Improved synthesis of the iodine-free thyromimetic GC-1

Article abstract of DOI:10.1016/S0960-894X(00)00531-X

Synthesis of the TRβ-selective thyromimetic GC-1 has been improved using methoxymethyl (MOM) and triisopropylsilyl (TiPS) substituents as phenolic protecting groups. The new synthetic route is adaptable to analogue design. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00531-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2607±2611
Improved Synthesis of the Iodine-Free Thyromimetic GC-1
Grazia Chiellini, Ngoc-Ha Nguyen, Hikari A. I. Yoshihara and Thomas S. Scanlan*
Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California,
San Francisco, CA 94143-0446, USA
Received 20 July 2000; accepted 11 September 2000
AbstractÐSynthesis of the TRb-selective thyromimetic GC-1 has been improved using methoxymethyl (MOM) and triisopropylsilyl
(TiPS) substituents as phenolic protecting groups. The new synthetic route is adaptable to analogue design. # 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
the retinoic acid receptor (RAR) and retinoid X recep-
tor (RXR).3 5 There are two major subtypes of the
thyroid hormone receptor, TRa and TRb, that are
coexpressed in di€erent ratios in di€erent tissues.6 Most
thyroid hormones do not discriminate between the two
TRs and bind both with similar anity.
Thyroid hormones, of which 3,5,30-triiodo-l-thyronine
(T3) is the major active form, regulate many di€erent
physiological processes in di€erent tissues in mam-
mals.1,2 A de®ciency of these hormones or hypothy-
roidism results in severe impairment of mental
development and growth in childhood. In the adult,
hypothyroidism leads to a slow metabolism, decreased
body temperature and heart rate, increased accumula-
tion of glycosaminoglycans in subcutaneous tissues
(mixedema), weight gain, and elevated cholesterol levels.
By contrast, an elevated level of thyroid hormones or
hyperthyroidism provokes tachycardia, increased meta-
bolism and body temperature, weight loss, and
decreased serum cholesterol levels. In current medical
practice, thyroid hormones are used mostly as replace-
ment therapy for patients with hypothyroidism, and to
suppress the pituitary gland stimulation of the thyroid
gland in patients with thyroid nodules or cancer. How-
ever, these hormones cannot be administered in high doses
because of signi®cant side e€ects, mainly on the heart.
Observations suggest that the a-form of the receptors
contribute in a substantial way to cardiac stimulating
side e€ects,7,8 and that a b-selective agonist would be
less likely to have this side e€ect. A few attempts have
been made to develop thyroid hormone analogues,
which induce a di€erential thyroid hormone response
and, for example, preferentially lower lipid levels but do
not increase heart rate.9,10 Such compounds might have
medical utility.
We have recently designed and synthesized a halogen-
free high-anity TRb-selective ligand, GC-1 (Fig. 1),
which is a member of a new class of thyromimetic
compounds that are more synthetically accessible than
traditional thyromimetics and have potentially useful
receptor-binding and ligand-activation properties.11
GC-1 was initially synthesized in our laboratory by a
convergent synthetic route wherein the key step is an
ecient aldehyde addition reaction that forms the di-
arylmethane structure.11 A major problem encountered
in the process was the ®nal mono-alkylation procedure
of bis-phenol 2, which unfortunately did not proceed
with the expected selectivity,12 leading to a mixture of
both 1- and 40-alkylated product 3, as well as the bis-
alkylated product 4. This problem of over-alkylation
could not be controlled and resulted in a 28% isolated
yield for the ®nal chemical step in the synthetic route
(Scheme 1).
Most of the physiological actions of T3 result from
transcriptional regulation T3-responsive genes that is
mediated through thyroid hormone receptors (TRs).
The TR belongs to the nuclear receptor superfamily of
ligand-activated transcription regulators that includes
steroid receptors such as the estrogen receptor (ER) and
glucocorticoid receptor (GR), as well as receptors that,
like TR, are activated by non-steroidal ligands such as
*Corresponding author. Tel.: +1-415-476-3620; fax: +1-415-502-
7220; e-mail: scanlan@cgl.ucsf.edu
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00531-X

2608
G. Chiellini et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2607±2611
Based on the encouraging in vitro results with GC-1, we
have begun to pursue in vivo experiments to ascertain
the physiological e€ects of GC-1 in di€erent animal
models. In order to perform these experiments, it was
necessary to optimize the synthesis of GC-1 such that
multigram quantities of the compound could be prepared.
