Synthesis of oxazolidinedione derived bicalutamide analogs

Article abstract of DOI:10.1016/j.tetlet.2006.03.146

The synthesis of chiral oxazolidinedione derived bicalutamide analogs has been discussed.

Full text of DOI:10.1016/j.tetlet.2006.03.146

Tetrahedron Letters 47 (2006) 3953–3955
Synthesis of oxazolidinedione derived bicalutamide analogs
a
a
a
Vipin A. Nair, Suni M. Mustafa, Michael L. Mohler,
b
a,
*
James T. Dalton and Duane D. Miller
a
Department of Pharmaceutical Sciences, University of Tennessee, 847 Monroe Avenue, RM 227 C, Memphis, TN 38163, USA
b
Department of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
Received 14 February 2006; revised 16 March 2006; accepted 16 March 2006
Available online 24 April 2006
Abstract—The synthesis of chiral oxazolidinedione derived bicalutamide analogs has been discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
In our earlier investigations, we developed a series of
second generation androgen receptor binding ligands
by the molecules, it was highly imperative to have a suit-
able molecular model, which did not have free hydroxyl
and amide protons and above all was conformationally
restricted to a structure similar to 1c. Accordingly, we
decided to interlock the amide nitrogen and the hydr-
oxyl oxygen by a carbonyl functionality, which led to
the design of structure 1d, an oxazolidinedione deriva-
tive. As of this day, no literature reports are available
on the synthesis of chiral oxazolidinedione derived bica-
lutamide analogs and hence we devised and attempted a
stereoselective synthesis of this molecule, the details of
which form the subject matter of the present letter.
1
b (Fig. 1), which were analogous to bicalutamide 1a
1
–4
in structure.
Biological testing of these compounds
exhibited high binding affinities and biological activi-
5
–8
ties.
Based on the results obtained and homology
modeling, we had earlier reported the binding interac-
tions between the androgen receptor and the ligands.9–11
Examination of torsional strain parameters and
hydrogen bonding interactions revealed that the mole-
cule adopts a conformation similar to 1c. The hydroxyl
group a to the carbonyl undergoes positioning in such a
manner that it enters into hydrogen bonding interaction
with Aspargine705 of the receptor. The amino group
forms a weak hydrogen bond with the back bone oxygen
of Leucine704. The computational predictions made
were in agreement with the results obtained from the
binding assays. However, to convincingly establish the
aforesaid interactions and the conformation adopted
Pyrrolidine-2-carboxylic acid 2 was acylated by Schotten
Baumann reaction to obtain methacryloyl pyrrolidine-2-
carboxylic acid 3, which was subsequently lactonized to
obtain bromolactone 4, according to the procedure that
1
2,13
we reported recently.
Nucleophilic substitution of
0
compound 4 with 4 -fluorobenzenethiol under alkaline
NC
F
R1
R2
R3
R1
R2
R3
R1
R2
R3
O
O
O
O
A
B
A
B
A
B
O
S
F3C
N
N
H
X
N
H
X
CH3
N
X
CH3
H
HO CH O
HO CH3
O
O
3
H
O
1
a
1b
1c
1d
(
R,S)-Bicalutamide
Figure 1. Reagents: R
1
= NO
2
, CN; R
2
= CF
3
3 2 2
, Cl, I; R = F, Cl, Br, I; X = O, NH, S, SO , CH .
Keywords: Oxazolidinedione; Bicalutamide; Enantiomers; Androgen; Receptor.
