Efficient resolution of rac-2-cyano-2-methyl-3-phenylpropanoic acid. An appropriate starting material for the enantioconvergent synthesis of (S)-α-methylphenylalanine on a large laboratory scale

Article abstract of DOI:10.1016/S0957-4166(03)00450-6

A large laboratory scale synthesis of (S)-α-methylphenylalanine from benzaldehyde and methyl cyanoacetate has been developed. The synthesis is based on the following sequence: (i) preparation of racemic 2-cyano-2-methyl-3-phenylpropanoic acid, (ii) resolu

Full text of DOI:10.1016/S0957-4166(03)00450-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2201–2207
Efficient resolution of rac-2-cyano-2-methyl-3-phenylpropanoic
acid. An appropriate starting material for the enantioconvergent
synthesis of (S)-a-methylphenylalanine on a large laboratory
scale
Ramo´n Badorrey, Carlos Cativiela, Mar´ıa D. D´ıaz-de-Villegas* and Jose´ A. Ga´lvez*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias-Instituto de Ciencia de Materiales de Arago´n,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 6 May 2003; accepted 9 June 2003
Abstract—A large laboratory scale synthesis of (S)-a-methylphenylalanine from benzaldehyde and methyl cyanoacetate has been
developed. The synthesis is based on the following sequence: (i) preparation of racemic 2-cyano-2-methyl-3-phenylpropanoic acid,
(ii) resolution of the enantiomers by crystallisation using norephedrine, and (iii) development of an efficient enantioconvergent
synthesis of (S)-a-methylphenylalanine from enantiopure (S)- and (R)-2-cyano-2-methyl-3-phenylpropanoic acid. The simplicity
of the experimental procedures, which avoid low temperature reactions, the need for an inert atmosphere and column
chromatography, combined with the use of inexpensive and readily available reagents make this method synthetically very
attractive.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
commercial antihypertensive (Aldomet™).6 Moreover,
these substances have been used as building blocks for
the synthesis of more elaborate compounds.7 An illus-
trative example is the hydantoin BIRT-377,8 derived
from a-methyl-p-bromophenylalanine, which has
recently been identified as a potent inhibitor of the
interaction between intercellular adhesion molecule-1
and lymphocyte function-associated antigen-1 and has
potential application for the treatment of inflammatory
and immune disorders.
Optically active a,a-disubstituted a-amino acids have
generated ever-increasing interest in biology and phar-
macology as well as in chemistry. Some of these com-
pounds are naturally occurring or are structural
components of natural products that have interesting
properties, e.g. as antibiotics.1 The presence of the
tetrasubstituted stereogenic carbon atom means that
the incorporation of these compounds into peptides
leads to restricted conformational flexibility,2 to stabili-
sation of defined secondary structures in small pep-
tides,3 and to higher resistance towards both enzymatic
and chemical hydrolysis.4 These compounds can there-
fore be used for the investigation of 3D structure–
bioactivity relationships and in the development of new
pharmaceutical agents with prolonged action and/or
more selective properties. Some enantiopure a,a-disub-
stituted a-amino acids have also become of significant
medicinal and biochemical interest as they are powerful
enzyme inhibitors.5 For example, (S)-a-methyl-DOPA,
an inhibitor of DOPA decarboxylase, is an important
The extensive use of chiral a,a-disubstituted a-amino
acids is only limited by their availability in enantiopure
form and in large quantities. Various methods have
been devised to obtain chiral a,a-disubstituted a-amino
acids in enantiomerically pure form9 and, among these,
the most noteworthy are asymmetric synthesis, which is
mainly based on stereoselective synthesis using chiral
auxiliaries, and enzymatic resolution of racemic
compounds.
