Novel bifunctional L-prolinamide derivatives as highly efficient organocatalysts for asymmetric nitro-Michael reactions

Article abstract of DOI:10.1016/j.tetasy.2016.08.019

A series of novel bifunctional L-prolinamide derivatives was synthesised, of which (S)-N-((S)-2-oxo-1-phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 was found to be the most effective catalyst in terms of both the yield and stereoselectivity for the nitro-Michael reaction of aldehydes to nitroalkenes. Under these optimized reaction conditions, 17 corresponding novel nitro-Michael addition adducts had high yields (up to 94%) and showed excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (up to 98 ee) under mild reaction conditions.

Full text of DOI:10.1016/j.tetasy.2016.08.019

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel bifunctional L-prolinamide derivatives as highly efficient
organocatalysts for asymmetric nitro-Michael reactions
a,
Dan Xu a,c,y, Junliang Wang b,y, Lijun Yan a, Mingquan Yuan b, Xiaotian Xie a,c, , Yongchao Wang
⇑
⇑
a School of Vocational and Technical Education, Yunnan Normal University, Kunming 650092, PR China
b School of Chemical Science and Technology (Yunnan University), Advanced Analysis and Measurement Center, Yunnan University, Kunming 650091, PR China
c School of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650092, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel bifunctional L-prolinamide derivatives was synthesised, of which (S)-N-((S)-2-oxo-1-
Received 1 July 2016
Accepted 29 August 2016
Available online xxxx
phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 was found to be the most effective catalyst
in terms of both the yield and stereoselectivity for the nitro-Michael reaction of aldehydes to nitroalk-
enes. Under these optimized reaction conditions, 17 corresponding novel nitro-Michael addition adducts
had high yields (up to 94%) and showed excellent diastereoselectivity (up to 99:1 dr) and enantioselec-
tivity (up to 98 ee) under mild reaction conditions.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
namides, have been developed as highly efficient catalysts in
asymmetric Aldol reactions10 and applied in the synthesis of
As a powerful, atom-economic and environmentally friendly
carbon–carbon bond-forming methodology, asymmetric nitro-
Michael reactions have promoted the progress of organic synthesis
and green chemistry.1 Specifically, asymmetric nitro-Michael
c
-nitroketones.11 To the best of our knowledge, proline-based
short peptides have rarely been used as organocatalysts to synthe-
sise -nitroaldehydes. Herein, based on the environmentally
c
friendly asymmetric organic synthesis principle, we have designed
several types of organocatalysts and applied them to asymmetric
Michael additions.12 We describe a highly efficient and stereoselec-
tive method for nitro-Michael addition reactions of aldehydes to
nitroalkenes catalyzed by bifunctional proline-based dipeptides
410b and 5–9 (Fig. 2). Our findings provide an effective method to
reactions have been used to synthesise
c-nitroaldehydes, which
are important starting materials and key intermediates in the
enantioselective syntheses of many pharmaceutical molecules
and natural products2 such as, (R)-Baclofen 1,3 (R)-Roliprom 24
and (+)-Femoxetine 3 (Fig. 1).5 Recently, the development of highly
efficient and stereoselective chiral catalysts for the asymmetric
nitro-Michael additions under mild conditions has attracted
widespread attention.1b,6
synthesise valuable c-nitroaldehydes.
2. Results and discussion
Studies on the reactivity, selectivity, and the mechanism of
asymmetric organic synthesis have led to the discovery of many
valuable catalysts for nitro-Michael addition reactions.7 In particu-
lar, organocatalytic enamine-active nitro-Michael additions have
been the subject of extensive development.8 For example, the most
widely used modern organocatalysis based on enamine activation,
chiral pyrrolidine derivatives, such as diarylprolinol silyl ethers
and prolinamides, have been designed and applied in asymmetric
Michael additions.9 In addition, proline-based dipeptides and
Four novel bifunctional L-proline-based dipeptides 5–8 were
designed and prepared in four easy steps from commercially
available materials (Scheme 1). These include, Step 1: homochiral
N-Boc-a-amino acids 10 were treated with tritylamine 11a or ben-
zhydrylamine 11b in the presence of dicyclohexylcarbodiimide
(DCC) in dichloromethane to obtain the corresponding intermedi-
ate amides 12a–12d; Step 2: chiral primary amines 13a–13d were
synthesized by deprotecting the Boc group of 12a–12d in the pres-
ence of TFA; Step 3: the acquired chiral primary amines were fur-
tripeptides, some of the most important of which are L-proli-
ther treated with N-Boc-L-proline 14a to prepare the intermediates
15a–15d in the presence of 3-(3-dimethylaminopropyl)-1-ethyl-
carbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine
(DMAP); Step 4: the N-Boc group of 15a–15d was deprotected to
synthesize the target compounds 5–8.
⇑
Corresponding authors.
E-mail addresses: 2445216004@qq.com (X. Xie), yongchaowang126@126.com
(Y. Wang).
y
These authors contributed equally to the work.
http://dx.doi.org/10.1016/j.tetasy.2016.08.019
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
OMe
NH
OH
O
O
NH3
Cl
O
MeO
N
Cl
Me
(R)-Baclofen.HCl 1
(R)-Roliprom 2
(+)-Femoxetine 33
Figure 1. Representative bioactive molecules from
c
-nitroaldehyde intermediates.
O
O
O
O
O
HN
HN
NH
NH
N
H
NH
NH
NH
4
5
6
O
O
O
O
O
O
NH
HN
HN
NH
HN
NH
NH
NH
NH
8
9
7
Figure 2. Bifunctional L-prolinamide derivatives 4–9.
NH2
R2
R2 = Ph 11a
R2 = H 11b
O
R1
HN
O
O
R2
TFA, CH2Cl2
0 oC to r. t.
OH
Boc
10
R2
R1
HN
R1
N
H
N
H
DCC, CH2Cl2
NH2
0 o
C
Boc
12a-12d
13a-13d
O
R1
R1
NH
O
O
N
OH
O
O
Boc
14a
R2
HN
R2
HN
NH
TFA, CH2Cl2
0 oC to r. t.
EDCI, DMAP
CH2Cl2, r. t.
N
NH
Boc
15a-15d
5-8
R1 = i-butyl, R2 = Ph 12a, 13a, 15a, 5
R1 = Ph, R2 = Ph 12b, 13b, 15b, 6
R1 = Bn, R2 = Ph 12c, 13c, 15c, 7
R1 = Ph, R2 = H 12d, 13d, 15d, 8
Scheme 1. The synthetic route of L-prolinamide derivatives 5–8.
Furthermore, a
D
-prolinamide derivative 9, as the epimer of 6,
activity (91% yield) and moderate enantioselectivity (84% ee,
Table 1, entry 2). -prolinamide 5 was able to catalyze the nitro-
Michael addition. Although the yield (89%) was high, the enantios-
electivity (63% ee) was low (Table 1, entry 3). When the bifunc-
tional L-prolinamide derivative 6 was used, relatively high yield
(92%), diastereoselectivity (95:5 dr) and enantioselectivity (90%
ee) were observed (Table 1, entry 4). To further understand the chi-
ral mechanism of organocatalysts in nitro-Michael addition, the
stereoisomer 9 (of 6) was analysed and an enantiomer was
obtained with relatively high yield (89%), diastereoselectivity
(94:6 dr) and enantioselectivity (88% ee) in the model reaction
was also prepared by using a similar synthetic method (Scheme 2).
The directed nitro-Michael addition of isovaleraldehyde 16a to
nitrostyrene 17a was selected as the model reaction to evaluate
the feasibility of our self-assembled organocatalysts 4–9 in the
presence of benzoic acid (10 mol %) in toluene at room tempera-
ture (Table 1). The results showed the model reaction failed when
it lacked a catalyst (Table 1, entry 1). The prolinamide organocata-
lysts 4–9 exhibited different catalytic activities and stereoselectiv-
ities for the model nitro-Michael addition. Among the
L
organocatalysts surveyed, L-prolinamide 4 showed high catalytic
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D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
O
N
OH
O
Boc
14b
O
O
O
TFA, CH2Cl2
0 oC to r. t.
O
H2N
HN
NH
HN
HN
NH
EDCI, DMAP
CH2Cl2, r. t.
N
NH
Boc
13b
15e
9
Scheme 2. The synthetic route of
D-prolinamide derivative 9.
