The synthesis of new diastereomers of (4S,8aS)- and (4R,8aS)-4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-dione

Article abstract of DOI:10.1016/j.tetasy.2007.08.025

The synthesis of new (4S,8aS)- and (4R,8aS)-4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-diones in the cyclocondensation reaction of the respective derivatives of l-prolineamide is described. The effect of the amount of NaOEt, temperature, and reaction time on the proportions of diastereomers formed in the cyclocondensation reaction was examined. The structures of the diastereomers were confirmed by GC/MS, HRMS, HPLC, XRD, and ¹H and ¹³C NMR investigations.

Full text of DOI:10.1016/j.tetasy.2007.08.025

Tetrahedron: Asymmetry 18 (2007) 2091–2098
The synthesis of new diastereomers of (4S,8aS)- and (4R,8aS)-
4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-dione
Franciszek Herold,a,* Maciej Dawidowski,a Irena Wolska,b Andrzej Chodkowski,a
Jerzy Kleps,a Jadwiga Turłoa and Andrzej Zimniakc
aDepartment of Drug Technology, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
bDepartment of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6 Str., 60-780 Poznan´, Poland
cDepartment of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
Received 10 July 2007; accepted 21 August 2007
Abstract—The synthesis of new (4S,8aS)- and (4R,8aS)-4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-diones in the cyclocondensation
reaction of the respective derivatives of L-prolineamide is described. The effect of the amount of NaOEt, temperature, and reaction time
on the proportions of diastereomers formed in the cyclocondensation reaction was examined. The structures of the diastereomers were
1
confirmed by GC/MS, HRMS, HPLC, XRD, and H and 13C NMR investigations.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
receptor complex. It also affects the lipophilicity of the
ligand molecule, which in turn has a significant effect on
its selectivity over other receptors, such as the 5-HT2A or
a1-adrenergic ones.6,10,11,13,20
Numerous derivatives of various heterocyclic systems pos-
sessing the imido group as a part of their structure exhibit
biological activity. The imido functionality is a significant
structural element of many new medicines from different
pharmacological groups.1–9
O
N
O
O
N
O
O
The discovery of synthetic methods for heterocyclic sys-
tems, which contain the imido group in their structure, is
important, particularly with respect to the well studied
group of compounds that exhibit affinity to the 5-HT1A
receptor. Among the most important of these agents, which
affect serotonin neurotransmission, are the long chain aryl
piperazines (LCAPs), which exhibit high affinity to the
5-HT1A receptor.5–17
R
R
N
R
O
Tandospirone
Gepirone
Buspirone
N
N
N
N
R=
R
N
O
H
N
Important representatives of the LCAPs group introduced
to therapeutics are Buspirone and Tandospirone (Fig. 1).
These medicines proved to be a milestone in the treatment
of anxiety through the mechanism of the serotoninergic
5-HT1A receptor.2,5–8,18,19
R
O
N
R
O
NH
O
WAY100135
WAY100635
NAN-190
The imide group in Buspirone occurs in its non-pharmaco-
phoric part, but plays a major role in stabilizing the ligand–
N
R=
N
MeO
*
Corresponding author. Tel./fax: +48 22 5720647; e-mail: herold@
farm.amwaw.edu.pl
Figure 1. Biologically active LCAPs.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.025

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F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
HO
H
Herein we report the synthesis of a new pyrrole[1,2-a]pyra-
COOH
H
zine and the preparation of its two diastereomers 5a and
5b, which may serve as synthons for new pharmacolo-
gically active derivatives of the LCAPs group.
COOMe
N
H
iii
i, ii
2. Results and discussion
2.1. Synthesis
Br
H
CONH2
N
H
H
COOMe
O
S
O
1
O
H
The syntheses of title compounds (4S,8aS)-4-phenyl-perhy-
dropyrrole[1,2-a]pyrazine-1,3-dione 5a and (4R,8aS)-4-
phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-dione 5b in the
form of pure diastereomers were performed according to
Schemes 1 and 2.
(R,S)-2
COOMe
(R,S)-3a,b
iv
iv
As the chiral substrate for the synthesis, (S)-prolineamide 1
was used, which was obtained by an esterification reaction
and (S)-proline ammonolysis.21,22 (S)-Prolineamide 1 was
N-alkylated by reaction with (R,S)-a-bromo-phenylacetic
methyl ester 2 or (R,S)-2-(4-toluenesulfonyloxy)-phenyl-
acetic acid methyl ester 3a, b, which afforded a mixture
of two diastereomers (2S,aS)-a-(2-carbamoylpyrrolidi-
nyl)-a-phenylacetic acid methyl ester (2S,aS)-4a and
(2S,aR)-a-(2-carbamoylpyrrolidynyl)-a-phenylacetic acid
methyl ester (2S,aR)-4b (Scheme 1). The content of the
diastereomers in the post-reaction mixture was established
CONH2
CONH2
H
2
N
2
H
N
1
1
H
H
+
COOMe
COOMe
(2S,aS)-4a
(2S,aR)-4b
Scheme 1. Reagents and conditions: (i) SOCl2, MeOH, reflux; (ii) NH3(g)
MeOH, rt; (iii) TsCl, Et3N, CH2Cl2, rt; (iv) K2CO3, CH3CN, reflux.
