Design, synthesis, and structure - Activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta]-2,4,6-trienoic acids

Article abstract of DOI:10.1021/jm020401k

Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARγ) and lipid metabolism (RXR/PPARα). Previously, we described a concise structure-activity relationship stud

Full text of DOI:10.1021/jm020401k

J . Med. Chem. 2003, 46, 4087-4103
4087
Design , Syn th esis, a n d Str u ctu r e-Activity Rela tion sh ip Stu d ies of Novel
6,7-Lock ed -[7-(2-a lk oxy-3,5-d ia lk ylben zen e)-3-m eth ylocta ]-2,4,6-tr ien oic Acid s
Pierre-Yves Michellys,*,§,+ Robert J . Ardecky,§ J yun-Hung Chen,§ J ennifer D’Arrigo,# Timothy A. Grese,X
Donald S. Karanewsky,§,+ Mark D. Leibowitz,| Sha Liu,| Dale A. Mais,# Christopher M. Mapes,×
Chahrzad Montrose-Rafizadeh,£ Katheen M. OgilvieX,† Anne Reifel-Miller,∇ Deepa Rungta,#
,§
Anthony W. Thompson,§,‡ J ohn S. Tyhonas,§ and Marcus F. Boehm
Departments of Medicinal Chemistry, Pharmacology, and New Leads Discovery, Ligand Pharmaceuticals, Inc.,
10275 Science Center Drive, San Diego, California 92121, and Division of Endocrine Research, Discovery Chemistry Research,
and Lead Optimization Biology, Eli Lilly Research Laboratories, Indianapolis, Indiana
Received September 12, 2002
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play
a critical role in the regulation of glucose (RXR/PPARγ) and lipid metabolism (RXR/PPARR).
Previously, we described a concise structure-activity relationship study of selective RXR
modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic
acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here
the design and synthesis of a novel series of RXR selective modulators possessing the same
aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid
moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclo-
pentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
In tr od u ction
and PPAR.5,6 RXR:PPAR heterodimers play a major role
in the regulation of both glucose (RXR/PPARγ) and lipid
metabolism (RXR/PPARR).7 Classic RXR agonists such
as Targretin and compound 2 (LG100268, Figure 1) are
known to be very effective insulin-sensitizing agents,6,8
but suffer from undesirable side effects such as a sup-
pression of the thyroid hormone axis and an increase of
plasma triglycerides.8b Recently, we demonstrated that
the RXR-selective modulator 4 (LG101506, Figure 1)
possesses good hypoglycemic efficacy (db/db mouse model)
and a different side effects profile from the classic RXR
agonists (e.g., 2) in a rat model (Sprague Dawley rats).9
Retinoids play a major role in a wide variety of
biological functions, such as cell differentiation, prolif-
eration, and embryonic development in vertebrates.1
Retinoids, such as all-trans-retinoic acid (ATRA), 13-
cis-retinoic acid (13-cis-RA), 9-cis-retinoic acid (9-cis-RA,
Panretin) and more recently 1 (LGD1069, Targretin,
Figure 1), are administered for treatment of numerous
skin diseases such as psoriasis, acne, Kaposi’s sarcoma,
and CTCL.2 In addition, these and other retinoids have
been evaluated in both chemotherapy and chemopre-
vention of various cancers.3 Retinoids exert their bio-
logical activity through retinoid receptors which belong
to the superfamily of intracellular nuclear receptors.
Activation of these receptors results in regulation of
gene transcription.4 The retinoid receptors are divided
into two distinct families of homologous receptors, the
retinoic acid receptors (RARs) and the retinoid X recep-
tors (RXRs). Each family is further divided into three
receptor subtypes R, â, and γ each encoded by a single
gene.5
RXR-selective molecules representing several struc-
turally different scaffolds are represented in Figure 1.10
Analogues of the potent RAR compound ALRT155011
(compounds 5 and 6) possess cyclopentyl or cyclopropyl
ring replacements of the 6-7-olefin in the trienoic acid
moiety.12,13 This effectively locks the 6,7-olefin in a cis
conformation, which instills potent RXR activity. The
thioethers 7a ,b and more recently the 1,2,3,4-tetrahy-
droquinoline-6-fluorotrienoic acid derivative 8 have also
been described as potent RXR selective ligands.14,15
Other structures such as the diazepinylbenzoic acid
derivative 14 (HX600, a potent RXR agonist),16 11
(AGN191701, an RXR selective pan-agonist that is an
effective modulator of endothelial cell proliferation),17
and compound 12 (SR11246, an RXR selective agonist
that shows antiproliferative activity on prostate cancer
cells)18 have been described. Compound 9 (AGN 194204)
has recently been reported to be a very potent hypogly-
cemic agent.19 Interestingly, its antipode does not show
any hypoglycemic activity. Heterodimer selectivity of 9
and its antipode is unknown, but one may speculate that
one antipode activates the RXR:PPARγ heterodimer
while the other does not.
RXR has long been recognized to form homodimers
(RXR:RXR) and heterodimers with various other nuclear
receptors, including RAR, TR, VDR, NGFIB, LXR, FXR,
* Correspondence author. Current address: Department of Medici-
nal Chemistry, Genomics Institute of Novartis Research Foundation,
San Diego, CA 92121. Phone: (858) 332 4781, Fax: (858) 812 1648.
E-mail: pmichellys@gnf.org
§ Department of Medicinal Chemistry, Ligand Pharmaceuticals.
| Department of Pharmacology, Ligand Pharmaceuticals.
∇ Division of Endocrine Research, Eli Lilly Research Laboratories.
X Discovery Chemistry Research, Eli Lilly Research Laboratories.
#
Department of New Leads Discovery, Ligand Pharmaceuticals.
Lead Optimization Biology, Eli Lilly Research Laboratories.
£
Current address: Conforma Therapeutics, San Diego, CA
+ Current address: Genomics Institute of Novartis Research Foun-
dation, San Diego, CA
‡ Current address: Roche Bioscience, Palo Alto, CA.
× Current address: J ohnson and J ohnson, San Diego, CA.
† Current address: Pfizer Inc., San Diego, CA.
Previous published results have already demon-
strated that similar molecules having a cyclopentyl-
10.1021/jm020401k CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003

4088 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
F igu r e 1. RXR-selective synthetic ligands.
locked or cyclopropyl-locked trienoic acid linked to a
substituted 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl moiety possess RXR agonist selectivity (see
5, 6, and 9, Figure 1). More recently, we discovered that
the use of a fluorinated alkoxy side chain greatly
increases the plasma concentration of compounds such
as 4 as compared to its nonfluorinated analogues.9 In
the course of our structure activity relationship studies
to design new and potentially more stable RXR modula-
tors, we combined the restricted locked-trienoic acid
motif of molecules 5 and 6 with the 3,5-dialkyl-6-
fluoroalkoxybenzene platform present in 4. We describe
here a structure-activity relationship study of new
RXR-selective modulators possessing various dienoic-
acids combined with fluorinated 6-alkoxy side-chains
(Figure 2) which results in comparable or improved in
vitro profiles over our lead compound 4.
Ch em istr y
Ortho-iodination of the 2,4-di-iso-propylphenol 15
proceeds in yields greater than 90% by using 1.1 equiv
of N-iodosuccinimide (NIS) and a catalytic amount (10%)
of TsOH in CH2Cl2. Introduction of the MOM protecting
group onto the free phenol 16 is achieved quantitatively
by using chloromethyl methyl ether and NaH in DMF.
The boronic acid 18 is obtained by lithiating 17 in a 1:2
mixture of THF/Et2O with n-BuLi (1.2 equiv) at -78
°C, followed by a quench with an excess (2.3 equiv) of
B(OMe)3. Once the sample is warmed to RT, the crude
boronate is stirred with 1 N HCl, releasing the corre-
sponding boronic acid 18 in good yield (80-90%). The
principle synthetic step involved in the preparation of
compounds 25a -c is a Suzuki coupling of 18 with the
commercially available ethyl-2-(trifluoromethylsulfonyl-
oxy)-1-cyclopentene-1-carboxylate using 10% Pd(PPh3)4
and 2 equiv of 2 N aq. Na2CO3 in refluxing toluene/
EtOH (1:1).20 Submitted to these conditions, the reaction
smoothly produced the adduct 19 in excellent yield
(>90%). The cyclization of 19 into the coumarin 20
proceeds quantitatively by simple acidic cleavage (6 N
HCl, THF, RT) of the MOM group. Reduction of 20 to
the phenolic alcohol 21 is achieved using 1 equiv of
NaAlH4 in THF at 0 °C. The alkoxy side chain is easily
introduced by a selective alkylation of the phenol (Cs2-
CO3 in DMF at room temperature), affording 22a -c in
almost quantitative yields. Oxidation of the resultant
allylic alcohols 22a -c with a catalytic amount (5-10%)
of tetrapropylammonium perruthenate (TPAP) and an
excess (1.5 eq.) of 4-methylmorpholine N-oxide (NMO)
in CH2Cl2 yields the corresponding aldehydes 23a -c.9,21
These aldehydes are directly subjected to a Horner-
F igu r e 2.

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4089
Sch em e 1 Cyclopentenyl Dienoic Acids Synthetic Patha
a
Reagents and conditions: (a) NIS, TsOH, CH2Cl2, RT. (b) NaH, MOMCl, DMF, 0 °C to RT. (c) n-BuLi, B(OMe)3, THF/diethyl ether,
-78 °C to RT then HCl. (d) Ethyl-2-(trifluoromethylsulfonyloxy)-1-cyclopentene-1-carboxylate, Pd(PPh3)4, 2 N aq. Na2CO3, toluene/ethanol,
reflux. (e) Aq. 6 N HCl, THF, RT. (f) NaAlH4, THF, 0 °C to RT. (g) R-Br, Cs2CO3, DMF, RT. (h) TPAP, NMO, CH2Cl2, RT. (i) Triethyl-
3-methylphosphonocrotonate, n-BuLi, THF/DMPU, -78 °C to RT. (j) 2 N aq. LiOH, EtOH, reflux then HCl and recrystallization from
CH3CN.
Wadsworth-Emmons reaction with the anion of triethyl-
3-methylphosphonocrotonate (previously prepared by
slow addition of n-BuLi to a solution of the phosphonate
in THF-DMPU (1:2) at -78 °C) to afford the corre-
sponding esters 24a -c in a combined yield greater than
85%.9,10d,22 Hydrolysis of the esters 24a -c with 2 N
LiOH in refluxing methanol/THF afford the crude
dienoic acids 25a -c. Recrystallization of these crude
acids from CH3CN delivers the pure (2Z,4E)-dienoic
acids in good yield and excellent isomeric purity (>95%).
Schemes 2 and 3 describe the synthesis of selected
aromatic and heteroaromatic dienoic acids. The phenols
16 and 26 were easily alkylated with various fluoroalkyl
bromides using the reaction condition described in
Scheme 1. Due to the high volatility and reduced
reactivity of the 2-bromo-1,1,1-trifluoroethane, a varia-
tion of this procedure was used to install the 2,2,2-
trifluoroethoxy side chains of 27c. The reaction was
conducted in a sealed tube at 50 °C for 16 h using 2
equiv of 2-bromo-1,1,1-trifluoroethane followed by usual
workup and column purification. Under these condi-
tions, 27c was obtained in 65% yield.9 Every locked
structure 29a -c, 32, 35a ,b, 36, 42, and 45 was syn-
thesized by using a Suzuki coupling between the iodides
27a -c or 28a ,b and the 2-formylfuran, 2-formylth-
iophene, and 2-formylbenzene boronic acids (Scheme 2)
or between 41 and 3-bromo-4-formyl pyridine or ethyl-
2-(trifluoromethylsulfonyloxy)-1-cyclopentene-1-carbox-
ylate (Scheme 3). In each case, the reactions were
conducted using standard coupling procedure (aq. Na2-
CO3, Pd(PPh3)4, in refluxing toluene/EtOH) except for
the synthesis of 32 where a solution of aqueous Na2-
CO3 and Pd(PPh3)4 (5-10%) in refluxing DME was used
(no desired product 32 was observed using the standard
conditions). This reaction was particularly capricious
due to the high reactivity of this boronic acid and
typically gave very low yields of desired product (<10%).
Otherwise 29a -c, 35a ,b 36, 42, and 45 (Scheme 2) were
obtained in very good yield (>90%). The boronic acid
41 (Scheme 3) was synthesized from the iodide 27c by
trapping the corresponding lithiated anion (prepared
from slow addition of n-BuLi to a solution of 27c in the
presence of TMEDA at -78 °C) with B(OMe)3 followed
by acidic workup. 29a -c, 32, 35a ,b, 36, 42, and 45 were
directly subjected to the reaction sequence described
previously in Scheme 1 to produce the crude acids 31a -
c, 34, 39a ,b, 40, 44, and 49 that were purified by
recrystallization from CH3CN.
Compounds 55a ,b (Scheme 4) were synthesized ac-
cording to the synthetic path described in Scheme 4 from
the commercially available 2-tert-butyl-4-ethylphenol 50
and represent a beginning for structure-activity rela-
tionship studies around the benzene core ring. The acids
55a ,b were purified by recrystallization from CH3CN.
Scheme 5 describes the introduction of the 3,3-
difluoropropoxy side-chain. Initial attempts to introduce
a 3,3,3-trifluoropropyl side chain using 3-bromo-1,1,1-
trifluoropropanewere unsuccessful. No desired product
was observed using various bases (NaH, K2CO3, CsF,
Cs2CO3) or solvents (DMF, THF, or DMSO) even with
the use of a pressure tube. However, subsequent at-
tempts to synthesize the 1,1-difluoropropoxy side chain
from the corresponding 3-hydroxypropoxy compound 56
were successful. Alkylation of the phenol 26 with tert-
butyldimethysilyloxy-3-bromopropane in DMF in the
presence of NaH at 0 °C, followed by cleavage of the
TBS group with TBAF, afforded the alcohol 56. Oxida-
tion of 56 with PCC/Celite in CH2Cl2 yielded the
corresponding aldehyde 57 directly followed by treat-
ment with DAST in CH2Cl2 at room temperature
overnight to give the fluorinated intermediate 58.23
Compound 58 was isolated in good overall yield (>75%).

4090 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
Sch em e 2. Thienyl, Furyl, and Phenyl Dienoic Acids Synthesisa
a
Reagents and conditions: (a) Cs2CO3, R-Br, DMF, RT, except for 27c (50 °C in a sealed tube, 16 h). (b) Pd(PPh3)4, 2-formylthiophene-
3-boronic acid, Na2CO3, toluene/EtOH, reflux. (c) Triethyl-3-methylphosphonocrotonate, n-BuLi, THF/DMPU, -78 °C to RT. (d) 2 N aq.
LiOH, EtOH, reflux then HCl and recrystallization from CH3CN. (e) 2-Formylfuran-3-boronic acid, Na2CO3, DME, reflux. (f)
2-Formylbenzene boronic acid, Na2CO3, toluene/EtOH, reflux.
Synthesis of 61 followed the synthetic path described
in Scheme 3 using the iodide 58 and 2-formylthiophene-
3-boronic acid. The acid 61 was purified by recrystalli-
zation from CH3CN.
animals. The results are shown in Table 3. At 2 h post
dose, the agonist 2 raised triglycerides substantially,
while the RXR modulator 4 did not. At 24 h post dose,
the agonist 2 caused a significant decrease in T4 levels
(2.2-fold) and 4 did not. In summary, compound 4
showed the same efficacy on the glucose endpoint as
either BRL49653 or 2 but did not raise triglycerides nor
decrease T4 levels in Sprague Dawley rats, overcoming
two of the physiological side effects associated with RXR
agonists such as 2 in these animal models. As a result,
compound 4 is used as our standard for in vitro profiling
of the new RXR-selective modulators described in this
communication.
Resu lts
P h a r m a cologica l R eleva n ce of R XR -Select ive
Mod u la tor s. The pharmacology of RXR-selective modu-
lators such as compound 4 was fully described in our
previous communication.9 The ability of 4 to lower
plasma glucose was evaluated in the db/db mouse and
is summarized in Table 1. These mice have a leptin
receptor defect rendering them progressively obese,
hyperglycemic, and hypertriglyceridemic with age and
are commonly used as a model of type 2 diabetes.
BRL49653 and 2 served as positive controls for glucose
lowering efficacy in these experiments and the data
were compared both to a vehicle treated group of db/db
animals and to a group of age-matched lean littermates.
Compound 4 was given orally as a single agent at 30
mg kg-1 day-1, while 2 and BRL49653 were used at 10
mg kg-1 day-1. After 7 days of treatment, compound 4
was as efficacious as BRL 49653, which typically gives
55% glucose reduction in our hands.
Biological Evalu ation of Com pou n ds 25a -c, 31a-
c, 34, 39a ,b, 40, 44, 49, 55a ,b, a n d 61. The binding to
RXRR,â,γ, RARR,â,γ, and PPARR,γ of each synthesized
3
compound was characterized by competition with [H]-
3
9-cis-RA for RXRs and [H]-ATRA for RARs (shown as
Ki, Table 3). The binding affinity for the PPARs was
characterized using a proprietary radioactive ligand as
described previously.25 The RXR transcriptional activa-
tion profile of each compound was determined in CV-1
cells with the AOX response element used as the
reporter. The efficacy was measured relative to LGD1069
for RXRs and ATRA for RARs (Table 4). For the RXR:
PPARγ heterodimer activity, the same AOX reporter
construct was used and the efficacy was measured
relative to BRL49653 for PPARγ.
Side effects (triglycerides and T4 levels) were evalu-
ated in the Sprague Dawley Rat, which is a more
sensitive model than the db/db mouse for triglycerides
and thyroid axis effects.24 Triglycerides and T4 levels
were measured at 2 and 24 h, respectively, following
administration of a single oral dose (30 mg/kg) to na¨ıve
It has been already demonstrated that RXR agonists
such as compound 2 (entry 1, Table 4) activate the RXR:

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4091
Sch em e 3. 3-Pyridyl Dienoic Acid Synthesisa
a
Reagents and conditions: (a) n-BuLi, TMEDA, THF, -78 °C then aq. HCl. (b) Pd(PPh3)4, 3-bromo-4-formylpyridine, Na2CO3, toluene/
EtOH, reflux. (c) Triethyl-3-methylphosphonocrotonate, n-BuLi, THF/DMPU, -78 °C to RT. (d) 2 N aq. LiOH, EtOH, reflux then HCl
and recrystallization from CH3CN. (e) Ethyl-2-(trifluoromethylsulfonyloxy)-1-cyclopentene-1-carboxylate, Pd(PPh3)4, 2 N aq. Na2CO3,
toluene/ethanol, reflux. (f) AlLiH4, THF, 0 °C to RT. (g) TPAP, NMO, CH2Cl2, RT.
Sch em e 4. Modified Benzene Core Ring Thienyl Dienoic Acids Synthesisa
a
Reagents and conditions: (a) NIS, TsOH (10%), CH2Cl2. (b) Cs2CO3, R-Br, DMF, RT. (c) Pd(PPh3)4, 2-formylthiophene-3-boronic
acid, toluene/ethanol, reflux. (d) Triethyl-3-methylphosphonocrotonate, n-BuLi, THF/DMPU, -78 °C to RT. (e) 2 N aq. LiOH, EtOH,
reflux then HCl and recrystallization from CH3CN.
PPARγ heterodimer when used alone and in a syner-
gistic manner when they are used in combination with
a PPARγ ligand (e.g., BRL49653).6 Other studies have
shown that this in vitro observation translates into a
similar in vivo effect.6 In the case of RXR modulators
(e.g., 4, Table 4, entry 3), the RXR:PPARγ heterodimer
activation is of a much lower amplitude than observed
with RXR agonists. Ultimately, no activation of the
RXR:PPARγ heterodimer is observed for full RXR
antagonists (data not shown). Again, when the same
RXR modulators are used in combination with a PPARγ
agonist (e.g., BRL49653), a much cleaner response with
a larger window of the activity was observed.9
To further characterize the compounds described in
this communication, we used compounds both alone or
in combination with BRL49653 to determine their RXR:
PPARγ activation (Table 4).
Previous data have shown that RXR homodimer
activity can be affected by elongation of the 6-alkoxy
side-chain of this type of molecule.9,26 As a general rule,
a short side-chain (e.g., methoxy or ethoxy) produces
RXR homodimer agonists, while a longer side-chain
results in RXR homodimer antagonists. We have dem-
onstrated that this activity can also be tuned by the use
of fluorine in this particular side chain to produce a
smooth transition between RXR homodimer agonist,
partial agonist, and antagonist activity. The switch from
agonist to antagonist typically happens between an
ethoxy and a propoxy side-chain. While the same
paradigm applies to the series of compounds presented
in this communication,27 we chose to focus on the
synthesis and biological evaluation of selected examples
of each series containing a 6-fluorinated alkoxy side
chain.
Bin d in g Da ta . All of the compounds shown in Table
3 bind with very high affinity to the RXR receptors R,
â, and γ subtype. In fact, one of the compounds (25b)
has sub-nanomolar affinity for RXRR, Table 3, entry 11).
In general, the compounds described in Table 3 tend to
exert some degree of selectivity for RXRR over RXRâ
and RXRγ (exceptions are 31a , 34, 44, 49, and 55b,
Table 3, entries 7, 13, 14, 16, and 4, respectively). No
RARâ or RARγ binding was observed (Ki > 5000 nM)
with the exception of compounds 25c and 44 which
exhibit respective Ki values of 2221 and 1109 nM for
RARγ (Table 3, entries 10 and 14) and compounds 31a ,

4092 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Sch em e 5. 3,3-Difluoropropoxy Side Chain Synthesisa
Michellys et al.
a
Reagents and conditions: (a) NaH, tert-butyldimethylsilyloxy-3-bromopropane, DMF, 0 °C, then TBAF in THF. (b) PCC/Celite/molecular
sieve, CH2Cl2. (c) DAST, CH2Cl2 RT. (d) 2-Formylthiophene-3-boronic acid, Na2CO3, toluene/EtOH, reflux. (e) Triethyl-3-methyl
phosphonocrotonate, n-BuLi, THF/DMPU, -78 °C to RT. (f) 2 N aq. LiOH, EtOH, reflux then HCl and recrystallization from CH3CN.
Ta ble 1. Hypoglycemic Activity of 4 in the db/ db Mouse Model after 7 days of Dosing
compounds
lean control (mg/dL)
db/db control (mg/dL)
drug treated db/db (mg/dL)
% normalization vs BRL46953a
BRL 49653
2
4
205 ( 5
207 ( 5
203 ( 5
750 ( 15
740 ( 15
749 ( 10
412 ( 10
400 ( 5
409 ( 6
100
101
101
aBRL49653 used as reference compound for efficacy (100%).
Ta ble 2. Triglycerides and T4 Levels Effect of 2 and 4 in Male
Sprague Dawley Rats at 24 h
respectively (Table 3, entries 5 and 4 respectively), and
are the only compounds with a Ki < 3000 nM for PPARγ.
compounds
triglycerides (mg/dL) 72 ( 10
T4 (ng/mL) 73 ( 4
control BRL 49653
2
4
Cotr a n sfection Eva lu a tion . When evaluated in the
cotransfection assay, the compounds shown in Table 4
are potent RXR homodimer inhibitors with IC50 values
ranging from 2 to 271 nM. The best compounds also
exhibit >79% inhibition of the RXR homodimer. Only
25b and 31a show low efficacy (38 and 42% respectively,
Table 4, entries 8 and 12) in the assay although both
exhibit good potency (5.1 and 11.4 nM, respectively).
Both compounds (25b and 31a ) possess a 2,2-difluoro-
ethoxy side chain and show a partial agonist profile (16
and 17% efficacy, respectively) in the cotransfection
assay. Compounds 39a and 55a also possess the same
78 ( 5
70 ( 3
152 ( 10 75 ( 5
37 ( 2 70 ( 5
44, and 49 that have respective Ki values of 4064, 2056,
and 4742 nM for RARâ (Table 3, entries 7, 14, and 16).
All of the compounds also have weak affinity for RARR
(Ki > 1300 nM). None of the described compounds show
any binding to PPARR. Evaluation of PPARγ activity
showed that the majority of the compounds bind weakly
(1750 < Ki < 6750 nM) or not at all, while two analogues
55a and 55b have Ki values of 1750 and 2607 nM,
Ta ble 3. Binding Affinity of Compounds 25a -c, 31a -c, 34, 39a ,b, 40, 44, 49, 55a ,b, and 61 for RXRR, â, γ, RARR,â,γ, and
PPARR,γa
RXRR
Ki (nm)
RXRâ
Ki (nM)
RXRγ
Ki (nM)
RARR
Ki (nM)
RARâ
Ki (nM)
RARγ
Ki (nM)
PPARR
Ki (nM)
PPARγ
Ki (nM)
entries
compds
1
2
3
4
5
6
7
8
2
4
18 ( 1
3 ( 2
20 ( 12
9 ( 4
18 ( 11
12 ( 6
>1000
2745
1399
>10000
5650
3410
2569
7500
>10000
2481
3726
>1000
3671
>10000
3442
8788
>1000
4687
5623
8064
8000
>1000
>1000
>1000
>10000
>10000
>10000
>10000
>10000
>10000
2221
>10000
>10000
>10000
1109
>10000
>10000
5409
>1000
>10000
>1000
>1000
5590
3224
1750
2607
3151
3149
>10000
>10000
4706
25a
55b
55a
31b
31a
39b
40
25c
25b
39a
34
1.9 ( 0.2
9.9 ( 3.8
3.2 ( 1.9
3.4 ( 0.8
2.2 ( 1.5
15.2 ( 2.7
20.9 ( 5.1
1.9 ( 1.3
0.9 ( 0.2
29.6 ( 12.3
6.2 ( 2.3
48.0 ( 25.4
8.7 ( 2.7
1.0 ( 0.8
1.9 ( 0.9
6.0 ( 0.3
6.9 ( 2.3
5.2 ( 3.0
2.9 ( 1.3
1.6 ( 1.0
23.9 ( 8.2
26.0 ( 4.3
5.7 ( 2.3
2.5 ( 1.4
42.1 ( 15.3
7.2 ( 2.3
51.5 ( 16.2
15.1 ( 8.3
0.9 ( 0.6
5.3 ( 3.1
4.9 ( 0.1
4.9 ( 2.1
6.9 ( 2.6
10.0 ( 3.4
2.5 ( 1.3
48.6 ( 31.2
154.7 ( 25.1
7.6 ( 2.8
1.9 ( 0.8
73.9 ( 30.0
6.6 ( 2.5
63.2 ( 31.0
18.1 ( 6.5
15.9 ( 11.0
13.9 ( 4.1
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
4064
>10000
>10000
8269
>10000
>10000
>10000
2056
9
10
11
12
13
14
15
16
17
4715
4285
>10000
>10000
6571
44
31c
49
>10000
4742
61
5409
>10000
6571
a
Ki calculated using [3H]-9-cis-RA for RXR, [3H]-ATRA for RAR, and proprietary [3H]-selective ligand for PPARR,γ. All data shown in
nM.

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4093
Ta ble 4. In Vitro Evaluation of RXR Modulators in CV-1 Cells. Ki Calculated Using [3H]-9-cis-RA for RXR and [3H]-ATRA for RARa
RXRR
RXRR
RXRR
RXRR
antagonist
IC50
RXRR/
PPARγ
efficacy
(%)
RXRR/
PPARγ
EC50
RXRR/
PPARγ
RXRR/
PPARγ
synergy
EC50 (nM)
RXR/
RAR
synergy
(fold)
agonist agonist antagonist
efficacy
(%)
EC50
(nM)
efficacy
(%)
synergy
entries
compds
(nM)
(nM)
efficacy (%)
1
2
3
4
5
6
7
8
BRL49653 NA
NA
NA
12
NA
0
100 ( 5 325 ( 15
NA
NA
NA
7.0
2.0
1.9
1.9
3.1
1.8
3.0
1.4
1.5
2.1
3.5
1.6
2.5
2.3
2.0
3.1
1.9
2
4
70 ( 21 11 ( 10
62
11
99 ( 11
166 ( 57
60 ( 29
140 ( 36
76 ( 19
89 ( 36
141 ( 21
145 ( 3
69 ( 12
23 ( 12
131 ( 36
181 ( 10
104 ( 11
207 ( 30
65 ( 19
117 ( 19
128 ( 25
66 ( 5
38 ( 20
4 ( 2
15 ( 6
3 ( 1
8 ( 2
3 ( 1
17 ( 3
1 ( 1
0 ( 0
2 ( 1
16 ( 3
3 ( 1
5 ( 3
2 ( 0
3 ( 0
13 ( 7
0 ( 0
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
84 ( 10
72 ( 6
83 ( 3
61 ( 13
79 ( 5
42 ( 7
87 ( 2
88 ( 1
80 ( 5
38 ( 6
81 ( 1
77 ( 11
89 ( 1
87 ( 2
79 ( 1
93 ( 1
8.0 ( 4.2
4.5 ( 3.2
10.3 ( 5.7
15.5 ( 10.5
6.8 ( 3.4
11.4 ( 0.1
49.6 ( 32.3
46.3 ( 2.4
3.3 ( 1.6
5.1 ( 0.7
79.9 ( 47.2
11.6 ( 7.7
131.5 ( 25.6
3 ( 1
25a
55b
55a
31b
31a
39b
40
43 ( 10 19.2 ( 27.3
4.4 ( 1.3
45 ( 11 202.6 ( 36.0
13.6 ( 7.1
15.3 ( 9.2
37.1 ( 14.7
117.4 ( 34.8
54.2 ( 12.6
23.8 ( 12.1
4.6 ( 2.5
44 ( 6
556.2 ( 251.6
55 ( 14 623.9 ( 365.8
52 ( 12 1716.1 ( 375.3
9
20 ( 5
2 ( 1
52 ( 7
59 ( 6
23 ( 8
736.7 ( 303.1
10
11
12
13
14
15
16
17
18
NC
25c
25b
39a
34
44
31c
49
1604.0 ( 303.4
8.8 ( 4.3
1723.8 ( 206.7
2.4 ( 0.6
155.8 ( 91.5
26.0 ( 3.7
136.6 ( 44.5
12.4 ( 6.4
7.1 ( 6.6
51 ( 17 173.6 ( 30.8
271.2 ( 80.3 28 ( 5
1272.7 ( 310.4
110.0 ( 36.9
10.4 ( 10.5
2.3 ( 1.9
8.7 ( 3.2
45 ( 3
43 ( 13 802.0 ( 299.1
16 ( 5 508.7 ( 150.2
61
15.0 ( 10.6
a
RXR:PPARγ synergy mode calculated using 100 nM of BRL49653, efficacy relative to BRL49653. RXR:RAR synergy calculated using
3 nM of TTNPB, fold elevation over DMSO background. NA: no activity, NC: not calculated. All data shown in nM.
2,2-difluoroethoxy side chain but associated to a differ-
ent locked-trienoic acid (phenyl instead of thienyl or
cyclopentyl for 39a ) or a different benzene core ring (3-
ethyl instead of 3-isopropyl for 55a ). Unlike 25b and
31a , 39a and 55a (Table 4, entries 13 and 6, respec-
tively) display a full RXR homodimer antagonists
profile. Moreover, many of the compounds represented
in Table 4 can activate the RXR:PPARγ heterodimer
when used alone. This result contrasts with the reported
activity of compounds belonging to the trienoic acid
series represented by 4 (Figure 2 and Table 4, entry 3)
which show very low efficacy on the RXR:PPARγ het-
erodimer when they are tested alone. However, only 25a
and 25b showed EC50 values below 20 nM, Table 4,
entries 4 and 12) while maintaining reasonable efficacy
(43-59%). Many of the other compounds were consider-
ably less potent (110 < EC50 < 1604 nM) but showed
reasonably high efficacy >50%).
As expected, the concomitant use of the RXR ligands
with BRL49653 produces a much greater response in
the RXR:PPARγ heterodimer assay than RXR or
BRL49653 ligands used alone. All showed a synergistic
increase in efficacy and potency response with the
exception of 31a , 39a , and 44 (EC50 > 100 nM, Table 4,
entries 8, 13, and 15). For example, compounds 25c and
49 (Table 4, entries 11 and 17) show an increase in
efficacy from 52 and 43%, to 131 and 117%, respectively.
This was also accompanied by an impressive increase
in the potency from 1604 and 802 nM to 4.6 and 7.1
nM, respectively. With the exception of 40 (Table 4,
entry 10), all the compounds from Table 4 showed
similar or better synergystic RXR:PPARγ response than
our lead compound 4.
(Table 4, entries 2 and 3). Similarly, we characterized
the compounds from this communication using the RXR:
RAR synergy assay. Results described as fold induction
over DMSO background are collected in Table 4. While
the RXR:RAR synergy closely correlated with the ago-
nist activity in the trienoic acid series (exemplified by
4),9 it clearly appeared that the locked derivatives show
a different profile in that assay. Most of the compounds
show reduced synergistic activity (<2-fold, Table 4,
entries 4, 5, 7, 9, 10, 13, 16, and 18, respectively,
compounds 25a , 55b, 31b, 39b, 40, 39a , 31c, and 49).
However, compounds such as 55a , 31a , 25b, 34, 44, and
49 show some level of RXR:RAR synergy (2.3<fold< 3.5,
Table 4, entries 6, 8, 12, 14, 15, and 17) while retaining
similar RXR homodimer antagonist activity.
Interestingly, for a given alkoxy side-chain, the RXR
homodimer activity can be modulated using different
locking structures and/or introducing different benzene
ring substitution patterns. For example, 25b, 31a , 39a ,
and 55a possess the same 2,2-difluoroethoxy side chain,
but 39a shows no RXR homodimer activation, while 25b
and 31a show weak RXR homodimer activation (Table
4, entries 4, 8, 13, and 6). Although 39a and 55a share
the same 3,5-di-iso-propyl-6-(2,2-difluoroethoxy)benzene
scaffold, 39a possesses a phenyl-locked structure instead
of a cyclopentyl or thienyl-locked moiety and is an RXR
homodimer activator, whereas 55a possesses a thienyl-
trienoic acid moiety (same pattern as 31a ) combined
with a 2-ethyl-5-tert-butylphenyl core instead of a 3,5-
di-iso-propyl core and does not activate the RXR ho-
modimer.
Discu ssion
In our previous communication, we described an RXR:
RAR synergy assay as a measure of potential side effects
associated with RAR activation. We used the RXR test
compound in combination with an EC30 of a potent RAR
agonist (TTNPB), a concentration which could produce
a synergistic response. The results showed that com-
pounds such as 4 dramatically decreased activation of
the RXR:RAR heterodimer compared to classic RXR
agonists such as 2 when evaluated in a synergy mode
From these structure activity relationship studies it
is apparent that the trienoic acid scaffold can be
replaced with a variety of locked-trienoic acid moieties
(cycloalkyl, aromatic, and heteroaromatic) without se-
vere loss of RXR activity or RXR selectivity. Cyclopentyl
and thienyl-locked trienoic acids are better replace-
ments of the trienoic acid moiety than phenyl and
pyridine-locked compounds which consistently show
weaker affinity for the RXR receptor (however, still in

