Molecular structures and ab initio molecular orbital calculations of the optically active derivatives of 1-aminocyclopropane-1-carboxylic acid

Article abstract of DOI:10.1016/S0022-2860(03)00255-2

The novel optically active derivatives of 2,2′-disubstituted-1-aminocyclopropane-1-carboxylic acid (-)-2 and (+)-3 were synthesised from the spiro-azlactone (+)-1. Oxidation of the diol moiety of (+)-3 gave by ring enlargement the racemic mixture of 2,3-dihydrofuran derivative (±)-6. This conversion is explained by stepwise rearrangement of the initially formed tetrasubstituted cyclopropanecarbaldehyde 4 through zwitterionic's reactive intermediate 5. The formation of (±)-6 is preferred energetically as established by ab initio calculations of the ground states and possible intermediates for that rearrangement. The crystal structure and absolute configuration of the compounds (+)-1, (-)-2, (+)-3 and (-)-7 were determined by single-crystal X-ray diffraction method. All four compounds possess Z-configuration of the cyclopropane ring. The dioxolane ring in the structures(+)-1 and (-)-2 adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (-)-2, (+)-3 and (-)-7 possess the anticlinal conformation. The molecules of the compound (+)-1 are connected by very weak intermolecular hydrogen bond of C-H?type. In the compounds (-)-2,(+)-3 and (-)-7 inter- and intramolecular hydrogen bonds of N-H?O type were observed. The spiro-compound (+)-1 exhibited a more pronounced inhibitory activity against the proliferation of murine leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.

Full text of DOI:10.1016/S0022-2860(03)00255-2

Journal of Molecular Structure 655 (2003) 229–241
www.elsevier.com/locate/molstruc
Molecular structures and ab initio molecular orbital
calculations of the optically active derivatives
of 1-aminocyclopropane-1-carboxylic acid
a
Zoran Dzolic , Mario Cetina , Damir Kovacek , Antonija Hergold-Brundic ,
b
c
d
´
Draginja Mrvos-Sermek , Ante Nagl , Neda Slade , Kresimir Pavelic , Jan Balzarini ,
ˇ
´
ˇ
d
b
e
e
f
ˇ
ˇ
´
Erik De Clercqf, Oliver Zerbeg, Gerd Folkersg, Leonardo Scapozzag, Mladen Mintasa,
*
aFaculty of Chemical Engineering and Technology, Department of Organic Chemistry, University of Zagreb, Marulicev trg 19,
10000 Zagreb, Croatia
bFaculty of Textile Technology, University of Zagreb, Pierottijeva 6, 10000 Zagreb, Croatia
cFaculty of Food Technology and Biotechnology, University of Zagreb, Pierottijeva 6, 10000 Zagreb, Croatia
dLaboratory of General and Inorganic Chemistry, Faculty of Science, University of Zagreb, Zvonimirova 8, 10000 Zagreb, Croatia
e
ˇ
´
ˇ
Division of Molecular Medicine, Rud⁄ er Boskovic Institute, Bijenicka cesta 54, P. O. Box 1016, 10001 Zagreb, Croatia
fRega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
g
¨ ¨
Department of Applied Biosciences, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Received 27 January 2003; revised 3 April 2003; accepted 8 April 2003
Abstract
The novel optically active derivatives of 2,20-disubstituted-1-aminocyclopropane-1-carboxylic acid (2)-2 and (þ)-3 were
synthesisedfromthespiro-azlactone(þ)-1.Oxidationofthediolmoietyof(þ)-3gavebyringenlargementtheracemicmixtureof
2,3-dihydrofuranderivative(^)-6. Thisconversionisexplainedbystepwiserearrangementoftheinitiallyformedtetrasubstituted
cyclopropanecarbaldehyde 4 through zwitterionic’s reactive intermediate 5. The formation of (^)-6 is preferred energetically as
establishedbyabinitiocalculationsofthegroundstatesandpossibleintermediatesforthatrearrangement.Thecrystalstructureand
absolute configuration of the compounds (þ)-1, (2)-2, (þ)-3 and (2)-7 were determined by single-crystal X-ray diffraction
method.AllfourcompoundspossessZ-configurationofthecyclopropanering.Thedioxolaneringinthestructures(þ)-1and(2)-2
adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (2)-2, (þ)-3 and
(2)-7 possess the anticlinal conformation. The molecules of the compound (þ)-1 are connected by very weak intermolecular
hydrogen bondof C-H· · ·O type. In thecompounds (2)-2, (þ)-3 and (2)-7 inter-and intramolecular hydrogen bonds ofN-H· · ·O
typewereobserved.Thespiro-compound(þ)-1exhibitedamorepronouncedinhibitoryactivityagainsttheproliferationofmurine
leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.
q 2003 Elsevier Science B.V. All rights reserved.
Keywords: 1-Aminocyclopropane-1-carboxylic acid derivatives; Synthesis; Rearrangement; Ab initio MO calculations; Density functional
theory, Single crystal X-ray analysis; Cytostatic activities; Antiviral activities
*
Corresponding author. Tel.: þ 385-1-4597-214; fax: þ 385-1-4597-250.
E-mail address: mladen.mintas@pierre.fkit.hr (M. Mintas).
0022-2860/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-2860(03)00255-2

