The synthesis and conformational analysis of optical isomers of 4-phenyl-perhydropyrido[1,2-a]pyrazine-1,3-dione: an example of 'solid state-frozen' dynamics in nitrogen-bridged bicyclic 2,6-diketopiperazines

Article abstract of DOI:10.1016/j.tetasy.2009.06.022

The synthesis, chemical properties, and conformational analysis of enantiopure (4R,9aS)-, (4S,9aR)-, (4S,9aS)-, and (4R,9aR)-4-phenyl-perhydropyrido[1,2-a]pyrazine-1,3-diones having potential biological activity are described. An interesting example of the coexistence of two invertomers of the (4R,9aR)-diastereomer in a single crystal unit cell is reported. The invertomers differ in the cis/trans-relationship between the fused rings and in the absolute configuration at the chiral nitrogen atom. The structure and equilibrium distributions of the respective conformers have been determined by NMR spectroscopy in both polar and non-polar solvents at various temperatures. The NMR spectra show that dynamic processes in the imide parts of the interconverting species are restrained by self-aggregation. The (4S,9aR)-diastereomer exists in a single conformation with insignificant dynamic effects.

Full text of DOI:10.1016/j.tetasy.2009.06.022

Tetrahedron: Asymmetry 20 (2009) 1759–1766
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis and conformational analysis of optical isomers of
4-phenyl-perhydropyrido[1,2-a]pyrazine-1,3-dione: an example of ‘solid
state–frozen’ dynamics in nitrogen-bridged bicyclic 2,6-diketopiperazines
a
b
a
c
a
Maciej Dawidowski a, , Franciszek Herold , Marcin Wilczek , Jerzy Kleps , Irena Wolska , Jadwiga Turło ,
*
Andrzej Chodkowski a, Paweł Widomski d, Anna Bielejewska d
a Department of Drug Technology, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland
b Laboratory of NMR Spectroscopy, Faculty of Chemistry, University of Warsaw, Pasteura 1 Str., 02-093 Warszawa, Poland
c
´
Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6 Str., 60-780 Poznan, Poland
d Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52 Str., 02-224 Warszawa, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis, chemical properties, and conformational analysis of enantiopure (4R,9aS)-, (4S,9aR)-,
(4S,9aS)-, and (4R,9aR)-4-phenyl-perhydropyrido[1,2-a]pyrazine-1,3-diones having potential biological
activity are described. An interesting example of the coexistence of two invertomers of the (4R,9aR)-dia-
stereomer in a single crystal unit cell is reported. The invertomers differ in the cis/trans-relationship
between the fused rings and in the absolute configuration at the chiral nitrogen atom. The structure
and equilibrium distributions of the respective conformers have been determined by NMR spectroscopy
in both polar and non-polar solvents at various temperatures. The NMR spectra show that dynamic pro-
cesses in the imide parts of the interconverting species are restrained by self-aggregation. The (4S,9aR)-
diastereomer exists in a single conformation with insignificant dynamic effects.
Received 18 May 2009
Accepted 26 June 2009
Available online 10 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
which allows the creation of libraries of chiral compounds for bio-
logical screening and structure-activity relationship (SAR) studies.4
Cyclic imides are widely recognized as valuable components of
biologically active molecules. Among the most important of these
agents are anticonvulsants,1 antiangiogenic agents,2 and the com-
pounds that affect serotonin (5-HT) neurotransmission.3 The imide
moiety is also present in various pharmacologically active natural
products.
Over the last few decades, much attention has been paid to 2,5-
diketopiperazines (2,5-DKPs) as useful scaffolds for the develop-
ment of pharmacologically active agents. The group of their consti-
tutional isomers bearing the imide moiety—2,6-diketopiperazines
(2,6-DKPs), has been slightly less explored. DKPs are known to pos-
sess various pharmaceutical activities, such as antitumor, anticon-
vulsant, and antiviral. Their usefulness for medicinal chemists is
greatly increased by several factors, such as the ability to mimic
peptidic pharmacophores, resistance to proteolytic enzymes, con-
formational rigidity, and the capability of forming hydrogen bonds.
Frequently, these small heterocyclic systems are derived from ami-
no acids, and in most cases, enantiopure compounds are easily
accessible through relatively simple synthetic procedures. More-
over, DKPs can also be obtained using combinatorial chemistry,
Recently, we described a convenient route to proline-derived
bicyclic 2,6-DKP scaffolds with base-promoted intramolecular
cyclocondensation as a key step.5 The ongoing medicinal chemistry
project required the synthesis of the six-membered homologues of
the above compounds in enantiopure forms. It was also of our
interest to determine the features that can contribute to SAR anal-
ysis, such as crystal structure, structure and flexibility in solution,
and hydrogen-bonding capability of the compounds obtained, with
particular focus on differentiating each respective diastereomeric
pair. As nitrogen-bridged bicyclic compounds are known to under-
go complex dynamic processes due to N-inversion,6 the conforma-
tional features of the molecules synthesized were characterized by
variable-temperature NMR measurements. An interesting example
of inversion on the chiral nitrogen that is ‘frozen’ in the solid state
is presented in the form of XRD data.
2. Results and discussion
2.1. Synthesis
Only the synthetic pathways to (4R,9aS)-4 and (4S,9aS)-6 are
presented for clarity. The same route from (R)-(+)-2-piperidine-
carboxylic acid (R)-1 was chosen for the antipodes (4S,9aR)-4 and
* Corresponding author. Tel.: +48 22 5720646; fax: +48 22 5720647.
E-mail address: maciej.dawidowski@wum.edu.pl (M. Dawidowski).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.022

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M. Dawidowski et al. / Tetrahedron: Asymmetry 20 (2009) 1759–1766
Table 1
(4R,9aR)-6 with equal results. The characterization details are pro-
vided in Section 4.
