A practical synthesis of 3-ethyl-l-norvaline

Article abstract of DOI:10.1016/j.tetasy.2006.02.002

An efficient process for the synthesis of 3-ethyl-l-norvaline has been developed. The route makes use of a Strecker reaction, whereby (S)-(-)-α-methylbenzylamine acts as a chiral auxiliary to provide nearly diastereomerically pure α-amino nitrile. Crystal

Full text of DOI:10.1016/j.tetasy.2006.02.002

Tetrahedron: Asymmetry 17 (2006) 846–849
A practical synthesis of 3-ethyl-L-norvaline
Lynn Resnicka,* and Rocco J. Galanteb
aWyeth Research, Chemical and Screening Sciences, PO Box CN 8000, Princeton, NJ 08543, USA
bWyeth Research, Chemical and Screening Sciences, 401 N. Middletown Road, Pearl River, NY 10965, USA
Received 30 January 2006; accepted 2 February 2006
Available online 28 February 2006
Abstract—An efficient process for the synthesis of 3-ethyl-L-norvaline has been developed. The route makes use of a Strecker reac-
tion, whereby (S)-(ꢀ)-a-methylbenzylamine acts as a chiral auxiliary to provide nearly diastereomerically pure a-amino nitrile. Crys-
tallization-induced asymmetric transformation enhances the yield and diastereomeric ratio and allows for efficient isolation of the
product. The amino nitrile intermediate is converted to enantiomerically pure 3-ethyl-L-norvaline in three steps.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The synthesis of unnatural, enantiomerically pure
a-amino acids has become increasingly important.1–3
Unnatural a-amino acids are used, for example, as inter-
mediates in the synthesis of drug candidates and natural
products, as substitutes of natural amino acids in pep-
tides and proteins, and as ligands for chiral induction.
Over the course of a drug development program, it
became essential to design a practical method for the
synthesis of 3-ethyl-L-norvaline 1. Although several
methods for the preparation of this compound have
been described,4–6 it was determined that these methods
are too cumbersome and/or expensive for the purposes
of a process scale preparation and, as such, we em-
barked on the development of a new route. This route
involves a chiral Strecker reaction, where (S)-(ꢀ)-a-
methylbenzylamine is used as a chiral auxiliary to pro-
vide an optically pure amino nitrile.7–12 This intermedi-
ate can be readily converted to the corresponding amino
acid by conventional functional group manipulation.
The first step in our synthesis of 3-ethyl-L-norvaline is
the chiral Strecker reaction (Scheme 1). Thus, (S)-(ꢀ)-
a-methylbenzylamine hydrochloride 3 was reacted with
2-ethylbutyraldehyde 2 and potassium cyanide to give
amino nitriles 4 and 5 in a 4:1 ratio as determined by
1H NMR spectroscopy (Table 1, entry 1). Subsequent
recrystallization with MeOH/H2O provided a 70% yield
of amino nitrile 4 with a diastereomeric ratio of >40:1
(entry 2). The stereochemical assignment of 4 was based
on literature precedence, where it has been shown that
the use of (S)-(ꢀ)-a-methylbenzylamine as a chiral auxi-
liary in the Strecker reaction gives the (S)-configuration
of the amino nitrile as the predominant stereoisomer.7–12
Additional proof, as will be described herein, was based
on the conversion of intermediate 4 to 3-ethyl-L-norval-
ine, whose specific rotation matched that of the value
reported in the literature.6
As our goal was to find the most efficient and highest
yielding process for scale-up, methods to improve the
Strecker reaction were sought. We realized that the yield
and efficiency of the reaction might be improved by
in situ crystallization of the product. To test this propo-
sition, the Strecker reaction was run with varying sol-
vent systems (entries 3–6). The use of H2O alone or
with MeOH in ratios of 1:4 and 2:1 resulted in the prod-
uct oiling out of solution. In the reaction with a 1:1 ratio
of H2O and MeOH, a white precipitate formed. After
this mixture was stirred for 24 h, the precipitate was
isolated by filtration and found to be amino nitrile 4
HO
NH2
O
1
*
Corresponding author. Tel.: +1 732 274 4780; fax: +1 732 274
4505; e-mail: resnicl@wyeth.com
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.002

