Adamantane-retropeptides, new building blocks for molecular channels

Article abstract of DOI:10.1016/j.tet.2007.05.066

Novel adamantane-oxalamide derivatives, N,N′-bis(1-adamantylglycine methyl ester)oxalamide (meso-1 and rac-1), N,N′-bis(3-aminoadamantane-1-carboxylic acid methyl ester)oxalamide (2) and N,N′-bis(3-aminoadamantane-1-carboxylic acid)oxalamide (3) were prepared and structurally characterized by spectroscopic methods and X-ray analysis. Crystal packing of the structures meso-1 and rac-1 is defined by one-dimensional α-networks of hydrogen-bonded chains. The crystal structures of 2 and 3 are characterized by two-dimensional β-networks of hydrogen bonds. The oxalamide 3 crystallizes as the solvates only. In the crystal structure of 3 the protic solvent participates in hydrogen bonding with the oxalamide moieties. However, in non-protic solvents 3 crystallizes as a solvate but the solvent does not participate in hydrogen bonding. The two-dimensional network of hydrogen bonds connecting molecules of 3 generates channels, which are filled by discrete solvent molecules.

Full text of DOI:10.1016/j.tet.2007.05.066

Tetrahedron 63 (2007) 7985–7996
Adamantane-retropeptides, new building blocks
for molecular channels
*
´
´
´
´
ꢀ
ꢀ
Nikola Basaric, Kresimir Molcanov, Marija Matkovic, Biserka Kojic-Prodic
*
´
and Kata Mlinaric-Majerski
´
RuCer Boꢀskovic Institute, Bijenicꢀka cesta 54, PO Box 180, 10 002 Zagreb, Croatia
Received 7 February 2007; revised 27 April 2007; accepted 17 May 2007
Available online 24 May 2007
Abstract—Novel adamantane-oxalamide derivatives, N,N0-bis(1-adamantylglycine methyl ester)oxalamide (meso-1 and rac-1), N,N0-bis(3-
aminoadamantane-1-carboxylic acid methyl ester)oxalamide (2) and N,N0-bis(3-aminoadamantane-1-carboxylic acid)oxalamide (3) were
prepared and structurally characterized by spectroscopic methods and X-ray analysis. Crystal packing of the structures meso-1 and rac-1
is defined by one-dimensional a-networks of hydrogen-bonded chains. The crystal structures of 2 and 3 are characterized by two-dimensional
b-networks of hydrogen bonds. The oxalamide 3 crystallizes as the solvates only. In the crystal structure of 3 the protic solvent participates in
hydrogen bonding with the oxalamide moieties. However, in non-protic solvents 3 crystallizes as a solvate but the solvent does not participate
in hydrogen bonding. The two-dimensional network of hydrogen bonds connecting molecules of 3 generates channels, which are filled by
discrete solvent molecules.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
acids6 and hydroxyacids, which incorporate adamantane as
a building block.7 The spacious adamantyl cage is a highly
lipophilic group and can affect the bioavailability of peptido-
mimetics significantly. We showed that incorporation of
unnatural amino acids derived from adamantanes in the
methionine-enkephalin peptide increased the lipophilicity
of the peptide facilitating its transport through the cell mem-
brane. Since methionine-enkephalin derivatives showed
good in vitro anticancer properties these molecules are
promising candidates for the development of new anticancer
agents.6
Synthesis of peptidomimetics has attracted considerable at-
tention in recent years, mainly because of their numerous
applications, primarily as biologically active molecules.1 A
special interest in the chemistry of peptidomimetics has
been directed towards the synthesis of cyclic peptides and
depsipeptides containing unnatural amino acids.2 These
compounds have shown extremely good properties in the
solid state forming tubular structures or ion channels.3 Since
these structures may find applications in nanotechnology,
the synthesis of new derivatives is under intensive investiga-
tion. Therefore, in continuation of that research it is impor-
tant to synthesize new synthons, which could be used later
on as building blocks in the coupling reactions and prepara-
tion of more complex molecules. Moreover, the structural
role of new synthons could be explored in the design of
new macrocycles or peptidomimetics with tailor-made struc-
tural and functional characteristics.
In this paper, we report the synthesis of four new oxalamide
retropeptides with adamantane subunits, meso-1, rac-1, 2
and 3 (Schemes 1 and 2), and their structural characteriza-
tion. The oxalamide derivatives have shown a tendency
to form two-dimensional hydrogen-bonding b-networks.8
Moreover, some oxalamide amino acid derivatives showed
good properties in forming gels with non-polar and polar
solvents.9 Incorporation of adamantanes as bulky substitu-
ents in these compounds is expected to affect conformational
mobility and the hydrogen-bonding motifs. Therefore, it is
anticipated that these oxalamide-adamantane derivatives
would show different structural motifs in the solid state,
depending on the substitution on the adamantane skeleton.
Additionally, knowledge of the structure of these oxalamides
may be useful for docking and prediction of potential biolog-
ical activity.
In the scope of our research on chemistry of polycyclic mol-
ecules4 and their application as versatile building blocks,5
we turned our attention to the synthesis of unnatural amino
Keywords: Adamantane-oxalamides; Molecular channels; Retropeptides;
Synthesis; X-ray structural analysis.
* Corresponding authors. Fax: +385 1 46 80 195 (K.M.-M.); fax: +385 1 46
80 245 (B.K.-P.); e-mail addresses: kojic@irb.hr; majerski@irb.hr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.066

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7986
O
HN
H
NH
O
O
H
Cl
SOCl2
CH3OH
COOCH3
COOCH3
NH3+Cl-
OH
Cl
NH3+Cl-
OCH3
O
meso-1
O
TEA
O
O
4
6
HN
H
NH
O
H
COOCH3
COOCH3
rac-1
Scheme 1.
