Determination of the Absolute Configuration and a Practical Chiral Synthesis of 5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methyl imidazolidine-2,4-dione as a Novel Liver X Receptor β-Selective Agonist

Article abstract of DOI:10.1055/s-0036-1588700

We determined that the absolute configuration of 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione (hydantoin) is the (S)-form for the liver X receptor (LXR) β-selective agonist through X-ray crystal structure analysis of the hydantoin hydrogen bromide salt. Furthermore, we established a practical synthesis of the chiral hydantoin with 99% ee by the optical resolution of racemic methyl 2-amino-2-[5-(1-methylethoxy)pyridin-2-yl]propanoate with d-(-)-mandelic acid on a multi-kilogram scale. Finally, we improved the synthesis method of the LXR β-selective agonist.

Full text of DOI:10.1055/s-0036-1588700

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
M. Koura et al.
Paper
Synthesis
Determination of the Absolute Configuration and a Practical
Chiral Synthesis of 5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methyl-
imidazolidine-2,4-dione as a Novel Liver X Receptor β-Selective
Agonist
Minoru Kouraa
Hisashi Sumidaa
Kimiyuki Shibuya*a
Shigeru Ohbab
O
N
N
D-(–)-mandelic acid
N
urea
O
MeO2C
MeO2C
H2N
HN
O
O
O
NH
(S)-(+)
H2N
racemate
(S)-(–)
a Tokyo New Drug Research Laboratories, Pharmaceutical
Division, Kowa Co., Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
b Research and Education Center for Natural Sciences,
Keio University, Hiyoshi 4-1-1, Kohoku-ku, Yokohama
223-8521, Japan
up to 99% ee
O
OH
O
N
F3C
O
N
O
F3C
NH
k-sibuya@kowa.co.jp
O
OH
(S)-(–)
LXR β-selective agonist
Received: 30.11.2016
Accepted after revision: 13.01.2017
Published online: 31.01.2017
DOI: 10.1055/s-0036-1588700; Art ID: ss-2016-f0821-op
O
N
OH
O
*
O
F3C
N
NH
F3C
Abstract We determined that the absolute configuration of 5-[5-(1-
methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione (hydanto-
in) is the (S)-form for the liver X receptor (LXR) β-selective agonist
through X-ray crystal structure analysis of the hydantoin hydrogen bro-
mide salt. Furthermore, we established a practical synthesis of the chi-
ral hydantoin with 99% ee by the optical resolution of racemic methyl 2-
amino-2-[5-(1-methylethoxy)pyridin-2-yl]propanoate with D-(–)-man-
delic acid on a multi-kilogram scale. Finally, we improved the synthesis
method of the LXR β-selective agonist.
O
O
OH
tail
linker
head
(
)-1
Figure 1 Discovery of liver X receptor (LXR) β-selective agonist (±)-1
CHCl3)} and (+)-1 {[α]D20 +56.1 (c 1.0, CHCl3)} from (+)-2·HCl
{[α]D +26.5 (c 1.0, MeOH)} and (–)-2·HCl {[α]D –26.6 (c
Key words liver X receptor, hydantoin, X-ray crystal structure analy-
sis, chiral synthesis, optical resolution, D-(–)-mandelic acid
20
20
1.0, MeOH)}, respectively, as shown in Scheme 1.
Liver X receptors (LXRs), comprising two isoforms of the
type LXRα and LXRβ, are ligand-activated transcription fac-
tors involved in cholesterol metabolism, glucose homeosta-
sis, inflammation, and lipogenesis. Recently, we reported
that a 2-hydroxyacetophenone derivative [(±)-1] is an out-
standing linker between 1,1-bis(trifluoromethyl)carbinol
(head) and imidazolidine-2,4-dione (tail) moieties, enhanc-
ing the potency and β-selectivity of LXR agonists for the
treatment of atherosclerosis,1 as shown in Figure 1.
(+)-2·HCl
(–)-1
chiral
separation
O
N
O
steps
HN
NH
(–)-2·HCl
(+)-1
O
(
)-2
Scheme 1 Chiral separation of (±)-2 and preparation of the corre-
sponding enantiomers (–)-1 and (+)-1 from (+)-2·HCl and (–)-2·HCl,
respectively
Having conducted the chiral separation of racemic 5-[5-
(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-
dione [(±)-2] using high-performance liquid chromatogra-
phy (HPLC) with a Chiralpak AY-H column, we prepared the
Evaluation of both enantiomers revealed that (–)-1
shows dramatically higher potency and selectivity toward
LXR β than (+)-1.1 In the previous synthesis, the desired (–)-
1 was produced by a coupling reaction of α-(tosyloxy)ace-
20
corresponding enantiomers1 (–)-1 {[α]D –56.5 (c 1.0,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
