Asymmetric synthesis of (S)-and (R)-α-methylserine based on the chiral recyclable reagent (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide

Article abstract of DOI:10.1023/A:1011321419512

Both enantiomers of α-methylserine were synthesized with the use of Ni^II complexes based on the chiral recyclable reagent (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide. Intermediate diastereomeric complexes were separated by crystal

Full text of DOI:10.1023/A:1011321419512

Russian Chemical Bulletin, International Edition, Vol. 50, No. 6, pp. 1037—1040, June, 2001
1037
Organic Chemistry
Asymmetric synthesis of (S)- and (R)-α-methylserine based
on the chiral recyclable reagent (S)-N-(2-benzoyl-
phenyl)-1-benzylpyrrolidine-2-carboxamide
«
Yu. N. Belokon´, V. I. Maleev, T. F. Savel´eva, and N. S. Ikonnikov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
2
8 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Å-mail: yubel@ineos.ac.ru
Both enantiomers of α-methylserine were synthesized with the use of NiII complexes
based on the chiral recyclable reagent (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carb-
oxamide. Intermediate diastereomeric complexes were separated by crystallization of their
O-acetyl derivatives.
Key words: asymmetric synthesis, chiral reagent, (S)-2-methylserine, (R)-2-methylserine,
NiII complexes.
Protein amino acids, which are of paramount impor-
tance and in great demand, are generally prepared by
microbiological methods.1 Presently, there is also a
need for non-protein amino acids because enan-
tiomerically pure α,α-disubstituted amino acids are con-
stituents of peptide antibiotics2 and are of great impor-
tance in contemporary pharmacology as potential amino
acid residue possesses rather high C—H-acidity6 due to
which these complexes readily react with different alkyl
halides and add substrates containing the C=O and
activated C=C bonds. The starting compounds, viz.,
BPB, Ni-BPB-Gly, and Ni-BPB-Ala, are available in
amounts of up to 1 kg.7
A concrete application of this procedure is the syn-
3
8
acid decarboxylase inhibitors, neuroendogenic regula-
thesis of α-methylserine (α-MeSer), which is an impor-
4
9
tors of hormonal systems, and medicines for the treat-
tant non-protein amino acid (peptide χ-spacer). It should
ment of epilepsy, Altzheimer's and Parkinson's diseases,
schizophrenia, ischemia, and Huntington's fever.5
We have developed (and successfully used over
be noted that the possibility of the synthesis of both
enantiomers of the amino acid in one experiment or
with the use of a single chiral inducing agent was taken
into account when developing the method proposed.
1
5 years) a method for the synthesis of protein, non-
protein, and isotopically labeled amino acids with the
use of a chiral recyclable reagent based on proline, viz.,
Results and Discussion
(
S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carb-
II
oxamide (BPB). In Ni complexes of Schiff's bases of
glycine and alanine with BPB (Ni-BPB-Gly and
Ni-BPB-Ala, respectively), the Cα atom of the amino
We used the Ni-BPB-(S,R)-Ala complex (1) as the
starting compound and performed its condensation with
formaldehyde (Scheme 1). The stereoselectivity of the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 993—996, June, 2001.
066-5285/01/5006-1037 $25.00 © 2001 Plenum Publishing Corporation
1