,
HO
H
HO
H
COOMe
COOMe
i
i
CONH2
N
H
H
1
O
S
O
S
O
O
O
H
O
H
COOMe
COOMe
ii
ii
(S)-3b
(R)-3a
CONH2
H
CONH2
H
2
N
2
N
1
1
H
H
COOMe
COOMe
α
α
(2S, S)-4a
(2S, R)-4b
iii
iii
H
O
1
H
O
8a
8a
N
N
4
1
NH
H
H
NH
4
3
3
O
O
(4R,8aS)-5b
(4S,8aS)-5a
Scheme 2. Reagents and conditions: (i) TsCl, Et3N, CH2Cl2, 0 ꢁC; (ii) K2CO3, CH3CN, reflux; (iii) EtONa, EtOH, rt.

F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
2093
by the GC/MS method (see Table 1). Crystallization of the
mixture of diastereomers 4a/4b from the hexane/ethyl
acetate mixture (2:1 v/v) resulted in an analytically pure iso-
mer 4a, the structure of which was confirmed by GC/MS,
1H NMR, and XRD. However, attempts to obtain pure
diastereomer 4b from the same mixture were unsuccessful.
intramolecular cyclocondensation of the particular diaste-
reomers 4a and 4b, respectively, relative to sodium ethoxy-
late. By cyclocondensation of diastereomer 4a, (4S,8aS)-4-
phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-dione 5a was
obtained with a very high excess of 5a isomer. Cyclization
of compound 4b afforded diastereomer (4R,8aS)-4-phenyl-
perhydropyrrole[1,2-a]pyrazine-1,3-dione 5b, but in a much
lower proportion (71.7:28.3) (see Table 2 and Scheme 2).
Table 1. N-Alkylation of L-prolineamide with a-phenylacetic acid methyl
ester derivatives
Entrya
Substrate
K2CO3 (equiv)
Yieldb (%)
dr of 4a/4bc
Table 2. Intramolecular cyclocondensation of 4a and 4b in basic medium
1
2
3
4
5
2
1
49
62
56
58
67
58:42
59:41
55:45
93:7
Entry Substrate EtONa Temperature Time
Yielda dr of
2
1/2
1/2
1/2
1/2
(equiv) (ꢁC)
(%)
10 min 82
10 min 96
3.5 h 91
10 min 73
10 min 89
5a/5bb
rac-3
3a
3b
1
2
3
4
5
6
4a
4a
4a
4b
4b
4b
2
rt
87:13
95:5
94:6
1.1
1.1
2
rt
12:88
ꢁ10 to ꢁ5
a For all entries the reaction was performed by heating the mixture in
rt
32:68
28:72
30:70
CH3CN for 5 h.
1.1
1.1
rt
b Isolated yield.
ꢁ10 to ꢁ5
3.5 h
80
c Estimated by means of GC/MS.
a Isolated yield.
b Estimated by means of HPLC.
In both reactions, diastereomer 4a was obtained in ꢀ10–
15% excess when compared to 4b, most probably as a result
of the stereoinductive effect of the stereogenic center of
L-proline. These results agree with the data of Hwang
et al., who also observed that diastereomer 4a formed more
rapidly and with higher yield than isomer 4b in this reac-
tion.23 These authors did not provide any physicochemical
data for the compounds obtained, except for elemental
analysis.
In the cyclocondensation reaction, the ratio between the
obtained diastereomers 5a/5b was largely affected by the
amount of EtONa, as well as by the temperature and reac-
tion time. An excess of two equivalents of ethoxylate
resulted in partial epimerization of substrate 4b (see Table 2).
Analytically pure diastereomers 5a and 5b were obtained
by crystallization of the reaction product from either a
MeOH/H2O mixture (1:1, v/v) or hexane/ethyl acetate mix-
ture (2:1, v/v).
Next, an alternative route for the N-alkylation reaction of
(S)-prolinamide 1 was performed using either the chiral
synthons of (R)-2-(4-toluenesulfonyloxy)-phenylacetic acid
methyl ester 3a or (S)-2-(4-toluenesulfonyloxy)-phenylace-
tic acid methyl ester 3b (Scheme 2). The aim of this proce-
dure was primarily to obtain pure diastereomer (2S,aR)-4b,
which was impossible to isolate from the post-reaction mix-
ture of diastereomers 4a/4b.
