New synthetic routes to thyroid hormone analogs: d6-sobetirome, 3H-sobetirome, and the antagonist NH-3

Article abstract of DOI:10.1016/j.tet.2015.05.049

Abstract New synthetic routes for the preparation of isotopically labeled versions of thyroid hormone agonist sobetirome were developed using Knochel's iodine-magnesium exchange. A more efficient synthesis of the thyroid hormone antagonist NH-3 was develo

Full text of DOI:10.1016/j.tet.2015.05.049

Tetrahedron 71 (2015) 5946e5951
Contents lists available at ScienceDirect
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New synthetic routes to thyroid hormone analogs: d6-sobetirome,
3H-sobetirome, and the antagonist NH-3
*
Andrew T. Placzek, Thomas S. Scanlan
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
New synthetic routes for the preparation of isotopically labeled versions of thyroid hormone agonist
sobetirome were developed using Knochel’s iodineemagnesium exchange. A more efficient synthesis of
the thyroid hormone antagonist NH-3 was developed from a common intermediate in the sobetirome
route. Using the new synthetic routes, d6-and 3H-sobetirome were prepared for their use in studying
biodistribution and the cellular uptake of sobetirome. The new route to NH-3 allows for a more rapid and
efficient synthesis and provides access to an advanced intermediate to facilitate antagonist analog
production in the final bond-forming synthetic step.
Received 23 March 2015
Received in revised form 13 May 2015
Accepted 14 May 2015
Available online 20 May 2015
Keywords:
Sobetirome
Thyroid hormone
NH-3
Ó 2015 Elsevier Ltd. All rights reserved.
Thyromimetics
1. Introduction
Sobetirome (also known as GC-1, Fig. 1) is a selective thyroid
hormone agonist, a class of experimental therapeutics often re-
ferred to as thyromimetics. Sobetirome was first synthesized and
its action at the thyroid hormone receptors (TR) characterized in
1998 by Chiellini and colleagues.1 Sobetirome was found to be
a potent thyromimetic with a 10-fold increase in binding affinity
and agonist potency at the thyroid hormone receptor
b-form
(TRb1) as compared to the TRa1. Sobetirome has been studied in
a wide range of cellular and animal models where it has proven
useful as a tool to probe the effects of tissue and TR isoform
selective activation.2 These studies eventually led to clinical
studies of sobetirome as a cholesterol-lowering agent where it
was found to be effective at lowering cholesterol in human
subjects.2 The sobetirome agonist scaffold can also be modified
at the 50-position of the outer ring to produce antagonists and
NH-3 (Fig. 1) is one of the few examples of a potent TR
antagonist.3
There has been considerable recent interest in the use of thy-
romimetics for the treatment of demyelinating neurological disor-
ders such as x-linked adrenoleukodystrophy4 and multiple
sclerosis.5 The use of thyromimetics for these indications would
seem to require efficient distribution of the agent from circulation
to the central nervous system. Stable and radioactive isotope la-
beled derivatives of sobetirome would be useful reagents for
Fig. 1. Chemical structures of TR agonist Sobetirome and the TR antagonist NH-3.
distribution studies. The original synthetic route to sobetirome1 as
well as and improved method6 are not readily amenable to in-
corporation of isotopic labels. We report here a new synthetic route
to sobetirome and sobetirome analogs such as the antagonist NH-3
that is more efficient than any of the previous syntheses and allows
for the incorporation of isotopic labels.
* Corresponding author. E-mail address: scanlant@ohsu.edu (T.S. Scanlan).
http://dx.doi.org/10.1016/j.tet.2015.05.049
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

A.T. Placzek, T.S. Scanlan / Tetrahedron 71 (2015) 5946e5951
5947
2. Results
The new sobetirome and NH-3 synthetic routes all utilized the
With the A-ring intermediate 2 already in hand from the d6-
sobetirome synthesis, the outer B-ring 10 was prepared by first
iodinating the para position of 2-isopropylphenol using NaI and
NaOCl13 and then protecting the phenol using MOM-Cl (Scheme 2).
The Knochel iodineemagnesium exchange9 was performed with
iPrMgCl, which when added to 10 provided the aryl Grignard re-
agent of 10. The aryl magnesium reagent was then cooled to ꢀ78 ꢁC
and a solution of 2 in THF was added. The coupling was kept at
ꢀ78 ꢁC to ensure the aldehyde of 2 was the only functional group
affected by the aryl Grignard reagent. This coupling produced car-
binol 11 in a 71% yield and allowed for the generation of a pro-
tected-sobetirome intermediate containing a site (carbinol) for
radiolabeling with NaB3H4. After optimization of a procedure de-
veloped by Gribble and colleagues14 for reducing carbinols to dia-
rylmethanes using TFA and NaBH4 for 11, 3H-sobetirome 12 was
prepared from 11 with NaB3H4 and TFA in DCM. Although the
tritium-labeling/deprotection procedure proceeded in only 11%
yield from 11, the fast reaction time (10 min) and high specific ac-
tivity (6.90 mBq) obtained made the labeling procedure a satisfac-
tory final step in the synthesis of 3H-sobetirome. In addition to the
4 step synthesis of 3H-sobetirome 12, this synthetic route has also
been used to prepare large quantities (>10 g) of sobetirome by
substituting the NaBH4/TFA step for the triethylsilane/TFA re-
duction (Scheme 1).
