A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol

Article abstract of DOI:10.1016/j.bmcl.2005.10.039

An asymmetric route was developed for the synthesis of a class of novel glucocorticoid receptor ligand derivatives 1. The key step of this synthesis involves a diastereoselective addition of chiral sulfoxide anion to a trifluoromethyl ketone precursor. Th

Full text of DOI:10.1016/j.bmcl.2005.10.039

Bioorganic & Medicinal Chemistry Letters 16 (2006) 654–657
A concise asymmetric route for the synthesis of a novel
class of glucocorticoid mimetics containing
a trifluoromethyl-substituted alcohol
Thomas W. Lee,* John R. Proudfoot and David S. Thomson
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road,
PO Box 368, Ridgefield, CT 06877-0368, USA
Received 9 August 2005; revised 7 October 2005; accepted 12 October 2005
Available online 2 November 2005
Abstract—An asymmetric route was developed for the synthesis of a class of novel glucocorticoid receptor ligand derivatives 1. The
key step of this synthesis involves a diastereoselective addition of chiral sulfoxide anion to a trifluoromethyl ketone precursor. The
resulting diastereomers are readily separable and can be converted to the corresponding chiral epoxide and chiral alkyne interme-
diates (2 and 3). This sequence of reactions is suitable for large-scale preparation of these chiral intermediates and derivatives of 1.
The absolute stereochemistry of the biologically active enantiomer of these GR ligands has also been determined.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Glucocorticoids (GCs) and their derivatives such as
dexamethasone and prednisolone1 belong to a class of
steroidal ligands that targets the glucocorticoid receptor
(GR). These agents, which modulate GR function, have
found wide use in the treatment of various inflammato-
ry, autoimmune, and allergic disorders.2 Recently, we
have disclosed a novel series of GR ligands that belongs
to the trifluoromethyl alcohol class typified by 1.3 To
access this class we have employed epoxide 2 and alkyne
3 as key intermediates.3 Described herein is an asymmet-
ric route to these two synthetic intermediates and its
application to the determination of the absolute stereo-
chemistry of the biologically active enantiomer of this
class of GC mimetics.
This chiral process can be illustrated by the synthesis of
chiral epoxide 7a and its enantiomer 7b as outlined in
Scheme 1. The key step involves a diastereoselective
addition of chiral sulfoxide anion to a trifluoromethyl
ketone to form the corresponding chiral b-hydroxy-b-
trifluoromethyl-sulfoxide adducts. In the literature,
there are limited examples of such diastereoselective
addition to fluorinated ketones.4 Thus, reaction of
trifluoromethyl ketone 4 with the lithium anion of (R)-
(+)-methyl p-tolylsulfoxide in THF at À78 ꢁC afforded a
mixture of the corresponding chiral sulfoxides 5a and b
(dr = 2.1:1). These diastereomers were easily separated
by column chromatography with the faster eluting
product being the major diastereomer 5a. The optical
purity was determined to be >99% de for both isomers
by HPLC analyses.5 X-ray crystallographic analysis
allowed assignment of 5a as the (S,R)-isomer (Fig. 1).6
CF3
R2
R1
HO
Each of the separated diastereomers was then reduced
using sodium iodide and trifluoroacetic anhydride in
acetone at À40 ꢁC to afford the corresponding thiol
ethers 6a and b in quantitative yields.7 Treatment of
the thiol ether enantiomers with trimethyloxonium
tetrafluoroborate in CH2Cl2 followed by addition of
aqueous potassium carbonate solution provided the
desired chiral epoxides 7a and b in optically pure form.8
This sequence of reactions was applied to the synthesis
of several other chiral epoxides (R)-2 and the results
are summarized in Table 1. In all cases, similar yields
1
CF3
HO
CF3
O
R1
R1
2
3
Keywords: Glucocorticoid receptor; Steroid mimetics; Asymmetric
synthesis.
*
Corresponding author. Tel.: +1 203 798 5016; fax: +1 203 791
6072; e-mail: tlee2@rdg.boehringer-ingelheim.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.039

