Organocatalytic enantioselective sulfa-Michael addition of thiocarboxylic acids to β-trifluoromethyl-α,β-unsaturated ketones for the construction of stereogenic carbon center bearing a sulfur atom and a trifluoromethyl group

Article abstract of DOI:10.1016/j.tet.2019.02.040

An organocatalyzed asymmetric sulfa-Michael addition of thiocarboxylic acids to β-trifluoromethyl-α,β-unsaturated ketones with a chiral bifunctional amine-squaramide as the catalyst is presented. A wide range of chiral ketone compounds bearing a sulfur at

Full text of DOI:10.1016/j.tet.2019.02.040

Accepted Manuscript
Organocatalytic enantioselective sulfa-Michael addition of thiocarboxylic acids to β-
trifluoromethyl-α,β-unsaturated ketones for the construction of stereogenic carbon
center bearing a sulfur atom and a trifluoromethyl group
Wen-Fei Hu, Jian-Qiang Zhao, Xiao-Zhen Chen, Ming-Qiang Zhou, Xiao-Mei Zhang,
Xiao-Ying Xu, Wei-Cheng Yuan
PII:
S0040-4020(19)30199-1
https://doi.org/10.1016/j.tet.2019.02.040
TET 30163
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 December 2018
Revised Date: 4 February 2019
Accepted Date: 18 February 2019
Please cite this article as: Hu W-F, Zhao J-Q, Chen X-Z, Zhou M-Q, Zhang X-M, Xu X-Y, Yuan W-C,
Organocatalytic enantioselective sulfa-Michael addition of thiocarboxylic acids to β-trifluoromethyl-α,β-
unsaturated ketones for the construction of stereogenic carbon center bearing a sulfur atom and a
trifluoromethyl group, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.02.040.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Organocatalytic enantioselective sulfa-Michael
addition of thiocarboxylic acids to
β-trifluoromethyl-α,β-unsaturated ketones for the
construction of stereogenic carbon center
bearing a sulfur atom and a trifluoromethyl group
Wen-Fei Hua,d, Jian-Qiang Zhaob, Xiao-Zhen Chenc, Ming-Qiang Zhoua, Xiao-Mei Zhanga, Xiao-Ying Xua,*
and Wei-Cheng Yuana,*
aNational Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu, 610041, China
bInstitute for Advanced Study, Chengdu University, Chengdu 610106, China
cChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
dUniversity of Chinese Academy of Sciences, Beijing, 100049, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Organocatalytic enantioselective sulfa-Michael addition of thiocarboxylic acids
to β-trifluoromethyl-α,β-unsaturated ketones for the construction of stereogenic
carbon center bearing a sulfur atom and a trifluoromethyl group
Wen-Fei Hua,d, Jian-Qiang Zhaob, Xiao-Zhen Chenc, Ming-Qiang Zhoua, Xiao-Mei Zhanga, Xiao-Ying
Xua, and Wei-Cheng Yuana,
a National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China
bInstitute for Advanced Study, Chengdu University, Chengdu, 610106, China
cChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
dUniversity of Chinese Academy of Sciences, Beijing, 100049, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An organocatalyzed asymmetric sulfa-Michael addition of thiocarboxylic acids to β-
trifluoromethyl-α,β-unsaturated ketones with a chiral bifunctional amine-squaramide as the
catalyst is presented. A wide range of chiral ketone compounds bearing a sulfur atom and a
trifluoromethyl group at the stereogenic carbon center could be obtained with excellent results
(up to 99% yield, 97% ee) under mild conditions. The developed catalytic system is well-
tolerated to both (E)-and (Z)-β-trifluoromethylated-α,β-unsaturated ketones.
Available online
Keywords:
Asymmetric sulfa-Michael addition
Organocatalysis
2009 Elsevier Ltd. All rights reserved.
β-Trifluoromethyl-α,β-unsaturated ketones
Thiocarboxylic acids
Bifunctional catalysts
1. Introduction
Asymmetric sulfa-Michael addition of sulfur-centered
nucleophiles to electron-deficient alkenes has received
tremendous attention and has been recognized as the most
efficient and straightforward method to create chiral C-S bonds.4
Meanwhile, well-documented approaches to access optically
active chiral trifluoromethylated compounds are booming in
recent years.5 Many approaches for the construction of chiral
skeletons bearing a sulfur atom and a trifluoromethyl group at the
stereogenic carbon center have been reported.6 However, most of
the developed methods were restricted to the sulfa-Michael
addition of thiols to trifluoromethyl-α,β-unsaturated substrates.
Furthermore, we found that thiocarboxylic acids,7 a class of good
sulfur-centered nucleophiles, have not been explored to react
with trifluoromethyl-α,β-unsaturated substrates for the synthesis
of such chiral skeletons. More recently, our group reported an
efficient organocatalyzed enantioselective conjugated addition of
sodium bisulfite to β-trifluoromethyl-α,β-unsaturated ketones to
access a series of optically active sulfonic acids, bearing a
tertiary stereocenter containing a trifluoromethyl group and a
SO3H group.8 As part of our interest in asymmetric
organocatalysis,9 during our studies, we have found that β-
trifluoromethyl-α,β-unsaturated ketones10 are able to react with
thiocarboxylic acids by using suitable chiral bifunctional
organocatalysts for the direct construction of chiral molecules
bearing a sulfur atom and a trifluoromethyl group at the
stereogenic carbon center. It is noteworthy that the developed
protocol is well-tolerated to both (E)-and (Z)-β-
Chiral sulfur-containing motifs are widespread in a broad
range of natural and unnatural biologically active products, as
well as pharmaceutically important compounds.1 On the other
hand, incorporating a trifluoromethyl group into an organic
molecular structure can greatly improve their physical, chemical,
and biological properties, such as enhanced binding selectivity,
higher lipophilicity, and increased metabolic stability.2 With the
objective to design potential new drugs, the development of
efficient strategies for the enantioselective synthesis of new
skeletons possessing a sulfur atom and a trifluoromethyl group
together into a carbon atom is valuable. As expected, numerous
biologically active compounds containing a sulfur atom and a
trifluoromethyl group at the stereogenic carbon center exist in
fact (Fig. 1).3 For example, (R)-γ-trifluoromethyl γ-sulfone
hydroxamate is the potent inhibitor of MNP-3.3a Therefore,
development of simple and convenient strategies for the
construction of chiral molecules bearing a sulfur atom and a
trifluoromethyl group at the stereogenic carbon center is not only
a necessity for biochemists and medicinal chemists, but also a
challenge for organic synthetic chemists.
Fig. 1. Biologically active compounds bearing a sulfur atom and a
trifluoromethyl group at the stereogenic carbon center.
———
Corresponding author. e-mail: xuxy@cioc.ac.cn
Corresponding author. e-mail: yuanwc@cioc.ac.cn

2
Tetrahedron
trifluoromethylated-α,β-unsaturated ketones. Herein we wish to
80% ee (Table 1, entry 16). We were gratified to find that the ee
ACCEPTED MANUSCRIPT
report our research results on this subject.
could be elevated to 84% by reducing the substrates
concentration (Table 1, entry 17). Ultimately, adding 50 mg 4 Å
molecular sieves (MS) into the reaction mixture, the ee value
could be further improved to 88% (Table 1, entry 18).
2. Results and discussion
Table 1
Optimization of reaction conditionsa
O
SCOR2
F (20 mol %)
O
O
+
MTBE/xylenes=1:5
R1
CF3
R1
CF3
R2
SH
4 Å MS, -40
6-12 h
C
2
1
3
Me
O
SAc
O
SAc
CF3
O
SAc
CF3
O
SAc
CF3
Me
CF3
MeO
Me
3b, 99% yield, 81% ee
3d, 99% yield, 42% ee
SAc
CF3
3c, 99% yield, 86% ee
SAc
3e, 99% yield, 77% ee
O
SAc
O
SAc
CF3
O
O
MeO
F
CF3
CF3
Cl
3i, 99% yield, 89% ee
F
3f, 99% yield, 89% ee
SAc
3g, 99% yield, 88% ee
3h, 99% yield, 91% ee
SAc
O
SAc
CF3
O
SAc
O
O
Cl
CF3
CF3
CF3
NC
3m, 99% yield, 86% ee
Br
3k, 99% yield, 90% ee
F3C
3l, 99% yield, 91% ee
3j, 99% yield, 87% ee
SAc
O
NO2 SAc
O
O
SAc
CF3
O
SAc
CF3
Cl
Cl
O2N
CF3
CF3
O2N
3n, 99% yield, 91% ee
3p, 99% yield, 69% ee
SAc
CF3
3q, 99% yield, 93% ee
3o, 99% yield, 89% ee
SAc
entry Cat.
solvent
T (oC) yield (%)b ee (%)c
O
SAc
O
O
O
SAc
CF3
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
A
B
C
D
E
F
G
H
I
F
F
F
F
F
F
F
F
F
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
xylenes
MTBE
CH3CN
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
-40
-40
-40
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
10
53
-6
52
-45
73
O2N
BnO
CF3
CF3
S
O
3u, 99% yield, 97% ee
3t, 99% yield, 85% ee
3s, 99% yield, 90% ee
3r, 99% yield, 92% ee
Cl
O
O
SCOPh
CF3
O
SAc
CF3
O
SAc
O
S
CF3
3w, 99% yield, 67% ee
Ph
CF3
3y, 99% yield, 68% ee
3x, 99% yield, 20% ee
3v, 99% yield, 84% ee
61
O
O
AcS
CF3
Ph
O
S
O
S
OMe
-66
-68
75
77
77
28
51
79
O
S
Ph
Ph
CF3
99% yield, 35% ee
Ph
CF3
3c',
99% yield, 38% ee
Ph
CF3
3a', trace
3b',
3z, 99% yield, 71% ee
O
S
Br
O
S
F
Ph
CF3
Ph
CF3
3e', 99% yield, 35% ee
3d', 99% yield, 39% ee
Scheme 1. Substrate scope of asymmetric sulfa-Michael addition of
thiocarboxylic acids to (E)-β-trifluoromethylated-α,β-unsaturated ketones.
