L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes

Article abstract of DOI:10.1016/j.tet.2019.04.015

An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-oxindoles were constructed by this catalytic protocol in excellent yields (90–99%), with high enantioselectivities (83–95%)and diastereoselectivities (79:21–97:3). The asymmetric aza-Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and gave the corresponding products in high to excellent yields (72–97%)with high enantioselectivities (up to 99%)and diastereoselectivities (up to >99:1).

Full text of DOI:10.1016/j.tet.2019.04.015

Accepted Manuscript
L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer
catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-
derived N-Boc ketimines with α-aryl nitromethanes
Jingdong Wang, Yu Liu, Yuxin Liu, Zhonglin Wei, Jungang Cao, Dapeng Liang,
Yingjie Lin, Haifeng Duan
PII:
S0040-4020(19)30405-3
https://doi.org/10.1016/j.tet.2019.04.015
TET 30260
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2019
Revised Date: 3 April 2019
Accepted Date: 4 April 2019
Please cite this article as: Wang J, Liu Y, Liu Y, Wei Z, Cao J, Liang D, Lin Y, Duan H, L-tert-Leucine
derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and
enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.015.
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L-tert-Leucine derived urea-ammonium salts
: efficient bifunctional phase transfer
catalysts for highly diastereo- and
enantioselective aza-Henry reaction of isatin-
derived N-Boc ketimines with α-aryl
nitromethanes
Leave this area blank for abstract info.
Jingdong Wang, Yu Liu, Yuxin Liu, Zhonglin Wei, Jungang Cao, Dapeng Liang, Yingjie Lin, and Haifeng
Duan
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun
130012, China.

1
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Tetrahedron
journal homepage: www.elsevier.com
L-tert-Leucine derived urea-ammonium salts : efficient bifunctional phase transfer
catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-
derived N-Boc ketimines with α-aryl nitromethanes
Jingdong Wang, Yu Liu, Yuxin Liu, Zhonglin Wei, Jungang Cao, Dapeng Liang, Yingjie Lin*, and
Haifeng Duan*
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl
nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium
center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-
oxindoles were constructed by this catalytic protocol in excellent yields (90-99%), with high
enantioselectivities (83-95%) and diastereoselectivities (79:21-97:3). The asymmetric aza-
Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and
gave the corresponding products in high to excellent yields (72-97%) with high
enantioselectivities (up to 99%) and diastereoselectivities (up to >99:1).
Available online
Keywords:
α-amino acids skeleton
asymmetric phase-transfer(APT) catalyze
isatin-derived ketimines
nitro-Mannich reaction
2009 Elsevier Ltd. All rights reserved
.
3-substituted 3-amino-oxindoles
1. Introduction
a-amino acid derived thiourea phosphonium salts8 to asymmetric
Strecker reaction. The same year, they published stereoselective
conjugate addition of oxindoles to electron-deficient
β-haloalkenes catalyzed by quaternary ammonium salts9. In 2018,
they reported 1,3-dipolar cycloaddition of imino esters with
benzofuranone derivatives catalyzed by thiourea-ammonium salt
with high enantioselectivities10. Encouraged by a series of
excellent work of Zhao’s group, we design a new kind of
multiple hydrogen-bonding donors catalysts derived from a-
The use of chiral phase transfer catalysts to catalyze
asymmetric reactions has become one of the main ways of
asymmetric synthesis. Previous reports in this filed indicate that,
most successful catalysts are based on the skeleton of cinchona
alkaloids1, 2, chiral binaphthyls3, 4. Amino acids due to their
inexpensive and accessible characteristics are attracting more and
more attention of chemists. To our delight, a series of excellent
work about amino acid-derived phase transfer catalyst has been
reported by the Zhao’ group in recent years. In 2013, Zhao’s
group report a novel class of chiral bifunctional thiourea
ammonium phase-transfer catalysts and chiral bifunctional
thiourea phosphonium salts5 derived from commercially
available a-amino acids6 and applied to aza-Henry reaction
successfully. They first imported thiourea groups into phase-
transfer catalysts based on acyclic natural amino acids, and
proposed a possible transition state model showed that the
thiourea moiety and the quaternary ammonium or quaternary
phosphonium centre both have very important influence and the
H-bonding interaction and electrostatic interaction both plays a
significant role in this reaction. Moreover, under the same
catalytic mechanism, they alter the thiourea moiety as well as
quaternary ammonium or quaternary phosphonium group on the
catalysts to expand a series of reactions. In 2013 year, they
reported the addition of thiols to imines reaction catalyzed by
chiral bifunctional thiourea ammonium phase-transfer catalysts
derived from a-amino acid7 to synthesize high enantio- and
diastereoselective chiral N,S-acetals. In 2017, they first applied
amino acids and applied to
a
highly enantio- and
diastereoselective nitro-Mannich reaction11. According to our and
Zhao’s results, we find that a-amino acid skeleton have a great
influence on stereocontrol and reactivity in nitro-Mannich
reaction. To the best of our knowledge, although a lot of
successful examples of aza-Henry reaction are based on
aldimines5, 12-22, the aza-Henry reaction of ketimines23-26 is still
rarely reported owing to their low reactivity and diffcult
enantiocontrol. We assume that such kind of catalysts should be
well applied in aza-Henry reaction of ketimines. The aza-Henry
reaction of isatin-derived ketimines is one of the most efficient
and rational approach to construct 3-substituted 3-amino-2-
oxindoles27-32, which contained a stereogenic centre and have
been recognized as key structures in a variety of natural products
and biologically active compounds27. For example, the
spirooxindole anti-malarial NITD60933, the spirocyclic
thioureawith p53/Hdm2 antagonist activity34, AG-041R, a
gastrin/cholecystokinin type B receptorantagonist, is effective in
repairing cartilage defects35 (Figure 1) . Recently our group

2
Tetrahedron
successfully catalyze aza-Henry reaction with N-Boc
ACCEPTED MANUSCRIPT
amidosulfones α-aryl nitromethanes. Herein, we would like to
report our results.
Starting from known (S)-N1,N1,3,3-tetramethylbutane-1,2-
diamine, the catalysts can be easily prepared through the three
steps reaction as outlined in Figure 2. (S)-N1,N1,3,3-
tetramethylbutane-1,2-diamine was synthesized from L-tert-
Leucine in four steps as reported.37 Firstly, treatment of (S)-
N1,N1,3,3-tetramethylbutane-1,2-diamine was transformed with
isothiocyanate or isocyanate to the corresponding urea or
thiourea, then urea or thiourea reacted with various benzyl
bromides and afforded catalysts 3b−3f.
Figure 1. Examples of biologically important 3-subtituted 3-
amino-2-oxindoles.
We began the aza-Henry reaction of isatin-derived N-Boc
ketimines 1a and with 1.5 equiv of (nitromethyl)benzene 2a in
the presence of 10 mol % catalyst 3a and 5 equiv LiOH·H2O at -
30 °C in CHCl3 (Table 1). In initial screening of catalysts 3a-3f,
we were glad to find catalyst 3f with 3,5-bis(trifluoromethyl) and
urea group gave good enantio- and diastereoselectivity (86% ee,
92:8 dr, entries 1-6). The product configuration is in agreement
with the data reported in the literature.38 In addition, well-
behaved catalyst 3a (our previous work)11 and 3b (reported by
Zhao’s group)6, which exhibited excellent asymmetric catalytic
reported a novel kind of organocatalysts, cinchona alkaloid-
derived phase-transfer catalysts bearing multiple hydrogen-
bonding donors, and successfully applied them to this reaction
with high diastereo- and enantioselectivities.36 In spite of this,
this existing catalytic system still can not
effectively
accommodate with some substrates with the electron-donating
groups at the C6-position or different group at the C7-position.
To this end, we try to develop and evaluate a series of novel
bifunctional phase-transfer catalysts derived from a-amino acid
for this reaction. In order to solve this problem, firstly we tried
amino acid-derived phase transfer catalysts with multiple
hydrogen bonding donors11 and amino acid-derived bifunctional
thiourea-ammonium catalysts6 respectively in this aza-Henry
reaction of isatin-derived ketimines and α-aryl nitromethanes but
did not afford satisfied results. To our surprised, when we modify
the structure of Zhao’s catalyst we find that change the thiourea
group to the urea group give a much better result. Encouraged by
Table 1. Optimization of Reaction Conditions
cat. (10 mol %)
LiOH·H2O (5 equiv)
Boc
O
N
Boc
NH
N
NO2
NO2
solvent, -30°C
24h
N
O
Bn
Bn
1a
2a
4a
2. Results and Discussion
entrya
1
cat
solvent
CHCl3
yieldb (%)
93
eec (%)
drd
3a
3b
3c
3d
3e
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
42
60
78
84
72
86
87
91
89
87
82
89
94
89
87
89
83:17
94:6
92:8
91:9
93:7
92:8
73:27
91:9
93:7
93:7
93:7
93:7
93:7
91:9
89:11
90:10
2
CHCl3
80
3
CHCl3
82
4
CHCl3
99
5
CHCl3
82
6
CHCl3
98
7
MTBE
99
8
DCM
97
9
Tol
99
10
11
12
13
14e
15f
16g
m-Xylene
DCM:Tol (1:1)
DCM:Tol (2:1)
DCM:Tol (1:2)
DCM:Tol (1:2)
DCM:Tol (1:2)
DCM:Tol (1:2)
95
99
97
99
95
90
94
aReactions were conducted at 0.1 mmol scale in 1 mL of solvent with 2a (1.5
equiv). bYield of isolated product. cDetermined by HPLC using a chiral
d
e
stationary phase. Determined by HPLC using a chiral stationary phase.
