Highly efficient direct a larger-scale aldol reactions catalyzed by a flexible prolinamide based-metal Lewis acid bifunctional catalyst in the presence of water

Article abstract of DOI:10.1016/j.jorganchem.2011.12.006

In this work, four prolinamide-based organocatalysts were readily synthesized and applied to the asymmetric direct aldol reactions of ketones and aromatic aldehydes in the presence of water. When TFA was used as an acidic additive, 10 mol % loading of 1c

Full text of DOI:10.1016/j.jorganchem.2011.12.006

Journal of Organometallic Chemistry 702 (2012) 19e26
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Highly efficient direct a larger-scale aldol reactions catalyzed by a flexible
prolinamide based-metal Lewis acid bifunctional catalyst in the presence of water
,
a
a,
Guodong Chen a, Xiangkai Fu a , Chao Li , Chuanlong Wu b, Qiang Miao a
*
a College of Chemistry and Chemical Engineering Southwest University, Research Institute of Applied Chemistry Southwest University, The Key Laboratory of Applied Chemistry of
Chongqing Municipality, Chongqing 400715, China
b Chongqing Unis Chemical Co. Ltd., Chongqing 402161, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, four prolinamide-based organocatalysts were readily synthesized and applied to the
asymmetric direct aldol reactions of ketones and aromatic aldehydes in the presence of water. When TFA
was used as an acidic additive, 10 mol % loading of 1c afforded aldol products with good diaster-
eoselectivity of up to 91/9 and enantioselectivity of up to 85%. When ZnCl2 was added as a metal Lewis
acid additive, the aldol product could be obtained with up to 99/1 dr and 96% ee. This novel prolinamide
based-metal Lewis acid bifunctional organocatalyst 1c can be efficiently used in a larger-scale reactions
with the enantioselectivities being maintained at the same level, which offers a great possibility for
application in industry.
Received 1 October 2011
Received in revised form
28 November 2011
Accepted 6 December 2011
Keywords:
Prolinamide base
Metal Lewis acid
Aldol reaction
Aqueous medium
A larger-scale
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
develop a novel class of metal Lewis acid-enamine bifunctional
catalysts with the intention to bridge more traditional transition-
Enantioselective organocatalysis has provided
a
research
metal catalysis with the newly established prosperous area of
organocatalysis.
avenue in which to explore the fundamental chemical parameters
such as reactivity, selectivity, and mechanism and in turn leads to
the discovery of many valuable reactions and catalysts [1e3].
Several efficient asymmetric methodologies for this reaction using
organocatalysts have been developed, of which the most remark-
able advances in the domain of proline and its derivative catalysts
were made by List [4e7] and Barbas [8e11], MacMillan [12e15],
Gong [16e20], Hayashi [21e24] and Xiao [25,26] et al. In the past
several years, major efforts on modifying proline and chiral
enamine catalysts have been focused on modification of the
carboxylic acid group by introducing electronic and/or steric factors
to optimize the interaction between the Brønsted acid and the aldol
acceptor through hydrogen bonding [27e32]. In searching for new
methodology, a lot of chiral bifunctional catalysts that tried to
imitate natural enzymatic processes have been designed in asym-
metric synthesis. Several examples of this sort have been reported
[33e36], in which a proline/pyrrolidine molecule was mixed with
a transition metal to establish the bi/multifunctional catalytic
system. We utilize a prolinamide and a metal Lewis acid and
The catalysts’ structure can be easily tuned by introducing
different metals and/or different simple chiral ligand. The combi-
nation of organocatalysis with transition-metal catalysis has
emerged as a promising strategy to discover new carbonecarbon
and carboneheteroatom forming reactions.
Metal complex in the presence of water is not trivial, since most
of them are decomposed under aqueous conditions. Nevertheless,
a few examples of water-tolerant Lewis acids have previously been
reported by Kobayashi and others [37e42]. Use of water clearly has
many advantages, such as its low cost, safety, and environmentally
benign nature. Several interesting reactions with unique reactivity
and selectivity have been demonstrated to proceed in water or
watereorganic solvents [43e47], but the development of an
asymmetric aqueous aldol reaction is still going on. The direct aldol
systems by using the methods analogue to the actions of aldolase
type II containing a zinc cofactor have still remained challenging. In
fact, there were only a few reports for direct aldol reactions
promoted by the metal complexes with N-donor ligands in the
presence of water until now [48e50]. So a highly efficient, stereo-
selective, and atom economical reaction in water is currently
a sought-after goal in chemistry.
* Corresponding author. Tel.: þ86 23 6825 3704; fax: þ86 23 6825 4000.
E-mail address: fxk@swu.edu.cn (X. Fu).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.12.006

20
G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
Despite the potentials of multi/bifunctional catalysts, the
development of these systems is a formidable task due to the
simultaneous requirements for the distance, rigidity, orientation
and interactions of these functional groups. According to the
mechanism of type II aldolase, four bidentate ligands tethered with
chiral amines were prepared (Fig. 1). We expect that the Zn2þ ion
may co-ordinate to ketone and can promote the formation of
ketone-enolate, although the asymmetric ligand provides a chiral
environment, resulting in the enantioselectivity of the current
system (Fig. 2) [33e35]. In this work, compared to the traditional
organocatalysts, the activity and diastereoselectivity of these
catalysts were significantly enhanced for the asymmetric direct
aldol reactions, and this catalyst can be used in a larger-scale
reactions with the enantioselectivity being maintained at the
same level, which offers a great possibility for application in
industry.
Fig. 2. Proposed transition state.
temperature. All the bifunctional catalysts showed activities.
Zn(OTf)2 and HgCl2 displayed high activities in terms of dr and
reaction time. However, the enantioselectivities were modest (90
and 92% ee; Table 2, entries 2, 6). Counteranions of the metal salts
also played a role in determining the yield and enantioselectivity.
Whereas CuCl2 and CuCl gave reasonable ee values of 92 and 93% in
modest yield, these results strongly suggest that metals participate
in the reactions. The effect of catalyst loading on the aldol reaction
of cyclohexanone with 4-nitrobenzaldehyde using ligand 1c/ZnCl2
was examined (Table 2, entries 1, 11, 12, 13). The use of 10 mol % of
1c seemed to be the best for the reaction (entry 1).