The target compounds (4R,9aS)-4-phenyl-perhydropyrido[1,2-
a]pyrazine-1,3-dione (4R,9aS)-4, and (4S,9aS)-4-phenyl-perhydro-
pyrido[1,2-a]pyrazine-1,3-dione (4S,9aS)-6, were synthesized by
the intramolecular cyclocondensation of the corresponding
One-pot N-alkylation of (S)-pipecolinamide and cyclocondensation to imides 4 and 6
H
TsO
COOMe
H
H
O
H
H
O
2
N
NH
O
N
NH
O
+
H
(2S,
a
R)- and (2S,
a
S)-a
-(2-carbamoylpiperidinyl)-
a-phenylacetic
K2CO3
MeCN
N
H
CONH2
acid methyl esters (2S,
a
R)-3 and (2S, S)-5, as outlined in Scheme 1.
a
(S)-1
(4S,9aS)-6
Yieldc (%)
(4R,9aS)-4
H
Entry
Alkylating agent
Conditionsa
drb
N
H
COOH
1
2
3
4
5
rac-2
(S)-2
(R)-2
(R)-2
(R)-2
2.0 equiv K2CO3, 2.5 h
76/24
70/30
81/19
67/33
54/46
65
52
nd
35
30
i, ii
1.5 equiv K2CO3, 1.5 h
1.0 equiv K2CO3, TBAB, 8 h
H
H
TsO
TsO
nd—not determined.
H
COOMe
COOMe
a
For each entry the reaction was carried out in refluxing MeCN.
dr of (4R,9aS)-4/(4S,9aS)-6.
N
H
CONH2
(S)-2
(R)-2
b
c
Isolated yield.
(S)-1
iii
iii
of potassium carbonate (1.0 equiv) and D2O (trace), led to the for-
mation of 7:3 equilibrium mixtures of (4R,9aS)-4/(4S,9aS)-6 in both
cases. Under these conditions, proton–deuterium exchange was ob-
served, with the complete disappearance of H-4 resonances from
the 1H NMR spectrum. The two H-9a signals corresponding to the
respective diastereomers remained unchanged, indicating that no
epimerization occurred at the C-9a stereocenter. Although no enan-
tiomeric mixtures were formed, the obtained mixture of (4R,9aS)-4
and (4S,9aS)-6 could not be efficiently separated on the required
(>1.5 mmol) scale. Moreover, the overall chemical yield was signifi-
cantly diminished, most probably due to the base-induced partial
decomposition of the starting tosylate 2.
H
H
2
H
2
H
N1
CONH2
N1
CONH2
α
α
COOMe
(2S,αR)-3
COOMe
(2S,αS)-5
iv
iv
8
9
9
8
O
H
H
H
O
7
9a
9a
1
7
1
To obtain target compounds of high enantiomeric purity, the
two-step route involving (1) the synthesis and isolation, and (2)
the subsequent cyclocondensation of the respective amidoesters
N
4
NH
NH
3
N
4
H
6
6
3
O
O
(2S,aR)-3 and (2S,aS)-5 was pursued (Scheme 1). In all cases, enan-
tiopure (S)-1 and (S)-2 or (R)-2 were used as the starting materials.
(4S,9aS)-6
(4R,9aS)-4
The results are summarized in Tables 2 and 3.
Scheme 1. Reagents and conditions: (i) SOCl2 (1.0 equiv), MeOH, reflux, 2 h; (ii)
NH3 (g), MeOH, rt, 48 h; (iii) MeCN, pyridine (1.0 equiv), reflux, 1 h; (iv) NaOH
(1.0 equiv), EtOH, rt, 15 min.
For the N-alkylation step, a polar aprotic solvent was chosen be-
cause it proved to ensure both the good solubility of the reactants
and excellent conversions even at room temperature. Considering
that the use of a strong base would most probably cause unwanted
side reactions, thus lowering both the enantiomeric purity and
yield of 3 (Table 2 and Ref. 5), a weak organic base was investi-
gated. Triethylamine was found to diminish the enantiomeric pur-
ity of the starting tosylate 2 under both prolonged and short times
of exposure. Pyridine was found to be more convenient for the N-
alkylation step, as it promoted neither the significant epimeriza-
tion of the base-sensitive tosylate nor the cyclocondensation of
Enantiopure (S)-(ꢀ)-2-piperidinecarboxylic acid was used as a
substrate for the synthesis. The esterification of the amino acid,
followed by ammonolysis of the resulting ester yielded enantiome-
rically pure (S)-(ꢀ)-2-piperidinecarboxamide (S)-1. (S)-(+)- and
(R)-(+)-2-(4-toluenesulfonyloxy)-phenylacetic acid methyl esters
(S)-2 and (R)-2, respectively, required for the synthesis were
obtained by well-established methods.5,7
the alkylation products 3. The (2S,
higher diastereomeric ratio (dr = 99/1) than (2S,
in analogous reactions, as estimated by HPLC of the crude post-
reaction mixtures. The analytically pure samples of (2S, R)-3 and
(2S, S)-5 were obtained using fractional recrystallization from a
non-polar solvent system.
a
S)-5 isomer was obtained in a
It appeared convenient to directly obtain the target cyclic imides
4 and 6 without isolating the intermediate amidoesters 3 and 5.
Therefore, one-pot N-alkylation of pipecolinamide (S)-1 with tosy-
lates 2, and the subsequent cyclocondensation using an excess of
potassium carbonate in rigorously dried acetonitrile were investi-
gated. The reaction was found to proceed with epimerization at
the C-4 stereocenter of the final product, leading to the mixtures
of (4R,9aS)-4 and (4S,9aS)-6. Compound (4R,9aS)-4 was found to
be the major product, regardless of whether (S)-2, (R)-2, or rac-2
was used as the starting material (Table 1). The epimerization can
be easily explained by the fact that the relatively acidic H-4 protons
of (4R,9aS)-4 and (4S,9aS)-6 are prone to enolization under pro-
longed exposure to basic conditions. The experiment, consisting of
refluxing pure (4R,9aS)-4 and (4S,9aS)-6, in CD3CN in the presence
aR)-3 (dr = 90/10)
a
a
Notably, the diastereomeric ratio (dr = 73/27) of the N-alkyl-
ation of (S)-(ꢀ)-pipecolinamide with racemic (R,S)-2-(4-toluene-
Separation by column chromatography failed due to two reasons: very similar Rf
values (TLC:
DRf <0.1) of the products and their poor solubility in the non-polar
solvent systems required for at least partial separation. Fractional recrystallization of
the mixture from lower alcohols was found to be only partially effective due to the
similar solubility of both diastereoisomers in the recrystallization solvents.

