Synthesis, structural characterization and conformational aspects of nostoclide analogues

Article abstract of DOI:10.1016/j.molstruc.2008.06.019

The synthesis and structural analysis of a set of nostoclide analogues with potential herbicide activity is described. The influence of intra- and intermolecular hydrogen bonding, as well as other interactions on the conformation and packing of the compounds is thoroughly described using DFT calculations and single crystal X-ray diffraction analyses. All lactones exhibited the Z configuration as confirmed by NOESY experiments and by single crystal X-ray diffraction measurements.

Full text of DOI:10.1016/j.molstruc.2008.06.019

Journal of Molecular Structure 917 (2009) 1–9
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, structural characterization and conformational aspects
of nostoclide analogues
c
d
d
e
R.R. Teixeira a,b, L.C.A. Barbosa a, , J.W.de M. Carneiro , R.S. Corrêa , J. Ellena , A.C. Doriguetto
*
a Department of Chemistry, Federal University of Viçosa, Avenida P.H. Rolfs, CEP 36570-000, Viçosa, MG, Brazil
b Chemistry Department, Federal University of Minas Gerais, Avenida Antônio Carlos, 6627, CEP 31270-9001, Belo Horizonte, MG, Brazil
c Inorganic Chemistry Department, Fluminense Federal University, Outeiro de São João Batista, s/n, Centro, CEP 24020-141, Niterói, RJ, Brazil
d São Carlos Physics Institute – USP, Cx. postal 369, CEP 13560-970, São Carlos, SP, Brazil
e Department of Exact Science, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, CEP 37130-000, Alfenas, MG, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 April 2008
Received in revised form 18 June 2008
Accepted 20 June 2008
Available online 26 June 2008
The synthesis and structural analysis of a set of nostoclide analogues with potential herbicide activity is
described. The influence of intra- and intermolecular hydrogen bonding, as well as other interactions on
the conformation and packing of the compounds is thoroughly described using DFT calculations and sin-
gle crystal X-ray diffraction analyses. All lactones exhibited the Z configuration as confirmed by NOESY
experiments and by single crystal X-ray diffraction measurements.
Ó 2008 Elsevier B.V. All rights reserved.
Keywords:
Nostoclide analogues
c
-Alkylidenebutenolides
DFT calculation
X-ray analysis
Herbicides
1. Introduction
ricyanide by isolated spinach chloroplasts [9]. Several compounds
exhibited inhibitory properties in the micromolar range against
Marine organisms are capable of producing a myriad of structur-
ally diverse secondary metabolites [1]. More than 17,000 com-
pounds have been described from marine sources [2] including
compounds from polar habitats [3]. Alongside exploring the diver-
sity found among the marine natural products for drug development
[4], these metabolitescanalsobe exploredeitheras herbicidesor no-
vel lead structures towards the development of weed controllers [5].
The metabolites known as nostoclides (1) (Fig. 1) were first iso-
lated in 1993 by Yang and co-workers. They are produced by a cya-
nobacterium (or blue-green algae; Nostoc sp.), which can live free
or in symbiosis, for instance, in the lichen Peltigera canina [6],
the basal electron flow from water to K3[Fe(CN)6]. Moreover, sev-
eral of the synthesized analogues were submitted to in vitro eval-
uation against different cancer cell lines using the MTT assay.
Some of the evaluated compounds exhibited moderate cytotoxicity
against at least one of the cell lines [10].
In addition to biological property studies, we have also been
interested in the molecular properties of the nostoclide analogues.
In a previous paper [11], a combined study using XRD techniques
and DFT calculations was carried out to characterize two nostoclide
analogues [compounds (5) and (6), Fig. 1] namely 5(Z)-3-benzyl-5-
(1,3-dioxalanebenzylidene)furan-2(5H)-one (5) and 5(E)-3-benzyl-
5-(2,4,6-trimethoxybenzylidene)furan-2(5H)-one (6). In order to
get further insight into the molecular properties of this type of lac-
tone, we conducted an investigation on a series of nostoclide ana-
logues employing a combination of NMR analyses, DFT calculations
and XRD techniques. Herein we describe the results of this
investigation.
and belong to a family of compounds know as c-alkylidenebuteno-
lides [7]. The nostoclides (1) resemble the substance cyanobacterin
(2) (Fig. 1), a lactone that is capable of inhibiting the photosyn-
thetic electron transport in isolated chloroplasts [8].
Because of the structural similarity between the nostoclides (1)
and cyanobacterin (2), we have considered the former as a poten-
tial new lead for herbicide development. As a consequence, a vari-
ety of nostoclide analogues [general structures (3) and (4), Fig. 1]
have been synthesized. Their biological activities were evaluated
in vitro as the ability to interfere with light-driven reduction of fer-
2. Experimental
2.1. Materials and methods
All reactions were carried out under a protective atmosphere
of dry nitrogen. Dichloromethane, tetrahydrofuran (THF), diethyl
* Corresponding author. Tel.: +55 31 3899 3068; fax: +55 31 3899 3065.
E-mail address: lcab@ufv.br (L.C.A. Barbosa).
0022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2008.06.019

2
R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
Cl
OH
O
X
O
O
O
O
O
O
O
HO
R
R
Cl
OMe
(3): X = Br
(4): X = H
Nostoclides (1)
Cyanobacterin (2)
MeO
OMe
O
O
O
O
MeO
(6)
O
O
(5)
Fig. 1. Structures of nostoclides (R = Cl, nostoclide I; R = H, nostoclide II), cyanobacterin and nostoclide analogues.
