Synthesis and structural features of cyclobutane-containing chiral bicyclic ureas

Article abstract of DOI:10.1016/j.tetasy.2010.01.020

Efficient and stereoselective synthetic routes have been developed for the preparation of chiral N-monoprotected cyclobutane bicyclic ureas in which one of the NH groups is protected as a benzyl or tert-butyl carbamate. Ureas in both enantiomeric forms were obtained from a common chiral precursor via the selective manipulation of functional groups. These compounds have been subjected to a structural study in solution and in the solid state. NMR, IR and TEM techniques evidence a strong tendency to aggregation in solution giving regular assemblies, which is a result of intermolecular urea N-H...O{double bond, long}C hydrogen bonding. In the solid state, X-ray analysis shows that two urea molecules interact through only one hydrogen bond yielding infinite chains. This fact and the almost complete coplanarity of both the urea and the carbamate carbonyl groups determine the crystal packing to be formed by a parallel molecular arrangement. All these structural features are well supported by theoretical calculations that allow us to conclude that the formation of a network based on hydrogen bonding is energetically favourable.

Full text of DOI:10.1016/j.tetasy.2010.01.020

Tetrahedron: Asymmetry 21 (2010) 339–345
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and structural features of cyclobutane-containing chiral bicyclic ureas
a,
a,
Esther Gorrea a, Pau Nolis b, Ángel Álvarez-Larena c, Eric Da Silva a, , Vicenç Branchadell , Rosa M. Ortuño
*
*
*
a Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
b Servei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
c Servei de Difracció de Raigs X, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient and stereoselective synthetic routes have been developed for the preparation of chiral N-mono-
protected cyclobutane bicyclic ureas in which one of the NH groups is protected as a benzyl or tert-butyl
carbamate. Ureas in both enantiomeric forms were obtained from a common chiral precursor via the
selective manipulation of functional groups. These compounds have been subjected to a structural study
in solution and in the solid state. NMR, IR and TEM techniques evidence a strong tendency to aggregation
in solution giving regular assemblies, which is a result of intermolecular urea N–Hꢀ ꢀ ꢀO@C hydrogen bond-
ing. In the solid state, X-ray analysis shows that two urea molecules interact through only one hydrogen
bond yielding infinite chains. This fact and the almost complete coplanarity of both the urea and the car-
bamate carbonyl groups determine the crystal packing to be formed by a parallel molecular arrangement.
All these structural features are well supported by theoretical calculations that allow us to conclude that
the formation of a network based on hydrogen bonding is energetically favourable.
Received 22 December 2009
Accepted 27 January 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Nevertheless, as far as we know, there are no precedents in the
literature on structural studies on cycloalkane bicyclic ureas with
Fused cycloalkane-1,3-imidazolidin-2-ones are interesting
compounds that have been used as versatile scaffolds to synthesize
useful products. For example, urea 2 (Chart 1) was prepared related
to a synthesis of a conveniently protected cis-cyclohexane-1,2-dia-
mine derivative,1 which is important in providing building blocks
for conformationally preorganized peptide nucleic acids2 and bio-
logically active small molecules.3 In other cases, these products
are relevant by themselves as ureas 3, which are N/OFQ receptor
antagonists.4 N/OFQ and its peptide analogues modulate a variety
of biological functions including central nervous system disorders.5
These bicyclic ureas have been prepared according to different
procedures. Cyclobutane ureas 1 are obtained from the reductive
rearrangement of aminocyclopropane precursors.6 In turn, cis-
bicyclic urea 2 comes from the intramolecular Curtius rearrange-
ment of a 2-aminocyclohexane-1-carboxylic derivative, which
was prepared by the asymmetric reduction of a b-enamino ester.1
Compounds of general formula 3 have been synthesized from
trans-cyclohexanediamine as a chiral precursor.4
intrinsic chirality. Therefore, according to our research programme
devoted to the investigation of folding and self-assembling proper-
ties of cyclobutane derivatives, we decided to prepare and study a
O
O
Bn
N
N
R1
R2
Boc
N
N
H
R1, R2 = H, alkyl
1
2
O
R3
N
N
N
R4
Several kinds of ureas have been the object of structural studies
to gain knowledge about their ability to fold and self-assemble.7
The results have been used in supramolecular chemistry8a and in
the design of new materials.8b Crystal engineering with ureas
and thioureas has also been the goal of several investigations.8c
R3 = H, Et, R4 = H, alkyl
3
* Corresponding authors. Tel.: +34 93 581 1602; fax: +34 93 581 1265.
