Synthesis and cytotoxic activity of fluorinated analogues of Goniothalamus lactones. Impact of fluorine on oxidative processes

Article abstract of DOI:10.1016/j.ejmech.2010.03.032

Novel fluorinated analogues of goniothalamin 1 and howiinol A 2 have been prepared from trifluorocrotonate derivatives. Trifluoromethyl goniothalamin (R/S) 4 showed a slightly lower activity than 1, while the trifluoromethyl howiinol A 16 exhibited similar activities on several cell lines in the micromolar range. Unlike (R) goniothalamin and howiinol A, trifluoromethyl parent compounds remained unchanged when submitted to biomimetic oxidative systems.

Full text of DOI:10.1016/j.ejmech.2010.03.032

European Journal of Medicinal Chemistry 45 (2010) 3213e3218
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and cytotoxic activity of fluorinated analogues of Goniothalamus
lactones. Impact of fluorine on oxidative processes
Lidia Dumitrescu a, Doan Thi Mai Huong b, Nguyen Van Hung b, Benoit Crousse a,
,
Danièle Bonnet-Delpon a
*
a UMR-CNRS 8076, Molécules fluorées et chimie médicinale, IFR 141, Faculté de Pharmacie, Université Paris-Sud, J. B. Clément, 5, rue Jean-Baptiste Clement,
92290 Châtenay-Malabry, France
b Laboratory of Terpenoid Chemistry, Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Caugiay, Hanoi, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fluorinated analogues of goniothalamin 1 and howiinol A 2 have been prepared from tri-
fluorocrotonate derivatives. Trifluoromethyl goniothalamin (R/S) 4 showed a slightly lower activity than
1, while the trifluoromethyl howiinol A 16 exhibited similar activities on several cell lines in the
micromolar range. Unlike (R) goniothalamin and howiinol A, trifluoromethyl parent compounds
remained unchanged when submitted to biomimetic oxidative systems.
Received 8 January 2010
Received in revised form
18 March 2010
Accepted 20 March 2010
Available online 25 March 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Styryl-lactones
Metabolism
Fluorine
Antitumor
1. Introduction
Although the mechanism of action is not yet elucidated,
goniothalamin has been reported to generate the apoptosis process
Naturally occurring styryl-lactones represent a homogeneous
group of secondary metabolites isolated from Goniothalamus. The
first member of this class, the styryl-pyrone goniothalamin 1 can be
considered as a biogenetic precursor of other structurally related
lactones in particular goniodiol, goniotriol, howiinol A 2 (Fig. 1) [1].
(R)-(þ)-goniothalamin 1 was isolated for the first time in 1967
[2]. It has shown a wide range of biological activities such as anti-
microbial [3], larvicidal [4e6], anti-inflammatory [7,8], and also
significant antifungal activities [4e6]. Moreover, goniothalamin
exhibited antiproliferative activity against various cancer cell lines:
via the mitochondrial respiratory chain but also via successive
activation of caspases [12,13].
The in vitro cytotoxicity of the natural (R)-goniothalamin 1 has
been further confirmed in vivo on mice but only in few reports [14].
However, side effects like genotoxicity [15] and embryotoxicity [16]
have also been reported. While numerous syntheses of goniotha-
lamin and related lactones have been described [17e24], structure/
activity relationship has been much less investigated. It neverthe-
less appears that the lactone moiety is essential for the activity. The
side chain interacts with a hydrophobic domain of the target but
the styryl moiety is not always required since the replacement of
the phenyl group by a cyclohexyl one also resulted in a good anti-
tumor activity [13]. Although it is difficult, in a general way, to
differentiate the antitumor activity from the toxicity, it seems likely
that side effects could be imparted to the facile in vivo oxidation of
the exocyclic double bond into epoxides. The goniothalamin
epoxide 3 has been postulated as the biogenetic precursor of other
styryl-lactone derivatives [12,25]. Furthermore, it has been isolated,
in a non negligible amount, from Goniothalamus macrophyllus,
a plant traditionally used for its abortive properties [16]. With the
aim to limit the oxidative metabolism of the reactive exocyclic
double bond, we envisaged to replace the phenyl group in gonio-
thalamin by an appropriate substituent.
mouse leukemia (P-388; IC50 ¼ 3.8
(WEHI164; IC50 8.5 M) [9], human hepatoma (Hep3B;
IC50 ¼ 5.4 M) [10], human hepatocellular carcinoma (HepG2;
IC50 ¼ 1.6 M) [10], human breast carcinoma (MCF-7, IC50 ¼ 4.5 M)
[10], and estrogen receptor breast cancer (MDA-MB-231,
M) [9]. Recently it has been reported that (S)-gonio-
mM) [9], mouse fibro sarcoma
¼
m
m
m
m
IC50 ¼ 5.4
m
thalamin 1 was also potent against some cancer cells [11].
* Corresponding author. UMR-CNRS 8076, Molécules fluorées et chimie médici-
nale, IFR 141, Faculté de Pharmacie, Université Paris-Sud, J. B. Clément, 5, rue Jean-
Baptiste Clement, 92290 Châtenay-Malabry, France.
E-mail address: daniele.bonnet-delpon@u-psud.fr (D. Bonnet-Delpon).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.032

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L. Dumitrescu et al. / European Journal of Medicinal Chemistry 45 (2010) 3213e3218
RCM reaction was performed using the Grubb’s second-generation
O
O
catalyst, and a further deprotection of the alcohol with fluoride
anion led to the cyclic lactone 10. The dehydration of tri-
fluoromethyl alcohols is often difficult and usually requires harsh
conditions (P2O5 or MsCl/strong base). Under these conditions
a complex mixture of products was obtained from the alcohol 10
probably due to the presence of reactive functions.
An alternative route to 4 was to start from the ethyl tri-
fluorocrotonate 11, previously described by dehydration with P2O5
[35]. Then the CF3-goniothalamin 4 was prepared as outlined in
Scheme 2. The only difference with the previous sequence is the
generation of the aldehyde 13 for which a two step oxidation/
reduction reaction has been proved to be more efficient.