T. W. Lee et al. / Bioorg. Med. Chem. Lett. 16 (2006) 654–657
655
O
S
CF3
HO
O
CF3
CF3
O
O
O
S
b
c
HO
6a
O
F
O
5a
7a
F
F
F
a
+
CF3
O
S
CF3
O
CF3
CF3
O
O
4
S
O
b
c
HO
5b
HO
6b
7b
F
F
F
Scheme 1. Reagents and conditions: (a) lithium diisopropylamide, (R)-(+)-methyl p-tolylsulfoxide, THF, À78 ꢁC, 91% (5a:5b = 2.1:1); (b) NaI,
trifluoroacetic anhydride, acetone, À40 ꢁC, >99%; (c) trimethyloxonium tetrafluoroborate, CH2Cl2, rt, then aq K2CO3, rt, 95%.
and selectivity were observed. The enantiomeric epox-
ides (S)-2, if desired, can be specifically targeted using
(S)-(À)-methyl p-tolylsulfoxide.
These chiral epoxides can be ring-opened by various car-
bon, oxygen, nitrogen, and sulfur nucleophiles to afford
derivatives of formula 1 or their precursors.3 As an
example, treatment of 7a with lithium trimethylsilylacet-
ylide in DMSO followed by desilylation afforded chiral
alkyne intermediate 8 (Scheme 2). The alkyne moiety
in 8 is a versatile synthetic handle and can be converted
to a variety of heteroaryl groups such as indoles and
azaindoles.3
In order to determine the absolute stereochemistry of
the more biologically active enantiomer of this class of
GR ligands, compounds 9a and b were separately
prepared from the corresponding chiral epoxides 7a
and b (Scheme 3) and tested in a glucocorticoid receptor
Figure 1. X-ray crystal structure of 5a.
CF3
HO
O
CF3
O
O
a,b
Table 1. Synthesis of chiral epoxides
CF3
O
7a
8
F
F
R1
Scheme 2. Reagents and conditions: (a) lithium trimethylsilylacetylide,
DMSO, rt; (b) tetrabutylammonium fluoride, THF, rt, 60% (two
steps).
(R) -2
Entry R1
Sulfoxide % Thiol ether % Epoxide %
yield
yield (dr)
yield
Cl
CF3
HO
O
CF3
O
O
a
1
85 (2.1:1)
>99
78
7a
9a
F
F
F
GR IC50 = 99 nM
O
Cl
2
3
80 (2.2:1)
65 (2.1:1)
99
99
95
95
CF3
HO
O
CF3
O
a
O
Cl
O
7b
9b
F
F
GR IC50 = 2000 nM
Scheme 3. Reagents and conditions: (a) p-chlorophenylmagnesium
bromide, CuI, ether, rt, 28–30%.
Br

