Enantioselective Hydrogenation of β,β-Disubstituted Unsaturated Carboxylic Acids under Base-Free Conditions

Article abstract of DOI:10.1021/acs.joc.6b00018

An additive-free enantioselective hydrogenation of β,β-disubstituted unsaturated carboxylic acids catalyzed by the Rh-(R,R)-f-spiroPhos complex has been developed. Under mild conditions, a wide scope of β,β-disubstituted unsaturated carboxylic acids were hydrogenated to the corresponding chiral carboxylic acids with excellent enantioselectivities (up to 99.3% ee). This methodology was also successfully applied to the synthesis of the pharmaceutical molecule indatraline.

Full text of DOI:10.1021/acs.joc.6b00018

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Article
Enantioselective Hydrogenation of beta,beta-Disubstituted
Unsaturated Carboxylic Acids under Base-free Conditions
Qiaozhi Yan, Duanyang Kong, Wei Zhao, Guofu Zi, and Guohua Hou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00018 • Publication Date (Web): 05 Feb 2016
Downloaded from http://pubs.acs.org on February 5, 2016
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Enantioselective Hydrogenation of β,β-Disubstituted Unsaturated
Carboxylic Acids under Base-free Conditions
Qiaozhi Yan, Duanyang Kong, Wei Zhao, Guofu Zi and Guohua Hou*
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University,
Beijing 100875, China
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Email: ghhou@bnu.edu.cn
ABSTRACT: An additive-free enantioselective hydrogenation of β,β-disubstituted unsaturated
carboxylic acids catalyzed by Rh-(R,R)-f-spiroPhos complex has been developed. Under mild
conditions, a wide scope of β,β-disubstituted unsaturated carboxylic acids were hydrogenated to
the corresponding chiral carboxylic acids with excellent enantioselectivities (up to 99.3% ee). This
methodology was also successfully applied to the synthesis of the pharmaceutical molecule,
indatraline.
INTRODUCTION
Optically active β,β-disubstituted propionic acids are important structural moieties which
widely exist in many biologically active compounds and pharmaceuticals, including Lyrica,1
5
baclofen,2 ar-turmerone,3 indatraline,4 R-106578, and natural products, such as cherylline and
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Heliannuols 6 (Figure 1). Accordingly, the development of methodologies for the enantioselective
synthesis of chiral β,β-disubstituted propionic acids is highly desirable and has attracted much
attention from synthetic chemists.
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Cl
NHCH3
H2N
O
Cl
Cl
COOH
H2N
COOH
Lyrica
baclofen
ar-turmerone
indatraline
HO
O
N
H2N
O
HO
Me
O
O
N
OH
O
H
O
OH
R-106578
cherylline
(-)-Heliannuol A
Figure 1. Key structural elements in chiral pharmaceuticals and natural products.
Up to now, there are many methods for approaching chiral β,β-disubstituted propionic acids,7
such as Cu-, Co- or Rh-catalyzed asymmetric 1,4-reduction of β,β-disubstituted unsaturated
acrylates or nitriles using moisture-sensitive hydrosilane derivatives or borohydride reagents,8 and
asymmetric 1,4-additions of nucleophilic reagents to α,β-unsaturated carbonyl compounds
catalyzed by Pd, Rh or Cu complexes.9 Among these, the direct enantioselective hydrogenation of
β,β-disubstituted unsaturated acrylic acids is the most straightforward and efficient method for
chiral β,β-disubstituted propionic acids in spite of the asymmetric hydrogenation of
β-arylbut-3-enoic acids and β,β-disubstituted unsaturated acrylates.10 However, contrasted with the
asymmetric hydrogenation of α-substituted unsaturated acrylic acids,10i,11 the enantioselective
hydrogenation of β,β-disubstituted unsaturated acrylic acids still remains a challenge and is less
explored. Rh catalysts with chiral phosphine ligands and the Ru-Binap complex were developed
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for asymmetric hydrogenations β,β-disubstituted unsaturated acrylic acids with good
enantioselectivity.12 A Pd catalyst with cinchona alkaloid could also be used in the hydrogenation
of β-CF3-substituted acrylic acids, but poor enantioselectivities were obtained.13 Recently, Ding
and co-workers developed a Rh catalyst containing a chiral monodentate phosphine (SPO) ligand
and an achiral Ph3P ligand, which exhibited excellent enantioselectivity for the asymmetric
hydrogenation of β,β-diarylacrylic acids and β-CF3-substituted acrylic acids.11f,14 Whereas in most
of reported cases of the asymmetric hydrogenation of unsaturated acrylic acids, a base additive
(NEt3 or morpholine) was required to achieve high efficiency and enantioselectivity.11-14
Accordingly, the development of more efficient catalysts for the asymmetric hydrogenation of
β,β-disubstituted acrylic acids is highly desirable. Inspired by the excellent performance of the
chiral diphosphine ligand f-spiroPhos in Rh- or Ir-catalyzed asymmetric hydrogenations of
α,β-unsaturated nitriles and nitroolefins,15 we evaluated this ligand for the hydrogenation of
β,β-disubstituted unsaturated acrylic acids including sterically similar β,β-diaryl unsaturated
acrylic acids and found that its Rh complex showing excellent enantioselectivities (up to 99.3% ee)
under mild reaction conditions without any additive (Scheme 1).
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Scheme 1
R2
*
R2
[Rh(COD)Cl]2 /(R,R)-f-spiroPhos (0.5 mol% )
COOH
COOH
R1
R1
H2 (10 atm), CH2Cl2, rt, 1 h
1
2
> 99% conversion
up to 99.3% ee
P
Fe
P
(R,R)-f-spiroPhos
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RESULTS AND DISCUSSION
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To optimize the reaction conditions, (E)-3-phenylbut-2-enoic acid 1a was used as the model
substrate, and the hydrogenation was initially performed without any additive using the complex
of (R,R)-f-spiroPhos and [Rh(COD)Cl]2 or [Ir(COD)Cl]2 as the catalyst under 50 atm of H2 in
CH2Cl2 at room temperature for 6 h. To our delight, the Rh-(R,R)-f-spiroPhos catalyst provided a
full conversion and high enantioselectivity, 93% ee (Table 1, entry 1), which was attributed to the
electron-rich property and rigidity of the ligand. Whereas poor results, 26% conversion and 35%
ee, were observed using [Ir(COD)Cl]2 precursor. Subsequently, some other chiral phosphorus
ligands illustrated in Figure 2 were investigated and the results revealed that most of them were
not efficient for this transformation giving either low conversions or poor enantioselectivities
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(entries 25) except for (S,S)-f-Binaphane, which provided
a good conversion and
enantioselectivty (entry 6). Good enantioselectivities and almost full conversions could be
achieved in most of solvents, such as THF, MeOH, toluene, and DME (entries 710). In addition
to CH2Cl2, 1,4-dioxane could also afford a similar enantioselectivity despite incomplete
conversion (entry 11). Moreover, decreasing the hydrogen pressure from 50 atm to 10 atm, this
transformation could still complete in 1 h with a slight higher enantioselectivity (entry 12). Lower
reaction temperature resulted in a much higher ee value, 97% ee, in spite of a little longer time
required for the full conversion (entry 13). Finally, we evaluated the effect of added base (10 mol%
NEt3) on catalyst performance under the optimized conditions, a moderate enantioselectivity and
incomplete conversion (72% ee, 27% conv.) was obtained. The asymmetric hydrogenation of the
corresponding (E)-methyl 3-phenylbut-2-enoate was also investigated, but a very poor reactivity
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(< 1% conv.) was observed. These results revealed that this catalyst should be more suitable for
the free acids and has good tolerance for acidic condition.
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H
H
PPh2
PPh2
PPh2
Cy2P
Fe
P
P
tBu
tBu
(S,R)-DuanPhos
(S)-BINAP
(R)-JosiPhos-1
O
P N
O
P
Fe
P
(S,S)-f-Binaphane
(S)-MonoPhos
Figure 2. Phosphine ligands tested for the hydrogenation of (E)-3-phenylbut-2-enoic acid 1a.