Reaction conditions: the reactions were carried out with 1 (0.1 mmol), 2
(0.12 mmol), 50 mg 4 Å MS, and 20 mol % catalyst F in 5.0 mL of
MTBE/xylenes (1:5) at -40 oC for 6-12 h. The ee values were determined
by chiral HPLC.
ethyl acetate
MTBE/xylenes= (1:5)
MTBE/xylenes= (1:5)
MTBE/xylenes= (1:5)
MTBE/xylenes= (1:5)
80
84d
88d,e
aUnless noted, the reactions were carried out with 1a (0.1 mmol), 2a
(0.12 mmol), and 20 mol % catalyst in 1.0 mL of solvent at specified
temperature for 4-6 h. MTBE = Methyl tert-butyl ether
bIsolated yield.
With the optimized reaction conditions in hand, the substrate
scope of the enantioselective sulfa-Michael addition of
thiocarboxylic acids to (E)-β-trifluoromethyl-α,β-unsaturated
ketones was examined. As shown in Scheme 1, installing an
electron-donating or electron-withdrawing group into the phenyl
ring of (E)-β-trifluoromethyl-α,β-unsaturated ketones, regardless
of their different positions, the (E)-β-trifluoromethyl-α,β-
unsaturated ketones could react smoothly with thioacetic acid,
delivering the corresponding products 3b-p in quantitative yields
with moderate to excellent ee values. It should be noted that the
substituent at ortho-position of the phenyl ring of (E)-β-
cEnantiomeric excess was determined by chiral HPLC analysis.
d5 mL of solvent was used.
e50 mg 4 Å MS was used.
We initiated our investigation by examining the model
reaction of (E)-β-trifluoromethylated-α,β-unsaturated ketone 1a
and thioacetic acid 2a with different organocatalysts in CH2Cl2 at
o
0 C. With 20 mol % commercial quinine A as catalyst, the
reaction gave the desired product 3a in 99% yield with only 10%
ee (Table 1, entry 1). And then, using cinchonidine-derived
thiourea bifunctional catalyst B for the reaction, 3a was obtained
in 99% yield with 53% ee (Table 1, entry 2). In the presence of
catalyst C, 3a was obtained in nearly racemate (Table 1, entry 3).
Furthermore, 3a could be obtained in 99% yield with 52% ee by
employing Takemoto’s catalyst D (Table 1, entry 4). Different
squaramide catalysts, which had a longer distance between the
two donor hydrogen atoms than that of thioureas,11 were screened
and quinine-derived squaramide catalyst F is better than other
squaramide catalysts E and G-H in term of enantioselectivity,
(Table 1, entry 6 vs entries 5 and 7-9). Afterwards, experiments
were carried out with different single solvents including toluene,
xylenes, MTBE, CH3CN and ethyl acetate, and it revealed that
xylenes and MTBE were better than other solvents (Table 1,
entry 10-14). Despite all this, the enantioselectivity was still
unsatisfactory. Therefore, we further screened different mixed
solvents and found that the mixture solvent of MTBE/xylenes
(v:v=1:5) gave 3a in quantitative yield with 79% ee (Table 1,
entry 15). Lowering the reaction temperature to -40 oC resulted in
trifluoromethyl-α,β-unsaturated
ketones
gave
poor
enantioselectivity, possibly due to the steric hinderance effect
(for products 3d and 3p). Moreover, products 3q and 3r bearing
two substituent groups could be readily obtained in quantitative
yields with 93% and 92% ee, respectively. Furthermore,
heteroaromatic ring substituted substrates also proved to be
amenable to this developed protocol, and the corresponding
products 3s-u could be obtained with satisfactory results.
Introducing sterically hindered 2-naphthyl substituent group into
the α,β-unsaturated ketone had no obvious effect on the reaction,
yielding 3v in 99% yield with 84% ee. Nevertheless, an aliphatic
substrate could still proceed smoothly under the standard
conditions and furnished product 3w in 99% yield with 67% ee.
On the other hand, a survey of thiocarboxylic acid substrates was
also conducted. Thiobenzoic acid could react with 1a, providing
3x in 99% yield with only 20% ee. Some aliphatic substituted
thiocarboxylic acids serving as nucleophiles addition to substrate
1a, the reaction provided the products 3y-z in quantitative yields

3
with moderate ee values. Unfortunately, the reaction with β-
trifluoromethyl-β,β-disubstituted-α,β-unsaturated ketone 1a' as
substrate proceeded slowly under the standard conditions, giving
3a' with only a trace amount, and maybe it was due to the highly
steric hindrance at the β-position. Finally, we tried to use
different thiophenols as nucleophiles to react with 1a in the
standard conditions, and the expected products 3b'-e' were
obtained with quantitative yields, but in low ee values.
the reaction could smoothly proceed to completion, affording
ACCEPTED MANUSCRIPT
the corresponding products in quantitative yields with 90-96% ee
with S-configuration. It suggests that the catalytic system is
compatible to both (E)-and (Z)-β-trifluoromethylated-α,β-
unsaturated ketones.
Scheme 2. Control experiments to evaluate the role of the CF3 group in
the sulfa-Michael addition reaction.
In order to evaluate the important role of the electron-
withdrawing CF3 group in the sulfa-Michael addition, some
control experiments were carried out (Scheme 2). With the
aforementioned standard conditions, the reaction of (E)-1-
phenylbut-2-en-1-one (1aa) with 2a became sluggish, and
afforded the desired product 3aa in 80% yield with only 10% ee
along with prolonging reaction time to 12 h (Scheme 2 (b)).
Similarly, changing the CF3 group of β-trifluoromethyl-α,β-
unsaturated ketone to phenyl group, the reaction also became
sluggish, and the corresponding product 3ab was formed in 75%
yield with 49% ee after 12 h (Scheme 2 (c)). Comparing the
results of the reactions of different β-trifluoromethyl-α,β-
unsaturated ketones with 2a (Scheme 2), we concluded that (1)
carbon-carbon double bond in α,β-unsaturated ketone was better
activated by the electron-withdrawing CF3 group than methyl or
phenyl group, and hence accelerated undergoing this sulfa-
Michael addition;6a-b,12 (2) it could be some extra H-bonding
between the catalyst and trifluoromethyl group which maybe lead
to higher stereoselectivity.6g
Scheme 4. Different transformations of the product 3q and 3r.
In order to highlight the potential utility of this methodology,
some transformations of the products into other compounds were
performed. Product 3q could be oxidized to sulfonic acid by
using 30% H2O2 and formic acid, giving compound 4 in 99%
yield without loss of the enantioselectivity. The reduction of the
carbonyl moiety of 3r into hydroxyl group with NaBH4 delivered
product 5 in 69% yield with 99:1 dr and 92% ee. The absolute
configuration of 5 was assigned by comparing electronic circular
dichroism (ECD) spectrum which was recorded in MeOH with
the theoretically calculated results.13 Treating 3r with 12 M HCl
o
in MeOH at 50 C for 24 h, the unprotected thiol 6 could be
obtained in 88% yield with 92% ee.
Fig. 2. X-ray crystal structure of 3r.
The absolute configuration of product 3r was determined to be
R-configuration by single-crystal X-ray analysis (Fig. 2).14
Assuming through a common reaction pathway, the absolute
configuration of the other products was assigned by analogy.
3. Conclusion
In summary, we have developed an efficient organocatalyzed
enantioselective sulfa-Michael addition of thiocarboxylic acids to
β-trifluoromethyl-α,β-unsaturated ketones using the cinchona-
derived squaramide bifunctional catalyst. With the developed
protocol, a wide range of chiral ketone compounds bearing a
sulfur atom and a trifluoromethyl group at the stereogenic carbon
center could be obtained with excellent results (up to 99% yield,
97% ee). Importantly, this catalytic system was well-tolerated to
both (E)- and (Z)-β-trifluoromethylated-α,β-unsaturated ketones.
The usefulness of the protocol was also demonstrated by the
conversions of the products into other compounds. Further
investigations on the synthetic application of this methodology
are ongoing in our laboratory.
Scheme 3. Substrate scope of asymmetric sulfa-Michael addition of
thioacetic acid to (Z)-β-trifluoromethylated-α,β-unsaturated ketones.
Reaction conditions: the reactions were carried out with (Z)-1 (0.1 mmol),
2a (0.12 mmol), 50 mg 4 Å MS, and 20 mol % catalyst F in 5.0 mL of
MTBE/xylenes (1:5) at -40 oC for 6-24 h. The ee values were determined
by chiral HPLC.
Importantly, (Z)-β-trifluoromethylated-α,β-unsaturated ketone
(Z)-1a could also react smoothly with thioacetic acid under the
standard conditions, giving (S)-3a in 99% yield with 94% ee.
