Copper-catalyzed asymmetric methylation of fluoroalkylated pyruvates with dimethylzinc

Article abstract of DOI:10.3762/bjoc.14.44

The catalytic asymmetric methylation of fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the presence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various α-fluoroalkylated tertiary alcohols with CF₃, CF₂H, CF₂Br, and n-C_nF_2n+1 (n = 2, 3, 8) groups in good-to-high yields and enantioselectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantioselectivity. Moreover, the methylation of simple perfluoroalkylated ketones is found to be facilitated by only chiral phosphines without copper.

Full text of DOI:10.3762/bjoc.14.44

Copper-catalyzed asymmetric methylation of fluoroalkylated
pyruvates with dimethylzinc
Kohsuke Aikawa, Kohei Yabuuchi, Kota Torii and Koichi Mikami*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 576–582.
Department of Chemical Science and Engineering, School of
Materials and Chemical Technology, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
doi:10.3762/bjoc.14.44
Received: 30 October 2017
Accepted: 19 February 2018
Published: 07 March 2018
Email:
Koichi Mikami* - mikami.k.ab@m.titech.ac.jp
This article is part of the Thematic Series "Organo-fluorine chemistry IV".
Guest Editor: D. O'Hagan
*
Corresponding author
Keywords:
asymmetric methylation; chiral phosphine ligand; copper catalyst;
dimethylzinc; trifluoropyruvate
© 2018 Aikawa et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The catalytic asymmetric methylation of fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the pres-
ence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various
α-fluoroalkylated tertiary alcohols with CF3, CF2H, CF2Br, and n-CnF2n+1 (n = 2, 3, 8) groups in good-to-high yields and enantio-
selectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantiose-
lectivity. Moreover, the methylation of simple perfluoroalkylated ketones is found to be facilitated by only chiral phosphines with-
out copper.
Introduction
The introduction of fluorine atoms into organic compounds methyl sources, trifluoropyruvate, has been utilized for a variety
plays an important role in the discovery of lead candidates with of catalytic asymmetric carbon–carbon bond forming reactions,
unique biological and physicochemical properties [1,2]. There- providing efficiently α-trifluoromethylated tertiary alcohols in
fore, the development of novel synthetic methods for the intro- high enantioselectivities [9-19]. Over the past decade we have
duction of fluorinated fragments, such as trifluoromethyl (CF3), also investigated several catalytic asymmetric reactions using
difluoromethyl (CF2H), and difluoromethylene (-CF2-), has at- trifluoropyruvate as an electrophile in the presence of a chiral
tracted a great deal of attention from synthetic organic chemists Lewis acid complex [20-27]. However, the synthetic method for
[
3-6]. Among these methods, many researchers including us chiral α-trifluoromethylated tertiary alcohols via methylation of
have studied the catalytic asymmetric synthesis of optically trifluoropyruvate is quite limited, although several drug candi-
active α-trifluoromethylated tertiary alcohols [7,8]. In these dates bearing this chiral trifluoromethylated moiety have so far
cases, one of commercially available and versatile trifluoro- been reported [7,28-30]. In 2007, Gosselin and Britton et al. re-
576

Beilstein J. Org. Chem. 2018, 14, 576–582.
ported that treatment of ethyl trifluoropyruvate (1a) with (R)- increase in the enantioselectivity. In the case of a biphenyl
BINOL-mediated organozincate as a chiral methylating regent backbone, MeO-BIPHEP showed the same level of enantiose-
provided the corresponding methylated tertiary alcohol 2a in lectivity as BINAP, while lower enantioselectivity was ob-
moderate enantioselectivity (Scheme 1, reaction 1) [31]. Kinetic tained by SEGPHOS (Table 1, entries 5 and 6). Exploring the
resolution of racemic α-trifluoromethylated tertiary alcohols 2a effect of substituents on phosphorus, DM-BINAP slightly
by an enzyme is also reported to give the corresponding alco- exceeded the level attained by BINAP, although Cy-BINAP and
hols 2a in high enantioselectivity (Scheme 1, reaction 2) [32]. DTBM-BINAP decreased the enantioselectivities (Table 1,
However, there has been no report for catalytic asymmetric entries 7–9). In sharp contrast to BINAP derivatives, DTBM-
methylation of trifluoropyruvate. Herein, we disclose the cata- SEGPHOS and DTBM-MeO-BIPHEP with extremely bulky
lytic asymmetric methylation of trifluoropyruvate derivatives as aryl groups increased the enantioselectivities (Table 1, entries
electrophiles and dimethylzinc as a methylating nucleophile by 10 and 11). Additionally, DTB-MeO-BIPHEP provided the
a chiral copper catalyst. This method is also applicable to the desired alcohol in 84% yield with 60% ee (Table 1, entry 12). In
asymmetric synthesis of various α-fluoroalkylated tertiary alco- toluene and CH2Cl2 as noncoordinating solvents (Table 1,
hols bearing CF2H, CF2Br, and n-CnF2n+1 (n = 2, 3, 8) groups.
