N-Methylation of adamantane-substituted oxalamide unit affects its conformational rigidity: A skew conformation of the oxalamide bridge

Article abstract of DOI:10.1016/j.molstruc.2007.06.024

The synthesis of adamantane functionalized retropeptides, N,N′-bis(2-adamantyl-2-carboxylic acid methyl ester)oxalamide (1) and N-methyl-N,N'-bis(2-adamantyl-2-carboxylic acid methyl ester)oxalamide (2), as well as the influence of the N-methylation on the conformational preferences of oxalamide group are described. In the solid state the oxalamide group of 1 is planar while in the retropeptide 2 adopts a skew-conformation.

Full text of DOI:10.1016/j.molstruc.2007.06.024

Available online at www.sciencedirect.com
Journal of Molecular Structure 876 (2008) 218–224
www.elsevier.com/locate/molstruc
N-Methylation of adamantane-substituted oxalamide unit
affects its conformational rigidity: A skew conformation
of the oxalamide bridge
a
b
c
d
ˇ
´
´
´
Zoran Dzˇolic , Renato Margeta , Marijana Vinkovic , Zoran Stefanic ,
d
b
a,
*
ˇ
´
´
´
´
Biserka Kojic-Prodic , Kata Mlinaric-Majerski , Mladen Zinic
a
Laboratory of Supramolecular and Nucleoside Chemistry, Division of Organic Chemistry and Biochemistry, Rudjer Bosˇkovic´ Institute,
P.O. Box 180, Bijenicˇka 54, 10002 Zagreb, Croatia
b
Laboratory of Synthetic Organic Chemistry, Division of Organic Chemistry and Biochemistry, Rudjer Bosˇkovic´ Institute, P.O. Box 180,
Bijenicˇka 54, 10002 Zagreb, Croatia
c
NMR Center, Rudjer Bosˇkovic´ Institute, P.O. Box 180, Bijenicˇka 54, 10002 Zagreb, Croatia
Laboratory for Chemical and Biological Crystallography, Division of Physical Chemistry, Rudjer Bosˇkovic´ Institute, P.O. Box 180,
Bijenicˇka 54, 10002 Zagreb, Croatia
d
Received 3 May 2007; received in revised form 18 June 2007; accepted 20 June 2007
Available online 1 July 2007
Abstract
The synthesis of adamantane functionalized retropeptides, N,N0-bis(2-adamantyl-2-carboxylic acid methyl ester)oxalamide (1) and N-
methyl-N,N’-bis(2-adamantyl-2-carboxylic acid methyl ester)oxalamide (2), as well as the influence of the N-methylation on the confor-
mational preferences of oxalamide group are described. In the solid state the oxalamide group of 1 is planar while in the retropeptide 2
adopts a skew-conformation.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: Adamantane; N-Methylation; Oxalamides; Retropeptides; X-ray structure analysis
1. Introduction
trans configuration. This type of conformation appears to
be independent of the type and size of the group attached
at the ends of the oxalamide moiety. However, we wanted
to examine the influence of bulky adamantane amino acid
on the conformation of oxalamide unit. Besides, the intro-
duction of adamantane moiety should change the overall
lipophilic properties of synthesized retropeptide [7,8].
On the other hand, it is documented that physico-chem-
ical properties and biological activity of peptide systems
are changed by N-methylation of amino acids. The N-
methylation affects pharmacological parameters such as
membrane permeability, conformational rigidity, and pro-
teolytic stability [9,10]. Peptides with N-methyl amino acids
exhibit antibiotic, anticancer, and antiviral activity [11,12].
N-Methylation of peptide bond provides a steric modifica-
tion that can change the conformation of the peptide and
aromatic amides, i.e. cis preference is general in N-methyl
The interest in the investigation of retropeptides with an
oxalamide unit (ANHACOACOANHA) has been
increased over the last two decades due to their potential
use as biomimetics and application in crystal engineering
[1,2]. A number of compounds of this class have been
designed and synthesized in order to investigate the delicate
interplay of structure, non-covalent interactions [3], and
gelating properties [4–6]. The oxalamide group serves as a
synthon to assemble molecules through intermolecular
NAHÆÆÆO hydrogen bonds into one-dimensional a-network,
in which the central oxalamide units adopts planar and
*
Corresponding author. Tel.: +385 1 4680217; fax: +385 1 4680195.
