Pyrrolidine-pyridine base catalysts for the enantioselective Michael addition of ketones to chalcones

Article abstract of DOI:10.1016/j.tet.2009.09.001

A series of pyrrolidine-pyridine base organocatalysts have been developed and 3a found to be a highly effective catalyst for the asymmetric Michael addition reactions of ketones to chalcones. The reaction generated the corresponding products 1, 5-diketone

Full text of DOI:10.1016/j.tet.2009.09.001

Tetrahedron 65 (2009) 9344–9349
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Pyrrolidine–pyridine base catalysts for the enantioselective Michael addition
of ketones to chalcones
*
Da-Zhen Xu, Sen Shi, Yingjun Liu, Yongmei Wang
Department of Chemistry, State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2009
Received in revised form 28 August 2009
Accepted 1 September 2009
Available online 4 September 2009
A series of pyrrolidine–pyridine base organocatalysts have been developed and 3a found to be a highly
effective catalyst for the asymmetric Michael addition reactions of ketones to chalcones. The reaction
generated the corresponding products 1, 5-diketones in excellent diastereoselectivities (up to >99:1 dr)
and enantioselectivities (up to 100% ee).
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we designed and synthesized a series of pyrrolidine–
pyridine organocatalysts, which were tested in the asymmetric
The Michael reaction is one of the most popular carbon–carbon
bond-forming reactions in organic synthesis.1 Over the past few
years, there has been a tremendous increase in research activities
on the development of organocatalysts for asymmetric carbon–
carbon bond-forming reactions,2 especially for the Michael addi-
tion reactions.3 However, most of the reactions employ highly
activated Michael acceptors, such as nitroalkenes.4 Enantioselective
catalytic conjugate addition of ketones with enones remains
a challenging reaction. Jørgensen and co-workers have reported
Michael additions of aldehydes to enones catalyzed by a chiral
organocatalyst pyrrolidine.5 List and Gellman have independently
used MacMillan’s imidazolidinones as organocatalysts for intra-
molecular and intermolecular Michael reactions of aldehydes with
enones.6 Only two papers have been published on the asymmetric
Michael addition of ketones to chalcones. Wang et al. studied this
reaction using a chiral pyrrolidinylmethylsulfonamide,7 and we
reported an amino acid ionic liquid serving as a catalyst for this
type Michael addition reaction.8 Unfortunately, these organo-
catalysts have some drawbacks, such as long reaction time (more
than 4 days) or high catalyst loading (200 mol %), and the later will
put up the cost and limit its application in the pharmaceutical in-
dustry. In addition, a large excess of ketones (normally 10 equiv) is
also generally required to achieve good enatioselectivity. Therefore,
the design and development of highly active chiral organocatalysts
aimed at overcoming these limitations to achieve high activities
with ketones and chalcones in Michael conjugate additions re-
mains a major challenge in synthetic organic chemistry.
Michael addition of ketones to chalcones providing high enantio-
selectivities and diastereoselectivities.
2. Results and discussion
A series of the pyrrolidine–pyridine type catalysts 3 were
prepared from the ‘chiral pool’ using Boc-
material.9 The synthetic procedures were quite straightforward.
First, Boc- -prolinol was coupled with an equivalent of bromopyr-
L-prolinol as the starting
L
idines followed by the treatment of TFA in CH2Cl2. The product,
such as 3a,10 was obtained in 65% overall yield (Scheme 1).11
1) NaH, THF
2)
TFA
OH
O
N
O
N
N
Boc
N
Boc
CH2Cl2
N
H
Br
N
3a
2a
1
N
R
3b: R=4-CH
3
O
3c: R=6-CH
O
N
3
N
H
3d: R=4-CF
N
H
3
3e
Scheme 1. Synthesis of the catalysts.
The preliminary experiments were conducted by taking cyclo-
hexanone 4a as a donor and chalcone 5a as an acceptor using
20 mol % of the synthesized pyrrolidine–pyridine type catalysts 3 in
THF (Table 1).
The catalyst 3a promoted the addition with a high diaster-
eoselectivity (97:3 dr) and enantioselectivity (86% ee) (Table 1,
entry 1). Chiral catalysts 3b and 3d also gave good diastereo-
selectivities (99:1 and 98:2 dr, respectively), but they gave lower
* Corresponding author. Fax: þ86 22 2350 2654.
E-mail address: ymw@nankai.edu.cn (Y. Wang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.001

D.-Z. Xu et al. / Tetrahedron 65 (2009) 9344–9349
9345
Table 1
of the product was obtained (Table 1, entry 6). When the reaction
was performed in Et2O, CH3OH or i-PrOH, the product 6a was
formed in low yields and moderate to high enantioselectivities
(Table 1, entries 7–9). Good results were observed when n-PrOH or
t-BuOH were used (97% and 99% ee, respectively) (Table 1, entries
10–11). If reduced the volume of t-BuOH, the reaction of cyclo-
hexanone 4a with chalcone 5a took place to form adduct 6a more
rapidly (in 58 h) with a remarkably high level of stereocontrol
(100% ee and 99:1 dr, Table 1, entry 13).