2.2. NMR spectroscopy and XRD investigation
2.2.1. NMR spectroscopy. The structures for the specific
diastereomers 4a and 4b, as well as 5a and 5b, were con-
firmed by analysis of the chemical shifts. For diastereomers
(S,S)-4a and (S,R)-4b, the steric arrangement of proton
H–C2 in relation to the remaining protons of the pyrrolidine
ring was similar in both molecules and can be assumed to
be pseudoaxial, as determined by the coupling constants
and the shapes of multiplets of proton H–C2 and proton
H–C8a, respectively. However, for diastereomers (S,S)-5a
and (S,R)-5b, the configurations of the protons of the pyr-
rolidine ring differ. This difference reflects the rigidity of the
molecular structure due to the coupling of the pyrrolidine
ring with the pyrazine ring in the bicyclic system. Further-
more, a different configuration of the proton of the pyrrol-
idine ring is observed in both diastereomers. In the isomer
(S,R)-5b, the H–C8a bond is probably situated outside of
this section of the H–C8–H0 plane (see Newman projection,
Fig. 2), which corresponds to the same coupling constants:
3J = 8.3 and the angles ꢀ30ꢁ and ꢀ140ꢁ (estimated accord-
ing to the Karplus curve). In the case of isomer (S,S)-5a,
this bond is probably situated inside the above-mentioned
section of the plane, which corresponds to the coupling
The pure enantiomeric synthons that were needed for the
next stage of investigations, such as 3a and 3b, were
obtained according to the procedure given by Curotto et al.
for compound 3b; compound 3a has not been described
in the literature.24,25 The purity of the enantiomers
obtained was er 99:1 (HPLC). The obtained enantiomers
(R)-3a and (S)-3b were subsequently subjected to reaction
with 1. Using 3a for the reaction, a mixture of diastereo-
mers was obtained with a very high excess of isomer
(2S,aS)-a-(2-carbamoylpyrrolidinyl)-a-phenylacetic acid
methyl ester 4a in comparison with (2S,aR)-a-(2-car-
bamoylpyrrolidinyl)-a-phenylacetic acid methyl ester 4b
(93.3–6.7 GC/MS).
Next, using 3b for the N-alkylation reaction, diastereoiso-
mer 4b was obtained, with a high excess in relation to iso-
mer 4a; the ratio of 4a to 4b was 11.6:88.4 (GC/MS) (see
Table 1).
3
3
constants J = 8.5 and J = 3.2 and the angles ꢀ30ꢁ and
ꢀ80ꢁ (Fig. 2).26,27 This interpretation is also confirmed
by the 13C NMR spectra, which indicate considerable
differences between the chemical shifts of the C8a carbons
Compounds 4a and 4b were isolated as pure diastereomers
by crystallization from a hexane/ethyl acetate system (3:1,
v/v). The final compounds 5a and 5b were obtained by

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F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
Table 3. Hydrogen-bonding geometry (A and deg.) for 4a and 5b
˚
D–Hꢂ ꢂ ꢂA
Compound 4a
d(D–H) d(Hꢂ ꢂ ꢂA) d(Dꢂ ꢂ ꢂA) <(DHA)
N9A–H9ABꢂ ꢂ ꢂO11B 0.86
2.58
2.60
2.48
2.70
2.08
2.49
2.11
2.45
2.45
3.004(2)
3.037(3)
3.387(3)
3.606(3)
2.935(2)
3.419(3)
2.969(2)
3.395(3)
3.368(3)
112
113
164
165
179
163
178
167
170
N9B–H9BBꢂ ꢂ ꢂO11A
C20A–H20Aꢂ ꢂ ꢂO11B
C20B–H20Bꢂ ꢂ ꢂO11A
N9A–H9AAꢂ ꢂ ꢂO8Bi
C13B–H13Eꢂ ꢂ ꢂO8Bi
N9B–H9BAꢂ ꢂ ꢂO8Aii
0.86
0.93
0.93
0.86
0.96
0.86
Figure 2. Newman projection of a C8a–C8 fragment of the molecules 5a
and 5b.
C13A–H13Bꢂ ꢂ ꢂO8Aii 0.96
C40B–H40Bꢂ ꢂ ꢂO8Biii
0.93
(for 5a: 57.3 ppm and for 5b: 65.1 ppm); differences are also
observed in the signals of carbons C6, C7, and C8.
Symmetry codes: (i) x ꢁ 1,y,z; (ii) x + 1,y,z;
(iii) ꢁx + 1,y ꢁ 0.5,ꢁz + 0.5.
Compound 5b
N2–H2Aꢂ ꢂ ꢂO3i
Since the absolute configuration of 5b proceeds from the
structure obtained by X-ray analysis (see Section 2.2.2
XRD investigations), the relative stereochemistry of 5a
0.86
0.97
2.01
2.60
2.856(3)
3.399(4)
168
140
C8–H8Bꢂ ꢂ ꢂO1ii
1
was ascertained by NOE H NMR experiment. Contrary
Symmetry codes: (i) ꢁx + 1,y ꢁ 0.5,ꢁz + 2; (ii) ꢁx,y + 0.5,ꢁz + 1.
to 5b, in the structure corresponding to configuration 5a
(4S,8aS) the interatomic distance between protons H-4
and H-8a should exclude any considerable NOE effect. In
fact, in 5b the irradiation of the H-8a resonance at
3.19 ppm resulted in a remarkable enhancement of the
H-4 signal at 4.05 ppm, whereas in 5a the analogous experi-
ment with H-8a at 3.68 and H-4 at 4.87 ppm gave only a
trace increase in intensity. The corresponding enhancement
values for 5b and 5a were 6.5 and 0.36 (in %), respectively.
