Amine-catalyzed decarboxylative aldol reaction of β-ketocarboxylic acids with trifluoropyruvates

Article abstract of DOI:10.3390/molecules24152773

Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C–C bond formation because carboxylic acids are an easily available class of compounds. In this study, we found that the decarboxylative aldol reaction of tertiary β-ketocarboxylic acids and trifluoropyruvates proceeded smoothly to yield the corresponding aldol products in high yields and with high diastereoselectivity in the presence of a tertiary amine catalyst. In this reaction, we efficiently constructed a quaternary carbon center and an adjacent trifluoromethylated carbon center. This protocol was also extended to an enantioselective reaction with a chiral amine catalyst, and the desired product was obtained with up to 73% enantioselectivity.

Full text of DOI:10.3390/molecules24152773

molecules
Communication
Amine-Catalyzed Decarboxylative Aldol Reaction
of β-Ketocarboxylic Acids with Trifluoropyruvates
Ryouta Kawanishi, Shinya Hattori, Seiji Iwasa and Kazutaka Shibatomi *
Department of Applied Chemistry and Life Science, Toyohashi University of Technology, 1-1 Hibarigaoka,
Tempaku-cho, Toyohashi 441-8580, Japan
* Correspondence: shiba@chem.tut.ac.jp
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editor: Norio Shibata
Received: 4 July 2019; Accepted: 25 July 2019; Published: 30 July 2019
Abstract: Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C–C
bond formation because carboxylic acids are an easily available class of compounds. In this
study, we found that the decarboxylative aldol reaction of tertiary
β-ketocarboxylic acids and
trifluoropyruvates proceeded smoothly to yield the corresponding aldol products in high yields
and with high diastereoselectivity in the presence of a tertiary amine catalyst. In this reaction,
we efficiently constructed a quaternary carbon center and an adjacent trifluoromethylated carbon
center. This protocol was also extended to an enantioselective reaction with a chiral amine catalyst,
and the desired product was obtained with up to 73% enantioselectivity.
Keywords: decarboxylation; aldol reaction; trifluoromethyl compounds; cinchona alkaloids;
enantioselective synthesis; chiral amine catalyst
1. Introduction
Decarboxylative functionalization of aliphatic carboxylic acids is a highly useful method in
synthetic organic chemistry [
functional group. In particular, the decarboxylative aldol reaction of
intensively studied in recent years [ 10 11] because these acids easily release carbon dioxide
to serve as a formal enolate equivalent [12 20]. A number of decarboxylative aldol reactions with
primary and secondary -oxocarboxylic acids have been reported, including a catalytic enantioselective
version [ 10 11 21 23]. Most of these reactions are thought to proceed via the aldol adduct of
the -oxocarboxylic acid and the acceptor, followed by decarboxylative protonation, to yield the
1
–
9] because the carboxyl group is a fundamental and easily available
β-oxocarboxylic acids has been
2,5,6, ,
–
β
2,5,6, , , –
β
desired product (Figure 1a). On the other hand, decarboxylative aldol reactions with tertiary carboxylic
acids have rarely been reported. To the best of our knowledge, there is only one report on the
decarboxylative aldol reaction with tertiary
carbon center [24], and there is no report on the enantioselective version, although there are some
examples of reactions with -difluoro- or -monofluorocarboxylic acids to form a fluorinated
tetrasubstituted carbon center [25 28]. These reactions proceed via an enol (or enolate) intermediate
formed by decarboxylation of the -oxocarboxylic acid, and the intermediate reacts with the aldol
β-oxocarboxylic acids to form an all-carbon quaternary
α
,α
α
–
β
acceptor to give the desired product (Figure 1b). Therefore, the difficulty in the decarboxylative aldol
reaction of tertiary carboxylic acids probably arises from the high steric hinderance of the trisubstituted
enolate intermediate. Recently, our research group found that the decarboxylative halogenation of
β-ketocarboxylic acids and 2-pyridylcarboxylic acids proceeds even with tertiary carboxylic acids as
the substrate [29–32]. We hypothesized that this smooth decarboxylative functionalization of tertiary
carboxylic acids was due to the high electrophilicity of the electrophilic halogenating agents, such as
N-chlorosuccinimide (NCS), N-fluorobenzenesulfonimide (NFSI), and Selectfluor. Our previous results
encouraged us to develop a decarboxylative aldol reaction of
β-ketocarboxylic acids by employing
Molecules 2019, 24, 2773; doi:10.3390/molecules24152773
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2773
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a highly electrophilic aldol acceptor. Trifluoropyruvates are known to be good aldol acceptors with
high electrophilicity [33 38], and the resulting aldol products, which have a trifluoromethylated
stereogenic carbon center, are attractive building blocks for medicinally relevant compounds [39 44].
Therefore, we examined the decarboxylative aldol reaction of tertiary -ketocarboxylic acids with
–
–
β
trifluoropyruvates to form the corresponding aldol adduct (Figure 1c), and we disclose the results
herein, including the application of this reaction to enantioselective synthesis.
a) Reaction with primary or secondary carboxylic acids
O
O
O
OH
R3
2 CO2H
O
OH
R3
R3
CO2H
R1
R1
R1
–CO2
R2
R2
R
b) Reaction with tertiary carboxylic acids (few examples)
O
O
O
OH
R3
OH
R4
CO2H
R3
R1
R1
R1
R2 R3
–CO2
R2
R2
c) This work: decarboxylative aldol reaction with tertiary carboxylic acids
O
O
O
HO CF3
CO2Me
amine (cat.)
–CO2
CO2H
R2 R3
+
R1
R1
F3C
CO2Me
R2 R3
Figure 1. Decarboxylative aldol reactions of
β-oxocarboxylic acids: (a) Reaction with primary and
secondary carboxylic acids; (b) Reaction with tertiary carboxylic acids; (c) This work.