The effect of catalysts 3 in asymmetric Michael additions of cyclohexanone 4a and
chalcone 5aa
O
Ph
O
O
O
cat 3
Ph
+
Ph
Ph
solvent
5a
6a
4a
Entry
Cat.
Solvent (1 mL)
Time (h)
Yieldb (%)
drc
eed (%)
Having established the optimal reaction conditions for Michael
addition of cyclohexanone 4a with chalcone 5a, we then examined
cyclohexanone 4a with other chalcones in t-BuOH catalyzed by 3a
(20 mol %) at room temperature to establish the general utility of
this asymmetric transformation. As shown in Table 2, the Michael
adducts obtained with good to excellent levels of enantioselectiv-
ities (80–100% ee) and exceptionally high diastereoselectivities
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3a
3a
3a
3a
3a
3a
3a
3a
THF
THF
THF
THF
THF
Cyclohexanone
Et2O
CH3OH
120
120
120
120
120
115
115
115
115
96
61
45
21
38
0
<5
30
21
45
40
44
57
73
97:3
99:1
92:8
98:2
d
86
85
63
83
d
nd
nd
78
83
85
97
99
99.4
100
99:1
98:2
99:1
98:2
>99:1
>99:1
99:1
9
i-PrOH
10
11
12
13
n-PrOH
t-BuOH
t-BuOHe
t-BuOHf
Table 2
118
112
58
Catalytic asymmetric Michael addition reactions of cyclohexanone 4a with chal-
cones 5a
O
a
O
Ar1
O
All reactions were conducted in solvent (1.0 mL) using 4a (0.1 mL, 1.0 mmol)
and 5a (41 mg, 0.2 mmol) in the presence of 20 mol % of the catalyst 3.
O
cat 3a
+
Ar2
b
1'R
Ar1
Ar2
2S
Isolated yield.
t-BuOH
c
Determined by 1H NMR spectroscopy.
d
Determined by HPLC analysis (Chiralcel AD-H column).
Solvent t-BuOH (0.5 mL) was used.
Solvent t-BuOH (0.2 mL) was used.
6
5
4a
e
f
Entry
1
Product
Time (h) Yieldb (%) drc
eed (%)
O
Ph
O
yields and enantioselectivities than 3a (Table 1, entries 2 and 4). The
catalyst 3c, with 6-methylpyridine, proceeded slowly in very low
yield (21% yield) with only a moderate enantioselectivity (63% ee)
(Table 1, entry 3). The catalyst 3e was not an effective catalyst for
this process (Table 1, entry 5). The possible reason is that the cat-
alyst 3e could not form the transition state A with ketones to
chalcones (Scheme 2).
58
73
99:1 100
Ph
6a
Cl
2
3
90
59
99:1
91
88
O
O
O
O
Ph
Ph
6b
NO2
O
N
N
O
I
48
57
93
58
>99:1
Ar1
Ar2
H2O
5
6c
O
Me
O
N
N
O
H
4
>99:1
86
O
O
O
4a
O
Ar2
O
N
Ph
N
Ar1
O
Ar1
A
6d
Ar2
F
I I
5e
48
72
70
65
>99:1
>99:1
84
86
O
N
O
O
N
H
Ph
Ph
3a
6e
O
Ar1
O
Cl
O
H2O
Ar2
6
6
6f
Scheme 2. Proposed mechanism for the 3a-catalyzed Michael addition.
Cl
O
Compound 3a was then taken as the catalyst of choice and
evaluated for the reaction in different solvents (Table 1, entries
6–13). The yields and enantioselectivities of 3a differed signifi-
cantly. When cyclohexanone was used as the solvent, less than 5%
O
7
72
54
>99:1
89
Ph
6g

9346
Table 2 (continued)
D.-Z. Xu et al. / Tetrahedron 65 (2009) 9344–9349
Table 3
Catalytic asymmetric Michael addition reactions of cyclic ketones 4 with chalcone 5aa
Entry
Product
Time (h) Yieldb (%) drc
eed (%)
88
O
Ph
O
O
O
cat 3a
Ph
1'R
+
2S
Ph
Ph
t-BuOH
O
8
72
48
>99:1
O
5a
6
4
Ph
6h
Entry
1
Product
Time (h)
58
Yieldb (%)
73
drc
eed (%)
100
O
O
Ph
O
O
O
O
Ph
99:1
93:7
Ph
Ph
9
96
48
48
48
45
90
63
56
>99:1
99:1
85
80
86
86
6i
6a
OMe
NO2
Ph
O
O
O
Ph
2
3
48
72
57
69
84
86
10
11
12
6n
O
O
6j
Ph
O
O
Ph
Ph
Ph
>99:1
>99:1
>99:1
6o
6k
Br
O
N
Ph
O
O
O
O
Ph
4
48
65
84:16
84
6p
6l
O
Ph
Cl
O
O
5
48
55
82:18
71
13
96
62
>99:1
89
Ph
6q
6m
a
OMe
All reactions were conducted in solvent (0.2 mL) using 4 (0.1 mL, 1.0 mmol) and
5a (41 mg, 0.2 mmol) in the presence of 20 mol % of the catalyst 3a(7 mg,
0.04 mmol).
