1530
Vol. 59, No. 12
1
as described of 8a from 5a as a pale yellow oil (yield 52% in 3 steps). H-
4.12 (q, Jꢃ7.1 Hz, 2H), 4.05 (m, 1H), 3.49 (m, 1H), 2.90—2.78 (m, 2H),
2.72 (m, 1H), 2.62 (q, Jꢃ7.7 Hz, 2H), 2.42—2.32 (m, 2H), 2.25 (t,
Jꢃ7.4 Hz, 2H), 2.24 (m, 1H), 1.73 (m, 1H), 1.71—1.66 (m, 2H), 1.50—1.20
(m, 6H), 1.26 (t, Jꢃ7.7 Hz, 3H), 1.25 (t, Jꢃ7.1 Hz, 3H).
NMR (300 MHz, CDCl3) d: 7.65—7.30 (m, 4H), 5.73 (dd, Jꢃ15.6, 5.6 Hz,
1H), 5.51 (ddd, Jꢃ15.6, 8.0, 1.2 Hz, 1H), 4.45 (m, 1H), 4.11 (q, Jꢃ7.4 Hz,
2H), 4.04 (m, 1H), 3.44 (m, 1H), 2.91 (d, Jꢃ6.6 Hz, 2H), 2.72 (m, 1H),
2.44—1.86 (m, 6H), 1.80—1.04 (m, 9H), 1.24 (t, Jꢃ7.4 Hz, 3H).
7-{(2R)-2-[(1E,3S)-3-Hydroxy-4-(3-ethylphenyl)-1-buten-1-yl]-5-oxo-
1-pyrrolidinyl}heptanoate (2e) Compound 2e was prepared from 8d ac-
cording to the same procedure as described of 2b from 8a as a colorless
oil(75 mg, yield 98%). IR (KBr): 2932, 1659, 1461, 1374, 1264, 1103, 1033,
7-((2R)-2-{(1E,3S)-3-Hydroxy-4-[3-(trifluoromethyl)phenyl]-1-buten-
1-yl}-5-oxo-1-pyrrolidinyl)heptanoate (2g) Compound 2g was prepared
from 8f according to the same procedure as described of 2b from 8a as a
white powder (yield 83%). IR (film): 2932, 1652, 1453, 1330, 1162, 1122,
1074, 1036, 975, 907, 800, 752, 705, 664 cmꢁ1; 1H-NMR (300 MHz, CDCl3)
d: 7.60—7.35 (m, 4H), 5.73 (dd, Jꢃ15.3, 5.9 Hz, 1H), 5.50 (ddd, Jꢃ15.3,
8.3, 0.9 Hz, 1H), 4.46 (m, 1H), 4.03 (m, 1H), 4.00—3.00 (m, 2H), 3.46 (m,
1H), 2.91 (d, Jꢃ6.3 Hz, 2H), 2.71 (m, 1H), 2.48—2.06 (m, 5H), 1.76—1.12
(m, 9H); MS (APCI) m/z: 426 (MꢁH)ꢁ; HR-MS-FAB (m/z): [MꢄH]ꢄ
Calcd for C22H29F3NO4, 428.2049; Found: 428.2057.
Methyl 4-{(2-{(2R)-2-[(1E)-4-(3-Trifluoromethylphenyl)-3-oxo-1-
buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio}butanoate (9c) Compound
9c was prepared from 5b using 10e instead of 10a according to the same
procedure as described of 8a from 5a as a colorless oil (90 mg, 30% in 3
steps). 1H-NMR (300 MHz, CDCl3) d: 7.59—7.39 (m, 4H), 5.77 (dd,
Jꢃ15.3, 5.4 Hz, 1H), 5.53 (dd, Jꢃ15.3, 8.6 Hz, 1H), 4.51—4.40 (m, 1H),
4.18—4.08 (m, 1H), 3.70—3.58 (m, 4H), 3.05—2.88 (m, 3H), 2.70—2.19
(m, 10H), 1.94—1.84 (m, 2H), 1.78—1.60 (m, 1H).