*
Corresponding author. Tel.: +1 901 448 6026; fax: +1 901 448 3446; e-mail: dmiller@utmem.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.146

3954
V. A. Nair et al. / Tetrahedron Letters 47 (2006) 3953–3955
H
H
H
H
a
b
c
O
O
COOH
N
N
N
COOH
N
O
O
H
O
O
Br
O
S
H C
H C
3
3
CH3
2
3
4
5
F
d
H
HO
O
OH
S
H
CBr3
O
HO
OH
e
f
g
N
O
O
O
H3C
O
O
Br
H3C
Br
O
H3C
Br
6
4
7
8
F
0
Scheme 1. Reagents: (a) methacryloyl chloride, NaOH, acetone; (b) NBS, DMF; (c) NaOH, 4 -fluorobenzenethiol, 2-propanol; (d) concd HCl; (e)
0
2
4% HBr; (f) tribromoacetaldehyde, concd H
2
SO
4
; (g) (1) NaOH, 4 -fluorobenzenethiol, 2-propanol, (2) concd HCl.
conditions in 2-propanol medium afforded compound 5.
However, hydrolysis of compound 5 under acidic
conditions did not afford the desired chiral hydroxy acid
tion of oxazolidinedione must have occurred through
the nucleophilic displacement of silver sulfide from the
imino carbon by the hydroxy group followed by a con-
certed cyclic rearrangement as illustrated by intermedi-
ate structures 11a and 11b depicted in Scheme 2; a
mechanism identical to that established by Shibuya
6
. Since our initial attempt failed to give 6, we decided to
reinvestigate the synthesis of chiral hydroxy acid 6
Scheme 1), as we knew from our earlier experiments
(
1
5
that the hydrolysis of bromolactone 4 using HBr solu-
et al. HPLC analysis of this product on a p accep-
tor/donor (R,R)-Whelk-O1 chiral column exhibited
two peaks in the ratio 70:30 corresponding to the two
enantiomers, with an enantiomeric excess of 40%.
Efforts are ongoing to extend the excellent separation
of the enantiomers obtained in the aforesaid analytical
chiral column to the corresponding preparative column
in order to obtain quantitative yields of the enantiomers
and thereby determine their absolute configurations
with exciton coupled vibrational circular dichroism
and infrared spectroscopy along with the aid of Guas-
sian empirical calculations. Studies will also be carried
out in determining the binding affinities between the
ligand and the androgen receptor, and also the structure
activity relationships. Future investigations will be
aimed at replacing the oxygen atom of the heterocyclic
ring system by an amino group so as to obtain enantio-
tion under reflux conditions would give 3-bromo-2-
1
2
hydroxy-2-methylpropanoic acid 7 in excellent yields.
The hydroxy and carboxyl groups of compound 7 were
then protected with tribromoacetaldehyde under acidic
1
4
conditions to obtain compound 8, which was coupled
0
with 4 -fluorobenzenethiol. Acidification of the reaction
mixture with concd HCl followed by workup and isola-
1
4
tion afforded chiral hydroxy acid 6 in good yields. Un-
like intermediate 5, in this case, the hydrolysis of the
protecting group was easily achieved upon acidification.
4
-Nitro-3-trifluoromethylaniline 9 was converted to the
corresponding isothiocyanate 10. Cyclocondensation of
isothiocyanate 10 with chiral hydroxy acid 6 afforded
oxazolidinedione 12 as an yellow oil, which was charac-
1
4
terized by spectral and elemental analyses. The forma-
O N
2
O N
2
i
O2N
F3C
N
O
O
CH3
h
S
S
HO
O
OH
..
F3C
NH2
F3C
NCS
Ag
HO
1
0
S
F
9
11a
H3C
6
F
O N
N
O
O
O2N
F3C
2
O
CH3
S
CH3
O
F3C
N
S
O
F
O
F
1
1b
12
3
Scheme 2. Reagents: (h) thiophosgene, chloroform, NaHCO ; (i) silver trifluoroacetate, triethylamine, acetonitrile.

V. A. Nair et al. / Tetrahedron Letters 47 (2006) 3953–3955
3955
meric hydantoin analogs of bicalutamide, which would
then provide an additional site for hydrogen bonding
interaction with the receptor.
extracted with ethyl acetate, dried over anhydrous sodium
sulfate, and concentrated to obtain compound 8, which
appeared as white crystals upon recrystallization from
ethyl acetate–hexane. The compound was characterized by
spectral and elemental analyses. Yield: 89%; mp 97 °C;
1
NMR ( H, 300 MHz, CDCl
3
): 1.8 (s, 3H, CH
3
), 3.7 (s, 2H,
Acknowledgments
CH ), 5.8 (s, 1H, CH); C H Br O Calcd: C, 16.17; H,
2
6
6
4
3
1
.36. Found: C, 16.08; H, 1.25.
