A practical synthesis for (S)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione and its application in the synthesis of a novel liver X receptor β-selective agonist

Article abstract of DOI:10.1016/j.tetasy.2015.11.007

In this manuscript, the chiral separation of novel liver X receptor (LXR) β-selective agonist (±)-1 revealed that (S)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (+)-2 was the essential moiety (tail) to express LXR β-selective agonistic a

Full text of DOI:10.1016/j.tetasy.2015.11.007

Tetrahedron: Asymmetry 27 (2016) 63–68
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A practical synthesis for (S)-5-(4-(1-methylethoxy)phenyl)-
5-methylimidazolidine-2,4-dione and its application in the
synthesis of a novel liver X receptor b-selective agonist
⇑
Minoru Koura, Hisashi Sumida, Yukiyoshi Yamazaki, Kimiyuki Shibuya
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this manuscript, the chiral separation of novel liver X receptor (LXR) b-selective agonist ( )-1 revealed
that (S)-5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione (+)-2 was the essential moiety
(tail) to express LXR b-selective agonistic activity in a head-to-tail molecular design. The requisite con-
figuration of (+)-2 was determined as the (S)-form by X-ray crystal structure analysis of (+)-halogenated
4. We obtained (S)-methyl 2-amino-2-(4-(1-methylethoxy)phenyl)propionate (+)-7 by resolution with
Received 16 October 2015
Accepted 21 November 2015
Available online 14 December 2015
L-mandelic acid and established a practical synthesis for (+)-2.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
the high-density lipoprotein cholesterol (HDL-C) levels and to
serve in cholesterol efflux and excretion.3
Recently we discovered that 3-(4-(4-(1,1,1,3,3,3-hexafluoro-
2-hydroxypropan-2-yl)-2,6-di-n-propylphenoxy)butyl)-5-(4-(1-
methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione ( )-1 acts
as a liver X receptor (LXR) b-selective agonist for the treatment of
atherosclerotic lesions (Fig. 1).1
Despite these therapeutic expectations, non-selective agonists,
including T0901317 and GW3965, exhibited elevations in plasma
and hepatic triglyceride levels as significant side effects.4 This lipo-
genesis originates from the expression of sterol regulatory ele-
ment-binding protein-1c (SREBP-1c), which is induced by LXR
a
activation. In order to suppress this undesirable effect in the LXR
agonist, we developed LXR b-selective agonists and discovered
( )-1. However, it has not been elucidated how much the chirality
of molecule 1 affects the LXRb agonistic activity. Therefore, our
attention was focused on the enantiomers of ( )-1, especially the
physiological role of the stereogenic center of 5-(4-(1-methy-
OH
F3C
O
F3C
*
O
N
O
O
NH
lethoxy)phenyl)-5-methyl-imidazolidine-2,4-dione
(hydantoin)
( )-2.1
1
Figure 1. Discovery of LXR b-selective agonist ( )-1.
2. Results and discussion
LXRs are ligand-activated transcription factors involved in
cholesterol metabolism, glucose homeostasis, inflammation, and
2.1. Direct chiral separation of racemate ( )-1 by HPLC and an
evaluation of both of the enantiomers in GAL4-LXR
luciferase assays
a and LXRb
lipogenesis.2 LXR
a (known as NR1H3) is the dominant subtype in
the liver, small intestine, and macrophages, whereas LXRb (known
as NR1H2) is distributed ubiquitously. LXR activation is known to
regulate the ATP-binding cassette transporter A1 (ABCA1), ABCG1,
and ABCG5/G8 expression and cholesterol metabolism to increase
In order to study the properties of each enantiomer, we sepa-
rated racemate ( )-1 using high performance liquid chromatogra-
phy (HPLC) on a CHIRALPAK AS-H column and evaluated the
obtained enantiomers in GAL4-LXR
Interestingly, (+)-1 {[
20 = +32.2 (c 1.0, MeOH)} showed potent
LXRb activity accompanied by weak LXR
a and LXRb luciferase assays.
a]
D
a
activity, whereas
⇑
Corresponding author. Tel.: +81 423916211; fax: +81 423950312.
E-mail address: k-sibuya@kowa.co.jp (K. Shibuya).
http://dx.doi.org/10.1016/j.tetasy.2015.11.007
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

64
M. Koura et al. / Tetrahedron: Asymmetry 27 (2016) 63–68
Figure 2. The in vitro activity of each enantiomer (+)-1 and (À)-1.
anti-pod (À)-1 {[
a
]
20 = À33.3 (c 1.0, MeOH)} markedly lost both of
2.3. Determination of the absolute configuration of (+)-2 using
halogenated hydantoins (+)-Cl-4 and (+)-Br-4
D
the LXRa and LXRb activities, as shown in Figure 2.
