Synthesis of novel estrone analogs by incorporation of thiophenols via conjugate addition to an enone side chain

Article abstract of DOI:10.1016/j.steroids.2013.07.005

Functionalized estrogen analogs have received interest due to their unique and differing biological activity compared to their parent compounds. The synthesis of a new class of 3-methoxyestrone analogs functionalized at the C17 position possessing both alkyl and aryl substituted α,β-unsaturated ketones is described, along with their thiophenol conjugate addition products.

Full text of DOI:10.1016/j.steroids.2013.07.005

Steroids 78 (2013) 1119–1125
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis of novel estrone analogs by incorporation of thiophenols via
conjugate addition to an enone side chain
⇑
Lucas C. Kopel, Mahmoud S. Ahmed, Fathi T. Halaweish
Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Received in revised form 9 July 2013
Accepted 18 July 2013
Available online 27 July 2013
Functionalized estrogen analogs have received interest due to their unique and differing biological activ-
ity compared to their parent compounds. The synthesis of a new class of 3-methoxyestrone analogs func-
tionalized at the C17 position possessing both alkyl and aryl substituted
described, along with their thiophenol conjugate addition products.
a,b-unsaturated ketones is
Ó 2013 Published by Elsevier Inc.
Keywords:
Estrone
Aldol
Sulfa-Michael addition
Enone
Thiol
1. Introduction
ucts, creating new hybrid molecules for testing [5]. Additional
estrogen hybrids or conjugates have also been synthesized to allow
for receptor specific targeted delivery of a known drug candidate in
an effort to increase its efficacy and minimize side effects [6].
While incorporating important chemical features of estrogens
and various natural products can be effective, this is not always
necessary to see evidence of modified activity.
The estradiol metabolite 2-methoxyestradiol is an example of
one of these types of compounds (Fig.1) [7]. It has been reported
to exhibit anticancer capabilities via microtubule disruption,
anti-angiogenesis activity, and upregulation of apoptotic pathways
while no longer exhibiting estrogenic characteristics [8]. However,
as a result of 2-methoxyestradiol’s (2) low bioavailability, research
has continued into the synthesis of analogs concentrating on mod-
ifications at C2, C3, and C17 of the estrogen skeleton in an effort to
optimize their activities (Fig.1) [9].
Even simple functionalization at the C2 position of estradiol with
an adamantyl moiety provides a substrate that exhibits estrogen
receptor-independent neuroprotection and vasoactive effects [10].
While modification of the A-ring of estrone (1) has received
substantial attention, it is not the only site shown to produce inter-
esting biological activity. Incorporation of various appendages at
C17 of ring D has produced analogs that induce apoptosis in pros-
tate cancer cell lines [11], while another is capable of simultaneous
induction of autophagy and apoptosis in breast cancer cells [12]
and others have shown modest cytotoxicity in human breast, lung
and epidermoid carcinoma cell lines [13].
Estrogens (estrone (1) (Fig. 1), estradiol, and estriol) are a set of
common steroids found in both women and men that play impor-
tant roles in various physiological processes [1]. Known more for
their hormonal activities and contribution to the progression of
estrogen-dependent breast cancer [2], estrogens and particularly
their analogs have gained an increased interest due to their ability
to affect other biological processes without producing the negative
side effects associated with estrogen treatment.
The fact that minor modifications of the estrane structure can
result in extensive changes in biological activity has led to the
development of various estrane derivatives. These can be classified
into two different categories. The first consists of modification of
the steroid ring system itself, either through substitution of an
estrane core carbon atom with a heteroatom [3], or modification
of the ring systems through expansion, contraction, or additional
cyclic features [4]. The second category involves addition of one
or more functional groups to the estrane core structure. The most
common of which tends to be the latter due to the extensive syn-
thetic work that is necessary for the incorporation of heteroatoms
into the steroid structure.
A number of research groups have been able to expand upon the
known biological activity of estrogen compounds by combining
them with important structural features from other natural prod-
⇑
Corresponding author. Address: Department of Chemistry
South Dakota State University, Box 2202, Brookings, SD 57007, USA. Tel.: +1 605
688 4269.
