Synthesis and anticancer activity of novel halolactones with β-aryl substituents from simple aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2013.09.094

A series of 20 novel racemic iodo-, bromo- and chlorolactones, possessing β-phenyl-γ-lactone or β-phenyl-δ-lactone framework, were synthesized from commercially available aromatic aldehydes in convenient five-step syntheses. Some of them showed noticeable cytotoxic effect against two cancer lines, Jurkat (human leukaemia) and D17 (canine osteosarcoma). The highest activity, comparable with carboplatin, was observed for cis-5-(1-iodoethyl)-4-(4′-isopropylphenyl)dihydrofuran-2-one against Jurkat cell line.

Full text of DOI:10.1016/j.tet.2013.09.094

Tetrahedron 69 (2013) 10414e10423
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and anticancer activity of novel halolactones with
substituents from simple aromatic aldehydes
b-aryl
,
a
a
a
Witold G1adkowski a , Andrzej Skrobiszewski , Marcelina Mazur , Monika Siepka ,
*
b
b
c
_
ꢀ
ꢀ
Aleksandra Pawlak , Bozena Obminska-Mrukowicz , Agata Bia1onska ,
Dominik Poradowski b, Angelika Drynda b, Mariusz Urbaniak d
a Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
b Department of Biochemistry, Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375
Wrocław, Poland
c Department of Crystallography, University of Wrocław, Joliot Curie 14, 50-383 Wrocław, Poland
d
ꢀ
Institute of Chemistry, Jan Kochanowski University, Swie˛tokrzyska 15 G, 25-406 Kielce, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2013
Received in revised form 7 September 2013
Accepted 24 September 2013
Available online 5 October 2013
A series of 20 novel racemic iodo-, bromo- and chlorolactones, possessing
b-phenyl-g-lactone or
b
-phenyl-d-lactone framework, were synthesized from commercially available aromatic aldehydes in
convenient five-step syntheses. Some of them showed noticeable cytotoxic effect against two cancer
lines, Jurkat (human leukaemia) and D17 (canine osteosarcoma). The highest activity, comparable with
carboplatin, was observed for cis-5-(1-iodoethyl)-4-(40-isopropylphenyl)dihydrofuran-2-one against Ju-
rkat cell line.
Keywords:
Lactones
Ó 2013 Elsevier Ltd. All rights reserved.
Aromatic ring
Halolactonization
Cytotoxic activity
1. Introduction
analogues,29,30 paraconic acid analogues,31 eupomatilones.32 In
many studies it was found that the presence of lipophilic aromatic
Compounds possessing a lactone ring are one of the most nu-
merous group of substances isolated from natural environment.
They are secondary metabolites of plants,1 insects,2 microorgan-
isms3 and marine organisms.4 Natural and synthetic lactones are
often carriers of pleasant odours5,6 and most of them are charac-
terized by useful biological activities, e.g., antifeedant,7e9 anti-
microbial10e12 and cytostatic.13e15 They often play the role of
pheromones in animals,16 insects17 and microorganisms.18
Interesting biological properties have been found for lactones
bearing an aromatic ring. They exhibit analgesic and anti-in-
flammatory,19 leishmanicidal,20 antibacterial,21 antifungal,22
antileukaemic,23 anti-HIV,24 antiplatelet,25 antiestrogenic26 and
anticonvulsant activity connected with stimulation of GABAA re-
ceptors.27 In this group of compounds special attention has been
paid to the natural and synthetic lactones, which exhibit anti-
cancer activity, e.g., enterolactone,28 isochaihulactone and its
substituents increases the cytotoxic activity of lactones.33e35 On
the other hand, the majority of the investigated lactones with
aromatic rings belonged to the lignane family and they possessed
the benzyl substituent at the lactone moiety but not the phenyl
one.
Taking these reports into consideration in our research we have
focused on the synthesis of lactones with b-phenyl substituents.
Numerous reports concerning the synthesis of lactones with aro-
matic rings have been published.36e46 In our earlier experiments
the convenient synthetic pathway leading from allylic alcohols to
lactones has been developed in which the key step was the lactone
ring closure by halolactonization of a,b-unsaturated acids. In this
way several halolactones with pinane,47 p-menthane48,49 and alkyl-
substituted cyclohexane system50e53 have been obtained. In this
work we report the application of this procedure to the synthesis of
new five- and six-membered lactones with benzene and alkyl-
substituted benzene rings, starting from simple aromatic alde-
hydes. We present also the results of their cytotoxic tests against
two cancer lines: Jurkat (human T-cell leukaemia) and D-17 (canine
osteosarcoma).
* Corresponding author. Tel.: þ48713205197; fax: þ48713283576; e-mail ad-
dress: glado@poczta.fm (W. G1adkowski).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.094

W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
10415
2. Results and discussion
2.1. Synthesis
Next step of the synthesis was the JohnsoneClaisen rearrange-
ment54 of allylic alcohols 3aec using triethylorthoacetate in the
presence of a catalytic amount of propionic acid. In this case the
reaction results in the formation of benzylic tertiary carbon atom
and has found application in the synthesis of many biologically
active compounds.55e57 The mechanism involves the etherification
of the alcohol followed by subsequent elimination of ethanol to
The
d-halo-g-lactones and
g-halo-d-lactones with the aryl sub-
stituents joined to the
b-position of the lactone ring were obtained
from corresponding 3-arylhex-4-enoic acids (5aec). These in-
termediates were produced in a four-step synthesis (Scheme 1).
form ketene acetal (Scheme 2). The latter is rearranged to the g,d-
O
OH
O
2'
O
1'
3'
H
2
4
NaBH4
1
3
6'
MeOH/H2O
0 oC
NaOH
R
4'
R
R
5'
3a-c
2a-c
1a-c
1
a: R=H
b: R=Me
c: R= i-Pr
COOEt
2
COOH
2'
5'
3
1'
3'
NaOH
EtOH
MeC(OEt)3
5
6
4
EtCOOH
138 oC
6'
4'
R
R
5a-c
4a-c
Scheme 1. Synthesis of 3-arylhex-4-enoic acids 5aec from aldehydes 1aec.
The starting materials were three, commercially available ar-
omatic aldehydes: benzaldehyde (1a), p-methylbenzaldehyde
(1b) and p-isopropylbenzaldehyde (1c). In the first step they
unsaturated esters in the [3.3] sigmatropic shift during heating. In
our case, the reaction afforded 3-arylhex-4-enoic acid ethyl esters
(4aec) in 80e84% yield.
OEt
OH
O
OEt
- 2 EtOH
H3C
OEt
C
OEt
+
OEt
3a-c
R
R
O
a: R=H
b: R=Me
c: R=i-Pr
R
4a-c
Scheme 2. JohnsoneClaisen rearrangement of alcohols 3aec.
were transformed in high yields (94e99%) into the correspond-
ing -unsaturated ketones 2aec via the ClaiseneSchmidt con-
The spectroscopic data confirmed the structure of the products.
Absorption bands at the range 1735e1736 cmꢀ1 and characteristic
signals in the 1H NMR spectrumdtriplets in the range
1.15e1.18 ppm and quartets in the range 4.05e4.08 ppm confirmed
the presence of carboethoxy group in compounds 4aec. The E
configuration of double bonds remained unchanged, which was
indicated by the value of coupling constant between olefinic pro-
tons H-4 and H-5 (e.g., J¼15 Hz for ester 4b). It was consistent with
the mechanism of JohnsoneClaisen rearrangement.
a,b
densation with acetone in basic conditions. The coupling
constant between the olefinic protons in the 1H NMR spectrum
(J¼16.2 Hz) confirmed the E configuration of double bond C3eC4.
Selective reduction of carbonyl group of ketones 2aec by treat-
ment with NaBH4 at low temperature afforded corresponding
allylic alcohols 3aec. Spectroscopic data, including the value of
coupling constant between H-3 and H-4 protons (J¼15.9 Hz for
3c) indicated that the double bond with E configuration has been
retained.
The esters 4aec were subsequently hydrolyzed in ethanolic
NaOH solutions to the corresponding acids 5aec in 85e91%

10416
W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
yield. Acids 5aec were subjected to three halolactonization re-
actions giving access to iodo-, bromo- and chlorolactones
(Scheme 3).
established on the basis of spectroscopic data and crystallographic
analysis. In the IR spectrum of both lactones 6a and 7a characteristic
absorption bands for
g-lactone ring, resulted from stretching C]O
COOH
5a-c
a: R=H
b: R=Me
c: R=i-Pr
R
NBS
I2, KI
NCS
THF, AcOH
NaHCO3
THF, AcOH
O
O
O
O
2
3
4
9a-c
1 O
O
2'
12a-c
6a-c
1'
5
3'
6
Br
Cl
6'
I
R
R
4'
R
7
5'
O
O
O
O
O
O
7a-c
13a-c
10a-c
I
Cl
Br
R
R
R
O
O
O
I
14a-c
O
11a-c
O
8a-c
O
Cl
Br
R
R
R
Scheme 3. Halolactonization of acids 5aec.