ether, and amines were purified as described by Perrin and
Armarego [12]. Commercially tert-butyldimethylsilyltrifluoro
methanesulfonate (TBDMSOTf), 8-diazabyciclo [5.4.0] undec-7-
ene (DBU), and phosphoryl chloride (POCl3) were purchased
from Aldrich and used without further purification. The com-
pound 3-bromobenzaldehyde was prepared from the corre-
sponding commercially available (Aldrich) benzylic alcohol by
Swern oxidation [13]. Other aldehydes were purchased from Al-
drich and used without further purifications. The preparation of
the silylenol ethers from 2-hydroxybenzaldehyde and 3-
hydroxybenzaldehyde was carried out by methodology previ-
ously described [14]. Lactone (7) was synthesized employing
methodology described by Näsman [15]. Commercially available
n-butyllithium hexane solutions (1.6 mol Lꢀ1) were titrated prior
to use [16]. The 1H and 13C NMR spectra were recorded on Bruc-
ker AVANCE DRX 400 spectrometer at 400 and 100 MHz. Mass
spectra were recorded on a SHIMADZU GCMS-QP5050A instru-
ment under electron impact (70 eV) conditions. IR spectra were
taken from Perkin Elmer Paragon 1000 FT-IR spectrophotometer,
using potassium bromide (1% v/v) disks, scanning from 400 to
4000 cmꢀ1. Melting points are uncorrected and were obtained
from MQAPF-301 melting point apparatus (Microquimica,
Brazil). Analytical thin layer chromatography analysis was
conducted on aluminum packed precoated silica gel plates. Col-
umn chromatography was performed over silica gel (60–230
mesh).
After separation, the organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure. The resulting material
was purified by column chromatography on silica gel eluted with
hexane-dichloromethane (2:1 v/v) to afford compound (10) as a
white solid in 66% yield (156 mg, 0.57 mmol).
Compounds (11) and (12) were prepared employing a similar
procedure to that described for compound (10) using 3-bromo-
benzaldehyde and 2-chloro-4-(N,N-dimethylamino)benzaldehyde
to yield compounds (11) and (12), respectively, as presented in
Fig. 2. Spectroscopic data for compounds (10–12) are available in
Supplementary material.
2.3. Synthesis of 5(Z)-3-benzyl-5-(3-hydroxybenzylidene)furan-2(5H)-
one (13)
A 25 mL round bottom flask, under nitrogen atmosphere, was
charged with 3-tert-butyldimethylsilyloxybenzaldehyde (0.243 g,
1.03 mmol), 3-benzylfuran-2(5H)-one (7), (150 mg, 0.86 mmol),
anhydrous
1.03 mmol) and diisopropylethylamine (450
resulting mixture was stirred at room temperature for 1 h and
after some time DBU (260 L, 1.72 mmol) was added. The reaction
dichloromethane
(4 mL),
TBDMSOTf
(250 lL,
lL, 2.58 mmol). The
l
mixture was then refluxed for a further 3 h before addition of
dichloromethane (70 mL). The resulting organic layer was washed
with 3 mol Lꢀ1 aqueous HCl solution (2 ꢁ 25 mL) and brine
(25 mL). After separation, the organic layer was dried over MgSO4,
filtered, and concentrated under reduced pressure to afford pale
yellow oil. To this oil, placed in a plastic flask, was added 3 mL
of MeCN/HF (1:1 v/v) solution. The resulting mixture was stirred
at room temperature for 3 h and then transferred to a separatory
funnel containing ethyl acetate (80 mL). The layers were sepa-
rated and the organic layer was washed with saturated sodium
bicarbonate solution (3 ꢁ 25 mL). The aqueous extracts were com-
bined and the resulting aqueous layer was extracted with ethyl
acetate (2 ꢁ 50 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The resulting crude product material was purified by silica gel col-
umn chromatography eluted with hexane–ethyl acetate (2:1 v/v)
2.2. Synthesis of (5Z)-3-benzyl-5-(3-methylbenzylidene)furan-2(5H)-
one (10)
To a two-neck round bottom flask, under nitrogen atmosphere,
were added 3-benzylfuran-2-(5H)-one (7) (150 mg, 0.86 mmol),
anhydrous dichloromethane
1.03 mmol), diisopropylethylamine (450
ualdehyde (124 mg, 1.03 mmol). The resulting mixture was stirred
at room temperature for 1 h. After adding DBU (260 L, 1.72 mmol),
(4 mL), TBDMSOTf (250
lL,
lL, 2.58 mmol) and m-tol-
l
the reaction mixture was refluxed for an additional 3 h and dichloro-
methane(70 mL)wasadded. Theresultingorganiclayerwaswashed
with 3 mol Lꢀ1 HCl aqueous solution (2 ꢁ 25 mL) and brine (25 mL).

R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
-BuLi, THF, -78 o
r.t.
3
1.
n
C
1. POCl3, Et3N,
CH2Cl2, r.t.
2. Benzyl bromide, THF,
O
P
NEt2
-78 o
r.t.
C
O
NEt2
O
O
O
O
O
3. Formic acid, r.t.
2.Et2NH, Et2O,
-20 o
C
35 o
C
(7)
TBDMSOTf, DIPEA,
CH2Cl2, r.t.
OTBDMS
(8)
O
CHO
R
i or ii
TBDMSO
O
O
Ar
O
O
(10-14)
R
(9)
Compound Ar Group
Yield*(%)
10
11
12
13
14
3-methylphenyl
3-bromophenyl
66
33
16
78
74
2-chloro-4-dimethylaminophenyl
3-hydroxyphenyl
2-hydroxyphenyl
7
*Yields based on compound ( )
Fig. 2. Scheme for the synthesis of the nostoclide analogues (10–14). (i) DBU, CH2Cl2, reflux (compounds 10, 11, and 12), (ii) DBU, CH2Cl2, reflux then MeCN/HF (1:1)
(compounds 13 and 14).
to afford compound (13) as a yellow solid in 78% yield (187 mg,
0.67 mmol).
Compound (14) was prepared employing a similar procedure to
that described for compound (13) and yield is presented in Fig. 2.
Spectroscopic data for compounds (13) and (14) are available in
Supplementary material.
