N. Yamakawa et al. / Bioorg. Med. Chem. 19 (2011) 3299–3311
3309
C21H21Na2O3: 367.1286). Anal. Calcd for C21H21NaO3ꢀ0.5H2O: C,
142.49 (d, JC–F = 1.9 Hz, Ar-C40), 183.28 (CO2Na), 222.98 (C@O).
HR-FAB-MS (m/z): 385.1188 (M++Na, calcd for C21H20FNa2O3:
385.1192). Anal. Calcd for C21H20FNaO3ꢀH2O: C, 66.31; H, 5.83.
Found: C, 66.44, H, 5.76.
71.22; H, 6.36. Found: C, 71.37, H, 6.27.
5.2.3.4. Sodium 2-{40-methyl-5-[(2-oxocyclopentyl)methyl]]bi-
phenyl-2-yl}propanoate (25). Yieldꢁ: 177%, three steps. IR (KBr)
1420, 1712 (CO2ꢁ), 1733 (C@O), cm 1H NMR (CD3OD) d: 1.21
(3H, dd, J = 7.3, 1.5 Hz,
-CH3), 1.54–2.44 (7H, m, H10, H30, H40,
m:
.
5.2.3.8. Sodium 2-{5-[(2-oxocyclopentyl)methyl]-40-(trifluoro-
methoxy)biphenyl-2-yl}propanoate (29). Yield: 56%, three steps.
a
H50), 2.36 (3H, s, Ar-CH3), 2.51 (1H, dd, J = 13.4, 9.3 Hz, CH2), 3.04
(1H, dd, J = 13.7, 9.3 Hz, CH2), 3.72 (1H, q, J = 7.1 Hz, CH), 6.92
(1H, t, J = 1.8 Hz, Ar-H3), 7.08 (1H, dt, J = 8.1, 1.8 Hz, Ar-H5), 7.18
(2H, d, J = 7.7 Hz, Ar-H30), 7.26 (2H, d, J = 7.7 Hz, Ar-H20), 7.44
IR (KBr)
d: 1.25 (3H, dd, J = 7.0, 1.1 Hz,
m
: 1421, 1709 (CO2ꢁ), 1731 (C@O), cmꢁ1. 1H NMR (CD3OD)
a
-CH3), 1.51–2.45 (7H, m, H10, H30,
H40, H50), 2.53 (1H, dd, J = 13.6, 9.5 Hz, CH2), 3.05 (1H, dd,
J = 13.6, 4.0 Hz, CH2), 3.62 (1H, q, J = 7.2 Hz, CH), 6.95 (1H, t,
J = 2.2 Hz, Ar-H3), 7.13 (1H, dt, J = 8.1, 2.2 Hz, Ar-H30), 7.28 (2H,
dd, J = 8.8, 0.7 Hz, Ar-H5,), 7.46–7.51 (3H, m, Ar-H6, Ar-H20). 13C
(1H, d, J = 8.1 Hz, Ar-H6). 13C NMR (CD3OD) d: 21.19 (
a-CH3),
21.47 (C50), 21.44 (C40), 30.08 (Ar-CH3), 36.07 (CH2), 39.08 (C30),
45.70 (CH), 52.12 (C10), 128.61 (Ar-C1), 128.80 (Ar-C5), 129.58
(Ar-C20), 130.53 (Ar-C30), 131.31 (Ar-C6), 137.33 (Ar-C3), 138.29
(Ar-C40), 140.52 (Ar-C2), 141.64 (Ar-C10), 143.09 (Ar-C4), 183.58
(CO2Na), 223.09 (C@O). HR-FAB-MS (m/z): 381.1439 (M++Na, calcd
for C22H23Na2O3: 381.1443). Anal. Calcd for C22H23NaO3ꢀ0.5H2O: C,
72.03; H, 6.66. Found: C, 71.92, H, 6.58.
NMR (CD3OD) d: 21.12 (a
-CH3), 21.44 (C50), 30.08 (C40), 35.99
(CH2), 39.04 (C30), 47.75 (CH), 52.04 (C10), 121.51 (Ar-C30), 128.77
(Ar-C1), 129.46 (Ar-C5), 131.17 (Ar-OCF3), 131.23 (Ar-C6), 132.37
(Ar-C20), 138.62 (Ar-C10), 141.52 (Ar-C3), 141.57 (Ar-C2), 142.58
(Ar-C4),, 149.45 (Ar-C40), 183.28 (CO2Na), 222.98 (C@O). HR-FAB-
MS (m/z): 451.1107 (M++Na, calcd for C22H20F3Na2O4: 451.1109).
Anal. Calcd for C22H20F3NaO4ꢀ0.5H2O: C, 60.41; H, 4.84. Found: C,
60.34, H, 4.98.
5.2.3.5. Sodium 2-{40-methoxy-5-[(2-oxocyclopentyl)methyl]bi-
phenyl-2-yl}propanoate (26). Yield: 70%, three steps. IR (KBr)
1416, 1711 (CO2ꢁ), 1732 (C@O), cmꢁ1 1H NMR (CD3OD) d: 1.22
(3H, dd, J = 7.0, 1.5 Hz,
-CH3), 1.53–2.40 (7H, m, H10, H30, H40,
m:
.