O
NH3+Cl-
Cl
NH2
1) SOCl2
Cl
CH3OH
O
O
H
N
COOCH3
2) NaHCO3
COOCH3
COOH
TEA
NH
H3COOC
O
5
7
2
CH3OH : H2O
(Na2CO3 10 %) = 1:2
O
H
COOH
N
NH
HOOC
O
3
Scheme 2.
2. Results and discussion
In order to obtain building blocks, which could be incorpo-
rated into bigger molecules, we transformed retropeptide-
esters 1 and 2 to the corresponding diacid derivatives. The
hydrolysis turned out to be difficult, probably due to the ste-
ric hindrance of bulky adamantane moieties. Thus, upon
treatment of retropeptide-esters 2 at rt with a 1 M solution
of LiOH or saturated NaOH, only starting material was re-
covered. However, the ester hydrolysis was accomplished
in a mixture of boiling methanol and 10% aqueous
Na2CO3 (in a ratio of 1:2). In that way, diacid 3 was isolated
in good yield, but diacids obtained from the mixture of dia-
stereomers 1 were highly insoluble and we could not proceed
with the diastereomer separation and their independent
characterization.
2.1. Synthesis
Synthesis of the adamantane amino acids 4 and 5 was per-
formed according to the described procedure,6,10 and the
corresponding hydrochlorides were transformed to their
methyl esters 6 and 7, respectively (Schemes 1 and 2).
Due to the steric bulkiness imposed by adamantane moiety,
the esterification was difficult, but it was accomplished in
a good yield after several days of refluxing in methanol in
the presence of SOCl2. Oxalamides 1 and 2 were obtained
from esters 6 and 7, respectively, in a reaction with oxalyl
chloride in the presence of triethylamine. The reaction of
glycine derivative 6 furnished mixture of two diastereomers
meso-1 and rac-1, which were separated by preparative
TLC. The oxalamide derivatives meso-1, rac-1 and 2 were
The ester derivatives of oxalamides meso-1, rac-1 and 2, as
well as diacid derivative 3 showed no tendency to form gels
with organic solvents or water.
1
characterized by spectroscopic methods. In their H NMR
spectra, a signal at d w7 ppm was present, which was as-
signed to the oxalamide NH protons. In the 13C NMR spectra
the corresponding oxalamide C]O signal was present at
w159 ppm, whereas signals at 169 ppm in the 13C NMR
spectra of 1 or 176 ppm in the 13C NMR spectra of 2 were
assigned to the chemical shifts of the ester C]O. The sig-
nals corresponding to the adamantane resonances in the
13C NMR spectra indicated highly symmetric structures
characterized by one singlet, one doublet and two triplets
in the spectra of meso-1 and rac-1, or two singlets, one dou-
blet and four triplets in the 13C NMR spectrum of 2.
2.2. Crystal structures
The single crystals of the ester derivatives meso-1, rac-1 and
2 were easily obtained, whereas unexpected problems were
encountered in attempts to crystallize compound 3. Appar-
ently it crystallizes only in the form of relatively unstable sol-
vates. Molecular structures of the compounds meso-1, rac-1,
2, 3$MeOH and 3$EtOAc are shown in Figures 1–5. Achiral
compounds meso-1, 2 and 3$MeOH (Figs. 1, 3 and 4, respec-
tively) have a molecular Ci symmetry (crystallographic

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7987
C4
O2
O3
C3
C2
C1
C5a
C9a
N1
C8a
C1a
C6a
O1
C2a
C4a
C7a
C3a
C10a
Figure 1. The molecular structure of meso-1 with the atom numbering scheme. Thermal ellipsoids are drawn at the 50% probability level. The molecular
symmetry is Ci.
C6b
C10a
C5b
C7a
C7b
C3a
C4b
C8a
C6a
C9b
O1
C5a
C10b
C1a
C8b
C4a
C3b
C2a
N1
C5
C1b
C9a
C1
N2
C2
C2b
C8
O3
O5
O4
C6
C3
C7
O2
O6
C4
Figure 2. The molecular structure of rac-1 with the atom numbering scheme. Thermal ellipsoids are drawn at the 50% probability level. The molecular
symmetry is C1.
C6a
C5a
C9a
N1
C7a
C8a
C1
C1a
C4a
C10a
C3a
C2a
O1
C2
O2
O3
C3
Figure 3. The molecular structure of 2 with the atom numberingscheme. Thermal ellipsoids are drawn at the 50% probability level. The molecular symmetry is Ci.

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7988
C16
C15
C18
C17
C20
C14
C19
O2
C11
N1
C13
C2
C1
C12
C21
O1
O3
O4
Figure 4. The molecular structure of 3$MeOH with the atom numbering scheme. Intermolecular hydrogen bond O–H/O connects solvent and the molecule of
3. Thermal ellipsoids are drawn at the 50% probability level. The molecular symmetry is Ci.
inversion centre located in the middle of the oxalamide
bridge)whereasrac-1(Fig. 2)ischiralandcrystallizesasara-
cemate. In the structure of 3$EtOAc there are two symmetry-
independent molecules, a and b (Fig. 5), both exhibiting an
approximate Ci molecular symmetry. In addition, molecules
a and b are related by a pseudo-inversion centre.
(a)
C26a
O2a
O3a
C25a
O4a
C27a
C12a
N1a
C29a
C2a
C13a
C21a
C28a
C11a
C1a
C3a
C20a
C18a
C23a
C4a
N2a
C22a
C14a
C19a
C17a
C16a
O1a
O5a
O6a
C15a
(b)
C28b
O5b
C17b
C30b
C20b
O4b
C27b
N1b
C4b
C18b
C11b
C1b
C21b
O6b
O3b
C3b
C13b
C26b
C24b
C19b
C29b
C2b
N2b
O1b
C15b
C25b
C14b
O2b
Figure 5. The molecular structures of two symmetry-independent molecules of 3$EtOAc (labelled as a and b) with the atom numbering scheme. Thermal
ellipsoids are drawn at the 50% probability level. Both molecules have an approximate molecular Ci symmetry.

