Synthesis of novel retinoid X receptor-selective retinoids

Article abstract of DOI:10.1021/jo0103064

Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was prepared in 98% yield using an AlCl₃-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis of 1 in 33% yield. FeCl₃-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethyl-terephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50% aqueous NH₂OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41 and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of compounds.

Full text of DOI:10.1021/jo0103064

5772
J . Org. Chem. 2001, 66, 5772-5782
Syn th esis of Novel Retin oid X Recep tor -Selective Retin oid s
Margaret M. Faul,* Andrew M. Ratz, Kevin A. Sullivan, William G. Trankle, and
Leonard L. Winneroski
Lilly Research Laboratories, A Division of Eli Lilly and Company, Chemical Process Research and
Development Division, Indianapolis, Indiana 46285-4813
faul•margaret•m@lilly.com
Received March 20, 2001
Retinoids 1-5 have been identified as potent RXR agonists for evaluation in the treatment of non-
insulin-dependent (type II) diabetes mellitus (NIDDM). Highly convergent syntheses of 1-5 have
been developed. The core tetrahydronaphthalene 7, employed in the synthesis of 1 and 2, was
prepared in 98% yield using an AlCl3-catalyzed (0.03 equiv) Friedel-Crafts alkylation of toluene
with 2,5-dichloro-2,5-dimethylhexane 6. A nitromethane-mediated Fridel-Crafts acylation of 7 with
chloromethylnicotinate 9 was developed to prepare ketone 10 in 68% yield. Chelate-controlled
addition of MeMgCl to 10 followed by dehydration afforded olefin 11 in 65% yield. Cyclopropanation
of 11 with trimethylsulfoxonium ylide, followed by saponification, completed a five-step synthesis
of 1 in 33% yield. FeCl3-catalyzed (0.05 equiv) Friedel-Crafts acylation of 7 with chloromethyl-
terephthalate 14 afforded ketone 15 in 81% yield. Saponification of 15 and reaction with 50%
aqueous NH2OH in AcOH afforded a 9:1 mixture of cis and trans oximes, from which the desired
cis-oxime 2 was isolated in 43% yield. The core bromo-dihydronaphthalene 29 required for the
synthesis of 3-5 was prepared by a Shapiro reaction. Transmetalation of 29 and reaction with
Weinreb amides 30b or 36 afforded ketones 32 and 37, which were converted into 3-5 using
chemistry comparable to the tetrahydronaphthylene series. Suzuki coupling of boronic acids 41
and 42 with vinyl triflate 43 provided an alternative approach to the synthesis of this class of
compounds.
Ch a r t 1
In tr od u ction
The retinoid receptors are members of the superfamily
of intracellular hormone receptors that function as
regulators of gene transcription.1-4 These receptors are
classified into two subfamilies: the retinoic acid receptors
(RARR, RARâ, and RARγ), and the retinoid X receptors
(RXRR, RXRâ, and RXRγ).5,6 This classification of retinoid
receptors is based upon differences in amino acid struc-
ture, responsiveness toward natural and synthetic ligands,
and ability to modulate gene expression of various target
genes. Ligands that interact with these receptors, the
retinoids, make up a structurally diverse group of
molecules. Among this class of compounds, Ligand Phar-
maceuticals Inc. has recently identified a new class of
retinoids, Targretin and SR11237, that are selective
activators of RXR and show little or no activation of RAR
(Chart 1).7 Targretin is currently under evaluation for
treatment of cancer.8-16
In 1997, Eli Lilly and Company and Ligand Pharma-
ceuticals Inc. initiated a collaborative agreement to
develop a novel series of potent RXR agonists for treat-
ment of non-insulin dependent (type II) diabetes mellitus
(NIDDM). In addition to Targretin this study involved
evaluation of the pyridyl cyclopropane derivative 117,18
and cis-oxime 2 (Chart 2).7,19 The latter compounds were
(9) Gamage, S.; Bischoff, E.; Burroughs, K.; Lamph, W.; Gottardis,
M.; Walker, C.; Fuchs-Young, R. J . Pharmacol. Exp. Ther. 2000, 295,
677-681.
(10) Bedikian, A.; Plager, C.; Papadopoulos, N.; Ellerhorst, J .; Smith,
T.; Benjamin, R. Oncol. Rep. 2000, 7, 883-886.
(11) Bengtson, E.; Rigas, J . Drugs 1999, 58, 57-69.
(12) Rizvi, N.; Marshall, J .; Dahut, W.; Ness, E.; Truglia, J .; Loewen,
G.; Gill, G.; Ulm, E.; Geiser, R.; J aunakais, D.; Hawkins, M. Clin.
Cancer Res. 1999, 5, 1658-1664.
(13) Otter, K.; Ziegler, A. Med. Monatsschr. Pharm. 1999, 22, 2-7.
(14) Bischoff, E.; Gottardis, M.; Moon, T.; Heyman, R.; Lamph, W.
Cancer Res. 1998, 58, 479-484.
(15) Miller, V.; Benedetti, F.; Rigas, J .; Verret, A.; Pfister, D.; Straus,
D.; Kris, M.; Crisp, M.; Heyman, R. J . Clin. Oncol 1997, 15, 790-795.
(16) Boehm, M.; Heyman, R.; Patel, S.; Stein, R.; Nagpal, S. Expert
Opin. Invest. Drugs 1995, 4, 593-617.
(17) Allegretto, E.; Shevde, N.; Zou, A.; Howell, S.; Boehm, M.; Hollis,
B.; Pike, J . J . Biol. Chem. 1995, 270, 23906-23909.
(18) Mukherjee, R.; Davies, P.; Crombie, D.; Bischoff, E.; Cesario,
R.; J ow, L.; Hamann, L.; Boehm, M.; Mondon, C.; Nadzan, A.; Paterniti,
J .; Heyman, R. Nature (London) 1997, 386, 407-410.
(1) Orfanos, C.; Ehlert, R.; Gollnick, H. Drugs 1987, 34, 459-503.
(2) Linney, E. In Current Topics in Developmental Biology; Academic
Press: Orlando, 1992; pp 309-350.
(3) Mangelsdorf, D.; Umesono, K.; Evans, R. In The Retinoid
Receptors, 2nd ed.; Raven Press, Ltd.: New York, 1994; pp 319-349.
(4) Sporn, M.; Roberts, A.; Goodman, D. The Retinoids: Biology,
Chemistry, and Medicine, 2nd ed.; Raven Press, Ltd.: New York, 1994.
(5) Mangelsdorf, D.; Umesono, K.; Evans, R. The Retinoids: Biology,
Chemistry, and Medicine, 2nd ed.; Raven Press, Ltd.: New York, 1994.
(6) Leid, M.; Kastner, P.; Chambon, P. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 3559-3563.
(7) Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D.
E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. J . Med.
Chem. 1994, 37, 2930-2941.
(8) Agarwal, V.; Bischoff, E.; Hermann, T.; Lamph, W. Cancer Res.
2000, 60, 6033-6038.
10.1021/jo0103064 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/02/2001

Retinoid X Receptor-Selective Retinoids
J . Org. Chem., Vol. 66, No. 17, 2001 5773
Ch a r t 2
Sch em e 1a
a
Initial conditions: (a) toluene (solvent), AlCl3 (3.0 equiv), 91%; (b) AlCl3 (3.0 equiv), CH2Cl2, 50%; (c) MePPh3Br, NaNH2, THF, 64%;
(d) Et2Zn, ClCH2I, CH2Cl2, 65%; (e) MeOH, KOH (aq), HCl, 80%. Developed conditions: (a) toluene (1.5 equiv), AlCl3 (0.03 equiv), CH2Cl2,
99%; (b) CH3NO2 (0.5 equiv), AlCl3 (2.7 equiv), CH2Cl2, 68%; (c) MeMgCl (1.25 equiv), THF; p-TsOH, toluene, 61%; (d) (Me)3SOI, tert-
KOBu, DMSO, THF, 82%; (d) NaOH, MeOH, HCl (aq), 99%.
reported to be 10 times more potent than Targretin.
Concerns with metabolism of these tetrahydronaphtha-
lene derivatives, vide infra, led to development of a
second generation of dihydronaphthalene analogues 3-5.
A synthesis of 1 and 2 has been published in the
literature,7,19,20 although no work on the dihydronaph-
thalene series has been reported. Our goal was to develop
a synthesis that would supply kilogram quantities of 1
and 2 and to identify a new synthetic route to prepare
multigram quantities of 3-5 for preclinical evaluation.
This manuscript is the first full disclosure of our work
on this class of compounds.
followed by saponification afforded 1 in 52% yield.
Although this route was successful, the yield of 1 was
low and the intermediates required chromatographic
purification. To develop a process to prepare multikilo-
gram quantities of 1 we sought to identify alternative
methods to perform the olefination and cyclopropanation
reactions that would avoid generation of Ph3PO, which
is difficult to remove on large scale, and eliminate the
use of pyrophoric diethylzinc and unstable chloroiodo-
methane. In addition, methods for crystallization of in-
termediates that would avoid chromatographic purifica-
tion would be evaluated.
Our initial strategy was to examine the Friedel-Crafts
acylation of 7 with chloromethylnicotinate 9. However,
upon examination of this reaction, vide infra, we deter-
mined that 7 was unstable to the acylation conditions
and in the presence of excess AlCl3 underwent competi-
tive dimerization. This caused us to reevaluate the
conditions employed for the synthesis of 7, which involved
Friedel-Crafts alkylation of 2,5-dichloro-2,5-dimethyl-
hexane 6 in toluene using AlCl3 (1.5 equiv).21 To minimize
exposure of 7 to a Lewis acid and reduce the potential
for decomposition on large scale, we determined that this
reaction could actually be preformed catalytically using
Resu lts a n d Discu ssion
Syn th esis of th e Tetr a h yd r on a p h th ylen e Der iva -
tives 1 a n d 2. A synthesis of 1, in 15% overall yield from
2,5-dichloro-2,5-dimethylhexane 6 has been reported
(Scheme 1).20 Friedel-Crafts acylation of 7 by chloro-
methylnicotinate 9, prepared in 88% yield from 5-(meth-
oxycarbonyl)pyridine-2-carboxylic acid 8, using AlCl3 (3.0
equiv) afforded ketone 10, albeit in low yields (20-50%).
Olefination of 10 with methyltriphenylphosphonium
bromide/NaNH2 provided olefin 11 in 64% yield. Cyclo-
propanation of 11 with diethylzinc and chloroiodomethane,
only 0.03 equiv of AlCl3
and 1.5 equiv of toluene in CH2-
Cl2 as solvent.22 This process was extremely robust,
affording 7 in reproducible yields of 99%.