974, 895, 796, 735, 704, 666, 578 cmꢁ1
;
1H-NMR (300 MHz, CDCl3) d:
7.24 (t, Jꢃ7.3 Hz, 1H), 7.11—6.97 (m, 3H), 5.74 (dd, Jꢃ15.1, 5.9 Hz, 1H),
5.50 (ddd, Jꢃ15.1, 8.3, 1.0 Hz, 1H), 4.42 (m, 1H), 4.04 (m, 1H), 3.45 (m,
1H), 2.84—2.80 (m, 2H), 2.75 (m, 1H), 2.63 (q, Jꢃ7.8 Hz, 2H), 2.43—2.32
(m, 2H), 2.35 (t, Jꢃ7.3 Hz, 2H), 2.21 (m, 1H), 1.71 (m, 1H), 1.68—1.57 (m,
2H), 1.54—1.20 (m, 6H), 1.24 (t, Jꢃ7.8 Hz, 3H); MS (APCI) m/z: 386
(MꢁH)ꢁ; HR-MS-FAB (m/z): [MꢄH]ꢄ Calcd for C23H34NO4, 388.2488;
Found: 388.2470.
3-(3-Propylphenyl)-2-oxopropanephosphonate (10d) Compound 10d
was prepared in the same procedure as described of 10k from (3-bro-
mophenyl)acetic acid as a colorless oil (2.96 g, yield 59% in 5 steps). 1H-
NMR (300 MHz, CDCl3) d: 7.29—7.01 (m, 4H), 3.86 (s, 2H), 3.82 (s, 3H),
3.76 (s, 3H), 3.10 (d, Jꢃ22.8 Hz, 2H), 2.57 (t, Jꢃ8.0 Hz, 2H), 1.76—1.50
(m, 2H), 0.93 (t, Jꢃ7.0 Hz, 3H).
Ethyl 7-{(2R)-2-[(1E,3S)-3-Hydroxy-4-(3-propylphenyl)-1-buten-1-yl]-
5-oxo-1-pyrrolidinyl}heptanoate (8e) Compound 8e was prepared from
5a using 10d instead of 10a according to the same procedure as described of
8a from 5a as a colorless oil (255 mg, yield 48% in 3 steps). 1H-NMR
(300 MHz, CDCl3) d: 7.26—7.19 (m, 1H), 7.08—6.99 (m, 3H), 5.75 (dd,
Jꢃ15.4, 5.6 Hz, 1H), 5.48 (ddd, Jꢃ15.4, 8.0, 1.2 Hz, 1H), 4.50—4.30 (m,
1H), 4.11 (q, Jꢃ7.2 Hz, 2H), 4.13—4.00 (m, 1H), 3.55—3.40 (m, 1H),
2.90—2.10 (m, 8H), 1.80—1.20 (m, 13H), 1.25 (t, Jꢃ7.2 Hz, 3H), 0.94 (t,
Jꢃ7.2 Hz, 3H).
4-[(2-{(2R)-2-[(1E,3S)-3-Hydroxy-4-(3-trifluoromethylphenyl)but-1-
enyl]-5-oxopyrrolidin-1-yl}ethyl)sulfanyl]butanoic Acid (3e) Compound
3e was prepared from 9c according to the same procedure as described of 2b
from 8a as a pale yellow oil (67 mg, 100%). IR (film): 3388, 2925, 1724,
1660, 1450, 1421, 1330, 1163, 1122, 1074, 1035, 976, 800, 754, 705 cmꢁ1
;
1H-NMR (300 MHz, CDCl3) d: 7.59—7.38 (m, 4H), 5.82—5.71 (m, 1H),
5.60—5.41 (m, 1H), 4.57—4.40 (m, 1H), 4.20—4.06 (m, 1H), 3.70—3.59
(m, 1H), 3.15—2.81 (m, 3H), 2.80—2.01 (m, 10H), 1.99—1.80 (m, 2H),
1.79—1.60 (m, 1H); MS (APCI) m/z: 444 (MꢁH)ꢁ; HR-MS-FAB (m/z):
[MꢁH]ꢁ Calcd for C21H25F3NO4S, 444.1456; Found: 444.1476
7-{(2R)-2-[(1E,3S)-3-Hydroxy-4-(3-propylphenyl)-1-buten-1-yl]-5-oxo-
1-pyrrolidinyl}heptanoate (2f) Compound 2f was prepared from 8e ac-
cording to the same procedure as described of 2b from 8a as a colorless oil
(47 mg, yield 96%). IR (film): 3389, 2931, 2862, 1728, 1660, 1632, 1487,
{3-[(2,2,2-Trifluoroethoxy)methyl]phenyl}acetate (21) To
a stirred
suspension of sodium hydride (63% in mineral oil, 770 mg, 20.2 mmol) in
THF (40 ml) was added trifluoroethanol (1.46 ml, 20.2 mmol) at 0 °C under
argon atmosphere. After being stirred for 10 min, to this resulting solution
was added a solution of 1,3-bis(bromomethyl)benzene (5.28 g, 20.2 mmol)
in THF (10 ml). After being stirred for additional 4 h, the reaction mixture
was poured into ice-cold aqueous NH4Cl, extracted with EtOAc, washed
with H2O, brine, and dried over MgSO4. The organic solvent was removed
by evaporation to give an ether. To a stirred solution of the above-described
ether in THF (30 ml) and MeOH (15 ml) were added potassium carbonate
(5.0 g, 36.0 mmol) and bis(triphenylphosphine)palladium dichloride
(280 mg, 0.40 mmol) under argon atmosphere, and the reaction vessel was
replaced with CO gas repeatedly. After being stirred at room temperature for
3 h, the resulting mixture was diluted with EtOAc and filtered through a pad
of Celite. The filtrate was evaporated and purified by column chromatogra-
phy on silica gel (hexane/EtOAc, 9/1) to afford 21 as a brown oil (3.28 g,
63%).