The new route to NH-3 (18) begins with the protection of the
phenol moiety of 4-iodo-2-isopropylphenol as a benzyl ether (13)
(Scheme 3). The aryl Grignard reagent of 13 was generated using
the Knochel procedure and then coupled with aldehyde 2. The
resulting carbinol 14 was then subjected to catalytic hydrogenation
conditions, using triethylsilane as the hydrogen donor,10 yielding
the t-butyl ester protected sobetirome 15 in a 70% overall yield from
13. Several iodination procedures were attempted on 15 with I2 and
aq NH3 proving to be the superior conditions for generation of the
50-aryliodide 16a. Following protection of the phenol with MOM-Cl
(16b), the Sonogashira coupling procedure to install the 4-
nitrophenylacetylene moiety was attempted between 16b and 4-
nitrophenylacetylene. The best conditions were found to require
THF as a solvent, Pd(PPh3)4 as the catalyst, and 50 ꢁC as the reaction
temperature, providing the protected NH-3 intermediate 17 in an
87% yield.
iodineemagnesium exchange developed by Knochel and col-
leagues.9 This iodineemagnesium exchange, accomplished with
iPrMgCl, enabled us to install the d6-isopropyl moiety of d6-sobe-
tirome and generate the carbon bridge between the two aryl rings
of 3H-sobetirome and NH-3. This method in conjunction with the
two triethylsilane-mediated carbinol reduction methods10,11 allows
for the preparation of the key common intermediates for the syn-
theses of d6-sobetirome, 3H-sobetirome, and NH-3.
The d6-sobetirome synthetic route is outlined in Scheme 1. The
original 8-step sobetirome synthesis described by Chiellini and
colleagues5 was altered to allow for the installation of the d6-outer
ring (B) later in the synthesis. For the A-aryl ring, 4-hydroxy-2,6-
dimethylbenzaldehyde 1 was first alkylated with t-butyl chlor-
oacetate to provide the desired product 2 in an 89% yield. The
aldehyde of 2 was then converted into the benzyl bromide via
reduction to the benzyl alcohol using NaBH4 followed by applying
the Corey-Kim bromination procedure12 to yield the desired
benzyl bromide 3 in a 57% yield over the two steps. The outer B-
aryl ring containing the d6-labeled isopropyl, was synthesized by
performing the Knochel iodineemagnesium exchange9 on 4-
bromo-2-iodophenol 4 with iPrMgCl. This procedure allowed for
the selective iodineemagnesium exchange while leaving the aryl
bromide intact. The corresponding aryl magnesium species was
then quenched with d6-Acetone to yield the carbinol 5. The car-
binol was then reduced using TFA and Et3SiH11 in DCM to yield the
desired 4-bromo-2-(d6-isopropyl)phenol in an 80% overall yield
from 4. Following protection of the phenol with TIPS, 6 was con-
verted into the Gilman reagent by generation of the corresponding
aryl lithium species with nBuLi, followed by the addition of CuI.
With the Gilman reagent generated, a solution of the benzyl
bromide 3 in THF was added and the diarylmethane 7 was pro-
duced in a 75% yield. To complete the synthesis of the d6-sobe-
tirome 8, the TIPS group was deprotected with TBAF, followed by
saponification of the ester with NaOH. The total synthetic se-
quence was completed in 6 linear steps with a 21% overall yield
from 1, which compares favorably in terms of efficiency with the
previously published synthesis.1,6
Scheme 1. Synthesis of d6-Sobetirome 8. Reagents and Conditions: (a) DMF, Cs2CO3, t-butyl chloroacetate, 89%; (b) NaBH4, MeOH, 0 ꢁC to rt, 76%; (c) DMS, NBS, DCM, 0 ꢁC to rt, 60%
2 steps; (d) (i) iPrMgCl, THF, rt; (ii) Acetone-D6, ꢀ78 ꢁC to rt; (e) Et3SiH, TFA, DCM, rt; (f) TIPS-Cl, Imidazole, DCM, rt, 51% (3 steps); (g) (i) nBuLi, THF, 4 A MS, ꢀ78 ꢁC; (ii) CuI, THF, 3,
ꢀ
ꢀ78 ꢁC to rt 75%; (h) TBAF, THF, rt; (i) MeOH, 5 M NaOH, rt 72% (two steps).