Table 1. Asymmetric Hydrogenation of (E)-3-Phenylbut-2-enoic Acid 1a, Optimizing
Reaction Conditions.a
entry
ligand
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
conversion (%)b
ee (%)c
93
1
2
3
4
5
6
7
8
9
(R,R)-f-spiroPhos
(S)-Binap
>99
2
42
(S,R)-DuanPhos
(R)-JosiPhos-1
(S)-MonoPhos
(S,S)-f-Binaphane
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
2
14
37
0.4
79
98
>99
97
15
ND
86
60
MeOH
Toluene
86
91
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(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
DME
95
88
94
94
97
11
dioxane
CH2Cl2
CH2Cl2
95
12d
13e
>99
>99
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a reaction conditions: [Rh(COD)Cl]2/diphosphine (monophosphine)/substrate ratio = 0.5 : 1.1
b
(2.1) : 100, 50 atm H2, 6 h, r.t. Determined by chiral GC. c Determined by chiral GC using a
Supelco Gamma-Dex 225 column (30 m × 0.25 mm × 0.25 μm). d 10 atm H2, 1 h. e 10 atm H2, -15
oC, 6 h.
Encouraged by the promising results obtained in the hydrogenation of substrate 1a, a series of
β,β-disubstituted unsaturated carboxylic acids 1b1t were successfully hydrogenated under
optimized reaction conditions to provide the corresponding chiral acids with excellent ee values,
91-99.3% ee, and complete conversions, regardless of the position or electronic property of
substituents on the phenyl ring (Table 2). For example, Substrates bearing an
electron-withdrawing substituent, F, Cl, Br, NO2 group or an electron-donating substituent, Me,
MeO group at the para- , meta- or ortho- position of the phenyl group were hydrogenated with
excellent enatioselectivities, up to 99.3% ee (entries 111). The substrate 1j with a methyl group
at the ortho-position of phenyl ring provided 2j with the highest enantioselectivity, 99.3% ee,
presumably due to the steric hindrance. The similar effect was also observed for substrates 1k with
an ortho-nitro group and 1l with a 1-naphthyl group, and excellent enantioselectivities were
provided even at room temperature (entries 1112). Gratifyingly, excellent ee values, 97 and 98%
i
ee respectively, were also obtained for the substrates with a larger alkyl group, Pr or cyclohexyl
(entries 1415). However, for the dialkyl substrates 1p and 1q, only moderate enantioselectivities
were observed possibly attributed to the flexibility of the alkyl groups (entries 1617). It is notable
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that this catalyst system was also efficient for the asymmetric hydrogenation of challenging
substrates β,β-diarylacrylic acids due to the difficult differentiation of a stereogenic center with
two sterically similar aryl groups, providing the corresponding β,β-diarylpropionic acids with
excellent enantioselectivities (entries 1820). In addition, a large scale (1.5 g) hydrogenation of 1b
could be performed smoothly with a full conversion and maintained ee value (entry 21).
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Table 2. Rh-Catalyzed Asymmetric Hydrogenation of β,β-Disubstituted Unsaturated
Carboxylic Acids 1.a
entry
1
R1
R2
product
2a
2b
2c
Conversion (%)b ee (%)c
(E)-C6H5(1a)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
91
97(S)
95(+)
97(+)
96(+)
97(+)
97(+)
91(+)
96(+)
93(-)
2
(E)-4-ClC6H4(1b)
(E)-4-NO2C6H4(1c)
(E)-3-FC6H4(1d)
(E)-3-BrC6H4(1e)
(E)-3-NO2C6H4(1f)
(E)-3-MeOC6H4(1g)
(E)-2-FC6H4(1h)
(E)-2-ClC6H4(1i)
(E)-2-MeC6H4(1j)
(E)-2-NO2C6H4(1k)
(E)-1-naphthyl(1l)
(E)-C6H5(1m)
3
4
2d
2e
5
6
2f
7
2g
2h
2i
8
9
10
11d
12d
13d
14d
15d
16d
17d
18e
2j
99.3(+)
97(-)
2k
2l
98(S)
94(S)
97(S)
98(S)
66(R)
73(-)
2m
2n
2o
2p
2q
2r
(E)-C6H5(1n)
iPr
(E)-C6H5(1o)
C6H11
Me
Me
C6H5
(E)-C6H5(CH2)2(1p)
(E)-C6H11(1q)
(Z)-3,4-ClC6H4(1r)
>99
97(S)
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19e
20e
21f
(Z)-2-FC6H4(1s)
(Z)-3-ClC6H4(1t)
(E)-4-ClC6H4(1b)
C6H5
C6H5
Me
2s
2t
>99
>99
>99
94(S)
97(-)
95(+)
7
2b
8
9
a
Unless otherwise mentioned, all reactions were carried out with
a
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[Rh(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of 0.5 : 1.1 : 100, CH2Cl2, 50 atm H2, -15oC, 6 h. b
1
c
Determined by H NMR spectroscopy or GC analysis. Determined by HPLC analysis using a
d
e
f
chiral stationary phase or chiral GC analysis. r.t., 10 atm H2, 1 h. 0oC, 10 atm H2, 4 h. 1.5 g
substrate.
To our delight, in addition to β,β-disubstituted unsaturated carboxylic acids, this catalyst system
exhibited excellent enantioselectivity for the asymmetric hydrogenation of β,β-disubstituted
unsaturated aldehydes and γ,γ-disubstituted unsaturated alcohols. Under the mild reaction
conditions, the unsaturated aldehyde 3 and γ,γ-disubstituted unsaturated alcohols 5a and 5b were
successfully hydrogenated affording chiral alcohols 4 and 6 in full conversions and excellent
enantioselectivities, up to 97% ee (scheme 2). But when this catalyst was applied to the substrates
bearing a neighboring polar group, such as an ester ((E)-4-methoxy-4-oxo-3-phenylbut-2-enoic) or
amide group ((Z)-4-oxo-3-phenyl-4-(phenylamino)but-2-enoic acid), very poor reactivities (< 10%
conv.) were observed for both substrates presumably due to the effect on the electronic property of
C=C bond by two polar groups.
Scheme 2
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To demonstrate the application of this method, this catalyst system was applied to the
preparation of the key intermediate 7 for the synthesis of indatraline, a non-selective monoamine
reuptake inhibitor.4 It could be readily afforded by this method from the hydrogenation product
β,β-diarylacrylic acid 1r in high yield and excellent enantioselectivity, 95% ee (Scheme 3).8c, 16
Scheme 3
According to the reported mechanism of rhodium catalyzed asymmetric hydrogenation of
unsaturated nitriles,15a a possible enantio-determining transition model were also proposed
(Scheme 4). The different bulk of two substituents at the beta carbon atom possibly had an
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influence on the coordination of the substrate to rhodium. It was revealed that the coordination
from the Re-face of the substrates was much more favorable resulting in the (S) products, which
was in agreement with the absolute configuration outcome of the hydrogenation products. For
3,3-diaryl-substituted substrates, the primary recognition element responsible for enantioselection
probably was the alpha C atom bearing a small H atom and a significantly larger carboxylic group.
The enantioselectivity probably mainly depends on the steric bulk difference between the two
substituents on the alpha C atom.10h, 11g
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Scheme 4
CONCLUSIONS
In conclusion, we have developed a method for Rh-catalyzed asymmetric hydrogenation of
β,β-disubstituted unsaturated carboxylic acids without any additive with high activities and
excellent enantioselectivities. This catalyst system is tolerant towards steric hindrance and is also
very efficient for the asymmetric hydrogenation of β,β-diarylacrylic acids, β,β-disubstituted
unsaturated aldehyde and γ,γ-disubstituted unsaturated alcohols with excellent enantioselectives.
EXPERIMENTAL SECTION
General Information: All the air or moisture sensitive reactions and manipulations were
performed by using standard Schlenk techniques and in a nitrogen-filled glovebox. DME, THF,
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dioxane and toluene were distilled from sodium benzophenone ketyl. CH2Cl2 was distilled from
calcium hydride. Anhydrous MeOH was distilled from magnesium.1H NMR spectra were
recorded on 400 MHz spectrometers. 13C NMR (proton-decoupled) spectra were obtained at 100
MHz. CDC13 or DMSO-d6 was the solvent used for the NMR analysis, with tetramethylsilane as
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1
the internal standard. Chemical shifts were reported upfield to TMS (0.00 ppm) for H NMR.
