Asymmetric fluorination of α-branched aldehydes by chiral primary amine catalysis: Reagent-controlled enantioselectivity switch

Article abstract of DOI:10.1021/acs.joc.8b00279

Asymmetric fluorination of α-branched aldehydes catalyzed by chiral primary amines under mild conditions has been developed. Both enantiomers could be obtained with good yields (up to 96%) and a high enantioselectivity (up to 90% ee) by a simple swap of t

Full text of DOI:10.1021/acs.joc.8b00279

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Asymmetric Fluorination of #-Branched Aldehydes by Chiral Primary
Amine Catalysis: Reagent-controlled Enantioselectivity Switch
Linfeng Cui, Yang'en You, Xueling Mi, and Sanzhong Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00279 • Publication Date (Web): 16 Mar 2018
Downloaded from http://pubs.acs.org on March 18, 2018
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Asymmetric Fluorination of αꢀBranched Aldehydes by Chiral Primary Amine Catalysis:
Reagentꢀcontrolled Enantioselectivity Switch
†
‡
,†
,‡
Linfeng Cui, Yang’en You, Xueling Mi* and Sanzhong Luo*
1
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†
College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China
‡
Key Laboratory for Molecular Recognition and Function, Institute of Chemistry, the Chinese Academy of Sciences,
Beijing 100190, China
Eꢀmail: xlmi@bnu.edu.cn; luosz@iccas.ac.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted)
O
S
O
S
Ph
O
Ph
O
OTf
N
F
N
F
O
O
O
R1
R1
R1
R2
H
H
H
R2
F
R2
F
N
N
S-
up to 90% ee
R-
up to 90% ee
NH2
NH2
Cat. B
Cat. A
Keywords: asymmetric fluorination, enantioselectivity switch, enamine catalysis, αꢀbranched aldehydes.
Abstract: Asymmetric fluorination of αꢀbranched aldehydes catalyzed by chiral primary amines under
mild conditions has been developed. Both enantiomers could be obtained with good yields (up to 96%) and
high enantioselectivity (up to 90% ee) by a simple swap of the fluorination reagents.
Stereoselective install of fluorine atom is of significant synthetic interests due to the prevalence of CꢀF
1
,2
bond in bioactive compounds. On this basis, tremendous efforts have been devoted to the development of
new methods for catalytic enantioselective construction of CꢀF bond. In this regard, aminocatalysis has
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become an enabling strategy for enantioselective αꢀCꢀF bond formation of carbonyls. In 2005, Jørgensen,
Barbas and MacMillan independently reported αꢀfluorination of linear aldehydes catalyzed by chiral
3
4
secondary amine catalysts. The same reaction has also received a plethora of further developments.
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However, αꢀbranched aldehydes remain difficult substrates despite of these advances. The lower tendency
to form enamine as well as the variable enamine geometry are two major issues impeding the enamine
5
reactions with αꢀbranched carbonyls including both ketones and aldehydes.
Chiral primary amines have been proved to be viable catalysts for the reactions with αꢀbranched
ketones/aldehydes. Recently, chiral primary amines have also been reported in the enantioselective
fluorination of αꢀbranched aldehydes. In 2006, Jørgensen reported a chiral amine catalyst for the reaction
6
of αꢀbranched aldehydes with good enantioselectivitiy, but low yields. In 2015, Jacobsen developed a
7
chiral primary amineꢀamide catalyst for the same reaction with improved activity. Very recently,
Shibatomi and coꢀworkers designed and synthesized a chiral binapthylꢀderived primary amine for
8
enantioselective fluorination of αꢀbranched aldehydes with generally good activity and enantioselectivity.
In principle, the stereospecific synthesis of both enantiomers of an organic compound requires the
1
1
employment of both enantiomers of a chiral catalyst, respectively. The use of a single chiral catalyst to
abtain both enantiomers of products is an attractive yet challenging aim in asymmetric catalysis, and
1
2
enantioselective switch with a single chiral resource has been actively pursued for this end. Recently, we
reported a chiral primary amine catalyzed asymmetric fluorination of βꢀketocarbonyls and simple swap of
9
,10
the fluoroꢀreagents led to opposite chiral induction with the same chiral primary amine catalyst.
This
reagentꢀswitching enantioselective fluorination was further explored in the αꢀfluorination of αꢀbranched
aldehydes. Herein, we reported a reagentꢀswitching enantioselective fluorination of αꢀbranched aldehydes
(Scheme 1).
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SCHEME 1. Asymmetric fluorination of aldehydes under enamine catalysis.
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Initially, we treated 2ꢀphenylpropionaldehyde 1a with fluorination reagent 2 in the presence of 20 mol%
3
of catalyst I/DNBA in CHCl for 12 h. Although the process proved to be feasible, no switch of chiral
induction was noted among different fluorination reagents (Table 1, entries 1ꢀ3). When we performed the
reaction in MeOH, the switch of enantioselectivity was clearly observed (Table 1, entries 5 and 6 vs entries
2
and 3). The use of cationic fluoroꢀreagents 2b and 2c led to opposite chiral induction compared to that
with a neutral reagent 2a. The reagent 2a and 2b were selected for the subsequent optimization. We then
found that using trifluoromethanesulfonic acid as coꢀcatalyst led to slightly better results (entries 7 and 8).
Further optimization of the reaction conditions was carried out by examing different solvents. It was found
that Rꢀselective process with 2a worked favorably in lowꢀpolar solvents such as CHCl , whereas
3
strongꢀpolar or protonic solvents favored the Sꢀselective process with 2b. The switch of solvent from
3
CHCl to methanol could even reverse the chiral induction with same fluorinated reagents (entries 2 and 3,
vs entries 5 and 6, respectively), indicating two coꢀexisting and competing stereoꢀcontrolling interactions
for this reaction. DMF was identified as the optimal solvent for the Sꢀselective process (entry 11).
Different chiral primary amine catalysts were then screened in order to improve the enantioselectivity.