Table 1
Screening of catalysts, catalyst loading and reaction temperaturea
O
catalyst
toluene
NO2
O
+
NO2
benzoic acid (10 mol%)
temperature
16a
17a
18a
Entry
Catalyst
Temperature
Time [h]
Yield [%]b
syn/antic
ee [%]d
1
2
3
4
None
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
36
24
24
<5
91
89
92
61
85
89
91
55
80
68
Nd
Nd
84
63
90
86
78
88
91
81
90
90
4 (10 mol %)
5 (10 mol %)
6 (10 mol %)
7 (10 mol %)
8 (10 mol %)
9 (10 mol %)
6 (5 mol %)
6 (1 mol %)
6 (5 mol %)
6 (5 mol %)
81:19
90:10
95:5
92:8
93:7
94:6
96:4
91:9
96:4
95:5
5
6
7e
8
9
10
11
0 °C
ꢀ20 °C
a
All reactions were carried out with 16a (1.5 mmol) and 17a (1.0 mmol) in the presence of catalyst and benzoic acid (10 mol %) in toluene (1.0 mL) at the corresponding
temperature (the numbers of catalyst were all marked in bold, the entry 8 represents the optimum reaction condition).
b
Yield of the isolated products.
c
Determined by 1H NMR analysis of the isolated products.
d
Determined by chiral HPLC, and the absolute configuration was established by comparing with the data from the literatures.10,13
e
The absolute configuration was (2S,3R), and established by comparison with the data from the literature.2b,14
(Table 1, entry 7). To explore the role of the catalysts,
L
-proli-
of catalyst 6 to the model nitro-Michael reaction was established
as 5 mol % at room temperature.
namides 7 and 8 were synthesized and screened (Table 1, entries
5 and 6) in model nitro-Michael additions, although the results
revealed moderate yield (61%, entry 5) and stereoselectivity (78%
To further optimize the reaction conditions, additional solvents
and additives were screened for the model reaction. Catalyst 6
(5 mol %) and benzoic acid (10 mol %) were analysed and the model
reaction was performed at the room temperature (Table 2). In
addition, a series of typical and practical solvents, including
toluene, MeOH, EtOH, CH2Cl2, CHCl3, THF, acetonitrile and 1,4-
dioxane were investigated in the model nitro-Michael reaction
(Table 2, entries 1–8). Our results indicated that toluene gave the
best results both in terms of the yield and stereoselectivity (Tables
2, entry 1). The other protic and aprotic solvents presented moder-
ate yields (59–87%) and enantioselectivities (70–85% ee) (Table 2,
entries 2–8). Therefore, toluene was established as the most effec-
tive solvent for the nitro-Michael reaction. As a proton donor, the
additives play an important role with regards to the yield and
stereoselectivity of the model reaction (Tables 2, entries 9–14).
Among all of the screened additives, benzoic acid exhibited the
best yield and stereoselectivity in the reaction (Tables 2, entry 1).
The effect of benzoic acid loading on the model reaction was fur-
ther investigated, and the results indicated that 10 mol % of ben-
zoic acid was the optimal reaction additive.
ee, entry 6). Based on these results, bifunctional L-prolinamide
(S)-N-((S)-2-oxo-1-phenyl-2-(tritylamino)ethyl)pyrrolidine-2-car-
boxamide 6 was confirmed to be the most effective catalyst in
terms of yield, diastereoselectivity and enantioselectivity for the
nitro-Michael reaction of aldehydes to nitroalkenes.
We examined the effects of catalyst loading on the model reac-
tion (Table 1, entries 8 and 9). When the loading of catalyst 6 was
reduced to 5 mol %, better enantioselectivity (91% vs 90% ee) was
achieved despite a slight reduction in the yield (92% vs 91%). How-
ever, when the catalyst loading was reduced to 1 mol %, relatively
poor yield (55%) and moderate enantioselectivity (81% ee) were
observed even when the reaction time was prolonged to 36 h
(Table 1, entry 9). When the effect of temperature on the nitro-
Michael additions was explored (Table 1, entries 8, 10 and 11),
the results indicated that the diastereoselectivity (both are 96:4
dr) and enantioselectivity (91% vs 90% ee) were very similar at both
room temperature and 0 °C (Table 1, entries 8 and 10). However,
when reducing the reaction temperature to ꢀ20 °C, the yield
decreased from 91% (found at room temperature) to 68%
(ꢀ20 °C) (Table 1, entries 8 and 11). In summary, the best loading
Based on the overall investigation and evaluation, the catalytic
system consisting of 5 mol % bifunctional chiral catalyst L-proli-
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D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 2
Screening of solvents and additives for the model reactiona
catalyst 66 (5 mol%)
Solvent
O
NO2
O
NO2
+
additive
r. t., 24h
16a
17a
18a
Entry
Solvent
Additive
Yield [%]b
syn/antic
ee [%]d
1
2
3
4
5
6
7
8
Toluene
MeOH
EtOH
CH2Cl2
CHCl3
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
Benzoic acid (10 mol %)
HCOOH (10 mol %)
CH3COOH (10 mol %)
CF3COOH (10 mol %)
p-TSA (10 mol %)
Benzoic acid (5 mol %)
Benzoic acid (1 mol %)
91
78
65
87
86
73
62
59
91
69
63
54
81
43
96:4
91
79
73
85
84
76
70
72
79
74
64
69
86
74
88:12
84:16
90:10
91:9
85:15
81:19
83:17
86:14
87:13
80:20
76:24
90:10
75:25
THF
1,4-Dioxane
Acetonitrile
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
12
13
14
a
All reactions were carried out with 16a (1.5 mmol) and 17a (1.0 mmol) in the presence of catalyst 6 (5 mol %) and the corresponding additive in solvents (1.0 mL) (entry 1
marked in bold represents the optimum reaction condition).
b
Yield of the isolated products.
c
Determined by 1H NMR analysis of the isolated products.
d
Determined by chiral HPLC.
Table 3
Asymmetric nitro-Michael reactions of aldehydes to aromatic nitroalkenes catalysed by 6a
O
R3
R1
catalyst 66 (5 mol%)
NO2
+
NO2
R3
O
Toluene
R2
benzoic acid (10 mol%)
r. t., 24h
R1
R2
17a-17g
16a-16b
18a-18k
Entry
Compounds 16
Compounds 17
NO2
Product 18
Yield [%]b
syn/antic
ee [%]d
O
O
16a
17a
NO2
1
91
96:4
91
H
18a
O
NO2
16a
O
17b
2
89
96:4
85
NO2
H
18b
CF3
O
NO2
F3C
16a
O
17c
3
86
96:4
97
NO2
H
18c
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D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Table 3 (continued)
Entry
Compounds 16
Compounds 17
Product 18
Yield [%]b
syn/antic
ee [%]d
O
NO2
Cl
Cl
16a
O
H
17d
4
5
6
88
97:3
94
NO2
18d
O
NO2
O
H
Cl
Cl
17e
16a
NO2
92
96:4
99
18e
Cl
O
NO2
Cl
Cl
16a
O
H
Cl
17f
82
99:1
94
NO2
18f
Br
O
NO2
Br
16a
O
H
17g
7
84
97:3
99
NO2
18g
O
NO2
O
H
16a
8
9
83
87
—
—
86
87
17a
NO2
18h
NO2
O
Me
16b
O
H
17b
NO2
NO2
NO2
18i
Cl
NO2
O
Cl
16b
O
H
17d
10
89
—
90
18j
Br
NO2
O
Br
16b
O
H
11
17g
82
—
86
18k
a
All reactions were carried out with 16 (1.5 mmol) and 17 (1.0 mmol) in the presence of catalyst 6 (5 mol %) and benzoic acid (10 mol %) in toluene (1.0 mL) at room
temperature.
b
c
Yield of the isolated products.
Determined by 1H NMR analysis of the isolated products.
Determined by chiral HPLC.
d
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D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
namide
(S)-N-((S)-2-oxo-1-phenyl-2-(tritylamino)ethyl)pyrro-
generality of this asymmetric catalytic system (Table 3, entries
1–7). As shown in Table 3, when isovaleraldehyde 16a was treated
with a series of nitrostyrenes 17a–17g bearing b-aryl substituents
with electron-withdrawing or electron-donating groups, high
yields (82–92%), excellent diastereoselectivities (96:4–99:1) and
enantioselectivities (85–99% ee) were achieved.
lidine-2-carboxamide 6 and 10 mol % benzoic acid in toluene at
room temperature was proposed to be the most efficient condition
for the asymmetric nitro-Michael addition model reaction of alde-
hydes to nitrostyrenes.