5948
A.T. Placzek, T.S. Scanlan / Tetrahedron 71 (2015) 5946e5951
Scheme 2. Synthesis of 3H-Sobetirome 12. Reagents and Conditions: (a) NaI, NaOCl, NaOH, MeOH, H2O, 75%; (b) MOM-Cl, DCM, TBAI, 10 M NaOH, 81%; (c) iPrMgCl, THF, 4 A MS, (ii)
2, THF, ꢀ78 ꢁC, 64%; (d) DCM, NaB3H4, TFA, 14%.
ꢀ
Intermediate 17 was first subjected to TFA conditions for re-
moving both the MOM-ether and t-butyl ester moieties simulta-
neously. However, TFA resulted in the formation of significant
amounts of a benzofuran side product (17a) (25%), resulting from
the cyclization of the phenol and acetylene motifs. The benzofuran
could not be separated from NH-3 (18) so the deprotection strategy
developed by Gopinathan and Rehder15 for NH-3 was utilized in-
stead. Following the hydrolysis of the ester with NaOH, the crude
product was then subjected to aqueous HCl providing the antago-
nist NH-3 (18), in a 61% overall yield without any benzofuran side
product (17a) contamination.
200 mmol). The resulting mixture was cooled to 0 ꢁC and t-butyl-
chloroacetate (17.9 mL, 125 mmol) was slowly added. The reaction
mixture was then stirred at rt for 3 h and subsequently slowly
poured into 800 mL H2O. The resulting solution was stirred for
15 min at rt and then extracted with diethyl ether (3ꢂ500 mL). The
combined organic fractions were washed with water (3ꢂ1 L), brine,
dried with MgSO4 and concentrated. Recrystallization of the resi-
due with hexanes gave 2 (23.6 g, 89%). 1H NMR (400 MHz, CD3OD):
d
10.43 (s, 1H), 6.65 (s, 2H), 4.65 (s, 2H), 2.58 (s, 6H), 1.49 (s, 9H).
HRMS exact mass calcd for C15H21O4 [MþH]þ: 265.14344. Found
265.14445.
tert-Butyl 2-(4-(bromomethyl)-3,5-dimethylphenoxy)acetate
(3). A solution of 2 (26.3 g, 99.5 mmol) in MeOH (400 mL) was
cooled to 0 ꢁC and NaBH4 (3.76 g, 99.5 mmol) was slowly added
over 5 min. The solution was stirred at room temperature for 1 h
and the reaction was quenched by pouring the solution into 800 mL
of 0.5 N HCl. The aqueous layer was then extracted three times with
ethyl acetate and the combined organic layers were then washed
with brine, dried with MgSO4 and concentrated. Purification of the
residue with flash chromatography (silica, 10%e30% ethyl acetate/
hexanes) yielded the benzyl alcohol (20.2 g, 76%). To a cooled so-
lution of NBS (26.7 g, 150 mmol) and DCM (300 mL) was added
dimethylsulfide (11.09 mL, 150 mmol). This solution was stirred at
3. Discussion
In summary, using the Knochel iodineemagnesium exchange
protocol three new syntheses were developed for producing the
isotopically labeled d6-sobetirome, 3H-sobetirome, and the TR an-
tagonist NH-3. The 4 step synthetic sequence for producing 3H-
sobetirome was also adaptable for producing large quantities of
unlabeled sobetirome, which is in our hands, the most efficient
process currently known for preparing this thyromimetic agent.
Lastly, the improved synthetic procedure for NH-3 includes
a shorter overall route than the previously published syntheses,3,15
and also allows access to a late stage 50-iodinated intermediate that
will allow for the incorporation of a variety of 50-antagonist ex-
tensions thus facilitating the preparation of new antagonist ana-
logs. The improved efficiency of this synthetic approach should
facilitate the development of these TR ligands as biological probes
and experimental therapeutics.
0
ꢁC for 5 min where then a solution of the benzyl alcohol (20 g,
75 mmol) and DCM (75 mL) was added. The reaction mixture was
stirred at 0 ꢁC for 1 h and then 30 min at room temperature. The
reaction was quenched with brine and the organic layer was iso-
lated. The aqueous layer was extracted two more time with dcm
and the combined organic layers were washed with brine, dried,
and concentrated. The resulting solid was collected with cold
hexanes to yield the desired benzyl bromide 3 (18.63 g, 75% (57%
4. Experimental
overall yield)). 1H NMR (400 MHz, CDCl3):
4.48 (s, 2H), 2.39 (s, 6H), 1.49 (s, 9H). 13C NMR (100 MHz, CDCl3):
168.03, 157.79, 139.49, 127.32, 114.55, 82.48, 65.56, 30.06, 28.14,
19.72.