5.2.3.9. Sodium 20-(1-carboxylatoethyl)-50-[(2-oxocyclopentyl)-
methyl]biphenyl-4-carboxylate (30). Yield: 74%, three steps. IR
a
H50), 2.51 (1H, dd, J = 13.6, 9.5 Hz, CH2), 3.04 (1H, dd, J = 13.4,
3.8 Hz, CH2), 3.73 (1H, q, J = 7.0 Hz, CH), 3.81 (3H, s, Ar-OCH3),
6.92–6.95 (3H, m, Ar-H3, Ar-H30), 7.07 (1H, d, J = 8.1 Hz, Ar-H5),
7.31 (2H, d, J = 8.4 Hz, Ar-H20), 7.43 (1H, d, J = 8.1 Hz, Ar-H6). 13C
(KBr)
(CD3OD) d: 1.22 (3H, dd, J = 7.1, 1.6 Hz,
m .
: 1420, 1689, 1712 (CO2ꢁ), 1727 (C@O), cmꢁ1 1H NMR
a-CH3), 1.33–2.42 (7H, m,
H10, H30, H40, H50), 2.53 (1H, dd, J = 13.6, 9.2 Hz, CH2), 3.06 (1H,
dd, J = 13.6, 4.0 Hz, CH2), 3.73 (1H, q, J = 7.1 Hz, CH), 6.96 (1H, st,
J = 1.6 Hz, Ar-H3), 7.11 (1H, dt, J = 8.1, 1.8 Hz, Ar-H5), 7.40 (2H, d,
J = 8.4 Hz, Ar-H20), 7.44 (1H, d, J = 8.1 Hz, Ar-H6), 7.99 (2H, d,
NMR (CD3OD) d: 21.23 (a
-CH3), 21.45 (C50), 30.08 (C40), 36.08
(CH2), 39.09 (C30), 45.70 (CH), 52.03 (C10), 55.72 (Ar-OCH3),
114.43 (Ar-C20), 128.60 (Ar-C1), 128.72 (Ar-C5), 131.44 (Ar-C6),
131.70 (Ar-C30), 135.81 (Ar-C3), 138.29 (Ar-C40), 141.73 (Ar-C2),
142.78 (Ar-C10), 160.07 (Ar-C4), 183.60 (CO2Na), 223.10 (C@O).
HR-FAB-MS (m/z): 397.1399 (M++Na, calcd for C22H23Na2O4:
397.1392). Anal. Calcd for C22H23NaO4ꢀH2O: C, 67.22; H, 6.38.
Found: C, 67.33, H, 6.42.
J = 8.4 Hz, Ar-H30). 13C NMR (CD3OD) d: 20.00 (
a-CH3), 21.45
(C50), 30.11 (C40), 36.06 (CH2), 39.05 (C30), 45.55 (CH), 52.11 (C10),
128.64 (Ar-C1), 129.18 (Ar-C50), 130.01 (Ar-C20), 130.10 (Ar-C30),
131.23 (Ar-C6), 137.37 (Ar-C3), 138.52 (Ar-C2), 141.47 (Ar-C40),
142.81 (Ar-C4), 145.50 (Ar-C10), 175.36 (Ar-CO2Na), 183.17
(CO2Na), 223.02 (C@O). HR-FAB-MS (m/z): 433.1001 (M++Na, calcd
for C22H20Na3O5: 433.1004). Anal. Calcd for C22H20Na2O5ꢀH2O: C,
61.68; H, 5.18. Found: C, 61.54, H, 5.06.
5.2.3.6. Sodium 2-(40-(methylthio)-5-((2-oxocyclopentyl)met-
hyl)biphenyl-2-yl)propanoate (27). Yield: 60%, three steps. IR
(KBr)
m
: 1417, 1712 (CO2ꢁ), 1730 (C@O), cmꢁ1
.
1H NMR (CD3OD)
5.2.3.10. Sodium 2-{40-hydroxy-5-[(2-oxocyclopentyl)methyl]-
d: 1.23 (3H, dd, J = 7.1, 1.3 Hz,
a
-CH3), 1.55–2.45 (7H, m, H10, H30,
biphenyl-2-yl}propanoate (31). Yield: 50%, three steꢁp1s. IR (KBr)
H40, H50), 2.49 (3H, s, Ar-SCH3), 2.52 (1H, dd, J = 13.9, 9.2 Hz,
CH2), 3.05 (1H, dd, J = 13.6, 4.0 Hz, CH2), 3.70 (1H, q, J = 7.2 Hz,
CH), 6.94 (1H, t, J = 1.8 Hz, Ar-H3), 7.10 (1H, dt, J = 8.1, 2.2 Hz,
Ar-H5), 7.31 (4H, dd, J = 14.5, 8.6 Hz, Ar-H20, Ar-H30), 7.45 (1H, d,
J = 8.1 Hz, Ar-H6). 13C NMR (CD3OD) d: 15.91 (Ar-SCH3), 21.21
m .
