Access to Chiral 2,5-Pyrrolidinyl Dispirooxindoles via Dinuclear Zinc-Catalyzed Asymmetric Cascade Reactions

Article abstract of DOI:10.1021/acs.joc.9b00645

A series of new nonsymmetric semi-azacrown ether ligands were developed and applied to the asymmetric Michael/cyclic keto-imine formation/Friedel-Crafts alkylation reactions of 3-amino oxindole hydrochlorides and β,γ-unsaturated α-keto amides. A diversity of 2,5-pyrrolidinyl dispirooxindoles containing two nonadjacent spiro-quaternary stereocenters were obtained in excellent diastereoselectivities and moderate to excellent enantioselectivities (up to 95% ee). A possible catalytic cycle was proposed to explain the origin of the asymmetric induction.

Full text of DOI:10.1021/acs.joc.9b00645

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Article
Access to Chiral 2,5-Pyrrolidinyl Dispirooxindoles via
Dinuclear Zinc Catalyzed Asymmetric Cascade Reactions
Xiao-Chao Yang, Meng-Meng Liu, François Mathey, Hua Yang, Yuan-Zhao Hua, and Min-Can Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00645 • Publication Date (Web): 30 May 2019
Downloaded from http://pubs.acs.org on May 31, 2019
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Access to Chiral 2,5-Pyrrolidinyl Dispirooxindoles via
Dinuclear Zinc Catalyzed Asymmetric Cascade
Reactions
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Xiao-Chao Yang, Meng-Meng Liu, François Mathey, Hua Yang, Yuan-Zhao Hua,* and
Min-Can Wang*
College of Chemistry and Molecular Engineering, School of Pharmaceutical Sciences, Zhengzhou University,
75 Daxue Street, Zhengzhou, Henan, 450052, P. R. China
R4
R4
Ar3
HO
N
Ar4
Ar4
OH
N
R3
L3d
Et2Zn: 20 mol%
CH3CN/CH2Cl2,
Et3N, -45 o
C
1)
: 10 mol%
Ar3
N
HCl
+
NH2
Ar
O
NH
OH
O
N
O
Ar
R3
O
N
R1
R2
2) TFA, CH2Cl2
N
O
R2
R1
25 examples
up to 85% yield
up to 95% ee
up to > 60:1 dr
L3d
Ar3 = p-CF3Ph
Ar4 = p-CH3Ph
Abstract: A series of new nonsymmetric semi-azacrown ether ligands were developed and applied to the asymmetric
Michael/cyclic keto-imine formation/Friedel-Crafts alkylation reactions of 3-amino oxindole hydrochlorides and
β,γ-unsaturated α-keto amides.
A diversity of 2,5-pyrrolidinyl dispirooxindoles containing two nonadjacent
spiro-quaternary stereocenters were obtained in excellent diastereoselectivities and moderate to excellent
enantioselectivities (up to 95% ee). A possible catalytic cycle was proposed to explain the origin of the asymmetric
induction.
INTRODUCTION
The 3,2’-pyrrolidinyl spirooxindole frameworks are privileged structural motifs that widely exist in a large
variety of natural and synthetic compounds.1 Among them, the enantiomerically pure 3,2’-pyrrolidinyl
spirooxindoles exhibit a broad spectrum of important biological and pharmaceutical activities2 including
antimycobacterial2a and cytotoxic to MCF-7 cells2b. Given the significance of this promising structural core in
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both organic and medicinal chemistry,3 some effective synthetic methods have been developed to
asymmetrically construct this prevalent structural skeletons in recent years.4 Among these elegant methods,
most of which are limited to the construction of 3,2’-pyrrolidinyl spirooxindoles bearing only one
spiro-quaternary stereocenter.
