New synthesis of enantiomerically pure (S)-3-amino-2-phenyl propanoic acid via the asymmetric transformation of its racemic N-phthaloyl derivative

Article abstract of DOI:10.1016/S0957-4166(98)00313-9

The synthesis of racemic N-phthalyl 3-amino-2-phenyl propanoic acid and its asymmetric transformation via the corresponding prochiral ketene have been investigated, allowing the preparation of enantiomerically pure (S)-3- amino-2-phenyl propanpic acid.

Full text of DOI:10.1016/S0957-4166(98)00313-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2845–2850
New synthesis of enantiomerically pure (S)-3-amino-2-phenyl
propanoic acid via the asymmetric transformation of its racemic
N-phthaloyl derivative
Monique Calmes ∗ and Françoise Escale
Laboratoire des Aminoacides, Peptides et Protéines, UMR 5810, Universités Montpellier I et II, UM II, Place E. Bataillon,
34095 Montpellier Cedex 5, France
Received 8 June 1998; accepted 3 August 1998
Abstract
The synthesis of racemic N-phthalyl 3-amino-2-phenyl propanoic acid and its asymmetric transformation via
the corresponding prochiral ketene have been investigated, allowing the preparation of enantiomerically pure (S)-
3-amino-2-phenyl propanoic acid. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
β-Amino acids and their derivatives are an important class of compounds. They are present in
biologically active peptides and in free form show interesting pharmacological effects.1 They are also
precursors of the β-lactam moiety found in some antibiotics.1
Many methods have been reported for the synthesis of racemic β-amino acids but only recently has
the preparation of enantiomerically pure compounds emerged.1,2
The 3-amino-2-phenyl propanoic acid 1, a counterpart of phenylalanine, is of particular interest since
its (ꢀ)-ethyl ester has neurological activity3 and (−)-1 is part of the side chain in semisynthetic penicillin
betacin.4 Indeed, only a few preparations of the homochiral compound 1 have been reported.4–6 In
1964, the racemic mixture was resolved via its (+)-camphor-10-sulfonate salt4 and the (S)-configuration
was for the first time assigned to the (+)-enantiomer by a chemical correlation with (+)-(S)-1-amino-
2-phenyl butane and ORD studies.7 Wyatt et al.5 later described the asymmetric synthesis of (+)-3-
amino-2-phenyl propanoic acid by aminomethylation of a chiral 3-(phenylacetyl)oxazolidinone with
1-(N-benzyloxycarbonyl aminomethyl) benzotriazole. However, an X-ray structure determination un-
ambiguously assigned the opposite (R)-configuration to this enantiomer. Then, an elaborate synthesis6
∗
Corresponding author. Fax: 04 67 14 48 66; e-mail: monique@ampir1.univ-montp2.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00313-9

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M. Calmes, F. Escale / Tetrahedron: Asymmetry 9 (1998) 2845–2850
using as key steps a palladium catalysed asymmetric allylic substitution and a modified Curtius reaction
to introduce nitrogen, has been used to form the (+)-2-phenyl t-butyloxycarbonylamino derivative 2 in
high enantiomeric excess but only moderate yield. Recently, the enantiomerically pure derivative 2 has
been also obtained by using as the key step the acylation of metallated phenylacetonitrile with sultan
carbonyl chloride.8
We showed in previous work9 concerning deracemisation reactions, that the asymmetric transforma-
tion of racemic mixtures involving prochiral ketenes was a simple, convenient and effective reaction. We
therefore decided to explore this method to prepare the homochiral 3-amino-2-phenyl propanoic acid.
2. Results and discussion
Prior to carrying out the asymmetric transformation, racemic 3-amino-2-phenyl propanoic acid had to
be prepared with the amine function totally protected in order to avoid NH addition to the ketene. We
developed a convenient method (Scheme 1) which directly produces the adequately N-protected substrate
starting from phenyl acetic benzyl ester 3 (easily prepared from the cheap commercially available
corresponding acid) and N-bromomethylphthalimide.
Scheme 1.
Alkylation of 3 was achieved in good yield (75%) in THF after deprotonation at low temperature
(−78°C) by using lithium diisopropylamine as base and DMPU10 as co-solvent. When the same reaction
was carried out without DMPU, 4 was obtained in only modest yield (35%) even if another additive such
as LiCl was used. The benzyl ester was easily cleaved by hydrogenolysis without degradation of the
phthalyl group and the N-phthalyl 3-amino-2-phenyl propanoic acid 5 racemic mixture was obtained in
quantitative yield.
According to the considered methodology, the asymmetric transformation of 5 involves the stereo-
selective addition of a chiral alcohol to the N-phthalyl-3-aminomethyl-2-phenyl ketene 7 (Scheme 2).
This reaction was performed in THF, and (R)-pantolactone, a very efficient commercially available chiral
auxiliary, was used as the chiral alcohol.
The ketene 7 was obtained in situ by dehydrochlorination of the corresponding acyl chloride 6 resulting
from 5 after treatment at room temperature with oxalyl chloride. As shown previously9,11 the tertiary
base, used in excess, both catalysed the diastereoselective addition of an alcohol to a ketene and enhanced
the stereoselectivity. Ketene formation and alcohol addition occurs in a one pot procedure.
First we controlled ketene formation. It could be assumed that, due to their similar structures, ketenes
derived from 6 and from aryl propionic acids have comparable stabilities and reactivities. Therefore, in

