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H. Marusawa et al. / Bioorg. Med. Chem. 7 (1999) 2635±2645
(200MHz, CDCl3) d 1.35 (3H, d, J=5 Hz), 1.6±1.8 (3H,
m), 1.9±2.2 (4H, m), 2.34 (2H, d, J=7.5Hz), 2.57 (1H, m),
3.69 (3H, s), 3.81 (1H, d, J=11.5 Hz), 3.98 (1H, d,
J=11.5 Hz), 4.79 (1H, q, J=5 Hz), 4.98 (1H, dd, J=3.5,
4.5 Hz), 5.4±5.6 (2H, m), 6.78 (1H, d, J=3.5 Hz), 8.00 (1H,
s). ESI-MS m/z: 286 (M+H)+. Methyl (Z)-7-{(1S,2R,4R)-
2-[(E)-2-aza-2-hydroxyvinyl]-4-methyl-3,5-dioxanyl}hept-5-
enoate (142 mg, 41.3%) was obtained from the second
J=5 Hz), 5.4±5.6 (2H, m), 7.04 (1H, t, J=7.3 Hz), 7.30
(2H, m), 7.45 (2H, d, J=7.5 Hz), 8.28 (1H, s). ESI-MS
m/z: 390 (M H) .
(Z)-7-{(1S,2R,4R)-4-Methyl-2-[2-((1-phthalazinylamino)
amino)methyl]-3,5-dioxanyl}hept-5-enoic acid (27). To a
solution of 41 (450mg, 1.09mmol) in a mixture of metha-
nol (4mL) and acetic acid (2 mL) was added sodium cy-
anoborohydride (125mg, 1.99mmol), and the mixture
stirred at room temperature for 2 h. The solution was
adjusted to pH 7 with saturated aqueous sodium hydrogen
carbonate and the resulting mixture diluted with chloro-
form. The solution was washed successively with water
and brine, dried over magnesium sulfate, and solvent eva-
porated in vacuo to give methyl (Z)-7-{(1S,2R,4R)-4-
methyl-2-[2-((1-phthalazinylamino)amino)methyl]-3,5-di-
oxanyl}hept-5-enoate that was dissolved in a mixture of
methanol (5mL) and 1 N aqueous sodium hydroxide
(2.00 mL, 2.00mmol). After stirring at room temperature
overnight, the mixture was neutralized with 1 N hydro-
chloric acid and the resulting solution evaporated to dry-
ness in vacuo. The residue was puri®ed by preparative thin
layer chromatography with a mixture of chloroform and
methanol (10:1) as eluent to give 96.3 mg (22.0% from 41)
of 27 as a pale yellow oil: 1H NMR (200MHz, CDCl3) d
1.44 (1H, d, J=5Hz), 1.5±1.9 (3H, m), 1.9±2.2 (3H, m),
2.3±2.6 (3H, m), 3.88 (1H, d. J=12.5 Hz), 4.15 (1H, d,
J=12.5 Hz), 4.70 (1H, m), 4.87 (1H, q, J=5Hz), 5.4±5.7
(2H, m), 7.57 (1H, m), 7.6±7.8 (2H, m), 7.9±8.1 (2H, m),
8.41 (1H, m), 9.60 (1H, s). ESI-MS m/z: 399 (M H) .
1
fractions as an oil: H NMR (200 MHz, CDCl3) d 1.37
(3H, d, J=5 Hz), 1.58 (1H, m), 1.6±1.8 (2H, m), 2.0±2.2
(2H, m), 2.27 (1H, m), 2.55 (1H, m), 2.85 (2H, t,
J=7.5 Hz), 3.69 (3H, s), 3.80 (1H, d, J=11.5Hz), 4.03
(1H, d, J=11.5Hz), 4.55 (1H, dd, J=2, 4.5Hz), 4.80 (1H,
q, J=5Hz), 5.3±5.6 (2H, m), 7.43 (1H, d, J=4.5 Hz), 7.83
(1H, s). ESI-MS m/z: 286 (M+H)+.
To a solution of methyl (Z)-7-{(1S,2R,4R)-2-[(E)-2-aza-
2-hydroxyvinyl]-4-methyl-3,5-dioxanyl}hept-5-enoate
(100mg, 0.350 mmol) in N,N-dimethylformamide (5 mL)
was added sodium hydride (14 mg, 60% in oil, 0.350
mmol) at 5ꢀC. After being stirred at the same temperature
for 30 min, bromodiphenylmethane (86.6 mg, 0.350 mmol)
was added and the mixture stirred in an ice bath for an
additional 2 h. The solution was diluted with ethyl acetate
and washed successively with water and brine, and dried
over magnesium sulfate. The solvent was evaporated in
vacuo and the crude residue was puri®ed by preparative
TLC with a mixture of n-hexane and ethyl acetate (4:1) as
1
eluent to give 130 mg (82.1%) of 42 as an oil: H NMR
(200MHz, CDCl3) d 1.34 (3 H, d, J=5 Hz), 1.49 (1H, m),
1.6±1.8 (3H, m), 2.0±2.2 (3H, m), 2.32 (2H, t, J=7.5 Hz),
2.55 (1H, m), 3.68 (3H, s), 3.70 (1H, d, J=11.5 Hz), 3.96
(1H, d, J=11.5 Hz), 4.49 (1H, dd, J=2, 5.5 Hz), 4.74 (1H,
q, J=5 Hz), 5.2±5.5 (2H, m), 6.23 (1H, s), 7.2±7.4 (11H,
m), 7.59 (1H, d, J=5.5 Hz). ESI-MS m/z: 452 (M+H)+.