M. Koura et al.
Paper
Synthesis
Next, we set a goal to develop a practical synthesis
method of (S)-(+)-2 with high optical purity on a scalable
production level in a convenient manner. From the view-
point of feasibility for large-scale production, there are very
few methods for the synthesis of a chiral hydantoin,3 how-
ever, many studies have been conducted on the asymmetric
synthesis of quaternary amino acids.4 Recently, Clayden et
al. demonstrated direct asymmetry arylation of α-amino
acid derivatives to afford an enantioselective hydantoin;5
however, this methodology does not satisfy our criteria, es-
pecially, regarding the issues of degraded optical purity (70
to 46% ee), anhydrous reaction using LDA, and additionally
required demethylation step to afford the desired hydantoin
(S)-(+)-2. Therefore, we adopted our already-established
method6 for the synthesis of α-phenyl-α-alkyl-substituted
amino acids by optical resolution after diastereomeric salt
formation.7 The chiral hydantoin (S)-(+)-2 was prepared as
depicted in Scheme 4.
Similar to previous reports, we prepared the racemic
hydantoin (±)-2 using the Bucherer–Bergs reaction8 of 1-[5-
(1-methylethoxy)pyridin-2-yl]ethan-1-one (4) with NaCN
and (NH4)2CO3, followed by the hydrolysis of (±)-2 to pro-
vide the racemic amino acid (±)-5. To block the bipolariza-
tion of (±)-5, the compound was esterified in the presence
of SOCl2 in MeOH to afford methyl ester (±)-6. Unexpected-
ly, decarboxylation of (±)-5 was observed to give 4 when
the reaction temperature was raised over 30 °C in the initial
process.9 The addition of SOCl2 should be performed at a
temperature less than –20 °C. To perform optical resolution
analysis of the diastereomeric salt, we similarly created a
complex of (±)-6 with an equimolar amount of L-(+)-man-
delic acid according to our protocol.6 The obtained crystals
were twice recrystallized from EtOH to afford salt 7 in high
grade (98% ee). Further, the precipitated 7 was filtered and
decomposed by addition of aqueous Na2CO3 to remove L-
(+)-mandelic acid, affording 6. This was followed by reac-
tion with an excess amount of urea to afford the chiral hy-
dantoin 2. Different from our expectation based on the pre-
vious study,6 2 showed an HPLC retention time of tR = 4.58
min [Lit.1 (R)-(–)-form tR = 4.55 min], revealing that this
procedure provided (R)-(–)-2. To obtain pure (S)-(+)-2, we
changed L-(+)-mandelic acid to D-(–)-mandelic acid as the
chiral source and conducted the same procedure, affording
the desired HPLC tR = 5.83 min [Lit.1 (S)-(+)-form tR = 5.81
min], consistent with that of (S)-(+)-2. Therefore, it is re-
vealed that a chirality change in 6 in the less-soluble diaste-
reomeric salt with L-(+)-mandelic acid occurs when the
benzene ring is replaced with a pyridine ring. Considering
the above result, it is noteworthy to refer to reports about
the formation of hydrogen bonding (pyN···H–O–C=O or
pyN+–H···–O–C=O) between the pyridyl (or pyridinium)
group and mandelic acid.10 Even the pyridine forms a co-
crystal with the mandelic acid, in which the carboxyl group
is bonded to the pyridine N atom.11 It is presumed that this
crystal packing affects the dielectrically controlled resolu-
OH
O
F3C
F3C
OTs
(+)-2
+
(–)-1
O
OBn
key intermediate
3
Scheme 2 The initial synthesis of (–)-1 in medicinal chemistry
tophenone 3 with (+)-2, followed by a deprotection
(Scheme 2).1
As part of our drug research and development plans, we
require an efficient synthesis method for (–)-1 on a hun-
dred-gram scale that can be easily scaled to pilot produc-
tion; however, there are two major issues. First, the abso-
lute configuration of the requisite compound (+)-2 must be
determined. Second, a practical chiral synthesis for produc-
ing the optically pure compound (+)-2 must be established.
To definitively determine the absolute configuration of
(+)-2 using X-ray crystal structure analysis, we prepared
the hydrogen halide salts of (+)-2 through treatment with
hydrogen chloride (HCl) or hydrogen bromide (HBr) to ob-
tain a significant anomalous scattering effect. Having ob-
tained both crystals of (+)-2·HCl and (+)-2·HBr after recrys-
tallization from MeOH, we chose (+)-2·HBr as the appropri-
ate single crystal for X-ray crystal structure analysis
because of their ability to exhibit a larger anomalous scat-
tering effect (Scheme 3).