4-Bromo-2-iodophenol (4). 2-Iodophenol (11 g, 50 mmol) was
d 6.57 (s, 2H), 4.55 (s, 2H),
1H NMR were taken on a Bruker 400. All 1H NMR were calibrated
to the NMR solvent reference peak (d6-DMSO, CDCl3, CD3OD). High
resolution mass spectrometry (HRMS) with electrospray ionization
was performed by the Bioanalytical MS Facility at Portland State
University. Inert atmosphere reactions were performed under ar-
gon gas passed through a small column of drierite and were con-
ducted in flame-dried rbfs. Anhydrous tetrahydrofuran (THF),
dichloromethane (DCM), and dimethylformamide (DMF) were ob-
tained from a Seca Solvent System. All other solvents used were
purchased from SigmaeAldrich or Fisher.
d
dissolved in DCM (200 mL) and MeOH (100 mL). Tetrabuty-
lammonium tribromide (TBATB) (25.31 g, 52.5 mmol) was then
added portionwise over 10 min. The solution was stirred at room
temperature for 2 h and then quenched with 1 N HCl (200 mL). The
DCM layer was extracted and the aqueous layer was extracted an-
other two times with DCM. The organic layers were then combined,
washed with brine, dried, and concentrated. Purification of the
residue with flash chromatography (silica, 50%e100% DCM/Hex-
tert-Butyl 2-(4-formyl-3,5-dimethylphenoxy)acetate (2). To
a
solution of 4-hydroxy-2,6-dimethylphenol (1) (15.02 g,
100 mmol) and DMF (400 mL) was added Cs2CO3 (65.2 g,
anes) yielded 4-bromo-2-iodophenol (10.2 g, 68%).
H NMR

A.T. Placzek, T.S. Scanlan / Tetrahedron 71 (2015) 5946e5951
5949
Scheme 3. Synthesis of NH-3. Reagents and Conditions: (a) NaI, NaOCl, NaOH, MeOH, H2O, 75%; (b) K2CO3, benzyl bromide, DMF, 75 ꢁC, 77%; (c) (i) iPrMgCl, THF, 4 oA MS, (ii) 3, THF,
ꢀ78 ꢁC; (d) MeOH, 10% Pd/C, Et3SiH, 55%(two steps); (e) Aq NH3, THF, I2,, 80%; (f) DMF, Cs2SO3, MOM-Cl, 78%; (g) NEt3, Pd(PPh3)4, CuI, THF, 4-nitrophenyl acetylene, 50 ꢁC, 87%; (h) (i)
MeOH, 2 N NaOH; (ii) THF, H2O, HCl, 61%.
matched the reported spectrum for 4-bromo-2-iodophenol as in
Marton Csekei et al. Tetrahedron 2008, 62, 8992e8996.
and Et3SIH (27.2 mL, 170 mmol) was added, followed by tri-
fluoroacetic acid (25 mL). The solution was stirred at room tem-
perature for 22 h and then concentrated. Purification of the
residue with flash chromatography (silica, 0%e60% DCM/Hexanes)
yielded 4-bromo-2-(D6-propan-2-yl)phenol (6.0 g, 80%). To a so-
lution of 4-bromo-2-(D6-propan-2-yl)phenol (6 g, 27 mmol) and
DCM (90 mL) was added TIPS-Cl (11.44 mL, 54 mmol) followed by
Imidazole (5.51 mL, 81 mmol). The reaction mixture was stirred at
room temperature for 18 h and then quenched with 0.5 M HCl. The
DCM layer was extracted and the aqueous layer was further
extracted two more times with DCM. The combined organic layers
were washed with brine, dried, and concentrated. Purification of
the residue with flash chromatography (silica, Hexanes) yielded 4-
bromo-2-[(1,1,1,3,3,3-2H₆)propan-2-yl]-phenoxytriisopropylsilane
4-Bromo-2-(2-hydroxy-(D6-propan-2-yl)phenol (5). A solution
ꢀ
of 4 (10.2 g, 34 mmol), THF (140 mL), and 4 A molecular sieves (2 g)
was placed under reduced pressure for 1 min and then placed
under argon for 1 min. This process was repeated three times to
ensure a deoxygenated solution. The solution was then cooled to
0
ꢁC and an iPrMgCl solution (2 M THF, 42.6 mL, 85.3 mmol) was
added. The reaction mixture was then stirred at rt for 2.5 h where it
was then cooled to ꢀ78 ꢁC. Acetone-D6 (170.5 mmol, 12.54 mL) was
added to the chilled solution and the reaction was allowed to warm
to room temperature over 6 h. The reaction was then quenched
with 0.5 M HCl and extracted with ethyl acetate three times. The
combined organic fractions were washed with brine, dried with
Mg2SO4, and concentrated under reduced pressure.