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Gratifyingly, upon changing the propyl secondary amine moiety to dimethyl tertiary amine, good values of
enantioselectivity were reached for Rꢀselective process (entry 9). A bulky diisopropyl tertiary amino group
was found to favor the Sꢀselective process (entry 12). The use of
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a
Table 1. Optimization of the reaction conditions
b
c
Entry
Amine catalyst Fluorination reagent
Solvent
Yield (%)
ee (%)
1
2
I/DNBA
I/DNBA
I/DNBA
I/DNBA
I/DNBA
I/DNBA
I/HOTf
2a
2b
2c
2a
2b
2c
2a
2b
2a
2b
2b
2b
2d
2a
2b
CHCl
3
66
43
74 (Rꢀ)
23
CHCl
3
3
CHCl3
MeOH
MeOH
MeOH
76
42
4
52
22
5
56
ꢀ64 (Sꢀ)
ꢀ39
79
6
72
7
CHCl
MeOH
CHCl
3
66
8
I/HOTf
62
ꢀ70
86
9
II/HOTf
II/HOTf
I/HOTf
3
81
10
MeOH
DMF
DMF
DMF
42
ꢀ53
ꢀ72
ꢀ86
ꢀ73
85
11
42
1
1
2
3
IV/HOTf
IV/HOTf
II/HOTf
IV/HOTf
46
34
d
14
CHCl
3
92(86)
84(82)
d
1
5
DMF
ꢀ85
a
All reactions were carried out with 1.5 equivalent of fluorination reagent
2
and 20 mol% of amine catalyst respect to
b
2
ꢀphenylpropionaldehyde 1a (0.10 mmol) in 0.5 ml solvent unless otherwise noted. DNBA: 2,4ꢀdinitrobenzoic acid. Yields were determined
1
c
by H NMR with 1,3,5ꢀtrimethoxybenzene as an internal standard. The yields in the parentheses are isolated. Determined by HPLC on a
d
chiral stationary phase. Reaction conditions: 1a (0.36 mmol), 2 (0.30 mmol), amine catalyst (20 mol%) in solvent (1.5 mL) at room
temperature for 12 h.
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unsubstituted pyridinium 2d showed slightly lower enantioselectivity (entry 13), indicating steric effect in
this case. The reaction could be conducted at 0.3 mmol scale with similar outcome (entries 14 and 15).
Thus, we have optimized the parameters required for optimal results. For the Rꢀselective process, the best
reaction condition is treating 2a with 1.2 equivalent of 1a in the presence of amine catalyst II/ HOTf (1:1)
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in CHCl at room temperature for 12 h, providing the product with 86% yield and 85% ee. For the
Sꢀselective process, the best reaction condition is treating 2b with 1.2 equiv. of 1a in the presence of amine
catalyst IV/ HOTf in DMF at room temperature for 12 h, providing the product with 82% yield and ꢀ85%
ee.
With the optimal results in hand, we firstly investigated the substrates scope for the Rꢀselective process.
a
Table 2. Scope of products
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a
General conditions: 1a (0.36 mmol), 2 (0.3 mmol), amine catalyst (20 mol%) in solvent at room temperature for 12 h. Absolute
configurations assigned based on comparison of optical rotations to published data. Isolated yield of 4 are described. Ee was determined by
b
GC or HPLC on a chiral stationary phase. Ee after recrystallization.
As shown in Table 2, a variety of αꢀalkylꢀαꢀaryl aldehydes bearing either electronꢀwithdrawing or
electronꢀdonating groups on the aryl ring were examined in present fluorination reaction with good yields
and high enantioselectivity (Table 2, 4aꢀ4g). Orthoꢀsubstituted aryl aldehydes such as 1h and 1k afforded
the products (4h and 4k) with inferior activity or enantioselectivity. Electronꢀrich aryl aldehyde 1l showed
good reactivity, however, the desired product could not be isolated likely due to its instability. An αꢀethyl
aldehyde 1o could also be applied with 81% yield and 60% ee. 2ꢀ(Pyridinꢀ2ꢀyl)propanal has also been
examined, showing unfortunately no reaction in both cases, and it is likely the basicity of pyridine moiety is
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detrimental to the electrophilic reaction. The reaction also worked well with a cyclic aldehyde 1p with 52%
yield and 86% ee. α, αꢀDialkyl aldehydes such as 1q and 1r have also been examined in the reactions,
showing unfortunately poor activity and enantioselectivity (4q and 4r).
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In the Sꢀselective reactions, we also tested the same substrates scope. The switch of enantioselectivity
took place in all cases. In most instances, the results were comparable to those obtained in the Rꢀselective
reactions. As shown with 4b, enantiomeric excess for both enantiomers could be enriched by a single
recrystallization from hexane.
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,9,10
On the basis of previous studies,
we proposed a Hꢀbonding mode (I) and an electrostatic repulsion
mode (II) to account for the R- and S- selectivity, respectively (Scheme 2). Chiral primary amine catalyst
would react with αꢀbranched aldehyde to form predominantly Eꢀenamine intermediate. Hꢀbonding between
the protonated tertiary amine and sulfonyl group of NFSI would facilitate Reꢀfacial fluorination. On the
other hand, a mixed steric and charge repulsion effect would disfavor the Reꢀfacial attack and push the
cationic Nꢀfluoropyridinium moiety for Siꢀfacial fluorination. The observed polar solvent effect is clearly
SCHEME 2. Proposed transition states.
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in line with this electrostatic repulsion effect, as polar reaction media would favor charge associated
interactions (Table 1, entries 1ꢀ6). In addition, the observation that less hindered NFPy 2d led to lower ee
(73% ee, Table 1, entry 13) provides further evidence to the charge repulsion mode.
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In conclusion, we have developed an organocatalytic asymmetric fluorination of αꢀbranched aldehydes 1.
By using two different fluorination reagents, opposite chiral induction could be achieved by the same
configured chiral primary amine catalyst with good yields and high enantioselectivity.
Experimental section
General Methods. All commercial reagents were used without further purification unless otherwise
noted. The corresponding aldehydes were prepared according to reported procedures. NMR spectra were
1
recorded on Bruker AV 400 and Bruker Avance 500 spectrometers. H NMR spectra were obtained at 400
13
3
or 500 MHz in CDCl unless otherwise noted. C NMR spectra were obtained at 101 or 126 MHz using a
protonꢀdecoupled pulse sequence and are tabulated by observed peak. Chemical shifts were reported in
parts per million (ppm) and referenced to 7.27 and 77.00 ppm respectively. Coupling constants were
expressed in Hertz (Hz). The following abbreviations were used: s = singlet, d = doublet, t = triplet, q =
1
9
quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, br = broad. F spectra were
obtained at 377 MHz using a protonꢀdecoupled pulse sequence in the presence of fluorobenzene as an
internal standard. High resolution mass spectra were obtained using electrospray ionization (APCI and EI).