(19) Canan-Koch, S.; Dardashti, L.; Cesario, R.; Croston, G.; Boehm,
M.; Heyman, R.; Nadzan, A. J . Med. Chem. 1999, 42, 742-750.
(20) Boehm, M.; Zhang, L.; Zhi, L.; McClurg, M.; Berger, E.;
Wagoner, M.; Mais, D.; Suto, C.; Davies, P.; Heyman, R.; Nadzan, A.
J . Med. Chem. 1995, 38, 3146-3155.
(21) Carpenter, M.; Easter, W.; Wood, T. In U.S. Patent 2,897,237,
1959.
(22) Pearson, D.; Buehler, C. Synthesis 1972, 10, 533-542.

5774 J . Org. Chem., Vol. 66, No. 17, 2001
Faul et al.
Sch em e 2a
F igu r e 1.
A critical factor for successful formation of 10 was
found to be the method employed to generate acid
chloride 9. Acid 8 is extremely hygroscopic and must be
rigorously dried prior to formation of 9. In addition only
1.0-1.1 equiv of (COCl)2 should be employed for prepara-
tion of 9, since excess (COCl)2 results in formation of
dimer 13 (Figure 1).23,24 By using these conditions to
generate 9 the yield of 10 was increased to 56%.
As a result of the instability of 7 to AlCl3, alternative
Lewis acids and solvents were evaluated to prepare 10.
Unfortunately, Lewis acids SnCl4, FeCl3, TiCl4, and ZnCl2
gave no reaction. The use of nitromethane, which is
known to reduce the activity of AlCl3 through reversible
complexation,25 resulted in minimal acylation of 7 after
1 h at room temperature, and decomposition occurred
upon heating the reaction to 90 °C. However, when the
reaction was conducted in CH2Cl2 containing 0.5 equiv
of nitromethane (relative to 8) the rate of acylation
slowed considerably, the selectivity increased, and 10 was
reproducibly isolated in 68% yield after crystallization
of the reaction mixture from MeOH.
a
(a) FeCl3, (0.05 equiv), Cl(CH2) 2Cl; (b) MeOH, 50% aq. NaOH;
(c) 50% aq NH2OH, HOAc, reflux.
Ch a r t 3
The Wittig reaction to incorporate the olefin was
avoided by using a chelate-controlled addition of MeMgCl
to ketone 10. This reaction afforded only the intermediate
3° alcohol with no addition to the carboxylate ester.
Dehydration of the alcohol using p-TsOH (1.0 equiv)
afforded a 61% yield of olefin 11 after recrystallization
from MeOH.
Cyclopropanation of R,â-unsaturated ketones using
trimethylsulfoxonium ylide is a well-known reaction.26
The presence of a p-carboxyester functionality in 11 led
us to examine the use of this reagent for the synthesis of
1. Thus, reaction of 11 with trimethylsulfoxonium ylide
(2.0 equiv), generated from trimethylsulfoxonium iodide/
NaH in DMSO, afforded 12 in 65% yield. However, olefin
11 was insoluble in DMSO, and the reaction proved
difficult to perform on large scale. To avoid this problem
the ylide was generated in THF using tert-KOBu as base.
This approach afforded cyclopropane 12 in reproducible
yields of 82% after trituration from MeOH. Saponification
of 12 afforded 1 in 99% yield.
The development outlined above completed a five-step
synthesis of the pyridyl derivative 1 in 33% yield. The
synthesis is extremely robust, involves no chromato-
graphic purification, and has been successfully employed
to provide 1 in kilogram quantities.
Cis-oxime 2, a more potent RXR agonist than the
corresponding trans-oxime 17,19 is prepared from ketone
15 generated by Friedel-Crafts acylation of 7 using AlCl3
(2.7 equiv) with commercially available chloromethyl-
terephthalate 14 (Scheme 2). Again, as a result of the
instability of 7 to AlCl3, we sought to develop a catalytic
method to prepare 15. Unfortunately, by using 0.05 equiv
of AlCl3 or SnCl4, 15 was obtained in only 5% and 14%
yield, respectively. Alternative Lewis acids such as BF‚
Et2O, ZnCl2, or I2 gave no reaction. However, acylation
of 7 with 14 using 0.05 equiv of FeCl3 afforded 15 in 81%
isolated yield. This afforded an extremely efficient process
for preparation of 15, a key intermediate for the synthesis
of oxime 2 and Targretin. Saponification of 15 afforded
acid 16 in quantitative yield.
Ligand reported a synthesis of 2 from 16 in 88% yield
using NH2OH‚HCl in pyridine/ethanol.19 However, upon
scale-up we found that reaction of 16 with NH2OH in
EtOH or DMSO/H2O was very slow (2-3 days) even at
reflux temperatures and generated a 7:3 mixture of cis-
and trans-oximes. Use of excess NH2OH in EtOH led to
slightly faster reaction rates, but esterification of 16 by
ethanol was observed. However, the rate of the reaction
was improved by performing the reaction with aqueous
NH2OH in AcOH at pH 4. This afforded cis- and trans-
oximes 2 and 17 in 99% yield and 9:1 selectivity.
Crystallization of the reaction mixture from 3:1 hexanes/
EtOAc afforded a 43% yield of cis-oxime 2, whose
structure was confirmed by comparison to the literature
data (Scheme 2).27 This work completed an efficient
synthesis of 2 in three steps and 34% yield from 7.
(23) Heirtzler, F.; Hopf, H.; J ones, P.; Bubenitschek, P.; Lehne, V.
J . Org. Chem. 1993, 58, 2781-2784.
(24) Dimer 13 was identified by GC-MS (MW
)
430). FTIR
1H NMR
confirmed the presence of a carbonyl stretch at 1655 cm-1
.
(300 MHz, CDCl3) δ 7.26 (s, 2H), 7.19 (s, 2H), 2.44 (s, 6H), 1.66 (s,
8H), 1.31 (s, 12H), 1.15 (s, 12H).
(25) Olah, G.; Kobayashi, S.; Tashiro, M. J . Am. Chem. Soc. 1972,
94, 7448-7461.
(26) Evans, D.; Tanis, S.; Hart, D. J . Am. Chem. Soc. 1981, 103,
5813-5821.

Retinoid X Receptor-Selective Retinoids
J . Org. Chem., Vol. 66, No. 17, 2001 5775
Sch em e 3a
a
(a) AlCl3 (4.0 equiv), Cl(CH2)2Cl; (b) MeP(Ph)3Br, KN(SiMe)2, THF/toluene; (c) NaBH4, MeOH; (d) POCl3, pyridine, 100 °C; (e) 50% aq
NaOH, MeOH, HCl (aq).
Sch em e 4a
Evaluation of 1 and 2 for the treatment of NIDDM was
problematic because of side effects. Although we hypoth-
esized that the side effects may be due to RAR activities
of the metabolites, represented by 18-21 for Targretin
(Chart 3), this does not appear to be the case, since the
metabolites were found to have minimal RAR activity.28
In an effort to eliminate this problem a second generation
of dihydronaphthalene analogues 3-5 were prepared for
evaluation.
Syn th esis of th e Dih yd r on a p h th a len e Der iva -
tives 3-5. The most direct approach to prepare 3-5
would involve Friedel-Crafts acylation of 22 with chlo-
romethylterephthalate 14 using a procedure similar to
that employed for the synthesis of 1, followed by incor-
poration of the dihydronaphthalene unit after coupling
via dehydration (Scheme 3). It has been reported that
conversion of a keto-tetrahydronaphthalene to a dihy-
dronaphthalene can successfully be performed using
a
(a) AlCl3, Br2, CH2Cl2; (b) TosNHNH2, p-TsOH, THF; (c)
MeLi‚LiBr complex, Et2O.
Sch em e 5a
POCl3/pyridine.29 Thus, reaction of keto-tetrahydronaph-
thalene 22, prepared in four steps and 50% overall yield
from p-tolylacetic acid,30 with 14 using AlCl3 (4.0 equiv)
afforded 23 in 62% yield. Olefination of 23 with methyl-
triphenylphosphonium ylide afforded olefin 24 in 57%
yield. Reduction of 24 with NaBH4 in MeOH gave alcohol
25 in 79% yield. Dehydration of 25 with POCl3 in pyridine
at 100 °C gave a quantitative yield of olefin 26. Although
26 appeared to be a single compound by TLC and 1H
NMR, HPLC analysis indicated that it was a 4:1 mixture
of compounds, and all attempts to purify 26 or its
corresponding acid 3 proved unsuccessful.31 It is assumed
that the acidic conditions used in the elimination afforded
a regioisomeric mixture of compounds, since this class
of compounds are known to undergo methyl shift and ring
contraction rearrangements.32,33 The lack of success in
(27) The minor trans-oxime 17 was obtained in high purity by
successive recrystallization of the reaction mixture from MeOH.
(28) Neel, D.; Grese, T.; Wells, K.; Howell, S.; Shirley, M.; Ulm, E.
In 220th National ACS Meeting; American Chemical Society: Wash-
ington, DC, 2000; Vol. MEDI-068.
(29) Zhang, L.; Badea, B.; Enyeart, D.; Berger, E.; Mais, D.; Boehm,
a
(a) 1.6 M n-BuLi in hexanes, THF; (b) Mg, 1,2-dibromoethane,
THF; (c) KOH, MeO(CH2)2OH, water, reflux 16 h; (d) 50% aq
NaOH, MeOH; (3) MeMgCl, THF; p-TsOH, toluene, reflux.
M. J . Labeled Compd. Radiopharm. 1995, 36, 701-712.
the synthesis of 3 by the Friedel-Crafts chemistry led
(30) Barclay, L.; Adams, K.; Foote, H.; Sanford, E.; Young, R. Can.
us to pursue a strategy in which the dihydronaphthylene
J . Chem 1970, 48, 2763-2775.
unit was prepared prior to incorporation of the aryl
ketone moiety.
The bromo-dihydronaphthylene 29 was identified as
the key intermediate for preparation of 3-5, since it
(31) Purification of 4 by preparative HPLC was impractical as a
result of solubility limitations of both compounds in the HPLC eluent.
(32) Naab, P.; Staab, H. Chem. Ber 1978, 111, 2982-2996.
(33) Staab, H.; Wittig, C.; Naab, P. Chem. Ber. 1978, 111, 2965-
2981.

5776 J . Org. Chem., Vol. 66, No. 17, 2001
Faul et al.
