Fluorine-substituted cyclofenil derivatives as estrogen receptor ligands: Synthesis and structure-affinity relationship study of potential positron emission tomography agents for imaging estrogen receptors in breast cancer

Article abstract of DOI:10.1021/jm0512037

In a search for estrogen receptor (ER) ligands to be radiolabeled with fluorine-18 for imaging of ER-positive breast tumors with positron emission tomography (PET), we investigated cyclofenil analogues substituted at the C3 or C4 position of the cyclohexyl group. McMurry coupling of 4,4′- dihydroxybenzophenone with various ketones produced key cyclofenil intermediates, from which C3 and C4 substituents containing alkyl and various oxygen or fluorine-substituted alkyl groups were elaborated. Binding assays to both ERα and ERβ revealed that the C3 site is more tolerant of steric bulk and polar groups than the C4 site, consistent with a computational model of the ERα ligand binding pocket. Fluorine substitution is tolerated very well at some sites, giving some compounds having affinities comparable to or higher than that of estradiol. These fluoro and fluoroalkyl cyclofenils merit further consideration as fluorine-18 labeled ER ligands for PET imaging of ERs in breast tumors.

Full text of DOI:10.1021/jm0512037

2496
J. Med. Chem. 2006, 49, 2496-2511
Fluorine-Substituted Cyclofenil Derivatives as Estrogen Receptor Ligands: Synthesis and
Structure-Affinity Relationship Study of Potential Positron Emission Tomography Agents for
Imaging Estrogen Receptors in Breast Cancer
Jai Woong Seo,† John S. Comninos,‡ Dae Yoon Chi,† Dong Wook Kim,‡ Kathryn E. Carlson,‡ and John A. Katzenellenbogen*,‡
Department of Chemistry, Inha UniVersity, 253 Yonghyundong Namgu, Inchon 402-751, Korea, and Department of Chemistry,
UniVersity of Illinois, 600 S. Mathews AVenue, Urbana, Illinois 61801
ReceiVed NoVember 29, 2005
In a search for estrogen receptor (ER) ligands to be radiolabeled with fluorine-18 for imaging of ER-
positive breast tumors with positron emission tomography (PET), we investigated cyclofenil analogues
substituted at the C3 or C4 position of the cyclohexyl group. McMurry coupling of 4,4′-dihydroxyben-
zophenone with various ketones produced key cyclofenil intermediates, from which C3 and C4 substituents
containing alkyl and various oxygen or fluorine-substituted alkyl groups were elaborated. Binding assays to
both ERR and ERâ revealed that the C3 site is more tolerant of steric bulk and polar groups than the C4
site, consistent with a computational model of the ERR ligand binding pocket. Fluorine substitution is tolerated
very well at some sites, giving some compounds having affinities comparable to or higher than that of
estradiol. These fluoro and fluoroalkyl cyclofenils merit further consideration as fluorine-18 labeled ER
ligands for PET imaging of ERs in breast tumors.
Introduction
The estrogen receptor (ER)a,1,2 is a ligand-dependent tran-
scription factor, whose conformation and activity are modulated
by the binding of endogenous steroid hormones, such as 17â-
estradiol (E2). Estrogens, acting through the ER, regulate many
important physiological processes, such as the maintenance of
bone mineral density,3,4 cardiovascular health,5,6 neuroprotec-
tion,7,8 and the development and function of the female
reproductive system.9,10
The discovery that there are two ER subtypes, ERR and
ERâ,11,12 provided impetus to develop novel estrogen pharma-
ceuticals able to activate or inhibit these subtypes selectively.
Most estrogen target tissues have both ERR and ERâ, though
in varying ratios; ERR is the principal subtype expressed in
breast and uterine tissue, while ERâ is found at higher levels
in ovary, prostate, bone, vascular epithelium, and certain brain
regions.13-15 While difficult to generalize, ERâ is usually less
Figure 1. ER ligands and a pharmacophore model.
active as a transcription factor and exerts a restraining effect
on the more active ERR.16-20 It is notable that in breast cancer
pocket is smaller than that of ERR.23,24 Otherwise, the pockets
the level of ERâ relative to ERR declines with disease
are very similar, with only 2 out of 24 residues being different,
progression21 as one might expect with the transition to a more
and these being conservative substitutions (Leu384 and Met421
proliferative and invasive tumor phenotype. Thus, if the
in ERR corresponding to Met and Ile in ERâ, respectively).
Despite this similarity, it has proved possible to develop ER
independent quantification of ERR and ERâ levels in breast
cancer could be achieved by imagingsusing fluorine-18 labeled
ER subtype-selective ligands with positron emission tomography
(PET)sit might provide information predictive of disease
ligands that bind to and activate either ERR or ERâ with a high
level of selectivity (as has been reviewed25-27), and a reasonable
pharmacophore model has been advanced to guide the design
staging and tumor response to hormone therapies. Differential
of subtype-selective ligands (Figure 1).28,29 ER ligands with
imaging of the two ER subtypes, however, has proved to be a
varying core structures have been reported: pyrazoles,30 pyr-
major challenge (see below).
roles,31 and furans31 as ERR-selective ligands; tetrahydrochry-
The ligand binding domains of ERR and ERâ have only 58%
senes,32 diarylpropionitriles,33 cyclofenils,34 and benzofused
sequence identity,22 and the volume of the ERâ ligand binding
heterocyclic analogues35-37 as ERâ-selective ligands. In prior
* To whom correspondence should be addressed. Address: Department
of Chemistry, University of Illinois, 461 Roger Adams Laboratory, Box
37-5, 600 S. Mathews Avenue, Urbana, IL 61801. Telephone: +1-217-
333-6310. Fax: +1-217-333-7325. E-mail: jkatzene@uiuc.edu.
† Inha University.
studies, we have investigated some fluorine-18 labeled analogues
of these ligands as PET imaging agents selective for ERR38 and
ERâ,39 but thus far our success has been limited.
Cyclofenil (bis-(4-hydroxyphenyl)methylidenecyclohexane, 4)
and its analogues, while only slightly ERâ-selective, have very
high binding affinity, often comparable to or greater than that
of estradiol.34 After cyclofenil was reported,40 its conformation
‡ University of Illinois.
a Abbreviations: E2, 17â-estradiol; ER, estrogen receptor; F-18, fluorine-
18; PET, positron emission tomography; SERM, selective estrogen receptor
modulator.
10.1021/jm0512037 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/21/2006

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2497
Scheme 1a
Figure 2. Two types of cyclofenil analogues.
was investigated by X-ray crystallography, and its binding to
uterine receptors41 was compared to that of estradiol (E2).42
Notably, cyclofenil has mixed agonist antagonist activity typical
for a nonsteroidal selective estrogen receptor modulator (SERM),
such as tamoxifen or raloxifene, and it has been used for
ovulation induction.43
Recently, we prepared cyclofenil derivatives that have bicyclic
core units to examine the degree to which a three-dimensional
topology in the central hydrophobic core of a ligand would be
tolerated by the ERs.34 It was encouraging to find that several
of the 1,1-diarylethylene motif bridged bicyclic or tricyclic core
cyclofenil analogues had very high binding affinities, up to 3-5
times greater than that of estradiol in both ER subtypes. The
torsion angles between the two hydroxyphenyl groups seem to
correlate with the binding affinity, although other factors such
as nonoptimal orientation of the phenyl ring and lack of ligand
steric complementarity with the binding pocket also play
important roles.44 These factors were not investigated in the SAR
and X-ray conformational studies of cyclofenil derivatives
reported previously.41,42
Thus, in our search for agents to image ERs in breast cancer
by PET, we undertook a further investigation of substituted
cyclofenil ligands to establish where it might be feasible to
introduce polar substituents such as fluorine, as would be needed
for labeling with the positron emitting radionuclide, fluorine-
18. Because we wanted to establish a structure-activity
relationship independent of effects that would result from
changes in the critical torsion angle of the dihydroxyphenyl
group, we investigated substituents only on the C3 and C4
positions of the cyclohexane ring (Figure 1), sites where
substitution is not expected to affect this torsion angle. We
thought that such C3- and C4-substituted cyclofenil derivatives
would help probe for differences in the largely similar hydro-
phobic ligand binding pockets of the ERR and ERâ. We hoped,
as well, to identify ERâ-selective ligands of high affinity33,45
that are tolerant of the fluorine substitution needed for F-18
labeled PET imaging agents.
Herein, we report the syntheses of 24 cyclofenil derivatives,
many of which are substituted at the C3 or C4 positions, as
well as ones with different ring sizes, and an evaluation of their
relative binding affinities (RBAs) to ERR and ERâ. Through
this study, we have established a useful structure-activity
relationship relating ERR and ERâ binding affinities to the size
and polarity of the C3 or C4 substituent in the cyclofenil series.
In addition, we have identified a few fluoro- or fluoroalkyl
cyclofenil analogues that have binding affinity for ERR and ERâ
comparable to or greater than that of the endogenous ligand,
estradiol, though their ER subtype selectivity is limited. These
compounds are being considered for further investigation as PET
imaging agents for ER in breast cancer.
a Reagents: (a) TiCl4, Zn, THF, reflux, 4 h.
of analogues (type I, compounds 2-5) has different cycloalkyl
core units, ranging from cyclobutane to cycloheptane. The other
series (type II) has a fixed cyclohexyl moiety onto which we
have introduced various substituents at the C3 or C4 position.
All of the cyclofenil derivatives or their precursors were
prepared by a McMurry coupling reaction between 4,4′-
dihydroxybenzophenone and a cyclic ketone. Some of the cyclic
ketones are commercially available or can be readily obtained
in a few steps from commercially available material. In many
cases, the substituents were elaborated from functional precur-
sors after the cyclofenil system was prepared by McMurray
coupling.
Synthesis of Type I Cyclofenil Analogues. McMurry
coupling reaction with low-valent titanium activated by zinc
was used to prepare the various ring sized cyclofenil analogues
2-5 (Scheme 1) according to a previously reported proce-
dure.34,46,47 It is of note that this coupling is tolerant of free
phenols. All of the reactions gave reasonable yields (62-83%)
except the cyclobutyl compound 2 (8%).
Synthesis of Cyclohexanone Precursors for Type II Cy-
clofenil Analogues. Scheme 2 shows how various cyclohex-
anone precursors, functionalized at the C4 or C3 position, were
prepared. 1,4-Dihydroxycyclohexane (6) was oxidized to 4-hy-
droxycyclohexanone (7) using freshly prepared Jones reagent
and was acetylated to give 4-acetoxycyclohexanone (8). A
Wittig reaction of cyclohexan-1,4-dione (9) with methyl (triph-
enylphosphoranylidene)acetate produced methyl (4-oxo-cyclo-
hexylidene)acetate, which, following hydrogenation over a
palladium catalyst, yielded the cyclohexyl acetate 10 that was
used as a source of two-carbon substituents at the C4 position.48
The C3-alkylated cyclohexanone precursor with one carbon
atom (12) was prepared by esterification of the commercially
available acid (11). The two-carbon substituent precursor (14)
was prepared by Michael addition of dimethyl malonate to
cyclohexanone (13).49 The synthesis of the cyclohexanone with
a linear three-carbon unit on the C3 position (15) involved
copper-catalyzed 1,4-addition to cyclohexenone of the organo-
magnesium reagent generated in two steps from 3-chloro-
propanol (via the 3-chloropropylmagnesium alkoxide), with
subsequently acetylation.50 All compounds functionalized at C3
position are chiral and were used as racemates.
Synthesis of C4-Substituted Cyclofenil Analogues. Scheme
3 shows the preparation of the C4-functionalized cyclofenil
derivatives. McMurry coupling of 4,4′-dihydroxybenzophenone
with 4-acetoxycyclohexanone (8) yielded the C4 acetoxy
analogue 16; the phenolic hydroxy groups were then protected
as methoxymethyl (MOM) ethers. The C4-hydroxy cyclofenil
17b, obtained after alkaline hydrolysis of the acetate, was
converted to the protected 4-fluorocyclofenil derivative 19 in
32% yield by treatment with (diethylamino)sulfur trifluoride
Results
Synthesis of Cyclofenil Analogues. The compounds we have
synthesized can be divided into two types (Figure 2). One series

2498 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Scheme 2. Syntheses of Cyclohexanonesa
Seo et al.
Scheme 3a
a Reagents: (a) Jones reagent, acetone, 0 °C to room temp, 45 min; (b)
Ac2O, pyridine, room temp, 24 h; (c) methyl (triphenylphosphoranyli-
dene)acetate, toluene, 110 °C, 8 h; (d) Pd/C, H2, EtOH, room temp, 6 h;
(e) SOCl2, MeOH, room temp, 3 h; (f) dimethyl malonate, NaOEt (catalyst),
room temp, 2 h; (g) (i) MeMgCl, THF, -78 °C to room temp, 20 min; (ii)
Mg, 1,2-dibromoethane, THF, room temp to 90 °C, 2 h; (iii) 13, CuBr,
THF, -78 to 0 °C, 1 h; (h) Ac2O, pyridine, CH2Cl2, room temp, 18 h.
a Reagents: (a) 8, TiCl4, Zn, THF, reflux, 4 h; (b) methoxymethyl
chloride, NaH, DMF, 0 °C to room temp, 1 h; (c) K2CO3, MeOH:H2O
(5:1), room temp, 12 h; (d) DAST, CH2Cl2, -78 °C to room temp, 1 h; (e)
HCl, MeOH, room temp, 12 h.
after reagent drying by azeotrope distillation.52 Reductive
cleavage of the methanesulfonates, followed by deprotection
of the MOM ethers, yielded the C4 methyl and ethyl cyclofenil
analogues (29a,b).
(DAST). Acid cleavage of the MOM groups in both 19 and
17b produced the C4-hydroxy and fluoro cyclofenil analogues
18 and 20 in 71% and 85% yield, respectively.
The preparation of cyclofenil derivatives with carbon chains
at the C4 position is shown in Scheme 4. Ethyl 4-oxocyclo-
hexanecarboxylate, a commercially available ketone that has a
one-carbon unit at the C4 position, or methyl (4-oxo-cyclo-
hexyl)acetate (10), which has a two-carbon unit at the C4
position (prepared as in Scheme 2), were reacted with 4,4-
dihydroxybenzophenone (1) using the same McMurry coupling
procedure. In this manner, we obtained cyclofenil 4-carboxylate
21a and acetate 21b in approximately 70% yield. The phenols
in both compounds were protected as MOM ethers, and the
carboxylic esters in both 22a and 22b were reduced to the
corresponding primary alcohols with lithium aluminum hydride.
These alcohols, 23a and 23b, served as intermediates for further
synthesis. After MOM deprotection, they gave the C4 hy-
droxymethyl and 2-hydroxyethyl cyclofenils (24a,b). As the
MOM ethers, they served as precursors of the C4-ethoxymethyl
compound 27 and the fluorobutyloxymethyl compound 28. They
were also converted to the methanesulfonates 25a,b. Fluoride
ion substitution to produce the fluoromethyl and fluoroethyl
analogues (26a,b) from these methanesulfonates was ac-
complished by reaction with cesium fluoride in an ionic liquid.51
The use of this medium for fluoride ion substitutions minimizes
side reactions, such as elimination, that would produce various
alkenes, which are sometimes difficult to separate from the
desired fluorine-substituted products. On the basis of precedent
in other systems, this ionic liquid fluorination would likely be
effective for labeling of these compounds with F-18, even in
the presence of small amounts water which typically remain
Synthesis of C3-Substituted Cyclofenil Analogues. We used
similar procedures to introduce substituents and functional
groups at the C3 position of cyclofenil (Scheme 5). A McMurry
reaction with the cyclohexanones 12, 14, and 15 produced
coupled ester compounds 30a, 30b, and 30c, respectively.
Hydrolysis of 30b and subsequent decarboxylation and esteri-
fication produced the C3 carboxymethyl compound 32. The
phenols of all three cyclofenil derivatives (30a, 30c, and 32)
were protected as MOM ethers. Reduction of 33a and 33b with
lithium aluminum hydride and hydrolysis of 33c with potassium
carbonate gave hydroxymethyl, hydroxyethyl, and hydroxy-
propyl cyclofenil derivatives (34a-c), respectively.
Fluoride substitution was accomplished by two different
procedures: in the case of 34a and 34c, the free hydroxyl group
was directly converted to fluoride by treatment with DAST, and
in case of 34b, the hydroxylethyl group was converted to a
fluoroethyl group by fluoride ion substitution on the methane-
sulfonate intermediate 36b. Removal of the MOM-protective
group to obtain the free fluoro compounds was attempted in
acidic media, but strangely the color of all three fluorinated
products (37a-c) slowly changed to red. Even after the
deprotected fluoro compounds were purified again by column
chromatography, they developed color upon standing. When
each compound was recrystallized, however, their stability
increased quite a bit, but they still decomposed slowly. It proved
to be especially difficult to obtain 37a in pure form, and because
of its instability, it was not evaluated for binding.