& Biochemistry,
In an attempt to investigate further the biological activity asso-
ciated with the C17 functionalized estrone (1) structure and its
E-mail address: fathi.halweish@sdstate.edu (F.T. Halaweish).
0039-128X/$ - see front matter Ó 2013 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.steroids.2013.07.005

1120
L.C. Kopel et al. / Steroids 78 (2013) 1119–1125
butoxide in 2 portions (7.36 g, 65.5 mmol) at room temperature
O
OH
for 1 h. To this solution was added estrone 3-methyl ether
(6.66 g, 23.4 mmol) in a mixture of THF:DMSO (1:1, 200 mL) and
then allowed to stir at 70 °C for 5 h. After cooling to room temper-
ature, saturated NH4Cl (150 mL) was added to quench the reaction
mixture and the aqueous layer was extracted with Et2O
(3 ꢀ 200 mL) and the combined organic layers were washed with
saturated NaCl (1x75 mL), dried (Na2SO4), and concentrated in va-
cuo. The crude material was purified by silica gel column chroma-
tography with hexanes/EtOAc (gradient; 95:5–9:1–4:1) to yield
alkene 6 (6.1 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3)
d 7.20 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 8.7, 2.8 Hz, 1H), 6.62 (d,
J = 2.7 Hz, 1H), 5.15 (qt, J = 7.2, 2.0 Hz, 1H), 3.77 (s, 3H), 2.96–
2.78 (m, 2H), 2.47–2.17 (m, 5H), 1.97–1.88 (m, 1H), 1.79–1.67
(m, 2H), 1.69 (dt, J = 7.2, 2.0 Hz, 3H), 1.61–1.23 (m, 5H), 0.91 (s,
3H); 13C NMR (100 MHz, CDCl3) d 157.5, 150.4, 138.1, 133.0,
126.4, 113.9, 113.5, 111.6, 55.3, 55.3, 44.7, 43.9, 38.5, 37.4, 31.6,
30.0, 27.7, 27.1, 24.3, 17.1, 13.3.
H
H
MeO
HO
H
H
H
H
HO
estrone (1)
2-methoxyestradiol (2)
17
C
D
2
3
A
B
Fig. 1. Estrone (1), 2-methoxyestradiol (2), significant sites for activity.
side chain, a new set of estrogen-derived targets were identified for
synthesis (Scheme 1). A key intermediate in the progression of this
understanding is enone 4. The utility of the enone functionality in
organic synthesis is widely demonstrated by its use in conjugate
addition [14], cycloaddition [15], organometallic [16] and many
other types of synthetic reactions. The usefulness of the enone here
is in the formation of b-substituted aromatic thioethers via a thiol
addition to alkyl and phenyl b-substituted enones[17].
2.3. Alcohol 7
A solution of 9-BBN (0.5 M in THF, 52 mL, 26 mmol) was added
to Wittig product 6 (2.0 g, 6.7 mmol) at room temperature. The
solution was stirred until the solid starting material was dissolved,
then allowed to stir at 60 °C for 18 h. After cooling to 0 °C, 50 mL of
10% NaOH and 90 mL of 30% H2O2 were slowly added and stirred
for 1 h at 0 °C, followed by 1 h at room temperature. The aqueous
layer was extracted with ethyl acetate (3 ꢀ 100 mL) and the com-
bined organic layers were washed with saturated sodium thiosul-
fate (1 ꢀ 75 mL), dried (Na2SO4), and concentrated in vacuo. The
crude material was purified by silica gel column chromatography
with hexanes/EtOAc (4:1) to yield alcohol 7 (2.0 g, 94%) as a white
solid. 1H NMR (400 MHz, CDCl3) d 7.18 (d, J = 8.7 Hz, 1H), 6.70 (dd,
J = 8.5, 2.7 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 3.77–3.68 (m, 1H), 3.76
(s, 3H), 2.94–2.77 (m, 2H), 2.32–2.12 (m, 3H), 1.83–1.68 (m, 1H),
1.68–1.18 (m, 8H), 1.25 (d, 3H), 0.69 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 157.5, 138.1, 132.9, 126.3, 113.8, 111.5, 70.4, 58.7, 55.4,
55.3, 43.8, 42.1, 39.0, 38.5, 30.0, 27.8, 26.5, 26.0, 23.9, 23.6, 12.7.