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7989
Table 1. Selected torsion angles (ꢀ) defining molecular conformations
Oxalamide bridges in meso-1, 2 and 3$MeOH are planar due
to symmetry requirements and hybridization involved: the
torsion angles O]C–C]O are 180ꢀ. However, the oxal-
amide bridges are distorted from 180ꢀ in the molecule b of
3$EtOAc for 2.5(4)ꢀ and in rac-1 for 11.6(2)ꢀ (Table 1).
In the studied retropeptides, the bulky adamantane cages
are in anti arrangement, as required by the Ci molecular sym-
metry, however, rac-1 having C1 molecular symmetry re-
veals a syn orientation. Thus, the steric hindrance imposed
by closely positioned adamantane cages and the crystal
structural pattern influence bending of the oxalyl bridge. A
similar distortion of the oxalamide group (10.8ꢀ) was also
reported in the case of crystal structure of N,N0-bis(S-
valyl)oxalamide, which forms a double helix of hydrogen-
bonded chains.9a
Structure
Torsion angle (ꢀ)
meso-1
C1a–C2–N1–C1
C3–C2–N1–C1
C2–N1–C1–C1i
C2–N1–C1–O1
N1–C1–C1i–N1i
O1–C1–C1i–O1i
106.9(2)
ꢁ128.4(2)
ꢁ174.9(2)
4.6(4)
180.0(2)
180.0(3)
rac-1
C1a–C2–N1–C1
C3–C2–N1–C1
C2–N1–C1–C5
C2–N1–C1–O1
N1–C1–C5–N2
O1–C1–C5–O4
O4–C5–N2–C6
C5–N2–C6–C1b
C5–N2–C6–C7
C1a–N1–C1–C1i
C1a–N1–C1–O1
N1–C1–C1i–N1i
O1–C1–C1i–O1i
ꢁ112.9(2)
123.9(2)
ꢁ177.3(3)
1.8(3)
ꢁ169.2(2)
ꢁ168.4(2)
2.9(3)
105.8(2)
ꢁ130.1(2)
178.3(1)
ꢁ1.9(2)
180.0(1)
180.0(2)
2
Crystal packings of meso-1 and rac-1 reveal one-dimen-
sional hydrogen bond network defined by infinite chains
of molecules interconnected by N–H/O interactions. In
meso-1 (Fig. 6, Table 2), the building units of the hydro-
gen-bonded chain are two distinctive ring skeletons of
R22ð10Þ topology.11,12 One is generated by pairs of symme-
try-related N1–H/O2 hydrogen bond connecting oxal-
amide and carboxyl groups whereas the other one
involves N1–H/O2 and C4–H/O1 interactions, both
generating an infinite chain along the direction [100]. An
additional C–H/O hydrogen bond (Table 2) between
adamantane methylene group and oxalamide oxygen
completes a network. There is no typical ‘ladder’ pat-
tern9,13 Cð4ÞCð4ÞR22ð10Þ that interconnects the oxalamide
moieties via N–H/O hydrogen bonds, which are charac-
teristic of a one-dimensional a-network.8,9b According to
the search of CSD (version 5.28, November 2006)14 out
of 74 observed oxalamide structures, 29 structures reveal
3$MeOH
3$EtOAc
C11–N1–C1–C1i
C11–N1–C1–O1
N1–C1–C1i–N1i
O1–C1–C1i–O1i
ꢁ178.6(3)
0.6(6)
180.0(3)
180.0(3)
C11a–N1a–C1a–O1a
C11a–N1a–C1a–C3a
N1a–C1a–C3a–N2a
O1a–C1a–C3a–O4a
C1a–C3a–N2a–C21a
O4a–C3a–N2a–C21a
C11b–N1b–C1b–O1b
C11b–N1b–C1b–C3b
N1b–C1b–C3b–N2b
O1b–C1b–C3b–O4b
C1b–C3b–N2b–C21b
O4b–C3b–N2b–C21b
3.6(7)
ꢁ177.7(3)
179.5(4)
ꢁ179.2(4)
ꢁ178.2(4)
1.7(7)
1.5(6)
179.6(3)
179.2(3)
ꢁ177.5(4)
179.1(4)
ꢁ2.6(7)
Symmetry code: (i) ꢁx, ꢁy, ꢁz.
Figure 6. The crystal packing of meso-1 with hydrophilic hydrogen-bonded chain embodied into hydrophobic adamantane layers. Symmetry code: (i) ꢁx, ꢁy,
2ꢁz.