The enantiomeric excesses were determined by HPLC analysis on Chiral Daicel Chiralpak ODꢀH, OJꢀH,
ASꢀH, ADꢀH or GC analysis on chiral stationary phases (CYCLOSILꢀB: 30mm · 0.250mm). Optical
2
5
rotation were measured on a commercial polarimeter and reported as follows: [α]D (c = g/100 mL,
solvent).
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General Procedure (A) for the Synthesis of (R)ꢀαꢀBranched Aldehydes: To a flameꢀdried tube
equipped with a magnetic stir bar were added αꢀbranched aldehyde (1, 0.36 mmol), amine catalyst
(
II/HOTf, 18mg, 0.06 mmol) and NFSI (2a, 94.5 mg, 0.30 mmol). The resulting mixture was then diluted
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with 1.5 mL of CHCl . The reaction was conducted at room temperature for 12 h, then poured into MeOH
3
4
(2 mL) at 0 °C. To this solution, NaBH (114 mg, 3.0 mmol, 10 equiv.) was added, and the mixture was
stirred at room temperature for 1 h. The reaction was quenched with saturated aq. NH Cl, and the mixture
4
2 2 2 4
was extracted with CH Cl (5 mL х 3). The organic layers were combined and dried over Na SO ,
2
concentrated, and chromatographed on silica gel with hexane:Et O solution (5:1 to 1:1) to give (R)ꢀ4.
General Procedure (B) for the Synthesis of (S)ꢀαꢀBranched Aldehydes: To a flameꢀdried tube
equipped with a magnetic stir bar were added αꢀbranched aldehyde (1, 0.36 mmol), amine catalyst
(IV/HOTf, 21mg, 0.06 mmol) and NFCOꢀOTf (2b, 86.7 mg, 0.30 mmol). The resulting mixture was diluted
with 1.5 mL of DMF. The reaction was conducted at room temperature for 12 h, then poured into MeOH (2
4
mL) at 0 °C. To this solution, NaBH (114 mg, 3.0 mmol, 10 equiv) was added, and the mixture was stirred
4
at room temperature for 1 h. The reaction was quenched with saturated aq. NH Cl, and the mixture was
2 2 2 4
extracted with CH Cl (5 mL х 3). The organic layers were combined and dried over Na SO , concentrated,
and chromatographed on silica gel with hexane:Et O solution (5:1 to 1:1) to give (S)ꢀ4.
2
2
ꢀfluoroꢀ2ꢀphenylpropanꢀ1ꢀol (4a): Following the procedure (A and B), the crude mixture was
purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4a (40.2 mg, 87%)
ꢀ1
and (S)ꢀ4a (36.9 mg, 80%) as colorless oil: IR (thin film, cm ) 3380 (br), 2961, 2928, 1496, 1448, 1379,
1
1028, 762; H NMR (500 MHz, CDCl
3
) δ 7.43 ꢀ 7.29 (m, 5 H), 3.97 ꢀ 3.59 (m, 2 H), 1.85 ꢀ 1.77 (m, 1 H),
13
1
.70 (d, J = 22.6 Hz, 3 H); C NMR (126 MHz, CDCl ) δ 141.6 (d, J = 21.4 Hz), 128.6 (d, J = 1.3 Hz),
3
19
128.0, 124.6 (d, J = 9.3 Hz), 98.0 (d, J = 172.2 Hz), 69.7 (d, J = 25.1 Hz), 23.3 (d, J = 24.6 Hz); F NMR
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(
377 MHz, CDCl ) δ ꢀ157.2 (s); HPLC analysis: Daicel Chiralpak ASꢀH, flow rate =1.0 ml/min, λ=210 nm,
3
25
hexane/isoꢀpropanol = 98:2, (R)ꢀ4a: 85% ee; [α]
D
= ꢀ10.5 (c = 1.10, CHCl
3
), retention time: 12.8 min
25
(
minor) and 14.6 min (major); (S)ꢀ4a: 85% ee; [α]
D
= 9.8 (c = 1.05, CHCl ), retention time: 12.6 min
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(major) and 14.4 min (minor); The spectroscopic data for 4a matched those described in the literature; For
23
D
7
the Rꢀenantiomer 80% ee; [α]
= ꢀ9.4 (c = 1.1, CHCl
3
) is reported in the literature. For the Sꢀenantiomer
2
2
8
9
5% ee; [α]D = 14.3 (c = 0.87, CHCl ) is reported in the literature.
3
2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀfluoropropanꢀ1ꢀol (4b): Following the procedure (A and B), the crude mixture
was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4b (52.6 mg,
ꢀ1
9
3%) and (S)ꢀ4b (46.4 mg, 82%) as white solid: IR (thin film, cm ) 3361(br),2995, 2924, 1599, 1493,
1
1
403, 1369, 1255, 1129, 1090, 751; H NMR (500 MHz, CDCl
3
) δ 7.36 (d, J = 8.5 Hz, 2 H), 7.31 (t, J = 5.8
1
3
Hz, 2 H), 3.88 – 3.66 (m, 2 H), 1.81 (s, 1 H), 1.68 (d, J = 22.6 Hz, 3 H); C NMR (126 MHz, CDCl ) δ
3
1
40.2 (d, J = 22.1 Hz), 134.0, 128.8 (d, J = 1.1 Hz), 126.1 (d, J = 9.3 Hz), 97.7 (d, J = 172.9 Hz), 69.5 (d, J
19
= 25.2 Hz), 23.3 (d, J = 24.6 Hz); F NMR (377 MHz, CDCl
3
) δ ꢀ156.82 (s); HPLC analysis: Daicel
25
Chiralpak ADꢀH, flow rate =1.0 ml/min, λ=210 nm, hexane/isoꢀpropanol = 95:5, (R)ꢀ4b: 85% ee; [α]
D
=
=
25
3
ꢀ11.6 (c = 1.45, CHCl ), retention time: 11.5 min (major) and 15.4 min (minor); (S)ꢀ4b: 86% ee; [α]
D
1
2.5 (c = 1.55, CHCl ), retention time: 11.5 min (minor) and 15.4 min (major); (R)ꢀ4b(after recrystallized
3
from pentane): 99 % ee; retention time: 11.3 min (major) and 14.6 min (minor); (S)ꢀ4b(after recrystallized
from pentane): 97 % ee; retention time: 11.3 min (major) and 14.6 min (minor); The spectroscopic data for
7
4
b matched those described in the literature.
