Aromatic l-prolinamide-catalyzed asymmetric Michael addition of aldehydes to nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2014.11.006

Two chiral aromatic l-prolinamides were synthesized in high overall yield (95%) from N-Boc-l-proline and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the optimized reaction conditions, (S)-N-tritylpyrrolidi

Full text of DOI:10.1016/j.tetasy.2014.11.006

Tetrahedron: Asymmetry 25 (2014) 1599–1604
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Aromatic L-prolinamide-catalyzed asymmetric Michael addition of
aldehydes to nitroalkenes
⇑
⇑
Yongchao Wang, Jun Lin , Kun Wei
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 September 2014
Accepted 4 November 2014
Two chiral aromatic L-prolinamides were synthesized in high overall yield (95%) from N-Boc-L-proline
and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the
optimized reaction conditions, (S)-N-tritylpyrrolidine-2-carboxamide 4 was found to be a highly efficient
organocatalyst for the Michael addition, and the corresponding Michael adducts were obtained in good
yields (up to 94%), with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to
99:1 dr).
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
reactions.10 We have designed and synthesized chiral aromatic
prolinamide in high overall yield from N-Boc- -proline, and found
L-
L
Asymmetric organocatalysis has emerged as a new, powerful,
and environmentally friendly methodology for the catalytic pro-
duction of enantiomerically pure organic compounds and is also
one of the most rapidly growing and competitive research areas
in synthetic organic chemistry.1 The organocatalytic asymmetric
Michael addition reaction has attracted growing attention in
organic synthesis to form carbonAcarbon bonds.2
that compound 4 was excellent for catalyzing asymmetric Michael
additions of aldehydes to nitroalkenes. Herein we report our preli-
minary results using our self-assembled organocatalysts in direct
Michael additions of aldehydes to nitroalkenes (Fig. 1).
O
Ph
OH
Ph
O
Ph
Ph
O
Ph
Ph
Ph
N
H
Among the various types of Michael addition, the conjugate
N
N
H
N
H
NH
OH
H
NH
addition of aldehydes or ketones with nitroalkenes to afford
c-
nitrocarbonyl compounds is especially important for their key role
in stereocontrolling steps in the enantioselective synthesis of chiral
biologically active compounds and natural products.3–5 Recently,
tremendous effort has been made in developing efficient organo-
1
2
3
4
Figure 1. Structure of aromatic L-proline derivative catalysts.
catalysts, including
L
-proline derivatives,6 chiral sulfonamides7
-proline 1 and its derivatives,
2. Results and discussion
and chiral thioureas.8 Among, then
L
such as (R)-diarylprolinol 2, diarylprolinol silyl ethers, prolina-
mides, and pyrrolidines, are commonly used in asymmetric cataly-
sis. Prolinamide derivatives have been demonstrated to be
excellent reagents in asymmetric enamine organocatalysis.9
Although these organocatalysts give good results in asymmetric
Michael addition reactions, the discovery of environmentally
friendly non-metal catalyzed asymmetric organocatalysts in
Michael addition reactions is still needed. To the best of our knowl-
Chiral aromatic
two steps from commercially available Boc-
sponding amine component in 95% overall yield (Scheme 1). Boc-
proline was treated separately with aminodiphenylmethane and
tritylamine in the presence of the corresponding additives to afford
the protected prolinamides 3a and 4a. Deprotection of the Boc
group using TFA in dry dichloromethane afforded chiral L-prolina-
mide catalysts 3 and 4.
Initially, the Michael reaction of acetaldehyde 5a and trans-b-
nitrostyrene 6a was selected as a model reaction (Table 1). The cat-
L
-prolinamides 3 and 4 were easily prepared in
L
-proline and the corre-
L
-
edge, there are only a few reports to date of aromatic L-prolinamide
derivatives used as organocatalyst in asymmetric Michael addition
alytic properties of L-proline 1, (R)-diphenylprolinol 2, and cata-
lysts 3 and 4 were evaluated by examining the addition reaction
in dichloromethane with 10% benzoic acid as the additive at room
⇑
Corresponding authors.
E-mail addresses: linjun@ynu.edu.cn (J. Lin), kunwei@ynu.edu.cn (K. Wei).
http://dx.doi.org/10.1016/j.tetasy.2014.11.006
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1600
Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 1599–1604
O
O
Ph
Ph
Ph
H2N
TFA, CH2Cl2
r. t.
Ph
N
H
N
H
Ph
Ph
N
NH
Boc
3a
3
O
N
Ph
Ph
Ph
OH
Boc
H2N
O
O
Ph
Ph
Ph
Ph
TFA, CH2Cl2
r. t.
Ph
N
H
N
H
NH
N
Ph
Boc
4a
4
Scheme 1. Synthesis of catalysts 3 and 4.