´
´
E-mail addresses: kojic@irb.hr (B. Kojic-Prodic), majerski@irb.hr (K.
ˇ
´
´
Mlinaric-Majerski), zinic@irb.hr (M. Zinic).
0022-2860/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2007.06.024

Z. Dzˇolic´ et al. / Journal of Molecular Structure 876 (2008) 218–224
219
O
O
H
N
H
N
CH3
H3COOC
H3COOC
COOCH3
N
H
N
COOCH3
O
O
1
2
Chart 1.
aromatic amides [13]. Also, the number of donor and
acceptor sites is reduced affecting hydrogen bonding.
In this paper, the synthesis and structural characteriza-
tion of adamantane functionalized oxalamide retropep-
tides, N,N’-bis(2-adamantyl-2-carboxylic acid methyl
ester)oxalamide (1) and N-methyl-N,N’-bis(2-adamantyl-
2-carboxylic acid methyl ester)oxalamide (2), are described
(Chart 1). An influence of the N-methylation on the oxala-
mide group conformation in the solid state and in the solu-
tion is discussed.
as yellowish oil and was used in the next reaction without
further purification.
Subsequently, to the mixture of products in CH2Cl2
(5 mL) and triethylamine (170 lL, 1.22 mmol), oxalyl chlo-
ride (51 lL, 0.60 mmol) was added at 0 ꢁC. After the addi-
tion was completed, the mixture was allowed to achieve
room temperature and stirring was continued overnight.
The reaction was then quenched by addition of water
(5 mL) and stirred for 10 min. The organic layer was
washed successively with water, saturated ammonium chlo-
ride, and water again, dried over anhydrous MgSO4 and fil-
tered. Evaporation of the filtrate followed by flash
chromatography (EtOAc/hexane 1:2) gave the retropep-
tides 1 (59 mg, 22%) and 2 (42 mg, 16%) as a white solids,
as well as nonreacted 6 (21 mg, 8%).
2. Experimental
2.1. General
The one- and two-dimensional homo- and heteronuclear
1H and 13C NMR spectra were recorded with a Bruker AV
600 spectrometer, operating at 600.133 MHz for the H
2.2.1. N,N’-bis(2-adamantyl-2-carboxylic acid methyl
ester)oxalamide (1)
1
nucleus and 150.917 MHz for the 13C nucleus. Samples
were measured from CDCl3 solutions at 25 ꢁC in 5 mm
NMR tubes. Chemical shifts, in ppm, are referred to
TMS as internal standard. IR spectra were recorded on a
FT-IR ABB Bomem MB 102 spectrophotometer at room
temperature. The diethyl ether solution of diazomethane
was prepared from N-methyl-N-nitroso-p-toluensulfona-
mide following a classical procedure. Caution: diazome-
thane is highly toxic. Hence, this reagent must be
handled carefully.
M.p. 218–219 ꢁC; 1H NMR (CDCl3) d/ppm: 7.68 (s, 2H,
ANH), 3.74 (s, 6H, AOCH3), 2.57 (s, 4H, H-1 and H-3),
1.68–2.03 (m, 24H); 13C NMR (CDCl3) d/ppm: 26.1 and
26.4 (C-5 and C-7), 32.2 (C-1 and C-3), 32.5 and 33.8 (C-
4 and C-8 + C-9 and C-10), 37.4 (C-6), 52.0 (OACH3),
63.6 (C-2), 158.1 (C@O), 171.6 (COO); IR (KBr):
m = 3394, 2922, 1746, 1678, 1497; IR (CDCl3, CaF2):
m = 3388, 2926, 1742, 1685, 1494. Anal. Calcd for
C26H36N2O6: C, 66.08; H, 7.68; N, 5.93%. Found: C,
66.15; H, 7.71; N 5.95%.