2ꢀfluoroꢀ2ꢀ(3ꢀnitrophenyl)propanꢀ1ꢀol (4c): Following the procedure (A and B), the crude mixture was
purified by silica gel column chromatography (hexane : diethyl ether = 1:1) to give (R)ꢀ4c (53.7 mg, 90%)
ꢀ1
and (S)ꢀ4c (54.9 mg, 92%) as yellow oil: IR (thin film, cm ) 3388(br), 2987, 2925, 1582, 1530, 1481, 1456,
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251, 1110, 843; H NMR (400 MHz, CDCl ) δ 8.24 (t, J = 1.8 Hz, 1 H), 8.18 (ddd, J = 8.1, 2.0, 0.8 Hz, 1
3
H), 7.71 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 3.94 – 3.73 (m, 2 H), 2.08 (s, 1 H), 1.73 (d, J = 22.5
13
Hz, 3 H); C NMR (101 MHz, CDCl
3
) δ 148.5, 144.0 (d, J = 22.7 Hz), 130.9 (d, J = 9.2 Hz), 129.7, 123.0,
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1
1
1
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0
1
2
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4
5
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0
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4
5
6
7
8
9
0
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4
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8
9
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0
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9
0
19
120.0 (d, J = 10.5 Hz), 97.4 (d, J = 174.7 Hz), 69.2 (d, J = 25.1 Hz), 23.4 (d, J = 24.4 Hz); F NMR (377
+
MHz, CDCl
3
) δ ꢀ156.93; HRMS (APCIꢀorbitrap) m/z: [M + H] Calcd for C
9
H11FNO
3
200.0717; Found
2
00.0710; HPLC analysis: Daicel Chiralpak OJꢀH, flow rate =0.5 ml/min, λ=210 nm, hexane/isoꢀpropanol
25
=
95:5, (R)ꢀ4c: 84% ee; [α]
D
3
= ꢀ8.2 (c = 1.20, CHCl ), retention time: 60.7 min (major) and 63.7 min
2
D
5
(
(
minor); (S)ꢀ4c: 87% ee; [α]
= 9.2 (c = 1.65, CHCl ), retention time: 61.2 min (minor) and 62.8 min
3
major).
2
ꢀfluoroꢀ2ꢀ(4ꢀfluorophenyl)propanꢀ1ꢀol (4d): Following the procedure (A and B), the crude mixture
was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4d (44.9 mg,
ꢀ1
8
7%) and (S)ꢀ4d (43.3 mg, 84%) as colorless oil: IR (thin film, cm ) 3366(br), 2932, 1605, 1512, 1456,
1
1408, 1232, 1192, 1015, 724; H NMR (400 MHz, CDCl
3
) δ 7.39 – 7.30 (m, 2 H), 7.07 (t, J = 8.5 Hz, 2 H),
13
3
.90 – 3.67 (m, 2 H), 1.84 (t, J = 6.6 Hz, 1 H), 1.69 (d, J = 22.6 Hz, 3 H); C NMR (126 MHz, CDCl
3
)
δ162.5 (d, J = 248.1 Hz), 137.5 (dd, J = 22.2, 3.2 Hz), 129.1 – 123.4 (m), 115.5 (d, J = 22.4 Hz), 97.7 (d, J
1
9
=
172.3 Hz), 69.7 (d, J = 25.4 Hz), 23.4 (d, J = 24.6 Hz); F NMR (377 MHz, CDCl ) δ ꢀ114.68, ꢀ155.76;
3
HPLC analysis: Daicel Chiralpak ADꢀH, flow rate =1 ml/min, λ=210 nm, hexane/isoꢀpropanol = 95:5,
25
(
(
R)ꢀ4d: 78% ee; [α]
D
3
= ꢀ9.1 (c = 1.50, CHCl ), retention time: 11.2 min (major) and 13.0 min (minor);
25
S)ꢀ4d: 84% ee; [α]
D
3
= 10.2 (c = 1.30, CHCl ), retention time: 11.2 min (minor) and 12.9 min (major);
8
The spectroscopic data for 4c matched those described in the literature.
2
ꢀfluoroꢀ2ꢀ(naphthalenꢀ1ꢀyl)propanꢀ1ꢀol (4e): Following the procedure (A and B), the crude mixture
was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4e (50.2 mg,
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ꢀ
1
8
2%) and (S)ꢀ4e (51.4 mg, 84%) as colorless oil: IR (thin film, cm ) 3384(br), 3051, 2932, 1599, 1510,
1
1455, 1381, 1189, 775; H NMR (400 MHz, CDCl
3
) δ 8.31 (d, J = 8.1 Hz, 1 H), 7.91 – 7.79 (m, 2 H), 7.58
(
d, J = 7.3 Hz, 1 H), 7.54 – 7.41 (m, 3 H), 4.37 – 3.97 (m, 2 H), 1.97 (d, J = 23.1 Hz, 3 H), 1.97 (s, 1 H);
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8
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
C NMR (101 MHz, CDCl
3
) δ 136.6 (d, J = 19.3 Hz), 134.8, 130.4, 129.7, 129.4, 126.3, 125.6, 125.6,
19
1
25.0, 124.0 (d, J = 12.3 Hz), 99.7 (d, J = 170.8 Hz), 68.8 (d, J = 25.0 Hz), 23.9 (d, J = 25.6 Hz); F NMR
(
377 MHz, CDCl ) δ ꢀ146.46 (s); HPLC analysis: Daicel Chiralpak ASꢀH, flow rate =1 ml/min, λ=280 nm,
3
25
hexane/isoꢀpropanol = 95:5, (R)ꢀ4e: 86% ee; [α]
D
3
= 5.1 (c = 1.30, CHCl ), retention time: 17.5 min (major)
25
and 21.3 min (minor); (S)ꢀ4e: 69% ee; [α]
D
= ꢀ3.3 (c = 1.73, CHCl
3
), retention time: 17.4 min (minor) and
7
2
1.2 min (major); The spectroscopic data for 4e matched those described in the literature.
