Direct Asymmetric Three-Component Mannich Reaction Catalyzed by Chiral Counteranion-Assisted Silver

Article abstract of DOI:10.1021/acs.joc.0c00031

Direct asymmetric three-component Mannich reaction involving simple ketones (such as cyclohexanone, acetone, and acetophenone) as donors and catalyzing by silver tartaric acid-derived phosphate was realized to afford a series of optically active β-amino-ketone derivatives in high yields (up to 96%) and good-to-high enantioselectivities (up to 97%) with moderate-to-good diastereoselectivities. This is the first example of direct catalytic asymmetric three-component Mannich reaction via a chiral counteranion-directed strategy.

Full text of DOI:10.1021/acs.joc.0c00031

Subscriber access provided by University of Birmingham
Article
Direct Asymmetric Three-Component Mannich Reaction
Catalyzed by Chiral Counteranion-Assisted Silver
Zhongyou Yin, JianXin Guo, Rui Zhang, Xiaoyun Hu, and Victor Borovkov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00031 • Publication Date (Web): 22 Jul 2020
Downloaded from pubs.acs.org on July 22, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Direct Asymmetric Three-Component Mannich Reaction
Catalyzed by Chiral Counteranion-Assisted Silver
Zhongyou Yin,† Jianxin Guo,† Rui Zhang,† Xiaoyun Hu,*,† and Victor Borovkov*,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of
Catalysis and Materials Science, South-Central University for Nationalities, Wuhan 430074, P. R. of China
‡Hubei Engineering Technology Research Center of Energy Polymer Materials, School of Chemistry and Materials
Science, South-Central University for Nationalities, Wuhan 430074, P. R. of China
R1
Ar
Ar
NH2
1e
(5mol%)
Ag2CO3 (5%mol)
PhCH3, 0 o
O
O
HO
HO
O
O
O
HN
P
O-
H
+
Ag+
+
R2
C
O
Ar
Ar
R1
R2
1e
, Ar = 4-MeC6H4
20 examples
up to 96% yield, 97% ee
ABSTRACT: Direct asymmetric three-component Mannich reaction involving simple ketones (such as cyclohexanone,
acetone and acetophenone) as donors and catalyzing by silver tartaric acid-derived phosphate was realized to afford a series
of optically active β-amino-ketone derivatives in high yields (up to 96%) and good to high enantioselectivities (up to 97%)
with moderate-to-good diastereoselectivities. This is the first example of direct catalytic asymmetric three-component
Mannich reaction via a chiral counteranion-directed strategy.
been reported yet,10 which is apparently due to the
complexity of the multicomponent reaction mechanism.11
INTRODUCTION
In order to develop this strategy, we applied a silver salt of
dihydroxyl phosphoric acid as a catalyst (Figure 1d).
The catalytic asymmetric direct Mannich reaction1 is one of
the most powerful C-C bond formation reactions for
preparation of enantiomerically enriched β-amino carbonyl
compounds and their derivatives, which have a wide-
O
O
NR2R3
R1
O
chiral catalyst
ranging biological significance2 and great versatility as
synthetic building blocks3. Due to its high atom economy
and efficiency, the direct asymmetric three-component
Mannich reaction especially attracted much attention of
synthetic chemists.4 Various types of catalysts have been
applied to this reaction so far. On the basis of different
mechanism pathways, there are several catalytic activation
modes as follows (Figure 1a-c). (a) Enamine activation; in
2000, List reported the first organocatalytic three-
component Mannich reaction catalyzed by (S)-proline.5 (b)
Brønsted acid activation; in 2007, Gong developed the first
example of chiral phosphoric-acid catalyzed three-
component Mannich reaction,6 while in 2013, Zhao applied
R5
+
NHR2R3
+
R4
R4
R1
H
R5
(a) Enamine activation
Representative catalyst5:
COOH
N
H
OBn
Ar
(b) Bronsted Acid activation
Representative catalyst6,7
CF3
:
OH
N
O
O
N
P
O
S
N
H
N
H
CF3
Ar
tBu
(c) Organometallic catalysis
Representative catalyst8,9
X
:
N
N
O
NCHMe
NCHMe
N
O
O
Rh
O
N
H
+
Ar
H
N
Ar
Sc(OTf)3
N
(d) Chiral counteranion-directed strategy
a
bifunctional quinidine thiourea derivative to this
This work:
Ar
tBu
X
reaction.7 (c) Organometallic catalysis; in 2013, Feng
described the catalytic synthesis of β-amino nitriles with
the assistance of chiral N,N’-dioxide scandium(III)
complex,8 while in 2017, Gong and co-workers reported the
use of chiral-at-metal rhodium Lewis acid catalyst in this
reaction.9 However, to best of our knowledge, no study on
the asymmetric counteranion-directed catalysis (ACDC)
applied for the direct asymmetric three-component
Mannich reaction involving simple ketones as donors has
Ar
Ar
HO
HO
O
P
O
O-
Ag+
O
Ar
Figure 1 Different catalytic activation modes of direct
three-component Mannich reaction.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
c dr = syn / anti ratio, as determined by crude 1H-NMR.
d Determined by chiral HPLC.
1
2
3
4
5
6
7
Ar
Ar
Ar
1a
1b
1c
1d
1e
: Ar = Ph
Then, a series of chiral dihydroxyl phosphoric acids 1b-
1e were tested at the same conditions. It is of note that 1e
showed the best performance yielding syn-5a in 1.5/1 dr
and 39% ee (entry 5). Though to our disappointment, the
variation of solvents (entries 6-10) and reaction
temperature (entries 11-13) did not improve the catalytic
efficiency. These results revealed that almost all dihydroxyl
phosphoric acids afforded the aimed product in good yields
with low dr and moderate ee.
Indeed, the ACDC methodology has been developed as
one of the most promising strategies for stereoselective
synthesis.13 This approach was found to be successful in
several reactions by Toste14, List15, Gong16, Sun17, Hu18 and
others19 to afford chiral products with excellent
enantioselectivity. It is known that the proton activity in
phosphoric acids is a key fact to promote the Mannich
reaction.20 Based on the above results, we assumed that the
proton activity is sufficient to promote this transformation,
while its small steric volume may be not enough for
effective enantioselective control during the activation
process.13c,20a We envisioned that introduction of a Lewis
acid bearing larger volume instead of the proton combined
with chiral phosphoric acids may considerably improve the
enantioselective control via the ACDC strategy due to its
steric hindrance.21
HO
HO
O
O
: Ar = 4-FC6H4
P
OH
t
: Ar = - BuC6H4
O
: Ar = 4-CF3C6H4
: Ar = 4-CH3C6H4
Ar
1
8
9
Figure 2 Chiral dihydroxyl phosphoric acids 1 developed
by our group.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our recent work demonstrated that chiral dihydroxyl
phosphoric acid 1a developed by our group (Figure 2) is a
new type of highly effective catalysts for asymmetric
Biginelli reaction.12 While these acids were applied to the
catalytic direct asymmetric three-component Mannich
reaction, they showed a low chiral induction efficiency (ee <
40%). However, a combination of Ag2CO3 and chiral
phosphoric acids dramatically improved the reaction
enantioselectivity (with ee up to 97%). Herein, we report
the detailed investigation of this new catalytic approach.
RESULTS AND DISCUSSION
For the initial experiment, we chose previously
developed 1a as a catalyst (Figure 2), cyclohexanone (2a),
4-methoxyaniline(3a) and 4-nitrobenzaldehyde (4a), as
substrates for the direct three-component Mannich
reaction. As shown in Table 1, this catalytic reaction was
firstly carried out with 5 mol% of 1a in toluene. As expected,
1a was able to promote this reaction, giving the product in
82% yield. However, 5a was formed in nearly1/1 syn/anti
diastereomericratio (dr) and 29% ee.
To verify this assumption, we first chose Ag2CO3 as a sole
reference catalyst (without any phosphoric acid) for this
reaction. As shown in Table 2, to our delight, 5 mol% Ag2CO3
Table 2. Optimization of reaction conditions via the ACDC
strategy a.
OMe
NH2
O
O
O
HN
1/additive
PhMe,0 o
Table 1. Optimization of reaction conditions with chiral
H
phosphoric acids 1a-ea.
+
+
C
OMe
O2N
NO2
NO2
OMe
NH2
O
2a
3a
4a
5a
1 (5 mol%)
O
HN
solvent, T o
C
+
entry catalyst (mol%) additive (mol%) yieldb drc
(%)
eed (%)
+
CHO
4a
NO2
OMe
3a
2a
5a
---
Ag2CO3(5)
Ag2CO3(5)
Ag2CO3(5)
Ag2CO3(5)
Ag2CO3(5)
Ag2CO3(5)
K2CO3(5)
76
72
84
46
95
94
78
68
73
74
36
22
94
1:1
2:1
3:1
4:1
3:1
4:1
3:1
3:1
3:1
4:1
4:1
4:1
4:1
0
1
2
entry catalyst
solvent
T
(oC)
0
yieldb
drc
ee
(%)d
1a(5)
1b(5)
1c(5)
1d(5)
1e(5)
1e(5)
1e(5)
1e(5)
1e(5)
1e(5)
1e(5)
1e(5)
54
74
52
69
90
38
37
25
69
65
60
79
(%)
82
78
48
62
76
81
-
3
1
2
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH3Cl
THF
1/1
1/1
1/1
1/1
29
4
0
34
5
3
0
28
6
4
0
31
7
5
0
1.5/1 39
Na2CO3(5)
CuCl2(5)
8
6
0
1.5/1 28
9
7
0
-
-
AgNO3(5)
Ag2CO3(10)
Ag2CO3(20)
Ag2CO3(2.5)
10
11
12
13
8
0
68
-
1.5/1 27
9
cyclohexane
toluene
0
-
-
11
12
13
-40
-20
10
49
61
83
1.5/1 35
1.5/1 36
toluene
a
Reaction conditions: a solution of 2a (2 mmol), 3a (0.2 mmol), 4a (0.2
38
toluene
1.5/1
mmol), and 1a-e in toluene (5 mL) was stirred for 48 h at 0 ºC.
b Isolated yield.
c dr = syn/anti ratio, as determined by crude 1H-NMR.
d Determined by chiral HPLC.
a Reaction conditions: a solution of 2a (2.0 mmol), 3a (0.2 mmol), 4a (0.2
mmol) and 1 (5 mol%) in a solvent (5 mL) was stirred for 48 h at the
indicated temperature.
b Isolated yield.
