(R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

Article abstract of DOI:10.1016/S0957-4166(98)00194-3

rac-α-Chlorocarboxylic acids, rac-9a-e, were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4, followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of (S)-α-chloropropanoic acid, a known precursor for the synthesis of (R)-α-aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a, or mecoprop-P, (R)-3b, which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (αRS,3S)-4,4- dimethyl-2-oxo-l-phenylpyrrolidin-3-yl α-bromopropanoate, (αRS,3S)-6, by reaction with the corresponding phenoxide followed by mild acid hydrolysis.

Full text of DOI:10.1016/S0957-4166(98)00194-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2065–2079
(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone
as chiral auxiliaries in the enantioselective preparation of
α-aryloxypropanoic acid herbicides and α-chlorocarboxylic
acids
Pelayo Camps,∗ Francesc Pérez and Núria Soldevilla
Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal s/n E-08028, Barcelona,
Spain
Received 25 March 1998; accepted 15 May 1998
Abstract
rac-α-Chlorocarboxylic acids, rac-9a–e, were formally deracemized by reaction of the corresponding acyl
chlorides with the chiral auxiliaries (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4,
followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of (S)-α-chloropropanoic
acid, a known precursor for the synthesis of (R)-α-aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a,
or mecoprop-P, (R)-3b, which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic
kinetic resolution from (αRS,3S)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (αRS,3S)-6,
by reaction with the corresponding phenoxide followed by mild acid hydrolysis. © 1998 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Some time ago, we described1 a multigram scale synthesis of both enantiomers of 3-hydroxy-4,4-
dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4, and their use for the formal deracemization of α-
arylpropanoic and α-substituted α-arylacetic acids.2,3 Also, their use in an enantioselective synthesis of
α-hydroxyacids based on the dynamic kinetic resolution of α-bromoesters derived from these chiral
auxiliaries with p-methoxyphenoxide was recently described.4 Compounds (R)- and (S)-4 are easily
crystallizable non-hygroscopic solids more lipophilic than pantolactone, which greatly facilitates their
recovery. Both enantiomers are readily available and their e.e.s can be easily obtained by chiral HPLC
under UV detection.
∗
Corresponding author. Tel: 34-934024536; fax: 34-934021886; e-mail: camps@farmacia.far.ub.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00194-3

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In this paper we describe the application of these chiral auxiliaries for the preparation of α-
aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a, mecoprop-P, (R)-3b, as well as their
enantiomers, from racemic precursors.
2. Results and discussion
To this end, several possibilities were envisaged. The first one, shown in Scheme 1, consisted of
the formal deracemization of the corresponding rac-α-aryloxypropanoic acid, in a method similar to
that used in the case of α-arylpropanoic2,5,6 and α-substituted-α-arylacetic acids.3 Dichlorprop, rac-
3a, and mecoprop, rac-3b, were prepared by known procedures.7 Reaction of rac-3a with phosphorus
pentachloride in CCl4 gave the corresponding acyl chloride which was reacted as a crude product
with the chiral auxiliary, (S)-4, under the standard conditions used for the formal deracemization of
α-arylpropanoic acids,2 to give in low yield a mixture of (αR,3S)- and (αS,3S)-5a in an approximate
ratio of 2:1 (1H NMR). A similar reaction, in which rac-3a was transformed into the corresponding
acyl bromide, by reaction with oxalyl bromide in toluene, and then reacted with (S)-4 gave a mixture of
(αR,3S)- and (αS,3S)-5a in better yield but with practically no diastereoselectivity (1H NMR). A similar
result was obtained starting from rac-3b. These results are in accord with those obtained starting from
α-(p-methoxyphenoxy)carboxylic acids.4
Scheme 1. Attempted diastereoselective syntheses of α-aryloxy esters 5a,b from rac-3a,b and (S)-4
Another approach, shown in Scheme 2, was based on the dynamic kinetic resolution8–13 of dia-
stereomeric mixtures of α-bromoesters (αRS,3S)-6 on reaction with 2,4-dichlorophenol, 2a, or 4-
chloro-2-methylphenol, 2b. The optimum reaction conditions4 found in the case of the reaction of p-
methoxyphenol with diastereomeric ester mixtures derived from different α-bromocarboxylic acids and
(R)- or (S)-4, were used. These conditions consist of: (i) the use of a small molar deficiency of sodium
hydride with respect to the phenol and α-bromo ester to avoid epimerization of the starting compounds
and/or products; (ii) the use of tetra-n-hexylammonium iodide (20% molar) as catalyst; and (iii) the
control of the temperature of the reaction mixture in the range −5 to 0°C. In this way, esters (αR,3S)-5a,b
1
were obtained in good yield and moderate diastereoselectivities (54% d.e. by H NMR). These results
are in accord with those previously found by our group in similar reactions using p-methoxyphenol.4
It is worth noting that the dynamic kinetic resolution of esters derived from these chiral auxiliaries
and other α-bromocarboxylic acids, such as α-bromo-β-methylbutanoic, α-bromo-α-phenylacetic and
α-bromo-β-phenylpropanoic acids, with p-methoxyphenoxide gave the corresponding substitution prod-
ucts in good diastereoselectivities (89–98%).4 The lower diastereoselectivity in the reactions of α-
bromopropanoates 6 might then be ascribed to a lower reactivity difference of both diastereomers towards
the phenoxides. The d.e.s of the thus-obtained diastereomeric mixtures of esters 5a,b were increased to
72–85% after one or two crystallizations from methanol. Hydrolysis of these diastereomerically enriched

P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
2067
Scheme 2. Enantioselective synthesis of (R)-3a,b by dynamic kinetic resolution from (α-RS,3S)-6
mixtures under the acid conditions used in related cases2–5 (3.2 ml 2 N HCl and 8 ml AcOH per mmol
of ester, 120°C, 3 h) gave the corresponding acids (R)- or (S)-3a,b. From the specific rotation of the
thus-obtained acids, their optical purities (o.p.) were calculated, showing that little or no epimerization
takes place during hydrolysis.
In a third approach to the enantioselective synthesis of α-aryloxypropanoic acids (R)-3a,b, we studied
the enantioselective preparation of (S)-α-chloropropanoic acid, (S)-9a (Scheme 3), since it is a known
precursor for this family of herbicides.7,14 Our previous experience on the enantioselective preparation of
α-bromoacids using (R)- or (S)-4 as chiral auxiliaries was not too promising,4 since although the reaction
of the chiral auxiliary with an activated form of the α-bromoacid was quite diastereoselective, the thus-
obtained esters easily epimerize at the α-ester stereocenter in chloroform solution at room temperature
or, especially, under the studied acid or base hydrolysis conditions.
Scheme 3. Enantioselective synthesis of (S)-α-chlorocarboxylic acids, (S)-9
A study of the reaction of rac-α-chloropropanoyl chloride, rac-7a, with (S)-4 in anhydrous methylene
dichloride at −20°C using different tertiary amines (2 equiv.) showed the enormous influence of the
amine on the diastereoselectivity of this reaction, a fact that had been previously observed by other
authors.15–17 Good yields of esters (92–99%) were attained in a 10 min period, except in the case
of N-methylmorpholine (25 min). The greatest diastereoselectivity (96% d.e. by HPLC, >95% by
1H NMR) was obtained by using triethylamine, giving (αR,3S)-8a, the main diastereomer. The same
kind but lower diastereoselectivity was observed by using ethyldiisopropylamine (49% d.e.) or N-
methylmorpholine (46% d.e.). The use of pyridine and its derived bases 2,6-dimethylpyridine and 4-
(dimethylamino)pyridine gave very poor and reversed diastereoselectivities [(αS,3S)-8a in 2, 8 and 9%
d.e.s, respectively]. Surprisingly, (αR,3S)-8a, contrary to the corresponding α-bromoester, appeared to
be quite stable in chloroform solution.
Hydrolysis of (αR,3S)-8a was studied under basic conditions with lithium hydroxide18 or
hydroperoxide,19 conditions previously used in related cases. Acid hydrolysis conditions (2 N
HCl/AcOH) were not tested since they had been shown to induce nearly complete epimerization of

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Table 1
Yields[a] and diastereomeric excesses (d.e.)[a] of α-chloro esters 8 and yields, specific rotations and
approx. enantiomeric excesses (o.p.) of α-chloro acids 9[b]
the α-ester stereocenter in the case of the corresponding α-bromo esters. Although lithium hydroxide
hydrolysis induced partial epimerization, the use of lithium hydroperoxide allowed us to isolate in good
yield and without any detectable epimerization the corresponding α-chloropropanoic acid, (R)-9a (85%
yield, 99% o.p.).
The optimum reaction conditions established for the conversion of rac-7a to (R)-9a were also applied
for the preparation of (S)-9a and other α-chlorocarboxylic acids, using either (S)- or (R)-4 as the chiral
auxiliary (see Scheme 3 and Table 1). As can be seen from this table, the d.e.s of esters 8 greatly depend
on the steric effect of the R group: 96–99% for R=methyl, 74% for R=ethyl, 59% for R=benzyl, 22% for
R=isopropyl. Solid esters 8 were crystallized from ethyl acetate or mixtures of hexane and ethyl acetate
which somewhat increases their d.e.s. (see Table 1). The main diastereomer of esters 8 derived from the
chiral auxiliary (R)-4 is generally the (αS,3R) while from (S)-4 it is the (αR,3S). Curiously, the reaction
of α-chloro-α-phenylacetyl chloride, rac-7e, with (S)-4, showed reversed diastereoselectivity, giving rise
to (αS,3S)-8e as the main diastereomer.
Hydrolysis of the diastereomerically enriched esters 8a–d was carried out with little or no epimeriza-
tion by treatment with lithium hydroperoxide as in the case of (R)-9a. However, hydrolysis of (αS,3S)-8e
under these conditions led to the formation of significant amounts of benzoic acid (30%) and rac-9e
(60%). Hydrolysis of this ester using lithium hydroxide in a mixture of THF/water allowed us to obtain
(S)-9e in good yield but low optical purity (32% o.p.), showing that a significant amount of epimerization
takes place during hydrolysis, a fact that must be due to the greater acidity of the α-ester hydrogen atom
in this case.
After hydrolysis of esters 8 and 5, the chiral auxiliaries (R)- and (S)-4 were always recovered in high
yield without epimerization.
Having (αR,3S)-8a (>95% d.e.) in hand, we also tried its conversion into (αS,3S)-5a through an
SN2 mechanism by reaction with the sodium salt of phenol 2a. When this reaction was carried out in
THF at room temperature, the starting compound, partially epimerized at the α-position (74% d.e.), was

P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
2069
recovered. At the reflux temperature, a mixture of (αR,3S)-5a and (αS,3S)-5a (39% yield, 22% d.e. by
1H NMR) was obtained with much of the epimerized starting compound also being recovered.
All of the new compounds (esters 5a,b and 8a,e) have been fully characterized as diastereomeric
mixtures through their spectroscopic data and elemental analysis. The NMR spectra of these compounds
have been fully assigned taking into account our previous work.1,2 The assignment of the signals of
the two diastereomers of each mixture could be easily carried out due to their different ratios. The
diastereomeric ratio of esters 8, obtained by HPLC assuming the relative areas of both diastereomers
to be equal to their molar ratio, were in good concordance with those obtained from the 1H NMR data,
through the integration of the signals of the CHCl protons. For the HPLC analysis of esters (αR,3S)- and
(αS,3R)-8a (>95% d.e.), nearly 1:1 mixtures of (αR,3S)-8a:(αS,3S)-8a and (αS,3R)-8a:(αR,3R)-8a were
obtained by reaction of rac-9a with (R)- or (S)-4 induced by DCC. Assignment of the configuration of the
α-ester stereocenter of esters 5a,b and 8a–e was carried out after their hydrolysis to the corresponding
acids 3a,b and 9a–e, respectively, of known configuration.
The great influence of the amine on the diastereoselectivity of the amine-catalyzed addition of
chiral enantiopure alcohols to ketenes has been explained through the formation of diastereomeric E/Z
enolates derived from the addition of the amine to the previously generated ketene, which then react
with the enantiopure alcohol.15,17 However, under our standard conditions for the deracemization of
α-halocarboxylic and α-substituted-α-arylacetic acids,2,3 a ketene is not previously formed. Usually,
the acyl chloride is added to the cold (−20–0°C) solution of the enantiopure alcohol and the amine (2
equiv.). Under such conditions, a possible alternative mechanism to explain the diastereoselectivity of
these reactions, which takes into account the important role played by the amine, is shown in Scheme 4.
Scheme 4. Possible mechanism for the diastereoselective formation of esters in the amine-induced reaction of chiral enantiopure
alcohols with rac-acyl chlorides having a trisubstituted stereogenic center at the α-position, based on the dynamic kinetic
resolution of enantiomeric acylammonium intermediates by the enantiopure alcohol
Reaction of the racemic acyl chloride with the amine can give a racemic mixture of acylammonium
cations which can be in rapid equilibrium via the corresponding E- and/or Z-enolates. These enolates may
alternatively be formed by addition of the amine to the in situ generated ketene. A slow reaction of these
enantiomeric acylammonium cations with an enantiopure alcohol may result in the diastereoselective
formation of one of the two possible esters through a dynamic kinetic resolution process,8–13 provided
the alcohol reacts faster with one of them, in such a way that equilibration of both enantiomeric
acylammonium cations can be achieved. This mechanism may be operative not only in the formal
deracemization of α-halocarboxylic acids herein described, but also in the formal deracemization of
other α-substituted carboxylic acids such as α-arylpropanoic acids, α-phthalimidocarboxylic acids, etc.

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In conclusion, the chiral auxiliaries (R)- and (S)-4 have shown their value for the formal deracemization
of some α-chlorocarboxylic acids, especially for the preparation of (R)- and (S)-α-chloropropanoic acids,
(R)- and (S)-9a, the last one being a key precursor for the synthesis of (R)-α-aryloxypropanoic acid
herbicides,24 such as dichlorprop-P,14 (R)-3a and mecoprop-P,7 (R)-3b. Also, an alternative moderately
enantioselective synthesis of acids (R)- and (S)-3a,b, based on the dynamic kinetic resolution of a
diastereomeric mixture of α-bromo ester 6 by reaction with the corresponding phenoxides, has been
developed. Moreover, the synthesis of (R)- and (S)-α-chlorocarboxylic acids herein described could be
of interest for the preparation of other enantiopure compounds such as oxiranes,25 α-amino acids,26
and several drugs.27–30 The increasing interest in enantiopure α-chlorocarboxylic acids is also shown by
several recent patent applications claiming the enantiopure preparation of (R)- or (S)-α-chloropropanoic
acids by enzymatic resolution of the racemic mixture.31–33
3. Experimental
Melting points were determined on a MFB 595010 M Gallenkamp melting point apparatus. 500
1
1
MHz H NMR spectra were performed on a Varian VXR 500 spectrometer, while 300 MHz H and
75.4 MHz 13C NMR spectra were carried out on a Varian Gemini 300. Except where otherwise stated,
1H NMR spectra were recorded at 500 MHz and 13C NMR spectra at 75.4 MHz, always in CDCl3.
Chemical shifts (δ) are reported in ppm referenced to internal tetramethylsilane. IR spectra were
recorded on an FT/IR Perkin–Elmer spectrometer, model 1600. Optical rotations were measured on a
Perkin–Elmer, model 241 polarimeter. HPLC analyses were performed on a Waters model 600 liquid
chromatograph provided with variable λ detector, working at λ=249 or 230 nm and always using, for
the stereospecific and non-stereospecific analyses, a Chiralcel OD-H column (25×0.46 cm) containing
the chiral stationary phase cellulose tris-(3,5-dimethylphenylcarbamate). Conditions A: a mixture of
hexane/isopropanol/trifluoroacetic acid in the ratio of 99/1/0.05 as eluent, flow 0.2 ml/min. Conditions
B: a mixture of hexane/isopropanol in the ratio of 93/7 as eluent, flow 0.35 ml/min. Solvents were of
analytical grade. Elemental analyses were carried out at the Microanalysis Service of the Centro de
Investigación y Desarrollo (C.I.D.), Barcelona, Spain.
3.1. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(2,4-dichlorophenoxy)propanoate,
(αS,3R)-5a, from rac-α-(2,4-dichlorophenoxy)propanoic acid, rac-3a, and (R)-4
Method A. A solution of rac-3a (235 mg, 1.00 mmol) in anhydrous CCl4 (25 ml) was treated with
PCl5 (209 mg, 1.00 mmol) for 1.5 h under reflux in an argon atmosphere. The volatile products were
distilled off at reduced pressure, the residue was taken in anhydrous CH2Cl2 (5 ml) and it was added
dropwise over a cold (0°C) solution of (R)-4 (195 mg, 0.95 mmol) and triethylamine (0.3 ml, 2 mmol)
in CH2Cl2 (5 ml) in an argon atmosphere. After addition was completed, stirring was continued for 1 h
at 0°C. The reaction mixture was washed with 2 N HCl (4×20 ml) and a saturated aqueous solution of
NaHCO3 (4×20 ml). The organic phase was dried with anhydrous Na2SO4 and concentrated in vacuo
to give a residue, which was purified by column chromatography [silica gel (15 g), CH2Cl2] to give a
mixture of (αS,3R)-5a and (αR,3R)-5a (191 mg, 48% yield, 28% d.e. by 1H NMR).
Method B. A solution of rac-3a (235 mg, 1.00 mmol) in anhydrous toluene (10 ml) was treated with
oxalyl bromide (0.54 g, 2.5 mmol) for 2 h under reflux in an argon atmosphere. The volatile products
were distilled off at reduced pressure, the residue was taken in anhydrous CH2Cl2 (5 ml) and it was

P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
2071
reacted as in Method A with (R)-4 (195 mg, 0.95 mmol) to give, after column chromatography, a mixture
of (αS,3R)-5a and (αR,3R)-5a (204 mg, 51% yield, 20% d.e. by 1H NMR).
3.2. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(4-chloro-2-methylphenoxy)propanoate,
(αS,3R)-5b, from rac-α-(4-chloro-2-methylphenoxy)propanoic acid, rac-3b, and (R)-4
Method A. Following the same procedure described above under Method A, from rac-3b (215 mg,
1.00 mmol), a mixture of (αS,3R)-5b and (αR,3R)-5b (189 mg, 49% yield, 42% d.e. by 1H NMR) was
obtained.
Method B. Following the same procedure described above under Method B, from rac-3b (215 mg,
1.00 mmol), a mixture of (αS,3R)-5b and (αR,3R)-5b (171 mg, 45% yield), in the approximate ratio 1:1
(by 1H NMR) was obtained.
3.3. General procedure for the reactions of α-bromo esters 6 with sodium 2,4-dichlorophenoxide or 4-
chloro-2-methylphenoxide
A THF solution of sodium 2,4-dichlorophenoxide or 4-chloro-2-methylphenoxide was prepared
by adding sodium hydride (0.95 mmol) to a stirred solution of 2,4-dichlorophenol or 4-chloro-2-
methylphenol (1.00 mmol) in dry THF (7 ml) at room temperature under an argon atmosphere. Stirring
was continued until evolution of hydrogen ceased. The resulting solution was then added dropwise via
cannula to a stirred, dried (1.0 g of 4 Å molecular sieves) THF solution (9 ml) of α-bromo ester 6 (1.00
mmol) and tetra-n-hexylammonium iodide (0.20 mmol) at −5 to 0°C under an argon atmosphere and
the solution was stirred at this temperature for 20 h. The mixture was concentrated in vacuo, CH2Cl2
(8 ml) was added to the residue and the solution was washed with water (3×5 ml) and saturated
aqueous NaHCO3 (3×5 ml), dried with anh. Na2SO4 and concentrated in vacuo. The residue was
chromatographed [silica gel (30 g) hexane/ethyl acetate] and the thus-obtained α-phenoxy ester 5a,b was
characterized as a diastereomeric mixture. Chemical yields refer to the total yield of both diastereomers.
3.4. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(2,4-dichlorophenoxy)propanoate,
(αS,3R)-5a
Following the above general procedure, from (αRS,3R)-6 (1.36 g, 4.00 mmol), (αS,3R)-5a (1.57
1
g, 93% yield, 52% d.e. by H NMR, 54% d.e. by HPLC) was isolated. After two crystallizations
from methanol (6 and 3 ml, respectively) solid (αS,3R)-5a was obtained (0.25 g, 15% yield), m.p.
1
83–85°C, [α]D20=+41.1 (c=0.94, CHCl3), 82% d.e. by H NMR, 83% d.e. by HPLC [conditions B:
main diastereomer (αS,3R)-5a, r.t. 68.7 min; (αR,3R)-5a, r.t. 77.8 min]. The integral of the 4-αCH3
group in both diastereomers (δ 1.06 and 1.09) allows us to calculate the ratio (αS,3R)-5a/(αR,3R)-5a
in each case. IR (KBr) ν: 1761 and 1716 (C_O st) cm−1. C21H21Cl2NO4 (422.32): calcd C 59.72%, H
5.02%, N 3.32%, Cl 16.79%. Found C 59.67%, H 5.20%, N 3.31%, Cl 16.59%.
3.4.1. Spectroscopic data of (αS,3R)-5a obtained from the spectra of the crystallized sample
1H NMR, δ: 1.06 (s, 3H, 4-αCH3), 1.21 (s, 3H, 4-βCH3), 1.79 (d, J=7.0 Hz, 3H, CHCH3), 3.51 (d,
J=9.5 Hz, 1H, 5α-H), 3.61 (d, J=9.5 Hz, 1H, 5β-H), 4.92 (q, J=7.0 Hz, 1H, CHCH3), 5.42 (s, 1H, 3-H),
6.93 (d, J=9.0 Hz, 1H, 6-H C6H3Cl2O–), 7.18 (m plus dd, J=9.0 Hz, J0=2.5 Hz, 2H, Hpara N-phenyl and 5-
H C6H3Cl2O–), 7.38 (m plus d, J=2.5 Hz, 3H, Hmeta N-phenyl and 3-H C6H3Cl2O–), 7.60 (dm, J=8.5 Hz,
2H, Hortho N-phenyl). 13C NMR, δ: 18.6 (CH3, CHCH3), 21.0 (CH3, 4-αCH3), 24.5 (CH3, 4-βCH3), 37.3

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P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
(C, C4), 57.6 (CH2, C5), 73.7 (CH, CHCH3), 78.7 (CH, C3), 115.4 (CH, C6 C6H3Cl2O–), 119.4 (CH,
Cortho N-phenyl), 124.2 (C, C2 C6H3Cl2O–), 125.1 (CH, Cpara N-phenyl), 126.8 (C, C4 C6H3Cl2O–),
127.6 (CH, C5 C6H3Cl2O), 129.0 (CH, Cmeta N-phenyl), 130.2 (CH, C3 C6H3Cl2O–), 138.8 (C, Cipso
N-phenyl), 152.0 (C, C1 C6H3Cl2O–), 168.1 (C, C2), 170.6 (C, COO).
3.4.2. Significant spectroscopic data of (αR,3R)-5a obtained from the spectra of (αS,3R)-5a of 54% d.e.
1H NMR, δ: 1.09 (s, 3H, 4-αCH3), 1.28 (s, 3H, 4-βCH3), 1.78 (d, J=7.0 Hz, 3H, CHCH3), 3.51 (d,
J=9.5 Hz, 1H, 5α-H), 3.60 (d, J=9.5 Hz, 1H, 5β-H), 4.90 (q, J=7.0 Hz, 1H, CHCH3), 5.41 (s, 1H, 3-H),
6.96 (d, J=9.0 Hz, 1H, 6-H C6H3Cl2O–). 13C NMR, δ: 18.5 (CH3, CHCH3), 21.2 (CH3, 4-αCH3), 24.7
(CH3, 4-βCH3), 37.3 (C, C4), 57.6 (CH2, C5), 74.4 (CH, CHCH3), 79.0 (CH, C3).
3.5. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(2,4-dichlorophenoxy)propanoate,
(αR,3S)-5a
Following the above general procedure, from (αRS,3S)-6 (1.19 g, 3.50 mmol), (αR,3S)-5a (1.35 g,
1
91% yield, 54% d.e. by H NMR, 58% d.e. by HPLC) was isolated. After one crystallization from
methanol (5 ml), solid (αR,3S)-5a was obtained (0.38 g, 26% yield), m.p. 81–83°C, [α]D20=−41.3
(c=1.00, CHCl3), 82% d.e. by 1H NMR, 85% d.e. by HPLC. C21H21Cl2NO4 (422.32): calcd C 59.72%,
1
H 5.02%, N 3.32%, Cl 16.79%. Found C 59.52%, H 5.20%, N 3.23%, Cl 17.01%. The IR and H and
13C NMR data coincide with those of their enantiomers.
3.6. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(4-chloro-2-methylphenoxy)propanoate,
(αS,3R)-5b
Following the above general procedure, from (αRS,3R)-6 (0.68 g, 2.0 mmol), (αS,3R)-5b (0.65 g,
1
86% yield, 62% d.e. by H NMR, 64% d.e. by HPLC) was isolated. After one crystallization from
methanol (5 ml), solid (αS,3R)-5b was obtained (0.31 g, 41% yield), m.p. 91–93°C, [α]D20=+30.1
(c=1.03, CHCl3), 76% d.e. by 1H NMR, 78% d.e. by HPLC [conditions B: main diastereomer (αS,3R)-
5b, r.t. 55.0 min; (αR,3R)-5b, r.t. 65.1 min]. The integral of the 4-αCH3 group in both diastereomers (δ
0.94 and 1.10) gave the ratio (αS,3R)-5b/(αR,3R)-5b in each case. IR (KBr) ν: 1763 and 1714 (C_O
st) cm−1. C22H24ClNO4 (401.91): calcd C 65.75%, H 6.02%, N 3.49%, Cl 8.82%. Found C 65.66%, H
6.06%, N 3.47%, Cl 9.37%.
3.6.1. Spectroscopic data of (αS,3R)-5b obtained from the spectra of the crystallized sample
1H NMR, δ: 0.94 (s, 3H, 4-αCH3), 1.13 (s, 3H, 4-βCH3), 1.74 (d, J=6.5 Hz, 3H, CHCH3), 2.23 [s,
3H, C6H3Cl(CH3)O–], 3.45 (d, J=9.5 Hz, 1H, 5α-H), 3.58 (d, J=9.5 Hz, 1H, 5β-H), 4.88 (q, J=6.5 Hz,
1H, CHCH3), 5.39 (s, 1H, 3-H), 6.71 [d, J=8.5 Hz, 1H, 6-H C6H3Cl(CH3)O–], 7.06–7.11 [compl. signal,
2H, 3-H and 5-H C6H3Cl(CH3)O–], 7.16 (tm, J=7.5 Hz, 1H, Hpara N-phenyl) 7.36 (m, 2H, Hmeta N-
phenyl), 7.59 (dm, J=8.0 Hz, 2H, Hortho N-phenyl). 13C NMR, δ: 16.2 (CH3, C6H3Cl(CH3)O–), 18.8
(CH3, CHCH3), 20.8 (CH3, 4-αCH3), 24.4 (CH3, 4-βCH3), 37.2 (C, C4), 57.5 (CH2, C5), 72.6 (CH,
CHCH3), 78.5 (CH, C3), 112.5 (CH, C6 C6H3Cl(CH3)O–), 119.4 (CH, Cortho N-phenyl), 125.0 (CH,
C
para N-phenyl), 125.8 [C, C4 C6H3Cl(CH3)O–], 126.3 [CH, C5 C6H3Cl(CH3)O–], 129.0 (CH, Cmeta N-
phenyl), 130.7 [CH, C3 C6H3Cl(CH3)O–], 138.8 (C, Cipso N-phenyl), 154.3 [C, C1 C6H3Cl(CH3)O–],
168.2 (C, C2), 171.4 (C, COO). The signal of C2 was not observed.

P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
2073
3.6.2. Significant spectroscopic data of (αR,3R)-5b obtained from the spectra of (αS,3R)-5b of 62% d.e.
1H NMR, δ: 1.10 (s, 3H, 4-αCH3), 1.25 (s, 3H, 4-βCH3), 1.73 (d, J=7.0 Hz, 3H, CHCH3), 2.24 [s,
3H, C6H3Cl(CH3)O–], 3.50 (d, J=9.5 Hz, 1H, 5α-H), 3.60 (d, J=9.5 Hz, 1H, 5β-H), 4.86 (q, J=7.0 Hz,
1H, CHCH3), 5.40 (s, 1H, 3-H), 6.68 [d, J=8.5 Hz, 1H, 6-H C6H3Cl(CH3)O–]. 13C NMR, δ: 16.2 [CH3,
C6H3Cl(CH3)O–], 18.6 (CH3, CHCH3), 21.1 (CH3, 4-αCH3), 24.7 (CH3, 4-βCH3), 37.2 (C, C4), 57.6
(CH2, C5), 72.8 (CH, CHCH3), 78.7 (CH, C3).
3.7. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(4-chloro-2-methylphenoxy)propanoate,
(αR,3S)-5b
Following the above general procedure, from (αRS,3S)-6 (0.85 g, 2.5 mmol), (αR,3S)-5b (0.85 g,
89% yield, 46% d.e. by 1H NMR, 48% d.e. by HPLC) was obtained, which after one crystallization from
methanol (7 ml) gave a solid (0.36 g, 38% yield), m.p. 92–94°C, [α]D20=−29.8 (c=1.02, CHCl3), 72%
d.e. by 1H NMR, 74% d.e. by HPLC. The integral of the 4-αCH3 group in both diastereomers (δ 0.97
and 1.13) gave the ratio (αR,3S)-5b/(αS,3S)-5b in each case. C22H24ClNO4 (401.91): calcd C 65.75%,
H 6.02%, N 3.49%, Cl 8.82%. Found C 65.52%, H 6.27%, N 3.43%, Cl 8.58%. The IR and NMR data
coincide with those of their enantiomers.
3.8. General procedure for the hydrolysis of α-phenoxy esters 5
A mixture of the α-phenoxy ester 5 (1.0 mmol), acetic acid (8 ml) and 2 N HCl (3.2 ml) was heated
at 120°C (bath temperature) until completion of the hydrolysis (3 h), this was followed by thin layer
chromatography (TLC). The mixture was allowed to cool to room temperature and the volatile products
were distilled off at reduced pressure. Water (10 ml) was added to the residue, the mixture was treated
with saturated aqueous NaHCO3 until a basic pH was achieved and it was extracted with CH2Cl2 (2×10
ml). The combined organic extracts were dried with anh. Na2SO4 and concentrated in vacuo to give the
chiral auxiliary, (R)- or (S)-4. The aqueous phase was acidified with 2 N HCl and extracted with ethyl
acetate (3×10 ml). The combined organic phases were dried with anh. Na2SO4 and concentrated in vacuo
to give the (R)- or (S)-α-phenoxypropanoic acid, (R)- or (S)-3. Chemical yields refer to the total yield of
both enantiomers.
3.9. (R)-α-(2,4-Dichlorophenoxy)propanoic acid, (R)-3a
From (αR,3S)-5a (0.29 g, 0.69 mmol, 85% d.e. by HPLC), (R)-3a (0.15 g, 93% yield) was obtained
as a solid, m.p. 108–110°C (hexane/ethyl acetate) (described: 116–117.5°C),24 [α]D20=+22.3 (c=1.00,
ethanol) [described: [α]D20=+26.6 (c=1.23, ethanol)],24 approx. 84% o.p., 84% e.e. by HPLC [conditions
A: main enantiomer (R)-3a, r.t. 121.1 min; (S)-3a, r.t. 111.2 min].
3.10. (S)-α-(2,4-Dichlorophenoxy)propanoic acid, (S)-3a
From (αS,3R)-5a (0.21 g, 0.50 mmol, 83% d.e. by HPLC), (S)-3a (0.11 g, 94% yield) was obtained as
a solid, m.p. 107–109°C (hexane/ethyl acetate), [α]D20=−19.7 (c=1.18, ethanol), 74% approx. o.p., 70%
e.e. by HPLC [conditions A: main enantiomer (S)-3a, r.t. 116.0 min, (R)-3a, r.t. 128.1 min].

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3.11. (R)-α-(4-Chloro-2-methylphenoxy)propanoic acid, (R)-3b
From (αR,3S)-5b (0.15 g, 0.37 mmol, 78% d.e. by HPLC), (R)-3b (0.07 g, 92% yield) was obtained
as a solid, m.p. 89–91°C (hexane/ethyl acetate) (described: 95°C),24 [α]D20=+20.8 (c=1.03, ethanol),
[described: [α]D20=+28.1 (ethanol)],24 74% approx. o.p.
3.12. (S)-α-(4-Chloro-2-methylphenoxy)propanoic acid, (S)-3b
From (αS,3R)-5b (0.26 g, 0.65 mmol, 76% d.e. by 1H NMR), (S)-3b (0.13 g, 90% yield) was obtained
as a solid, m.p. 89.5–91.5°C (hexane/ethyl acetate) [α]D20=−21.3 (c=1.00, ethanol), 76% approx. o.p.
3.13. General procedure for the reaction of rac-α-chloroacyl chlorides with (R)- or (S)-4
To a dried and cooled solution (−20°C) of (R)- or (S)-4 (1.00 mmol) and triethylamine (2.0 mmol)
in CH2Cl2 under an argon atmosphere, a solution of rac-7 (1.05 mmol) in CH2Cl2 was added dropwise
over a period of 10 min and the mixture was magnetically stirred for 10 min at −20°C. The mixture was
washed with 1 N HCl (3×3.75 ml), a saturated aqueous solution of NaHCO3 (3×3.75 ml), dried (anh.
Na2SO4) and concentrated in vacuo.
3.14. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-chloropropanoate, (αS,3R)-8a
Following the above general procedure, from (R)-4 (4.10 g, 20.0 mmol) and rac-7a (2.0 ml, 20.6
mmol), (αS,3R)-8a (5.90 g, >99% yield, 96% d.e. by HPLC) was obtained as a solid. Crystallization
from a mixture of hexane (40 ml) and ethyl acetate (4 ml) gave the analytical sample (4.55 g, 77%
global yield), m.p. 79–80°C, [α]D20=+50.3 (c=1.05, CHCl3), >99% d.e. by HPLC [conditions B: main
diastereomer (αS,3R)-8a, r.t. 59.0 min; (αR,3R)-8a, r.t. 57.0 min]. IR (KBr) ν: 1770, 1756 and 1703
(C_O st) cm−1. C15H18ClNO3 (295.78): calcd C 60.91%, H 6.14%, N 4.74%, Cl 11.99%. Found C
61.02%, H 6.21%, N 4.76%, Cl 12.00%. 1H NMR, δ: 1.16 (s, 3H, 4-αCH3), 1.31 (s, 3H, 4-βCH3), 1.79
(d, J=7.0 Hz, 3H, CHCH3), 3.53 (d, J=9.5 Hz, 1H, 5α-H), 3.62 (d, J=9.5 Hz, 1H, 5β-H), 4.56 (q, J=7.0
Hz, 1H, CHCl), 5.40 (s, 1H, 3-H), 7.16 (tm, J=7.5 Hz, 1H, Hpara), 7.37 (m, 2H, Hmeta), 7.60 (dm, J=8.0
Hz, 2H, Hortho). 13C NMR, δ: 21.0 (CH3, 4-αCH3), 21.8 (CH3, CHCH3), 24.8 (CH3, 4-βCH3), 37.5 (C,
C4), 52.8 (CH, CHCl), 57.7 (CH2, C5), 79.3 (CH, C3), 119.4 (CH, Cortho), 125.0 (CH, Cpara), 128.9 (CH,
C
meta), 138.8 (C, Cipso), 168.0 (C, C2), 169.4 (C, COO).
3.15. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-chloropropanoate, (αR,3S)-8a
Following the above general procedure, from (S)-4 (0.41 g, 2.0 mmol) and rac-7a (0.2 ml, 2.1
mmol), (αR,3S)-8a (0.59 g, 99% yield, >99% d.e. by HPLC) was obtained as a solid. Crystallization
from a mixture of hexane (4.5 ml) and ethyl acetate (0.5 ml) gave the analytical sample (0.41 g, 69%
global yield), m.p. 79.5–80°C, [α]D20=−51.0 (c=1.03, CHCl3), >99% by HPLC [conditions B: main
diastereomer (αR,3S)-8a, r.t. 37.0 min; (αS,3S)-8a, r.t. 32.7 min]. C15H18ClNO3 (295.78): calcd C
60.91%, H 6.14%, N 4.74%, Cl 11.99%. Found C 60.92%, H 6.13%, N 4.78%, Cl 11.99%. The IR
and NMR spectra are coincident with those of its enantiomer.

P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
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3.16. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-chlorobutanoate, (αR,3S)-8b
Following the above general procedure, from (S)-4 (4.10 g, 20.0 mmol) and rac-7b (2.96 g, 21.0
mmol), (αR,3S)-8b (6.19 g, >99% yield, 74% d.e. by HPLC) was obtained as a solid. Crystallization
from ethyl acetate (8 ml) gave the analytical sample (3.30 g, 53% global yield), m.p. 49.5–50°C,
[α]D20=−50.5 (c=1.12, CHCl3), 82% d.e. by HPLC [conditions B: main diastereomer (αR,3S)-8b, r.t.
32.5 min; (αS,3S)-8b, r.t. 29.4 min]. IR (KBr) ν: 1750 and 1711 (C_O st) cm−1. C16H20ClNO3 (309.81):
calcd C 62.03%, H 6.51%, N 4.52%, Cl 11.44%. Found C 61.92%, H 6.63%, N 4.53%, Cl 11.51%.
3.16.1. Spectroscopic data of (αR,3S)-8b obtained from the spectra of the mixture
1H NMR, δ: 1.10 (t, J=7.5 Hz, 3H, CH3CH2), 1.16 (s, 3H, 4-αCH3), 1.30 (s, 3H, 4-βCH3), 2.04 (m,
1H) and 2.10 (m, 1H) (CH3CH2), 3.53 (d, J=9.5 Hz, 1H, 5α-H), 3.62 (d, J=9.5 Hz, 1H, 5β-H), 4.40 (dd,
J=5.5 Hz, J0=7.5 Hz, 1H, CHCl), 5.42 (s, 1H, 3-H), 7.16 (tm, J=7.5 Hz, 1H, Hpara), 7.36 (m, 2H, Hmeta),
7.60 (dm, J=7.5 Hz, 2H, Hortho). 13C NMR, δ: 10.4 (CH3, CH3CH2), 21.0 (CH3, 4-αCH3), 24.8 (CH3,
4-βCH3), 28.5 (CH2, CH3CH2), 37.5 (C, C4), 57.6 (CH2, C5), 59.0 (CH, CHCl), 79.1 (CH, C3), 119.4
(CH, Cortho), 125.0 (CH, Cpara), 128.9 (CH, Cmeta), 138.8 (C, Cipso), 168.0 (C, C2), 168.9 (C, COO).
3.17. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-chloro-β-methylbutanoate, (αR,3S)-8c
Following the above general procedure, from (S)-4 (2.87 g, 14.0 mmol) and rac-7c (2.33 g, 15.0
mmol), (αR,3S)-8c (4.52 g, >99% yield, 22% d.e. by HPLC) was obtained as a solid. Crystallization from
ethyl acetate (6 ml) gave the analytical sample (2.31 g, 51% global yield), m.p. 69–70°C, [α]D20=−50.1
(c=1.05, CHCl3), 24% d.e. by HPLC [conditions B: main diastereomer (αR,3S)-8c, r.t. 27.8 min; (αS,3S)-
8c, r.t. 25.7 min]. IR (KBr) ν: 1756 and 1708 (C_O st) cm−1. C17H22ClNO3 (323.84): calcd C 63.05%,
H 6.85%, N 4.33%, Cl 10.95%. Found C 62.85%, H 6.84%, N 4.31%, Cl 10.88%.
3.17.1. Spectroscopic data of (αR,3S)-8c obtained from the spectra of the mixture
1H NMR, δ: 1.09 (d, J=7.0 Hz, 3H) and 1.12 (d, J=7.0 Hz, 3H) [CH(CH3)2], 1.163 (s, 3H, 4-αCH3),
1.298 (s, 3H, 4-βCH3), 2.38 (oct., J=7.0 Hz, 1H, CH(CH3)2), 3.52 (d, J=9.5 Hz, 1H, 5α-H), 3.62 (d, J=9.5
Hz, 1H, 5β-H), 4.27 (d, J=7.0 Hz, 1H, CHCl), 5.439 (s, 1H, 3-H), 7.16 (tm, J=7.5 Hz, 1H, Hpara), 7.36
(m, 2H, Hmeta), 7.60 (dm, J=8.5 Hz, 2H, Hortho). 13C NMR, δ: 18.0 (CH3) and 19.6 (CH3) [CH(CH3)2],
21.06 (CH3, 4-αCH3), 24.7 (CH3, 4-βCH3), 32.7 (CH, CH(CH3)2), 37.5 (C, C4), 57.58 (CH2, C5), 64.5
(CH, CHCl), 79.1 (CH, C3), 119.4 (CH, Cortho), 125.0 (CH, Cpara), 129.0 (CH, Cmeta), 138.9 (C, Cipso),
168.1 (C, C2), 168.7 (C, COO).
3.17.2. Significant spectroscopic data of (αS,3S)-8c obtained from the spectra of the mixture
1H NMR, δ: 1.107 (d, J=7.0 Hz, 3H) and 1.110 (d, J=7.0 Hz, 3H) [CH(CH3)2], 1.160 (s, 3H, 4-αCH3),
1.304 (s, 3H, 4-βCH3), 2.42 (oct., J=7.0 Hz, 1H, CH(CH3)2), 3.52 (d, J=9.5 Hz, 1H, 5α-H), 3.62 (d, J=9.5
Hz, 1H, 5β-H), 4.29 (d, J=6.0 Hz, 1H, CHCl), 5.436 (s, 1H, 3-H). 13C NMR, δ: 17.8 (CH3), 19.6 (CH3)
[CH(CH3)2], 21.1 (CH3, 4-αCH3), 24.7 (CH3, 4-βCH3), 32.5 (CH, CH(CH3)2), 37.4 (C, C4), 57.6 (CH2,
C5), 63.8 (CH, CHCl), 79.2 (CH, C3), 168.1 (C, C2), 168.9 (C, COO).
3.18. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-chloro-β-phenylpropanoate, (αS,3R)-8d
Following the above general procedure, from (R)-4 (4.68 g, 22.8 mmol) and rac-7d (4.74 g, 23.3
mmol), (αS,3R)-8d (8.43 g, 99% yield, 59% d.e. by HPLC) was obtained as an oil, [α]D20=+60.6

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(c=1.21, CHCl3). HPLC (conditions B): main diastereomer (αS,3R)-8d, r.t. 70.3 min; (αR,3R)-8d, r.t.
77.9 min. IR (NaCl) ν: 1754 and 1716 (C_O st) cm−1. C21H22ClNO3 (371.88): calcd C 67.83%, H
5.97%, N 3.77%, Cl 9.53%. Found C 67.75%, H 5.98%, N 3.75%, Cl 9.57%.
3.18.1. Spectroscopic data of (αS,3R)-8d obtained from the spectra of the mixture
1H NMR, δ: 0.98 (s, 3H, 4-αCH3), 1.18 (s, 3H, 4-βCH3), 3.24 (dd, J=14.0 Hz, J0=7.0 Hz, 1H) and
3.47 (dd, J=14.0 Hz, J0=7.5 Hz, 1H) (C6H5–CH2), 3.48 (d, J=9.5 Hz, 1H, 5α-H), 3.58 (d, J=9.5 Hz,
1H, 5β-H), 4.56 (pseudo t, J=7.5 Hz, 1H, CHCl), 5.37 (s, 1H, 3-H), 7.17 (tm, J=7.5 Hz, 1H, Hpara N-
phenyl), 7.23–7.34 (compl. signal, 5H, C6H5–CH2), 7.36 (m, 2H, Hmeta N-phenyl), 7.59 (dm, J=9.0 Hz,
2H, Hortho N-phenyl). 13C NMR, δ: 20.7 (CH3, 4-αCH3), 24.5 (CH3, 4-βCH3), 37.4 (C, C4), 41.3 (CH2,
Ar–CH2), 57.3 (CH, CHCl), 57.5 (CH2, C5), 79.2 (CH, C3), 119.4 (CH, Cortho N-phenyl), 124.9 (CH,
Cpara N-phenyl), 127.3 (CH, Cpara benzyl), 128.6 (CH), 128.9 (CH), 129.3 (CH) (rest of Ar–CH), 135.5
(C, Cipso benzyl), 138.8 (C, Cipso N-phenyl), 167.9 (C, C2), 168.5 (C, COO).
3.18.2. Significant spectroscopic data of (αR,3R)-8d obtained from the spectra of the mixture
1H NMR, δ: 1.15 (s, 3H, 4-αCH3), 1.30 (s, 3H, 4-βCH3), 3.22 (dd, J=14.5 Hz, J0=9.0 Hz, 1H) and
3.49 (dd, J=14.5 Hz, J0=5.5 Hz, 1H) (C6H5–CH2), 3.52 (d, J=9.5 Hz, 1H, 5α-H), 3.62 (d, J=9.5 Hz, 1H,
5β-H), 4.64 (dd, J=9.0 Hz, J0=5.5 Hz, 1H, CHCl), 5.42 (s, 1H, 3-H). 13C NMR, δ: 20.8 (CH3, 4-αCH3),
24.7 (CH3, 4-βCH3), 37.5 (C, C4), 40.3 (CH2, Ar–CH2), 57.1 (CH, CHCl), 57.6 (CH2, C5), 79.4 (CH,
C3), 168.0 (C, C2), 168.8 (C, COO).
3.19. (αS,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-chloro-α-phenylacetate, (αS,3S)-8e
Following the above general procedure, from (S)-4 (1.03 g, 5.02 mmol) and rac-7e (0.8 ml, 5.2 mmol),
(αS,3S)-8e (1.69 g, 95% yield, 72% d.e. by HPLC) was obtained as a solid. Crystallization from ethyl
acetate (2 ml) gave the analytical sample (1.01 g, 57% global yield), m.p. 65–66°C, [α]D20=−20.2
(c=1.62, CHCl3), 98% d.e. by HPLC [conditions B: main diastereomer (αS,3S)-8e, r.t. 71.6 min; (αR,3S)-
8e, r.t. 56.7 min]. IR (KBr) ν: 1761 and 1716 (C_O st) cm−1. C20H20ClNO3 (357.85): calcd C 67.13%,
1
H 5.64%, N 3.91%, Cl 9.91%. Found C 67.25%, H 5.71%, N 3.88%, Cl 10.24%. H NMR, δ: 1.13 (s,
3H, 4-αCH3), 1.29 (s, 3H, 4-βCH3), 3.51 (d, J=9.5 Hz, 1H, 5α-H), 3.60 (d, J=9.5 Hz, 1H, 5β-H), 5.39
(s, 1H, 3-H), 5.51 (s, 1H, CHCl), 7.15 (tm, J=7.0 Hz, 1H, Hpara N-phenyl), 7.33–7.42 (comp. signal, 5H),
7.55–7.60 (compl. signal, 4H) (rest of Ar–H). 13C NMR, δ: 20.8 (CH3, 4-αCH3), 24.6 (CH3, 4-βCH3),
37.3 (C, C4), 57.4 (CH2, C5), 58.1 (CH, CHCl), 79.6 (CH, C3), 119.3 (CH, Cortho N-phenyl), 124.8
(CH, Cpara N-phenyl), 128.0 (CH), 128.6 (CH), 128.8 (CH), 129.2 (CH) (rest of Ar–CH), 134.8 (C, Cipso
C–phenyl), 138.7 (C, Cipso N-phenyl), 167.6 (C), 167.8 (C) (COO and C2).
3.20. General procedure for the hydrolysis of α-chloro esters 8
Method A:18 To a cooled solution (0°C) of α-chloro ester 8 (1.0 mmol) in a mixture of THF (1.9 ml)
and water (0.6 ml), H2O2 (0.35 ml, 33% w/v) and LiOH·H2O (2.0 mmol) were added and the mixture
was magnetically stirred at 0°C till completion of the hydrolysis (15 min), following the reaction by TLC.
An aqueous solution of Na2S2O3 (6.0 ml, 10%) was added to the mixture and it was extracted with ether
(3×10 ml). The combined organic phases were dried (anh. Na2SO4) and concentrated in vacuo to give
the chiral auxiliary which was crystallized from ethanol (0.2 ml). The aqueous phase was acidified with
35% HCl (until pH=1), saturated aqueous solution of NaCl (10 ml) was added and it was extracted with

P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
2077
ether (5×10 ml). The combined organic phases were dried (anh. Na2SO4) and concentrated in vacuo to
give the (R)- or (S)-α-chloro acid, (R)- or (S)-9.
Method B:19 To a cooled solution (0°C) of α-chloro ester 8 (1.0 mmol) in a mixture of THF (4 ml)
and water (2 ml), solid LiOH·H2O (1.5 mmol) was added and the mixture was magnetically stirred at
0°C until completion of the hydrolysis (15 min), following the reaction by TLC. Water (6 ml) was added
to the mixture and it was extracted with ether (3×10 ml). The combined organic phases were dried (anh.
Na2SO4) and concentrated in vacuo to give the chiral auxiliary which was crystallized from ethanol
(0.2 ml). The aqueous phase was acidified with 35% HCl (until pH=1), solid NaCl (3 g) was added
and it was extracted with ether (5×10 ml). The combined organic phases were dried (anh. Na2SO4) and
concentrated in vacuo to give the (R)- or (S)-α-chloro acid, (R)- or (S)-9.
3.21. (S)-α-Chloropropanoic acid, (S)-9a
Following method A, from (αS,3R)-8a (4.43 g, 15.0 mmol, >99% d.e. by HPLC), (S)-9a (1.40 g, 86%
yield) was isolated as an oil, [α]D20=−15.6 (c=1.09, CHCl3), described19 [α]D20=−15.9 (c=1.0, CHCl3),
98% approx. o.p.
3.22. (R)-α-Chloropropanoic acid, (R)-9a
Following method A, from (αR,3S)-8a (1.50 g, 5.08 mmol, >99% d.e. by HPLC), (R)-9a (0.47 g, 85%
yield) was isolated as an oil, [α]D20=+15.7 (c=1.12, CHCl3), 99% approx. o.p.
3.23. (R)-α-Chlorobutanoic acid, (R)-9b
Following method A, from (αR,3S)-8b (1.30 g, 4.20 mmol, 82% d.e. by HPLC), (R)-9b (0.45 g,
87% yield) was isolated as an oil, [α]D20=+10.3 (c=0.84, methanol), described20 [α]D20=+12.7 (c=0.4,
methanol), 81% approx. o.p.
3.24. (R)-α-Chloro-β-methylbutanoic acid, (R)-9c
Following method A, from (αR,3S)-8c (3.24 g, 10.0 mmol, 24% d.e. by HPLC), (R)-9c (1.21 g, 89%
yield) was isolated as an oil, [α]D20=−0.44 (c=8.01, ethanol), described for (S)-9c21, [α]D20=2.12 (c=8.7,
ethanol), 21% approx. o.p.
3.25. (S)-α-Chloro-β-phenylpropanoic acid, (S)-9d
Following method A, from (αS,3R)-8d (0.56 g, 1.51 mmol, 59% d.e. by HPLC), (S)-9d (0.27 g, 98%
yield) was isolated as an oil, [α]D20=+6.0 (c=2.09, benzene), described22 [α]D20=+10.2 (c=2.8, benzene),
59% approx. o.p.
3.26. (S)-α-Chloro-α-phenylacetic acid, (S)-9e
Following method B, from (αS,3S)-8e (0.24 g, 0.67 mmol, 98% d.e. by HPLC), (S)-9e (0.11 g, 99%
yield) was isolated as a solid, [α]D20=+52.4 (c=2.99, ethanol), described for (R)-9e23, [α]D20=−163
(ethanol), 32% approx. o.p.

2078
P. Camps et al. / Tetrahedron: Asymmetry 9 (1998) 2065–2079
3.27. Attempted preparation of (αS,3S)-5a, by reaction of (αR,3S)-4,4-dimethyl-2-oxo-1-
phenylpyrrolidin-3-yl α-chloropropanoate, (αR,3S)-8a, with sodium 2,4-dichlorophenoxide
To a cold (0°C) mixture of (αR,3S)-8a (250 mg, 0.85 mmol, >99% d.e. by HPLC) in anhydrous THF
(10 ml) under an argon atmosphere, a THF suspension of the sodium salt of 2a [prepared by reacting 2a
(139 mg, 0.85 mmol) with NaH (33 mg, 0.77 mmol) in anhydrous THF (9 ml) until hydrogen formation
ceased] was added, and the mixture was heated under reflux for 20 h. The solvent was evaporated
in vacuo, the residue was taken in CH2Cl2 (50 ml), washed with water (3×50 ml), then a saturated
solution of Na2CO3 (3×50 ml), dried with anhydrous Na2SO4 and concentrated in vacuo. The residue
was chromatographed [silica gel (20 g), CH2Cl2] to give 106 mg (42% yield) of a mixture of (αR,3S)-8a
and (αS,3S)-8a in the approximate ratio 1:1 (by 1H NMR), and 132 mg of a mixture of (αR,3S)-5a and
(αS,3S)-5a (39% yield, 22% d.e. by 1H NMR).
When this reaction was carried out at room temperature for 15 h, only the starting (αR,3S)-8a (90 mg,
65% yield, 74% d.e. by 1H NMR) was obtained.
Acknowledgements
A fellowship from the Comissionat per a Universitats i Recerca (CUR) of the Generalitat de Catalunya
(GC) to N. Soldevilla and financial support from the Comisión Interministerial de Ciencia y Tecnología
(CICYT) (Programa Nacional de Tecnología de los Procesos Químicos, Project QUI96-0828) and the
CUR (Project 1997SGR 00140) are gratefully acknowledged. We thank the Serveis Científico-Tècnics
of the Universitat de Barcelona for recording the NMR spectra, and P. Domènech from the Centro de
Investigación y Desarrollo (C.I.D.) of Barcelona, for carrying out the elemental analyses.
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