Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

Article abstract of DOI:10.1016/j.bmc.2016.12.009

Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions, the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by 4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82 ± 0.01–59.7 ± 3.12 μM. The biological activity was also rationalized on the bases of docking studies.

Full text of DOI:10.1016/j.bmc.2016.12.009

Accepted Manuscript
Synthesis, Functionalization and Biological Activity of Arylated Derivatives of
(+)-Estrone
Anton Ivanov, Syeda Abida Ejaz, Syed Jawad Ali Shah, Peter Ehlers, Alexander
Villinger, Eva Frank, Gyula Schneider, János Wölfling, Qamar Rahman,
Jamshed Iqbal, Peter Langer
PII:
S0968-0896(16)31388-8
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.12.009
BMC 13436
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2016
6 December 2016
7 December 2016
Please cite this article as: Ivanov, A., Abida Ejaz, S., Jawad Ali Shah, S., Ehlers, P., Villinger, A., Frank, E.,
Schneider, G., Wölfling, J., Rahman, Q., Iqbal, J., Langer, P., Synthesis, Functionalization and Biological Activity
of Arylated Derivatives of (+)-Estrone, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/
j.bmc.2016.12.009
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1
Synthesis, Functionalization and Biological Activity of Arylated
Derivatives of (+)-Estrone
Anton Ivanov,a Syeda Abida Ejaz,d Syed Jawad Ali Shah,d Peter Ehlers,a,b Alexander Villinger,a Eva
Frank,c Gyula Schneider,c János Wölfling,c Qamar Rahman,e Jamshed Iqbal,d Peter Langera,b
*
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock,
Germany; peter.langer@uni-rostock.de
c Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
d Center for Advanced Drug Research, COMSATS Institute of Information Technology,
Abbottabad-22060, Pakistan
e Amity University, Lucknow Campus, Viraj Khand-5, Gomti Nagar, Lucknow - 226010, India
Abstract.
Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-
Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions,
the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions
and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained
by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization
reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid
moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the
compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by
4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82 0.01 to
59.7 3.12 µM. The biological activity was also rationalized on the bases of docking studies.
Graphical abstract

2
Introduction
Obesity is the fifth leading cause of death in the world and has gained much attention because of its role
in different types of cancers, including breast (postmenopausal), pancreatic, gallbladder and liver
cancer.1a The exact biological mechanisms relating obesity and cancer are complex and still not clearly
defined. However, these mechanism may include obesity-related hormones especially estrogen, growth
factors, modulation of energy balance and calorie restriction affecting the cancer cell promotion and
growth.1b Therefore, control of obesity can minimize the risk of cancer. Within the human body lipid
metabolism is controlled by the group of enzymes known as lipases.2 This group of enzymes includes
pancreatic and gastric lipases, which are responsible for the hydrolysis of triacylglycerols into free fatty
acids.3 In muscles, these free fatty acids act as a source of energy, whereas in adipose tissue they undergo
re-esterification and are ultimately stored. In comparison to gastric lipase, pancreatic lipase is mainly
involved in the digestion of dietary fats up to 50-70%.4 Thus, dietary fat is an important factor that
contributes to hyperlipidemia and associated to a variety of diseases including obesity, hypertension,
diabetes and cardiovascular problems.5 It means the inhibition of lipases can help in limiting the
hydrolysis of dietary fats which will in turn help to control the obesity.6a As a result, further complications
arising from obesity can also be prevented.
6c
Different synthetic derivatives including phenethylamine (sibutramine),6b carboxamide (rimonabant)
and lipstatin (orlistat) 6c are avialable on the market and are being used as anti-obesity drugs. Sibutramine
is a centrally acting drug which causes the inhibition of reuptake of nor-adrenaline, serotonin and
dopamine.6b Whilst, rimonabant acts through the inhibition of cannabinoid-1 receptors. Although being
effective antiobesity drugs, both of these drugs are associated with several side effects including
insomnia, headache, hypertension, palpitation, dizziness, constipation and anxiety disorders.6b,c

3
1
2
3
Figure 1: Currently avvailable anti-obesity drug (1) Sibutramine (2) rimonabant (3) orlistat.6b-c
Among above mentioned derivatives, only orlistat is considered to be acting directly through inhibition of
pancreatic lipase and is able to prevent absorption of approximately 30% of dietary fat.7a Apart from its
antiobesity activity, it can also modestly decrease blood pressure, prohibit the onset of diabetes type-2 and
improve oral glucose tolerance. The mechanism of lipase inhibition by orlistat is via its covalent bonding
to the serine which is present in the active site of the lipase.7b Despite the promising results of orlistat for
obesity treatment, it is associated with certain unpleasant gastrointestinal side effects. The most important
adverse effects are diarrhea, liquid stools, fecal urgency, flatulence, oily spotting and abdominal
cramping.8 Due to the adverse effects of orlistat, it may not be well tolerated. Many derivative of
alkaloids,9a glycosides,9b carotinoids,9c saponins,9d terpenes9e and polyphenoles9f have also been isolated
from plants and reported as pancreatic lipase inhibitors (Figure 2). Hence, it is crucial to identify different
compounds (from natural and synthetic source) to overcome obesity and its associated complications.
Therefore more researches have been focused on the identification of newer pancreatic lipase inhibitors
with less unpleasant adverse effects.
(IC50 = 15.83 1.10 µM)
(IC50 = 12 µg/mL)
(IC50 = 41.8 µM)
(IC50 >20 µM)
1
2
3
4
Figure 2: Previously reported pancreatic lipase inhibitors (1) ursolic acid (2) carnosic acid (3) cassiamin
A (4) (-)-epicatechin.9e,f
Within the human body many steroidal molecules are playing specific physiological functions. For
example, cholesterol is an essential structural component of all animal cell membranes, whereas steroid
hormones are important part of a signal system within the organisms.10 Among the steroidal hormones,
female primary sex hormones (estrogens) promote the development of female secondary sexual
characteristics and regulate the menstrual cycle.11a (+)-Estrone (1) in Figure 3, is an interesting example of
such steroidal molecules. 11b Different derivatives of estrones have been reported as anticancer agents and
used as component of oral contraceptive pills.12 Moreover, different studies have been reported on 2- and
4-substituted estrones e.g. 1-adamantyl compound ZYC-26 (2) as neuroprotective molecule against

4
cerebralischemia/reperfusion injury13a,b and 2- and 4-substituted estrones (3) derivatives as steroid
sulfatase (STS) inhibitors (Figure 3).14a-c There are, however, no studies concerning the effects of the
presence of aryl groups located at positions 2 and/or 4 on the bioactivity of steroids.
O
O
O
1
R
2
HO
HO
HO
2
4
R
Me
, ZYC-26
1
, R = H, F, CN, NO ;
2
3
2
1
, (+)-Estrone
2
R = H, NO
2
Figure 3. Estrone and its biologically active derivatives12-14
As mentioned before, 2- and/or 4-aryl-substituted estrones have only been scarcely studied and there are
only a few preparative methods towards these compounds in the literature focusing on transition metal
catalyzed CH-activation.15a, 11b However, these methods suffer from either moderate yields, requirement
of a directing group or the restriction of special nucleophiles. Moreover, non-selective arylation by
stoichiometric organo-bismuth derivatives are known to give access to the target products in low
yields.16a,b Thus, we decided to investigate the scope and limitations of the synthesis of arylated estrone
derivatives. On the basis of previous studies,9e,f it was observed that steroid derivatives isolated from
plants inhibited the pancreatic lipase, therefore, we tested our compounds as lipase inhibitors.
Results and Discussions
The Suzuki-Miyaura cross-coupling reaction is a convenient and powerful tool for diaryl synthesis and
the reaction is characterized by a good functional group tolerance. Therefore, we decided to apply this
reaction using 2- and 4-bromoestrone and 2,4-dibromoestrone as starting materials. All substrates were
easily synthesized by simple bromination17 using either N-bromosuccinimide or 1,3-dibromo-5,5-
dimethylhydantoin starting from estrone (Scheme 1).
Scheme 1. Synthesis of substrates 6 a-c. Conditions: i, 1 (1.0 equiv.), N-bromosuccinimide (1.1 equiv.),
CCl4, reflux, 3h; ii, 1 (1.0 equiv.), N-bromosuccinimide (1.1 equiv.), DCM, 20°C, 1h; iii, 1 (1.0 equiv.),
1,3-dibromo-5,5-dimethylhydantoin (1.1 equiv.), DCM, 20 °C, 1h.

5
4-Arylestrones. As a first step we decided to study the Suzuki-Miyaura reaction of 4-bromoestrone. To
our delight, application of standard reaction conditions, using 5 mol% of Pd (PPh3)4, gave the desired 4-
arylestrones 7 a-m in good to excellent yields (Scheme 2, Table 1). The application of boronic acids
containing electron-donating as well as electron-withdrawing groups gave equally good results, while
more sterically hindered o-substituted boronic acids (7 k-m) resulted in lower yields. Reduction of the
amount of catalyst to 2.5 mol% resulted in a slightly reduced yield. Using DMF instead of dioxane
resulted in a dramatically decreased yield.
Scheme 2. Synthesis of 4-arylestrones 7 a-m. Conditions: i, 6 a (1.0 equiv.), boronic acid (1.5 equiv.),
Pd(PPh3)4 (5 mol%), K3PO4 (2.0 equiv.), dioxane, 101°C, 8 h
Table 1. Synthesis of 4-arylestrones 7 a-m.
7
Ar
C6H5
7 [%]a
88
A
B
4-MeC6H4
98
C
4-t-BuC6H4
4-(MeO)C6H4
4-(F3C)C6H4
4-(F3CO)C6H4
3-FC6H4
90
D
99
E
91
F
96
G
92
H
3,5-(MeO)2C6H3
4-EtC6H4
97
I
99
J
4-ClC6H4
87
K
2-FC6H4
94
L
M
2,3,4-(MeO)3C6H2
2-(EtO)C6H4
67
79
a Isolated yields.
It is worth to be noted that, in case of o-substituted products 7 k-m new atropisomers are formed due to
hindered rotation, thus forming a mixture of two diastereomers. This was proven by the observation of
two sets of NMR signals. Interestingly, even small atoms, such as Fluor, were sufficient for the

6
occurrence of the described effect (Figure 4). The structure of 7 c was independently confirmed by X-ray
analysis (Figure 5).
Figure 4. M- and P-Atropisomers of 7 k.
Figure 5. Molecular structure of 7c (Ortep plot showing thermal ellipsoids at the 50% probability level).
2-Arylestrones. The reaction of 2-bromoestrone (6 b) with p-tolylboronic acid was next studied (Table
2). We first tested the application of the same conditions as applied for 4-bromoestrone. However, the
reactions were unsuccessful and resulted in the formation of complex mixtures. Afterwards, we applied
different catalysts, ligands, bases and solvents to find appropriate conditions. Thus, we found that the use
of Buchwald’s ligands RuPhos and SPhos were crucial to obtain desired arylated product. The use of
RuPhos gave the best yields (Table 2). The requirement of such sophisticated catalytic systems was
somehow surprising as transition metal catalysts exclusively gave 2-arylated instead of 4-arylated
15a, 11b
products in CH-activation reactions.
In particular, Bedford et al. described CH-arylation of
carbamate protected estrones with aryliodides which were mainly governed by steric effects. However, in
our case the cross-coupling reaction might be effected primarily by electronic effects as the sterically less
hindered position 2 is only addressed by a sophisticated catalyst system.

7
Table 2. Optimization of the Suzuki reaction for 2-tolylestrone 8 b.
i
Conditions: 6 b (1.0 equiv.), p-tolylboronic acid (1.5 equiv.), catalyst (5.0 mol%), ligand (5.0 mol%),
base (2.0 equiv.), solvent.
Entry
1
Catalyst
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Ligand
-
Base
Solvent T [oC] Time [h] Yield [%]
b
K3PO4
dioxane
101
101
130
130
101
101
101
101
101
101
101
105
105
101
101
20
18
20
20
22
22
22
22
28
28
28
20
20
20
20
-
-
-
-
b
b
b
2
-
Cs2CO3 dioxane
3
-
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
DMF
4
BINAP
SPhos
XPhos
RuPhos
PCy3·HBF4
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
PCy3·HBF4
-
DMF
5
dioxane
dioxane
dioxane
dioxane
dioxane
66a
b
6
-
7
75a
35a
69a
40a
63a
73a
8
9
10
11
12
13
14
15
Cs2CO3 dioxane
KF
dioxane
toluene
DMF
K2CO3
K2CO3
K2CO3
K2CO3
c
-
d
b
Pd(OAc)2
dioxane
-
b
PdCl2(PPh3)2
dioxane
-
a Isolated yields. b Low conversion of starting material. c Inseparable mixture. d 10 mol%.
With this knowledge in hand, we obtained 2-arylestrones 8 a-h in good yields. As expected, all yields
were significantly lower in comparison with the corresponding yields of 4-arylestrones, due to the lower
reactivity of this position (Table 3). Electronic properties of the substituents were not affecting the yield.
Application of o-sustituted arylboronic acids as well as p-chlorophenylboronic acid was unsuccessful.
The latter can be explained by the occurrence of the competing cross-coupling reaction between two

8
molecules of arylboronic acids. The structures of 8 c and 8 e were independently confirmed by X-ray
crystal structure analyses (Figures 6 and 7).
Table 3. Synthesis of 2-arylestrones 8 a-k.
Conditions: i, 6 b (1.0 equiv.), boronic acid (1.5 equiv.), Pd(PPh3)4 (5 mol%), RuPhos (5 mol%), K2CO3
(2.0 equiv.), dioxane, 101°C, 16 h.
8
A
B
C
D
E
F
G
H
I
Ar
8 [%]a
75
C6H5
4-MeC6H4
75
4-t-BuC6H4
4-(MeO)C6H4
4-(F3C)C6H4
4-(F3CO)C6H4
3-FC6H4
82
80
72
77
79
3,5-(MeO)2C6H3
2-FC6H4
84
b
-
b
J
2,3,4-(MeO)3C6H2
4-ClC6H4
-
b
K
-
a Isolated yields. b Inseparable mixture.

