Efficient enantioconvergent synthesis of (S)-α-benzyl-α-methyl-β-alanine from (R)- and (S)-2-cyano-2-methyl-3-phenylpropanoic acid

Article abstract of DOI:10.1016/S0957-4166(03)00443-9

An efficient synthesis of (S)-α-benzyl-α-methyl-β-alanine in 59% overall yield from benzaldehyde and methyl cyanoacetate has been developed. Enantioconvergent approaches to the synthesis of the target α,α-disubstituted β-amino acid from both enantiomers o

Full text of DOI:10.1016/S0957-4166(03)00443-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2209–2214
Efficient enantioconvergent synthesis of
(S)-a-benzyl-a-methyl-b-alanine from (R)- and
(S)-2-cyano-2-methyl-3-phenylpropanoic acid
Ramo´n Badorrey, Carlos Cativiela, Mar´ıa D. D´ıaz-de-Villegas,* Jose´ A. Ga´lvez* and Ana Gil
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 5 June 2003
Abstract—An efficient synthesis of (S)-a-benzyl-a-methyl-b-alanine in 59% overall yield from benzaldehyde and methyl cyano-
acetate has been developed. Enantioconvergent approaches to the synthesis of the target a,a-disubstituted b-amino acid from both
enantiomers of previously resolved 2-cyano-2-methyl-3-phenylpropanoic acid constitute the key steps in the proposed methodol-
ogy. The use of inexpensive and readily available reagents and the simplicity of the experimental procedures make the present
protocol synthetically attractive and of great potential for scale up.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
a,a-disubstituted b-amino acids. Preparation of this
kind of b-amino acid in its enantiomerically pure form
has already been extensively reviewed by Seebach.7
Numerous methodologies have been described for the
synthesis of such systems and each approach has its
own advantages and limitations. Today the develop-
ment of an efficient process that is suitable for large-
scale preparations, which as well as being easy to
operate, practical and inexpensive, remains a significant
challenge.
The synthesis of enantiopure b-amino acids has long
been of interest,1 partly due to their presence in a
number of biologically active compounds2 (antibiotics,
antitumoural agents, enzyme inhibitors, etc.) and their
use as intermediates in the synthesis of b-lactam antibi-
otics. A currently active area of research is the confor-
mational study of oligomers of b-amino acids, which
are also known as b-peptides. It has been reported that
short-chain b-peptides fold into turns, helices, and
sheet-like structures3 analogous to the secondary struc-
tures of proteins. Moreover, b-peptides are chemically
stable and resistant to enzymatic degradation,3g,4 sug-
gesting that they might provide an attractive tool for
the construction of peptidomimetics. These compounds
are therefore intriguing candidates for the development
of novel drugs.5
In the preceding paper,8 we reported an efficient, large
scale laboratory preparation of enantiomerically pure
a,a-disubstituted a-amino acid (S)-methylphenylalanine
from benzaldehyde and methyl cyanoacetate. The syn-
thetic methodology described involves the synthesis and
resolution of racemic 2-cyano-2-methyl-3-phenyl-
propanoic acid and the subsequent transformation of
each isolated enantiomer via independent pathways
into the enantiomerically pure target amino acid. The
simplicity of the experimental procedure and its use of
inexpensive and readily available reagents make this
methodology interesting from an economic point of
view.
Structural investigations have recently been carried out
with b-peptides constituted by achiral a,a-disubstituted
b-amino acids and, as predicted, these oligomers
provide exciting new secondary structures.6 In order to
be able to identify structurally other b-peptides contain-
ing such residues and to establish the handness of
secondary structures they may form, it is important to
have access to procedures that provide homochiral
We envisioned that (R)- and (S)-a,a-disubstituted a-
cyanoacetic acids would also act as precursors for
chiral a,a-disubstituted b-amino acids of determinate
configuration in enantiomerically pure form if we were
* 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)00443-9

2210
R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2209–2214
able to develop efficient enantioconvergent syntheses
using both enantiomers of the cyanoacetic acid as start-
ing materials. Such an approach would be possible if
both the cyano and the acid functional groups in the
starting compound could be independently transformed
into the carboxylic and the aminomethyl groups of the
target a,a-disubstituted-b-amino acid (Fig. 1).