2. Experimental
2.1. General
1H and 13C NMR spectra were acquired on a Bruker AVANCE-
400 MHz NMR spectrometer, in CDCl3 using TMS (d = 0 ppm) as
the internal standard for 1H NMR and CDCl3 (d = 77.16 ppm) for
13C NMR, with the reporting of coupling constants in Hz and the
signal multiplicities are reported as singlet (s), doublet (d), triplet
(t), quartet (q), doublet of doublets (dd), doublet of triplets (dt),
multiplet (m), or broad (br). HRMS data was obtained using EI ion-
ization on a ThermoFinnigan MAT 95 XL mass spectrometer. X-ray
crystal structure of 8 was obtained on a Bruker APEXII diffractom-
eter. TLC analysis was performed using pre-coated silica gel PE
sheets. Products were purified via column chromatography using
silica gel 40–63um (230–400 mesh), prep-plates, and reverse
phase HPLC (Alltech preparative column, Econosil C18 10u, length
250 mm, ID 22 mm). All reagents and solvents were obtained from
commercial suppliers and used as received. All chemical reactions
requiring anhydrous conditions were performed with oven-dried
glassware under an atmosphere of nitrogen.
2.4. Ketone 5
To a stirred solution of alcohol 7 (2.0 g, 6.36 mmol) in CH2Cl2
(30 mL) was added 4 Å powdered molecular sieves (2.5 g), NaOAc
(2.5 g, 30.5 mmol), and PCC (2.7 g, 12.7 mmol). The reaction mix-
ture was stirred for 2 h and then Et2O was added and the mixture
was filtered over a pad of silica gel, washing with Et2O. The filtrate
was concentrated in vacuo to give the crude material that was puri-
fied by silica gel column chromatography with hexanes/EtOAc
(4:1) to yield ketone 5 (1.9 g, 95%) as a white solid. 1H NMR
(400 MHz, CDCl3) d 7.19 (d, J = 8.6 Hz, 1H), 6.71 (dd, J = 8.6,
2.8 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 3.77 (s, 3H), 2.95–2.78 (m,
2H), 2.61 (dd, J = 9.2, 9.2 Hz, 1H), 2.34 (dddd, J = 12.9, 3.6, 3.6,
3.6 Hz, 1H), 2.29–2.19 (m, 2H), 2.19–2.12 (m, 1H), 2.15 (s, 3H),
1.94–1.85 (m, 1H), 1.84–1.24 (m, 8H), 0.65 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 209.6, 157.6, 138,0, 132.5, 126.3, 113.9,
111.6, 63.9, 55.8, 55.3, 44.5, 43.8, 39.1, 38.8, 31.6, 29.9, 27.8,
26.8, 24.2, 23.0, 13.5.
2.2. Alkene 6
To a stirred solution of ethyltriphenylphosphonium bromide
(26.1 g, 70.2 mmol) in THF (140 mL) was added potassium tert-
O
O
SR2
R1
HO
H
HO
H
20
H
H
R1
H
H
H
H
MeO
MeO
4
3
2.5. OTMS cyanohydrin 8
O
H
O
H
H
To a stirred solution of ketone 5 (1.8 g, 5.76 mmol) in CH2Cl2
(12 mL) was added ZnI2 (0.054 g, 0.17 mmol) and TMSCN (1.0 mL,
7.4 mmol). The reaction mixture was stirred for 3 h. Most of the
solvent was evaporated and the remaining slurry was taken up
in a water/EtOAc mixture (1:2, 90 mL) and the aqueous layer was
subsequently extracted with EtOAc (2 ꢀ 50 mL), dried with Na2-
H
H
H
H
HO
MeO
estrone (1)
5
Scheme 1. Retrosynthetic analysis of estrone analogs.