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230
this work we also calculated the energies of the most
1. Introduction
stable conformers for that rearrangement and com-
pared them with the oxidation of the corresponding
trisubstituted cyclopropane derivative (2)-7, which
under the same reaction condition do not rearrange [6].
Cyclopropane derivatives occupy an important role
in the synthetic organic chemistry, notably in the
synthesis of several natural products [1]. Considerable
efforts were directed toward the synthesis of 1-amino-
cyclopropane-1-carboxylic acid [2] (ACC) and its
2-substituted and 2,20-disubstituted derivatives [3].
Enantiomerically enriched ACC’s have been exten-
sively used in the design and synthesis of confor-
mational constrained peptidomimetics [4,5]. The
present study deals with the synthesis of the optically
active derivatives of 2,20-disubstituted 1-aminocyclo-
propane-1-carboxylic acids (2)-2 and (þ)-3 and it
was undertaken initially to evaluate their cytostatic
and antiviral activities. Since exact stereostructure of
these molecules were of importance for biological
activities and in particular for elucidation of the
mechanism of the [1,3]-sigmatropic rearrangement of
tetrasubstituted cyclopropane derivative (þ)-3 to
2,3-dihydrofuran derivative (^)-6 (Scheme 1), the
X-ray crystal structure analyses were performed. In
2. Results and discussion
2.1. Synthesis
The synthesis of 2,20-disubstituted-1-aminocyclo-
propane-1-carboxylic acid derivatives (2)-2 and
(þ)-3 and the rearrangement of (þ)-3 into
2,3-dihydrofuran derivative (^)-6 was accomplished
as described in Scheme 1. Methanolysis of the
azlactone ring of the spiro-compound (þ)-1 [7]
gave 1-aminocyclopropane-1-carboxylic acid deriva-
tive (2)-2 possessing geminally substituted benz-
amido and carboxymethyl ester groups. Subsequent
acid hydrolysis of the dioxolane moiety of (2)-2
afforded tetrasubstituted cyclopropane derivative
Scheme 1. Reagents: (i) CH3ONa, CH3OH; (ii) HCl, CH3OH; (iii) NaIO4, THF.

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Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
231
Scheme 2. Reagent: (i) NaIO4, THF.
(þ)-3. Oxidation of the diol moiety of (þ)-3 gave the
racemic mixture of the 2,3-dihydrofuran derivative
(^)-6. The formation of this product is explained by
the rearrangement of the initially formed tetra-
substituted cyclopropanecarbaldehyde 4 through
zwitterionic’s reactive intermediate 5. The structure
of the rearranged product (^)-6 was deduced from
their one- and two-dimensional 1H and 13C NMR
spectra (see Experimental part).
The dioxolane ring in the compounds (þ)-1 and
(2)-2 exhibits half-chair conformation twisted
around the bonds O1–C3 in (þ)-1 (Fig. 1) and
C4–C5 in (2)-2 (Fig. 2). Both compounds exhibit an
almost identical conformation of the moiety consist-
ing of the cyclopropane and dioxolane ring; this is
On the contrary, oxidation of trisubstituted cyclo-
propane derivative (2)-7 led under the same reaction
condition to the formation of trisubstituted cyclo-
propanecarbaldehyde (2)-8 [6] (Scheme 2).
2.2. X-Ray crystal structure study
Molecular Structures.-In order to elucidate the
mechanism of the rearrangement of (þ)-3 to (^)-6
the structures of the compounds (þ)-1, (2)-2, (þ)-3
and (2)-7 were determined by X-ray crystallographic
analysis. The compounds (þ)-1, (2)-2, (þ)-3 and
(2)-7 (Schemes 1 and 2) crystallized in the mono-
clinic space group P21 and their perspective views
with the atom numbering scheme are displayed in
Figs 1–4. The absolute configuration of the carbon
atoms C8, C6 and C5 in all four compounds was
determined to be S, R and S.
Fig. 1. The molecular structure and labelling of the compound (þ)-
1. Displacement ellipsoids are drawn at the 20% probability level.
The skeleton of the spiro-compound (þ)-1 consists
of the cyclopropane, azlactone, phenyl and dioxolane
ring (Fig. 1). The values of the bond distances and
angles in the cyclopropane, azlactone and phenyl ring
are consistent with those found in structurally related
derivatives of 1-spiro-(40(20-phenyl-50(40H)-oxazolo-
ne))cyclopropane [8–10]. The dihedral angle between
the planes of the cyclopropane and azlactone ring
amounts to 88.0(2)8; that is, those rings are almost
perpendiculartoeachother. Onthecontrary, thephenyl
and azlactone ring are nearly coplanar; the dihedral
angle between the l.s. planes of those rings is 6.8(1)8.
Fig. 2. The molecular structure and labeling of the compound (2)-
2. Displacement ellipsoids are drawn at the 20% probability level.
Disordered atoms C1 and C2 are represented in the Figure in the
positions of higher occupancy factor.

