L-Proline amide-catalyzed direct asymmetric aldol reaction of aldehydes with chloroacetone

Article abstract of DOI:10.1016/j.tet.2005.09.061

L-Proline amides were evaluated for catalyzing the direct aldol reaction of 4-nitrobenzaldehyde with chloroacetone. The presence of 30 mol% (S)-pyrrolidine-2-carboxylic acid (2,4,6-trimethyl-phenyl)-amide catalyzed the direct aldol reactions of a range of

Full text of DOI:10.1016/j.tet.2005.09.061

Tetrahedron 62 (2006) 346–351
L-Proline amide-catalyzed direct asymmetric aldol reaction
of aldehydes with chloroacetone
a,b,c
a,b
Zhuo Tang, Lin-Feng Cun, Ai-Qiao Mi, Yao-Zhong Jiang
a,b
a,b
a,b
Long He,
a,b,
and Liu-Zhu Gong
*
a
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, People’s Republic of China
b
Graduate School of Chinese Academy of Sciences, Beijing, People’s Republic of China
College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637002, China
c
Received 5 July 2005; revised 24 August 2005; accepted 9 September 2005
Available online 10 October 2005
Abstract—L-Proline amides were evaluated for catalyzing the direct aldol reaction of 4-nitrobenzaldehyde with chloroacetone. The presence
of 30 mol% (S)-pyrrolidine-2-carboxylic acid (2,4,6-trimethyl-phenyl)-amide catalyzed the direct aldol reactions of a range of aldehydes
with chloroacetone to give anti-a-chloro-b-hydroxyketones with high regio-, diastereo- and enantioselectivity.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
reaction of fluoroacetone with aldehydes to regio- and
diastereoselectively afford anti-a-fluoro-b-hydroxy-
aketones with good enantioselectivities (up to 87% ee).
1
3
The aldol reaction has emerged as one of the most powerful
1
carbon–carbon bond-forming reactions. The asymmetric
However, the aldol reaction with chloroacetone as a donor
has not yet been documented. Optically active a-chloro-
carbonyl compounds are very useful in organic synthesis,
the development of efficient method to access these
molecules is therefore, of great importance. An important
advance has been made on the asymmetric catalytic
electronic a-chloronation of carbonyl compounds, which
is considered a direct method to obtain optically active
2
direct aldol reaction, because of its atom-economy, has
recently received great attention, and thus many chiral
3
catalyst including biocatalysts,
4
transition metal
have been discov-
–6
7–12
complexes,
and organocatalysts
ered for this transformation. The direct aldol reaction of an
unsymmetric ketone with an aldehyde principally generates
the b-hydroxyketone as a mixture of its regio-, diastereo-,
and enantiomers. It is quite difficult to control the reaction to
produce a single isomer. b-Hydroxyketones have been used
as donors in the direct aldol reactions promoted by
1
4
a-chloroketone or -esters. The direct aldol reaction of
chloroacetone with aldehydes provides an alternative to
a-chloronation for preparing a-chloroketones (Scheme 1).
Encouraged by our recent success in the L-proline amide
3
4b,5b
biocatalysts, chiral transition metal complexes,
7
and
Both 1,2- and 1,4-diols with high
i–k,11
10
organocatalysts.
catalyzed direct aldol reactions, we herein extend the
enantioselectivities can be regioselectively approached
under suitable reaction conditions. Very recently, Zhong
and Barbas reported a L-prolinol catalyzed direct aldol
application of these organocatalysts (Fig. 1) to the direct
aldol reaction of chloroacetone. As a result, high
enanantioselectivities of up to 98% ee were provided for
Scheme 1. Aldol reactions of aldehydes with chloroacetone.
Keywords: Organocatalyst; L-proline amides; Direct aldol reaction; Asymmetric catalysis; Chloroacetone.
