Synthesis of N-Boc-(R)-α-phenyl-γ-aminobutyric acid using an in situ diastereoselective protonation strategy

Article abstract of DOI:10.1016/S0957-4166(02)00075-7

The synthesis of (±)-N-phthalyl α-phenyl-γ-aminobutyric acid and its asymmetric transformation via ketene formation have been investigated, allowing, after hydrolysis and amine protection, the preparation of the enantiomerically pure N-Boc-(R)-α-phenyl-γ-

Full text of DOI:10.1016/S0957-4166(02)00075-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 293–296
Synthesis of N-Boc-(R)-a-phenyl-g-aminobutyric acid using an
in situ diastereoselective protonation strategy
Monique Calme`s,* Franc¸oise Escale and Jean Martinez
Laboratoire des Aminoacides, Peptides et Prote´ines, UMR-CNRS 5810-Universite´s Montpellier I et II, UM II,
Place E. Bataillon, 34095 Montpellier cedex 5, France
Received 5 February 2002; accepted 13 February 2002
Abstract—The synthesis of ( )-N-phthalyl a-phenyl-g-aminobutyric acid and its asymmetric transformation via ketene formation
have been investigated, allowing, after hydrolysis and amine protection, the preparation of the enantiomerically pure N-Boc-(R)-
a-phenyl-g-aminobutyric acid. © 2002 Published by Elsevier Science Ltd.
1. Introduction
2. Results and discussion
g-Aminobutyric acid (GABA) is an important
inhibitory neurotransmitter in the central nervous
system1 and its derivatives, in particular those ana-
logues bearing a phenyl group in the a, b or g position,
have received much attention.2
The synthesis of compound 1 consists of: (a) the prepa-
ration of the racemic g-amino acid with the amine
function totally protected by a phthalimido group
(Scheme 1); (b) transformation of the acid function into
the corresponding acyl chloride followed by the
stereoselective addition of a chiral alcohol to the
prochiral ketene generated in situ (Scheme 2); (c) the
acid-hydrolysis of both the ester and the amine protect-
ing group followed by Boc protection of the amino
group to yield the optically active N-Boc-g-amino acid
derivative (Scheme 2).
We have previously described an efficient asymmetric
transformation of racemic carboxylic acids involving a
prochiral ketene which is well adapted to the synthesis
of optically active a-aryl-substituted compounds.3
Extending our investigations, we now wish to report
our results concerning the asymmetric synthesis of N-
Boc-(R)-a-phenyl-g-aminobutyric acid 1.
Cyanomethylation of the enolate of methyl phenyl ace-
tate (formed at low temperature using lithium hexa-
methyldisilazide) with bromoacetonitrile, followed by
saponification of the methyl ester 3 afforded the cyano
acid 4 in good yield. Reduction of the cyano group with
lithium triethylborohydride4 gave the corresponding
racemic g-amino acid in moderate yield, which was then
BocHN
O
OH
H
1
O
N
H
O-Li+
NC
O
NC
O
O
O
OCH3
OCH3
OH
H
H
OH
H
_
(+)-5
4
3
2
Scheme 1. Synthesis of racemic N-phthalyl a-phenyl-g-aminobutyric acid.
* Corresponding author. Fax: 04 67 14 48 66; e-mail: monique@univ-montp2.fr
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00075-7

294
M. Calme`s et al. / Tetrahedron: Asymmetry 13 (2002) 293–296
O
N
O
N
O
N
O
O
(COCl)2
NEt3
O
O
O
C
O
OH
Cl
H
H
rac-5
7
6
O
N
BocHN
R*OH: (R)-Pantolactone
O
O
H
OH
OH
O
H
OR*
3'
H
1
8
O
O
Scheme 2. Stereoselective synthesis of (R)-N-Boc protected a-phenyl-g-aminobutyric acid.
ture data2d indicating that the (R,R)-ester was mainly
formed during this asymmetric transformation process.
directly converted to the target N-phthalyl derivative
( )-5 (Scheme 1).