4094 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
on a Bru¨ker AC 400 or a Varian VXR 500 S spectrometer.
Melting points were taken on an Electrothermal IA9100
Digital apparatus and are uncorrected. Mass spectra were
taken on a Gilson 215 LC-MS apparatus. “Brine” refers to a
saturated aqueous solution of NaCl. Unless otherwise speci-
fied, solutions of common inorganic salts used in workups are
aqueous solutions. All moisture sensitive reactions were car-
ried out using oven-dried or flame-dried round-bottomed flasks
and glassware under an atmosphere of dry nitrogen. All
reagents and solvents were used without further purification
unless otherwise noted. Most reactions were monitored by thin-
layer chromatography (TLC) using Merck TLC glass plate
precoated with silica gel F254 (0.2-mm thick). Flash chroma-
tography was performed using Merck silica gel 60. HPLC of
the final carboxylic acids were realized on a KROMASIL
column (C18 100 Å, 5 µM) using reverse phase (eluent: MeOH/
H2O + 0.1% TFA).
the low nanomolar). This is probably due to a slight
change in the tortional angle between the locked-trienoic
acid and the aromatic scaffold. Previous communica-
tions have shown that this angle is critical for RXR
activity.28 Interestingly, we found that the cyclopentyl-
trienoic acids are significantly less chemically stable
than the parent trienoic acid whereas thienyl, phenyl,
and pyridyl-trienoic acids display a comparable or better
chemical stability relative to the reference trienoic
acids.29 Nearly all of the compounds from Table 4 show
weak activation (<2-fold) of the RXR:RAR heterodimer
when used in combination with 3 nM of an RAR agonist
(e.g., TTNPB) except 49, 31a , 25b, 34, and 55a (Table
4, entries 17, 8, 12, 14, and 6, respectively) which show
greater than 2-fold activation. In most of the cases, the
RXR:RAR synergy observed is comparable or lower than
that measured with 4.
To synthesize these compounds, we constructed com-
plex molecules in relatively few steps using simple and
reproducible chemical reactions including transition
metal catalysis (Suzuki coupling), phenol alkylation,
Horner-Wadsworth-Emmons reaction and saponifica-
tion. Fluorinated alkoxy side chains were introduced
using procedures previously described, except for com-
pound 61. Due to the unavailability of the 3-bromo-1,1-
difluoropropane, we introduced this particular side
chain at an earlier stage of the synthesis. Although each
intermediate can be purified by silica gel chromatogra-
phy, in most of the cases, the whole synthetic sequence
could be performed using minimal purification over a
silica plug for each intermediate, with crystallization
of the final dienoic-acids from CH3CN. Most of the
intermediates including 16, 20, 26, and 41 are chemi-
cally stable and can be stored for several months.
2,4-Di-iso-p r op yl-6-iod op h en ol (16). To a solution of 52.2
g (0.293 mol) of 15 and 5.6 g (0.029 mol) of p-toluenesulfonic
acid in 300 mL of CH2Cl2 was added 72.6 g (0.322 mol) of
N-iodosuccinimide (NIS) portionwise at room temperature.
After complexion of the reaction (TLC monitored), 200 mL of
a 10% aqueous Na2S2O3 was added and the mixture was
stirred until the aqueous layer became milky. After separation,
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL) and
the organic layers were combined and dried over MgSO4. After
filtration and concentration, the residue was purified over
silica gel (eluent: ethyl acetate/hexane, 5/95) to afford 89.1 g
1
(0.29 mol, yield: 99%) of 16 as a deep red oil. H NMR (400
MHz, CDCl3) δ 7.33 (d, J ) 2.1 Hz, 1H), 7.00 (d, J ) 2.0 Hz,
1H), 4.83 (s, 1H), 3.28 (heptet, J ) 6.9 Hz, 1H), 2.80 (heptet,
J ) 6.9 Hz, 1H), 1.23 (d, J ) 6.8 Hz, 6H), 1.21 (d, J ) 6.8 Hz,
6H).
3,5-Di-iso-p r op yl-6-m eth oxym eth oxy Iod op h en ol (17).
To a slurry of sodium hydride (1.6 g, 0.04 mol) dissolved in
225 mL of anhydrous N,N-dimethyl-formamide (DMF) in a
flame dried 500 mL round-bottom flask at 0 °C was added
dropwise 10.0 g (0.033 mol) of 16 in 25 mL of DMF. The
mixture was stirred at 0 °C for 30 min followed by dropwise
addition of 3.22 g (0.04 mol) of methyl chloromethyl ether. The
resultant reaction mixture was allowed to warm to ambient
temperature and stirred for 3.0 h. The contents of the flask
were poured into iced brine (200 mL) and stirred for 0.5 h.
The aqueous layer was extracted with diethyl ether (2 × 200
mL) and the organic layers were combined, washed (brine),
dried (MgSO4), and concentrated under reduced pressure. The
concentrated product was filtered through a silica gel plug
(eluting with diethyl ether) and concentrated under reduced
pressure to give 11.3 g (0.032 mol, yield: 97%) of 17 as a red
oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J ) 1.8 Hz, 1H),
7.06 (d, J ) 1.8 Hz, 1H), 5.05 (s, 2H), 3.65 (s, 3H), 3.40 (heptet,
J ) 6.9 Hz, 1H), 2.81 (heptet, J ) 6.9 Hz, 1H), 1.26 (d, J ) 6.5
Hz, 6H), 1.21 (d, J ) 6.6 Hz, 6H).
3,5-Di-iso-p r op yl-6-(m eth oxym eth oxy)ben zen e Bor on -
ic Acid (18). To 10.0 g (0.029 mol) of compound 17 dissolved
in 150 mL of a 1:2 mixture of diethyl ether-THF in a flame
dried 300 mL round-bottom flask at -78 °C was added 21.9
mL (0.035 mol) of a 1.6 M solution of n-BuLi in hexanes. The
mixture was stirred at -78 °C for 20 min followed by addition
of 6.6 mL (0.058 mol) of trimethyl borate in one portion via
syringe. The resultant mixture is allowed to stir at -78 °C for
0.5 h, warmed to ambient temperature, and stirred for a
further 2 h. Thirty milliliters of aqueous 1 N HCl was added
and the mixture stirred for an additional 0.5 h. The organic
layer was separated and the aqueous layer was extracted with
EtOAc (2 × 30 mL). The organic layers were combined, washed
(water, then 10% aqueous Na2S2O3, then brine), dried (MgSO4),
and concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, hexanes/EtOAc, 9:1) yielded
6.6 g (0.025 mol, yield: 86%) of 18 as a pale yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.50 (d, J ) 2.3 Hz, 1H), 7.23 (d, J
) 2.3 Hz, 1H), 5.94 (s, 2H), 5.00 (s, 2H), 3.57 (s, 3H), 3.21
(heptet, J ) 6.9 Hz, 1H), 2.89 (heptet, J ) 6.9 Hz, 1H), 1.25
(d, J ) 6.9 Hz, 6H), 1.24 (d, J ) 6.9 Hz, 6H).
Con clu sion
In summary, we have described the synthesis and
structure activity relationship studies of a new series
of locked-trienoic acids based on the 3,5-dialkyl-6-
fluoroalkoxybenzene scaffold. These compounds repre-
sent a second generation of RXR-selective modulators
which possess high affinity for the RXRs, are synergistic
with PPARγ when used in combination with PPARγ
agonists, and in most cases show reduced synergy on
the RXR:RAR heterodimer when used in combination
with an RAR agonist. We demonstrated that the trienoic
acid scaffold can be successfully replaced with various
locked-trienoic acids such as cyclopentyl, phenyl, thie-
nyl, furyl, and pyridyl-trienoic acids, the best replace-
ments being the cyclopentyl and thienyl-locked trienoic
acids. The thienyl scaffold was particularly attractive
because the synthetic route employed to make thienyl
derivatives used the commercially available 2-formylth-
iophene-3-boronic acid and simple alkylated iodo- or
bromophenols. This provided us with a versatile syn-
thetic tool which was used to rapidly and conveniently
transform a wide variety of substituted phenols into
potent RXR ligands. 55a and 55b are representative
examples of highly selective RXR modulators that can
be synthesized in only five steps from the inexpensive
phenol 50.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Ch em ica l P r oced u r es. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4095
E t h yl-2-[3,5-d i-iso-p r op yl-6-(m e t h oxym e t h oxy)b e n -
zen e] cyclop en ten e-1-ca r boxyla te (19). To 6.6 g (0.025 mol)
of 18 dissolved in 300 mL of 1:1 toluene-ethanol in a 500 mL
round-bottom flask, was added 7.86 g (0.027 mol) of ethyl-2-
(trifluoromethylsulfonyloxy)-1-cyclopentene-1-carboxylate, 5.3
g (0.05 mol) of 2 N aqueous Na2CO3 and 2.89 g (0.0025 mol) of
Pd(PPh3)4. The reaction mixture was heated to 90 °C for 15.0
h, then cooled to room temperature, poured into brine (200
mL), and stirred for 0.3 h. The aqueous layer was extracted
with EtOAc (2 × 200 mL) and the organic layers were
combined, dried (MgSO4), and concentrated under reduced
pressure. Purification by flash column chromatography (silica
gel, 9:1 hexanes-EtOAc) gave 8.0 g (0.022 mol, yield: 89%)
mixture was stirred at ambient temperature for 1.5 h. After
such time, the reaction mixture was filtered through a plug of
silica gel (eluting with CH2Cl2) and concentrated under
reduced pressure to yield 2.13 g (6.21 mmol, yield: 91%) of
1
23a as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 9.69 (s,
1H), 7.11 (d, J ) 2.1 Hz, 1H), 6.85 (d, J ) 2.0 Hz, 1H), 3.55 (t,
J ) 6.4 Hz, 2H), 3.33 (heptet, J ) 6.9 Hz, 1H), 2.99 (t, J ) 7.4
Hz, 2H), 2.87 (heptet, J ) 6.9 Hz, 1H), 2.72 (t, J ) 7.5 Hz,
2H), 2.03 (m, 2H), 1.67 (m, 2H), 1.28 (d, J ) 7.1 Hz, 6H), 1.23
(d, J ) 7.0 Hz, 6H), 0.96 (t, J ) 7.4 Hz, 3H).
Eth yl-(2E,4E)-3-m eth yl-6,7-cyclop en ten yl-7-(3,5-d i-iso-
p r op yl-6-p r op oxyben zen e) P en ta n ed ien oa te (24a ). To
5.38 g (20.4 mmol) of triethyl 3-methyl-4-phosphonocrotonate
dissolved in 60.0 mL of a 1:2 mixture of THF-DMPU in a flame
dried 200 mL round-bottom flask at -78 °C, was added
dropwise 13.6 mL (21.7 mmol) of 1.6 M n-BuLi in hexanes.
The mixture was allowed to stir for 20 min followed by
dropwise addition of 2.33 g (6.80 mmol) of aldehyde 23a in 10
mL of a 1:2 THF-DMPU solution. The reaction mixture was
allowed to stir at -78 °C for 0.5 h, warmed to ambient
temperature, and stirred for an additional 2 h. Water (100 mL)
was added and the mixture was stirred for 0.5 h. The aqueous
layer was separated and extracted with EtOAc (2 × 100 mL),
and the organic layers were combined, washed (brine), dried
(MgSO4), and concentrated under reduced pressure. Purifica-
tion by flash column chromatography (silica gel, 9:1 hexanes-
EtOAc) gave 2.74 g (6.45 mmol, yield: 95%) of ester 24a as a
1
of 19 as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.03 (d, J
) 2.2 Hz, 1H), 6.77 (d, J ) 2.2 Hz, 1H), 4.81 (s, 2H), 3.98 (q,
J ) 7.1 Hz, 2H), 3.49 (s, 3H), 3.38 (heptet, J ) 6.9 Hz, 1H),
2.82 (m, 5H), 1.99 (m, 2H), 1.22 (d, J ) 6.8 Hz, 6H), 1.21 (d, J
) 6.8 Hz, 6H), 0.95 (t, J ) 7.1 Hz, 3H).
3,4-Cyclop en ten yl-6,8-d i-iso-p r op ylcou m a r in (20). To
8.0 g (0.022 mol) of 19 dissolved in 150 mL of THF in a 300
mL round-bottom flask was added 6 N aqueous HCl (25.0 mL,
0.15 mol). The resulting mixture was stirred at ambient
temperature for 65.0 h. After such time, the solvent was
removed under reduced pressure and the residue was taken
up in water (100 mL). The aqueous layer was extracted with
EtOAc (2 × 100 mL) and the organic layers were combined,
washed (water then brine), dried (MgSO4), and concentrated
under reduced pressure. Purification by flash column chro-
matography (silica gel, 9:1 hexanes-EtOAc) gave 5.9 g (0.022
mmol, yield: 99%) of coumarin 20 as a yellow-orange oil which
solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 7.28
(d, J ) 1.7 Hz, 1H), 7.10 (d, J ) 1.8 Hz, 1H) 3.65 (heptet, J )
6.9 Hz, 1H), 3.08 (t, J ) 7.6 Hz, 2H), 2.93 (m, 3H), 2.21 (m,
2H), 1.29 (d, J ) 7.4 Hz, 6H), 1.28 (d, J ) 7.2 Hz, 6H).
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.03 (d, J ) 2.2 Hz,
1H), 6.85 (d, J ) 15.8 Hz, 1H) 6.79 (d, J ) 2.2 Hz, 1H), 6.21
(d, J ) 15.8 Hz, 1H), 5.79 (s, 1H), 4.15 (q, J ) 7.1 Hz, 2H),
3.53 (t, J ) 6.5 Hz, 2H), 3.34 (heptet, J ) 6.9 Hz, 1H), 2.86
(m, 3H), 2.66 (t, J ) 7.3 Hz, 2H), 2.22 (s, 3H), 2.01 (m, 2H),
1.65 (m, 2H), 1.27 (t, J ) 7.1 Hz, 3H) 1.24 (d, J ) 7.0 Hz, 6H),
1.23 (d, J ) 6.8 Hz, 6H), 0.95 (t, J ) 7.4 Hz, 3H).
2-[3,5-Di-iso-p r op yl-6-h yd r oxyben zen e]cyclop en ten e-
1-m eth a n ol (21). To 2.0 g (7.4 mmol) of coumarin 20 dissolved
in 75 mL of anhydrous THF in a flame dried 200 mL round-
bottom flask at 0 °C was added 400 mg (7.4 mmol) of NaAlH4
portion-wise. The resultant mixture is allowed to warm to
ambient temperature and stirred for 4.0 h. After such time,
water (0.14 mL, 7.4 mmol) was added, followed by 6 N aqueous
sodium hydroxide (2.5 mL, 14.8 mmol). The resultant mixture
was allowed to stir for 0.5 h, filtered through a plug of silica
gel (eluting with diethyl ether) and concentrated under
reduced pressure to give 2.0 g (7.3 mmol, yield: 99%) of 21 as
(2E,4E)-3-Meth yl-6,7-cyclopen ten yl-7-(3,5-di-iso-pr opyl-
6-p r op oxyben zen e) p en ta n ed ien oic Acid (25a ). To 2.74 g
(6.45 mmol) of ester 24a dissolved in 75 mL of ethanol in a
200 mL round-bottom flask was added 10 mL (20.0 mmol) of
a 2 M aqueous LiOH solution. The mixture was heated to 90
°C for 3.0 h, then cooled and concentrated under reduced
pressure. The residue was taken up in 100 mL of 1 N aqueous
HCl and the flask was shaken for 1 min. The resultant
suspension was extracted with EtOAc (2 × 100 mL) and the
organic layers were combined, washed (brine), dried (MgSO4),
and concentrated under reduced pressure. The concentrate was
filtered through a short plug of silica gel (eluting with EtOAc),
concentrated under reduced pressure and crystallized from
acetonitrile to give 2.41 g (5.68 mmol, yield: 88%) of corre-
sponding acid 25a as light yellow crystals (mp ) 134.1-135.4
°C). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J ) 2.1 Hz, 1H),
6.90 (d, J ) 15.8 Hz, 1H) 6.79 (d, J ) 2.1 Hz, 1H), 6.23 (d, J
) 15.7 Hz, 1H), 5.81 (s, 1H), 3.53 (t, J ) 6.5 Hz, 2H), 3.33
(heptet, J ) 6.9 Hz, 1H), 2.88 (m, 3H), 2.66 (t, J ) 7.3 Hz,
2H), 2.23 (s, 3H), 2.03 (m, 2H), 1.65 (m, 2H), 1.24 (d, J ) 6.8
Hz, 6H), 1.23 (d, J ) 6.9 Hz, 6H), 0.95 (t, J ) 7.4 Hz, 3H).
Anal. (C26H36O3); C: calcd, 78.75, found, 78.24; H: calcd, 9.15,
found, 9.31. MS (EI, 70 eV) 396 m/z 396 (MH+, 100), 396 (100),
378 (30). 296 (30). HRMS for C26H37O3 (MH+): calcd, 396.2664;
found, 396.2870.
1-[3,5-Di-iso-p r op yl-6-(2,2-d iflu or oeth oxy)ben zen e] cy-
clop en ten e-2-m eth a n ol (22b). 22b was synthesized from
0.152 g (0.56 mmol) of 21 and 0.097 g (0.67 mmol) of 1-bromo-
2,2-difluoroethane in the presence of 0.54 g (1.7 mmol) of CsF
according to the procedure described for the synthesis of 22a .
0.163 g (0.48 mmol, yield: 87%) of 22b was isolated as a brown
oil. 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J ) 2.2 Hz, 1H),
6.80 (d, J ) 2.2 Hz, 1H), 5.97 (tt, J ) 55.2, 4.1 Hz, 1H), 4.07
(d, J ) 4.4 Hz, 2H), 3.85 (dt, J ) 13.9, 4.1 Hz, 2H), 3.31 (heptet,
J ) 6.9 Hz, 1H), 2.85 (heptet, J ) 6.9 Hz, 1H), 2.74 (t, J ) 7.3
Hz, 2H), 2.65 (t, J ) 7.4 Hz, 2H), 2.01 (m, 2H), 1.23 (d, J )
6.8 Hz, 6H), 1.22 (d, J ) 6.8 Hz, 6H).
1
a colorless oil. H NMR (400 MHz, CDCl3) δ 6.97 (d, J ) 2.1
Hz), 6.75 (d, J ) 2.2 Hz, 1H), 5.55 (s, 1H), 5.07 (s, 2H), 3.29
(heptet, J ) 6.9 Hz, 1H), 2.82 (heptet, J ) 6.9 Hz, 1H), 2.70
(m, 4H), 2.02 (m, 2H), 1.62 (broad s, 1H), 1.25 (d, J ) 6.9 Hz,
6H), 1.22 (d, J ) 7.1 Hz, 6H).
1-(3,5-Di-iso-p r op yl-6-p r op oxyben zen e)cyclop en ten e-
2-m eth a n ol (22a ). To 2.0 g (7.3 mmol) of 21 dissolved in 75
mL of anhydrous DMF in a flame dried 200 mL round-bottom
flask, was added 1.00 g (8.1 mmol) of 1-bromopropane followed
by 4.5 g (29.6 mmol) of CsF. The mixture was allowed to stir
at room temperature for 18 h. Water (100 mL) was added and
the mixture was allowed to stir for an additional 0.5 h. The
aqueous layer was extracted with EtOAc (2 × 100 mL), and
the organic layers were combined, washed (brine), dried
(MgSO4), and concentrated under reduced pressure. Purifica-
tion by silica gel flash column chromatography (eluent: 9/1
hexanes-EtOAc) yielded 2.15 g (6.79 mmol, yield: 93%) of 22a
1
as a brown oil. H NMR (400 MHz, CDCl3) δ 6.99 (d, J ) 2.2
Hz, 1H), 6.78 (d, J ) 2.2 Hz, 1H), 3.98 (d, J ) 5.0 Hz, 2H),
3.57 (t, J ) 6.7 Hz, 2H), 3.32 (heptet, J ) 6.9 Hz, 1H), 2.84
(heptet, J ) 6.9 Hz, 1H), 2.74 (t, J ) 7.3 Hz, 2H), 2.64 (t, J )
7.3 Hz, 2H), 2.00 (m, 2H), 1.71 (m, 2H), 1.22 (d, J ) 6.9 Hz,
6H), 1.17 (d, J ) 6.9 Hz, 6H), 0.97 (t, J ) 7.4 Hz, 3H).
1-(3,5-Di-iso-p r op yl-6-h yd r oxyben zen e)-2-for m ylcyclo-
p en ten e (23a ). To 2.15 g (6.80 mmol) of 22a dissolved in 70
mL of anhydrous CH2Cl2 in a flame dried 200 mL round-
bottom flask, was added 1.19 g (10.2 mmol) of 4-methylmor-
pholine-N-oxide (NMO) followed by 0.119 g (0.34 mmol) of
tetrapropylammonium perruthenate (TPAP). The resulting
1-[3,5-Di-iso-p r op yl-6-(3-flu or op r op oxy)b en zen e] cy-
clop en ten e-2-m eth a n ol(22c). 22c was synthesized from 0.51
g (1.8 mmol) of 21 and 0.31 g (2.2 mmol) of 1-bromo-2,2-