2.2. Synthesis of retropeptides 1 and 2
2.2.2. N-Methyl-N,N’-bis(2-adamantyl-2-carboxylic acid
methyl ester)oxalamide (2)
A solution of diazomethane in diethyl ether was added
cautiously dropwise to a stirred (0 ꢁC) solution of 2-amino-
adamantyl-2-carboxylic acid (3, 0.22 g, 1.1 mmol) in meth-
anol (5 mL) in a stoppered flask protected from the light.
The resulting mixture was stirred under an inert atmo-
sphere (N2) for about 30 min and then treated with anhy-
drous CaCl2 to destroy excess of diazomethane. The
solution was filtered and concentrated to dryness. The mix-
ture of products, 2-aminoadamantyl-2-carboxylic acid
methyl ester (4), N-methyl-2-aminoadamantyl-2-carboxylic
acid methyl ester (5) and N,N’-dimethyl-2-aminoadaman-
tyl-2-carboxylic acid methyl ester (6), was thereby obtained
M.p. 158–159 ꢁC; 1 H NMR (CDCl3) d/ppm: 7.15 (s,
1H, ANH), 3.77 and 3.73 (2s, 6H, 2· AOCH3), 3.08 (s,
3H, NACH3), 2.54 (m, 4H, H-1 and H-3), 1.72–1.98 (m,
24H); 13C NMR (CDCl3) d/ppm: 26.0, 26.1, 26.3, 26.6
(C-5 and C-7), 31.7 and 32.3 (C-1 and C-3), 32.8 (NACH3)
32.8 and 33.8 (C-4 and C-8), 32.8, 33.2, 34.4, 34.7 (C-9 and
C-10), 37.0 and 37.4 (C-6), 51.9 (OACH3), 63.6 and 70.2
(C-2), 160.8 and 166.2 (C@O), 171.3 and 172.2 (COO).
IR (KBr): m = 3394, 3287, 2907, 1734, 1718, 1681, 1665,
1551, 1453 cmꢀ1; IR (CDCl3, CaF2): m = 3394, 2920,
1741, 1722, 1690, 1658, 1507, 1458 cmꢀ1. Anal. Calcd for

220
Z. Dzˇolic´ et al. / Journal of Molecular Structure 876 (2008) 218–224
Table 1
C27H38N2O6: C, 66.64; H, 7.87; N, 5.76%. Found: C, 66.60;
H, 7.81; N, 5.69%.
Crystal data and summary of data collection and refinement for
compounds 1 and 2
In order to obtain symmetrical, N,N’-dimethylated
oxalamide derivative, we separated monomethylated
amino acid 5 from other two derivatives 4 and 6 by flash
chromatography (CH2Cl2/methanol 100:1), and subjected
to the reaction with oxalyl chloride under the same condi-
tion. However, 1H NMR spectrum did not indicate the for-
mation of desired N,N’-dimethylated oxalamide derivative.
1
2
Formula
C26H36N2O6
472.57
0.2 · 0.1 · 0.1
Colourless
Monoclinic
P21/c
13.1184(4)
6.7477(2)
13.9360(4)
98.320(2)
1220.62(6)
2
C27H38N2O6
486.59
0.2 · 0.3 · 0.3
Colourless
Monoclinic
P21/a
9.7714(18)
10.421(13)
24.36(3)
95.05(7)
2471(4)
4
1.308
1048
0:12; 0:13; ꢀ30:30
Formula weight
Crystal size (mm)
Crystal colour
Crystal system
Space group
˚
a (A)
˚
b (A)
2.2.3. 2-Aminoadamantyl-2-carboxylic acid methyl ester (4)
M.p. 57 ꢁC (lit. [14] 58 ꢁC); 1H NMR (CDCl3, 600 MHz)
d/ppm: 3.72 (s, 3H, AOCH3), 1.56–2.24 (m, 16H, Ada-
H + NH2); 13C NMR (CDCl3, 150 MHz) d/ppm: 27.0
and 27.3 (C-5 and C-7), 34.3 (C-1 and C-3), 32.0 and
35.3 (C-4 and C-8 + C-9 and C-10), 37.9 (C-6), 51.8
(OACH3), 61.9 (C-2), 177.1 (COO).