·HBr
O
N
HBr
O
HN
O
(+)-2
MeOH
rt, 1 h
51%
NH
(+)-2·HBr
Scheme 3 Synthesis of (+)-2·HBr
We performed X-ray crystal structure analysis of (+)-
2·HBr and determined its absolute configuration to be the
(S)-form. The pyridine ring at N7 is protonated and the mo-
lecular structure is shown in Figure 2.2
Figure 2 ORTEP view of (+)-2·HBr
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
M. Koura et al.
Paper
Synthesis
SOCl2
MeOH
–20 °C
O
O
NaCN
(NH4)2CO3
O
N
N
N
N
NaOH (aq)
O
O
O
HN
NH
HO
O
MeO
O
EtOH (aq)
100 °C, 10 h
87%
100 °C, 72 h
99%;
H2N
(
then
30 °C, 24 h
86%
H2N
(
O
4
(
)-2
)-5
)-6
O
O
O
L-(+)-mandelic
acid
N
N
N
OH
Na2CO3 (aq)
rt
urea
O
O
O
MeO
HN
O
MeO
EtOH
reflux to rt
145 °C, 4 h
99%
COOH
H2N
(+)-6
NH
H2N
16% for 2 steps
(R)-(–)-2
7
(
)-6
D-(–)-mandelic
acid
O
O
O
N
N
N
OH
COOH
Na2CO3 (aq)
urea
O
O
O
MeO
HN
O
MeO
rt
MeCN
reflux to rt
145 °C, 5 h
99%
H2N
NH
H2N
18% for 2 steps
(–)-6
(S)-(+)-2
8
Scheme 4 Synthesis of chiral hydantoin (S)-(+)-2
tion.12 Recently, Hirose et al. reported a solvent-induced
chirality switch and reciprocal optical resolution of man-
delic acid and erythro-2-amino-1,2-diphenylethanol.13 It
can be noted that the resolving solvent significantly affect-
ed the resolution; therefore, both enantiomers were ob-
tained using a single enantiomer of the resolving agent by
solvent switching. Following this report, we intensively in-
vestigated the solvent effect of optical resolution, however,
we did not observe the reversal of the stereoselectivity
upon changing the solvent, as shown in Table 1. Using EtOH
as a dissolving solvent, L-(+)-mandelic acid afforded the an-
tipode (R)-(–)-2 with high optical purity (98% ee), whereas
D-(–)-mandelic acid gave (S)-(+)-2 with low optical purity
(66% ee) (entry 1 vs 3).14 The diastereomeric salt did not
dissolve in EtOAc or cyclopentyl methyl ether (CPME) (en-
tries 10 and 11). Overall, the result of MeCN for the optical
purity (90% ee) and chemical yield (26%) was satisfactory
(entry 6).
After optimization of parameters (F), we successfully
demonstrated optical resolution on a multi-kilogram scale
production for the practical chiral synthesis of (S)-(+)-2.
In a previous synthesis of (S)-(–)-1, the yield of the final
coupling reaction of (+)-2 with tosylate 3 was only 21%.1
Therefore, we studied the reaction conditions and synthesis
of α-bromoacetophenone 10 in place of 3. (S)-(–)-1 was
prepared as depicted in Scheme 5. The short and improved
synthesis of 10 starting from 2-propylaniline (9) is de-
scribed in the Supporting Information. We performed the
coupling reaction of 10 with (S)-(+)-2 in the presence of po-
tassium carbonate in DMF at room temperature to afford
the benzyl ether 11 in 90% yield. Finally, the hydrogenolysis
of 11 with Pd(OH)2/C under a hydrogen atmosphere gave
the desired (S)-(–)-1 in 96% yield. This drug substance pos-
sessed excellent chemical purity (>99.7% by HPLC) and opti-
cal purity (>99.2% ee by chiral HPLC).
In conclusion, we conducted X-ray crystal structure
analysis of (+)-2·HBr and determined it to be in the (S)-form
as the requisite absolute configuration of (+)-2, the essen-
tial tail moiety for a potent LXR β-selective agonist. Further-
more, we established a method for optical resolution of
methyl 2-amino-2-[5-(1-methylethoxy)pyridin-2-yl]pro-
panoate [(±)-6] with D-(–)-mandelic acid in a multi-kilo-
Table 1 Optical Resolution of Racemic 6 with L-(+)- or D-(–)-Mandelic
Acid
Entry
Mandelic Solvent
acid
Volumea Yield
ee
(%)
Fb
Config.