Table 1
Table 2
Screening of the catalysts and solventsa
Screening of additives and temperaturesa
catalyst (10%)
solvent
O
Ph
O
Ph
4
catalyst (10%)
toluene
(R)
NO2
(R)
NO2
NO2
O
NO2
O
+
(S)
H
(S)
+
H
Ph
Ph
benzoic acid (10%)
r. t.
additive (10%)
temperature
Me
Me
5a
Entry
6a
T (°C)
7a
5a
Entry
6a
7a
Time Yieldb
syn/antic
ee(syn)d
(%)
Additive
Time
(h)
Yieldb
(%)
syn:antic
ee(syn)d
(%)
Catalyst
Solvent
(h)
(%)
1
2
3
4
5
None
H2O
Et3N
rt
48
48
48
48
48
<5
<5
<5
<10
<10
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
1
2
3
4
5
6
7
8
1
2
3
4
4
4
4
4
4
4
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
24
36
66:34
64:36
89:11
67:33
64:33
62:38
75:25
70:30
72:28
74:26
70:30
40
92
72
84
72
54
36
76
43
85
82
rt
rt
rt
rt
12
24
18
18
24
36
36
36
12
36
54
91
87
85
67
61
55
54
93
68
p-TSA
Tartaric
acid
CF3COOH
CHOOH
CH3COOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
THF
6
7
8
9
rt
rt
rt
rt
rt
48
12
18
12
24
18
24
48
48
<10
94
87
93
51
92
91
59
27
nd
nd
70
80
85
82
87
89
91
93
CH3CN
Hexane
i-Propanol
Toluene
Toluene
65:35
70:30
74:26
65:35
70:30
64:36
69:31
67:33
9
10
10e
11
12
13
14
11e
0
a
All reactions were carried out with 5a (3.0 mmol), 6a (1.0 mmol), and benzoic
acid (10 mol %) in the presence of catalyst (10 mol %) in solvent (1.0 mL) at room
temperature.
À20
À40
À78
b
Yield of the isolated product.
a
Determined by 1H NMR analysis of the crude products.
c
All reactions were carried out with 5a (3.0 mmol) and 6a (1.0 mmol) in the
presence of catalyst 4 (10 mol %) in toluene (1.0 mL).
d
Determined by chiral HPLC. The absolute configuration was established by
b
comparison with literature date.11
Yield of the isolated product.
Determined by 1H NMR analysis of the crude products.
c
e
5 mol % of catalyst 4 was used.
d
Determined by chiral HPLC. The absolute configuration was established by
comparison with literature data.11
e
5 mol % of PhCOOH was used.
temperature. As shown in Table 1, L-proline could catalyze this
reaction, but rather poor yields and stereoselectivity were
observed (Table 1, entry 1). Although (R)-diarylprolinol 2 could
efficiently promote the enantioselectivity (92% ee, entry 2), the
moderate yields (54%) were unsatisfactory. Prolinamide 3 was also
evaluated (entry 3). Although an excellent yield (91%) was
obtained, the enantioselectivity (72% ee) was moderate. When aro-
different additives was tested and the results are summarized in
Table 2. The reaction proceeded very slowly in the absence of acid
additives and gave poor yield and enantioselectivity after 48 h
(Table 2, entries 1–3). When benzoic acid was used as an acid addi-
tive, better results were observed with an excellent yield (93%) and
enantioselectivity (85%, ee) (Table 2, entry 9). Although other acid
additives, such as HCOOH and CH3COOH, were beneficial for this
reaction, their yields and enantioselectivities were slightly lower
than the results with PhCOOH (Table 2, entries 7 and 8). The addi-
tion of a strong acid, such as p-TSA or TFA, was not favorable to the
reaction (Table 2, entries 4 and 6). In addition, when tartaric acid
was employed, it gave poor yield and enantioselectivities (Table 2,
entry 5). We found that temperature had an important influence
on the yield and stereoselectivity of the reaction. It was obvious
that good enantioselectivity could be obtained with a low reaction
temperature. Based on the overall evaluation, À20 °C was selected
to be the optimal reaction temperature.
matic L-prolinamide 4 was used, the best result was observed with
a high yield (87%), good diastereoselectivities (syn/anti = 67:33)
and enantioselectivity (84% ee) (entry 4). According to the above
result, catalyst 4 was confirmed to be the most effective catalyst
in terms of both the yield and enantioselectivity of the reaction.
To further optimize the reaction conditions, some reaction
parameters, including the solvent, additive, temperature, and
amount of catalyst were examined, and the results are shown in
Tables 1 and 2. A range of typical solvents was first screened in
the presence of benzoic acid (10 mol %) and catalyst 4 (10 mol %)
at room temperature. Among the solvents screened, toluene
(Table 1, entry 9) exhibited the best performance for both the yield
(93%) and stereoselectivity (85% ee). Moreover, we examined the
influence of catalyst loading on the reaction. When reducing the
catalyst loading from 10 mol % to 5 mol %, the reaction rate rapidly
decreased from 93% to 68% (entry 11). Next, the effect of a series of
Thus, the catalytic system consisting of 10 mol % of 4 and
10 mol % of benzoic acid in toluene solution at À20 °C was proposed
to be the most efficient conditions for the asymmetric Michael
addition of aldehydes to nitrostyrene. Under the above optimized

Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 1599–1604
1601
conditions, the scope of the asymmetric Michael addition was
Table 3 (continued)
investigated by applying different aldehydes and nitrostyrene
(Table 3). The results showed that this catalytic system had good
compatibility with various aldehydes and nitrostyrene. Products
were obtained with good yields (79–94%) and excellent enantiose-
Entry
Product
Yieldb (%)
88
syn:antic
ee (syn)d (%)
O
O
C6H4-2-Cl
NO2
15
99:1
97
99
H
H
iPr
7o
7p
S
Table 3
Asymmetric Michael additions of aldehydes to nitroalkenes catalyzed by 4a
16
89
99:1
NO2
O
R2
4
catalyst (10%)
toluene
iPr
(R)
NO2
O
NO2
+
(S)
H
R1
R2
a
benzoic acid (10%)
-20 °C, 24h
R1
All reactions were carried out with nitroalkenes (1.0 mmol) and aldehydes
(3.0 mmol) in the presence of catalyst 4 (10 mol %) in toluene (1.0 mL) at 0 °C.