The most successful diastereoselective syntheses involve
the alkylation of chiral, nonracemic enolates that are
commonly derived from proteinogenic amino acids.9a
This reaction normally requires the use of very strong
and sensitive bases and it is therefore usually carried
* Corresponding author. Tel.: +34-976-762274; fax: +34-976-761210;
e-mail: loladiaz@unizar.es; jagl@unizar.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00450-6

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R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2201–2207
out under anhydrous conditions and at low tempera-
ture. These reaction conditions do not allow this
methodology to be applied to economical and/or large-
scale synthesis. Recently the use of iminic substrates has
allowed diastereoselective alkylation under mild
conditions10 and application of asymmetric phase trans-
fer catalysis and other enantioselective processes to the
synthesis of a,a-dialkylamino acids in enantiomerically
pure form.11
Figure 1. Complementary synthesis of (R)- and (S)-a,a-
dialkylcyanoacetates.
There are also several enzymatic processes and, of
these, the chemo-enzymatic synthesis developed by
DSM Research,12 which involves a combination of
Strecker synthesis (to gain access to
a racemic
aminoamide) and kinetic resolution (using a broadly
specific amino acid amidase), is the most general
approach to the synthesis of a,a-disubstituted a-amino
acids in enantiomerically pure form. The only draw-
back associated with this procedure is that the maxi-
mum theoretical yield is 50%, which is dependent on
the enzyme specificity, as the undesired enantiomer can
not be racemised.
Figure 2. Enantiodivergent synthesis of (R)- and (S)-a,a-
dialkylamino acids from an enantiomerically pure a,a-dialkyl-
cyanoacetate.
widely used in industry and furnishes a large propor-
tion of those optically active drugs that are not derived
from natural products.15 The maximum theoretical
yield of 50% for each enantiomer sets a low ceiling on
the productivity of such processes. For this reason, easy
racemisation of the undesired isomer is a prerequisite
for the economic success of this technology. When
racemisation is not possible, as is the case in com-
pounds with a quaternary stereogenic centre, the devel-
opment of enantioconvergent processes is an attractive
alternative. In an enantioconvergent synthesis, an enan-
tiomerically pure product is formed in 100% theoretical
yield from a racemate because each enantiomer reacts
via an independent and complementary stereochemical
pathway.
As a part of our research programme aimed at estab-
lishing the conformational preferences of acyclic a,a-
disubstituted a-amino acids,13 we needed to prepare
several of these amino acids in enantiomerically pure
form and on a multi-gram scale. In an attempt to
achieve this goal we became interested in developing a
new, practical and efficient synthetic route. In recent
years we have described the preparation of several
a,a-disubstituted a-amino acids using
a synthetic
methodology based on the diastereoselective alkylation
of a-cyanoesters derived from (1S,2R,4R)-10-dicyclo-
hexylsulfamoylisoborneol.14 The most attractive fea-
tures of our methodology are:
1) It allows the synthesis of new enantiomerically
pure a,a-dialkylamino acids combining two side
chains of proteinogenic or non-proteinogenic amino
acids at the same alpha-carbon.
With this idea in mind, we envisaged a new synthetic
approach for the preparation of enantiomerically pure
a,a-disubstituted-a-amino acids on a large laboratory
scale from inexpensive aldehydes and methyl cyanoac-
etate. This new approach involves the synthesis of a
specific rac-a,a-disubstituted a-cyanoacetic acid, its res-
olution and the development of an efficient enantiocon-
vergent synthesis from the two isolated enantiomers
(Fig. 3). In order to demonstrate the feasibility of the
proposed methodology, we decided to apply it to the
synthesis of (S)-a-methylphenylalanine. This compound
2) Both enantiomers of the same amino acid can be
obtained in enantiomerically pure form using differ-
ent synthetic variants. (i) In the alkylation step, chiral
2-alkylcyanoacetate and alkyl halide can be appropri-
ately combined to provide the same a,a-dialkyl-
cyanoacetate with the (R)- or (S)-configuration (Fig.