ACS Paragon Plus Environment

Page 3 of 10
The Journal of Organic Chemistry
itself did promote this reaction smoothly to give the desired using 4-methoxyphenylamine as a substrate, it was found
1
2
3
4
5
6
7
8
product in 75% yield (entry 1). Then with 5 mol % of 1a-1e
and 5 mol % of Ag2CO3 in toluene at 0 °C, all the reactions
proceeded efficiently to give the desired product 5a in
good-to-high ee (entries 2-6). That is to say, the addition of
Ag2CO3 in this catalytic system dramatically improves the
enantioselective control for asymmetric Mannich reaction,
especially in term of the ee and dr values being increased by
up to 50% for 1e (entry 6).
that the stereochemical outcome depends significantly on
the electronic properties and steric hindrance of
benzaldehyde’s substituent. Hence, the electron-
withdrawing groups such as NO2 and Cl gave 90% and 97%
ee (entry 1, 2), while sterically hindered tBu was not able to
afford the aimed product (entry 3). When phenylamine was
used as a substrate, 4-chlorobenzaldehyde also gave
excellent ee (entry 4), while the ee values in the case of 4-
fluoro- and 4-bromobenzaldehydes were slightly lower
(entries 5, 8). The influence of fluorine group at the ortho-,
meta-, and para-positions of benzaldehyde was examined
with almost the same enantioselectivities obtained (entries
6, 7, 8). The enantioselectivities and reactivities were
further decreased upon using electron-withdrawing groups
in the case 4-trifluoromethyl- and 4-cyanobenzaldehydes
(entries 9, 10). The influence of 4-methyl substitution of
To further confirm a special role of Ag+ in this asymmetric
catalysis, other carbonates such as K2CO3 and Na2CO3 were
tested in the presence of 1e in toluene at 0 °C. As one can
see, a significant decrease of the optical purity of 5a was
observed (entries 7, 8). Also, another Lewis acid, such as
CuCl2, was tried, but it showed the lowest ee value of only
25% (entry 9). In the case of AgNO3 the ee value was found
to be 69% (entry 10), hence indicating a positive role of Ag+
in this catalytic system. To further confirm this deduction,
both increasing and decreasing the Ag2CO3 loading were
studied and noticeable lowering the ee values was observed
(entries 11-13). Obviously, addition of the equimolar
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
arylamine
was
also
analyzed
by
using
4-
methylphenylamine and 4-bromo- or 4-chlorobenz-
aldehydes, which furnished the aimed products in 70 and
74% ee, respectively (entries 11, 12). Hence, it is clear that
both the electronic properties and steric hindrance of the
substituent on benzaldehydes and anilines strongly affect
the reaction stereoselectivity, with the diastereomeric
ratios ranging from 1/1 to 4/1.
To further examine the scope of arylamines for this
asymmetric catalytic reaction, differently substituted
anilines were investigated using 4-nitrobenzaldehyde as a
substrate. As shown in Table 4, in general the electron-
2-
amount of CO3 anion is favorable for the generation of
chiral phosphoric acid anion, which in turn is able to
effectively form an ion pair with Ag+. These control
experiments further confirmed that the equimolar amounts
of Ag+ and 1e result in the efficient enantioselective control
via the ACDC strategy.
With the optimized conditions in hand, the direct
Mannich reaction of various benzaldehydes, 4-substituted
arylamines and cyclohexanone was examined by using the
ACDC strategy. As shown in Table 3, the majority of
reactions proceeded smoothly in the presence of the
established combination of 5 mol % of 1e and Ag2CO3 to
yield the corresponding syn-form as the main product in
good-to-excellent enantioselectivities. For example, upon
donating groups had
a
positive effect on the
enantioselectivity and furnished the Mannich reaction
products in excellent yields with up to 97% ee (entries 1, 2),
while the electron-withdrawing groups had a deleterious
effect (entries 3, 4, 5). However, introducing the electron-
withdrawing groups such as Br and NO2 at the meta-
position had a positive impact on the ee values, apparently
as a result of reduction of the electron-withdrawing effect
due to decreasing the corresponding π conjugation (entries
6, 7).
Table 3. The scope of three-component direct asymmetric
Mannich reactions catalyzed via ACDC strategya.
R1
NH2
1e(5mol%)
O
O
O
HN
Ag2CO3(5%mol)
PhCH3, 0 o
Table 4. The scope of three-component direct asymmetric
H
+
+
R2
C
Mannich reactions by using differently substituted anilines.a
R1
R
R2
5
1e
(5mol%)
NH2
O
O
O
HN
Ag2CO3(5%mol)
entry
R1
R2
5
yield (%)b
drc
ee (%)d
H
+
PhCH3, 0 o
C
+
O2N
OMe
OMe
OMe
H
4-NO2
4-Cl
4-tBu
4-Cl
4-Br
3-F
5a
5b
--
94
68
--
4:1
3:1
--
90
97
--
1
2
R
NO2
5
3
entry
R
5
yield (%)b
drc
ee (%)d
5c
5d
5e
5f
87
85
87
75
47
54
35
73
75
2:1
3:1
2:1
1:1
3:1
3:1
3:1
4:1
4:1
96
85
85
84
85
77
73
74
70
4
H
4-H
5l
95
96
56
59
53
73
67
3:1
4:1
2:1
1:1
1:1
1:1
1:1
90
97
47
77
59
90
89
5
1
2
3
4
5
6
7
H
6
4-CH3
4-Br
5m
5n
5o
5p
5q
5r
H
2-F
7
H
4-F
5g
5h
5i
8
4-Cl
H
4-CF3
4-CN
4-Cl
4-Br
9
4-NO2
3-Br
H
10
11
12
CH3
CH3
5j
3-NO2
5k
a These reactions were performed on 0.2mmol scale for 48 h at 0 ºC.
b Isolated yield.
a These reactions were performed on 0.2mmol scale for 48 h at 0 ºC.
b Isolated yield.
c dr = syn/anti, determined by crude 1H-NMR.
d Determined by chiral HPLC.
c dr = syn/anti ratio, as determined by 1H-NMR.
d Determined by chiral HPLC.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
It should be pointed out that beside cyclohexanone
Page 4 of 10
1
2
3
4
5
6
7
8
acyclic ketones such as acetone and acetophenone can be
used in the ACDC reaction. As shown in Scheme 1, the
reaction of acetone, 4-methoxyaniline and 4-
nitrobenzaldehyde catalyzed by 1e and Ag2CO3 furnished
the target product in 94% ee (Scheme 1). However, the
reaction of acetophenone, aniline and 4-nitrobenzaldehyde
gave the desired product in 45% ee. Obviously, the
introduction of phenyl into ketone substrate not only
decreased the reactivity (only trace desired product was
obtained when the reaction was carried at 0 °C), but also
reduced the stereoselectivity. It was found that
stereoselectivity was also related to the reaction
temperature. For example, the reaction gave the target
product in 34% ee at 20 °C.
Scheme 3 Synthesis of chiral phosphoric acid 1f.
Ar
Ar
Ar
Ar
1. PCl3/Et3N
Ar
Ar
MeO
MeO
HO
HO
O
1) NaH
2) CH3I
MeO
MeO
OH 2. I2/Py-H2O
O
OH
OH
Ar
P
OH
OH 3. H3O+
Ar
O
Ar
Ar
Ar
Ar
7
8
1f
Ar =
Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
catalyzed by using 1f via ACDC strategy under the optimized
conditions, afforded the corresponding product in 67%
yield and 63% ee. Compared with 1e, both the yield and
enantioselectivity of this reaction dropped dramatically.
Obviously, the free hydroxyl groups in chiral phosphoric
acids 1e played an important role in this enantioselective
transformation.
Scheme 1 ACDC reaction of acyclic ketones.
Based on these results and Rueping’s work23, a plausible
mechanism was proposed as follows. As shown in Figure 3,
Ag+ activates the imine, which is formed by condensation of
aromatic aldehyde with aromatic amine. The two free
hydroxyl groups form both a five-numbered intramolecular
and seven-numbered intermolecular H bond rings with
corresponding enolizable ketone. This rigid transition state
structure is favorable for stereoselective attack of enol on
the imine. Once the two hydroxyl groups are etherified, the
enolizable ketone was activated by the oxygen atom of
phosphoryl group resulting in the loss of rigid structure and
consequently leading to low enantioselectivity.