5
6
7a-7k
b
Yield of the isolated product.
Determined by 1H NMR analysis of the crude products.
c
Entry
Product
Yieldb (%)
91
syn:antic
ee (syn)d (%)
d
Determined by chiral HPLC. The absolute configuration was established by
O
Ph
Ph
Ph
comparison with literature data.11
NO2
1
63:37
89
H
Me
7a
7b
7c
7d
7e
7f
lectivities (89–99%). The steric hindrance of the R1 group for ali-
phatic aldehydes increased the diastereoselectivity to a large
degree (entries 1–4 and 12–16). Moreover, various styrene-type
nitroolefins reacted smoothly with various aldehydes in good to
excellent yields (83–94%) and with high enantioselectivity (89–
99%) (entries 1–10 and 12–15). Excellent enantioselectivities (93–
99% ee) were also observed for the Michael addition of aldehydes
to nitroalkenes containing heteroaryl groups (entries 11 and 16).
In order to account for the good enantioselectivity of the reac-
tion, a plausible transition-state model is proposed in Scheme 2.
The pyrrolidine activates the aldehyde through the formation of
an enamine intermediate, and the nitro group of trans-b-nitrosty-
rene is directed toward the amide group by a hydrogen bond
between the NH group of the amide and the nitro group. The
enamine formed in situ attacks the Si face of the nitroalkene to fur-
nish the Michael adduct. It is noteworthy that the bulky aromatic
group is considered to be important with regards to the high cata-
lytic activity and enantioselectivity and diastereoselectivity of the
catalyzed reactions. Our previous research11 and some other liter-
ature12,13 could be used to support the proposed transition-state
model.
O
O
O
O
O
O
O
O
O
NO2
NO2
NO2
2
90
87
79
93
90
83
83
94
92
61:39
57:43
99:1
90
90
96
90
92
89
91
96
89
H
H
H
H
H
H
H
H
H
Et
3
nPr
Ph
4
iPr
Et
Et
Et
Et
Et
C6H4-4-Br
NO2
5
61:39
57:43
63:35
65:35
85:15
93:7
C6H4-4-Cl
NO2
6
C6H4-2-Cl
NO2
7
7g
C6H4-4-OMe
NO2
8
7h
O
N
C6H4-4-Me
NO2
9
N
Ph
Ph
H
7i
O
O
Ph
N
C6H4-4-CF3
Si
NO2
10
Scheme 2. Possible transition state of the reaction.
Et
O
7j
O
O
O
O
3. Conclusions
11
87
84:16
93
NO2
H
H
H
H
In conclusion, we have synthesized two new
and 4 as catalysts from commercially available Boc-
L
-prolinamides 3
Et
7k
7l
C6H4-4-Me
NO2
L
-proline in high
yield (95%). These catalysts were found to efficiently catalyze asym-
metric Michael addition reactions of aldehydes and nitroalkenes
under mild conditions. In the presence of (S)-N-tritylpyrrolidine-
2-carboxamide 4 (10%), the asymmetric Michael addition reaction
proved to be applicable to a variety of aldehydes and nitroalkenes,
affording the products in high yields of 94%, and with excellent dia-
stereoselectivity (up to 99:1 dr) and enantioselectivity (up to 99%).
Further applications of these chiral amides are currently underway
in our laboratory.
12
13
14
91
92
90
99:1
98:2
96:4
98
99
96
iPr
iPr
iPr
C6H4-4-Br
NO2
7m
7n
C6H4-4-F
NO2

1602
Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 1599–1604
1H), 7.32–7.19 (m, 10H), 6.21 (d, J = 8.8 Hz, 1H), 3.80–3.76 (m,
4. Experimental
4.1. General
1H), 3.25–3.19 (m, 1H), 3.03–2.87 (m, 1H), 2.18–2.08 (m, 1H),
1.99–1.92 (m, 1H), 1.76–1.67 (m, 2H); 13C NMR (100 MHz, CDCl3,
TMS): d 174.2, 142.0, 128.6, 128.6, 127.5, 127.3, 127.2, 127.1,
60.6, 56.1, 47.3, 30.8, 26.3.
Reagents and materials were of the highest commercially avail-
able grade and used without further purification. Solvents were
purified by standard procedures and distilled before use. The
NMR spectra were recorded on a Bruker DRX400 (1H: 400 MHz,
13C: 100 MHz) with TMS as the internal standard, chemical shifts
(d) are expressed in ppm, J values are given in Hz, and deuterated
CDCl3 was used as the solvent. High resolution mass spectrometry
(HRMS) was recorded on a VG Auto Spec-3000 spectrometer. Opti-
cal rotations were measured on a JASCO DIP-370 polarimeter. IR
spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using
KBr pellet. The mass spectroscopic data were obtained at the Agi-
lent 1100 LC/MSD Trap LC-mass spectrometer. HPLC analysis was
performed with a Shimadzu LC-10A instrument equipped with
Daicel HPLC columns. The reactions were monitored by thin layer
chromatography (TLC) using silica gel GF254. Column chromatogra-
phy was performed on silica gel (200–300 mesh). Compounds were
visualized by UV and spraying with H2SO4 (10%) in ethanol fol-
lowed by heating.
