Highly diastereoselective synthesis of chimeras of proline and glutamate

Article abstract of DOI:10.1002/jhet.5570430608

Azomethine ylides have been generated from aromatic aldimines of α-amino acid methyl esters under treatment with LiBr/Et₃N and trapped with tert-butyl acrylate yielding racemic orthogonally protected cis-5-arylpyrrolidine-2,4-dicarboxylates reg

Full text of DOI:10.1002/jhet.5570430608

Nov-Dec 2006
1461
Highly Diastereoselective Synthesis of Chimeras of Proline and
Glutamate
Konstantin V. Kudryavtsev,* Mikhail Yu. Tsentalovich, Anton S. Yegorov, and
Eugene L. Kolychev
Department of Chemistry, Moscow State University, Leninskie Gory, 119992, Moscow, Russian Federation;
e-mail: kudr@org.chem.msu.ru
Received November 21, 2005
HO2 C
3 st eps
R2
CO2Me
O
R1
O
+
N
NH2
R2
Me
R1
(+/ -)
O
Azomethine ylides have been generated from aromatic aldimines of ꢀ-amino acid methyl esters under
treatment with LiBr/Et3N and trapped with tert-butyl acrylate yielding racemic orthogonally protected
cis-5-arylpyrrolidine-2,4-dicarboxylates regio- and stereo-selectively in high yields. Subsequent
N-methylation and deprotection of 4-carboxylic group of cycloaddition products led to novel proline-
glutamate cis-chimeras with substituents at 2 and 5 positions of pyrrolidine scaffold.
J. Heterocyclic Chem., 43, 1461 (2006).
Introduction.
R2-substituent and stepwise modification of
orthogonally protected carboxylic functions. cis-5-
Arylpyrrolidine-2,4-dicarboxylates (4) have been
planned to use as building blocks for construction of
appropriate libraries and subsequent high throughput
screening [7]. This purpose prompted us to develop
stereoselective, scalable and effective approach to
pyrrolidine-glutamate chimeras 4 and the results of
synthetic efforts towards the goal are presented here.
Combination of two amino acids fragments in one
scaffold, typically conformationally constrained, is an
actively used approach to non-proteinogenic ꢀ-amino
acids and subsequent construction of peptidomimetics.
Pyrrolidine 2,4-dicarboxylic acid (1) contains structural
features of proline and glutamic acid, and can be
considered as a chimera of these two proteinogenic ꢀ-
amino acids. trans-Isomer of 1 was isolated from the
seeds of Afzelia bella [1] and a potent competitive
inhibition of glutamate transport was demonstrated for
this compound [2]. Both cis- and trans-isomers of 1
have been used for synthesis of conformationally
restricted glutathione analogues [3]. Bulky substituent
in 5-position of proline ring influences on cis-/trans-
population of a peptide bond formed by nitrogen atom
of proline [4]. From other side aryl substituent in 5-
position improves pharmacological properties of
proline derivatives, namely mercaptoacyl 5-phenyl
proline (2) was identified as 3-fold more active than
captopril in inhibition of angiotensin converting
enzyme (ACE) [5]. The insertion of a phenyl group to
the 5-position of proline in a series of 2-mercapto-3-
phenylpropanoyl-Gly-(5-Ph)-Pro compounds led to
discovery of very potent orally active dual inhibitor 3
of neutral endopeptidase (NEP) and ACE endowed
with a long duration of action [6]. During our
discovery program there were needed cis-pyrrolidine-
2,4-dicarboxylates (4) with diverse aryl substituents in
5-position. Additional diversity points were designed at
2- and 4-positions of pyrrolidine ring by insertion of
MeO2C
HO2C
CO2H
N
CO2H
N
H
O
1
2
SH
HO
R3O2C
CO2H
OH
N
R2
CO2R4
O
N
O
NH
R5
R1
HS
4
3
Figure 1. Structural formula of proline-glutamate chimeras and 5-aryl-
prolines discussed in the introduction.

1462
K. Kudryavtsev, M. Tsentalovich, A. Yegorov, and E. Kolychev
Vol 43
Table 1
majority of recent published methods of similar diversity-
oriented cycloadditions [13,14]. Lithium bromide is also
typical reagent for metallo-1,3-dipole generation, but in
many cases cycloaddition is accompanied with Michael
addition products [10]. Nevertheless we have tried to
apply lithium bromide on the basis of it lower cost for
production of N-metalated azomethine ylides 6 and
succeeded in isolation of orthogonally protected prolines
7 in 80-97% yield as single stereoisomers (Table 1,
Scheme 2).
Substituents in synthesized compounds.
compound R1
R2
compound
R1
R2
a
b
c
d
e
f
2-F
H
g
h
i
2-Cl
4-Cl
4-MeO
4-F
Me
Me
Et
2,3-diF
2-F-5-MeO
3-Cl
H
H
H
j
Et
i-Bu
H
2-Me
Me
Me
k
3-pyridyl
Stereochemistry of synthesized racemates 7 is a result of
regio- and stereo-selective endo-cycloaddition process
controlled by lithium chelation of both syn dipole 6 and
tert-butyl acrylate (Scheme 2) and has been assigned by 1H
NMR spectroscopy. The cone anisotropy effect of the
phenyl ring at C-5 causes a characteristic upfield shift on
the protons of substituents at C-4 that are cis with regard to
that phenyl group. For example, the proton signals of the
Results and Discussion.
