Synthesis of γ,γ-difluoro-β-hydroxy-δ-lactones as new precursors of HMG-CoA reductase inhibitor

Article abstract of DOI:10.1016/j.jfluchem.2011.09.014

A series of γ,γ-difluoro-β-hydroxy-δ-lactones 1 were efficiently synthesized as new precursors of HMG-CoA reductase inhibitor in one pot by treatment of readily prepared gem-difluoromethylenated acetonides 3 with trifluoroacetic acid. Contrarily, acetonid

Full text of DOI:10.1016/j.jfluchem.2011.09.014

Journal of Fluorine Chemistry 133 (2012) 178–183
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of
g,g-difluoro-b-hydroxy-d-lactones as new precursors of HMG-CoA
reductase inhibitor
a
b
a
Xiaoguang Wang a, Xiang Fang a, , Hongyuan Xiao , Yan Yin , Huimin Xia , Fanhong Wu
*
a,b,**
a Key Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
b School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 120 Caobao Road, Shanghai 200235, China
A R T I C L E I N F O
A B S T R A C T
-difluoro-b-hydroxy-d-lactones 1 were efficiently synthesized as new precursors of HMG-
Article history:
A series of
CoA reductase inhibitor in one pot by treatment of readily prepared gem-difluoromethylenated
acetonides 3 with trifluoroacetic acid. Contrarily, acetonides 3 could be transformed to the -gem-
through hydrolyzation and lactonization in
g
,
g
Received 4 July 2011
Received in revised form 22 September 2011
Accepted 28 September 2011
Available online 6 October 2011
g,g
difluoromethylenated
refluxing toluene.
a,b-unsaturated d-lactones 2
ß 2011 Elsevier B.V. All rights reserved.
This paper is dedicated to Professor
Wei-Yuan Huang on the occasion
of his 90th birthday.
Keywords:
Statin
HMG-CoA reductase inhibitor
Precursor
g,g-Difluoro-b-hydroxy-d-lactones
1. Introduction
Abeles have disclosed series of fluorinated hydroxyl valerolactones
as HMG-CoA reductase inhibitors till date [4].
Statins are well-known inhibitors of 3-hydroxy-3-methylglu-
taryl-coenzyme A (HMG-CoA) reductase, which have become the
most frequently prescribed agents for the treatment of hypercho-
lesterolemia due to their compelling action on significantly
reducing the rates of cardiovascular events [1]. A large number
of statin analogs including Lovastatin, Pravastatin, Fluvastatin,
Simvastatin, Atorvastatin, Rosuvastatin and Pitavastatin (Fig. 1)
have been synthesized, in which modifications were mainly
focused on the variation of their lipophilic fragment to improve the
biological activity and reduce the side effects [2]. It has been
revealed by structure–activity relationship (SAR) studies that the
hydroxyl-valerolactone fragment was essentially responsible for
the biological activity of statins [3], whereas studies on the
modification of the hydroxyl-valerolactone precursor have rarely
been documented. To the best of our knowledge, only Reardon and
The strong electronegativity and relatively small size of fluorine
atom combined with the chemical inertness of C-F bonds make
fluorine-substitution a powerful tool for medicinal chemistry
study [5]. Recently, special attention has been paid to the gem-
difluoromethylene group because many compounds with this
functional group exhibited extraordinary biological activities with
potential pharmaceutical applications [6]. With a long-term
interest in the methodology studies on fluorine-containing
lactones [7] and other related bioactive small molecules, the
introduction of gem-difluoromethylene group (CF2) to -hydroxy
-lactones at the -position (Fig. 2) was investigated. Herein, we
described the synthesis of -difluoro- -hydroxy- -lactones as
d-
b
d
g
g
,g
b
d
new precursors of HMG-CoA reductase inhibitor.
2. Results and discussion
gem-Difluoromethylenated acetonides 3 were first obtained in
their syn forms in 15–20% overall yields (Scheme 1) according to
literature methods [8]. Zinc-mediated Reformatsky reaction of
cinnamyl aldehyde derivatives 4 with ethyl bromodifluoroacetate
gave the corresponding esters 5. Subsequent Claisen condensation
* Corresponding author. Tel.: +86 21 64253530.
** Corresponding author at: School of Chemical and Environmental Engineering,
Shanghai Institute of Technology, 120 Caobao Road, Shanghai 200235, China.
