4,4′-Unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors

Article abstract of DOI:10.1016/j.bmc.2013.10.051

A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthes

Full text of DOI:10.1016/j.bmc.2013.10.051

Bioorganic & Medicinal Chemistry 22 (2014) 917–926
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
4,40-Unsymmetrically substituted 3,30-biphenyl alpha helical
proteomimetics as potential coactivator binding inhibitors
Patrick T. Weiser a, Ching-Yi Chang b, Donald P. McDonnell b, Robert N. Hanson a,
⇑
a Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA
b Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomi-
metics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor
coactivator binding domain. These compounds were synthesized in good overall yields in seven steps
starting from 2-bromoanisole. The final products were evaluated using cotransfection reporter gene
assays and mammalian two-hybrid competitive inhibition assays to demonstrate their effectiveness as
competitive binding inhibitors. The results from this study indicate that these proteomimetics possess
the ability to inhibit coactivator–receptor interactions, but via a mixed mode of inhibition.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 May 2013
Revised 21 October 2013
Accepted 29 October 2013
Available online 8 November 2013
Keywords:
Proteomimetic
Co-activator binding inhibition
Nuclear receptor
1. Introduction
including indanes,7 terphenyls,8 and pyrimidines9 have been
shown to mimic alpha helical structure and a number of the com-
Protein–protein interactions (PPI) play a key role in regulating
many cellular pathways, particularly by providing important rec-
ognition and activation functions. Because such recognition func-
tions are often up-regulated in disease states, disruption of the
protein–protein interface is an attractive, but challenging,
objective.1 Targeting these interactions with low molecular weight
compounds is difficult because proteins tend to be large, have non-
contiguous binding regions and often lack distinctive structural
features that one can use as a basis for disruptor design. One strat-
egy under current consideration is to use a small molecule to mi-
mic the binding motif of one of the protein partners directly at
the binding site.2 One of the most common recognition patterns in-
volves the interaction between a short alpha helical peptidic com-
ponent of one protein and a complementary groove in the second
protein. Examples of such PPI include Bcl-2/Bak,3 MDM2/p53,4 and
nuclear receptor/coregulator (NR–CoR) interactions.5
The alpha helix is the most common element found in proteins,
comprising nearly 40% of all protein secondary structure. The
structure is generated by hydrogen bonding between the carbonyls
and primary amides of amino acids sited on adjacent turns of the
helix.6 The concept that the central core of the helical peptide
can be replaced by a nonpeptidyl scaffold and that the side chains
of the amino acids can be represented by appropriate substituents
on that scaffold has generated a class of compounds termed ‘prote-
omimetics.’ Many different helical core-replacing moieties,
pounds also demonstrated the capacity to disrupt discrete PPI that
require an alpha helical motif. It is unnecessary for this class of
inhibitors to mimic exactly the natural, peptidyl segment, but only
to provide a similar interaction with the binding subpocket.10
We previously described the synthesis of a small series of
3,30-symmetrically substituted bipolar–biphenyl alpha helical
proteomimetics that were disruptors of estrogen receptor
(ER
) coactivator binding (see Fig. 1).11 These compounds, de-
signed to mimic the -helical LXXLL motif of the NR Box of the
ER
coactivator proteins,12 were prepared using commercially
a
a
a
a
available 2-substituted phenols. The phenols were selectively
brominated at the 4-position, at which point they served as inter-
mediates for both termini of the biphenyl derivatives. The
3,30-dibenzyl substituted derivatives were the most effective coac-
tivator binding inhibitors (CBIs). Furthermore, the importance of
substitution pattern on the dibenzyl, as well as the dimethyl, deriv-
ative was studied.13 The objective of our current study was to
incorporate larger hydrophobic side chains into our scaffold in an
attempt to make these compounds a better fit for the hydrophobic
coactivator binding pocket (CBP). The synthetic approach that we
envisioned relied upon the appropriate 2-substituted-4-brom-
ophenols. Because these derivatives were not readily available, a
versatile and reliable procedure for their synthesis was necessary.
2. Results and discussion
The most direct approach to the preparation of the requisite
2-substituted 4-bromophenols involves the Friedel–Crafts
⇑
Corresponding author. Tel.: +1 617 373 3313; fax: +1 617 373 8795.
E-mail address: r.hanson@neu.edu (R.N. Hanson).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.10.051

918
P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
ate esters proceeded in excellent yields. The Fries rearrangement
reactions were again conducted using conditions typical for this
reaction, however, yields were poor and inconsistent. The mecha-
nism for this rearrangements proceeds by generation of the acyloni-
um ion followed by its migration to the most electron-rich center.
Generation of the acyl cation was observed under our reaction con-
ditions, however, the subsequent ortho-acylation was not observed.
The 4-bromo substituent had a clearly unfavorable influence on pro-
moting the C–C bond formation at the 2-position. Whether this was
due to electronic or resonance effects was unclear.
The procedure that was adopted was not as direct as the Friedel–
Crafts or Fries approaches, but was applicable to a wider variety of
starting materials. In this strategy we envisioned introduction of
the 2-substituent by addition of the Grignard reagent derived from
2-bromoanisole to the requisite aldehyde. Subsequent reduction
of the benzylic alcohol followed by para-bromination and
deprotection of the methyl ether would give the desired series of
2-substituted-4-bromophenols (Scheme 2). The specific substitu-
ents were chosen to further expand the pharmacophoric model
generated from the initial series in which the benzylic derivative
was one of the most active coactivator binding inhibitors. The
cyclohexylmethyl and heptyl derivatives would provide similar
steric dimensions, and similar carbon number, but with greater
conformational flexibility. Resonance may also be an influencing
factor. Compared to the benzyl group, the 2-naphthylmethyl and
4-biphenyl derivatives present similar aromatic character, but with
significantly increased steric demands.
The addition of the anisolyl-2-magnesium bromide to the alde-
hydes gave the crude products which were purified via chromatog-
raphy to give secondary alcohols 4a–d (75–100% yield).20 The
intermediate alcohols 4a–d were readily reduced under mild con-
ditions, using tetraethylsilane and trifluoroacetic acid in dichloro-
methane to give 5a–d (75–87% yield).21 Deprotection with boron
tribromide yielded the 2-substituted phenols 6a–d (91–95%).22
Selective 4-bromination using tetrabutylammonium tribromide
gave the 4-brominated 2-substituted phenols 7a–d (79–91%
yield).23 The 4-bromo-2-substituted bromophenols 7a–d and the
unsubstituted 4-bromophenol 7e provided the key intermediates
from which the two polar termini of the target proteomimetics
were prepared (Scheme 3). The unsubstituted phenol 7e was in-
cluded to make mono-substituted bipolar biphenyls in addition
to the di-substituted bipolar biphenyls. The 4-bromophenols
7a–e underwent Miyaura boronation using PdCl2(dppf) and
bis(pinacolato)diboron to give the 4-hydroxyphenylboronate
esters 8a–e in 45–53% isolated yields.24,25 Alkylation of the
4-hydroxy group of the 4-bromophenols 7a–e using sodium
Figure 1. Alpha helical proteomimetic. Adapted from Williams et al.11 (A)
Co-activator NR Box forms an
scaffold. (C) Target compounds1a–m with varying substitution (see Table 1).
a
-helix with an LXXLL motif. (B) 4,40-Biphenyl
acylation of 4-bromophenol, followed by reduction of the ketone.
This approach had a literature precedent as benzoylation of 4-chlo-
rophenol gave the 2-benzoyl-4-chlorophenol.14 Our scheme re-
quired the bromo- rather than the chlorophenol as we would
later employ Miyaura boronation, which is more difficult with
chloro-substrates. Therefore, we used a Friedel–Crafts acylation
with a variety of acid chlorides (Scheme 1) to attach a carbonyl
at the 2-position of 4-bromophenol.15 While the reaction pro-
ceeded satisfactorily for the benzoyl derivative, other acid chlo-
rides gave much poorer yields. However, the bromine could not
be introduced at a later stage due to the possibility of acylation
at para- and not the ortho-position. One possible explanation for
the failure of this approach is that the free phenol can poison the
AlCl3 catalyst, thereby generating a weaker aluminum phenoxide
catalyst. Protection of the phenol as the methyl ether (4-bromoani-
sole) did not improve reaction yields. Efforts using BF3–Et2O, which
would give a stable intermediate with phenolic hydroxyl, were
likewise unsuccessful.16,17
We next evaluated the Fries rearrangement of the acylated phe-
nyl esters as the method for introducing the ortho substituent. In this
approach 4-bromophenol was O-acylated and the ester was sub-
jected to conditions that promote migration of the carbonyl to the
ortho-position, yielding the requisite 2-acylated-4-bromophe-
nol.18,19 There was precedent for this strategy, however, for a very
limited set of 4-halogenated phenols. Preparation of the intermedi-
OMe OH
OMe
OMe
Br
a
b
OH
R
R
OR
Br
O
OR
Friedel-Crafts
acylation
Reduction
R
R
X
3
5a-d
4a-d
OH
Br
OH
Br
Br
O
c
d
R
R
OH
OH
OR
O
O
R
Fries
Reduction
Rgmnt.
O-acylation
R
R
R
R
6a-d
X
7a-d
Br
Br
Br
OMe
Br
a) R = 4-biphenyl
b) R = cyclohexyl
c) R = n-heptane
d) R = 2-naphthyl
OMe
OH
OMe OH
Bromination
Br
Reduction
Grignard
R
Scheme 2. Reagents and conditions: (a) (i) Magnesium, iodine, tetrahydrofuran,
reflux; (ii) R-aldehyde, rt, 91%; (b) triethylsilane, trifluoroacetic acid, dichloro-
methane, rt, 87%; (c) borontribromide, dichloromethane, rt, 95%; (d) tetrabutylam-
monium tribromide, chloroform, rt, 90%.
