Total synthesis of γ-trifluoromethylated analogs of goniothalamin and their derivatives

Article abstract of DOI:10.1016/j.jfluchem.2013.07.017

An efficient method for the construction of chiral γ- trifluoromethylated α,β-unsaturated δ-lactone, a widely existing pharmacophore, has been developed and successfully applied for synthesis of γ-trifluoromethylated goniothalamins. The key steps included Evans-Aldol reaction of chiral titanium enolate of α-CF₃ imide, Wittig olefination and lactonization. The transformation of γ-trifluoromethylated α,β-unsaturated δ-lactone to a series of trifluoromethylated styryllactones was also investigated.

Full text of DOI:10.1016/j.jfluchem.2013.07.017

Journal of Fluorine Chemistry 155 (2013) 143–150
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Total synthesis of
their derivatives
g-trifluoromethylated analogs of goniothalamin and
Jun-Ling Chen a, Zheng-Wei You b, Feng-Ling Qing a,c,
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China
b State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University,
2999 North Renmin Road, Shanghai 201620, China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road,
Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient method for the construction of chiral g-trifluoromethylated a,b-unsaturated d-lactone, a
Received 26 April 2013
Accepted 25 July 2013
Available online 2 August 2013
widely existing pharmacophore, has been developed and successfully applied for synthesis of
trifluoromethylated goniothalamins. The key steps included Evans-Aldol reaction of chiral titanium
enolate of -CF3 imide, Wittig olefination and lactonization. The transformation of -trifluoromethy-
lated -unsaturated -lactone to a series of trifluoromethylated styryllactones was also investigated.
ß 2013 Elsevier B.V. All rights reserved.
g-
a
g
a
,b
d
Keywords:
Trifluoromethylated
Goniothalamin
a,b-Unsaturated d-lactone
1. Introduction
2. Results and discussion
Goniothalamin and its analogs having
unsaturated -lactone moiety have been demonstrated to possess
interesting biological activities [1]. The structure–activity rela-
tionship studies revealed that the -unsaturated -lactone
moiety plays a key role in their bioactivities, as it is an excellent
potential Michael acceptor for nucleophilic amino acid residues of
target enzymes [2]. We hypothesized that the introduction of
a
common
a
,
b
-
The retrosynthetic analysis of compound 4 is outlined in
Scheme 1. Lactone 4 could be made using the intramolecular ester
d
exchange reaction of linear
a,b-unsaturated ester 5, which could
a
,
b
d
be assembled from aldehyde 6 via Wittig olefination. The aldehyde
6 could be prepared from the key chiral intermediate 7. The Evans-
Aldol reaction of the chiral
a-CF3 imide derived from 3,3,3-
trifluoropropanoic acid should provide compound 7 [5].
fluorine or fluorinated group into the
rated -lactone would make the double bond more electron-
deficient and lead to a better Michael acceptor. Accordingly, two
kinds of fluorine-containing analogs of goniothalamin 1, -gem-
difluoromethylenated goniothalamin 2 and -monofluorinated
goniothalamin 3, have been designed and successfully synthesized
by our group (Fig. 1) [3]. The trifluoromethyl group (–CF3) is one of
the most electronegative groups and has widely been incorporated
into medicinal compounds [4]. Thus, we are interested in the
g
-position of
a
,
b
-unsatu-
Our synthesis commenced with the stereocontrolled construc-
tion of the chiral vicinal hydroxyl and trifluoromethyl groups. The
TiCl4-catalyzed Evans-Aldol reaction of oxazolidinone 8 with
d
g
cinnamaldehyde went smoothly to deliver a-CF3-b-OH imide 9 in
g
high diastereoselectivity (11:1 dr; Scheme 2) [5]. However, the
removal of the Evans’ chiral auxiliary of imide 9 in the presence of
NaBH4 gave cinnamyl alcohol instead of the desired trifluoro-
methylated aldehyde 6. The proposed mechanism for the
formation of cinnamyl alcohol is shown in Scheme 2. As the
trifluoromethyl group (CF3–) is a strong electron-withdrawing
group, the C3 hydroxyl group of imide 9 was transformed to alkoxy
anion under the base reaction conditions and the subsequent
cleavage of the carbon–carbon bond between C2 and C3 resulted in
the formation of cinnamaldehyde. Finally, reduction of cinnamal-
dehyde with NaBH4 gave cinnamyl alcohol. To address this
problem, the protection of the free hydroxyl group of compound
9 with t-butyldimethylsilyl (TBS) group gave silyl ether 10
(Scheme 2). However, the removal of the Evans’ oxazolidinone
introduction of a trifluoromethyl group into the
g-position of
goniothalamin. Herein, we report the total synthesis of trifluor-
omethylated analogs of goniothalamin 4 (Fig. 1).
*
Corresponding author at: Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling
Road, Shanghai 200032, PR China. Tel.: +86 2154925187.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.07.017

144
J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
O
O
Michael acceptor
Ph
Essential for its bioactivity
Introducing fluorine or fluoroalkyl
substituents may lead to better
Michael acceptor
1 Goniothalamin
Scheme 1. Retrosynthetic analysis of g-trifluoromethylated goniothalamin 4.
O
O
O
O
This work
O
O
corresponding aldehyde was investigated. Treatment of alcohol 16
with I2, PPh3 and imidazole yielded iodide 18 in 95% yield. Finally,
the reaction of 18 with PPh3 gave the desired phosphonium salt 19
in high yield.
Ph
Ph
Ph
CF3
F
F
F
3
2
4
The Wittig reaction of 19 with ethyl glyoxalate in the presence
Fig. 1. Design of fluorinated goniothalamin.
of n-BuLi at ꢀ78 8C proceeded smoothly to afford the linear
a,b-
unsaturated ester 20 in 57% with a Z/E selectivity of C255C3 double
bond up to 6.9/1. Treatment of 20 with Et3Nꢁ3HF provided alcohol
21 in 96% yield (Scheme 4).
chiral auxiliary of 10 under a number of reaction conditions
(NaBH4, LiAlH4, and H2O2/LiOH/H2O) failed to give the desired
product, and compound 11 was formed.
