M. Ohashi et al. / Bioorg. Med. Chem. 21 (2013) 2319–2332
2329
was left to stand overnight, then poured into a saturated aqueous
solution of sodium hydrocarbonate, and the whole was extracted
with ethyl acetate. The extract was washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The residue was
purified by silica gel column chromatography (eluant; n-hexane/
ethyl acetate = 1:2 v/v) to afford 170 mg (54%) of the intermediate
compound as a colorless oil. 1H NMR (400 MHz, CDCl3) d 8.71 (d,
J = 5.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.80–7.73 (m, 4H), 7.30–
7.15 (m, 11H), 6.90–6.87 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.66 (t,
J = 5.4 Hz, 1H), 4.69 (dd, J = 14.6, 5.8 Hz, 1H), 4.64–4.55 (m, 2H),
4.41–4.35 (m, 1H), 4.00–3.92 (m, 2H), 3.90 (dd, J = 8.8, 2.4 Hz,
1H), 3.74 (t, J = 8.4 Hz, 1H), 3.08 (dd, J = 13.6, 8.8 Hz, 1H), 2.98
(dd, J = 13.2, 8.8 Hz, 1H), 2.92–2.79 (m, 3H), 2.51 (dd, J = 13.6,
8.8 Hz, 1H), 1.87–1.78 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H); MS (FAB)
668 (M+H)+.
on a Shimadzu HPLC system, with CH3CN/0.1% TFA = 3:1 v/v as the
eluant and detection at 254 nm.
4.10. (R)-2-Benzyl-3-(4-propoxy-3-((4-(thiophen-2-
yl)benzamido)methyl)phenyl)propanoic acid ((R)-7f)
This compound was prepared by means of a procedure similar
to that used for 7g and 7a.
1H NMR (400 MHz, DMSO-d6)
d 12.05 (s, 1H), 8.81 (t,
J = 5.6 Hz, 1H), 7.94 (t, J = 8.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H),
7.64 (dd, J = 3.6, 1.2 Hz, 1H), 7.62 (dd, J = 5.2, 1.2 Hz, 1H), 7.19–
7.15 (m, 3H), 7.12–7.09 (m, 3H), 7.02–6.99 (m, 2H), 6.86 (d,
J = 8.4 Hz, 1H), 4.49–4.38 (m, 2H), 3.92 (t, J = 6.2 Hz, 2H), 2.81–
2.71 (m, 3H), 2.68–2.56 (m, 2H), 1.77–1.68 (m, 2H), 0.98 (t,
J = 7.4 Hz, 3H); 13C NMR (300 MHz, DMSO-d6) d 175.64, 165.75,
154.51, 142.39, 139.42, 136.31, 133.18, 130.55, 128.79, 128.24,
128.23, 127.81, 126.83, 126.75, 126.13, 125.13, 124.92, 111.18,
69.06, 48.85, 37.74, 37.26, 36.79, 22.24, 10.64; MS (FAB) 514
This compound was treated with 30% hydrogen peroxide, as de-
scribed for 7a.
1H NMR (400 MHz, DMSO-d6) d 8.91 (t, J = 5.8 Hz, 1H), 8.74(d,
J = 4.4 Hz, 1H), 8.19–8.13 (m, 3H), 8.09–8.03 (m, 3H), 7.53 (t,
J = 6.0 Hz, 1H), 7.19–7.16 (m, 2H), 7.12–7.09 (m, 3H), 7.03–7.01
(m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 4.51–4.40 (m, 2H), 3.93 (t,
J = 6.4 Hz, 2H), 2.80–2.70 (m, 3H), 2.67–2.57 (m, 2H), 1.77–1.69
(m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (300 MHz, CDCl3) d
178.72, 166.91, 156.23, 155.71, 149.54, 141.71, 139.04, 137.22,
134.84, 131.02, 130.36, 129.21, 128.93, 128.40, 127.47, 127.11,
126.35, 125.79, 122.82, 121.19, 111.11, 69.48, 49.44, 40.32,
37.86, 36.94, 22.66, 10.75; MS (FAB) 509 (M+H)+; calcd for
(M+H)+; calcd for C31H32NO4 S 514.2051, found 514.2070; [
ꢁ8.6° (c 0.25, CH3CN). The enantiomeric excess (ee) of this com-
pound was determined to be 96% by chiral HPLC using
a]
D
a
4.6 ꢀ 250 mm CHIRALPAK IA column (Diacel Chemical Industries,
Ltd), eluting at a flow rate of 0.5 mL/min with 2-propanol/n-hex-
ane/TFA (1:2:0.03 v/v/v): retention time 17.6 min (the S enantio-
mer has
a retention time of 15.6 min); HPLC purity was
estimated to be 99.2% by means of reversed-phase HPLC, using
a Pegasil ODS sp100 column (4.6 ꢀ 250 mm, Senshu Chemical,
Japan) fitted on a Shimadzu HPLC system, with CH3CN/0.1%
TFA = 3:1 v/v as the eluant and detection at 285 nm.