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7990
Table 2. Geometrical parameters of hydrogen bonds of meso-1, rac-1, 2 and solvates of 3
D–H/A/ꢀ
Symm. operation on A
˚
D–H /A
˚
Structure
Hydrogen bond
H/A/A
D–H/A//
meso-1
N1–H1/O2
C4–H4a/O1
C9a–H9a/O2
N1–H1/O1a
0.90(3)
1.04(4)
1.04(3)
0.90(3)
2.30(3)
2.34(3)
2.50(3)
2.35(3)
3.162(3)
3.325(4)
3.463(3)
2.710(3)
160(2)
158(3)
154(2)
104(2)
ꢁx, ꢁy, 2ꢁz
1+x, y, z
ꢁx, ꢁy, 2ꢁz
ꢁ1ꢁx, ꢁy, 2ꢁz
rac-1
N2–H2n/O1
C2–H2/O5
C2b–H2c/O4
C8b–H8f/O4
N1–H1n/O4a
N2–H2n/O1a
0.87(2)
0.98
0.97
0.97
0.82(2)
0.87(2)
2.19(2)
2.71
2.72
2.56
2.24(2)
2.41(2)
3.056(2)
3.618(4)
3.564(4)
3.447(2)
2.647(2)
2.761(2)
173.9(16)
154
146
152
111.3(19)
105.0(15)
ꢁx, 1ꢁy, 1ꢁz
ꢁx, 1ꢁy, 1ꢁz
ꢁx, ꢁy, 1ꢁz
ꢁx, ꢁy, 1ꢁz
x, y, z
x, y, z
2
N1–H1n/O3
C3–H3b/O3
C9a–H9a/O3
N1–H1n/O1a
0.895(17)
1.01(3)
0.984(16)
0.895(17)
2.286(17)
2.66(3)
2.587(16)
2.240(16)
3.136(2)
3.626(3)
3.163(2)
158.6(15)
161(2)
117.5(12)
110.7(13)
x, ꢁ1+y, z
1ꢁx, 2ꢁy, 2ꢁz
x, ꢁ1+y, z
2.6902(19)
1ꢁx, ꢁy, 1ꢁz
x, y, z
1/2+x, 1/2ꢁy, 1/2+z
1/2ꢁx; ꢁ1/2+y; 1/2ꢁz
1/2ꢁx, ꢁ1/2+y, 1/2ꢁz
1/2+x, 1/2ꢁy, 1/2+z
ꢁx, ꢁy, ꢁz
3$MeOH
O2–H2/O4
O4–H4/O1
N1–H1/O3
C20–H20a/O3
C21–H21a/O3
N1–H1/O1a
0.99(5)
0.85(5)
0.79(5)
1.09(5)
0.95(3)
0.79(5)
1.65(5)
1.95(6)
2.60(5)
2.65(5)
2.64(4)
2.36(6)
2.628(7)
2.788(7)
3.346(8)
3.220(8)
3.581(7)
2.690(6)
175(3)
166(9)
158(5)
112(3)
169(4)
107(5)
3$EtOAc
N1a–H1a/O4b
N1b–H1b/O4a
N2a–H2a/O1b
N2b–H2b/O1a
O2a–H3a/O6b
O2b–H3b/O6a
O5a–H5a/O3b
O5b–H5b/O3a
C12a–H12b/O4b
C20b–H20b/O4a
C22a–H22a/O1b
C29b–H29d/O1a
N1a–H1a/O4aa
N2a–H2a/O1aa
N1b–H1b/O4ba
N2b–H2b/O1ba
0.86
0.86
0.86
0.86
0.82
0.82
0.82
0.82
0.97
0.97
0.97
0.97
0.86
0.86
0.86
0.86
2.48
2.46
2.48
2.45
1.83
1.80
1.80
1.84
2.64
2.58
2.67
2.58
2.26
2.26
2.29
2.26
3.117(6)
3.175(6)
3.121(6)
3.171(6)
2.648(6)
2.613(6)
2.614(6)
2.655(6)
3.457(7)
3.358(7)
3.477(7)
3.350(7)
2.670(5)
2.677(5)
2.704(5)
2.678(5)
131
141
132
142
172
172
171
173
142
137
141
137
109
110
110
110
ꢁ1+x, y, z
1+x, y, z
x, y, z
x, y, z
ꢁ1+x, ꢁ1+y, z
x, ꢁ1+y, z
x, 1+y, z
1+x, 1+y, z
ꢁ1+x, ꢁ1+y, z
1+x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
a
Intramolecular pseudo-C5 hydrogen bond is analogous to the C5 in peptides. Crystallographically independent molecules are marked by a and b.
no interaction between the oxalamide moieties. In such
cases, the most frequent motif is R22ðnÞ, rings with n being
8–12, as detected in the structure of meso-1. Bulky ada-
mantane cages obstruct oxalamide/oxalamide hydrogen
bonds; therefore, the oxalamide group acts as a proton do-
nor to an ester O (sp2) generating a hydrogen-bonded ring
with graph-set symbol R22ð10Þ.
In spite of the efforts to obtain crystals of 3, only solvates
were crystallized. In the methanol solvate (3$MeOH),
both oxalamide and carboxyl moieties are hydrogen bonded
by O–H/O to the methanol molecule forming rings of
R33ð11Þ topology (Fig. 9). Each molecule of 3$MeOH
participates in formation of four symmetry-related rings
generating layers parallel to the plane (10ꢁ1) (Fig. 9). In
the crystal structure of the ethyl acetate solvate (3$EtOAc),
two distinctive intermolecular hydrogen-bonding motifs
are present. Oxalamide moieties of two symmetrically inde-
pendent molecules a and b are interconnected by hydrogen
bonds N–H/O forming ribbons of Cð4ÞCð4ÞR22ð10Þ topol-
ogy; typical oxalamide ‘ladder’ patterns9b,13,14 occur
(Fig. 10a). They extend in the direction [100]. The hydro-
gen-bonded carboxyl groups of molecules a and b form
eight-membered rings R22ð8Þ; this hydrogen-bonded motif
is typical of carboxylic acids.14,16,17 They link molecules
into double chains parallel to the direction [110]
(Fig. 10b) forming a channel-like structure (Fig. 10c).
The channels extending in the direction [100] are filled
with ethyl acetate molecules (Fig. 10c). Interestingly, the
solvent molecules do not participate in hydrogen bonds
at all.