The reverse order of irradiation, consisting in saturation of
H-4 and analysis of the changes in the H-8a resonance, led
to similar results and gave 6.9% and 0.35% enhancement,
respectively, for 5b and 5a.
2.2.2. XRD investigation. The structure and stereochemis-
try of 4a and 5b were fully elucidated from a single crystal
X-ray study.
The X-ray crystallographic analysis of 4a showed two
molecules, A and B, in the asymmetric unit cell with a
Figure 4. Molecules A and B of 4a connected via intramolecular
interactions.
Figure 3. X-ray diffraction structure of molecule A of 4a.
Figure 5. X-ray diffraction structure of 5b.

F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
2095
Figure 6. The packing arrangement of 5b along the a-axis.
(S,S)-absolute configuration in both molecules (Fig. 3).
This configuration was confirmed by the Flack parameter,
which was refined to a value of ꢁ1.2(10).28
the cyclocondensation was initiated with 4b, a much smal-
ler yield of 5b was obtained.
In the case of the N-alkylation of L-prolineamide 1, a high
yield of diastereomer (S,S)-4a was observed, and its subse-
quent cyclization to compound (S,S)-5a proceeded with a
very high excess of 5a in comparison with isomer 5b. In
the case of diastereomer (S,R)-4b, both its yield and cycli-
zation proceeded to lesser extent than the comparable com-
pounds 4a and 5a.
The solid state conformation of 4a is stabilized by intra-
and intermolecular hydrogen bonds (Table 3). The mole-
cules A and B from the asymmetric unit are connected by
N9ꢂ ꢂ ꢂO11 and weak C20ꢂ ꢂ ꢂO11 interactions (Fig. 4). The
other intermolecular contacts join the molecules, forming
a three-dimensional network of interactions.
The X-ray diffraction analysis revealed that compound 5b
has an (S,R)-absolute configuration, as depicted in Figure
5. It was confirmed by the Flack parameter, which was
refined to a value of ꢁ0.3(5).28 The crystal structure of
5b is stabilized by the intermolecular Nꢂ ꢂ ꢂO and Cꢂ ꢂ ꢂO
interactions (see Table 3 and Fig. 6).
In the cyclization reaction, the proportions between the
obtained diastereomers 5a/5b were affected by the amount
of EtONa used as well as by the time and temperature of
the reaction.
4. Experimental
3. Conclusions
4.1. General methods
N-Alkylation of L-prolineamide 1 using (R)-2-(4-toluene-
sulfonyloxy)-phenylacetic acid methyl ester 3a or (S)-2-(4-
toluenesulfonyloxy)-phenylacetic acid methyl ester 3b
afforded pure diastereomers (2S,aS)-a-(2-carbamoylpyrro-
lidinyl)-a-phenylacetic acid methyl ester 4a and (2S,aR)-a-
(2-carbamoylpyrrolidine)-a-phenylacetic acid methyl ester
4b. In an analogous reaction that used (R,S)-a-bromo-
methyl phenyl acetates 2a and 2b for N-alkylation, a mix-
ture of diastereomers was obtained with the compound 4a
in excess in comparison with 4b, a result of stereoinduction
by the stereogenic center of L-prolineamide 1 in this
reaction.
Melting points were determined on an Electrothermal 9100
apparatus with open capillary tubes and are uncorrected.
The IR spectra were recorded on a Shimadzu FTIR-8300
spectrometer. The 1H and 13C NMR spectra were obtained
on a Bruker AVANCE 400WB instrument. In some cases,
1H NMR spectra were recorded on a Varian UNITY plus-
500 spectrometer. The NOE 1H NMR experiment was
performed on a Bruker DRX 500 Avance instrument at
30 ꢁC in CDCl3. Chemical shifts (d) are expressed in parts
per million relative to tetramethylsilane used as the internal
reference. Coupling constants (J) are in Hertz (Hz). GC/
LRMS analyses were performed on a Hewlett Packard
HP 5890 apparatus with an MSD 5972 spectrometer.
HRMS (ESI) analyses were recorded on a Mariner (PE
Biosystems) instrument. Specific rotations were measured
with a Perkin–Elmer 341 Polarimeter at 20 ꢁC. Thin-layer
chromatography was run on Merck Silica Gel 60 F254
In the reaction of the intramolecular cyclization to EtONa
of diastereomers 4a or 4b, appropriate mixtures of diaste-
reomers 5a/5b were obtained with a very high excess of
compound 5a as compared with 5b. Even in the case where

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F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
plates. The compounds were visualized by UV light
(254 nm) or iodine. Flash column chromatography was
carried out on Merck Silica Gel 60 (230–400 mesh ASTM).
Chiral HPLC was performed on Chiralpak IA
46 · 250 mm (Daicel Chemical Industries Ltd) column with
225 nm detector. L-Proline, (S,R)-, (S)-(+)-, and (R)-(ꢁ)-
methyl mandelate were high-grade commercial products
purchased from Lancaster and used without further purifi-
cation. Other reagents and solvents were purified by stan-
dard procedures.
