Doubly stereocontrolled asymmetric Michael addition of acetylacetone to nitroolefins promoted by an isosteviol-derived bifunctional thiourea

Article abstract of DOI:10.1016/j.tetasy.2012.03.020

A novel class of chiral bifunctional thioureas bearing a chiral lipophilic beyerane scaffold and a tertiary amino group was designed and prepared. The thioureas were proven to be effective for catalyzing the doubly stereocontrolled asymmetric Michael addi

Full text of DOI:10.1016/j.tetasy.2012.03.020

Tetrahedron: Asymmetry 23 (2012) 443–448
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Tetrahedron: Asymmetry
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Doubly stereocontrolled asymmetric Michael addition of acetylacetone
to nitroolefins promoted by an isosteviol-derived bifunctional thiourea
Zhi-wei Ma a, Yu-xia Liu a,b, Li-juan Huo a, Xiang Gao a, Jing-chao Tao a,
⇑
a New Drug Research and Development Center, College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, PR China
b Department of Material and Chemistry Engineering, Henan Institute of Engineering, Zhengzhou 450007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of chiral bifunctional thioureas bearing a chiral lipophilic beyerane scaffold and a tertiary
amino group was designed and prepared. The thioureas were proven to be effective for catalyzing the
doubly stereocontrolled asymmetric Michael addition between acetylacetone and nitroolefins. The corre-
sponding adducts were obtained in high yields (up to 95%) and with good to excellent enantioselectivities
(up to 97%). In addition, the reaction of tert-butyl acetoacetate and trans-b-nitrostyrene also proceeded
smoothly with good enantioselectivity.
Received 3 February 2012
Accepted 26 March 2012
Available online 1 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
S
R
S
S
N
H
N
H
O
Both enantiomers of a chiral compound are often useful and
versatile in terms of the pharmaceutical industry and organic syn-
thesis.1 However, the efficient preparation of both enantiomers of a
chiral compound still represents a daunting task, and to the best of
our knowledge, the number of examples on effective double asym-
metric inductions on metal-free organocatalytic reactions is lim-
ited.2 As a result, developing an effective organocatalytic method
to prepare optionally both the enantiomers of chiral compounds
is a highly desirable goal.
Over the past few years, bifunctional tertiary amine-thiourea
organocatalysts have emerged as new and efficient organocatalysts
for asymmetric reactions.3 Despite their tremendous utility, these
organocatalysts are derived from a very limited range of chiral
structural scaffolds, including cyclohexane-1,2-diamine,4 1,10-
binaphthyl-2,20-diamine,5 and cinchona alkaloids.6 Therefore, the
development of bifunctional tertiary amine-thiourea organocata-
lysts with novel chiral scaffolds for doubly stereocontrolled asym-
metric transformations would be highly desirable.
R
R
R
N
O
N
H
N
H
N
H
N
H
NH2
NH2
3
1a
1b
S
S
R
N
H
N
H
N
H
N
H
N
N
R
2a
2b
COOEt
Figure 1. Novel multifunctional thiourea catalysts.
2. Results and discussion
Starting from the commercially available natural product stevi-
oside, isothiocyanate 4 was conveniently prepared.9 N,N-Dimethyl
cyclohexane-1,2-diamine 5a/5b was synthesized starting from
cyclohexane-1,2-diamine through mono amino protection with
phthalic anhydride, N,N-dimethylation, and subsequently depro-
tection.10 N-Phthaloyl-1,2-diaminocyclohexane 6 was also synthe-
sized. Coupling of compound 4 and 5/6 afforded the desired
bifunctional thiourea catalyst 2/3 in good yield (Scheme 1). Follow-
ing the same procedure, these catalysts could be easily prepared on
a gram scale.
As part of our continuing interests in natural product7 and
asymmetric catalysis,8 we have recently reported a novel class of
easily prepared, inexpensive, and tunable chiral bifunctional pri-
mary amine-thiourea organocatalysts by combining a novel chiral
scaffold (isosteviol) and cyclohexane-1,2-diamine, 1a and 1b, and
their application in doubly stereocontrolled asymmetric Michael
additions.9 Herein we report the discovery that thioureas, 2a and
2b, efficiently promote the Michael reaction of acetylacetone and
nitroolefins with good levels of enantioselectivity (Fig. 1).
With the novel bifunctional thioureas in hand, we initially
screened their catalytic activities for asymmetric Michael additions
with acetylacetone and trans-b-nitrostyrene as the model reaction
⇑
Corresponding author. Tel./fax: +86 371 67767200.
E-mail address: jctao@zzu.edu.cn (J.-c. Tao).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.020

444
Z. Ma et al. / Tetrahedron: Asymmetry 23 (2012) 443–448
Table 2
S
Optimization of the reaction conditionsa
N
CH2Cl2
R
RNCS
N
H
N
H
O
O
r.t., 12 h
O
O
N
N
N
NH2
Cat. 2a X mol%
NO2
Ph
4
5a
2a
solvent, rt
NO2
Ph
8a
S
7
9a
N
CH2Cl2
R
R
RNCS
N
N
H
r
.t., 12 h
Entry
Solvent
X (mol %)
T (°C)
Time (h)
Yieldb (%)
Eec (%)
H
NH2
1
2
3
4
5
6
7
8
9
Hexane
Ether
CH2Cl2
CHCl3
Toluene
CH3CN
i-PrOH
H2O
15
15
15
15
15
15
15
15
15
15
15
15
15
10
5
25
25
25
25
25
25
25
25
25
25
0
ꢀ40
ꢀ60
ꢀ40
ꢀ40
2
2
3
3
3
3
2
2
2
2
4
6
36
10
36
70
74
84
86
88
74
72
68
90
82
86
91
89
90
92
82
83
85
87
89
59
67
63
72
83
90
94
92
94
90
4
2b
5b
S
O
N
H
N
H
O
N
CH2Cl2
RNCS
O
O
r.t., 24 h
NH2
Brine
Neat
d
10
4
6
3
11
12
13
14
15
Toluene
Toluene
Toluene
Toluene
Toluene
R
a
Unless otherwise specified, all reactions were carried out using trans-b-nitro-
styrene (0.20 mmol), acetylacetone (0.40 mmol), and 15 mol % of catalyst 2a in
0.5 mL of solvent at room temperature.