2. Results and Discussion
First, we chose tetralone-derived β-ketocarboxylic acids 1a as the model substrate and then
screened various amine catalysts for the decarboxylative aldol reaction with methyl trifluoropyruvate
as the acceptor (Table 1). Tertiary amines showed superior catalytic activity than primary and secondary
amines (entries 1–8). Bicyclic tertiary amines with bridgehead nitrogen(s) showed particularly high
reactivity, diastereoselectivity (92:8–93:7 dr), and chemoselectivity between aldol product 2a and
protonated product 3a (entries 7 and 8). Taking the reactivity, selectivity, and cost into account,
we chose 1,4-diazabicyclo [2.2.2]octane (DABCO) as the best catalyst. Decreasing the catalyst loading
to 15 mol% led to a satisfactory level of reactivity and selectivity (entry 9). Optimization of various
reaction solvents revealed that toluene was the best choice for the model reaction (entries 9–13).

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Table 1. Optimization of the amine catalyst 1.
O
(3 equiv.)
CO2Me
O
O
O
F3C
HO CF3
CO2Me
CO2H
Me
Me
cat. (30 mol%)
rt
Me
+
2a
1a
Entry
3a
Yield (%) 2
dr 3
Catalyst
none
PhCH2CH2NH2
(PhCH2)2NH
Time (h)
Solvent
2a
3a
1
2
3
toluene
toluene
toluene
4
4
4
<1
2
58
20
10
10
66:33
55:45
92:8
4
toluene
4
19
12
88:12
N
H
5
6
7
pyridine
DMAP
Et3N
toluene
toluene
toluene
4
4
4
6
39
96
4
9
1
68:32
82:18
86:14
8
toluene
toluene
2
2
98
94
1
3
93:7
92:8
N
(quinuclidine)
N
N
9
(DABCO)
DABCO
DABCO
DABCO
DABCO
DABCO
10 4
11 4
12 4
13 4
14 4
toluene
MeCN
Et2O
CH2Cl2
MeOH
8
2
2
2
2
92
62
47
57
0
3
94:6
71:29
74:26
84:16
–
10
48
9
55
1
All reactions were carried out at room temperature with 3 equiv. of methyl trifluoropyruvate in the presence of
30 mol% catalyst, unless otherwise noted. Isolated yield. Determined by 1H-NMR analysis. 15 mol% DABCO
2
3
4
was used.
With the optimized reaction conditions in hand, next we focused on the substrate scope
of the reaction. The results are summarized in Figure 2. The use of ethyl trifluoropyruvate
gave the corresponding aldol product 2b in good yield and with high diastereoselectivity.
Substituents on the benzoyl moiety or at the
on the reactivity and diastereoselectivity (2c and 2d). Indanone-derived
α
-position of the carbonyl group had little effect
-ketocarboxylic acids
β
1e and 1f also afforded the corresponding products 2e and 2f in high yields and with high
diastereoselectivity, whereas benzosuberone- and cyclohexanone-derived substrates 1g and 1h yielded
poor diastereoselectivity of the respective products 2g and 2h. This reaction was also applicable to an
acyclic substrate 1i. In addition, the reaction of
α-fluoro-β-ketocarboxylic acids furnished the desired
tertiary fluorides 2j and 2k in high yields, and with good diastereoselectivity.

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O
O
HO CF3
O
DABCO (15 mol%)
toluene, rt
CO2H
R2 R3
R1
R1
+
CO2Me
F3C
CO2Me
R2 R3
3 equiv.
O
1
2
O
O
HO CF3
O
HO CF3
HO CF3
CO2Me
HO CF3
CO2Me
Br
CO2Me
Me
CO2Et
Me
Me
2a
8 h, 92%
94:6 dr
2b
9 h, 85%
95:5 dr
2c
4 h, 88%
92:8 dr
2d
2 h, 88%
92:8 dr
O
HO CF3
CO2Me
O
HO CF3
O
O
HO
HO
CF3
CF3
CO2Me
Me
MeCO2Me
MeCO2Me
MeO
Ph
2h
2 h, 65%
63:37 dr
2g
1 h, 77%
52:48 dr
2f
2e
3 h, 90%
95:5 dr
5 h, 82%
92:8 dr
O
O
O
HO CF3
CO2Me
HO CF3
CO2Me
HO CF3
CO2Me
Me
Ph
Ph
F
F
Me Me
2j
2k
2i
2 h, 94%
77:23 dr
2 h, 88%
75:25 dr
5 h, 71%
1
1
Figure 2. Substrate scope . All reactions were carried out at room temperature in toluene with
3 equiv. of trifluoropyruvates in the presence of 15 mol% DABCO. Isolated yields were described.
Diastereomeric ratios were determined by 1H-NMR analyses.
Next, we attempted to apply our method to catalytic enantioselective synthesis. First, we employed
chiral primary amine C1 for the reaction of 1a with methyl trifluoropyruvate in toluene, because C1
showed high enantioselectivity in the decarboxylative chlorination of 1a in our previous study. To our
surprise, the present reaction only yielded the desired aldol adduct in a moderate yield, with no
enantioselectivity (Table 2, entry 1). The probable reason for this result was that the primary amine
moiety of C1 reacted with the highly reactive keto carbonyl group of methyl trifluoropyruvate to
form an imine or a hemiaminal, thereby causing C1 to lose its catalytic activity. Considering that
quinuclidine and DABCO showed high catalytic activity (Table 1), we used cinchona alkaloids and
their derivatives in the reaction of 1a and methyl trifluoropyruvate. As expected, all the tested catalysts
showed high activity, with chemo- and diastereo-selectivity (Table 2, entries 2–9). Among simple
cinchona alkaloids C2–C5, cinchonine C4 showed the best enantioselectivity of 56% ee (entries 2–5).
Introducing benzoyl and thiourea moieties at the hydroxy group of cinchonine did not improve the
enantioselectivity (entries 6 and 7). The use of dimeric cinchona alkaloids C8 and C9 also led to
decreased enantioselectivity (entries 8 and 9). Therefore, we selected cinchonine as the best catalyst at
present. Optimization of solvents revealed that the reaction showed higher enantioselectivity (73% ee,
entry 12) in acetonitrile.