The most satisfactory conditions for conducting the
synthesis of compounds 4 were found to be those favored
by Tsuge [8,9] and Grigg [10,11]. Both groups exten-
sively studied 1,3-cycloaddition of electron-deficient
olefins to metallo-azomethine ylides generated from
ꢀ-amino acid esters Schiff bases.
Scheme 1
R1
R1
HO2C
t-BuO2C
t-BuO2C
R2
R2
CO2Me
+
+
CO2Me
N
N
O
H2N
N
H
Me
R2
R2
R1
R1
O
O
O
O
Retrosynthesis of orthogonally protected N-methyl-5-arylpyrrolidine-2,4-dicarboxylates.
Since we aimed to have orthogonally protected
tert-butoxycarbonyl group at C-4 in compounds 7 appear
around 1.0 ppm. This value is 0.4 ppm more shielded than
that of the tert-butoxycarbonyl groups protons in tert-butyl
esters of aliphatic carboxylic acids (typically at 1.4 ppm).
This effect is also observed in the protons of the methyl
group at C-4 of similar pyrrolidine-2,4-dicarboxylates
[8,15]. It is worth to note that 1,3-dipolar cycloaddition
occurs with sterically hindered imine 5k (R2=i-Bu) under
the general used conditions while the cycloaddition of
iminoester with R2=i-Pr is reported to take place only
under treatment with stronger base DBU [8].
carboxylic functions and methylated nitrogen atom [12] at
the pyrrolidine scaffold 4 the retrosynthetic Scheme 1 was
developed. It is based on cycloaddition of tert-butyl
acrylate with 1,3-dipole generated from iminoester
obtained in its turn from benzaldehyde and ꢀ-amino acid
methyl ester.
Required iminoesters 5 were readily obtained from
substituted benzaldehydes and methyl esters of glycine,
alanine, 2-aminobutyric acid, leucine under dehydrating
conditions (Scheme 2). Silver (I) salts were used in the
Scheme 2
t-
BuO2C
Me
Me
O
O
b)
a)
R2
R2
OMe
R1
R1
O
_
+
R2
O
Me
CO2Me
N
N
MeO
NH2
R2
N
H
+
R1
O
Li
OMe
O
R1
5a-k, 90-98%
6
(+/-)7a-k, 80-97%
Reaction conditions: a) MgSO4, Et3N, CH2Cl2, rt; b) t-Bu acrylate, LiBr, Et3N, THF, rt.

Nov-Dec 2006
Highly Diastereoselective Synthesis of Chimeras of Proline and Glutamate
1463
Two approaches were used for subsequent
N-methylation and appropriate deprotection of
4-carboxylic function in pyrrolidine-2,4-dicarboxylates
(7). The first is a two-step consequent alkylation - acidic
cleavage of tert-butyl ester procedure (Scheme 3, steps a
and b). It works quite acceptable for simple 5-aryl
substituents (2-F-phenyl (a), phenyl (e)) but in the case of
3-pyridyl substituent (compound 7k) the quaternization of
heteroaromatic nitrogen was the only observed process
under CH3I treatment. This problem has been overcome
with reductive methylation of pyrrolidine 7k using
formaldehyde and formic acid (Scheme 3, step c) resulted
in formation of nicotine analog 9k. The same procedure
was applied for compounds 7b-d, f-j and N-methyl-
pyrrolidine-2,4-dicarboxylates (9b-d, f-j) were isolated in
35-65% yield that is comparable with 35-50% combined
yield for two-step procedure.
establish stereochemistry of amino acids 9 X-ray analysis
of dicarboxylate 9b has been done [16]. In the molecule
9b, all bond lengths lie in the ordinary ranges for organic
compounds. In crystal, two enantiomeric molecules
related by symmetry centre are combined into hydrogen-
bonded dimeric units (figure 2).
In conclusion, an effective method of synthesis of N-
methyl-cis-5-arylpyrrolidine-2,4-dicarboxylates (9) based
on 1,3-dipolar cycloaddition was developed. Different
protection of carboxylic functionalities in chimeras 7 and
9 allows their subsequent independent transformations.
EXPERIMENTAL
Melting points are uncorrected. 1H NMR spectra were
recorded on a Bruker AMX-400 spectrometer in dimethyl
sulfoxide-d6 solutions. Chemical shifts (ꢀ, ppm) were referenced
Scheme 3
c)
HO2C
t-BuO2C
t-
BuO2C
R2
R2
R2
a)
b)
CO2Me
CO2Me
CO2Me
N
N
N
H
Me
Me
R1
R1
R1
(+/-)7a-k
Reaction conditions: a) CH3I, DMF, rt; b) HCl, CH2Cl2, rt; c) HCO2H, HCOH, reflux.
(+/-)8, 66-94%
(+/-)9a-k, 35-67%
to dimethyl sulfoxide-d5 signal (ꢀ H = 2.50 ppm) and coupling
constants (J) are indicated in Hz.
One of the marked features of compounds 9 is a big
3
magnitude of J(H4-H5) coupling constant according 1H
NMR experiments – 10.0-10.5 Hz. To undoubtedly
General Procedure for the Synthesis of Iminoesters 5 [14].
Under inert atmosphere corresponding benzaldehyde (1.0 eq)
was added to a suspension of amino acid methyl ester hydro-
chloride (1.1 eq), MgSO4 (2.0 eq), and NEt3 (1.1 eq) in CH2Cl2.