Reactions in which water is used as the solvent are another
important issue and the development of enantioselective reactions
in aqueous media is a partner [51,52]. To prove the principle, the
bifunctional catalysts were prepared by stirring ligand 1c with
metal salts in a molar ratio of 1:1 in corresponding solvent(s)
extensively investigated topic. In this regard, direct aldol reactions
in the presence of water seem to be a challenging issue which needs
to be intensively explored. From Table 2, the use of an EtOHeH2O
solution instead of THFeH2O and DMSOeH2O mixtures improved
the reaction further (Table 2, entries 1, 9, 10), and finally, at higher
concentration and still at room temperature, the reaction pro-
ceeded in higher yield and with high selectivity. We also review the
ratio of EtOH and water (entries 1, 7, 8, 14, 15), the best result was
observed when the ratio of ethanol to water was 1:1 (1 mL), and
2. Results and discussion
2.1. Screening of catalysts in the reaction between cyclohexanone
and p-nitrobenzaldehyde
In this report we present the combination of a chiral metal
complex catalyst for asymmetric aldol reactions which proceed in
aqueous organic solvent. Here we present our studies toward the
identification of chiral metal complexes that function as efficient
aldol reaction catalysts. These ligands can be readily obtained
through coupling reactions of cyclohexanediamine with amino
acids. The reactions were carried out between cyclohexanone and
p-nitrobenzaldehyde in aqueous media. As shown by Table 1, all the
designed chiral prolinamide derivatives worked well in the direct
aldol reactions and gave the desired
b-hydroxy ketone in good
yields and good enantioselectivities. Addition of ZnCl2 could obvi-
ously improve the diastereoselectivities and enantioselectivities
(entries 2, 4, 6, 8). Furthermore, the reaction time consumedly
reduced. The best result with respect to yield and enantioselectivity
was observed with prolinamide ligand 1c and ZnCl2 as additive 99%
yield, 99:1 dr (anti/syn), and 96% ee (anti). The loading amount of
ZnCl2 in the reaction was also investigated. The use of 10 mol % of
ZnCl2 seemed to be the best for the reaction (entry 6). Although
lower loading of ZnCl2 slightly decreased in both yields and selec-
tivities (entry 11), no improvement was detected when more than
5 mol % ZnCl2 was used (entries 9, 10).
Table 1
Screening of catalysts in the reaction between cyclohexanone and p-nitrobenzaldehyde.a
2.2. Effects of catalyst loading, solvents and various metal salts on
the organocatalyzed direct aldol reaction
In our case, the prolinamide ligand 1c could activate the ketone
via an enamine intermediate and at the same time interact with
various metal salts to activate the aldehyde for 2e4 h at room
Entry
Cat.
ZnCl2 (mol%)
Time
Yieldb [%]
anti:sync [%]
eed [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1c
1c
1c
0
10
0
10
0
10
0
10
20
15
5
36
24
36
24
36
24
36
24
7
90
97
85
95
92
99
91
95
99
99
90
89:11
99:1
86:14
90:10
91:9
99:1
96:4
99:1
90:10
92:8
76
86
69
85
85
96
74
92
79
93
94
9
10
11
12
36
94:6
a
The reaction was performed with p-nitrobenzaldehyde (0.25 mmol), cyclo-
hexanone (4 equiv.), catalyst (10 mol %), ZnCl2 (10 mol %) in the EtOHeH2O (1:1,
1.0 mL) at room temperature.
b
Isolated yield after chromatography on silica gel.
c
Determined by chiral 1H NMR analysis, major product is anti.
d
Determined by chiral HPLC analysis of the anti-product.
Fig. 1. Structure of the prolinamide-based ligand 1 used in this study.

G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
21
Table 2
Table 3
The direct catalytic asymmetric aldol reaction in the presence of water catalyzed by
The asymmetric aldol reactions of cyclohexanone with various aryl aldehydes in the
prolinamide 1c (10 mol %) with various additives, metal salt, solvent.a
presence of water.a
Entry
1
Product
No.
2
Yieldb [%]
99
anti:sync [%]
eed [%]
Entry Metal
Solvent
Time Yielde[%] anti:synf [%] eeg[%]
1
ZnCl2
EtOHeH2O
EtOHeH2O
24
24
36
36
24
24
5
99
95
90
92
95
97
99
99
95
95
99
99
90
97
95
99:1
99:1
91:9
90:10
93:7
95:5
87:13
85:15
91:9
93:7
90:10
92:8
95:5
91:9
92:8
96
90
92
93
88
92
85
87
90
91
90
92
94
82
75
93:7
96
2
Zn(OTf)2
3
CuCl2$2H2O EtOHeH2O
4
CuCl
EtOHeH2O
EtOHeH2O
EtOHeH2O
H2O
EtOH
THFeH2O
5
6
7
8
FeCl3$6H2O
HgCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
2
3
4
3
4
5
97
90
95
94:6
91:9
99:1
87
91
99
5
12
9
10
11b
12c
13d
14h
15i
DMSOeH2O 24
EtOHeH2O
EtOHeH2O
EtOHeH2O
EtOHeH2O
EtOHeH2O
10
20
36
20
20
a
The reaction was performed with p-nitrobenzaldehyde (0.25 mmol), cyclo-
hexanone (4 equiv.), catalyst 1c (10 mol %), metal salt (10 mol %) in the solvent
(1.0 mL) at room temperature.
b
20 mol % 1c was additive.
15 mol % 1c was additive.
5 mol % 1c was additive.
c
5
6
93
99:1
99
d
e
Isolated yield after chromatography on silica gel.
f
Determined by chiral 1H NMR analysis.
g
Determined by chiral HPLC analysis of the anti-product.
h
6
7
8
7
8
9
90
92
95
90:10
96:4
95:5
93
94
85
VEtOH/VH2O ¼ 5:1.
I
VEtOH/VH2O ¼ 1:5.
99% chemical yield and 96% ee value were obtained. As expected,
when EtOH or H2O were used alone as the solvent, the results is not
satisfactory (entries 7, 8).
2.3. The asymmetric aldol reactions of ketone with various aryl
aldehydes in the presence of water
To test the substrate generality of this organocatalyzed direct
aldol reaction, the reactions of various aromatic aldehydes with
cyclohexanone were studied under the optimized conditions. The
results are summarized in Table 3. It can be seen that a wide range
of aromatic aldehydes can effectively participate in the aldol reac-
tion, and aldol adducts 2e14 derived from their corresponding
aromatic aldehydes and cyclohexanone could be accessed. In the
presence of 10 mol % catalyst 1c and ZnCl2 (10 mol %), most reac-
tions between cyclohexanone and various aromatic aldehydes
afforded the aldol products in excellent yields and perfect ee values.