Corresponding author. Fax: C86 28 85223978; e-mail: gonglz@cioc.ac.cn
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.061

L. He et al. / Tetrahedron 62 (2006) 346–351
347
Figure 1. L-proline amides evaluated in this study.
7
i–k,11
anti-a-chloro-b-hydroxyketones by an optimal L-proline
amide.
chloroacetone relative to hydroxyacetone
and fluoro-
1
3
acetone. The L-proline amides 4a and 4c, which exhibited
higher enantioselectivity than their diastereomers 4b and 4d
at catalyzing the direct aldol reaction of aldehydes with
acetone, however, catalyzed the reaction of 4-nitrobenz-
aldehyde with chloroacetone in lower yields and enantio-
selectivities (entries 1–4). We previously reported that
simple L-proline amides such as 5a–g catalyzed the direct
aldol reaction of 4-nitrobenzaldehyde with acetone with
very low enantioselectivity (up to 45% ee). Surprisingly,
most of them showed higher enantioselectivities than 4a–d,
of which 5a–d mediated the reaction with higher than 90%
ees (entries 5–8). Results from organocatalysts 5a–c
demonstrated that the electron-nature of the substituent on
the phenyl group of L-proline amide does not affect the
enantiochemical outcome dramatically (entries 5–7). The
sterical bulkiness of the aryl group in the organocatalyst
trends to be an important factor to influence the reaction
selectivity, for example, 5d enabled the best result in the
2
. Results and discussion
2
.1. The direct aldol reaction of 4-nitrobenzaldehyde
with chloroacetone catalyzed by L-proline amides 4 and
: catalyst screening
5
The catalytic efficiency of L-proline amides 4 and 5 was
evaluated by the direct aldol reaction of 4-nitrobenzalde-
hyde with chloroacetone at room temperature in THF. The
results are summarized in Table 1.
All the L-proline amides catalyzed the reaction to give anti-
3
0
as a favored product, however, low to moderate yields for
-chloro-4-hydroxy -4-(4 -nitro-phenyl)-butan-2-one (2a)
2
a were obtained probably due to low reactivity of
a
Table 1. Screening organocatalysts 4 and 5
b
c
d
e
Entry
Catalyst
Yield (%)
Regioselectivity (2a/3a)
dr (anti/syn)
ee (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
5a
5b
5c
5d
23
37
19
36
25
24
29
42
33
28
Trace
8
4:1
5:1
8:1
4:1
4:1
4:1
3:1
7:1
5:1
O20:1
—
3:1
9:2
3:1
9:2
6:1
9:1
9:1
12:1
9:2
12:1
—
82
89
78
88
92
90
92
94
87
86
—
74
5e
5f
5g
1
1
1
0
1
2
L-proline
—
—
a
b
c
d
e
Unless indicated otherwise, the reaction of aldehyde (0.5 mmol) with chloroacetone (l.0 mL) in THF (1.0 mL) in the presence of 20 mol% organocatalyst.
Isolated yield of 2a.
The ratio of 2a/3a is that of the diastereomers/regioisomer, and calculated on the basis of the isolated yields of 2a and 3a.
Determined by H NMR.
Determined by HPLC.
1

348
L. He et al. / Tetrahedron 62 (2006) 346–351
a
Table 2. Effect of catalyst loading on the reaction
b
c
d
e
Entry
Amount of 5d (mol%)
Yield (%)
Regioselectivity
dr (anti/syn)
ee (%)
1
2
3
4
5
20
30
40
45
50
42
57
56
55
53
7:1
7:1
7:1
7:1
6:1
12:1
7:1
5:1
5:1
4:1
94
91
89
88
86
a
The reaction of aldehyde (0.5 mmol) with chloroacetone (l mL) was performed in THF (1.0 mL).
Isolated yield of 2a.
b
c
d
e
The ratio of 2a/3a is that of the diastereomers/regioisomer, and calculated on the basis of the isolated yields of 2a and 3a.
Determined by H NMR.
Determined by HPLC.