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Scheme 1. Strategies for the Synthesis of Pyrrolidinyl Dispirooxindoles
previous work for the synthesis of 2,3-pyrrolidinyl despirooxindole derivatives:
N
O
EtO2C
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Bis-PA
a)
O
+
+ H2N
up to 99% yield
> 19:1 dr, 98% ee
O
N
NH
O
N
Bn
N
Bn
CO2Et
H
N
O
NBoc
O
CO2Et
(DHQD)2PHAL
b)
+
O
up to 87% yield
> 20:1 dr, 98% ee
NH
O
N
N
H
N
this work for the synthesis of 2,5-pyrrolidinyl despirooxindole derivatives:
R4
R4
HCl
+
NH2
dinuclear zinc
synergistic catalyst
N
R3
O
c)
Ar
N
O
NH
O
Ar
R3
N
R1
O
R2
O
N
R1
R2
Owing to the more complex structures of pyrrolidinyl dispirooxindoles, which contain two spiro-quaternary
stereocenters and more chiral carbon atoms, only a few catalytic asymmetric examples have been reported for
the synthesis of pyrrolidinyl dispirooxindoles up to now.5 In 2015, the Tu group reported the synthesis of
2,3-pyrrolidinyl dispirooxindoles by a chiral bis-phosphoric acid (Bis-PA) catalyzed asymmetric 1,3-dipolar
cycloadditions of isatin-derived azomethine ylides and methyleneindolinones (Scheme 1a).5a In 2016, Enders
and co-workers described a novel one-pot (DHQD)2PHAL catalyzed Mannich/deprotection/aza-Michael
sequence, leading to a series of 2,3-pyrrolidinyl dispirooxindole derivatives (Scheme 1b).5b Notably, all the
catalysts used in above approaches were confined to organocatalysts, but the metal-catalysed asymmetric
synthesis of pyrrolidinyl dispirooxindoles has not been reported to date. In addition, the two spiro-quaternary
stereocenters of the corresponding products are all vicinal (2-, 3-position of pyrrolidine, Scheme 1). Therefore,
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it is highly desirable to develop new catalytic system and new methodology for the construction of pyrrolidinyl
dispirooxindoles.
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α-Hydroxy carbonyl compounds as nucleophiles have been widely applied in catalytic asymmetric reactions
promoted by organocatalysts6c-d and metallic catalysts.6e-l α-Amino carbonyl compounds, as the analogues of
α-hydroxy carbonyl compounds, are also used in organocatalytic asymmetric reactions.7 However, to our best
knowledge, there have been no reports on the use of α-amino carbonyl compounds as donator in
metal-catalytic asymmetric reactions. The possible reasons are: 1) the reactivity of α-amino carbonyl
compounds is relatively lower than α-hydroxy carbonyl compounds; 2) the amino group has a strong ability to
chelate metal, and this may lead to the destruction of the catalytic cycle. Therefore, it would be a formidable
challenge to conquer these problems.
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During the past few years, we have concentrated on the applications of dinuclear zinc synergistic catalysts in
a number of efficient catalytic enantioselective transformations.8 As part of our ongoing efforts towards this
study, we recently find that it is effective to improve the reactivity of α-amino carbonyl compounds as
nucleophiles through a bimetallic cooperative catalyst.
Herein, we report a Michael/cyclic keto-imine formation/Friedel-Crafts alkylation cascade reactions of
3-amino oxindole hydrochloride 1 and β,γ-unsaturated α-keto amides 2 catalyzed by a dinuclear zinc catalyst.
A diversity of novel pyrrolidinyl dispirooxindoles containing two nonadjacent spiro-quaternary stereocenters (2-,
5-position of pyrrolidine, Scheme 1c) were obtained in excellent diastereoselectivities and moderate to
excellent enantioselectivities (up to 60:1 dr, 95% ee).
RESULTS AND DISCUSSION
The research work began with the evaluation of the ability of dinuclear zinc synergistic catalysts in the
Michael/cyclic keto-imine formation/Friedel-Crafts alkylation cascade reactions of 3-amino oxindole
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hydrochloride 1a and β,γ-unsaturated α-keto amides 2a. Gratifyingly, in the presence of catalyst, generated
from 10 mol% ligand L1a, 20 mol% ZnEt2, the reaction proceeded smoothly at 20 °C for 3 h, and gave the
desired product 2,5-pyrrolidinyl dispirooxindole 3a in 62% yield with only 24% ee (Table 1, entry 1).