Figure 2. Synthesis of the Catalyst
The reaction conducted at -20°C. fThe reactions was performed with
(nitromethyl)benzene 2a (1.2 equiv ). gThe reactions was performed with 3f
(5 mol %).
better experimental results, we developed a series of chiral phase
transfer catalysts with a quaternary ammonium center derived of
L-tert Leucine and after screening, we successfully used catalyst
3f in the aza-Henry reaction of isatin-derived N-Boc ketimines
and α-aryl nitromethanes. To our delight, electron-donating
group at C6-position and different group at the C7-position also
provide the great diastereo- and enantioselectivities ( up to ee
95%, dr 96:4). To our surprise, the catalyst 3d can also
activity in the aza-Henry reaction of nitromethane and its alkyl
congeners, was also evaluated under the identical reaction
conditions. However, compared with catalyst 3f, catalyst 3a and
3b did not have a positive impact on the enantioselectivity
(entris 1 and 2). By comparsion, the catalyst 3d with urea group
gets higher enantioselectivity than catalyst 3c with thiourea group
(entries
3
and 4), and catalyst 3f with 3,5-

3
bis(trifluoromethyl)benzyl gave the best result (98% yield, 86%
ee, 92:8 dr, entry 6) . In the screening of solvent (entries 7-10),
dichloromethane gave higher enantioselectivity and toluene gave
higher diastereoselectivity. So mixed solvent optimization was
performed (entries 11-13), and a mixture of dicholoromethane
and toluene (1:2) was chosen as the best solvent (99% yield, 94%
ee, 93:7 dr).
Finally, when the loading of (nitromethyl)benzene 2a was
ACCEPTED MANUSCRIPT
reduced to 1.2 equiv, high enantio- and diastereoselectivity was a
little decreased (entry 15). Suprisingly, high enantio- and
diastereoselectivity of the product was still achieved although the
catalyst loading was reduced to 5 mol% (entry 16). After
screening and optimization, the optimal reaction conditions are
as follows: 1.5 equiv aryl nitromethanes in the presence of 10
mol% catalyst 3f and 5 equiv LiOH·H2O at −30 °C in
dichloromethane and toluene (1:2).
Then, the optimization of reaction temperature was performed, -
30 °C was chosen as the optimal temperature (entries 13 vs 14).
Table 2. Substrate Scope of the reaction
entrya
1
1
R1
2
R2
4
yield (%)b
98
ee (%)c
94
90
91
91
91
91
90
90
92
92
93
93
95
94
92
91
93
94
90
95
83
drd
time (h)
24
24
24
24
24
24
24
24
24
24
24
12
12
12
12
24
24
24
24
24
24
1a
1b
1c
1d
1e
1f
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
H
4a
4b
4c
4d
4e
4f
93:7
91:9
93:7
94:6
97:3
93:7
94:6
93:7
92:8
93:7
92:8
91:9
96:4
92:8
92:8
91:9
95:5
92:8
92:8
79:21
92:8
2
5-F
5-Cl
5-Br
5-I
H
98
3
H
99
4
H
99
5
H
97
6
5-Me
5-OMe
6-F
6-Cl
6-Br
6-OMe
7-Cl
7-Br
7-Me
7-CF3
H
H
95
7
1g
1h
1i
H
4g
4h
4i
96
8
H
99
9
H
99
10
11
12
13
14
15
16
17
18
19
20
21
1j
H
4j
97
1k
1l
H
4k
4l
95
H
94
1m
1n
1o
1a
1a
1a
1a
1a
1a
H
4m
4n
4o
4p
4q
4r
4s
4t
98
H
99
H
98
p-Cl
98
H
p-Br
p-OMe
m-OMe
o-OMe
β-naphthyl
97
H
96
H
99
H
95
H
2g
4u
85
aReactions were conducted at 0.1 mmol scale in 1 mL of solvent with (nitromethyl)benzene 2a (1.5 equiv). bYield of isolated product. cDetermined by HPLC
using a chiral stationary phase. dDetermined by HPLC using a chiral stationary phase.
With optimal conditions in hand, the substrate scope of the
aza-Henry reactions was investigated using α-aryl nitromethanes
and various substituted isatin-derived ketimines as substrates, and
corresponding results were show in Table 2. All corresponding
products were obtained in excellent yields (85–99%) and high to
reacted smoothly with 2a could provide 4b-4g in 96-99% yields,
91:9-97:3 dr and 90-91% ee. Istain-derived ketimines containing
different halogen atoms (F, Cl, Br) at the C6-position reacted
with 2a provided the corresponding adducts 4h-4j in 97-99%
yields, 92:8-93:7 dr and 90-92% ee. Especially an electron-
donating group (OMe) at the C6-position could also react
efficiently with 2a (95% yield, 92:8 dr and 93% ee). Different
groups (Cl, Br, Me, CF3) at C7-position could also provided 4l-
4o in 94-99% yields, 91:9-96:4 dr and 93-95% ee. It is worth
noting that reactivity and stereoselectivity of substrates (1k-1o)
excellent
enantioselectivities
(83–95%
ee)
and
diastereoselectivities (79:21-97:3). Different substrates of isatin-
derived N-Boc ketimines bearing either electron-withdrawing or
electron-donating worked well. The ketimines containing
different groups (F, Cl, Br, I, Me, OMe) at the C5-position

4
Tetrahedron
ACCEPTED MANUSCRIPT
with the electron-donating group at the C6-position or various
groups in ortho-, meta- as well as para- position were well
different groups at C6, C7-position have been solved effectively
using this protocol, and corresponding product was obtanied in
higher diastereo- and enantioselectivities. However, only low
reactivity and stereoselectivity of substrate (1k-1o) was obtained
in previous work38,36. Subsequently, we set out to investigate the
generality of the reaction with other α-aryl nitromethanes.
Suprisingly, aryl nitromethanes with either electron-rich or -poor
tolerated and corresponding products were obtained in 85-99%
yields, 83-95% ee and 79:21-95:5 dr. In all cases, high to
excellent yields (70−99%) and excellent ee values (90−97% ee)
were obtained. Subsequently, we attempted to apply our catalytic
systems in other aza-Henry reaction. When we chose N-Boc
amidosulfones as substrates, after screening and optimization, the
optimal reaction conditions are as follows: 1.2 equiv of aryl
Table 3. Substrate scope of aza-Henry reation
entrya
1
5
Ar1
2
Ar2
6
yieldb (%)
97
eec (%)
98
drd
time (h)
36
5a
5b
5c
5d
5e
5f
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2h
2d
2f
Ph
6a
6b
6c
6d
6e
6f
>99:1
95:5
96:4
98:2
>99:1
>99:1
97:3
98:2
98:2
96:4
98:2
94:6
93:7
98:2
99:1
98:2
97:3
2
o-FC6H4
o-MeOC6H4
m-ClC6H4
p-FC6H4
p-ClC6H4
p-MeC6H4
p-MeOC6H4
p-CF3C6H4
2-furyl
2-thienyl
Ph
Ph
97
91
72
3
Ph
89
92
48
4
Ph
91
97
72
5
Ph
94
98
72
6
Ph
90
98
72
7
5g
5h
5i
Ph
6g
6h
6i
72
95
96
8
Ph
93
97
48
9
Ph
90
97
72
10
11
11
12
13
14
15e
16
5j
Ph
6j
94
93
48
5k
5a
5a
5a
5a
5a
5a
Ph
6k
6l
96
97
48
o-FC6H4
m-MeOC6H4
p-BrC6H4
p-MeC6H4
p-MeOC6H4
2-naphthyl
85
99
72
Ph
6m
6n
6o
6p
6q
87
97
72
Ph
92
95
72
Ph
2i
93
98
72
Ph
2e
2b
80
96
72
Ph
97
95
72
aUnless otherwise noted, reations were carried out with 0.1 mmol of 5a, 0.12 mmol of 2a, and 5 mol% of catalyst in 1.0 mL of solvent at -40°C, for 36 h . bYield
of isolated product. cDetermined by HPLC using a chiral stationary phase. dDiastereomeric ratios determined by 1HNMR.
nitromethanes, 5 mol% of catalyst 3d, 5 equiv of LiOH·H2O in
CHCl3, at -40 °C. To our delight, N-Boc amidosulfones having
either electron-rich or –poor groups were well tolerated, and the
position of the substituents seemed to have limited influence
(Table 3). The reaction tolerates electron donating and electron
withdrawing groups within the phenyl group of the nitro
substrate.