entries 14 and 15), the reaction gave lower enantioselectivities,
but TBME gave the best result in 90% yield and 67% ee
(Table 1, entry 16). The use of methyl trifluoropyruvate (1b)
Results and Discussion
Our initial investigation was focused on the methylation of instead of 1a resulted in a lower enantioselectivity (Table 1,
ethyl trifluoropyruvate (1a) with Me2Zn in the presence of a entry 17). The absolute configuration of 2b was determined to
copper salt bearing a chiral bidentate phosphine ligand be S by comparison with the optical rotation of reported data
(
Table 1). We were delighted to find that the reaction proceeded [32]. The absolute configurations of other alcohol products 2a
smoothly in the presence of CuTC (TC: 2-thiophenecarboxy- and 2c–k were tentatively assigned by analogy to 2b.
late, 2.5 mol %) and (R)-BINAP (2.7 mol %) in Et2O at −78 °C,
furnishing the methylated product 2a in 99% yield with 38% ee Additionally, the reaction conditions were fine-tuned as exem-
(
Table 1, entry 1). The effect of the Cu salt was also surveyed. plified in Table 2. It was found that reactions without CuTC and
The use of CuOAc resulted in slightly decreased enantioselec- phosphine ligand (Table 2, entry 1) or only without phosphine
tivities, and (CuOTf)·C6H6 and CuI led to a racemic product ligand (Table 2, entry 2) provided the alcohol as a racemic mix-
(
Table 1, entries 2–4). Chiral phosphine ligands instead of ture even at −78 °C. In contrast, the chiral product was ob-
BINAP were further assayed with the aim of enhancing the en- tained in 64% yield in the absence of a copper salt but in low
antioselectivity. Indeed, the investigation of the effect of axial enantioselectivity (Table 2, entry 3). Therefore, decreasing the
backbones and substituents on the phosphorus atoms led to an amount of phosphine ligand (2.4 mol %) to less than that of
Scheme 1: Synthesis of chiral α-fluoroalkylated tertiary alcohols.
577

Beilstein J. Org. Chem. 2018, 14, 576–582.
Table 1: Copper-catalyzed asymmetric methylation.
entry
ligand
Cu salt
solvent
yield (%)a
ee (%)
1
2
3
4
5
6
7
8
9
(R)-BINAP
CuTC
CuOAc
(CuOTf)·C6H6
CuI
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
99
43
13
38
81
85
92
70
73
67
99
84
85
98
90
90
71
38
36
0
(R)-BINAP
(R)-BINAP
(R)-BINAP
0
(R)-SEGPHOS
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
26
38
3
(R)-MeO-BIPHEP
(R)-Cy-BINAP
(R)-DM-BINAP
41
17
55
50
60
57
38
9
(R)-DTBM-BINAP
(R)-DTBM-SEGPHOS
(R)-DTBM-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
10
11
12
13
14
15
16
17b
toluene
CH2Cl2
TBME
TBME
67
59 (S)
aYields were determined by 19F NMR analysis using benzotrifluoride (BTF) as an internal standard. bMethyl trifluoropyruvate (1b) was used instead of
ethyl trifluoropyruvate (1a).
copper salt led to an enhancement of the enantioselectivity to Various fluoroalkylated pyruvates were applicable to this cata-
7
0% ee (Table 2, entries 4 vs 5). In addition, the selection of lytic transformation under the optimized reaction conditions
BTFM-Garphos instead of DTB-MeO-BIPHEP afforded a (Scheme 2). Alkyl substituents on the ester moiety of the triflu-
higher enantoselectivity (Table 2, entry 6), and consequently, a oropyruvate were found to influence the stereoselectivity drasti-
lower reaction temperature (−90 °C) gave the best result with cally. The reaction of trifluoropyruvates (1c–e) bearing steri-
8
6% yield and 89% ee (Table 2, entry 7).
cally demanding substituents such as isopropyl, cyclopentyl,
578

Beilstein J. Org. Chem. 2018, 14, 576–582.