Molecules of rac-1 form centrosymmetric dimers by pairs of
symmetry-related N2–H/O1 between oxalamide bridges
generating rings with R22ð10Þ topology. Additionally,
C2–H/O5 supports dimer formation. Two pairs of symme-
try-related C–H/O hydrogen bonds (Fig. 7, Table 2) con-
nect dimers into infinite chains parallel to the direction
[010]. The hydrogen-bonded dimer of R22ð10Þ topology
observed in rac-1 is also detected in the two structures,
N,N0-oxalyl-bis(valine)retropeptide9b and catena(diaqua-
2,20-bipyridyl-(m2-oxalamide-N,N0-di-3-propionato-O,O0)-
copper(II) monohydrate)15 in CSD.14
In compound 2 (Fig. 8) pairs of symmetry-related N1–H/
O3 and C9a–H/O3 hydrogen bonds connect molecules
into infinite chains parallel to the direction [001]. The
weak hydrogen bond C3–H/O3 links the chains into layers
parallel to the plane (100) (Table 2). The alternating hydro-
philic and hydrophobic regions are running along [001].
Thecrystalpackingofretropeptideshavingoxalylbridgesand
adamantyl groups in the terminal positions optimizes the

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7991
Figure 7. The crystal packing of rac-1 having pronounced separation of hydrophilic region by hydrogen-bonded rings connected into chains, and adamantane
hydrophobic layers. Symmetry codes: (i) ꢁx, 1ꢁy, 1ꢁz; (ii) ꢁx, ꢁy, 1ꢁz.
Figure 8. The crystal packing of 2 with two-dimensional hydrogen-bonding network in the plane (101) separated by hydrophobic adamantane cages. Symmetry
codes: (i) x, ꢁ1+y, z; (ii) 1ꢁx, 2ꢁy, 2ꢁz.
influences of chirality and steric hindrance (bulky adamantyl
group). The compounds meso-1 and rac-1 having chiral
centres in the crystals exhibit one-dimensional a-networks
ofhydrogenbonding8 (Figs. 6and7). Inbothcrystal structures
hydrogen-bonded molecules are related by an inversion sym-
metry operation generating meso-layers. In meso-1 molecular
fractions of different chirality are connected into a meso-layer
whereas in rac-1 hydrogen-bonded enantiomers R and S form
meso hydrophilic layer (Fig. 7). In the crystals, however, achi-
ral 2, 3$MeOH and 3$EtOAc generate the two-dimensional
hydrogen-bonded b-network8 with alternating hydrophobic
and hydrophilic layers (Figs. 8–10).
On the contrary, in 3$EtOAc, the aprotic solvent, ethyl
acetate, does not participate in hydrogen bonding at all.
Hydrogen-bonded oxalamide/oxalamide and carboxyl/
carboxyl groups of two symmetrically independent mole-
cules generate the two-dimensional network with channels
accommodating ethyl acetate molecules. By the selection
of a solvent molecule of appropriate polarity and size, one
can design the crystal packing.
3. Conclusions
Novel adamantane-oxalamide derivatives, meso-1, rac-1, 2
and 3 were prepared in a single step by direct condensation
of oxalyl chloride and the corresponding adamantane deri-
vatives. Their chemical and physical properties were
In the crystal packing of 3$MeOH, methanol, as a protic and
highly polar solvent, acts as proton donor to the oxalyl oxy-
gen and an acceptor to the OH group of carboxyl moiety.

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7992
Figure 9. The crystal packing of 3$MeOH involves the two-dimensional hydrogen-bonding network. The alternating hydrophilic and hydrophobic regions
characterize the b-network. Symmetry code: (i) ½+x, ½ꢁy, ½+z.
investigated by spectroscopic methods and X-ray structural
analysis. The crystal packings of the studied derivatives
are different. Whereas bulkiness of adamantanes does not
allow formation of the b-network in meso-1 and rac-1, this
type of self-assembly was feasible in the oxalamides 2 and
3. Retropeptides meso-1 and rac-1 self-assemble into struc-
tures, which are governed by one-dimensional a-networks of
hydrogen bonds. The ester derivatives of oxalamides meso-
1, rac-1 and 2 as well as diacid derivative 3 showed no ten-
dency to form gels with organic solvents or water. The bulky
adamantane substituent prevents oxalamide/oxalamide
hydrogen bonding. Thus, imposed steric requirements of
adamantane cages prevent the reorganization of self-assem-
bled molecules, which is needed for gelation in order to
release space for solvent molecules to be trapped. The
oxalamide 3 crystallizes in the form of solvates. The protic
solvent (MeOH) incorporates into the crystal structure par-
ticipating in the hydrogen bonding between the oxalamide
and carboxyl moieties. On the other hand, non-protic solvent
(EtOAc) does not participate in hydrogen bonding. The crys-
tal packing of 3$EtOAc showed a two-dimensional network
with channels that can accommodate EtOAc molecules. To
the best of our knowledge, this is the first example of such
a packing of oxalamides. Knowledge of the packing pattern
of adamantane-oxalamides may be useful for the supramo-
lecular synthesis of new materials characterized by the pres-
ence of nanochannels of different size and geometry.
coherence (HMQC). High-resolution mass spectra
(HRMS) were measured on an Extrel FTMS 2001 DD using
electron impact ionization mode. Melting points were ob-
tained using an Original Kofler Mikroheitztisch apparatus
(Reichert, Wien) and are uncorrected. Silica gel (Merck
0.05–0.2 mm) was used for chromatographic purifications.
Solvents were purified by distillation. Adamantane amino
acids: (1-adamantyl)glycine (4)6,10a and 3-aminoadaman-
tane-1-carboxylic acid (5)6,10b,c were prepared according
to the procedure described in literature.
