Stereoselective synthesis of both enantiomers of N-Boc-α-aryl- γ-aminobutyric acids

Article abstract of DOI:10.1016/j.tetasy.2003.10.035

Esterification of racemic α-aryl-β-cyanopropionic acid chlorides with either (R)- or (S)-N-phenylpantolactam as the chiral auxiliary in the presence of Et₃N resulted in the predominant formation of (αR,3′R)- or (αS,3′S)-configured pantolactam c

Full text of DOI:10.1016/j.tetasy.2003.10.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 311–321
Stereoselective synthesis of both enantiomers of
N-Boc-a-aryl-c-aminobutyric acids
*
*
~
Pelayo Camps, Diego Munoz-Torrero and Laura Sanchez
ꢀ
Laboratori de Quꢀımica Farmacꢁeutica (Unitat Associada al CSIC), Facultat de Farmꢁacia, Universitat de Barcelona,
Av. Diagonal 643, E-08028 Barcelona, Spain
Received 6 October 2003; accepted 30 October 2003
Abstract—Esterification of racemic a-aryl-b-cyanopropionic acid chlorides with either (R)- or (S)-N-phenylpantolactam as the
chiral auxiliary in the presence of Et3N resulted in the predominant formation of (aR,30R)- or (aS,30S)-configured pantolactam
cyano ester, respectively, in nearly quantitative yields with diastereomeric ratios of up to 93:7. Column chromatography of the
diastereoenriched cyano esters, followed by hydrolysis of the resulting diastereopure cyano esters under essentially nonracemizing
conditions gave enantiopure a-aryl-b-cyanopropionic acids, which were readily converted in high yields into enantiopure (aR)- and
(aS)-configured N-tert-butoxycarbonyl-a-aryl-c-aminobutyric acid (GABA) derivatives of potential biological interest.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
chiral auxiliary, and (iv) controlled hydrolysis of the
resulting diastereoenriched pantolactone esters. A wide
range of carboxylic acids bearing different substituents
at the a-position, including a-arylpropionic acids,
a-haloalkanoic acids, as well as a-, b-, c-, and d-amino
acids, have been deracemized with (R)-pantolactone,
with diastereomeric ratios (dr) ranging from 85:15 to
>98:2 in most cases.1–13
(R)-Pantolactone, (R)-1 (Fig. 1), is a known chiral
auxiliary, which has been widely used in different
asymmetric transformations. In particular, (R)-panto-
lactone has proven to be an efficient chiral auxiliary in
the deracemization of a,a-disubstituted carboxylic acids,
through a process, which usually implies: (i) conversion
of the racemic mixture of the carboxylic acid into a
racemic mixture of acid chlorides, (ii) the formation of
the corresponding prochiral ketene, (iii) the diastereo-
selective amine-catalyzed nucleophilic addition of the
Several years ago we developed two alternative multi-
gram syntheses of (R)- and (S)-N-phenylpantolactam,
(R)- and (S)-2 (Fig. 1),14;15 as pantolactone analogues
displaying several advantages as chiral auxiliaries rela-
tive to pantolactone: (1) easy availability of both
enantiomers; (2) easy recovery as a consequence of their
crystallizability, lipophilicity, and nonhygroscopic
character; (3) easy detection by chiral HPLC with a UV
detector, due to the presence of the aniline chromo-
phore. Regarding their efficiency as chiral auxiliaries,
(R)- and (S)-2 were used in a series of asymmetric
transformations such as Diels–Alder reactions,16 nucle-
ophilic substitution reactions on a-halo esters,17–19 and
deracemization of a-arylpropionic acids,20 a-substituted
a-arylacetic acids,21 a-halo acids,17;18 and a-amino
acids,19 leading to diastereoselectivities roughly parallel
or even slightly superior to those obtained in similar
cases using (R)-1.
OH
OH
O
O
O
N
Ph
(R)-pantolactone,
(R)-1
(R)-N-phenylpantolactam,
(R)-2
Figure 1. Structures of the chiral auxiliaries (R)-pantolactone and
(R)-N-phenylpantolactam.
Keywords: N-Phenylpantolactam; Chiral auxiliaries; Deracemization
reactions; a-Aryl-GABA derivatives.
* Corresponding authors. Tel.: +34-93-4024536/42; fax: +34-93-4035-
941; e-mail addresses: camps@farmacia.far.ub.es; dmunoz@
farmacia.far.ub.es
In the most recent example of (R)-pantolactoneꢀs use
as a chiral auxiliary in a deracemization reaction,
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.035

312
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
ꢁ
Calmes et al. reported the stereoselective synthesis of the
(R)-enantiomer of N-tert-butoxycarbonyl-(N-Boc)-a-
phenyl-c-aminobutyric acid, (R)-8a, through an eight-
step synthetic sequence in which the key step was the
deracemization of the N-phthalyl derivative of a-phenyl-
c-aminobutyric acid, which was prepared in only 25%
overall yield from racemic a-phenyl-b-cyanopropionic
acid, ( )-5a.12 Curiously, while deracemization of the N-
phthalyl derivative of the desired c-amino acid pro-
ceeded in 75% yield and 85:15 dr, the initially attempted
deracemization of the cyano acid precursor ( )-5a also
with (R)-1, which would have shortened the synthetic
sequence and probably improved its overall yield, was
reported to fail, leading in all attempts to a 1:1 mixture
of the two diastereomeric (R)-pantolactone esters.12 The
good performance of (R)- and (S)-2 as chiral auxiliaries
in deracemization reactions relative to (R)-1, and the
high biological interest of a-substituted derivatives of
the major inhibitory neurotransmitter c-aminobutyric
acid (GABA),22–27 prompted us to check the efficiency of
(R)- and (S)-2 as chiral auxiliaries in the deracemization
system where (R)-pantolactone had failed. Herein we
report the efficient use of (R)- and (S)-2 as chiral aux-
iliaries in the deracemization of a series of a-aryl-b-
cyano acids, ( )-5a–c, and the conversion of the result-
ing highly diastereoenriched N-phenylpantolactam
esters into the corresponding enantiopure (R)- and (S)-N-
(Boc)-a-aryl-c-aminobutyric acids, (R)- and (S)-8a–c, as
GABA derivatives with a potential affinity at the GABA
receptors.
2. Results and discussion
The known a-aryl-b-cyano acid ( )-5a12 and the new
ones ( )-5b,c that were to be deracemized were prepared
from the commercially available 3a and the known
methyl arylacetates 3b28 and 3c,29 respectively, following
the procedure described for ( )-5a,12 which implied an
initial cyanomethylation with bromoacetonitrile of the
lithium enolate of the esters 3a–c in THF from )78 ꢁC to
room temperature, followed by saponification of the
resulting cyano esters ( )-4a–c (Scheme 1). The initial
deracemization studies were carried out with ( )-5a
using racemic N-phenylpantolactam. In contrast with
the usual one-pot deracemization methodologies using
(R)-pantolactone as the chiral auxiliary, in which a
prochiral ketene is preformed from the racemic acid
chloride and a tertiary amine before the addition of the
chiral auxiliary,1–13 our methodology involves a rapid
mixture of the acid chloride, the chiral auxiliary, and the
tertiary amine usually in CH2Cl2 at 0 ꢁC, therefore
without preformation of the ketene, thus avoiding
problems related to its hydrolysis or dimerization before
reacting with the chiral auxiliary.17–21 Under these con-
ditions, a dynamic kinetic resolution process has also
been proposed to explain the outcome of these reac-
tions.19 Thus, ( )-5a was reacted with PCl5 in CCl4 with
the resulting crude acid chloride ( )-6a used directly in
slight excess (1.5 equiv) in the subsequent reaction with
( )-2 and excess of Et3N (3.2 equiv) in anhydrous
ꢂ
CH2Cl2 at 0 ꢁC in the presence of 3 A molecular sieves,
NC
NC
Ar
NC
Ar
PCl5
CCl4
OMe
OMe
OH
Cl
HMDS, n-BuLi
1 N NaOH
EtOH
Ar
Ar
bromoacetonitrile,
THF
O
3a−c
O
O
O
( )-4a−c
( )-5a−c
( )-6a−c
NC
O
O
Ar
N
Ph
(αR,3'R)-7 [or (αS,3'S)-7]
a dr > 98:2 dr > 98:2
b dr > 98:2 dr > 98:2
O
column
chromatography
LiOH·H2O
H2O2, THF
(R)-2 [or (S)-2]
(αR,3'R)-7 [or (αS,3'S)-7]
c dr 97:3
dr 97:3
Et3N, CH2Cl2
a dr 91:9
b dr 93:7
c dr 91:9
dr 90:10
dr 87:13
dr 92:8
1) H2, AcOH,
10% Pd / C
NC
NHBoc
(R)-5a−c [or (S)-5a−c]
+ (R)-2 [or (S)-2]
OH
2) Boc2O, NaOH,
H2O / dioxane
ee > 99%
(ee > 99%)
Ar
OH
O
Ar
O
(R)-5
[or (S)-5]
1) cyclohexylamine
a ee 90% ee 97%
b ee 97% ee 98%
c ee 94% ee 91%
2) 1 N HCl
or recrystallization from
AcOEt for (R)- and (S)-5c
(R)-8a−c [or (S)-8a−c]
ee > 99%
4−8a: Ar = phenyl; 4−8b: Ar = 4-isobutylphenyl; 4−8c: Ar = 6-methoxy-2-naphthyl
Scheme 1.