M. Dawidowski et al. / Tetrahedron: Asymmetry 20 (2009) 1759–1766
1761
Table 2
N-Alkylation of (S)-1 and L-prolineamide with 2-(4-toluenesulfonyloxy)-phenylacetic acid methyl esters
Entry
Substrate
-Prolineamide
Alkylating agent
Conditionsa
drb
Yielde (%)
1
2
3
4
5
6
7
8
9
L
rac-2
rac-2
(S)-2 or (R)-2
rac-2
(S)-2
(R)-2
(S)-2
(R)-2
rac-2
Et3N, MeCN, rt, 48 h
43/57c
27/73d
27/73
30/70
43/57
14/86
90/10
1/99
88
92
nd
95
nd
nd
84
90
63
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
Pyridine, MeCN, rt, 48 h
Et3N, MeCN, reflux, 1 h
Pyridine, MeCN, reflux, 1 h
Pyridine, PhCH3, reflux, 1.5 h
30/70
nd—not determined.
a
For each entry 1.1 equiv of base was used.
b
c
dr of (2S,
dr of (2S,
a
a
R)-3/(2S,
R)-/(2S,
a
S)-5 estimated by HPLC of the crude products.
aS)-isomer, as in Ref. 5.
d
e
Estimated by GC/MS of the crude post-reaction mixture.
Isolated yield.
Table 3
axial-position of H-9a with respect to the piperidine framework,
with the H-C9a bond situated outside the H-9ax–C9–H-9eq plane.
The relative stereochemistry of (4S,9aR)-4 was ascertained by
the strong mutual NOE effects between H-4 and H-9a. Other inter-
actions were observed between H-4 and H-6ax, H-6eq, aromatic
NaOH-catalyzed cyclocondensation of (2S,aR)-3 and (2S,aS)-5
Entry
Substrate
dra
erb
Yieldc (%)
1
2
(2S,
(2S,
a
a
R)-3
S)-5
91/9
3/97
>99/1
>99/1
92
94
protons and between H-9a and H-9eq, H-8ax, H-6ax
.
a
dr of (4R,9aS)-4/(4S,9aS)-6.
Estimated by chiral HPLC analysis of the crude products.
Isolated yield.
Considering the above results, at room temperature, the solu-
tion structure of (4S,9aR)-4 is consistent with the model generated
by theoretical calculations (Fig. 1) and it indicates a persistence of
the trans-chair/sofa conformation exclusively. Most probably, ring
inversion is disfavored due to steric reasons. Moreover, it also ap-
pears that the piperidine framework is particularly rigid; thus,
interconversion cannot be observed in the temperature range of
ꢀ60 to 50 °C (CDCl3) used for the NMR experiments.
b
c
sulfonyloxy)-phenylacetic acid methyl ester rac-2 under mild con-
ditions was about threefold higher compared to the analogous
reaction for its homologue, L-prolineamide (dr = 57/43, refer Table
1 and Ref. 5). The sense of diastereoinduction in both cases was the
same and it favored the (S,S) products. This suggests that the mech-
anism of this partial stereoselectivity is similar in both cases and
could be due to the geometric differences between a five-mem-
bered ring and a six-membered ring. All attempts toward diaste-
reomeric resolution from this mixture, either by column
chromatography or by fractional crystallization, failed.
Compounds (2S,aR)-3 and (2S,aS)-5 obtained from enantiopure
(S)-1 and (S)-2 or (R)-2, respectively, were then converted to the
corresponding cyclic imides (4R,9aS)-4 and (4S,9aS)-6 through
base-catalyzed intramolecular cycloaddition in a polar protic sol-
vent (EtOH). Since cyclocondensation catalyzed by weak bases in
heterogeneous system is slow, requires heating, and consequently
results in significant epimerization of the products, the reaction
was hastened by using a strong base under homogenous conditions
(see also Ref. 5). The reaction proceeded rapidly with 1.0 equiv of
NaOH and was followed by immediate quenching and standard
work-up, yielding almost pure stereoisomers, as estimated by chi-
ral HPLC analysis of the crude products. Notably, the cycloconden-
sation of (2S,aR)-3 was accompanied by a slightly higher degree of
epimerization at C-4 than in the case of (2S,
a
S)-5. Analytical sam-
ples of the target compounds were then prepared by a single
recrystallization from absolute ethanol.
Figure 1. The optimized structure of (4S,9aR)-4, together with the numbering of
atoms essential for the conformational analysis. The analysis of torsion angles
indicates the trans-chair/sofa conformation of the fused piperidine and piperazine-
1,3-dione rings. The arrangement of the hydrogen H-4 and the nitrogen N-5 lone
pair is trans-diaxial, with respect to the piperazine framework. The chiral N-5 atom
adopts the (S)-configuration.
2.2. Structural investigations
At room temperature, each of the multiplets in the aliphatic re-
gion of the 1H NMR spectrum of (4S,9aR)-4 in CDCl3 was a sharp
signal, which enabled the accurate estimation of the geminal and
vicinal coupling constants.
According to the XRD measurements, (4R,9aR)-6 crystallizes in
the monoclinic P21 space group with two distinct invertomers A
and B in the asymmetric unit cell. These conformers are joined
through N2A–H2Aꢂ ꢂ ꢂO1B (ꢀx, y + 1/2, ꢀz + 1) and N2B–H2Bꢂ ꢂ ꢂO1A
(ꢀx, y ꢀ 1/2, ꢀz + 1) links, forming AB dimers (Figs. 2 and 3, Table 4).