L.C. Kopel et al. / Steroids 78 (2013) 1119–1125
1121
SO4, and concentrated in vacuo to give the crude product. This
material was purified by silica gel column chromatography with
hexanes/EtOAc (9:1) to yield OTMS cyanohydrin 8 (1.75 g, 82%)
as a white solid. X-ray quality crystals were prepared by recrystal-
lization from hexanes. 1H NMR (400 MHz, CDCl3) d 7.17 (d,
J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.7 Hz, 1H), 6.61 (d, J = 6.7 Hz,
1H), 3.75 (s, 3H), 2.94–2.76 (m, 2H), 2.32–2.09 (m, 3H), 1.92–
1.14 (m, 11H), 1.60 (s, 3H), 0.97 (s, 3H), 0.27 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 157.5, 137.9, 132.7, 126.3, 122.1, 113.8,
111.5, 72.4, 60.5, 55.2, 54.9, 43.8, 43.8, 40.0, 38.2, 30.8, 29.8,
27.7, 26.5, 24.9, 23.9, 12.8, 1.5, 1.5, 1.5; HRMS calcd for C25H37NO2-
Si 4111.2594, found 411.2596.
gel column chromatography with hexanes/EtOAc (9:1) to yield two
diastereomers, with alkyl thioether 11a (100 mg, 39%) eluting fas-
ter than alkyl thioether 11b (110 mg, 43%) and both recovered as a
white solid. alkyl thioether11a 1H NMR (400 MHz, CDCl3) d 7.35
(d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H),
6.71 (dd, J = 8.5, 2.6 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 3.92 (s, 1H),
3.77 (s, 3H), 3.60 (dd, J = 9.9, 2.8 Hz, 1H), 3.02 (dd, J = 18.0,
10.0 Hz, 1H), 2.94–2.77 (m, 2H), 2.69 (dd, J = 17.9, 2.8 Hz, 1H),
2.38–2.14 (m, 3H), 1.91–0.99 (m, 11H), 1.42 (s, 3H), 1.01 (s, 9H),
0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) d 212.0, 157.6, 138.0,
136.6, 134.0, 132.8, 131.4, 131.4, 129.7, 129.7, 126.4, 113.9,
111.6, 80.4, 56.3, 55.7, 55.3, 55.3, 44.4, 43.9, 40.7, 38.8, 38.2,
36.2, 29.9, 27.8, 27.8, 27.8, 27.7, 26.7, 24.6, 23.8, 22.3, 21.2, 13.7;
HRMS calcd for C35H48O3S 548.3324, found 548.3318; alkyl thioe-
ther 11b 1H NMR (400 MHz, CDCl3) d 7.38 (d, J = 8.1 Hz, 2H), 7.19
(d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.70 (dd, J = 8.6, 2.6 Hz,
1H), 6.62 (d, J = 2.6 Hz, 1H), 3.82 (s, 1H), 3.77 (s, 3H), 3.62 (dd,
J = 8.0, 4.1 Hz, 1H), 2.89–2.77 (m, 3H), 2.38–2.14 (m, 3H), 2.31 (s,
3H), 1.91–0.99 (m, 11H), 1.48 (s, 3H), 1.00 (s, 9H), 0.90 (s, 3H);
13C NMR (100 MHz, CDCl3) d 212.3, 157.5, 138.1, 136.7, 133.8,
132.8, 131,5, 131.5, 129.8, 129.8, 126.3, 113.9, 111.6, 80.5, 55.6,
55.4, 55.4, 55.3, 44.4, 43.9, 40.7, 38.9, 38.2, 36.2, 30.0, 27.8, 27.8,
27.8, 27.7, 26.8, 24.7, 23.7, 21.7, 21.2, 13.6; HRMS calcd for
2.6. Hydroxy ketone 9
To a stirred solution of OTMS cyanohydrin 8 (1.7 g, 4.13 mmol)
in Et2O (10 mL) was added MeLi (1.6 M in Et2O, 8.0 mL, 12.4 mmol)
drop-wise at 0 °C. The reaction mixture was stirred for 2 h at 0 °C
before quenching the reaction mixture with glacial acetic acid
(1.6 mL), followed by stirring for 30 min at 0 °C. The acetic acid
was neutralized with saturated NaHCO3, the aqueous layer was
extracted with CH2Cl2 (3 ꢀ 50 mL), dried with Na2SO4, and concen-
trated in vacuo. The crude product was purified by silica gel column
chromatography with hexanes/EtOAc (9:1) to yield
a-hydroxy
C35H48O3S 548.3324, found 548.3307.