9
Figure 6. Molecular structure of 8 (Ortep plot showing thermal ellipsoids at the 50% probability level). A
solvent molecule (methanol) has been omitted for clarity.
Figure 7. Molecular structure of 8 e (Ortep plot showing thermal ellipsoids at the 50% probability level).
The disordered atoms of the CF3 group have been omitted for clarity.2,4-Diarylestrones. The conditions
used for the synthesis of 2-bromoestrone (6 b) were successfully applied to 2,4-dibromoestrone (6 c). In
contrast, the application of milder conditions used for 4-bromoestrone (6 a) resulted in the formation of
an inseparable mixture of starting material, di- and mono-substituted products. To exclude formation of
the latter we prolonged the reaction time (40 h), applied higher temperature (110 °C) and, hence, used
toluene as the solvent. The reactions provided the pure disubstituted products 9 a-o in excellent yields
(Table 4). The electronic properties of the arylboronic acids did not affect the yields, while sterically
hindered o-arylboronic acids surprisingly gave the corresponding products in good yields. In general, in
comparison with the 2-arylestrones, the products were obtained in higher yields. That fact makes us
assume that position 2 is strongly affected by the presence of either a bromine atom or an arylring located
at position 4, which influences the reactivity of this position and facilitates the reaction. The application
of only one equivalent of arylboronic acid gave an inseparable mixture of starting material, mono- and di-
arylated products, which underlines the higher reactivity of 6 c or an 4-arylated intermediated compared
to 6 b. Similar to 4-arylestrones, ortho-substituted products 9 j, 9 m and 9 n exist as a mixture of two
diastereomers. Interestingly, the presence of ortho-substituted aryl groups at position 2 did not result in
formation of an additional stereogenic axis, which can be observed by NMR spectroscopy.
Table 4. Synthesis of 2,4-arylestrones 9 a-o.

10
Conditions: i, 6 c (1.0 equiv.), boronic acid (3 equiv.), Pd(PPh3)4 (5 mol%), RuPhos (5 mol%), K2CO3
(4.0 equiv.), toluene, 110 °C, 40 h.
9
A
B
C
D
E
F
Ar
C6H5
9 [%]a
99
4-MeC6H4
4-t-BuC6H4
4-(MeO)C6H4
4-(F3C)C6H4
4-(F3CO)C6H4
3-FC6H4
91
85
99
89
79
G
H
I
85
3,5-(MeO)2C6H3
4-EtC6H4
70
99
J
2-FC6H4
97b
K
L
M
N
O
3,5-Me2C6H3
4-ClC6H4
99
24
36b
2,3,4-(MeO)3C6H2
2-(EtO)C6H4
4-FC6H4
72
74
a Isolated yields. b Reaction time: 72 h.
Further functionalization. We next synthesized, based on the Suzuki reactions described above, novel
polycyclic ring structures which contain a steroid and a dibenzofuran moiety. Treatment of 7 k with
K2CO3 in DMF at 150 °C afforded the desired product 10 in 69% yield (Scheme 3). Likewise, product 11
was synthesized starting with 9 j. Fortunately, cyclized product 11 was obtained as the only product and
no other isomer, which might derive from cyclization of the 2-fluorophenyl moiety was observed. The
structure of 11 was unambiguously confirmed by NMR spectroscopy. During the optimization, we
modified a protocol mentioned in a patent18 for a related transformation and used DMF instead of N-
methylpyrrolidone and applied a lower temperature than that reported. We also tried to prepare 10 and 11
directly from 6 a and 6 c by a one-pot protocol (Suzuki coupling and subsequent base mediated
cyclization). In this case, products 10 and 11 were isolated in 34% and 65% overall yields. Thus, the
stepwise procedure is better in terms of the yield.

11
Scheme 3. Synthesis of cyclized products 10 and 11. Conditions: i, 7 k or 9 j (1.0 equiv.), K2CO3 (2.0
equiv.), DMF, 150 °C, 4 h.
In a similar manner, we planned to perform a synthesis of lactone 12. Unfortunately, we did not achieve
to prepare the required o-carboxyphenyl derivative of any of the three substrates as an inseparable
mixture of starting material, product and side-products was obtained in all cases. However, the harsh
conditions used for the arylation of 2,4-bromoestrone, applied for 4-bromoestrone, resulted in a direct
one-pot formation of the desired lactone in good yield (Scheme 4). The structure of 12 was independently
confirmed by X-ray crystal structure analysis (Figure 8).
Scheme 4. Synthesis of lactone 12. Conditions: i, 6 a (1.0 equiv.), ortho-ethoxycarbonylphenylboronic
acid (3 equiv.), Pd(PPh3)4 (5 mol%), RuPhos (5 mol%), K2CO3 (4.0 equiv.), toluene, 110 °C, 72 h.

12
Figure 8. Molecular structure of 12 (Ortep plot showing thermal ellipsoids at the 50% probability level).
Lipase Inhibition Studies and SAR:
Different derivatives of 4-arylestrones, 2-arylestrones and 2,4-diarylestrones were synthesized and tested
for their inhibitory potential against lipase. Initial screening was performed at the final concentration of
100 µM. Most of the derivatives were found as potent inhibitors of lipase. It was observed that 4-
arylestrones exhibited a higher inhibition of lipase as compared to 2-arylestrones and 2,4-diarylestrones
derivatives. Among the 4-arylestrone derivatives, compound 7 e were found as the most potent inhibitor
having the inhibitory value of IC50 SEM = 0.82 0.01 µM. The inhibitory potential of 7 e (4-arylestrone)
was higher than 8 e (the corresponding 2-arylestrone derivative) and 9 e (the corresponding 2,4-
diarylestrone derivative) having the same substituent located at the benzene ring. Table 5 shows, that
substitution of the phenyl ring has substantial effects on the activity. Especially the introduction of
fluorine containing groups (particularly compounds 7 e and 7 g) improved the activity. Interestingly,
compound 7 c (IC50 SEM = 1.78 0.05 µM) with donating tBu-group exhibited good inhibitory activity,
too. Except compound 7 h (IC50 SEM = 59.7 3.12 µM) and 7 i (IC50 SEM = 13.6 0.99 µM), the
inhibitory activities (IC50 SEM) were in the range of 0.82 0.01 to 6.42 0.44 µM. Similarly in case of 2-
arylestrones and 2,4-diarylestrones inhibitory activity was substantially effected by the substitution
pattern. 2-Arylestrones were less active compared to their regioisomers 7, except 2-tolylestrone 8 b which
showed good activity (IC50 SEM = 1.21 0.02µM). Regarding diarylestrones, compound 9 o showed very
high activity (IC50 SEM = 0.82 0.02µM), containing again a fluorine substituent in para-position of the
arylrings. Remarkably, benzofuran derivative 11 performed very well in the studies
(IC50 SEM = 0.93 0.04µM), while 9 j with the same substituent in position 2 showed very low activity.

13
Table 5. Porcine Pancreatic lipase inhibition in the presence of the synthesized compounds.
Antilipase
acivity
Antilipase
acivity
Antilipase
acivity
Compound
Compound
Compound
IC50 (µM) SEM/% inhibition
7a
7b
7c
7d
7e
7f
1.54 0.11
38%
8c
8d
8e
8f
5.66 0.76
12.3 0.78
16.3 1.09
2.54 0.11
16.3 1.11
16.4 1.23
25.6 1.67
39%
9i
9j
41%
43%
1.78 0.05
42%
9k
24.1 1.21
1.75 0.07
37%
9l
0.82 0.01
6.42 0.44
1.34 0.11
59.7 3.12
13.6 0.99
45%
8g
8h
9a
9b
9c
9d
9e
9f
9m
9o
0.82 0.02
32%
7g
7h
7i
10
11
0.93 0.04
1.36 0.02
0.31 0.02
8.29 0.66
5.28 0.66
42%
12
7j
Orlistat
7l
43%
8a
8b
39%
1.21 0.03
7.19 0.32
1.21 0.02
9g
The experiment was carried out in triplicate at final conc. of 100 µM and IC50 values are expressed as mean SEM . IC50 is the
concentration at which 50% of the enzyme activity is inhibited.
Conclusion
In the present study, we have developed conditions for the arylation of bromoestrones by Suzuki-Miyaura
reactions. This method allows the preparation of 2-aryl-, 4-aryl- and 2,4-diaryl-estrones in good to
excellent yields. Further transformations gave access to hybrids of dibenzofuran and benzocoumarin.
Their biological activity studies showed that the synthesized compounds inhibited porcine pancreas lipase
enzyme in up to sub-micromolar concentrations. 4-Arylestrone 7 e and 2,4-diarylestrone 9 o showed the
highest inhibitory activity with an IC50=0.82 0.01 µM, followed by bezofuran-derivative 11 with
IC50 SEM = 0.93 0.04µM.
Experimental section
Chemistry
If not otherwise stated NMR data were recorded at room temperature on a Bruker AVANCE 250 MHz,
1
300 MHz or 500 MHz. Chemical shifts in ppm of H and 13C NMR spectra were referenced to residual
protons of deuterated solvents CDCl3 (1H, 7.26 ppm; 13C, 77.16 ppm) or DMSO-d6 (1H, 2,50 ppm; 13C,
39.52 ppm). Peak characterization: s = singlet, brs = broad singlet, d = doublet, t = triplet, m = multiplet,

14
dd = doublet of doublets. Infrared spectra were recorded on a Nicolet 550 FT - IR spectrometer with ATR
sampling technique. Gas-chromatography-mass-analysis was carried out on an Agilent HP-5890
instrument with an Agilent HP-5973 Mass Selective Detector (EI) and HP-5 capillary column using
helium carrier gas. ESI HRMS measurements were performed on an Agilent 1969A TOF mass
spectrometer. For High Resolution MS (HRMS) Finnigan MAT 95 XP was used. X-Ray single crystal
structure analysis was performed on a Bruker-Nonius Apex X8 CCD-diffractometer. Data of X-Ray
crystal structure analyses were deposited at the CCDC.19 Melting points were determined on a Micro-Hot-
Stage GalenTM III Cambridge Instruments. The melting points are not corrected.
4-Phenyl-3-hydroxyestra-1,3,5(10)-trien-17-one (7 a):16 4-Bromoestrone (6 a) (100 mg, 0.286 mmol),
boronic acid (1.5 equiv.), Pd(PPh3)4 (17.0 mg, 0.05 equiv.), K3PO4 (121.5 mg, 2.0 equiv.) and dioxane (4
ml) were added in a pressure tube under argon atmosphere. The mixture was stirred at 101 °C overnight.
The solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel,
heptane/EtOAc = 1:5). 7 a was isolated as a light yellow solid (87 mg, 88%), mp = 89
– 90 °C, [α]D =
+86.4° (c 1.00, CHCl3) (lit. [α]D = +83.1° (c 1.77, EtOH)). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H,
CH3), 1.31 – 1.39 (m, 1H, aliphatic), 1.45 – 1.65 (m, 5H, aliphatic), 1.87 – 2.16 (m, 4H, aliphatic), 2.26 –
3
2.33 (m, 1H, aliphatic), 2.42 – 2.58 (m, 4H, aliphatic), 4.62 (br.s, 1H, OH), 6.86 (d, JH-H = 8.6 Hz, 1H,
CHAr ), 7.24 – 7.30 (m, 3H, CHAr + CDCl3), 7.40 – 7.45 (m, 1H, CHAr), 7.48 – 7.455 (m, 2H, CHAr). 13
C
NMR (75 MHz, CDCl3): δ = 13.9 (CH3), 21.6 (CH2), 26.2 (CH2), 26.5 (CH2), 28.5 (CH2), 31.6 (CH2),
35.9 (CH2), 37.8 (CH), 44.4 (CH), 48.0 (C), 50.4 (CH), 112.6 (CH), 125.9 (CH), 127.5 (C), 128.2 (CH),
129.5 (2CH), 130.1 (CH), 130.5 (CH), 132.0 (C), 135.41 (C), 135.45 (C), 150.9 (C), 2.9 (C=O). IR (ATR,
cm−1 ):
˜ = 3363 (w), 2924 (m), 1733 (s), 1587 (w), 1472 (m), 1166 (m), 762 (m), 701 (s). MS (EI, 70
ν
eV): m/z (%) = 346 (100) [M+], 347 (27), 261 (28), 248 (14), 235 (10), 222 (28), 221 (12), 207 (10), 202
(14), 189 (10), 181 (14), 178 (10), 165 (15), 55 (11), 41 (15). HRMS (EI, 70 eV): calcd. for C24H26O2
[M+] 346.19273; found 346.19267.
4-(p-Tolyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 b): light yellow solid (102 mg, 99%), mp = 104
–
105 °C, [α]D = +78.4° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H, CH3), 1.28 – 1.39
(m, 1H, aliphatic), 1.49 – 1.63 (m, 5H, aliphatic), 1.86 – 2.18 (m, 4H, aliphatic), 2.26 – 2.34 (m, 1H,
aliphatic), 2.49 (s, 3H, CH3), 2.49 – 2.53 (m, 4H, aliphatic), 4.68 (br.s, 1H, OH), 6.84 (d, 3JH-H = 8.54 Hz,
1H, CHAr), 7.13-7.19 (m, 2H, CHAr), 7.23 – 7.26 – (m, 1H, CHAr + CDCl3), 7.30 – 7.34 (m, 2H, CHAr).
13C NMR (63 MHz, CDCl3): δ = 13.8 (CH3), 21.3 (CH3), 21.5 (CH2), 26.1 (CH2), 26.5 (CH2), 28.5
(CH2), 31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.3 (CH), 48.0 (C), 50.4 (CH), 112.5 (CHAr), 125.8 (CHAr),
127.4 (CAr), 129.9 (CHAr), 130.23 (CHAr), 130.26 (CHAr), 130.3 (CHAr), 131.9 (CAr), 132.1 (CAr), 135.5
(CAr), 137.9 (CAr), 151.0 (CAr), 220.9 (C=O). IR (ATR, cm−1 ):
(s), 1588 (w), 1473 (s), 1258 (m), 1165 (m), 1054 (m), 1008 (m), 816 (s). MS (EI, 70 eV): m/z (%) = 360
ν˜ = 3370 (w), 2923 (m), 2861 (w), 1734