The conformation of A can be described as a cis-chair/sofa with
a cis-axial/equatorial arrangement of the nitrogen N-5 lone pair and
The multiplet of H-9a proton at annelation (doublet of doublets)
was found to be particularly helpful in conformational analysis.
3
3
The two vicinal coupling constants, J9a-9ax = 11.2 Hz and J9a-9eq
=
2.8 Hz, corresponded to the dihedral angles of ꢁ180° and ꢁ50°
(estimated according to the Karplus equation8), and indicated the

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M. Dawidowski et al. / Tetrahedron: Asymmetry 20 (2009) 1759–1766
The aliphatic region of the 1H NMR spectrum of (4R,9aR)-6 re-
corded in CDCl3 at room temperature was composed of broadened
and overlapped signals, which indicated that the 1H NMR spectrum
of (4R,9aR)-6 was largely affected by dynamic processes. Indeed, in
acetone-d6 the coalescence of most peaks took place at about
ꢀ41 °C, followed by the development of two sets of signals in a ra-
tio of 1.3:1 (Fig. 4). The low-temperature 2D (1H–1H COSY; HSQC)
experiments, the analysis of the integral values and the chemical
shifts of each signal established the peak assignments shown in Ta-
ble 5.
The H-6ax proton of B lay in the relatively high-field region of
the spectrum, whereas the corresponding signal in the A conformer
was significantly shifted toward the lower field (DdA–B = 0.75 ppm,
acetone-d6). The remarkable high-field shift of H-6ax can be attrib-
uted to the anisotropic effect of the phenyl ring present in the spa-
tial vicinity of the B conformer. On the contrary, no such effect can
be considered in A due to the large distance between H-6ax and the
phenyl moiety.
Figure 2. The AB dimers of (4R,9aR)-6.
The intensities of the low-temperature 1H–1H COSY cross-peaks
H-9a/H-9ax and H-9a/H-9eq in the B conformer differed, which
could be attributed to the unequal couplings of H-9a with neigh-
boring protons. This suggested that the H-C9a bond was situated
outside the H-9ax–C9–H-9eq plane. On the contrary, the corre-
sponding cross-peaks in A were of similar intensities, thus the H-
C9a bond was located inside the above-mentioned plane.
The populations of the two conformers determined from the 1H
NMR spectra in acetone-d6 corresponded to a very small free-energy
difference of 0.5 kJ/mol at ꢀ41 °C, as calculated using the Eyring
equation for the H-4 proton.9 Energy optimization with the AM1
semiempirical method showed that the gas-phase conformations
were essentially isoenergetic, with an energy difference of 0.1 kJ/
mol favoring the B invertomer. Slightly different equilibrium distri-
butions were elucidated from the 1H NMR spectra in other solvents.
Thus, the B/A ratio was 1:1.3 in CDCl3 and 1.5:1 in CD3OD. In general,
in the solvent with a more polar nature, the trans-sofa/chair confor-
mation appears to be increasingly favored. If the above conclusion
can be at least roughly extrapolated to biological systems mostly
containing water, this feature can be of importance for correlating
the biological activity of a molecule with its structure.
Figure 3. Projection of the crystal structure of (4R,9aR)-6. The AB dimers are linked
by C4A–H4Aꢂ ꢂ ꢂO3B(ꢀx + 1, y + 1/2, ꢀz + 1) interactions to form chains parallel to
the a-axis (blue and green color). The other contacts (refer Table 4) join the chains
to create a three-dimensional network.
A careful study of the 1H and 13C NMR temperature spectra in
CDCl3 showed an unusual feature. Below the coalescence, two sets
of signals of the H-2 protonsand the C-1 and C-3 carbons of the imide
moiety were visible in the NMR spectra. Notably, when the sample
was warmed to room temperature, the imide-NH peaks remained
split at the same ratio for a short period of time (see Fig. 5), whereas
theremainingpartofthe 1HNMRspectrumwasaveraged. Moreover,
for the C-1 and C-3 imide carbon signals, a reminiscence of the con-
formational freeze-out was observed. Interestingly, the chemical
shifts of the split imide signals on both 1H and 13C NMR spectra were
equal to those observed in regular room temperature spectra.
The linear negative temperature dependence of the imide-NH
Table 4
Hydrogen-bonding geometry for (4R,9aR)-6 (Å and °)
D–Hꢂ ꢂ ꢂA
d(D–H)
d(Hꢂ ꢂ ꢂA)
d(Dꢂ ꢂ ꢂA)
<(DHA)
Compound (4R,9aR)-6
N2A–H2Aꢂ ꢂ ꢂO1Bi
N2B–H2Bꢂ ꢂ ꢂO1Aii
C8B–H8BAꢂ ꢂ ꢂO1Bi
C4A–H4Aꢂ ꢂ ꢂO3Biii
C4’B–H4’Bꢂ ꢂ ꢂO1Aiv
C8B–H8BBꢂ ꢂ ꢂO3Bv
C7B–H7BAꢂ ꢂ ꢂO3Bv
0.86
0.86
0.97
0.98
0.93
0.97
0.97
2.07
2.26
2.69
2.66
2.58
2.71
2.63
2.922(1)
3.073(2)
3.572(2)
3.565(2)
3.420(2)
3.305(2)
3.318(2)
169
159
151
153
150
120
128
chemical shifts in CDCl3
(D
dNH
/D
T
values of ꢀ0.020 and
ꢀ0.019 ppm, respectively, for A and B) suggests the formation of
intermolecular hydrogen bonds between the respective invertom-
ers, most probably similar to those observed in the solid state.