1). (ii) A particular enantiopure a,a-dialkyl cyanoac-
etate can be conveniently elaborated to afford both
enantiomers of the same amino acid. The stereodiver-
gent synthesis is possible because both the carboxyl-
ate and the cyano groups are immediate precursors,
through hydrolysis or rearrangement processes, of
both the carboxylic acid and the amino groups of the
final amino acid (Fig. 2).
However, due to the high molecular weight of the chiral
auxiliary used in the synthesis, this methodology can
hardly be applied to obtain a,a-disubstituted a-amino
acids on a large scale.
Figure 3. Enantioconvergent approach to the synthesis of
(R)- or (S)-a,a-dialkylamino acids from both enantiomers of
a chiral a,a-dialkylcyanoacetate.
Despite its ‘low technology’ image, classical resolution
by crystallisation of diastereomeric compounds is

R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2201–2207
2203
has been used, amongst other things, in the preparation
of an analogue of a commercial sweetener (aspartame)
possessing the same sweetness but superior stability.16
In this paper we describe the results obtained in the
practical preparation of this amino acid on ca. 15 g
scale.
resolving agents to a solution of a racemate, a treat-
ment that generally causes very rapid precipitation of
the crystalline diastereomeric salt in high diastereomeric
purity and yield. Unfortunately, in our case a ‘family’
of resolving agents composed of an equimolecular mix-
ture
of
(R)-1-phenylethylamine,
(R)-1-(4-nitro-
phenyl)ethylamine and (R)-1-(4-methylphenyl)ethyl-
amine led to unsatisfactory results.
2. Results and discussion
Among the three commercially available optically
active amines tested, (1R,2S)-(−)-norephedrine (−)-5
gave the best results and of the solvents examined for
improving the efficiency of the resolution, a mixture of
chloroform and hexane (1:1) was found to be the most
effective. The resolution was therefore carried out on
multi-gram scale as depicted in Scheme 2.
Racemic 2-cyano-2-methyl-3-phenylpropanoic acid rac-
4 was efficiently prepared by the four-step procedure
outlined in Scheme 1.
Scheme 1. Reagents and conditions: (i) NH4AcO, AcOH; (ii)
H2, Pd/C, THF; (iii) K2CO3, CH3I, acetone; (iv) KOH,
methanol.
The Knoevenagel condensation of inexpensive and
commercially available benzaldehyde and methyl
cyanoacetate afforded methyl (E)-2-cyanocinnamate 1
as a solid, which was filtered off and submitted to
hydrogenation using palladium on carbon as a catalyst.
In the next step, crude 2-cyano-3-phenylpropanoate
rac-2 was deprotonated under mild conditions employ-
ing potassium carbonate in acetone and the resulting
enolate was alkylated with methyl iodide to give methyl
2-cyano-2-methyl-3-phenylpropanoate rac-3, which was
sufficiently pure for use in the next step. Finally,
hydrolysis of cyano ester rac-3 was accomplished with
KOH in methanol and the resulting carboxylate salt
was purified by a standard acid-base extraction to
provide 2-cyano-2-methyl-3-phenylpropanoic acid rac-4
as a yellowish powder in 92% overall yield from the
starting materials. All reactions in this synthesis were
carried out at room temperature and strictly anhydrous
conditions were not required.
Scheme 2. Chemical resolution of rac-4.