Due to the volatility of the aldehyde 13, the allylation reaction
under Barbier conditions was directly achieved from the crude
product. The CF3-goniothalamin 4 was obtained successfully by
ring closing metathesis with 10 mol% of Grubb’s II catalyst in
refluxing dichloromethane for 16 h.
O
O
(R)-Goniothalamin 1
(S)-Goniothalamin 1
O
O
O
Ph
O
O
O
H
O
H
OH OH
Howiinol A 2
goniothalamine oxide 3
Fig. 1. Structure of styryl-lactones.
The incorporation of fluorine into molecules has become a good
tool in medicinal chemistry for improving the pharmacological
profile of bioactive compounds, in particular for increasing the
metabolic stability [26e31]. Indeed the presence of fluoroalkyl
groups slows down the oxidative and hydrolytic processes, there-
fore avoiding the formation of toxic secondary metabolites. In
addition, fluoroalkyl groups, at the same time highly hydrophobic,
and sterically demanding, are able to mimic phenyl or benzyl
groups with beneficial effects [32,33]. To our knowledge, only one
fluorinated analogue of goniothalamin has been reported, where
a gem difluoro was introduced onto the cyclic lactone part, but no
information about its activity was given [34].
3. Biological results
Cytotoxicity activities of the (R/S)-CF3-goniothalamin 4 were
evaluated against the following cancer cell lines: KB (human oral
epidermoid carcinoma), MCF-7, HT29 (human colon cancer cells),
HepG2, A549 (human lung carcinoma) (Table 1).
Assays performed at 0.1, 1 and 10
showed an IC50 > 10 M. We next studied the inhibition of the
considered cancer cell lines at 50 M, and percentage ranged from
73% to 97%. These values let suppose an IC50 between 10 and 50 M.
For comparison we also prepared and evaluated the CF3-
analogue 16 of howiinol A 2, where the CF3 group also replaces
a phenyl in a styryl chain. Howiinol A 2 is described as a potent in
vitro inhibitor of a variety of cancer cells, with IC50 ranging from 1 to
mM with CF3-goniothalamin 4
m
m
m
Here we report the impact of the replacement of a phenyl group
by a trifluoromethyl substituent in two natural styryl-lactone
derivatives, goniothalamin and howiinol A.
5 mg/mL (around 3e15 mM) [36,37]. To our knowledge its in vivo
activity is poorly reported with no mention on its toxicity [38].
2. Results and discussion
The CF3-howiinol 16 was synthesized as shown in Scheme 3. The
intermediate 17 was previously described from
D-glycero-D-gulo-
In the literature cyclic lactones are prepared through two
principal ways, intramolecular lactonisation or ring closing
metathesis (RCM). This latter was chosen for the synthesis of the (R/
S)-CF3-goniothalamin 4, starting from the commercially available
ethyl trifluoroacetyl acetate 5 (Scheme 1).
heptano- -lactone for the synthesis of howiinol A 2 [39]. CF3-
g
howiinol 16 was obtained from 17 by esterification with
trifluorocrotonic acid followed by a deprotection in acidic medium.
This compound was evaluated against the same cancer cell lines
as for goniothalamin derivatives (Table 2).
After reduction of 5 [35] and protection of the alcohol with
TBDMSCl, the ester 6 was reduced into the aldehyde 7. This latter
reacted under Barbier conditions to afford the allylic alcohol 8 as
a 60/40 mixture of diastereomers, which further reacted with
acryloyl chloride to provide the di-unsaturated compound 9. The
Interestingly, the CF3-howiinol 16 exhibited cytotoxicity against
all cancer cell lines in the same range than that of the natural
compound 2.
For a preliminary evaluation of the compared metabolic stability
of natural compounds 1 and 2, and their CF3-analogues 4 and 16,
O
O
OP
O
OP
O
OP OH
c
a, b
d
F3C
OEt
F3C
OEt
F3C
H
F3C
5
6
7
8
P = TBDMS
f
ratio : 60/40
O
O
O
e
OP
O
OH
O
O
X
F3C
F3C
CH3
F3C
CF3-Goniothalamin 4
H3C
9
10
CH3
N
N
H3C
H3C
Cl
CH3
Ru
Grubb's II
Cl
Ph
P(Cy)3
Scheme 1. Reagents and conditions: (a) NaBH4, (0.3 eq) Et2O, 0 ꢀC to rt; (b) TBDMSCl (1.2 eq), imidazole (2.5 eq), 0 ꢀC to rt 75% (2 steps); (c) DIBAL-H (1.5 eq), toluene, ꢁ78 ꢀC to rt,
94%; (d) allyl bromide (1.2 eq), Zn (1.3 eq)/TMSCl cat, DMF, rt, 94%; (e) acryloyl chloride (2 eq), DMAP cat., TEA, DCM, ꢁ78 ꢀC to rt, 60%; (f) 1) Grubb’s II 10 mol%, DCM, reflux, 2) TBAF
(2.5 eq), THF, 70%.

L. Dumitrescu et al. / European Journal of Medicinal Chemistry 45 (2010) 3213e3218
3215
O
O
O
d
c
a, b
F3C
OH
F3C
O
F3C
OEt
F3C
OEt
5
11
12
13
O
O
OH
e
g
f
O
O
F3C
F3C
F3C
CF3-Goniothalamin 4
14
15
Scheme 2. Reagents and conditions: (a) NaBH4, (0.3 eq) Et2O, 0 ꢀC to rt; (b) P2O5 (2.0 eq) 66% (2 steps); (c) LiAlH4 (1.5 eq)/AlCl3 (1.5 eq), Et2O, 82%; (d) PCC (1.0 eq), DCM; (e) allyl
bromide (1.2 eq), Zn (1.3 eq)/TMSCl cat., DMF, rt, 60% (2 steps); (f) acryloyl chloride (2 eq), DMAP cat., TEA, DCM, ꢁ78 ꢀC to rt, 6 h, 60%; (g) Grubb’s II 10 mol%, DCM, reflux, 16 h, 70%.