At this stage, we thought that the more stable auxiliary would
make the C1 carbonyl group of imide to be easily attacked by
reduction agents. Accordingly, an alternative synthetic route using
oxazolidinethione instead of oxazolidinone as the chiral auxiliary
was investigated. The coupling reaction of 3,3,3-trifluoropropanoic
The lactonization of linear ester 21 was initially carried out in
toluene in the presence of p-toluenesulfonic acid (0.2 equiv.) at
80 8C for 3 h. No target molecular 4 was detected, while compound
21 was totally consumed (Table 1, entry 1). When the reaction
temperature was decreased to 30 8C, the expected
g-trifluor-
omethylated goniothalamin 4a was formed in 74% yield along
with the epimer 4b in 11% yield (entry 2). Interestingly, the higher
concentration of TsOH was, the more epimer 4b was formed
(entries 2–4). When the dosage of TsOH was increased to
1.0 equiv., the epimer 4b was formed as the major product (entry
5). When CF3CO2H was used instead of TsOH, the epimerization
was significantly suppressed and thus 4a was formed as the single
product (entry 6). Overall, a practical way was developed to
control the epimerization during lactonization of linear ester 21,
acid and oxazolidinethione 12 gave
a-CF3 imide 13 in high yield
(Scheme 3) [6,7]. Treatment of 13 with TiCl4 (1.1 equiv.) and
TMEDA (2.5 equiv.) and followed by cinnamaldehyde (1.5 equiv.)
provided compound 14 in 81% yield and excellent diastereoselec-
tivity (>97:2 dr) [7]. Protection of the free hydroxyl of imide 14
with TBS group afforded silyl ether 15 in 93% yield. As we expected,
the removal of the oxazolidinethione of 15 in the presence of
LiAlH4 at ꢀ78 8C gave the desired alcohol 16 in 83% yield with a
nearly quantitative recovery of chiral auxiliary 12. However, the
oxidization of primary alcohol 16 led to a complex reaction,
enabling efficient synthesis of two diastereoisomers of target g-
trifluoromethylated goniothalamins 4a and 4b. The absolute
configuration of product 4b was assigned to be 5R, 6S by X-ray
crystal analysis of compound 22 (Fig. 2) [8]. The Michael addition
of 4-methylbenzenethiol with 4b in the presence of 1,
probably due to the instability of the resulting
a-CF3 aldehyde 17
(Scheme 3). Thus, an alternative route based on the Wittig
olefination between phosphonium salt derived from 16 and the
O
O
O
O
1) PivCl, Et3N
O
1) TMSOTf, Et3N
F3C
F3C
N
O
OH
2)
Ph
O
LiN
O
Bn
TiCl4
55%
2)
Bn
8
50%
OH
O
O
O
O
OH
1
O
NaBH4
NaBH4
Ph
N
O
3
Ph
N
O
2
Ph
Ph
CF3
CF3
Bn
Bn
9
TBSOTf
80%
NaBH4
TBSO
O
O
or LiAlH4
TBSO
O
Bn
or H2O2, LiOH
OH
Ph
N
1
O
Ph
N
H
CF3
CF3
11
Bn
10
Scheme 2. Synthesis of chiral
a-CF3-b-OH imide 9 and attempts to remove its auxiliary.

J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
145
1) TiCl4
2) TMEDA
S
O
OH
O
S
DCC, DMAP,
S
3)
F3C
O
Ph
F3CCH2COOH
O
N
O
Ph
N
O
+
HN
Bn
O
F3C
81%
88%
OH
CF3
Bn
13
dr > 98: 2
Bn
14
12
S
OTBS
TPAP, NMO
or SO3•Py
TBSO
O
S
OTBS
LiAlH4
HN
Bn
TBSOTf
93%
O
Ph
OH
+
Ph
N
O
X
Ph
O
CF3
CF3
83%
99%
12
CF3
Bn
16
95%
17
15
I2
PPh3
imidazole
OTBS
OTBS
PPh3
Ph
88%
PPh3I
Ph
I
CF3
CF3
18
19
Scheme 3. Synthesis of chiral the
a-CF3 phosphonium salt 19.
OH
OTBS
OTBS
1. n-BuLi
3
Et3N·3HF
2
Ph
Ph
PPh3I
Ph
6
O
96%
CF3 COOEt
21
CF3
CF3 COOEt
2.
OEt
20
19
H
57%
O
Scheme 4. Synthesis of
a,b-unsaturated ester 20.
8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave compound 22 in
86% yield (Scheme 5).
As goniothalamin is the mother structure of a family of
bioactive natural products including goniodiols and goniothalamin
NMR; Scheme 6). The major product 23 was isolated in 64% yield
and its absolute configuration was determined to be 5R, 6S, 7S, 8S
by X-ray crystal analysis (Scheme 6) [8]. The epoxidation of 4b
with m-CPBA furnished two inseparable diastereomers 24a and
24b in 65% yield (2:1 determined by 19F NMR).
The dihydroxylation of 4a was implemented in the presence of
K2OsO4ꢁH2O, K3Fe(CN)6, DABCO (1,4-diazabicyclo[2.2.2]octane)
and K2CO3. After stirring at room temperature for 20 min,
compound 4a was totally consumed and some new products
were detected by TLC monitoring. However, these products
oxides [1], we expected
could serve as an intermediate to synthesize diverse
g
-trifluoromethylated goniothalamin
-trifluor-
g
omethylated styryllactones. Accordingly, the epoxidations and the
dihydroxylations of 4a and 4b were investigated. The epoxidation
of 4a with m-CPBA produced g-trifluoromethylated goniothalamin
oxide 23 in moderate diastereoselectivity (6:1 determined by 19F
Table 1
Synthesis of two diastereoisomers of g-trifluoromethylated goniothalamins from precursor 21.
.
Entrya
Catalyst
Dosage of catalyst (equiv)
Solvent
Vsol.
4a:4bb
Yieldc
4a
4b
1d
2
TsOHꢁH2O
TsOHꢁH2O
TsOHꢁH2O
TsOHꢁH2O
TsOHꢁH2O
CF3CO2H
0.2 eq.
0.2 eq.
0.2 eq.
0.2 eq.
1.0 eq.
1.0 eq.
Toluene
Benzene
Benzene
Benzene
Benzene
CH2Cl2
2.5 ml
2.5 ml
1.0 ml
0.5 ml
0.5 ml
2.5 ml
–
Complicated
74%
6.15:1
5.03:1
2.85:1
1:3.65
39:1
11%
15%
21%
65%
–
3
70%
4
56%
5
15%
6
79%
a
Reaction conditions unless noted otherwise: 21 (0.5 mmol); reaction temperature: 30 8C; reaction time: 24 h.
The ratio of the two lactones was determined by 19F NMR.
Isolated yield.
b
c
d
Reaction temperature: 80 8C; reaction time: 3 h.

146
J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
Fig. 2. ORTEP drawing of the X-ray crystallographic structure of 22.
O
O
Me
HS
Me
O
O
2
(R)
(S)
DBU (cat.)
-20 oC
86%
Ph
Ph
S
5
CF3
CF3
22
4b
dr, 94: 6
Scheme 5. Michael addition reaction of 4b.