Br
Scheme 1. Synthetic routes to 2-substituted phenols.

P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
919
Table 2
OH
B
Co-transfection reporter gene assay
R
Compound
Vehicle
1 nM Estradiol
N
1a
1b
1c
1d
1e
1f
0
0
O
OH
ꢀꢀꢀ
ꢀꢀꢀ
O
O
++
0
R1
R1
a
ꢀꢀꢀ
++
ꢀꢀꢀ
8a-e
OH
0
c
d
+++a
0
0a
0
R
1g
1h
1i
1j
1k
1l
1m
2a
2b
2c
2d
2e
2f
2g
2h
2i
Br
b
+++
+++
ꢀꢀꢀ
+
0
0
R2
O
R2
Br
7a-e
O
O
O
O
ꢀꢀꢀ
R
O
0
O
+++a
+
0a
0
O
O
2a-m
1a-m
+++
0
+
0
0
0
9a-e
7-9
+
+
0
a R = 4-methylbiphenyl
b R = methylcyclohexyl
c R = n-heptyl
a
0a
0
0
0
+++
0
0
0
0
d R = 2-methylnapthyl
e
R = H
Scheme 3. Reagents and conditions: (a) PdCl2(dppf), B2pin2, KOAc, dioxane, 80 °C;
(b) 2-ethoxycarbonylethyl bromide, NaH, THF, rt; (c) PdCl2(P(otol)3)2, P(otol)3,
Na2CO3, dichloromethane/water (3:2), reflux; (d) 2-chloro-N,N-dimethylethylamine
hydrochloride, K2CO3, acetone, reflux.
2j
2k
2l
0
0
0
0
0
++
+++
+
2m
(+) Denotes a greater than 50% increase in reporter gene activity at compound
concentration <20 M.
(++) Denotes a greater than 50% increase in reporter gene activity at compound
concentration between 20–50 M.
(+++) Denotes a greater than 50% increase in reporter gene activity at compound
concentration >50 M.
(ꢀ) Denotes a greater than 50% decrease in reporter gene activity at compound
concentration >50 M.
(ꢀꢀ) Denotes a greater than 50% decrease in reporter gene activity at compound
concentration <between 20–50 M.
(ꢀꢀꢀ) Denotes a greater than 50% decrease in reporter gene activity at compound
concentration <20 M.
hydride and ethyl bromoacetate gave, after flash chromatography,
ethyl 2-(4-bromo-2-substituted-phenoxy) acetates 9a–e, in 69–
91% isolated yields.
l
l
The aryl bromides, 9a–e, and the aryl boronates, 8a–e, were
coupled in various combinations to give multiple biphenyl phenols
(2a–m) as shown in Table 1. 3-Substituted, 30-substituted, and a
3,30-disubstituted variants were prepared for each side chain, as
well as an unsubstituted biphenyl. Coupling under Suzuki condi-
tions with PdCl2(P(otol)3)2, P(otol3), and sodium carbonate in
dichloromethane and water gave, after purification via flash chro-
matography, the biphenyl phenol/esters 2a–m. P(otol3) was used
because when PPh3 ligand was used, reductive elimination of a
phenyl group and the aryl bromide was commonly observed, lead-
ing to a dead end side biphenyl side product. The ortho-tolyl group
completely eliminated this competing side reaction.
l
l
l
l
(0) Denotes a less than 20% change in reporter gene activity. 4 Hydroxytamoxifen
was used as an antagonist control.
bDenotes precipitation of compound from solution.
a
Denotes cell death at concentration greater than 50 lM.
(Table 2). 3xERE-TATA-luciferase and estrogen receptor
The biphenyl phenol/esters were then converted to the biphe-
nyl amine/esters (1a–m) by alkylation with dimethylaminoethyl
chloride.
(RST7—ERa) were transfected into ER-negative SKBR3 breast can-
cer cells along with normalization control pCMV-b-gal.26 Cells
were then treated with serial twofold dilutions of our biphenyls
with and without 1 nM E2 and incubated for 40 h before assaying.
To test the effectiveness of our proteomimetics to inhibit ER
a
activity, we subjected biphenyl phenol-esters 2a–m and biphenyl
ERa activity was measured as a function of increasing proteomi-
amine-esters 1a–m to
a cotransfection reporter gene assay
metic concentration. We expected to see no activity in the absence
of E2 since our compounds were designed to block NR-CoR interac-
tions at the coactivator binding pocket (CBP) and not to bind at the
ligand binding pocket (LBP) where E2 binds. In the presence of E2,
Table 1
Substitution patterns of phenol/ester biphenyls
we expected to see a decrease in ERa activity. 2a–m had little or no
Starting material
Bromide Boranate
Biphenyl product
Substituents
30
effect in the absence of E2 and basically no effect in the presence of
E2. These results suggested that our compounds most likely were
binding at the LBP, but competed weakly compared to E2. Com-
pounds 1b, 1d, and 1j behaved as inhibitors in the presence and ab-
sence of E2 by showing a decrease in reporter gene activity of
3
9a
9e
9a
9b
9e
9b
9c
9e
9c
9d
9e
9d
9e
8e
8a
8a
8e
8b
8b
8e
8c
8c
8e
8d
8d
8e
2a
2b
2c
2d
2e
2f
2g
2h
2i
4MeBP
H
4MeBP
MeCy
H
MeCy
n-Hept
H
n-Hept
2MeNp
H
H
4MeBP
4MeBP
H
MeCy
MeCy
H
n-Hept
n-Hept
H
2MeNp
2MeNp
H
greater than 50% at concentrations below 20 lM. Complete graphs
and conditions can be found in the Supplemental section.
Compounds 2a–m and 1a–m were then subjected to a mamma-
lian two-hybrid competitive inhibition assay employing the estro-
gen receptor (VP16-ER
LxxLL2 (Table 3). Disrupting the interaction between ER
a
) and the co-activator peptide pM-GRIP1
and the
2j
2k
2l
a
2MeNp
H
GRIP1 derived peptide would lead to a decrease in reporter gene
activity, measured here as a reduction in luciferase biolumines-
cence. This would provide further evidence that these compounds
are true CBIs and are inhibiting at the CBP. HepG2 cells were
2m
4MeBP = 4-methylbiphenyl, MeCy = methylcylcohexane, 2MeNp = 2-methylnaph-
thalene.

920
P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
Table 3
Mammalian two-hybrid competitive inhibition assay
Compound
1a
1b
1c
Vehicle
1 nM Estradiol
0a
a
ꢀ
a
a
ꢀꢀꢀ
ꢀꢀꢀ
0
0
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
2a
2b
2c
ꢀꢀꢀ
++
0
0
+++
+++
ꢀꢀꢀ
0
ꢀ
ꢀ
0
0
a
a
ꢀꢀꢀ
ꢀꢀꢀ
b
b
+
+
+++a,b
0a,b
0
0
+++a,b
0a,b
ꢀꢀ
0
ꢀꢀ
0
2d
2e
2f
2g
2h
2i
0
0
0
ꢀ
0a
0a
0
0
+++a
0a
0
0
2j
2k
2l
0
ꢀ
+++a,b
0a,b
0
0
+
2m
+++
(+) Denotes a greater than 50% increase in reporter gene activity at compound
concentration <20 M.
(++) Denotes a greater than 50% increase in reporter gene activity at compound
concentration between 20–50 M.
(+++) Denotes a greater than 50% increase in reporter gene activity at compound
concentration >50 M.
(ꢀ) Denotes a greater than 50% decrease in reporter gene activity at compound
concentration >50 M.
(ꢀꢀ) Denotes a greater than 50% decrease in reporter gene activity at compound
concentration <between 20–50
(ꢀꢀꢀ) Denotes a greater than 50% decrease in reporter gene activity at compound
concentration <20 M.
l
l
l
l
l
M
Figure 2. ERa competitive binding assay with estradiol.
l
(0) Denotes a less than 20% change in reporter gene activity. 4 Hydroxytamoxifen
was used as an antagonist control.
a
Denotes cell death at concentration greater than 50
Denotes precipitation of compound from solution.
lM.
None of the n-heptyl compounds had any inhibitory effect on
a–coactivator interaction, which may be due to the extreme
b
ER
flexibility of the group which does not allow the biphenyl to pen-
etrate the binding pocket and adopt the proper conformation. Fur-
thermore, none of di-substituted compounds showed any
inhibitory activity. This could be because these compounds are
too large to fit in the ERa CBP. These compounds will also be tested
in the future as androgen receptor (AR)-coactivator inhibitors, as
transfected with the activated fusion receptor VP16-ERa, the
LXXLL peptide fused with yeast Gal4-DBD, and the 5xGal4Luc3 re-
porter gene as described.26 Cells were then treated with serial two-
fold dilutions of test compounds +/ꢀ1 nM estradiol (E2) and
incubated for 40 h before assaying. 1b and 1j both exhibited great-
er than 50% decrease in reporter gene activity at concentrations
the AR has a larger hydrophobic groove at its CBP.