a
All reactions were conducted in solvent (0.2 mL) using 4a (0.1 mL, 1.0 mmol)
and 5 (0.2 mmol) in the presence of 20 mol % of the catalyst 3a (7 mg, 0.04 mmol).
b
b
Isolated yield.
Isolated yield.
c
c
Determined by 1H NMR spectroscopy.
Determined by 1H NMR spectroscopy.
d
d
Determined by HPLC analysis (Chiralcel AD-H column).
Determined by HPLC analysis (Chiralcel AD-H column).
Determined by HPLC analysis (Chiralcel OD-H column).
e
ketones with chalcones. The main advantages of this catalyst are
the ease of synthesis and the use of small excess of ketones
(5 equiv). In the presence of the (S)-pyrrolidine–pyridine catalyst
3a, the process is carried out under mild reaction conditions, and
ketones could react with various chalcones to afford synthetically
useful 1,5-dicarbonyl compounds in moderate to good yields with
high to excellent levels of enantioselectivities and diaster-
eoselectivities. Further investigations of this novel transformation
and the application of these organocatalysts in asymmetric catal-
ysis are still in progress.
(ꢀ99:1 dr) regardless of the electronic nature of the aromatic
substituents.
Other cyclic ketones were also found to be compatible with 3a
under the optimized conditions (Table 3). Reactions with six-
membered ring ketone gave the Michael adducts with high to ex-
cellent enantioselectivities (84–100% ee) (Table 3, entries 1–4).
However, when cyclopentanone was used as substrate, only mod-
erate enantioselectivity was obtained (Table 3, entry 5).
The absolute stereochemical results can be explained by the
concept of an acyclic synclinal transition state, as proposed by
Seebach and Golinski.12 It is accepted that when primary or sec-
ondary chiral amines are used as organocatalysts, the reaction
clearly involves an enamine pathway. As shown in Scheme 2, first,
the catalyst 3a forms a chiral enamine I with cyclohexenone 4a,
then the Michael reaction of the enamine-activated I and the
chalcone 5 leads to formation of the corresponding product 6 via
the transition state A. The catalyst 3a continues the subsequent
catalytic cycle. The transition state A is very important in this
asymmetric Michael addition of ketones to chalcones, in which the
pyridine ring plays an important role in shielding the si-face of
enamine double bond and activating chalcones, if the catalyst could
not form transition state A, such as 3e, the catalyst would be not
effective for this reaction.
4. Experimental
4.1. General information
All the solvents were purified according to standard procedures.
The 1H NMR spectra were recorded at 300 MHz or 400 MHz, 13C
NMR spectra were recorded at 75 MHz or 100 MHz. 1H and 13C NMR
chemical shifts were calibrated to tetramethylsilane as an external
reference. Coupling constants are given in hertz. The following
abbreviations are used to indicate the multiplicity: s, singlet; d,
doublet; t, triplet; m, multiplet. HRMS were recorded on an IonSpec
FT-ICR mass spectrometer with ESI resource. Melting points were
measured on an RY-I apparatus and were reported uncorrected.
Optical rotations were measured on a Perkin–Elmer 341 Polari-
meter at 20 ꢁC. HPLC analysis was performed on Shimadzu CTO-10AS
by using a Chiralpak AD-H or OD-H column purchased from Daicel
Chemical Industries.
3. Conclusions
In summary, we have designed and synthesized a series of
novel pyrrolidine–pyridine organocatalysts, developed a pro-
cedure for catalytic asymmetric Michael addition reaction of
The chemicals were purchased from commercial suppliers
(Aldrich, USA and Shanghai Chemical Company, China), and were

D.-Z. Xu et al. / Tetrahedron 65 (2009) 9344–9349
9347
used without purification prior to use. All reactions unless other-
wise noted were carried out directly under air.