Under the optimal reaction conditions mentioned above, we
further explored the scope of the asymmetric nitro-Michael addi-
tion of aldehydes to nitrostyrenes. Initially, isovaleraldehyde 16a
was selected as a representative Michael donor to evaluate the
The enamine activation of
a,a-disubstituted aldehydes suffers
from several drawbacks, such as the steric hindrance and irre-
versible nature of
a,a-disubstituted intermediates. These draw-
Table 4
Asymmetric nitro-Michael reactions of aldehydes to aliphatic nitroalkenes catalysed by 6a
catalyst 66 (5 mol%)
toluene
NO2
R1
O
+
O
R2
benzoic acid (10 mol%)
r. t., 24h
NO2
16a-16g
19
R1
R2
20a-20f
Entry
Compounds 16
Product 20
Yield [%]b
syn/antic
ee [%]d
O
1
91
88:12
86
16c
O
H
NO2
20a
O
2
3
4
5
90
65:35
64:36
90:10
99:1
99
99
99
99
16d
O
H
NO2
20b
O
94
93
93
16e
O
H
NO2
NO2
NO2
O
20c
16a
O
H
20d
O
16f
O
H
20e
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D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
Table 4 (continued)
Entry
Compounds 16
Product 20
Yield [%]b
syn/antic
ee [%]d
O
H
O
6
NO2
94
60:40
97
16g
20f
a
All reactions were carried out with 16 (1.5 mmol) and 18 (1.0 mmol) in the presence of catalyst 6 (5 mol %) and benzoic acid (10 mol %) in toluene (1.0 mL) at room
temperature.
b
c
Yield of the isolated products.
Determined by 1H NMR analysis of the isolated products.
Determined by chiral HPLC.
d
backs would limit the success in developing stereoselective car-
bon–carbon bond-forming reactions of
-branched aldehydes.15
Catalyst 6 could be used for the organocatalytic nitro-Michael reac-
tions of -disubstituted aldehydes to nitrostyrenes with superior
yields (82–89%) and enantioselectivities (86–90% ee), to provide
group plays an important role with regards to the high stereoselec-
tivity. In addition, it is noteworthy that we found that the addition
of benzoic acid to promote the formation of the hydrogen bonds
between the NH groups of the peptide and the nitro group can have
a positive effect on the enantioselectivity and diastereoselectivity.
Some typical empirical research discoveries and theoretical com-
putation insights were used to support this possible transition-
state model.17
a
a,a
access to valuable
(Table 3, entries 8–11).
a,a-disubstituted blocks-c-nitroaldehyde
Based on the conditions described above, the catalytic nitro-
Michael reactions of aldehydes to aliphatic nitroalkenes catalysed
by catalyst 6 were also investigated to further explore the scope
of the asymmetric Michael addition reaction (see Table 4). The
results indicated that the steric hindrance of aliphatic chain alde-
hydes had a strong influence on the diastereoselectivity and enan-
tioselectivity. The nitro-Michael addition of propionaldehyde 16c
and aliphatic nitroalkenes 19 displayed moderate enantioselectiv-
ity (86% ee, Table 4, entry 1), while that of n-butanal 16d exhibited
excellent stereoselectivity (99% ee, Table 4, entry 2). In addition, a
series of aliphatic chain aldehydes, including n-pentanal, i-pen-
tanal, n-hexaldehyde and phenylpropionaldehyde were also
employed as Michael reaction donors, and the corresponding novel
nitro-Michael adducts were obtained in high yield (90–94%), with
excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity
(up to 99% ee). Based on these results, the steric hindrance of ali-
phatic chain aldehydes is suspected to be beneficial for increasing
the diastereoselectivity of nitro-Michael reactions.
3. Conclusions
In conclusion, we have synthesised a series of novel bifunctional
prolinamide derivatives 5–9 and developed a highly efficient cat-
alytic system using bifunctional L-prolinamide (S)-N-((S)-2-oxo-1-
phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 (5 mol
%) in the presence of benzoic acid (10 mol %) in toluene at room
temperature. This catalytic system exhibited universal application,
high catalytic efficiency (up to 94% yield), excellent diastereoselec-
tivity (up to 99:1 dr) and enantioselectivity (up to 99% ee). Its
application to additional catalysts and catalytic systems is cur-
rently under investigation.
4. Experimental
4.1. General
We propose a possible transition-state model (Scheme 3) that
accounts for the high stereoselectivity of organocatalytic nitro-
Michael reactions found herein. In our experiments, the addition
and function of chiral pyrrolidine is to activate the aldehyde
through the formation of an enamine intermediate. As a conse-
quence, the increase in energy to the HOMO frontier orbital of
the enamine intermediate can lead to the formation of an active
nucleophile.16 Based on our findings, this bulky aromatic amide
All commercially available reagents and materials were used
without further purification, and solvents were purified by stan-
dard procedures and distilled prior to column chromatography.
The reactions were monitored by thin layer chromatography
(TLC) using silica gel GF254, all compounds were visualized by UV
and spraying with H2SO4 (10%) in ethanol and followed by heating.
Column chromatography was performed on silica gel (200–300
mesh). Mass spectroscopic data were obtained from an Agilent
1100 LC/MSD Trap LC-mass spectrometer. The NMR spectra were
recorded on a Bruker DRX400 (1H: 400 MHz, 13C: 100 MHz) and
DRX500 (1H: 500 MHz, 13C: 125 MHz) with TMS as the internal
standard. Chemical shifts (d) are expressed in ppm and J values
are given in Hz. Deuterated CDCl3 was used as the solvent. HPLC
analysis was performed with a Shimadzu LC-10A equipped with
Daicel HPLC columns. IR spectra were recorded on a FT-IR Thermo
Nicolet Avatar 360 using KBr pellet. Optical rotations were
recorded on a Perkin-Elmer 341 polarimeter in a 10 mm cell and
the melting points were determined with an XT-4A melting-point
apparatus.
O
O
N
H
N
N
R1
H
O
N
O
R2
Scheme 3. Possible transition-state model for the nitro-Michael reactions.
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D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.2. Procedures for the synthesis of catalysts
solution of tert-butyl S-(4-methyl-1-oxo-1-(tritylamino)pentan-2-
yl)carbamate 12a (1.88 g, 4 mmol) in dry CH2Cl2 (10 mL) at 0 °C,
and then stirred for 30 min. The solution was concentrated under
vacuum to leave a glutinous phase. The pH of the mixture was
raised to 12 by the addition of 2 M NaOH. The aqueous phase
was extracted with ethyl acetate (3 ꢁ 50 mL). The ethyl acetate
extracts were pooled, washed with brine (30 mL), dried over anhy-
drous Na2SO4, filtered off and the solvent was evaporated at low
pressure to obtain a crude residue, which was further purified by
column chromatography to obtain pure (S)-2-amino-4-methyl-N-
tritylpentanamide 13a. 96% yield; White solid; mp 89–90 °C;
4.2.1. Procedures for the synthesis of intermediates 12a–12d
4.2.1.1. Procedures for the synthesis of tert-butyl (S)-(4-methyl-
1-oxo-1-(tritylamino)pentan-2-yl)carbamate 12a.
At first,
EDCI (1.22 g, 5.5 mmol) was added into a stirring solution of
(tert-butoxycarbonyl)leucine 10 (1.16 g, 5.0 mmol) and DMAP
(210 mg, 1.5 mmol) in dry dichloromethane (15 mL). The mixture
was stirred for 15 min and then cooled to 0 °C. Triphenyl-
methanamine 11a (1.04 g, 4 mmol) was added to the mixture
and stirred at the same temperature for 30 min. The resulting solu-
tion was stirred at room temperature until complete consumption
of triphenylmethanamine (monitored by TLC). The reaction was
quenched with water (50 mL) and extracted with dichloromethane
(3 ꢁ 50 mL). The combined organic layers were washed with satu-
rated brine solution (30 mL), followed by drying over Na2SO4 and
evaporation in vacuo. The crude product was purified by column
chromatography to give pure tert-butyl (S)-(4-methyl-1-oxo-1-
(tritylamino)pentan-2-yl)carbamate 12a. 94% yield; White solid,
[a]
20 = ꢀ29.9 (c 1.0, CHCl3); IR (KBr) 634, 703, 748, 867, 1034,
D
1387, 1448, 1515, 1680, 2875, 2960, 3287 cmꢀ1; HRMS (EI) calcd
C25H28N2O, [M+Na]+ 395.2093, found for 305.2093; 1H NMR
(400 MHz, CDCl3): d 8.88 (s, 1H), 7.30–7.20 (m, 15H), 3.38–3.35
(m, 1H), 1.73–1.68 (m, 2H), 1.47 (s, 2H), 1.35 (t, J = 18.4 Hz, 1H),
0.94 (d, J = 5.6 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 174.3, 145.1, 128.7, 128.5, 128.0, 127.7,
127.1, 127.0, 69.6, 54.2, 49.0, 44.0, 29.7, 25.7, 25.0, 23.5, 21.4.
mp 68–69 °C; [
a
]
20 = ꢀ38.3 (c 1.0, CHCl3); IR (KBr) 628, 699,
D
1168, 1367, 1449, 1492, 1690, 2958, 3303 cmꢀ1; HRMS (EI) calcd
for C30H36N2O3 [M+Na]+ 495.2618, found 495.2616; 1H NMR
(400 MHz, CDCl3): d 7.48 (s, 1H), 7.29–7.19 (m, 15H), 4.88 (t,
J = 8.0 Hz, 1H), 4.22 (s, 1H), 1.63 (d, J = 2.0 Hz, 2H), 1.42 (s, 9H),
0.92–0.88 (m, 6H); 13C NMR (100 MHz, CDCl3): d 171.0, 156.1,
144.6, 128.6, 127.9, 127.0, 80.3, 70.3, 53.9, 40.0, 28.3, 24.7, 22.9,
22.0.