Thus, it would be tempting to ascribe the aforementioned spectro-
scopic features to the head-to-head molecular self-assembly of A
and B to form a cyclic dimer AB at low temperatures. This interpre-
tation would lead to the assumptions that (1) the temporarily ar-
rested dynamics of the imide fragment of the molecule is not
observed in hydrogen-bonding competing solvents; (2) the forma-
tion of the dimeric form AB (not AA, BB) takes place exclusively at
low temperatures; (3) the energy of the hydrogen bonding is high-
er than the interconversion barriers of A to B at room temperature;
(4) the equilibrium between the hydrogen-bonded and the non-
hydrogen-bonded species is the cause of averaging of the NMR res-
Symmetry codes: (i) ꢀx, y + 1/2, ꢀz + 1; (ii) ꢀx, y ꢀ 1/2, ꢀz + 1; (iii) ꢀx + 1, y + 1/2,
ꢀz + 1; (iv) x, y, z ꢀ 1; (v) x, y + 1, z.
the hydrogen at annelation (H-9a), with respect to the piperidine
ring.
Molecule B adopts the trans-chair/sofa conformation with a
trans-diaxial arrangement of the nitrogen N-5 lone pair and the
hydrogen at annelation (H-9a).
For the respective conformers, the absolute configuration on the
chiral nitrogen atom at the annelation (N-5) is different and can be
assigned as follows: (R)- for A and (S)- for B.

M. Dawidowski et al. / Tetrahedron: Asymmetry 20 (2009) 1759–1766
1763
Figure 4. Aliphatic region of the low-temperature 1H NMR (500 MHz, acetone-d6) spectra of (4R,9aR)-6.
Table 5
tration dependence of the averaged chemical shift of the imide-NH
resonance. Nevertheless, the complete evaluation of the proposed
explanation requires further investigations in detail, which will
be presented in due course.
Selected 1H and 13C NMR shifts (500 MHz, acetone-d6, ꢀ88 °C) of (4R,9aR)-6 (ppm)
Position
Conformer A
Conformer B
dH
dC
dH
dC
2
4
6
10.99
4.79
11.15
4.91
3. Conclusions
69
50.6
68.1
50.2
3.18 (eq)
2.63 (ax)
1.73 (eq)
1.65 (ax)
1.64 (eq)
1.20 (ax)
2.22 (eq)
1.50 (ax)
3.55
3.02 (eq)
1.88 (ax)
1.60 (eq)
1.49 (ax)
1.77 (eq)
1.14 (ax)
2.25 (eq)
1.44 (ax)
3.01
4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-diones (4R,9aS)-4,
(4S,9aR)-4, (4S,9aS)-6, and (4R,9aR)-6 having potential biological
activity can be prepared in enantiopure forms using a simple and
efficient synthetic pathway. The results of the 1H NMR experi-
ments and chiral HPLC analyses show that no epimerization at
the C-9a stereocenter of the reaction products occurs during expo-
sure to bases. The partial epimerization of the relatively acidic H-4
proton can be avoided when a strong base is used at room temper-
ature for the rapid cyclocondensation reaction of 3 to 4.
Elucidation of structure using NMR and XRD shows very pro-
nounced differences between the diastereomeric (4R,9aR)-6/
(4S,9aR)-4 pair. Analysis of the dynamic processes influencing
the 1H NMR spectra of (4R,9aR)-6 shows the coexistence of two
7
25.4
20.6
24
24.6
23.6
28
8
9
9a
53.7
56.5
onances in the imide moiety shortly after decooling to room tem-
perature. Indeed, the temperature spectra recorded in CD3OD did
not divulge any division of the imide C-1 and C-3 resonances after
warming. Moreover, the self-association of (4R,9aR)-6 appears to
be distinct at room temperature, as judged from a positive concen-
Figure 5. Signals of NH proton (left) and C-1, C-3 carbons (right) of the imide moiety of (4R,9aR)-6 at (a) room temperature, (b) ꢀ65 °C, and (c) after warming to room
temperature (500 MHz, CDCl3).

1764
M. Dawidowski et al. / Tetrahedron: Asymmetry 20 (2009) 1759–1766
invertomers in solution. It is probable that self-aggregation of the
conformers restrains the dynamic processes in the imide parts of
the molecules. The NMR-derived model of the respective inver-
tomers is in agreement with the XRD data, which shows the unu-
sual coexistence of both species in the solid state. On the contrary,
due to steric reasons, (4S,9aR)-4 exists in a single conformation and
tends to be especially rigid in solution.
4.2.1. (S)-(ꢀ)-2-Piperidinecarboxamide (S)-1
Yield: 71%; white solid; mp 163–165 °C {lit.11 mp 162–163 °C};
[a]
D = ꢀ33.4 (c 3.2, EtOH); {lit.11
[a
]D = ꢀ32.4 (c 3.2, H2O)}; IR
(KBr): 1319, 1408, 1636, 2831, 2939, 3194, 3306, 3387; 1H NMR
(CDCl3, 500 MHz): d 1.39–1.50 (m, 3H), 1.56–1.61 (m, 1H), 1.69
(br s, 1H), 1.80–1.84 (m, 1H), 1.96–2.00 (m, 1H), 2.66–2.71 (m,
1H), 3.02–3.06 (m, 1H), 3.20–3.23 (m, 1H), 5.41 (br s, 1H), 6.67
(br s, 1H); 13C NMR (CDCl3, 125 MHz): d 24.1, 26.0, 30.0, 45.8,
60.3, 177.2
4. Experimental
4.2.2. (R)-(+)-2-Piperidinecarboxamide (R)-1
Yield: 83%; white solid; mp = 164–166 °C {lit.12 mp 114–
4.1. General methods
115 °C}; [a] [a]D = +31.6 (c 2.3, EtOH)}.
D = +33.5 (c 2.3, EtOH) {lit.11
Melting points were determined on an Electrothermal 9100
apparatus with open capillary tubes and are uncorrected. The IR
spectra were obtained on a Shimadzu FTIR-8300 spectrometer.
The 1H, 13C, NOE, and 2D-NMR spectra were recorded on a Varian
Unity Plus–500 MHz spectrometer. In some cases, the 1H NMR
spectra were obtained on a Varian NMR–700 MHz apparatus.