M. Calmes, F. Escale / Tetrahedron: Asymmetry 9 (1998) 2845–2850
2847
Scheme 2.
a first attempt we used the same experimental conditions as those previously used for aryl propionic
acids, i.e. generation of the ketene by treatment of 6 with triethylamine for 3 h at room temperature, but
under these conditions side reactions were observed to take place. We next modified the experimental
conditions: concentration, temperature and reaction time. We noted that a lower concentration was
advisable because of, in particular, the low solubility of 6 in THF. In addition, only a small amount of
ketene was formed using a lower temperature (0°C to −20°C). On the other hand, treatment of the acyl
chloride 6 with triethylamine, first at 0°C then for 1 h at room temperature, allowed effective generation
of the ketene, the corresponding methyl ester being quantitatively formed with high Cα deuteriation by
trapping the mixture with CH3OD. Subsequent addition of (R)-pantolactone to 7 at the same temperature
afforded the N-phthalyl-(S,R)-3-amino-2-phenyl propanoic pantolactonyl ester 8 both in high chemical
yield (88%) and with high diastereoisomeric excess (d.e.=94%).
The optically pure (S,R)-N-phthalyl pantolactonyl ester was easily obtained after one recrystallisation.
Hydrolysis of 8 under acidic conditions9 gave the corresponding (S)-3-amino-2-phenyl propanoic acid
9 without racemisation as verified by NMR analysis.12 The (S)-configuration of 9 was assigned by
comparison with the specific optical rotation value previously described,5 thus enabling us to establish
that of the ester 8.
In conclusion, we have described an effective and highly stereoselective synthesis of (S)-3-amino-
2-phenyl propanoic acid using as the key step a base-catalysed addition of (R)-pantolactone to the
corresponding N-phthalyl ketene.
3. Experimental
Tetrahydrofuran (THF) was freshly distilled under argon from sodium and benzophenone; triethyl-
amine (NEt3) was distilled from KOH and ninhydrin; DMPU was stirred over CaH2 for 1 h and then
distilled at reduced pressure before use. Thin layer chromatography (TLC) was carried out on silica
gel (60 F254, Merck 5715) and spots were located with UV light or iodine vapour. (R)-Pantolactone
(chemical and enantiomeric purities >99%) was purchased from Fluka Chemical Co. All other chemicals
were commercially pure compounds and were used as received. Melting points were determined with a
Büchi apparatus and are uncorrected. Optical rotation was measured on a Perkin–Elmer, 241 polarimeter.
HPLC analysis was performed on a Waters 510 instrument with a variable detector. 1H NMR spectra were
recorded on a Bruker AC 250 spectrometer. Data are reported as follows: chemical shifts (δ) in ppm with