Ultimately, to investigate the mechanism of our catalyst,
according to previous report6, two control experiments were
carried out (Scheme 1). Compared with catalyst 3f, the catalyst
3g with one block H-bond has also show lower catalytic activity
and gave product 4a with lower ee 41% and 90:10 dr. We also
find that catalyst 7 without a quaternary ammonium center, gave
product with lower ee 64% and 90:10 dr. These results show that
the H-bond and quaternary ammonium center play a crucial role
Scheme 1. Control Experiment for Mechanistic Study
in the reaction.
To demonstrate that this reaction can be operated scalability
and practicality on large scale, we performed a gram scale
reaction using isatin derived ketimine 1a and 1.5 equiv of 2a.

5
Surprisingly, the reaction can still react smoothly and affording
the corresponding adduct in 91% yield with 90% ee and 98:2 dr
(Scheme 2).
7.26 ppm for proton NMR, δ 77.16 ppm for carbon NMR).
ACCEPTED MANUSCRIPT
Data are presented as follows: chemical shift, integration,
multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet) and coupling constant in Hertz (Hz). Mass
spectra were recorded on the Bruker Agilent 1290 MicrOTOF Q
II. Melting points were measured on a melting point apparatus
and were uncorrected. The ee values determination was carried
out using chiral HPLC (Waters) with Chiracel IA-3 column,
Chiracel IC-3 column Chiracel AD-H column. Optical rotations
were measured on a Shanghai ShenGuang SGW-2 Polarimeter at
25
D
λ = 589 nm. Optical rotations are reported as follows: [α]
(c=g/100 mL, solvent).
Scheme 2. Gram-scale reaction
4.2. Starting materials
(S)-N1,N1,3,3-tetramethylbutane-1,2-diamine and (S)-N1,N1,N2,
3,3-Pentamethylbut- ane-1,2-diamine was prepared according to
reported procedure.6 Catalyst 3a has been reported by our
group.11 Catalyst 3b has been reported by Zhao’s group.6 All
amidosulfones (5a-5j) were prepared using reported procedures
from corresponding aldehydes.39-41 All aldehydes was purchased
from commercial suppliers and sued directly. All ketimines (1a-
1o) were prepared using reported procedures from corresponding
isatins.42 All a-Aryl Nitromethanes (2a-2g) were prepared using
reported procedures.43
On the basis of previous experiment results and relevant
work50, a possible transition state can be considered. We propose
a model to explain the binding model of the catalyst and the
substrate. The urea motif captures the isatin-derived ketimines by
H-bond interaction, and the nitro group anion of the nucleophile
would pair with ammonium motif by electrostatic interaction.
Such an assembly would direct the nitro compound to attack
from the Re face of isatin-derived ketimines.
4.3. Preparation and characterization of the chiral Catalysts.
Corresponding diamine (200 mg, 1 equiv) was dissolved in
CH2Cl2, then added isothiocyanate or isocyanate (1.1 equiv) to
the system and stirred over night at room temperature. The
mixture was concentrated and purified by flash chromatography
(CH2Cl2/MeOH = 20:1). The product (200 mg, 1 equiv) was
dissolved in THF/CH3CN (0.1 M), Then various benzyl bromide
(1.2 equiv) was added, the mixture was stirred over night at room
temperature, the mixture was concentrated and purified by flash
chromatography (CH2Cl2/MeOH = 30:1).
Figure 3. Proposed transition state.
3. Conclusions
In summary, we have developed a series of bifunctional
phase-transfer catalysts derived from L-tert-Leucine, and
successfully applied them to the aza-Henry reactions of N-Boc
ketimines and amidosulfones with α-aryl nitromethanes. A
variety of N-Boc ketimines and amidosulfones with α-aryl
nitromethanes were investigated and corresponding products
were obtained in high yields with excellent diastereo- and
enantioselectivity. Detail mechanism study on this reaction, and
further application of amino acid-derived bifunctional phase
transfer catalysts are underway in our laboratory.
4.3.1 (S)-N-(3,5-di-tert-butylbenzyl)-N,N,3,3-tetramethyl-2-(3-(4-
nitrophenyl)thioureido)butan-1-aminium bromide (3c).
Obtained according to the general procedure. Little yellow
25
solid, 124 mg, 44% yield, mp = 125-126 ℃, [a]D = -95.2 (c =
1
0.5, CHCl3). H NMR (300 MHz, CDCl3) δ 10.65 (s, 1H), 9.74
(d, J = 9.6 Hz, 1H), 8.17 – 8.02 (m, 4H), 7.67 – 7.54 (m, 1H),
7.27 (d, J = 2.0 Hz, 2H), 5.26 – 5.14 (m, 1H), 4.77 (d, J = 12.6
Hz, 1H), 4.52 (d, J = 12.5 Hz, 1H), 4.21 (dd, J = 13.5, 10.0 Hz,
1H), 3.59 (d, J = 13.8 Hz, 1H), 3.29 (s, 3H), 3.14 (s, 3H), 1.33 (s,
18H), 1.12 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 181.09,
152.48, 152.31, 145.80, 144.98, 143.10, 127.25, 125.48, 125.26,
124.25, 120.99, 67.48, 56.23, 50.96, 49.39, 37.11, 34.98, 31.34,
4. Experimental section
4.1. General Information.
26.48. HRMS (ESI): calculated for C30H47N4O2S[M-Br]+
527.3414, found 527.3416.
:
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without purification. All solvents
were obtained from commercial sources and were purified
according to standard procedures. For thin-layer chromatography
(TLC), silica gel plates (HSGF 254) were used and compounds
were visualized by irradiation with UV light. Purification of
reaction products was carried out by flash column
4.3.2.(S)-N-(3,5-di-tert-butylbenzyl)-N,N,3,3-tetramethyl-2-(3-(4-
nitrophenyl)thioureido)butan-1-aminium bromide (3d).
Obtained according to the general procedure. Little yellow solid, 146 mg,
1
51% yield, mp = 131-132 ℃, [a]D25 = -72.6 (c = 0.5, CHCl3). H NMR (300
MHz, CD3OD) δ 8.18 – 8.12 (m, 2H), 7.70 – 7.60 (m, 3H), 7.45 (d, J = 1.8
Hz, 2H), 4.66 (dd, J = 27.0, 12.6 Hz, 2H), 4.25 (d, J = 8.8 Hz, 1H), 3.74 (d,
J = 13.7 Hz, 1H), 3.55 (dd, J = 13.9, 9.1 Hz, 1H), 3.12 (s, 3H), 3.10 (s, 3H),
1.36 (s, 18H), 1.04 (s, 9H). 13C NMR (101 MHz, CD3OD) δ 156.54, 153.32,
147.23, 143.35, 128.71, 127.97, 125.91, 125.86, 118.71, 71.54, 67.44,
53.71, 37.28, 35.86, 31.74, 26.35. HRMS (ESI): calculated for C30H47N4O3
[M-Br]+:511.3643, found 511.3640. 1.36 (s, 18H), 1.04 (s, 9H).
1
chromatography using silica gel (200-300 mesh). H and 13C
NMR spectra were recorded on a Varian Mercury-300BB (300
MHz) or a Bruker NMR Spectrometer (400 MHz), Bruker NMR
Spectrometer (500 MHz). All chemical shifts (δ) were given in
ppm. Chemical shifts ( δ ppm) are relative to the resonance of the
deuterated solvent as the internal standard (CD3OD-d4, δ 3.31
ppm for proton NMR, δ 49.00 ppm for carbon NMR; CDCl3, δ

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.3.3.(S)-N-benzyl-N,N,3,3-tetramethyl-2-(3-(4-
of the starting materialsdetected by TLC, 2 ml sat. aq. NH4Cl was
nitrophenyl)ureido) butan-1-aminium bromide (3e).
added, the aqueous was extracted with ethylacetate (3×5 mL),
then the organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was
purified by flash chromatography (PE/EA).