Sch em e 6a
a
(a) Mg, 1,2-dibromoethane, THF; (b) MeMgCl, THF; p-TsOH, toluene; (c) (Me)3SOI, tert-KOBu, DMSO, THF; (d) NaOH, MeOH, then
HCl.
would allow incorporation of the appropriate aryl ketone
(a) 50% NH2OH, HOAc, reflux). A 9:1 mixture of cis- and
by either conversion into the corresponding organo-
lithium or Grignard reagent and reaction with a suitable
electrophile or by application of a Suzuki cross coupling
reaction. Since acidic conditions had proved unsuccessful
for incorporation of the olefin,34 we decided to examine a
synthesis of 29 from 22 using the Shapiro reaction
(Scheme 4).35 In addition, because of potential problems
with bromination after the olfein was introduced, it was
decided to incorporate the bromide into 22 prior to
elimination. Thus, reaction of 22 with Br2 and AlCl3 (3.0
equiv) in CH2Cl2 afforded keto-bromide 27 in 86% yield.
Treatment of 27 with p-toluenesulfonylhydrazide and
catalytic p-TsOH in THF afforded tosylhydrazone 28 in
77% yield. Shapiro reaction of 28 with MeLi in Et2O or
methyl tert-butyl ether afforded a 99% yield of 29 with
no rearrangement products or halogen metal exchange.36
This completed an efficient seven-step synthesis of
bromide 29 from p-tolyl acetic acid in 43% overall yield.
Conversion of 29 into the corresponding organolithium
or Grignard reagent was achieved using either n-BuLi/-
78 °C or Mg/1,2-dibromoethane, respectively (Scheme 5).
Although reaction of the organolithium reagent with acid
chloride 9 afforded multiple products, by using Weinreb
amide 30a a 16% yield of 31 was obtained in addition to
19% over addition products, due to competitive reaction
at the ester functionality. However, when Weinreb amide
30b was employed, nitrile 32 was prepared in 81% yield.
Reaction of the Grignard reagent of 29 with 9 afforded a
53% yield of 31, while using the Weinreb amide 30b the
yield was 51%. In addition to the lower yield the Grignard
reactions were problematic because of competing forma-
tion of phenol 34, which was extremely difficult to
remove, even when THF, freshly distilled over Na, was
utilized.
trans-oximes 4 and 35 were obtained, in addition to 3-6%
of saturated analogue 2. Recrystallization of the reaction
mixture from 3:1 hexanes/EtOAc afforded 2 in 58%
yield.37 This completed a synthesis of 4 in nine steps and
20% yield.
The pyridyl analogue 5 was prepared using conditions
similar to those used for 3 (Scheme 6). Coupling of
Weinreb amide 36 with 2.0 equiv of the Grignard reagent
derived from 29 afforded 37 in 81% yield. Reaction of 37
with MeMgCl, followed by dehydration with p-TsOH (0.5
equiv) afforded 38 in 73% yield. Cyclopropanation of 38
using trimethylsulfoxonium iodide/tert-KOBu in DMSO/
THF afforded 39 in 78% yield. Saponification of 39
completed an 11-step synthesis of 5 in 18% overall yield.
Our final strategy to prepare this class of compounds
was based upon the Suzuki cross coupling reaction.38
Qing has examined coupling of the boronic acid derived
from 40 in the synthesis of novel retinoid analogues.39-44
By using chemistry that we developed for the synthesis
of 29, bromide 40 was prepared in 85% yield from 7 by
Saponification of 31 or hydrolysis of 32 afforded 33 in
97% and 99% yield, respectively. Subsequent treatment
of 33 with MeMgCl followed by dehydration using p-
TsOH (0.1 equiv) completed a 10-step synthesis of 3 in
23% overall yield.
(37) Attempts to remove the 2 by further recrystallization from
toluene or 9:1 ACN/IPA failed. Compound 2 was isolated by HPLC
purification. This somewhat surprising result indicates that hydrogen
was generated under the reaction conditions, and the effect of adding
cyclohexene or some other simple additive to remove the hydrogen
should be examined in future reactions.
(38) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(39) Qing, F.-L.; Yue, X.-J . Chin. J . Chem 2000, 18, 76-84.
(40) Qing, F.-L.; Yue, X.-J . Tetrahedron Lett. 1997, 38, 8067-8070.
(41) Qing, F.-L.; Fan, J .; Sun, H.-B.; Yue, X.-J . J . Chem. Soc., Perkin
Trans. 1 1997, 20, 3053-3057.
cis-Oxime 4 was prepared by treatment of acid 34 with
50% aqueous NH2OH in refluxing AcOH for 1 h (eq 1;
(34) Attempted elimination of a variety of leaving groups (MsO, TsO)
from the alcohol of 22 proved was unsuccessful in formation of the
dihydronaphthylene.
(42) Qing, F.-L.; Fan, J . Bioorg. Med. Chem. Lett. 1997, 7, 2117-
2120.
(35) Shapiro, R.; Heath, M. J . Am. Chem. Soc. 1967, 89, 5734-5735.
(36) Shapiro reaction of the tosylhydrazone generated from ketone
23 was also examined but was unsuccessful as a result of the competing
reaction at the ketone and ester functionality under the basic condi-
tions required for the elimination.
(43) Yue, X.; Qing, F.-L.; Sun, H.-B.; Fan, J . Tetrahedron Lett. 1996,
37, 8213-8216.
(44) Wu, Q.; Dawson, M.; Zheng, Y.; Hobbs, P.; Agadir, A.; J ong, L.;
Li, Y.; Liu, R.; Lin, B.; Zhang, X.-K. Mol. Cell. Biol. 1997, 17, 6598-
6608.

Retinoid X Receptor-Selective Retinoids
J . Org. Chem., Vol. 66, No. 17, 2001 5777
Sch em e 7a
treatment with Br2/AlCl3 (eq 2; (a) AlCl3, Br2, CH2Cl2;
(b) (i) n-BuLi, THF; (ii) B(O-i-Pr)3 at -78 °C, THF).
Bromides 40 and 29 were converted into the correspond-
ing boronic acids 41 and 42 by treatment with n-BuLi
and B(O-i-Pr)3 at -78 °C in 91% and 81% yield, respec-
tively. Vinyl triflate 43 was synthesized in 89% yield by
treatment of methyl 4-acetylbenzoate with excess triflic
anhydride and anhydrous Na2CO3 in CH2Cl2.45
Initial examination of the conditions reported by Qing
to effect Suzuki coupling of vinyl triflate 43 and boronic
acid 41 using Pd(PPh3)4 in dioxane with either anhydrous
bases or aqueous Na2CO3 afforded <35% yield of 44, in
addition to substantial decomposition. The yield of 44
increased to 56% when 3.0 equiv of vinyl triflate 43 was
employed.
A variety of other catalysts [Pd(OAc)2/PPh3, Pd(dba)2,
(Ph3P)2PdCl2] were examined but also afforded 44 in
<30% yield. The optimal conditions identified for the
Suzuki reaction were found to employ Pd(OAc)2/P(o-Tol)3
with Et3N at 50 °C in DMF, which provided 44 in 88%
yield (Scheme 7). This strategy completed a five-step
synthesis of Targretin in 63% overall yield and is
competitive with the reported process.7 Using similar
conditions 31 was prepared in 83% yield from 43 and 42.
This completed a 10-step synthesis of 3 in 22% overall
yield and afforded a synthesis that was competitive with
the organometallic approach.
a
(a) Pd(OAc)2, P(o-Tol)3, DMF, Et3N, 50 °C.
completed an efficient alternative synthesis of 3 and 44,
a penultimate intermediate in the synthesis of Targretin.
These syntheses have been successfully employed to
prepare multigram quantities of material for preclinical
evaluation.
Exp er im en ta l Section
Unless otherwise noted, reagents and solvents were used
as received from commercial suppliers. TLC was performed
on Kiesegel 60 F254 plates (Merck) using reagent grade
solvents. Flash chromatography was performed using Merck
silica gel 60 (230-400 mesh). 1H NMR were performed at 300
MHz and 13C NMR at 75 MHz in CDCl3 unless otherwise
specified. Chemical shifts are in ppm downfield from internal
tetramethylsilane. Mass spectral, combustion analysis, and IR
were performed by the Eli Lilly and Co. Physical Chemistry
Department.
1,1,4,4-Tetr a m eth yl-1,2,3,4-tetr a h yd r on a p h th ylen e (7).
2,5-Dimethyl-2,5-hexanediol (391 g, 2.67 mol) was combined
with reagent grade concentrated HCl (6 L) and stirred at
ambient temperature for 3 h. Water (4 L) and CH2Cl2 (4 L)
were then added to dissolve the solids. The layers were
separated and the aqueous layer back-extracted with ad-
ditional CH2Cl2 (1 L). The combined organic layers were dried
(MgSO4) and filtered using CH2Cl2 (1 L) to rinse. Toluene (372
g, 430 mL, 4.04 mol) was added to the CH2Cl2 solution and
AlCl3 (17.5 g, 0.131 mol) was added in portions over 25 min at
ambient temperature while scrubbing vigorous HCl off-gas-
sing. The reaction, which was complete upon addition of AlCl3,
was quenched with deionized water (4 L) while keeping the
reaction temperature <25 °C. Heptane (4 L) was added and
the organic layer was removed. The aqueous layer was back-
extracted with additional heptane (1 L). The combined organic
layers were washed with water (4 L) and brine (2 L) and dried
(MgSO4) and the solvent was removed in vacuo to give 538 g
(99%) of 7 as a colorless oil that crystallized upon cooling.
P yr id in e 2,5-Dica r boxylic Acid 5-Meth yl Ester (8). To
a suspension of dimethyl 2,5-pyridinedicarboxylate (1.26 kg,
6.45 mol) in MeOH (11.3 L) was added NaOH pellets (274 g,
6.85 mol) in one portion, and the mixture was stirred and
heated to reflux for 1-4 h. Aqueous 2.0 N HCl (4.75 L, 10.7
mol) was then added dropwise at 60-75 °C over 20-60 min
and the resultant slurry was allowed to stir and cool gradually
to 15-20 °C with an ice-water bath. The reaction was filtered,
rinsed with 2:1 MeOH/water (1.5 L), and then water (2 L). The
wet cake was dried in a vacuum oven at 50-60 °C to yield
803 g (69%) of 8 as an off-white solid.