1
038
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
Belokon´ et al.
Scheme 1
Ph
O
O
O
N
O
N
O
N
O
N
H
Ni
Ni
Ni
a
Me
CH OH
2
+
N
Me
O
CH OH
2
Me
(S)-2
(R)-2
1
b
HO
O
O
N
O
O
O
CH OAc
d
Ni
Ni
Me
Me
CH OH
2
H N
N
2
CH OAc
2
2
Me
(S)-4, ee > 99%
(R)-3, de 60%
(
S)-3, de >95%
precipitate
solution
Mixture of diastereomers
chromatographic
ñ
(
BPB
separation or
regeneration of BPB)
total yield
0%
9
O
O
HO
O
d
Ni
CH OH
CH OH
2
2
N
H N
2
Me
Me
(R)-4, ee 99%
(R)-2, de > 95%
precipitate
Reagents and conditions: a, CH O/KOH, MeOH; b, 1) Ac O, MeCN, 75 °C, 2) Crystallization from
2
2
MeOH; c, 1) MeONa, 2) Crystallization from an MeOH + H O mixture; d, HCl—MeOH
2
reaction carried out under conditions of both kinetic
and thermodynamic control was at most 35%.8 We
failed to improve the stereoselectivity by changing the
structure of the chiral reagent due apparently to a small
complex from the mixture (containing the diastereomeric
complexes in a ratio of ∼ 1 : 1) failed.
In the course of these attempts, we found the follow-
ing empirical regularity: the diastereomeric complexes
are inseparable by crystallization if the (S)-2/(R)-2 ratio
is in the range of 1.25—0.8.
In the present study, we separated the diastereomeric
complexes by crystallization of the O-acetyl derivatives
(S)-3 and (R)-3 prepared by acylation of the initial
mixture of (S)-2 and (R)-2 in the ratio of 2 : 1. In this
case, the major isomer (S)-3 was isolated much more
completely. The ratio between the diastereomers (S)-3
and (R)-3 that remained in the mother liquor was 1 : 4,
difference in the size of the Me and CH OH groups.
2
Previously, both enantiomers of α-MeSer have been
obtained using chromatographic separation of the
diastereomeric complexes Ni-BPB-(S)-α-MeSer ((S)-2)
8
and Ni-BPB-(R)-α-MeSer ((R)-2). Attempts to crys-
tallize the reaction mixture made it possible to isolate
(
in poorly reproducible experiments) only the prevailing
diastereomeric complex (S)-2 in the pure form. There-
after attempts to isolate any diastereomerically pure