Hence, in order to explore the effect of cis- and trans-isomers of
β-trifluoromethylated-α,β-unsaturated ketones on the reaction, we
further examined the scope of asymmetric addition of thioacetic
acid to diverse (Z)-β-trifluoromethylated-α,β-unsaturated ketones
under the standard conditions (Scheme 3). By incorporating
various groups on the aromatic ring of (Z)-β-trifluoromethylated-
α,β-unsaturated ketones, irrespective of the substitution pattern,
4. Experimental section Conclusion
4.1. General
Reagents were purchased from commercial sources and were
used as received unless mentioned otherwise. Reactions were
monitored by TLC. 1H NMR and 13C NMR spectra were
1
recorded in CDCl3 and DMSO-d6. H NMR chemical shifts are
reported in ppm relative to tetramethylsilane (TMS) with the

4
Tetrahedron
solvent resonance employed as the internal standard (CDCl3 at
128.6, 128.6, 125.9 (d, J = 276.2 Hz), 125.3, 40.5 (q, J = 30.8
ACCEPTED MANUSCRIPT
7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows:
chemical shift, multiplicity (s = singlet, br s = broad singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling constants
(Hz) and integration. 13C NMR chemical shifts are reported in
ppm from tetramethylsilane (TMS) with the solvent resonance as
the internal standard (CDCl3 at 77.20 ppm, DMSO-d6 at 39.51
ppm). Melting points were recorded on a Buchi Melting Point B-
545.
Hz), 36.9, 30.0, 21.2; HRMS (ESI-TOF) Calcd. for
C13H13F3O2SNa [M+Na]+: 313.0481, found: 313.0485.
4.2.4
(R)-S-(1,1,1-Trifluoro-4-oxo-4-(o-tolyl)butan-2-yl)
ethanethioate (3d). Colorless oil; 28.9 mg; 99% yield; 42% ee;
20
[α]D = -45.2 (c 1.49, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 3/97; flow rate = 0.7 mL/min; UV detection at 254 nm;
tR = 10.84 min (major), 9.59 min (minor); H NMR (300 MHz,
1
4.2. General experimental procedures for asymmetric
synthesis of compounds 3. In an ordinary vial equipped with a
magnetic stirring bar, the compounds 1 (0.10 mmol), 50 mg dried
4 Å MS and catalyst F (20 mol %) were dissolved in 5.0 mL of
MTBE/xylenes (1:5), stirred for 15 minutes at -40 °C and then
the compounds 2 (0.12 mmol) was added. After completion of
the reaction at -40 °C, the reaction mixture was directly purified
by flash chromatography on silica gel (petroleum ether/
dichloromethane = 4:1~1:1) to give the desired product 3.
CDCl3) δ 7.59 (d, J = 7.8 Hz, 1H), 7.44–7.35 (m, 1H), 7.32–7.22
(m, 2H), 4.97–4.79 (m, 1H), 3.51–3.26 (m, 2H), 2.48 (s, 3H),
2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.1, 190.9, 138.8,
136.4, 132.2, 132.0, 128.4, 125.9 (q, J = 276.3 Hz), 125.8, 40.6
(q, J = 30.8 Hz), 39.5, 30.0, 21.2; HRMS (ESI-TOF) Calcd. for
C13H13F3O2SNa [M+Na]+: 313.0481; found: 313.0482.
4.2.5 (R)-S-(1,1,1-Trifluoro-4-(4-methoxyphenyl)-4-oxobutan-2-
yl) ethanethioate (3e). Colorless oil; 30.4 mg; 99% yield; 77%
ee; [α]D20 = -117.2 (c 1.56, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
4.2.1
(R)-S-(1,1,1-Trifluoro-4-oxo-4-phenylbutan-2-yl)
ethanethioate (3a). Colorless oil; 27.4 mg; 99% yield; 88% ee;
20
1
[α]D = -104.1 (c 1.50, CHCl3); the enantiomeric excess was
tR = 18.71 min (major), 13.40 min (minor); H NMR (300 MHz,
determined by HPLC on Chiralpak IA column: i-propanol/n-
CDCl3) δ 7.97–7.82 (m, 2H), 7.01–6.88 (m, 2H), 5.01–4.82 (m,
1H), 3.86 (s, 3H), 3.42 (d, J = 6.7 Hz, 2H), 2.37 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 192.1, 191.1, 164.0, 130.4, 129.0,
126.0 (d, J = 276.2 Hz), 114, 55.5, 40.4 (q, J = 30.8 Hz), 36.4,
30.1; HRMS (ESI-TOF) Calcd. for C13H13F3O3SNa [M+Na]+:
329.0430, found: 329.0431.
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 8.69 min (major), 7.81 min (minor); H NMR (300 MHz,
CDCl3) δ 7.98–7.88 (m, 2H), 7.63–7.55 (m, 1H), 7.52–7.42 (m,
2H), 5.02–4.82 (m, 1H), 3.54–3.38 (m, 2H), 2.36 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 193.6, 190.9, 135.8, 133.7, 128.7,
128.0, 125.9 (q, J = 276.0 Hz), 40.2 (q, J = 30.8 Hz), 36.9, 29.9;
HRMS (ESI-TOF) Calcd. for C12H11F3O2SNa [M + Na]+:
299.0324; found: 299.0325.
4.2.6 (R)-S-(1,1,1-Trifluoro-4-(3-methoxyphenyl)-4-oxobutan-2-
yl) ethanethioate (3f). Colorless oil; 30.1 mg; 99% yield; 89% ee;
20
[α]D = +94.3 (c 1.39, CHCl3); the enantiomeric excess was
(S)-S-(1,1,1-Trifluoro-4-oxo-4-phenylbutan-2-yl) ethanethioate
(3a). Colorless oil; 27.5 mg; 99% yield; 94% ee; [α]D20 = +107.2
(c 1.38, CHCl3); the enantiomeric excess was determined by
HPLC on Chiralpak IA column: i-propanol/n-hexane = 5/95;
flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 7.92 min
(major), 8.93 min (minor).
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 7.89 min (major), 9.43 min (minor); H NMR (300 MHz,
CDCl3) δ 7.53–7.43 (m, 2H), 7.42–7.33 (m, 1H), 7.17–7.06 (m,
1H), 5.01–4.81 (m, 1H), 3.84 (s, 3H), 3.54–3.37 (m, 2H), 2.38 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 193.5, 190.9, 160.0, 137.2,
129.8, 125.9 (q, J = 276.3 Hz), 120.6, 120.3, 112.3, 55.4, 40.3 (q,
J = 30.8 Hz), 37.1, 30.0; HRMS (ESI-TOF) Calcd. for
C13H13F3O3SNa [M+Na]+: 329.0430; found: 329.0433.
4.2.2
(R)-S-(1,1,1-Trifluoro-4-oxo-4-(p-tolyl)butan-2-yl)
ethanethioate (3b). Colorless oil; 29.1 mg; 99% yield;81% ee;
20
[α]D = -118.3 (c 1.48, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
4.2.7 (R)-S-(1,1,1-Trifluoro-4-(4-fluorophenyl)-4-oxobutan-2-yl)
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 9.24 min (major), 8.72 min (minor); H NMR (300 MHz,
ethanethioate (3g). Colorless oil; 29.1 mg; 99% yield; 88% ee;
[α]D = -100.6 (c 1.50, CHCl3); the enantiomeric excess was
1
20
CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.01–
4.81 (m, 1H), 3.45 (d, J = 6.3 Hz, 2H), 2.41 (s, 3H), 2.37 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 193.2, 190.9, 144.7, 133.5, 129.4,
128.2, 126.0 (d, J = 276.2 Hz), 40.4 (q, J = 30.9 Hz), 36.8, 30.0,
21.6; HRMS (ESI-TOF) Calcd. for C13H13F3O2SNa [M+Na]+:
313.0481, found: 313.0489.
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 9.75 min (major), 7.73 min (minor); H NMR (300 MHz,
CDCl3) δ 8.06–7.88 (m, 2H), 7.21–7.05 (m, 2H), 4.99–4.81 (m,
1H), 3.55–3.36 (m, 2H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 192.1, 190.8, 166.1 (d, J = 254.6 Hz), 132.4 (d, J = 3.0 Hz),
130.8 (d, J = 9.4 Hz), 125.9 (q, J = 276.3 Hz), 116.0 (d, J = 22.0
Hz), 40.3 (q, J = 30.9 Hz), 36.9, 30.0; HRMS (ESI-TOF) Calcd.
for C12H10F4O2SNa [M+Na]+: 317.0230, found: 317.0231.
(S)-S-(1,1,1-Trifluoro-4-oxo-4-(p-tolyl)butan-2-yl) ethanethioate
(3b). Colorless oil; 29.0 mg; 99% yield; 93% ee; [α]D20 = +124.5
(c 1.46, CHCl3); the enantiomeric excess was determined by
HPLC on Chiralpak IA column: i-propanol/n-hexane = 5/95;
flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 7.86 min
(major), 9.70 min (minor).
4.2.8 (R)-S-(1,1,1-Trifluoro-4-(3-fluorophenyl)-4-oxobutan-2-yl)
ethanethioate (3h). Colorless oil; 29.2 mg; 99% yield; 91% ee;
20
[α]D = -104.1 (c 1.52, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
4.2.3
(R)-S-(1,1,1-Trifluoro-4-oxo-4-(m-tolyl)butan-2-yl)
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
ethanethioate (3c). Colorless oil; 28.7 mg; 99% yield; 86% ee;
1
tR = 7.55 min (major), 6.61 min (minor); H NMR (300 MHz,
20
[α]D = -111.2 (c 1.43, CHCl3); the enantiomeric excess was
CDCl3) δ 7.74–7.67 (m, 1H), 7.65–7.57 (m, 1H), 7.52–7.42 (m,
1H), 7.34–7.25 (m, 1H), 4.99–4.81 (m, 1H), 3.58–3.31 (m, 2H),
2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.5 (d, J = 2.2 Hz),
190.8, 162.9 (d, J = 247.2 Hz), 138.0 (d, J = 6.2 Hz), 130.5 (d, J
= 7.7 Hz), 125.8 (q, J = 276.3 Hz), 123.8 (d, J = 3.1 Hz), 120.8 (d,
J = 21.4 Hz), 114.9 (d, J = 22.4 Hz), 40.3 (q, J = 31.1 Hz), 37.3,
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 6.98 min (major), 6.44 min (minor); H NMR (300 MHz,
CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.46–7.32 (m, 2H), 5.01–4.84
(m, 1H), 3.47 (d, J = 6.3 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 193.8, 190.9, 138.7, 135.9, 134.5,
1

5
30.0; HRMS (ESI-TOF) Calcd. for C12H10F4O2SNa [M+Na]+:
317.0230, found: 317.0226.