4.3. Procedure for the synthesis of catalysts 4
4.3.1. Procedure for the synthesis of 4a
A solution of N-t-butyloxycarbonyl-L-proline (2.58 g, 12 mmol)
and tritylamine (2.59 mg, 10 mmol) in dry dichloromethane
(15 mL) was allowed to stir for 15 min and then cooled to 0 °C after
which a dichloromethane (10 mL) solution of dicyclohexylcarbodi-
imide (2.678 g, 13 mmol) was added. After 20 min, the resulting
solution was stirred at room temperature until the complete con-
sumption of the nitroalkene (monitored by TLC). The reaction was
quenched with water and extracted with dichloromethane
(3 Â 100 mL). The combined organic layers were washed with satu-
rated brine solution (100 mL), followed by drying over Na2SO4 and
then evaporated in vacuo. The crude product was purified by col-
umn chromatography to give pure tert-butyl (S)-2-(tritylcarba-
moyl)pyrrolidine-1-carboxylate 4a as an amorphous powder, 96%
yield. [
a
]
20 = À38.4 (c 1.0, CHCl3); IR (KBr) 702, 759, 1164, 1392,
D
1507, 1695, 2925, 2974, 3321 cmÀ1
; HRMS (EI) calcd for
4.2. Procedure for the synthesis of catalysts 3
4.2.1. Procedure for the synthesis of 3a
C
29H32N2O3 [M+Na]+ 479.2305, found 479.2303. 1H NMR
(400 MHz, CDCl3, TMS): d 8.31 (s, 1H), 7.27–7.21 (m, 15H), 4.48–
4.41 (m, 1H), 3.43–3.37 (m, 2H), 2.31 (s, 1H), 1.81–1.76 (m, 5H),
1.42 (s, 9H); 13C NMR (100 MHz, CDCl3, TMS): d 171.1, 154.1,
144.8, 128.6, 127.9, 126.9, 80.6, 70.2, 58.4, 54.4, 50.1, 47.1, 31.4,
28.4, 28.3, 26.1, 24.6.
To a stirred solution of N-t-butyloxycarbonyl-L-proline (1.075 g,
5 mmol) in dry dichloromethane (15 mL) was added DMAP
(210 mg, 1.5 mmol). The mixture was allowed to stir for 15 min
and then cooled to 0 °C after which EDCI (1.22 g, 5.5 mmol) was
added. After 20 min,
a solution of 1,1-diphenylmethylamine
(676 mg,4 mmol) in dichloromethane (15 mL) was added to the
above reaction mixture. The resulting solution was stirred at room
temperature until complete consumption of the nitroalkene (mon-
itored by TLC). The reaction was quenched with water and
extracted with dichloromethane (3 Â 50 mL). The combined
organic layers were washed with saturated brine solution
(20 mL), followed by drying over Na2SO4 and evaporation in vacuo.
The crude product was purified by column chromatography to give
pure tert-butyl (S)-2-(benzhydrylcarbamoyl)pyrrolidine-1-carbox-
4.3.2. Procedure for the synthesis of 4
To a solution of tert-butyl (S)-2-(tritylcarbamoyl)pyrrolidine-1-
carboxylate 4a (10 mmol) in CH2Cl2 (30 mL) was added TFA
(10 mL). After stirring at 0 °C for 2.5 h, the solution was concen-
trated under vacuum to leave a glutinous phase. The pH of the mix-
ture was brought to 12 by the addition of 2 M NaOH. The aqueous
phase was extracted with ethyl acetate. The ethyl acetate extracts
were combined, washed with brine, dried over anhydrous Na2SO4,
filtered off and the solvent was evaporated at low pressure to give
a crude residue, which was purified by column chromatography to
give pure (S)-N-tritylpyrrolidine-2-carboxamide 4 as a amorphous
ylate 3a as an amorphous powder, 97% yield. [
a]
20 = À78.6 (c 1.0,
D
CHCl3); IR (KBr) 698, 1160, 1245, 1384, 1540, 1654, 1699, 2974,
3288 cmÀ1; HRMS (EI) calcd for C23H28N2O3 [M+Na]+ 403.1992,
found 403.1993. 1H NMR (400 MHz, CDCl3, TMS): d 7.97 (s, 1H),
7.38–7.24 (m, 10H), 6.24 (d, J = 27.2 Hz, 1H), 4.35 (d, J = 26.8 Hz,
1H), 3.39 (d, J = 59.2 Hz, 1H), 2.42 (s, 1H), 2.19 (s, 1H), 1.88 (s,
3H), 1.46 (s, 5H), 1.32 (s, 4H); 13C NMR (100 MHz, CDCl3, TMS): d
170.8, 156.1, 141.8, 128.6, 128.5, 127.5, 127.2, 127.0, 126.9, 80.5,
61.3, 59.7, 56.7, 47.2, 31.1, 28.3, 27.5, 24.7, 23.9.
powder, 99% yield. [
a
]
20 = À27.0 (c 1.0, CHCl3); IR (KBr) 632, 694,
D
755, 1094, 1176, 1446, 1491, 1674, 2859, 2921, 3260, 3321 cmÀ1
;
HRMS (EI) calcd for
C
24H24N2O [M+Na]+ 379.1780, found
379.1778.1H NMR (400 MHz, CDCl3, TMS): d 9.13 (s, 1H), 7.24–
7.14 (m, 15H), 3.70–3.67 (m, 1H), 3.03–2.97 (m, 1H), 2.93–2.88
(m, 1H), 2.05–1.90 (m, 3H), 1.73–1.64 (m, 2H); 13C NMR
(100 MHz, CDCl3, TMS): d 173.9, 145.2, 128.6, 127.9, 126.9, 69.4,
61.4, 47.4, 30.5, 26.3.
