Thiophosphoramide catalyzed asymmetric Michael addition of cyclopentanone to chalcones

Article abstract of DOI:10.1016/j.tetasy.2011.02.015

Thiophosphoramide 1b was found to be an effective bifunctional organocatalyst in the asymmetric Michael reaction of cyclopentanone to various chalcones, affording the corresponding adducts in satisfactory yields with moderate to excellent diastereo- (up t

Full text of DOI:10.1016/j.tetasy.2011.02.015

Tetrahedron: Asymmetry 22 (2011) 476–479
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Thiophosphoramide catalyzed asymmetric Michael addition
of cyclopentanone to chalcones
⇑
⇑
Yunfeng Liu, Yang Wu, Aidang Lu, Youming Wang , Guiping Wu, Zhenghong Zhou , Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiophosphoramide 1b was found to be an effective bifunctional organocatalyst in the asymmetric
Michael reaction of cyclopentanone to various chalcones, affording the corresponding adducts in satisfac-
tory yields with moderate to excellent diastereo- (up to 90/10 dr) and enantioselectivities (up to 92% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 29 December 2010
Accepted 9 February 2011
Available online 22 March 2011
1
. Introduction
The asymmetric Michael addition reaction, which enables ac-
2. Results and discussion
Recently, we have demonstrated that functionalized thiophos-
phoramides can function as efficient hydrogen-bond donor cata-
lysts in asymmetric nitro-Michael addition reactions.11 Hence, a
series of chiral pyrrolidine-based thiophoramide catalysts 1a–d
were chosen as catalyst candidates (Fig. 1); the conjugate addition
of cyclopentanone to chalcone 2a was selected as a model reaction.
At first, the conjugate addition to chalcone 2a was performed in
neat cyclopentanone in the presence of 20 mol % of each of these
catalysts as well as 10 mol % of benzoic acid as cocatalyst (Table 1).
The results listed in Table 1 indicate that all the thiophosphora-
mide catalysts tested are active for this transformation. However,
both the diastereo- and enantioselectivity are highly dependent
on the substituents at the phosphorus atom. For example, the
use of acyclic thiophosphoramidate catalysts 1a and 1b resulted
in the formation of an anti-diastereomer as the major product,
whereas syn-selectivity was observed for the cyclic thiophosph-
oramidate catalysts 1c, 1d (Table 1, entries 1 and 2 vs entries 3–
5). Moreover, thiophosphoramidate (S,aR)-1d and (R,aR)-1d both
cess to a variety of optically active adducts, is widely recognized
as one of the most powerful carbon–carbon bond-forming reac-
tions in organic synthesis. Over the past decade, significant pro-
1
gress has been made in the field of organocatalyzed asymmetric
Michael addition to highly active Michael acceptors, such as nitro-
2
olefins. In contrast, the organocatalyzed asymmetric Michael
additions of less reactive
a,b-unsaturated ketones have received
little attention. Jørgensen developed the highly enantioselective
3
chiral imidazolidine catalyzed addition of nitroalkanes and malo-
4
nates to
a
,b-unsaturated enones. Asymmetric intramolecular and
intermolecular Michael reactions of aldehydes with enones have
5
been achieved in the presence of chiral imidazolidinones or chiral
6
pyrrolidines. Most recently, the asymmetric vinylogous Michael
reactions of
a,b-unsaturated ketones with c-butenolide were also
7
documented. We noticed that organocatalytic asymmetric
Michael addition reactions of simple ketones, especially cyclopen-
tanones, with chalcones still remain a challenge, probably due to
the low reactivity and high steric hindrance of the substrates.
Employing (S)-pyrrolidinesulfonamide8 and (S)-prolinol ether as
the catalysts, highly enantioselective Michael additions of cyclo-
hexanone to chalcones were realized. However, the reaction of
cyclopentanone and chalcone gave only 73% and 71% ee, respec-
tively. Therefore, the development of a novel organocatalytic sys-
tem to achieve highly enantioselective Michael additions of the
bearing an (R)-binaphthol skeleton derived from L- and D-proline,
9
respectively, afforded product 3a with opposite stereochemistry,
indicating that the stereochemistry of the newly formed stereo-
genic center is determined by the chirality of the pyrrolidine part
rather than that of the binaphthol. In terms of enantioselectivity
of the major diastereomer, catalyst 1b gave the best results. Hence
we chose thiophosphoramide 1b as the catalyst for further
1
2
problematic cyclopentanone to chalcones remains
a
major
optimization.
challenge in synthetic organic chemistry. Herein, we report the
asymmetric Michael addition of cyclopentanone to chalcones
catalyzed by a chiral bifunctional thiophosphoramide catalyst,
affording the corresponding adducts with good to excellent
To further improve the diastereo- and enantioselectivity of this
reaction, the effect of different solvents on the reaction was inves-
tigated in the presence of 20 mol % catalyst 1b and 10 mol % ben-
zoic acid. In general, a marked decrease in reaction rate was
observed when performing the reaction in a different solvent (Ta-
ble 1, entries 6–10). However, the employment of toluene as a sol-
vent resulted in a dramatical improvement both in terms of the
diastereo- and enantioselectivity of the reaction, providing the
1
0
enantioselectivities.