2
ꢀfluoroꢀ2ꢀ(naphthalenꢀ2ꢀyl)propanꢀ1ꢀol (4f): Following the procedure (A and B), the crude mixture
was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4f (58.7 mg,
ꢀ1
9
6%) and (S)ꢀ4f (51.4 mg, 84%) as white solid: IR (thin film, cm ) 3377(br), 2984, 2930, 1601, 1507, 1455,
1
1379, 1194, 1050, 747; H NMR (400 MHz, CDCl
3
) δ 7.91 – 7.79 (m, 4 H), 7.55 – 7.48 (m, 2 H), 7.45 (dd,
13
J = 8.7, 1.6 Hz, 1 H), 4.03 – 3.73 (m, 2 H), 2.00 (s, 1 H), 1.80 (d, J = 22.6 Hz, 3 H); C NMR (101 MHz,
CDCl
3
) δ 139.0 (d, J = 21.5 Hz), 133.2, 132.9, 128.4, 128.3, 127.7, 126.6, 126.4, 123.8, 123.7, 122.6 (d, J =
19
8
.4 Hz), 98.2 (d, J = 172.5 Hz), 69.6 (d, J = 25.2 Hz), 23.4 (d, J = 24.7 Hz); F NMR (377 MHz, CDCl ) δ
3
ꢀ
156.55 (s); HPLC analysis: Daicel Chiralpak ODꢀH, flow rate =1.0 ml/min, λ=210 nm,
25
D
hexane/isoꢀpropanol = 97:3, (R)ꢀ4f: 85% ee; [α]
3
= ꢀ14.2 (c = 1.95, CHCl ), retention time: 20.8 min
2
D
5
(
minor) and 24.8 min (major); (S)ꢀ4f: 88% ee; [α]
= 14.7 (c = 2.00, CHCl
3
), retention time: 20.6 min
7
(major) and 24.6 min (minor); The spectroscopic data for 4f matched those described in the literature.
2
ꢀfluoroꢀ2ꢀ(4ꢀnitrophenyl)propanꢀ1ꢀol (4g): Following the procedure (A and B), the crude mixture was
purified by silica gel column chromatography (hexane : diethyl ether = 2:1) to give (R)ꢀ4g (50.2 mg, 84%)
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ꢀ
1
and (S)ꢀ4g (48.9 mg, 82%) as yellow oil: IR (thin film, cm ) 3443(br),2928, 1607, 1521, 1456, 1409, 1186,
1
1098, 1054, 755; H NMR (400 MHz, CDCl
3
) δ 8.24 (d, J = 8.5 Hz, 2 H), 7.54 (d, J = 8.8 Hz, 2 H), 3.93 –
13
3
.76 (m, 2 H), 2.00 (t, J = 6.7 Hz, 1 H), 1.71 (d, J = 22.5 Hz, 3 H); C NMR (126 MHz, CDCl
3
) δ 148.9 (d,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
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6
7
8
9
0
J = 22.1 Hz), 147.7, 125.8 (d, J = 9.8 Hz), 123.8 (d, J = 1.5 Hz), 97.7 (d, J = 175.1 Hz), 69.2 (d, J = 24.9
19
Hz), 23.4 (d, J = 24.5 Hz); F NMR (377 MHz, CDCl
3
) δ ꢀ157.51 (s); HPLC analysis: Daicel Chiralpak
25
ODꢀH, flow rate =1.0 ml/min, λ=210 nm, hexane/isoꢀpropanol = 95:5, (R)ꢀ4g: 83% ee; [α]D = ꢀ15.4 (c =
25
1
2
.90, CHCl
3
), retention time: 10.6 min (minor) and 11.8 min (major); (S)ꢀ4g: 87% ee; [α]
D
= 17.8 (c =
.60, CHCl
3
), retention time: 10.6 min (major) and 11.7 min (minor); The spectroscopic data for 4g
7
matched those described in the literature.
2
ꢀ(2ꢀbromophenyl)ꢀ2ꢀfluoropropanꢀ1ꢀol (4h): Following the procedure (A and B), the crude mixture
was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4h (55.9 mg,
ꢀ1
8
0%) and (S)ꢀ4h (52.4 mg, 75%) as yellow oil: IR (thin film, cm ) 3373(br), 2931, 2873, 1469, 1432, 1375,
1
1274, 1041, 1732; H NMR (400 MHz, CDCl
3
) δ 7.66 (dd, J = 8.0, 1.6 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H),
7
.40 – 7.33 (m, 1 H), 7.17 (td, J = 7.8, 1.6 Hz, 1 H), 4.19 (dddd, J = 23.8, 20.1, 12.6, 6.9 Hz, 2 H), 1.85 (d,
1
3
J = 24.4 Hz, 3 H), 1.81 (s, 1 H); C NMR (126 MHz, CDCl
3
) δ140.3 (d, J = 22.0 Hz), 135.0 (d, J = 2.2 Hz),
1
2
29.6, 127.9 (d, J = 17.2 Hz), 127.8, 118.6 (d, J = 5.2 Hz), 99.1 (d, J = 173.1 Hz), 67.0 (d, J = 23.4 Hz),
1
9
+
3
1.8 (d, J = 25.1 Hz); F NMR (377 MHz, CDCl ) δ ꢀ147.05 (s); HRMS (EIꢀTOF) m/z: [M] Calcd for
9
C H10BrFO 231.9899, 233.9879; Found 231.9901, 233.9878; HPLC analysis: Daicel Chiralpak OJꢀH, flow
2
5
rate =1.0 ml/min, λ=210 nm, hexane/isoꢀpropanol = 97:3, (R)ꢀ4h: 74% ee; [α]
D
= ꢀ 0.2 (c = 1.00, CHCl
3
),
),
2
D
5
retention time: 16.1 min (minor) and 17.2 min (major); (S)ꢀ4h: 78% ee; [α]
= 0.4 (c = 1.75, CHCl
3
retention time: 16.0 min (major) and 17.1 min (minor).