L. Resnick, R. J. Galante / Tetrahedron: Asymmetry 17 (2006) 846–849
847
KCN,
solvent
+
H2N
HCl.
Ph
+
Ph
N
NC
Ph
N
NC
(Table 1)
H
O
H
H
2
3
4
5
Scheme 1.
Table 1. Reaction conditions for the chiral Strecker reactiona
Entry
Solvent
Ratio
Conc. (M)
T (h)
Reaction appearance
Isolation procedureb
Yield (%)
Ratio of 4 to 5c
1
2
3
4
5
6
7
8
9
MeOH
MeOH
1.0
1.0
0.1
0.1
0.1
0.1
0.1
0.4
0.4
24
24
24
24
24
24
24
24
36
Solution
Solution
Oil
Oil
Oil
Precipitate
Precipitate
Precipitate
Precipitate
A
B
95
70
79
81
79
74
79
98
99
4:1
>40:1
4:1
4:1
4:1
>40:1
24:1
19:1
>40:1
MeOH/H2O
MeOH/H2O
H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
1:4
2:1
C
C
C
D
C
D
D
1:1
1:1
1:1d
1:1d
a Reactions were carried out with equal molar amounts of 2-ethylbutyraldehyde, (S)-(ꢀ)-a-methylbenzylamine hydrochloride, and KCN at room
temperature.
b A: filtration, concentration of filtrate; B: A, followed by recrystallization with MeOH/H2O, 1:1; C: extraction with EtOAc from H2O; D: filtration.
c Diastereomeric ratios were determined by 1H NMR and HPLC. >40:1 means 5 was not detected by either method.
d (S)-(ꢀ)-a-Methylbenzylamine free base was used in place of the HCl salt and 1 equiv of HCl was added in 3 N aqueous solution.
(diastereomeric ratio >40:1), which was isolated in 74%
yield (entry 6).
a-methylbenzylamine as the chiral auxiliary. Boesten
et al. have recently reported the use of (R)-phenylglycine
amide for in situ crystallization-induced asymmetric
transformation of Strecker reactions.14
Next, we were interested in determining if crystalliza-
tion-induced asymmetric transformation occurred dur-
ing the reaction. This is a process where a single
diastereomer crystallizes preferentially from a solution
of equilibrating stereoisomers, thus increasing the ratio
of the less soluble diastereomer to more soluble diaste-
reomer.13 Indeed, in the reaction run as described in
entry 6, but where the product was isolated by extrac-
tion from EtOAc instead of filtration, the diastereomeric
ratio of amino nitrile 4 to amino nitrile 5 was 24:1 (entry
7). This is far greater than the 4:1 ratio that was
obtained from the reaction, where the product remained
in the solution (entry 1). Additionally, it has been dem-
onstrated that the enhancement of diastereomeric selec-
tivity is not due to the presence of H2O alone, since the
reactions described entries 3, 4, and 5 where H2O is pres-
ent, but precipitation did not occur, all gave diastereo-
meric ratios of 4:1.
With large quantities of readily available amino nitrile 4,
the synthesis of amino acid 1 was completed in a three-
step sequence (Scheme 2). Hydrolysis of nitrile 4 with
sulfuric acid provided amide 6 in quantitative yield.
Removal of the a-methylbenzyl chiral auxiliary by
palladium-catalyzed hydrogenation under 100 psi of
pressure provided amine 7, which after hydrolysis with
concentrated hydrochloric acid, yielded 3-ethyl-L-norval-
ine hydrochloride 8 with 1 equiv of ammonium chloride
in 73% yield. The free base and salt free form of the amino
acid was obtained by purification with DOWEX ion
exchange resin (acidic form) to give amino acid 1 with a
specific rotation that matches that in the literature.6
H2, Pd/C,
MeOH
conc. H2SO4
100%
The trial reactions described above were performed on
an 8 mmol scale (entries 1–7). Upon scale-up to 1 mol,
reactions were run at 0.35 M concentration of each
reagent instead of 0.10 M. The higher concentration
and increased scale provided a better yield, but lower
diastereomeric purity (entry 8, 98% yield, 19:1 diaster-
eomeric ratio). By increasing the run time from 24 to
36 h, a nearly quantitative yield product with a diaste-
reomeric purity of >97% was obtained. The improve-
ment in diastereomeric purity with increased time
further validates the mechanism of crystallization-
induced asymmetric transformation.
H2N
4
H2N
NH2
Ph
85%
N
O
H
7
O
6
DOWEX
(acid form)
+
NH4Cl
NH3+ Cl-
conc. HCl
HO
HO
NH2
73%
1
O
8
O
Scheme 2.
3. Conclusion
A
precedence for in situ crystallization-induced
asymmetric transformation of Strecker reactions exists;
however, the phenomenon was never claimed with
A scalable synthesis of 3-ethyl-L-norvaline has been de-
scribed. The key step, a Strecker reaction, takes place

