Watanabe et al. / Steroids 70 (2005) 856–866
3
(270 MHz, CDCl3): δH 1.12 (s, 3H, C-18, CH3), 1.47–2.46
(m, 3H, ArH), 7.48 (d, 1H, J 4.9 Hz), 9.93 (s, 1H, CHO);
13C NMR (100 MHz, CDCl3): δC 16.5, 26.4, 27.5, 29.3,
29.6,34.6, 37.4, 43.9, 51.5, 54.0, 55.2, 111.6, 113.8, 125.9,
127.4, 128.2, 129.9, 132.2, 133.8, 137.9, 140.3, 157.6, 164.5,
190.6; MS (70 eV): m/z (%) 378 (M+, 100); HRMS found:
378.1653, calcd. for C24H26O2S: 378.1654; anal. calcd. for
C24H26O2S + 0.1H2O: C 75.79, H 6.94; found: C 75.72, H
6.98.
(m, 10H), 2.76–2.97 (m, 3H), 5.06 (s, 2H, OCH2Ph), 6.77
4
3
4
(d, 1H, J 2.5Hz, C-4), 6.80 (dd, 1H, J 8.5Hz, J 2.5Hz,
C-2), 7.13–7.51(m, 6H, C-1 and Ph), 9.95 (s, 1H, CHO);
13C NMR (100 MHz, CDCl3) δC 16.5, 26.4, 27.5, 29.3, 29.6,
34.6, 37.4, 43.9, 51.5, 54.0, 70.0, 112.4, 114.9, 126.0, 127.4,
127.4, 127.9, 128.2, 128.6, 129.9, 132.5, 133.8, 137.3, 137.9,
140.4, 156.9, 164.5, 190.7; MS (FAB, 3-nitrobenzyl alco-
hol): m/z (%) 455 (MH+, 44.1), 454 (M+, 31.89); HRMS
found: 455.2043, calcd. for C30H31O2S: 455.2045; anal.
calcd. for C30H31O2S: C 79.26, H 6.65; found: C 79.04,
H 6.63.
2.4. 16-Formyl-17-(2ꢀ-furyl)-3-methoxyestra-1,3,5(10),
16-tetraene (6b)
Furan (1.5 mL, 20 mmol) in dry THF (20 mL) was reacted
with tert-butyllithium in pentane (1.47 M, 13 mL) and then
with a solution of 4a (1.47 g, 4 mmol) in dry THF (20 mL)
according to general procedure B, using the reaction times
given in the preparation of 6a. Subsequently water (5 mL)
and p-toluensulfonic acid (1.52 g, 8 mmol) were added, the
mixture was stirred for 24 h and then subjected to a work-
up according to general procedure B. The crude material
was subjected to column chromatography on silica gel (hex-
ane:ether:dichloromethane = 5:1:1) to give 6b (948 mg, 65%)
as colorless prisms; mp: 193–194 ◦C; IR (KBr): 3115, 2988,
2933, 2853, 1644, 1612, 1586, 1497, 1463, 1327, 1281, 1255,
2.6. 17-(Benzothien-2ꢀ-yl)-3-benzyloxy-
16-formyl-estra-1,3,5(10),16-tetraene (6d)
Benzothiophene (1.9 mL, 16 mmol) in dry Et2O (40 mL)
was reacted with n-butyllithium in pentane (1.6 M, 10 mL)
and thereafter with a solution of 4b (3.56 g, 8 mmol) in dry
THF (20 mL) according to general procedure B. Thereafter,
water (5 mL) and p-toluenesulfonic acid (4.57 g, 24 mmol)
were added, the mixture was stirred for 25 h and subjected to
work-up according to general procedure B. The crude mate-
rial was separated by column chromatography on silica gel
(hexane:ether:dichloromethane = 5:1:1) to give 6d (3.42 g,
85%) as a yellow powder; mp: 162–168 ◦C; IR (KBr): 2924,
1656, 1608, 1573, 1497, 1454, 1377, 1281, 1228, 1159,
1233, 1151, 1126, 1038, 883, 871, 779, 761, 746 cm−1
;
1H NMR (270 MHz, CDCl3): δH 1.11 (s, 3H, CH3, C-18),
1.42–2.02 (m, 6H), 2.17–2.46 (m, 4H), 2.75–2.95(m, 3H),
3.79 (s, 3H, OCH3), 6.53 (dd, 1H, 3J 1.8 Hz, 3J 3.3 Hz), 6.65
1024, 860, 837, 781, 748, 696 cm−1; H NMR (270 MHz,
1
CDCl3): δH 1.15 (s, 3H, CH3, C-18), 1.26–2.45 (m, 10H),
4
3
4
(d, 1H, J 2.6 Hz, C-1), 6.72 (dd, 1H, J 8.6 Hz, J 2.6 Hz,
3
4
2.82 (dd, 1H, J 15.6 Hz, J 6.4 Hz), 2.90–2.96 (m, 2H),
5.04 (s, 2H, OCH2Ph), 6.75 (d, 1H, 4J 2.6Hz, C-4), 6.79 (dd,
1H, 3J 8.4 Hz, 4J 2.8 Hz, C-2), 7.19 (d, 1H, 3J 8.6 Hz, C-1),
7.29–7.45 (m, 6H), 7.81–7.87 (m, 2H); 13C NMR (100 MHz,
CDCl3): δC 16.5, 26.4, 27.5, 29.4, 29.6, 34.5, 37.4, 44.0, 51.7,
54.1, 70.0, 112.4, 114.9, 120.5, 122.1, 124.0, 124.9, 125.4,
126.0, 126.6, 127.4, 127.9, 128.6, 132.5, 134.1, 137.3, 139.1,
140.8, 141.9, 156.9, 164.8, 190.5; MS (FAB, 3-nitrobenzyl
alcohol): m/z (%) 505 (MH+, 6.2), 504 (M+, 4.8); HRMS
found: 505.2198, calcd. for C34H33O2S: 505.2201 (MH+,
FAB); anal. calcd. for C34H32O2S: C 80.91, H 6.39; found:
C 80.88, H 6.41.
3
3
C-2), 7.89 (d, 1H, J 8.7Hz, C-3), 7.59 (d, 1H, J 1.6 Hz);
13C NMR (100 MHz, CDCl3): δC 16.8, 26.6, 27.4, 29.4, 29.6,
35.3, 37.2, 43.8, 50.3, 53.8, 55.2, 111.6, 111.8, 113.5, 113.8,
124.7, 125.9, 137.8, 137.9, 144.8, 149.5, 156.1, 157.6, 191.8;
MS (70eV): m/z (%) 363 (MH+, 26), 262 (M+, 100), 347
(M+ − 15, 5); HRMS found: 362.1884 calcd. for C24H26O3:
362.1882; anal. calcd. for C24H26O3: C 79.53, H 7.23; found:
C 79.29, H 7.25.