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Table 2. Screening of chiral amine catalyst 1.
O
(3 equiv.)
O
F3C
CO2Me
O
O
HO CF3
CO2Me
CO2H
Me
Me
cat. (30 mol%)
+
Me
rt
1a
2a
3a
Ar
X
N
X
OH
N
OBz
NH2
N
N
CO2Et
OH
N
N
Ar
C4 X = H
C5 X = OMe
C2 X = H
C3 X = OMe
Ar = 3,5-(tBu)2C6H3
C1
C6
Ar
Et
Et
NH
NH
Et
Et
O
N
N
N
N
S
N N
H
H
O
O
O
O
H
H
O
MeO
OMe
MeO
H
H
OMe
H
H
N
N
N
N
N
N
C7
Ar = 3,5-(CF3)2C6H3
C8
C9
Yield (%) 2
%ee 4
(Major/Minor)
dr 3
Entry
Catalyst
Time (h)
Solvent
2a
3a
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
C9
C4
C4
C4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
31
10
7
9
3
5
33
1
0.5
4
7
25
99
91
89
80
88
40
83
96
99
89
98
50
0
6
0
10
3
53
10
4
0
8
73:27
92:8
93:7
94:6
94:6
90:10
74:26
92:8
94:6
93:7
92:8
92:8
0/0
–41/–28
–33/–22
50/33
44/31
–45/–63
–2/0
5/44
33/58
57/35
65/32
73/42
10
11
12
CH2Cl2
MeCN
10
0
1
All reactions were carried out at room temperature with 3 equiv. of methyl trifluoropyruvate in the presence
of 30 mol% chiral amine catalyst. Isolated yield. Determined by 1H-NMR analysis. Determined by chiral
2
3
4
high-performance liquid chromatography (HPLC) analysis.
Finally, we performed enantioselective decarboxylative aldol reactions with several
-ketocarboxylic acids (Figure 3). The use of ethyl trifluoropyruvate caused a slight decrease in
β
both the diastereoselectivity and enantioselectivity (see 2b). The reaction of 7-bromotetralone-derived
-ketocarboxylic acid 1c with methyl trifluoropyruvate gave the corresponding product with high
diastereoselectivity and good enantioselectivity. Introducing allyl and fluoro groups at the -position
β
α
of the keto carbonyl group of the substrate significantly decreased the enantioselectivity (2d and 2i).
The use of indanone- and benzosuberone-derived substrates 1e and 1g, as well as acyclic substrate 1i,
resulted in poor enantioselectivity.

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1
1
Figure 3. Enantioselective decarboxylative aldol reaction of 1 . All reactions were carried out
at room temperature in acetonitrile with 3 equiv. of trifluoropyruvates in the presence of 30 mol%
1
C4. Isolated yields were described. Diastereomeric ratios were determined by H-NMR analyses.
Enantiomeric excess was determined by chiral HPLC analysis.
In conclusion, we revealed that the decarboxylative aldol reaction of tertiary β-ketocarboxylic
acids with trifluoropyruvates proceeded smoothly in the presence of a tertiary amine catalyst to
afford the corresponding aldol product with high diastereoselectivity. We also examined a catalytic
enantioselective reaction examined using cinchonine as the catalyst to obtain the product with
moderate-to-good enantioselectivity (up to 73% ee). This was the first example of the enantioselective
decarboxylative aldol reaction of tertiary β-ketocarboxylic acids to form an all-carbon quaternary
stereogenic center. Since the reaction led to the simultaneous formation of a trifluoromethylated chiral
carbon and an adjacent quaternary chiral carbon, it would be useful for the preparation of medicinally
relevant compounds.
3. Materials and Methods
3.1. General
All non-aqueous reactions were carried out in dried glassware under an argon atmosphere
and stirred using magnetic stir-plates. Thin-layer chromatography analyses were performed using
pre-coated silica gel plates with a fluorescent indicator (F254) (Merck Millipore, Darmstadt, Germany).
Visualization was accomplished using ultraviolet (UV) light (254 nm), phosphomolybdic acid,
or p-anisaldehyde. Flash column chromatography was performed using silica gel 60 (mesh size
40–100) supplied by Kanto Chemical Co., Inc. (Tokyo, Japan). 1H, 13C, and 19F nuclear magnetic
resonance (NMR) spectra were recorded on a JNM-ECS400 (400 MHz 1H, 100 MHz 13C, 376 MHz 19F)
or a JNM-ECX500 (500 MHz 1H, 126 MHz 13C, 470 MHz 19F) instrument (JEOL Ltd., Tokyo, Japan).
Chemical shift values (
δ
) are reported in ppm (tetramethylsilane
δ
0.00 ppm for 1H; hexafluorobenzene
δ
77.0 ppm for 13C). Direct analyses in real time (DART) mass
δ −162.2 ppm for 19F; residual chloroform
(positive mode) analyses were performed on a JMS-T100TD time-of-flight mass spectrometer (JEOL
Ltd., Tokyo, Japan). Optical rotations were measured on a P-1030 digital polarimeter (JASCO Co.,
Ltd., Tokyo, Japan). Analytical high-performance liquid chromatography (HPLC) was performed on

Molecules 2019, 24, 2773
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a PU1586 instrument with a MD-2018 plus diode array detector (JASCO Co., Ltd., Tokyo, Japan) using
a chiral column under the conditions described below. The enantiomeric purity of the compounds was
determined by HPLC analysis using chiral stationary phase columns. The 1H, 13C, and 19F-NMR spectra
of compounds 1c and
2 and HPLC data of compounds 2 are available in the Supplementary Material.
3.2. Materials
Commercial grade reagents and solvents were used without further purification unless otherwise
noted. Anhydrous acetonitrile was purchased from Sigma-Aldrich (St. Louis, MO, USA). Anhydrous
toluene, dichloromethane, tetrahydrofurane (THF) were purchased from Kanto Chemical Co., Inc.