4096 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
difluoroethane in the presence of 1.8 g (5.6 mmol) of CsF
according to the procedure described for the synthesis of 22a .
0.53 g (1.6 mmol, yield: 85%) of 22c was isolated as a brown
oil. 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J ) 2.1 Hz, 1H),
6.78 (d, J ) 2.2 Hz, 1H), 4.63 (dt, J ) 47.1, 5.7 Hz, 2H), 4.02
(d, J ) 5.4 Hz, 2H), 3.75 (t, J ) 6.2 Hz, 2H), 3. (heptet, J )
6.9 Hz, 1H), 2.84 (heptet, J ) 6.9 Hz, 1H), 2.74 (t, J ) 7.2 Hz,
2H), 2.64 (t, J ) 7.3 Hz, 2H), 2.20 (t, J ) 5.9 Hz, 1H), 2.09 (m,
2H), 1.99 (m, 2H), 1.23 (d, J ) 6.8 Hz, 6H), 1.22 (d, J ) 6.9
Hz, 6H).
1-[3,5-Di-iso-p r op yl-6-(2,2-d iflu or oeth oxy)ben zen e]-2-
for m ylcyclop en ten e (23b). 23b was synthesized from 0.163
g (0.48 mmol) of 22b and 0.08 g (0.72 mmol) NMO in the
presence of 0.008 g (0.024 mmol) of TPAP according to the
procedure described for the synthesis of 23a . 0.162 g (0.48
mmol, yield: 100%) of 23b was isolated as a brown oil. 1H
NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 7.14 (d, J ) 2.1 Hz,
1H), 6.88 (d, J ) 2.2 Hz, 1H), 5.93 (tt, J ) 55.0, 4.0 Hz, 1H),
3.83 (dt, J ) 13.6, 3.9 Hz, 2H), 3.31 (heptet, J ) 6.9 Hz, 1H),
2.98 (t, J ) 7.4 Hz, 2H), 2.88 (heptet, J ) 6.9 Hz, 1H), 2.74 (t,
J ) 4.5 Hz, 2H), 2.05 (m, 2H), 1.24 (d, J ) 7.0 Hz, 6H), 1.23
(d, J ) 6.9 Hz, 6H).
1-[3,5-Di-iso-p r op yl-6-(3-flu or op r op oxy)b e n ze n e ]-2-
for m ylcyclop en ten e (23c). 23c was synthesized from 0.53
g (1.6 mmol) of 22c and 0.28 g (2.4 mmol) of NMO in the
presence of 0.03 g (0.08 mmol) of TPAP according to the
procedure described for the synthesis of 23a . 0.52 g (1.6 mmol,
yield: 100%) of 23c was isolated as a brown oil. 1H NMR (400
MHz, CDCl3) δ 9.67 (s, 1H), 7.12 (d, J ) 2.2 Hz, 1H), 6.87 (d,
J ) 2.2 Hz, 1H), 4.58 (dt, J ) 47.1, 5.7 Hz, 2H), 3.71 (t, J )
5.9 Hz, 2H), 3.28 (heptet, J ) 6.9 Hz, 1H), 2.98 (t, J ) 7.5 Hz,
2H), 2.87 (heptet, J ) 6.9 Hz, 1H), 2.73(t, J ) 7.6 Hz, 2H),
2.01 (m, 4H), 1.24 (d, J ) 6.9 Hz, 12H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-cyclop en ten yl-7-[3,5-d i-
iso-p r op yl-6-(2,2-d iflu or o eth oxyben zen e] p en ta n e-2,4,6-
tr ien oa te (24b). Reaction of 0.162 mg (0.48 mmol) of 23b in
the presence of the anion of triethyl-3-methyl-phosphonocro-
tonate (generated from 0.35 mL, 1.4 mmol of of triethyl-3-
methyl-phosphonocrotonate and 0.97 mL of nBuLi in hexanes
2.5 M in THF-DMPU, 1.5 mmol) according to the procedure
described for the synthesis of 24a affords 0.202 g (0.45 mmol,
yield: 93%) of the corresponding ester 24b as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J ) 2.1 Hz,
1H), 6.82 (d, J ) 2.3 Hz, 1H), 6.79 (d, J ) 16.0 Hz, 1H), 6.24
(d, J ) 15.8 Hz, 1H), 5.90 (tt, J ) 55.4, 4.8 Hz, 1H), 5.81 (s,
1H), 4.17 (q, J ) 7.0 Hz, 2H), 3.80 (dt, J ) 13.8, 4.0 Hz, 2H),
3.31 (heptet, J ) 6.9 Hz, 1H), 2.87 (m, 3H), 2.68 (t, J ) 7.3
Hz, 2H), 2.21 (s, 3H), 2.03 (m, 4H), 1.28 (t, J ) 6.8 Hz, 3H),
1.25 (d, J ) 6.8 Hz, 6H), 1.24 (d, J ) 6.8 Hz, 6H).
J ) 14.9 Hz, 1H), 6.81 (d, J ) 2.3 Hz, 1H), 6.25 (d, J ) 15.8
Hz, 1H), 5.99 (tt, J ) 56.8, 4.8 Hz, 1H), 5.83 (s, 1H), 3.71 (t, J
) 5.8 Hz, 2H), 3.24 (heptet, J ) 6.9 Hz, 1H), 2.86 (m, 3H),
2.69 (t, J ) 7.2 Hz, 2H), 2.21 (s, 3H), 2.10 (m, 4H), 1.24 (d, J
) 6.9 Hz, 6H), 1.23 (d, J ) 6.8 Hz, 6H). Anal. (C25H32F2O3) C,
H. MS (EI, 70 eV) 418 m/z 418 (MH+, 90), 435 (100), 418 (90),
400 (80), 372 (85), 358 (45). HRMS for C25H33F2O3 (MH+); calcd,
418.2320, found, 418.2435.
(2E,4E,6Z)-3-Meth yl-6,7-cyclopen ten yl-7-[3,5-di-iso-pr o-
p yl-6-(3-flu or op r op oxy) ben zen e]p en ta n e-2,4,6-tr ien oic
Acid (25c). Saponification of 657 mg (1.5 mmol) of 24c in the
presence of 2.3 mL of LiOH (2 M aqueous solution) in a 1/1
mixture of THF/MeOH (7.5/7.5 mL) according to the procedure
described for the synthesis of 25a affords 499.0 mg (1.21 mmol,
yield: 81%) of the desired acid 25c as a single stereoisomer
(off white solid, mp 151.3-153.2 °C, CH3CN). 1H NMR (400
MHz, CDCl3) δ 7.04 (d, J ) 2.2 Hz, 1H), 6.86 (d, J ) 15.8 Hz,
1H), 6.81 (d, J ) 2.2 Hz, 1H), 6.24 (d, J ) 15.7 Hz, 1H), 5.82
(s, 1H), 4.57 (dt, J ) 47.1, 5.8 Hz, 2H), 3.69 (t, J ) 5.9 Hz,
2H), 3.28 (heptet, J ) 6.9 Hz, 1H), 2.86 (m, 3H), 2.68 (t, J )
7.4 Hz, 2H), 2.22 (s, 3H), 2.00 (m, 4H), 1.25 (d, J ) 6.9 Hz,
6H), 1.24 (d, J ) 6.8 Hz, 6H). Anal. (C26H35FO3‚ 0.2 H2O); C,
H. MS (EI, 70 eV) 414 m/z 414 (MH+, 100), 414 (100), 396 (98),
368 (70), 354 (80). HRMS for C26H36FO3 (MH+); calcd, 414.2570,
found: 414.2635.
2,4-Di-ter t-bu tyl-6-iod op h en ol (26). Iodination of 50.0 g
(0.24 mol) of 2,4-ditert-butylphenol in the presence of 65.4 g
(0.29 mol) of NIS and 4.6 g (0.024 mol) of p-toluenesulfonic
acid using the procedure described for the synthesis of 16
affords 76.4 g (0.23 mol, yield: 96%) of 2,4-ditertbutyl-6-
iodophenol 26 as a pale yellow solid (mp ) 76.3-77.6 °C
-methanol-). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J ) 2.1 Hz,
1H), 7.27 (d, J ) 2.1 Hz, 1H), 5.35 (s, 1H), 1.39 (s, 9H), 1.27
(s, 9H).
3,5-Di-iso-p r op yl-6-(2,2-d iflu or oeth oxy) iod oben zen e
(27a ). To a solution of 250 mg (0.82 mmol) of 16 and 131 mg
(0.91 mmol) of 1-bromo-2,2-difluoroethane in 10.0 mL of dry
DMF was added 402 mg (1.2 mmol) of Cs2CO3 at room
temperature. The mixture was stirred overnight at room
temperature and water was added (15.0 mL). The solution was
extracted twice with ethyl acetate and the organic layers were
washed (with water and brine successively) and dried (MgSO4).
After concentration, the residue was purified over silica gel
column chromatography (eluent: 95/5 hexane/ethyl acetate)
to afford 300 mg (0.81 mmol, yield: 99%) of 27a as a clear
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.47 (d, J ) 2.1 Hz,
1H), 7.07 (d, J ) 2.1 Hz, 1H), 6.21 (tt, J ) 55.2 Hz, J ) 4.1
Hz, 1H), 4.08 (dt, J ) 13.1 Hz, J ) 4.0 Hz, 2H), 3.30 (m, 1H),
2.82 (m, 1H), 1.22 (d, J ) 7.0 Hz, 12H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-cyclop en ten yl-7-[3,5-d i-
iso-p r op yl-6-(3-flu or o p r op oxy)b en zen e]p en t a n e-2,4,6-
tr ien oa te (24c). Reaction of 0.52 g (1.6 mmol) of 23c in the
presence of the anion of triethyl-3-methyl-phosphonocrotonate
(generated from 1.15 mL, 4.7 mmol of triethyl-3-methyl-
phosphonocrotonate, and 3.2 mL of nBuLi in hexanes 2.5 M
in THF-DMPU 15.8 mL) according to the procedure described
for the synthesis of 24a affords 657 mg (1.5 mmol, yield: 94%)
of the corresponding ester 24c as a mixture of isomers. 1H
NMR (400 MHz, CDCl3) δ 7.04 (d, J ) 2.1 Hz, 1H), 6.82 (d, J
) 15.7 Hz, 1H), 6.81 (d, J ) 2.2 Hz, 1H), 6.22 (d, J ) 15.8 Hz,
1H), 5.80 (s, 1H), 4.58 (dt, J ) 47.1, 5.8 Hz, 2H), 4.15 (q, J )
6.9 Hz, 2H), 3.69 (t, J ) 5.9 Hz, 2H), 3.29 (heptet, J ) 6.9 Hz,
1H), 2.86 (m, 3H), 2.67 (t, J ) 7.4 Hz, 2H), 2.21 (s, 3H), 2.07
(m, 4H), 1.26 (t, J ) 7.2 Hz, 3H), 1.25 (d, J ) 6.8 Hz, 6H),
1.24 (d, J ) 6.8 Hz, 6H).
(2E,4E,6Z)-3-Meth yl-6,7-cyclopen ten yl-7-[3,5-di-iso-pr o-
p yl-6-(2,2-d iflu or oeth oxy) ben zen e]p en ta n e-2,4,6-tr ien o-
ic Acid (25b). Saponification of 0.202 g (0.45 mmol) of 24b in
the presence of 0.70 mL of LiOH (2 M aqueous solution) in a
1/1 mixture of THF/MeOH (2.5/2.5 mL) according to the
procedure described for the synthesis of 25a affords 87.7 mg
(0.21 mmol, yield: 47%) of the desired acid 25b as a single
stereoisomer (off white solid, mp ) 162.3-165.1 °C, CH3CN).
1H NMR (400 MHz, CDCl3) δ 7.05 (d, J ) 2.0 Hz, 1H), 6.83 (d,
3,5-Di-iso-pr opyl-6-(3-flu or opr opoxy)iodoben zen e (27b).
Alkylation of 2.30 g (7.56 mmol) of 16 in the presence of 1.07
g (7.56 mmol) of 1-bromo-3-fluoropropane and 3.70 g (11.30
mmol) of Cs2CO2 according to the procedure described for the
synthesis of 27a affords 2.80 g (7.50 mmol, yield: 99%) of 27b
as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J ) 1.8
Hz, 1H), 7.06 (d, J ) 2.0 Hz, 1H), 4.75 (dt, J ) 47.3 Hz, J )
5.8 Hz, 2H), 3.95 (t, J ) 5.9 Hz, 2H), 3.27 (m, 1H), 2.81 (m,
1H), 2.24 (dt, J ) 26.0, 6.0 Hz, 2H), 1.22 (d, J ) 7.0 Hz, 6H),
1.21 (d, J ) 7.0 Hz, 6H).
3,5-Di-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxy) iod oben zen e
(27c). To a solution of 1.13 g (3.7 mmol) of 16 and 1.21 g (7.4
mmol) of 1-bromo-2,2,2-trifluoroethane in 15 mL of dry DMF
in a 50 mL pressure tube was added 2.41 g (7.4 mmol) of Cs2-
CO3 at room temperature. The tube was sealed and the
mixture was stirred overnight at 50 °C. After cooling the
sample to room temperature, the tube was carefully open and
water was added (30 mL). The solution was extracted with
ethyl acetate (2 × 50 mL) and the organic layers were washed
(with water and brine successively) and dried (MgSO4). After
concentration, the residue was purified over silica gel column
chromatography (eluent: 97.5/2.5 hexane/ethyl acetate) to
afford 1.29 g (33.6 mmol, yield: 91%) of 27c as a clear colorless
oil. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J ) 2.0 Hz, 1H),
7.08 (d, J ) 2.0 Hz, 1H), 4.29 (d, J ) 8.3 Hz, 1H), 4.25 (d, J )