(minor); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H),
A
CCEPTED MANUSCRIPT
7.75 (d, J = 8.2 Hz, 2H), 5.03–4.79 (m, 1H), 3.61–3.40 (m, 2H),
2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.9, 190.8, 138.6,
135.1 (q, J = 32.9 Hz), 128.5, 125.9 (q, J = 3.8 Hz), 125.8 (q, J =
276.2 Hz), 123.4 (q, J = 271.1 Hz), 40.3 (q, J = 31.3 Hz), 37.4,
4.2.9 (R)-S-(4-(4-Chlorophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
ethanethioate (3i). Colorless oil; 31.4 mg; 99% yield; 89% ee;
20
[α]D = -125.3 (c 1.55, CHCl3); the enantiomeric excess was
30.0 (d,
J = 2.6 Hz); HRMS (ESI-TOF) Calcd. for
determined by HPLC on Chiralpak IA column: i-propanol/n-
C13H10F6O2SNa [M+Na]+: 367.0198; found: 367.0194.
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 11.03 min (major), 8.94 min (minor); H NMR (300 MHz,
(S)-S-(1,1,1-Trifluoro-4-oxo-4-(4-(trifluoromethyl)phenyl)butan-
2-yl) ethanethioate (3l). Colorless oil; 34.2 mg; 99% yield; 93%
ee; [α]D20 = +86.1 (c 1.71, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 7.63 min (major), 9.92 min (minor).
CDCl3) δ 7.87 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 5.01–
4.77 (m, 1H), 3.55–3.34 (m, 2H), 2.38 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 192.5, 190.9, 140.4, 134.2, 129.5, 129.2, 125.8 (q,
J = 276.3 Hz), 40.2 (q, J = 31.0 Hz), 37.0, 30.1; HRMS (ESI-
TOF) Calcd. for C12H10ClF3O2SNa [M+Na]+: 332.9934; found:
332.9941.
4.2.13 (R)-S-(4-(4-Cyanophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
(S)-S-(4-(4-Chlorophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
ethanethioate (3m). Colorless oil; 29.7 mg; 99% yield; 86% ee;
[α]D = -97.9 (c 1.49, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
20
ethanethioate (3i). White solid; 31.5 mg; 99% yield; 93% ee;
20
[α]D = +86.7 (c 1.92, CHCl3); m.p. = 54.9-55.7 °C; the
enantiomeric excess was determined by HPLC on Chiralpak IA
column: i-propanol/n-hexane = 5/95; flow rate = 1.0 mL/min; UV
detection at 254 nm; tR = 8.31 min (major), 10.89 min (minor).
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 25.60 min (major), 23.51 min (minor); H NMR (300 MHz,
1
CDCl3) δ 8.08–7.96 (m, 2H), 7.85–7.71 (m, 2H), 4.99–4.77 (m,
1H), 3.61–3.34 (m, 2H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 192.6, 190.7, 138.7, 132.6, 128.5, 125.7 (q, J = 276.3 Hz),
117.6, 117.1, 40.2 (q, J = 31.1 Hz), 37.5, 30.0; HRMS (ESI-TOF)
Calcd. for C13H10F3NO2SNa [M+Na]+: 324.0277, found:
324.0283.
4.2.10 (R)-S-(4-(3-Chlorophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
ethanethioate (3j). Colorless oil; 30.6 mg; 99% yield; 87% ee;
20
[α]D = -106.8 (c 1.58, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak AD-H column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 8.61 min (major), 7.50 min (minor); H NMR (300 MHz,
4.2.14 (R)-S-(1,1,1-Trifluoro-4-(4-nitrophenyl)-4-oxobutan-2-yl)
CDCl3) δ 7.93–7.86 (m, 1H), 7.85–7.76 (m, 1H), 7.62–7.52 (m,
1H), 7.49–7.38 (m, 1H), 5.00–4.81 (m, 1H), 3.57–3.34 (m, 2H),
2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.5, 190.8, 137.4,
135.2, 133.7, 130.1, 128.2, 126.2, 125.8 (d, J = 276.3 Hz), 40.2
(q, J = 31.0 Hz), 37.2, 30.0; HRMS (ESI-TOF) Calcd. for
C12H10ClF3O2SNa [M+Na]+: 332.9934, found: 332.9947.
ethanethioate (3n). White solid; 31.8 mg; 99% yield; 91% ee;
[α]D = -121.1 (c 1.49, CHCl3); m.p. = 109.2-110.1 °C; the
20
enantiomeric excess was determined by HPLC on Chiralpak IC
column: dichloromethane/n-hexane = 30/70; flow rate = 1.0
mL/min; UV detection at 254 nm; tR = 22.07 min (major), 19.69
1
min (minor); H NMR (300 MHz, CDCl3) δ 8.41–8.27 (m, 2H),
8.17–8.02 (m, 2H), 5.06–4.57 (m, 1H), 3.82–3.32 (m, 2H), 2.41
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.4, 190.7, 150.8, 140.2,
129.2,125.7 (q, J = 276.5), 124.1, 40.2 (q, J = 31.1 Hz), 37.8,
30.1; HRMS (ESI-TOF) Calcd. for C12H10F3NO4SNa [M+Na]+:
344.0175, found: 344.0166.
(S)-S-(4-(3-Chlorophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
ethanethioate (3j). Colorless oil; 31.4 mg; 99% yield; 92% ee;
20
[α]D = +109.7 (c 1.57, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak AD-H column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 6.95 min (major), 8.30 min (minor).
(S)-S-(1,1,1-Trifluoro-4-(4-nitrophenyl)-4-oxobutan-2-yl)
ethanethioate (3n). White solid; 31.8 mg; 99% yield; 93% ee;
[α]D = +132.9 (c 0.92, CHCl3); m.p. = 108.5-108.9 °C; the
enantiomeric excess was determined by HPLC on Chiralpak IC
column: dichloromethane/n-hexane = 30/70; flow rate = 1.0
mL/min; UV detection at 254 nm; tR = 19.16 min (major), 23.43
min (minor).
4.2.11 (R)-S-(4-(4-Bromophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
20
ethanethioate (3k). White solid; 35.0 mg; 99% yield; 90% ee;
20
[α]D = -108.1 (c 1.85, CHCl3); m.p. = 69.1-70.1 °C; the
enantiomeric excess was determined by HPLC on Chiralpak IA
column: i-propanol/n-hexane = 5/95; flow rate = 1.0 mL/min; UV
detection at 254 nm; tR = 11.93 min (major), 9.12 min (minor); 1H
NMR (300 MHz, CDCl3) δ 7.86–7.73 (m, 2H), 7.67–7.56 (m,
2H), 5.08–4.71 (m, 1H), 3.57–3.27 (m, 2H), 2.39 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 192.7, 190.8, 134.6, 132.1, 129.5,
129.1, 125.8 (q, J = 276.3 Hz), 40.3 (q, J = 30.9 Hz), 37.0, 30.0;
HRMS (ESI-TOF) Calcd. for C12H10BrF3O2SNa [M+Na]+:
376.9429, found: 376.9440.
4.2.15 (R)-S-(1,1,1-Trifluoro-4-(3-nitrophenyl)-4-oxobutan-2-yl)
ethanethioate (3o). Colorless oil; 31.9 mg; 99% yield; 89% ee;
20
[α]D = -108.6 (c 1.61, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 17.57 min (major), 15.64 min (minor); H NMR (300 MHz,
CDCl3) δ 8.82–8.67 (m, 1H), 8.55–8.37 (m, 1H), 8.34–8.21 (m,
1H), 7.80–7.64 (m, 1H), 5.00–4.83 (m, 1H), 3.65–3.43 (m, 2H),
2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 191.8, 190.7, 148.5,
137.1, 133.6, 130.2, 128.0, 125.7 (d, J = 276.5 Hz), 123.0, 40.2
(q, J = 31.1 Hz), 37.5, 30.1; HRMS (ESI-TOF) Calcd. for
C12H10F3NO4SNa [M+Na]+: 344.0175, found: 344.0177.
(S)-S-(4-(4-Bromophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)
ethanethioate (3k). White solid; 35.1 mg; 99% yield; 93% ee;
20
[α]D = +98.1 (c 2.34, CHCl3); m.p. = 71.2-71.7 °C; the
enantiomeric excess was determined by HPLC on Chiralpak IA
column: i-propanol/n-hexane = 5/95; flow rate = 1.0 mL/min; UV
detection at 254 nm; tR = 8.84 min (major), 11.73 min (minor)。
(S)-S-(1,1,1-Trifluoro-4-(3-nitrophenyl)-4-oxobutan-2-yl)
4.2.12
(R)-S-(1,1,1-Trifluoro-4-oxo-4-(4-
ethanethioate (3o). Colorless oil; 31.8 mg; 99% yield; 90% ee;
(trifluoromethyl)phenyl)butan-2-yl) ethanethioate (3l). Colorless
oil; 34.1 mg; 99% yield; 91% ee; [α]D20 = -84.6 (c 1.77, CHCl3);
the enantiomeric excess was determined by HPLC on Chiralpak
IA column: i-propanol/n-hexane = 5/95; flow rate = 1.0 mL/min;
UV detection at 254 nm; tR = 10.24 min (major), 7.95 min
20
[α]D = +105.7 (c 1.61, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 15.59 min (major), 17.69 min (minor).