1% ammonia in methanol as the solvent. This proce-
dure afforded the target amino acid (S)-2, albeit only in
moderate yield (50%). In an attempt to improve on
this result, various catalysts (Rh/Al2O3, PtO2, Pd/C)
were tested in this hydrogenation reaction but none of
these worked efficiently under mild conditions. Finally,
compound (S)-2 was obtained with a considerably
increased yield through an alternative multi-step proce-
dure consisting of hydrogenation with Raney nickel of
methyl (S)-2-cyano-2-methyl-3-phenylpropanoate (S)-
3, obtained from (S)-1 and methyl iodide in the pres-
ence of Cs2CO3 and hydrolysis of the resulting amino
ester (S)-4 with 10% KOH/MeOH at room tempera-
ture. Enantiomerically pure (S)-a-benzyl-a-methyl-b-
alanine (S)-2 can easily be isolated by ion-exchange
chromatography in 88% overall yield from (S)-1.
Although all compounds were isolated for characterisa-
tion purposes, it is worth mentioning that all crude
intermediates were pure enough to carry out subse-
quent steps without the need for purification—a factor
that is advantageous for use on a large scale.
Figure 1. Enantioconvergent approach to the synthesis of
(R)- or (S)-a,a-disubstituted-b-amino acids from both enan-
tiomers of a chiral a,a-dialkylcyanoacetate
Conversion of enantiopure (R)-2-cyano-2-methyl-3-
phenylpropanoic acid (R)-1 into (S)-a-benzyl-a-methyl-
b-alanine (S)-2 was conveniently performed by two
alternative routes, both of which are shown in Scheme
2.
As a model for establishing the methodology, the enan-
tioconvergent synthesis of (S)-a-benzyl-a-methyl-b-ala-
nine from (R)- and (S)-2-cyano-2-methyl-3-phenyl-
propanoic acid was selected.
Crude methyl ester (R)-3, obtained from (R)-1 by
reaction with methyl iodide and Cs2CO3, was quantita-
tively reduced with sodium borohydride at room tem-
perature in a mixture of THF/H2O. The subsequent
reaction of the crude cyano alcohol (R)-5 with
methanesulfonyl chloride at room temperature gave the
corresponding mesylate (R)-6 in a nearly quantitative
yield. This compound was submitted to a substitution
process using sodium azide as a nucleophile in DMF at
reflux. Cyano azide (R)-7 was smoothly hydrogenated
using Pd/C as catalyst to afford cyano amine (S)-8,
which was hydrolysed, without purification, by reflux-
ing with 20% aqueous HCl. Elution of the amino acid
hydrochloride through an ion-exchange column yielded
enantiomerically pure (S)-a-benzyl-a-methyl-b-alanine
(S)-2 in 65% overall yield from (R)-1. Although all
compounds were isolated for characterisation purposes,
it is again noteworthy that all crude intermediates were
sufficiently pure to carry out to next step without any
purification.
2. Results and discussion
Racemic 2-cyano-2-methyl-3-phenylpropanoic acid was
prepared in 92% overall yield from benzaldehyde and
methyl cyanoacetate. The mixture was resolved into
(S)-2-cyano-2-methyl-3-phenylpropanoic acid (S)-1 [(ee
>96%, 41% yield)] and (R)-2-cyano-2-methyl-3-phenyl-
propanoic acid (R)-1 [(ee >96%, 38% yield)] by crys-
tallisation of its diastereomeric norephedrine salts as
described in the preceding paper.8
Transformation of (S)-2-cyano-2-methyl-3-phenyl-
propanoic acid (S)-1 into (S)-a-benzyl-a-methyl-b-ala-
nine (S)-2 was conveniently performed as shown in
Scheme 1.
As an alternative, we assessed the possibility of substi-
tution of the hydroxy group in cyano alcohol (R)-5
without prior activation and this was achieved using
Mitsunobu reaction conditions. Thus, treatment of
alcohol (R)-5 with an excess of phthalimide,
triphenylphosphine and diethyl azodicarboxylate
(DEAD) led to the phthalimido derivative (S)-9 in 89%
yield. This compound was purified by column chro-
matography and subsequently hydrolysed with hydro-
Scheme 1. Reagents and conditions: (i) H2, Ni(Raney), 1%
ammonia/methanol; (ii) Cs2CO3, CH3I, acetone; (iii) KOH,
methanol, D.
chloric
acid
under
reflux.