In general, the reaction between cyclohexanone and aromatic
9
10
11
12
13
14
85
83
80
90
92
82:18
93:7
90
96
87
92
90
10
11
12
90:10
93:7
aldehydes bearing electron-withdrawing substituents furnished b-
hydroxy carbonyl aldol products in excellent yields (80e99%)
enantioselectivities (85e99% ee for anti-isomer) and excellent
diastereoselectivities (anti/syn 80:20 to 99:1; Table 3, entries 1e13).
The feasibility of using other cyclic and acyclic ketones as aldol
donors was then examined. As showed in Table 4, when 4-
methylclohexanone was used as an aldol donor, a good dr of 98:2
with excellent ee 96% for the antisomer were received. We also
examined the feasibility of using acyclic ketones, such as hydrox-
yacetone, acetone et al. as aldol donors. Although a longer reaction
time was required in comparison with cyclic ketones, satisfactory
results were obtained. The proline derivative organocatalyst 1c
13
92:8
a
The reaction was performed with p-nitrobenzaldehyde (0.25 mmol), cyclo-
hexanone (4 equiv.), catalyst 1c (10 mol %), metal salt (10 mol %) in the solvent
(1.0 mL) at room temperature.
b
Isolated yield after chromatography on silica gel.
c
Determined by chiral 1H NMR analysis.
d
Determined by chiral HPLC analysis of the anti-product.

22
G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
Table 5
Large-scale asymmetric aldol reactions.a
Table 4
Direct asymmetric aldol reactions between ketones and aromatic aldehydes in the
presence of water, catalyzed by 1c.a
Entry Product
Time Yieldb [%] anti:sync [%] eed [%]
1
24
95
98:2
96
Entry
1
Product
No. Time Yieldb[%] anti:sync[%] eed[%]
15 24
95
92
90:10
92:8
96
95
2
3
24
24
24
93
92
87
97:3
98:2
90:10
99
99
87
2
16 24
4
3
4
17 24
97
90
98:2
8:92
92
95
a
The reaction was performed with aldehyde (20 mmol), ketone (4 equiv.),
catalyst 1c (10 mol %), ZnCl2 (10 mol %) in the EtOHeH2O (1:1, 80 mL) at room
temperature.
b
The combined isolated yield of the diastereomers.
18 36
c
Determined by 1H NMR analysis, major product is anti.
d
Determined by HPLC analysis of the anti-product.
catalyzed direct aldol reactions of hydroxyacetone and acetone
et al. (Table 4, entries 4e10) and the aldol products were obtained
in high yields (up to 97%) with excellent enantioselectivities (up to
99% ee).
5
6
19 36
92
97
11:89
18:82
96
20 36
>99
2.4. The screen of a larger-scale reactions between cyclohexanone
and aryl aldehydes
A larger-scale asymmetric aldol reactions were then performed
with 20 mmol of aromatic aldehydes and 4 equiv. of ketones. The
same catalyst loading of 10 mol % as used in the experimental scale
was used. The larger-scale experiments proceeded smoothly using
the same procedure as for the experimental scale reactions. As can
be seen from the results summarized in Table 5, the enantiose-
lectivities were maintained at the same level for the larger-scale
reactions which offers great possibilities for applications in
industry.
7
8
21 36
92
90
e
e
79
95
22 36
9
23 36
87
94
e
93
85
3. Conclusion
In summary, a series of chiral prolinamides based on cyclo-
hexanediamine were designed and were successfully used as chiral
ligands in metal-assisted asymmetric direct aldol reactions in
aqueous media. This catalytic direct aldol provides an easy access to
10
24 36
80:20
a
the chiral b-hydroxy ketones with good diastereoselectivities (dr up
The reaction was performed with aldehyde (0.25 mmol), ketone (4 equiv.),
catalyst 1c (10 mol %), ZnCl2 (10 mol %) in the EtOHeH2O (1:1, 1.0 mL) at room
temperature.
to 99:1) and high enantioselectivities (up to 99% ee). The catalysts’
structure can be easily tuned by introducing different metals and/or
different chiral prolinamides. The present study reveals an inter-
esting area of aqueous asymmetric aldol reactions between appli-
cation of metal salt and organocatalysis. This novel prolinamide
based-metal Lewis acid bifunctional organocatalyst 1c can be
b
Isolated yield after chromatography on silica gel.
c
Determined by chiral 1H NMR analysis.
d
Determined by chiral HPLC analysis of the anti-product.

G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
23
O
OH
R
O
N
O
O
O
O
N
TFA/DCM
Et2O
NH
O
BOC
N
H N
2
N
NH
O
N
BOC
O
EDCI/DMAP/DCM/rt
R
R
NH
TFA
NH -NH
2
2
1a R=CH2
1b R= S
EtOH
O
O
O
TFA/DCM
Et2O
K CO /CH CN
2
3
3
NH NH
NH
N
NH
N
2
Br
Ph
Ph
Ph
Ph
R
N
BOC
R
NH
R
N
BOC
TFA
1c R=CH2
1d R= S
Scheme 1. Synthesis of catalysts 1ae1d.
efficiently used in a larger-scale reactions with the enantiose-
lectivities being maintained at the same level, which offers a great
possibility for application in industry.
was purified by silica gel column chromatography to give the pure
aldol adduct.
The crude product before SiO2 chromatography was submitted
to 1H NMR analysis to determine diastereomeric ratio. The product
after SiO2 chromatography was analyzed by HPLC to determine the
enantiomeric as well as the diastereomeric ratios; the latter
matched, within allowable limits, the values determined by 1H
NMR analysis. The syn and anti diastereomers of the aldols were
readily distinguished in 1H NMR spectroscopy by the diagnostic
chemical shifts of eCHOHe proton, cf. SI for the chemical shift data.
The characterization data of all the aldol reaction products has been
reported by the literature [31e33,46e50], and the detailed char-
acterization data can be seen by the supplementary material.
4. Experimental
4.1. General information
The starting reagents used during the course of preparing pro-
linamide ligands 1ae1d were purchased from the Aldrich
Company. All chemicals were used as received unless otherwise
noted. Reagent grade solvents were distilled prior to use. Reactions
were monitored by thin-layer chromatography (TLC) carried out on
0.25 mm silica gel plates visualized with UV light and/or by staining
with ethanolic phosphomolybdic acid (PMA) and/or ninhydrin both
in ethanol stain. THF was freshly distilled from sodium-
benzophenone ketyl radical under an argon atmosphere immedi-
ately prior to use, CH2Cl2 was distilled after drying over anhydrous
CaH2 and stored over 4 Å molecular sieves. Flash column chroma-
tography was performed on silica gel (200e300 mesh). NMR
spectra were recorded on a 300 MHz instrument. Chemical shifts
(d) are given in ppm relative to TMS as the internal reference,
coupling constants (J) in Hz. IR spectra were recorded on a spec-
trometer. Melting points were measured on a digital melting point
apparatus. Mass spectra (MS) were measured with a spectrometer.