Table 2: Optimization of reaction conditions.
entry
X (mol %/Cu)
Y (mol %/ligand)
ligand
yield (%)a
ee (%)
1
2
3
4
5
6
0
0
–
17
15
64
90
94
88
86
–
2.5
0
0
–
–
2.5
2.7
2.4
2.4
2.4
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-BTFM-Garphos
(R)-BTFM-Garphos
7
2.5
2.5
2.5
2.5
67
70
73
89
7b
aYields were determined by 19F NMR analysis using benzotrifluoride (BTF) as an internal standard. bReaction temperature was −90 °C.
and cyclohexyl led to a higher level of enantioselectivities
(
90–94% ee), compared to the corresponding ethyl ester 1a. In
contrast, trifluoropyruvate 1f with an extremely bulky substitu-
ent caused a decrease of enantioselectivity. Ethyl difluoropyru-
vate (1g) and ethyl bromodifluoropyruvate (1h) also underwent
the reactions in good enantioselectivities, although a slight de-
crease in yield was observed due to the steric hindrance of the
CF2Br group. Significantly, ethyl perfluoropyruvates 1i–k with
longer alkyl chains were also converted to the desired tertiary
alcohols in good enantioselectivities.
The catalytic asymmetric methylation using the simple per-
fluoroalkylated ketone 3a instead of pyruvate derivatives was
further examined (Scheme 3). In contrast to the pyruvate
system, the combination of CuTC and BINAP did not facilitate
the reaction even at −78 °C, but also afforded the racemic prod-
uct (25% yield, 0% ee). Interestingly, the use of only BINAP
without CuTC led to higher reactivity and enantioselectivity
(
54% yield, 8% ee), while BTFM-Garphos decreased the reac-
tivity (7% yield, 8% ee). After screening of phosphines, DTB-
MeO-BIPHEP was found to smoothly catalyze the asymmetric
methylation to give the desired alcohol 4a in 87% yield and
Scheme 2: Scope of fluoroalkylated pyruvates. Yields were deter-
mined by 19F NMR analysis using benzotrifluoride (BTF) as an internal
standard. aReaction temperature was −78 °C.
2
4% ee.
579

Beilstein J. Org. Chem. 2018, 14, 576–582.
After the reaction mixture was cooled to 0 °C, p-nitrobenzoyl
chloride (56 mg, 0.3 mmol) was added. Then the mixture was
warmed to room temperature and stirred for 1 h. After 1 N HCl
(
5.0 mL) was added to the reaction mixture, the organic layer
was separated and the aqueous layer was extracted twice with
Et2O. The combined organic layer was washed with saturated
aq. NaHCO3, water, and brine, and then dried over anhydrous
MgSO4 and evaporated under reduced pressure. The residue
was purified by silica gel column chromatography to give
p-nitrobenzoylated alcohol 2’. The enantiomeric excess was de-
termined by chiral HPLC analysis.
Scheme 3: Catalytic asymmetric methylation of the simple perfluoro-
alkylated ketone 3a. Yields were determined by 19F NMR analysis
using benzotrifluoride (BTF) as an internal standard. aReaction was
carried out without CuTC.