Obtained according to the general procedure. Little yellow
solid, 178mg, 58% yield, mp = 60-61 ℃, [a]D25 = -24.4 (c = 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3) δ 9.56 (s, 1H), 8.09 (d, J =
9.2 Hz, 2H), 7.78 (d, J = 9.6 Hz, 1H), 7.68 (d, J = 9.2 Hz, 2H),
7.51 (dd, J = 15.7, 6.6 Hz, 5H), 4.92 (d, J = 12.3 Hz, 1H), 4.68 (d,
J = 12.5 Hz, 1H), 4.32 – 4.04 (m, 2H), 3.73 (d, J = 13.1 Hz, 1H),
3.23 (s, 3H), 3.12 (s, 3H), 1.07 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 155.47, 146.14, 133.19, 131.56, 129.69, 126.47, 125.17,
117.65, 112.56, 69.84, 53.18, 49.63, 47.14, 36.46, 26.49. HRMS
(ESI): calculated for C15H24N4O3 [M-Br]+: 399.2391, found
399.2390.
Aldimines: Without protection of inert gases, α-Aryl
nitoalkane (0.12 mmol, 1.2 equiv), amidosulfones (0.1 mmol)
and catalyst 3d (5 mol%) were dissolved in dry chloroform (1.0
mL ). The mixture was cooled to –40 °C, freshly grounded
LiOH·H2O (20.98 mg, 5 equiv) was added in one portion, the
resulting suspention was vigorously stirred at –40 °C. After 36 h,
2 mL sat. aq. NH4Cl was added and the solution was allowed to
warm to room temperature, the aqueous was extracted with
ethylacetate (3×5 mL), then the organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (PE/EA).
4.3.4.(S)-N-(3,5-bis(trifluoromethyl)benzyl)-N,N,3,3-tetramethyl-
2-(3-(4-nitrophenyl)ureido)butan-1-aminium bromide (3f).
Obtained according to the general procedure. Little yellow
25
solid, 137 mg, 51% yield, mp = 119-120 ℃, [a]D = -16.8 (c =
0.5, CHCl3). 1H NMR (400 MHz, MeOD) δ 8.30 (s, 2H), 8.23 (s,
1H), 8.16 – 8.12 (m, 2H), 7.67 – 7.63 (m, 2H), 4.94 (d, J = 12.9
Hz, 1H), 4.82 (d, J = 13.0 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 4.13
– 4.06 (m, 1H), 3.85 (d, J = 13.8 Hz, 1H), 3.76 – 3.66 (m, 1H),
3.18 (d, J = 8.8 Hz, 6H), 2.01 (s, 1H), 1.08 (s, 9H). 13C NMR
(126 MHz, DMSO) δ 154.97, 147.18, 141.21, 134.48, 131.24 (q,
J = 33.3 Hz, CF3), 130.84, 125.60, 124.64, 122.47, 117.43, 66.81,
66.21, 52.27, 49.64, 49.47, 36.57, 26.09. HRMS (ESI): calculated
for C24H29F6N4O3 [M-Br]+ :535.2138,found 535.2138
4.6. Characterization data of products 4a-4u
4.6.1tert-butyl((R)-1-benzyl-3-((S)-nitro(phenyl)methyl)-2-
oxoindo-lin-3-yl)carbamate (4a).
White solid, 47.2 mg, 99% yield, mp = 69 -70 ℃, [a]D25 = 13.5 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 17.502 min, tminor = 6.833 min), Minor- (tmajor
= 94%, dr = 93:7
=
1
15.540 min, tminor = 10.211 min)]. H NMR (300 MHz, CDCl3) δ
7.55 (d, J = 7.6 Hz, 1H), 7.43 – 7.35 (m, 1H), 7.24 (d, J = 1.3 Hz,
1H), 7.22 – 7.09 (m, 6H), 7.08 – 7.01 (m, 2H), 6.69 (d, J = 6.5
Hz, 2H), 6.49 (d, J = 7.8 Hz, 1H), 6.08 (s, 1H), 5.96 (s, 1H), 4.84
(d, J = 16.0 Hz, 1H), 4.45 (d, J = 15.8 Hz, 1H), 1.32 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.36
4.3.5. (S)-N-(3,5-bis(trifluoromethyl)benzyl)-N,N,3,3-tetramethyl-2-(1-
methyl-3-(4-nitrophenyl)ureido)butan-1-aminium bromide (3g).
Obtained according to the general procedure. White solid, 143mg,
25
49% yield, mp = 201-202 ℃, [a]D = -17.2 (c = 0.5, CHCl3). 1H
NMR (400 MHz, CDCl3) δ 8.36 (s, 2H), 8.21 (s, 1H), 8.11 (d, J =
9.2 Hz, 2H), 7.73 (d, J = 9.2 Hz, 2H), 5.07 – 4.99 (m, 2H), 4.93
(d, J = 12.9 Hz, 1H), 4.86 (s, 2H), 4.20 (dd, J = 14.3, 9.8 Hz, 1H),
3.81 (d, J = 14.4 Hz, 1H), 3.25 (s, 2H), 3.19 (d, J = 4.9 Hz, 5H),
1.11 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 160.78, 149.86,
146.48, 137.55, 136.21 (d, J = 33.8 Hz, CF3), 134.37, 128.31,
127.99, 125.60, 123.51, 70.19, 67.42, 59.68, 52.85, 52.58, 52.19,
51.98, 51.77, 51.56, 51.34, 51.13, 50.92, 40.71, 34.71, 30.24.
HRMS (ESI): calculated for C25H31F6N4O3[M-Br]+ : 549.2295,
found 549.2295.
4.6.2.tert-butyl((R)-1-benzyl-5-fluoro-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4b).
White solid, 48.4 mg, 98% yield, mp = 86-87 ℃, [a]D25 = 10 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee = 90%, dr = 91:9
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 11.995 min, tminor = 6.349 min), Minor- (tmajor
=
15.941 min, tminor = 9.994min)]. 1H NMR (300 MHz, CDCl3) δ
7.44 – 7.39 (m, 1H), 7.39 – 7.34 (m, 1H), 7.25 – 7.11 (m, 5H),
7.11 – 7.05 (m, 2H), 6.98 – 6.83 (m, 1H), 6.68 (d, J = 6.4 Hz,
2H), 6.38 (dd, J = 8.6, 4.2 Hz, 1H), 6.06 (s, 1H), 5.88 (s, 1H),
4.81 (d, J = 15.9 Hz, 1H), 4.46 (d, J = 16.1 Hz, 1H), 1.35 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.36
4.4. General procedure for mixtures of Stereoisomers aza-Henry
reaction of imines.
Without protection of inert gases, α-aryl nitromethanes (0.15
mmol, 1.5 equiv), TBAB (20 mol %) and imines (0.1 mmol)
were dissolved in CHCl3 (1 mL ), the mixture was stirred at room
temperature, freshly grounded K2CO3 (69.1 mg, 5 equiv) was
added in one portion, the resulting suspention was stirred at room
temperature. Until complete disappearance of the starting
materials detected by TLC, 2 mL sat. aq. NH4Cl was added, the
aqueous was extracted with ethylacetate (3×5 mL), then the
organic layer was dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (PE/EA).
4.6.3.tert-butyl((R)-1-benzyl-5-chloro-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4c).
White solid, 50.1 mg, 99% yield, mp = 60-61 ℃, [a]D25 = 18 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 11.991 min, tminor = 6.203 min), Minor- (tmajor
= 91%, dr = 93:7
=
15.604 min, tminor = 10.083 min)]. 1H NMR (300 MHz, CDCl3) δ
7.59 (d, J = 2.1 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.25 (d, J = 5.6 Hz,
1H), 7.21 – 7.15 (m, 3H), 7.15 – 7.11 (m, 1H), 7.10 – 7.05 (m,
2H), 6.68 (d, J = 6.6 Hz, 2H), 6.38 (d, J = 8.4 Hz, 1H), 6.04 (s,
1H), 5.91 (s, 1H), 4.78 (d, J = 16.0 Hz, 1H), 4.47 (d, J = 16.0 Hz,
1H), 1.35 (s, 9H). Analytical and spectral data were in agreement
with the literature data.36
4.5. General procedure for enantio- and diastereoselective aza-
Henry reaction.
Ketimines: Without protection of inert gases, α-aryl
nitromethane (0.15 mmol, 1.5 equiv), catalyst 3f (10 mol%) and
ketimines (0.1 mmol) were dissolved in chloroform (1 ml), the
mixture was cooled to -30 °C freshly grounded LiOH·H2O (20.98
mg, 5 equiv) was added in one portion, the resulting suspention
was vigorously stirred at –30 °C. Until complete disappearance

7
4.6.4.tert-butyl((R)-1-benzyl-5-bromo-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4d).