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4097
8.4 Hz, 1H), 3.32 (heptet, J ) 6.9 Hz, 1H), 2.83 (heptet, J )
6.9 Hz, 1H), 1.21 (d, J ) 6.9 Hz, 12H).
tr ien oa te (30b). Reaction of 159 mg (0.46 mmol) of 29b in
the presence of the anion of triethyl-3-methyl-phosphonocro-
tonate (generated from 0.33 mL, 1.4 mmol of of triethyl-3-
methyl-phosphonocrotonate and 0.6 mL of nBuLi in hexanes
2.5 M in THF-DMPU 5.0 mL) according to the procedure
described for the synthesis of 24a affords 200 mg (0.44 mmol,
yield: 95%) of the corresponding ester 30b as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J ) 5.2 Hz,
1H), 7.14 (d, J ) 4.9 Hz, 1H), 7.11 (d, J ) 2.1 Hz, 1H), 7.02 (d,
J ) 15.9 Hz, 1H), 6.92 (d, J ) 2.4 Hz, 1H), 6.64 (d, J ) 15.9
Hz, 1H), 5.85 (s, 1H), 4.43 (dt, J ) 47.0, 6.1 Hz, 2H), 4.17 (q,
J ) 7.0 Hz, 2H), 3.49 (t, J ) 6.0 Hz, 2H), 3.32 (m, 1H), 2.89
(m, 1H), 2.25 (d, J ) 1.2 Hz, 3H), 1.83 (dt, J ) 24.7, 6.0 Hz,
2H), 1.29 (t, J ) 7.1 Hz, 3H), 1.28 (d, J ) 7.0 Hz, 6H), 1.25 (d,
J ) 6.8 Hz, 6H).
E t h yl-(2E,4E,6Z)-[3-m et h yl-6,7-(2,3-t h ien yl)-7-[3,5-d i-
iso-pr opyl-6-(2,2,2-tr iflu or oeth oxy)ben zen e]pen tan e-2,4,6-
tr ien oa te (30c). Reaction of 102.0 mg (0.27 mmol) of 29c in
the presence of the anion of triethyl-3-methyl-phosphonocro-
tonate (generated from 0.20 mL, 0.83 mmol of triethyl-3-
methyl-phosphonocrotonate and 0.35 mL of n-BuLi in hexanes
2.5 M in THF-DMPU 5.0 mL) according to the procedure
described for the synthesis of 24a affords 132.0 mg (0.27 mmol,
yield: 100%) of the corresponding ester 30c as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J ) 5.2 Hz,
1H), 7.16 (d, J ) 5.2 Hz,), 7.14 (d, J ) 2.0 Hz, 1H), 7.00 (d, J
) 15.8 Hz, 1H), 6.94 (d, J ) 2.1 Hz, 1H), 6.68 (d, J ) 15.8 Hz,
1H), 5.87 (s, 1H), 4.17 (q, J ) 7.1 Hz, 2H), 3.67 (q, J ) 8.5 Hz,
2H), 3.41 (m, 1H), 2.91 (m, 1H), 2.26 (s, 3H), 1.29 (t, J ) 7.2
Hz, 3H), 1.27 (d, J ) 6.6 Hz, 6H), 1.25 (d, J ) 6.7 Hz, 6H).
(2E,4E,6Z)-[3-Meth yl-6,7-(2,3-th ien yl)-7-[3,5-d i-iso-p r o-
pyl-6-(2,2-diflu or opr opoxy) ben zen e]pen tan e-2,4,6-tr ien o-
ic a cid (31a ). Saponification of 272.0 mg (0.59 mmol) of 30a
in the presence of 0.90 mL of LiOH (2 M aqueous solution) in
a 1/1 mixture of THF/MeOH (3.0/3.0 mL) according to the
procedure described for the synthesis of 25a affords 101.3 mg
(0.25 mmol, yield: 42%) of the desired acid 31a as a single
stereoisomer (yellow solid, mp ) 158.5-160.9 °C, CH3CN). 1H
NMR (400 MHz, CDCl3) δ 7.31 (d, J ) 5.1 Hz, 1H), 7.16 (d, J
) 5.0 Hz, 1H), 7.13 (d, J ) 2.1 Hz, 1H), 7.05 (d, J ) 15.8 Hz,
1H), 6.93 (d, J ) 2.2 Hz, 1H), 6.69 (d, J ) 15.8 Hz, 1H), 5.89
(s, 1H), 5.68 (tt, J ) 55.4, 4.2 Hz, 1H) 3.56 (dt, J ) 13.7, 4.1
Hz, 2H), 3.37 (m, 1H), 2.91 (m, 1H), 2.27 (s, 3H), 1.28 (d, J )
6.9 Hz, 6H), 1.26 (d, J ) 7.1 Hz, 6H). Anal. (C24H28F2O3S) C,
H, S. MS (EI, 70 eV) 434 m/z 434 (MH+, 50), 416 (100), 374
(35). 334 (20). HRMS for C24H29F2O3S (MH+): calcd, 434.1727;
found, 434.1854.
(2E,4E,6Z)-[3-Meth yl-6,7-(2,3-th ien yl)-7-[3,5-d iiso-p r o-
p yl-6-(3-flu or op r op oxy) ben zen e]p en ta n e-2,4,6-tr ien oic
Acid (31b). Saponification of 200 mg (0.44 mmol) of 30b in
the presence of 0.7 mL of LiOH (2 M aqueous solution) in a
1/1 mixture of THF/MeOH (2.5/2.5 mL) according to the
procedure described for the synthesis of 25a affords 46.7 mg
(0.11 mmol, yield: 25%) of the desired acid 31b as a single
stereoisomer (yellow solid, mp ) 145.2-147.7 °C, CH3CN). 1H
NMR (400 MHz, CDCl3) δ 7.28 (d, J ) 5.1 Hz, 1H), 7.14 (d, J
) 5.0 Hz, 1H), 7.12 (d, J ) 2.2 Hz, 1H), 7.07 (d, J ) 15.8 Hz,
1H), 6.92 (d, J ) 2.2 Hz, 1H), 6.67 (d, J ) 15.8 Hz, 1H), 5.89
(s, 1H), 4.42 (dt, J ) 47.1, 6.0 Hz, 2H), 3.49 (t, J ) 6.0 Hz,
2H), 3.32 (m, 1H), 2.90 (m, 3H), 2.27 (s, 3H), 1.83 (dp, J ) 6.0
Hz, 2H), 1.28 (d, J ) 7.5 Hz, 6H), 1.26 (d, J ) 7.5 Hz, 6H).
Anal. (C25H31FO3S); C: calcd, 69.74; found: 69.60; H: calcd,
7.26; found: 7.34; S: calcd, 7.45; found: 7.30. MS (EI, 70 eV)
430 m/z 430 (MH+, 30), 412 (100), 370 (40). 330 (25). HRMS
Calcd for C25H32FO3S: 430.1978. Found: 430.2072.
3,5-Di-ter t-b u t yl-6-(2,2-d iflu or oet h oxy) iod ob en zen e
(28a ). Alkylation of 3.0 g (9.03 mmol) of 26 in the presence of
1.57 g (10.84 mmol) of 1-bromo-2,2-difluoroethane and 520 mg
(10.84 mmol) of NaH according to the procedure described for
the synthesis of 17 affords 3.29 g (8.31 mmol, yield: 92%) of
1
28a as a clear oil. H NMR (400 MHz, CDCl3) δ 7.66 (d, J )
2.4 Hz, 1H), 7.35 (d, J ) 2.4 Hz, 1H), 6.28 (tt, J ) 55.2, 4.3
Hz, 1H), 4.23 (td, J ) 13.4, 4.3 Hz, 2H), 2.56 (dd, J ) 15.2, 7.6
Hz, 2H), 1.39 (s, 9H), 1.29 (s, 9H).
3,5-Di-ter t-bu tyl-6-(3-flu or opr opoxy)iodoben zen e (28b).
Alkylation of 4.00 g (12.04 mol) of 26 in the presence of 2.03
g (14.48 mol) of 1-bromo-3-fluoropropane and 695 mg (14.48
mol) of NaH according to the procedure described for the
synthesis of 17 affords 4.39 g (11.97 mol, yield: 93%) of 28b
as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J ) 2.4
Hz, 1H), 7.33 (d, J ) 2.4 Hz, 1H), 4.80 (t, J ) 6.0 Hz, 1H),
4.71 (t, J ) 6.0 Hz, 1H), 4.11 (t, J ) 6.1 Hz, 2H), 2.31 (m, 1H),
2.26 (m, 1H), 1.39 (s, 9H), 1.29 (s, 9H).
1-[3,5-Di-iso-p r op yl-6-(2,2-d iflu or oeth oxy)ben zen e]-2-
for m ylth iop h en e (29a ). Reaction of 300 mg (0.82 mmol) of
27a and 152 mg (0.98 mmol) of 2-formylthiophene-3-boronic
acid in the presence of 94 mg (0.082 mmol, 5%) of Pd(PPh3)4
according to the procedure described for the synthesis of 19
affords 219 mg (0.62 mmol, yield: 76%) of the corresponding
adduct 29a . 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.76
(d, J ) 5.1 Hz, 1H), 7.26 (d, J ) 5.0 Hz, 1H), 7.20 (d, J ) 2.1
Hz, 1H), 7.02 (d, J ) 2.2 Hz, 1H), 5.69 (tt, J ) 55.2, 4.1 Hz,
1H), 3.59 (dd, J ) 13.5, 4.0 Hz, 1H), 3.55 (dd, J ) 13.5, 4.1
Hz, 1H), 3.37 (septet, J ) 6.9 Hz, 1H), 2.92 (septet, J ) 6.9
Hz, 1H), 1.27 (d, J ) 6.9 Hz, 6H), 1.26 (d, J ) 7.0 Hz, 6H).
1-[3,5-Di-iso-p r op yl-6-(3-flu or op r op oxy)b e n ze n e ]-2-
for m ylth iop h en e (29b). Reaction of 200 mg (0.55 mmol) of
27b and 103 mg (0.66 mmol) of 2-formylthiophene-3-boronic
acid in the presence of 63.0 mg (0.055 mmol, 5%) of Pd(PPh3)4
according to the procedure described for the synthesis of 19
1
affords 159 mg (0.46 mmol, yield: 83%) of 29b. H NMR (400
MHz, CDCl3) δ 9.77 (d, J ) 0.9 Hz, 1H), 7.74 (dd, J ) 4.9 Hz,
J ) 0.8 Hz, 1H), 7.24 (d, J ) 4.9 Hz, 1H), 7.18 (d, J ) 2.2 Hz,
1H), 7.01 (d, J ) 2.2 Hz, 1H), 4.43 (dt, J ) 47.1, 5.9 Hz, 2H),
3.49 (t, J ) 6.0 Hz, 2H), 3.32 (septet, J ) 6.9 Hz, 1H), 2.91
(septet, J ) 6.9 Hz, 1H), 1.82 (m, 2H), 1.27 (d, J ) 6.9 Hz,
6H), 1.26 (d, J ) 6.9 Hz, 6H).
1-[3,5-Di-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxy)ben zen e]-
2-for m ylth iop h en e (29c). Reaction of 250.0 mg (0.65 mmol)
of 27c in the presence of 120.0 mg (0.71 mmol) of 2-formylth-
iophene-3-boronic acid and 75.0 mg (0.065 mmol) of Pd(PPh3)4
according to the procedure described for the synthesis of 19,
affords 102.0 mg (0.27 mmol, yield: 42.4%) of 29c as a clear
oil. 1H NMR (400 MHz, CDCl3) δ 9.79 (d, J ) 1.0 Hz, 1H),
7.78 (dd, J ) 4.9, 1.1 Hz, 1H), 7.28 (d, J ) 4.9 Hz, 1H), 7.21
(d, J ) 2.2 Hz, 1H), 7.02 (d, J ) 2.2 Hz, 1H), 3.69 (dd, J )
16.7, 8.4 Hz, 2H), 3.38 (septet, J ) 6.9 Hz, 1H), 2.92 (septet,
J ) 6.9 Hz, 1H), 1.27 (d, J ) 7.0 Hz, 6H), 1.26 (d, J ) 7.0 Hz,
6H).
E t h yl-(2E,4E,6Z)-[3-m et h yl-6,7-(2,3-t h ien yl)-7-[3,5-d i-
iso-p r op yl-6-(2,2-d iflu or oeth oxy)ben zen e]p en ta n e-2,4,6-
tr ien oa te (30a ). Reaction of 219 mg (0.62 mmol) of 29a in
the presence of the anion of triethyl-3-methyl-phosphonocro-
tonate (generated from 0.45 mL, 1.9 mmol of of triethyl-3-
methyl-phosphonocrotonate and 0.80 mL of nBuLi in hexanes
2.5 M in THF-DMPU 7.0 mL) according to the procedure
described for the synthesis of 24a affords 272 mg (0.59 mmol,
yield: 94%) of the corresponding ester 30a as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J ) 5.2 Hz,
1H), 7.15 (d, J ) 5.2 Hz, 1H), 7.12 (d, J ) 2.1 Hz, 1H), 6.99 (d,
J ) 15.9 Hz, 1H), 6.93 (d, J ) 2.1 Hz, 1H), 6.66 (d, J ) 15.9
Hz, 1H), 5.86 (s, 1H), 5.68 (tt, J ) 55.2, 3.8 Hz, 1H), 4.17 (q,
J ) 7.0 Hz, 2H), 3.56 (dt, J ) 13.7, 4.2 Hz, 2H), 3.37 (m, 1H),
2.90 (m, 1H), 2.25 (s, 3H), 1.29 (t, J ) 7.0 Hz, 3H), 1.27 (d, J
) 7.0 Hz, 6H), 1.26 (d, J ) 7.0 Hz, 6H).
(2E,4E,6Z)-[3-Meth yl-6,7-(2,3-th ien yl)-7-[3,5-d i-iso-p r o-
pyl-6-(2,2,2-tr iflu or oeth oxy) ben zen e]pen tan e-2,4,6-tr ien o-
ic Acid (31c). Saponification of 132.0 mg (0.27 mmol) of 30c
in the presence of 0.41 mL of LiOH (2 M aqueous solution) in
a 1/1 mixture of THF/MeOH (2.0/2.0 mL) according to the
procedure described for the synthesis of 25a affords 24.9 mg
(0.054 mmol, yield: 20%) of the desired acid 31c as a single
stereoisomer (pale yellow solid, mp ) 149-151.5 °C, CH3CN).
1H NMR (400 MHz, CDCl3) δ 7.32 (d, J ) 5.1 Hz, 1H), 7.17 (d,
E t h yl-(2E,4E,6Z)-[3-m et h yl-6,7-(2,3-t h ien yl)-7-[3,5-d i-
iso-p r op yl-6-(3-flu or op r op oxy)b en zen e]p en t a n e-2,4,6-