(S)-3-Ethoxy-1,1,1-trifluoro-2-methyl-3-
oxopropan-2-yl 4-nitrobenzoate (2a’)
Conclusion
The yield of alcohol 2a (86%) was determined by 19F NMR
In summary, we have succeeded in the catalytic enantioselec- analysis. p-Nitrobenzoylated alcohol 2a’ was purified by silica-
tive methylation of fluoroalkylated pyruvates in the presence of gel column chromatography (EtOAc/hexane 1:40) as a color-
chiral diphosphine–copper complexes, providing the corre- less liquid (53% yield for 2 steps, 89% ee). 1H NMR (300 MHz,
sponding tertiary alcohols with an RF group such as CF3, CF2H, CDCl3) δ 8.34–8.31 (m, 2H), 8.24–8.20 (m, 2H), 4.33 (q, 4H, J
CF2Br, and n-CnF2n+1 (n = 2, 3, 8) in good-to-high yields and = 6.9 Hz), 1.97 (d, 3H, J = 0.9 Hz), 1.28 (t, 3H, J = 7.0 Hz);
enantioselectivities. This is the first report on catalytic asym- 13C NMR (75 MHz, CDCl3) δ 164.3, 162.3, 151.1, 134.0,
metric methylation with fluoroalkylated pyruvates. Moreover, a 131.2, 123.7, 122.7 (q, J C-F = 282.9 Hz), 80.7 (q, J C-F = 30.4
simple perfluoroalkyl ketone was also found to be methylated Hz), 63.2, 16.6, 13.8; 19F NMR (282 MHz, CDCl3) δ −78.4 (s,
enantioselectively with dimethylzinc and a catalytic amount of a 3F); HRMS (APCI-TOF): [M]−· calcd for C13H12F3NO6,
chiral diphosphine, but without copper.
335.0617; found, 335.0623; FTIR (neat, cm−1) 784, 813, 849,
76, 927, 1011, 1109, 1149, 1273, 1342, 1387, 1452, 1525,
1602, 1740, 1763, 2857, 2920, 2952, 2996, 3087, 3116; [α]D22
8
Experimental
Typical procedure for copper-catalyzed asymmetric methyl- −28.94 (c 0.20, CHCl3); HPLC (column, CHIRALCEL OJ-3,
ation of fluoroalkylated pyruvates: To a mixture of CuTC hexane/2-propanol 91:9, flow rate 0.6 mL/min, 20 °C detection
(
1.0 mg, 0.005 mmol) and (R)-BTFM-Garphos (5.7 mg, UV 254 nm) tR of major isomer 13.1 min, tR of minor isomer
.0048 mmol) was added CH2Cl2 (1.0 mL) at room tempera- 23.8 min.
ture under an argon atmosphere, and the solution was stirred for
2 h. The solvent was removed under reduced pressure, and the
0
(
S)-1-Ethoxy-3,3-difluoro-2-methyl-1-
1
prepared catalyst was dissolved in TBME (0.5 mL) under an oxopropan-2-yl benzoate (2g’)
argon atmosphere. After the solution was cooled to −90 °C, Reaction temperature was −78 °C. The yield of alcohol 2g
Me2Zn (1.0 M in heptane, 0.4 mL, 0.4 mmol) followed by fluo- (89%) was determined by 19F NMR analysis. In the protection
roalkylated pyruvate 1 (0.2 mmol) in TBME (0.5 mL) were of alcohol, benzoyl chloride was used instead of p-nitrobenzoyl
added over 30 min. The reaction mixture was stirred at the same chloride. Benzoylated alcohol 2g’ was purified by silica gel
temperature for 1 h. The reaction mixture was quenched with column chromatography (EtOAc/hexane 1:40) as a colorless
saturated aq NH4Cl solution. The organic layer was separated liquid (41% yield for 2 steps, 89% ee). 1H NMR (300 MHz,
and the aqueous layer was extracted twice with Et2O. The CDCl3) δ 8.05 (dd, J = 8.3, 1.3 Hz, 2H). 7.61 (tt, J = 6.7, 1.3
combined organic layer was dried over anhydrous Na2SO4 and Hz, 1H), 7.49–7.44 (m, 2H), 6.30 (dd, JH-F = 56.8, 54.8 Hz,
evaporated under reduced pressure (350 mmHg). The concen- 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.77 (t, JH-F = 1.6 Hz, 3H), 1.27
trated solution was used without purification for the next (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6, 164.8,
protection reaction. The yield of alcohol product 2 was deter- 133.7, 130.0, 128.8, 128.5, 122.9 (dd, JC-F = 250.0, 245.0 Hz),
mined by 19F NMR analysis using benzotrifluoride (BTF) as an 79.7 (dd, JC-F = 27.5, 21.9 Hz), 62.3, 14.6 (t, JC-F = 3.2 Hz)
internal standard.