Crystals of compounds (10–14) were obtained by gently warm-
ing each compound in hexane, followed by addition of dichloro-
methane dropwise until the solid was completely dissolved. The
resulting solution was left undisturbed at room temperature. After
24 h, white [prisms for compound (10); needles for compound
(11)] and yellow [prisms for compounds (12–14)] crystals, suitable
for X-ray analyses, were formed. They were separated, washed
with cold hexane, and dried.
the software Denzo-SMN and Scalepack [18]. Since the absorp-
tion coefficient is insignificant for (10), (13), and (14) (Table 1),
no absorption correction was applied. For compounds (11) and
(12), it was applied the analytical method [19]. The structure
was solved using the software SHELXS-97 [20], and refined using
the software SHELXL-97 [21]. Non-hydrogen atoms of the mole-
cules were clearly solved and full-matrix least-squares refine-
ment of these atoms with anisotropic thermal parameters was
carried on. The CAH hydrogen atoms were positioned stereo-
chemically and were refined with fixed individual displacement
parameters [Uiso(H) = 1.2Ueq (Csp2) or 1.5Ueq (Csp3)] using a riding
model with aromatic CAH bond length of 0.93 Å, methyl CAH
one of 0.96 Å, and methylene CAH one of 0.97 Å. The hydroxyl
H atoms in (13) and (14) were located by difference Fourier syn-
thesis and were set as isotropic. Tables were generated by
WinGX [22] and the structure representations by ORTEP-3 [23]
and MERCURY [24]. In spite of being non-centrosymmetric space
groups, the Flack parameter was not refined during the X-ray
crystallographic analysis for (10) and (14). The most electron-
rich atom is oxygen, which did not have anomalous scattering
2.4. X-ray Crystallography
Suitably sized clear crystals of the lactones (10–14) were se-
lected for the X-ray diffraction experiments and the intensity
data were measured at room temperature (298 K) for com-
pounds (10), (12), (13), and (14) and at 150 K for compound
large enough (using MoKa radiation) to permit determination
(11) with MoK
chromator, using the Enraf–Nonius
cell refinements were performed using the software Collect
[17] and Scalepack [18], and the final cell parameters were
obtained on all reflections. Data reduction was carried out using
a
radiation (k = 0.71073 Å) from a graphite mono-
-CCD diffractometer. The
of the absolute structure present by X-ray diffraction. Therefore,
Friedel pairs were averaged before refinement, which justify the
poor relationship reflection/parameters for (10) and (14). The
main crystal, collection and structure refinement data for com-
pounds (10–14) are summarized in Table 1.
j

4
R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
Table 1
Crystal data and structure refinement for nostoclide derivatives (10–14)
Compounds
10
11
12
13
14
Empirical formula
Formula weight
Temperature
C19H16O2
276.32
298(2)
C36H26Br2O4
682.39
150(2)
C20H18Cl1N1O2
339.80
298(2)
C18H14O3
278.29
298(2)
C18H14O3
278.29
298(2)
Crystal system
Space group
Orthorhombic
P212121
Orthorhombic
Pca21
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
P21
Unit cell (Å, °)
a = 6.1227(4)
b = 13.7737(6)
c = 17.601(1)
a = 13.3625(4)
b = 6.0659(2)
c = 35.270(1)
a = 12.6814(5)
b = 6.7234(3)
c = 20.848(1)
b = 105.367(3)
a = 13.7492(5)
b = 6.7967(3)
c = 15.4538(6)
b = 93.946(2)
a = 6.3571(4)
b = 7.5692(5)
c = 14.9216(9)
b = 99.303(4)
Volume (Å3)
1484.3(2)
4
1.236
2858.8(2)
4
1.585
1714.0(1)
4
1.317
1440.7(1)
4
1.283
708.56(8)
2
1.304
Z
Density (Mg/m3)
l
(mmꢀ1
)
0.079
2.877
0.234
0.087
0.088
F(000)
584
1376
712
584
292
Crystal size (mm3)
h Range (°)
0.05 ꢁ 0.17 ꢁ 0.23
3.18 to 27.53
7316
1946
0.0459
0.03 ꢁ 0.05 ꢁ 0.31
3.05 to 25.68
24302
5398
0.0811
0.14 ꢁ 0.25 ꢁ 0.29
2.94 to 26.02
12518
3326
0.0579
0.06 ꢁ 0.15 ꢁ 0.20
2.97 to 27.46
17530
3057
0.0639
0.08 ꢁ 0.10 ꢁ 0.14
3.25 to 26.59
8569
1558
0.0607
Reflections collected
Independent reflections
R(int)
Completeness to hmax
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices
98.6 %
1946/0/190
1.018
R1 = 0.0486,
wR2 = 0.1174
99.9%
5398/1/380
0.993
R1 = 0.0399,
wR2 = 0.0835
98.4%
3326/0/217
1.025
R1 = 0.0474,
wR2 = 0.1238
93.1%
3057/0/194
1.019
R1 = 0.0497,
wR2 = 0.1294
97.1%
1558/1/194
1.059
R1 = 0.0409,
wR2 = 0.0915
[I > 2r(I)]
R indices (all data)
R1 = 0.0834,
R1 = 0.0551,
R1 = 0.0828,
R1 = 0.0737,
R1 = 0.0624,
wR2 = 0.1381
0.158 and ꢀ0.167
wR2 = 0.0893
1.173 and ꢀ0.413
wR2 = 0.1398
0.232 and ꢀ0.242
wR2 = 0.1500
0.118 and ꢀ0.121
wR2 = 0.1026
0.117 and ꢀ0.115
D
qmax and D )
qmin (e Åꢀ3
The molecular conformation analyses of (10–14) were carried
Briefly, reaction of lactone (7), prepared as shown in Fig. 2, with
pertinent aldehydes in the presence of tert-butyldimethylsilyltri-
fluoromethanesulfonate and diisopropylethylamine followed by
treatment of the silyl ether generated in situ with DBU afforded
compounds (10–14) in yields ranging from 16% to 78% (Fig. 2). It
is important to note that in the preparation of compounds (13)
and (14), tert-butyldimethylsilyloxy aldehydes were employed.