White solid, 54.6 mg, 99% yield, mp = 55-56 ℃, [a]D25 = 22 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
were established by HPLC analysis, ee = 90%, dr = 93:7
ACCEPTED MANUSCRIPT
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 12.360 min, tminor = 5.801 min), Minor- (tmajor
=
1
14.887 min, tminor = 8.423)]. H NMR (500 MHz, CDCl3) δ 7.58
– 7.52 (m, 1H), 7.43 – 7.38 (m, 1H), 7.24 – 7.13 (m, 5H), 7.07 (d,
J = 7.5 Hz, 2H), 6.84 – 6.78 (m, 1H), 6.69 (d, J = 6.8 Hz, 2H),
6.22 (d, J = 8.6 Hz, 1H), 6.06 (s, 1H), 5.95 (s, 1H), 4.81 (d, J =
15.9 Hz, 1H), 4.44 (d, J = 15.8 Hz, 1H), 1.35 (s, 9H). Analytical
and spectral data were in agreement with the literature data.36
established by HPLC analysis, ee
[Chiralpak IA-3, hexane/i-PrOH =80:20, 254 nm, 1 mL/min,
Major - (tmajor = 13.330 min, tminor = 7.011 min), Minor - (tmajor
= 91%, dr = 94:6
=
16.954 min, tminor = 15.893 min)]. 1H NMR (300 MHz, CDCl3) δ
7.71 (d, J = 2.0 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.35 (dd, J = 8.4,
2.0 Hz, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 7.19 (s, 1H), 7.18 – 7.16
(m, 1H), 7.14 (d, J = 1.5 Hz, 1H), 7.13 – 7.04 (m, 3H), 6.68 (d, J
= 6.5 Hz, 2H), 6.33 (d, J = 8.4 Hz, 1H), 6.03 (s, 1H), 5.92 (s, 1H),
4.77 (d, J = 16.0 Hz, 1H), 4.47 (d, J = 16.0 Hz, 1H), 1.35 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.36
4.6.9.tert-butyl((R)-1-benzyl-6-chloro-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4i).
White solid, 50.2 mg, 99% yield, mp = 74-75 ℃, [a]D25 = 20 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 11.290 min, tminor = 5.610 min), Minor- (tmajor
= 92%, dr = 92:8
4.6.5.tert-butyl((R)-1-benzyl-5-iodo-3-((S)-nitro(phenyl)methyl)-
2-oxoindolin-3-yl)carba mate (4e).
=
1
15.221 min, tminor = 7.508)]. H NMR (500 MHz, CDCl3) δ 7.52
(d, J = 8.0 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.25 – 7.19 (m, 3H),
7.19 – 7.14 (m, 2H), 7.14 – 7.06 (m, 3H), 6.71 (d, J = 6.7 Hz,
2H), 6.50 (s, 1H), 6.02 (d, J = 41.7 Hz, 2H), 4.81 (d, J = 16.0 Hz,
1H), 4.45 (d, J = 15.9 Hz, 1H), 1.36 (s, 9H).Analytical and
spectral data were in agreement with the literature data.36
25
White solid, 58.3 mg, 97% yield, mp = 99-100 ℃, [a]D
=
41.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 91%, dr = 97:3
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major - (tmajor = 11.897 min, tminor = 10.394 min), Minor - (tmajor
=
19.406 min, tminor = 11.170 min)]. 1H NMR (300 MHz, CDCl3)) δ
7.85 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.2, 1.8 Hz, 1H), 7.46 –
7.36 (m, 1H), 7.25 – 7.11 (m, 5H), 7.09 – 7.02 (m, 2H), 6.72 –
6.62 (m, 2H), 6.23 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H), 5.93 (s, 1H),
4.76 (d, J = 15.9 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 1.35 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.36
4.6.10.tert-butyl((R)-1-benzyl-6-bromo-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4j).
White solid, 53.4 mg, 97% yield, mp = 74-75 ℃, [a]D25 = 23.2
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 92%, dr = 93:7
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 11.588 min, tminor = 5.736 min), Minor- (tmajor
=
4.6.6.tert-butyl((R)-1-benzyl-5-methyl-3-((S)
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4f).
White solid, 46.7 mg, 95% yield, mp = 93-94 ℃, [a]D25 = 28.4
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 91%, dr = 92:8
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
15.897 min, tminor = 7.610)]. 1H NMR (500 MHz, CDCl3) δ 7.42
(dd, J = 17.6, 7.8 Hz, 2H), 7.28 (d, J = 1.4 Hz, 1H), 7.25 – 7.19
(m, 3H), 7.19 – 7.14 (m, 2H), 7.08 (d, J = 7.6 Hz, 2H), 6.70 (d, J
= 7.2 Hz, 2H), 6.64 (d, J = 1.2 Hz, 1H), 6.04 (s, 1H), 5.92 (s, 1H),
4.79 (d, J = 16.0 Hz, 1H), 4.45 (d, J = 16.0 Hz, 1H), 1.35 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.36
Major- (tmajor = 17.729 min, tminor = 6.270 min), Minor- (tmajor
=
14.179min, tminor = 8.838 min)]. 1H NMR (300 MHz, CDCl3) δ
7.42 – 7.37 (m, 1H), 7.36 – 7.32 (m, 1H), 7.23 – 7.18 (m, 2H),
7.17 – 7.14 (m, 2H), 7.14 – 7.12 (m, 1H), 7.08 – 7.00 (m, 3H),
6.70 (d, J = 6.3 Hz, 2H), 6.37 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H),
5.98 (s, 1H), 4.78 (d, J = 15.9 Hz, 1H), 4.44 (d, J = 15.9 Hz, 1H),
2.36 (s, 3H), 1.33 (s, 9H). Analytical and spectral data were in
agreement with the literature data.36
4.6.11.tert-buty((R)-1-benzyl-6-methoxy-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4k).
White solid, 53.6 mg, 97% yield, mp = 74-75 ℃, [a]D25 = 16 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 20.787 min, tminor = 7.153 min), Minor- (tmajor
= 92%, dr = 93:8
=
1
4.6.7.tert-butyl((R)-1-benzyl-5-methoxy-3-((S)-
nitro(phenyl)methyl) -2-oxoindolin-3-yl)carbamate (4g).
19.369 min, tminor = 9.655)]. H NMR (300 MHz, CDCl3) δ 7.46
(d, J = 8.4 Hz, 1H), 7.43 – 7.35 (m, 1H), 7.30 (d, J = 6.9 Hz, 1H),
7.24 – 7.12 (m, 5H), 7.08 (d, J = 8.1 Hz, 2H), 6.67 (d, J = 6.8 Hz,
2H), 6.60 (dd, J = 8.4, 2.3 Hz, 1H), 6.07 (s, 1H), 5.91 (s, 1H),
4.82 (d, J = 16.0 Hz, 1H), 4.42 (d, J = 16.4 Hz, 1H), 3.73 (s, 3H),
1.34 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 173.29, 161.50,
153.52, 145.21, 134.80, 130.48, 129.98, 128.64, 128.36, 128.01,
127.35, 126.80, 126.44, 116.43, 106.66, 97.64, 93.08, 81.01,
77.30, 77.04, 76.79, 63.65, 55.37, 53.45, 44.43, 31.59, 28.14,
22.66, 14.11. HRMS (ESI): calculated for C30H47N4O3[M+H]+ :
504.2129, found 504.2128.
25
White solid, 49.5 mg, 98% yield, mp = 117-118 ℃, [a]D
=
35.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 90%, dr=94:6
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 21.460 min, tminor = 7.349 min), Minor- (tmajor
=
19.203 min, tminor = 12.636min)]. 1H NMR (300 MHz, CDCl3) δ
7.43 – 7.34 (m, 1H), 7.24 – 7.18 (m, 2H), 7.18 – 7.11 (m, 4H),
7.10 – 7.03 (m, 2H), 6.76 (dd, J = 8.6, 2.5 Hz, 1H), 6.68 (d, J =
6.5 Hz, 2H), 6.37 (d, J = 8.6 Hz, 1H), 6.06 (s, 1H), 5.96 (d, J =
4.4 Hz, 1H), 4.79 (d, J = 15.9 Hz, 1H), 4.43 (d, J = 16.0 Hz, 1H),
3.80 (s, 3H), 1.33 (s, 9H). Analytical and spectral data were in
agreement with the literature data.36
4.6.12.tert-butyl((R)-1-benzyl-7-chloro-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4l).
White solid, 50.5 mg, 99% yield, mp = 74-75 ℃, [a]D25 = 12.8
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 93%, dr = 91:9
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
4.6.8.tert-butyl((R)-1-benzyl-6-fluoro-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4h).