4.2.2. Procedure for the synthesis of 3
4.4. General procedure for the enantioselective Michael reaction
To a solution of tert-butyl (S)-2-(benzhydrylcarbamoyl)pyrroli-
dine-1-carboxylate (4 mmol) in CH2Cl2 (10 mL) was added TFA
(3 mL). After stirring at 0 °C for 2.5 h, the solution was concen-
trated under vacuum to leave a glutinous phase. The pH of the mix-
ture was brought to 12 by the addition of 2 M NaOH. The aqueous
phase was extracted with ethyl acetate. The ethyl acetate extracts
were combined, washed with brine, dried over anhydrous Na2SO4,
filtered off and the solvent was evaporated off at low pressure to
give a crude residue, which was purified by column chromatogra-
phy to give pure (S)-N-benzhydrylpyrrolidine-2-carboxamide 3 as
To a stirred mixture of the corresponding nitroolefin (1 mmol,
1.0 equiv) in 2 mL of the indicated solvent, the catalyst and benzoic
acid were added, after which the mixture was stirred at the indi-
cated temperature for 30 min, then freshly distilled aldehyde
(3 mmol, 3.0 equiv) was added. The resulting solution was stirred
at the same temperature and monitored by TLC. It was then
quenched with ice water (2 mL), and extracted with ethyl acetate
(3 Â 2 mL). The combined organic phase was dried over Na2SO4
and after removing the solvent, the crude product was purified
by flash chromatography to afford the corresponding Michael
adducts. The enantiomeric excess was determined by chiral HPLC
analysis.
an amorphous powder, 98% yield. [
a
]
20 = À59.0 (c 1.0, CHCl3); IR
D
(KBr) 694, 751, 918, 1106, 1495, 1662, 2851, 2953, 3309 cmÀ1
;
HRMS (EI) calcd for C18H20N2O, [M+H]+ 281.1648, found
281.1650. 1H NMR (400 MHz, CDCl3, TMS): d 8.42 (d, J = 8.4 Hz,

Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 1599–1604
1603
4.4.1. (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal 7a11
Pale yellow oil, 91% yield. [
20 = +8.3 (c 1.0, CHCl3), 1H NMR
4.4.7. (2R,3S)-3-(2-Chlorophenyl)-2-ethyl-4-nitrobutanal 7g11
Pale yellow oil, 84% yield. [
20 = +11.8 (c 1.0, CHCl3), 1H NMR
a]
D
a]
D
(400 MHz, CDCl3): d 9.71 (s, 1H), 9.53 ((s, 1H), 7.36–7.28 (m, 6H),
7.21–7.16 (m, 4H), 4.82–4.78 (m, 2H), 4.71–4.65 (m, 1H), 3.86–
3.78 (m, 2H), 2.83–2.75 (m, 2H), 1.21 (d, J = 7.2 Hz, 2H), 0.99 (d,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 202.4, 202.3, 136.6,
129.1, 129.1, 128.1, 128.1, 78.1, 48.7, 48.4, 44.8, 44.0, 12.1, 11.7;
HPLC (Chiralcel OD-H, Hexane:i-PrOH = 90:10, flow rate: 1.0 mL/
min, k = 254 nm), Tmajor = 31.9, Tminor = 23.9, 89% ee.
(400 MHz, CDCl3):d 9.73 (d, J = 2.0 Hz, 1H), 9.57 (d, J = 2.4 Hz, 1H),
7.43–7.28 (m, 2H), 7.24–7.20 (m, 4H), 4.89–4.76 (m, 2H), 4.71–
4.67 (m, 1H), 4.48–4.47 (m, 1H), 4.38–4.33 (m, 1H), 2.95 (s, 1H),
2.80–2.75 (m, 1H), 1.76–1.73 (m, 1H), 1.61–1.52 (m, 3H), 0.98 (t,
J = 14.8 Hz, 2H), 0.87 (d, J = 15.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 202.8, 202.3, 134.5, 130.6, 129.3, 129.3, 127.5, 76.7,
76.2, 54.5, 54.0, 39.5, 39.2, 29.7, 20.4, 19.9, 11.6, 10.7; HPLC (Chiral-
cel AD-H, Hexane:i-PrOH = 98.5:1.5, flow rate: 1.0 mL/min,
k = 254 nm), Tmajor = 17.5, Tminor = 19.6, 89% ee.
4.4.2. (2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal 7b11
Pale yellow oil, 90% yield. [a]
20 = +8.8 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.71 (d, J = 2.4 Hz, 1H), 9.48 (d, J = 2.8 Hz),
7.36–7.28 (m, 6H), 7.18 (d, J = 6.8, 3H), 4.82–4.70 (m, 2H), 4.65–
4.60 (m, 1H), 3.83–3.76 (m, 1H), 2.71–2.65 (m, 1H), 2.61–2.55
(m, 1H), 1.76–1.70 (m, 2H), 1.68–1.63 (m, 2H), 1.51 (t,
J = 11.6 Hz, 2H), 1.48 (t, J = 11.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 202.3, 203.2, 136.8, 129.1, 128.2, 128.2, 128.0, 78.6,
77.9, 55.0, 54.9, 44.1, 42.7, 20.6, 20.4, 11.5, 10.7; HPLC (Chiralcel
AD-H, Hexane:i-PrOH = 99: 1, flow rate: 0.8 mL/min, k = 254 nm),
Tmajor = 27.7, Tminor = 33.6, 90% ee.