(Tokyo, Japan) and they were used after purification via a Glass Contour solvent dispensing system
(Pure Process Technology, Nashua, NH, USA). α,α-dialkyl-β-ketocarboxylic acid 1a, 1d, 1e, 1h [29], 1f,
1g [30], 1i [45], 1j, 1k [31], catalyst C6 [46], and C7 [47] were prepared according to literature procedures.
3.3. Synthesis of α,α-dialkyl-β-ketocarboxylic Acid 1c
Potassium hydroxide (22.0 mmol) was added to
a
solution of methyl
7-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (660 mg, 2.2 mmol) in
MeOH, H2O, and CH2Cl2 (6 mL, 3mL, 0.6 mL), and the mixture was stirred at ambient temperature.
After the reaction completed, the reaction mixture was diluted with H2O and washed with ethyl
acetate. The resulting aqueous layer was acidified with 1.2N HCl until the solution became pH 1.0,
and then extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated.
The title compound was obtained as a colorless powder (430 mg, 68% yield).
1H-NMR (500 MHz)
1H), 3.07–3.00 (m, 1H), 2.96–2.90 (m, 1H), 2.57–2.52 (m, 1H), 2.19–2.14 (m, 1H), 1.54 (m, 3H); 13C-NMR
(126 MHz)
195.8, 142.0, 136.7, 132.6, 131.0, 130.6, 121.0, 32.8, 25.3, 20.8; HRMS (DART): [M + NH4]+
δ 8.18 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 8.0, 2.3 Hz, 1H), 7.14 (d, J = 8.0 Hz,
δ
calcd. for C12H15Br1N1O3, 300.02353; found, 300.02335.
3.4. General Procedure for the Decarboxylative Aldol Reaction
α,α-Dialkyl-β-ketocarboxylic acid 1 was added to a stirred solution of DABCO (15 mol%) and
trifluoropyruvates (3 equiv.) in toluene (0.1 M). Then, the mixture was stirred at ambient temperature.
The reaction mixture was directly subjected to silica gel column chromatography purification to give
aldol products. Some starting compounds
1 contained 2–10% of decarboxylated by-product and used
as is in the aldol reaction, because they decomposed spontaneously even at ambient temperature.
Methyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (2a)
Following general procedure, the reaction of 1a (0.53 mmol) was stirred for 7.5 h. The crude
product was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2a
(92% yield 152.0 mg, 94:6 d.r.) as a colorless oil. The diastereomeric ratio of 2a was determined to be
94:6 by the analysis of 1H-NMR.
1H-NMR (500 MHz)
1H), 7.26 (d, J = 8.0 Hz, 1H), 5.02 (s, 1H), 3.76 (s, 3H), 3.22–3.15 (m, 1H), 3.01–2.88 (m, 2H), 2.23–2.18
δ 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (dt, J = 7.6, 1.2 Hz, 1H), 7.32 (t, J = 7.6 Hz,
(m, 1H), 1.55 (s, 3H); 13C-NMR (126 MHz)
δ 201.6, 169.8, 142.5, 134.2, 130.2, 128.6, 128.2, 126.9,
123.4 (q, J = 287.9 Hz), 80.6 (q, J = 27.6 Hz), 53.6, 51.5, 30.5, 25.3, 16.7; 19F-NMR (470 MHz)
HRMS (DART): [M + NH4]+ calcd. for, C15H19F3N1O4, 334.1266; found, 334.1267.
δ –71.3;
Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (2b)
Following general procedure, the reaction of 1a (0.49 mmol) was stirred for 9 h. The crude product
was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2b (85% yield
136.6 mg, 95:5 d.r.) as a colorless oil. The diastereomeric ratio of 2b was determined to be 95:5 by the
analysis of 1H-NMR.

Molecules 2019, 24, 2773
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1H-NMR (500 MHz)
δ
7.99 (dd, J = 8.0, 1.2 Hz, 1H), 7.52 (dt, J = 7.6, 1.2 Hz, 1H), 7.32 (t, J = 7.6 Hz,
1H), 7.25 (d, J = 8.0 Hz, 1H), 4.95 (s, 1H), 4.23 (q, J = 7.3 Hz, 2H), 3.22–3.15 (m, 1H), 3.00–2.89 (m, 2H),
2.22–2.18 (m, 1H), 1.55 (s, 3H), 1.17 (t, J = 7.3 Hz, 3H); 13C-NMR (126 MHz)
δ
201.2, 169.2, 142.5,
134.1, 130.3, 128.6, 128.2, 126.9, 123.5 (q, J = 291.5 Hz), 80.6 (q, J = 27.6 Hz), 63.1, 51.4, 30.6, 25.4,
16.7, 13.7; 19F-NMR (470 MHz)
found, 331.1156.
δ
–71.3; HRMS (DART): [M + H]+ calcd. for, C16H18F3O4, 331.1157;
Methyl2-(7-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate(2c
)
Following general procedure, the reaction of 1c (0.18 mmol) was stirred for 4 h. The crude product
was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2c (88% yield
59.8 mg, 92:8 d.r.) as a colorless oil. The diastereomeric ratio of 2c was determined to be 92:8 by the
analysis of 1H-NMR.
1H-NMR (500 MHz)
1H), 4.83 (s, 1H), 3.79 (s, 3H), 3.14–3.06 (m, 1H), 2.97–2.86 (m, 2H), 2.22–2.18 (m, 1H), 1.53 (s, 3H);
δ 8.01 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.0, 1.9 Hz, 1H), 7.15 (d, J = 8.0 Hz,
13C-NMR (126 MHz)
δ 200.1, 169.7, 141.1, 136.9, 131.7, 130.9, 130.3, 123.3 (q, J = 289.1 Hz), 120.9, 80.4
(q, J = 27.6 Hz), 53.8, 51.4, 30.3, 24.9, 16.6; 19F-NMR (470 MHz) δ −71.4; HRMS (DART): [M + H]+ calcd.
for, C15H15BrF3O4, 395.0106; found, 395.0105.
