Wolfe et al.
931
6.72 Hz), 3.99 (1H, dd, 8.32, 5.48 Hz), 3.75 (1H, dd, 8.50,
6.60 Hz), 2.88 (1H, dd, 16.36, 6.60 Hz), 2.71 (1H, dd, 16.36,
6.96 Hz), 2.68 (1H, dd, 16.36, 6.80 Hz). CI-MS (m/z): 209
([M + 1]).
Methyl 3,4-dihydroxybutanoate
DL-Malic acid (20 g, 0.15 mol) was dissolved in a solution
prepared by addition of acetyl chloride (6.7 mL) (Fisher) to
methanol (134 mL). The solution was stirred at room tem-
perature for 13 h and then concentrated. The product was
purified by flash chromatography (60% ethyl acetate – hex-
anes) to give a colourless oil (18.5 g, 77%). IR (film, cm–1):
3470, 1732. 1H NMR (CDCl3) δ: 4.44 (1H, br), 3.75 (3H, s),
3.65 (3H, s), 3.18 (1H, br), 2.81 (1H, dd, 16.48, 4.36 Hz),
2.74 (1H, dd, 16.48, 6.12 Hz). CI-MS (m/z):163 ([M + 1]).
Anal. calcd. for C6H10O5: C44.44, H 6.17; found: C 44.20,
H 6.13.
Coupling of 47 and N-hydroxyglycine tert-butyl ester
Dicyclohexylcarbodiimide (0.859 g, 4.16 mmol) (BDH)
was added to a cooled solution of 47 (0.87 g, 4.16 mmol)
and N-hydroxyglycine tert-butyl ester (0.60 g, 4.09 mmol) in
dichloromethane (20 mL). The cloudy mixture was stirred at
0 °C for 0.5 h and at room temperature for 4 h and then fil-
tered and the filtrate concentrated. Purification of the oil by
flash chromatography (60% ethyl acetate – hexane) gave
0.650 g (47%) of the product 48. IR (film, cm–1): 3249,
Borane–dimethylsulfide (11 mL of 10 mol/L, 0.11 mol)
was added dropwise to a solution of dimethylmalate (17.80 g,
0.11 mol) in tetrahydrofuran (220 mL). The solution was
stirred at 20 °C for 30 min, and sodium borohydride (0.208 g,
5.5 mmol) (BDH) was added in one portion. Stirring was
continued for 30 min, methanol (70 mL) was added
dropwise, and after an additional 30 min the solvent was re-
moved under reduced pressure. The product was purified by
flash chromatography (60% ethyl acetate – hexanes) to give
a colourless viscous oil (12.27 g, 83%). IR (film, cm–1):
1
1739, 1641. H NMR (CDCl3) δ: 7.49–7.35 (5H, m, Ar),
5.96 (1H, s), 5.86 (1H, s), 4.59–4.62 (1H, m), 4.45 (1H, d,
17.72 Hz), 4.39 (1H, dd, 8.56, 6.08 Hz), 4.38 (1H, d,
17.76 Hz), 4.31 (1H, d, 17.76 Hz), 4.29 (1H, d, 17.72 Hz),
4.25 (1H, dd, 8.20, 6.80 Hz.), 3.89 (1H, dd, 8.20, 5.84 Hz),
3.79 (1H, dd, 8.56, 7.12 Hz), 3.20 (1H, dd, 15.92, 6.12 Hz),
3.02 (1H, dd, 15.54,5.60 Hz), 2.92 (1H, dd, 15.54, 7 Hz),
2.81 (1H, dd, 15.92, 7.16 Hz), 1.48 (9H, s, tert-butyl). CI-
MS (m/z): 338 ([M + 1]). Anal. calcd. for C17H23NO6:
C60.53, H 6.82, N 4.15; found: C 60.84, H 7.07, N 4.36.
1
3414, 1738. H NMR (CDCl3) δ: 4.07 (1H, m), 3.66 (3H, s),
3.61 (1H, dd, 11.36, 3.52 Hz), 3.46 (1H, dd, 11.36, 6.2 Hz),
2.80 (2H, br), 2.50 (1H, dd, 16.64, 8.52 Hz), 2.44 (1H, dd,
16.64, 4.16 Hz). CI-MS (m/z): 135 ([M + 1]). Anal. calcd.
for C5H10O4: C 44.78, H 7.46; found: C 44.12, H 7.55.
Hydrogenolysis of 48
Palladium on carbon (10%) (0.400 g) was added to a solu-
tion of 48 (0.400 g, 1.19 mmol) in tetrahydrofuran (15 mL).