27.91, 46.59, 56.95, 69.80, 107.82, 112.18, 123.97, 140.95, 148.18,
164.21; HRMS calcd for C11H13F3N2OHþ (MþH)þ 247.1053, found
20
247.1056; [
a
]
¼þ9.6ꢁ (c¼0.5, CH2Cl2).
D
4.2. General procedure for the synthesis of catalysts
4.2.5. 4-(((S)-Pyrrolidin-2-yl)methoxy)pyridine(3e). This was pre-
pared as per our general procedure to afford the product 3a as
4.2.1. 2-(((S)-Pyrrolidin-2-yl)methoxy)pyridine (3a). A solution of 1
(3.02 g, 15 mmol) in dry THF (30 mL) under N2 was cooled to 0 ꢁC
and stirred for 10 min. NaH (2.16 g, 90 mmol) was added and the
mixture was stirred for 20 min. The mixture was warmed to room
temperature and stirred overnight, then a solution of 2-bromo-
pyridine (1.7 g,15 mmol) in THF (5 mL) was added. The mixture was
heated to reflux for 24 h. After evaporation of the THF, ethyl acetate
(80 mL) was added, and the solution was washed with water
(30 mL), brine (30 mL), and dried over Na2SO4, then filtered. The
ethyl acetate was concentrated under reduced pressure. The crude
product was purified by column chromatography with petroleum
ether/ethyl acetate (8:1) to afford 2.9 g (71%) of 2a as a colorless oil.
To a solution of 2a (1.0 g, 3.6 mmol) in CH2Cl2 (10 mL) was added
dropwise TFA (8 mL) at 0 ꢁC. The mixture was warmed to room
temperature and stirred overnight. After removal of the organic
solvents under vacuum, the residue was dissolved in CH2Cl2
(10 mL) and treated with saturated Na2CO3 solution (30 mL) for 1 h
at room temperature. The aqueous layer was extracted with CH2Cl2
three times (15 mLꢂ3) and the combined extracts were washed
with brine (15 mL), then dried over anhydrous Na2SO4. Concen-
tration in vacuo after filtration gave 3a as colorless oil (587 mg,
92%).
a yellow liquid; yield 91%; 1H NMR (300 MHz, CDCl3):
d (ppm) 1.48–
1.60 (m, 1H),1.73–1.87 (m, 2H),1.92–2.01 (m, 1H), 2.34 (s, 1H), 2.92–
3.02 (m, 2H), 3.49–3.58 (m, 1H), 3.85–3.97 (m, 2H), 6.79–6.81 (m,
2H), 8.40–8.42 (m, 2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 25.28,
27.97, 46.60, 56.78, 71.28, 110.23, 151.01, 164.89; HRMS calcd for
20
C10H14N2ONaþ (MþNa)þ 201.0998, found 201.0999; [
(c¼0.5, CH2Cl2).
a]
¼þ9.6ꢁ
D
4.3. Typical procedure for Michael addition reaction
Catalyst 3a (7.0 mg, 0.04 mmol) was added to a vial containing
cyclohexanone (0.1 mL, 1.0 mmol) and chalcone 5a (41 mg,
0.2 mmol) in t-BuOH (0.2 mL) at room temperature. The mixture
was stirred vigorously and monitored by TLC. When the reaction
was finished, the mixture was concentrated under vacuum. The
residue was purified by flash silica gel chromatography (ethyl ac-
etate/hexane¼1:6) to afford the adduct as a white solid; yield:
55 mg (73%; 99:1 dr (determined by 1H NMR) and 100% ee); Chir-
alpak AD-H column (i-PrOH/hexane¼10:90, flow rate 1.0 mL/min,
l¼254 nm): tR¼19.37 min (major) and 22.74 min (minor).
1H NMR (400 MHz, CDCl3):
d
(ppm) 1.72–1.81 (m, 1H), 1.90–1.97
4.3.1. (S)-2-((R)-3-Oxo-1,3-diphenylpropyl)cyclohexanone
(m, 2H), 2.04–2.13 (m, 1H), 3.09–3.23 (m, 2H), 3.81–3.87 (m, 1H),
4.31 (dd, 1H, J1¼6.8 Hz, J2¼11.6 Hz), 4.51 (dd, 1H, J1¼3.6 Hz,
J2¼11.6 Hz), 6.79 (d, 1H, J¼8.4 Hz), 6.89–6.92 (m, 1H), 7.57–7.62 (m,
(6a)13. The ee was determined by HPLC analysis (Chiralpak AD-H,
i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR (major)¼19.37 min,
20
tR (minor)¼22.74 min), 100% ee; [
a
]
¼ꢃ56.8 (c 0.79, CH2Cl2).