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2499
Scheme 4a
a Reagents: (a) TiCl4, Zn, THF, reflux, 4 h; (b) methoxymethyl chloride, NaH, DMF, 0 °C to room temp, 1 h; (c) LAH (1 M solution in THF), THF, 0
°C to room temp, 1 h; (d) methanesulfonyl anhydride, TEA, CH2Cl2, 0 °C to room temp, 1 h; (e) CsF, H2O, 1-butyl-3-methylimidazolium tetrafluoroborate
([bmim][BF4]), acetonitrile, 100 °C, 2 h; (f) HCl, MeOH, room temp, 12 h; (g) bromoethane, NaH, DMF, 100 °C, 24 h; (h) 1-bromo-4-fluorobutane, NaH,
DMF, 0-100 °C, 24 h.
Estrogen Receptor Binding Assay. The relative binding
affinities (RBAs) of cyclofenil analogues were determined using
a competitive radiometric binding assay with purified full-length
human ERR and ERâ, according to published procedures.53 The
RBA value was expressed as binding affinity relative to that of
estradiol (100%). RBA values of the 24 cyclofenil analogues
evaluated are listed in Table 1. It is notable that the tracer and
standard, estradiol, has a modest binding preference for ERR
(Kd(ERR) ) 0.2 nM and Kd(ERâ) ) 0.5 nM).
Binding Affinity of Type I Compounds. We have previously
reported a structure-activity relationship (SAR) of 1,1-diaryl-
ethylene derivatives that have bridged bicyclic cores, but from
this earlier study, it was not obvious what effect the bicyclic
core size had on binding affinity.34 Thus, we prepared the first
type of cyclofenil analogues (2-5, type I) to evaluate the RBA
values of cyclofenil compounds having different ring size core
units (Figure 1 and Table 1). In general, the RBA values range
from 5.6 to 124 for ERR and from 20 to 354 for ERâ.
Interestingly, when the ring size is increased from cyclobutyl 2
to cycloheptyl 5, binding affinities for both ERR and ERâ
increase, and all compounds (2-5) show selectivity for ERâ
of ca. 3-fold in terms of the RBA â/R ratio (which is comparable
to that of estradiol, 2.5; see Table 1, footnote b), except for the
cyclopentyl compound 3, which on this scale was 7.7-fold ERâ
selective (the most ERâ selective of all compounds prepared).
These data suggest that an increase in lipophilic character in
the cyclic core could lead to high binding affinity for both ERR
and ERâ but not a large increase in ERâ selectivity.
Binding Affinity of Type II Compounds with C4 Substit-
uents. Twelve cyclofenil derivatives with different C4 substit-
uents, such as alkyl (29a,b), hydroxyalkyl (18, 24a,b), alkyl
carboxylate (21a,b, 27, 28), and fluoroalkyl substituents (20,
26a,b), were investigated to compare the effects on ER binding
affinity of introducing alkyl groups of different carbon lengths
and substitution of these groups with electronegative and/or polar
units (fluoride and hydroxide).
In all cases (except the C4 methyl compound 29a with ERâ),
any substitution at C4 reduced binding affinity to both ERR
and ERâ, but the degree to which binding was lowered depended
on substituent size and polarity. In general, groups that were
small and/or nonpolar had the highest binding affinity. Thus,
the C4 methyl and ethyl compounds (29a,b) still had good
binding affinity compared to the cyclofenil parent (4). Direct
substitution at C4 with fluorine (20) caused some reduction in
ER binding but much less than direct substitution with hydroxyl
(18); the latter (hydroxy) substitution dropped ERR binding 380-
fold and ERâ binding 930-fold. Similar trends are noted for
fluorine and hydroxy substitution in the C4 methyl series (29a,
26a, and 24a) and the C4 ethyl series (29b, 26b, and 24b):
both substituents lower binding, but fluorine, which is less polar,
is tolerated much better than hydroxy. These trends are
consistent with computational models of the C4-substituted
compounds in the ligand binding pocket of ERR (see below
and Figure 3), in which these C4 substituents are shown to
project into a constrained, hydrophobic environment. The other
four analogues (27, 28, 21a, and 21b) are all of intermediate

2500 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Seo et al.
Scheme 5a
a Reagents: (a) TiCl4, Zn, THF, reflux, 4 h; (b) 2 M NaOH, MeOH, reflux, 2 h; (c) diglyme, 160 °C, 1 h; (d) SOCl2, MeOH, room temp, 90 min; (e)
methoxymethyl chloride, NaH, DMF, 0 °C to room temp, 1 h; (f) (i) in the case of 33a,b, LAH (1 M solution in THF), THF, 0 °C to room temp, 1 h and
(ii) in the case of 30c and 33c, K2CO3, MeOH-H2O (5:1), room temp, 12 h; (g) methanesulfonyl anhydride, TEA, CH2Cl2, 0 °C to room temp, 1 h; (h) CsF,
H2O, 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]), acetonitrile, 100 °C, 2 h; (i) HCl, MeOH, room temp, 12 h; (j) DAST, CH2Cl2, -78 °C
to room temp, 1 h.
polarity, and all have relatively low affinity. It is of note that
the highest binding C4-substitued cyclofenil containing fluorine
is the direct 4-fluorocyclofenil (20), with ERR and ERâ RBA
values of 27 and 62, respectively.
homologous C3 fluoroethyl and propyl compounds (37b,c) have
rather similar ERR and ERâ relative binding affinities; this is
true to a somewhat lesser degree with the C4 fluoroalkyl
compounds (20, 26a,b), where increasing size causes a some-
what greater decrease in affinity. In the C3-substituted cyclofenil
series, both fluorine-substituted compounds (37b,c) are high-
affinity ligands for both ERs.
It is worthwhile to consider not just the ERR and ERâ binding
affinities but also the ERR/ERâ binding selectivities of these
cyclofenil analogues. One notes an overall trend that when a
more polar group is attached to a C4-alkyl group, the â/R RBA
ratio decreases. This is clearly evident in the C4 methyl series:
methyl 29a (â/R ) 4.1), fluoromethyl 26a (â/R ) 2.3), and
hydroxylmethyl 24a (â/R ) 0.99). Also, this is reasonably
evident in the C4-ethyl series: ethyl 29b (â/R )1.2), fluoroethyl
26b (â/R )1.2), and hydroxyethyl 24b (â/R ) 0.14). Despite
this shift in ER-subtype binding preference from ERâ to ERR,
the overall RBA values for both ERs decrease considerably,
consistent with the generally poor tolerance of polarity in the
core of ER ligands. If one looks at â/R RBA ratios as a function
of the length of homologous substituents (alkanes 4, 29a,b;
fluoroalkanes 20, 26a,b; hydroxyalkanes 18, 24a,b), in each
case, the selectivity for ERâ seems to be highest with the two-
carbon species. This preference for substituents of intermediate
length is also apparent, to some degree, in the other C4
analogues (27, 28, and 21a,b). Of greatest interest to this study,
however, is the fact that among the C4-substituted cyclofenils,
there is one fluorine-substituted analogue, 4-fluorocyclofenil
(20), that has a binding affinity for ERâ that is nearly
comparable to that of estradiol.
A particularly dramatic difference between the C3 and C4
series is noted in the ER’s binding affinity of the C3 hydroxy-
ethyl (35b; RBA R ) 34, â ) 58) and the C4 hydroxyethyl
(24b; RBA R ) 2.6, â ) 0.37) compounds; the affinity ratio is
154-fold in case of ERâ in favor of the C3-substituted series.
A similar, though somewhat less dramatic comparison can be
made with the hydroxymethyl C3 and C4 analogues (35a RBA
R ) 25, â ) 40 vs 24a RBA R ) 0.85, â ) 0.84), again with
the C3-substituted systems having higher affinities. These trends
are consistent with computational models of the ERR ligand
binding pocket (see below and Figure 3) in which it can be
seen that the C3 substituent encounters less steric hindrance
and has an opportunity to extend toward and interact with a
key histidine residue (H524 in ERR and H474 in ERâ). Again,
of principal interest to this study is the fact that we have
identified two cyclofenil analogues, compounds 37b and 37c,
that bind better to ERR and, in the case of 37b, also to ERâ
better than does estradiol.
Molecular Modeling of C4- and C3-Substituted Cyclo-
fenils in ER Ligand Binding Pocket of ERr. To understand
why the estrogen receptor differed so greatly in its tolerance of
the bulk and polarity of substituents at the C4 and C3 positions
of cyclofenil, we examined how some of these compounds fit
into the ligand binding pocket of ERR by computational
modeling (Figure 3). A model for the ERR ligand binding
domain was generated from the ERR-estradiol structure (1ERE
in the RCSB) by deleting the ligand and then placing various
Binding Affinity of Type II Compounds with C3 Substit-
uents. In those cases where the RBA values of C3-substituted
cyclofenils can be directly compared to their C4-substituted
analogues having the same substituents (37b with 26b, 35a with
24a, 35b with 24b, and 32 with 21b), the C3-substituted
cyclofenils have significantly greater binding affinity and a
greater tolerance for polar substituents. It is notable that the

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2501
Table 1. Relative Binding Affinity (RBA)a of Cyclofenil Derivatives for the Estrogen Receptors R and â
a Relative binding affinity (RBA) values are determined by a competitive radiometric binding assay with [3H]estradiol and full length human ERR and
ERâ, using methods described in the Experimental Section. The RBA of estradiol (E2) is defined as 100, and the measured RBA values represent the mean
of two or more independent determinations (CV < 0.3). b The binding affinity of the tracer estradiol to the ERs is Kd(ERR) ) 0.2 nM and Kd(ERâ) ) 0.5
nM. Thus, on an absolute scale of binding affinities, the â/R ratios would be reduced by a factor of 2.5.
C3- and C4-substituted cyclofenils into this pocket using the
FlexiDoc routine within the Sybyl 7.1 molecular modeling
software (Tripos Inc.). The initial docking orientation of
substituted cyclofenil was based on initial models with unsub-
stituted cyclofenil (data not shown), where one phenol occupies
a position equivalent to that of the A-ring of estradiol, the second
projects in roughly a “steroid 11â direction”, and the cyclohexyl
ring occupies roughly the “steroid 7R subpocket” (see Figure
3, part A).
To challenge this ligand orientation, the cyclofenil analogues
were initially modeled with one phenol as the steroid A-ring
mimic, but intentionally “misorienting” the cyclohexyl ring in
the “steroid 11â direction” of the binding pocket (opposite of
what was found on cyclofenil), so that the other phenol occupied
the “steroid 7R subpocket”. Despite this deliberate initial
misorientation of the ligand, the FlexiDoc routine reoriented
the cyclofenil core in a characteristic manner. In all cases, one
of the phenol rings of cyclofenil remained in place of the A-ring
of estradiol, where the hydroxyl group could engage in the
canonical hydrogen bonds with the Glu and Arg residues (353
and 394 in ERR and 305 and 346 in ERâ, respectively). In all
but a few cases, the cyclofenil core was reoriented to place the
other phenol in a roughly “steroid 11â direction”; in this
orientation, the second hydroxyl is within 3 Å of a threonine
residue (T347 in ERR and T299 in ERâ). Final optimization of
the model included a three-step minimization process that has
been reported elsewhere (see Experimental Section).
Modeling of the achiral C4-substituted cyclofenils was
relatively straightforward; in these, the cyclohexane ring can
adopt two chair conformations on each of which the substituent
can be either axial or equatorial. Many of these cases were
modeled to give stable structures. Docking always revealed one
phenol as the steroidal A-ring mimic and typically placed the
second pendent phenol in the “steroid 11â direction.” In most
cases, the C4 substituents project toward a region of the ligand
binding pocket that is somewhat flexible but essentially
hydrophobic (I424 and L428 in ERR or I376 and L380 in ERâ)
(see Figure 3, part B). This view is consistent with the behavior
of these analogues in which alkyl groups (29a,b) were very
well tolerated, the electronegative fluoro (20) and fluoroalkyl

2502 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Seo et al.
Figure 3. Schematic and computational model of substituted cyclofenil interaction with the ligand binding pocket of the estrogen receptor, ERR:
(A) schematic picture of the interactions of the phenolic hydroxyls and the C3 and C4 cyclofenil substituents with residues in the ligand binding
pocket. ERR residue numbers precede ERâ residue numbers. (B) Representative computational model of 4-fluorocyclofenil (20) in the ligand
binding pocket of ERR. The hydrophobic residues near the C4 position are indicated. The surface shown is the ERR binding pocket displayed as
dots mapped with the lipophilic potential. Residues identities are for ERR. (C) Representative computational model of 3-(2-fluoropropyl)cyclofenil
(37c) in the ligand binding pocket of ERR. The surface is the same as in panel B. Residues identities are for ERR.
groups (26a,b) were reasonably well tolerated, but the polar
hydroxy (18) and hydroxyalkyl groups (24a,b) bind very poorly.
The chiral C3-substituted cyclofenils present a greater chal-
lenge for modeling, because each enantiomer can adopt two
chair conformations, each of which can have the substituent
disposed in an axial or equatorial position. Modeling was done
with some analogues in most of these orientations, from which
a consistent pattern also emerged, as is illustrated in Figure 3,
part C. By alternate choice of the phenols and chair conforma-
tion, each C3-substituted enantiomer can adopt an orientation
in which the substituent can be extended toward His 524, the
residue in ERR with which the 17â-hydroxyl group of estradiol
forms a hydrogen bond. Thus, this model provides a satisfying
rationale for the fact that at this site the ER can tolerate both
bulky and electronegative fluoroalkyl (37b,c) as well as the more
polar hydroxyalkyl (35a-c) groups. It is of note that substituents
originating from the C4 carbon cannot access His 524. Attempts
were not made to explain the relatively modest ERR versus ERâ
binding selectivities of the compounds in this series by
modeling.
thereby, to discover ER ligands in which an electronegative
substituent, s fluorine in particular, smight be well tolerated,
perhaps even ones in which the fluorine-substituted analogue
would retain the “higher than estradiol” binding affinity of the
cyclofenil parent, so that they might be useful as PET imaging
agents for ER in breast tumors.
From the binding affinities of the 24 compounds we have
investigated, we find that cyclofenils with six- and seven-
membered rings bind best to ER. Except for one case, introduc-
tion of the various C3 and C4 substituents into the cyclohexane
ring of cyclofenil decreases binding affinity, particularly when
the substituents bear polar and/or electronegative groups, but
less so with fluorine than with hydroxyl. In general, groups that
are small or of intermediate size are better tolerated, and those
substituted at C3 bind better than those substituted at C4, in
some cases dramatically better. The pattern of affinity depen-
dence on the site of substitution and the size and polarity of
the substituent can be nicely rationalized by computational
modeling of the ligand binding pocket. Overall, however, there
appears to be relatively little binding selectivity for either ERR
or ERâ.
The principal motivation for this study was to identify
cyclofenil analogues in which a fluorine substituent could be
introduced with retention of high ERR and/or ERâ binding
affinity, as would be needed to develop F-18 labeled ligands
for PET imaging of the ERs in breast tumors. In terms of binding
affinity, our study was successful, because we have found three
fluorine-substituted compounds, 4-fluorocyclofenil (20), 3-
fluoroethylcyclofenil (37b), and 3-fluoropropylcyclofenil (37c),
Conclusions
In summary, in our search for PET imaging agents for the
estrogen receptors, we have focused on the preparation of C3-
and C4-substituted cyclofenil derivatives so that we could
explore the introduction of alkyl and functionalized alkyl
substituents in a manner that would not affect the rotational
mode of both bis(hydroxyphenyl) groups, a conformational
parameter that is very important for ER binding. We hoped,