OCH3), 5.79 (s, 1H, CH), 7.25–7.38 (m, 7H, C20H, C30H,
3
C40H, C50H, C60H, C300H, C500H), 7.76 (d, J = 8.0, 2H,
C200H, C600H). 13C NMR (CDCl3, 100 MHz): d 21.8
(CH3), 53.1 (OCH3), 79.0 (CH), 127.7 (C20, C60), 128.3
(C200, C600), 129.0 (C30, C50), 129.8 (C40), 129.9 (C300,
C500), 133.0 (C100), 133.6 (C10), 145.3 (C400), 168.0 (C@O);
HRMS (ESI): (M+Na)+ calcd for C16H16O5NaS,
343.0611; found, 343.0618; HPLC: er = 99:1 (Chiralpak
IA 46 · 250 mm column with a 225 nm detector, mobile
phase: hexane/ethanol 95:5, flow rate: 0.8 mL/min, sample:
5 lL, sample concentration: 0.1 mg/mL temperature:
25 ꢁC, retention time: 20.0 min).
4.2. L-Prolineamide 1
To a stirred, cooled (ꢁ20 ꢁC) solution of L-proline (50 g,
0.434 mol) in anhydrous methanol (200 mL, 4.938 mol)
thionyl chloride (32.8 mL, 0.450 mol) was added dropwise,
keeping the temperature at ꢁ5 to +5 ꢁC. The mixture was
then allowed to reach room temperature and then heated at
reflux until sulfur dioxide ceased to evolve (2 h). The solu-
tion was then concentrated under reduced pressure. The
resulting pale yellow oil was allowed to stand in a vacuum
dessicator over potassium hydroxide overnight. The crude
oil was suspended in ethyl acetate (200 mL) and triethyl-
amine (69.0 mL, 0.495 mol) was added in one portion.
The resulting solid was filtered off and washed with ethyl
acetate. The combined filtrates were dried with anhydrous
sodium sulfate, filtered, and concentrated under reduced
pressure. The resulting oil was distilled under reduced pres-
sure. The fraction collected at 95–97 ꢁC (34 mmHg) was
dissolved in methanol (150 mL). The solution was satu-
rated with gaseous ammonia at ꢁ20 ꢁC and allowed to
stand at room temperature for 4 days. The mixture was
concentrated under reduced pressure. The resulting solid
was recrystallized from ethyl acetate to yield 35.7 g (72%)
of title compound 1. White solid, mp 98–101 ꢁC;
4.3.2. (S)-(+)-2-(4-Toluenesulfonyloxy)-phenylacetic acid
methyl ester 3b. Yield: 52%; white wax; mp 56–58 ꢁC;
[a]D = +61.4 (c 2, CHCl3) {lit.25 mp 57–58 ꢁC;
[a]D = +61.7 (c 1.085, CHCl3)}; IR (KBr): 1175, 1364,
1760; TLC (hexane/ethyl acetate 2:1): Rf = 0.57; 1H
NMR (CDCl3, 400 MHz): d 2.42 (s, 3H, CH3) 3.67 (s,
3H, OCH3), 5.79 (s, 1H, CH), 7.25–7.38 (m, 7H, C20H,
C30H, C40H, C50H, C60H, C300H, C500H), 7.76 (d,
3J = 8.0, 2H, C200H, C600H). 13C NMR (CDCl3, 100
MHz): d 21.8 (CH3), 53.1 (OCH3), 79.0 (CH), 127.7 (C20,
C60), 128.3 (C200, C600), 129.0 (C30, C50), 129.8 (C40),
129.9 (C300, C500), 133.0 (C100), 133.6 (C10), 145.3 (C400),
168.0 (C@O); HRMS (ESI): (M+Na)+ calcd for
C16H16O5NaS, 343.0611; found, 343.0626; HPLC:
er = 99:1 (Chiralpak IA 46 · 250 mm column with
225 nm detector, mobile phase: hexane/ethanol 95:5, flow
rate: 0.8 mL/min, sample: 5 lL, sample concentration:
0.1 mg/mL temperature: 25 ꢁC, retention time: 21.7 min).