4.2. 3-Aminoadamantane-1-carboxylic acid methyl
ester (7)
In a round bottom flask 1.00 g of amino acid hydrochloride 5
was dissolved in 50 mL of dry methanol (molecular sieves
ꢀ
˚
3 A). The solution was cooled to ꢁ5 C and 1 mL of thionyl-
chloride was added. After stirring at ꢁ5 ꢀC over 15 min, the
reaction was stirred at rt for an h and heated at temperature of
reflux for 24 h. The solvent was removed and to the residue
50 mL of saturated aqueous solution of NaHCO3 was added.
Extractions with dichloromethane were carried out (4ꢂ
25 mL) and collected extracts were dried over anhydrous
MgSO4. After filtration and evaporation of the solvent, crude
ester was obtained (900 mg,w99%) and was used in the next
step without further purification. For the purpose of analysis,
a small amount of ester 7 was purified by column chromato-
graphy on silica gel using CH2Cl2/CH3OH (up to 5%) as
eluent.
4. Experimental
4.1. General
Ester 7: oily solid, mpw20 to 25 ꢀC; IR (KBr) n 2909 (NH),
1727 (CO); H NMR (CDCl3, 600 MHz) d 3.58 (s, 3H,
1
OCH3), 2.10 (br s, 2H), 1.73 (d, 2H, J¼12.3 Hz), 1.67 (d,
2H, J¼12.3 Hz), 1.63 (s, 2H), 1.56 (br s, 2H, NH), 1.40–
1.55 (m, 6H); 13C NMR (CDCl3, 150 MHz) d 176.98 (s),
51.34 (q), 47.35 (s), 47.12 (t), 44.72 (t), 42.72 (s), 37.51
(t), 34.89 (t), 29.14 (d); MS (m/z) 210 (M+H+, 60), 153
(75), 151 (60), 120 (30), 94 (100); HRMS calcd for
C12H20NO2: 210.1489, found: 210.1485.
1H and 13C NMR spectra were recorded on a Bruker AV-300
or 600 Spectrometer at 300 or 600 MHz, respectively. All
NMR spectra were measured in CDCl3 or DMSO-d6 using
tetramethylsilane as a reference. The assignment of the sig-
nals is based on two-dimensional homonuclear correlated
spectroscopy (COSY) and heteronuclear multiple quantum

´
N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7993
Figure 10. The crystal packing of 3$EtOAc with the two-dimensional hydrogen-bonding network: (a) hydrogen-bonded chains between oxalamide moieties
extending in the direction [100]; (b) hydrogen bonds connecting carboxyl groups form chains extended in the direction [110]; (c) double layers parallel to [001]
with solvent-filled channels running parallel to the direction [100]. Solvent molecules are drawn within the frame of the unit cell whereas other channels are left
blank to emphasize the channels in the crystal packing. Symmetry codes: (i) ꢁ1+x, y, z; (ii) x, ꢁ1+y, z.

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7994
4.3. Preparation of N,N0-bisoxalamide derivatives:
general procedure
d 176.40 (s), 159.03 (s), 51.82 (s), 51.53 (q), 42.24 (s),
41.44 (t), 39.85 (t), 37.52 (t), 34.91 (t), 28.71 (d); MS
(m/z) 473 (M+H+, 60), 193 (100); HRMS calcd for
C26H37N2O6: 473.2646, found: 473.2650.
In a round bottom flask under a stream of N2 was placed
1 equiv of amino acid methyl ester (6 or 7) and dissolved
in 10 mL of dry CH2Cl2. To the solution, dry triethylamine
(1.5–2 mL) was added. The reaction mixture was cooled to
ꢁ5 ꢀC and to the cooled solution under N2, half an equiva-
lent of oxalyl chloride was added in several portions by
use of a syringe. The reaction mixture was stirred at ꢁ5 ꢀC
for 1 h, allowed to reach rt and stirred at rt for 2 days. After
2 days, reaction mixture was diluted by the addition of
50 mL of CH2Cl2 and washed with 5% aqueous solution
of acetic acid (3ꢂ50 mL) followed by washing with satu-
rated aqueous NaHCO3 (3ꢂ50 mL). The organic layer was
dried over anhydrous MgSO4 and filtered. The solvent was
removed on a rotary evaporator to furnish crude product.
4.4. Ester hydrolysis: general procedure
In a round bottom flask was placed w300 to 500 mg of the
ester derivatives 1 or 2, and a mixture of CH3OH (10 mL)
and 10% aqueous Na2CO3 (20 mL) was added. The mixture
was heated at the temperature of reflux for 2 days until the
solid was completely dissolved. The cooled reaction mixture
was washed with CH2Cl2 (3ꢂ25 mL) and the aqueous layer
acidified with 1 M HCl until it reached pH 2. The acidic mix-
ture was extracted with ethyl acetate (4ꢂ25 mL), extracts
were dried over anhydrous MgSO4, filtered and the solvent
was removed under reduced pressure to afford the crude
product.
4.3.1. N,N0-Bis(1-adamantylglycine methyl ester)oxal-
amide (1). The reaction was carried out starting from
250 mg (1.12 mmol) of hydrochloride of 66 and 49 mL
(0.56 mmol) of oxalyl chloride in the presence of 0.5 mL
of triethylamine to yield 270 mg (98%) of the crude product.
Reaction yielded a mixture of diastereomers in a ratio of 1:1,
which were separated on a thin layer of silica gel using
CH2Cl2 as a solvent [meso-1: Rf (CH2Cl2)¼0.36; rac-1: Rf
(CH2Cl2)¼0.20].
N,N0-Bis(3-aminoadamantane-1-carboxylic acid)oxalamide
(3) was obtained by hydrolyzing 500 mg (1.06 mmol) of 2.
The crude product (370 mg, 79%) was purified by recrystal-
lization using methanol as a solvent.