Methyl 2-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate (2d)
Following general procedure, the reaction of 1d (0.32 mmol) including 10% of decarboxylative
product was stirred for 2 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 10: 1) to provide 2d (88% yield 154.7 mg, 92:8 d.r.) as a pale yellow oil. The diastereomeric
ratio of 2d was determined to be 92:8 by the analysis of 1H-NMR.
1H-NMR (500 MHz)
1H), 5.85–5.77 (m, 1H), 5.00 (s, 1H), 4.98–4.93 (m, 2H), 3.72 (s, 3H), 3.25–3.18 (m, 1H), 2.99–2.93 (m, 2H),
2.84–2.78 (m, 1H), 2.70–2.65 (m, 1H), 2.34–2.31 (m, 1H); 13C-NMR (126 MHz)
200.2, 169.9, 142.8, 134.5,
δ 7.97–7.95 (m, 1H), 7.51 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz,
δ
134.2, 132.0, 128.7, 128.1, 127.0, 123.4 (q, J = 287.9 Hz), 118.4, 81.5 (q, J = 27.6 Hz), 54.6, 53.7, 36.6, 29.0
(d, J = 3.6 Hz), 25.4; 19F-NMR (470 MHz) δ −70.4; HRMS (DART): [M + H]+ calcd. for, C17H18F3O4,
343.1157; found, 343.1159.
Methyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1-oxo-2,3-dihydro-1H-inden-2-yl)propanoate (2e)
Following general procedure, the reaction of 1e (0.38 mmol) including 9% of decarboxylative
product was stirred for 3 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 20: 3) to provide 2e (90% yield 108.8 mg, 95:5 d.r.) as a colorless oil. The diastereomeric
ratio of 2e was determined to be 95:5 by the analysis of 1H-NMR.
1H-NMR (500 MHz)
(t, J = 7.5 Hz, 1H), 5.32 (s, 1H), 3.84 (d, J = 17.6 Hz, 1H), 3.59 (s, 3H), 2.97 (d, J = 17.6 Hz, 1H), 1.47 (s,
δ 7.77 (d, J = 7.6 Hz, 1H), 7.67 (m, 1H), 7.47 (d, J = 8.0 Hz, 1 H), 7.42
3H); 13C-NMR (126 MHz)
δ 208.3, 168.5, 152.4, 136.1, 133.5, 127.9, 126.5, 124.8, 123.0 (q, J = 287.9 Hz),
80.4 (q, J = 28.8 Hz), 53.3, 51.6, 38.3, 20.6; 19F-NMR (470 MHz) δ −72.0; HRMS (DART): [M + H]+ calcd.
for, C14H14F3O4, 303.0844; found, 303.0846.
Methyl 3,3,3-trifluoro-2-hydroxy-2-(5-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-inden-2-yl)propanoate (2f)
Following general procedure, the reaction of 1f (0.29 mmol) including 6% of decarboxylative
product was stirred for 5 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 10: 1) to provide 2f (82% yield 79.7 mg, 92:8 d.r.) as a colorless oil. The diastereomeric
ratio of 2f was determined to be 92:8 by the analysis of 1H-NMR.
1H-NMR (500 MHz)
5.63 (s, 1H), 3.90 (s, 3H), 3.81 (d, J = 17.8, 1H), 3.56 (s, 3H), 2.93 (d, J = 17.8 Hz, 1H), 1.47 (d, J = 1.2 Hz,
δ 7.70 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.4, 2.9 Hz, 1H), 6.88 (d, J = 1.9 Hz, 1H),
3H); 13C-NMR (126 MHz)
δ 206.7, 168.5, 166.4, 155.9, 126.6, 126.4, 123.1 (q, J = 287.9 Hz), 116.3, 109.4,
80.6 (q, J = 28.8 Hz), 55.7, 53.2, 51.4, 38.3, 20.7; 19F-NMR (470 MHz) δ −72.0; HRMS (DART): [M + H]+
calcd. for, C15H16F3O5, 333.0950; found, 333.0951.

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Methyl 3,3,3-trifluoro-2-hydroxy-2-(6-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)propanoate (2g
)
Following general procedure, the reaction of 1g (0.40 mmol) including 9% of decarboxylative
product was stirred for 1 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 10: 1) to provide 2g (77% yield 101.7 mg, 52:48 d.r.) as a colorless oil. The diastereomeric
ratio of 2g was determined to be 52:48 by the analysis of 1H-NMR.
Major diastereomer; 1H-NMR (500 MHz)
1H), 4.49 (s, 1H), 3.90 (s, 3H), 2.87–2.85 (m, 2H), 2.61–2.57 (m, 1H), 2.06–1.92 (m, 3H), 1.42 (s, 3H);
13C-NMR (126 MHz)
209.8, 170.2, 140.2, 137.1, 130.7, 128.5, 128.0, 126.5, 123.8 (q, J = 289.1 Hz), 79.9 (q,
J = 27.6 Hz), 57.8, 53.9, 34.0, 32.3, 23.2, 18.7; 19F-NMR (470 MHz) ; –70.1; Minor diastereomer; 1H-NMR
(500 MHz) 7.40–7.32 (m, 1H), 7.28–7.21 (m, 2H), 7.13–7.11 (m, 1H), 4.52 (s, 1H), 3.99 (s, 3H), 2.96–2.90
(m, 1H), 2.77–2.71 (m, 1H), 2.28–2.26 (m, 1H), 2.06–1.92 (m, 3H), 1.42 (s, 3H); 13C-NMR (126 MHz)
δ 7.40–7.32 (m, 1H), 7.28–7.21 (m, 2H), 7.13–7.11 (m,
δ
δ
δ
δ
212.0, 170.3, 140.2, 137.3, 131.3, 128.4, 127.7, 126.5, 123.8 (q, J = 289.1 Hz), 81.4 (q, J = 27.6 Hz), 56.2, 54.3,
32.2, 30.4, 22.8, 19.5; 19F-NMR (470 MHz) δ −70.5; HRMS (DART): [M + H]+ calcd. for, C16H18F3O4,
331.1157; found, 331.1158.