Analytical high performance liquid chromatography (HPLC) was
carried out on Agilent 1200 instrument using Chiralpak AD-H
(4.6 mm ꢀ 250 mm), Chiralcel OD-H (4.6 mm ꢀ 250 mm)
columns. Optical rotations were measured on a JASCO P-1010
4.3. General procedure for the preparation of catalysts 1ae1d
4.3.1. Typical procedure for the synthesis of 1a/1b [49]
Compound 1a is referred to as an example: all prolinamides
were synthesized starting from (1R,2R)-N-phthaloyl-1,2-
diaminocyclohexane, under a dry Ar atmosphere, to a stirred
solution of N-Boc-L-proline (215 mg, 1 mmol, 1 equiv), DMAP
(42 mg, 0.3 equiv), EDCI (244 mg, 1.1 equiv), and amine (235 mg,
0.8 equiv) were dissolved in dichloromethane (10 mL). The result-
ing mixture was stirred at room temperature for 2 days. Then the
mixture was concentrated to half of the volume in vacuo and the
resulting mixture was partitioned between EtOAc (100 mL) and
0.5 M aqueous HCl (50 mL). The organic layer was washed with
half-saturated brine (25 mL), dried (Na2SO4), filtered, and concen-
trated followed by flash column chromatography (AcOEt/petro-
Polarimeter at
l
¼ 589 nm.
leum ether ¼ 1:4) to give N-Boc-
L-prolinamide. To a stirred solution
of N-Boc- -prolinamide (442 mg, 1 mmol) in dichloromethane
L
4.2. The general procedure of aldol reactions
(10 mL), TFA (4.0 mL) was added and stirred at room temperature
for 12 h. After evaporation of the solvent, the resulting residue was
deluted with Et2O and recrystallized, obtained pure product 1a as
an off-white solid. (Scheme 1)
A mixture of catalyst (0.025 mmol), metal salt (0.025 mmol),
ketone (1 mmol) contained in 1.0 mL of EtOHeH2O (1:1) was stirred
at room temperature for
2 h. Subsequently, the aldehyde
(0.25 mmol) was introduced. The reaction mixture was stirred at
room temperature until the reaction was judged to be complete
based on TLC analysis. The reaction was quenched by adding
saturated NH4Cl solution, and the organic material was extracted
with ethyl acetate (2 ꢀ 20 mL). The combined organic extract was
dried with Na2SO4 and concentrated in vacuo. The crude product
4.3.2. Typical procedure for the synthesis of 1c/1d [49]
Compound 1c is referred to as an example: A solution of (S)-tert-
butyl-2-((1R, 2R)-2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamoyl)
pyrrolidine-1-carboxylate (0.44 g, 1 mmol) in 10 mL ethanol was
refluxed with hydrazine monohydrate (0.2 mL) for 5 h. The reaction
mixture was then cooled to room temperature and diethyl ether was

24
G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
added to it to precipitate phthaloyl hydrazide completely. The white
solid was filtered and the filtrate was evaporated to afford (S)-
tert-butyl-2-((1R, 2R)-2-aminocyclohexylcarbamoyl)pyrrolidine-1-
carboxylate as light yellow solid. This was used in the following
step without further purification. To a solution of (S)-tert-butyl-2-
((1R, 2R)-2-aminocyclohexylcarbamoyl)pyrrolidine-1-carboxylate
(0.244 g, 1 mmol) in 20 mL abs. CH3CN and K2CO3 (0.32 g,
2.3 mmol) was added benzyl bromide (0.3 mL, 2.5 mmol) and the
resulting mixture was heated to reflux for 24 h. The reaction mixture
was cooled to ambient temperature and the solvent was removed in
vacuo. The residue was dissolved in dichloromethane (20 mL) and
water (20 mL); the organic layer was separated and the aqueous
layer (pH w10) was extracted with dichloromethane (3 ꢀ 15 mL).
The combined organic layer was dried over anh. Na2SO4 and the
solvent was removed in vacuo to obtain pure production as an off-
(m, 1H), 1.17e1.41 (m, 3H), 1.62e1.66 (d 1H), 1.80e1.86 (d, 2H),
2.11e2.15 (d, 1H), 2.37e2.41 (d, 2H), 3.16e3.22 (m, 1H), 3.32e3.39
(m, 3H), 3.75e3.85 (m 3H), 3.98e4.02 (t, 1H), 4.16e4.28 (m, 2H),
7.25e7.35 (m, 10H); 13C NMR(75 MHz, CDCl3) (ppm)
d
¼ 22.98,
24.62, 25.40, 32.59, 35.56, 50.14, 53.35, 54.10, 60.52, 66.52, 127.05,
128.27, 129.13, 139.74, 170.34; HRMS (ESI): calcd. for (C24H31N3OS)þ
409.2235, found 409.2238.
4.3.2.5. (2R,10S)-2-(Hydroxy-(4-nitrophenyl)methyl)cyclohexan-1-
one 2 [47,53]. Yield 99%, (anti/syn) ¼ 99:1, ee ¼ 96% of anti-dia-
stereomer determined by HPLC (Dicael Chiralpak AD-H column; i-
PrOH/Hexane ¼ 20:80; flow rate 0.5 mL/min, 25 ꢃC,
l
¼ 254 nm;
tR ¼ 43.3 min (anti, major), tR ¼ 34.0 min (anti, minor)). 1H NMR
(300 MHz, CDCl3):
d
¼ 8.21 (d, 2H, J ¼ 8.7 Hz), 7.51 (d, 2H,
J ¼ 8.7 Hz), 4.90 (dd, 1H, J ¼ 8.4, 3.0 Hz), 4.09 (d, 1H, J ¼ 3.0 Hz),
2.65e2.45 (m, 2H), 2.36 (td, 1H, J ¼ 13.2, 5.7 Hz), 2.17e2.06 (m, 1H),
1.87e1.78 (m, 1H), 1.67e1.51 (m, 3H), 1.45e1.31 (m, 1H).
white crystalline solid. To a stirred solution of N-Boc-L-prolina-
mide (491 mg, 1 mmol) in dichloromethane (10 mL), TFA (4.0 mL)
was added and stirred at room temperature for 12 h. After evapo-
ration of the solvent, the resulting residue was diluted with Et2O and
recrystallized, obtained pure product 1c as an off-white solid.