4.4.8. (2R,3S)-2-Ethyl-3-(4-methoxyphenyl)-4-nitrobutanal 7h11
Pale yellow oil, 83% yield. [a]
20 = +10.4 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.71 (d, J = 2.4 Hz, 1H), 9.46 (d, J = 2.8 Hz,
1H), 7.10 (d, J = 8.8, 3H), 6.88–6.84 (m, 3H), 4.79–4.67 (m, 2H),
4.61–4.55 (m, 1H), 3.79–3.74 (m, 5H), 2.66–2.60 (m, 1H), 2.54–
2.52 (m, 1H), 1.75–1.65 (m, 2H), 1.55–1.47 (m, 2H), 1.25 (t,
J = 14.8 Hz, 1H), 1.00 (d, J = 14.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 202.5, 203.3, 159.3, 129.3, 129.0, 114.5, 78.8, 78.2, 55.2,
55.1, 55.0, 43.5, 42.0, 20.7, 20.3, 11.5, 10.7; HPLC (Chiralcel AD-H,
Hexane:i-PrOH = 96:4, flow rate: 1.0 mL/min, k = 254 nm),
Tmajor = 17.3, Tminor = 21.0, 91% ee.
4.4.3. (R)-2-((S)-2-Nitro-1-phenylethyl)pentanal 7c11
Pale yellow oil, 87% yield. [a]
20 = +6.8 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.70 (d, J = 2.4 Hz, 1H), 9.47 (d, J = 2.8 Hz,
1H), 7.37–7.28 (m, 6H), 7.17 (d, J = 7.2, 3H), 4.81–4.72 (m, 2H),
4.70–4.62 (m, 2H), 3.81–3.76 (m, 2H), 2.73–2.71 (m, 1H), 2.68–
2.63 (m, 1H), 1.68–0.94 (m, 10H), 0.91 (t, J = 18.4 Hz, 2H), 0.80 (t,
J = 18.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 203.4, 203.2,
136.8, 136.2, 129.1, 128.2, 128.1, 128.0, 78.4, 77.9, 53.8, 53.3,
44.5, 43.2, 29.6, 29.5, 20.3, 19.8, 14.0, 13.9; HPLC (Chiralcel OD-
H, Hexane:i-PrOH = 96:4, flow rate: 1.0 mL/min, k = 254 nm),
Tmajor = 34.3, Tminor = 27.9, 90% ee.
4.4.9. (2R,3S)-2-Ethyl-4-nitro-3-(p-tolyl)butanal 7i11
Pale yellow oil, 94% yield. [a]
20 = +13.1 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.66 (d, J = 1.6 Hz, 1H), 9.44 (d, J = 2.0 Hz),
7.54 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 4.75–4.68 (m, 1H),
4.62–4.56 (m, 1H), 3.85–3.79 (m, 1H), 2.68–2.65 (m, 1H), 1.50–
1.37 (m, 2H), 0.95 (t, J = 14.8 Hz, 1H), 0.77 (d, J = 14.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 202.4, 141.1, 128.5, 126.1, 126.1, 78.1,
54.5, 42.3, 20.4, 10.5; HPLC (Chiralcel OD-H, Hexane:i-PrOH = 92:8,
flow rate: 0.5 mL/min, k = 254 nm), Tmajor = 40.2, Tminor = 34.9, 96%
ee.
4.4.4. (2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal 7d11
Pale yellow oil, 79% yield. [a]
20 = +25.6 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.93 (s, 1H), 7.36–7.27 (m, 3H), 7.19 (d,
J = 7.2, 2H), 4.69–4.65 (m, 1H), 4.60–4.55 (m, 1H), 3.93–3.87 (m,
1H), 2.80–2.76 (m, 1H), 1.76–1.59 (m, 2H), 1.10 (d, J = 6.8 Hz,
3H), 0.88 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.4,
129.4, 129.2, 128.0, 79.0, 58.8, 42.0, 27.9, 21.7, 17.0; HPLC (Chiral-
cel AD-H, Hexane:i-PrOH = 97: 3, flow rate: 0.5 mL/min,
k = 254 nm), Tmajor = 23.9, Tminor = 28.6, 96% ee.
4.4.10. (2R,3S)-2-Ethyl-4-nitro-3-(4-(trifluoromethyl)phenyl)-
butanal 7j11
Pale yellow oil, 92% yield. [a]
20 = +9.8 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.66 (d, J = 1.6 Hz, 1H), 9.44 (d, J = 4.0 Hz),
7.54 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 4.75–4.68 (m, 1H),
4.62–4.56 (m, 1H), 3.85–3.79 (m, 1H), 2.69–2.65 (m, 1H), 1.49–
1.37 (m, 2H), 0.96 (t, J = 14.8 Hz), 0.77 (t, J = 14.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 202.4, 141.1, 128.5, 126.1, 126.1, 78.1, 54.5,
42.3, 20.4, 10.5; HPLC (Chiralcel AS-H, Hexane:i-PrOH = 93:7, flow
rate: 0.5 mL/min, k = 254 nm), Tmajor = 27.2, Tminor = 29.6, 89% ee.