2.5. 3-Benzyloxy-16-formyl-17-(2-thienyl)-estra-
1,3,5(10),16-tetraene (6c)
2-Bromothiophene (1.6 mL, 16 mmol) in dry THF
(20 mL) was reacted with n-butyllithium in pentane (1.6 M,
10 mL) and then with a solution of 4b (3.56 g, 8 mmol) in dry
THF (40 mL) according to general procedure B, using the
reaction times given for the preparation of 6a. Then, water
(5 mL) and p-toluenesulfonic acid (7.61 g, 40 mmol) were
added, the resulting mixture was stirred for 25 h and there-
after subjected to a work-up according to general procedure
B. Column chromatography of the crude material on silica
gel (hexane:ether:dichloromethane = 5:1:1) gave 6c (2.98 g,
82%) as a yellow powder; mp: 167–168 ◦C; IR(KBr): 3075,
3032, 2928, 2901, 2846, 1650, 1610, 1573, 1496, 1457, 1431,
1376, 1319, 1279, 1250, 1227, 1168, 1123, 1091, 1017,
2.7. 3-Benzoyloxy-16-formyl-17-(thien-2ꢀ-yl)-
estra-1,3,5(10),16-tetraene (6e)—general procedure C
A mixture of bromoaldehyde 9 (183 mg, 0.4 mmol),
2-thienylboronic acid (127 mg, 1.0 mmol), Pd(PPh3)2Cl2
(15 mg, 0.02 mmol) and PPh3 (15 mg, 0.06 mmol) in DME
(3.5 mL) and 2 M aqueous Na2CO3 solution (2.5 mL) was
held at 65 ◦C for 14 h. Thereafter, the cooled solution
was poured into water (15 mL) and extracted with chlo-
roform (3 × 15 mL). The organic phase was dried over
anhydrous MgSO4 and concentrated in vacuo. The residue
was subjected to column chromatography on silica gel
(hexane:ether:CHCl3 = 4:1:1) to give 6e (170 mg, 91%) as
pale yellow crystals, mp: 203 ◦C; IR (KBr): 3078, 2928,
864, 839, 816, 787, 754, 735, 714, 698 cm−1 1H NMR
;

M. Watanabe et al. / Steroids 70 (2005) 856–866
859
(m, 4H), 8.20 (m, 2H), 10.40 (s, 1H, CHO); 13C NMR
(67.8 MHz, CDCl3) δC 16.79, 26.41, 27.22, 29.36, 35.23,
36.81, 43.93, 50.20, 53.75, 111.85, 113.51, 118.76, 121.73,
126.08, 128.52, 129.63, 130.13, 133.50, 137.58, 137.70,
138.25, 144.85, 148.79, 149.40, 156.02, 165.50, 191.83; MS
(FAB, 3-nitrobenzyl alcohol) m/z (%) 453 (MH+, 23.5);
HRMS found: 453.2069, calcd. for C30H29O4: 453.2066;
anal. calcd. for C30H28O4: C 79.62, H 6.24; found: C 79.54,
H 6.12.
2852, 1734, 1660, 1496, 1452, 1260, 1233, 1219, 1153, 1063,
1024, 709 cm−1; 1H NMR (270 MHz, CDCl3) δH 1.11 (s, 3H,
CH3, C-18), 1.56–2.32 (m, 10H), 2.81 (dd, 1H, 2J 16.5 Hz, 3J
6.5 Hz), 2.95 (m, 2H), 6.96–7.14 (m, 2H), 7.15–7.19 (m, 2H),
7.33 (d, 1H, 3J 8.4 Hz), 7.48–7.54 (m, 3H), 7.61 (m, 1H), 8.20
(d, 2H, 3J 8.1 Hz), 9.94 (s, 1H, CHO); 13C NMR (67.8 MHz,
CDCl3) δC 16.48, 26.22, 27.28, 29.27, 29.36, 34.52, 36.98,
44.08, 51.45, 53.94, 118.77, 121.74, 126.09, 127.43, 128.27,
128.53, 129.62, 129.93, 130.13, 133.51, 133.75, 137.58,
138.23, 140.26, 148.79, 164.43, 166.01, 190.69; MS (FAB, 3-
nitrobenzyl alcohol): m/z (%) 469 (4.1, MH+); HRMS found:
469.1841, calcd. for C30H29O3S: 469.1837 (MH+, FAB);
anal. calcd. for C34H32O2S: C 76.89, H 6.02; found: C 76.55,
H 6.02.
2.10. 16-Formyl-17-(thien-2ꢀ-yl)-estra-
1,3,5(10),16-tetraen-3-ol (10)
A solution of 6e (38 mg, 0.08 mmol) and NaOMe (30 mg,
0.55 mmol) in a mixture of MeOH (5 mL), THF (5 mL)
and water (1 mL) was held at reflux for 5 h. Thereafter, the
cooled solution was acidified with conc. HCl, diluted with
water (10 mL) and extracted with chloroform (3 × 15 mL).
The organic phase was dried over anhydrous MgSO4 and
concentrated in vacuo. The residue was subjected to col-
umn chromatography on silica gel (chloroform:Et2O = 1:1)
to give 10 (21 mg, 71%) as a colorless solid; mp: 207 ◦C;
IR (KBr) 3354 (s, OH), 2924, 2850, 1639, 1581, 1501,
2.8. 3-Benzoyloxy-16-formyl-17-(benzothien-2ꢀ-yl)-
estra-1,3,5(10),16-tetraene (6f)
A mixture of 9 (189 mg, 0.4 mmol), 2-benzothieny-
lboronic acid (178 mg, 1.0 mmol), Pd(PPh3)2Cl2 (15 mg,
0.02 mmol) and PPh3 (15 mg, 0.06 mmol) in DME (3.5 mL)
and 2 M aqueous Na2CO3 solution (2.5 mL) was held at
65 ◦C for 14 h. Thereafter, the solution was worked up
according to procedure C. Column chromatography of the
crude material on silica gel (hexane:ether:CHCl3 = 4:1:1)
gave 6f (155 mg, 75%) as a colorless solid; mp 184 ◦C;
IR (KBr): 2928, 1737, 1662, 1493, 1263, 1216, 1064, 746,
707 cm−1; 1H NMR (270 MHz, CDCl3) δH 1.17 (s, 3H, CH3,
1
1450, 1231, 1174 cm−1; H NMR (270 MHz, CDCl3) δH
1.10 (s, 3H, CH3, C-18), 1.40–2.44 (m, 10H), 2.78 (dd, 1H,
2J 15.5 Hz, J 6.6 Hz), 2.89 (m, 2H), 4.62 (bs, 1H, OH),
3
6.60 (dd, 1H, 3J 8.4 Hz, 4J 2.7 Hz), 6.65 (d, 1H, 4J 2.7 Hz),
7.11–7.18 (m, 3H), 7.49 (m, 1H), 9.93 (s, 1H, CHO); 13C
NMR (67.8 MHz, CDCl3) δC 16.51, 26.38, 27.40, 29.26,
29.41, 34.53, 37.30, 43.86, 51.51, 53.91, 112.76, 115.33,
120.89, 126.17, 127.41, 128.24, 129.91, 132.28, 138.19,
140.29, 153.43, 164.60, 190.72; MS (FAB, 3-nitrobenzyl
alcohol): m/z (%) 365 (MH+, 15.4). HRMS found: 365.1572,
calcd. for C23H25O2S: 365.1575 (MH+, FAB).