4.3.2.6. (2R,10S)-2-(Hydroxy-(2-nitrophenyl)methyl)cyclohexan-1-
one 3 [47,53]. Yield: 97%; (anti/syn) ¼ 94:6, ee ¼ 87%. Enantiomeric
excess was determined by HPLC with a Chiralpak OD-H column
(hexane/2-propanol ¼ 95/5), 25 ꢃC, 254 nm, 0.5 mL/min; major anti
enantiomer tR ¼ 41.9 min and minor enantiomer tR ¼ 50.7 min. 1H
4.3.2.1. (S)-N-((1R,2R)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyrro-
lidine-2-carboxamide(1a). White solid. Yield: 90%; ½a D20
¼ ꢂ44.4
ꢁ
(c ¼ 0.33, CHCl3); FT-IR nmax (neat)/cmꢂ1: 3327.01, 3292.64,
NMR (300 MHz, CDCl3):
d
¼ 7.84 (d, J ¼ 8.1 Hz, 1H), 7.77 (d,
2934.35, 1766.21, 1709.90, 1663.27, 1466.95, 1450.19, 719.05 cmꢂ1
;
J ¼ 7.8 Hz, 1H), 7.63 (t, J ¼ 7.5 Hz, 1H), 7.43 (t, J ¼ 7.8 Hz, 1H), 5.45 (d,
J ¼ 6.6 Hz, 1H), 3.90 (br, 1H), 2.82e2.70 (m, 1H), 2.50e2.40 (m, 1H),
2.34 (td, J ¼ 12.3 Hz and J ¼ 5.7 Hz, 1H), 2.15e2.06 (m, 1H),
1.90e1.55 (m, 4H).
1H NMR (300 MHz, CDCl3) (ppm)
d
¼ 1.25e1.56 (m, 6H), 1.71e2.06
(m, 7H), 2.49e2.63 (m, 1H), 2.73e2.76 (m, 1H), 2.83e2.89 (m, 1H),
3.49e3.54 (dd, J ¼ 9.4, 4.9 Hz, 1H), 3.91e3.97 (td, J ¼ 12.3, 3.7 Hz,
1H), 4.39e4.51 (qd, J ¼ 11.2, 4.3 Hz,1H), 7.51e7.53 (d, 1H), 7.66e7.68
(m, 2H), 7.79e7.82 (m, 2H); 13C NMR(75 MHz, CDCl3) (ppm)
4.3.2.7. (2R,10S)-2-(Hydroxy-(3-nitrophenyl)methyl)cyclohexan-1-
one 4 [47,53]. Yield: 90%; (anti/syn) ¼ 91:9, ee ¼ 91%. Enantiomeric
excess was determined by HPLC with a Chiralpak AD-H column
(hexane/2-propanol ¼ 80/20), 25 ꢃC, 254 nm, 0.5 mL/min; major
anti enantiomer tR ¼ 41.9 min and minor anti enomer tR ¼ 32.3 min.
d
¼ 24.58, 25.41, 25.73, 28.51, 30.46, 32.92, 47.02, 48.62, 54.97,
60.08, 122.92, 131.9, 133.72, 168.42, 174.62; HRMS (ESI): calcd. for
(C19H23N3O3)þ 341.1718, found 341.1719.
4.3.2.2. (R)-N-((1R,2R)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)thia-
1H NMR (300 MHz, CDCl3):
d
¼ 8.21(d, J ¼ 8.7 Hz, 2H), 7.51(d,
zolidine-4-carboxamide(1b). White solid. Yield: 92%; ½a D20
ꢁ
¼ ꢂ51.3
J ¼ 8.7 Hz, 2H), 4.90(dd, J ¼ 8.4 Hz and J ¼ 3.0 Hz, 1H), 4.09(d,
J ¼ 3.0 Hz, 1H), 2.65e2.45 (m, 2H), 2.36 (td, J ¼ 13.2 Hz and
J ¼ 5.7 Hz, 1H), 2.17e2.06 (m, 1H), 1.87e1.78 (m, 1H), 1.67e1.51 (m,
3H), 1.45e1.31 (m, 1H).
(c ¼ 0.33, CHCl3); FT-IR nmax (neat)/cmꢂ1: 3335.07, 3298.67,
2964.22, 1773.23, 1711.60, 1668.25, 1458.45, 1435.26, 720.08 cmꢂ1
;
1H NMR(300 MHz, CDCl3) (ppm)
d
¼ 1.18e1.39 (m, 3H), 1.44e1.57
(m, 1H) 1.80e1.91 (m, 3H), 2.05e2.09 (d, 1H), 2.54e2.59 (m 1H),
2.75e2.82 (m, 2H), 3.72e3.75 (d 1H), 3.92e4.0 (m 2H), 4.07e4.10 (d
1m), 4.43e4.55 (qd J ¼ 10.2, 4.4, 1H), 6.97e7.0 (d 1H), 7.66e7.69 (m
4.3.2.8. (2R,10S)-2-(Hydroxy-(4-cyanophenyl)methyl)cyclohexan-1-
one 5 [47,53]. Yield: 95%; (anti/syn) ¼ 99:1, ee ¼ 99%. Enantiomeric
excess was determined by HPLC with a Chiralpak AD-H column
(hexane/2-propanol ¼ 80/20), 25 ꢃC, 254 nm, 0.5 mL/min; major
anti enantiomer tR ¼ 22.5 min and minor enantiomer tR ¼ 18.0 min.
2H), 7.80e7.83 (m 2H); 13C NMR(75 MHz, CDCl3) (ppm)
d
¼ 24.53,
25.34, 28.44, 32.81, 33.07, 49.21, 53.14, 54.85, 63.64, 123.12, 133.76,
170.25; HRMS (ESI) : calcd. for (C18H21N3O3S)þ 359.1335, found
359.1337.
1H NMR (300 MHz, CDCl3):
d
¼ 7.65 (d, J ¼ 8.1 Hz, 2H), 7.45 (d,
J ¼ 8.1 Hz, 2H), 4.85 (dd, J ¼ 8.1 Hz and J ¼ 3.0 Hz, 1H), 4.11 (d,
J ¼ 3.0 Hz, 1H), 2.65e2.44 (m, 2H), 2.37 (td, J ¼ 12.9 Hz and
J ¼ 6.0 Hz, 1H), 2.17e2.06 (m, 1H), 1.88e1.77 (m, 1H), 1.72e1.47 (m,
3H), 1.44e1.31 (m, 1H).