Ion-exchange
chromatography of the resulting material gave enan-
tiomerically pure (S)-a-benzyl-a-methyl-b-alanine (S)-2
in 74% overall yield based on the starting cyano acid
(R)-2.
Hydrogenation of the cyano group in compound (S)-1
was cleanly achieved at atmospheric pressure at 35°C
by using Raney nickel as the catalyst and a solution of

R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2209–2214
2211
Scheme 2. Reagents and conditions: (i) Cs2CO3, CH3I, acetone; (ii) NaBH4, THF/H2O; (iii) MsCl, Et3N, CH2Cl2; (iv) NaN3,
DMF; (v) H2, Pd/C, methanol; (vi) 20% HCl, D; ion-exchange chromatography; (vii) Phthalimide, PPh3, THF, DEAD.
The methodology described here also constitutes a for-
mal synthesis (R)-a-benzyl-a-methyl-b-alanine on the
basis that (R)-2-cyano-2-methyl-3-phenylpropanoic
acid and its enantiomer, (S)-2-cyano-2-methyl-3-
phenylpropanoic acid, can be used as starting materials
in synthetic routes depicted in Schemes 1 and 2, respec-
tively, with similar results to those described above.
coated silica gel polyester plates and products were
visualised under UV light (254 nm) or using ninhydrin,
anisaldehyde or phosphomolybdic acid developers.
Column chromatography was performed using silica gel
(Kieselgel 60). (R)- and (S)-2-Cyano-2-methyl-3-
phenylpropanoic acid were obtained as described in the
preceding paper.8
4.2. Synthesis of methyl (S)-2-cyano-2-methyl-3-phenyl-
propanoate, (S)-3
3. Conclusion
We have developed a practical and efficient procedure
for the enantioconvergent synthesis of (S)-a-benzyl-a-
methyl-b-alanine in 59% overall yield from benzalde-
hyde and methyl 2-cyanoacetate. The apparent
synthetic advantages of the methodology described
include the ready availability of the starting materials
and the extremely simple experimental procedure. The
synthesis avoids low temperature reactions and difficult
purifications, thus making it amenable to large-scale
synthesis. Extension of this method to the synthesis of
other important a,a-disubstituted b-amino acids is cur-
rently under way.
Cs2CO3 (3.59 g, 11 mmol) was added to a solution of
(S)-2-cyano-2-methyl-3-phenylpropanoic acid (S)-1
(1.89 g, 10 mmol) in methanol (30 mL). The resulting
mixture was stirred at room temperature for 30 min
and then evaporated to dryness. The resulting residue
was dissolved in DMF (30 mL), methyl iodide (1.70 g,
12 mmol) was added and the reaction mixture stirred at
room temperature for 32 h. When the reaction was
complete, ether (50 mL) was added and the resulting
solution washed with saturated aqueous NaCl solution
(4×20 mL), dried over anhydrous MgSO4, filtered and
concentrated in vacuo to afford 1.97 g (97% yield) of
crude methyl (S)-2-cyano-2-methyl-3-phenylpropanoic
acid (S)-3. This material was pure enough to be used in
the next step without further purification. An analyti-
cally pure sample of (S)-3 was obtained by purification
of the crude product by column chromatography on
silica gel (ether/hexane 1:3). Oil; [h]2D5=+31.2 (c 1, in
CHCl3), {lit.9 [h]D25=+2.9 (neat)}; IR (Nujol) 2243, 1743
4. Experimental
4.1. General
Melting points were determined using a Gallenkamp
apparatus and are uncorrected. IR spectra were regis-
1
cm−1; H NMR (CDCl3, 300 MHz) l 1.61 (s, 3H), 3.04
tered on a Mattson Genesis FTIR spectrophotometer;
(d, 1H, J=13.5 Hz), 3.22 (d, 1H, J=13.5 Hz), 3.73 (s,
3H), 7.26–7.34 (m, 5H); 13C NMR (CDCl3, 75 MHz) l
23.1, 43.7, 45.3, 53.4, 119.6, 127.9, 128.6, 129.9, 134.0,
169.5.