Oxalamide 3: colourless crystals (CH3OH), mp >310 ꢀC; IR
(KBr) n 3000–3600 (COOH), 2939 (CH), 1719 (CO-acid),
1665 (CO-amide); 1H NMR (DMSO-d6, 300 MHz)
d 12.00 (br s, 2H, COOH), 7.75 (br s, 2H, NH), 2.12 (br s,
4H), 2.05 (br s, 4H), 1.96 (d, 4H, J¼11.9 Hz), 1.87 (d, 4H,
J¼11.9 Hz), 1.72 (br s, 8H), 1.50–1.60 (m, 4H); 13C NMR
(DMSO-d6, 75 MHz) d 177.03 (s), 159.02 (s), 51.36 (s),
41.31 (t), 41.27 (s), 39.36 (t), 37.32 (t), 34.61 (t), 28.30
(d); MS (m/z) 445 (M+H+, 30), 399 (30) 357 (60), 196
(60), 179 (100), 161 (40), 133 (40); HRMS calcd for
C24H33N2O6: 445.2333, found: 445.2330.
Oxalamide meso-1: colourless crystals (acetone/CH2Cl2/
CHCl3¼200:10:3), mp 238–241 ꢀC; IR (KBr) n 3337
1
(NH), 2903 (CH), 1737 (CO-ester), 1677 (CO-amide); H
NMR (CDCl3, 300 MHz) d 7.86 (d, 2H, J¼9.9 Hz, NH),
4.27 (d, 2H, J¼9.9 Hz, CH-gly), 3.75 (s, 6H, OCH3), 2.00
(br s, 6H, H-ad), 1.50–1.75 (m, 24H, H-ad); 13C NMR
(CDCl3, 75 MHz) d 169.92 (s, CO-ester), 158.91 (s, CO-
amide), 61.44 (d, CH-gly), 51.78 (q, OCH3), 38.46 (t, ad),
36.72 (s, ad), 36.36 (t, ad), 28.01 (d, ad); MS (m/z) 501
(M+H+, 80), 135 (100); HRMS calcd for C28H41N2O6:
501.2959, found: 501.2962.
The mixture of stereoisomers of N,N0-bis(1-adamantylgly-
cine)oxalamide was obtained from 270 mg of the mixture
of esters rac-1 and meso-1. The reaction furnished 50 mg
(20%) of the mixture of the diacid diastereomers, which
was hardly soluble in most of the solvents (only slightly in
alcohols and EtOAc) and therefore difficult to separate and
Oxalamide rac-1: colourless crystals (acetone/CH2Cl2/
CHCl3¼12:3:2), mp 215–218 ꢀC; IR (KBr) n 3399 (NH),
3291 (NH), 2906 (CH), 1736 (CO-ester), 1676 (CO-amide);
1H NMR (CDCl3, 300 MHz) d 7.84 (d, 2H, J¼9.8 Hz, NH),
4.25 (d, 2H, J¼9.8 Hz, CH-gly), 3.74 (s, 6H, OCH3), 2.02
(br s, 6H, H-ad), 1.55–1.75 (m, 24H, H-ad); 13C NMR
(CDCl3, 75 MHz) d 169.85 (s, CO-ester), 159.05 (s, CO-
amide), 61.54 (d, CH-gly), 51.77 (q, OCH3), 38.48 (t, ad),
36.46 (s, ad), 36.35 (t, ad), 28.00 (d, ad).
1
purify. H NMR (DMSO-d6, 300 MHz) d 12.5 (br s, 2H,
COOH), 7.92–8.00 (br s, 2H, NH), 3.96–4.00 (m, 2H,
CH), 1.96 (br s, 6H), 1.50–1.70 (m, 24H); 13C NMR
(DMSO-d6, 75 MHz) d 172.93 (s, COO-1), 170.69 (s,
COO-2), 159.11 (s, CONH-1), 158.89 (s, CONH-2), 61.47
(d, CH-1), 61.32 (d, CH-2), 34.0–39.0 (2ꢂad 1s, 2t), 27.77
(d, C-ad-1), 27.68 (d, C-ad-2). MS (m/z) 471 (MꢁH+, 20),
425 (20), 281 (70), 280 (100); HRMS calcd for
C26H35N2O6: 471.2500, found: 471.2503.
4.3.2. N,N0-Bis(3-aminoadamantane-1-carboxylic acid
methyl ester)oxalamide (2). The reaction was carried out
starting from 700 mg (3.35 mmol) of 7 and 150 mL
(1.67 mmol) of oxalyl chloride to yield 750 mg (94%) of
the crude product 2, which was purified by recrystallization
using CH2Cl2 as a solvent.