E-mail address: rosa.ortuno@uab.es (R.M. Ortuño).
Chart 1. Structure of chiral bicyclic ureas.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.020

340
E. Gorrea et al. / Tetrahedron: Asymmetry 21 (2010) 339–345
O
O
O
O
Ref [9b]
Ref [10]
Ref [9b]
OH
O
OMe
O
OH
O
OMe
OH
NH
NH
NH
O
O
O
O
4
5
6
7
DPPA, TEA
DPPA, TEA
Ref [9b]
Δ
Δ
H
H
4
5
6
N
3
N
O
O
O
3
O
O
7
N
N
8
2
O
O
1
DPPA, TEA
NH
O
O
N
8
Δ
9 O
O
10
N
OH
H
O
9
10
11
8
Scheme 1. Synthetic pathways to bicyclic ureas 8, 10 11.
new family of ureas anchored to a cyclobutane moiety. We have
shown in earlier works the ability of the small and rigid cyclobu-
tane ring to promote defined structures in different families of chi-
ral b-peptides, both in the solution and in the solid state.9 Herein
we report on the synthesis and study of cyclobutane-containing
chiral cis-fused N-monoprotected bicyclic ureas 8, 10 and 11
(Scheme 1). Easy and efficient synthetic routes have been devel-
intramolecular Curtius rearrangement1 afforded ureas 8, 10 and
11, respectively, in 70–80% yield.
These new compounds are crystalline solids, which were fully
characterized. Their ability to associate giving aggregates was
investigated by means of several techniques in solution and in
the solid state.
Transmission Electron Microscopy (TEM) showed nano-sized fi-
bres produced by 8 and 10 from 5 mM solutions in MeOH. Selected
TEM images are presented in Figure 1. One can observe that the fi-
bres are more regular and defined for 8 than for 10.
The tendency to aggregate was also verified by IR spectroscopy.
For instance, Figure 2 shows the IR spectrum, at the N–H stretching
region, of urea 10 in 0.10, 0.05 and 0.01 M solutions in CDCl3. Only
one sharp band is exhibited at 3460 cmꢁ1 for the 0.01 M solution
corresponding to a free N–H. As concentration increases, this band
diminishes in favour of a new broad one at 3260 cmꢁ1, due to N–H
association.
oped to prepare enantiomeric ureas from
precursor.
a common chiral
The presence of only one free N–H group in these products pro-
vides a defined site to link each molecule to another through
hydrogen bonding. The tendency to form aggregates in solution
has been shown by IR, high-resolution NMR techniques and trans-
mission electron microscopy (TEM) and their arrangement in the
crystal packing has been stated by X-ray structural analysis and
supported by theoretical calculations.