COOEt
b
Isolated yield.
Determined by chiral HPLC analysis.
c
Scheme 1. Synthesis of thiourea-amine multifunctional catalysts.
d
0.80 equiv of acetylacetone were used.
Table 1
tivities were obtained (Table 2, entries 8 and 9). This was probably
due to the negative effect of the hydrogen bonding interactions be-
tween the substrates and the protic solvents, which disturbed the
efficient aggregation of the reactants surrounding the bifunctional
catalyst. When the Michael reaction was performed without a sol-
vent, it also furnished the product in good yield and enantioselec-
tivity (Table 2, entry 10). A survey of solvents revealed that toluene
was the optimal solvent.
a
Comparison of catalytic activities of thioureas for the model reaction
O
O
O
O
Cat. 15 mol%
CH2Cl2, rt, 4 h
NO2
Ph
NO2
*
Ph
8a
7
9a
Entry
Catalyst
Yieldb (%)
Eec (%)
The reaction temperature was found to be an essential factor
with regard to the enantioselectivity of this reaction. The
stereoselectivity was gradually increased by decreasing the reac-
tion temperature from 25 to ꢀ40 °C (Table 2, entries 5, 11 and
12). However, when decreasing the temperature to ꢀ60 °C, the
reaction time was prolonged and the enantiomeric excess of the
reaction reduced slightly (Table 2, entry 13). A decrease in the cat-
alyst loading from 15 to 10 mol % did not affect the enantioselec-
tivity or the yield, although a prolonged reaction time was
necessary. When the catalyst loading was reduced to 5 mol %, the
enantioselectivity and yield were not significantly affected, but
the reaction time was prolonged. Thus, the optimized catalyst
loading was chosen as 10 mol %.
1
2
3
4
5
1a
1b
2a
2b
3
nrd
nde
nrd
nde
84
83
Trace
85 (S)
82 (R)
nde
a
Unless otherwise specified, all reactions were carried out using trans-b-nitro-
styrene (0.20 mmol), acetylacetone (0.40 mmol), and 15 mol % of catalyst in 0.5 mL
of CH2Cl2 at room temperature.
b
Isolated yield.
Determined by chiral HPLC analysis.
No reaction.
Not determined.
c
d
e
(Table 1). The results showed that catalysts 1 and 3 exhibited
unobservable activities for the model reaction (Table 1, entries 1,
2, and 5). The newly designed catalysts 2 proved to be the best
choice for this asymmetric Michael addition. More importantly,
thioureas 2a and 2b exhibited a reversed sense of asymmetric
induction (Table 1, entry 3 vs entry 4).
In further experiments, other influencing factors, such as sol-
vent, reaction temperature and catalyst loading, were thoroughly
investigated employing 2a as the catalyst. The results are listed
in Table 2. Solvent evaluation revealed that both the yield and
the enantioselectivity were highly dependent on the solvent. Apro-
tic solvents such as n-hexane, ether, CH2Cl2, CHCl3, and toluene
gave higher yields and enantioselectivities (Table 2, entries 1–5).
When a protic solvent or more polar solvent, such as i-PrOH,
CH3CN, were used, both the yield and enantioselectivity decreased
remarkably (Table 2, entries 6 and 7). In addition, when an aqueous
medium such as H2O or brine was employed, lower enantioselec-
Based on all of the above results, a set of acceptable reaction
conditions, 7 (0.40 mmol, 2.0 equiv) and 8 (0.20 mmol, 1.0 equiv)
in 0.5 mL of toluene with 10 mol % of catalyst 2a at ꢀ40 °C were
established. We next investigated the scope and limitations of this
asymmetric Michael addition. All the nitrostyrenes bearing either
electron-donating or electron-withdrawing substituents on the
aromatic ring gave the desired Michael adducts in high yields
and enantioselectivities (Table 3, entries 1–8). For 2-nitro-substi-
tuted-b-nitro styrene, Zhou’s catalyst was not efficient.4d However,
when our newly designed catalyst was used, the reaction occurred
smoothly and afforded the desired product with the best
enantioselectivity (97% ee, Table 3, entry 5). With respect to the
electron-donating group substituted nitroalkenes, within a longer
reaction time, the corresponding adducts were obtained in higher
yields and with similar enantioselectivities (Table 3, entries
6–8). Naphthylnitroalkenes 8i/8j and heteroaromatic nitroalkenes
8k/8l also gave Michael adducts in good yields and with high

Z. Ma et al. / Tetrahedron: Asymmetry 23 (2012) 443–448
445
Table 3
O
O
Substrate studies of the Michael addition between acetylacetone and nitroolefins
O
O
Cat. 2a 10 mol%
toluene, -40 oC, 20 h
NO2
promoted by 2aa
Ot-Bu
NO2
Ph
Ot-Bu
O
O
Ph
O
O
8a
10
11
Cat. 2a 10 mol%
toluene, -40 oC
NO2
R
yield: 92 %
dr: 2/1
NO2
R
ee: 94/82 %
8
7
9
Entry
R
Time (h)
Product
Yieldb (%)
Eec (%)
O
O
O
O
Cat. 2a 10 mol%
toluene, -40 oC, 20 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
10
12
12
12
12
24
24
24
48
48
24
24
72
72
72
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
—
—
91
86
89
84
81
91
95
92
90
87
91
82
79
nrd
nrd
94
93
94
90
97
93
95
96
92
94
92
95
82
—
NO2
EtO
OEt
Ph
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
2-NO2-C6H4
4-CH3-C6H4
3-OCH3-C6H4
4-OCH3-C6H4
1-Naphthyl
2-Naphthyl
2-Furanyl
EtO
OEt
NO2
Ph
8a
13
12
No reaction
Scheme 2. Asymmetric Michael addition of other nucleophiles to nitroolefin 8a
catalyzed by 2a.