Resolving agent (−)-5 was added to a solution of rac-4
in chloroform/hexane (1:1) and the resulting mixture
was stirred for 5 min under reflux. On cooling to room
temperature an almost pure diastereomeric salt precipi-
tated. The composition of the mixture could be directly
determined by 1H NMR spectroscopy,19 which indi-
cated a diastereomeric ratio (+)-4(−)-5/(−)-4(−)-5 of 95/
5. A further recrystallisation in chloroform afforded the
diastereomerically pure salt (+)-4(−)-5. Enantiomeri-
cally pure (+)-2-cyano-2-methyl-3-phenylpropanoic acid
(+)-4 was recovered in 41% yield (maximum theoretical
yield=50%) upon hydrolysis of the salt with aqueous
HCl and dichloromethane extraction. The measured
specific rotation of (+)-4 {[h]2D5=27.2 (c 2 in CHCl3)} is
in good agreement with the literature value for the
(S)-enantiomer20 and confirmed both the high enan-
tiomeric excess and absolute configuration of com-
pound (S)-4. The opposite enantiomer was obtained by
The resolution of rac-4 was investigated by crystallisa-
tion of the diastereomeric salts formed with chiral
amines. Owing to the well-documented lack of pre-
dictability in identifying a successful resolving agent for
classical resolutions, the selection was made by trial and
error.17 The following components were included in the
study: (i) resolving agents: (R)-(+)-1-phenylethylamine,
(1R,2S)-(−)-norephedrine
and
(R)-(−)-2-amino-2-
phenylethanol, (ii) solvents: ethanol, butanone, ethyl
acetate, diisopropyl ether, chloroform, toluene and
hexane.
Moreover, an alternative combinatorial approach
recently proposed by Vries et al.18 was also tested. This
approach is based on the addition of a ‘family’ of

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R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2201–2207
evaporation of the combined mother liquors, followed
by decomposition of the salt by the addition of 0.5N
hydrochloric acid and dichloromethane extraction. The
enantiomeric purity of (R)-4 could be increased to
e.e.>96% by reaction with an equimolecular amount of
(1S,2R)-(+)-norephedrine (+)-5 and precipitation of the
diastereomeric salt (−)-4(+)-5 from a chloroform/hex-
ane (1:1) mixture. Hydrolysis of (−)-4(+)-5 provided
(R)-4 with a chemical yield of 38% {[h]2D5=−27.8 (c 2,
CHCl3)}.
hydrolysed, without purification, by refluxing with
aqueous hydrochloric acid. The next step involved the
usual treatment using an ion exchange column to give
enantiomerically
pure
(S)-a-methylphenylalanine
{[h]2D5=−21.6 (c 1, H2O)} in 89% overall yield based on
starting cyano acid (R)-4. It is worth mentioning that
all crude intermediate products were pure enough to be
used in the next step without purification—a fact that
would be advantageous on a large scale—and that the
physical and spectroscopic data of isolated analytically
pure samples of compounds (R)-821 and (S)-922 are
fully consistent with those previously reported in the
literature.
Having obtained both enantiomers of 4, we proceeded
to study the development of an efficient and practical
enantioconvergent synthesis of (S)-a-methylphenylala-
nine. Compound (S)-4 was transformed successfully
into the target amino acid via the synthetic route shown
in Scheme 3. The acid chloride prepared by treatment
of (S)-4 with thionyl chloride was reacted with sodium
azide in aqueous acetone to afford crude acyl azide
(S)-5. This compound was immediately rearranged by
refluxing in a mixture of toluene/methanol and the
resulting cyano urethane (S)-6 was hydrolysed with
20% hydrochloric acid under reflux. Elution of the
crude amino acid hydrochloride salt through an ion
exchange column yielded enantiomerically pure (S)-a-
methylphenylalanine (S)-7 in 90% overall yield from
(S)-4. The specific rotation value {[h]2D5=−21.8 (c 1,
H2O), lit.12a [h]D25=−22 (c 1, H2O)} allowed us to
confirm the enantiomeric purity of the final product. It
should be noted that crude intermediates were used
directly in all steps of the synthetic scheme and a
purification step was not required in the entire
sequence. Furthermore, the course of all reactions
could be easily monitored by IR spectroscopy. Finally,
the physical and spectroscopic data of an isolated ana-
lytically pure sample of compound (S)-6 are fully con-
sistent with those previously reported in the
literature.14e
The specific rotation values for samples of (S)-7,
obtained through both synthetic routes, demonstrated
that both Curtius and Hofmann rearrangements pro-
ceeded with retention of configuration, as reported in
the literature.23
The methodology described here also constitutes a for-
mal synthesis of (R)-a-methylphenylalanine on the
basis that (R)-2-cyano-2-methyl-3-phenylpropanoic
acid and its enantiomer, (S)-2-cyano-2-methyl-3-
phenylpropanoic acid, could be used as starting materi-
als for a complementary enantioconvergent synthesis of
the amino acid of R configuration, with similar results
expected to those described above.