Iodolactonization processes were carried out with the applica-
tion of iodine and potassium iodide in alkaline solution (NaHCO3).
In these conditions three products were formed according to GC
analysis (Table 1). Apart from product 8c they were isolated and
purified by silica gel column chromatography.
vibrations were observed at 1779 cmꢀ1 and 1781 cmꢀ1, respectively.
Crystal structures (Figs. 1 and 2) confirmed the orientation of the
aromatic substituent at C-4 and iodoethyl group at C-5 towards the
g-lactone ring in both isomers. Those assignments were in accor-
dance with the conclusions drawn on the basis of 1H NMR analysis.
Table 1
The composition [%] of the halolactonization products of acids 5aec (according to GC)
Entry
Substituent
R
Iodolactonization
Bromolactonization
Chlorolactonization
cis-g
-Lactone
trans-
g-Lactone
d
-Lactone
cis-
g-Lactone
trans-
g-Lactone
d
-Lactone
cis-
g-Lactone
trans-
g-Lactone
d-Lactone
1
2
3
H
6a
43
6b
55
6c
57
7a
33
7b
23
7c
29
8a
24
8b
22
8c
14
9a
24
9b
51
9c
25
10a
17
10b
28
10c
24
11a
59
11b
21
11c
51
12a
19
12b
21
12c
29
13a
29
13b
19
13b
22
14a
52
14b
60
14c
48
Me
i-Pr
In the result of iodolactonization of acid 5a two products formed
by 5-exo cyclization (diastereoisomeric -iodo- -lactones 6a and 7a)
as well as one product formed by 6-endo cyclization ( -iodo- -lac-
tone 8a) were isolated and purified. Their structures were
In the case of the cis isomer (6a) proton H-6 was located in the
shielding cone of the aromatic ring, which caused its absorption at
relatively high field (3.47 ppm). The coupling constant between H-6
and H-5 (J¼10.8 Hz) is the result of antiperiplanar location of the
d
g
g
d

W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
10417
antiperiplanar. The C6eI1 bond is shown on Fig. 2 with dashed line.
The accurate location of methyl group in that minor compound,
thus its whole structure, could not be determined but taking into
consideration the reaction mechanism the diastereoisomerism at
the C-6 atom is rather excluded. Likely, these two molecules can be
regarded as conformers syn and anti and the conformational
equilibrium was probably forced by the energetically favourable
minimization of repulsions between the electrons of the aromatic
ring and electrons of the iodine atom. These interactions existed in
the trans isomer formed in the result of 5-exo cyclization. Because
of these electronic effects the rotation around C5eC6 bond took
place (Scheme 4) leading to more stable conformer syn in which the
iodine atom is far away from the benzene ring.
These two conformers are distinguishable in the 1H NMR
spectrum: apart from the major signals of conformer syn the minor
signals belonging to the conformer anti are also visible. The dif-
ference in chemical shift of H-5 proton is observed: in syn con-
former this proton is deshielded more (4.26 ppm) than in anti
conformer (3.79 ppm), which was probably caused by its different
location towards the shielding region of benzene ring. The different
coupling constants with H-6 proton were also determined
(J¼5.4 Hz in the case of syn conformer and J¼2.5 Hz in the case of
anti conformer). The dependence of chemical shift from the loca-
tion towards the benzene ring can be also observed for the protons
from CH3-7 group: in the syn conformer they are located in the
shielding cone of aromatic ring and their signal is shifted upfield by
0.11 ppm in comparison to the signal from these protons on the
spectrum of anti conformer. In both conformers the H-6 proton was
located outwards from the shielding space of aromatic ring, which
significantly shifted its multiplet downfield (4.38 and 4.24 ppm) in
comparison to cis isomer (3.47 ppm). The 1H NMR spectra of
iodolactones 7b and 7c also revealed the presence of second minor
conformers, at 12% and 7%, respectively.
Fig. 1. Crystal structure of the iodolactone 6a with the numbering consistent with
NMR description.
The structure of
troscopic measurements. The band at 1721 cmꢀ1 in the IR spectrum
proved the presence of the -lactone ring. The multiplet from H-6
g-iodo-d-lactone 8a was confirmed by spec-
d
proton was shifted to 4.78 ppm through the deshielding effect of
the oxygen atom from the lactone ring. The signal from H-5 proton
appeared at 4.05 ppm as a triplet with the same coupling con-
stant (J¼10.2 Hz) with the protons H-4 and H-6. This value univo-
cally indicates the pseudoaxial position of these protons, which
confirms the relative orientations of three substituents at the lac-
tone ring. They are in energetically favourable pseudoequatorial
positions, with the iodine at C-5 located trans towards both ben-
zene ring at C-4 and methyl group at C-6. Analysis of 6-endo cy-
clization mechanism (Scheme 5) indicated that the formation of
Fig. 2. Crystal structure of the iodolactone 7a with the numbering consistent with
NMR description.
second stereoisomeric d-lactone is disfavoured because of energetic
reasons: in the considered isomer iodine (or phenyl ring in second
theoretically possible conformer) would have to occupy the pseu-
doaxial position.
Assignment of the structures of iodolactonization products with
p-methylphenyl (6b, 7b and 8b) and p-isopropylphenyl substituent
(6c and 7c) was carried out by comparative analysis of their spec-
troscopic data with the data obtained for lactones 6a, 7a and 8a. In
all cases (Table 1) preferential 5-exo cyclization was observed. Be-
C5eH5 and C6eH6 bond and is consistent with the corresponding
torsion angle (ꢀ179.14ꢁ).
The mechanism of iodolactonization involves the formation of
three-membered halonium cation, which is subsequently opened
by the intramolecular nucleophilic attack of the carboxylate oxygen
to form the lactone ring.58 According to the mechanism, during the
5-exo cyclization the carboxylate ion approaches to the carbon C-5
always from the opposite side of the halonium ion, which should
cause the antiperiplanar orientation of the forming CeO and CeI
bonds.
sides, cis d-iodo-g-lactones predominated over their trans stereo-
isomers, making up from 43 to 57% of the product mixture. These
results could be expected taking into consideration the kinetic re-
action conditions in which the predomination of products, which
are formed at higher rate is observed. In this case formation of cis
isomer proceeds faster because the electrostatic interactions be-
tween halonium ion and the large aromatic substituent in the
transition state are minimized.
The bromo- and chlorolactonization of acids 5aec were carried
out with N-bromo- and N-chlorosuccinimide, respectively. Unlike
iodolactonization, the products of 6-endo cyclization predominated
This structural feature is clearly seen in the crystal structure of
lactone 6a (Fig. 1) and confirmed by the torsion angle IeC6eC5eO1
(178.30ꢁ) but in case of trans lactone 7a one can see an interesting
phenomenon (Fig. 2). In fact, two molecules can be observed: the
major one (94%) in which the bonds CeI and CeO are in "gauche"
conformation, with torsion angle IeC6eC5eO1 being 59.23ꢁ and
the minor one (6%) in which these two bonds are clearly

10418
W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
Ph
Ph
H
H
Ph
H
I2
NaHCO3
I
+
O
6a-c
I
_
H
O
H
O
H
H
O
5a-c
OH
O
I2
NaHCO3
Ph
O
Ph
Ph
H
I
H
+
rotation around
C5-C6 bond
I
H
H
O
7a-c
O
_
O
7a-c
I
O
O
H
conformer anti (minor)
conformer syn (major)
Scheme 4. The formation of
d
-iodo-
g
-lactones 6aec, 7aec during 5-exo iodolactonization of acids 5aec.