4-bromo-2-isopropylphenol13 is converted to the corre-
sponding methoxymethyl ether 5 by treatment of the
phenoxide with chloromethyl methyl ether.14 For the A-
aryl ring half the 4-bromo-3,5-dimethylphenol is treated
with triisopropylsilylchloride to provide the triisopro-
pylsilyl ether 6,15 which is subsequently formylated via
lithium±halogen exchange followed by treatment with
dimethylformamide to provide the aldehyde 7.16 Bro-
mide 5 and aldehyde 7 are then coupled via the addition
of lithiated 5 to aldehyde 7 to give the biaryl alcohol 8.17
Hydrogenolysis of alcohol 8 provides the biarylmethane
compound 9.18 Subsequent treatment of 9 with tetra-
butylammonium ¯uoride allows selective removal of the
phenolic silyl ether protecting group, providing the free
phenol 10.19 Phenol 10 is then mono-alkylated using a-
chloro-t-butylacetate, which successfully solves the main
problem with the original route, providing the desired
mono-ester 11.20 The target compound GC-1 is then
obtained from 11 by removal of the methoxymethyl
phenolic protecting group under acidic conditions, fol-
lowed by basic saponi®cation of the tert-butyl ester.21
Although tert-butyl esters are usually hydrolyzed under
acidic conditions, we found that hydrolysis with base
resulted in less decomposition and higher chemical
yields for this step.
Chemistry
The new chemical synthesis of GC-1 is outlined in
Scheme 2. The two aryl halves of GC-1 are constructed
®rst and the phenols are di€erentiated at this stage with
di€erent protecting groups. For the B-aryl ring half
Results and Discussion
The new synthetic route described here allows one to
prepare multigram quantities of GC-1 and is more
adaptable to analogue design than our original synth-
esis. Di€erentiating the two phenols early in the route
with the appropriate protecting groups remedies the
problem of overalkylation in the ®nal step resulting in a
Figure 1. Chemical structure of thyroid hormone (T3) and the syn-
thetic thyromimetic compound GC-1.
Scheme 1. Steps 6 and 7 of the original synthesis of GC-1. For the complete synthesis see ref 11.

G. Chiellini et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2607±2611
2609
Scheme 2. Synthetic route used for the preparation of GC-1.
substantial improvement in the overall yield of GC-1.
This improved route provides GC-1 in 22% overall yield
from 4-bromo-3,5-dimethylphenol, whereas our original
route resulted in a 7% yield of GC-1 from this same
starting material. We have used the new route to pre-
pare multigram quantities of GC-1 for use in animal
studies. In addition to this improvement in eciency,
the di€erentiated phenol protecting groups o€er a che-
mical handle for selective modi®cation of the thyronine
skeleton to produce new derivatives. The methoxy-
methyl protecting group can be used to direct
orthometalation chemistry leading to new derivatives
substituted at the 50-position.22 We are currently inves-
tigating this chemistry to produce a series of these new
50-substituted thyronine analogues.
Acknowledgements
This work was supported by a grant from the National
Institutes of Health (DK 52798). T.S.S. is an Alfred P.
Sloan Research Fellow.

2610
G. Chiellini et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2607±2611
DMF (12.3 g, 0.168 mol) was added. The reaction mixture was
References and Notes
stirred for 1 h at 78 ꢀC and for 1.5 h at room temperature,
diluted with 200 mL of ether, and washed with 100 mL of
water, acidi®ed with 1 N HCl, and 5Â50 mL of brine. The
organic portion was dried (MgSO4), ®ltered, and evaporated
to give the crude product, which was puri®ed by ¯ash column
chromatography (silica gel, 90:10 hexane:ethyl acetate) to yield
7 (18 g, 0.059 mol, 70%) as a clear oil; 1H NMR (CDCl3,
300 MHz) d 1.1 (d, 18H, J=6.9 Hz), 1.26 (m, 3H), 2.57 (s, 6H),
6.56 (s, 2H), 10.47 (s, 1H); 13C NMR (CDCl3, 300 MHz) d
12.6, 17.8, 20.9, 119.5, 120.8, 144.4, 159.8, 191.8. HR-MS
calcd for C18H30O2Si: 306.2015, found: 306.2014.
1. Greenspan F. S. In Basic & Clinical Endocrinology, 4th
edn.; Baxter, J. D., Greenspan, F. S., Eds.; Appleton & Lange:
Norwalk, 1994.
