Vinylglycinol, Vigabatrin, and Ethambutol Synthesis
J. Am. Chem. Soc., Vol. 122, No. 25, 2000 5975
in hexanes). IR (CDCl3): 3412, 1648, 1602, 1510, 1435, 1313 cm-1
to remove the pyridinium trifluoromethanesulfonate. The organic phase
was washed with 2 × 100 mL of 2 N hydrochloric acid, 2 × 100 mL
of water, and 1 × 100 mL of saturated aqueous sodium chloride. The
organic phase was dried over magnesium sulfate and concentrated in
vacuo. The product was purified by flash chromatography on silica
gel (5 cm × 12 cm, 10% ethyl acetate in hexanes) to give 25.3 g (89%)
of a yellow oil, Rf ) 0.62 (1:1 hexanes/ethyl acetate). IR (neat 1583,
1512, 1425, 966, 833, 617 cm-1. 1H NMR (200 MHz, CDCl3): δ 8.12
(m, 1H), 8.00 (d, J ) 9.2 Hz, 1H), 7.89 (m, 1H), 7.68-7.54 (m, 2H),
7.40 (d, J ) 9.2 Hz, 1H), 7.89 (m, 1H), 7.68-7.54 (m, 2H), 7.40 (d,
J ) 9.2 Hz, 1H), 4.07 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.2,
144.7, 133.1, 132.3, 130.6, 128.7, 128.3, 127.6, 125.6, 123.6, 119.0,
118.7 (q, JCF ) 321 Hz), 52.6. HRMS: Calcd for C20H9F3O5S:
334.0123. Found: 334.0122.
.
1H NMR (300 MHz, CDCl3): δ 7.8 (d, J ) 8.2 Hz, 2H), 7.7 (d, J )
9.1 Hz, 2H), 7.6 (d, J ) 8.9, 2H), 7.2-7.4 (m, 22H), 7.0 (m, 4H), 6.6
(d, J ) 5.5 Hz, 2H), 3.8 (m, 2H), 2.3 (m, 2H), 1.7 (m, 2H), 1.2-1.3
(m, 4H). 13C NMR (75 MHz, CDCl3): δ 169.2 (d, J ) 4.2 Hz), 142.0
(d, J ) 34.2 Hz), 136.8 (d, J ) 11.3 Hz), 136.8 (d, J ) 11.3 Hz),
133.5 (d, J ) 19.6 Hz), 133.4 (d, J ) 19.3 Hz), 133.3, 131.3 (d, J )
18.1 Hz), 129.9 (d, J ) 7.9 Hz), 129.4, 129.2, 128.7, 128.7, 128.6,
128.5, 128.4 (d, J ) 6.7 Hz), 127.7, 127.2, 126.9, 125.6, 54.7, 31.5,
24.4. Anal. Calcd for C52H44N2O2P2: C, 78.97; H, 5.61; N, 3.54; P,
7.83. Found: C, 78.76; H, 5.86; N, 3.38; P, 7.67.
2-(S)-N-Phthalimido-3-buten-1-ol (12). A mixture of 14.6 mg
(0.004 mmol) of π-allylpalladium chloride dimer (11) 94.6 mg (0.012
mmol) of (R,R)-17, 53.0 mg (0.05 mmol) of sodium carbonate and
1.47 g (10 mmol) of phthalimide was purged with nitrogen for 1 h.
After addition of 80 mL of dichloromethane, the resulting mixture was
stirred 10 min at room temperature at which point butadiene monoe-
poxide (810 µL, 10 mmol) was added. The resulting mixture was stirred
at room temperature under nitrogen for 14 h and concentrated in vacuo,
and the residue was purified by flash-chromatography on silica gel
(gradient diethyl ether:hexanes 4:6 to 6:4) to give 2.1 g (98%) of 12 as
a crystalline white solid, mp 62 °C, in 96% ee as determined by chiral
HPLC. The enantiomeric excess was raised to g99% by two recrys-
Preparation of Methyl 2-diphenylphosphino-1-naphthoate. To
3.34 g (10 mmol) of 1-carbomethoxy-2-naphthyl trifluoromethane-
sulfonate was added 91 mg (0.25 mmol) of bis(benzonitrile)palladium
dichloride, 25 mL of toluene, and 4.39 g (17 mmol) of trimethylsilyl-
diphenylphosphine.20 The reaction was heated at reflux for 26 h. After
cooling to room temperature, the reaction was diluted with 80 mL of
chloroform. The organic phase was washed with 1 × 40 mL of saturated
aqueous sodium chloride, dried over sodium sulfate, and concentrated
in vacuo. The product was absorbed onto 8 g of silica gel and purified
by flash chromatography on silica gel (5 cm × 11 cm, 10% ethyl acetate
in hexanes) to give 3.5 g (95%) of the phosphine as a waxy solid, mp
107-108 °C, Rf ) 0.33 (9:1 hexanes/ethyl acetate). IR (CDCl3): 1729,
tallizations from diisopropyl ether, [R]28 ) -72.2 (c 2.02, CH2Cl2),
D
Rf ) 0.65 (diethyl ether). IR (film) 3450, 1767, 1704, 1644, 1614, 1469,
1386 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.8 (m, 2H), 7.7 (m, 2H),
6.1 (ddd, J ) 17.3, 10.2, 6.9 Hz, 1H), 5.3 (m, 2H), 4.9 (m, 1H), 4.1-
4.2 (m, 1H), 3.9-4.0 (m, 1H), 2.9 (bs, 1H). 13C NMR (75 MHz,
CDCl3): δ 168.4, 133.9, 132.0, 131.4, 123.0, 118.6, 61.7, 55.5. Anal.