S
5-Cl-2-thienyl
PhCH@CH
n-Pr
N
H
O
N
H
O
N
PhCH2CH2
—
N
O
H
a
COOEt
Unless otherwise specified, all reactions were carried out using trans-b-nitro-
O
styrene (0.20 mmol), acetylacetone (0.40 mmol), and 10 mol % catalyst 2a in 0.5 mL
of toluene at ꢀ40 °C.
b
Isolated yield.
c
Determined by chiral HPLC analysis.
No reaction.
d
Figure 2. Proposed transition state.
Table 4
lower enantioselectivities (Table 4). In our earlier work,9 when pri-
mary amine-thioureas 1a and 1b were used independently for the
asymmetric Michael reaction, nearly the same results with regard
to activity and enantioselectivity were obtained. In the case of ter-
tiary amine-thioureas 2a and 2b, there were some slight differ-
ences, especially with regard to enantioselectivities. Based on our
previous theoretical calculations,9a we speculated that the confor-
mation of the transition state may generate a slight change when
the primary amino group is replaced by a tertiary amino group,
causing the enantioselectivity to be slightly lower.
The asymmetric Michael additions of other nucleophiles to
nitroolefin 8a using 2a as catalyst were also investigated. As shown
in Scheme 2, the unsymmetrical 1,3-dicarbonyl compound, tert-
butyl acetoacetate, also worked well to give the desired products
in high yield and with good diastereoselectivity (2/1) and enant-
ioselectivty (94% and 82% ee for the major and the minor diastereo-
mer, respectively). However, in the case of diethyl malonate, no
reaction took place.
Substrate studies of the Michael addition between acetylacetone and nitroolefins
promoted by 2ba
O
O
O
O
Cat. 2b 10 mol%
NO2
R
Toluene, -40 o
C
NO2
R
ent-9
8
7
Entry
R
Time (h)
Product
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
8a
10
12
12
12
12
24
24
24
48
48
24
24
72
72
72
ent-9a
ent-9b
ent-9c
ent-9d
ent-9e
ent-9f
ent-9g
ent-9h
ent-9i
ent-9j
ent-9k
ent-9l
ent-9m
—
90
86
87
86
85
94
91
93
90
88
90
84
76
nrd
nrd
86
82
85
83
85
91
87
85
77
82
85
90
79
—
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
2-NO2-C6H4
4-CH3-C6H4
3-CH3O-C6H4
4-CH3O-C6H4
1-Naphthyl
2-Naphthyl
2-Furanyl
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
5-Cl-2-thienyl
PhCH@CH
n-Pr
Although the precise reaction mechanism needs further study, a
possible transition state has been proposed based on the observed
stereoselectivities of the asymmetric Michael addition of acetyl-
acetone to nitroolefins. In Figure 2, a thiourea moiety of catalyst
2a interacts through hydrogen bonding with the b-nitro group of
8m
8n
8o
PhCH2CH2
—
—
a
Unless otherwise specified, all reactions were carried out using trans-b-nitro-
styrene (0.20 mmol), acetylacetone (0.40 mmol), and 10 mol % of catalyst 2b in
0.5 mL of toluene at ꢀ40 °C.
the nitroalkene and enhances the electrophilicity of the
a-alkene
b
carbon, while the tertiary amine deprotonates an acidic proton of
the 2,4-pentandione, generating a ternary complex. The synergistic
steric hindrance from the chiral isosteviol moiety of bifunctional
catalyst 2a might be responsible for the increased stereocontrol
of the Michael addition reaction. Nevertheless, the precise catalytic
mechanism still requires further investigation.
Isolated yield.
Determined by chiral HPLC analysis.
No reaction.
c
d
enantioselectivities (Table 3, entries 9–12). When the reaction was
performed with conjugated nitroalkene 8m, the yield and enanti-
oselectivity were slightly lower (Table 3, entry 13). However, the
reactions of aliphatic nitroolefins 8n and 8o were very sluggish
under the same condition (Table 3, entries 14 and 15).
3. Conclusion
When thiourea 2b was used to catalyze this Michael reaction,
the structural inversed products were also obtained with slightly
In conclusion, we have developed a novel class of chiral bifunc-
tional tertiary amine-thiourea catalysts 2a and 2b bearing a chiral

446
Z. Ma et al. / Tetrahedron: Asymmetry 23 (2012) 443–448
lipophilic beyerane scaffold and a tertiary amino group. The effec-
tiveness of these novel organocatalysts has been demonstrated by
catalysis of the doubly stereocontrolled asymmetric Michael reac-
tion of acetylacetone with nitroolefins with good enantioselectivity.