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T. W. Lee et al. / Bioorg. Med. Chem. Lett. 16 (2006) 654–657
binding assay.9 Compound 9a was shown to be the more
potent enantiomer in this binding assay with a GR bind-
ing IC50 of 99 nM. In contrast, compound 9b was less
active in this assay (IC50 = 2000 nM).10 It should be not-
ed that the desired enantiomer 9a is derived from the
major sulfoxide diastereomer 5a.
À78 ꢁC was added lithium diisopropylamide (LDA)
mono(tetrahydrofuran) (1.5 M solution in cyclohexane,
122 mL, 183 mmol) for over 30 min. The resulting clear
yellow solution was stirred for 15 min. 1,1,1-Trifluoro-4-(5-
fluoro-2-methoxyphenyl)-4-methylpentan-2-one 4 (46.3 g,
166 mmol) dissolved in 125 mL THF was then added via
cannula over 30 min. After 1.5 h at À78 ꢁC, the reaction
mixture was quenched with water and extracted with
EtOAc. The combined organic phases were washed with
saturated aqueous sodium bicarbonate (NaHCO3) solu-
tion, washed with brine, dried over sodium sulfate
(Na2SO4), filtered, and concentrated in vacuo. Purification
by column chromatography with silica gel (eluted with 10–
30% EtOAc/hexanes) afforded sequentially (S)-1,1,1-triflu-
oro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-
4-sulfinylmethyl)pentan-2-ol 5a (44.2 g, 62%) and (R)-1,1,1-
trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-tol-
uene-4-sulfinylmethyl)pentan-2-ol 5b (20.6 g, 29%). The
diastereomeric excess was determined to be >99% for both
isomers (HPLC peak area).5
In summary, a concise asymmetric route was developed
for the synthesis of a class of glucocorticoid receptor li-
gand derivatives 1. The key step of this synthesis is a dia-
stereoselective addition of chiral sulfoxide anion to a
trifluoromethyl ketone precursor. The resulting diaste-
reomers are readily separable and can be converted to
the corresponding chiral epoxide and chiral alkyne inter-
mediates. This sequence of reactions is suitable for large-
scale preparation of these chiral intermediates and deriv-
atives of formula 1. The absolute stereochemistry of the
more biologically active enantiomer of these GR ligands
has also been determined.
(b) To a suspension of (S)-1,1,1-trifluoro-4-(5-fluoro-2-
methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pen-
tan-2-ol 5a (44.2 g, 102 mmol) and sodium iodide (46.0 g,
307 mmol) in 600 mL of anhydrous acetone at À40 ꢁC was
added a solution of trifluoroacetic acid anhydride (72.2 mL,
511 mmol) in 200 mL of anhydrous acetone via an addition
funnel dropwise over 30 min. A greenish brown mixture was
formed instantaneously. After 15 min, the reaction mixture
was quenched with saturated aqueous sodium sulfite
(Na2SO3) solution, and neutralized with saturated aqueous
sodium carbonate (Na2CO3) solution. The brown color
disappeared and the crude product was concentrated to
remove most of the acetone solvent. The resulting material
was diluted with water and extracted with ether. The
combined organic phases were washed with brine, dried
over magnesium sulfate (MgSO4), filtered, and concentrat-
ed in vacuo to afford (S)-1,1,1-trifluoro-4-(5-fluoro-2-
methoxyphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-
2-ol 6a as an orange oil (42.7 g, >99%).
(c) To a solution of (S)-1,1,1-trifluoro-4-(5-fluoro-2-meth-
oxyphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol 6a
(42.7 g, 102 mmol) in 250 mL of anhydrous dichlorometh-
ane was added trimethyloxonium tetrafluoroborate (22.7 g,
153 mmol). The resulting suspension was stirred at room
temperature for 4.5 h. A solution of potassium carbonate
(42.4 g, 307 mmol) in 250 mL of water was then added.
After 16 h, the reaction mixture was poured into saturated
aqueous sodium bicarbonate solution and extracted with
dichloromethane. The combined organic phases were
washed with brine, dried over magnesium sulfate, filtered,
and concentrated in vacuo. Purification by column chro-
matography with silica gel (eluted with 0–2% EtOAc/
hexanes) afforded the title compound 7a as a pale yellow oil
(28.3 g, 95%).
References and notes
1. Parente, L. In Glucocorticoids; Goulding, N. J., Flowers,
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references cited therein.
2. Toogood, J. In Glucocorticoids; Goulding, N. J., Flowers,
R. J., Eds.; Birkhauser: Boston, 2001; pp 161–174, and the
references cited therein.
3. (a) Bekkali, Y.; Cardozo, M. G.; Kirrane, T. M.;
Kuzmich, D.; Proudfoot, J. R.; Takahashi, H.; Thomson,
D.; Wang, J.; Zindell, R.; Harcken, C. H. J. J.; Razavi, H.
PCT Int. Appl. WO 03/082787, 2003. (b) Bekkali, Y.;
Betageri, R.; Gilmore, T. A.; Cardozo, M. G.; Kirrane, T.
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Kuzmich, D.; Lee, T. W.; Proudfoot, J. R.; Regan, J. R.;
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Kolytcheva, M. T.; Kukhar, V. P.; Meille, S. V.; Viani,
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5. HPLC analyses were done using a Supelco SUPELCO-
SILTM ABZ + Plus column (4.6 mm · 10 cm) and a gradi-
ent elution from 5% acetonitrile/95%water (+0.05% TFA)
to 100% acetonitrile (+0.05% TFA).
6. CCDC 286063 contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
9. Fluorescence polarization competitive binding assays were
performed to quantitate the ability of test compounds to
displace ligands from GR in solution. Binding reactions
were assembled in 96-well microplates and consisted of
Baculovirus lysate containing GR, 5 nM tetramethyl–rho-
damine conjugates of dexamethasone, and test compound
dilutions in an assay buffer containing 10 mM TES, 50 mM
KCl, 20 mM sodium molybdate, 1.5 mM EDTA, 0.04% w/
v CHAPS, 10% v/v glycerol, and 1 mM DTT, pH = 7.4.
IC50 values reported are means from at least two separate
experiments each consisting of duplicate 11-point concen-
tration-effect curves. The authors would like to acknowl-
edge Dr. Richard M. Nelson and his group (Department of
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuti-
cals Inc.) for testing 9a and b in this assay.
´
´
7. Arnone, A.; Biagini, G.; Cardillo, R.; Resnati, G.; Begue,
J.-P.; Bonnet-Delpon, D.; Kornilov, A. Tetrahedron Lett.
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reduction method for the synthesis of chiral b-hydroxy-b-
trifluoromethyl thiol ether and its subsequent conversion
to a chiral trifluoromethyl-substituted epoxide.
8. Representative procedures: synthesis of (R)-2-[2-(5-fluoro-
2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxira-
ne.
(a) To a suspension of (R)-(+)-methyl p-tolylsulfoxide
(28.2 g, 183 mmol) in 200 mL of anhydrous THF at

T. W. Lee et al. / Bioorg. Med. Chem. Lett. 16 (2006) 654–657
657
10. Betageri, R.; Zhang, Y.; Zindell, R. M.; Kuzmich, D.;
Kirrane, T. M.; Bentzien, J.; Cardozo, M.; Capolino,
A. J.; Fadra, T. N.; Nelson, R. M.; Paw, Z.; Shih,
D.-T.; Shih, C.-K.; Zuvela-Jelaska, L.; Nabozny, G.;
Thomson, D. S. Bioorg. Med. Chem. Lett. 2005, 15,
4761, Additional biological data and SAR information
of this class of GC mimetics will be reported in due
course.