OMe
NH2
1e
(5mol%)
O
O
O
HN
Ag2CO3(5%mol)
PhCH3, 0 o
H
+
+
C
O2N
NO2
6a
48% yield, 94% ee
OMe
NH2
1e
(5mol%)
Ag2CO3(5%mol)
PhCH3, 10 o
O
O
O
HN
H
+
+
Ph
Ph
C
O2N
NO2
6b
52% yield, 45% ee
The catalytic results prompted us to further examine the
feasibility of its scale-up. Then the asymmetric catalytic
reaction of cyclohexanone (2a), 4-methoxyaniline (3a) and
4-nitrobenzaldehyde (4a) was scaled up to 1.0 mmol. After
performing the reaction under the optimal conditions for 60
hours, an isolated yield of 87% with 90% ee was obtained
(Scheme 2). The scaled-up catalytic synthesis reduces the
yield, while the stereoselectivity was not affected.
Ar1
Ar2
N
N
Ar1
Ar
Ar2
Ag+
O
O
Ar
Ag+
O-
Ar
Ar
Ar
O
O-
H
H
O
P
O
O
P
O
O
H
H
H
H
O
O
O
O
Ar
Ar
Ar
favored transition state
disfavored transition state
Scheme 2 Scale-up of the ACDC reaction of cyclohexanone,
4-methoxyaniline, and 4-nitrobenzaldehyde.
OMe
Figure 3 The proposed activation model and reaction
pathway of the stereogenic step in the direct asymmetric
Mannich reactions catalyzed via the ACDC strategy.
1e
(5mol%)
Ag2CO3(5%mol)
PhCH3, 0 o
O
NH2
O
O
HN
H
+
+
C
O2N
NO2
OMe
2a
3a
4a
(1 mmol)
5a
87% yield, 90% ee
(1 mmol) (1 mmol)
CONCLUSION
In conclusion, we developed a new catalytic system for the
direct asymmetric three-component Mannich reaction
catalyzed by silver tartaric acid-derived phosphate system.
It was established that the equimolar (5 mol%) amount of
phosphoric acid 1e and Ag2CO3 efficiently increase the
reaction performance of a range of aromatic aldehydes and
amines, affording anti-β-amino carbonyls in high yields,
good to high enantioselectivities (up to 97%), and
To further confirm the importance of two free hydroxyl
groups of chiral phosphoric acids 1 in the catalytic
asymmetric direct Mannich reaction, chiral phosphoric acid
1f with methylated OH groups was synthesized according to
the previously reported method22 (Scheme 3).
As a result, the control reaction of cyclohexanone, 4-
methylbenzeneamine and 4-nitrobenzaldehyde, which was
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
moderate-to-good diastereomeric ratios. The control
(5R,6R)-4,4,7,7-tetrakis(4-(tert-butyl)phenyl)-2,5,6-
1
2
3
4
5
6
7
8
experiment indicated that the presence of two free hydroxyl
groups has an important influence for both the reaction
yield and enantioselectivity. Based on these results, a
possible activation model was proposed. This is the first
report of catalytic direct asymmetric three-component
Mannich reaction involving simple ketones (such as
cyclohexanone, acetone and acetophenone) as donors via
the ACDC strategy.
trihydroxy-1,3,2-dioxaphosphepane 2-oxide (1c): The
product was obtained as a white solid (43% ,1.53 g), m.p.:
162-165 °C, [α]D25= -51.2(c = 0.30, MeOH). 1H NMR (400
MHz, DMSO-d6) δ 7.43 (d, J = 8.1 Hz, 8H), 7.32-7.28 (m,
8H), 5.63 (s, 2H), 4.67 (s, 2H), 1.25 (d, J = 13.7 Hz, 36H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 148.8, 144.0, 139.8,
128.5, 127.7, 124.3, 84.4, 34.5, 31.7. Anal. calc. for
C44H57O6P: C 74.13, H 8.06; found: C 74.08, H 8.03.
(5R,6R)-2,5,6-trihydroxy-4,4,7,7-tetrakis(4-(trifluoro-
methyl)phenyl)-1,3,2-dioxaphosphepane 2-oxide (1d)： The
product was obtained as a light yellow solid (56%, 2.13 g),
m.p.: 157-160 °C, [α]D25= -38(c = 0.30, MeOH).1H NMR
(400 MHz, DMSO-d6) δ 7.71 (d, J = 10.5 Hz, 12H), 7.53 (d,
J = 8.2 Hz, 4H), 5.99 (s, 2H, OH), 4.73 (s, 2H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 149.2, 145.1, 129.6, 128.5
(J= 32.3 Hz), 125.1 (J= 3.5 Hz), 124.7 (J= 272.7 Hz), 82.6,
72.1. Anal. calc. for C32H21F12O6P: C 50.54, H 2.78; found:
C 50.51, H 2.77.
9
EXPERIMENTAL SECTION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Materials and methods. H and 13C NMR spectra were
obtained on a 600 or 400 MHz NMR spectrometer. The
chemical shifts are referenced to signals at 7.26 or 2.50
ppm, respectively, using CDCl3 or DMSO-d6 as solvents.
Silica gel (300-400 mesh) was used for flash column
chromatograph, HPLC analysis was performed on Waters-
Breeze (2487 Dual Absorbance Detector and 1525 Binary
HPLC Pump). Chiralpak AS, AD, OJ were purchased from
Daicel Chemical Industries, LTD. Solvents for the column
chromatography were distilled before use. The racemic
standards used in HPLC studies were prepared according to
literatures.
General Procedure for the Synthesis of (5R,6R)-1.
Under an argon atmosphere, the flask was poured into
freshly-purified THF (10 mL), evaporated to Et3N (2.8 mL,
20 mmol), and slowly re-evaporated PCl3 (1.3 mL, 15 mmol)
and stirred at 0 °C for 15 min. Chiral cyclic sulfite esters24
bearing dihydroxyl groups (5 mmol) in THF was slowly
added dropwise to the reaction flask. After the addition was
completed, the mixture was stirred for 1 h, then Et3N and
H2O (1:1, 4 mL) were added. Stirring was continued for 1 h,
the temperature was slowly raised to 25 °C and stirred for
30 min. Further, an aqueous solution of I2 (4.1 g, 16 mmol)
and Py (2.6 mL, 32 mmol) in THF (15 mL) was added, and
stirred at 25 °C for 1 h. Saturated NaHSO3 solution (25 mL)
was added and stirred for 30 min. Then 2 mol/L sodium
hydroxide solution was added and adjusted the pH to 10,
the reaction solution was slowly dropped into a beaker
containing 3% dilute hydrochloric acid (80 mL). The
isolated white solid was filtered and recrystallized from
ethanol.
(5R,6R)-2,5,6-trihydroxy-4,4,7,7-tetra-p-tolyl-1,3,2-
dioxaphosphepane 2-oxide (1e): The product was obtained
as a white solid (52%, 1.42 g), m.p.: 175-180 °C, [α]D25= -
1
58.7(c = 0.30, MeOH). H NMR (400 MHz, DMSO-d6) δ
7.45 (d, J = 7.9 Hz, 4H), 7.23 (d, J = 7.8 Hz, 4H), 7.03 (d, J
= 7.9 Hz, 4H), 6.96 (d, J = 7.9 Hz, 4H), 5.25 (s, 2H), 4.79 (s,
2H), 2.23 (d, J = 19.0 Hz, 12H).13C{1H} NMR (101 MHz,
DMSO-d6) δ 144.9, 140.7, 135.4, 129.0, 128.3, 127.8, 83.3,
72.0, 21.1. Anal. calc. for C32H33O6P: C 70.58, H 6.11;
found: C 70.55, H 6.09.
Procedure for the Synthesis of 1f. A dried round
bottom flask was charged with 1,1,4,4-tetratolyl-1,4-diol25
(1 mmol), sodium hydride (2 mmol) and dried THF (12 mL).
The mixture was stirred at room temperature for 2 h, and
then added methyl iodide (2.1 mmol) and stirred overnight
at room temperature. To the stirred reaction mixture was
added distilled water (10 mL) and diethyl ether (15 mL) to
form a two-phase solution. The upper organic phase was
separated, dried over anhydrous sodium sulfate, then the
solution was concentrated to dryness and the solid residue
was recrystallized with ethanol to afford diol 8. And then 1f
was prepared according to the above procedure.
(2R,3R)-2,3-dimethoxy-1,1,4,4-tetrap-tolylbutane-1,4-
diol (8): The product was obtained as a white solid (64%,
0.33 g), m.p.:107-110 °C, [α]D25= -46.7(c = 0.12, MeOH).
1H NMR (400 MHz, Chloroform-d) δ 7.50 (dd, J = 21.9, 8.0
Hz, 8H), 7.25 (d, J = 8.0 Hz, 4H), 7.06 (d, J = 8.0 Hz, 4H),
4.93 (s, 2H), 4.42 (s, 2H), 2.61 (s, 6H), 2.39 (s, 6H), 2.26 (s,
6H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 143.0,
142.3, 136.6, 136.2, 129.1, 128.6, 126.0, 125.7, 85.4, 80.0,
77.4, 77.1, 76.8, 61.1, 21.1, 20.9. Anal. calc. for C34H38O4:
C 79.97, H 7.50; found: C 79.93, H 7.47.