4.2.2.2. Procedures for the synthesis of (S)-2-Amino-2-phenyl-
N-tritylacetamide 13b. The synthetic method of 13b was similar
to that of 13a. 96% yield; White solid, mp 162–165 °C; [
a]
20 = ꢀ0.9
D
(c 1.0, CHCl3); IR (KBr) 638, 696, 754, 964, 1190, 1444, 1490, 1672,
3273 cmꢀ1; HRMS (EI) calcd C27H24N2O, [M+H]+ 393.1961, found
for 393.1962; 1H NMR (400 MHz, CDCl3): d 8.50 (s, 1H), 7.46 (d,
J = 1.6 Hz, 2H), 7.44–7.34 (m, 3H), 7.30–7.23 (m, 9H), 7.19–7.15
(m, 6H), 4.55 (s, 1H), 1.91 (s, 2H); 13C NMR (100 MHz, CDCl3): d
171.6, 144.8, 140.8, 128.8, 128.6, 128.0, 128.0, 127.0, 126.8, 69.8,
60.6.
4.2.1.2. Procedures for the synthesis of tert-Butyl (S)-(2-oxo-1-
phenyl-2-(tritylamino)ethyl)carbamate 12b. The synthetic
method of 12b was similar to that of 12a. 93% yield; White solid,
mp 84–87 °C; [
a
]
20 = ꢀ32.6 (c 1.0, CHCl3); IR (KBr) 697, 1165,
4.2.2.3. Procedures for the synthesis of (S)-2-Amino-3-phenyl-
N-tritylpropanamide 13c. The synthetic method of 13c was
similar to that of 13a. 90% yield; White solid, mp 64–66 °C;
D
1246, 1366, 1490, 1683, 1717, 2978, 3307 cmꢀ1; HRMS (EI) calcd
for C32H32N2O3 [M+Na]+ 515.2305, found 515.2307; 1H NMR
(400 MHz, CDCl3): d 7.39–7.30 (m, 5H), 7.28–7.23 (m, 9H), 7.10
(t, J = 7.6 Hz, 6H), 6.87 (s, 1H), 5.88 (s, 1H), 5.26 (s, 1H), 1.42 (s,
9H); 13C NMR (100 MHz, CDCl3): d 176.2, 168.8, 155.4, 144.1,
138.0, 129.1, 128.5, 128.0, 127.3, 127.1, 80.1, 70.6, 59.4, 28.3, 20.7.
[a]
20 = +77.5 (c 0.5, CHCl3); IR (KBr) 698, 748, 1033, 1447, 1490,
D
1627, 1676, 2850, 2928 cmꢀ1; HRMS (EI) calcd C28H26N2O, [M
+Na]+ 3429.1937, found for 429.1936; 1H NMR (400 MHz, CDCl3):
d 8.95 (s, 1H), 7.38–7.31 (m, 12H), 7.29–7.24 (m, 8H), 3.67–3.64
(m, 1H), 3.30–3.25 (m, 1H), 2.09 (s, 1H), 1.31 (t, J = 14.4 Hz, 2H),;
13C NMR (100 MHz, CDCl3): d 172.9, 145.0, 138.0, 129.5, 128.7,
128.0, 127.0, 126.8, 69.8, 57.1, 40.6.
4.2.1.3. Procedures for the synthesis of tert-Butyl (S)-(1-oxo-3-
phenyl-1-(tritylamino)propan-2-yl)carbamate 12c. The synthetic
method of 12c was similar to that of 12a. 88% yield; Amorphous
solid; [a D
1244, 1311, 1576, 1627, 2850, 2916, 3328 cmꢀ1; HRMS (EI) calcd
33H34N2O3, [M+H]+ 507.2642, found for 507.2645; 1H NMR
]
20 = +13.0 (c 1.0, CHCl3); IR (KBr) 695, 892, 1087, 1167,
4.2.2.4. Procedures for the synthesis of (S)-2-Amino-N-ben-
zhydryl-2-phenylacetamide 13d. The synthetic method of 13d
was similar to that of 13a. 89% yield; White solid, mp 124–
C
(400 MHz, CDCl3): d 7.32–7.24 (m, 12H), 7.20 (d, J = 7.2 Hz, 2H),
7.14–7.08 (m, 6H), 5.04 (s, 1H), 4.45 (d, J = 6.4 Hz, 1H), 3.45 (s, 1H),
3.16–2.99 (m, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3): d
169.5, 156.8, 144.3, 136.8, 129.5, 128.8, 128.6, 127.9, 127.0, 70.3,
49.2, 37.5, 34.0, 28.2, 25.6, 25.0.
127 °C; [
a
]
20 = ꢀ49.0 (c 1.0, CHCl3); IR (KBr) 639, 700, 754, 1028,
D
1453, 1511, 1583, 1666, 3023, 3370 cmꢀ1
; HRMS (EI) calcd
C
21H20N2O, [M+H]+ 317.1648, found for 317.1646; 1H NMR
(400 MHz, CDCl3): d 7.82 (d, J = 8.0 Hz, 1H), 7.38–7.33 (m, 3H),
7.30–7.27 (m, 9H), 7.26–7.14 (m, 3H), 6.22 (d, J = 8.8 Hz, 1H),
4.55 (s, 1H), 1.82 (s, 2H); 13C NMR (100 MHz, CDCl3): d 172.0,
141.6, 141.6, 141.0, 128.9, 128.6, 128.6, 128.0, 127.4, 127.3,
127.3, 127.0, 59.9, 56.5.
4.2.1.4. Procedures for the synthesis of tert-Butyl (S)-(2-(ben-
zhydrylamino)-2-oxo-1-phenylethyl)carbamate 12d. The syn-
thetic method of 12d was similar to that of 12a. 89% yield;
White solid, mp 136–138 °C; [
a
]
20 = ꢀ0.7 (c 1.0, CHCl3); IR (KBr)
4.2.3. Procedures for the synthesis of intermediates 15a–15e
4.2.3.1. Procedures for the synthesis of tert-butyl (S)-2-(((S)-4-
methyl-1-oxo-1-(tritylamino)pentan-2-yl)carbamoyl)pyrro-
lidine-1-carboxylate 15a. At first, EDCI (887 mg, 4 mmol) was
D
704, 1152, 1370, 1496, 1527, 1647, 2978, 3275, 3347 cmꢀ1; HRMS
(EI) calcd for C26H28N2O3 [M+Na]+ 439.1992, found 439.1995; 1H
NMR (400 MHz, CDCl3): d 7.34–7.24 (m, 9H), 7.23–7.15 (m, 5H),
6.93–6.89 (m, 1H), 6.49 (d, J = 7.6 Hz, 1H), 6.18 (d, J = 8.0 Hz, 1H),
5.80 (s, 1H), 5.22 (s, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 169.3, 155.2, 141.0, 141.0, 138.3, 129.0, 128.7, 128.5, 128.4,
127.7, 127.6, 127.4, 127.3, 127.0, 80.1, 58.8, 57.1, 28.3.
added to a stirred solution of N-t-butyloxycarbonyl-L-proline 14a
(753 mg, 3.5 mmol) and DMAP (140 mg, 1 mmol) in dry dichloro-
methane (10 mL). The mixture was stirred for 15 min and then
cooled to 0 °C, after which (S)-2-amino-4-methyl-N-tritylpen-
tanamide 13a (780 mg, 3 mmol) was added and stirred at the same
temperature for 30 min. The resulting solution was finally stirred
at room temperature until complete consumption of 13a (moni-
tored by TLC). The reaction was quenched with water (50 mL)
4.2.2. Procedures for the synthesis of intermediates 13a–13d
4.2.2.1. Procedures for the synthesis of (S)-2-amino-4-methyl-
N-tritylpentanamide 13a. At first, TFA (3 mL) was added to a
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.019

D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9
and extracted with dichloromethane (3 ꢁ 50 mL). The combined
organic layers were washed with saturated brine solution
(30 mL), followed by drying over Na2SO4 and evaporation in vacuo.
The crude product was purified by column chromatography to
obtain pure tert-butyl (S)-2-(((S)-4-methyl-1-oxo-1-(tritylamino)
pentan-2-yl)carbamoyl)pyrrolidine-1-carboxylate 15a. 90% yield;
127.9, 127.3, 127.0, 80.6, 70.7, 60.8, 60.2, 59.0, 57.4, 46.9, 31.1,
28.3, 23.7, 20.8.
4.2.4. Procedures for the synthesis of bifunctional
derivatives 5–9
L-prolinamide
4.2.4.1. Procedures for the synthesis of (S)-N-((S)-4-methyl-1-
oxo-1-(tritylamino)pentan-2-yl)pyrrolidine-2-carboxamide 5.
