Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective ligands for estrogen receptor β, as positron-emission tomographic imaging agents

Article abstract of DOI:10.1016/j.bmc.2009.02.064

We have investigated halogen-substituted non-steroidal estrogens with selective binding affinity for the estrogen receptor β (ERβ that might be used for imaging the levels of this ER-subtype in breast tumors by positron emission tomography (PET). Based on

Full text of DOI:10.1016/j.bmc.2009.02.064

Bioorganic & Medicinal Chemistry 17 (2009) 3479–3488
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective
ligands for estrogen receptor b, as positron-emission tomographic imaging
agents
Byung Seok Moon a,b, Kathryn E. Carlson c, John A. Katzenellenbogen c, Tae Hyun Choi a, Dae Yoon Chi d,
a,
Jung Young Kim a, Gi Jeong Cheon a, Hun Yeong Koh b, Kyo Chul Lee a, , Gwangil An
*
*
a Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
b Department of Chemistry, Inha University, Inchon 402-751, Republic of Korea
c Department of Chemistry, University of Illinois, 600 South Matthews Avenue, Urbana, IL 61801, USA
d Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We have investigated halogen-substituted non-steroidal estrogens with selective binding affinity for the
estrogen receptor b (ERb that might be used for imaging the levels of this ER-subtype in breast tumors by
positron emission tomography (PET). Based on diarylpropionitrile (DPN, 1a), a compound previously
reported that has a 72-fold binding selectivity for ERb, we developed a series of DPN analogs having
methyl-, hydroxyl-, and halogen substituents, including fluoroethyl and fluoropropyl groups. In compet-
Received 29 January 2009
Revised 24 February 2009
Accepted 25 February 2009
Available online 9 March 2009
itive radiometric binding assays with [3H]estradiol, all of these DPN analogs showed high ERb/ER
tivity; while the selectivity varied, in some cases it reached nearly 300-fold (RBA: ER
a
selec-
Keywords:
Estrogen receptor b
Diarylpropionitrile analogues
DPN estrogen analogues
Breast tumor
a
, 0.023%; ERb,
6.25%). The absolute ERb binding affinities, however, were not sufficient to merit further consideration
for developing these ligands as PET imaging agents.
Ó 2009 Elsevier Ltd. All rights reserved.
Positron emission tomography (PET)
1. Introduction
and the respective roles that they play in both normal estrogen-
regulated physiology as well as in various diseases, such as breast
The estrogen receptor (ER) cloned in 19861 was believed to be
the only ER that mediated the actions of estrogens, and for many
years the clinical management of breast cancer was guided, to a
large extent, by the status (presence or absence) of this estrogen
receptor. A second form of the ER, with its variant isoforms, was
unexpectedly discovered by Gustafsson and co-workers in 1996,
during a search for novel androgen receptors in a rat prostate cDNA
library.2 This gene was called ERb to distinguish it from the long-
cancer, prostate cancer, endometriosis, and inflammation.4 Recent
findings that ER
cell proliferation, with ERb often having a moderating effect on the
ER
activity, have added further interest.5
ER and ERb have different tissue distributions and appear to
mediate different physiological functions. Although widely found
in many tissues, ER is predominantly expressed in reproductive
a is generally more active in driving breast cancer
a
a
a
tissues, kidney, liver, and central nervous system, whereas ERb is
expressed in bone, lungs, bladder, ovaries, endothelium, and pros-
tate. The two ERs have modest overall sequence identity, differing
primarily in their N-terminus domains, with higher sequence con-
servation in their DNA-binding domains (about 95% identity) and
moderate (58% amino acid sequence identity) in their ligand bind-
ing domains (LBDs).2b Despite only moderate homology in their
LBDs, X-ray structures have shown that the ligand binding pockets
known ER, which was then re-termed ERa. The discovery of ERb
made definition of the ER status of breast cancers more complex,
because, potentially, the phenotype of breast tumors might be con-
trolled by either or both ER-subtypes.3 In fact, the approximately
30% of breast cancers classified as ER negative by immunohisto-
chemical assays for ERa, might actually be positive for ERb expres-
sion. The potential for ERb to be a diagnostic or therapeutic target
of importance provided motivation to define its physiological role
in mediating estrogen action, and consequently, much attention
has been given to understanding the structures of the two ERs
of ER
idue different (ER
Ile373).6,7 Overall, however, the ERb ligand binding pocket is smal-
ler than that of ER , a difference that appears to be an important
factor in the binding of ER-subtype selective ligands.6,8 Despite
the structural similarity of the ER and ERb ligand binding sites,
a
and ERb are remarkably similar, with only 2 out of 24 res-
a
Leu384?ERb Met336 ER Met421?ERb
;
a
a
* Corresponding authors. Tel.: +82 2 970 1358; fax: +82 2 970 2409 (G.A.).
E-mail addresses: kyochul@kirams.re.kr (K.C. Lee), gwangil@kirams.re.kr (G. An).
a
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.02.064

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B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
it has proved possible to develop ER ligands that bind to and acti-
vate either ER or ERb with impressive selectivity, and a reason-
6d–f, and 11a–b) are shown in Scheme 1. Various a-cyanostilbenes
a
(4a, c and d–f) were prepared in 32–92% yield by the condensation
of 3-substituted 4-methoxybenzaldehyde analogues (2a, 2c–f) and
4-methoxyphenylacetonitrile (3) with NaOMe in EtOH at room
able pharmacophore model has been advanced to guide the
design of such subtype-selective ligands.7,9
The pharmacological use of ER-subtype-selective ligands is un-
der active investigation, but radioisotope-labeled versions of these
ligands for imaging the levels of ERa and ERb in various target tis-
sues by positron emission tomography (PET) or single photon
emission computed tomography (SPECT) might also be very useful
in assessing these receptors as targets for various estrogen thera-
temperature for 12 h.12 In case of 2b, the hydroxy-
a-cyanostilbene
could not be obtained without MEM protection. Bis-(methoxy-
phenyl)-propionitriles (5a, c and d–f) were obtained in excellent
yield upon reduction of the corresponding acrylonitriles with
NaBH4 in EtOH at 70 °C for 12 h. Subsequent deprotection of the
methyl ethers with BBr3 afforded the desired methyl, hydroxy
and halogen-substituted bisphenolic propionitriles (6a, b and
d–f) in 94–98% yields. The methyl ether of 6b was completely
removed by treatment with BBr3 after deprotection of MEM group
with 1 N HCl in CH3CN at 70 °C for 1 h, giving material with high
yield and purity.
To prepare the fluoroalkylated DPN analogs (11a–b), bisphenol-
ic nitrile (6f) was reprotected with MOMCl and NaH to give the
MOM-protected analog 7 in 82% yield. This change of protecting
groups was important, because in previous studies done on methyl
ether-protected materials, we found that the final methyl ether-
deprotection step, needed to obtain the desired fluoroalkyl bisphe-
nol products, also caused cleavage the C–F bond.11,13 The MOM
group was selected because it is stable to the type of basic condi-
tions used in the fluorination step, yet can easily be cleaved under
mild acidic conditions.
pies. In breast tumors, the level of ERb relative to ERa declines with
disease progression, as one might expect with transition of the
cancer to a more proliferative and malignant state.10 Thus, if it
were possible to measure ER
PET or SPECT, using radioisotope-labeled versions of ligands that
were highly selective for ER and ERb, one might obtain informa-
a and ERb levels non-invasively by
a
tion regarding disease stage and prognosis, and might even be able
to predict tumor response to endocrine therapies.
Among the various ERb pharmacophores, diarylpropionitrile
(DPN, 1a, Table 1) has good selectivity (72-fold ERb affinity prefer-
ence) with full agonistic character.9d A number of variants on the
DPN pharmacophore have been studied, and some of these (e.g.,
1b, 1c) had increased ERb binding affinity though reduced selectiv-
ity. On the basis of this structure–activity relationship, the F-18 la-
beled DPN analogue, FEDPN (1d), was prepared previously and
studied as a potential agent for PET imaging in rats and in ER
a
or
To prepare the allyl-, vinyl-substituted intermediates 8a–b, the
MOM-protected 7 was treated with allyl or vinyl tributylstannane
and Pd(II)(PPh3)2Cl2 in anhydrous 1,4-dioxane at 90 °C for 12 h,
thus giving the meta-allyl or vinyl bisphenyl nitrile 8a–b in 44–
64% yields. Hydroboration of alkenes 8a–b using a borane–THF
complex in THF at À10 °C for 12 h (for 9a) or room temperature
for 6 h (for 9b), and subsequent oxidation with aqueous NaOH/
H2O2, gave the terminal alcohols 9a–b (36–68%), which were
converted in high yields to the tosylates 10a–b, precursors of
fluorination, by treatment with toluenesulfonic anhydride and
triethylamine in CH2Cl2 at room temperature for 30 min. The
ether-protected fluoroethyl and fluoropropyl DPN analogs were
obtained from the tosylates 10a–b using CsF in tert-butanol at
100 °C for 16 h (>65%),13,14 followed by deprotection of the MOM
group with 1 N HCl/CH3CN at 70 °C for 1 h, to give designed fluoro-
alkyl DPN analogues (11a–b).