NMR Spectroscopy is a valuable tool in corroborating molecular
aggregation.11 Investigation of 1H-concentration dependence and
diffusion spectroscopy (DOSY) experiments was undertaken in or-
der to gain insight into self-assembling features of these ureas, 10
being used as a representative compound. After its full character-
ization by 1D and 2D NMR experiments, 1H-concentration depen-
dence in CDCl3 was investigated. The N–H proton becomes
2. Results and discussion
2.1. Synthesis and aggregation studies
The stereoselective synthesis of some cyclobutane-containing
bicyclic ureas with opposite chirality and bearing different N-pro-
tecting groups was achieved according to Scheme 1. Half-ester 5
was the only chiral precursor used to induce the absolute configu-
ration of the title molecules. It was prepared through an enantiose-
lective and chemoenzymatic hydrolysis of a precursor meso-
diester.10 Compound 5 was transformed into N-Cbz enantiomeric
amino acids 710 and 9,9b and N-Boc derivative 49b following syn-
thetic procedures previously developed in our laboratory, which
involve the selective manipulation of functional groups. The one-
pot reaction of these products with diphenylphosphoryl azide
(DPPA) in the presence of triethylamine (TEA) and subsequent
noticeably deshielded (
concentration as can be seen in Figure 3.
D
d ꢂ1.5 ppm) when increasing the sample
This fact suggests that the urea molecules associate via inter-
molecular hydrogen-bond formation which is in agreement with
IR results.
Furthermore, aggregation was confirmed by serial concentra-
tion-dependent DOSY experiments. Translational diffusion coeffi-
cients (D) were measured for solutions of 10 in CDCl3 and in
MeOD, respectively, at 298 K

E. Gorrea et al. / Tetrahedron: Asymmetry 21 (2010) 339–345
341
Figure 1. TEM images of fibres formed by (A) urea 8 and (B) urea 10 from 5 mM solutions in MeOH (1 day incubation) placed onto a carbon-film-coated copper grid and
stained with 2% uranyl acetate.
cyclobutane ring is more distorted showing a higher deviation
from the mean plane C1–C5–C6–C7 of 0.078(3) Å for
8 and
0.108(2) Å for 10. The dihedral angle between imidazoline and
cyclobutane mean planes is 116°, as usual in bicyclo[3.2.0]hep-
tane.12 The carbonyl groups in the carbamate and in the urea point
in the same direction and the tert-butyl and benzyl groups point
away from the bicyclic core.
The crystal structures of both compounds contain infinite
chains of molecules linked by N–Hꢀ ꢀ ꢀO@C hydrogen bonds, one
bond between two molecules (Fig. 6, Table 2). All chains or ribbons
are lined up along one crystallographic direction (a) defining a zig-
zag arrangement.
2.3. Theoretical calculations
To better understand and support the experimental results,
both in the solution and in the solid state, theoretical calculations
were carried out. Starting from the crystal structure of urea 10, we
have optimized the geometries of aggregates of 2, 3 and 4 urea
molecules at the M05-2X/6-31G(d) level of calculation. The struc-
tures obtained are shown in Figure 7. For the dimeric aggregate,
the calculation evolves to the cyclic structure 10-IIa, in which the
two urea molecules interact through two intermolecular hydrogen
bonds involving NH4 and CO3.
The NH4 of one molecule and the CO3 of the other can be
blocked through the interaction with a formaldehyde and a
dimethylamine molecule, respectively. In this way, structure 10-
IIb is obtained. In this structure the two urea molecules interact
through only one hydrogen bond, as observed in the crystal struc-
ture (Fig. 6).
For the trimeric (10-III) and tetrameric (10-IV) aggregates, the
hydrogen-bonding pattern observed in the crystal packing is pre-
served and the introduction of blocking molecules is no longer
necessary.
As can be observed, 10-IIa is the structure with the strongest
hydrogen bonds. Regarding the structures with only one urea-urea
intermolecular hydrogen bond, the results show that the strength
of the hydrogen bonds increases with the number of urea
molecules.
Figure 2. IR spectrum at the N–H stretching region of urea 10 in CDCl3 solution at
different concentrations.
A linear relationship was found between the concentration and
D values when measured in both the solvents as shown in Figure 4.
In general, a fall in the diffusion coefficients is inversely propor-
tional to the size of the diffusing species. Therefore, in this case,
the decrease in D values when increasing concentration is inver-
sely related to the growth of the aggregates.