After various attempts, the removal of the tert-butyldimethylsilyl
protecting group was achieved with a mixture of MeCN/HF
(1:1 v/v) [33].
out using the MOGUL [25], a knowledge base of molecular
geometry derived from the CSD-Cambridge Structural Database
that provides rapid access to information on the preferred values
of bond lengths, valence angles and acyclic torsion angles (see
Supplementary material) [26]. It was found that all bond lengths
and bond angles are in agreement with the expected values. The
main differences occurred in the acyclic torsion angles, which
are influenced either by intermolecular or intramolecular
forces.
Crystallographic data for the structures in this paper have been
deposited in the Cambridge Crystallographic Data Centre as a Sup-
plementary publication (10, CCDC 665352; 11, CCDC 665353; 12,
CCDC 665354; 13, CCDC 665355; 14, CCDC 665356). Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB12 1EZ, UK [fax: +44 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk].
The identity of the synthesized lactones (10–14) was confirmed
based on spectroscopic (NMR and IR) as well as spectrometric (MS)
data. The presence of the correlation peak from H4 and H6 in the
NOESY contour plots of the lactones led to the Z configuration
assignment concerning the exocyclic double bounds. This stereo-
chemical assignment was unambiguously confirmed by single
crystal X-ray diffraction. Table 1 summarizes the main crystallo-
graphic data for compounds (10–14).
2.5. Computational details
It is important to note that lactone (11) crystallizes in the non-
centrosymmetric space group Pca21 with two independent mole-
cules in the asymmetric unit hereafter labeled as (11A) and (11B)
(Fig. 3). Comparison of these molecules by the method of Kabsch
shown them to be very similar, related by improper non-crystal-
lographic symmetry (the approximate rotational matrix is
ꢀ1000-10 00-1) and with a root mean square deviation between
the 21 homologous atoms of 0.1 Å. These facts suggested that the
crystal could belong to a centrosymmetric space group, with just
one molecule per asymmetric unit. Closer scrutiny, however,
showed this not to be the case, since the affin transformation
(rotation + translation) relating the two moieties did not match
any of those belonging to another space group. The refined Flack
parameter observed for compound (11) is 0.48(1). Therefore,
compound (11) can be considered an inversion twin, which con-
sists of centrosymmetrically related crystalline domain. The sym-
metry operation relating domain structures is that of a center of
symmetry as highlighted by the method of Kabsch [34]. Hereafter,
since the intramolecular structure of (11A) and (11B) are very
To determine the most stable conformers for each derivative,
the semi-empirical AM1 procedure [27] was employed using the
conformer distribution subroutine of the TITAN software [28].
The six most stable, albeit not identical conformers in each case
were fully optimized at the DFT level using the B3LYP functional
[29] with the 6-31g(d) basis set [30]. Relative energies are given
at this level. Solvent effects were evaluated by reoptimization of
the geometries using the CPCM continuum solvation model [31],
again with the B3LYP/6-31g(d) combination. Solvent effects were
simulated in water and in n-heptane. All DFT calculations were car-
ried out using the Gaussian03W software package [32].
3. Results and discussion
As previously reported [11], the synthesis of compounds (10–
14) was accomplished via the vinylogous aldol reaction between
the silyloxy diene furan synthon and the appropriate aldehydes.

R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
5
Fig. 3. ORTEP-3 view of (11) showing the molecules (11A) and (11B). The intramolecular H bond and the halogen-
line. Symmetry code: x, y+1, z.
p-aril intermolecular contacts are shown as single dotted
i
similar (Fig. 3), only structure (11A) will be discussed in terms of
intramolecular geometry.
In spite of not having the property of chirality, the compounds
(10) and (14) spontaneously crystallized into the chiral space
group under the aforementioned re-crystallization conditions. In
fact, a number of space groups that strongly favors molecules with
symmetry C1 are chiral. Thus, an enantiomerically pure substance
can be obtained when a molecule that does not possess an inver-
sion centre or mirror plane crystallizes in a chiral space group.
However, any molecule (possessing any symmetry) may crystallize
in a chiral crystal structure [35], and there is hundreds of known
chiral crystal structures formed of achiral molecules [36]. Examin-
ing the space-group preference in the CSD [26] (updated JAN
2008), in which can be found more than 430,000 structures depos-
ited, it is noted that the majority of the organic compounds can be
found within one of three space groups, P21/c, P21 and P212121.
This skewed distribution, which contain the two chiral space
groups observed for (10) and (14), is related to the presence of spe-
cific symmetry elements within these space groups that, in turns,
optimize intermolecular interactions between neighboring mole-
cules [36].
Fig. 4. ORTEP-3 view of (10) showing the arbitrary atom labelling. Ellipsoids
represent 30% probability level. The intermolecular H bond is shown as single
dotted line.
motif appears to play an important role in the stabilization of the Z
isomer. For compound (6) (Fig. 1), the presence of the methoxy
groups attached to the ortho positions precludes the formation of
the hydrogen bond aforementioned leading to the adoption of
the E configuration.
It is important to note that (14) can be considered a donor-
acceptor
p-electron chromophore having conjugated bridges,
which is a requirement for molecular compounds to exhibit second
order non-linear optical (NLO) properties. More recently, organic
materials are under investigation since their potential NLO effi-
ciency is significantly higher than that of inorganic ones. Another
obligatory requirement for NLO materials is non-centrosymmetric
orientation of polar molecules in bulk samples [37]. This require-
ment might be achieved by creating acentric crystal structures,
which is considered a challenging goal in crystal engineering ap-
plied to crystalline NLO materials. Since this requirement is
achieved by the molecule (14), it can be considered a promising
chromophore for opto-electronic applications.
In the structural investigation carried out with compounds
5(Z)-3-benzyl-5-(1,3-dioxalanebenzylidene)furan-2(5H)-one (5) and
5(E)-3-benzyl-5-(2,4,6-trimethoxybenzylidene)furan-2(5H)-one (6)
(Fig. 1), it was demonstrated that the fact the isomers 5Z and 6E
are found within the solid state, is not the result of supramolecular
forces, but rather is due to the fact that these two structures being
the lowest energy forms [11]. In the present investigation, com-
pounds (10–14) were obtained as Z stereoisomers, as exemplified
in Fig. 4 for compound (10).