ERb knockout mice.11 Its ER-specific uptake in ERb target tissues
such as the ovary, however, was only modest, not enough for
[
18F]FEDPN to be useful for imaging ERb.11 Thus, there was a clear
need to develop PET imaging agents that would be more optimized
in terms of ERb binding affinity and selectivity than [18F]FEDPN. In
this regard, one ring-substituted DPN analog, the ortho-methyl
analog 1e, looked promising in terms of its in vitro receptor bind-
ing profile (Table 1). To extend this work, we describe in this report
the design, synthesis and preliminary biological evaluation of a
series of DPN analogs substituted in the synthetically more acces-
sible meta-position with several substituents of varying size and
polarity. Some of these are fluoroalkylated DPN analogs in which
it would be possible to introduce F-18, producing products that
might be candidate for ERb-selective PET tracers.
The iodinated DPN analog 13 was prepared as shown in Scheme
2. The MOM-protected aryl stannane 12 was obtained in 70% yield
from MOM-protected 7 by treatment with bis(tributyltin) and
Pd(II)(PPh3)2Cl2 at 100 °C. Iodination of stannane 12 with 1 M ICl/
CH2Cl2, followed by deprotection of the MOM group with 1 N
HCl/CH3CN at 70 °C for 1 h, gave phenolic iodo-DPN 13 in 78%
yield.
2. Results and discussion
2.1. Chemical synthesis
The routes for the preparation of the methyl-, hydroxy-, halo-
(F, Cl, and Br) and fluoroalkyl diarylpropionitriles (DPNs) (6a, 6b,
The hydroxymethyl analogue of DPN (20) was prepared as out-
lined in Scheme 3. Methyl ether-protected methyl-a-cyanostilbene
Table 1
(4a) was deprotected with BBr3, affording the desired bisphenolic
nitrile (14) in 94% yield. For the reasons described above, the free
phenol groups in 14 were then reprotected with MOMCl and
Relative binding affinity (RBA) of DPN estrogen ligands for the ER
a and ERb
OH
R1
NaH to give the MOM-protected analog 15 in 74% yield. a-Cyano-
stilbene brominated in the benzylic position (16) was prepared in
61% yield by treatment with NBS and benzoyl peroxide in CCl4 at
reflux, and the bromide was then substituted by treatment with
CN
HO
R2
TBAF-3H2O to give the fluoromethyl-a-stilbene moiety (17) in
Compound
R1
R2
RBA (E2 = 100)
a ERb
ERb/ERa ratio
74% yield. After conjugate reduction of unsaturated nitrile with
NaBH4 in EtOH (18, 96%), removal of the MOM group was at-
tempted. Deprotection of MOM, however, with various reagents,
such as 1 N HCl in MeOH, pyridinium p-toluenesulfonate in tert-
BuOH, AcCl in MeOH CF3COOH in CH2Cl2, or other conditions gave
only the hydroxymethyl DPN analogue (20). We suspect that the
sensitivity of this system is the result of its propensity for the
1,4-elimination of HF to form an orthoquinone methide species,
ER
1a
1b
1c
1d
1e
H
CH3
CH2CH3
CH2CH2F
H
H
H
H
H
0.25 0.15
1.7 0.3
18
48
75
2
3
6
72
11
4
21
69
17
5
0.42 0.09
0.87 0.18
8.74 1.87
60 11
CH3
Data are taken from Refs. 9d and 11.

B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
3481
O
OCH3
OCH3
OCH3
H
b
c
+
NC
H3CO
CN
CN
H3CO
H3CO
R
R
R
2a, R = CH3
2b, R = OH
3
4a, c, d-f
5a, c, d-f
a
2c, R = OMEM
2d, R = F
2e, R = Cl
2f, R = Br
OMOM
OMOM
OH
d,
f
e for 6b
g
CN
CN
MOMO
CN
MOMO
HO
n
Br
R
8a, n = 1
8b, n = 2
6a, b, d-f
7
OMOM
OH
OMOM
h
i
j
CN
CN
CN
MOMO
HO
MOMO
n
n
n
OH
F
OTs
9a, n = 1
9b, n = 2
11a, n = 1
11b, n = 2
10a, n = 1
10b, n = 2
Scheme 1. Reagents and conditions: (a) DIEA, MEMCl, CH2Cl2, reflux, 6 h; (b) NaOMe, EtOH, rt, 12 h; (c) NaBH4, EtOH, 70 °C, 12 h; (d) BBr3, CH2Cl2, À10 °C to rt, 12 h; (e) (i)
1 N HCl, CH3CN, 70 °C, 1 h; (ii) BBr3, CH2Cl2, À10 °C to rt, 12 h; (f) NaH, MOMCl, THF, À10 °C to 70 °C, 2 h; (g) allyltributyltin (or vinyltributyltin), Pd(II)(PPh3)2Cl2, 1,4-dioxane,
12 h; (h) BH3–THF complex, 4 N NaOH, 30% H2O2, THF, À10 °C, 12 h for 9a; À10 °C to rt, 6 h for 9b; (i) Ts2O, TEA, CH2Cl2, rt, 30 min; (j) (i) CsF, tert-BuOH, 100 °C, 16 h; (ii) 1 N
HCl, CH3CN, 70 °C, 1 h.
OH
OMOM
OMOM
b
a
CN
CN
CN
HO
MOMO
MOMO
I
SnBu3
Br
13
7
12
Scheme 2. Reagents and conditions: (a) Bistributyltin, Pd(II)(PPh3)2Cl2, 1,4-dioxane, 100 °C, 12 h; (b) (i) ICl, CH2Cl2, rt, 10 min; (ii) 1 N HCl, CH3CN, 70 °C, 1 h.
which then becomes hydrated, forming the hydroxy byproduct. Be-
cause of these difficulties, no further efforts toward fluoromethyl
DPN (19) were made.
ence for this ER-subtype, and all of the DPN analogues we have
investigated share this ERb selectivity to varying degrees. Although
the addition of a methyl group at the ortho-position of DPN (1e, Ta-
ble 1) results in a significantly increased affinity for ERb with main-
2.2. Relative binding affinity
tenance of high selectivity (60 11 for ERb and 0.87 0.18 for ER
a,
b/ = 69-fold), we found that changing the position of this substi-
a
The smaller substituted diarylpropionitrile estrogen analogues
(6a–b, 6d–f, 11a–b, 13, and 20) were evaluated in competitive
radiometric binding assays by previously described methods to
tuent from the ortho- to the meta-position (compound 6a, Table
2) resulted in a 36-fold loss in ERb binding affinity but, surpris-
ingly, a two-fold increase in b/
ring meta-substituted DPN analogues (6a–b, 6d–f, 13) showed
lower binding affinities for both ER and ERb subtypes than estra-
a selectivity. In fact, all of the aryl
measure their affinities for human ERa
and ERb.15,16 Affinities ob-
tained with these competitive binding assays are expressed as rel-
ative binding affinity (RBA) values, that is, relative to the that of
[3H]estradiol, which is 100% by definition. The binding affinities
a
diol, and also than DPN. While the ERb binding affinities of the ana-
logues having small substituents (namely, compounds 6a–b, 6d–f,
for the new DPN analogues we prepared and their ERb/ER
ratios are summarized in Table 2.
a
affinity
13) are around 1–6% that of estradiol (100%), because their ER
affinities are all less than 0.025% that of estradiol, their ERb/ER
a
a
Analogues of the ERb-selective ligand diarylpropionitrile (DPN,
1a) containing substituents in the meta-position were investigated
to establish the tolerance that ERb has at this position for small
substituents such as CH3, OH, F, Cl, Br, and I. The lead compound,
DPN (1a), has high ERb binding selectivity, with a 72-fold prefer-
selectivities range from 106 to 272. The size and electronic nature
of these six substituents had relatively little effect on both their
ER
a
and ERb binding affinities.
