Modulation of Retinoic Acid Receptor Subtypes by 5- and 8-Substituted (Naphthalen-2-yl)-based Arotinoids

Article abstract of DOI:10.1002/cmdc.201500150

Retinoid receptors (RARs and RXRs) transduce the signals of their natural and synthetic ligands (retinoids and rexinoids) to cellular transcriptional machinery to induce gene programs that control diverse biological and physiological effects on organisms.

Full text of DOI:10.1002/cmdc.201500150

DOI: 10.1002/cmdc.201500150
Full Papers
Modulation of Retinoic Acid Receptor Subtypes by 5- and
8-Substituted (Naphthalen-2-yl)-based Arotinoids
Susana lvarez,[a] Michele Lieb,[b] Claudio Martínez,[a] Harshal Khanwalkar,[b]
Fµtima Rodríguez-Barrios,[a] Rosana lvarez,*[a] Hinrich Gronemeyer,*[b] and
Angel R. de Lera*[a]
Retinoid receptors (RARs and RXRs) transduce the signals of
their natural and synthetic ligands (retinoids and rexinoids) to
cellular transcriptional machinery to induce gene programs
that control diverse biological and physiological effects on or-
ganisms. All-trans-retinoic acid, the natural ligand for RARs, is
used therapeutically for the treatment of acute promyelocytic
leukemia (APL), whereas the synthetic rexinoid bexarotene (a
representative member of the aromatic retinoids or arotinoids)
is approved for the treatment of cutaneous T-cell lymphoma
(CTCL). Other retinoids have found applications in the topical
treatment of skin disorders. In continuation of previous work
on the naphthalene-based arotinoid scaffold, we synthesized
a new series of (3-halo)benzoic acids connected to C5- or C8-
substituted naphthyl rings via (E)-ethenyl and amide and, for
the C5 series, (E)-chalcone linkers. These compounds were
evaluated as RAR modulators in comparison with previously
described dihydronaphthalene arotinoids with the same substi-
tution pattern. Transactivation studies in this series revealed an
absence of synergy between small halogen atoms (F, Cl) at C3
and the groups at C5 or C8, as had been observed on some of
the dihydronaphthalene analogues. Instead, non-halogenated
4-(2-naphthamido)benzoic acid derivatives transactivated
toward the RARb subtype in preference to the paralogues. The
derivatives with bulkier substituents at C8 were characterized
as dual RARb/RARa antagonists, and (E)-4-[(8-(phenylethynyl)-
naphthalene-2-yl)ethenyl]benzoic acid (11 c), with an ethenyl
connector, was shown to be a potent antagonist of RARa.
Introduction
RAR–RXR,[1] the heterodimeric as-
sociation of retinoic acid recep-
tors (RARs, subtypes RARa,b,g)[2]
and retinoic X receptors (RXRs,
subtypes RXRa,b,g)[3] transduce
the signaling of all-trans-retinoic
acid (1; Figure 1), its isomer 9-
cis-retinoic acid (2), and other
natural
retinoids
in
the
embryo[4–6] and throughout the
adult lifespan.[7,8] Binding of
these native retinoids and syn-
thetic analogues to their recep-
Figure 1. Natural RAR ligands (1 and 2) and previously described RAR modulators based on the 5-substituted (4
and 5) and 8-substituted (6) dihydronaphthalene cores inspired by the structure of parent arotinoid TTNPB (3).
tors regulate many important biological networks that affect
[a] Dr. S. lvarez, Dr. C. Martínez, Dr. F. Rodríguez-Barrios, Prof. Dr. R. lvarez,
Prof. Dr. A. R. de Lera
cell growth, proliferation, apoptosis, development, and homeo-
stasis.[9–12] The RAR–RXR heterodimeric functional unit[1,13] pro-
vides a binding interface with other recruited protein com-
plexes that sense the activation status of the receptor(s) en-
coded in the ligand structure, and bind to DNA regulatory ele-
ments in the promoter regions of target genes to modulate
transcription.[14,15] Agonist binding triggers the exchange of co-
repressor (CoR) protein complexes with co-activator (CoA)
complexes and also of chromatin-remodeling enzymes, shifting
the condensed transcriptionally inactive chromatin to the acti-
vated accessible chromatin state, ultimately leading to gene
transcription.[15–18] Both the CoR- and CoA-bound states of the
Departamento de Química Orgµnica, Facultade de Química
Universidade de Vigo, CINBIO and IBI
As Lagoas-Marcosende, 36310 Vigo (Spain)
E-mail: qolera@uvigo.es
rar@uvigo.es
[b] M. Lieb, Dr. H. Khanwalkar, Dr. H. Gronemeyer
Department of Cancer Biology
Institut de GØnetique et de Biologie Moleculaire et Cellulaire
(IGBMC)/CNRS/INSERM/ULP
BP 163, Ilkirch Cedex, C.U. de Strasbourg (France)
E-mail: hinrich.gronemeyer@igbmc.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201500150.
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receptor are exquisitely sensitive to ligand action (as agonists,
antagonists, or inverse agonists) and therefore, to their struc-
ture.[13,19–24] The C-terminal helix H12 of these canonical anti-
parallel twelve-a-helical sandwich structures acts as the posi-
tional interpreter of changes in the receptor. RAR–RXR hetero-
dimers are “non-permissive”, as their functional activation re-
quires agonist binding to RAR, but not to RXR, a phenomenon
called “RXR subordination”.[25,26]
In previous work,[27,28] we reported systematic ligand modifi-
cations at the hydrophobic dihydronaphthalene ring of the stil-
bene-based arotinoid scaffold[29,30] and attempted to correlate
structural changes at the C5 and C8 positions with the activi-
ties of the new ligands in comparison with that of the potent
RAR pan-agonist TTNPB (3).[31] Analogues that were found to
differ in the size/bulk of the C5 group [phenyl, p-tolyl, and
(phenyl)ethynyl] and in the nature of the linker unit (chalcone,
oxime, allylic alcohol) showed intriguing selective modulatory
profiles with particular RAR subtypes. For example, chalcone
4a (R=Ph, Y=O) was characterized as an RAR pan-agonist
that synergized at high concentration selectively with TTNPB-
bound RARa but not RARb or RARg, and thus was described as
an RARa “super-agonist”. Similarly, 4c [R=(phenyl)ethynyl, Y=
Although it represents a minor structural modification with
respect to the dihydronaphthalene cores of ligands 4–6, the
lack of ring conformational mobility in the new arotinoids 7–
12 was expected to differently impact RAR binding site archi-
tecture, thus affecting H12 positioning and the induced co-ac-
tivator recruitment, which are at the basis of receptor activa-
tion.[13,19–24] To allow comparison with series 4–6, we limited
the study to phenyl, p-tolyl, and (phenyl)ethynyl substituents
at the C5 and C8 positions of the naphthalene core. Small hal-
ogen atoms were incorporated at C3 of the benzoic acid termi-
nus, as they showed synergistic effects with bulky groups on
RAR modulatory activity in previous studies.[27] Two- or three-
atom functionalities, including olefin (9,11), amide (10,12),
chalcone (a,b-unsaturated ketone 7) and chalcone oxime (8)
were included as connectors. Herein we present the prepara-
tion and functional studies of the series of C5- and C8-substi-
tuted naphthalene-based arotinoids (compounds 7–12). Ana-
logues with substituents at both the C5- and C8-naphthalene
core positions having olefin and amide connectors have been
reported elsewhere.[32]
O] acted as an RARg “super-agonist” with RARa,b-antagonist Results and Discussion
activity. Moreover, 4b (R=p-tolyl, Y=O) was found to be
a strong RARa,b-selective antagonist without agonist or antag-
onist activities toward RARg.[28]
Chemistry
For the straightforward incorporation of substituents at the
Similar transient transactivation studies indicated very weak
agonistic activities with the RAR subtypes of the positional iso-
mers substituted at C8 [phenyl 6a, p-tolyl 6b, and (phenyl)e-
thynyl 6c], except the series of C3-halogenated derivatives
with a phenyl group at C8 (series 6a; X=F, Cl) which func-
tioned as RARb agonists, as anticipated.[27] We also noticed the
synergy between the C8-naphthyl substituents and the C3-hal-
ogen atoms at the benzoic acid on the functional role of these
stilbene arotinoids (as agonist, partial agonist/antagonist, pure
antagonist, or inverse agonist) with a given RAR subtype. In
general, increasing the size of the halogen decreased the activ-
ity of the ligands relative to their smaller analogues, particular-
ly in the case of RARb.[27]
naphthalene C5-position, the palladium-catalyzed biaryl and
aryl/alkynyl bond construction was selected as synthetic meth-
odology[33] starting from methyl 5-iodonaphthoate (14). Com-
pound 14 was acquired by iodination of methyl naphthoate
(13) at the C5 position with Barluenga’s reagent [bis(pyridi-
ne)iodonium(I) tetrafluoroborate, Ipy2BF4, 1.25 equiv] and tri-
fluoromethanesulfonic (triflic) acid[34] in moderate yield (44%);
it was accompanied by small quantities (3%) of a secondary
product identified as methyl 5,8-diiodo-2-naphthoate.[32] Suzuki
coupling using the commercial phenyl- and p-tolylboronic
acids [Pd(PPh3)4, Na2CO3, THF/H2O] assisted by microwave irra-
diation (1108C, 200 W)[35–38] led, after 10 min, to the corre-
sponding 5-phenyl and 5-p-tolyl derivatives 15a and 15b, re-
spectively (Scheme 1). The structure of 15b was corroborated
by X-ray crystallographic analysis (Supporting Information),
which confirmed the anticipated regioselectivity of the iodina-
tion reaction and thence, the substitution pattern of the series.
These promising biological results prompted us to carry out
a similar comprehensive study of the retinoid receptor transac-
tivation profiles of a new series of arotinoids with naphthalen-
2-yl substructures (compounds 7–12, Figure 2) that differ from
the series 4–6 by the presence
of the fully aromatic naphtha-
lene ring. It was anticipated that
the naphthalene scaffold would
be more easily functionalized
with the desired positional selec-
tivity at C5 and C8 than the di-
hydronaphthalene series of aroti-
noids (compounds 4–6), thus
overcoming the main drawbacks
(lengthy syntheses, >10 steps)
of the synthetic route to the
latter.[27,28]
Figure 2. Novel RAR modulators 7–12 based on the naphthalene core.
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tions using palladium-catalysis
procedures[34] was also chosen as
strategy. Quantitative conversion
of 20 into the corresponding tri-
fluoromethanesulfonate (triflate)
21 was followed by treatment
of the latter with excess
(1.75 equiv) Barluenga’s reagent
(Ipy2BF4) in the presence of triflic
acid,[34] which afforded selective-
ly the 8-iodo derivative 22 in
66% yield. The crystal structure
(Supporting Information) of
amide 32c, described below,
confirmed the substitution of
this series of naphthalenes at
the C8 position.
Scheme 1. Reagents and conditions: a) Ipy2BF4 (1.25 equiv), TfOH, CH2Cl2, 258C, 16 h (14: 44%, methyl 5,8-diiodo-2-
naphthoate: 3%); b) Suzuki reactions: Pd(PPh3)4 (0.1 equiv), PhB(OH)2, or p-TolB(OH)2 (1.5 equiv), Na2CO3
(2.0 equiv), THF/H2O (1:1), MW, 1108C, 5 min (15a: 77%, 15b: 70%); Sonogashira reaction: PdCl2(PPh3)2
(0.02 equiv), CuI (0.04 equiv), ethynylbenzene (2.0 equiv), THF/Et3N (4:1), 258C, 14 h (15c: 81%); c) MeLi (1 equiv),
Me3SiCl (3.0 equiv), THF, À788C, 1 h (16a: 71% brsm, 16b: 98% brsm, 16c: 60%); d) aq. NaOH, MeOH, 258C, 1 h
(7a: 80%, 7b: 70%, 7c: 78%).
Despite the anticipated differ-
ence in reactivity between aryl
Sonogashira coupling[39,40] of 14 with phenylacetylene co-cata-
lyzed by PdCl2(PPh3)2 and copper(I) iodide in THF containing
Et3N afforded the 5-(phenyl)ethynyl derivative 15c in 81%
yield.
iodides and aryl triflates in palladium-catalyzed cross-coupling
reactions,[33] attempts to selectively couple the iodide with
either phenylboronic acid (Suzuki reaction; Pd(PPh3)4, Na2CO3,
608C, 2 h)[42] or phenyl zinc bromide (Negishi reaction modified
The preparation of chalcones started with the low-
temperature (À788C) addition of methyl lithium
(1 equiv) and trimethylsilyl chloride (3 equiv) to esters
15a–c to provide naphthophenones 16a–c, respec-
tively (Scheme 1). The classical Claisen–Schmidt con-
densation of ketones 16a–c with methyl 4-formyl-
benzoate (17) under the conditions described previ-
ously (NaOH in MeOH at 258C),[41] produced concomi-
tantly the saponification of the ester and afforded
the final products 7a–c in good yields. Attempts to
prepare the oximes 8 derived from 7 using hydroxyl-
amine in pyridine at 808C unfortunately led to highly
unstable compounds and complex mixtures upon at-
tempts at purification.
Scheme 2 summarizes the reaction conditions and
yields of the route to the final arotinoids with an eth-
enyl group connecting both aryl rings. Reduction of
naphthoates 15a,b with DIBAL-H at À788C followed
by benzylic oxidation provided aldehydes 18a,b.
Horner–Wadsworth–Emmons condensation of naph-
thaldehydes 18a,b and the phosphonate-stabilized
anions obtained by treatment of benzylphospho-
nates 19a–c[32] with nBuLi in THF in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(DMPU) stereoselectively produced the condensation
compounds as E-isomers (3JHÀH between 16 and
1
18 Hz for the vinyl protons in the H NMR spectra) in
Scheme 2. Reagents and conditions: a) 1. DIBAL-H, CH2Cl2, À788C, 4 h, 2. MnO2, CH2Cl2,
258C, 3 h (18a: 44%, 18b: 57%, 27a: 49%, 27b: 75%, 27c: 66%); b) 1. nBuLi, THF,
DMPU, À788C, 2. KOH, MeOH, 508C, 3 h (9a: 38%, 9b: 48%, 9d: 62%, 9e: 60%, 9g:
good yields.[27] These were used in the next saponifi-
cation step to provide the final arotinoids 9a–h with-
out further purification, due to their ease of isomeri- 60%, 9h: 76%, 11 c: 53%, 11 f: 33%, 11 i: 67%, combined yields); c) Tf2O, pyridine, 47 h
(21: 99%); d) Ipy2BF4, TfOH, CH2Cl2, RT, 22 h (22: 66%); e) Suzuki reactions: Pd(PPh3)4,
zation to the Z isomers.