Chiral synthesis of (S)- and (R)-α-methylserine
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
1039
unlike 1 : 1 obtained in the case of the nonacylated
complexes. The mixture of the diastereomers from the
mother liquors was deacetylated and recrystallized. This
made it possible to isolate the second diastereomeric
complex (R)-2 in the pure form. An insignificant amount
of a mixture of the diastereomeric complexes remained
in the mother liquor can be separated by column chro-
matography to obtain an additional amount of each
remove traces of Ac2O and recrystallized from MeOH (20 mL).
The mixture was kept at 0 °C for 1 h and the precipitate that
formed was filtered off, washed with cold MeOH, and dried in
air. Pure complex (S)-3 was obtained as bright-red crystals in a
yield of 4.88 g (8.4 mmol, 46%), m.p. 240—242 °C. Found (%):
C, 64.06; H, 5.36; N, 7.21. Calculated for C31H31N NiO :
3
5
C, 63.72; H, 5.35; N, 7.19. 1H NMR (CDCl ), δ: 1.25 (s, 3 H,
3
Me); 1.9—2.2 (m, 2 H, CH , β,γ-Pro); 2.31 (s, 3 H, OAc);
2
2.4—2.6 (m, 1 H, CH , β-Pro); 2.6—2.8 (m, 1 H, CH , γ-Pro);
2
2
8
3.4—3.6 (m, 2 H, CH , δ-Pro); 3.6—3.8 (m, 1 H, CH, α-Pro);
diastereomer as described previously. After decomposi-
tion of the diastereomerically pure complexes, the target
amino acids, viz., (S)- and (R)-α-MeSer, (S)-4 and
2
3
4
.97 and 4.03 (AB, 2 H, CH OAc, J
= 11.5 Hz); 3.70 and
AB
2
.43 (AB, 2 H, ArCH N, J
= 12.8 Hz); 6.5—8.1 (m, 14 H,
AB
2
Ar). The mother liquor was concentrated to dryness and the
residue was recrystallized from CCl4 (20 mL) and dried in air.
A product containig diastereomeric complexes (S)-3 and (R)-3
in a ratio of 1 : 4 (NMR spectral data) was obtained in a yield
of 3.85 g (6.6 mmol).
(
9
R)-4, were obtained with the optical purity higher than
9%. The chiral reagent BPB was regenerated in 90%
7
yield. The optical activity of BPB is retained and the
reagent was re-usable.
To summarize, we developed a procedure for the
preparation of both enantiomers of important non-
protein amino acid α-MeSer using the single chiral
recyclable reagent BPB, the diastereomeric nickel com-
plexes (S)-3 and (R)-3 being separated by crystalli-
zation.
Synthesis of diastereomeric complexes (S)-2 and (R)-2. A
4
.6 M MeONa solution (0.21 mL, 6.6 mmol) was added to a
solution of the mixture of diastereomeric complexes (S)-3 and
R)-3 (3.85 g, 6.6 mol) in MeOH (50 mL). The reaction
mixture was kept at 25 °C for 2 h, neutralized with AcOH
0.2 mL), and concentrated to dryness. The dry residue was
(
(
crystallized from a 2 : 1 MeOH—H O mixture (25 mL). The
2
precipitate that formed was filtered off and washed successively
with 2 : 1 and 1 : 1 MeOH—H O mixtures to obtain pure (R)-2
2
Experimental
in a yield of 2.13 g (3.94 mmol). Mother liquors were concen-
trated to dryness. The dry residue (1.43 g, (S)-2 : (R)-2 = 0.85)
can be decomposed to regenerate BPB, chromatographed to
isolate the diastereomers, or repeatedly acetylated (a solution of
The amino acids used were purchased from Reanal (Hun-
gary). All solvents were distilled before use. The NMR spectra
were recorded on a Bruker WP-200 instrument with Me Si
Ac O (4 mL) in MeCN (12 mL)) and then crystallized as
4
2
(
δ 0.00; in organic solvents) and formic acid (δ 8.20; in aqueous
described above. Crystallization from MeOH afforded pure
(R)-3 as bright-red crystals in a yield of 0.43 g (0.74 mmol),
m.p. 221—223 °C. Found (%): C, 64.12; H, 5.56; N, 7.12.
solutions) as the internal standards. The optical rotation was
measured on a Perkin—Elmer 241 polarimeter in a thermostati-
cally controlled cell at 25 °C. Enantiomeric analysis of the
amino acids as N-trifluoroacetyl derivatives of their n-propyl
esters was carried out by GLC on 40 m ½ 0.23-mm capillary
quartz columns with the Chirasil-L-Val chiral phase (thickness
C
31H31N NiO . Calculated (%): C, 63.72; H, 5.35; N, 7.19.
3 5
1
H NMR (CDCl ), δ: 1.68 (s, 3 H, Me); 1.95—2.25 (m, 2 H,
3
CH , β,γ-Pro); 2.16 (s, 3 H, OAc); 2.4—2.55 (m, 1 H, CH ,
2
2
β-Pro); 2.55—2.7 (m, 1 H, CH , γ-Pro); 3.3—3.5 (m, 2 H,
2
0
.12 µm) at 125 °C using helium as the carrier gas. The starting
CH , δ-Pro, CH, α-Pro); 3.55—3.7 (m, 1 H, CH , δ-Pro);
2
2
complex Ni—BPB-(S,R)-Ala was prepared according to a known
procedure.7
3.17 and 4.09 (AB, 2 H, CH OAc, J
= 12 Hz); 3.62 and
AB
2
4.50 (AB, 2 H, ArCH N, J
= 12.6 Hz); 6.5—8.1 (m,
AB
2
Condensation of complex
1
with formaldehyde. The
14 H, Ar).
Ni—BPB-(S,R)-Ala complex (1) (10 g, 0.0195 mol) and
Isolation of (S)-α-methylserine ((S)-4). 6 M HCl (24 mL)
was added to a solution of complex (S)-3 (4.88 g, 8.4 mmol) in
MeOH (12 mL). The reaction mixture was refluxed for 20 min
and MeOH was evaporated. The precipitate of BPB hydrochlo-
ride that formed was filtered off, washed several times with
water, and dried in air. The yield was 3.2 g (90%). The aqueous
layer was neutralized with a 25% NH3 solution and BPB that
(
(
CH O)n (11.7 g, 0.39 mol) were added to a solution of KOH
8.2 g, 0.146 mol) in MeOH (50 mL) under argon at 25 °C.
2
The reaction mixture was stirred under argon at 25 °C for 6 h
and neutralized with AcOH (10 mL). Then H O (21 mL) was
2
added to precipitate a mixture of diastereomers (S)-2 and
(
R)-2. Precipitation was completed in 10—12 h. The precipitate
was filtered off, washed with water, and dried in air. The
remained was extracted with CHCl . (S)-4 was isolated from
3
mixture of complexes (S)-2 and (R)-2 (2 : 1) with an admixture
the aqueous solution by ion-exchange chromatography on a
KU-2 (H ) cation-exchange resin; the amino acid was eluted
+
(
less than 2.5%) of the starting alanine complex (according to
the 1H NMR spectral data) was obtained in a yield of 8 g.
Storage of the mother liquor for additional 24 h gave an oil,
which slowly crystallized on seeding with complex (S)-2 to give
the precipitate (1.87 g) consisting of (S)-2 and the initial
complex 1 in a ratio of ∼ 7 : 1 ( H NMR spectral data). The
total yield of the crude mixture of complexes (S)-2 and (R)-2
was 9.87 g (89%), their ratio was ∼ 3 : 1.
from the column with aqueous NH . The eluate was concen-
3
trated and the residue (0.74 g) was crystallized from 80%
aqueous EtOH (9 mL). The yield was 0.6 g (63%), colorless
crystals, m.p. 293 °C. Found (%): C, 40.08; H, 7.41; N, 11.70.
C H NO . Calculated (%): C, 40.33; H, 7.62; N, 11.75.
1
4
9
3
2
5
25
[α]D –3.31 (c 5, 6 M HCl) (cf. Ref. 10: [α]D –3.4 (c 1.2, 6 M
HCl)). H NMR (D O), δ: 1.33 (s, 3 H, Me); 3.56 and 3.81
1
2
Synthesis of complexes 3. Ac O (30 mL, 0.318 mol) was
(AB, 2 H, CH , J
= 12 Hz). According to the data from
AB
2
2
added to a solution of the resulting mixture of diastereomers 2
enantiomeric analysis, the optical purity of amino acid (S)-4
was 98.8%.
(
9.87 g) in dry MeCN (65 mL) and the reaction mixture was
refluxed for 3—4 h. The course of the reaction was monitored
by TLC on silica gel in a 7 : 1 CHCl —Me CO solvent system.
After completion of the reaction, the solvent was distilled off in
vacuo. The residue was twice concentrated with PhMe to
Decomposition of a mixture of (R)-2 and (R)-3 and isola-
tion of (R)-α-methylserine ((R)-4) were carried out as de-
scribed above for the complexes with the (S)-amino acid. The
yield of BPB hydrochloride was 1.75 g (88%). (R)-4 was
3
2