It is noteworthy that this dependence is slightly less pro-
nounced in MeOD than in CDCl3. This fact can be explained by
the competition between urea aggregation and urea-MeOD hydro-
gen-bond formation.
2.2. X-ray structural analysis of ureas 8 and 10
The formation energies of the different aggregates of urea 10 are
shown in Table 3. The formation of the cyclic dimeric aggregate 10-
IIa, which involves two hydrogen bonds, is much more favourable
than the interaction through only one urea-urea hydrogen bond
(10-IIb).
The values calculated for 10-III and 10-IV correspond to the
addition of one urea molecule from 10-IIa and 10-III, respectively
(Table 3). In the first case, the number of hydrogen bonds does
not change during the process, meaning that the energy stabiliza-
tion is modest (ꢁ1.6 kcal molꢁ1 in chloroform). On the other hand,
Few examples on ureas with a bicyclo[3.2.0] skeleton are de-
scribed in the literature.12,13 A detailed study was carried out to
determine the structural arrangement of ureas 8 and 10 in the solid
state. Refined molecular structures are shown in Figure 5, and crys-
tal data and structure refinement parameters are listed in Table 1.
Both the compounds present similar molecular conformations
and crystal packings. The 1,3-imidazolidin-2-one ring is planar,
with a mean deviation of 0.057(2) Å for 8 and 0.080(3) Å for 10
from the least-squares plane trough atoms C1–N2–C3–N4–C5. The

342
E. Gorrea et al. / Tetrahedron: Asymmetry 21 (2010) 339–345
Figure 3. 1H NMR experiments recorded at 500 MHz and 298 K for solutions of 10 in CDCl3 at different concentrations. (A) 5 mM, (B) 16 mM, (C) 27 mM, (D) 54 mM, (E)
81 mM, (F) ꢂ100 mM (saturated sample).
in the formation of 10-IV from 10-III, the number of hydrogen
1.1
CDCl3
MeOD
bonds increases and the energy stabilization is much larger
(ꢁ7.1 kcal molꢁ1 in chloroform).
1.05
These results are in accordance with the intermolecular hydro-
1
gen-bond lengths that decrease from 10-III to 10-IV. In the second,
the calculated NH4ꢀ ꢀ ꢀOC3 length between the two central mole-
0.95
cules is 2.00 Å (Fig. 7), which is close to the 1.96 Å measured in
the crystal for urea 10 (Table 2).
0.9
0.85
Table 1
0
10
20
30
40
50
60
70
80
90
Crystal data and structure refinement parameters for 8 and 10
sample concentration (mM)
8
10
Figure 4. Linear dependence of self-diffusion coefficients (D) on concentration for
solutions of urea 10 in CDCl3 (blue) and MeOD (red).
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
C10H16N2O3
212.25
Orthorhombic
P212121
6.1225 (7)
11.6440 (14)
16.794 (2)
4
1197.3 (2)
1.178
C13H14N2O3
246.26
Orthorhombic
P212121
6.5978 (6)
9.7463 (9)
20.4034 (19)
4
1312.0 (2)
1.247
b (Å)
c (Å)
Z
V (Å3)
qcalcd (Mg mꢁ3
)
Absorption coefficient 0.087
(mmꢁ1
F(0 0 0)
0.090
)
456
520
Crystal size (mm)
Theta (°) range for
data collection
Index ranges
0.42 ꢃ 0.15 ꢃ 0.05
0.48 ꢃ 0.14 ꢃ 0.11
2.13–28.99
2.32–28.61
ꢁ8 6 h 6 8,
ꢁ8 6 h 6 6, ꢁ12 6 k 6 9,
ꢁ25 6 l 6 25
ꢁ15 6 k 6 13,
ꢁ16 6 l 6 22
8343
Reflections collected
Independent
8239
2925 [R(int) = 0.0472]
3018 [R(int) = 0.0521]
reflections
Data/restraints/
parameters
2925/0/143
3018/0/166
Goodness-of-fit on F2
Final R indices
[I > 2o(I)]
1.000
0.956
R(F) = 0.0559,
Rw(F2) = 0.1128
R(F) = 0.1322,
Rw(F2) = 0.1376
R(F) = 0.0504,
Rw(F2) = 0.1109
R(F) = 0.0857,
Rw(F2) = 0.1262
0.168 and ꢁ0.165
R indices (all data)
Largest diff. peak and 0.117 and ꢁ0.117
hole (e Åꢁ3
)
Figure 5. ORTEP diagrams of 8 (left) and 10 (right) showing 30% probability
ellipsoids.