PhB(OH)2, or p-TolB(OH)2 (1.5 equiv), Na2CO3, THF/H2O (1:1), MW, 1108C, 5 min (23a: 98%,
For preparation of the positional isomers at C8, the
23b: 88%); Sonogashira reaction: PdCl2(PPh3)2 (0.02 equiv), CuI (0.04 equiv), ethynylben-
selective halogenation of commercial 2-naphthol (20,
zene (2.0 equiv), THF/Et3N (4:1), 258C (23c: 69%); f) Pd(OAc)2, Et3N, dppp, CO, DMSO/
Scheme 2) and subsequent CÀC bond-forming reac- MeOH, 708C, 2 h (25a: 67%, 25b: 70%, 25c: 86%).
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by Knochel: Pd2(dba)3 with either dppf or tfp, THF, 258C)[43]
met with little success in the case of 22, with the former lead-
ing to the bis-coupled product, and the latter to recovered
starting material under these conditions. The Sonogashira cou-
pling[38] of phenylacetylene with 22 as described before afford-
ed a 1:4 mixture of the bis- and monosubstituted naphtha-
lenes 24c and 23c, respectively, in quantitative yield, which
could be separated by column chromatography. Triflate 23c
was then converted into the methyl ester 25c by palladium-
catalyzed carbonylation using Pd(OAc)2/dppp, CO, and Et3N,[44]
followed by trapping the intermediate with MeOH. Treatment
with benzylphosphonates 19a–c[32] and saponification led to
arotinoids 11.
For preparation of the amides corresponding to the C5- and
C8-substituted analogues, we selected the amidation of the 4-
halo or 3,4-dihalobenzoates 30a–c with the corresponding
naphthamides 29 and 32 obtained from naphthoic acids 28
and 31 by treatment with EDCI and HOBt in the presence of
NH3 in MeOH.[45] The X-ray crystal structure of 32c confirmed
the regioselectivity of the electrophilic substitution of the
naphthalene derivative 21 and the substitution pattern of the
series. The amidation of aryl halides (Goldberg reaction) has
undergone recent improvements[46,47] that have turned it into
a robust synthetic method,[33] allowing for regioselective cou-
pling of a variety of bi-functionalized substrates.[48–51] The
greater reactivity of the iodine at the C4 position of 30b,c in
the Goldberg reaction with amides 29 and 32 using the opti-
mized conditions developed by Buchwald,[48,52,53] [CuI, (1S,2S)-
cyclohexane-1,2-diamine, and K2CO3 in dioxane at 1408C] pro-
duced the corresponding 4-anilide benzoates, the saponifica-
tion of which led to carboxylic acids 10 and 12, respectively
(Scheme 3).
Scheme 3. Reagents and conditions: a) aq. KOH, MeOH, 608C, 3 h (28a: 80%,
28b: 78%, 31a: 99%, 31b: 98%, 31c: 75%); b) EDCI, HOBt, NH3 (2m in
MeOH), 258C, 5 h (29a: 81%, 29b: 72%, 32a: 62%, 32b: 65%, 32c: 69%);
c) 1. CuI, (1S,2S)-cyclohexane-1,2-diamine, K2CO3, dioxane, 1408C, 17 h, 2. aq.
KOH, MeOH, 608C, 3 h (10a: 57%, 10d: 34%, 10g: 40%, 10b: 51%, 10e:
58%, 10h: 64%, 12a: 50%, 12b: 52%, 12c: 71%, 12i: 32%, 12 f: 57%,
combined yields).
tivity). As anticipated from ligand design, these derivatives
were generally inactive as RXR agonists and could therefore
act as (potentially selective) ligands for the RAR subtypes. Ex-
ceptions are compounds 10g, 12b, and 12a, which exerted
weak-to-moderate RXR agonist activities relative to 9-cis retino-
ic acid 2.
Transcriptional activation studies
To evaluate the effects of the described retinoids on RARa-,
RARb-, RARg-, and RXRb-mediated transactivation, a previously
described reporter assay with genetically engineered HeLa cell
lines[22,29] was used. A single RXR reporter cell line (expressing
the RXRb ligand binding domain (LBD)) is assumed to reveal
the ligand responsiveness as readout for all three RXRs, given
the identity of the amino acids constituting the ligand binding
pockets of the RXR subtypes. The reporter cell lines are engi-
neered to express a fusion protein that comprises the LBD of
the corresponding receptor and the DNA binding domain of
the yeast GAL4 transcription factor. In addition, the cells con-
tain a stably integrated luciferase reporter gene, which is con-
trolled by five Gal4 response elements in front of a b-globin
promoter, the so-called “(17m)5-bG-Luc” construct.[25,54] This re-
porter system is insensitive to endogenous receptors, which
cannot recognize the GAL4 binding site. The transcriptional ac-
tivity of the various compounds was compared with the activi-
ty of the RAR pan-agonist TTNPB 3 and 9-cis-retinoic acid 2
(Figure 1) as positive controls for RAR and RXR, respectively.
The transcriptional data of selected naphthalene-based aroti-
noids with the RAR subtypes and with RXRb are shown in
Figure 3 (agonist activity) and Figures 4 and 5 (antagonist ac-
However, the observed RAR isotype selectivity is generally
low among the tested analogues. The three-atom connector
chalcones did not show activity as agonists. Stilbene arotinoids
with phenyl (9a) and p-tolyl (9b) groups at C5 exhibit similar
moderate-to-weak agonistic activity with RARb and RARg; only
9a and, to a lesser extent, 9b act as RARa agonists. Naphtha-
mides were generally inactive except at higher concentrations
with RARb. The positional isomers with substituents at C8
were characterized, in general, as devoid of RAR agonism (in
particular the analogues with an olefin connector are inactive).
Interestingly, 12a and 12b showed RXR agonistic activities
(Figure 3).
In agreement with the transactivation results, competition
studies between TTNPB (3) or 9-cis-retinoic acid (2) and the
synthesized arotinoids in the C5 series revealed their moderate
activity as RAR antagonists (Figure 4). The stilbene analogues,
which exhibit pan-agonist activity with varying potencies
(Figure 3), display little if any RAR antagonist activity. An excep-
tion is the analogue with a p-tolyl group at C5 (9b) that
showed some RARa antagonism and can be considered
a “mixed” RARa agonist/antagonist (Figures 3 and 4). The ap-
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“super-activation” is likely due to its dual RAR and RXR agonist
activities, as it can act as agonist for endogenous RXRs and
RARs to synergize with the primary ligand in the antagonist
assays. In support of this interpretation, the synergistic effect is
most pronounced with 10g, and no synergy is observed for
the other naphthamides of this series, which do not exhibit
RAR, RXR agonist activity.
With regard to the positional isomers, 12 f showed signifi-
cant antagonistic activities with RARb and is therefore a mixed
agonist/antagonist for this subtype. Moreover, 12b behaved as
pan-antagonist of the RAR subtypes (Figure 5). Remarkably,
11 c was characterized as a potent and selective antagonist of
RARa (Figure 4).
The selectivity of 11 c with RARa was unanticipated, as it
does not feature the amide connector common to many of
the described selective modulators of this subtype, or halo-
gens at C2/C6 of the benzoic acid, which are deemed structur-
al factors responsible for their subtype selectivity.[55] The great-
er planarity of the hydrophobic region and thus the better-de-
fined orientation of the C8 substituents in this series appears
to contribute to the discrimination of RARa versus RARb and
RARg exhibited by this ligand. It is also noted that the retinoid
with the same substitution at C8 in the dihydronaphthalene
series (compound 6c) is an inverse agonist of the three sub-
types.[20]
Compound 11 c was chosen for docking studies in an at-
tempt to correlate structure with activity. A model of the
RARa–11 c complex was constructed using the X-ray crystal
structure of the receptor bound to antagonist BMS195,614 at
2.50 Š resolution (PDB code: 1DKF).[56] The structure of human
RARb complexed with TTNPB (PDB code: 1XAP)[57] provided
a template for the highly homologous 210–216 region of
RARa, which is disordered in the antagonist-bound conforma-
tion crystal structure of RARa. Ligand 11 c was positioned in
the active site on the basis of the canonical positions revealed
by the crystal structures.[57–61] Preferred docking sites for func-
tional groups were evaluated with the program GRID,[62] which
assisted in the selection of binding modes, by following a previ-
ously described protocol.[27]
The resulting model showed the (phenyl)ethynyl moiety run-
ning almost perpendicular to the agonistic part of the ligand
(buried in a predominantly hydrophobic pocket; Figure 6). To
assess the feasibility of the proposed binding orientation and
to study the mutual adaptation between RARa and the reti-
noid ligand, the complex was refined by energy minimization,
and its dynamic behavior was simulated with unrestrained mo-
lecular dynamics (MD).[27] After the equilibration period, the
progression of the root-mean-square deviations (RMSD) of the
coordinates of the Ca atoms with respect to the initial struc-
ture showed a notably stable behavior, reflecting that the over-
all architecture of the protein was preserved for the whole
length of the simulation.
Figure 3. In vivo dose–response luciferase reporter assays revealing the ago-
nist activities (at RAR subtypes and RXRb) of selected naphthalene arotinoids
described herein, relative to agonists TTNPB (compound 3, Figure 1) and 9-
cis-retinoic acid (compound 2, Figure 1). See the Experimental Section for
details on the assay system. Data are derived from at least three independ-
ent experiments; standard deviations are indicated.
parent selective RARa antagonism is most likely due to it
being a weaker agonist for RARa than for RARb and RARg. As
was the case for the parent compound 10a (X=H), the other
naphthamides generally showed no antagonistic activities,
which is most likely due to inefficient binding. The only excep-
tion was the chlorine derivative 10g, which showed weak
RARb,g agonism and interestingly substantial RXR agonist ac-
tivity as well (Figure 3). This compound exhibited an apparent
synergy with both TTNPB and 9-cis retinoic acid in tests for
RAR or RXR antagonist activity, respectively (Figure 4). This
The evolution of the RMSD of 11 c with respect to the initial
structure shows a value lower than 0.5 Š (Supporting Informa-
tion). An analysis of the van der Waals and electrostatic contri-
butions of residues to binding (Supporting Information) indi-
cate four consistently favorable and large van der Waals inter-
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Figure 4. In vivo dose–response luciferase reporter assays revealing the RAR subtype and RXRb antagonist activities of the retinoids synthesized in this study.
The agonists TTNPB (compound 3, Figure 1) and 9-cis-retinoic acid (compound 2, Figure 1) were challenged with increasing amounts of the various retinoids,
and luciferase activity was monitored. The decreased activity relative to TTNPB or 9-cis-retinoic acid reveals antagonism. See the Experimental Section for fur-
ther details on the assay system. Data are derived from at least three independent experiments; standard deviations are indicated.
actions with Phe228, Ser232, Leu269, and Met406; the positive
van der Waals interaction with Asp288 was also notable. On
the other hand, favorable electrostatic interactions were estab-
lished with Arg272, Ser287, and Arg394, whereas unfavorable
interactions were measured with Glu230 and Asp288.
10g exhibited the ability to modestly activate both RAR and
RXR, and this “super-activation” is likely due to synergy. Finally,
the (E)-4-(2-(naphthalen-2-yl)vinyl)benzoic acid with a C8’’-
(phenyl)ethynyl substituent (11 c) is a potent and selective
RARa antagonist, and MD studies are consistent with this be-
havior.
Docking poses were also obtained for the complex of RARa
with 12b. In this case, two solutions were found (Supporting
Information), with different positioning of the antagonist p-
tolyl group and the receptor, which might explain its de-
creased antagonistic potential.
Relative to the dihydronaphthalene series described before,
the greater planarity of the naphthalene analogues results in
rigidified ligands that cannot easily adapt to restrictive binding
pockets. The SAR studies reported herein and elsewhere[32] for
the naphthalene stilbenoid class of arotinoids, together with
those reported for the 5,6-dimethyl-5,6-dihydronaphthalene
analogues[27,28] provide significant advances to our understand-
ing of the modulation of retinoid receptors with small mole-
cules.
Conclusions
To summarize, C5- and C8-substituted (E)-4-(2-(naphthalen-2-
yl)vinyl)benzoic acids, the corresponding 4-(2-naphthamido)-
benzoic acids with the same substitution pattern, and the chal-
cones of the former series were prepared and evaluated as po-
tential RAR subtype-selective antagonists. Transactivation stud-
ies in this series revealed a variety of modulation modes that
are not easily rationalized. In general, given the increase in size
of the naphthalene ring at the putative hydrophobic pocket,
the synthesized ligands lack agonistic profiles. Most of these
analogues display antagonistic activity, potently in a few cases
(12b, 11 c). There is also a remarkable absence of RAR-subtype
selectivity, despite the fact that similar ligands with dihydro-
naphthalene scaffolds are endowed with subtype selectivity
profiles. Selected ligands were characterized as showing dual
or mixed agonism/antagonism for a particular subtype. Amide
Experimental Section
Chemistry: general procedures[28]
For fluorine-containing compounds, multiplicities and 13C–19F cou-
pling constants are given in parentheses after the 13C–1H multiplici-
ties assigned by DEPT.
Methyl 5-iodo-2-naphthoate 14. To a solution of methyl 2-naph-
thoate 13 (1.1 g, 5.86 mmol) in CH2Cl2 (150 mL) were added Ipy2BF4
(1.82 g, 7.33 mmol) and TfOH (0.66 mL, 5.86 mmol), and the mix-
ture was stirred at 258C for 22 h. A saturated aqueous solution of
Na2S2O3 was added (100 mL), and the mixture was extracted with
CH2Cl2 (3”200 mL). The combined organic layers were dried
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Figure 5. In vivo dose–response luciferase reporter assays revealing the RAR
subtype antagonist activity of retinoid 12b. The agonist TTNPB (compound
3, Figure 1) was challenged with increasing amounts of 12b, and luciferase
activity was determined. The decreased activity relative to TTNPB reveals an-
tagonism. See the Experimental Section for further details on the assay
system. Data are derived from at least three independent experiments; stan-
dard deviations are indicated.