: 1318 (Ar-OH), 1421, 1710 (CO2ꢁ), 1731 (C@O), cm 1H NMR
(CD3OD) d: 1.22 (3H, dd, J = 7.3, 1.5 Hz, a-CH3), 1.52–2.42 (7H, m,
H10, H30, H40, H50), 2.50 (1H, d, J = 13.9 Hz, CH2), 3.02 (1H, d,
J = 13.6 Hz, CH2), 3.75 (1H, q, J = 7.2 Hz, CH), 6.80 (2H, d,
J = 8.4 Hz, Ar-H30), 6.92 (1H, s, Ar-H3), 7.05 (1H, d, J = 8.1 Hz, Ar-
H5), 7.21 (2H, d, J = 8.4 Hz, Ar-H20), 7.42 (1H, d, J = 8.1 Hz, Ar-H6).
(a
-CH3), 21.45 (C50), 30.09 (C40), 36.06 (CH2), 39.06 (C30), 45.73
(CH), 52.12 (C10), 127.36 (Ar-C30), 128.70 (Ar-C1), 128.98 (Ar-C5),
129.05 (Ar-C6), 131.17 (Ar-C20), 138.33 (Ar-C3), 138.44 (Ar-C2),
140.32 (Ar-C10), 141.61 (Ar-C4), 142.49 (Ar-C40), 183.42 (CO2Na),
223.01 (C@O). HR-FAB-MS (m/z): 413.1165 (M++Na, calcd for
13C NMR (CD3OD) d: 21.32 ( -CH3), 30.10 (C50), 36.10 (C40), 39.09
a
(CH2), 45.72 (C30), 52.20 (CH), 58.31 (C10), 116.15 (Ar-C30), 128.40
(Ar-C1), 128.54 (Ar-C5), 131.51 (Ar-C6), 131.66 (Ar-C20), 134.03
(Ar-C10), 138.19 (Ar-C3), 141.76 (Ar-C2), 143.24 (Ar-C4), 158.47
(Ar-C40), 183.81 (CO2Na), 219.16 (C@O). HR-FAB-MS (m/z):
361.1414 (M++H, calcd for C21H22NaO4: 361.1416). Anal. Calcd for
C
22H23Na2SO3: 413.1163). Anal. Calcd for C22H23NaSO3ꢀH2O: C,
64.54; H, 6.10. Found: C, 64.69, H, 6.17.
C21H21NaO4ꢀH2O: C, 68.28; H, 6.00. Found: C, 68.30, H, 6.09.
5.2.3.7. Sodium 2-{40-fluoro-5-[(2-oxocyclopentyl)methyl]bi-
phenyl-2-yl}propanoate (28). Yield: 64%, three stepꢁs.1 IR (KBr)
1204 (Ar-F), 1414, 1710 (CO2ꢁ), 1730 (C@O), cm 1H NMR
-CH3), 1.55–2.41 (7H, m,
m
:
5.2.4. Synthesis of the alcohol derivative of 31 (32, 33)
A methyl ester intermediate derived from 31 was reduced by
NaBH4 (see below) and alkaline hydrolyzed.
.
(CD3OD) d: 1.22 (3H, dd, J = 7.3, 1.1 Hz,
a
H10, H30, H40, H50), 2.52 (1H, dd, J = 13.6, 9.2 Hz, CH2), 3.05 (1H,
dd, J = 13.6, 4.0 Hz, CH2), 3.64 (1H, q, J = 7.2 Hz, CH), 6.93 (1H, t,
J = 1.8 Hz, Ar-H3), 7.13–7.07 (3H, m, Ar-H5, Ar-H30), 7.38–7.46
5.2.4.1. Reduction of methyl ester intermediate derived from 31
with NaBH4. To a stirred solution of methyl ester intermediate
derived from 31 (1 equiv, ca. 1.8 mmol) in EtOH, NaBH4 (1.3 equiv,
ca. 2.4 mmol) was added, stirred for 1 h at room temperature,
quenched by the addition of a few ice chips, and the resulting
solution was extracted with CH2Cl2. The extracts were dried over
anhydrous Na2SO4 and filtrated. The filtrate was evaporated to
(3H, m, Ar-H6, Ar-H20). 13C NMR (CD3OD) d: 21.08 (
a-CH3), 21.45
(C50), 30.09 (C40), 36.04 (CH2), 39.06 (C30), 45.73 (CH), 52.09 (C10),
115.60 (d, JC–F = 21.1 Hz, Ar-C30), 128.68 (Ar-C1), 129.19 (Ar-C5),
131.32 (Ar-C6), 132.46 (d, JC–F = 8.1 Hz, Ar-C20), 138.50 (Ar-C3),
139.57 (d, JC–F = 3.7 Hz, Ar-C10), 141.64 (Ar-C2), 142.02 (Ar-C4),