3. Conclusion
We have developed a practical and efficient procedure
for the synthesis of (S)-a-methylphenylalanine on a
large laboratory scale starting from readily available
and inexpensive reagents. The most remarkable charac-
teristic of this methodology is the high overall yield
(63% from benzaldehyde and methyl 2-cyanoacetate)
obtained using simple and mild reaction conditions that
avoid the use of difficult purification procedures. This
sequence may be easily scaled up, meaning that this
methodology is very promising for the preparation of
a,a-disubstituted a-amino acids that are now very
important on an industrial scale.
Alternatively, (R)-4 was converted successfully into (S)-
7 as shown in the synthetic route in Scheme 3. Com-
pound (R)-8 was prepared by treatment of (R)-4 with
sodium hydroxide and H2O2, with the resulting product
submitted to a Hofmann-type rearrangement to afford
the N-carboxyanhydride (S)-9. This material was
Scheme 3. Reagents and conditions: (i) SOCl2; (ii) NaN3, acetone/H2O; (iii) D, toluene/methanol; (iv) 20% HCl, reflux; (v)
ion-exchange chromatography; (vi) NaOH, H2O2; (vii) C6H5I(OAc)2, methanol.

R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2201–2207
2205
4. Experimental
hyde. Mp=93°C, (lit.20 mp=93–94°C); IR (Nujol)
1
2262, 1747 cm−1; H NMR (CDCl3, 300 MHz) l 1.64
4.1. General
(s, 3H), 3.06 (d, 1H, J=13.5 Hz), 3.26 (d, 1H, J=13.5
Hz), 7.26–7.34 (m, 5H), 10.25 (brs, 1H); 13C NMR
(CDCl3, 75 MHz) l 22.8, 43.2, 44.3, 118.9, 128.0, 128.7,
130.0, 133.6, 174.1
Melting points were determined using a Gallenkamp
apparatus and are uncorrected. IR spectra were regis-
tered on a Mattson Genesis FTIR spectrophotometer;
1
wmax is given for the main absorption bands. H and 13
C
4.3. Resolution of rac-4 by crystallisation of its
(1R,2S)-(−)-norephedrine and (1S,2R)-(+)-norephedrine
salts
NMR spectra were recorded on a Varian Unity-300 or
a Bruker ARX-300 apparatus at room temperature,
using the residual solvent signal as the internal stan-
dard; chemical shifts (l) are quoted in ppm, and cou-
pling constants (J) are measured in hertz. Optical
rotations were measured in a cell with a 10 cm path-
length at 25°C using a JASCO P-1020 polarimeter.
Elemental analyses were carried out on a Perkin–Elmer
200 C, H, N, S analyser. TLC was performed on
Polygram® sil G/UV254 precoated silica gel polyester
plates and products were visualised under UV light (254
nm) or using ninhydrin, anisaldehyde or phospho-
molybdic acid developers.
(1R,2S)-(−)-Norephedrine (15.1 g, 0.1 mol) was added
to a solution of racemic 2-cyano-2-methyl-3-phenyl-
propanoic acid rac-4 (18.9 g, 0.1 mmol) in a 1/1
mixture of chloroform/hexane (1 L). The mixture was
stirred and heated under reflux for 5 min, the resulting
solution was allowed to cool to room temperature and
a white solid began to precipitate. The mixture was
kept overnight at room temperature to complete the
precipitation. The solid was filtered off and recrys-
tallised from hot chloroform. The product was dis-
solved in 0.5N aq. HCl (150 mL) and extracted three
times with ether. The combined organic layers were
dried over anhydrous MgSO4, filtered and evaporated
under reduced pressure, to afford 7.78 g of the enan-
tiomerically pure cyano acid (S)-4 [mp 88°C, [h]2D5=
+27.2 (c 2, in CHCl3)] as colourless crystals (yield 41%).