4.3.2.3. (S)-N-((1R,2R)-2-(dibenzylamino)cyclohexyl)pyrrolidine-2-
carboxamide (1c). Light yellow solid. Yield: 75%; ½a D20
¼ 6.0
ꢁ
(c ¼ 0.33, CHCl3); FT-IR nmax (neat)/cmꢂ1: 3340.69, 2926.94,
2855.59, 1650.32, 1512.42, 1498.89, 1451.35, 752.30, 701.25 cmꢂ1
;
1H NMR(300 MHz, CDCl3) (ppm)
d
¼ 0.79e0.90 (m, 1H), 1.03e1.16
4.3.2.9. (2R,10S)-2-(Hydroxy-(4-(trifluoromethyl)phenyl)methyl)
cyclohexan-1-one 6 [47,53]. Yield: 99%; (anti/syn) ¼ 99:1, ee ¼ 99%.
Enantiomeric excess was determined by HPLC with a Chiralpak AD-H
column (hexane/2-propanol ¼ 90/10), 25 ꢃC, 254 nm, 0.5 mL/min;
major anti enantiomer tR ¼ 34.3 min and minor enantiomer
(m, 1H), 1.23e1.38 (m, 2H), 1.59e1.63 (d, 1H), 1.80e2.03 (m, 4H),
2.09e2.28 (m, 3H), 2.35e2.45 (m, 2H), 3.16e3.20 (m, 2H),
3.35e3.39 (d, 2H), 3.69e3.82 (m, 4H), 7.22e7.35 (m, 10H); 13C
NMR(75 MHz, CDCl3) (ppm)
d
¼ 23.17, 24.66, 25.48, 26.36, 30.30,
32.70, 47.36, 49.95, 33.25, 60.24, 60.85, 126.84, 128.11, 128.89,
140.13,174.50; HRMS (ESI): calcd. for (C25H33N3O)þ 391.2654, found
391.2657.
tR ¼ 26.9 min. 1H NMR (300 MHz, CDCl3):
¼ 7.74e7.55 (m, 3H), 7.40
d
(t, J ¼ 7.2 Hz, 1H), 5.30 (d, J ¼ 9.3 Hz, 1H), 4.03 (t, J ¼ 3.0 Hz, 1H),
2.81e2.69 (m, 1H), 2.55e2.45 (m, 1H), 2.37 (td, J ¼ 12.9 Hz and
J¼ 4.8Hz,1H),2.15e2.03(m,1H),1.81e149(m, 3H),1.48e1.23(m,1H).
4.3.2.4. (R)-N-((1R,2R)-2-(dibenzylamino)cyclohexyl)thiazolidine-4-
carboxamide (1d). Light yellow solid. Yield: 70%; ½a D20
ꢁ
¼ 3.3
4.3.2.10. (2R,10S)-2-(Hydroxy-(4-chlorophenyl)methyl)cyclohexan-
1-one 7 [47,53]. Yield: 90%; (anti/syn) ¼ 90:10, ee ¼ 93%. Enantio-
meric excess was determined by HPLC with a Chiralpak AD-H
column (hexane/2-propanol ¼ 90/10), 25 ꢃC, 220 nm, 0.5 mL/min;
(c ¼ 0.33, CHCl3); FT-IR nmax (neat)/cmꢂ1: 3322.44, 2926.58,
1647.70, 1564.28, 1492.76, 1449.95, 1109.28, 732.67, 700.86 cmꢂ1
;
1H NMR(300 MHz, CDCl3) (ppm)
d
¼ 0.84e0.95 (m, 1H), 1.04e1.16

G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
25
major anti enantiomer tR ¼ 39.2 min and minor enantiomer
4.3.2.18. (2R,10S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)-4-methyl-
cyclohexan-1-one 15 [47,53]. Yield 95%, (anti/syn) ¼ 90:10, enan-
tiomeric excess: 96% of anti-diastereomer determined by HPLC
(Dicael Chiralpak AD-H column; i-PrOH/Hexane ¼ 10:90; flow rate
tR ¼ 33.2 min. 1H NMR (300 MHz, CDCl3):
d
¼ 7.29 (dd, J ¼ 20.4 Hz
and J ¼ 8.4 Hz, 4H), 4.76 (dd, J ¼ 8.7 Hz and J ¼ 2.7 Hz, 1H), 3.99 (d,
J ¼ 3.0 Hz, 1H), 2.61e2.44 (m, 2H), 2.35 (td, J ¼ 12.9 Hz and
J ¼ 5.4 Hz, 1H), 2.15e2.05 (m, 1H), 1.85e1.75 (m, 1H), 1.70e1.50 (m,
3H), 1.37e1.20 (m, 1H).
1.0 mL/min, 25 ꢃC,
tR
l
¼ 254 nm; tR ¼ 41.3 min (anti, minor),
¼
36.3 min (anti, major)). 1H NMR (300 MHz, CDCl3):
¼ 8.18e8.23 (m, 2H), 7.47e7.52 (m, 2H), 4.92 (d, J ¼ 8.6 Hz, 1H),
d
3.82 (br, 1H), 2.72e2.78 (m, 1H), 2.48e2.50 (m, 1H), 2.36e2.43 (m,
1H), 2.07e2.09 (m, 1H), 1.89e1.93 (m, 1H), 1.78e1.81 (m, 1H),
1.54e1.60 (m, 1H), 1.33 (m, 1H), 1.05 (d, J ¼ 6.9 Hz, 3H).