Ph
Ph
-
+
I
O
O
I
O
Ph
8a-c
O
I2
OH
I
NaHCO3
I
Ph
Ph
O
5a-c
+
O
O
-
O
O
this stereoisomer
is not formed
Scheme 5. The formation of
g-iodo-d-lactones 8aec during 6-endo iodolactonization of acids 5aec.
in almost all cases (Table 1). Only bromolactonization of acid 5b
gave cis- -bromo- -lactone 9b as the main product. The higher
to find some correlations between the structure of tested lactones
and their anticancer activity. The lactones 7b,c and 8a,b could not
be tested because of their insolubility in the majority of solvents
commonly used in cytotoxic assay, i.e., DMSO, water or ethanol. For
evaluation of the cytotoxic activity of tested substances MTT assay
was applied in which mitochondrial dehydrogenase activity within
living cells is determined. This enzyme can reduce yellow MTT to
the purple formazan, which can be determined spectrophotomet-
rically. The production of formazan is proportional to the number of
viable cells. The synthesized halolactones were tested at concen-
d
g
preference for 6-endo cyclization in the case of bromo- and chlor-
olactonization in comparison to iodolactonization arises from the
fact that the rate-determining step in this case is the attack of
bromine or chlorine on the double bond to give the halonium ion
whereas in the iodolactonization the rate-determining step is the
attack of the carboxylate ion on the iodine-double bond complex.59
Despite our efforts, we were unable to separate pure trans
d
d
-
-
bromo-
bromo-
g
g
-lactones and their chloro analogues, apart from trans
-lactone 10b. However, we isolated cis
-lactones. Close structural similarity of obtained
g
-lactones and, in
tration range of 0.1e50 mg/mL and the positive control was carbo-
platin, widely used in the treatment of various types of cancers in
human and canine patients. It was tested at the concentration
almost all cases,
d
products with iodolactones 6e8 was very helpful in establishing
their structures. In all spectra of products the signal shifted down to
the highest field was assigned to that located nearest to the oxygen
of the lactone ring. The differences in chemical shifts for protons
range 0.05e50
as the number of dead cells after treatment with tested compounds
at the concentration of 50 g/mL.
mg/mL. The results, shown in Table 2 are expressed
m
H-6 in the series of cis-g-lactones (6, 9 and 12) and H-5 in the series
The results indicated that some of the synthesized compounds
of d-lactones (8, 11 and 14) were the results of different deshielding
exhibited significant activity against selected tumour cell lines. The
effect of iodine, bromine and chlorine atom, respectively. However,
the multiplicities and coupling constants of corresponding protons
observed on 1H NMR spectra differed insignificantly.
activity of cis d-iodo-g-lactone with p-isopropylphenyl substituent
(6c) against Jurkat cell line was as high as that observed for car-
boplatin. These compounds reduced the number of viable cells by
83.7% and 81.6%, respectively. In the case of D17 cell line, the ac-
tivity of iodolactone 6c accounted for more than half of the activity
2.2. Cytotoxic activity
observed for the control. The trans d-bromo-g-lactone 10b was
Most of the synthesized halolactones were subjected to in vitro
cytotoxic assay against two selected cancer cell lines: Jurkat (hu-
man T-cell leukaemia) and D-17 (canine osteosarcoma). We hoped
noticeably active against both Jurkat and D17 cell line causing cell
mortality at levels 47.6% and 51.1%, respectively. The latter is also
close to the activity of carboplatin. D-17 cell line seemed to be more

W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
10419
Table 2
The percentages of dead cells of the selected cell lines treated with halolactones 6aec, 7a, 9aec, 10b, 11a, 11c, 12aec, 14aec at the concentration of 50 mg/mL
Cell line Lactone
Carbop-
latina
6a
6b
6c
7a
9a
9b
9c
10b
11a
11c
12a
12b 12c
14a
14b
14c
D17
20.6ꢃ3.6 5.9ꢃ2.4 35.2ꢃ9.6 13.6ꢃ3.7
7.2ꢃ4.3 0.0
0.0
51.1ꢃ8.9 22.6ꢃ7.9 5.5ꢃ2.0 8.9ꢃ3.3 0.0
31.3ꢃ3.5 0.0
21.4ꢃ0.8 6.3ꢃ3.0 65.7ꢃ3.9
Jurkat 23.2ꢃ2.4 25.8ꢃ3.5 83.7ꢃ5.7 21.3ꢃ12.7 37.6ꢃ5.3 30.2ꢃ 21.1ꢃ 47.6ꢃ6.4 32.4ꢃ8.9 12.3ꢃ8.6 31.1ꢃ4.9 20.0ꢃ 26.2ꢃ5.4 14.5ꢃ 9.7ꢃ4.5 23.7ꢃ5.2 81.6ꢃ1.7
8.0
6.3
2.8
7.8
a
positive control.
resistant to the tested substances than Jurkat cell line. Four of ex-
amined compounds (9b,c, 12b and 14a) did not display any activity
towards this cell line and most of our lactones were more active
against Jurkat cell lines. Generally, bromolactones caused higher
mortality of Jurkat cell line than their iodo and chloro analogues.
technique on a Bruker micrOTOF-Q II system. The melting points
(uncorrected) were determined on Boetius apparatus. The indexes
of refraction were measured on Carl Zeiss Jena refractometer.
X-ray data were collected on a Kuma KM4CCD diffractometer
ꢁ
(Mo K
a
radiation;
l
¼0.71073 A). X-ray data were collected at 100 K
The activities of
tonesdamong five
some activity (32.4% of dead cells in Jurkat cell line and 22.6% in D17
line). The cis -bromo- -lactone and cis -chloro- -lactone with
d-lactones were predominantly lower than
g-lac-
using an Oxford Cryosystem device. Data reduction and analysis
were carried out with the CrysAlice ‘RED’ program (Oxford Dif-
fractiondPoland, Wroc1aw, 2001, 2003). Analytical numeric ab-
d
-lactones only -bromo- -lactone 11a showed
g
d
d
g
d
g
sorption correction using a multifaceted crystal model was
unsubstituted benzene ring (9a and 12a) were relatively active
against Jurkat cell line (37.6% and 31.1% of dead cells, respectively)
whereas lactones with isopropyl group at benzene ring (6c and 12c)
showed noticeable activity against D17 cell line (35.2% and 31.3% of
dead cells, respectively).
applied.60 The space groups were determined using the XPREP
program. Structures were solved by direct methods using the
SHELXS program and refined using all F2 data, as implemented by
the SHELXL97 program.61 Non-hydrogen atoms were refined with
anisotropic displacement parameters. All H atoms were placed at
calculated positions. Before the last cycle of refinement all H atoms
were fixed and were allowed to ride on their parent atoms. Crystal
data for 6a and 7a reported in this paper, have been deposited with
the Cambridge Crystallographic Data Centre (CCDC) as supple-
mentary publication numbers 944820 and 944821, respectively.
Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union road, Cambridge CB12 1EZ, UK (fax: þ44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
3. Conclusions
In conclusion, a versatile synthetic route was used for the pro-
duction of 20 novel racemic halolactones from commercially
available aromatic aldehydes. The halolactonization was the crucial
step giving rise to iodolactones, bromolactones and chlorolactones.
All new products and intermediates were characterized in detail by
spectral methods and for two iodolactones 6a and 7a the crystal-
lographic analysis was performed, which enabled to determine
the steric structure of the compounds. For most lactones their cy-
totoxic activity was evaluated and cis-5-(1-iodoethyl)-4-(40-iso-
propylphenyl)dihydrofuran-2-one (6c) turned out to be the most
active against Jurkat cell line. Further research is needed on the use
of these drugs in the adjuvant therapy of cancers.
The reagents were purchased from SigmaeAldrichÒ and POCh
(Poland) and were used without purification.
4.2. General procedure for the synthesis of ketones 2aec via
ClaiseneSchmidt condensation
A solution of aldehyde 1 (33 mmol) in acetone (10 mL) and
water (1 mL) was placed in a water bath. The reaction mixture was
stirred and 10% solution of NaOH (1 mL) was added slowly. The
reaction mixture was then stirred for 6 h at room temperature and
acidified with 1 M HCl to pH¼2. The product was extracted with
methylene chloride (3ꢂ40 mL). The organic layer was washed with
brine, dried over anhydrous MgSO4 and filtered. After evaporation
of solvent in vacuo pure ketone 2 was obtained.
4. Experimental
4.1. General section
Silica gel (Kieselgel 60, 230e400 mesh, Merck) was used as the
stationary phase for the purification of the products by column
chromatography. Progress of reactions and purity of the isolated
products were checked by thin layer chromatography on silica gel
coated aluminium plates (DC-Alufolien Kieselgel 60 F254, Merck) as
well on gas chromatography (GC).
4.2.1. (E)-4-Phenylbut-3-en-2-one (2a). Colourless crystals (4.7 g,
99%); mp 40e41 ꢁC (lit. 39e42 ꢁC); spectroscopic data in accor-
dance with literature reports.62
GC analysis was performed on Agilent Technologies 6890N in-
strument equipped with autosampler, split injection (50:1) and FID
detector using DB-17 column ((50%-phenyl)-methylpolysiloxane,
4.2.2. (E)-4-(40-Methylphenyl)but-3-en-2-one (2b). Light brown
liquid (5.1 g, 98%); n2D0¼1.5899 (not reported in literature); spec-
troscopic data in accordance with literature reports.63
30 mꢂ0.25 mmꢂ0.25
mm) with hydrogen as carrier gas. For the
analysis of halolactones the following temperature programme was
applied: injector 280 ꢁC, detector (FID) 280 ꢁC, column temperature:
220 ꢁC, 220e240 ꢁC (rate 3 ꢁC/min), 240e280 ꢁC (rate 30 ꢁC/min),
280 ꢁC (hold 2 min). For the analysis of intermediate products the
column temperature was as follows: 80 ꢁC (hold 1 min), 80e200 ꢁC
(rate 20 ꢁC/min), 200e300 ꢁC (rate 30 ꢁC/min), 300 ꢁC (hold 2 min).