5. Crystallography
The single crystals of the oxalamides meso-1, rac-1, 2 and 3
were obtained by slow evaporation of the mixture of solvents
Oxalamide 2: colourless crystals (CH2Cl2), mp 215–216 ꢀC;
IR (KBr) n 3318 (NH), 2918 (CH), 1719 (CO-ester), 1678
(CO-amide); 1H NMR (CDCl3, 600 MHz) d 7.25 (br s, 2H,
NH), 3.58 (s, 6H, OCH3), 2.16 (br s, 4H), 2.10 (s, 4H),
1.95 (d, 4H, J¼11.3 Hz), 1.86 (d, 4H, J¼11.3 Hz), 1.78 (s,
8H), 1.45–1.65 (m, 4H); 13C NMR (CDCl3, 150 MHz)
acetone/CH2Cl2/CHCl3¼200:10:3
(meso-1),
acetone/
CH2Cl2/CHCl3¼12:3:2 (rac-1), CH2Cl2 (2) and CH3OH or
ethyl acetate (3), respectively. The methanol solvate
(3$MeOH) decays in air, losing the solvent molecules within
several days. The room-temperature structure, although poor
due to gradual decomposition of the crystals during the data

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N. Basaric et al. / Tetrahedron 63 (2007) 7985–7996
7995
Table 3. Crystallographic data and structural refinement data for the crystal structures of meso-1, rac-1, 2, 3$MeOH and 3$EtOAc
Compound
meso-1
rac-1
2
3$MeOH
3$EtOAc
Empirical formula
Formula wt./gmolꢁ1
Crystal dimensions/mm
Space group
C28H40N2O6
500.62
C28H40N2O6
500.62
C26H36N2O6
472.57
C26H40N2O8
508.60
C28H40N2O8
532.62
0.25ꢂ0.18ꢂ0.10
0.29ꢂ0.20ꢂ0.08
0.20ꢂ0.20ꢂ0.15
0.30ꢂ0.20ꢂ0.10
0.30ꢂ0.12ꢂ0.12
Pꢁ1
Pꢁ1
Pꢁ1
P21/n
Pꢁ1
˚
a/A
7.7292(7)
8.5884 (6)
10.7116(8)
75.003(6)
88.137(7)
76.271(7)
1
8.9634(5)
10.9877(6)
14.6301(7)
68.194(4)
75.594(4)
86.838(4)
2
7.1677(5)
7.9060(4)
11.0085(3)
104.690(3)
94.530(4)
98.980(5)
1
9.378(6)
10.40(2)
13.55(2)
90
108.90(10)
90
10.2482(10)
10.2611(12)
27.00(3)
87.60 (6)
83.92(6)
74.536(8)
4
˚
b/A
˚
c/A
a/ꢀ
b/ꢀ
g/ꢀ
Z
2
3
˚
V/A
666.89(10)
1.247
0.707
1294.60(12)
1.284
0.728
591.43(6)
1.327
0.653
1250(3)
1.351
0.823
2721(3)
1.30
0.782
1.65–76.45
Dcalcd/g cmꢁ3
m/mmꢁ1
q range/ꢀ
Range of h, k, l
4.27–76.24
3.36–76.48
4.18–76.09
5.06–77.65
ꢁ9>h>9, ꢁ10>k>0, ꢁ11>h>11, 0>k>13, ꢁ9>h>8, 0>k>9, ꢁ11>h>11, ꢁ13>k>0, 0>h>12, ꢁ12>k>12,
ꢁ13>l>13
ꢁ17>l>18
ꢁ13>l>13
ꢁ17>l>17
ꢁ33>l>34
11,998
11,341
5089
0.0422
0.0797
0.3108
1.087
Reflections collected
Independent reflections
2885
2698
5719
5424
2638
2454
5060
2578
Observed reflections (Iꢃ2s) 1706
3810
2073
1702
Rint
0.0643
0.0241
0.0435
0.1185
1.019
334
0.20, ꢁ0.169
0.0109
0.0388
0.1075
1.066
227
0.218, ꢁ0.139
0.1428
0.0997
0.3157
1.074
244
0.504, ꢁ0.491
R(F)I>2s(I)
Rw(F2)I>2s(I)
Goodness of fit
No. of parametersꢁ3
0.0528
0.161
1.001
244
0.197, ꢁ0.226
685
0.383, ꢁ0.487
˚
Drmax, Drmin (eA
)
collection, was nevertheless good enough to show packing
patterns and the hydrogen-bonding scheme. Another type
of problem was encountered with the ethyl acetate solvate
(3$EtOAc). The solvent molecules, which do not participate
in hydrogen bonding, displayed large thermal motion. Their
geometries and atomic displacement parameters were held
rigid in the first few cycles of refinement, but the restraints
were released in the latter stage of the refinement, to obtain
more reasonable geometric parameters. The C–C bond
lengths in molecules of ethyl acetate were restrained to
Molecular geometric calculations were performed with
PLATON98,22 and molecular graphics were prepared using
ORTEP-3,23 and CCDC-Mercury.24 Crystallographic and
refinement data for structures meso-1, rac-1, 2, 3$MeOH
and 3$EtOAc are shown in Table 3.
Acknowledgements
We thank the Ministry of Science, Education and Sports of
the Republic of Croatia for financing (grants no. 098-
0982933-2911 and 098-1191344-2943). We also thank
˚
1.50(1) A, only. Since both structures, 3$MeOH and
3$EtOAc, showed no unreasonable geometric parameters,
data collection was not repeated at low temperature. The
crystal structure of 3$EtOAc comprises two molecules in
asymmetric units; each of them has an approximate Ci mo-
lecular symmetry. These two molecules are related by
pseudo-inversion symmetry. The distribution of E-values
reveals the hypercentric symmetry.
´
Dr. Milan Jokic for the help in gelling experiments.
Supplementary data
Supplementary crystallographic data for this paper can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/re-
trieving.html (or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
CCDC: 635479–635483 contain the supplementary crystal-
lographic data for this paper. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.05.066.
Data collections were performed on an Enraf Nonius CAD4
diffractometer, using a graphite monochromated Cu Ka
˚
(1.54179 A) radiation at rt [293(2) K]. The WinGX standard
procedure was applied for data reduction.18 Three standard
reflections were measured every 120 min as intensity con-
trol. The absorption correction based on 8c-scan reflec-
tions19 was performed for structures 2 and rac-1. No
absorption correction was applied for structures meso-1,
3$MeOH and 3$EtOAc. The structure was solved with
SHELXS9720 and refined with SHELXL97.21 The models
were refined using the full matrix least squares refinement.
Hydrogen atoms were located from difference Fourier
maps and refined as free entities for meso-1, 2 and 3$MeOH
and as mixed free and riding entities for rac-1. For structure
3$EtOAc, due to the inferior quality of the measured data,
hydrogen atoms were generated at positions expected by ste-
reochemistry and refined as riding entities. The atomic scat-
tering factors were those included in SHELXL97.21
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