Optical rotation was determined using a polarimeter. HRMS were recorded on a mass
spectrometer with APCI.
General procedure for the synthesis and characterization data for compounds 1: To a
suspension of sodium hydride (0.7-1.5 g, 20.9-43.7 mmol, 1.5 equiv, 70% in mineral oil) in THF
(140 mL) was added dropwise the corresponding triethyl phosphonoacetate (4.7-9.8 g, 20.9-43.7
mmol, 1.5 equiv) at 0 oC. The resulting solution was stirred for 3.0 h until gas evolution had
ceased. And the corresponding ketone (3.5 g, 13.9-29.1 mmol, 1.0 equiv) in THF (14 mL) was
added via syringe. The solution was stirred at room temperature until no starting material was
detected by TLC. Then the reaction mixture was quenched with saturated aqueous NH4Cl solution.
The layers were separated and the aqueous phase was extracted with diethyl ether. The combined
organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4 and
concentrated in vacuo. Purification by column chromatography (PE : EA = 50:1-20:1) afforded the
corresponding acrylate.
The corresponding acrylate (500.0 mg, 1.6-2.6 mmol) was placed in a 50 mL round bottom flask,
then EtOH (5.4 mL) was added, the reaction mixture was stirred and NaOH (10%, 10.8 mL) was
added. The reaction mixture was stirred at room temperature until no starting material was
detected by TLC. Then adjust PH to 1.0 with HCl (1 N). The mixture was extracted with diethyl
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ether. The combined organic layer was washed with saturated aqueous NaCl solution, dried over
Na2SO4 and concentrated in vacuo. Purification by recrystallization provided the corresponding
carboxylic acid 1.17
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(E)-3-phenylbut-2-enoic acid (1a): Purification by recrystallization (EA / PE) afforded the product
as white solid; yield: 423 mg, > 99%; 1H NMR (400 MHz, CDCl3) δ = 12.01 (s, 1H), 7.53-7.50 (m,
2H), 7.44-7.39 (m, 3H), 6.20 (d, J = 0.9 Hz, 1H), 2.63 (d, J = 0.8 Hz, 3H); 13C{1H}NMR (100
MHz, CDCl3) δ = 172.7, 158.5, 141.9, 129.3, 128.5, 126.3, 116.5, 18.2; MP: 90-92 oC. The
analytical data are consistent with the literature.14
(E)-3-(4-chlorophenyl)but-2-enoic acid (1b): Purification by recrystallization (EA / PE) afforded
the product as white solid; yield: 434 mg, > 99%; 1H NMR (400 MHz, CDCl3) δ = 7.44-7.42 (m,
2H), 7.38-7.35 (m, 2H), 6.15 (d, J = 1.2 Hz, 1H), 2.58 (d, J = 1.2 Hz, 3H); 13C{1H}NMR (100
MHz, CDCl3) δ = 172.5, 157.2, 140.3, 135.4, 128.8, 127.8, 116.8, 18.2; MP: 130-132 oC. The
analytical data are consistent with the literature.18
(E)-3-(4-nitrophenyl)but-2-enoic acid (1c): Purification by recrystallization (EA / PE) afforded the
product as white solid; 437 mg, yield: > 99%; 1H NMR (400 MHz, CDCl3) δ = 8.27-8.25 (m, 2H),
7.65-7.63 (m, 2H), 6.22 (d, J = 1.3 Hz, 1H), 2.62 (d, J = 1.3 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ = 171.4, 155.9, 148.2, 148.1, 127.4, 123.9, 119.2, 18.4; MP: 164-166 oC. The analytical
data are consistent with the literature.19
(E)-3-(3-fluorophenyl)but-2-enoic acid (1d): Purification by recrystallization (EA / PE) afforded
the product as white solid; yield: 430 mg, > 99%; 1H NMR (400 MHz, CDCl3) δ = 7.39-7.33 (m,
1H), 7.20-7.19 (m, 1H), 7.18-7.17 (m, 1H), 7.11-7.06 (m, 1H), 6.17 (d, J = 1.2 Hz, 1H), 2.58 (d, J
1
= 1.2 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 172.3, 162.7 (d, JC-F = 245.0 Hz), 156.9,
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113.5 (d, J = 22.2 Hz), 18.2; MP: 129-131 C. The analytical data are consistent with the
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(E)-3-(3-bromophenyl)but-2-enoic acid (1e): Purification by recrystallization (EA / PE) afforded
the product as white solid; yield: 446 mg, > 99%; 1H NMR (400 MHz, CDCl3) δ = 7.63-7.62 (m,
1H), 7.53-7.50 (m, 1H), 7.43-7.40 (m, 1H), 7.29-7.25 (m, 1H), 6.15 (d, J = 1.2 Hz, 1H), 2.57 (d, J
= 1.2 Hz, 3H); 13C{1H}NMR (100 MHz, DMSO-d6) δ = 167.8, 152.4, 144.4, 132.2, 131.1, 129.3,
125.8, 122.5, 119.3, 17.6; MP: 156-158 oC. The analytical data are consistent with the literature.21
(E)-3-(3-nitrophenyl)but-2-enoic acid (1f): Purification by recrystallization (EA / PE) afforded the
1
product as white solid; yield: 430 mg, 98%; H NMR (400 MHz, CDCl3) δ = 8.36 (m, 1H),
8.26-8.24 (m, 1H), 7.83-7.81 (m, 1H), 7.61-7.57 (m, 1H), 6.25 (s, 1H), 2.64 (d, J = 0.9 Hz, 3H);
13C NMR (100 MHz, DMSO-d6) δ = 167.8, 151.5, 148.5, 143.5, 133.2, 130.6, 124.0, 121.3, 120.2,
17.6; MP: 188-190 oC. The analytical data are consistent with the literature.22
(E)-3-(3-methoxyphenyl)but-2-enoic acid(1g): Purification by recrystallization (EA / PE) afforded
the product as white solid; yield: 430 mg, 99%; 1H NMR (400 MHz, CDCl3) δ = 7.33-7.29 (m,
1H), 7.10-7.07 (m, 1H), 7.01-7.00 (m, 1H), 6.94-6.92 (m, 1H), 6.17 (d, J = 1.3 Hz, 1H), 3.84 (s,
3H), 2.59 (d, J = 1.3 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 172.5, 159.6, 158.4, 143.5,
129.5, 118.8, 116.6, 114.7, 112.1, 55.3, 18.4; MP: 94-96 oC. The analytical data are consistent with
the literature.23
(E)-3-(2-fluorophenyl)but-2-enoic acid (1h): Purification by recrystallization (EA / PE) afforded
the product as white solid; yield: 434 mg, > 99%; 1H NMR (400 MHz, CDCl3) δ = 7.36-7.28 (m,
13
2H), 7.17-7.07 (m, 2H), 6.05 (d, J = 1.2 Hz, 1H), 2.56 (t, J = 1.6 Hz, 3H); C{1H}NMR (100
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MHz, CDCl3) δ = 172.2, 159.4 (d, 1JC-F = 248.4 Hz), 155.1, 130.7 (d, J = 13.1 Hz), 130.3 (d, J =
8.5 Hz), 129.1 (d, J = 3.5 Hz), 124.2 (d, J = 2.4 Hz), 119.8 (d, J = 2.4 Hz), 116.1 (d, J = 22.1 Hz),
19.8 (d, J = 3.6 Hz); MP: 90-92 oC. The analytical data are consistent with the literature.20
(E)-3-(2-chlorophenyl)but-2-enoic acid (1i): Purification by recrystallization (EA / PE) afforded
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the product as white solid; yield: 240 mg, 83%; H NMR (400 MHz, CDCl3) δ = 7.41-7.39 (m,
1H), 7.28-7.25 (m, 2H), 7.20-7.17 (m, 2H), 5.88 (d, J = 1.4 Hz,1H), 2.52 (d, J = 1.4 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ = 172.2, 158.9, 142.4, 131.1, 129.9, 129.3, 128.8, 126.8, 120.1,
20.6; MP: 102-104 oC. The analytical data are consistent with the literature.24
(E)-3-(o-tolyl)but-2-enoic acid (1j): Purification by column chromatography ( PE : EA = 2:1)
1
afforded the product as light yellow solid; yield: 140 mg, 90%; H NMR (400 MHz, CDCl3) δ =
7.25-7.16 (m, 3H), 7.09-7.08 (m, 1H), 5.82 (d, J = 1.1 Hz, 1H), 2.47 (d, J = 1.3 Hz, 3H), 2.30 (s,
3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 172.4, 161.4, 143.7, 133.7, 130.5, 127.9, 126.9, 125.8,
118.9, 21.2, 19.7; MP: 83-85 oC. The analytical data are consistent with the literature.25
(E)-3-(2-nitrophenyl)but-2-enoic acid (1k): Purification by recrystallization (EA / PE) afforded the
1
product as light orange solid; yield: 440 mg, > 99%; H NMR (400 MHz, CDCl3) δ = 8.08-8.05
(m, 1H), 7.66-7.62 (m, 1H), 7.54-7.50 (m, 1H), 7.33-7.31 (m, 1H), 5.84 (d, J = 1.4 Hz, 1H), 2.48
(d, J = 1.3 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 171.5, 158.0, 146.7, 139.3, 133.6, 129.8,
o
129.1, 124.8, 118.4, 20.8; MP: 122-124 C. APCI-HRMS: Calcd. for C10H10NO4 [M+H+]:
208.0304, found 208.0308.