The results from this study were compared with those previously
reported11,13 and the comparison provides a clearer picture of the
potential of the biphenyl scaffold as the basis for co-regulatory pro-
tein inhibition. The earlier study examineda limited set of 2,20-, 2,30-,
and 3,20-disubstituted biphenyl derivatives from which 6 com-
less than 20 lM. However, at concentrations above 50 lM, these
compounds become toxic to the cells. Compound 1e also exhibited
a decrease in reporter gene activity at concentrations less than
20 lM, but did not become toxic. Once again, 1b, 1d, and 1j
showed inhibitory activity in the absence of E2. These results indi-
pounds demonstrated significant (low lM) activity against the CBP
cated that the compounds may be binding at both the CBP and LBP.
of ER- or AR-LBP. Those compounds also showed little if any compet-
itive activity against the hormone binding site, as compared 1d
derivative, the best compound in the current series. These observa-
tions highlight the influence of the 2- or 20-substituents on selectiv-
ity of binding as well as upon CBP binding affinity. The absence of
2- or 20-substitution relieves conformational constraints at the
1,1-biphenyl junction and thereby allows the compounds to assume
a more planar structure. More planar conformations demonstrate
estrogen binding site affinity as demonstrated by simple biphenyls
as well as phenyl carboranes. The presence of a substituent at either
the 2- or 20-position imparts enough conformational restraint (tor-
sional strain) to substantially reduce or eliminate binding at the
estrogen binding site. Affinity to the CBP as well as a preference for
To provide insight into the mechanism of inhibition, the ER
a
cotransfection reporter gene assay was repeated with 1b, 1d, and
1j and increasing concentrations of E2 (Fig. 2). If these compounds
are true CBIs, one should expect an inhibition of the maximum re-
sponse without a shift in the E2 EC50. Compounds 1b and 1j
showed an increased E2 EC50 at increasing concentrations as well
as a slight decrease in activity at maximum concentrations, with
overall IC50 of 3.1 and 3.2 lM respectively. These findings suggest
that these compounds are directly competing with E2 for binding
at the LBP. Compound 1d showed an increased E2 EC50 at increas-
ing concentrations with an IC50 of 12.7 lM, but a decreased activity
at maximum concentration. This result indicates that 1e may have
a mixed mode of inhibition, although the apparent affinity for the
CBP is significantly lower than for LBP.
ERa versus AR results from the identity of the groups at the 3- and

P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
921
30-positions as well as at the 2- and 20-positions. Based upon the re-
sults this and previous studies, it would appear that the optimal
derivatives would have a staggered conformation with either a 2,30
or 3,20 substitution pattern. The remaining 3- or 30-position would
then be substituted with a variety of functional groups selected to
provide enhanced affinity and CBP selectivity. Introduction of the
terminal groups would then provide the proper orientation within
the binding site as well as enhanced affinity. It is clear from these,
as well as previous results, that the amine terminus is necessary
for CBP inhibition as the phenolic biphenyls did not show any inhib-
itory activity. The previous study was limited by the commercial
availability of 2- and 3-substituted 4-bromophenol precursors. With
the development of the methods described in this report, it is now
possible to explore in greater detail the effects of individual substit-
uents on binding affinity and selectivity.
temperature overnight, turning white-gray, and quenched with sat-
urated ammonium chloride. The mixture was then eluted with
ethyl acetate and washed with water (ꢁ2), brine (ꢁ2) and dried
over magnesium sulfate. The solvent was evaporated and the crude
product (4.4 g yellow oil) was purified via by chromatography on
silica gel (hexane/EtOAc, 90:10). The desired product (0.938 g,
85%) was isolated as a clear yellow oil. 1H NMR (500 MHz, CDCl3):
d = 7.33 (dd, J = 7.5, 2 Hz, 1H), 7.27 (td, J = 7, 1.5 Hz, 1H), 6.98 (td,
J = 7, 1 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 4.89 (q, J = 7 Hz, 1H), 3.87 (s,
3H), 2.65 (d, J = 5 Hz, 1H), 1.76–1.84 (m, 2H), 1.47–1.51 (m, 1H),
1.28–1.38 (m, 6H), 0.91 (t, J = 6.5 Hz, 3H) ppm.
4.1.1.1. 4-Biphenyl (2-methoxyphenyl)methanol (4a).
Same
synthesis 4c. Product isolated in 91% yield as a white solid. 1H NMR
(500 MHz, CDCl3): d = 7.61 (dd, J = 8.5, 1.5 Hz, 2H), 7.58 (dd, J = 9.0,
2.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (td,
J = 8.0, 2.0 Hz, 1H), 7.34 (dd, J = 7.5, 1.5 Hz, 1H), 7.30 (td, J = 8.0,
1.0 Hz, 1H), 7.00 (td, J = 7.5, 1.0 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H),
6.14 (d, J = 5.5, 1H), 3.84 (s, 3H), 3.27 (d, J = 5.5 Hz, 1H) ppm.
3. Conclusions
In summary we have described the facile preparation of a novel
series of bipolar biphenyl proteomimetics derived from 2-bromo-
anisoles. The Grignard reaction can be utilized to with a wide vari-
ety of aldehydes to give 2-substituted phenols which can
subsequently be converted to aryl bromides and aryl boronates.
These intermediates readily undergo Suzuki coupling to generate
the desired intermediate phenolic biphenyls and ultimately the
biphenyl amino-esters. Evaluation of the products using cotrans-
fection reporter gene assays and mammalian two-hybrid compet-
itive inhibition assays, demonstrated that only 1b, 1d, and 1j
possessed significant inhibitory activity. Of these, only 1d appeared
to bind at the CBP, however it retained a competitive inhibition at
the LBP. Combining these results with those from previous studies
provides a rational basis for designing subsequent generations of
CBIs. These studies suggest that future agents should combine
the ligand domain binding reducing effects of 2-20-substitution
with the affinity and selectivity-enhancing effects of 3-30-substitu-
ents. Studies to demonstrate the effectiveness of this strategy are
in progress and will be described in subsequent publications.
4.1.1.2. Cyclohexyl (2-methoxyphenyl)methanol (4b).
Same sy
nthesis as 4c. Product isolated in quantitative yield as a yellow oil. 1H
NMR (500 MHz, CDCl3): d = 7.33 (dd, J = 7.5, 2 Hz, 1H), 7.27 (td, J = 7.0,
1.5 Hz, 1H), 6.98 (td, J = 7.0, 1.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H) Hz, 1H),
3.84 (s, 3H), 3.27 (d, J = 5.5 Hz, 1H) ppm.
4.1.1.3.
(2-Methoxyphenyl)(naphthalen-2-yl)methanol
(4d). Same synthesis as 4c. Product isolated in 75% yield as a white
solid. 1H NMR (500 MHz, CDCl3): d = 7.87 (s, 1H), 7.79–7.83 (m, 2H),
7.78 (s, 1H), 7.48 (dd, J = 8.5, 1.5 Hz, 1H), 7.42–7.46 (m, 2H), 7.27 (td,
J = 8.5, 1.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 6.94 (t, J = 7.5 Hz,1H),6.90(d,
J = 8 Hz, 1H), 6.23 (s, 1H), 3.82 (s, 3H) ppm.
4.1.2. Synthesis of 1-heptyl-2-methoxybenzene (5c)
Triethylsilane (2.290 g, 19.7 mmol) was added to 4c (0.868 g,
3.94 mmol) in a solution of dichloromethane. Trifluoroacetic acid
(2.246 g, 19.7 mmol) was added via syringe and the reaction mixture
was stirred under nitrogen at room temperaturefor one hour. The mix-
ture was quenched with saturated sodium bicarbonate and washed
with dichloromethane (3ꢁ). The organic layers were combined and
washed with brine. The organic layer was separated and dried over
magnesium sulfate which was then filtered off. The solvent was evap-
orated and the crude product (1.4 g brown oil) was purified by flash
chromatography on silica gel (100% hexane). The desired product
(0.680 g, 84%) was isolated as a yellow oil. 1H NMR (500 MHz, CDCl3):
d = 7.20 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 6.91 (td, J = 7.0,
1.5 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 3.84 (s, 3H), 2.63–2.66 (m, 2H),
1.57–1.65 (m, 2H), 1.32–1.37 (m, 8H), 0.91–0.94 (m, 3H) ppm.
4. Experimental section
4.1. General procedures
All commercially available reagents were purchased from Sig-
ma-Aldrich and used without further purification. Solvents were
distilled and reactions requiring inert conditions were performed
under N2 or argon. Column chromatography was performed using
silica gel unless otherwise indicated. Flash chromatography was
performed using the Argonaut Flash Master Solo with an FC204
fraction collector. Thin layer chromatography was used to monitor
reactions using Selecto Scientific 200 micron silica gel flexible TLC
plates. 1H was recorded on a Varian Unity-INOVA 500 MHz spec-
trometer. 13C NMR were recorded on a Varian 400 MHz spectrom-
eter. High resolution mass spectral data were obtained by direct
flow injection (injection volume = 1, 5 or 50 mL) ElectroSpray Ioni-
zation (ESI) on a Waters Qtof API US instrument in the positive
mode at the Boston University Chemical Instrumentation Center.
4.1.2.1. 1-(4-Biphenylmethyl)-2-methoxybenzene (5a).
Same
synthesis as 5c, but from 4a. Product isolated in 87% yield as a white
solid. 1H NMR (500 MHz, CDCl3): d = 7.56 (dd, J = 8.5, 1H, 2H), 7.49
(d, J = 8.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H),
7.27 (d, J = 7.0 Hz, 2H), 7.20 (td, J = 7.0, 2.0 Hz, 1H), 7.11 (dd,
J = 7.0, 1.5 Hz, 1H), 6.89 (td, J = 7.5, 1.0 Hz, 1H), 6,87 (d, J = 8.5 Hz,
1H), 4.01 (s, 2H), 3.81 (s, 3H) ppm.
4.1.1. Synthesis of 1-(2-methoxyphenyl)heptan-1-ol (4c)
4.1.2.2. 1-(Cyclohexylmethyl)-2-methoxybenzene (5b).