15
(100) [M+], 361 (27), 275 (30), 262 (12), 236 (22), 195 (13). HRMS (EI, 70 eV): calcd. for C25H28O2 [M+]
360.20838; found 360.20841.
4-(p-tert-Butylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 c): light yellow solid (104 mg, 90%),
mp = 150
–
151 °C, [α]D = +71.5° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.92 (s, 3H, CH3),
1.32 – 1.38 (m, 1H, aliphatic), 1.38 (s, 9H, C(CH3)3), 1.49 – 1.61 (m, 5H, aliphatic), 1.87 – 2.16 (m, 4H,
aliphatic), 2.27 – 2.33 (m, 1H, aliphatic), 2.42 – 2.53 (m, 4H, aliphatic), 4.67 (br.s, 1H, OH), 6.86 (d, 3JH-
= 8.5 Hz, 1H, CHAr), 7.18 – 7.26 (m, 3H, CHAr + CDCl3), 7.50 – 7.53 (m, 2H, CHAr). 13C NMR (75
H
MHz, CDCl3): δ = 13.9 (CH3), 21.5 (CH2), 26.2 (CH2), 26.5 (CH2), 28.6 (CH2), 31.4 (C(CH3)3), 31.6
(CH2), 34.7 (C(CH3)3), 35.9 (CH2), 37.9 (CH), 44.4 (CH), 48.0 (C), 50.4 (CH), 112.5 (CHAr), 125.7
(CHAr), 126.42 (CHAr), 126.47 (CHAr), 127.4 (CAr), 129.6 (CHAr), 130.1 (CHAr), 131.9 (CAr), 132.1 (CAr),
135.7 (CAr), 151.05 (CAr), 151.10 (CAr), 221.0 (C=O). IR (ATR, cm−1):
˜ = 3306 (w), 2954 (m), 1718 (s),
ν
1585 (w), 1288 (s), 1201 (m), 1056 (m), 819 (s). MS (EI, 70 eV): m/z (%) = 402 (100) [M+], 403 (31),
387 (26), 317 (15), 278 (10), 57 (20), 55 (10), 41 (17). HRMS (EI, 70 eV): calcd. for C28H34O2 [M+]
402.25533; found 402.25473.
4-(p-Methoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 d): yellow solid (107 mg, 99%), mp =
1
97
–
98 °C, [α]D = +60.0° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.92 (s, 3H, CH3), 1.31 –
1.39 (m, 1H, aliphatic), 1.49 – 1.62 (m, 5H, aliphatic), 1.87 – 2.16 (m, 4H, aliphatic), 2.25 – 2.32 (m, 1H,
aliphatic), 2.42 – 2.53 (m, 4H, aliphatic), 3.87 (s, 3H, OCH3), 4.69 (br.s, 1H, OH), 6.85 (d, 3JH-H = 8.6 Hz,
1H, CHAr), 7.01 – 7.06 (m, 2H, CHAr), 7.16 – 7.26 (m, 3H, CHAr + CDCl3). 13C NMR (63 MHz, CDCl3):
δ = 13.8 (CH3), 21.5 (CH2), 26.1 (CH2), 26.6 (CH2), 28.5 (CH2), 31.6 (CH2), 35.9 (CH2), 37.8 (CH), 44.3
(CH), 48.0 (C), 50.4 (CH), 55.3 (OCH3), 112.4 (CHAr), 114.9 (CHAr), 115.0 (CHAr), 125.8 (CHAr), 127.1
(2CAr), 131.2 (CHAr), 131.6 (CHAr), 131.9 (CAr), 135.8 (CAr), 151.2 (CAr), 159.4 (CAr), 221.0 (C=O). IR
(ATR, cm−1 ):
˜ = 3391 (w), 2924 (m), 1733 (s), 1512 (s), 1472 (s), 1282 (m), 1242 (s), 1174 (s), 1031
ν
(s), 830 (s), 809 (s). MS (EI, 70 eV): m/z (%) = 376 (100) [M+], 377 (27), 291 (17), 252 (18). HRMS (EI,
70 eV): calcd. for C25H28O3 [M+] 376.20330; found 376.20304.
4-(p-Trifluoromethylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 e): light brown solid (108 mg,
91%), mp = 104
–
105 °C, [α]D = +85.3° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H,
CH3), 1.33 – 1.40 (m, 1H, aliphatic), 1.53 – 1.59 (m, 5H, aliphatic), 1.89 – 2.16 (m, 4H, aliphatic), 2.26 –
3
2.37 (m, 1H, aliphatic), 2.44 – 2.54 (m, 4H, aliphatic), 4.59 (br.s, 1H, OH), 6.84 (d, JH-H = 8.5 Hz, 1H,
CHAr), 7.26 – 7.29 (m, 1H, CHAr + CDCl3), 7.39 – 7.44 (m, 2H, CHAr), 7.75 – 7.78 (m, 2H, CHAr). 13C
NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 21.5 (CH2), 26.1 (CH2), 26.4 (CH2), 28.6 (CH2), 31.6 (CH2),
1
35.8 (CH2), 37.8 (CH), 44.3 (CH), 48.0 (C), 50.4 (CH), 113.1 (CHAr), 124.1 (q, JC-F = 271.7 Hz, CF3),
3
2
126.2 (m, J not given, 2CHAr), 126.40 (CAr), 126.44 (CHAr), 130.2 (q, JC-F = 32.5 Hz, CAr-CF3), 130.6
(CHAr), 130.9 (CHAr), 132.4 (CAr), 135.3 (CAr), 140.0 (CAr, 150.6 (CAr), 220.9 (C=O). 19F NMR
(282 MHz, CDCl3): δ = 62.6 (CF3). IR (ATR, cm−1):
˜ = 3318 (w), 2926 (m), 1716 (m), 1616 (w) 1321
ν

16
(s), 1159 (s), 1117 (s), 1065 (s), 835 (m). MS (EI, 70 eV): m/z (%) = 414 (100) [M+], 415 (27), 357 (12),
330 (12), 329 (25), 316 (18), 304 (12), 303 (13), 301 (10), 291 (10), 290 (27), 289 (10), 55 (12), 41 (14).
HRMS (EI, 70 eV): calcd. for C25H25O2F3 [M+] 414.18012; found 414.17903.
4-(p-Trifluoromethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 f): light yellow solid (118
1
mg, 96%), mp = 94
–
95 °C, [α]D = +83.3° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.92 (s,
3H, CH3), 1.33 – 1.39 (m, 1H, aliphatic), 1.49 – 1.63 (m, 5H, aliphatic), 1.88 – 2.16 (m, 4H, aliphatic),
2.25 – 2.33 (m, 1H, aliphatic), 2.42 – 2.54 (m, 4H, aliphatic), 4.57 (br.s, 1H, OH), 6.85 (d, 3JH-H = 8.6 Hz,
1H, CHAr), 7.25 – 7.38 (m, 5H, CHAr + CDCl3). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 21.5
(CH2), 26.1 (CH2), 26.5 (CH2), 28.9 (CH2), 31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.3 (CH), 48.0 (C), 50.4
1
(CH), 112.9 (CHAr), 120.5 (q, JC-F = 257.1 Hz, CF3), 121.8 (2CHAr), 126.2 (CAr), 126.3 (CHAr), 131.7
3
(CHAr), 132.0 (CHAr), 132.3 (CAr), 134.4 (CAr), 135.5 (CAr), 149.0 (q, JC-F = 1.9 Hz, CAr-OCF3), 150.8
(CAr), 220.9 (C=O). 19F NMR (282 MHz, CDCl3): δ = 57.7 (CF3). IR (ATR, cm−1
) ˜ = 3350 (w), 2928
ν
(w), 1723 (m), 1587 (w), 1475 (m), 1251 (s), 1154 (s), 1009 (m), 812 (m). MS (EI, 70 eV): m/z (%) = 430
(100) [M+], 431 (26), 346 (12), 345 (30), 332 (15), 320 (10), 319 (11), 306 (23), 69 (15), 55 (10), 41 (11).
HRMS (EI, 70 eV): calcd. for C25H25O3F3 [M+] 430.17503; found 430.17490.
4-(m-Fluorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 g): light yellow solid (96 mg, 92%), mp
= 98
–
99 °C, [α]D = +112.5° (c 1.00, CHCl3). A mixture of diastereomers. 1H NMR (300 MHz, CDCl3):
δ = 0.92 and 0.93 (s, 3H, CH3), 1.33 – 1.40 (m, 1H, aliphatic), 1.45 – 1.64 (m, 5H, aliphatic), 1.88 – 2.16
(m, 4H, aliphatic), 2.25 – 2.33 (m, 1H, aliphatic), 2.41 – 2.54 (m, 4H, aliphatic), 4.63 (br.s, 1H, OH), 6.85
(d, 3JH-H = 8.6 Hz, 1H, CHAr), 6.97 – 7.16 (m, 3H, CHAr), 7.18 (d, 3JH-H = 8.5 Hz, 1H, CHAr), 7.43 – 7.53
(m, 1H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 21.5 (CH2), 26.13 and 26.15 (CH2), 26.5
(CH2), 28.4 and 28.5 (CH2), 31.6 (CH2), 35.9 (CH2), 37.78 and 37.80 (CH), 44.28 and 44.34 (CH), 48.0
2
2
(C), 50.4 (CH), 112.9 (CHAr), 115.0 and 115.3 (CHAr), 117.24 (d, JC-F = 26.6 Hz) and 117.52 (d, JC-F
=
2
2
26.6 Hz) (CHAr), 125.90 (d, JC-F = 30.4 Hz) and 125.94 (d, JC-F = 30.6 Hz) (CHAr), 126.25 and 126.29
3
3
(CHAr), 126.41 (CAr), 131.03 (d, JC-F = 8.5 Hz) and 131.05 (d, JC-F = 8.7 Hz) (CHAr), 132.17 (CAr),
3
3
135.30 and 135.33 (CAr), 137.95 (d, JC-F = 7.4 Hz) and 137.97 (d, JC-F = 7.5 Hz) (CAr), 150.7 (CAr),
163.33 (d, 1JC-F = 248.3 Hz) and 163.40 (d, 1JC-F = 248.1 Hz) (CAr-F), 220.9 (C=O). 19F NMR (282 MHz,
CDCl3): δ = -111.45 and -111.53 (CF). IR (ATR, cm−1):
˜ = 3340 (w), 2925 (m), 1723 (s), 1580 (s),
ν
1472 (s), 1261 (m), 1152 (m), 1055 (m), 785 (s). MS (EI, 70 eV): m/z (%) = 364 (100) [M+], 365 (27),
307 (10), 280 (10), 279 (27), 266 (16), 253 (11), 240 (26), 239 (11), 220 (14), 199 (11), 183 (12), 55 (10),
41 (14). HRMS (EI, 70 eV): calcd. for C24H25O2F [M+] 364.18331; found 364.18327.
4-(3,5-Dimethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 h): light yellow solid (102 mg,
1
88%), mp = 95
–
96 °C, [α]D = +90.9° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.92 (s, 3H,
CH3), 1.33 – 1.40 (m, 1H, aliphatic), 1.49 – 1.65 (m, 5H, aliphatic), 1.88 – 2.16 (m, 4H, aliphatic), 2.25 –
2.34 (m, 1H, aliphatic), 2.41 – 2.60 (m, 4H, aliphatic), 3.80 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.78 (br.s,