Fax: +86 21 64253074.
of 5 with tert-butyl acetate produced
which were then reduced to b,d-diols 7 in the presence of NaBH4.
d-hydroxy-b-keto esters 6
E-mail addresses: fangxiang@ecust.edu.cn (X. Fang), wfh@sit.edu.cn,
wfh@ecust.edu.cn (F. Wu).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.09.014

X. Wang et al. / Journal of Fluorine Chemistry 133 (2012) 178–183
179
OH
HO
HO
H
O
O
HO
H
O
OH
O
O
O
O
F
O
O
N
HO
Pravastatin
HO
Lovastatin
HO
Fluvastatin
HO
OH
O
OH
OH
O
OH
OH
O
OH
F
F
F
N
O
N
S
N
N
HN
N
O
O
Pitavastatin
Rosuvastatin
Atorvastatin
Fig. 1. The reported HMG-CoA reductase inhibitors.
Considering the difficulty in separating syn and anti diols, crude
diols 7 were transformed to the desired acetonide 3 without
further purification in the presence of iso-propylidene acetal which
is useful for removing traces of the hydroxy epimers produced in
After successfully obtaining the new gem-difluoromethyle-
nated -lactone precursors, we further projected to produce the
d
lipophilic fragment-varied derivatives in which the phenyl rings
are replaced by heterocyclic cores for establishing SAR studies. The
most commonly used Wittig reaction for the preparation of statins
by coupling aryl groups with fully O-protected 3,5-dihydroxy-6-
oxohexenoic acids will be adopted [14]. As shown in Scheme 3, we
preliminarily attempted the ozonolysis cleavage of 3a, which led to
gem-difluoromethylenated aldehyde 9 in 80% yield. This interme-
diate could be further coupled with various heterocyclic rings via
Wittig reaction and then converted into the gem-difluoromethy-
the stereoselective reduction of the
d-hydroxy-b-keto esters 6.
Finally, the intermediates 3a–3e were isolated as single syn forms
by column chromatography on silica gel [9].
With acetonides 3 in hand, we then examined the conversion of
3 into the desired
g,g-difluoro-b-hydroxy-d-lactones 1 (Scheme
2). Treatment of 3 with TsOH and then NaOH for hydrolyzing,
respectively, the acetonide and ester protecting groups led to the
crude dihydroxy acids 8, which was then subjected to the
lactonization reaction under the condition (in dry toluene at
lenated
d-lactones via the method established in this study,
providing a novel class of statin analogs as new inhibitors of HMG-
CoA reductase. The synthesis and biological assessments will be
presented in due course.
110 8C for 5 h) reported by Reddy’s group [10]. However, the
difluoro- -unsaturated- -lactones were unexpectedly
obtained in 30–70% yields instead of the titled products 1.
We deduced that at high reaction temperature, acids 8 were
converted correspondingly to the -unsaturated -lactones 2
g,g-
a
,b
d
2
In conclusion, we have reported the efficient synthesis of
g,g-
difluoro- -hydroxy- -lactones 1 as new precursors of HMG-CoA
b
d
a
,b
d
reductase inhibitor. The important gem-difluoromethylenated
acetonide intermediates 3 were obtained via a straightforward
4-step sequence, which could also be converted into gem-
difluoromethylenated aldehydes via ozonolysis cleavage for
further structural modifications. The synthesis and biological
study of other statin analogs are currently underway in our
laboratories.
[12], similar to the reported synthesis of 2a through ring-closing
metathesis (RCM) reaction by Qing et al. [11]. Since route I failed to
give the desired products, an alternative method reported by
Takahashi et al. which may convert the acetonides into d-lactones
in one-pot was attempted [13]. To our delight, the desired lactones
1 were thus obtained in 40–50% yields by treating acetonides 3
with CF3COOH in CH2Cl2 (Scheme 2, route II).
3. Experimental
3.1. General
β
β
HO
O
HO
F
O
IR spectra were measured on
a Nicolet Magna IR-550
γ
γ
O
O
spectrometer. High-resolution mass spectra were carried out on
a Finnigan GC-MS-4021 spectrometer. 1H (400 MHz) and 13C
(100.6 MHz) NMR spectra were recorded on a Bruker AC-500
spectrometer with Me4Si as an internal standard. 19F NMR spectra
were obtained on a Bruker AC-500 (367.5 MHz) spectrometer in
CDCl3 with CFCl3 as an external standard, in which downfield shifts
F
Ar
Ar
Fig. 2. Design of new precursors of HMG-CoA reductase inhibitor.

180
X. Wang et al. / Journal of Fluorine Chemistry 133 (2012) 178–183
O
OH
O
a
b
H
O
BrCF2COOEt
F
F
R
R
R
4
5
OH OH
O
OH
F
O
O
O
c
O
F
F
R
F
7
6
O
O
O
d
R = H (a) , Cl (b) , Br (c) , CH3 (d) , OCH3 (e)
O
F
F
R
3
Scheme 1. Reagents and conditions: (a) Zn, THF, 60 8C; (b) tert-butyl acetate, LDA, À70 8C; (c) NaBH4, THF/MeOH; (d) acetone, (CH3O)2C(CH3)2, TsOH.
were designated as negative. All chemical shifts (
in parts per million and coupling constants (J) are given in hertz.
d
) are expressed
vacuum. The remaining residue was purified by column
chromatography on silica gel eluting with petroleum ether/ethyl
acetate (6:1) to give 5a (3.3 g, 66% yield).