The NOESY experiments showed one important aspect with re-
spect to compounds (12) and (14). The expected NOE correlation
peak from H200 and H6 was not observed. It was hypothesized that
this fact should be related to a preferential conformation attained
by the compounds. In order to alleviate the non-bonding steric
repulsion between the O-1 electronic lone pairs and the X ortho
group, the aforementioned compounds preferentially attain con-
formation II (Fig. 5). In this conformation, the distance between
the hydrogen atoms H200 and H6 is longer when compared with
the corresponding distance in conformation I. Thus, the cross-peak
between these hydrogen atoms is not observed. To shed light on
this proposal, DFT calculations and XRD analyses were carried out.
DFT calculations, conducted with compounds (12) and (14), re-
vealed a divergent behavior in the gas phase. As predicted in the
case of (12), steric interactions (or Pauli repulsion) between the
two electronegative chlorine and oxygen atoms strongly destabi-
lize conformation I (Fig. 5) by 6.8 kcal molꢀ1. On the other hand,
in the case of the hydroxyl substituted derivative (14), conforma-
tion I is more stable than conformation II by 1.7 kcal molꢀ1. In this
case, a strong hydrogen bond between the hydrogen of the hydro-
xyl group and the oxygen atom of the lactone group is responsible
for this preferential stabilization. This order of stability is contrary
to that found in the solid state by crystallographic XRD analyses
The weak non-classical intramolecular hydrogen bond involv-
ing C6AH6. . .O2, shown in Fig. 4 (single dotted line), is a common
feature for all the remaining structures investigated (Table 2) as
well as for compound (5) (Fig. 1). Therefore, this hydrogen-bonding

6
R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
Table 2
Main hydrogen bonding for nostoclide derivatives (10–14) (Å,°). Others non-classical
H bonds that stabilized the packing are shown in the Supplementary material figures
Lactone
DAH...A*,
H...A
D...A
DAH...A
10
11A
12
12
12
13
13
14
14
14
14
C6AH6...O2
C6AH6...O2
2.340
2.380
2.420
2.564
2.608
2.320
1.853
2.310
1.810
2.962
3.075
2.970(4)
3.009(6)
3.012(2)
3.393(2)
3.343(2)
2.957(2)
2.802(2)
2.955(4)
2.787(4)
3.674(4)
3.827(4)
124
125
122
149
136
125
169
126
167
135
139
C6AH6...O2
C7AH7...O1i
C9AH9...O1i
C6AH6...O2
O3AHO3...O1i
C6AH6...O2
O3AHO3...O1ii
C14iiiAH14iii...Ct
C17ivAH17iv...Ct
DAH is equal to 0.93 and 0.96 Å for CAH and OAH, respectively.
Symmetry codes for (12), (13), and (14) as in Figs. 7, 10, and 11, respectively.
*
Fig. 6. ORTEP-3 view of (12) showing the arbitrary atom labelling. Ellipsoids
represent 30% probability level. The intramolecular H bond is shown as single
dotted line.
5'
3'
5'
7
2
7
1'
1'
B
B
4
4
compounds (12) and (14) is at least for the most part due to intra-
molecular effects. However, it is well know that molecular shape
does not necessarily manifest itself in a predictable manner in
the crystalline lattice either in terms of intra or intermolecular
geometry [35]. Indeed, since each crystal structure is the result
of a delicate balance between a range of intermolecular forces, they
may play significant role in stabilization of the conformer II. For in-
stance, the formation of the chain along [010] stabilized by bifur-
cated intermolecular H bond for compounds (12) can also affect
the molecular conformation (Fig. 7).
2
3'
H
H
A
6
A
6
O
O
O
O
1"
1"
X
H
H
X
5"
R3
C
C
3"
R1
5"
3"
R1
R3
R2
R2
Conformation I
Conformation II
The lactones (10,11) and (13,14) are almost flat regarding the
molecular moiety containing the atoms that form the rings A and
C, including O1, C7, C12, and all non-hydrogen atoms present in
the substituted C ring, as exemplified in Fig. 4 for compound
(10). The largest deviations from the least-square plane through
the two-ring system are 0.059(2), ꢀ0.119(5), 0.126(2), and
ꢀ0.1105(2) Å for compounds (10), (11), (13), and (14) respectively.
The observed dihedral C8–C7–C1–C2 angles are ꢀ1,7 (4) [com-
pound (10)], 2.6 (10) [compound (11)], 1.4 [compound (13)], and
5.7 (5) [compound (14)]. These results are in good agreement with
DFT calculations which shows that in the most stable conforma-
tion, the C5–C6–C100–C200(600) dihedral angle is near or equal to
0.0°. The extended electron delocalization and the weak non-clas-
sical intra-molecular hydrogen bond involving C6AH6. . .O2 (Table
Fig. 5. Two preferential conformations (I and II) for compounds (12) (X = Cl;
R1 = R3=H; R2 = NMe2) and (14) (X = OH; R1 = R2 = R3 = H).
(vide infra). One reason to this divergence may be found in the
medium effect, although supramolecular interactions in the solid
state may also operate. Therefore we decided to calculate solvent
effects on the relative stability of the several conformations.
Solvent effects were calculated in both polar (water) and non-
polar (n-heptane) solvents. While differential solvation effects are
negligible for compound (12), with both solvents changing relative
stabilities by no more than 0.4 kcal molꢀ1, for compound (14), the
solvent effect is relatively large. Even in the non-polar solvent n-
heptane conformation II becomes more stable by 0.4 kcal molꢀ1
.
The preferential stabilization of conformation II is much stronger
in the case of the polar solvent water. In this solvent, conformation
II is more stable by 3.4 kcal molꢀ1 therefore completely reversing
the stability order. This result comes from differential solvation
of both conformers. While the solvation energy (in water) of con-
formation II is 16.8 kcal molꢀ1, for conformation I, it is only
11.7 kcal molꢀ1. Based on these results, we were led to conclude
that a hydrogen bond between the ortho hydroxyl substituent
and the lactone oxygen atom stabilizes conformation I in the gas
phase. This stabilization vanishes in a non-polar solvent, however,
and is reversed in the case of a polar solvent, where conformation
II is more stable.
