Synthesis, characterization and antiproliferative activity of β-aryl-ω-iodo-γ-lactones

Article abstract of DOI:10.1016/j.molstruc.2013.05.010

A convenient pathway for the synthesis of new of β-aryl-ω-iodo- γ-lactones is described. The synthetic route led to both cis and trans isomers which were separated by column chromatography or crystallization. The structures of synthesized compounds were confirmed by spectroscopic methods: IR, NMR and HR-MS. For lactones with naphthyl ring (6e and 7e) the crystal structures were also obtained. The lactones were screened for biological evaluation against cancer line HL-60 (human promyelocytic leukemia). The tests showed that the presence of substituent at the benzene ring does not significantly affect the antiproliferative activity of the compound.

Full text of DOI:10.1016/j.molstruc.2013.05.010

Journal of Molecular Structure 1047 (2013) 160–168
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, characterization and antiproliferative activity of
b-aryl-d-iodo-c-lactones
a
b
a
a
Alicja Wzorek a, , Barbara Gawdzik , Witold Gładkowski , Mariusz Urbaniak , Anita Baranska ,
⇑
´
c
c
d
d
´
´
´
Maura Malinska , Krzysztof Wozniak , Katarzyna Kempinska , Joanna Wietrzyk
a
´
Institute of Chemistry, Jan Kochanowski University, Swie˛tokrzyska 15 G, 25-406 Kielce, Poland
b Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
c Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warszawa, Poland
d Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Department of Experimental Oncology, Weigla 12, 53-114 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient pathway for the synthesis of new of b-aryl-d-iodo-c-lactones is described. The synthetic
Received 8 February 2013
Received in revised form 6 May 2013
Accepted 6 May 2013
route led to both cis and trans isomers which were separated by column chromatography or crystalliza-
tion. The structures of synthesized compounds were confirmed by spectroscopic methods: IR, NMR and
HR-MS. For lactones with naphthyl ring (6e and 7e) the crystal structures were also obtained. The lac-
tones were screened for biological evaluation against cancer line HL-60 (human promyelocytic leukemia).
The tests showed that the presence of substituent at the benzene ring does not significantly affect the
antiproliferative activity of the compound.
Available online 11 May 2013
Keywords:
Lactones
Iodolactonization
Crystal structure
Intermolecular interactions
Antiproliferative activity
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
2. Results and discussion
Compounds with a lactone ring are widespread in nature [1].
Their diversity is related to numerous functions in both animal
and vegetable kingdoms. For instance, they are responsible for aro-
mas and tastes of flowers and fruits [2] and also function as insects
antifeedants [3,4]. In the world of animals lactones are the compo-
nents of insect pheromones [5]. Furthermore, a great deal of com-
pounds containing lactone moiety with characteristic flavor and
fragrance can be found in food products [6] as well as in alcoholic
beverages [7].
Naturally occurring lactones display a wide range of biological
activities [8,9]. For instance, the lactones isolated from plant Gonio-
thalamus show cytotoxic activity against human liver cancer cell
lines (HepG2, HepG2-R) [10].
2.1. Synthesis
Several methods can be applied in the synthesis of lactones with
aromatic substituents [14]. Aromatic aldehydes are relatively cheap
substrates in these syntheses and they can easily be transformed to
lactones starting from aldol condensation with acetone [15].
In this work, we present another synthetic pathway using com-
mercially available aromatic aldehydes 1a–e as the starting mate-
rials. The synthetic route for the synthesis of b-aryl-d-iodo-
lactones is outlined in Scheme 1. In the first step aldehydes 1a–e
were converted into known ,b-unsaturated methyl esters 2a–e
by Doebner condensation with monomethyl malonate [16]. Spec-
troscopic data of the compounds obtained were in full agreement
with literature data [17]. The coupling constant between olefinic
protons (J = 15.9 Hz) confirmed the E configuration of double bond.
The yields of the products ranged from 42% to 94%. Selective reduc-
tion of the ester group in compounds 2a–e using lithium borohy-
dride (LiBH4) in diethyl ether afforded known [18] allylic alcohols
3a–e with the retention of E configuration of double bond. The
alcohols were obtained in yields 74–90%.
c-
a
Taking into consideration the fact that synthetic lactones have
also interesting biological properties as antifeedant [11], antimi-
crobial [12] or anticancer [13], the subject of our research was
the synthesis of new lactone compounds and evaluation of their
antiproliferative activities.
The Johnson–Claisen rearrangement of allylic alcohols 3a–e led
to four new (4a,b,d,e) and one known (4c)
c,d-unsaturated ethyl
⇑
Corresponding author.
E-mail address: awzorek@ujk.edu.pl (A. Wzorek).
esters [19]. The strong IR absorption band (1719 cmꢀ1 for 4a,
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.05.010

A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
161
COOMe
pyridine
COOMe
piperydine
LiBH4
R-CHO
1 a-e
+
Et2O, 0oC
R
COOH
OH
2 a-e
R
KOH/EtOH
MeC(OEt)3
EtCOOH 138oC
COOEt
R
3 a-e
4 a-e
O
O
R
I2/KI
O
O
COOH
+
NaHCO3
I
I
R
R
5 a-e
6 a-e
7 a-e
R
(a) 4-Cl-C6H4
(b) 4-CH3-C6H4
(c) 4-CH3O-C6H4
(d) 4-iPr-C6H4
(e) 1-C10H7
Scheme 1. Five-step synthesis of diastereoisomeric b-aryl-d-iodo-c-lactones 6a–e and 7a–e.
1718 cmꢀ1 for 4b, 1736 for 4d and 1732 cmꢀ1 for 4e) typical for the
stretching vibrations of the C@O bond in ester group, as well as
characteristic signals from the ethyl group (triplet at 1.18 ppm
and quartet at the range 4.08–4.11 ppm) confirmed the structure
of the products. Subsequent hydrolysis of the esters with ethanolic
KOH solution gave high yields pure carboxylic acids 5a–e. While
acids 5a–c were previously described in the literature [20], com-
pounds 5d–e were new ones. The confirmation of the presence of
free carboxyl group were two bands: one broad band in the range
of 2830–3036 cmꢀ1 from stretching vibrations of OAH bond and
the stretching vibrations band of C@O bond at 1712 cmꢀ1. No sig-
nals from the ethyl group were present in the 1H NMR spectra.
mixtures of lactones were separated by column chromatography
in the hexane–ethyl acetate as an eluent. In case of the reaction
of acid 5e having naphthyl ring, the lactones precipitated directly
from the reaction mixture during heating, therefore, ethyl acetate
was used for the extraction of the products as a replacement for
diethyl ether and the separation was conducted using methylene
chloride. The diastereoisomers of iodolactones obtained from acids
containing p-methylphenyl and p-methoxyphenyl ring (6b–c and
7b–c) had the same value of retention factors in all solvents tested.
We were able to separate these mixtures by applying the differ-
ence in solubility of both isomers. The pure cis isomers of lactones
(7b and 7c) precipitated from hexane–ethyl acetate (5:1) mixture
after 24 h cooling. After filtration of the cis isomer of lactone with
p-methyl substituted phenyl ring (7b), the filtrate contained pure
trans isomer (6b). In the case of mixture of lactones with p-
methoxyphenyl ring our attempts to isolate pure trans isomer
failed. The filtrate contained the mixture of both cis and trans iso-
mers in ratio 53:47 on the basis of 1H NMR analysis.