3.2. General procedure for preparation of 5 [15]
3.3. General procedure for preparation of 6 [16]
To a stirring mixture of THF (22 mL) and freshly activated zinc
powder (1.7 g, 25.6 mmol), ethyl 2-bromo-2,2-difluoroacetate
(5.0 g, 24.6 mmol) was added dropwise at r.t. Then, cinnamyl
aldehyde 4a (2.6 g, 19.7 mmol) dissolved in THF (22 mL) was
added dropwise to the reaction mixture. After completion of the
addition, the mixture was heated to 60 8C and remained for 5 h,
followed by the addition of saturated ammonium chloride for
quenching the reaction. The excess zinc was removed by suction
filtration and the filter cake was washed with ethyl acetate. The
combined filtrate was extracted with ethyl acetate, washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
Keeping the inner temperature below 0 8C, n-butyllithium
(10.9 mL, 2.2 mol LÀ1, 24 mmol) was added to a solution of
diisopropylethylamine (dried over KOH) (3.4 mL, 24 mmol) in
THF (5 mL) over 20 min under Ar atmosphere. The reaction
mixture was stirred at À5 to À10 8C for 30 min, then was cooled to
À30 to À40 8C. tert-Butyl acetate (6.5 mL, 24 mmol) was added
over 5 min. The reaction mixture was stirred for another 30 min
with the inner temperature below À20 8C. Then the mixture was
cooled to approximately À70 8C, and a solution of 5 (2.0 g,
8.0 mmol) in THF (6 mL) was added over 25 min. The reaction
Scheme 2. Reagents and conditions: route I: (a) i. TsOH, MeOH, ii. NaOH, iii. HCl; (b) toluene, reflux; route II: TFA, r.t.

X. Wang et al. / Journal of Fluorine Chemistry 133 (2012) 178–183
181
J = 241.8 Hz), À121.5 (d, 1F, J = 241.8 Hz,). 13C NMR (CDCl3,
100.6 MHz)
d 28.1, 28.9, 33.8, 68.9 (t, J = 26.9 Hz), 72.9 (t,
O
O
O
O
O
O
O
H
1) O3
J = 27.2 Hz), 81.2, 100.1, 120.5 (t, J = 235.2 Hz), 122.2, 128.1,
128.8, 134.0, 134.5, 134.7, 169.3. IR (cmÀ1, KBr) 2980, 1725,
1174, 1101, 844. EI-MS (m/z) 404 (M++2, 5), 402 (M+, 13), 346 (37),
271 (86), 268 (100), 167 (54), 165 (41), 138 (28), 131 (33), 57 (65).
HRMS calcd for C20H25ClF2O4: 402.1409, found: 402.1410.
O
O
2) PPh3
F
F
F
F
9
3a
Scheme 3. Ozonolysis cleavage of 3a.
3.5.3. tert-Butyl 2-(6-(4-bromostyryl)-5,5-difluoro-2,2-dimethyl-
1,3-dioxan-4-yl)acetate (3c)
mixture was stirred for 1 h, and then the temperature was raised to
0 8C over 30 min. The reaction was quenched with saturated
aqueous ammonium chloride solution (10 mL) and stirred for
15 min. The aqueous layer was extracted with ethyl acetate
(2 Â 20 mL) and the combined organic layer was washed with
brine and dried over anhydrous sodium sulfate. After evaporation
of the solvent, the residue 6 was used for the next step directly.
1H NMR (CDCl3, 400 MHz)
d 1.47 (s, 9H), 1.50 (s, 3H), 1.62 (s, 3H),
2.50–2.72 (m, 2H), 4.44–4.60 (m, 2H), 6.22 (dd, 1H, J = 16 Hz,
J = 6.8 Hz), 6.72 (d, 1H, J = 16 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.45 (d, 2H,
J = 8.4 Hz). 19FNMR(CDCl3, 367.5 MHz)
d
À134.9(d, 1F, J = 241.4 Hz),
À121.6 (d, 1F, J = 241.4 Hz). 13C NMR (CDCl3, 100.6 MHz)
d28.1, 28.9,
33.8, 68.6 (t, J = 26.5 Hz), 73.1(t, J = 26.8 Hz), 81.3, 100.1, 120.6 (t,
J = 228.1 Hz), 122.2,128.4,128.9, 131.7, 134.7,134.9, 169.3. IR(cmÀ1
,
KBr) 2982, 1726, 1173, 1103, 840. EI-MS (m/z) 448 (M++2, 13), 446
(M+, 13), 392 (31), 312 (100), 211 (65), 131 (42), 57 (65). HRMS calcd
for C20H25BrF2O4: 446.0904, found: 446.0935.