The most stable conformer (Conformer II, Fig. 5) was found
within the crystal structure of compounds (12) and (14), as exem-
plified in Fig. 6 for compound (12). The presence of the most stable
conformer can be ascribed to the hindrance effect that keeps the
substituent away from O2 atom, and to the formation of the in-
tra-molecular hydrogen bond C6AH6. . .O2.
In spite of being very difficult to attribute structural features as
a function of only intramolecular forces, our results suggested that
the fact that conformation II is found within the solid state for
Fig. 7. ORTEP-3 view of (12) showing two neighboring molecules (symmetry code:
ix, yꢀ1, z). Ellipsoids represent 30% probability level. The intermolecular H bonds
are shown as single dotted line.

R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
7
bond lengths and bond angles found for compound (12) do not dif-
fer significantly when compared with the structures of the other
derivatives investigated regarding the moiety involving the dihe-
dral angle C8AC7AC1AC2 (see Supplementary material).
5'
3'
5'
7
7
2
1'
1'
B
B
4
4
2
3'
H
H
A
6
A
6
O
O
O
O
Similar to what was previously described for compounds (12)
and (14), two preferential conformers may be considered regarding
the orientation of the meta substituent attached to the C ring, one
with the substituent faced to the lactone ring, and the other one
with the substituent faced to the opposite direction (Fig. 8).
Regarding compound (10), DFT calculations found that there is
no remarkable energy difference between the conformers III and
IV. On the other hand, for compound (11) conformer IV is more sta-
ble by 0.3 kcal molꢀ1, while for compound (13) conformer III is
more stable by 1.0 kcal molꢀ1. Although the energy differences
are small, it is worth to note that the most stable conformer in each
case [compounds (11) and (13)] nicely fits the experimental X-ray
diffraction observation, as observed in Fig. 3 for compound (11).
Even though there is some agreement between the results
found by DFT calculations in gas phase and XRD analysis, it seems
that the presence of conformer III or IV (Fig. 8) in the crystal struc-
ture of compounds (10), (11), and (13) is a result of crystal packing
forces or intermolecular bonding motifs as depicted in Fig. 9 for
compound (11) [crystal packing figures for compounds (10) and
(13) can be found in the Supplementary material].
It is observed that the substituent attached to the C ring plays
an important role in the formation of the double chains for the
nostoclide derivatives (10) and (11). For compound (13), the for-
mation of a 16-fold ring, leading to a planar dimer, seems to be
responsible for the most stable conformer observed (Fig. 10).
The conformational behavior of nostoclide analogues (10–14) is
determined not only by rotation around the C100AC6 single bond
but also by rotation around the C3AC7 bond. The several conform-
ers obtained by rotation around the latter single bond have relative
energies that differ by less than 0.4 kcal molꢀ1. The gas-phase cal-
culations for the derivatives (10–14) showed that in the most sta-
1"
1"
H
H
H
H
5"X
C
C
3"
H
H3"
X 5"
H
H
Conformation III
Conformation IV
Fig. 8. Two preferential conformations for compounds (10), (11) and (13) (X = Me,
Br, and OH, respectively).
2) are the structural features responsible for maintaining the
coplanarity of the rings A and C.
Compound (12) is an exception to the generalization mentioned
above. In this case, the lack of planarity between the rings A and C
was attributed to the presence of the bulky chlorine atom attached
to the ortho position in the C ring, which gives rise to a hindrance
effect between neighbor molecules in the crystalline solid state
(Fig. 7). If all atoms in the rings A and C were in a plane, the inter-
molecular distance Cl. . .O2i (i = x, yꢀ1, z) would become very short,
0
< 3 ÅA. The chlorine and oxygen atoms have van der Waals radii
0
approximately equal to 1.90 and 1.50 ÅA, respectively [38]. Since
no hydrogen is present between these two electronegative atoms,
the distance Cl. . .O2 cannot fall below that expected from the van
der Waals radii sum (ꢂ 3.4 Å). As consequence, in spite of being
individually planar, the least-squares plane through the phenyl C
0
ring (Rms deviation of fitted atoms = 0.0058 ÅA) forms an angle of
19.2(1) with the least-square plane) passing thr0 ough the lactone
A ring (Rms deviation of fitted atoms = 0.0062 ÅA. In this way, the
0
chorine atom deviates 1.031(1) AÅ from the individual least-square
ble arrangement they assume
a conformation where the
C4AC3AC7AC10 dihedral angle is near or equal to 0.0°. This result
is significantly different from the results found by XRD analyses.
The observed dihedral angles are ꢀ25.1(4)° [compound (10)],
ꢀ91.4(8)° [compound (11)], ꢀ99.4(2)° [compound (12)], ꢀ28.5(3)°
plane through A ring resulting in a distance Cl...O2 equal to
0
3.496(2) ÅA, which is greater than the sum of their van der Waals ra-
dii. The break of the extended electron delocalization cannot be in-
voked to explain the aforementioned absence of planarity since the
Fig. 9. View of the double chain linked by halogen. . .p-aryl interaction parallel to [010] which stabilizes the packing of (11).

8
R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
along [100] direction, is linked by intermolecular non-classical
hydrogen bonds of the type H. . . -aryl. Considering compounds
p
(12) or (13), their double chains raise along the [010] direction.
In the case of compound (12), the double chain is stabilized
by the intermolecular hydrogen bonds of the type H. . .
between the methylic hydrogen of the dimethylamino group
(donor) and the acceptor of the B ring. Taking compound (13)
into consideration, the double chains are linked by the H. . . -aryl
interactions involving the hydrogen attached directly to the C ring
(donor) and the acceptor of the B ring.
p-aryl
p
p
p
Finally, in the case of compound (14), it forms an infinite chain
along the [101] direction in which the molecules are linked by the
classical hydrogen bond involving the hydroxyl group of the C ring
and the carboxyl group of the lactone ring (Fig. 11).