White solid, 48.7 mg, 99% yield, mp = 88-89 ℃, [a]D25 = 11.2
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
Major- (tmajor = 16.840 min, tminor =6.361 min), Minor- (tmajor
=
1
15.441 min, tminor = 8.660)]. H NMR (500 MHz, CDCl3) δ 7.46

8
Tetrahedron
ACCEPTED MANUSCRIPT
– 7.40 (m, 2H), 7.29 – 7.27 (m, 1H), 7.25 – 7.21 (m, 2H), 7.17
White solid, 55 mg, 99% yield, mp = 66-67 ℃, [a]D25 = 32.4 (c
– 7.14 (m, 3H), 7.10 – 7.06 (m, 1H), 7.03 (d, J = 7.7 Hz, 2H),
6.78 (s, 2H), 6.06 (s, 1H), 6.02 (s, 1H), 5.17 – 4.83 (m, 2H), 1.35
(s, 9H). Analytical and spectral data were in agreement with the
literature data.36
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee 93%, dr 95:4
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
=
=
Major- (tmajor = 24.683 min, tminor = 6.616 min), Minor- (tmajor
=
22.483 min, tminor = 10.684)]. 1H NMR (300 MHz, CDCl3) δ 7.56
– 7.50 (m, 1H), 7.32 – 7.29 (m, 1H), 7.29 – 7.26 (m, 2H), 7.25 –
7.20 (m, 3H), 7.14 (d, J = 7.6, 1.0 Hz, 1H), 6.91 – 6.84 (m, 2H),
6.72 (dd, J = 6.4, 2.9 Hz, 2H), 6.56 (d, J = 7.8 Hz, 1H), 6.05 (s,
1H), 5.96 (s, 1H), 4.93 (d, J = 15.8 Hz, 1H), 4.41 (d, J = 15.8 Hz,
1H), 1.32 (s, 9H). Analytical and spectral data were in agreement
with the literature data.36
4.6.13.tert-butyl((R)-1-benzyl-7-bromo-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4m).
White solid, 54.3 mg, 98% yield, mp = 76-77 ℃, [a]D25 = 16.4
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 95%, dr = 96:4
[Chiralpak IC-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 11.115 min, tminor = 9.713 min), Minor- (tmajor
=
4.6.18.tert-butyl((R)-1-benzyl-3-((S)-(4-
methoxyphenyl)(nitro)meth-yl)-2-oxoindolin-3-yl)carbamate (4r).
White solid, 49.7 mg, 99% yield, mp = 52-53 ℃, [a]D25 = 20.8
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 94%, dr = 92:8
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
20.131 min, tminor = 22.413)]. 1H NMR (300 MHz, CDCl3)) δ 7.49
– 7.39 (m, 3H), 7.31 – 7.26 (m, 1H), 7.25 – 7.21 (m, 1H), 7.18 –
7.10 (m, 3H), 7.06 – 6.97 (m, 3H), 6.79 – 6.69 (m, 2H), 6.03 (s,
1H), 6.00 (s, 1H), 5.09 (d, J = 16.7 Hz, 1H), 4.98 (d, J = 16.7 Hz,
1H), 1.35 (s, 9H). Analytical and spectral data were in agreement
with the literature data.36
Major- (tmajor = 18.630 min, tminor = 7.132 min), Minor- (tmajor
=
4.6.14.tert-butyl((R)-1-benzyl-7-methyl-3-((S)-
nitro(phenyl)methyl)-2-oxoindolin-3-yl)carbamate (4n).
White solid, 43.9 mg, 90% yield, mp = 71-72 ℃, [a]D25 = 29.6
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 94%, dr = 92:8
[Chiralpak AD-H, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
20.159 min, tminor = 11.272)]. 1H NMR (300 MHz, CDCl3) δ 7.52
– 7.47 (m, 1H), 7.31 – 7.27 (m, 1H), 7.25 – 7.21 (m, 1H), 7.20 –
7.14 (m, 2H), 7.13 – 7.08 (m, 2H), 6.94 – 6.88 (m, 2H), 6.70 –
6.66 (m, 2H), 6.64 (s, 2H), 6.51 (d, J = 7.7 Hz, 1H), 6.01 (s, 1H),
5.97 (d, J = 10.3 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.39 (d, J =
15.6 Hz, 1H), 3.76 (s, 3H), 1.31 (s, 9H). Analytical and spectral
data were in agreement with the literature data.36
Major - (tmajor = 33.219 min, tminor = 8.496 min), Minor - (tmajor
=
36.065 min, tminor = 39.560)]. 1H NMR (300 MHz, CDCl3) δ 7.48
– 7.40 (m, 1H), 7.37 – 7.26 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H),
7.18 – 7.11 (m, 3H), 7.08 – 7.01 (m, 4H), 6.67 (d, J = 3.8 Hz,
2H), 6.08 (s, 1H), 6.04 (s, 1H), 4.94 – 4.74 (m, 2H), 2.05 (d, J =
2.8 Hz, 4H), 1.35 (s, 9H). Analytical and spectral data were in
agreement with the literature data.36
4.6.19.tert-butyl((R)-1-benzyl-3-((S)-(3methoxyphenyl)(nitro)
methyl) - 2- oxoindolin-3-yl) carbamate (4s).
White solid, 48.5 mg, 97% yield, mp = 61-62 ℃, [a]D25 = 18
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 90%, dr = 92:8
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
4.6.15.tert-butyl(R)-1-benzyl-3-((S)-nitro(phenyl)methyl)-2-oxo-
7-(trifluoromethyl)indolin-3-yl)car-bamate (4o).
White solid, 52.7 mg, 98% yield, mp = 52-53 ℃, [a]D25 = 24.4
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 92%, dr = 92:8
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 15.569 min, tminor = 7.446 min), Minor- (tmajor
=
16.730 min, tminor = 8.528)]. 1H NMR (300 MHz, CDCl3) δ 7.43 –
7.35 (m, 1H), 7.35 – 7.26 (m, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.18
– 7.05 (m, 5H), 6.76 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (s, 1H), 6.68
(s, 1H), 6.37 (d, J = 8.6 Hz, 1H), 6.06 (s, 1H), 5.95 (s, 1H), 4.79
(d, J = 15.9 Hz, 1H), 4.44 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H), 1.34
(s, 9H). Analytical and spectral data were in agreement with the
literature data.36
Major- (tmajor = 11.172 min, tminor = 5.048 min), Minor- (tmajor
=
10.039 min, tminor = 6.275)]. 1H NMR (300 MHz, CDCl3) δ 7.68
(dd, J = 7.8, 4.2 Hz, 2H), 7.47 – 7.40 (m, 1H), 7.28 (d, J = 2.4 Hz,
1H), 7.25 – 7.21 (m, 2H), 7.16 – 7.11 (m, 3H), 6.96 (dd, J = 8.3,
1.1 Hz, 2H), 6.79 (s, 1H), 6.05 (s, 1H), 5.98 (s, 1H), 4.85 – 4.66
(m, 2H), 1.35 (s, 9H). Analytical and spectral data were in
agreement with the literature data.36
4.6.20.tert-butyl((R)-1-benzyl-3-((S)-(2-methoxyphenyl)
(nitro)methyl) -2-oxoindolin-3-yl)carbamate (4t).
White solid, 47.4 mg, 95% yield, mp = 64-65 ℃, [a]D25 = 57.6
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 95%, dr = 79:21
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
4.6.16.tert-butyl((R)-1-benzyl-3-((S)-(4-
chlorophenyl)(nitro)methyl)-2-oxoindolin-3-yl)caramate (4p).
White solid, 50.6 mg, 99% yield, mp = 74-75 ℃, [a]D25 = 46
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 91%, dr = 91:8
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 11.137 min, tminor = 7.631 min), Minor- (tmajor
=
8.870 min, tminor = 8.276)]. 1H NMR (300 MHz, CDCl3) δ 7.42 –
7.36 (m, 1H), 7.35 – 7.30 (m, 2H), 7.23 – 7.19 (m, 1H), 7.19 –
7.12 (m, 3H), 7.10 – 7.02 (m, 1H), 6.97 – 6.84 (m, 2H), 6.83 –
6.75 (m, 3H), 6.72 (s, 1H), 6.66 (d, J = 7.1 Hz, 1H), 6.53 (d, J =
7.8 Hz, 1H), 6.32 (s, 1H), 4.94 (d, J = 16.0 Hz, 1H), 4.45 (d, J =
15.8 Hz, 1H), 3.72 (s, 3H), 1.29 (s, 9H). Analytical and spectral
data were in agreement with the literature data.36
Major- (tmajor = 23.641 min, tminor = 6.568 min), Minor- (tmajor
=
21.613 min, tminor = 11.171)]. 1H NMR (300 MHz, CDCl3) δ 7.54
(d, J = 6.4 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.25 – 7.20 (m, 3H),
7.16 – 7.10 (m, 3H), 6.94 (d, J = 8.6 Hz, 2H), 6.72 (dd, J = 6.4,
2.7 Hz, 2H), 6.56 (d, J = 7.8 Hz, 1H), 6.06 (s, 1H), 5.98 (s, 1H),
4.92 (d, J = 15.8 Hz, 1H), 4.41 (d, J = 15.8 Hz, 1H), 1.32 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.36
4.6.21.tert-butyl((R)-1-benzyl-3-((S)-naphthalen-2-
yl(nitro)methyl)-2-oxoindolin-3-yl)carbamate (4u).