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2503
General Procedure for Methanesulfonylation. A two-necked
round-bottom flask, which contained the alcohol compound (0.23
mmol), was charged with nitrogen. Freshly distilled CH2Cl2 (5 mL)
was added to the round-bottom flask, and the reaction was stirred
in an ice-bath. Methanesulfonic anhydride (94 mg, 0.54 mmol) was
added in several portions, followed by the slow addition of small
portions of triethylamine (68 mg, 0.68 mmol). The reaction mixture
was stirred at room temperature for about 1 h. The reaction was
quenched by water (10 mL) and vigorous stirring, and the mixture
was extracted with additional CH2Cl2 (50 mL). The organic layer
was dried over MgSO4 and concentrated under reduced pressure.
Flash column chromatography (EtOAc/hexane; 4:6) gave each
alcohol product.
that bind to the ERs with an affinity that is comparable to or
greater than that of estradiol. We did not find compounds having
marked affinity preference or either ERR or ERâ, however.
Further work on the radiolabeling and in vivo evaluation of some
of these compounds will be reported elsewhere.
Experimental Section
All reagents and solvents were purchased from Aldrich, Acros,
or Fisher. Anhydrous THF, Et2O, and CH2Cl2 were collected using
a solvent dispensing system built by J. C. Meyer based on a design
developed by Pangborn.54 Reaction progress was followed by TLC
on 0.25 mm silica gel glass plates containing F-254 indicator
(Merck). Visualization on TLC was monitored by UV light or
phosphomolybdic acid indicator. The chemical shifts were reported
in parts per million and were referenced to the internal solvent
peaks. Coupling constants were reported in hertz. 1H spectra were
obtained on 400 or 500 MHz spectrometers. 13C NMR spectra were
acquired at 100 or 125 MHz. Melting points were checked using a
Thomas-Hoover capillary melting point apparatus and are un-
corrected. Low- and high-resolution electron impact (EI, 70 eV)
spectra were obtained on a Micromass 70-VSE spectrometer.
Elemental analyses were performed by the Microanalytical Service
Laboratory of the University of Illinois or the Center for Collabora-
tive Instruments at Inha University. Reactions were performed under
a nitrogen atmosphere unless noted otherwise.
General Procedure for McMurry Coupling Reaction. A two-
necked, round-bottom flask containing zinc powder (1.2 g, 18
mmol) was fitted with a reflux condenser, evacuated for 10 min,
and charged with nitrogen gas. After THF (15 mL) was added, the
reaction mixture was cooled in an acetone-water bath (-10 °C)
and then titanium(IV) chloride (1.64 g, 8.62 mmol) was added
slowly. Addition of titanium(IV) chloride released a yellow fume,
and the reaction mixture turned a yellow-green color. The reaction
was refluxed for 2 h at 100 °C and then cooled to room temperature.
A solution of dihydroxybenzophenone (1, 500 mg, 2.33 mmol) and
each ketone (2.33 mmol) dissolved in THF (15 mL) was injected
by syringe, and the reaction was refluxed for 2 h. The cooled
reaction mixture was slowly poured into a NaHCO3 solution (200
mL), and Et2O (200 mL) was added with vigorous stirring. The
heterogeneous solution was filtered through Celite. After the organic
layer was decanted and saved, the aqueous layer was extracted with
additional Et2O (100 mL). The combined organic layer was dried
over MgSO4 and concentrated. Flash column chromatography
(EtOAc/hexane; 3:7 or 4:6) gave each coupled compound. Com-
pounds for bioassay were recrystallized from Et2O and hexane or
from EtOAc and hexane.
General Procedure for MOM Protection. To a solution of
bisdihydroxyphenyl (4.4 mmol) in anhydrous DMF (15 mL) was
added sodium hydride (10 mmol) in an ice-bath with N2. The
cooling was removed, and methoxymethyl chloride (9.7 mmol) was
slowly added dropwise by syringe with stirring. Almost at the end
of the addition, the mixture turned into an off-white solution and
was stirred 1 h more. After the ice-bath was replaced, the reaction
was quenched by water (1.0 µL) and transferred to a separatory
funnel. Saturated ammonium chloride solution (100 µL) was added
to remove the DMF, and the organic layer was extracted with
EtOAc (100 µL). This was washed with brine (2 × 100 µL), dried
over MgSO4, and concentrated under reduced pressure. Flash
column chromatography (EtOAc/hexane; 2:8) gave the MOM
protected compound.
General Procedure for Reduction. A mixture of LiAlH4
solution in THF (1 M, 5.7 mL) and THF (15 mL) was slowly added
to each ester compound (5.7 mmol) under ice-bath cooling. After
addition, the cooling was removed, and the reaction was stirred
for about 1 h. The ice-bath was replaced, and the reaction was
quenched carefully by water (100 µL), 2 M sodium hydroxide
solution (100 µL), and water (100 µL) in turn. Additional stirring
for about 20 min gave a white precipitate that was filtered through
Celite. The filtrate was concentrated, and flash column chroma-
tography (EtOAc/hexane; 3:7) of the residue gave each alcohol
product.
General Procedure for Fluorination with Cesium Fluoride.51
To methanesulfonate (0.35 mmol) and cesium fluoride (1.75 mmol)
in a 10 mL vial was added N-butyl-N′-methylimidazolium
tetrafluoroborate (1.5 mL), acetonitrile (1.5 mL), and H2O (50 µL).
After the vial was tightly capped, the reaction mixture was stirred
for 2 h at 100 °C. After the mixture was cooled, Et2O was added
to the reaction mixture, which was shaken and decanted five times.
The combined organic layer was dried over MgSO4 and concen-
trated. Flash column chromatography (EtOAc/hexane; 1:9) gave
each fluorinated compound.
General Procedure for MOM Deprotection. Concentrated HCl
(200 µL) was added to a solution of the MOM protected compound
(0.31 mmol) in methanol (10 mL). In the case of some compounds,
Et2O (5 mL) was added to dissolve the compounds. The reaction
mixture was stirred for 12 h, then quenched by water (10 mL), and
extracted by EtOAc (50 mL). After removal of the solvent, short
flash column chromatography (EtOAc/hexane; 1:1) gave bis-
(dihydroxyphenyl)methylene compounds. Compounds for bioassay
were recrystallized from Et2O and hexane or from EtOAc and
hexane.
Bis(4-hydroxyphenyl)methylenecyclobutane (2). According to
the general procedure for the McMurry coupling reaction with 4,4′-
dihydroxybenzophenone (1, 500 mg, 2.33 mmol), cyclobutanone
(163 mg, 2.33 mmol), Zn (1.2 g, 18 mmol), and titanium(IV)
chloride (1.64 g, 8.62 mmol), 2 (45 mg, 8%) was obtained as a
white solid: mp 177-179 °C; 1H NMR (400 MHz, acetone-d6) δ
6.97 (d, J ) 8.8 Hz, 4H), 6.76 (d, J ) 8.8 Hz, 4H), 2.86 (t, J ) 8.0
Hz, 4H), 1.99 (quintet, J ) 8.0 Hz, 2H); 13C NMR (100 MHz,
acetone-d6) δ 156.6, 137.7, 133.4, 133.1, 130.7, 115.6, 32.5, 17.7;
MS (EI) m/z 252 (M+, 100), 223, 107. HRMS (EI) m/z calcd for
C17H16O2, 252.1150; found, 252.1152. Anal. (C17H16O2‚0.1H2O)
C, H.
Bis(4-hydroxyphenyl)methylenecyclopentane (3). According
to the general procedure for the McMurry coupling reaction with
4,4′-dihydroxybenzophenone (1, 500 mg, 2.33 mmol), cyclopen-
tanone (196 mg, 2.33 mmol), Zn (1.2 g, 18 mmol), and titanium-
(IV) chloride (1.64 g, 8.62 mmol), 3 (518 mg, 83%) was obtained
1
as a white solid: mp 194-195 °C; H NMR (400 MHz, DMSO-
d6) δ 6.90 (d, J ) 8.4 Hz, 4H), 6.66 (d, J ) 8.4 Hz, 4H), 2.26 (bt,
J ) 6.4 Hz, 4H), 1.60 (bt, J ) 6.4 Hz, 4H); 13C NMR (100 MHz,
DMSO-d6) δ 155.4, 139.9, 134.2, 132.2, 129.9, 114.7, 32.7, 26.5;
MS (EI) m/z 266 (M+, 100), 223, 168, 141, 115. Anal. (C18H18O2)
C, H.
Bis(4-hydroxyphenyl)methylenecyclohexane (4). According to
the general procedure for the McMurry coupling reaction with 4,4′-
dihydroxybenzophenone (1, 500 mg, 2.33 mmol), cyclohexanone
(229 mg, 2.33 mmol), Zn (1.2 g, 18 mmol), and titanium(IV)
chloride (1.64 g, 8.62 mmol), 4 was obtained as a white solid (518
1
mg, 83%): mp 235-237 °C; H NMR (400 MHz, DMSO-d6) δ
6.83 (d, J ) 8.4 Hz, 4H), 6.66 (d, J ) 8.8 Hz, 4H), 2.10-2.21 (m,
4H), 1.42-1.60 (m, 6H); 13C NMR (100 MHz, DMSO-d6) δ 155.6,
136.3, 133.9, 133.7, 130.4, 114.7, 31.9, 28.2, 26.3; MS (EI) m/z
280 (M+), 199 (100), 107. Anal. (C19H20O2) C, H.
Bis(4-hydroxyphenyl)methylenecycloheptane (5). According
to the general procedure for the McMurry coupling reaction with
4,4′-dihydroxybenzophenone (1, 500 mg, 2.33 mmol), cyclohex-
anone (261 mg, 2.33 mmol), Zn (1.2 g, 18 mmol), and titanium-
(IV) chloride (1.64 g, 8.62 mmol), 5 (518 mg, 83%) was obtained

2504 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Seo et al.
1
as a white solid: mp 198-199 °C; H NMR (400 MHz, acetone-
(4.4 g, 33 mmol) in THF (20 mL) was added potassium tert-
butoxide (330 mg, 3.0 mmol). The reaction mixture was stirred at
room temperature for 2 h. Water (5 mL) was added to the reaction
mixture, and then more water (200 mL) was added. The organic
layer was extracted with EtOAc (100 mL) and dried over MgSO4.
EtOAc was evaporated under reduced pressure, and flash column
chromatography (EtOAc/hexane; 3:7) gave 14 (5.8 g, 85%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.74 (s,
3H), 3.34 (d, J ) 8.0 Hz, 1H), 2.48-2.59 (m, 1H), 2.36-2.46 (m,
2H), 2.20-2.30 (m, 2H), 2.02-2.12 (m, 1H), 1.89-1.97 (m, 1H),
1.60-1.75 (m, 1H), 1.44-1.56 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 209.5, 168.25, 168.16, 56.6, 53.0, 45.1, 41.0, 38.1, 28.8,
24.5. Registry No. 33646-18-3.
d6) δ 6.96 (d, J ) 8.8 Hz, 4H), 6.74 (d, J ) 8.8 Hz, 4H), 2.26-
2.34 (m, 4H), 1.50-1.61 (m, 8H); 13C NMR (100 MHz, acetone-
d6) δ 156.3, 139.0, 138.2, 136.1, 131.0, 115.5, 33.9, 29.9, 28.8;
MS (EI) m/z 294 (M+, 100), 237, 199, 107. HRMS (EI) m/z calcd
for C20H22O2, 294.1620; found, 294.1618. Anal. (C20H22O2) C, H.
4-Hydroxyhexanone (7). In a three-necked round-bottom flask
(500 mL) fitted with a mechanical stirrer, cyclohexane-1,4-diol (5.8
g, 50 mmol) was dissolved in 200 mL of acetone. The solution
was cooled in an ice bath, and freshly prepared Jones reagent (1.6
M in acetone) was added over 25 min. The green-blue solution
was allowed to warm to room temperature over 15 min. The reaction
mixture was filtered through Celite and then evaporated. Flash
column chromatography (EtOAc/hexane; 7:3) gave 7 (3.0 g, 53%)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.17-4.23 (m,
1H), 2.55-2.66 (m, 2H), 2.25-2.36 (m, 2H), 1.91-2.11 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 211.0, 66.3, 37.1, 33.7. Registry
No. 13482-22-9.
4-Acetoxycyclohexanone (8). To a solution of 7 (2.0 g, 18
mmol) in CH2Cl2 (20 mL) was added acetic anhydride (2.1 g, 21
mmol). Pyridine was added dropwise to the reaction mixture, which
was stirred for 24 h at room temperature. The solvent was
evaporated under reduced pressure, and the residual oil was
dissolved in EtOAc (100 mL). The EtOAc layer was washed with
2 M HCl solution (100 mL), saturated NaHCO3 solution (100 mL),
and brine (100 mL). The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. Flash
column chromatography (EtOAc/hexane; 4:6) gave 8 (1.5 g, 56%)
as an oil: 1H NMR (400 MHz, CDCl3) δ 5.15 (m, 1H), 2.49-2.57
(m, 2H), 2.32-2.37 (m, 2H), 2.09 (s, 3H), 2.03-2.08 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 21.2, 30.7, 37.2, 170.4, 209.8.
Registry No. 41043-88-3.
Methyl (4-Oxocyclohexylidene)acetate. A mixture of 1,4-
cyclohexanedione (4.7 g, 42 mmol) and methyl (triphenylphos-
phoranylidene)acetate (7.0 g, 21 mmol) in toluene (100 mL) was
heated to 110 °C for 8 h. After the reaction was cooled to room
temperature, the solvent was evaporated. Et2O (200 mL) was added,
and the precipitate was filtered. The filtered organic layer was
concentrated, and the residual oil was absorbed on silica gel. Flash
column chromatography (EtOAc/hexane; 4:6) gave methyl (4-
oxocyclohexylidene)acetate (3.1 g, 88%) as a white solid: 1H NMR
(500 MHz, CDCl3) δ 5.85 (bt, J ) 1.5 Hz, 1H), 3.72 (s, 3H), 3.21
(td, J ) 7.5, 2.0 Hz, 2H), 2.66 (td, J ) 6.0, 1.5 Hz, 2H), 2.46-
2.53 (m, 2H). Registry No. 91158-10-0.
Methyl (4-Oxocyclohexyl)acetate (10). To a solution of methyl
(4-oxocyclohexylidene)acetate (2.97 g, 1.77 mmol) in ethanol (10
mL) was added 10% palladium charcoal (300 mg), and it was placed
in a hydrogenation system. The reaction mixture was stirred at room
temperature for 6 h. The solution was filtered through Celite and
concentrated under reduced pressure. Flash column chromatography
(EtOAc/hexane; 2:8) gave 10 (1.5 g, 50%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 2.42-2.35 (m, 4H), 2.22-
2.35 (m, 2H), 2.04-2.13 (m, 2H), 1.04-1.54 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 211.2, 172.8, 51.6, 40.5, 40.0, 33.1, 32.4.
Registry No. 66405-41-2.
3-(3-Acetoxy-n-propyl)cyclohexanone (15). 3-Chloropropanol
(1.9 g, 20 mmol) was added to a two-necked, round-bottom flask
containing freshly distilled THF (40 mL), and the reaction was
cooled to -78 °C under nitrogen. Methylmagnesium chloride (6.8
mL, 20 mmol, 22 w/w % in THF) solution was added slowly by
syringe. The mixture was allowed to warm, and it was stirred at
room temperature for 20 min. After addition of Mg (583 mg, 24
mmol), the reaction mixture was heated at 90 °C, and 1,2-
dibromoethane (37 µL, 0.48 mmol) was added. The solution was
refluxed for 1 h. After cooling, the reaction mixture was slowly
added dropwise over 30 min by cannulus to a one-necked flask
containing 2-cyclohexen-1-one (1.94 mL, 20 mmol) and copper(I)
bromide (286 mg, 2 mmol) in THF at -78 °C. As soon as the
addition was finished, the reaction temperature was increased to 0
°C and decreased again to -78 °C. The reaction was quenched by
HCl, and it was dissolved in ether (1.0 M, 40 mL) and saturated
ammonium chloride (15 mL). The reaction temperature was
increased to room temperature. The mixture was filtered, and the
solvent was evaporated under reduced pressure. The residual oil
was dissolved with EtOAc (100 mL) and washed with ammonium
chloride solution (100 mL) and brine (100 mL). The organic layer
was dried by sodium sulfate, and flash column chromatography
(EtOAc/hexane; 6:4) gave 3-(3-hydroxy-n-propyl)cyclohexanone
(590 mg, 19%) as an oil: 1H NMR (400 MHz, CDCl3) δ 3.57 (d,
J ) 6.0 Hz, 2H), 2.15-2.52 (m, 4H), 1.92-2.10 (m, 2H), 1.82-
1,92 (m, 1H), 1.69-1.82 (m, 1H), 1.46-1.68 (m, 3H), 1.24-1.67
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 212.2, 62.5, 48.0, 41.3,
38.8, 32.5, 31.1, 29.6, 25.1. Registry No. 69441-81-2. Purified 3-(3-
hydroxy-n-propyl)cyclohexanone (580 mg, 3.71 mmol) was stirred
with acetic anhydride (450 µL, 4.83 mmol) and pyridine (780 mL,
9.65 mmol) in CH2Cl2 (15 mL) at room temperature. After the
solution was stirred for 18 h, CH2Cl2 (50 mL) was added, and the
reaction was placed in a separatory funnel. The organic layer was
washed with a saturated NaHCO3 solution and saturated ammonium
chloride solution, dried over Na2SO4, filtered, and concentrated.
Flash column chromatography (EtOAc/hexane; 3:7) gave 15 (329
mg, 45%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.03
(t, J ) 6.4 Hz, 2H), 2.38-2.46 (m, 1H), 2.31-2.38 (m, 1H), 2.18-
2.29 (m, 1H), 2.18-2.09 (m, 2H), 2.03 (s, 3H), 1.85-1.94 (m,
1H), 1.71-1.83 (m, 1H), 1.57-1.70 (m, 3H), 1.27-1.45 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 211.5, 171.1, 64.3, 48.0, 41.2, 38.7,
32.7, 31.1, 25.8, 25.1, 20.9; MS (EI) m/z 198 (M+), 155, 138, 110,
97 (100), 84, 67. HRMS (EI) m/z calcd for C11H18O3, 198.1256;
found, 198.1253.
Methyl 3-Oxocyclohexanecarboxylate (12). To a solution of
3-oxo-1-cyclohexanecarboxylic acid (1.0 g, 7.03 mmol) in methanol
(12 mL) was added thionyl chloride (1.0 g, 8.4 mmol), slowly, at
room temperature. The reaction mixture was stirred for 3 h and
then quenched slowly by three drops of H2O in an ice bath. The
reaction was neutralized by saturated NaHCO3 solution, and the
organic layer was extracted with EtOAc (30 mL). The organic layer
was washed by H2O (10 mL) and dried over Na2SO4. After removal
of the solvent, flash column chromatography (EtOAc/hexane; 2:8)
gave 12 (0.803 g, 73%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 3.69 (s, 3H), 2.75-2.84 (m, 1H), 2.53 (d, J ) 8.0 Hz,
2H), 2.25-2.40 (m, 2H), 2.00-2.14 (m, 2H), 1.76-1.88 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 209.1, 174.1, 52.0, 43.1, 43.0, 40.9,
27.7, 24.4. Registry No. 13148-83-9.
4-Acetoxy-1-[bis(4-hydroxyphenyl)methylene]cyclohexane (16).
According to the general procedure for the McMurry coupling
reaction with 4,4′-dihydroxybenzophenone (1, 1.17 g, 5.4 mmol),
8 (850 mg, 5.4 mmol), Zn (2.7 g, 41 mmol), and titanium(IV)
chloride (3.8 g, 20.1 mmol), 16 (1.5 g, 83%) was obtained as a
white solid: mp 208-210 °C; 1H NMR (400 MHz, acetone-d6) δ
6.93 (d, J ) 8.4 Hz, 4H), 6.75 (d, J ) 8.4 Hz, 4H), 4.90 (septet,
J ) 4.0 Hz, 1H), 2.55-2.45 (m, 2H), 2.11-2.21 (m,, 2H), 1.93 (s,
3H), 1.92-1.83 (m, 2H), 1.62-1.51 (m, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 169.9, 155.8, 135.2, 133.8, 133.4, 130.3, 114.7, 72.2,
32.2, 28.1, 21.1; MS m/z (EI) 338 (M+), 278 (100). HRMS (EI)
m/z calcd for C21H22O4, 338.1518; found, 338.1517.
Dimethyl [2-(3-Oxocyclohexyl)]malonate (14). To a solution
of 2-cyclohexen-1-one (2.9 g, 30 mmol) and dimethyl malonate
4-Acetoxy-1-[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane (17a). According to the general procedure for MOM

