Y. Aoyama et al. / Bioorg. Med. Chem. 9 (2001) 3065–3075
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J=6.0 Hz), 3.01 (1H, dd, J=14.6, 8.9 Hz), 3.30 (1H, dd,
J=14.4, 5.4 Hz), 3.62(1H, ddd, J=8.9, 5.3, 1.0 Hz),
4.52(1H, quintet, J=6.0 Hz), 5.50 (1H, d, J=0.9 Hz),
6.36 (1H, s), 6.74 (2H, d, J=8.7 Hz), 6.84 (1H, dd,
J=8.4, 1.2Hz), 6.91 (1H, td, J=7.8, 1.2Hz), 7.08 (1H,
s), 7.19–7.45 (12H, m), 8.00 (2H, d, J=9.0 Hz).
m), 3.66 (3H, s), 4.77 (1H, q, J=7.5 Hz), 5.80 (1H, d,
J=1.2Hz), 6.81 (1H, d, J=8.4 Hz), 6.90 (1H, t,
J=7.5 Hz), 6.91 (2H, d, J=9.0 Hz), 7.13–7.39 (8H, m),
7.91 (2H, d, J=9.0 Hz); HR-MS (FAB, [M+H]+) calcd
for [C28H28O6N2+H]+ 489.2026, found 489.2024.
(3S,4S)-3-(2-Ethoxybenzyl)4-(4-carboxy)phenoxy-1-[(R)-
1 - (phenylpropyl)aminocarbonyl]azetidin - 2 - one (22).
Using essentially the same procedures as for the pre-
paration of 21, the following compound was prepared
from 18. White amorphous solid, [a]D +2.0ꢁ (c 0.50,
99.5% EtOH); IR nmax cmꢀ1: 1778, 1709, 1691; 1H
NMR (CDCl3): d 0.92(3H, t, J=7.2Hz), 1.28 (3H, t,
J=7.1 Hz), 1.84 (1H, qdd, J=7.4, 13.8, 3.3 Hz), 1.87
(1H, qdd, J=7.4, 13.8, 3.3 Hz), 2.00 (1H, br s), 2.98
(1H, dd, J=13.8, 9.3 Hz), 3.27 (1H, dd, J=14.0,
5.6 Hz), 3.70 (1H, ddd, J=9.0, 5.7, 1.4 Hz), 3.93 (2H, q,
J=7.1 Hz), 4.77 (1H, q, J=7.8 Hz), 5.78 (1H, d,
J=1.2Hz), 6.80 (1H, d, J=7.8 Hz), 6.88 (1H, t,
J=7.5 Hz), 6.89 (2H, d, J=9.0 Hz), 7.16 (1H, dd,
J=7.5, 1.8 Hz), 7.19–7.39 (7H, m), 7.90 (2H, d,
J=9.0 Hz); HR-MS (FAB, [M+H]+) calcd for
[C29H30O6N2+H]+ 503.2182, found 503.2188.
(3S,4S)-4-(4-Carboxy)phenoxy-3-(2-methoxybenzyl)-1-
[(R)-1-(phenylethyl)aminocarbonyl]azetidin-2-one (20).
Using essentially the same procedures as for the pre-
paration of 9a, the following compound was prepared
from 17. White amorphous solid; [a]D +102.3ꢁ (c 0.51,
CHCl3). IR nmax cmꢀ1: 1778, 1708, 1691; 1H NMR
(CDCl3): d 1.54 (3H, d, J=7.2Hz), 1.80 (1H, br s), 3.00
(1H, dd, J=14.3, 8.7 Hz), 3.24 (1H, dd, J=14.4,
5.4 Hz), 3.64 (1H, ddd, J=8.7, 5.4, 1.2Hz), 3.68 (3H, s),
5.03 (1H, quintet, J=7.4 Hz), 5.81 (1H, d, J=1.2Hz),
6.83 (1H, d, J=8.1 Hz), 6.85 (1H, t, J=8.3 Hz), 6.92
(2H, d, J=8.7 Hz), 7.17 (1H, dd, J=7.5, 1.5 Hz), 7.23–
7.40 (7H, m), 7.92(2H, d, J=9.0 Hz); HR-MS (FAB,
[M+H]+) calcd for [C27H26O6N2+H]+ 475.1869,
found 475.1870.
(3S,4S)-4-(4-Carboxy)phenoxy-3-(2-methoxybenzyl)-1-
[(R)-1-(phenylpropyl)aminocarbonyl]azetidin-2-one (21).