4098 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
J ) 5.0 Hz,), 7.14 (d, J ) 2.0 Hz, 1H), 7.05 (d, J ) 15.8 Hz,
1H), 6.94 (d, J ) 2.0 Hz, 1H), 6.70 (d, J ) 15.8 Hz, 1H), 5.89
(s, 1H), 3.67 (q, J ) 8.5 Hz, 2H), 3.41 (m, 1H), 2.91 (m, 1H),
2.27 (s, 3H), 1.27 (d, J ) 6.4 Hz, 6H), 1.26 (d, J ) 6.6 Hz, 6H).
Anal. (C24H27F3O3S) C, H, S. MS (EI, 70 eV) 452 m/z 452 (MH+,
100), 434 (90), 392 (30), 352 (40). HRMS for C24H28F3O3S
(MH+); calcd, 452.1663, found: 452.1770.
2-[3,5-Di-iso-p r op yl-6-(3-flu or op r op oxy)b e n ze n e ]-3-
for m ylfu r a n (32). Reaction of 1.05 g (2.88 mmol) of 27b and
610 mg (4.30 mmol) of 3-formylfuran-2-boronic acid in the
presence of 166 mg (0.14 mmol, 5%) of Pd(PPh3)4 and 2.9 mL
of a 2 N Na2CO2 aqueous solution in refluxing DME (25 mL)
afford after workup and silica gel column chromatography
(eluent: 95/5 and 90/10 hexane/ethyl acetate) 108 mg (0.32
mmol, yield: 11%) of the corresponding adduct 32. 1H NMR
(400 MHz, CDCl3) δ 10.12 (s, 1H), 7.52 (d, J ) 1.9 Hz, 1H),
7.25 (d, J ) 2.2 Hz, 1H), 7.17 (d, J ) 2.2 Hz, 1H), 6.89 (d, J )
1.9 Hz, 1H), 4.56 (t, J ) 5.7 Hz, 1H), 4.45 (t, J ) 5.7 Hz, 1H),
3.63 (t, J ) 6.1 Hz, 2H), 3.32 (m, 1H), 2.92 (m, 1H), 1.95 (m,
1H), 1.88 (m, 1H), 1.27 (d, J ) 6.9 Hz, 12H).
E t h yl-(2E,4E,6Z)-3-m et h yl-6,7-(3,4-fu r yl)-7-[3,5-d i-iso-
p r o p y l-6-(3-flu o r o p r o p o x y b e n z e n e ]p e n t a n e -2,4,6-
tr ien oa te (33). Reaction of 108 mg (0.32 mmol) of 32 in the
presence of the anion of triethyl-3-methyl-phosphonocrotonate
(generated from 0.20 mL (0.81 mmol) of of triethyl-3-methyl-
phosphonocrotonate and 0.6 mL of nBuLi in hexanes 1.6 M in
THF-DMPU 5/0.5 mL) according to the procedure described
for the synthesis of 24a affords 140 mg (0.31 mmol, yield: 97%)
of the corresponding ester 33 as a mixture of isomers. 1H NMR
(400 MHz, CDCl3) δ 7.49 (d, J ) 1.7 Hz, 1H), 7.16 (d, J ) 2.2
Hz, 1H), 7.09 (d, J ) 2.2 Hz, 1H), 6.94 (d, J ) 15.9 Hz, 1H),
6.70 (d, J ) 2.0 Hz, 1H), 6.54 (d, J ) 15.9 Hz, 1H), 5.83 (s,
1H), 4.57 (t, J ) 5.8 Hz, 1H), 4.45 (t, J ) 5.8 Hz 1H), 4.17 (dd,
J ) 14.5, 7.3 Hz, 2H), 3.62 (t, J ) 6.0 Hz, 2H), 3.34(m, 1H),
2.93 (m, 1H), 2.29 (s, 3H), 1.95 (m, 1H), 1.81 (m, 1H), 1.43 (s,
9H), 1.28 (t, J ) 7.2 Hz, 3H), 1.26 (t, J ) 7.2 Hz, 12H).
1H), 7.46 (d, J ) 7.4 Hz, 1H), 7.18 (d, J ) 2.2 Hz, 1H), 7.02 (d,
J ) 2.2 Hz, 1H), 4.46-4.10 (m, 2H), 3.52 (m, 1H), 3.30 (septet,
J ) 6.9 Hz, 1H), 3.24 (m, 1H), 2.93 (septet, J ) 6.9 Hz, 1H),
1.67 (m, 2H), 1.28 (d, J ) 6.9 Hz, 6H), 1.27 (d, J ) 6.9 Hz,
6H).
1-[3,5-d i-t er t -b u t yl-6-(3-flu or op r op oxy)b e n ze n e ]-2-
for m ylben zen e (36). Reaction of 1.83 g (5.3 mmol) of 28b
and 874 mg (5.8 mmol) of 2-formylbenzeneboronic acid in the
presence of 306 mg (0.2 mmol, 4%) of Pd(PPh3)4 according to
the procedure described for the synthesis of 19 affords 512 mg
(1.4 mmol, yield: 27%) of the corresponding adduct 36. 1H
NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 8.03 (dd, J ) 8.0, 1.5
Hz, 1H), 7.69 (ddd, J ) 8.0, 7.0, 1.5 Hz, 1H), 7.52-7.48 (m,
2H), 7.42(d, J ) 2.4 Hz, 1H), 7.16 (d, J ) 2.4 Hz, 1H), 4.35
(dddd, J ) 47, 9.2, 6.7, 5.4 Hz, 1H), 4.19 (dddd, J ) 47, 9.2,
6.0, 5.9 Hz, 1H), 3.55(ddd, J ) 9.1, 6.1, 5.9 Hz, 1H), 3.23 (ddd,
J ) 9.2, 6.1, 5.9 Hz, 1H), 1.65 (m, 2H), 1.42 (s, 9H), 1.34 (s,
9H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-cycloh exan edien yl-7-[3,5-
diiso-pr opyl-6-(2,2-diflu or oeth oxyben zen e] pen tan e-2,4,6-
tr ien oa te (37a ). Reaction of 1.48 g (4.3 mmol) of 35a in the
presence of the anion of triethyl-3-methyl-phosphonocrotonate
(generated from 3.21 g, 12.2 mmol, of triethyl-3-methyl-
phosphonocrotonate and 5.0 mL of n-BuLi in hexanes 2.5 M
in THF-DMPU 20/10 mL) according to the procedure described
for the synthesis of 24a affords 1.80 g (4.0 mmol, yield: 93%)
of the corresponding ester 37a as a mixture of isomers. 1H
NMR (400 MHz, CDCl3) δ 7.71 (d, 1H, J ) 7.4 Hz, 1H), 7.41-
7.35 (m, 3H), 7.13 (d, J ) 2.1 Hz, 1H), 6.89 (d, J ) 2.1 Hz,
1H),), 6.83 (d, J ) 16 Hz, 1H), 6.74 (d, J ) 16 Hz, 1H), 5.86 (s,
1H), 5.47 (tt, J ) 55, 4.2 Hz, 1H), 4.17 (q, J ) 7.2 Hz, 2H),
3.53-3.40 (m, 2H), 3.35 (septet, J ) 6.9 Hz, 1H), 2.90 (septet,
J ) 6.9 Hz, 1H), 2.17 (s, 3H), 1.33-1.20 (m, 15H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-cycloh exan edien yl-7-[3,5-
d iiso-p r op yl-6-(3-flu or op r op oxyben zen e] p en ta n e-2,4,6-
tr ien oa te (37b). Reaction of 1.54 g (4.5 mmol) of 35b in the
presence of the anion of triethyl-3-methyl-phosphonocrotonate
(generated from 3.575 g, 13.5 mmol, of triethyl-3-methyl-
phosphonocrotonate and 5.4 mL of nBuLi in hexanes 2.5 M in
THF-DMPU 20/10 mL) according to the procedure described
for the synthesis of 24a affords 1.90 g (4.2 mmol, yield: 93%)
of the corresponding ester 37b as a mixture of isomers. 1H
NMR (400 MHz, CDCl3) δ 7.70 (d, 1H, J ) 7.2 Hz, 1H), 7.40-
7.35 (m, 3H), 7.12 (d, J ) 1.9 Hz, 1H), 6.87 (d, J ) 1.9 Hz,
1H), 6.85 (d, J ) 16 Hz, 1H), 6.73 (d, J ) 16 Hz, 1H), 5.85 (s,
1H), 4.27 (m, 2H), 4.17 (q, J ) 7.1 Hz, 2H), 3.47-3.39 (m, 2H),
3.30 (septet, J ) 6.9 Hz, 1H), 2.89 (septet, J ) 6.9 Hz, 1H),
2.17 (s, 3H), 1.69 (m, 2H), 1.25 (m, 15H).
Eth yl-3-[3,5-d i-iso-p r op yl-6-(3-flu or op r op oxyben zen e]-
4-[(2E,4E)-3-m eth yl-pen tadien e-2,4-dien oate]ben zen e (38).
Reaction of 521 mg (1.4 mmol) of 36 in the presence of the
anion of triethyl-3-methyl-phosphonocrotonate (generated from
1.1 g, 4.2 mmol, of triethyl-3-methyl-phosphonocrotonate and
1.6 mL of n-BuLi in hexanes 2.5 M in THF-DMPU 15/5 mL)
according to the procedure described for the synthesis of 24a
affords 279 mg (0.58 mmol, yield: 41%) of the corresponding
ester 38 as a mixture of isomers.1H NMR (500 MHz, CDCl3) δ
7.71 (m, 1H), 7.36 (m, 4H), 7.02 (d, J ) 2.4 Hz, 1H), 6.88 (d, J
) 16 Hz, 1H), 6.76 (d, J ) 16 Hz, 1H), 5.86 (s, 1H), 4.25 (m,
2H), 4.17(q, J ) 7.0 Hz, 2H), 3.44 (m, 2H), 2.18 (d, J ) 0.9 Hz,
3H), 1.68 (m, 2H), 1.39 (s, 9H), 1.31 (s, 9H), 1.30 (t, J ) 7.0
Hz, 3H).
(2E,4E,6Z)-3-Meth yl-6,7-(3,4-fu r yl)-7-[3,5-d i-iso-p r op yl-
6-(3-flu or op r op oxyben zen e] p en ta n e-2,4,6-tr ien oic Acid
(34). Saponification of 130 mg (0.29 mmol) of 33 in the
presence of 1.5 mL of LiOH (2 M aqueous solution) in a 1/1
mixture of THF/MeOH (5/5 mL) according to the procedure
described for the synthesis of 25a affords 87 mg (0.23 mmol,
yield: 77%) of the desired acid 34 as a single stereoisomer
1
(yellow solid, mp 138 °C CH3CN). H NMR (400 MHz, CDCl3)
δ 7.50 (d, J ) 1.9 Hz, 1H), 7.17 (d, J ) 2.3 Hz, 1H), 7.09 (d, J
) 2.3 Hz, 1H), 6.99 (d, J ) 15.9 Hz, 1H), 6.72 (d, J ) 1.9 Hz,
1H), 6.57 (d J ) 15.9 Hz, 1H), 5.86 (s, 1H), 4.57 (t, J ) 5.9 Hz,
1H), 4.45 (t, J ) 5.8 Hz, 1H), 3.63 (t, J ) 6.0 Hz, 2H), 3.34 (dt,
J ) 13.9, 6.9 Hz, 1H), 2.91 (dt, J ) 13.9, 6.9 Hz, 1H), 2.31 (s,
3H), 1.95 (m, 1H), 1.90 (m, 1H), 1.27 (d, J ) 6.9 Hz, 6H), 1.26
(d, J ) 6.9 Hz, 6H). Anal. (C25H31FO4) C, H. MS (EI, 70 eV)
415 m/z 415 (MH+, 15), 397 (80), 375 (95), 357 (45), 293 (100),
275 (55). HRMS for C25H32FO4 (MH+); calcd, 415.2282, found:
415.2301.
1-[3,5-Di-iso-p r op yl-6-(2,2-d iflu or oeth oxy)ben zen e]-2-
for m ylben zen e (35a ). Reaction of 1.93 g (5.3 mmol) of 27a
and 0.87 g (5.8 mmol) of 2-carboxybenzeneboronic acid in the
presence of 303 mg (0.26 mmol, 5%) of Pd(PPh3)4 according to
the procedure described for the synthesis of 19 affords 1.48 g
(4.3 mmol, yield: 81%) of the corresponding adduct 35a . 1H
NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 8.05 (d, J ) 7.6 Hz,
1H), 7.68 (dd, J ) 7.6, 7.4 Hz, 1H), 7.53 (dd, J ) 7.6, 7.4 Hz,
1H), 7.46 (d, J ) 7.4 Hz, 1H), 7.20 (d, J ) 2.3 Hz, 1H), 7.01 (d,
J ) 2.3 Hz, 1H), 5.53 (tt, J ) 55, 4.2 Hz, 1H), 3.55 (m, 1H),
3.34 (m, 2H), 2.93 (septet, J ) 6.9 Hz, 1H), 1.67 (m, 2H), 1.28
(d, J ) 6.9 Hz, 6H), 1.27 (d, J ) 6.9 Hz, 6H).
(2E,4E,6Z)-3-Meth yl-6,7-cycloh exan edien yl-7-[3,5-diiso-
pr opyl-6-(2,2-diflu or oeth oxyben zen e]pen tan e-2,4,6-tr ien o-
ic Acid (39a ). Saponification of 1.80 g (4.0 mmol) of 37a in
the presence of 0.50 g of LiOH-H2O (11.9 mmol) in a 2/2/1
mixture of THF/EtOH/H2O (20/20/10 mL) according to the
procedure described for the synthesis of 25a affords 1.049 g
(2.45 mmol, yield: 62%) of the desired acid 39a as a single
1-[3,5-Di-iso-p r op yl-6-(3-flu or op r op oxy)b e n ze n e ]-2-
for m ylben zen e (35b). Reaction of 2.15 g (5.9 mmol) of 27b
and 0.975 g (6.5 mmol) of 2-carboxybenzeneboronic acid in the
presence of 341 mg (0.29 mmol, 5%) of Pd(PPh3)4 according to
the procedure described for the synthesis of 19 affords 1.544
1
stereoisomer (pale yellow solid, mp 157-159 °C, CH3CN). H
NMR (400 MHz, CDCl3) δ 7.72 (dd, J ) 7.2, 2.3 Hz, 1H), 7.43-
7.35 (m, 3H), 7.14 (d, J ) 2.2 Hz, 1H), 6.89 (d, J ) 2.2 Hz,
1H), 6.88 (d, J ) 16 Hz, 1H), 6.76 (d, J ) 16 Hz, 1H), 5.88 (s,
1H), 5.48 (tt, J ) 55.5, 4.2 Hz, 1H), 3.48 (dtd, J ) 27, 12.8, 4.2
1
g (4.5 mmol, yield: 76%) of the corresponding adduct 35b. H
NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.02 (d, J ) 7.6 Hz,
1H), 7.66 (dd, J ) 7.6, 7.4 Hz, 1H), 7.50 (dd, J ) 7.6, 7.4 Hz,