2
3
C-18), 1.50–2.50 (m, 10H), 2.84 (dd, 1H, J 15.5 Hz, J
6.3 Hz), 2.97 (m, 2H), 6.97–7.88 (m, 10H), 7.33 (d, 1H,
3J 8.4 Hz), 8.20 (m, 2H), 9.99 (s, 1H, CHO); 13C NMR
(67.9 MHz, CDCl3) δC 16.42, 26.21, 27.30, 29.37, 34.44,
36.99, 44.10, 51.60, 54.09, 118.79, 121.75, 122.08, 122.17,
123.71, 123.97, 124.86, 124.92, 125.37, 126.11, 126.71,
127.80, 127.96, 129.62, 130.14, 133.51, 137.53, 138.19,
141.79, 148.81, 164.65, 190.55; MS (FAB, 3-nitrobenzyl
alcohol) m/z (%) 519 (MH+, 5.6); HRMS found: 519.1993,
calcd. forC34H31O3S:519.1994;anal. calcd. forC34H30O3S:
C 78.73, H 5.83; found: C 78.73, H 5.83.
2.11. 16-(2ꢀ,2ꢀ-Dibromoethenyl)-3-methoxy-
17-(thien-2ꢀꢀ-yl)estra-1,3,5(10),16-tetraene
(7a)—general procedure D
A solution of carbontetrabromide (CBr4) (995 mg,
3 mmol) in dry CH2Cl2 (10 mL) was added to 6a (757 mg,
2 mmol) in dry CH2Cl2 (15 mL) at 0 ◦C. The reaction
mixture was stirred at RT for 17 h. Then it was poured
into water (40 mL) and extracted with CH2Cl2 (100 mL).
The organic phase was dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was subjected to column
chromatography on silica gel (hexane:ether = 4:1) to give
7a (632 mg, 58%) as colorless prisms; mp: 153–157 ◦C;
[α]D = +130◦ (chloroform, c = 0.02); IR (KBr): 3104, 3004,
2987, 2926, 2880, 2851, 1606, 1572, 1497, 1459, 1425,
1277, 1256, 1230, 1155, 1123, 1038, 870, 821, 799, 781,
705 cm−1; 1H NMR (270 MHz, CDCl3): δH 0.96 (s, 3H, CH3,
C-18), 1.46–1.78 (m, 6H), 1.99–2.11 (m, 2H), 2.30–2.42
2.9. 3-Benzoyloxy-16-formyl-17-(fur-2ꢀ-yl)-
estra-1,3,5(10),16-tetraene (6g)
A mixture of 9 (83 mg, 0.17[6] mmol), 2-furylboronic acid
(88 mg, 0.53 mmol), Pd(PPh3)2Cl2 (10 mg, 0.013 mmol) and
PPh3 (10 mg, 0.04 mmol) in DME (2.5 mL) and 2 M aqueous
Na2CO3 solution (2.0 mL) was held at 65 ◦C for 14 h. There-
after, the solution was worked up according to procedure
C. Column chromatography of the crude material on silica
gel (hexane:ether:CHCl3 = 4:1:1) gave 6g (20 mg, 25%) as
a colorless solid; mp 185 ◦C; IR (KBr) 2920, 2854, 1737,
1652, 1492, 1256, 1233, 1214, 1060, 1023, 756, 713 cm−1
;
1H NMR (270 MHz, CDCl3) δH 1.12 (s, 3H, CH3, C-18),
1.50–2.50 (m, 10H), 2.82 (dd, 1H, 2J 15.5 Hz, 3J 6.3 Hz), 2.95
(m, 2H), 6.54 (dd, 1H, 3J 3.8 Hz, 4J 1.6 Hz), 6.78 (d, 1H, 3J
3.8 Hz), 6.95–7.01(m, 2H), 7.32(d, 1H, 3J8.4 Hz), 7.48–7.64
3
4
(m, 2H), 2.57 (dd, 1H, J 15.6 Hz, J 10.5 Hz), 2.90–3.02
(m, 3H), 3.78 (s, 3H, OCH3), 6.65 (d, 1H, 4J 2.6Hz,
C-4), 6.72 (dd, 1H, 3J 8.6 Hz, 4J 2.8 Hz, C-2), 6.98 (dd, 1H,

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M. Watanabe et al. / Steroids 70 (2005) 856–866
4
3
3
3J 3.6 Hz, J 1.2 Hz), 7.08 (dd, 1H, J 5.1 Hz, J 3.6 Hz),
7.19 (d, 1H, 3J 8.6 Hz, C-1), 7.35–7.37 (m, 2H); 13C NMR
(100 MHz, CDCl3): δC 16.2, 26.5, 27.7, 29.7, 33.6, 35.2,
37.4, 44.0, 49.2, 54.8, 55.2, 88.4, 111.5, 113.8, 126.0,
126.1, 127.0, 127.7, 132.6, 134.6, 135.6, 136.4, 137.8,
150.2, 157.5; MS (FAB, 3-nitrobenzyl alcohol): m/z (%) 536
(81Br2M+, 0.98), 534 (79Br–81BrM+, 1.54); HRMS found:
534.0051 calcd. for C25H26OS79Br81Br: 534.0052; anal.
calcd. for C25H26OSBr2: C 56.19, H 4.90; found: C 56.38,
H 4.99.
(FAB, 3-nitrobenzyl alcohol): m/z (%) 612 (81Br2M+, 2),
610 (79Br–81Br M+, 2), 608 (79Br2M+, 1). HRMS found:
610.0370; calcd. for C31H30O79Br81Br: 608.0366; anal.
calcd. for C31H30OBr2: C 60.99, H 4.96; found: C 60.83,
H 5.05.