The final step of the synthesis was the iodolactonization of c,d-
unsaturated acids 5a–e carried out in the presence of I2 in KI in a
two-phase system: ethyl ether/NaHCO3 solution. In these alkaline
conditions, the mixtures of diastereoisomeric c-iodolactones: trans
(6a–e) and cis (7a–e) were formed.
In all cases, the cis isomers were the major ones making up 63–
72% of the product mixtures (Table 1). They were characterized by
lower value of Rf and lower solubility in solvents compared to the
trans isomers. After iodolactonization of acids 5a and 5d, the
Iodolactones 6–7a with chlorine substituent were previously de-
scribed in literature [21]. The structures of the new lactones 6–7b–e
were elucidated by detailed spectroscopic analysis and additionally
for both isomers of 4-(a-naphthyl)-5-iodomethyltetrahydrofuran-
2-one (6–7e) by X-ray diffraction studies. Crystal data and other
parameters related to data collection are summarized in Table 2.
The following crystal structures have been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposi-
tion numbers CCDC 849589 and 849590.
Table 1
The composition (%) of product mixtures after iodolactonisation of acids 5a–e
(according to GC analysis).
Substrate
Products
trans d-Iodo-
c
-lactones 6a–e
cis-d-Iodo-c-lactones 7a–e
Both isomers of lactone bearing naphthyl ring crystallize in the
monoclinic Pn and P21/c space groups, respectively, with one mol-
ecule in the asymmetric unit. The setting of hydrogen atoms H-3
and H-4 with respect to the lactone ring is the main difference be-
tween both isomers. In the case of bond lengths in lactone ring, the
difference is only for C4AC5 bond, which is 1.556(3) Å for the trans
5a
5b
5c
5d
5e
33.3
27.5
28.3
36.5
30.0
66.7
72.5
71.7
63.5
70.0

162
A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
Table 2
Experimental details of the crystallographic analysis for lactones 6e and 7e.
Parameter
trans-4-(
(6e)
a-Naphthyl)-5-iodomethyltetrahydrofuran-2-one
cis-4-(
(7e)
a-Naphthyl)-5-iodomethyltetrahydrofuran-2-one
Crystal data
Empirical formula
C
15H13IO2
C15H13IO2
Mr
352.15
352.15
Crystal system, space group
Monoclinic, Pn
Monoclinic, P21/c
Temperature (K)
a, b, c (Å)
b (°)
100
100
4.7978(3), 10.4518(7), 12.5179(9)
10.278(1), 10.957(1), 11.369(1)
97.690(4)
622.07(7)
2
100.897(2)
1257.3(2)
4
V (Å3)
Z
Radiation type
l
MoK
2.56
a
MoK
2.54
a
(mmꢀ1
)
Crystal size (mm)
0.20 ꢂ 0.20 ꢂ 0.02
0.20 ꢂ 0.10 ꢂ 0.10
Data collection
Diffractometer
Absorption correction
Kappa ApexII Ultra CCD diffractometer
Multi-scan SADABS2008/1 – Bruker Nonius area detector
scaling and absorption correction
0.628, 0.951
Kappa ApexII Ultra CCD diffractometer
Multi-scan SADABS2008/1 – Bruker Nonius area detector
scaling and absorption correction
0.631, 0.786
Tmin, Tmax
No. of measured, independent and
12,530, 2861, 2803
17,677, 2388, 2242
observed [I > 2r(I)] reflections
Rint
0.023
0.042
Refinement
R[F2 > 2 (F2)], wR(F2), S
r
0.014, 0.034, 1.10
0.020, 0.050, 1.07
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
2861
163
2
2388
163
0
H-atom parameters constrained
0.50, ꢀ0.21
H-atom parameters constrained
0.46, ꢀ0.32
D
imax,
D
imin (eÅꢀ3
)
Computer programs: Bruker SMART, Bruker SAINT, SHELXS97 (Sheldrick, 1990), SHELXL97 (Sheldrick, 1997), WinGX, Mercury, Bruker SHELXTL.
isomer 6e and 1.564(3) for the cis isomer (7e). The bend of the lac-
tone ring is bigger for the cis isomer 7e, for which the
O1AC2AC3AC4 torsion angle is 22.9(3)°. For the trans isomer 6e
the equivalent torsion angle is ꢀ14.4(3)°. In the crystal lattice of
the trans isomer 6e molecules interact by weak interactions e.g.
Cambridge Structural Database (CSD) for such interactions returns
15 hits defined by the following condition: R < 5%, only organic
contact distances ob-
tained for these hits are between 3.492 Å and 3.673 Å with the
average value 3.564 Å.
(CSD version 5.32, November 2010). The Iꢁ ꢁ ꢁ
p
weak CAHꢁ ꢁ ꢁO hydrogen bonds, CAHꢁ ꢁ ꢁ
p
and Iꢁ ꢁ ꢁ
p
interactions
Molecules of the cis isomer 7e form dimers which are connected
by two hydrogen atoms forming the 12-atom rings with the inver-
sion center at its center (Fig. 2; for the definition of symmetry
operators see the caption). The length of the CAHꢁ ꢁ ꢁO interaction
between O2ꢁ ꢁ ꢁC6#3 is 3.506(3) Å. Another interaction of this kind
also occurs between O2 and C40#2 with the length 3.465(3) Å.
The molecules also forms layers connected by weak hydrogen
and halogen bonds (I1ꢁ ꢁ ꢁI1#1). The contact distance between the
iodine atoms is 3.5657(4) Å. Interactions within the layer are more
(Fig. 1). The lengths of weak C80AH80ꢁ ꢁ ꢁO2#2 and C6AH6ꢁ ꢁ ꢁO2#2
hydrogen bonds is 3.384(4) Å and 3.266(3) Å respectively (for sym-
metry codes see the caption of Fig. 1). The CAHꢁ ꢁ ꢁO interactions oc-
cur also between the lacton ring O1 oxygen atom and the H4 #3
hydrogen atom from the neighboring molecule [3.401(3) Å]. Mole-
cules connected by the above interactions form molecular layers
connected by short Iꢁ ꢁ ꢁ
p interactions. The distance between I1
and the C50#1 atom in the phenyl ring is 3.508(2) Å. A search of
Fig. 1. (a) Visualization of interactions in the crystal lattice of the trans isomer 6e with labeled atoms and symmetry codes; #1 = (x, y ꢀ 1, z); #2 = (x ꢀ ½, 1 ꢀ y, ½ + z);
#3 = (1 + x, y, z); #4 = (½ + x, 2 ꢀ y, z ꢀ ½) and (b) packing of the trans isomer 6e structure along the Z-axis.

A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
163
Fig. 2. (a) Molecular structure and interaction in the crystal lattice in the cis isomer 7e structure with labeled atoms forming interactions and their symmetry codes;
#1 = (1 ꢀ x, ꢀy, ꢀz); #2 = (ꢀ1 ꢀ x, ꢀy, ꢀz); #3 = (1 ꢀ x, 1 ꢀ y, ꢀz); #4 = (2 ꢀ x, 1 ꢀ y, 1 ꢀ z) and (b) packing of the cis isomer 7e structure along the Y-axis.
hydrophobic with the predominant role of the
p
ꢁ ꢁ ꢁ
p
stacking. The
to quartet. Proton H-4 gave doublet of triplets at 4.67 ppm in case
of trans isomer 6e, while the signal from this proton in the spec-
trum of the cis isomer 7e appeared as triplet of doublets at
5.25 ppm.
shortest distance between the phenyl rings is 3.577(3) Å
(C100ꢁ ꢁ ꢁC80#4).