We concluded that the chirality of hydantoin plays a key role in
the expression of the LXR b-selective activity.
In order to determine the absolute configuration of (+)-2 defi-
nitely using X-ray crystal structure analysis, we halogenated
hydantoins (+)-2 with N-chlorosuccinimide (NCS) and N-bromo-
succinimide (NBS) to give (+)-Cl-4 and (+)-Br-4, which were
recrystallized from EtOAc as a single crystal in 51% and 79% yields,
respectively (Scheme 3).
We performed X-ray structure analyses of (+)-Cl-4 and (+)-Br-4
and determined the absolute configuration of (+)-Cl-4 and (+)-Br-4
as the (S)-form based on the Flack parameter.5a The molecular
structure of (+)-Cl-4 is shown in Figure 3.5b
2.2. Direct chiral separation of racemate ( )-2 by HPLC and the
synthesis of (+)-1 and (À)-1
Next, our task was to determine which enantiomer of the race-
mate hydantoin ( )-2 could contribute to the agonistic activity of
LXR. We performed a direct chiral separation of ( )-2 by HPLC on
a CHIRALPAK AD-H column to afford (+)-2 and (À)-2 in 49% and
49% yield, respectively (Scheme 1).
With (+)-2 and (À)-2 in hand, we prepared (+)-1 and (À)-1,
as depicted in Scheme 2. The reaction of (+)-2 and (À)-2 with
2-(4-bromobutoxy)-5-(1,1,1,3,3,3-hexafluoro-2-(methoxy-methoxy)
propan-2-yl)-1,3-di-n-propylbenzene 31 in the presence of K2CO3
in N,N-dimethylformamide (DMF) gave the corresponding alky-
lated compounds, which was followed by the deprotection of
methoxymethoxy (MOM) ether under acidic conditions to yield
(+)-1 and (À)-1 in 80% and 91% yields, respectively.
We concluded that the expression of LXR b-selective agonistic
action requires the (S)-form of hydantoin (+)-2 as an essential part
of (+)-1.
2.4. Practical synthesis of chiral hydantoin (S)-(+)-2
Next, we wanted to establish a practical synthesis for (S)-(+)-2.
Although there are reported synthetic methods to provide 5,5-dis-
The obtained (+)-1 and (À)-1 showed [
a
]
D
20 = +30.8 (c 1.0,
ubstituted hydantoin6 from the corresponding
a
,
a
-disubstituted
amino acids, we were challenged with the problem of obtaining chi-
ral -phenyl- -alkyl-substituted amino acids with high enan-
MeOH) and [
a
]
D
20 = À29.9 (c 1.0, MeOH), respectively. The rotation
and magnitude of the former (+)-1 were identical to those of the
previously separated (+)-1 from racemate ( )-1. From these
results, we determined that (+)-2 should be a hydantoin part of
(+)-1.
a
a
tiomeric purity. There are few reports about the asymmetric
synthesis of quaternary amino acids in a practical manner.7
Considering the feasibility of a practical large-scale production,
O
O
O
a
O
O
O
+
HN
O
HN
O
HN
O
NH
NH
NH
(+)-2
(-)-2
2
( )-
Scheme 1. Reagents and conditions: (a) chiral separation by HPLC on a CHIRALPAK AD-H column.

M. Koura et al. / Tetrahedron: Asymmetry 27 (2016) 63–68
65
OH
a
F3C
F3C
O
2
(+)-
b
O
N
O
O
OMOM
NH
F3C
F3C
(+)-1
Br
O
OH
a
F3C
F3C
O
2
(-)-
b
O
N
O
3
O
NH
(-)-1
Scheme 2. Reagents and conditions: (a) 2-(4-bromobutoxy)-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1,3-di-n-propylbenzene, K2CO3, DMF, rt; (b) 4 M
HCl/EtOAc, MeOH, rt.
O
3. Conclusion
a
O
HN
O
2
(+)-
Herein, we revealed that (+)-2 was an essential part for the
expression of LXR b-selective agonistic activity in 1. The requisite
configuration of (+)-2 was determined as the (S)-form by X-ray
structure analyses of (+)-halogenated 4. We have obtained (S)-
methyl 2-amino-2-(4-(1-methylethoxy)phenyl)-propionate (+)-7
NH
X
Cl-4
Br-4
(+)-
(+)-
(X = Cl )
(X = Br)
by resolution with L-mandelic acid and established a practical syn-
thesis of (+)-2.