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232
at the atom C8 of the cyclopropane ring. Beside this,
the compounds (þ)-3 and (2)-7 have the common
diol-substituent at the atom C6 of the cyclopropane
ring as well as two crystallographically independent
molecules in the unit cell. All three compounds
possess Z-configuration of the cyclopropane ring. The
values of the torsion angle N1–C8–C6–C5 only
slightly deviate from the standard value for cis-
substituted cyclopropanes (Table 1).
The cyclopropane ring has many properties which
are found to be more similar to those of the vinyl
group; e.g. the hybrid orbitals are closer to sp2 than
sp3, while a conformation-dependent conjugative
ability is exhibited with p-acceptor substituents.
Thus, the carbonyl group induces distal bond short-
ening and adjacent bond lengthening of the cyclopro-
pane ring [12–14]. Such influence of the carbonyl
group was observed in the compounds (2)-2, (2)-7
and one crystallographically independent molecule of
the compound (þ)-3 where the shortest bond was
found to be C62C7 (Table 1). The values of the
endocyclic bond angles in the cyclopropane ring of
(2)-2, (þ)-3 and (2)-7 are close to 608 what is in
accord with the expected ones. The smallest angle in
the cyclopropane ring of (2)-2, (2)-7 and one
crystallographically independent molecule of the
compound (þ)-3 was observed at the atom C8. The
exocyclic bond angle N1–C8–C9 in (2)-2, (þ)-3
and (2)-7 varies in the range from 113.3(2) to
115.4(2)8; that is, it deviates significantly from the
tetrahedral angle value (Table 1). This marked angle
deviation may be attributed to the steric congestion
Fig. 3. The molecular structure and labeling of the compound (þ)-3.
Displacement ellipsoids are drawn at the 20% probability level.
shown by the values of the torsion angles C4–C5–
C6–C7 and O2–C5–C6–C7 amounting 156.6(2)8
and 287.0(3) in (þ)-1 appropriate and 156.0(2)8 and
288.8(2)8 in (2)-2.
The bond distances between the equatorial
ðC12C3Þ and axial (C2–C3) bond of the dioxolane
ring in (þ)-1 were found to be equal within standard
˚
uncertainties [1.499(4) and 1.504(4) A], although the
difference between those bond distances in the similar
dioxolane substituted cyclopropanes were found to be
˚
even 0.11 A [11].
The common structural feature of the compounds
(2)-2 (Fig. 2), (þ)-3 (Fig. 3) and (2)-7 (Fig. 4) is
benzamido and methylcarboxylate group substituted
Fig. 4. The molecular structure and labeling of the compound (2)-7. Displacement ellipsoids are drawn at the 20% probability level.

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Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
233
Table 1
moieties. The methyl ester group in the compounds
(2)-2 and (þ)-3 adopts synperiplanar conformation
[the torsion angle O32C92O42C10 amounting
25.7(4)8 in (2)-2 and 6.9(5) and 5.5(5)8 in (þ)-3]
with the carbonyl O3 atom eclipsing the cyclopropane
ring. The corresponding torsion angle M–C8–C9–
O3, where M is the midpoint of the distal bond of the
cyclopropane ring (C6–C7) is 8.2(3)8. In two
crystallographically independent molecules of (þ)-3
the torsion angle M–C8–C9–O3 amounts to
217.4(6)8 and 231.2(5)8. Although the synperipla-
nar conformation prevails in derivatives of cyclopro-
pane, the synclinal and anticlinal conformations have
also been observed due to conjugative interactions of
the substituents with the cyclopropane ring [12,15].
Two crystallographically independent molecules of
(2)-7 exhibit the antiperiplanar, i.e. anticlinal
conformation with the oxygen atom O4 eclipsing the
cyclopropane ring. The values of the torsion angle
M–C8–C9–O3 in these two independent molecules
are 164.5(3) and 147.1(3)8.
˚
Selected bond distances (A), bond and torsion angles (8) for the
compounds (2)-2, (þ)-3 and (2)-7
(2)-2
(þ)-3
(2)-7
C6–C7
1.495(3)
1.498(4),
1.506(3),
1.516(3)
1.533(3)
1.530(3)
1.521(3),
1.518(3)
1.425(3),
1.431(3)
1.510(3),
1.505(3)
1.515(3),
1.514(3)
1.505(4)
1.547(4)
1.528(4)
1.511(4),
1.496(4)
1.426(4),
1.443(4)
1.498(5),
1.489(4)
1.524(4),
1.525(4)
61.9(2),
61.2(2)
C6–C8
1.546(3)
1.516(2)
1.434(2)
1.496(3)
1.517(3)
61.8(1)
C7–C8
C8–N1
C8–C9
C6–C5
C6–C7–C8
C6–C8–C7
C7–C6–C8
N1–C8–C9
60.9(1),
60.6(1)
58.4(1)
58.7(2),
59.7(2)
59.1(1),
59.7(1)
59.8(1)
59.5(2),
59.1(2)
60.1(1),
59.8(1)
115.4(2)
114.7(3),
114.0(2)
113.3(2),
113.3(2)
The geometries of the structures (2)-2, (þ)-3 and
C5–C6–C18
C5–C6–C3
115.0(2)
–
–
–
–
115.7(3),
115.5(3)
(2)-7 are not significantly different from the structu-
rally
related
alkyl
1-benzamido-1-cyclo-
C7–C6–C5–C4
N1–C8–C6–C5
–156.0(2)
2154.9(2),
2154.6(3)
0.1(4),
2169.3(2),
2169.8(2)
25.1(3),
propanecarboxylic acid derivatives [7,16–20] and
1,2-dihydroxyethyl substituted cylopropane deriva-
tives [21–22]. The methyl ester group and benzamido
moiety adopt antiperiplanar conformation, defined by
the torsion angles C8–N1–C11–C12 and C8–C9–
O4–C10 in all three structures (Table 1). The values of
the torsion angle N1–C8–C9–O4 in (2)-7 deviate
significantly from the corresponding one of the
compounds (2)-2 and (þ)-3. This torsion angle
depends on the bond angle N1–C8–C9 which is
widened in (2)-2 and (þ)-3 to release close contacts
between the main chain atoms of the neighbouring
residues.Thisisinaccordwiththatwhathasbeenfound
for structurally related derivatives of cylopropanes
[8,23–25]. The conformation of the 1,2-dihydrox-
yethyl group in the structure of the compound (2)-7
defined by the torsion angle C6–C5–C4–O1 is
antiperiplanar, while the conformation of that group
in the compound (þ)-3 is synclinal.
20.3(2)
4.2(4)
23.9(3)
C8–N1–C11–C12 2179.4(2)
173.0(3),
171.1(3)
2171.2(3),
2176.2(3)
268.9(4),
256.4(4)
217.1(4),
232.5(4)
63.4(3),
2179.0(2),
2175.6(2)
2177.5(2),
2177.4(2)
58.0(3),
C8–C9–O4–C10
C11–N1–C8–C9
N1–C8–C9–O4
C6–C5–C4–O1
175.2(2)
65.8(2)
59.7(3)
3.3(2)
2158.8(2),
2162.7(2)
178.4(2),
2140.7(2)
68.9(4)
2 179.0(2)
around the cyclopropane ring, which forces two
geminal benzamido and methylcarboxylate groups
to be remoted from each other. The torsion angles
defined by the cyclopropane ring atoms and connected
nitrogen atom N1 (C6–C7–C8–N1; C7–C6–C8–
N1) as well as the corresponding carbon atom C9 of
the carboxylate group (C6–C7–C8–C9; C7–C6–
C8–C9) in (2)-2, (þ)-3 and (2)-7, respectively vary
in the range of 103.7(2) 2 111.3(2)8. These values
corroborate the anticlinal conformation of those
The dihedral angles between the plane of the
cyclopropane ring and the plane defined by atoms
N1–C8–C9 in (2)-2, (þ)-3 and (2)-7 are 88.6(2),
89.0(4) and 89.0(3)8 [the mean values for (þ)-3