ketone 9 (1.4 g, 82%) as a white solid. 1H NMR (400 MHz, CDCl3)
d 7.16 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 8.5, 2.6 Hz, 1H), 6.62 (d,
J = 2.6 Hz, 1H), 3.97 (s, 1H), 3.76 (s, 3H), 2.93–2.75 (m, 2H), 2.36–
2.11 (m, 3H), 2.22 (s, 3H), 1.94–1.15 (m, 11H), 1.46 (s, 3H), 0.92
(s, 3H); 13C NMR (100 MHz, CDCl3) d 211.8, 157.5, 138.0, 132.6,
126.2, 113.8, 111.5, 80.1, 55.7, 55.2, 55.1, 44.2, 43.8, 40.7, 38.1,
29.9, 27.7, 26.7, 24.6, 23.7, 23.3, 22.1, 13.5; HRMS calcd for
2.9. Aryl enone 12
To a stirred solution of diisopropylamine (0.57 mL, 3.7 mmol) in
THF (11.6 mL) at ꢂ78 °C was added n-BuLi (2.5 M in hexanes,
1.52 mL, 3.7 mmol) drop-wise and stirred for 1 h at ꢂ78 °C. A solu-
tion of
a-hydroxy ketone 9 (0.40 g, 1.09 mmol) in THF (2.18 mL)
C
23H32O3 356.2351, found 356.2348.
was then added to the reaction and stirred for an additional 1 h at
ꢂ78 °C. A solution of p-methoxybenzaldehyde (0.29 g, 2.18 mmol)
in THF (14.5 mL) was then added at ꢂ78 °C and the solution was al-
lowed to slowly warm to room temperature and stirred for 20 h. The
reaction was quenched by the addition of saturated NH4Cl (20 mL),
followed by extraction of the aqueous layer with EtOAc (3 ꢀ 50 mL),
dried with Na2SO4, and concentrated in vacuo. The crude product
was purified by silica gel prep-plate chromatography, developing
6ꢀ with hexanes/EtOAc (95:5) to yield aryl enone 12 (0.30 g, 57%)
as a white solid. 1H NMR (400 MHz, CDCl3) d 7.81 (d, J = 15.5 Hz,
1H), 7.57 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 6.92 (d,
J = 8.7 Hz, 2H), 6.92 (d, J = 15.4 Hz, 1H), 6.71 (dd, J = 11.1 Hz, 1H),
6.62 (d, J = 2.6 Hz, 1H), 4.27 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.95–
2.75 (m, 2H), 2.41–2.12 (m, 3H), 1.97–1.16 (m, 11H), 1.55 (s, 3H),
0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) d 201.9, 162.1, 157.5,
145.6, 138.0, 132.8, 130.6, 130.6, 127.1, 126.3, 116.0, 114.5, 114.5,
113.8, 111.5, 79.1, 55.8, 55.5, 55.3, 55.3, 44.3, 43.9, 40.8, 38.2, 29.9,
2.7. Alkyl enone 10
To a stirred solution of a-hydroxy ketone 9 (0.50 g, 1.36 mmol)
in a 1:1 mixture of THF:water (10 mL) was added LiOHꢁH2O (0.50 g,
7.0 mmol) and pivaldehyde (0.30 mL, 2.73 mmol). The reaction
mixture was stirred at reflux for 6 h. The reaction mixture was
cooled to room temperature and the organic solvents were re-
moved. The remaining slurry was taken up in a water/CH2Cl2 mix-
ture (1:1, 80 mL) and the aqueous layer was subsequently
extracted with CH2Cl2 (2 ꢀ 40 mL), dried with Na2SO4, and concen-
trated in vacuo. The crude product was purified by silica gel column
chromatography with hexanes/EtOAc (9:1) to yield alkyl enone 10
(0.35 g, 59%) as a white solid. 1H NMR (400 MHz, CDCl3) d 7.21 (d,
J = 8.2 Hz, 1H), 7.14 (d, J = 15.5 Hz, 1H), 6.71 (dd, J = 8.5, 2.6 Hz),
6.63 (d, J = 2.5 Hz, 1H), 4.18 (s, 1H), 3.78 (s, 3H), 2.96–2.76 (m,