2. Utiger, R. D. N. Engl. J. Med. 1995, 333, 1562.
3. Mangelsdorf, D. J.; Evans, R. M. Cell 1995, 83, 841.
4. Manglesdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.;
Schultz, G.; Umesono, K.; Blumberg, B.; Kastner, P.; Mark,
M.; Chambon, P.; Evans, R. M. Cell 1995, 83, 835.
5. Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Chem.
Biol. 1996, 3, 529.
17. 3,5-Dimethyl-4-(30-isopropyl-40-O-methoxymethylbenzylhy-
droxy)-O-triisopropylsilylphenol (8). To 5 (10 g, 0.038 mol) in
100 mL of tetrahydrofuran at 78 ꢀC was added 29.0 mL of n-
butyllithium (2.0 M in pentane) and the reaction mixture was
stirred for 30 min at 78 ꢀC under argon. The aldehyde 7
(11.8 g, 0.039 mol) in THF anhydrous (100 mL) was added and
the mixture was stirred for 1 h at 78 ꢀC and for 6 h at room
temperature. Then, the reaction mixture was diluted with
150 mL of ether, washed with 200 mL of water and 5Â50 mL
of brine. The combined extracts were dried over MgSO4, ®l-
tered, and evaporated to give the crude product, which was
puri®ed by ¯ash chromatography (silica gel, 90:10 hex-
ane:ethyl acetate) to yield 8 (12 g, 0.024 mol, 68%) as an oil;
1H NMR (CDCl3, 300 MHz) d 1.1 (d, 18H, J=6.9 Hz), 1.2
(dd, 6H, J=6.6, 6.9 Hz), 1.26 (m, 3H), 2.20 (s, 6H), 3.3 (hep-
tet, 1H, J=6.9 Hz), 3.48 (s, 3H), 5.17 (s, 2H), 6.22 (s, 1H), 6.55
(s, 2H), 6.93 (m, 2H), 7.15 (s, 1H); 13C NMR (CDCl3,
300 MHz) d 12.7, 17.7, 20.8, 22.7, 27.0, 31.6, 56.03, 70.9, 94.63,
113.6, 120.4, 123.7, 132.2, 136.4, 137.2, 138.4, 153.1, 154.9.
HR-MS calcd for C29H46O4Si: 486.3165, found: 486.3159.
18. 3,5-Dimethyl-4-(30-isopropyl-40-O-methoxymethylbenzyl)-O-
triisopropylsilyl phenol (9). A solution of 8 (7.3 g, 0.015 mol) in
50 mL of 9% (v/v) AcOH in EtOH containing 10% Pd/C
(500 mg) was hydrogenated at 1 atm at room temperature.
When hydrogen uptake was complete (12 h), the catalyst was
®ltered o€ and the ®ltrate was diluted with 250 mL of ether,
washed with sat. NaHCO3 solution (3Â50 mL). The solvent
was evaporated to yield 5.65 g (0.012 mol, 80%) of 9 as an oil.
This material was used in the next step without further pur-
6. Lazar, M. A. Endocrine Rev. 1993, 14, 184.
7. Wikstrom, L.; Johansson, C.; Salto, C.; Barlow, C.; Barros,
A. C.; Baas, F.; Forrest, D.; Thoren, P.; Vennstrom, B.
EMBO J. 1998, 17, 455.
8. Johansson, C.; Vennstrom, B.; Thoren, P. Am. J. Physiol.-
Regulat. Integrat. Comparat. Physiol. 1998, 44, R640.
9. Underwood, A. H.; Emmett, J. C.; Ellis, D.; Flynn, S. B.;
Leeson, P. D.; Benson, G. M.; Novelli, R.; Pearce, N. J.; Shah,
V. P. Nature 1986, 324, 425.
10. Taylor, A. H.; Stephan, Z. F.; Steele, R. E.; Wong, N. C.
W. Mol. Pharmacol. 1997, 52, 542.
11. Chiellini, G.; Apriletti, J. W.; Yoshihara, H. A. I.; Baxter, J.
D.; Ribeiro, R. C. J.; Scanlan, T. S. Chem. Biol. 1998, 5, 299.
12. Yokoyama, N.; Walker, G. N.; Main, A. J.; Stanton, J.
L.; Morrissey, M. M.; Boehm, C.; Engle, A.; Neubert, A. D.;
Wasvary, J. M.; Stephan, Z. F.; Steele, R. E. J. Med. Chem.
1995, 38, 695.
13. Berthelot, J.; Guette, C.; Desbene, P. L.; Basselier, J. J.;
Chaquin, P.; Masure, D. Can. J. Chem. 1989, 67, 2061.
