Indolinylmethanol catalyzed enantioselective Reformatsky reaction with ketones

Article abstract of DOI:10.1016/j.tetasy.2010.11.004

A series of chiral indolinylmethanol ligands have been applied for the first time in the asymmetric Reformatsky reaction of an α-bromoester with ketones. In the presence of NiBr₂ and zinc powder, up to 75% yield and 87% ee were obtained for a v

Full text of DOI:10.1016/j.tetasy.2010.11.004

Tetrahedron: Asymmetry 21 (2010) 2816–2824
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Indolinylmethanol catalyzed enantioselective Reformatsky reaction
with ketones
⇑
Ning Lin , Miao-Miao Chen , Ren-Shi Luo, Yan-Qiu Deng, Gui Lu
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral indolinylmethanol ligands have been applied for the first time in the asymmetric Refor-
matsky reaction of an a-bromoester with ketones. In the presence of NiBr2 and zinc powder, up to 75%
yield and 87% ee were obtained for a variety of aromatic and aliphatic ketones. The use of Ni(acac)2
resulted in 96% ee although the corresponding yield was low. This process provided a convenient method
to access synthetically useful chiral b-hydroxyesters.
Received 1 October 2010
Accepted 2 November 2010
Available online 21 December 2010
This paper is dedicated to celebrate the 60th
birthday of Professor Albert S. C. Chan
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tions,11,17–20 but the systems still need to be further improved
upon since good enantioselectivities were only obtained for alde-
The Reformatsky reaction was realized in 1887 and is still
widely used in organic synthesis.1–3 It involves the zinc-induced
hyde substrates. On the other hand, we noticed that chiral in-
dole-derived catalysts have recently been successfully applied in
many reactions, such as diethylzinc addition to aldehydes,21 ke-
tone reduction,22 ring openings of meso-epoxides,23–25 desymmet-
rization of cyclic carbamates,26 aldol reactions27, and so on. Our
group also reported the application of new dihydroindole and per-
hydroindole derivatives in the asymmetric Michael reaction of
aldehydes to nitroalkenes and obtained good yields, high diastere-
oselectivities and enantioselectivities.28 Compared with pyrroli-
dine analogs, indole derivatives possessing additional
cyclohexane or phenyl rings in the backbone, may exert stronger
influences on the orientation of substrates, hence improving the
stereoselectivities for the asymmetric reaction. Herein, a series of
chiral indolinylmethanol ligands were applied for the first time
formation of b-hydroxy alkanoates from
a-halocarbonyl com-
pounds and aldehydes or ketones. The mild reaction conditions,
the excellent functional group tolerance, and the use of inexpen-
sive non-toxic metals have made it an important alternative to
the base-catalyzed aldol reaction. However, the usual heteroge-
neous reaction conditions have made the development of catalytic
stereoselective variants quite difficult. Recently, significant
improvements have been achieved in the enantioselective Refor-
matsky reaction with aldehydes,4,5 but only a few examples of ke-
tones have been reported6,7 due to the low reactivity and
decreased steric discrimination even though the resulting chiral
tertiary alcohols are important structural units present in many
biologically active compounds and synthetic intermediates.
in the asymmetric Reformatsky reaction of
ketones.
a-bromoester with
Cozzi et al. described the first practical catalytic enantioselec-
tive Reformatsky reaction to ketones using 20 mol % ClMn(salen)
1 (Fig. 1) as the chiral catalyst.8,9 Later, they developed an efficient
dimethylzinc mediated, air promoted Reformatsky reaction of both
aldehydes and ketones, employing commercially available (1R,2S)-
2. Results and discussions
2.1. Effect of ligands
N-pyrrolidinylephedrine
2
as the chiral ligand.10–12 Recently,
Feringa et al. reported a general asymmetric catalytic Reformatsky
reaction of ketones based on the use of BINOL derivatives 3.13,14
They also extended this catalytic system to more challenging dia-
rylketone substrates.15 Subsequently Hayashi et al. examined the
reaction of acetophenone with ethyl iodoacetate using chiral Schiff
base 4 to afford the adduct in 63% ee.16
At first, experiments were carried out on the Reformatsky-type
reaction of ethyl bromoacetate to acetophenone. Using an excess of
Et2Zn and 10 mol % of NiBr2, with THF as solvent and dihydroindole
derived amino alcohol as the chiral ligand, the desired product was
isolated in low yield (25%) and 96% enantioselectivity (Fig. 2). The
slow addition of Et2Zn over several hours was crucial for high ste-
reoselectivity, but was detrimental for good yield and repeatability
due to the air-sensitive organozinc reagents.
Chiral b-amino alcohols, especially pyrrolidine derivatives, have
already been used in catalytic asymmetric Reformatsky reac-
To further simplify the reaction conditions, we reasoned that a
controlled and mild formation of the zinc reagent using the less
reactive Zn powder in the presence of a chiral zinc complex, should
lead to considerable enantioselectivity but high yield. When zinc
⇑
Corresponding author. Fax: +86 20 39943048.
E-mail address: lugui@mail.sysu.edu.cn (G. Lu).
These authors contributed equally to this paper.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.004

N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
2817
TMS
N
O
N
O
Ph
Ph
OH
OH
t-Bu
Mn
Cl
t-Bu
N
OH
t-Bu
t-Bu
N
OH
TMS
t-Bu
t-Bu
OH
1 ClMn(salen)
2
3
4
Figure 1. Some efficient catalysts for the asymmetric Reformatsky reaction of ketones.
Bn
Bn
OH
Et2Zn (2.5 equiv.)