C
32H33N2O4 509.2440, found 509.2421;
[
a
]
ꢁ7.3° (c 0.25,
D
CH3CN). The enantiomeric excess (ee) of this compound was
determined to be 97% by chiral HPLC using a 4.6 ꢀ 250 mm
CHIRALPAK IA column (Diacel Chemical Industries, Ltd), eluting
4.11. (R)-2-Benzyl-3-(4-propoxy-3-((4-(pyridin-3-yl)benzamido)
methyl)phenyl)propanoic acid ((R)-7h)
at
a flow rate of 0.5 mL/min with 2-propanol/n-hexane/TFA
(3:2:0.03 v/v/v): retention time 11.8 min (the S enantiomer has
a retention time of 10.8 min); HPLC purity was estimated to be
97.2% by means of reversed-phase HPLC, using a Pegasil ODS
sp100 column (4.6 ꢀ 250 mm, Senshu Chemical, Japan) fitted
on a Shimadzu HPLC system, with CH3CN/0.1% TFA = 3:1 v/v as
the eluant and detection at 254 nm.
This compound was prepared by means of a procedure similar
to that used for 7g and 7a.
1H NMR (400 MHz, DMSO-d6) d 12.05 (s, 1H), 8.96 (d, J = 1.6 Hz,
1H), 8.88(t, J = 5.6 Hz, 1H), 8.60 (dd, J = 4.8, 1.6 Hz, 1H), 8.15 (dt,
J = 8.8, 1.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H),
7.51 (dd, J = 8.0, 4.8 Hz, 1H), 7.19–7.09 (m, 5H), 7.03–7.00 (m,
2H), 6.87 (d, J = 8.0 Hz, 1H), 4.51–4.40 (m, 2H), 3.93 (t, J = 6.4 Hz,
2H), 2.80–2.70 (m, 3H), 2.67–2.57 (m, 2H), 1.78–1.68 (m, 2H),
0.99 (t, J = 7.4 Hz, 3H); 13C NMR (300 MHz, DMSO-d6) d 175.65,
165.84, 154.50, 149.60, 147.84, 139.69, 139.45, 134.38, 133.95,
130.58, 128.77, 128.21, 128.14, 128.04, 127.77, 126.85, 126.71,
126.11, 124.01, 111.18, 111.11, 69.06, 48.87, 37.76, 37.24, 36.80,
22.23, 10.63; MS (FAB) 509 (M+H)+; calcd for C32H33N2O4
4.9. (R)-2-Benzyl-3-(3-((30-fluoro-[1,10-biphenyl]-4-ylcarboxamido)
methyl)-4-propoxy-phenyl)propanoic acid ((R)-7d)
This compound was prepared by means of a procedure similar
to that used for 7g and 7a.
1H NMR (400 MHz, DMSO-d6) d 8.87 (t, J = 5.6 Hz, 1H), 8.00 (d,
J = 8.4, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.61–7.58 (m, 2H), 7.55–7.49
(m, 1H), 7.23 (dt, J = 8.8, 1.6 Hz, 1H), 7.19–7.15 (m, 2H), 7.12–
7.09 (m, 3H), 7.03–7.00 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.50–
4.40 (m, 2H), 3.92 (t, J = 6.4 Hz, 2H), 2.79–2.71 (m, 3H), 2.69–2.56
(m, 2H), 1.77–1.69 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR
509.2440, found 509.2421; [
a]D ꢁ8.3° (c 0.25, CH3CN). The enantio-
meric excess (ee) of this compound was determined to be >98% by
chiral HPLC using a 4.6 ꢀ 250 mm CHIRALPAK IA column (Diacel
Chemical Industries, Ltd), eluting at a flow rate of 0.5 mL/min with
2-propanol/n-hexane/TFA (1:2:0.03 v/v/v): retention time 30.7 min
(the S enantiomer was not detectable); HPLC purity was estimated
to be 99.6% by means of reversed-phase HPLC, using a Pegasil ODS
sp100 column (4.6 ꢀ 250 mm, Senshu Chemical, Japan) fitted on a
Shimadzu HPLC system, with CH3CN/0.1% TFA = 3:1 v/v as the elu-
ant and detection at 290 nm.
(300 MHz, CDCl3)
d 179.11, 166.86, 164.78, 161.52, 155.75,
142.74, 142.71, 142.29, 142.19, 138.85, 138.83, 130.84, 130.46,
130.45, 130.44, 130.34, 129.21, 128.90, 128.44, 127.57, 127.15,
126.43, 125.86, 122.83, 122.79, 114.88, 114.60, 114.21, 113.92,
111.13, 69.50, 49.40, 40.33, 37.77, 36.89, 22.74, 10.76; MS (FAB)
526 (M+H)+; calcd for C33H33FNO4 526.2394, found 526.2399;
[
a
]
ꢁ7.6° (c 0.25, CH3CN). The enantiomeric excess (ee) of this
D
4.12. (R)-2-Benzyl-3-(4-propoxy-3-((4-(pyridin-4-
yl)benzamido)methyl)phenyl)propanoic acid ((R)-7i)
compound was determined to be 96% by chiral HPLC using a
4.6 ꢀ 250 mm CHIRALPAK IA column (Diacel Chemical Industries,
Ltd), eluting at a flow rate of 0.5 mL/min with 2-propanol/n-hex-
ane/TFA (1:2:0.03 v/v/v): retention time 18.7 min (the S enantio-
mer has a retention time of 16.2 min). The purity was estimated
to be 99.7% by means of reversed-phase HPLC, using a Pegasil
ODS sp100 column (4.6 ꢀ 250 mm, Senshu Chemical, Japan) fitted
This compound was prepared by means of a procedure similar
to that used for 7g and 7a.
1H NMR (400 MHz, DMSO-d6) d 8.99 (t, J = 5.2 Hz, 1H), 8.88 (d,
J = 4.8 Hz, 2H), 8.23 (d, J = 5.2 Hz, 2H), 8.11–8.05 (m, 4H), 7.19–
7.09 (m, 5H), 7.03–7.00 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.51–