Encouraged by this result, we examined a series of C2-symmetric ligands L19 and L2 with various substitutions.
The results were summarized in Table 1 (entries 2-8). Unfortunately, it was found that all of these ligands gave
the inferior results in terms of enantioselectivities (up to 33% ee).
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Table 1. Screening of Ligandsa
N
L
1) : 10 mol%
HCl
+
NH2
O
Ph
N
Et2Zn: 20 mol%
THF, Et3N, 20 o
Ph
NH
C
O
O
Ph
O
N
O
2) TFA, CH2Cl2
N
1a
Ar1
2a
3a
Ar2
Ar2
OH
Ar2
Ar2
Ar1
Ar1
HO
OH
N
HO
OH
Ar1
: Ar1 = Ph
: Ar2 = Ph
L1a
L1b
L1c
L1d
L1e
L2a
N
OH
N
N
: Ar1 = p-CH3Ph
: Ar1 = p-CF3Ph
: Ar1 = p-ClPh
: Ar2 = p-CH3Ph
: Ar2 = p-CF3Ph
L2b
L2c
1
: Ar = 2-thienyl
entry
ligand
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
L1a
L1b
L1c
L1d
L1e
L2a
L2b
L2c
62
58
62
68
56
61
53
60
24
33
25
21
9
10
8
4
aReaction conditions: Unless otherwise noted, all reactions were conducted with 1a (0.25 mmol), 2a (0.275 mmol), Et3N (0.325 mol), 10
mol% of L, 20 mol% of ZnEt2 (1 M in hexanes) in THF (2.5 mL) under nitrogen for 3 h. After evaporation of the solvent, CH2Cl2 (2.0 mL)
and TFA (2.0 mL) were added. bYield of isolated product 3a. cDetermined by chiral HPLC analysis. All dr value were up to >20:1
detected by 1H NMR.
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Based on previous work, we found that chiral space of the catalysts greatly affected the catalytic
performances in the asymmetric reactions. The fine adjustment of catalysts’ structure, which could lead to the
change of their chiral microenvironment, made them suitable for different reaction systems and substrates.8,9 In
addition, there was no fundamental reason why C2-symmetric ligands must be superior to their nonsymmetrical
counterparts, and in some reactions, the C1-symmertric ligands with electronically and sterically divergent units
performed more effective stereocontrol than C2-symmetric ligands.10 Therefore, this propelled us to design and
synthesize more C1-symmertric ligands with different chiral nitrogen heterocycles and electronically different
aromatic rings (Scheme 2). By changing the symmetrical characteristic of the ligands, we sought to improve the
enantioselectivities of this Michael/cyclic keto-imine formation/Friedel-Crafts alkylation cascade reactions of
3-amino oxindole hydrochloride 1a and β,γ-unsaturated α-keto amides 2a.
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Scheme 2. Synthesis of a New Family of Nonsymmetric Semi-azacrown Ether Ligands L3
Ar3
Ar3
HO
N
Ar4
Ar4
OH
N
OH
N
Ar3
Ar4
Ar3
Ar3
Ar3
OH
Ar4
OH
Cl OH
O
N
N
OH
O
H
H
OH
5
7
K2CO3
DMF, rt
EtOH, rt
then NaBH4
4
6a-6c
L3
: Ar3 = Ph, Ar4 = Ph,
3
: Ar = Ar4 = p-CF3Ph,
L3a
L3b
L3c
L3d
L3e
L3f
: Ar3 = p-CH3Ph, Ar4 = Ph,
: Ar3 = Ar4 = p-CH3Ph,
: Ar3 = Ph, Ar4 = p-CH3Ph,
: Ar3 = Ph, Ar4 = p-CF3Ph.