Same
Magnesium shavings (0.547 g, 22.5 mmol) were added to a
3-neck round bottom flask fitted with a condenser. The entire appa-
ratus was flame-dried, a chip of iodine was added and the system
was sealed and flushed with Ar. THF (20 mL) and 2-bromoanisole
(3) (2.805 g, 15 mmol) were added via syringe. The mixture turned
red initially and then gray after 10 min. The reaction was heated at
reflux for 6 h, cooled to room temperature and heptanal (0.571 g,
5 mmol) was added via syringe. The reaction was stirred at room
synthesis as 5c, but from 4b. Product isolated in 75% yield as a clear
oil. 1H NMR (500 MHz, CDCl3): d = 7.16 (td, J = 7.5, 1.5 Hz, 1H), 7.07
(dd, J = 7.0, 2.0 Hz, 1H), 6.86 (t, J = 7.0 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H),
3.80 (s, 3H), 2.48 (d, J = 2.0 Hz, 2H).
4.1.2.3. 2-(2-methoxybenzyl)naphthalene (5d).
Same synthe-
sis as 5c, but from 4d. Product isolated in 76% yield as a white solid.
1H NMR (500 MHz, CDCl3): d = 7.95 (d, J = 7.5 Hz, 1H), 7.91 (d,

922
P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
J = 8 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.59 (td, J = 8.0,
1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.55 (td, J = 8.0, 1.5 Hz, 1H),
7.37 (td, J = 8.0, 1.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.05 (td, J = 7.5,
1.0 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.32 (s, 2H), 3.95 (s, 3H) ppm.
(d, J = 7.5 Hz, 2H), 1.61–1.72 (m, 5H), 1.5–1.59 (m, 1H), 1.12–1.23
(m, 3H), 0.91–1.02 (m, 2H) ppm.
4.1.4.3.
4-Bromo-2-((naphthalen-2-yl)methyl)phenol
(7d). Same synthesis as 7c, but from 6d. Product isolated in 90%
yield as a yellow oil. 1H NMR (500 MHz, CDCl3): d = 7.80 (d, J = 9.0 Hz,
1H), 7.78 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.64 (s, 1H), 7.46
(td, J = 8.0, 1.5 Hz, 1H), 7.44 (td, J = 7.0, 2.0 Hz, 1H), 7.34 (dd, J = 8.0,
2.0 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.5, 2.5 Hz, 1H), 6.67
(d, J = 8.5 Hz, 1H), 5.19 (br s, 1H), 4.10 (s, 3H) ppm.
4.1.3. Synthesis of 2-heptylphenol (6c)
Boron tribromide (1.771 g, 7.07 mmol) was added slowly via
syringe to 5c (0.486 g, 2.36 mmol) in a solution of dichlorometh-
ane. The reaction was stirred at room temperature overnight and
was quenched with water. The mixture was eluted with dichloro-
methane, washed with brine (ꢁ2) and dried over magnesium sul-
fate. The solvent was evaporated and the crude mixture (0.527 g
brown oil) was purified by flash chromatography on silica gel (hex-
ane/EtOAc, 80:20). The desired product (0.433 g, 95%) was isolated
as a yellow oil. 1H NMR (500 MHz, CDCl3): d = 7.17 (d, J = 7.5 Hz,
1H), 7.11 (t, J = 7.5 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.79 (d,
J = 8.0 Hz, 1H), 5.21 (s, 1H), 2.65 (t, J = 8.0 Hz, 2H), 1.67 (5let,
J = 7.5 Hz, 2H), 1.33–1.41 (m, 8H), 0.94 (t, J = 7.0 Hz, 3H) ppm.
4.1.5. Synthesis of 2-heptyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenol (8c)
Compound 7c (0.235 g, 0.867 mmol), potassium acetate
(0.256 g, 2.6 mmol), and PdCl2dppf (0.043 g, 6 mol %) were added
to a round bottom flask and flushed with nitrogen. Dry dioxane
(20 mL) was added via syringe and the reaction was stirred at
80 °C for 2 h. Bis(pinacolato)diboron (0.242 g, 0.953 mmol) in dry
dioxane (5 mL) was added via syringe and the reaction was stirred
at 80 °C overnight. The solvent was evaporated, filtered though
Celite with ethylacetate and evaporated. The crude mixture was
eluted with ethylacetate, washed with saturated ammonium chlo-
ride, water (ꢁ2), and brine (ꢁ2), and dried over magnesium sulfate.
The solvent was evaporated and the crude mixture (0.600 g brown
oil) was purified by flash chromatography on silica gel (hexane/
EtOAc 95:5). The desired product (0.125 g, 45%) was isolated as a
yellow oil. 1H NMR (500 MHz, CDCl3): d = 7.63 (s, 1H), 7.56 (dd,
J = 7.0, 1.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.82 (s, 1H), 2.63 (t,
J = 7.5 Hz, 2H), 1.59–1.62 (m, 2H), 1.38 (s, 12H), 1.26–1.42 (m,
8H), 0.92 (t, J = 7.0 Hz, 3H) ppm.
4.1.3.1. 2-(4-Biphenylmethyl)phenol (6a).
Same synthesis as
6c, but from 5a. Product isolated in 94% as a white solid. 1H NMR
(500 MHz, CDCl3): d = 7.65 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 6.5 Hz, 1H),
7.50 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.0 Hz, 1H), 7.39 (d, J = 7.5 Hz, 2H),
7.24 (d, J = 7.0 Hz, 1H), 7.21 (td, J = 7.5, 1.5 Hz, 1H), 6.99 (td, J = 7.5,
1 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 5.18 (s, 1H), 4.12 (s, 3H) ppm.
4.1.3.2. 2-(Cyclohexylmethyl)phenol (6b).
Same synthesis as
6c, but from 5b. Product isolated in 95% yield. 1H NMR (500 MHz,
CDCl3): d = 7.07 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.85 (t,
J = 8.0 Hz, 1H), 6.76 (d, J = 7.0 Hz, 1H), 4.70 (s, 3H), 2.48 (d, J = 7.0 Hz,
2H), 1.60–1.75 (m, 5H), 1.50–1.60 (m, 1H), 1.11–1.25 (m, 3H), 0.92–
1.02 (m, 2H) ppm.
4.1.5.1. 2-(4-Biphenylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dio
xaborolan-2-yl)phenol (8a).
Synthesis same as 8c, but from
4.1.3.3. 2-((Naphthalen-2-yl)methyl)phenol (6d).
Same syn-
7a. Product isolated in 50% yield as a white solid. 1H NMR
(400 MHz, acetone-d6): d = 8.80 (s, 1H), 7.59–7.64 (m, 3H), 7.51–
7.57 (m, 3H), 7.42 (t, J = 6.8 Hz, 2H), 7.37 (d, J = 8 Hz, 1H), 7.32 (d,
J = 7.2 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 4.06 (s, 2H), 1.29 (s, 12H) ppm.
thesis as 6c, but from 5d. Product isolated in 91% yield as a yellow oily
solid. 1H NMR (500 MHz, CDCl3): d = 7.76 (dd, J = 8.5, 2.5 Hz, 1H), 7.72
(d, J = 8.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.63 (s, 1H), 7.37–7.42 (m,
2H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.09 (t,
J = 7.5 Hz, 1H), 6.84 (td, J = 8.0, 1.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H),
6.05 (br s, 1H), 4.14 (s, 2H) ppm.
4.1.5.2. 2-(Cyclohexylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)phenol (8b).
Synthesis same as 8c, but from 7b.
Product isolated in 50% yield as a yellow oil. 1H NMR (400 MHz,
CDCl3): d =7.50–7.55 (m, 2H), 6.75 (d, J = 6.8 Hz, 1H), 5.80 (br s, 1H),
2.48 (d, J = 9.0 Hz, 2H), 1.60–1.70 (m, 6H), 1.34 (s, 12H), 1.16–1.20
(m, 3H), 0.60-1.10 (m, 2H) ppm.
4.1.4. Synthesis of 4-bromo-2-heptylphenol (7c)
Tetrabutylammoniumtribromide(1.147 g, 2.38 mmol)wasadded
to a solution of 6c (0.381 g, 1.98 mmol) in chloroform. The solution
was stirred at room temperature overnight. The solution was then
evaporated and the crude product was eluted with ether and washed
with water (ꢁ2), 1 N HCl (ꢁ2), and brine (ꢁ2). The organic layer was
separated and dried over magnesium sulfate. The solvent was evapo-
rated and the crude mixture (0.474 g brown oil) was purified by flash
chromatography on silica gel (100% hexane). The desired product
(0.426 g, 79%) was isolated as a yellow oil. 1H NMR (500 MHz, CDCl3):
d = 7.24 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.5, 3.0 Hz, 1H), 6.23 (d,
J = 9.0 Hz, 1H), 5.14 (s, 1H), 2.56 (t, J = 7.5 Hz, 2H), 1.56–1.64 (m,
2H), 1.24–1.40 (m, 8H), 0.90 (t, J = 7.0 Hz, 3H) ppm.
4.1.5.3.
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-
Synthesis same as 8c,
((naphthalen-2-yl)methyl)phenol (8d).
but from 7d. Product isolated in 53% yield as a yellow oil. 1H NMR
(500 MHz, CDCl3): d = 7.70–7.80 (m, 4H), 7.63 (s, 1H), 7.62 (dd,
J = 8.5, 2.0 Hz, 1H), 7.39–7.45 (m, 2H), 7.37 (dd, J = 9.0, 2.0 Hz, 1H),
6.75 (d, J = 8.0 Hz, 1H), 5.52 (br s, 1H), 4.14 (s, 2H), 1.32 (s, 12H) ppm.