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234
Fig. 5. Crystal packing diagram of the compound (2)-2.
and (2)-7 are given]; that is, those planes are
almost perpendicular to each other.
the N-H· · ·O type (Table 2) build seven-membered
ring (Fig. 6). Two crystallographically independent
molecules are connected in the crystal structure by
intermolecular hydrogen bond O11· · ·O22. The mole-
cules are additionally connected by three inter-
molecular hydrogen bonds of the O-H· · ·O type
forming three-dimensional network.
Crystal Structures.-In the crystal structure of the
compound (þ)-1 the molecules are connected by very
weak intermolecular hydrogen bond C14· · ·O3 with
˚
D· · ·A distance of 3.378(4) A and D-H· · ·A angle of
145.5(2)8 [symmetry code: x, þ y þ 1, þ z]. The
azlactone and phenyl ring of the molecule are oriented
parallel to the crystallographic axis b with the
corresponding dihedral angles of 3.4(1) and 2.9(1)8.
In the 1-aminocyclopropane-1-carboxylic acid
derivatives (2)-2, (þ)-3 and (2)-7 inter- and
intramolecular hydrogen bonds of the N H· · ·O type,
characteristic for the amide bond were observed. Such
very weak intermolecular hydrogen bond in the
crystal structure of the compound (2)-2 connecting
the molecules along axis a forming infinite chains
The hydrogen bonding pattern of the compound
(2)-7 (Fig. 7) is different to that of an almost similar
compound (þ)-3. Two hydrogen bonds N1· · ·O3 form
ten-membered ring of the R22(10) type. Each indepen-
dent molecule is additionally bonded by hydrogen
bonds O1· · ·O2 and O2· · ·O5 with its symmetry related
molecules forming two almost identical two-dimen-
sional networks. In one of these networks all hydrogen
bonds are slightly longer (Table 2). Furthermore, the
hydrogen bond pattern of the compound (2)-7 has
remarkable influence on the density, which is found to
be higher than those of the compounds (þ)-1, (2)-2
and particularly comparing to the density of its
methylated derivative (þ)-3.
˚
(Fig. 5) with N1· · ·O5 distance of 3.113(2) A and
angle of 156.5(1)8 [symmetry code: x þ 1, þ y, þ z].
In both independent molecules of the compound
(þ)-3 two intramolecular hydrogen bonds of

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Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
235
Table 2
˚
Hydrogen-bonding geometry (A, 8) for the compounds (þ)-3 and (2)-7
˚
D· · ·A(A)
Compound
D–H· · ·A
D–H· · ·A(8)
Symmetry code
(þ)-3
N11–H11N· · ·O11
N12–H12N· · ·O12
O11–H11· · ·O22
O12–H12· · ·O52
O21–H21· · ·O51
O22–H22· · ·O21
N11–H11N· · ·O31
O11–H11· · ·O21
O21–H21· · ·O51
N12–H12N· · ·O32
O12–H12· · ·O22
O22–H22· · ·O52
2.865(4)
2.871(4)
2.829(4)
2.811(4)
2.745(4)
2.804(3)
3.062(3)
2.901(3)
2.771(3)
3.023(3)
2.865(2)
2.733(2)
143(3)
145(4)
155(1)
169(5)
169(3)
165(1)
173(3)
163(1)
170(1)
161(3)
156(1)
175(1)
x, þ y 2 1, þ z
2x, þ y 2 1/2, 2z
2x þ 1, þ y þ 1/2, 2z
2x þ 2, þ y 2 1/2, 2z
2x þ 1, þ y þ 1/2, 2z
x, þ y 2 1, þ z
(2)-7
2x þ 1, þ y 2 1/2, 2z þ 1
2x þ 2, þ y þ 1/2, 2z þ 1
x, þ y 2 1, þ z
2.3. Ab initio MO calculations
of the ground states and possible intermediates for that
process and the hypothetical one of 8 to II were
performed (Table 3). All calculations were carried out
on DFT [26] pBN/DN** level with the SPARTAN
To clarify the mechanism of the rearrangement of
(þ)-3 to (^)-6 (Scheme 1) the ab initio calculations
Fig. 6. Crystal packing diagram of the compound (þ)-3 view down the crystallographic axis b.