1
wmax is given for the main absorption bands. H and 13
C
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.
TLC was performed on Polygram® sil G/UV254 pre-
4.3. Synthesis of (S)-a-benzyl-a-methyl-b-alanine methyl
ester, (S)-4
A solution of crude methyl (S)-2-cyano-2-methyl-3-
phenylpropanoic acid (S)-3 (1.97 g) in 0.5% ammonia/

2212
R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2209–2214
methanol (50 mL) was hydrogenated at room tempera-
ture and atmospheric pressure using Raney nickel (5
mL) as a catalyst. The reaction was monitored by TLC
and, on completion (2 h), the catalyst was filtered off
and washed with several portions of methylene chlo-
ride. The filtrate was evaporated to dryness in vacuo to
afford 1.84 g (92% yield) of crude (S)-a-benzyl-a-
methyl-b-alanine methyl ester (S)-4, which was pure
enough to be used in the next step without further
purification. An analytically pure sample of (S)-4 was
obtained by filtration of the crude product through a
short pad of silica gel (methylene chloride/ethanol 9:1).
Oil; [h]2D5=−18.0 (c 1, in CHCl3); IR (Nujol)) 3397,
(1.89 g, 10 mmol) in methanol (30 mL). The resulting
mixture was stirred at room temperature for 30 min
and then evaporated to dryness. The resulting residue
was dissolved in DMF (30 mL), methyl iodide (1.70 g,
12 mmol) was added and the reaction mixture stirred at
room temperature for 32 h. When the reaction was
complete, ether (50 mL) was added and the resulting
solution washed with saturated aqueous NaCl solution
(4×20 mL), dried over anhydrous MgSO4, filtered and
concentrated in vacuo to afford 1.97 g (97% yield) of
crude methyl (R)-2-cyano-2-methyl-3-phenylpropanoic
acid (R)-3. This material was pure enough to be used in
the next step without further purification. An analyti-
cally pure sample of (R)-3 was obtained by purification
of the crude product by column chromatography on
silica gel (ether/hexane 1:3). Oil; [h]2D5=−30.9 (c 1, in
1
3335, 1727 cm−1; H NMR (CDCl3, 300 MHz) l 1.10
(s, 3H), 1.31 (brs, 2H), 2.65 (bd, J=12 Hz), 2.74 (d, 1H,
J=13.2 Hz), 2.95 (d, 1H, J=13.5 Hz), 2.95 (bd, 1H,
J=12 Hz), 3.65 (s, 3H), 7.05–7.10 (m, 2H), 7.16–7.27
(m, 3H); 13C NMR (CDCl3, 75 MHz) l 19.6, 42.7, 49.6,
49.7, 51.7, 126.5, 128.1, 130.0, 137.2, 176.6
1
CHCl3); IR (neat) 2243, 1743 cm−1; H NMR (CDCl3,
300 MHz) l 1.61 (s, 3H), 3.05 (d, 1H, J=13.5 Hz), 3.22
(d, 1H, J=13.5 Hz), 3.72 (s, 3H), 7.26–7.34 (m, 5H);
13C NMR (CDCl3, 75 MHz) l 23.1, 43.6, 45.3, 53.3,
119.6, 127.9, 128.7, 129.9, 134.0, 169.3.
4.4. Final step in the synthesis of (S)-a-benzyl-a-methyl-
b-alanine, (S)-2, using (S)-2-cyano-2-methyl-3-phenyl-
propanoic acid (S)-1 as the precursor
4.6. Synthesis of (R)-2-hydroxymethyl-2-methyl-3-phenyl-
propionitrile, (R)-5
Method a. A solution of crude (S)-a-benzyl-a-methyl-b-
alanine methyl ester (S)-4 (1.84 g) in 10% KOH in
methanol (30 mL) was stirred at room temperature for
1 h. On completion of the reaction the solvent was
evaporated in vacuo and the residue diluted with water
(100 mL) and washed with ether. The aqueous layer
was acidified with concentrated aqueous HCl, washed
with ether and evaporated in vacuo to give the crude
amino acid hydrochloride, which was submitted to
ion-exchange column chromatography on Dowex
50Wx8 to afford 1.72 g [quantitative yield, 89% overall
yield form (S)-1] of (S)-a-benzyl-a-methyl-b-alanine
(S)-2 as a white powder.