⇑
Corresponding authors.
E-mail address: z.h.zhou@nankai.edu.cn (Z. Zhou).
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.015

Y. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 476–479
477
Table 2
Substrate scope of 1b catalyzed asymmetric Michael addition of cyclopentanone to
chalcones
H
N
OPh
OPh
a
H
N
OEt
OEt
O
O
S
P
S
N
H
P
S
N
P
Ar1
O
H2
N
H
O
1b (20 mol%)
O
O
Et3N (20 mol%)
CF3CO2-
NH2
+
Ar
Ar1
Ar
PhCO2H (10 mol%)
Toluene, 25 °C
CF3CO2-
1
a-CF3CO2H
1b
2
a-j
3a-j
(
S,aS)-1c
Entry Ar, Ar1
Time (d) Yieldb (%) anti/sync Eed (%)
1
2
3
4
5
6
7
8
9
1
Ph, Ph a
Ph, 2-NO
Ph, 4-CF
Ph, 4-BrC
Ph, 4-MeC
7
10
3
6
6
7
2
2
6
98
42
90
93
77
54
89
83
59
64
90/10
60/40
65/35
71/29
90/10
85/15
80/20
60/40
64/36
72/28
92/77
71/71
66/61
61/58
62/46
65/63
59/55
64/27
60/51
58/53
O
O
O
P
O
2 6 4
C H
b
S
S
P
3 6 4
C H c
N
H
N
H
6
H
4
d
NH2
NH2
CF3CO2-
6
H
4
e
Ph, 4-MeOC
6
H
4
f
CF3CO2-
4-BrC , Ph g
6
H
4
4-NO
4-NO
2
C
6
H
H
4
, 2-MeOC
, 4-MeOC
6
H
H
4
4
h
i
(
S,aR)-1d
(R,aR)-1d
2
C
6
4
6
0
4-MeC
6
H
4
, Ph j
10
Figure 1. Different pyrrolidine-based organocatalysts.
a
Reaction conditions: cyclopentanone (2 mmol, 10 equiv), chalcones
2
(
0.2 mmol) in toluene (0.5 mL), 25 °C.
b
Yield of the isolated product after chromatography on silica gel.
anti-diastereomer with an ee value of 92% as the major product. No
improvement in results was obtained by either adjusting the
catalyst loading (Table 1, entry 11 vs entry 10) or changing the
c
Determined by 1H NMR.
d
Determined by chiral HPLC analysis.
1
3
co-catalyst.
did not influence the enantioselectivity, the diastereoselectivity
of the reaction was significantly influenced by the nature of the
substituents on Ar . Generally, an electron-donating group on Ar
Table 1
1
1
a
Catalyst evaluation and optimization of reaction conditions
is obviously favorable for the anti-selectivity of the reaction, while
O
Ph
*
O
1
O
the introduction of an electron-withdrawing group on Ar resulted
O
Catalyst (20 mol%)
Et3N (20 mol%)
+
*
Ph
in marked decrease in diastereoselectivity (Table 2, entries 5 and 6
vs entries 2–4).
Ph
Ph
PhCO2H (10 mol%)
Solvent, 25 °C
2
a
The relative and absolute configuration of the compounds 3a
and 3j were determined by comparison of specific rotation values
and the retention times of each stereomer in the chiral HPLC spec-
3a
Yieldb
(%)
Eed (%)
Entry Catalyst
Solvent Time
h)
anti/
10
(
sync
tra with the reported results in the literature. The stereochemis-
try of the other products was assigned by analogy.
1
2
3
4
1a
1b/Et
1c/Et
Neat
Neat
Neat
Neat
11
55
68
79
80
69/31
67/33
28/72
38/62
66/100
71/98
70/66
74/49
Based on the experimental results, a possible transition state for
this reaction was proposed to account for the observed diastereo-
and enantioselectivity. As shown in Fig. 2, the free base of 1b func-
tioned as a bifunctional catalyst. The pyrrolidine ring will first react
with cyclopentanone to form an enamine with the aid of benzoic
acid. Subsequently, the acidic hydrogen will activate and orientate
the carbonyl group of chalcone through a hydrogen-bonding inter-
action so that the enamine will undertake preferentially nucleo-
philic attack from its Re-face onto the Re-face of the chalcone to
give the (S,S)-product as the major stereoisomer.