Scheme 6. The epoxidations of 4a and 4b.
decomposed during the work-up. The dihydroxylation of 4b gave
the similar result. Thus, we decided to perform dihydroxylation of
linear ester 20 prior to the construction of the lactone ring. To our
delight, the dihydroxylation of 20 in achiral system (K2OsO4ꢁH2O,
K3Fe(CN)6, DABCO (1,4-diazabicyclo[2.2.2]octane), and K2CO3)
went smoothly to give the intramolecular Michael addition
product 26 in a good diastereoselectivity (Table 2, entry 1). The
structure and absolute configuration of compound 26 were
Table 2
Dihydroxylation of compound 20.
TBSO
CF3
OTBS
OH OTBS
Intramolecular
(S)
(R)
(R)
Michael addition
Dihydroxylation
(R)
HO
COOEt
Ph
Ph
O
Ph (S)
CF3 COOEt
20
OH CF3 COOEt
26
25
.
Entry
Conditions
Results/yield
dr
1
2
3
K2OsO4ꢁH2O, K3Fe(CN)6, DABCO
74%a
67%b
N.R.c
8.2:1
>98:2
–
AD-mix-
AD-mix-
a
b
a
b
c
Isolated yield of two diastereomers.
18% of 20 recovered.
No reaction.

J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
147
7.26 ppm). In the assignments, the chemical shift (in ppm) is
given first, followed, in brackets, by the multiplicity of the signal (s,
singlet; d, doublet; t, triplet; dd, doublet of doublets; m, multiplet),
the value of the coupling constants in Hz if applicable, the number
of protons implied and finally the assignment.
4.2. Synthesis of 9
To a dried three-necked flask was added imide 8 [5d] (1.13 g,
3.94 mmol) in CH2Cl2 (20 ml) under N2. To the mixture were added
TMSOTf (1.1 ml, 5.91 mmol) and Et3N (0.82 ml, 5.91 mmol) at
ꢀ20 8C. After stirring at reflux temperature for 0.5 h, the solution
was cooled to 0 8C. Then cinnamaldehyde (618 mg, 4.73 mmol) and
TiCl4 (0.20 ml, 1.97 mmol) were added to it. After stirring at that
temperature for 5 h, the solution was poured into cooled water.
The mixture was extracted with CH2Cl2 (30 ml ꢂ 4). The combined
extracts were dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (petroleum ether:-
ethyl acetate = 6:1) to afford pure 9 (900 mg, 55%) as a white solid.
Mp = 108.1–109.3 8C:
(400 MHz, CDCl3)
½
a 2D4:0
ꢃ
ꢀ30 (c 0.89, CHCl3); 1H NMR
d
7.46–7.18 (m, 8H), 7.05 (d, J = 5.0 Hz, 2H),
6.71 (d, J = 15.8 Hz, 1H), 6.34 (dd, J = 15.8, 7.6 Hz, 1H), 5.36–5.27
(m, 1H), 4.99 (t, J = 7.5 Hz, 1H), 4.72–4.68 (m, 1H), 4.19 (t, J = 8.2 Hz,
1H), 4.08 (d, J = 8.8 Hz, 1H), 3.20 (d, J = 13.4 Hz, 1H), 2.51 (s, 1H),
2.32 (t, J = 11.8 Hz, 1H); 13C NMR (101 MHz, CDCl3)
d 165.3 (q,
J = 2.9 Hz), 153.3, 135.6, 134.8, 134.2, 129.2, 129.0, 128.8, 128.5,
127.4, 126.8, 126.4, 124.0 (q, J = 283 Hz), 71.6, 66.1, 55.4, 52.5 (q,
J = 25.3 Hz), 37.4; 19F NMR (377 MHz, CDCl3)
J = 7.9 Hz, 3F); IR (thin film) vmax 3442, 2921, 1784, 1699, 1639,
1391, 1245, 1156 cmꢀ1; Anal. calcd for C22H20F3NO4: C, 63.00; H,
4.81; N, 3.34. Found: C, 62.71, H, 4.93; N, 3.42.
d
ꢀ62.56 (d,
Fig. 3. ORTEP drawing of the X-ray crystallographic structure of 26.
determined by 1H NMR and X-ray crystal analysis (Fig. 3) [8]. The
formation of compound 26 was due to the strong electron-
withdrawing effect of
g
-trifluoromethyl group, which made the
4.3. Synthesis of 10
a,b
-conjugated double bond of the dihydroxylation product 25 to
be an excellent Michael acceptor (Table 2). As expected, the
To a solution of 9 (110 mg, 0.263 mmol) in CH2Cl2 (3 ml) was
added 2,6-lutidine (56 mg, 0.526 mmol) at ꢀ78 8C. Then TBSOTf
(0.10 ml, 0.41 mmol) was added slowly, and the mixture was
stirred for another 1 h at 0 8C. The mixture was quenched with
brine (10 ml) and was extracted with CH2Cl2 (15 ml ꢂ 2). The
combined organic extracts were concentrated and purified by flash
chromatography on silica gel (petroleum ether:ethyl ace-
diastereoselectivity was significantly improved using chiral
dihydroxylation reagent AD-mix-
NMR, entry 2) [9], while no reaction took place in the case of AD-
mix- (entry 3).
a
(>98:2 determined by 19F
b
3. Conclusion
tate = 20:1) to afford 10 (112 mg, 80%) as
Mp = 116.0–117.1 8C:
+35 (c 0.95, CHCl3); 1H NMR
(400 MHz, CDCl3) 7.39–7.20 (m, 8H), 7.00 (s, 2H), 6.57 (d,
J = 16.0 Hz, 1H), 6.26 (dd, J = 15.9, 8.5 Hz, 1H), 5.50–5.26 (m, 1H),
4.96 (t, J = 8.7 Hz, 1H), 4.73–4.65 (m, 1H), 4.13 (t, J = 8.4 Hz, 1H),
3.99 (d, J = 9.1 Hz, 1H), 3.19 (d, J = 13.4 Hz, 1H), 2.08 (t, J = 12.0 Hz,
1H), 0.93 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H); 13C NMR (101 MHz,
a white solid.
We have successfully synthesized two chiral trifluoromethy-
lated analogs of goniothalamin 4a and 4b from readily available
3,3,3-trifluoropropanoic acid. The key steps included TiCl4-
½ ꢃ
a 2D1:0
d
mediated Evans-Aldol reaction of chiral
a-CF3 imide, Wittig
olefination, and lactonization with controlled epimerization. The
diverse analogs of styryllactones including trifluoromethylated
goniothalamin oxides 23, 24a, and 24b and highly functionalized
tetrahydrofuran compound 26 were efficiently prepared via facile
post-transformations. By simply using other aldehydes as starting
materials instead of cinnamaldehyde, the synthetic strategy
developed here could be readily utilized to prepare a large family
CDCl3)
d 165.7 (q, J = 3.0 Hz), 152.8, 135.7, 135.0, 133.6, 129.0,
128.9, 128.8, 128.4, 128.1, 127.3, 126.7, 123.9 (q, J = 283 Hz), 73.1,
65.8, 55.4, 53.1(q, J = 25.1 Hz), 37.4, 25.6, 17.9, ꢀ4.0, ꢀ5.1; 19F NMR
(377 MHz, CDCl3)
d
ꢀ62.31 (d, J = 7.6 Hz, 3F); IR (thin film) vmax
2938, 1784, 1704, 1638, 1389, 1250, 1157 cmꢀ1; Anal. calcd for
of
g
-trifluoromethylated analogs of
a
,
b
-unsaturated
d
-lactone
C28H34F3NO4Si: C, 63.02; H, 6.42; N, 2.62. Found: C, 62.61, H, 6.28;
N, 2.52. HRMS (EI): m/z [M]+ calcd for C28H34F3NO4Si: 533.2209.
containing natural products [10].