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236
Fig. 7. Crystal packing diagram of the compound (2)-7 view down the crystallographic axis b.
[27] program. The results in Table 3 show that the
zwitterionic’s intermediate 5 is more stable than
the ground state of the molecule 4. Furthermore, the
methyl-substituted dihydrofuran derivative 6 has
lower energy than the reactive intermediate 5 by
0.00493 atomic units. The zwitterionic’s reactive
intermediate I is less stable than the ground state of
the molecule 8 by 0.00100 atomic units and II is less
stable than 8 by 0.00325 atomic units. This means that
formation of 6 is energetically preferred what is in
agreement with our experimental finding. The mech-
anism of this rearrangement is also in accord with the
reported one for 1,2-aminocyclopropane alcohol
[28], trialkylsiloxy substituted vinylcyclopropane-
carbaldehydes [29] and Cram’s work on cis/trans
isomerizations of substituted cyclopropane deriva-
tives via 1,3-zwitterions. [30–31].
Comparison of the calculated ab initio HF/6-31G*
and DFT pBN/DN** selected geometrical parameters
for (þ)-3 and (2)-7 with the experimental X-ray data
are displayed in Table 4. The average absolute error of
the differences between the experimental bond lengths
and those obtained by HF/6-31G* basis set are
˚
0.013 and 0.014 A for two independent molecules of
˚
(þ)-3 and 0.013, i.e. 0.012 A for two independent
molecules of (2)-7. DFT geometry is also in a very

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237
Table 3
DFT calculated energies of the most stable conformers of the tetra- and trisubstituted cyclopropanecarbaldehydes 4 and 8, zwitterionic’s
intermediates 5 and I and 2,3-dihydrofurane derivatives 6 and II (in atomic units)
4 (R ¼ CH3)
8 (R ¼ H)
2898.50236
2859.18432
5 (R ¼ CH3)
I (R ¼ H)
2898.50665
2859.18332
6 (R ¼ CH3)
II (R ¼ H)
2898.51158
2859.18107
Table 4
˚
Selected bond distances (A) of (þ)-(3) and (2)-7 derived from X-ray crystallography and ab initio (HF/6-31G* and DFT pBN/DN**)
calculations. For numbering of the atoms see Fig. 3 and Fig. 4
Bond
(þ) 2 (3)
(2) 2 (7)
Experimentala
HF/6-31G*
DFT
Experimentala
HF/6-31G*
DFT
O11–C41
O12–C42
O21–C51
O22–C52
O31–C91
O32–C92
O41–C91
O42–C92
O41–C101
O42–C102
O51–C111
O52–C112
N11–C111
N12–C112
N11–C81
N12–C82
C31–C61
C32–C62
C41–C51
C42–C52
C51–C61
C52–C62
C61–C71
C62–C72
C61–C81
C62–C82
C71–C81
C72–C82
C81–C91
C82–C92
C111–C121
C112–C122
1.427(4)
1.419(4)
1.438(3)
1.436(3)
1.203(4)
1.209(4)
1.339(4)
1.331(4)
1.453(5)
1.447(4)
1.233(4)
1.244(3)
1.347(4)
1.342(4)
1.426(4)
1.443(4)
1.508(4)
1.514(4)
1.523(4)
1.512(4)
1.524(4)
1.525(4)
1.498(4)
1.505(4)
1.547(4)
1.528(4)
1.511(4)
1.496(4)
1.498(5)
1.489(4)
1.493(4)
1.483(4)
1.409
1.407
1.190
1.321
1.416
1.201
1.361
1.426
1.521
1.521
1.530
1.497
1.525
1.498
1.507
1.502
1.442
1.438
1.221
1.359
1.449
1.236
1.378
1.438
1.520
1.531
1.536
1.512
1.550
1.515
1.514
1.509
1.417(3)
1.417(3)
1.433(3)
1.431(3)
1.200(3)
1.209(3)
1.329(3)
1.329(3)
1.449(3)
1.447(3)
1.235(3)
1.233(3)
1.352(3)
1.354(3)
1.425(3)
1.431(3)
–
1.409
1.405
1.192
1.319
1.417
1.200
1.361
1.421
–
1.445
1.439
1.221
1.356
1.451
1.235
1.378
1.433
–
–
1.514(3)
1.513(3)
1.515(3)
1.514(3)
1.506(3)
1.516(3)
1.533(3)
1.530(3)
1.521(3)
1.518(3)
1.510(3)
1.505(3)
1.490(3)
1.497(3)
1.521
1.514
1.491
1.513
1.500
1.502
1.502
1.532
1.518
1.507
1.532
1.513
1.514
1.510
a
X-ray crystallograhic determination.