3
N
N
36
26
26
3
(S,aR)-1d/
Et
(R,aR)-1d/
Et
3
N
5
Neat
11
82
26/74
ꢀ61/
3
N
ꢀ66
6
7
8
9
1
1
1b/Et
1b/Et
1b/Et
1b/Et
1b/Et
1b/Et
3
N
3
N
3
N
3
N
3
N
3
N
EtOH
6 d
10 d
7 d
10 d
7 d
10 d
75
62
85
50
98
50
68/32
85/15
82/18
87/13
90/10
84/16
74/74
71/62
77/69
68/65
92/77
80/62
CH
CH
2
Cl
CN
2
3
THF
PhCH
PhCH
0
1
3
3
e
a
Reaction conditions: cyclopentanone (2 mmol, 10 equiv), chalcone 2a
(
0.2 mmol) in solvent (0.5 mL), 25 °C.
S
P
b
Yield of the isolated product after chromatography on silica gel.
c
d
e
Determined by 1H NMR.
OPh
OPh
N
H
Determined by Chiral HPLC analysis.
N
With 15 mol % of catalyst 1b.
O
With the optimized reaction conditions in hand, we next
Ph
studied the generality of the reaction with a variety of chalcones.
The results were summarized in Table 2.
Ph
Figure 2. Possible transition state for the present reaction.
As shown in Table 2, the reaction has a broad applicability with
respect to chalcones. However, the enantioselectivity of the reac-
tion is greatly dependent on the nature of the chalcone substrates.
Unsubstituted chalcone 2a was the optimal substrate, giving the
conjugate addition product 3a with a high level of enantioselectiv-
ity (Table 2, entry 1, 92% ee). The introduction of a substituent on
3. Conclusions
We have demonstrated that chiral pyrrolidine-based thiophos-
phoramides are efficient catalysts for the asymmetric Michael
addition of cyclopentanone to chalcone. In the presence of
20 mol % of 1b, the reaction of different chalcones proceeded
smoothly to afford the corresponding adducts with moderate to
excellent levels of diastereo- and enantioselectivities.
1
either Ar or Ar led to a decrease in enantioselectivity, affording the
desired product with only moderate ee values (ranging from 58% to
7
1% ee for the major diastereomer, Table 2, entries 2–10). More-
over, when Ar was a phenyl group (Table 2, entries 1–6), although
1
the electronic nature of the substituents on Ar in the chalcones

4
78
Y. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 476–479
4
4
. Experimental
(100.6 MHz, CDCl
3
): 20.2 (anti), 20.4 (syn), 27.0 (syn), 28.0 (anti),
3
8.7 (anti), 39.4 (syn), 40.5 (anti), 40.6 (syn), 42.5, 52.6 (anti), 53.2
.1. General procedure for thiophosphoramide 1b catalyzed
(syn), 125.4, 128.0, 128.1, 128.6, 128.7, 128.8, 133.1, 133.2, 136.8,
asymmetric Michael addition of cyclopentanone to chalcones
146.5, 146.7, 198.0 (anti), 198.3 (syn), 219.2 (anti), 219.7 (syn). HRMS
+
(
ESI) m/z calcd for C21
H
19
F
3
O
2
[M+Na] : 383.1229, found 383.1236.
A mixture of thiophosphoramide 1b (0.04 mmol), triethylamine
HPLC analysis (Chiralpak OD-H column, hexane/2-propanol = 99:1,
flow rate = 1.0 mL/min, wavelength = 220 nm): R = 24.35 (minor,
syn-isomer), 26.60 (major, syn-isomer), 30.56 (minor, anti-isomer)
and 33.92 min (major, anti-isomer).
(
(
(
0.04 mmol) and cyclopentanone (2 mmol, 10 equiv) in toluene
0.5 mL) was stirred at 25 °C for 15 min. Then, benzoic acid
2.4 mg, 0.02 mmol) was added, and the reaction mixture was stir-
t
red for 15 min. To the resulting mixture was added chalcone 2
0.2 mmol) at the same temperature. After the reaction was com-
plete (monitored by TLC), the mixture was purified by column
chromatography on silica gel (100–200 mesh, PE/EtOAc) to afford
the desired conjugate addition product 3.