3.4. General procedure for preparation of 7 [17]
A 100 mL, three-necked, round-bottomed flask equipped with a
mechanical stirrer, funnel, and thermometer was charged with
THF (12 mL) and cooled to À45 8C. Sodium borohydride (0.90 g,
24 mmol) was added and the suspension was stirred for 5 min.
Then, a solution of 6 (8 mmol) in THF (10 mL) and MeOH (16 mL)
was added over 25 min. The reaction mixture was stirred for
another 1.5 h at À45 8C, and then was charged with saturated
aqueous sodium bicarbonate solution (16 mL) for another 10 min.
The aqueous layer was extracted with ethyl acetate (2 Â 20 mL)
and the combined organic phase was washed with brine and dried
over anhydrous sodium sulfate. After evaporation of the solvent,
the residue 7 was used for the next step directly.
3.5.4. (E)-tert-butyl 2-(6-(4-methylstyryl)-5,5-difluoro-2,2-
dimethyl-1,3-dioxan-4-yl) acetate (3d)
1H NMR (CDCl3, 400 MHz)
d 1.46 (s, 9H), 1.50 (s, 3H), 1.62 (s,
3H), 2.33 (s, 3H), 2.50–2.73 (m, 2H), 4.43–4.58 (m, 2H), 6.18 (dd,
1H, J = 16 Hz, J = 6.8 Hz), 6.74 (d, 1H, J = 16 Hz), 7.13 (d, 2H,
J = 8.0 Hz), 7.32 (d, 2H, J = 8.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
À134.9 (d, 1F, J = 241.4 Hz), À121.5 (d, 1F, J = 241.8 Hz). 13C NMR
(CDCl3, 100.6 MHz)
d 21.3, 28.1, 28.9, 33.8, 69.0 (t, J = 26.9 Hz),
73.4(t, J = 26.7 Hz), 81.2, 100.0, 113.6, 118.6 (t, J = 247.6 Hz), 126.8,
129.3, 133.2, 136.1, 138.2, 169.4. IR (cmÀ1, KBr) 2985, 1728, 1174,
1093, 866, 841. EI-MS (m/z) 382 (M+, 22), 326 (17), 251 (71), 248
(100), 189 (38), 147 (65), 131 (63), 57 (36). HRMS calcd for
3.5. General procedure for preparation of 3
C21H28F2O4: 382.1956, found: 382.1959.
2,2-Dimethoxypropane (1.5 mL, 12 mmol) and p-toluensulfo-
nic acid (21 mg, 0.12 mmol) were added to a solution of diol 7a
(8.0 mmol) in dry acetone (15 mL) and the solution was stirred at
35–40 8C for 24 h. The reaction mixture was neutralized with
saturated aqueous sodium bicarbonate solution. The aqueous layer
was extracted with ethyl acetate (2 Â 20 mL) and combined
organic layers were washed with brine and dried over anhydrous
sodium sulfate. After evaporation of the solvent, the resulting
residue was purified by flash column chromatography (petroleum
ether/ethyl acetate = 10:1) to give 3a (530 mg, in 18% isolated yield
over the three steps).
3.5.5. (E)-tert-butyl 2-(6-(4-methoxystyryl)-5,5-difluoro-2,2-
dimethyl-1,3-dioxan-4-yl)acetate (3e)
1H NMR (CDCl3, 400 MHz)
d 1.46 (s, 9H), 1.50 (s, 3H), 1.62 (s,
3H), 2.50–2.73 (m, 2H), 3.81 (s, 3H), 4.42–4.57 (m, 2H), 6.09 (dd,
1H, J = 16 Hz, J = 6.8 Hz), 6.72 (d, 1H, J = 16 Hz), 6.85 (d, 2H,
J = 8.8 Hz), 7.36 (d, 2H, J = 8.8 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
À135.3 (d, 1F, J = 241.4 Hz), À121.4 (d, 1F, J = 241.8 Hz). 13C NMR
(CDCl3, 100.6 MHz)
d 28.1, 28.9, 33.8, 55.3, 69.0 (t, J = 26.8 Hz),
73.4(t, J = 27.3 Hz), 81.2, 100.0, 112.8, 116.2 (t, J = 248.6 Hz), 117.4,
128.2, 128.8, 135.8, 159.8, 169.4. IR (cmÀ1, KBr) 2979, 1723, 1513,
1174, 1092, 843. EI-MS (m/z) 398 (M+, 39), 327 (17), 284 (17), 267
(59), 264 (36), 162 (100), 134 (22), 57 (33). HRMS calcd for
3.5.1. (E)-tert-butyl 2-(5,5-difluoro-2,2-dimethyl-6-styryl-1,3-
C21H28F2O5: 398.1905, found: 398.1906.