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´
Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
238
good agreement with the X-ray data; average absolute
errors for pBN/DN** calculated bond distances are
the mechanism of that process. The result of these
calculations support the predicted mechanism of the
rearrangement of (þ)-3 to (^)-6 via the zwitter-
ionic’s reactive intermediate. The DFT method is
also shown to be a valuable tool for predicting
structure-reactivity relationship. The evaluated com-
pounds didn’t show significant cytotoxic and anti-
viral activities of the examined cell lines; the
exception being the spiro-compound (þ)-1 which
showed a more pronounced inhibitory activity
against the proliferation of murine leukemia and
human T-lymphocytes cells than other type of tumor
cell lines and normal human fibroblast cells.
˚
˚
˚
0.015 A, i.e. 0.018 A for (þ)-3 and 0.015, i.e. 0.014 A
for (2)-7. The results of ab initio calculations show
that both, HF/6-31G* and DFT pBN/DN** agree
quite well with the X-ray structure data.
2.4. Cytostatic and antiviral activity
Compounds (þ)-1, (2)-2, (þ)-3 and ( 6 )-6 were
evaluated for their cytostatic activity against malig-
nant tumor cell lines: murine leukemia (L1210/0),
human T-lymphocyte (Molt4/C8 and CEM/0), cervi-
cal carcinoma (HeLa), breast carcinoma (MCF7),
colon carcinoma (CaCo-2), pancreatic carcinoma
(MIAPaCa-2) and laryngeal carcinoma (Hep-2), as
well as human fibroblast cells (WI-38). The spiro-
azlactone (þ)-1 exhibited the most pronounced
antiproliferative activity against murine leukemia
(L1210/0; IC50¼41 mM) and human T-lymphocyte
cells (Molt4/C8; IC50 ¼ 42 mM; CEM/0;
IC50¼40 mM).
Compounds (þ)-1, (2)-2, (þ)-3 and (^)-6 were
also evaluated against varicella-zoster virus (VZV)
and cytomegalovirus (CMV) in human embryonic
lung (HEL) cells and against human immuno-
deficiency virus type 1 (HIV-1) and HIV-2 in
human limphocyte CEM cells. None of the com-
pounds showed appreciable antiviral activity at
subtoxic concentrations, except for some very slight
activity of (þ)-1 against CMV.
4. Experimental
Melting points were determined on a Kofler micro
hot-stage apparatus (Reichert, Wien) and are uncor-
rected. Precoated Merck silica gel 60F-254 plates
were used for thin-layer chromatography (TLC) and
the spots were detected under UV light (254 nm).
Column chromatography was performed using silica
gel (0.05–0.2 mm, Merck); glass column was slurry-
packed under gravity. The electron impact mass
spectra were recorded with an EXTREL FT MS 2001
instrument with ionizing energy of 70 eV. The IR
spectra were recorded on a Nicolet-Magna IR 760
spectrometer and UV spectra on a Hewlett-Packard
8452 spectrometer. Optical rotations were measured
with an Optical Activity AA-10 Automatic Polarimeter
in a 1 dm cell; c in g/100 ml, at r.t. (ca.208).
Elemental analyses were performed by the Central
ˇ
´
Analytical Service, Rud⁄ er Boskovic Institute, Zagreb.
1
3. Conclusions
The H- and 13C- NMR spectra were recorded on a
Bruker AMX-300 (1H 300.13; 13C 75 MHz). Chemi-
cal shifts in NMR spectra are given in ppm relative to
internal TMS (d scale), Jin Hz; the chemical shifts
assignments of (^)-6 (c.f. Scheme 1) are based on
two-dimensional (1H,1H(- DQF-COSY, and long
range (1H,13C(-HSQC and HMBC experiments at
500 MHZ (1H) frequency.
The aims of the presented work were to evaluate
the novel 2,20-disubstituted-1-aminocyclopropane-1-
carboxylic acid derivatives (2)-2 and (þ)-3, the
spiro-azlactone (þ)-1 and 2,3-dihydrofuran deriva-
tive (^)-6 on cytostatic and antiviral activities and
to elucidate the mechanism of the rearrangement of
(þ)-3 to (^)-6. For these reasons the exact
stereostructures, particularly the absolute configur-
ation of (þ)-1, (2)-2, (þ)-3 and the related
trisubstituted cyclopropane derivative (2)-7 were
determined by X-ray crystal structure analysis.
Additionally, the ab initio HF/6-31G* and DFT
pBN/DN** calculations were performed to clarify
4.1. Compounds preparation
Methyl(2)-(1S, 2R)-1-benzamido-2-methyl-2-((S)-
2,2-dimethyl-1,3-dioxolan-4yl(cyclopropanecarboxy-
late (2). A suspension of (þ)-1 [7] (0.86 g, 2.85 mmol)