14. 4-Bromo-2-isopropyl phenyl methoxymethyl ether (5).
4-Bromo-2-isopropylphenol (22.0 g, 0.120 mol) was added
dropwise to a slurry of sodium hydride pellets (3.70 g,
0.128 mol) in dimethylformamide (100 mL) at room tempera-
ture. Stirring at this temperature was continued until the evo-
lution of hydrogen ceased (20 min). Monochloromethylether
(9.47 g, 0.117 mol) was then added during 30 min and stirring
was continued for an additional 30 min after which excess
sodium hydride was destroyed by cautious addition of metha-
nol (30 mL). The reaction mixture was diluted with 200 mL of
ether and washed with 3Â100 mL of water and 5Â100 mL of
brine. The organic portion was dried (MgSO4), ®ltered, and
evaportated to give an oil, which was puri®ed by ¯ash column
chromatography (silica gel, 95:5 hexane:ethyl acetate) to give
the pure product 5 (24.0 g, 0.093 mol, 90%); 1H NMR (CDCl3,
i®cation; 1H NMR (CDCl3, 300 MHz)
d 1.1 (d, 18H,
J=6.9 Hz), 1.16 (d, 6H, J=6.9 Hz), 1.23 (m, 3H), 2.16 (s, 6H),
3.27 (heptet, 1H, J=6.9 Hz), 3.48 (s, 3H), 3.91 (s, 2H), 5.15 (s,
2H), 6.59 (s, 2H), 6.67 (dd, 1H, J=2.4, 8.4 Hz), 6.9 (m, 2H);
13C NMR (CDCl3, 300 MHz) d 12.7, 17.0, 20.32, 22.78, 26.9,
33.73, 55.97, 94.71, 113.9, 119.4, 125.5, 129.8, 133.4, 137.3,
138.1, 152.4, 153.8. HR-MS calcd for C29H46O3Si: 470.3216,
found 470.3194.
300 MHz)
d 1.2 (d, 6H, J=6.9 Hz), 3.29 (heptet, 1H,
J=6.9 Hz), 3.47 (s, 3H), 5.17 (s, 2H), 6.94 (d, 1H, J=8.7 Hz),
7.22 (dd, 1H, J=8.7, 2.7 Hz), 7.30 (d, 1H, J=2.7 Hz); 13C
NMR (CDCl3, 300 MHz) d 22.6, 26.9, 56.03, 94.5, 114.4,
115.7, 129.2, 139.9, 153.4. HR-MS calcd for C11H15O2Br:
258.0255, found: 258.0253.
19. 3,5-Dimethyl-4-(30 -isopropyl-40 -O-methoxymethylbenzyl)
phenol (10). Compound 9 (4 g, 8.5 mmol) and tetra-n-butyl-
ammonium ¯uoride (10.6 mmol, 1.0 M in THF) were combined
in a round-bottom ¯ask. Deprotection was determined to be
nearly instantaneous by TLC. The reaction mixture was dilu-
ted with ethyl acetate (100 mL) and washed with water
(2Â75 mL) and brine (100 mL), dried and concentrated. The
crude product was puri®ed by ¯ash column chromatography
(80:20 hexane:ethyl acetate) to yield 10 (2.40 g, 7.60 mmol,
90%); 1H NMR (CDCl3, 300 MHz) d 1.17 (d, 6H, J=6.9 Hz),
2.18 (s, 6H), 3.28 (heptet, 1H, J=6.9 Hz), 3.47 (s, 3H), 3.89 (s,
2H), 5.15 (s, 2H), 6.55 (s, 2H), 6.65 (dd, 1H, J=2.4, 8.4 Hz),
6.88 (d, 1H, J=8.4 Hz), 6.94 (d, 1H, J=2.4 Hz); 13C NMR
(CDCl3, 300 MHz) d 20.52, 23.01, 27.18, 33.9, 56.2, 94.88,
114.2, 114.9, 125.5, 126.1, 129.8, 133.5, 137.6, 138.8, 153.6.
HR-MS calcd for C20H26O3: 314.1882, found 314.1869.