(Na2SO4), and the solvent was evaporated. The residue was purified
by column chromatography (C18 silica gel, 70:30 CH3CN/H2O) to
afford 0.80 g (44%) of 14 as a white solid and 0.08 g (3%) of
methyl 5,8-diiodo-2-naphthoate as a white solid. Data for 14: mp:
1
758C (hexane/EtOAc); H NMR (400.16 MHz, CDCl3): d=8.55 (s, 1H),
Figure 6. Top: Proposed docking site for 11 c in the RARa-bound antagonist
conformation. The Ca trace of the receptor is shown as a green ribbon. The
side chains of Phe228, Glu230, Ser232, Leu269, Arg272, Ser287, Asp288,
Arg394, and Met406 are shown as sticks, with carbon atoms rendered in
green. Ligands are also displayed as sticks, but with carbon atoms in grey.
Bottom: Close-up view of the LBP of RARa bound to ligands 11 c (green)
and BMS195,614 (grey).
8.21 (d, J=7.4 Hz, 1H), 8.2–8.1 (m, 2H), 7.97 (d, J=8.2 Hz, 1H), 7.17
(t, J=7.7 Hz, 1H), 4.02 ppm (s, 3H); 13C NMR (100.62 MHz, CDCl3):
d=166.5 (s), 139.4 (d), 136.1 (s), 132.9 (s), 132.2 (d), 131.3 (d), 130.1
(d), 127.9 (s), 127.4 (d), 126.7 (d), 99.0 (s), 52.2 ppm (q); MS (EI): m/z
(%) 312 [M]+, (100), 281 (80), 253 (31), 127 (16), 126 (52); HRMS
(EI): calcd for C9H12IO2: 311.9647, found: 311.9645; IR (NaCl): n˜ =
2922 (w, CÀH), 2851 (w, CÀH), 1702 (s, C=O), 1278 cmÀ1 (s); Anal.
calcd for C12H9IO2: C 46.18, H 2.91, found: C 46.19, H 2.91.
95:5 hexane/EtOAc) to afford 0.33 g (77%) of 15a as a yellow oil.
1H NMR (400.16 MHz, CDCl3): d=8.71 (d, J=1.6 Hz, 1H), 8.0 (dd, J=
8.9, 1.6 Hz, 1H), 7.97 (t, J=7.9 Hz, 2H), 7.7–7.6 (m, 1H), 7.6–7.5 (m,
6H), 3.99 ppm (s, 3H); 13C NMR (100.62 MHz, CDCl3): d=167.1 (s),
140.2 (s), 140.0 (s), 133.6 (s), 132.9 (s), 131.3 (d), 129.9 (d, 2”), 129.1
(d), 128.9 (d), 128.3 (d, 2”), 127.5 (d), 127.2 (s), 126.3 (d), 126.1 (d),
125.2 (d), 52.2 ppm (q); HRMS (ESI+): calcd for C18H15O2 [M+H]+:
263.10722, found: 263.1066; IR (NaCl): n˜ =3056 (w, CÀH), 3024 (w,
CÀH), 2949 (w, CÀH), 2925 (w, CÀH), 2853 (w, CÀH), 1719 cmÀ1 (s,
C=O).
Methyl 5-phenyl-2-naphthoate 15a. General procedure for Suzuki
cross-coupling. To a solution of methyl 5-iodo-2-naphthoate 14
(0.5 g, 1.61 mmol) in THF/H2O (5 mL, 1:1 v/v) were added Pd(PPh3)4
(0.19 g, 0.16 mmol), PhB(OH)2 (0.29 g, 2.41 mmol), and Na2CO3
(0.34 g, 3.22 mmol), and the mixture was heated under microwave
irradiation (60W, 10 min, 110 8C). H2O was added (5 mL), and the
mixture was extracted with EtOAc (3”20 mL). The combined or-
ganic layers were dried (Na2SO4), and the solvent was evaporated.
The residue was purified by column chromatography (silica gel,
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Methyl 5-(Phenylethyn-1-yl)-2-naphthoate 15c. General procedure
for Sonogashira coupling. To a solution of methyl 5-iodo-2-naph-
thoate 14 (0.25 g, 0.80 mmol) in THF/Et3N (15 mL, 4:1 v/v) was
added PdCl2(PPh3)2 (0.011 g, 0.016 mmol), CuI (0.006 g,
0.032 mmol), and ethynylbenzene (0.16 g, 1.6 mmol), and the mix-
ture was stirred at 258C for 14 h. A saturated aqueous solution of
NH4Cl was added (20 mL) and the mixture was extracted with
CH2Cl2 (3”50 mL). The combined organic layers were dried
(Na2SO4), and the solvent was evaporated. The residue was purified
by column chromatography (silica gel, 95:5 hexane/EtOAc) to
5-Phenyl-2-naphthaldehyde 18a. General procedure for the two-
step reduction of esters and oxidation of alcohols. To a cooled
(À788C) solution of 5-phenyl-2-naphthoate 15a (0.1 g, 0.42 mmol)
in THF (6 mL) was added DIBAL-H (1.26 mL, 1m in hexane,
1.26 mmol), and the mixture was stirred for 4 h. The mixture was
treated with a 10% aqueous HCl solution and extracted with
EtOAc (3”10 mL). The combined organic layers were dried
(Na2SO4), and the solvent was evaporated. The residue was purified
by column chromatography (silica gel, 90:10 hexane/EtOAc) to
afford 0.064 g of the corresponding alcohol, which was used with-
out purification. To a cooled (08C) solution of the alcohol obtained
above (0.064 g, 0.27 mmol) in CH2Cl2 (6 mL) was added MnO2
(0.42 g, 4.86 mmol), and the mixture was stirred for 3 h at 258C.
The reaction mixture was filtered through Celite, and the residue
was purified by column chromatography (silica gel, 95:5 hexane/
EtOAc), to afford 0.043 g (44%) of 18a as a yellow oil. 1H NMR
(400.13 MHz, CDCl3): d=10.19 (s, 1H), 8.41 (s, 1H), 8.04 (d, J=
8.5 Hz, 2H), 7.92 (d, J=8.9 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.62 (t,
J=6.8 Hz, 1H), 7.6–7.5 ppm (m, 5H); 13C NMR (100.16 MHz, CDCl3):
d=192.3 (d), 140.7 (s), 139.9 (s), 134.8 (d), 134.6 (s), 133.9 (s), 133.1
(s), 130.1 (d), 130.0 (d, 2”), 129.3 (d), 128.5 (d, 2”), 127.7 (d), 127.3
(d), 126.7 (d), 122.9 ppm (d); MS (FAB+): m/z (%) 233 [M+ +1],
(100), 232 [M]+, (85), 205 (45), 204 (32), 203 (59), 202 (64), 191 (21),
189 (29), 167 (37) 166 (27), 165 (36); HRMS (FAB+): calcd for
C17H13O [M+H]+: 233.0966, found: 233.0969; IR (NaCl): n˜ =3056 (w,
CÀH), 3025 (w, CÀH), 2818 (w, CÀH), 1694 cmÀ1 (s, C=O).
1
afford 0.19 g (81%) of 15c as a colorless oil. H NMR (400.16 MHz,
CDCl3): d=8.65 (s, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.8 Hz,
1H), 7.9–7.8 (m, 2H), 7.7–7.6 (m, 2H), 7.53 (dd, J=8.3, 7.1 Hz, 1H),
7.4–7.3 (m, 4H), 4.03 ppm (s, 3H); 13C NMR (100.62 MHz, CDCl3):
d=167.2 (s), 135.4 (s), 132.5 (s), 132.4 (d), 132.3 (s), 131.7 (d, 2”),
131.4 (d), 130.0 (d), 129.1 (d), 128.5 (d, 2”), 126.6 (d, 128.3 (s),
128.0 (s), 126.1 (d), 126.2 (d), 94.8 (s), 86.9 (s), 52.5 ppm (q); MS (EI):
m/z (%) 286 [M]+, (100), 255 (52), 227 (24), 226 (77), 225 (11), 224
(14); HRMS (EI): calcd for C20H14O2 [M]+: 286.0994, found: 286.1004;
IR (NaCl): n˜ =3055 (w, CÀH), 2951 (m, CÀH), 2870 (w, CÀH),
1721 cmÀ1 (s, C=O).
(E)-1-(5-Phenylnaphthalen-2-yl)ethan-1-one 16a. General proce-
dure for the transformation of methyl esters into ketones. To a solu-
tion of methyl 5-phenyl-2-naphthoate 15a (0.5 g, 1.92 mmol) in
THF (16 mL) was added Me3SiCl (1.22 mL, 9.6 mmol) at À788C.
After 15 min MeLi (1.5 mL, 1.6m in Et2O, 2.4 mmol) was added, and
the reaction mixture was stirred for 5 h at À788C. At 08C H2O
(5 mL) was added followed by a 1m aqueous solution of HCl
(5 mL), and the mixture was extracted with EtOAc (3”10 mL). The
combined organic layers were dried (Na2SO4), and the solvent was
evaporated. The residue was purified by column chromatography
(silica gel, 98:2 hexane/EtOAc) to afford 0.25 g (53%) of 16a as
a pale-yellow solid and 0.13 g (26%) of recovered 15a. 1H NMR
(400.16 MHz, CDCl3): d=8.55 (s, 1H), 8.0–7.9 (m, 3H), 7.7–7.5 (m,
7H), 2.77 ppm (s, 3H); 13C NMR (100.62 MHz, CDCl3): d=198.1 (s),
140.4 (s), 140.1 (s), 134.3 (s), 133.8 (s), 132.9 (s), 130.5 (d), 130.0 (d,
2”), 129.5 (d), 129.2 (d), 128.5 (d, 2”), 127.6 (d), 126.7 (d), 126.4 (d),
124.0 (d), 26.8 ppm (q); MS (EI): m/z (%) 247 [M+1]+, (8), 246 ([M]+
, 56), 231 (100), 203 (63), 202 (96), 201 (16), 200 (16); HRMS (EI):
calcd for C18H14O ([M]+), 246.1045, found: 246.1055; IR (NaCl): n˜ =
3056 (w, CÀH), 3024 (w, CÀH), 2965 (w, CÀH), 2924 (w, CÀH), 2855
(w, CÀH), 1680 cmÀ1 (s, C=O).
(E)-4-[(5-Phenylnaphthalen-2-yl)ethenyl]benzoic acid 9a. General
procedure for the Horner–Wadsworth–Emmons reaction and hydroly-
sis of esters. To a cooled (08C) solution of methyl 4-(diethoxyphos-
phoryl)benzoate 19a (0.074 g, 0.26 mmol) in THF (2 mL) were
added DMPU (0.5 mL) and nBuLi (0.17 mL, 1.43m in hexane,
0.25 mmol), and the mixture was stirred for 30 min. The reaction
was cooled to À788C, a solution of 5-phenyl-2-naphthaldehyde
18a (0.03 g, 0.13 mmol) in THF (2 mL) was added, and the mixture
was stirred at 258C for 12 h. A saturated aqueous solution of NH4Cl
was added, and the mixture was extracted with EtOAc (3”10 mL).
The combined organic layers were washed with H2O (3”30 mL)
and brine (3”30 mL), dried (Na2SO4), and the solvent was evapo-
rated. The residue was purified by column chromatography (silica
gel, 95:5 hexane/EtOAc), to produce 0.03 g of the ester as a white
solid, which was not purified. To a solution of the ester obtained
above (0.03 g, 0.082 mmol) in MeOH (9 mL) was added a 2m aque-
ous solution of KOH (1.36 mL, 2m in H2O, 2.72 mmol), and the mix-
ture was heated at 508C for 3 h. The reaction was cooled to room
temperature, CH2Cl2 (10 mL) and brine (10 mL) were added, and
the layers were separated. The aqueous layer was treated with
a 10% aqueous HCl solution until ~pH 3 was reached, and the
mixture was extracted with CH2Cl2 (3”20 mL). The combined or-
ganic layers were dried (Na2SO4), and the solvent was removed.
The residue was purified by column chromatography (silica gel,
90:10 CH2Cl2/MeOH) 0.017 g (38% combined) of 9a as a white
(E)-4-[3-Oxo-3-(5-phenylnaphthalen-2-yl)prop-2-en-1-yl]benzoic
acid 7a. General procedure for Claisen–Schmidt condensation with
saponification. To a solution of 1-(5-phenylnaphthalen-2-yl)ethan-1-
one 16a (23.5 mg, 0.09 mmol) in MeOH (2 mL) were added ethyl 4-
formylbenzoate 17 (14.7 mg, 0.090 mmol) and an aqueous solution
of NaOH (1m, 0.6 mL), and the reaction mixture was stirred at
room temperature for 18 h. The reaction mixture was concentrat-
ed, acidified with a 1m aqueous solution of HCl and extracted with
CH2Cl2 (5”). The combined organic layers were dried (Na2SO4), and
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, 95:5 CH2Cl2/MeOH) to afford 27 mg
1
solid; mp: 2008C (MeOH); H NMR (400.16 MHz, CDCl3): d=8.09 (d,
J=8.3 Hz, 2H), 7.9–7.7 (m, 6H), 7.59 (d, J=8.3 Hz, 2H), 7.5–7.4 (m,
6H), 7.17 ppm (d, J=16.2 Hz, 1H); 13C NMR (100.62 MHz, CDCl3):
d=170.9 (s), 142.7 (s), 140.5 (s), 137.6 (s), 137.1 (s), 134.3 (s), 133.7
(s), 132.2 (d), 132.1 (d), 131.8 (s), 130.7 (d, 2”), 130.1 (d), 130.0 (d),
129.1 (d), 128.9 (d), 128.4 (d), 127.7 (d), 127.5 (d), 126.4 (d, 2”),
126.2 (d), 125.9 (d), 122.9 (d), 122.8 ppm (d); HRMS (ESI+): calcd for
C25H19O2 [M+H]+: 351.1380, found: 351.1377; IR (NaCl): n˜ =3600–
3000 (br, OÀH), 2961 (w, CÀH), 2922 (w, CÀH), 2850 (w, CÀH),
1
(80%) of 7a as a yellow solid. H NMR (400.16 MHz, (CD3)2CO): d=
9.01 (d, J=1.9 Hz, 1H), 8.3–8.2 (m, 5H), 8.0–7.9 (m, 4H), 7.93 (d, J=
15.9 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.6–
7.5 ppm (m, 4H); 13C NMR (100.62 MHz, CDCl3): d=188.6 (s), 142.4
(d), 140.3 (s), 140.0 (s), 139.5 (s), 135.2 (s), 133.5 (s), 133.3 (s), 131.9
(s), 130.9 (d), 130.2 (d), 130.1 (d, 2”), 129.9 (d, 2”), 129.6 (d), 129.5
(d), 128.6 (d, 2”), 128.5 (d, 2”), 127.6 (d), 126.5 (d), 126.3 (d), 124.4
(d), 124.2 ppm (d); HRMS (ESI+): calcd for C26H19O3 [M+H]+:
379.1328, found: 379.1325.