Methyl 2-(1-benzyl-2-oxocyclohexyl)-3,3,3-trifluoro-2-hydroxypropanoate (2h)
Following general procedure, the reaction of 1h (0.88 mmol) including 2% of decarboxylative
product was stirred for 2 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 20: 3) to provide 2h (65% yield 179.2 mg, 63:37 d.r.) as a colorless oil. The diastereomeric
ratio of 2h was determined to be 63:37 by the analysis of 1H-NMR.
Major diastereomer; 1H-NMR (500 MHz)
1 H), 3.03 (d, J = 14.1 Hz, 1H), 2.59–2.41 (m, 1H), 2.38–2.27 (m,3H), 2.20–2.12 (m, 1H), 1.84–1.23 (m,
4H); 13C-NMR (126 MHz)
215.1, 170.0, 137.2, 130.8, 128.3, 126.9, 123.3 (q, J = 289.1 Hz), 82.0 (q,
J = 27.6 Hz), 58.4, 53.7, 42.3, 40.8, 33.2, 23.8, 21.4; 19F-NMR (470 MHz)
–69.8; Minor diastereomer;
1H-NMR (500 MHz)
7.27–7.08 (m, 5H), 4.02 (s, 3H), 3.75 (d, J = 13.2 Hz, 1H), 2.93 (d, J = 14.1 Hz,
δ 7.27–7.08 (m, 5H), 3.84 (s, 3H), 3.64 (d, J = 14.1 Hz,
δ
δ
δ
1H), 2.59–2.41 (m, 1H), 2.38–2.27 (m,3H), 2.20–2.12 (m, 1H), 1.84–1.23 (m, 4H); 13C-NMR (126 MHz) δ
214.1, 169.9, 136.7, 130.7, 128.5, 126.9, 123.3 (q, J = 289.1 Hz), 81.0 (q, J = 27.6 Hz), 59.4, 54.2, 42.8, 41.9,
30.7, 22.0, 21.5; 19F-NMR (470 MHz) δ −69.5; HRMS (DART): [M + NH4]+ calcd. for, C17H23F3N1O4,
362.1579; found, 362.1578.
Methyl 2-hydroxy-3,3-dimethyl-4-oxo-4-phenyl-2-(trifluoromethyl)butanoate (2i)
Following general procedure, the reaction of 1i (0.52 mmol) was stirred for 4.5 h. The crude
product was purified by flash column chromatography (hexane: ethyl acetate = 6: 1) to provide 2i (71%
yield 112.5 mg) as a colorless oil.
1H-NMR (500 MHz)
13C-NMR (126 MHz)
δ 7.52–7.38 (m, 5H), 4.57 (s, 1H), 3.96 (s, 3H), 1.60 (dd, J = 33.8, 1.0 Hz, 6H);
δ
209.1, 170.2, 138.4, 128.0, 127.1, 123.7 (q, J = 287.9 Hz), 80.1 (q, J = 27.6 Hz), 55.1,
54.1, 23.5 (d, J = 2.4 Hz), 22.8 (d, J = 2.4 Hz); 19F-NMR (470 MHz) δ −70.6; HRMS (DART): [M + NH4]+
calcd. for, C14H19F3N1O4, 322.1266; found, 322.1266.
Methyl 3,3,3-trifluoro-2-(2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-hydroxypropanoate (2j)
Following general procedure, the reaction of 1j (0.48 mmol) was stirred for 2 h. The crude product
was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2j (94% yield
144.2 mg, 77:23 d.r.) as a colorless oil. The diastereomeric ratio of 2j was determined to be 77:23 by the
analysis of 1H-NMR.
1
Major diastereomer; H-NMR (500 MHz)
δ 7.98 (dd, J = 7.6, 1.2 Hz), 7.57 (dt, J = 7.6, 1.2 Hz),
7.36 (t, J = 7.6 Hz), 7.29 (d, J = 7.6 Hz), 4.63 (s, 3H), 3.36–3.30 (m, 1H), 3.01 (dt, J = 17.2, 4.4 Hz, 1H),
2.95–2.88 (m, 1H), 2.78–2.71 (m, 1H); 13C-NMR (126 MHz)
δ
191.2 (d, J = 20.4 Hz), 167.4, 143.4, 134.9,
130.3, 128.6, 128.6, 127.2, 122.3 (q, J = 287.9 Hz), 93.4 (d, J = 192.0 Hz), 79.6–78.9 (m), 54.3, 30.5 (dd,
J = 22.8, 2.4 Hz), 24.5 (d, J = 7.2 Hz); 19F-NMR (470 MHz) δ −72.7,
−
172.1; Minor diastereomer; 1H-NMR
(500 MHz), 7.99 (dd, J = 8.0, 0.8 Hz, 1H), 7.55 (dt, J = 7.6, 1.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.29

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(8.0 Hz, 1H), 4.36 (s, 1H), 4.04 (s, 3H), 3.29–3.20 (m, 1H), 3.05–3.00 (m, 1H), 2.79–2.65 (m, 1H); 13C-NMR
(126 MHz), 189.0 (d, J = 19.2 Hz), 169.4, 143.7, 139.4–139.1 (m), 136.8–136.6 (m), 134.8, 130.3, 128.7, 128.5,
127.2, 122.9 (q, J = 288.5 Hz), 93.6 (d, J = 196.5 Hz), 76.4–75.9 (m), 54.8, 29.4 (d, J = 22.0 Hz), 24.0 (d,
J = 4.8 Hz); 19F-NMR (470 MHz);
338.1016; found, 338.1014.