Chemical shifts (d) are expressed in parts per million relative to
tetramethylsilane used as the internal reference. Coupling con-
stants (J) are in hertz (Hz). GC/MS analyses were conducted on a
Hewlett Packard HP-5890 apparatus with an MSD 5972 spectrom-
eter. ESI-HRMS analyses were done on a Mariner (PE Biosystems)
instrument. EI-HRMS and EI-LRMS spectra were obtained on
AMD 604 (AMD Intectra GmbH) spectrometer. Specific rotations
were measured with a PolAA 32 (Optical Activity Ltd) Polarimeter
at 20 °C. Thin-layer chromatography was run on Merck Silica Gel-
60 F254 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). HPLC analyses
were carried out for compound 3 on a Chiralpak AD column,
4.3. General procedure for the preparation of (2-carbamoyl-
piperidinyl)- -phenylacetic acid methyl esters 3
a
A mixture of 1 (0.32 g, 2.5 mmol), 2 (0.80 g, 2.5 mmol), and pyr-
idine (0.22 mL, 2.8 mmol) in acetonitrile (15 mL) was stirred at re-
flux for 1 h. The volatiles were then evaporated under reduced
pressure, and the pale yellow semisolid residue was partitioned
between ethyl acetate (40 mL) and water (15 mL). The mixture
was transferred to a separatory funnel, and the layers were sepa-
rated. The aqueous layer was extracted with ethyl acetate
(15 mL). The combined organic extracts were washed with water
(10 mL) and brine (10 mL), dried with anhydrous magnesium sul-
fate, 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 furnish the desired products.
Analytical samples of the pure diastereomers were prepared by
recrystallization from n-heptane/diethyl ether (1:1, v/v).
10
95:5, flow rate 1.0 mL/min; and for compound 4 on Chiralcel OD
column, 10
flow rate: 0.5 mL/min (both columns from Daicel Chiral Technolo-
gies Europe, Cedex, France). The sample concentration was approx-
l
m, 250 ꢃ 4.6 mm, with mobile phase: n-hexane/ethanol
4.3.1. (2S,
methyl ester (2S,
White solid; mp 111–112 °C; [
(KBr): 694, 733, 1686, 1744, 2858, 2932, 3221, 3263, 3441; TLC
(hexane/ethyl acetate 1:2): Rf = 0.34; 1H NMR (CDCl3, 500 MHz):
d 1.25–1.33 (m, 1H, H-5ax), 1.36–1.43 (m, 1H, H-4ax), 1.43–1.50
(m, 1H, H-5eq), 1.52–1.61 (m, 1H, H-4eq), 1.78–1.86 (m, 8 lines,
a
R)-
a
-(2-Carbamoylpiperidinyl)-
a-phenylacetic acid
aR)-3
lm, 250 ꢃ 4.6 mm, with mobile phase: 2-propanol,
a]D = ꢀ125.0 (c 1, CHCl3); IR
imately 0.2 mg/mL, injection: 10 lL, temperature: 25 °C, detection
220 nm. All reagents were purchased from commercial sources and
were used as received. (R)-(+)- and (S)-(ꢀ)-2-piperidinecarboxylic
acids,10 (R)-(ꢀ)- and (S)-(+)-2-(4-toluenesulfonyloxy)-phenylacetic
acid methyl esters5,7 were obtained in high enantiomeric purities
(ee P 99%) by known procedures, and their physicochemical con-
stants were in agreement with literature data.
3
3
3
2J3ax-3eq = 14.0, J3ax-4ax = 9.5, J3ax-4eq = 5.0, J3ax-2eq = 5.0, 1H, H-
3ax), 1.92–1.99 (m, 1H, H-3eq), 2.20–2.26 (m, 8 lines, 2J6ax-6eq = 13.0,
3J6ax-5ax = 6.5, J6ax-5eq = 3.5, 1H, H-6ax), 2.82–2.91 (m, 7 lines,
3
3
3
2J6eq-6ax = 13.0, J6eq-5ax = 9.0, J6eq-5eq = 3.0, 1H, H-6eq), 3.17 (pt,
3J2-3ax,3eq = 5.0, 1H, H-2), 3.69 (s, 3H, OCH3), 4.74 (s, 1H, H-
a),
6.04 (bs, 1H, NH), 7.25 (bs, 1H, NH’), 7.32–7.39 (m, 5H, H-20, H-30,
H-40, H-50, H-60); 13C NMR (CDCl3, 125 MHz): d 21.9 (C-4), 22.2
4.2. Preparation of (S)-(ꢀ)- and (R)-(+)-2-piperidinecarboxamides 1
(C-5), 24.3 (C-3), 45.3 (C-6), 52.2 (C-OCH3), 61.8 (C-2), 68.6 (C-a),
128.5 (C-40), 128.6 (C-20, C-60), 129.4 (C-30, C-50), 134.1 (C-10),
172.7 (CONH2), 176.0 (COOMe); HPLC: retention time: 21.5 min;
GC/LRMS: retention time: 35.3 min, LRMS (EI, 70 eV) m/z (relative
intensity): 232 ([MꢀCONH2]+, 100), 217 (7), 172 (13), 149 (19),
121(53), 91(13), 84(10), 77(9);HRMS(ESI)calcdforC15H20N2O3Na:
299.1366 [M+Na]+; found 299.1364.
To a stirred, cooled (ꢀ20 °C) solution of the amino acid (14 g,
0.108 mol) in anhydrous methanol (200 mL, 4.938 mol), thionyl
chloride (7.9 mL, 0.108 mol) was added dropwise, while maintain-
ing the temperature below 0 °C. The mixture was then allowed to
reach room temperature and heated at reflux until sulfur dioxide
ceased to evolve (2 h). The solution was then concentrated under
reduced pressure, and traces of unreacted thionyl chloride were
coevaporated with dry toluene (2 ꢃ 20 mL). The resulting white so-
lid was suspended in ethyl acetate (100 mL), and triethylamine
(15.1 mL, 0.108 mol) was added in one portion. The suspension
was stirred at room temperature overnight. The solids were filtered
off and washed with ethyl acetate. The combined filtrates were
dried with anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The resulting pale yellow oil was dis-
solved in saturated methanolic ammonia (100 mL), and the result-
ing mixture was allowed to stand at room temperature for two
days. The solution was then concentrated under reduced pressure
to yield a pale yellow solid, which gave the title compound after
recrystallization from toluene.