To a solution of crude methyl (R)-2-cyano-2-methyl-3-
phenylpropanoic acid (R)-3 (1.97 g) in THF (40 mL)
was added a solution of NaBH4 (3.8 g, 0.1 mol) in
THF/H2O (5:1, 30 mL). The reaction mixture was
stirred at room temperature for 1 h. The solution was
quenched with 10% HCl and THF was removed by
evaporation in vacuo. The aqueous solution was
extracted with ether and the combined organic layers
washed with saturated aqueous NaHCO3 and water.
The organic layer was dried over anhydrous MgSO4
and the solvent evaporated in vacuo to give 1.70 g
(quantitative yield) of (R)-2-hydroxymethyl-2-methyl-3-
phenylpropionitrile (R)-5. This material was pure
enough to be used in the next step without further
purification. An analytically pure sample of (R)-5 was
obtained by purification of the crude product by
column chromatography on silica gel (ether/hexane
1:1). Oil; [h]2D5=−9.9 (c 1, in CHCl3); IR (neat) 3550–
Method b.
A solution of (S)-2-cyano-2-methyl-3-
phenylpropanoic acid (S)-1 (1.13 g, 6 mmol) in 1%
ammonia/methanol (40 mL) was hydrogenated at 35°C
and atmospheric pressure using Raney nickel (4 mL) as
a catalyst. The reaction was monitored by TLC and, on
completion (6 h), the catalyst was filtered off and
washed with several portions of water. The filtrate was
evaporated to dryness in vacuo and the residue was
dissolved in 1N HCl. The solution was purified by
ion-exchange column chromatography on Dowex
50Wx8 to afford 579 mg (50% yield) of (S)-a-benzyl-a-
methyl-b-alanine (S)-2 as a white solid. Mp=246°C,
(lit.10 mp=205–206°C); [h]D25=+20.7 (c 1, in H2O),
{lit.10 [h]D25=+17.8 (c 1, in H2O)}; IR (Nujol)) 3550–
1
3450, 2239 cm−1; H NMR (CDCl3, 300 MHz) l 1.29
(s, 3H), 2.33 (s, 1H), 2.80 (d, 1H, J=13.4 Hz), 3.01 (d,
1H, J=13.4 Hz), 3.62 (s, 2H), 7.26–7.38 (m, 5H); 13C
NMR (CDCl3, 75 MHz) l 20.5, 40.6, 41.2, 67.2, 123.0,
127.3, 128.4, 130.2, 134.8.
4.7.Synthesisof(R)-2-mesyloxymethyl-2-methyl-3-phenyl-
propionitrile, (R)-6
1
2500, 1658 cm−1; H NMR (D2O, 300 MHz) l 1.07 (s,
Methanesulfonyl chloride (1.37 g, 12 mmol) was added
dropwise to a solution of crude (R)-2-hydroxymethyl-2-
methyl-3-phenylpropionitrile (R)-5 (1.70 g) and triethyl-
amine (1.21 g, 12 mmol) in methylene chloride (50 mL)
at 0°C and the resulting solution was stirred at this
temperature for 30 min. Upon completion of the reac-
tion, the mixture was washed with brine, dried over
anhydrous MgSO4, filtered and evaporated in vacuo to
afford 2.38 g (97% yield) crude mesylate (R)-6. This
material was pure enough to be used in the next step
without further purification. An analytically pure sam-
3H); 2.67 (d, 1H, J=13.5 Hz); 2.75 (d, 1H, J=12.9
Hz); 2.85 (d, 1H, J=13.5 Hz); 2.95 (d, 1H, J=12.9 Hz);
7.09–7.23 (m, 5H); 13C NMR (D2O, 75 MHz) l 21.0,
43.5, 46.1, 46.2, 127.0, 128.5, 130.0, 137.1, 181.7.