E. Gorrea et al. / Tetrahedron: Asymmetry 21 (2010) 339–345
343
Figure 6. View of infinite chains parallel to the crystallographic a axis for 8 (left) and 10 (right). Dashed lines represent hydrogen bonds.
sured in CDCl3. DOSY experiments were performed with
a
Table 2
500 MHz Bruker spectrometer. Chemical shifts were recorded in
ppm relative to CDCl3 as the internal standard. All solvents were
distilled from suitable drying reagents right before use: Toluene
(Na, benzophenone). The normal work-up included extraction, dry-
ing over Mg2SO4 and evaporation of volatile materials in vacuo.
Geometries of the intermolecular hydrogen bonds forming infinite chains in the
crystal structures of compounds 8 and 10
Compound N4ꢀ ꢀ ꢀO3(s)a H4ꢀ ꢀ ꢀO3(s)a N4–
s
H4ꢀ ꢀ ꢀO3(s)b
8
2.858(3)
2.961(3)
1.85
1.96
164
x ꢁ 1/2, ꢁy + 1/2 + 1,
ꢁz + 1
10
163
x + 1/2, ꢁy + 1/2 + 2,
ꢁz + 2
4.2. General procedure for intramolecular Curtius
rearrangement
s is the symmetry code of the neighbour molecule. Values normalized following Ref.
14 with N4–H4: 1.03 Å.
As a representative example, the preparation of 8 is described.
a
In Angstroms (Å).
Diphenylphosphoryl azide (120
lL, 1.2 equiv) and freshly distilled
b
In degrees (°).
dry TEA (78 L, 1.2 equiv) were successively added to a solution of
l
aminocyclobutan-1-carboxylic acid 4 (100 mg, 1 equiv), prepared
according to Ref. 9b, in dry toluene (15 mL). The mixture was stir-
red and heated at reflux overnight. The solvent was removed under
high vacuum and the residue was poured into EtOAc (25 mL). The
organic phase was washed with saturated aqueous NaHCO3
(4 ꢃ 20 mL). The organic layer was dried over MgSO4, filtered off
and the solvent was concentrated. The residue was purified by col-
umn chromatography on BakerÒ silica gel using 1:1 ethyl acetate–
pentane as an eluent to afford pure final compound 8.
Regarding the values corresponding to the formation energy per
urea molecule (D
E0), we can observe a slight decrease in the abso-
lute value when going from two to three molecules, while the va-
lue increases again for the tetrameric aggregate. According to these
results, a network of hydrogen bonds similar to that observed in
the crystal structure seems to be energetically favourable when
the number of urea molecules is larger than 3.