The analysis of the 1H NMR spectra of both iodolactonization
products shows the differences in chemical shifts of the protons
in the methylene group CH2AI. In both NMR spectra, the diastereo-
topic protons CH2AI give ABX system in which two doublets of
doublets at 3.39 ppm and 3.55 ppm for the isomer trans 6e and
at 2.75 ppm and 2.79 ppm for the isomer cis 7e are observed. The
signals of these protons observed in the spectrum of the trans iso-
The reason for various multiplicity of the signals discussed are
the values of dihedral angles between the corresponding bonds
which results in different coupling of the corresponding protons.
The chemical shift differences between the protons described
above are caused by different location of the naphthalene ring rel-
ative to the substituent linked to C-5 in both diastereoisomers. In
the case of lactone 7e, opposite to its trans isomer 6e, the protons
of the CH2AI group are located in the region of shielding cone of
the aromatic ring and their signals are shifted upfield. In turn, in
case of the trans isomer 6e, the H-3 and H-4 protons experience
a significant shielding effect due to the ring current of the aromatic
mer 6e are shifted downfield by
Dd = 0.64 ppm and Dd = 0.79 ppm,
respectively.
The characteristic differences have been also noted in the chem-
ical shifts and multiplicities of H-3 and H-4 protons. The signal of
the H-3 proton in the case of trans isomer 6e appeared at
4.35 ppm as triplets of doublets whereas for the cis isomer 7e this
signal was shifted downfield by 0.43 ppm and its shape was close
p
electrons. As a result, the absorption of these protons occurs in
the higher field compared to the spectrum of the cis isomer. The
Fig. 3. The crystal structure of the trans-4-(a-naphthyl)-5-iodomethyltetrahydrofuran-2-one (6e) with the atom numbering scheme.

164
A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
Fig. 4. The crystal structure of cis-4-(a-naphthyl)-5-iodomethyltetrahydrofuran-2-one (7e) with the atom numbering scheme.
location of aromatic ring in both diastereoisomers is illustrated by
crystal structures obtained for lactones 6e and 7e (Figs. 3 and 4).
The comparative analysis of the spectra 6e and 7e with the
spectra of other isolated products let us to identify the lactones
6a–d and 7a–d as trans or cis isomers, respectively.
3. Conclusion
The efficient and convenient method for the synthesis of new b-
aryl-d-iodo-c-lactones was described starting from commercially
available aromatic aldehydes. Detailed spectroscopic analysis (IR,
NMR, HR-MS) for all lactones was performed. For lactones 6e and
7e, X-ray crystal analysis was also carried out which showed
numerous weak interactions in their crystal lattices including
2.2. Antiproliferative activity
CAHꢁ ꢁ ꢁO hydrogen bonds, CAHꢁ ꢁ ꢁ
p
and Iꢁ ꢁ ꢁ
p interactions in 6e
The synthesized b-aryl-d-iodo-c-lactones were subjected to
and CAHꢁ ꢁ ꢁO and I(1)ꢁ ꢁ ꢁI(1) interactions in 7e. All the lactones
were screened for cytotoxic activity towards HL-60 cells. Synthesis
of next series of lactones with different electron-withdrawing or
electron-donating substituents at the aromatic ring in the search
of more sophisticated structure–activity correlation is in progress.
antiproliferative activity bioassays towards human promyelocytic
leukemia cells (HL-60) with carboplatin as the reference com-
pound. In order to evaluate influence of substituents in phenyl
group on compounds activity, both geometric isomers: 6f and 7f
with unsubstituted phenyl ring were synthesized according to
the procedure described in literature [22]. The isomers were suc-
cessfully separated by taking advantage of their differing solubili-
ties in acetone/hexane (4/1).
4. Experimental
The results are shown in Table 3.
4.1. General methods
The cytotoxicities of the lactones were about 10–20 times lower
than those observed for carboplatin. No significant differences in
activity between the compounds with different substituents at
the phenyl ring were observed. Synthesis of new series of the com-
pounds with other substituents is needed to search for more active
compounds.
All reagents used in this work were purchased from Fluka. NMR
spectra were recorded in solutions (CDCl3) on Bruker Avance DRX
300 spectrometer. Mass spectra were recorded on QTOF-II Bruker
with the electrospray (ESI) technique at the Structural Research
Laboratory of the UJK University. Melting points (uncorrected)
were recorded on a Boetius melting point instrument. IR spectra
were recorded on a Specord M-80 Carl Zeiss Jena Spectrometer.
Refractive indexes were determined on Carl Zeiss Jena
refractometer.
Table 3
Activity of b-aryl-d-iodo-
c
-lactones 6, 7a-f towards HL-60 cells.
Gas chromatography (GC) was performed on a Hewlett-Packard
5890 A II apparatus using DB-5 HT capillary column. The temper-
atures during GC analysis were as follows: injector 160 °C, detector
(FID) 300 °C, column temperature: 90 °C, 90–200 °C (rate 20 °C/
min), 200–320 °C (rate 30 °C/min), 300 °C (hold 1 min). Analytical
thin layer chromatography (TLC) was carried out on silica gel G
(Merck), various developing systems were applied. Compounds
were detected in the iodide chamber. Column chromatography
was performed on silica gel (Kieselgel 60, 230–400 mesh, Merck).
The crystallographic data were collected using the BRUKER
KAPPA APEXII ULTRA controlled by APEXII software [23], equipped
Compound
Substituent R
4-ClAC6H4
IC50 (lg/mL)
6a
7a
6b
7b
6c
7c
6d
7d
6e
7e
6f
7f
27.31 5.66
30.24 3.01
36.98 6.49
30.11 3.05
Not determined
58.30 7.10
29.69 3.98
28.71 4.93
46.78 5.56
69.74 4.24
31.36 4.67
38.43 6.31
2.9 0.1
4-CH3AC6H4
4-CH3OAC6H4
4-iPrAC6H4
1-C10H7
C6H5
with MoKa rotating anode X-ray source (k = 0.71073 Å, 50.0 kV,
Carboplatin
–
22.0 mA) monochromatized by multi-layer optics and APEX-II

A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
165
CCD detector. The experiments were carried out at 100 K using the
4.3. Reduction of esters 2a–e
Oxford Cryostream cooling device. The crystal was mounted on
Mounted CryoLoop with a droplet of Pantone–N oil and immedi-
ately cooled. Indexing, integration and initial scaling were per-
formed with SAINT [24] and SADABS [25] software (Bruker, 2008).
The data collection and processing statistics are reported in tables
for according structures.
In each data collection, the crystal was positioned at 50 mm
from the CCD camera. 600 frames were measured at 2° intervals
with a counting time of 2 s.