At first, TFA (3 mL) was added to a solution of tert-butyl (S)-2-(((S)-
4-methyl-1-oxo-1-(tritylamino)pentan-2-yl)carbamoyl)pyrro-
lidine-1-carboxylate 15a (1.41 g, 3 mmol) in dry CH2Cl2 (10 mL) at
0 °C and stirred for 30 min. The solution was then concentrated
under vacuum to leave a glutinous phase. The pH of the mixture
was raised to 12 by the addition of 2 M NaOH. The aqueous phase
was extracted with ethyl acetate (3 ꢁ 50 mL). The ethyl acetate
extracts were pooled, washed with brine (30 mL), dried over
anhydrous Na2SO4, and filtered off. The resulting solvent was evap-
orated at low pressure to obtain a crude residue, which was further
purified by column chromatography to obtain pure (S)-N-((S)-
4-methyl-1-oxo-1-(tritylamino)pentan-2-yl)pyrrolidine-2-carbox-
White solid, mp 73–74 °C; [
a
]
20 = ꢀ56.8 (c 1.0, CHCl3); IR (KBr)
D
701, 769, 1125, 1164, 1367, 1389, 1449, 1525, 1700, 3307 cmꢀ1
;
HRMS (EI) calcd for
C
35H43N3O4 [M+Na]+ 592.3145, found
592.3141; 1H NMR (400 MHz, CDCl3): d 7.70 (s, 1H), 7.28–7.18
(m, 15H), 4.66–4.64 (m, 1H), 4.38–4.26 (m, 1H), 4.13–4.10 (m,
1H), 3.44–4.42 (m, 2H), 2.04 (s, 9H), 1.93–1.85 (m, 4H), 1.27–
1.23 (m, 3H), 0.88 (d, J = 15.6 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 176.3, 144.4, 128.6, 127.8, 126.9, 80.6, 60.4, 59.0, 52.7, 46.9, 29.7,
28.3, 24.7, 23.6, 22.9, 21.8, 21.0, 20.7, 14.2.
4.2.3.2. Procedures for the synthesis of tert-Butyl (S)-2-(((S)-2-
oxo-1-phenyl-2-(tritylamino)ethyl)carbamoyl)pyrrolidine-1-
carboxylate 15b. The synthetic method of 15b was similar to
that of 15a. 92% yield; Amorphous solid; [
a]
20 = ꢀ57.5 (c 1.0,
amide 5. 90% yield; Amorphous powder; [
a]
20 = ꢀ21.9 (c 0.5,
D
D
CHCl3); IR (KBr) 1135, 1167, 1375, 1396, 1515, 1677, 1778, 2312,
3275 cmꢀ1; HRMS (EI) calcd for C37H39N3O4 [M+Na]+ 612.2832,
found 612.2830; 1H NMR (400 MHz, CDCl3): d 9.89 (s, 2H), 7.25–
7.22 (m, 15H), 7.08 (s, 5H), 5.76–5.64 (m, 1H), 4.33–4.16 (m, 2H),
3.55–3.44 (m, 5H), 2.06 (m, 9H); 13C NMR (100 MHz, CDCl3): d
178.6, 176.7, 176.1, 168.5, 154.0, 144.0, 137.1, 129.0, 128.5,
127.9, 127.0, 81.0, 80.5, 80.3, 70.7, 59.0, 46.9, 46.3, 30.8, 29.0,
28.4, 28.3, 24.3, 23.7, 20.8.
CHCl3); IR (KBr) 626, 699, 757, 1449, 1513, 1653, 1700, 2869,
3295 cmꢀ1; HRMS (EI) calcd C30H35N3O2, [M+H]+ 470.2802, found
for 470.2803; 1H NMR (400 MHz, CDCl3): d 8.03–7.98 (m, 2H),
7.29–7.19 (m, 15H), 4.56–4.51 (m, 1H), 4.35–4.25 (m, 2H),
3.78–3.72 (m, 1H), 3.03–2.98 (m, 1H), 2.92–2.88 (m, 1H),
2.15–2.08 (m, 1H), 2.03–1.98 (m, 1H), 1.86–1.82 (m, 1H),
1.72–1.52 (m, 4H), 0.98–0.87 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 175.4, 170.5, 144.5, 128.4, 128.4, 127.6, 127.6, 126.6, 126.6, 69.8,
60.0, 51.7, 47.0, 40.3, 40.1, 40.0, 39.7, 39.4, 30.7, 25.9. 24.6, 22.9,
21.7.
4.2.3.3. Procedures for the synthesis of tert-Butyl (S)-2-(((S)-1-
oxo-3-phenyl-1-(tritylamino)propan-2-yl)carbamoyl)pyrro-
lidine-1-carboxylate 15c. The synthetic method of 15c was sim-
4.2.4.2. Procedures for the synthesis of (S)-N-((S)-2-Oxo-1-
phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6.
The synthetic method of 6 was similar to that of 5. 95% yield;
20
ilar to that of 15a. 88% yield; White solid, mp 76–77 °C; [
a]
=
D
+10.7 (c 0.5, CHCl3); IR (KBr) 699, 748, 1163, 1248, 1395, 1449,
1492, 1700, 2976 cmꢀ1; HRMS (EI) calcd for C38H41N3O4 [M+Na]+
626.2989, found 626.2987; 1H NMR (400 MHz, CDCl3): 9.88 (s,
2H), 7.29–7.21 (m, 15H), 7.08 (s, 5H), 5.36–5.34 (m, 1H), 4.38–
4.14 (m, 2H), 3.54–3.45 (m, 5H), 2.70–2.67 (m, 2H), 2.06 (m, 9H);
13C NMR (100 MHz, CDCl3): d 176.6, 169.5, 144.2, 136.6, 129.5,
128.6, 127.8, 126.9, 80.7, 76.7, 70.5, 60.4, 59.0, 55.2, 47.1, 33.6,
28.3, 25.5, 24.8, 23.7, 21.0, 20.7, 14.2.
White solid, mp 235–237 °C; [
a
]
D
20 = ꢀ39.6 (c 1.0, CHCl3); IR (KBr)
697, 1037, 1447, 1510, 1648, 1695, 3298, 3338 cmꢀ1; HRMS (EI)
calcd C32H31N3O2, [M+H]+ 490.2489, found for 490.2489; 1H NMR
(400 MHz, CDCl3): d 8.49 (d, J = 7.6 Hz, 1H), 7.35–7.26 (m, 5H),
7.24–7.18 (m, 10H), 7.10–7.03 (m, 5H), 5.63 (d, J = 7.6 Hz, 1H),
3.66–3.62 (m, 1H), 2.93–2.79 (m, 2H), 2.43 (s, 1H), 2.05–1.96 (m,
1H), 1.83–1.75 (m, 1H), 1.68–1.54 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 175.2, 168.7, 144.2, 137.6, 128.9, 128.6, 128.3, 128.2,
127.9, 127.8, 127.6, 127.3, 127.0, 126.9, 70.5, 60.4, 57.5, 47.2,
30.8, 26.1.
4.2.3.4. Procedures for the synthesis of tert-Butyl (S)-2-(((S)-
2-(benzhydrylamino)-2-oxo-1-phenylethyl)carbamoyl)pyrro-
lidine-1-carboxylate 15d. The synthetic method of 15d was
similar to that of 15a. 90% yield; Amorphous solid; [
a
]
20 = ꢀ61.5
4.2.4.3. Procedures for the synthesis of (S)-N-((S)-1-Oxo-3-
phenyl-1-(tritylamino)propan-2-yl)pyrrolidine-2-carboxamide
7. The synthetic method of 7 was similar to that of 5. 95% yield;
D
(c 1.0, CHCl3); IR (KBr) 699, 1129, 1161, 1367, 1391, 1535, 1644,
1700, 2977, 3294 cmꢀ1; HRMS (EI) calcd for C31H35N3O4 [M+Na]+
536.2519, found 536.2517; 1H NMR (400 MHz, CDCl3): d 9.77 (s,
2H), 7.53–7.46 (m, 3H), 7.35–7.18 (m, 10H), 7.00 (s, 2H), 6.21 (d,
J = 8.0 Hz, 1H), 5.91 (s, 1H), 4.34–4.10 (m, 2H), 3.54–3.37 (m, 4H),
2.02 (s, 9H), 1.87–1.78 (m, 1H); 13C NMR (100 MHz, CDCl3): d
176.2, 169.4, 154.0, 141.0, 137.3, 128.8, 128.6, 128.4, 128.2,
127.7, 127.5, 127.3, 127.1, 80.6, 80.3, 59.0, 57.2, 47.0, 46.8, 46.3,
31.2, 30.8, 29.3, 28.4, 28.2, 28.1, 24.3, 23.6, 20.7.