4.3.3. (2S,aS)-a-(2-Carbamoylpyrrolidinyl)-a-phenylacetic
acid methyl ester 4a. A solution of 3a (1.41 g, 4.4 mmol),
1 (0.51 g, 4.4 mmol), and potassium carbonate (0.30 g,
2.2 mmol) in acetonitrile (25 mL) was stirred at reflux until
TLC showed no further reaction (5 h). The mixture was
cooled, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography
(hexane/ethyl acetate 2:1, v/v, then ethyl acetate) to yield
0.66 g (58%) of 4a and 4b (dr = 93:7). Recrystallization
from hexane/ethyl acetate (2:1, v/v) afforded pure 4a diaste-
reomer. White crystals; mp 124–125 ꢁC; [a]D = +29.7 (c 2,
MeOH); IR (KBr): 1161, 1200, 1682, 1751, 3175, 3410;
TLC (toluene/ethanol 6:1): Rf = 0.28; 1H NMR
(500 MHz, MeOD): d 1.77 (m, 1H, H0-4), 1.80–1.90 (m,
1
[a]D = ꢁ92.8 (c 2, MeOH); H NMR (CDCl3, 400 MHz):
d 1.74 (m, 2H, C4H2), 1.93 (m, 1H, C3H00), 2.15 (m, 1H,
C3H0), 2.47 (s, 1H, N1H), 2.95 (m, 1H, C5H00), 3.01 (m,
1H, C5H0), 3.44 (m, 1H, C2H), 6.27 (br s, 1H, NH00),
7.44 (br s, 1H, NH0); 13C NMR (CDCl3, 100 MHz): d
26.4 (C4), 30.8 (C3), 40.4 (C5), 60.6 (C2), 170.0 (CO).
4.3. Preparation of (R)-(ꢁ)- and (S)-(+)-2-(4-toluenesulfon-
yloxy)-phenylacetic acid methyl esters 3a and 3b
To a stirred, cooled (ꢁ15 ꢁC) solution of 4-toluenesulfonyl
chloride (11.44 g, 60 mmol) in dry dichloromethane
(100 mL), (R)-(ꢁ)-, or (S)-(+)-methyl mandelate (2.49 g,
15 mmol) and triethylamine (2.09 mL, 15 mmol) were
added in one portion. The solution was stirred at ꢁ5 to
+5 ꢁC for 7.5 h. The mixture was then washed with diluted
hydrochloric acid (100 mL) and brine (100 mL), dried with
anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (cyclohexane/ethyl acetate 5:1, then 3:1,
v/v) to yield the title compound.
2
2H, H0-3, H-4), 2.14 (m, 1H, H-3), 2.80 (m, 1H, J = 9.5,
3
2
3
3J = 9.5, J = 5.7, H0-5), 3.10 (m, 1H, J = 9.3, J = 7.2,
3J = 2.9, H-5), 3.31 (dd, 1H, 3J = 10.3, 3J = 2.9, H-2),
3.68 (s, 3H, CH3), 4.52 (s, 1H, H-a), 7.31–7.36 (m, 3H, H-
30, H-40, H-50), 7.37–7.43 (m, 2H, H-20, H-60). 13C NMR
(100 MHz, MeOD): d 25.5 (C-4), 32.3 (C-3), 52.7 (CH3),
53.2 (C-5), 65.6 (C-2), 71.5 (C-a), 129.7 (C-40), 129.8 (C-
30, C-50), 130.3 (C-20, C-60), 137.9 (C-10), 174.4 (C-7),
181.3 (C-6); GC/MS (LR): m/z = 218 (MꢁCONH2)+,
retention time: 34.13 min; HRMS (ESI): (M+Na)+ calcd
for C14H18N2O3Na, 285.1210; found, 285.1215.
4.3.1. (R)-(ꢁ)-2-(4-Toluenesulfonyloxy)-phenylacetic acid
methyl ester 3a. Yield: 61%; white wax; mp 58–59 ꢁC;
[a]D = ꢁ63.3 (c 2, CHCl3); IR (KBr): 1177, 1366, 1759;
TLC (hexane/ethyl acetate 2:1): Rf = 0.57; 1H NMR
(CDCl3, 400 MHz): d 2.42 (s, 3H, CH3), 3.67 (s, 3H,
4.3.4. (2S,aR)-a-(2-Carbamoylpyrrolidinyl)-a-phenylacetic
acid methyl ester 4b. A solution of 3b (1.35 g, 4.2 mmol),
1 (0.48 g, 4.2 mmol), and potassium carbonate (0.29 g,
2.1 mmol) in acetonitrile (25 mL) was stirred under reflux

F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
2097
until TLC showed no further reaction (5 h). The mixture
was cooled, filtered, and concentrated under reduced pres-
sure. The crude product was purified by column chroma-
tography (hexane/ethyl acetate 2:1, v/v, then ethyl
acetate) to yield 0.74 g (67%) of 4a and 4b (dr = 12:88).
Recrystallization from heptane/ethyl acetate (3:1, v/v)
afforded pure 4b diastereomer. White crystals; mp 89–
90 ꢁC; [a]D = ꢁ116.4 (c 2, MeOH); IR (KBr): 1161, 1204,
1627, 1728, 3186, 3406; TLC (toluene/ethanol 6:1):
crystals; mp 198–199 ꢁC; [a]D = ꢁ138.5 (c 2, CHCl3); IR
(KBr): 1678, 1709; TLC (toluene/ethanol 6:1): Rf = 0.39;
1H NMR (500 MHz, CDCl3): d 1.75–1.91 (m, 2H, H-7,
H0-7), 2.10–2.28 (m, 3H, H0-6, H-8, H0-8), 2.82 (m, 1H,
2J = 8.5, J = 9.5, J = 2.4, H-6), 3.19 (t, 1H, J = 8.3, H-
8a), 4.05 (s, 1H, H-4), 7.34–7.43 (m, 5H, H-20, H-30, H-
40, H-50, H-60), 7.89 (br s, 1H, NH). 13C NMR
(100 MHz, CDCl3): d 21.2 (C-7), 25.0 (C-8), 52.3 (C-6),
65.1 (C-8a), 71.8 (C-4), 128.9 (C-30, C-50), 129.0 (C-40),
129.3 (C-20, C-60), 136.0 (C-10), 171.5 (C-3), 172.4 (C-1);
HRMS (ESI): (M+H)+ calcd for C13H15N2O2, 231.1128;
found, 231.1121.