dioxan-4-yl)acetate (3a)
1H NMR (CDCl3, 400 MHz)
d
1.46 (s, 9H), 1.50 (s, 3H), 1.62 (s,
3.6. General procedure for preparation of 2
3H), 2.51–2.73 (m, 2H), 4.38–4.60 (m, 2H), 6.23 (dd, 1H, J = 16 Hz,
J = 6.8 Hz), 6.77 (d, 1H, J = 16 Hz), 7.28–7.36 (m, 5H). 19F NMR
p-Toluensulfonic acid (30 mg, 0.026 mmol) was added in one
portion to a solution of the acetonide 3 (368 mg, 1 mmol) in MeOH
(10 mL), and the mixture was stirred for 1 h at r.t. Et3N (20 mL,
(CDCl3, 367.5 MHz)
d
À135.1 (d, 1F, J = 241.4 Hz), À121.5 (d, 1F,
23.8, 28.1, 33.9, 69.0 (t,
J = 241.4 Hz). 13C NMR (CDCl3, 100.6 MHz)
d
J = 26.7 Hz), 73.3 (t, J = 26.8 Hz), 81.2, 100.0, 119.8 (t, J = 232.0 Hz),
126.9, 128.3, 128.6, 135.3, 136.0, 136.1, 169.3. IR (cmÀ1, KBr) 2997,
1724, 1155, 1096, 694. EI-MS (m/z) 368 (M+, 3), 312 (22), 237 (40),
234 (40), 133 (51), 57 (100), 43 (36). HRMS calcd for C20H26F2O4:
368.1799, found: 368.1800.
0.288 mmol) was then added, and the reaction mixture was
concentrated in vacuo. The resulting residue was hydrolyzed with
aqueous 1 M NaOH (1.5 mL, 1.5 mmol)in MeOH (5 mL) for 24 h at r.t.
Subsequent acidic extraction gave a crude acid, which was heated in
drytoluene(8 mL)at110 8Cfor6 h. Themixture wasthenevaporated
in vacuo and the resulting residue subjected to flash column
chromatography (petroleum ether/ethyl acetate = 10:1) to give 2.
3.5.2. tert-Butyl 2-(6-(4-chlorostyryl)-5,5-difluoro-2,2-dimethyl-1,3-
dioxan-4-yl)acetate (3b)
1H NMR (CDCl3, 400 MHz)
3H), 2.50–2.72 (m, 2H), 4.43–4.60 (m, 2H), 6.21 (dd, 1H, J = 16 Hz,
J = 6.8 Hz), 6.74 (d, 1H, J = 16 Hz), 7.29 (d, 2H, J = 8.4 Hz), 7.35 (d,
2H, J = 8.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
1.47 (s, 9H), 1.50 (s, 3H), 1.62 (s,
3.6.1. (E)-5,5-difluoro-6-styryl-5,6-dihydropyran-2-one (2a) [11]
1H NMR (CDCl3, 500 MHz)
d 5.15–5.21 (m, 1H), 6.27 (dd, 1H,
J = 16 Hz, J = 6.9 Hz), 6.36 (d, 1H, J = 10.1 Hz), 6.84–6.92 (m, 2H),
7.31–7.46 (m, 5H).
d
À134.9 (d, 1F,

182
X. Wang et al. / Journal of Fluorine Chemistry 133 (2012) 178–183
3.6.2. (E)-6-(4-chlorostyryl)-5,5-difluoro-5,6-dihydropyran-2-one
(dd, 1H, J = 16 Hz, J = 7.2 Hz), 6.80 (d, 1H, J = 16 Hz), 7.31 (d, 2H,
(2b)
J = 8.4 Hz), 7.35 (d, 2H J = 8.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
1H NMR (CDCl3, 400 MHz)
d
5.13–5.20 (m, 1H), 6.24 (dd, 1H,
À124.2 (dd, 2F, J = 432.2 Hz, J = 254.3 Hz). 13C NMR (CDCl3,
J = 16 Hz, J = 6.8 Hz), 6.36 (d, 1H, J = 10.0 Hz), 6.84–6.89 (m, 2H),
7.33 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.4 Hz). 19F NMR (CDCl3,
100.6 MHz) d 36.0, 65.8 (t, J = 26.6 Hz), 76.2 (t, J = 29.8 Hz),
116.5, 117.9 (t, J = 238.4 Hz), 128.2, 129.0, 133.8, 134.7, 136.4,
167.1. IR (cmÀ1, KBr) 3283, 2925, 1704, 1492, 1086, 821. EI-MS (m/
z) 290 (M++2, 13), 288 (M+, 44), 169 (29), 167 (100), 131 (24). HRMS
calcd for C13H11ClF2O3: 288.0365, found: 288.0355.