6
Tetrahedron
4.2.16 (R)-S-(1,1,1-Trifluoro-4-(2-nitrophenyl)-4-oxobutan-2-yl)
determined by HPLC on Chiralpak IA column: i-propanol/n-
ACCEPTED MANUSCRIPT
ethanethioate (3p). Colorless oil; 31.9 mg; 99% yield; 69% ee;
[α]D = -42.7 (c 1.65, CHCl3); the enantiomeric excess was
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
20
1
tR = 10.91 min (major), 9.27 min (minor); H NMR (300 MHz,
determined by HPLC on Chiralpak IC column: ethanol/n-hexane
= 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm; tR =
18.05 min (major), 13.30 min (minor); 1H NMR (300 MHz,
CDCl3) δ 8.13 (dd, J = 8.2, 1.0 Hz, 1H), 7.80–7.71 (m, 1H),
7.69–7.60 (m, 1H), 7.40 (dd, J = 7.5, 1.3 Hz, 1H), 4.96–4.72 (m,
1H), 3.43 (dd, J = 18.5, 4.1 Hz, 1H), 3.24 (dd, J = 18.5, 9.2 Hz,
1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 196.0, 190.9,
145.6, 136.5, 134.4, 131.1, 127.5, 125.6 (q, J = 276.4 Hz), 124.6,
41.0 (d, J = 1.6 Hz), 39.9 (q, J = 31.1 Hz), 30.0; HRMS (ESI-
TOF) Calcd. for C12H10F3NO4SNa [M+Na]+: 344.0175, found:
344.0174.
CDCl3) δ 7.72 (dd, J = 3.8, 1.0 Hz, 1H), 7.69 (dd, J = 5.0, 1.1 Hz,
1H), 7.15 (dd, J = 4.9, 3.9 Hz, 1H), 4.99–4.75 (m, 1H), 3.51–3.31
(m, 2H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.7, 186.5,
143.0, 134.6, 132.4, 128.3, 125.8 (d, J = 276.5 Hz), 40.41 (q, J =
31.0 Hz), 37.5, 30.0; HRMS (ESI-TOF) Calcd. for
C10H9F3O2S2Na [M+Na]+: 304.9888; found: 304.9893.
4.2.21 (R)-S-(1,1,1-Trifluoro-4-oxo-4-(pyridin-2-yl)butan-2-yl)
ethanethioate (3u). Colorless oil; 27.5 mg; 99% yield; 97% ee;
20
[α]D = -115.9 (c 1.33, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
4.2.17 (R)-S-(4-(3,4-Dichlorophenyl)-1,1,1-trifluoro-4-oxobutan-
tR = 8.21 min (major), 6.97 min (minor); H NMR (300 MHz,
2-yl) ethanethioate (3q). White solid; 34.2 mg; 99% yield; 93%
ee; [α]D = -119.8 (c 1.58, CHCl3); m.p.= 89.1-90.2 °C ; the
CDCl3) δ 8.71–8.63 (m, 1H), 8.06–7.98 (m, 1H), 7.89–7.77 (m,
1H), 7.55–7.45 (m, 1H), 5.07–4.80 (m, 1H), 3.82 (dd, J = 18.6,
9.4 Hz, 1H), 3.69 (dd, J = 18.6, 4.4 Hz, 1H), 2.36 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 195.7, 191.2, 152.2, 149.0, 137.0,
127.7, 125.9 (d, J = 276.3 Hz), 122.0, 40.2 (q, J = 31.0 Hz),
36.46 (d, J = 1.2 Hz), 30.0; HRMS (ESI-TOF) Calcd. for
C11H10F3NO2SNa [M+Na]+: 300.0277; found: 300.0271.
20
enantiomeric excess was determined by HPLC on Chiralpak IA
column: i-propanol/n-hexane = 5/95; flow rate = 1.0 mL/min; UV
detection at 254 nm; tR = 8.71 min (major), 7.91 min (minor); 1H
NMR (300 MHz, CDCl3) δ 8.00 (d, J = 2.0 Hz, 1H), 7.75 (dd, J =
8.4, 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 4.98–4.79 (m, 1H),
3.53–3.30 (m, 2H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
191.6, 190.8, 138.5, 135.3, 133.6, 131.0, 130.1, 127.0, 125.7 (d, J
= 276.3 Hz), 40.2 (q, J = 31.1 Hz), 37.1, 30.1; HRMS (ESI-TOF)
Calcd. for C12H9Cl2F3O2SNa [M+Na]+: 366.9545, found:
366.9557.
4.2.22 (R)-S-(1,1,1-Trifluoro-4-(naphthalen-2-yl)-4-oxobutan-2-
yl) ethanethioate (3v). Colorless oil; 32.4 mg; 99% yield; 84%
ee; [α]D20 = -184.2 (c 1.57, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
4.2.18 (R)-S-(4-(4-(benzyloxy)-3-nitrophenyl)-1,1,1-trifluoro-4-
tR = 11.60 min (major), 9.58 min (minor); H NMR (300 MHz,
oxobutan-2-yl) ethanethioate (3r). White solid; 42.1 mg; 99%
yield; 92% ee; [α]D = -104.9 (c 2.07, CHCl3); m.p.= 95.8-
CDCl3) δ 8.43 (s, 1H), 8.05–7.93 (m, 2H), 7.94–7.83 (m, 2H),
7.68–7.51 (m, 2H), 5.09–4.93 (m, 1H), 3.71–3.56 (m, 2H), 2.39
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.6, 190.9, 135.8, 133.3,
132.4, 129.9, 129.6, 128.9, 128.7, 127.8, 127.0, 126.0 (q, J =
276.3 Hz), 123.52, 40.5 (q, J = 30.9 Hz), 37.0, 30.0; HRMS
(ESI-TOF) Calcd. for C16H13F3O2SNa [M+Na]+: 349.0481; found:
349.0482.
20
96.4 °C ; the enantiomeric excess was determined by HPLC on
Chiralpak IA column: i-propanol/n-hexane = 5/95; flow rate =
1.0 mL/min; UV detection at 254 nm; tR = 54.80 min (major),
1
60.00 min (minor); H NMR (300 MHz, CDCl3) δ 8.40 (d, J =
2.2 Hz, 1H), 8.09 (dd, J = 8.8, 2.2 Hz, 1H), 7.51–7.30 (m, 5H),
7.22 (d, J = 8.9 Hz, 1H), 5.32 (s, 2H), 4.99–4.80 (m, 1H), 3.53–
3.34 (m, 2H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.8,
190.7, 155.6, 139.8, 134.5, 133.6, 128.8, 128.5, 128.4, 126.9,
125.8, 125.8 (q, J = 276.3 Hz), 114.89, 71.5, 40.2 (q, J = 31.0
Hz), 36.9, 30.0; HRMS (ESI-TOF) Calcd. for C19H16F3NO5SNa
[M+Na]+: 450.0593; found: 450.0575.
4.2.23
(R)-S-(1,1,1-Trifluoro-4-oxo-5-phenylpentan-2-yl)
ethanethioate (3w). Colorless oil; 28.7 mg; 99% yield; 67% ee;
20
[α]D = -51.6 (c 1.40, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 7.02 min (major), 6.42 min (minor); H NMR (300 MHz,
(S)-S-(4-(4-(benzyloxy)-3-nitrophenyl)-1,1,1-trifluoro-4-
CDCl3) δ 7.41–7.25 (m, 3H), 7.23–7.14 (m, 2H), 4.78–4.60 (m,
1H), 3.72 (s, 2H), 3.00 (dd, J = 18.1, 4.4 Hz, 1H), 2.86 (dd, J =
18.1, 9.2 Hz, 1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
201.7, 190.8, 132.9, 129.4, 128.9, 127.4, 125.6 (q, J = 276.3 Hz),
50.0, 39.9 (q, J = 31.0 Hz), 39.8, 30.0; HRMS (ESI-TOF) Calcd.
for C13H13F3O2SNa [M+Na]+: 313.0481, found: 313.0476.
oxobutan-2-yl) ethanethioate (3r). White solid; 42.3 mg; 99%
20
yield; 96% ee; [α]D = +98.6 (c 2.12, CHCl3); m.p.= 95.8-
96.7 °C ; the enantiomeric excess was determined by HPLC on
Chiralpak IA column: i-propanol/n-hexane = 5/95; flow rate =
1.0 mL/min; UV detection at 254 nm; tR = 59.83 min (major),
56.47 min (minor).