17
1H, OH), 6.40 – 6.43 (m, 2H, CHAr), 6.50 – 6.52 (m, 1H, CHAr), 6.85 (d, 3JH-H = 8.6 Hz, 1H, CHAr), 7.23
– 7.26 (m, 1H, CHAr + CDCl3). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 21.6 (CH2), 26.1 (CH2),
26.5 (CH2), 28.2 (CH2), 31.6 (CH2), 35.9 (CH2), 37.9 (CH), 44.3 (CH), 48.0 (C), 50.4 (CH), 55.4
(2OCH3), 100.3 (CHAr), 107.5 (CHAr), 108.0 (CHAr), 112.6 (CHAr), 126.0 (CHAr), 127.5 (CAr), 131.9 (CAr),
135.2 (CAr), 137.3 (CAr), 150.7 (CAr), 161.7 (CAr), 161.8 (CAr), 220.9 (C=O). IR (ATR, cm−1):
˜ = 3400
ν
(w), 2927 (w), 1733 (m), 1587 (s), 1452 (m), 1343 (m), 1202 (s), 1150 (s), 1060 (m), 817 (m). MS (EI, 70
eV): m/z (%) = 406 (100) [M+], 407 (27), 321 (17), 282 (12), 281 (10), 55 (11), 41 (12). HRMS (ESI, 70
eV): calcd. for C26H30O4 [M+] 406.21386; found 406.21368.
4-(p-Ethylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 i): yellow solid (106 mg, 99%), mp =
110
–
111 °C, [α]D = +78.5° (c 1.02, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H, CH3), 1.31
(t, 3JH-H = 7.6 Hz, 3H, CH2CH3), 1.28 – 1.35 (m, 1H, aliphatic), 1.49 – 1.61 (m, 5H, aliphatic), 1.87 – 2.16
3
(m, 4H, aliphatic), 2.26 – 2.34 (m, 1H, aliphatic), 2.42 – 2.53 (m, 4H, aliphatic), 2.73 (q, JH-H = 7.6 Hz,
2H, CH2CH3), 4.59 (br.s, 1H, OH), 6.85 (d, 3JH-H = 8.5 Hz, 1H, CHAr), 7.16 – 7.21 (m, 2H, CHAr), 7.23 –
7.26 (m, 1H, CHAr + CDCl3), 7.32 – 7.36 (m, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3),
15.4 (CH2CH3), 21.5 (CH2), 26.1 (CH2), 26.5 (CH2), 28.5 (CH2), 28.6 (CH2CH3), 31.6 (CH2), 35.9 (CH2),
37.8 (CH), 44.3 (CH), 48.0 (C), 50.4 (CH), 112.5 (CHAr), 125.7 (CHAr), 127.5 (CAr), 129.0 (CHAr), 129.03
(CHAr), 129.9 (CHAr), 130.4 (CHAr), 131.9 (CAr), 132.4 (CAr), 135.6 (CAr), 144.2 (CAr), 151.0 (CAr), 221.0
(C=O). IR (ATR, cm−1):
˜ = 3369 (w), 2926 (m), 1734 (s), 1587 (m), 1472 (s), 1259 (s), 1165 (m), 830
ν
(s). MS (EI, 70 eV): m/z (%) = 374 (100) [M+], 375 (30), 289 (22), 276 (11), 250 (20). HRMS (EI, 70
eV): calcd. for C26H30O2 [M+] 374.22403; found 374.22323.
4-(p-Chlorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 j): light yellow solid (95 mg, 87%), mp
= 109
–
110 °C, [α]D = +71.8° (c 1.01, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.92 (s, 3H, CH3), 1.31
– 1.39 (m, 1H, aliphatic), 1.49 – 1.61 (m, 5H, aliphatic), 1.87 – 2.16 (m, 4H, aliphatic), 2.25 – 2.31 (m,
1H, aliphatic), 2.41 – 2.54 (m, 4H, aliphatic), 4.57 (br.s, 1H, OH), 6.84 (d, 3JH-H = 8.6 Hz, 1H, CHAr), 7.18
– 7.27 (m, 3H, CHAr + CDCl3), 7.46 – 7.51 (m, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3),
21.5 (CH2), 26.1 (CH2), 26.5 (CH2), 28.6 (CH2), 31.6 (CH2), 35.9 (CH2), 37.8 (CH), 44.3 (CH), 48.0 (C),
50.4 (CH), 112.8 (CHAr), 126.2 (CHAr), 126.4 (CAr), 129.7 (2CHAr), 131.5 (CHAr), 131.9 (CHAr), 132.2
(CAr), 134.1 (CAr), 134.2 (CAr), 135.4 (CAr), 150.8 (CAr), 220.9 (C=O). IR (ATR, cm−1):
˜ = 3344 (w),
ν
2926 (m), 1723 (s), 1586 (m), 1473 (s), 1285 (m), 1166 (m), 1088 (s), 1014 (m), 820 (s). MS (EI, 70 eV):
m/z (%) = 380 (100) [M+], 382 (37), 381 (26), 297 (11), 296 (10), 295 (28), 282 (18), 270 (10), 269 (12),
256 (26), 215 (13), 202 (13), 189 (11), 178 (10), 165 (11), 67 (10), 55 (16), 41 (17), 39 (10), 29 (10).
HRMS (EI, 70 eV): calcd. for C24H25O2Cl [M+] 380.15376; found 380.15281; calcd. for C24H25O237Cl
[M+] 382.15081; found 382.15141.
4-(o-Fluorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 k): brown solid (98 mg, 94%), mp = 95
–
1
96 °C, [α]D = +82.1° (c 1.44, CHCl3). A mixture of diastereomers. H NMR (300 MHz, CDCl3): δ =

18
0.92 and 0.93 (2s, 3H, CH3), 1.33 – 1.42 (m, 1H, aliphatic), 1.50 – 1.66 (m, 5H, aliphatic), 1.88 – 2.28 (m,
4H, aliphatic), 2.25 – 2.35 (m, 1H, aliphatic), 2.40 – 2.63 (m, 4H, aliphatic), 4.60 (br.s, 1H, OH), 6.85 (d,
3JH-H = 8.6 Hz, 1H, CHAr), 7.19 – 7.29 (m, 4H, CHAr + CDCl3), 7.40 – 7.47 (m, 1H, CHAr). 13C NMR (75
MHz, CDCl3): δ = 13.8 and 13.9 (CH3), 21.6 (CH2), 26.0 and 26.1 (CH2), 26.5 (CH2), 27.62 and 28.2
(CH2), 31.64 and 31.66 (CH2), 35.9 (CH2), 37.73 and 37.83 (CH), 44.21 and 44.35 (CH), 48.00 and 48.03
(C), 50.44 and 50.48 (CH), 112.85 and 112.87 (CHAr), 116.48 (d, 2JC-F = 22.2) and 116.57 (d, 2JC-F = 22.3)
(CHAr), 121.24 and 121.31 (CAr), 122.95 (d, 2JC-F = 17.8 Hz) and 122.98 (d, 2JC-F = 17.6 Hz) (CAr), 124.95
3
3
– 125.02 (several signals, CHAr, CAr), 126.6 (CHAr), 130.39 (d, JC-F = 8.0 Hz) and 130.41 (d, JC-F = 8.1
Hz) (CHAr), 132.1 – 132.4 (several signals, CHAr), 136.21 and 136.37 (CAr), 151.06 and 151.16 (CAr),
160.1 (d, 1JC-F = 246.6 Hz) and 160.4 (2d, 1JC-F = 246.9 Hz) (CAr-F), 220.97 and 221.01 (C=O). 19F NMR
(75 MHz, CDCl3): δ = -112.8 and -112.5 (CF). IR (ATR, cm−1 ):
˜ = 3342 (w), 2925 (m), 1721 (s), 1588
ν
(w), 1451 (m), 1214 (m), 1056 (m), 755 (s). MS (EI, 70 eV): m/z (%) = 364 (100) [M+], 365 (29), 280
(11), 279 (30), 266 (16), 254 (10), 253 (14), 240 (32), 239 (14), 55 (10), 41 (11). HRMS (EI, 70 eV):
calcd. for C24H25O2F [M+] 364.18331; found 364.18433.
4-(2,3,4-Trimethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 l): light yellow solid (84 mg,
1
67%), mp = 121
–
122 °C, [α]D = +82.5° (c 1.00, CHCl3). A mixture of diastereomers. H NMR (300
MHz, CDCl3): δ = 0.88 and 0.89 (2s, 3H, CH3), 1.39 – 1.69 (m, 6H, aliphatic), 1.81 – 1.99 (m, 3H,
aliphatic), 2.05 – 2.13 (m, 1H, aliphatic), 2.24 – 2.29 (m, 1H, aliphatic), 2.34 – 2.52 (m, 4H, aliphatic),
3.58 and 3.60 (2s, 3H, OCH3), 3.81 and 3.82 (2s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.68 – 6.76 (m, 2H,
CHAr), 6.83 – 6.88 (m, 1H, CHAr), 7.14 (d, 3JH-H = 8.5 Hz, 1H, CHAr), 8.800 and 8.803 (2s, 1H, OH). 13
C
NMR (63 MHz, CDCl3): δ = 13.8 and 13.9 (CH3), 21.5 (CH2), 25.9 and 26.1 (CH2), 26.5 and 26.6 (CH2),
27.5 and 28.4 (CH2), 31.6 (CH2), 35.9 (CH2), 37.8 and 37.9 (CH), 44.3 (CH), 48.0 (C), 50.45 and 50.53
(CH), 56.0 (OCH3), 61.1 (OCH3), 61.2 (OCH3), 108.1 and 108.2 (CHAr), 112.3 and 112.6 (CHAr), 121.25
and 121.33 (CAr), 123.8 and 123.9 (CAr), 125.6 and 125.9 (CHAr), 125.90 and 125.93 (CHAr), 131.9 and
132.1 (CAr), 136.3 and 136.6 (CAr), 142.9 and 143.1 (CAr), 151.1 and 151.2 (CAr), 152.0 (CAr), 154.0 (CAr),
C=O not given. IR (ATR, cm−1):
˜ = 3415 (w), 2923 (m), 1725 (s), 1588 (w), 1461 (s), 1408 (m), 1271
ν
(s), 1093 (s), 1008 (s), 795 (m). MS (EI, 70 eV): m/z (%) = 436 (100) [M+], 437 (27). HRMS (EI, 70 eV):
calcd. for C27H32O5[M+] 436.22443; found 436.22402.
4-(o-Ethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (7 m): light yellow solid (88 mg, 79%), mp
1
= 144
–
145 °C, [α]D = +77.7° (c 2.31, CHCl3). A mixture of diastereomers. H NMR (300 MHz,
3
CDCl3): δ = 0.92 and 0.93 (2s, 3H, CH3), 1.26 and 1.27 (2t, JH-H = 7.0 Hz, 3H, 2CH2CH3), 1.32 – 1.40
(m, 1H, aliphatic), 1.47 – 1.61 (m, 5H, aliphatic), 1.86 – 2.16 (m, 4H, aliphatic), 2.25 – 2.37 (m, 1H,
3
aliphatic), 2.42 – 2.53 (m, 4H, aliphatic), 4.05 (q, JH-H = 7.0 Hz, 3H, 2CH2CH3), 4.67 and 4.72 (2br.s,
3
1H, OH), 6.84 and 6.85 (2d, JH-H = 8.5 Hz, 1H, CHAr), 7.00 – 7.09 (m, 2H, CHAr), 7.14 – 7.18 (m, 1H,
CHAr), 7.22 – 7.26 (m, 1H, CHAr + CDCl3), 7.36 – 7.42 (m, 1H, CHAr). 13C NMR (63 MHz, CDCl3): δ =
13.84 and 13.87 (CH3), 14.6 and 14.7 (CH3), 21.55 and 21.57 (CH2), 25.9 and 26.1 (CH2), 26.5 and 26.6

19
(CH2), 27.2 and 28.3 (CH2), 31.7 (CH2), 35.9 (CH2), 37.8 and 37.9 (CH), 44.2 and 44.4 (CH), 47.99 and
48.01 (C), 50.5 and 50.6 (CH), 63.8 and 64.0 (CH2CH3), 112.3 and 112.6 (CHAr), 112.99 and 113.07
(CHAr), 121.3 and 121.4 (CHAr), 124.1 and 124.2 (CAr), 124.2 and 124.4 (CAr), 125.5 and 125.7 (CHAr),
129.78 and 129.83 (CHAr), 131.6 and 131.8 (CAr), 132.0 and 132.3 (CHAr), 136.0 and 136.3 (CAr), 150.9
and 151.1 (CAr), 156.3 and 156.9 (CAr), 220.6 (C=O). IR (ATR, cm−1):
˜ = 3397 (w), 2925 (w), 1733 (s),
ν
1590 (w), 1447 (s), 1341 (m), 1228 (s), 1040 (s), 922 (m), 753 (s). MS (EI, 70 eV): m/z (%) = 390 (100)
[M+], 391 (28), 305 (17), 266 (12), 29 (25). HRMS (ESI, 70 eV): calcd. for C26H30O3 [M+] 390.21895;
found 390.21851.
2-Phenyl-3-hydroxyestra-1,3,5(10)-trien-17-one (8 a):11b 2-Bromoestrone (6 b) (100 mg, 0.286 mmol),
boronic acid (1.5 equiv.), Pd(PPh3)4 (17.0 mg, 0.05 equiv.), RuPhos (6.7 mg, 0.05 equiv.), K2CO3 (79.1
mg, 2.0 equiv.) and dioxane (4 ml) were added in a pressure tube under argon atmosphere. The mixture
was stirred 16 h at 101°C. The solvent was evaporated in vacuo. The residue was purified by column
chromatography (silica gel, heptane/EtOAc = 1:5). 8a was isolated as a white solid (74 mg, 75%), mp =
197
–
198 °C (lit. 169 °C), [α]D = +161.1° (c 1.00, CHCl3) (lit. [α]D = +112.0° (c 1.00, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 0.93 (s, 3H, CH3), 1.42 – 1.70 (m, 6H, aliphatic), 1.93 – 2.20 (m, 4H, aliphatic),
2.25 – 2.35 (m, 1H, aliphatic), 2.37 – 2.57 (m, 2H, aliphatic), 2.91 – 2.96 (m, 2H, aliphatic), 5.17 (br.s,
1H, OH), 6.75 (s, 1H, CHAr), 7.17 (s, 1H, CHAr), 7.34 – 7.41 (m, 1H, CHAr), 7.46 – 7.48 (m, 4H, CHAr).
13C NMR (63 MHz, CDCl3): δ = 13.9 (CH3), 21.6 (CH2), 26.0 (CH2), 26.5 (CH2), 29.3 (CH2), 31.6
(CH2), 35.9 (CH2), 38.4 (CH), 44.0 (CH), 48.0 (C), 50.4 (CH), 115.7 (CHAr), 125.8 (CAr), 127.2 (CHAr),
127.6 (CHAr), 129.1 (2CHAr), 129.2 (2CHAr), 132.2 (CAr), 137.4 (CAr), 137.7 (CAr), 150.4 (CAr), 221.1
(C=O). IR (ATR, cm−1):
˜ = 3329 (w), 2928 (m), 1723 (s), 1614 (w), 1409 (s), 1200 (m), 893 (m), 769
ν
(s), 698 (s). MS (EI, 70 eV): m/z (%) = 346 (100) [M+], 347 (23), 261 (25), 248 (13), 222 (23), 221 (11),
202 (13), 178 (11), 165 (12), 55 (10), 41 (12). HRMS (ESI, 70 eV): calcd. for C24H26O2 [M+] 346.19273;
found 346.19267.
2-(p-Tolyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 b):11b white solid (77 mg, 75%), mp = 201
– 202
°C, [α]D = +160.5° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H, CH3), 1.47 – 1.65 (m,
6H, aliphatic), 1.93 – 2.19 (m, 4H, aliphatic), 2.25 – 2.33 (m, 1H, aliphatic), 2.38 – 2.56 (m, 2H,
aliphatic), 2.41 (s, 3H, CH3), 2.91 – 2.95 (m, 2H, aliphatic), 5.26 (br.s, 1H, OH), 6.74 (s, 1H, CHAr), 7.16
3
(s, 1H, CHAr), 7.26 – 7.30 (m, 2H, CHAr + CDCl3), 7.36 (d, JH-H = 7.9 Hz, 2H, CHAr). 13C NMR (63
MHz, CDCl3): δ = 13.9 (CH3), 21.2 (CH3), 21.6 (CH2), 26.0 (CH2), 26.6 (CH2), 29.3 (CH2), 31.6 (CH2),
35.9 (CH2), 38.4 (CH), 44.0 (C), 48.0 (CH), 50.4 (CH), 115.6 (CHAr), 125.8 (CAr), 127.2 (CHAr), 128.9
(2CHAr), 129.9 (2CHAr), 132.1 (CAr), 134.4 (CAr), 137.4 (CAr), 137.5 (CAr), 150.5 (CAr), 221.1 (C=O). IR
(ATR, cm−1):
˜ = 3342 (w), 2925 (m), 1723 (s), 1491 (s), 1237 (s), 1051 (m), 822 (s). MS (EI, 70 eV):
ν
m/z (%) = 360 (100) [M+], 361 (26), 275 (19), 236 (18). HRMS (ESI, 70 eV): calcd. for C25H28O2 [M+]
360.20838; found 360.20759.