4.4.5. (2R,3S)-3-(4-Bromophenyl)-2-ethyl-4-nitrobutanal 7e11
Pale yellow oil, 93% yield. [a]
20 = +7.6 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.71 (s, 1H), 9.49 (d, J = 2.4 Hz, 1H), 7.49–7.45
(m, 4H), 7.07 (d, J = 8.0, 3H), 4.81–4.70 (m, 2H), 4.62–4.56 (m,
1H), 3.80–3.75 (m, 1H), 2.69–2.65 (m, 1H), 2.60–2.56 (m, 1H),
1.76–1.64 (m, 2H), 1.56–1.46 (m, 2H), 0.99 (t, J = 14.8 Hz, 2H),
0.87 (d, J = 14.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 202.8,
202.7, 132.3, 132.2, 130.0, 129.7, 78.3, 54.8, 54.6, 43.4, 42.1, 20.5,
20.3, 11.4, 10.5; HPLC (Chiralcel AD-H, Hexane:i-PrOH = 98.5:1.5,
flow rate: 1.0 mL/min, k = 254 nm), Tmajor = 31.5, Tminor = 48.3, 90%
ee.
4.4.11. (2R,3R)-2-Ethyl-3-(furan-2-yl)-4-nitrobutanal 7k11
Pale yellow oil, 87% yield. [a]
20 = +17.2 (c 1.0, CHCl3), 1H NMR
D
(400 MHz, CDCl3): d 9.71 (s, 1H), 9.61 (s), 7.37 (s, 1H), 6.31 s,
1H), 6.20 (s, 1H), 4.75–4.65 (m, 3H), 4.05–3.99 (m, 1H), 2.79–2.74
(m, 1H), 1.58–1.52 (m, 2H), 0.99 (t, J = 14.8 Hz, 1H), 0.90 (d,
J = 14.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 202.9, 202.4,
150.1, 142.7, 110.5, 110.4, 109.0, 108.8, 76.2, 76.0, 53.6, 53.4,
37.7, 37.0, 20.5, 20.0, 11.6, 10.9; HPLC (Chiralcel AS-H, Hexane:i-
PrOH = 96:4, flow rate: 0.5 mL/min, k = 254 nm), Tmajor = 39.4,
Tminor = 35.3, 93% ee.
4.4.6. (2R,3S)-3-(4-Chlorophenyl)-2-ethyl-4-nitrobutanal 7f11
Pale yellow oil, 90% yield. [a]
20 = +9.5 (c 1.0, CHCl3),1H NMR
D
(400 MHz, CDCl3): d 9.71 (s, 1H), 9.49 (s, 1H), 7.34–7.30 (m,4H),
7.13 (d, J = 7.6, 4H), 4.82–4.71 (m, 3H), 4.62–4.57 (m, 1H), 3.84–
3.76 (m, 2H), 2.69–2.65 (m, 1H), 2.60–2.58 (m, 1H), 1.78–1.46
(m, 4H), 1.01 (t, J = 14.8 Hz, 4H), 0.86 (d, J = 14.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 202.8, 202.7, 129.6, 129.4, 129.3, 78.3,
77.6, 54.8, 54.7, 43.3, 42.0, 20.5, 20.3, 11.4, 10.5; HPLC (Chiralcel
4.4.12. (2R,3S)-2-Isopropyl-4-nitro-3-(p-tolyl)butanal 7l
Pale yellow oil, 91% yield. [a]
20 = +66.1 (c 1.0, CHCl3), 1H NMR
D
(500 MHz, CDCl3): d 9.93 (d, J = 2.1 Hz, 1H), 7.16 (d, J = 7.8 Hz,
2H), 7.08 (d, J = 7.9 Hz, 2H), 4.68–4.65 (m, 1H), 4.58–4.54 (m,
1H), 3.90–3.85 (m, 1H), 2.77–2.74 (m, 1H), 2.34 (s, 3H), 1.76–
1.73 (m, 1H), 1.00 (d, J = 7.3 Hz, 3H), 0.89 (d, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3): d 204.9, 138.2, 134.4, 130.2, 128.2, 79.5,
AD-H,
Hexane:i-PrOH = 98.5:1.5,
flow
rate:
1.0 mL/min,
k = 254 nm), Tmajor = 28.7, Tminor = 42.8, 92% ee.

1604
Y. Wang et al. / Tetrahedron: Asymmetry 25 (2014) 1599–1604
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59.2, 42.0, 28.3, 22.1, 21.5, 17.4; HPLC (Chiralcel AD-H, Hexane:i-
PrOH = 97:3, flow rate: 1.0 mL/min, k = 254 nm), Tmajor = 11.6,
Tminor = 10.8, 98% ee.
4.4.13. (2R,3S)-3-(4-Bromophenyl)-2-isopropyl-4-nitrobutanal 7m
Pale yellow oil, 92% yield. [a]
20 = +92.5 (c 1.0, CHCl3), 1H NMR
D
(500 MHz, CDCl3): d 9.92 (d, J = 2.0 Hz,1H), 7.48 (d, J = 8.3 Hz, 2H),
7.09 (d, J = 8.3 Hz, 2H), 4.70–4.67 (m, 1H), 4.57–4.52 (m, 1H),
3.90–3.86 (m, 1H), 2.78–2.74 (m, 1H), 1.72–1.69 (m, 1H), 1.12 (d,
J = 7.2 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 204.3, 136.6, 132.8, 130.1, 122.5, 79.1, 58.9, 41.8, 28.4, 22.0, 17.4;
HPLC (Chiralcel AD-H, Hexane:i-PrOH = 97:3, flow rate: 1.0 mL/
min, k = 254 nm), Tmajor = 32.9, Tminor = 27.5, 99% ee.