848
L. Resnick, R. J. Galante / Tetrahedron: Asymmetry 17 (2006) 846–849
with crystallization-induced asymmetric transformation
and provides an optimal yield of nearly diastereomeri-
cally pure a-amino nitrile 4. From intermediate 4, enan-
tiomerically pure 3-ethyl-L-norvaline 1 was prepared in
a high-yielding three-step sequence.
mer elutes at 33.65 min, (R,S)-isomer elutes at
33.10 min].
25
Mp = 57–58 ꢁC; ½aꢁD ¼ ꢀ187:4 (c 1.0, MeOH); 1H
NMR (400 MHz, DMSO-d6) d 7.30–7.34 (m, 4H),
7.22–7.26 (m, 1H), 3.85–3.89 (d, 1H, J = 6.6 Hz), 3.00
(dd, 1H, J = 5.8, 11.6 Hz), 2.93 (d, 1H, J = 11.6 Hz),
1.49–1.58 (m, 1H), 1.35–1.48 (m, 3H), 1.29 (d, 3H,
J = 6.6 Hz), 1.20–1.30 (m, 1H), 0.69–0.83 (m, 6H); MS
(ES+) m/z 272 (M+ACN+H), 231 (M+H), 204; IR
(ATR) 3300, 2950, 2925, 2875, 1450 cmꢀ1; Anal. Calcd
for C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C,
77.90; H, 9.75; N, 12.32.
4. Experimental
4.1. General
The starting materials were purchased from commercial
sources and used without further purification. Melting
points were taken on a Mel-Temp 3.0 capillary melting
point apparatus and are uncorrected. NMR spectra
were determined on a 500 MHz Varian Inova or a
400 MHz Varian Unity Plus spectrometer using Me4Si
as the internal standard. Mass spectra were obtained
on a Micromass LCT mass spectrometer. Optical
rotation were obtained with a Jasco P-1020 polarimeter
with a 30 mm cell. IR were obtained on a Avatar 360
FT-IR.
4.3. 3-Ethyl-N2-[(1S)-1-phenylethyl]-L-norvalinamide 6
Concentrated sulfuric acid (400 mL) was cooled to 4 ꢁC
and amino nitrile 4 (200 g, 868 mmol) added. After the
mixture was stirred at room temperature for 24 h it
was poured onto ice and then concentrated NH4OH
(1 L) added until the pH was 8. The mixture was
extracted with EtOAc, dried over Na2SO4, and concen-
trated to give 215 g (100% yield) of a pale yellow oil.
25
½aꢁD ¼ ꢀ68:4 (c 1.0, MeOH); 1H NMR (400 MHz,
4.2. (2S)-3-Ethyl-2-{[(1S)-1-phenylethyl]amino}-
pentanenitrile 4
DMSO-d6) d 7.26–7.30 (m, 5H), 7.17–7.21 (m, 1H),
6.97 (s, 1H), 3.50 (q, 1H, J = 6.5 Hz), 2.57 (br s, 1H),
2.04 (br s, 1H), 1.40–1.47 (m, 1H), 1.21 (d, 3H, J =
6.6 Hz), 1.14–1.25 (m, 4H), 0.68 (t, 3H, J = 7.2 Hz),
0.57 (t, 3H, J = 7.3 Hz); MS (ES+) m/z 249 (M+H);
IR (ATR) 3450, 3300, 3200, 1670 cmꢀ1; Anal. Calcd
for C15H24N2O: C, 72.54; H, 9.74; N, 11.28. Found:
C, 72.24; H, 10.04; N, 11.01.
4.2.1. Small scale preparation and trial reactions.
A
mixture of (S)-(ꢀ)-a-methylbenzylamine hydrochloride
(315 mg, 2.00 mmol), potassium cyanide (130 mg,
2.00 mmol), and 2-ethylbutyraldehyde (250 lL, 2.00
mmol) in solvent (20 mL, see Table 1) was stirred for
24 h. Products were isolated by method A, B, C, or D.
Product purity and diastereomeric ratios were
determined by LC/MS and 1H NMR as described
below:
4.4. 3-Ethyl-L-norvalinamide 7
Benzyl amino amide 6 (40 g, 0.16 mol) and 5% Pd/C
(5.9 g) in MeOH (400 mL) were hydrogenated at
100 psi for 24 h. The catalyst was removed via filtration
through Celite. Concentration of the filtrate gave 19.7 g
(85% yield) of a solid. ½aꢁD ¼ þ3:4 (c 1.0, MeOH); H
NMR (400 MHz, DMSO-d6) d 7.29 (s, 1H), 6.89 (s,
1H), 3.07 (d, 1H, J = 4.6 Hz), 1.52 (br s, 2H), 1.40–
1.46 (m, 1H), 1.24–1.34 (m, 3H), 1.09–1.20 (m, 1H),
0.84 (t, 3H, J = 7.3 Hz), 0.79 (t, 3H, J = 7.5 Hz); MS
(ES+) m/z 186 (M+ACN+H), 145 (M+H); IR (ATR)
3500, 3200, 2970, 2925, 2880, 1650 cmꢀ1; Anal. Calcd
for C7H16N2O+0.1 H2O: C, 57.58; H, 11.18; N, 19.18.
Found: C, 57.83; H, 11.19; N, 18.92.
Method A: The reaction mixture was filtered to remove
salts and then the filtrate was concentrated
in vacuo.
Method B: The reaction mixture was filtered and then
the filtrate was concentrated in vacuo.
Recrystallization of the resulting residue
from MeOH/H2O, 1:1 provided the title
compound.
Method C: Water was added to the reaction mixture. It
was then extracted with ethyl acetate, dried
over Na2SO4, and concentrated.
Method D: The reaction mixture was filtered and the
precipitate collected and dried.
25
1
4.5. 3-Ethyl-L-norvaline, hydrochloride 8
4.2.2. Large-scale preparation. A mixture of (S)-(ꢀ)-a-
methylbenzylamine (135 g, 1.11 mol), potassium cyanide
(72.5 g, 1.11 mol), and 2-ethylbutyraldehyde (118 g,
1.18 mol) in 3 M HCl (375 mL), water (1.2 L), and
MeOH (1.6 L) was stirred at room temperature for 3
days. The resulting solids were collected via filtration
and air dried to give 254 g (98% yield) of a white preci-
pitate, with >30:1 diastereomeric purity as judged by
HPLC [Phenomenex LUNA C8 (z) 100 · 2.0 mm,
3 mm particle size, A (95% water/5% acetonitrile) with
ammonium acetate additive, B (95% acetonitrile/5%
water) with ammonium acetate additive, gradient:
100% A for 1 min, to 100% B at time 40 min, (S,S)-iso-
Amino amide 7 (47.9 g, 0.33 mol) in concd HCl was
heated at reflux for 24 h. The mixture was then concen-
trated under vacuum to give a solid. Trituration with
acetone gave 56.4 g (73% yield) of a solid, which con-
sisted of amino acid hydrochloride salt and 1 equiv of
25
NH4Cl. ½aꢁD ¼ þ13:9 (c 1.0, H2O); 1H NMR
(400 MHz, DMSO-d6) d 8.19 (br s, 3H), 7.19 (t, 4H,
J = 50.7 Hz), 3.84 (d, 1H, J = 3.05 Hz), 1.65–1.69 (m,
1H), 1.40–1.48 (m, 1H), 1.30–1.47 (m, 2H), 1.20–1.29
(m, 1H), 0.86–0.91 (m, 6H); MS (ES+) m/z 146
(M+H); IR (ATR) 3350, 2900, 1720 cmꢀ1
.