4.3.2.11. (2R,10S)-2-(Hydroxyl-(2-chlorophenyl)methyl)cyclohexan-
1-one 8 [47,53]. Yield: 92%; (anti/syn) ¼ 96:4, ee ¼ 94%. Enantio-
meric excess was determined by HPLC with Chiralcel OD-H (hexane/
i-PrOH ¼ 95/5), 25 ꢃC, 220 nm, flow rate 1.0 mL/min, major anti
enantiomer tR ¼ 9.7 min and minor anti enantiomer tR ¼ 12.3 min.1H
4.3.2.19. (2R,10S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)-4-methyl-
cyclohexan-1-one 16 [47,53]. Yield 92%, (anti/syn) ¼ 92:8, enan-
tiomeric excess: 95% of anti-diastereomer determined by HPLC
(Dicael Chiralpak AD-H column; i-PrOH/Hexane ¼ 10:90; flow rate
NMR (300 MHz, CDCl3):
5.35 (d, J ¼ 8.0 Hz,1H), 3.88 (s,1H), 2.65e2.71 (m,1H), 2.46e2.49 (m,
1H), 2.31e2.39 (m, 1H), 2.05e2.13 (m, 1H), 1.53e1.84 (m, 5H).
d
¼ 7.56 (d, J ¼ 8.4 Hz,1H), 7.20e7.34 (m, 3H),
0.8 mL/min, 25 ꢃC,
l
¼ 254 nm; tR ¼ 34.7 min (anti, minor),
tR ¼ 32.5 min (anti, major)). 1H NMR (300 MHz, CDCl3):
d
¼
4.3.2.12. (2R,10S)-2-(Hydroxy-(4-bromophenyl)methyl)cyclohexan-1-
one 9 [47,53]. Yield: 95%; (anti/syn) ¼ 95:5, ee ¼ 85%. Enantiomeric
excess was determined by HPLC with a Chiralpak AD-H column
(hexane/2-propanol ¼ 90/10), 25 ꢃC, 220 nm, 0.8 mL/min; major
7.81e7.84 (m, 1H), 7.72e7.74 (m, 1H), 7.62 (m, 1H), 7.40e7.45 (m,
1H), 5.42 (d, J ¼ 7.2 Hz, 1H), 3.95 (br, 1H), 2.89e2.92 (m, 1H),
2.44e2.46 (m, 1H), 2.33e2.39 (m, 2H), 2.09e2.11 (m, 1H),
1.74e1.93 (m, 3H), 1.52 (m, 1H), 1.07 (d, J ¼ 6.9 Hz, 3H).
anti enantiomer tR
¼
27.0 min and minor anti enantiomer
tR ¼ 22.4 min. 1H NMR (300 MHz, CDCl3):
¼ 7.47 (d, J ¼ 8.1 Hz, 2H),
d
7.20 (d, J ¼ 8.7 Hz, 2H), 4.75 (dd, J ¼ 8.7 Hz and J ¼ 2.7 Hz, 1H), 3.99
(d, J ¼ 3.0 Hz, 1H), 2.61e2.44 (m, 2H), 2.35 (td, J ¼ 12.9 Hz and
J ¼ 6.3 Hz, 1H), 2.15e2.04 (m, 1H), 1.85e1.75 (m, 1H), 1.70e1.50 (m,
3H), 1.37e1.20 (m, 1H).
4.3.2.20. (2R,10S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)-4-methyl-
cyclohexan-1-one 17 [47,53]. Yield 97%, (anti/syn) ¼ 98:2, enan-
tiomeric excess: 92% of anti-diastereomer determined by HPLC
(Dicael Chiralpak AD-H column; i-PrOH/Hexane ¼ 10:90; flow rate
0.5 mL/min, 25 ꢃC,
l
¼ 254 nm; tR ¼ 63.4 min (anti, major),
tR ¼ 46.5 min (anti, minor)). 1H NMR (300 MHz, CDCl3):
¼ 8.11 (s,
d
4.3.2.13. (2R,10S)-2-[Hydroxy-(4-methoxy-phenyl)methyl]cyclohexan-
1-one 10 [47,53]. Yield: 85%; (anti/syn) ¼ 82:18, enantiomeric excess:
90% (anti-diastereomer) determined by HPLC (Daicel Chiralpak AD-H
1H, Ar), 7.53e7.86 (m, 3H, Ar), 5.20 (d, J ¼ 8.4 Hz, 1H), 3.93 (br, 1H),
2.85e2.90 (m, 1H), 2.45e2.47 (m, 1H), 2.35e2.42 (m, 2H),
2.38e2.79 (m, 2H), 1.90e1.93 (m, 1H), 1.64e1.75 (m, 3H), 1.43 (m,
1H), 1.06 (d, J ¼ 6.9 Hz, 3H).
column; i-PrOH/hexane ¼ 10:90; 0.8 mL/min, 25 ꢃC,
l
¼ 221 nm)
tR ¼ 32.5 min (anti, major) and tR ¼ 30.8 min (anti, minor). 1H NMR
(300 MHz, CDCl3):
d
¼ 7.27 (d, J ¼ 8.4 Hz, 2H), 6.90 (d, J ¼ 8.8 Hz, 2H),
4.76 (d, J ¼ 7.6 Hz, 1H), 3.94 (s, 1H), 3.83 (s, 3H), 2.34e2.65 (m, 3H),
2.08e2.14 (m, 1H), 1.55e1.82 (m, 6H), 1.20e1.40 (m, 2H) ppm.
4.3.2.21. (3R,4S)-3,4-Dihydroxy-4-(4-nitrophenyl)butan-2-one 18
[47,53]. Yield 90%, (anti/syn) ¼ 8:92, enantiomeric excess: 95%
of syn-diastereomer determined by HPLC (Daicel Chiralpak AD-H
column; i-PrOH/hexane ¼ 20:80; 0.8 mL/min, 25 ꢃC,
¼ 254 nm)
l
4.3.2.14. (2R,10S)-2-(Hydroxy-(3-methoxy-phenyl)-methy-l)cyclohexan-
1-one 11 [47,53]. Yield: 83%; (anti/syn) ¼ 93:7, ee ¼ 96%. Enantiomeric
excess was determined by HPLC with a Chiralpak AD-H column
(hexane/2-propanol ¼ 90/10), 25 ꢃC, 220 nm, 0.5 mL/min; major anti
enantiomer tR ¼ 56.3 min and minor enantiomer tR ¼ 51.1 min. 1H
tR ¼ 21.7 min (syn, major) and tR ¼ 16.2 min (syn, minor). 1H NMR
(300 MHz, CDCl3):
2H), 5.20e5.22 (m,1H), 4.40e4.42 (m,1H), 3.71 (d, J ¼ 4.6 Hz,1H),
2.68 (d, J ¼ 8.1 Hz, 1H), 2.36e2.43 (m, 1H), 2.36 (s, 3H).
d
¼ 8.27 (d, J ¼ 8.8 Hz, 2H), 7.63 (d, J ¼ 8.8 Hz,
NMR (300 MHz, CDCl3):
4.75e4.85(d, J¼ 8.7Hz,1H), 3.85(s,3H), 2.30e2.75(m, 3H), 2.00e2.15
(m, 1H), 1.55e1.90 (m, 4H), 1.20e1.40 (m, 1H).