˚
c (A)
b (ꢁ)
3
˚
V (A )
Z
D (g cmꢀ3
F (000)
)
1.286
508
ꢀ16:16; 0:8; 0:17
Index range for data
collection
Collected reflections
Independent
2689
2575(0.014)
5496
5171(0.036)
2.2.4. N-Methyl-2-aminoadamantyl-2-carboxylic acid
methyl ester (5)
reflections/(Rint
Data/restrains/
parameters
)
2,575, 214
5,171, 320
1/
Colourless oil; 1H NMR (CDCl3, 600 MHz) d/ppm:
3.71 (s, 3H, AOCH3), 2.20 (s, 3H, NACH3), 1.49–2.19
(m, 15H, Ada-H + NH); 13C NMR (CDCl3, 150 MHz) d/
ppm: 27.2 and 27.5 (C-5 and C-7), 29.0 (C-1 and C-3),
32.0 (N-CH3), 32.0 and 35.1 (C-4 and C-8 + C-9 and C-
10), 38.0 (C-6), 51.2 (OACH3), 66.4 (C-2), 175.2 (COO).
Weighting parameters 1/
[r2(Fo2) + (0.0634P)2 + [r2(Fo2) + (0.1009P)2 +
0.3331P]
0.8155P]
where P = (Fo2+2Fc2)/ where P = (Fo2+2Fc2)/
3
3
1.04
0.0640
0.1933
ꢀ0.40, 0.47
Goodness-of-fit on F2 1.14
R
wR
0.0471
0.1339
ꢀ0.28, 0.23
2.2.5. N,N’-Dimethyl-2-aminoadamantyl-2-carboxylic acid
methyl ester (6)
Min/max residual
electron density
Colourless oil which partially solidified; 1H NMR
(CDCl3, 600 MHz) d/ppm: 3.70 (s, 3H, AOCH3), 2.16 (s,
6H, NACH3), 1.48–2.34 (m, 14H, Ada-H); 13C NMR
(CDCl3, 150 MHz) d/ppm: 26.7 and 27.0 (C-5 and C-7),
30.3 (C-1 and C-3), 31.8 and 35.3 (C-4 and C-8 + C-9
and C-10), 37.8 (C-6), 37.9 (NACH3), 50.1 (OACH3),
69.2 (C-2), 170.6 (COO).
Atomic scattering factors were those included in
SHELXL97.
Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC-611811 and CCDC-
611812. Copies of data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
2.3. X-ray crystallographic analysis of 1 and 2
Single crystals of 1 and 2 were grown by slow evapora-
tion from an ethanol solution. Intensities were measured
on an Enraf Nonius CAD4 diffractometer, with graphite
3. Results and discussion
˚
monochromated CuKa radiation, wavelength 1.54180 A,
using the x/2h scan-technique. The crystallographic data,
and details of data collections and refinements are listed
in Table 1. During data collections there were no signifi-
cant variations in intensities of the three control reflections,
which were measured every 120 min. The data were cor-
rected for Lorentz and polarization effects [15]. The
absorption correction was based on a w-scan of seven
reflections. Structures were solved using WinGX package
[16] and refined by the package SHELXL97 [17]. Molecular
geometry calculations and illustrations of the crystal pack-
ing were prepared by PLATON98 [18]. The molecule of 1
involves the crystallographic inversion symmetry and an
asymmetric unit comprises a half of molecule (Z = 2).
The new oxalamide derivatives were synthesized using 2-
aminoadamantyl-2-carboxylic acid 3 prepared as described
previously [19,20]. The direct N-methylation of 3, per-
formed with a large excess of diazomethane, provided mix-
ture of three products, amino acid methyl ester 4, and the
corresponding mono- and dimethylated derivatives 5 and
6 in the ratio of 4.5:2:1, respectively. The mixture of methyl
esters 4, 5 and 6 was then subjected to the reaction with
oxalyl chloride in the presence of triethylamine and retro-
peptides 1 and 2 as well as the nonreacted dimethylated
derivative 6 were obtained (Scheme 1).