13.9; 19F NMR (282 MHz, CDCl3) δ −128.40 (dd, J = 290.2
Hz, JF-H =54.7 Hz, 1F), −132.76 (dd, J = 289.90 Hz, JF-H =
To a solution of DMAP (2.4 mg, 0.02 mmol) and the crude 56.4 Hz, 1F); HRMS (APCI-TOF): [M + Na]+ calcd for
alcohol 2 in CH2Cl2 (2.0 mL) was added NEt3 (56 μL, C13H14F2NaO4, 295.0758; found, 295.0761; FTIR (neat, cm−1)
0
.4 mmol) at room temperature under an argon atmosphere. 1026, 1093, 1114, 1216, 1279, 1388, 1452, 1602, 1730, 1747,
580

Beilstein J. Org. Chem. 2018, 14, 576–582.
2
938, 2985, 3021; [α]D25 −7.47 (c 1.01, CHCl3); HPLC gel column chromatography (EtOAc/hexane 1:50) as a color-
(
column, CHIRALCEL OJ-3, hexane/2-propanol 99:1, flow rate less oil (48% yield for 2 steps, 78% ee). 1H NMR (300 MHz,
0
.6 mL/min, 20 °C detection UV 220 nm) tR of major isomer CDCl3) δ 8.35–8.31 (m, 2H) 8.21–8.16 (m, 2H), 4.36–4.29 (m,
1.2 min, tR of minor isomer 22.6 min. 2H), 2.07 (q, JH-F = 1.3 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H);
3C NMR (75 MHz, CDCl3) δ 164.2 162.2, 151.0, 134.1, 131.0,
23.8, 117.6 (qt, JC-F = 286.9, 33.9 Hz), 113.6 (tt, JC-F = 263.9,
30.9 Hz), 122.9 (tq, JC-F = 266.9, 37.4 Hz), 82.2 (t, JC-F = 25.7
Reaction temperature was −78 °C. The yield of alcohol 2h Hz), 63.4, 16.8, 13.7; 19F NMR (282 MHz, CDCl3) δ −80.65
53%) was determined by 19F NMR analysis. p-Nitrobenzoy- (m, 3F), −117.75 (d, J = 288.5 Hz, 1F), −119.60 (d, J = 288.2
2
1
(S)-1-Bromo-3-ethoxy-1,1-difluoro-2-methyl-
1
3
-oxopropan-2-yl 4-nitrobenzoate (2h’)
(
lated alcohol 2h’ was purified by silica gel column chromatog- Hz, 1F), −123.882 (s, 2F); HRMS (APCI-TOF): [M]−· calcd for
raphy (EtOAc/hexane 1:50) as a white solid (32% yield for C15H12F7NO6, 435.0553; found, 435.0547; FTIR (neat, cm−1)
2
2
1
1
8
steps, 82% ee). 1H NMR (300 MHz, CDCl3) δ 8.34–8.31 (m, 1090, 1140, 1200, 1233, 1349, 1387, 1534, 1609, 1744, 1761,
H), 8.25–8.21 (m, 2H), 4.32 (q, 2H, J = 7.2 Hz), 2.02 (s, 3H), 2942, 2988, 3059; [α]D25 −22.60 (c 0.94, CHCl3); HPLC
.29 (t, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 164.3, (column, CHIRALCEL OJ-3, hexane/2-propanol 99:1, flow rate
62.4, 151.2, 134.3, 131.3, 123.9, 121.0 (t, JC-F = 311.6 Hz), 0.6 mL/min, 20 °C detection UV 220 nm) tR of major isomer
4.8 (dd, JC-F = 25.6, 23.4 Hz), 63.4, 18.4, 14.0; 19F NMR 12.2 min, tR of minor isomer 15.5 min.
(
282 MHz, CDCl3) δ −56.9 (d, 1F, J = 168.6 Hz), −58.9 (d, 1F,
(S)-1-Ethoxy-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,
J = 165.3 Hz); HRMS (APCI-TOF): [M]−· calcd for
10,10-heptadecafluoro-2-methyl-1-oxodecan-
C13H12BrF2NO6, 394.9816; found, 394.9835; FTIR (KBr
pellet, cm−1) 716, 843, 876, 961, 1020, 1106, 1146, 1280, 1347, 2-yl p-nitrobenzoate (3k’)
1
446, 1528, 1610, 1751, 2866, 2936, 2988; [α]D22 −11.99 (c The yield of alcohol 2k (92%) was determined by 19F NMR
1
.55, CHCl3); HPLC (column, CHIRALCEL OD-3, hexane/2- analysis. p-Nitrobenzoylated alcohol 2k’ was purified by silica-
propanol 91:9, flow rate 0.6 mL/min, 20 °C detection UV gel column chromatography (EtOAc/hexane 1:50) as a white
2
1
54 nm) tR of major isomer 18.2 min, tR of minor isomer solid (85% yield for 2 steps, 73% ee). 1H NMR (300 MHz,
2.5 min.