The key step in this asymmetric synthesis, i.e. ketene
formation and chiral alcohol addition was completed
using a one-pot procedure (Scheme 2). The best result
was obtained when the ketene 7 was formed in situ by
treatment of the acyl chloride 6 at room temperature
with 1.2 equiv. of triethylamine over 15 min. Subse-
quent addition of (R)-pantolactone at the same temper-
ature afforded the corresponding pantolactonyl ester 8
in good yield (75%) as an 85/15 diastereoisomeric mix-
ture. When the generation time of the ketene at room
temperature was higher than 15 min, we observed both
lower yield and stereoselectivity. Proton NMR analysis
after trapping the ketene with CH3OD indicated that
beside the corresponding Ca deuterated methyl ester,
side products are formed (probably resulting from poly-
merization of the ketene). No improvement in the
stereoselectivity or yield resulted from the use of either
lower temperature or a different tertiary amine.
3. Experimental
Tetrahydrofuran (THF) was freshly distilled under
argon from sodium and benzophenone; triethylamine
(NEt3) was distilled from KOH and ninhydrin. Thin-
layer chromatography (tlc) was carried out on silica gel
(60 F254, Merck 5715) and spots located with UV light
or iodine vapors. All other chemicals were commer-
cially pure compounds and were used as received. Melt-
ing points were determined with a Bu¨chi apparatus and
are uncorrected. Optical rotations were measured on a
Perkin–Elmer, 241 polarimeter. HPLC analysis were
performed on a Waters 510 instrument with a variable
detector using a reverse phase nucleosil C18, 5 mm
(250×10 mm), flow: 1 mL/min, H2O/CH3CN/0.1% TFA
gradient 0–100% (15 min). 1H NMR spectra were
recorded on a Bruker AC 250 or Bruker A DRX 400
spectrometers. Data are reported as follows: chemical
shifts (l) in ppm with respect to TMS, multiplicity
(s=singlet, d=doublet, t=triplet, q=quartet, m=mul-
tiplet, br=broad), coupling constants (J) in Hz. The
ESI mass spectra were recorded with a platform II
Moreover, it should be noted that different attempts to
directly transform the racemic cyano acid 4 into the
corresponding enantiomerically enriched ester by the
same procedure, always afforded the corresponding
racemic pantolactonyl 3-cyano-2-phenyl propionic
ester.
quadrupole
mass
spectrometer
(Micromass,
Manchester, UK) fitted with an electrospray source.
The diastereomerically pure (R,R)-N-phthalyl panto-
lactonyl ester 8 could be obtained after meticulous
column chromatography on silica gel. Several crystal-
lization attempts failed. The diastereoisomeric excess
(d.e.) of 8 was determined for the crude product from
the 1H NMR spectra (CDCl3) by integration of the
methyl signal of the pantolactonyl moiety of the two
diastereoisomers.
3.1. Phenylacetic acid methyl ester 2
The phenylacetic methyl ester 2 was prepared from
phenyl acetic acid (4.08 g, 30.0 mmol), thionyl chloride
and methanol as previously described in the literature5
(4.27 g, 28.5 mmol, 95% yield). It was obtained as a
colorless oil; tlc (eluent hexane/diethyl ether 1/1) Rf=
1
0.75; H NMR (CDCl3) l=3.64 (s, 2H, C6H5CH2CO),
3.70 (s, 3H, OCH3), 7.31 (m, 5H, H-phenyl).
Hydrolysis of the diastereoisomerically pure (R,R)-8
under acidic conditions afforded the corresponding (R)-
g-amino acid hydrochloride, which was directly con-
verted into its N-Boc derivative 1 using di-tert-
butyldicarbonate. The (R)-configuration was assigned
by comparison of the specific rotation of 1 with litera-
3.2. 3-Cyano-2-phenyl propionic acid methyl ester 3
A solution of n-butyllithium (2.5 M) in hexane (8.7 mL,
22.0 mmol) was added dropwise over 5 min to a stirred

M. Calme`s et al. / Tetrahedron: Asymmetry 13 (2002) 293–296
295
solution of hexamethyldisilazane (4.8 mL, 24.0 mmol)
in dry THF (45 mL) at −78°C under argon and the
mixture was stirred for 1 h at −78°C. A solution of 2
(3.0 g, 20.0 mmol) in THF (27 mL) was then added
over 10 min, keeping the temperature below −78°C
during the addition. After stirring the mixture for 1 h at
−78°C, bromoacetonitrile (2.4 mL, 36.0 mmol) was
added dropwise in dry THF (27 mL) at the same
temperature. The mixture was stirred for an additional
1 h at −78°C, and then warmed slowly to room temper-
ature. After stirring at room temperature for 16 h, the
reaction mixture was quenched with 1N aqueous HCl
(100 mL) and THF was removed at reduced pressure.