Preparation of compound 6: Compound 8 (4.8 mmol,
.1 g), dissolved in a 1:1 mixture of 2-propanol and 1 M
Financial supports in the form of grants from the
Department of Defense (DOD) (Grant No: DAMD17-
2
0
1-1-0103), the National Institute of Health (NIH)
NaOH, was stirred at room temperature. After 3 h, when
no starting material was detectable by TLC, 4 -fluoroben-
(
Grant No: DK 065227), GTx Inc., and a pre-doctoral
0
fellowship for Michael L. Mohler from the American
Chemical Society (Division of Medicinal Chemistry)
are gratefully acknowledged.
zenethiol (4.8 mmol, 0.6 g) was added and the reaction
mixture was stirred overnight. The reaction mixture was
then adjusted to pH 1 with concd HCl, extracted with
ethyl acetate, and dried over anhydrous sodium sulfate.
The organic layer was concentrated to obtain an oil. Flash
column chromatography of the reaction mixture in
hexane–ethyl acetate–acetic acid mixture followed by
recrystallization in ethyl acetate–hexane afforded com-
pound 6 as colorless needle shaped crystals. The product
was characterized by spectral and elemental analyses.
References and notes
1
. Dalton, J. T.; Mukherjee, A.; Zhu, Z.; Kirkovsky, L.;
Miller, D. D. Biochem. Biophys. Res. Commun. 1998, 244,
1
.
2
5
Yield: 65%; mp 54 °C; ½aꢀ +24.85 (c 1.0, MeOH); NMR
2
. Mukherjee, A.; Kirkovsky, L. I.; Kimura, Y.; Marvel, M.
D
1
(
3 3
H, 300 MHz, CDCl ): 1.5 (s, 3H, CH ), 3.2 (d, 1H, CH),
M.; Miller, D. D.; Dalton, J. T. Biochem. Pharmacol.
3
2
.4 (d, H, CH), 7.0 (m, 2H, Ar, J = 2.0, 8.9 Hz), 7.5 (m,
H, Ar, J = 2.0, 8.9 Hz); MS: No parent ion peak;
1
999, 58, 1259.
3
. Kirkovsky, L.; Mukherjee, A.; Yin, D.; Dalton, J. T.;
Miller, D. D. J. Med. Chem. 2000, 43, 581.
10 3
C H11FO S Calcd: C, 52.16; H, 4.82. Found: C, 52.05;
H, 4.76.
Preparation of compound 12: 4-Nitro-3-trifluoromethyl-
aniline 9 (23.0 mmol, 4.7 g) was converted to the corre-
sponding isothiocyanate 10 by adding thiophosgene
4
. Marhefka, C. A.; Moore, B. M., II; Bishop, T. C.;
Kirkovsky, L. I.; Mukherjee, A.; Dalton, J. T.; Miller, D.
D. J. Med. Chem. 2001, 44, 1729.
5
. Yin, D.; Gao, W.; Kearbey, J. D.; Xu, H.; Chung, K.; He,
Y.; Marhefka, C. A.; Veverka, K. A.; Miller, D. D.;
Dalton, J. T. J. Pharmacol. Exp. Ther. 2003, 304, 1334.
. Yin, D.; Xu, H.; He, Y.; Kirkovsky, L. I.; Miller, D. D.;
Dalton, J. T. J. Pharmacol. Exp. Ther. 2003, 304, 1323.