4.1.6. Synthesisofethyl2-(4-bromo-2-heptylphenoxy) acetate (9c)
Sodium hydride (60% in oil, 0.04 g, 0.986 mmol) was added
slowly to a solution of 7c (0.191 g, 0.704 mmol) in dry THF
(20 mL). The solution was stirred at room temperature for 1.5 h.
Ethyl bromoacetate (0.165 g, 0.986 mmol) was added and the reac-
tion was stirred overnight at room temperature. The solvent was
evaporated and the white crude material was eluted with ethyl
acetate, washed with saturated sodium bicarbonate, water (ꢁ2),
brine (ꢁ2), and dried over magnesium sulfate. The solvent was
evaporated and the crude mixture was (0.324 g clear, yellow oil)
was purified by flash chromatography on silica gel (100% hexane).
The desired product (0.219 g, 87%) was isolated as a clear oil. 1H
NMR (500 MHz, CDCl3): d = 7.29 (d, J = 2.0 Hz, 1H), 7.24 (dd,
J = 8.5, 2.5 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.62 (s, 2H), 4.28 (q,
4.1.4.1. 4-Bromo-2-(4-biphenylmethyl)phenol (7a).
Same
synthesis as 7c, but from 6a. Product isolated in 79% yield as a white
solid. 1H NMR (500 MHz, CDCl3): d = 7.61 (d, J = 7.5 Hz, 2H), 7.56 (d,
J = 6. 7c, but 5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H),
7.32 (d, J = 5.0 Hz, 2H), 7.31 (s, 1H), 7.27 (dd, J = 8.5, 1.5 Hz, 1H), 6.72
(d, J = 8.0 Hz, 1H), 4.86 (br s, 1H), 4.02 (s, 2H) ppm.
4.1.4.2. 4-Bromo-2-(cyclohexylmethyl)phenol (7b).
Same
synthesis as 7c, but from 6b. Product isolated in 77% yield as a light
yellow oil. 1H NMR (500 MHz, CDCl3): d = 7.17 (dd, J = 7, 2.5 Hz, 1H),
7.15 (d, J = 2.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 4.20 (br s, 1H), 2.43

P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
923
J = 8.0 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.58–1.66 (m, 2H), 1.26–1.38
(m, 8H), 0.91 (t, J = 7.0 Hz, 3H) ppm.
(100 MHz, CDCl3/CD3OD): d = 169.6, 156.8, 154.2, 141.3, 140.3,
138.9, 135.1, 132.5, 129.4, 129.2, 128.8, 128.0, 127.9, 127.2,
127.1, 127.1, 125.9, 115.6, 115.0, 65.6, 61.7, 35.7, 14.2 ppm.
4.1.6.1. Ethyl 2-(4-bromo-2-(4-biphenylmethyl)phenoxy)ace-
tate (9a).
Same synthesis as 9c, but from 7a. Product isolated
4.1.7.3. Ethyl 2-(1,10-biphenyl-3,30-(di(4-biphenylmethyl))-40-ol-
in 69% yield as a white solid. 1H NMR (400 MHz, CDCl3): d = 7.57 (d,
J = 7.2 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.29–7.35 (m, 3H), 7.23–7.35
(m, 2H), 6.62 (d, J = 5.6 Hz, 2H), 4.60 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H),
4.04 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm.
4-oxy) acetate (2c).
Product isolated in
Same synthesis as 2m with 8a and 9a.
70% yield as yellow solid (mp
a
a
185–186 °C). 1H NMR (400 MHz, acetone-d6): d = 7.61 (d,
J = 7.2 Hz, 4H), 7.53 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H),
7.34–7.47 (m, 11H), 7.27–7.34 (m, 3H), 6.94 (d, J = 8.8 Hz, 1H),
6.92 (d, J = 8.0 Hz, 1H), 4.78 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.11
(s, 2H) 4.06 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(100 MHz, acetone-d6): d =
4.1.6.2. Ethyl 2-(4-bromo-2-(cyclohexylmethyl)phenoxy)acetate
(9b).
Same synthesis as 9c, but from 7b. Product isolated in
91% yield as a yellow oil. 1H NMR (500 MHz, CDCl3): d = 7.19–
7.23 (m, 2H), 6.57 (d, J = 9.0 Hz, 1H), 4.59 (s, 2H), 4.25 (q,
J = 7.0 Hz, 2H), 2.51 (d, J = 8.0 Hz, 2H), 1.54–1.71 (m, 6H), 1.28 (t,
J = 7.5 Hz, 3H), 1.12–1.22 (m, 3H), 0.92–1.02 (m, 2H) ppm.
4.1.7.4. Ethyl 2-(1,10-biphenyl-3-cyclohexylmethyl-40-ol-4-oxy)
acetate (2d).
Same synthesis as 2m with 8e and 9b. Product
isolated in quantitative yield as a yellow solid (mp 152–153 °C).
1H NMR (400 MHz, CDCl3/CD3OD): d = 7.40 (d, J = 8.0 Hz, 2H),
7.26–7.32 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 9.6 Hz, 1H),
4.66 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.22 (br s, 1H), 2.60 (d,
J = 6.8 Hz, 2H), 1.58–1.76 (m, 6H), 1.31 (t, J = 7.0 Hz, 3H),
1.12–1.24 (m, 3H), 0.94–1.08 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3/CD3OD): d = 169.8, 156.0, 155.1, 134.2, 132.6, 130.7, 129.6,
127.9, 124.8, 115.6, 111.6, 65.8, 61.5, 38.5, 38.2, 33.4, 26.7, 26.4,
14.1 ppm.
4.1.6.3. Ethyl 2-(4-bromo-2-((naphthalen-2-yl)methyl) phen-
oxy)acetate (9d).
Same synthesis as 9c, but from 7d. Product
isolated in 83% yield as a yellow oily solid. 1H NMR (500 MHz,
CDCl3): d = 7.78 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.74 (d,
J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.40 (t,
J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.22-7.27 (m, 2H), 6.60 (d,
J = 8.0 Hz, 1H), 4.57 (s, 2H), 4.24 (q, J = 7.0 Hz, 2H), 4.15 (s, 2H),
1.26 (t, J = 7.0 Hz, 3H) ppm.
4.1.7. Synthesis of Ethyl 2-(1,10-biphenyl-40-ol-4-oxy) acetate
(2m)
4.1.7.5. Ethyl 2-(1,10-biphenyl-30-cyclohexylmethyl-40-ol-4-oxy)
acetate (2e).
Same synthesis as 2m with 8b and 9e. Product
Compound 9e (0.167 g, 0.45 mmol), sodium carbonate (0.095 g,
0.9 mmol), PdCl2(P(otol)3)2 (0.018 g, 5 mol %), and P(otol)3 (0.007 g,
5 mol %) added to test tube and flushed with argon. Solvent was
added via syringe (dichloromethane/water 3:2 mL) and the test
tube was sealed and heated at 80 °C for 30 min. Reaction was
cooled to room temperature, 8e (0.198 g, 0.9 mmol) was added;
test tube was resealed, heated at 80 °C, and stirred overnight.
The solvent was evaporated and the crude material was eluted
with ethyl acetate, washed with saturated ammonium chloride,
brine (ꢁ2) water (ꢁ2), and dried over magnesium sulfate. Solvent
was evaporated and the crude material was purified by flash chro-
matography on silica gel (hexane/EtOAc, 80:20). The desired prod-
uct was isolated (0.105 g, 86%) as a white solid (mp 131–132 °C).
1H NMR (400 MHz, CDCl3): d = 7.45 (d, J = 8.8 Hz, 2H), 7.49 (d,
J = 8.8 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H),
5.41(br s, 1H), 4.67 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 1.32 (t,
J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): d = 169.5, 157.1,
155.2, 134.8, 133.4, 128.2, 128.0, 155.9, 115.1, 65.7, 61.8, 14.4 ppm.
isolated in 73% yield as a white solid (mp 140–141 °C). 1H NMR
(400 MHz, CDCl3): d = 7.46 (d, J = 8.8 Hz, 2H), 7.24 (br s, 2H), 6.96
(d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 4.78 (s, 1H), 4.65 (s,
2H), 4.29 (q, J = 7.2 Hz, 2H), 2.53 (d, J = 7.6 Hz, 2H), 1.62–1.78 (m,
6H), 1.32 (t, J = 7.0 Hz, 3H), 1.13–1.24 (m, 3H), 0.96–1.06 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3): d =
4.1.7.6. Ethyl 2-(1,10-biphenyl-3,30-di(cyclohexylmethyl)-40-ol-4-
oxy) acetate (2f).
Same synthesis as 2m with 8b and 9b.
Product isolated in 50% yield as a white solid (mp 118–119 °C).
1H NMR (400 MHz, acetone-d6): d = 8.19 (br s, 1H), 7.31–7.37 (m,
2H), 7.29 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.0, 2.0 Hz, 1H), 6.88 (d,
J = 8.4 Hz, 2H), 4.74 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.61 (d,
J = 6.8 Hz, 2H), 2.56 (d, J = 6.8 Hz, 2H), 1.58–1.76 (m, 12H), 1.26
(t, J = 7.6 Hz, 3H), 1.12–1.23 (m, 6H), 0.96–1.18 (m, 4H) ppm; 13C
NMR (100 MHz, acetone-d6): d = 168.9, 155.4, 154.7, 134.2, 132.1,
130.2, 129.5, 129.3, 127.9, 125.1, 124.9, 115.5, 111.8, 65.4, 60.8,
38.5, 38.4, 38.3, 38.2, 33.4, 33.4, 26.7, 26.4, 13.9 ppm.