(Z)-7-{(1S,2R,4R)-4-Methyl-2-[((2-thienylearbonyl)ami-
no)methyl]-3,5-dioxanyl}hept-5-enoic acid (28). By the
procedure used for 40 and 27, 20 (47.0 mg, 0.174 mmol),
hydrazino(2-thienyl)methan-1-one (27.0 mg, 0.171 mmol)
and sodium cyanoborohydride (20.0 mg, 0.318 mmol), 1
N sodium hydroxide (0.40 mL, 0.40mmol) gave 55.0mg
(Z)-7-{(1S,2R,4R)-2-[(E)-2-Aza-2-(diphenylmethoxy)vi-
nyl]-4-methyl-3,5-dioxanyl}hept-5-enoic acid (25). By the
procedure used for 8a, 42 (95 mg, 0.210 mmol) and 1 N
sodium hydroxide (1.00 mL, 1.00mmol) gave 62.0 mg
(67.5%) of 25 as an oil: 1H NMR (200MHz, CDCl3) d 1.34
(3H, d, J=5 Hz), 1.50 (1H, m), 1.6±1.8 (3H, m), 2.0±2.2
(3H, m), 2.85 (2H, t, J=7.5Hz), 2.59 (1H, m), 3.77 (1H,
m), 3.96 (1H, d, J=11.5 Hz), 4.50 (1H, dd, J=2.5, 5.5 Hz),
4.74 (1H, m), 5.00 (1H, dd, J=2.5, 4.5 Hz), 5.2±5.6 (2H,
m), 6.22 (1H, s), 6.78 (1H, d, J=4.5 Hz), 7.2±7.4 (11H, m),
7.56 (1H, d, J=5.5Hz). ESI-MS m/z: 436 (M H) .
1
(85.9% from 20) of 28 as an oil: H NMR (200MHz,
CDCl3) d 1.34 (3H, d, J=5Hz), 1.5±1.9 (2H, m), 2.0±2.5
(4H, m), 2.36 (2H, t, J=7Hz), 3.03 (1H, dd, J=3.8,
12.5Hz), 3.18 (1H, dd, J=8.1, 12.5Hz), 3.74 (2H, m), 4.04
(3H, m), 4.75 (1H, q, J=5Hz), 5.3±5.6 (2H, m), 7.10 (1H,
m), 7.55 (2H, m). ESI-MS m/z: 367 (M H) .
(Z)-7-{(1S,2R,4R)-4-Methyl-2-[(2-pyridylmethylamino)-
methyl]-3,5-dioxanyl}hept-5-enoic acid (29). By the pro-
cedure used for 40 and 27, 20 (200 mg, 0.740 mmol), 2-
(aminomethyl)pyridine (0.150 mL, 1.46 mmol) and
sodium cyanoborohydride (100mg, 1.59mmol), and 1 N
sodium hydroxide (3.00 mL, 3.00mmol) gave 135 mg
(Z)-7-{(1S,2R,4R)-4-Methyl-2-[(((N-phenycarbamoyl)
amino)amino)methyl]-3,5-dioxanyl}hept-5-enoic acid (26).
To a solution of 7a (48 mg, 0.123 mmol) in ethanol (2 mL)
was added sodium cyanoborohydride (15 mg,
0.239 mmol) and acetic acid (1 drop), and the mixture
stirred at room temperature for 2 h. The solvent was eva-
porated in vacuo and the residue was extracted with
chloroform at pH 3. The organic layer were combined and
dried over magnesium sulfate. Solvent was evaporated in
vacuo and the crude product puri®ed by preparative TLC
with ethyl acetate to give 22mg (45.6%) of 26 as an oil: 1H
NMR (200MHz, CDCl3) d 1.32 (3H, d, J=5Hz), 1.6±1.9
(2H, m), 2.0±2.2 (4H, m), 2.36 (2H, t, J=7Hz), 2.4±2.6
(1H, m), 2.85 (1H, dd, J=2.6, 12.8 Hz), 3.05 (1H, dd,
J=9.7, 12.8 Hz), 3.72 (1H, m), 4.01 (1H, m), 4.70 (1H, q,
1
(57.6% from 20) of 29 as an oil: H NMR (200MHz,
CDCl3) d 1.27 (1H, m), 1.30 (1H, d, J=5Hz), 1.45 (1H,
m), 1.5±1.8 (2H, m), 2.05 (1H, m), 2.2±2.4 (4H, m), 2.8±3.0
(2H, m), 3.72 (1H, dd, J=1.5, 11.5Hz), 3.9±4.2 (4H, m),
4.73 (1H, q, J=5Hz), 5.3±5.6 (2H, m), 5.94 (1H, broad),
7.2±7.4 (2H, m), 7.72 (1H, dt, J=1.5, 10Hz), 8.65 (1H, d,
J=5Hz). ESI-MS m/z: 347 (M H) .
Methyl (Z)-7-{(1S,2R,4R)-2-[(1,3-dioxoisoindolin-2-yl)-
methyl]-4-methyl-3,5-dioxanyl}hept-5-enoate (30). To a
solution of 19 (456 mg, 1.64 mmol) in pyridine (2 mL) was
added p-toluenesulfonyl chloride (640mg, 3.36mmol) and
the mixture was stirred at room temperature for 2 h. The