D
1H), 8.10–8.12 (m, 1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 24.29,
27.02, 45.48, 58.25, 65.84, 111.23, 117.49, 139.08, 146.51, 162.98;
4.3.2. (S)-2-((R)-1-(4-Chlorophenyl)-3-oxo-3-phenylprop-yl)cyclo-
HRMS calcd for C10H14N2ONaþ (MþNa)þ 201.0998, found 201.0992;
hexanone (6b)7. The ee was determined by HPLC analysis (Chir-
20
[
a]
¼þ33.6ꢁ (c¼0.5, CH2Cl2).
alpak AD-H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR
D
20
(minor)¼17.15 min, tR (major)¼20.60 min), 91% ee; [
a
]
¼ꢃ64.0 (c
D
4.2.2. 2-(((S)-Pyrrolidin-2-yl)methoxy)-4-methylpyridine (3b). This
was prepared as per our general procedure to afford the product 3b
as a light yellow solid; yield 92%; mp 58–59 ꢁC; 1H NMR (400 MHz,
0.81, CH2Cl2).
4.3.3. (S)-2-((R)-1-(4-Nitrophenyl)-3-oxo-3-phenylprop-yl)cyclo-
CDCl3):
d
(ppm) 1.52–1.63 (m, 1H), 1.71–2.01 (m, 3H), 2.28 (s, 3H),
hexanone (6c)7. The ee was determined by HPLC analysis (Chir-
2.95–3.08 (m, 2H), 3.54–3.66 (m, 1H), 3.88 (s, 1H), 4.16 (dd, 1H,
J1¼10 Hz, J2¼14.4 Hz), 4.33 (dd, 1H, J1¼5.2 Hz, J2¼14 Hz), 6.58 (s,
1H), 6.70 (d, 1H, J¼6.8 Hz), 7.98 (d, 1H, J¼7.2 Hz); 13C NMR
alpak AD-H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR
20
(minor)¼44.96 min, tR (major)¼54.436 min), 88% ee; [
a
]
¼ꢃ15.3
D
(c 0.79, CH2Cl2).
(100 MHz, CDCl3):
d (ppm) 20.90, 25.19, 27.77, 46.34, 57.41, 68.46,
111.17, 118.45, 146.24, 150.00, 164.04; HRMS calcd for
4.3.4. (S)-2-((R)-3-Oxo-3-phenyl-1-p-tolylpropyl)cyclohexanone
20
C11H16N2O5Naþ (MþNa)þ 215.1155, found 215.1162; [
(c¼0.5, CH2Cl2).
a]
¼þ14.1ꢁ
(6d)14. The ee was determined by HPLC analysis (Chiralpak AD-H,
D
i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR (minor)¼13.37 min,
20
tR (major)¼18.76 min), 86% ee; [
a]
¼ꢃ18.2 (c 0.81, CH2Cl2).
D
4.2.3. 2-(((S)-Pyrrolidin-2-yl)methoxy)-6-methylpyridine (3c). This
was prepared as per our general procedure to afford the product 3c
4.3.5. (S)-2-((R)-1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)-cyclo-
as a brown oil; yield 95%; 1H NMR (400 MHz, CDCl3):
d
(ppm) 1.65–
hexanone (6e). syn/anti¼>99:1 (by 1H NMR); 1H NMR (400 MHz,
1.74 (m, 1H),1.85–1.92 (m, 2H),1.97–2.07 (m,1H), 2.43 (s, 3H), 3.03–
3.15 (m, 2H), 3.66–3.77 (m, 1H), 4.24 (dd, 1H, J1¼6.8 Hz, J2¼11.6 Hz),
4.41 (dd, 1H, J1¼3.6 Hz, J2¼11.6 Hz), 6.57 (d, 1H, J¼8 Hz), 6.74 (d, 1H,
CDCl3): d 1.21–1.27 (m, 1H), 1.53–1.81 (m, 4H), 1.97–2.05 (m, 1H),
2.32–2.43 (m, 1H), 2.48–2.56 (m, 1H), 2.72 (dt, 1H, J1¼10.0 Hz,
J2¼4.8 Hz), 3.15 (dd, 1H, J1¼10.0 Hz, J2¼16.0 Hz), 3.49 (dd, 1H,
J1¼4.0 Hz, J2¼16.0 Hz), 3.67 (dt, 1H, J1¼10.0 Hz, J2¼4.0 Hz), 7.07 (t,
2H, J¼8.8 Hz), 7.13–7.18 (m, 3H), 7.23–7.27 (m, 2H), 7.93–7.97 (m,
J¼7.2 Hz), 7.47 (t, 1H, 8 Hz); 13C NMR (100 MHz, CDCl3):
d (ppm)
22.99, 24.05, 26.38, 44.88, 56.86, 66.86, 106.59, 115.37, 138.31,
155.06, 162.02; HRMS calcd for C11H16N2OHþ (MþH)þ 193.1335,
2H); 13C NMR (75 MHz, CDCl3):
d (ppm) 24.22, 28.56, 32.59, 41.42,
20
found 193.1339; [
a
]
¼ꢃ20.0ꢁ (c¼0.5, CH2Cl2).