4.1.7.1. Ethyl 2-(1,10-biphenyl-3-(4-biphenylmethyl)-40-ol-4-
4.1.7.7. Ethyl 2-(1,10-biphenyl-3-n-heptyl-40-ol-4-oxy) acetate
oxy) acetate (2a).
Same synthesis as 2m with 8e and 9a.
(2g).
Same synthesis as 2m with 8e and 9c. Product isolated
Product isolated in 78% yield as a white (mp 182–183 °C). 1H
NMR (400 MHz, CDCl3/CD3OD): d = 7.35 (d, J = 7.2 Hz, 2H), 7.28
(d, J = 8.0 Hz, 2H), 7.05–7.21 (m, 9H), 6.64 (d, J = 8.8 Hz, 2H), 6.59
(d, J = 8.0 Hz, 1H), 4.44 (s, 2H), 4.27 (s, 1H), 4.05 (q, J = 8.8 Hz,
2H), 3.91 (s, 2H), 1.09 (t, J = 7.8 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3/CD3OD): d = 169.6, 156.1, 154.7, 141.1, 140.1, 138.7, 134.8,
132.3, 130.4, 129.4, 129.0, 128.6, 127.8, 126.9, 126.9, 126.8,
125.4, 115.5, 112.0, 65.8, 61.4, 35.7, 13.9 ppm.
in 95% yield as an oily white solid (mp 69–70 °C). 1H NMR
(400 MHz, CDCl3): d = 7.49 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 1.6 Hz,
1H), 7.27 (dd, J = 8.8, 2.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.75 (d,
J = 8.8 Hz, 1H), 5.37 (br s, 1H), 4.68 (s, 2H), 4.29 (q, J = 7.1 Hz,
2H), 2.72 (t, J = 7.6 Hz, 2H), 1.65 (m, 2H), 1.24–1.42 (m, 8H), 1.32
(t, J = 6.8 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d = 169.7, 155.1, 155.0, 134.4, 133.8, 132.5, 128.9, 128.2,
125.0, 115.8, 111.6, 65.9, 61.6, 32.1, 30.6, 30.2, 29.9, 29.5, 22.9,
14.4, 14.4 ppm.
4.1.7.2. Ethyl 2-(1,10-biphenyl-30-(4-biphenylmethyl)-40-ol-4-
oxy) acetate (2b).
Same synthesis as 2m with 8a and 9e.
white solid solid
4.1.7.8. Ethyl 2-(1,10-biphenyl-30-n-heptyl-40-ol-4-oxy) acetate
(2h).
in 84% yield as
(400 MHz, CDCl3): d = 7.46 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 2.0 Hz,
1H), 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.80 (d,
J = 8.0 Hz, 1H), 4.88 (br s, 1H), 4.65 (s, 2H), 4.29 (q, J = 8.8 Hz,
2H), 2.64 (t, J = 8.0 Hz, 2H), 1.60–1.69 (m, 2H), 1.23–1.42 (m, 8
Product isolated in 73% yield as
a
Same synthesis as 2m with 8c and 9e. Product isolated
(mp 155–156 °C). 1H NMR (400 MHz, CDCl3/CD3OD): d = 7.49 (d,
J = 6.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.30–7.38 (m, 5H), 7.27
(d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 7.19 (dd, J = 8.0, 2.0 Hz, 1H), 6.85
(d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.0 Hz, 1H), 4.56 (s, 2H), 4.20 (q,
J = 7.6 Hz, 2H), 3.40 (s, 2H), 1.23 (t, J = 8.4 Hz, 3H) ppm; 13C NMR
a
white solid (mp 128–129 °C). 1H NMR

924
P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
H), 1.31 (t, J = 8.4 Hz, 3H), 0.88 (t, J = 6.6 Hz, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d = 169.4, 157.0, 153.0, 135.1, 133.5, 129.2,
128.8, 128.1, 125.5, 115.7, 115.1, 65.8, 61.7, 32.1, 30.4, 30.1, 29.8,
29.5, 22.9, 14.4, 14.4 ppm.
(0.032 g white solid) was purified by flash chromatography on
silica gel (hexane/EtOAc, 50:50). The desired product was isolated
as a white solid (0.026 g, 76% yield). 1H NMR (400 MHz, acetone-
d6): d = 7.53 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 6.99 (d,
J = 8.8 Hz, 4H), 4.75 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.11(t,
J = 6.4 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.28 (s, 6H), 1.26 (t,
J = 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, acetone-d6): d = 168.7,
158.5, 157.6, 134.1, 133.1, 127.7, 127.6, 115.1, 115.0, 66.6, 65.2,
60.8, 58.3, 45.5, 13.8 ppm.
4.1.7.9. Ethyl 2-(1,10-biphenyl-3,30-di-n-heptyl-40-ol-4-oxy) ace-
tate (2i).
Same synthesis as 2m with 8c and 9c. Product iso-
lated in 86% yield as an oily yellow solid (mp 73–74 °C). 1H NMR
(400 MHz, CDCl3): d = 7.32 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.0 Hz,
1H), 7.27 (dd, J = 10.0, 2.8 Hz, 1H), 7.23 (dd, J = 8.6, 1.4 Hz, 1H),
6.79 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.04 (br s, 1H),
4.67 (s, 2H), 4.28 (q, J = 6.8 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 2.64
(t, J = 7.6 Hz, 2H), 1.58–1.70 (m, 4H), 1.20–1.43 (m, 16H), 1.31 (t,
J = 7.2 Hz, 3H), 0.88 (t, J = 7.0 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3): d = 169.6, 155.1, 153.0, 134.7, 133.8, 132.4, 129.1, 128.9,
128.9, 125.6, 125.1, 115.7, 111.7, 66.0, 61.6, 32.1, 32.1, 30.7, 30.3,
30.2, 29.9, 29.8, 29.5, 29.5, 22.9, 22.9, 14.4, 14.4, 14.4 ppm.
4.1.8.1.
Ethyl
2-(1,10-biphenyl-3-(4-biphenylmethyl)-40-[2-
Same synthe-
(dimethylamino)ethoxy]-4-oxy) acetate (1a).
sis as 1m from 2a. Product isolated in 31% yield as a white solid
(mp 76–77 °C). 1H NMR (400 MHz, acetone-d6): d = 7.62 (d,
J = 7.2 Hz, 2H), 7.50–7.60 (m, 5H), 7.40–7.48 (m, 5H), 7.32 (t,
J = 7.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H),
4.73 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.13 (t, J = 5.8 Hz, 2H), 4.07
(s, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.28 (s, 6H), 1.25 (t, J = 7.0 Hz, 3H)
ppm; 13C NMR (100 MHz, acetone-d6): d = 168.8, 157.5, 156.2,
141.2, 140.9, 138.7, 134.3, 133.1, 130.4, 129.7, 129.0, 128.8,
127.7, 127.2, 126.9, 126.9, 125.7, 115.1, 112.2, 66.9, 65.2, 60.8,
58.4, 45.6, 35.9, 13.8 ppm
4.1.7.10. Ethyl 2-(1,10-biphenyl-3-(naphthalen-2-yl)methyl-40-
ol-4-oxy) acetate (2j).
Same synthesis as 2m with 8e and
9d. Product isolated in 80% yield as a white solid (mp 154–
155 °C). 1H NMR (400 MHz, CDCl3/CD3OD): d = 7.60–7.68 (m, 3H),
7.57 (s, 1H), 7.26–7.33 (m, 5H), 7.15 (d, J = 6.8 Hz, 1H), 7.14 (s,
1H), 6.78 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.8 Hz, 1H), 4.50 (s, 2H),
4.15 (q, J = 7.2 Hz, 2H), 4.07 (s, 2H), 1.18 (t, J = 6.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3/CD3OD): d = 169.6, 156.7, 154.3, 138.7,
135.1, 133.8, 132.3, 132.2, 129.2, 127.9, 127.9, 127.8, 127.8,
127.6, 127.6, 127.0, 125.8, 125.8, 125.2, 115.5, 114.9, 65.6, 61.7,
36.1, 14.1 ppm.
4.1.8.2.
Ethyl
2-(1,10-biphenyl-30-(4-biphenylmethyl)-40-[2-
(dimethylamino)ethoxy]-4-oxy) acetate (1b). Same synthesis
as 1m from 2b. Product isolated in 70% yield as a white solid (mp
100–101 °C). 1H NMR (400 MHz, acetone-d6): d = 7.62 (d, J = 7.6 Hz,
2H), 7.55 (d, J = 8.8 Hz, 2H), 7.45–7.55 (m, 5H), 7.38–7.45 (m, 3H),
7.32 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 3H), 4.79 (s, 2H), 4.25 (q,
J = 7.2 Hz, 2H), 4.14 (s, 2H), 4.09 (t, J = 6.0 Hz, 2H), 2.67 (t,
J = 6.2 Hz, 2H), 2.26 (s, 6H), 1.28 (t, J = 7.4 Hz, 3H) ppm; 13C NMR
(100 MHz, acetone-d6): d = 168.8, 158.5, 155.2, 141.2, 140.8, 138.7,
134.2, 133.2, 130.7, 129.8, 129.0, 128.9, 127.7, 127.2, 126.9, 126.9,
125.5, 115.0, 112.4, 66.6, 65.6, 60.9, 58.3, 45.5, 35.6, 13.9 ppm.
4.1.7.11. Ethyl 2-(1,10-biphenyl-30-(naphthalen-2-yl)methyl-40-
ol-4-oxy) acetate (2k).
Same synthesis as 2m with 8d and 9e.