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4099
Hz, 2H), 3.35 (septet, J ) 6.9 Hz, 1H), 2.90 (septet, J ) 6.9
Hz, 1H), 2.18 (s, 3H), 1.25 (d, J ) 6.9 Hz, 12H). Anal.
(C26H30F2O3) C, H. MS (EI, 70 eV) 428 m/z 428 (MH+, 25), 410
(60), 368 (100), 328 (85), 286 (75). HRMS for C26H31F2O3 (MH+);
calcd, 428.2163, found, 428.2249.
ated from 2.194 g, 8.30 mmol, of of triethyl-3-methyl-phospho-
nocrotonate and 3.4 mL of n-BuLi in hexanes 2.5 M in THF-
DMPU 15/15 mL) according to the procedure described for the
synthesis of 24a affords 1.0876 g (2.28 mmol, yield: 83%) of
1
the corresponding ester 43 as a mixture of isomers. H NMR
(400 MHz, CDCl3) δ 8.60 (s, 1H), 8.59 (d, J ) 5.3 Hz, 1H),
7.54 (d, J ) 5.3 Hz, 1H), 7.20 (d, J ) 2.1 Hz, 1H), 6.92 (d, J )
2.1 Hz, 1H), 6.89 (d, J ) 16 Hz, 1H), 6.74 (d, J ) 16 Hz, 1H),
5.93 (s, 1H), 4.18 (q, J ) 7.0 Hz, 2H), 3.65 (m, 1H), 3.56 (m,
1H), 3.35 (septet, J ) 6.9 Hz, 1H), 2.93 (septet, J ) 6.9 Hz,
1H), 2.19 (s, 3H), 1.29 (t, J ) 7.0 Hz, 3H), 1.27 (d, J ) 6.9 Hz,
6H), 1.26 (d, J ) 6.9 Hz, 6H).
3-[3,5-Di-iso-p r op yl-6-(2,2,2-t r iflu or oet h oxyb en zen e]-
4-[(2E,4E)-3-m et h yl-p en t a d ien e-2,4-d ien oic a cid ]p yr i-
d in e (44). Saponification of 1.0876 g (2.28 mmol) of 43 in the
presence of 0.4798 g of LiOH (11.4 mmol) in a 2/2/1 mixture
of THF/EtOH/H2O (12/12/6 mL) according to the procedure
described for the synthesis of 25a affords 665.2 mg (1.49 mmol,
yield: 65%) of the desired acid 44 as a single stereoisomer
(white solid, mp 262-263 °C, CH3CN). 1H NMR (400 MHz,
CDCl3) δ 8.62 (s, 1H), 8.61 (d, J ) 5.3 Hz, 1H), 7.56 (d, J ) 5.3
Hz, 1H), 7.21 (d, J ) 2.1 Hz, 1H), 6.93 (d, J ) 2.1 Hz, 1H),
6.92 (d, J ) 16 Hz, 1H), 6.79 (d, J ) 16 Hz, 1H), 5.97 (s, 1H),
3.67 (m, 1H), 3.56 (m, 1H), 3.35 (septet, J ) 6.9 Hz, 1H), 2.93
(septet, J ) 6.9 Hz, 1H), 2.21 (s, 3H), 1.27 (d, J ) 6.9 Hz, 12H).
Anal. (C25H28F3NO3) C, H, N. MS (EI, 70 eV) 447 m/z 447
(MH+, 100), 447 (100). HRMS for C25H29F3NO3 (MH+); calcd,
447.2021, found, 447.2178.
Eth yl-2-[3,5-d i-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxy)ben -
zen e]cyclop en ten e-1-ca r boxyla te (45). Reaction of 200.0
mg (0.66 mmol) of 41 in the presence of 208.0 mg (0.16 mL,
0.72 mmol) of triflate and 76.0 mg (0.066 mmol) of Pd(PPh3)4
according to the procedure described for the synthesis of 19,
affords 258.0 mg (0.65 mmol, yield: 98%) of 45 as a clear oil.
1H NMR (400 MHz, CDCl3) δ 7.04 (d, J ) 1.9 Hz, 1H), 6.74 (d,
J ) 1.9 Hz, 1H), 4.10 (d, J ) 8.6 Hz, 1H), 4.05 (d, J ) 8.6 Hz,
1H), 3.99 (q, J ) 7.1 Hz, 2H), 3.32 (septet, J ) 6.9 Hz, 1H),
2.83 (m, 5H), 2.01 (m, 4H), 1.23 (d, J ) 7.0 Hz, 6H), 1.21 (d, J
) 7.0 Hz, 6H), 0.98 (t, J ) 7.1 Hz, 3H).
(2E,4E,6Z)-3-Met h yl-6,7-cycloh exa n ed ien yl-7-[3,5-d i-
iso-p r op yl-6-(3-flu or op r op oxy b en zen e]p en t a n e-2,4,6-
tr ien oic Acid (39b). Saponification of 1.90 g (4.2 mmol) of
37b in the presence of 0.88 g of LiOH-H2O (21.0 mmol) in a
2/2/1 mixture of THF/MeOH/H2O (50 mL) according to the
procedure described for the synthesis of 25a affords 1.02 g (2.4
mmol, yield: 57%) of the desired acid 39b as a single
1
stereoisomer (white solid, mp 161-163 °C, CH3CN). H NMR
(400 MHz, CDCl3) δ 7.71 (d, 1H, J ) 7.5 Hz, 1H), 7.40-7.35
(m, 3H), 7.12 (d, J ) 2.1 Hz, 1H), 6.91 (d, J ) 16 Hz, 1H), 6.87
(d, J ) 2.1 Hz, 1H), 6.76 (d, J ) 16 Hz, 1H), 5.87 (s, 1H), 4.29
(dt, J ) 17.9, 6.1 Hz, 1H), 4.18 (dt, J ) 17.9, 6.1 Hz, 1H), 3.45
(t, J ) 6.0 Hz, 1H), 3.40 (t, J ) 6.0 Hz, 1H), 3.30 (septet, J )
6.9 Hz, 1H), 2.89 (septet, J ) 6.9 Hz, 1H), 2.18 (s, 3H), 1.69
(m, 2H), 1.25 (d, J ) 6.9 Hz, 12H). Anal. (C27H33FO3) C, H.
MS (EI, 70 eV) 424 m/z 424 (MH+, 15), 406 (70), 364 (100),
322 (40), 282 (40). HRMS Calcd C27H34FO3 (MH+); calcd,
424.2414, found, 424.2471.
3-[3,5-Di-t er t -b u t yl-6-(3-flu or op r op oxyb e n ze n e ]-4-
[(2E,4E)-3-m eth yl-p en ta d ien e-2,4-d ien oic a cid ]ben zen e
(40). Saponification of 279 mg (0.58 mmol) of 38 in the
presence of 243 mg of LiOH (5.8 mmol) in a 2/2/1 mixture of
THF/EtOH/H2O (6/6/3 mL) according to the procedure de-
scribed for the synthesis of 25a affords 260 mg (0.57 mmol,
yield: 99%) of the desired acid 40 as a single stereoisomer
(white solid, mp 177-178 °C, CH3CN). 1H NMR (500 MHz,
CDCl3) δ 7.73 (m, 1H), 7.38 (m, 4H), 7.02 (d, J ) 2.4 Hz, 1H),
6.93 (d, J ) 15.9 Hz, 1H), 6.78 (d, J ) 15.9 Hz, 1H), 5.89 (s,
1H), 4.26 (m, 2H), 3.44 (m, 2H), 2.19 (d, J ) 0.7 Hz, 3H), 1.68
(m, 2H), 1.43 (s, 9H), 1.31 (s, 9H). Anal. (C29H37FO3) C, H. MS
(EI, 70 eV) 452 m/z 452 (MH+, 15), 396 (30), 378 (100), 322
(55). HRMS for C29H38FO3 (MH+); calcd, 452.2727, found,
452.2786.
Syn th esis of 3,5-Di-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxy)-
ben zen e Bor on ic Acid (41). To a flame-dried 300 mL round-
bottomed flask was charged with 100 mL of anhydrous Et2O,
27c (3.86 g, 10.0 mmol) and TMEDA (2.3 mL, 15.0 mmol). The
resulting solution was cooled to -78 °C using a dry ice/acetone
bath and 6.0 mL of n-BuLi solution (2.5 M in hexanes) was
added dropwise via a syringe. The mixture was kept at -78
°C for 15 min and 3.4 mL of B(OMe)3 (30.0 mmol) was added
slowly. This resulting mixture was stirred at -78 °C for 1 h,
slowly warmed to 0 °C. The reaction mixture was quenched
with 50 mL of 1.0 M aqueous HCl solution and stirred at 23
°C for 1 h. The reaction mixture was extracted with EtOAc (2
× 150 mL). The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2, 5 × 20
cm, 15% EtOAc/hexane as eluent) to give desired boronic acid
1-[3,5-di-iso-pr opyl-6-(2,2,2-tr iflu or oeth oxy)ben zen e] cy-
clop en ten e-2-m eth a n ol (46). To 0.258 g (0.65 mmol) of 45
dissolved in 10 mL of anhydrous diethyl ether in a flame dried
25 mL round-bottom flask at 0 °C was added 0.030 g (0.78
mmol) of LiAlH4 portion-wise. The resultant mixture is stirred
for 1.0 h at 0 °C. After such time, water (0.014 mL, 0.78 mmol)
was added, followed by 6 N aqueous sodium hydroxide (0.26
mL, 1.55 mmol). The resultant mixture was allowed to warm
to ambient temperature, stirred for 0.5 h, filtered through a
plug of silica gel (eluting with diethyl ether) and concentrated
under reduced pressure to give 0.225 g (0.63 mmol, yield: 97%)
1
of alcohol 46 as a colorless oil. H NMR (400 MHz, CDCl3) δ
7.02 (d, J ) 2.2 Hz, 1H), 6.80 (d, J ) 2.2 Hz, 1H), 4.09 (s, 2H),
4.00 (d, J ) 8.5 Hz, 1H), 3.97 (d, J ) 8.5 Hz, 1H), 3.33 (heptet,
J ) 6.9 Hz, 1H), 2.85 (heptet, J ) 6.9 Hz, 1H), 2.74 (t, J ) 7.2
Hz, 2H), 2.65 (t, J ) 7.4 Hz, 2H), 2.01 (m, 2H), 1.52 (broad s,
1H), 1.23 (d, J ) 6.8 Hz, 6H), 1.22 (d, J ) 7.1 Hz, 6H).
1
41 1.38 g (46%) as white solid. H NMR (400 MHz, CDCl3) δ
7.54 (d, J ) 2.1 Hz, 1H), 7.26 (d, J ) 2.1 Hz, 1H), 5.62 (s, 2H),
4.16 (q, J ) 8.2 Hz, 2H), 3.25 (septet, J ) 6.9 Hz, 1H), 2.91
(septet, J ) 6.9 Hz, 1H), 1.26 (d, J ) 6.9 Hz, 6H), 1.25 (d, J )
6.9 Hz, 6H).
1-[3,5-Di-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxy)ben zen e]-
2-for m ylcyclop en ten e (47). 47 was synthesized from 0.225
g (0.66 mmol) of 46 and 0.11 g (0.95 mmol) NMO in the
presence of 0.011 g (0.031 mmol) of TPAP according to the
procedure described for the synthesis of 23a . 0.222 g (0.63
2-[3,5-Di-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxy)ben zen e]-
4-for m ylp yr id in e (42). Reaction of 174.1 mg (0.57 mmol) of
41 and 106.5 mg (0.57 mmol) of 3-bromo-4-carboxypyridine in
the presence of 33 mg (0.029 mmol, 5%) of Pd(PPh3)4 according
to the procedure described for the synthesis of 19 affords 150
mg (0.41 mmol, yield: 72%) of the corresponding adduct 42.
1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.85 (d, J ) 4.9 Hz,
1H), 8.81(s, 1H), 7.82 (d, J ) 4.9 Hz, 1H), 7.27 (d, J ) 2.2 Hz,
1H), 7.07 (d, J ) 2.2 Hz, 1H), 3.74 (m, 1H), 3.47 (m, 1H), 3.33
(septet, J ) 6.9 Hz, 1H), 2.97 (septet, J ) 6.9 Hz, 1H), 1.29 (d,
J ) 6.9 Hz, 12H).
1
mmol, yield: 95%) of 47 was isolated as a brown oil. H NMR
(400 MHz, CDCl3) δ 9.69 (s, 1H), 7.14 (d, J ) 2.2 Hz, 1H),
6.88 (d, J ) 2.1 Hz, 1H), 3.99 (d, J ) 8.4 Hz, 1H), 3.96 (d, J )
8.3 Hz, 1H), 3.31 (heptet, J ) 6.9 Hz, 1H), 2.98 (m, 2H), 2.88
(heptet, J ) 6.9 Hz, 1H), 2.73 (t, J ) 7.6 Hz, 2H), 2.04 (m,
2H), 1.25 (d, J ) 6.5 Hz, 6H), 1.23 (d, J ) 6.7 Hz, 6H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-cyclop en ten yl-7-[3,5-d i-
iso-pr opyl-6-(2,2,2-tr iflu or o eth oxyben zen e]pen tan e-2,4,6-
tr ien oa te (48). Reaction of 222.0 mg (0.63 mmol) of 47 in the
presence of the anion of triethyl-3-methyl-phosphonocrotonate
(generated from 0.46 mL, 1.9 mmol of triethyl-3-methyl-
phosphonocrotonate and 0.81 mL of n-BuLi in hexanes 2.5 M
in THF-DMPU 8.0 mL) according to the procedure described
Eth yl-3-[3,5-d i-iso-p r op yl-6-(2,2,2-tr iflu or oeth oxyben -
zen e]-4-[(2E,4E)-3-m eth yl-p en ta d ien e-2,4-d ien oa te]p yr i-
d in e (43). Reaction of 1.011 g (2.77 mmol) of 42 in the presence
of the anion of triethyl-3-methyl-phosphonocrotonate (gener-

4100 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
for the synthesis of 24a affords 293 mg (0.63 mmol, yield:
100%) of the corresponding ester 48 as a mixture of isomers.
1H NMR (400 MHz, CDCl3) δ 7.06 (d, J ) 2.1 Hz, 1H), 6.82 (d,
J ) 2.2 Hz, 1H), 6.79 (d, J ) 15.8 Hz, 1H), 6.26 (d, J ) 15.8
Hz, 1H), 5.81 (s, 1H), 4.16 (q, J ) 7.1 Hz, 2H), 3.94 (q, J ) 8.5
Hz, 2H), 3.35 (heptet, J ) 6.9 Hz, 1H), 2.87 (m, 3H), 2.68 (t, J
) 7.4 Hz, 2H), 2.21 (s, 3H), 2.03 (p, J ) 7.4 Hz, 2H), 1.28 (t, J
) 7.2 Hz, 3H), 1.25 (d, J ) 6.9 Hz, 6H), 1.24 (d, J ) 7.0 Hz,
6H).
(2E,4E,6Z)-3-Meth yl-6,7-cyclopen ten yl-7-[3,5-di-iso-pr o-
pyl-6-(2,2,2-diflu or oeth oxy ben zen e]pen tan e-2,4,6-tr ien o-
ic Acid (49). Saponification of 293 mg (0.63 mmol) of 48 in
the presence of 0.94 mL of LiOH (2M aqueous solution) in a
1/1 mixture of THF/MeOH (4.0/4.0 mL) according to the
procedure described for the synthesis of 25a affords 76.3 mg
(0.18 mmol, yield: 28%) of the desired acid 49 as a single
stereoisomer (yellow solid, mp ) 159.9-163.0 °C, CH3CN). 1H
NMR (400 MHz, CDCl3) δ 7.07 (d, J ) 2.1 Hz, 1H), 6.83 (d, J
) 15.7 Hz, 1H), 6.81 (d, J ) 2.2 Hz, 1H), 6.28 (d, J ) 15.7 Hz,
1H), 5.84 (s, 1H), 3.94 (q, J ) 8.5 Hz, 2H), 3.35 (heptet, J )
6.9 Hz, 1H), 2.87 (m, 3H), 2.69 (t, J ) 7.3 Hz, 2H), 2.22 (s,
3H), 2.04 (p, J ) 7.4 Hz, 2H), 1.25 (d, J ) 6.5 Hz, 6H), 1.23 (d,
J ) 6.4 Hz, 6H). Anal. (C25H31F3O3) C, H. MS (EI, 70 eV) 436
m/z 436 (MH+, 100), 418 (50), 390 (80), 376 (30), 438 (30).
HRMS for C25H32F3O3 (MH+); calcd, 436.2225, found, 436.2281.
Hz, 1H), 7.00 (d, J ) 2.1 Hz, 1H), 4.45 (t, J ) 5.9 Hz, 1H),
4.34 (t, J ) 5.9 Hz, 1H), 3.50 (m, 2H), 2.64 (dd, J ) 15.2, 7.6
Hz, 2H), 1.84 (m, 1H), 1.78 (m, 1H), 1.42 (s, 9H), 1.26 (t, J )
7.7 Hz, 3H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-(2,3-th ien yk )-7-[3-eth yl-
5-ter t-bu tyl-6-(2,2-diflu or o eth oxyben zen e] pen tan e-2,4,6-
tr ien oa te (54a ). Reaction of 243 mg (0.69 mmol) of 53a in
the presence of the anion of triethyl-3-methyl-phosphonocro-
tonate (generated from 0.62 mL, 2.5 mmol of of triethyl-3-
methyl-phosphonocrotonate and 1.0 mL of n-BuLi in hexanes
2.5 M in THF-DMPU 5/0.5 mL) according to the procedure
described for the synthesis of 24a affords 190 mg (0.41 mmol,
yield: 60%) of the corresponding ester 54a as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J ) 5.2 Hz,
1H), 7.19 (d, J ) 2.2 Hz, 1H), 7.10 (d, J ) 5.2 Hz, 1H), 6.95 (d,
J ) 2.2 Hz, 1H), 6.94 (d, J ) 15.8 Hz, 1 Hz, 2H), 5.86 (s, 1H),
5.63 (tt, J ) 55.4, 4.1 Hz, 1H), 4.17 (dd, J ) 14.2, 7.1 Hz, 2H),
3.59 (td, J ) 13.5, 4.2, 2H), 2.63 (dd, J ) 15.2, 7.6 Hz, 2H),
2.24 (s, 3H), 1.43 (s, 9H), 1.28 (t, J ) 7.2 Hz, 3H), 1.25 (t, J )
7.3 Hz, 3H).
Eth yl-(2E,4E,6Z)-3-m eth yl-6,7-(2,3-th ien yl)-7-[3-eth yl-
5-ter t-bu tyl-6-(3-flu or o p r op oxyben zen e]p en ta n e-2,4,6-
tr ien oa te (54b). Reaction of 161 mg (0.46 mmol) of 53a in
the presence of the anion of triethyl-3-methyl-phosphonocro-
tonate (generated from 0.29 mL, 1.2 mmol of of triethyl-3-
methyl-phosphonocrotonate and 0.6 mL of nBuLi in hexanes
1.6 M in THF-DMPU 5/0.5 mL) according to the procedure
described for the synthesis of 24a affords 208 mg (0.45 mmol,
yield: 98%) of the corresponding ester 54b as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J ) 5.2 Hz,
1H), 7.17 (d, J ) 2.0 Hz, 1H), 7.09 (d, J ) 5.0 Hz, 1H), 6.97 (d,
J ) 15.8 Hz, 1H), 6.93 (d, J ) 2.1 Hz, 1 Hz, 2H), 6.63 (d, J )
15.8 Hz, 1H), 5.85 (s, 1H), 4.45 (t, J ) 6.0 Hz, 1H), 4.33 (t, J
) 6.0 Hz 1H), 4.17 (dd, J ) 14.3, 7.3 Hz, 2H), 3.50 (t, J ) 5.8
Hz, 2H), 2.62 (dd, J ) 15.1, 7.6 Hz, 2H), 2.23 (s, 3H), 1.84 (m,
1H), 1.75 (m, 1H), 1.43 (s, 9H), 1.28 (t, J ) 7.1 Hz, 3H), 1.25
(t, J ) 7.2 Hz, 3H).
(2E,4E,6Z)-3-Meth yl-6,7-(2,3-th ien yl)-7-[3-eth yl-5-ter t-
bu tyl-6-(2,2-diflu or oeth oxy ben zen e]pen tan e-2,4,6-tr ien o-
ic Acid (55a ). Saponification of 155 mg (0.34 mmol) of 54a in
the presence of 2 mL of LiOH (2 M aqueous solution) in a 1/1
mixture of THF/MeOH (5/5 mL) according to the procedure
described for the synthesis of 25a affords 110 mg (0.27 mmol,
yield: 80%) of the desired acid 55a as a single stereoisomer
(yellow solid, mp 135 °C CH3CN). 1H NMR (400 MHz, CDCl3)
δ 7.34 (d, J ) 5.2 Hz, 1H), 7.19 (d, J ) 1.9 Hz, 1H), 7.11 (d, J
) 5.0 Hz, 1H), 6.99 (d, J ) 15.9 Hz, 1H), 6.95 (d, J ) 1.9 Hz,
1H), 6.68 (d, J ) 15.9 Hz, 1H), 5.89 (s, 1H), 5.63 (tt, J ) 55.4,
4.2 Hz, 1H), 3.58 (m, 2H), 2.64 (dd, J ) 15.2, 7.6 Hz, 2H), 2.25
(s, 3H), 1.43 (s, 9H), 0.88 (t, J ) 6.5 Hz, 3H). Anal. (C24H28F2O3S)
C, H, S. MS (EI, 70 eV) 434 m/z 434 (MH+, 100), 451 (100),
378 (60), 360 (70), 278 (30). HRMS for C24H29F2O3S (MH+);
calcd, 434.1727, found, 434.1594.
(2E,4E,6Z)-3-Meth yl-6,7-(2,3-th ien yl)-7-[3-eth yl-5-ter t-
bu tyl-6-(3-flu or op r op oxy ben zen e]p en ta n e-2,4,6-tr ien oic
Acid (55b). Saponification of 160 mg (0.35 mmol) of 54b in
the presence of 2 mL of LiOH (2 M aqueous solution) in a 1/1
mixture of THF/MeOH (5/5 mL) according to the procedure
described for the synthesis of 25a affords 105 mg (0.26 mmol,
yield: 75%) of the desired acid 55b as a single stereoisomer
(yellow solid, mp 128 °C CH3CN). 1H NMR (400 MHz, CDCl3)
δ 7.32 (d, J ) 5.1 Hz, 1H), 7.17 (d, J ) 2.0 Hz, 1H), 7.10 (d, J
) 5.2 Hz, 1H), 7.00 (d, J ) 15.8 Hz, 1H), 6.93 (d, J ) 1.9 Hz,
1H), 6.65 (d, J ) 15.8 Hz, 1H), 5.87 (s, 1H), 4.45 (t, J ) 5.4,
Hz, 1H), 4.32 (t, J ) 5.4 Hz, 1H), 3.51 (m, 2H), 2.63 (dd, J )
15.2, 7.6 Hz, 2H), 2.24 (s, 3H), 1.85 (m, 1H), 1.75 (m, 1H), 1.43
(s, 9H), 1.25 (t, J ) 7.5 Hz, 3H). Anal. (C25H31FO3S) C, H, S.
MS (EI, 70 eV) 430 m/z 430 (MH+, 70), 447 (100), 430 (70),
412 (95). HRMS for C25H32FO3S (MH+); calcd, 430.1978, found,
430.2202.
2-ter t-Bu tyl-4-eth yl-6-iod op h en ol (51). Iodination of 50.0
g (0.30 mol) of 2-tert-butyl-4-methylphenol 50 in the presence
of 74.2 g (0.33 mol) of NIS and 5.7 g (0.03 mol) of p-
toluenesulfonic acid acid using the procedure described for the
synthesis of 16 affords 88.2 g (0.29 mol, yield: 97%) of
2-tertbutyl-4-ethyl-6-iodophenol 51 as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ 7.36 (d, J ) 1.8 Hz, 1H), 7.06 (d, J ) 1.9
Hz, 1H), 5.33 (s, 1H), 2.53 (dd, J ) 15.2, 7.6 Hz, 2H), 1.38 (s,
9H), 1.19 (t, J ) 7.6 Hz, 3H).
2-(2,2-Diflu or oeth oxy)-3-ter t-bu tyl-5-eth ylben zen e (52a).
Alkylation of 478 mg (1.57 mmol) 51 with 273 mg (1.88 mmol)
of 1-bromo-2,2-difluoroethane in the presence of 765 mg (2.35
mmol of Cs2CO3 in 3 mL of dry DMF according to the
procedure described for the synthesis of 27a affords 552 mg
1
(1.50 mmol, yield: 97%) of 52a as a clear yellow oil. H NMR
(400 MHz, CDCl3) δ 7.53 (d, J ) 1.9 Hz, 1H), 7.14 (d, J ) 1.9
Hz, 1H), 6.27 (tt, J ) 55.5, 4.3 Hz, 1H), 4.23 (td, J ) 13.2, 4.3
Hz, 2H), 2.56 (dd, J ) 15.2, 7.6 Hz, 2H), 1.39 (s, 9H), 1.21 (t,
J ) 7.4 Hz, 3H).
2-(3-F lu or op r op oxy)-3-ter t-bu tyl-5-eth ylben zen e (52b).
Alkylation of 417 mg (1.37 mmol) 51 with 289 mg (2.06 mmol,
0.19 mL) of 1-bromo-3-fluoropropane in the presence of 669
mg (2.06 mmol of Cs2CO3 in 3 mL of dry DMF according to
the procedure described for the synthesis of 27a affords 489
mg (1.34 mmol, yield: 98%) of 52b as a clear yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.51 (d, J ) 1.8 Hz, 1H), 7.12 (d, J
) 1.8 Hz, 1H), 4.80 (t, J ) 5.9 Hz, 1H), 4.68 (t, J ) 5.9 Hz,
1H), 4.09 (t, J ) 6.4 Hz, 2H), 2.54 (dd, J ) 15.2, 7.6 Hz, 2H),
2.26 (m, 1H), 2.23 (m, 1H), 1.37 (s, 9H), 1.20 (t, J ) 7.6 Hz,
3H).
1-[3-Eth yl-5-ter t-bu tyl-6-(2,2-d iflu or oeth oxy)ben zen e]-
2-for m ylth iop h en e (53a ). Reaction of 261 mg (0.71 mmol)
of 52a and 165 mg (1.06 mmol) of 2-formylthiophene-3-boronic
acid in the presence of 41 mg (0.035 mmol, 5%) of Pd(PPh3)4
according to the procedure described for the synthesis of 19
affords 243 mg (0.69 mmol, yield: 97%) of the corresponding
adduct 53a . 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.79
(d, J ) 4.9 Hz, 1H), 7.27 (d, J ) 4.9 Hz, 1H), 7.26 (d, J ) 2.2
Hz, 1H), 7.02 (d, J ) 2.2 Hz, 1H), 5.67 (tt, J ) 55.0, 4.1 Hz,
1H), 3.58 (td, J ) 13.4, 4.1 Hz, 2H), 2.65 (dd, J ) 15.2, 7.6 Hz,
2H), 2.24 (s, 3H), 1.42 (s, 9H), 1.25 (t, J ) 7.6 Hz, 3H).
1-[3-Eth yl-5-ter t-bu tyl-6-(3-flu or op r op oxy)ben zen e]-2-
for m ylth iop h en e (53b). Reaction of 213 mg (0.58 mmol) of
52b and 137 mg (0.88 mmol) of 2-formylthiophen-3-boronic
acid in the presence of 34 mg (0.03 mmol, 5%) of Pd(PPh3)4
according to the procedure described for the synthesis of 19
affords 161 mg (0.46 mmol, yield: 79%) of the corresponding
adduct 53b. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 7.77
(d, J ) 5.2 Hz, 1H), 7.28 (d, J ) 5.2 Hz, 1H), 7.27 (d, J ) 2.1
3,5-Di-iso-p r op yl-6-(3-h yd r oxyp r op oxy)iod ob en zen e
(56). Alkylation of 3.22 g (10.0 mmol) of 26 in the presence of
3.04 g (11.0 mmol) of 1-bromo-3-(tert-butyl dimethylsiloxy)-
propane and 576 mg (12.0 mol) of NaH according to the

Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4101
procedure described for the synthesis of 17 affords the corre-
sponding crude protected alcohol as a clear oil. This one was
directly treated with 15 mL of TBAF (1.0 M in THF) and
stirred until complexion (TLC monitoring). After evaporation
of the solvents, the residue was purified over silica gel column
chromatography to afford 3.55 g (9.1 mmol, yield: 91%) of 56
as an oil. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J ) 2.2 Hz,
1H), 7.33 (d, J ) 2.2 Hz, 1H), 4.14 (t, J ) 5.8 Hz, 2H), 3.98
(m, 2H), 2.13 (m, 2H), 1.37 (s, 9H), 1.28 (s, 9H), 0.95 (s, 9H),
0.01 (s, 6H).
3,5-Di-iso-pr opyl-6-(3-for m ylpr opoxy)iodoben zen e (57).
To a mixture of 8.28 g (38.0 mmol) of PCC, 8.3 g of Celite and
8.3 g of molecular sieve in 50 mL of CH2Cl2 was added 3.5 g
(8.96 mmol) of 56 (disolved in 15 mL of CH2Cl2) at RT. After
complexion of the reaction (TLC monitoring), the mixture was
filtrated and the solvents removed under reduced pressure.
Purification of the crude oil over silica gel column chromatog-
raphy (eluent: 95/5 hexane/ethyl acetate) affords 2.27 g (5.85
mol, yield: 65%) of 57 as a clear oil. 1H NMR (400 MHz, CDCl3)
δ 10.04 (d, J ) 1.8 Hz, 1H), δ 7.65 (d, J ) 2.3 Hz, 1H), 7.33 (d,
J ) 2.3 Hz, 1H), 4.33 (t, J ) 6.5 Hz, 2H), 3.00 (td, J ) 6.5, 1.8
Hz, 2H), 1.37 (s, 9H), 1.28 (s, 9H).
0.6 H2O) C, H. MS (EI, 70 eV) 476 m/z 476 (MH+, 40), 458
(45), 420 (45), 402 (100). HRMS for C27H35F2O3S (MH+); calcd,
476.2197, found: 476.2382.
Biology. Cotr a n sfection Assa y. All cotransfections were
carried out in 96-well plates in an automated workstation with
CV-1 cells as previously described by Boehm and al.28
Cotransfection assays were performed in CV-1 cells trans-
fected with an expression vector for each of the RXR subtypes
and a luciferase reporter gene under the control of the
appropriate RXR response element (RXRE).28 A CRBPII-tk-
Luc reporter construct was used for RXRR. Similarly, for the
heterodimer assay, RXRR was cotransfected into CV-1 cells
along with an expression vector for hPPARγ; activation of the
RXR:hPPARγ heterodimer was tested on the PPRE-tk-Luc
reporter as described.28 The luciferase reported contains three
copies of the AOX PPRE driving luciferase expression. Com-
pounds were tested in three separate experiments in log
dilutions from 1 × 10-5 to 1 × 10-12 M, with triplicate
determinations at each concentration. Typically, CV-1 cells
were transiently cotransfected with the receptor expression
vector, the receptor plasmid, and a â-galactosidase (RSV-â-
Gal) internal control (used to calculate normalized lucferase
response). The cells were incubated in the presence of the test
compound and assayed for luciferase and â-galactosidase
activity as described previously.28 The luciferase data are
presented as percent normalized response with the maximal
response (100%) elicited by the control retinoid (all-trans-
retinoic acid for the RXR assays and BRL49653 for the RXR:
hPPARγ heterodimer assay). Synergy assays were performed
using the same protocol except that a combination of the test
compound plus the agonist of the heterodimeric partner were
incubated concomitantly in the same dose-response paradigm.
For the RXR:hPPARγ synergy assay, the test compound was
incubated simultaneously with 100 nM of BRL49653 and for
the RXR:RAR synergy assay, the test compound was incubated
simultaneously with 3 nM of TTNPB.
3,5-Di-ter t-bu t yl-6-(3,3-d iflu or op r op oxy)iod ob en zen e
(58). To a mixture of 2.20 g (5.66 mmol) of 57 in 30 mL of
CH2Cl2 was added dropwise 3.1 mL (3.77 g, 23.4 mmol) of
DAST. The mixture was stirred overnight at room temperature
and carefully quenched with 2 N aq Na2CO3 solution. After
extraction with CH2Cl2, the organic fractions were collected,
dried over MgSO4, filtrated and concentrated. Purification of
the crude oil over SiO2 column chromatography (eluent:
hexanes/EtOAc: 95/5) affords 2.06 g (5.0 mmol, yield: 88%)
1
of 58 as a clear oil. H NMR (400 MHz, CDCl3) δ 7.65 (d, J )
2.1 Hz, 1H), 7.33 (d, J ) 2.1 Hz, 1H), 6.21 (tt, J ) 55.0, 4.3
Hz, 1H), 4.12 (t, J ) 6.0 Hz, 2H), 2.40 (m, 2H), 1.37 (s, 9H),
1.28 (s, 9H).
1-[3,5-Di-ter t-bu tyl-6-(3,3-d iflu or op r op oxy)ben zen e]-2-
for m ylth iop h en e (59). Reaction of 250.0 mg (0.61 mmol) of
58 in the presence of 114.0 mg (0.73 mmol) of boronic acid
and 70.0 mg (0.061 mmol) of Pd(PPh3)4 according to the
procedure described for the synthesis of 19, affords 192.0 mg
(0.49 mmol, yield: 80%) of 59 as a clear oil. (400 MHz, CDCl3)
δ 9.75 (d, J ) 1.2 Hz, 1H), 7.79 (dd, J ) 4.8 Hz, J ) 1.1 Hz,
1H), 7.43 (d, J ) 2.5 Hz, 1H), 7.25 (d, J ) 5.0 Hz, 1H), 7.14 (d,
J ) 2.5 Hz, 1H), 5.83 (tt, J ) 56.6, 4.7 Hz, 1H), 3.53 (m, 2H),
1.96 (m, 1H), 1.42 (s, 9H), 1.33 (s, 9H).
Bin d in g Stu d ies. Receptor binding assays for RARs and
RXRs were performed in a similar manner as described in
Boehm et al. using [3H]-9-cis-RA as the radioligand for RXRs,
[3H]-ATRA (purchased from NEN-DuPont) for the RARs.28
Receptor binding assays for PPARs were performed in a
similar manner using proprietary radioactive ligands as
described in recent patent applications.25 Ki values for the
analogues were determined by application of the Cheng-
Prussof equation.
E t h yl-(2E,4E,6Z)-3-m et h yl-6,7-(2,3-t h ien yl)-7-[3,5-d i-
ter t-bu tyl-6-(3,3-d iflu or op r op oxyben zen e]p en ta n e-2,4,6-
tr ien oa te (60). Reaction of 192.0 mg (0.49 mmol) of 59 in the
presence of the anion of triethyl-3-methyl-phosphonocrotonate
(generated from 0.36 mL, 1.5 mmol of of triethyl-3-methyl-
phosphonocrotonate and 0.63 mL of n-BuLi in hexanes 2.5 M
in THF-DMPU 2.5/2.5 mL) according to the procedure de-
scribed for the synthesis of 24a affords 240.0 mg (0.47 mmol,
yield: 97%) of the corresponding ester 60 as a mixture of
isomers. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J ) 2.5 Hz,
1H), 7.31 (d, J ) 5.2 Hz, 1H), 7.11 (d, J ) 5.1 Hz, 1H), 7.07 (d,
J ) 2.4 Hz, 1H), 6.97 (d, J ) 15.9 Hz, 1H), 6.65 (d, J ) 15.9
Hz, 1H), 5.86 (s, 1H), 5.82 (tt, J ) 56.8 Hz, J ) 4.8 Hz, 1H),
4.17 (q, J ) 7.1 Hz, 2H), 3.54 (t, J ) 5.8 Hz, 2H), 2.24 (s, 3H),
1.93 (m, 2H), 1.43 (s, 9H), 1.32 (s, 9H), 1.29 (t, J ) 7.1 Hz,
3H).
d b/d b Mou se Stu d ies. db/db mice were obtained from
J ackson Laboratories (Bar Harbor, ME) at 5 weeks of age.
Animals were housed in groups of 6 on a 12L:12D light cycle
(lights on at 0600 h) with food (Purina 5008) and tap water
continuously available. Blood samples were obtained via the
tail vein 3 h after dosing on the indicated day. For chronic
treatment, mice were gavaged with vehicle + compound of
interest. At the end of the experiments, animals were weighed
and anesthetized. Blood was collected by cardiac puncture
prior to euthanization with CO2. Plasma was used within 1
week for analysis of glucose and triglycerides.
Sp r a gu e Da w ley R a t St u d ies. Seven-week-old male
Sprague-Dawley rats (∼200 g body weight) were purchased
from Harlan Sprague Dawley (Indianapolis, IN). The animals
had free access to Purina 5008 diet (Ralston Purina Co., St.
Louis, MO) and tap water, with a 12-h dark, 12-h light cycle
(lights on from 06:00 to 18:00). Animals were acclimated in
our facility for 5-6 days before treatment and were dosed via
oral gavage with 1 mL vehicle each day for 3 days prior to the
experiment to acclimate them to the dosing procedure. The
vehicle consists of 0.085% povidone (ISP Technologies Inc.,
New Milford, CT), 1.5% lactose (Quest International, New
York, NY), 0.026% Tween-80 (Sigma, St. Louis, MO) and 0.2%
v/v Antifoam (Dow Corning, Midland, MI). For experiments
animals were dosed by oral gavage with either vehicle alone,
or a suspension of compound in the vehicle. Blood was collected
from the tail vein of conscious animals. Plasma was prepared
and kept frozen at -20 °C until analyzed.
(2E,4E,6Z)-3-Meth yl-6,7-(2,3-th ien yl)-7-[3,5-d i-ter t-bu -
tyl-6-(3,3-d iflu or op r op oxy ben zen e]p en ta n e-2,4,6-tr ien o-
ic Acid (61). Saponification of 240.0 mg (0.47 mmol) of 60 in
the presence of 0.75 mL of LiOH (2 M aqueous solution) in a
1/1 mixture of THF/MeOH (2.5/2.5 mL) according to the
procedure described for the synthesis of 25a affords 29.4 mg
(0.061 mmol, yield: 16%) of the desired acid 61 as a single
1
stereoisomer (yellow solid, mp 145 °C CH3CN). H NMR (400
MHz, CDCl3) δ 7.37 (d, J ) 2.4 Hz, 1H), 7.33 (d, J ) 5.1 Hz,
1H), 7.12 (d, J ) 5.1 Hz, 1H), 7.07 (d, J ) 2.4 Hz, 1H), 7.03 (d,
J ) 15.9 Hz, 1H), 6.68 (d, J ) 15.8 Hz, 1H), 5.88 (s, 1H), 5.82
(tt, J ) 56.7, 4.8 Hz, 1H), 3.35 (t, J ) 5.9 Hz, 2H), 2.25 (s,
3H), 1.94 (m, 2H), 1.42 (s, 9H), 1.32 (s, 9H). Anal. (C27H34F2O3S‚

4102 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Michellys et al.
efficient stereospecific synthesis of the dimer-selective ret-
inoid X receptor modulator (2E, 4E, 6Z)-7-[5,6,7,8-tertrahydro-
5,5,8,8-tetramethyl-2-(n-propoxy)naphthalen-3-yl]-3-methylocta-
2,4,6-trienoic acid. J . Org. Chem. 2000, 65, 3233-3235. (e)
Cannan Koch, S. S.; Dardashti, L. J .; Hebert, J . J .; White, S.
K.; Croston, G. E.; Flatten, K. S.; Heyman, R. A.; Nazdan, A. M.
Identification of the first retinoic X receptor homodimer antago-
nist. J . Med. Chem. 1996, 39, 3229-3234.
Su p p or t in g In for m a t ion Ava ila b le: Purity of com-
pounds 25a , 25b, 25c, 31a , 31b, 31c, 34, 39a , 39b, 40, 44,
49, 55a , 55b, and 61 determined by HPLC. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(25) See patent WO/02100813A2 and WO/0216331A1.
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Novel RXR Selective Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4103
(27) Mapes, C. M.; Ardecky, R. J .; Chen, J . H.; Crombie, D. L.; Etgen,
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(29) Data collected in the solid state at room temperature. Unpub-
lished results.
J M020401K