ˇ
´
Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
239
in a solution of sodium metoxide (0.02 g) in absolute
methanol (50 ml) was stirred at room temperature for
30 min. The solvent was then evaporated, the residue
dissolved in dichloromethane, washed with water and
the organic layer dried over MgSO4. After removal of
thesolventacolourless solid of(2)-2was obtainedina
quantitative yield. mp 133–134 8C (from MeOH);
[a]D 2 24.0 8 (c 0.25 in MeOH); nmax (KBr)/cm21
3350, 1733, 1644; lmax (MeOH) 204 (log e 4.13) and
228 (log e 4.14); dH (CDCl3) 1.25 (s, 3H), 1.34 (s, 3H)
and 1.41 (s, 3H) (2 £ CH3), 1.40 (d, J 5.67, 1H,
CH2cyclopro), 1.81 (d, J 5.67, 1H, CH2cyclopro), 3.70 (s,
3H, OCH3), 3.89 (dd, J 7.12 and 8.54, 1H, CH2), 4.10
(dd, J6.50 and 8.57, 1H, CH2), 4.23 (t, J 6.78, 1H, CH),
7.19 (s, 1H, NH), 7.39–7.75 (m, 5H, C6H5); dC 14.16
(C2–C H3), 24.18 (C3), 25.16 and 26.19 (2 £ C20 –
C H3), 31.4 (C20), 42.93 (C1), 52.48 (OC H3), 67.68
(C50),78.15(C40),109.37(C20),126.95,128.48,131.72
and133.71(C–Ph),168.17(CO–amide),170.48(CO–
ester);m/z(EI)333.4(Mþ);Anal.calcdforC18H23NO5:
C, 64.85; H, 6.95; N, 4.20. Found: C, 64.92; H, 7.02;
N, 4.12.
0.594 mmol) in THF (50 ml). The mixture was then
stirred at room temperature for 6 h and the resultant
suspension was filtered. The solvent was removed
and the resulting residue was dissolved in dichlor-
omethane, washed with water, dried over MgSO4,
filtered and concentrated in vacuo. Purification of
the residue by silica gel column chromatography
(ethyl acetate: dichloromethane 3: 2) afforded (^)-
6 (0.112 g, 72.2%) as a white solid. mp 162–
163 8C (from EtOH); n (KBr)/cm21 3321, 1739,
1650, 1530 cm21; lmax (MeOH) 204 (log e 4.06)
and 228 (log e 4.02); dH (CDCl3) 1.71 (s, 3H,
CH3), 2.97 (d, J 16.4, 1H, CH2), 3.24 (d, J 16.4,
1H, CH2), 3.86 (s, 3H, OCH3), 6.12 (s, 1H, CH),
7.27 (s 1H, NH), 7.43–7.83 (m, 5H, C6H5); dC
10.45 (C4–C H3), 43.65 (C4), 53.26 (OCH3), 91.60
(C5), 109.47 (C3), 127.20, 128.57, 132.14 and
133.11 (C–Ph), 138.09 (C2), 166.81 (CO–amide),
169.49 (CO–ester); (1H,1H( DQF-COSY (CDCl3),
cross peaks between: C4–CH3 and CHAHB (CH2);
C4–CH3 and CH; CH and CHAHB (CH2);
(1H,13C(-HSQC (CDCl3), cross peaks between:
CHAHB (CH2) and C4; CH and C2; (1H,13C(-
HMBC (CDCl3), cross peaks between: CHA (CH2)
and C4–C H3; CH and C4; NH and C4; CHA
(CH2) and C5; NH and C5; CH and C3; NH and
C6H5; C4–CH3 and C2; CHAHB (CH2) and C2;
NH and CO–amide; C6H5 and CO–amide; NH and
CO–ester; OCH3 and CO-ester; CHAHB (CH2) and
CO-ester; m/z (EI) 261.3 (Mþ); Anal. calcd for
C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found:
C, 64.30; H, 5.89; N, 5.45.
Methyl(þ)-(1S, 2R)-1-benzamido-2-methyl-2-((S)-
1,2-dihydroxyethyl( cyclopropanecarboxylate (3). 3 M
Hydrochloric acid (1.2 ml) was added to a solution of
(2)-2 (0.6 g, 1.80 mmol) in methanol (50 ml) and the
mixture was stirred at room temperature for 24 h. The
solvent was evaporated to afford (þ)-3 as a white solid
in quantitative yield. Mp 143–146 8C (from water);
[a]D þ 26.78 (c 0.34 in MeOH); n (KBr)/cm21 3444,
3352, 3315, 1736, 1651; lmax (MeOH) 204 (log e 4.00)
and230(loge 4.00); dH (DMSO-d6)1.09(d, J5.27, 1H,
CH2cyclopro), 1.70 (d, J 5.25, 1H, CH2cyclopro), 3.47 (t,
1H, CH, superimposed with CH2OH), 3.48 (1H) and
3.59 (1H) (2 £ dd, CH2, superimposed with OCH3 and
CH2OH), 3.58 (s, 3H, OCH3), 5.07 (d, J 4.37, 1H,
CHOH), 5.61 (t, J 3.65, 1H, CH2OH), 7.48–7.74 (m,
5H,C6H5),8.86(s,1H,NH);dC(DMSO-d6)10.89(C2–
C H3), 28.36 (C3), 32.18 (C2), 42.39 (C1), 52.07
(OCH3), 61.93 (C50), 73.49 (C40), 126.72, 128.09,
131.74 and 133.69 (C–Ph), 166.33 (CO–amide), 171
(CO–ester); m/z (EI) 294.3 (MHþ); Anal. calcd for
C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found: C,
61.34; H, 6.59; N, 4.68.
Methyl (-)-(1S, 2R)-1-benzamido-2-((S)-1,2-dihy-
droxyethyl(cyclopropanecarboxylate (7) and methyl
(2)-(1S, 2R)-1-benzamido-2-formylcyclopropane-
carboxylate (8) were prepared following the
procedure given in the literature [6]. The spectro-
scopic data were in agreement with the reported
ones.
4.2. X-ray structure determination
Single crystals suitable for X-ray structure
analysis were prepared by growth under slow
evaporation at room temperature of a very dilute
ethanol solution for the compounds (þ)-1 and (2)-
2 and water solution for the compounds (þ)-3 and
(2)-7. The intensities were collected at room
(^)-Methyl-2-benzamido-2,3-dihydro-4-methyl-2-
furancarboxylate.(6) A suspension of NaIO4
(0.133 g, 0.621 mmol) in water (3 ml) was added
dropwise to a stirred solution of (þ)-3 (0.174 g,