L3g
: Ar3 = p-CF3Ph, Ar4 = p-CH3Ph,
The synthesis of designed ligands L3 with C1-symmetry was shown in Scheme 2. Starting from the source of
3-(chloromethyl)-2-hydroxy-5-methyl-benzaldehyde 4,11 which could be prepared from commercially available
p-cresol, the synthetic route consisted of two steps. The intermolecular nucleophilic substitution reaction of the
benzyl chloride 4 and the prolinol 5 afforded the aldehyde 6 under basic conditions. A series of desired
nonsymmetric ligands L3a-3g were achieved through a reductive amination of 6 and the azetidino alcohol 78a
that was prepared by our previously developed procedures.
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With these new ligands L3a-L3g in hand, we re-examined the Michael/cyclic keto-imine
formation/Friedel-Crafts alkylation cascade reactions. The results were shown in Table 2. It was found that
changing the ligand’s symmetric nitrogen heterocyclic backbones to nonsymmetric frameworks led to an
increase of the reaction’s enantioselectivity (Table 2, entries 1, 3, and 5 vs Table 1, entries 1-3 and 6-8
respectively). Meanwhile, the electronic nature of aromatic rings in the ligands also had an obvious influence on
enantioselectivity of the reaction.10b,12 Through the screening of these ligands L3a-3g (Table 2), ligand L3d was
relatively effective, and the corresponding product 3a was obtained in 67% yield with an increased ee value
from 33% to 49% (Table 2, entry 4). This result encouraged us to screen other conditions in detail.
Table 2. Evaluation of the New Ligands L3a
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N
L3
1) : 10 mol%
HCl
+
NH2
O
Ph
N
Et2Zn: 20 mol%
THF, Et3N, 20 o
Ph
NH
C
O
Ph
O
O
N
O
2) TFA, CH2Cl2
N
1a
2a
3a
entry
ligand
yieldb (%)
eec (%)
1
2
3
4
5
6
7
L3a
L3b
L3c
L3d
L3e
L3f
L3g
66
45
55
67
56
62
61
37
45
38
49
35
39
18
aReaction conditions: Unless otherwise noted, all reactions were conducted with 1a (0.25 mmol), 2a (0.275 mmol), Et3N (0.325 mol), 10
mol% of L3, 20 mol% of ZnEt2 (1 M in hexanes) in THF (2.5 mL) under nitrogen for 3 h. After evaporation of the solvent, CH2Cl2 (2.0 mL)
and TFA (2.0 mL) were added. bYield of isolated product 3a. cDetermined by chiral HPLC analysis. All dr value were up to >20:1
detected by 1H NMR.
As known to all, solvents usually played a crucial role in catalytic asymmetric reactions. The effect of solvents
was investigated deeply. In THF (Table 3, entry 1), halogenated solvents (Table 3, entries 2 and 3) or toluene
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(Table 3, entry 4), the reaction yield were higher, but the enantioselectivities were lower than in 1,4-dioxane
(Table 3, entry 5). Fortunately, CH3CN afforded the much better results, and the product 3a was obtained in a
much-improved 76% ee (Table 3, entry 6). Then, mixed solvents were also examined (Table 3, entries 7-9). It
was found that CH3CN/CH2Cl2 (1:1) was the more suitable combination, and afforded the product 3a in 76%
yield with 80% ee (Table 3, entry 7).