1H NMR, 13C NMR, DEPT 135, HMQC and COSY spectra were
4.2.3. (E)-4-(40-Isopropylphenyl)but-3-en-2-one
(2c). Yellow
liquid (6.1 g, 99%); n2D0¼1.5609 (lit. n2D0¼1.5610); spectroscopic data
in accordance with literature reports.64
4.3. General procedure for preparation of allylic alcohols
3aec
€
recorded in CDCl3 solutions on a Bruker Avance AMX 300 spec-
trometer. IR spectra were determined using Mattson IR 300 Thermo
Nicolet spectrophotometer using KBr pellets or as neat. Mass
spectra were recorded at the Structural Research Laboratory of the
UJK University in Kielce using electron spray ionization (ESI)
Ketone 2 (30 mmol) was dissolved in methanol (100 mL) and the
solution was placed in an ice bath. An aqueous solution of NaBH4
(1.66 g in 10 mL) was added dropwise to the stirring solution. The
reaction mixture was first stirred 1 h in the ice bath and then 2 h at

10420
W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
room temperature. Afterwards hot water was added and the
product was extracted with methylene chloride (3ꢂ40 mL). The
organic layer was washed with brine, dried over anhydrous MgSO4
and filtered. The solvent was evaporated in vacuo and pure alcohol
3 was obtained.
vacuo the residue was diluted with water and organic impurities
were removed by the extraction with diethyl ether (3ꢂ40 mL). The
water layer was acidified with 0.1 M HCl and the product was
extracted with diethyl ether (3ꢂ40 mL). The ethereal fractions were
washed with brine and dried over anhydrous MgSO4. Evaporation
of solvent in vacuo afforded pure acid 5.
4.3.1. (E)-4-Phenylbut-3-en-2-ol (3a). Colourless oil (4.4 g, yield
98%); spectroscopic data consistent with literature reports.65
4.5.1. (E)-3-Phenylhex-4-enoic acid (5a). Brown liquid (2.5 g, 87%);
n2D0¼1.5162 (not reported in literature); spectroscopic data in ac-
cordance with those previously reported.68
4.3.2. (E)-4-(40-Methylphenyl)but-3-en-2-ol (3b). Yellow oil (3.9 g,
80%); spectroscopic data in accordance with literature reports.66
4.5.2. (E)-3-(40-Methylphenyl)hex-4-enoic acid (5b). Brown liquid
(3.2 g, 91%); n2D0¼1.5233; IR: 2700e3550, 1710, 1514, 1439, 1266,
4.3.3. (E)-4-(40-Isopropylphenyl)but-3-en-2-ol
(3c). Yellow
oil
1H
(5.5 g, 96%); n2D0¼1.5382; IR: 3350, 1610, 1055, 969, 813 cmꢀ1
;
968, 815, 738 cmꢀ1
;
1H NMR (300 MHz):
d
1.68 (d, J¼5.4 Hz, 3H,
NMR (300 MHz):
d
1.25 (d, J¼6.9 Hz, 6H, (CH3)2CHe), 1.37 (d,
CH3-6), 2.33 (s, 3H, PheCH3), 2.73 (m, 2H, CH2-2), 3.78 (m, 1H, H-3),
5.51 (dq, J¼15.3, 5.4 Hz, 1H, H-5), 5.60 (dd, J¼15.3, 7.2 Hz, 1H, H-4),
J¼6.3 Hz, 3H, CH3-1), 2.90 (septet, J¼6.9 Hz, 1H, (CH3)2CHe), 4.48
(m,1H, H-2), 6.22 (dd, J¼15.9, 6.3 Hz,1H, H-3), 6.55 (d, J¼15.9 Hz,1H,
7.09e7.15 (2m, 4H, p-C6H4), 13C NMR (75 MHz):
d 17.9 (C-6), 21.0
H-4), 7.17e7.33 (2m, 4H, p-C6H4); 13C NMR (75 MHz):
d
23.4 (C-1),
(PheCH3), 40.6 (C-2), 44.0 (C-3), 125.6 (C-5), 127.2 (C-20 and C-60),
129.3 (C-30 and C-50), 133.0 (C-4), 136.1 (C-10), 140.1 (C-40), 178.0 (C-
1); HRMS: calcd for C13H16O2[MþNa]þ: 227.1048, found 227.1074.
23.9 ((CH3)2CH), 33.8 ((CH3)2CH), 69.0 (C-2), 126.4 (C-20 and C-60),
126.6 (C-30 and C-50), 129.3 (C-4), 132.7 (C-3), 134.6 (C-10), 148.5 (C-
40); HRMS: calcd for C13H18O [MþK]þ: 229.0995, found 229.1035.
4.5.3. (E)-3-(40-Isopropylphenyl)hex-4-enoic acid (5c). Brown liquid
(1.1 g, 85%); n2D0¼1.5183; IR: 3023e2670, 1710, 1511, 1419, 1287,
4.4. General procedure for synthesis of esters 4aec by John-
soneClaisen rearrangement
1055, 967, 829 cmꢀ1
;
1H NMR (300 MHz):
d
1.23 (d, J¼6.9 Hz, 6H,
(CH3)2CHe), 1.65 (d, J¼5.1 Hz, 3H, CH3-6), 2.72 (m, 2H, CH2-2), 2.88
(septet, J¼6.9 Hz, 1H, (CH3)2CHe), 3.76 (m, 1H, H-3), 5.51 (dq,
J¼15.3, 5.1 Hz, 1H, H-5), 5.59 (dd, J¼15.3, 6.9 Hz, 1H, H-4), 7.11e7.18
A
mixture of alcohol 3 (19.4 mmol), triethylorthoacetate
(318 mmol) and drop of propionic acid was heated in 138 ꢁC with
continuous distilling off the ethanol. When the substrate reacted
completely (24 h, TLC) the mixture was subjected to column
chromatography (silica gel, hexane/acetone, 10:1) to afford pure
ester 4.
(2m, 4H, p-C6H4), 13C NMR (75 MHz):
d 18.0 (C-6), 24.0 ((CH3)2CH),
33.7 ((CH3)2CH), 40.6 (C-2), 44.1 (C-3), 125.7 (C-5), 126.7 (C-20 and
C-60), 127.2 (C-30 and C-50), 133.0 (C-4), 140.5 (C-10), 147.1 (C-40),
177.7 (C-1); HRMS: calcd for C15H20O2 [MþNa]þ: 255.1361, found
255.1404.
4.4.1. (E)-3-Phenylhex-4-enoic acid ethyl ester (4a). Yellow liquid
(3.3 g, 80%); n2D0¼1.5030 (not reported in literature); spectroscopic
data in accordance with literature reports.67
4.6. Preparation of iodolactones 6e8
The mixture of acid 5 (3.7 mmol), diethyl ether (20 mL) and
saturated solution of NaHCO3 (10 mL) was stirred for 1 h at room
temperature. Then a solution of I2 (3.5 g) and KI (6 g) in water
(3 mL) was added dropwise to the stirred mixture until a stable
brown colour was obtained. After 24 h the mixture was diluted
with diethyl ether and washed with Na2S2O3 solution. The ethereal
fraction was washed with saturated NaHCO3, brine and dried over
anhydrous MgSO4. After evaporation of solvent the mixture of
products (the composition shown in Table 1) was subjected to
column chromatography (hexane/acetone, 20:1). The data of iso-
lated lactones 6e8 are given below:
4.4.2. (E)-3-(40-Methylphenyl)hex-4-enoic
acid
ethyl
ester
(4b). Yellow liquid (3.7 g, 82%); n2D0¼1.5050; IR: 1736, 1514, 1248,
1158, 1037, 968, 816 cmꢀ1
;
1H NMR (300 MHz):
d
1.18 (t, J¼7.2 Hz,
3H, eOCH2CH3), 1.65 (d, J¼6.6 Hz, 3H, CH3-6), 2.31 (s, 3H, PheCH3),
2.65 (dd, J¼15.0, 7.2 Hz, 1H, one of CH2-2), 2.68 (dd, J¼15.0, 8.4 Hz,
1H, one of CH2-2), 3.77 (m, 1H, H-3), 4.08 (q, J¼7.2 Hz, 2H,
eOCH2CH3), 5.49 (dq, J¼15.0, 6.6 Hz,1H, H-5), 5.58 (ddq, J¼15.0, 7.2,
1.2 Hz, 1H, H-4), 7.09e7.12 (2m, 4H, p-C6H4), 13C NMR (75 MHz):
d
14.2 (eOCH2CH3), 17.9 (C-6), 21.0 (PheCH3), 41.1 (C-2), 44.5 (C-3),
60.2 (eOCH2CH3), 125.4 (C-5), 127.2 (C-20 and C-60), 129.2 (C-30 and
C-50), 133.3 (C-4), 136.0 (C-10), 140.4 (C-40), 172.1 (C-1); HRMS: calcd
for C15H20O2 [MþNa]þ: 255.1361, found 255.1336.