(5R,6R)-2-hydroxy-5,6-dimethoxy-4,4,7,7-tetrap-tolyl-
butane-1,3,2-dioxaphosphepane 2-oxide (1f): The product
was obtained as a white solid (56%, 0.21 g), m.p.:200-
204 °C, [α]D25= -92.0 (c = 0.10, MeOH).1H NMR (400 MHz,
Chloroform-d) δ 7.36 (d, J = 7.2 Hz, 4H), 7.25 (d, J = 7.0
Hz, 5H), 7.02 (d, J = 7.9 Hz, 4H), 6.91 (d, J = 7.6 Hz, 4H),
4.66 (s, 2H), 2.84 (s, 6H), 2.26 (s, 6H), 2.20 (s, 6H). 13C{1H}
NMR (101 MHz, Chloroform-d) δ 142.0, 138.8, 136.7,
136.3, 129.0, 128.3, 127.7, 127.5, 84.8, 79.5, 58.8, 21.0, 21.0,
(5R,6R)-2,5,6-trihydroxy-4,4,7,7-tetraphenyl-1,3,2-
dioxaphosphepane 2-oxide (1a)12: The product was obtained
as a white solid (65% ,1.59 g), m.p.: 100-101 °C, [α]D25= -
1
76.1(c = 0.30, MeOH). H NMR (400 MHz, DMSO-d6) δ
7.50 (d, J = 7.8 Hz, 4H), 7.35-7.19 (m, 16H, Ar-H), 5.67 (s,
2H, OH), 4.75 (s, 2H, CH). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 145.4, 141.3, 128.7, 127.8, 86.6, 71.6.
(5R,6R)-4,4,7,7-tetrakis(4-fluorophenyl)-2,5,6-
trihydroxy-1,3,2-dioxaphosphepane 2-oxide (1b): The
product was obtained as a white solid (51% ,1.43 g), m.p.:
158-160 °C, [α]D25= -71.3(c = 0.15, MeOH). 1H NMR (400
MHz, DMSO-d6) δ 7.56 (dd, J = 8.4, 5.8 Hz, 4H), 7.35 (dd,
J = 8.5, 5.8 Hz, 4H), 7.04 (dt, J = 22.5, 8.8 Hz, 8H), 5.43 (s,
2H), 4.72 (s, 2H). 13C{1H} NMR (151 MHz, DMSO-d6) δ
162.2 (J = 23.7 Hz), 160.6 (J = 23.6 Hz), 130.9 (J = 7.8 Hz),
130.08 (J = 7.9 Hz), 114.2 (J = 8.3 Hz), 114.0 (J = 8.1 Hz),
82.6, 72.1. Anal. calc. for C28H21F4O6P: C 60.01, H 3.78;
found: C 59.97, H 3.77.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
20.9, 20.9. Anal. calc. for C34H37O6P: C 71.31, H 6.51; (400 MHz, Chloroform-d) δ 7.33-7.23 (m, 6H), 6.69-6.63 (m,
1
2
3
4
5
6
7
8
found: C 71.27, H 6.49.
2H), 6.50-6.42 (m, 2H), 4.66 (d, J = 4.1 Hz, 1H), 4.51 (d, J
= 6.8 Hz, 1H), 3.68 (d, J = 2.4 Hz, 3H), 2.70 (d, J = 14.8 Hz,
1H), 2.48-2.28 (m, 2H), 1.99 (d, J = 33.3 Hz, 3H), 1.84 (dd,
J = 22.0, 9.9 Hz, 3H).13C{1H} NMR (101 MHz, Chloroform-
d) δ 212.5, 140.5, 132.8, 129.0, 128.8, 128.6, 128.5, 115.7,
115.3, 114.7, 58.6, 57.4, 55.7, 42.0, 31.4, 27.8, 24.0. The
enantiomeric excess is 96% determined by HPLC (Daicel
Chirapak AS-H, hexane/ isopropanol= 95: 5, flow rate 1.0
mL/min): syn-diastereomer, tR = 11.6 min (major), tR = 15.2
min (minor).
General Procedure of Asymmetric Mannich Reaction.
A tube (10 mL) were charged with aniline (0.2 mmol),
aromatic aldehyde (0.22 mmol), 1e (5.4 mg, 0.01 mmol) and
toluene (5 mL). After being stirred at room temperature for
30 minutes, the reaction mixture was cooled down to 0 °C
and cyclohexanone (0.4 mL, 4 mmol) was added to the
mixture. The resultant reaction solution was stirred at 0 °C
until the reaction was complete (monitored by TLC). After
removal of the solvent, the residue was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 8:1 to 3:1) to yield pure product 5.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-2-((S)-(4-bromophenyl)(phenylamino)methyl)
cyclohexanone (5d)27: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 8:1) and obtained as brown oil (85%, 61.5 mg),
Scale-up Synthesis. To a round-bottom flask were
charged 4-methoxyaniline (0.123 g, 1.0 mmol), 4-
nitrobenzaldehyde (0.166 g, 1.1 mmol), 1e (0.027 g, 0.05
mmol) and toluene (15 mL), and the mixture was stirred at
room temperature for 30 minutes. Then cyclohexanone (2.0
mL, 20 mmol) was added after the reaction mixture cooled
down to 0 °C, and the resultant reaction solution was stirred
at 0 °C for 60 hours. The solvent was removed and the
residue was purified through column chromatography on
silica gel to afford product 5a (0.301 g, 90% ee, 87% yield).
(S)-2-((S)-(4-methoxyphenylamino)(4-nitrophenyl)
1
syn/anti = 3:1; [α]D25= +18.4(c = 0.10, CHCl3). H NMR
(400 MHz, Chloroform-d) δ 7.41 (dd, J = 8.4, 3.5 Hz, 2H),
7.29-7.22 (m, 3H), 7.12-7.03 (m, 2H), 6.65 (q, J = 7.2 Hz,
1H), 6.55-6.45 (m, 2H), 4.72 (d, J = 4.2 Hz, 1H), 4.58 (d, J
= 6.3 Hz, 1H), 2.74 (s, 1H), 2.40 (t, J = 9.8 Hz, 1H), 2.37-
2.26 (m, 1H), 2.05-1.86 (m, 3H), 1.74-1.55 (m, 3H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 212.3, 147.0,
140.9, 131.6, 131.5, 129.4, 129.1, 118.0, 117.8, 114.1, 113.6,
57.6, 57.3, 57.1, 56.4, 42.4, 42.0, 31.5, 28.9, 27.8, 27.0, 24.0.
The enantiomeric excess is 85% determined by HPLC
(Daicel Chirapak AS-H, hexane/ isopropanol= 95: 5, flow
rate 1.0 mL/min): syn-diastereomer, tR = 12.2 min (major),
tR = 15.6 min (minor).
methyl)cyclohexanone (5a)6: The product was purified
through column chromatography on silica gel (petroleum
ether: ethyl acetate = 3:1) and obtained as light yellow oil
(94%, 67.2 mg), syn/anti = 4:1; [α]D25= +27.6 (c = 0.15,
1
CHCl3). H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J =
(S)-2-((S)-(3-fluorophenyl)(phenylamino)methyl)
8.8 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.9 Hz,
2H), 6.45 (d, J = 9.0 Hz, 2H), 4.63 (d, J = 5.6 Hz, 1H), 3.68
(s, 3H), 2.89-2.75 (m, 1H), 2.46-2.27 (m, 2H), 1.94 (s, 3H),
1.73 (t, J = 10.6 Hz, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 211.8, 152.6, 150.0, 147.1, 140.7, 128.6,
128.4, 123.7, 123.6, 115.7, 115.2, 114.8, 114.7, 58.8, 57.1,
55.7, 42.4, 31.9, 27.8, 24.5. The enantiomeric excess is 90%
determined by HPLC (Daicel Chirapak AD-H, hexane/
isopropanol= 70: 30, flow rate 1.0 mL/min): syn-
diastereomer, tR = 10.5 min (major), tR = 11.7 min (minor).