367.5 MHz)
(CDCl3, 100.6 MHz)
d
À107.7 (dd, 2F, J = 431.6 Hz, J = 281.7 Hz). 13C NMR
d 79.9 (t, J = 28.2 Hz), 117.7 (t, J = 238.2 Hz),
126.6, 128.3, 129.0, 133.6, 134.8, 136.5, 137.8, 138.1, 160.1. IR
(cmÀ1, KBr) 3090, 2924, 1738, 1491, 1072, 811. EI-MS (m/z) 272
(M++2, 12), 270 (M+, 37), 138 (18), 131 (18), 104 (100). HRMS calcd
for C13H9ClF2O2: 270.0259, found: 270.0261.
3.7.3. (E)-6-(4-bromostyryl)-5,5-difluoro-4-hydroxy-
tetrahydropyran-2-one (1c)
1H NMR (CDCl3, 400 MHz)
d 2.92–2.98 (m, 1H), 3.04–3.10 (m,
3.6.3. (E)-6-(4-bromostyryl)-5,5-difluoro-5,6-dihydropyran-2-one
1H), 4.32–4.35 (m, 1H), 5.39 (dt, 1H, J = 20.3 Hz, J = 5.6 Hz), 6.22
(dd, 1H, J = 16 Hz, J = 7.2 Hz), 6.80 (d, 1H, J = 16 Hz), 7.29 (d, 2H,
(2c)
1H NMR (CDCl3, 400 MHz)
d
5.12–5.20 (m, 1H), 6.26 (dd, 1H,
J = 8.4 Hz), 7.47 (d, 2H J = 8.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
J = 6.2 Hz, J = 16.2 Hz), 6.36 (d, 1H, J = 10.0 Hz), 6.82–6.89 (m, 2H),
7.31 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4 Hz). 19F NMR (CDCl3,
À124.2 (dd, 2F, J = 433.8 Hz, J = 254.5 Hz). 13C NMR (CDCl3,
100.6 MHz)
d 35.9, 65.9 (t, J = 28.4 Hz), 76.0 (t, J = 29.5 Hz),
367.5 MHz)
(CDCl3, 100.6 MHz)
d
À107.7 (dd, 2F, J = 473.2 Hz, J = 281.7 Hz). 13C NMR
116.4, 118.1 (t, J = 229.8 Hz), 122.8, 128.5, 131.9, 134.2, 136.4,
166.7. IR (cmÀ1, KBr) 3382, 2925, 1724, 1488, 1092, 815. EI-MS (m/
z) 334 (M++2, 33), 332 (M+, 33), 213 (80), 211 (100), 131 (42). HRMS
calcd for C13H11BrF2O3: 331.9860, found: 331.9859.
d 79.9 (t, J = 30.4 Hz), 117.8 (t, J = 238.2 Hz),
123.0, 126.6, 126.7, 128.5, 132.0, 134.1, 136.6, 137.8, 160.1. IR
(cmÀ1, KBr) 3088, 2924, 1738, 1487, 1070, 809. EI-MS (m/z) 315
(M++2, 26), 313 (M+, 28), 181 (14), 131 (14), 104 (100). HRMS calcd
for C13H9BrF2O2: 313.9754, found: 331.9755.
3.7.4. (E)-6-(4-methylstyryl)-5,5-difluoro-4-hydroxy-
tetrahydropyran-2-one (1d)
3.6.4. (E)-6-(4-methylstyryl)-5,5-difluoro-5,6-dihydropyran-2-one
1H NMR (CDCl3, 400 MHz)
d 2.35 (s, 3H), 2.68–2.76 (m, 2H),
(2d)
4.22–4.28 (m, 1H), 5.36 (d, 1H, J = 2.0 Hz), 6.09–6.13 (m, 1H), 6.50
(dd, 1H, J = 10.4 Hz, J = 3.2 Hz), 7.17 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H,
1H NMR (CDCl3, 400 MHz)
d 2.36 (s, 3H), 5.12–5.19 (m, 1H), 6.21
(dd, 1H, J = 16 Hz, J = 7.2 Hz), 6.35 (d, 1H, J = 10.0 Hz), 6.84–6.88 (m,
2H), 7.17 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 8.0 Hz). 19F NMR (CDCl3,
367.5 MHz)
(t,J = 30.3 Hz),112.1(t,J = 228.2 Hz),115.9, 126.6,127.0,129.5,132.4,
137.9, 138.0, 139.1, 160.4. IR (cmÀ1, KBr) 3086, 2924, 1738, 1291,
1074,811.EI-MS(m/z)250(M+,67),146(20),131(100), 118(22), 104
(54). HRMS calcd for C14H12F2O2: 250.0805, found: 250.0807.