Different interactions involved in the formation of the double
chains and infinite chain can account for the different dihedral an-
gle values, between rings A and B, found by XRD analyses. In addi-
tion, non-classical hydrogen bonds, van der Waals interactions,
Fig. 10. View of the planar dimer of compound (13), which is linked by
intermolecular hydrogen bonds. Symmetry code: ꢀx + 1,ꢀy + 1, ꢀz.
i
and aromatic p–p stacking forces link the double chains together
stabilizing the packing along other crystallographic directions
and forming 2D and 3D infinite structural networks (all crystal
packing are available in the Supplementary material).
[compound (13)], and ꢀ27.4(4)° [compound (14)]. Another way to
analyze this structural feature can be made by looking at the angle
between the individual least-square planes through rings A and B.
It is observed that the unsubstituted phenyl B ring in the lactones
(10–14) adopts angles of 81.8(2) [compound (10)], 72.5(4)° [com-
pound (11)], 72.6(1)° [compound (12)], 77.9(1)° [compound (13)],
and 83.2(2)° [compound (14)] with the corresponding lactone
rings. The fact that the lowest energy form determined by DFT cal-
culations for the C9AC10AC12AC13 moiety (dihedral angle = 0.0°)
is not found within the solid state is the result of crystal packing
forces or intermolecular bonding motifs such as hydrogen bonds,
4. Conclusions
The structural investigation of a series of nostoclide ana-
logues using DFT calculations and single crystal XRD techniques
was carried out and the compounds were described in terms of
relevant inter- and intramolecular geometric features including
the stereoisomerism Z and E, and the conformers determined
by the substitution pattern in the benzylidene moiety. All lac-
tones exhibited the Z configuration, confirmed by bidimensional
NOESY experiments and by single crystal X-ray diffraction mea-
surements. The preferred conformer of the ortho substituted
benzylidene derivatives found within the crystal structure
showed the substituent in an anti-orientation in relation to the
lactone ring. For the meta-substituted analogues, although there
is some agreement between the results from DFT calculations in
the gas phase and XRD analyses, it seems that the preferential
conformation in the crystal structure is a result of crystal pack-
ing forces or intermolecular bonding motifs. The knowledge
gained from this investigation will aid in the analysis of new
compounds and, importantly, aid future exploration of struc-
aromatic p–p stacking, steric repulsion, and van der Waals forces.
One last point, regarding the crystal structures of the investi-
gated lactones, deserves comments. All nostoclide analogues, with
the exception of compound (14), form infinite double chains linked
in a head-to-tail fashion along specific crystallographic directions,
as depicted in Figs. 3 and 9 for compound (11). Considering (11),
the intermolecular force that stabilizes the double chain corre-
sponds to the halogen. . .p-0 aryl interaction (Br1. . .Ct02i = 3.515(5)
and Br2. . .Ct01 = 3.604(5) ÅA). This indicates that the independent
molecules (11A) and (11B) (Fig. 3) are linked together by halo-
gen. . .
p-aryl interactions. On the other hand, the double chain
found in the crystal structure of compound (10), which takes place
Fig. 11. View of the network of hydrogen bonds parallel to [110] which stabilize the packing of (14). Symmetry codes: i xꢀ1, yꢀ1, z; ii x+1, y+1, z; iii ꢀx+1, yꢀ1/2, ꢀz; iv ꢀx+2,
y+1/2, ꢀz. Ct is a centroid of the rings B.

R.R. Teixeira et al. / Journal of Molecular Structure 917 (2009) 1–9
9
[11] R.R. Teixeira, L.C.A. Barbosa, J.O. Santana, D.P. Veloso, J. Ellena, A.C. Doriguetto,
M.G.B. Drew, F.M.D. Ismail, J. Molec. Struct. 837 (2007) 197–205.
[12] D.D. Perrin, W.L.F. Armarego, Purification of Laboratory Chemicals, third ed.,
Pergamon, Oxford, 1988.
ture-activity relationships for ascertaining the nostoclide phar-
macophore and the binding requirements of the receptor.
[13] A.J. Mancuso, S.L. Huang, D. Swern, J. Org. Chem. 43 (1978) 2480.
[14] G.R. Pettit, M.P. Grealish, K. Jung, E. Harmel, R.K. Pettit, J.C. Chaput, J.M.
Schmidt, J. Med. Chem. 45 (2002) 2534.
[15] J.H. Näsman, Org. Synth. 6 (1990) 162.
[16] M.F. Lipton, C.M. Sorensen, A.C. Sadler, R.H. Shapiro, J. Organomet. Chem. 186
(1980) 155.
[17] Enraf-Nonius COLLECT, Nonius BV, Delft, The Netherlands, 1997-2000.
[18] Z. Otwinowski, W. Minor, in: C.W. Carter Jr., R.M. Sweet (Eds.), Methods in
Enzymology, vol. 276, Academic Press, New York, 1997, p. 307.
[19] C. Katayama, Acta Crystallogr. Sect A 42 (1986) 19.
[20] G.M. Sheldrick, SHELXS-97, Program for Crystal Structure Resolution,
University of Göttingen, Göttingen, Germany, 1997.
Acknowledgements
We thank the Brazilian Research Council CNPq (Conselho Nac-
ional de Desenvolvimento Científico e Tecnológico) for research
fellowships (LCAB, RRT, JWMC) and FAPEMIG (Fundação de Amparo
à Pesquisa do Estado de Minas Gerais) for financial support.
Appendix A. Supplementary data
[21] G.M. Sheldrick, SHELXL-97, Program for Crystal Structures Analysis, University
of Göttingen, Göttingen, Germany, 1997.
[22] L.J. Farrugia, J. Appl. Crystallogr. 32 (1999) 837.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2008.06.019.
[23] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565.
[24] I.J. Bruno, J.C. Cole, M. Kessler, J. Luo, W.D.S. Motherwell, L.H. Purkis, B.R. Smith,
R. Taylor, R.I. Cooper, S.E. Harris, A.G. Orpen, J. Chem. Inf. Comput. Sci. 44
(2004) 2133.