NiBr2 (10 mol%)
O
O
HO
O
+
O
Br
N
H
L
O
L (20 mol% ), THF
-20oC
6a
5a
25% yield
96% ee
Figure 2. Homogeneous Ni-catalyzed Reformatsky reaction with Et2Zn as the zinc source.
powder was used in the model reaction, we did observe a signifi-
cant improvement in yield (Table 1 entry 5). Next, we turned our
attention to the screening of various perhydroindole- and dihydr-
oindole-derived amino alcohol ligands.
the large steric hindrance as well as the strong electron-withdraw-
ing property of the 3,5-di(trifluoromethyl)phenyl substituent (en-
try 6). The highest enantioselectivity was observed for
dihydroindoline derived L5, which may be due to its suitable steric
structure, the nearly planar dihydroindoline moiety for the exis-
tence of the phenyl ring, and sp2 hybridized nitrogen. We also ob-
tained the crystal structures of L3 and L5, which were quite similar
to their molecular structures (Fig. 3 vs 4)
Table 1
Stereoselective Reformatsky reaction catalyzed by indole-derived chiral ligandsa
Zn ( 3.0 equiv )
O
O
NiBr2 ( 25 mol%)
HO
O
L (25 mol%)
Br
+
O
O
CF3COOH (12.5 mol%)
THF, 18oC
2.2. Influence of solvents
5a
6a
The effect of solvents on the catalytic Reformatsky reaction was
examined in the presence of L5 and the results are listed in Table 2.
It seems that ether solvents (such as Et2O, 1,4-dioxane and THF)
were effective in terms of both reactivity and selectivity. For exam-
ple 1,4-dioxane afforded up to 94% yield and 57% ee (entry 7), but
its high melting point (12 °C) limited its application under low
temperature. Thus we chose THF as the optimal solvent, which also
afforded comparable ee but a slightly lower yield (entry 8).
In THF, when decreasing the amount of L5 from 25 to 10 mol %,
the enantioselectivity dropped significantly from 58% to 28%, albeit
the yield rose from 71% to 93% (entries 8 vs 9). Normally a low
temperature is helpful for stereoselectivity, hence we also carried
out the reaction at 0 °C and observed a higher enantioselectivity
(81% ee) and good yield (entry 10). Increasing the reaction time
from 48 to 64 h did not influence the ee or yield (entries 10–11).
H
H
H
Ph
Bn
Bn
OH
Ph
Ph
OH
Ph
Ph
OH
Ph
N
OH
N
H
L4
N
H
N
H
H
H
L2
L1
L3
F3C
CF3
CF3
CF3
H
Bn
Bn
OH
N
N
H
OH
L6
H
H
L5
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
64
64
64
64
64
64
74
71
68
67
71
20
19
31
55
33
58
23
2.3. Influence of nickel salts29–31
Various nickel salts, such as NiBr2, NiCl2(PPh3), NiBr2ꢀdiglyme,
NiCl2, and Ni(acac)2 were examined for the Reformatsky reaction
of bromoester to ketones and the results are summarized in
Table 3. High yield (61%) and enantioselectivity (81% ee) were
achieved with NiBr2 (entry 3). When the catalyst loading was in-
creased from 15 to 25 mol %, an increase in both yield and enanti-
oselectivity were observed, but a further increase to 35 mol % only
showed considerable reactivity and selectivity with the original
25 mol % (entries 2–4). In the absence of any nickel salt, the
reaction also proceeded smoothly to give the corresponding
b-hydroxyester in relative low yield but comparable ee under
otherwise the same conditions (entry 1), which revealed that the
nickel salt may act only as a Lewis acid in this process, and the
chiral ligand that was able to coordinate with zinc was crucial
for chirality transfer.
a
b
c
Reaction conditions: PhCOMe/Zn/ligand/BrCH2CO2Et = 1.0:3.0:0.25:1.5.
Isolated yield.
Determined by HPLC analysis using a Daicel Chiralcel AS-H column.
With respect to the selectivity, monocyclic pyrrolidine derived
amino alcohol L1 showed poor enantioselectivity (19% ee) for the
asymmetric Reformatsky reaction (Table 1 entry 1). When a rigid
cyclohexane ring was attached to the pyrrolidine ring as in L2,
the ee increased slightly to 31% (entry 2). Changing the cyclohex-
ane ring to a planar benzene ring as in L3 resulted in better ee
(55%, entry 3). Chiral ligands with bulkier, less flexible phenyl sub-
stituents at the hydroxyl-bearing carbon atom L1–L3 (see Fig. 3)
showed little difference with regards to the enantioselectivity
when compared with benzyl substituents L4 and L5 (Table 1 en-
tries 2 vs 4, entries 3 vs 5). Compound L6 provided low ee due to

2818
N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
Figure 3. Molecular structures of L1–L5. The hydrogen atoms are omitted for the purpose of clarity. The indicated bond angles were estimated by Chem Draw 3D calculations
MM2).
(
Figure 4. X-ray crystal structures of L3 and L5.
The most promising results were achieved with Ni(acac)2,
A high reaction temperature led to high yield but a significant
decrease in enantioselectivity was also observed (entry 10). In view
of both reactivity and selectivity, we chose NiBr2 as the optimal
nickel salt.
which gave up to 96% ee in the Reformatsky reaction of bromoester
to acetophenone although the yield was low (18%, entry 8). The
low yield can be explained by the relatively weaker Lewis acidity
of Ni(acac)2, which can be further improved upon by increasing
the ratio of organic acid, such as CF3COOH; however, high acidity
was detrimental to the stereoselectivity (entries 8 vs 9). Other
nickel salts, such as NiBr2ꢀdiglyme, NiCl2, and NiCl2(PPh3) afforded
62–93% ees but low to moderate yields (entries 5–7). More exper-
iments and results were still needed to establish the relationship
between the sequence of Lewis acidity of the metal salts and the
yields.