White solid, mp 161–162 °C; [a]
20 = +12.1 (c 1.0, CHCl3); IR (KBr)
D
697, 1168, 1289, 1515, 1661, 1689, 3305, 3332 cmꢀ1; HRMS (EI)
calcd C33H33N3O2, [M+H]+ 526.2464, found for 526.2464; 1H
NMR (400 MHz, CDCl3): d 8.05 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H),
7.29–7.15 (m, 14H), 7.10–7.04 (m, 6H), 4.74–4.68 (m, 1H), 4.12–
4.09 (m, 2H), 3.75–3.71 (m, 1H), 3.75–3.12 (m, 1H), 2.99–2.90
(m, 2H), 2.83–2.78 (m, 1H), 2.06–2.00 (m, 1H), 1.70–1.46 (m,
2H); 13C NMR (100 MHz, CDCl3): d 175.4, 169.3, 144.4, 137.0,
129.5, 128.6, 127.9, 127.6, 126.9, 126.8, 70.3, 59.9, 55.1, 47.0,
36.8, 30.2, 28.0, 25.9.
4.2.3.5. Procedures for the synthesis of tert-Butyl (R)-2-(((S)-
2-oxo-1-phenyl-2-(tritylamino)ethyl)carbamoyl)pyrrolidine-1-
carboxylate 15e. The synthetic method of 15e was similar to
that of 15a. 93% yield; Amorphous solid; [
a
]
20 = ꢀ7.1 (c 1.0, CHCl3);
4.2.4.4. Procedures for the synthesis of (S)-N-((S)-2-(Benzhydry-
lamino)-2-oxo-1-phenylethyl)pyrrolidine-2-carboxamide 8.
The synthetic method of 8 was similar to that of 5. 96% yield;
D
IR (KBr) 1142, 1175, 1374, 1388, 1564, 1687, 1788, 2321,
3287 cmꢀ1; HRMS (EI) calcd for C37H39N3O4 [M+Na]+ 612.2832,
found 612.2834; 1H NMR (400 MHz, CDCl3): d 9.78–9.37 (m, 2H),
7.62–7.05 (m, 20H), 5.72–5.60 (m, 1H), 4.31–4.14 (m, 1H), 3.43–
3.31 (m, 2H), 2.07 (s, 9H), 1.47–1.41 (m, 2H), 1.28–1.15 (m, 2H);
13C NMR (100 MHz, CDCl3): d 177.2, 168.6, 144.0, 129.1, 128.5,
White solid, mp 164–167 °C; [
a
]
20 = ꢀ76.5 (c 1.0, CHCl3); IR (KBr)
D
700, 1214, 1532, 1638, 3215, 3312, 3330 cmꢀ1; HRMS (EI) calcd
C
26H27N3O2, [M+H]+ 414.2176, found for 414.2175; 1H NMR
(400 MHz, CDCl3): d 8.68 (d, J = 8.0 Hz, 1H), 7.40–7.33 (m, 3H),
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10
D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7.29–7.16 (m, 11H), 7.00–6.98 (m, 2H), 6.18 (d, J = 8.0 Hz, 1H), 5.77
(d, J = 8.0 Hz, 1H), 3.61–3.57 (m, 1H), 2.96–2.88 (m, 2H),
1.98 (s, 1H), 1.94–1.85 (m, 1H), 1.75–1.54 (m, 3H); 13C NMR
(100 MHz, CDCl3): d 175.2, 169.4, 141.2, 137.9, 128.8, 128.6,
128.4, 128.2, 127.7, 127.5 127.4, 127.2, 127.1, 60.5, 57.2, 56.5,
47.2, 30.6, 26.2.
4.3.3. Procedures for the synthesis of (2R,3S)-2-Isopropyl-4-
nitro-3-(4-(trifluoromethyl)phenyl)butanal 18c
86% yield; yellow liquid; [a]
20 = +49.2 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C14H16F3NO3 [MꢀH]ꢀ 302.1009, found 302.1008; 1H
NMR (400 MHz, CDCl3):
d 9.92 (d, J = 1.6 Hz, 1H), 7.62 (d,
J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.75–4.70 (m, 1H), 4.63–
4.58 (m, 1H), 4.02–3.96 (m, 1H), 2.84–2.80 (m, 1H), 1.70–1.65
(m, 1H), 1.13 (d, J = 7.2 Hz, 3H), 0.94 (d, J = 4.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 203.7, 141.4, 133.8, 130.6, 130.2, 130.2,
128.5, 128.5, 128.3, 126.2, 126.2, 126.1, 125.2, 122.5, 78.5, 58.4,
41.7, 28.0, 21.6, 17.0; HPLC (Chiralcel AD-H, n-hexane:
i-PrOH = 96:4, flow rate: 1.0 mL minꢀ1, k = 254 nm), Tmajor = 15.4,
Tminor = 16.7, 97% ee.
4.2.4.5. Procedures for the synthesis of (R)-N-((S)-2-Oxo-1-
phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 9. The
synthetic method of 9 was similar to that of 5. 93% yield; White
solid, mp 236–239 °C; [a D
]
20 = ꢀ16.7 (c 1.0, CHCl3); IR (KBr) 712,
1033, 1453, 1517, 1620, 1685, 3278, 3344 cmꢀ1; HRMS (EI) calcd
C
32H31N3O2, [M+H]+ 490.2489, found for 490.2489; 1H NMR
(400 MHz, CDCl3): d 8.63 (s, 1H), 7.30–7.07 (m, 20H), 5.64 (s, 1H),
3.65 (s, 1H), 2.91 (d, J = 5.2 Hz, 2H), 2.30 (s, 2H), 2.01 (d,
J = 21.6 Hz, 2H), 1.71–1.60 (m, 2H); 13C NMR (100 MHz, CDCl3): d
175.0, 168.6, 144.3, 144.2 138.0 129.0, 128.6128.5, 128.3, 127.9,
127.5, 127.3, 127.0, 70.6, 60.4, 57.4, 47.2, 30.7, 26.1.
4.3.4. Procedures for the synthesis of (2R,3S)-3-(4-Chlorophenyl)-
2-isopropyl-4-nitrobutanal 18d
88% yield; yellow liquid; [a]
20 = +50.4 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C13H16ClNO3 [MꢀH]ꢀ 268.0745, found 268.0744; 1H NMR
(400 MHz, CDCl3): d 9.92 (d, J = 2.4 Hz, 1H), 7.36–7.26 (m, 2H), 7.19
(d, J = 7.2 Hz, 2H), 4.70–4.65 (m, 1H), 4.60–4.54 (m, 1H), 3.93–3.87
(m, 1H), 2.80–2.75 (m, 1H), 1.73–1.68 (m, 1H), 1.09 (d, J = 7.2 Hz,
3H), 0.87 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.4,
137.1, 129.2, 128.0, 79.0, 58.7, 42.0, 28.0, 21.7, 17.0; HPLC (Chiral-
4.3. General procedures for the enantioselective Michael
reactions
Additives and catalysts were added to a stirred mixture of the
corresponding freshly distilled aldehyde (1.5 mmol, 1.5 equiv) in
the indicated solvent (1 mL). The mixture was stirred at the indi-
cated temperature for 30 min, then the corresponding nitroalkene
(1.0 mmol, 1.0 equiv) was added and stirred at the same tempera-
ture until complete consumption of the nitroalkene (monitored by
TLC). The solvent was quenched with ice water (10 mL), and
extracted with ethyl acetate (3 ꢁ 10 mL). Then the combined
organic phase was dried over Na2SO4, after removing the solvent,
the crude products was purified by flash chromatography to obtain
the corresponding Michael adducts. All newly synthesised com-
pounds were characterized by 1H NMR, 13C NMR, HRMS, and IR
spectroscopy. Enantioselectivity was determined by chiral HPLC
analysis.
cel AD-H, n-hexane:i-PrOH = 97:3, flow rate: 1.0 mL minꢀ1
k = 254 nm), Tmajor = 12.1, Tminor = 14.5, 94% ee.
,
4.3.5. Procedures for the synthesis of (2R,3S)-3-(2-Chlorophenyl)-
2-isopropyl-4-nitrobutanal 18e
92% yield; yellow liquid; [a]
20 = +103.2 (c 1.0, CHCl3); HRMS (EI)
calcd for C13H16ClNO3 [MꢀH]ꢀ D268.0745, found 268.0745; 1H NMR
(400 MHz, CDCl3): d 9.92 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H),
7.27–7.18 (m, 4H), 4.87–4.81 (m, 1H), 4.68–4.64 (m, 1H), 4.46–4.41
(m, 1H), 3.09 (d, J = 6.4 Hz, 1H), 1.79–1.74 (m, 1H), 1.17 (d,
J = 7.2 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 204.0, 134.6, 134.3, 133.8, 130.7, 130.2, 129.2, 128.5, 127.5, 77.0,
57.5, 28.3, 21.7, 17.7; HPLC (Chiralcel AD-H, n-hexane:i-
PrOH = 96:4, flow rate: 1.0 mL minꢀ1, k = 254 nm), Tmajor = 8.8,
Tmajor = 9.3, 99% ee.