1463, 1422, 1376, 1263, 1103, 1034, 973, 903 cmꢁ1
;
1H-NMR (300 MHz,
CDCl3) d: 7.25—7.19 (m, 1H), 7.08—7.00 (m, 3H), 5.75 (dd, Jꢃ15.3,
5.7 Hz, 1H), 5.51 (ddd, Jꢃ15.3, 8.4, 0.9 Hz, 1H), 4.41 (m, 1H), 4.05 (m,
1H), 3.48 (m, 1H), 2.90—2.70 (m, 3H), 2.57 (t, Jꢃ7.2 Hz, 2H), 2.50—2.10
(m, 5H), 1.80—1.20 (m, 11H), 0.94 (t, Jꢃ7.2 Hz, 3H); MS (APCI) m/z: 400
(MꢁH)ꢁ; HR-MS-FAB (m/z): [MꢄH]ꢄ Calcd for C24H36NO4, 402.2644;
Found: 402.2633.
Methyl 4-{(2-{(2R)-2-[(1E)-4-(3-Propylphenyl)-3-oxo-1-buten-1-yl]-5-
oxo-1-pyrrolidinyl}ethyl)thio}butanoate (9b) Compound 9b was pre-
pared from 5b using 10d instead of 10a according to the same procedure as
described of 8a from 5a as a colorless oil (155 mg, 49% in 3 steps). 1H-
NMR (200 MHz, CDCl3) d: 7.30—7.20 (m, 1H), 7.10—7.00 (m, 3H), 5.77
(dd, Jꢃ15.4, 5.6 Hz, 1H), 5.52 (dd, Jꢃ15.4, 9.4 Hz, 1H), 4.50—4.35 (m,
1H), 4.20—4.00 (m, 1H), 3.80—3.55 (m, 1H), 3.67 (s, 3H), 3.05—2.85 (m,
1H), 2.85—2.75 (m, 2H), 2.75—2.10 (m, 11H), 2.00—1.80 (m, 3H), 1.80—
1.50 (m, 3H), 0.94 (t, Jꢃ6.8 Hz, 3H).
3-[3-(2,2,2-Trifluoroethoxymethyl)phenyl]-2-oxopropanephosphonate
(10f) Compound 10f was prepared from 21 according to the same proce-
dure as described of 10d from 20a as a colorless oil (2.28 g, yield 52% in 3
steps). 1H-NMR (200 MHz, CDCl3) d: 7.40—7.12 (m, 4H), 4.66 (s, 2H),
3.92 (s, 2H), 3.83 (q, Jꢃ8.8 Hz, 2H), 3.82 (s, 3H). 3.76 (s, 3H), 3.17 (d,
Jꢃ22.8 Hz, 2H).