Calcd for C12H11NO3: C, 66.35; H, 5.11; N, 6.45. Found: C, 66.60;
H, 5.33; N, 6.65.
1
1434, 743, 696 cm-1. H NMR (300 MHz, CDCl3): δ 7.94 (m, 1H),
7.83 (m, 1H), 7.79 (d, J ) 9.1 Hz, 1H), 7.59-7.53 (m, 2H), 7.38-
7.34 (m, 10H), 7.20 (dd, J ) 8.5, 3.3 Hz, 1H), 3.91 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 169.8 (d, J ) 2.5 Hz), 139.0 (d, J ) 34.7 Hz),
137.0 (d, J ) 10.6 Hz), 133.7 (d, J ) 20.0 Hz), 133.5 (d, J ) 18.2
Hz), 133.4, 130.0, 129.9 (d, J ) 7.5 Hz), 129.7, 128.8, 128.7 (d, J )
6.8 Hz), 128.3, 127.6, 127.4, 125.5, 51.9. Anal. Calcd for C24H19O2P:
C, 77.83; H, 5.17; P, 8.36; MW, 370.1123. Found: C, 77.87; H, 5.34;
P, 8.33; MW, 370.1113.
2-(S)-N-Phthalimido-3-butenyl Triflate (21b). To a solution of 12
(109 mg, 0.502 mmol) and triethylamine (92 µL, 0.547 mmol) in 4
mL of dichloromethane at 0 °C was added trifluoromethanesulfonic
anhydride (76 µL, 0.547 mmol) in 1 mL of methylene chloride
dropwise. The resulting mixture was stirred at 0 °C, under nitrogen
for 1 h. The reaction mixture was then concentrated in vacuo and
purified by flash chromatography on silica gel (hexanes:ethyl acetate
8:2) to give 169 mg (97%) of 21b as a clear syrup which solidified
Preparation of 2-Diphenylphosphino-1-naphthoic Acid. A solution
of 2.85 g (7.7 mmol) of methyl 2-diphenylphosphino-1-naphthoate and
14.8 g (47.0 mmol) of barium hydroxide octahydrate in 47 mL of
methanol was heated at reflux for 25 h. After cooling to room
temperature, the reaction mixture was neutralized with 200 mL of 1 N
sodium bisulfate. The aqueous phase was extracted with 4 × 100 mL
dichloromethane, and the combined organic phases were dried over
sodium sulfate and concentrated in vacuo. The product was absorbed
onto 8 g silica gel and filtered through a short column of silica gel (4
cm × 6 cm, 100% ethyl acetate) to give 2.42 g (88%) of the acid as a
yellow solid (mp 190 °C decomposes) which was used without further
purification. Rf ) 0.56 (100% ethyl acetate). IR (KBr): 3414, 1685,
upon cooling, [R]26 ) -86 (c 2.62, CH2Cl2). IR (neat) 1753, 1693,
D
1655, 1468, 1387, 1333, 1290, 1205, 1132, 1104, 1087 cm-1. 1H NMR
(300 MHz, CDCl3): δ 7.88-7.84 (m, 2H), 7.78 (m, 2H), 5.45 (d, J )
17.1 Hz, 1H), 5.20-5.10 (m, 2H), 4.80-4.68 (m, 2H). 13C NMR (75
MHz, CDCl3): δ 167.56, 134.55, 134.29, 131.56, 129.13, 123.74,
123,50, 122.12, 120.65, 116.40, 73.25, 52.44. HRMS: Calcd for
C13H10NO5F3S: 349.0232. Found: 349.0221.