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M. Calmes, F. Escale / Tetrahedron: Asymmetry 9 (1998) 2845–2850
respect to TMS, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad). The
1
diastereoisomeric excess (d.e.) of 8 was determined for the crude product from the H NMR spectra
(CDCl3) by integration of the 30–CH signal of the pantolactonyl moiety of the pair of diastereoisomers
and/or by HPLC (Chiracel OD column, 25 cm×4 mm, flow rate: 1 mL/min, hexane:isopropanol=80:20.
To obtain racemic samples of the pantolactonyl ester 8, (SR)-5 was esterified with (R)-pantolactone in
the presence of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP). Racemisation
during acid hydrolysis of 8 was verified by NMR analysis12 (DMSO-d6) after derivatisation with
Marfey’s reagent (1-fluoro 2,4-dinitrophenyl 5-(S) alanine amide).13
3.1. Phenyl acetic benzyl ester 3
The phenyl acetic benzyl ester 3 was prepared from phenyl acetic acid (1.36 g, 10 mmol) and benzyl
alcohol as previously described in the literature14 as an oil (2.1 g, 9.3 mmol, 93% yield); TLC (eluent
1
hexane:AcOEt) Rf=0.53; H NMR (CDCl3) δ=3.74 (s, 2H, C6H5CH2CO), 5.21 (s, 2H, OCH2C6H5),
7.38 (m, 10H, H-phenyl).
3.2. N-Phthalyl-(RS)-3-amino-2-phenyl propanoic benzyl ester 4
A solution of n-butyllithium (2.5 M) in hexane (2.4 mL, 6 mmol) was added dropwise over 5 min to
a stirred solution of diisopropylamine (0.91 mL, 6.5 mmol) in dry THF (12 mL) at −78°C under argon.
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.5 mL) was added in one portion, and the mixture
was then stirred at −78°C for 1 h. A solution of phenyl acetic benzyl ester (1.13 g, 5 mmol) in THF (7
mL) was added over 10 min, keeping the temperature below −78°C during the addition. After stirring
the mixture for 1 h at −78°C, the N-bromomethylphthalimide (1.44 g, 6 mmol), was added dropwise in
dry THF (9 mL) at the same temperature. The mixture was stirred for an additional hour at −78°C, and
then allowed to warm slowly to room temperature. After being stirred for 16 h at room temperature, the
reaction mixture was quenched with 1 M HCl (60 mL) and then extracted with ether (3×100 mL). The
combined ether extracts were washed with water, dried and evaporated in vacuo to leave a yellowish solid.
The solid was then purified by chromatography on silica gel (eluent CH2Cl2) Rf=0.55, to give 4 (1.45
1
g, 3.75 mmol, 75% yield), as white crystals. M.p. 98°C; H NMR (CDCl3) δ=4.20 (dd, J=8.4 Hz and
J=13.6 Hz, 1H, HCH–N), 4.31 (dd, J=7.6 Hz and J=13.6 Hz, 1H, HCH–N), 4.38 (dd, J=8.4 Hz and J=7.6
Hz, 1H, CH–CH2–N), 5.11 (d, J=12.4 Hz, 1H, HCHC6H5), 5.17 (d, J=12.4 Hz, 1H, HCHC6H5), 7.17
(m, 5H, H–phenyl), 7.59 (m, 2H, H–phthalyl), 7.67 (m, 2H, H–phthalyl). Anal. calcd for C24H19NO4: C
74.79, H 4.97, N 3.63. Found: C 74.65, H 4.88, N 3.59.
3.3. N-Phthalyl-(RS)-3-amino-2-phenyl propanoic acid 5
N-Phthalyl-(RS)-3-amino-2-phenyl propanoic benzyl ester 4 (578 mg, 1.5 mmol) was added to a
cooled (−20°C) solution of 20% palladium hydroxide on carbon (100 mg) in ethyl acetate (4 mL). The
mixture was then stirred for 5–6 h at room temperature under H2 (monitoring the reaction by TLC).
After filtration through Celite, concentration of the filtrate gave the expected compounds 5 (420 mg,
1.4 mmol, 95% yield) as a white solid. M.p. 175°C (lit.,15 m.p. 178–180°C); 1H NMR (CDCl3) δ=4.23
(m, 3H, CH2–N and CH–CH2–N), 7.28 (m, 5H, H–phenyl), 7.67 (m, 2H, H–phthalyl), 7.80 (m, 2H,
H–phthalyl). Anal. calcd for C17H13NO4: C 69.15, H 4.44, N 4.74. Found: C 69.21, H 4.35, N 4.67.