Found: 533.2214.
4. Experimental
4.4. Synthesis of 11
4.1. General
To a solution of compound 10 (110 mg, 0.207 mmol) in THF
(5 ml) and H2O (1 ml) were added NaBH4 (41 mg, 1.034 mmol).
The reaction mixture was stirred vigorously for 24 h at 0 8C. The
organic layer was separated and the aqueous phase was then
extracted with ethyl acetate (10 ml ꢂ 2). The combined extracts
were washed with water and brine, dried over anhydrous Na2SO4,
All reagents were commercially available and used without
additional purification. All solvents were purified by well-
established techniques. NMR spectra for 1H, 13C, 19F were acquired
on BRUKER Ascend 400 spectrometers. The spectra were refer-
enced to residual proton-solvent references (1H, CDCl3 at

148
J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (petroleum ether:ethyl
combined organic extracts were concentrated and purified by flash
chromatography on silica gel (petroleum ether:ethyl ace-
acetate = 5:1) to afford 11 (81 mg, 77%) as
Mp = 133.4–134.3 8C:
+65.0 (c 0.89, CHCl3); 1H NMR
(400 MHz, CDCl3) 7.37–7.24 (m, 5H), 7.23–7.16 (m, 3H), 7.10
a
white solid.
tate = 25:1) to afford 15 (2.19 g, 99%) as a colorless oil: ½a D24:4
ꢃ
½
a 2D4:0
ꢃ
+138 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.39–7.33 (m, 5H),
d
7.33–7.25 (m, 3H), 6.70–6.48 (d, J = 7.0 Hz, 2H), 6.65–6.60 (m, 1H),
6.56 (d, J = 15.9 Hz, 1H), 6.26 (dd, J = 15.9, 8.4 Hz, 1H), 4.93 (t,
J = 8.4 Hz, 1H), 4.71–4.67 (m, 1H), 4.17 (d, J = 9.3 Hz, 1H), 3.69 (t,
J = 8.3 Hz, 1H), 3.21 (d, J = 13.4 Hz, 1H), 2.95–2.64 (m, 1H), 0.94 (s,
(d, J = 6.4 Hz, 2H), 6.65 (d, J = 15.8 Hz, 1H), 6.48 (d, J = 7.2 Hz, 1H),
6.09 (dd, J = 15.8, 7.0 Hz, 1H), 4.89 (t, J = 6.7 Hz, 1H), 4.16–4.08 (m,
1H), 3.60 (d, J = 11.0 Hz, 1H), 3.53 (dd, J = 11.0, 2.6 Hz, 1H), 3.27–
3.11 (m, 1H), 2.79 (dd, J = 13.7, 6.1 Hz, 1H), 2.72 (dd, J = 13.6, 8.1 Hz,
1H), 2.18 (s, 1H), 0.94 (s, 9H), 0.15 (s, 3H), 0.10 (s, 3H); 13C NMR
9H), 0.17 (s, 3H), 0.09 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 185.0,
166.77 (q, J = 3.0 Hz), 135.6, 134.7, 132.8, 129.4, 129.0, 128.9,
128.5, 128.0, 127.5, 126.5, 124.0 (q, J = 283 Hz), 73.5, 70.0, 60.4,
53.4 (q, J = 25.1 Hz), 37.4, 25.6, 18.0, ꢀ4.03, ꢀ5.1; 19F NMR
(101 MHz, CDCl3)
d 164.9, 137.3, 135.9, 133.2, 129.1, 128.7, 128.6,
128.2, 127.3, 126.7, 126.6, 124.1 (q, J = 282 Hz), 71.1, 63.0, 58.0 (q,
J = 24.3 Hz), 53.0, 36.7, 25.7, 18.0, ꢀ4.2, ꢀ5.2; 19F NMR (377 MHz,
(377 MHz, CDCl3)
d
ꢀ61.69 (d, J = 7.6 Hz, 3F); IR (thin film) vmax
CDCl3)
d
ꢀ63.44 (d, J = 8.2 Hz, 3F); IR (thin film) vmax 3437, 3088,
3031, 2958, 2859, 1702, 1647, 1355, 1249, 1163 cmꢀ1; Anal. calcd
for C28H34F3NO3SSi: C, 61.18; H, 6.23; N, 2.55. Found: C, 61.02, H,
6.24; N, 2.5
2936, 2860, 1527, 1254, 1151 cmꢀ1; Anal. calcd for C27H36F3NO3Si:
C, 63.88; H, 7.15; N, 2.76. Found: C, 63.89, H, 7.18; N, 2.50.
4.5. Synthesis of 13
4.8. Synthesis of 16
To a stirred solution of (S)-4-benzyloxazolidine-2-thione 12 [7]
(8.56 g, 44.35 mmol) in CH2Cl2 was added 3,3,3-trifluoropropanoic
acid (6.37 g, 48.79 mmol) and DMAP (757 mg, 6.21 mmol) and DCC
(11.07 g, 53.22 mmol) under nitrogen at 0 8C. After stirring for
30 min, the precipitated DCU was filtered and the filtrate was
concentrated and then chromatographed over silica gel (petroleum
ether:ethyl acetate = 8:1) to give pure 13 (11.83 g, 88%) as a
slightly yellow solid: Mp = 53.4–54.5 8C. 1H NMR (400 MHz, CDCl3)
A solution of 15 (3.50 g, 6.375 mmol) in dry THF (90 ml) was
added to a solution of lithium aluminum hydride (445 mg,
11.475 mmol) at ꢀ78 8C. After stirring for 1 h, the reaction mixture
was quenched with saturated potassium sodium tartrate aqueous
solution (200 ml) and stirred for 1 h at room temperature. Then the
mixture was extracted with ethyl acetate (100 ml ꢂ 3). The
combined organic extracts was concentrated and purified by flash
chromatography on silica gel (petroleum ether: ethyl acetate = 20:
1 to 2:1) to afford 16 (1.90 g, 83%) as a yellow oil and the purified
d
7.37–7.22 (m, 5H), 4.99 (m, 1H), 4.46–4.32 (m, 3H), 4.32–4.20 (m,
1H), 3.31 (d, J = 13.3 Hz, 1H), 2.83 (t, J = 11.6 Hz, 1H).