4.5. Synthesis of methyl (R)-2-cyano-2-methyl-3-phenyl-
propanoate, (R)-3
Cs2CO3 (3.59 g, 11 mmol) was added to a solution of
(S)-2-cyano-2-methyl-3-phenylpropanoic acid (S)-1

R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2209–2214
2213
ple of (R)-6 was obtained by purification of the crude
product by column chromatography on silica gel (ether/
hexane 4:1). Oil; [h]D25=−3.3 (c 1, in CHCl3); IR (neat)
trated in vacuo and the crude product purified by
column chromatography on silica (methylene chloride/
hexane 4:1) to give 1.08 g (89% yield) of (S)-2-benzyl-3-
(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-methylpropioni-
trile (S)-9 as a white solid. Mp=132°C; [h]2D5=+2.8 (c
1
2241, 1359, 1178 cm−1; H NMR (CDCl3, 300 MHz) l
1.38 (s, 3H), 2.87 (d, 1H, J=13.5 Hz), 2.99 (d, 1H,
J=13.5 Hz), 3.10 (s, 3H), 4.12 (s, 2H), 7.24–7.35 (m,
5H); 13C NMR (CDCl3, 75 MHz) l 21.0, 37.9, 38.3,
41.5, 71.3, 121.0, 127.9, 128.8, 130.2, 133.4.
1
1, in CHCl3); H NMR (CDCl3, 300 MHz) l 1.32 (s,
3H), 2.79 (d, 1H, J=13.5 Hz), 3.09 (d, 1H, J=13.5
Hz), 3.86 (d, 1H, J=13.8 Hz), 3.99 (d, 1H, J=13.8 Hz),
7.24–7.33 (m, 5H), 7.74–7.90 (m, 4H); 13C NMR
(CDCl3, 75 MHz) l 22.6, 39.7, 43.7, 45.1, 122.0, 123.8,
127.6, 128.5, 130.3, 131.7, 134.4, 134.5, 168.1.
4.8. Synthesis of (S)-3-azido-2-benzyl-2-methylpropioni-
trile, (S)-7
To a solution of sodium azide (1.3 g, 20 mmol) in DMF
(30 mL) was added crude (R)-2-mesyloxymethyl-2-
methyl-3-phenylpropionitrile (R)-6 (2.38 g) and the
mixture stirred under reflux for 12 h. The reaction
mixture was allowed to cool, dissolved in ether (50 mL)
and the resulting solution was washed with saturated
aqueous NaCl solution (4×20 mL), dried over anhy-
drous MgSO4, filtered and evaporated in vacuo to
afford 1.70 g (91% yield) of (S)-3-azido-2-benzyl-2-
methylpropionitrile, (S)-7. An analytically pure sample
of (S)-7 was obtained by filtration of the crude product
through a short pad of silica gel (ether/hexane 4:1). Oil;
[h]2D5=−9.2 (c 1, in CHCl3); IR (neat) 2236, 2107 cm−1;
1H NMR (CDCl3, 300 MHz) l 1.34 (s, 3H), 2.83 (d,
1H, J=13.7 Hz), 2.95 (d, 1H, J=13.7 Hz), 3.37 (d, 1H,
J=12.2 Hz), 3.42 (d, 1H, J=12.2 Hz), 7.24–7.38 (m,
5H); 13C NMR (CDCl3, 75 MHz) l 22.0, 38.8, 42.1,
57.0, 121.9, 127.7, 128.6, 130.2, 134.2.
4.11. Final step in the synthesis of (S)-a-benzyl-a-
methyl-b-alanine, (S)-2, using (R)-2-cyano-2-methyl-3-
phenylpropanoic acid (R)-1 as the precursor
Method a. Crude (S)-3-azido-2-benzyl-2-methylpropi-
onitrile (S)-8 (1.34 g) in 20% aqueous HCl (50 mL) was
heated under reflux for 7 d. The solvent was removed
under reduced pressure to afford a solid, which was
dissolved in water, washed with ether and evaporated in
vacuo to give the crude amino acid hydrochloride. This
material was submitted to ion-exchange column chro-
matography on Dowex 50Wx8 to afford 1.25 g [81%
yield, 65% overall yield from (R)-1] of (S)-a-benzyl-a-
methyl-b-alanine (S)-2 as a white powder.