Scheme 3. Reagents and conditions: (a) NCS or NBS, DMF, rt, overnight.
4. Experimental
4.1. General
Commercially available reagents and solvents were used with-
out further purification. Thin layer chromatography (TLC) analyses
were performed on silica gel 60 F254 plates (Merck). 1H NMR and
13C NMR spectra were obtained on a JEOL JNM-LA 400 MHz spec-
trometer using CDCl3, CD3OD, or DMSO-d6 as the solvent with
tetramethylsilane as the internal standard. Infrared (IR) spectra
were recorded on a Thermo Nicolet 370 FT-IR spectrometer. Mass
spectra were obtained on a JEOL MS-BU20 mass spectrometer. Ele-
mental analyses (C, H, N) were performed using a Yanaco MT-5
instrument. Melting points were determined in open glass capillar-
ies on a Buchi B-545 melting point apparatus. Optical rotations
were measured on a JASCO P2200 polarimeter operating at the
sodium D line at room temperature. Chiral HPLC analyses were
performed on a Shimazu LC-2010A HT liquid chromatograph.
Figure 3. ORTEP of (+)-Cl-4.
we adopted an ‘already-established approach’, including
diastereomeric salt formation to obtain a chiral quaternary amino
acid.8 The chiral hydantoin (S)-(+)-2 was prepared as depicted in
Scheme 4. First, we conducted the hydrolysis of ( )-2, which was
easily prepared for a Bucherer–Bergs reaction9 of 4-isopropoxyace-
tophenone 5 using NaCN and (NH4)2CO3 to obtain racemic amino
acid ( )-6. To block the bipolarization of ( )-6, we esterified ( )-6
in the presence of conc. H2SO4 in MeOH to afford methyl ester
( )-7. To perform optical resolution analysis of the diastereomeric
salt, we created a complex of ( )-7 with an equimolar amount of
4.2. General procedures
4.2.1. Resolution of ( )-1 by HPLC
HPLC was used to optically separate ( )-1 on a CHIRALPAK AS-H
column. Each separated elution was concentrated to give (À)-1 and
(+)-1 as white amorphous solids. The chiral HPLC conditions to
separate ( )-1 were as follows.
L
-(+)-mandelic acid. The resultant mixture was refluxed in a mix-
ture of EtOAc and EtOH (10:1) until a clear solution was obtained,
and then the solution was allowed to cool to room temperature.
Crystals were precipitated and aged. The obtained crystals were
recrystallized from EtOAc and EtOH (10:1) twice to afford the salts
4.2.1.1. Analytical chiral HPLC conditions.
PAK AS-H,
EtOH = 90:10 (v/v); Flow rate: 1.0 mL/min; column temperature:
40 °C; wavelength: 230 nm; retention time: (R)-(À)-form
6.87 min/(S)-(+)-form 11.52 min.
Column: CHIRAL-
m, 0.46 Â 250 mm; Mobile phase: n-hexane/
5
l
of (+)-7 and
(+)-7, salt 8 was treated with sodium carbonate to remove
-(+)-mandelic acid to give (+)-7. The reaction of (+)-7 with an
L-(+)-mandelic acid with a high grade. To obtain pure
L
excess amount of urea afforded the desired (S)-(+)-2 in 89% yield
with 99% ee.
Thus, we established a practical synthesis of (S)-(+)-2 in a large-
scale preparation and introduced a method to explore more potent
LXR b-selective agonists.
4.2.1.2. Preparative chiral HPLC conditions.
ALPAK AS-H,
EtOH = 90:10 (v/v); flow rate: 1.0 mL/min; column temperature:
40 °C; wavelength: 230 nm; retention time: (R)-(À)-form
6.90 min/(S)-(+)-form 11.50 min.
Column: CHIR-
m, 20 Â 250 mm; mobile phase: n-hexane/
5
l

66
M. Koura et al. / Tetrahedron: Asymmetry 27 (2016) 63–68
O
O
a
b
O
O
O
O
HN
O
HO
O
NH
d
H2N
5
( )-2
( )-6
O
c
OH
COOH
O
O
O
O
MeO
MeO
MeO
H2N
H2N
7
( )-
8
O
O
e
f
HN
O
H2N
NH
7
(+)-
(S)-(+)- 2
Scheme 4. Reagents and conditions: (a) NaCN, (NH4)2CO3, EtOH aq, 100 °C; (b) NaOH, H2O, 100 °C; (c) H2SO4, MeOH, reflux; (d)
(e) Na2CO3, rt; (f) urea, 140 °C.