20
2-(p-tert-Butylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 c): white solid (94 mg, 82%), mp =
229
–
230 °C, [α]D = +129.6° (c 1.00, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 0.92 (s, 3H, CH3), 1.37
(s, 9H, C(CH3)3), 1.47 – 1.66 (m, 6H, aliphatic), 1.92 – 2.19 (m, 4H, aliphatic), 2.24 – 2.34 (m, 1H,
aliphatic), 2.34 – 2.57 (m, 2H, aliphatic), 2.90 – 2.95 (m, 2H, aliphatic), 5.17 (br.s, 1H, OH), 6.74 (s, 1H,
CHAr), 7.17 (s, 1H, CHAr), 7.37 – 7.41 (m, 2H, CHAr), 7.48 – 7.52 (m, 2H, CHAr). 13C NMR (63 MHz,
CDCl3): δ = 13.9 (CH3), 21.6 (CH2), 26.0 (CH2), 26.6 (CH2), 29.3 (CH2), 31.3 (C(CH3)3), 31.6 (CH2),
34.6 (C(CH3)3), 35.9 (CH2), 38.4 (CH), 44.0 (CH), 48.0 (C), 50.4 (CH), 115.6 (CHAr), 125.7 (CAr), 126.2
(2CHAr), 127.2 (CHAr), 128.7 (2CHAr), 132.1 (CAr), 134.3 (CAr), 137.5 (CAr), 150.5 (CAr), 150.7 (CAr),
221.0 (C=O). IR (ATR, cm−1):
˜ = 3347 (w), 2920 (m), 1723 (s), 1613 (w), 1500 (m), 1395 (m), 1257
ν
(m), 1193 (s), 896 (m), 828 (s), 752 (s). MS (EI, 70 eV): m/z (%) = 402 (100) [M+], 403 (32), 388 (26),
287 (86), 57 (14), 41 (14). HRMS (ESI, 70 eV): calcd. for C28H34O2 [M+] 402.25533; found 402.25513.
2-(p-Methoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 d): light yellow solid (86 mg, 80%),
mp = 183
–
184 °C, [α]D = +137.0° (c 1.00, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 0.92 (s, 3H, CH3),
1.47 – 1.64 (m, 6H, aliphatic), 1.92 – 2.19 (m, 4H, aliphatic), 2.22 – 2.32 (m, 1H, aliphatic), 2.37 – 2.57
(m, 2H, aliphatic), 2.89 – 2.94 (m, 2H, aliphatic), 3.85 (s, 3H, OCH3), 5.15 (br.s, 1H, OH), 6.73 (s, 1H,
CHAr), 6.97 – 7.03 (m, 2H, CHAr), 7.14 (s, 1H, CHAr), 7.35 – 7.41 (m, 2H, CHAr). 13C NMR (63 MHz,
CDCl3): δ = 13.9 (CH3), 21.6 (CH2), 26.0 (CH2), 26.5 (CH2), 29.2 (CH2), 31.6 (CH2), 35.9 (CH2), 38.4
(CH), 44.0 (CH), 48.0 (C), 50.4 (CH), 55.4 (OCH3), 114.6 (2CHAr), 115.6 (CHAr), 125.5 (CAr), 127.2
(CHAr), 129.5 (CAr), 130.2 (2CHAr), 132.1 (CAr), 137.3 (CAr), 150.5 (CAr), 159.2 (CAr), 221.0 (C=O). IR
(ATR, cm−1):
˜ = 3350 (w), 2925 (m), 1720 (s), 1609 (m), 1501 (s), 1242 (s), 1177 (s), 1033 (s), 828 (s).
ν
MS (EI, 70 eV): m/z (%) = 376 (100) [M+], 377 (28), 291 (11), 252 (11). HRMS (ESI, 70 eV): calcd. for
C25H28O3 [M+] 376.20330; found 376.20276.
2-(p-Trifluoromethylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 e): white solid (85 mg, 72%),
mp = 250
–
251 °C, [α]D = +123.6° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H, CH3),
1.48 – 1.65 (m, 6H, aliphatic), 1.94 – 2.19 (m, 4H, aliphatic), 2.27 – 2.34 (m, 1H, aliphatic), 2.39 – 2.57
(m, 2H, aliphatic), 2.91 – 2.94 (m, 2H, aliphatic), 5.18 (br.s, 1H, OH), 6.73 (s, 1H, CHAr), 7.18 (s, 1H,
3
3
CHAr), 7.62 (d, JH-H = 8.1 Hz, 2H, CHAr), 7.70 (d, JH-H = 8.1 Hz, 2H, CHAr). 13C NMR (75 MHz,
CDCl3): δ = 13.9 (CH3), 21.6 (CH2), 26.0 (CH2), 26.5 (CH2), 29.2 (CH2), 31.5 (CH2), 35.9 (CH2), 38.3
(CH), 43.9 (CH), 48.0 (C), 50.4 (CH), 116.2 (CHAr), 124.6 (CAr), 124.2 (q, 1JC-F = 272.0 Hz, CF3), 125.7
3
2
(q, JC-F = 3.7 Hz, 2CHAr), 127.4 (CHAr), 129.41 (q, JC-F = 32.6 Hz, CAr-CF3), 129.48 (2CHAr), 132.7
(CAr), 138.5 (CAr), 141.6 (CAr), 150.4 (CAr), 221.2 (C=O). 19F NMR (282 MHz, CDCl3): δ = -62.5 (CF3).
IR (ATR, cm−1):
˜ = 3365 (w), 2937 (w), 1722 (s), 1612 (m), 1324 (s), 1109 (s), 1067 (s), 1013 (m), 840
ν
(s). MS (EI, 70 eV): m/z (%) = 414 (100) [M+], 415 (28), 357 (12), 330 (10), 329 (23), 316 (17), 304 (11),
303 (14), 301 (12), 290 (22), 289 (12), 55 (12), 41 (13). HRMS (ESI, 70 eV): calcd. for C25H25O2F3 [M+]
414.18012; found 414.17980.

21
2-(p-Trifluoromethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 f): white solid (95 mg, 77%),
mp = 109
–
110 °C, [α]D = +122.2° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.92 (s, 3H, CH3),
1.47 – 1.64 (m, 6H, aliphatic), 1.93 – 2.19 (m, 4H, aliphatic), 2.25 – 2.33 (m, 1H, aliphatic), 2.38 – 2.56
(m, 2H, aliphatic), 2.90 – 2.94 (m, 2H, aliphatic), 5.06 (br.s, 1H, OH), 6.72 (s, 1H, CHAr), 7.15 (s, 1H,
3
CHAr), 7.30 (d, JH-H = 8.1 Hz, 2H, CHAr), 7.48 – 7.53 (m, 2H, CHAr). 13C NMR (63 MHz, CDCl3): δ =
13.8 (CH3), 21.6 (CH2), 26.0 (CH2), 26.5 (CH2), 29.2 (CH2), 31.5 (CH2), 35.9 (CH2), 38.3 (CH), 43.9
1
(CH), 48.0 (C), 50.4 (CH), 116.0 (CHAr), 120.5 (q, JC-F = 257.5 Hz, CF3), 121.4 (2CHAr), 124.6 (CAr),
3
127.4 (CHAr), 130.6 (2CHAr), 132.5 (CAr), 136.4 (CAr), 138.1 (CAr), 148.5 (q, JC-F = 2.3 Hz, CAr-OCF3),
150.3 (CAr), 220.9 (C=O). 19F NMR (282 MHz, CDCl3): δ = -57.8 (CF3). IR (ATR, cm−1):
˜ = 3334 (w),
ν
2924 (m), 1721 (s), 1615 (w), 1499 (m), 1249 (s), 1202 (s), 1155 (s). MS (EI, 70 eV): m/z (%) = 430
(100) [M+], 431 (24), 346 (10), 345 (21), 332 (14), 319 (10), 306 (19), 69 (19), 55 (10). HRMS (ESI, 70
eV): calcd. for C25H25O3F3 [M+] 430.17503; found 430.17478.
2-(m-Fluorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 g): light yellow solid (82 mg, 79%), mp
1
= 132
–
133 °C, [α]D = +129.8° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H, CH3),
1.48 – 1.64 (m, 6H, aliphatic), 1.94 – 2.19 (m, 4H, aliphatic), 2.25 – 2.39 (m, 1H, aliphatic), 2.39 – 2.56
(m, 2H, aliphatic), 2.90 – 2.94 (m, 2H, aliphatic), 5.20 (br.s, 1H, OH), 6.73 (s, 1H, CHAr), 7.03 – 7.09 (m,
1H, CHAr), 7.16 – 7.27 (m, 3H, CHAr + CDCl3), 7.38 – 7.46 (m, 1H, CHAr). 13C NMR (75 MHz, CDCl3):
δ = 13.9 (CH3), 21.6 (CH2), 26.0 (CH2), 26.5 (CH2), 29.2 (CH2), 31.5 (CH2), 35.9 (CH2), 38.3 (CH), 43.9
2
2
(CH), 48.0 (C), 50.4 (CH), 114.4 (d, JC-F = 21.0 Hz, CHAr), 116.0 (CHAr), 116.2 (d, JC-F = 21.6 Hz,
4
4
3
CHAr), 124.65 (d, JC-F = 3.0 Hz, CHAr), 124.7 (d, JC-F = 2.0 Hz, CAr), 127.2 (CHAr), 130.5 (d, JC-F = 8.5
Hz, CHAr), 132.4 (CAr), 138.2 (CAr), 139.9 (d, 3JC-F = 7.8 Hz, CAr), 150.3 (CAr), 163.1 (d, 1JC-F = 247.0 Hz,
CAr-F), 221.2 (C=O). 19F NMR (282 MHz, CDCl3): δ = -112.1 (CF). IR (ATR, cm−1):
˜ = 3348 (w),
ν
2921 (m), 1721 (s), 1612 (m), 1579 (m), 1402 (s), 1254 (s), 1012 (m), 874 (s), 782 (s). MS (EI, 70 eV):
m/z (%) = 364 (100) [M+], 365 (25), 279 (22), 266 (17), 253 (12), 251 (12), 240 (19), 239 (11), 220 (10),
55 (11), 41 (14). HRMS (ESI, 70 eV): calcd. for C24H25O2F [M+] 364.18331; found 364.18303.
2-(3,5-Dimethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (8 h): light yellow solid (116 mg,
1
84%), mp = 115
–
116 °C, [α]D = +161.6° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.92 (s,
3H, CH3), 1.47 – 1.64 (m, 6H, aliphatic), 1.93 – 2.18 (m, 4H, aliphatic), 2.25 – 2.33 (m, 1H, aliphatic),
2.37 – 2.56 (m, 2H, aliphatic), 2.90 – 2.94 (m, 2H, aliphatic), 3.82 (s, 6H, 2OCH3), 5.32 (br.s, 1H, OH),
4
4
6.48 (pt, JH-H = 2.3 Hz, 1H, CHAr), 6.57 (d, JH-H = 2.3 Hz, 2H, CHAr), 6.74 (s, 1H, CHAr), 7.17 (s, 1H,
CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.8 (CH3), 21.6 (CH2), 26.0 (CH2), 26.5 (CH2), 29.3 (CH2),
31.5 (CH2), 35.9 (CH2), 38.4 (CH), 43.9 (CH), 48.0 (C), 50.4 (CH), 55.4 (2OCH3), 99.7 (CHAr), 106.9
(2CHAr), 115.6 (CHAr), 125.6 (CAr), 126.8 (CHAr), 132.1 (CAr), 137.9 (CAr), 139.3 (CAr), 150.3 (CAr), 161.5
(2CAr), 221.0 (C=O). IR (ATR, cm−1):
˜ = 3369 (w), 2924 (m), 1720 (s), 1591 (s), 1453 (m), 1399 (s),
ν
1341 (m), 1192 (s), 1149 (s), 1057 (s), 833 (s). MS (EI, 70 eV): m/z (%) = 406 (100) [M+], 407 (28), 321
(11), 282 (10). HRMS (ESI, 70 eV): calcd. for C26H30O4 [M+] 406.21386; found 406.21387.