Among the meta-halogen-substituted systems that might be
radiolabeled for PET or SPECT imaging, fluoro-DPN (6d), which

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B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
OCH3
OMOM
OH
b
c
a
CN
CN
CN
H3CO
MOMO
HO
CH3
CH3
CH3
4a
14
15
OMOM
OMOM
OMOM
e
d
CN
18
CN
CN
MOMO
f
MOMO
MOMO
F
F
Br
17
16
f
OH
OH
CN
CN
HO
HO
OH
F
20
19
Scheme 3. Reagents and conditions: (a) BBr3, CH2Cl2, À10 °C to rt, 12 h; (b) NaH, MOMCl, THF, À10 °C to 70 °C, 2 h; (c) NBS, Bz2O2, CCl4, 70 °C, 2 h; (d) TBAF-3H2O, CH3CN,
70 °C, 30 min; (e) NaBH4, EtOH, 70 °C, 12 h; (f) 1 N HCl, MeOH or pyridinium p-toluenesulfonate, tert-BuOH, or AcCl, MeOH or CF3COOH, CH2Cl2.
might be labeled with fluorine-18, has the most favorable binding
affinities, 6.25% for ERb and 0.023% for ER , giving an ERb/ER ratio
of 272-fold. Iodo-DPN (13), which might be labeled with iodine-
123 or 124, showed 2.95% for ERb and 0.021% for ER , giving a
selectivity of 140-fold, and bromo-DPN (6f), which could be la-
beled with bromine-76 or 77, had somewhat lower ERb binding
affinity and selectivity. None of these, however, would be particu-
larly favorable for in vivo imaging.
Therefore, we investigated the meta-fluoroalkyl-DPN ana-
logues, fluoromethyl- (19), fluoroethyl- (11a), or fluoropropyl-
DPN (11b), into which it might be possible to introduce fluo-
rine-18 relatively easily by nucleophilic aliphatic substitution.
By contrast, the methods to label the fluorophenol unit in 6d
with fluorine-18 are relatively inefficient. Despite numerous at-
tempts, we were unable to prepare fluoromethyl-DPN (19); all
of the various deprotection conditions we used gave only
hydroxymethyl DPN (20), an analog which has very low affinity
ciently promising for them to be considered further as potential
PET or SPECT imaging radiotracers.
a
a
a
3. Conclusions
In conclusion, in an exploration to prepare ligands with good
binding affinity and selectivity for the estrogen receptor b (ERb)
that might be explored further as PET imaging agents, we prepared
nine new derivatives of the known ERb-selective ligand, diarylpro-
pionitrile (DPN), bearing substituents in the meta-position of the
distal phenol ring. These included ones having fluoroethyl and flu-
oropropyl groups as well as methyl, hydroxymethyl, and halo-
substituted DPN analogs to explore the structure–binding affinity
relationship at this site. In competitive radiometric binding assays
with [3H]estradiol, most DPN derivatives showed greater ERb/ER
selectivity than that of DPN. Among these, the meta-fluoro analog,
6d, had the greatest ERb/ER selectivity 272-fold, with affinities
that were 0.023% for ER and 6.25% for ERb relative to that of estra-
a
a
for both ER
selectivity (19-fold). The affinity of fluoroethyl-DPN (11a) for
ER 0.024%) was similar to that of fluoropropyl-DPN 11b,
0.020%), while its affinity for ERb 1.38%) was slightly higher than
that of 11b (0.896%); the ERb/ER ratios of these two com-
a (0.002%) and ERb (0.037%), and a modest ERb/ERa
a
diol. Despite the good ERb binding selectivities of many members
of this series, their absolute binding affinities for ERb are not good
enough for them to be considered useful as potential PET or SPECT
imaging agents for ERb. In addition, preparation of the ortho-fluoro
phenol unit in the most favorable compound (6d) in fluorine-18 la-
beled form would be challenging. Thus, ligands with more opti-
mized ERb binding affinity and adequate selectivities are likely
be required for in vivo imaging of this estrogen receptor subtype.
a
a
pounds were 58- and 45-fold, respectively. In terms of both
ERb binding affinity and selectivity, the fluoroethyl-DPN (11a)
is the better of the two fluoroalkyl derivatives.
Overall, although some of the DPN analogues we prepared
had very high ERb/ER
a selectivities, one reaching almost 300-
fold, none of them showed an affinity for ERb that was better
than that of DPN itself. From previously reported results,9d it is
known that some DPNs with more optimized ERb binding affin-
ity and selectivity need to contain a linear core functional group,
for example, nitriles or acetylenes, with relatively few other
changes in the DPN structure. The fact that the binding affinity
of the DPN analogues bearing small substituents in the meta-po-
sition, as characterized in this study, showed a several-fold drop
in affinity is, unfortunately, consistent with these trends. Thus,
the binding characteristics of these DPN analogs are not suffi-
4. Experimental
4.1. Chemistry
4.1.1. General
All commercial reagents and solvents were used without fur-
ther purification unless otherwise specified. Reagents and solvents
were commercially purchased from Sigma–Aldrich (USA), Merck
(Germany) and TCI (Japan). Reaction progress was monitored by

B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
3483
ratio
Table 2
Table 2 (continued)
Relative binding affinity (RBA)a values for ER
a and ERb and the selectivity for ERb as
Compound
RBA (%)
b/a
determined by b/a ratio
hER
a
hERb
Compound
RBA (%)
hERb
b/a ratio
hER
a
OH
OH
0.020 0.004
0.896 0.19
45
CN
HO
0.25 0.15
18
2
72
11b, n = 3
CN
n
F
HO
1a, DPN
OH
OH
0.002 0.00
0.037 0.008
19
CN
HO
HO
0.012 0.001
1.67 0.32
1.27 0.31
6.25 1.4
139
20
CN
HO
Determined by a competitive radiometric binding assay with [3H]estradiol and
full length human ER and ERb. The RBA of estradiol (E2) is defined as 100 and the
measured RBA values are reported as the mean range or SD (n = 2 or 3).
a
6a
CH3
a
OH
OH
OH
analytical thin layer chromatography (TLC) with Merck 60 F-254
silica plates and visualized by UV light (254 nm) or phosphomolyb-
dic acid indicator. Flash column chromatography was performed
on silica gel (Merck, 230–400 mesh ASTM). 1H and 13C NMR spectra
were recorded on a Bruker-300 instrument, and chemical shifts (d,
ppm) are reported in parts per million downfield from tetrameth-
ylsilane. Low- and high-resolution electron impact (EI) and chem-
ical ionization (CI) mass spectra were obtained on a JMS700
spectrometer (JEOL Co., Japan).
0.012 0.004
0.023 0.003
0.010 0.001
0.012 0.004
106
272
112
108
CN
HO
HO
HO
HO
6b
OH
CN
4.1.2. 3-Methoxyethoxymethyl-4-methoxybenzaldehyde (2c)
Methoxyethoxymethyl chloride (1.12 mL, 9.86 mmol) was
added dropwise to a CH2Cl2 (40 mL) containing 3-hydroxy-4-
methoxybenzaldehyde (1.0 g, 6.57 mmol) and DIEA (3.43 mL,
19.7 mmol) at À10 °C. The reaction mixture was refluxed at 60 °C
for 6 h and then cooled to room temperature. After the mixture
was extracted with CH2Cl2, the organic layer was dried over so-
dium sulfate. The crude product was purified by flash column chro-
matography (40% EtOAc/hexane) to give 2c (1.39 g, 88%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) d 9.84 (br s, 1H), 7.69 (d,
J = 1.8 Hz, 1H), 7.54 (dd, J = 8.4, 1.8 Hz, 1H), 6.99 (d, J = 8.4 Hz,
1H), 5.36 (s, 2H), 3.95 (s, 3H), 3.88–3.85 (m, 2H), 3.57–3.54 (m,
2H), 3.36 (s, 3H); 13C NMR (75 MHz, CDCl3) d 190.7, 155.1, 146.9,
130.2, 126.5, 116.0, 111.2, 94.4, 71.5. 68.2, 59.1, 56.2; MS (EI) m/
z: 240, 165, 151, 137, 109, 90 (100), 59 (100). HRMS (EI) calcd
for C12H16O5 (M+) 240.0998, found 240.0998.
6d
F
1.12 0.04
CN
6e
Cl
OH
1.30 0.13
CN
Br
6f
4.1.3. General method for (Z)-2-(3-methyl (4a)-, methoxyeth-
oxymethyl (4c)-, fluoro (4d)-, chloro (4e)-, bromo (4f)-4-
methoxyphenyl)-3-(4-methoxyphenyl)acrylonitrile
OH
OH
a
-Cyanostilbenes (4a, c–f) were prepared by the condensation
of arylaldehydes (2a, c–f) and arylacetonitriles (3) according to a
reported method with little modification.1 Briefly, for 4f, a solution
of 3-bromo-4-methoxybenzaldehydes (2f, 2.0 g, 9.3 mmol) and 4-
methoxyphenylacetonitrile (3, 1.26 mL, 9.3 mmol) in absolute
EtOH (6.5 mL, 0.7 mL/mmol) was treated with 0.5 N NaOMe
(1.86 mL, 0.93 mmol) portionwise and then stirred at room tem-
perature for 12 h. The reaction mixture was placed in a À24 °C
freezer for 1 h, and the precipitate was collected by filtration. The
precipitate was washed with cold ethanol to give 4f (2.9 g, 91%)
as a white solid: 1H NMR (300 MHz, CDCl3) d 7.97–7.92 (m, 2H),
7.56 (d, J = 9.0 Hz, 2H), 7.27 (s, 1H), 6.98–6.93 (m, 3H), 3.95 (s,
3H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) d 160.4, 157.1, 138.0,
0.021 0.001
2.95 0.34
140
CN
HO
HO
13
I
0.024 0.001
1.38 0.33
58
CN
11a
, n = 2
n
F

3484
B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
134.5, 129.2, 128.0, 127.2, 126.9, 118.2, 114.5, 112.0, 111.8, 110.0,
56.4, 55.5; MS (EI) m/z: 345 (M++2, 100), 343 (M+, 100), 330, 328,
221. HRMS (EI) calcd for C17H14NO2Br (M+) 343.0207, found
343.0200.