−
72.2,
167.4; HRMS (DART): [M + NH4]+ calcd. for, C14H16F4N1O4,
−
Methyl 3-benzyl-3-fluoro-2-hydroxy-4-oxo-2-(trifluoromethyl)pentanoate (2k)
Following general procedure, the reaction of 1k (0.72 mmol) including 2% of decarboxylative
product was stirred for 2 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 10: 1) to provide 2k (88% yield, 203.8 mg, 75:25 d.r.) as a colorless oil. The diastereomeric
ratio of 2k was determined to be 75:25 by the analysis of 1H-NMR.
1
Major diastereomer; H-NMR (500 MHz)
δ
7.30–7.25 (m, 3H), 7.15–7.13 (m, 2H), 4.54 (s, 1H),
208.0 (d, J = 30.0 Hz),
3.92 (s, 3H), 3.51–3.28 (m, 2H), 1.70 (d, J = 5.7 Hz, 3H); 13C-NMR (126 MHz)
δ
167.6, 132.5, 130.9, 128.4, 127.4, 121.1 (dq, J = 287.3, 2.4 Hz), 100.6 (d, J = 203.3 Hz), 80.1–79.1 (m),
54.4, 38.6 (d, J = 20.4 Hz), 28.0; 19F-NMR (470 MHz) δ −71.8 (d, J = 14.7 Hz), –166.9 (d, J = 44.0 Hz);
Minor diastereomer; 1H-NMR (500 MHz)
δ 7.30–7.25 (m, 3H), 7.15–7.13 (m, 2H), 4.47 (s, 1H), 4.05 (s,
3H), 3.58–3.36 (m, 2H), 1.70 (d, J = 5.7 Hz, 3H); 13C-NMR (126 MHz)
δ 208.6 (d, J = 31.2 Hz), 166.5 (d,
J = 6.0 Hz), 130.9, 132.5, 128.5, 127.5, 122.4 (q, J = 287.9 Hz), 101.5 (d, J = 226.3 Hz), 80.1–79.1 (m), 54.9,
39.1 (d, J = 22.8 Hz), 28.3; 19F-NMR (470 MHz) δ −71.9 (d, J = 14.7 Hz),
−
168.7 (d, J = 44.0 Hz); HRMS
(DART): [M + NH4]+ calcd. for, C14H18F4N1O4, 340.1172; found, 340.1173.
3.5. General Procedure of the Enantioselective Decarboxylative Aldol Reaction
α,α-Dialkyl-β-ketocarboxylic acid 1 was added to a stirred solution of cinchonine (30 mol%) and
trifluoropyruvates (3.0 equiv.) in toluene (0.1 M). Then, the reaction mixture was stirred at ambient
temperature. The mixture was purified by flash column chromatography on silica gel to give aldol
products. When the reactions were performed, some starting compounds
1 contained 5–33% of
decarboxylated by-product as an impurity, as noted in the description of each compound, because
some of 1 decomposed slowly while standing at ambient temperature.
Methyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (2a)
Following general procedure, the reaction of 1a (0.30 mmol) was stirred for 10 h. The crude
product was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2a
(98% yield 151.9 mg, 92:8 d.r., 73% e.e. (major), 42% e.e. (minor)) as a colorless oil. The diastereomeric
ratio of 2a was determined to be 92:8 by the analysis of 1H-NMR.
28
[
α
]
= 38.1 (c 0.5, CHCl3) (diastereomeric mixture); Major diastereomer; The enantiomeric
−
D
purity of the title compound was determined by HPLC analysis (DAICEL CHIRALPAK IC-3, hexane:
2-propanol = 200: 1, flow rate = 1.0 mL/min, retention time; 37.8 min (minor enantiomer) and
44.9 min (major enantiomer)), Minor diastereomer; The enantiomeric purity of the title compound
was determined by HPLC analysis (DAICEL CHIRALPAK IC-3, hexane: 2-propanol = 200: 1,
flow rate = 1.0 mL/min, retention time; 22.6 min (major enantiomer), 29.4 min (minor enantiomer)).
Ethyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (2b)
Following general procedure, the reaction of 1b (0.25 mmol) was stirred for 7 h. The crude product
was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2b (97% yield
76.5 mg, 87:13 d.r., 61% e.e. (major), 36% e.e. (minor)) as a colorless oil. The diastereomeric ratio of 2b
was determined to be 87:13 by the analysis of 1H-NMR.
28
[α
]
= 26.5 (c 0.72, CHCl3) (diastereomeric mixture); Major diastereomer; The enantiomeric
−
D
purity of the title compound was determined by HPLC analysis (DAICEL CHIRALPAK ID and ID-3,
hexane: 2-propanol = 100: 1, flow rate = 1.0 mL/min, retention time; 52.7 min (minor enantiomer)
and 57.1 (major enantiomer)), Minor diastereomer; The enantiomeric purity of the title compound

Molecules 2019, 24, 2773
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was determined by HPLC analysis (DAICEL CHIRALPAK ID and ID-3, hexane: 2-propanol = 100: 1,
flow rate = 1.0 mL/min, retention time; 32.7 min (major enantiomer), 45.6 min (minor enantiomer)).
Methyl 2-(7-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate (2c
)
Following general procedure, the reaction of 1c (0.35 mmol) was stirred for 7 h. The crude product
was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2c (93% yield
124.0 mg, 90:10 d.r., 65% e.e. (major), 32% e.e. (minor)) as a colorless oil. The diastereomeric ratio of 2c
was determined to be 90:10 by the analysis of 1H-NMR.
28
[
α
]
= 22.7 (c 1.6, CHCl3) (diastereomeric mixture); Major diastereomer; The enantiomeric
−
D
purity of the title compound was determined by HPLC analyses (DAICEL CHIRALPAK ID-3, hexane:
2-propanol = 50: 1, flow rate = 1.0 mL/min, retention time; 19.9 min (minor enantiomer) and 23.5 min
(major enantiomer), Minor diastereomer; The enantiomeric purity of the title compound was determined
by HPLC analysis (DAICEL CHIRALPAK ID-3, hexane: 2-propanol = 50: 1, flow rate = 1.0 mL/min,
retention time;13.5 min (major enantiomer), 17.7 min (major enantiomer)).