(E)-3-(naphthalen-1-yl)but-2-enoic acid (1l): Purification by recrystallization (EA / PE) afforded
the product as light yellow solid; yield: 398 mg, 90%; 1H NMR (400 MHz, CDCl3) δ = 7.93-7.83
(m, 3H), 7.55-7.45 (m, 3H), 7.33-7.32 (m, 1H), 6.08-6.07 (m, 1H), 2.69-2.68 (m, 3H);
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13C{1H}NMR (100 MHz, CDCl3) δ = 172.5, 160.3, 141.8, 133.6, 129.8, 128.5, 128.4, 126.4, 126.0,
125.1, 124.1, 120.0, 22.0; MP: 90-92 oC. The analytical data are consistent with the literature.26
(E)-3-phenylpent-2-enoic acid (1m): Purification by recrystallization (EA / PE) afforded the
product as white solid; yield: 410 mg, 95%; 1H NMR (400 MHz, CDCl3) δ = 7.48 -7.46 (m, 2H),
7.41-7.38 (m, 3H), 6.06 (s, 1H), 3.16-3.11 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (100
MHz, CDCl3) δ = 172.3, 165.0, 140.8, 129.2, 128.5, 126.7, 116.1, 24.5, 13.6; MP: 94-96 oC. The
analytical data are consistent with the literature.27
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(E)-4-methyl-3-phenylpent-2-enoic acid (1n): Purification by recrystallization (EA / PE) afforded
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the product as white solid; yield: 353 mg, 81%; H NMR (400 MHz, CDCl3) δ = 7.36-7.32 (m,
3H), 7.22-7.20 (m, 2H), 5.75 (s, 1H), 4.18-4.09 (m, 1H), 1.10 (d, J = 7.0 Hz, 6H); 13C{1H}NMR
(100 MHz, CDCl3) δ = 172.0, 170.2, 140.5, 127.8, 127.7, 127.5, 117.9, 29.7, 21.3; MP: 96-98 oC.
The analytical data are consistent with the literature.25
(E)-3-cyclohexyl-3-phenylacrylic acid (1o): Purification by recrystallization (EA / PE) afforded
1
the product as white solid; yield: 160 mg, 90%; H NMR (400 MHz, CDCl3) δ = 7.35 -7.29 (m,
3H), 7.10-7.07 (m, 2H), 5.82 (d, J = 0.9 Hz, 1H), 2.28-2.22 (m, 1H), 1.80-1.75 (m, 4H), 1.26-1.10
(m, 6H); 13C{1H}NMR (100 MHz, CDCl3) δ = 171.6, 167.0, 139.9, 127.7, 127.4, 127.0, 115.2,
47.7, 31.6, 26.4, 26.0; MP: 140-142 oC. The analytical data are consistent with the literature.28
(E)-3-methyl-5-phenylpent-2-enoic acid (1p): Purification by recrystallization (EA / PE) afforded
1
the product as white solid; yield: 427 mg, 98%; H NMR (400 MHz, CDCl3) δ = 7.34-7.31 (m,
2H), 7.23-7.20 (m, 3H), 5.74 (s, 1H), 2.85-2.81 (m, 2H), 2.53-2.49 (m, 2H), 2.25 (s, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ = 172.6, 162.3, 140.9, 128.6, 128.3, 126.2, 115.7, 43.0, 33.9,
19.4; MP: 50-52 oC. The analytical data are consistent with the literature.29
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(E)-3-cyclohexylbut-2-enoic acid (1q): Purification by recrystallization (EA / PE) afforded the
product as white solid; yield: 427 mg, > 99%; 1H NMR (400 MHz, CDCl3) δ = 5.68 (t, J = 1.0 Hz,
1H), 2.15 (d, J = 1.2 Hz, 3H), 2.04-1.98 (m, 1H), 1.84-1.69 (m, 5H), 1.37-1.11 (m, 5H);
13C{1H}NMR (100 MHz, CDCl3) δ = 173.0, 168.1, 113.5, 49.0, 31.2, 26.3, 26.0, 17.7; MP: 74-76
oC. The analytical data are consistent with the literature.30
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(Z)-3-(3,4-dichlorophenyl)-3-phenylacrylic acid (1r): Purification by recrystallization (EA / PE)
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afforded the product as white solid; yield: 447 mg, 98%; H NMR (400 MHz, CDCl3) δ =
7.47-7.07 (m, 8H), 6.38 (s, 1H); 13C{1H}NMR (100 MHz, DMSO- d6) δ = 166.8, 152.0, 140.1,
o
139.7, 131.2, 131.1, 131.0, 130.6, 130.1, 129.8, 129.2, 128.3, 120.2; MP: 174-176 C. The
analytical data are consistent with the literature.14
(Z)-3-(2-fluorophenyl)-3-phenylacrylic acid (1s): Purification by recrystallization (EA / PE)
1
afforded the product as white solid; yield: 358 mg, 80%; H NMR (400 MHz, CDCl3) δ = 7.40
-7.30 (m, 6H), 7.18-7.08 (m, 3H), 6.48 (s, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ = 170.9, 159.4
(d, 1JC-F = 246.1 Hz), 152.2, 139.5, 130.7, 130.1 (d, J = 8.0 Hz), 129.9, 128.5, 127.8, 126.0 (d, J =
15.8 Hz), 123.7, 118.5, 115.4 (d, J = 21.8 Hz); MP: 156-158 oC. The analytical data are consistent
with the literature.14
(Z)-3-(3-chlorophenyl)-3-phenylacrylic acid (1t): Purification by recrystallization (EA / PE)
1
afforded the product as white solid; yield: 263 mg, > 99%; H NMR (400 MHz, CDCl3) δ =
7.38-7.28 (m, 5H), 7.24-7.23 (m, 2H), 7.16 (s, 1H), 7.09-7.07 (m, 1H), 6.32 (s, 1H); 13C{1H}NMR
(100 MHz, CDCl3) δ = 171.2, 157.5, 140.0, 139.9, 133.8, 130.0, 129.2, 129.0, 128.5, 128.4, 128.3,
127.4, 117.0; MP: 137-139 oC. APCI-HRMS: Calcd. For C15H12ClO2 [M+H+]: 259.0520, Found:
259.0523.
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The procedure for the synthesis and characterization data for the compound 3:
(E)-3-phenylbut-2-enenitrile (500.0 mg, 3.5 mmol, 1.0 eq)15a was placed in an oven-dried 50 mL,
three-neck round bottom flask. THF (5 mL) was added under nitrogen. The reaction mixture was
cooled and DibAl-H (5.2 ml, 1.0 M, 5.2 mmol, 1.5 eq) was added dropwise with stirring at -10 oC.