3
3
3
1
Rf = 0.28; H NMR (500 MHz, MeOD): d 1.72–1.80 (m,
2H, H-4, H0-4), 1.87 (m, 1H, H0-3), 2.20 (m, 1H, H-3),
2
3
3
2.57 (m, 1H, J = 9.8, J = 9.8, J = 6.3, H0-5), 3.06 (m,
1H, 2J = 9.5, 3J = 6.6, 3J = 2.4, H-5), 3.57 (dd, 1H,
3J = 10.2, J = 2.4, H-2), 3.65 (s, 3H, CH3), 4.61 (s, 1H,
4.4. X-ray crystallographic determination of compounds 4a
and 5b
3
H-a), 7.30–7.36 (m, 3H, H-30, H-40, H-50), 7.37–7.44 (m,
2H, H-20, H-60). 13C NMR (100 MHz, MeOD): d 25.4
(C-4), 32.5 (C-3), 52.5 (CH3), 53.9 (C-5), 65.1 (C-2), 71.4
(C-a), 129.6 (C-40), 129.8 (C-30, C-50), 131.3 (C-20, C-60),
137.9 (C-10), 173.9 (C-7), 181.8 (C-6); GC/MS (LR):m/z =
218 (MꢁCONH2)+, retention time: 33.71 min; HRMS
(ESI): (M+Na)+ calcd for C14H18N2O3Na, 285.1210;
found, 285.1220.
The crystal and molecular structures of 4a and 5b have
been determined by X-ray diffraction. Crystals suitable
for X-ray analysis were grown from hexane/ethyl acetate
(2:1, v/v) solution by slow evaporation. Diffraction data
were collected on an Oxford Diffraction KM4CCD diffrac-
tometer29 for 4a and on a KM4 KUMA diffractometer30
for 5b at 293 K, using graphite-monochromated MoKa
˚
˚
4.3.5.
(4S,8aS)-4-Phenyl-perhydropyrrole[1,2-a]pyrazine-
(k = 0.71073 A) and CuKa (k = 1.54178 A) radiation for
4a and 5b, respectively. For 4a, the accurate unit cell
dimensions were obtained by the least-squares fit of setting
angles of 12,852 highest-intensity reflections chosen from
the whole experiment and for 5b of setting angles of 41
reflections (16ꢁ < 2h < 63ꢁ). Intensity data were corrected
for the Lorentz and polarization effects.31,32 The structures
were solved by direct methods by use SHELXS-97 program33
and full-matrix, least-squares refinements on F2 were per-
1,3-dione 5a. To a stirred solution of sodium ethoxylate
(50 mg, 2.1 mmol of sodium) in absolute ethanol (25 mL),
4a (0.50 g, 1.9 mmol) was added in one portion. The solu-
tion was then stirred at room temperature for 10 min. The
mixture was poured on ice/water (150 mL), acidified with a
5% solution of sulfuric acid, and extracted with dichloro-
methane (3 · 50 mL). The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure to yield 0.42 g (96%) of a
mixture of 5a and 5b (dr = 95:5). Recrystallization from
methanol/water (1:1, v/v) afforded pure 5a diastereomer.
White needles; mp 125–126 ꢁC; [a]D = ꢁ138.15 (c 2,
CHCl3); IR (KBr): 1669, 1703; TLC (toluene/ethanol
formed by use of the SHELXL-97 program.34 The function
P
2
2 2
w(jFoj ꢁ jFcj ) was minimized with wꢁ1 = [r2(Fo)2 +
(0.0897P)2] for 4a and
w
ꢁ1 = [r2(Fo)2 + (0.1286P)2 +
0.0845P] for 5b, where P ¼ ðF 2o þ 2F c2Þ=3. All non-hydro-
gen atoms were refined anisotropically, positions of hydro-
gen atoms were generated geometrically and refined as a
riding model. Thermal parameters of all hydrogen atoms
were calculated as 1.2 (1.5 for methyl group) times Ueq of
the respective carrier carbon atom. An empirical extinction
correction was also applied according to the formula
1
6:1): Rf = 0.44; H NMR (500 MHz, CDCl3): d 1.84–1.99
(m, 2H, H-7, H07), 2.25 (m, 1H, H0-8), 2.30 (m, 1H,
2
3
H-8), 2.81 (pq, 1H, J = 8.8, J = 8.8, H0-6), 3.20 (m, 1H,
2J = 8.8, J = 8.8, J = 3.9, H-6), 3.68 (dd, 1H, J = 8.5,
3J = 3.2, H-8a), 4.87 (s, 1H, H-4), 7.31–7.36 (m, 1H,
H-40), 7.36–7.41 (m, 2H, H-30, H-50), 7.41–7.46 (m, 2H,
H-20, H-60), 8.30 (br s, 1H, NH). 13C NMR (100 MHz,
CDCl3): d 22.6 (C-7), 27.5 (C-8), 51.9 (C-6), 57.3 (C-8a),
64.2 (C-4), 127.3 (C-30, C-50), 128.6 (C-40), 129.1 (C-20,
C-60), 134.2 (C-10), 172.0 (C-3), 174.2 (C-1); HRMS
(ESI): (M+H)+ calcd for C13H15N2O2, 231.1128; found,
231.1124.