L
-(+)-mandelic acid, EtOAc–EtOH, reflux to rt;
(+)-1: IR (neat): 3307, 2961, 2935, 1707, 1266, 1148 cmÀ1
;
1H
6.52; N, 11.02; [
>99% ee.
a]
20 = +89.7 (c 1.0, MeOH); enantiomeric purity:
D
NMR (400 MHz, CD3OD) d 0.92 (6H, t, J = 7.6 Hz), 1.28 (6H, d,
J = 5.6 Hz), 1.60 (4H, qt, J = 7.6, 7.6 Hz), 1.74 (3H, s), 1.76–1.90
(4H, m), 2.59 (4H, t, J = 7.6 Hz), 3.59 (2H, t, J = 6.8 Hz), 3.78 (2H, t,
J = 6.0 Hz), 4.57 (1H, sept, J = 5.6 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.35
(2H, s), 7.39 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CD3OD) d
14.3 (2C), 22.3 (2C), 24.9 (2C), 25.3, 26.1, 28.6, 33.4 (2C), 39.3,
64.3, 71.0, 74.0, 78.4 (septet, J = 29.2 Hz), 116.9 (2C), 124.6 (q,
J = 287 Hz) (2C), 127.6, 127.7 (2C), 127.8 (2C), 132.3, 136.8 (2C),
158.0, 158.4, 159.3, 178.1; MS (EI) m/z 646 [M]+; Anal. Calcd for
(À)-2: mp 167–169 °C; MS (EI) m/z 248 [M+]; Anal. Calcd for
C
13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.72; H, 6.49;
N, 11.16; [
a]
20 = À89.7 (c 1.0, MeOH); enantiomeric purity: >99%
D
ee. The IR, 1H NMR, and 13C NMR spectra of (À)-2 were identical
to those of (+)-2.
4.2.3. Synthesis of (S)-(+)-1 and (R)-(À)-1
4.2.3.1. (S)-3-(4-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-
yl)-2,6-di-n-propylphenoxy)butyl)-5-(4-(1-methylethoxy)-phe-
C
32H40N2F6O5: C, 59.43; H, 6.23; N, 4.33. Found: C, 59.23; H,
6.07; N, 4.40; [
a
]
D
20 = +32.2 (c 1.0, MeOH); enantiomeric purity:
nyl)-5-methylimidazolidine-2,4-dione (S)-(+)-1.
To a stirred
>99% ee.
suspension of (S)-5-(4-(1-methylethoxy)phenyl)-5-methylimida-
zolidine-2,4-dione (+)-2 (3.03 g, 12.2 mmol) and K2CO3 (2.25 g,
16.3 mmol) in DMF (80 mL) was added dropwise a solution of 2-
(4-bromobutoxy)-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)
propan-2-yl)-1,3-di-n-propylbenzene1 (4.26 g, 8.14 mmol) in DMF
(10 mL) at 0 °C. The reaction mixture was stirred at room temper-
ature for 16 h. After completion of the reaction, the reaction
mixture was diluted with water at 0 °C and extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by silica
gel column chromatography (n-hexane/EtOAc = 5:2) to give (S)-3-
(4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-
2,6-di-n-propylphenoxy)butyl)-5-(4-(1-methylethoxy)-phenyl)-5-
methylimidazolidine-2,4-dione (5.57 g, 99%) as a white amorphous
solid. 1H NMR (400 MHz, CD3OD) d 0.92 (6H, t, J = 7.3 Hz), 1.31 (6H,
d, J = 5.9 Hz), 1.53–1.90 (11H, m), 2.56 (4H, t, J = 7.6 Hz), 3.56 (3H,
s), 3.61 (2H, t, J = 7.0 Hz), 3.74 (2H, t, J = 6.4 Hz), 4.04 (2H, s), 4.52
(1H, sept, J = 5.9 Hz), 5.90 (1H, s), 6.86 (2H, d, J = 8.9 Hz), 7.36
(2H, s), 7.37 (2H, d, J = 8.9 Hz); MS (EI) m/z 690 [M]+.