Resulted mixture was stirred at rt overnight. The solid was
removed by filtration and the filtrate was washed once with
H2O. The aqueous phase was extracted once with CH2Cl2 and
the combined organic layers were washed with brine. The
organic phase was dried over Na2SO4, filtered and concentrated.
Products were sufficiently pure by 1H NMR and used in the next
step without additional purification.
General Procedure for the Cycloaddition Reactions of tert-Butyl
acrylate with Aldimines 5.
Solution of 4.18 g (48.0 mmol) of LiBr in dry THF (16 ml)
was added dropwise to the stirred mixture of 5.10 ml (35.2
mmol) of tert-butyl acrylate, 32 mmol of aldimine 5 and 54 ml
of dry THF under inert atmosphere. After cooling to 5°C 5.40 ml
(38.4 mmol) of Et3N were added dropwise with the rate not
allowing the reaction temperature exceed 20°C. The mixture was
stirred at rt 24 h. The reaction was quenched by addition of a
saturated aqueous solution of NH4Cl (60 ml) and extracted with
Et2O (3 x 40 ml). The combined organic layers were washed
with brine, dried over Na2SO4, and the solvent was evaporated.
Figure 2. Hydrogen – bonded dimers in the crystal structure of 9b.
O(1)-H(1) 0.90(2), H(1)…O(2A) 1.76(2), O(1)…O(2A) 2.657(1)
Å; O(1)-H(1)...O(2A) 177(2)°

1464
K. Kudryavtsev, M. Tsentalovich, A. Yegorov, and E. Kolychev
Vol 43
The crude products were purified by column chromatography on
silica gel using hexane/AcOEt as an eluent.
(s, 3H, COOCH3); 4.75 (d, J 8.5, 1H, H-5); 7.06-7.15 (m, 3H,
Ar); 7.33-7.39 (m, 1H, Ar).
Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found:
C, 68.19; H, 8.20; N, 4.39.
(2S*,4S*,5R*)-5-(2-Fluorophenyl)pyrrolidine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-methyl ester (7a).
(2S*,4S*,5R*)-5-(2-Chlorophenyl)-2-methylpyrrolidine-2,4-dicar-
boxylic acid 4-tert-butyl ester 2-methyl ester (7g).
This compound was obtained as a white solid, mp 53°C. Yield
1
93%. H NMR: ꢀ 0.96 (s, 9H, t-C4H9); 2.15-2.23 (m, 1H, H-3);
This compound was obtained as a white solid, mp 102-104°C.
1
2.26-2.34 (m, 1H, H-3); 3.23 (dd, 1H, J 14.9, 7.1, H-4); 3.70 (s,
3H, COOCH3); 3.86 (dd, 1H, J 7.6, 7.6, H-2); 4.63 (m, 1H, H-5);
7.09-7.18 (m, 2H, Ar); 7.30 (dddd, 1H, J 13.5, 7.6, 5.4, 1.7, Ar);
7.51 (ddd, 1H, J 7.6, 1.7, 1.7, Ar).
Anal. Calcd for C17H22FNO4: C, 63.14; H, 6.86; N, 4.33.
Found: C, 62.95; H, 6.80; N, 4.24.
Yield 87%. H NMR: ꢀ 0.93 (s, 9H, t-C4H9); 1.38 (s, 3H, CH3);
1.96 (dd, J 13.1, 8.3, 1H, H-3); 2.59 (dd; J 13.1, 6.1, 1H, H-3);
3.14 (br s, 1H, NH); 3.44 (ddd, J 8.3, 8.3, 6.1, 1H, H-4); 3.69 (s,
3H, COOCH3); 4.91 (d, J 8.3, 1H, H-5); 7.22-7.32 (m, 2H, Ar);
7.38 (dd, J 7.5, 1.8, 1H, Ar); 7.59 (dd, J 7.5, 1.8, 1H, Ar).
Anal. Calcd for C18H24ClNO4: C, 61.10; H, 6.84; N, 3.96.
Found: C, 61.29; H, 6.90; N, 4.09.
(2S*,4S*,5R*)-5-(2,3-Difluorophenyl)pyrrolidine-2,4-dicarbox-
ylic acid 4-tert-butyl ester 2-methyl ester (7b).
(2S*,4S*,5R*)-5-(4-Chlorophenyl)-2-methylpyrrolidine-2,4-
dicarboxylic acid 4-tert-butyl ester 2-methyl ester (7h).
This compound was obtained as a white solid, mp 89°C. Yield
92%. H NMR: ꢀ 1.00 (s, 9H, t-C4H9); 2.16-2.33 (m, 2H, H-3);
1
3.25-3.31 (m, 1H, H-4); 3.69 (s, 3H, COOCH3); 3.82-3.91 (m,
1H, H-2); 4.71 (dd, J 7.6, 7.6, 1H, H-5); 7.13-7.20 (m, 1H, Ar);
7.26-7.33 (m, 1H, Ar); 7.33-7.39 (m, 1H, Ar).
Anal. Calcd for C17H21F2NO4: C, 59.82; H, 6.20; N, 4.10.
Found: C, 59.59; H, 6.12; N, 4.20.
This compound was obtained as a white solid, mp 110-111°C.