. Gao, W.; Kearbey, J. D.; Nair, V. A.; Chung, K.; Parlow,
A. F.; Miller, D. D.; Dalton, J. T. Endocrinology 2004,
(
25 mmol, 1.9 mL) and excess sodium bicarbonate in
chloroform medium at 0 °C, followed by overnight stirring
at room temperature. The reaction mixture was concen-
trated, extracted into ethyl acetate and purified by flash
column chromatography using hexane–ethyl acetate mix-
ture to afford compound 10, which appeared as an yellow
oil. To the mixture of hydroxy acid 6 (4.1 mmol, 0.9 g) and
6
7
1
45, 5420.
4
-nitro-3-trifluoromethylphenylisothiocyanate 10 (3.9
8
. Chen, J.; Hwang, D. J.; Bohl, C. E.; Miller, D. D.; Dalton,
J. T. J. Pharmacol. Exp. Ther. 2005, 312, 546.
. Marhefka, C. A.; Gao, W.; Chung, K.; Kim, J.; He, Y.;
Yin, D.; Bohl, C.; Dalton, J. T.; Miller, D. D. J. Med.
Chem. 2004, 47, 993.
mmol, 0.9 g) in acetonitrile, silver trifluoroacetate (8.2
mmol, 1.8 g), and triethyl amine (12.3 mmol, 1.8 mL) were
added with stirring and the reaction mixture was heated to
reflux for 1 h. After removal of silver sulfide by filtration
and evaporation of the solvent under reduced pressure, the
resulting residue was washed with water, extracted into
ethyl acetate, and concentrated. The desired product,
isolated by flash column chromatography using a hexane–
ethyl acetate mixture, appeared as an yellow oil. The
compound was identified on the basis of spectral and
9
1
0. Bohl, C. E.; Chang, C.; Mohler, M. L.; Chen, J.; Miller,
D. D.; Swaan, P. W.; Dalton, J. T. J. Med. Chem. 2004,
4
7, 3765.
1
1
1. Bohl, C. E.; Gao, W.; Miller, D. D.; Bell, C. E.; Dalton, J.
T. Proc. Natl. Acad. Sci. 2005, 102, 6201.
2. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Fisher, S. J.;
Dalton, J. T.; Miller, D. D. Tetrahedron Lett. 2004, 45,
2
5
analytical data. Yield : 52%; ½aꢀ +39.7 (c 1.0, MeOH);
D
1
NMR ( H, 500 MHz, CDCl ): 1.8 (s, 3H, CH ), 3.2 (s, 1H,
9
475.
3
3
CH), 3.3 (s, 1H, CH), 6.9 (m, 2H, Ar, J = 2.0, 8.9 Hz), 7.2
m, 2H, Ar, J = 2.0, 8.9 Hz), 7.9 (m, 1H, Ar, J = 2.1,
.0 Hz ), 8.0 (m, 1H, Ar, J = 0.5, 2.1 Hz), 8.1 (m, 1H, Ar,
1
3. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Yang, J.;
Kirkovsky, L. I.; Dalton, J. T.; Miller, D. D. Tetrahedron
Lett. 2005, 46, 4821.
(
9
1
3
J = 0.5, 9.0 Hz); NMR ( C, 500 MHz, CDCl ): 22.8,
1
4. Preparation of compound 8: Tribromoacetaldehyde
3
4
1
3.4, 86.7, 117.0, 117.3, 124.4, 124.5, 124.6, 125.0, 126.8,
29.3, 134.2, 134.3, 135.3, 164.9, 172.8; MS: No parent ion
(
26.0 mmol, 2.8 mL) and compound 7 (22.0 mmol, 4.0 g)
were cooled to 0 °C under argon atmosphere, and concd
sulfuric acid (10 mL) was added drop-wise with stirring.
After 2 h the solution turned dark; the ice bath was
removed and the reaction mixture was stirred overnight at
room temperature. The solution was diluted with ice and
peak; C H F N O S Calcd: C, 48.65; H, 2.72; N, 6.30.
18 12
4
2
5
Found: C, 48.59; H, 2.70; N, 6.31.
1
5. Shibuya, I.; Goto, M.; Shimizu, M.; Yanagisawa, M.;
Gama, Y. Heterocycles 1999, 51, 2667.