(6) (6.60 g, 65%). 1H NMR (400 MHz, CDCl3):
d 7.29 (d, 1H,
4-Bromo-2-[(1,1,1,3,3,3-2H6)propan-2-yl]-phenoxytriisopropy
lsilane (6). The crude residue was then dissolved in DCM (75 mL)
J¼2.5 Hz), 7.15 (dd, 1H, 8.6 Hz, J¼2.5 Hz), 6.66 (d, 1H, J¼8.6 Hz),
3.30 (s, 1H), 1.34 (sept, 3H, J¼7.2 Hz), 1.34 (d, 18H, J¼7.2 Hz). 13C

5950
A.T. Placzek, T.S. Scanlan / Tetrahedron 71 (2015) 5946e5951
NMR (100 MHz, CDCl3):
26.6, 18.1, 13.3.
d
152.5, 141.1, 129.4, 129.1, 119.5, 113.3,
organic fractions were washed with brine, dried with Mg2SO4, and
concentrated under reduced pressure. Purification of the residue
with flash chromatography (silica, 25%e50% dcm/hexanes) yielded
tert-Butyl 2-[3,5-dimethyl-4-({3-[(1,1,1,3,3,3-2H₆)propan-2-yl]-
4-{[tris(propan-2-yl)silyl]oxy}phenyl}methyl)phenoxy]acetate (7).
10 (10.21 g, 82%). 1H NMR (400 MHz, CDCl3):
d
7.5 (d, 1H, J¼2.2 Hz),
ꢀ
A solution of 6 (1.66 g, 4.4 mmol), THF (20 mL), and 4 A molecular
7.44 (dd, 1H, J¼8.7 Hz, 2.2 Hz), 6.85 (d, 1H, J¼8.7 Hz), 5.20 (s, 2H),
sieves (1 g) was placed under reduced pressure for 1 min and then
placed under argon for 1 min. This process was repeated three
times to ensure a deoxygenated solution. The solution was then
stirred at ꢀ78 ꢁC and a nBuLi solution (2.5 M hexanes, 2 mL,
5 mmol) was added. The reaction mixture was stirred at ꢀ78 ꢁC for
1.5 h and CuI (419 mg, 2.2 mmol) was then added. The reaction
mixture was stirred for 5 min at ꢀ78 ꢁC and 20 min at 0 ꢁC. The
solution was cooled back to ꢀ78 ꢁC and a solution of 3 (658 mg,
2.0 mmol) and THF (5 mL) was added. The reaction mixture was
then allowed to slowly warm to room temperature over 16 h. The
reaction was quenched with 10% NH4Cl and the aqueous layer was
extracted three times with ether. The combined organic layers were
washed with brine, dried, and concentrated. Purification of the
residue with flash chromatography (silica, 0%e7.5% ethyl acetate/
hexanes) yielded tert-butyl 2-[3,5-dimethyl-4-({3-[(1,1,1,3,3,3-2H₆)
propan-2-yl]-4-{[tris(propan-2-yl)silyl]oxy}phenyl}methyl)phe-
noxy]acetate (7) (818 mg, 75%).
3.49 (s, 3H), 3.29 (sept, 1H, J¼7 Hz), 1.22 (d, 6H, J¼7 Hz). 13C NMR
(100 MHz, CDCl3):
d 154.38, 140.44, 135.49, 135.33, 116.24, 94.44,
85.01, 56.18, 27.01, 22.78.
tert-Butyl
2-(4-(hydroxy(3-isopropyl-4-(methoxymethoxy)
phenyl)methyl)-3,5-dimethylphenoxy)acetate (11). A solution of 10
ꢀ
(10.21 g, 33.33 mmol), THF (140 mL), and 4 A molecular sieves (3 g)
was placed under reduced pressure for 1 min and then placed
under argon for 1 min. This process was repeated three times to
ensure a deoxygenated solution. The solution was then cooled to
0 ꢁC and an iPrMgCl solution (2 M THF, 25 mL, 50 mmol) was added.
The reaction mixture was then stirred at rt for 2.5 h where it was
then cooled to ꢀ78 ꢁC. A solution of 2 (5.87 g, 22.22 mmol) and THF
(11 mL) was then added and the reaction mixture was stirred at
ꢀ78 ꢁC for 2 h and at room temperature for 0.5 h. The reaction was
quenched with a 10% NH4Cl(aq) solution (200 mL) and extracted
with ethyl acetate (3ꢂ200 mL). The combined organic fractions
were washed with brine, dried with Mg2SO4, and concentrated
under reduced pressure. Purification of the residue with flash
chromatography (silica, 5%e20% ethyl acetate/hexanes) yielded 11
D6-Sobetirome (8). To a 0 ꢁC solution of 7 (818 mg, 1.50 mmol)
and THF (10 mL) was added TBAF (7 mL, 7 mmol). The solution was
stirred at room temperature for 1 h and then the reaction was
quenched with 0.5 M HCl. The aqueous layer was extracted three
times with ethyl acetate. The combined organic layers were washed
with brine, dried, and concentrated. Purification of the residue with
flash chromatography (silica, 0%e20% ethyl acetate/hexanes) yiel-
ded the desired product as a yellow residue. The residue was then
dissolved in methanol (20 mL) and 5 M NaOH (3 mL, 15 mmol) was
slowly added. The reaction mixture was stirred at room tempera-
ture for 1 h and then acidified with 1 M HCl. The aqueous mixture
was then extracted with ethyl acetate three times. The combined
organic layers were washed with brine, dried, and concentrated.