22
2,4-Diphenyl-3-hydroxyestra-1,3,5(10)-trien-17-one (9 a): 2,4-Dibromoestrone (6 c) (100 mg, 0.234
mmol), boronic acid (3 equiv.), Pd(PPh3)4 (13.5 mg, 0.05 equiv.), RuPhos (5.5 mg, 0.05 equiv.), K2CO3
(129.4 mg, 4.0 equiv.) and dioxane (4 ml) were added in a pressure tube under argon atmosphere. The
mixture was stirred 40 h (or 72 h, see Table 4) at 101 °C. The solvent was evaporated in vacuo. The
residue was purified by column chromatography (silica gel, heptane/EtOAc = 1:4). 9a was isolated as a
1
light yellow solid (98 mg, 99%), mp = 110
–
111 °C (lit.8 118 °C), [α]D = +81.3° (c 1.00, CHCl3). H
NMR (300 MHz, CDCl3): δ = 0.95 (s, 3H, CH3), 1.38 – 1.67 (m, 6H, aliphatic), 1.91 – 2.20 (m, 4H,
aliphatic), 2.33 – 2.41 (m, 1H, aliphatic), 2.46 – 2.57 (m, 4H, aliphatic), 4.84 (s, 1H, OH), 7.31 – 7.37 (m,
4H, CHAr), 7.42 – 7.47 (m, 3H, CHAr), 7.50 – 7.60 (m, 4H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.9
(CH3), 21.6 (CH2), 26.2 (CH2), 26.6 (CH2), 28.6 (CH2), 31.6 (CH2), 35.9 (CH2), 37.9 (CH), 44.3 (CH),
48.0 (C), 50.4 (CH), 125.8 (CAr), 127.0 (CHAr), 127.2 (CHAr), 128.1 (CHAr), 128.2 (CAr), 128.5 (2CHAr),
129.3 (2CHAr), 129.4 (2CHAr), 130.1 (CHAr), 130.4 (CHAr), 132.1 (CAr), 135.1 (CAr), 135.9 (CAr), 138.2
(CAr), 147.7 (CAr), 220.9 (C=O). IR (ATR, cm−1):
˜ = 3530 (w), 2922 (m), 1734 (s), 1601 (w), 1461 (m),
ν
1438 (m), 1410 (m), 1230 (m), 1145 (m), 755 (m), 699 (s) . MS (EI, 70 eV): m/z (%) = 422 (100) [M+],
423 (40), 337 (14), 298 (13), 265 (13), 41 (12). HRMS (ESI, 70 eV): calcd. for C30H30O2 [M+] 422.22403;
found 422.22350.
2,4-Di-(p-tolyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 b): light yellow solid (96 mg, 91%), mp =
134
–
135 °C, [α]D = +72.2° (c 1.02, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.94 (s, 3H, CH3), 1.46 –
1.64 (m, 5H, aliphatic), 1.91 – 2.17 (m, 4H, aliphatic), 2.40 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.27 – 2.57
3
(m, 6H, aliphatic), 4.87 (s, 1H, OH), 7.19 – 7.34 (m, 7H, CHAr + CDCl3), 7.47 (d, JH-H = 8.1 Hz, 2H,
CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.8 (CH3), 21.2 (CH3), 21.3 (CH3), 21.6 (CH2), 26.2 (CH2),
26.6 (CH2), 28.6 (CH2), 31.6 (CH2), 35.9 (CH2), 37.9 (CH), 44.4 (CH), 48.0 (C), 50.4 (CH), 125.6 (CAr),
126.8 (CH), 128.0 (C), 129.1 (2CH), 129.2 (2CH), 129.9 (CH), 130.09 (CH), 130.10 (CH), 130.2 (CH),
131.9 (CAr), 132.7 (CAr), 135.0 (CAr), 135.3 (CAr), 136.8 (CAr), 137.7 (CAr), 147.9 (CAr), 221.0 (C=O). IR
(ATR, cm−1):
˜ = 3526 (w), 2921 (m), 2860 (m), 1737 (s), 1512 (m), 1454 (s), 1256 (m), 1232 (m), 1145
ν
(m), 818 (s). MS (EI, 70 eV): m/z (%) = 450 (100) [M+], 451 (38), 365 (9), 326 (9), 285 (8). HRMS (ESI,
70 eV): calcd. for C32H34O2 [M+] 450.25533; found 450.25665.
2,4-Di-(p-tert-butylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 c): yellow solid (106 mg, 85%),
mp = 141
–
142 °C, [α]D = +66.1° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.94 (s, 3H, CH3),
1.36 (s, 9H, C(CH3)3), 1.40 (s, 9H, C(CH3)3), 1.50 – 1.64 (m, 6H, aliphatic), 1.95 – 2.16 (m, 4H,
aliphatic), 2.33 – 2.39 (m, 1H, aliphatic), 2.45 – 2.54 (m, 4H, aliphatic), 4.91 (s, 1H, OH), 7.23 – 7.25 (m,
2H, CHAr + CDCl3), 7.31 (s, 1H, CHAr), 7.43 – 7.53 (m, 6H, CHAr). 13C NMR (63 MHz, CDCl3): δ =
13.9 (CH3), 21.6 (CH2), 26.2 (CH2), 26.6 (CH2), 28.6 (CH2), 31.4 (2C(CH3)3), 31.6 (CH2), 34.5
(C(CH3)3), 34.7 (C(CH3)3), 35.9 (CH2), 37.9 (CH), 44.4 (CH), 48.0 (C), 50,4 (CH), 114.7 (CHAr), 125.4
(CHAr), 125.5 (CAr), 126.25 (CHAr), 126.30 (CHAr), 126.35 (CHAr), 126.8 (CHAr), 128.0 (CAr), 128.9

23
(CHAr), 129.6 (CHAr), 130.0 (CHAr), 131.9 (CAr), 132.6 (CAr), 135.0 (CAr), 135.3 (CAr), 148.0 (CAr), 149.9
(CAr), 150.9 (CAr), 221.0 (C=O). IR (ATR, cm−1):
˜ = 3530 (w), 2953 (m), 1738 (s), 1610 (w), 1515 (w),
ν
1456 (s), 1259 (s), 1149 (m), 1017 (m), 830 (s). MS (EI, 70 eV): m/z (%) = 534 (100) [M+], 535 (43), 520
(15), 519 (38), 57 (31), 41 (11). HRMS (ESI, 70 eV): calcd. for C38H46O2 [M+] 534.34923; found
534.34874.
2,4-Di-(p-methoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 d): light yellow solid (112 mg,
99%), mp = 117
–
118 °C, [α]D = +84.2° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.94 (s, 3H,
CH3), 1.46 – 1.64 (m, 6H, aliphatic), 1.91 – 2.17 (m, 4H, aliphatic), 2.32 – 2.39 (m, 1H, aliphatic), 2.46 –
2.54 (m, 4H, aliphatic), 3.84 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.87 (s, 1H, OH), 6.97 (d, 3JH-H = 8.7 Hz,
3
3
2H, CHAr), 7.05 (d, JH-H = 8.2 Hz, 2H, CHAr), 7.21 – 7.28 (m, 3H, CHAr), 7.51 (d, JH-H = 8.7 Hz, 2H,
CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.8 (CH3), 21.5 (CH2), 26.2 (CH2), 26.6 (CH2), 28.6 (CH2),
31.6 (CH2), 35.9 (CH2), 37.9 (CH), 44.4 (CH), 48.0 (C), 50.4 (CH), 55.29 (OCH3), 55.30 (OCH3), 113.9
(2CHAr), 114.8 (CHAr), 114.9 (CHAr), 125.3 (CAr), 126.7 (CHAr), 127.6 (CAr), 127.7 (CAr), 130.3 (2CHAr),
130.6 (CAr), 131.2 (CHAr), 131.6 (CHAr), 131.9 (CAr), 135.0 (CAr), 148.1 (CAr), 158.8 (CAr), 159.3 (CAr),
220.9 (C=O). IR (ATR, cm−1):
˜ = 3521 (w), 2925 (m), 1734 (s), 1607 (m), 1510 (s), 1456 (s), 1241 (s),
ν
1174 (s), 1031 (s), 829 (s). MS (EI, 70 eV): m/z (%) = 482 (100) [M+], 483 (33), 397 (3), 358 (5), 317 (5).
HRMS (ESI, 70 eV): calcd. for C32H34O4 [M+] 482.24516; found 482.24510.
2,4-Di-(p-trifluoromethylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 e): yellow solid (116 mg,
89%), mp = 127
–
128 °C, [α]D = +52.1° (c 1.55, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.94 (s, 3H,
CH3), 1.37 – 1.64 (m, 6H, aliphatic), 1.97 – 2.17 (m, 4H, aliphatic), 2.36 – 2.48 (m, 5H, aliphatic), 4.73
(s, 1H, OH), 7.33 (s, 1H, CHAr), 7.45 – 7.49 (m, 2H, CHAr), 7.69 (m, 4H, CHAr), 7.79 – 7.81 (m, 2H,
CHAr). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 21.5 (CH2), 26.2 (CH2), 26.4 (CH2), 28.6 (CH2),
1
31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.2 (CH), 47.9 (C), 50.4 (CH), 124.3 (q, JC-F = 272.2 Hz, CF3),
3
1
124.8 (CAr), 125.4 (q, JC-F = 3.7 Hz, 2CHAr), 125.6 (q, JC-F = 272.4 Hz, CF3), 126.36 (CHAr), 126.39
2
2
(CHAr), 127.2 (CAr), 127.5 (CHAr), 129.3 (q, JC-F = 32.4 Hz, CAr), 129.6 (2CHAr), 130.5 (q, JC-F = 32.6
Hz, CAr), 130.7 (CHAr), 130.9 (CHAr), 132.9 (CAr), 135.8 (CAr), 139.8 (CAr), 141.7 (CAr), 147.5 (CAr),
220.6 (C=O). 19F NMR (282 MHz, CDCl3): δ = -62.6 (CF3), -62.5 (CF3). IR (ATR, cm−1):
˜ = 3275 (w),
ν
2928 (w), 1725 (m), 1615 (m), 1461 (m), 1398 (m), 1319 (s), 1160 (s), 1105 (s), 1064 (s), 1016 (s), 838
(m). MS (EI, 70 eV): m/z (%) = 558 (100) [M+], 559 (34), 539 (11), 473 (15), 460 (12), 434 (17), 12 (55).
HRMS (ESI, 70 eV): calcd. for C32H28O2F6 [M+] 558.19880; found 558.19935.
2,4-Di-(p-trifluormethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 f): light yellow solid
(109 mg, 79%), mp = 97
–
98 °C, [α]D = +73.1° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.94
(s, 3H, CH3), 1.39 – 1.64 (m, 6H, aliphatic), 1.97 – 2.17 (m, 4H, aliphatic), 2.32 – 2.39 (m, 1H, aliphatic),
2.46 – 2.55 (m, 4H, aliphatic), 4.69 (s, 1H, OH), 7.26 – 7.29 (m, 3H, CHAr + CDCl3), 7.36 – 7.37 (m, 4H,
CHAr), 7.58 (d, 3JH-H = 8.6 Hz, 2H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 21.5 (CH2), 26.2

24
(CH2), 26.5 (CH2), 28.6 (CH2), 31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.3 (CH), 47.9 (C), 50.4 (CH),
1
1
120.49 (q, JC-F = 257.7 Hz, OCF3), 120.52 (q, JC-F = 257.0 Hz, OCF3), 120.9 (2CHAr), 121.8 (2CHAr),
124.6 (CAr), 127.0 (CAr), 127.3 (CHAr), 130.7 (2CHAr), 131.7 (CHAr), 132.0 (CHAr), 132.6 (CAr), 134.3
(CAr), 135.6 (CAr), 136.7 (CAr), 147.6 (CAr), 148.4 (CAr), 149.1 (CAr), 220.7 (C=O). 19F NMR (282 MHz,
CDCl3): δ = 57.8 (CF3), -57.7 (CF3). IR (ATR, cm−1):
˜ = 3545 (w), 2928 (w), 1732 (m), 1507 (m), 1460
ν
(m), 1250 (s), 1203 (s), 1153 (s), 1019 (m), 831 (m). MS (EI, 70 eV): m/z (%) = 590 (100) [M+], 591
(33), 505 (19), 466 (14), 69 (18), 55 (12). HRMS (ESI, 70 eV): calcd. for C32H28O4F6 [M+] 590.18863;
found 590.18736.
2,4-Di-(m-fluorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 g): light yellow solid (91 mg, 85%),
1
mp = 111
–
112 °C, [α]D = +108.0° (c 1.00, CHCl3). A mixture of diastereomers. H NMR (300 MHz,
CDCl3): δ = 0.939 and 0.943 (2s, 3H, CH3), 1.37 – 1.65 (m, 6H, aliphatic), 1.92 – 2.20 (m, 4H, aliphatic),
2.31 – 2.39 (m, 1H, aliphatic), 2.46 – 2.55 (m, 4H, aliphatic), 4.80 and 4.81 (s, 1H, OH), 7.00 – 7.17 (m,
4H, CHAr), 7.27 – 7.43 (m, 4H, CHAr), 7.46 – 7.54 (m, 1H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.8
(CH3), 21.5 (CH2), 26.2 (CH2), 26.5 (CH2), 28.4 and 28.5 (CH2), 31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.2
2
2
and 44.3 (CH), 47.9 (C), 50.4 (CH), 114.1 (d, JC-F = 21.1 Hz, CHAr), 115.2 (d, JC-F = 21.0 Hz, CHAr),
116.1 and 116.5 (CHAr), 117.2 (d, 2JC-F = 20.9 Hz) and 117.5 (d, 2JC-F = 21.0 Hz) (CHAr), 124.66 – 124.72
4
2
2
(several signals, CAr), 124.8 (d, JC-F = 2.8 Hz, CHAr), 125.85 (d, JC-F = 20.5 Hz) and 125.90 (d, JC-F
=
20.4 Hz) (CHAr), 127.16 (CAr), 127.18 (d, 4JC-F = 2.8 Hz, CHAr), 129.9 (d, 3JC-F = 8.5 Hz, CHAr), 131.0 (d,
3
3JC-F = 8.4 Hz) and 131.1 (d, JC-F = 8.6 Hz) (CHAr), 132.5 (CAr), 135.47 and 135.50 (CAr), 137.9 and
138.0 (CAr), 140.2 and 140.3 (CAr), 147.5 (CAr), 162.8 (d, 1JC-F = 245.8 Hz, CAr-F), 163.3 (d, 1JC-F = 248.3
Hz) and 163.4 (d, 1JC-F = 248.3 Hz) (CAr-F), 220.7 (C=O). 19F NMR (235 MHz, CDCl3): δ = -113.10 and -
113.07 (CF), -111.45 and -111.40 (CF). IR (ATR, cm−1):
˜ = 3539 (w), 2924 (m), 1733 (s), 1581 (s),
ν
1458 (m), 1403 (m), 1260 (s), 1194 (s), 873 (m), 785 (s). MS (EI, 70 eV): m/z (%) = 458 (100) [M+], 459
(28), 373 (17), 360 (11), 334 (12), 55 (15), 41 (12). HRMS (ESI, 70 eV): calcd. for C30H28O2F2 [M+]
458.20519; found 458.20528.
2,4-Di-(3,5-dimethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 h): light yellow solid (89 mg,
70%), mp = 114
–
115 °C, [α]D = +52.4° (c 1.00, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 0.93 (s, 3H,
CH3), 1.32 – 1.41 (m, 1H, aliphatic), 1.51–1.63 (m, 5H, aliphatic), 1.92 – 2.17 (m, 4H, aliphatic), 2.31 –
2.39 (m, 1H, aliphatic), 2.45 – 2.61 (m, 4H, aliphatic), 3.81 (br.s, 12H, 4OCH3), 5.07 (s, 1H, OH), 6.45 –
6.47 (m, 3H, CHAr), 6.51 – 6.53 (m, 1H, CHAr), 6.71 (d, 4JH-H = 2.3 Hz, 2H, CHAr), 7.31 (br.s, 1H, CHAr).
13C NMR (63 MHz, CDCl3): δ = 13.8 (CH3), 21.5 (CH2), 26.2 (CH2), 26.5 (CH2), 28.2 (CH2), 31.6
(CH2), 35.8 (CH2), 37.9 (CH), 44.3 (CH), 48.0 (C), 50.4 (CH), 55.4 (4OCH3), 99.5 (CH), 100.1 (CH),
107.3 (2CHAr), 107.5 (CHAr), 108.0 (CHAr), 125.6 (CAr), 126.7 (CHAr), 128.2 (CAr), 132.0 (CAr), 135.2
(CAr), 137.8 (CAr), 140.1 (CAr), 147.6 (CAr), 160.8 (2CAr), 161.55 (CAr) 161.58 (CAr), 220.8 (C=O). IR
(ATR, cm-1):
˜ = 3508 (w), 2926 (m), 1733 (s), 1589 (s), 1453 (m), 1336 (m), 1201 (s), 1150 (s), 1058
ν