2-[2-(R)-N-Phthalimido-but-3-enyl]-malonate (23). To a solution
of 21b (400 mg, 1.14 mmol) in 5 mL of THF were added 5 mL of a
solution of dimethyl sodiomalonate which, in turn, was prepared by
slowly adding dimethyl malonate (520 µL, 4.58 mmol) into a suspension
of sodium hydride (60%, 184.0 mg, 4.60 mmol) in 10 mL of THF.
The resulting mixture was stirred at room temperature for 6 h. The
reaction mixture was then evaporated in vacuo and purified by flash
chromatography (gradient hexanes/ethyl acetate 9/1 to 7/3) to give 242
1
1434, 1287, 1252 cm-1. H NMR (300 MHz, DMSO-d6): δ 8.0 (d, J
) 8.2 Hz, 1H), 7.8 (d, J ) 8.0 Hz, 1H), 7.78 (d, J ) 8.5 Hz, 1H),
7.5-7.6 (m, 2H), 7.25 (m, 10H), 7.15 (dd, J ) 8.3, 2.8 Hz, 1H). 13C
NMR (75 MHz, DMSO-d6): δ 170.4 (d, J ) 3.4 Hz), 141.6 (d, J )
38.0 Hz), 137.0 (d, J ) 10.7 Hz), 133.1 (d, J ) 19.1 Hz), 132.1, 131.9,
130.7 (d, J ) 17.0 Hz), 129.6, 129.3, 129.2, 128.9 (d, J ) 6.9 Hz),
128.7, 128.5, 127.8, 125.5. Anal. Calcd for C23H17O2P: C, 77.52; H,
4.81; P, 8.69. Found: C, 77.38; H, 5.00; P, 8.51.
Preparation of (-)-(1R,2R)-Diamino-1N,2N-bis(2′-diphenylphos-
phino-1′naphthoyl)cyclohexane 17. To a solution of 1.90 g (5.33
mmol) of 2-diphenylphosphino-1-naphthoic acid in 42 mL of dichlo-
romethane at 0 °C was added 1.78 g (17.6 mmol) of triethylamine
followed by 1.58 g (5.87 mmol) of diphenylchlorophosphite added over
2-3 min. After warming to room temperature over 5 h, the mixture
was transferred via cannula to a solution of 304 mg (2.66 mmol) of
(1R,2R)-diaminocyclohexane and 30.5 mg (0.25 mmol) of DMAP in
11 mL of dichloromethane and stirred at 25 °C for 12 h. The reaction
mixture was then diluted with 50 mL of dichloromethane, washed with
1 × 50 mL of saturated aqueous sodium bicarbonate, dried over sodium
sulfate, and concentrated in vacuo. The product was purified by flash
chromatography on silica gel (4.5 cm × 11 cm, 25% ethyl acetate in
hexanes) to give 1.07 g (51%) of a white solid which was crystallized
from 5 mL of 1:1 chloroform: hexanes as a white powder (mp 148-
150 °C), [R]D ) +13.9° (c 1.19, CH2Cl2), Rf ) 0.64 (50% ethyl acetate
mg (64%) of 23 as a syrup, [R]26 ) -27 (c 1.2, CH2Cl2). IR (neat):
D
1770, 1468, 1437, 1385, 1357, 1335 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 7.83 (m, 2H), 7.72 (m, 2H), 6.19 (ddd, J ) 17.3, 10.2, 7.6
Hz, 1H), 5.27 (d, J ) 10.2 Hz, 1H), 4.78 (m, 2H), 3.74 (s, 3H), 3.64
(s, 3H), 3.35 (dd, J ) 8.2, 6.9 Hz, 1H), 2.72 (ddd, J ) 14.3, 9.4, 6.9
Hz, 1H), 2.56 (ddd, J ) 14.3, 8.2, 6.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 169.13, 167.93, 134.47, 134.20, 131.87, 123.42, 118.70,
52.72, 52.64, 51.81, 48.92, 31.86. HRMS: Calcd for C17H17NO6:
331.1056. Found: 331.1067.
(R)-Vigabatrin (24). A solution of 23 (170 mg, 0.513 mmol) in 5
mL of a 6 N aqueous solution of hydrochloric acid was stirred at 100
°C for 14 h. The reaction mixture was then cooled to 0 °C, filtered
through cotton, and evaporated in vacuo. The residue was purified by
flash chromatography on silica gel (2-propanol/ethyl acetate/water 3/3/
1) to give 81.8 mg (yield 96%) of a yellowish compound, the
1
hydrochloride salt. H NMR (300 MHz, D2O): δ 5.80 (m, 1H), 5.46
(d, J ) 9.7 Hz, 1H), 5.44 (d, J ) 17.5 Hz, 1H), 3.83 (m, 1H), 2.47 (m,