4.3.1. Procedures for the synthesis of (2R,3S)-2-Isopropyl-4-
nitro-3-phenylbutanal 18a
91% yield; yellow liquid; [
a]
20 = +30.0 (c 1.0, CHCl3); HRMS (EI)
4.3.6. Procedures for the synthesis of (2R,3S)-3-(2,4-Dichloro-
D
calcd for C13H17NO3 [M+H]+ 236.1281, found 236.1285; 1H NMR
(400 MHz, CDCl3): d 9.93 (d, J = 2.4 Hz, 1H), 7.36–7.27 (m, 3H),
7.19 (d, J = 7.2 Hz, 2H), 4.70–4.65 (m, 1H), 4.60–4.55 (m, 1H),
3.93–3.87 (m, 1H), 2.80–2.76 (m, 1H), 1.74–1.70 (m, 1H), 1.09 (d,
J = 7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 204.4, 191.0, 141.0, 137.1, 134.7, 131.0, 129.5, 129.2, 128.4,
128.1, 128.0, 127.8, 79.0, 58.7, 41.9, 27.9, 21.7, 17.0; HPLC (Chiral-
phenyl)-2-isopropyl-4-nitrobutanal 18f
82% yield; yellow liquid; [a]
20 = +33.0 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C13H15Cl2NO3 [MꢀH]ꢀ 302.0356, found 302.0360; 1H
NMR (400 MHz, CDCl3): d 9.91 (s, 1H), 7.62–7.43 (m, 1H), 7.27–
7.24 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.85–4.80 (m, 1H), 4.68–
4.64 (m, 1H),4.41–4.35 (m, 1H), 3.06 (d, J = 5.6 Hz, 1H), 1.77–1.72
(m, 1H), 1.18 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 203.8, 135.0, 133.7, 133.3, 131.0, 130.5,
130.2, 129.5, 128.5, 127.9, 76.8, 57.4, 28.4, 21.7, 17.7; HPLC (Chiral-
cel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 0.5 mL minꢀ1
k = 254 nm), Tmajor = 21.5, Tminor = 25.4, 91% ee.
,
cel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 1.0 mL minꢀ1
k = 254 nm), Tmajor = 14.3, Tminor = 16.7, 94% ee.
,
4.3.2. Procedures for the synthesis of (2R,3S)-2-Isopropyl-4-
nitro-3-(p-tolyl)butanal 18b
4.3.7. Procedures for the synthesis of (2R,3S)-3-(4-Bromophenyl)-
89% yield; yellow liquid; [a]
20 = +46.5 (c 1.0, CHCl3); HRMS (EI)
D
2-isopropyl-4-nitrobutanal 18g
calcd for C14H19NO3 [M+Na]+ 272.1257, found 272.1260; 1H NMR
(400 MHz, CDCl3): d 9.92 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.0 Hz,
2H), 7.06 (d, J = 8.0 Hz, 2H), 4.67–4.63 (m, 1H), 4.57–4.52 (m,
1H), 3.90–3.83 (m, 1H), 2.77–2.72 (m, 1H), 2.30 (s, 3H), 1.75–1.70
(m, 1H), 1.11 (d, J = 5.2 Hz, 3H), 0.95 (d, J = 3.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 204.6, 137.8, 133.9, 130.2, 129.9, 129.5,
129.5, 128.5, 127.8, 79.1, 58.8, 41.6, 27.9, 21.7, 21.1, 17.0; HPLC
84% yield; yellow liquid; [a]
20 = +41.3 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C13H16BrNO3 [MꢀH]ꢀ 312.0240, found 312.0243; 1H NMR
(400 MHz, CDCl3): d 9.91 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.12–7.08
(m, 2H), 4.73–4.65 (m, 1H), 4.57–4.51 (m, 1H), 3.91–3.85 (m, 1H),
2.77–2.73 (m, 1H), 1.72–1.68 (m, 1H), 1.10 (d, J = 0.8 Hz, 3H), 0.91
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.0, 136.2,
132.4, 129.7, 129.5, 122.1, 78.7, 58.5, 41.4, 28.0, 21.6, 17.0; HPLC
(Chiralcel AD-H, n-hexane:i-PrOH = 98:2, flow rate: 1.0 mL minꢀ1
k = 254 nm), Tmajor = 13.1, Tminor = 18.0, 85% ee.
,
(Chiralcel AD-H, n-hexane:i-PrOH = 99:1, flow rate: 0.6 mL minꢀ1
k = 254 nm), Tmajor = 20.4, Tminor = 16.9, 99% ee.
,
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.019

D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
11
4.3.8. Procedures for the synthesis of (R)-2,2-Dimethyl-4-nitro-
(100 MHz, CDCl3): d 203.2, 203.0, 140.5, 133.8, 130.2, 128.7,
128.7, 128.5, 128.3, 128.3, 126.4, 126.4, 77.4, 53.9, 53.8, 36.6,
36.2, 33.3, 33.0, 31.0, 30.7, 19.0, 18.7, 12.0, 12.0; HPLC (Chiralcel
3-phenylbutanal 18h
83% yield; yellow liquid; [
a]
20 = ꢀ9.3 (c 0.5, CHCl3); HRMS (EI)
D
calcd for C12H15NO3 [MꢀH]ꢀ 220.0979, found 220.0975; 1H NMR
(400 MHz, CDCl3): d 9.53 (s, 1H), 7.62 (t, J = 14.8 Hz, 2H), 7.48 (t,
J = 15.6 Hz, 3H), 4.86 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H),
3.80–3.77 (m, 1H), 1.14 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 204.3, 133.8, 130.2, 129.4, 129.1, 128.7, 128.5, 128.2,
125.4, 76.3, 48.5, 48.2, 21.7, 18.9; HPLC (Chiralcel AD-H, n-hex-
AD-H, n-hexane:i-PrOH = 90:10, flow rate: 0.5 mL minꢀ1
k = 210 nm), Tmajor = 35.2, Tminor = 37.4, 99% ee.
,
4.3.14. Procedures for the synthesis of (2R,3R)-3-(Nitromethyl)-
5-phenyl-2-propylpentanal 20c
94% yield; yellow liquid; [a]
20 = +10.2 (c 1.0, CHCl3); HRMS (EI)
D
ane:i-PrOH = 97:3, flow rate: 0.5 mL minꢀ1
Tmajor = 25.6, Tminor = 27.0, 86% ee.
,
k = 254 nm),
calcd for C15H21NO3 [M+H]+ 264.1594, found 264.1599; 1H NMR
(400 MHz, CDCl3): d 9.64 (d, J = 6.8 Hz, 1H), 7.29–7.18 (m, 5H),
4.54–4.37 (m, 2H), 2.74–2.60 (m, 2H), 2.59–2.49 (m, 1H), 2.49–
2.04 (m, 1H), 1.80–1.45 (m, 2H), 1.44–1.22 (m, 2H), 0.95–0.89
(m, 5H); 13C NMR (100 MHz, CDCl3): d 203.2, 203.0, 140.5, 140.5,
128.6, 128.3, 128.3, 126.4, 126.4, 77.4, 77.0, 52.2, 52.0, 36.8, 36.6,
33.3, 33.1, 31.0, 30.7, 27.9, 27.6, 20.8, 20.8, 14.1, 14.0; HPLC (Chiral-
4.3.9. Procedures for the synthesis of (R)-2,2-Dimethyl-4-nitro-
3-(p-tolyl)butanal 18i
87% yield; yellow liquid; [
a
]
20 = ꢀ3.4 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C13H17NO3 [MꢀH]ꢀ 234.1135, found 234.1136; 1H NMR
(400 MHz, CDCl3): d 9.45 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.99 (d,
J = 8.4 Hz, 2H), 4.75 (d, J = 1.2 Hz, 1H), 4.60 (d, J = 4.0 Hz, 1H),
3.68–3.64 (m, 1H), 2.24 (s, 3H), 1.04 (s, 3H), 0.92 s, 3H); 13C NMR
(100 MHz, CDCl3): d 204.5, 172.1, 133.8, 130.3, 129.4, 129.2,
128.9, 76.4, 48.3, 48.2, 21.6, 18.9; HPLC (Chiralcel AD-H, n-hex-
cel AD-H, n-hexane:i-PrOH = 90:10, flow rate: 0.5 mL minꢀ1
k = 210 nm), Tmajor = 31.5, Tminor = 34.1, 99% ee.
,
4.3.15. Procedures for the synthesis of (2R,3R)-2-Isopropyl-3-
(nitromethyl)-5-phenylpentanal 20d
ane:i-PrOH = 97:3, flow rate: 0.5 mL minꢀ1, k = 254 nm), Tmajor
28.4, Tminor = 25.6, 87% ee.