oxazolidinethione (1.22 g, 99%). ½a D26:2
ꢃ
ꢀ150 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3)
d 7.41–7.27 (m, 5H), 6.68 (d, J = 15.9 Hz, 1H),
4.6. Synthesis of 14
6.26 (dd, J = 15.9, 6.4 Hz, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.06 (dd,
J = 11.2, 7.3 Hz, 1H), 3.89 (d, J = 10.5 Hz, 1H), 2.82–2.62 (m, 1H),
2.54 (s, 1H), 0.95 (s, 9H), 0.16 (s, 3H), 0.12 (s, 3H); 13C NMR
To a solution of 13 (4.45 g, 14.69 mmol) in CH2Cl2 (75 ml) was
added TiCl4 (1.78 ml, 16.16 mmol) at ꢀ78 8C. After stirring for
(101 MHz, CDCl3)
d 136.2, 132.4, 128.7, 128.0, 127.4, 126.6, 125.9
30 min, N,N,N0,N0-tetramethyl-ethane-1,2-diamine
(5.50 ml,
(q, J = 282 Hz), 71.3 (d, J = 2.4 Hz), 58.3 (d, J = 3.0 Hz), 51.8 (q,
36.72 mmol) was added dropwise at the same temperature. After
stirring for 1 h, trans-cinnamaldehyde (2.88 g, 22.03 mmol) was
added at ꢀ78 8C. After stirring for 20 min, the solution was slowly
warmed to ꢀ20 8C, and stirred for 2 h. The solution was then
warmed to 0 8C and stirred for another 1 h. The solution was then
poured into 1 M HCl (400 ml). After extraction with CH2Cl2, the
combined organic layers are washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude
material was purified by silica gel column chromatography
(petroleum ether:ethyl acetate = 6:1) to afford pure 14 (5.11 g,
J = 22.9 Hz), 25.7, 18.1, ꢀ4.4, ꢀ5.2; 19F NMR (377 MHz, CDCl3)
d
ꢀ65.40 (d, J = 9.6 Hz, 3F); IR (thin film) vmax 3443, 2944, 2861,
1657, 1256, 1131, 1081 cmꢀ1; MS (ESI): m/z 383.1 [M+Na]+; HRMS
(ESI): m/z [M+Na]+ calcd for C18H27F3NaO2Si: 383.1630. Found:
383.1626.
4.9. Synthesis of 18
Toa solutionofalcohol16(3.70 g, 10.28 mmol)inCH2Cl2 (80 ml),
triphenylphosphine (5.92 g, 22.61 mmol), imidazole (1.75 g,
25.70 mmol), and iodine (5.74 g, 22.61 mmol) were added in this
order. The reaction mixture was kept at room temperature for 2 h
and the reaction mixture was filtered and washed with CH2Cl2. The
organic layers were then washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (pure petroleum ether) to afford 18
80%) as an yellow oil: ½a D23:6
ꢃ
+232 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3)
d 7.38–7.32 (m, 5H), 7.32–7.25 (m, 3H), 7.20 (d, J = 7.0 Hz,
2H), 6.72–6.64 (m, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.32 (dd, J = 15.9,
7.9 Hz, 1H), 4.98 (t, J = 7.8 Hz, 1H), 4.88–4.68 (m, 1H), 4.24 (dd,
J = 9.3, 1.7 Hz, 1H), 3.89 (t, J = 8.4 Hz, 1H), 3.24 (dd, J = 13.4, 2.8 Hz,
1H), 2.81 (dd, J = 13.4, 9.9 Hz, 1H), 2.39 (s, 1H); 13C NMR (101 MHz,
CDCl3)
129.1, 128.9, 128.7, 127.6, 126.7, 126.1, 124.0 (q, J = 283 Hz), 72.0,
70.2, 60.3, 52.5 (q, J = 25.2 Hz), 37.4; 19F NMR (377 MHz, CDCl3)
d
185.24, 166.4 (q, J = 3.0 Hz), 135.4, 134.6, 133.8, 129.4,
(4.59 g, 95%) as a colorless oil: ½a D26:0
ꢃ
ꢀ61.7 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3)
d 7.59–7.08 (m, 5H), 6.72 (d, J = 15.9 Hz, 1H), 6.23
d
(dd, J = 15.8, 6.7 Hz, 1H), 4.79–4.75 (m, 1H), 3.46 (dd, J = 10.3, 6.3 Hz,
1H), 3.26 (dd, J = 10.5, 5.0 Hz, 1H), 2.73–2.64 (m, 1H), 0.97 (s, 9H),
ꢀ61.88 (d, J = 7.7 Hz, 3F); IR (thin film) vmax 3441, 3031, 2962,
1702, 1358, 1254, 1165 cmꢀ1; MS (ESI): m/z 458.0 [M+Na]+; HRMS
(ESI): m/z [M+Na]+ calcd for C22H20F3NNaO3S: 458.1014. Found:
458.1009.
0.18 (s, 3H), 0.12 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 136.2, 132.4,
128.7, 128.2, 128.0, 126.7, 125.5 (q, J = 259 Hz), 72.2, 52.6 (q,
J = 23.8 Hz), 25.7, 18.1, ꢀ4.1, ꢀ5.1; 19F NMR (377 MHz, CDCl3)
d
ꢀ64.65 (d, J = 8.5 Hz, 3F); IR (thin film)
vmax 3032, 2941, 2860, 1650,
4.7. Synthesis of 15
1463, 1370, 1256, 1175, 1109 cmꢀ1; Anal. calcd for C18H26F3IOSi: C,
45.96; H, 5.57. Found: C, 45.74, H, 5.65.
To a solution of 14 (3.50 g, 8.06 mmol) in CH2Cl2 (80 ml) was
added 2,6-lutidine (2.80 ml, 12.10 mmol) and TBSOTf (1.9 ml,
16.13 mmol) at ꢀ78 8C. Then the solution was slowly warmed to
0 8C, and stirred for 1 h. The mixture was quenched with saturated
brine solution and was extracted with CH2Cl2 (100 ml ꢂ 3). The
4.10. Synthesis of 19
In a flame-dried 25 ml round-bottom flask, iodide 18 (3.15 g,
6.70 mmol) and triphenylphosphine (14.05 g, 53.62 mmol) were

J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
149
placed. The reaction mixture was kept at 95 8C and stirred for 24 h.