Method b. Crude (S)-2-benzyl-3-(1,3-dioxo-1,3-dihy-
droisoindol-2-yl)-2-methylpropionitrile (S)-9 (1.08 g) in
20% aqueous HCl (25 mL) and acetic acid (25 mL) was
heated under reflux conditions for 7 d. The solvent was
removed under reduced pressure to afford a solid,
which was dissolved in water, washed with methylene
chloride and evaporated in vacuo to give the crude
amino acid hydrochloride. This material was submitted
to ion-exchange column chromatography on Dowex
50Wx8 to afford 589 mg [86% yield, 75% overall yield
form (R)-1] of (S)-a-benzyl-a-methyl-b-alanine (S)-2 as
a white powder.
4.9. Synthesis of (S)-3-amino-2-benzyl-2-methylpropio-
nitrile, (S)-8
A solution of crude (S)-3-azido-2-benzyl-2-methylpro-
pionitrile (S)-7 (1.70 g) in methanol (40 mL) was
hydrogenated at room temperature and atmospheric
pressure using 10% Pd/C (300 mg) as a catalyst. The
reaction was monitored by TLC and, on completion (4
h), the catalyst filtered off and the filtrate evaporated to
dryness in vacuo to afford 1.34 g (91% yield) of pure
(S)-3-azido-2-benzyl-2-methylpropionitrile (S)-8. Oil;
[h]2D5=−11.8 (c 1, in CHCl3); IR (neat) 3500–3300, 2233
The physical and spectroscopic data of the compound
obtained were in complete agreement with those of
(S)-a-benzyl-a-methyl-b-alanine (S)-2 obtained using
(S)-2-cyano-2-methyl-3-phenylpropanoic acid (S)-1 as
the precursor.
1
cm−1; H NMR (CDCl3, 300 MHz) l 1.25 (s, 3H), 1.40
(brs, 2H), 2.71 (d, 1H, J=13.4 Hz), 2.75 (d, 1H,
J=13.2 Hz), 2.85 (d, 1H, J=13.2 Hz), 2.97 (d, 1H,
J=13.4 Hz), 7.24–7.33 (m, 5H); 13C NMR (CDCl3, 75
MHz) l 21.5, 41.1, 42.4, 50.0, 123.4, 127.3, 128.4,
130.2, 135.2.
Acknowledgements
4.10. Synthesis of (S)-2-benzyl-3-(1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-2-methylpropionitrile, (S)-9
This work was carried out with the financial support of
Ministerio de Ciencia y Tecnolog´ıa and FEDER (pro-
ject PPQ2001-1834). A.M.G. would like to thank CSIC
for a I3P grant.
A 100 mL round-bottomed flask was charged with
phthalimide (1.47 g, 10 mmol), dry THF (30 mL), PPh3
(2.63 g, 10 mmol), and (R)-2-hydroxymethyl-2-methyl-
3-phenylpropionitrile (R)-5 (0.7 g, 4 mmol) (obtained as
described above) in the order stated. The resulting
solution was cooled to 0°C and kept under an argon
atmosphere. DEAD (1.74 g, 10 mmol) was added drop-
wise to the stirred reaction mixture. After completion of
the addition, the resulting yellow solution was stirred at
40°C for 7 d. The reaction mixture was then concen-
References
1. (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991–8035;
(b) Juaristi, E. Enantioselective Synthesis of i-Amino
Acids; Wiley-VCH: New York, 1997; (c) Cardillo, G.;

2214
R. Badorrey et al. / Tetrahedron: Asymmetry 14 (2003) 2209–2214
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117–128; (d)
Cole, D. C. Tetrahedron 1994, 50, 9517–9582.
bach, D.; Overhand, M.; Ku¨hnle, F. N. M.; Martinoni,
B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim.
Acta 1996, 79, 913–941; (h) Seebach, D.; Ciceri, P. E.;
Overhand, M.; Jaun, B.; Rigo, D.; Oberer, L.; Hommel,
U.; Amstutz, R.; Widmer, H. Helv. Chim. Acta 1996, 79,
2043–2066; (i) Appella, D. H.; Christianson, L. A.; Karle,
I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc.
1996, 118, 13071–13072.
2. (a) Spiteller, P.; Ru¨th, M.; von Nussbaum, F.; Steglich,
W. Angew. Chem., Int. Ed. 2000, 39, 2754–2756; (b) Shih,
C.; Gossett, L. S.; Gruber, J. M.; Grossman, C. S.;
Andis, S. L.; Schultz, R. M.; Worzalla, J. F.; Corbett, T.