25
(s), 830 (s). MS (EI, 70 eV): m/z (%) = 542 (100), 544 (9), 543 (49), 271 (18). HRMS (EI, 70 eV): calcd.
for C34H38O6 [M+] 542.26629; found 542.26555.
2,4-Di-(p-ethylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 i): light yellow solid (111 mg, 99%),
mp = 113
–
114 °C, [α]D = +74.0° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (s, 3H, CH3),
1.25 – 1.33 (m, 7 H, 2CH2CH3 + aliphatic), 1.50–1.63 (m, 5H, aliphatic), 1.89 – 2.19 (m, 4H, aliphatic),
2.31 – 2.39 (m, 1H, aliphatic), 2.45 – 2.57 (m, 4H, aliphatic), 2.65 – 2.77 (m, 4H, 2CH2CH3), 4.88 (s, 1H,
OH), 7.21 – 7.29 (m, 5H, CHAr + CDCl3), 7.33 – 7.35 (m, 2H, CHAr), 7.47 – 7.50 (m, 2H, CHAr).
13C NMR (75 MHz, CDCl3): δ = 13.8 (CH3), 15.3 (CH3), 15.5 (CH3), 21.5 (CH2), 26.2 (CH2), 26.6
(CH2), 28.54 (CH2), 28.56 (CH2), 28.61 (CH2), 31.6 (CH2), 35.8 (CH2), 37.9 (CH), 44.3 (CH), 48.0 (C),
50.4 (CH), 125.6 (CAr), 126.8 (CHAr), 128.0 (2CHAr), 128.1 (CAr), 128.82 (CHAr), 128.84 (CHAr), 129.2
(2CHAr), 129.9 (CHAr), 130.3 (CHAr), 131.9 (CAr), 132.9 (CAr), 135.0 (CAr), 135.5 (CAr), 143.1 (CAr), 144.0
(CAr), 147.9 (CAr), 221.0 (C=O). IR (ATR, cm-1):
˜ = 3527 (w), 2927 (m), 1737 (s), 1511 (m), 1455 (s),
ν
1399 (m), 1257 (m), 1145 (m), 829 (s). MS (EI, 70 eV): m/z (%) = 478 (100) [M+], 479 (55), 152 (12),
151 (13), 133 (19), 57 (10), 55 (12), 41 (12), 36 (10). HRMS (ESI, 70 eV): calcd. for C34H38O2 [M+H]
479.29446; found 479.29408.
2,4-Di-(o-fluorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 j): light yellow solid (104 mg, 97%),
1
mp = 118
–
119 °C, [α]D = +92.2° (c 1.00, CHCl3). A mixture of diastereomers. H NMR (300 MHz,
CDCl3): δ = 0.93 and 0.94 (2s, 3H, CH3), 1.34 – 1.42 (m, 1H, aliphatic), 1.50 – 1.64 (m, 5H, aliphatic),
1.95 – 2.17 (m, 4H, aliphatic), 2.36 – 2.54 (m, 5H, aliphatic), 4.69 and 4.71 (2s, 1H, OH), 7.14 – 7.36 (m,
7H, CHAr + CDCl3), 7.39 – 7.46 (m, 2H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.8 and 13.9 (CH3),
21.5 (CH2), 26.0 and 26.1 (CH2), 26.4 (CH2), 27.6 and 28.3 (CH2), 31.55 and 31.58 (CH2), 35.8 (CH2),
37.71 and 37.77 (CH), 44.1 and 44.2 (CH), 47.9 and 48.0 (C), 50.39 and 50.43 (CH), 115.72 and 115.76
(CHAr), 116.1 – 116.2 (several signals, CHAr), 116.5 and 116.6 (CHAr), 120.1 (CAr), 121.9 and 122.0 (CAr),
2
2
123.19 (d, JC-F = 17.7 Hz) and 123.28 (d, JC-F = 17.4 Hz) (CAr), 124.2 – 124.3 (several signals, CHAr),
2
2
124.8 – 124.9 (several signals, CHAr), 125.29 (d, JC-F = 15.8 Hz) and 125.39 (d, JC-F = 16.0 Hz) (CAr),
128.2 (CHAr), 129.4 (d, 3JC-F = 8.2 Hz) and 129.5 (d, 3JC-F = 7.9 Hz) (CHAr), 130.20 (d, 3JC-F = 7.9 Hz) and
3
130.24 (d, JC-F = 8.1 Hz) (CHAr), 131.9 – 132.3 (several signals, 2CHAr + 2CAr), 136.6 and 136.7 (CAr),
1
148.3 and 148.4 (CAr), 160.0 (d, JC-F = 246.8 Hz, 2CAr-F), 220.9 (C=O). 19F NMR (235 MHz, CDCl3):
δ = -112.7 and -112.9 (CF), -114.016 and -114.024 (CF). IR (ATR, cm-1):
˜ = 3550 (w), 2925 (w), 1731
ν
(m), 1576 (w), 1444 (m), 1414 (m), 1206 (m), 755 (s). MS (EI, 70 eV): m/z (%) = 458 (100) [M+], 459
(31), 373 (20), 360 (11), 334 (24), 55(11). HRMS (EI, 70 eV): calcd. for C30H28O2F2: 458.20519; found
458.20501.
2,4-Di-(3,5-dimethylphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 k): light yellow solid (111 mg,
1
99%), mp = 111
–
112 °C, [α]D = +104.1° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.94 (s,
3H, CH3), 1.36 – 1.64 (m, 6H, aliphatic), 1.90 – 2.17 (m, 4H, aliphatic), 2.36 – 2.37 (m, 13H, 4CH3 +

26
aliphatic), 2.46 – 2.59 (m, 4H, aliphatic), 4.94 (br.s, 1H, OH), 6.92 (s, 1H, CHAr), 6.94 (s, 1H, CHAr), 6.98
(s, 1H, CHAr), 7.05 (s, 1H, CHAr), 7.17 (m, 2H, CHAr), 7.26 (s, 1H, CHAr + CDCl3). 13C NMR (75 MHz,
CDCl3): δ = 13.9 (CH3), 21.39 (2CH3), 21.41 (2CH3), 21.6 (CH2), 26.2 (CH2), 26.6 (CH2), 28.5 (CH2),
31.7 (CH2), 35.9 (CH2), 38.0 (CH), 44.4 (CH), 48.0 (C), 50.5 (CH), 125.8 (CAr), 126.6 (CHAr), 127.0
(2CHAr), 127.6 (CHAr), 128.0 (CHAr), 128.3 (CAr), 128.9 (CHAr), 129.6 (CHAr), 131.8 (CAr), 134.8 (CAr),
135.9 (CAr), 138.0 (2CAr), 138.2 (CAr), 138.86 (CAr), 138.88 (CAr), 147.7 (CAr), 221.0 (C=O). IR (ATR,
cm−1):
˜ = 3525 (w), 2917 (s), 1737 (s), 1599 (s), 1453 (s), 1203 (m), 1035 (m), 847 (s), 706 (s). MS (EI,
ν
70 eV): m/z (%) = 478 (100) [M+], 479 (38). HRMS (ESI, 70 eV): calcd. for C34H38O2 [M+] 478.28663;
found 478.28554.
2,4-Di-(p-chlorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 l): dark yellow solid (28 mg, 24%),
mp = 119
–
120 °C, [α]D = +58.2° (c 0.65, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.93 (m, 3H, CH3),
1.32 – 1.36 (m, 1H, ailiphatic), 1.55–1.62 (m, 5H, aliphatic), 1.96 – 2.17 (m, 4H, aliphatic), 2.29 – 2.37
(m, 1H, aliphatic), 2.44 – 2.55 (m, 4H, aliphatic), 4.71 (s, 1H, OH), 7.25 – 7.30 (m, 3H, CHAr + CDCl3),
7.38 – 7.41 (m, 2H, CHAr), 7.46 – 7.54 (m, 4H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.8 (CH3), 21.5
(CH2), 26.2 (CH2), 26.5 (CH2), 28.6 (CH2), 31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.2 (CH), 47.9 (C), 50.4
(CHAr), 124.7 (CAr), 127.1 (CHAr), 128.6 (2CHAr), 129.7 (2CHAr), 130.6 (2CHAr), 130.59 (CAr), 131.5
(CHAr), 131.8 (CHAr), 132.5 (CAr), 133.2 (CAr), 134.1 (CAr), 134.3 (CAr), 135.4 (CAr), 136.5 (CAr), 147.54
(CAr), 220.8 (C=O). IR (ATR, cm-1):
˜ = 3533 (w), 2922 (m), 1731 (s), 1490 (s), 1455 (s), 1230 (m), 1087
ν
(s), 1014 (s), 819 (s), 802 (s), 732 (m), 720 (m), 693 (m), 665 (m), 640 (m), 581 (m). MS (EI, 70 eV):
m/z (%) = 490 (100) [M+], 494 (14), 493 (21), 492 (69), 491 (34). HRMS (EI, 70 eV): calcd. for
C30H28O2Cl2 [M+] 490.14609; found 490.14496; calcd. for C30H28O2Cl37Cl [M+] 492.14314; found
492.14362.
2,4-Di-(2,3,4-trimethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 m): light yellow solid
(52 mg, 37%), mp = 105
–
106 °C, [α]D = +43.4° (c 1.00, CHCl3). A mixture of diastereomers. 1H NMR
(300 MHz, CDCl3): δ = 0.94 and 0.95 (2s, 3H, CH3), 1.54 – 1.62 (m, 6H, aliphatic), 1.91 – 2.17 (m, 4H,
aliphatic), 2.30 – 2.37 (m, 1H, aliphatic), 2.45 – 2.54 (m, 4H, aliphatic), 3.68 – 3.75 (m, 6H, 2OCH3),
3.89 – 3.93 (m, 12H, 4OCH3), 6.40 and 6.42 (2s, 1H, OH), 6.76 – 6.89 (m, 3H, CHAr), 7.06 – 7.09 (m,
1H, CHAr), 7.22 – 7.26 (d, 3JH-H = 4.5 Hz, 1H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.86 and 13.93
(CH3), 21.5 (CH2), 26.0 and 26.2 (CH2), 26.6 and 27.4 (CH2), 28.3 and 29.7 (CH2), 31.6 (CH2), 35.9
(CH2), 37.7 and 37.9 (CH), 44.3 (CH), 48.0 (C), 50.5 and 50.6 (CH), 55.9 and 56.1 (2OCH3), 60.8 – 61.1
(several signals, 3OCH3), 61.50 and 61.53 (OCH3), 107.54 and 107.59 (CHAr), 108.5 (CHAr), 122.8 and
123.0 (CAr), 124.0 (CAr), 125.30 and 125.33 (CHAr), 125.52 and 125.56 (CAr), 126.06 and 126.12 (CAr),
126.2 (CHAr), 127.2 and 127.4 (CHAr), 131.9 and 132.1 (CAr), 136.3 and 136.5 (CAr), 142.2 (CAr), 148.9
and 149.0 (CAr), 150.34 and 150.36 (CAr), 151.5 (CAr), 152.0 (CAr), 153.05 and 153.14 (CAr), 153.2 (CAr),
C=O not given. IR (ATR, cm−1 ):
˜ = 2924 (w), 1734 (m), 1596 (w), 1494 (m), 1455 (s), 1405 (s), 1289
ν