(
4.1.4. 2-((S)-1-(4-Bromophenyl)-3-oxo-3-phenylpropyl)-
cyclopentanone 3d
2
D
0
Yellow oil, 93% yield, ½
71, 58% ee for syn-isomer and 60% ee for anti-isomer. H NMR
400 MHz, CDCl ): d 1.45–1.73 (m, 2H), 1.83–1.94 (m, 2H), 2.02–
.11 (m, 1H), 2.23–2.30 (m, 1H), 2.40–2.52 (m, 1H), 3.31 (dd,
aꢁ
¼ ꢀ27:4 (c 1.0, CHCl
3
), syn/anti: 29/
1
(
3
2
4
.1.1. 2-((S)-3-Oxo-1,3-diphenylpropyl)cyclopentanone 3a
J = 8.0 and 16.8 Hz, 0.71H), 3.48 (dd, J = 9.6 and 18.8 Hz, 0.29H),
3.65–3.74 (m, 1.29H), 3.85 (dd, J = 5.6 and 17.2 Hz, 0.71H), 7.10
(d, J = 8.4 Hz, 2Harom), 7.38 (d, J = 8.4 Hz, 2Harom), 7.40–7.54 (m,
20
Pale yellow solid, 98% yield, mp 74 °C. ½
CHCl ), syn/anti: 10/90, 77% ee for syn-isomer and 92% ee for
anti-isomer. H NMR (CDCl
.02–2.12 (m, 1H), 2.21–2.28 (m, 1H), 2.42–2.54 (m, 1H), 3.36
dd, J = 7.6 and 16.8 Hz, 0.90H), 3.47 (dd, J = 10.0 and 20.0 Hz,
aꢁ
¼ ꢀ25:4 (c 1.0,
D
3
1
13
3
, 400 MHz): d 1.48–1.94 (m, 4H),
3Harom), 7.89–7.96 (m, 2Harom). C NMR (100.6 MHz, CDCl ):
3
2
(
20.2 (anti), 20.4 (syn), 27.1 (syn), 27.8 (anti), 38.7 (anti), 39.6
(syn), 40.2 (syn), 40.3 (anti), 40.7 (syn), 42.6 (anti), 52.7 (anti),
53.0 (syn), 120.4 (anti), 120.5 (syn), 128.0 (anti), 128.1 (syn),
128.5, 130.0 (anti), 130.2 (syn), 131.4 (anti), 131.5 (syn), 133.0
(anti), 133.1 (syn), 136.9, 141.3 (syn), 141.4 (anti), 198.2 (anti),
198.5 (syn), 219.3 (anti), 220.1 (syn). HRMS (ESI) m/z calcd for
0
3
2
.10H), 3.68–3.90 (m, 2H), 7.15–7.28 (m, 5Harom), 7.39–7.53 (m,
Harom), 7.90–7.98 (m, 2Harom). 13C NMR (CDCl
, 100.6 MHz):
0.2 (anti), 20.5 (syn), 27.1 (syn), 27.9 (anti), 38.8 (anti), 39.6
3
(
(
syn), 40.8 (anti), 41.0 (syn), 42.9, 52.9 (anti), 53.0 (syn), 126.6
anti), 126.7 (syn), 128.0 (anti), 128.1 (syn), 128.2, 128.3, 128.4,
7
9
+
C20H19 BrO2 [M+Na] : 398.0461, found 398.0468. HPLC analysis
(Chiralpak AD-H column, hexane/2-propanol = 90:10, flow
1
28.5, 132.8, (anti), 133.0 (syn), 137.0, 142.3 (syn), 142.5 (anti),
1
98.6 (anti), 199.0 (syn), 219.8 (anti), 220.5 (syn). HRMS (ESI) m/z
rate = 1.0 mL/min, wavelength = 220 nm): R = 13.99 (major, syn-
t
+
calcd for C20
H
20
O
2
[M+Na] : 315.1355, found 315.1355. HPLC anal-
isomer), 21.95 (minor, syn-isomer), 24.39 (major, anti-isomer)
ysis (Chiralpak AD-H column, hexane/2-propanol = 95:5, flow
rate = 1.0 mL/min, wavelength = 220 nm): R = 16.96 (major, syn-
and 31.10 min (minor, anti-isomer).
t
isomer), 20.38 (minor, syn-isomer), 31.53 (major, anti-isomer)
and 50.52 min (minor, anti-isomer).
4.1.5. 2-((S)-1-(4-Methylphenyl)-3-oxo-3-phenylpropyl)-
cyclopentanone 3e
2
D
0
Yellow oil, 77% yield, ½
a
ꢁ
¼ ꢀ39:2 (c 1.0, CHCl
3
), syn/anti: 10/
1
4
.1.2. 2-((S)-3-Oxo-3-phenyl-1-(4-trifluoromethylphenyl)-
90, 46% ee for syn-isomer and 62% ee for anti-isomer. H NMR
propyl)cyclopentanone 3b
(400 MHz, CDCl ): d 1.51–1.58 (m, 1H), 1.65–1.75 (m, 1H), 1.86–
3
2
D
0
Yellowish-green oil, 42% yield, ½
aꢁ
¼ ꢀ93:4 (c 1.0, CHCl
3
), syn/
1.90 (m, 2H), 2.03–2.12 (m, 1H), 2.21–2.24 (m, 1H), 2.29 (s, 3H),
anti: 40/60, 71% ee for syn-isomer and 71% ee for anti-isomer.