(À)-1: MS (EI) m/z 646 [M]+; Anal. Calcd for C32H40N2F6O5: C,
59.43; H, 6.23; N, 4.33. Found: C, 59.21; H, 6.29; N, 4.37;
[
a
]
20 = À33.3 (c 1.0, MeOH); optical purity: >99% ee. The IR, 1H
D
NMR, and 13C NMR spectra of (À)-1 were identical to those of
(+)-1.
4.2.2. Resolution of ( )-2 by HPLC
Hydantoin ( )-2 was optically separated by HPLC on a CHIRAL-
PAK AD-H column. Each separated elution was concentrated to
give (À)-2 and (+)-2 as colorless crystals. The chiral HPLC condi-
tions to separate ( )-2 were as follows.
4.2.2.1. Analytical chiral HPLC conditions.
PAK AD-H,
EtOH = 40:60; flow rate: 1.0 mL/min; column temperature: 40 °C;
wavelength: 254 nm; retention time: (R)-(À)-form 4.51 min/(S)-
(+)-form 9.50 min.
Column: CHIRAL-
5
l
m, 0.46 Â 250 mm; mobile phase: n-hexane/
4.2.2.2. Preparative chiral HPLC conditions.
ALPAK AD-H, 5
flow rate: 12 mL/min; column temperature: 40 °C; wavelength:
254 nm; retention time: (R)-(À)-form 6.02 min/(S)-(+)-form
13.94 min.
Column: CHIR-
m, 20 Â 250 mm; mobile phase: MeOH = 100;
To a stirred solution of (S)-3-(4-(4-(1,1,1,3,3,3-hexafluoro-2-
(methoxymethoxy)propan-2-yl)-2,6-di-n-propylphenoxy)-butyl)-
5-(4-(1-methylethoxy)phenyl)-5-methylimidazolidine-2,4-dione
(5.57 g, 8.06 mmol) in MeOH (100 mL) was slowly added 4 M HCl–
EtOAc (10 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 1 h and then concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/
EtOAc = 2:1) to give the title compound (4.2 g, 81%) as a white
amorphous solid. MS (EI) m/z 646 [M]+; Anal. Calcd for C32H40N2F6O5:
C, 59.43; H, 6.23; N, 4.33. Found: C, 59.23; H, 6.07; N, 4.40;
l
(+)-2: mp 166–169 °C; IR (KBr): 3282, 3207, 1770, 1727, 1512,
1256 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.32 (6H, d, J = 5.6 Hz),
;
1.80 (3H, s), 4.53 (1H, sept, J = 5.6 Hz), 6.57 (1H, br s), 6.87 (2H,
d, J = 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz), 8.57 (1H, br s); 13C NMR
(100 MHz, CDCl3) d 22.0 (2C), 25.2, 64.9, 70.0, 116.0 (2C), 126.5
(2C), 129.9, 156.6, 158.1, 176.2; MS (EI) m/z 248 [M+]; Anal. Calcd
for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.93; H,
[a]
20 = +30.8 (c 1.0, MeOH); optical purity: 99% ee. The IR, 1H
D
NMR, and 13C NMR spectra of (S)-1 were identical to those of (+)-1.

M. Koura et al. / Tetrahedron: Asymmetry 27 (2016) 63–68
67
4.2.3.2. (R)-3-(4-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-
yl)-2,6-di-n-propylphenoxy)butyl)-5-(4-(1-methylethoxy)-phenyl)-
4.2.5.2. Racemic methyl 2-amino-2-(4-(1-methylethoxy)phe-
nyl)-propanoate ( )-7. To a stirred solution of ( )-6 (70 g,
5-methylimidazolidine-2,4-dione (R)-(À)-1.
Compound
270 mmol) in MeOH (700 mL) was added concd H2SO4 (70 mL) at
room temperature. The reaction mixture was stirred at the same
temperature for 3 h and then refluxed for 24 h. The reaction mix-
ture was concentrated in vacuo. The residue was dissolved in water
(500 mL) and diluted with CH2Cl2 (500 mL). The aqueous layer was
adjusted to pH 9–10 by adding 3 M NaOH aq at 5 °C or below. The
aqueous layer was extracted with CH2Cl2 (500 mL Â 2). The com-
bined organic layers were washed with brine (100 mL), dried over
Na2SO4 and concentrated in vacuo to give the title compound
(44.8 g, 70%) as a yellow oil. IR (neat): 3381, 2976, 1732, 1509,
(R)-(À)-1 was also prepared according to the above procedure. MS
(EI) m/z 646 [M]+; Anal. Calcd for C32H40N2F6O5: C, 59.43; H, 6.23;
N, 4.33. Found: C, 59.21; H, 6.29; N, 4.37; [
a]
20 = À29.9 (c 1.0,
D
MeOH). The IR, 1H NMR and 13C NMR spectra of (R)-1 were
identical to those of (+)-1.