General procedure: A 2 M solution of LiBH4 in THF (16.5 mL) was
added dropwise to a solution of ester 2a–e (0.0165 mol) in anhy-
drous diethyl ether (50 mL) at 0 °C. The mixture was stirred at
room temperature for 16 h, poured onto ice and diluted HCl was
added carefully to quench the excess of hydride reagent. The aque-
ous and ethereal layers were separated. The aqueous layer was ex-
tracted three times with diethyl ether (15 mL). The combined
etheral solutions were washed with saturated brine, H2O, dried
over MgSO4 and concentrated in vacuo to give crude alcohols 3a–
e. After purification by column chromatography with hexane–ethyl
acetate (3:1) as eluent, pure alcohols 3a–e were obtained as color-
less oils. Their physical and spectral data were the same as re-
ported in literature [18].
The structures were solved by direct methods approach using
the SHELXS-97 [26] program and refined with the SHELXL-97
[27]. Multi-scan absorption correction have been applied in the
scaling procedure.
The refinement was based on F2 for all reflections except those
with negative intensities. Weighted R factors wR and all goodness-
of-fit S values were based on F2, whereas conventional R factors
were based on the amplitudes, with F set to zero for negative F2.
4.3.1. (E)-3-(p-chlorophenyl)prop-2-en-1-ol (3a)
Yield = 74%, 1H NMR (CDCl3) d: 1.77 (s, 1H, AOH), 4.32 (dd,
J = 5.4 Hz, 1.5 Hz, 2H, ACH2OH), 6.35 (dt, J = 15.9 Hz, 5.7 Hz, 1H,
@CHACH2A), 6.57 (dt, J = 15.9 Hz, 1.5 Hz, 1H, ArCH@), 7.28–7.29
(m, 4H, p-C6H4).
The F20 > 2
r
ðF20Þ criterion was applied only for R factors calculation
was not relevant to the choice of reflections for the refinement. The
R factors based on F2 are for all structures about twice as large as
those based on F. The hydrogen atoms were located in idealized
geometrical positions, except hydrogen in solvent molecule. Scat-
tering factors were taken from Tables 4.2.6.8 and 6.1.1.4 from the
International Crystallographic Tables, vol. C [28].
4.3.2. (E)-3-(p-methylphenyl)prop-2-en-1-ol (3b)
Yield = 90%, 1H NMR (CDCl3) d: 1.68 (s, 1H, AOH), 2.35 (s, 3H,
ACH3), 4.31 (dd, J = 5.7 Hz, 1.2 Hz, 2H, ACH2OH), 6.32 (dt,
J = 15.9 Hz, 5.7 Hz, 1H, @CHACH2A), 6.59 (d, J = 15.9 Hz, 1H,
ArCH@), 7.12–7.15 (m, 2H, p-C6H4), 7.23–7.30 (m, 2H, p-C6H4).
4.2. Doebner condensation [17]
General procedure: A mixture of aldehyde 1a–e (0.02 mol),
monomethyl malonate (0.04 mol, 4.72 g) in pyridine as a solvent
(10 mL), in the presence of catalytic amount of piperidine
(0.25 mL) was refluxed for 6 h. Then, the solvent was removed in
vacuo and the oily residue was purified by column chromatography
on silica gel with hexane–acetone (9:1) as eluent. According to this
procedure, pure esters 2a–e with good yields were obtained as a
colorless oils. Their physical and spectral data were in accordance
with those reported in the literature [16].
4.3.3. (E)-3-(p-methoxyphenyl)prop-2-en-1-ol (3c)
Yield = 85%, 1H NMR (CDCl3) d: 1.61 (s, 1H, AOH), 3.81 (s, 3H,
AOCH3), 4.29 (dd, J = 6.0 Hz, 1.2 Hz, 2H, ACH2OH), 6.23 (dt,
J = 15.9 Hz, 6.0 Hz, 1H, @CHACH2A), 6.84–6.87 (m, 2H, p-C6H4),
7.11 (d, J = 15.9 Hz, 1H, ArCH@), 7.31–7.34 (m, 2H, p-C6H4).
4.3.4. (E)-3-(p-isopropylphenyl)prop-2-en-1-ol (3d)
Yield = 81%, 1H NMR (CDCl3) d: 1.25 (d, J = 6.9 Hz, 6H,
ACH(CH3)2), 1.59 (broad s, 1H, AOH), 2.91 (septet, J = 6.9 Hz, 1H,
CH(CH3)2), 4.31 (dd, J = 6.0 Hz, 1.2 Hz, 2H, ACH2OH), 6.33 (dt,
J = 5.9 Hz, 6.0 Hz, 1H, @CHACH2A), 6.60 (d, J = 15.9 Hz, 1H, ArCH),
7.18–7.20 (m, 2H, p-C6H4), 7.31–7.34 (m, 2H, p-C6H4).
4.2.1. (E)-Methyl 3-(p-chlorophenyl)prop-2-enoate (2a)
Yield = 42%; 1H NMR (CDCl3) d: 3.81 (s, 3H, ACO2CH3), 6,54 (d,
J = 15.9 Hz, 1H, @CHCO2CH3), 7.36 (d, J = 15.9 Hz, 1H, ArCH@),
7.41–7.47 (m, 2H, p-C6H4), 7.58–7.66 (m, 2H, p-C6H4).
4.3.5. (E)-3-(a-naphtyl)prop-2-en-1-ol (3e)
Yield = 84%, 1H NMR (CDCl3) d: 1.63 (s, 1H, AOH), 4.45 (dd,
J = 5.7 Hz, 1.5 Hz, 2H, ACH2OH), 6.41 (dt, J = 15.6 Hz, 5.7 Hz, 1H,
@CHACH2A), 7.36–7.88 (m, 7H, ArH), 8.10 (dd, J = 15.6 Hz, 1H,
ArCH@).
4.2.2. (E)-Methyl 3-(p-methylphenyl)prop-2-enoate (2b)
Yield = 94%; 1H NMR (CDCl3), d: 1.27 (s, 3H, ACH3), 3.81(s, 3H,
AOCH3), 6.41 (d, J = 15.9 Hz, 1H, @CHCO2CH3), 7.69 (d,
J = 15.9 Hz, 1H, ArCH@), 7.24–7.27 (m, 2H, p-C6H4), 7.46–7.48 (m,
2H, p-C6H4).
4.4. Claisen rearrangement
4.2.3. (E)-Methyl 3-(p-methoxyphenyl)prop-2-enoate (2c)
Yield = 76%, 1H NMR (CDCl3) d: 3.71 (s, 3H, ACO2CH3), 3.83 (s,
3H, AOCH3), 6.31 (d, J = 15.9 Hz, 1H, @CHCO2CH3), 7.65 (d,
J = 15.9 Hz, 1H, ArCH@), 6.88–6.91 (m, 2H, p-C6H4), 7.46–7.49 (m,
2H, p-C6H4).
General procedure: A mixture of alcohol 3a–e (0.013 mol), ethyl
orthoacetate (24 mL, 0.13 mol) and propionic acid (0.1 mL,
0.001 mol) was heated (138 °C) for 5 h with simultaneous distilling
off the ethanol formed. Then orthoacetate was distilled off and the
crude products were purified by column chromatography (hex-
ane–ethyl acetate, 80:1) to afford pure esters 4a–e.