column chromatography (30% EtOAc/hexane) to give 5f (2.51 g,
95%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) d 7.26 (d,
J = 2.1 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.03 (dd, J = 8.4, 2.1 Hz,
1H), 6.87 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H), 3.93–3.87 (m,
4H), 3.80 (s, 3H), 3.11–2.97 (m, 2H); 13C NMR (75 MHz, CDCl3) d
159.4, 155.1, 133.9, 129.8, 129.4, 128.6, 126.8, 120.4, 114.4,
111.8, 111.5, 56.2, 55.3, 41.0, 39.0; MS (EI) m/z: 347 (M++2, 9.1)
345 (M+, 9.8), 201 (100), 199 (100), 146, 121, 105, 90, 77. HRMS
(EI) calcd for C17H14NO2Br (M+) 345.0364, found 345.0367.
4.1.3.1. (Z)-2-(3-Methyl-4-methoxyphenyl)-3-(4-methoxy-
phenyl)acrylonitrile (4a). This material was prepared by a proce-
dure similar to that used for the preparation of 4f, described above
(yellow solid, 32%): 1H NMR (300 MHz, CDCl3) d 7.77 (dd, J = 8.4,
2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.33
(s, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 3.89 (s,
3H). 3.85 (s, 3H), 2,26 (s, 3H); 13C NMR (75 MHz, CDCl3) d 160.0,
159.4, 140.3, 131.7, 128.5, 127.6, 127.2, 127.0, 126.3, 118.8,
114.4, 110.0, 107.9, 55.5, 55.4, 16.3; MS (EI) m/z: 279 (M+), 220,
191, 177, 163, 135 (100), 121, 107, 95. HRMS (EI) calcd for
C18H17O2 N (M+) 279.1259, found 279.1261.
4.1.4.1. 2-(3-Methyl-4-methoxyphenyl)-3-(4-methoxy-
phenyl)propionitrile (5a). This material was prepared by a pro-
cedure similar to that used for the preparation of 5f, described
above (pale yellow solid, 97%): 1H NMR (300 MHz, CDCl3) d 7.17
(d, J = 8.7 Hz, 2H), 6.94–6.85 (m, 4H), 6.73 (d, J = 7.8 Hz, 1H),
3.92–3.85 (m, 1H), 3.81 (s, 6H), 3.11–2.99 (m, 2H), 2.18 (s, 3H);
13C NMR (75 MHz, CDCl3) d 159.4, 157.0, 131.5, 128.6, 128.1,
127.5, 126.7, 120.8, 114.3, 109.9, 55.4, 55.3, 41.6, 39.4, 16.2; MS
(EI) m/z: 281 (M+), 146, 135 (100), 120, 91. HRMS (EI) calcd for
C18H19NO2 (M+) 281.1416, found 281.1416.
4.1.3.2. (Z)-2-(3-Methoxyethoxymethyl-4-methoxyphenyl)-3-
(4-methoxyphenyl)acrylonitrile (4c). This material was pre-
pared by a procedure similar to that used for the preparation of
4f, described above. The purification of 4c, however, was achieved
by flash column chromatography (40% EtOAc/hexane) to give 4c
(92%) as a pale green oil: 1H NMR (300 MHz, CDCl3) d 7.65–7.64
(m, 4H), 7.57 (d, J = 9.0 Hz, 1H), 6.97–6.93 (m, 3H), 5.23 (s, 2H),
3.92–3.89 (m, 5H), 3.84 (s, 3H), 3.60–3.57 (m, 2H), 3.37 (s, 3H);
13C NMR (75 MHz, CDCl3) d 160.2, 151.44, 146.4, 139.8, 127.3,
127.14, 127.10, 123.9, 118.5, 117.7, 114.4, 111.7, 109.1, 94.7,
71.53, 68.0, 59.0, 56.0, 55.4; MS (EI) m/z: 369 (M+, 100), 339, 293,
281, 89. HRMS (EI) calcd for C21H23NO5 (M+) 369.1576, found
369.1573.
4.1.4.2. 2-(3-Methoxyethoxymethyl-4-methoxyphenyl)-3-(4-
methoxyphenyl)propionitrile (5c). This material was prepared
by a procedure similar to that used for the preparation of 5f, de-
scribed above (white oily solid, 93%): 1H NMR (300 MHz, CDCl3)
d 7.15 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 1.5 Hz, 1H), 6.87–6.73 (m,
4H), 5.25 (s, 2H), 3.90 (t, J = 7.4 Hz, 1H), 3.85–3.82 (m, 5H), 3.78
(s, 3H), 3.55–3.52 (m, 2H), 3.36 (s, 3H), 3.10–2.96 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 159.3, 148.9, 146.4, 129.0, 128.7, 127.3,
123.2, 120.7, 117.3, 114.3, 111.6, 94.4, 71.5, 67.7, 59.0, 55.9, 55.3,
41.7, 39.2; MS (EI) m/z: 371 (M+), 296, 225 (100), 195, 151, 137,
89, 59. HRMS (EI) calcd for C21H25NO5 (M+) 371.1732, found
371.1730.
4.1.3.3. (Z)-2-(3-Fluoro-4-methoxyphenyl)-3-(4-methoxy-
phenyl)acrylonitrile (4d). This material was prepared by a proce-
dure similar to that used for the preparation of 4f, described above
(pale yellow solid, 90%): 1H NMR (300 MHz, CDCl3) d 7.69–7.56 (m,
4H), 7.29–7.26 (m, 1H), 7.04–6.93 (m, 3H), 3.94 (s, 3H), 3.85 (s,
3H); 13C NMR (75 MHz, CDCl3) d 160.4, 152.1 (d, J = 245.5 Hz),
149.2 (d, J = 10.9 Hz), 138.5 (d, J = 2.3 Hz), 127.2, 127.1, 126.9,
126.1 (d, J = 3.3 Hz), 118.2, 116.4 (d, J = 19.4 Hz), 114.5, 113.2 (d,
J = 2.2 Hz), 109.9, 56.3, 55.5; MS (EI) m/z: 283 (M+, 100), 268,
225, 208, 196, 142. HRMS (EI) calcd for C17H14NO2F (M+)
283.1008, found 283.1009.
4.1.4.3. 2-(3-Fluoro-4-methoxyphenyl)-3-(4-methoxy-
phenyl)propionitrile (5d). This material was prepared by a pro-
cedure similar to that used for the preparation of 5f, described
above (white solid, 89%): 1H NMR (300 MHz, CDCl3) d 7.14 (d,
J = 8.7 Hz, 2H), 6.89–6.79 (m, 5H), 3.91 (t, J = 7.4 Hz, 1H) 3.87 (s,
3H), 3.80 (s, 3H), 3.12–2.99 (m, 2H); 13C NMR (75 MHz, CDCl3) d
159.5, 152.1 (d, J = 244.7 Hz), 146.9 (d, J = 10.4 Hz), 129.1 (d,
J = 6.2 Hz), 128.6, 126.8, 125.1 (d, J = 3.5 Hz), 120.5, 116.9 (d,
J = 18.3 Hz), 114.4, 113.3 (d, J = 2.0 Hz), 56.2, 55.3, 41.3, 38.9; MS
(EI) m/z: 285 (M+), 139 (100), 105, 96, 77. HRMS (EI) calcd for
C17H16NO2F (M+) 285.1165, found 285.1166.
4.1.3.4. (Z)-2-(3-Chloro-4-methoxyphenyl)-3-(4-methoxy-
phenyl)acrylonitrile (4e). This material was prepared by a proce-
dure similar to that used for the preparation of 4f, described above
(pale green solid, 83%): 1H NMR (300 MHz, CDCl3) d 7.86 (dd,
J = 8.7, 2.4 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H),
7.27 (s, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 3.95
(s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d 160.4, 156.3,
138.2, 131.3, 128.6, 127.5, 127.2, 126.9, 122.9, 118.2, 114.5,
112.0, 110.0, 56.3, 55.5; MS (EI) m/z: 301 (M++2, 47), 299 (100),
284, 221, 206, 178, 151. HRMS (EI) calcd for C17H14NO2Cl (M+)
299.0713, found 299.0712.