4.2.1. (1S,5R)-tert-Butyl 3-oxo-2,4-diazabicyclo[3.2.0]-heptane-
2-carboxylate 8
3. Conclusions
Yield: 67 mg, 68%. Crystals, mp 89–93 °C (from ethyl acetate–
General procedures have been developed for the stereoselective
synthesis of N-monoprotected cyclobutane chiral bicyclic ureas in
both enantiomeric forms. NMR, IR and TEM techniques show that
these products have a strong tendency to aggregate in solution giv-
ing regular assemblies, which is the result of intermolecular urea
NHꢀ ꢀ ꢀOC hydrogen bonding. The presence of only one free NH in
the urea favours such a defined self-assembly. In fact, in the solid
state, X-ray analysis shows that two urea molecules interact
through only one hydrogen bond affording infinite chains. These
features and the almost complete coplanarity of both urea and car-
bamate carbonyl groups determine the crystal packing to be
formed by a parallel molecular arrangement. Theoretical calcula-
tions reproduce this geometry well and predict that the formation
of a network based on hydrogen bonding is energetically favour-
able for tetramers and higher aggregates. The use of these com-
pounds in the design of new materials is currently under
investigation.
pentane). [
a
]
D = +42.8 (c 0.56, CH2Cl2). IR (ATR): 3343, 3269,
2973, 2941, 1769, 1754, 1695, 1456, 1076 cmꢁ1
.
1H NMR
(360 MHz, CDCl3): 1.50 (s, 9H), 2.10 (m, 1H), 2.29 (m, 2H), 2.51
(m, 1H), 4.12 (m, 1H), 4.61 (m, 1H), 6.66 (br s, 1H). 13C (90 MHz,
CDCl3): 28.1, 28.2 (3C), 28.6, 48.2, 54.7, 82.1, 151.1, 157.7. HRMS
(EI): calcd for C10H16N2O3Na (M+Na): 235.1050. Experimental:
235.1053.
4.2.2. (1R,5S)-Benzyl 3-oxo-2,4-diazabicyclo[3.2.0]heptane-2-
carboxylate 10
Yield: 70 mg, 71%. Crystals, mp = 86–89 °C (from ethyl acetate–
pentane). [
a]
D = ꢁ60 (c 0.59, MeOH). IR (ATR): 3239, 2948, 1789,
1738, 1700, 1586, 1545, 1499, 1461 cmꢁ1
.
1H NMR (250 MHz,
CDCl3): 2.21–2.54 (m, 4H), 4.15 (m, 1H), 4.67 (m, 1H), 5.24 (s,
2H), 6.64 (br s, 1H), 7.37 (m, 5H). 13C (62.5 MHz, CDCl3): 28.1,
28.5, 48.4, 54.5, 67.5, 128.1 (2C), 128.2, 128.5 (2C), 135.6, 151.2,
157. HRMS (EI): calcd for C13H14N2O3Na (M+Na): 269.0897. Exper-
imental: 269.0899.
4. Experimental section
4.1. General information
4.2.3. (1S,5R)-Benzyl 3-oxo-2,4-diazabicyclo[3.2.0]heptane-2-
carboxylate 11
NMR spectra were recorded with a Bruker spectrometer (250
and 360 MHz for 1H NMR, 62.5 and 90 MHz for 13C NMR) and mea-
Yield: 79 mg, 80%. Crystals, mp 88–91 °C (from ethyl acetate–
pentane). [a]D = +60 (c 0.87, MeOH). IR (ATR): 3229, 2959, 1737,

344
E. Gorrea et al. / Tetrahedron: Asymmetry 21 (2010) 339–345
Figure 7. Structures of aggregates of urea 10 obtained at the M05-2X/6-31G(d) level of calculation. Selected interatomic distances in Å.
4.3. DOSY experimental details
Table 3
Energiesa associated to the formation of urea aggregates
DOSY experiments were performed at different concentrations
of urea 10 in CDCl3 and in MeOD (5.4 mM, 27.0 mM, 54.1 mM
and 81.2 mM). The NMR pulse sequence for diffusion measurement
using stimulated echo and LED was used directly as implemented
in BRUKER spectrometers (pulse sequence named ledbpgp2s).15
b
D
E
D
E0
10-IIa
10-IIb
10-III
10-IV
ꢁ18.3c
ꢁ4.9d
ꢁ6.1e
(ꢁ6.7)
(0.5)
ꢁ9.2
(ꢁ3.3)
(ꢁ1.6)
ꢁ8.1
(ꢁ2.7)
(ꢁ3.8)
ꢁ15.9f
(ꢁ7.1)
ꢁ10.1
Diffusion time delay
was set to 1000 s. Spoil gradient pulses were set to 600
ent recovery delay was set to 0.2 ms. Eddy current delay was set to
5 ms. Proton 90° pulse length was calibrated to be 7.6 s at 0 dB.