1682 cmÀ1 (s, C=O); purity: 92% (HPLC–UV, Sunfire C18, 1 mLminÀ1
95:5 CH3CN/H2O, tR =25 min).
,
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(E)-3-Fluoro-4-[(5-phenylnaphthalen-2-yl)ethenyl]benzoic
acid
(0.036 g, 0.093 mmol) and KOH (1.54 mL, 2m in H2O, 3.06 mmol) in
MeOH (9 mL), afforded, after purification by column chromatogra-
phy (silica gel, 90:10 CH2Cl2/MeOH), 0.022 g (48% combined) of 9b
9d. Following the general procedure for the Horner–Wadsworth–
Emmons reaction, the reaction of methyl 4-(diethoxyphosphoryl)-3-
fluorobenzoate 19b (0.079 g, 0.26 mmol), DMPU (0.5 mL), nBuLi
(0.17 mL, 1.43m in hexane, 0.25 mmol) and 5-phenyl-2-naphthalde-
hyde 18a (0.03 g, 0.13 mmol) in THF (4 mL) afforded, after purifica-
tion by column chromatography (silica gel, 95:5 hexane/EtOAc),
0.036 g of the ester as a white solid. Following the general proce-
dure for the hydrolysis of esters, the reaction of the ester obtained
above (0.036 g, 0.094 mmol) and KOH (1.6 mL, 2m in H2O,
3.2 mmol) in MeOH (10 mL) afforded, after purification by column
chromatography (silica gel, 90:10 CH2Cl2/MeOH), 0.03 g (62% com-
bined) of 9d as a white solid; mp: 1898C (MeOH); 1H NMR
(400.16 MHz, [D6]DMSO): d=8.20 (s, 1H), 8.0–7.9 (m, 3H), 7.81 (d,
J=8.9 Hz, 2H), 7.7–7.6 (m, 2H), 7.57 (d, J=4.2 Hz, 1H), 7.54 (d, J=
7.1 Hz, 1H), 7.5–7.4 (m, 3H), 7.47 (d, J=15.1 Hz, 1H), 7.44 ppm (d,
J=9.5 Hz, 1H); 13C NMR (100.62 MHz, [D6]DMSO): d=166.5 (s),
1
as a white solid; mp: 2388C (MeOH); H NMR (400.13 MHz, CDCl3/
CD3CO2D): d=8.11 (d, J=8.3 Hz, 2H), 8.0–7.8 (m, 4H), 7.71 (dd, J=
8.9, 1.4 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.6–7.5 (m, 4H), 7.4–7.3 (m,
2H), 7.28 (d, J=16.2 Hz, 1H), 2.50 ppm (s, 3H); 13C NMR
(100.16 MHz, CDCl3/CD3CO2D): d=171.8 (s), 142.8 (s), 140.3 (s),
137.6 (s), 137.1 (s), 134.0 (s), 133.9 (s), 131.6 (d), 131.5 (s), 130.7 (d,
2”), 129.9 (d, 2”), 129.1 (d, 2”), 127.9 (s), 127.8 (d), 127.7 (d), 127.6
(d), 127.4 (d), 126.7 (d), 126.4 (d, 2”), 126.1 (d), 123.4 (d), 21.3 ppm
(q); HRMS (ESI+): calcd for C26H21O2 [M+H]+: 365.1536, found:
365.1536; IR (NaCl): n˜ =3600–3000 (br, OÀH), 3019 (w, CÀH), 2921
(w, CÀH), 1677 cmÀ1 (s, C=O); purity: 97% (HPLC–UV, Sunfire C18,
1 mLminÀ1, 95:5 CH3CN/H2O, tR =25 min).
(E)-3-Fluoro-4-[(5-p-tolylnaphthalen-2-yl)ethenyl]benzoic
acid
1
159.7 (s) (d, JCÀF =249.0 Hz), 140.3 (s), 140.0 (s), 134.4 (s), 134.1 (s),
9e. Following the general procedure for the Horner–Wadsworth–
Emmons reaction, the reaction of methyl 4-(diethoxyphosphoryl)-3-
fluorobenzoate 19b (0.097 g, 0.32 mmol), DMPU (0.6 mL), nBuLi
(0.20 mL, 1.6m in hexane, 0.31 mmol) and 5-p-tolyl-2-naphthalde-
hyde 18b (0.04 g, 0.16 mmol) in THF (5 mL) afforded, after purifica-
tion by column chromatography (silica gel, 95:5 hexane/EtOAc),
0.048 g of the ester as a white solid. Following the general proce-
dure for the hydrolysis of esters, the reaction of the ester obtained
above (0.04 g, 0.1 mmol) and KOH (1.65 mL, 2m in H2O, 3.30 mmol)
in MeOH (10 mL) afforded, after purification by column chromatog-
raphy (silica gel, 90:10 CH2Cl2/MeOH), 0.031 g (60% combined) of
9e as a white solid; mp: 2308C (MeOH); 1H NMR (400.13 MHz,
CDCl3): d=8.04 (s, 1H), 8.0–7.9 (m, 2H), 7.93 (d, J=7.2 Hz, 1H),
7.9–7.8 (m, 2H), 7.77 (d, J=8.7 Hz, 1H), 7.6–7.4 (m, 4H), 7.43 (d, J=
8.1 Hz, 2H), 7.37 (d, J=7.6 Hz, 2H), 2.50 ppm (s, 3H); 13C NMR
(100.16 MHz, CDCl3): d=159.9 (s) (d, 1JCÀF =250.1 Hz), 140.3 (s),
133.8 (d) (d, 3JCÀF =4.6 Hz), 132.0 (s) (d, 3JCÀF =7.4 Hz), 131.2 (s),
2
130.3 (d), 130.2 (d, 2”), 129.4 (s) (d, JCÀF =12.1 Hz), 129.0 (d, 2”),
128.4 (d) (d, JCÀF =6.9 Hz), 128.1 (d), 128.0 (d), 127.9 (d), 127.8 (d),
126.5 (d) (d, 2JCÀF =35.7 Hz), 126.1 (d), 124.5 (d), 120.5 (d),
117.0 ppm (d) (d, JCÀF =23.4 Hz); HRMS (ESIÀ): calcd for C25H15FO2
([MÀH]À), 367.1140, found: 367.1138; IR (NaCl): n˜ =3600–3000 (br,
OÀH), 2954 (w, CÀH), 2924 (s, CÀH), 2853 (w, CÀH), 1684 cmÀ1 (s,
C=O); purity: 95% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/
H2O, tR =25 min).
(E)-3-Chloro-4-[(5-phenylnaphthalen-2-yl)ethenyl]benzoic
acid
9g. Following the general procedure for the Horner–Wadsworth–
Emmons reaction, the reaction of methyl 4-(diethoxyphosphoryl)-3-
chlorobenzoate 19c (0.083 g, 0.26 mmol), DMPU (0.5 mL), nBuLi
(0.17 mL, 1.43m in hexane, 0.25 mmol) and 5-phenyl-2-naphthalde-
hyde 18a (0.03 g, 0.13 mmol) in THF (4 mL) afforded, after purifica-
tion by column chromatography (silica gel, 95:5 hexane/EtOAc),
0.036 g of the ester as a white solid. Following the general proce-
dure for the hydrolysis of esters, the reaction of the ester obtained
above (0.036 g, 0.09 mmol) and KOH (1.5 mL, 2m in H2O, 3.0 mmol)
in MeOH (10 mL) afforded, after purification by column chromatog-
raphy (silica gel, 90:10 CH2Cl2/MeOH), 0.03 g (60% combined) of
9g as a white solid; mp: 2048C (MeOH); 1H NMR (400.16 MHz,
[D6]DMSO): d=8.21 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.99 (d, J=
8.2 Hz, 1H), 7.96 (d, J=1.4 Hz, 1H), 7.91 (dd, J=8.3, 1.2 Hz, 1H),
7.87 (d, J=15.3 Hz, 1H), 7.84 (d, J=15.3 Hz, 1H), 7.7–7.6 (m, 4H),
7.55 (d, J=7.2 Hz, 2H), 7.50 (d, J=7.2 Hz, 2H), 7.45 ppm (d, J=
6.9 Hz, 1H); 13C NMR (100.62 MHz, [D6]DMSO): d=166.4 (s), 140.2
(s), 140.0 (s), 139.2 (s), 134.3 (d), 134.2 (s), 134.1 (s), 132.7 (s), 131.7
(s), 131.2 (s), 130.8 (d), 130.2 (d, 2”), 129.0 (d, 2”), 128.6 (d), 128.5
(d), 128.4 (d), 128.0 (d), 127.9 (d), 127.4 (d), 126.8 (d), 126.5 (d),
124.6 (d), 123.9 ppm (d); HRMS (ESIÀ): calcd for C25H1535ClO2
([MÀH]À), 383.0844, found: 383.0843; IR (NaCl): n˜ =3600–3000 (br,
OÀH), 2924 (w, CÀH), 2851 (w, CÀH), 1689 cmÀ1 (s, C=O); purity:
98% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =
26 min).
3
137.4 (s), 137.2 (s), 134.0 (s), 133.9 (s), 133.7 (d) (d, JCÀF =4.4 Hz),
131.6 (s), 129.8 (d, 2”), 129.0 (d, 2”), 128.1 (d), 127.7 (d), 127.5 (d),
3
127.0 (d) (d, JCÀF =3.6 Hz), 126.7 (d), 126.4 (s), 126.1 (d) (d, JCÀF
3.3 Hz), 125.9 (d), 123.4 (d), 120.1 (s), 120.0 (d), 117.3 (d) (d, JCÀF
=
=
24.2 Hz), 20.9 ppm (q); HRMS (ESIÀ): calcd for C26H18FO2 ([MÀH]À),
381.1296, found: 381.1296; IR (NaCl): n˜ =3600–3000 (br, OÀH),
2924 (w, CÀH), 2853 (w, CÀH), 1692 cmÀ1 (s, C=O); purity: 94%
(HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =26 min).
(E)-3-Chloro-4-[(5-p-tolylnaphthalen-2-yl)ethenyl]benzoic
acid
9h. Following the general procedure for the Horner–Wadsworth–
Emmons reaction, the reaction of methyl 4-(diethoxyphosphoryl)-3-
chlorobenzoate 19c (0.077 g, 0.24 mmol), DMPU (0.5 mL), nBuLi
(0.12 mL, 1.43m in hexane, 0.16 mmol) and 5-p-tolyl-2-naphthalde-
hyde 18b (0.03 g, 0.12 mmol) in THF (4 mL) afforded, after purifica-
tion by column chromatography (silica gel, 95:5 hexane/EtOAc),
0.041 g of the ester as a white solid. Following the general proce-
dure for the hydrolysis of esters, the reaction of the ester obtained
above (0.034 g, 0.08 mmol) and KOH (1.32 mL, 2m in H2O,
2.64 mmol) in MeOH (8 mL) afforded, after purification by column
chromatography (silica gel, 90:10 CH2Cl2/MeOH), 0.03 g (76% com-
bined) of 9h as a white solid; mp: 2048C (MeOH); 1H NMR
(400.13 MHz, CDCl3): d=8.17 (s, 1H), 8.0–7.9 (m, 3H), 7.9–7.7 (m,
3H), 7.67 (d, J=16.3 Hz, 1H), 7.6–7.4 (m, 5H), 7.36 (d, J=8.9 Hz,
2H), 2.51 ppm (s, 3H); 13C NMR (100.16 MHz, CDCl3): d=170.0 (s),
140.6 (s), 140.5 (s), 137.5 (s), 137.2 (s), 134.4 (d), 134.1 (s), 133.9 (s),
133.4 (s), 131.8 (s), 131.7 (d), 129.9 (d, 2”), 129.1 (d, 2”), 129.0 (d,
2”), 128.4 (d), 127.6 (d), 127.3 (d), 127.1 (d), 126.5 (s), 126.1 (d),
123.7 (d), 122.6 (d), 23.1 ppm (q); HRMS (ESI+): calcd for
C26H1835ClO2 [M+H]+: 397.1000, found: 397.1001; IR (NaCl): n˜ =
3600–3000 (br, OÀH), 3048 (w, CÀH), 2997 (w, CÀH), 2922 (w, CÀH),
(E)-4-[(5-p-Tolylnaphthalen-2-yl)ethenyl]benzoic acid 9b. Follow-
ing the general procedure for the Horner–Wadsworth–Emmons re-
action, the reaction of methyl 4-(diethoxyphosphoryl)benzoate
19a (0.069 g, 0.24 mmol), DMPU (0.5 mL), nBuLi (0.16 mL, 1.43m in
hexane, 0.23 mmol) and 5-p-tolyl-2-naphthaldehyde 18b (0.03 g,
0.12 mmol) in THF (4 mL) afforded, after purification by column
chromatography (silica gel, 95:5 hexane/EtOAc), 0.036 g of the
ester as a white solid. Following the general procedure for the hy-
drolysis of esters, the reaction of the ester obtained above
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Full Papers
2852 (w, CÀH), 1691 cmÀ1 (s, C=O); purity: 95% (HPLC–UV, Sunfire
C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =28 min).