2H), 2.40–2.16 (m, 3H), 1.92–1.09 (m, 11H), 1.48, (s, 3H), 1.12 (s,
9H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) d 202.5, 160.9,
157.6, 138.1, 132.9, 126.4, 117.2, 113.9, 111.6, 79.1, 55.8, 55.3,
55.1, 44.4, 44.0, 40.8, 38.3, 34.3, 30.0, 28.8, 28.8, 28.7, 27.8, 26.8,
24.4, 23.8, 22.1, 13.7; HRMS calcd for C28H40O3H 424.2977, found
424.2972.
27.7, 26.7, 24.5, 23.7, 22.1, 13.7; HRMS calcd for
474.2770, found 474.2763.
C31H38O4
2.10. Aryl thioether 13
To
a
stirred solution of 4-methylthiophenol (0.104 g,
0.84 mmol) in petroleum ether (2.0 mL) was added Et3N
(0.116 mL, 0.84 mmol). This reaction mixture was then added to
a solution of aryl enone 12 (0.20 g, 0.42 mmol) dissolved in a 1:1
solution of THF:petroleum ether (2 mL), followed by stirring for
24 h. The solvent was removed and the remaining slurry was taken
up in a water/CH2Cl2 mixture (1:1, 50 mL) and the aqueous layer
was subsequently extracted with CH2Cl2 (2 ꢀ 25 mL), dried with
Na2SO4, and concentrated in vacuo. The crude product was purified
by reverse phase HPLC using MeOH:H2O to yield two diastereo-
mers, with aryl thioether 13a (45 mg, 36%) eluting faster than aryl
thioether 13b (56 mg, 44%) and both recovered as a white solid.
aryl thioether13a 1H NMR (400 MHz, CDCl3) d 7.24–7.17 (m,
2.8. Alkyl thioether 11
To
a
stirred solution of 4-methylthiophenol (0.116 g,
0.94 mmol) in petroleum ether (4.0 mL) was added Et3N
(0.127 mL, 0.94 mmol). This reaction mixture was then added to
a solution of alkyl enone 10 (0.20 g, 0.468 mmol) dissolved in
petroleum ether (4 mL), followed by stirring for 24 h. The solvent
was removed and the remaining slurry was taken up in a water/
CH2Cl2 mixture (1:1, 50 mL) and the aqueous layer was subse-
quently extracted with CH2Cl2 (2 ꢀ 25 mL), dried with Na2SO4,
and concentrated in vacuo. The crude product was purified by silica

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L.C. Kopel et al. / Steroids 78 (2013) 1119–1125
5H), 7.05 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.71 (dd, J = 8.5,
2.6 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 4.69 (dd, J = 8.4, 5.8 Hz, 1H),
3.77 (s, 3H), 3.77 (s, 3H), 3.72 (s, 1H), 3.18 (dd, J = 17.6 8.7 Hz,
1H), 3.04 (dd, J = 17.8, 5.9 Hz, 1H), 2.92–2.76 (m, 2H), 2.33–2.12
(m, 3H), 2.30 (s, 3H), 1.85–1.76 (m, 1H), 1.60–0.77 (m, 9H), 1.43
(s, 3H), 0.84 (s, 3H), 0.47–0.34 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 211.1, 159.0, 157.6, 138.1, 137.8, 133.0, 133.0, 133.0, 132.8,
130.8, 129.8, 129.8, 129.0, 129.0, 126.4, 113.9, 113.9, 113.9,
111.6, 80.3, 55.7, 55.3, 55.3, 55.2, 48.0, 44.4, 43.9, 42.8, 40.7,
38.2, 30.0, 27.8, 26.7, 24.1, 23.8, 22.1, 21.3 13.6; HRMS calcd for
[C38H46O4S, –H2O, –HSC6H4CH3] 456.2664 (13a), found 456.2658;
HRMS calcd for
C38H46O4S 598.3117 (mixture of 13a and
13b),found 598.3099;aryl thioether13b 1H NMR (400 MHz, CDCl3)