(mL)
(%)
1
2
L
EtOH
0.4
0.3
0.4
0.8
0.5
0.6
0.4
0.5
0.7
>1c
>1c
16
98
0.16
R
D
D
D
D
D
D
D
D
D
D
MeOH
EtOH
trace
20
–
–
3
66
62
87
90
86
77
25
0.13
0.19
0.22
0.23
0.20
0.08
0.13
S
S
S
S
S
S
S
4
i-PrOH
acetone
MeCN
THF
30
5
25
6
26
7
23
8
CHCl3
toluene
EtOAc
CPME
10
9
52
10
11
a (±)-6 (100 mg) and L-(+)- or D-(–)-mandelic acid (64 mg) were dissolved in
the solvent.
b F = [yield (%) × ee (%)]/10000.
c Insoluble in this solvent.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
M. Koura et al.
Paper
Synthesis
OBn
O
F3C
F3C
Br
+
(S)-(+)-2
NH2
O
OBn
9
10
O
N
N
OBn
O
O
F3C
F3C
H2
NH
Pd(OH)2/C
K2CO3
(S)-(–)-1
DMF
rt, 36 h
90%
MeOH
rt, 10 h
96%
O
O
OBn
11
Scheme 5 Improved synthesis of LXR β-selective agonist (S)-(–)-1
gram scale, followed by preparation of (S)-(+)-2 with 99% ee
on a hectogram scale. Finally, we improved the synthesis of
(S)-(–)-1, resulting in high chemical and chiral purity. The
effective use of the undesired isomers (R)-(–)-6 for recy-
cling is currently under study.
MS (EI): m/z = 249 [M]+.
Anal. Calcd for C12H16BrN3O3: C, 43.65; H, 4.88; N, 12.73. Found: C,
43.64; H, 4.85; N, 12.67.
Racemic 2-Amino-2-[5-(1-methylethoxy)pyridin-2-yl]propanoic
Acid [(±)-5]
To a stirred solution of (±)-21 (3.5 kg, 14.0 mol) in water (14 kg), NaOH
(2.8 kg, 70.2 mol) was added at rt. The mixture was stirred at 100 °C
for 72 h, allowed to cool to rt, then neutralized with 6 M HCl at 0 °C.
The precipitate was filtered and washed with water (3 × 5 kg) to give
the product (3.15 kg, 99%) as a colorless solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.13 (d, J = 2.7 Hz, 1 H), 7.57 (d, J =
9.0 Hz, 1 H), 7.33 (dd, J = 2.7, 9.0 Hz, 1 H), 4.64 (sept, J = 6.1 Hz, 1 H),
1.74 (s, 3 H), 1.31 (d, J = 6.1 Hz, 6 H).
Commercially available reagents and solvents were used without fur-
ther purification. TLC analyses were performed on silica gel 60 F254
plates (Merck). 1H and 13C NMR spectra were obtained on a Jeol JNM-
LA or ECS 400 MHz spectrometer using CDCl3, CD3OD, or DMSO-d6 as
the solvent with TMS as the internal standard. IR spectra were re-
corded on a Thermo Nicolet 370 FT-IR spectrophotometer. Mass spec-
tra were obtained on a Jeol MS-BU20 mass spectrometer. Elemental
analyses (C, H, N) were performed using a Yanaco MT-5 instrument.
Melting points were determined in open glass capillaries on a Buchi
B-545 melting point apparatus. Optical rotations were measured on a
Jasco P2200 polarimeter operating at the Na-D line at rt. The chiral
HPLC analyses were performed on a Shimadzu LC-2010A high tem-
perature liquid chromatograph.
MS (EI): m/z = 224 [M]+.
The product was used in the next step without further purification.
Racemic Methyl 2-Amino-2-[5-(1-methylethoxy)pyridin-2-yl]pro-
panoate [(±)-6]
To a stirred solution of (±)-5 (3.15 kg, 14.0 mol) in MeOH (35 kg), SO-
Cl2 (2.05 kg, 17.2 mol) was added at –20 °C over 1 h (the internal tem-
perature was maintained at less than –3 °C to prevent formation of
the byproduct 4). After gas evolution ceased, the mixture was stirred
at 30 °C for 24 h and then neutralized with sat. aq NaHCO3 at 0 °C and
concentrated in vacuo to remove the MeOH. The aqueous layer was
extracted with EtOAc (3 × 10 L) and the combined organic layers were
washed with brine (3 L) and concentrated in vacuo. The residue was
added to THF (3 L) and filtered, after which the solid was repeatedly
washed with THF. The filtrate was concentrated in vacuo to give the
product (2.86 kg, 86%) as a brown oil.
The analytical chiral HPLC conditions for 2 were previously reported.1
(S)-5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methylimidazolidine-
2,4-dione Hydrochloride [(S)-(+)-2·HCl]
The preparation and data were previously reported.1
(S)-5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methylimidazolidine-
2,4-dione Hydrobromide [(S)-(+)-2·HBr]
To a stirred solution of (+)-2 (300 mg, 1.20 mmol) in MeOH (3.0 mL),
HBr (121 mg, 1.50 mmol) was added at 0 °C. The mixture was stirred
at rt for 1 h and then concentrated under vacuum. The solid was re-
crystallized (MeOH) to give the product (203 mg, 51%) as colorless
crystals; mp 237–240 °C; [α]D20 +181 (c 1.0, MeOH).