1
model reaction (entry 8). The proton on the amide function
of the organocatalyst determines the catalytic efficacy.
Thus, small organic molecule 5g, which was derived from
Another possibility to enhance the conversion is variation of
the amount of chloroacetone. In the presence of 30 mol%
catalyst 5d, the direct aldol reaction of 4-nitrobenzaldehyde
with different amounts of chloroacetone was carried out.
As shown in Table 3, the yield, diastereo- and enantio-
selectivity are independent on the amount of chloroacetone.
However, regioselectivity gradually decreases as the
amount of chloroacetone increases (entries 1–5). Study on
the temperature effect revealed that the yield could be
improved by performing the reaction at low temperature
5
d by a methylation, failed to catalyze the reaction (entry
11). However, the reaction proceeded incompletely in the
presence of 20 mol% L-proline to give 2a in only 8% yield
with 74% ee (entry 12).
2
.2. Optimization of reaction conditions
(
entries 6–8). However, both diastereo- and enantioselec-
L-proline amide 5d was found to be the best for the reaction
in terms of enantioselectivity among all the organocatalysts
tested (Table 1), but it gave only moderate yield. In
principle, variation of the catalyst loading will change the
reaction conversion. We therefore, investigated the relation-
ship between the amount of organocatalyst 5d and reaction
conversion, and hoped that the yield of the desired product
tivity dropped as the decrease in the reaction temperature.
For example, when the reaction was carried on at K10 8C,
significantly high yield of 76% was isolated, but the dr of
anti/syn was only 2:1 and enantioselectivity was decreased
to 87% ee (entry 8).
In organocatalyzed direct aldol reactions, the solvent affects
the reaction performance dramatically. Some common
organic solvents were therefore, examined for the reaction
of chloroacetone with 4-nitrobenzaldehyde. The related
results are presented in Table 4. It was found that the use of
THF, diethyl ether or 1-dioxane as a solvent gave better
results in terms of both yield and enantioselectivity than the
use of other organic solvents (entries 1–7). Performing the
2
a would be improved by using increased amounts of 5d.
The reaction of 4-nitrobenzaldehyde with chloroacetone
was performed in THF at room temperature with various
amounts of 5d. The results are recorded in Table 2. The
yield was increased to 57% by using 30 mol% 5d (entry 2),
however, the yield could not be further improved as the
catalyst loading was increased (entries 3–5). In addition to
that, both diastereo- and enantioselectivity dropped to some
degree with the increase of the catalyst loading (entries
reaction in a polar solvent, for example, in either CH CN or
3
DMSO, provided an excellent enantioselectivity, but a poor
yield (entries 4 and 5). Neither chloroform nor toluene is a
good solvent for the reaction. Although fair yields were
1–5). In terms of the yield and enantioselectivity, 30 mol%
of 5d can be considered an optimal catalyst loading.
a
Table 3. Effects of the amount of chloroacetone and the reaction temperature
b
c
d
e
Entry
Amount of
chloroacetone (mL)
Temperature (8C)
Yield (%)
Regioselectivity
dr (anti/syn)
ee (%)
1
2
3
4
5
6
7
8
0.4
0.6
0.8
1
2
1
25
25
25
25
25
10
0
56
56
56
57
50
58
68
76
17:1
10:1
7:1
7:1
8:1
5:1
5:1
6:1
6:1
7:1
7:1
7:1
6:1
5:1
3:1
2:1
89
89
89
91
89
89
88
87
1
1
K10
a
The reaction was performed on a 0.5 mmol scale in THF (1.0 mL) in the presence of 30 mol% 5d.
Isolated yield of 2a.
The ratio of 2a/3a is that of the diastereomers/regioisomer, and calculated on the basis of the isolated yields of 2a and 3a.
Determined by H NMR.