More importantly, with the two structurally reversed thioureas as
catalysts, the enantiomeric Michael adducts could be obtained pre-
dominantly. In addition, the reaction of tert-butyl acetoacetate was
also effective in obtaining the corresponding adducts with good
enantioselectivities, albeit with low diastereoselectivities. Further
investigation of these organocatalysts in other asymmetric reac-
tions as well as a more detailed mechanism is currently ongoing
in our laboratory.
4.03–4.14 (m, 2H); 13C NMR (100 MHz, CHCl3): d 13.4, 14.1, 18.9,
20.5, 21.7, 22.9, 24.1, 24.4, 25.1, 28.9, 32.8, 34.4, 38.0, 39.9, 40.6,
42.3, 43.7, 54.0, 55.9, 56.0, 57.1, 59.9, 62.3, 67.1, 177.6, 182.6; IR
(KBr, cmꢀ1):
m 749, 1029, 1096, 1149, 1180, 1234, 1368, 1466,
1538, 1666, 1720, 2672, 2758, 2849, 2938, 3058, 3281, 3427;
HRMS: calcd for C31H54N3O2S [M+H]+: 532.3937, found 532.3937.
4.2.4. 1-(Ethyl ent-beyeran-19-oate-16-yl)-3-((1S,2S)-2-(N-
phthaloylamino)cyclohexyl) thiourea 3
White solid; yield: 71%; mp: 150–152 °C; ½a D20
¼ þ12:1 (c 2.0,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d 0.66 (s, 3H, –CH3),
0.78–0.88 (m, 5H), 0.94–1.08 (m, 5H), 1.17 (s, 3H, –CH3), 1.28 (t,
J = 7.2 Hz, 3H), 1.26–1.43 (m, 8H), 1.49–1.58 (m, 6H), 1.69 (s, 2H),
1.81–1.89 (m, 6H), 2.17 (d, J = 13.2 Hz, 1H), 2.28 (s, 1H), 3.97–
4.02 (m, 1H), 4.10–4.15 (m, 2H), 5.89 (s, 1H), 7.68–7.76 (m, 4H);
13C NMR(100 MHz, CHCl3): d 13.4, 14.1, 14.2, 18.9, 20.4, 21.1,
21.6, 24.7, 25.0, 25.3, 28.9, 33.3, 38.0, 39.9, 41.3, 43.6, 55.7, 57.0,
59.9, 60.4, 123.2, 131.8, 134.0, 168.9, 171.2, 177.5, 181.7; IR (KBr,
4. Experimental section
4.1. General remarks
cmꢀ1):
1539, 1613, 1713, 1769, 2848, 2938, 3066, 3352; HRMS: calcd for
37H52N3O4S [M+H]+: 634.3679, found 634.3672.
m 718, 869, 974, 1092, 1153, 1233, 1332, 1373, 1467,
All reagents were obtained from commercial suppliers without
further purification. Commercial grade solvents were dried and
purified by standard procedures. Chemicals were used as received
unless otherwise noted. Reagent grade solvents were redistilled
prior to use. 1H NMR and 13C NMR spectra were collected on a Bru-
ker DPX 400 NMR spectrometer with TMS as internal reference. IR
spectra were determined on a Thermo Nicolet IR200 unit. High res-
olution mass spectra (HRMS) were obtained on a Waters Micro-
mass Q-Tof Micro™ instrument using the ESI technique.
Chromatography was performed on silica gel (200–300 mesh).
Melting points were determined using aXT5 Apparatus and were
uncorrected. Optical rotations were determined on a Perkin Elmer
341 polarimeter. Enantiomeric excess was determined by chiral
HPLC at room temperature using Labtech 2006 pump equipped
with Labtech UV600 ultra detector with Chiral columns (Chiralcel
OD-H, Chiralpak AD-H and AE.LICHROM-AM2–5).
C
4.3. Typical procedure for the Michael addition
Acetylacetone 7 (0.40 mmol) was added to a mixture of cata-
lyst 2 (11 mg, 10 mol %) and the corresponding nitroolefin 8
(0.20 mmol) in toluene (0.5 mL). The reaction mixture was stirred
at ꢀ40 °C for the required time. After the nitroolefin was consumed
by TLC analysis, the reaction mixture was subjected to thin layer
chromatography on silica gel (ethyl acetate/petroleum ether) to
afford the pure product. The enantiomeric excess of the products
was determined by chiral HPLC analysis using Chiral columns.
4.3.1. (S)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione 9a4d
1H NMR (CDCl3, 400 MHz): d = 1.94 (s, 3H), 2.29 (s, 3H), 4.22–
4.28 (m, 1H), 4.38 (d, 1H, J = 10.8 Hz), 4.59–4.68 (m, 2H), 7.18–
7.20 (m, 2H), 7.27–7.35 (m, 3H). 13C NMR (CDCl3, 100 MHz):
29.6, 30.5, 42.8, 70.7, 78.2, 127.9, 128.6, 129.3, 136.0, 201.0,
201.8. HPLC analysis (Chiralpak AD-H column, i-propanol/hexane =
90/10, flow rate = 0.7 mL/min, wavelength = 210 nm): Rt =
18.2 min (major), 25.6 min (minor).