IR (neat): 3377, 2979, 1734, 1475, 1245, 1110 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 3.2 Hz, 1 H), 7.42 (d, J = 8.4
Hz, 1 H), 7.17 (dd, J = 3.2, 8.4 Hz, 1 H), 4.56 (sept, J = 6.4 Hz, 1 H), 3.71
(s, 3 H), 2.20 (br s, 2 H), 1.71 (s, 3 H), 1.35 (d, J = 6.4 Hz, 6 H).
IR (KBr): 3175, 2804, 1738, 1280 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 8.38 (d, J = 2.8 Hz, 1 H), 8.17 (dd, J =
2.8, 9.1 Hz, 1 H), 8.08 (d, J = 9.1 Hz, 1 H), 4.89 (sept, J = 5.9 Hz, 1 H),
1.93 (s, 3 H), 1.41 (d, J = 5.9 Hz, 6 H).
13C NMR (100 MHz, CD3OD): δ = 175.4, 158.5, 157.8, 145.6, 133.0,
132.9, 126.8, 74.5, 65.1, 24.4, 21.8 (2 C).
13C NMR (100 MHz, CDCl3): δ = 176.6, 154.0, 153.1, 137.9, 123.0,
119.9, 70.7, 61.9, 52.5, 26.0, 21.9 (2 C).
MS (EI): m/z = 238 [M]+.
Anal. Calcd for C12H18N2O3: C, 60.49; H, 7.61; N, 11.76. Found: C,
60.24; H, 7.72; N, 11.58.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
M. Koura et al.
Paper
Synthesis
Methyl (R)-2-Amino-2-[5-(1-methylethoxy)pyridin-2-yl]propa-
noate [(+)-6]
The obtained salt 8 (900 g) was added to a solution of CH2Cl2 (4.5 kg)
and water (5.0 kg). The aqueous layer was made alkaline by adding
Na2CO3 until a pH of 8 below 10 °C was achieved. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2 (3 ×
3.0 L). The combined organic layers were washed with brine (600 mL),
dried (Na2SO4), and concentrated in vacuo to give the product (510 g,
18%, 99% ee) as a pale yellow oil; [α]D20 –22.3 (c 1.0, CHCl3).
To a stirred solution of (±)-6 (100 mg, 0.42 mmol) in EtOH (0.4 mL), L-
(+)-mandelic acid (64 mg, 0.42 mmol) was added at rt. The mixture
was refluxed for 30 min until a clear solution was obtained and then
stirred at rt for 16 h. The precipitate was filtered, and the filter cake
was washed with EtOH and recrystallized (EtOH, 420 μL). This crys-
tallization was repeated twice to give the L-mandelic acid salt 7 (30.4
mg) as a white solid.
All spectra of (–)-6 were identical to those of (±)-6.
To a solution of CH2Cl2 (1.0 mL) and water (1.0 mL), the obtained salt 7
was added. The aqueous layer was made alkaline by adding Na2CO3
until a pH of 8 below 10 °C was achieved. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3 × 1.0 mL).
The combined organic layers were washed with brine (1.0 mL), dried
(Na2SO4), and concentrated in vacuo to give the product (15.8 mg,
16%, 98% ee) as a pale yellow oil; [α]D20 +22.1 (c 1.0, CHCl3).
(S)-5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methylimidazolidine-
2,4-dione [(S)-(+)-2]
Urea (1.29 kg, 21.4 mol) was heated at 145 °C. To this stirred solution,
(–)-6 (510 g, 2.14 mol) was added in a dropwise fashion at 145 °C. The
mixture was stirred at the same temperature for 5 h and then cooled
to 70 °C. The mixture was diluted with water (1.0 L) and EtOAc (2.5 L)
at 70 °C. This solution was then allowed to cool to rt. The aqueous lay-
er was extracted with EtOAc (8 × 800 mL) and the combined organic
layers were washed with brine (600 mL), dried (Na2SO4), and concen-
trated in vacuo to give the product (529 g, 99%, 99% ee) as a yellow
amorphous solid; [α]D20 +26.5 (c 1.0, MeOH).
All spectra of (+)-6 were identical to those of (±)-6.
Analytical chiral HPLC conditions for 6 (column: Chiralpak OD-H, 5
μm, 0.46 × 250 mm; mobile phase: n-hexane/EtOH/Et2NH 95:5:0.1;
flow rate: 1.0 mL/min; column temperature: 40 °C; wavelength: 234
nm): tR = 9.00 [(R)-form], 9.80 min [(S)-form].