4.3.2. (2R,
methyl ester (2R,
White solid; mp 110–112 °C; [a]D = +124.6 (c 1, CHCl3); HPLC:
aS)-
a
-(2-Carbamoylpiperidinyl)-
a-phenylacetic acid
a
S)-3
retention time: 30.4 min; HRMS (ESI) calcd for C15H20N2O3Na:
299.1366 [M+Na]+; found 299.1376.
4.3.3. (2S,
methyl ester (2S,
White solid; mp 92–93 °C; [a]D = +3.0 (c 1, CHCl3); IR (KBr): 698,
aS)-
a
-(2-Carbamoylpiperidinyl)-
a-phenylacetic acid
aS)-5
748, 1682, 1736, 2851, 2932, 2931, 3209, 3321, 3460; TLC (hexane/
ethyl acetate 1:2): Rf = 0.28; 1H NMR (CDCl3, 500 MHz): d 1.30–
1.35 (m, 1H, H-5ax), 1.50–1.72 (m, 4H, H-3ax, H-4ax, H-4eq, H-5eq),

M. Dawidowski et al. / Tetrahedron: Asymmetry 20 (2009) 1759–1766
1765
2
1.83–1.90 (m, 1H, H-3eq), 2.74–2.80 (m, 8 lines, J6ax-6eq = 13.7,
2924, 2943, 3086, 3198, 3221; TLC (hexane/ethyl acetate 5:3):
3J6ax-5ax = 5.6, J6ax-5eq = 3.8, 1H, H-6ax), 2.91–2.98 (m, 7 lines,
Rf = 0.41; H NMR (CDCl3, 700 MHz): d 1.43–1.52 (m, 2H, H0-8, H-
3
1
2J6eq-6ax = 13.7, J6eq-5ax = 9.5, J6eq-5eq = 3.2, 1H, H-6eq), 3.19 (pt,
8), 1.64–1.70 (m, 2H, H0-7, H-7), 1.79–1.86 (m, 1H, H0-9), 2.00–
2.06 (m, 1H, H-9), 2.64–2.69 (m, 1H, H0-6), 2.71–2.76 (m, 1H, H-
6), 3.41 (pt, 1H, H-9a), 4.61 (s, 1H, H-4), 7.33–7.40 (m, 5H, H-20,
H-30, H-40, H-50, H-60), 8.13 (br s, 1H, NH, D2O washable); 13C
NMR (CDCl3, 125 MHz): d 21.6 (C-8), 24.9 (C-7), 25.3 (C-9), 50.8
(C-6), 55.1 (C-9a), 69.2 (C-4), 127.9 (C-20, C-60), 128.5 (C-40),
128.8 (C-30, C-50), 132.7 (C-10), 171.6 (C-3), 172.7 (C-1); HPLC:
retention time: 11.2 min; LRMS (EI, 70 eV) m/z (rel. intensity):
244 ([M]+,32), 172 (100), 91 (8), 84 (81); HRMS (EI) calcd for
C14H16N2O2: 244.1212; found 244.1217.
3
3
3J2-3ax,3eq = 4.5, 1H, H-2), 3.70 (s, 3H, OCH3), 4.77 (s, 1H, H-
a),
6.03 (bs, 1H, NH), 7.20 (bs, 1H, NH’), 7.31–7.37 (m, 3H, H-30, H-40,
H-50), 7.41 (dt, 3J = 9.0, J = 2.0, 2H, H-20, H-60); 13C NMR (CDCl3,
4
125 MHz): d 21.6 (C-5), 22.0 (C-4), 23.8 (C-3), 46.5 (C-6), 52.0 (C-
OCH3), 59.9 (C-2), 67.9 (C-a
), 128.4 (C-20, C-60), 128.8 (C-30, C-50),
128.8 (C-40), 136.0 (C-10), 172.2 (CONH2), 176.1 (COOMe); HPLC:
retention time: 24.9 min); GC/MS: retention time: 35.6 min, LRMS
(EI, 70 eV) m/z (rel. intensity): 232 ([M-CONH2]+, 100), 217 (10),
172 (23), 149 (29), 121 (56), 91 (17), 84 (18), 77 (12); HRMS
(ESI) calcd for C15H20N2O3Na: 299.1366 [M+Na]+; found 299.1365.
4.4.4. (4R,9aR)-4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-
dione (4R,9aR)-6
4.3.4. (2R,
methyl ester (2R,
White solid; mp 93–94 °C; [
a
R)-
a
-(2-Carbamoylpiperidinyl)-
a-phenylacetic acid
aR)-5
Colorless crystals, mp 150–151 °C (dec.); [a]D = +96.6 (c 1,
a]
D = ꢀ3.7 (c 1, CHCl3); HPLC: reten-
CHCl3); HPLC: retention time: 10.1 min; LRMS (EI, 70 eV) m/z (rel.
intensity): 244 ([M]+,30), 172 (100), 91 (6), 84 (48); HRMS (EI)
calcd for C14H16N2O2: 244.1212; found 244.1215.
tion time: 28.1 min; HRMS (ESI) calcd for C15H20N2O3Na: 299.1366
[M+Na]+; found 299.1361.