these compounds have been submitted to biomimetic oxidation
systems. Experiments were performed with H2O2/imidazole or
mCPBA as oxidants, by using three metalloporphyrin catalytic
systems, developed for mimicking the activity of cytochromes P450
[40,41]. Among them, one allowed a complete disappearance of
goniothalamin 1 after 24 h, and GC/MS analyses showed the
generation of three main oxidized products (M þ 16) obtained in
similar proportions. Two of them are the epoxide 3 and its dia-
stereomer, as determined by comparison with authentic samples
prepared according to literature [16]. In MS spectra they exhibit the
same important transannular fragments of aryl epoxides
(m/z ¼ 216, 105, 97, 91, 82, 69). The third one is obviously oxidized
at a different site but its structure could not be unambiguously
determined. Under the same conditions, the CF3-goniothalamin 4
was completely recovered unchanged. As postulated, CF3-gonio-
thalamin epoxides, analogues of 3, were not formed, but surpris-
ingly, the replacement of the phenyl group of the side chain by a CF3
group seems to protect other sites from oxidation.
procedures. Pure products were obtained after flash chromatog-
raphy using Merck silica gel 60 (40e63 m). TLC analyses were
m
performed with 0.25 mm 60 F254 silica plates (Merck). Element
analyses (C, H, N) were performed on a PerkineElmer CHN, Analyser
2400. IR spectra were recorded on a Bruker Vector 22 FT-IR spec-
trometer. Melting points were determined on a Kofler melting point
apparatus. NMR spectra were recorded on a Bruker AMX 200, (1H,
200 MHz,19F: 188 MHz 13C, 50 MHz). Chemical shift
d are in ppm and
the following abbreviations are used: singlet (s), doublet (d), triplet
(t), quadruplet (q), multiplet (m), broad singlet (brs).
5.1.1. Ethyl 3-(tert-butyldimethylsilyloxy)-4,4,4-trifluorobutanoate (6)
To a solution of ethyl 4,4,4-trifluoro-3-hydroxybutanoate (5.0 g,
26.8 mmol) in dry dimethylformamide (10 mL), at 0 ꢀC, imidazole
(4.6 g, 67.0 mmol) was added followed by tert-butyldimethylsilyl
chloride (4.9 g, 32.2 mmol). Then, the reaction mixture was warmed
to room temperature and stirred for 28 h. Dichloromethane (50 mL)
was added, and the resulting mixture was successively washed with
an aqueous hydrochloric acid solution (0.1 M, 10 mL), a saturated
aqueous solution of NaHCO3 (15 mL), and with brine (10 mL). The
organic layer was dried over anhydrous MgSO4. Filtration and
removalof thesolventprovided the product 6 (7.0 g, 87%)asanyellow
oilwhichcanbeusedwithoutpurification.1HNMR(300MHz,CDCl3):
Submitted to the same oxidative systems, howiinol A 2 was
proved to be much more resistant with a 15% conversion into
oxidized products (M þ 16) after 24 h. No oxidation at all was
observed with CF3-howiinol 16.
d
0.08 (s, 3H); 0.13 (s, 3H); 0.87 (s, 9H); 1.27 (t, J ¼ 7.2 Hz, 3H); 2.58 (dd,
J ¼ 15.9, 7.9 Hz, 1H); 2.68 (dd, J ¼ 15.9, 4.3 Hz, 1H); 4.16 (q, J ¼ 7.2 Hz,
2H); 4.51 (m, 1H). 13C NMR (75 MHz, CDCl3):
ꢁ3.2; ꢁ3.1; 13.8; 17.7;
4. Conclusion
d
The replacement of a phenyl group by a trifluoromethyl group in
goniothalamin and howiinol A resulted in a slightly lower or similar
cytotoxicity against various cancer cell lines. In contrast a great
impact of the CF3 substituent was exhibited in a biomimetic
oxidative metabolism experiment. All sites of molecules were
protected from oxidation. In vivo assays are currently under
investigation in order to confirm the beneficial impact of the flu-
oroalkyl substituent.
25.2; 36.9; 60.8; 68.3 (q, J ¼ 31.7 Hz, CHCF3); 124.4 (q, J ¼ 282.2 Hz,
CF3); 169.5. 19F NMR (188 MHz, CDCl3):
d
ꢁ79.6 (d, J ¼ 6.9 Hz, CF3). IR
(cmꢁ1): 2941; 1710.
5.1.2. 3-(tert-Butyldimethylsilyloxy)-4,4,4-trifluorobutanal (7)
Diisobutylaluminium hydride (35.0 mL, 1.0
M in hexane,
35.0 mmol) was added drop by drop for 1h at ꢁ78 ꢀC to a solution of
5. Experimental section
O
OH
OH OH
H
O
H
O
O
a ,b, c
d, e
f, g
CHO
5.1. Chemistry
O
HO
OHC
OH
Ph
OH
HO
O
O
O
OH
General chemical techniques: usual solvents were purchased
from commercial sources and dried and distilled by standard
D-glycero-D-gulo-heptano-γ-lactone
O
O
O
O
O
O
OH
O
F3C
O
O
h
i
F3C
O
O
Ph
Ph
Table 1
Ph
O
O
O
OH OH
IC50
(mM) of (R/S) goniothalamin 1, (R/S)-CF3-goniothalamin 4, against cancer cell
lines. IC50 means the concentration that elicits cell growth inhibition by 50%.
17
18
16
Compounds
KB
MCF-7
HT29
HepG2
A549
9.1
>10
Scheme 3. (a) ZnCl2, H3PO4, acetone, rt, 24 h, 87%; (b) CH3COOH, H2O, rt, 48 h, 70%; (c)
NaIO4, MeOH, H2O, rt, 30 min; (d) PhMgBr, THF, 0 ꢀC, 2 h, 56%; (e) NaIO4, MeOH, H2O,
rt, 30 min; (f) Ph3P ¼ CHCOOMe, MeOH, t.a., 2 h, 79%; (g) DBU cat., THF, reflux, 70%;
(h) trifluorocrotonic acid, EDC/DMAP cat., DCM, 0 ꢀC to rt, 94%; (i) CH3COOH aq. 50%,
80 ꢀC, 60%.