All spectra of (S)-(+)-2 were identical to those of our reported (+)-2.1
Chiral HPLC (conditions see 6): tR = 5.83 min.
(R)-5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methylimidazolidine-
2,4-dione [(R)-(–)-2]
(S)-3-[2-(2-(Benzyloxy)-4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluo-
ropropan-2-yl]-2-propylphenoxy}phenyl)-2-oxoethyl]-5-[5-(1-
methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione
(11)
Urea (39.8 mg, 0.66 mmol) was heated at 145 °C. To this stirred solu-
tion, (+)-6 (15.8 mg, 66 μmol) was added in a dropwise fashion at 145
°C. The mixture was stirred at the same temperature for 4 h and al-
lowed to cool to rt. The mixture was directly purified by column chro-
matography (silica gel, CHCl3/MeOH 20:1) to give the product (16.4
To a stirred suspension of (S)-(+)-2 (27.2 g, 109 mmol) and K2CO3
(22.7 g, 164 mmol) in DMF (220 mL), a solution of 10 (76.0 g, 109
mmol) in DMF (550 mL) at 0 °C was added in a dropwise fashion over
40 min. The mixture was stirred at rt for 36 h. After the completion of
the reaction, the mixture was filtered through a pad of Celite (100 g)
and rinsed with EtOAc (2 L). The filtrate was then added to water (800
mL) and the organic layer was separated. The aqueous layer was ex-
tracted with EtOAc (1 L). The combined organic layers were washed
with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, n-hex-
ane/EtOAc 3:1 to 1:1) to give the product (84.7 g, 90%) as a colorless
amorphous solid; [α]D20 –40.0 (c 1.0, CHCl3).
20
mg, 99%, 98% ee) as a yellow amorphous solid; [α]D –26.6 (c 1.0,
MeOH).
All spectra of (R)-(–)-2 were identical to those of our reported (+)-2.1
Chiral HPLC (conditions as for 6): tR = 4.58 min.
Methyl (S)-2-Amino-2-[5-(1-methylethoxy)pyridin-2-yl]propa-
noate [(–)-6]
To a stirred solution of (±)-6 (2.86 kg, 12.0 mol) in MeCN (14.3 L),
D-(–)-mandelic acid (1.83 kg, 12.0 mol) was added at rt. The mixture
was refluxed for 30 min until a clear solution was obtained and then
stirred at rt for 16 h. The precipitate was filtered and the filter cake
was washed with MeCN. The solid was recrystallized (MeCN, 1.43 L).
This crystallization was repeated twice (Table 2) to give D-mandelic
acid salt 8 (900 g) as a white solid.
IR (film): 2978, 1718, 1217, 1111, 1015 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 8.18 (d, J = 2.4 Hz, 1 H), 7.91 (d, J = 8.8
Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.54 (s, 1 H), 7.51 (d, J = 8.0 Hz, 1 H),
7.27–7.42 (m, 11 H), 7.06 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 2.4 Hz, 1 H),
6.59 (dd, J = 2.4, 8.8 Hz, 1 H), 5.26 (s, 2 H), 4.85 (s, 2 H), 4.70 (s, 2 H),
4.68 (sept, J = 6.0 Hz, 1 H), 2.49 (t, J = 7.6 Hz, 2 H), 1.88 (s, 3 H), 1.49
(qt, J = 7.3, 7.6 Hz, 2 H), 1.33 (d, J = 6.0 Hz, 6 H), 0.82 (t, J = 7.3 Hz, 3 H).
Table 2 Optical Resolution Conditions and Results
13C NMR (100 MHz, CD3OD): δ = 191.9, 177.5, 164.9, 164.6, 162.2,
158.4, 156.0, 155.5, 150.0, 139.6, 137.6, 137.3, 136.5, 134.4, 132.1,
129.9 (2 C), 129.8 (2 C), 129.5, 129.4, 128.9, 128.8 (2 C), 128.4 (2 C),
125.4, 124.2, 124.0 (q, J = 291.3 Hz, 2 C), 122.7, 121.9, 121.0, 110.9,
103.5, 84.4 (sept, J = 28.3 Hz), 72.0, 71.9, 69.4, 66.5, 33.1, 24.0, 23.6,
22.1 (2 C), 14.0.
Entry
Solvent
1st Crystallization
2nd Crystallization
MeCN (14.3 L)
MeCN (1.43 L)
D-Mandelic acid salt
1530 g
33
900 g
59
Yield (%)
eea (%)
Fb
MS (EI): m/z = 863 [M]+.
90
99
Anal. Calcd for C46H43F6N3O7: C, 63.96; H, 5.02; N, 4.86. Found: C,
63.84; H, 5.12; N, 4.76.