References
[1] J.W. Blunt, B.R. Copp, W-P. Hu, M.H.G. Munro, P.T. Northcote, M.R. Prinsep, Nat.
Prod. Rep. 24 (2007) 31.
[25] I.J. Bruno, J.C. Cole, P.R. Edgington, M.K. Kessler, C.F. Macrae, P. McCabe, J.
Pearson, R. Taylor, Acta Crystallogr. B58 (2002) 389.
[2] MarinLit Database, Department of Chemistry, University of Canterbury,
Canterbury, http://www.chem.canterbury.ac.nz/marinlit/marinlit.shtml.
[3] M.D. Lebar, J.L. Heimbegner, B.J. Baker, Nat. Prod. Rep. 24 (2007) 774.
[4] [a] C.-Y. Wang, M.-Y. Geng, H.-S. Guan, Chin. J. New Drugs. 14 (2005) 278;
[26] F.H. Allen, Acta Crystallogr. B58 (2002) 380.
[27] M.J.S. Dewar, E.G. Zoebisch, E.F. Healy, J.J.P. Stewart, J. Am. Chem. Soc. 107
(1985) 3902.
[28] TITAN, Wavefunction Inc., 1999.
[b] A.M.S. Mayer, M.T. Hamann, Comp. Biochem. Physiol. Part
Pharmacol. 140 (2005) 265;
[c] M.S. Butler, Nat. Prod. Rep. 22 (2005) 162;
[d] G.M. Cragg, D.J. Newman, Pure Appl. Chem. 77 (2005) 1923;
[e] G.M. Cragg, D.J. Newman, Pure Appl. Chem. 77 (2005) 7;
[f] H. Groos, Konig. Phytochem. Rev. 5 (2006) 115.
C
Toxicol.
[29] A.D. Beck, J. Chem. Phys. 98 (1993) 5648.
[30] P.C. Hariharan, J.A. Pople, Theor. Chim. Acta 28 (1973) 213.
[31] M. Cossi, N. Rega, G. Scalmani, V. Barone, J. Comput. Chem. 24 (2003) 669.
[32] GAUSSIAN03W, Revision C.02, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E.
Scuseria, M.A. Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery, R.E.
Stratmann, J.C. Burant, S. Dapprich, J.M. Millam, A.D. Daniels, K.N. Kudin, M.C.
Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C.
Pomelli, C. Adamo, S. Cli.ord, J. Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui, K.
Morokuma, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.
Cioslowski, J.V. Ortiz, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R. Gomperts, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y.
Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe, P.M.W. Gill, B. Johnson, W.
Chen, M.W. Wong, J.L. Andres, M. Head-Gordon, E.S. Replogle, J.A. Pople,
GAUSSIAN98 program, Gaussian Inc., Pittsburgh, PA, 2003.
[33] T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, third ed.,
Wiley, New York, 1990.
[5] [a] J. Peng, X. Shen, K.A.E. Sayed, D.C. Dunbar, T.L. Perry, S.P. Wilkins, M.T.
Hamann, J. Agric. Food Chem. 51 (2003) 2246;
[b] L.C.A. Barbosa, A.J. Demuner, C.R.A. Maltha, P.S. Silva, A.A. Silva, Quim. Nova
26 (2003) 655;
[c] L.C.A. Barbosa, A.V. Costa, D.P. Veloso, J.L.C. Lopes, M.G. Hernandez-
Terrones, B. King-Diaz, B. Lotina-Hennsen, Naturforsch 59c (2004) 803.
[6] Y. Xuemin, S. Yuzuru, J.R. Steiner, J. Clardy, Tetrahedron Lett. 34 (1993) 761.
[7] [a] E. Negishi, M. Kotora, Tetrahedron 53 (1997) 6707;
[b] R. Bruckner, Chem. Commun. (2001) 141;
[c] R. Bruckner, Curr. Org. Chem. 5 (2001) 679.
[8] [a] J.J. Pignatello, J. Porwoll, R.E. Carlson, A. Xavier, F.K. Gleason, J. Org. Chem.
48 (1983) 4035;
[34] W. Kabsch, Acta Crystallogr. A 32 (1976) 922.
[35] C.B. Aakeroy, Acta Crystallogr. B53 (1997) 569.
[b] T. Jong, P.G. Williard, J.P. Porwoll, J. Org. Chem. 49 (1984) 735;
[c] F.K. Gleason, J. Porwoll, J. Org. Chem. 51 (1986) 1615;
[d] F.K. Gleason, FEMS Microb. Lett. 68 (1990) 77.
[36] [a] E. Pidcock, W.D.S. Motherwell, J.C. Cole, Acta Crystallogr. B59 (2003) 634;
[b] H.D. Flack, Helv. Chim. Acta 86 (2003) 905;
[c] M. Cianci, J.R. Helliwell, M. Helliwell, V. Kaucic, N.Z. Logar, G. Mali, N.N.
Tusar, Crystallogr. Rev. 11 (2005) 245.
[37] [a] T.V. Timofeeva, V.N. Nesterov, R.D. Clark, B. Penn, D. Frazier, M.Y. Antipin, J.
Mol. Struct. 647 (2003) 181;
[b] D.R. Kanis, M.A. Ratner, T.J. Marks, Chem. Rev. 94 (1994) 195.
[38] J.E. Huheey, E.A. Keiter, R.L. Keiter, Inorganic Chemistry: Principles of Structure
and Reactivity, fourth ed., HarperCollins, New York, USA, 1993.
[9] [a] L.C.A. Barbosa, M.E. Rocha, R.R. Teixeira, C.R.A. Maltha, G. Forlani, J. Agric.
Food Chem. 55 (2007) 8562;
[b] R.R. Teixeira, L.C.A. Barbosa, G. Forlani, D.P. Veloso, J.W.de M. Carneiro, J.
Agric. Food Chem. 56 (2008) 2321.
[10] R.R. Teixeira, L.C.A. Barbosa, C.R.A. Maltha, M.E. Rocha, D.P. Bezerra, L.V.C.
Lotufo, C. Pessoa, M.O. Moraes, Molecules 12 (2007) 1101.