White solid, 52.2 mg, 99% yield, mp = 82-83 ℃, [a]D25 = 80 (c
= 0.5, CHCl3). Enantiomeric excess and diastereomer ratio were
established by HPLC analysis, ee
[Chiralpak IA-3, hexane/i-PrOH = 80:20, 254 nm, 1 mL/min,
Major- (tmajor = 25.432 min, tminor = 7.215 min), Minor- (tmajor
20.976 min, tminor = 20.277)]. 1H NMR (300 MHz, CDCl3) δ 7.83
= 83%, dr = 92:8
4.6.17.tert-butyl((R)-1-benzyl-3-((S)-(4-
bromophenyl)(nitro)methyl)-2-oxoindolin-3-yl)carbamate (4q).
=

9
25
– 7.76 (m, 1H), 7.70 – 7.66 (m, 1H), 7.66 – 7.62 (m, 1H), 7.60
(dd, J = 8.5, 2.8 Hz, 2H), 7.57 – 7.51 (m, 2H), 7.51 – 7.44 (m,
1H), 7.29 – 7.26 (m, 1H), 7.22 (dd, J = 10.8, 1.3 Hz, 1H), 7.16
(dd, J = 7.6, 1.0 Hz, 1H), 7.04 – 6.88 (m, 3H), 6.69 – 6.55 (m,
2H), 6.45 (d, J = 7.8 Hz, 1H), 6.36 (d, J = 7.4 Hz, 2H), 6.25 (s,
1H), 6.05 (s, 1H), 4.89 (d, J = 16.0 Hz, 1H), 4.30 (d, J = 15.9 Hz,
1H), 1.32 (s, 9H). Analytical and spectral data were in agreement
with the literature data.36
White solid, 33.9 mg, 94% yield, mp = 191-193 ℃, [a]D =
ACCEPTED MANUSCRIPT
22 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 98%, dr >99:1
[Chiralpak IA-3, hexane/EtOH = 95:5, 230 nm, 1.0 mL/min,
Major- (tmajor =14.48min, tminor =13.90 min), Minor- (tmajor = 16.82
min, tminor = 26.62 min)]. 1H NMR (300 MHz, CDCl3) δ 7.60 –
7.51 (m, 2H), 7.46 – 7.39 (m, 3H), 7.34 (dd, J = 8.6, 5.2 Hz, 2H),
7.10 – 7.00 (m, 2H), 5.83 – 5.53 (m, 2H), 4.89 (s, 1H), 1.26 (s,
9H). Analytical and spectral data were in agreement with the
literature data.45
4.7. Characterization data of products 6a-6p
4.7.1 tert-butyl (1S,2R)-2-nitro-1,2-diphenylethyl carbamate
(6a).
White solid, 33.1 mg, 97% yield, mp = 200-202 ℃, [a]D25 = 80
(c = 0.5, CHCl3). Enantiomeric excess and diastereomer ratio
were established by HPLC analysis, ee = 98%, dr >99:1
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
4.7.9. tert-butyl (1S,2R)-1-(4-chlorophenyl)-2-nitro-2-phenylethyl
carbamate (6f).
25
White solid, 34.3 mg, 90% yield, mp = 196-197 ℃, [a]D
=
21.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 98%, dr >99:1
[Chiralpak AD-H, hexane/i-PrOH = 90:10, 214 nm, 1.0 mL/min,
Major- (tmajor = 18.14 min., tminor = 15.99 min), Minor- (tmajor
=
25.92 min, tminor = 12.52 min)]. 1H NMR (300 MHz, CDCl3) δ
7.61 – 7.52 (m, 2H), 7.49 – 7.40 (m, 3H), 7.37 – 7.29 (m, 3H),
7.28 (d, J = 1.9 Hz, 1H), 5.82 – 5.58 (m, 2H), 4.84 (s, 1H), 1.26
(s, 9H). Analytical and spectral data were in agreement with the
literature data.44
Major- (tmajor = 21.66 min, tminor = 34.58 min), Minor- (tmajor
=
32.26 min., tminor = 23.78 min)]. 1H NMR (300 MHz, CDCl3) δ
7.58 (dd, J = 7.2, 2.3 Hz, 2H), 7.47 – 7.40 (m, 3H), 7.39 – 7.31
(m, 4H), 5.83 – 5.61 (m, 2H), 4.77 (d, J = 8.9 Hz, 1H), 1.25 (s,
9H). Analytical and spectral data were in agreement with the
literature data.45
4.7.2 tert-butyl(1S,2R)-1-(2-fluorophenyl)-2-nitro-2-phenylethyl
carbamate (6b).
4.7.10. tert-butyl (1S,2R)-2-nitro-2-phenyl-1-(p-tolyl)ethyl
carbamate (6g).
25
White solid, 35.1 mg, 97% yield, mp = 181-183 ℃, [a]D
54.4 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 91%, dr = 95:5
[Chiralpak IC-3, hexane/EtOH = 16:1, 210 nm, 0.5 mL/min,
=
25
White solid, 25.7 mg, 72% yield, mp = 190-192 ℃, [a]D
32.8 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 95%, dr = 97:3
=
[Chiralpak AD-H, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
Major- (tmajor = 12.17 min, tminor = 13.13 min), Minor- (tmajor
=
17.92 min, tminor = 15.15 min)]. 1H NMR (300 MHz, CDCl3) δ
Major- (tmajor = 16.36 min, tminor = 14.88 min), Minor- (tmajor
=
25.02 min, tminor = 11.38 min)]. 1H NMR (300 MHz, CDCl3) δ
7.62 – 7.54 (m, 2H), 7.46 – 7.36 (m, 3H), 7.26 (d, J = 0.5 Hz,
1H), 7.22 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H), 5.80 – 5.58 (m, 2H),
4.76 (d, J = 9.1 Hz, 1H), 2.34 (s, 3H), 1.24 (s, 9H). Analytical
and spectral data were in agreement with the literature data.44
7.66 – 7.59 (m, 2H), 7.46 – 7.39 (m, 4H), 7.38 – 7.29 (m, 1H),
7.17 – 7.13 (m, 1H), 7.13 – 7.07 (m, 1H), 5.91 – 5.82 (m, 2H),
5.06 (s, 1H), 1.22 (s, 9H). Analytical and spectral data were in
agreement with the literature data.44
4.7.3 tert-butyl (1S,2R)-1-(2-methoxyphenyl)-2-nitro-2-
phenylethyl carbamate (6c).
4.7.11.tert-butyl (1S,2R)-1-(4-methoxyphenyl)-2-nitro-2-
phenylethyl carbamate (6h).
25
White solid, 33.1 mg, 89% yield, mp = 185-187 ℃, [a]D
27.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 92%, dr = 96:4
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
=
25
White solid, 34.6 mg, 93% yield, mp = 191-193 ℃, [a]D
=
25.6 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 97%, dr = 98:2
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
Major- (tmajor = 8.99 min, tminor = 28.42 min), Minor- (tmajor
=
10.50 min, tminor = 18.63 min)]. 1H NMR (300 MHz, CDCl3) δ
7.64 (s, 2H), 7.40 (s, 3H), 7.35 – 7.28 (m, 2H), 7.00 – 6.89 (m,
2H), 6.04 – 5.94 (m, 1H), 5.87 – 5.75 (m, 1H), 5.58 – 5.47 (m,
1H), 3.98 (s, 3H), 1.20 (s, 9H). Analytical and spectral data were
in agreement with the literature data.43
Major- (tmajor = 20.38 min, tminor = 65.56 min), Minor- (tmajor
=
36.25 min, tminor = 22.29 min)]. 1H NMR (300 MHz, CDCl3) δ
7.61 – 7.54 (m, 2H), 7.46 – 7.38 (m, 3H), 7.32 – 7.26 (m, 1H),
6.97 – 6.84 (m, 3H), 5.72 (dd, J = 23.3, 9.5 Hz, 2H), 4.75 (d, J =
9.0 Hz, 1H), 3.80 (s, 3H), 1.25 (s, 9H). Analytical and spectral
data were in agreement with the literature data.44
4.7.4.tert-butyl (1S,2R)-1-(3-chlorophenyl)-2-nitro-2-phenylethyl
carbamate (6d)
4.7.12. tert-butyl (1S,2R)-2-nitro-2-phenyl-1-(4(trifluoromethyl)-
phenyl) ethyl]carbamate (6i).