Product isolated in 95% yield as a white solid. (mp 162 163 °C). 1
H
NMR (400 MHz, CDCl3/CD3OD): d = 7.72–7.81 (m, 4H), 7.39–7.48
(m, 3H), 7.32–7.38 (m, 4H), 6.84 (d, J = 7.2 Hz, 2H), 6.82 (d,
J = 9.6 Hz, 1H), 4.65 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.26 (s, 2H),
1.23 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3/CD3OD):
d = 169.6, 156.1, 154.8, 138.5, 134.9, 133.7, 132.4, 132.1, 130.5,
129.2, 127.9, 127.9, 127.8, 127.6, 127.6, 127.2, 125.8, 125.6,
125.2, 115.6, 112.1, 66.0, 61.5, 36.4, 14.1 ppm.
4.1.8.3. Ethyl 2-(1,10-biphenyl-3,30-di(4-biphenylmethyl)-40-[2-
(dimethylamino)ethoxy]-4-oxy) acetate (1c).
Same synthe-
sis as 1m from 2c. Product isolated in 35% yield as a clear oil. 1H
NMR (400 MHz, acetone-d6): d = 7.60 (d, J = 8.0 Hz, 4H), 7.48–7.56
(m, 16H), 7.31 (t, J = 7.6 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.96 (d,
J = 8.8 Hz, 1H), 4.78 (s, 2H), 4.24 (q, J = 7.6 Hz, 2H), 4.12 (t,
J = 6.2 Hz, 2H), 4.12 (s, 2H), 4.05 (s, 2H), 2.71 (t, J = 5.8 Hz, 2H),
2.72 (s, 6H), 1.27 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, ace-
tone-d6): d = 168.8, 156.2, 155.2, 141.2, 140.8, 140.7, 138.7, 138.7,
134.3, 130.7, 130.3, 129.8, 129.7, 129.0, 129.0, 128.8, 128.8,
127.2, 127.2, 126.9, 126.9, 126.9, 126.9, 125.7, 125.6, 112.4,
112.1, 66.9, 65.6, 60.9, 58.4, 45.6, 35.8, 35.6, 13.9 ppm.
4.1.7.12.
Ethyl
2-(1,10-biphenyl-3,30-(di(naphthalen-2-yl))
Same synthesis as 2m with
methyl-40-ol-4-oxy) acetate (2l).
8d and 9d. Product isolated in 40% yield as a yellow solid (mp 142–
144 °C). 1H NMR (400 MHz, CDCl3/CD3OD): d = 7.73–7.90 (m, 8H),
7.51 (dd, J = 8.8, 1.6 Hz, 1H), 7.39–7.48 (m, 7H), 7.34 (dd, J = ⁄8.0,
2.0 Hz, 1H), 7.26 (dd, J = 8.0, 2.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H),
6.91 (d, J = 8.8 Hz, 1H), 4.76 (s, 2H), 4.23 (q, J = 7.6 Hz, 2H), 4.22 (s,
2H), 4.17 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3/CD3OD): d = 169.4, 155.1, 153.5, 138.6, 137.7, 134.7, 133.9,
133.8, 132.4, 132.3, 130.7, 129.7, 129.5, 128.5, 128.1, 128.0, 127.9,
127.8, 127.8, 127.8, 127.8, 127.6, 127.4, 127.4, 127.0, 126.5, 126.3,
126.0, 125.9, 125.7, 125.4, 116.3, 112.1, 66.1, 61.6, 36.9, 36.6,
14.4 ppm.
4.1.8.4. Ethyl 2-(1,10-biphenyl-3-cyclohexylmethyl-40-[2-(dim
ethylamino)ethoxy]-4-oxy) acetate (1d).
Same synthesis as
1m from 2d. Product isolated in 36% yield as a yellow oil. 1H NMR
(400 MHz, acetone-d6): d = 13C NMR (100 MHz, acetone-d6): d = 168.
4.1.8.5.
Ethyl
2-(1,10-biphenyl-30-cyclohexylmethyl-40-[2-
4.1.8. Synthesis of ethyl 2-(1,10-biphenyl-40-[2-(dimethylamino)
ethoxy]-4-oxy) acetate (1m)
(dimethylamino)ethoxy]-4-oxy) acetate (1e). Same synthesis
as 1m from 2e. Product isolated in 67% yield as a clear oil. 1H NMR
(400 MHz, acetone-d6): d = 7.53 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 7.2,
2.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.99 (d, 8.8 Hz, 2H), 4.74 (s, 2H),
4.22 (q, J = 6.8 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6.2 Hz,
2H), 2.55 (d, J = 6.8 Hz, 2H), 2.30 (s, 6H), 1.58–1.72 (m, 6H), 1.26 (t,
J = 7.0 Hz, 3H), 1.10–1.22 (m, 3H), 0.94–1.06 (m, 2H) ppm; 13C NMR
(100 MHz, acetone-d6): d = 168.8, 157.5, 156.6, 134.5, 132.5, 130.1,
129.2, 127.6, 125.1, 115.1, 111.8, 67.0, 65.2, 60.8, 58.5, 45.7, 38.5,
38.4, 33.4, 26.7, 26.4, 13.8 ppm.
Compound 2m (0.027 mg, 0.1 mmol), potassium carbonate
(0.014 mg, 0.5 mmol), and acetone (2 mL) were added to a test
tube which was flushed with argon, sealed and heated at reflux
for 1 h. The reaction was then cooled to room temperature, 2-
dimethylaminoethylchloride hydrochloride (0.015 mg, 0.3 mmol)
was added, and the reaction was heated to reflux overnight.
Solvent was evaporated, and the crude mixture was eluted with
ethyl acetate, washed with water (ꢁ2), brine (ꢁ2), and dried with
magnesium sulfate. Solvent was evaporated and the crude mixture

P. T. Weiser et al. / Bioorg. Med. Chem. 22 (2014) 917–926
925
4.1.8.6. Ethyl 2-(1,10-biphenyl-3,30-(cyclohexylmethyl)-40-[2-
(dimethylamino)ethoxy]-4-oxy) acetate (1f). Same synthesis
as 1m from 2f. Product isolated in 65% yield as a yellow oil. 1H
NMR (400 MHz, acetone-d6): d = 7.32–7.40 (m, 4H), 6.98 (d,
J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H), 4.22 (q,
J = 7.2 Hz, 2H), 4.11 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.61
(d, J = 6.4 Hz, 2H), 2.55 (d, J = 6.8 Hz, 2H), 2.30 (s, 6H), 1.58–1.76
(m, 12H), 1.27 (t, J = 6.8 Hz, 3H), 1.12–1.24 (m, 6H), 0.94–1.09 (m,
4H) ppm; 13C NMR (100 MHz, acetone-d6): d = 168.9, 156.8, 155.5,
133.9, 132.8, 130.3, 130.0, 129.4, 129.2, 125.2, 125.0, 111.9, 111.8,
67.0, 65.4, 60.8, 58.5, 45.7, 38.5, 38.5, 38.4, 38.3, 33.4, 33.4, 26.7,
26.4, 26.4, 26.4, 13.8 ppm.
1H NMR (400 MHz, acetone-d6): d = 7.76–7.84 (m, 4H), 7.46–7.54
(m, 4H), 7.38–7.44 (m, 3H), 7.04 (d, J = 8.8 Hz, 1H), 6.97 (d,
J = 8.8 Hz, 2H), 4.73 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 4.20 (s, 2H),
4.12 (t, J = 6.0 Hz, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.26 (s, 6H), 1.25 (t,
J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, acetone-d6): d = 168.9,
157.5, 156.3, 139.2, 134.2, 134.0, 133.0, 132.4, 130.3, 128.8,
128.1, 127.8, 127.7, 127.7, 127.7, 127.3, 126.0, 125.7, 125.3,
115.1, 112.2, 66.9, 65.2, 60.8, 58.5, 45.6, 36.4, 13.8 ppm.
4.1.8.12. Ethyl 2-(1,10-biphenyl-3,30-di(naphthalen-2-yl)methyl-
40-[2-(dimethylamino)ethoxy]-4-oxy) acetate (1l).
Same
synthesis as 1m from 2l. Product isolated in 58% yield as a clear
oil. 1H NMR (400 MHz, acetone-d6): d = 7.85 (s, 1H), 7.83 (s, 1H),
7.73–7.82 (m, 6H), 7.35–7.54 (m, 10H), 6.99 (d, J = 8.8 Hz, 1H),
6.94 (d, J = 8.0 Hz, 1H), 4.77 (s, 2H), 4.23 (s, 2H), 4.22 (q,
J = 7.2 Hz, 2H), 4.16 (s, 2H), 4.10 (t, J = 6.0 Hz, 2H), 2.69 (t,
J = 6.0 Hz, 2H), 2.25 (s, 6H), 1.25 (t, J = 6.4 Hz, 3H) ppm; 13C NMR
(100 MHz, acetone-d6): d = 168.9, 156.3, 155.2, 139.1, 139.0,
134.3, 134.0, 133.1, 132.4, 132.4, 130.6, 130.2, 129.0, 128.9,
128.1, 128.1, 127.9, 127.8, 127.7, 127.7, 127.7, 127.7, 127.3,
127.2, 126.0, 126.0, 125.8, 125.6, 125.3, 125.3, 112.4, 112.1, 66.9,
65.6, 60.8, 58.4, 45.5, 36.4, 36.1, 13.8 ppm.
4.1.8.7.