4.4.14. (2R,3S)-3-(4-Fluorophenyl)-2-isopropyl-4-nitrobutanal 7n
Pale yellow oil, 90% yield. [a]
20 = +78.3 (c 1.0, CHCl3), 1H NMR
D
(500 MHz, CDCl3): d 9.91 (s, 1H), 7.17 (t, J = 13.5 Hz, 2H), 7.04 (t,
J = 16.9 Hz, 2H), 4.69–4.66 (m, 1H), 4.56–4.52 (m, 1H), 3.91–3.89
(m, 1H), 2.71–2.70 (m, 1H), 1.19–1.09 (m, 3H), 0.94–0.86 (m,
3H); 13C NMR (125 MHz, CDCl3): d 204.5, 204.4, 163.7, 161.7,
130.4, 130.0, 129.9, 116.7, 116.5, 79.4, 59.1, 58.9, 41.8, 41.6, 28.3,
22.1, 22.0, 17.3; HPLC (Chiralcel AD-H, Hexane:i-PrOH = 97:3, flow
rate: 1.0 mL/min, k = 254 nm), Tmajor = 18.2, Tminor = 15.9, 96% ee.
4.4.15. (2R,3S)-3-(2-Chlorophenyl)-2-isopropyl-4-nitrobutanal 7o
Pale yellow oil, 88% yield. [a]
20 = +107.1 (c 1.0, CHCl3), 1H NMR
D
(500 MHz, CDCl3): d 9.93 (s,1H), 7.43 (d, J = 7.0 Hz,1H), 7.27–7.20
(m, 3H), 4.87–4.83 (m, 1H), 4.69–4.66 (m, 1H), 4.45 (s, 1H), 3.12
(s, 1H), 1.79–1.74 (m, 1H), 1.18 (d, J = 7.1 Hz, 3H), 0.90 (d,
J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 204.6, 135.0, 131.1,
129.7, 127.9, 18.1, 58.0, 30.1, 28.8, 22.1, 18.2; HPLC (Chiralcel
AD-H, Hexane:i-PrOH = 99:1, flow rate: 0.7 mL/min, k = 254 nm),
Tmajor = 19.0, Tminor = 19.9, 97% ee.
4.4.16. (2R,3R)-2-Isopropyl-4-nitro-3-(thiophen-2-yl)butanal 7p
Pale yellow oil, 89% yield. [a]
20 = +29.3 (c 1.0, CHCl3), 1H NMR
D
(500 MHz, CDCl3): d 9.90 (d, J = 2.5 Hz,1H), 7.51–7.48 (m,1H),
7.28 (s, 2H), 6.95–6.94 (m, 1H), 4.67–4.54 (m, 2H), 4.10–4.06 (m,
1H), 2.79–2.76 (m, 1H), 1.82–1.76 (m, 1H), 1.14–1.10 (m, 3H),
0.98–0.89 (m, 3H); 13C NMR (125 MHz, CDCl3): d 204.7, 138.0,
127.5, 126.7, 123.7, 79.1, 63.7, 59.3, 45.2, 37.9, 28.4, 27.0, 22.0,
17.7; HPLC (Chiralcel AD-H, Hexane:i-PrOH = 96:4, flow rate:
1.0 mL/min, k = 254 nm), Tmajor = 22.0, Tminor = 28.5, 99% ee.
Acknowledgments
10. Xu, J.-W.; Fu, X.-K.; Wu, C.-L.; Hu, X.-Y. Tetrahedron: Asymmetry 2011, 22, 840.
11. Wang, Y.-C.; Ji, S.; Wei, K.; Lin, J. RSC Adv. 2014, 4, 30850.
12. (a) Duschmalé, J.; Wiest, J.; Wiesner, M.; Wennermers, H. Chem. Sci. 2013, 4,
1312. For some selected references including similar N-protected chiral
catalysts in this area, see; (b) Bächle, F.; Duschmalé, J.; Ebner, C.; Pfaltz, A.;
Wennemers, H. Angew. Chem., Int. Ed. 2013, 52, 12619; (c) Arakawa, Y.;
Wiesner, M.; Wennemers, H. Adv. Synth. Catal. 2011, 353, 1201; (d) Luo, R.-S.;
Weng, J.; Ai, H.-B.; Lu, G.; Chan, A. S. C. Adv. Synth. Catal. 2009, 351, 2449.
This work was supported by Program for Changjiang Scholars
and Innovative Research Team in University (IRT13095), Training
Plan for Young Teachers of Yunnan University and National Natural
Science Foundation of China (No. U1202221) and Scholarship
Award for Excellent Doctoral Student of Yunnan Province.
´
13. (a) Tsybizova, A.; Remeš, M.; Vesely, J.; Hybelbauerová, S.; Roithová, J. J. Org.
Chem. 2014, 79, 1563. For some selected references for empirical discoveries in
this area, see; (b) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014,
114, 2390; (c) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang,
Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2013, 125, 5262; (d) Mukherjee, S.; Yang, J. W.;
Huffman, S.; List, B. Chem. Rev. 2007, 107, 5471; (e) Pedatella, S.; Nisco, M. D.;
Mastroianni, D.; Naviglio, D.; Nucci, A.; Caputo, R. Adv. Synth. Catal. 2011, 353,
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