25
White solid, 34.2 mg, 91% yield, mp = 192-194 ℃, [a]D
=
25
White solid, 36.9 mg, 90% yield, mp = 191-193 ℃, [a]D
=
18.7 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 97%, dr = 98:2
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
31.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 97%, dr = 95:5
[Chiralpak IA-3, hexane/i-PrOH = 95:5, 210 nm, 1.0 mL/min,
Major- (tmajor = 12.16 min, tminor = 13.43 min), Minor- (tmajor
=
15.89 min, tminor = 9.78 min)]. 1H NMR (300 MHz, CDCl3) δ 7.55
(dd, J = 7.4, 1.9 Hz, 2H), 7.48 – 7.38 (m, 3H), 7.37 – 7.28 (m,
3H), 7.26 – 7.19 (m, 1H), 5.81 – 5.54 (m, 2H), 4.85 (s, 1H), 1.26
(s, 9H). Analytical and spectral data were in agreement with the
literature data.43
Major- (tmajor = 37.70 min, tminor = 24.99 min), Minor - (tmajor
=
44.09 min., tminor = 33.22 min)]. 1H NMR (300 MHz, CDCl3)δ
7.63 (d, J = 8.2 Hz, 2H), 7.58 – 7.53 (m, 2H), 7.52 – 7.46 (m,
2H), 7.46 – 7.40 (m, 3H), 5.86 – 5.65 (m, 2H), 4.82 (d, J = 8.9
Hz, 1H), 1.26 (s, 9H). Analytical and spectral data were in
agreement with the literature data.45
4.7.8.tert-butyl (1S,2R)-1-(4-fluorophenyl)-2-nitro-2-phenylethyl
carbamate (6e).
4.7.13. tert-butyl (1S,2R)-1-(furan-2-yl)-2-nitro-2-phenylethyl
carba-mate (6j).

10
Tetrahedron
25
White solid, 31.2 mg, 94% yield, mp = 163-165 ℃, [a]D
4.7.17 tert-butyl (1S,2R)-2-nitro-1-phenyl-2-(p-tolyl)ethyl
ACCEPTED MANUSCRIPT
= 89.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee =93%, dr = 96:4
[Chiralpak IC-3, hexane/i-PrOH = 98:2, 210 nm, 1.0 mL/min,
carbamate (6o).
25
White solid, 33.2mg, 93% yield, mp = 184-186 ℃, [a]D
=
37.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 98%, dr = 99:1
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
Major- (tmajor = 22.60 min, tminor = 35.46 min), Minor- (tmajor
=
47.18 min, tminor = 41.18 min)]. 1H NMR (300 MHz, CDCl3) δ
7.58 – 7.49 (m, 1H), 7.46 – 7.34 (m, 3H), 6.34 (s, 1H), 5.82 (s,
1H), 4.87 (s, 1H), 1.26 (s, 9H). Analytical and spectral data were
in agreement with the literature data.44
Major- (tmajor = 17.38 min, tminor = 15.31 min), Minor- (tmajor
=
1
26.97 min, tminor = 11.73 min)]. H NMR (300 MHz, CDCl3) δ
7.37 (d, J = 8.1 Hz, 2H), 7.27 (s, 4H), 7.20 – 7.09 (m, 2H), 5.63
(t, J = 15.2 Hz, 2H), 4.81 (s, 1H), 2.28 (d, J = 5.8 Hz, 3H), 1.17
(d, J = 6.0 Hz, 9H). Analytical and spectral data were in
agreement with the literature data.44
4.7.14. tert-butyl ((1R,2R)-2-nitro-2-phenyl-1-(thiophen-2-
yl)ethyl)carbamate (6k)
25
White solid, 34.7 mg, 99% yield, mp = 165-166 ℃, [a]D
=
42.5 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee =97%, dr = 98:2
[Chiralpak IC-3, hexane/EtOH = 16:1 , 210 nm, 0.5 mL/min,
4.7.18. tert-butyl (1S,2R)-2-(4-methoxyphenyl)-2-nitro-1-
phenylethyl carbamate (6p).
25
White solid, 29.7 mg, 80% yield, mp = 181-182 ℃, [a]D
30.5 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 96%, dr = 98:2
=
Major- (tmajor = 14.380 min, tminor = 16.068 min), Minor- (tmajor
=
21.715 min, tminor = 19.196 min)]. 1H NMR (400 MHz, CDCl3) δ
7.58 – 7.51 (m, 2H), 7.45 – 7.37 (m, 3H), 7.28 (dd, J = 5.1, 0.9
Hz, 1H), 7.06 (d, J = 3.4 Hz, 1H), 6.96 (dd, J = 5.0, 3.6 Hz, 1H),
6.00 – 5.91 (m, 1H), 5.86 (d, J = 9.4 Hz, 1H), 4.80 (d, J = 8.3 Hz,
1H), 1.28 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 154.06, 140.40,
131.47, 130.26, 128.87, 128.63, 127.08, 126.42, 125.80, 94.55,
80.62, 52.62, 28.07. HRMS (ESI): calculated for C17H20N2O4S
[M+Na]+: 371.1041, found 371.1039.Analytical and spectral data
were in agreement with the literature data.44
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210nm, 1.0 mL/min,
Major- (tmajor = 23.73 min, tminor = 19.25 min), Minor- (tmajor
=
1
39.97 min, tminor = 15.59 min)]. H NMR (300 MHz, CDCl3) δ
7.54 – 7.46 (m, 2H), 7.39 – 7.29 (m, 5H), 6.95 – 6.88 (m, 2H),
5.76 – 5.58 (m, 2H), 4.81 – 4.70 (m, 1H), 3.82 (s, 3H), 1.29 –
1.24 (m, 9H). Analytical and spectral data were in agreement
with the literature data.44
4.7.19. tert-butyl (1S,2R)-2-(naphthalen-2-yl)-2-nitro-1-
phenylethyl carbamate (6q).
4.7.14. tert-butyl (1S,2R)-2-(2-fluorophenyl)-2-nitro-1-
phenylethyl carbamate (6l).
25
White solid, 38.1 mg, 97% yield, mp = 183-185 ℃, [a]D
25.6 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 95%, dr = 97:3
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 1.0 mL/min,
=
25
White solid, 30.6 mg, 85% yield, mp = 175-176 ℃, [a]D
=
43.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 99%, dr = 94:6
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, 0.5 mL/min,
Major- (tmajor = 34.79 min, tminor = 18.33 min), Minor- (tmajor
Major- (tmajor = 31.65 min, tminor = 26.50 min),Minor- (tmajor
=
36.84 min., tminor =15.03 min)]. 1H NMR (300 MHz, CDCl3[) δ
8.03 (s, 1H), 7.95 – 7.82 (m, 3H), 7.69 (d, J = 8.7 Hz, 1H), 7.58 –
7.50 (m, 2H), 7.37 (d, J = 6.8 Hz, 5H), 5.97 (d, J = 9.9 Hz, 1H),
5.85 – 5.69 (m, 1H), 4.80 (d, J = 8.5 Hz, 1H), 1.16 (s, 9H).
Analytical and spectral data were in agreement with the literature
data.44
1
=28.33min, tminor =20.26min)]. H NMR (300 MHz, CDCl3) δ
7.84 – 7.75 (m, 1H), 7.37 (s, 6H), 7.22 (d, J = 7.5 Hz, 1H), 7.16 –
7.08 (m, 1H), 6.21 (d, J = 10.4 Hz, 1H), 5.72 (s, 1H), 4.90 (d, J =
9.2 Hz, 1H), 1.23 (s, 9H). Analytical and spectral data were in
agreement with the literature data.44
4.7.75. tert-butyl (1S,2R)-2-(3-methoxyphenyl)-2-nitro-1-
phenylethyl carbamate (6m).
Acknowledgments
25
White solid, 32.5mg, 87% yield, mp = 179-181 ℃, [a]D
=
We thank the financial support from the National Natural
Science Foundation of China (No. 51373067).
29.2 (c = 0.5, CHCl3). Enantiomeric excess and diastereomer
ratio were established by HPLC analysis, ee = 97%, dr = 93:7
[Chiralpak IA-3, hexane/i-PrOH = 90:10, 210 nm, Major- (tmajor
=
=
References and notes
42.36 min, tminor = 21.51 min), Minor- (tmajor = 23.19 min, tminor
17.15 min)]. 1H NMR (300 MHz, CDCl3) δ 7.41 – 7.32 (m, 6H),
7.32 – 7.28 (m, 1H), 7.15 – 7.09 (m, 2H), 7.00 – 6.93 (m, 1H),
5.79 – 5.63 (m, 2H), 4.77 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 1.27
(s, 9H). Analytical and spectral data were in agreement with the
literature data.44
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ACCEPTED MANUSCRIPT
1. A series of bifunctional APT catalysts derived from L-tert-Leucine
2. excellent yields, high diastereo- and enantioselectivities (ee 83-95%; dr 79:21-97:3).
3. this catalyst can also catalyze aza-Henry reaction with N-Boc amidosulfones.