2.45 (q, J = 8.4 Hz, 1H), 3.34 (dd, J = 7.2 and 16.8 Hz, 0.90H), 3.45
(dd, J = 6.0 and 16.0 Hz, 0.10H), 3.67 (dd, J = 7.2 and 14.0 Hz, 1H),
3.84 (dd, J = 6.0 and 16.8 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2Harom),
7.11 (d, J = 8.4 Hz, 2Harom), 7.42 (t, J = 7.6 Hz, 2Harom), 7.52 (t,
1
3
H NMR (400 MHz, CDCl ): d 1.68–1.74 (m, 2H), 1.79–1.88 (m,
1
3
4
7
2
H), 2.00–2.10 (m, 1H), 2.22–2.37 (m, 2H), 2.55–2.73 (m, 1H),
.40 (dd, J = 10.0 and 18.0 Hz, 0.60H), 3.59 (d, J = 6.8 Hz, 0.40H),
.10–4.39 (m, 2H), 7.29–7.32 (m, 1Harom), 7.38–7.44 (m, 2Harom),
.46–7.53 (m, 3Harom), 7.74 (t, J = 8.0 Hz, 1Harom), 7.87–7.90 (m,
1
3
J = 7.2 Hz, 1Harom), 7.91–7.99 (m, 2Harom).
C NMR
(100.6 MHz, CDCl ): 20.1 (anti), 20.4 (syn), 20.9, 27.0 (syn), 27.7
3
1
3
3
Harom). C NMR (100.6 MHz, CDCl ): 20.2 (anti), 20.4 (syn), 27.2
(anti), 38.7 (anti), 39.6 (syn), 40.3 (anti), 40.5 (syn), 40.8 (syn),
(
(
1
syn), 29.0 (anti), 34.2 (anti), 35.0 (syn), 38.8 (anti), 39.0 (syn), 40.8
syn), 43.0 (anti), 51.9 (anti), 53.0 (syn), 124.1 (anti), 124.3 (syn),
27.1 (anti), 127.2 (syn), 128.0, 128.4 (anti), 128.5 (anti), 128.7
42.9 (anti), 52.9 (anti), 53.0 (syn), 127.9, 128.0, 128.4, 129.0,
132.7 (anti), 132.9 (syn), 135.9 (anti), 136.1 (syn), 137.0, 139.1
(syn), 139.3 (anti), 198.6 (anti), 199.0 (syn), 219.8 (anti), 220.5
+
(
(
(
syn), 128.9 (syn), 132.3 (syn), 132.5 (anti), 133.0 (anti), 133.2
syn), 136.4 (anti), 137.0 (syn), 150.7 (syn), 150.8 (anti), 197.5
syn), 197.7 (anti), 218.9 (syn), 219.6 (anti). HRMS (ESI) m/z calcd
(syn). HRMS (ESI) m/z calcd for C21H22O [M+Na] : 329.1512, found
2
329.1508. HPLC analysis (Chiralpak AD-H column, hexane/2-pro-
panol = 95:5, flow rate = 1.0 mL/min, wavelength = 220 nm):
Rt = 17.90 (major, syn-isomer), 23.96 (minor, syn-isomer), 30.49
(major, anti-isomer) and 35.19 min (minor, anti-isomer).
+
for C20
H19NO
4
[M+Na] : 320.1206, found 320.1208. HPLC analysis
(
Chiralpak AD-H column, hexane/2-propanol = 60:40, flow
rate = 1.0 mL/min, wavelength = 220 nm): R = 8.89 (major, syn-
t
isomer), 10.60 (minor, syn-isomer), 15.01 (major, anti-isomer)
and 33.45 min (major, anti-isomer).