Then the reaction mixture was purified by flash chromatography
on silica gel (dichloromethane:methanol = 10:1) to afford 19
4.24 (q, J = 7.1 Hz, 2H), 2.93 (s, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) 166.3, 137.4 (q, J = 2.9 Hz), 136.2, 132.6,
128.6, 128.0, 126.9, 126.7, 126.1, 125.5 (q, J = 282 Hz), 71.34 (q,
J = 2.0 Hz), 61.0, 48.5(q, J = 25.2 Hz), 14.1; 19F NMR (377 MHz,
d
(4.32 g, 88%) as a slightly yellow solid: Mp = 87.6–88.7 8C. ½a D26:3
ꢃ
ꢀ35.5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.83–7.68 (m,
CDCl3)
d
ꢀ66.45 (d, J = 8.9 Hz, 3F); IR (thin film)
v
max 3441, 2985,
9H), 7.65–7.62 (m, 6H), 7.47 (d, J = 7.5 Hz, 2H), 7.21 (t, J = 7.4 Hz,
2H), 7.15–7.13 (m, 1H), 6.69 (d, J = 15.8 Hz, 1H), 6.25 (dd, J = 15.7,
7.6 Hz, 1H), 4.91–4.57 (m, 1H), 4.04 (dt, J = 16.6, 10.5 Hz, 1H), 3.78
(t, J = 16.2 Hz, 1H), 2.64–2.50 (m, 1H), 0.66 (s, 9H), ꢀ0.10 (s, 3H),
1714, 1654, 1419, 1198, 1025 cmꢀ1
; MS (ESI): m/z 337.0
[M+Na]+; HRMS (ESI): m/z [M+Na]+ calcd for C16H17F3NaO3:
337.1028. Found: 337.1033.
ꢀ0.15 (s, 3H); 13C NMR (101 MHz, D2O)
d
137.9, 137.9, 137.0,
4.13. Synthesis of 4a
136.1, 136.0, 133.1, 133.0, 130.9, 130.6, 129.6, 128.4, 125.3 (q,
J = 283 Hz), 120.0, 119.2, 71.9, 45.8 (q, J = 25.2 Hz), 25.7, 19.8 (d,
To a solution of 21 (157 mg, 0.5 mmol) in dry benzene
(2.5 ml) at 30 8C was added TsOHꢁH2O (19 mg, 0.1 mmol). The
mixture was stirred for 24 h and then diluted with water (10 ml)
and extracted with ethyl acetate. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated.
Flash chromatography on silica gel (petroleum ether:ethyl
acetate = 4:1) of the residue yielded 21 (99 mg, 74%) as a lightly
J = 53.3 Hz), 17.9, ꢀ4.1, ꢀ4.9; 19F NMR (377 MHz, CDCl3)
d
ꢀ63.93
(d, J = 7.9 Hz, 3F); IR (thin film) vmax 3053, 2940, 2860, 1644, 1438,
1260, 1112 cmꢀ1; MS (EI): m/z 605.2 [MꢀI]+; HRMS (EI): m/z
[MꢀI]+ calcd for C36H41F3OPSi: 605.2616. Found: 605.2628.
4.11. Synthesis of 20 and 200
yellow solid: Mp = 77.2–78.7 8C. ½a D24:9
ꢃ
ꢀ156 (c 1.0, CHCl3); 1H
To a solution of 19 (5.28 g, 7.21 mmol) in THF (75 ml) at
ꢀ5 8C under nitrogen atmosphere was added n-BuLi (6.76 ml,
1.6 M in THF, 10.82 mmol). The mixture was cooled to ꢀ78 8C
NMR (400 MHz, CDCl3) d 7.50–7.29 (m, 5H), 6.87 (dd, J = 9.6,
5.0 Hz, 1H), 6.84 (d, J = 16.3 Hz, 1H), 6.36 (d, J = 9.4 Hz, 1H), 6.34
(dd, J = 7.4, 16.3 Hz, 1H), 5.34 (t, J = 5.9 Hz, 1H), 3.52–3.45 (m,
and stirred for 30 min and
a
solution of ethyl glyoxalate
1H); 13C NMR (101 MHz, CDCl3)
d
161.6, 137.6 (q, J = 2.7 Hz, 5H),
135.4, 128.7, 126.9, 125.1, 124.4 (q, J = 282 Hz), 123.00 (s, 1H),
121.0, 77.0, 42.7 (q, J = 27.2 Hz); 19F NMR (377 MHz, CDCl3)
(7.93 mmol, 50% in toluene) was then added dropwise. The
mixture was stirred for 10 min at ꢀ78 8C and then diluted with
brine and extracted with ethyl acetate. The combined organic
d
ꢀ65.08 (d, J = 8.7 Hz, 3F); IR (thin film) vmax 2928, 2860, 1735,
1651, 1379, 1253, 1132 cmꢀ1; MS (EI): m/z 268 [M]+; HRMS (EI):
m/z [M]+ calcd for C14H11F3O2: 268.0711. Found: 268.0714.
layers
were dried over anhydrous Na2SO4, filtered, and
concentrated. Flash chromatography on silica gel (petroleum
ether:ethyl acetate = 200:1) of the residue yielded 20 (1.54 g,
50%) and 200 (220 mg, 7%).
4.14. Synthesis of 4b
20: ½a 2D6:3
ꢃ
ꢀ491 (c 0.72, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.40–7.33 (m, 4H), 7.30–7.26 (m, 1H), 6.58 (d, J = 15.9 Hz, 1H), 6.23
(dd, J = 15.9, 6.9 Hz, 1H), 6.17–6.02 (m, 2H), 4.91–4.73 (m, 1H), 4.67
(t, J = 6.2 Hz, 1H), 4.20 (q, J = 6.8 Hz, 2H), 1.28 (d, J = 7.1 Hz, 3H), 0.92
To a solution of 21 (157 mg, 0.5 mmol) in benzene (0.5 ml) at
30 8C was added TsOHꢁH2O (95 mg, 0.5 mmol). The mixture was
stirred for 24 h and then diluted with water (10 ml) and extracted
with ethyl acetate. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated. Flash chromatogra-
phy on silica gel (petroleum ether:ethyl acetate = 8:1) of the
residue yielded 4b (87 mg, 65%) as a white solid: Mp = 81.9–
(s, 9H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 165.4,
138.1 (q, J = 2.7 Hz), 136.4, 131.8, 128.7, 128.6, 127.8, 126.6, 125.6(q,
J = 246 Hz), 125.3, 72.4, 60.4, 48.4 (q, J = 24.8 Hz), 25.7, 18.1, 14.1,
ꢀ4.3, ꢀ5.2; 19F NMR (377 MHz, CDCl3)
ꢀ65.26 (d, J = 9.0 Hz, 3F); IR
d
(thin film)
v
max 2942, 2861, 1722, 1652, 1458, 1253, 1192 cmꢀ1; MS
82.5 8C. ½a 2D6:7
ꢃ
ꢀ1.3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ESI): m/z 451.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ calcd for
7.42–7.27 (m, 5H), 6.78 (d, J = 16.4 Hz, 1H), 6.78 (dd, J = 5.7,
10.1 Hz, 1H), 6.33 (dd, J = 10.0, 1.4 Hz, 1H), 6.22 (dd, J = 15.8, 6.8 Hz,
1H), 5.33 (t, J = 6.1 Hz, 1H), 3.42–3.18 (m, 1H); 13C NMR (101 MHz,
C
22H31F3NaO3Si: 451.1893. Found: 451.1893.