L. Resnick, R. J. Galante / Tetrahedron: Asymmetry 17 (2006) 846–849
849
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4.6. 3-Ethyl-L-norvaline 1
3-Ethyl-L-norvaline, hydrochloride
1.07 mmol) was dissolved in 1 M HCl (10 mL) and
applied to a column of Dowex-50W-hydrogen, strongly
acidic (50W X 8-400) ion-exchange resin. Salts were
eluted with MeOH/H2O, 1:1 (50 mL), and then the
amino acid was eluted with 1 M ammonium hydro-
8
(250 mg,
xide (150 mL) to give 123 mg (79% recovery) of the
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title compound. ½aꢁD ¼ þ40 (c 0.5, 5 M HCl); 1H
NMR (400 MHz, DMSO-d6) d 7.10 (br s, 3H), 3.15
(d, J = 2.6 Hz), 1.60 (m, 1H), 1.08–1.42 (m, 4H),
0.70–0.90 (m, 6H); MS (ES-) m/z 144 (MꢀH); Anal.
Calcd for C7H15NO2+0.1 H2O: C, 57.19; H, 10.42; N,
9.53. Found: C, 56.91; H, 10.28; N, 9.68.
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¨
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´
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Dielemans, H. J. A.; Elsenberg, H. L. M.; Kaptein, B.;
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