3
3
3
F 0c ¼ kF c½1 þ ð0:001vF 2ck3= sin 2hÞꢃꢁ1=4
,
34 and the extinction
coefficient v was equal to 0.016(2) for 4a and 0.026(6) for
5b. The figures were drawn with MERCURY program.35
The deposition numbers CCDC 652248 for 4a and 652249
for 5b contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
4.3.6.
(4R,8aS)-4-Phenyl-perhydropyrrole[1,2-a]pyrazine-
1,3-dione 5b. To a stirred solution of sodium ethoxylate
(50 mg, 2.1 mmol of sodium) in absolute ethanol (25 mL),
4b (0.50 g, 1.9 mmol) was added in one portion. The solu-
tion was then stirred at room temperature for 10 min. The
mixture was poured onto ice/water (150 mL), acidified with
a 5% solution of sulfuric acid, and extracted with dichloro-
methane (3 · 50 mL). The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concen-
trated under reduced pressure to yield 0.39 g (89%) of 5a
and 5b (dr = 28:72). Recrystallization from hexane/ethyl
acetate (2:1, v/v) afforded pure 5b diastereomer. White
4.4.1. Crystal data for 4a. C14H18N2O3, M = 262.30,
Dc = 1.231 g/cm3, orthorhombic, P212121, a = 8.7828(3)
3
˚
˚
˚
˚
A, b = 16.2593(6) A, c = 19.8168(7) A, V = 2829.9(2) A ,
Z = 8, F(000) = 1120, l = 0.087 mmꢁ1. The reflections
collected were 28,243 of which 7408 unique [R(int) =
0.0286]; 5439 reflections I > 2r(I), R1 = 0.0474 and
wR2 = 0.1327 for 5439 [I > 2r(I)] and R1 = 0.0658 and
wR2 = 0.1432 for all (7408) intensity data. Goodness of

2098
F. Herold et al. / Tetrahedron: Asymmetry 18 (2007) 2091–2098
14. Caliendo, G.; Fiorino, F.; Grieco, P.; Perissutti, E.; Santa-
garda, V.; Albrizio, S.; Spadola, L.; Bruni, G.; Romeo, M. R.
Eur. J. Med. Chem. 1999, 34, 719–727.
fit = 1.028, residual electron dꢁen3sity in the final Fourier
˚
map was 0.288 and ꢁ0.151 e A
.
´
15. Herold, F.; Krol, M.; Kleps, J.; Nowak, G. Eur. J. Med.
4.4.2. Crystal data for 5b. C13H14N2O2, M = 230.26,
Chem. 2006, 41, 125–134.
16. Aznavour, N.; Zimmer, L. Neuropharmacology 2007, 52, 695–
707.
17. Marchais-Oberwinkler, S.; Nowicki, B.; Pike, V. W.; Halldin,
C.; Sandell, J.; Chou, Y. H.; Gulyas, B.; Brennum, L. T.;
Farde, L.; Wikstro¨m, H. V. Bioorg. Med. Chem. 2005, 13,
883–893.
18. Peroutka, S. J. CNS Drugs 1995, 4, 18–28.
19. Fletcher, A.; Cliffe, J. A.; Dourish, C. T. Trends Pharmacol.
Sci. 1993, 14, 441–448.
Dc = 1.290 g/cm3, monoclinic, P21, a = 9.070(1) A,
˚
˚
˚
b = 5.8728(6) A, c = 11.983(1) A, b = 111.73(1)ꢁ, V =
3
592.9(1) A , Z = 2, F(000) = 1120, l = 0.719 mmꢁ1. The
˚
reflections collected were 1407 of which 1344 unique
[R(int) = 0.0803]; 1327 reflections I > 2r(I), R1 = 0.0551
and wR2 = 0.1752 for 1327 [I > 2r(I)] and R1 = 0.0556
and wR2 = 0.1761 for all (1344) intensity data. Goodness
of fit = 1.105, residual electron ꢁd3ensity in the final Fourier
˚
map was 0.208 and ꢁ0.280 e A
.
20. Peglion, J. L.; Canton, H.; Bervoets, K.; Andinot, V.; Brocco,
M.; Gobert, A.; Le Marouille-Griardon, S.; Millan, M. J. J.
Med. Chem. 1995, 38, 4044–4055.
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