2.4. Scope and limitations of the catalytic system
Next, we investigated the scope of the reaction. A variety of aro-
matic and aliphatic ketones were used in this reaction, affording
the desired b-hydroxyesters in good yields and stereoselectivities
(Table 4). The enantioselectivity was not affected by the electronic
properties of the substituents on the phenyl ring of the ketone. For

N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
2819
Table 2
Influences of solventsa
Bn
Bn
OH
Zn ( 3.0 equiv )
O
O
HO
O
NiBr2 ( 25 mol%)
Br
+
O
L5
N
H
L5
(25 mol%)
O
CF3COOH (12.5 mol%)
solvent
6a
5a
Entry
Solvent
T (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
DMF
Et2O
Toluene
DCM
CH3CN
Hexane
1,4-Dioxane
THF
THF
THF
THF
22
22
22
22
18
18
13
22
22
0
24
36
36
36
45
64
60
36
36
48
64
59
59
70
87
70
43
94
71
93
61
60
10
45
17
16
36
65
57
58
28
81
81
9d
10
11
0
a
Reaction conditions: PhCOMe/Zn/ligand/BrCH2CO2Et = 1.0:3.0:0.25:1.5.
Isolated yield.
Determined by HPLC analysis using a Daicel Chiralcel AS-H column.
10 mol % ligand.
b
c
d
Table 3
Influences of nickel saltsa
Bn
Zn ( 3.0 equiv )
Nickel salt
L5
O
O
HO
O
Bn
Br
+
O
N
H
L5
OH
O
CF3COOH (12.5 mol%)
THF, 0oC, 48h
6a
5a
Entry
Catalyst
Nickel salt (mol %)
L5 (mol %)
Yield (%)b
eec (%)
1
2
3
4
5
6
7
8
—
—
25
15
25
35
25
25
25
25
25
25
44
52
61
59
43
26
23
18
38
57
76
77
81
80
62
89
93
96
81
57
NiBr2
NiBr2
NiBr2
NiCl2(PPh3)
15
25
35
25
25
25
25
25
25
NiBr2ꢀdiglyme
NiCl2
Ni(acac)2
Ni(acac)2
Ni(acac)2
9d
10e
a
Reaction conditions: PhCOMe/Zn/BrCH2CO2Et = 1.0:3.0:1.5.
Isolated yield.
Determined by HPLC analysis using a Daicel Chiralcel AS-H column.
25 mol % CF3COOH.
b
c
d
e
Reaction was performed at 18 °C.
example, electron-donating p-methyl and p-methoxy substituted
ketones afforded comparable ees with electron-withdrawing p-
chloro, p-bromo, and p-fluoro substituted ketones (entries 2 and
3 vs entries 6–8). The steric effects of the aromatic rings of ketones
were significant; the highly sterically hindered o-chloro substi-
tuted ketone afforded 87% ee for a preferable adduct, while
m- and p-chloro substituted ketones gave 78% ee and 83% ee,
respectively (entries 4–6). 1-Tetralone and 1-indanone were con-
verted into the desired product in high enantioselective manner al-
beit with moderate yields (entries 11 and 12), presumably because
their large steric hindrances retarded the addition of the active
nucleophile. Compound L5 was also used to catalyze the Reformat-
sky reaction of heterocyclic 2-furylacetone and 2-thienylacetone
and provided the product with a bit low enantioselectivities (en-
tries 13 and 14). The poor ee might be due to the strong coordina-
tion of the oxygen and sulfur atoms in the substrate to the
organozinc reagents.
To further explore the scope of the substrates, we also investi-
gated the effectiveness of the catalyst in the asymmetric addition
to aliphatic ketones, including both saturated and unsaturated ke-
tones (entries 15 and 16). The ee for the unsaturated ketone such
as (E)-4-phenyl-3-buten-2-one was substantially higher than for
the analogous saturated ketone, which can be attributed to the de-
creased steric discrimination within aliphatic ketones.
2.5. Possible mechanism for the NiBr2–Zn catalyzed asymmetric
Reformatsky reaction
A possible mechanism is proposed in Scheme 1.32,33 The bromo-
ester reacted with zinc powder to form the Reformatsky reagent,
which coordinated with the chiral ligand to liberate active catalyst
L⁄-ZnBr and ethyl acetate. Then L⁄-ZnBr added to the acetophe-
none to form a tetra-coordinated zinc intermediate, where the ori-
entation of ketone was regulated by the steric hindrance of the

2820
N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
Table 4
Catalytic enantioselective Reformatsky reaction with various ketonesa
Zn ( 3.0 equiv )
NiBr2 ( 25 mol%)
L5 (25 mol%)
Bn
Bn
OH
O
HO R2
R1
O
O
+
N
H
L5
Br
R1
5a-p
R2
CF3COOH (12.5 mol%)
THF, 0oC
O
O
6a-p
Entry
Ketone
Acetophenone 5a
Time (h)
Yieldb (%)
eec (%)
Config.
1
2
3
4
5
6
7
8
48
60
60
48
48
48
48
48
48
48
48
48
60
60
48
48
61
60
56
73
67
68
65
70
50
65
52
57
53
64
72
75
81
87
81
87
78
83
86
82
81
70
82
71
51
62
42
28
(S)
(+)
(+)
(ꢁ)
(+)
(+)
(S)
(+)
(+)
(+)
(ꢁ)
(S)
(+)
(+)
(ꢁ)
(ꢁ)
4-Methylacetophenone 5b
4-Methoxyacetophenone 5c
2-Chloroacetophenone 5d
3-Chloroacetophenone 5e
4-Chloroacetophenone 5f
4-Bromoacetophenone 5g
4-Fluoroacetophenone 5h
2-Acetonaphthone 5i
Propiophenone 5j
1-Tetralone 5k
1-Indanone 5l
2-Furylacetone 5m
2-Thienylacetone 5n
9
10
11
12
13d
14d
15
16
(E)-4-Phenyl-3-buten-2-one 5o
4-Phenylbutan-2-one 5p
a
b
c
Reaction conditions: ketone/Zn/ligand/BrCH2CO2Et = 1.0:3.0:0.25:1.5.