M. Calmes, F. Escale / Tetrahedron: Asymmetry 9 (1998) 2845–2850
2849
3.4. N-Phthalyl-(RS)-3-amino-2-phenyl propanoic acid chloride 6
A mixture of the N-phthalyl-(RS)-3-amino-2-phenyl propanoic acid (1 equiv.) and oxalyl chloride
(10 equiv.) was stirred under argon at 30°C for 12 h. Evaporation of excess oxalyl chloride gave the
corresponding N-phthalyl-(RS)-3-amino-2-aryl propionic acid chloride which was used as such in the
following step.
3.5. Preparation of the racemic N-phthalyl pantolactonyl ester 8
To N-phthalyl-(RS)-3-amino-2-phenyl propanoic acid (295 mg; 1 mmol), (R)-pantolactone (130 mg,
1 mmol) and 4-dimethylaminopyridine (122 mg, 1 equiv.) in 6 mL of CH2Cl2, was added 1 equiv. of
dicyclohexylcarbodiimide (206 mg) at 0°C. The mixture was then stirred at room temperature for an
additional 12 h. The resulting mixture was filtered and washed with saturated aqueous solutions of citric
acid (3×6 mL) and saturated NaHCO3 (3×6 mL) dried over Na2SO4 and concentrated in vacuo. The
racemic mixtures (S,R)/(R,R) of the pantolactonyl esters 8, were analysed by NMR spectroscopy and
HPLC.
3.6. Diastereoselective addition of (R)-pantolactone to N-phthalylaminomethyl phenyl ketene 7
To a stirred solution under argon of N-phthalyl-(RS)-3-amino-2-phenyl propanoic acid chloride 6 (313
mg; 1 mmol) in 3 mL of anhydrous THF cooled to 0°C, was added 154 µL (1.1 equiv.) of NEt3 in THF (1
mL). After being stirred for 1 h at room temperature, a solution of 153 mg (1.2 mmol) of (R)-pantolactone
in 1 mL of THF was added. After 3 h at this temperature (the reaction being monitored by TLC), a 1 N
citric acid solution (5 mL) was added at 0°C and the solution was extracted with AcOEt (3×10 mL). The
organic layer was then washed successively with water and a NaHCO3 solution and finally dried over
Na2SO4. Evaporation under vacuum gave mainly the (S,R)-pantolactonyl ester 8 (358 mg; 0.88 mmol;
88%) which was analysed by NMR spectroscopy and HPLC: d.e.=94%. Enantiomerically pure (S,R)-8
was obtained by recrystallisation (ethyl acetate:ether). M.p. 156°C.
The HPLC and NMR data of compound 8 were deduced by comparison of the data of the racemic
mixture and enantiomerically pure compound obtained above.
3.7. N-Phthalyl-3-amino-2-phenyl propanoic pantolactonyl ester 8
(S,R)-8: HPLC: r.t. 18.70 min; 1H NMR (CDCl3) δ=0.94 (s, 3H, 40-CH3), 1.06 (s, 3H, 40-CH3), 3.89
(d, J=9 Hz, 1H, 50-HCH), 3.92 (d, J=9 Hz, 1H, 50-HCH), 4.12 (dd, J=8 Hz and J=13.8 Hz, 1H, HCH–N),
4.27 (dd, J=8 Hz and J=13.8 Hz, 1H, HCH–N), 4.41 (t, J1=J2=8 Hz, 1H, HC–C6H5), 5.30 (s, 1H, 30-CH),
7.20 (m, 3H, H–phenyl), 7.30 (m, 2H, H–phenyl), 7.60 (m, 2H, H–phthalyl), 7.72 (m, 2H, H–phthalyl).
(R,R)-8: HPLC: r.t. 20.80 min; 1H NMR (CDCl3) δ=0.70 (s, 3H, 40-CH3), 1.06 (s, 3H, 40-CH3), 3.92
(s, 2H, 50-CH2), 4.18 (dd, J=8.5 Hz and J=13.5 Hz, 1H, HCH–N), 4.26 (dd, J=7.2 Hz and J=13.5 Hz, 1H,
HCH–N), 4.46 (dd, J=7.2 and J=8.5 Hz, 1H, HC–C6H5), 5.36 (s, 1H, 30-CH), 7.20 (m, 3H, H–phenyl),
7.30 (m, 2H, H–phenyl), 7.60 (m, 2H, H–phthalyl), 7.72 (m, 2H, H–phthalyl).
Anal. calcd for C23H21NO6: C 67.81, H 5.20, N 3.44. Found: C 67.78, H 5.13, N 3.36.

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M. Calmes, F. Escale / Tetrahedron: Asymmetry 9 (1998) 2845–2850
3.8. Hydrolysis of N-phthalyl-3-amino-2-phenyl propanoic pantolactonyl ester 8
A mixture of the N-phthalyl pantolactonyl ester 8 (0.5 mmol), acetic acid (1.4 mL) and a 6 N HCl
solution (14 mL) was refluxed until completion of the hydrolysis (4–5 h), the reaction being monitored
by TLC. The mixture was allowed to warm to room temperature and the volatile products were distilled
at reduced pressure. Water (15 mL) was added to the residue and the mixture was washed with AcOEt
(3×15 mL). Evaporation under vacuum of the aqueous layer followed by propylene oxide treatment
gave the free (S)-3-amino-2-phenyl propanoic acid 9. M.p. 220–222°C (lit.,5 m.p. 222–224°C); 1H NMR
(DMSO-d6) δ=3.00 (dd, J=6 Hz and J=12.8 Hz, 1H, HCH–N), 3.40 (dd, J=8.5 Hz and J=12.8 Hz, 1H,
HCH–N), 4.00 (dd, J=6 Hz and J=8.5 Hz, 1H, HC–C6H5), 7.36 (m, 5H, H–phenyl); [α]D=−92 (c=0.2 in
H2O).
Acknowledgements
We thank Dr. J. Daunis for his support and helpful discussions.
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