4.2. General procedure for the preparation of catalysts 2 and 3
4.2.1. Catalyst 2
Isothiocyanate 4 (0.778 g, 2.0 mmol) was added to a stirred
solution of N,N-cyclohexane-1,2-diamine 5a/5b (0.284 g,
2.0 mmol) in dry dichloromethane (25 mL). The reaction mixture
was stirred overnight at room temperature. The solvent was re-
moved under reduced pressure and the crude product was purified
using column chromatography eluting with CHCl3/MeOH = 50:1.
4.3.2. (S)-3-[1-(4-Fluorophenyl)-2-nitroethyl]pentane-2,4-dione
9b6g
1H NMR (CDCl3, 400 MHz): d = 1.96 (s, 3H), 2.29 (s, 3H), 4.22–
4.27 (m, 1H), 4.33 (d, 1H, J = 10.4 Hz), 4.61 (d, 2H, J = 6.4 Hz),
7.00–7.05 (m, 2H), 7.16–7.20 (m, 2H). 13C NMR (CDCl3,
100 MHz): 29.7, 30.4, 42.1, 70.7, 78.1, 116.4, 129.8, 131.8, 161.3,
163.7, 200.8, 201.5. HPLC analysis (Chiralpak AD-H column,
i-propanol/hexane = 90/10, flow rate = 0.7 mL/min, wavelength =
210 nm): Rt = 22.6 min (major), 47.2 min (minor).
4.2.2. 1-(Ethyl ent-beyeran-19-oate-16-yl)-3-((1S,2S)-2-
(dimethylamino)cyclohexyl) thiourea 2a
White solid; yield: 89%; mp: 95–97 °C; ½a D20
¼ ꢀ70:8 (c 2.0,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d 0.71 (s, 3H, –CH3), 0.83–
0.91 (m, 2H), 0.97 (s, 3H, –CH3), 0.99–1.12 (m, 4H), 1.17 (s, 3H,
–CH3), 1.25 (t, J = 7.2 Hz, 3H), 1.23–1.43 (m, 10H), 1.55–1.90 (m,
13H), 2.16 (d, J = 13.6 Hz, 1H), 2.36 (s, 6H, 2–CH3), 3.82 (m, 1H),
4.00–4.16 (m, 2H); 13C NMR (100 MHz, CHCl3): d 13.4, 14.1, 18.9,
21.7, 25.1, 28.9, 32.8, 38.0, 39.9, 41.5, 42.3, 54.0, 55.9, 56.0, 57.1,
4.3.3. (S)-3-[1-(4-Chlorophenyl)-2-nitroethyl]pentane-2,4-dione
9c4d
59.9, 67.1, 177.6, 182.6; IR (KBr, cmꢀ1):
m 753, 1040, 1095, 1151,
1H NMR (CDCl3, 400 MHz): d = 1.98 (s, 3H), 2.30 (s, 3H),
4.20–4.26 (m, 1H), 4.33 (d, 1H, J = 10.8 Hz), 4.59–4.62 (m, 2H),
7.14 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.4 Hz). 13C NMR (CDCl3,
100 MHz): 29.7, 30.5, 42.1, 70.5, 77.9, 129.3, 129.6, 134.6, 200.6,
201.4. HPLC analysis (Chiralpak AD-H column, i-propanol/hexane =
80/20, flow rate = 0.6 mL/min, wavelength = 210 nm): Rt =
16.5 min (major), 44.6 min (minor).
1180, 1232, 1370, 1461, 1531, 1722, 2676, 2847, 2934, 3307, 3440;
HRMS: calcd for C31H54N3O2S [M+H]+: 532.3937, found 532.3934.
4.2.3. 1-(Ethyl ent-beyeran-19-oate-16-yl)-3-((1R,2R)-2-
(dimethylamino)cyclohexyl) thiourea 2b
White solid; yield: 86%; mp: 89–91 °C; ½a D20
¼ ꢀ149:5 (c 2.0,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d 0.72 (s, 3H, –CH3),
0.83–0.88 (m, 1H), 0.92 (s, 3H, –CH3), 0.96–1.10 (m, 4H), 1.16 (s,
3H, –CH3), 1.25 (t, J = 7.2 Hz, 3H), 1.23–1.43 (m, 10H), 1.55–1.59
(m, 2H), 1.63–1.73 (m, 6H), 1.78–1.82 (m, 2H), 1.84–1.98 (m,
4H), 2.16 (d, J = 12.0 Hz, 1H), 2.40 (s, 6H, 2–CH3), 3.95 (m, 1H),
4.3.4. (S)-3-[1-(4-Bromophenyl)-2-nitroethyl]pentane-2,4-dione
9d6g
1H NMR (CDCl3, 400 MHz): d = 1.98 (s, 3H), 2.29 (s, 3H), 4.19–
4.25 (m, 1H), 4.33 (d, 1H, J = 10.4 Hz), 4.1 (d, 2H, J = 6.0 Hz), 7.08

Z. Ma et al. / Tetrahedron: Asymmetry 23 (2012) 443–448
447
(d, 2H, J = 8.4 Hz), 7.46 (d, 2H, J = 8.4 Hz). 13C NMR (CDCl3,
100 MHz): 29.7, 30.5, 42.2, 70.4, 77.8, 122.7, 129.7, 132.5, 135.1,
200.6, 201.4. HPLC analysis (Chiralpak AD-H column, i-propanol/
hexane = 85/15, flow rate = 0.6 mL/min, wavelength = 210 nm):
Rt = 21.4 min (major), 74.6 min (minor).