(S)-2-((S)-(4-chlorophenyl)(4-methoxyphenylamino)
cyclohexanone (5e)28: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 8:1) and obtained as light yellow oil (87%, 57.2
1
mg), syn/anti = 2:1; [α]D25= +12.7(c = 0.30, CHCl3). H
NMR (400 MHz, Chloroform-d) δ 7.30-7.24 (m, 1H), 7.21-
7.03 (m, 4H), 6.91 (t, J = 8.3 Hz, 1H), 6.67 (q, J = 7.3 Hz,
1H), 6.60-6.47 (m, 2H), 4.79 (d, J = 4.0 Hz, 1H), 4.62 (d, J
= 6.5 Hz, 1H), 2.78 (s, 1H), 2.38 (dd, J = 31.5, 5.2 Hz, 2H),
1.91 (d, J = 10.5 Hz, 2H), 1.83- 1.55 (m, 3H). 13C{1H} NMR
(101 MHz, Chloroform-d) δ 212.2, 164.3, 161.9, 147.1 (J =
13.8 Hz), 129.9 (J = 8.1 Hz), 129.1 (J = 6.6 Hz), 123.0 (d, J
= 2.7 Hz), 118.0, 117.8, 114.1, 113.6, 57.7, 57.3, 57.1, 56.4,
42.4, 42.0, 31.5, 28.8, 27.9, 27.8, 27.0, 24.9, 24.0. The
enantiomeric excess is 85% determined by HPLC (Daicel
Chirapak OJ-H, hexane/ isopropanol= 85: 15, flow rate 1.0
mL/min): syn-diastereomer, tR = 12.8 min (major), tR = 15.3
min (minor).
methyl)cyclohexanone (5b)26: The product was purified
through column chromatography on silica gel (petroleum
ether: ethyl acetate = 6:1) and obtained as yellow oil (68%,
47.5 mg), syn/anti = 3:1; [α]D25= +46.7(c = 0.20, CHCl3). 1H
NMR (400 MHz, Chloroform-d) δ 7.33-7.23 (m, 6H), 6.69-
6.63 (m, 2H), 6.50-6.42 (m, 2H), 4.66 (d, J = 4.1 Hz, 1H),
4.51 (d, J = 6.8 Hz, 1H), 3.68 (d, J = 2.4 Hz, 3H), 2.70 (d, J
=14.8 Hz, 1H), 2.48-2.28 (m, 2H), 1.99 (d, J = 33.3 Hz,
3H),1.84 (dd, J = 22.0, 9.9 Hz, 3H).13C{1H} NMR (101
MHz, Chloroform-d) δ 212.5, 140.5, 132.8, 129.0, 128.8,
128.6, 128.5, 115.6, 115.3, 114.7, 58.6, 57.4, 55.7, 42.0, 31.4,
27.8, 24.0. The enantiomeric excess is 97% determined by
HPLC (Daicel Chirapak AD-H, hexane/isopropanol= 95:5,
flow rate 1.0 mL/min): syn-diastereomer, tR = 19.6 min
(major), tR = 23.2 min (minor).
(S)-2-((S)-(2-fluorophenyl)(phenylamino)methyl)
cyclohexanone (5f)28: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 7:1) and obtained as light yellow oil (75%, 45.2
1
mg), syn/anti = 1:1; [α]D25= +51.4(c = 0.20, CHCl3). H
NMR (400 MHz, Chloroform-d) δ 7.53-7.41 (m, 1H), 7.19
(dd, J = 13.5, 6.2 Hz, 1H), 7.14-6.95 (m, 4H), 6.72-6.53 (m,
3H), 5.14 (d, J = 5.3 Hz, 1H), 4.94 (d, J = 6.5 Hz, 1H), 4.75
(s, 1H), 3.01-2.81 (m, 1H), 2.50-2.27 (m, 2H), 2.18 (d, J =
10.5 Hz, 1H), 2.11-1.78 (m, 4H), 1.79-1.52 (m, 3H).13C{1H}
NMR (101 MHz, Chloroform-d) δ 211.3, 162.1 (J = 30.6
Hz), 159. (J = 31.1 Hz), 147.0 (J = 18.8 Hz), 129.9 (J = 4.4
Hz), 129.17 (J = 4.5 Hz), 124.4 (J = 3.3 Hz), 124.2 (J = 3.2
Hz), 115.2, 113.8, 113.4, 56.3 , 51.0, 42.5, 42.4, 42.1, 32.0,
(S)-2-((S)-(4-chlorophenyl)(phenylamino)methyl)
cyclohexanone (5c)27: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 8:1) and obtained as yellow oil (87%, 55.6 mg),
syn/anti = 2:1; [α]D25= +29.1(c = 0.16, CHCl3). H NMR
1
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
29.2, 28.1 27.3, 24.8, 24.0. The enantiomeric excess is 84%
= 4:1; [α]D25= +12.8(c = 0.15, CHCl3). 1H NMR (400 MHz,
1
2
3
4
5
6
7
8
determined by HPLC (Daicel Chirapak OJ-H, hexane/
isopropanol= 95: 5, flow rate 1.0 mL/min): syn-diastereomer,
tR = 14.4 min (major), tR = 21.6 min (minor).
Chloroform-d) δ 7.30 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 6.9 Hz,
3H), 6.88 (d, J = 8.2 Hz, 2H), 6.42 (d, J = 8.2 Hz, 2H), 4.70
(d, J = 4.3 Hz, 1H), 4.57 (d, J = 6.6 Hz, 1H), 2.71 (s, 1H),
2.41 (t, J = 9.5 Hz, 1H), 2.37-2.26 (m, 1H), 2.17 (d, J = 3.0
Hz, 3H), 1.93 (dd, J = 33.0, 28.4 Hz, 3H), 1.75 (d, J = 48.2
Hz, 3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 212.4,
144.9, 144.7, 140.5, 140.2, 132.7, 132.6, 129.6, 129.0, 128.7,
128.6, 128.5, 127.2, 127.0, 114.3, 113.8, 113.8, 57.8, 57.4,
42.0, 31.4, 27.8, 23.9, 20.3. The enantiomeric excess is 74%
determined by HPLC (Daicel Chirapak AD-H, hexane/
isopropanol= 80:20, flow rate 1.0 mL/min): syn-
diastereomer, tR = 9.1 min (major), tR = 11.0 min (minor).
(S)-2-((R)-(p-toluidino)(4-bromophenyl)methyl)cyclo-
(S)-2-((S)-(4-fluorophenyl)(phenylamino)methyl)
cyclohexanone (5g)28: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 8:1) and obtained as light yellow oil (47%, 28.6
1
mg), syn/anti = 3:1; [α]D25= +15.2(c = 0.20, CHCl3). H
NMR (400 MHz, Chloroform-d) δ 7.39-7.29 (m, 2H), 7.13-
7.04 (m, 2H), 6.98 (dd, J = 10.9, 6.4 Hz, 2H), 6.65 (q, J =
7.1 Hz, 1H), 6.52 (t, J = 6.9 Hz, 2H), 4.75 (d, J = 4.5 Hz,
1H), 4.61 (d, J = 6.6 Hz, 1H), 2.87-2.67 (m, 1H), 2.37 (dd, J
= 26.6, 5.1 Hz, 2H), 1.92 (dd, J = 15.2, 10.8 Hz, 3H), 1.80-
1.55 (m, 3H).13C{1H} NMR (101 MHz, Chloroform-d) δ
212.6, 163.1, 160.6, 147.1 (J = 20.0 Hz), 129.1 (J = 6.1 Hz),
128.8 (J = 8.0 Hz), 117.8 (J = 17.9 Hz), 115.3 (J = 31.5 Hz),
115.2 (J = 34.5 Hz), 114.1, 113.6, 57.5, 57.4, 56.9, 56.5, 42.5,
42.0, 31.4, 29.0, 27.9, 27.1, 24.9, 23.9. The enantiomeric
excess is 85% determined by HPLC (Daicel Chirapak AS-
H, hexane/ isopropanol= 85: 15, flow rate 1.0 mL/min): syn-
diastereomer, tR = 11.5 min (major), tR = 28.9 min (minor).
(S)-2-((S)-(phenylamino)(4-(trifluoromethyl)phenyl)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
hexanone (5k)29: The product was purified through column
chromatography on silica gel (petroleum ether: ethyl acetate
= 7:1) and obtained as yellow oil (75%, 56.4 mg), syn/anti =
1
4:1; [α]D25= +16.4 (c = 0.18, CHCl3). H NMR (400 MHz,
Chloroform-d) δ 7.41 (d, J = 8.3 Hz, 2H), 7.28-7.21 (m, 4H),
6.88 (d, J = 8.1 Hz, 2H), 6.43 (t, J = 6.8 Hz, 2H), 4.68 (s,
1H), 4.55 (d, J = 6.6 Hz, 2H), 2.70 (s, 1H), 2.41 (d, J = 13.4
Hz, 1H), 2.32 (d, J = 5.3 Hz, 1H), 2.17 (s, 3H), 1.89 (d, J =
9.0 Hz, 4H), 1.69 (s, 2H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 212.4, 144.7, 141.1, 131.5, 131.4, 129.6,
129.4, 129.1, 127.0, 120.8, 114.3, 113.8, 57.8, 57.3, 42.0,
31.4, 27.8, 24.0, 20.3. The enantiomeric excess is 70%
determined by HPLC (Daicel Chirapak AD-H, hexane/
isopropanol= 80: 20, flow rate 1.0 mL/min): syn-
diastereomer, tR = 9.7 min (major), tR = 11.1 min (minor).