2.14. 17-(Benzothien-2ꢀ-yl)-3-benzyloxy-16-
(2ꢀꢀ,2ꢀꢀ-dibromoethenyl)-estra-1,3,5(10),16-tetraene (7d)
A solution of CBr4 (2.49 g, 7.5 mmol) in CH2Cl2 (30 mL)
was (RT, 20 h) was allowed to react with a solution of
triphenylphosphine (3.93 g, 15 mmol) and steroid 6d (2.52 g,
5 mmol) in CH2Cl2 (30 mL) and worked-up according to
general procedure D (RT, 20 h). The crude material was
subjected to column chromatography on silica gel (hex-
ane:ether = 10:1) to give 7d (2.03 g, 61.5%) as a light brown
solid; mp: 86–88 ◦C; IR (KBr) 3058, 3030, 2924, 2852, 1605,
1574, 1497, 1454, 1432, 1373, 1311, 1281, 1229, 1156,
1135, .1109, 1026, 934, 901, 857, 815, 795, 745, 726, 695,
652 cm−1; 1H NMR (270 MHz, CDCl3): δH 1.04 (s, 3H, CH3,
C-18), 1.44–1.84 (m, 5H), 2.01–2.15 (m, 2H), 2.27–2.42 (m,
2H), 2.56–2.66 (m, 1H), 2.91–3.09 (m, 3H), 5.05 (s, 2H,
2.12. 16-(2ꢀ,2ꢀ-Dibromoethenyl)-17—(fur-2ꢀꢀ-yl)-
3-methoxyestra-1,3,5(10),16-tetraene (7b)
CBr4 (2.59 g, 7.81 mmol) and PPh3 (4.09 g, 15.6 mmol) in
dry CH2Cl2 (15 mL) was allowed to react (17 h, RT) with 6b
(558 mg, 1.56 mmol)inCH2Cl2 (10 mL)accordingtogeneral
procedure D. Column chromatography of the crude on silica
gel (ether:hexane = 1:4) gave 7b (227 mg, 28%) as colorless
prisms. The product decomposes quickly and must be used
1
for the next step as soon as possible. H NMR (270 MHz,
CDCl3): δH 1.00 (s, 3H, CH3, C-18), 1.43–2.57 (m, 10H),
2.89–2.99 (m, 3H), 3.78 (s, 3H, OCH3), 6.35–6.39 (m, 1H),
6.44 (d, 1H, 4J 1.0 Hz), 6.65 (d, 1H, 4J 2.6Hz, C-4), 6.72 (dd,
4
3
OCH2Ph), 6.75 (d, 1H, J 2.6 Hz, C-3), 6.79 (dd, 1H, J
4
8.6 Hz, J 2.8 Hz, C-2), 7.18–7.21 (m, 2H, C-1 and ArH),
3
4
3
7.29–7.46 (m, 8H), 7.79–7.85 (m, 2H); 13C NMR (100 MHz,
CDCl3): δC 16.2, 26.5, 27.7, 29.6, 33.7, 35.2, 37.3, 44.0, 49.3,
54.9, 70.0, 89.1, 114.8, 115.0, 122.0, 123.5, 124.2, 124.3,
124.4, 126.0, 126.0, 127.4, 127.8, 128.5, 132.8, 134.3, 134.4,
136.9, 137.2, 137.3, 137.9, 139.5, 140.3, 150.4, 156.8; MS
(FAB, 3-nitrobenzyl alcohol): m/z (%) 661 (MH+, 7), 660
(M+, 7).
1H, J 8.7Hz, J 2.5Hz, C-2), 7.20 (d, 1H, J 8.6Hz, C-1),
7.49–7.72 (m, 1H); 13C NMR (100 MHz, CDCl3): δC 16.4,
26.6, 27.7, 29.7, .30.9, 33.8, 35.5, 37.2, 43.9, 48.3, 54.9, 89.2,
110.6, 111.2, 111.5 112.9, 113.8, 126.0, 133.5, 134.6, 135.0,
137.8, 142.5, 152.7, 157.5; MS (FAB, 3-nitrobenzyl alcohol):
m/z (%) 520 (81Br2M+, 2), 518 (79Br–81BrM+, 3), (79Br2M+,
52); HRMS found: 518.0285, calcd. for C25H26O2:79Br81Br:
518.0281.
2.15. 16-Ethynyl-3-methoxy-17-(thien-2ꢀ-yl)-
estra-1,3,5(10),16-tetraene (8a)
2.13. 3-Benzyloxy-16-(2ꢀ,2ꢀ-dibromoethenyl)-
17-(thien-2ꢀꢀ-yl)estra-1,3,5(10),16-tetraene (7c)
A solution of n-butyllithum in pentane (1.58 M, 2 mL)
was added to 7a (534 mg, 1 mmol) in dry THF (15 mL) at
−78 ◦C under an argon atmosphere and the resulting mix-
ture was stirred for 5 h at −78 ◦C. To the green solution was
added water (5 mL) and it was warmed to RT. After 30 min,
the organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was subjected to column chromatography
on silica gel (hexane:ether = 4:1) to give 8a (322 mg, 86%) as
colorless prisms; mp: 152–155 ◦C (dec); [α]D = +50◦ (chlo-
roform, c = 0.02); IR (KBr): 3271, 2933, 2873, 1612, 1574,
1497, 1456, 1376, 1281, 1255, 1152, 1125, 1049, 867, 843,
816, 788, 712, 650, 611 cm−1; 1H NMR (395 MHz, CDCl3)
δH 1.09 (s, 3H, CH3, C-18), 1.45–1.96 (m, 7H), 2.29–2.54
(m, 4H), 2.89–2.94 (m, 2H), 3.44 (s, 1H, alkyne), 3.79 (s, 3H,
OCH3), 6.65 (d, 1H, 4J 2.9Hz, C-4), 6.72 (dd, 1H, 3J 8.5Hz,
A solution of CBr4 (9.95 g, 30 mmol) and PPh3 (15.73 g,
60 mmol) in CH2Cl2 was allowed to react (RT, 17 h) with
6c (757 mg, 2 mmol) in CH2Cl2 (150 mL combined vol-
ume) and worked up according to general procedure D. The
crude material was subjected to column chromatography
on silica gel (hexane:ether = 4:1) to give 7c (2.55 g, 70%)
as yellow prisms; mp: 144–152 ◦C; [α]D = +135◦ (chloro-
form, c = 0.02); IR (KBr): 3102, 3030, 2992, 2929, 2854,
1606, 1573, 1542, 1498, 1453, 1427, 1372, 1280, 1234,
1171, 1122, 1027,820, 797, 732, 711, 692, 669, 652 cm−1
;
1H NMR (270 MHz, CDCl3): δH 0.99 (s, 3H, CH3, C-18),
1.48–1.86 (m, 5H), 2.02–2.19 (m, 2H), 2.32–2.43 (m, 2H),
2
3
2.58 (dd, 1H, J 15.4 Hz, J 11.4 Hz), 2.91–3.04 (m, 3H),
4
5.06 (s, H, OCH2), 6.76 (d, 1H, J 2.6 Hz, C-4), 6.81 (dd,
3
4
3
1H, J 8.5 Hz, J 2.6 Hz, C-2), 7.00 (d, 1H, J 3.5 z), 7.09
3
4
3
(dd, 1H, J 5.1 Hz, J 3.6 Hz), 7.21(d, 1H, J 8.6 Hz, C-1),
7.28–7.46 (m, 7H); 13C NMR (100 MHz, CDCl3): δC 16.2,
26.5, 27.7, 29.7, 33.6, 35.2, 37.4, 44.1, 49.2, 54.8, 70.0, 88.4,
112.3, 114.9, 126.0, 126.1, 127.0, 127.4, 127.7, 127.8, 128.5,
132.9,134.7, 135.6, 136.4, 137.3, 137.9, 150.2, 156.8; MS
4J 2.6Hz, C-2), 7.06 (dd, 1H, J 5.1Hz, J 3.9Hz), 7.20 (d,
1H, 3J 8.8 Hz), 7.30 (dd, 1H, 3J 4.9 Hz, 4J 1.0 Hz), 7.59 (dd,
1H, 3J 3.9Hz, 4J 1.0Hz); 13C NMR (100 MHz, CDCl3): δC
16.1, 26.6, 27.5, 29.6, 35.7, 37.0, 37.2, 43.8, 49.6, 54.9, 55.2,
3
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M. Watanabe et al. / Steroids 70 (2005) 856–866
861
82.9, 85.0, 111.5, 113.8, 116.7, 125.1, 126.0, 126.4, 126.7,
132.4,137.3, 137.9, 153.0, 157.6; MS (FAB, 3-nitrobenzyl
alcohol): m/z (%) 375 (MH+, 13), 374 (M+, 16); HRMS
found:374.1708, calcd. forC25H26OS:374.1704;anal. calcd.