The aqueous layer was extracted with diethyl ether
(3×150 mL) and the combined extracts were washed
with water, dried and concentrated at reduced pressure.
Column chromatography on silica gel, eluting with
diethyl ether/hexane (1/1, Rf=0.39), yielded the pure
compound 3 as a white solid (2.9 g, 15.4 mmol, 77%
yield). Mp 53–54°C; HPLC: rt 10.75 min; 1H NMR
(CDCl3) l=2.80 (dd, J=7.6 Hz and J=16.8 Hz, 1H,
HCH-CN), 3.03 (dd, J=7.6 Hz and J=16.8 Hz, 1H,
HCH-CN), 3.71 (s, 3H, OCH3), 3.94 (t, J1=J2=7.6
Hz, 1H, CH-CO2CH3), 7.27 (m, 2H, H-phenyl), 7.36
(m, 3H, H-phenyl).
azeotropic distillation (Dean–Stark). Phthalic anhy-
dride (1.5 equiv.) was then added and the reaction
mixture was heated under reflux for 5 h (the formed
water was removed as described previously). After elim-
ination of the volatile products at reduced pressure, a
1N HCl solution (50 mL) was added to the residue and
the mixture was extracted with ethyl acetate (3×100
mL). The combined organic extracts were dried over
Na2SO4 and concentrated at reduced pressure. Flash
column chromatography on silica gel of the crude
compound, eluting with ethyl acetate/hexane (1/1, Rf=
0.18), yielded the pure compound 5 as a white solid
(0.77 g, 2.5 mmol, 25% yield). Mp 140–141°C; HPLC:
1
rt 11.02 min; H NMR (DMSO-d6) l=2.01 (m, 1H,
HCH-CH2NPht), 2.35 (m, 1H, HCH-CH2NPht), 3.60
(m, 3H, CH-CO2H and CH2-NPht), 7.26 (m, 5H, H-
phenyl), 7.84 (m, 4H, H-phthalyl); MS (ESI) m/z:
292.1, 310.0 [(M+H)+], 263.9, 641.4 [(2M+Na)+].
3.5. N-Phthalyl-( )-4-amino-2-phenylbutyric acid chlo-
ride 6
A mixture of N-phthalyl-( )-4-amino-2-phenylbutyric
acid 5 (1 equiv.) and oxalyl chloride (10 equiv.) was
stirred under argon at 35°C for 12 h. Evaporation of
oxalyl chloride excess yielded the corresponding N-
phthalyl-( )-4-amino-2-phenylbutyric acid chloride 6,
which was used without further purification in the
following step.
3.3. ( )-3-Cyano-2-phenylpropionic acid 4
To a solution of compound 3 (2.27 g, 12.0 mmol) in
ethanol (80 mL) was added at room temperature a 1N
sodium hydroxide solution (18 mL, 1.5 equiv.). The
mixture was stirred until disappearance of the starting
material (about 4 h, monitoring the reaction by tlc).
The volatile products were distilled at reduced pressure.
Water (60 mL) was added to the residue and the
mixture was washed with ethyl acetate (100 mL). Then,
the aqueous solution was acidified with a 1N HCl
solution (pH 2–3) and extracted with ethyl acetate
(3×100 mL). The combined organic extracts were dried
over Na2SO4 and concentrated at reduced pressure to
afford the expected compound 4 as a white solid (1.94
g, 11.1 mmol, 93% yield). Mp 87–88°C; HPLC: rt 8.56
3.6. N-Phthalyl-3-amino-2-phenylbutyric acid panto-
lactonyl ester 8
To a stirred solution of N-phthalyl-( )-4-amino-2-
phenylbutyric acid chloride 6 (1.0 mmol) in anhydrous
THF (5 mL) cooled to 0°C and under argon, was added
NEt3 (0.17 mL, 1.2 equiv.) in THF (0.5 mL). After 15
min stirring at room temperature, a solution of (R)-
pantolactone (0.13 g, 1 equiv.) in THF (0.5 mL) was
added. The mixture was stirred for 16 h at room
temperature, then 1N aqueous HCl solution (5 mL) was
added at 0°C and the mixture was extracted with ethyl
acetate (3×10 mL). After concentration of the com-
bined organic extracts at reduced pressure, a column
chromatography on silica gel, eluting with ethyl ace-
tate/hexane (1/1, Rf=0.62), yielded the pure compound
8 as a colorless oil (0.31 g, 75% yield, 70% d.e.). A
second column chromatography on silica gel eluting
with CH2Cl2/ethyl acetate (10/0.4, Rf=0.55) yielded
optically pure (R,R)-8 as a colorless oil (0.19 g, 45%
yield, >99% d.e.). HPLC: rt 13.13 min; [h]2D0=−21
1
min; H NMR (CDCl3) l=2.82 (dd, J=7.5 Hz and
J=16.8 Hz, 1H, HCH-CN), 3.04 (dd, J=7.5 Hz and
J=16.8 Hz, 1H, HCH-CN), 4.03 (t, J1=J2=7.5 Hz,
1H, CH-CO2H), 7.30 (m, 2H, H-phenyl), 7.40 (m, 3H,
H-phenyl).
3.4. N-Phthalyl-( )-4-amino-2-phenylbutyric acid 5
To a vigorously stirred solution of compound 4 (1.75 g,
10 mmol) in THF (30 mL) at 0°C was added slowly a
THF solution of lithium triethylborohydride (1 M, 20
mL, 2 equiv.). After stirring at room temperature for 20
h, the reaction mixture was slowly neutralized with
dilute hydrochloric acid (pH 4–5) with ice-cooling. The
mixture was stirred for 1 h at room temperature and
THF was evaporated at reduced pressure. The resulting
aqueous phase was washed with ethyl acetate before
concentration at reduced pressure. To the oily-solid
residue was added 2 equiv. of triethylamine (2.8 mL) in
toluene (100 mL) and the reaction mixture was heated
under reflux for 4 h while water was removed by
1
(c=1.5, CH2Cl2); H NMR (CDCl3) l=0.98 (s, 3H,
4%-CH3), 1.10 (s, 3H, 4%-CH3), 2.26 (m, 1H, HCH-
CH2N), 2.43 (m, 1H, HCH-CH2N), 3.69 (m, 3H, CH-
C6H5 and CH2N), 3.89 (d, J=9 Hz, 1H, 5%-HCH), 3.93
(d, J=9 Hz, 1H, 5%-HCH), 5.24 (s, 1H, 3%-CH), 7.13
(m, 1H, H-phenyl), 7.23 (m, 4H, H-phenyl), 7.62 (m,
2H, H-phthalyl), 7.72 (m, 2H, H-phthalyl); 13C NMR
(CDCl3) l 18.78 (CH3), 21.96 (CH3), 30.30 (CH2-
CH2N), 35.08 (CH2N), 39.14 (C(CH3)2), 48.16 (CH-
C6H5), 74.36 (C-3%), 75.12 (C-5%), 122.18 (CH-phthalyl),
126.65, 126.97, 127.71 (CH-phenyl), 130.97 (C-
phthalyl), 132.92 (CH-phthalyl), 135.90 (C-phenyl),

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M. Calme`s et al. / Tetrahedron: Asymmetry 13 (2002) 293–296
167.18, 170.69, 170.88 (CO); MS (ESI) m/z: 292.0,
422.0 [(M+H)+], 444.0 [(M+Na)+], 865.2 [(2M+Na)+].