4.1.4.4. 2-(3-Chloro-4-methoxyphenyl)-3-(4-methoxy-
phenyl)propionitrile (5e). This material was prepared by a proce-
dure similar to that used for the preparation of 5f, described above
(white solid, 97%): 1H NMR (300 MHz, CDCl3) d 7.15 (d, J = 8.7 Hz,
2H), 7.10 (d, J = 2.1 Hz, 1H), 6.98 (dd, J = 8.7, 2.1 Hz, 1H), 6.89–
6.82 (m, 3H), 3.93–3.83 (m, 4H), 3.80 (s, 3H), 3.11–2.98 (m, 2H);
13C NMR (75 MHz, CDCl3) d 159.5, 154.3, 130.9, 129.4, 128.7,
128.6, 126.8, 122.3, 120.4, 114.4, 112.0, 56.1, 55.4, 41.1, 39.0; MS
(EI) m/z: 303 (M++2, 3.0)301 (M+, 8.9), 157 (41), 155 (100), 146,
105, 91, 77. HRMS (EI) calcd for C17H16NO2Cl (M+) 301.0869, found
301.0870.
4.1.4. General method for the 2-(3-methyl (5a)-, methoxyeth-
oxymethyl (5c)-, fluoro (5d)-, chloro (5e)-, bromo (5f)-4-
methoxyphenyl)-3-(4-methoxyphenyl)propionitrile
Bismethoxyphenyl nitriles (5a, c–f) were prepared by the con-
jugate reduction of unsaturated nitriles with NaBH4 in EtOH.
Briefly, for 5f, NaBH4 (576 mg, 15.2 mmol) was added to a solution
4.1.5. General method for the 2-(3-methyl (6a)-, hydroxy (6b)-,
fluoro (6d)-, chloro (6e)-, bromo (6f)-4-hydroxyphenyl)-3-(4-
hydroxyphenyl)propionitrile
of
a
-cyanostilbene 4f (2.6 g, 7.61 mmol) in 40 mL of anhydrous
Bisphenolic nitriles (6a, b, d–f) were prepared by removal of
methyl ether with 1 M BBr3/CH2Cl2. Briefly, for 6f, boron tribro-
mide (1.0 M in CH2Cl2, 41.6 mL) was added slowly dropwise to a
EtOH under argon atmosphere. After the reaction mixture was
warmed to 70 °C for 12 h, the solution was cooled to room temper-
ature. The mixture was extracted with ethyl acetate (Â3), and the
organic layer was dried over sodium sulfate and purified by flash
stirred solution containing bismethoxyphenylacrylonitrile
5
(2.4 g, 6.9 mmol) in CH2Cl2 (80 mL) at À10 °C. After stirring for

B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
3485
30 min, the ice bath was removed, and stirring was continued for
12 h. The solution was cooled in an ice bath, and then slowly
quenched with small amounts of water. The mixture solution
was extracted with ethyl acetate (Â3) and washed with brine.
The organic layer was dried over sodium sulfate and purified by
flash column chromatography (50% EtOAc/hexane) to give 6f
(2.15 g, 98%) as a white oily solid: 1H NMR (300 MHz, MeOD-d4)
d 7.25 (d, J = 2.1 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.93 (dd, J = 8.1,
2.1 Hz, 1H), 6.79–6.73 (m, 3H), 4.10 (t, J = 7.4 Hz, 1H), 3.00 (d,
J = 7.4 Hz, 2H); 13C NMR (75 MHz, MeOD-d4) d 157.1, 153.1,
133.5, 129.4, 129.3, 128.5, 126.1, 120.8, 115.6, 115.3, 109.2, 40.3,
38.2; MS (CI) m/z: 320 (MH++2, 55.3), 318 (MH+, 56.1), 293
(99.0), 291 (100), 240, 213. HRMS (CI) calcd for C15H13NO2Br
(MH+) 318.0129, found 318.0131.
water in an ice bath. The solution was diluted with ethyl acetate
and then washed with water. The combined organic layer was
dried over sodium sulfate and concentrated. The crude product
was purified by flash column chromatography (25% EtOAc/hexane)
to give 7 (2.4 g, 82%) as a white oily solid: 1H NMR (300 MHz,
CDCl3) d 7.28 (d, J = 2.1 Hz, 1H), 7.16 (d, 8.7 Hz, 2H), 7.06–7.01
(m, 4H), 5.23 (s, 2H), 5.18 (s, 2H), 3.93–3.88 (m, 1H), 3.5 (s, 3H),
3.48 (s, 3H). 3.06–3.02 (m, 2H); 13C NMR (75 MHz, CDCl3) d
157.2, 153.1, 134.0, 131.2, 129.3, 128.6, 128.1, 120.3, 116.8,
116.1, 112.8, 95.1, 94.4, 56.4, 56.1, 41.1, 39.0; MS (EI) m/z: 407
(M++2), 405 (M+), 234, 232, 221 (100), 201, 191. HRMS (EI) calcd
for C19H20NO4Br (M+) 405.0575, found 405.0576.
4.1.7. 2-(3-Vinyl-4-methoxymethoxyphenyl)-3-(4-methoxy-
methoxyphenyl)propionitrile (8a)
4.1.5.1. 2-(3-Methyl-4-hydroxyphenyl)-3-(4-hydroxyphenyl)pro-
pionitrile (6a). This material was prepared by a procedure similar
to that used for the preparation of 6f, described above (pale yellow
solid, 97%): 1H NMR (300 MHz, MeOD-d4) d 7.08 (d, J = 8.7 Hz, 2H),
6.85–6.72 (m, 4H), 6.62 (d, J = 8.1 Hz, 1H), 4.04 (t, J = 7.5 Hz, 1H).
2.95 (d, J = 7.5 Hz, 2H), 2.12 (s, 3H); 13C NMR (75 MHz, MeOD-d4)
d 157.0, 154.2, 131.4, 128.4, 127.6, 127.2, 126.6, 124.1, 121.1,
115.2, 114.0, 41.1, 38.6; MS (CI) m/z: 254 (MH+), 227 (100), 121.
HRMS (CI) calcd for C16H16NO2 (MH+) 254.1181, found 254.1185.
Pd(II)(PPh3)2Cl2 (86 mg, 0.123 mmol) and vinyltributyltin
(1.08 mL, 3.69 mmol) was added to a solution of MOM protected
propionitrile
7 (1.0 g, 2.46 mmol) in anhydrous 1,4-dioxane
(40 mL) under argon atmosphere. The reaction mixture was heated
to 100 °C for 2 h. The solution was removed in a vacuum and the
crude product purified by flash chromatography (25% EtOAc/hex-
anes) to give vinyl 8a (590 mg, 68%) as a yellow oil: 1H NMR
(300 MHz, CDCl3) d 7.19–7.16 (m, 3H), 7.06–6.96 (m, 5H), 5.62
(dd, J = 18, 1.5 Hz, 1H), 5.25 (dd, J = 11.4, 1.5 Hz, 1H), 5.19 (s, 2H),
5.17 (s, 2H), 3.94–3.90 (m, 1H), 3.480 (s, 3H), 3.476 (s, 3H), 3.15–
3.03 (m, 2H); 13C NMR (75 MHz, CDCl3) d 157.1, 153.6, 131.3,
129.7, 129.6, 128.7, 128.5, 127.6, 127.3, 120.6, 116.7, 115.0,
114.9, 94.7, 94.4, 56.2, 56.1, 41.6, 39.2; MS (EI) m/z: 353 (M+),
231, 221, 177, 145 (100), 117. HRMS (EI) calcd for C21H23NO4
(M+) 353.1627, found 353.1628.
4.1.5.2. 2-(3-Hydroxy-4-hydroxyphenyl)-3-(4-hydroxyphenyl)pro-
pionitrile (6b). This material was prepared by a procedure similar to
that used for the preparation of 6f, described above. The preparation of
6b, however, was achieved by 1 M BBr3/CH2Cl2 after MEM deprotec-
tion with 1 N HCl in CH3CN at 70 °C for 1 h: 1H NMR (300 MHz,
MeOD-d4) d 7.07 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.65 (d,
J = 8.1 Hz, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.47 (dd, J = 8.1, 2.1 Hz, 1H),
4.03 (t, J = 7.4 Hz, 1H), 2.93 (d, J = 7.4 Hz, 2H); 13C NMR (75 MHz,
MeOD-d4) d 156.9, 144.7, 144.0, 128.44, 128.40, 126.5, 121.1, 120.4,
116.1, 115.2, 114.9, 41.2, 38.5; MS (EI) m/z: 255 (M+), 123, 105, 77.
HRMS (EI) calcd for C15H13NO3 (M+) 255.0895, found 255.0892.