70.7, 78.2, 125.0, 126.7, 126.8, 127.5, 127.7, 128.0, 129.4, 133.0,
133.3, 201.0, 201.8. HPLC analysis (Chiralpak AD-H column, i-pro-
panol/hexane = 15/1,
flow
rate = 0.7 mL/min,
wave-
length = 210 nm): Rt = 40.6 min (major), 54.3 min (minor).
4.3.11. (R)-3-[1-(Furan-2-yl)-2-nitroethyl]pentane-2,4-dione
9k4d
4.3.5. (S)-3-(2-Nitro-1-(2-nitrophenyl)ethyl)pentane-2,4-dione
9e6c
1H NMR (CDCl3, 400 MHz): d = 2.09 (s, 3H), 2.28 (s, 3H), 4.33–
4.41 (m, 2H), 4.67 (d, 2H, J = 5.6 Hz), 6.18 (d, 1H, J = 3.6 Hz), 6.31
(dd, 1H, J = 3.2, 2.0 Hz), 7.36 (m, 1H). 13C NMR (CDCl3, 100 MHz):
29.3, 30.7, 36.6, 67.9, 75.8, 108.9, 110.8, 142.9, 149.4, 200.8,
201.5. HPLC analysis (Chiralpak AD-H column, i-propanol/hexane =
40/1, flow rate = 0.75 mL/min, wavelength = 210 nm): Rt =
35.2 min (major), 44.8 min (minor).
1H NMR (CDCl3, 400 MHz): d = 2.14 (s, 3H), 2.32 (s, 3H), 4.68 (d,
1H, J = 8.8 Hz), 4.74 (dt, 1H, J = 8.0, 6.8 Hz), 4.84 (dd, 1H, J = 13.6,
3.6 Hz), 4.97 (dd, 1H, J = 13.2, 7.2 Hz), 7.36 (d, 1H, J = 7.6 Hz), 7.49
(t, 1H, J = 8.0 Hz), 7.59 (t, 1H, J = 7.6 Hz), 7.93 (d, 1H, J = 8.0 Hz). 13
C
NMR (CDCl3, 100 MHz): 29.4, 31.3, 37.1, 69.1, 76.6, 125.6, 129.2,
129.4, 131.2, 133.5, 149.8, 200.6, 201.6. HPLC analysis (Chiralcel
OD-H column, i-propanol/hexane = 90/10, flow rate = 0.7 mL/min,
wavelength = 210 nm): Rt = 71.6 min (major), 92.2 min (minor).
4.3.12. (R)-3-(1-(5-Chlorothiophen-2-yl)-2-nitroethyl)pentane-
2,4-dione 9l
4.3.6. (S)-3-[1-(4-Methylphenyl)-2-nitroethyl]pentane-2,4-
dione 9f4d
1H NMR (CDCl3, 400 MHz): d = 1.16 (s, 6H), 1.47 (s, 3H), 2.06 (s,
1H), 2.31 (s, 2H), 3.92 (d, 0.3H, J = 9.6 Hz), 4.01 (d, 0.7H,
J = 10.4 Hz), 4.66–4.76 (m, 1.4H), 4.79–4.89 (m, 0.7H), 7.20–7.22
(m, 2H), 7.27–7.33 (m, 3H). 13C NMR (CDCl3, 100 MHz): 27.4,
27.8, 29.7, 30.1, 42.3, 42.5, 62.7, 63.0, 82.9, 83.5, 128.0, 128.2,
128.3, 128.8, 129.1, 136.6, 165.8, 166.6, 200.6, 201.4. HPLC analysis
(Chiralpak AD-H column, i-propanol/hexane = 95/5, flow rate =
0.7 mL/min, wavelength = 215 nm): major diastereomer: Rt =
14.4 min (major), 20.3 min (minor); minor diastereomer:
22.2 min (minor), 41.6 min (major)
1H NMR (CDCl3, 400 MHz): d = 1.97 (s, 3H), 2.29 (s, 3H), 3.78 (s,
3H), 4.19–4.24 (m, 1H), 4.37 (d, 1H, J = 10.8 Hz), 4.61–4.63 (m, 2H),
6.72–6.83 (m, 3H), 7.22–7.27 (m, 1H). 13C NMR (CDCl3, 100 MHz):
29.6, 30.5, 42.8, 55.2, 70.6, 78.1, 113.6, 114.1, 119.9, 130.4, 137.6,
160.1, 201.0, 201.8. HPLC analysis (Chiralpak AD-H column,
i-propanol/hexane = 85/15, flow rate = 0.65 mL/min, wavelength =
210 nm): Rt = 16.9 min (major), 22.4 min (minor).
4.3.7. (S)-3-[1-(3-Methoxyphenyl)-2-nitroethyl]pentane-2,4-
dione 9g4d
4.3.13. (R)-3-[(E)-1-Nitro-4-phenylbut-3-en-2-yl)pentane-2,4-
dione 9m4d
1H NMR (CDCl3, 400 MHz): d = 1.97 (s, 3H), 2.29 (s, 3H), 3.78 (s,
3H), 4.19–4.24 (m, 1H), 4.37 (d, 1H, J = 10.8 Hz), 4.60–4.67 (m, 2H),
7.16 (t, 1H, J = 2.0 Hz), 6.76 (d, 1H, J = 7.6 Hz), 6.81 (dd, 2H, J = 2.0,
8.0 Hz), 7.24 (t, 1H, J = 8.0 Hz). 13C NMR (CDCl3, 100 MHz): 29.7,
30.5, 42.8, 55.2, 70.6, 78.1, 113.6, 114.2, 119.9, 130.4, 137.6,
160.1, 201.0, 201.8. HPLC analysis (Chiralpak AD-H column,
i-propanol/hexane = 85/15, flow rate = 0.5 mL/min, wavelength =
210 nm): Rt = 21.3 min (major), 28.0 min (minor).