Isolated yield.
Determined by HPLC analysis using Daicel Chiralcel OD-H, AD-H or AS-H columns. The absolute configurations of the products were determined by comparison with the
literature values.
d
The reaction was performed at 15 °C.
BrCH2COOEt
Zn
CH3COOEt
Br
H
N
OH
Bn
Bn
Zn
L5
O
N
Bn
Bn
(L*-ZnBr)
O
O
H+
O
HO
BrZnO
Ph
Ph
Ph
OEt
OEt
(S)
Ph
Ph
OEt
O
Br
N
O
Br
N
Zn
BrZnO
O
Bn
Bn
Zn
O
Bn
Bn
BrZnCH2COOEt
Scheme 1. Possible mechanism for the asymmetric Reformatsky reaction.
chiral ligand. Direct attack of BrZnCH2COOEt to the ketone on the
Si-face established the (S)-configuration of the organic product,
which may be readily cleaved using an acid to provide the free
alcohol. Next, L⁄-ZnBr was released from the catalytic system,
regenerating the active species and completing the catalytic cycle.
Here we postulate that the nickel salt worked only as a Lewis acid
to activate zinc,34 albeit the classical Ni0/NiII catalytic cycles have
been proposed.5,31
to enantioselectivities as high as 96% ee although the correspond-
ing yields were low. This process provided a convenient method to
access synthetically useful chiral b-hydroxyesters. Modification of
the ligand structure, as well as the development of other efficient
catalytic systems for the asymmetric Reformatsky reaction is cur-
rently underway and will be reported in due course.
4. Experimental
3. Conclusions
4.1. General methods
In conclusion, we have developed a highly enantioselective
All reactions were carried out in flame-dried glassware under a
nitrogen atmosphere. All solvents were freshly distilled prior to
use. Unless otherwise stated, commercial reagents purchased from
Alfa Aesar, Acros, and Aldrich chemical companies were used
without further purification. Purification of reaction products was
Reformatsky reaction of an
a-bromoester with various ketones
using a chiral indolinylmethanol ligand. In the presence of NiBr2
and zinc powder, b-hydroxyesters were obtained in good yields
and enantioselectivities. Changing the nickel salt to Ni(acac)2 led

N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
2821
Bn
Bn
(i) SOCl2, MeOH
BnMgBr, Et2O
COOH
COOMe
r.t., 24 h
88%
(ii) Et3N, Boc2O
91%
N
H
N
Boc
N
O
7
8
9
O
Bn
Bn
OH
KOH, MeOH,
reflux, 15 h
83 %
N
H
L5
Scheme 2. Synthesis of L5.
carried out by flash chromatography using Qing Dao Sea Chemical
Reagent silica gel (200–300 mesh). 1H NMR spectra were recorded
on a Bruker Advance III spectrometer (400 MHz) and the spectra
were referenced internally to the residual proton resonance
in CDCl3 (d = 7.26 ppm), or with tetramethylsilane (TMS, d =
0.00 ppm) as the internal standard. Chemical shifts were reported
as parts per million (ppm) in the d scale downfield from TMS. 13C
NMR spectra were recorded on a Bruker Advance III spectrometer
(400 MHz) with complete proton decoupling, and chemical shifts
were reported in ppm from TMS with the solvent as the internal
reference (CDCl3, d = 77.0 ppm). HPLC analyses were conducted
on a Shimadzu 10A instrument using Daicel Chiralcel OD-H, AD-
H, or AS-H columns (0.46 cm diameter ꢂ 25 cm length). Optical
rotations were recorded on a Perkin–Elmer polarimeter (Model
341). Mass spectra were recorded on an ESI-ion trap Mass spec-
trometer (Shimadzu LC–MS-IT-TOF). Analytical TLC was performed
using EM separations percolated silica gel 0.2 mm layer UV 254
fluorescent sheets.
oxazolo[3,4-a]indol-3(1H)-one 9 (4.67 g, 13.2 mmol, 88% yield)
(Scheme 2). 1H NMR (400 MHz, CDCl3): d 2.91 (m, 3H), 3.18 (dd,
J = 14.3, 23.4 Hz, 2H), 3.29 (dd, J = 9.2, 16.3 Hz, 1H), 4.85
(t, J = 9.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 7.12–7.30 (m, 13H); 13C
NMR (100 MHz, CDCl3):
d 29.84, 41.03, 42.33, 65.23, 86.77,
114.43, 124.25, 125.28, 127.10, 127.34, 128.10, 128.35, 128.70,
130.62, 131.10, 132.39, 134.42, 134.81, 139.97, 154.70. HRMS
(ESI-TOF): m/z calcd for C24H21NO2Na [M+Na]+ 378.1470; found:
378.1465.
KOH (14 g, 250 mmol) was added at 0 °C to a solution of the
above residue (3.27 g, 10 mmol) in MeOH (50 mL). The reaction
mixture was refluxed overnight. After cooling, the solvent was
evaporated under reduced pressure, and then 50 mL H2O was
added. The aqueous phase was extracted with CH2Cl2, washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by column chromatography to afford (S)-
2-(indolin-2-yl)-1,3-diphenylpropan-2-ol L5 (2.73 g, 8.3 mmol,
83% yield). ½a 2D0
ꢃ
¼ ꢁ18:4 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d 2.42 (s, 1H), 2.70 (d, J = 13.8 Hz, 1H), 2.78 (s, 2H), 3.10 (m, 3H),
3.56 (br s, 1H), 3.93 (t, J = 9.5 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H),
6.68 (t, J = 7.4 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.2 Hz,
1H), 7.20–7.32 (m, 10H); 13C NMR (100 MHz, CDCl3): d 31.55,
42.22, 44.10, 65.85, 75.36, 109.56, 119.03, 124.57, 126.56, 126.70,
127.34, 128.30, 128.46, 128.51, 130.31, 130.86, 137.21, 137.56,
4.2. Procedures for the preparation of ligands
Ligands L135 and L2–L428 were synthesized following the proce-
dure described in the literatures.