Purification of the residue with flash chromatography (silica, 0%e
5% MeOH/(DCMþ2% AcOH)) yielded D6-Sobetirome (8) (361 mg,
(7.0 g, 71%). 1H NMR (400 MHz, CDCl3):
d
7.23 (d, 1H, J¼2 Hz), 6.94
(d, 1H, J¼8 Hz), 6.88 (dd, 1H, J¼8.5 Hz, 2 Hz), 6.23 (d, 1H, J¼3.5 Hz),
5.17 (s, 2H), 4.49 (s, 2H), 3.48 (s, 3H), 3.30 (sept, 1H, J¼7 Hz), 2.23 (s,
6H), 1.49 (s, 9H), 1.19 (t, 6H, J¼7 Hz). 13C NMR (100 MHz, CDCl3):
d
168,156.8,153.2,138.8, 137.3, 136.2, 132.9,123.9,123.8,115.1, 113.7,
94.7, 82.4, 70.8, 56.1, 28.1, 27.2, 22.9, 21.1. HRMS exact mass calcd for
C
26H36O6 [MþNa]þ: 467.24041. Found 467.24053.
3H-Sobetirome (12). To a vial containing Sodium Borohydride
[3H] (American Radiolabeled Chemicals Inc., ART 0121, 250 mCi/
mmol, 25 mCi, 0.10 mmol) was added TFA (153 uL, 2.0 mmol).
This solution was stirred at rt for 10 min or until all of the solid
NaB3H4 dissolved. A solution of 11(14.8 mg, 0.033 mmol) and 500
uL of DCM was then added to the reaction vial and the contents
were stirred at room temperature for 10 min. The reaction was
quenched by adding 1.5 mL of water and the solution was stirred
for 5 min at room temperature. DCM (1 mL) was next added and
the organic layer was separated. The aqueous layer was further
extracted two more times with DCM and the combined organic
layers were washed with brine, dried, and concentrated with air.
The crude mixture was purified via preparatory TLC (silica, 5%
Methanol/DCMþ1% AcOH) to yield 12 (1.5 mg, 14%). A cold
standard of Sobetirome was spotted on the prep TLC plate and
the band corresponding to Sobetirome was scraped off the plate
and isolated from the silica gel with ethyl acetate. The specific
activity of the 3H-Sobetirome (12) was determined to be 6.90
mBq.
54%). 1H NMR (400 MHz, CD3OD):
6.52 (d,1H, J¼8.2 Hz), 6.44 (dd,1H, J¼8.2 Hz, 2 Hz), 4.55 (s, 2H), 3.82
(s, 2H), 3.10 (s, 1H), 2.14 (s, 6H). 13C NMR (100 MHz, CDCl3):
174.0,
d
6.76 (d,1H, J¼2 Hz), 6.58 (s, 2H),
d
155.4, 150.9, 138.9, 134.3, 132.1, 131.4, 126.3, 125.4, 115.3, 114.2, 64.9,
33.9, 26.8, 20.6. LRMS (ESI-): 333.32. HRMS exact mass calcd for
C
20H18D6O4 [MꢀH]ꢀ: 333.19675. Found 333.19710.
4-Iodo-2-isopropyl-1-(methoxymethoxy)benzene
(10).
To
a stirring solution of 2-isopropylphenol (9) (13.62 g, 100 mmol),
sodium iodide (14.98 g, 100 mmol) and methanol (300 mL), was
added 10 mL of a 10 M NaOH solution. The reaction mixture was
then cooled to 4 ꢁC and a solution of NaOCl (6% aq, 129 mL,
115 mmol) was slowly added dropwise over 18 h. The reaction
mixture was then allowed to stir at room temperature for 2 h. A 10%
Na2S2O3 solution (300 mL) was added followed by acidificiation of
the solution to neutral pH with conc. HCl. The solution was then
extracted with diethyl ether (3ꢂ300 mL). The combined organic
fractions were washed with brine, dried with MgSO4 and concen-
trated. Purification of the residue with flash chromatography (silica,
0%e75% dichloromethane/hexanes) gave 4-iodo-isopropylphenol
1-(Benzyloxy)-4-iodo-2-isopropylbenzene (13). To a solution of
4-iodo-isopropylphenol (16.18 g, 61.73 mmol) in DMF (200 mL) was
added K2CO3 (25.6 g, 185.2 mmol) and benzyl bromide (11 mL,
92.6 mmol). The reaction mixture was then stirred at 75 ꢁC for 16 h.