d
¼ 7.28e7.33 (m, 1H), 6.80e7.00 (m, 3H),
4.3.2.22. (3R,4S)-3,4-Dihydroxy-4-(2-nitrophenyl)butan-2-one
19
[47,53]. Yield: 92%, (anti/syn) ¼ 11:89, enantiomeric excess: 96% of
syn-diastereomer determined by HPLC (Daicel Chiralpak AD-H
column; i-PrOH/hexane ¼ 20:80; 0.8 mL/min, 25 ꢃC,
l
¼ 254 nm)
4.3.2.15. (2R,10S)-2-(Hydroxy-(phenyl)-methyl)cyclohexan-1-one 12
[47,53]. Yield: 80%; (anti/syn) ¼ 90:10, ee ¼ 87%. Enantiomeric
excess was determined by HPLC with a Chiralpak OD-H column
(hexane/2-propanol ¼ 90/10), 25 ꢃC, 220 nm, 0.5 mL/min; major
anti enantiomer tR ¼ 19.6 min and minor enantiomer tR ¼ 30.6 min.
tR ¼ 14.0 min (syn, major) and tR ¼ 12.9 min (syn, minor). 1H NMR
(300 MHz, CDCl3):
d
¼ 8.09e8.11 (dd, J ¼ 8.0, 0.8 Hz, 1H), 7.79e7.81
(d, J ¼ 8.0 Hz, 1H), 7.70e7.74 (t, J ¼ 8.0 Hz, 1H), 7.48e7.53 (t,
J ¼ 8.0 Hz, 1H), 5.89 (m, 1H), 4.45e4.56 (m, 1H), 2.51 (s, 3H).
1H NMR (300 MHz, CDCl3):
J ¼ 9.0 Hz, 1H), 4.00 (m, 1H), 2.70e2.56 (m, 1H), 2.55e2.44 (m, 1H),
2.34 (td, J ¼ 12.3, 5.4 Hz, 1H), 2.16e2.03 (m, 1H), 1.87e1.73 (m, 1H),
1.72e1.50 (m, 3H), 1.40e1.22 (m, 1H).
d
¼ 7.50e7.24 (m, 5H), 4.80 (d,
4.3.2.23. (3R,4S)-3,4-Dihydroxy-4-(3-nitrophenyl)butan-2-one
20
[47,53]. Yield: 97%, (anti/syn) ¼ 18:82, enantiomeric excess: 99% of
syn-diastereomer determined by HPLC (Daicel Chiralpak AD-H
column; i-PrOH/hexane ¼ 15:85; 1.0 mL/min, 25 ꢃC,
l
¼ 254 nm)
tR ¼ 21.0 min (syn, major) and tR ¼ 16.0 min (syn, minor). 1H NMR
4.3.2.16. (R)-2-((S)-Furan-2-yl(hydroxy)methyl)cyclohexanone 13 [47]. ee
and dr was determined by HPLC analysis(Chiralpak AD-H, Hexane:
i-PrOH ¼ 95:5, 0.5 mL/min, 254 nm; tR (minor) ¼ 47.143min, tR
(major) ¼ 54.962min).
(300 MHz, CDCl3):
1H), 7.79 (m,1H), 7.60 (t, J ¼ 7.9 Hz,1H), 5.21e5.24 (m,1H), 4.42e4.47
d
¼ 8.33 (m,1H, ArH), 8.21 (ddd, J ¼ 8.1, 2.3,1.1 Hz,
(m, 1H), 3.74e3.75 (m, 1H), 2.72 (d, J ¼ 8.1 Hz, 1H), 2.38 (s, 3H).
4.3.2.17. (R)-2e((S)-hydroxy(thiophen-2-yl)methyl)cyclohexanone 14
[47]. ee and dr was determined by HPLC analysis (Chiralpak AD-H,
4.3.2.24. (S)-4-hydroxy-4-(4-nitrophenyl)butan-2-one 21 [47]. ee
and dr was determined by HPLC analysis (AS-H, Hexane:2-
PrOH ¼ 80:20, 0.5 mL/min, 254 nm; tR (minor) ¼ 21.312min, tR
(major) ¼ 23.777 min).
Hexane:i-PrOH
¼
90:10, 1.0 mL/min, 254 nm; tR (minor)
¼
16.609min, tR (major) ¼ 14.857 min).

26
G. Chen et al. / Journal of Organometallic Chemistry 702 (2012) 19e26
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4.3.2.25. (4S)-4-(2-Chlorophenyl)-4-hydroxybutan-2-one 22 [47,53].
Yield 90% enantiomeric excess: 95% determined by HPLC (Daicel
Chiralpak AD-H column; i-PrOH/hexane ¼ 5:95; 1.0 mL/min, 20 ꢃC,
l
¼ 262 nm) tR ¼ 14.5 min (R-isomer, major) and tR ¼ 12.3 min (S-
isomer, minor).1H NMR (300 MHz, CDCl3):
d
¼ 7.64 (dd, J ¼ 7.6, 1.6 Hz,
1H, ArH), 7.19e7.34 (m, 3H, ArH), 5.56 (m, 1H), 3.61 (br., 1H),
2.64e3.03 (m, 2H), 2.22 (s, 3H) ppm.
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346e351.
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4.3.2.26. ((4S)-4-(3-Chlorophenyl)-4-hydroxy-4butan-2-one 23 [47,53].
Yield 87% enantiomeric excess: 93% determined by HPLC (Daicel
Chiralpak AD-H column; i-PrOH/hexane ¼ 5:95; 1.0 mL/min, 20 ꢃC,
l
¼ 225 nm) tR ¼ 19.0 min (R-isomer, major) and tR ¼ 16.8 min (S-
isomer, minor). 1H NMR (300 MHz, CDCl3):
d
¼ 7.47 (s, 1H, ArH), 7.19 (m,
1H, ArH), 7.13 (d, J ¼ 7.2 Hz, 1H, ArH), 7.09 (m, 1H, ArH), 5.50 (m, 1H),
3.66 (br, 1H), 2.75, (t, J ¼ 4.6 Hz, 2H), 2.21 (s, 3H) ppm.
4.3.2.27. (1R,2S)-1-Hydroxy-2-methyl-1-(4-nitrophenyl)pentan-3-one
24 [47]. ee and dr was determined by HPLC analysis (OJ-H, Hexane:2-
PrOH ¼ 80:20, 1.0 mL/min, 254 nm; tR (minor) ¼ 16.866min, tR
(major) ¼ 15.780 min).
Acknowledgments
Authors are grateful to Southwest University of China for
financial support.
Appendix. Supplementary material
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2011.12.
006.
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