The structures of retropeptides 1 and 2 were confirmed by
one- and two-dimensional homo- and heteronuclear 1H and

Z. Dzˇolic´ et al. / Journal of Molecular Structure 876 (2008) 218–224
221
H
H3C
CH3
CH3
NH2
COOCH3
NH2
COOH
N
N
(COCl)2
CH2N2
Et2O
COOCH3
COOCH3
1 + 2 (+ 6)
+
+
Et3N, CH2Cl2
3
4
5
6
Scheme 1. Synthesis of retropeptides 1 and 2.
13C NMR measurements. The adamantane-proton reso-
nance appeared as a multiplet at 1.6–2.6 ppm in both H
NMR spectra of 1 and 2. The amide proton of 2 is shifted
upfield by about 0.5 ppm relative to their counterpart in 1.
The role of the oxalamide functions in the self-assem-
bling of 1 and 2 could be probed through the NMR and
IR measurements. Temperature-variable 1H NMR mea-
surements of 1 and 2 in the CDCl3 (5 mM) within the range
1
Fig. 1. Molecular structures and atom labelling of 1 and 2. The molecular symmetry of 1 is Ci whereas 2 reveals a pseudo twofold axis perpendicular to the
bond C1AC11. The methyl groups in 1 and N-methyl group in 2 are disordered over two positions. Displacement ellipsoids are drawn at the 30%
probability level.

222
Z. Dzˇolic´ et al. / Journal of Molecular Structure 876 (2008) 218–224
of 298–325 K show a relatively low temperature depen-
dence for the chemical shifts of the amide proton (Dd/
DT = ꢀ1.4 ppb/K for 1 and ꢀ2.7 ppb/K for 2, respec-
tively). Furthermore, 1H NMR spectra recorded upon add-
ing up to 20% DMSO-d6 to solutions of 1 and 2 in CDCl3
show that the signal of the NH proton exhibits no change
for 1 and the small change for 2 (Dd = 0.19 ppm) with
increasing amounts of DMSO-d6. These results suggest
that no intermolecular hydrogen bonds are formed in chlo-
roform solution. Further support for the absence of inter-
molecular hydrogen bonds between oxalamide units in
solution came from the lack of any concentration depen-
dence (30–5 mM) of the IR spectra of 1 and 2 in chloro-
form solution; the IR spectra showed a weak band at
3388 cmꢀ1 (for 1) and 3394 cmꢀ1 (for 2), respectively.
In solid state (KBr matrix), the IR spectrum of retropep-
both intramolecular as well as intermolecular hydrogen
bonding between oxalamide units in solid state. Further
support for the existence of intramolecular and intermolec-
ular hydꢀro1gen bonding are two amide I bands at 1658 and
1551 cmꢀ1 (amide II). Due to a disruption of the intermo-
lecular hydrogen bonds between the oxalamide groups of
the adamantane molecules, in the IR spectrum of the
CDCl3 solutions of 2, one of the amide I band is shifted
to higher wave number (1690 cmꢀ1). On the other hand,
the NH bending peak is shifted to lower wave number
(1507 cmꢀ1).
Single crystals of 1 and 2 suitable for X-ray structure
analysis were successfully prepared from ethanol solutions.
The results of structure analysis of 1 and 2 (Fig. 1) are in
agreement with spectroscopic evidences obtained by
NMR and FT-IR measurements.
1681 cm
and the NH bending peaks at 1453 and
tide 1 showed a single broad band appearing at 3394 cmꢀ1
.
There are also the amide I band at 1678 cmꢀ1 and the NH
bending peak at 1497 cmꢀ1 (amide II) indicating the intra-
molecular hydrogen bonding [5,6]. However, the IR spec-
trum of N-methylated derivative 2, showed a weak band
at 3394 cmꢀ1 and a strong peak at 3287 cmꢀ1 indicating
The overall molecular conformations of 1 and 2 are dif-
ferent (Fig. 1 and Table 2). The orientation of the bulky
adamantane moieties with respect to the oxalamide group
is anti in 1 whereas in N-methylated analogue 2 is syn.
The central oxalamide unit in the molecule 1 is strictly pla-
nar due to the symmetry (the crystallographic and molecu-
lar symmetry Ci), whereas in the compound 2 it deviates
substantially from the planarity (Fig. 2) [torsional angle
O1AC1AC11AO11 is ꢀ132.7(2)ꢁ, Table 2].