0.30
0.58
a The ee (%) of (–)-6 was measured after removing D-mandelic acid from
salt 8 by treating with Na2CO3. The analytical chiral HPLC conditions for
(–)-6 were as described for (R)-(–)-2.
b F = yield (%) × ee (%)/10,000.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
M. Koura et al.
Paper
Synthesis
(S)-3-(2-{4-[4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-2-
propylphenoxy]-2-hydroxyphenyl}-2-oxoethyl)-5-[5-(1-methyl-
ethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione [(S)-(–)-1]
(3) (a) Yee, N. K. Org. Lett. 2000, 2, 2781. (b) Chowdari, N. S.; Barbas,
C. F. III Org. Lett. 2005, 7, 867. (c) A reviewer suggested authors
to make a comment on the possibility of directly optical resolu-
tion of racemic hydantoin (±)-2. According to the ref. 3d, we fol-
lowed the protocol and conducted an optical resolution of
racemic 5-[4-(1-methylethoxy)phenyl]-5-methylimidazolidine-
2,4-dione with (+)-phenethylamine in a direct manner, but
failed to obtain a satisfactory result (0 to 15% ee). Therefore, we
have no option to apply this method to hydantoin (±)-2.
(d) Coquerel, G.; Petit, M.-N.; Bouaziz, R.; Depernet, D. Chirality
1992, 4, 400.
(4) (a) Lim, D. S. W.; Anderson, E. A. Synthesis 2012, 44, 983.
(b) Shibasaki, M.; Kanai, M. Asymmetric Synthesis and Applica-
tion of α-Amino Acids, ACS Symposium Series 1009; Soloshonok,
V. A.; Izawa, K., Eds.; American Chemical Society: Washington
DC, 2009, Chap. 7, 102. (c) Masumoto, S.; Usuda, H.; Suzuki, M.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
(d) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2004, 45, 3147. (e) Vachal, P.; Jacobsen, E. N. Org. Lett.
2000, 2, 867. (f) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 10012. (g) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.; Liu,
X.; Feng, X. Angew. Chem. Int. Ed. 2007, 46, 8468. (h) Huang, J.;
Liu, X.; Wen, Y.; Qin, B.; Feng, X. J. Org. Chem. 2007, 72, 204.
(i) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656.
(j) Kanemitsu, T.; Furukoshi, S.; Miyazaki, M.; Nagata, K.; Itoh, T.
Tetrahedron: Asymmetry 2015, 26, 214. (k) Ishihara, K.;
Hamamoto, H.; Matsugi, M.; Shioiri, T. Tetrahedron Lett. 2015,
56, 3169. (l) Green, J. E.; Bender, D. M.; Jackson, S.; O’Donnell, M.
J.; McCarthy, J. R. Org. Lett. 2009, 11, 807–810.
To a stirred solution of 11 (84.7 g, 98.0 mmol) in MeOH (330 mL), 10%
Pd(OH)2/C (8.5 g) was added. The mixture was stirred at rt for 10 h
under a H2 atmosphere and then filtered through a pad of Celite (40 g)
and rinsed with MeOH (500 mL). The filtrate was concentrated in vac-
uo. The residue was purified by column chromatography (silica gel, n-
hexane/EtOAc 3:1 to 1:1) to give the product (64.4 g, 96%) as a color-
less amorphous solid.
Analytical Chemical HPLC conditions for 1 [column: Inertsil ODS-3V,
5 μm, 4.6 × 150 mm; mobile phase: solvent A; 0.1% TFA, solvent B;
MeOH, conditions; B 80% (12 min), 80% to 90% (10 min), 90% (5 min);
flow rate: 1.0 mL/min; column temperature: 40 °C; wavelength: 225
nm]: tR = 8.53 min.
Chemical purity: 99.7%.
Analytical Chiral HPLC conditions for 1 (column: Chiralpak AS-H, 5
μm, 0.46 × 250 mm; mobile phase: n-hexane/i-PrOH 70:30; flow rate:
1.0 mL/min; column temperature: 40 °C; wavelength: 264 nm): tR
8.75 [(R)-(+)-form], 12.97 min [(S)-(–)-form].
=
Chiral purity: 99.2% ee.
[α]D20 –56.5 (c 1.0, CHCl3).