for C25H26OS; C 80.17, H 7.00; found: C 80.08, H 7.14.
115.0 116.7, 125.1, 126.0, 126.4, 126.7, 127.5, 128.6, 132.8,
137.4, 137.9, 153.0, 156.9; MS (FAB, 3-nitrobenzylalcohol):
m/z (%) 451 (MH+, 2), 450 (M+, 2); HRMS found: 450.2016,
calcd. for C31H30OS: 450.2017.
2.18. 3-Benzyloxy-16-ethynyl-17-(benzothien-2ꢀ-yl)-
estra-1,3,5(10),16-tetraene (8d)
2.16. 16-Ethynyl-17-(fur-2ꢀ-yl)-3-methoxyestra-
1,3,5(10),16-tetraene (8b)
Dibromide 7d (119 mg, 0.18 mmol) was added to a
solution of tetrabutylammonium fluoride (Bu4NF) (282 mg,
1.08 mmol) in THF (3.6 mL) and the resulting solution
was stirred at RT for 20 h. Thereafter, the reaction mix-
ture was concentrated in vacuo and neutralized with NH4Cl.
Water (10 mL) was added and the mixture was extracted
with chloroform (3 × 15 mL), the organic phase was dried
over anhydrous MgSO4 and concentrated in vacuo. The
residuewassubjectedtocolumnchromatographyonsilicagel
(hexane:ether:CHCl3 = 3:1:1) to give 8d (57 mg, 63%) with
an impurity of the corresponding 16-bromoethynyl deriva-
tive (10 mol%); IR (KBr): 3300, 3060, 2930, 2246, 1608,
1500, 1455, 1283, 1250, 1025, 908, 730 cm−1; MS (FAB, 3-
nitrobenzyl alcohol): m/z (%) 501 (MH+, 2.9), 500 (M+, 3.3).
HRMS found: 500.2168, calcd. for C35H32OS: 500.2174.
The material was used immediately for the next step.
n-BuLi (1.58 M in pentane, 1.5 mL) was added to 7b
(196 mg, 0.38 mmol) in dry THF (5 mL) at −78 ◦C. After
4 h, water (1mL) was added and the temperature was raised
to RT. The solution was diluted with CH2Cl2 (40 mL) and
washed with water. The organic layer was dried over anhy-
drous Na2SO4 and was concentrated in vacuo. The residue
was subjected to column chromatography on silica gel (hex-
ane:ether = 4:1) to give 8b (96 mg, 71%) as a colorless
solid; mp: 149–153 ◦C; [α]D = +20◦ (chloroform, c = 0.02);
IR (KBr): 3257, 2926, 2854, 1606, 1498, 1463, 1371, 1310,
1287, 1236, 1160, 1033, 934, 897, 856, 795, 751, 630,
595 cm−1; H NMR (270 MHz, CDCl3): δH 1.06 (s, 3H,
1
CH3, C-18), 1.26–2.55 (m, 11H), 2.88–2.94 (m, 2H), 3.49
(s, 1H, alkyne), 3.78 (s, 3H, OCH3), 6.46 (dd, 1H, 3J 3.5Hz,
4
3
4J 1.8 Hz), 6.55 (d, 1H, J 2.6 Hz, C-4), 6.72 (dd, 1H, J
8.5 Hz, 4J 2.6 Hz, C-2), 7.06 (d, 1H, 3J 3.3 Hz), 7.20 (d, 1H,
3J 8.3 Hz, C-1), 7.41(d, 1H, 3J 1.8 Hz); 13C NMR (100 MHz,
CDCl3) δC 16.2, 26.6, 27.6, 29.7, 35.6, 36.9, 37.1, 44.0,
48.8, 54.8, 55.2, 82.7, 84.8, 110.1, 111.3, 111.5, 113.8, 114.9,
126.0, 132.6, 137.8, 141.3, 149.2, 151.2, 157.5; MS (FAB,
3-nitrobenzyl alcohol): m/z (%) 359 (MH+, 16), 358 (M+,
22); HRMS (FAB) found: 358.1932, calcd. for C25H26O2:
358.1933.