Table 2
Selected torsional angles
1
2
The non-planarity of the central unit in 2 is induced by
sterical hindrances of the methyl group attached to N11.
The results of crystal packing analysis of 1 and 2 are con-
sistent with the spectroscopic data. In the solid state and
in the solution analyses reveal that there are no intermo-
lecular hydrogen bonds in 1 whereas in 2 shows a pres-
O1AC1AC11AO11
180.0
ꢀ132.7(2)
ꢀ172.4(2)
ꢀ165.85(19)
ꢀ86.6(3)
ꢀ92.3(2)
ꢀ61.5(3)
ꢀ63.9(3)
ꢀ107.0(3)
ꢀ85.9(3)
C2AAN1AC1AC1i(C11)
C2BAN11AC11AC1
C1AN1AC2AAC3
ꢀ179.38(12)
–
ꢀ50.43(17)
C11AN11AC2AAC31
N1AC2AAC1AAC8A
N11AC2BAC1BAC8B
N1AC2AAC3AO2
–
ꢀ59.81(15)
˚
ence of the intermolecular NAHÆÆÆO [d(HÆÆÆA) = 2.08 A,
–
˚
131.88(17)
–
d(D–A) = 2.95 A and a(D–HÆÆÆA) = 162.8ꢁ] hydrogen
N11AC2BAC31AO21
bonds.
Fig. 2. Crystal packing of 1 dominated by van der Waals contacts. Hydrogen atoms are omitted.

Z. Dzˇolic´ et al. / Journal of Molecular Structure 876 (2008) 218–224
223
Fig. 3. Crystal packing of 2, with hydrogen bonded chains along the a axis (dashed lines).
The substitution of bulky adamantane cages on both
terminal sides of the molecules prevents the intermolecular
hydrogen bond between central oxalamide units. Although
the oxalamide units are in proper orientation, i.e. they are
coplanar; the separation distance is too large. The charac-
teristic distance for oxalamide units in the presence of
The methyl substitution increases steric hindrance leading
to non-planar conformation of oxalamide unit.
4. Conclusions
Two new retropeptides, conformationally restricted ada-
˚
NAHÆÆÆO hydrogen bonds is about 5 A [5,6,21]. In the com-
mantane-substituted oxalamide derivatives 1 and 2 were
1
pound 1, this distance is exactly the length of the crystallo-
synthesized in a moderate yields. Both H NMR and FT-
˚
graphic b axis, i.e. 6.75 A (Fig. 2). However, two
IR studies in the solution are in agreement with results
obtained in the solid state by X-ray structure analysis.
The oxalamide group of 1 is planar while in the monome-
thylated derivative 2 the oxalyl-carbonyls are in a skew-
conformation. The conformational preferences of other
methylated oxalamide derivatives are under current
investigation.
symmetrically and chemically identical intramolecular
˚
˚
NAHÆÆÆO [d(HÆÆÆA) = 2.25 A, d(D–A) = 2.69 A and a(D–
HÆÆÆA) = 110.7ꢁ] hydrogen bonds within oxalamide bridge
of a pseudo-C5 type are present stabilizing the planarity
of the oxalamide group.
In the crystal structure of the compound 2 the neigh-
˚
bouring molecules are separated by a/2 = 4.88 A, which
Acknowledgments
is less than the characteristic distance in oxalamides con-
nected by two parallel hydrogen bonds [22]. Thus, the close
contacts between oxalamide donor and acceptor sites are
not obstructed by the bulky adamantane cages (Fig. 3)
and the non-planar oxalamide units can be packed closely.
The non-methylated nitrogen atom N1 forms intermolecu-
lar hydrogen bond with O1 atom of the oxalamide unit of
the molecule operated by the glide plane in the a direction
We thank the Croatian Ministry of Science, Education
and Sports of the Republic of Croatia for financial support
of this study (Grant Nos. 098-0982904-2912, 098-0982929-
2917, 098-0982933-2911 and 098-119134-2943).
References
˚
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180ꢁ gave conformer which is by 9.51 kcal molꢀ1 less stable
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