Yield 97%. H NMR: ꢀ 0.98 (s, 9H, t-C4H9); 1.35 (s, 3H, CH3);
1.91 (dd, J 13.1, 7.8, 1H, H-3); 2.44-2.54 (m; 1H, H-3); 3.13 (br
s, 1H, NH); 3.25-3.36 (m, 1H, H-4); 3.68 (s, 3H, COOCH3);
4.60 (d, J 8.8, 1H, H-5); 7.27-7.38 (m, 4H, Ar).
1
Anal. Calcd for C18H24ClNO4: C, 61.10; H, 6.84; N, 3.96.
Found: C, 61.25; H, 6.80; N, 4.19.
(2S*,4S*,5R*)-5-(2-Fluoro-5-methoxyphenyl)pyrrolidine-2,4-
dicarboxylic acid 4-tert-butyl ester 2-methyl ester (7c).
(2S*,4S*,5R*)-2-Ethyl-5-(4-methoxyphenyl)pyrrolidine-2,4-
dicarboxylic acid 4-tert-butyl ester 2-methyl ester (7i).
This compound was obtained as a white solid, mp 62-63°C.
Yield 80%. H NMR: ꢀ 1.00 (s, 9H, t-C4H9); 2.14-2.31 (m, 2H,
1
1
This compound was obtained as an oil. Yield 97%. H NMR:
H-3); 3.20 (ddd, J 8.3, 8.3, 8.3, 1H, H-4); 3.69 (s 3H, ArOCH3);
3.71 (s, 3H, COOCH3); 3.85 (dd, J 8.5, 8.5, 1H, H-2); 4.63 (d, J
8.3, 1H, H-5); 6.81 (ddd, J 8.8, 3.3, 3.3, 1H, Ar); 7.00-7.11 (m,
2H, Ar).
Anal. Calcd for C18H24FNO5: C, 61.18; H, 6.85; N, 3.96.
Found: C, 60.90; H, 6.85; N, 3.89.
ꢀ 0.79 (t, J 7.3, 3H, CH2CH3); 1.00 (s, 9H, t-C4H9); 1.57-1.77
(m, 2H, CH2CH3); 1.98 (dd, J 13.5, 7.8, 1H, H-3); 2.43 (dd, J
13.5, 5.6, 1H, H-3); 2.95 (d, J 9.5, 1H, NH); 3.20 (ddd, J 7.8,
7.8, 5.6, 1H, H-4); 3.71 (s, 3H, COOCH3); 3.72 (s, 3H,
ArOCH3); 4.43 (dd, J 9.5, 7.8, 1H, H-5); 6.87 (d, J 8.6, 2H, Ar);
7.18 (d, J 8.6, 2H, Ar).
(2S*,4S*,5R*)-5-(3-Chlorophenyl)pyrrolidine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-methyl ester (7d).
Anal. Calcd for C20H29NO5: C, 66.09; H, 8.04; N, 3.85. Found:
C, 65.95; H, 8.00; N, 3.70.
1
This compound was obtained as an oil. Yield 95%. H NMR:
(2S*,4S*,5R*)-2-Ethyl-5-(4-fluorophenyl)pyrrolidine-2,4-dicar-
boxylic acid 4-tert-butyl ester 2-methyl ester (7j).
ꢀ 1.02 (s, 9H, t-C4H9); 2.13-2.29 (m, 2H, H-3); 3.22 (ddd, J 7.8,
7.8, 8.6, 1H, H-4); 3.27 (s, 1H, NH); 3.69 (s, 3H, COOCH3);
3.86 (dd, J 8.3, 8.3, 1H, H-2); 4.46 (d, J 8.6, 1H, H-5); 7.26-7.32
(m, 3H, Ar); 7.39-7.41 (m, 1H, Ar).
This compound was obtained as a white solid, mp 39°C. Yield
1
95%. H NMR: ꢀ 0.80 (t, J 7.3, 3H, CH2CH3); 1.00 (s, 9H, t-
C4H9); 1.59-1.78 (m, 2H, CH2CH3); 1.99 (dd, J 13.5, 7.8, 1H, H-
3); 2.45 (dd, J 13.5, 5.7, 1H, H-3); 3.04 (br s, 1H, NH); 3.24
(ddd, J 7.8, 7.8, 5.7, 1H, H-4); 3.70 (s, 3H, COOCH3); 4.51 (m,
1H, H-5); 7.10-7.16 (m, 2H, Ar); 7.28-7.35 (m, 2H, Ar).
Anal. Calcd for C19H26FNO4: C, 64.94; H, 7.46; N, 3.99.
Found: C, 65.05; H, 7.58; N, 3.79.
Anal. Calcd for C17H22ClNO4: C, 60.09; H, 6.53; N, 4.12.
Found: C, 60.30; H, 6.65; N, 4.00.
(2S*,4S*,5R*)-2-Methyl-5-phenylpyrrolidine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-methyl ester (7e).
This compound was obtained as a white solid, mp 50-52°C.
1
Yield 85%. H NMR: ꢀ 0.96 (s, 9H, t-C4H9); 1.38 (s, 3H, CH3);
1.97 (dd, 1H, J 13.1, 7.8, H-3); 2.47-2.55 (m, 1H, H-3); 3.30-
3.37 (m, 1H, H-4); 3.71 (s, 3H, COOCH3); 4.59 (d, 1H, J 8.3, H-
5); 7.19-7.26 (m, 1H, Ar); 7.27-7.32 (m, 4H, Ar).