4.1.6. 2-((S)-1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl)-
cyclopentanone 3f
2
D
0
Yellow oil, 54% yield, ½
a
ꢁ
¼ ꢀ30:2 (c 1.0, CHCl
3
), syn/anti: 15/
1
4
.1.3. 2-((S)-3-Oxo-3-phenyl-1-(4-trifluoromethylphenyl)-
85, 63% ee for syn-isomer and 65% ee for anti-isomer. H NMR
propyl)cyclopentanone 3c
(400 MHz, CDCl ): d 1.50–1.60 (m, 1H), 1.67–1.79 (m, 1H), 1.90–
3
2
D
0
Yellow oil, 90% yield, ½
a
ꢁ
¼ ꢀ23:2 (c 1.1, CHCl
3
), syn/anti: 35/65,
1.92 (m, 2H), 2.02–2.11 (m, 1H), 2.23–2.29 (m, 1H), 2.41–2.51
1
6
1% ee for syn-isomer and 66% ee for anti-isomer. H NMR (400 MHz,
(m, 1H), 3.35 (dd, J = 7.6 and 16.4 Hz, 0.85H), 3.47 (dd, J = 6.4 and
16.4 Hz, 0.15H), 3.69 (dd, J = 7.2 and 14.0 Hz, 1H), 3.77 (s, 3H),
3.83 (dd, J = 6.0 and 16.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2Harom),
7.15 (d, J = 8.4 Hz, 2Harom), 7.42–7.54 (m, 3Harom), 7.92–8.00
CDCl ): d 1.44–1.76 (m, 2H), 1.84–1.94 (m, 2H), 1.99–2.16 (m, 1H),
3
2.25–2.33 (m, 1H), 2.45–2.57 (m, 1H), 3.39 (dd, J = 8.0 and 17.2 Hz,
0.65H), 3.54 (dd, J = 8.0 and 17.2 Hz, 0.35H), 3.70–3.80 (m, 1H),
3.84–3.96 (m, 1H), 7.36 (d, J = 8.0 Hz, 2Harom), 7.44 (d, J = 8.0 Hz,
2
Harom), 7.52–7.57 (m, 3Harom), 7.90–7.96 (m, 2Harom). 13C NMR
1
3
(m, 2Harom). C NMR (100.6 MHz, CDCl ): 20.2 (anti), 20.5 (syn),
3
27.1 (syn), 27.6 (anti), 38.8 (anti), 39.7 (syn), 40.0 (syn), 41.1 (anti),

Y. Liu et al. / Tetrahedron: Asymmetry 22 (2011) 476–479
479
4
1
1
3.0, 53.0, 55.1, 113.7, 128.0 (anti), 128.1 (syn), 128.4, 129.2 (anti),
29.4 (syn), 132.8 (anti), 132.9 (syn), 134.1 (syn), 134.3 (anti),
(100.6 MHz, CDCl
3
): 20.2 (anti), 20.5 (syn), 27.0 (anti), 28.5 (syn),
29.7 (syn), 38.9 (anti), 39.8 (syn), 40.5 (anti), 41.7 (syn), 44.0 (anti),
52.9 (syn), 55.2 (anti), 113.9, 123.8, 129.0 (anti), 129.1 (anti), 129.2
(syn), 129.3 (syn), 133.5 (syn), 134.2 (anti), 141.4 (syn), 141.6 (anti),
150.1 (anti), 150.2 (syn), 158.3 (anti), 158.5 (syn), 197.4 (anti),
37.0, 158.1 (anti), 158.2 (syn), 198.7 (anti), 199.1 (syn), 219.9
+
(anti), 220.8 (syn). HRMS (ESI) m/z calcd for C21
H
22
O
3
[M+Na] :
3
45.1461, found 345.1458. HPLC analysis (Chiralpak AD-H column,
hexane/2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength =
197.9 (syn), 220.2 (anti), 221.0 (syn). HRMS (ESI) m/z calcd for
+
2
1
20 nm): R
t
= 10.56 (major, syn-isomer), 15.35 (minor, syn-isomer),
C
21
H21NO
5
[M+Na] : 390.1312, found 390.1312. HPLC analysis
6.61 (major, anti-isomer) and 21.10 min (minor, anti-isomer).
(Chiralpak AD-H column, hexane/2-propanol = 65:35, flow
rate = 1.0 mL/min, wavelength = 220 nm): R = 18.50 (major, syn-
t
4
.1.7. 2-((S)-3-(4-Bromophenyl)-3-oxo-1-phenylpropyl)-
isomer), 29.74 (minor, syn-isomer), 31.90 (major, anti-isomer)
and 33.69 min (minor, anti-isomer).
cyclopentanone 3g
2
D
0
White solid, 89% yield, mp 110–112 °C, ½
a
ꢁ
¼ ꢀ21:6 (c 1.0,
4
.1.10. 2-((S)-1-(4-Methoxyphenyl)-3-(4-nitrophenyl)-3-
3
CHCl ), syn/anti: 20/80, 55% ee for syn-isomer and 59% ee for
1
oxopropyl)cyclopentanone 3j
anti-isomer. H NMR (400 MHz, CDCl
.09–2.18 (m, 1H), 2.24–2.33 (m, 1H), 2.43–2.57 (m, 1H), 3.32
dd, J = 7.6 and 16.8 Hz, 0.80H), 3.45 (dd, J = 10.6 and 17.2 Hz,
3
): d 1.52–1.97 (m, 4H),
2
D
0
White solid, 64% yield, mp 126–128 °C. ½
aꢁ
¼ ꢀ15:3 (c 0.30,
2
(
3
CHCl ), syn/anti: 28/72, 53% ee for syn-isomer and 57% ee for anti-
