1008
W. Lin et al.
SHORT PAPER
1H NMR (400 MHz, DMSO-d6): = 3.79 (m, 2 H, CH2), 4.40 (t, 1
H, J = 4.08 Hz, CHNH2), 7.63–7.67 (m, 2 H, Ar-H), 7.76–7.80 (m,
1 H, Ar-H), 8.06–8.08 (m, 2 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): = 42.8, 52.3, 132.5, 133.4,
138.6, 139.7, 174.6, 200.8.
IR (film): = 3126, 2926, 1743, 1670 cm–1.
MS: m/z = 194 (M + 1, free base, 100%), 193 (M+, free base), 161,
afforded L-2-amino-4-oxo-4-phenylbutanoic acid hydro-
chloride (4) in 82% yield, which upon hydrogenolysis in
the presence of 10% palladium on carbon under 1 atm. hy-
drogen pressure at 55°C provided 1 in quantitative yield
with >99% ee by HPLC. The overall yield amounted to
80% in three steps. Excitingly, in the reaction of 3 with
benzene in the presence of aluminum chloride, no C-1 car-
bonyl reacted product was obtained. Thus, the Friedel–
Crafts reaction occurred at the C-4 carbonyl group.
148, 129, 121, 114, 97, 65.
Anal. Calcd for C10H11NO3HCl: C 52.29, H 5.23, N 6.10, Cl 15.47.
Found: C 52.33, H 5.12, N 6.10, Cl 15.20.
With L-homophenylalanine (1) in hand, L-homophenyla-
lanine ethyl ester hydrochloride (5) was prepared by treat-
ment of 1 with anhydrous ethyl alcohol and thionyl
chloride at refluxing temperature in 92% yield without ra-
cemization (Scheme 2), which is a crucial building block
of more than 10 presently marketed angiotensin convert-
ing enzyme inhibitors, such as enalapril, benazepril,
cilazapril, lisinopril, and quinapril.
L-Homophenylalanine (1)
To a solution of 4 (50.0 g, 0.22 mol) in 2 N HCl (300 mL) was added
10% Pd/C (4.0 g). The mixture was hydrogenated at 55°C under 1
atm hydrogen pressure. When the reaction was over as determined
by TLC, the mixture was filtered through Celite. The filtrate was
basified with aq ammonia to pH 5.6 to precipitate the product,
which was filtered and recrystallised from 50% aq AcOH to give 1
19
(38.8 g, quantitative) as white leaflets; mp >250°C; [ ]D + 45.5
(c = 1, 3 N HCl); ee >99% [determined by HPLC, CR column,
HClO4 (aq, pH 2), 0.8 mL/min, T 18°C, UV 215 nm].
1H NMR (300 MHz, D2O + TFA):
= 1.72–1.81 (m, 2 H,
PhCH2CH2), 2.27–2.35 (m, 2 H, PhCH2), 3.57–3.61 (t, 1 H, J = 6.18
Hz, NCHCO), 6.80–6.92 (m, 5 H, Ar-H).
13C NMR (75 MHz, D2O + TFA): = 28.1, 29.0, 50.5, 124.3, 125.7,
126.3, 136.5, 169.1.
Scheme 2
IR (KBr): = 3435, 1654, 1623, 1581 cm–1.
MS: m/z = 179 (M+), 162, 134, 115 (100%), 103, 91.
In summary, our three-step process provided a practical
and convenient synthetic route to L–homophenylalanine
in 80% overall yield from easily available L-aspartic acid
and with 99% optical purity, which also showed an exam-
ple of amino acid anhydride hydrochloride as acylating
agent in Friedel–Crafts reaction. This synthetic procedure
has the superiority of short steps, high yield, no loss in op-
tical activity and the ease of the process in large scale.
This strategy should also be applicable to the synthesis of
other optically active substituted L-homophenylalanine.
Further studies of amino acid anhydride hydrochlorides as
acylating agents in Friedel–Crafts reaction are in progress.
Anal. Calcd for C10H13NO2: C 67.02, H 7.31, N 7.82. Found: C
67.28, H 7.12, N 7.86.
L-Homophenylalanine Ethyl Ester Hydrochloride (5)
To a suspension of 1 (13.2 g, 0.074 mol) in anhyd EtOH (150 mL)
was added SOCl2 (8 mL) dropwise at 0–5°C. The solution was
stirred at refluxing temperature for 5 h, and evaporated under re-
duced pressure. The residue was recrystallized from EtOH and Et2O
to give 5 (16.5 g, 92%) as white crystals; mp 150–151°C; [ ]D
+38.65 (c = 1, H2O); ee >99% [determined by HPLC, CR column,
HClO4 (aq, pH 2), 0.8 mL/min, T 18°C, UV 215 nm].
25
1H NMR (400 MHz, DMSO-d6): = 1.33 (t, 3 H, J = 7.04 Hz, CH3),
2.15–2.19 (m, 2 H, CH2CHN), 2.70–2.73 (m, 1 H, PhCHH), 2.82–
2.87 (m, 1 H, PhCHH), 4.09 (t, 1 H, J = 6.20 Hz, CHNH2), 4.26–
4.32 (m, 2 H, OCH2), 7.28–7.32 (m, 3 H, Ar-H), 7.38–7.42 (m, 2 H,
Ar-H), 8.66 (s, 3 H, NH3Cl).
13C NMR (100 MHz, DMSO-d6): = 18.4, 34.7, 36.3, 56.0, 66.2,
130.6, 132.8, 132.9, 144.8, 173.7.
All melting points were determined on a electrothermal digital melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on a Nicolet MX-1 spectrometer. Mass spectra were recorded on a
VG7070E GC/MS/DS (England) instrument. 1H and 13C NMR were
measured on Bruker 300 MHz and Bruker 400 MHz spectrometers.
Elemental analysis data were recorded on a Carlo Erba-1106 instru-
ment. The enantiomeric excesses were determined by means of
HPLC with a CR column on Shimadzu chromatography with UV/
Vis detector. Optical rotations were measured on a Perkin-Elmer
341 polarimeter. THF, nitromethane and benzene were dried over
3Å molecular sieves.
IR (film): = 3022, 1747, 1523, 1264, 1206, 1203, 702 cm–1.
MS: m/z = 208 (M + 1, free base, 100%), 193, 161, 134, 129, 114,
97, 65.
Anal. Calcd for C12H17NO2HCl: C 59.13, H 7.39, N 5.75, Cl 14.58.
Found: C 59.07, H 7.24, N 5.73, Cl 14.30.
L-2-Amino-4-oxo-4-phenylbutanoic Acid Hydrochloride (4)
Finely powdered anhyd AlCl3 (112.2 g, 0.84 mol) was dissolved in
anhyd benzene (290 mL) and anhyd nitromethane (108.0 mL) with
cooling of ice and water. After 3 (48.0 g, 0.32 mol)6 was added in
portions to the above mixture, it was stirred vigorously at refluxing
temperature for 15 h, and poured into 4 N HCl (300 mL), and stirred
for 2 h. The precipitates were filtered, washed with H2O, and dried
to give 4 (67.7 g, 82%) as a white powder; mp 207–209°C (dec.);
[ ]D20 +34.7 (c = 0.098, 6 N HCl).
Acknowledgement
We are extremely grateful to the National Natural Science Founda-
tion of China for funding this research (No 29790124). We thank
Yijian Deng, Guoshu Chen and Yuanhua Wang for their help.
Synthesis 2001, No. 7, 1007–1009 ISSN 0039-7881 © Thieme Stuttgart · New York