4.2.4. Synthesis of (+)-Cl-4 and (+)-Br-4
4.2.4.1. (S)-5-(3-Chloro-4-(1-methylethoxy)phenyl)-5-methyl-
imidazolidine-2,4-dione (+)-Cl-4.
To a stirred solution of
(+)-2 (300 mg, 1.21 mmol) in DMF (4.0 mL) was added N-chloro-
succinimide (202 mg, 1.51 mmol) at room temperature. The reac-
tion mixture was stirred at the same temperature overnight. The
reaction mixture was diluted with water (5 mL) and extracted with
EtOAc (10 mL). The organic layer was washed with water (5 mL)
and brine (5 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(n-hexane/EtOAc = 2:1) to yield crystals (210 mg). The product
was recrystallized from EtOAc to give the title compound
(175 mg, 51%) as colorless crystals. Mp 202–204 °C; IR (KBr):
3292, 2972, 1717, 1501, 1263, 1110 cmÀ1; 1H NMR (400 MHz, CD3-
OD) d 1.33 (6H, d, J = 6.0 Hz), 1.72 (3H, s), 4.63 (1H, sept, J = 6.0 Hz),
7.07 (1H, d, J = 8.8 Hz), 7.37 (1H, dd, J = 2.4, 8.8 Hz), 7.49 (1H, d,
J = 2.4 Hz); 13C NMR (100 MHz, CD3OD) d 22.2 (2C), 25.4, 65.4,
73.0, 116.7, 125.1, 126.0, 128.5, 134.0, 154.8, 158.7, 179.0; MS
(EI) m/z 282 [M+]; Anal. Calcd for C13H15ClN2O3: C, 55.23; H,
5.35; Cl, 12.54; N, 9.91. Found: C, 55.38; H, 5.37; Cl, 12.50; N,
1245, 954 cmÀ1 1H NMR (400 MHz, CDCl3)
; d 1.32 (6H, d,
J = 6.0 Hz), 1.68 (3H, s), 1.95 (2H, br s), 3.70 (3H, s), 4.53 (1H, sept,
J = 6.0 Hz), 6.84 (2H, d, J = 9.2 Hz), 7.37 (2H, d, J = 9.2 Hz); 13C NMR
(100 MHz, CDCl3) d 22.0 (2C), 27.5, 52.5, 60.1, 69.8, 115.5 (2C),
126.3 (2C), 136.0, 157.2, 176.9; MS (EI) m/z 237 [M+]; Anal. Calcd
for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.55; H,
8.11; N, 5.88.
4.2.5.3. (S)-Methyl 2-amino-2-(4-(1-methylethoxy)phenyl)-pro-
panoate (+)-7.
233 mmol) in EtOAc (390 mL) and EtOH (39 mL) was added
To
a
stirred solution of ( )-7 (55.4 g,
-man-
L
delic acid (35.5 g, 233 mmol) at room temperature. The reaction
mixture was refluxed for 30 min until a clear solution was obtained
and then stirred at room temperature for 16 h. The precipitate was
filtered off. The filter cake was washed with EtOAc/EtOH (=10:1,
100 mL) and then crystallized from EtOAc/EtOH (=10:1). This crys-
tallization was repeated twice to give
L-mandelic acid salt 8 (20.1 g,
9.89; [a]
20 = +81.4 (c 1.0, MeOH).
D
99% ee⁄) as a white solid (Table 1).
4.2.4.2. (S)-5-(3-Bromo-4-(1-methylethoxy)phenyl)-5-methyl-
imidazolidine-2,4-dione (+)-Br-4. To a stirred solution of
Table 1
% ee of (+)-7 was measured after removing L-mandelic acid from salt 8 by treating
with Na2CO3. The HPLC conditions are described below
(+)-2 (300 mg, 1.21 mmol) in DMF (4.0 mL) was added N-bromo-
succinimide (269 mg, 1.51 mol) at room temperature. The reaction
mixture was stirred at the same temperature overnight. The reac-
tion mixture was diluted with water (5 mL) and extracted with
EtOAc (10 mL). The organic layer was washed with water (5 mL)
and brine (5 mL), dried over Na2SO4 and concentrated in vacuo.
