Notes
J . Org. Chem., Vol. 63, No. 7, 1998 2353
added dropwise to a stirred solution of the recovered (S)-3-amino-
3-phenylpropanoic acid hydrochloride (1) (3.75 mmol, 0.62 g) and
triethylamine (13 mmol, 1.81 mL) in water (15 mL) and acetone
(5 mL) at -5 °C. The mixture was stirred for 2 h at -5 °C and
for 3 h at room temperature. After the precipitate of triethy-
lammonium chloride was filtered off, the acetone was removed
under reduced pressure and the residue was extracted twice with
ethyl acetate. Then 2 M HCl was added to the aqueous layer
until pH 2 was reached, and the solution was extracted with
ethyl acetate, dried over Na2SO4, and concentrated to give 0.75
g of N-benzoyl derivative. A solution of SOCl2 (5.6 mmol, 0.4
mL) in methanol (50 mL) was stirred for 2 h at -15 °C, and
then the previously obtained N-benzoyl amide was added in one
portion. The mixture was gradually warmed to room temper-
ature overnight. The solution was concentrated under reduced
pressure, and compound 3 was obtained in 67% overall yield
(0.71 g, 2.5 mmol) after flash chromatography (cyclohexane/ethyl
acetate 6:4 as eluant): mp ) 108-112 °C; IR (Nujol) 3358, 1720,
1649 cm-1; 1H NMR (CDCl3) δ 3.00 (ABX, 2H, J ) 5.5, 5.7, 15.9
Hz), 3.63 (s, 3H), 5.65 (ddd, 1H, J ) 5.5, 5.7, 8.4 Hz), 7.25 (m,
10H), 7.82 (d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 39.6, 49.7,
51.8, 126.2, 127.0, 127.6, 128.5 128.6, 131.5, 134.1, 140.5, 166.5,
172.0; [R]D ) -17.9 (c 4.52, CHCl3); HRMS calcd for (M+)
283.120 843 6, found 283.121 449 2.
ester. The key step is the iodination reaction of the
lithium dianion of methyl (3R)-N-benzoyl-3-amino-3-
phenylpropanoate, which directly affords the correspond-
ing trans oxazoline with high yield and diastereoselec-
tivity. The enantiomerically pure â-amino acid was
obtained by enzymatic kinetic resolution of the N-
(phenylacetyl)amide of the racemate with PGA.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded at 300
or 200 MHz. 13C NMR spectra were recorded at 75 MHz.
Chemical shifts are reported in ppm relative to the solvent peak
of CHCl3, defined to be δ 7.27 ppm. Infrared spectra were
recorded with an FT-IR spectrometer. Melting points were
determined in open capillaries and are uncorrected. HPLC
analyses were performed utilizing a CHIRALCEL OD-H column
(cellulose derivative coated on 5 µm silica gel as packing
material, column size 0.46 cm i.d. × 25 cm, flow rate 0.5 mL/
min, maximum column pressure 50 kg/cm2, operating temper-
ature 0-40 °C). Flash chromatography was performed with
Merck silica gel 60 (230-400 mesh). THF was distilled from
sodium benzophenone ketyl.
(()-3-Am in o-3-p h en ylp r op a n oic Acid (1). Benzaldehyde
(20 mmol, 2 mL), malonic acid (20 mmol, 2.08 g), and ammonium
acetate (40 mmol, 3.08 g) were refluxed in ethanol (30 mL) for
6 h. The reaction mixture was decanted overnight. The amino
acid 1 precipitated from the reaction mixture as a white solid
and was isolated by filtration in 75% yield: mp 216-218 °C dec
(4S,5R)-2,4-Dip h en yl-5-(m et h oxyca r bon yl)-2-oxa zolin e
(4). To a stirred solution of ester 3 (2.5 mmol, 0.7 g) in dry THF
(10 mL) was added LiHMDS (5.5 mmol, 5.5 mL, 1 M solution in
THF) in one portion under argon at 0 °C. After 1 h, the mixture
was cooled to -60 °C, and a solution of iodine (6 mmol, 1.52 g)
in THF (5 mL) was added dropwise. The reaction was quenched
after 1 h with an aqueous saturated solution of NH4Cl (10 mL),
and the solvent was removed under reduced pressure. The
residue was dissolved in ethyl acetate and washed twice with a
solution of Na2S2O3. The organic layer was dried over Na2SO4
and concentrated. Compound 4 was obtained as an oil in 93%
yield (0.65 g, 2.32 mmol) after flash chromatography on silica
gel (cyclohexane/ethyl acetate 9:1 as eluant): IR (film) 1760,
1655 cm-1; 1H NMR (CDCl3) δ 3.87 (s, 3H), 4.93 (d, 1H, J ) 6.5
Hz), 5.47 (d, 1H, J ) 6.5 Hz), 7.40 (m, 10H); 13C NMR (CDCl3)
δ 52.6, 74.5, 83.0, 126.3, 126.4, 126.6, 128.3, 128.6, 128.7, 131.8,
1
(lit.10d mp 218-219 °C dec); H NMR (D2O) δ 2.70 (ABX, 2H, J
) 6.7, 7.9, 16.2 Hz), 4.47 (dd, 1H, J ) 6.7, 7.9 Hz), 7.28 (m, 5H);
13C NMR (D2O) δ 30.8, 52.2, 126.5, 128.8, 128.9, 135.1, 176.5.
Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found:
C, 65.39; H, 6.84; N, 8.46.
(()-N-(P h en yla cetyl)-3-a m in o-3-p h en ylp r op a n oic Acid
(2). Phenylacetyl chloride (13 mmol, 1.72 mL) in acetone (5 mL)
was added dropwise to a stirred solution of (()-3-amino-3-
phenylpropanoic acid (1) (10 mmol, 1.65 g) and triethylamine
(24 mmol, 3.35 mL) in water (15 mL) and acetone (5 mL) at -5
°C. The mixture was stirred for 2 h at -5 °C and then for 3 h
at room temperature. After the precipitate of triethylammonium
chloride was filtered off, the acetone was removed under reduced
pressure and the residue was extracted twice with ethyl acetate.
Then 2 M HCl was added to the aqueous layer until pH 2 was
reached, and the solution was extracted with ethyl acetate, dried
over Na2SO4, and concentrated to give 2.1 g of compound 2 (75%
yield): mp ) 138-140 °C (lit.10d mp 134-140 °C); IR (Nujol)
141.0, 163.8, 170.4; [R]D ) +14.0 (c 0.8, CHCl3) (lit.6d [R]D
)
+13.0 (c 1, CHCl3)); HRMS calcd for (M+) 281.105 193 5, found
281.106 003 3.
(2S,3R)-N-Ben zoyl-3-p h en ylisoser in e Meth yl Ester (5).
A solution of compound 4 (2.3 mmol, 0.65 g) in methanol (15
mL) and 1 N HCl (5 mL) was refluxed for 5 h. After the solvent
was removed under reduced pressure, the residue was dissolved
in CH2Cl2 and washed twice with water. The organic layer was
dried over Na2SO4 and concentrated. Compound 5 was obtained
pure in 85% yield (0.65 g) after flash chromatography on silica
gel (cyclohexane/ethyl acetate 8:2 as eluant): mp ) 182-184
°C (lit.6e mp ) 184-185 °C); IR (Nujol) 1733, 1638 cm-1; 1H NMR
(CDCl3) δ 3.40 (bs, 1H), 3.84 (s, 3H), 4.64 (d, 1H, J ) 2.0 Hz),
5.75 (dd, 1H, J ) 2.0, 9.1 Hz), 7.03 (d, 1H, J ) 9.1 Hz), 7.40 (m,
10H); 13C NMR (CDCl3) δ 53.3, 54.8, 73.2, 126.9, 127.1, 127.9,
128.5, 128.6, 131.8, 138.7, 166.3, 173.4; [R]D ) -47.6 (c 0.6, CH3-
1
3278, 1702, 1653 cm-1; H NMR (CDCl3) δ 2.83 (ABX, 2H, J )
5.8, 6.0, 16.1 Hz), 3.61 (s, 2H), 5.41 (m, 1H), 6.53 (d, 1H, J ) 8.5
Hz), 7.30 (m, 10H), 9.20-9.70 (bs, 1H); 13C NMR (CDCl3) δ 39.4,
43.8, 49.3, 126.1, 127.5, 127.7, 128.8, 129.0, 129.4, 133.7, 139.8,
170.4, 176.0; HRMS calcd for (M+) 283.120 843 6, found
283.120 339 3. Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05;
N, 4.94. Found: C, 72.12; H, 6.01; N, 4.97.
En zym a tic Hyd r olysis of (±)-N-(P h en yla cetyl)-3-a m in o-
3-p h en ylp r op a n oic Acid (2). PGA immobilized on Eupergit
(200 mg) was added to a pH 7 solution of the amide acid 2 (7.5
mmol, 2.12 g) in 1 M phospate buffer (50 mL) and ethanol (7
mL). The reaction mixture was allowed to stir at room temper-
ature for 4 h. Then, after the immobilized enzyme was filtered
off, the ethanol was removed under reduced pressure and 2 M
HCl was added to the aqueous solution until pH 3. The mixture
was extracted twice with ethyl acetate, dried over Na2SO4, and
concentrated to recover phenylacetic acid and the unhydrolyzed
amide (1.51 g, 100% yield, 3.75 mmol of (3R)-2 and 3.75 mmol
of phenylacetic acid). The aqueous layer concentrated gave (S)-
3-amino-3-phenylpropanoic acid as hydrochloride. The amino
acid hydrochloride was used in the following step without further
purification.
OH) (lit.6e [R]D ) -48 (c 0.92, CH3OH)). Anal. Calcd for C17H17
-
NO4: C, 68.22; H, 5.72; N, 4.68. Found: C, 68.30; H, 5.69; N,
4.74.
Ack n ow led gm en t. This work was supported in part
by MURST (40%), by CNR, by University of Bologna
(funds for Selected Research Topics), and by a NATO
Collaborative Research Grant with Professor J oseph P.
Konopelski of the University of Santa Cruz (CRG
950049). We are also thankful to Recordati S.p.A. Unita`
De.Bi. for a kind gift of 50 g of penicillin G acylase
supported on Eupergit.
(3S)-Meth yl N-Ben zoyl-3-a m in o-3-p h en ylp r op a n oa te (3).
Benzoyl chloride (4.88 mmol, 0.57 mL) in acetone (5 mL) was
J O9714066