42.40, 44.29, 55.81, 115.35, 115.64, 126.69, 128.28, 128.51, 130.76,
130.89, 141.82, 197.25, 213.60; HRMS calcd for C21H21FO2Naþ
(MþNa)þ 347.1419, found 347.1422. The ee was determined by HPLC
analysis (Chiralpak OD-H, i-PrOH/hexane¼10:90, 1.0 mL/min,
D
4.2.4. 2-(((S)-Pyrrolidin-2-yl)methoxy)-4-(trifluoromethyl)-pyridine
(3d). This was prepared as per our general procedure to afford the
product 3c as a colorless oil; yield 98%; 1H NMR (400 MHz, CDCl3):
254 nm, tR (minor)¼7.10 min, tR (major)¼9.22 min), 84% ee;
20
d
(ppm) 1.48–1.56 (m, 1H), 1.70–1.97 (m, 3H), 2.23 (s, 1H), 2.91–3.04
[a
]
¼ꢃ74.2 (c 0.81, CH2Cl2).
D
(m, 2H), 3.49–3.56 (m, 1H), 4.19 (dd, 1H, J1¼7.6 Hz, J2¼10.4 Hz), 4.33
(dd, 1H, J1¼4.4 Hz, J2¼10.8 Hz), 6.98 (s, 1H), 7.04 (d, 1H, J¼5.2 Hz),
4.3.6. (S)-2-((R)-1-(3-Chlorophenyl)-3-oxo-3-phenylprop-yl)cyclo-
8.27 (d, 1H, J¼5.2 Hz); 13C NMR (100 MHz, CDCl3):
d
(ppm) 25.36,
hexanone (6f). syn/anti¼>99:1 (by 1H NMR); 1H NMR (400 MHz,

9348
D.-Z. Xu et al. / Tetrahedron 65 (2009) 9344–9349
CDCl3):
d
1.21–1.29 (m, 1H), 1.53–1.81 (m, 4H), 1.99–2.04 (m, 1H),
J1¼3.9 Hz, J2¼15.9 Hz), 3.78 (dt, 1H, J1¼9.9 Hz, J2¼3.9 Hz), 7.16–7.32
2.34–2.42 (m, 1H), 2.46–2.52 (m, 1H), 2.70 (dt, 1H, J1¼10.0 Hz,
J2¼4.8 Hz), 3.22 (dd, 1H, J1¼9.6 Hz, J2¼16.4 Hz), 3.49 (dd, 1H,
J1¼3.6 Hz, J2¼16.4 Hz), 3.71 (dt, 1H, J1¼9.6 Hz, J2¼3.6 Hz), 7.08–7.20
(m, 4H), 7.42 (t, 2H, J¼7.6 Hz), 7.52 (t, 1H, J¼7.2 Hz), 7.90 (d, 2H,
(m, 5H), 7.50–7.59 (m, 2H), 7.81–7.84 (m, 2H), 7.92–7.97 (m, 2H),
8.49 (s, 1H); 13C NMR (100 MHz, CDCl3):
d (ppm) 24.13, 28.60, 32.53,
41.42, 42.38, 44.36, 55.91, 124.02, 126.59, 126.65, 127.70, 128.25,
128.29, 128.50, 129.65, 129.95, 132.52, 136.30, 135.48, 141.97, 198.76,
213.80; HRMS calcd for C25H24O2Naþ (MþNa)þ379.1669, found
379.1663. The ee was determined by HPLC analysis (Chiralpak AD-
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3):
d (ppm) 24.36, 28.51, 31.60,
40.74, 42.47, 43.85, 55.49, 126.85, 128.13, 128.35, 128.53, 129.71,
133.00, 134.25, 136.84, 144.36, 198.31, 213.04; HRMS calcd for
C21H22ClOþ2 (MþH)þ 341.1303, found 341.1299. The ee was de-
termined by HPLC analysis (Chiralpak AD-H, i-PrOH/hexane¼10:90,
H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR (major)¼
20
25.86 min, tR (minor)¼34.87 min), 86% ee; [
a]
¼ꢃ41.0 (c 0.80,
D
CH2Cl2).
1.0 mL/min, 254 nm, tR (minor)¼11.62 min, tR (major)¼21.16 min),
20
86% ee; [
a
]
¼ꢃ72.9 (c 0.79, CH2Cl2).