(2S*,4S*,5R*)-2-Isobutyl-5-pyridin-3-yl-pyrrolidine-2,4-dicar-
boxylic acid 4-tert-butyl ester 2-methyl ester (7k).
1
This compound was obtained as an oil. Yield 92%. H NMR:
ꢀ 0.83 (d, 3H, J 6.4, CH2CH(CH3)2); 0.91 (d, 3H, J 6.4,
CH2CH(CH3)2); 0.99 (s, 9H, t-C4H9); 1.61-1.81 (m, 3H,
CH2CH(CH3)2; 2.05 (dd, 1H, J 13.2, 7.8, H-3); 2.45 (dd, 1H, J
13.2, 6.4, H-3); 3.36 (ddd, 1H, J 7.8, 7.8, 6.4, H-4); 3.73 (s, 3H,
COOCH3); 4.60 (m, 1H, H-5); 7.37 (dd, 1H, J 7.8, 4.9, Ar); 7.69
(ddd, 1H, J 7.8, 1.7, 1.7, Ar); 8.46 (dd, 1H, J 4.9, 1.7, Ar); 8.52
(d, 1H, 1.7, Ar).
Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.80; H, 7.95; N, 4.59.
(2S*,4S*,5R*)-2-Methyl-5-o-tolylpyrrolidine-2,4-dicarboxylic
acid 4-tert-butyl ester 2-methyl ester (7f).
This compound was obtained as a white solid, mp 115-116°C.
1
Yield 89%. H NMR: ꢀ 0.89 (s, 9H, t-C4H9); 1.39 (s, 3H, CH3);
Anal. Calcd for C20H30N2O4: C, 66.27; H, 8.34; N, 7.73.
Found: C, 66.18; H, 8.30; N, 7.90.
1.97 (dd, J 13.0, 8.3, 1H, H-3); 2.34 (s, 3H, ArCH3); 2.51-2.55
(m; 1H, H-3); 2.99 (br s, 1H, NH); 3.35-3.41 (m, 1H, H-4); 3.71

Nov-Dec 2006
Highly Diastereoselective Synthesis of Chimeras of Proline and Glutamate
1465
General Procedure for N-Methylation of Compounds 7 with
CH3I.
General One-step Procedure for the Preparation of Compounds 9
from 7.
CH3I (0.38 ml, 6.1 mmol) was added dropwise to the mixture
of 4.1 mmol of 7, 2.31 g (18.3 mmol) of K2CO3 and 17 ml of dry
DMF. The mixture was stirred 24 h at rt. The solid was removed
by filtration and the filtrate was concentrated in vacuum.
Chromatography of the residue on silica gel using hexane/
AcOEt as an eluent afforded pure product 8.
Corresponding compound 7 (36.0 mmol) was dissolved in 180
ml of 98% formic acid, 27 ml of 37% aqueous formaldehyde
were added and reaction mixture was heated at 100°C during 30-
40 min. After cooling to rt 150 ml of water were added and the
mixture was neutralized with Na2CO3. Resulting mixture was
extracted with CHCl3 (5 x 70 ml). Organic extracts were dried
over Na2SO4, and the solvent was evaporated. The crude
products were purified by column chromatography on silica gel
using hexane/AcOEt as an eluent.
(2S*,4S*,5R*)-5-(2-Fluorophenyl)-1-methylpyrrolidine-2,4-
dicarboxylic acid 4-tert-butyl ester 2-methyl ester (8a).
1
This compound was obtained as an oil. Yield 94%. H NMR:
(2S*,4S*,5R*)-5-(2,3-Difluorophenyl)-1-methylpyrrolidine-2,4-
dicarboxylic acid 2-methyl ester (9b).
ꢀ 0.93 (s, 9H, t-C4H9); 2.13 (s, 3H, N-CH3); 2.18-2.37 (m, 2H,
H-3); 3.20-3.35 (m, 2H, H-2, H-4); 3.70 (s, 3H, COOCH3); 4.09
(d, 1H, J 10.0, H-5); 7.07-7.22 (m, 2H, Ar); 7.24-7.35 (m, 1H,
Ar); 7.47(ddd, 1H, J 7.6, 7.6, 1.0, Ar).
This compound was obtained as a white solid, mp 140°C.
1
Yield 40%. H NMR: ꢀ 2.18 (s, 3H, N-CH3); 2.24-2.33 (m, 2H,
Anal. Calcd for C18H24FNO4: C, 64.08; H, 7.17; N, 4.15.
Found: C, 63.96; H, 7.20; N, 4.30.
H-3); 3.29-3.40 (m, 2H, H-4, H-2); 3.70 (s, 3H, COOCH3); 4.17
(d, J 10.0, 1H, H-5); 7.13-7.20 (m, 1H, Ar); 7.24-7.34 (m, 2H,
Ar); 11.90 (s, 1H, COOH).
Anal. Calcd for C14H15F2NO4: C, 56.19; H, 5.05; N, 4.68.
Found: C, 56.35; H, 5.10; N, 4.89.
(2S*,4S*,5R*)-1,2-Dimethyl-5-phenylpyrrolidine-2,4-dicarbox-
ylic acid 4-tert-butyl ester 2-methyl ester (8e).
1
This compound was obtained as an oil. Yield 66%. H NMR:
(2S*,4S*,5R*)-5-(2-Fluoro-5-methoxyphenyl)-1-methylpyrrol-
idine-2,4-dicarboxylic acid 2-methyl ester (9c).