1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H), 2.28 (s, 3H), 3.70–
3.77 (m, 1H), 4.06 (d, 1H, J = 9.2 Hz), 4.52–4.59 (m, 2H), 6.02 (dd,
1H, J = 16.0, 9.6 Hz), 6.55 (d, 1H, J = 16.0 Hz), 7.25–7.31 (m, 5H).
13C NMR (CDCl3, 100 MHz): 30.0, 30.6, 40.9, 69.1, 77.4, 123.1,
126.6, 128.5, 128.7, 135.6, 201.6, 201.9. HPLC analysis (Chiralpak
AD-H column, i-propanol/hexane = 90/10, flow rate = 0.7 mL/min,
wavelength = 210 nm): Rt = 20.3 min (major), 26.0 min (minor).
4.3.14. (3S)-tert-Butyl 2-acetyl-4-nitro-3-phenylbutanoate 1111
1H NMR (CDCl3, 400 MHz): d = 1.16 (s, 6H), 1.47 (s, 3H), 2.06 (s,
1H), 2.31 (s, 2H), 3.92 (d, 0.3H, J = 9.6 Hz), 4.01 (d, 0.7H,
J = 10.4 Hz), 4.11–4.22 (m, 1H), 4.66–4.76 (m, 1.4H), 4.79–4.89
(m, 0.7H), 7.20–7.22 (m, 2H), 7.27–7.33 (m, 3H). 13C NMR (CDCl3,
100 MHz): 27.4, 27.8, 29.7, 30.1, 42.3, 42.5, 62.7, 63.0, 82.9, 83.5,
128.0, 128.2, 128.3, 128.8, 129.1, 136.6, 165.8, 166.6, 200.6,
201.4. HPLC analysis (Chiralpak AD-H column, i-propanol/
hexane = 95/5, flow rate = 0.7 mL/min, wavelength = 215 nm): the
major diastereomer: Rt = 14.4 min (major), 20.3 min (minor); the
minor diastereomer: 22.2 min (minor), 41.6 min (major).
4.3.8. (S)-3-[1-(4-Methoxyphenyl)-2-nitroethyl]pentane-2,4-
dione 9h4d
1H NMR (CDCl3, 400 MHz): d = 1.94 (s, 3H), 2.29 (s, 3H), 3.77 (s,
3H), 4.18–4.23 (m, 1H), 4.33 (d, 1H, J = 10.8 Hz), 4.59 (d, 2H,
J = 6.4 Hz), 6.84 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.8 Hz). 13C
NMR (CDCl3, 100 MHz): 29.5, 30.4, 42.1, 55.2, 70.9, 78.5, 114.7,
127.6, 129.1, 159.5, 201.2, 201.9. HPLC analysis (Chiralpak AD-H
column, i-propanol/hexane = 85/15, flow rate = 0.65 mL/min,
wavelength = 210 nm): Rt = 21.2 min (major), 33.4 min (minor).
4.3.9. (S)-3-[1-(Naphthalen-1-yl)-2-nitroethyl]pentane-2,4-
dione 9i4d
1H NMR (CDCl3, 400 MHz): d = 1.86 (s, 3H), 2.31 (s, 3H), 4.69–
4.75 (m, 2H), 4.81 (dd, 1H, J = 12.0, 8.4 Hz), 5.20 (m, 1H), 7.27 (d,
1H, J = 7.2 Hz), 7.40 (t, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 7.2 Hz), 7.63
(dt, 1H, J = 7.6, 1.2 Hz), 7.80 (d, 1H, J = 8.0 Hz), 8.17 (d, 1H,
J = 8.4 Hz). 13C NMR (CDCl3, 100 MHz): 28.7, 31.1, 36.3, 70.4,
77.8, 121.9, 124.8, 125.3, 126.3, 127.4, 129.2, 129.5, 130.8, 131.9,
134.3, 200.8, 202.4. HPLC analysis (AE.LICHROM-AM2–5 column,
i-propanol/hexane = 40/1, flow rate = 0.8 mL/min, wavelength =
210 nm): Rt = 109.2 min (major), 149.8 min (minor).
Acknowledgments
We are grateful for the financial support of the National Natural
Science Foundation of China (NSFC 20772113) and the Doctoral
Foundation of Henan Institute of Engineering (D09002).
References
1. For reviews, see: (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46–58; (b) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Chem.
Soc. Rev. 2003, 32, 115–129.
2. For some selected examples: (a) Jiang, X.-X.; Zhang, Y.-F.; Chan, A. S. C.; Wang,
R. Org. Lett. 2009, 11, 153–156; (b) Chen, J.-R.; Cao, Y.-J.; Zou, Y.-Q.; Tan, F.; Fu,
L.; Zhu, X.-Y.; Xiao, W.-J. Org. Biomol. Chem. 2010, 8, 1275–1279; (c) Pu, X.-W.;
Peng, F.-Z.; Zhang, H.-B.; Shao, Z.-H. Tetrahedron 2010, 66, 3655–3661; (d)
Chen, J.-R.; Zou, Y.-Q.; Fu, L.; Ren, F.; Tan, F.; Xiao, W.-J. Tetrahedron 2010, 66,
5367–5372.