IR (film): 3130, 2985, 1740, 1545, 1240, 934 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 8.20 (d, J = 2.8 Hz, 1 H), 7.95 (d, J = 9.2
Hz, 1 H), 7.71 (d, J = 2.8 Hz, 1 H), 7.64 (dd, J = 2.8, 8.8 Hz, 1 H), 7.60 (d,
J = 8.8 Hz, 1 H), 7.39 (dd, J = 2.8, 8.8 Hz, 1 H), 7.12 (d, J = 8.8 Hz, 1 H),
6.55 (dd, J = 2.4, 9.2 Hz, 1 H), 6.34 (d, J = 2.4 Hz, 1 H), 4.98 (s, 2 H), 4.68
(sept, J = 6.0 Hz, 1 H), 2.59 (t, J = 7.6 Hz, 2 H), 1.90 (s, 3 H), 1.61 (qt, J =
7.2, 7.6 Hz, 2 H), 1.33 (d, J = 6.0 Hz, 6 H), 0.90 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CD3OD): δ = 195.9, 177.3, 166.1, 165.1, 158.1,
155.5, 155.0, 150.0, 139.6, 136.1, 133.4, 131.2, 129.7, 127.7, 124.5 (q,
J = 285.7 Hz, 2 C), 124.2, 122.5, 122.2, 115.2, 110.0, 105.2, 78.3 (sept,
J = 29.8 Hz), 71.9, 66.5, 45.8, 33.2, 24.3, 23.6, 22.1 (2 C), 14.0.
(5) (a) An efficient synthesis of 5,5-disubstituted hydantoin via Pd-
catalyzed C-arylation of amino acid derived hydantoin was
reported, but the products were racemic: Nieto, F. F.; Rosello, J.
M.; Lenoir, S.; Hardy, S.; Clayden, J. Org. Lett. 2015, 17, 3838.
(b) Atkinson, R. C.; Nieto, F. F.; Rosello, J. M.; Clayden, J. Angew.
Chem. Int. Ed. 2015, 54, 8961.
(6) Koura, M.; Sumida, H.; Yamazaki, Y.; Shibuya, K. Tetrahedron:
Asymmetry 2016, 27, 63.
MS (EI): m/z = 683 [M]+.
(7) (a) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids;
Vols. 1–3; John Wiley: New York, 1961. (b) Shiraiwa, T.; Baba,
Y.; Miyazaki, H.; Sakata, S.; Kawamura, S.; Uehara, M.;
Kurokawa, H. Bull. Chem. Soc. Jpn. 1993, 66, 1430. (c) Murakami,
H.; Sakai, K. J. Synth. Org. Chem. Jpn. 1990, 48, 850. (d) Corson, P.
J.; Korte, D. E.; Turner, N. J. Tetrahedron: Asymmetry 1998, 9,
2587. (e) Washburn, W. N.; Sun, C. Q.; Bisacchi, G.; Wu, G.;
Cheng, P. T.; Sher, P. M.; Ryono, D.; Gavai, A. V.; Poss, K.; Girotra,
R. N.; McCann, P. J.; Mikkilineni, A. B.; Dejneka, T. C.; Wang, T.
C.; Merchant, Z.; Morella, M.; Arbeeny, C. M.; Harper, T. W.;
Slusarchyk, D. A.; Skwish, S.; Russell, A. D.; Allen, G. T.;
Tesfamariam, B.; Frohlich, B. H.; Abboa-Offei, B. E.; Cap, M.;
Waldron, T. L.; George, R. J.; Young, D.; Dickinson, K. E.;
Seymour, A. A. Bioorg. Med. Chem. Lett. 2004, 14, 3525.
Anal. Calcd for C32H31F6N3O7: C, 56.22; H, 4.57; N, 6.15. Found: C,
56.07; H, 4.61; N, 6.08.
Acknowledgment
We thank Dr. S. Tanabe, Managing Director, Member of the Board, To-
kyo New Drug Research Laboratories, Kowa Co., Ltd, for his support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588700.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) (a) Bergs, H. DE 566094, 1932. (b) Bucherer, H. T.; Fischbeck, H.
T. J. Prakt. Chem. 1934, 140, 69. (c) Bucherer, H. T.; Steiner, W. T.
J. Prakt. Chem. 1934, 140, 291. (d) Ware, E. Chem. Rev. 1950, 46,
403.
(9) When the analogue substrate, 2-amino-2-[4-(1-methyleth-
oxy)phenyl]propanoic acid was reacted with SOCl2 in MeOH at
r.t., the desired methyl ester was obtained in quantitative yield
without accompanying with decarboxylation and side product.
The cyclic sulfinate intermediates were reported in the follow-
ing references: (a) Dubuffet, T.; Lecouve, J.-P. EP 1367061, 2003.
(b) Bhirud, S. B.; Ahmed, S.; Chandrasekhar, B.; Purushotham, V.
L. A. US 2005171165, 2005. The examples of decarboxylation
References
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see Supporting Information.
(2) CCDC 1484011 [(S)-(+)-2·HBr] contains the supplementary
crystallographic data for this paper. The data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
M. Koura et al.
Paper
Synthesis
reaction were reported as follows: (c) Kamogawa, H.; Kasai, T.;
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G