The solution was stirred at rt for 2.0 h. Then, the reaction mixture was quenched with water and
HCl (5%) slowly maintaining the temperature at -10 oC. The mixture extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The
residue was purification by chromatography (PE : EA = 15:1) on silica gel to give 3 (yellow liquid,
240.3 mg, 47.1%).31 1H NMR (400 MHz, CDCl3) δ = 10.2 (d, J = 7.9 Hz, 1H), 7.55-7.53 (m, 2H),
7.42-7.41 (m, 3H), 6.39 (d, J = 7.9 Hz, 1H), 2.57 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ =
191.1, 157.5, 140.3, 129.9, 128.5, 127.0, 126.1, 16.1; The analytical data are consistent with the
literature.32
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General procedure for the synthesis and characterization data for compounds 5: The
corresponding acrylate (0.7 g, 3.7 mmol for 5a; 0.9 g, 4.1 mmol for 5b) was placed in an
oven-dried 50 mL, three-neck round bottom flask. THF (20 mL) was added under nitrogen. The
reaction mixture was cooled and LiAlH4 (140 mg for 5a; 150 mg for 5b, 1.0 eq) was added
dropwise with stirring at -78 oC. The solution was stirred at room temperature for 1 h. Then, the
reaction mixture was quenched with water and HCl (5%) slowly maintaining the trmperature at
-78 oC. The mixture extracted with ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated. The residue was purification by chromatography (PE :
EA = 5:1) on silica gel to give 5a (400 mg colourless liquid 73.4%) and 5b (646 mg colourless
liquid 95%).17a, 31c
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(E)-3-phenylbut-2-en-1-ol (5a): Purification by recrystallization (EA / PE) afforded the product as
yellow liquid; yield: 400 mg, 73%; 1H NMR (400 MHz, CDCl3) δ = 7.29-7.27 (m, 2H), 7.21-7.18
(m, 2H), 7.15-7.11 (m, 1H), 5.84 (t, J = 6.6 Hz, 1H), 4.23 (d, J = 6.6 Hz, 2H), 1.95 (s, 3H), 1.42 (s,
1H); 13C{1H}NMR (100 MHz, CDCl3) δ = 142.6, 136.9, 128.0, 126.9, 126.5, 125.5, 59.4, 15.7;
The analytical data are consistent with the literature.33
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(E)-3-(2-fluorophenyl)but-2-en-1-ol (5b): Purification by recrystallization (EA / PE) afforded the
product as yellow liquid; yield: 646 mg, 95%; 1H NMR (400 MHz, CDCl3) δ = 7.12-7.07 (m, 2H),
6.97-6.93 (m, 1H), 6.91-6.86 (m, 1H), 5.67 (t, J = 6.3 Hz, 1H), 4.21 (d, J = 5.3 Hz, 2H), 1.91 (s,
3H), 1.60 (s, 1H); 13C{1H}NMR (400 MHz, CDCl3) δ = 159.8 (d, 1JC-F = 245.5 Hz), 134.1, 131.7
(d, J = 14.0 Hz), 130.0, 129.6 (d, J = 4.1 Hz), 128.6 (d, J = 8.2 Hz), 124.0 (d, J = 3.2 Hz), 115.7 (d,
J = 22.5 Hz), 59.3, 17.1 (d, J = 3.6 Hz); APCI-HRMS Calcd. for C10H12FO [M+H+]: 167.0872,
found 167.0873.
General procedure for asymmetric hydrogenation and characterization data for products: A
stock solution was made by mixing [Rh(COD)Cl]2 (1.3 mg) with (R,R)-f-spirophos (4.3 mg) in a
1:2.2 molar ratio in CH2Cl2 (4.0 mL) at room temperature for 20 min in a nitrogen-filled glovebox.
An aliquot of the catalyst solution (1.0 mL, 0.00132 mmol) was transferred by syringe into the
vials charged with different substrates (0.125 mmol for each) in anhydrous CH2Cl2 (2.0 mL). The
vials were subsequently transferred into an autoclave which hydrogen gas was charged. The
reaction was then stirred under H2 (10 atm) at -15 oC for 6 h. The hydrogen gas was released
slowly and carefully. The solution was passed through a short column of silica gel to remove the
metal complex then concentrated in vacuo. The residue dissolved in CH2Cl2, then aniline, EDC
and DMAP were added at 0 oC. The solution stirred for 4-10h. The residue was purified by
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chromatography. The ee values of amides were determined by HPLC analysis on a chiral
stationary phase.
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The procedure for the large scale asymmetric hydrogenation of 1b: The catalyst solution was
made by mixing [Rh(COD)Cl]2 (17.1 mg, 0.035 mmol) with (R,R)-f-spirophos (56.5 mg, 0.0765
mmol) in a 1:2.2 molar ratio in CH2Cl2 (2.0 mL) at room temperature for 20 min in a
nitrogen-filled glovebox, and then transferred by syringe into the vials charged with 1b (1.5 g,
7.65 mmol) in anhydrous CH2Cl2 (4.0 mL). The vials were subsequently placed into an autoclave
which hydrogen gas was charged. The reaction was then stirred under H2 (10 atm) at -15 oC for 6 h.
The resulting solution was passed through a short column of silica gel to remove the metal
complex then concentrated in vacuo. The residue dissolved in CH2Cl2, followed by addition of
aniline, EDC and DMAP at 0 oC and stirred for 10 h. The corresponding amide was purified by
chromatography and then subjected to determine the ee value by HPLC analysis on a chiral
stationary phase.
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(S)-3-phenylbutanoic acid (2a): Light yellow liquid; 20.1 mg, 98% yield; 97% ee; [α]D20 = +12.2
(c = 0.7, CH2Cl2), GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25
µm), N2 1.0 mL/min, programmed 100 oC – 1 oC /min - 200 oC - 50 min; tR = 44.5 min (major), tR
= 45.2 min (minor). 1H NMR (400 MHz, CDCl3) δ = 11.37 (s, 1H), 7.23-7.20 (m, 2H), 7.14-7.10
(m, 3H), 3.22-3.14 (m, 1H), 2.60-2.45 (m, 2H), 1.23 (d, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ = 179.1, 145.3, 128.5, 126.6, 126.5, 42.6, 36.0, 21.8. The absolute configuration of
(S)-2a was determined by comparison with optical rotation data for the reported literature.10d
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(+)-3-(4-chlorophenyl)butanoic acid (2b): Light yellow solid; 24.1 mg, 97% yield; 95% ee; [α]D
= +44.94 (c = 1.07, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
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20:80, 1mL/min, 254 nm; tR = 7.5 min (minor), tR = 9.1 min (major). 1H NMR (400 MHz, CDCl3)
δ = 10.19 (s, 1H), 7.21-7.19 (m, 2H), 7.09-7.07 (m, 2H), 3.22-3.13 (m, 1H), 2.59-2.47 (m, 2H),
1.22 (d, J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 178.6, 143.8, 132.1, 128.7, 128.1,
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42.4, 35.6, 21.9; MP: 60-62 oC. The analytical data are consistent with the literature.10c
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(+)-3-(4-nitrophenyl)butanoic acid (2c): Light yellow solid; 25.1 mg, 96% yield; 97% ee; [α]D
=
+45.8 (c = 1.3, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex = 20:80,
1mL/min, 254 nm; tR = 12.6 min (minor), tR = 19.3 min (major). 1H NMR (400 MHz, CDCl3) δ =
8.17-8.15 (m, 2H), 7.40-7.37 (m, 2H), 3.43-3.34 (m, 1H), 2.72-2.61 (m, 2H), 1.34 (d, J = 7.0 Hz,
3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 177.8, 152.8, 146.7, 127.7, 123.9, 41.8, 36.0, 21.7; MP:
120-122 oC. The analytical data are consistent with the literature.34
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(+)-3-(3-fluorophenyl)butanoic acid (2d): Light yellow liquid; 22.1 mg, 97% yield; 96% ee; [α]D
= +25.5 (c = 1.1, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
20:80, 1mL/min, 254 nm; tR = 7.6 min (minor), tR = 9.0min (major). 1H NMR (400 MHz, CDCl3)