Con clu sion
Efficient synthesis of RXR agonists 1-5 have been
developed. This chemistry employs two novel catalytic
Friedel-Crafts reactions for the synthesis of 1 and 2. A
nitromethane-mediated Friedel-Crafts acylation of 7 was
critical for successful synthesis of 1. The presence of the
pyridyl nitrogen allowed a selective chelate-controlled
addition of MeMgCl to ketone 10 followed by elimination
to generate olefin 11. Cyclopropanation of ketone 10 with
trimethylsulfoxonium ylide followed by saponification
completed the synthesis of 1 in five steps and 33% yield.
This synthesis has been employed to prepare kilogram
quantities of 1 for clinical evaluation. cis-Oxime 2 was
prepared in three steps and 34% yield using aqueous
NH2OH in AcOH. For the dihydronaphthylenes 3-5, the
key bromo-dihydronaphthalene derivative 29, was pre-
pared in seven steps and 47% yield, from p-tolylacetic
acid, by application of the Shapiro reaction. Conversion
of 29 into 3 and 4 was completed in three steps with 53%
and 47% yield, respectively. The pyridyl analogue 5 was
prepared from 29 in four steps and 43% yield. Suzuki
coupling of boronic acids 41 and 42 with vinyl triflate 43
Met h yl 6-[(3,5,5,8,8-P en t a m et h yl-5,6,7,8-t et r a h yd r o-
n a p h th a len -2-yl)ca r bon yl]n icotin a te (10). To a suspension
of 7 (750 g, 4.14 mol) in CH2Cl2 (5.3 L) under N2 was added a
catalytic amount of DMF (9.4 mL, 0.110 mol) followed by oxalyl
chloride (380 mL, 4.35 mol) dropwise at 15-30 °C over 10-60
min. The reaction mixture was stirred at 15-30 °C for 1-4 h.
(45) Garcia Martinez, A.; Herrera, A.; Martinez, R.; Teso, E.; Garcia,
A.; Osio, J .; Pargada, L.; Unanue, R.; Subramanian, L.; Hanack, M. J .
Heterocycl. Chem. 1988, 25, 1237-1241.

5778 J . Org. Chem., Vol. 66, No. 17, 2001
Faul et al.
Nitromethane (115 mL, 2.12 mol) and 7 (922 g, 4.56 mol) were
charged, and the resulting mixture was stirred and cooled to
5-15 °C using an ice-water bath. AlCl3 (1658 g, 12.4 mol)
was added in portions at 5-30 °C over 10-30 min. The dark
reaction mixture was allowed to stir at 15-30 °C for 12-24
h. The reaction mixture was added dropwise over 45-90 min
at 15-35 °C to a separate flask containing deionized water
(7.4 L) stirring in an ice-water bath. The quenched reaction
mixture was stirred at 15-35 °C for 10-30 min and then the
layers were separated. The upper aqueous layer was extracted
with CH2Cl2 (1.4 L) and the combined organic layers were
dried (MgSO4). The reaction was filtered and rinsed with CH2-
Cl2 (1.5 L). The filtrate was concentrated in vacuo to a solid
residue (1.54 kg). MeOH (6.2 L) was added, and the mixture
was heated until all solids went into solution. The solution
was allowed to stir and gradually cool to ambient temperature
over 12-24 h to crystallize the product. After stirring in an
ice-water bath at 0-10 °C for 1-2 h, the product was isolated
by vacuum filtration and rinsed with cold MeOH (3.0 L). The
wet cake was dried in a vacuum oven at 50-60 °C to yield
1033 g (68%) of 10 as an off-white solid.
slurry was heated to 60-70 °C for 0.5-2 h until all solids went
into solution and the reaction was complete. The hot solution
was filtered and the filtrate solution was treated with aqueous
6.0 N HCl (1.5 L, 9.00 mol), added over 45-90 min at 50-70
°C, to precipitate the product. Deionized water (3.5 L) was
added in one portion to dissolve the sodium chloride and the
resultant slurry was stirred at 50-70 °C for 20-60 min and
then cooled to 20-25 °C using an ice-water bath. After
stirring at 20-25 °C for 0.5-2 h, the product was isolated by
vacuum filtration, rinsed with 1:1 MeOH/water (1.2 L) and
deionized water (3 L). The wet cake was dried in a vacuum
oven at 50-60 °C to yield 1.04 kg (99%) of 1 as a white to
off-white solid.
Meth yl 4-[(3,5,5,8,8-P en ta m eth yl-5,6,7,8-tetr a h yd r o-2-
n a p h th yl)ca r bon yl]ben zoa te (15). To a solution of 7 (20.0
g, 98.8 mmol) and 14 (20.7 g, 98.8 mmol) in dichloroethane
(20 mL) was added FeCl3 (0.80 g, 4.93 mmol) and the reaction
was heated to 75 °C for 16 h. The reaction was cooled and
MeOH (60 mL) was added. The resultant light green slurry
was stirred overnight at ambient temperature, then filtered,
and rinsed with cold MeOH (60 mL) to give 29.3 g (81%) of
15.
Met h yl 6-[(3,5,5,8,8-P en t a m et h yl-5,6,7,8-t et r a h yd r o-
n a p h th a len -2-yl)eth en yl]n icotin a te (11). To a solution of
10 (3.40 kg, 9.3 mol) in toluene (34 L) at -10 to -5 °C under
N2 was added a 3.0 M solution of MeMgCl in THF (3.95 kg)
over 15-120 min. Toluene (5.7 L) was used to rinse the
MeMgCl solution. The reaction mixture was warmed to 20-
25 °C, then quenched by addition to 1.0 N HCl (23 L) with
stirring at 15-25 °C over 15-30 min. The reaction mixture
was rinsed into the quench solution with more toluene (10 L).
The layers were separated, and the organic layer was washed
with deionized water (24 L). The combined aqueous layers
were back extracted with toluene (10 L). The combined organic
layers were filtered over MgSO4 (5 kg) and rinsed with toluene
(10 L). The filtrate was stirred at 20-25 °C as p-TsOH‚H2O
(1.77 kg) was added. The solution was heated to reflux for
3-15 h to azeotrope water. The reaction solution was concen-
trated by atmospheric distillation to a total volume of ∼30 L.
A solution of Na2CO3 (2.6 kg) in deionized water (48 L) was
added to the concentrated reaction solution at 20-25 °C over
1-60 min, and the layers were separated. The lower aqueous
layer was back extracted with toluene (10 L). The combined
organic layers were concentrated by atmospheric distillation
to a total volume of ∼14 L. MeOH (60 L) was added, and the
mixture was again concentrated by atmospheric distillation
to a total volume of ∼35 L. MeOH (15 L) was added, and the
mixture was again concentrated by atmospheric distillation
to a total volume of 14-20 L. The resulting slurry of product
was stirred at 22-28 °C for 1-3 h, then filtered by nitrogen
pressure, and rinsed with MeOH (10 L). After drying in a
vacuum oven at 40-50 °C, 2.07 kg (61%) of 11 was obtained.
Met h yl 6-[(3,5,5,8,8-P en t a m et h yl-5,6,7,8-t et r a h yd r o-
n a p h th a len -2-yl)cyclop r op yl]n icotin a te (12). To a stirred
suspension of trimethylsulfoxonium iodide (726 g, 3.30 mol)
in dry DMSO (2.4 L) was added potassium tert-butoxide, 20
wt % in THF (1876 g, 3.34 mol). A solution of 11 (800 g, 2.20
mol) in dry THF (9.6 L) was prepared separately and then
added to the above suspension over 20-60 min at 20-30 °C.
The reaction was stirred at 20-30 °C for 30-60 min and then
quenched by addition of aqueous 2.0 N HCl (1.7 L, 3.5 mol
HCl, 1.54 equiv) over 5-30 min. The two phase mixture was
stirred at 20-35 °C for 15-60 min and deionized water (1.5
L) was added. The aqueous layer was back-extracted with
EtOAc (2.0 L) and the combined organic layers were concen-
trated in vacuo to a solid residue (1491 g). MeOH (6.2 L) was
added, and the resulting slurry was stirred at 40-50 °C for
30-60 min, then cooled to 15-25 °C. After stirring at 15-25
°C for 1-2 h, the product was isolated by vacuum filtration
and rinsed with MeOH (3 L). The wet cake was dried in a
vacuum oven at 50-60 °C to yield 681 g (82%) of 12 as a white
to off-white solid.
4-[(3,5,5,8,8-P en t a m et h yl-5,6,7,8-t et r a h yd r o-2-n a p h -
th yl)ca r bon yl]ben zoic Acid (16). A suspension of 15 (29.3
g, 80.3 mmol) in MeOH (290 mL) was treated with 50 wt %
NaOH (19.3 g, 12.7 mL, 0.24 mol) and the reaction was heated
to reflux for 1-2 h. The reaction was then cooled to 55 °C and
concentrated HCl (20.1 mL, 0.24 mol) added dropwise at <60
°C. The resultant slurry was cooled in an ice bath for 1 h and
filtered to give 30.1 g (100%) of 16.
4-[Hydr oxyim in o-(3,5,5,8,8-P en tam eth yl-5,6,7,8-tetr ah y-
d r o-2-n a p h th yl)]ben zoic Acid (2). To a suspension of 12
(5.00 g, 14.3 mmol) in HOAc (100 mL) was added 50% aqueous
NH2OH (28.3 g, 26.2 mL, 0.43 mol). The reaction was heated
to a gentle reflux for ∼1 h. Upon cooling in an ice bath the
cis- and trans-oximes crystallized and were filtered, washed
with water (40 mL), and dried to give 5.16 g (99%) of 2:17 in
a ratio of 94:6 (HPLC). A portion of this material (5.00 g) was
recrystallized from 3:1 hexanes/EtOAc (225 mL) to give 1.98
g of 2 (40% recovery and overall yield): 1H NMR (300 MHz,
DMSO-d6) δ 12.92 (s, 1H), 11.47 (s, 1H), 7.86 (d, 2H, J ) 8.35
Hz), 7.41 (d, 2H, J ) 8.36 Hz), 7.19 (s, 1H), 6.87 (s, 1H), 1.59
(s, 4H), 1.95 (s, 2H), 1.18 (s, 6H), 1.11 (s, 6H); 13C (75 MHz,
DMSO-d6) δ 166.94, 154.89, 144.23, 141.66, 140.43, 132.36,
130.90, 130.77, 129.45, 127.44, 126.14, 125.59, 34.63, 34.58,
33.68, 33.49, 31.56, 18.59; IR (CHCl3) ν 2961, 2928, 2862, 1693
cm-1. Anal. Calcd for C23H27NO3: C, 75.59; H, 7.45; N, 3.83.