ꢀ 0.90 (s, 9H, t-C4H9); 1.25 (s, 3H, CH3); 1.87 (dd, 1H, J 12.0,
7.9, H-3); 2.03 (s, 3H, N-CH3); 2.59 (dd, 1H, J 12.0, 12.0, H-3);
3.40 (ddd, 1H, J 10.7, 10.7, 7.9, H-4); 3.69 (s, 3H, COOCH3);
3.95 (d, J 10.7, 1H, H-5); 7.15-7.34 (m, 5H, Ar).
This compound was obtained as a white solid, mp 95°C. Yield
1
46%. H NMR: ꢀ 2.15 (s, 3H, N-CH3); 2.27 (td, 2H, J 8.3, 4.0,
Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20.
Found: C, 68.66; H, 8.20; N, 4.37.
H-3); 3.23-3.31 (m, 2H, H-4, H-2); 3.69 (s, 6H, COOCH3,
ArOCH3); 4.06 (d, J 9.9, 1H, H-5); 6.79 (dt; J 8.8, 3.7, 1H, Ar);
6.98-7.05 (2H, m; Ar); 11.85 (br s, 1H, COOH).
Anal. Calcd for C15H18FNO5: C, 57.87; H, 5.83; N, 4.50.
Found: C, 57.99; H, 5.75; N, 4.71.
General Procedure for the Preparation of Compounds 9 from 8.
4.0 mmol of corresponding compound 8 were dissolved in 50
ml of dry CH2Cl2. Dry HCl was passed through the solution
during 1 h at 5°C. The mixture was stirred overnight at rt, washed
with H2O (2 x 10 ml), 10% aqueous solution of NaHCO3 (2 x 10
ml). Aqueous phases were extracted with CH2Cl2 (2 x 20 ml). The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel using hexane/AcOEt as an eluent.
(2S*,4S*,5R*)-5-(3-Chlorophenyl)-1-methylpyrrolidine-2,4-
dicarboxylic acid 2-methyl ester (9d).
This compound was obtained as a white solid, mp 120-122°C.
1
Yield 57%. H NMR: ꢀ 2.15 (s, 3H, N-CH3); 2.17-2.34 (m, 2H,
H-3); 3.23-3.33 (m, 2H, H-4, H-2); 3.70 (s, 3H, COOCH3); 3.85
(d, J 10.0, 1H, H-5); 7.26-7.33 (m, 3H, Ar); 7.38 (dd, J 1.7, 1.7,
1H, Ar).
Anal. Calcd for C14H16ClNO4: C, 56.48; H, 5.42; N, 4.70.
Found: C, 56.54; H, 5.46; N, 4.81.
(2S*,4S*,5R*)-5-(2-Fluorophenyl)-1-methylpyrrolidine-2,4-
dicarboxylic acid 2-methyl ester (9a).
This compound was obtained as a white solid, mp 126°C.
1
(2S*,4S*,5R*)-1,2-Dimethyl-5-o-tolylpyrrolidine-2,4-dicarbox-
ylic acid 2-methyl ester (9f).
Yield 51%. H NMR: ꢀ 2.15 (s, 3H, N-CH3); 2.23-2.36 (m, 2H,
H-3); 3.24-3.35 (m, 2H, H-4, H-2); 3.70 (s, 3H, COOCH3); 4.11
(d, 1H, J 10.0, H-5); 7.09 (ddd, 1H, J 9.5, 8.3, 1.0, Ar); 7.15
(ddd, 1H, J 7.6, 7.6, 1.0, Ar); 7.23-7.30 (m, 1H, Ar); 7.50 (ddd,
1H, J 7.6, 7.6, 1.7, Ar); 11.80 (s, 1H, COOH).
Anal. Calcd for C14H16FNO4: C, 59.78; H, 5.73; N, 4.98.
Found: C, 60.01; H, 5.69; N, 4.79.
This compound was obtained as a white solid, mp 121-122°C.
1
Yield 50%. H NMR: ꢀ 1.28 (s, 3H, CH3); 1.93 (dd, J 12.0, 8.1,
1H, H-3); 2.02 (s, 3H, N-CH3); 2.33 (s, 3H, ArCH3); 2.61 (dd, J
12.0, 10.3, 1H, H-3); 3.43 (ddd, J 10.3, 10.3, 8.1, 1H, H-4); 3.70
(s, 3H, COOCH3); 4.22 (d, J 10.3, 1H, H-5); 7.03-7.14 (m, 3H,
Ar); 7.50 (d, J 7.3, 1H, Ar).
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.70; H, 7.20; N, 5.03.
(2S*,4S*,5R*)-1,2-Dimethyl-5-phenylpyrrolidine-2,4-dicarbox-
ylic acid 2-methyl ester (9e).
This compound was obtained as a white solid, mp 156°C.
1
(2S*,4S*,5R*)-5-(2-Chlorophenyl)-1,2-dimethylpyrrolidine-2,4-
dicarboxylic acid 2-methyl ester (9g).
Yield 50%. H NMR: ꢀ 1.27 (s, 3H, CH3); 1.89 (dd, 1H, J 11.7,
7.8, H-3); 2.06 (s, 3H, N-CH3); 2.60 (dd, 1H, J 11.7, 11.7, H-3);
3.40 (ddd, 1H, J 10.5, 10.5, 7.8, H-4); 3.70 (s, 3H, COOCH3);
3.99 (d, 1H, J 10.5, H-5); 7.16-7.29 (m, 3H, Ar); 7.31-7.35 (m,
2H, Ar); 11.72 (s, 1H, COOH).
Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05.
Found: C, 64.78; H, 6.93; N, 5.25.
This compound was obtained as a white solid, mp 130-131°C.
1
Yield 35%. H NMR: ꢀ 1.30 (3H, s, CH3); 1.97 (dd, J 12.2, 8.1,
1H, H-3); 2.06 (s, 3H, N-CH3); 2.61 (dd, J 12.2, 9.8, 1H, H-3);
3.45 (td, J 10.0, 8.1, 1H, H-4); 3.70 (s, 3H, COOCH3); 4.43 (d, J
10.0, 1H, H-5); 7.23 (ddd, J 7.6, 1.7, 1.7, 1H, Ar); 7.30 (ddd, J

1466
K. Kudryavtsev, M. Tsentalovich, A. Yegorov, and E. Kolychev
Vol 43
7.6, 1.5, 1.5, 1H, Ar); 7.34 (dd, J 7.6, 1.5, 1H, Ar); 7.58 (dd, J
7.6, 1.7, 1H, Ar).
Anal. Calcd for C15H18ClNO4: C, 57.79; H, 5.82; N, 4.49.
Found: C, 57.85; H, 5.80; N, 4.30.
CCD diffractometer. Crystal data: C14H15F2N1O4, M = 299.27,
monoclinic, a = 10.2002(7), b = 10.9433(7), c = 12.4771(8) Å,
ꢀ = 98.236(1)°, V = 1378.38(16) Å3, space group P21/n, Z = 4,
Dc = 1.442 g/cm3, F(000) = 624, μ(Mo-Kꢁ) = 0.123 mm-1. Total
of 8677 reflections (3318 unique, Rint = 0.0247) were measured
using graphite monochromatized Mo-Kꢁ radiation (ꢂ = 0.71073
Å) at 120.0(2) K. Data were collected in the range 2.42 < ꢁ <
28.00 (-8 ꢀ h ꢀ 13, -14 ꢀ k ꢀ 14, -16 ꢀ 1 ꢀ 14). Omega scan
mode with the step of 0.3 deg (15 sec. per step) was used. The
structure was solved by direct methods [17] and refined by full
matrix least-squares on F2 [18] with anisotropic thermal
parameters for all non-hydrogen atoms. All H atoms were found
from difference Fourier syntheses and refined in an isotropic
approximation. The final residuals were: R1 = 0.0366, wR2 =
0.0867 for 2621 reflections with I > 2ꢃ(I) and 0.0530, 0.0926 for
all data and 250 parameters. Goof = 1.036, maximum ꢄꢅ =
0.314 e/Å3.
(2S*,4S*,5R*)-5-(4-Chlorophenyl)-1,2-dimethylpyrrolidine-2,4-
dicarboxylic acid 2-methyl ester (9h).
This compound was obtained as a white solid, mp 135-137°C.
1
Yield 50%. H NMR: ꢀ 1.27 (s, 3H, CH3); 1.90 (dd, J 11.7, 7.8,
1H, H-3); 2.06 (s, 3H, N-CH3); 2.56 (dd, J 11.7, 11.7, 1H, H-3);
3.41 (ddd, J 10.5, 10.5, 7.8, 1H, H-4); 3.70 (s, 3H, COOCH3);
4.02 (d, J 10.5, 1H, H-5); 7.30-7.37 (m, 4H, Ar); 11.81 (br s, 1H,
COOH).
Anal. Calcd for C15H18ClNO4: C, 57.79; H, 5.82; N, 4.49.
Found: C, 57.77; H, 5.70; N, 4.32.
(2S*,4S*,5R*)-2-Ethyl-5-(4-methoxyphenyl)-1-
methylpyrrolidine-2,4-dicarboxylic acid 2-methyl ester (9i).
This compound was obtained as a white solid, mp 94-95°C.
Yield 36%. 1H NMR: ꢀ 0.84 (t, J 7.3, 3H, CH2CH3); 1.53 (ddd, J
7.3, 7.3, 7.3, 1H, CH2CH3); 1.92 (ddd J 7.3, 7.3, 7.3, 1H,
CH2CH3); 2.00 (dd, J 12.5, 7.8, 1H, H-3); 2.17 (s, 3H, N-CH3);
2.67 (dd, J 12.5, 12.5, 1H, H-3); 3.24-3.33 (m, 1H, H-4); 3.69 (s,
3H, COOCH3); 3.71 (s, 3H, ArOCH3); 4.01 (d, J 10.3, 1H, H-5);
6.81 (d, J 8.8, 2H, Ar); 7.18 (d, J 8.8, 2H, Ar); 11.69 (br s, 1H,
COOH).
REFERENCES AND NOTES
[1] A. Welter, M. Marliert, and G. Dardenne, Phytochemistry,
17, 131 (1978).
[2] R. J. Bridges, M. S. Stanley, M. W. Anderson, C. W.
Cotman, and A. R. Chamberlin, J. Med. Chem., 34, 717 (1991).
[3] M. P. Paradisi, A. Mollica, I. Cacciatore, A. Di Stefano, F.