1a
3.0
>10
3.5
>10
10.1
>10
2.4
>10
4b
a
R/S goniothalamin has been prepared according to ref. [18,19].
% inhibition at 50 mM was found to be around 90%.
b

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L. Dumitrescu et al. / European Journal of Medicinal Chemistry 45 (2010) 3213e3218
Table 2
1.92 (m, 2H); 2.4 (ddd, J ¼ 7.2, 2.6, 1.1 Hz, 1H); 2.46 (ddd, J ¼ 7.2, 2.9,
IC50 (mM) of howiinol A 2 and CF3-howiinol 16 against cancer cell lines.
1.1 Hz, 1H); 4.0 (m, 1H); 5.07 (m, 1H); 5.14 (m, 2H); 5.71 (m, 1H);
5.82 (dd, J ¼ 12.0, 2.6 Hz, 1H); 6.08 (dd, J ¼ 17.2, 5.3 Hz, 1H); 6.36
Compounds
2a
16
KB
MCF-7
HT29
HepG2
A549
(dd, J ¼ 17.3, 1.7 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d
ꢁ5.1; ꢁ5.0;
0.9
1.4
1.1
1.6
2.6
4.5
1.6
1.8
1.5
3.0
18.1; 25.6; 35.2; 38.8; 68.0 (q, J ¼ 31.3 Hz, CHCF3); 69.7; 118.6; 129.7
(q, J ¼ 282.3 Hz, CF3); 128.4; 131.0; 132.4; 165.5. 19F NMR (188 MHz,
a
Howiinol A 2 was prepared according to ref. [39].
CDCl3):
d
ꢁ79.0 (d, J ¼ 6.9 Hz, CF3). IR (cmꢁ1): 2980; 1722; 1637;
1188; 1043. Minor diastereoisomer 1H NMR (300 MHz, CDCl3):
d
0.103 (s, 3H); 0.115 (s, 3H); 0.91 (s, 9H); 1.92 (m, 2H); 2.36 (m, 2H);
ester 6 (7.0 g, 23.3 mmol) in dry toluene (10 mL). After stirring for
2 h under an inert atmosphere, the reaction was carefully quenched
at ꢁ78 ꢀC with methanol (40 mL). Citric acid (10% aqueous solution,
30 mL) was then added, and the mixture was allowed to warm to
room temperature for 30 min. The resulting residue was removed
by filtration, and the aqueous phase was extracted with dichloro-
methane (3 ꢂ 20 mL). The combined organic layers were washed
with brine (10 mL), dried over anhydrous MgSO4, filtered and
concentrated under reduce pressure to give the crude aldehyde 7
(5.6 g, 94%) as an yellow oil, which was used on the next step
4.01 (m, 1H); 4.0 (m, 1H); 5.07 (m, 1H); 5.14 (m, 2H); 5.71 (m, 1H);
5.81 (dd, J ¼ 8.6, 2.5 Hz, 1H); 6.13 (dd, J ¼ 17.3, 5.3 Hz, 1H); 6.45 (dd,
J ¼ 17.3, 1.1 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d
ꢁ5.1; ꢁ5.0; 18.0;
25.5; 35.9; 38.4; 68.4 (q, J ¼ 31.3 Hz, CHCF3); 69.6; 118.5; 129.6 (q,
J ¼ 282.3 Hz, CF3); 128.5; 130.9; 132.5; 165.3. 19F NMR (188 MHz,
CDCl3): ꢁ78.7 (d, J ¼ 6.2 Hz, CF3). IR (cmꢁ1): 2980; 1722; 1637;
1188; 1043.
5.1.5. 6-(3,3,3-Trifluoro-2-hydroxypropyl)-5,6-dihydro-2H-
pyran-2-one (10)
without purification. 1H NMR (300 MHz, CDCl3):
d
0.19 (s, 3H); 0.24
Grubb’s II catalyst (99.3 mg, 0.1 mmol, 10 mol%) was added to
a solution of 9 (820.0 mg, 2.3 mmol) in dry dichloromethane (6 mL).
The reaction was heated 16 h under reflux. The reaction mixture
was filtered through Celite, and the filtrate was evaporated under
reduced pressure. The crude product was purified with column
chromatography (cyclohexane/EtOAc: 80/20) to afford the corre-
sponding lactone (521.5 mg, 70%) as a pale yellow oil (mixture of
two diastereoisomers : 60/40). Major diastereoisomer 1H NMR
(s, 3H); 0.96 (s, 9H); 2.80 (ddd, J ¼ 17.5, 3.8, 0.9 Hz, 1H); 2.90 (ddd,
J ¼ 17.5, 10.0, 1.7 Hz, 1H); 4.65 (dqd, J ¼ 10.4, 6.6, 3.8 Hz, 1H); 9.86 (s,
1H). 13C NMR (75 MHz, CDCl3):
d
ꢁ3.1; ꢁ3.0; 18.0; 25.5; 45.3; 66.8
(q, J ¼ 32.5 Hz, CHCF3); 124.7 (q, J ¼ 282.2 Hz, CF3); 197.7. 19F NMR
(188 MHz, CDCl3):
d
ꢁ79.4 (d, J ¼ 6.2 Hz, CF3). IR (cmꢁ1): 2933; 1720.