Determined by HPLC.
b
c
d
e
1

L. He et al. / Tetrahedron 62 (2006) 346–351
349
a
Table 4. Solvent effect
b
c
d
e
Entry
Solvent
THF
Yield (%)
Regioselectivity
dr (anti/syn)
ee (%)
1
2
3
4
5
6
7
57
45
34
23
22
33
49
7:1
8:1
5:1
4:1
9:1
5:1
7:1
7:1
5:1
5:1
4:1
6:1
3:1
2:1
91
90
90
90
92
74
79
Et
Dioxane
CH CN
DMSO
CHCl
Toluene
2
O
3
3
a
The reaction of 4-nitrobenzaldehyde (0.5 mmol) with chloroacetone (1 mL) was performed in a solvent (1.0 mL) in the presence of 30 mol% 5d at room
temperature.
b
c
d
e
Isolated yield of 2a.
The ratio of 2a/3a is that of the diastereomers/regioisomer, and calculated on the basis of the isolated yields of 2a and 3a.
1
Determined by H NMR.
Determined by HPLC.
observed when the reaction were carried out in chloroform
and toluene, diastereo- and enantioselectivity were much
lower than those with THF as the solvent (entries 6 and 7).
3. Conclusion
A series of L-prolinamides, derived from L-proline and
optically pure 1,2-diphenyl-2-aminoethanols, simple ali-
phatic, and aromatic amines, were evaluated for catalyzing
the direct aldol reaction of chloroacetone and 4-nitro-
benzaldehyde. The proton of the amide function in the
organocatalyst determined its catalytic efficacy. An
L-proline amide 5d, which was prepared from L-proline
and 2,4,6-trimethyl-phenylamine, was found to be the best
catalyst. Under the optimal conditions, the direct adol
reactions of chloroacetone with aldehydes catalyzed by
2
.3. Scope and limitations
Under the optimal conditions, a range of aldehydes
including aromatic and aliphatic ones were examined to
react with chloroacetone. As demonstrated in Table 5, the
organocatalyst 5d exhibited generally excellent enantio-
selectivities ranging from 91–98% ee for most of aldehydes
tested, with exception of the case involving 2-chloro-
benzaldehyde, in which 86% ee was provided (entry 5).
The ortho-substituted benzaldehydes reacted much more
diastereoselectively than para- and meta-substituted benz-
aldehydes with chloroacetone (entries 1–8). Diastereomeric
ratios of anti/syn from 10:1 to 30:1 were obtained for
benzaldehyde derivatives bearing an ortho-substituent
30 mol% 5d gave rise to anti-a-chloro-b-hydroxyketones
with high diastereo- and enantioselectivity.
4
. Experimental
4.1. General
(
entries 2, 5, 7, and 8). On the contrary, much lower drs
of anti/syn from 5:1 to 7:1 were given for para- and meta-
substituted benzaldehydes (entries 1, 3, 4, and 6). The
aliphatic aldehyde is less reactive than aromatic aldehydes
toward chloroacetone. Low yield of 18% was therefore,
observed for cyclohexylformaldehyde, but a very high
enantioselectivity of 98% ee was induced (entry 9).
Chemicals were purchased from Acros and organic solvents
were distilled before use. NMR spectra were recorded on a
Bruker-300 MHz spectrometer. High-resolution mass
spectra were recorded on a Bruker BIO TOF Q mass
spectrometer. Infrared spectra were recorded on a Nicolet
MX-1E FT-IR spectromter. HPLC analysis was performed
a
Table 5. Study on the scope and limitation of aldehydes
b
c
d
e
Entry
Product
R
Yield (%)
Regioselectivity
dr (anti/syn)
ee (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
4-NO
2-NO
3-NO
2
2
2
C
C
C
6
6
6
H
H
H
4
4
4
57
35
37
31
52
40
28
43
18
7:1
4:1
7:1
30:1
5:1
7:1
19:1
6:1
10:1
29:1
31:1
91
93
94
91
86
O20:1
O20:1
O20:1
O20:1
5:1
4-CNC
2-ClC
4-MeO
2-FC
2-BrC
c-C
6
H
4
6
H
4
f
2
CC
6
H
4
91
f
6
H
4
97
91
f
6
H
4
5:1
O20:1
f
6
H
11
98
a
Unless indicated otherwise, the reaction of aldehyde (0.5 mmol) with chloroacetone (l mL) was performed in THF (1.0 mL).