d 7.24–7.15 (m, 5H), 7.06 (d, J = 7.9 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H),
6.71 (dd, J = 8.6, 2.9 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 4.68 (dd, J = 9.4,
5.0 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.73 (s, 1H), 3.21 (dd, J = 17.7,
5.3 Hz, 1H), 2.93–2.77 (m, 2H), 2.36–2.13 (m, 3H), 2.30 (s, 3H),
1.90–1.81 (m, 1H), 1.74–1.10 (m, 9H), 1.16 (s, 3H), 0.91–0.82 (m,
1H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3) d 211.1, 159.0,
157.6, 138.1, 137.8, 133.0, 133.0, 133.0, 132.8, 130.8, 129.8,
129.8, 129.0, 129.0 126.4, 113.9, 113.9, 113.9, 111.6, 80.3, 55.7,
55.3, 55.3, 55.2, 48.0, 44.4, 43.9, 42.8, 40.7, 38.2, 30.0, 27.8, 26.7,
24.1, 23.8, 22.1, 21.3, 13.6; HRMS calcd for [C38H46O4S, –H2O, –
HSC6H4CH3] 456.2664 (13b), found 456.2664; HRMS calcd for
Fig. 2. X-ray crystal structure of 8.
the angular methyl to give alcohol 7. This was followed by an
oxidation with PCC to form ketone 5 in 92% yield [20]. Treatment
of ketone 5 with catalytic zinc iodide and TMSCN resulted in the
formation of desired nitrile 8 in 90% yield, as a single diastereomer
[21]. Although this stereocenter has previously been made via
other nucleophilic processes [22], this is the first known report
being formed via an OTMS cyanohydrin formation. The configura-
tion of the new stereocenter at C20 was shown to be (R) through
X-ray crystallography (Fig. 2) [23].
C38H46O4S 598.3117 (mixture of 13a and 13b),found 598.3099.
3. Results and discussion
The final step in the strategy for the synthesis of the estrone
analogs was designed to be a conjugate addition of an aryl thiol
to the
a
,b-unsaturated ketone of compound 4 (Scheme 1). The
Initial trials to extend the estrone side chain by one carbon
commenced by treatment of hindered nitrile 8 with methylmagne-
sium bromide with heating to 60 °C [24], failing to provide any of
the desired ketone 9. Changing reagents to the more nucleophilic
methyl lithium reagent allowed for the addition to nitrile 8, pro-
enone of 4 can be envisioned forming through an aldol coupling
reaction between the desired ketone and various aldehydes. The
required ketone for use in the aldol reaction can be formed from
either methyl Grignard or methyl lithium addition to a nitrile, with
the nitrile resulting from the OTMS cyanohydrin formation from
ketone 5. Intermediate 5 can be synthesized in 4-steps from
estrone (1) through the use of modified literature procedures.
The synthesis of ketone 9 began with protection of the C3
hydroxyl of commercially available estrone (1) as a methyl ether
[18], followed by a Wittig reaction with the ketone on ring D
(Scheme 2) [19]. This reaction provided the required olefin for
installation of the C17 side chain and C20 oxygenation. Hydrobora-
viding the
a-hydroxyl ketone 9 after an acetic acid work-up
(Scheme 2) [25].