1
isomer. H NMR (400 MHz, CDCl
3
): d 1.60–1.79 (m, 3H), 1.85–1.92
0
0
.20H), 3.63–3.82 (m, 1.20H), 3.90 (dd, J = 6.0 and 16.8 Hz,
.80H), 7.19–7.32 (m, 5Harom), 7.58 (d, J = 8.8 Hz, 2Harom), 7.80
(
m, 1H), 2.07–2.13 (m, 1H), 2.18–2.24 (m, 1H), 2.37 (s, 3H), 2.42–
1
3
2.52 (m, 1H), 3.31 (dd, J = 7.6 and 16.8 Hz, 0.28H), 3.41 (dd, J = 10.6
(
(
3
5
1
d, J = 8.4 Hz, 1.60Harom), 7.86 (d, J = 8.8 Hz, 0.40Harom). C NMR
100.6 MHz, CDCl ): 20.2 (anti), 20.5 (syn), 27.0 (syn), 28.2 (anti),
8.8 (anti), 39.6 (syn), 40.8 (syn), 41.0 (anti), 43.4, 52.8 (anti),
and 16.8 Hz, 0.72H), 3.65–3.82 (m, 2H), 7.15–7.23 (m, 7Harom),
3
1
3
7
2
4
1
3
.78–7.86 (m, 2Harom). C NMR (100.6 MHz, CDCl ): 20.5 (anti),
1.5 (syn), 27.1 (anti), 29.6 (syn), 39.7 (syn), 39.6 (anti), 40.7 (anti),
0.8 (syn), 41.0 (anti), 42.7 (syn), 52.9 (syn), 53.0 (anti), 26.5, 126.6,
28.1, 128.2, 128.4, 129.1, 134.6, 142.4 (syn), 142.5 (anti), 143.6
3.0 (syn), 126.7 (anti), 126.8 (syn), 128.0 (syn), 128.1 (anti),
28.3 (syn), 128.4 (anti), 128.5, 131.8 (anti), 131.9 (syn), 135.7
(syn), 135.8 (anti), 142.0 (syn), 142.4 (anti), 197.6 (anti), 198.1
(
syn), 143.7 (anti), 198.2 (syn), 198.6 (anti), 219.7 (syn), 220.4 (anti).
(syn), 219.9 (anti), 220.6 (syn). HRMS (ESI) m/z calcd for
+
7
9
+
HRMS (ESI) m/z calcd for C21H22O2 [M+Na] : 329.1512, found
29.1511. HPLC analysis (Chiralpak AD-H column, hexane/2-propa-
nol = 60:40, flow rate = 1.0 mL/min, wavelength = 220 nm): R
.41 (major, syn-isomer), 12.57 (minor, syn-isomer), 14.07 (major,
C
20 2
H19 BrO [M+Na] : 393.0461, found 393.0470. HPLC analysis
3
(
Chiralpak AD-H column, hexane/2-propanol = 60:40, flow
t
=
rate = 1.0 mL/min, wavelength = 220 nm): R = 9.36 (major, syn-
isomer), 12.71 (minor, syn-isomer), 14.80 (major, anti-isomer)
and 26.01 min (minor, anti-isomer).
t
9
anti-isomer) and 27.94 min (minor, anti-isomer).
Acknowledgments
4
.1.8. 2-((S)-1-(2-Methoxyphenyl)-3-(4-nitrophenyl)-3-
oxopropyl)cyclopentanone 3h
20
We are grateful to the National Natural Science Foundation of
China (Nos. 20772058, 20972070), the National Basic research Pro-
gram of China (973 program 2010CB833300) and the Key labora-
tory of Elemento-Organic Chemistry for generous financial
support for our programs.
Yellow oil, 59% yield, ½
0, 27% ee for syn-isomer and 64% ee for anti-isomer. H NMR
400 MHz, CDCl ): d 1.58–1.89 (m, 3H), 1.92–2.11 (m, 1.5H), 2.21–
a
ꢁ
¼ ꢀ16:8 (c 0.70, CHCl
3
), syn/anti: 40/
D
1
6
(
3
2.33 (m, 1.5H), 2.55–2.71 (m, 1H), 3.37 (dd, J = 8.4 and 16.8 Hz,
0.60H), 3.41 (dd, J = 7.6 and 16.4 Hz, 0.40H), 3.66–3.74 (m, 1H),
3.77 (s, 3H), 4.12 (dd, J = 4.8 and 16.4 Hz, 0.60H), 4.28–4.32 (m,
0.40H), 6.84–6.90 (m, 2Harom), 7.12–7.21 (m, 2Harom), 8.05 (d,
References
J = 8.8 Hz, 1.20Harom), 8.10 (d, J = 9.2 Hz, 0.80Harom), 8.25 (d,
1
.
(a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, 1992; For recent review of organocatalyzed conjugate addition
reactions, see: (b) Alma ßs i, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry
1
3
J = 8.8 Hz, 2Harom). C NMR (100.6 MHz, CDCl
3
): 20.2 (anti), 20.5
(
(
(
syn), 26.7 (syn), 29.5 (anti), 33.5 (anti), 37.8 (syn), 38.8 (syn), 39.2
anti), 40.5 (syn), 42.8 (anti), 51.3 (anti), 52.0 (syn), 55.2, 110.6
syn), 110.9 (anti), 120.7, 123.6 (anti), 123.7 (syn), 127.9 (syn),
2
007, 18, 299–365.