4.6.1. cis-5-(1-Iodoethyl)-4-phenyldihydrofuran-2-one
(6a). Colourless crystals (327 mg, 28%); mp 115e118 ꢁC; IR: 1779,
4.4.3. (E)-3-(40-Isopropylphenyl)hex-4-enoic
acid
ethyl
ester
1416, 1183, 1136, 1005, 755, 706, 535 cmꢀ1 1H NMR (300 MHz):
;
(4c). Yellow liquid; (4.2 g, 84%); n2D0¼1.5000; IR: 1736, 1623, 1510,
d
2.01 (d, J¼6.6 Hz, 3H, CH3-7), 2.71 (dd, J¼17.7, 0.9 Hz, 1H, one of
1251, 1159, 968, 831 cmꢀ1
;
1H NMR (300 MHz):
d
1.17 (t, J¼6.9 Hz,
CH2-3), 3.14 (dd, J¼17.7, 8.7 Hz, 1H, one of CH2-3), 3.47 (dq, J¼10.8,
6.6 Hz, 1H, H-6), 3.91 (dd, J¼8.4, 5.1 Hz, 1H, H-4), 4.82 (dd, J¼10.8,
5.1 Hz, 1H, H-5), 7.25e7.35 (2m, 5H, aromatic), 13C NMR (75 MHz):
3H, eOCH2CH3), 1.23 (d, J¼6.9 Hz, 6H, (CH3)2CHe), 1.65 (d, J¼5.7 Hz,
3H, CH3-6), 2.66 (m, 2H, CH2-2), 2.87 (septet, J¼6.9 Hz, 1H,
(CH3)2CHe), 3.77 (m, 1H, H-3), 4.07 (q, J¼6.9 Hz, 2H, eOCH2CH3),
5.50 (dq, J¼15.3 and 5.7 Hz, 1H, H-5), 5.59 (ddq, J¼15.3, 6.9, 0.9 Hz,
d
23.3 (C-6), 25.5 (C-7), 38.9 (C-3), 45.0 (C-4), 87.8 (C-5), 128.0 (C-
40), 128.6 (C-20 and C-60), 128.7 (C-30 and C-50), 137.3 (C-10), 176.5 (C-
1H, H-4), 7.11e7.17 (2m, 4H, p-C6H4), 13C NMR (75 MHz):
d
14.2
2); HRMS: calcd for
338.9874.
C
12H13IO2 [MþNa]þ: 338.9858, found:
(eOCH2CH3), 18.0 (C-6), 24.0 ((CH3)2CH), 33.7 ((CH3)2CH), 41.2 (C-
2), 44.7 (C-3), 60.3 (eOCH2CH3), 125.5 (C-5), 126.6 (C-20 and C-60),
127.3 (C-30 and C-50), 133.3 (C-4), 140.8 (C-10), 147.0 (C-40), 172.2 (C-
1); HRMS: calcd for C17H24O2 [MþNa]þ: 283.1673, found 283.1674.
Crystal data for 6a: C12H13IO2, M¼316.12, colourless block,
crystal dimensions 0.28ꢂ0.16ꢂ0.09 mm, monoclinic, space group
3
ꢁ
ꢁ
P21/c, a¼6.100(2), b¼12.782(2), c¼15.764(5) A, V¼1157.5(6) A ,
Z¼4, Dc¼1.814 Mg mꢀ3, T¼100 K, R¼0.021, wR¼0.047 (2229 re-
4.5. General procedure for preparation of acids 5aec
flections with I>2s(I) for 136 variables). CCDC No. 944820.
Ester 4 (15.2 mmol) was heated under reflux for 3 h in 2.5%
ethanol solution of NaOH (100 mL). After evaporation of ethanol in
4.6.2. cis-5-(1-Iodoethyl)-4-(40-methylphenyl)dihydrofuran-2-one
(6b). Colourless crystals (271 mg, 21%); mp 68e72 ꢁC; IR: 1791,

W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
10421
1449, 1180, 1139, 960, 829, 498 cmꢀ1; 1H NMR (300 MHz):
d
2.01 (d,
J¼18.3, 9.9 Hz,1H, one of CH2-3), 3.60 (ddd, J¼9.9, 6.6, 5.4 Hz,1H, H-
4), 4.26 (t, J¼5.4 Hz, 1H, H-5), 4.38 (qd, J¼7.2, 5.4 Hz, 1H, H-6),
7.16e7.24 (2m, 4H, p-C6H4); additional signals from minor con-
former I shown on Scheme 4 (7% according to 1H NMR): 1.96 (dd,
J¼7.1 Hz, 3H, CH3-7), 2.79 (dd, J¼18.0, 9.5 Hz,1H, one of CH2-3), 3.06
(dd, J¼18.0, 9.5 Hz, 1H, one of CH2-3), 3.51 (td, J¼9.5, 7.2 Hz, 1H, H-
4), 3.74 (dd, J¼7.2, 2.3 Hz, 1H, H-5), 4.24 (qd, J¼7.1, 2.3 Hz, 1H, H-6);
J¼6.9 Hz, 3H, CH3-7), 2.34 (s, 3H, PheCH3), 2.68 (d, J¼17.4 Hz, 1H,
one of CH2-3), 3.13 (dd, J¼17.4, 8.4 Hz, 1H, one of CH2-3), 3.46 (dq,
J¼10.8, 6.9 Hz, 1H, H-6), 3.86 (dd, J¼8.4, 5.1 Hz, 1H, H-4), 4.80 (dd,
J¼10.8, 5.1 Hz, 1H, H-5), 7.10e7.17 (2m, 4H, p-C6H4), 13C NMR
(75 MHz):
d 21.0 (PheCH3), 23.5 (C-6), 25.5 (C-7), 38.9 (C-3), 44.6
(C-4), 87.8 (C-5), 128.4 (C-20 and C-60), 129.4 (C-30 and C-50), 134.2
(C-10), 137.7 (C-40), 176.6 (C-2); HRMS: calcd for C13H15IO2
[MþNa]þ: 353.0014, found: 352.9989.
13C NMR (75 MHz):
d 23.4 (C-7), 23.9 ((CH3)2CHe), 28.3 (C-6), 33.7
((CH3)2CHe), 37.7 (C-3), 45.0 (C-4), 89.6 (C-5), 126.9 (C-20 and C-60),
127.3 (C-30 and C-50), 138.6 (C-10), 148.5 (C-40), 175.0 (C-2), HRMS:
calcd for C15H19IO2 [MþK]þ: 397.0067, found 397.0107.
4.6.3. cis-5-(1-Iodoethyl)-4-(40-isopropylphenyl)dihydrofuran-2-one
(6c). Colourless solid (371 mg, 30%); mp 50e53 ꢁC; IR: 1789, 1511,
1178, 1135, 962, 838, 527 cmꢀ1
;
1H NMR (300 MHz):
d
1.25 (d,
4.6.7. 5-t-Iodo-6-c-methyl-4-r-phenyltetrahydropyran-2-one
J¼6.9 Hz, 6H, (CH3)2CHe), 2.00 (d, J¼6.9 Hz, 3H, CH3-7), 2.70 (d,
J¼17.7 Hz, 1H, one of CH2-3), 2.90 (septet, J¼6.9 Hz, 1H, (CH3)2CHe),
3.12 (dd, J¼17.7, 8.4 Hz, 1H, one of CH2-3), 3.48 (dq, J¼10.8, 6.9 Hz,
1H, H-6), 3.88 (dd, J¼8.4, 5.1 Hz, 1H, H-4), 4.80 (dd, J¼10.8, 5.1 Hz,
(8a). Yellow crystals (50 mg, 4%); mp 65e70 ꢁC; IR: 1721, 1453,
1253, 1226, 1043, 968, 759, 701, 538 cmꢀ1 1H NMR (300 MHz):
;
d
1.75 (d, J¼6.3 Hz, 3H, CH3-7), 2.68 (dd, J¼17.7, 10.2 Hz, 1H, one of
CH2-3), 2.99 (dd, J¼17.7, 6.3 Hz, 1H, one of CH2-3), 3.50 (td, J¼10.2,
6.3 Hz,1H, H-4), 4.05 (t, J¼10.2 Hz,1H, H-5), 4.78 (dq, J¼10.2, 6.3 Hz,
1H, H-5), 7.18 (m, 4H, p-C6H4); 13C NMR (75 Hz):
d 23.6 (C-6), 23.8
and 23.9 ((CH3)2CHe), 25.5 (C-7), 33.7 ((CH3)2CHe), 38.9 (C-3), 44.6
(C-4), 87.9 (C-5), 126.7 (C-30 and C-50), 128.5 (C-20 and C-60), 134.5
(C-10), 148.6 (C-40), 176.7 (C-2); HRMS: calcd for C15H19IO2 [MþK]þ:
HRMS: calcd for C15H19IO2 [MþNa]þ: 397.0067, found 397.0047.