4.2.4. (E)-Methyl 3-(p-isopropylphenyl)prop-2-enoate (2d)
Yield = 89%, 1H NMR (CDCl3) d: 1.26 (d, J = 6.9 Hz, 6H,
ACH(CH3)2), 2.88 (septet, J = 6.9 Hz, 1H, CH(CH3)2), 3.81 (s, 3H,
ACO2CH3), 6.41 (d, J = 15.9 Hz, 1H, @CHCO2CH3), 7.23–7.28 (m,
2H, p-C6H4), 7.44–7.48 (m, 2H, p-C6H4), 7.67 (d, J = 15.9 Hz, 1H,
ArCH@).
4.4.1. Ethyl 3-(p-chlorophenyl)pent-4-enoate (4a)
Yield = 65%, n2D0 = 1,5723; IR (KBr,
m
cmꢀ1): 1719, 1645, 1526,
1494, 1411, 1353, 1237, 1155, 971, 814; 1H NMR (CDCl3) d: 1.18
(t, J = 7.2 Hz, 3H, AOCH2CH3), 2.65 (dd, J = 15.3 Hz, 7.8 Hz, 1H,
one of ACH2CO2Et), 2.74 (dd, J = 15.3 Hz, 7.8 Hz, 1H, one of ACH2-
CO2Et), 3.86 (m, 1H, AArCHA), 4.07 (q, J = 7.2 Hz, 2H, AOCH2CH3),
5.06 (dt, J = 17.1 Hz, 1.2 Hz, 1H, one of CH2@), 5.09 (dt, J = 10.5 Hz,
1.2 Hz, 1H, one of CH2@), 5.94 (ddd, J = 17.1 Hz, 10.5 Hz, 6.6 Hz; 1H,
ACH@), 7.15 (m, 2H, p-C6H4), 7.27 (m, 2H, p-C6H4); 13C NMR
(CDCl3) d: 14.131 (AOCH2CH3), 40.12 (C2), 44.90 (C3), 60.48
4.2.5. (E)-Methyl 3-(a-naphthyl)prop-2-enoate (2e)
Yield = 87%, 1H NMR (CDCl3) d: 3.86 (s, 3H, AOCH3), 6.54 (d,
J = 15.9 Hz, 1H, @CHCO2CH3), 7.46–8.21 (m, 7H, ArH), 8.54 (d,
J = 15.9 Hz, 1H, ArCH@).

166
A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
(AOCH2CH3), 115.14 (C5), 6 CAr: 128.65, 128.96, 129.14, 129.17,
140.87, 143.11; 139.79 (C4), 171.57 (C1). HRMS [M+Na]+:
261.0655 (calculated for [M+Na]+: 261.0658).
and the crude product was extracted with ether (7 ꢂ 50 mL). The
etheral solution was dried over MgSO4. The ether was distilled
off and pure acids 5a–e were obtained as yellow solids.
The physical and spectral data of 5a–c were the same with
those reported in literature [20].
4.4.2. Ethyl 3-(p-methylphenyl)pent-4-enoate (4b)
Yield = 84%, n2D0 = 1,4893; IR (KBr,
m
cmꢀ1): 1718, 1631, 1542,
1472, 1409, 1372, 1243, 1164, 968, 851; 1H NMR (CDCl3) d: 1.19
(t, J = 7.2 Hz, 3H, AOCH2CH3), 2.32 (s, 1H, ACH3), 2.67 (dd,
J = 15.0 Hz, 7.5 Hz, 1H, one of ACH2CO2Et), 2.76 (dd, J = 15.0 Hz,
8.1 Hz, 1H, one of ACH2CO2Et), 3.84 (m, 1H, ArCHA), 4.08 (q,
J = 7.2 Hz, 2H, AOCH2CH3), 5.04 (dt, J = 17.7 Hz, 1.2 Hz, 2H, 1H,
one of CH2@), 5.09 (dt, J = 11.4 Hz, 1.2 Hz, 1H, one of CH2@), 5.97
(ddd, J = 17.7 Hz, 11.4 Hz, 6.9 Hz, 1H, ACH@), 7.09–7.14 (m, 4H,
p-C6H4). 13C NMR (CDCl3) d: 14.14 (AOCH2CH3), 20.97 (CH3),
4.5.1. 3-(p-Chlorophenyl)pent-4-enoic acid (5a)
Yield = 72%, 1H NMR (CDCl3) d: 2.70 (dd, J = 15.9 Hz, 7.5 Hz, 1H,
one of ACH2CO2Et), 2.79 (dd, J = 15.9 Hz, 7.5 Hz, 1H, one of ACH2-
CO2Et), 3.83 (m, 1H, ArCHA), 5.07 (dt, J = 17.1 Hz, 1.2 Hz, one of
CH2@), 5.11 (dt, J = 10.2 Hz, 1.2 Hz, one of CH2@), 5.94 (ddd,
J = 17.1 Hz, 10.2 Hz, 6.6 Hz, 1H, ACH@), 7.13–7.16 (m, 2H, p-
C6H4), 7.27–7.30 (m, 2H, p-C6H4).
40.33 (C2), 45.21 (C3), 60.31 (AOCH2CH3), 114.51 (C5), 6 CAr
:
4.5.2. 3-(p-Methylphenyl)pent-4-enoic acid (5b)
127.34, 129.20, 136.15, 140.44; 139.42 (C4), 171.89 (C1); HRMS
Yield = 88%, 1H NMR (CDCl3) d: 2.33 (s, 1H, CH3), 2.72 (dd,
J = 15.6 Hz, 7.2 Hz, 1H, one of ACH2CO2Et), 2.79 (dd, J = 15.6 Hz,
7.8 Hz, 1H, one of ACH2CO2Et), 3.83 (m, 1H, ArCHA), 5.04 (dt,
J = 17.7 Hz, 1.2 Hz, 1H, one of CH2@), 5.09 (dt, J = 10.2 Hz, 1.2 Hz,
1H, one of CH2@), 5.97 (ddd, J = 17.7 Hz, 10.2 Hz, 6.9 Hz, 1H,
ACH@), 7.12–7.16 (m, 4H, p-C6H4).
[M+Na]+: 241.1205 (calculated for [M+Na]+: 241.1204).
4.4.3. Ethyl 3-(p-methoxyphenyl)pent-4-enoate (4c)
Its physical and spectral data coincided with that of literature
[19].
Yield = 35%, 1H NMR (CDCl3) d: 1.18 (t, J = 6.9 Hz, 3H, AOCH2-
CH3), 2.65 (dd, J = 15.0 Hz, 7.8 Hz, 1H, one of ACH2CO2Et), 2.73
(dd, J = 15.0 Hz, 7.8 Hz, 1H, one of CH2CO2Et), 3.78 (s, 1H, AOCH3),
3.82 (m, 1H, ArCHA), 4.07 (q, J = 7.2 Hz, 2H, AOCH2CH3), 5.05 (dt,
J = 17.4 Hz, 1.2 Hz, 2H, 1H, one of CH2@), 5.09 (dt, J = 11.1 Hz,
1.2 Hz, 1H, one of CH2@), 5.96 (ddd, J = 17.4 Hz, 11.1 Hz, 6.9 Hz,
1H, ACH@), 6.84 (m, 2H, p-C6H4), 7.13 (m, 2H, p-C6H4).