4.2.1. Synthesis of (S)-2-(indolin-2-yl)-1,3-diphenylpropan-2-ol
L5
150.63. HRMS (ESI-TOF): m/z calcd for
C
23H24NO[M+H]+
330.1858; found: 330.1850.
At first, BnMgBr (1 M in Et2O, 60 mL, 60 mmol) was added drop-
wise at 0 °C to a solution of methyl ester 828 (4.16 g, 15 mmol) in
Et2O (30 mL). The resulting mixture was warmed to room temper-
ature and gradually heated at reflux overnight under a nitrogen
atmosphere. The reaction was quenched with saturated NH4Cl,
and the aqueous phase was extracted with Et2O. The combined or-
ganic extracts were washed with brine, dried over MgSO4, and con-
centrated under reduced pressure. The residue was purified by
column chromatography to afford (S)-1,1-dibenzyl-9,9a-dihydro-
4.2.2. Synthesis of (S)-(3,5-bis(trifluoromethyl)phenyl)-
((2S,3aS,7aS)-octahydro-1H-indol-2-yl) phenyl) methanol L6
At first, ClCOOEt (6.0 mL, 63 mmol) was added to a solution of
10 (4.89 g, 28.9 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 40 mL of
MeOH, then the reaction mixture was stirred at room temperature
for 48 h. The solvent was evaporated and 50 mL of saturated
Na2CO3 was added. The aqueous phase was extracted with CH2Cl2,
and the combined organic extracts were dried with anhydrous
F3C
F3C
CF3
CF3
CF3
H
H
H
H
H
H
MgBr
ClCOOEt
COOMe
N
OH
COOEt
COOH
Et2O, 0 o
92%
C
K2CO3, MeOH, rt
98%
N
N
H
CF3
COOEt
10
12
11
F3C
CF3
CF3
H
KOH, MeOH
N
H
OH
85 oC
91%
H
CF3
L6
Scheme 3. Synthesis of L6.

2822
N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
Na2SO4 and concentrated under reduced pressure to afford product
1.0 mL/min, UV detection at 208 nm, tminor = 7.67 min, tmajor =
9.05 min, ee 81%.
1128 as an oil (7.23 g, 98% yield) (Scheme 3). 1H NMR (400 MHz,
CDCl3):
d 1.05–1.27 (m, 5H), 1.31–1.43 (m, 2H), 1.54–1.67
(m, 3H), 1.91–2.05 (m, 3H), 2.25 (d, J = 4.2 Hz, 1H), 3.68 (s, 3H),
3.70–3.83 (m, 1H), 3.96–4.07 (m, 2H), 4.16–4.25 (m, 1H).
4.3.2. (+)-Ethyl 3-hydroxy-3-p-tolylbutanoate 6b36
½
a 2D0
ꢃ
¼ þ7:1 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.14
A solution of methyl ester 11 (3.0 g, 16.4 mmol) in Et2O (10 mL)
was added dropwise to a solution of 3,5-di-CF3-PhMgBr (3 M in
Et2O, 22 mL, 65 mmol) at 0 °C. The resulting mixture was stirred
at 0 °C for 3 h. The reaction was quenched with aqueous saturated
NH4Cl, and the aqueous phase was extracted with Et2O. The com-
bined organic extracts were washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography to afford product 12 as a white
solid (9.8 g, 92% yield). 1H NMR (400 MHz, CDCl3): d 0.74–0.89
(m, 2H), 1.14–1.29 (m, 7H), 1.38–1.67 (m, 3H), 1.84–1.91
(m, 1H), 2.13–2.21 (m, 1H), 3.67–3.74 (m, 1H), 3.97–4.05
(m, 1H), 4.12–4.20 (m, 1H), 4.87 (dd, J = 7.0, 11.0 Hz, 1H), 7.79
(s, 1H), 7.83 (d, J = 6.7 Hz, 3H), 7.89 (s, 2H), 8.22 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 14.37, 20.07, 23.47, 25.38, 27.11, 32.30,
35.29, 59.46, 62.77, 67.81, 80.84, 121.92, 124.50, 127.94, 128.98,
131.01, 131.34, 131.60, 131.93, 144.17, 146.36, 159.38.
KOH (21.12 g, 377 mmol) was added at 0 °C to a solution of 12
(9.8 g, 15.08 mmol) in MeOH (75 mL). The reaction mixture was re-
fluxed overnight. After cooling, the solvent was evaporated under
reduced pressure, 100 mL of H2O was added. The aqueous phase
was extracted with CH2Cl2, washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography to afford pure product L6 as a
(t, J = 7.1 Hz, 3H), 1.52 (s, 3H), 2.32 (s, 3H), 2.77 (d, J = 15.9 Hz,
1H), 2.95 (d, J = 15.9 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 4.33 (s, 1H),
7.13 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d 14.00, 20.93, 30.71, 46.45, 60.67, 72.62, 124.37, 128.91,
136.36, 143.97, 172.72. HPLC conditions: Daicel Chiralcel AS-H
column, hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection
at 214 nm, tminor = 7.55 min, tmajor = 8.72 min, ee 87%.