Found: C, 75.77; H, 7.40; N, 3.87 (PX 035379). A portion of
the filtrate was purified to provide the trans-oxime 17: 1H
NMR (300 MHz, DMSO-d6) δ 12.96 (s, 1H), 11.47 (s, 1H), 7.90
(d, 2H, J ) 8.25 Hz), 7.46 (d, 2H, J ) 8.24 Hz), 7.09 (s, 2H),
1.95 (s, 3H), 1.57 (s, 4H), 1.23 (s, 6H), 1.19 (s, 6H); 13C (75
MHz, DMSO-d6) δ 166.87, 154.61, 144.65, 141.58, 138.09,
133.95, 133.01, 130.50, 129.32, 128.87, 128.28, 127.74, 34.54,
34.48, 33.60, 33.40, 31.52, 31.43, 19.74; IR (CHCl3) ν 2926,
2863, 1692, 1288 cm-1. Anal. Calcd for C23H27NO3: C, 75.59;
H, 7.45; N, 3.83. Found: C, 75.85; H, 7.47; N, 3.69.
1,1,4,4,6-P en ta m eth yl-1,3,4-tr ih ydr on a ph th a len e-2-on e
(22). A solution of 2-methyl-2-(p-tolyl)propanoic acid (10.0 g,
56.1 mmol) in CH2Cl2 and DMF (0.15 mL) was treated
dropwise with oxalyl chloride (7.48 g, 5.14 mL, 58.9 mmol) and
stirred at room temperature under N2 for 2 h. The reaction
was then cooled to -30 °C and catalytic SnCl4 (2.23 g, 1.00
mL, 8.55 mmol) was added. After stirring at <-30 °C for 15
min, isobutylene (12.6 g, 0.224 mol) was condensed into the
reaction at -78 °C via cannula. The reaction was allowed to
warm to room temperature over 1.5 h and then heated to reflux
for 2.5 h. The reaction was cooled and quenched with water
(50 mL), and then the organic layer was washed with aqueous
1 N NaOH (50 mL) and dried (MgSO4). The solvent was
removed in vacuo to give 13.6 g of 22 as an oil that was
crystallized from MeOH (30 mL) to afford 7.36 g (61%) of 22:
1H NMR (500 MHz, CDCl3) δ 7.25 (d, 1H, J ) 8.05 Hz), 7.21
(s, 1H), 7.11 (d, 1H, J ) 8.19 Hz), 2.69 (s, 2H), 2.39 (s, 3H),
1.52 (s, 6H), 1.34 (s, 6H); 13C (125 MHz, CDCl3) 214.8, 143.9,
6-[1-(3,5,5,8,8-P en ta m eth yl-5,6,7,8-tetr a h yd r on a p h th a -
len -2-yl)cyclop r op yl]n icotin ic Acid (1). To a stirred sus-
pension of 12 (1.09 kg, 2.89 mol) in MeOH (10.9 L) was added
aqueous 50% sodium hydroxide (460 mL, 8.79 mol), and the

Retinoid X Receptor-Selective Retinoids
J . Org. Chem., Vol. 66, No. 17, 2001 5779
140.7, 136.4, 128.2, 127.6, 125.4, 52.0, 48.1, 38.3, 31.0, 28.9,
21.5; IR (KBr) ν 2965, 2928, 2870, 1711, 1499, 1462, 1380,
1366, 1313, 1237, 822 cm-1; HRMS (FAB+) m/z exact mass
calcd for C15H21O 217.1592, found 217.1589.
from MeOH (8 mL) to give 3.40 g (86%) of 27: 1H NMR (500
MHz, CDCl3) δ 7.47 (s, 1H), 7.24 (s, 1H), 2.63 (s, 2H), 2.42 (s,
3H), 1.45 (s, 6H), 1.31 (s, 6H); 13C (125 MHz, CDCl3) δ 213.6,
143.3, 136.4, 131.4, 127.3, 123.7, 51.7, 48.1, 38.0, 30.9, 28.9,
22.9; IR (KBr) ν 2973, 1714, 1482, 1237, 1081 cm-1; HRMS
(FAB+) m/z exact mass calcd for C15H20OBr 295.0696, found
295.0698.
[Aza (7-br om o-1,1,4,4,6-p en ta m eth yl(2-1,3,4-tr ih yd r o-
n a p h t h ylid e n e ))m e t h yl][(4-m e t h ylp h e n yl)-su lfon yl]-
a m in e (28). A suspension of 27 (30.5 g, 0.10 mol), p-toluene-
sulfonylhydrazide (22.1 g, 0.119 mol), and p-toluenesulfonic
acid monohydrate (4.92 g, 25.9 mmol) in MeOH (611 mL) was
heated at reflux under N2 for 24 h. The resultant reaction
slurry was cooled for 1 h in an ice bath, filtered, and rinsed
with cold MeOH (150 mL) to give 36.8 g (77%) of 28: 1H NMR
(500 MHz, CDCl3) δ 7.88 (d, 2H, J ) 8.17 Hz), 7.77 (bs, 1H),
7.45 (s, 1H), 7.30 (d, 2H, J ) 8.06 Hz), 2.45 (s, 2H), 2.42, (s,
3H), 2.36 (s, 3H), 1.41 (s, 6H), 1.15 (s, 6H); 13C (125 MHz,
CDCl3) δ 164.2, 144.4, 143.5, 143.1, 136.0, 135.7, 131.1, 129.7,
128.6, 127.4, 123.5, 43.3, 37.4, 36.8, 30.5, 30.3, 22.8, 21.9; IR
(KBr) ν 3222, 2973, 1597, 1482, 1470, 1388, 1378, 1366, 1346,
1185, 1169, 1075, 1011, 815, 707, 675, 566 cm-1; MS (EI+) calcd
for C22H27N2O2BrS 463, found m/z 463 (100%). Anal. Calcd for
Meth yl 4-[(3,5,5,8,8-P en ta m eth yl-7-oxo-2-5,6,8-tr ih y-
d r on a p h th yl)ca r bon yl]ben zoa te (23). A solution of 22 (4.01
g, 18.5 mmol) and 14 (3.68 g, 18.5 mmol) in CH2Cl2 (60 mL)
at 0 °C was treated with AlCl3 (9.89 g, 74.2 mmol) in five
portions over 20 min under N2. The reaction mixture was
heated to 45 °C, then the heating removed and the reaction
was allowed to cool and stir at room temperature for 4 h. The
reaction was cooled in an ice bath, quenched with water (200
mL), and extracted into EtOAc. The organic layer was dried
(MgSO4), and the solvent was removed in vacuo to give 7.20 g
of crude product that was triturated in hot MeOH (35 mL)
and filtered to give 4.37 g of 23 (62%): 1H NMR (500 MHz,
CDCl3) δ 8.16 (d, 2H, J ) 8.38 Hz), 7.88 (d, 2H, J ) 8.27 Hz),
7.32 (s, 1H), 7.30 (s, 1H), 3.97 (s, 3H), 2.69 (s, 2H), 2.39 (s,
3H), 1.41 (s, 6H), 1.39 (s, 6H); 13C (125 MHz, CDCl3) δ 213.9,
197.8, 166.7, 166.7, 147.0, 141.8, 140.8, 136.8, 136.1, 134.3,
134.2, 130.4, 130.1, 130.0, 129.0, 128.0, 52.9, 52.8, 51.6, 48.1,
38.5, 28.8, 20.5; IR (KBr) ν 1717, 1662, 1281, 1234 cm-1; HRMS
(FAB+) m/z exact mass calcd for C24H27O4 379.1909, found
379.1912.
C
22H27N2O2BrS: C, 57.02; H, 5.87; N, 6.04; Br, 17.24. Found:
C, 57.08; H, 6.04; N, 6.08; Br, 17.54.
Meth yl 4-[1-(3,5,5,8,8-P en ta m eth yl-7-oxo-2,5,6,8-tr ih y-
d r on a p h th yl)vin yl]ben zoa te (24). Methyl triphenylphos-
phonium bromide (9.79 g, 27.4 mmol) was suspended in dry
THF (60 mL), cooled to -30 °C under N2, and treated with a
0.5 M solution of potassium bis(trimethylsilyl) amide in toluene
(57 mL, 29 mmol) and warmed to 0 °C. The ylide solution was
recooled to -30 °C and treated with a solution of 23 (4.15 g,
10.9 mmol) in dry THF (50 mL). The reaction was warmed to
0 °C for 45 min, quenched with water (150 mL), and extracted
into Et2O. The organic layer was dried (MgSO4), and the
solvent removed in vacuo to give 11.0 g of crude product that
was column purified using 6:1 hexanes/EtOAc to give 2.36 g
(57%) of 23: 1H NMR (500 MHz, CDCl3) δ 7.99 (d, 2H, J )
8.43 Hz), 7.36 (d, 2H, J ) 8.27 Hz), 7.19 (s, 1H), 7.17 (s, 1H),
5.89 (s, 1H), 5.36 (s, 1H), 3.93 (s, 3H), 2.69 (s, 2H), 2.05 (s,
3H), 1.47 (s, 6H), 1.37 (s, 6H); 13C (125 MHz, CDCl3) δ 214.4,
167.1, 149.1, 145.5, 143.5, 141.2, 140.0, 134.5, 130.1, 129.9,
129.7, 129.1, 126.9, 126.6, 117.4, 52.3, 52.0, 48.1, 38.2, 31.0,
28.9, 20.2; IR (CHCl3) ν 3021, 2962, 1713, 1607, 1437, 1281
cm-1; HRMS (FAB+) m/z exact mass calcd for C25H28O3
376.2039, found 376.2042.