27
(s), 1212 (m), 1093 (s), 1006 (s), 797 (m). MS (EI, 70 eV): m/z (%) = 602 (100) [M+], 604 (12), 603 (56),
43 (13). HRMS (EI, 70 eV): calcd. for C36H42O8 [M+] 602.28742; found 602.28714.
2,4-Di-(o-ethoxyphenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 n): dark yellow solid (86 mg, 72%),
1
mp = 94
–
95 °C, [α]D = +52.4° (c 1.00, CHCl3). A mixture of diastereomers. H NMR (250 MHz,
CDCl3): δ = 0.94 and 0.95 (2s, 3H, CH3), 1.21 – 1.28 (m, 4H, CH2CH3 + aliphatic), 1.31 – 1.38 (m, 3H,
CH2CH3), 1.49 – 1.64 (m, 5H, aliphatic), 1.89 – 2.17 (m, 4H, aliphatic), 2.31 – 2.59 (m, 5H, aliphatic),
4.00 – 4.14 (m, 4H, 2CH2CH3), 6.06 and 6.07 (2s, 1H, OH), 6.99 – 7.20 (m, 5H, CHAr), 7.24 – 7.26 (m,
1H, CHAr + CDCl3), 7.29 – 7.44 (m, 3H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 13.87 and 13.92 (CH3),
14.7 (CH2CH3), 14.8 and 14.9 (CH2CH3), 21.6 (CH2), 25.95 and 26.09 (CH2), 26.6 and 26.7 (CH2), 27.1
and 28.0 (CH2), 31.7 (CH2), 35.9 (CH2), 37.9 (CH), 44.4 (CH), 48.0 (C), 50.58 and 50.62 (CH), 64.04 and
64.2 (CH2CH3), 64.98 (CH2CH3), 113.12 (CHAr), 113.2 and 113.4 (CHAr), 120.92 and 120.96 (CHAr),
121.93 and 121.96 (CHAr), 123.50 and 123.56 (CAr), 126.45 and 126.48 (CAr), 127.2 and 127.33 (CAr),
127.34 and 127.43 (CHAr), 128.63 – 128.72 (several signals, 2CHAr + CAr), 131.59 – 131.69 (several
signals, CHAr + CAr), 132.5 (CHAr), 136.0 and 136.2 (CAr), 148.97 and 149.10 (CAr), 155.01 and 155.05
(CAr), 156.16 and 156.55 (CAr), 221.1 (C=O). IR (ATR, cm-1):
˜ = 3371 (w), 2924 (w), 1736 (m), 1596
ν
(w), 1579 (w), 1439 (m), 1227 (m), 1116 (m), 1084 (m), 1038 (m), 750 (s). MS (EI, 70 eV): m/z (%) =
510 (100) [M+], 511 (36), 317 (9), 271 (7), 107 (8), 29 (9). HRMS (EI, 70 eV): calcd. for C34H38O4:
510.27646; found 510.27613.
2,4-Di-(p-fluorophenyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (9 o): yellow solid (89 mg, 75%), mp =
126
–
127 °C, [α]D = +50.3° (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl ): δ = 0.93 (s, 3H, CH3), 1.50–
3
1.63 (m, 6H, aliphatic), 1.96 – 2.19 (m, 4H, aliphatic), 2.36 (m, 1H, aliphatic), 2.46 – 2.55 (m, 4H,
aliphatic), 4.70 (s, 1H, OH), 7.09 – 7.14 (m, 2H, CHAr), 7.21 – 7.27 (m, 5H, CHAr + CDCl3), 7.50 – 7.54
(m, 2H, CHAr). 13C NMR (63 MHz, CDCl ): δ = 13.8 (CH3), 21.5 (CH2), 26.2 (CH2), 26.5 (CH2), 28.6
3
(CH2), 31.6 (CH2), 35.8 (CH2), 37.8 (CH), 44.3 (CH), 47.9 (C), 50.4 (CH), 115.3 (2JC-F=21.3 Hz, 2CHAr),
116.5 (2JC-F=21.4 Hz, 2CHAr), 124.8 (CAr), 127.1 (CHAr), 127.2 (CAr), 130.9 (3JC-F=7.9 Hz, 2CHAr), 131.4
(4JC-F = 3.0 Hz, CAr), 131.6 (3JC-F=8.1 Hz, CHAr), 132.1 (3JC-F=8.0 Hz, CHAr), 132.3 (CAr), 134.0 (4JC-F
3.1 Hz, CAr), 135.3 (CAr), 147.7 (CAr), 162.1 (1JC-F = 245.7 Hz, CFAr), 162.5 (1JC-F = 248.1 Hz, Car-F),
221.1 (C=O). IR (ATR, cm-1):
= 3540 (w), 2924 (m), 1732 (s), 1599 (w), 1507 (s), 1457 (m), 1217 (s),
=
ν
˜
1156 (m), 831 (s). MS (EI, 70 eV): m/z (%) = 458 (100), 459 (28), 373 (10). HRMS (EI, 70 eV): calcd.
for C30H28O2F2: 458.20519; found 458.20512.
General procedure for the synthesis of compounds 10 and 11: 4-(o-fluorophenyl)-estrone (7 k) or
2,4-di-(o-fluorophenyl)-estrone (9 j) (0.274 mmol), K2CO3 (75.9 mg, 2.0 equiv.) and DMF were added in

28
a round-bottom 50 ml flask and stirred 4 h at 150 °C. The solvent was evaporated in vacuo and the
residue was purified by column chromatography (silica gel, heptane/EtOAc = 3:1).
Benzofuro[2’,3’;3,4]estra-1,3,5(10)-trien-17-one (10): according to the general procedure compound 10
was isolated as a white solid (65 mg, 69%), mp = 268
–
269 °C, [α]D = +97.6° (c 1.00, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.95 (s, 3H, CH3), 1.58 – 1.73 (m, 6H, aliphatic), 1.99 – 2.04 (m, 1H, aliphatic),
2.12 – 2.29 (m, 3H, aliphatic), 2.44 – 2.58 (m, 3H, aliphatic), 3.25 – 3.37 (m, 1H, aliphatic), 3.46 – 3.55
(m, 1H, aliphatic), 7.32 – 7.48 (m, 4H, CHAr), 7.58 (d, 3JH-H = 8.0 Hz, 1H, CHAr), 8.01 (d, 3JH-H = 7.7 Hz,
1H, CHAr). 13C NMR (63 MHz, CDCl3): δ = 12.9 (CH3), 20.6 (CH2), 25.3 (CH2), 25.5 (CH2), 26.8 (CH2),
30.7 (CH2) 34.9 (CH2), 37.0 (CH), 43.4 (CH), 46.9 (C), 49.4 (CH), 107.7 (CHAr), 110.5 (CHAr), 121.3
(CAr), 121.5 (CHAr), 121.7 (CHAr), 123.6 (CHAr), 123.9 (CAr), 125.4 (CHAr), 131.3 (CAr), 133.0 (CAr),
153.4 (CAr), 155.4 (CAr), C=O not given. IR (ATR, cm−1 ):
˜ = 2961 (w), 1733 (w), 1258 (s), 1208 (w),
ν
1012 (s), 799 (s), 746 (s). MS (EI, 70 eV): m/z (%) = 344 (100) [M+], 345 (27), 287 (10), 259 (22), 246
(15), 234 (10), 233 (15), 232 (10), 231 (15), 220 (28), 219 (26), 218 (23), 207 (13), 205 (22), 189 (12),
181 (15). HRMS (EI, 70 eV): calcd. for C24H24O2[M+] 344.17708; found 344.17727.
2-(o-Fluorophenyl)-benzofuro[2’,3’;3,4]estra-1,3,5(10)-trien-17-one (11): according to the general
procedure compound 11 was isolated as a light yellow solid (74 mg, 77%), mp = 256
– 257 °C, [α]D =
1
+96.3° (c 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.96 (s, 3H, CH3), 1.60 – 1.81 (m, 6H,
aliphatic), 2.05 – 2.32 (m, 4H, aliphatic), 2.51 – 2.60 (m, 3H, aliphatic), 3.30 – 3.42 (m, 1H, aliphatic),
3.52 – 3.60 (m, 1H, aliphatic), 7.29 – 7.47 (m, 5H, CHAr), 7.53 – 7.58 (m, 2H, CHAr), 7.63 – 7.69 (m, 1H,
CHAr), 8.03 – 8.06 (m, 1H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 13.9 (CH3), 21.7 (CH2), 26.3 (CH2),
26.6 (CH2), 27.8 (CH2), 31.7 (CH2), 35.9 (CH2), 38.0 (CH), 44.4 (CH), 47.9 (C), 50.4 (CH), 111.7 (CHAr),
116.9 (d, 2JC-F = 22.4 Hz, CHAr), 117.3 (CAr), 122.60 (CHAr), 122.64 (CAr), 122.70 (CHAr), 124.1 (d, 4JC-F
=
3.4 Hz, CHAr), 124.5 (d, 2JC-F = 15.0 Hz, CAr), 124.9 (CAr), 126.0 (d, 4JC-F = 2.5 Hz, CHAr), 126.5 (CHAr),
129.5 (d, 3JC-F = 8.3 Hz, CHAr), 131.8 (d, 3JC-F = 3.3 Hz, CHAr), 132.2 (CAr), 134.2 (CAr), 151.8 (CAr), 156.4
(CAr), 156.8 (d, 1JC-F = 245.2 Hz, CAr-F), 220.9 (C=O). 19F NMR (282 MHz, CDCl3): δ = -114.6 (CF). IR
(ATR, cm−1 ):
˜ = 2923 (m), 1730 (s), 1445 (m), 1254 (m) 1212 (s), 1010 (m), 749 (s). GC/MS (EI, 70
ν
eV): m/z (%) = 438 (100) [M+], 439 (28), 353 (12), 327 (9), 314 (21), 313 (16), 312 (11), 299 (15), 275
(22). HRMS (EI, 70 eV): calcd. for C30H27O2F [M+] 438.19896; found 438.19875.
Isocoumarino[3’,4’;3,4]estra-1,3,5(10)-trien-17-one (12): 4-Bromoestrone (6 a) (200 mg, 0.574 mmol),
o-ethoxycarbonylphenyl boronic acid (340 mg, 3.0 equiv.), Pd(PPh3)4 (33.2 mg, 0.05 equiv.), RuPhos
(13.4 mg, 0.05 equiv.), K2CO3 (318.0 mg, 4.0 equiv.) and dioxane (4 ml) were added in a pressure tube
under argon atmosphere. The mixture was stirred at 110 °C 72 h. The solvent was evaporated in vacuo.
The residue was purified by column chromatography (silica gel, heptane/EtOAc = 2:1). 12 was isolated as
1
a pale pink solid (158 mg, 74%), mp = 235
–
236 °C, [α]D = +131.4° (c 1.00, CHCl3). H NMR (300

29
MHz, CDCl3): δ = 0.97 (s, 3H, CH3), 1.36 – 1.46 (m, 1H, aliphatic), 1.55 – 1.74 (m, 5H, aliphatic), 1.98 –
2.23 (m, 4H, aliphatic), 2.37 – 2.44 (m, 2H, aliphatic), 2.49 – 2.58 (m, 1H, aliphatic), 3.28 – 3.36 (m, 1H,
aliphatic), 3.41 – 3.52 (m, 1H, aliphatic), 7.21 (d, 3JH-H = 8.7 Hz, 1H, CHAr), 7.46 (d, 3JH-H = 8.7 Hz, 1H,
CHAr), 7.53 – 7.59 (m, 1H, CHAr), 7.75 – 7.81 (m, 1H, CHAr), 8.35 (d, 3JH-H = 8.4 Hz, 1H, CHAr), 8.46 (dd,
3
4JH-H = 1.5 Hz, JH-H = 7.8 Hz, 1H, CHAr). 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 21.5 (CH2),
26.68 (CH2), 26.75 (CH2), 31.8 (CH2), 32.5 (CH2), 35.9 (CH2), 37.6 (CH), 45.6 (CH), 48.0 (C), 50.3
(CH), 115.7 (CHAr), 117.3 (CAr), 122.6 (CAr), 127.2 (CHAr), 127.92 (CHAr), 127.95 (CHAr), 130.8 (CHAr),
133.8 (CHAr), 135.7 (CAr), 135.9 (CAr), 136.9 (CAr), 150.3 (CAr), 161.4 (CAr), 220.3 (C=O). IR (ATR,
cm−1):
˜ = 2935 (w), 2922 (w), 1714 (s), 1487 (m), 1401 (w), 1256 (s), 1002 (m), 958 (m), 782 (s), 691
ν
(s). GC/MS (EI, 70 eV): m/z (%) = 372 (100) [M+], 373 (28), 248 (14), 202 (12), 189 (12), 165 (10).
HRMS (EI, 70 eV): calcd. for C25H24O3 [M+] 372.17200; found 372.17175.
Protocol of Lipase Assay
The lipase inhibitory activity of synthesized derivatives was carried out with the slight modifications in
previously reported method.20 Initially, all of the derivatives were tested at the a concentration of 0.1 mM.
The assay buffer was composed of 100 mM Tris-HC1 (pH 7.0) and 5 mM CaCl2. The enzyme buffer
was prepared by adding 10 mM MOPS (morpholinepropanesulphonic acid) and 1 mM EDTA and the
pH of buffer was adjusted to 6.8. Total assay volume of 200 µL, contained 160 µL assay buffer, 20 µL of
test compound and 10 µL of the pancreatic lipase enzyme (0.5 µg per well). The reaction mixture was
o
allowed to incubate for 10 min at 37 C. Then the absorbance was measured as pre-read at 405 nm by
using micro-plate reader (BioTekTM ELx800, Instruments, Inc. USA). After that the reaction was initiated
by the addition of 10 µL of p-NPB (p-nitrophenylbutyrate) as substrate solution and the absorbance was
measured after 20 min of incubation. Orlistat was used as a positive control. The compounds with
percentage inhibition of above 50 were further dilluted to different concentrations for the determination of
IC50 values. All the experiments were performed in triplicate. IC50 values were calculated by non-linear
regression analysis of program PRISM 5.0 (GraphPad, San Diego, California, USA).
Acknowledgements.
Financial support by the DAAD (scholarships for A. I. and program Deutsch-Pakistanische
Hochschulzusammenarbeit) is gratefully acknowledged. J. Iqbal is thankful to the Organization for the
Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands and Higher Education
Commission of Pakistan for the financial support through Project No. 20-3733/NRPU/R&D/ 14/520 for
the financial support.