Ethyl
2-(1,10-biphenyl-3-n-heptyl-40-[2-(dimethyl-
amino)ethoxy]-4-oxy) acetate (1g). Same synthesis as 1m from
2g. Product isolated in 93% yield as a clear oil. 1H NMR (400 MHz,
acetone-d6): d = 7.53 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.38 (dd,
J = 8.8, 2.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 3H), 4.74 (s, 2H), 4.22 (q,
J = 7.0 Hz, 2H), 4.12 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.67 (t,
J = 7.8 Hz, 2H), 2.30 (s, 6H), 1.59–1.68 (m, 2H), 1.28–1.40 (m, 8H),
1.26 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(100 MHz, acetone-d6): d = 168.9, 158.4, 155.4, 133.8, 131.9, 128.4,
127.7, 124.9, 115.0, 111.9, 66.5, 65.4, 60.8, 58.2, 45.5, 32.0, 30.5,
30.2, 29.6, 22.7, 13.8, 13.7 ppm.
Acknowledgments
4.1.8.8.
Ethyl
2-(1,10-biphenyl-30-n-heptyl-40-[2-(dimethyl-
This work was supported in part by the Department of Defense
PCRP Concept Grant W81XWH-04-1-0647 (to R.N.H.), PCRP
Training Award W81XWH-09-1-0208 (to P.T.W.), and Public
Health Service Award CA139818 (to D.P.M).
amino)ethoxy]-4-oxy) acetate (1h). Same synthesis as 1m from
2h. Product isolated in 53% yield as a clear oil. 1H NMR (400 MHz,
acetone-d6): d = 7.53 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.38 (dd,
J = 8.0, 2.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 3H), 4.74 (s, 2H), 4.22 (q,
J = 7.0 Hz, 2H), 4.12 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.67 (t,
J = 7.8 Hz, 2H), 2.30 (s, 6H), 1.58–1.68 (m, 2H), 1.28–1.40 (m, 8H),
1.26 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H) ppm; 13C NMR
(100 MHz, acetone-d6): d = 168.8, 157.5, 156.3, 134.5, 132.8, 131.6,
128.3, 127.6, 125.1, 115.1, 111.8, 67.0, 65.2, 60.8, 58.5, 45.7, 32.0,
30.6, 30.3, 29.7, 29.3, 22.7, 13.8, 13.7 ppm.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmc.2013.
10.051.
4.1.8.9. Ethyl 2-(1,10-biphenyl-3,30-di-n-heptyl-40-[2-(dimethyl-
References and notes
amino)ethoxy]-4-oxy) acetate (1i).
Same synthesis as 1m
from 2i. Product isolated in 72% yield as a clear oil. 1H NMR
(400 MHz, acetone-d6): d = 7.33–7.44 (m, 4H), 6.97 (d, J = 8.0 Hz,
1H), 6.89 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 4.22 (q, J = 6.8 Hz, 2H),
4.12 (t, J = 6.2 Hz, 2H), 2.70–2.77 (m, 4H), 2.67 (t, J = 8.0 Hz, 2H),
1.59–1.72 (m, 4H), 1.30–1.43 (m, 16H), 1.27 (t, J = 7.2 Hz, 3H),
0.89 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, acetone-d6):
d = 168.8, 156.2, 155.3, 134.2, 133.2, 131.8, 131.6, 128.4, 128.3,
125.1, 124.9, 111.9, 111.8, 66.9, 65.4, 60.8, 58.5, 45.6, 32.0, 32.0,
30.6, 30.5, 30.3, 30.2, 29.7, 29.7, 29.3, 29.3, 22.7, 22.7, 13.8, 13.7,
13.7 ppm.
1. Cummings, C. G.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2010, 14, 341.
2. Fry, D. C. Curr. Protein Pept. Sci. 2008, 9, 240.
3. Sattler, M. L. H.; Nattesheim, D.; Meadoes, R. P.; Harlan, J. E.; Eberstadt, M.;
yoon, H. S.; Shuker, S. B.; Change, B. S.; Minn, A. J.; Thompson, C. B.; Fesik, S. W.
Science 1997, 275, 983.
4. Kussie, P. H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.; Levine, A. J.;
Pavletich, N. Science 1996, 274, 948.
5. Rodriguez, A. L. T.; Tamrazi, A.; Collins, L.; Katzenellenbogen, J. A. J. Med. Chem.
2004, 47, 600.
6. Scott, J. E. Biochemistry 1987, 12, 318.
7. Nolan, W. P.; Ratcliffe, R.; Rees, D. C. Tetrahedron Lett. 1992, 33, 6879.
8. Yin, H. L.; Lee, G.; Sedey, K. A.; Kutzki, O.; Park, H. S.; Orner, B. P.; Ernst, J. T.;
Wang, H. G.; Sebti, S. M.; Hamilton, A. D. J. Am. Chem. Soc. 2006, 127, 10191.
9. Parent, A. A.; Gunther, J. R.; Katzenellenbogen, J. A. J. Med. Chem. 2009, 51, 6512.
10. Caboni, L.; Lloyd, D. G. Med. Res. Rev. 2013, 33, 1081.
11. Williams, A. B.; Weiser, P. T.; Hanson, R. N.; Gunther, J. R.; Katzenellenbogen, J.
A. Org. Lett. 2009, 11, 5370.
4.1.8.10. Ethyl 2-(1,10-biphenyl-3-(naphthalen-2-yl)methyl-40-
[2-(dimethylamino)ethoxy]-4-oxy) acetate (1j).
Same syn-
12. Savkur, R. S.; Burris, T. P. J. Peptide Res. 2004, 63, 207.
13. Weiser, P. T.; Williams, A. B.; Chang, C.-Y.; McDonnell, D. P.; Hanson, R. N.
Bioorg. Med. Chem. Lett. 2012, 22, 6587.
14. Ishar, MPS.; Singh, G.; Signh, S.; Sreenivasan, K. K.; Sign, G. Bioorg. Med. Chem.
Lett. 2006, 16, 1366.
15. Beaulieu, P. L.; Gillard, J.; Bykowski, D.; Brochu, C.; Dansereau, N.; Duceppe, J.;
Hache, B.; Jakalian, A.; Lagace, L.; LaPlante, S.; McKercher, G.; Moreau, E.;
Perreault, S.; Stammers, T.; Thauvette, L.; Warrington, J.; Kukolj, G. Bioorg. Med.
Chem. Lett. 2006, 16, 4987.
16. Tang, G.; Ding, K.; Nikolovska-Coleska, Z.; Yang, C.; Qui, S.; Shangary, S.; Wang,
R.; Guo, J.; Gao, W.; Meagher, J.; Stuckey, J.; Krajewski, K.; Jiang, S.; Roller, P. P.;
Wang, S. J. Med. Chem. 2007, 50, 3163.
17. Khodaei, M. M.; Bahrami, K.; Shahbazi, F. Chem. Lett. 2008, 37, 844.
18. Pallavicini, M.; Budriesi, R.; Fumagalli, L.; Ioan, P.; Chiarini, A.; Bolchi, C.;
Ugenti, MP; Colleoni, S.; Gobbi, M.; Valoti, E. J. Med. Chem. 2006, 49, 7140.
19. Valoti, E.; Pallavicini, M.; Villa, L.; Pezzetta, D. J. Org. Chem. 2001, 66, 1018.
20. Agai, B.; Proszenyak, A.; Tarkanyi, G.; Vida, L.; Faigl, F. Eur. J. Org. Chem. 2004,
3623.
thesis as 1m from 2j. Product isolated in 63% yield as a white solid
(mp 90–91 °C). 1H NMR (400 MHz, acetone-d6): d = 7.89 (s, 1H),
7.78–7.84 (m, 3H), 7.57 (dd, J = 8.0, 2.0 Hz, 1H), 7.52 (d, J = 2.4 Hz,
1H), 7.48 (d, J = 8.8 Hz, 2H), 7.38–7.45 (m, 3H), 6.99 (d, J = 8.0 Hz,
1H), 6.96 (d, J = 8.8 Hz, 2H), 4.80 (s, 2H), 4.26 (s, 2H), 4.24 (q,
J = 7.2 Hz, 2H), 4.09 (t, J = 5.8 Hz, 2H), 2.66 (t, J = 5.8 Hz, 2H), 2.26
(s, 6H), 1.27 (t, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, acetone-
d6): d = 168.8, 158.5, 155.3, 139.1, 134.1, 134.2, 133.2, 132.4, 130.6,
128.9, 128.1, 127.9, 127.7, 127.7, 127.7, 127.3, 126.0, 125.6, 125.3,
115.0, 112.4, 66.6, 65.6, 60.9, 58.3, 45.5, 36.1, 13.8 ppm.
4.1.8.11. Ethyl 2-(1,10-biphenyl-30-(naphthalen-2-yl)methyl-40-
[2-(dimethylamino)ethoxy]-4-oxy) acetate (1k).
Same syn-
thesis as 1m from 2k. Product isolated in 44% yield as a clear oil.

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21. Hummel, C. W.; Geiser, A. G.; Bryant, H. U.; Cohen, I. R.; Dally, R. D.; Fong, K. C.;
Frank, S. A.; Hinklin, R.; Jones, S. A.; Lewis, G.; McCann, D. J.; Rudmann, D. G.;
Shepherd, T. A.; Tian, H.; Wallace, O. B.; Wang, M.; Wang, Y.; Dodge, J. A. J. Med.
Chem. 2005, 48, 6772.
23. Ren, Y. J. Med. Chem. 2006, 49, 2829.
24. Ishiyama, T. J. Org. Chem. 1995, 60, 7508.
25. Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem 1997, 62, 6458.
26. Chang, C.-Y.; Norris, J. D.; Fowlkes, D.; Gron, H.; Hamilton, P. T.; Kenan, D. J.;
McDonnell, D. P.; Paige, L. A. Mol. Cell. Biol. 1999, 19, 8226.
22. Punna, S.; Meunier, S.; Finn, M. G. Org. Lett. 2004, 6, 2777.