2.19. 3-Methoxyestra-1,3,5(10),16-tetraeno[17,16-g]-1-
thianaphthene (11a)
Acetylene 8a (318 mg, 0.85 mmol) was added to
Ru(p-cymene)Cl2PPh3 (24.2 mg, 42.6 ␮mol) and NH4PF6
(13.9 mg, 85.3 ␮mol) in dry CH2Cl2 (11 mL). The solution
was heated at 45 ◦C for 24 h under an Ar atmosphere. After
the reaction, the mixture was subjected to column chromatog-
raphy on silica gel (hexane:ether = 4:1) to give 11a (312 mg,
98%) as a pale yellow solid; mp: 179–184 ◦C; [α]D = +55◦
(chloroform, c = 0.02); IR (KBr): 3088, 3070, 2979, 2927,
2869, 2833, 1611, 1574, 1498, 1462, 1440, 1373, 1280, 1255,
1177, 1152, 1112, 1099, 1047, 1034, 975, 896, 879, 862, 843,
812, 795, 778, 714, 626 cm−1; 1H NMR (270 MHz, CDCl3):
δH 1.08 (s, 3H, CH3, C-18), 1.51–2.09 (m, 7H), 2.35–2.78
(m, 3H), 2.92–3.00 (m, 3H), 3.80 (s, 3H, OCH3), 6.67 (d,
2.17. 3-Benzyloxy-16-ethynyl-17-(thien-2ꢀ-yl)estra-
1,3,5(10),16-tetraene (8c)
A solution of CH3Li in dry diethyl ether (1.19 M, 7.35 mL,
8.1 mmol) was added to 7c (1.23 g, 2.02 mmol) in dry THF
(30 mL) at −78 ◦C under an argon atmosphere. After 5 h, the
solution was quenched with water (5 mL). The temperature
was raised to RT and the solution was diluted with CH2Cl2
(100 mL). The solution was washed with water (2 × 100 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was subjected to column chromatography on silica
gel (hexane:ether = 10:1) to give 8c (790 mg, 87%) as pale
yellow needles; mp 101 ◦C (dec); [α]D = +25◦ (chloroform,
c = 0.02); IR (KBr): 3279, 3032, 2928, 2854, 1606, 1574,
1497, 1454, 1375, 1281, 1233, 1159, 1026, 842, 794, 733,
696, 634 cm−1; 1H NMR (270 MHz, CDCl3): δH 1.09 (s, 3H,
C-18), 1.48–1.90 (m, 6H), 2.33–2.53 (m, 5H), 2.88–2.94 (m,
2H), 3.43 (s, 1H, alkyne), 5.04 (s, 2H, PhCH2O), 6.73 (d, 1H,
4J 2.8Hz, C-4), 6.79 (dd, 1H, 3J 8.5 Hz, 4J 2.8 Hz, C-2), 7.05
(dd, 1H, 3J 5.1 Hz, 3J 3.8 Hz), 7.19 (d, 1H, 3J 8.2Hz, C-1),
4
3
4
1H, J 2.8 Hz, C-4), 6.75 (dd, 1H J 8.7Hz, J 2.8 Hz, C-
2), 7.24–7.35 (m, 4H), 7.62 (d, 1H, J 7.9Hz); 13C NMR
3
(100 MHz, CDCl3): δC 16.3, 26.6, 27.9, 32.5, 35.1, 37.6,
44.3, 46.9, 55.2, 56.9, 111.5, 113.9, 121.4, 121.9, 124.1,
125.0, 126.1, 132.7, 133.5, 137.9, 138.3, 139.3, 146.9, 157.5;
MS (FAB, 3-nitrobenzyl alcohol): m/z (%) 375 (MH+, 14),
374 (M+, 20); HRMS (FAB) found: 374.1701, calcd. for
C25H26OS: 374.1704; anal. calcd. for C25H26OS–0.3H2O:
C 79.03, H 7.06; found: C 79.13, H 7.17.
2.20. 3-Methoxyestra-1,3,5(10),16-tetraeno[17,16-g]-1-
oxaindene (11b)
7.28–7.45 (m, 5H), 7.58 (dd, 1H, 3J 3.8 Hz, 4J 0.8 Hz); 13
C
NMR (100 MHz, CDCl3): δC 16.1, 26.7, 27.5, 29.7, 35.7,
37.0 37.2, 43.9, 49.6, 54.9, 70.0, 82.9, 85.1, 112.7, 114.8,
To a solution of 8b (72 mg, 0.2 mmol) in dry CH2Cl2
(3 mL) was added Ru(p-cymene)Cl2PPh3 (5.7 mg, 10 ␮mol)

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M. Watanabe et al. / Steroids 70 (2005) 856–866
and NH4PF6 (3.3 mg, 20 ␮mol) and the resulting mixture was
refluxed gently for 15 h under an argon atmosphere. The reac-
tion mixture was subjected directly to column chromatogra-
phy on silica gel (hexane:ether:dichloromethane = 4:1:1) to
give 11b (55 mg, 77%) as colorless prisms; mp: 179–180 ◦C;
chromatography on silica gel (hexane:ether = 10:1) to give
11d (19.3 mg, 47%) as a colorless solid; mp. 176 ◦C; IR
(KBr) ν 3057, 2962, 2925, 2851, 1734, 1608, 1570, 1496,
1450, 1435, 1385, 1281, 1261, 1232, 802, 763, 743, 726,
689 cm−1; 1H NMR (270 MHz, CDCl3) δH 1.11 (s, 3H, CH3,
C18), 1.52–1.63 (m, 1H), 1.74–1.83 (m, 2H), 1.86–2.08 (m,
3H), 2.38–2.57 (m, 2H), 2.66–2.82 (m, 2H), 2.93–3.03 (m,
3H), 5.06 (s, 2H, OCH2), 6.77 (d, 1H, 4J 2.6 Hz, C-4), 6.83
(dd., 1H, 3J 8.6 Hz, 4J 2.6 Hz, C-2), 7.31 (d, 1H, 3J 8.5 Hz,
C-1), 7.36–7.46 (m, 8H), 7.83–7.87 (m, 1H), 8.00 (d, 1H, 3J
7.6 Hz), 8.11–8.15 (m, 1H); 13C NMR (67.8 MHz, CDCl3)
δC 16.28, 26.51, 29.74, 32.64, 35.08, 37.52, 44.26, 46.91,
48.12, 56.73, 69.95, 112.29, 114.88, 119.36, 121.28, 121.89,
122.76, 124.22, 126.14, 126.23, 127.45, 127.85, 128.54,
128.66, 132.89, 134.92, 135.62, 137.28, 137.93, 139.31,
141.30, 147.19, 156.79;MS(FAB, 2-nitrobenzylalcohol)m/z
(%) 501 (MH+, 3.5), 500 (M+, 4.7); HRMS found: 500.2175;
calcd. for C35H32OS: 500.2174.
◦
[α]D = +55 (chloroform, c = 0.02); IR (KBr): 2970, 2916,
2854, 1611, 1575, 1495, 1419, 1281, 1254, 1141, 1033, 808,
800, 742 cm−1 1H NMR (270 MHz, CDCl3): δH 1.10(s,
;
3H, CH3, C-18), 1.51–2.08 (m, 6H), 2.36–2.51 (m, 2H,),
2.69–2.78 (m, 2H), 2.90–2.98 (m, 3H), 3.79 (s, 3H, OCH3),
6.67 (d, 1H, 4J 2.8 Hz, C-4), 6.72–6.76 (m, 2H, C-2 & ArH),
3
3
7.15 (d, 1H, J 7.8Hz, ArH), 7.26 (d, 1H, J x.2 Hz, ArH),
3
3
7.37 (d, 1H, J 7.7 Hz, ArH), 7.57(d, 1H, J 2.3 Hz, ArH);
13C NMR (100 MHz, CDCl3): δC 17.7, 26.6, 27.9, 29.8, 32.7,
35.6, 37.5, 44.3, 45.7, 106.6, 111.5, 113.9, 118.5, 120.0,
126.1, 126.5, 132.8, 136.2, 137.9, 139.5, 144.3, 150.7, 157.5;
MS (FAB, 3-nitrobenzyl alcohol): m/z (%) 359 (MH+, 26),
358 (M+, 38); HRMS found: 358.1937, calcd. for C25H26O2:
358.1933; anal. calcd. for C25H26O2–0.1H2O: C 83.34 H
7.33; found: C 83.17; H 7.51.
2.23. Cyclization of steroidal heteroaryl-ene-ynes using
Pt catalysts
2.21. 3-Benzyloxy-estra-1,3,5(10)16-tetraeno[17,16-g]-
1-thianaphthene (11c)
(a) PtCl2 (4.0 mg, 0.015 mmol) was added to a solution of
3-methoxy-16-ethynyl-17-(thien-2ꢀ-yl)-estra-1,3,5(10),
16-tetraene (8a) (56 mg, 0.15 mmol) in CH2Cl2
(2 mL) and the resulting mixture was stirred for 60 h
under reflux. The reaction mixture was subjected
to column chromatography on SiO2 (Hexane:ether:
CH2Cl2 = 6:1:1) to give 11a (35 mg, 62%).