Meth yl 4-[1-(7-Hydr oxy-3,5,5,8,8-pen tam eth yl-2-5,6,7,8-
tetr a h yd r on a p h th yl)vin yl]ben zoa te (25). A slurry of 24
(2.35 g, 6.24 mmol) in MeOH (80 mL) was treated with NaBH4
(0.71 g, 18.8 mmol) in three portions at room temperature. The
reaction mixture was heated until all of the solids dissolved,
then cooled to room temperature and stirred for 1 h before
being quenched with 1.0 N HCl (150 mL). The mixture was
extracted into EtOAc, the organic layer was dried (MgSO4),
and the solvent was removed in vacuo to give crude product
that was column purified using a gradient of 4:1 to 3:1 hexanes/
EtOAc to give 1.87 g (79%) of 25: 1H NMR (500 MHz, CDCl3)
δ 7.98 (d, 2H, J ) 8.45 Hz), 7.36 (d, 2H, J ) 8.41 Hz), 7.18 (s,
1H), 7.09 (s, 1H), 5.85 (s, 1H), 5.34 (s, 1H), 3.93 (s, 3H), 1.99
(s, 3H), 1.93 (t, 1H, J ) 12.52 Hz), 1.78 (dd, 1H, J ) 3.46 Hz,
J ) 12.80 Hz), 1.62 (bs, 1H), 1.43 (s, 3H), 1.41 (s, 3H), 1.37 (s,
3H), 1.21 (s, 3H); 13C (125 MHz, CDCl3) δ 167.3, 149.5, 145.8,
143.5, 141.8, 139.2, 133.7, 130.0, 129.6, 128.5, 128.4, 126.9,
117.9, 117.1, 73.1, 52.3, 43.6, 40.1, 35.5, 33.6, 32.8, 27.7, 24.8,
20.2; IR (CHCl3) ν 3605, 3003, 2965, 2926, 2866, 1715, 1607,
1437, 1282 cm-1; HRMS (FAB+) m/z exact mass calcd for
6-Br om o-1,1,4,4,7-p en t a m et h yl-1,4-d ih yd r on a p h t h a -
len e (29). A suspension of 28 (20.0 g, 43.2 mmol) in MTBE
(400 mL) was treated with a 1.5 M solution of MeLi as a
complex with LiBr in Et2O (86.3 mL, 0.13 mol) at room
temperature under N2. The reaction was stirred at room
temperature for 1 h, cooled to 0 °C, and quenched with water
(500 mL). The reaction was extracted with MTBE (1 L), the
organic layer was dried (MgSO4), and the solvent was removed
in vacuo to give 12.0 g (99%) of 29 as a white solid: 1H NMR
(500 MHz, CDCl3) δ 7.52 (s, 1H), 7.23 (s, 1H), 5.52 (s, 2H),
2.41 (s, 3H), 1.35 (s, 12H); 13C (125 MHz, CDCl3) δ 142.8, 142.3,
135.4, 133.2, 133.1, 130.3, 129.0, 122.8, 35.5, 35.4, 32.9, 32.9,
22.9; IR (KBr) ν 3014, 2961, 2922, 2864, 1485, 1455, 1080, 889,
765 cm-1; MS (FD) calcd for C15H19Br 279, found m/z 279
(100%). Anal. Calcd for C15H19Br: C, 64.52; H, 6.86; Br, 28.62.
Found: C, 64.99; H, 6.76; Br, 28.30.
Met h yl 4-(N-m et h oxy-N-m et h ylca r b a m oyl)b en zoa t e
(30a ). A solution of K2CO3 (19.1 g, 0.14 mol) in water (75 mL)
was cooled to -5 °C and treated with N,O-dimethylhy-
droxyamine hydrochloride (6.14 g, 62.9 mmol) and MTBE (75
mL). To the reaction was added 9 (15.0 g, 75.5 mmol) in
portions over 10 min and the resultant mixture was warmed
to room temperature for 1 h. The reaction was diluted with
water and extracted with EtOAc and the organic layer was
dried (MgSO4). The solvent was removed in vacuo to give 15.9
g of product that was purified by column chromatography
using 1:1 hexanes/EtOAc to give 8.56 g (61%) of 30a : 1H NMR
(500 MHz, CDCl3) δ 8.07 (d, 2H, J ) 8.24 Hz), 7.72 (d, 2H,
J ) 8.32 Hz), 3.94 (s, 3H), 3.53 (s, 3H), 3.37 (s, 3H); 13C (125
MHz, CDCl3) δ 169.4, 166.8, 138.8, 132.2, 129.6, 128.5, 61.6,
52.7, 33.8; IR (KBr) ν 1722, 1639, 1438, 1282, 1118, 1109 cm-1
;
MS (EI+) calcd for C11H13NO4 223, found m/z 224 (M + 1,
100%). Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27.
Found: C, 59.15; H, 5.92; N, 6.29.
(4-Cyan oph en yl)-N-m eth oxy-N-m eth ylfor m am ide (30b).
4-Cyanobenzoyl chloride (8.00 g, 48.3 mmol), N,O-dimethyl-
hydroxyamine hydrochloride (7.07 g, 72.5 mmol), and K2CO3
(10.0 g, 72.5 mmol) were combined in a mixture of ACN (100
mL) and water (50 mL) and stirred for 16 h at room temper-
ature. The reaction was diluted with water and extracted with
EtOAc, the organic layer was dried (MgSO4), and the solvent
was removed in vacuo to give 7.63 g (83%) of 30b: 1H NMR
(300 MHz, CDCl3) δ 7.76 (d, 2H, J ) 8.14 Hz), 7.70 (d, 2H,
J ) 8.40 Hz), 3.51 (s, 3H), 3.37 (s, 3H); 13C (125 MHz, CDCl3)
δ 168.4, 138.8, 132.2, 129.2, 118.5, 114.6, 61.7, 33.6; IR (KBr)
ν 3020, 2233, 1641, 1423, 1386, 982, 848 cm-1; MS (EI+) calcd
for C10H10N2O2 190, found m/z 191 (M + 1, 100%). Anal. Calcd
for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.01;
H, 5.36; N, 14.98.
C
25H30O3 378.2196, found 378.2199.
7-Br om o-1,1,4,4,6-p en ta m eth yl-1,3,4-tr ih yd r on a p h th a -
len -2-on e (27). A solution of 22 (2.90 g, 13.4 mmol) in CH2-
Cl2 (20 mL) at 0 °C was treated with powdered AlCl3 (3.58 g,
26.8 mmol) and stirred at 0 °C for 5 min. Bromine (2.25 g,
14.1 mmol) in CH2Cl2 (10 mL) was added dropwise and the
reaction was stirred at 0 °C for 30 min. The reaction was
poured onto ice and extracted with EtOAc. The solvent was
removed in vacuo to give 4.31 g of an oil that was crystallized

5780 J . Org. Chem., Vol. 66, No. 17, 2001
Faul et al.
4-[(3,5,5,8,8-P en ta m eth yl-2-5,8-d ih yd r on a p h th yl)ca r -
bon yl]ben zen eca r bon itr ile (32). A -78 °C solution of 29
(2.00 g, 7.16 mmol) in dry THF (25 mL) was treated dropwise
with 1.6 M n-BuLi in hexanes (5.40 mL, 8.60 mmol) over 10
min and the reaction was stirred at -78 °C for 20 min under
N2. The reaction solution was transferred via cannula to a -78
°C solution of 30b (1.23 g, 6.47 mmol) in dry THF (10 mL).
The combined reaction mixture was stirred for 15 min at -78
°C and then warmed to room temperature before being
quenched with 1.0 N HCl (75 mL). The reaction was extracted
with EtOAc, the organic layer was dried (MgSO4), and the
solvent was removed in vacuo to give 2.70 g of product that
was purified by column chromatography using 9:1 hexanes/
EtOAc to give 1.73 g (81%) of 32: 1H NMR (500 MHz, CDCl3)
δ 7.93 (d, 2H, J ) 8.27 Hz), 7.79 (d, 2H, J ) 8.30 Hz), 7.32, (s,
1H), 7.31 (s, 1H), 5.56 (s, 2H), 2.40 (s, 3H), 1.41 (s, 6H), 1.30
(s, 6H); 13C (125 MHz, CDCl3) δ 197.0, 146.7, 142.2, 140.4,
135.4, 135.0, 133.1, 133.1, 132.6, 130.8, 129.7, 128.3, 118.4,
116.5, 35.8, 35.3, 33.1, 33.0, 32.9, 32.8, 20.4; IR (KBr) ν 3025,
2962, 2924, 2229, 1671, 1460, 1444, 1361, 1313, 1298, 1262,
was then cooled to room temperature. The reaction was diluted
with water and extracted with EtOAc. The organic layer was
dried (MgSO4), and the solvent was removed in vacuo to give
3.29 g of trans- and cis-oximes as a 1:9 ratio, as well as 6% of
the reduced cis-oxime 2. This material was recrystallized from
3:1 hexanes/EtOAc (70 mL) and placed in the freezer over-
night. The slurry was filtered using 10 mL of cold 3:1 hexanes/
EtOAc as a rinse to give 1.20 g of 4 (58%) as a white solid
that contained no trans-oxime but still contained 8% of the
reduced cis-oxime 2. A portion of this material was purified
by preparative HPLC to remove 2: 1H NMR (500 MHz, DMSO-
d6) δ 11.49 (s, 1H), 7.93 (d, 2H, J ) 8.31 Hz), 7.49 (d, 2H, J )
8.35 Hz), 7.35 (s, 1H), 7.04 (s, 1H), 5.54 (s, 2H), 2.06 (s, 3H),
1.36 (s, 6H), 1.26 (s, 6H); 13C (125 MHz, DMSO-d6) δ 167.8,
155.7, 142.9, 141.3, 140.5, 133.7, 132.2, 131.7, 130.4, 128.1,
127.0, 126.2, 117.8, 35.6, 35.5, 33.1, 33.1, 19.9; IR (KBr) ν 3015,
2961, 2924, 2867, 1694, 1285 cm-1; HRMS (FAB+) m/z exact
mass calcd for C24H26NO3 364.1913, found 364.1915.
Meth yl 6-(N-Meth oxy-N-m eth ylca r ba m oyl)p yr id in e-3-
ca r boxyla te (36). A solution of 8 (22.8 g, 0.13 mol) in CH2Cl2
(250 mL) was treated with 2 drops of DMF followed by oxalyl
chloride (15.9 g, 11.0 mL, 0.13 mmol). The reaction stirred at
room temperature under N2 for 1 h and then cooled to -5 °C
and N,O-dimethylhydroxyamine hydrochloride (12.9 g, 0.13
mol) and pyridine (21.9 g, 22.0 mL, 0.28 mol) were added. The
reaction was warmed to room temperature until complete and
then quenched with aqueous NH4Cl. The mixture was ex-
tracted with EtOAc and the organic layer was washed with
1.0 N HCl and dried (Na2SO4). The solvent was removed in
vacuo to give an oil from which residual pyridine was removed
by azeotrope with heptane, and the crude product was
recrystallized from hexanes/EtOAc to give 14.4 g of 36. An
additional 7.86 g of material was obtained by column purifica-
tion of the filtrate using 1:4 hexanes/EtOAc to give a total of
22.3 g of 36 (79%): 1H NMR (500 MHz, CDCl3) δ 9.21 (d, 1H,
J ) 0.94 Hz), 8.38 (dd, 1H, J ) 1.96 Hz, 8.16 Hz), 7.70 (bs,
1H), 3.98 (s, 3H), 3.74 (bs, 3H), 3.41 (bs, 3H); 13C (125 MHz,
CDCl3) δ 165.8, 157.4, 150.4, 138.4, 127.4, 123.1, 62.4, 53.3,
33.3; IR (KBr) ν 1720, 1656, 1591, 1276, 1115, 1019, 1002, 747
cm-1; MS (EI+) calcd for C10H12N2O4 224, found m/z 225 (M +
1, 100%). Anal. Calcd for C10H12N2O4: C, 53.57; H, 5.39; N,
12.49. Found: C, 53.38; H, 5.38; N, 12.54.
1243, 1180, 885, 857, 778, 769 cm-1; MS (EI+) calcd for C23H23
-
-
NO 329, found m/z 330 (M + 1, 100%). Anal. Calcd for C23H23
NO: C, 83.85; H, 7.04; N, 4.25. Found: C, 84.06; H, 7.23; N,
4.33.