1H, H-6), 7.16e7.41 (2m, 5H, aromatic), 13C NMR (75 MHz):
d 22.3
(C-7), 34.3 (C-5), 37.8 (C-3), 48.6 (C-4), 81.2 (C-6), 126.9 (C-20 and C-
60), 128.0 (C-40), 129.1 (C-30 and C-50), 142.3 (C-10), 169.5 (C-2);
HRMS: calcd for C12H13IO2 [MþNa]þ: 338.9858, found 338.9889.
4.6.4. trans-5-(1-Iodoethyl)-4-phenyldihydrofuran-2-one
4.6.8. 5-t-Iodo-6-c-methyl-4-r-(40-methylphenyl)tetrahydropyran-2-
(7a). Colourless crystals (175 mg, 15%); mp 72e75 ꢁC; IR: 1781,
one (8b). Yellow crystals (90 mg, 7%); mp 78e82 ꢁC; IR: 1724, 1516,
1494, 1200, 1149, 1027, 768, 700, 524 cmꢀ1
;
1H NMR (300 MHz):
1257, 1233, 1095, 527 cmꢀ1; 1H NMR (300 MHz):
d
1.74 (d, J¼6.3 Hz,
d
1.86 (d, J¼6.9 Hz, 3H, CH3-7), 2.68 (dd, J¼18.3, 6.6 Hz, 1H, one of
3H, CH3-7), 2.35 (s, 3H, PheCH3), 2.65 (dd, J¼17.7,10.2 Hz,1H, one of
CH2-3), 2.96 (dd, J¼17.7, 6.6 Hz, 1H, one of CH2-3), 3.45 (td, J¼10.5,
6.6 Hz,1H, H-4), 4.04 (t, J¼10.5 Hz,1H, H-5), 4.77 (dq, J¼10.5, 6.3 Hz,
1H, H-6), 7.05 (m, 2H, H-30 and H-50), 7.18 (m, 2H, H-20 and H-60), 13C
CH2-3), 3.16 (dd, J¼18.3, 10.2 Hz, 1H, one of CH2-3), 3.64 (ddd,
J¼10.2, 6.6, 5.4 Hz, 1H, H-4), 4.26 (t, J¼5.4 Hz, 1H, H-5), 4.38 (qd,
J¼6.9, 5.4 Hz, 1H, H-6), 7.26e7.41 (m, 5H, aromatic); additional
signals from minor anti conformer shown on Scheme 4 (6%
NMR (75 MHz):
d 21.2 (C-7), 22.4 (PheCH3), 34.9 (C-5), 38.0 (C-3),
according to crystallographic analysis):
d
1.97 (d, J¼6.9 Hz, 3H, CH3-
48.2 (C-4), 81.3 (C-6), 126.8 (C-20 and C-60), 129.8 (C-30 and C-50),
137.8 (C-40), 139.4 (C-10), 169.7 (C-2); HRMS: calcd for C13H15IO2
[MþK]þ: 368.9754, found 368.9745.
7), 2.81 (dd, J¼17.9, 9.5 Hz, 1H, one of CH2-3), 3.11 (dd, J¼17.9,
9.5 Hz, 1H, one of CH2-3), 3.55 (td, J¼9.5, 7.1 Hz, 1H, H-4), 3.79 (dd,
J¼7.1, 2.5 Hz, 1H, H-5), 4.24 (qd, J¼6.9, 2.5 Hz, 1H, H-6); 13C NMR
(75 MHz):
d
23.4 (C-7), 28.4 (C-6), 37.7 (C-3), 45.4 (C-4), 89.5 (C-5),
4.7. Preparation of bromolactones 9e11
127.0 (C-20 and C-60), 127.7 (C-40), 129.3 (C-30 and C-50), 141.2 (C-10),
174.8 (C-2); HRMS: calcd for C12H13IO2 [MþK]þ: 354.9597, found
354.9653.
A solution of acid 5 (3.7 mmol) and N-bromosuccinimide
(6.5 mmol) in THF (50 mL) and a drop of acetic acid was stirred at
room temperature for 24 h. The mixture was diluted with diethyl
ether, washed with saturated NaHCO3 solution and brine. The or-
ganic layer was dried over anhydrous MgSO4 and the solvent was
evaporated in vacuo. The mixture of products (composition shown
in Table 1) was subjected to column chromatography (hexane/ac-
etone, 10:1). Data of isolated lactones 9e11 are given below:
Crystal data for 7a: C12H13IO2, M¼316.12, colourless plate, crystal
dimensions 0.26ꢂ0.20ꢂ0.08 mm, monoclinic, space group P21/c,
3
ꢁ
ꢁ
a¼13.478(4), b¼9.305(3), c¼9.827(3) A, V¼1157.5(6) A , Z¼4,
Dc¼1.799 Mg mꢀ3, T¼100 K, R¼0.026, wR¼0.052 (2080 reflections
with I>2s(I) for 146 variables). CCDC no. 944821.
4.6.5. trans-5-(1-Iodoethyl)-4-(40-methylphenyl)dihydrofuran-2-one
(7b). Oily liquid (155 mg, 12%); IR: 1782, 1516, 1149, 1185, 1030, 814,
4.7.1. cis-5-(1-Bromoethyl)-4-phenyldihydrofuran-2-one
539 cmꢀ1; 1H NMR (300 MHz):
d
1.85 (d, J¼7.2 Hz, 3H, CH3-7), 2.34
(9a). Colourless crystals (149 mg, 15%); mp 110e112 ꢁC; IR: 1782,
(s, 3H, Ph-CH3), 2.65 (dd, J¼18.3, 6.6 Hz, 1H, one of CH2-3), 3.13 (dd,
J¼18.3, 10.2 Hz, 1H, one of CH2-3), 3.59 (ddd, J¼10.2, 6.6, 5.4 Hz, 1H,
H-4), 4.23 (t, J¼5.4 Hz, 1H, H-5), 4.37 (qd, J¼7.2, 5.4 Hz, 1H, H-6),
7.13e7.20 (2m, 4H, p-C6H4); additional signals from minor anti
1454, 1189, 1137, 1012, 755, 707, 634 cmꢀ1 1H NMR (300 MHz):
;
d
1.76 (d, J¼6.6 Hz, 3H, CH3-7), 2.72 (d, J¼17.7 Hz, 1H, one of CH2-3),
3.12 (d, J¼17.7, 8.4 Hz,1H, one of CH2-3), 3.44 (dq, J¼10.5, 6.6 Hz,1H,
H-6), 3.88 (dd, J¼8.4, 5.1 Hz, 1H, H-4), 4.68 (dd, J¼10.5, 5.1 Hz, 1H,
conformer shown on Scheme 4 (12% according to 1H NMR)
d: 1.96
H-5), 7.21e7.36 (2m, 5H, aromatic); 13C NMR (75 MHz):
d 23.3 (C-7),
(d, J¼7.1 Hz, 3H, CH3-7), 2.78 (dd, J¼18.3, 9.5 Hz, 1H, one of CH2-3),
3.07 (dd, J¼18.3, 9.5 Hz,1H, one of CH2-3), 3.50 (td, J¼9.5, 7.3 Hz,1H,
H-4), 3.74 (dd, J¼7.3, 2.5 Hz, 1H, H-5), 4.21 (qd, J¼7.1, 2.5 Hz, 1H, H-
38.4 (C-3), 44.0 (C-4), 45.3 (C-6), 86.6 (C-5), 128.0 (C-40), 128.4 (C-20
and C-60), 128.7 (C-30 and C-50), 137.5 (C-10), 176.3 (C-2); HRMS:
calcd for C12H13BrO2 [MþNa]þ: 290.9996, found 290.9982.
6); 13C NMR (75 MHz):
d 21.1 (C-7), 23.5 (PheCH3), 28.5 (C-6), 37.9
(C-3), 45.1 (C-4), 89.6 (C-5), 127.0 (C-20 and C-60), 130.0 (C-30 and C-
50), 137.6 (C-40), 138.3 (C-10), 175.0 (C-2); HRMS: calcd for C13H15IO2
[MþK]þ: 368.9754, found 368.9796.