H.; Metz, J. T. Bioorg. Med. Chem. Lett. 1999, 9, 69–74;
(c) Takashiro, E.; Hayakawa, I.; Nitta, T.; Kasuya, A.;
Miyamoto, S.; Ozawa, Y.; Yagi, R.; Yamamoto, S.;
Shibayama, T.; Yabe, I. Bioorg. Med. Chem. 1999, 7,
2063–2072; (d) Matsunaga, S.; Fusetami, N. J. Org.
Chem. 1995, 60, 1177–1188; (e) Trimurtulu, G.; Ohtani,
I.; Patterson, G. M. L.; Moore, R. E.; Corbett, T. H.;
Valeriote, F. A.; Demchik, L. J. Am. Chem. Soc. 1994,
116, 4729–4737; (f) Iizuka, K.; Kamijo, T.; Harada, H.;
Akahane, K.; Kubota, T.; Umeyama, H.; Kiso, Y. J.
Chem. Soc., Chem. Commun. 1989, 1678–1680; (g) Shina-
gawa, S.; Kanamaru, T.; Harada, S.; Asai, M.; Okazaki,
H. J. Med. Chem. 1987, 30, 1458–1463; (h) Crews, P.;
Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27,
2797–2800; (i) Drey, C. N. C. In Chemistry and Biochem-
istry of Amino Acids; Barrett, G. C., Ed.; Chapman and
Hall: London, 1985; (j) Spatola, A. F. In Chemistry and
Biochemistry of Amino Acids; Weinstein, B., Ed.; Marcel
Dekker: New York, 1983.
3. (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
Rev. 2001, 101, 3219–3232; (b) Hill, D. J.; Mio, M. J.;
Price, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev.
2001, 101, 3893–4011; (c) Gellman, S. H. Acc. Chem. Res.
1998, 31, 173–180; (d) Seebach, D.; Matthews, J. L. J.
Chem. Soc., Chem. Commun. 1997, 2015–2022; (e)
Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell,
D. R.; Huang, X. L.; Barchi, J. J.; Gellman, S. H. Nature
1997, 387, 381–384; (f) Navas, J. J.; Alema´n, C.; Mun˜oz-
Guerra, S. J. Org. Chem. 1996, 61, 6849–6855; (g) See-
4. (a) Seebach, D.; Abele, S.; Schreiber, J. V.; Martinoni, B.;
Nussbaum, A. K.; Schild, H.; Schulz, H.; Hennecke, H.;
Woessner, R.; Bitsch, F. Chimia 1998, 52, 734–739; (b)
Hintermann, T.; Seebach, D. Chimia 1997, 51, 244–247;
(c) Hintermann, T.; Seebach, D. Synlett 1997, 437–438.
5. (a) Porter, E. A.; Weisblum, B.; Gellman, S. H. J. Am.
Chem. Soc. 2002, 124, 7324–7330; (b) Liu, D.; DeGrado,
W. F. J. Am. Chem. Soc. 2001, 123, 7553–7559; (c)
Porter, E. A.; Wang, X. F.; Lee, H. S.; Weisblum, B.;
Gellman, S. H. Nature 2000, 404, 565–565; (d) Hamuro,
Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc.
1999, 121, 12200–12201; (e) Werder, M.; Hauser, H.;
Abele, S.; Seebach, D. Helv. Chim. Acta 1999, 82, 1774–
1783.
6. (a) Abele, S.; Seiler, P.; Seebach, D. Helv. Chim. Acta
1999, 82, 1559–1571; (b) Seebach, D.; Abele, S.; Sifferlen,
T.; Ha¨nggi, M.; Gruner, S.; Seiler, P. Helv. Chim. Acta
1998, 81, 2218–2243.
7. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15.
8. Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.;
Ga´lvez, J. A. Tetrahedron: Asymmetry 2003, 14, preced-
ing paper.
9. Terashima, S.; Lee, K. K.; Yamada, I. Chem. Pharm.
Bull. 1969, 17, 2533–2539.
10. Juaristi, E.; Balderas, M.; Ram´ırez-Quiro´s, Y. Tetra-
hedron: Asymmetry 1998, 9, 3881–3888.