Anal. calcd for C24H23NO6: C, 68.40; H, 5.50; N,
3.32%. Found: C, 67.86; H, 5.70; N, 3.10%.
19.19 min; 1H NMR (CDCl3) l=1.42 (s, 9H, C(CH3)3),
1.94 (m, 1H, HCH-CH2N), 2.30 (m, 1H, HCH-CH2N),
3.12 (m, 2H, CH2N), 3.62 (t, J1=J2=7 Hz,, 1H, CH),
4.61 and 6.13 (br, 1H, NHBoc), 7.31 (m, 5H, H-
phenyl); MS (ESI) m/z: 223.9, 280.1 [(M+H)+], 302.1
[(M+Na)+], 559.3 [(2M+H)+], 581.2 [(2M+Na)+].
The minor diastereoisomer (S,R)-8 has the following
NMR physical data:6,7 1H NMR (CDCl3) l=0.60 (s,
3H, 4%-CH3), 0.87 (s, 3H, 4%-CH3), 2.26 (m, 1H, HCH-
CH2N), 2.43 (m, 1H, HCH-CH2N), 3.69 (m, 3H, CH-
C6H5 and CH2N), 3.84 (s, 2H, 5%-CH2), 5.25 (s, 1H,
3%-CH), 7.13 (m, 1H, H-phenyl), 7.23 (m, 4H, H-
phenyl), 7.62 (m, 2H, H-phthalyl), 7.72 (m, 2H, H-
phthalyl); 13C NMR (CDCl3) l 18.20 (CH3), 21.78
(CH3), 29.81 (CH2-CH2N), 34.81 (CH2N), 39.41
(C(CH3)2), 47.83 (CH-C6H5), 74.00 (C-3%), 75.04 (C-5%),
122.18 (CH-phthalyl), 126.71, 126.97, 127.27 (CH-
phenyl), 127.81 (C-phthalyl), 132.86 (CH-phthalyl),
136.54 (C-phenyl), 167.16, 170.87, 171.25 (CO).
References
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3.7. N-Boc-(R)-3-amino-2-phenylbutyric acid (R)-1
A mixture of the N-phthalyl pantolactonyl ester (R,R)-
8 (100 mg, 0.24 mmol), acetic acid (0.66 mL) and a 6N
HCl solution (6.65 mL) was heated under reflux until
completion of the hydrolysis (4 h–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. To a solution of the
residue in dioxane/H2O (2/1, 10 mL) at 0°C was added
sodium hydroxide (1 equiv.) and di-tert-butyldicarbon-
ate (57 mg, 1.1 equiv.). After stirring the mixture for 12
h at room temperature the dioxane was evaporated at
reduced pressure and water was added (10 mL). The
resulting aqueous phase was successively washed with
ethyl acetate (3×15 mL), acidified with 1N aqueous HCl
solution (pH 2–3) and extracted with CH2Cl2 (3×15
mL). The combined CH2Cl2 extracts were dried over
Na2SO4 and concentrated at reduced pressure to afford
the expected compound N-Boc-(R)-3-amino-2-phenyl-
butyric acid 1 as a colorless solid (39 mg, 59% yield).
Mp 98–100°C; [h]D20=−67 (c=0.6, CH2Cl2); HPLC: rt
3. (a) Calme`s, M.; Escale, F.; Glot, C.; Rolland, M.; Mar-
tinez, J. Eur. J. Org. Chem. 2000, 2459–2466; (b) Calme`s,
M.; Escale, F.; Juan, E.; Rolland, M.; Martinez, J. Tetra-
hedron: Asymmetry 2000, 11, 1263–1266.
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Chem. 1980, 45, 1.
5. Brenner, M.; Huber, W. Helv. Chim. Acta 1953, 1109.
6. NMR data for compound 8 deduced from comparison of
the data of the racemic mixture and the enantiomerically
pure compound obtained.
7. To obtain a diastereoisomeric mixture of the pantolactonyl
ester 8, ( )-5 was esterified with (R)-pantolactone in the
presence of dicyclohexylcarbodiimide (DCC) and dimethy-
laminopyridine (DMAP) (96% yield, (R,R)/(R,S): 45/55).