After cooling the solution the room temperature, the mixture was
then slowly poured into 600 mL of H2O and subsequently stirred at
rt for 15 min. The mixture was then extracted with hexanes
(3ꢂ500 mL). The combined organic fractions were washed with
water (3ꢂ500 mL), brine, dried with Mg2SO4, and concentrated
under reduced pressure. Purification of the residue with flash
chromatography (silica, 0%e2% ethyl acetate/hexanes) yielded 5
(19.6 g, 75%). 1H NMR (400 MHz, CDCl3)
d (ppm): 7.45 (1H, d,
j¼2 Hz), 7.35 (1H, dd, J¼8.4 Hz, 2 Hz), 6.52 (1H, d, J¼8.4 Hz), 3.14
(1H, septet, J¼7.2 Hz), 1.23 (6H, d, J¼7.2 Hz). To a solution of 4-iodo-
isopropylphenol (12.6 g, 48 mmol) in DCM (200 mL) was added
TBAI (1.77 g, 4.8 mmol) and 10 M NaOH (48 mL, 480 mmol). This
solution was stirred at room temperature for 10 min and MOM-Cl
(6 M in methyl acetate, 192 mmol, 32 mL) was then added. The
reaction mixture was then stirred at room temperature for 3 h. The
mixture was next diluted with 200 mL of H2O and subsequently
extracted with dichloromethane (3ꢂ200 mL). The combined
(16.7 g, 77%). 1H NMR (400 MHz, CDCl3):
d 7.41e7.24 (m, 5H), 6.91
(d, 1H, J¼2 Hz), 6.76 (d, 1H, J¼8.4 Hz), 6.63 (m, 3H), 4.97 (s, 2H), 4.58
(s, 2H), 3.89 (s, 2H), 3.30 (sept, 1H, J¼7.1 Hz), 2.17 (s, 6H), 1.14 (d, 6H,
J¼7.1 Hz). 13C NMR (100 MHz, CDCl3):
d 155.8, 140.3, 137.1, 134.5,
135.3, 128.7, 128.0, 127.2, 114.1, 83.9, 70.1, 27.0, 22.6.

A.T. Placzek, T.S. Scanlan / Tetrahedron 71 (2015) 5946e5951
5951
tert-Butyl
2-(4-((4-(benzyloxy)-3-isopropylphenyl)(hydroxy)
chromatography (silica, 5%e20% ethyl acetate/hexanes) yielded 17
(1.12 g, 87%). 1H NMR (400 MHz, CDCl3):
methyl)-3,5-dimethylphenoxy)acetate (15). The procedure to syn-
thesize 11 was used to synthesize 14. The partially purified solution
was then subjected to catalytic hydrogenation conditions. A solu-
tion of 14 (12.06 g, 25 mmol), 95% EtOH (150 mL) was placed under
reduced pressure for 1 min and then placed under argon for 1 min.
This process was repeated three times to ensure a deoxygenated
solution. With argon flowing into the rbf, 10% Pd/C (3 g) was added.
Lastly, Et3SiH (60 mL, 375 mmol) was added dropwise. The solution
was allowed to stir at room temperature for 24 h. The reaction
mixture was then filtered over Celite and concentrated. Purification
of the residue with flash chromatography (silica, 0%e20% ethyl
acetate/hexanes) yielded 15 (6.72 g, 70% overall yield (2 steps)). 1H
d
8.19 (d, 2H, J¼8.66 Hz),
7.62 (d, 2H, J¼8.72 Hz), 7.05 (d, 1H, J¼2.2 Hz), 6.85 (d, 1H, J¼2.2 Hz),
6.64 (s, 2H), 5.23 (s, 2H), 4.52 (s, 2H), 3.92 (s, 2H), 3.62 (s, 3H), 3.40
(sept, 1H, J¼7.26 Hz), 2.23 (s, 6H), 1.52 (s, 9H), 1.21 (d, 6H,
J¼7.26 Hz). 13C NMR (100 MHz, CDCl3):
d 168.5, 156.3, 154.4, 147.0,
142.4, 138.6, 136.3, 132.2, 130.49, 129.8, 129.54, 128.1, 123.8, 115.7,
114.4, 100.2, 92.6, 91.0, 82.4, 65.8, 57.8, 33.9, 28.2, 26.63, 23.5, 20.7.
HRMS exact mass calcd for C34H39NO7 [MþNH4]þ: 591.30648 found
591.30738.
{4-[4-Hydroxy-3-isopropyl-5-(4-nitrophenylethynyl)-benzyl]-
3,5-dimethylphenoxy}acetic acid (NH-3, 18). To a solution of 17
(201 mg, 0.351 mmol) and MeOH (5 mL) was added 2 M NaOH
(4.06 mL, 8.11 mmol). The reaction mixture was allowed to stir at
room temperature for 2 h and then concentrated to remove the
methanol. The mixture was then acidified with 20 mL of 1 M HCl
and the resulting aqueous layer was extracted three times with
DCM. The combined organic fractions were washed with brine,
dried with Mg2SO4, and concentrated under reduced pressure. The
crude mixture was then dissolved in 20 mL of THF and 6 mL of H2O.