5.1.3. 6-(tert-Butyldimethylsilyloxy)-7,7,7-trifluorohept-1-
en-4-ol (8)
(300 MHz, CDCl3):
2H); 2.35 (m, 1H); 2.41 (m, 2H); 4.60 (m, 1H); 6.06 (br dt, J ¼ 9.6,
1.9 Hz, 1H); 6.87 (m, 1H). 13C NMR (75 MHz, CDCl3):
d 0.13 (s, 3H); 0.14 (s, 3H); 0.90 (s, 9H); 2.12 (m,
To a solution of 7 (2.0 g, 7.9 mmol) in anhydrous dime-
thylformamide (6 mL) were added allyl bromide (1.1 g, 9.4 mmol),
granular zinc (670.0 mg, 10.2 mmol) and two drops of TMSCl. After
being stirred at room temperature for 3 h, the reaction mixture was
quenched with a saturated solution of NH4Cl (15 mL) and extracted
with ethyl acetate (3 ꢂ 15 mL). The organic layers were washed
with brine (15 mL), dried over anhydrous MgSO4, and filtered. The
solvent was removed under reduced pressure and the crude
product was purified by chromatography on silica gel (cyclohexane/
EtOAc : 80/20) to afford 8 (2.2 g, 94%) as a yellow oil (mixture of two
d
ꢁ5.2; ꢁ5.0;
18.1; 25.6; 29.7; 36.0; 66.8 (q, J ¼ 30.9 Hz, CHCF3); 72.6; 121.4; 124.9
(q, J ¼ 282.2 Hz, CF3); 145.1; 163.4. 19F NMR (188 MHz, CDCl3):
d
ꢁ78.28 (d, J ¼ 6.2 Hz, CF3). Minor diastereoisomer 1H NMR
(300 MHz, CDCl3): d 0.11 (s, 3H); 0.15 (s, 3H); 0.89 (s, 9H); 1.85 (ddd,
J ¼ 14.1, 10.7, 2.5 Hz, 1H); 2.08 (m, 1H); 2.38 (m, 2H); 4.39 (m, 1H);
4.60 (m, 1H); 6.05 (br td, J ¼ 9.7, 1.8 Hz, 1H); 6.91 (m, 1H). 13C NMR
(75 MHz, CDCl3):
d
ꢁ5.1; ꢁ4.9; 18.3; 25.7; 29.8; 36.2; 66.9 (q,
J ¼ 30.9 Hz, CHCF3); 72.5; 121.1; 125.2 (q, J ¼ 282.2 Hz, CF3); 145.4;
diastereoisomers
(300 MHz, CDCl3):
:
d
60/40). Major diastereoisomer 1H NMR
0.125 (s, 3H); 0.133 (s, 3H); 0.905 (s, 9H); 1.72
163.6. 19F NMR (188 MHz, CDCl3):
(cmꢁ1): 2932; 1722; 1264; 1135.
d
ꢁ79.237 (d, J ¼ 6.2 Hz, CF3). IR
(m, 2H); 2.27 (m, 2H); 3.84 (m, 1H); 4.23 (m, 1H); 5.12 (m, 1H); 5.19
To a solution of lactone (6-(2-(tert-butyldimethylsilyloxy)-3,3,3-
trifluoropropyl)-5,6-dihydro-2H-pyran-2-one) (260.0 mg, 0.8 mmol)
in dry tetrahydrofuran (4 mL), tert-butylammonium fluoride
(0.6 mL, 1.0 M in THF, 2.0 mmol) was added at room temperature.
The reaction mixture was stirred for 24 h, then hydrolyzed with
a saturated aqueous solution of NaHCO3 (10 mL), and extracted
with diethyl ether (3 ꢂ 10 mL). The combined organic layers were
washed with brine (10 mL), dried over anhydrous MgSO4, filtered
and concentrated under reduce pressure. The crude product was
purified by chromatography on silica gel (cyclohexane/EtOAc: 30/
70) to give 10 (129.4 mg, 77%) as a colorless oil. Major diastereo-
(m, 1H); 5.83 (m, 1H). 13C NMR (75 MHz, CDCl3):
d
ꢁ3.3; ꢁ3.1; 18.1;
25.6; 37.4; 42.5; 65.5; 68.3 (q, J ¼ 30.9 Hz, CHCF3); 118.8; 125.3 (q,
J ¼ 282.3 Hz, CF3); 134.0. 19F (188 MHz, CDCl3):
d
ꢁ78.9 (d,
J ¼ 6.9 Hz, CF3). Minor diastereoisomer 13C NMR (75 MHz, CDCl3) e
d
ꢁ3.2; ꢁ3.0; 18.0; 25.5; 38.2; 41.9; 67.5; 69.4 (q, J ¼ 30.9 Hz,
CHCF3); 118.6; 125.2 (q, J ¼ 282.3 Hz, CF3); 134.0. 19F NMR
(188 MHz, CDCl3) e
2982; 1952.
d
ꢁ78.6 (d, J ¼ 6.2 Hz, CF3). IR (cmꢁ1): 3650;
5.1.4. 6-(tert-Butyldimethylsilyloxy)-7,7,7-trifluorohept-1-en-4-yl
acrylate (9)
isomer 1H NMR (300 MHz, CDCl3):
d
1.88 (ddd, J ¼ 14.0, 8.4, 2.4 Hz,
Triethylamine (1.5 g, 15.0 mmol) and a catalytic amount of
DMAP (18.0 mg, 0.2 mmol, 3 mol%) were added to a solution of 8
(1.5 g, 5.0 mmol) in anhydrous dichloromethane (10 mL) at ꢁ78 ꢀC
under an inert atmosphere. Acryloyl chloride (mL, 10.0 mmol) was
then added drop by drop for 10 min. After being stirred for 6 h, the
mixture was hydrolyzed by a saturated aqueous solution of NaHCO3
(15 mL), and extracted with dichloromethane (3 ꢂ 15 mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered and concentrated under reduce pressure. The crude
product was purified with chromatography on silica gel (cyclo-
hexane/CH2Cl2: 80/20) to afford 9 (1.1 g, 60%) as a yellow oil
(mixture of two diastereoisomers : 60/40). Major diastereoisomer
1H); 2.06 (ddd, J ¼ 13.9, 10.6, 2.4 Hz, 1H); 2.38 (ddd, J ¼ 7.2, 3.3,
2.2 Hz, 1H); 2.41 (ddd, J ¼ 7.2, 4.4, 1.8 Hz, 1H); 4.43 (m, 2H); 4.76
(dqd, J ¼ 10.3, 8.3, 2.5,1H); 6.00 (br dt, J ¼ 9.8,1.8 Hz,1H); 6.92 (ddd,
J ¼ 9.8, 4.5, 3.5 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d 29.6; 34.7; 66.1
(q, J ¼ 31.7 Hz CHCF3); 73.2; 121.3; 125.1 (q, J ¼ 283.0 Hz, CF3);
145.4; 164.1. 19F NMR (188 MHz, CDCl3):
d
ꢁ80.7 (d, J ¼ 6.2 Hz, CF3).