4-[(2-{(2R)-2-[(1E,3S)-3-Hydroxy-4-(3-propylphenyl)but-1-enyl]-5-ox-
opyrrolidin-1-yl}ethyl)sulfanyl]butanoic Acid (3d) Compound 3d was
prepared from 9b according to the same procedure as described of 2b from
8a as a pale yellow oil (yield 99%). IR (film): 3387, 2927, 2870, 1726, 1660,
1445, 1419, 1384, 1235, 1103, 1032, 975, 909, 784, 705, 667 cmꢁ1
;
1H-
Ethyl 7-[(2R)-2-{(1E,3S)-3-Hydroxy-4-[3-(2,2,2-trifluoroethoxy-
methyl)phenyl]-1-buten-1-yl]}-5-oxo-1-pyrrolidinyl]heptanoate (8g)
Compound 8g was prepared from 5a using 10f instead of 10a according to
the same procedure as described of 8a from 5a as a colorless oil (61 mg,
NMR (200 MHz, CDCl3) d: 7.30—7.20 (m, 1H), 7.10—7.00 (m, 3H), 5.78
(dd, Jꢃ15.4, 5.4 Hz, 1H), 5.52 (dd, Jꢃ15.4, 8.4 Hz, 1H), 4.50—4.40 (m,
1H), 4.20—4.05 (m, 1H), 3.75—3.55 (m, 1H), 3.20—2.10 (m, 14H), 2.00—
1.80 (m, 2H), 1.80—1.55 (m, 3H), 0.94 (t, Jꢃ7.2 Hz, 3H); MS (APCI) m/z:
418 (MꢁH)ꢁ; HR-MS-FAB (m/z): [MꢁH]ꢁ Calcd for C23H32NO4S,
418.2052; Found: 418.2049.
N-Methoxy-N-methyl-2-[3-(trifluoromethyl)phenyl]acetamide (18e)
Compound 18e was prepared from 3-(trifluoromethyl)phenylacetic acid ac-
cording to the same procedure as described of 18a from (2-methyl-
phenyl)acetic acid as a yellow oil.
1
yield 17% in 3 steps). H-NMR (300 MHz, CDCl3) d: 7.40—7.10 (m, 4H),
5.74 (dd, Jꢃ15.4, 5.6 Hz, 1H), 5.51 (dd, Jꢃ15.4, 8.4 Hz, 1H), 4.66 (s, 2H),
4.50—4.35 (m, 1H), 4.11 (q, Jꢃ7.2 Hz, 2H), 4.15—3.95 (m, 1H), 3.85 (q,
Jꢃ8.8 Hz, 2H), 3.60—3.40 (m, 1H), 3.00—2.65 (m, 3H), 2.45—2.10 (m,
3H), 2.28 (t, Jꢃ7.4 Hz, 2H), 2.28 (t, Jꢃ7.4 Hz, 2H), 1.85—1.15 (m, 10H),
1.25 (t, Jꢃ7.2 Hz, 3H).
7-((2R)-2-{(1E,3S)-3-Hydroxy-4-[3-(2,2,2-trifluoroethoxymethyl)-
phenyl]-1-buten-1-yl}-5-oxo-1-pyrrolidinyl)heptanoate (2h) Compound
2h was prepared from 8g according to the same procedure as described of
2b from 8a as a pale yellow oil (36 mg, 100%). IR (film): 3389, 2933, 2862,
1720, 1656, 1460, 1422, 1375, 1279, 1159, 1111, 1034, 968, 913, 793, 732,
3-[3-(Trifluoromethyl)phenyl]-2-oxopropanephosphonate (10e)
Compound 10e was prepared from 18e according to the same procedure as
described of 10a from 18a as a colorless oil (yield 57% in 2 steps). 1H-NMR
(300 MHz, CDCl3) d: 7.60—7.40 (m, 4H), 3.99 (s, 2H), 3.82 (s, 3H), 3.78
(s, 3H), 3.14 (d, Jꢃ22.8 Hz, 2H).
Ethyl 7-[(2R)-2-{(1E,3S)-3-Hydroxy-4-[3-(trifluoromethyl)phenyl]-1-
buten-1-yl]}-5-oxo-1-pyrrolidinyl]heptanoate (8f) Compound 8f was
prepared from 5a using 10e instead of 10a according to the same procedure
705, 667 cmꢁ1
;
1H-NMR (300 MHz, CDCl3) d: 7.40—7.10 (m, 4H), 5.75
(dd, Jꢃ15.6, 5.6 Hz, 1H), 5.52 (dd, Jꢃ15.6, 8.4 Hz, 1H), 4.67 (s, 2H),
4.50—4.35 (m, 1H), 4.10—3.98 (m, 1H), 3.86 (q, Jꢃ8.8 Hz, 2H), 3.60—