4.5.3. 3-(p-Methoxyphenyl)pent-4-enoic acid (5c)
Yield = 75%, 1H NMR (CDCl3) d: 2.70 (dd, J = 15.6 Hz, 7.5 Hz, 1H,
one of CH2CO2Et), 2.78 (dd, J = 15.6 Hz, 8.1 Hz, 1H, one of CH2CO2-
Et), 3.79 (s, 3H, AOCH3), 3.85 (m, 1H, ACH2ACHA), 5.05 (dt,
J = 17.4 Hz, 1.2 Hz, 2H, 1H, one of CH2@), 5.09 (dt, J = 11.1 Hz,
1.2 Hz, 1H, one of CH2@), 5.96 (ddd, J = 17.4 Hz, 11.1 Hz, 6.6 Hz,
1H, ACH@), 6.84–6.87 (m, 2H, p-C6H4), 7.12–7.15 (m, 2H, p-C6H4).
4.4.4. Ethyl 3-(p-isopropylphenyl)pent-4-enoate (4d)
Yield = 82%, n2D0 = 1,5004; IR (KBr,
m
cmꢀ1): 1736, 1640, 1512,
4.5.4. 3-(p-Isopropylphenyl)pent-4-enoic acid (5d)
1488, 1400, 1368, 1256, 1164, 976, 832; 1H NMR (CDCl3) d: 1.18
(t, J = 6.9 Hz, 3H, AOCH2CH3), 1.23 (d, J = 6.9 Hz, 6H, ACH(CH3)2),
2.67 (dd, J = 15.0 Hz, 5.5 Hz, 1H, one of ACH2CO2Et), 2.74 (dd,
J = 15.0 Hz, 8.7 Hz, 1H, one of ACH2CO2Et), 2.88 (septet, J = 6.9 Hz,
1H, CH(CH3)2), 3.84 (m, 1H, ArCHA), 4.08 (q, J = 6.9 Hz, 2H, AOCH2-
CH3), 5.08 (ddd, J = 17.1 Hz, 2.4 Hz, 1.2 Hz, 1H, one of CH2@), 5.09
(dd, J = 10.5 Hz, 1.5 Hz, 1H, one of CH2@), 5.98 (ddd, J = 17.1 Hz,
10.5 Hz, 7.2 Hz, 1H, ACH@), 7.12–7.18 (m, 4H, p-C6H4); 13C NMR
(CDCl3) d: 14.12 (AOCH2CH3), 23.95 (CH3), 33.65 (CH), 40.38 (C2),
45.28 (C3), 60.30 (AOCH2CH3), 114.53 (C5), 6 CAr: 126.41, 127.33,
128.26, 147.14; 140.40 (C4), 171.94 (C1); HRMS [M+Na]+:
269.1495 (calculated for [M+Na]+: 269.1517).
Yield = 87%, m.p. = 35–35.5 °C, IR (KBr, m
cmꢀ1): 2830–3036,
1712, 1640, 1512, 1416, 1284, 1112, 1056, 920, 832; 1H NMR
(CDCl3) d: 1.23 (d, J = 6.9 Hz, 6H, ACH(CH3)2), 2.77 (dd, J = 8.1 Hz,
3.9 Hz, 2H, ACH2A), 2.90 (septet, J = 6.9 Hz, 1H, CH(CH3)2), 3.85
(q, J = 7.2 Hz, 1H, ACH2ACHA), 5.09 (dd, J = 11.1 Hz, 1.5 Hz, 1H,
one of CH2@), 5.11 (dt, J = 17.1 Hz, 1.5 Hz, 1H, one of CH2@), 5.99
(ddd, J = 17.1 Hz, 11.1 Hz, 7.1 Hz, 1H, ACH@), 7.13–7.20 (m, 4H,
p-C6H4); 13C NMR (CDCl3): 23.95 (CH3), 33.67 (CH), 39.93 (C2),
44.81 (C3), 114.81 (C5), 6 CAr: 126.41, 126.66, 127.31, 139.47;
140.11 (C4), 171.72 (C1); HRMS [M+Na]+: 241.1227 (calculated
for [M+Na]+: 241.1204).
4.5.5. 3-(
Yield = 71%, m.p. = 89–90.5 °C; IR (KBr,
1712, 1432, 1304, 1264, 1016, 928, 784 cmꢀ1
a-Naphtyl)pent-4-enoic acid (5e)
4.4.5. Ethyl 3-(
Yield = 77%; n2D0 = 1.5680; IR (KBr,
1256, 1172, 1032, 920, 776 cmꢀ1 1H NMR (CDCl3) d: 1.18 (t,
J = 7.2 Hz, 3H, AOCH2CH3), 2.89 (d, J = 7.5 Hz, 2H, ACH2CO2Et),
4.11 (q, J = 7.2 Hz, 2H, AOCH2CH3), 4.76 (m, 1H, ArCHA), 5.15
(dd, J = 17.8 Hz, 1.2 Hz, 1H, one of CH2@), 5.16 (dd, J = 9.6 Hz,
1.2 Hz, 1H, one of CH2@), 6.12 (ddd, J = 17.8 Hz, 9.6 Hz, 6.5 Hz,
1H, ACH@), 7.36–7.58, (four m, 4H, ArH), 7.75, 7.86 and 8.19 (three
m, 3H, ArH); 13C NMR (CDCl3) d: 14.13 (AOCH2CH3), 39.91 (C2),
a
-naphtyl)pent-4-enoate (4e)
m
cmꢀ1): 2833–3032,
m
cmꢀ1):, 1732, 1512, 1368,
;
1H NMR (CDCl3) d:
;
2.89–2.98 (m, 2H, ACH2C(O)A), 4.75 (m, 1H, ACH2ACHA), 5.17
(dd, J = 17.0 Hz, 1.5 Hz, 1H, one of CH2@), 5.18 (dd, J = 10.6 Hz,
1.5 Hz, 1H, one of CH2@), 6.13 (ddd, J = 17.0 Hz, 10.6 Hz, 6.4 Hz,
1H, ACH@), 7.36–7.56 (four m, 4H, ArH), 7.76, 7.87 and 8.16 (three
m, 3H, ArH); 13C NMR (CDCl3) d: 39.48 (C2), 39.95 (C3), 115.67
(C5), 10 CAr: 123.18, 124.04, 125.43, 125.61, 126.19, 127.47,
128.95, 131.15, 134.03, 138.09; 139.40 (C4), 178.19 (C1); HRMS
[M+K]+: 265.0631 (calculated for [M+K]+: 265.0684).
40.32 (C3), 60.46 (AOCH2CH3), 115.33 (C5), 10 CAr
: 123.30,
124.09, 125.39, 125.53, 126.05, 127.31, 128.95, 131.25, 133.99,
138.47; 139.81 (C4), 171.99 (C1); HRMS [M+K]+: 293.0927 (calcu-
lated for [M+K]+: 293.0944).