D
was set to 100 ms. Gradient pulse (dꢀ0.5)
In kcal molꢁ1. In parentheses values computed in chloroform solution.
E0 corresponds to the average energy per urea molecule (formation of the
a
l
l
s. Gradi-
b
D
aggregate from n urea molecules divided by n).
c
Relative to two urea molecules.
Relative to urea-formaldehyde + urea-dimethylamine.
l
d
DOSY signal decay was measured using a linear gradient ramp of
20 points from 95% to 2% of maximum gradient strength (56G/
cm). Gradients used were sine shaped. Data obtained for proton
H1 are logarithmically plotted. Self-diffusion coefficient values
(D) are obtained from the slope of the linear tendency.
e
Relative to 10-IIa + urea.
Relative to 10-III + urea.
f
1698, 1499, 1461, 1390, 1343 cmꢁ1 1H NMR (250 MHz, CDCl3):
.
4.4. X-ray crystallography
2.11–2.55 (m, 4H), 4.16 (m, 1H), 4.70 (m, 1H), 5.26 (s, 2H), 6.04
(br s, 1H), 7.33–7.38 (m, 5H). 13C (62.5 MHz, CDCl3): 28.1, 28.5,
48.5, 54.5, 67.5, 128.0 (2C), 128.2, 128.5 (2C), 135.7, 151.2, 157.1.
HRMS (EI): calcd for C13H14N2O3Na M+Na): 269.0897. Experimen-
tal: 269.0900.
Colourless single crystals were obtained by the slow diffusion of
pentane into 0.1 M solution of compound 8 (C10H16N2O3) or 10
(C13H14N2O3) in ethyl acetate at 4 °C. Crystal data and selected

E. Gorrea et al. / Tetrahedron: Asymmetry 21 (2010) 339–345
345
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GAUSSIAN 03, Revision E.01 Gaussian, Inc.: Wallingford CT, 2004.
tion and absorption corrections were applied using Bruker SAINT
and SADABS software. Structures were solved by direct methods
(
SHELXS97) and refined by full-matrix least-squares methods on F2
for all reflections (SHELXL97).16 Non-hydrogen atoms were refined
anisotropically. Hydrogen atoms bonded to carbon atoms were in-
cluded with riding model constraints and isotropic displacement
parameters fixed at 1.5 (methyl H) or 1.2 (the rest) times the Ueq
of the corresponding carbon atoms.
CCDC 750428 (for 8) and CCDC 750429 (for 10) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
4.5. Computational details
Calculations have been carried out with the GAUSSIAN-03 pro-
gram17 using the M05-2X18 density functional with the 6-31G(d)
basis set.19 Geometries have been fully optimized and the struc-
tures obtained have been characterized as energy minima through
the calculation of harmonic vibrational frequencies. The effect of
the solvent has been taken into account through single-point cal-
culations at the geometries optimized in the gas phase using the
Conductor-like Polarizable Continuum Model (CPCM).20 The sol-
vent considered is chloroform (e = 4.9).
Acknowledgements
Authors thank financial support from Spanish Ministerio de
Ciencia e Innovación (grant CTQ2007-61704/BQU) and Generalitat
de Catalunya (grant 2009SGR-733, and XRQTC). Time allocated in
the Servei de Ressonància Magnètica Nuclear and Servei de Micros-
còpia Electrónica (UAB) and in the Centre de Supercomputació de
Catalunya (CESCA) is gratefully acknowledged.
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