The physical14e,20 and spectroscopic data14e for the
product agree with those described in the literature for
(S)-2-cyano-2-methyl-3-phenylpropanoic acid.
4.2. Synthesis of rac-2-cyano-2-methyl-3-phenyl-
propanoic acid, rac-4
A mixture of methyl cyanoacetate (9.9 g, 0.1 mol),
benzaldehyde (10.6 g, 0.1 mol), glacial acetic acid (4.8
g, 0.08 mol) and ammonium acetate (1.54 g, 0.02 mol)
was stirred at room temperature for several minutes
until it solidified. The resulting paste was allowed to
stand at room temperature overnight and the solid was
filtered off and washed with hexane. The solid was
dissolved in ethyl acetate and washed successively with
saturated aqueous NaHCO3 and water. The organic
phase was dried over anhydrous MgSO4, filtered and
the solvent removed in vacuo to afford crude methyl
(E)-2-cyanocinnamate 1. The crude material was dis-
solved in THF (75 mL) and hydrogenated at atmo-
spheric pressure and room temperature using 10%
palladium on charcoal (300 mg) as the catalyst. The
reaction was monitored by TLC and, on completion (1
day), the catalyst was filtered off and the filtrate was
evaporated to dryness to provide crude methyl 2-cyano-
3-phenylpropanoate rac-2. Potassium carbonate (13.8
g, 0.1 mol) was added to a well-stirred solution of crude
rac-2 and methyl iodide (17.03 g, 7.5 mL, 0.12 mol) in
acetone (75 mL) and the resulting mixture was stirred
at room temperature for 12 h. After the reaction was
complete, the solvent was evaporated and the residue
dissolved in ether. The solution was filtered and con-
centrated in vacuo to afford crude methyl 2-cyano-2-
methyl-3-phenylpropanoate rac-3. Crude rac-3 was
dissolved in a 10% solution of KOH in methanol (125
mL) and the reaction mixture was stirred at room
temperature for 1 h. The solvent was evaporated in
vacuo, the residue diluted with water (100 mL) and the
solution washed with ether. The aqueous layer was
acidified with concentrated aqueous HCl and extracted
several times with ether. The combined organic layers
were dried over anhydrous MgSO4, filtered and concen-
trated in vacuo to afford 17.4 g of 2-cyano-2-methyl-3-
phenylpropanoic acid rac-4 as a white solid (92%
overall yield from methyl cyanoacetate and benzalde-
Evaporation of the mother liquors furnished a beige
paste, which was acidified with 0.5N HCl and extracted
three times with ether. The combined organic layers
were dried over anhydrous magnesium sulfate and
evaporated under reduced pressure to afford 11.1 g of
partially resolved cyano acid (R)-4, which was dissolved
in a 1/1 mixture of chloroform/hexane (600 mL).
(1S,2R)-(+)-Norephedrine (8.88 g, 58.8 mmol) was
added and the mixture was refluxed until all of the solid
had dissolved. The resulting solution was allowed to
cool to room temperature and, after 12 h, the resulting
colourless precipitate was filtered off. The solid was
dissolved in 0.5N aq. HCl (150 mL) and extracted three
times with ether. The combined organic layers were
dried over anhydrous magnesium sulfate, filtered and
evaporated under reduced pressure to afford 7.2 g of
the enantiomerically pure cyano acid (R)-4 {mp 88°C,
[h]2D5=−27.8 (c 2, in CHCl3)} as colourless crystals
(yield 38%). The physical20 data for the product agree
with those reported in the literature for (R)-2-cyano-2-
methyl-3-phenylpropanoic acid. IR (Nujol) 2267, 1743
1
cm−1; H NMR (CDCl3, 300 MHz) l 1.64 (s, 3H), 3.06
(d, 1H, J=13.5 Hz), 3.26 (d, 1H, J=13.5 Hz), 6.25
(brs, 1H), 7.26–7.34 (m, 5H); 13C NMR (CDCl3, 75
MHz) l 22.9, 43.2, 44.5, 118.9, 128.1, 128.7, 130.0,
133.6, 174.2.