Methyl 2-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3,3,3-trifluoro-2-hydroxypropanoate (2d)
Following general procedure, the reaction of 1d (0.32 mmol) including 5% of decarboxylative
product was stirred for 27 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 10: 1) to provide 2d (90% yield 91.5 mg, 90:10 d.r., 49% e.e. (major), 9% e.e. (minor))
as a pale yellow oil. The diastereomeric ratio of 2d was determined to be 90:10 by the analysis of
1H-NMR.
28
[α
]
= 32.3 (c 0.77, CHCl3) (diastereomeric mixture); Major diastereomer; The enantiomeric
−
D
purity of the title compound was determined by HPLC analysis (DAICEL CHIRALPAK IE-3, hexane:
2-propanol = 200: 1, flow rate = 1.0 mL/min, retention time; 35.5 min (major enantiomer) and
40.2 min (minor enantiomer)), Major diastereomer; The enantiomeric purity of the title compound
was determined by HPLC analysis (DAICEL CHIRALPAK IE-3, hexane: 2-propanol = 200: 1,
flow rate = 1.0 mL/min, retention time; 22.0 min (major enantiomer), 30.2 min (minor enantiomer)).
Methyl 3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1-oxo-2,3-dihydro-1H-inden-2-yl)propanoate (2e)
Following general procedure, the reaction of 1e (0.38 mmol) including 5% of decarboxylative
product was stirred for 3 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 20: 3) to provide 2e (91% yield 76.4 mg, 90:10 d.r., 11% e.e. (major), 26% e.e. (minor)) as
a colorless oil. The diastereomeric ratio of 2e was determined to be 90:10 by the analysis of 1H-NMR.
Major diastereomer; The enantiomeric purity of the title compound was determined by HPLC
analysis (DAICEL CHIRALPAK IE-3, hexane: 2-propanol = 200: 1, flow rate = 1.0 mL/min, retention time;
52.7 min (minor enantiomer) and 68.5 min (major enantiomer)), Minor diastereomer; The enantiomeric
purity of the title compound was determined by HPLC analysis (DAICEL CHIRALPAK IE-3,
hexane: 2-propanol = 200: 1, flow rate = 1.0 mL/min, retention time; 34.0 min (minor diastereomer,
minor enantiomer), 43.2 min (minor diastereomer, major enantiomer)).
Methyl 3,3,3-trifluoro-2-hydroxy-2-(6-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)propanoate (2g
)
Following general procedure, the reaction of 1g (0.20 mmol) including 33% of decarboxylative
product was stirred for 2 h. The crude product was purified by flash column chromatography (hexane:
ethyl acetate = 10: 1) to provide 2g (91% yield 66.1 mg, 68:32 d.r., 32% e.e. (major), 16% e.e. (minor)) as
a colorless oil. The diastereomeric ratio of 2g was determined to be 52:48 by the analysis of 1H-NMR.
Major diastereomer; The enantiomeric purity of the title compound was determined by HPLC
analysis (DAICEL CHIRALPAK IB-3, hexane: 2-propanol = 200: 1, flow rate = 1.0 mL/min, retention time;
20.8 min (major enantiomer) and 33.0 min (minor enantiomer)), Minor diastereomer; The enantiomeric
purity of the title compound was determined by HPLC analysis (DAICEL CHIRALPAK IB-3, hexane:
2-propanol = 200: 1, flow rate = 1.0 mL/min, retention time; 12.9 min (major enantiomer), 15.7 min
(minor enantiomer)).

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Methyl 2-hydroxy-3,3-dimethyl-4-oxo-4-phenyl-2-(trifluoromethyl)butanoate (2i)
Following general procedure, the reaction of 1i (0.39 mmol) was stirred for 4.5 h. The crude
product was purified by flash column chromatography (hexane: ethyl acetate = 6: 1) to provide 2i (82%
yield 97.3 mg, 31% e.e.) as a colorless oil.
[α]
28 = +7.6 (c 1.2, CHCl3); The enantiomeric purity of the title compound was determined by
D
HPLC analysis (DAICEL CHIRALPAK IA-3, hexane: 2-propanol = 200: 1, flow rate = 1.0 mL/min,
retention time; 24.8 min (major enantiomer), 29.5 min (minor enantiomer)).
Methyl 3,3,3-trifluoro-2-(2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-hydroxypropanoate (2j)
Following general procedure, the reaction of 1j (0.48 mmol) was stirred for 2 h. The crude product
was purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to provide 2j (97% yield
148.0 mg, 70:30 d.r., 30% e.e. (major), 31% e.e. (minor)) as a colorless oil. The diastereomeric ratio of 2j
was determined to be 70:30 by the analysis of 1H-NMR.
28
Major diastereomer; [
α
]
= +21.1 (c 0.9, CHCl3); The enantiomeric purity of the title compound
D
was determined by HPLC analysis (DAICEL CHIRALPAK IC-3, hexane: 2-propanol = 10: 1, flow
rate = 1.0 mL/min, retention time; 11.1 min (major enantiomer), 17.2 min (minor enantiomer)); Minor
28
diastereomer; [
α
]
= +6.3 (c 1.0, CHCl3); The enantiomeric purity of the title compound was
D
determined by HPLC analysis (DAICEL CHIRALPAK IC-3, hexane: 2-propanol = 10: 1, flow rate = 1.0
mL/min, retention time; 5.7 min (major enantiomer), 6.2 min (minor enantiomer)).
Supplementary Materials: The following are available online, 1H, 13C, and 19F-NMR spectra of compounds
and HPLC data of compound 2.
2
Author Contributions: K.S. conceived and designed the project; R.K. and S.H. performed the experiments and
analyzed the data while discussing with S.I. and K.S.; R.K. and K.S. wrote the paper.
Funding: This study was supported by the Grants-in-Aid for Scientific Research (B) (18H01974) and
Daiko Foundation.
Conflicts of Interest: The authors declare no conflict of interest.
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