δ = 7.16-7.11 (m, 1H), 6.89-6.87 (m, 1H), 6.82-6.75 (m, 2H), 3.20-3.11 (m, 1H), 2.56-2.42 (m,
2H), 1.19 (d, J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 178.6, 162.9 (d, 1JC-F = 243.8
Hz), 148.0 (d, J = 6.7 Hz), 130.0 (d, J = 8.2 Hz), 122.4, 113.6 (d, J = 21.2 Hz), 113.4 (d, J = 21.1
Hz), 42.3, 35.9, 21.7. The analytical data are consistent with the literature.10c
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(+)-3-(3-bromophenyl)butanoic acid (2e): Light yellow liquid; 29.2 mg, 96% yield; 97% ee; [α]D
= +28.4 (c = 1.6, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
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10:90, 0.5 mL/min, 254 nm; tR = 40.6 min (minor), tR = 42.4 min (major). H NMR (400 MHz,
CDCl3) δ = 7.36-7.33 (m, 2H), 7.19-7.14 (m, 2H), 3.29-3.20 (m, 1H), 2.68-2.54 (m, 2H), 1.31 (d,
J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 178.5, 147.7, 130.1, 129.9, 129.6, 125.4,
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122.6, 42.3, 35.8, 21.7. The analytical data are consistent with the literature.35
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(+)-3-(3-nitrophenyl)butanoic acid (2f): Light yellow solid; 25.6 mg, 98% yield; 97% ee; [α]D
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+28.7 (c = 1.3, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex = 20:80,
1mL/min, 254 nm; tR = 10.1 min (minor), tR = 13.1 min (major). 1H NMR (400 MHz, CDCl3) δ =
8.09-8.06 (m, 2H), 7.57-7.55 (m, 1H), 7.49-7.45 (m, 1H), 3.43-3.34 (m, 1H), 2.73-2.60 (m, 2H),
1.36 (d, J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 178.3, 148.4, 147.4, 133.3, 129.6,
121.7, 42.1, 35.8, 21.7; MP: 164-166 oC. The analytical data are consistent with the literature.36
(+)-3-(3-methoxyphenyl)butanoic acid (2g): Light yellow liquid; 23.8 mg, 98% yield; 91% ee;
[α]D20 = +30.2 (c = 1.2, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex
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= 20:80, 1mL/min, 254 nm; tR = 11.7 min (minor), tR = 16.2 min (major). H NMR (400 MHz,
CDCl3) δ = 9.31 (s, 1H), 7.35-7.30 (m, 1H), 6.93-6.91 (m, 1H), 6.87-6.84 (m, 2H), 3.89 (s, 3H),
3.39-3.32 (m, 1H), 2.79-2.63 (m, 2H), 1.41 (d, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3)
δ = 178.9, 159.6, 147.1, 129.5, 119.0, 112.7, 111.5, 55.1, 42.5, 36.1, 21.7. The analytical data are
consistent with the literature.10c
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(+)-3-(2-fluorophenyl)butanoic acid (2h): Light yellow liquid; 22.3 mg, 98% yield; 96% ee; [α]D
= +18.4 (c = 1.14, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
5:95, 1mL/min, 254 nm; tR = 41.1 min (minor), tR = 43.1 min (major). 1H NMR (400 MHz, CDCl3)
δ = 7.26-7.17 (m, 2H), 7.11-7.07 (m, 1H), 7.04-7.00 (m, 1H), 3.61-3.52 (m, 1H), 2.78-2.60 (m,
2H), 1.34 (d, J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 178.7, 160.6 (d, 1JC-F = 244.2
Hz), 131.9 (d, J = 14.1 Hz), 128.0 (d, J = 1.8 Hz), 127.9 (d, J = 5.6 Hz), 124.2 (d, J = 3.4 Hz),
115.6 (d, J = 22.3 Hz), 40.8, 30.1, 20.4. The analytical data are consistent with the literature.37
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(-)-3-(2-chlorophenyl)butanoic acid (2i): Light yellow liquid; 24.3 mg, 98% yield; 93% ee; [α]D
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= -16.4 (c = 1.22, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
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20:80, 1mL/min, 254 nm; tR = 10.1 min (major), tR = 11.6 min (minor); H NMR (400 MHz,
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CDCl3) δ = 7.38-7.27 (m, 1H), 7.25-7.22 (m, 2H), 7.18-7.14 (m, 1H), 3.85-3.76 (m, 1H),
2.79-2.53 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 178.6, 142.4,
133.5, 129.8, 127.6, 127.1, 126.9, 41.0, 32.1, 20.2. The analytical data are consistent with the
literature.38
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(+)-3-(o-tolyl)butanoic acid (2j): Light yellow solid; 21.8 mg, 98% yield; 99.3% ee; [α]D20 = +16.2
(c = 1.11, CH2Cl2), [lit[13]: [α]D20 = +8.8 (c = 1.00 CHCl3) for 16% ee]; HPLC condition: Lux 5u
Cellulose-1 (250 × 4.60mm ), ipa : hex = 10:90, 1mL/min, 254 nm; tR = 21.0 min (major), tR =
22.9 min (minor). 1H NMR (400 MHz, CDCl3) δ = 9.52 (s, 1H), 7.21-7.117 (m, 4H), 3.60-3.51 (m,
1H), 2.73-2.55 (m, 2H), 2.39 (s, 3H), 1.30 (d, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ
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=179.4, 143.7, 135.3, 130.6, 126.4, 126.2, 125.0, 42.1, 31.3, 21.3, 19.5; MP: 41-43 C. The
analytical data are consistent with the literature.10d
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(-)-3-(2-nitrophenyl)butanoic acid (2k): Light yellow liquid; 25.4 mg, 97% yield; 97% ee; [α]D
=
-93.5 (c = 1.0, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60mm ), ipa : hex = 8:92,
1mL/min, 254 nm; tR = 39.6 min (minor), tR = 43.6 min (major). 1H NMR (400 MHz, CDCl3) δ =
7.68-7.66 (m, 1H), 7.50-7.46 (m, 1H), 7.36-7.34 (m, 1H), 7.29-7.25 (m, 1H), 3.77-3.68 (m, 1H),
2.72-2.52 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 177.9, 149.8,
139.4, 132.8, 127.7, 127.2, 124.2, 41.7, 30.3, 21.3. The analytical data are consistent with the
literature.10d
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(S)-3-(naphthalen-1-yl)butanoic acid (2l): Light yellow solid; 26.0 mg, 97% yield; 98% ee; [α]D
= +7.3 (c = 1.2, CH2Cl2), HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex = 20:80,
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1mL/min, 254 nm; tR = 10.5 min (major), tR = 14.4 min (minor); 1H NMR (400 MHz, CDCl3) δ =
9.70 (s,1H), 8.20-7.19 (m, 1H), 7.91-7.89 (m, 1H), 7.77-7.75 (m, 1H), 7.59-7.52 (m, 3H),
7.50-7.41 (m, 1H), 4.24-4.16 (m, 1H), 2.96-2.91 (m, 1H), 2.72-2.66 (m, 1H), 1.50 (d, J = 6.8 Hz,
3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 179.5, 141.4, 134.1, 131.1, 129.1, 127.1, 126.2, 125.6,
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123.0, 122.4, 42.3, 30.6, 21.2; MP: 82-84 C. The analytical data are consistent with the
literature.10d
(S)-3-phenylpentanoic acid (2m): Light yellow liquid; 21.8 mg, 98% yield; 94% ee; [α]D20 = +22.5
(c = 1.1, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex = 20:80,
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1mL/min, 254 nm; tR = 8.5 min (major), tR = 9.4 min (minor). H NMR (400 MHz, CDCl3) δ =
7.32-7.28 (m, 2H), 7.23-7.17 (m, 3H), 3.03-2.96 (m, 1H), 2.70-2.59 (m, 2H), 1.78-1.58 (m, 2H),
0.80 (t, J = 7.3 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 179.0, 143.7, 128.3, 127.4, 126.4,
43.5, 41.5, 29.0, 11.8. The analytical data are consistent with the literature.39
(S)-4-methyl-3-phenylpentanoic acid (2n): Light yellow liquid; 23.6 mg, 98% yield; 97% ee;
[α]D20 = -23.5 (c = 1.2, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa :
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hex = 20:80, 1mL/min, 254 nm; tR = 6.5 min (major), tR = 9.0 min (minor). H NMR (400 MHz,