IR (cmꢁ1): 3651; 2948; 1716; 1266; 1132. Anal. for C8H9F3O3: calcd.
C, 45.72; H, 4.32; found C, 45.47; H, 4.33.
5.1.6. 4,4,4-Trifluoro-but-2-enoic acid ethyl ester (11)
To a suspension of NaBH4 (1.23 g, 32.6 mmol) in anhydrous
diethyl ether (10 mL) at 0 ꢀC under an inert atmosphere was slowly
added a solution of 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester 5
1H NMR (300 MHz, CDCl3):
d 0.06 (s, 3H); 0.07 (s, 3H); 0.90 (s, 9H);

L. Dumitrescu et al. / European Journal of Medicinal Chemistry 45 (2010) 3213e3218
3217
(20.0 g, 108 mmol) in anhydrous diethyl ether (10 mL). The mixture
was stirred at 0 ꢀC for 5 h. Then, a 1 M aqueous hydrochloric acid
solution (15 mL) was carefully added to the media, stirred for
30 min, and the resulting residue was removed by filtration. The
aqueous layer was extracted with diethyl ether (3 ꢂ 20 mL). The
combined organic layers were washed with brine (15 mL), dried
over anhydrous MgSO4, filtered and concentrated under reduce
pressure to give crude ethyl 4,4,4-trifluoro-3-hydroxybutanoate
(17.5 g, 87%) as an yellow oil, which was used on the next step
CF3). IR (cmꢁ1): 3356; 2956; 2933; 1641; 1462; 1144; 1036. Anal. for
C7H9F3O3: calcd. C, 50.60; H, 5.46; found C, 50.72; H, 5.58.
5.1.9. Acrylic acid 1-allyl-4,4,4-trifluoro-but-2-enyl ester (15)
To a solution of 14 (2.1 g, 12.6 mmol) in dry dichloromethane
(10 mL), under an argon atmosphere, were added triethylamine
(3.2 g, 31.6 mmol) and a catalytic amount of DMAP (46.3 mg,
0.4 mmol, 3 mol%). The solution was then cooled to ꢁ78 ꢀC, and
acryloyl chloride (2.1 mL, 25.3 mmol) was added drop by drop. The
reaction mixture was stirred at ꢁ78 ꢀC for 6 h, then a saturated
aqueous solution of NaHCO3 (20 mL) was added. The aqueous layer
was extracted by dichloromethane (3 ꢂ 15 mL). The combined
organic layers were dried over anhydrous MgSO4, and filtered. The
solvent was removed under reduced pressure and the crude
product was purified by chromatography on silica gel (cyclohexane/
CH2Cl2: 50/50) to give 15 (1.7 g, 60%) as a yellow oil. 1H NMR
without purification. 1H NMR (300 MHz, CDCl3):
3H); 2.68 (d, J ¼ 4Hz, 2H); 3.72 (brs, 1H); 4.20 (q, J ¼ 7.2 Hz, 2H);
d
1.28 (t, J ¼ 7.2 Hz,
4.43 (m, 1H). 13C NMR (75 MHz, CDCl3):
d 13.8; 34.9; 61.5; 67.0 (q,
J ¼ 32.5 Hz, CHCF3); 124.5 (q, J ¼ 280.7 Hz, CF3); 170.8. 19F NMR
(188 MHz, CDCl3):
d
ꢁ80.3 (d, J ¼ 6.2 Hz, CF3).
Phosphorus pentoxide (15.3 g, 107.5 mmol) was added to the
crude ethyl 4,4,4-trifluoro-3-hydroxybutanoate (10.0 g, 53.7 mmol)
and the mixture was distillated to afford 11 (6.8 g, 76%) as an yellow
(300 MHz, CDCl3):
d 2.48 (m, 2H); 5.15 (m, 2H); 5.52 (m, 1H); 5.79
oil. 1H NMR (300 MHz, CDCl3):
d
1.32 (t, J ¼ 7.2 Hz, 3H); 4.27 (q,
J ¼ 7.2 Hz, 2H); 6.48 (dq, J ¼ 15.8, 1.9 Hz, 1H); 6.77 (dq, J ¼ 15.8,
6.4 Hz, 1H). 13C NMR (75 MHz, CDCl3):
14.0; 61.7; 122.0 (q,
J ¼ 270.6 Hz, CF3); 128.9 (q, J ¼ 6.0 Hz); 131.3 (q, J ¼ 35.7 Hz, CHCF3);
160.9. 19F NMR (188 MHz, CDCl3):
ꢁ66.2 (dd, J ¼ 6.2, 1.4 Hz, CF3).
(m, 2H); 5.90 (dd, J ¼ 10.5, 1.3 Hz, 1H); 6.15 (dd, J ¼ 17.3, 10.3 Hz,
1H); 6.37 (m, 1H); 6.46 (dd, J ¼ 17.3, 1.3 Hz, 1H). 13C NMR (75 MHz,
d
CDCl3):
d
38.2; 70.8; 119.2; 119.3 (q, J ¼ 34.0 Hz, CHCF3); 122.7 (q,
J ¼ 269.5 Hz, CF3); 127.9; 131.7; 131.8; 137.5 (q, J ¼ 6.6 Hz); 164.9. 19
F
d
NMR (188 MHz, CDCl3):
2979; 2939; 1722; 1637; 1188; 1043. Anal. for C10H11F3O2: calcd. C,
54.55; H, 5.04; found C, 54.68; H, 5.14.
d
ꢁ64.8 (dt, J ¼ 6.2, 2.1 Hz, CF3). IR (cmꢁ1):
5.1.7. 4,4,4-Trifluoro-but-2-en-1-ol (12)
A solution of AlCl3 (1.67 g,12.5 mmol) in anhydrous diethyl ether
(5 mL) was added at 0 ꢀC, under an atmosphere of argon, to
a suspension of LiAlH4 (1.01 g, 26.7 mmol) in diethyl ether (10 mL).