4.3.13. (S)-2-((R)-1-(2-Chlorophenyl)-3-(4-methoxyphenyl)-3-oxo-
propyl)cyclohexanone (6m)8. The ee was determined by HPLC
analysis (Chiralpak AD-H, i-PrOH/hexane¼30:70, 1.0 mL/min,
D
4.3.7. (S)-2-((R)-1-(2-Chlorophenyl)-3-oxo-3-phenylprop-yl)-cyclo-
hexanone (6g)7. The ee was determined by HPLC analysis (Chir-
254 nm, tR (minor)¼15.14 min, tR (major)¼28.04 min), 89% ee;
20
alpak AD-H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR
[a
]
¼ꢃ76.0 (c 0.80, CH2Cl2).
D
20
(minor)¼12.81 min, tR (major)¼21.37 min), 89% ee; [
a]
¼ꢃ126.8 (c
D
0.81, CH2Cl2).
4.3.14. (R)-Tetrahydro-3-((R)-3-oxo-1,3-diphenylpropyl)-pyran-4-
one (6n). syn/anti¼93:7 (by 1H NMR); 1H NMR (400 MHz, CDCl3):
4.3.8. (S)-2-((R)-1-(Naphthalen-1-yl)-3-oxo-3-phenylprop-yl)cyclo-
d2.39–2.43 (m, 1H), 2.64–2.74 (m, 2H), 2.86–3.02 (m, 4H), 7.19–7.24
hexanone (6h). syn/anti¼>99:1 (by 1H NMR); 1H NMR (400 MHz,
(m, 3H), 7.38–7.42 (m, 3H), 7.47–7.51 (m, 2H), 7.87 (d, 2H, J¼6.4 Hz);
CDCl3):
d
1.25–1.30 (m, 1H), 1.46–1.78 (m, 4H), 1.95–2.04 (m, 1H),
13C NMR (75 MHz, CDCl3):
d
(ppm) 38.79, 42.37, 43.78, 57.14, 68.85,
2.37–2.46 (m, 1H), 2.50–2.58 (m, 1H), 2.87 (dt, 1H, J1¼10.0 Hz,
J2¼4.8 Hz), 3.45 (dd, 1H, J1¼10.0 Hz, J2¼16.0 Hz), 3.69 (dd, 1H,
J1¼3.6 Hz, J2¼16.4 Hz), 3.68 (dt, 1H, J1¼9.6 Hz, J2¼3.6 Hz), 7.34–7.47
(m, 7H), 7.67–7.72 (m, 1H), 7.80–7.86 (m, 3H), 8.11–8.25 (m, 1H); 13C
71.14, 125.54, 127.02, 128.03, 128.20, 128.48, 128.75, 132.93, 136.97,
141.15, 198.02, 208.96; HRMS calcd for C20H20O3Naþ (MþNa)þ
330.6464, found 330.6468. The ee was determined by HPLC anal-
ysis (Chiralpak AD-H, i-PrOH/hexane¼15:85, 0.7 mL/min, 254 nm,
20
NMR (100 MHz, CDCl3):
d
(ppm) 19.17, 24.62, 28.70, 29.71, 32.77,
tR (minor)¼25.92 min, tR (major)¼27.39 min), 84% ee; [
(c 0.80, CH2Cl2).
a]
¼ꢃ25.7
D
42.63, 44.71, 123.57, 125.45, 125.98, 127.03, 128.12, 128.39, 128.76,
132.73, 137.04, 198.83, 213.89; HRMS calcd for C25H24O2Naþ
(MþNa)þ 379.1669, found 379.1672. The ee was determined by
HPLC analysis (Chiralpak AD-H, i-PrOH/hexane¼10:90, 1.0 mL/min,
4.3.15. (2S)-4-Methyl-2-((R)-3-oxo-1,3-diphenylpropyl)-cyclohexa-
none (6o). syn/anti¼>99:1 (by 1H NMR); 1H NMR (300 MHz,
254 nm, tR (minor)¼13.26 min, tR (major)¼26.39 min), 88% ee;
CDCl3):
d
0.88 (d, 3H, J¼6.6 Hz), 1.25–1.35 (m, 1H), 1.40–1.54 (m,
20
[
a]
¼ꢃ179.5 (c 0.81, CH2Cl2).
2H), 2.00–2.09 (m, 1H), 2.11–2.21 (m, 1H), 2.63–2.74 (m, 2H), 3.19
(dd, 1H, J1¼4.5 Hz, J2¼17.4 Hz), 3.35 (dd, 1H, J1¼8.4 Hz, J2¼17.4 Hz),
3.82–3.90 (m, 1H), 7.16–7.31 (m, 5H), 7.35–7.40 (m, 2H), 7.47–7.52
D
4.3.9. (S)-2-((R)-3-(4-Methoxyphenyl)-3-oxo-1-phenylprop-yl)cy-
clohexanone (6i)7. The ee was determined by HPLC analysis (Chir-
(m, 1H), 7.83 (d, 2H, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm)
alpak AD-H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR
20.65, 26.23, 35.25, 37.82, 38.82, 40.84, 43.93, 54.89, 126.78, 127.99,
128.10, 128.44, 128.67, 132.91, 137.00, 142.14, 198.26, 215.07. The ee
was determined by HPLC analysis (Chiralpak AD-H, i-PrOH/
20
(minor)¼66.36 min, tR (major)¼71.18 min), 85% ee; [
a]
¼ꢃ8.9 (c
D
0.81, CH2Cl2).