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2505
protection with 16 (1.5 g, 4.4 mmol), methoxymethyl chloride (779
mg, 9.7 mmol), sodium hydride (380 mg, 10 mmol), and DMF (15
mL), 17a (1.5 g, 78%) was obtained as a colorless oil: 1H NMR
(500 MHz, CDCl3) δ 7.01 (d, J ) 9.0 Hz, 4H), 6.95 (d, J ) 9.0
Hz, 4H), 5.15-5.18 (m, 4H), 5.03-4.93 (m, 1H), 3.46-3.50 (m,
6H), 2.51-2.56 (m, 2H), 2.13-2.18 (m, 2H), 2.04-2.07 (m, 3H),
1.89-1.92 (m, 2H), 1.61-1.64 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 170.6, 155.7, 136.5, 135.5, 135.0, 130.7, 115.6, 94.4,
71.9, 56.0, 32.6, 28.5, 21.4; MS (EI) m/z 426 (M+), 366 (100).
HRMS (EI) m/z calcd for C25H30O6, 426.2042; found, 426.2036.
4-[Bis(4-methoxymethoxyphenyl)methylene]cyclohexanol (17b).
Compound 16 (1.4 g, 3.3 mmol) was dissolved in methanol (15
mL) and H2O (3 mL). After the addition of potassium carbonate
(2.3 g, 16 mmol), the reaction mixture was stirred at room
temperature for 12 h. The reaction mixture was slowly added to a
two-phase solution of EtOAc (100 mL) and H2O (100 mL) with
stirring, and the mixture was neutralized by 2 M HCl solution. The
organic layer was collected and dried over sodium sulfate. After
the solvent was removed, flash column chromatography (EtOAc/
hexane; 4:6) gave 17b (1.2 g, 95%) as a white solid: mp 74-76
°C; 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J ) 9.0 Hz, 4H), 6.94
(d, J ) 9.0 Hz, 4H), 5.15 (s, 4H), 3.89 (septet, J ) 4.5 Hz, 1H),
3.48 (s, 6H), 2.57 (dt, J ) 11.2, 4.3 Hz, 2H), 2.01-2.11 (m, 2H),
1.98-1.88 (m, 2H), 1.54-1.42 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 155.7, 136.7, 136.1, 134.7, 130.7, 115.6, 94.4, 69.7, 56.0,
36.3, 28.7; MS m/z (EI) 384 (M+, 100), 366. HRMS (EI) m/z calcd
for C23H28O5, 384.1937; found, 384.1928.
Ethyl 4-[Bis(4-hydroxyphenyl)methylene]cyclohexanecar-
boxylate (21a). According to the general procedure for the
McMurry coupling reaction with 4,4′-dihydroxybenzophenone (1,
2.1 g, 10 mmol), ethyl 4-oxocyclohexanecarboxylate (1.7 g, 10
mmol), Zn (4.9 g, 75 mmol), and titanium(IV) chloride (7.0 g, 37
mmol), 21a (2.7 g, 77%) was obtained as a white solid: mp 198-
1
200 °C; H NMR (400 MHz, acetone-d6) δ 7.01 (d, J ) 8.5 Hz,
4H), 6.94 (d, J ) 8.5 Hz, 4H), 4.08 (q, J ) 7.2 Hz, 2H), 2.49-
2.64 (m, 3H), 1.90-2.10 (m, 4H), 1.50-1.64 (m, 2H), 1.21 (t, J )
7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 206.2, 175.4,
156.7, 136.2, 135.9, 135.2, 131.5, 115.5, 60.5, 43.6, 31.3, 29.6,
14.5; MS (EI) m/z 352 (M+, 100), 278, 237, 199, 107. HRMS (EI)
m/z calcd for C22H24O4, 352.1675; found, 352.1677. Anal. (C22H24O4‚
0.2H2O) C, H.
Ethyl
4-[Bis(4-methoxymethylphenyl)methylene]cyclo-
hexanecarboxylate (22a). According to the general procedure for
MOM protection with 21a (2.1 g, 6.0 mmol), methoxymethyl
chloride (1.6 g, 20 mmol), sodium hydride (440 mg, 13 mmol),
and DMF (15 mL), 22a (2.5 g, 95% yield) was obtained as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J ) 8.8 Hz,
4H), 6.93 (d, J ) 8.4 Hz, 4H), 5.15 (s, 4H), 4.13 (q, J ) 7.2 Hz,
2H), 3.48 (s, 6H), 2.60 (bd, J ) 12.8 Hz, 2H), 2.48-2.68 (m, 1H),
1.92-2.06 (m, 4H), 1.54-1.69 (m, 2H), 1.25 (t, J ) 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 175.6, 155.6, 136.5, 136.1, 134.7,
130.7, 115.6, 94.4, 60.2, 56.0, 43.1, 30.7, 30.5, 14.2; MS (EI) m/z
440 (M+, 100). HRMS (EI) m/z calcd for C26H32O6, 440.2199;
found, 440.2204.
4-Hydroxymethyl[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane (23a). According to the general procedure for reduc-
tion with 22a (2.5 g, 5.7 mmol), LiAlH4 in THF solution (1 M, 5.7
mL), and THF (15 mL), 23a (2.0 g, 89%) was obtained as a white
foam: mp 72 °C; 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J ) 8.8
Hz, 4H), 6.94 (d, J ) 8.8 Hz, 4H), 5.15 (s, 4H), 3.49 (d, J ) 6.4
Hz, 2H), 3.48 (s, 6H), 2.65 (bd, J ) 13.6 Hz, 2H), 1.90-2.01 (m,
2H), 1.81-1.90 (m, 2H), 1.63-1.80 (m, 1H), 1.03-1.18 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 155.5, 137.7, 136.8, 133.9, 130.8,
115.5, 94.4, 68.0, 56.0, 40.4, 31.1, 31.0; MS (EI) m/z 398 (M+),
303 (100), 247, 111. HRMS (EI) m/z calcd for C24H30O5, 398.2093;
found, 398.2101.
4-[Bis(4-hydroxyphenyl)methylene]cyclohexanol (18). Accord-
ing to the general procedure for MOM deprotection with 17b (120
mg, 0.31 mmol), HCl (200 µL), and methanol (10 mL), 18 (78
mg, 85%) was obtained as an off-white solid: mp 209 °C; 1H NMR
(400 MHz, DMSO-d6) δ 6.82 (d, J ) 8.4 Hz, 4H), 6.66 (d, J ) 8.8
Hz, 4H), 3.60-3.70 (m, 1H), 2.34-2.44 (m, 2H), 1.90-2.00 (m,
2H), 1.70-1.82 (m, 2H), 1.24-1.36 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 155.6, 135.3, 134.2, 133.7, 130.4, 114.7, 67.6, 36.3,
28.5; MS (EI) m/z 296 (M+, 100), 278, 237, 199, 107. HRMS (EI)
m/z calcd for C19H20O3, 296.1412; found, 296.1419. Anal. (C19H20O3‚
0.2H2O) C, H.
4-Fluoro[bis(4-methoxymethoxyphenyl)methylene]cyclo-
hexane (19). In a one-necked round-bottom flask, which contained
17b (200 mg, 0.52 mmol), CH2Cl2 (5 mL) was added under
nitrogen, and the reaction mixture was cooled to -78 °C. Diethy-
laminosulfur trifluoride (120 mg, 0.62 mmol) was dropped very
slowly by syringe at -78 °C. The cooling was removed, and the
reaction mixture was stirred for 1 h at room temperature. The
reaction mixture was cooled again to -78 °C, and methanol (200
µL) was added. The solution was additionally stirred for 30 min
after removal of the dry ice bath, and the reaction was quenched
by saturated NaHCO3 solution and extracted with excess EtOAc.
The organic layer was dried over sodium sulfate and concentrated.
Flash column chromatography (EtOAc/hexane; 1:9) gave 19 (65
mg, 32%) as a slightly yellow oil: 1H NMR (500 MHz, CDCl3) δ
7.01 (d, J ) 8.5 Hz, 4H), 6.94 (d, J ) 8.5 Hz, 4H), 5.16 (s, 4H),
4-Hydroxymethyl[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (24a). According to the general procedure for MOM
deprotection with 23a (100 mg, 0.25 mmol), HCl (300 µL), and
methanol (4 mL), 24a (69 mg, 90%) was obtained as a white
1
solid: mp 211-212 °C; H NMR (400 MHz, acetone-d6) δ 6.91
(d, J ) 8.8 Hz, 4H), 6.74 (d, J ) 8.8 Hz, 4H), 3.38 (d, J ) 6.0 Hz,
2H), 2.62 (bd, J ) 13.6 Hz, 2H), 1.80-1.98 (m, 4H), 1.61-1.73
(m, 1H), 1.02-1.15 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ
156.6, 137.7, 135.6, 135.4, 131.5, 115.4, 67.7, 41.6, 32.1, 32.0;
MS (EI) m/z 310 (M+), 256 (100), 225, 199, 107, 64. HRMS (EI)
m/z calcd for C20H22O3, 310.1569; found, 310.1562. Anal. (C20H22O3)
C, H.
4-Methanesulfonyloxymethyl[bis(4-methoxymethoxyphenyl)-
methylene]cyclohexane (25a). According to the general procedure
for methanesulfonylation with 24a (90 mg, 0.23 mmol), methane-
sulfonic anhydride (94 mg, 0.54 mmol), triethylamine (68 mg, 0.68
mmol), and CH2Cl2 (5 mL), 25a (102 mg, 95%) was obtained as
an off-white solid: mp 79-80 °C; 1H NMR (500 MHz, CDCl3) δ
7.01 (d, J ) 9.0 Hz, 4H), 6.94 (d, J ) 9.5 Hz, 4H), 5.15 (s, 4H),
4.08 (d, J ) 6.5 Hz, 2H), 3.48 (s, 6H), 3.00 (s, 3H), 2.66 (bd, J )
13.5 Hz, 2H), 1.97-2.04 (m, 3H), 1.84-1.96 (m, 2H), 1.14-1.24
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 155.6, 136.5, 136.4, 134.7,
130.7, 115.6, 94.4, 74.1, 55.9, 37.4, 37.1, 30.7, 30.5; MS (EI) m/z
476 (M+, 100), 446, 41, 380, 335. HRMS (EI) m/z calcd for
C25H32O7S, 476.1869; found, 476.1873.
4-Fluoromethyl[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane. According to the general procedure for fluorination
with 25a (167 mg, 0.35 mmol), cesium fluoride (266 mg, 1.8
mmol), H2O (50 µL) in 1-butyl-3-methyl-imidazolium tetra-
fluoroboronate (1.5 mL), and acetonitrile (1.5 mL), 4-fluoromethyl-
[bis(4-methoxymethoxyphenyl)methylene]cyclohexane (89 mg, 63%)
was obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δ
2
4.81 (dm, JHF ) 48.5 Hz, 1H), 3.48 (s, 6H), 2.45-2.52 (m, 2H),
2.16-2.25 (m, 2H), 1.78-1.93 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 155.7, 136.5, 135.4, 135.1, 130.7, 115.7, 94.4, 90.5 (d,
2
3
1JCF ) 168.6 Hz), 56.0, 33.3 (d, JCF ) 19.3 Hz), 27.3 (d, JCF
)
6.4 Hz); MS (EI) m/z 386 (M+, 100). HRMS (EI) m/z calcd for
C23H27O4F, 386.1893; found, 386.1889.
4-Fluoro[bis(4-hydroxyphenyl)methylene]cyclohexane (20).
According to the general procedure for MOM deprotection with
19 (45 mg, 0.12 mmol), HCl (100 µL), and methanol (4 mL), 20
(25 mg, 71%) was obtained as an off-white solid: mp 202-203
1
°C; H NMR (500 MHz, acetone-d6) δ 6.93 (d, J ) 9.0 Hz, 4H),
2
6.75 (d, J ) 8.5 Hz, 4H), 4.78 (dm, JHF ) 49.0 Hz, 1H), 2.41-
2.48 (m, 2H), 2.16-2.24 (m, 2H), 1.82-1.95 (m, 2H), 1.69-1.79
(m, 2H); 13C NMR (125 MHz, acetone-d6) δ 156.79, 136.72, 135.23,
135.05, 131.48, 115.55, 90.53 (d, 1JCF ) 168.6 Hz), 34.05 (d, 2JCF
3
) 19.3 Hz), 28.11 (d, JCF ) 6.38 Hz); MS (EI) m/z 298 (M+),
184, 141, 128, 115, 77 (100). HRMS (EI) m/z calcd for C19H19O2F,
298.1369; found 298.1362. Anal. (C19H19O2F‚0.1H2O) C, H.