Conc. HCl (2.0 mL) was added and the solution was stirred at room
temperature for 48 h. The reaction mixture was then diluted with
H2O and the resulting aqueous layer was extracted three times with
DCM. The combined organic fractions were washed with brine,
dried with Mg2SO4, and concentrated under reduced pressure.
Purification of the residue with flash chromatography (silica, 0%e
4% MeOH/DCMþ1% AcOH) yielded (NH-3, 18) (102 mg, 61%). 1H
NMR (400 MHz, CDCl3):
d
6.93 (d, 1H, J¼2 Hz), 6.63 (s, 2H), 6.58 (m,
2H), 4.70 (s, 1H), 4.52 (s, 2H), 3.91 (s, 2H), 3.17 (sept, 1H, J¼7 Hz),
2.24 (s, 6H), 1.5 (s, 9H), 1.27 (d, 6H, J¼7 Hz). 13C NMR (100 MHz,
CDCl3):
d 168.5, 156.0, 150.9, 138.5, 134.3, 132.3, 130.6, 126.2, 125.5,
115.2, 114.2, 82.3, 65.8, 33.8, 28.2, 27.2, 22.7, 20.6. HRMS exact mass
calcd for C24H32O4 [MþNa]þ: 407.21928. Found 407.21974.
tert-Butyl 2-(4-{[4-hydroxy-3-iodo-5-isopropylphenyl]methyl}-
3,5-dimethylphenoxy)acetate (16a). To a solution of 14(2.37 g,
6.16 mmol) and THF (45 mL) was added conc. NH3 (aq) (45 mL),
followed by I2 (1.88 g, 7.39 mmol). The reaction mixture was stirred
at room temperature for 2 h and then diluted with water. The
aqueous mixture was extracted with diethyl ether (3x) and the
combined organic layers were washed with brine, dried, and con-
centrated. Purification of the residue with flash chromatography
(silica, 5%e10% ethyl acetate/hexanes) yielded 16a (2.51 g, 80%). %).
1H NMR (400 MHz, CDCl3): 6.99 (d, 1H, J¼2 Hz), 6.88 (d,1H, J¼2 Hz),
6.65 (s, 2H), 5.18 (s, 1H), 4.54 (s, 2H), 3.88 (s, 2H), 3.26 (sept, 1H,
J¼7 Hz), 2.22 (s, 6H), 1.52 (s, 9H), 1.19 (d, 6H, J¼7 Hz). HRMS exact
mass calcd for C24H31IO4 [MþNa]þ: 533.11592 Found 533.11615.
tert-Butyl 2-(4-(3-iodo-5-isopropyl-4-(methoxymethoxy)benzyl)-
3,5-dimethylphenoxy)acetate (16b). To a solution of 16b (1.54 g,
3.39 mmol) in DMF (20 mL) was added Cs2CO3 (3.31 g, 10.17 mmol).
This solution was then cooled to 0 ꢁC and then MOM-Cl (6.5 M
Methyl Acetate, 0.783 mL, 5.09 mmol) was added. The solution was
allowed to slowly warm to room temperature over two hours. The
reaction mixture was then diluted with 100 mL of H2O and sub-
sequently extracted with diethyl ether (3ꢂ200 mL). The combined
organic fractions were washed with brine, dried with Mg2SO4, and
concentrated under reduced pressure. Purification of the residue
with flash chromatography (silica, 10% ethyl acetate/hexanes)
NMR (400 MHz, CDCl3):
d
8.20 (d, 2H, J¼8.7 Hz), 7.64 (d, 2H,
J¼8.7 Hz), 7.02 (d, 1H, J¼2 Hz), 6.70 (d, 1H, J¼2 Hz), 6.66 (s, 2H), 5.30
(br, 1H), 4.69 (s, 2H), 3.90 (s, 2H), 3.26 (sept, 1H, J¼6.8 Hz), 2.21 (s,
6H), 1.20 (d, 6H, J¼6.8 Hz). Matches the reported spectrum of
Nguyen, NeH., et al. J Med Chem. 2002, 45, 3310e3320.
Acknowledgements
This work was supported by a grant from the National Institutes
of Health (DK-52798, T.S.S.)
Supplementary data
Supplementary data (1H NMR spectra of the following com-
pounds (2, 3, 6, 8, 10, 11, 13, 15, 16a, 16b, 17, 18). ) related to this
article can be found at http://dx.doi.org/10.1016/j.tet.2015.05.049.
yielded 10 (1.47 g, 78%). 1H NMR (400 MHz, CDCl3):
d 7.18 (d, H,
J¼2 Hz), 6.91 (d, 1H, J¼2 Hz), 6.64 (s, 2H), 5.03 (s, 2H), 4.53 (s, 2H),
References and notes
3.90 (s, 2H), 3.66 (s, 3H), 3.38 (sept, 1H, J¼7 Hz), 2.21 (s, 6H), 1.53 (s,
9H), 1.15 (d, 6H, J¼7 Hz). 13C NMR (100 MHz, CDCl3):
d 168.43, 156.2,
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