1
040
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
Belokon´ et al.
isolated from the mixture of (R)-2 and (R)-3 (2.56 g) as
colorless crystals in a yield of 0.35 g (67%), m.p. 294 °C.
Found (%): C, 40.24; H, 7.58; N, 11.75. C H NO . Calcu-
4. D. W. Brann and V. B. Mahesh, Front. Neuroendocrinol.,
1994, 15, 3.
5. V. Bruno, G. Battaglia, A. Copani, R. G. Giffard, R. Riffale,
H. Schinozaki, and F. Nicoletti, Eur. J. Neurosci.,
1995, 61, 21.
6. M. I. Terekhova, Yu. N. Belokon´, V. I. Maleev, N. I.
Chernoglazova, K. A. Kochetkov, V. M. Belikov, and E. S.
Petrov, Izv. Akad. Nauk SSSR, Ser. Khim., 1986, 905 [Bull.
Acad. Sci. USSR, Div. Chem. Sci., 1986, 25, 824 (Engl.
Transl.)].
4
9
3
lated (%): C, 40.33; H, 7.62; N, 11.75. [α]D2 +3.48
5
2
5
(
1
c 5, 6 M HCl) (cf. Ref. 11: [α]D +3.6 (c 2.5, 5 M HCl)).
H
NMR (D O), δ: 1.32 (s,
3
H, Me); 3.57 and 3.82
2
(
AB, 2 H, CH O, J
2 AB
= 12 Hz). According to the data from
enantiomeric analysis, the optical purity of amino acid (R)-4
was 99%.
7
. Y. N. Belokon´, V. I. Tararov, V. I. Maleev, T. F. Savel´eva,
and M. G. Ryzhov, Tetrahedron: Asymmetry, 1998, 9, 4249.
. Yu. N. Belokon´, V. I. Tararov, and T. F. Savel´eva, Izv.
Akad. Nauk, Ser. Khim., 1991, 1175 [Russ. Chem. Bull.,
This work was financially supported by the Inter-
national Science and Technology Center (ISTC,
Grant A-356).
8
1
991, 40, 1054 (Engl. Transl.)].
. S. E. Gibson, N. Guillo, and M. J. Tozer, Tetrahedron,
999, 55, 585.
9
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