=
93% yield; yellow liquid; [a]
20 = +38.6 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C15H21NO3 [M+H]+ 264.1594, found 264.1596; 1H NMR
(400 MHz, CDCl3): d 9.81 (d, J = 2.4 Hz, 1H), 7.29 (t, J = 14.8 Hz,
2H), 7.21 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 15.2 Hz, 2H), 4.57–4.50 (m,
1H), 4.48–4.45 (m, 1H), 2.70–2.62 (m, 4H), 2.49–2.45 (m, 1H),
2.12–2.04 (m, 2H), 1.79–1.73 (m, 2H), 1.08 (d, J = 7.2 Hz, 3H), 0.97
(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.8, 140.6,
128.7, 128.6, 128.4, 128.3, 126.3, 58.0, 35.6, 32.6, 31.8, 27.1, 21.0,
19.7; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 90:10, flow rate:
0.5 mL minꢀ1, k = 210 nm), Tmajor = 21.0, Tminor = 24.6, 99% ee.
4.3.10. Procedures for the synthesis of (R)-3-(4-Chlorophenyl)-
2,2-dimethyl-4-nitrobutanal 18j
89% yield; yellow liquid; [
a
]
20 = ꢀ8.8 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C12H14ClNO3 [MꢀH]ꢀ 254.0589, found 254.0590; 1H
NMR (400 MHz, CDCl3): d 9.50 (s, 1H), 7.48 (t, J = 15.2 Hz, 2H),
7.31 (d, J = 8.4 Hz, 2H), 4.82 (d, J = 1.2 Hz, 1H), 4.71 (d, J = 4.4 Hz,
1H), 3.79–3.75 (m, 1H), 1.21 (s, 3H), 1.00 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 203.9, 134.2, 134.0, 130.4, 130.2, 129.0,
128.5, 76.2, 48.2, 48.0, 21.7, 18.9; HPLC (Chiralcel AD-H, n-hex-
ane:i-PrOH = 96:4, flow rate: 1.0 mL minꢀ1, k = 254 nm), Tmajor
14.2, Tminor = 19.8, 90% ee.
=
4.3.16. Procedures for the synthesis of (R)-2-((R)-1-Nitro-4-
phenylbutan-2-yl)hexanal 20e
93% yield; yellow liquid; [a]
20 = +21.5 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C16H23NO3 [M+H]+ 278.1751, found 278.1749; 1H NMR
(400 MHz, CDCl3): d 9.86 (s, 1H), 7.82–7.80 (m, 2H), 7.30–7.13
(m, 3H), 4.84–4.38 (m, 2H), 2.65–2.33 (m, 4H), 1.76–1.67 (m,
4H), 1.44–1.31 (m, 4H), 0.91 (d, J = 5.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 203.0, 140.5, 128.6, 128.3, 128.3, 126.4, 77.4,
52.3, 36.6, 33.1, 31.0, 29.7, 25.2, 22.7, 13.8; HPLC (Chiralcel AD-H,
4.3.11. Procedures for the synthesis of (R)-3-(4-Bromophenyl)-
2,2-dimethyl-4-nitrobutanal 18k
82% yield; yellow liquid; [
a
]
20 = ꢀ4.0 (c 0.5, CHCl3); HRMS (EI)
D
calcd for C12H14BrNO3 [MꢀH]ꢀ 298.0084, found 298.0088; 1H
NMR (400 MHz, CDCl3): d 9.50 (s, 1H), 7.56–7.46 (m, 4H), 4.82 (d,
J = 1.2 Hz, 1H), 4.71 (d, J = 4.4 Hz, 1H), 3.78–3.74 (m, 1H), 1.13 (s,
3H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3): d 203.8, 133.7,
132.8, 132.0, 130.7, 130.4, 1302, 129.4, 128.5, 76.1, 48.1, 48.0,
21.8, 19.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow
rate: 1.0 mL minꢀ1, k = 254 nm), Tmajor = 15.0, Tminor = 22.8, 86% ee.
n-hexane:i-PrOH = 96:4, flow rate: 0.5 mL minꢀ1
Tmajor = 16.0, Tminor = 16.5, 99% ee.
, k = 210 nm),
4.3.17. Procedures for the synthesis of (2R,3R)-2-Benzyl-3-
(nitromethyl)-5-phenylpentanal 20f
94% yield; yellow liquid; [a]
20 = +6.2 (c 1.0, CHCl3); HRMS (EI)
D
4.3.12. Procedures for the synthesis of (2R,3R)-2-Methyl-3-
(nitromethyl)-5-phenylpentanal 20a
calcd for C19H21NO3 [M+H]+ 312.1594, found 312.1591; 1H NMR
(400 MHz, CDCl3): d 9.64 (s, 1H), 7.63–7.42 (m, 5H), 7.32–6.96
(m, 5H), 4.57–4.50 (m, 2H), 3.08–3.04 (m, 2H), 2.76–2.65 (m,
3H), 1.90–1.85 (m, 3H); 13C NMR (100 MHz, CDCl3): d 202.6,
202.3, 140.3, 138.0, 137.8, 133.8, 130.2, 129.0, 128.8, 128.7,
128.7, 128.5, 128.4, 128.3, 127.0, 126.9, 126.5, 126.4, 77.4, 54.2,
53.7, 36.8, 36.6, 33.4, 33.2, 32.0, 31.7, 31.2, 30.4; HPLC (Chiralcel
91% yield; yellow liquid; [
a
]
20 = ꢀ0.6 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C13H17NO3 [M+H]+ 236.1281, found 236.1284; 1H NMR
(400 MHz, CDCl3): d 9.61 (s, 1H), 7.31–7.27 (m, 2H), 7.25–7.19
(m, 2H), 7.17–7.14 (m, 1H), 4.55–4.51 (m, 1H), 4.46–4.41 (m,
1H), 2.82–2.72 (m, 1H), 2.70–2.63 (m, 1H), 2.61–2.54 (m, 2H),
1.71–1.64 (m, 2H), 1.62 (d, J = 5.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 202.6, 140.5, 128.7, 128.3, 126.4, 77.4, 47.0, 36.8, 33.2,
30.2, 9.1; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 90:10, flow
rate: 0.5 mL minꢀ1, k = 210 nm), Tmajor = 15.5, Tminor = 12.8, 86% ee.
AD-H,
n-hexane:i-PrOH = 96:4,
flow
rate:
0.5 mL minꢀ1
,
k = 210 nm), Tmajor = 25.5, Tminor = 24.6, 97% ee.
Acknowledgments
4.3.13. Procedures for the synthesis of (2R,3R)-2-Ethyl-3-
We are grateful to Dr. Kevin S. Burgess from Columbus State
University, USA for his assistance in improving the English. This
work was supported by Doctor Research Project of Yunnan Normal
University (No. 150025), Yunnan Applied Basic Research Project
(Youth Project) and Fellowship for Outstanding PhD Student in
Yunnan Province.
(nitromethyl)-5-phenylpentanal 20b
90% yield; yellow liquid; [a]
20 = +21.4 (c 1.0, CHCl3); HRMS (EI)
D
calcd for C14H19NO3 [M+H]+ 250.1438, found 250.1435; 1H NMR
(400 MHz, CDCl3): d 9.67 (d, J = 3.6 Hz, 1H), 7.46–7.11 (m, 5H),
4.55–4.40 (m, 2H), 2.72–2.57 (m, 4H), 2.47–2.43 (m, 1H), 1.83–
1.67 (m, 4H), 1.57–1.50 (m, 1H), 1.00–0.91 (m, 3H); 13C NMR
Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.019

12
D. Xu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Desmarchelier, A.; Coeffard, V.; Moreau, X.; Greck, C. Tetrahedron 2014, 70,
A. Supplementary data
2491.
9. For selected examples on the application of proline and proline derivatives
catalysts for asymmetric nitro-Michael reactions, see: (a) Jensen, K. L.;
Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jorgensen, K. A. Acc. Chem. Res. 2012, 45,
248; (b) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876; (c) Xu, L.-
W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243; (d) Lu, D.-F.; Gong, Y.-F.;
Wang, W.-Z. Adv. Synth. Catal. 2010, 352, 644; (e) Panday, S. K. Tetrahedron:
Asymmetry 1817, 2011, 22; (f) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922.
10. (a) Samanta, S.; Liu, J.-Y.; Dodda, R.; Zhao, C.-G. Org. Lett. 2005, 7, 5321; (b)
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Supplementary data (1H and 13C NMR spectra for all synthe-
sised intermediates and chiral catalysts and the 1H, 13C NMR and
HPLC spectrum of compounds 18a–18k, 20a–20f) are associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetasy.2016.08.019.
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Please cite this article in press as: Xu, D.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.019