4.2.24
(R)-S-(1,1,1-Trifluoro-4-oxo-4-phenylbutan-2-yl)
4.2.19
(R)-S-(1,1,1-Trifluoro-4-(furan-2-yl)-4-oxobutan-2-yl)
benzothioate (3x). Colorless oil; 33.6 mg; 99% yield; 20% ee;
[α]D = -8.0 (c 1.83, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
20
ethanethioate (3s). Colorless oil; 26.4 mg; 99% yield; 90% ee;
20
[α]D = -115.3 (c 1.38, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
tR = 17.14 min (major), 15.88 min (minor); H NMR (300 MHz,
1
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
tR = 11.77 min (major), 9.38 min (minor); H NMR (300 MHz,
CDCl3) δ 8.06–7.88 (m, 4H), 7.66–7.54 (m, 2H), 7.53–7.39 (m,
4H), 5.31–5.15 (m, 1H), 3.61 (d, J = 6.7 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 193.6, 187.2, 136.0, 135.7, 134.1, 133.7, 128.8,
128.8, 128.1, 127.6, 126.1 (q, J = 276.5 Hz), 40.0 (t, J = 30.8 Hz),
CDCl3) δ 7.66–7.55 (m, 1H), 7.24 (d, J = 3.6 Hz, 1H), 6.60–6.51
(m, 1H), 4.95–4.76 (m, 1H), 3.43–3.20 (m, 2H), 2.36 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 190.8, 182.8, 151.9, 146.9, 125.8 (q, J
= 276.4 Hz), 117.8, 112.6, 40.0 (q, J = 31.1 Hz), 36.7, 30.0;
HRMS (ESI-TOF) Calcd. for C10H9F3O3SNa [M+Na]+: 289.0117,
found: 289.0112.
37.4; HRMS (ESI-TOF)
Calcd. for C17H13F3O2SNa [M+Na]+:
361.0481, found: 361.0464.
4.2.25 (R)-S-(1,1,1-Trifluoro-4-oxo-4-phenylbutan-2-yl) 2-(4-
chlorophenyl)ethanethioate (3y). colorless oil; 38.4 mg; 99%
yield; 68% ee; [α]D20 = -38.3 (c 2.03, CHCl3); the enantiomeric
excess was determined by HPLC on Chiralpak IA column: i-
4.2.20 (R)-S-(1,1,1-Trifluoro-4-oxo-4-(thiophen-2-yl)butan-2-yl)
20
ethanethioate (3t). Colorless oil; mg; 99% yield; 85% ee; [α]D
= -103.2 (c 1.44, CHCl3); the enantiomeric excess was

7
propanol/n-hexane = 5/95; flow rate = 1.0 mL/min; UV detection
4.2.30
(R)-3-((4-Bromophenyl)thio)-4,4,4-trifluoro-1-
ACCEPTED MANUSCRIPT
1
at 254 nm; tR = 15.60 min (major), 10.05 min (minor); H NMR
(300 MHz, Chloroform-d) δ 7.90 (d, J = 7.5 Hz, 2H), 7.65–7.56
(m, 1H), 7.52–7.44 (m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.18 (d, J =
8.3 Hz, 2H), 5.02–4.86 (m, 1H), 3.84 (s, 2H), 3.55–3.38 (m, 2H);
13C NMR (75 MHz, Chloroform-d) δ 193.5, 192.5, 135.8, 133.8,
133.7, 131.0, 130.8, 128.9, 128.8, 128.0, 125.8 (q, J = 278.2 Hz),
phenylbutan-1-one (3e’). colorless oil; 38.7 mg; 99% yield; 35%
ee; [α]D20 = -31.3 (c 1.80, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak IA column: ethanol/n-hexane
= 1/99; flow rate = 1.0 mL/min; UV detection at 254 nm; tR =
9.69 min (major), 14.39 min (minor); 1H NMR (400 MHz,
Chloroform-d) δ 8.06–7.93 (m, 2H), 7.69–7.62 (m, 1H), 7.58–
7.45 (m, 6H), 4.37–4.22 (m, 1H), 3.52 (dd, J = 18.0, 10.1 Hz,
1H), 3.37 (dd, J = 18.0, 3.1 Hz, 1H); 13C NMR (101 MHz,
Chloroform-d) δ 194.3, 136.2, 135.6, 133.9, 132.4, 131.8, 128.9,
128.2, 126.8 (q, J = 277 Hz), 123.4, 47.4 (q, J = 29.8 Hz), 37.6;
HRMS (ESI-TOF) Calcd. for C16H12BrF3OSNa [M+Na]+:
410.9637, found: 410.9650.
49.0, 40.3 (q, J = 31.0 Hz), 36.9; HRMS (ESI-TOF)
Calcd.
for C18H14ClF3O2SNa [M+Na]+:409.0253, found:409.0266.
4.2.26 (R)-S-(1,1,1-Trifluoro-4-oxo-4-phenylbutan-2-yl) 3-
phenylpropanethioate (3z). colorless oil; 36.4 mg; 99% yield;
71% ee; [α]D20 = -45.8 (c 2.11, CHCl3); the enantiomeric excess
was determined by HPLC on Chiralpak IA column: i-propanol/n-
hexane = 5/95; flow rate = 1.0 mL/min; UV detection at 254 nm;
4.2.31 (S)-S-(4-Oxo-4-phenylbutan-2-yl) ethanethioate (3aa).
Colorless oil; 17.8 mg; 80% yield; 10% ee; [α]D20 = -5.9 (c 1.20,
CHCl3); the enantiomeric excess was determined by HPLC on
Chiralpak IC column: ethanol /n-hexane = 2/98; flow rate = 0.7
mL/min; UV detection at 254 nm; tR = 13.07 min (major), 11.87
1
tR = 10.48 min (major), 8.10 min (minor); H NMR (300 MHz,
Chloroform-d) δ 7.99–7.91 (m, 2H), 7.67–7.58 (m, 1H), 7.55–
7.46 (m, 2H), 7.33–7.25 (m, 2H), 7.24–7.15 (m, 3H), 5.07–4.91
(m, 1H), 3.59–3.37 (m, 2H), 3.07–2.97 (m, 2H), 2.96–2.86 (m,
2H); 13C NMR (75 MHz, Chloroform-d) δ 193.8, 193.6, 139.5,
135.9, 133.8, 128.8, 128.5, 128.3, 128.1, 126.4, 125.9 (q, J =
278.1 Hz), 45.2, 40.0 (q, J = 31.1 Hz), 37.0, 31.1; HRMS (ESI-
1
min (minor); H NMR (300 MHz, CDCl3) δ 8.02–7.91 (m, 2H),
7.61–7.51 (m, 1H), 7.50–7.41 (m, 2H), 4.17–4.00 (m, 1H), 3.43
(dd, J = 16.7, 5.0 Hz, 1H), 3.12 (dd, J = 16.7, 8.3 Hz, 1H), 2.29 (s,
3H), 1.39 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
197.3, 195.7, 136.5, 133.3, 128.6, 128.1, 45.0, 35.2, 30.6, 20.3;
HRMS (ESI-TOF)Calcd. for C12H14O2SNa [M+Na]+: 245.0607,
found: 245.0608.
TOF)
Calcd.
for
C19H17F3O2SNa
[M+Na]+:389.0799,
found:389.0815.
4.2.27
(R)-4,4,4-trifluoro-1-phenyl-3-(phenylthio)butan-1-one
(3b’). colorless oil; 30.8 mg; 99% yield; 35% ee; [α]D20 = -17.3 (c
0.78, CHCl3); the enantiomeric excess was determined by HPLC
on Chiralpak AD-H column: ethanol/n-hexane = 1/99; flow rate
= 1.0 mL/min; UV detection at 254 nm; tR = 8.43 min (major),
4.2.32 (R)-S-(3-Oxo-1,3-diphenylpropyl) ethanethioate (3ab).
White solid; 21.4 mg; 75% yield; 49% ee; [α]D20 = -83.3 (c 1.28,
CHCl3); m.p.= 90.4-91.3 °C ; the enantiomeric excess was
determined by HPLC on Chiralpak IC column: i-propanol/n-
hexane = 1/99; flow rate = 1.0 mL/min; UV detection at 254 nm;
1
10.19 min (minor); H NMR (300 MHz, Chloroform-d) δ 8.05–
7.91 (m, 2H), 7.70–7.57 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H), 7.38–
7.29 (m, 3H), 4.41– 4.25 (m, 1H), 3.50 (dd, J = 18.0, 9.8 Hz, 1H),
3.34 (dd, J = 18.0, 3.4 Hz, 1H); 13C NMR (75 MHz, Chloroform-
d) δ 194.4, 136.3, 134.0, 133.7, 132.5, 129.2, 128.8, 128.8, 128.1,
126.8 (q, J = 276.7 Hz), 47.1 (q, J = 29.4 Hz), 37.7; HRMS (ESI-
TOF) Calcd. for C16H13F3OSNa [M+Na]+: 333.0531, found:
333.0521.
1
tR = 44.48 min (major), 31.36 min (minor); H NMR (300 MHz,
CDCl3) δ 7.99–7.89 (m, 2H), 7.60–7.51 (m, 1H), 7.48–7.41 (m,
2H), 7.41–7.34 (m, 2H), 7.33–7.17 (m, 3H), 5.28 (dd, J = 7.9, 6.5
Hz, 1H), 3.77–3.58 (m, 2H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 196.3, 194.4, 140.5, 136.4, 133.2, 128.6, 128.0, 127.7,
127.5, 44.5, 43.5, 30.3; HRMS (ESI-TOF) Calcd. for
C17H16O2SNa [M+Na]+: 307.0763, found: 307.0765.
4.2.28
(R)-4,4,4-Trifluoro-3-((4-methoxyphenyl)thio)-1-
phenylbutan-1-one (3c’). colorless oil; 33.9 mg; 99% yield; 38%
ee; [α]D20 = -26.1 (c 1.60, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak AD-H column: ethanol/n-
hexane = 1/99; flow rate = 1.0 mL/min; UV detection at 254 nm;
4.3 Procedure for the oxidation of 3q. A mixture of formic acid
(98%, 1 mL) and hydrogen peroxide (30%, 0.4 mL) was stirred at
0 °C for 30 min ( peroxyformic acid solution was prepared in
situ), then a solution of 3q (89.7 mg, 0.26 mmol) in THF (1 mL)
was added dropwise. The reaction mixture was stirred at room
temperature for 12 h until completion (monitored by TLC) and
water (5 mL) was added. The mixture was washed with
dichloromethane (5×3 mL). The aqueous solution was dried first
under reduced pressure and finally in high vacuum. Finally, the
crude product was chromatographed on silica gel eluting with
DCM/MeOH = 20:1 ~ 10:1 to afford the desired sulfonic acid 4.