Et3N (0.22 mL, 2.13 mmol), Pd(OAc)2 (5.7 mg, 0.025 mmol) and 1,3-
bis(diphenylphosphino)propane (10.5 mg, 0.026 mmol). The reac-
tion mixture was saturated with carbon monoxide and heated for
2 h at 708C under a CO atmosphere. The mixture was cooled to
room temperature, poured into H2O and extracted with EtOAc (3”
20 mL). The combined organic layers were dried (Na2SO4), and the
solvent was removed. The residue was purified by column chroma-
tography (silica gel, 95:5 hexane/EtOAc), to afford 0.15 g (67%) of
Naphthalen-2-yl trifluoromethanesulfonate 21. To a solution of
naphthalen-2-ol 20 (5.0 g, 34.7 mmol) in CH2Cl2 (160 mL) at 258C
were added Tf2O (8.60 mL, 52.1 mmol) and pyridine (3.1 mL,
38.2 mmol), and the mixture was stirred for 16 h. A saturated aque-
ous solution of NH4Cl was added (100 mL) and the mixture was ex-
tracted with CH2Cl2 (3”150 mL). The combined organic layers were
dried (Na2SO4), and the solvent was evaporated. The residue was
purified by column chromatography (silica gel, 80:20 hexane/
EtOAc) to afford 9.50 g (99%) of 21 as a yellow oil. 1H NMR
(400.16 MHz, CDCl3): d=7.93 (d, J=9.1 Hz, 1H), 7.9–7.8 (m, 2H),
7.76 (d, J=1.7 Hz, 1H), 7.6–7.5 (m, 2H), 7.38 ppm (dd, J=9.0,
2.2 Hz, 1H); 13C NMR (100.62 MHz, CDCl3): d=146.9 (s), 133.2 (s),
132.2 (s), 130.4 (d), 127.8 (d), 127.7 (d), 127.3 (d), 127.0 (d), 119.3
(d), 119.2 (d), 118.4 ppm (s) (q, JCÀF =320 Hz, CF3); MS (EI): m/z (%)
276 ([M]+, 17), 143 (20), 115 (100); HRMS (EI): calcd for C11H7F3O3S,
276.0068, found: 276.0063; IR (NaCl): n˜ =3063 (w, CÀH), 2929 (w,
CÀH), 1510 (m), 1424 (s), 1200 cmÀ1 (s).
1
25a as a yellow oil. H NMR (400.16 MHz, CDCl3): d=8.73 (s, 1H),
8.17–8.05 (m, 1H), 7.97 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H),
7.65 (t, J=7.6 Hz, 1H), 7.61–7.41 (m, 6H), 3.93 ppm (s, 3H);
13C NMR (100.62 MHz, CDCl3): d=167.4 (s), 141.9 (s), 140.0 (s), 135.9
(s), 130.8 (d), 130.0 (s), 129.2 (d, 2”), 128.6 (d), 128.4 (d, 2”), 127.8
(d), 127.8 (d), 127.7 (d), 127.6 (s), 127.5 (d), 125.2 (s), 52.2 ppm (q);
HRMS (ESI+): calcd for C18H15O2 [M+H]+: 263.1066, found:
263.1067; IR (NaCl): n˜ =3054 (w, CÀH), 3025 (w, CÀH), 2949 (w, CÀ
H), 2863 (w, CÀH), 1719 cmÀ1 (s, C=O).
(E)-4-[(8-(Phenylethynyl)naphthalene-2-yl)ethenyl]benzoic acid
11 c. Following the general procedure for the Horner–Wadsworth–
Emmons reaction, the reaction of methyl 4-(diethoxyphosphoryl)-
benzoate 19a (0.069 g, 0.24 mmol), DMPU (0.5 mL), nBuLi (0.16 mL,
1.43m in hexane, 0.23 mmol), and 8-(phenylethynyl)-2-naphthalde-
hyde 27c (0.03 g, 0.12 mmol) in THF (4 mL) afforded, after purifica-
tion by column chromatography (silica gel, 95:5 hexane/EtOAc),
0.031 g of the ester of a white solid. Following the general proce-
dure for the hydrolysis of esters, the reaction of 11 c (0.031 g,
0.08 mmol) and KOH (1.33 mL, 2m in H2O, 2.66 mmol) in MeOH
(8 mL) afforded, after purification by column chromatography
(silica gel, 90:10 CH2Cl2/MeOH), 0.024 g (53% combined) of 11 c as
a white solid; mp: 2318C (MeOH); 1H NMR (400.16 MHz, CDCl3/
CD3CO2D): d=8.44 (d, J=8.7 Hz, 1H), 8.11 (d, J=7.1 Hz, 2H), 7.93
(s, 1H), 7.86 (d, J=8.3 Hz, 2H), 7.76 (d, J=7.2 Hz, 1H), 7.7–7.6 (m,
4H), 7.49 (t, J=7.1 Hz, 1H), 7.5–7.4 (m, 4H), 7.31 ppm (d, J=
17.1 Hz, 1H); 13C NMR (100.62 MHz, CDCl3/CD3CO2D): d=171.8 (s),
142.6 (s), 134.7 (s), 133.5 (s), 133.2 (s), 131.6 (d, 2”), 131.4 (d), 130.7
(d, 2”), 130.6 (d), 128.9 (d), 128.5 (d), 128.4 (d, 2”), 128.2 (d), 128.0
(s), 127.6 (d), 126.9 (d), 126.5 (d, 2”), 125.9 (d), 124.4 (d), 123.3 (s),
120.9 (s), 94.4 (s), 87.3 ppm (s); MS (EI): m/z (%): 374 ([M]+, 100),
330 (28), 329 (57), 328 (38), 327 (43), 326 (42), 313 (20), 252 (38),
250 (21), 225 (14), 163 (13); HRMS (EI): calcd for C27H18O2, 374.1307,
found: 374.1317; IR (NaCl): n˜ =3600–3000 (s, OÀH), 3055 (w, CÀH),
3003 (w, CÀH), 2969 (w, CÀH), 2889 (w, CÀH), 1690 cmÀ1 (s, C=O);
purity: 93% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O,
tR =26 min).
8-Iodonaphthalen-2-yltrifluoromethanesulfonate 22. To a solution
of naphthalen-2-yltrifluoromethanesulfonate 21 (3.1 g, 11.3 mmol)
in CH2Cl2 (300 mL) were added Ipy2BF4 (4.9 g, 19.8 mmol) and TfOH
(1.3 mL, 11.3 mmol), and the mixture was stirred at 258C for 22 h.
A saturated aqueous solution of Na2S2O3 was added (200 mL) and
the mixture was extracted with CH2Cl2 (3”200 mL). The combined
organic layers were dried (Na2SO4), and the solvent was evaporat-
ed. The residue was purified by column chromatography (silica gel,
98:2 hexane/EtOAc) to afford 3.0 g (66%) of 22 as a colorless oil.
1H NMR (400.16 MHz, CDCl3): d=8.13 (d, J=7.2 Hz, 1H), 8.06 (s,
1H), 7.86 (d, J=7.2 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.41 (d, J=
8.9 Hz, 1H), 7.11 ppm (t, J=8.7 Hz, 1H); 13C NMR (100.62 MHz,
CDCl3): d=148.5 (s), 139.0 (d), 132.9 (s), 134.9 (s), 131.6 (d), 128.8
(d), 128.2 (d), 124.1 (d), 120.6 (d), 116.3 (s) (q, JCÀF =320 Hz, CF3),
98.7 ppm (s); MS (EI): m/z (%) 401 ([M]+, 100), 277 (16), 275 (38),
269 (45), 268 (21), 240 (24), 239 (15), 154 (19), 153 (41); HRMS (EI):
calcd for C11H6F3IS, 401.9035, found: 401.9035; IR (NaCl): n˜ =3062
(w, CÀH), 2928 (w, C-H) 1424 (s), 1212 cmÀ1 (s).
8-(Phenyl)naphthalen-2-yltrifluoromethanesulfonate 23a. Gener-
al procedure for the Suzuki coupling of triflates. To a solution of 8-io-
donaphthalen-2-yltrifluoromethanesulfonate 22 (0.50 g, 1.24 mmol)
in THF/H2O (6 mL, 1:1 v/v) was added Pd(PPh3)4 (0.14 g,
0.124 mmol), Na2CO3 (0.26 g, 2.48 mmol) and phenylboronic acid
(0.17 mL, 1.36 mmol), and the mixture was heated in the micro-
wave reactor (200 W) at 110 8C for 10 min. The residue was diluted
with H2O and extracted with EtOAc (3”20 mL). The combined or-
ganic layers were dried (Na2SO4), and the solvent was evaporated.
The residue was purified by column chromatography (silica gel,
hexane) to afford 0.42 g (98%) of 23a as a colorless oil. 1H NMR
(400.16 MHz, CDCl3): d=8.01 (d, J=9.0 Hz, 1H), 7.92 (d, J=8.1 Hz,
1H), 7.83 (d, J=2.3 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.60–7.46 (m,
4H), 7.41 (dd, J=9.0, 2.4 Hz, 1H), 7.36 (s, 1H), 7.28 ppm (d, J=
8.6 Hz, 1H); 13C NMR (100.62 MHz, CDCl3): d=147.5 (s), 140.7 (s),
139.4 (s), 133.9 (d), 133.7 (d), 132.8 (s), 131.8 (d), 130.9 (d), 129.8 (s),
128.8 (d, 2”), 128.6 (d, 2”), 128.4 (d), 127.9 (d), 126.8 (d),
118.8 ppm (s) (q, JCÀF =240.9 Hz, CF3); HRMS (ESI+): calcd for
C17H12F3O3S [M+H]+: 353.04538, found: 353.04561; IR (NaCl): n˜ =
3058 (w, CÀH), 1510 (m), 1424 (s), 1213 cmÀ1 (s).
(E)-3-Fluoro-4-[(8-(phenylethynyl)naphthalen-2-yl)ethenyl]benzo-
ic acid 11 f. Following the general procedure for the Horner–Wads-
worth–Emmons reaction, the reaction of methyl 3-fluoro-4-(dieth-
oxyphosphoryl)benzoate 19b (0.073 g, 0.24 mmol), DMPU (0.5 mL),
nBuLi (0.16 mL, 1.43m in hexane, 0.23 mmol) and 8-(phenylethyn-
yl)-2-naphthaldehyde 27c (0.03 g, 0.12 mmol) in THF (4 mL) afford-
ed, after purification by column chromatography (silica gel, 95:5
hexane/EtOAc), 0.034 g of the ester as a white solid. Following the
general procedure for the hydrolysis of esters, the reaction of the
ester obtained above (0.034 g, 0.084 mmol) and KOH (1.38 mL, 2m
in H2O, 2.76 mmol) in MeOH (8 mL) afforded, after purification by
column chromatography (silica gel, 90:10 CH2Cl2/MeOH), 0.015 g
(33% combined) of 11 f as a white solid; mp: 2258C (MeOH);
1H NMR (400.16 MHz, [D6]DMSO): d=8.38 (d, J=8.7 Hz, 1H), 8.2–
8.1 (m, 1H), 8.05 (t, J=8.9 Hz, 1H), 7.99 (d, J=8.0 Hz, 2H), 7.82 (d,
J=7.5 Hz, 2H), 7.8-7-7 (m, 5H), 7.63 (d, J=15.4 Hz, 1H), 7.6–
7.4 ppm (m, 3H); 13C NMR (100.62 MHz, [D6]DMSO): d=165.9 (s),
Methyl 8-(phenyl)-2-naphthoate 25a. General procedure for the
carbonylation/MeOH trapping of triflates. To a stirred solution of 8-
(2-phenyl-1-yl)naphthalen-2-yltrifluoromethanesulfonate
23a
1
(0.30 g, 0.85 mmol) in DMSO (6 mL) and MeOH (6 mL) were added
159.2 (s) (d, JCÀF =249.2 Hz), 134.7 (s), 133.0 (s), 132.9 (s), 132.3 (s),
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132.1 (s), 131.5 (d), 131.4 (d, 2”), 130.7 (d), 129.3 (d), 128.9 (d) (d,
4-{[5-(Phenylnaphthalen-2-yl)carbonyl]amino}benzoic acid 10a.
General procedure for the amidation of aryl halides. In a sealed tube
were added 5-phenyl-2-naphthamide 29a (0.03 g, 0.12 mmol),
ethyl 4-iodobenzoate 30a (0.017 mL, 0.1 mmol), (1S,2S)-cyclohex-
ane-1,2-diamine (0.003 g, 0.024 mmol), K2CO3 (0.033 g, 0.24 mmol)
and CuI (0.002 g, 0.012 mmol) in dioxane (2 mL), and the mixture
was stirred at 1408C for 17 h. The mixture was filtered though
Celite, and the residue was purified by column chromatography
(silica gel, 95:5 hexane/EtOAc) to afford 0.031 g of the ester as
a white solid. Following the general procedure for the hydrolysis of
esters, the reaction of the ester obtained above (0.031 g,
0.079 mmol) and KOH (1.31 mL, 2m in H2O, 2.61 mmol) in MeOH
(6 mL) afforded, after purification by column chromatography
(silica gel, 95:5 CH2Cl2/MeOH), 0.021 g (57%) of 10a as a white
solid; mp: 1028C (MeOH); 1H NMR (400.16 MHz, [D6]DMSO): d=
10.74 (s, 1H), 8.70 (s, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.00 (dd, J=8.9,
1.8 Hz, 1H), 8.0–7.9 (m, 4H), 7.92 (d, J=8.9 Hz, 1H), 7.71 (t, J=
8.2 Hz, 1H), 7.6–7.4 ppm (m, 6H); 13C NMR (100.62 MHz, [D6]DMSO):
d=167.3 (s), 165.7 (s), 142.9 (s), 139.5 (s), 139.4 (s), 132.5 (s), 132.0
(s), 131.8 (s), 130.1 (d, 2”), 129.8 (s), 129.7 (d, 2”), 128.8 (d), 128.7
(d), 128.6 (d), 128.5 (d, 2”), 127.6 (d), 126.5 (d), 125.5 (d), 124.8 (d),
119.4 ppm (d, 2”); HRMS (ESI+): calcd for C24H16NO3 [M+H]+:
366.1133, found: 366.1133; IR (NaCl): n˜ =3600–3000 (br, OÀH), 3318
(s, NÀH), 2923 (w, CÀH), 2852 (w, CÀH), 1678 (s, C=O), 1654 cmÀ1 (s,
C=O); purity: 92% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/
H2O, tR =21 min).