Overall yield of anti-2 and syn-2.
The ratios of 2/3 were calculated on the basis of the isolated yields of 2 and 3, and the enantioselectivities of 3 were not determined.
Determined by H NMR.
Determined by HPLC.
The reaction was performed at 0 8C.
b
c
d
e
f
1

350
L. He et al. / Tetrahedron 62 (2006) 346–351
0
one (2d). Yield: 31%, as a 7:1 inseparable mixture of
on Waters-Breeze (2487 Dual l Absorbance Detector and
525 Binary HPLC Pump). Chiralpak AS, AD columns
were purchased from Daicel Chemical Industries, LTD.
Chiral GC analysis was performed on VARIAN CP-3380
with a CP CHIPASIL-DEX column.
4.2.4. 3-Chloro-4-hydroxy-4-(4 -cyanophenyl)-butan-2-
1
1
anti-2d and syn-2d. Anti-2d: H NMR (300 MHz, CDCl ): d
3
(ppm) 2.38 (d, JZ3.6 Hz, 3H), 3.28 (d, JZ4.2 Hz, 1H),
4.24 (d, JZ8.1 Hz, 1H), 5.07 (dd, JZ8.1, 4.2 Hz, 1H), 7.51
1
3
(
d, JZ8.3 Hz, 2H), 7.67 (d, JZ8.3 Hz, 1H); C NMR
(75 MHz, CDCl ): 28.0, 63.6, 74.0, 112.4, 118.5, 127.9,
132.2, 143.9, 202.9; IR (KBr): g 3438, 2921, 2230, 1718,
4.2. General procedure for the direct aldol reaction of
chloracetone with aldehydes
3
K1
1
360, 1052, 837, 795 cm . Enantiomeric excess:
To a solution of an aldehyde (0.5 mmol) and chloroacetone
(
91%; determined by HPLC (Daicel Chiralpak AS,
i-PrOH/hexaneZ15:85), UV 254 nm, flow rate 1.0 mL/
min, tRminorZ21.30 min; tRmajorZ25.27 min; HR-MS for
1.0 mL) in anhydrous THF (1.0 mL) was added L-pro-
linamide 5d (34.8 mg, 0.15 mmol). After being stirred at
room temperature for 96 h, the reaction was quenched with
saturated aqueous ammonium chloride. The aqueous layer
was extracted with ethyl acetate (3!15 mL). The combined
organic layers were washed with brine (3!10 mL) and
C
H
10ClNO
: calcd 223.0395; found: 223.0399.
11
2
0
one (2e). Yield: 52%, as a 19:1 inseparable mixture of anti-
4.2.5. 3-Chloro-4-hydroxy-4-(2 -chlorophenyl)-butan-2-
1
2e and syn-2e. Anti-2e: H NMR (300 MHz, CDCl ): d
dried over anhydrous MgSO . After removal of solvent
4
3
under reduced pressure, the residue was purified through a
flash column chromatography on silica gel to give desired
aldol products 2.