J = 8.0 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
À107.7 (dd, 2F,
J = 848.3 Hz, J = 267.4 Hz). 13C NMR (CDCl3, 100.6 MHz)
21.2,
32.9, 68.9 (t, J = 23.5 Hz), 73.8 (t, J = 29.7 Hz), 113.5, 121.8 (t,
J = 231.5 Hz), 128.0, 129.2, 133.1, 137.1, 138.6, 175.5. IR (cmÀ1
d
d
À107.6 (s, 2F). 13C NMR (CDCl3, 100.6 MHz)
d21.3, 80.4
,
KBr) 3422, 2925, 1737, 1324, 1145, 789. EI-MS (m/z) 268 (M+, 0.3),
248 (20), 189 (100), 119 (17). HRMS calcd for C14H14F2O3:
268.0911, found: 268.0914.
3.7. General procedure for preparation of 1
3.7.5. (E)-6-(4-methoxystyryl)-5,5-difluoro-4-hydroxy-
tetrahydropyran-2-one (1e)
A solution of trifluoroacetic acid (1.7 g, 15 mmol) in methy-
lene chloride (15 mL) was added to a solution of 3 (1 mmol) in
methylene chloride (15 mL) at 0 8C dropwise within 30 min. Then
the reaction mixture was stirred at room temperature for 12 h
and cooled with ice water bath. 5% sodium bicarbonate solution
was then added, and the mixture was extracted with methylene
chloride. The combined organic phase was washed with brine
and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the remaining residue was
purified through column chromatography (petroleum ether/
ethyl acetate = 3:1) to obtain 1.
1H NMR (CDCl3,400 MHz)
d 2.68–2.86 (m, 2H), 3.73 (s, 3H),
4.24–4.31 (m, 1H), 5.10–5.12 (m, 1H), 6.92–6.97 (m, 1H), 6.14 (dd,
1H, J = 10.4 Hz, J = 1.2 Hz), 6.82 (d, 2H, J = 8.8 Hz), 7.18 (d, 2H,
J = 8.4 Hz). 19F NMR (CDCl3, 367.5 MHz)
d
À107.7 (dd, 2F,
J = 848.3 Hz, J = 267.4 Hz). 13C NMR (CDCl3, 100.6 MHz)
31.6,
54.3, 68.9 (t, J = 24.5 Hz), 72.6 (t, J = 29.3 Hz), 113.1, 119.8 (t,
J = 234.2 Hz), 120.1, 127.8, 129.6, 137.9, 158.9, 174.2. IR (cmÀ1
d
,
KBr) 3422, 2962, 1701, 1258, 1034, 812. EI-MS (m/z) 268 (M+, 11),
264 (11), 205 (100), 135 (80). HRMS calcd for C14H14F2O4:
284.0860, found: 284.0861.
Acknowledgements
3.7.1. (E)-5,5-difluoro-4-hydroxy-6-styryl-tetrahydropyran-2-one
(1a)
The authors thank the National Natural Science Foundation of
China (No. 20972050 and No. 21172148) and Science and
Technology Commission of Shanghai Municipality (No.
10540501300) for financial support.
1H NMR (CDCl3, 500 MHz)
d 2.95 (dd, 1H, J = 18.2 Hz, J = 1.4 Hz),
3.06–3.11 (m, 1H), 4.33–4.37 (m, 1H), 5.37–5.43 (m, 1H), 6.24 (dd,
1H, J = 15.9 Hz, J = 7.1 Hz), 6.87 (d, 1H, J = 15.9 Hz), 7.30–7.45 (m,
5H). 19F NMR (CDCl3, 367.5 MHz)
d
À124.2 (dd, 2F, J = 433.8 Hz,
J = 254.5 Hz). 13C NMR (CDCl3, 100.6 MHz)
d
34.9, 66.9 (t,
References
J = 27.5 Hz), 77.0 (t, J = 30.4 Hz), 114.5, 116.4 (t, J = 242.4 Hz),
118.1, 122.9, 132, 134.2, 136.4, 167. IR (cmÀ1, KBr) 3382, 2924,
1723, 1487, 1092, 815. EI-MS (m/z) 254 (M+, 58), 146 (28), 133
(100), 131 (54), 115 (44), 77 (31). HRMS calcd for C13H12F2O3:
254.0755, found: 254.0753.