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´
Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
240
temperature on a Philips PW1100 diffractometer
updated by Stoe and Cie [32,33] using Mo-Ka
radiation. The crystal structures of all compounds
were solved by direct methods using SHELXS86
[34] program. All non-hydrogen atoms were refined
anisotropically by full-matrix least-squares calcu-
lations based on F 2 by application of SHELXL97
[35] program. The coordinates of hydrogen atoms
were included in structure factor calculations. The
carbon atoms C1 and C2 of the compound (2)-2
are disordered. The site occupancy factors are 57(4)
and 43(4)% for the atom C1 and 53(4) and 47(4)%
for the atom C2. The distances between occupation
sites of the0 disordered atoms C1 and C10 and atoms
The molecular and crystal structure drawings were
prepared by ORTEP-3 [36] and PLUTON93 [37]
programs. Crystal data, data collection and refine-
ment for the compounds (þ)-1, (2)-2, (þ)-3 and
(2)-7 are summarized in Table 5. Crystallographic
data excluding structure factors for the structures
(þ)-1, (2)-2, (þ)-3 and (2)-7 reported in this
paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary
publication numbers CCDC-167403, CCDC-
167404, CCDC-167405 and CCDC-167406. Copies
of data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ 44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk].
˚
C2 and C2 are 0.72(4) and 0.77(4) A, respectively.
Table 5
The crystal data, data collection and refinement for the compounds (þ)-1, (2)-2, (þ)-3 and (2)-7
Compound
(þ)-1
(2)-2
(þ)-3
(2)-7
Formula
C17H19NO4
301.33
C18H23NO5
333.37
C15H19NO5
293.31
C14H17NO5
279.29
Formula weight
Temperature [K]
Crystal size [mm]
Crystal colour
Crystal system
Space group
295
295
293
295
0.50 £ 0.45 £ 0.40
colourless
monoclinic
P21
0.70 £ 0.50 £ 0.45
colourless
monoclinic
P21
0.89 £ 0.42 £ 0.15
colourless
monoclinic
P21
0.50 £ 0.40 £ 0.35
colourless
monoclinic
P21
˚
a[A]
˚
b[A]
˚
c[A]
5.725(1)
10.609(2)
13.186(3)
93.15(1)
799.7(3)
2
5.239(1)
14.998(3)
11.377(2)
100.56(1)
878.8(3)
2
11.078(6)
7.570(4)
18.544(12)
102.57(6)
1517.8(15)
4
13.530(3)
6.479(1)
15.489(3)
90.43(1)
1357.7(5)
4
b[8]
3
˚
V [A ]
Z
D
calc.[gcm23
]
1.251
1.260
1.284
1.366
m[mm21
F(000)
]
0.089
0.092
0.097
0.104
320
356
624
592
Scan-mode
v
v–u
v
v
u range for data collection [8]
Index ranges
3.09 to 28.98
27 # h # 7
214 # k # 14
217 # l # 17
4410
2.27 to 27.91
26 # h # 6
219 # k # 19
214 # l # 14
4302
3.23 to 28.04
214 # h # 14
29 # k # 9
221 # l # 24
7727
3.01 to 29.01
218 # h # 18
28 # k # 8
221 # l # 21
7785
Collected reflections
Independent reflections/Rint.
Reflection number I ^ 2s(I)
Refinement method
Data/restrains/parameters
Weighting parameters a,ba
Goodness-of-fit on F 2
R [I ^ 2s(I)]
4197/0.0739
2183
4147/0.0833
7226/0.0535
7167/0.0761
4658
3407
2917
Full-matrix least-squares on F2
2183/1/200
0.1000, 0
0.935
3407/1/239
0.0803, 0.1136
1.018
2917/1/400
0.0697, 0
0.824
4658/1/372
0.1000, 0
1.108
0.0581
0.0449
0.0437
0.0630
WR
0.1350
0.1205
0.1020
0.1518
23
˚
Max.min. elect. dens. [eA
]
0.315/ 2 0.268
0.220/ 2 0.176
0.219/ 2 0.177
0.479/ 2 0.444
w ¼ 1/[s 2(F2o) þ (aP)2 þ bP], where P ¼ (Fo2 þ 2F2c)/3.
a

ˇ
´
Z. Dzolic et al. / Journal of Molecular Structure 655 (2003) 229–241
241
[10] M.L. Martinez, F.H. Cano, S. Garcia-Blanco, Acta Crystal-
logr. B34 (1978) 593.
Acknowledgements
[11] C. Cativiela, M.D. Diaz-de-Villegas, J.A. Galvez, A.I.
Jimenez, M.P. Lopez, Acta Crystallogr. C52 (1996) 3210.
[12] F.H. Allen, Acta Crystallogr. B36 (1980) 81.
[13] F.H. Allen, Acta Crystallogr. B37 (1981) 890.
This study was performed in the framework of the
COST Chemistry Action D-13 Programme: New
molecules towards human health. We are grateful to
the Ministry of Science and Technology of Croatia for
support of this work through a grant to M.M.(Project
Number 0125003). M.M. is also grateful to Prof. Gerd
Folkers and Prof. Leonardo Scapozza for giving him
the opportunity to spend a sabbatical stay at the
Institute of Pharmaceutical Sciences ETH Zu¨rich.
ˇ
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