After 15 min a solution of 4,4,4-trifluoro-but-2-enoic acid ethyl
ester 11 (3.0 g, 17.8 mmol) in diethyl ether (10 mL) was dropped at
5.1.10. (E)-6-(3,3,3-trifluoroprop-1-enyl)-5,6-dihydro-2H-
pyran-2-one (4)
Grubb’s II catalyst (169.8 mg, 0.2 mmol, 10 mol%) was added to
a solution of 15 (500.0 mg, 2.3 mmol) in dry dichloromethane
(10 mL). The reaction was heated 16 h under reflux. The reaction
mixture was filtered through Celite, and the filtrate was evaporated
under reduced pressure. The crude product was purified by column
chromatography (cyclohexane/EtOAc: 60/40) to afford 4 (300.5 mg,
0
ꢀC. After 2 h of stirring, the reaction mixture was carefully
quenched by a saturated aqueous solution of Na2SO4 (40 mL), then
extracted with diethyl ether (3 ꢂ 20 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered and evaporated.
The crude product was purified by distillation (96 ꢀC, 760 mmHg) to
give 12 (2.0 g, 88%) as an yellow oil. 1H NMR (300 MHz, CDCl3):
70%) as a colorless oil. 1H NMR (300 MHz, CDCl3):
d ppm: 2.51 (m,
2H); 5.07 (m,1H); 6.04 (m,1H); 6.10 (m,1H); 6.36 (ddq, J ¼ 15.8, 6.0,
d
4.19 (brs, 2H); 5.88 (m, 1H); 6.42 (m, 1H). 13C NMR (75 MHz,
2.0 Hz, 1H); 6.86 (ddd, J ¼ 9.4, 5.6, 2.8 Hz, 1H). 13C NMR (75 MHz,
CDCl3):
d
60.5; 117.5 (q, J ¼ 34.0 Hz, CHCF3); 123.20 (q, J ¼ 269.0 Hz,
CDCl3):
d
ppm: 28.9; 74.5; 120.4 (q, J ¼ 34.6 Hz, CHCF3); 121.6; 122.6
CF3); 139.2 (q, J ¼ 6.0 Hz). 19F NMR (188 MHz, CDCl3):
J ¼ 6.2, 2.8 Hz, CF3).
d
ꢁ64.7 (dd,
(q, J ¼ 269.5 Hz, CF3); 135.6 (q, J ¼ 6.6 Hz); 144.0; 162.6. 19F NMR
(188 MHz, CDCl3):
2914; 1729; 1125; 1085. Anal. for C8H7F3O2: calcd. C, 50.01; H, 3.67;
found C, 50.19; H, 3.88.
d
ꢁ65.1 (dt, J ¼ 6.2, 2.1 Hz, CF3). IR (cmꢁ1): 2989;
5.1.8. 7,7,7-Trifluoro-hepta-1,5-dien-4-ol (14)
To a solution of 12 (2.0 g, 16.8 mmol) in anhydrous CH2Cl2 (8 mL)
was added pyridinium chlorochromate (3.4 g, 16.8 mmol). The
mixture was stirred until complete disappearance of the starting
material (monitored by 19F NMR). After 2.5 h of stirring at room
temperature, the reaction mixture was filtered through a short pad
of Celite and Fluorisil. Due to its high volatility, the compound was
kept on dichloromethane. 1H NMR showed a peak at 9.6 and 19F
NMR showed only one doublet at ꢁ66.2 ppm corresponding to the
aldehyde 13.
A solution of allyl bromide (1.7 g, 14.4 mmol) in anhydrous DMF
(10 mL) was then introduced at room temperature to the solution of
the aldehyde followed by granular zinc (1.0 g, 15.7 mmol) and 2
drops of TMSCl. After being stirred under an inert atmosphere for
4 h, the reaction mixture was quenched by a saturated aqueous
solution of NH4Cl (20 mL) and extracted with ethyl acetate
(3 ꢂ 20 mL). The organic layers were dried over anhydrous MgSO4,
filtered and evaporated under reduced pressure. The crude product
was purified by chromatography on silica gel (cyclohexane/EtOAc:
60/40) to afford 14 (2.1 g, 75%) as a yellow oil. 1H NMR (300 MHz,
5.1.11. (E)-((R)-((4R,4aR,8aS)-2,2-dimethyl-6-oxo-4,4-a,6,8a-
tetrahydropyrano[3,2-d][1,3]dioxin-4-yl)(phenyl)methyl) 4,4,4-
trifluorobut-2-enoate (18)
To a solution of 17 (50.0 mg, 0.2 mmol) in dichloromethane
(10 mL) were added 4,4,4-trifluorocrotonic acid (42.0 mg,
0.3 mmol), EDC (100.0 mg, 0.5 mmol) and DMAP (115.0 mg,
0.9 mmol). The mixture was then stirred at room temperature for
3 h. Water (10 mL) was added and the aqueous layer was extracted
with dichloromethane (3 ꢂ 10 mL). The combined organic phases
were dried over anhydrous MgSO4. After filtration and removal of
the solvent, the resulting residue was purified by chromatography
on silica gel (CH2Cl2/MeOH: 98/2) to give 18 (74.0 mg, 94%) as white
solid. 1H NMR (300 MHz, CDCl3):
d 1.31 (s, 3H); 1.36 (s, 3H); 4.33
(brt, J ¼ 1.9 Hz, 1H); 4.36 (dd, J ¼ 9.0, 1.9 Hz, 1H); 4.40 (dd, J ¼ 6.0,
2.1 Hz, 1H); 6.13 (d, J ¼ 9.0 Hz, 1H); 6.26 (d, J ¼ 9.6 Hz, 1H); 6.48 (dq,
J ¼ 15.8, 1.9 Hz, 1H); 6.80 (dq, J ¼ 15.8, 6.4 Hz, 1H); 6.90 (dd, J ¼ 9.6,
6.0 Hz, 1H); 7.37 (m, 5H). 13C NMR (75 MHz, CDCl3):
d 18.5; 28.9;
60.1; 68.9; 71.3; 73.7; 99.7; 121.8 (q, J ¼ 270.6 Hz, CF3); 125.5; 127.4;
CDCl3):
d
2.30 (ddd, J ¼ 13.9, 7.3, 0.9 Hz, 1H); 2.41 (ddd, J ¼ 13.9, 6.4,
128.2 (q, J ¼ 6.0 Hz); 128.4; 128.6; 132.1 (q, J ¼ 31.3 Hz, CHCF3);
1.1 Hz, 1H); 4.33 (brs, 1H); 5.20 (m, 2H); 5.84 (m, 2H); 6.41 (ddq,
136.6; 140.4; 161.8; 162.4. 19F NMR (188 MHz, CDCl3):
d
ꢁ66.0 (dd,
J ¼ 15.6, 4.1, 2.07 Hz,1H).13C NMR (75 MHz, CDCl3):
d
41.1; 69.0; 118.1
J ¼ 6.7, 2.1 Hz, CF3). IR (cmꢁ1): 3050; 2920; 2912; 1720; 1261; 1131.