200: ½a 2D1:0
ꢃ
ꢀ132 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.39–7.27 (m, 5H), 6.81 (dd, J = 15.8, 9.4 Hz, 1H), 6.59 (d,
J = 15.8 Hz, 1H), 6.13 (dd, J = 15.8, 7.1 Hz, 1H), 6.06 (d,
J = 15.8 Hz, 1H), 4.70 (t, J = 6.0 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H),
3.34–3.07 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 0.94 (s, 9H), 0.13 (s, 3H),
CDCl3)
126.9, 125.2, 124.5 (q, J = 282 Hz), 123.5, 76.4 (q, J = 2.0 Hz), 43.3
(q, J = 27.7 Hz); 19F NMR (377 MHz, CDCl3)
d 161.1, 136.66 (q, J = 2.6 Hz), 135.4, 135.2, 128.8, 128.8,
d
ꢀ68.58 (d, J = 8.5 Hz,
3F); IR (thin film) vmax 3070, 2927, 1737, 1621, 1378, 1258,
1174 cmꢀ1; MS (EI): m/z 268 [M]+; HRMS (EI): m/z [M]+ calcd for
0.08 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 165.2, 137.1 (q,
J = 2.4 Hz), 136.2, 132.6, 128.6, 128.0, 127.9, 127.8, 126.7, 125.2 (q,
J = 282 Hz), 71.7, 60.6, 54.0 (q, J = 25.0 Hz), 25.7, 18.1, 14.1, ꢀ4.2,
C14H11F3O2: 268.0711. Found: 268.0716.
ꢀ5.1; 19F NMR (377 MHz, CDCl3)
d
ꢀ65.54 (d, J = 8.8 Hz, 3F); IR
4.15. Synthesis of 22
(thin film) vmax 2956, 2862, 1724, 1658, 1461, 1257, 1168 cmꢀ1
;
MS (ESI): m/z 451.1 [M+Na]+; HRMS (ESI): m/z [M+Na]+ calcd for
22H31F3NaO3Si: 451.1893. Found: 451.1892.
To a solution of 4b (50 mg, 0.187 mmol) in tert-butyl methyl
ether (4 ml) at ꢀ40 8C was added 4-methylbenzenethiol (35 mg,
0.280 mmol) and DBU (5.7 mg, 0.037 mmol). The mixture was
stirred for 10 minandthenwarmed toꢀ20 8Cand stirred foranother
20 min. Then the mixture was concentrated. Flash chromatography
on silica gel (petroleum ether:ethyl acetate = 10:1) of the residue
yielded 22 (63 mg, 86%) as a white solid: Mp = 135.0–136.3 8C.
C
4.12. Synthesis of 21
To a solution of 20 (1.44 g, 3.36 mmol) in MeCN (8 ml) at 30 8C
was added Et3Nꢁ3HF (5.4 ml, 33.6 mmol). The mixture was
stirred for 12 h and then diluted with water (30 ml) and
extracted with ethyl acetate. The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated. Flash
chromatography on silica gel (petroleum ether:ethyl ace-
tate = 5:1) of the residue yielded 21 (1.01 g, 96%) as a colorless
½
a D24:9 +87 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.43 (d,
ꢃ
J = 8.0 Hz, 2H), 7.40–7.28 (m, 5H), 7.19 (d, J = 7.9 Hz, 2H), 6.73 (d,
J = 15.9 Hz, 1H), 6.11 (dd, J = 15.9, 6.4 Hz, 1H), 5.06 (t, J = 6.8 Hz, 1H),
3.70 (dd, J = 9.1, 5.1 Hz, 1H), 2.86 (dd, J = 16.1, 5.5 Hz, 1H), 2.78 (td,
J = 8.7, 3.7 Hz, 1H), 2.70 (dd, J = 16.1, 5.1 Hz, 1H),2.36 (s, 3H); 13C
oil. ½a 2D1:0
ꢃ
ꢀ804 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.40–
NMR (101 MHz, CDCl3)
131.1, 131.0, 129.7, 129.2, 128.1 (q, J = 282 Hz), 126.3, 77.6, 50.4 (q,
J = 25.3 Hz, 1H), 41.7, 36.5, 23.6;19FNMR(282 MHz, CDCl3)
ꢀ69.07
d 171.3, 142.3, 137.7, 137.6, 137.3, 132.7,
7.26 (m, 5H), 6.70 (d, J = 15.8 Hz, 1H), 6.24 (dd, J = 15.6, 6.3 Hz,
1H), 6.20–6.11 (m, 2H), 4.81 (t, J = 5.8 Hz, 1H), 4.76–4.69 (m, 1H),
d

150
J.-L. Chen et al. / Journal of Fluorine Chemistry 155 (2013) 143–150
(d, J = 8.8 Hz, 3F); IR (thin film)
v
max 2917, 1766, 1646, 1376, 1253,
(77 mg, 67%) as a white solid: Mp = 71.2–72.0 8C. ½a D25:7
ꢃ
+35.8(c 1.0,
1180, 1114 cmꢀ1; MS (EI): m/z 392 [M]+; HRMS (EI): m/z [M]+ calcd
CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.42–7.28 (m, 5H), 4.68 (dd,
for C21H19F3O2S: 392.1058. Found: 392.1054.