CDCl3) δ 8.36–8.31 (m, 2H), 8.20–8.16 (m, 2H), 4.36–4.29 (m,
H), 2.08 (s, 3H), 1.28 (t, 3H, J = 7.3 Hz); 13C NMR (75 MHz,
2
(
S)-1-Ethoxy-3,3,4,4,4-pentafluoro-2-methyl-
CDCl3) δ 164.3, 162.4, 151.2, 134.3, 131.2, 123.9, 118.4–104.7
(m), 117.3 (qt, JC-F = 288.4, 33.2 Hz), 82.8 (t, JC-F = 25.4 Hz),
1
-oxobutan-2-yl p-nitrobenzoate (2i’)
The yield of alcohol 2i (87%) was determined by 19F NMR 63.5, 17.1, 13.8; 19F NMR (282 MHz, CDCl3) δ –80.7 (m, 3F),
analysis. p-Nitrobenzoylated alcohol 2i’ was purified by silica –116.4 to −126.0 (m, 14F); HRMS (APCI-TOF): [M]−· calcd
gel column chromatography (EtOAc/hexane 1:40) as a white for C20H12F17NO6, 685.0393; found, 685.0362; FTIR (KBr
solid (48% yield for 2 steps, 86% ee). 1H NMR (300 MHz, pellet cm−1) 847, 969, 1009, 1142, 1214, 1246, 1297, 1472,
CDCl3) δ 8.35–8.30 (m, 2H) 8.21–8.16 (m, 2H), 4.37–4.27 (m, 1530, 1613, 1732, 1757, 2339, 2360, 2860, 2922, 2997, 3112,
2
H), 2.04 (q, JH-F = 0.6 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 3454, 3493; [α]D22 −11.93 (c 0.48, CHCl3); HPLC (column,
3C NMR (75 MHz, CDCl3) δ 164.2, 162.2 (d, JC-F = 2.0 Hz), CHIRALPAK AD-3 and AD-H, hexane/2-propanol 99.5:0.5,
1
1
1
1
51.0, 134.1, 131.0, 123.8, 118.6 (qt, JC-F = 286.1, 35.6 Hz), flow rate 0.6 mL/min, 20 °C detection UV 254 nm) tR of major
12.0 (tq, JC-F = 263.0, 36.8 Hz), 81.3 (t, JC-F = 25.4 Hz), 63.3, isomer 16.8 min, tR of minor isomer 24.4 min.
6.6, 13.7; 19F NMR (282 MHz, CDCl3) δ −79.19 (s, 3F),
−
121.42 (d, J = 280.9 Hz, 1F), −122.98 (d, J = 279.7 Hz, 1F);
Supporting Information
HRMS (APCI-TOF): [M]−· calcd for C14H12F5NO6, 385.0585;
found, 385.0582; FTIR (KBr pellet, cm−1) 1014, 1142, 1208,
Supporting Information File 1
1
222, 1281, 1350, 1385, 1533, 1747, 2942, 2987, 3059; [α]D25
27.75 (c 1.02, CHCl3); HPLC (column, CHIRALCEL OJ-3,
Experimental details and characterization data of new
compounds with copies of 1H, 13C and 19F NMR spectra.
−
hexane/2-propanol 99:1, flow rate 0.6 mL/min, 20 °C detection
[https://www.beilstein-journals.org/bjoc/content/
UV 220 nm) tR of major isomer 16.2 min, tR of minor isomer
supplementary/1860-5397-14-44-S1.pdf]
3
1.4 min.
(S)-1-Ethoxy-3,3,4,4,5,5,5-heptafluoro-2-
Acknowledgements
methyl-1-oxopentan-2-yl p-nitrobenzoate (2j’) This work was financially supported by JST (ACT-C: Ad-
The yield of alcohol 2j (98%) was determined by 19F NMR vanced Catalytic Transformation program for Carbon utiliza-
analysis. p-Nitrobenzoylated alcohol 2j’ was purified by silica- tion), JSPS KAKENHI Grant Number 25410036, and the
581

Beilstein J. Org. Chem. 2018, 14, 576–582.
2
2
2
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