3JCÀF =4.3 Hz), 128.8 (d, 2”), 127.7 (d), 127.6 (d), 127.3 (d), 125.9 (d)
2
(d, JCÀF =19.4 Hz), 125.2 (d), 125.1 (d), 124.9 (d), 122.1 (s), 119.6 (s),
116.1 (d) (2JCÀF =23.4 Hz), 94.3 (s), 87.0 ppm (s); MS (EI): m/z (%)
392 ([M]+, 100), 348 (21), 347 (18), 346 (25), 345 (15), 344 (24), 326
(20), 270 (18); HRMS (EI): calcd for C27H17FO2, 392.1213, found:
392.1216; IR (NaCl): n˜ =3600–3000 (br, OÀH), 3054 (w, CÀH), 2923
(s, CÀH), 2852 (m, CÀH), 1686 cmÀ1 (s, C=O); purity: 94% (HPLC–
UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =26 min).
(E)-3-Chloro-4-[(8-(phenylethynyl)naphthalen-2-yl)ethenyl]ben-
zoic acid 11 i. Following the general procedure for the Horner–
Wadsworth–Emmons reaction, the reaction of methyl 3-chloro-4-
(diethoxyphosphoryl)benzoate 19c (0.077 g, 0.24 mmol), DMPU
(0.5 mL), nBuLi (0.16 mL, 1.43m in hexane, 0.23 mmol) and 8-(phe-
nylethynyl)-2-naphthaldehyde 27c (0.03 g, 0.12 mmol) in THF
(4 mL) afforded, after purification by column chromatography
(silica gel, 95:5 hexane/EtOAc), 0.037 g of the ester as a white solid.
Following the general procedure for the hydrolysis of esters, the
reaction of the ester obtained above (0.034 g, 0.08 mmol) and KOH
(1.32 mL, 2m in H2O, 2.64 mmol) in MeOH (8 mL) afforded, after
purification by column chromatography (silica gel, 90:10 CH2Cl2/
MeOH), 0.03 g (67% combined) of 11 i as a white solid; mp: 2308C
(MeOH); 1H NMR (400.16 MHz, CDCl3/CD3CO2D): d=8.47 (s, 1H),
8.07 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.9–7.8 (m, 2H), 7.78 (d, J=
8.1 Hz, 2H), 7.72 (d, J=7.0 Hz, 1H), 7.7–7.6 (m, 2H), 7.4–7.3 ppm
(m, 6H); 13C NMR (100.62 MHz, CDCl3/CD3CO2D): d=170.5 (s), 140.3
(s), 134.8 (s), 133.4 (s), 133.3 (s), 131.6 (d, 2”), 131.5 (d), 130.9 (d),
129.2 (d), 129.1 (s), 128.9 (d), 128.5 (d), 128.4 (d, 2”), 128.3 (d),
126.2 (d), 126.1 (d), 126.0 (d), 125.8 (d), 124.3 (d), 124.2 (s), 124.0
(d), 123.2 (s), 121.1 (s), 94.9 (s), 87.1 ppm (s); MS (EI): m/z (%) 408
([M]+, 83), 374 (26), 373 (20), 364 (16), 330 (22), 329 (81), 328 (100),
327 (79), 326 (92), 325 (18), 324 (28), 313 (24), 252 (30), 251 (15),
250 (25), 228 (14), 226 (29), 163 (21), 162 (17); HRMS (EI): calcd for
C27H1735ClO2, 408.0917, found: 408.0919; IR (NaCl): n˜ =3600–3000
(br, OÀH), 2923 (w, CÀH), 2853 (w, CÀH), 1691 cmÀ1 (s, C=O);
purity: 99% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O,
tR =25 min).
3-Fluoro-4-{[5-(phenylnaphthalen-2-yl)carbonyl]amino}benzoic
acid 10d. Following the general procedure for the amidation of
aryl halides, the reaction of 5-phenyl-2-naphthamide 29a (0.03 g,
0.12 mmol),
ethyl 3-fluoro-4-iodobenzoate
30b
(0.032 g,
0.11 mmol), (1S,2S)-cyclohexane-1,2-diamine (0.003 g, 0.026 mmol),
K2CO3 (0.036 g, 0.26 mmol) and CuI (0.002 g, 0.013 mmol) in diox-
ane (2 mL) afforded, after purification by column chromatography
(silica gel, 95:5 hexane/EtOAc), 0.022 g of the ester as a white solid.
Following the general procedure for the hydrolysis of esters, the
reaction of the ester obtained above (0.022 g, 0.051 mmol) and
KOH (0.84 mL, 2m in H2O, 1.68 mmol) in MeOH (5 mL) afforded,
after purification by column chromatography (silica gel, 95:5
CH2Cl2/MeOH), 0.015 g (34% combined) of 10d as a white solid;
1
mp: 2038C (MeOH); H NMR (400.16 MHz, [D6]DMSO): d=10.45 (s,
5-Phenyl-2-naphthamide 29a. General procedure for the amidation
of carboxylic acids. To a solution of 5-phenyl-2-naphthoic acid 28a
(0.38 g, 1.53 mmol) in DMF (10 mL) were added HOBt (0.26 g,
1.69 mmol) and EDC (0.32 g, 1.69 mmol), and the mixture was
stirred for 3 h at 258C. The residue was cooled to 08C, a solution
of NH3 (0.48 mL, 2m in MeOH) was added, and the mixture was
stirred at 258C for 2.5 h. A saturated aqueous solution of NaHCO3
was added (10 mL) and the mixture was extracted with EtOAc (3”
30 mL). The combined organic layers were washed with H2O (3”
50 mL) and brine (3”50 mL). The combined organic layers were
dried (Na2SO4), and the solvent was evaporated. The residue was
purified by column chromatography (silica gel, 95:5 CH2Cl2/MeOH),
1H), 8.72 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H),
3
7.92 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.78 (d, JHÀF
=
11.2 Hz, 1H), 7.7–7.6 (m, 1H), 7.6–7.5 (m, 3H), 7.5–7.4 ppm (m, 3H);
13C NMR (100.62 MHz, [D6]DMSO): d=165.9 (s), 165.4 (s), 154.4 (s)
1
(d, JCÀF =248.1 Hz), 139.4 (s), 139.3 (s), 132.5 (s), 132.2 (s), 130.9 (s),
130.2 (s), 130.1 (s), 129.8 (d), 129.7 (d, 2”), 129.0 (d), 128.8 (d),
2
128.5 (d, 2”), 127.6 (d), 126.5 (d), 125.6 (d) (d, JCÀF =20.0 Hz), 125.5
(d), 124.8 (d), 116.3 (d) (d, JCÀF =20.0 Hz), 116.2 ppm (d); HRMS
(ESI+): calcd for C24H17FNO3 [M+H]+: 386.1184, found: 386.1184; IR
(NaCl): n˜ =3600–3000 (s, OH), 3219 (s, NÀH), 2953 (s, CÀH), 2848 (s,
CÀH), 1685 (s, C=O), 1655 cmÀ1 (s, C=O); purity: 96% (HPLC–UV,
Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =21 min).
1
0.30 g (81%) of 29a as a white solid; mp: 1308C (MeOH); H NMR
(400.16 MHz, [D6]DMSO): d=8.57 (s, 1H), 8.15 (s, 2H, NH), 8.05 (d,
J=8.2 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.7–
7.6 (m, 1H), 7.6–7.5 ppm (m, 6H); 13C NMR (100.62 MHz,
[D6]DMSO): d=167.7 (s), 139.5 (s), 139.4 (s), 132.6 (s), 131.9 (s),
131.5 (s), 129.7 (d, 2”), 128.6 (d), 128.5 (d, 2”), 128.3 (d), 128.2 (d),
127.5 (d), 126.2 (d), 125.2 (d), 124.7 ppm (d); MS (EI): m/z (%) 247
([M]+, 29), 230 (15), 229 (99), 228 (100), 227 (72), 203 (27), 202 (61),
201 (37), 200 (24); HRMS (EI): calcd for C17H13NO, 247.0996, found:
247.0997; IR (NaCl): n˜ =3309 (s, NÀH), 3185 (s, NÀH), 3055 (w, CÀH),
2923 (s, CÀH), 2852 (s, CÀH), 1655 (s, C=O), 1605 (m, C=C),
1395 cmÀ1 (m).
3-Chloro-4-{[5-(phenylnaphthalen-2-yl)carbonyl]amino}benzoic
acid 10g. Following the general procedure the amidation of aryl
halides, the reaction of 5-phenyl-2-naphthamide 29a (0.032 g,
0.13 mmol), ethyl 3-chloro-4-iodobenzoate 30c (0.034 g,
0.11 mmol), (1S,2S)-cyclohexane-1,2-diamine (0.003 g, 0.026 mmol),
K2CO3 (0.036 g, 0.26 mmol) and CuI (0.002 g, 0.013 mmol) in diox-
ane (2 mL) afforded, after purification by column chromatography
(silica gel, 95:5 hexane/EtOAc), 0.03 g of the ester as a white solid.
Following the general procedure for the hydrolysis of esters, the
reaction of the ester obtained above (0.023 g, 0.054 mmol) and
ChemMedChem 2015, 10, 1378 – 1391
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Full Papers
KOH (0.90 mL, 2m in H2O, 1.80 mmol) in MeOH (5 mL) afforded,
after purification by column chromatography (silica gel, 95:5
CH2Cl2/MeOH), 0.018 g (40% combined) of 10g as a white solid;
mp: 2518C (MeOH); 1H NMR (400.16 MHz, [D6]DMSO): d=8.93 (d,
J=1.8 Hz, 1H), 8.3–8.2 (m, 2H), 8.05 (dd, J=8.4, 1.4 Hz, 1H), 7.99
(d, J=8.2 Hz, 2H), 7.74 (dd, J=8.2, 7.2 Hz, 1H), 7.6–7.5 ppm (m,
8H); 13C NMR (100.62 MHz, [D6]DMSO): d=167.3 (s), 162.4 (s), 150.0
(s), 141.6 (s), 140.3 (s), 139.6 (s), 139.4 (s), 133.0 (s), 131.9 (s), 129.8
(d), 129.7 (d, 2”), 128.8 (d), 128.5 (d, 2”), 127.9 (d), 127.6 (d), 126.7
(d), 126.4 (d), 126.1 (d), 123.9 (s), 123.8 (d), 117.5 (d), 110.6 ppm (d);
HRMS (ESI+): calcd for C24H16NO3 [MÀCl]+: 366.1125, found:
366.1111; IR (NaCl): n˜ =3600–3000 (br, OÀH), 2959 (w, CÀH), 2924
(w, CÀH), 2854 (w, CÀH), 1715 (s, C=O), 1697 cmÀ1 (s, C=O); purity:
91% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =
24 min).
22 Hz), 20.7 ppm (q); HRMS (ESI+): calcd for C25H19FNO3 [M+H]+:
400.1349, found: 400.1341; IR (NaCl): n˜ =3600–3000 (br, OÀH),
3476 (m, NÀH), 3380 (m, NÀH), 2955 (s, CÀH), 2926 (s, CÀH), 2855
(s, CÀH), 1691 (s, C=O), 1614 cmÀ1 (s, C=C); purity: 92% (HPLC–UV,
Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =23 min).
3-Chloro-4-{[5-p-(tolylnaphthalen-2-yl)carbonyl]amino}benzoic
acid 10h. Following the general procedure the amidation of aryl
halides, the reaction of 5-p-tolyl-2-naphthamide 32b (0.024 g,
0.092 mmol), ethyl 3-chloro-4-iodobenzoate 30c (0.024 g,
0.077 mmol),
(1S,2S)-cyclohexane-1,2-diamine
(0.002 g,
0.018 mmol), K2CO3 (0.025 g, 0.18 mmol) and CuI (0.002 g,
0.01 mmol) in dioxane (2 mL) afforded, after purification by column
chromatography (silica gel, 95:5 hexane/EtOAc), 0.024 g of the
ester as a white solid. Following the general procedure for the hy-
drolysis of esters, the reaction of the ester obtained above
(0.015 g, 0.034 mmol) and KOH (0.56 mL, 2m in H2O, 1.11 mmol) in
MeOH (3 mL) afforded, after purification by column chromatogra-
phy (silica gel, 95:5 CH2Cl2/MeOH), 0.022 g (64%) of 10h as a white
solid; mp: 2688C (MeOH); 1H NMR (400.13 MHz, [D6]DMSO): d=
10.34 (s, 1H), 8.72 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.1–8.0 (m, 2H),
8.0–7.9 (m, 2H), 7.87 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.56
(d, J=6.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H),
2.43 ppm (s, 3H); 13C NMR (100.16 MHz, [D6]DMSO): d=165.8 (s),
165.3 (s), 139.5 (s), 138.8 (s), 136.9 (s), 136.5 (s), 132.5 (s), 132.3 (s),
130.8 (s), 130.2 (d), 129.6 (d, 2”), 129.1 (d, 2”), 128.8 (d), 128.7 (d),
128.6 (d), 128.4 (d), 128.2 (s), 127.1 (d), 126.6 (s), 126.5 (d), 125.7
(d), 124.5 (d), 20.7 ppm (q); HRMS (ESI+): calcd for C25H18NO3
[MÀCl]+: 380.1281, found: 380.1281; IR (NaCl): n˜ =3600–3000 (br,
OÀH), 2921 (w, CÀH), 2852 (w, CÀH), 1715 (s, C=O), 1686 cmÀ1 (s,
C=O); purity: 96% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/
H2O, tR =25 min).
4-{[5-p-(Tolylnaphthalen-2-yl)carbonyl]amino}benzoic acid 10b.