20. [3,5-Dimethyl-4-(30 -isopropyl-40 -O-methoxymethylbenzyl)
phenoxy] tert-butylacetate (11). To cesium carbonate (10.4 g,
0.032 mol) and 10 (2 g, 0.0064 mol) in 50 mL of DMF was
added tert-butylchloroacetate (1.2 g, 0.008 mol). The reaction
15. O-Triisopropylsilyl-4-bromo-3,5-dimethylphenol (6).
A
solution of 4-bromo-3,5-dimethylphenol (30 g, 0.149 mol) imi-
dazole (25.3 g, 0.327 mol) and triisopropylsilyl chloride (27.3 g,
0.142 mol) in CH2Cl2 (300 mL) was stirred for 1 h. The reac-
tion mixture was diluted with 600 mL of CH2Cl2, washed with
water (500 mL), brine (500 mL), dried (MgSO4), ®ltered and
evaporated to give an oil, which was puri®ed by ¯ash column
chromatography (silica gel, 90:10 hexane:ethyl acetate) to give
43.4 g (0.121 mol, 81%) of 6 as an oil; 1H NMR (CDCl3,
300 MHz) d 1.09 (d, 18H, J=6.9 Hz), 1.26 (m, 3H), 2.34 (s,
6H), 6.61 (s, 2H); 13C NMR (CDCl3, 300 MHz) d 12.7, 17.7,
23.9, 117.5, 119.6, 138.9, 155.9. HR-MS calcd for
C17H29OBrSi: 358.1150, found: 358.1144.
16. 2,6-Dimethyl-4-O-triisopropylsilylbenzaldehyde (7). To 6
(30 g, 0.084 mol) in 200 mL of tetrahydrofuran at 78 ꢀC was
added 92.0 mL of n-butyllithium (2.0 M in pentane). The
reaction mixture was stirred for 30 min at 78 ꢀC and then

G. Chiellini et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2607±2611
2611
mixture was stirred for 30 min at room temperature, poured
into 100 mL of cold 1 N HCl, and extracted with ethyl acetate
(3Â100 mL). The combined organic portions were dried
(MgSO4) and evaporated to yield 3.0 g of crude, which was
puri®ed using ¯ash column chromatography (silica gel, 90:10
with ethyl acetate (2Â75 mL). The combined organic portions
were dried (MgSO4) and evaporated to yield 1.70 g of the cor-
responding O-methoxymethyl deprotected phenol, which was
used directly in the following step. To the above phenol
(1.50 g, 0.0039 mol) in 40 mL of methanol was added 26 mL of
1 N NaOH. The reaction mixture was stirred for 1 h at room
temperature, acidi®ed with 30 mL of 2 N HCl, and extracted
with ethyl acetate (2Â100 mL). The combined organic por-
tions were dried (MgSO4) and evaporated to give GC-1
(1.20 g, 0.0037 mol, 79%); 1H NMR (CD3OD, 300 MHz) d
1.15 (d, 6H, J=6.6 Hz), 2.18 (s, 6H), 3.21 (heptet, 1H,
J=6.6 Hz), 3.86 (s, 2H), 4.40 (s, 2H), 6.49±6.62 (m, 2H), 6.65
(s, 2H), 6.84 (s, 1H); 13C NMR (CD3OD, 300 MHz): d 20.8,
23.0, 27.6, 34.4, 68.3, 115.2, 115.6, 126.0, 126.4, 126.5, 131.6,
135.6, 139.1, 152.8, 157.0, 177.9. HR-MS calcd for C20H24O4:
328.1675, found: 328.1679.
1
hexane:ethyl acetate) to yield 11 (2.50 g, 0.0058 mol 90%); H
NMR (CDCl3, 300 MHz) d 1.16 (d, 6H, J=6.9 Hz), 1.50 (s,
9H), 2.2 (s, 6H), 3.27 (heptet, 1H, J=6.9 Hz), 3.47 (s, 3H),
3.90 (s, 2H), 4.49 (s, 2H), 5.14 (s, 2H), 6.61 (s, 2H), 6.67 (s,
1H), 6.9 (m, 2H); 13C NMR (CDCl3, 300 MHz) d 20.73, 23.01,
27.18, 28.28, 29.92, 34.01, 56.2, 82.35, 94.89, 114.2, 125.6,
126.1, 120.64, 133.37, 137.6, 138.61, 152.7, 156.09, 168.57.
HR-MS calcd for C26H36O5: 428.2563, found 428.2567.
21. [3,5-Dimethyl-4-(40-hydroxy-30-isopropylbenzyl) phenoxy]
acetic acid (GC-1). To the ester 11 (2.0 g, 0.00470 mol) in
40 mL of a 50% (v/v) mixture of i-PrOH and THF was added
2.0 mL of 1 N HCl. The reaction mixture was stirred for 2 h at
room temperature, diluted with 50 mL of water and extracted
22. Townsend, C. A.; Bloom, L. M. Tetrahedron Lett. 1981,
22, 3923.