4.6. Iodolactonization of acids 5a–e
General procedure: A 0.5 M solution of NaHCO3 (20 mL) was
added to a solution of carboxylic acid 5 (0.006 mol) in diethyl ether
(25 mL). The reaction mixture was stirred at room temperature for
30 min. Then the mixture of iodine (0.01 mol) and KI (0.03 mol)
dissolved in water (30 mL) was added dropwise and the reaction
mixture was refluxed for 5 h. Then the mixture was cooled to room
temperature, diluted with ethyl acetate (50 mL) and washed with
aqueous saturated solution of sodium thiosulfate. The water layer
was extracted by ethyl ether (or with ethyl acetate in case of
4.5. Hydrolysis of esters 4a–e
General procedure: A solution of KOH (0.05 mol) in ethanol
(25 mL) was added to ester 4a–e (0.01 mol). The reaction mixture
was refluxed for 6 h. The progress of the reaction was monitored by
TLC. Then ethanol was distilled off and the crude product was
solved in water (20 mL) and washed with diethyl ether (100 mL).
Next the aqueous layer was acidified with 0.1 M HCl (pH ꢃ 1)

A. Wzorek et al. / Journal of Molecular Structure 1047 (2013) 160–168
167
products of iodolactonization of acid 5e). The combined organic
solution was washed with aqueous saturated NaHCO3 solution,
brine and dried over MgSO4. After evaporation of the solvent the
crude products mixture was separated by column chromatography
with hexane–ethyl acetate 5:1 (in case of pairs of isomers 6a and
7a, 6d and 7d) or methylene chloride (in case of isomers 6e and
7e) as eluent or by crystallization from hexane:ethyl acetate 5:1
in case of pairs of isomers 6b and 7b, 6c and 7c.
(OCH3), 83.16 (C5), CAr: 114.30, 129.10, 159.29; 175.830 (C2);
HRMS [M+Na]+: 354.9863 (calculated for [M+Na]+: 354.9807).
4.6.4. 4-(p-Isopropylphenyl)-5-iodomethyltetrahydrofuran-2-one
Isomer trans (6d): Yield = 22%, m.p. = 94.5–95.5 °C; IR (KBr,
m
cmꢀ1): 1776, 1512, 1460, 1429, 1392, 1280, 1144, 116, 981, 860,
572; 1H NMR (CDCl3) d: 1.25 (d, J = 6.9 Hz, 6H, ACH(CH3)2), 2.83
(dd, J = 18.0 Hz, 9.0 Hz, 1H, one of C(O)ACH2A), 2.91 (septet,
J = 6.9 Hz, 1H, CH(CH3)2), 3.05 (dd, J = 18.0 Hz, 9.0 Hz, 1H, one of
C(O)ACH2A), 3.33 (dd, J = 11.1 Hz, 4.5 Hz, 1H, one of ACH2I), 3.49
(dd, J = 11.1 Hz, 4.5 Hz, 1H, one of ACH2I), 3.50 (td, J = 9.0 Hz,
7.5 Hz, 1H, >CHAAr), 4.29 (dt, J = 7.5 Hz, 4.5 Hz, >CHACH2I),
7.16–7.23 (m, 4H, p-C6H4). 13C NMR (CDCl3) d: 6.35 (C6), 23.89
(CH3), 33.75 (CH), 37.00 (C3), 46.96 (C4), 84.24 (C5), CAr: 127.09,
127.34, 135.48, 148.91; 174.47 (C2); HRMS [M+Na]+: 367.0225
(calculated for [M+Na]+: 367.0171).
4.6.1. 4-(p-Chlorophenyl)-5-iodomethyltetrahydrofuran-2-one
The physical and spectral data of 6–7a were the same with
those reported in literature [21].
Isomer trans (6a): Yield = 17%, 1H NMR (CDCl3) d: 2.78 (dd,
J = 18.0 Hz, 9.3 Hz, 1H, one of C(O)ACH2A), 3.07 (dd, J = 18.0 Hz,
9.3 Hz, 1H, one of C(O)ACH2A), 3.33 (dd, J = 11.1 Hz, 4.8 Hz, 1H,
one of ACH2I), 3.47 (dd, J = 11.1 Hz, 4.8 Hz, 1H, one of ACH2I),
3.52 (td, J = 9.3 Hz, 7.2 Hz, >CHAAr), 4.29 (dt, J = 7.2 Hz, 4.8 Hz,
>CHACH2I), 7.19–7.22 (m, 2H, p-C6H4), 7.35–7.38 (m, 2H, p-C6H4).
Isomer cis (7a): Yield = 38%, 1H NMR (CDCl3) d: 2.66 (dd,
J = 10.2 Hz, 8.1 Hz, 1H, one of ACH2I), 2.78 (dd, J = 17.7 Hz, 3.0 Hz,
1H, one of C(O)ACH2A), 3.10 (dd, J = 17.7 Hz, 8.4 Hz, 1H, one of
C(O)ACH2A), 3.15 (dd, J = 10.2 Hz, 6.0 Hz, 1H, one of ACH2I), 3.87
(ddd, J = 8.4 Hz, 6.0 Hz, 3.0 Hz, >CHAAr), 4.94 (dt, J = 8.1 Hz,
6.0 Hz, >CHACH2I), 7.15–7.18 (m, 2H, p-C6H4), 7.32–7.35 (m, 2H,
p-C6H4).
Isomer cis (7d): Yield = 48%, m.p. = 88–89 °C; IR (KBr,
m
cmꢀ1):
1784, 1617, 1512, 1467, 1418, 1369, 1272, 1182, 1076, 976, 919,
821, 568; 1H NMR (CDCl3) d: 1.24 (d, J = 6.9 Hz, 6H, ACH(CH3)2),
2.74 (dd, J = 10.5 Hz, 7.2 Hz, 1H, one of ACH2I), 2.83 (dd,
J = 17.7 Hz, 3.3 Hz, 1H, one of C(O)ACH2A), 2.90 (septet,
J = 6.9 Hz, 1H, CH(CH3)2), 3.04 (dd, J = 17.7 Hz, 8.7 Hz, 1H, one of
C(O)CH2A), 3.07 (dd, J = 10.5 Hz, 6.3 Hz, 1H, one of ACH2J), 3.85
(ddd, J = 8.7 Hz, 6.0 Hz, 3.3 Hz, 1H, >CHAAr), 4.94 (m, 1H,
>CHACH2I), 7.11–7.14 (m, 2H, p-C6H4), 7.19–7.22 (m, 2H, p-
C6H4). 13C NMR (CDCl3) d: 1.79 (C6), 23.84 (CH3), 23.87 CH3),
33.70 (CH), 36.83 (C3), 43.77 (C4), 83.19 (C5), CAr
: 127.00,
127.93, 133.55, 148.85; 175.80 (C2); HRMS [M+Na]+: 367.0277
4.6.2. 4-(p-Methylphenyl)-5-iodomethyltetrahydrofuran-2-one
Isomer trans (6b): Yield = 15%, n2D0 = 1.5771, IR (KBr,
m
cmꢀ1):
(calculated for [M+Na]+: 367.0171).
1765, 1691, 1548, 1247, 1112, 839, 667, 558; 1H NMR (CDCl3) d:
2.35 (s, 3H, ACH3), 2.81 (dd, J = 18.0 Hz, 9.3 Hz, 1H, one of
C(O)ACH2A), 3.05 (dd, J = 18.0 Hz, 9.3 Hz, 1H, one of C(O)ACH2A),
3.32 (dd, J = 11.4 Hz, 4.5 Hz, 1H, one of ACH2I), 3.48 (dd, J = 11.1 Hz,
4.5 Hz, 1H, one of ACH2I), 3.49 (td, J = 9.3 Hz, 7.5 Hz, >CHAAr), 4.28
(dt, J = 7.5 Hz, 4.5 Hz, >CHACH2I), 7.13–7.21 (m, 4H, p-C6H4), 13C
NMR (CDCl3) d: 6.22 (C6), 21.03 (CH3), 37.02 (C3), 46.95 (C4),
84.26 (C5), CAr: 127.01,129.95, 135.22, 137.94; 174.42 (C2); HRMS
[M+Na]+: 338.9903 (calculated for [M+Na]+: 338.9858).