The residue was purified by silica gel column chromatography
(n-hexane/EtOAc = 2:1) to yield crystals (389 mg). The product
was recrystallized from EtOAc to give the title compound
(312 mg, 79%) as colorless crystals. Mp 207–212 °C; IR (KBr):
Entry
1st
2nd
3rd
% ee
Solvent
49% ee
92% ee
99% ee
EtOAc (390 mL)/
EtOH (39 mL)
33.5 g
EtOAc (340 mL)/
EtOH (34 mL)
23.9 g
EtOAc (240 mL)/
EtOH (24 mL)
20.1 g
L-Mandelic
acid salt
4.2.5.4. Analytical chiral HPLC conditions.
PAK AS-H, 5
DEA = 92:8:0.1 (v/v/v); flow rate: 1.0 mL/min; column tempera-
ture: 30 °C; wavelength: 234 nm; retention time: (S)-form
7.36 min/(R)-form 8.59 min.
Column: CHIRAL-
3265, 2981, 1727, 1493, 1261, 1108 cmÀ1 1H NMR (400 MHz,
;
l
m, 0.46 Â 250 mm; mobile phase: n-hexane/i-PrOH/
CDCl3) d 1.37 (6H, d, J = 6.1 Hz), 1.81 (3H, s), 4.55 (1H, sept,
J = 6.1 Hz), 6.48 (1H, br s), 6.89 (1H, d, J = 8.8 Hz), 7.36 (1H, dd,
J = 2.4, 8.8 Hz), 7.66 (1H, d, J = 2.4 Hz), 8.48 (1H, br s); 13C NMR
(100 MHz, CDCl3) d 22.0 (2C), 25.3, 64.4, 72.2, 114.0, 115.3, 125.4,
130.4, 131.5, 154.8, 156.0, 175.3; MS (EI) m/z 327 [M+]; Anal. Calcd
for C13H15BrN2O3: C, 47.72; H, 4.62; Br, 24.42; N, 8.56. Found: C,
To a solution of CH2Cl2 (60 mL) and water (120 mL) was added
the obtained salt. The aqueous layer was alkalinized by adding
Na2CO3 until obtaining pH 9–10 below 10 °C. The organic layer
was separated. The aqueous layer was extracted with CH2Cl2
(500 mL Â 3). The combined organic layers were washed with
brine (250 mL), dried over Na2SO4, and concentrated in vacuo to
give the title compound (11.2 g, 20%) as a yellow oil.
47.87; H, 4.61; Br, 24.41; N, 8.49; [a]
20 = +79.7 (c 0.98, MeOH).
D
4.2.5. Practical synthesis of (S)-2
4.2.5.1. Racemic 2-amino-2-(4-(1-methylethoxy)phenyl)propa-
The IR, 1H NMR, and 13C NMR spectra of (+)-7 were identical to
those of ( )-7. The hydrochloric acid salt of (+)-7 was easily pre-
pared with HCl in MeOH. A sample was recrystallized from MeOH
to yield colorless crystals for analysis. Hydrochloric acid salt of (+)-
7; mp 195–197 °C; IR (KBr): 2977, 2874, 1747, 1516, 1263,
noic acid ( )-6. To
a
stirred solution of ( )-21 (110 g,
443 mmol) in water (700 mL) was added NaOH (90 g, 2.25 mol)
at room temperature. The reaction mixture was stirred at 100 °C
for 48 h. The reaction mixture was neutralized with 6 M HCl. The
precipitate was filtered off and washed with water (200 mL Â 3)
to give the title compound (99 g, 99%) as a colorless solid. 1H
NMR (400 MHz, DMSO-d6) d 1.22 (6H, d, J = 6.0 Hz), 1.36 (3H, s),
4.51 (1H, sept, J = 6.0 Hz), 6.70 (2H, d, J = 8.8 Hz), 7.43 (2H, d,
J = 8.8 Hz). The product was used in the next step without further
purification.