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ꢀfluoroꢀ2ꢀ(pꢀtolyl)propanꢀ1ꢀol (4i): Following the procedure (A and B), the crude mixture was purified
by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4i (45.3 mg, 90%) and (S)ꢀ4i
ꢀ1
(
40.8 mg, 81%) as colorless oil: IR (thin film, cm ) 3374 (br), 2984, 2924, 1615, 1515, 1455, 1378, 1189,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
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1
2
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7
8
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0
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4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
1052, 772; H NMR (400 MHz, CDCl
3
) δ 7.29 – 7.22 (m, 2 H), 7.19 (d, J = 8.2 Hz, 2 H), 3.93 – 3.62 (m, 2
13
H), 2.35 (s, 3 H), 1.77 (ddd, J = 8.1, 5.6, 1.1 Hz, 1 H), 1.69 (d, J = 22.6 Hz, 3 H); C NMR (101 MHz,
CDCl ) δ138.7 (d, J = 21.8 Hz), 137.8, 129.3 (d, J = 1.1 Hz), 124.6 (d, J = 9.0 Hz), 98.0 (d, J = 171.7 Hz),
3
19
6
9.8 (d, J = 25.3 Hz), 23.3 (d, J = 24.6 Hz), 21.2; F NMR (377 MHz, CDCl
3
) δ ꢀ156.31 (d, J = 6.0 Hz);
HPLC analysis: Daicel Chiralpak ADꢀH, flow rate =1.0 ml/min, λ=210 nm, hexane/isoꢀpropanol = 95:5,
2
D
5
(
(
R)ꢀ4i: 85% ee; [α]
3
= ꢀ 12.8 (c = 1.80, CHCl ), retention time: 12.9 min (minor) and 15.1 min (major);
25
S)ꢀ4i: 84% ee; [α]
D
3
= 11.5 (c = 1.65, CHCl ), retention time: 12.9 min (major) and 15.1 min (minor); The
7
spectroscopic data for 4i matched those described in the literature.
2ꢀfluoroꢀ2ꢀ(mꢀtolyl)propanꢀ1ꢀol (4j): Following the procedure (A and B), the crude mixture was
purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4j (41.3 mg, 82%)
ꢀ1
and (S)ꢀ4j (44.3 mg, 88%) as colorless oil: IR (thin film, cm ) 3384(br), 2984, 2866, 1609, 1489, 1455,
1
1
3
3
1
378, 1120, 1053, 785; H NMR (400 MHz, CDCl
3
) δ 7.27 (t, J = 7.9 Hz, 1 H), 7.15 (dd, J = 15.6, 7.9 Hz,
H), 3.79 (ddd, J = 37.5, 20.5, 12.3 Hz, 2 H), 2.37 (d, J = 5.6 Hz, 3 H), 1.90 (s, 1 H), 1.68 (d, J = 22.7 Hz,
1
3
H); C NMR (101 MHz, CDCl
21.6 (d, J = 9.2 Hz), 98.0 (d, J = 172.2 Hz), 69.7 (d, J = 25.2 Hz), 23.3 (d, J = 24.7 Hz), 21.7; F NMR
377 MHz, CDCl ) δ ꢀ156.91 (s); HPLC analysis: Daicel Chiralpak ASꢀH, flow rate =1.0 ml/min, λ=210
3
) δδ 141.6 (d, J = 21.3 Hz), 138.3, 128.7,128.5, 125.2 (d, J = 9.3 Hz),
19
(
3
25
nm, hexane/isoꢀpropanol = 95:5, (R)ꢀ4j: 84% ee; [α]
D
3
= ꢀ 8.4 (c = 1.10, CHCl ), retention time: 8.8 min
25
(
minor) and 9.5 min (major); (S)ꢀ4j: 87% ee; [α]D = 8.6 (c = 1.75, CHCl ), retention time: 8.8 min (major)
3
7
and 9.5 min (minor); The spectroscopic data for 4j matched those described in the literature.
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ꢀfluoroꢀ2ꢀ(oꢀtolyl)propanꢀ1ꢀol (4k): Following the procedure (A and B), the crude mixture was
purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4k (14.1 mg, 28%)
ꢀ1
and (S)ꢀ4k (20.2 mg, 40%) as colorless oil: IR (thin film, cm ) 3365(br), 2964, 2931, 1490, 1457, 1381,
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1100, 1011, 758; H NMR (500 MHz, CDCl
3
) δ 7.34 – 7.29 (m, 1 H), 7.23 – 7.16 (m, 3 H), 3.94 (dddd, J =
2
3.2, 20.7, 12.5, 6.9 Hz, 2 H), 2.48 (d, J = 3.7 Hz, 3 H), 1.85 – 1.79 (m, 1 H), 1.75 (d, J = 23.0 Hz, 3 H);
13
C NMR (126 MHz, CDCl ) δ139.0 (d, J = 20.3 Hz), 135.4, 132.7, 128.2, 126.1 (d, J = 1.7 Hz), 125.9 (d, J
3
19
=
11.8 Hz), 99.5 (d, J = 171.4 Hz), 68.5 (d, J = 24.7 Hz), 23.2 (d, J = 25.6 Hz), 21.8 (d, J = 7.5 Hz); F
NMR (377 MHz, CDCl
3
) δ ꢀ150.65 (s); HPLC analysis: Daicel Chiralpak ASꢀH, flow rate =1.0 ml/min,
25
λ=210 nm, hexane/isoꢀpropanol = 98:2, (R)ꢀ4k: 86% ee; [α]
D
3
= ꢀ 1.4 (c = 1.20, CHCl ), retention time:
25
D
1
5.1 min (minor) and 16.7 min (major); (S)ꢀ4k: 75% ee; [α]
= 0.5 (c = 1.35, CHCl
3
), retention time: 14.9
7
min (major) and 16.5 min (minor); The spectroscopic data for 4k matched those described in the literature.
2ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ2ꢀfluoropropanꢀ1ꢀol (4m): Following the procedure (A and B), the crude
mixture was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4m
ꢀ1
(
57.3 mg, 83%) and (S)ꢀ4m (49.7 mg, 72%) as white solid: IR (thin film, cm ) 3361 (br), 2918, 2850, 1488,
1
1
403, 1258, 1051, 726; H NMR (400 MHz, CDCl
3
) δ 7.61 (dd, J = 10.0, 7.9 Hz, 4 H), 7.45 (dd, J = 7.7,
13
5
.7 Hz, 4 H), 7.36 (t, J = 7.3 Hz, 1 H), 3.98 – 3.70 (m, 2 H), 1.87 (s, 1 H), 1.75 (d, J = 22.6 Hz, 3 H); C
NMR (101 MHz, CDCl
3
) δ140.9 (d, J = 24.3 Hz), 140.7, 140.5, 129.0, 127.6, 127.4, 127.3, 125.1 (d, J =
1
9
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.2 Hz), 98.0 (d, J = 172.2 Hz), 69.7 (d, J = 25.2 Hz), 23.4 (d, J = 24.7 Hz); F NMR (377 MHz, CDCl
3
) δ
ꢀ
156.79 (s); HPLC analysis: Daicel Chiralpak ADꢀH, flow rate =1 ml/min, λ=210 nm, hexane/isoꢀpropanol
25
D
= 95:5, (R)ꢀ4m: 90% ee; [α]
3
= ꢀ19.7 (c = 0.40, CHCl ), retention time: 17.6 min (major) and 21.0 min
25
(
minor); (S)ꢀ4m: 87% ee; [α]D = 16.6 (c = 1.60, CHCl ), retention time: 17.6 min (minor) and 20.9 min
3
7
(major); The spectroscopic data for 4m matched those described in the literature.