2506 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Seo et al.
7.02 (d, J ) 9.0 Hz, 4H), 6.94 (d, J ) 9.0 Hz, 4H), 5.16 (s, 4H),
4.26 (dd, 2JHF ) 47.5 Hz, J ) 6.0 Hz, 2H), 3.48 (s, 6H), 2.66 (bd,
J ) 13.5 Hz, 2H), 1.89-2.02 (m, 3H), 1.81-1.89 (m, 2H), 1.12-
1.24 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 155.6, 137.1, 136.7,
134.4, 130.8, 115.6, 94.5, 88.0 (d, 1JCF ) 166.6 Hz), 56.0, 38.5 (d,
mg, 0.63 mmol), HCl (200 µL), methanol (5 mL), and Et2O (2.5
mL), 29a (152 mg, 82%) was obtained as an off-white solid: mp
183-184 °C; H NMR (400 MHz, methanol-d4) δ 6.86 (d, J )
8.8 Hz, 4H), 6.66 (d, J ) 8.8 Hz, 4H), 2.57 (bd, J ) 14.0 Hz, 2H),
1.94 (td, J ) 13.4, 3.6 Hz, 2H), 1.69-1.79 (m, 2H), 1.53-1.67
(m, 1H), 0.97-1.10 (m, 2H), 0.92 (d, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, methanol-d4) δ 156.7, 137.9, 136.2, 135.9, 131.9, 115.5,
38.0, 34.1, 32.8, 22.5; MS (EI) m/z 294 (M+, 100), 199, 107. Anal.
(C20H22O2‚0.1H2O) C, H.
1
3
2JCF ) 18.3 Hz), 30.9, 30.0 (d, JCF ) 5.5 Hz); MS (EI) m/z 400
(M+, 100), 355, 149. HRMS (EI) m/z calcd for C24H29O4F,
400.2050; found, 400.2045.
4-Fluoromethyl[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (26a). According to the general procedure for MOM
deprotection with 4-fluoromethyl[bis(4-methoxymethoxyphenyl)-
methylene]-cyclohexane (89 mg, 0.22 mmol), HCl (100 µL), and
methanol (8 mL), 26a (38 mg, 55%) was obtained as a white
Methyl {4-[Bis(4-hydroxyphenyl)methylene]cyclohexyl}acetate
(21b). According to the general procedure for the McMurry
coupling reaction with 4,4′-dihydroxybenzophenone (1, 957 mg,
4.5 mmol), 10 (760 mg, 4.5 mmol), Zn (2.2 g, 34 mmol), and
titanium(IV) chloride (3.1 g, 17 mmol), 21b (1.1 g, 71%) was
1
solid: mp 201-202 °C; H NMR (500 MHz, acetone-d6) δ 6.92
2
1
(d, J ) 8.5 Hz, 4H), 6.75 (d, J ) 8.5 Hz, 4H), 4.28 (dd, JHF
)
obtained as a white solid: mp 201-203 °C; H NMR (400 MHz,
47.5 Hz, J ) 6.0 Hz, 2H), 2.64 (bd, J ) 13.5 Hz, 2H), 1.86-2.01
(m, 3H), 1.78-1.85 (m, 2H), 1.12-1.22 (m, 2H); 13C NMR (125
MHz, acetone-d6) δ 156.7, 136.8, 135.9, 135.4, 131.5, 115.5, 88.5
(d, 1JCF ) 165.8 Hz), 39.4 (d, 2JCF ) 18.3 Hz), 31.6, 30.7 (d, 3JCF
) 5.5 Hz); MS (EI) m/z 312 (M+, 100), 199, 149, 107. HRMS
(EI) m/z calcd for C20H21O2F, 312.1526, found, 312.1524. Anal.
(C20H21O2F) C, H.
acetone-d6) δ 6.91 (d, J ) 8.8 Hz, 4H), 6.74 (d, J ) 8.8 Hz, 4H),
3.60 (s, 3H), 2.59 (bd, J ) 13.6 Hz, 2H), 2.23 (d, J ) 6.8 Hz, 2H),
1.89-2.02 (m, 3H), 1.76-1.85 (m, 2H), 1.06-1.18 (m, 2H); 13C
NMR (100 MHz, acetone-d6) δ 173.3, 156.6, 136.8, 135.7, 135.4,
131.5, 115.4, 51.4, 41.5, 35.7, 35.0, 32.0; MS (EI) m/z 352 (M+),
166, 107 (100), 77. HRMS (EI) m/z calcd for C22H24O4, 352.1675;
found, 352.1670. Anal. (C22H24O4) C, H.
4-Ethoxymethyl[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane. To a solution of 23a (200 mg, 0.49 mmol) in DMF
(7 mL), which was contained in a pressure tube, was added sodium
hydride (35 mg, 0.97 mmol) under N2. After the solution was stirred
for 10 min, bromoethane (158 mg, 0.15 mmol) was added. The
pressure tube was tightly capped, and the temperature of the reaction
mixture was increased to 100 °C. The mixture was stirred for 24 h
and cooled. The mixture was poured into H2O (50 mL) and Et-
OAc (100 mL) solution. The extracted organic layer was washed
with saturated ammonium chloride (100 mL × 2) solution and
saturated brine (100 mL) and dried (MgSO4). The organic layer
was concentrated, and flash column chromatography (EtOAc/
hexane; 15:85) gave 4-ethoxymethyl[bis(4-methoxymethoxy-
phenyl)methylene]cyclohexane (74 mg, 36%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.02 (d, J ) 8.8 Hz, 4H), 6.93 (d, J )
8.8 Hz, 4H), 5.15 (s, 4H), 3.44-3.52 (m, 7H), 3.27 (d, J ) 6.0 Hz,
2H), 2.62 (bd, J ) 13.6 Hz, 2H), 1.76-2.01 (m, 5H), 1.20 (t, J )
6.8 Hz, 3H), 1.14-1.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
155.5, 138.0, 136.9, 133.8, 130.8, 115.5, 94.4, 75.9, 66.4, 56.0,
38.1, 31.7, 31.2, 15.2; MS (EI) m/z 426 (M+, 100), 302, 287, 149;
HRMS (EI) m/z calcd for C26H34O5, 426.2406; found, 426.2400.
4-Ethoxymethyl[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (27). According to the general procedure for MOM
deprotection with 4-ethoxymethyl[bis(4-methoxymethoxyphenyl)-
methylene]cyclohexane (74 mg, 0.17 mmol), HCl (200 µL), and
methanol (5 mL), 27 (43 mg, 73%) was obtained as a white
crystal: mp 209-210 °C; 1H NMR (400 MHz, acetone-d6) δ 6.91
(d, J ) 8.8 Hz, 4H), 6.74 (d, J ) 8.8 Hz, 4H), 3.41 (q, J ) 6.8 Hz,
2H), 3.23 (d, J ) 6.0 Hz, 2H), 2.61 (bd, J ) 13.6 Hz, 2H), 1.87-
1.98 (m, 2H), 1.71-1.86 (m, 3H), 1.03-1.16 (m, 5H); 13C NMR
(100 MHz, acetone-d6) δ 156.5, 137.5, 135.5, 135.4, 131.5, 115.4,
76.3, 66.7, 39.1, 32.4, 31.9, 15.5; MS (EI) m/z 338 (M+, 100), 199,
149. HRMS (EI) m/z calcd for C22H26O3, 338.1882; found,
338.1887. Anal. (C22H26O3) C, H.
Methyl {4-[Bis(4-methoxymethoxyphenyl)methylene]cyclo-
hexyl}acetate (22b). According to the general procedure for MOM
protection with 21b (980 mg, 2.8 mmol), methoxymethyl chloride
(736 mg, 9.1 mmol), sodium hydride (309 mg, 9.1 mmol), and DMF
(15 mL), 22b (1.2 g, 97%) was obtained as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.00 (d, J ) 9.0 Hz, 4H), 6.92 (d, J )
8.5 Hz, 4H), 5.15 (s, 4H), 3.66 (s, 3H), 3.48 (s, 6H), 2.60 (bd, J )
14.0 Hz, 2H), 2.24 (d, J ) 7.5 Hz, 2H), 1.92-2.08 (m, 3H), 1.78-
1.86 (m, 2H), 1.08-1.19 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
173.5, 155.6, 137.2, 136.8, 134.1, 130.8, 115.6, 94.4, 56.0, 51.4,
41.2, 34.8, 34.4, 31.3; MS (EI) m/z 440 (M+), 320, 210, 180, 151,
121 (100), 84. HRMS (EI) m/z calcd for C26H32O6, 440.2199; found,
440.2196.
4-(2-Hydroxyethyl)[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane (23b). According to the general procedure for reduc-
tion with 22b (1.15 g, 2.6 mmol), LiAlH4 in THF solution (1 M,
2.6 mL), and THF (10 mL), 23b (1.0 g, 96%) was obtained as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.01 (d, J ) 8.5 Hz,
4H), 6.93 (d, J ) 9.0 Hz, 4H), 5.15 (s, 4H), 3.70 (t, J ) 6.5 Hz,
2H), 3.48 (s, 6H), 2.60 (bd, J ) 14.0 Hz, 2H), 1.89-1.99 (m, 2H),
1.79-1.85 (m, 2H), 1.62-1.71 (m, 1H), 1.52 (q, J ) 6.5 Hz, 2H),
1.05-1.15 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 155.5, 138.0,
136.9, 136.7, 130.8, 115.6, 94.5, 60.9, 56.00, 55.99, 39.6, 34.8,
34.2, 31.6; MS (EI) m/z 412 (M+, 100). HRMS (EI) m/z calcd for
C25H32O5, 412.2250; found, 412.2246.
4-(2-Hydroxyethyl)[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (24b). According to the general procedure for MOM
deprotection with 23b (45 mg, 0.11 mmol), HCl (200 µL), and
methanol (5 mL), 24b (30 mg, 84%) was obtained as a white
solid: mp 183 °C; 1H NMR (400 MHz, acetone-d6) δ 6.91 (d, J )
8.8 Hz, 4H), 6.74 (d, J ) 6.8 Hz, 4H), 3.58 (bt, J ) 6.4 Hz, 2H),
2.59 (bd, J ) 13.2 Hz, 2H), 1.94 (td, J ) 13.2, 4.4 Hz, 2H), 1.77-
1.86 (m, 2H), 1.61-1.75 (m, 1H), 1.44 (q, J ) 6.8 Hz, 2H), 1.00-
1.13 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 156.5, 137.7,
135.6, 135.2, 131.6, 115.4, 60.3, 40.6, 35.6, 35.1, 32.3; MS (EI)
m/z 324 (M+, 100), 137, 199, 107. HRMS (EI) m/z calcd for
C21H24O3, 324.1725; found, 324.1726. Anal. (C21H24O3) C, H.
4-(2-Methanesulfonyloxyethyl)[bis(4-methoxymethoxyphen-
yl)methylene]cyclohexane (25b). According to the general pro-
cedure for methanesulfonylation with 24b (448 mg, 1.1 mmol),
methanesulfonic anhydride (284 mg, 1.6 mmol), triethylamine (331
mg, 3.3 mmol), and CH2Cl2 (6 mL), 25b (500 mg, 93%) was
obtained as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.00
(d, J ) 8.8 Hz, 4H), 6.93 (d, J ) 8.8 Hz, 4H), 5.15 (s, 4H), 4.28
(t, J ) 6.4 Hz, 2H), 3.48 (s, 6H), 3.30 (s, 3H), 2.61 (bd, J ) 13.6
Hz, 2H), 1.95 (td, J ) 13.2, 3.6 Hz, 2H), 1.78-1.87 (m, 2H), 1.65-
1.75 (m, 3H), 1.05-1.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
155.6, 137.2, 137.0, 134.1, 130.8, 115.6, 94.4, 68.2, 56.0, 37.4,
4-Methyl[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane. According to the general procedure for reduction with
25a (300 mg, 0.63 mmol), LiAlH4 in THF solution (1 M, 900 µL),
and THF (8 mL), 4-methyl[bis(4-methoxymethoxyphenyl)meth-
ylene]cyclohexane (240 mg, 99%) was obtained as an oil: 1H NMR
(400 MHz, CDCl3) δ 7.03 (d, J ) 8.8 Hz, 4H), 6.94 (d, J ) 8.8
Hz, 4H), 5.16 (s, 4H), 3.49 (s, 6H), 2.59 (bd, J ) 13.6 Hz, 2H),
1.94 (td, J ) 12.8, 4.0 Hz, 2H), 1.72-1.80 (m, 2H), 1.55-1.68
(m, 1H), 1.01-1.14 (m, 2H), 0.93 (d, J ) 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.4, 138.2, 137.0, 133.4, 130.8, 115.5, 94.4,
56.0, 36.8, 32.7, 31.7, 22.0; MS (EI) m/z 382 (M+, 100). HRMS
(EI) m/z calcd for C24H30O4, 382.2144; found, 382.2135.
4-Methyl[bis(4-hydroxyphenyl)methylene]cyclohexane (29a).
According to the general procedure for MOM deprotection with
4-methyl[bis(4-methoxymethoxyphenyl)methylene]cyclohexane (240