Acetylene 8c (225 mg, 0.5 mmol) was added to a solu-
tion of Ru(p-cymene)Cl2PPh3 (14.2 mg, 25 ␮mol) and
ammonium hexafluorophosphate (8.15 mg, 50 ␮mol) in dry
CH2Cl2 (6.4 mL). The solution was heated at 45 ◦C for
20 h under an argon atmosphere. The reaction mixture was
subjected to column chromatography on silica gel (hex-
ane:ether = 10:1) to give 11c (198 mg, 88%) as white prisms;
mp: 70–72 ◦C; [α]D = +50◦ (chloroform, c = 0.02); IR (KBr):
3033, 2927, 1606, 1574, 1497, 1454, 1382, 1311, 1281,
1235, 1180, 1154, 1110, 1026, 880, 843, 814, 795, 733, 696,
628 cm−1; 1H NMR (270 MHz, CDCl3): δH 1.09 (s, 3H, CH3,
C-18), 1.21–2.08 (m, 9H), 2.37–3.00 (m, 4H), 5.06 (s, 2H,
(b) To a solution of the 3-methoxy-16-ethynyl-17-(thien-2ꢀ-
yl)-estra-1,3,5(10),16-tetraene (8a) (49 mg, 0.13 mmol)
in CH2Cl2 (2 mL), 10% Pt on carbon nano-fiber
(25.5 mg, 0.013 mmol Pt) was added and the resulting
mixture was stirred for 60 h under reflux. Then, the
catalyst was filtered off and the reaction mixture was
subjected to the column chromatography on SiO2
(hexane:ether = 4:1) to give starting material and
4
3
OCH2Ph), 6.78 (d, 1H, J 2.8 Hz, C-4), 6.82 (dd, 1H, J
4
8.3 Hz, J 2.8 Hz, C-2), 7.21–7.46 (m, 8H), 7.63 (d, 1H, J
1
7.9Hz); 13C NMR (100 MHz, CDCl3): δC 16.3, 26.6, 27.8,
29.7, 32.5, 35.1, 37.5, 44.3, 46.9, 56.8, 69.0, 70.0, 112.4,
114.8, 121.4, 121.9, 124.1, 125.0, 126.1, 127.4, 127.8, 128.5,
133.0, 133.5, 137.3, 138.0, 139.3, 146.9, 156.8; MS (FAB, 3-
nitrobenzylalcohol): m/z (%) 451 (MH+, 3.3), 450 (M+, 4.7);
HRMS found: 450.2016, calcd. for C31H30OS: 450.2017;
anal. calcd. for C31H30OS–0.5H2O: C 81.01, H 6.80; found:
C 81.00, H 6.72.
product 11a (4.5 mg, 9%) as determined by H NMR
spectroscopy.
(c) To a solution of the 3-benzyloxy-16-ethynyl-17-
(thien-2ꢀ-yl)estra-1,3,5(10),16-tetraene (8c) (135 mg,
0.3 mmol) in CH2Cl2 (5 mL), 20% PtRu on carbon
nano-fiber (44.5 mg, 0.03 mmol PtRu) was added and
the resulting mixture was stirred for 15 h under reflux.
The reaction mixture was filtrated over a short column
of SiO2 (CH2Cl2). 11c, as determined by 1H NMR
spectroscopy, was obtained in 21% yield.
2.22. 3-Benzyloxyestra-1,3,5(10),16-tetraeno[17,16-a]-
(d) To a solution of 3-benzyloxy-16-ethynyl-17-(2-thienyl)
estra-1,3,5(10),16-tetraene (8c) (135 mg, 0.3 mmol) in
CH2Cl2 (5 mL), 10% PtCl2 on carbon nano-fiber (80 mg,
0.03 mmol Pt) was added and the resulting mixture was
stirred for 15 h under reflux. Then, the reaction mixture
was filtered over a short column of SiO2 (CH2Cl2). 11c,
9-thiafluorene (11d)
Acetylene 8d (40.8 mg, 81 × 10−3 mmol) was added
to the solution of Ru(p-cymene)PPh3Cl2 (9.3 mg, 16.2 ×
10−3 mmol) and NH4PF6 (5.3 mg, 32.4 × 10−3 mmol) in
dry CH2Cl2 (4 mL) under Ar atmosphere. The solution was
stirred for 20 h under reflux. The reaction mixture was con-
centrated in vacuo. The residue was purified by column
1
as determined by H NMR spectroscopy, was obtained
in 25% yield.

M. Watanabe et al. / Steroids 70 (2005) 856–866
863
Scheme 1. Preparation of 16-ethynyl-17-hetarylestra-l,3,5(10),16-tetraen-3-ols.
3. Results and discussion
prepared by Suzuki coupling reaction of thienylboronic
acid and benzothienylboronic acid with 3-O-protected
A number of routes to substrates 8 for the final
heteroaryl-ene-yne cyclization can be envisaged, including
a Sonogashira coupling at C-16 and a Suzuki coupling at
C-17. While potentially, these reactions can even be run
in the same flask, the preparation of 16,17-dihaloestra-
1,3,5(10),16-tetraene is not straightforward. For this reason
the synthetic strategy, shown in Scheme 1, was chosen
that made use of the 1,2-addition of a lithiated arene or
heteroarene to the 17-keto group of an estrane derivative
with a protected formyl group at C-16, in form of a tert-butyl
enol ether. After regeneration of the C-16 formyl group by
hydrolysis, reaction of 6 with PPh3/CBr4 with subsequent
dehydrohalogenation [19] and debromination of the 16-
(dibromoethenyl)-substituted intermediates 7 furnished the
ene-ynes 8, substrates for the heteroaryl-ene-yne cyclization.
It must be noted that the thienyl and benzothienyl-substituted
estra-1,3,5(10),16-tetraen-16-carbaldehydes can also be
17-bromoestra-1,3,5(10),16-tetraen-16-als,
which
are
known direct Arnold–Vilsmeier reaction products of 3-O-
protected estrones [17,20], the transformation being shown
in Scheme 2. In the case of the reaction with furanboronic
acid, this transformation gave the desired product only in
poor yield, and in this case the first approach to the molecule
should be favored.
In this first approach, O-methyl and O-benzyl pro-
tected estrones 2 were transformed to the corresponding
16-hydroxymethylene derivatives in a known reaction
of 3a and 3b, respectively, with ethyl formate in the
presence of sodium methoxide. Subsequent reaction of
3a/3b with tert-butyl alcohol under acid catalysis led to
the tert-butyloxymethyleneketones 4a/4b, which effectively
protected the enolized aldehyde function in 3a/3b while
leaving a reactive keto group at C-17. After the reaction,
sometimes a small amount of starting material remained
Scheme 2. Preparation of 17-hetarylestra-l,3,5(10),16-tetraen-3-ols by Suzuki-Miyaura reaction.