4.6.5. 4-(a-Naphthyl)-5-iodomethyltetrahydrofuran-2-one
Isomer trans (6e): Yield = 14%, m.p. = 159–160 °C, IR (KBr,
m
cmꢀ1): 1786, 1424, 1296, 1176, 1160, 1140, 964, 924, 800, 784,
672, 584, 544; 1H NMR (CDCl3) d: 2.88 (dd, J = 18.0 Hz, 8.4 Hz,
1H, one of C(O)ACH2A), 3.27 (dd, J = 18.0 Hz, 8.4 Hz, 1H, one of
C(O)ACH2A), 3.39 (dd, J = 11.4 Hz, 4.5 Hz, 1H, one of ACH2I), 3.55
(dd, J = 11.4 Hz, 4.5 Hz, 1H, one of ACH2I), 4.35 (td, J = 8.4 Hz,
6.6 Hz, >CHAAr), 4.67 (dt, J = 6.6 Hz, 4.5 Hz, >CHACH2I), 7.44–
7.64 (four m, 4H, ArH), 7.83, 7.92 and 8.06 (three m, 3H, ArH);
13C NMR (CDCl3) d: 7.12 (C-6), 37.44 (C-3), 41.96 (C-4), 83.63 (C-
5), 7 CAr: 122.34, 123.73, 125.58, 126.21, 126.94, 128.59, 129.38;
174.51 (C-2); HRMS [M+K]+: 391.2527 (calculated for [M+K]+:
391.2653).
Isomer cis (7b): Yield = 42%, m.p. = 104–105 °C; IR (KBr,
m
cmꢀ1):
1769, 1587, 1285, 1246, 974, 836, 724, 543; 1H NMR (CDCl3) d:
2.34 (s, 3H, ACH3), 2.72 (dd, J = 10.5 Hz, 7.5 Hz, 1H, one of ACH2I),
2.80 (dd, J = 17.7 Hz, 3.3 Hz, 1H, one of C(O)ACH2A), 3.06 (dd,
J = 17.7 Hz, 8.7 Hz, 1H, one of C(O)ACH2A), 3.07 (dd, J = 10.5 Hz,
6.3 Hz, 1H, one of ACH2I), 3.84 (ddd, J = 8.7 Hz, 6.0 Hz, 3.3 Hz,
>CHAAr), 4.93 (m, >CHACH2I), 7.08–7.16 (m, 4H, p-C6H4).
Isomer cis (7e): Yield = 28%, m.p. = 189.5–192 °C, IR (KBr,
m
cmꢀ1): 1772, 1408, 1320, 1164, 1048, 1000, 992, 776, 688; 1H
NMR (CDCl3) d: 2.75 (dd, J = 11.1 Hz, 5.5 Hz, 1H, one of ACH2I),
2.79 (dd, J = 11.1 Hz, 7.4 Hz, 1H, one of CH2I) 3.04 (dd, J = 17.5 Hz,
8.6 Hz, 1H, one of C(O)ACH2A), 3.22 (dd, J = 17.5 Hz, 8.0 Hz, 1H,
one of C(O)ACH2A), 4.78 (m, 1H, >CHAAr), 5.25 (td, J = 7.4 Hz,
5.5 Hz, >CHACH2I), 7.39 and 7.49 (two m, 2H, ArH), 7.53–7.64
(two m, 2H, ArH), 7.86, 7.92 and 8.00 (three m, 3H, ArH); 13C
NMR (DMSO-d6) d: 4.68 (C-6), 31.97 (C-3), 39.59 (C-4), 81.14 (C-
5), 7 CAr: 123.33, 124.33, 125.33, 125.97, 126.70, 128.06, 128.72;
175.25 (C-2); HRMS [M+K]+: 391.2516 (calculated for [M+K]+:
391.2653).
13C NMR (CDCl3) d: 1.58 (C6), 21.04 (CH3), 36.94 (C3), 43.73
(C4), 83.08 (C5), CAr: 127.89,129.63, 133.28, 137.93; 175.80 (C2);
HRMS [M+Na]+: 338.9915 (calculated for [M+Na]+: 338.9858).
4.6.3. 4-(p-Methoxyphenyl)-5-iodomethyltetrahydrofuran-2-one
Isomer trans (6c): (in mixture with cis isomer 7c), 1H NMR
(CDCl3) d: 2.79 (dd, J = 17.4 Hz, 9.9 Hz, 1H, one of C(O)ACH2A),
3.02 (dd, J = 17.7 Hz, 9.9 Hz, 1H, one of C(O)ACH2A), 3.32 (dd,
J = 11.1 Hz, 4.5 Hz, 1H, one of ACH2I), 3.46 (dd, J = 11.1 Hz, 4.5 Hz,
1H, one of ACH2I), 3.48 (td, J = 9.9 Hz, 7.5 Hz, >CHAAr), 3.80 (s,
3H. AOCH3), 4.25 (dt, J = 7.5 Hz, 4.5 Hz, >CHACH2I), 6.88–6.92 (m,
2H, p-C6H4), 7.14–7.19 (m, 2H, p-C6H4).
4.7. Antiproliferative assay in vitro
Isomer cis (7c): Yield = 35%, m.p. = 95.0–95.5 °C; IR (KBr,
m
cmꢀ1): 1975, 1772, 1615, 1548, 1286, 1198, 912, 681, 573; 1H
NMR (CDCl3) d: 2.70 (dd, J = 10.2 Hz, 7.5 Hz, 1H, one of ACH2I),
2.79 (dd, J = 17.4 Hz, 3.0 Hz, 1H, one of C(O)ACH2A), 3.06 (dd,
J = 17.4 Hz, 8.7 Hz, 1H, one of C(O)CH2A), 3.10 (dd, J = 10.2 Hz,
6.3 Hz, 1H, one of ACH2I), 3.81 (s, 3H, AOCH3), 3.84 (ddd,
J = 8.7 Hz, 6.3 Hz, 3.0 Hz, >CHAAr), 4.92 (dt, J = 7.5 Hz, 6.3 Hz,
>CHACH2I), 6.85–6.90 (m, 2H, p-C6H4), 7.11–7.16 (m, 2H, p-
C6H4).13C NMR (CDCl3) d: 1.56 (C6), 37.06 (C3), 43.33 (C4), 55.27
4.7.1. Cell line
The established in vitro cancer line HL-60 (human promyelo-
cytic leukemia) was applied. This line was obtained from American
Type Culture Collection (Rockville, Maryland, USA) and is being
maintained in the Institute of Immunology and Experimental Ther-
apy, Wrocław, Poland.
HL-60 cells were cultured in RPMI1640 medium (Gibco, Scot-
land, UK) with 10% fetal bovine serum (FBS), 1 mM sodium

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l
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