The suspension was flushed thrice with hydrogen, then
stirred under hydrogen for 3 h, filtered through Celite, and
the filtrate concentrated. The residue was purified by PLC
(80% ethyl acetate – hexanes) to give 49 as a viscous golden
Benzylidene derivative of methyl 3,4-
dihydroxybutanoate
A solution of methyl 3,4-dihydroxybutanoate (11.44 g,
85.36 mmol), benzaldehyde dimethyl acetal (11 mL,
11.15 g, 3.16 mmol), and p-toluenesulfonic acid mono-
hydrate (812 mg, 4.27 mmol) (Fisher) in dimethylformamide
(20 mL) was stirred at room temperature for 24 h and then
poured into ice-water (50 mL) and extracted with ethyl ace-
tate (5 × 40 mL). The organic extract was washed with satu-
rated sodium chloride (30 mL), dried over anhydrous sodium
sulfate, and concentrated. Purification by column chroma-
tography (60% ethyl acetate – hexanes) gave 18.5 g (77%)
1
oil (0.150 g, 51%). IR (film, cm–1): 3362, 1737, 1635. H
NMR (D2O) δ: 4.37 (1H, d, 17.72 Hz), 4.30 (1H, d,
17.72 Hz), 4.13 (1H, m), 3.62 (1H, dd, 11.76, 4 Hz), 3.53
(1H, dd, 11.76, 6.88 Hz), 2.78 (1H, dd, 15.15, 8.24 Hz), 2.71
(1H, dd, 15.15, 4.96 Hz), 1.49 (9H, s). CI-MS (m/z): 250
([M + 1]). Anal. calcd. for C10H19NO6.1.5H2O: C43.47, H
7.37, N 5.07; found: C 43.45, H 7.29, N 5.26.
of a colourless oil. IR (film, cm–1): 3034, 1737 (C=O). H
1
NMR (CDCl3) δ: 7.49–7.35 (5H, m, Ar), 5.96 (1H, s), 5.86
(1H, s), 4.68–4.60 (1H, m), 4.21 (1H, dd, 8.28, 6.72 Hz),
4.12 (1H, dd, 8.44, 6.16 Hz), 3.98 (1H, dd, 8.44, 6.60 Hz),
3.86 (1H, dd, 8.28, 5.68 Hz), 2.85 (1H, dd, 16.06, 6.36 Hz),
2.82 (1H, dd, 16.06, 6.36 Hz), 2.66 (1H, dd, 16.06, 7.20 Hz),
2.65 (1H, dd, 16.06, 7.32 Hz). CI-MS (m/z): 223 ([M + 1]).
Cyclization of 49
A mixture of the diol 49 (68.8 mg, 0.28 mmol), triphenyl-
phosphine (78.3 mg, 0.30 mmol), and diethylazodicar-
boxylate (65 µL, 72 mg, 0.41 mmol) in tetrahydrofuran
(9 mL) was stirred for 24 h at room temperature and then
concentrated under reduced pressure. The residue was puri-
fied by PLC (60% ethyl acetate – hexanes) to give 50
1
Preparation of 47
(68 mg). IR (film, cm–1): 3279, 1735. H NMR (CDCl3) δ:
Sodium hydroxide (25 mL of 1 mol/L, 25 mmol) was
added to a solution of the benzylidene methyl ester (5.75 g,
25.9 mmol) in methanol (40 mL). The reaction mixture was
stirred for 30 min, and the solvent was then removed. The
residue was dissolved in ethyl acetate (50 mL) and water
(30 mL). The aqueous phase was acidified with N-hydro-
chloric acid and extracted with dichloromethane (4 ×
30 mL). This extract was dried over anhydrous sodium sul-
fate and concentrated to give 3.16 g (59%) of product. IR
4.64–4.59 (1H, m), 4.37 (1H, d, 17.84 Hz), 3.98 (1H, d,
17.84 Hz), 3.86 (1H, dd, 12.64, 2.68 Hz), 3.65 (1H, dd,
12.64, 4.16 Hz), 2.89 (1H, dd, 16.56, 8.52 Hz), 2.85 (1H, dd,
16.56, 6.64 Hz), 1.47 (9H, s). EI-MS (m/z): 231 ([M]+). CI-
MS (m/z): 232. This compound was dissolved in trifluoro-
acetic acid (0.5 mL) and stirred under a nitrogen atmosphere
for 1.5 h. The solution was then freeze-dried to give 28 mg
1
(57%) of 39. H NMR (D2O) δ: 4.74 (1H, m), 4.36 (1H, d,
18.16 Hz), 4.34 (1H, d, 18.16 Hz), 3.78 (1H, dd, 12.88,
3.2 Hz), 3.74 (1H, dd, 12.88, 5.64 Hz), 3.02 (1H, dd, 17.0,
8.76 Hz), 2.79 (1H, dd, 17.0, 7.68 Hz). CI-MS (m/z): 176
([M + 1]).
1
(film, cm–1): 3037, 1713 (C=O). H NMR (CDCl3) δ: 7.49–
7.36 (5H, m, Ar), 5.96 (1H, s), 5.82 (1H, s), 4.68–4.60
(1H, m), 4.37 (1H, dd, 8.50, 6.20 Hz), 4.11 (1H, dd, 8.32,
© 2003 NRC Canada