4.3.3. (+)-Ethyl 3-hydroxy-3-(4-methoxyphenyl)butanoate 6c37
½
a 2D0
ꢃ
¼ þ4:2 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.15
(t, J = 7.1 Hz, 3H), 1.52 (s, 3H), 2.76 (d, J = 15.8 Hz, 1H), 2.94
(d, J = 15.8 Hz, 1H), 3.79 (s, 3H), 4.06 (q, J = 7.1 Hz, 2H), 4.34
(s, 1H), 6.86 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d 14.01, 30.73, 46.53, 55.22, 60.70, 72.48,
113.52, 125.65, 139.07, 158.40, 172.74. HPLC conditions: Daicel
Chiralcel AS-H column, hexane/i-PrOH 99:1, flow rate 1.0 mL/min,
UV detection at 234 nm, tminor = 17.66 min, tmajor = 21.48 min, ee
81%.
4.3.4. (ꢁ)-Ethyl 3-(2-chlorophenyl)-3-hydroxybutanoate 6d9
½
a 2D0
ꢃ
¼ ꢁ5:6 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.09
(t, J = 7.1 Hz, 3H), 1.72 (s, 3H), 2.94 (d, J = 16.0 Hz, 1H), 3.57
(d, J = 15.9 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 4.69 (s, 1H), 7.19
(t, J = 7.5 Hz, 1H), 7.30 (m, 2H), 7.86 (dd, J = 1.2, 7.9 Hz, 1H); 13C
white solid (13.7 g, 91% yield). ½a D20
ꢃ
¼ ꢁ50:6 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): d 1.23–1.36 (m, 3H), 1.46–1.69 (m, 8H),
2.05–2.13 (m, 1H), 3.31 (dd, J = 5.6, 11.3 Hz, 1H), 4.39
(t, J = 8.1 Hz, 1H), 5.24 (s, 1H), 7.76 (d, J = 6.7 Hz, 2H), 7.96
(s, 2H), 8.06 (s, 2H). 13C NMR (100 MHz, CDCl3): d 21.97, 23.35,
28.26, 30.34, 32.08, 36.98, 56.64, 63.91, 75.79, 121.25, 121.50,
121.84, 124.54, 125.57, 126.00, 131.62, 131.91, 131.95, 132.24,
NMR (100 MHz, CDCl3): d 13.91, 27.18, 43.77, 60.71, 73.08,
126.94, 128.02, 128.56, 130.43, 131.16, 142.92, 172.92. HPLC con-
ditions: Daicel Chiralcel AS-H column, hexane/i-PrOH 99:1, flow
rate 1.0 mL/min, UV detection at 214 nm, tminor = 6.78 min, tmajor
=
7.48 min, ee 87%.
146.53, 149.47. HRMS (ESI-TOF): m/z calcd for
C25H20NOF12
4.3.5. (+)-Ethyl 3-(3-chlorophenyl)-3-hydroxybutanoate 6e
[MꢁH]+ 578.1353; found: 578.1354.
½
a 2D0
ꢃ
¼ þ2:9 (c 0.8, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.15
(t, J = 7.1 Hz, 3H), 1.52 (s, 3H), 2.78 (d, J = 16.0 Hz, 1H), 2.94
(d, J = 16.0 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 4.47 (s, 1H), 7.25 (m,
3H), 7.47 (t, J = 1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 13.98,
30.52, 46.14, 60.88, 72.50, 122.73, 125.03, 127.01, 129.54, 134.25,
149.10, 172.48. HRMS (ESI-TOF): m/z calcd for C12H15O3ClNa
[M+Na]+ 265.0607; found: 265.0586. HPLC conditions: Daicel Chi-
ralcel OD-H column, hexane/i-PrOH 99:1, flow rate 0.5 mL/min, UV
detection at 226 nm, tminor = 17.12 min, tmajor = 18.23 min, ee 78%.
4.3. Typical procedure for the Reformatsky reaction of ketones
with ethyl bromoacetate
Under a nitrogen atmosphere, zinc powder (97.5 mg, 1.5 mmol),
NiBr2 (27.3 mg, 0.125 mmol), ligand L5 (41.2 mg, 0.125 mmol), and
anhydrous THF (1 mL) were added to a dried Schlenk flask. Then
the mixture was stirred at 0 °C, after which the ketone (0.5 mmol)
and ethyl bromoacetate (83
flask via syringe. The suspension was stirred for 10 min, and
then CF3COOH (5 L, 0.0625 mmol) was added to activate the zinc
lL, 0.75 mmol) were added to the
4.3.6. (+)-Ethyl 3-(4-chlorophenyl)-3-hydroxybutanoate 6f9
l
½
a 2D0
ꢃ
¼ þ14:8 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.15
powder. The reaction mixture was stirred at 0 °C for 48 h and
quenched with 1 M hydrochloric acid (8 mL). Then 8 mL of diethyl
ether were added. The aqueous layer was extracted with Et2O
(8 mL ꢂ 2) and the combined organic layers were washed with
saturated brine (4 mL), and dried over Na2SO4. Evaporation of
the solvent and flash chromatography (hexane/ethyl acetate
20:1) gave a colorless oil. The enantiomeric excess was deter-
mined by HPLC with Daicel Chiralcel OD-H, AD-H or AS-H
columns.
(t, J = 7.1 Hz, 3H), 1.52 (s, 3H), 2.77 (d, J = 16.0 Hz, 1H), 2.93
(d, J = 16.0 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 4.43 (s, 1H), 7.30
(d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d 13.99, 30.62, 46.20, 60.88, 126.04, 128.35, 132.69,
145.47, 172.55. HPLC conditions: Daicel Chiralcel AS-H column,
hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at
208 nm, tminor = 10.06 min, tmajor = 11.71 min, ee 83%.