4.1.8. 2-(3-Allyl-4-methoxymethoxyphenyl)-3-(4-methoxy-
methoxyphenyl)propionitrile (8b)
This material was prepared by a procedure similar to that used
for the preparation of vinyl 8a, described above, and obtained allyl
8b (44%) as colorless oil: 1H NMR (300 MHz, CDCl3) d 7.16 (d,
J = 8.7 Hz, 2H), 7.02–7.00 (m, 4H), 6.86 (d, J = 1.8 Hz, 1H), 5.96–
5.85 (m, 1H), 5.17 (s, 4H), 5.04–4.97 (m, 2H), 3.92–3.87 (m, 1H),
3.48 (s, 3H), 3.90 (s, 3H), 3.34 (d, J = 6.3 Hz, 2H), 3.08–2.98 (m,
2H); 13C NMR (75 MHz, CDCl3) d 157.0, 154.2, 136.7, 130.9,
129.5, 129.3, 128.7, 128.6, 128.1, 120.6, 116.7, 115.6, 114.1, 94.4
(two), 56.1 (two), 41.6, 39.2, 34.2; MS (EI) m/z: 367 (M+), 191
(100), 159. HRMS (EI) calcd for C22H25NO4 (M+) 367.1783, found
367.1783.
4.1.5.3. 2-(3-Fluoro-4-hydroxyphenyl)-3-(4-hydroxyphenyl)pro-
pionitrile (6d). This material was prepared by a procedure similar
to that used for the preparation of 6f, described above (white solid,
96%): 1H NMR (300 MHz, MeOD-d4) d 7.08 (d, J = 8.4 Hz, 2H), 6.88–
6.73 (m, 5H), 4.10 (t, J = 7.4 Hz, 1H), 2.99 (d, J = 7.4 Hz, 2H); 13C NMR
(75 MHz, MeOD-d4) d 157.1, 151.2 (d, J = 238.8 Hz), 143.7 (d,
J = 13.0 Hz), 128.6 (d, J = 6.0 Hz), 128.4, 126.2, 125.1 (d, J = 3.2 Hz),
120.8, 117.1 (d, J = 3.0 Hz), 116.3 (d, J = 18.6 Hz), 115.2, 40.6, 38.2;
MS (CI) m/z: 258 (MH+), 231 (100), 125. HRMS (CI) calcd for
C15H13NO2F (MH+) 258.0930, found 258.0932.
4.1.9. 2-(3-Hydroxyethoxy-4-methoxymethoxyphenyl)-3-(4-
methoxymethoxyphenyl)propionitrile (9a)
BH3–THF complex (1 M, 2.16 mmol, 2.16 mL) was added drop-
wise to an anhydrous tetrahydrofuran (30 mL) solution of vinyl
8a (510 mg, 1.44 mmol) at À10 °C. The reaction mixture was stir-
red at 0 °C for 12 h under an argon atmosphere. The mixture was
quenched with small amounts of water. Sodium hydroxide (4 M,
7 mL) and 30% H2O2 (8 mL) were added, and the resulting reaction
mixture was stirred for 30 min more in an ice bath. The solution
was extracted with ethyl acetate, and the combined organic layer
was dried over sodium sulfate and concentrated. The crude prod-
uct was purified by flash column chromatography (50% EtOAc/hex-
ane) to give hydroxyethoxy 9a (196 mg, 36%) as colorless oil: 1H
NMR (300 MHz, CDCl3) d 7.16 (d, J = 8.7 Hz, 2H), 7.03–7.00 (m,
4H), 6.88 (d, J = 2.1 Hz, 1H), 5.19 (s, 2H), 5.17 (s, 2H), 3.91 (t,
J = 7.2 Hz, 1H), 3.78 (t, J = 6.6 Hz, 2H), 3.48 (s, 3H), 3.47 (s, 3H),
3.07–3.03 (m, 2H), 2.85 (t, J = 6.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 157.1, 154.6, 132.0, 129.5, 128.7, 128.51, 128.47, 127.7,
120.6, 116.7, 114.1, 94.5, 94.4, 62.7, 56.2, 56.1, 41.5, 39.3, 33.9;
MS (EI) m/z: 371 (M+), 310, 221, 195, 163, 133 (100). HRMS (EI)
calcd for C21H25NO5 (M+) 371.1732, found 371.1732.
4.1.5.4. 2-(3-Chloro-4-hydroxyphenyl)-3-(4-hydroxyphenyl)pro-
pionitrile (6e). This material was prepared by a procedure similar
to that used for the preparation of 6f, described above (white solid,
96%): 1H NMR (300 MHz, MeOD-d4) d 7.08–7.05 (m, 3H), 6.87 (dd,
J = 8.4, 2.1 Hz, 1H), 6.81–6.75 (m, 3H), 4.05 (t, J = 7.4 Hz, 1H), 2.97
(d, J = 7.4 Hz, 2H); 13C NMR (75 MHz, MeOD-d4) d 157.0, 151.9,
130.4, 129.1, 128.7, 128.5, 126.1, 120.8, 120.0, 116.1, 115.3, 40.4,
38.2; MS (CI) m/z: 276 (MH++2, 13.6), 274 (MH+, 38.2), 249 (35.5),
247 (100), 141. HRMS (CI) calcd for C15H13NO2Cl (MH+) 274.0635,
found 274.0640.
4.1.6. 2-(3-Bromo-4-methoxymethoxyphenyl)-3-(4-methoxy-
methoxyphenyl)propionitrile (7)
Chloromethyl methyl ether (2.2 mL, 28.92 mmol) was added in
solution of 6f (2.3 g, 7.23 mmol) in anhydrous THF (80 mL) at
À10 °C. After stirring for 5 min, NaH (60%, 1.15 g, 28.92 mmol)
was added in several portions over 5 min. The reaction mixture
was refluxed for 2 h and then quenched with small amounts of

3486
B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
4.1.10. 2-(3-Hydroxypropoxy-4-methoxymethoxyphenyl)-3-(4-
methoxymethoxyphenyl)propionitrile (9b)
chromatography (30% EtOAc/hexane) to give ether-protected 11a.
The collected compound was dissolved in CH3CN (15 mL) and stir-
red with 1 N HCl (6 mL) for 1 h at 80 °C. The solution was extracted
with ethyl acetate, and combined organic layer was dried over so-
dium sulfate and concentrated. The crude product was purified by
flash column chromatography (50% EtOAc/hexane) to give fluoroe-
thylate 11a (74 mg, 78%) as a white solid: 1H NMR (300 MHz,
MeOD-d4) d 7.60 (d, J = 8.4 Hz, 2H), 6.87–6.83 (m, 2H), 6.75 (d,
J = 8.4 Hz, 2H), 6.66 (d, J = 8.7 Hz, 1H), 4.50 (dt, J = 47.4, 7.0 Hz,
2H), 4.06 (t, J = 7.4 Hz, 1H), 3.00–2.86 (m, 4H); 13C NMR (75 MHz,
MeOD-d4) d 157.0, 154.4, 131.7, 128.43, 128.38, 127.6, 126.4,
122.9, 122.8, 121.0, 115.2, 114.4, 82.4 (d, J = 166.4 Hz), 41.0, 38.5,
31.2 (d, J = 20.9 Hz); MS (CI) m/z: 286 (MH+), 266 (100), 259, 239,
153, 133. HRMS (CI) calcd for C17H17O2NF (MH+) 286.1243, found
286.1243.
This material was prepared by a procedure similar to that used
for the preparation of allyl 9a, described above: 1 M BH3–THF com-
plex (2.12 mmol, 2.12 mL) was added in anhydrous tetrahydrofu-
ran solution (30 mL) of vinyl 8b (520 mg, 1.42 mmol) dropwise at
À10 °C. The reaction mixture was stirred at 0 °C for 30 min and
stirred for 6 h more at room temperature under an argon atmo-
sphere. The solution was quenched with small amounts of water.
Sodium hydroxide (4 M, 7.0 mL) and 30% H2O2 (8.0 mL) was added,
and the resulting reaction mixture was stirred for 30 min more in
an ice bath. The mixture was extracted with ethyl acetate, and the
combined organic layer was dried over sodium sulfate and concen-
trated. The crude product was purified by flash column chromatog-
raphy (50% EtOAc/hexane) to give hydroxypropoxy 9b (370 mg,
68%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) d 7.15 (d,
J = 8.7 Hz, 2H), 7.03–6.94 (m, 4H), 6.85 (d, J = 2.1 Hz, 1H), 5.19 (s,
2H), 5.17 (s, 2H), 3.91 (t, J = 7.2 Hz, 1H), 3.55 (t, J = 6.0 Hz, 2H),
3.48 (s, 6H), 3.07–3.03 (m, 2H), 2.68 (t, J = 7.4 Hz, 2H), 1.83–1.74
(m, 3H, –CH2, OH); 13C NMR (75 MHz, CDCl3) d 157.0, 154.4,
131.5, 130.6, 129.5, 128.7, 128.6, 127.9, 120.6, 116.7, 114.0, 94.6,
94.4, 61.6, 56.2, 56.1, 41.5, 39.3, 32.6, 26.0; MS (EI) m/z: 385
(M+), 292, 209, 177, 147 (100). HRMS (EI) calcd for C22H27NO5
(M+) 385.1889, found 385.1890.