(ppm) 2.31 (s, 3H), 3.36 (d, JZ5.2 Hz, 1H), 4.54 (d, JZ
6.5 Hz, 1H), 5.48 (dd, JZ6.5, 5.2 Hz, 1H), 7.25–7.35 (m,
2H), 7.37–7.40 (m, 1H), 7.48–7.51 (m, 1H); C NMR
13
(75 MHz, CDCl ): d (ppm) 28.1, 46.6, 63.2, 127.2, 128.1,
129.7, 129.7, 132.9, 136.2, 202.8; IR (neat): g 3453, 2926,
3
0
one (2a). Yield: 57%, as a 7:1 inseparable mixture of
4
.2.1. 3-Chloro-4-hydroxy-4-(4 -nitrophenyl)-butan-2-
K1
1721, 1439, 1358, 1032, 756, 699 cm . Enantiomeric
1
anti-2a and syn-2a. Anti-2a: H NMR (300 MHz, CDCl ): d
excess: 86%, determined by HPLC (Daicel Chiralpak AS,
i-PrOH/hexaneZ15:85), UV 254 nm, flow rate 1.0 mL/min,
3
(
ppm) 2.38 (s, 3H), 3.86 (d, JZ4.2 Hz, 1H), 4.26 (d, JZ
8
.1 Hz, 1H), 5.12 (dd, JZ8.1, 4.2 Hz, 1H), 7.57 (d, JZ
.7 Hz, 2H), 8.19 (d, JZ8.7 Hz, 2H); C NMR (75 MHz,
t
C
RminorZ6.726 min; tRmajorZ8.411 min; HR-MS for
10Cl : calcd 232.0052; found: 232.0062.
1
3
8
CDCl ): d (ppm) 27.9, 63.5, 73.8, 123.5, 127.3, 128.1,
10
H
O
2 2
3
1
1
9
45.9, 202.9; IR (neat): g 3488, 2947, 1718, 1606, 1519,
4.2.6. 4-(2-Chloro-1-hydroxy-3-oxo-butyl)-benzoic acid
methyl ester (2f). Yield: 40%, as a 6:1 inseparable mixture
K1
348, 1085, 857, 699 cm . Enantiomeric excess:
1%, determined by HPLC (Daicel Chiralpak AS,
1
of anti-2f and syn-2f. Anti-2f: H NMR (300 MHz CDCl ):
3
i-PrOH/hexaneZ15:85), UV 254 nm, flow rate 1.0 mL/
min, tRminorZ18.498 min; tRmajorZ23.248 min; HR-MS for
C H ClNO : calcd 243.0294; found: 243.0314.
d 2.36 (s, 3H), 3.17 (d, JZ4.2 Hz, 1H), 3.92 (s, 3H), 4.30 (d,
JZ7.9 Hz, 1H), 5.07 (dd, JZ7.9, 4.2 Hz, 1H), 7.47 (d, JZ
8.2 Hz, 2H), 8.03 (d, JZ8.2 Hz, 2H); C NMR (75 MHz,
1
3
1
0
10
4
CDCl ): d (ppm) 27.9, 52.2, 63.9, 74.5, 127.1, 128.7, 129.7,
143.6, 166.7, 203.0; IR (neat): g 3510, 2956, 1726, 1709,
3
0
one (2b). Yield: 35%, as a 30:1 inseparable mixture of
4
.2.2. 3-Chloro-4-hydroxy-4-(2 -nitrophenyl)-butan-2-
K1
1700, 1435, 1291, 1118, 1107, 1047, 767, 705 cm
.
1
anti-2b and syn-2b. Anti-2b: H NMR (300 MHz, CDCl ): d
Enantiomeric excess: 91%; determined by HPLC (Daicel
Chiralpak AD, i-PrOH/hexaneZ15:85), UV 254 nm, flow
rate 1.0 mL/min, tRminorZ8.687 min; tRmajorZ11.108 min;
3
(
ppm) 2.40 (s, 3H), 2.82 (br s, 1H), 4.55 (d, JZ7.0 Hz, 1H),
5
2
2
2
8
9
.73 (d, JZ7.0 Hz, 1H), 7.49–7.55 (m, 1H), 7.65–7.74 (m,
13
H), 7.97 (m, 1H); C NMR (75 MHz, CDCl ): d (ppm)
HR-MS for C12
H
13ClO
: calcd 256.0497; found: 256.0488.