4.3.7. (S)-(+)-Ethyl 3-(4-bromophenyl)-3-hydroxybutanoate 6g9
½
a 2D0
ꢃ
¼ þ13:9 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.15
4.3.1. (S)-(ꢁ)-Ethyl 3-hydroxy-3-phenylbutanoate 6a9
a 2D0
ꢃ
¼ ꢁ12:1 (c 1.7, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.13
(t, J = 7.1 Hz, 3H), 1.51 (s, 3H), 2.77 (d, J = 16.0 Hz, 1H), 2.93
(d, J = 16.0 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 4.43 (s, 1H), 7.33
(d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz,
½
(t, J = 7.1 Hz, 3H), 1.54 (s, 3H), 2.79 (d, J = 15.9 Hz, 1H), 2.97
(d, J = 15.9 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 4.37 (s, 1H), 7.23
(dt, J = 4.0, 7.2 Hz, 1H), 7.33 (t, J = 7.3 Hz, 2H), 7.45 (d, J = 7.9 Hz,
2H). 13C NMR (CDCl3, 100 MHz): d 13.98, 30.63, 46.47, 60.71,
72.75, 124.46, 126.84, 128.22, 146.85, 172.68. HPLC conditions:
Daicel Chiralcel AS-H column, hexane/i-PrOH 99:1, flow rate
CDCl3):
d 14.00, 30.56, 46.15, 60.87, 72.50, 120.82, 126.43,
131.29, 146.03, 172.50. HPLC conditions: Daicel Chiralcel OD-H
column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV detection
at 234 nm, tminor = 5.56 min, tmajor = 6.09 min, ee 86%.

N. Lin et al. / Tetrahedron: Asymmetry 21 (2010) 2816–2824
2823
4.3.8. (+)-Ethyl 3-(4-fluorophenyl)-3-hydroxybutanoate 6h
110.15, 141.52, 158.47, 172.30. HPLC conditions: Daicel Chiralcel
OD-H column, hexane/i-PrOH 98:2, flow rate 1.0 mL/min, UV
detection at 254 nm, tmajor = 8.89 min, tminor = 12.25 min, ee 51%.
½
a 2D0
ꢃ
¼ þ7:5 (c 0.7, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.14
(t, J = 7.1 Hz, 3H), 1.53 (s, 3H), 2.77 (d, J = 15.9 Hz, 1H), 2.94
(d, J = 15.9 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 4.44 (s, 1H), 7.01
(t, J = 8.7 Hz, 2H), 7.42 (m, 2H). 13C NMR (100 MHz, CDCl3): d
12.95, 29.65, 45.45, 59.77, 71.47, 113.79, 114.00, 125.22, 125.30,
141.70, 141.73, 159.50, 161.93, 171.56. HRMS (ESI-TOF): m/z calcd
for C12H15O3FNa [M+Na]+ 249.0903; found: 249.0889. HPLC condi-
tions: Daicel Chiralcel OD-H column, hexane/i-PrOH 99:1, flow rate
4.3.14. (+)-Ethyl 3-hydroxy-3-(thiophen-2-yl)butanoate 6n13
½
a 2D0
ꢃ
¼ þ4:2 (c 0.8, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.19 (t,
J = 7.1 Hz, 3H), 1.63 (s, 3H), 2.81 (d, J = 15.9 Hz, 1H), 2.98 (d,
J = 15.9 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.74 (s, 1H), 6.89 (dd,
J = 1.2, 3.5 Hz, 1H), 6.92 (dd, J = 3.6, 5.0 Hz, 1H), 7.18 (dd, J = 1.1,
5.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 14.02, 31.40, 46.96,
60.91, 71.87, 122.01, 124.00, 126.68, 152.25, 172.38. HPLC condi-
tions: Daicel Chiralcel OD-H column, hexane/i-PrOH 98:2, flow rate
0.5 mL/min, UV detection at 254 nm, tminor = 15.34 min, tmajor
18.78 min, ee 82%.
=
4.3.9. (+)-Ethyl 3-hydroxy-3-(naphthalen-2-yl)butanoate 6i
1.0 mL/min, UV detection at 234 nm, tmajor = 8.85 min, tminor =
10.43 min, ee 62%.
½
a 2D0
ꢃ
¼ þ15:4 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.09 (t,
J = 7.1 Hz, 3H), 1.62 (s, 3H), 2.87 (d, J = 15.9 Hz, 1H), 3.07 (d,
J = 15.9 Hz, 1H), 3.99–4.05 (m, 2H), 4.54 (s, 1H), 7.42–7.47 (m,
2H), 7.54 (d, J = 8.9 Hz, 1H), 7.81 (t, J = 7.7 Hz, 3H), 7.93 (s, 1H).
13C NMR (100 MHz, CDCl3): d 13.99, 30.64, 46.36, 60.76, 72.93,
123.08, 123.17, 125.79, 126.08, 127.48, 128.01, 128.21, 132.40,
133.21, 144.29, 172.68. HRMS (ESI-TOF): m/z calcd for C16H18O3Na
[M+Na]+ 281.1154; found: 281.1163. HPLC conditions: Daicel Chi-
ralcel AD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min, UV
detection at 234 nm, tminor = 8.31 min, tmajor = 10.45 min, ee 81%.
4.3.15. (ꢁ)-(E)-Ethyl 3-hydroxy-3-methyl-5-phenylpent-4-
enoate 6o9
½
a 2D0
ꢃ
¼ ꢁ14:3 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.23 (t,
J = 7.1 Hz, 3H), 1.42 (s, 3H), 2.65 (d, J = 15.5 Hz, 2H), 4.06 (s, 1H),
4.14 (q, J = 7.1 Hz, 2H), 6.27 (d, J = 16.0 Hz, 1H), 6.64 (d,
J = 16.0 Hz, 1H), 7.20–7.30 (m, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.36
(d, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 14.16, 28.44,
45.67, 60.77, 71.28, 126.50, 127.51, 127.87, 128.53, 134.85,
136.76, 172.43. HPLC conditions: Daicel Chiralcel AS-H column,
hexane/i-PrOH 99:1, flow rate 1.0 mL/min, UV detection at
226 nm, tminor = 17.81 min, tmajor = 22.68 min, ee 42%.