For reviews, see: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
002, 1877–1894; (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716.
3. Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331–8338.
2.
2
1
1
1
2
28.0 (anti), 128.4 (syn), 129.1 (anti), 129.2 (anti), 129.8 (syn),
30.0 (syn), 130.2 (anti), 141.6 (syn), 142.0 (anti), 150.0 (anti),
50.2 (syn), 157.0 (syn), 157.3 (anti), 198.0 (anti), 198.1 (syn),
4
5
.
.
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661–665.
(a) Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004, 43, 3958–
3960; (b) Peelen, T. J.; Chi, Y.-G.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127,
20.4 (syn), 221.2 (anti). HRMS (ESI) m/z calcd for C21
H21NO
5
11598–11599.
+
6
.
.
(a) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253–4256; (b) Melchiorre, P.;
Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151–4157.
(a) Wang, J.; Qi, C.; Ge, Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 46, 2124–2126;
(b) Huang, H.; Yu, F.; Jin, Z.; Li, W.; Wu, W.; Liang, X.; Ye, J. Chem. Commun.
2010, 46, 5957–5959; (c) Zhang, Y.; Yu, C.; Ji, Y.; Wang, W. Chem. Asian J. 2010,
[
M+Na] : 390.1312, found 390.1310. HPLC analysis (Chiralpak AD-
H column, hexane/2-propanol = 65:35, flow rate = 1.0 mL/min,
wavelength = 220 nm): R = 14.46 (major, syn-isomer), 15.30 (min-
7
t
or, anti-isomer), 16.65 (minor, syn-isomer) and 18.36 min (major,
anti-isomer).
5
, 1303–1306.
8
9
.
.
Wang, J.; Li, H.; Zu, L.; Wang, W. Adv. Synth. Catal. 2006, 348, 425–428.
Xu, D.-Z.; Shi, S.; Liu, Y.; Wang, Y. Tetrahedron 2009, 65, 9344–9349.
4
.1.9. 2-((S)-1-(4-Methoxyphenyl)-3-(4-nitrophenyl)-3-
10. Over course of this study, Li reported a highly enantioselective Michael
addition of cyclopentanone to chalcones, see: Wang, J.; Wang, X.; Ge, Z.; Cheng,
T.; Li, R. Chem. Commun. 2010, 46, 1751–1753.
oxopropyl)cyclopentanone 3i
2
D
0
Yellow oil, 83% yield, ½
4, 51% ee for syn-isomer and 60% ee for anti-isomer. H NMR
400 MHz, CDCl ): d 1.48–1.56 (m, 1H), 1.67–1.96 (m, 3H), 2.09–
.18 (m, 1H), 2.22–2.33 (m, 1H), 2.42–2.52 (m, 1H), 3.29 (dd,
a
ꢁ
3
¼ ꢀ10:0 (c 1.0, CHCl ), syn/anti: 36/
11. (a) Lu, A.; Wu, R.; Wang, Y.; Zhou, Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org. Chem.
2010, 2057–2061; (b) Lu, A.; Liu, T.; Wu, R.; Wang, Y.; Zhou, Z.; Wu, G.; Fang, J.;
Tang, C. Eur. J. Org. Chem. 2010, 5777–5781; (c) Lu, A.; Wu, R.; Wang, Y.; Zhou,
Z.; Wu, G.; Fang, J.; Tang, C. Eur. J. Org. Chem. 2011, 122–127; (d) Wu, Y.; Lu, A.;
Liu, Y.; Yu, X.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Tetrahedron:
Asymmetry 2010, 21, 2988–2992.
1
6
(
2
3
J = 8.0 and 16.8 Hz, 0.64H), 3.45–3.58 (m, 1H), 3.66–3.71 (m,
.36H), 3.76 (s, 3H), 3.82 (dd, J = 3.2 and 16.8 Hz, 0.36H), 3.97
12. In a control experiment, similar results (89/11 anti/syn, 91% ee for the anti-
0
isomer) were obtained by directly employing the free amine of 1b as the
(
(
dd, J = 5.6 and 16.8 Hz, 0.64H), 6.81 (d, J = 8.8 Hz, 2Harom), 7.10
d, J = 8.8 Hz, 2Harom), 8.04 (d, J = 8.8 Hz, 1.28Harom), 8.11 (d,
catalyst.
t
13. Cocatalyst, yield, anti/syn, ee: AcOH, 70, 68/32, 67/90; BuCO H, 70, 76/24, 70/
2
1
3
91; PhOH, no reaction.
J = 8.8 Hz, 0.72Harom), 8.27 (d, J = 8.0 Hz, 2Harom).
C NMR