hexane¼10:90, 1.0 mL/min, 254 nm, tR (minor)¼12.86 min, tR
20
4.3.10. (S)-2-((R)-3-(4-Nitrophenyl)-3-oxo-1-phenylpropyl)-cyclo-
(major)¼13.38 min), 86% ee; [
a]
¼ꢃ45.2 (c 0.81, CH2Cl2).
D
hexanone (6j)15. The ee was determined by HPLC analysis (Chir-
alpak OD-H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR
4.3.16. (R)-1-Methyl-3-((R)-3-oxo-1,3-diphenylpropyl)piperidin-4-
20
(minor)¼20.88 min, tR (major)¼31.39 min), 80% ee; [
a
]
¼ꢃ37.2 (c
one (6p)16. The ee was determined by HPLC analysis (Chiralpak
D
0.80, CH2Cl2).
AD-H, i-PrOH/hexane¼20:80, 0.6 mL/min, 254 nm, tR (minor)¼
20
17.46 min, tR (major)¼22.31 min), 84% ee; [
a
]
¼ꢃ63.4 (c 0.81,
D
4.3.11. (S)-2-((R)-3-(4-Bromophenyl)-3-oxo-1-phenylprop-yl)cyclo-
CH2Cl2).
hexanone (6k). syn/anti¼>99:1 (by 1H NMR); 1H NMR (400 MHz,
CDCl3):
d
1.18–1.27 (m, 1H), 1.53–1.80 (m, 4H), 1.96–2.01 (m, 1H),
4.3.17. (S)-2-((R)-3-Oxo-1,3-diphenylpropyl)cyclopentanone
2.35–2.43 (m, 1H), 2.47–2.53 (m, 1H), 2.71 (dt, 1H, J1¼10.0 Hz,
J2¼4.8 Hz), 3.13 (dd, 1H, J1¼9.6 Hz, J2¼15.6 Hz), 3.48 (dd, 1H,
J1¼4.0 Hz, J2¼16.0 Hz), 3.65 (dt, 1H, J1¼10.0 Hz, J2¼4.0 Hz), 7.12–7.18
(m, 3H), 7.23–7.27 (m, 2H), 7.55 (d, 2H, J¼8.4 Hz), 7.78 (d, 2H,
(6q)17. The ee was determined by HPLC analysis (Chiralpak OD-H,
i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm, tR (major)¼8.10 min, tR
20
(minor)¼10.62 min), 71% ee; [
a
]
¼ꢃ33.5 (c 0.79, CH2Cl2).
D
J¼8.8 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm) 22.63, 25.34, 28.57,
Acknowledgements
31.57, 41.43, 44.36, 55.78, 126.72, 128.26, 128.53, 129.76, 131.75,
135.76, 141.71, 197.87, 214.22; HRMS calcd for C21H22BrOþ2 (MþH)þ
385.0798, found 385.0800. The ee was determined by HPLC anal-
This work was financially supported by the National Natural
Science Foundation of China (grant no. 20672061, China) and 863
Project (no. 2007AA05Z102, China). We also thank the Nankai
University State Key Laboratory of Elemento-Organic Chemistry for
support.
ysis (Chiralpak AD-H, i-PrOH/hexane¼10:90, 1.0 mL/min, 254 nm,
20
tR (major)¼28.83 min, tR (minor)¼31.29 min), 86% ee; [
(c 0.81, CH2Cl2).
a]
¼ꢃ25.9
D
4.3.12. (S)-2-((R)-3-(Naphthalen-3-yl)-3-oxo-1-phenylprop-yl)cy-
clohexanone (6l). syn/anti¼>99:1 (by 1H NMR); 1H NMR (300 MHz,
Supplementary data
CDCl3):
d 1.23–1.33 (m, 1H), 1.51–1.83 (m, 4H), 1.97–2.04 (m, 1H),
2.29–2.46 (m, 1H), 2.51–2.61 (m, 1H), 2.77 (dt, 1H, J1¼10.2 Hz,
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.09.001.
J2¼5.1 Hz), 3.34 (dd, 1H, J1¼9.6 Hz, J2¼15.9 Hz), 3.63 (dd, 1H,

D.-Z. Xu et al. / Tetrahedron 65 (2009) 9344–9349
9349
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