4.3.10. (S)-(+)-Ethyl 3-hydroxy-3-phenylpentanoate 6j9
½
a 2D0
ꢃ
¼ þ11:8 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.77 (t,
J = 7.4 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H), 1.81 (dq, J = 4.5, 7.2 Hz, 2H),
2.79 (d, J = 15.8 Hz, 1H), 2.96 (d, J = 15.8 Hz, 1H), 4.02 (q, J = 7.1 Hz,
2H), 4.33 (s, 1H), 7.23 (dd, J = 8.4, 15.6 Hz, 1H), 7.32 (t, J = 7.7 Hz,
2H), 7.39–7.41 (m, 2H). 13C NMR (100 MHz, CDCl3): d 7.74, 13.89,
35.85, 45.04, 60.55, 75.17, 125.16, 126.63, 127.99, 145.25, 172.83.
HPLC conditions: Daicel Chiralcel OD-H column, hexane/i-PrOH
95:5, flow rate 0.8 mL/min, UV detection at 210 nm, tminor = 13.83
min, tmajor = 15.38 min, ee 70%.
4.3.16. (ꢁ)-Ethyl 3-hydroxy-3-methyl-5-phenylpentanoate 6p9
½
a 2D0
ꢃ
¼ ꢁ2:0 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.28 (t,
J = 7.1 Hz, 3H), 1.31 (s, 3H), 1.81–1.89 (m, 2H), 2.49 (d, J = 15.6 Hz,
1H), 2.57 (d, J = 15.6 Hz, 1H), 2.68–2.75 (m, 2H), 3.65 (s, 1H), 4.18
(q, J = 7.1 Hz, 2H), 7.17–7.20 (m, 3H), 7.25–7.29 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 14.06, 14.20, 26.75, 30.32, 43.90, 45.07,
46.04, 60.67, 61.72, 70.83, 125.80, 128.35, 128.42, 142.29, 172.88.
HPLC conditions: Daicel Chiralcel OD-H column, hexane/i-PrOH
95:5, flow rate 0.5 mL/min, UV detection at 210 nm, tminor = 15.76 -
min, tmajor = 18.07 min, ee 28%.
4.3.11. (ꢁ)-Ethyl 2-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-
yl) acetate 6k9
½
a 2D0
ꢃ
¼ ꢁ10:2 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.26 (t,
J = 7.1 Hz, 3H), 1.75–1.83 (m, 1H), 1.89–2.00 (m, 2H), 2.06–2.12 (m,
1H), 2.74 (d, J = 15.5 Hz, 1H), 2.78–2.82 (m, 2H), 2.86 (d, J = 15.5 Hz,
1H), 4.00 (s, 1H), 4.18 (q, J = 14.1 Hz, 2H), 7.06 (d, J = 7.0 Hz, 1H),
7.14–7.21 (m, 2H), 7.54–7.56 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 14.17, 19.99, 29.46, 36.35, 46.14, 60.78, 71.12, 126.32, 126.38,
127.38, 128.86, 136.47, 140.65, 172.49. HPLC conditions: Daicel
Chiralcel AD-H column, hexane/i-PrOH 95:5, flow rate 1.0 mL/min,
UV detection at 208 nm, tminor = 8.96 min, tmajor = 11.02 min, ee
82%.
4.4. Crystal structure determination
Diffraction data were collected on a Bruker Smart Apex CCD dif-
fractometer with graphite monochromated Mo-K
a radiation
(k = 0.71073 Å). All intensity data were corrected for Lorentz and
polarization effects, and empirical absorption corrections based
on equivalent reflections were applied (SADABS). The structures were
solved with direct methods and refined with the full-matrix least-
squares method on F2 with SHELXTL program package.38 All non-
hydrogen atoms were refined with anisotropic displacement
parameters. The hydrogen atoms were generated geometrically.
CCDC-770575 (L3), 770576 (L5) contained the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
4.3.12. (S)-(ꢁ)-Ethyl 2-(1-hydroxy-2,3-dihydro-1H-inden-1-yl)-
acetate 6l9
½
a 2D0
ꢃ
¼ ꢁ6:1 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.27 (t,
J = 7.1 Hz, 3H), 2.28 (t, J = 6.8 Hz, 2H), 2.69 (d, J = 15.8 Hz, 1H),
2.81–2.85 (m, 1H), 2.88 (d, J = 15.8 Hz, 1H), 3.01–3.08 (m, 1H),
4.12 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 7.20–7.27 (m, 3H), 7.33–7.35
(m, 1H); 13C NMR (100 MHz, CDCl3): d 14.15, 29.38, 40.31, 43.95,
60.86, 81.05, 122.86, 124.96, 126.80, 128.48, 142.73, 146.00,
172.72. HPLC conditions: Daicel Chiralcel OD-H column, hexane/
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 20772161), Scientific Research Foundation for the Returned
Overseas Chinese Scholars and the Program for New Century Excel-
lent Talents in University (both from the State Education Ministry
of China) for the financial support of this study.
i-PrOH 95:5, flow rate 1.0 mL/min, UV detection at 210 nm, tminor
8.66 min, tmajor = 10.59 min, ee 71%.
=
4.3.13. (+)-Ethyl 3-(furan-2-yl)-3-hydroxybutanoate 6m9
½
a 2D0
ꢃ
¼ þ7:1 (c 0.8, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.22 (t,
J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 2.72 (d, J = 15.8 Hz, 1H), 2.98
(d, J = 15.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.35 (s, 1H), 6.24 (d,
J = 3.2 Hz, 1H), 6.29–6.30 (m, 1H), 7.32 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 14.02, 27.63, 44.47, 60.79, 69.64, 104.56,
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