4.4. Synthesis of (S)-a-methylphenylalanine (S)-7 from
(S)-4
Thionyl chloride (75 mL) was added to (S)-2-cyano-2-
methyl-3-phenylpropanoic acid (S)-4 (9.45 g, 50 mmol)

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R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2201–2207
and the mixture was heated under reflux for 12 h.
The excess thionyl chloride was removed in vacuo,
the residue was dissolved in acetone (18 mL) and this
solution was added to a solution of NaN3 (3.93 g, 60
mmol) in water (18 mL). The mixture was stirred for
40 min at room temperature, the acetone was evapo-
rated in vacuo at room temperature and the resulting
aqueous solution was extracted with ether. The
organic layer was dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The residue was
dissolved in a mixture of toluene (75 mL) and
methanol (25 mL) and the solution was stirred and
heated under reflux for 4 h. The solvents were evapo-
rated in vacuo to afford crude cyano urethane (S)-6.
This compound was hydrolysed with 20% aqueous
HCl (180 mL) under reflux for 36 h. The liquids were
removed in vacuo and the residue was dissolved in
water, washed with ether and introduced into an ion
exchange column (Dowex 50 W×8). Elution of the
column with 5% aqueous ammonia and subsequent
solvent evaporation in vacuo afforded 8.06 g of (S)-
a-methylphenylalanine 7 [90% overall yield from (S)-
4]. The physical12a,14e and spectroscopic data14e of the
product agree with those reported in the literature for
(S)-a-methylphenylalanine.
Acknowledgements
This work was carried out with the financial support
of Ministerio de Ciencia y Tecnolog´ıa and FEDER
(project PPQ2001-1834).
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4.5. Synthesis of (S)-a-methylphenylalanine (S)-7 from
(R)-4
1N Aqueous NaOH (63 mL) was added to (R)-2-
cyano-2-methyl-3-phenylpropanoic acid (R)-4 (9.45 g,
50 mmol) until all of the solid had dissolved. 35%
H2O2 (116 mL) was added with caution and 10%
aqueous NaOH (90 mL) was then added slowly. The
reaction mixture was stirred at room temperature
overnight and then acidified with concentrated
aqueous HCl until pH 2. This mixture was ex-
tracted with CH2Cl2 (4×50 mL) and the combined
organic layers were dried over anhydrous MgSO4,
filtered and concentrated in vacuo to afford 9.75 g
(94%) of crude (R)-2-benzyl-2-methylmalonic acid
monoamide (R)-8. Iodobenzene diacetate (17.4 g, 54
mmol) was added to a solution of crude (R)-2-benzyl-
2-methylmalonic acid monoamide (R)-8 (9.31 g, 45
mmol) in methanol (150 mL). The resulting mixture
was stirred at room temperature for 2 h. The solvent
was evaporated and the residue partitioned between
CH2Cl2 and water. The aqueous layer was extracted
with CH2Cl2 (3×50 mL) and the combined organic
layers were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Crude (S)-4-benzyl-4-methyl-
oxazolidin-2,5-dione (S)-9 was hydrolysed with 20%
aqueous HCl (200 mL) under reflux for 5 h. The
liquids were removed in vacuo and the residue was
dissolved in water, washed with CH2Cl2 and intro-
duced into an ion exchange column (Dowex 50 W×8).
Elution of the column with 5% aqueous ammonia
followed by solvent evaporation in vacuo afforded
7.17 g of (S)-a-methylphenylalanine (S)-7 [89% over-
all yield from (R)-4]. The physical12a,14e and spectro-
scopic data14e of the product agree with those
reported in the literature for (S)-a-methylphenylala-
nine.
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