This set the stage for diverging the syntheses of the estrone ana-
logs by reacting ketone 9 with either an alkyl or aromatic aldehyde
through an aldol reaction, with in situ elimination to provide the
desired enone. Optimized reaction conditions in the aldol reaction
of ketone 9 and pivaldehyde required the use of lithium hydroxide
as a base in a refluxing mixture of THF:H2O to produce enone 10 in
59% yield (Scheme 3) [26]. Formation of the lithium enolate derived
from ketone 9 and treatment with pivaldehyde only resulted in
tion of alkene
proceeded selectively upon heating to 60 °C in THF, opposite of
6 with 9-borabicyclo[3.3.1]nonane (9-BBN)
OH
H
O
1. MeI, KOH,
DMSO, 88%
i. 9-BBN, THF, 60 °C
ii. NaOH, H2O2
H
H
H
H
H
H
H
H
H
91%
2. THF, DMSO,
70 °C,
HO
MeO
MeO
estrone (1)
7
6
Ph3P
88%
PCC, NaOAc,
4Å MS, CH2Cl2,
92%
O
HO
TMSO
N
O
H
20
H
H
TMSCN, ZnI2,
CH2Cl2, 90%
MeLi, Et2O, 0 °C
82%
H
H
H
H
H
H
H
H
H
MeO
MeO
MeO
9
8
5
Scheme 2. Synthesis of hydroxy ketone 9.

L.C. Kopel et al. / Steroids 78 (2013) 1119–1125
1123
O
HO
H
H
H
H
MeO
O
9
O
H
H
OMe
LiOH, THF, H2O,
reflux, 59%
i. LDA, THF –78 °C
ii. THF, aldehyde
–78 °C to rt, 57%
O
O
HO
H
HO
H
H
H
H
H
H
H
OMe
MeO
MeO
12
10
HS
HS
80%,
82%,
dr 47:53
dr 48:52
Et3N, PE,
Et3N, PE, THF
O
H
O
S
S
HO
HO
H
H
H
H
H
H
OMe
H
MeO
MeO
13a/13b
11a/11b
Scheme 3. Analog synthesis via an aldol reaction and 1,4-conjugate addition of 4-methylthiophenol.
recovery of unreacted starting material. With material in hand, the
sulfa-Michael addition of 4-methylthiophenol to the acyclic ,b-
Acknowledgements
a
unsaturated ketone of 10 was attempted using triethylamine as
the base and a solvent mixture of THF and petroleum ether [17]. This
resulted in an easily separable mixture of thioether diastereomers
11 in an almost 1:1 diastereomeric ratio and good yield.
Returning to ketone 9 and p-anisaldehyde, enolate formation
using lithium diisopropylamine for the aldol reaction and in situ
elimination was determined to be optimal here compared to the
lithium hydroxide procedure previously described (Scheme 3)
[26]. These reaction conditions resulted in a greater percent con-
We wish to acknowledge the South Dakota Board of Regents-
2010 BCAAP (Biological Control and Analysis by Applied Photonics)
Center for financial support. We are also grateful to Dr. Andrew
Sykes and Vinothini Balasubramanian (University of South Dakota)
for their help in determining the X-ray structure of the OTMS cya-
nohydrin product 8 and Dr. Alice Bergmann (University of Buffalo)
for performing the high-resolution mass spectrometry.
Appendix A. Supplementary data
version and a more respectable yield. The a,b-unsaturated ketone
12 was subjected to a similar thiol addition procedure as before,
with modification of the solvent system. Again, an almost 1:1 dia-
stereomeric mixture of thioether products 13 were obtained like
before, this time requiring separation by reverse-phase HPLC
[17]. Although the sulfa-Michael addition of 4-methylthiophenol
to either enone proved to be non-selective, once the stereochemis-
try needed for activity is identified, this problem has the potential
to be resolved in the future by applying known ligands for asym-
metric conjugate addition of thiols [27].
In conclusion, novel estrone analogs featuring either alkyl or
aromatic substituted enones were synthesized and reacted with
4-methylthiophenol to form b-substituted thioethers. The biologi-
cal activity of these new estrone derived compounds are currently
being investigated and will be reported in due course, along with
additional analogs, taking advantage of the synthesized enone
functionality and the previously described reaction sequence.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.2013.07.
005.
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