3
4
8.1, 63.3, 70.9, 124.8, 129.2, 129.4, 133.4, 133.8, 148.5,
02.9; IR (neat): g 3485, 2925, 1718, 1525, 1344, 1097,
0
one (2g). Yield: 28%, as a 10:1 inseparable mixture of
4.2.7. 3-Chloro-4-hydroxy-4-(2 -fluorophenyl)-butan-2-
K1
57, 789, 744, 703 cm
.
Enantiomeric excess:
3%, determined by HPLC (Daicel Chiralpak AS,
1
anti-2g and syn-2g. Anti-2g: H NMR (300 MHz, CDCl ): d
3
i-PrOH/hexaneZ15:85), UV 254 nm, flow rate 1.0 mL/
min, tRminorZ13.707 min; tRmajorZ15.46 min; HR-MS for
C H ClNO : calcd 243.0293; found: 243.0288.
(ppm) 2.35 (s, 3H), 3.27 (br s, 1H), 4.46 (d, JZ7.7 Hz, 1H),
5.31 (d, JZ7.7 Hz, 1H), 7.04–7.44 (m, 4H); C NMR
13
(75 MHz, CDCl ): d (ppm) 27.8, 63.1, 69.7, 115.4 (d, JZ
1
0
10
4
3
2
1.7 Hz), 124.4 (d, JZ2.9 Hz), 125.9 (d, JZ12.8 Hz),
0
one (2c). Yield: 37%, as a 5:1 inseparable mixture of anti-
4
.2.3. 3-Chloro-4-hydroxy-4-(3 -nitrophenyl)-butan-2-
128.4 (d, JZ3.5 Hz), 130.2 (d, JZ8.3 Hz), 158.6 (d, JZ
245.4 Hz), 202.9; IR (neat): g 3431, 2924, 1718, 1490,
1358, 1228, 1030, 757 cm . Enantiomeric excess:
1
c and syn-2c. Anti-2c: H NMR (300 MHz, CDCl ): d
K1
2
3
(
4
(
8
ppm) 2.40 (d, JZ2.5 Hz, 3H), 3.46 (d, JZ3.2 Hz, 1H),
.27 (d, JZ8.3 Hz, 1H), 5.12 (dd, JZ8.3, 3.2 Hz, 1H), 7.53
m, 1H), 7.72 (d, JZ7.7 Hz, 1H), 8.18–8.21 (m, 1H), 8.27–
97%; determined by HPLC (Daicel Chiralpak AS,
i-PrOH/hexaneZ15:85), UV 254 nm, flow rate 1.0 mL/
min; tRminorZ8.601 min; tRmajorZ9.142 min; HR-MS for
1
3
.30 (m, 1H); C NMR (75 MHz, CDCl ): d (ppm) 27.9,
C
10
H10ClFO
2
: calcd 216.0348; found:216.0341.
3
6
IR (neat): g 3482, 2928, 1719, 1531, 1352, 1096, 737,
6
3.5, 73.7, 122.1, 123.5, 129.4, 133.4, 141.0, 148.1, 203.0;
0
one (2h). Yield: 43%, as a 29:1 inseparable mixture of anti-
4.2.8. 3-Chloro-4-hydroxy-4-(2 -bromophenyl)-butan-2-
K1
92 cm . Enantiomeric excess: 94%; determined by
1
2h and syn-2h. Anti-2h: H NMR (300 MHz, CDCl ): d
HPLC (Daicel Chiralpak AS, i-PrOH/hexaneZ15:85),
UV 254 nm, flow rate 1.0 mL/min; tRminorZ15.024 min;
tRmajorZ16.960 min; HR-MS for C H ClNO : calcd
3
(ppm) 2.32 (s, 3H), 3.35 (br s, 1H), 4.56 (d, JZ6.4 Hz, 1H),
5.46 (dd, JZ6.4, 4.9 Hz, 1H), 7.18–7.26 (m, 1H), 7.34–7.39
(m, 1H), 7.46 (dd, JZ7.8, 1.7 Hz, 1H), 7.56 (dd, JZ8.0,
10
10
4
2
43.0293; found: 243.0305.