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2507
35.7, 34.3, 34.0, 31.3; MS (EI) m/z 490 (M+), 446, 427 (100).
HRMS (EI) m/z calcd for C26H34O7S, 490.2025; found 490.2024.
4-(2-Fluoroethyl)[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane. According to the general procedure for fluorination
with 25b (150 mg, 0.31 mmol), cesium fluoride (235 mg, 1.6
mmol), H2O (20 µL), 1-butyl-3-methyl-imidazolium tetrafluorobo-
ronate (1.0 mL), and acetonitrile (1.0 mL), 4-(2-fluoroethyl)[bis-
(4-methoxymethoxyphenyl)methylene]cyclohexane (106 mg, 82%)
was obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δ
7.03 (d, J ) 8.5 Hz, 4H), 6.95 (d, J ) 8.5 Hz, 4H), 5.16 (s, 4H),
4.51 (dt, 2JHF ) 47 Hz, J ) 6.0 Hz, 2H), 3.49 (s, 6H), 2.63 (bd, J
) 13.5 Hz, 2H), 1.96 (td, J ) 13.0, 3.5 Hz, 2H), 1.81-1.90 (m,
2H), 1.60-1.78 (m, 3H), 1.07-1.18 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 155.5, 137.7, 136.8, 133.8, 130.8, 115.5, 94.4, 82.4 (d,
4-Ethyl[bis(4-methoxymethoxyphenyl)methylene]cyclo-
hexane. According to the general procedure for reduction with 25b
(175 g, 0.35 mmol), LiAlH4 in THF solution (1 M, 700 µL), and
THF (10 mL), 4-ethyl[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane (130 mg, 92%) was obtained as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.01 (d, J ) 8.5 Hz, 4H), 6.93 (d, J )
9.0 Hz, 4H), 5.15 (s, 4H), 3.48 (s, 6H), 2.59 (bd, J ) 13.5 Hz,
2H), 1.91 (td, J ) 13.0, 4.0 Hz, 2H), 1.77-1.84 (m, 2H), 1.32-
1.43 (m, 1H), 1.19-1.30 (m, 3H), 0.98-1.08 (m, 2H), 0.89 (t, J )
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.5, 138.7, 137.1,
133.3, 130.9, 115.5, 94.5, 56.0, 39.4, 34.5, 31.7, 29.3, 11.6; MS
(EI) m/z 396 (M+, 100), 251, 287. HRMS (EI) m/z calcd for
C25H32O4, 396.2301; found, 396.2307.
4-Ethyl[bis(4-hydroxyphenyl)methylene]cyclohexane (29b).
According to the general procedure for MOM deprotection with
4-ethyl[bis(4-methoxymethoxyphenyl)methylene]cyclohexane (130
mg, 0.33 mmol), HCl (200 µL), methanol (2.5 mL), and THF (2.5
mL), 29b (85 mg, 84%) was obtained as a white solid: mp 188
°C; 1H NMR (500 MHz, CDCl3) δ 6.97 (d, J ) 8.5 Hz, 4H), 6.73
(d, J ) 7.5 Hz, 4H), 2.58 (bd, J ) 13.0 Hz, 2H), 1.91 (td, J )
13.5, 3.5 Hz, 2H), 1.33-1.42 (m, 1H), 1.25 (quintet, J ) 7.5 Hz,
2H), 0.98-1.08 (m, 2H), 0.89 (t, J ) 7.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 153.7, 138.5, 136.1, 133.2, 114.7, 39.4, 34.5, 31.7,
29.4, 11.6; MS (EI) m/z 308 (M+, 100), 199. Anal. (C21H24O2) C,
H.
2
1JCF ) 163.0 Hz), 55.94, 55.91, 37.0 (d, JCF ) 19.3 Hz), 34.5,
3
34.0 (d, JCF ) 4.6 Hz), 31.4; MS (EI) m/z 414 (M+, 100), 149.
HRMS (EI) m/z calcd for C25H31O4F, 414.2206; found, 414.2202.
4-(2-Fluoroethyl)[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (26b). According to the general procedure for MOM
deprotection with 4-(2-fluoroethyl)[bis(4-methoxymethoxyphenyl)-
methylene]cyclohexane (100 mg, 0.24 mmol), HCl (200 µL), and
methanol (5 mL), 26b (66 mg, 84%) was obtained as a white
1
solid: mp 192-193 °C; H NMR (500 MHz, acetone-d6) δ 6.91
2
(d, J ) 8.5 Hz, 4H), 6.74 (d, J ) 8.5 Hz, 4H), 4.49 (dt, JHF
)
48.0 Hz, J ) 6.0 Hz, 2H), 2.60 (bd, J ) 14.0 Hz, 2H), 1.94 (td, J
) 13.5, 3.5 Hz, 2H), 1.80-1.87 (m, 2H), 1.64-1.74 (m, 1H), 1.62
Methyl
3-[Bis(4-hydroxyphenyl)methylene]cyclohexane-
(dq, JHF ) 25.5 Hz, J ) 6.5 Hz, 2H), 1.05-1.17 (m, 2H); 13C
3
carboxylate (30a). According to the general procedure for the
McMurry coupling reaction with 4,4′-dihydroxybenzophenone (1,
1.1 g, 5.1 mmol), 12 (0.8 g, 5.1 mmol), Zn (2.5 g, 38 mmol), and
titanium(IV) chloride (3.6 g, 19 mmol), 30a (1.4 g, 81%) was
NMR (125 MHz, acetone-d6) δ 156.6, 137.3, 135.54, 135.46, 131.6,
1
2
115.5, 82.9 (d, JCF ) 162.0 Hz), 37.8 (d, JCF ) 19.3 Hz), 35.3,
34.96 (d, JCF ) 4.6 Hz), 32.2; MS (EI) m/z 326 (M+), 168, 141,
3
1
obtained as a white solid: mp 144-146 °C; H NMR (400 MHz,
115, 77, 57 (100). HRMS (EI) m/z calcd for C21H23O2F, 326.1682;
found, 326.1680. Anal. (C21H23O2F‚0.1H2O) C, H.
acetone-d6) δ 6.83 (d, J ) 8.8 Hz, 2H), 6.82 (d, J ) 8.0 Hz, 2H),
6.67 (d, J ) 8.8 Hz, 2H), 6.65 (d, J ) 8.0 Hz, 2H), 3.53 (s, 3H),
2.63 (bd, J ) 10.4 Hz, 1H), 2.34-2.46 (m, 2H), 2.02 (t, J ) 12.4
Hz, 1H), 1.72-1.96 (m, 3H), 1.45-1.61 (m, 1H), 1.28-1.42 (m,
3H); 13C NMR (100 MHz, acetone-d6) δ 174.7, 155.7, 135.7, 133.4,
133.3, 130.29, 130.26, 114.7, 114.6, 51.3, 43.6, 33.9, 30.9, 28.7,
26.2; MS (EI) m/z 338 (M+, 100), 278, 199. HRMS (EI) m/z calcd
for C21H22O4, 338.1518; found, 338.1518. Anal. (C21H22O4) C, H.
Methyl 3-[Bis(4-methoxymethoxyphenyl)methylene]cyclo-
hexanecarboxylate (33a). According to the general procedure for
MOM protection with 30a (1.2 g, 3.6 mmol), methoxymethyl
chloride (0.66 g, 8.2 mmol), sodium hydride (0.4 g, 8.9 mmol),
and DMF (15 mL), 33a (1.3 g, 84%) was obtained as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J ) 8.8 Hz, 2H), 7.00
(d, J ) 9.2 Hz, 2H), 6.93 (d, J ) 8.8 Hz, 4H), 5.153 (s, 2H), 5.15
(s, 2H), 3.62 (s, 3H), 3.481 (s, 3H), 3.476 (s, 3H), 2.73-2.81 (m,
1H), 2.51-2.61 (m, 1H), 2.40-2.49 (m, 1H), 2.15 (t, J ) 12.4
Hz, 1H), 1.97-2.07 (m, 1H), 1.82-1.96 (m, 2H), 1.58-1.70 (m,
1H), 1.34-1.48 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 175.8,
155.73, 155.69, 136.6, 136.3, 135.6, 135.2, 130.73, 130.72, 115.7,
115.6, 94.5, 77.2, 56.0, 51.6, 44.6, 34.1, 31.5, 29.4, 26.9; MS (EI)
m/z 426 (M+), 302, 286 (100), 241, 165. HRMS (EI) m/z calcd for
C25H30O6, 426.2042; found, 426.2041.
3-Hydroxymethyl[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane (34a). According to the general procedure for reduc-
tion with 33a (0.65 g, 1.5 mmol), LiAlH4 in THF solution (1 M,
1.5 mL), and THF (10 mL), 34a (0.59 g, 98%) was obtained as an
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J ) 8.8 Hz,
2H), 7.01 (d, J ) 8.4 Hz, 2H), 6.93 (d, J ) 8.4 Hz, 4H), 5.149 (s,
2H), 5.148 (s, 2H), 3.48 (s, 6H), 3.64-3.67 (m, 2H), 2.61 (d, J )
10 Hz, 1H), 2.55 (d, J ) 13.6 Hz, 1H), 1.78-1.98 (m, 3H), 1.62-
1.75 (m, 2H), 1.35-1.48 (m, 2H), 1.17-1.29 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 155.60, 155.57, 136.9, 136.73, 136.70, 134.4,
130.7, 115.7, 115.6, 94.5, 68.0, 56.0, 42.1, 34.9, 32.1, 29.4, 27.0;
MS (EI) m/z 398 (M+), 302 (100). HRMS (EI) m/z calcd for
C24H30O5, 398.2093; found, 398.2956.
4-[2-(4-Fluorobutoxy)ethyl][bis(4-methoxymethoxyphenyl)-
methylene]cyclohexane. To a solution of 23b (120 mg, 0.29 mmol)
in DMF (4 mL) was added sodium hydride (15 mg, 0.44 mmol) at
0 °C under nitrogen. After addition of 1-bromo-4-fluorobutane (54
mg, 0.35 mmol), the reaction mixture was stirred at 100 °C for 24
h and cooled to room temperature. The mixture was poured into
H2O (50 mL) and EtOAc (100 mL) solution, and the organic layer
was extracted. This was washed with saturated ammonium chloride
(100 mL × 2) solution and saturated brine (100 mL) and dried
over MgSO4. After removal of the solvent, flash column chroma-
tography (EtOAc/hexane; 3:7) gave 4-[2-(4-fluorobutoxy)ethyl][bis-
(4-methoxymethoxyphenyl)methylene]cyclohexane (37 mg, 26%)
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.01(d, J ) 9.0
2
Hz, 4H), 6.93 (d, J ) 9.0 Hz, 4H), 5.15 (s, 4H), 4.45 (dt, JHF
)
47.0 Hz, J ) 6.0 Hz, 2H), 3.48 (s, 6H), 3.46 (t, J ) 6.0 Hz, 2H),
3.44 (t, J ) 6.0 Hz, 2H), 2.59 (bd, J ) 13.5 Hz, 2H), 1.94 (td, J
) 13.0, 3.5 Hz, 2H), 1.58-1.86 (m, 7H), 1.52 (q, J ) 7.0 Hz,
2H), 1.04-1.14 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 155.5,
138.2, 136.9, 133.5, 130.8, 115.5, 94.4, 84.0 (d, 1JCF ) 163.9 Hz),
2
70.2, 68.8, 55.97, 55.96, 36.4, 34.8, 34.6, 31.6, 27.3 (d, JCF
)
20.1 Hz), 25.5 (d, JCF ) 5.5 Hz); MS (EI) m/z 486 (M+, 100),
426, 287, 149, 121. HRMS (EI) m/z calcd for C29H39O5F, 486.2781;
found, 486.2778.
3
4-[2-(4-Fluorobutoxy)ethyl][bis(4-hydroxyphenyl)methylene]-
cyclohexane (28). According to the general procedure for MOM
deprotection with 4-[2-(4-fluorobutoxy)ethyl][bis(4-methoxymeth-
oxyphenyl)methylene]cyclohexane (32 mg, 0.066 mmol), HCl (200
µL), and methanol (3 mL), 28 (20 mg, 76%) was obtained as a
1
white solid: mp 129 °C; H NMR (500 MHz, acetone-d6) δ 6.91
2
(d, J ) 8.5 Hz, 4H), 6.74 (d, J ) 9.0 Hz, 4H), 4.44 (dt, JHF
)
47.5 Hz, J ) 6.0 Hz, 2H), 3.44 (t, J ) 6.5 Hz, 2H), 3.41 (t, J )
6.0 Hz, 2H), 2.59 (bd, J ) 13.5 Hz, 2H), 1.92 (td, J ) 13.0, 4.0
Hz, 2H), 1.77-1.85 (m, 2H), 1.59-1,77 (m, 5H), 1.48 (q, J ) 7.0
Hz, 2H), 1.03-1.13 (m, 2H); 13C NMR (125 MHz, acetone-d6) δ
156.6, 137.6, 135.6, 135.3, 131.6, 115.4, 84.5 (d, 1JCF ) 162.1 Hz),
70.7, 69.3, 37.3, 35.60, 35.57, 32.3, 28.2 (d, 2JCF ) 20.1 Hz), 26.3
3-Hydroxymethyl[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (35a). According to the general procedure for MOM
deprotection with 34a (0.34 g, 0.84 mmol), HCl (200 µL), and
methanol (7.0 mL), 35a (178 mg, 68%) was obtained as a white
3
(d, JCF ) 5.5 Hz); MS (EI) m/z 446 (M+, 100), 398, 199, 107.
HRMS (EI) m/z calcd for C25H31O3F, 398.2257; found, 398.2265.
Anal. (C21H24O3‚0.1H2O) C, H.

2508 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Seo et al.
1
solid: mp 219-221 °C; H NMR (400 MHz, DMSO-d6) δ 6.82
chloride (1.2 g, 14 mmol), sodium hydride (1.0 g, 30 mmol), and
DMF (15 mL), 23b (2.5 g, 95%) was obtained as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.01 (d, J ) 8.8 Hz, 2H), 6.99 (d,
J ) 8.8 Hz, 2H), 6.93 (d, J ) 8.8 Hz, 4H), 5.15 (s, 4H), 3.59 (s,
3H), 3.48 (s, 3H), 3.47 (s, 3H), 2.48-2.61 (m, 2H), 2.15-2.27
(m, 2H), 1.94-2.04 (m, 1H), 1.73-1.94 (m, 3H), 1.62-1.73 (m,
1H), 1.35-1.48 (m, 1H), 1.12-1.28 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 173.2, 155.5, 136.7, 136.55, 136.53, 134.5, 130.8, 115.5,
94.40, 94.38, 55.99, 55.95, 51.4, 41.3, 38.2, 36.5, 32.7, 31.7, 27.0;
MS (EI) m/z 440 (M+, 100), 366, 167. HRMS (EI) m/z calcd for
C26H32O6, 440.2199; found, 440.2198.
(d, J ) 8.4 Hz, 4H), 6.66 (d, J ) 8.4 Hz, 2H), 6.65 (d, J ) 8.4 Hz,
2H), 3.11-3.26 (m, 2H), 2.54 (bd, J ) 11.6 Hz, 1H), 2.44 (bd, J
) 12.8 Hz, 1H), 1.68-1.87 (m, 3H), 1.42-1.60 (m, 2H), 1.21-
1.35 (m, 1H), 1.10-1.20 (m, 1H); 13C NMR (100 MHz, DMSO-
d6) δ 155.50, 155.49, 135.5, 134.2, 133.9, 133.7, 130.43, 130.36,
114.6, 66.2, 42.0, 35.0, 31.9, 29.3, 26.8; MS (EI) m/z 310 (M+,
100). HRMS (EI) m/z calcd for C20H22O3, 310.1569; found,
310.1573. Anal. (C20H22O3) C, H.
Dimethyl 2-{3-[Bis(4-hydroxyphenyl)methylene]cyclohexyl}-
malonate (30b). According to the general procedure for the
McMurry coupling reaction with 4,4′-dihydroxybenzophenone (1,
4.3 g, 20 mmol), 14 (4.6 g, 20 mmol), Zn (9.9 g, 150 mmol), and
titanium(IV) chloride (14 g, 74 mmol), 30b (6.1 g, 74%) was
3-(2-Hydroxyethyl)[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane (34b). According to the general procedure for reduc-
tion with 33b (2.4 g, 5.5 mmol), LiAlH4 in THF solution (1 M,
5.5 mL), and THF (25 mL), 34b (2.1 g, 93%) was obtained as a
1
obtained as a white solid: mp 148-149 °C; H NMR (400 MHz,
methanol-d4) δ 6.87(d, J ) 8.8 Hz, 2H), 6.85 (d, J ) 8.4 Hz, 2H),
6.68 (d, J ) 8.4 Hz, 2H), 6.67 (d, J ) 8.8 Hz, 2H), 3.67 (s, 3H),
3.49 (s, 3H), 3.26 (d, J ) 9.6 Hz), 2.45-2.56 (m, 2H), 2.13-2.25
(m, 1H), 1.86-1.98 (m, 1H), 1.72-1.85 (m, 3H), 1.32-1.46 (m,
1H), 1.21-1.32 (m, 1H); 13C NMR (100 MHz, methanol-d4) δ
170.5, 170.3, 156.9, 156.8, 137.5, 135.8, 135.7, 135.6, 131.87,
131.81, 115.60, 115.58, 58.4, 52.8, 52.7, 40.9, 37.0, 32.7, 31.8,
30.0; MS (ESI) m/z 411 (M+ + 1), 279 (100). HRMS (ESI) m/z
calcd for C24H26O6, 441.1808; found, 441.1812. Anal. (C24H26O6)
C, H.
1
white solid: mp 72-74 °C; H NMR (400 MHz, methanol-d4) δ
6.98 (d, J ) 8.8 Hz, 2H), 6.95 (d, J ) 8.8 Hz, 2H), 6.92 (d, J )
8.8 Hz, 2H), 6.91 (d, J ) 8.8 Hz, 2H), 5.141 (s, 2H), 5.137 (s,
2H), 3.49 (td, J ) 6.8, 2.0 Hz, 2H), 3.434 (s, 3H), 3.429 (s, 3H),
2.58 (bd, J ) 9.2 Hz, 1H), 2.49 (bd, J ) 9.2 Hz, 1H), 1.74-1.97
(m, 3H), 1.56-1.70 (m, 2H), 1.33-1.49 (m, 3H), 1.13-1.26 (m,
1H); 13C NMR (100 MHz, methanol-d4) δ 157.12, 157.09, 138.5,
138.2, 138.1, 116.72, 116.70, 95.51, 95.49, 60.7, 56.14, 56.11, 40.5,
39.8, 37.3, 34.2, 33.2, 28.4; MS (EI) m/z 412 (M+, 100), 278.
HRMS (EI) m/z calcd for C25H32O5, 412.2250; found, 440.2251.
2-{3-[Bis(4-hydroxyphenyl)methylene]cyclohexyl}malonic Acid
(31). To a solution of 30b (4.5 g, 11 mmol) in methanol (20 mL)
was added NaOH (2 M, 25 mL), and then the reaction mixture
was refluxed at 100 °C for 2 h. After the reaction was cooled to
room temperature, it was acidified with HCl (2 M, 40 mL) in an
ice bath. Water (10 mL) was added, and a precipitate appeared
which was collected by filtration. The white powder obtained was
dried under vacuum, providing 31 (3.8 g, 90%) as white solid: mp
3-(2-Hydroxyethyl)[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (35b). According to the general procedure for MOM
deprotection with 34b (250 mg, 0.61 mmol), HCl (200 µL),
methanol (7.0 mL), 35b (172 mg, 87%) was obtained as a white
solid: mp 203-205 °C; 1H NMR (400 MHz, methanol-d4) δ 6.87
(d, J ) 8.8 Hz, 2H), 6.85 (d, J ) 8.4 Hz, 2H), 6.68 (d, J ) 8.8 Hz,
2H), 6.67 (d, J ) 8.4 Hz, 2H), 3.43-3.54 (m, 2H), 2.58 (bd, J )
9.6 Hz, 1H), 2.52 (bd, J ) 13.6 Hz, 1H), 1.73-1.95 (m, 3H), 1.53-
1.68 (m, 2H), 1.31-1.48 (m, 3H), 1.12-1.23 (m, 1H); 13C NMR
(100 MHz, methanol-d4) δ 156.7, 137.4, 136.20, 136.16, 136.0,
131.91, 131.86, 115.5, 60.7, 40.6, 39.8, 37.3, 34.3, 33.3, 28.5; MS
(EI) m/z 324 (M+, 100), 278, 199, 149. Anal. (C21H24O3) C, H.
3-(2-Methanesulfonyloxyethyl)[bis(4-methoxymethoxyphen-
yl)methylene]cyclohexane (36b). According to the general pro-
cedure for methanesulfonylation with 35b (349 mg, 0.82 mmol),
methanesulfonic anhydride (215 mg, 1.2 mmol), triethylamine (331
mg, 2.5 mmol), and CH2Cl2 (10 mL), 36b (393 mg, 98%) was
obtained as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.002
(d, J ) 8.8 Hz, 2H), 6.999 (d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 8.8
Hz, 2H), 6.93 (d, J ) 8.8 Hz, 2H), 5.154 (s, 2H), 5.153 (s, 2H),
4.21-4.23 (m, 2H), 3.479 (s, 3H), 3.477 (s, 3H), 2.88 (s, 3H), 2.60
(bd, J ) 10.0 Hz, 1H), 2.53 (bd, J ) 13.6 Hz, 1H), 1.75-1.97 (m,
3H), 1.60-1.74 (m, 4H), 1.34-1.47 (m, 1H), 1.12-1.26 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 155.62, 155.58, 136.7, 136.56,
136.51, 134.5, 130.77, 130.75, 115.7, 115.6, 94.4, 68.1, 56.03,
56.02, 38.0, 37.0, 35.6, 35.5, 32.7, 32.0, 27.0; MS (EI) m/z 490
(M+, 100), 211, 141. HRMS (EI) m/z calcd for C26H34O7S,
490.2025; found, 490.2015.
1
207-208 °C; H NMR (400 MHz, DMSO-d6) δ 6.81 (d, J ) 8.4
Hz, 2H), 6.80 (d, J ) 8.8 Hz, 2H), 6.65 (d, J ) 8.4 Hz, 2H), 6.62
(d, J ) 8.8 Hz, 2H), 3.99 (d, J ) 9.2 Hz, 1H), 2.57 (bd, J ) 12.0
Hz, 1H), 2.40 (bd, J ) 12.8 Hz, 1H), 1.96-2.11 (m, 1H), 1.62-
1.88 (m, 4H), 1.24-1.32 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 169.9, 169.7, 155.6, 155.5, 135.1, 134.4, 133.8, 133.2, 130.5,
114.7, 114.6, 57.8, 38.5, 35.4, 31.6, 30.2, 26.7; MS (ESI) m/z 383
(M+ + H), 279 (100). HRMS (ESI) m/z calcd for C22H22O6,
383.1495; found, 383.1499.
Methyl 2-{3-[Bis(4-hydroxyphenyl)methylene]cyclohexyl}-
acetate (32). Compound 31 (3.8 g, 9.9 mmol) was dissolved with
diglyme (15 mL), and the reaction mixture was heated to 160 °C
for 1 h. When no bubbles were detected, the reaction mixture was
cooled, and diglyme was removed under vacuum. The organic
mixture was filtered through short silica gel and eluted with solvents
(50% EtOAc, 47% hexane, 2% methanol, and 1% acetic acid), and
the solvents were evaporated. Without further purification, the
residual oil was dissolved in methanol (10 mL) under nitrogen.
Thionyl chloride (1.3 g, 11 mmol) was added slowly at room
temperature, and the mixture was stirred for 1.5 h. The reaction
was quenched by saturated NaHCO3 solution (50 mL) under ice
bath cooling, and H2O (100 mL) was added. The product was
extracted by ethyl acetate, and the organic layer was washed by
brine. After drying with MgSO4, the extract was concentrated and
purified by flash column chromatography (EtOAc/hexane; 4:6).
Recrystallization (Et2O and hexane) gave 32 (2.6 g, 74%) as a off-
3-(2-Fluoroethyl)[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane. According to the general procedure for fluorination
with 36b (350 mg, 0.71 mmol), cesium fluoride (541 mg, 3.6
mmol), H2O (20 µL), 1-butyl-3-methyl-imidazolium tetrafluorobo-
ronate (2.0 mL), and acetonitrile (2.0 mL), 3-(2-fluoroethyl)[bis-
(4-methoxymethoxyphenyl)methylene]cyclohexane (235 mg, 80%)
was obtained as a slightly yellow oil: 1H NMR (400 MHz, CDCl3)
δ 7.01 (d, J ) 8.8 Hz, 2H), 7.00 (d, J ) 8.8 Hz, 2H), 6.938 (d, J
) 8.8 Hz, 2H), 6.935 (d, J ) 8.8 Hz, 2H), 5.161 (s, 2H), 5.156 (s,
1
white solid: mp 157-158 °C; H NMR (400 MHz, methanol-d4)
δ 6.87 (d, J ) 8.8 Hz, 2H), 6.85 (d, J ) 8.4 Hz, 2H), 6.674 (d, J
) 8.8 Hz, 2H), 6.670 (d, J ) 8.4 Hz, 2H), 3.55 (s, 3H), 2.47-2.60
(m, 2H), 2.10-2.28 (m, 2H), 1.72-1.99 (m, 4H), 1.60-1.69 (m,
1H), 1.32-1.46 (m, 1H), 1.23-1.27 (m, 1H); 13C NMR (100 MHz,
methanol-d4) δ 175.0, 156.77, 156.75, 136.9, 136.5, 135.9, 135.8,
131.86, 131.84, 115.5, 51.9, 42.1, 39.2, 38.0, 34.0, 32.8, 28.2; MS
(EI) m/z 352 (M+), 278, 167 (100). HRMS (EI) m/z calcd for
C22H24O4, 352.1675; found, 352.1670. Anal. (C22H24O4) C, H.
2
2H), 4.42 (dm, JHF ) 47.6 Hz, 2H), 3.49 (s, 3H), 3.48 (s, 3H),
2.60 (bd, J ) 9.2 Hz, 1H), 2.54 (bd, J ) 14 Hz, 1H), 1.74-1.97
(m, 3H), 1.54-1.73 (m, 4H), 1.33-1.46 (m, 1H), 1.14-1.27 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 155.57, 155.52, 137.0, 136.8,
136.7, 134.2, 130.80, 130.76, 115.56, 115.54, 94.46, 94.43, 136.7,
136.56, 136.51, 134.5, 130.77, 130.75, 115.7, 115.6, 94.46, 94.43,
81.4 (d, 1JCF ) 162.4 Hz), 56.02, 55.99, 38.4, 37.0 (d, 2JCF ) 18.9
Methyl
2-{3-[Bis(4-methoxymethoxyphenyl)methylene]-
cyclohexyl}acetate (33b). According to the general procedure for
MOM protection with 32 (2.1 g, 5.9 mmol), methoxymethyl