4.7.2. cis-5-(1-Bromoethyl)-4-(40-methylphenyl)dihydrofuran-2-one
(9b). Colourless crystals (220 mg, 21%); mp 108e110 ꢁC; IR: 1770,
1515, 1188, 1146, 1014, 887, 632 cmꢀ1; 1H NMR (300 MHz):
d 1.75 (d,
J¼6.6 Hz, 3H, CH3-7), 2.34 (s, 3H, PheCH3), 2.68 (d, J¼17.7 Hz, 1H,
one of CH2-3), 3.10 (dd, J¼17.7, 8.4 Hz, 1H, one of CH2-3), 3.45 (dq,
J¼10.5, 6.6 Hz, 1H, H-6), 3.84 (dd, J¼8.4, 5.4 Hz, 1H, H-4), 4.65 (dd,
J¼10.5, 5.4 Hz, 1H, H-5), 7.09e7.15 (m, 4H, p-C6H4); 13C NMR
4.6.6. trans-5-(1-Iodoethyl)-4-(40-isopropylphenyl)dihydrofuran-2-
one (7c). Oily liquid (119 mg, 9%); IR: 1785, 1513, 1184, 1150, 1028,
829, 564 cmꢀ1
;
1H NMR (300 MHz):
d
1.24 (d, J¼6.9 Hz, 6H,
(CH3)2CHe), 1.86 (d, J¼7.2 Hz, 3H, CH3-7), 2.66 (dd, J¼18.3, 6.6 Hz,
(75 MHz): d 21.0 (Ph-CH3), 23.2 (C-7), 38.4 (C-3), 43.7 (C-4), 45.4 (C-
1H, one of CH2-3), 2.90 (septet, J¼6.9 Hz, 1H, (CH3)2CHe), 3.13 (dd,
6), 86.7 (C-5), 128.3 (C-20 and C-60), 129.4 (C-30 and C-50), 134.4 (C-

10422
W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
10), 137.7 (C-40), 176.4 (C-2); HRMS: calcd for C13H15BrO2 [MþNa]þ:
1455, 1190, 1138, 1015, 747, 678 cmꢀ1; 1H NMR (300 MHz):
d 1.55 (d,
305.0153, found 305.0181.
J¼6.6 Hz, 3H, CH3-7), 2.71 (dd, J¼17.7, 0.9 Hz, 1H, one of CH2-3), 3.11
(dd, J¼17.7, 8.7 Hz,1H, one of CH2-3), 3.43 (dq, J¼10.2, 6.6 Hz, 1H, H-
6), 3.86 (dd, J¼8.7, 5.4 Hz, 1H, H-4), 4.53 (dd, J¼10.2, 5.4 Hz, 1H, H-
4.7.3. cis-5-(1-Bromoethyl)-4-(40-isopropylphenyl)dihydrofuran-2-
one (9c). Colourless solid (126 mg, 11%); mp 81e84 ꢁC; IR: 1790,
5), 7.19e7.37 (2m, 5H, aromatic); 13C NMR (75 MHz):
d 22.4 (C-7),
1508,1186,1136,1012, 886, 633 cmꢀ1; 1H NMR (300 MHz):
d
1.25 (d,
38.0 (C-3), 43.5 (C-4), 53.8 (C-6), 86.4 (C-5), 128.3 (C-20 and C-60),
127.9 (C-40), 128.7 (C-30 and C-50), 137.6 (C-10), 176.2 (C-2); HRMS:
calcd for C12H13ClO2 [MþNa]þ: 247.0502, found 247.0551.
J¼6.9 Hz, 6H, (CH3)2CHe), 1.76 (d, J¼6.6 Hz, 3H, CH3-7), 2.70 (dd,
J¼17.4, 0.6 Hz, 1H, one of CH2-3), 2.90 (septet, J¼6.9 Hz, 1H,
(CH3)2CHe), 3.09 (dd, J¼17.4, 8.4 Hz, 1H, one of CH2-3), 3.47 (dq,
J¼10.5, 6.6 Hz, 1H, H-6), 3.85 (dd, J¼8.4, 5.4 Hz, 1H, H-4), 4.66 (dd,
J¼10.5, 5.4 Hz, 1H, H-5), 7.14 (m, 2H, H-30 and H-50), 7.19 (m, 2H, H-
4.8.2. cis-5-(1-Chloroethyl)-4-(40-methylphenyl)dihydrofuran-2-one
(12b). Colourless crystals (79 mg, 9%); mp 104e106 ꢁC; IR: 1772,
20 and H-60); 13C NMR (75 MHz):
d
23.3 (C-7), 23.8 and 23.9
1508, 1188, 1144, 1019, 777, 676 cmꢀ1; 1H NMR (300 MHz):
d 1.55 (d,
((CH3)2CHe), 33.7 ((CH3)2CHe), 38.4 (C-3), 43.7 (C-4), 45.4 (C-6),
86.7 (C-5), 126.7 (C-30 and C-50), 128.3 (C-20 and C-60), 134.7 (C-10),
148.6 (C-40), 176.4 (C-2); HRMS: calcd for C15H19BrO2 [MþNa]þ:
333.0466, found 333.0458.
J¼6.3 Hz, 3H, CH3-7), 2.34 (s, 3H, PheCH3), 2.69 (d, J¼17.4 Hz, 1H,
one of CH2-3), 3.09 (dd, J¼17.4, 8.4 Hz, 1H, one of CH2-3), 3.43 (dq,
J¼9.9, 6.3 Hz, 1H, H-6), 3.83 (dd, J¼8.4, 5.4 Hz, 1H, H-4), 4.52 (dd,
J¼9.9, 5.4 Hz, 1H, H-5), 7.07e7.16 (2m, 4H, p-C6H4); 13C NMR
(75 MHz):
d 21.0 (PheCH3), 22.3 (C-7), 38.0 (C-3), 43.1 (C-4), 53.8
4.7.4. trans-5-(1-Bromoethyl)-4-(40-methylphenyl)dihydrofuran-2-
(C-6), 86.5 (C-5), 128.2 (C-20 and C-60), 129.4 (C-30 and C-50), 134.5
(C-10), 137.7 (C-40), 176.3 (C-2); HRMS: calcd for C13H15ClO2
[MþNa]þ: 261.0658, found 261.0658.
one (10a). Oily liquid (52 mg, 5%); IR: 1785, 1517, 1185, 1033, 814,
635 cmꢀ1; 1H NMR (300 MHz):
d
1.67 (d, J¼6.9 Hz, 3H, CH3-7), 2.34
(s, 3H, Ph-CH3), 2.63 (dd, J¼18.3, 6.6 Hz, 1H, one of CH2-3), 3.12 (dd,
J¼18.3, 9.9 Hz, 1H, one of CH2-3), 3.67 (ddd, J¼9.9, 6.6, 5.1 Hz, 1H, H-
4), 4.30 (qd, J¼6.9, 5.1 Hz, 1H, H-6), 4.51 (t, J¼5.1 Hz, 1H, H-5), 7.13
(m, 2H, H-20 and H-60), 7.17 (m, 2H, H-30 and H-50); 13C NMR
4.8.3. cis-5-(1-Chloroethyl)-4-(40-isopropylphenyl)dihydrofuran-2-
one (12c). Colourless crystals (88 mg, 9%); mp 88e93 ꢁC; IR: 1790,
1507, 1182, 1135,1018, 886, 678 cmꢀ1; 1H NMR (300 MHz):
d 1.24 (d,
(75 MHz):
d
21.0 (PheCH3), 21.4 (C-7), 37.6 (C-3), 43.1 (C-4), 50.0 (C-
J¼6.9 Hz, 6H, (CH3)2CHe), 1.56 (d, J¼6.3 Hz, 3H, CH3-7), 2.70 (dd,
J¼17.7, 0.9 Hz, 1H, one of CH2-3), 2.90 (septet, J¼6.9 Hz, 1H,
(CH3)2CHe), 3.08 (d, J¼17.7, 8.4 Hz, 1H, one of CH2-3), 3.45 (dq,
J¼10.2, 6.3 Hz, 1H, H-6), 3.83 (dd, J¼8.4, 5.4 Hz, 1H, H-4), 4.52 (dd,
J¼10.2, 5.4 Hz, 1H, H-5), 7.12 (m, 2H, H-20 and H-60), 7.19 (m, 2H, H-
6), 89.0 (C-5), 126.8 (C-20 and C-60), 129.9 (C-30 and C-50), 137.5 (C-
40), 138.5 (C-10), 175.1 (C-2); HRMS: calcd for C13H15BrO2 [MþNa]þ:
305.0153, found 305.0175.