Anal. for C20H19F3O6: calcd. C, 58.25; H, 4.64; found C, 58.25; H,
4.59. m.p. (ꢀC): 148 (recrystallization in pentane).
(q, J ¼ 34.0 Hz, CHCF3); 119.6; 126.8 (q, J ¼ 271.7 Hz, CF3); 132.8; 141.3
(q, J ¼ 6.6 Hz). 19F NMR (188 MHz, CDCl3):
ꢁ64.5 (dt, J ¼ 6.2, 2.1 Hz,
d

3218
L. Dumitrescu et al. / European Journal of Medicinal Chemistry 45 (2010) 3213e3218
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71 (2005) 153e159.
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622e631.
5.1.12. (E)-((1R,2R)-2-hydroxy-2-((2R,3S)-3-hydroxy-6-oxo-
3,6-dihydro-2H-pyran-2-yl)-1-phenylethyl) 4,4,4-trifluorobut-
2-enoate (16)
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(1999) 161e170.
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583e586.
[19] A. De Fatima, A. Pilli, Arkivoc 10 (2003) 118e126.
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18 (50.0 mg, 0.1 mmol) was dissolved in an 80% aqueous acetic
acid solution (5 mL) and warmed at 90 ꢀC for 3 h. The solvent was
then removed under reduce pressure, and the resulting residue was
purified by chromatography on silica gel (CH2Cl2/MeOH: 95/5) to
give 16 (25.0 mg, 57%) as white solid. 1H NMR (300 MHz, CDCl3):
d
4.33 (dd, J ¼ 4.8, 3.2 Hz, 1H); 4.43 (m, 1H); 4.53 (dd, J ¼ 6.2, 4.9 Hz,
1H); 6.00 (d, J ¼ 6.3 Hz, 1H); 6.06 (dd, J ¼ 9.7, 6.5 Hz, 1H); 6.64 (d,
J ¼ 15.8 Hz,1H); 6.99 (m, 2H); 7.36 (m, 5H).13C NMR (75 MHz, CDCl3):
d
62.0; 72.6; 76.7; 79.6; 122.2; 123.1(q, J ¼ 269.6 Hz, CF3); 128.1;
128.7; 128.9; 129.2; 129.7 (q, J ¼ 6.2 Hz); 132.0 (q, J ¼ 35.1 Hz,
CHCF3); 137.4; 141.1; 145.7; 163.4; 164.9. 19F NMR (188 MHz, CDCl3):
d
ꢁ66.0 (dd, J ¼ 6.3, 1.8 Hz, CF3). IR (cmꢁ1): 3670; 3050; 2920; 1727;
1257; 1131. Anal. for C17H15F3O6: calcd. C, 54.84; H, 4.06; found C,
54.78; H, 4.02. m.p. (ꢀC): 123 (recrystallization in pentane).
Acknowledgments
[24] M. Gruttadauria, P. Lo Meo, R. Noto, Tetrahedron Lett. 45 (2004) 83e85.
[25] P. Harsh, G.A. O’Doherty, Tetrahedron 65 (2009) 5051e5055.
[26] J.-P. Bégué, D. Bonnet-Delpon, J. Fluor. Chem. 127 (2006) 992e1012.
[27] W.K. Hagmann, J. Med. Chem. 51 (2008) 4359e4369.
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[30] J.P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine.
Wiley-Hoboken Ltd., 2008.
We thank the European Community for the financial support
(Marie Curie Early Stage Training Fellowship of the European
Community’s Sixth Framework Programme: contract BioMedChem
(for L.D.), CNRS for a French-Vietnamese joint program (PICS), and
Ile de France Region for support. Thierry Cresteil and Geneviève
Aubert (Cibliothèque cellulaire de l’ICSN, UPR CNRS 2301, 91190 Gif
sur Yvette, France) are acknowledged for the biological tests.
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Materials and Pharmaceuticals. Elsevier Science Ltd., 2008.
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D Kuduk,
S. Charkravarty, A. Abouabdellah, J.P. Bégué, D. Bonnet-Delpon, J.M. Veith,
P. Pera, R.J. Bernacki, in: I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical
Frontiers of Fluorine Chemistry, ACS Symposium Series, 1996, pp. 228e243
Washington DC (Chapter 17).
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