952 cmÀ1 1H NMR (400 MHz, CD3OD) d 1.30 (6H, d, J = 5.6 Hz),
;
1.95 (3H, s), 3.82 (3H, s), 4.64 (1H, sept, J = 5.6 Hz), 6.99 (2H, d,
J = 9.2 Hz), 7.40 (2H, d, J = 9.2 Hz); 13C NMR (100 MHz, CD3OD) d
22.1 (2C), 22.2, 54.2, 62.4, 71.1, 117.3 (2C), 128.3 (2C), 128.5,
160.4, 172.5; MS (EI) m/z 237 [M+]; Anal. Calcd for C13H20ClNO3:

68
M. Koura et al. / Tetrahedron: Asymmetry 27 (2016) 63–68
3. Hong, C.; Tontonoz, P. Nat. Rev. Drug Disc. 2014, 13, 433–444.
4. (a) Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.;
Wang, S.; Thoolen, M.; Mangelsdorf, D. J.; Lustig, K. D.; Shan, B. Genes Dev. 2000,
14, 2831–2838; (b) Quinet, E. M.; Savio, D. A.; Halpern, A. R.; Chen, L.; Schuster,
G. U.; Gustafsson, J.-Å.; Basso, M. D.; Nambi, P. Mol. Pharmacol. 2006, 70, 1340–
1349.
5. (a) Parsons, S.; Flack, H. D.; Wagner, T. Acta Cryst. 2013, B69, 249–259; (b) A
detailed data and discussion for X-ray crystal structure analyses of (+)-Cl-4 and
(+)-Br-4 will be reported elsewhere. Crystallographic data for (+)-Cl-4 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 1436066.
C, 57.04; H, 7.36; N, 5.12. Found: C, 57.04; H, 7.30; N, 5.26;
20 = +79.8 (c 1.0, MeOH); enantiomeric purity: >99% ee.
[a]
D
4.2.5.5.
lidine-2,4-dione (S)-(+)-2.
(S)-5-(4-(1-Methylethoxy)phenyl)-5-methylimidazo-
Urea (28.3 g, 472 mmol) was
heated at 140 °C. To this stirred solution was added dropwise
(+)-7 (11.2 g, 47.2 mmol) at 140 °C. The reaction mixture was stir-
red at the same temperature for 5 h and then cooled to 70 °C. The
reaction mixture was diluted with water (200 mL) and EtOAc
(300 mL) at the same temperature. The aqueous layer was
extracted with EtOAc (200 mL Â 3). The combined organic layers
were washed with brine (100 mL), dried over Na2SO4 and concen-
trated in vacuo. The residue was suspended in n-heptane (40 mL)
and stirred at room temperature for 2 h. The precipitate was fil-
tered off and rinsed with n-heptane (10 mL) to give the title com-
pound (10.4 g, 89%) as a white solid. Mp 166–168 °C; MS (EI) m/z
248 [M+]; Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28.
6. (a) Marsh, D.; Lazzell, C. L. J. Am. Chem. Soc. 1940, 62. 1306–1306; (b) Sarges, R.;
Howard, H. R., Jr; Kelbaugh, P. R. J. Org. Chem. 1982, 47, 4081–4085; (c) Glombik,
H. Tetrahedron 1990, 46, 7745–7750; (d) Fernandez-Nieto, F.; Rosello, J. M.;
Lenoir, S.; Hardy, S.; Clayden, J. Org. Lett. 2015, 17, 3838–3841.
7. (a) Shibasaki, M.; Kanai, M. Asymmetric Synthesis and Application of
a-Amino
Acids In Vadim, A., Kunisuke, Izawa, Eds.; ; ACS Symposium Series, 2009; Vol.
1009, pp 102–115. Chapter 7; (b) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634–5635; (c) Kato, N.; Suzuki,
M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147–3151; (d) Vachal,
P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867–870; (e) Vachal, P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 10012–10014; (f) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang,
X.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468–8470; (g) Huang, J.; Liu,
X.; Wen, Y.; Qin, B.; Feng, X. J. Org. Chem. 2007, 72, 204–208; (h) Hashimoto, T.;
Maruoka, K. Chem. Rev. 2007, 107, 5656–5682; (i) Kanemitsu, T.; Furukoshi, S.;
Miyazaki, M.; Nagata, K.; Itoh, T. Tetrahedron: Asymmetry 2015, 26, 214–218; (j)
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McCarthy, J. R. Org. Lett. 2009, 11, 807–810.
Found: C, 62.93; H, 6.52; N, 11.02; [a]
20 = +89.7 (c 1.0, MeOH);
D
enantiomeric purity: 99% ee. The IR, 1H NMR, and 13C NMR spectra
of (S)-2 were identical to those of (+)-2.
Acknowledgments
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We thank Dr. S. Tanabe, Managing Director of Tokyo New Drug
Research Laboratories, Kowa Co., Ltd, for his support. We appreci-
ate Dr. S. Ohba, Professor at Keio University, for the X-ray structure
analysis.
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