4-[(3,5,5,8,8-p en ta m eth yl-2-5,8-d ih yd r on a p h th yl)ca r -
bon yl]ben zoic Acid (33). A suspension of 32 (1.62 g, 4.92
mmol) in 2-methoxyethanol (20 mL) was treated with 85%
KOH (1.62 g, 24.5 mmol) in water (10 mL), and the mixture
was heated to reflux for 16 h to give a yellow solution. The
reaction was cooled, quenched with 1.0 N HCl (50 mL), and
extracted with EtOAc. The organic layer was dried (MgSO4),
and the solvent was removed in vacuo using toluene to
azeotropically remove residual 2-methoxyethanol to give 1.66
g (97%) of 33 as a white solid: 1H NMR (500 MHz, DMSO-d6)
δ 13.22 (bs, 1H), 8.09 (d, 2H, J ) 8.24 Hz), 7.81 (d, 2H, J )
8.33 Hz), 7.42 (s, 1H), 7.36 (s, 1H), 5.56 (s, 2H), 2.27 (s, 3H),
1.36 (s, 6H), 1.25 (s, 6H); 13C (125 MHz, DMSO-d6) δ 197.9,
167.5, 146.0, 141.7, 140.3, 136.2, 135.4, 134.7, 133.5, 133.4,
130.5, 130.4, 129.7, 127.9, 35.8, 35.4, 32.9, 32.9, 20.3; IR (KBr)
ν 2963, 2956, 2924, 1691, 1658, 1427, 1314, 1296, 1262, 1254,
767, 745 cm-1; HRMS (FAB+) m/z exact mass calcd for
C23H25O3 349.1804, found 349.1800.
Meth yl 6-[(3,5,5,8,8,-P en ta m eth yl-2-5,8-d ih yd r on a p h -
th yl)ca r bon yl]p yr id in e-3-ca r boxyla te (37). A suspension
of magnesium turnings (0.12 g, 4.85 mmol) in dry THF (0.5
mL) was treated with 3 drops of 1,2-dibromoethane under N2
followed by a solution of 29 (0.90 g, 3.22 mmol) in dry THF (4
mL), allowing the reaction to exotherm during the addition.
The Grignard solution was stirred at room temperature for 1
h and transferred via cannula to a -78 °C solution of 36 (0.36
g, 1.61 mmol) in dry THF (4 mL). The reaction mixture was
stirred for 15 min at -78 °C, then warmed to room tempera-
ture and stirred for 1 h. The reaction was quenched with 1.0
N HCl (10 mL) and extracted with EtOAc. The organic layer
was dried (MgSO4), and the solvent was removed in vacuo to
give the product, which was purified by column chromatog-
raphy using 9:1 hexanes/EtOAc to give 0.47 g (81%) of 37 as
a solid: 1H NMR (500 MHz, CDCl3) δ 9.29 (d, 1H, J ) 1.62
Hz), 8.51 (dd, 1H, J ) 1.94 Hz, J ) 8.07 Hz), 8.13 (d, 1H, J )
8.23 Hz), 7.53 (s, 1H), 7.30 (s, 1H), 5.54 (s, 2H), 4.02 (s, 3H),
2.44 (s, 3H), 1.39 (s, 6H), 1.31 (s, 6H); 13C (125 MHz, CDCl3)
δ 196.2, 165.5, 159.0, 150.4, 147.0, 139.9, 138.5, 136.4, 134.3,
133.3, 133.1, 130.3, 129.7, 128.2, 124.1, 53.0, 35.8, 35.3, 32.8,
32.7, 20.9; IR (KBr) ν 2958, 2969, 2953, 1730, 1660, 1432, 1274,
1114, 1021, 750 cm-1; HRMS (FAB+) m/z exact mass calcd for
4-[1-(3,5,5,8,8-P en ta m eth yl-2-5,8-d ih yd r on a p h th yl)vi-
n yl]ben zoic Acid (3). A 3.0 M solution of MeMgCl in THF
(1.53 mL, 4.60 mmol) was diluted with dry THF (3 mL) and
cooled to -10 °C under N2. A solution of 33 (0.40 g, 1.15 mmol)
in THF (4 mL) was added dropwise at < -5 °C, and the
reaction was stirred at 0-5 °C for 4 h until complete. The
reaction was quenched with 1.0 N HCl (15 mL) and extracted
with toluene and water and the solvent was removed in vacuo
to give the intermediate tertiary alcohol as a white solid. This
intermediate was combined with p-toluenesulfonic acid mono-
hydrate (0.02 g, 0.116 mmol) and toluene (30 mL) and heated
to reflux, allowing the distillate to condense in a Dean-Stark
trap prefilled with toluene. The dehydration was complete
after 2 h and the reaction cooled and was extracted with water
and EtOAc. The organic layer was dried (MgSO4), and the
solvent was removed in vacuo to give 0.37 g of crude product
that was purified by column chromatography using 100%
EtOAc to give 0.26 g (66%) of 3 as a solid: 1H NMR (500 MHz,
DMSO-d6) δ 12.83 (s, 1H), 7.91 (d, 2H, J ) 8.29 Hz), 7.37 (d,
2H, J ) 8.30), 7.25 (s, 1H), 7.17 (s, 1H), 5.93 (s, 1H), 5.54 (s,
2H), 5.30 (s, 1H), 1.95 (s, 3H), 1.39 (s, 6H), 1.29 (s, 6H); 13C
(125 MHz, DMSO-d6) δ 167.9, 149.0, 145.2, 142.4, 140.6, 139.1,
133.8, 133.4, 130.8, 130.5, 129.0, 128.4, 127.8, 127.1, 118.0,
35.5, 35.4, 33.2, 33.1, 20.4; IR (KBr) ν 3070, 3020, 2964, 2953,
2920, 2901, 2865, 2666, 2541, 1676, 1608, 1460, 1420, 1358,
1316, 1279, 1112, 909, 904, 866, 787, 760 cm-1; HRMS (FAB+)
m/z exact mass calcd for C24H27O2 347.2011, found 347.2006.
C
23H26NO3 364.1913, found 364.1908.
Meth yl 6-[1-(3,5,5,8,8-P en ta m eth yl-2-5,8-d ih yd r on a p h -
th yl)vin yl]p yr id in e-3-ca r boxyla te (38). A solution of 37
(1.22 g, 3.36 mmol) in dry THF (18 mL) was cooled to -25 °C
under N2 and treated dropwise with a 3.0 M solution of
MeMgCl in THF (1.40 mL, 4.20 mmol) at < -20 °C. The
reaction was warmed to room temperature and stirred for 2 h
until complete. The reaction was quenched with 1 N HCl (75
mL), extracted with toluene, and dried (MgSO4), and the
solvent was removed in vacuo to give 1.28 g of the tertiary
4-[(H yd r oxyim in o)(3,5,5,8,8-p en t m et h yl(2-5,8-d ih y-
d r on a p h th yl))m eth yl]ben zoic Acid (4). A suspension of 34
(2.00 g, 5.74 mmol) in glacial acetic acid (20 mL) was treated
with 50% aqueous NH2OH (7.0 mL, 0.11 mol) and the mixture
was heated to a gentle reflux for 1.5 h to give a solution that

Retinoid X Receptor-Selective Retinoids
J . Org. Chem., Vol. 66, No. 17, 2001 5781
alcohol intermediate. This intermediate was combined with
p-toluenesulfonic acid monohydrate (0.32 g, 1.68 mmol) in
toluene (75 mL) and heated to reflux, allowing the distillate
to condense in a Dean-Stark trap prefilled with toluene. The
dehydration was complete after 11 h, and the reaction was
cooled and extracted with aqueous 5% NaHCO3 (75 mL) and
EtOAc. The organic layer was dried (MgSO4), and the solvent
was removed in vacuo to give 1.18 g of crude product that was
purified by column chromatography using 9:1 hexanes/EtOAc
to give 0.89 g (73%) of 38 as a solid: 1H NMR (500 MHz,
CDCl3) δ 9.26 (d, 1H, J ) 2.10 Hz), 8.18 (dd, 1H, J ) 2.04 Hz,
J ) 8.26 Hz), 7.22 (d, 2H, J ) 11.24 Hz), 7.06 (d, 1H, J ) 8.26
Hz), 6.60 (d, 1H, J ) 1.92 Hz), 5.57, (s, 1H), 5.56 (s, 2H), 3.97
(s, 3H), 2.06 (s, 3H), 1.40 (s, 6H), 1.36 (s, 6H); 13C (125 MHz,
CDCl3) δ 166.2, 161.5, 151.1, 148.4, 142.7, 140.8, 138.1, 137.7,
133.6, 133.5, 133.4, 128.2, 128.1, 124.7, 121.5, 52.7, 35.5, 35.4,
33.1, 20.3; IR (KBr) ν 2966, 2952, 1722, 1592, 1437, 1285, 1270,
J ) 4.3 Hz, 1H), 5.50 (d, J ) 4.3 Hz, 1H), 3.94 (s, 3 H); 13C
NMR (DMSO-d6, 75 MHz) δ 165.4, 151.3, 135.4, 132.0, 131.0,
130.0, 129.3, 125.3, 108.8, 52.3 ppm; IR (CHCl3) 2900, 1723,
1423, 1285, 1141, 942 cm-1; Anal. Calcd for C11H9F3O5S: C,
42.59; H, 2.92. Found: C, 42.58; H, 2.95.
5,6,7,8-Tet r a h yd r o-3,5,5,8,8-p en t a m et h yl-2-n a p h t h a -
len yl-bor on ic Acid (41). To a -78 °C solution of n-BuLi
(9.84 mL, 1.30 M in hexane, 12.8 mmol) in 30 mL of THF was
added a solution of bromide 40 (3.00 g, 10.7 mmol) in 8 mL of
THF (5 mL THF rinse) via cannula over 20 min. The resulting
solution was stirred for 10 min, and a solution of B(O-i-Pr)3
(4.01 g, 21.3 mmol) in 10 mL of THF was added over 20 min.