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Table 3. Optimization of Solvents, Temperature, Additives and Catalysts Loadingsa
N
L3d
Et2Zn: 20 mol%
1)
: 10 mol%
HCl
NH2
O
Ph
N
Ph
NH
solvent, Et3N, T
O
O
+ Ph
O
N
2) TFA, CH2Cl2
O
N
3a
1a
2a
entry
solvent
THF
T (oC)
yieldb (%)
eec (%)
1
20
67
75
77
80
66
76
76
79
76
80
80
84
85
81
70
78
68
83
76
49
42
15
37
59
76
80
79
79
83
83
87
89
87
84
79
54
86
73
2
CH2Cl2
CHCl3
toluene
20
3
20
4
20
5
1,4-dioxane
CH3CN
20
6
20
7
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:3)
CH3CN/CH2Cl2(3:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
CH3CN/CH2Cl2(1:1)
20
8
20
9
20
10
11
12
13d
14e
15e
16f
17g
18h
19i
0
-20
-40
-45
-50
-60
-45
-45
-45
-45
aReaction conditions: Unless otherwise noted, all reactions were conducted with 1a (0.25 mmol), 2a (0.275 mmol), Et3N (0.325 mol), 10
mol% of L3d, 20 mol% of ZnEt2 (1 M in hexanes) in solvent (2.5 mL) under nitrogen for 3-24 h. After evaporation of the solvent, CH2Cl2
(2.0 mL) and TFA (2.0 mL) were added. bYield of isolated product 3a. cDetermined by chiral HPLC analysis. All dr value were up to
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>20:1 detected by 1H NMR. dThe reaction time was 18 h. eThe reaction time is 24 h. f4Å molecular sieve (50 mg) was used. g5 mol% of
L3d was used. h15 mol% of L3d was used. iMg(n-Bu)2 was used.
7
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Next, temperature, additives and catalysts loading were also explored. When the reaction temperature was
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o
lowered from 20 to 0, -20, -40, -45 C, the ee of product 3a increased to 89% progressively (Table 3, entries
o
10-13). Further lowering the temperature to -50, -60 C led to a small decrease ee of product 3a (Table 3,
entries 14 and 15). The addition of 4Å MS showed a negative effect on enantioselectivity (Table 3, entry 16).
o
Finally, the catalyst loadings were explored without additives at -45 C. Disappointingly, a larger loss in yield
and enantioselectivity was obtained once the catalyst loading is reduced to 5 mol% (Table 3, entry 17).
Increasing the catalyst loading to 15 mol% resulted in a slight reduction of the product’s ee value (Table 3, entry
13 vs entry 18). In addition, the use of Mg(n-Bu)2 led to an obvious decrease of the product’s ee value (entry
19).
Table 4. Generality of the Cascade Reaction Catalyzed by New Dinuclear Zinc Catalystsa-d
R4
R4
N
R3
L3d
Et2Zn: 20 mol%
CH3CN/CH2Cl2, Et3N, -45 o
1)
: 10 mol%
HCl
+
NH2
O
Ar
NH
O
N
C
O
Ar
R3
O
N
R1
2) TFA, CH2Cl2
O
R2
N
R2
R1
3a-y
2a-v
1a-d
: R1 = Me, R2 = H; : R1 = Bn, R2 = H
1a
1c
1b
: R1 = Me, R2 = 5-Me; : R1 = Me, R2 = 5-F
1d
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MeO
5
N
Bn
N
N
6
7
8
Ph
Ph
Ph
N
N
NH
NH
NH
O
O
O
NH
O
NH
O
O
O
O
O
O
N
N
N
N
N
9
3a
3b
3c
3d
3e
, 81%
17:1 dr, 79% ee
, 85%
, 82%
> 20:1 dr, 54% ee > 25:1 dr, 70% ee
Cl
, 82%
, 74%
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> 20:1 dr, 89% ee
Br
> 20:1 dr, 89% ee
O2N
F
N
N
N
N
N
H
N
H
N
N
H
N
N
H
O
H
O
N
N
O
N
O
N
N
O
O
O
O
O
O
3f
3g
3h
3i
3j
, 74%
, 84%
, 82%
, 66%
22:1 dr, 43% ee
, 72%
> 20:1 dr, 68% ee > 20:1 dr, 65% ee
Br
> 20:1 dr, 70% ee
> 60:1 dr, 84% ee
O
O
O
S
N
N
N
N
N
NH
O
NH
NH
NH
N
H
O
O
O
O
O
O
N
N
N
O
N
N
O
O
3k
3l
3m
3n
3o
, 82%
, 79%
, 68%
, 82%
, 70%
> 20:1 dr, 90% ee
25:1 dr, 84% ee
> 20:1 dr, 68% ee
> 20:1 dr, 68% ee
> 20:1 dr, 83% ee
Cl
F
MeO
N
N
N
N
Ph
Ph
Ph
Ph
NH
O
O
N
NH
NH
O
NH
O
O
N
N
H
O
O
O
O
N
N
O
N
N
3p
3q