Following the general procedure the amidation of aryl halides, the
reaction of 5-p-tolyl-2-naphthamide 29b (0.04 g, 0.15 mmol), ethyl
4-iodobenzoate 30a (0.022 mL, 0.13 mmol), (1S,2S)-cyclohexane-
1,2-diamine (0.004 g, 0.03 mmol), K2CO3 (0.041 g, 0.3 mmol) and
CuI (0.003 g, 0.015 mmol) in dioxane (2 mL) afforded, after purifica-
tion by column chromatography (silica gel, 95:5 hexane/EtOAc),
0.05 g of the ester as a white solid. Following the general proce-
dure for the hydrolysis of esters, the reaction of the ester obtained
above (0.05 g, 0.12 mmol) and KOH (2.22 mL, 2m in H2O,
4.44 mmol) in MeOH (12 mL) afforded, after purification by column
chromatography (silica gel, 95:5 CH2Cl2/MeOH), 0.029 g (51% com-
bined) of 10b as a white solid; mp: 2298C (MeOH); 1H NMR
(400.13 MHz, [D6]DMSO): d=10.73 (s, 1H), 8.68 (s, 1H), 8.12 (d, J=
8.2 Hz, 1H), 8.0–7.9 (m, 5H), 7.94 (d, J=8.9 Hz, 1H), 7.55 (d, J=
7.7 Hz, 1H), 7.4–7.3 (m, 4H), 2.43 ppm (s, 3H); 13C NMR
(100.16 MHz, [D6]DMSO): d=166.9 (s), 165.8 (s), 143.2 (s), 139.4 (s),
136.8 (s), 136.5 (s), 132.5 (s), 132.2 (s), 131.7 (s), 130.2 (d, 2”), 129.5
(d, 2”), 129.0 (d, 2”), 128.6 (d), 128.5 (d), 126.5 (d), 125.6 (d), 125.5
(s), 124.7 (d), 119.5 (d), 119.4 (d, 2”), 20.7 ppm (q); HRMS (ESI+):
calcd for C25H20NO3 [M+H]+: 382.1443, found: 382.1437; IR (NaCl):
n˜ =3600–3000 (br, OÀH), 3295 (s, NÀH), 2922 (w, CÀH), 2852 (w, CÀ
H), 1684 (s, C=O), 1655 (s, C=O), 1594 cmÀ1 (s, C=C); purity: 99%
(HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =22 min).
4-{[8-(Phenylnaphthalen-2-yl)carbonyl]amino}benzoic acid 12a.
Following the general procedure the amidation of aryl halides, the
reaction of 8-phenyl-2-naphthamide 32a (0.021 g, 0.085 mmol),
ethyl 4-iodobenzoate 30a (0.018 g, 0.068 mmol), (1S,2S)-cyclohex-
ane-1,2-diamine (0.002 g, 0.016 mmol), K2CO3 (0.002 g, 0.014 mmol)
and CuI (0.001 g, 0.010 mmol) in dioxane (2 mL) afforded, after pu-
rification by column chromatography (silica gel, 95:5 hexane/
EtOAc), 0.020 g of the ester as a white solid. Following the general
procedure for the hydrolysis of esters, the reaction of the ester ob-
tained above (0.014 g, 0.036 mmol) and KOH (0.6 mL, 2m in H2O,
1.2 mmol) in MeOH (3 mL) afforded, after purification by column
chromatography (silica gel, 95:5 CH2Cl2/MeOH), 0.011 g (50% com-
bined) of 12a as a white solid. 1H NMR (400.16 MHz, [D6]DMSO):
d=12.71 (s, 1H), 10.65 (s, 1H), 8.44 (s, 1H), 8.18 (d, J=8.6 Hz, 1H),
8.1–8.0 (m, 2H), 7.93 (d, J=8.9 Hz, 2H), 7.88 (d, J=9.0 Hz, 2H), 7.72
(dd, J=8.2, 7.1 Hz, 1H), 7.6–7.5 ppm (m, 5H); 13C NMR
(100.62 MHz, [D6]DMSO): d=166.9 (s), 166.1 (s), 143.2 (s), 140.7 (s),
139.5 (s), 134.8 (s), 132.4 (s), 130.2 (d, 2”), 129.9 (s), 129.9 (d, 2”),
128.6 (d, 3”), 127.9 (d), 127.7 (d), 127.5 (d), 126.3 (d), 125.6 (s),
124.2 (d), 119.5 ppm (d, 3”); HRMS (ESI+): calcd for C24H18NO3 [M+
H]+: 368.1281, found: 368.1293.
3-Fluoro-4-{[5-p-(tolylnaphthalen-2-yl)carbonyl]amino}benzoic
acid 10e. Following the general procedure the amidation of aryl
halides, the reaction of 5-p-tolyl-2-naphthamide 29b (0.03 g,
0.11 mmol),
0.092 mmol),
ethyl
3-fluoro-4-iodobenzoate
(1S,2S)-cyclohexane-1,2-diamine
30b
(0.027 g,
(0.003 g,
0.022 mmol), K2CO3 (0.03 g, 0.22 mmol) and CuI (0.002 g,
0.011 mmol) in dioxane (2 mL) afforded, after purification by
column chromatography (silica gel, 95:5 hexane/EtOAc), 0.029 g of
the ester as a white solid. Following the general procedure for the
hydrolysis of esters, the reaction of the ester obtained above
(0.028 g, 0.066 mmol) and KOH (1.1 mL, 2m in H2O, 2.2 mmol) in
MeOH (7 mL) afforded, after purification by column chromatogra-
phy (silica gel, 95:5 CH2Cl2/MeOH), 0.022 g (58% combined) of 10e
as
a
white solid; mp: 2408C (MeOH); 1H NMR (400.13 MHz,
4-{[8-(p-Tolylnaphthalen-2-yl)carbonyl]amino}benzoic acid 12b.
Following the general procedure for the amidation of aryl halides,
the reaction of 8-(p-tolyl)-2-naphthamide 32b (0.070 g, 0.27 mmol),
ethyl 4-iodobenzoate 30a (0.064 g, 0.225 mmol), (1S,2S)-cyclohex-
ane-1,2-diamine (0.006 g, 0.054 mmol), K2CO3 (0.006 g, 0.045 mmol)
and CuI (0.001 g, 0.010 mmol) in dioxane (5 mL) afforded, after pu-
rification by column chromatography (silica gel, 95:5 hexane/
EtOAc), 0.064 g of the ester as a white solid. The reaction of the
ester obtained above (0.01 g, 0.024 mmol), KOH (0.4 mL, 2m in
H2O, 0.79 mmol) in MeOH (2 mL) afforded, after purification by
[D6]DMSO): d=10.54 (s, 1H), 8.71 (s, 1H), 8.12 (d, J=8.1 Hz, 1H),
8.00 (dd, J=8.9, 1.7 Hz, 1H), 7.9–7.8 (m, 2H), 7.83 (d, J=8.6 Hz,
3
1H), 7.78 (d, JHÀF =11.1 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.56 (d, J=
7.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H),
2.42 ppm (s, 3H); 13C NMR (100.16 MHz, [D6]DMSO): d=166.1 (s),
1
165.4 (s), 154.3 (s) (d, JCÀF =247.9 Hz), 139.5 (s), 136.9 (s), 136.5 (s),
132.5 (s), 132.3 (s), 130.8 (s), 130.1 (s), 129.6 (d, 2”), 129.1 (d, 2”),
128.9 (d), 128.7 (d), 128.6 (d), 126.5 (d), 125.6 (d), 125.5 (s) (d,
3JCÀF =20 Hz), 125.4 (d), 125.3 (d), 124.7 (d), 116.4 (d) (d, JCÀF
=
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column chromatography (silica gel, 95:5 CH2Cl2/MeOH), 0.01 g
(52% combined) of 12b as a white solid. 1H NMR (400.16 MHz,
[D6]DMSO): d=10.54 (s, 1H), 8.35 (s, 1H), 8.07 (d, J=8.6 Hz, 1H),
8.0–7.9 (m, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.6–
7.5 (m, 1H), 7.43 (d, J=7.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.28 (d,
J=7.9 Hz, 2H), 2.33 ppm (s, 3H); 13C NMR (100.62 MHz, [D6]DMSO):
d=166.8 (s), 166.1 (s), 143.1 (s), 140.7 (s), 139.9 (s), 136.5 (s), 134.8
(s), 132.2 (s), 130.1 (d, 2”), 129.9 (d), 129.1 (d, 2”), 128.5 (d), 127.7
(d), 127.5 (d), 127.2 (d), 126.3 (d), 125.5 (s), 123.9 (d), 119.5 (d, 2”),
20.7 ppm (q); HRMS (ESI+): calcd for C25H20NO3 [M+H]+: 382.1437,
found: 382.1436; IR (NaCl): n˜ =3050 (br, OÀH), 2956 (s, CÀH), 2853
(s, CÀH), 1695 (s, C=O), 1693 cmÀ1 (s, C=O).
thamide 33c (0.03 g, 0.11 mmol), ethyl 4-iodobenzoate 30d
(0.016 mL, 0.092 mmol), (1S,2S)-cyclohexane-1,2-diamine (0.003 g,
0.022 mmol), CuI (0.002 g, 0.011 mmol) and K2CO3 (0.03 g,
0.22 mmol) in dioxane (2 mL) afforded, after purification by column
chromatography (silica gel, 95:5 hexane/EtOAc), 0.025 g of the
ester as a yellow solid. The reaction of the ester obtained above
(0.025 g, 0.057 mmol) and KOH (0.03 g, 1.90 mmol) in MeOH (5 mL)
afforded, after purification by column chromatography (silica gel,
95:5 CH2Cl2/MeOH), 0.022 g (57% combined) of 12 f as a white
solid. 1H NMR (400.16 MHz, [D6]DMSO): d=10.72 (s, 1H), 8.99 (s,
1H), 8.18 (d, J=8.5 Hz, 1H), 8.2–8.1 (m, 2H), 7.99 (t, J=7.9 Hz, 1H),
7.94 (dd, J=7.2, 0.9 Hz, 1H), 7.8–7.7 (m, 5H), 7.69 (s, 1H), 7.5–
7.4 ppm (m, 3H); 13C NMR (100.62 MHz, [D6]DMSO): d=166.5 (s),
4-{[8-(Phenylethyn-1-yl-2-naphthalenyl)carbonyl]amino}benzoic
acid 12c. Following the general procedure for the amidation of
aryl halides, the reaction of 8-(phenylethyn-1-yl)-2-naphthamide
32c (0.03 g, 0.11 mmol), ethyl 4-iodobenzoate 30a (0.016 mL,
1
156.4 (s), 153.9 (s) (d, JCÀF =247.9 Hz), 134.9 (s), 132.8 (s), 132.1 (s),
132.0 (d, 2”), 131.8 (d), 130.8 (s), 129.7 (d), 129.4 (d), 130.8 (s),
129.3 (d, 2”), 128.2 (d), 126.8 (d) (d, JCÀF =35.2 Hz), 126.1 (d), 126.0
(d), 125.8 (d), 122.6 (s), 121.5 (s), 117.0 (d) (d, JCÀF =21.3 Hz), 116.8
(d), 95.7 (s), 87.3 ppm (s); HRMS (ESI+): calcd for C26H17FNO3 [M+
H]+: 410.1163, found: 410.1137; IR (NaCl): n˜ =3500–3200 (br, OÀH),
3353 (s, NÀH), 2923 (s, CÀH), 2853 (s, CÀH), 1699 (s, C=O), 1598 (s,
C=C), 1524 (m), 1275 cmÀ1 (s).
0.092 mmol),
(1S,2S)-cyclohexane-1,2-diamine
(0.003 g,
0.022 mmol), CuI (0.002 g, 0.011 mmol) and K2CO3 (0.03 g,
0.22 mmol) in dioxane (2 mL) afforded, after purification by column
chromatography (silica gel, 95:5 hexane/EtOAc), 0.036 g of the
ester as a yellow solid. The reaction of the ester obtained above
(0.025 g, 0.060 mmol) and KOH (0.03 g, 0.22 mmol) in MeOH (5 mL)
afforded, after purification by column chromatography (silica gel,
95:5 CH2Cl2/MeOH), 0.021 g (71% combined) of 12c as a white
solid; mp: 2498C (MeOH); 1H NMR (400.16 MHz, [D6]DMSO): d=
10.92 (s, 1H), 8.95 (s, 1H), 8.2–8.1 (m, 3H), 8.0–7.9 (m, 5H), 7.7–7.6
(m, 3H), 7.5–7.4 ppm (m, 3H); 13C NMR (100.62 MHz, [D6]DMSO):
d=167.0 (s), 143.1 (s), 134.2 (s), 133.2 (s), 131.5 (s), 131.4 (d, 2”),
131.2 (d), 130.2 (d, 2”), 129.1 (d), 128.9 (d, 2”), 128.9 (d), 127.5 (d),
127.4 (d), 126.3 (s), 126.1 (s), 125.9 (d), 125.1 (d), 122.1 (s), 120.9 (s),
119.5 (d, 2”), 95.1 (s), 86.8 ppm (s); HRMS (ESI+): calcd for
C26H17NO3 [M+H]+: 391.1124, found: 391.1123; IR (NaCl): n˜ =3600–
3000 (br, OÀH), 3308 (s, NÀH), 2923 (s, CÀH), 2853 (s, CÀH), 1698 (s,
C=O), 1685 (s, C=O), 1598 (s, C=C), 1524 (m), 1275 cmÀ1 (s); purity:
97% (HPLC–UV, Sunfire C18, 1 mLminÀ1, 95:5 CH3CN/H2O, tR =
22 min).
Biochemical methods
Cell lines. HeLa reporter cells were stably transfected with an
(17m)5-bG-Luc-Neo reporter and with Gal4-mRARa (respectively b,
g) or Gal4-hRXRb plasmids. They were maintained in Dulbecco’s
modified Eagle’s medium (DMEM) containing 5% fetal calf serum
(FCS), supplemented with geneticin G418 (0.8 mgmLÀ1), puromycin
(0.3 mgmLÀ1), hygromycin (0.2 mgmLÀ1; added additionally only for
the Gal4-hRXRb-engineered HeLa cell line), and gentamycin
(40 mgmLÀ1).