The reaction mixture was stirred at -78 °C for 1 h, warmed
to room temperature for 2 h, and quenched with 35 mL of
aqueous 3 M HCl. After 2 h at room temperature, the mixture
was diluted with EtOAc (60 mL) and the phases were
separated. The aqueous layer was extracted with EtOAc (50
mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo. The resulting crude white
solid was filtered through silica gel with 25% EtOAc in hexane
to provide 2.38 g (91%) 41 that was used without further
purification: 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 7.20
(s, 1H), 2.80 (s, 3H), 1.72 (s, 4H), 1.35 (s, 6H), 1.33 (s, 6H); IR
1115, 767 cm-1; HRMS (FAB+) m/z exact mass calcd for C24H28
-
NO2 362.2123, found 362.2120.
Meth yl 6-[(3,5,5,8,8-P en ta m eth yl-2-5,8-d ih yd r on a p h -
th yl)cyclop r op yl]p yr id in e-3-ca r boxyla te (39). A suspen-
sion of trimethylsulfoxonium iodide (0.80 g, 3.65 mmol) in dry
DMSO (8 mL) was treated with a 1.0 M solution of tert-KOBu
in THF (3.70 mL, 3.69 mmol) at room temperature under N2,
and the resultant ylide solution was stirred for 30 min. A
solution of 38 (0.88 g, 2.43 mmol) in dry THF (16 mL) was
added dropwise to the ylide solution at room temperature and
the reaction was stirred for 1 h. The reaction was quenched
with 1 N HCl (50 mL) and extracted with EtOAc, the organic
layer was dried (MgSO4), and the solvent was removed in
vacuo to give the crude product that was purified by column
chromatography using 9:1 hexanes/EtOAc to give 0.71 g (78%)
of 39 as a solid: 1H NMR (500 MHz, CDCl3) δ 9.12 (d, 1H,
J ) 1.77 Hz), 8.01 (dd, 1H, J ) 2.11 Hz, J ) 8.36 Hz), 7.37 (s,
1H), 7.21 (s, 1H), 6.80 (d, 1H, 8.31 Hz), 5.56 (s, 2H), 3.97 (s,
3H), 2.18 (s, 3H), 1.88 (d, 2H, J ) 3.04 Hz), 1.40 (s, 8H), 1.36
(s, 6H); 13C (125 MHz, CDCl3) δ 169.6, 166.5, 150.9, 142.0,
140.9, 138.1, 137.0, 136.6, 133.6, 133.5, 129.3, 128.4, 122.7,
121.1, 117.9, 52.5, 35.4, 35.4, 33.1, 33.1, 30.8, 20.6, 19.7; IR
(KBr) ν 2965, 2953, 1716, 1595, 1440, 1289, 1272, 1117, 1138,
1022, 787, 765 cm-1; HRMS (FAB+) m/z exact mass calcd for
(CHCl3) ν 2963, 2928, 2862, 1604, 1392, 1380, 1342, 1333 cm-1
.
3,5,5,8,8-P en t a m et h yl-5,8-d ih yd r on a p h t h a len e-2-b o-
r on ic Acid (42). To a -78 °C solution of n-BuLi (4.92 mL,
1.60 M in hexane, 7.88 mmol) in 20 mL of THF was added a
solution of bromide 29 (2.00 g, 7.16 mmol) in 5 mL of THF (5
mL THF rinse) via cannula over 20 min. The resulting solution
was stirred for 10 min, and a solution of B(O-i-Pr)3 (2.69 g,
14.3 mmol) in 5 mL of THF was added over 20 min. The
reaction mixture was stirred at -78 °C for 2 h and was
warmed to room temperature for 1 h. The resulting suspension
was quenched with 3 M HCl (30 mL). After 30 min at room
temperature, the mixture was diluted with EtOAc (75 mL) and
the phases were separated. The organic layer was washed with
saturated aqueous NaCl (35 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The resulting crude white solid was
filtered through silica gel with 33% EtOAc in hexane to provide
1.42 g (81%) 42 that was used without further purification:
1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.20 (s, 1H), 5.42
(m, 2H), 2.80 (s, 3H), 1.35 (s, 6H), 1.30 (s, 6H); IR (CHCl3) ν
C
25H30NO2 376.2281, found 376.2277.
6-[(3,5,5,8,8-P en t a m et h yl-2-5,8-d ih yd r on a p h t h yl)cy-
3008, 2962, 1606, 1462, 1392, 1367, 1360, 1289, 1113 cm-1
.
clop r op yl]p yr id in e-3-ca r boxylic Acid (5). A suspension of
39 (0.70 g, 1.86 mmol) in MeOH (35 mL) was treated with
50% aqueous NaOH (0.75 g, 9.38 mmol) and heated to reflux
for 1.5 h until the hydrolysis was complete. The hot reaction
solution was acidified using 1 N HCl (11 mL) at which point
the product crystallized. The slurry was cooled to room
temperature, stirred for 2 h, and filtered using the filtrate as
an initial rinse and then water (20 mL) as a final rise to give
0.639 g (95%) of 5 after drying the solid in a vacuum oven at
50 °C: 1H NMR (500 MHz, CDCl3) δ 13.13 (bs, 1H), 8.98 (s,
1H), 8.04 (d, 1H, J ) 7.40 Hz), 7.36 (s, 1H), 7.27 (s, 1H), 6.75
(d, 1H, J ) 8.15 Hz), 5.53 (s, 2H), 2.20 (s, 3H), 1.74 (s, 2H),
1.32 (s, 8 H), 1.29 (s, 6H); 13C (125 MHz, DMSO-d6) δ 168.7,
167.1, 151.0, 141.8, 140.8, 138.4, 137.9, 136.6, 133.8, 133.8,
129.2, 128.7, 124.0, 121.0, 35.5, 33.2, 33.1, 31.0, 20.5, 19.8; IR
(KBr) ν 3014, 2965, 2922, 2866, 1680, 1595, 1422, 1379, 1296,
1275 cm-1; HRMS (FAB+) m/z exact mass calcd for C24H28NO2
362.2120, found 362.2116. Anal. Calcd for C24H27NO2: C,
79.74; H, 7.53; N, 3.87. Found: C, 79.98; H, 7.40; N, 3.75.
Meth yl 4-{1-[(Tr iflu or om eth yl)su lfon yloxy]vin yl}ben -
zoa te (43). To a solution of methyl 4-acetylbenzoate (4.00 g,
22.4 mmol) in 34 mL of CH2Cl2 at room temperature was added
Na2CO3 (4.75 g, 44.8 mmol). Triflic anhydride (10.4 mL, 67.4
mmol) in 46 mL of CH2Cl2 was added dropwise, and the
resulting suspension was stirred vigorously for 40 h. The
reaction was filtered through Celite, and the filtrate was
washed with 2 × 100 mL saturated aqueous NaHCO3 and
saturated aqueous NaCl, dried (MgSO4), filtered, and concen-
trated in vacuo. The resulting yellow solid was purified by
column chromatography using 20% EtOAc in hexane to
provide 6.18 g (89%) of triflate 43: 1H NMR (300 MHz, CDCl3)
δ 8.10 (d, J ) 8.9 Hz, 2H), 7.62 (d, J ) 8.9 Hz, 2H), 5.73 (d,
Meth yl 4-[1-(5,6,7,8-Tetr a h yd r o-3,5,5,8,8-p en ta m eth yl-
2-n a p h th a len yl)eth en yl]-ben zoa te (44). A solution of bo-
ronic acid 41 (0.10 g, 0.41 mmol), triflate 43 (0.18 g, 0.56
mmol), Pd(OAc)2 (0.005 g, 0.024 mmol), P(o-Tol)3 (14.6 g, 0.05
mmol), and Et3N (0.17 mL, 1.22 mmol) in DMF (2 mL) was
heated to 50 °C for 2 h. The reaction mixture was cooled to
room temperature and diluted with EtOAc (20 mL) and H2O
(15 mL). The organic layer was washed with H2O (10 mL) and
saturated aqueous NaCl (10 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The brown solid was chromatographed
using 5% EtOAc in hexane to provide 0.13 g (88%) 44.
Meth yl 4-[(3,5,5,8,8-P en ta m eth yl-2-5,8-d ih yd r on a p h -
th yl)ca r bon yl]ben zoa te (31). A solution of boronic acid 42
(0.10 g, 0.41 mmol), triflate 43 (0.18 mg, 0.57 mmol), Pd(OAc)2
(0.005 g, 0.02 mmol), P(o-Tol)3 (0.015 g, 0.05 mmol), and Et3N
(0.17 mL, 1.22 mmol) in DMF (2.0 mL) was heated to 50 °C
for 2 h. The reaction mixture was cooled to room temperature
and diluted with EtOAc (20 mL) and H2O (15 mL). The organic
layer was washed with H2O (10 mL) and saturated aqueous
NaCl (10 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. The brown solid was purified by column chromatogra-
phy using 5% EtOAc in hexane to provide 0.12 g (83%) 31:
1H NMR (300 MHz, CDCl3) δ 7.97 (d, J ) 8.4 Hz, 2H), δ 7.36
(d, J ) 8.4 Hz, 2H), 7.20 (s, 1H), 7.15 (s, 1H), 5.84 (s, 1H),
5.54 (s, 2H), 5.35 (s, 1H), 3.91 (s, 3H), 1.98 (s, 3H), 1.37 (s,
6H), 1.34 (s, 6H); 13C NMR (DMSO-d6, 75 MHz) δ 165.9, 147.9,
144.7, 141.5, 139.7, 138.1, 132.8, 132.5, 129.5, 129.0, 128.6,
127.6, 127.0 126.6, 117.7, 52.0, 34.6, 34.5, 32.2, 32.2, 19.5 ppm;
IR (CHCl3) 2961, 1716, 1607, 1437, 1283, 1111 cm-1; exact
mass calcd for C25H29O2 361.2167, found 361.2171.

5782 J . Org. Chem., Vol. 66, No. 17, 2001
Faul et al.
Ack n ow led gm en t. The authors would like to thank
Professor Marvin Miller and Professor Bill Roush for
helpful discussions during the course of this work. Dr.
Timothy Grese, Mr. David Neel, Mr. Donald Matthews,
Dr. Alan Warshawsky, and Ms. Christine Krumrich are
also acknowledged for helpful discussions.
J O0103064