864
M. Watanabe et al. / Steroids 70 (2005) 856–866
but this could easily be separated from the product by
column chromatography. These modified keto aldehydes
can be reacted with lithiated heteroaromatics, obtained from
2-thienyl bromide with n-BuLi, from furan with tert-BuLi
and from benzothiophene with n-BuLi, to give alcohols
5. The reaction gave better yields of 5 when using ether
as a solvent instead of THF. The alcohols were used in
the next step without further purification. For the cleavage
of the tert-butyl group and elimination of the hydroxyl
function, compounds 5 were treated with p-TsOH to give the
heteroaromatic ring substituted ␣,␤-unsaturated aldehydes
6a–6d in satisfactory yield. The subsequent reaction of
catalytic system for the cyclization [22]. Steroids 8 reacted
in good yield when the reactions were run in refluxing
dichloromethane. Interestingly, this reaction proceeds with-
out decomposition of the starting material. After the reaction,
sometimes a small amount of starting material remained as
can be identified by TLC analysis, but it can be separated
easily from the product by column chromatography. In many
cases, though, it was enough to remove the catalyst in the
purification of the product. The cyclization most likely pro-
ceeds via a metallo-allenylidene species [22], with a strong
polarization between the terminal acetylene and the metal
with electron density being transferred from the acetylenic
unit to the metal. No intermolecular coupling products were
observed such as those from a possible intermolecular reac-
tion of the metallocarbene with the electron rich A-ring of
the steroidal system (Scheme 3).
Next, platinum salts were used as catalysts in the
heteroaryl-ene-yne cyclization (Scheme 4). Here, the initial
idea was to induce complexation of a platinum(0) species to
the alkyne moiety in ␩2-fashion. The subsequent complex
would have significant triene character and was expected to
undergo cyclization with subsequent cleavage of the metal
species. Recently, Fuerstner and Mamane reported on the
Pt-catalyzed cyclization of 2-ethynylbiphenyls to phenan-
threnes, which incorporates aspects of the diene-yne cycliza-
tion [23]. In our case, initial experiments on the cyclization
of dihydronaphthalene based diene-ynes with Pt(PPh3)4 as
catalyst failed, however, to give any cyclized product. The
reluctance of these substrates to undergo cyclization was
thought to be due to the steric demand of Pt(PPh3)4, where
it must be noted that the alkyne moiety of the substrates
carried a terminal phenyl substituent. In the present work,
6
with carbontetrabromide/triphenylphosphine formed
dibromoethenyl substituted 7 in good yield in the case of the
thienyl and benzothienyl substituted substrates; however,
the reaction of the furan carrying 6b proceeded in lower
yield. This may be because the vinylidene bromides of the
thienyl and benzothienyl substituted compounds 6a, 6c and
6d are stable in air both as solids and in solution, while
furan-substituted 6b is not as stable under these conditions.
The yield in the case of 6b was increased a little with short-
ening of the reaction time. The compound should be used
immediately in the next reaction. In the final step to the ene-
yne products 8, the dibromovinylidenes 7 were treated with
alkyllithium, in the case of 7a and 7b with n-butyllithium or
methyllithium. Methyllithium cannot be used in the case of
benzothienyl carrying 7d as MeLi deprotonates benzothienyl
at the 6-position. However, 7d can be transformed to 8d by
reaction with Bu4NF in THF in a procedure analogous to
that reported by Katsumura and co-workers [21].
At first, a combination of Ru(p-cymene)PPh3Cl2 and
ammonium hexafluorophosphate (NH4PF6) was used as the
Scheme 3. Cyclization of 16-ethynyl-17-hetarylestra-l,3,5(10),16-tetraen-3-ols using a Ru-catalyst.

M. Watanabe et al. / Steroids 70 (2005) 856–866
865
Scheme 4. Proposed mechanism for the ruthenium catalyzed hetaryl-ene-yne cyclization according to Merlic and Pauly [22].
Table 1
Cyclization of 16-ethynyl-17-hetarylestra-l,3,5(10),16-tetraen-3-olsusingPt-catalysts under homogeneous and heterogeneous conditions
Catalyst
Ratio of metal (mol%)
Substrate
Time (h)
Yield (%
Ru(p-cymene)Cl2PPh3
PtCl2
10 wt%-PtonCNF
10 wt%-PtCl2onCNF
20 wt%-PtRu on CNF (calcd. on Pt/Rul:l)
5
10
10
10
10
8c
8a
8a
8c
8c
20
60
60
15
15
88
62
9
25
21
the much smaller PtCl2 was used as catalyst. Reaction with
thienyl-containing 8a in refluxing dichloromethane again led
to the desired cyclization product, however, in lower yield
than in the case of using Ru(p-cymene)PPh3Cl2 as catalyst.
It must also be noted that as 8a carries a non-substituted
alkyne unit, and the mechanism of the reaction in this case
is not certain, as both a ␩2-complexation of the platinum and
an end-on complexation are possible. Such end-on complex-
ations have been discussed in the absorption of acetylene
itself on Pt-surfaces, where the upright bridge bonded ␮-
vinylidene of the form Pt2 C CH2 has been characterized
by vibrational spectroscopy [24]. Laser ablated Pt atoms have
also been found to react with acetylene to form platinum
vinylidene (Pt C CH2) [25]. Interestingly, in our case, the
reaction still proceeds when run with solid supported plat-
inum species, where the solid support consists of carbon
nano-fibers [26,27]. PtCl2 doped, Pt–Ru doped as well as
Pt-doped materials could be used. While the yields need to
be optimized, cyclization occurred in all three cases. It is not
clear whether the reactions themselves take place on the sur-
face of the carbon nano-fiber or whether leached Pt is also
acting as catalyst, especially in the case of the PtCl2 doped
nano-fibers, as there have been recent studies [28] on the dis-
solution of metals such as Pd species from carbon supports
and their crystallization on the support. Further investigations
on the effect of leaching of Pt species on the activity of the
catalyst in heteroaryl-ene-yne and diene-yne cyclizations is
underway (Table 1).
Acknowledgements
The authors thank Prof. Dr. I. Mochida and Prof. Dr.
S.-H. Yoon of Kyushu University for generous gifts of CNF

866
M. Watanabe et al. / Steroids 70 (2005) 856–866
[CN28-580 ◦C, HCl treated], and the catalysts 10 wt% Pt
on CNF and 20 wt% PtRu on CNF. Ms. Yasuko Tanaka has
carried out MS and HRMS (EI and FAB) measurements.
Elemental analyses were performed at the Center for Instru-
mental Analysis, Hakozaki Campus, Kyushu University.
Part of this work has been carried out within the framework
of a CREST program. Financial support from the Japan
Science and Technology Corporation (JST) is gratefully
acknowledged.
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