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ꢀ(3ꢀbromophenyl)ꢀ2ꢀfluoropropanꢀ1ꢀol (4n): Following the procedure (A and B), the crude mixture
was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4n (58.2 mg,
ꢀ1
8
4%) and (S)ꢀ4n (52.6 mg, 76%) as yellow oil: IR (thin film, cm ) 3360 (br), 2985, 2927, 1596, 1568,
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1477, 1417, 1121, 1053, 784; H NMR (500 MHz, CDCl
3
) δ 7.53 (t, J = 2.8 Hz, 1 H), 7.45 (dt, J = 7.0, 1.8
Hz, 1 H), 7.30 – 7.24 (m, 2 H), 3.89 – 3.68 (m, 2 H), 1.92 (t, J = 6.8 Hz, 1 H), 1.67 (d, J = 22.6 Hz, 3 H);
13
C NMR (101 MHz, CDCl ) δ144.0 (d, J = 22.0 Hz), 131.1, 130.2, 127.9 (d, J = 10.3 Hz), 123.3 (d, J =
3
19
9
.1 Hz), 122.9, 97.4 (d, J = 174.0 Hz), 69.5 (d, J = 25.0 Hz), 23.3 (d, J = 24.6 Hz); F NMR (377 MHz,
CDCl ) δ ꢀ157.13 (s); HPLC analysis: Daicel Chiralpak ASꢀH, flow rate =1.0 ml/min, λ=210 nm,
3
25
D
hexane/isoꢀpropanol = 95:5, (R)ꢀ4n: 85% ee; [α]
3
= ꢀ 7.4 (c = 1.20, CHCl ), retention time: 10.7 min
25
(
minor) and 12.1 min (major); (S)ꢀ4n: 85% ee; [α]
D
3
= 7.7 (c = 1.85, CHCl ), retention time: 10.6 min
7
(major) and 12.1 min (minor); The spectroscopic data for 4n matched those described in the literature.
2ꢀfluoroꢀ2ꢀphenylbutanꢀ1ꢀol (4o): Following the procedure (A and B), the crude mixture was purified
by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4o (40.8 mg, 81%) and
ꢀ1
(
S)ꢀ4o (41.3 mg, 82%) as colorless oil: IR (thin film, cm ) 3377 (br), 2973, 2934, 1496, 1448, 1340, 1146,
1
1
058, 1023, 759; H NMR (500 MHz, CDCl
3
) δ 7.39 (t, J = 7.6 Hz, 2 H), 7.35 – 7.28 (m, 3 H), 3.97 – 3.68
13
(
m, 2 H), 2.25 – 2.06 (m, 1 H), 1.99 – 1.82 (m, 1 H), 1.75 (t, J = 6.8 Hz, 1 H), 0.82 (t, J = 7.4 Hz, 3 H); C
NMR (126 MHz, CDCl ) δ139.9 (d, J = 21.9 Hz), 128.6 (d, J = 1.7 Hz), 127.8, 125.0 (d, J = 10.1 Hz),
3
1
9
1
00.5 (d, J = 175.6 Hz), 68.9 (d, J = 24.6 Hz), 29.1 (d, J = 23.5 Hz), 7.3 (d, J = 5.0 Hz); F NMR (377
3
MHz, CDCl ) δ ꢀ170.41 (s); HPLC analysis: Daicel Chiralpak OJꢀH, flow rate =1.0 ml/min, λ=210 nm,
25
hexane/isoꢀpropanol = 95:5, (R)ꢀ4o: 60% ee; [α]
D
3
= ꢀ 0.4 (c = 1.70, CHCl ), retention time: 16.5 min
25
(
minor) and 21.6 min (major); (S)ꢀ4o: 69% ee; [α]D = 1.76 (c = 1.65, CHCl ), retention time: 16.3 min
3
7
(major) and 21.9 min (minor); The spectroscopic data for 4o matched those described in the literature.
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ꢀfluoroꢀ1,2,3,4ꢀtetrahydronaphthaleneꢀ1ꢀol (4p): Following the procedure (A and B), the crude
mixture was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4p
ꢀ1
(
28.1 mg, 52%) and (S)ꢀ4p (29.7 mg, 55%) as colorless oil: IR (thin film, cm ) 3391(br), 2937, 2870, 1489,
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1452, 1339, 1202, 1013, 728; H NMR (500 MHz, CDCl
3
) δ 7.49 – 7.42 (m, 1 H), 7.28 – 7.20 (m, 2 H),
7
1
1
.13 (d, J = 6.6 Hz, 1 H), 3.97 (t, J = 12.2 Hz, 1 H), 3.71 (ddt, J = 28.3, 12.5, 4.3 Hz, 1 H), 2.91 – 2.79 (m,
H), 2.80 – 2.67 (m, 1 H), 2.40 (tdd, J = 13.6, 7.4, 3.1 Hz, 1 H), 2.11 (d, J = 4.3 Hz, 1 H), 2.09 – 1.99 (m,
1
3
3
H), 1.99 – 1.90 (m, 1 H), 1.86 – 1.75 (m, 1 H); C NMR (126 MHz, CDCl ) δ138.3 (d, J = 4.0 Hz), 135.0
(
d, J = 19.7 Hz), 129.0, 128.8 (d, J = 2.5 Hz), 126.7 (d, J = 5.0 Hz), 126.4 (d, J = 1.6 Hz), 95.9 (d, J =
19
1
71.1 Hz), 67.9 (d, J = 29.6 Hz), 30.1 (d, J = 21.2 Hz), 29.4 (d, J = 1.3 Hz), 20.1 (d, J = 7.2 Hz); F NMR
+
(
377 MHz, CDCl
3
) δ ꢀ143.86 (s); HRMS (APCIꢀorbitrap) m/z: [M + H] Calcd for C11
H14FO 181.1023;
+
Found 181.1011; HRMS (APCI) calcd for C H FO : 181.1023, found 181.1011; HPLC analysis: Daicel
11
14
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Chiralpak ASꢀH, flow rate =1 ml/min, λ=210 nm, hexane/isoꢀpropanol = 95:5, (R)ꢀ4p: 86% ee; [α]
D
=
=
25
D
ꢀ18.3 (c = 0.95, CHCl
3
), retention time: 16.0 min (major) and 19.8 min (minor); (S)ꢀ4p: 90% ee; [α]
2
5.6 (c = 1.05, CHCl
3
), retention time: 16.0 min (minor) and 19.7 min (major).