(S)-2-((S)-(4-nitrophenyl)(phenylamino)methyl)
methyl)cyclohexanone (5h)28: The product was purified
through column chromatography on silica gel (petroleum
ether: ethyl acetate = 5:1) and obtained as brown oil (54%,
37.2 mg), syn/anti = 3:1; [α]D25= +7.8(c = 0.25, CHCl3). 1H
NMR (400 MHz, Chloroform-d) δ 7.61-7.44 (m, 4H), 7.10
(t, J = 7.3 Hz, 2H), 6.68 (dd, J = 14.5, 7.3 Hz, 1H), 6.53 (d,
J = 7.7 Hz, 2H), 4.85 (d, J = 4.2 Hz, 1H), 4.69 (d, J = 5.9 Hz,
1H), 2.88-2.75 (m, 1H), 2.38 (ddd, J = 18.8, 11.2, 3.6 Hz,
2H), 2.10-1.89 (m, 3H), 1.70 (ddd, J = 46.9, 21.0, 10.6 Hz,
3H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 211.0,
147.0, 129.2, 129.1, 128.0, 127.7, 125.4, 118.1, 117.9, 114.1,
113.6, 113.5, 57.8, 57.2, 56.3, 42.4, 42.2, 31.8, 28.9, 27.8,
27.0, 24.9, 24.2. The enantiomeric excess is 77% determined
by HPLC (Daicel Chirapak AS-H, hexane/ isopropanol= 90:
10, flow rate 1.0 mL/min): syn-diastereomer, tR = 13.0 min
(major), tR = 17.9 min (minor).
cyclohexanone (5l)6: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 5:1) and obtained as a yellow oil (95%, 62.2 mg),
1
syn/anti = 3:1; [α]D25= +34.2(c = 0.15, CHCl3). H NMR
(400 MHz, Chloroform-d) δ 8.15 (d, J = 8.7 Hz, 2H), 7.57
(t, J = 8.0 Hz, 2H), 7.09 (t, J = 7.6 Hz, 2H), 6.68 (d, J = 6.1
Hz, 1H), 6.50 (d, J = 8.1 Hz, 2H), 4.86 (d, J = 4.4 Hz, 1H),
4.72 (d, J = 5.3 Hz, 1H), 2.86 (dd, J = 10.5, 5.3 Hz, 1H),
2.49-2.27 (m, 2H), 2.00 (dt, J = 30.0, 6.2 Hz, 3H), 1.85-1.54
(m, 3H).13C NMR{1H} (101 MHz, Chloroform-d) δ 210.7,
149.9, 149.6, 147.0, 146.7, 129.3, 129.2, 128.6, 128.3, 123.7,
118.4, 118.1, 114.1, 113.5, 57.8, 57.2, 57.1, 56.2, 42.5, 32.1,
29.1, 27.8, 27.1, 24.5. The enantiomeric excess is 90%
determined by HPLC (Daicel Chirapak AD-H, hexane/
isopropanol= 95: 5, flow rate 1.0 mL/min): syn-diastereomer,
tR = 8.8 min (major), tR = 12.6 min (minor).
4-((S)-((S)-2-oxocyclohexyl)(phenylamino)methyl)
benzonitrile (5i)28: The product was purified through column
chromatography on silica gel (petroleum ether: ethyl acetate
= 5:1) and obtained as light yellow oil (35%, 21.6 mg),
syn/anti = 3:1; [α]D25= +34.4(c = 0.16, CHCl3). 1H NMR
(400 MHz, Chloroform-d) δ 7.59 (d, J = 8.3 Hz, 2H), 7.50
(t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.9 Hz, 2H), 6.67 (d, J = 6.4
Hz, 1H), 6.48 (d, J = 7.7 Hz, 2H), 4.80 (d, J = 4.4 Hz, 1H),
4.65 (d, J = 5.5 Hz, 1H), 2.88-2.75 (m, 1H), 2.49-2.26 (m,
2H), 2.12-1.89 (m, 3H), 1.84-1.59 (m, 3H).13C{1H} NMR
(101 MHz, Chloroform-d) δ 211.7, 147.7, 147.4, 146.7,
132.3, 132.2, 129.3, 129.2, 128.5, 128.2, 58.0, 57.9, 57.4,
57.1, 56.2, 42.5, 42.4, 32.0, 29.1, 27.8, 27.0, 25.0, 24.4. The
enantiomeric excess is 73% determined by HPLC (Daicel
Chirapak AS-H, hexane/ isopropanol= 80: 20, flow rate 1.0
mL/min): syn-diastereomer, tR = 19.7 min (minor), tR = 28.9
min (major).
(S)-2-((S)-(p-toluidino)(4-nitrophenyl)methyl)cyclo-
hexanone (5m)29: The product was purified through column
chromatography on silica gel (petroleum ether: ethyl acetate
= 5:1) and obtained as a light yellow oil (96%, 65.1 mg),
1
syn/anti = 4:1; [α]D25= +26.5(c = 0.20, CHCl3). H NMR
(400 MHz, Chloroform-d) δ 8.14 (d, J = 8.7 Hz, 2H), 7.56
(t, J = 8.1 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.41 (d, J = 8.4
Hz, 2H), 4.82 (d, J = 4.3 Hz, 1H), 4.68 (d, J = 5.4 Hz, 1H),
2.83 (dd, J = 10.2, 5.3 Hz, 1H), 2.50-2.27 (m, 2H), 2.18 (d,
J = 8.6 Hz, 3H), 2.05-1.89 (m, 3H), 1.82-1.66 (m, 3H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 211.9, 150.0,
147.0, 144.3, 129.8, 129.7, 128.6, 128.3, 127.4, 123.7, 114.3,
113.7, 58.0, 57.1, 42.4, 32.0, 27.8, 24.5, 20.3. The
enantiomeric excess is 97 % determined by HPLC (Daicel
(S)-2-((S)-(p-toluidino)(4-chlorophenyl)methyl) cyclo-
hexanone (5j)29: The product was purified through column
chromatography on silica gel (petroleum ether: ethyl acetate
= 7:1) and obtained as a yellow oil (73%, 48.3 mg), syn/anti
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
Chirapak AD-H, hexane/ isopropanol= 80: 20, flow rate 1.0
mL/min): syn-diastereomer, tR = 12.6 min (major), tR =15.5
min (minor).
syn/anti = 1:1; [α]D25= +32(c=0.35, CHCl3). 1H NMR (400
1
2
MHz, Chloroform-d) δ 8.16 (d, J = 8.3 Hz, 2H), 7.54 (dd, J
= 8.6, 5.3 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.92 (td, J = 8.0,
2.9 Hz, 1H), 6.77 (dd, J = 14.1, 7.1 Hz, 1H), 6.64 (dd, J =
3.9, 2.0 Hz, 1H), 6.47-6.33 (m, 1H), 5.04 (s, 1H), 4.80 (d, J
= 4.4 Hz, 1H), 4.71 (d, J = 5.9 Hz, 1H), 4.63 (s, 1H), 2.96-
2.77 (m, 1H), 2.57 (d, J = 7.6 Hz, 1H), 2.50-2.27 (m, 2H),
2.25-2.19 (m, 1H), 2.14-1.85 (m, 3H), 1.77 (dd, J = 20.7,
10.3 Hz, 2H). 13C{1H} NMR (101 MHz, Chloroform-d) δ
210.5, 149.2, 148.7, 148.1, 147.2, 130.6, 128.9, 128.6,
128.1, 123.8, 123.3, 123.1, 121.3, 121.0, 116.8, 116.2,
115.1, 112.5, 112.1, 57.9, 57.2, 56.9, 56.0, 42.6, 42.4, 32.4,
29.8, 29.3, 29.1, 27.9, 26.9, 24.9, 24.6. The enantiomeric
excess is 90% determined by HPLC (Daicel Chirapak AD-
H, hexane/ isopropanol= 90:10, flow rate 0.8 mL/min): syn-
diastereomer, tR = 15.5 min (major), tR = 24.5 min (minor).
(S)-2-((S)-(4-nitrophenyl)(3-nitrophenylamino)methyl)
cyclohexanone (5r)29: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 3:1) and obtained as yellow oil (67%, 49.6 mg),
syn/anti =1:1; [α]D25= +6.7(c=0.30, CHCl3). 1H NMR (400
MHz, Chloroform-d) δ 8.18 (dd, J = 8.7, 1.7 Hz, 2H), 7.58
(dd, J = 8.7, 3.2 Hz, 2H), 7.54-7.46 (m, 1H), 7.30 (d, J = 8.8
Hz, 1H), 7.21 (d, J = 4.2 Hz, 1H), 6.79 (ddd, J = 13.6, 8.0,
2.1 Hz, 1H), 5.38 (s, 1H), 5.10 (d, J = 6.2 Hz, 1H), 4.93-4.85
(m, 1H), 4.70 (s, 1H), 2.98-2.82 (m, 1H), 2.39 (ddd, J = 23.2,
19.1, 9.2 Hz, 2H), 2.19-1.88 (m, 3H), 1.83-1.49 (m, 4H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 210.6, 148.5,
148.0, 147.7, 147.5, 129.9, 128.6, 128.2, 123.9, 119.7,
119.5, 113.0, 112.8, 107.9, 107.1, 56.8, 55.7, 42.8, 42.4,
32.7, 28.9, 28.0, 26.9 24.9, 24.7. The enantiomeric excess is
89% determined by HPLC (Daicel Chirapak AD-H,
hexane/isopropanol= 80:20, flow rate 1.0 mL/min): syn-
diastereomer, tR = 12.9 min (major), tR = 15.8 min (minor).
(S)-4-(4-methoxyphenylamino)-4-(4-nitrophenyl)butan-
2-one (6a)27: The product was purified through column
chromatography on silica gel (petroleum ether: ethyl acetate
= 3:1) and obtained as a slight yellow oil (48%, 32.1 mg),
[α]D25= +5.4(c = 0.18, CHCl3).1H NMR (400 MHz,
Chloroform-d)) δ 8.17 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6
Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 6.45 (d, J = 8.8 Hz, 2H),
4.85 (t, J = 6.1 Hz, 1H), 4.29 (s, 1H), 3.72 (d, J = 21.9 Hz,
3H), 2.95 (d, J = 6.2 Hz, 2H), 2.15 (s, 3H). 13C{1H} NMR
(101 MHz, Chloroform-d) δ 206.0, 152.9, 150.7, 147.3,
140.2, 127.4, 124.0, 115.5, 114.9, 60.4, 55.7, 54.8, 50.7, 30.7,
21.0, 14.2. The enantiomeric excess is 94% determined by
HPLC (Daicel Chirapak AD-H, hexane/ isopropanol= 70:30,
flow rate 1.0 mL/min): syn-diastereomer, tR = 8.8 min
(major), tR = 12.6 min (minor).