4.1.14. 2-[3-(3-Fluoropropyl-4-hydroxyphenyl)-3-(4-hydroxy-
phenyl)]propionitrile (11b)
This material was prepared by a procedure similar to that used
for the preparation of fluoroethylate 11a, described above, and pro-
duced fluoropropylate 11b (83%) as a white solid: 1H NMR
(300 MHz, MeOD-d4) d 7.06 (d, J = 8.7 Hz, 2H), 6.84–6.79 (m, 2H),
6.74 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.1 Hz, 1H), 4.36 (dt, J = 41.4,
12.3 Hz, 2H), 4.06 (t, J = 7.2 Hz, 1H), 3.00 (d, J = 7.2 Hz, 2H), 2.61
(t, J = 7.5 Hz, 2H), 1.96–1.83 (m, 2H); 13C NMR (75 MHz, MeOD-
d4) d 157.0, 154.1, 131.0, 128.4, 127.7, 127.5, 127.3, 126.4, 121.0,
115.2, 114.4, 83.0 (d, J = 162.7 Hz), 41.0, 38.5, 30.2 (d, J = 19.4 Hz),
25.4 (d, J = 6.1 Hz); MS (CI) m/z: 300 (MH+), 280 (100), 273, 253,
167, 147. HRMS (CI) calcd for C18H19NO2F (MH+) 300.1400, found
300.1401.
4.1.11. 2-(3-p-Toluenesulfonyloxyethyl-4-methoxymethoxy-
phenyl)-3-(4-methoxymethoxyphenyl)propionitrile (10a)
p-Toluenesulfonic anhydride (237 mg, 0.73 mmol), TEA (203 lL,
1.46 mmol) were added to a CH2Cl2 (20 mL) solution of hydroxy-
ethyl 9a (180 mg, 0.49 mmol) and stirred 30 min. The solution
was extracted with ethyl acetate and the combined organic layer
was dried over sodium sulfate and concentrated. The crude prod-
uct was purified by flash column chromatography (35% EtOAc/hex-
ane) to give tosylate 10a (250 mg, 98%) as colorless oil: 1H NMR
(300 MHz, CDCl3) d 7.67 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H),
7.17 (d, J = 8.7 Hz, 2H), 7.03–6.92 (m, 4H), 6.84 (d, J = 1.8 Hz, 1H),
5.17 (s, 2H), 5.07 (s, 2H), 4.18 (t, J = 7.0 Hz, 2H), 3.88 (t, J = 7.4 Hz,
1H), 3.47 (s, 3H), 3.37 (s, 3H), 3.03–3.01 (m, 2H), 2.94 (t,
J = 7.1 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) d 157.1,
154.5, 144.5, 133.2, 131.8, 129.7, 129.6, 129.1, 128.6, 128.5,
127.8, 125.1, 120.5, 116.7, 113.8, 94.4, 94.3, 69.4, 56.1, 41.4, 39.2,
30.5, 21.6; MS (EI) m/z: 525 (M+), 462, 349, 221, 133 (100). HRMS
(EI) calcd for C28H31NO7S (M+) 525.1821, found 525.1822.
4.1.15. 2-(3-Tributylstannyl-4-methoxymethoxyphenyl)-3-(4-
methoxymethoxyphenyl)propionitrile (12)
MOM-protected 7 (500 mg, 1.23 mmol) was dissolved in anhy-
drous 1,4-dioxane (25 mL), and the following reagents were added:
Pd(II)(PPh3)2Cl2 (43 mg, 0.06 mmol) and bis(tributyltin) (925 lL,
1.85 mmol). The reaction mixture was heated at 100 °C for 12 h un-
der an argon atmosphere. The reaction mixture was collected by
filtration, and then the solvent removed in a vacuum. The crude
product purified by flash chromatography (30% EtOAc/hexanes)
to give 12 (530 mg, 70%) as a pale yellow oil: 1H NMR (300 MHz,
CDCl3) d 7.16 (d, J = 8.7 Hz, 2H), 7.08–6.91 (m, 5H), 5.16 (s, 2H),
5.12 (s, 2H), 3.89 (t, J = 7.2 Hz, 1H), 3.48 (s, 3H), 3.45 (s, 3H),
3.15–3.01 (m, 2H), 1.53–1.47 (m, 6H), 1.34–1.27 (m 6H), 1.03–
0.98 (m, 6H), 0.90–0.85 (m, 9H); 13C NMR (75 MHz, CDCl3) d
161.6, 157.1, 137.8, 130.9, 130.6, 129.5, 128.73, 128.68, 120.7,
116.6, 112.0, 94.4, 94.2, 56.1, 55.9, 41.5, 39.3, 29.1, 27.3, 13.7,
9.8; MS (CI) m/z: 618 (MH+, 100), 560, 530, 328, 296, 257. HRMS
(CI) calcd for C31H46NO4Sn (MH+) 618.2605, found 618.2602.
4.1.12. 2-(3-p-Toluenesulfonyloxypropyl-4-methoxymethoxy-
phenyl)-3-(4-methoxymethoxyphenyl)propionitrile (10b)
This material was prepared by a procedure similar to that used
for the preparation of ethyl tosylate 10a, described above, and pro-
duced tosylate 10b (82%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) d 7.78 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.18 (d,
J = 8.7 Hz, 2H), 7.03–6.96 (m, 4H), 6.85 (d, J = 1.8 Hz, 1H), 5.17 (s,
2H), 5.15 (s, 2H), 4.08–3.98 (m, 2H), 3.92 (t, J = 7.4 Hz, 1H), 3.47
(s, 3H), 3.44 (s, 3H), 3.02–2.97 (m, 2H), 2.64 (t, J = 7.4 Hz, 2H),
2.43 (s, 3H), 1.95–1.86 (m, 2H); 13C NMR (75 MHz, CDCl3) d
157.0, 154.4, 144.7, 131.1, 129.8, 129.6, 129.5, 128.7, 128.6,
128.3, 127.9, 120.6, 116.7, 113.9, 94.42, 93.37, 70.0, 56.08, 56.07,
41.6, 39.3, 29.0, 26.3, 21.6; MS (EI) m/z: 539 (M+), 363, 147 (100).
HRMS (EI) calcd for C29H33NO7S (M+) 539.1978, found 539.1978.
4.1.16. 2-[3-(3-Iodo-4-hydroxyphenyl)-3-(4-hydroxyphenyl)]-
propionitrile (13)
The stannane 12 (140 mg, 0.23 mmol) and 1 M ICl in CH2Cl2
(230
lL, 0.23 mmol) were added to methylene chloride (15 mL)
and stirred at room temperature for 10 min. The reaction was
quenched by sodium sulfite solution and extracted with ethyl ace-
tate, and combined organic layer was dried over sodium sulfate
and concentrated. The crude product was purified by flash column
chromatography (30% EtOAc/hexane) to give MOM-protected 13.
The collected compound was dissolved in CH3CN (15 mL) and stir-
red with 1 N HCl (6 mL) for 1 h at 70 °C. The solution was extracted
with ethyl acetate, and combined organic layer was dried over so-
dium sulfate and concentrated. The crude product was purified by
flash column chromatography (50% EtOAc/hexane) to give the iodo
compound 13 (65 mg, 78%) as a white solid: 1H NMR (300 MHz,
MeOD-d4) d 7.45 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.94
4.1.13. 2-[3-(2-Fluoroethyl-4-hydroxyphenyl)-3-(4-hydroxy-
phenyl)]propionitrile (11a)
Tosylate 10a (175 mg, 0.33 mmol) and CsF (506 mg, 3.30 mmol)
were dissolved in anhydrous tert-butanol (15 mL) and stirred at
100 °C for 16 h. The reaction mixture was extracted with ethyl ace-
tate, and the combined organic layer was dried over sodium sulfate
and concentrated. The crude product was purified by flash column

B. S. Moon et al. / Bioorg. Med. Chem. 17 (2009) 3479–3488
3487
(dd, J = 8.4, 2.1 Hz, 1H), 6.77–6.66 (m, 3H), 4.07 (t, J = 7.4 Hz, 1H),
2.96 (d, J = 7.4 Hz, 2H); 13C NMR (75 MHz, MeOD-d4) d 157.1,
155.7, 139.7, 130.2, 130.1, 128.5, 126.1, 120.8, 115.3, 114.8,
114.1, 40.1, 38.3; MS (CI) m/z: 366 (MH+), 339 (100), 280, 240,
213, 107. HRMS (CI) calcd for C15H13O2NI (MH+) 365.9991, found
365.9994.
114.1, 109.6, 94.3, 94.2, 80.0 (d, J = 165.2 Hz), 56.4, 56.1; MS (EI)
m/z: 357 (M+, 100), 327, 293, 261, 232, 190. HRMS (EI) calcd for
C20H20O2NF (M+) 357.1376, found 357.1374.