2ꢀfluoroꢀ3ꢀ(4ꢀisopropylphenyl)ꢀ2ꢀmethylpropanꢀ1ꢀol (4q): Following the procedure (A and B), the
crude mixture was purified by silica gel column chromatography (hexane : diethyl ether = 4:1) to give
ꢀ1
(
R)ꢀ4q (39.1 mg, 62%) and (S)ꢀ4q (35.9 mg, 57%) as colorless oil: IR (thin film, cm ) 3365(br), 2959,
1
2
927, 1512, 1460, 1418, 1381, 1050, 770; H NMR (400 MHz, CDCl
3
) δ 7.16 (s, 4 H), 3.58 (d, J = 19.4 Hz,
2
H), 2.99 (s, 1 H), 2.93 (t, J = 3.7 Hz, 1 H), 2.92 – 2.83 (m, 1 H), 1.79 (s, 1 H), 1.26 (dd, J = 14.4, 12.7 Hz,
1
3
9 H); C NMR (101 MHz, CDCl
3
) δ 147.4, 133.3, 130.4, 126.5, 97.5 (d, J = 170.0 Hz), 67.7 (d, J = 23.9
19
Hz), 42.1 (d, J = 23.0 Hz), 33.9, 24.2, 21.1 (d, J = 23.8 Hz); F NMR (377 MHz, CDCl ) δ ꢀ154.23 (s);
3
HPLC analysis: Daicel Chiralpak OJꢀH, flow rate =1.0 ml/min, λ=210 nm, hexane/isoꢀpropanol = 97:3,
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(
R)ꢀ4q: 52% ee, retention time: 9.4 min (minor) and 10.6 min (major); (S)ꢀ4q: 27% ee, retention time: 9.4
8
min (major) and 10.6 min (minor); The spectroscopic data for 4q matched those described in the literature.
2ꢀEthylꢀ2ꢀfluorohexanꢀ1ꢀol (4r): Following the procedure (A and B), the crude mixture was purified by
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silica gel column chromatography (hexane : diethyl ether = 4:1) to give (R)ꢀ4r (11.1 mg, 25%) and (S)ꢀ4r
ꢀ1
1
(5.3 mg, 12%) as colorless oil: IR (thin film, cm ) 3391(br), 2873, 1054, 748; H NMR (400 MHz, CDCl
3
)
δ 3.61 (dd, J = 20.5, 6.2 Hz, 2 H), 1.75 – 1.57 (m, 4 H), 1.43 (s, 1 H), 1.39 – 1.22 (m, 4 H), 0.96 – 0.84 (m,
1
3
6
H); C NMR (101 MHz, CDCl
3
) δ 99.9 (d, J = 168.6 Hz), 66.3 (d, J = 24.1 Hz), 32.9 (d, J = 22.4 Hz),
19
2
6.4 (d, J = 23.3 Hz), 25.4 (d, J = 6.7 Hz), 23.3, 14.1, 7.7 (d, J = 7.9 Hz); F NMR (377 MHz, CDCl
3
) δ
o
ꢀ161.31 (s); GC analysis: CYCLOSILꢀB, isotherm 110 C, N
2
, (R)ꢀ4r: 7% ee; retention time: 26.7 min
(
major) and 28.2 min (minor); (S)ꢀ4r: 0 ee.; retention time: 26.7 min and 28.2 min. The spectroscopic data
6
for 4r matched those described in the literature.
th
Acknowledgement. This paper is dedicated to Prof. JinꢀPei Cheng on the occasion of his 70 birthday.
We are grateful to the National Natural Science Foundation of China (No. 21202009 and 21672217) for
financial support.
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Supporting Information available: H and C, F NMR spectra, HPLC chart for the products. This
material is available free of charge via the Internet at http://pubs.acs.org.
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4
. For recent enantioselective fluorination of linear aldehydes, see: (a) Hu, X.; Lawer, A.; Peterson, M. B.;
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. Sánchez, D.; Bastida, D.; Burés, J.; Isart, C.; Pineda, O.; Vilarrasa, J. Org. Lett. 2012, 14, 536.
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. Shibatomi, K.; Kitahara, K.; Okimi, T.; Abe, Y.; Iwasa, S. Chem. Sci. 2016, 7, 1388.
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0. You, Y.; Zhang, L.; Luo, S. Chem. Sci. 2017, 8, 621.
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11. For recent reviews on switching selectivity, see: (a) Zanoni, G.; Castronovo, F.; Franzin, M..; Vidari, G.;
Giannini, E. Chem. Soc. Rev. 2003, 32, 115. (b) Comprehensive Asymmetric Catalysis; Jacobsen, E., Ed.;
Springer: Berlin, 1999. (c) Catalytic Asymmetric Synthesis; Ojima. I., Ed.; WileyꢀVCH: New York, 2000.
(d) Blanco V.; Leigh, D. A.; Marcos, V. Chem. Soc. Rev. 2015, 44, 5341. (e) Jiang, X.; Wang, R. Chem. Rev.
2
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013, 113, 5515. (f) Tanaka, T.; Hayashi, M. Synthesis. 2008, 3361. (g) Bartók, M. Chem. Rev. 2010, 110,
663. (h) Escorihuela, J.; Burgueteand, M. I.; Luis, S. V. Chem. Soc. Rev. 2013, 42, 5595.
2. For organocatalytic enantioselectivity switch, see: (a) Sohtome, Y.; Tanaka, S.; Takada, K.; Yamaguchi,
T.; Nagasawa, K. Angew. Chem., Int. Ed. 2010, 49, 9254. (b) Garzan, A.; Jaganathan, A.; Salehi Marzijarani,
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