CDCl3) δ = 9.30 (s, 1H), 7.05-7.01 (m, 2H), 6.97-6.95 (m, 1H), 6.93-6.89 (m, 2H), 2.66-2.52 (m,
2H), 2.39-2.33 (m, 1H), 1.66-1.58 (m, 1H), 0.70 (d, J = 6.7 Hz, 3H), 0.52 (d, J = 6.7 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ = 179.1, 142.5, 128.2, 128.1, 126.4, 48.3, 38.1, 33.0, 20.5,
20.1. The analytical data are consistent with the literature.40
(S)-3-cyclohexyl-3-phenylpropanoic acid (2o): Light yellow solid; 28.5 mg, 98% yield; 98% ee;
[α]D20 = -58.2(c = 1.3, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
20:80, 1mL/min, 254 nm; tR = 6.9 min (minor), tR = 9.7 min (major). 1H NMR (400 MHz, CDCl3)
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δ = 7.29-7.25 (m, 2H), 7.21-7.17 (m, 1H), 7.13-7.12 (m, 2H), 2.91-2.80 (m, 2H), 2.62-2.55 (m,
1H), 1.82-1.72 (m, 2H), 1.62-1.59 (m, 2H), 1.52-1.43 (m, 2H), 1.27-1.16 (m, 1H), 1.13-1.05 (m,
2H), 1.02-0.89 (m, 1H), 0.87-0.75 (m, 1H); 13C{1H}NMR (100 MHz, DMSO-d6) δ = 174.3, 143.8,
128.7, 128.3, 126.4, 47.9, 42.7, 38.1, 30.9, 30.6, 26.4, 26.3; MP: 92-94 oC. The analytical data are
consistent with the literature.39
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(R)-(+)-3-methyl-5-phenylpentanoic acid (2p): Light yellow liquid; 23.6 mg, 98% yield; 66% ee;
[α]D20 = +1.2 (c = 1.3, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60mm ), ipa : hex =
20:80, 1mL/min, 254 nm; tR = 7.2 min (minor), tR = 8.7 min (major). 1H NMR (400 MHz, CDCl3)
δ = 7.32-7.28 (m, 2H), 7.21-7.19 (m, 3H), 2.74-2.58 (m, 2H), 2.46-2.41 (m, 1H), 2.26-2.21 (m,
1H), 2.10-2.01 (m, 1H), 1.77-1.68 (m, 1H), 1.62-1.52 (m, 1H), 1.07 (d, J = 6.6 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ = 179.7, 142.2, 128.3, 128.2, 125.7, 41.7, 38.4, 33.2, 29.9,
19.5. The analytical data are consistent with the literature.41
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(-)-3-cyclohexylbutanoic acid (2q): Light yellow liquid; 20.9 mg, 98% yield; 73% ee; [α]D
=
-22.8 (c = 1.1, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex =
20:80, 1mL/min, 254 nm; tR = 6.6 min (minor), tR = 8.1 min (major). 1H NMR (400 MHz, CDCl3)
δ = 11.1 (s, 1H), 2.44 (m, 1H), 2.16 (m, 1H), 1.85 (s, 1H), 1.73 (m, 2H), 1.63 (m, 3H), 1.25-1.08
(m, 4H), 1.00-0.94 (m, 2H), 0.92-0.90 (m, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 180.5, 42.6,
39.7, 35.3, 30.2, 28.9, 26.7, 26.6, 26.6, 16.4. The analytical data are consistent with the
literature.42
(S)-3-(3,4-dichlorophenyl)-3-phenylpropanoic acid (2r): Light yellow liquid; 36.2 mg, 98% yield;
97% ee; [α]D20 = -1.0 (c = 1.4, CH2Cl2); HPLC condition: Lux 5u Cellulose-3 (250 × 4.60mm ),
ipa : hex = 20:80, 1mL/min, 254 nm ; tR = 12.5 min (major), tR = 15.8 min (minor). 1H NMR (400
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MHz, CDCl3) δ = 7.29-7.22 (m, 4H), 7.19-7.11 (m, 3H), 7.02-7.00 (m, 1H), 4.41 (t, J = 7.9 Hz,
1H), 3.04-2.93 (m, 2H). 13C{1H}NMR (100 MHz, CDCl3) δ = 177.5, 143.4, 141.9, 132.6, 130.7,
130.5, 129.6, 128.9, 127.4, 127.1, 127.0, 45.7, 40.0. The analytical data are consistent with the
literature.14
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(S)-3-(2-fluorophenyl)-3-phenylpropanoic acid (2s): Light yellow solid; 29.3 mg, 96% yield; 94%
ee; [α]D25 = +5.2 (c = 1.36, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa :
hex = 20:80, 1mL/min, 254 nm; tR = 12.1 min (major), tR = 13.4 min (minor); 1H NMR (400 MHz,
CDCl3) δ = 7.25-7.10 (m, 7H), 7.04-7.00 (m, 1H), 6.97-6.92 (m, 1H), 4.76 (t, J = 7.9 Hz, 1H),
3.06 (d, J = 8.0 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ = 177.9, 160.4 (d, 1JC-F = 244.9 Hz),
141.9, 130.2 (d, J = 14.2 Hz), 128.6, 128.4 (d, J = 4.2 Hz), 128.3 (d, J = 8.4 Hz), 127.6, 126.8,
124.2 (d, J = 3.4 Hz), 115.7 (d, J = 22.4 Hz), 40.0, 39.2; MP: 120-122 oC. The analytical data are
consistent with the literature.14
(-)-3-(3-chlorophenyl)-3-phenylpropanoic acid (2t): Light yellow solid; 31.6 mg, 97% yield; 97%
ee; [α]D20 = -12.3 (c = 1.62, CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa :
hex = 10:90, 1mL/min, 254 nm ; tR = 28.9 min (major), tR = 31.9 min (minor); 1H NMR (400 MHz,
CDCl3) δ = 7.32-7.29 (m, 2H), 7.24-7.17 (m, 6H), 7.14-7.12 (m, 1H), 4.50 (t, J = 7.9 Hz, 1H),
3.07 (d, J = 7.9 Hz, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ = 177.8, 145.2, 142.4, 134.4, 129.9,
128.8, 127.8, 127.5, 126.9, 126.9, 125.8, 46.2, 40.1; MP: 112-114 oC. The analytical data are
consistent with the literature.4
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(S)-3-phenylbutan-1-ol (4): Light yellow liquid; 18.4 mg, 98% yield; 88% ee; [α]D = -10.5 (c =
0.6, CH2Cl2); GC condition: Supelco alpha DexTM 120 column (30 m × 0.25 mm × 0.25 µm), N2
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min (major). 1H NMR (400 MHz, CDCl3) δ = 7.31-7.29 (m, 2H), 7.23-7.19 (m, 3H), 3.61-3.50 (m,
2H), 2.94-2.85 (m, 1H), 1.89-1.84 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ = 146.8, 128.3, 126.8, 125.9, 60.7, 40.7, 36.2, 22.2. The analytical data are consistent
with the literature.43
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(S)-3-phenylbutan-1-ol (6a): Light yellow liquid; 18.4 mg, 98% yield; 94% ee; [α]D20 = -11.5 (c =
0.6, CH2Cl2); GC condition: Supelco alpha DexTM 120 column (30 m × 0.25 mm × 0.25 µm), N2
1.0 mL/min, programmed 90 oC– 0.5 oC /min – 200 oC - 50 min; tR = 50.8 min (minor), tR = 51.6
min (major). 1H NMR (400 MHz, CDCl3) δ = 7.31-7.29 (m, 2H), 7.23-7.19 (m, 3H), 3.61-3.50 (m,
2H), 2.94-2.85 (m, 1H), 1.89-1.84 (m, 2H), 1.29 (d, J = 7.0 Hz, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ = 146.8, 128.3, 126.8, 125.9, 60.7, 40.7, 36.2, 22.2. The analytical data are consistent
with the literature.43
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(-)-3-(2-fluorophenyl)butan-1-ol (6b): Light yellow liquid; 20.2 mg, 96% yield; 97% ee; [α]D
=
-11.5 (c = 0.8, CH2Cl2), GC condition: Supelco gamma DexTM 120 column (30 m × 0.25 mm ×
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0.25 µm), N2 1.0 mL/min, programmed 100 C – 0.5 C /min - 200 C - 50 min; tR = 43.9 min
(minor), tR = 44.4 min (major). 1H NMR (400 MHz, CDCl3) δ = 7.11-7.00 (m, 2H), 6.97-6.93 (m,
1H), 6.89-6.84 (m, 1H), 3.43-3.42 (m, 2H), 3.15-3.06 (m, 1H), 1.76-1.71 (m, 2H), 1.41 (d, J =
1
16.6 Hz, 1H), 1.15 (d, J = 6.9 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ = 160.6 (d, JC-F
=
242.7 Hz), 133.0 (d, J = 14.4 Hz), 127.9 (d, J = 5.2 Hz), 127.2 (d, J = 8.3 Hz), 124.1 (d, J = 3.4
Hz), 115.2 (d, J = 22.9 Hz), 60.9, 39.7, 29.1, 20.8. The analytical data are consistent with the
literature.44
Synthesis of (-)-indatraline precursor 7: Chlorosulfonic acid (0.1 mL, 2.1 mmol) was slowly
added by a syringe to a solution of the acid 2r (54.0 mg, 0.18 mmol) in CH2Cl2 (2.0 mL) at room
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temperature under nitrogen. After the start material was completely consumed, the resulted
mixture was then quenched with water and extracted with CH2Cl2 for three times. The combined
organic layer was washed with brine, dried over Na2SO4, and concentrated by rotary evaporator.