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2509
3
Hz), 35.7 (d, JCF ) 4.6 Hz), 32.8, 32.1, 27.2; MS (EI) m/z 414
layer was washed with saturated ammonium chloride solution (50
mL) and concentrated. Flash column chromatography (EtOAc/
hexane; 4:6) gave 35c (75 mg, 65%) as an off-white solid: mp
175-176 °C; 1H NMR (400 MHz, DMSO-d6) δ 6.810 (d, J ) 8.8
Hz, 2H), 6.807 (d, J ) 8.4 Hz, 2H), 6.64 (d, J ) 8.4 Hz, 4H), 3.30
(dd, J ) 7.6, 6.4 Hz, 2H), 2.41 (bd, J ) 13.2 Hz, 1H), 1.65-1.87
(m, 3H), 1.47-1.57 (m, 1H), 1.20-1.41 (m, 4H), 1.00-1.20 (m,
3H); 13C NMR (100 MHz, DMSO-d6) δ 155.55, 155.52, 135.7,
134.1, 133.8, 133.7, 130.4, 114.6, 61.0, 38.2, 32.9, 31.8, 31.0, 29.9,
27.1, 22.1; MS (EI) m/z 338 (M+, 100), 215, 199. HRMS (EI) m/z
calcd for C22H26O3, 338.1882; found, 338.1878. Anal. (C22H26O3)
C, H.
(M+, 100). HRMS (EI) m/z calcd for C25H31O4F, 414.2206; found,
414.2205.
3-(2-Fluoroethyl)[bis(4-hydroxyphenyl)methylene]cyclo-
hexane (37b). According to the general procedure for MOM
deprotection with 3-(2-fluoroethyl)[bis(4-methoxymethoxyphenyl)-
methylene]cyclohexane (215 mg, 0.52 mmol), HCl (200 µL),
methanol (3.0 mL), and Et2O (1 mL), 37b (172 mg, 87%) was
1
obtained as a white solid: mp 100-105 °C; H NMR (400 MHz,
methanol-d4) δ 6.87 (d, J ) 8.8 Hz, 4H), 6.68 (d, J ) 8.4 Hz, 2H),
6.67 (d, J ) 8.8 Hz, 2H), 6.935 (d, J ) 8.8 Hz, 2H), 4.36 (dm,
2JHF ) 47.6 Hz, 2H), 2.61 (bd, J ) 9.2 Hz, 1H), 2.52 (bd, J )
13.2 Hz, 1H), 1.73-1.97 (m, 3H), 1.44-1.69 (m, 4H), 1.32-1.44
(m, 1H), 1.14-1.31 (m, 1H); 13C NMR (100 MHz, methanol-d4) δ
156.76, 156.73, 137.1, 136.4, 136.1, 136.0, 131.9, 115.54, 115.53,
82.9 (d, 1JCF ) 162.3 Hz), 39.4, 38.3 (d, 2JCF ) 19.7 Hz), 37.1 (d,
3JCF ) 3.8 Hz), 34.2, 33.2, 28.4; MS (EI) m/z 326 (M+, 100), 199.
HRMS (EI) m/z calcd for C21H23O2F, 326.1682; found, 326.1672.
3-(3-Acetoxy-n-propyl)-1-[bis(4-hydroxyphenyl)methylene]-
cyclohexane (30c). According to the general procedure for the
McMurry coupling reaction with 4,4′-dihydroxybenzophenone (1,
0.35 g, 1.6 mmol), 15 (0.32 g, 1.6 mmol), Zn (0.79 g, 12 mmol),
and titanium(IV) chloride (1.1 g, 6.0 mmol), 30c (0.43 g, 70%)
was obtained as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
6.91-6.96 (m, 4H), 6.738 (d, J ) 8.8 Hz, 2H), 6.733 (d, J ) 8.4
Hz, 2H), 4.00 (t, J ) 6.8 Hz, 2H), 2.54 (bt, J ) 13.6 Hz, 2H), 2.05
(s, 3H), 1.72-1.93 (m, 3H), 1.47-1.65 (m, 3H), 1.30-1.47 (m,
3H), 1.38-1.47 (m, 1H), 1.30-1.38 (m, 1H), 1.19-1.30 (m, 2H),
1.06-1.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.2, 153.89,
153.85, 137.1, 135.8, 135.6, 133.9, 131.0, 130.9, 114.73, 114.68,
65.2, 39.1, 38.5, 33.0, 32.8, 32.2, 27.3, 25.8, 21.1; MS (EI) m/z
380 (M+), 214 (100). HRMS (EI) m/z calcd for C24H28O4, 380.1987;
found, 380.1993.
3-(3-Fluoropropyl)[bis(4-methoxymethoxyphenyl)methylene]-
cyclohexane. To a solution of 34c (190 mg, 0.45 mmol) in CH2-
Cl2 (5 mL) was added slowly diethylaminosulfur trifluoride (865
mg, 0.5 mmol) at -78 °C under nitrogen. The cooling was removed,
and the reaction mixture was stirred for 1 h at room temperature.
It was then placed in an ice-bath, and methanol (200 µL) and H2O
(200 µL) were added. The ice-bath was removed, and the mixture
was allowed to stir for 30 min. EtOAc (50 mL) was added, and
the organic layer was washed with NaHCO3 solution (50 mL) and
ammonium chloride solution (50 mL). The organic layer was dried
over sodium sulfate and concentrated. Flash column chromatog-
raphy (EtOAc/hexane; 1:9 to 3:7) gave 3-(3-fluoro-n-propyl)-1-
[bis(4-methoxymethoxyphenyl)methylene]cyclohexane (71 mg, 37%)
as an oil: 1H NMR (400 MHz, CDCl3) δ 6.99-7.04 (m, 4H), 6.92-
2
6.97 (m, 4H), 5.164 (s, 2H), 5.158 (s, 2H), 4.39 (dt, JHF ) 47.6,
6.4 Hz, 2H), 3.489 (s, 3H), 3.482 (s, 3H), 2.30-2.64 (m, 2H), 1.75-
1.95 (m, 3H), 1.63-1.75 (m, 3H), 1.40-1.63 (m, 1H), 1.24-1.40
(m, 3H), 1.08-1.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
155.50, 155.45, 137.48, 136.9, 136.8, 133.8, 130.80, 130.75, 115.50,
115.49, 94.43, 94.38, 84.4 (d, 1JCF ) 163 Hz), 55.98, 55.96, 39.2,
2
38.5, 32.9, 32.15, 32.12, 27.7 (d, JCF ) 18.9 Hz), 27.3; MS (EI)
m/z 428 (M+), 302 (100), 286, 165. HRMS (EI) m/z calcd for
C26H33O4F, 428.2363; found, 428.2353.
3-(3-Acetoxy-n-propyl)-1-[bis(4-methoxymethoxyphenyl)-
methylene]cyclohexane (33c). According to the general procedure
for MOM protection with 30a (0.43 g, 1.1 mmol), methoxymethyl
chloride (0.20 g, 2.5 mmol), sodium hydride (69 mg, 2.8 mmol),
and DMF (10 mL), 33c (191 mg, 36%) was obtained as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 7.013 (d, J ) 8.8 Hz, 2H),
7.008 (d, J ) 9.2 Hz, 2H), 6.38 (d, J ) 8.8 Hz, 2H), 6.932 (d, J )
8.8 Hz, 2H), 5.16 (s, 2H), 5.15 (s, 2H), 4.01 (t, J ) 6.8 Hz, 2H),
3.48 (s, 3H), 3.47 (s, 3H), 2.50-2.63 (m, 2H), 2.04 (s, 3H), 1.72-
1.95 (m, 3H), 1.30-1.68 (m, 5H), 1.20-1.30 (m, 2H), 1.09-1.20
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 171.1, 155.44, 155.41,
137.4, 136.8, 136.7, 133.8, 130.73, 130.71, 115.46, 115.43, 94.4,
94.3, 64.7, 55.90, 55.87, 39.1, 38.5, 32.86, 32.83, 32.1, 27.3, 25.8,
20.9; MS (EI) m/z 468 (M+, 100), 446, 302, 286. HRMS (EI) m/z
calcd for C28H36O6, 468.2512; found, 468.2498.
3-(3-Hydroxypropyl)[bis(4-methoxymethoxyphenyl)methyl-
ene]cyclohexane (34c). To a solution of 33c (185 mg, 0.39 mmol)
in methanol (4 mL), Et2O (1 mL), and H2O (1 mL) was added
K2CO3 (450 mg, 3.3 mmol). The mixture was stirred at room
temperature for 4 h. It was then quenched by H2O and extracted
with EtOAc (50 mL). The organic layer was washed with saturated
ammonium chloride solution (50 mL) and concentrated. Flash
column chromatography (EtOAc/hexane; 3:7) gave 34c (159 mg,
95%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J
) 8.8 Hz, 2H), 7.08 (d, J ) 8.8 Hz, 2H), 6.93 (d, J ) 8.4 Hz, 4H),
5.150 (s, 2H), 5.147 (s, 2H), 3.56 (t, J ) 6.4 Hz, 2H), 3.478 (s,
3H), 3.473 (s, 3H), 2.59 (d, J ) 14.4 Hz, 1H), 2.53 (d, J ) 13.2
Hz, 1H), 1.74-2.15 (m, 3H), 1.31-1.67 (m, 5H), 1.21-1.31 (m,
2H), 1.08-1.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.4,
137.7, 136.9, 136.8, 133.6, 130.77, 130.75, 115.49, 115.46, 94.39,
94.34, 63.1, 55.95, 55.92, 39.4, 38.6, 33.0, 32.8, 32.2, 30.0, 27.4;
MS (EI) m/z 426 (M+, 100). HRMS (EI) m/z calcd for C26H34O5,
426.2406; found, 426.2415.
3-(3-Fluoro-n-propyl)-1-[bis(4-hydroxyphenyl)methylene]-
cyclohexane (37c). According to the general procedure for MOM
deprotection with 3-(3-fluoropropyl)[bis(4-methoxymethoxy-
phenyl)methylene]cyclohexane (70 mg, 0.16 mmol), concentrated
HCl (200 µL) in methanol (4.0 mL), and Et2O (1 mL), 37c (36
mg, 69%) was obtained as an off-white solid: mp 85 °C
(decomposed to dark brown color): 1H NMR (400 MHz, DMSO-
d6) δ 6.82 (d, J ) 8.4 Hz, 4H), 6.65 (d, J ) 8.4 Hz, 4H), 4.38 (dt,
2JHF ) 47.6 Hz, J ) 6.4 Hz, 2H), 2.36-2.52 (bm, 2H), 1.67-1.90
(m, 3H), 1.44-1.64 (m, 3H), 1.34-1.44 (m, 1H), 1.16-1.34 (m,
3H), 1.02-1,16 (m, 1H); 13C NMR (100 MHz, acetone-d6) δ 156.6,
1
156.5, 137.0, 135.6, 135.5, 131.6, 115.5, 115.4, 84.7 (d, JCF
)
3
164 Hz), 40.1, 39.2, 33.9, 32.5 (d, JCF ) 5.3 Hz), 32.9, 28.5 (d,
2JCF ) 19.7 Hz), 28.1; MS (EI) m/z 340 (M+, 100), 199. HRMS
(EI) m/z calcd for C22H25O2F, 340.1839; found, 340.1841.
Molecular Modeling. The experimental details of the compu-
tational method used have been reported elsewhere.55 Briefly, 4 of
8 possible docking orientations of C4-substituted molecules were
individually examined using the FlexiDoc routine in Sybyl 7.1
(Tripos Inc.) to account for both the axial/equatorial orientation of
the ring substituent and the ring flips of the cyclohexane ring.
Docking of the C3-substituted cyclofenils was further complicated
because they were prepared as a mixture of enantiomers, so 8 of
16 orientations were examined. We eliminated half of the docking
orientations by starting from an unfavorable orientation where one
pendent phenol was overlaid with the A-ring of estradiol while the
other phenol was placed away from a hydrogen-bonding partner
(Thr347/299). The docking routine typically reoriented the cyclo-
fenil core, placing the second phenol within hydrogen-bonding
distance with the Thr residue. The top ranked docking orientation
in the ER binding pocket was minimized by a three-step process
that has been reported elsewhere.55
3-(3-Hydroxy-n-propyl)-1-[bis(4-hydroxyphenyl)methylene]-
cyclohexane (35c). To a solution of 30c (130 mg, 0.34 mmol) in
methanol (7.5 mL) and H2O (2.5 mL) was added K2CO3 (500 mg,
3.6 mmol). The mixture was stirred at room temperature for 4 h,
quenched by H2O, and extracted with EtOAc (50 mL). The organic
Estrogen Receptor Binding Affinity. Relative binding affinities
were determined by a competitive radiometric binding assay as
previously described,52 using 10 nM [3H]estradiol as tracer ([6,7-
3H]estra-1,3,5,(10)-triene-3,17-â-diol, 51-53 Ci/mmol, Amersham