Determination of RAR and RXR agonist and antagonist ligand activi-
ty. The ligand binding assays were performed in DMEM without
red phenol with 5% charcoal-treated FCS. To determine the RARa,
RARb, and RARg induction potential of the ligands, equal aliquots
(160000 cells per well) of the corresponding cell line were seeded
in a 24-well plate, and 12 h later the medium was replaced by a so-
lution of the corresponding ligand in medium. The cells were incu-
bated at 378C in 5% CO2 for 12 h. Afterward, the cells were
washed (PBS) and lysed (50 mL lysis buffer: 25 mm Tris phosphate
(pH 7.8), 2 mm EDTA, 1 mm DTT, 10% glycerol, and 1% Triton X-
100) for 15 min. Equal aliquots (50 mL) of the cell lysates were
transferred to an Optiplate-96, and the luminescence in relative lu-
minescence units (RLU) was determined on a MicroLumat LB96P
luminometer (“Berthold”) after automatic injection of 50 mL of luci-
ferin buffer (20 mm Tris phosphate (pH 7.8), 1.07 mm MgCl2,
2.67 mm MgSO4, 0.1 mm EDTA, 33.3 mm DTT, 0.53 mm ATP,
0.47 mm luciferin, and 0.27 mm coenzyme A). The receptor activa-
tion potential of each compound was presented as fold induction
measured as the ratio of RLU of the compound over the RLU of
the vehicle control.
3-Chloro-4-{[8-(phenylethyn-1-ylnaphthalen-2-yl)carbonyl]ami-
no}benzoic acid 12i. Following the general procedure for the ami-
dation of aryl halides, the reaction of 8-(phenylethyn-1-yl)-2-naph-
thamide 33c (0.03 g, 0.11 mmol), ethyl 4-iodobenzoate 30d
(0.016 mL, 0.092 mmol), (1S,2S)-cyclohexane-1,2-diamine (0.003 g,
0.022 mmol), CuI (0.002 g, 0.011 mmol) and K2CO3 (0.03 g,
0.22 mmol) in dioxane (2 mL) afforded, after purification by column
chromatography (silica gel, 95:5 hexane/EtOAc), 0.025 g of the
ester as a yellow solid. The reaction of the ester obtained above
(0.025 g, 0.056 mmol) and KOH (0.03 g, 1.85 mmol) in MeOH (5 mL)
afforded, after purification by column chromatography (silica gel,
95:5 CH2Cl2/MeOH), 0.012 g (32% combined) of 12i as a white
1
solid. H NMR (400.16 MHz, [D6]DMSO): d=9.19 (s, 1H), 8.36 (d, J=
11.8 Hz, 2H), 8.24 (d, J=8.5 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.04 (d,
J=8.3 Hz, 1H), 7.94 (dd, J=7.1, 4.7 Hz, 2H), 7.77 (d, J=7.5 Hz, 2H),
7.71 (d, J=7.7 Hz, 1H), 7.6–7.7 ppm (m, 3H); 13C NMR (100.62 MHz,
[D6]DMSO): d=166.7 (s), 150.1 (s), 145.1 (s), 134.3 (s), 131.8 (s),
131.7 (d), 131.5 (d, 2”), 129.3 (d), 129.2 (d), 129.1 (d), 128.9 (d, 2”),
128.3 (s), 127.9 (d), 126.3 (d), 125.4 (d), 124.4 (s), 124.4 (d), 121.9 (s),
120.8 (s), 119.6 (d), 112.2 (s), 112.1 (d), 95.2 (s), 86.5 ppm (s); HRMS
(ESI+): calcd for C26H16NO3Cl [M+H]+: 413.2352, found: 413.2653;
IR (NaCl): n˜ =3500–3000 (br, OÀH), 2957 (s, CÀH), 2924 (s, CÀH),
1729 (s, C=O), 1556 cmÀ1 (s, C=C).
Acknowledgements
This work was supported by grants from the Spanish MINECO
(SAF2010-17935, Juan de la Cierva Contract to F.R.-B.; SAF2013-
48397R), the Xunta de Galicia (grant 08CSA052383PR from DXI+
D+i; Consolidación 2006/15 from DXPCTSUG; INBIOMED-FEDER
“Unha maneira de facer Europa”; ngeles AlvariÇo Contract to
S.A.), and EU FP7 (BIOCAPS 316265/REGPOT-2012-2013.1). Work
3-Fluoro-4-{[8-(phenylethyn-1-ylnaphthalen-2-yl)carbonyl]ami-
no}benzoic acid 12 f. Following the general procedure for the ami-
dation of aryl halides, the reaction of 8-(phenylethyn-1-yl)-2-naph-
ChemMedChem 2015, 10, 1378 – 1391
www.chemmedchem.org
1390
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
[27] S. lvarez, H. Khanwalkar, R. lvarez, C. Erb, C. MartÌnez, F. Rodríguez-
Barrios, P. Germain, H. Gronemeyer, A. R. de Lera, ChemMedChem 2009,
4, 1630.
[28] S. lvarez, R. lvarez, H. Khanwalkar, P. Germain, G. R. Lemaire, F. Rodrí-
guez-Barrios, H. Gronemeyer, A. R. de Lera, Bioorg. Med. Chem. 2009, 17,
4345.
[29] J. Y. Chen, S. Penco, J. Ostrowski, P. Balaguer, M. Pons, J. E. Starrett, P.
Reczek, P. Chambon, H. Gronemeyer, EMBO J. 1995, 14, 1187–1197.
[30] F. C. Zusi, V. Vivat-Hannah, M. V. Lorenzi, Drug Discovery Today 2002, 7,
1165.
[31] P. Loeliger, W. Bollag, H. Mayer, Eur. J. Med. Chem. 1980, 15, 9–15.
[32] C. Martínez, M. Lieb, S. lvarez, F. Rodríguez-Barrios, R. lvarez, H. Khan-
walkar, H. Gronemeyer, A. R. de Lera, ACS Med. Chem. Lett. 2014, 5, 533.
[33] A. de Meijere, S. Bräse, M. Oestreich, Metal-Catalyzed Cross-Coupling Re-
actions and More, Weinheim, Wiley-VCH, 2014.
in the research group of H.G. is supported by the Ligue National
Contre le Cancer (laboratoire labelisØ), the Association pour la Re-
cherche sur le Cancer, the Institut National du Cancer (INCa), the
Fondation pour la Recherche MØdical (FRM), and the Aviesan/
ITMO Cancer. We are grateful to Prof. JosØ M. Gonzµlez (Universi-
dad de Oviedo) for his generous gift of Ipy.
Keywords: agonists · antagonists · arotinoids · naphthalenes ·
retinoid receptors · transactivation
[1] R. M. Evans, D. J. Mangelsdorf, Cell 2014, 157, 255.
[2] P. Germain, P. Chambon, G. Eichele, R. M. Evans, M. A. Lazar, M. Leid,
A. R. de Lera, R. Lotan, D. J. Mangelsdorf, H. Gronemeyer, Pharmacol.
Rev. 2006, 58, 712.
[34] J. Barluenga, M. A. Rodriguez, P. J. Campos, J. Org. Chem. 1990, 55,
3104.
[3] P. Germain, P. Chambon, G. Eichele, R. M. Evans, M. A. Lazar, M. Leid,
A. R. de Lera, R. Lotan, D. J. Mangelsdorf, H. Gronemeyer, Pharmacol.
Rev. 2006, 58, 760.
[4] M. Clagett-Dame, D. Knutson, Nutrients 2011, 3, 385.
[5] M. Rhinn, P. DollØ, Development 2012, 139, 843.
[6] S. Shimozono, T. Iimura, T. Kitaguchi, S.-I. Higashijima, A. Miyawaki,
Nature 2013, 496, 363.
[7] L. Altucci, M. D. Leibowitz, K. M. Ogilvie, A. R. de Lera, H. Gronemeyer,
Nat. Rev. Drug Discovery 2007, 6, 793.
[8] R. lvarez, B. Vaz, H. Gronemeyer, A. R. de Lera, Chem. Rev. 2014, 114, 1.
[9] L. Altucci, H. Gronemeyer, Nat Rev. Cancer 2001, 1, 181.
[10] S. Y. Sun, R. Lotan, Crit. Rev. Oncol. Hematol. 2002, 41, 41.
[11] M. Mark, N. Ghyselinck, P. Chambon, Annu. Rev. Pharmacol. Toxicol.
2006, 46, 451.
[12] X.-H. Tang, L. J. Gudas, Ann. Rev. Pathol. 2011, 6, 345.
[13] P. Huang, V. Chandra, F. Rastinejad, Chem. Rev. 2014, 114, 233.
[14] V. Laudet, H. Gronemeyer, The Nuclear Receptor Facts Book, San Diego,
Academic Press, 2002.
[15] H. Gronemeyer, J.-A. Gustafsson, V. Laudet, Nat. Rev. Drug Discovery
2004, 3, 950.
[16] O. Hermanson, C. K. Glass, M. G. Rosenfeld, Trends Endocrinol. Metab.
2002, 13, 55.
[17] K. Jepsen, O. Hermanson, T. M. Onami, A. S. Gleiberman, V. Lunyak, R. J.
McEvilly, R. Kurokawa, V. Kumar, F. Liu, E. Seto, S. M. Hedrick, G. Mandel,
C. K. Glass, D. W. Rose, M. G. Rosenfeld, Cell 2000, 102, 753.
[18] C. L. Smith, B. W. O’Malley, Endocr. Rev. 2004, 25, 45.
[19] Y. Sato, N. Ramalanjaona, T. Huet, N. Potier, J. Osz, P. Antony, C. Peluso-
Iltis, P. Poussin-Courmontagne, E. Ennifar, Y. MØly, A. Dejaegere, D.
Moras, N. Rochel, PLoS ONE 2010, 5, e15119.
[20] P. Germain, C. Gaudon, V. Pogenberg, S. Sanglier, N. Potier, A. Van Dors-
selaer, C. A. Royer, M. A. Lazar, W. Bourguet, H. Gronemeyer, Chem. Biol.
2009, 16, 479.
[35] N. E. Leadbeater, M. Marco, Org. Lett. 2002, 4, 2973.
[36] N. E. Leadbeater, M. Marco, J. Org. Chem. 2003, 68, 888.
[37] X. Wu, J. K. Ekegren, M. Larhed, Organometallics 2006, 25, 1434.
[38] N. E. Leadbeater, Chem. Commun. 2005, 2881.
[39] R. Chinchilla, C. Nµjera, Chem. Rev. 2007, 107, 874.
[40] R. Chinchilla, C. Najera, Chem. Soc. Rev. 2011, 40, 5084.
[41] P. Lorenzo, R. Alvarez, M. A. Ortiz, S. Alvarez, F. J. Piedrafita, A. R. de Lera,
J. Med. Chem. 2008, 51, 5431.
[42] S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633.
[43] M. Rottländer, N. Palmer, P. Knochel, Synlett 1996, 573.
[44] J. A. Marshall, M. A. Wolf, E. M. Wallace, J. Org. Chem. 1997, 62, 367.
[45] S.-Y. Han, Y.-A. Kim, Tetrahedron 2004, 60, 2447.
[46] J. F. Hartwig, Nature 2008, 455, 314.
[47] G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054.
[48] A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc.
2001, 123, 7727.
[49] M. Wolter, A. Klapars, S. L. Buchwald, Org. Lett. 2001, 3, 3803.
[50] A. Klapars, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 7421.
[51] F. Y. Kwong, A. Klapars, S. L. Buchwald, Org. Lett. 2002, 4, 581.
[52] X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L. Buchwald, J.
Am. Chem. Soc. 2003, 125, 6653.
[53] E. R. Strieter, D. G. Blackmond, S. L. Buchwald, J. Am. Chem. Soc. 2005,
127, 4120.
[54] V. Vivat, C. Zechel, J.-M. Wurtz, W. Bourguet, H. Kagechika, H. Umemiya,
K. Shudo, D. Moras, H. Gronemeyer, P. Chambon, EMBO J. 1997, 16,
5697.
[55] A. R. de Lera, W. Bourguet, L. Altucci, H. Gronemeyer, Nat. Rev. Drug Dis-
covery 2007, 6, 811.
[56] W. Bourguet, V. Vivat, J.-M. Wurtz, P. Chambon, H. Gronemeyer, D.
Moras, Mol. Cell 2000, 5, 289.
[57] P. Germain, S. Kammerer, E. PØrez, C. Peluso-Iltis, D. Tortolani, F. C. Zusi,
J. E. Starrett, P. Lapointe, J.-P. Daris, A. Marinier, A. R. de Lera, N. Rochel,
H. Gronemeyer, EMBO Rep. 2004, 5, 877.
[58] B. P. Klaholz, J.-P. Renaud, A. Mitschler, C. Zusi, P. Chambon, H. Grone-
meyer, D. Moras, Nat. Struct. Biol. 1998, 5, 199.
[21] A. le Maire, C. Teyssier, C. Erb, M. Grimaldi, S. Alvarez, A. R. de Lera, P. Ba-
laguer, H. Gronemeyer, C. A. Royer, P. Germain, W. Bourguet, Nat. Struct.
Mol. Biol. 2010, 17, 801.
[22] “Inverse Agonists and Antagonists of Retinoid Receptors”, W. Bourguet,
A. R. de Lera, H. Gronemeyer in Methods in Enzymology (Ed.: P. M.
Conn), Academic Press, New York, 2010, Vol. 485, pp. 161–195.
[23] E. PØrez, W. Bourguet, H. Gronemeyer, A. R. de Lera, Biochim. Biophys.
Acta Mol. Cell Biol. Lipids 2012, 1821, 57.
[59] B. P. Klaholz, A. Mitschler, M. Belema, C. Zusi, D. Moras, Proc. Natl. Acad.
Sci. USA 2000, 97, 6322.
[60] B. P. Klaholz, A. Mitschler, D. Moras, J. Mol. Biol. 2000, 302, 155.
[61] B. P. Klaholz, D. Moras, Structure 2002, 10, 1197.
[62] P. J. Goodford, J. Med. Chem. 1985, 28, 849.
[24] A. le Maire, S. Alvarez, P. Shankaranarayanan, A. R. de Lera, W. Bourguet,
H. Gronemeyer, Curr. Top. Med. Chem. 2012, 12, 505–527.
[25] P. Germain, J. Iyer, C. Zechel, H. Gronemeyer, Nature 2002, 415, 187.
[26] A. I. Shulman, C. Larson, D. J. Mangelsdorf, R. Ranganathan, Cell 2004,
116, 417.
Received: April 7, 2015
Published online on May 26, 2015
ChemMedChem 2015, 10, 1378 – 1391
www.chemmedchem.org
1391
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim