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

Article abstract of DOI:10.1016/S0957-4166(99)00018-X

rac-α-Amino acids (rac-1a-d) were formally deracemized by a four-step reaction sequence: (a) protection of the amino function as the phthalimido derivative; (b) acyl chloride formation; (c) diastereoselective reaction with the chiral auxiliaries (R)- or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2- pyrrolidinone, (R)- or (S)-3; and (d) acid hydrolysis to deprotect both the ester and phthalimido functions. Diastereoselectivities of the intermediate esters 4 were good (82-96% d.e.), except for the case of 4b (41% d.e.), the precursor of valine. The main diastereoisomer of esters 4 was (αR,3S)- or (αS,3R)-, except for 4d: in this case, working at -78°C, the (αR,3R)- diastereoisomer was the main product, which epimerizes easily at the α- position when at room temperature. Acid hydrolysis of esters 4 directly gave the deprotected α-amino acids, with little or no epimerization at the α- position of the α-amino acid and complete recovery of the chiral auxiliary. Only (αR,3R)-4d on acid hydrolysis partially epimerized at the α-position. Moreover, some α-amino acids and their N,N-dibenzyl derivatives were obtained by dynamic kinetic resolution of diastereoisomeric mixtures of α- bromo esters 5 derived from the chiral auxiliaries (R)- or (S)-3 during reaction with dibenzylamine.

Full text of DOI:10.1016/S0957-4166(99)00018-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 493–509
(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone
as chiral auxiliaries in the enantioselective preparation of
α-amino acids
Pelayo Camps,∗ Francesc Pérez, Núria Soldevilla and Miguel A. Borrego
Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028,
Barcelona, Spain
Received 7 December 1998; accepted 14 January 1999
Abstract
rac-α-Amino acids (rac-1a–d) were formally deracemized by a four-step reaction sequence: (a) protection
of the amino function as the phthalimido derivative; (b) acyl chloride formation; (c) diastereoselective reaction
with the chiral auxiliaries (R)- or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- or (S)-3; and (d) acid
hydrolysis to deprotect both the ester and phthalimido functions. Diastereoselectivities of the intermediate esters 4
were good (82–96% d.e.), except for the case of 4b (41% d.e.), the precursor of valine. The main diastereoisomer of
esters 4 was (αR,3S)- or (αS,3R)-, except for 4d: in this case, working at −78°C, the (αR,3R)-diastereoisomer was
the main product, which epimerizes easily at the α-position when at room temperature. Acid hydrolysis of esters
4 directly gave the deprotected α-amino acids, with little or no epimerization at the α-position of the α-amino
acid and complete recovery of the chiral auxiliary. Only (αR,3R)-4d on acid hydrolysis partially epimerized at the
α-position. Moreover, some α-amino acids and their N,N-dibenzyl derivatives were obtained by dynamic kinetic
resolution of diastereoisomeric mixtures of α-bromo esters 5 derived from the chiral auxiliaries (R)- or (S)-3 during
reaction with dibenzylamine. © 1999 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)-3, and their use for the formal deracemization of
α-arylpropanoic, α-substituted α-arylacetic2,3 and α-chloro acids.4 We also described their use in
an enantioselective synthesis of α-hydroxy acids5 and α-aryloxypropanoic acid herbicides, such as
dichlorprop-P and mecoprop-P, based on the dynamic kinetic resolution of α-bromo esters derived from
∗
Corresponding author. Tel: 34-934024536; fax: 34-934035941; e-mail: camps@farmacia.far.ub.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00018-X

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these chiral auxiliaries on reaction with substituted phenoxides.4,5 A key point of these transformations
is the efficient recovery of the chiral auxiliary.
Although natural L-α-amino acids are readily available, there is an increasing demand for enantiopure
non-natural α-amino acids, since they are being used as precursors for many drugs6 and bioactive
compounds,7 as well as intermediates for the preparation of chiral auxiliaries,8 or important chiral
building blocks.9
Much work has been done on the asymmetric synthesis of α-amino acids, which has been the
subject of many reviews.10,11 Well-established methods for the synthesis of enantiopure α-amino acids
include the enantioselective hydrogenation of α-acylamino dehydroacids;12 the enzymatic kinetic reso-
lution of racemic mixtures of α-amino esters;13 the diastereoselective electrophilic amination of acid
derivatives;14,15 the nucleophilic16–18 and radical19 additions to C_N bonds, including the asymmetric
Strecker synthesis;20,21 and the α-amino enolate alkylations22,23 among others. Other procedures imply
the formal deracemization of racemic precursors: (a) by reaction of a prochiral ketene intermediate
with an enantiopure alcohol such as D-pantolactone24,25 or (b) by dynamic kinetic resolution26–30 of
diastereoisomeric mixtures of α-substituted acid derivatives derived from chiral auxiliaries such as the
Oppolzer’s sultam,31 D-pantolactone,32,33 imidazolidin-2-ones,34 oxazolidin-2-ones,35 etc.
In this paper we describe the application of the chiral auxiliaries (R)- and (S)-3 in the preparation of
enantioenriched α-amino acids from racemic precursors in two ways: (1) by formal deracemization of
rac-α-amino acids; and (2) by dynamic kinetic resolution of rac-α-halo esters derived from these chiral
auxiliaries.
2. Results and discussion
Firstly, we studied the formal deracemization of rac-α-amino acids using the chiral auxiliaries (R)- or
(S)-3 through the four-step reaction sequence shown in Scheme 1 which consists of: (a) the protection
of the amino group of rac-α-amino acids as the corresponding phthalimido derivative, as described;24,36
(b) the transformation of the acid function into the corresponding acyl chloride by reaction with thionyl
chloride; (c) the diastereoselective reaction of acyl chloride with (R)- or (S)-3; and (d) the controlled acid
hydrolysis of both the ester and phthalimido groups to give enantioenriched α-amino acid. The use of
the phthalimido protecting group has the advantage of its ease of introduction and removal.
Scheme 1. Formal deracemization of α-amino acids, rac-1a–d, by diastereoselective esterification of the protected racemic acyl
chloride with the chiral auxiliaries (R)- or (S)-3

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495
The key step of this reaction sequence, i.e. the diastereoselective reaction of the acyl chloride and (R)-
or (S)-3, was carried out in a similar manner to that developed by our group for the formal deracemization
of α-arylpropanoic2 and α-substituted-α-arylacetic acids,3 which consists of the rapid mixture of the acyl
chloride, the chiral auxiliary and triethylamine in the selected solvent (THF, in this case), usually at room
temperature, without preformation of the intermediate ketene, in contrast with the method described by
Larsen et al.,37 in which the ketene was previously formed. Under these reaction conditions, a ketene
may be formed in situ which could experience a diastereoselective addition of the enantiopure alcohol
to give the corresponding diastereoisomerically enriched ester 4. However, as we pointed out recently,5
a dynamic kinetic resolution of acylammonium intermediates on reaction with the enantiopure alcohol
could also explain the diastereoselectivity of these reactions.
Very recently, Calmes et al.24,25 described a similar reaction using D-pantolactone as the chiral
auxiliary, showing the enormous influence of the tertiary amine,38,39 solvent and temperature on the
diastereoselectivity of these reactions. They used two different procedures to carry out the diastereose-
lective ester formation. In one of them the ketene was previously formed at −78°C, then D-pantolactone
was added, performing the reaction at this temperature or at 0°C. Under these reaction conditions, yields
and diastereoselectivities were low, except for the phenylglycine derivative working at −78°C. In another
procedure the ketene was not previously generated: a solution of D-pantolactone and triethylamine was
added to the acyl chloride solution at the desired temperature. In this case, yields and diastereoselectivities
highly increased, except for the phenylglycine derivative. These results may be indicative of a different
reaction course or of the concurrence of different reaction mechanisms when the ketene is not previously
formed.
As can be seen from Table 1, under our standard conditions, and working at room temperature, yields
and diastereoselectivities were high for the derivatives of alanine 4a and phenylalanine 4c, the main
diastereoisomer being (αR,3S) or (αS,3R). The yield was also high for the derivative of valine 4b, the
main diastereoisomer also (αS,3R) but the diastereoselectivity was low (41% d.e.). In the case of the
phenylglycine derivative, (αR,3R)-4d (11% d.e.) was obtained. However, working at −78°C, (αR,3R)-4d
was obtained in high yield and diastereoselectivity. In this case, the main diastereoisomer was different
from that obtained in the other cases, as had also been observed by Calmes et al. when using D-
pantolactone.24 When the reaction of the acyl chloride derived from rac-2d and (R)-3 was carried out
at −78°C for 2.5 h as usual, and the reaction mixture was allowed to warm to room temperature, then
stopped at different times, the d.e. of the isolated (αR,3R)-4d showed lower values at longer reaction
times (32, 14 and 12% d.e., after 1, 3 and 18 h at r.t., respectively), demonstrating that this product
epimerizes under the reaction conditions. In an attempt to improve the d.e. of (αS,3R)-4b, the reaction
of the acyl chloride derived from rac-2b and (R)-3 was carried out at −78°C. However, no reaction was
observed at this temperature after 5 h. Moreover, the reaction of the acyl chloride derived from rac-2a
and (S)-3 using 4-(dimethylamino)pyridine (DMAP) instead of triethylamine in THF at −20°C led to
(αS,3S)-4a (22% d.e.), showing the enormous influence of the amine on the diastereoselectivity of this
reaction.25,38,39
Hydrolysis of the diastereoisomerically enriched esters 4a–c with simultaneous cleavage of the
protecting phthalimido group was performed in one step by treatment with a 10:1 mixture of 6 N HCl
and acetic acid,24 leading to the corresponding enantioenriched α-amino acid hydrochlorides 1a–c·HCl
with little or no epimerization. However, when this treatment was applied to ester (αR,3R)-4d, (R)-
1d·HCl was obtained in good yield but low enantiomeric excess (55% e.e.), showing that an important
degree 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. Curiously, a similar situation had not been previously observed
in the hydrolysis of the corresponding D-pantolactone ester.24 Other procedures to transform (αR,3R)-

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Table 1
Yields[a] and diastereomeric excesses (d.e.s)[a] of α-phthalimido esters 4 and yields, specific rotations
and approximate enantiomeric excesses (e.e.) of α-amino acid hydrochlorides 1·HC1[b]
[a]All these reactions were carried out by the general standard procedure described in Section 3.2 at the indicated
temperatures. Yields and d.e.s of α-phthalimido esters 4 correspond to crude material; values in parentheses
correspond to yields or d.e.s of the crystallized (4a) or chromatographed (4b–d) products used in the hydrolysis
step. The d.e.s of esters 4 were obtained by HPLC, assuming the relative areas of the peaks to be equal to their
relative molar ratios.
[b]Hydrolysis of the phthalimido esters 4 was carried out by reaction with a mixture of 6 N HCl (30 ml/mmol) and
AcOH (3 ml/mmol). The values for the specific rotations of standard α-amino acid hydrochlorides 1·HCl were
obtained from samples prepared from the corresponding commercially available α-amino acids and are given in
parentheses. The experimental values were obtained by using the same solvent and a concentration close to that used
for the standard sample. In the case of (R)-1a·HCl, the given value corresponds to its enantiomer.
[c]This reaction was carried out by the standard procedure, except for the use of DMAP instead of triethylamine
working at −20°C.
4d into (R)-1d·HCl gave still worse results. Attempted deprotection of the amino group by reaction
with hydrazine following described procedures,40 led to the recovery of a 1:1 mixture of (αR,3R)- and
(αS,3R)-4d. Basic hydrolysis of the ester function with lithium hydroperoxide, before the cleavage of
the protecting group, led mainly to benzoic acid (80% yield), while lithium hydroxide hydrolysis of the
ester function followed by 6 N HCl/AcOH hydrolysis of the phthalimido group, did not improve the
enantiomeric excess of (R)-1d·HCl.
Another approach to the preparation of enantioenriched α-amino acids (Scheme 2), was based on the
dynamic kinetic resolution26–35 of diastereoisomeric mixtures of α-bromoesters (αRS,3R)- or (αRS,3S)-
5a–d5 on reaction with dibenzylamine or potassium phthalimide. Firstly, we carried out a model study
using dibenzylamine as the nucleophile and mixtures of α-bromoesters (αRS,3RS)-/(αRS,3SR)-5a–d.

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497
The reaction of a stereoisomeric mixture of (αRS,3RS)-/(αRS,3SR)-5a with dibenzylamine was carried
out in different solvents (DMSO, acetonitrile and THF) using either NaI (20 equiv., for reactions carried
out in DMSO or acetonitrile) or tetrahexylammonium iodide (0.2 equiv., for reactions carried out in
THF) as the catalyst (Scheme 2 and Table 2, entry 1). The best diastereoselectivities were attained in
acetonitrile or in THF. However, the yield of the reaction carried out in acetonitrile was higher (96%).
Better diastereoselectivities but lower yields were obtained in the reaction of the stereoisomeric mixture
of (αRS,3RS)-/(αRS,3SR)-5d with dibenzylamine (Scheme 2 and Table 2, entry 4). The reaction of the
stereoisomeric mixtures of (αRS,3RS)-/(αRS,3SR)-5b and (αRS,3RS)-/(αRS,3SR)-5c with dibenzyla-
mine always gave the corresponding elimination products, (RS)-8b and (RS)-8c, no matter which solvent
was used (Scheme 3 and Table 2, entries 2 and 3).
Scheme 2. Dynamic kinetic resolution of α-bromo esters (αRS,3R)-5a and (αRS,3S)-5d on reaction with dibenzylamine
The best reaction conditions [acetonitrile, 60°C, NaI (20 equiv.)] found in the reaction of the stereoiso-
meric mixtures of (αRS,3RS)-/(αRS,3SR)-5a,d with dibenzylamine, were applied to the dynamic kinetic
Table 2
Reaction conditions, yields[a] and diastereomeric excesses (d.e.s)[a,b] of α-dibenzylamino esters 6 and
yields of esters 8 from the reaction of α-bromoesters 5 and dibenzylamine
[a]Yields and d.e.s of α-dibenzylamino esters 6 correspond to crude material; values in parentheses correspond to
yields or d.e.s of the crystallized [(αR,3S)-6d] or chromatographed [(αRS,3SR)-6d and (αS,3R)-6a] products used
in the hydrolysis step. The catalyst was always NaI (20 equiv.) for reactions carried out in DMSO or acetonitrile
and tetrahexylammonium iodide (0.2 equiv.) for reactions carried out in THF.
[b]The d.e.s were obtained by HPLC, assuming the relative areas of the peaks to be equal to their relative molar
ratios.
[c]The same products were obtained in any one of the three solvents (DMSO, THF or acetonitrile) used. Yields were
somewhat higher in acetonitrile.

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Scheme 3. Attempted dynamic kinetic resolution of α-bromo esters (αRS,3SR)-/(αRS,3SR)-5b,c on reaction with dibenzyl-
amine: formation of the elimination products (RS)-8b,c
resolution of (αRS,3R)-5a and (αRS,3S)-5d, thus obtaining (αS,3R)-6a and (αR,3S)-6d, respectively, in
good yields and d.e.s (Scheme 2 and Table 2, entries 5 and 6).
Hydrolysis of the α-dibenzylamino ester (αS,3R)-6a was carried out by reaction with lithium
hydroxide41 without noticeable epimerization to give the α-dibenzylamino acid (S)-7a in high yield. The
sign of the specific rotation of (S)-7a42 established its configuration and that of its precursor (αS,3R)-
6a. The e.e. of (S)-7a could be easily increased to >99% by crystallization from a mixture of ethyl
acetate/hexane. In the case of (αR,3S)-6d, lithium hydroxide hydrolysis gave an α-dibenzylamino acid,
(R)-7d, whose configuration and e.e. could not be established since, to the best of our knowledge, it had
not been previously described. However, partial epimerization during hydrolysis was evident since the
specific rotation of the crude product was lower than that of the crystallized product. A higher degree
of epimerization (lower specific rotation of the crude acid) was observed when hydrolysis was carried
out by heating (αR,3S)-6d with a mixture of 2 N HCl in AcOH at 120°C for 18 h. We were not able to
establish the e.e. of this product by chiral HPLC under different conditions. Hydrogenolysis of the benzyl
groups of (R)-7d in a mixture of ethanol and water in the ratio of 1:1, containing an excess of HCl, 10%
Pd–C as catalyst and working at 1 atm gave α-amino acid hydrochloride (R)-1d·HCl, whose specific
rotation let us assign its configuration and that of its precursors, (αR,3S)-6d and (R)-7d. Comparison of
the specific rotation of the obtained (R)-1d·HCl with that of a standard sample showed a 67% e.e., thus
confirming partial epimerization during ester hydrolysis which does not preclude possible epimerization
during hydrogenolysis.
When potassium phthalimide was used as the nucleophile in the dynamic kinetic resolution of
the model stereoisomeric mixture of esters (αRS,3RS)-/(αRS,3SR)-5a, diastereoselectivities were al-
ways low. The corresponding reaction of potassium phthalimide with the stereoisomeric mixtures of
(αRS,3RS)-/(αRS,3SR)-5b and (αRS,3RS)-/(αRS,3SR)-5c led mainly or exclusively to the elimination
products (RS)-8b and (RS)-8c (Scheme 3), respectively, while the reaction with the stereoisomeric
mixture of (αRS,3RS)-/(αRS,3SR)-5d, where elimination of hydrogen bromide cannot take place, led
in medium yield to alcohol (RS)-3 as the only isolated neutral product, showing that hydrolysis of the
starting ester had taken place, probably via an elimination process through a ketene intermediate, due to
the greater acidity in this case of the α-ester hydrogen atom, which is also benzylic.
After hydrolysis of esters 4 and 6, the chiral auxiliaries (R)- and (S)-3 were always recovered in high
yield without epimerization.
The new compounds (esters 4a–d, 6a,d as diastereoisomeric mixtures and ester 8b as a racemic
mixture) have been fully characterized through their spectroscopic data and elemental analysis. The 1H
and 13C NMR spectra of these compounds have been fully assigned taking into account our previous
work.1,2 The assignment of the signals of the diastereoisomeric mixtures could be easily carried out due

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
499
to their different ratio. The diastereoisomeric ratio of esters 4a–d and 6a,d, obtained by HPLC assuming
the relative areas of both diastereoisomers to be equal to their molar ratio, were in good agreement with
those obtained from the 1H NMR data, through the integration of the signals of the 3-H protons for 4a,d
and 6a,d, 4α-CH3 protons for 4c and CHN proton for 4b. Nearly 1:1 mixtures of esters 4a–d and 6a,d
were prepared by standard procedures (see Experimental, Sections 3.8 and 3.11) for the HPLC analysis
and to facilitate the assignment of the spectroscopic data, in cases where the diastereoisomeric excesses
of the diastereoselectively obtained products were high. Assignment of the configuration of the α-ester
stereocenter of esters 4a–d and 6a,d was carried out after their hydrolysis to the corresponding α-amino
acid hydrochlorides, 1a–d·HCl and 7a, of known configuration.
In conclusion, the chiral auxiliaries (R)- and (S)-3 have shown their value for the formal deracemization
of several α-amino acids, via the corresponding phthalimido derivatives. Enantiomeric excesses are
mainly dependent on the bulk of the alkyl substituent at the α-stereocenter: the e.e. was high for alanine
(R=Me), not so high for phenylalanine (R=benzyl), and low for valine (R=i-Pr). Phenylglycine is a special
case since the corresponding ester 4d epimerizes rapidly at the α-position under the reaction conditions at
room temperature and thus, working at −78°C was required. Moreover, diastereoselectivity was reversed
in this case, the main diastereoisomer having the (αR,3R) configuration, while for the rest of the studied
cases it was (αR,3S) or (αS,3R). In addition, the enantioselective synthesis of α-amino acids based on
the dynamic kinetic resolution of diastereoisomeric mixtures of α-bromoesters (αRS,3R)- or (αRS,3S)-5
derived from the chiral auxiliaries (R)- or (S)-3 by reaction with dibenzylamine, seems to have a limited
scope due to the competitive elimination of hydrogen bromide, which depends on the acidity of the β-
hydrogen atom (phenylalanine) and the steric crowding around the α-carbon atom (valine). The dynamic
kinetic resolution works well for the enantioselective preparation of alanine where the steric crowding at
the α-position is low and of phenylglycine, where HBr elimination cannot take place, although in this
case, an important degree of epimerization takes place during hydrolysis of the ester function. According
to the results of O’Meara et al.33 using (R)-pantolactone, this reaction must also work for other α-amino
acids having primary alkyl substituents at the α-stereocenter different from benzyl.
3. Experimental
Melting points were determined on an MFB 595010 M Gallenkamp melting point apparatus. 500
MHz 1H NMR spectra were performed on a Varian VXR 500 spectrometer and 300 MHz 1H and 75.4
1
MHz 13C NMR spectra on a Varian Gemini 300. Except where otherwise stated, H 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 related 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 nm and using column A: Chiralcel OD-H column (25×0.46 cm) containing
the chiral stationary phase cellulose tris-(3,5-dimethylphenylcarbamate) or column B: a (15×0.46 cm)
column, containing cellulose bis-(3,5-dichlorophenylcarbamate), covalently bonded to silica Nucleosil
(100 Å–5 µm), prepared by Prof. C. Minguillón’s research group. Condition A: column A, mixture of
hexane:isopropanol in the ratio of 75:25 as eluent, flow 0.60 ml/min. Condition B: column 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.

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
3.1. General procedure for the preparation of rac-α-phthalimido acyl chlorides
A solution of the rac-α-phthalimido acid (10 mmol), prepared by previously described procedures,24,36
in thionyl chloride (15 ml) was heated under reflux for 15 h and concentrated in vacuo to give rac-α-
phthalimido acyl chloride as a solid, which was used without further purification in the following step.
3.2. General procedure for the reaction of rac-α-phthalimidoacyl chlorides with (R)- or (S)-3
Solid rac-α-phthalimido acyl chloride (1.2 mmol) was added to a dried solution (4 Å molecular sieves,
1.5 g) of (R)- or (S)-3 (1.0 mmol) and triethylamine (2.5 mmol) in anhydrous THF (14 ml) under an
argon atmosphere, at room temperature and the mixture was magnetically stirred for 2.5 h. After adding
CH2Cl2 (20 ml), the mixture was washed with 1 N HCl (3×20 ml) and saturated aqueous solution of
NaHCO3 (3×20 ml), dried with anh. Na2SO4, and concentrated in vacuo to give the α-phthalimidoesters
4. Chemical yields refer to the total yield of both diastereoisomers.
3.3. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimidopropanoate, (αR,3S)-4a
Following the above general procedure, from (S)-3 (1.02 g, 5.00 mmol) and rac-2a (1.42 g, 6.00
mmol), (αR,3S)-4a (2.02 g, >99% yield, 96% d.e. by HPLC) was obtained as a solid. Crystallized from
a mixture of hexane (30 ml) and ethyl acetate (20 ml), (αR,3S)-4a (1.43 g, 71% yield) showed m.p.
187–189°C, [α]D20=−35.5 (c=1.02, CHCl3), >99% d.e. by H0PLC [Condition A: main diastereoisomer
0
(αR,3S)-4a, r.t. 26.4 min; (αS,3S)-4a, r.t. 30 min, k1 =3.9, k2 =4.6, α=1.2, Rs=1.8]. IR (KBr) ν: 1776,
1751 and 1709 (C_O st) cm−1. C23H22N2O5 (406.45): calcd C, 67.97%; H, 5.46%; N, 6.89%. Found:
1
C, 67.86%; H, 5.43%; N, 6.87%. H NMR δ: 1.18 (s, 3H, 4α-CH3), 1.34 (s, 3H, 4β-CH3), 1.77 (d,
J=7.5 Hz, 3H, CHCH3), 3.51 (d, J=9.5 Hz, 1H, 5α-H), 3.61 (d, J=9.5 Hz, 1H, 5β-H), 5.20 (q, J=7.5 Hz,
1H, CHN), 5.44 (s, 1H, 3-H), 7.15 (tm, J=7.0 Hz, 1H, Hpara N-phenyl), 7.36 (dd, J=8.5 Hz, J0=7.0 Hz,
2H, Hmeta N-phenyl), 7.59 (dm, J=8.5 Hz, 2H, Hortho N-phenyl), 7.72 [m, 2H, 5(6)-H phthalimido],
7.85 [m, 2H, 4(7)-H phthalimido]. 13C NMR δ: 15.4 (CH3, CHCH3), 21.1 (CH3, 4α-CH3), 24.8 (CH3,
4β-CH3), 37.7 (C, C4), 47.7 (CH, CHN), 57.7 (CH2, C5), 79.4 (CH, C3), 119.5 (CH, Cortho N-phenyl),
123.5 [CH, C4(7) phthalimido], 125.0 (CH, Cpara N-phenyl), 128.9 (CH, Cmeta N-phenyl), 131.9 [C,
C3a(7a) phthalimido], 134.1 [CH, C5(6) phthalimido], 138.9 (C, Cipso N-phenyl), 167.3 (C), 168.2 (C)
and 169.2 (C) [C1(3) phthalimido, COO and C2].
3.4. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimidopropanoate, (αS,3R)-4a
Following the above general procedure, from (R)-3 (0.50 g, 2.40 mmol) and rac-2a (0.70 g, 2.90
mmol), (αS,3R)-4a (0.98 g, 99% yield, 95% d.e. by HPLC) was obtained as a solid. Crystallized from
a mixture of hexane (25 ml) and ethyl acetate (12 ml), (αS,3R)-4a (0.75 g, 76% yield) showed m.p.
187–189°C, [α]D20=+34.9 (c=1.00, CHCl3), >99% d.e. by HPLC0[Condition A: main diastereoisomer
0
(αS,3R)-4a, r.t. 30.5 min; (αR,3R)-4a, r.t. 44.7 min, k1 =4.6, k2 =7.3, α=1.6, Rs=4.7]. C23H22N2O5
(406.45): calcd C, 67.97%; H, 5.46%; N, 6.89%. Found: C, 67.79%; H, 5.44%; N, 6.89%. The IR and
NMR spectra are coincidental with those of its enantiomer.

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
501
3.5. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimido-β-methylbutanoate, (αS,3R)-
4b
Following the above general procedure, from (R)-3 (0.50 g, 2.40 mmol) and rac-2b (0.78 g, 2.90
mmol), (αS,3R)-4b (1.05 g, 99% yield, 41% d.e. by HPLC) was obtained as an oil. After column
chromatography [alumina (25 g), CH2Cl2], (αS,3R)-4b (0.98 g, 92% yield) showed [α]D20=+3.2 (c=1.02,
CHCl3), 39% d.e. by HPLC [Condition A: main diastereoisomer (αS,3R)-4b, r.t. 23.8 min; (αR,3R)-4b,
0
0
r.t. 40.9 min, k1 =3.4, k2 =6.6, α=1.9, Rs=7.1]. IR (KBr) ν: 1755 and 1719 (C_O st) cm−1. C25H26N2O5
(434.51): calcd C, 69.11%; H, 6.04%; N, 6.45%. Found: C, 68.93%; H, 6.04%; N, 6.25%.
3.5.1. Spectroscopic data of (αS,3R)-4b obtained from the spectra of the mixture
1H NMR δ: 0.96 (d, J=7.0 Hz, 3H) and 1.22 (d, J=7.0 Hz, 3H) [CH(CH3)2], 1.17 (s, 3H, 4α-CH3),
1.32 (s, 3H, 4β-CH3), 2.85 [d heptet, J=8.5 Hz, J0=7.0 Hz, 1H, CH(CH3)2], 3.49 (d, J=9.5 Hz, 1H, 5α-H),
3.59 (d, J=9.5 Hz, 1H, 5β-H), 4.76 (d, J=8.5 Hz, 1H, CHN), 5.436 (s, 1H, 3-H), 7.13 (tm, J=7.5 Hz, 1H,
Hpara N-phenyl), 7.33 (dd, J=8.5 Hz, J=7.5 Hz, 2H, Hmeta N-phenyl), 7.56 (dm, J=8.5 Hz, 2H, Hortho
N-phenyl), 7.72 [m, 2H, 5(6)-H phthalimido], 7.86 [m, 2H, 4(7)-H phthalimido]. 13C NMR δ: 19.5
(CH3) and 21.1 (CH3) [CH(CH3)2], 21.2 (CH3, 4α-CH3), 24.7 (CH3, 4β-CH3), 28.4 [CH, CH(CH3)2],
37.6 (C, C4), 57.6 (CH2, C5), 58.0 (CH, CHN), 79.3 (CH, C3), 119.4 (CH, Cortho N-phenyl), 123.5
[CH, C4(7) phthalimido], 124.8 (CH, Cpara N-phenyl), 128.9 (CH, Cmeta N-phenyl), 131.7 [C, C3a(7a)
phthalimido], 134.1 [CH, C5(6) phthalimido], 138.9 (C, Cipso N-phenyl), 167.62 (C), 168.1 (C) and
168.3 (C) [C1(3) phthalimido, COO and C2].
3.6. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimido-β-phenylpropanoate,
(αS,3R)-4c
Following the above general procedure, from (R)-3 (1.02 g, 5.00 mmol), and rac-2c (1.90 g, 6.00
mmol), (αS,3R)-4c (2.40 g, quantitative yield, 82% d.e. by HPLC) was obtained as an oil. After column
chromatography [silica gel (80 g), CH2Cl2], (αS,3R)-4c (2.29 g, 95% yield) showed [α]D20=−65.1
(c=1.00, CHCl3), 78% d.e. by HPLC [Condition A: main diastereoisomer (αS,3R)-4c, r.t. 38.3 min;
0
0
(αR,3R)-4c, r.t. 64.7 min, k1 =6.1, k2 =11.0, α=1.8, Rs=5.6]. IR (KBr) ν: 1781, 1756 and 1716 (C_O
st) cm−1. C29H26N2O5 (482.55): calcd C, 72.18%; H, 5.43%; N, 5.81%. Found: C, 72.31%; H, 5.64%;
N, 5.52%.
3.6.1. Spectroscopic data of (αS,3R)-4c obtained from the spectra of the mixture
1H NMR δ: 1.20 (s, 3H, 4α-CH3), 1.36 (s, 3H, 4β-CH3), 3.53 (d, J=9.5 Hz, 1H, 5α-H), 3.616 (dd,
J=11.5 Hz, J0=14.0 Hz, 1H) and 3.68 (dd, J=5.0 Hz, J0=14.0 Hz, 1H) (Ar–CH2), 3.623 (d, J=9.5 Hz, 1H,
5β-H), 5.38 (dd, J=11.5 Hz, J0=5.0 Hz, 1H, CHN), 5.48 (s, 1H, 3-H), 7.14–7.18 (complex signal, 6H,
Hpara N-phenyl and Ar–H C-phenyl), 7.36 (dd, J=7.5 Hz, J0=8.5 Hz, 2H, Hmeta N-phenyl), 7.60 (dm,
J=8.5 Hz, 2H, Hortho N-phenyl), 7.65 [m, 2H, 5(6)-H phthalimido], 7.75 [m, 2H, 4(7)-H phthalimido].
13C NMR δ: 21.2 (CH3, 4α-CH3), 24.9 (CH3, 4β-CH3), 34.5 (CH2, Ar–CH2), 37.7 (C, C4), 53.4 (CH,
CHN), 57.7 (CH2, C5), 79.6 (CH, C3), 119.5 (CH, Cortho N-phenyl), 123.4 [CH, C4(7) phthalimido],
125.0 (CH, Cpara N-phenyl), 126.9 (CH, Cpara C-phenyl), 128.6 (CH), 128.8 (CH) and 129.0 (CH)
[Cortho C-phenyl, Cmeta N-phenyl and Cmeta C-phenyl), 131.5 [C, C3a(7a) phthalimido], 134.0 [CH,
C5(6) phthalimido], 136.3 (C, Cipso C-phenyl), 138.9 (C, Cipso N-phenyl), 167.3 (C), 168.1 (C), 168.2
(C) [C1(3) phthalimido, COO and C2].

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
3.7. (αR,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimido-α-phenylacetate,
(αR,3R)-4d
Following the above general procedure except for the temperature (−78°C), from (R)-3 (0.50 g, 2.40
mmol) and rac-2d (0.88 g, 2.91 mmol), (αR,3R)-4d (1.07 g, 94% yield, 86% d.e. by HPLC) was
obtained as an oil. After column chromatography [silica gel (50 g), CH2Cl2], (αR,3R)-4d (0.96 g, 84%
yield) showed [α]D20=+3.5 (c=0.57, CHCl3), >99% d.e. 0by HPLC [Condition A: main diastereoisomer
0
(αR,3R)-4d, r.t. 67.5 min; (αS,3R)-4d, r.t. 39.6 min, k1 =6.3, k2 =11.5, α=1.8, Rs=5.1]. IR (KBr) ν:
1760, 1772 and 1718 (C_O st) cm−1. C28H24N2O5·0.5H2O (477.53): calcd C, 70.43%; H, 5.28%; N,
5.87%. Found: C, 70.50%; H, 5.16%; N, 5.97%.
3.7.1. Spectroscopic data of (αR,3R)-4d obtained from the spectra of the mixture
1H NMR δ: 0.93 (s, 3H, 4α-CH3), 1.32 (s, 3H, 4β-CH3), 3.43 (d, J=9.5 Hz, 1H, 5α-H), 3.59 (d,
J=9.5 Hz, 1H, 5β-H), 5.54 (s, 1H, 3-H), 6.20 (s, 1H, CHN), 7.13 (tm, J=7.5 Hz, 1H, Hpara N-phenyl),
7.30–7.38 (complex signal, 5H, Hmeta N-phenyl and Hmeta and Hpara C-phenyl), 7.56 (dm, J=8.5 Hz,
2H, Hortho C-phenyl), 7.60 (dm, J=8.5 Hz, 2H, Hortho N-phenyl), 7.71 [m, 2H, 5(6)-H phthalimido],
7.85 [m, 2H, 4(7)-H phthalimido]. 13C NMR δ: 20.9 (CH3, 4α-CH3), 24.4 (CH3, 4β-CH3), 37.4 (C,
C4), 55.5 (CH, CHN), 57.5 (CH2, C5), 79.6 (CH, C3), 119.4 (CH, Cortho N-phenyl), 123.6 [CH, C4(7)
phthalimido], 124.9 (CH, Cpara N-phenyl), 128.6 (CH), 128.7 (CH), 128.9 (CH) 129.7 (CH) [Cortho C-
phenyl, Cpara C-phenyl, Cmeta N-phenyl and Cmeta C-phenyl), 131.7 [C, C3a(7a) phthalimido], 134.1
(C, Cipso C-phenyl), 134.3 [CH, C5(6) phthalimido], 138.9 (C, Cipso N-phenyl), 166.9 (C), 167.5 (C),
168.0 (C) [C1(3) phthalimido, COO and C2].
3.8. General procedure for the preparation of the diastereoisomeric mixtures of α-phthalimido esters 4
A mixture of rac-2 (1.0 mmol), dicyclohexylcarbodiimide (DCC, 1.0 mmol), DMAP (0.05 mmol) and
(R)- or (S)-3 (1.0 mmol) in CH2Cl2 (10 ml) was stirred at room temperature under an argon atmosphere
for 4 days. The mixture was filtered, the filtrate was washed with a saturated aqueous solution of citric
acid (3×8 ml) and saturated aqueous NaHCO3 (3×8 ml), dried with anh. Na2SO4, concentrated in vacuo
and the residue was submitted to column chromatography [silica gel (20 g), CH2Cl2], to give pure esters
4 as diastereoisomeric mixtures.
3.8.1. (αRS,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimidopropanoate, (αRS,3S)-4a
Following the above general procedure, from rac-2a (0.11 g, 0.5 mmol) and (S)-3 (0.10 g, 0.5 mmol),
(αRS,3S)-4a (0.20 g, 99% yield) was obtained. For the spectroscopic data of (αR,3S)-4a see Section 3.3.
3.8.1.1. Significant spectroscopic data of (αS,3S)-4a, obtained from the spectra of the mixture. 1H
NMR δ: 0.89 (s, 3H, 4α-CH3), 1.25 (s, 3H, 4β-CH3), 1.74 (d, J=7.5 Hz, 3H, CHCH3), 3.41 (d, J=9.5 Hz,
1H, 5α-H), 3.56 (d, J=9.5 Hz, 1H, 5β-H), 5.16 (q, J=7.5 Hz, 1H, CHN), 5.430 (s, 1H, 3-H). 13C NMR
δ: 15.3 (CH3, CHCH3), 20.8 (CH3, 4α-CH3), 24.4 (CH3, 4β-CH3), 37.3 (C, C4), 47.4 (CH, CHN), 57.5
(CH2, C5), 79.1 (CH, C3).
3.8.2. (αRS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimidopropanoate, (αRS,3R)-4a
Following the above general procedure, from rac-2a (0.11 g, 0.5 mmol) and (R)-3 (0.10 g, 0.5 mmol),
(αRS,3R)-4a (0.19 g, 95% yield) was obtained. The 1H and 13C NMR spectra are coincidental with those
of (αRS,3S)-4a.

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503
3.8.3. (αRS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimido-β-methylbutanoate,
(αRS,3R)-4b
Following the above general procedure, from rac-2b (0.12 g, 0.5 mmol) and (R)-3 (0.10 g, 0.5
mmol), (αRS,3R)-4b (0.22 g, 99% yield) was obtained. For the spectroscopic data of (αS,3R)-4b see
Section 3.5.1.
3.8.3.1. Significant spectroscopic data of (αR,3R)-4b, obtained from the spectra of the mixture. 1H
NMR δ: 0.85 (s, 3H, 4α-CH3), 0.95 (d, J=7.0 Hz, 3H) and 1.20 (d, J=7.0 Hz, 3H) [CH(CH3)2], 1.22 (s,
3H, 4β-CH3), 2.83 (d heptet, J=8.5 Hz, J=7.0 Hz, 1H [CH(CH3)2], 3.40 (d, J=9.5 Hz, 1H, 5α-H), 3.55
(d, J=9.5 Hz, 1H, 5β-H), 4.78 (d, J=8.5 Hz, 1H, CHN), 5.438 (s, 1H, 3-H). 13C NMR δ: 19.3 (CH3)
and 20.8 (CH3) [CH(CH3)2], 21.2 (CH3, 4α-CH3), 24.3 (CH3, 4β-CH3), 28.8 [CH, CH(CH3)2], 37.3 (C,
C4), 57.4 (CH2, C5), 58.0 (CH, CHN), 78.8 (CH, C3).
3.8.4. (αRS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimido-β-phenylpropanoate,
(αRS,3R)-4c
Following the above general procedure, from rac-2c (0.15 g, 0.5 mmol) and (R)-3 (0.10 g, 0.5
mmol), (αRS,3R)-4c (0.21 g, 88% yield) was obtained. For the spectroscopic data of (αS,3R)-4c see
Section 3.6.1.
3.8.4.1. Significant spectroscopic data of (αR,3R)-4c, obtained from the spectra of the mixture. 1H
NMR δ: 0.89 (s, 3H, 4α-CH3), 1.27 (s, 3H, 4β-CH3), 3.42 (d, J=9.5 Hz, 1H, 5α-H), 3.57 (d, J=9.5 Hz,
1H, 5β-H), 3.58 (dd, J=14.0 Hz, J0=11.5 Hz, 1H), 3.67 (dd, J=14.0 Hz, J0=5.5 Hz, 1H) (Ar–CH2), 5.34
(dd, J=11.0 Hz, J0=5.5 Hz, 1H, CHN), 5.46 (s, 1H, 3-H). 13C NMR δ: 20.7 (CH3, 4α-CH3), 24.4 (CH3,
4β-CH3), 34.8 (CH2, Ar–CH2), 37.2 (C, C4), 53.0 (CH, CHN), 57.4 (CH2, C5), 79.3 (CH, C3).
3.8.5. (αRS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-phthalimido-α-phenylacetate,
(αRS,3R)-4d
Following the above general procedure, from rac-2d (0.14 g, 0.5 mmol) and (R)-3 (0.10 g, 0.5
mmol), (αRS,3R)-4d (0.23 g, 98% yield) was obtained. For the spectroscopic data of (αR,3R)-4d see
Section 3.7.1.
3.8.5.1. Significant spectroscopic data of (αS,3R)-4d, obtained from the spectra of the mixture. 1H
NMR δ: 0.88 (s, 3H, 4α-CH3), 1.33 (s, 3H, 4β-CH3), 3.42 (d, J=9.5 Hz, 1H, 5α-H), 3.57 (d, J=9.5
Hz, 1H, 5β-H), 5.50 (s, 1H, 3-H), 6.24 (s, 1H, CHN). 13C NMR δ: 20.8 (CH3, 4α-CH3), 24.2 (CH3,
4β-CH3), 37.3 (C, C4), 56.1 (CH, CHN), 57.4 (CH2, C5), 79.6 (CH, C3).
3.9. General procedure for the hydrolysis of α-phthalimidoesters 4
A mixture of the α-phthalimidoester 4 (1.0 mmol), acetic acid (3.0 ml), and 6 N HCl (30 ml) was
heated at 120°C (bath temperature) till completion of the hydrolysis (4 h), following the reaction by thin
layer chromatography (TLC). The mixture was allowed to cool to room temperature and the volatile
product distilled off at reduced pressure. Water (30 ml) was added to the residue and extracted with
ethyl acetate (3×30 ml). The aqueous layer was concentrated in vacuo to give (R)- or (S)-1·HCl. The
combined organic layers were dried with anh. Na2SO4 and concentrated in vacuo. The residue was taken
up in CH2Cl2 (10 ml) and filtered. The filtrate was concentrated in vacuo to give (R)- or (S)-3.

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
3.9.1. (S)-α-Aminopropanoic acid hydrochloride (L-alanine hydrochloride), (S)-1a·HCl
From (αS,3R)-4a (0.60 g, 1.48 mmol, >99% d.e. by HPLC), (S)-1a·HCl (0.18 g, 95% yield) was
obtained as a solid, m.p. 207–209°C (dec.), [α]D20=+8.03 (c=1.01, H2O), approx. 98% o.p. A standard
sample of (S)-1a·HCl, obtained from L-alanine (Fluka), showed [α]D20=+8.2 (c=1.02, H2O).
3.9.2. (R)-α-Aminopropanoic acid hydrochloride (D-alanine hydrochloride), (R)-1a·HCl
From (αR,3S)-4a (1.00 g, 2.46 mmol, >99% d.e. by HPLC), (R)-1a·HCl (0.29 g, 94% yield) was
obtained as a solid, m.p. 206–208°C (dec.), [α]D20=−7.92 (c=1.00, H2O), approx. 97% o.p.
3.9.3. (S)-α-Amino-β-methylbutanoic acid hydrochloride (L-valine hydrochloride), (S)-1b·HCl
From (αS,3R)-4b (0.37 g, 0.85 mmol, 39% d.e. by HPLC), (S)-1b·HCl (0.12 g, 92% yield) was
obtained as a solid, m.p. 228–230°C (dec.), [α]D20=+5.75 (c=1.04, H2O), approx. 40% o.p. A standard
sample of (S)-1b·HCl, obtained from L-valine (Fluka), showed [α]D20=+14.5 (c=1.01, H2O).
3.9.4. (S)-α-Amino-β-phenylpropanoic acid hydrochloride (L-phenylalanine hydrochloride),
(S)-1c·HCl
From (αS,3R)-4c (0.85 g, 1.76 mmol, 78% d.e. by HPLC), (S)-1c·HCl (0.33 g, 94% yield) was
obtained as a solid, m.p. 229–231°C (dec.), [α]D20=−11.4 (c=0.98, H2O), approx. 77% o.p. A standard
sample of (S)-1c·HCl, obtained from L-phenylalanine (Sigma), showed [α]D20=−14.8 (c=1.01, H2O).
3.9.5. (R)-α-Amino-α-phenylacetic acid hydrochloride (D-phenylglycine hydrochloride), (R)-1d·HCl
From (αR,3R)-4d (0.70 g, 1.50 mmol, >99% d.e. by HPLC), (R)-1d·HCl (0.27 g, 98% yield) was
obtained as a solid, m.p. 254–256°C (dec.), [α]D20=−61.1 (c=1.15, H2O), approx. 54% o.p. A standard
sample of (R)-1d·HCl, obtained from D-phenylglycine (Fluka), showed [α]D20=−112.3 (c=1.01, H2O).
3.10. General procedure for the reaction of α-bromoesters 5 with dibenzylamine
A mixture of α-bromoester 55 (1.0 mmol), dibenzylamine (3.0 mmol) and sodium iodide (20 mmol)
in anh. acetonitrile (60 ml) was heated under reflux in an argon atmosphere for 48 h. The mixture was
concentrated in vacuo, CH2Cl2 (100 ml) was added to the residue and the solution was washed with
5% aqueous citric acid solution (3×30 ml) and saturated aqueous NaHCO3 solution (3×30 ml). The
organic layer was dried with anh. Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography [alumina, CH2Cl2] or by crystallization.
3.10.1. (αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(N,N-dibenzylamino)propanoate,
(αS,3R)-6a
Following the above general procedure, from (αRS,3R)-5a (1.70 g, 5.00 mmol), (αS,3R)-6a (2.79 g,
82% d.e. by HPLC) was obtained as a crude product which after purification by column chromatography
[alumina (50 g), CH2Cl2] gave analytical grade oily (αS,3R)-6a [1.77 g, 78% yield, 81% d.e. by
0
HPLC, Condition A: main diastereoisomer (αS,3R)-6a, r.t. 13.1 min; (αR,3R)-6a, r.t. 21.1 min, k1 =1.4,
k2 =2.9, α=2.1, Rs=7.3]. [α]D20=−54.7 (c=1.07, CHCl3). IR (NaCl) ν: 1737 and 1716 (C_O st) cm−1.
0
C29H32N2O3 (456.60): calcd C, 76.28%; H, 7.07%; N, 6.14%. Found: C, 76.21%; H, 7.13%; N, 6.07%.
1
Main diastereoisomer: H NMR δ: 1.16 (s, 3H, 4α-CH3), 1.29 (s, 3H, 4β-CH3), 1.39 (d, J=7.0 Hz,
3H, CH3CH), 3.55 (d, J=9.5 Hz, 1H, 5α-H), 3.63 (d, J=9.5 Hz, 1H, 5β-H), 3.65 (q, J=7.0 Hz, 1H, CHN),
3.79 (d, J=14.0 Hz, 2H) and 3.89 (d, J=14.0 Hz, 2H) (2CH2 N-benzyl), 5.50 (s, 1H, 3-H), 7.17 (tm,
J=7.5 Hz, 1H, Hpara N-phenyl), 7.20 (tm, J=7.5 Hz, 2H, Hpara N-benzyl), 7.28 (tm, J=7.5 Hz, 4H,

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
505
Hmeta N-benzyl), 7.38 (dd, J=7.5 Hz, J0=8.5 Hz, 2H, Hmeta N-phenyl), 7.41 (broad d, J=7.5 Hz, 4H,
Hortho N-benzyl), 7.64 (dm, J=8.5 Hz, 2H, Hortho N-phenyl). 13C NMR δ: 15.7 (CH3, CH3CH), 21.4
(CH3, 4α-CH3), 24.7 (CH3, 4β-CH3), 37.2 (C, C4), 54.1 (CH2, N-benzyl), 55.9 (CH, CHN), 57.7 (CH2,
C5), 78.1 (CH, C3), 119.5 (CH, Cortho N-phenyl), 124.9 (CH, Cpara N-phenyl), 126.8 (CH, Cpara
N-benzyl), 128.1 (CH, Cortho N-benzyl), 128.7 (CH, Cmeta N-benzyl), 129.0 (CH, Cmeta N-phenyl),
139.1 (C, Cipso N-phenyl), 139.9 (C, Cipso N-benzyl), 168.8 (C, C2), 172.7 (C, COO).
3.10.2. (RS)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl β-methyl-α-butenoate, (RS)-8b
Following the above general procedure, from a mixture of (αRS,3RS)-/(αRS,3SR)-5b (0.18 g, 0.49
mmol) and after purification by column chromatography [silica gel (15 g), CH2Cl2], (RS)-8b (0.16 g,
90% yield) was isolated as a solid, m.p. 71–73°C (ethyl acetate/hexane). IR (NaCl) ν: 1713 (C_O st),
1648 (C_C st) cm−1. C17H21NO3 (287.37): calcd C, 71.05%; H, 7.37%; N, 4.87%. Found: C, 70.89%;
1
H, 7.34%; N, 4.87%. H NMR (300 MHz) δ: 1.13 (s, 3H, 4α-CH3), 1.31 (s, 3H, 4β-CH3), 1.94 (d,
J=1.3 Hz, 3H, CH_C–CH3-anti), 2.22 (d, J=1.2 Hz, 3H, CH_C–CH3-syn), 3.51 (d, J=9.5 Hz, 1H,
5α-H), 3.62 (d, J=9.5 Hz, 1H, 5β-H), 5.45 (s, 1H, 3-H), 5.85 (m, 1H, α-H), 7.16 (tm, J=7.5 Hz, 1H,
Hpara N-phenyl), 7.38 (dd, J=8.5 Hz, J0=7.5 Hz, 2H, Hmeta N-phenyl), 7.64 (dm, J=8.5 Hz, 2H, Hortho
N-phenyl). 13C NMR δ: 20.5 (CH3, CH_CCH3-syn), 21.2 (CH3, 4α-CH3), 24.9 (CH3, 4β-CH3), 27.5
(CH3, CH_CCH3-anti), 37.4 (C, C4), 57.7 (CH2, C5), 77.3 (CH, C3), 115.1 (CH, Cα) 119.4 (CH, Cortho
N-phenyl), 124.7 (CH, Cpara N-phenyl), 128.9 (CH, Cmeta N-phenyl), 139.1 (C, Cipso N-phenyl), 158.9
(C, Cβ), 165.5 (C, COO), 169.4 (C, C2).
3.10.3. (RS)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl cinnamate, (RS)-8c
Following the above general procedure, from (αRS,3RS)-/(αRS,3SR)-5c (0.42 g, 1.01 mmol), and after
purification by column chromatography [silica gel (20 g), CH2Cl2], (RS)-8c (0.34 g, >99% yield) was
isolated as a solid.5
3.10.4. (αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(N,N-dibenzylamino)-α-phenylacetate,
(αR,3S)-6d
Following the above general procedure, from (αRS,3S)-5d (2.40 g, 5.97 mmol), (αS,3R)-6d (3.89 g,
>99% d.e. by HPLC) was obtained as a crude product which, after purification by crystallization [ethyl
acetate (70 ml)], gave analytical grade (αR,3S)-6d [2.08 g, 67% yield, >99% d.e. by HPLC, Condition B:
0
0
main diastereoisomer (αR,3S)-6d, r.t. 25.4 min; (αS,3S)-6d, 35.9 min, k1 =1.5, k2 =2.7, α=1.8, Rs=7.8],
m.p. 181–183°C (ethyl acetate), [α]D20=−13.4 (c=1.19, CHCl3). IR (KBr) ν: 1738 and 1708 (C_O st)
cm−1. C34H34N2O3 (518.68): calcd. C, 78.73%; H, 6.61%; N, 5.40%. Found: C, 79.01%; H, 6.70%; N,
5.44%. 1H NMR δ: 0.99 (s, 3H, 4α-CH3), 1.28 (s, 3H, 4β-CH3), 3.50 (d, J=9.5 Hz, 1H, 5α-H), 3.63 (d,
J=9.5 Hz, 1H, 5β-H), 3.83 (s, 4H, 2CH2 N-benzyl), 4.75 (s, 1H, CHN), 5.62 (s, 1H, 3-H), 7.17 (tm, J=7.5
Hz, 1H, Hpara N-phenyl), 7.20 (tm, J=7.0 Hz, 2H, Hpara N-benzyl), 7.26–7.44 (complex signal, 15H,
Hortho N-benzyl, Hortho C-phenyl, Hpara C-phenyl, Hmeta N-phenyl, Hmeta N-benzyl and Hmeta
C-phenyl), 7.64 (dm, J=8.5 Hz, 2H, Hortho N-phenyl). 13C NMR δ: 21.2 (CH3, 4α-CH3), 24.7 (CH3,
4β-CH3), 37.2 (C, C4), 54.0 (CH2, N-benzyl), 57.7 (CH2, C5), 65.5 (CH, CHN), 78.2 (CH, C3), 119.5
(CH, Cortho N-phenyl), 124.9 (CH, Cpara N-phenyl), 126.9 (CH, Cpara N-benzyl), 127.8 (CH, Cpara
C-phenyl), 128.2 (CH, Cortho N-benzyl), 128.3 (CH), 128.7 (CH) and 128.97 (CH) (Cortho C-phenyl,
Cmeta C-phenyl, Cmeta N-phenyl), 129.01 (CH, Cmeta N-benzyl), 136.6 (C, Cipso C-phenyl), 139.0 (C,
Cipso N-phenyl), 139.4 (C, Cipso N-benzyl), 168.6 (C, C2), 171.1 (C, COO).

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
3.11. Procedure for the preparation of diastereoisomeric mixtures of α-(N,N-dibenzylamino) esters
(αRS,3R)-6a and (αRS,3S)-6d
Diastereoisomeric mixtures of α-(N,N-dibenzylamino) esters, (αRS,3R)-6a and (αRS,3S)-6d, in a
ratio close to 1:1, were prepared from mixtures of α-bromo esters (αRS,3R)-5a or (αRS,3S)-5d by a
variation of the general procedure given in Section 3.10, in which sodium iodide was not added, toluene
was used as the solvent, and the reaction was carried out at the reflux temperature.
3.11.1. (αRS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(N,N-dibenzylamino)propanoate,
(αRS,3R)-6a
From a mixture of (αRS,3R)-5a (340 mg, 1.0 mmol), (αRS,3R)-6a (410 mg, 91% yield) was obtained.
The spectroscopic data of (αS,3R)-6a were described in Section 3.10.1.
3.11.1.1. Significant spectroscopic data of (αR,3R)-6a, obtained from the spectra of the mixture. 1H
NMR δ: 1.24 (s, 3H, 4α-CH3), 1.34 (s, 3H, 4β-CH3), 1.43 (d, J=7.5 Hz, 3H, CH3CH), 3.53 (d, J=9.5
Hz, 1H, 5α-H), 3.629 (d, J=9.5 Hz, 1H, 5β-H), 3.68 (q, J=7.0 Hz, 1H, CHN), 3.74 (d, J=14.0 Hz, 2H)
and 3.91 (d, J=14.0 Hz, 2H) (2CH2 N-benzyl), 5.47 (s, 1H, 3-H). 13C NMR δ: 15.4 (CH3, CH3CH),
21.5 (CH3, 4α-CH3), 24.8 (CH3, 4β-CH3), 37.2 (C, C4), 54.4 (CH2, N-benzyl), 56.4 (CH, CHN), 57.74
(CH2, C5), 78.1 (CH, C3).
3.11.2. (αRS,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-(N,N-dibenzylamino)-α-phenyl-
acetate, (αRS,3S)-6d
From a mixture of (αRS,3S)-5d (300 mg, 0.8 mmol), (αRS,3S)-6d (360 mg, 92% yield) was obtained.
The spectroscopic data of (αR,3S)-6d were described in Section 3.10.4.
3.11.2.1. Significant spectroscopic data of (αS,3S)-6d, obtained from the spectra of the mixture. 1H
NMR δ: 1.09 (s, 3H, 4α-CH3), 1.39 (s, 3H, 4β-CH3), 3.51 (d, J=9.5 Hz, 1H, 5α-H), 3.65 (d, J=9.5 Hz,
1H, 5β-H), 3.80 (d, J=14.5 Hz, 2H) and 3.90 (d, J=14.5 Hz, 2H) (2CH2 N-benzyl), 4.81 (s, 1H, α-H),
5.64 (s, 1H, 3-H). 13C NMR δ: 21.4 (CH3, 4α-CH3), 24.8 (CH3, 4β-CH3), 37.2 (C, C4), 54.2 (CH2,
N-benzyl), 57.7 (CH2, C5), 65.7 (CH, Cα), 78.3 (CH, C3).
3.12. General procedure for the reaction of α-bromo esters 5 with potassium phthalimide
A mixture of α-bromo ester 5 (1.0 mmol), potassium phthalimide (1.0 mmol) and sodium iodide (20
mmol) in acetonitrile (80 ml) was heated at 60°C in an argon atmosphere for 48 h. The mixture was
concentrated in vacuo, CH2Cl2 (100 ml) was added to the residue and the solution was then washed
with H2O (3×30 ml). The organic layer was dried with anh. Na2SO4 and concentrated in vacuo and the
residue purified by column chromatography [silica gel (20 g), CH2Cl2]. A similar procedure was used for
the reactions carried out in DMSO as solvent. For the reactions carried out in THF, tetrahexylammonium
iodide (0.2 mmol) was used as a catalyst instead of sodium iodide.
3.13. General procedure for the hydrolysis of α-(N,N-dibenzylamino) esters 6
Solid LiOH·H2O (1.5 mmol) was added to a solution of α-(N,N-dibenzylamino) ester 6 (1.0 mmol)
in a mixture of THF (20 ml) and water (5 ml), and the mixture magnetically stirred at room temperature

P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
507
until completion of the hydrolysis (3 days), following the reaction by thin layer chromatography (TLC).
The mixture was concentrated in vacuo, 0.5 N NaOH (30 ml) was added to the residue and then the
mixture was extracted with CH2Cl2 (2×10 ml).
Work-up A [for (αS,3R)-6a]: the combined organic layers were dried with anh. Na2SO4 and concen-
trated in vacuo to give (R)-3. The aqueous layer was made acidic with acetic acid and extracted with
CH2Cl2 (5×20 ml). The combined organic layers were dried with anh. Na2SO4, concentrated in vacuo
and dried for 8 h at 60°C/1 torr to give (S)-7a.
Work-up B [for (αR,3S)-6d]: the combined organic layers were dried with anh. Na2SO4 and concen-
trated in vacuo to give a mixture of (S)-3 and (R)-7d. Column chromatography [alumina (7 g)] of this
mixture gave (S)-3 on elution with a mixture of CH2Cl2/methanol in the ratio of 99.5:0.5, and (R)-7d on
elution with a mixture of CH2Cl2:methanol:acetic acid in the ratio of 99:0.5:0.5.
3.13.1. (S)-α-(N,N-Dibenzylamino)propanoic acid, (S)-7a
From (αS,3R)-6a (603 mg, 1.30 mmol, 81% d.e.), following the above reaction procedure and work-
up A, (S)-7a [334 mg, 94% yield, [α]D20=−34.5 (c=2.01, methanol)] was obtained as a solid, which
was crystallized from a mixture of ethyl acetate (2 ml) and hexane (15 ml) to give (S)-7a (207 mg, 59%
yield), m.p. 84–86°C, [α]D20=−44.9 (c=2.00, methanol) [described in Velluz et al.42 [α]D20=−45 (c=2.00
methanol)] >99% o.p. IR (KBr) ν: 3500–2000 (O–H st), 1719 and 1617 (C_O st) cm−1. 1H NMR (300
MHz) δ: 1.40 (d, J=7.1 Hz, 3H, CH3CH), 3.58 (q, J=7.1 Hz, 1H, CHN), 3.67 (d, J=13.5 Hz, 2H) and 3.88
(d, J=13.5 Hz, 2H) (2CH2 N-benzyl), 7.34 (complex signal, 10H, Ar–H N-benzyl), 9.1–9.8 (broad s, 1H,
+NH). 13C NMR δ: 11.2 (CH3, CH3CH), 54.5 (CH2, N-benzyl), 57.5 (CH, CHN), 127.8 (CH, Cpara N-
benzyl), 128.6 (CH, Cortho N-benzyl), 129.0 (CH, Cmeta N-benzyl), 137.0 (C, Cipso N-benzyl), 175.3
(C, COO).
3.13.2. (R)-α-(N,N-Dibenzylamino)-α-phenylacetic acid, (R)-7d
From (αR,3S)-6d (518 mg, 1.00 mmol, >99% d.e.), following the above general procedure and work-
up B, (R)-7d [309 mg, 93% yield, [α]D20=−49.2 (c=0.22, CHCl3)] was obtained as a solid, which was
crystallized from a mixture of ethyl acetate (2.5 ml) and hexane (17 ml) to give (R)-7d (234 mg, 71%
yield), m.p. 78–79.5°C, [α]D20=−56.6 (c=0.20, CHCl3). The e.e. of this product could not be established
by chiral HPLC using columns A and B, under several different conditions. IR (KBr) ν: 3500–2200 (O–H
st), 1713 and 1622 (C_O st) cm−1. C22H21NO2 (331.43): calcd. C, 79.73%; H, 6.39%; N, 4.23%. Found:
1
C, 79.73%; H, 6.48%; N, 4.34%. H NMR (300 MHz) δ: 3.60 (d, J=13.7 Hz, 2H) and 3.92 (d, J=13.7
Hz, 2H) (2 CH2 N-benzyl), 4.71 (s, 1H, CHN), 7.34 (complex signal, 15H, Ar–H), 9.0–10.0 (broad s,
+
1H, NH). 13C NMR δ: 54.5 (CH2, N-benzyl), 66.8 (CH, CHN), 127.7 (CH, Cortho C-phenyl), 128.4
(CH, Cpara C-phenyl), 128.5 (CH, Cpara N-benzyl), 128.6 (CH, Cortho N-benzyl), 129.0 (CH, Cmeta
N-benzyl), 129.7 (CH, Cmeta C-phenyl), 133.8 (C, Cipso C-phenyl), 137.3 (C, Cipso N-benzyl), 174.6
(C, COO).
3.14. (R)-α-Amino-α-phenylacetic acid hydrochloride (D-phenylglycine hydrochloride), (R)-1d·HCl
A mixture of (R)-7d (140 mg, 0.42 mmol), conc. HCl (0.2 ml), 10% Pd–C (0.5 g) in a mixture of
ethanol/water in the ratio of 1:1 (20 ml) was hydrogenated at 1 atm for 1 h. The mixture was filtered and
the filtrate was concentrated in vacuo to give (R)-1d·HCl (77 mg, 98% yield), [α]D20=−75.5 (c=1.07,
H2O), o.p. 67%.

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P. Camps et al. / Tetrahedron: Asymmetry 10 (1999) 493–509
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 (CID) of Barcelona, for carrying out the elemental analyses. We also thank
Professor Dr. Cristina Minguillón for her advice and HPLC facilities for the analysis of compound 7d.
-0.5cm
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