4.7.5. 5-t-Bromo-6-c-methyl-4-r-phenyltetrahydropyran-2-one
30 and H-50); 13C NMR (75 MHz):
d 22.3 (C-7), 23.8 and 23.9
(11a). Colourless crystals (189 mg, 19%); mp 83e86 ꢁC; IR: 1723,
((CH3)2CHe), 33.7 ((CH3)2CHe), 38.0 (C-3), 43.1 (C-4), 53.8 (C-6),
86.6 (C-5), 126.7 (C-30 and C-50), 128.2 (C-20 and C-60), 134.8 (C-10),
148.6 (C-40), 176.3 (C-2); HRMS: calcd for C15H19ClO2 [MþNa]þ:
289.0971, found 289.0988.
1455, 1258, 1232, 1053, 763, 705, 623 cmꢀ1 1H NMR (300 MHz):
;
d
1.66 (d, J¼6.3 Hz, 3H, CH3-7), 2.73 (dd, J¼17.7, 10.2 Hz, 1H, one of
CH2-3), 3.06 (dd, J¼17.7, 6.9 Hz, 1H, one of CH2-3), 3.46 (td, J¼10.2,
6.9 Hz,1H, H-4), 3.97 (t, J¼10.2 Hz,1H, H-5), 4.66 (dq, J¼10.2, 6.3 Hz,
1H, H-6), 7.19e7.41 (2m, 5H, aromatic); 13C NMR (75 MHz):
d
20.6
4.8.4. 5-t-Chloro-6-c-methyl-4-r-phenyltetrahydropyran-2-one
(C-7), 37.7 (C-3), 47.1 (C-4), 54.1 (C-5), 79.7 (C-6), 127.0 (C-20 and C-
60), 127.9 (C-40), 129.1 (C-30 and C-50), 140.7 (C-10), 169.2 (C-2);
HRMS: calcd for C12H13BrO2 [MþNa]þ: 290.9996, found 291.0056.
(14a). Colourless crystals (107 mg, 13%); mp 52e55 ꢁC; IR: 1733,
1410, 1222, 1256, 1058, 776, 760, 701 cmꢀ1 1H NMR (300 MHz):
;
d
1.60 (d, J¼6.3 Hz, 3H, CH3-7), 2.75 (dd, J¼18.0, 10.2 Hz, 1H, one of
CH2-3), 3.07 (dd, J¼18.0, 6.6 Hz, 1H, one of CH2-3), 3.35 (td, J¼10.2,
6.6 Hz,1H, H-4), 3.90 (t, J¼10.2 Hz,1H, H-5), 4.53 (dq, J¼10.2, 6.3 Hz,
4.7.6. 5-t-Bromo-4-r-(40-isopropylphenyl)-6-c-methyltetrahy-
dropyran-2-one (11c). Colourless crystals (218 mg, 19%); mp
89e93 ꢁC; IR: 1741, 1507, 1255, 1219, 1058, 829, 638 cmꢀ1; 1H NMR
1H, H-6), 7.21e7.41 (2m, 5H, aromatic); 13C NMR (75 MHz):
d 19.6
(C-7), 37.2 (C-3), 46.6 (C-4), 62.1 (C-5), 79.4 (C-6), 127.1 (C-20 and C-
60), 127.9 (C-40), 129.0 (C-30 and C-50), 140.0 (C-10), 169.1 (C-2);
HRMS: calcd for C12H13ClO2 [MþNa]þ: 247.0502, found 247.0529.
(300 MHz):
d
1.25 (d, J¼6.9 Hz, 6H, (CH3)2CHe), 1.65 (d, J¼6.3 Hz,
3H, CH3-7), 2.71 (dd, J¼17.7, 10.2 Hz, 1H, one of CH2-3), 2.91 (septet,
J¼6.9 Hz, 1H, (CH3)2CHe), 3.04 (d, J¼17.7, 6.9 Hz, 1H, one of CH2-3),
3.44 (td, J¼10.2, 6.9 Hz, 1H, H-4), 3.95 (t, J¼10.2 Hz, 1H, H-5), 4.64
(dq, J¼10.2, 6.3 Hz, 1H, H-6), 7.09e7.24 (2m, 4H, p-C6H4); 13C NMR
4.8.5. 5-t-Chloro-6-c-methyl-4-r-(40-methylphenyl)tetrahydropyran-
2-one (14b). Colourless crystals (61 mg, 7%); mp 64e65 ꢁC; IR:
(75 MHz):
d
20.6 (C-7), 23.9 ((CH3)2CHe), 33.7 ((CH3)2CHe), 37.7 (C-
1740, 1516, 1230, 1218, 1057, 815, 667 cmꢀ1 1H NMR (300 MHz):
;
3), 46.8 (C-4), 54.4 (C-5), 79.7 (C-6), 126.9 (C-20 and C-60), 127.1 (C-30
d
1.60 (d, J¼6.3 Hz, 3H, CH3-7), 2.35 (s, 3H, PheCH3), 2.72 (dd,
and C-50), 138.2 (C-10), 148.5 (C-40), 169.4 (C-2); HRMS: calcd for
J¼17.7, 9.9 Hz, 1H, one of CH2-3), 3.04 (dd, J¼17.7, 6.9 Hz, 1H, one of
CH2-3), 3.31 (td, J¼9.9, 6.9 Hz, 1H, H-4), 3.88 (t, J¼9.9 Hz, 1H, H-5),
4.51 (dq, J¼9.9, 6.3 Hz, 1H, H-6), 7.10 (m, 2H, H-20 and H-60), 7.19 (m,
C
15H19BrO2 [MþNa]þ: 333.0466, found 333.0508.
4.8. Preparation of chlorolactones 12e14
2H, H-30 and H-50); 13C NMR (75 MHz):
d 19.7 (C-7), 21.0 (PheCH3),
37.4 (C-3), 46.3 (C-4), 62.3 (C-5), 79.5 (C-6), 127.0 (C-20 and C-60),
129.7 (C-30 and C-50), 137.0 (C-10), 137.7 (C-40), 169.1 (C-2); HRMS:
calcd for C13H15ClO2 [MþNa]þ: 261.0658, found 261.0704.
A solution of acid 5 (3.7 mmol) and N-chlorosuccinimide
(7.6 mmol) in THF (50 mL) and a drop of acetic acid was stirred at
room temperature for 48 h. The mixture was diluted with diethyl
ether, washed with saturated NaHCO3 solution and brine. The or-
ganic layer was dried over anhydrous MgSO4 and the solvent was
evaporated in vacuo. The mixture of products (composition shown
in Table 1) was subjected to column chromatography (hexane/ac-
etone, 10:1). Data of isolated lactones 12 and 14 are given below:
4.8.6. 5-t-Chloro-4-r-(40-isopropylphenyl)-6-c-methyltetrahy-
dropyran-2-one (14c). Colourless crystals (138 mg, 14%); mp
74e77 ꢁC; IR: 1741, 1507, 1255, 1220, 1058, 829, 667 cmꢀ1; 1H NMR
(300 MHz):
d
1.25 (d, J¼6.9 Hz, 6H, (CH3)2CHe), 1.59 (d, J¼6.3 Hz,
3H, CH3-7), 2.73 (dd, J¼17.7, 9.9 Hz, 1H, one of CH2-3), 2.91 (septet,
J¼6.9 Hz, 1H, (CH3)2CHe), 3.05 (dd, J¼17.7 and 6.9 Hz, 1H, one of
CH2-3), 3.33 (td, J¼9.9, 6.9 Hz, 1H, H-4), 3.88 (t, J¼9.9 Hz, 1H, H-5),
4.51 (dq, J¼9.9, 6.3 Hz, 1H, H-6), 7.12e7.24 (2m, 4H, p-C6H4); 13C
4.8.1. cis-5-(1-Chloroethyl)-4-phenyldihydrofuran-2-one
(12a). Colourless crystals (66 mg, 8%); mp 100e102 ꢁC; IR: 1767,

W. Gładkowski et al. / Tetrahedron 69 (2013) 10414e10423
10423
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d 19.6 (C-7), 23.8 ((CH3)2CHe), 33.7 ((CH3)2CHe),
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5
mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
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275 mL distilled water) were added. The optical density (OD) of
formazan formed from MTT was measured after 24 h using
a spectrophotometric microplate reader (Elx800, BioTek) at refer-
ence wavelength of 570 nm. Percentages of dead cells were de-
termined according to the following formula: [1ꢀ(ODtꢀODm/
ODcꢀODm)]ꢂ100, where ODt is the optical density of formazan
formed in treated cells, ODc is the optical density of formazan
formed in control (untreated) cells and ODm is the optical density of
medium only. The results presented in Table 2 are mean valuesꢃSD
obtained from three independent experiments (4 wells each).
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