J = 13.0, 6.2 Hz, 1H), 4.62 (d, J = 6.9 Hz, 1H), 4.40 (t, J = 3.6 Hz, 1H),
4.16 (q, J = 7.2 Hz, 2H), 4.05 (dd, J = 6.9, 3.7 Hz, 1H), 2.81–2.67 (m,
3H), 2.66 (s, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.76 (s, 9H), ꢀ0.12 (s, 3H),
4.16. Synthesis of 23
ꢀ0.33 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 172.2, 142.0, 131.0,
To a solution of 4a (154 mg, 0.575 mmol), NaHCO3 (290 mg,
130.7, 129.6, 128.6 (q, J = 279 Hz), 92.7, 76.94 (q, J = 2.5 Hz), 76.29
(q, J = 2.0 Hz), 74.7, 63.2, 60.4 (q, J = 26.2 Hz), 42.0, 27.8, 19.9, 16.5,
˚
3.45 mmol) and 4 A MS (20 mg, powder) in dry CH2Cl2 (5 ml) at
room temperature was added m-CPBA (purity quotient 85%)
(351 mg, 1.724 mmol). After stirring for 24 h, the reaction mixture
was quenched with a saturated solution of Na2S2O3 and extracted
with CH2Cl2. The combined organic extracts were dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum
ether:ethyl acetate = 4:1) to afford 23 (104 mg, 64%) as a white
ꢀ3.1, ꢀ3.2; 19F NMR (376 MHz, cdcl3)
d
ꢀ67.86 (d, J = 9.9 Hz, 3F);
IR (thin film) vmax 3455, 3072, 2942, 2861, 1735, 1638, 1264, 1146,
1048 cmꢀ1; MS (ESI): m/z 485.2 [M+Na]+; HRMS (ESI): m/z [M+Na]+
calcd for C22H33F3NaO5Si: 485.1947. Found: 485.1958.
Acknowledgements
solid, Mp = 88.2–89.3 8C: ½a D26:4
ꢃ
ꢀ141(c 1.0, CHCl3); 1H NMR
The National Natural Science Foundation of China (21072028
and 21272036) and the National Basic Research Program of China
(2012CB21600) are greatly acknowledged for funding this work.
(400 MHz, CDCl3)
d 7.45–7.28 (m, 5H), 6.91 (dd, J = 9.7, 6.0 Hz, 1H),
6.37 (d, J = 9.8 Hz, 1H), 4.54 (s, 1H), 4.04 (s, 1H), 3.51–3.27 (m, 2H);
13C NMR (101 MHz, CDCl3)
160.7, 137.5 (q, J = 2.6 Hz), 135.2,
128.8, 128.6, 125.8, 125.7, 124.3 (q, J = 283 Hz), 75.8, 58.6, 58.3,
39.7 (q, J = 28.5 Hz); 19F NMR (377 MHz, CDCl3)
d
Appendix A. Supplementary data
d
ꢀ64.79 (d,
J = 8.4 Hz, 3F); IR (thin film) vmax 3072, 2952, 1743, 1638, 1376,
1248, 1132 cmꢀ1; MS (EI): m/z 284 [M]+; HRMS (EI): m/z [M]+ calcd
for C14H11F3O3: 284.0660. Found: 284.0665.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013
.07.017.
4.17. Synthesis of 24a,b
References
To a solution of 4b (160 mg, 0.60 mmol), NaHCO3 (252 mg,
˚
3.0 mmol) and 4 A MS (20 mg, powder) in dry CH2Cl2 (6 ml) at room
1 (a) M.T. Davies-Coleman, D.E.A. Rivett, Prog. Chem. Org. Nat. Prod. 55 (1989) 1–33;
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temperature was added m-CPBA (purity quotient 85%) (364 mg,
1.80 mmol). After stirring for 24 h, the reaction mixture was
quenched with a saturated solution of Na2S2O3 and extracted with
CH2Cl2. The combined organic extracts were dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate = 6:1)
to afford two inseparable diastereomers 24a and 24b (111 mg, 65%).
ˆ
(d) A. de Fa´tima, L.K. Kohn, J.E. de Carvalho, R.A. Pilli, Bioorg. Med. Chem. 14 (2006)
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ˆ
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15694–15695;
1H NMR (400 MHz, CDCl3)
d 7.41–7.18 (m, 5H), 6.80 (dd, J = 9.9,
5.5 Hz, 0.6 H), 6.73 (dd, J = 9.9, 4.4 Hz, 0.4 H), 6.34 (d, J = 10.0 Hz, 0.6
H), 6.29(d, J = 10.0 Hz, 0.4 H), 4.95(s, 0.4 H), 4.57(d, J = 5.7 Hz, 0.6H),
4.03 (s, 0.4 H), 3.92 (s, 0.6 H), 3.41–3.38 (m, 1H), 3.24 (s, 0.4 H), 3.22
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2032;
(s, 0.6 H); 13C NMR (101 MHz, CDCl3)
d 162.5, 162.0, 138.08 (q,
(j) Z. Tian, S. Chen, Y. Zhang, M. Huang, L. Shi, F. Huang, C. Fong, M. Yang, P. Xiao,
Phytomedicine 13 (2006) 181–186;
J = 2.3 Hz), 137.6 (q, J = 2.9 Hz), 137.5, 137.2, 131.3, 131.2, 131.0,
131.0, 128.0, 127.9, 126.7 (q, J = 282 Hz), 126.7 (q, J = 282 Hz), 78.0
(q, J = 2.1 Hz,), 74.9 (q, J = 2.1 Hz), 64.3, 62.5, 61.1, 57.2, 43.2 (q,
ˆ
(k) A. de Fa´tima, L.V. Modolo, L.S. Conegero, R.A. Pilli, C.V. Ferreira, L.K. Kohn, J.E. de
Carvalho, Curr. Med. Chem. 13 (2006) 3371–3384;
J = 28.8 Hz), 42.0 (q, J = 29.3 Hz); 19F NMR (282 MHz, CDCl3)
d
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ꢀ69.25 (d, J = 8.4 Hz, 3F), ꢀ69.50 (d, J = 8.5 Hz, 3F); IR(thinfilm) vmax
2955, 1743, 1638, 1380, 1262, 1123 cmꢀ1; MS (ESI): m/z 307.1
[M+Na]+; HRMS (ESI): m/z [M+Na]+ calcd for C14H11F3NaO3:
307.0558. Found: 307.0560.
ˆ
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15694–15695.
4.18. Synthesis of 26
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A suspension of AD-mix-
a (350 mg), methanesulfonamide
(27 mg, 0.275 mmol) in water (1 ml) and t-BuOH (1 ml) was cooled
to 0 8C before 20 (107 mg, 0.25 mmol) was added. The reaction was
stirred over 3d before it was quenched by addition of sodium
sulfite (200 mg). After the suspension was stirred for 20 min, the
product was extracted with ethyl acetate. The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by flash chromatography
on silica gel (petroleum ether:ethyl acetate = 15:1) to afford 26
(d) K.L. Kirk, Org. Process Res. Dev. 12 (2008) 305–321.
5 T. Shimada, M. Yoshioka, T. Konno, T. Ishihara, Org. Lett. 8 (2006) 1129–1131.
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8 Further details of the crystal data can be obtained from the Cambridge Crystallo-
graphic Data Centre (CCDC deposition No. 920348 for compound 22, 920163 for
compound 23, 920164 for compound 26).
9 H.C. Kolb, M.S. VanNieuwenhze, K.B. Sharpless, Chem. Rev. 94 (1994) 2483–2547.
10 J.A. Marco, M. Carda, J. Murga, E. Falomir, Tetrahedron 63 (2007) 2929–2958.