4.3.10. (S)-3-[1-(Naphthalen-2-yl)-2-nitroethyl]pentane-2,4-
dione 9j
1H NMR (CDCl3, 400 MHz): d = 1.94 (s, 3H), 2.31 (s, 3H), 4.39–
4.45 (m, 1H), 4.50 (d, 1H, J = 10.8 Hz), 4.67–4.77 (m, 2H), 7.30
(dd, 1H, J = 8.8, 1.6 Hz), 7.47–7.51 (m, 2H), 7.65 (d, 1H, J = 1.2 Hz),
7.77–7.84 (m, 3H). 13C NMR (CDCl3, 100 MHz): 29.6, 30.5, 42.9,

448
Z. Ma et al. / Tetrahedron: Asymmetry 23 (2012) 443–448
3. For reviews concerning thiourea catalysis, see: (a) Takemoto, Y. Org. Biomol.
14417; (d) Zhu, Q.; Lu, Y. Org. Lett. 2009, 8, 1721–1724; (e) Pham, T. S.; Balázs,
L.; Petneházy, I.; Jászay, Z. Tetrahedron: Asymmetry 2010, 21, 346–351; (f)
Marcos, V.; Alemán, J.; Ruano, J. L. G.; Marini, F.; Tiecco, M. Org. Lett. 2011, 12,
3052–3055; (g) Shi, X.; He, W.; Li, H.; Zhang, X.; Zhang, S. Tetrahedron Lett.
2011, 52, 3204–3207.
Chem. 2005, 3, 4299–4306; (b) Connon, S. J. Chem. Eur. J. 2006, 12, 5419–5427;
(d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–1543; (e)
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; (f) Connon, S. J.
Chem. Commun. 2008, 44, 2499–2510; (g) Zhang, Z.-G.; Schreiner, P. R. Chem.
Soc. Rev. 2009, 38, 1187–1198.
7. (a) Wu, Y.; Dai, G.-F.; Yang, J.-H.; Zhang, Y.-X.; Zhu, Y.; Tao, J.-C. Bioorg. Med.
Chem. Lett. 2009, 19, 1818–1821; (b) Wu, Y.; Yang, J.-H.; Dai, G.-F.; Liu, C.-J.;
Tian, G.-Q.; Ma, W.-Y.; Tao, J.-C. Bioorg. Med. Chem. 2009, 17, 1464–1473; (c)
Wu, Y.; Liu, C.-J.; Liu, X.; Dai, G.-F.; Du, J.-Y.; Tao, J.-C. Helv. Chim. Acta. 2010, 93,
2052–2069.
8. For selected studies: (a) Fu, Y.-Q.; Li, Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.;
Tang, M.-S. Tetrahedron: Asymmetry 2006, 17, 3351–3357; (b) Fu, Y.-Q.; An, Y.-
J.; Liu, W.-M.; Li, Z.-C.; Zhang, G.; Tao, J.-C. Catal. Lett. 2008, 124, 397–404; (c)
An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu, Z.-M.; Pi, C.; Tao, J.-C. Tetrahedron:
Asymmetry 2010, 21, 688–694; (d) An, Y.-J.; Wang, C.-C.; Xu, Y.-Z.; Wang, W.-
J.; Tao, J.-C. Catal. Lett. 2011, 141, 1123–1129.
4. For selected examples: (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 119–125; (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 6366–6370; (c) Yalalov, D. A.; Tsogoeva, S. B.;
Shubina, T. E.; Martynova, I. M.; Clark, T. Angew. Chem., Int. Ed. 2008, 47, 6624–
6628; (d) Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C. Eur. J. Org. Chem. 2008,
4563–4566; (e) Zhao, S.-L.; Zheng, C.-W.; Zhao, G. Tetrahedron: Asymmetry
2009, 20, 1046–1051; (f) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 5, 1008–1011; (g)
Jin, Z.; Xiao, W.; Huang, H.; Liang, X.; Ye, J. Org. Lett. 2011, 4, 564–567.
5. For selected examples: (a) Rampalakos, C.; Wulff, W. D. Adv. Synth. Catal. 2008,
350, 1785–1790; (b) Chen, D.-Z.; Lu, N.; Zhang, G.-Q.; Mi, S.-Z. Tetrahedron:
Asymmetry 2009, 20, 1365–1368; (c) Rahaman, H.; Madarász, Á.; Pápai, I.;
Pihko, P. M. Angew. Chem., Int. Ed. 2011, 50, 1–6; (d) Deng, H.-P.; Wei, Y.; Shi, M.
Eur. J. Org. Chem. 2011, 10, 1956–1960.
9. (a) Ma, Z.-W.; Liu, Y.-X.; Zhang, W.-J.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Eur.
J. Org. Chem. 2011, 6747–6754; (b) Ma, Z.-W.; Liu, Y.-X.; Li, P.-L.; Ren, H.; Zhu,
Y.; Tao, J.-C. Tetrahedron: Asymmetry 2011, 22, 1740–1748.
6. For selected examples: (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 18,
10. Kaik, M.; Gawron´ ski, J. Tetrahedron: Asymmetry 2003, 14, 1559–1563.
11. Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958–9959.
9
6048–6049; (b) Vakulya, B.; Varga, S.; Soos, T. J. Org. Chem. 2008, 9, 3475–3480;
(c) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–