3
4
5
6
7
8
9
(R)-2-((S)-(4-bromophenylamino)(4-nitrophenyl)methyl)
cyclohexanone (5n)29 The product was purified through
:
column chromatography on silica gel (petroleum ether: ethyl
acetate = 5:1) and obtained as brown oil (56%, 45.7 mg),
anti/syn=1:1; [α]D25= +6.4 (c=0.25, CHCl3).1H NMR (400
MHz, Chloroform-d) δ 8.16 (d, J = 7.9 Hz, 2H), 7.53 (dd, J
= 8.5, 6.1 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.37 (dd, J =
8.9, 2.0 Hz, 2H), 4.79 (d, J = 3.3 Hz, 1H), 4.62 (d, J = 5.2
Hz, 1H), 2.91-2.78 (m, 1H), 2.38 (dt, J = 33.7, 13.1 Hz, 2H),
1.99 (d, J = 42.3 Hz, 4H), 1.82-1.65 (m, 2H). 13C{1H} NMR
(101 MHz, Chloroform-d) δ 211.9, 148.9, 145.7, 132.0,
131.9, 128.6, 128.2, 123.8, 115.7, 115.1, 110.3, 109.9, 58.0,
57.3, 57.0, 56.0, 42.6, 42.4, 32.3, 28.9, 27.9, 27.0, 24.9, 24.6.
The enantiomeric excess is 47% determined by HPLC
(Daicel Chirapak AD-H, hexane/ isopropanol= 80:20, flow
rate 1.0 mL/min): syn-diastereomer, tR = 14.2 min (major),
tR = 15.7 min (minor).
(S)-2-((S)-(4-chlorophenylamino)(4-nitrophenyl)methyl)
cyclohexanone (5o)29: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 5:1) and obtained as light yellow oil (59%, 42.3
mg), syn/anti = 1:1; [α]D25= +24.3 (c=0.21, CHCl3).1H NMR
(400 MHz, Chloroform-d) δ 8.16 (d, J = 8.1 Hz, 2H), 7.53
(dd, J = 8.5, 6.2 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.48-6.32
(m, 2H), 4.80 (d, J = 4.1 Hz, 1H), 4.63 (d, J = 5.2 Hz, 1H),
2.84 (dd, J = 10.9, 5.5 Hz, 1H), 2.37 (ddd, J = 27.7, 26.2,
14.1 Hz, 2H), 1.98 (dd, J = 40.1, 7.3 Hz, 3H), 1.58 (dd, J =
23.9, 11.9 Hz, 3H). 13C{1H} NMR (101 MHz, Chloroform-
d) δ 210.3, 148.9, 147.2, 145.2, 129.1, 128.6, 128.2, 123.7,
115.2, 114.6, 58.1, 57.4, 57.0, 56.0, 42.6, 42.5, 42.4, 32.2,
28.9, 27.80, 26.9, 24.9, 24.6. The enantiomeric excess is
77% determined by HPLC (Daicel Chirapak AD-H, hexane/
isopropanol= 80:20, flow rate 1.0 mL/min): syn-
diastereomer, tR = 13.3 min (major), tR = 15.3 min (minor).
(S)-2-((S)-(4-nitrophenyl)(4-nitrophenylamino)methyl)
cyclohexanone (5p): The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 3:1) and obtained as yellow oil (53%, 39.2 mg),
syn/anti =1:1; [α]D25= +7.5 (c=0.16, CHCl3). 1H NMR (400
MHz, Chloroform-d) δ 8.27-8.15 (m, 2H), 8.06-7.94 (m, 2H),
7.55 (d, J = 8.5 Hz, 2H), 6.48 (dd, J = 8.9, 6.2 Hz, 2H), 5.83
(d, J = 7.9 Hz, 1H), 5.58 (d, J = 7.0 Hz, 1H), 4.96-4.86 (m,
1H), 4.73 (dd, J = 7.9, 4.6 Hz, 1H), 2.95 (dd, J = 17.4, 12.4
Hz, 1H), 2.42 (dd, J = 37.1, 13.7 Hz, 2H), 2.16-1.91 (m, 3H),
1.79 (dd, J = 22.4, 10.3 Hz, 2H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ210.4, 152.2, 148.1, 147.4, 128.7, 128.0,
126.3, 126.2, 123.9, 112.3, 112.0, 58.0, 57.2, 56.6, 55.3, 42.8,
42.3, 32.9, 29.3, 28.0, 26.6, 24.8. Anal. calc. for C19H19N3O5:
C 61.78, H 5.18, N 11.38; found: C 61.72, H 5.15, N 11.31.
The enantiomeric excess is 59% determined by HPLC
(Daicel Chirapak AD-H, hexane/isopropanol= 80:20, flow
rate 1.0 mL/min): syn-diastereomer, tR = 22.6 min (major),
tR= 33.2 min (minor).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-3-(4-nitrophenyl)-1-phenyl-3-(phenylamino)propan-
1-one (6b)6: The product was purified through column
chromatography on silica gel (petroleum ether: ethyl acetate
= 5:1) and obtained as a slight yellow oil (52%, 36.0 mg).
[α]D25= +8.9 (c = 0.18, CHCl3). 1H NMR (600 MHz,
Chloroform-d) δ 8.18 (d, J = 8.7 Hz, 2H ), 7.91 (s, 2H), 7.64
(d, J = 8.7 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8
Hz, 2H), 7.10 (dd, J = 8.3, 7.6 Hz, 2H), 6.71 (t, J = 7.3 Hz,
1H), 6.52 (d, J = 7.8 Hz, 2H), 5.35 (t, J = 4.7 Hz, 1H), 5.11
(t, J = 6.1 Hz, 1H), 3.51 (d, J = 6.2 Hz, 2H). 13C{1H} NMR
(151 MHz, Chloroform-d) δ 197.3, 150.7, 147.2, 146.3,
(S)-2-((S)-(3-bromophenylamino)(4-nitrophenyl)methyl)
cyclohexanone (5q)29: The product was purified through
column chromatography on silica gel (petroleum ether: ethyl
acetate = 5:1) and obtained as brown oil (73%, 60.3 mg),
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
136.3, 133.9, 129.3, 128.9, 128.2, 127.5, 124.1, 118.5, 113.8,
enantioselective synthesis of 1, 2-amino alcohols. J. Am. Chem.
1
2
3
4
5
6
7
8
54.2, 45.7. The enantiomeric excess is 45% determined by
HPLC (Daicel Chirapak OD-H, hexane/ isopropanol= 80:20,
flow rate 1.0 mL/min): syn-diastereomer, tR = 23.8 min
(major), tR = 28.6 min (minor).
Soc. 2002, 124, 827-833. (b) B. List, The direct catalytic
asymmetric three-component Mannich reaction. J. Am. Chem.
Soc. 2000, 122, 9336-9337.
(6) Guo, Q. X.; Liu, H.; Guo, C.; Luo, S. W.; Gu, Y.; Gong, L. Z. Chiral
Brønsted acid-catalyzed direct asymmetric Mannich reaction.
J. Am. Chem. Soc. 2007, 129, 3790-3791.
(7) Guo, Q.; Zhao, J. C. G. Highly enantioselective three-component
direct mannich reactions of unfunctionalized ketones
catalyzed by bifunctional organocatalysts. Org. Lett. 2013, 15,
508-511.
ASSOCIATED CONTENT
Supporting Information
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/
(8) Zhao, J.; Liu, X.; Luo, W.; Xie, M.; Lin, L.; Feng, X. Asymmetric
Synthesis of β-Amino Nitriles through a ScIII-Catalyzed Three-
Component Mannich Reaction of Silyl Ketene Imines. Angew.
Chem. Int. Ed. 2013, 52, 3473-3477.
(9) Feng, L.; Dai, X.; Meggers, E.; Gong, L. Three-Component
Asymmetric Mannich Reaction Catalyzed by a Lewis Acid with
Rhodium-Centered Chirality. Chem. Asian J. 2017, 12, 963-967.
(10) Chen, J.; Wen, X.; Wang, Y.; Du, F.; Cai, L.; Peng, Y. Asymmetric
Mannich Reaction of Isatin-Based Ketimines with α-
Diazomethylphosphonates Catalyzed by Chiral Silver
Phosphate. Org. Lett. 2016, 18, 4336-4339.
1H NMR and 13C NMR spectra for all compounds
HPLC spectra for 5a-5r, 6a, 6b.
AUTHOR INFORMATION
Corresponding Author
* xyhu@mail.scuec.edu.cn.
* victor.borovkov@taltech.ee
ORCID
Xiaoyun Hu: 0000-0002-5251-2521
Victor Borovkov: 0000-0001-7898-0457
(11) For a review on three-component Mannich reactions, see: M.
Syamala, Recent progress in three-component reactions. An
update. Org. Prep. Proc. Int. 2009, 41, 1-68.
Notes
The authors declare no competing financial interest.
(12) Hu, X.; Zhang, R.; Xie, J.; Zhou, Z.; Shan, Z. Synthesis of a novel
sterically hindered chiral cyclic phosphoric acid derived from
L-tartaric acid and application to the asymmetric catalytic
Biginelli reaction. Tetrahedron: Asymmetry. 2017, 28, 69-74.