The residue was subsequently purified by column chromatography (PE/EtOAc = 10:1) to give
compound 7 as a white solid (46.6 mg, 95%). MP: 107-109 oC; 95% ee; [α]D20 = - 43.8 (c = 0.5,
CH2Cl2); HPLC condition: Lux 5u Cellulose-1 (250 × 4.60mm ), ipa : hex = 10:90, 1.0 mL/min,
230 nm ; tR = 9.1 min (minor), tR = 10.5 min (major); 1H NMR (400 MHz, CDCl3) δ = 7.83 (d, J =
7.7 Hz, 1H), 7.61 (m, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.27-7.25 (m, 1H),
7.22 (d, J = 2.1 Hz, 1H), 6.95 (dd, J1= 8.3 Hz, J2= 2.1 Hz, 1H), 4.55 (dd, J1= 8.1 Hz, J2= 3.8 Hz,
1H), 3.23 (dd, J1= 19.2 Hz, J2= 8.2 Hz, 1H), 2.62 (dd, J1= 19.2 Hz, J2= 3.9 Hz, 1H); 13C{1H}NMR
(100 MHz, CDCl3) δ = 204.5, 156.3, 143.8, 136.5, 135.1, 132.6, 130.8, 130.7, 129.4, 128.1, 126.9,
126.5, 123.4, 46.2, 43.3. The analytical data are consistent with the literature.15a,16a
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ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Grant No. 21272026, 21172022,
21472013), the Ministry of Education of China (the Fundamental Research Funds for the Central
Universities, Specialized Research Fund for the Doctoral Program of Higher Education of China,
Program for Changjiang Scholars and Innovative Research Team in University), and Beijing
Municipal Commission of Education for generous financial support.
SUPPORTING INFORMATION
NMR, GC and HPLC spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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REFERENCES
6
7
8
9
(1) Jeong, K. H.; Woo, H. S.; Kim, C. J.; Lee, K. H.; Jeon, Jun. Y. ; Lee, S. Y.; Kang, J.-H.;
Lee, S.; Choi,Y. W. Int. J. Pharm. 2015, 495, 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 4907.
(3) Rupe, H.; Gassmann, A. Helv. Chim. Acta. 1936, 19, 569.
(4) Bøgesø, K. P.; Christensen A. V.; Hyttel, J.; Liljefors, T. J. Med. Chem. 1985, 28, 1817.
(5) Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey, D. T.; J. Org. Chem. 1970, 35,
1100.
(6) Manabe, Y.; Kanematsu, M.; Osaka, M.; Yoshida, M.; Shishido, K. Heterocycles 2014, 88,
441.
(7) (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (b) Takaya, Y.; Senda, T.;
Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047. (c) Sakuma,
S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951. (d) Hayashi, T.; Yamasaki, K.;
Chem. Rev. 2003, 103, 2829. (e) Hillier, M. C.; Desrosiers, J.-N.; Marcoux, J.-F.; Grabowski, E. J.
J. Org. Lett. 2004, 6, 573.
(8) (a) Taylor, J. G.; Correia, C. R. D. J. Org. Chem. 2011, 76, 857. (b) Itoh, K.; Tsuruta, A.; Ito,
J.; Yamamoto, Y.; Nishiyama, H. J. Org. Chem. 2012, 77, 10914. (c) Yoo, K.; Kim, H.; Yun, J.
Chem. -Eur. J. 2009, 15, 11134. (d) Shuto, Y.; Yamamura, T.; Tanaka, S.; Yoshimura, M.;
Kitamura, M. ChemCatChem. 2015, 7, 1547.
(9) For reviews, see: (a) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169. (b) Tietze, L. F.;
Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453. (c) Alexakis, A.; Bäckvall, J.-E.; Krause, N.;
Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796.
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Page 29 of 32
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7
8
9
(10) (a) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki,
K.; Takaya, H. J. Org. Chem. 1996, 61, 5510. (b) Saburi, M.; Takeuchi, H.; Ogasawara, M.;
Tsukahara, T.; Ishii, Y.; Ikariya, T.; Takahashi, T.; Uchida, Y. J. Organomet. Chem. 1992, 428, 155.
(c) Sun, X.; Zhou, L.; Wang, C.-J.; Zhang, X. Angew. Chem., Int. Ed. 2007, 46, 2623. (d) Dong, K.;
Li, Y.; Wang, Z.; Ding, K. Org. Chem. Front. 2014, 1, 155. (e) Mazuela, J.; Norrby, P.-O.;
Andersson, P. G.; Pàmies, O.; Diéguez, M. J. Am. Chem. Soc. 2011, 133, 13634. (f) Diéguez, M.;
Mazuela, J.; Pàmies, O.; Verendel, J. J.; Andersson, P. G. J. Am. Chem. Soc. 2008, 130, 7208. (g)
Rageot, D.; Woodmansee, D. H.; Pugin, B.; Pfaltz, A. Angew. Chem., Int. Ed. 2011, 50, 9598. (h)
Li, J.-Q.; Quan, X.; Andersson, P. G. Chem. -Eur. J. 2012, 18, 10609. (i) Khumsubdee, S.; Fan, Y.;
Burgess, K. J. Org. Chem. 2013, 78, 9969.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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35
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40
41
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43
44
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51
52
53
54
55
56
57
58
59
60
(11) (a) Cheng, X.; Zhang, Q.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed.
2005, 44, 1118. (b) Yamada, I.; Yamaguchi, M.; Yamagishi, T. Tetrahedron: Asymmetry 1996, 7,
3339. (c) Zirakzadeh, A.; Groß, M. A.; Wang, Y.; Mereiter, K.; Weissensteiner, W.
Organometallics 2014, 33, 1945. (d) Li, S.; Zhu, S.-F.; Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am.
Chem. Soc. 2008, 130, 8584. (e) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.;
Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Angew.
Chem., Int. Ed. 2005, 44, 4209. (f) Dong, K.; Li, Y.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed.
2013, 52, 14191. (g) Verendel, J. J.; Pàmies, O.; Diéguez, M.; Andersson, P. G. Chem. Rev. 2014,
114, 2130.
(12) (a) Morrison, J. D.; Burnett, R. E.; Aguiar, A. M.; Morrow, C. J.; Phillips, C. J. Am. Chem.
Soc. 1971, 93, 1301. (b) Ikemoto, T.; Nagata, T.; Yamano, M.; Ito, T.; Mizuno, Y.; Tomimatsu, K.
Tetrahedron Lett. 2004, 45, 7757. (c) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori. R. J.
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