To a solution of (R)-phenylbutyric acid (616 mg,
3.8 mmol) in methylene chloride (6 mL) were added
triethylamine (523 mL, 3.8 mmol) and diphenylphos-
phoryl azide (808 mL, 3.7 mmol) and then the reaction
mixture was stirred at room temperature for 2.5 h. To
the reaction mixture were added a solution of 17
(740 mg, 1.5 mmol) in methylene chloride (4 mL), trie-
thylamine (523 mL, 3.8 mmol) and DMAP (10 mg, cata-
lyst). The reaction mixture was stirred at 45 ꢁC for 5 h,
diluted with EtOAc and poured into a mixture of ice
and 1 N HCl. The layers were separated and the aqu-
eous layer was reextracted with EtOAc. The organic
layers were each washed with brine, combined, dried
over Na2SO4 and evaporated. The residue was purified
by elution (toluene/EtOAc) through a silica gel column
and gave 880 mg (90%) of (3S,4S) - 4 - (4 - diphenyl-
methoxycarbonyl)phenoxy-3-(2-methoxybenzyl)-1-[(R)-1-
(phenylpropyl)aminocarbonyl]azetidin - 2- one 25. 1H
NMR (CDCl3): d 0.91 (3H, t, J=7.4 Hz), 1.81 (1H, qdd,
J=7.6, 13.8, 1.4 Hz), 1.88 (1H, qdd, J=7.6, 13.8,
1.4 Hz), 3.00 (1H, dd, J=14.1, 9.1 Hz), 3.21 (1H, dd,
J=14.3, 5.5 Hz), 3.59–3.70 (1H, m), 3.64 (3H, s), 4.76
(1H, q, J=7.1 Hz), 5.78 (1H, d, J=1.3 Hz), 6.78 (1H, d,
J=8.1 Hz), 6.87 (1H, t, J=7.8 Hz), 6.95 (2H, d,
J=9.0 Hz), 7.07 (1H, s), 7.10–7.48 (18H, m), 7.98 (2H,
d, J=9.0 Hz). To a solution of 25 (655 mg, 1.0 mmol) in
anisole (3.2mL) was added precooled TFA (0.8 mL) at
5 ꢁC. After 1.5 h at 5 ꢁC, the reaction mixture was
poured into sodium bicarbonate solution and extracted
with two portions of EtOAc. The EtOAc layers were
each washed with brine, dried over Na2SO4 and evapo-
rated. The residue was crystallized from hexane to give
415 g (85%) of 21 as a white amorphous solid, [a]D
+2.0ꢁ (c 0.50, 99.5% EtOH); IR nmax cmꢀ1: 1778, 1709,
(3S,4S)-4-(4-Carboxy)phenoxy-1-[diphenylmethyl)amino-
carbonyl]-3-(2-ethoxybenzyl)azetidin-2-one (23). To a
solution of diphenylacetic acid (182mg, 0.86 mmol) in
methylene chloride (2mL) were added triethylamine
(144 mL, 1.0 mmol) and diphenylphosphoryl azide
(222 mL, 1.0 mmol) and then the reaction mixture was
stirred at room temperature for 2.5 h. To the reaction
mixture were added
a solution of 18 (300 mg,
0.59 mmol) in methylene chloride (5 mL), triethylamine
(144 mL, 1.0 mmol) and DMAP (10 mg, catalyst). The
reaction mixture was stirred at 45 ꢁC for 5 h, diluted
with EtOAc and poured into a mixture of ice and 1 N
HCl. The layers were separated and the aqueous layer
was reextracted with EtOAc. The organic layers were
each washed with brine, combined, dried over Na2SO4
and evaporated. The residue was purified by elution
(toluene/EtOAc) through a silica gel column and gave
398 mg (94%) of (3S,4S) - 4 - (4 - diphenylmethoxy-
carbonyl)phenoxy-1-[(diphenylmethyl)aminocarbonyl]-3
-(2-ethoxybenzyl)azetidin-2-one 26. 1H NMR (CDCl3): d
1.28 (3H, t, J=6.9 Hz), 3.00 (1H, dd, J=14.3, 8.6 Hz),
3.29 (1H, dd, J=14.1, 6.1 Hz), 3.65–3.75 (1H, m), 3.94
(2H, q, J=6.8 Hz), 5.83 (1H, d, J=1.5 Hz), 6.15 (1H, d,
J=8.4 Hz), 6.81 (1H, d, J=8.0 Hz), 6.89 (1H, t,
J=7.8 Hz), 6.94 (2H, d, J=8.9 Hz), 7.07 (1H, s), 7.10–
7.48 (18H, m), 7.97 (2H, d, J=8.9 Hz). To a solution of
26 (392mg, 0.55 mmol) in anisoꢁle (0.42mL) was added
precooled TFA (0.42mL) at 5 C. After 1.5 h at 5 ꢁC,
the reaction mixture was poured into sodium bicarbo-
nate solution and extracted with two portions of
EtOAc. The EtOAc layers were each washed with brine,
dried over Na2SO4 and evaporated. The residue was
crystallized from hexane to give 242 g (80%) of 23 as a
white amorphous solid, [a]365ꢀ2.0ꢁ (c 0.51, CHCl3). IR
1
nmax cmꢀ1: 1778, 1709, 1691; H NMR (CDCl3): d 1.29
1
1691; H NMR (CDCl3): d 0.92(3H, t, J=7.5 Hz), 1.84
(3H, t, J=7.0 Hz), 2.97 (1H, dd, J=14.3, 9.3 Hz), 3.30
(1H, dd, J=13.7, 5.9 Hz), 3.66–3.76 (1H, m), 3.95 (2H,
q, J=7.0 Hz), 5.84 (1H, d, J=1.3 Hz), 6.16 (1H, d,
J=8.4 Hz), 6.79–6.95 (4H, m), 7.15–7.40 (12H, m), 7.91
(1H, qdd, J=7.7, 13.8, 3.0 Hz), 1.87 (1H, qdd, J=7.7,
13.8, 3.0 Hz), 2.00 (1H, br s), 3.00 (1H, dd, J=14.1,
9.3 Hz), 3.23 (1H, dd, J=14.1, 5.7 Hz), 3.59–3.70 (1H,