4.4. General procedure for the preparation of 4-phenyl-perhy-
dropyrido[1,2-a]pyrazine-1,3-diones 4
4.5. X-ray crystallographic determination of (4R,9aR)-6
The crystalline and molecular structures were determined by X-
ray diffraction. Crystals suitable for X-ray analysis were grown
from EtOH solution by slow evaporation. The data were collected
on an Oxford Diffraction KM4CCD diffractometer,13 using graph-
To the stirred solution of 3 (0.40 g, 1.6 mmol) in absolute etha-
nol (10 mL), sodium hydroxide (65 mg, 1.6 mmol) pellet was added
at room temperature. After complete dissolution of the hydroxide,
the mixture was stirred for an additional 5 min and quenched with
saturated aqueous ammonium chloride (30 mL). The resulting
cloudy solution was extracted with ethyl acetate (2 ꢃ 30 mL).
The combined organic extracts were sequentially washed with
water (10 mL) and brine (10 mL), dried with magnesium sulfate,
filtered, and concentrated under reduced pressure. Analytically
pure isomers were obtained by a single recrystallization from min-
imal amount of absolute ethanol.
ite-monochromated Mo Ka radiation, at 293 K. The unit-cell
parameters were determined by the least-squares treatment of set-
ting angles of highest-intensity reflections chosen from the whole
experiment. Intensity data were corrected for the Lorentz and
polarization effects.14 The structure was solved by the direct meth-
od using the SHELXS-97 program15 and refined by the full-matrix
least-squares method with the SHELXL97 program.16 The function
R
w(|Fo|2 ꢀ |Fc|2)2 was minimized with wꢀ1 = [
r
2(Fo)2 + (0.0478P)2
+0.0394P] for (4R,9aR)-6, where P = (F2o+2Fc22)/3. An empirical
extinction correction was also applied for (4R,9aR)-6, according
4.4.1. (4R,9aS)-4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-
dione (4R,9aS)-4
to the formula F0 = kFc[1 + (0.001
v
Fc2k3/sin 2h)]ꢀ1/4 16
,
and the
c
Colorless crystals; mp 188–189 °C (dec.); [
a
]
D = ꢀ137.4 (c 1,
extinction coefficient
v was equal to 0.040(3). All non-H atoms
CHCl3); IR (KBr): 698, 760, 1231, 1693, 1732, 2851, 2924, 3213;
were refined anisotropically; positions of hydrogen atoms were
generated geometrically and refined as a riding model. Thermal
parameters of all hydrogen atoms were calculated as 1.2 times
Ueq of the respective carrier carbon atom. The figures were drawn
using the MERCURY program.17
The deposition number CCDC 725959 for (4R,9aR)-6 contains the
supplementary crystallographic data from this study. These data can
be obtained free of charge through www.ccdc.cam.ac.uk/data_re-
quest/cif, or by emailing data_request@ccdc.cam.ac.uk, or by con-
tacting The Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
TLC (hexane/ethyl acetate 5:3): Rf = 0.33; 1H NMR (CDCl3,
3
700 MHz): d 1.34 (4t, 2J = 3Jax-ax = 13.3, Jax-eq = 3.5, 1H, H-8ax),
3
1.42 (4t, 2J = 3Jax-ax = 12.6, Jax-eq = 3.5, 1H, H-7ax), 1.55 (2quin,
2J = 15.6, 1H, H-7eq), 1.59–1.66 (m, 1H, H-9ax), 1.84 (td, 2J = 3Jax-ax
=
3
11.9, Jax-eq = 2.8, 1H, H-6ax), 1.86–1.90 (m, 2J = 12.6, 1H, H-8eq),
3
2.42 (2quin, 1H, H-9eq), 2.75 (dt, 2J = 11.2, Jax-eq,eq-eq = 2.1, 1H, H-
3
3
6eq), 2.99 (dd, J9a-9ax = 11.2, J9a-9eq = 2.8, 1H, H-9a), 3.93 (s, 1H,
H-4), 7.33–7.40 (m, 5H, H-20, H-30, H-40, H-50, H-60), 8.18 (br s,
1H, NH, D2O washable); 13C NMR (CDCl3, 125 MHz): 23.5 (C-8),
25.0 (C-7), 27.1 (C-9), 53.3 (C-6), 63.2 (C-9a), 72.1 (C-4), 128.5
(C-20, C-60), 128.6 (C-40), 129.2 (C-30,C-50), 136.2 (C-10), 170.9
(C-3), 171.5 (C-1); HPLC: retention time: 17.5 min; LRMS (EI,
70 eV) m/z (rel. intensity): 244 ([M]+, 21), 172 (100), 91 (12),
84 (40); HRMS (EI) calcd for C14H16N2O2: 244.1212; found
244.1223.
4.5.1. Crystal data for (4R,9aR)-6
C14H16N2O2, M = 244.29, Dcalcd = 1.290 g/cm3, monoclinic, P21,
a = 11.4703(3) Å, b = 8.5759(2) Å, c = 13.2163(4) Å, b = 104.700(3)°,
V = 1257.51(6) Å3, Z = 4, F(0 0 0) = 520,
l
= 0.088 mmꢀ1. The reflec-
tions collected numbered 28615, of which 4728 were unique
[R(int) = 0.0203]; 4088 reflections I > 2 (I), R1 = 0.0274 and
wR2 = 0.0711 for 4088 [I > 2 (I)] and R1 = 0.0351 and wR2 = 0.0785
4.4.2. (4S,9aR)-4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-
dione (4S,9aR)-4
r
r
Colorless crystals; mp 187–189 °C (dec.); [a]D = +138.3 (c 1,
for all (4728) intensity data. Goodness of fit = 1.087; residual elec-
CHCl3); HPLC: retention time: 19.6 min; LRMS (EI, 70 eV) m/z
(rel. intensity): 244 ([M]+, 27), 172 (100), 91 (4), 84 (36); HRMS
(EI) calcd for C14H16N2O2: 244.1212; found 244.1218.
tron densities in the final Fourier map were 0.124 and ꢀ0.132 e Åꢀ3
.
References
4.4.3. (4S,9aS)-4-Phenyl-perhydropyrido[1,2-a]pyrazine-1,3-
dione (4S,9aS)-6
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