L. He et al. / Tetrahedron 62 (2006) 346–351
351
1
.2 Hz, 1H); C NMR (75 MHz, CDCl ): d (ppm) 28.2,
3
1
(b) Trost, B. M.; Ito, H.; Siloff, E. R. J. Am. Chem. Soc. 2001,
123, 3367.
3
6
IR (neat): g 3439, 2944, 1716, 1357, 1031, 762 cm
3.2, 74.1, 123.0, 127.8, 128.3, 130.0, 132.9, 137.8, 202.8;
K1
.
6. Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc.
2003, 125, 8706.
Enantiomeric excess: 91%; determined by HPLC (Daicel
Chiralpak AS, i-PrOH/hexaneZ15:85), UV 254 nm, flow
rate 1.0 mL/min; tRminorZ7.056 min; tRmajorZ8.289 min;
HR-MS for C H ClBrO : calcd 275.9547; found:
7. For reviews, see: (a) List, B. Tetrahedron 2002, 58, 5573.
(b) List, B. Synlett 2001, 1675. (c) Alcaide, B.; Almendros, P.
Angew. Chem., Int. Ed. 2003, 42, 858. (d) List, B. Acc. Chem.
Res. 2004, 37, 548. (e) Notz, W.; Tanaka, F.; Barbas, C. F., III
Acc. Chem. Res. 2004, 37, 580. (f) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. For leading literatures.
see: (g) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615. (h) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int.
Ed. Engl. 1971, 10, 496. (i) List, B.; Lerner, R. A.; Barbas,
C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (j) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001,
1
0
10
2
2
75.9554.
4
.2.9. 4-Cyclohexyl-3-chloro-4-hydroxy-butan-2-one
2i). Yield: 18%, as a 31:1 inseparable mixture of anti-2i
(
and syn-2i. Anti-2i: H NMR (300 MHz CDCl ): d (ppm)
1
3
1
2
.09–1.32 (m, 6H), 1.58–1.76 (m, 5H), 2.36 (s, 3H), 2.37–
.42 (m, 1H), 3.76 (m, 1H), 4.19 (d, JZ7.8 Hz, 1H);
1
3
C
NMR (75 MHz, CDCl ): d (ppm) 25.7, 25.9, 26.2, 27.6,
3
2
9.8, 38.9, 61.8, 76.1, 203.9; IR (neat): g 3461, 2958, 2929,
1
23, 5260. (k) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122,
K1
718, 1357, 1083, 789 cm . Enantiomeric excess: 98%,
1
determined by chiral GC analysis (CP CHIRASIL-DEX),
7
386. (l) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798. (m) C o´ rdova, A.; Notz, W.; Barbas,
C. F., III J. Org. Chem. 2002, 67, 301. (n) Bøgevig, A.;
Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun.
inject temperature 240 8C, column temperature 145 8C, FID
Oven temperature 260 8C, inlet pressure 10 psi, tRminorZ
6
calcd 204.0911; found: 204.0908.
.465 min, tRmajorZ6.732 min; HR-MS for C H ClO ,
10 17 2
2
002, 620. (o) Pidathala, C.; Hoang, L.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2003, 42, 2785. (p) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 2152. (q) Casas, J.; Engqvist, M.;
Ibrahem, I.; Kaynak, B.; C o´ rdova, A. Angew. Chem., Int. Ed.
Acknowledgements
2
005, 44, 1343.
. (a) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
004, 15, 1831. (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito,
We are grateful for financial support from National Natural
Science Foundation of China (projects 20472082,
8
9
2
2
03900505 and 20325211).
S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. For
review, see: (c) Saito, S.; Yamamoto, H. Acc. Chem. Res.
2
004, 37, 570.
. (a) Martin, H. J.; List, B. Synlett 2003, 1901. (b) Kofoed, J.;
Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13,
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