2510 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Seo et al.
(16) Mueller, S. O.; Korach, K. S. Estrogen receptors and endocrine
diseases: lessons from estrogen receptor knockout mice. Curr. Opin.
Pharmacol. 2001, 1, 613-619.
(17) Stossi, F.; Barnett, D. H.; Frasor, J.; Komm, B.; Lyttle, C. R.;
Katzenellenbogen, B. S. Transcriptional profiling of estrogen regu-
lated gene expression via estrogen receptor (ER) R or ERâ in human
osteosarcoma cells: distinct and common target genes for these
receptors. Endocrinology 2004, 145, 3473-3486.
(18) Kian, T. M.; Rogatsky, I.; Tzagarakis-Foster, C.; Cvoro, A.; An, J.;
Christy, R. J.; Yamamoto, K. R.; Leitman, D. C. Estradiol and
selective estrogen receptor modulators differentially regulate target
genes with estrogen receptors R and â. Mol. Biol. Cell 2004, 15,
1262-1272.
BioSciences, Piscataway, NJ), and purified full-length human ERR
and ERâ were purchased from PanVera/Invitrogen (Carlsbad, CA).
Incubations were for 18-24 h at 0 °C. Hydroxyapatite (BioRad,
Hercules, CA) was used to absorb the receptor-ligand complexes,
and free ligand was washed away. The binding affinities are
expressed as relative binding affinity (RBA) values with the RBA
of estradiol set to 100%. The values given are the average ( range
or SD of two to three independent determinations. Estradiol binds
to ERR and uterine cytosol ER with a Kd of 0.2 nM and to ERâ
with a Kd of 0.5 nM.
Acknowledgment. This work was supported by grants from
the National Institutes of Health (Grant No. PHS 5R37CA25836),
the National Research and Development Program of MOST,
Korea (Grant No. 2005-03184), and the Postdoctoral Fellowship
Program of Korea Science and Engineering Foundation
(KOSEF).
(19) Monroe, D. G.; Getz, B. J.; Johnsen, S. A.; Riggs, B. L.; Khosla, S.;
Spelsberg, T. C. Estrogen receptor isoform-specific regulation of
endogenous gene expression in human osteoblastic cell lines express-
ing either ERR or ERâ. J. Cell. Biochem. 2003, 90, 315-326.
(20) Lindberg, M. K.; Moverare, S.; Skrtic, S.; Gao, H.; Dahlman-Wright,
K.; Gustafsson, J. A.; Ohlsson, C. Estrogen receptor (ER)-beta
reduces ERalpha-regulated gene transcription, supporting a “ying
yang” relationship between ERalpha and ERbeta in mice. Mol.
Endocrinol. 2003, 17, 203-208.
(21) (a) Roger, P.; Sahla, M. E.; Makela, S.; Gustafsson, J. A.; Baldet,
P.; Rochefort, H. Decreased expression of estrogen receptor â protein
in proliferative preinvasive mammary tumors. Cancer Res. 2001, 61,
2537-2541. (b) Palmieri, C.; Cheng, G. J.; Saji, S.; Zelada-Hedman,
M.; Warri, A. Weihua, Z.; Van Noorden, S.; Wahlstrom, T.;
Coombes, R. C.; Warner, M.; Gustafsson, J. A. Estrogen receptor
beta in breast cancer. Endocr.-Relat. Cancer 2002, 9, 1-13. (c)
Speirs, V.; Carder, P. J.; Lansdown, M. R. J. Oestrogen receptor
beta: how should we measure this? Br. J. Cancer 2002, 87, 687,
688-689 (author reply). (d) Omoto, Y.; Kobayashi, S.; Inoue, S.;
Ogawa, S.; Toyama, T. Yamashita, H.; Muramatsu, M.; Gustafsson,
J. A.; Iwase, H. Evaluation of oestrogen receptor b wild-type and
variant protein expression, and relationship with clinicopathological
factors in breast cancers. Eur. J. Cancer 2002, 38, 380-386.
(22) Mosselman, S.; Polman, J.; Dijkema, R. ERâ: Identification and
characterization of a novel human estrogen receptor. FEBS Lett. 1996,
392, 49-53.
(23) Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.; Bonn,
T.; Engstro¨m, O.; Ohman, L.; Greene, G. L.; Gustafsson, J.-Å.;
Carlquist, M. Molecular basis of agonism and antagonism in the
oestrogen receptor. Nature 1997, 389, 753-758.
(24) Pike, A. C.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.; Thorsell,
A. G.; Engstrom, O.; Ljunggren, J.; Gustafsson, J.; Carlquist, M.
Structure of the ligand-binding domain of oestrogen receptor beta in
the presence of a partial agonist and a full antagonist. EMBO J. 1999,
18, 4608-4618.
(25) Lonard, D. M.; Smith, C. L. Molecular perspectives on selective
estrogen receptor modulators (SERMs): Progress in understanding
their tissue-specific agonist and antagonist actions. Steroids 2002,
67, 15-24.
(26) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch, C. Comparative
QSAR analysis of estrogen receptor ligands. Chem. ReV. 1999, 99,
723-744.
(27) Meegan, M. J.; Lloyd, D. G. Advances in the science of estrogen
receptor modulation. Curr. Med. Chem. 2003, 10, 181-210.
(28) Anstead, G. M.; Carlson, K. E.; Katzenellenbogen, J. A. The estradiol
pharmacophore: ligand structure-estrogen receptor binding affinity
relationships and a model for the receptor binding site. Steroids 1997,
62, 268-303.
(29) Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
Katzenellenbogen, J. A. Novel structural templates for estrogen-
receptor ligands and prospects for combinatorial synthesis of
estrogens. Chem. Biol. 1999, 6, 205-219.
(30) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson,
K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.
Pyrazole ligands: structure-affinity/activity relationships of estrogen
receptor-R-selective agonists. J. Med. Chem. 2000, 43, 4934-4947.
(31) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Synthesis and
biological evaluation of a novel series of furans: ligands selective
for estrogen receptor R. J. Med. Chem. 2001, 44, 3838-3848.
(32) Meyers, M. J.; Sun, J.; Carlson, K. E.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. Estrogen receptor subtype-selective
ligands: asymmetric synthesis and biological evaluation of cis- and
trans-5,11-dialkyl-5,6,11,12-tetrahydrochrysenes. J. Med. Chem.
1999, 42, 2456-2468.
Supporting Information Available: Elemental analysis data
of 2-5, 18, 20, 21a,b, 24a,b, 26a,b, 27, 28, 29a,b, 30a,b, 32, and
1
35a-c, HPLC purity data and traces of 37b,c, H and 13C NMR
spectra of 2-5, 7, 10, 12, 14-16, 17a,b, 18-20, 21a,b, 22a,b,
23a,b, 24a,b, 25a,b, 26a,b, 28, 29b, 30a-c, 31, 32, 33a-c, 34a-
c, 35a-c, 36b, and 37b,c, and some key intermediates. This material
is available free of charge via a Internet at http://pubs.acs.org.
References
(1) Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen receptor
transcription and transactivation: estrogen receptor alpha and estrogen
receptor beta: regulation by selective estrogen receptor modulators
and importance in breast cancer. Breast Cancer Res. 2000, 2, 335-
344.
(2) Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Nuclear hormone
receptors: ligand-activated regulators of transcription and diverse
cell responses. Chem. Biol. 1996, 3, 529-536.
(3) Turner, R. T.; Rickard, D.; Spelsberg, T. C.; Sibonga, J. D. The basic
biology of estrogen and bone. Osteoporosis; Humana Press: 2002;
pp 309-330.
(4) Maran, A.; Turner, R. T. Effects of estrogen on bone. Recent Res.
DeV. Endocrinol. 2001, 327.
(5) Mendelsohn, M. E.; Karas, R. H. The protective effects of estrogen
on the cardiovascular system. N. Engl. J. Med. 1999, 340, 1801-
1811.
(6) Mendelsohn, M. E. Protective effects of estrogen on the cardio-
vascular system. Am. J. Cardiol. 2002, 89, 12E-17E, 17E-18E
(discussion).
(7) Behl, C. Oestrogen as a neuroprotective hormone. Nat. ReV. Neurosci.
2002, 3, 433-442.
(8) Zhao, L.; Wu, T.-W.; Brinton, R. D. Estrogen receptor subtypes alpha
and beta contribute to neuroprotection and increased Bcl-2 expression
in primary hippocampal neurons. Brain Res. 2004, 1010, 22-34.
(9) Katzenellenbogen, B. S. Estrogen receptors: bioactivities and interac-
tions with cell signaling pathways. Biol. Reprod. 1996, 54, 287-
293.
(10) Katzenellenbogen, J. A.; O’Malley, B. W.; Katzenellenbogen, B. S.
Tripartite steroid hormone receptor pharmacology: interaction with
multiple effector sites as a basis for the cell- and promoter-specific
action of these hormones. Mol. Endocrinol. 1996, 10, 119-131.
(11) Weihua, Z.; Andersson, S.; Cheng, G.; Simpson, Evan, R.; Warner,
M.; Gustafsson, J.-Å. Update on estrogen signaling. FEBS Lett. 2003,
546, 17-24.
(12) Kuiper, G. G. J. M.; Enmark, E.; Pelto-Huikko, M.; Nilsson, S.;
Gustafsson, J.-Å. Cloning of a novel estrogen receptor expressed in
rat prostate and ovary. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 5925-
5930.
(13) Kuiper, G. G. J. M.; Carlsson, B.; Grandien, K.; Enmark, E.;
Ha¨ggblad, J.; Nilsson, S.; Gustafsson, J.-Å. Comparison of the ligand
binding specificity and transcript tissue distribution of estrogen
receptor R and â. Endocrinology 1997, 138, 863-870.
(14) Register, T. C.; Adams, M. R. Coronary artery and cultured aortic
smooth muscle cells express mRNA for both the classical estrogen
receptor and the newly described estrogen receptor beta. J. Steroid
Biochem. Mol. Biol. 1998, 64, 187-191.
(33) Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenel-
lenbogen, B. S.; Katzenellenbogen, J. A. Estrogen receptor-â potency-
selective ligands: structure-activity relationship studies of diaryl-
propionitriles and their acetylene and polar analogues. J. Med. Chem.
2001, 44, 4230-4251.
(15) Mitra, S. W.; Hoskin, E.; Yudkovitz, J.; Pear, L.; Wilkinson, H. A.;
Hayashi, S.; Pfaff, D. W.; Ogawa, S.; Rohrer, S. P.; Schaeffer, J.
M.; McEwen, B. S.; Alves, S. E. Immunolocalization of estrogen
receptor â in the mouse brain: comparison with estrogen receptor
R. Endocrinology 2003, 144, 2055-2067.

Fluorine-Substituted Cyclofenil DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2511
(34) Muthyala, R. S.; Sheng, S.; Carlson, K. E.; Katzenellenbogen, B.
S.; Katzenellenbogen, J. A. Bridged bicyclic cores containing a 1,1-
diarylethylene motif are high-affinity subtype-selective ligands for
the estrogen receptor. J. Med. Chem. 2003, 46, 1589-1602.
(35) Malamas, M. S.; Gunawan, I.; Harris, H. A.; Keith, J. C.; Albert, L.
M. Preparation of Naphthyl Benzoxazoles and Benzisoxazoles as
Estrogenic Agents. U.S. Patent Application 20030171412 (Wyeth,
Madison, NJ), 2003, 28 pp.
(45) Compton, D. R.; Sheng, S.; Carlson, K. E.; Rebacz, N. A.; Lee, I.
Y.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Pyrazolo[1,5-
a]pyrimidines: estrogen receptor ligands possessing estrogen receptor
â antagonist activity. J. Med. Chem. 2004, 47, 5872-5893.
(46) Coe, P. L.; Scriven, C. E. Cross coupling of functionalized ketones
by low valent titanium (the McMurry reaction); a new stereoselective
synthesis of tamoxifen. J. Chem. Soc., Perkin Trans. 1 1986, 3, 475-
477.
(36) Barlaam, B.; Bernstein, P.; Dantzman, C.; Warwick, P. Preparation
of Benzoxazoles and Benzothiazoles as Selective Ligands for Human
b-Estrogen Receptor. PCT Int. Appl. WO, 2002 (Astrazeneca AB,
Sweden).
(37) Bernstein, P. Preparation of Aminobenzothiazoles as Selective ER-â
Ligands for Treatment of Alzheimer’s Disease, Anxiety Disorders,
Depressive Disorders, Osteoporosis, Cardiovascular Disease, Rheu-
matoid Arthritis or Prostate Cancer. PCT Int. Appl. WO, 2003
(Astrazeneca AB, Sweden).
(38) Vijaykumar, D.; Al-Qahtani, M. H.; Welch, M. J.; Katzenellenbogen,
J. A. Synthesis and biological evaluation of a fluorine-18 labeled
estrogen receptor-alpha selective ligand: [18F] propyl pyrazole triol.
Nucl. Med. Biol. 2003, 4, 397-404.
(39) Yoo, J.; Dence, C. S.; Sharp, T. L.; Katzenellenbogen, J. A.; Welch,
M. J. Synthesis of an estrogen receptor beta-selective radioligand:
5-[18F]fluoro-(2R,3S)-2,3-bis(4-hydroxy-phenyl)pentanenitrile and com-
parison of in vivo distribution with 16R-[18F]fluoro-17â-estradiol.
J. Med. Chem. 2005, 48, 6366-6378.
(47) Detsi, A.; Koufaki, M.; Calogeropoulou, T. Synthesis of (Z)-4-
hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-
butenyl]phenoxyacetic acid. J. Org. Chem. 2002, 67, 4608-4611.
(48) Suemune, H.; Oda, K.; Sakai, K. Ring cleavage and reconstruction
of five and six membered ring. Tetrahedron Lett. 1987, 28, 3373-
3376.
(49) Labaree, D. C.; Zhang, J.; Harris, H. A.; O’Connor, C.; Reynolds,
T. Y.; Hochberg, R. B. Synthesis and evaluation of B-, C-, and
D-ring-substituted estradiol carboxylic acid esters as locally active
estrogens. J. Med. Chem. 2003, 46, 1886-1904.
(50) Cahiez, G.; Alexakis, A.; Normant, J. F. Derives organomagnesiens
ω-alcoolates: preparation et proprietes. (Preparation and properties
of derived organomagnesium ω-alcoholates.) Tetrahedron Lett. 1978,
19, 3013-3014.
(51) (a)Kim, D. W.; Song, C. E.; Chi, D. Y. New method of fluorination
using potassium fluoride in ionic liquid: significantly enhanced
reactivity of fluoride and improved selectivity. J. Am. Chem. Soc.
2002, 124, 10278-10279. (b) Kim, D. W.; Song, C. E.; Chi, D. Y.
Significantly enhanced reactivities of the nucleophilic substitution
reactions in ionic liquid. J. Org. Chem. 2003, 68, 4281-4285.
(52) Kim, D. W.; Choe, Y. S.; Chi, D. Y. A new nucleophilic fluorine-
18 labeling method for aliphatic mesylates: reaction in ionic liquids
shows tolerance of water. Nucl. Med. Biol. 2003, 30, 345-350.
(53) (a) Katzenellenbogen, J. A.; Johnson, H. J., Jr.; Myers, H. N.
Photoaffinity labels for estrogen binding proteins of rat uterus.
Biochemistry 1973, 12, 4085-4092. (b) Carlson, K. E.; Choi, I.; Gee,
A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Altered ligand
binding properties and enhanced stability of a constitutively active
estrogen receptor: evidence that an open pocket conformation is
required for ligand interaction. Biochemistry 1997, 36, 14897-14905.
(54) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Safe and convenient procedure for solvent purification.
Organometallics 1996, 15, 1518-1520.
(40) Miques, J.-F.; Wahlstam, H.; Olsson, K.; Suxdbeck, B. Synthesis of
unsymmetrical diphenylalkenes. J. Med. Chem. 1963, 6, 771-780.
(41) (a) Hospital, M.; Busetta, B.; Courseille, C.; Precigoux, G. X-ray
conformation of some estrogens and their binding to uterine receptors.
J. Steroid Chem. 1975, 6, 221-225. (b) Precigoux, P. G.; Busetta,
B.; Courseille, C.; Hospital, M.; Miquel, J. F. Structure de composes
oestrogenes: Structure crystalline de trios analogues du cyclofenil.
(Structure of estrogens: Crystal structure of three analogues of
cyclofenil.) Acta Crystallogr. 1978, B34, 3300-3305.
(42) Garg, S.; Bindal, R. E.; Durani, S.; Kapil, R. S. Structure-activity
relationship of estrogens: A study involving cyclofenil as the model
compound. J. Steroid Biochem. 1983, 18, 89-95.
(43) (a) McDonnell, D. P.; Connor, C. E.; Wijayaratne, A.; Chang, C.
Y.; Norris, J. D. Definition of the molecular and cellular mechanisms
underlying the tissue-selective agonist/antagonist activities of selective
estrogen receptor modulators. Recent Prog. Horm. Res. 2002, 57,
295-316. (b) Silfen, S. L.; Ciaccia, A. V.; Bryant, H. U. Selective
estrogen receptor modulators: tissue selectivity and differential
uterine effects. Climacteric 1999, 2, 268-283.
(55) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson,
K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.
Pyrazole ligands: structure-affinity/activity relationships and es-
trogen receptor-R selective agonists. J. Med. Chem. 2000, 43,
4934-4947.
(44) Miquel, J. F. Molecular structure and estrogenic activities-I. Un-
symmetrical diphenylethylenes and triphenylethylenes. Tetrahedron
1960, 8, 205-216.
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