1
tR = 16.05 min (major), 19.97 min (minor); H NMR (400 MHz,
Chloroform-d) δ 8.04–7.95 (m, 2H), 7.68–7.47 (m, 5H), 6.93–
6.82 (m, 2H), 4.25–4.10 (m, 1H), 3.83 (s, 3H), 3.48 (dd, J = 17.9,
10.0 Hz, 1H), 3.30 (dd, J = 17.9, 3.2 Hz, 1H); 13C NMR (101
MHz, Chloroform-d) δ 194.6, 160.6, 137.0, 136.4, 133.8, 128.9,
128.2, 127.0 (q, J = 278.4 Hz), 122.6, 114.7, 55.4, 47.6 (q, J =
29.2 Hz), 37.5; HRMS (ESI-TOF) Calcd. for C17H15F3O2SNa
[M+Na]+: 363.0637, found: 363.0631.
4.3.1 (R)-4-(3,4-Dichlorophenyl)-1,1,1-trifluoro-4-oxobutane-2-
4.2.29
(R)-4,4,4-Trifluoro-3-((4-fluorophenyl)thio)-1-
sulfonic acid (4). Pale brown oil; 90.4 mg; 99% yield; 93% ee;
[α]D = +1.2 (c 1.96, EtOH); the enantiomeric excess was
20
phenylbutan-1-one (3d’). colorless oil; 32,6 mg; 99% yield; 39%
ee; [α]D20 = -32.8 (c 1.60, CHCl3); the enantiomeric excess was
determined by HPLC on Chiralpak AD-H column: ethanol/n-
hexane = 1/99; flow rate = 1.0 mL/min; UV detection at 254 nm;
determined by HPLC on Chiralpak IA column after esterification
with CH3C(OCH3)3: i-propanol/n-hexane = 5/95; flow rate = 1.0
mL/min; UV detection at 254 nm; tR = 11.20 min (major), 11.94
min (minor); 1H NMR (300 MHz, D2O) δ 7.77 (s, 1H), 7.62 (d, J
= 8.2 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 4.54–4.39 (m, 1H), 3.67
(dd, J = 18.6, 4.8 Hz, 1H), 3.42 (dd, J = 18.6, 5.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 194.5, 137.8, 134.8, 132.6, 130.6,
129.60 127.3, 123.9 (q, J = 279.5 Hz), 57.0 (q, J = 27.7 Hz), 34.9;
HRMS (ESI-TOF) Calcd. for C10H6Cl2F3O4S [M-H]-: 348.9321,
found: 348.9330.
1
tR = 8.10 min (major), 12.12 min (minor); H NMR (400 MHz,
Chloroform-d) δ 8.03–7.97 (m, 2H), 7.70–7.61 (m, 3H), 7.59–
7.47 (m, 2H), 7.10–6.99 (m, 2H), 4.31–4.16 (m, 1H), 3.50 (dd, J
= 18.0, 10.2 Hz, 1H), 3.35 (dd, J = 18.0, 3.0 Hz, 1H); 13C NMR
(101 MHz, Chloroform-d) δ 194.4, 163.4 (d, J = 249.7 Hz), 136.8
(d, J = 8.5 Hz), 136.2, 133.9, 128.9, 128.2, 127.6 (d, J = 3.5 Hz),
126.9 (q, J = 276 Hz), 116.3 (d, J = 22.0 Hz), 47.8 (q, J = 30.3
Hz), 37.5; HRMS (ESI-TOF) Calcd. for C16H12F4OSNa [M+Na]+:
351.0437, found: 351.0439.
4.4 Procedure for the reduction of 3r. 3r (85.7 mg, 0.20 mmol)
was dissolved in 1 mL of ethanol and cooled to 0 °C on an ice

8
Tetrahedron
ACCEPTED MANUSCRIPT
Angew. Chem. Int. Ed. 2005, 44, 214; (c) Purser, S.; Moore, P. R.;
bath. NaBH4 (4.7 mg, 0.12 mmol) was added portion wise. The
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (d) Smits, R.;
Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc. Rev. 2008, 37, 1727;
(e) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2010, 111, 455.
(a) Sani, M.; Candiani, G.; Pecker, F.; Malpezzi, L.; Zanda, M.
Tetrahedron Lett. 2005, 46, 2393; (b) Wang, J.; Sanchez-Rosello, M.;
Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V.
A.; Liu, H. Chem. Rev. 2014, 114, 2432; (c) O’Hagan, D. J. Fluorine
Chem. 2010, 131, 1071; (d) Rodgers, J. D.; Cocuzza, A. J.; Bilder, D. M.
U. S. Patent 6204262, 2001;(e) Bindschaedler, P.; Von Deyn, W.;
Koerber, K.; Kaiser, F.; Rack, M.; Culbertson, D. L.; Neese, P.; Braun, F.
J. U. S. Patent 9732051, 2017.
reaction mixture was stirred for 2 h at the same temperature.
After completion of the reaction, ethanol was evaporated off and
brine (3 ml) was added to the residue. The mixture was extracted
with ethyl acetate (2×5 ml) and concentrated. The crude products
were purified by column chromatography with petroleum
ether/ethyl acetate = 20:1~10:1 to afford the desired product 5.
3
4.4.1 S-((2R,4R)-4-(4-(benzyloxy)-3-nitrophenyl)-1,1,1-trifluoro-
4-hydroxybutan-2-yl) ethanethioate (5). Light yellow green oil;
59.5 mg; 69% yield; 92% ee; 99:1 dr; [α]D = -10.2 (c 0.94,
CHCl3); the enantiomeric excess was determined by HPLC on
Chiralpak IA column: ethanol/n-hexane = 5/95; flow rate = 1.0
mL/min; UV detection at 254 nm; tR = 26.48 min (major), 19.70
20
4
5
For reviews on asymmetric sulfa-Michael addition, see: (a) Enders, D.;
Luettgen, K.; Narine, A. A. Synthesis 2007, 7, 959; (b) Chauhan, P.;
Mahajan, S.; Enders, D. Chem. Rev. 2014, 114, 8807; (c) Shaw, S.; White,
J. D. Synthesis 2016, 48, 2768.
1
For reviews of asymmetric reactions to synthesis of trifluoromethylated
compounds, see: (a) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron:
Asymmetry 2008, 19, 2633; (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F.
D. Chem. Rev. 2015, 115, 826; (c) Noda, H.; Kumagai, N.; Shibasaki, M.
Asian J. Org. Chem. 2018, 7, 599. For recent examples, see: (d) Wu, Y.;
Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445; (e) Hu, L.; Wu, Y.; Li, Z.;
Deng, J. Am. Chem. Soc. 2016, 138, 15817; (f) Chen, P.; Yue, Z.; Zhang,
J.; Lv, X.; Wang, L.; Zhang, J. Angew. Chem. Int. Ed. 2016, 55, 13316; (g)
Calvo, R.; Comas-Vives, A.; Togni, A.; Katayev, D. Angew. Chem. Int.
Ed. 2018, 57, 1; (h) Chen, X.-Y.; Liu, Q.; Chauhan, P.; Enders, D. Angew.
Chem. Int. Ed. 2018, 57, 3862; (i) Wang, H.; Zhang, L.; Tu, Y.; Xiang, R.;
Guo, Y. L.; Zhang, J. Angew. Chem. Int. Ed. 2018, 57, 15787; (j) Hu, B.;
Bezpalko, M. W.; Fei, C.; Dickie, D. A.; Foxman, B. M.; Deng, L. J. Am.
Chem. Soc. 2018, 140, 13913; (k) Hu, B.; Deng, L. Angew. Chem. Int. Ed.
2018, 57, 2233; (l) Li, Z.; Hu, B.; Wu, Y.; Fei, C.; Deng, L. Proc Natl
Acad Sci U S A 2018, 115, 1730; (m) Hu, B.; Deng, L. J. Org. Chem.
2019, 84, 994; (n) Martinez-Pardo, P.; Blay, G.; Vila, C.; Sanz-Marco, A.;
Munoz, M. C.; Pedro, J. R. J. Org. Chem. 2019, 84, 314; (o) Wang, C.; Li,
N.; Zhu, W.-J.; Gong, J.-F.; Song, M.-P. J. Org. Chem. 2019, 84,191.
(a) Dong, X.-Q.; Fang, X.; Wang, C.-J. Org. Lett. 2011, 13, 4426; (b)
Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Adv. Synth.
Catal. 2012, 354, 1141; (c) Fang, X.; Li, Q.-H.; Tao, H.-Y.; Wang, C.-J.
Adv. Synth. Catal. 2013, 355, 327; (d) Su, Y.; Ling, J.-B.; Zhang, S.; Xu,
P.-F. J. Org. Chem. 2013, 78, 11053; (e) Fang, X.; Dong, X.-Q.; Liu, Y.-
Y.; Wang, C.-J. Tetrahedron Lett. 2013, 54, 4509; (f) Chen, W.; Jing, Z.;
Chin, K. F.; Qiao, B.; Zhao, Y.; Yan, L.; Tan, C.-H.; Jiang, Z. Adv. Synth.