(13) (a) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. The progression of
chiral anions from concepts to applications in asymmetric
catalysis. Nat. Chem. 2012, 4, 603-614; (b) Mahlau, M.; List, B.
Asymmetric counteranion ‐ directed catalysis: concept,
definition, and applications. Angew. Chem. Int. Ed. 2013, 52,
518-533. (c) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
Complete field guide to asymmetric BINOL-phosphate
derived Brønsted acid and metal catalysis: history and
classification by mode of activation; Brønsted acidity,
hydrogen bonding, ion pairing, and metal phosphates. Chem.
Rev. 2014, 114, 9047-9153.
(14) (a) Biswas, S.; Kubota, K.; Orlandi, M.; Turberg, M.; Miles, D. H.;
Sigman, M. S.; Toste, F. D. Enantioselective Synthesis of N, S-
Acetals by an Oxidative Pummerer-Type Transformation
using Phase-Transfer Catalysis. Angew. Chem. Int. Ed. 2018, 57,
589-593. (b) Coelho, J. A.; Matsumoto, A.; Orlandi, M.; Hilton,
M. J.; Sigman, M. S.; Toste, F. D. Enantioselective fluorination
of homoallylic alcohols enabled by the tuning of non-covalent
interactions. Chem. Sci. 2018, 9, 7153-7158.
ACKNOWLEDGMENT
We are grateful to the National Nature Science Foundation of
China (No. 21302233), the Nature Science Foundation of Hubei
Province of China (No. 2012FFB07410), the Fundamental
Research Funds for the Central Universities, South-Central
University for Nationalities (CZY20016), and the start-up
research grant (YZZ16005) from South-Central University for
Nationalities for financial support.
REFERENCES
(1) Mannich, C.; Krösche, W. Ueber ein kondensationsprodukt aus
formaldehyd, ammoniak und antipyrin. Arch. Pharm. 1912,
250, 647-667.
(2) (a) Cai, X.-H.; Xie, B.; Recent advances on organocatalysed
asymmetric Mannich reactions. ARKIVOC 2013 264-293. (b)
Córdova, A. The direct catalytic asymmetric Mannich reaction.
Acc. Chem. Res. 2004, 37, 102–112. (c) Verkade, J. M. M.;
Hemert, L. J. C. V.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T.
Organocatalysed asymmetric Mannich reactions. Chem. Soc.
Rev. 2008, 37, 29-41. (d) Arrayas, R. G.; Carretero, J. C.
Catalytic asymmetric direct Mannich reaction: a powerful tool
for the synthesis of α, β-diamino acids. Chem. Soc. Rev. 2009,
38, 1940-1948.
(3) Graaff, C. de; Ruijter,E.; Orru, R. V. A. Recent developments in
asymmetric multicomponent reactions. Chem. Soc. Rev. 2012,
41, 3969-4009.
(4) Weiner, B.; Szymanski, W.; Jaussen, D. B.; Minnaard, A.J.;
Feringa, B. L. Recent advances in the catalytic asymmetric
synthesis of β-amino acids. Chem. Soc. Rev. 2010, 39, 1656-
1691.
(15) (a) Gatzenmeier, T.; Kaib, P. S. J.; Lingnau, J. B.; Goddard, R.;
List, B. The Catalytic Asymmetric Mukaiyama–Michael
Reaction of Silyl Ketene Acetals with α, β-Unsaturated Methyl
Esters. Angew. Chem. Int. Ed. 2018, 57, 2464-2468. (b) Bae, H.
Y.; Höfler, D.; Kaib, P. S. J.; Kasaplar, P.; De, C. K.; Döhring, A.;
Lee S.; Kaupmees, K.; Leito, I.; List, B. Approaching sub-ppm-
level asymmetric organocatalysis of a highly challenging and
scalable carbon-carbon bond forming reaction. Nat. Chem.,
2018, 10, 888-894.
(5) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. The proline-
catalyzed direct asymmetric three-component Mannich
reaction: scope, optimization, and application to the highly
(16) Jiang, H. J.; Liu, K.; Yu, J.; Zhang, L.; Gong, L. Z. Switchable
stereoselectivity in bromoaminocyclization of olefins: using
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 10
Brønsted acids of anionic chiral cobalt (III) complexes. Angew.
Chem., Int. Ed., 2017, 56, 11931-11935.
South-Central University for Nationalities (Nat. Sci. Edition).
2019, 38, 22-26.
1
2
(17) Qian, D.; Chen, M.; Bissember, A. C.; Sun, J. Counterion
‐
(23) Rueping, M.; Antonchick, A. P.; Brinkmann, C. Dual Catalysis:
3
Induced Asymmetric Control in Ring
‐Opening of
A Combined Enantioselective Brønsted Acid and Metal
‐
4
5
Azetidiniums: Facile Access to Chiral Amines. Angew. Chem.,
Int. Ed., 2018, 57, 3763-3766.
Catalyzed Reaction-Metal Catalysis with Chiral Counterions.
Angew. Chem. Int. Ed. 2007, 46, 6903-6906.
(18) Kang, Z.; Wang, Y.; Zhang, D.; Wu, R.; Xu, X.; Hu, W. Asymmetric
Counter-Anion-Directed Aminomethylation: Synthesis of
Chiral β-Amino Acids via Trapping of an Enol Intermediate. J.
Am.Chem. Soc., 2019, 141, 1473-1478.
(24) Hu, X.; Chen, D.; Lan, J.; Shan, Z. The intramolecular S = O···H-
O hydrogen bond in a chiral cyclic sulfite ester: How it
affects the reaction behavior and spectral properties.
Phosphorus, Sulfur, and Silicon and the Related Elements. 2016,
191, 1291-1296.
6
7
8
9
(19) (a) Li, F.; Korenaga, T.; Nakanishi, T.; Kikuchi, J.; Terada, M.
Chiral Phosphoric Acid Catalyzed Enantioselective Ring
Expansion Reaction of 1, 3-Dithiane Derivatives: Case Study
of the Nature of Ion-Pairing Interaction. J. Am. Chem. Soc.
2018, 140, 2629-2642. (b) Alvim, H. G.; Pinheiro, D. L.;
Carvalho-Silva, V. H.; Fioramonte, M.; Gozzo, F. C.; da Silva, W.
A.; Amarante, G. W.; Neto, B. A. Combined Role of the
Asymmetric Counteranion-Directed Catalysis (ACDC) and
Ionic Liquid Effect for the Enantioselective Biginelli
Multicomponent Reaction. J. Org. Chem. 2018, 83, 12143-
12153. (c) Morse, P. D.; Nguyen, T. M.; Cruz, C. L.; Nicewicz, D.
A. Enantioselective counter-anions in photoredox catalysis:
The asymmetric cation radical Diels-Alder reaction.
Tetrahedron. 2018, 74, 3266-3272.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(25) Shan, Z. X.; Hu, X. Y.; Zhou, Y.; Peng, X. T.; Li,
Z.
A
Convenient Approach to C2-Chiral 1,1,4,4-
Tetrasubstituted Butanetetraols: Direct Alkylation or
Arylation of Enantiomerically Pure Diethyl Tartrates. Helv.
Chim. Acta 2010, 93, 497-503.
(26) Gu, Q.; Gong, J. J.; Feng, J.; Wu, X. Y.; Zhou, Q. L.
Organocatalytic Direct Asymmetric Mannich Reactions of
Hydroxyacetone by (2S, 5S)-Pyrrolidine-2, 5-dicarboxylic
Acid. Chin. J. Chem. 2008, 26, 1902–1906.
(27) Zheng, X.; Qian, Y. B.; Wang, Y. 2-Pyrrolidinecarboxylic acid
ionic liquid as a highly efficient organocatalyst for the
asymmetric one-pot Mannich reaction. Eur. J. Org. Chem.,
2010, 3, 515-522.
(28) Chen, Y. Y.; Jiang, Y. J. Fan,; Y. S.; Sha, D.; Wang, Q.; Zhang, G.;
Zhang, S. Double axially chiral bisphosphorylimides as novel
Brønsted acids in asymmetric three-component Mannich
reaction. Tetrahedron: Asymmetry, 2012. 23, 904-909.
(29) An, Y. J.; Wang, C. C.; Liu, Z. P.; Tao, J. C. Isosteviol Proline
Conjugates as Highly Efficient Amphiphilic Organocatalysts
for Asymmetric Three-Component Mannich Reactions in the
Presence of Water. Helv. Chim. Acta, 2012, 95, 43-51.
(20) (a) Doyle, A. G.; Jacobsen, E. N. Small-molecule H-bond donors
in asymmetric catalysis. Chem. Rev.2007, 107, 12, 5713-5743.
(b) Terada, M. Binaphthol-derived phosphoric acid as a
versatile catalyst for enantioselective carbon-carbon bond
forming reactions. Chem. Commun., 2008, 4097-4112.
(21) Pellissier,
H.
Enantioselective
silver-catalyzed
transformations. Chem. Rev. 2016, 116, 14868-14917.
(22) Hu, X.; Yin, Z.; Tang, Y.; Wu, L. A practical approach to (2R,3R)-
2,3-dimethoxy-1,1,4,4-tetraphenylbutane-1,4-diol. Journal of
ACS Paragon Plus Environment