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
313
to afford a diastereomeric mixture of N-phenylpanto-
lactam esters greatly enriched in one of the two possible
diastereomeric racemic pairs (dr 93:7 as revealed from
ica gel allowed the isolation of (aR,30R)-7a,b and
1
(aS,30S)-7a,b as single diastereomers by H NMR (dr
>98:2) in around 60% overall yield. In the c series, the
1
the integration in the H NMR spectrum of the signals
chromatographic separation was slightly less efficient,
1
corresponding to the protons of the CH3 group at the
4a-position of the pantolactam moiety). Regarding the
sense of asymmetric induction of this transformation, it
is known from deracemization reactions of a,a-disub-
stituted carboxylic acids using (R)-1, (R)-2, or (S)-2 as
chiral auxiliaries and Et3N as the tertiary amine that the
(aR)-configured pantolactone or pantolactam ester is
preferentially formed from the (30R)-configured auxil-
iary, and vice versa.4;20;21 Accordingly, the racemic
mixture (aR,30R)-7a/(aS,30S)-7a [(aR*,30R*)-7a] was
assumed to be the main product in this reaction.
producing (aR,30R)-7c and (aS,30S)-7c (dr >98:2 by H
NMR) in only 10% and 3% overall yield, respectively,
and highly diastereoenriched (aR,30R)-7c and (aS,30S)-
7c (dr 97:3 by 1H NMR) in 27% and 43% yield,
respectively. Hydrolysis of a sample of (aR,30R)-7a (dr
90:10) with LiOHÆH2O in THF/H2O from 0 ꢁC to room
temperature resulted in complete racemization of the
resulting cyano acid 5a, while the hydrolysis under the
optimized conditions found in the model studies, that is,
with LiOHÆH2O/30% w/v H2O2 in dioxane at room
temperature, proceeded in excellent yield (92%) but with
a significant degree of racemization [40% enantiomeric
excess of (R)-5a]. Fortunately, when the reaction of a
sample of (aR,30R)-7a (dr >98:2) was carried out in
THF at 0 ꢁC for 5 h, (R)-5a was obtained in 95% yield
and 90% enantiomeric excess (ee), as determined by
chiral HPLC, and the chiral auxiliary (R)-2 was recov-
ered in 76% yield in enantiopure form. Moreover,
enantiopure (R)-5a (ee >99% by chiral HPLC) was
obtained in 66% overall yield [from (aR,30R)-7a] by
precipitation of the cyclohexylammonium salt of the
crude product (ee 90%), followed by recrystallization
from isopropanol and reisolation of the acid after
Diastereoenriched N-phenylpantolactam esters have
been usually hydrolyzed to the corresponding enantio-
enriched carboxylic acids, recovering the chiral auxiliary
without racemization, either under acidic conditions
(mixture HOAc/aq HCl)19–21 or under basic conditions
(LiOHÆH2O, or LiOHÆH2O/H2O2).17;18 In order to select
the most appropriate hydrolysis methodology for esters
7, the above-mentioned racemic (aR*,30R*)-7a (dr 93:7)
was used as
a model compound. Reaction of
(aR*,30R*)-7a with a 2.5:1 mixture of AcOH and 2 M
HCl at 120 ꢁC afforded the cyano acid ( )-5a in only
51% yield, while its reaction with LiOHÆH2O in a 2:1
mixture THF/H2O from 0 ꢁC to room temperature
afforded ( )-5a in 66% yield. The optimal results were
obtained when the hydrolysis of (aR*,30R*)-7a was
carried out with LiOHÆH2O and 30% w/v H2O2
in dioxane at room temperature, in which cyano acid
( )-5a was obtained in 76% yield. It is worthy of note
that in all cases, ( )-2 was easily recovered in essentially
quantitative yields through acid–base washings, and
only in the reaction with LiOHÆH2O was a small amount
of hydrolysis of the cyano group of ( )-5a to the cor-
responding amide observed.
treatment with 1 M HCl. Comparison of the specific
20
D
rotation of this enantiopure compound {½aꢀ ¼ )155
(c 0.94, CH2Cl2)} with that described for (S)-5a
28
D
{½aꢀ ¼ +154 (c 1.04, CH2Cl2)}26 confirmed the (aR)-
configuration assigned to this compound and to the
ester precursor 7a, and the sense of asymmetric induc-
tion predicted for the deracemization process with this
kind of chiral auxiliaries. Hydrolysis of (aS,30S)-7a (dr
>98:2) under the best reaction conditions found for the
hydrolysis of its enantiomer (aR,30R)-7a proceeded in
similar yield with respect to both (S)-5a and the chiral
auxiliary (S)-2, but with a lower degree of racemization,
obtaining cyano acid (S)-5a with 97% ee. Analogously,
enantiopure (S)-5a (ee >99% by chiral HPLC) was
obtained in 54% overall yield [from (aS,30S)-7a] via the
cyclohexylammonium salt of the crude product. The
improved hydrolysis conditions were also applied to
(aR,30R)- and (aS,30S)-7b (dr >98:2), and to (aR,30R)-
and (aS,30S)-7c (dr 97:3), obtaining the corresponding
cyano acids (R)- and (S)-5b,c in high yields (87–97%)
and with essentially no racemization (Scheme 1).
Enantiopure (R)- and (S)-5b,c (ee >99% by chiral
HPLC) were obtained in 52–64% overall yield (from the
corresponding diastereopure esters 7b,c) via the cyclo-
hexylammonium salt of the crude products [for (R)- and
(S)-5b] or by direct recrystallization of the crude product
[for (R)- and (S)-5c]. Worthy of note, in the hydrolysis
of esters (aR,30R)- and (aS,30S)-7b,c, (R)- and (S)-2 were
recovered in 94–96% yield in enantiopure form. As
previously described for (S)-5a,26 hydrogenation of the
enantiopure a-aryl-b-cyano acids (R)-5a–c and (S)-5b,c,
followed by protection of the amino group of the
resulting c-amino acids led to the enantiopure N-(Boc)-
a-aryl-c-amino acids (R)-8a–c and (S)-8b,c (ee >99% by
chiral HPLC) in 52–79% overall yield for the last two
steps (Scheme 1). The sign of the optical rotations of
Finally, following a reported procedure,26 cyano acid
( )-5a was converted into the N-(Boc)-a-aryl-c-amino
acid ( )-8a in 66% yield by hydrogenation with 10% Pd/
C in AcOH at 4 atm, followed by the reaction of the
resulting crude c-amino acid with di-tert-butyl dicar-
bonate (Boc2O) and NaOH in a 1:2 mixture H2O/diox-
ane at room temperature.
The good results obtained in these model studies
prompted us to apply these methodologies to the con-
version of cyano acids ( )-5a–c into enantiopure a-aryl-
substituted GABA derivatives (R)- and (S)-8a–c, using
(R)- and (S)-2 as chiral auxiliaries. Thus, diastereoen-
riched N-phenylpantolactam esters (aR,30R)-7a–c and
(aS,30S)-7a–c were obtained in essentially quantitative
yields with diastereomeric ratios (dr 87:13 to 93:7) sim-
ilar to that obtained in the model study, by the reaction
of the acid chlorides ( )-6a–c, derived from cyano acids
( )-5a–c, with (R)- or (S)-2, respectively, under our
standard reaction conditions (Scheme 1).
Interestingly, carefully conducted column chromato-
graphy of these diastereoenriched esters through sil-

314
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
compounds (R)- and (S)-5b,c and 8b,c coincide with
those of the known (R)- and (S)-5a and 8a, respectively,
being in accord with their assigned configurations and
those of (aR,30R)- and (aS,30S)-7b,c based on the
asymmetric induction predicted for the deracemization
process with these chiral auxiliaries, confirmed in this
work in the phenyl (a) series.
1H/13C experiments using the HMQC sequence with
an indirect detection probe were performed. IR spectra
were run on a FT/IR Perkin–Elmer model 1600 spec-
trophotometer. Absorption values are expressed as wave
numbers (cmꢁ1); only significant absorption bands are
given. Column chromatography was performed on silica
gel 60 ACC (70–200 mesh, SDS, ref 2100027). Thin-layer
chromatography (TLC) was performed with aluminum-
backed sheets with silica gel 60 F254 (Merck, ref
1.05554), and spots were visualized with UV light and
1% aqueous solution of KMnO4. Optical rotations were
measured on a Perkin–Elmer model 241 polarimeter.
Chiral HPLC analyses were performed on a Waters
model 600 liquid chromatograph provided with a
Waters model 486 variable k detector using a Chiralcel
OD-H column (25 · 0.46 cm) containing the chiral
stationary phase cellulose tris(3,5-dimethylphenylcar-
bamate), with a flow of 0.8 mL/min and UV detection at
k ¼ 254 nm. Condition A: mixture of hexane/isopropanol/
trifluoroacetic acid in the ratio of 93:7:0.1 as eluent.
Condition B: mixture of hexane/EtOH/trifluoroacetic
acid in the ratio of 98:2:0.1 as eluent. Condition C:
mixture of hexane/isopropanol/trifluoroacetic acid in the
ratio of 95:5:0.1 as eluent. Condition D: mixture of
hexane/EtOH/trifluoroacetic acid in the ratio of 99:1:0.1
as eluent. Condition E: mixture of hexane/EtOH/triflu-
oroacetic acid in the ratio of 90:10:0.1 as eluent. Con-
dition F: mixture of hexane/EtOH/trifluoroacetic acid in
the ratio of 95:5:0.1 as eluent. Analytical grade solvents
were used for crystallization and chiral HPLC analyses,
while pure for synthesis solvents were used in the reac-
tions, extractions, and column chromatography. NMR
3. Conclusion
Thus, a-aryl-substituted GABA derivatives (R)- and (S)-
8a–c of potential biological interest have been prepared
in enantiopure form (ee >99%) from the readily avail-
able methyl arylacetates 3a–c, through a seven-step
synthetic sequence, involving as the key step the
deracemization of cyano acids ( )-5a–c using (R)- or
(S)-N-phenylpantolactam as chiral auxiliaries. In sharp
contrast with the reported absolute lack of efficiency of
(R)-pantolactone as chiral auxiliary in the deracemiza-
tion of this kind of cyano acids, the use of (R)- and (S)-
N-phenylpantolactam led to the corresponding panto-
lactam esters in almost quantitative yields, with high
levels of diastereoselectivity (dr up to 93:7), and with
predictable sense of asymmetric induction [(aR)-config-
ured esters are formed from (R)-2, and (aS)-configured
esters are formed from (S)-2]. Moreover, (aR,30R)- and
(aS,30S)-configured pantolactam esters in highly diaste-
reoenriched form (dr >98:2 or 97:3) were obtained by
column chromatography of the diastereoenriched crude
materials resulting from the deracemization reactions.
Hydrolysis of these esters under essentially nonrace-
mizing conditions, followed by recrystallization of the
resulting crude cyano acids or their cyclohexylammo-
nium salts, and subsequent reisolation of the carboxylic
acids in the last cases, led to enantiopure a-aryl-b-cyano
acids (R)- and (S)-5a–c, which were transformed in good
yields into the N-(Boc)-a-aryl-substituted GABA deriv-
atives (R)- and (S)-8a–c through a standard procedure.
ꢀ
ꢁ
spectra were performed at the Serveis Cientıfico-Tecnics
of the University of Barcelona, while elemental analyses
were carried out at the Mycroanalysis Service of the
IIQAB (CSIC, Barcelona, Spain).
4.2. ( )-3-Cyano-2-phenylpropionic acid ( )-5a12
Chiral HPLC, condition A: (R)-5a, tR ¼ 20:6 min,
k10 ¼ 4:06; (S)-5a, tR ¼ 22:2 min, k20 ¼ 4:46; a ¼ 1:10;
Res ¼ 3.58.
4. Experimental
4.1. General
Melting points were determined in open capillary tubes
with a MFB 595010M Gallenkamp melting point
apparatus. 300 MHz 1H NMR and 75.4 MHz 13C NMR
spectra were recorded on a Varian Gemini 300 spec-
4.3. (aR,30R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl 3-cyano-2-phenylpropionate (aR,30R)-7a
A solution of cyano acid ( )-5a (1.00 g, 5.71 mmol) and
PCl5 (1.40 g, 6.72 mmol) in CCl4 (9 mL) was stirred at
40 ꢁC for 30 min. Evaporation of the volatile products
from the reaction mixture gave the acid chloride ( )-6a
(1.10 g, 99%), which was used in the following step
without further purification. 1H NMR (200 MHz,
CDCl3) d: 2.86 (dd, J ¼ 16:8 Hz, J0 ¼ 7:8 Hz, 1H) and
3.09 (dd, J ¼ 16:8 Hz, J0 ¼ 7:0 Hz, 1H) (3-H2), 4.33
(pseudo t, J ꢂ 7:3 Hz, 1H, 2-H), 7.26–7.34 (m, 2H, Ar-
Hortho), 7.42–7.50 (m, 3H, Ar-Hmeta, and Ar-Hpara).
1
trometer and 200 MHz H NMR spectra on a Varian
Gemini 200 spectrometer. The chemical shifts are
reported in ppm (d scale) relative to internal TMS, and
coupling constants are reported in hertz (Hz). For the
pantolactam esters 7, the terms a or b are assigned to
hydrogen atoms or methyl groups of the pantolactam
moiety, which are cis or trans relative to the acyloxy
substituent, respectively. For the assigment of the sig-
nals corresponding to the aromatic quaternary carbon
atoms of compound 4b, HETCOR long-range experi-
ments were performed, while for the assigment of the
signals corresponding to the aromatic hydrogen and
To a cooled (0 ꢁC) solution of (R)-2 (0.82 g, 4.00 mmol)
in anhydrous CH2Cl2 (12 mL) solution previously dried
1
carbon atoms of compounds 4c and 5c, COSY H/1H
by stirring at 0 ꢁC for 45 min with 4 g of 3 A molecular
ꢂ
ꢂ
sieves, a dried (6 g of 3 A molecular sieves) solution of
experiments using standard procedures and COSY

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
315
acid chloride ( )-6a (1.10 g, 5.68 mmol) in anhydrous
ꢂ
CH2Cl2 (18 mL), and a dried (12 g of 3 A molecular
pension was extracted with AcOEt (3 · 6 mL). The
combined organic extracts were washed with H2O
(3 · 6 mL), dried with anhydrous Na2SO4, and evapo-
rated at reduced pressure to give enantiopure (R)-5a
sieves) solution of Et3N (1.84 mL, 13.2 mmol) in anhy-
drous CH2Cl2 (24 mL) were successively added. The
reaction mixture was stirred at 0 ꢁC for 3 h, was washed
with 1 N HCl (2 · 30 mL) and a saturated aqueous
solution of NaHCO3 (2 · 30 mL), dried with anhydrous
Na2SO4 and concentrated in vacuo to give a diastereo-
meric mixture of (R)-pantolactam esters greatly enriched
in the (aR,30R)-7a diastereomer (1.43 g, 99%, dr 91:9 by
1H NMR). An aliquot part of this residue (0.94 g) was
submitted to column chromatography [silica gel (50 g),
hexane/AcOEt mixtures]. On elution with hexane/
AcOEt 75:25, (aR,30R)-7a (570 mg, 60%, dr >98:2) and a
mixture (aR,30R)-7a/(aS,30R)-7a (76 mg, dr 70:30) were
successively isolated as a light brown oil and a light
brown solid, respectively.
(139 mg, 66% overall, ee >99% by chiral HPLC) as a
20
D
white solid. ½aꢀ ¼ )155 (c 0.94, CH2Cl2) [lit.26
28
D
½aꢀ ¼ +154 (c 1.04, CH2Cl2) for (S)-5a]. Chiral HPLC,
condition A: (R)-5a, tR ¼ 20:7 min. Mp: 84–85 ꢁC (iso-
propanol). Rf 0.09 (SiO2, hexane/AcOEt 1:1). IR (KBr)
m: 3600–2500 (O–H st), 2261 (CN st), 1737 (C@O st)
cmꢁ1
.
1H NMR (300 MHz, CDCl3) d: 2.79 (dd,
J ¼ 16:8 Hz, J0 ¼ 7:5 Hz, 1H) and 3.00 (dd, J ¼ 16:8 Hz,
J0 ¼ 7:5 Hz, 1H) (3-H2), 3.96 (dd, J ꢂ J0 ꢂ 7:5 Hz, 1H,
2-H), 7.26–7.30 (m, 2H, Hortho), 7.30–7.42 (m, 3H,
Hmeta and para), 11.10 (br s, 1H, COOH). 13C NMR
(75.4 MHz, CDCl3) d: 21.2 (CH2, C3), 47.4 (CH, C2),
117.2 (C, CN), 127.5 (CH, Ar-Cortho), 128.7 (CH, Ar-
Cpara), 129.2 (CH, Ar-Cmeta), 134.8 (C, Ar-Cipso),
176.5 (C, C1). Anal. Calcd for C10H9NO2Æ0.8H2O: C,
63.35; H, 5.64; N, 7.39. Found: C, 63.36; H, 5.75; N,
7.36.
20
(aR,30R)-7a (dr >98:2): ½aꢀ ¼ )14.2 (c 0.66, CH2Cl2). Rf
D
0.29 (SiO2, hexane/AcOEt 75:25). IR (NaCl) m: 2214
(CN st), 1744 (C@O st ester), 1713 (C@O st lactam)
1
cmꢁ1. H NMR (300 MHz, CDCl3) d: 1.11 (s, 3H, 40a-
CH3), 1.30 (s, 3H, 40b-CH3), 2.90 (dd, J ¼ 17:0 Hz,
J0 ¼ 7:4 Hz, 1H) and 3.12 (dd, J ¼ 17:0 Hz, J0 ¼ 7:7 Hz,
1H) (3-H2), 3.50 (d, J ¼ 9:8 Hz, 1H, 50a-H), 3.60 (d,
J ¼ 9:8 Hz, 1H, 50b-H), 4.12 (pseudo t, J ꢂ 7:4 Hz, 1H,
2-H), 7.16 (tdm, J ¼ 7:4 Hz, J0 ¼ 1:3 Hz, 1H, Hpara N-
phenyl), 7.30–7.43 (complex signal, 7H, Ar-H C-phenyl,
and Hmeta N-phenyl), 7.54–7.60 (m, 2H, Hortho N-
phenyl). 13C NMR (75.4 MHz, CDCl3) d: 21.1 (CH3,
40a-CH3), 22.0 (CH2, C3), 24.8 (CH3, 40b-CH3), 37.3 (C,
C40), 47.8 (CH, C2), 57.7 (CH2, C50), 79.4 (CH, C30),
117.4 (C, CN), 119.4 (CH, Cortho N-phenyl), 124.9 (CH,
Cpara N-phenyl), 127.7 (CH, Cortho C-phenyl), 128.5
(CH, Cpara C-phenyl), 128.9 (CH, Cmeta N-phenyl),
129.1 (CH, Cmeta C-phenyl), 135.0 (C, Cipso C-phenyl),
138.8 (C, Cipso N-phenyl), 167.8 (C, C20), 170.3 (C, C1).
Anal. Calcd for C22H22N2O3Æ4/5H2O: C, 70.12; H, 6.32;
N, 7.43. Found: C, 70.33; H, 6.40; N, 7.13.
4.5. (R)-4-(tert-Butoxycarbonylamino)-2-phenylbutanoic
acid (R)-8a12
A mixture of (R)-5a (100 mg, 0.57 mmol, ee >99%),
AcOH (15 mL) and 10% Pd/C (86 mg) was hydrogenated
at 4 atm and at room temperature for 24 h. The catalyst
was filtered off in vacuo through Celiteꢂ, and the filtrate
was evaporated under reduced pressure to give crude
(R)-4-amino-2-phenylbutanoic acid (135 mg) as a color-
less oil, which was taken in H2O (3 mL), cooled to 0 ꢁC,
and basified with 2 M NaOH (0.5 mL). To the cold basic
solution, dioxane (6 mL) and Boc2O (245 mg, 1.12 mmol)
were successively added, and the reaction mixture was
stirred at room temperature for 12 h. The organic solvent
was evaporated at reduced pressure and the resulting
mixture was diluted with H2O (15 mL), washed with
AcOEt (3 · 20 mL), acidified with 1 N HCl (4 mL), and
extracted with CH2Cl2 (3 · 20 mL). The combined
organic extracts were dried with anhydrous Na2SO4 and
evaporated at reduced pressure to yield (R)-8a (112 mg,
70% overall, ee >99% by chiral HPLC) as a pale yellow
oil. The analytical sample of (R)-8a was obtained by
precipitation of its cyclohexylammonium salt as
described for (R)-5a. From a solution of crude (R)-8a
(100 mg, 0.36 mmol) in Et2O (5 mL) and cyclohexyl-
amine (0.04 mL, 0.35 mmol), pure (R)-8a (60 mg) was
4.4. (R)-3-Cyano-2-phenylpropionic acid (R)-5a
To a 0 ꢁC-cooled solution of compound (aR,30R)-7a
(469 mg, 1.30 mmol, dr >98:2) in THF (21 mL) were
added LiOHÆH2O (71 mg, 1.68 mmol) and 30% w/v
H2O2 (0.3 mL, 2.65 mmol). The reaction mixture was
stirred at 0 ꢁC for 5 h and then treated with 1.5 N
aqueous Na2SO3 (11.6 mL). The resulting mixture was
extracted with CH2Cl2 (3 · 25 mL), and the combined
organic extracts were dried with anhydrous Na2SO4 and
evaporated at reduced pressure, recovering pantolactam
(R)-2 (202 mg, 76%, ee >99% by chiral HPLC). The
aqueous phase was acidified with 1 N HCl and extracted
with AcOEt (3 · 25 mL). The combined organic extracts
were dried with anhydrous Na2SO4 and evaporated at
reduced pressure to yield cyano acid (R)-5a (216 mg,
95%, ee 90%) as a white solid. An aliquot part of this
crude product (199 mg, 1.14 mmol) was dissolved in
Et2O (5 mL) and treated with cyclohexylamine (0.13 mL,
1.14 mmol) and the precipitate thus formed was filtered
in vacuo and crystallized from isopropanol (8 mL). The
solid was treated with 1 M HCl and the resulting sus-
obtained, after reisolation of the acid from its salt, as a
20
D
colorless oil, which solidified on standing. ½aꢀ ¼ )61
28
(c 0.93, CH2Cl2) [lit.12 ½aꢀ ¼ )67 (c 0.6, CH2Cl2)]. Chiral
D
HPLC, condition B: (R)-8a, tR ¼ 21:9 min. Mp: 97–98 ꢁC
(CH2Cl2) [lit.12 98–100 ꢁC (CH2Cl2)].
4.6. (aS,30S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl 3-cyano-2-phenylpropionate (aS; 30S)-7a
It was prepared in a similar manner to that described for
(aR,30R)-7a. From (S)-2 (820 mg, 4.00 mmol), acid
chloride ( )-6a (1.10 g, 5.68 mmol), and Et3N (1.84 mL,

316
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
13.2 mmol), a diastereomeric mixture of (S)-pantolac-
tam esters greatly enriched in the (aS,30S)-7a dia-
stereomer (1.43 g, 99%, dr 90:10 by 1H NMR) was
obtained. An aliquot part of this residue (1.22 g) was
submitted to column chromatography [silica gel (75 g),
hexane/AcOEt mixtures]. On elution with hexane/
AcOEt 75:25, (aS,30S)-7a (715 mg, 58%, dr >98:2) and a
mixture (aS,30S)-7a/(aR,30S)-7a (470 mg, dr 77:23) were
successively isolated as a light brown oil and a brown
solid, respectively.
pressure and the remaining aqueous layer was extracted
with Et2O (3 · 125 mL). The combined organic extracts
were washed with H2O (75 mL), dried with anhydrous
Na2SO4, and evaporated at reduced pressure to give a
brown oily residue (3.02 g), which was submitted to
column chromatography [silica gel (150 g), hexane/Et2O
mixtures]. On elution with hexane/Et2O 55:45, pure
cyano ester ( )-4b was isolated as a colorless oil (2.22 g,
76%). Rf 0.37 (SiO2, hexane/Et2O 1:1). IR (NaCl) m: 2250
(CN st), 1737 (C@O st) cmꢁ1 1H NMR (300 MHz,
.
CDCl3) d: 0.90 [d, J ¼ 6:6 Hz, 6H, CH(CH3)2], 1.85 [m,
1H, CH(CH3)2], 2.46 (d, J ¼ 7:2 Hz, 2H, Ar-CH2CH),
2.78 (dd, J ꢂ 16:8 Hz, J0 ꢂ 7:5 Hz, 1H) and 3.02 (dd,
J ꢂ 16:8 Hz, J0 ꢂ 7:7 Hz, 1H) (3-H2), 3.72 (s, 3H,
OCH3), 3.92 (pseudo t, J ¼ 7:5 Hz, 1H, 2-H), 7.12–7.19
(complex signal, 4H, Ar-H). 13C NMR (75.4 MHz,
CDCl3): 21.8 (CH2, C3), 22.3 [CH3, CH (CH3)2], 30.1
[CH, CH(CH3)2], 45.0 (CH2, Ar-CH2CH), 47.2 (CH,
C2), 52.7 (CH3, OCH3), 117.6 (C, CN), 127.1 (CH) and
129.8 (CH) [Ar-C2(6) and Ar-C3(5)], 132.9 (C, Ar-C1),
142.0 (C, Ar-C4), 171.5 (C, C1). Anal. Calcd for
C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.56;
H, 7.80; N, 5.72.
20
D
(aS,30S)-7a (dr >98:2): ½aꢀ ¼ +17.5 (c 0.71, CH2Cl2). Rf
0.30 (SiO2, hexane/AcOEt 75:25). IR (NaCl) m: 2249
(CN st), 1744 (C@O st ester), 1712 (C@O st lactam)
cmꢁ1. The NMR data coincide with those of (aR,30R)-
7a. Anal. Calcd for C22H22N2O3: C, 72.91; H, 6.12; N,
7.73. Found: C, 72.97; H, 6.12; N, 7.69.
4.7. (S)-3-Cyano-2-phenylpropionic acid (S)-5a
It was prepared in a similar manner to that described
for (R)-5a. From (aS, 30S)-7a (596 mg, 1.65 mmol, dr
>98:2), 30% w/v H2O2 (0.38 mL, 3.35 mmol), and
LiOHÆH2O (90 mg, 2.15 mmol), pantolactam (S)-2
(256 mg, 76%, ee >99% by chiral HPLC) and cyano acid
(S)-5a (255 mg, 88%, ee 97%) were separately obtained.
Enantiopure (S)-5a (127 mg, 54% overall, ee >99%) was
obtained as a white solid from the crude product
4.10. ( )-3-Cyano-2-(4-isobutylphenyl)propionic acid
( )-5b
To a solution of cyano ester ( )-4b (1.51 g, 6.16 mmol)
in EtOH (50 mL) was added 1 N NaOH (7.3 mL,
7.3 mmol), and the reaction mixture was stirred at room
temperature for 3 h, and concentrated in vacuo. The
resulting residue was partitioned between H2O (35 mL)
and AcOEt (60 mL). The aqueous phase was acidified
with 1 N HCl (pH 2–3) and extracted with AcOEt
(3 · 60 mL). The combined organic extracts were dried
over anhydrous Na2SO4 and evaporated at reduced
pressure to afford the cyano acid ( )-5b as a white solid
(1.36 g, 96%). Chiral HPLC, condition C: (S)-5b,
tR ¼ 16:1 min, k10 ¼ 3:36; (R)-5b, tR ¼ 19:6 min, k20 ¼
4:32; a ¼ 1:29; Res ¼ 7.87. Mp: 122–123 ꢁC (AcOEt). Rf
0.14 (SiO2, hexane/Et2O 1:1). IR (KBr) m: 3300–2500
(208 mg, 1.19 mmol) via its cyclohexylammonium salt as
20
D
described for (R)-5a. ½aꢀ ¼ +153 (c 0.72, CH2Cl2) [lit.26
28
½aꢀ ¼ +154 (c 1.04, CH2Cl2)]. Chiral HPLC, condition
D
A: (S)-5a, tR ¼ 22:2 min. Mp: 87–88 ꢁC (isopropanol)
[lit.26 95–97 ꢁC (Et2O/petrol ether)].
4.8. (S)-4-(tert-Butoxycarbonylamino)-2-phenylbutanoic
acid (S)-8a26
20
D
28
D
½aꢀ ¼ +68 (c 0.92, CH2Cl2) [lit.26 ½aꢀ ¼ +62 (c 0.7,
CH2Cl2)]. Chiral HPLC, condition B: (S)-8a, tR ¼
23:2 min. Mp: 108–109 ꢁC (CH2Cl2) [lit.26 106–108 ꢁC
(CH2Cl2)].
1
(O–H st), 2251 (CN st), 1705 (C@O st) cmꢁ1. H NMR
(300 MHz, CDCl3) d: 0.89 [d, J ¼ 6:6 Hz, 6H,
CH(CH3)2)], 1.85 [m, 1H, CH(CH3)2], 2.46 (d,
J ¼ 6:9 Hz, 2H, Ar-CH2CH), 2.78 (dd, J ꢂ 16:8 Hz,
J0 ꢂ 7:4 Hz, 1H) and 3.00 (dd, J ¼ 16:8 Hz, J0 ¼ 7:5 Hz,
1H) (3-H2), 3.94 (pseudo t, J ¼ 7:5 Hz, 1H, 2-H), 7.13–
7.21 (br signal, 4H, Ar-H), 10.48 (br signal, 1H,
COOH). 13C NMR (75.4 MHz, CDCl3) d: 21.3 (CH2,
C3), 22.4 [CH3, CH(CH3)2], 30.1 [CH, CH(CH3)2], 45.0
(CH2, Ar-CH2CH), 47.2 (CH, C2), 117.3 (C, CN), 127.2
(CH) and 129.9 (CH) [Ar-C2(6) and Ar-C3(5)], 132.1 (C,
Ar-C1), 142.4 (C, Ar-C4), 176.7 (C, C1). Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.60;
H, 7.66; N, 5.97.
4.9. ( )-Methyl 3-cyano-2-(4-isobutylphenyl)propionate
( )-4b
A 2.5 M solution of n-butyllithium in hexane (5.2 mL,
13.0 mmol) was added dropwise over 5 min to a stirred
solution of hexamethyldisilazane (2.85 mL, 13.5 mmol)
in anhydrous THF (27 mL) at )78 ꢁC under argon, and
the mixture was stirred at )78 ꢁC for 1 h. To the resulting
mixture, a solution of methyl (4-isobutylphenyl)acetate,
3b (2.45 g, 11.9 mmol) in anhydrous THF (22 mL) was
added at )78 ꢁC over 10 min, and the mixture was stirred
at the same temperature for 1 h, and then treated drop-
wise with a solution of bromoacetonitrile (1.45 mL,
20.8 mmol) in anhydrous THF (16 mL). The reaction
mixture was stirred at )78 ꢁC for 1 h, warmed slowly to
room temperature, stirred at room temperature for an
additional 16 h period, and quenched with 1 N HCl
(60 mL). The organic solvent was evaporated at reduced
4.11. (aR,30R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl 3-cyano-2-(4-isobutylphenyl)propionate (aR,30R)-7b
( )-3-Cyano-2-(4-isobutylphenyl)propionyl chloride
( )-6b was prepared in a similar manner to that

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
317
described for ( )-6a. From ( )-5b (1.01 g, 4.37 mmol),
PCl5 (1.02 g, 4.90 mmol), and CCl4 (6.5 mL), ( )-6b
(1.07 g, quantitative yield) was obtained as a brown
solid. 1H NMR (200 MHz, CDCl3) d: 0.91 [d,
J ¼ 6:6 Hz, 6H, CH(CH3)2], 1.88 [m, 1H, CH(CH3)2],
2.50 (d, J ¼ 7:0 Hz, 2H, Ar-CH2CH), 2.84 (dd,
J ¼ 16:8 Hz, J0 ¼ 7:6 Hz, 1H) and 3.07 (dd, J ¼ 16:8 Hz,
J0 ¼ 7:6 Hz, 1H) (3-H2), 4.30 (t, J ¼ 7:6 Hz, 1H, 2-H),
7.16–7.27 (br signal, 4H, Ar-H).
tR ¼ 19:3 min. Mp: 100–101 ꢁC (isopropanol). Rf 0.14
(SiO2, hexane/Et2O 1:1). IR (KBr) m: 3500–2800 (O–H
st), 2238 (CN st), 1728 and 1683 (C@O st) cmꢁ1. The 1H
and 13C NMR spectra are coincidental with those of ( )-
5b. Anal. Calcd for C14H17NO2Æ0.1H2O: C, 72.14; H,
7.44; N, 6.01. Found: C, 71.94; H, 7.65; N, 5.93.
4.13. (R)-4-(tert-Butoxycarbonylamino)-2-(4- isobutyl-
phenyl)butanoic acid (R)-8b
The (R)-pantolactam ester (aR,30R)-7b was prepared in
a similar manner to that described for (aR,30R)-7a.
From (R)-2 (609 mg, 2.97 mmol), acid chloride ( )-6b
(1.07 g, 4.29 mmol), and Et3N (1.33 mL, 9.54 mmol), a
diastereomeric mixture of (R)-pantolactam esters greatly
enriched in the (aR,30R)-7b diastereomer (1.22 g, 98%,
It was prepared in a similar manner to that described for
(R)-8a. From (R)-5b (136 mg, 0.59 mmol, ee >99%),
AcOH (15 mL), and 10% Pd/C (90 mg), followed by
treatment of a solution of the intermediate crude amino
acid (211 mg) in H2O (3 mL) with 2 N NaOH (2.4 mL),
dioxane (6 mL), and Boc2O (258 mg, 1.17 mmol), (R)-8b
(103 mg, 52% overall, ee >99% by chiral HPLC) was
obtained as a pale yellow oil. The analytical sample of
(R)-8b was obtained via its cyclohexylammonium salt as
described for (R)-5a. From a solution of crude (R)-8b
(100 mg, 0.30 mmol) in Et2O (5 mL) and cyclohexyl-
amine (0.05 mL, 0.44 mmol), pure (R)-8b (65 mg) was
1
dr 93:7 by H NMR) was obtained, and submitted to
column chromatography [silica gel (65 g), hexane/AcOEt
mixtures]. On elution with hexane/AcOEt 75:25, pure
(aR,30R)-7b (784 mg, 63%, dr >98:2) and a mixture
(aR,30R)-7b/(aS,30R)-7b (148 mg, dr 76:24) were succes-
sively isolated as light brown oils.
20
(aR,30R)-7b (dr >98:2): ½aꢀ ¼ )29.4 (c 0.36, CH2Cl2). Rf
obtained, after reisolation of the acid from its salt, as a
D
20
D
0.38 (SiO2, hexane/AcOEt 75:25). IR (NaCl) m: 2250
(CN st), 1747 (C@O st ester), 1716 (C@O st lactam)
colorless oil. ½aꢀ ¼ )63 (c 1.19, CH2Cl2). Chiral HPLC,
condition D: (R)-8b, tR ¼ 18:1 min. Rf 0.21 (SiO2, hex-
cmꢁ1
.
1H NMR (300 MHz, CDCl3) d: 0.89 [d,
ane/AcOEt 1:1). IR (NaCl) m: 3500–2750 (O–H st and
J ¼ 6:6 Hz, 6H, CH(CH3)2], 1.11 (s, 3H, 40a-CH3), 1.30
(s, 3H, 40b-CH3), 1.85 [m, 1H, CH (CH3)2], 2.45 (d,
J ¼ 6:9 Hz, 2H, Ar-CH2CH), 2.89 (dd, J ¼ 16:8 Hz,
J0 ¼ 7:2 Hz, 1H) and 3.11 (dd, J ¼ 16:8 Hz, J0 ¼ 7:8 Hz,
1H) (3-H2), 3.50 (d, J ¼ 9:9 Hz, 1H, 50a-H), 3.60 (d,
J ¼ 9:9 Hz, 1H, 50b-H), 4.10 (pseudo t, J ¼ 7:5 Hz, 1H,
2-H), 5.42 (s, 30-H), 7.14–7.38 (complex signal, 7H, Ar-
H C-phenyl and Hpara and Hmeta N-phenyl), 7.55–7.59
(m, 2H, Hortho N-phenyl). 13C NMR (75.4 MHz,
CDCl3) d: 21.1 (CH3, 40a-CH3), 22.0 (CH2, C3), 22.4
[CH3, CH(CH3)2], 24.8 (CH3, 40b-CH3), 30.1 [CH,
CH(CH3)2], 37.3 (C, C40), 45.0 (CH2, Ar-CH2CH), 47.5
(CH, C2), 57.7 (CH2, C50), 79.3 (CH, C30), 117.5 (C,
CN), 119.4 (CH, Cortho N-phenyl), 124.9 (CH, Cpara
N-phenyl), 127.3 [CH, C2(6) C-phenyl], 128.9 (CH,
Cmeta N-phenyl), 129.8 [CH, C3(5) C-phenyl], 132.2 (C,
C1 C-phenyl), 138.8 (C, Cipso N-phenyl), 140.0 (C, C4
C-phenyl), 167.8 (C, C20), 170.4 (C, C1). Anal. Calcd for
C26H30N2O3: C, 74.61; H, 7.23; N, 6.69. Found: C,
74.37; H, 7.46; N, 6.55.
N–H st), 1707 (C@O st) cmꢁ1 1H NMR (300 MHz,
.
CDCl3) d: 0.89 [d, J ¼ 6:6 Hz, 6H, CH(CH3)2], 1.41 [s,
9H, C(CH3)3], 1.83 [m, 1H, CH(CH3)2], 1.92 (m, 1H)
and 2.27 (m, 1H) (3-H2), 2.43 (d, J ¼ 7:2 Hz, 2H, Ar-
CH2CH), 3.11 (m, 2H, 4-H2), 3.58 (dd, J ¼ J0 ¼ 7.5 Hz,
1H, 2-H), 4.60 (br s, 0.6H, NH, main rotamer), 6.10 (br
signal, 0.4H, NH, minor rotamer), 7.08 (d, J ¼ 8:1 Hz,
2H) and 7.20 (d, J ¼ 8:1 Hz, 2H) (Ar-H). The signal
corresponding to COO–H was not observed. 13C NMR
(75.4 MHz, CDCl3), main rotamer, d: 22.4 [CH3,
C(CH3)3], 28.4 [CH3, CH(CH3)2], 30.2 [CH, CH(CH3)2],
33.2 (CH2, C3), 38.8 (CH2, C4), 45.0 (CH2, Ar-CH2CH),
48.7 (CH, C2), 79.4 [C, C(CH3)3], 127.6 (CH) and 129.4
(CH) [Ar-C2(6) and Ar-C3(5)], 135.2 (C, Ar-C1), 141.0
(C, Ar-C4), 155.9 (C, OCONH), 178.6 (C, C1). 13C
NMR (75.4 MHz, CDCl3), differentiated signals of the
minor rotamer, d: 40.0 (CH2, C4), 81.0 [C, C (CH3)3],
158.0
(C,
OCONH).
Anal.
Calcd
for
C19H29NO4Æ0.1H2O: C, 67.67; H, 8.73; N, 4.15. Found:
C, 67.50; H, 8.80; N, 4.10.
4.12. (R)-3-Cyano-2-(4-isobutylphenyl)propionic acid
(R)-5b
4.14. (aS,30S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl 3-cyano-2-(4-isobutylphenyl)propionate (aS,30S)-7b
It was prepared in a similar manner to that described for
(R)-5a. From (aR,30R)-7b (719 mg, 1.72 mmol, dr
>98:2), 30% w/v H2O2 (0.43 mL, 3.79 mmol), and
LiOHÆH2O (94 mg, 2.24 mmol), pantolactam (R)-2
(337 mg, 96%, ee >99% by chiral HPLC) and cyano acid
(R)-5b (351 mg, 88%, ee 97%) were separately obtained
as white solids. Enantiopure (R)-5b (207 mg, 52% over-
all, ee >99%) was obtained as a white solid from the
It was prepared in a similar manner to that described for
(aR,30R)-7a. From (S)-2 (900 mg, 4.39 mmol), acid
chloride ( )-6b (1.61 g, 6.45 mmol), and Et3N (1.99 mL,
1.44 mmol), a diastereomeric mixture of (S)-pantolac-
tam esters greatly enriched in the (aS,30S)-7b diaste-
reomer (1.82 g, 99%, dr 87:13 by 1H NMR) was
obtained, and submitted to column chromatography
[silica gel (100 g), hexane/AcOEt mixtures]. On elution
with hexane/AcOEt 75:25, (aS,30S)-7b (1.14 g, 62%, dr
>98:2) and a mixture (aS,30S)-7b/(aR,30S)-7b (240 mg,
dr 76:24) were successively isolated as light brown oils.
crude product (351 mg, 1.52 mmol) via its cyclohexyl-
20
D
0.83, CH2Cl2). Chiral HPLC, condition C: (R)-5b,
ammonium salt as described for (R)-5a. ½aꢀ ¼ )131 (c

318
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
20
D
(aS,30S)-7b (dr >98:2): ½aꢀ ¼ +25.6 (c 0.39, CH2Cl2). Rf
anhydrous THF (11 mL), and a solution of bromo-
acetonitrile (0.98 mL, 14.1 mmol) in anhydrous THF
(11 mL), followed by column chromatography [silica gel
(65 g), hexane/AcOEt mixtures] of the crude product
(1.94 g), ( )-4c (1.58 g, 73%) was obtained as a white
solid. Mp: 150–151 ꢁC (sublimed at 160 ꢁC/0.5 Torr). Rf
0.51 (SiO2, hexane/AcOEt 1:1). IR (KBr) m: 2244 (CN
st), 1734 (C@O st) cmꢁ1. 1H NMR (300 MHz, CDCl3) d:
2.89 (dd, J ¼ 16:8 Hz, J0 ¼ 7:5 Hz, 1H) and 3.12 (dd,
J ¼ 16:8 Hz, J0 ¼ 7:5 Hz, 1H) (3-H2), 3.73 (s, 3H, CO-
OCH3), 3.92 (s, 3H, Ar-OCH3), 4.08 (dd,
J ¼ J0 ¼ 7:5 Hz, 1H, 2-H), 7.12 (d, J ¼ 2:7 Hz, 1H, Ar-
5-H), 7.18 (dd, J ¼ 9:0 Hz, J0 ¼ 2:7 Hz, 1H, Ar-7-H),
7.33 (dd, J ¼ 8:4 Hz, J0 ¼ 1:8 Hz, 1H, Ar-3-H), 7.67 (d,
J ꢂ 1:8 Hz, 1H, Ar-1-H), 7.72 (d, J ꢂ 9:0 Hz, 1H, Ar-8-
H), superimposed in part 7.75 (d, J ꢂ 8:4 Hz, 1H, Ar-4-
H). 13C NMR (75.4 MHz, CDCl3) d: 21.8 (CH2, C3),
47.6 (CH, C2), 52.8 (CH3, COOCH3), 55.3 (CH3, Ar-
OCH3), 105.5 (CH, Ar-C5), 117.6 (C, CN), 119.5 (CH,
Ar-C7), 125.1 (CH, Ar-C3), 126.7 (CH, Ar-C1), 127.9
(CH, Ar-C4), 128.7 (C, Ar-C8a), 129.3 (CH, Ar-C8),
130.6 (C, Ar-C2), 134.2 (C, Ar-C4a), 158.1 (C, Ar-C6),
171.5 (C, C1). Anal. Calcd for C16H15NO3: C, 71.36; H,
5.61; N, 5.20. Found: C, 71.50; H, 5.66; N, 5.31.
0.38 (SiO2, hexane/AcOEt 75:25). IR (NaCl) m: 2242
(CN st), 1745 (C@O st ester), 1716 (C@O st lactam)
cmꢁ1. The NMR data coincide with those of (aR,30R)-
7b. Anal. Calcd for C26H30N2O3: C, 74.61; H, 7.23; N,
6.69. Found: C, 74.44; H, 7.25; N, 6.60.
4.15. (S)-3-Cyano-2-(4-isobutylphenyl)propionic acid
(S)-5b
It was prepared in a similar manner to that described for
(R)-5a. From (aS,30S)-7b (979 mg, 2.34 mmol, dr >98:2),
30% w/v H2O2 (0.60 mL, 5.29 mmol), and LiOHÆH2O
(131 mg, 3.12 mmol), pantolactam (S)-2 (459 mg, 96%,
ee >99% by chiral HPLC) and cyano acid (S)-5b
(525 mg, 97%, ee 98%) were separately obtained as white
solids. Enantiopure (S)-5b (310 mg, 57% overall, ee
>99%) was obtained from the crude product (525 mg,
2.27 mmol) via its cyclohexylammonium salt as
20
D
described for (R)-5a. ½aꢀ ¼ +125 (c 0.89, CH2Cl2).
Chiral HPLC, condition C: (S)-5b, tR ¼ 16:4 min. Mp:
98–99 ꢁC (isopropanol). Rf 0.14 (SiO2, hexane/Et2O 1:1).
IR (KBr) m: 3500–2800 (O–H st), 2248 (CN st), 1727 and
1
1683 (C@O st) cmꢁ1. The H and 13C NMR spectra are
coincidental with those of ( )-5b. Anal. Calcd for
C14H17NO2Æ0.1H2O: C, 72.14; H, 7.44; N, 6.01. Found:
C, 72.19; H, 7.49; N, 6.01.
4.18. ( )-3-Cyano-2-(6-methoxy-2-naphthyl)propionic
acid ( )-5c
It was prepared in a similar manner to that described for
( )-5b. From ( )-4c (1.10 g, 4.09 mmol), 1 N NaOH
(4.3 mL, 4.30 mmol), and EtOH (28 mL), cyano acid ( )-
5c (0.93 g, 89%) was obtained as a white solid. Chiral
HPLC, condition E: (R)-5c, tR ¼ 21:5 min, k10 ¼ 4:52;
(S)-5c, tR ¼ 24:4 min, k20 ¼ 5:26; a ¼ 1:16; Res ¼ 6.47.
Mp: 160–161 ꢁC (AcOEt). Rf 0.12 (SiO2, hexane/AcOEt
1:1). IR (KBr) m: 3500–2700 (O–H st), 2268 (CN st),
4.16. (S)-4-(tert-Butoxycarbonylamino)-2-(4-isobutyl-
phenyl)butanoic acid (S)-8b
It was prepared in a similar manner to that described for
(R)-8a. From (S)-5b (428 mg, 1.85 mmol, ee >99%),
AcOH (50 mL), and 10% Pd/C (268 mg), followed by
treatment of a solution of the intermediate crude amino
acid (664 mg) in H2O (10 mL) with 2 N NaOH (5 mL),
dioxane (19 mL), and Boc2O (795 mg, 3.64 mmol), (S)-
8b (423 mg, 68% overall, ee >99% by chiral HPLC) was
obtained as a pale yellow oil. The analytical sample of
(S)-8b was obtained via its cyclohexylammonium salt as
described for (R)-5a. From a solution of crude (S)-8b
(423 mg, 1.26 mmol) in Et2O (10 mL) and cyclohexyl-
amine (0.15 mL, 1.31 mmol), pure (S)-8b (274 mg) was
1
1732 (C@O st) cmꢁ1. H NMR (300 MHz, CD3OD) d:
2.97 (dd, J ¼ 16:8 Hz, J0 ¼ 7:5 Hz, 1H) and 3.12 (dd,
J ¼ 16:8 Hz, J0 ¼ 7:5 Hz, 1H) (3-H2), 3.88 (s, 3H,
OCH3), 4.11 (dd, J ¼ J0 ¼ 7:5 Hz, 1H, 2-H), 4.89 (s,
COOH), 7.13 (dd, J ¼ 8:7 Hz, J0 ¼ 2:7 Hz, 1H, Ar-7-H),
7.21 (d, J ꢂ 2:7 Hz, 1H, Ar-5-H), 7.39 (dd, J ¼ 8:4 Hz,
J0 ¼ 1:8 Hz, 1H, Ar-3-H), 7.728 (d, J 8.7 Hz, 1H, Ar-8-
H), 7.732 (br s, 1H, Ar-1-H), 7.76 (d, J ꢂ 8:4 Hz, 1H,
Ar-4-H). 13C NMR (75.4 MHz, CD3OD) d: 22.0 (CH2,
C3), 48.7 (CH, C2), 55.7 (CH3,OCH3), 106.6 (CH, Ar-
C5), 119.5 (C, CN), 120.3 (CH, Ar-C7), 126.7 (CH, Ar-
C3), 127.8 (CH, Ar-C1), 128.6 (CH, Ar-C4), 130.2 (C,
Ar-C8a), 130.3 (CH, Ar-C8), 133.2 (C, Ar-C2), 135.6 (C,
Ar-C4a), 159.4 (C, Ar-C6), 174.5 (C, C1). Anal. Calcd
for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C,
70.43; H, 5.25; N, 5.44.
obtained, after reisolation of the acid from its salt, as a
20
D
colorless oil. ½aꢀ ¼ +61 (c 0.65, CH2Cl2). Chiral HPLC,
condition D: (S)-8b, tR ¼ 16:1 min. Rf 0.23 (SiO2, hex-
ane/AcOEt 1:1). IR (NaCl) m: 3500–2750 (O–H st and
1
N–H st), 1708 (C@O st) cmꢁ1. The H and 13C NMR
spectra are coincidental with those of (R)-8b. Anal.
Calcd for C19H29NO4: C, 68.03; H, 8.71; N, 4.18.
Found: C, 68.14; H, 8.72; N, 4.09.
4.17. ( )-Methyl 3-cyano-2-(6-methoxy-2-naphthyl)pro-
pionate ( )-4c
4.19. (aR,30R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl 3-cyano-2-(6-methoxy-2-naphthyl)propionate
(aR,30R)-7c
It was prepared in a similar manner to that described for
( )-4b. From
(1.92 mL, 9.10 mmol) in anhydrous THF (18 mL), a
2.5 M solution of n-butyllithium in hexane (3.5 mL,
8.75 mmol), a solution of ester 3c (1.84 g, 8.00 mmol) in
a
solution of hexamethyldisilazane
( )-3-Cyano-2-(6-methoxy-2-naphthyl)propionyl chlo-
ride ( )-6c was prepared in a similar manner to that
described for ( )-6a. From ( )-5c (707 mg, 2.77 mmol),
PCl5 (686 mg, 3.29 mmol), and CCl4 (4.5 mL), ( )-6c

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
319
(762 mg, quantitative yield) was obtained as a brown
solid. 1H NMR (200 MHz, CDCl3) d: 2.94 (dd,
J ¼ 17:0 Hz, J0 ¼ 7:8 Hz, 1H) and 3.16 (dd, J ¼ 17:0 Hz,
J0 ¼ 6:8 Hz, 1H) (3-H2), 3.94 (s, 3H, OCH3), 4.46 (dd,
J ꢂ J0 ꢂ 7:4 Hz, 1H, 2-H), 7.15 (d, J ¼ 2:6 Hz, 1H, Ar-
5-H), 7.22 (dd, J ¼ 8:8 Hz, J0 ¼ 2:6 Hz, 1H, Ar-7-H),
7.30 (dd, J ꢂ 8:4 Hz, J0 ¼ 1:8 Hz, 1H, Ar-3-H), 7.71 (d,
J ¼ 1:8 Hz, 1H, Ar-1-H), 7.76 (d, J ꢂ 8:8 Hz, 1H, Ar-8-
H), 7.82 (d, J ¼ 8:4 Hz, 1H, Ar-4-H).
Recrystallization of the crude cyano acid from AcOEt
(1.5 mL) afforded enantiopure (R)-5c (73 mg, 64%, ee
20
D
>99%) as a white solid. ½aꢀ ¼ )124 (c 0.20, THF).
Chiral HPLC, condition E: (R)-5c, tR ¼ 21:5 min. Mp:
161–162 ꢁC (AcOEt). Rf 0.12 (SiO2, hexane/AcOEt 1:1).
IR (KBr) m: 3400–2700 (O–H st), 2269 (CN st), 1733
(C@O st) cmꢁ1. The 1H and 13C NMR spectra are
coincidental with those of ( )-5c. Anal. Calcd for
C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.43;
H, 5.09; N, 5.38.
The pantolactam ester (aR, 30R)-7c was prepared in a
similar manner to that described for (aR,30R)-7a. From
(R)-2 (402 mg, 1.96 mmol), acid chloride ( )-6c (762 mg,
2.79 mmol), and Et3N (0.90 mL, 6.46 mmol), a diaste-
reomeric mixture of (R)-pantolactam esters greatly
enriched in the (aR, 30R)-7c diastereomer (860 mg, 99%,
4.21. (R)-4-(tert-Butoxycarbonylamino)-2-(6-methoxy-
2-naphthyl)butanoic acid (R)-8c
It was prepared in a similar manner to that described for
(R)-8a. From (R)-5c (105 mg, 0.41 mmol, ee >99%),
AcOH (15 mL), and 10% Pd/C (68 mg), followed by
treatment of a solution of the intermediate crude amino
acid (124 mg) in H2O (2 mL) with 2 N NaOH (1.7 mL),
dioxane (4 mL), and Boc2O (168 mg, 0.77 mmol), (R)-8c
(91 mg, 62% overall, ee >99% by chiral HPLC) was
obtained as a pale yellow oil. The analytical sample of
(R)-8c was obtained via its cyclohexylammonium salt as
described for (R)-5a. From a solution of crude (R)-8c
(91 mg, 0.25 mmol) in CH2Cl2 (5 mL) and cyclohexyl-
amine (0.03 mL, 0.26 mmol), pure (R)-8c (65 mg) was
1
dr 91:9 by H NMR) was obtained, and submitted to
column chromatography [silica gel (45 g), hexane/AcOEt
mixtures]. On elution with hexane/AcOEt 75:25,
(aR,30R)-7c (88 mg, 10%, dr >98:2) and diastereoen-
riched (aR,30R)-7c [(232 mg, 27%, dr 97:3) and (400 mg,
dr 90:10)] were successively isolated as light brown
solids.
20
(aR,30R)-7c (dr >98:2): ½aꢀ ¼ )14.3 (c 1.02, CH2Cl2).
D
Mp: 60–61 ꢁC (hexane/AcOEt 75:25). Rf 0.20 (SiO2,
hexane/AcOEt 75:25). IR (KBr) m: 2249 (CN st), 1745
1
(C@O st ester), 1712 (C@O st lactam) cmꢁ1. H NMR
obtained, after reisolation of the acid from its salt, as a
20
D
(300 MHz, CDCl3) d: 1.11 (s, 3H, 40a-CH3), 1.30 (s, 3H,
40b-CH3), 2.97 (dd, J ¼ 16:8 Hz, J0 ꢂ 7:5 Hz, 1H) and
3.20 (dd, J ¼ 16:8 Hz, J0 ¼ 7:5 Hz, 1H) (3-H2), 3.49 (d,
J ¼ 9:6 Hz, 1H, 50a-H), 3.58 (d, J ¼ 9:6 Hz, 1H, 50b-H),
3.91 (s, 3H, OCH3), 4.25 (dd, J ꢂ J0 ꢂ 7:5 Hz, 1H, 2-H),
5.44 (s, 30-H), 7.11–7.18 [complex signal, 3H, 5-H and 7-
H naphthyl, and Hpara N-phenyl], 7.34 (m, 2H, Hmeta
N-phenyl), 7.44 (dd, J ¼ 8:7 Hz, J0 ¼ 1:8 Hz, 1H, 3-H
naphthyl), 7.55 (m, 2H, Hortho N-phenyl), 7.74 (d,
J ¼ 8:7 Hz, 1H, 8-H naphthyl), 7.76 (d, J ꢂ 8:7 Hz, 1H,
4-H naphthyl), 7.78 (br s, 1H, 1-H naphthyl). 13C NMR
(75.4 MHz, CDCl3) d: 21.2 (CH3, 40a-CH3), 22.1 (CH2,
C3), 24.8 (CH3, 40b-CH3), 37.3 (C, C40), 47.8 (CH, C2),
55.3 (CH3, OCH3), 57.7 (CH2, C50), 79.4 (CH, C30),
105.6 (CH, C5 naphthyl), 117.5 (C, CN), 119.4 (3CH,
C7 naphthyl, and Cortho N-phenyl), 124.9 (CH, Cpara
N-phenyl), 125.4 (CH, C3 naphthyl), 127.0 (CH, C1
naphthyl), 127.9 (CH, C4 naphthyl), 128.7 (C, C8a
naphthyl), 128.9 (CH, Cmeta N-phenyl), 129.5 (CH, C8
naphthyl), 130.0 (C, C2 naphthyl), 134.3 (C) (C2, C4a
naphthyl), 138.8 (C, Cipso N-phenyl), 158.0 (C, C6
naphthyl), 167.8 (C, C20), 170.4 (C, C1). Anal. Calcd for
C27H26N2O4Æ0.6H2O: C, 71.54; H, 6.05; N, 6.18. Found:
C, 71.45; H, 5.75; N, 5.96.
colorless oil. ½aꢀ ¼ )57 (c 0.70, CH2Cl2). Chiral HPLC,
condition F: (R)-8c, tR ¼ 16:9 min. Rf 0.15 (SiO2, hex-
ane/AcOEt 1:1). IR (NaCl) m: 3600–2600 (O–H st and
N–H st), 1706 (C@O st) cmꢁ1 1H NMR (300 MHz,
.
CDCl3) d: 1.40 [s, 9H, C(CH3)3], 1.92–2.08 (m, 1H) and
2.24–2.44 (m, 1H) (3-H2), 2.97–3.19 (m, 2H, 4-H2), 3.74
(dd, J ꢂ J0 ꢂ 7:6 Hz, 1H, 2-H), 3.90 (s, 3H, OCH3), 4.63
(br signal, 0.6H, NH, main rotamer), 6.12 (br signal,
0.4H, NH, minor rotamer), 7.08 (d, J ꢂ 2:4 Hz, 1H, Ar-
5-H), 7.12 (dd, J ¼ 8:7 Hz, J0 ¼ 2:4 Hz, 1H, Ar-7-H),
7.38 (d, J ¼ 8:4 Hz, 1H, Ar-3-H), superimposed 7.659
(br s, 1H, Ar-1-H), 7.665 (d, J ¼ 8:7 Hz, 1H, Ar-8-H),
7.672 (d, J ꢂ 8:4 Hz, 1H, Ar-4-H). The signal corre-
sponding to COO–H was not observed. 13C NMR
(75.4 MHz, CDCl3), main rotamer, d: 28.4 [CH3,
C(CH3)3], 33.2 (CH2, C3), 38.8 (CH2, C4), 48.9 (CH,
C2), 55.3 (CH3, OCH3), 79.5 [C, C(CH3)3], 105.5 (CH,
Ar-C5), 119.0 (CH, Ar-C7), 126.2 (CH, Ar-C3), 126.7
(CH, Ar-C1), 127.3 (CH, Ar-C4), 128.8 (C, Ar-C8a),
129.2 (CH, Ar-C8), 133.1 (C, Ar-C2), 133.8 (C, Ar-C4a),
157.6 (2C, Ar-C6, and OCONH), 178.3 (C, C1). 13C
NMR (75.4 MHz, CDCl3), differentiated signals of the
minor rotamer, d: 39.8 (CH2, C4), 80.8 [C, C(CH3)3],
155.9 (C, OCONH). Anal. Calcd for C20H25NO5Æ1/
5H2O: C, 66.17; H, 7.05; N, 3.86. Found: C, 66.27; H,
7.38; N, 3.53.
4.20. (R)-3-Cyano-2-(6-methoxy-2-naphthyl)propionic
acid (R)-5c
4.22. (aS,30S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-
3-yl 3-cyano-2-(6-methoxy-2-naphthyl)propionate
(aS,30S)-7c
It was prepared in a similar manner to that described for
(R)-5a. From (aR,30R)-7c (200 mg, 0.45 mmol, dr 97:3),
30% w/v H2O2 (0.11 mL, 0.97 mmol), and LiOHÆH2O
(25 mg, 0.59 mmol), pantolactam (R)-2 (88 mg, 95%, ee
>99% by chiral HPLC) and cyano acid (R)-5c (100 mg,
87%, ee 94%) were separately obtained as white solids.
It was prepared in a similar manner to that described for
(aR,30R)-7a. From (S)-2 (631 mg, 3.08 mmol), acid
chloride ( )-6c (1.16 g, 4.24 mmol), and Et3N (1.4 mL,

320
P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
10.1 mmol), a diastereomeric mixture of (S)-pantolac-
tam esters greatly enriched in the (aS,30S)-7c diastereo-
mer (1.35 g, 99%, dr 92:8 by H NMR) was obtained,
and submitted to column chromatography [silica gel
(90 g), hexane/AcOEt mixtures]. On elution with hexane/
AcOEt 75:25, (aS,30S)-7c (36 mg, 3%, dr >98:2) and
diastereoenriched (aS,30S)-7c [(592 mg, 43%, dr 97:3)
and (282 mg, dr 90:10)] were successively isolated as
light brown solids.
Acknowledgements
1
A fellowship from the Generalitat de Catalunya to L.
ꢀ ꢀ
Sanchez and financial support from the Direccion
ꢀ
General de Investigacion of Ministerio de Ciencia y
Tecnologıa and FEDER (project PPQ2002-01080) and
Comissionat per a Universitats i Recerca of the Gener-
alitat de Catalunya (project 2001-SGR-00085) are
gratefully acknowledged. We thank the Serveis
ꢀ
ꢀ
Cientıfico-Tecnics of the University of Barcelona for
NMR facilities and Ms. P. Domenech from the IIQAB
(CSIC, Barcelona, Spain) for carrying out the elemental
analyses.
ꢁ
20
D
(aS,30S)-7c (dr >98:2): ½aꢀ ¼ +16.5 (c 1.01, CH2Cl2).
ꢁ
Mp: 58–59 ꢁC (hexane/AcOEt 75:25). Rf 0.18 (SiO2,
hexane/AcOEt 75:25). IR (KBr) m: 2249 (CN st), 1745
(C@O st ester), 1714 (C@O st lactam) cmꢁ1. The 1H and
13C NMR spectra are coincidental with those of
(aR,30R)-7c. Anal. Calcd for C27H26N2O4: C, 73.28; H,
5.93; N, 6.33. Found: C, 73.23; H, 6.02; N, 6.15.
References and notes
1. Ammazzalorso, A.; Amoroso, R.; Bettoni, G.; De Filipis,
B. Chirality 2001, 13, 102–108.
2. Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.;
Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650–
7651.
3. Senanayake, C. H.; Larsen, R. D.; Bill, T. J.; Liu, J.;
Corley, E. G.; Reider, P. J. Synlett 1994, 199–200.
4. Calmes, M.; Daunis, J.; Jacquier, R.; Natt, F. Tetrahedron
1994, 50, 6875–6880.
5. Meyer, M. D.; Hancock, A. A.; Tietje, K.; Sippy, K. B.;
Prasad, R.; Stout, D. M.; Arendsen, D. L.; Donner, B. G.;
Carroll, W. A. J. Med. Chem. 1997, 40, 1049–1062.
6. Durst, T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799–
6802.
7. Calmes, M.; Daunis, J.; Mai, N.; Natt, F. Tetrahedron
Lett. 1996, 37, 379–380.
8. Calmes, M.; Daunis, J.; Mai, N. Tetrahedron: Asymmetry
1997, 8, 1641–1648.
9. Calmes, M.; Daunis, J.; Mai, N. Tetrahedron 1997, 53,
13719–13726.
10. Calmes, M.; Escale, F. Tetrahedron: Asymmetry 1998, 9,
2845–2850.
4.23. (S)-3-Cyano-2-(6-methoxy-2-naphthyl)propionic
acid (S)-5c
It was prepared in a similar manner to that described for
(R)-5a. From (aS,30S)-7c (550 mg, 1.24 mmol, dr 97:3),
30% w/v H2O2 (0.30 mL, 2.65 mmol), and LiOHÆH2O
(67.6 mg, 1.61 mmol), pantolactam (S)-2 (240 mg, 94%,
ee >99% by chiral HPLC) and cyano acid (S)-5c
(285 mg, 90%, ee 91%) were separately obtained as white
solids. Enantiopure (S)-5c (169 mg, 53%, ee >99%) was
obtained as a white solid by recrystallization of the
20
D
crude product from AcOEt (5 mL). ½aꢀ ¼ +129 (c 0.62,
THF). Chiral HPLC, condition E: (S)-5c, tR ¼ 24:4 min.
Mp: 154–155 ꢁC (AcOEt). Rf 0.12 (SiO2, hexane/AcOEt
1:1). IR (KBr) m: 3400–2700 (O–H st), 2270 (CN st),
1
1732 (C@O st) cmꢁ1. The H and 13C NMR spectra are
coincidental with those of ( )-5c. Anal. Calcd for
C15H13NO3Æ0.1H2O: C, 70.08; H, 5.18; N, 5.45. Found:
C, 70.04; H, 5.08; N, 5.40.
ꢁ
11. Calmes, M.; Escale, F.; Glot, C.; Rolland, M.; Martinez,
J. Eur. J. Org. Chem. 2000, 2459–2466.
4.24. (S)-4-(tert-Butoxycarbonylamino)-2-(6-methoxy-
2- naphthyl)butanoic acid (S)-8c
ꢁ
12. Calmes, M.; Escale, F.; Martinez, J. Tetrahedron: Asym-
metry 2002, 13, 293–296.
13. Calmes, M.; Escale, F.; Juan, E.; Rolland, M.; Martinez,
J. Tetrahedron: Asymmetry 2000, 11, 1263–1266.
It was prepared in a similar manner to that described for
(R)-8a. From (S)-5c (126 mg, 0.49 mmol, ee >99%),
AcOH (15 mL), and 10% Pd/C (83 mg), followed by
treatment of a solution of the intermediate crude amino
acid (150 mg) in H2O (3 mL) with 2 N NaOH (2 mL),
dioxane (5 mL), and Boc2O (212 mg, 0.97 mmol), (S)-8c
(104 mg, 59% overall, ee >99% by chiral HPLC) was
obtained as a pale yellow oil. The analytical sample of
(S)-8c was obtained via its cyclohexylammonium salt as
described for (R)-5a. From a solution of crude (S)-8c
(104 mg, 0.29 mmol) in CH2Cl2 (5 mL) and cyclohexyl-
amine (0.03 mL, 0.26 mmol), pure (S)-8c (63 mg) was
ꢀ
14. Camps, P.; Gimenez, S.; Font-Bardia, M.; Solans, X.
Tetrahedron: Asymmetry 1995, 6, 985–990.
ꢀ
15. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron Lett.
1999, 40, 6853–6856.
ꢀ
ꢀ
16. Camps, P.; Font-Bardia, M.; Gimenez, S.; Perez, F.;
Solans, X.; Soldevilla, N. Tetrahedron: Asymmetry 1999,
10, 3123–3138.
ꢀ
17. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asym-
metry 1997, 8, 1877–1894.
ꢀ
18. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asym-
metry 1998, 9, 2065–2079.
ꢀ
19. Camps, P.; Perez, F.; Soldevilla, N.; Borrego, M. A.
Tetrahedron: Asymmetry 1999, 10, 493–509.
obtained, after reisolation of the acid from its salt, as a
20
D
ꢀ
20. Camps, P.; Gimenez, S. Tetrahedron: Asymmetry 1995, 6,
colorless oil. ½aꢀ ¼ +61 (c 0.99, CH2Cl2). Chiral HPLC,
991–1000.
21. Camps, P.; Gimenez, S. Tetrahedron: Asymmetry 1996, 7,
condition F: (S)-8c, tR ¼ 21:2 min. Rf 0.15 (SiO2, hex-
ꢀ
ane/AcOEt 1:1). IR (NaCl) m: 3500–2700 (O–H st and
1227–1234.
22. Ito, H.; Omodera, K.; Takigawa, Y.; Taguchi, T. Org.
Lett. 2002, 4, 1499–1501.
23. Martin, C. J.; Rawson, D. J.; Williams, J. M. J. Tetrahe-
dron: Asymmetry 1998, 9, 3723–3730.
1
N–H st), 1707 (C@O st) cmꢁ1. The H and 13C NMR
spectra are coincidental with those of (R)-8c. Anal.
Calcd for C20H25NO5Æ1/5H2O: C, 66.17; H, 7.05; N,
3.86. Found: C, 66.19; H, 6.82; N, 3.64.

P. Camps et al. / Tetrahedron: Asymmetry 15 (2004) 311–321
321
24. Prager, R. H.; Schafer, K. Aust. J. Chem. 1997, 50, 813–823.
25. Chebib, M.; Vandenberg, R. J.; Johnston, G. A. R. Br. J.
Pharmacol. 1997, 122, 1551–1560.
26. Azam, S.; DꢀSouza, A. A.; Wyatt, P. B. J. Chem. Soc.,
Perkin Trans. 1 1996, 621–627.
27. Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull. 1995, 43,
1302–1306.
28. Oppolzer, W.; Rosset, S.; De Brabander, J. Tetrahedron
Lett. 1997, 38, 1539–1540.
ꢀ
29. Gonzalez, A. Synth. Commun. 1991, 21, 1353–1360.