[1] (a) D.M. Bowles, D.C. Boyles, C. Choi, J.A. Pfefferkorn, S. Schuyler, E.J. Hessler, Org.
Process Res. Dev. 15 (2011) 148–157;
(b) S.M. Grundy, J. Intern. Med. 241 (1997) 295–306.
[2] (a) S. Ahmad, et al. J. Med. Chem. 51 (2008) 2722–2733;
(b) J.A. Pfefferkorn, et al. J. Med. Chem. 51 (2008) 31–45.
[3] (a) F. Bennett, D.W. Knight, G. Fenton, Tetrahedron Lett. 29 (1988) 4865–4868;
(b) E.A. Mash, J.B. Arterburn, S.K. Nimkar, J. Carbohydr. Chem. 11 (1992) 415–424.
[4] J.E. Reardon, R.H. Abeles, Biochemistry 26 (1987) 4717–4722.
[5] (a) I. Ojima, ChemBioChem 5 (2004) 628–635;
3.7.2. (E)-6-(4-chlorostyryl)-5,5-difluoro-4-hydroxy-
tetrahydropyran-2-one (1b)
1H NMR (CDCl3, 400 MHz)
d
2.92–2.96 (m, 1H), 3.03–3.09 (m,
(b) H.J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Muller, U. Obst-Sander,
M. Stahl, ChemBioChem 5 (2004) 637–643.
1H), 4.31–4.34 (m, 1H), 5.40 (dt, 1H, J = 20.4 Hz, J = 5.8 Hz), 6.20

X. Wang et al. / Journal of Fluorine Chemistry 133 (2012) 178–183
[11] (a) Z.W. You, Y.Y. Wu, F.L. Qing, Tetrahedron Lett. 45 (2004) 9479–9481;
183
[6] (a) J.M. Percy, Chim. Oggi. 22 (2004) 18–20;
(b) M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619–8683.
[7] X.W. Zou, F.H. Wu, Y.J. Shen, S. Xu, W.Y. Huang, Tetrahedron 59 (2003)
2555–2560.
[8] (a) N. Miyachi, Y. Yanagawa, H. Iwasaki, Y. Ohara, T. Hiyama, Tetrahedron Lett. 34
(1993) 8267–8270;
(b) Z.W. You, Z.X. Jiang, B.L. Wang, F.L. Qing, J. Org. Chem. 71 (2006) 7261–7267.
[12] T. HIyama, T. Minami, K. Takahashi, Bull. Chem. Soc. Jpn. 68 (1995) 364–372.
[13] (a) K. Takahashi, T. Minami, Y. Ohara, T. Hiyama, Bull. Chem. Soc. Jpn. 68 (1995)
2649–2656;
(b) Z. Cai, W. Zhou, L. Sun, Bioorg. Med. Chem. 15 (2007) 7809–7829;
(c) S. Zhao, W. Zhou, J. Liu, Bioorg. Med. Chem. 17 (2009) 7915–7923.
[14] L.A. Sorbera, P.A. Leeson, J. Castaner, Drugs Future 23 (1998) 847–859.
[15] (a) J. Fried, E.A. Hallinan, Tetrahedron Lett. 25 (1984) 2301–2302;
(b) Y. Shen, M.J. Qi, J. Fluorine Chem. 67 (1994) 229–232.
(b) G. Bertolini, C. Casagrande, G. Norcini, F. Santangelo, Syn. Commun. 24 (1994)
1833–1845;
(c) B.D. Roth, D.F. Ortwine, M.L. Hoefle, C.D. Stratton, D.R. Sliskovic, M.W. Wilson,
R.S. Newton, J. Med. Chem. 33 (1990) 21–31.
[9] (a) P.V. Ramachandran, A. Chatterjee, Org. Lett. 10 (2008) 1195–1198;
(b) X.G. Zhang, H.R. Xia, X.C. Dong, J. Jin, W.D. Meng, F.L. Qing, J. Org. Chem. 68
(2003) 9026–9033.
[16] J.E. Lynch, R.P. Volante, R.V. Wattley, I. Shinkai, Tetrahedron Lett. 28 (1987)
1385–1388.
[17] O. Tempkin, S. Abel, C.P. Chen, R. Underwood, K. Prasad, K.M. Chen, O. Repic, T.J.
Blacklock, Tetrahedron 53 (1997) 10659–10670.
[10] G.B. Reddy, T. Minami, T. Hanamoto, T. Hiyama, J. Org. Chem. 56 (1991) 5752–5754.