4.1.21. 2-(3-Fluoromethyl-4-methoxymethoxyphenyl)-3-(4-
methoxymethoxyphenyl)propionitrile (18)
This material was prepared by a procedure similar to that used
for the preparation of 5f, described above (pale yellow oily solid,
96%): 1H NMR (300 MHz, CDCl3) d 7.20 (d, J = 8.7 Hz, 2H), 7.16–
7.01 (m, 5H), 5.42 (d. J = 47.7 Hz, 2H), 5.20 (s, 2H), 5.17 (s, 2H),
3.92 (t, J = 7.4 Hz, 1H), 3.48 (s, 3H), 3.47 (s, 3H), 3.11–3.07 (m,
2H); 13C NMR (75 MHz, CDCl3) d 157.1, 154.1 (d, J = 4.4 Hz),
130.8 (d, J = 2.8 Hz), 129.8 (d, J = 7.4 Hz), 129.7, 128.6, 128.4,
125.7 (d, J = 17.0 Hz), 120.5, 116.7, 114.2, 94.4, 94.4, 80.2 (d,
J = 164.1 Hz), 56.2, 56.1, 41.5, 39.2; MS (EI) m/z: 359 (M+), 221,
191, 183 (100), 153, 119, 104, 91.HRMS (EI) calcd for C20H22O4NF
(M+) 359.1533, found 359.1533.
4.1.17. (Z)-2-(3-Methyl-4-hydroxyphenyl)-3-(4-hydroxy-
phenyl)acrylonitrile (14)
This material was prepared by a procedure similar to that used
for the preparation of 6f, described above (yellow solid, 94%): 1H
NMR (300 MHz, MeOD-d4) d 7.63–7.60 (m, 2H), 7.49–7.43 (m,
3H), 6.85–6.78 (m, 3H), 2.21 (s, 3H); 13C NMR (75 MHz, MeOD-
d4) d 157.9, 157.6, 140.1, 131.8, 128.0, 126.6, 126.2, 125.6, 124.8,
118.7, 115.4, 114.3, 106.5, 14.8; MS (EI) m/z: 252 (M+), 233, 145,
131, 117 (100), 88. HRMS (EI) calcd for C16H14O2 N (M+)
252.1024, found 252.1027.
4.1.18. (Z)-2-(3-Methyl-4-methoxymethoxyphenyl)-3-(4-meth-
oxymethoxyphenyl)acrylonitrile (15)
4.1.22. 2-(3-Hydroxymethyl-4-hydroxyphenyl)-3-(4-hydroxy-
phenyl)propionitrile (20)
This material was prepared by a procedure similar to that used
for the preparation of 7, described above (white solid, 74%): 1H
NMR (300 MHz, CDCl3) d 7.71–7.68 (m, 2H), 7.56 (d, J = 8.7 Hz,
2H), 7.34 (s, 1H), 7.12–7.07 (m, 3H), 5.26 (s, 2H), 5.21 (s, 2H),
3.494 (s, 3H), 3.490 (s, 3H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 157.7, 157.0, 140.5, 131.7, 128.54, 128.52, 127.8, 127.3, 127.1,
118.5, 116.6, 113.5, 108.4, 94.3, 94.1, 56.14, 56.10, 16.3; MS (EI)
m/z: 339 (M+), 309, 294, 279, 264, 239, 221, 209, 193, 179, 165,
141, 125, 111, 97, 71, 57. HRMS (EI) calcd for C20H21O4 N (M+)
339.1470, found 339.1470.
The fluoromethyl DPN 18 (250 mg, 0.70 mmol) was dissolved in
MeOH (10 mL). To this stirred mixture, 1 N HCl (3 mL) was added,
and stirring was continued for 30 min at 70 °C. The reaction mix-
ture was extracted with ethyl acetate, and combined organic layer
was dried over sodium sulfate and concentrated. The crude prod-
uct was purified by flash column chromatography (60% EtOAc/hex-
ane) to give 20 (156 mg, 82%) as a white solid: 1H NMR (300 MHz,
MeOD-d4) d 7.12–7.08 (m, 3H), 6.88 (dd, J = 8.1, 2.1 Hz, 1H), 6.75 (d,
J = 8.7 Hz, 2H), 6.87 (d, 8.1 Hz, 1H), 4.61 (s, 2H), 4.07 (t, J = 7.5 Hz,
1H), 3.00 (d, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 157.0,
154.0, 128.94, 128.87, 128.4, 127.6, 127.1, 126.5, 121.1, 115.2,
114.5, 59.7, 41.1, 38.6; MS (CI) m/z: 268 (MH+), 252 (100), 243,
137, 117, 88. HRMS (CI) calcd for C16H14O3 N (MH+) 268.0974,
found 268.0971.
4.1.19. (Z)-2-(3-Bromomethyl-4-methoxymethoxyphenyl)-3-
(4-methoxymethoxyphenyl)acrylonitrile (16)
A stirred solution of 15 (1.35 g, 3.97 mmol), N-bromosuccini-
mide (776 mg, 4.36 mmol) and benzoyl peroxide (64 mg) in carbon
tetrachloride (60 mL) was heated at reflux under an argon atmo-
sphere for 2 h. The suspension was then cooled to 0 °C, filtered
and concentrated in vacuo. The crude product was purified by flash
column chromatography (25% EtOAc/hexane) to give 16 as a
4.2. Relative binding affinity assay
Binding affinities of DPN derivatives were determined by a
competitive radiometric binding assay with 2 nM [3H]estradiol as
tracer ([2,4,6,7-3H]estra-1,3,5,(10)-triene-3,17b-diol, 70–120 Ci/
mmol, GE Healthcare, Piscataway, NJ), using purified full-length
slightly yellow solid mixed with methyl
a-stilbene (15). Recrystal-
lization from EtOAc/hexane gave pure bromoethyl
a-stilbene 16
(1.02 g, 61%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) d
7.85–7.83 (m, 2H), 7.57 (d, J = 9.0 Hz, 2H), 7.34 (s, 1H), 7.17 (d,
J = 9.3 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), 5.33 (s, 2H), 5.22 (s, 2H),
4.59 (s, 2H), 3.53 (s, 3H), 3.49 (s, 3H); 13C NMR (75 MHz, CDCl3) d
157.9, 156.3, 139.4, 131.9, 131.1, 128.2, 127.6, 127.3, 127.1,
118.2, 116.6, 114.3, 109.6, 94.3, 94.0, 56.5, 56.1, 28.2; MS (EI)
m/z: 419 (M++2, 18.8), 417 (M+, 18.8), 338, 293, 261, 248, 232,
203, 190, 177. HRMS (EI) calcd for C20H20O4NBr (M+) 417.0575,
found 417.0575.
human ER
a and ERb (PanVera/Invitrogen), as previously de-
scribed.15,16 Incubations were for 18–24 h at 0 °C. Hydroxyapatite
(Bio-Rad, Hercules, CA) was used to absorb the receptor-ligand
complexes, and free ligand was washed away. The binding affini-
ties are expressed as RBA values, where the RBA of estradiol is
100%. The values given are the average range or SD of two or
three independent determinations. Estradiol binds to ER
a with a
Kd of 0.2 nM and to ERb with a Kd of 0.5 nM.
Acknowledgments
4.1.20. (Z)-2-(3-Fluoromethyl-4-methoxymethoxyphenyl)-3-(4-
methoxymethoxyphenyl)acrylonitrile (17)
This study was supported by Korea Science and Engineering
Foundation (KOSEF) (M20702010001-07N0201-00110) and Minis-
try of Science & Technology (MOST), Republic of Korea, through its
National Nuclear Technology Program. We were also supported by
the National Institutes of Health (PHS 2R01CA25836 to J.A.K.).
The bromomethyl a-stilbene 16 (600 mg, 1.43 mmol) and tetra-
butylammonium fluoride-3H2O (71 mg, 0.47 mmol) were dis-
solved in anhydrous CH3CN (30 mL) and stirred at 70 °C for
30 min. The reaction mixture was extracted with ethyl acetate,
and combined organic layer was dried over sodium sulfate and
concentrated. The crude product was purified by flash column
chromatography (25% EtOAc/hexane) to give 17 (380 mg, 74%) as
a yellow solid: 1H NMR (300 MHz, CDCl3) d 7.94 (d, J = 8.7 Hz,
1H), 7.84 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.38 (s, 1H), 7.20 (d,
J = 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 5.50 (d, J = 47.7 Hz, 2H),
5.28 (s, 2H), 5.21 (s, 2H), 3.49 (s, 6H); 13C NMR (75 MHz, CDCl3) d
157.9, 156.1 (d, J = 4.1 Hz), 139.7, 130.6 (d, J = 2.6 Hz), 130.4 (d,
J = 7.8 Hz), 128.2, 127.6, 127.2, 126.0 (d, J = 16.9 Hz), 118.3, 116.6,
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