Pinnen, A. M. Caccuri, G. Ricci, S. Dupre, A. Spirito, and G. Lucente,
Bioorg. Med. Chem., 11, 1677 (2003).
Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found:
C, 63.66; H, 7.20; N, 4.57.
[4] E. A. A. Wallen, J. A. M. Christiaans, J. Gynther, and J.
Vepsalainen, Tetrahedron Lett., 44, 2081 (2003).
[5] M. M. Murphy, J. R. Schullek, E. M. Gordon, and M. A.
Gallop, J. Am. Chem. Soc., 117, 7029 (1995).
[6] M. Fournie-Zaluski, P. Coric, V. Thery, W. Gonzalez, H.
Meudal, S. Turcaud, J. Michel, and B. P. Roques, J. Med. Chem., 39,
2594 (1996).
[7] The libraries construction and screening experiments are in
progress. These results will be presented elsewhere.
[8] O. Tsuge, S. Kanemasa, and M. Yoshioka, J. Org. Chem., 53,
1384 (1988).
[9] O. Tsuge, and S. Kanemasa, in Advances in Heterocyclic
Chemistry, Vol 45, A. R. Katritzky, ed, Academic Press, SanDiego,
1989, pp 231–349.
[10] D. A. Barr, R. Grigg, H. Q. N. Gunaratne, J. Kemp, P.
McMeekin, and V. Sridharan, Tetrahedron, 44, 557 (1988).
[11] R. Grigg, Chem. Soc. Rev., 16, 89 (1987).
[12] L. Aurelio, R. T. C. Brownlee, and A. B. Hughes, Chem.
Rev., 104, 5823 (2004).
[13] M. Nyerges, D. Bendell, A. Arany, D. E. Hibbs, S. J. Coles,
M. B. Hursthouse, P. W. Groundwater, and O. Meth-Cohn, Synlett, 947
(2003).
[14] C. Chen, X. Li, and S. L. Schreiber, J. Am. Chem. Soc., 125,
10174 (2003).
(2S*,4S*,5R*)-2-Ethyl-5-(4-fluorophenyl)-1-methylpyrrolidine-
2,4-dicarboxylic acid 2-methyl ester (9j).
This compound was obtained as a white solid, mp 123-125°C.
1
Yield 67%. H NMR: ꢀ 0.85 (t, J 7.3, 3H, CH2CH3); 1.50-1.60
(m, 1H, CH2CH3); 1.88-1.98 (m, 1H, CH2CH3); 2.02 (dd, J 13.0,
7.8, 1H, H-3); 2.18 (s, 3H, N-CH3); 2.66 (dd, J 13.0, 10.8, 1H,
H-3); 3.33 (ddd, J 10.8, 10.3, 7.8, 1H, H-4); 3.69 (s, 3H,
COOCH3); 4.09 (d, J 10.3, 1H, H-5); 7.04-7.10 (m, 2H, Ar);
7.29 (ddd, J 12.0, 5.4, 3.1, 2H, Ar); 11.78 (s, 1H, COOH).
Anal. Calcd for C16H20FNO4: C, 62.13; H, 6.52; N, 4.53.
Found: C, 62.31; H, 6.38; N, 4.54.
(2S*,4S*,5R*)-2-Isobutyl-1-methyl-5-pyridin-3-yl-pyrrolidine-
2,4-dicarboxylic acid 2-methyl ester (9k).
This compound was obtained as a white solid, mp 156°C.
1
Yield 37%. H NMR: ꢀ 0.81 (d, 3H, J 6.6, CH2CH(CH3)2); 0.94
(d, 3H, J 6.6, CH2CH(CH3)2); 1.43 (dd, 1H, J 13.0, 5.1,
CH2CH(CH3)2); 1.53-1.62 (m, 1H, CH2CH(CH3)2); 1.78-1.87
(m, 2H, H-3, CH2CH(CH3)2); 2.15 (s, 3H, N-CH3); 2.73 (dd, 1H,
J 12.7, 12.7, H-3); 3.04 (ddd, 1H, J 12.7, 10.5, 7.1, H-4); 3.66 (s,
3H, COOCH3); 3.84 (d, 1H, J 10.5, H-5); 7.14 (dd, 1H, J 7.8,
4.7, Ar); 7.60 (ddd, 1H, J 7.8, 1.7, 1.7, Ar); 8.27 (dd, 1H, J 4.7,
1.7, Ar); 8.38 (d, 1H, J 1.7, Ar).
[15] P. B. Woller, and N. H. Cromwell, J. Org. Chem., 35, 888,
(1970); S. Cabrera, R. G. Arrayas, and J. C. Carretero, J. Am. Chem.
Soc., 127, 16394 (2005).
[16] Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-
604160. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: int.code +
44(1223)336-033; E-mail: deposit@ccdc.cam.ac.uk].
[17] G. M. Sheldrick, Acta Cryst., A46, 467 (1990).
[18] G. M. Sheldrick, SHELXL-97, Program for the Refinement
of Crystal Structures. University of Gottingen, 1997.
Anal. Calcd for C17H24N2O4: C, 63.73; H, 7.55; N, 8.74.
Found: C, 63.61; H, 7.48; N, 8.84.
Crystal Structure Determination of Compound 9b.
The single crystal of 9b of approximate dimensions 0.30 x
0.20 x 0.10 mm was mounted in inert oil on the top of glass fibre
and transferred to a cold nitrogen stream on the Bruker SMART