Catal. 2014, 356, 1292; (g) Chen, J.; Meng, S.; Wang, L.; Tang, H.;
Huang, Y. Chem. Sci. 2015, 6, 4184; (h) Wang, Y.-F.; Wu, S.; Karmaker,
P. G.; Sohail, M.; Wang, Q.; Chen, F.-X. Chen, Synthesis 2015, 47, 1147;
For selected examples, see: (a) Li, H.; Wang, J.; Zu, L.; Wang, W.
Tetrahedron Lett. 2006, 47, 2585; (b) Li, H.; Zu, L.; Wang, J.; Wang, W.
Tetrahedron Lett. 2006, 47, 3145; (c) Kimmel, K. L.; Robak, M.. T.;
Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 8754; (d) Monaco, M. R.;
Prevost, S.; List, B. J. Am. Chem. Soc. 2014, 136, 16982; (e) Phelan, J. P.;
Patel, E. J.; Ellman, J. A. Angew. Chem. Int. Ed. 2014, 53, 11329; (f)
Wang, R.; Liu, J.; Xu, J. Adv. Synth. Catal. 2015, 357, 159; (g) Dong, N.;
Zhang, Z. P.; Xue, X. S.; Li, X.; Cheng, J. P. Angew. Chem. Int. Ed. 2016,
55, 1460; (h) Wang, Y. F.; Chu, M.; Zhang, C.; Shao, J.; Qi, S.; Wang, B.;
Du, X. H.; Xu, D. Q. Adv. Synth. Catal., 2017, 359, 4170.
min (minor); H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 2.2 Hz,
1H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.47–7.33 (m, 5H), 7.14 (d, J
= 8.7 Hz, 1H), 6.00 (dd, J = 8.5, 6.5 Hz, 1H), 5.24 (s, 2H), 2.99–
2.83 (m, 1H), 2.47–2.34 (m, 1H), 2.26–2.14 (m, 1H), 2.07 (s, 3H),
1.93 (d, J = 8.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.7,
152.1, 140.2, 135.2, 132.7, 130.9, 128.7, 128.3, 126.9, 125.7 (q, J
= 277.6 Hz), 124.1, 115.4, 72.0, 71.3, 38.9 (q, J = 31.5 Hz), 36.8,
21.0; HRMS (ESI-TOF) Calcd. for C19H18F3NO5SNa [M+Na]+:
452.0750, found: 452.0745.
4.5 Procedure for the deacetylation of 3r. 3r (69.3 mg, 0.16
mmol) was dissolved in 2 mL of methanol/DCM (v/v=1/1) at
room temperature. To the solution was added 12M aqueous HCl
(0.5 mL). The reaction mixture was stirred at 50 oC for 24 h until
the disappearance of the starting material was detected by TLC.
After the solvent was evaporated the residue was dissolved in
dichloromethane and dried over Na2SO4. After concentration
under reduced pressure the crude product was purified by column
chromatography (petroleum ether/DCM=2/1~1/1, v/v) to afford
the desired product 6.
6
4.5.1
(R)-1-(4-(benzyloxy)-3-nitrophenyl)-4,4,4-trifluoro-3-
mercaptobutan-1-one (6). Off white solid; 54.6 mg; 88% yield;
92% ee; [α]D20 = +7.3 (c 2.73, CHCl3); m.p.= 138.6-139.4 °C; the
enantiomeric excess was determined by HPLC on Chiralpak IC
column: dichloromethane/n-hexane = 30/70; flow rate = 1.0
mL/min; UV detection at 254 nm; tR = 28.43 min (major), 25.62
7
1
min (minor); H NMR (300 MHz, Chloroform-d) δ 8.44 (d, J =
2.0 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 7.49–7.34 (m, 5H),
7.22 (d, J = 8.9 Hz, 1H), 4.16–3.98 (m, 1H), 3.42 (qd, J = 17.8,
6.3 Hz, 2H), 2.15 (d, J = 8.8 Hz, 1H); 13C NMR (75 MHz,
Chloroform-d) δ 191.3, 155.7, 139.8, 134.5, 133.7, 128.9, 128.6,
126.9, 126.0 (q, J = 277.3 Hz), 125.9, 114.9, 71.5, 40.6, 36.7 (q,
J = 31.7 Hz); HRMS (ESI-TOF) Calcd. for C17H14F3NO4SNa
[M+Na]+: 408.0493, found: 408.0484.
8
9
Hu, W.-F.; Zhao, J.-Q.; Chen, Y.-Z.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-
C. J. Org. Chem. 2018, 83, 5771.
For selected examples from our group, see: (a) Zhao, J.-Q.; Zhou, M.-Q.;
Wu, Z.-J.; Wang, Z.-H.; Yue, D.-F.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-
C. Org. Lett. 2015, 17, 2238; (b) You, Y.; Cui, B.-D.; Zhou, M.-Q.; Zuo,
J.; Zhao, J.-Q.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem.
2015, 80, 5951; (c) You, Y.; Wu, Z.-J.; Wang, Z.-H.; Xu, X.-Y.; Zhang,
X.-M.; Yuan, W.-C. J. Org. Chem. 2015, 80, 8470; (d) Wang, Z.-H.; Wu,
Z.-J.; Yue, D.-F.; Hu, W.-F.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C.
Chem. Commun., 2016, 52, 11708; (e) Zhao, J.-Q.; Yue, D.-F.; Zhang, X.-
M.; Xu, X.-Y.; Yuan, W.-C. Org. Biomol. Chem. 2016, 14, 10946; (f)
You, Y.; Lu, W.-Y.; Wang, Z.-H.; Chen, Y.-Z.; Xu, X.-Y.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2018, 20, 4453.
Acknowledgements
We are grateful for financial support from the National
Natural Science Foundation of China (No. 21572223, 21572224,
21602217, 21871252), Sichuan Youth Science and Technology
Foundation (2016JQ0024).
References and notes
1
(a) Nudelman, A.; Chemistry of Optically Active Sulfur Compounds;
Gordon and Breach: New York, 1984; (b) Damani, L. A. Sulphur-
Containing Drugs and Related Organic Compounds: Chemistry,
Biochemistry and Toxicology; Ellis Horwood: Chichester, 1989; (c)
Chatgilialoglu, C.; Asmus, K.-D. Sulfur-Centered Reactive Intermediates
in Chemistry and Biology; Springer: New York, 1990; (d) Clayden, J.;
MacLellan, P. Beilstein J. Org. Chem. 2011, 7, 582; (e) Moran, L. K.;
Gutteridge, J. M.; Quinlan, G. J. Curr. Med. Chem. 2001, 8, 763; (f)
Pachamuthu, K.; Schmidt, R. R. Chem. Rev. 2006, 106, 160.
10 For selected examples, see: (a) Blay, G.; Fernandez, I.; Muñoz, M. C.;
Pedro, J. R.; Vila, C. Chem. -Eur. J. 2010, 16, 9117; (b) Wang, W.; Lian,
X.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Chem Commun. 2011, 47, 7821;
(c) Li, Q.-H.; Tong, M.-C.; Li, J.; Tao, H.-Y.; Wang, C.-J. Chem.
Commun. 2011, 47, 11110; (d) Kawai, H.; Kitayama, T.; Tokunaga, E.;
Matsumoto, T.; Sato, H.; Shiro, M.; Shibata, N. Chem. Commun. 2012, 48,
4067; (e) Kawai, H.; Yuan, Z.; Kitayama, T.; Tokunaga, E.; Shibata, N.
Angew. Chem. Int. Ed. 2013, 52, 5575; (f) Morigaki, A.; Tanaka, T.;
Miyabe, T.; Ishihara, T.; Konno, T. Org. Biomol. Chem. 2013, 11, 586; (g)
Kwiatkowski, P.; Cholewiak, A.; Kasztelan, A. Org. Lett. 2014, 16, 5930;
(h) Sanz-Marco, A.; Garcia-Ortiz, A.; Blay, G.; Pedro, J. R. Chem.
2
For selected reviews, see: (a) Kusumoto, T.; Hiyama, T. In
Enantiocontrolled
Synthesis
of
Fluoro-Organic
Compounds:
Stereochemical Challenges and Biomedicinal Targets; Soloshonok, V. A.,
Ed.; Wiley: Chichester, 1999; Chapter 12; (b) Shimizu M.; Hiyama, T.

9
Commun. 2014, 50, 2275; (i) Kasten, K.; Cordes, D. B.; Slawin, A. M.;
Smith, A. D. Eur. J. Org. Chem. 2016, 3619; (j) Yang, G.-J.; Du, W.;
Chen, Y.-C. J. Org. Chem., 2016, 81, 10056; (k) Yuan, X.; Zhang, S.-J.;
Du, W.; Chen, Y.-C. Chem.-Eur. J. 2016, 22, 11048; (l) Jiang, Q.; Guo, T.;
Yu, Z. J. Org. Chem. 2017, 82, 1951; (m) Li, Y.; Wang, H.; Su, Y.; Li, R.;
Li, C.; Liu, L.; Zhang, J. Org. Lett. 2018, 20, 6444; (n) Yang, Q.-Q.; Xiao,
W.; Du, W.; Ouyang, Q.; Chen, Y.-C. Chem. Commun. 2018, 54, 1129; (o)
Zhao, M. X.; Zhu, G. Y.; Zhu, H. K.; Zhao, X. L.; Ji, M.; Shi, M. Eur. J.
Org. Chem. 2018, 29, 3997.
11 (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008,
ACCEPTED MANUSCRIPT
130, 14416; (b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem.-
Eur. J. 2011, 17, 6890; (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.;
Enders, D. Adv. Synth. Catal. 2015, 357, 253.
12 Zhang, F.; Liu, Z.-J.; Liu, J.-T. Tetrahedron 2010, 66, 6864.
13 See Supporting Information for more details.
14 CCDC-1882017 (3r) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.