3r
3s
3t
, 83%
, 82%
, 84%
, 79%
, 80%
29:1 dr, 78% ee
29:1 dr, 72% ee
> 20:1 dr, 73% ee > 20:1 dr, 70% ee
> 20:1 dr, 95% ee
Cl
Br
O
N
O
N
N
N
N
Ph
Ph
Ph
Ph
NH
NH
O
NH
F
NH
O
O
N
NH
O
O
O
O
O
O
O
N
N
N
N
Bn
3u
3v
3w
3x
3y
, 75%
, 85%
, 73 %
, 73%
, 82%
> 20:1 dr, 70% ee
> 20:1 dr, 60% ee
> 20:1 dr, 90% ee
> 20:1 dr, 91% ee > 20:1 dr, 74% ee
aReaction conditions: Unless otherwise noted, all reactions were conducted with 1 (0.25 mmol), 2 (0.275 mmol), Et3N (0.325 mol), 10
mol% of L3d, 20 mol% of ZnEt2 (1 M in hexanes) in CH3CN/CH2Cl2 (1/1, 2.5 mL) under nitrogen for 18 h. After evaporation of the
solvent, CH2Cl2 (2.0 mL) and TFA (2.0 mL) were added. bYield of isolated product 3. cDetermined by 1H NMR. dDetermined by chiral
HPLC analysis.
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With the optimal reaction conditions established, we subsequently explored the substrate scope, and the
results were compiled in Table 4. First, the substrates 2b and 2c with different bulky protecting group R3 (ethyl
and benzyl) on nitrogen atom were examined under the standard conditions. The corresponding products
3b-3c were obtained in good yield with excellent dr and 54%, 70% ee, respectively. A series of β,γ-unsaturated
α-keto amides 2 with various substituents at the aromatic ring were tested. Substrates 2d-2i with different
electronic nature groups at the para position of the aromatic ring (Ar) gave the corresponding products in 66-84%
yields with 43-89% ee. It was found that the electron-donating groups (MeO-, Me-) at the para position on the
aromatic ring (Ar) led to higher enantioselectivities than electron-withdrawing groups (Br-, Cl-, F-, O2N-). These
results enlightened us to test substrates 2j-2k bearing more electron-rich groups (3,4-dimethylphenyl and
γ-pipernoyl). Treatment of 2j and 2k with 3-amino oxindole 1a, respectively, gave good results in terms of 84%
and 90% ee. The substrates 2l-2m with the substituents at the meta position of the aromatic ring (Ar) were
tolerated. This protocol was also suitable for γ-heteroaromatic ring substrates 2n-2o and γ-naphthyl ring
substrate 2p, providing the corresponding products in good yields, with excellent diastereoselectivities and
moderate to good enantioselectivities (up to 83% ee). The influences of substituents R4 on the other aromatic
ring (at the side of N atom) were also explored. Both electron-donating and electron-withdrawing R4 (MeO-,
CH3-, F-, Cl-, Br-) at the para position of the aromatic ring were tolerated in this reaction, furnishing the desired
products 3q-3u in good yields and moderate to good enantioselectivities. In addition, there was a dramatically
improvment of the reaction enantioselectivity (95% ee of products 3t) when substrate 2t with Cl group was
treated with 3-amino oxindole under the standard condition. And the reaction of substrate 2v and 3-amino
oxindole 1a was also carried out, affording the corresponding product 3v in 73% yield with 60% ee.
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To further investigate the scope of the asymmetric cascade reaction, we examined the different nucleophiles
1b-1d (Table 4). It was found that changing the substituent R1 on the nitrogen atom of the substrate 1 from Me
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to benzyl had a slight influence on the reaction. The corresponding product 3w was obtained in 73 yield with >
20:1 dr and 90% ee. Furthermore, 3-amino oxindoles 1c-d with electron-donating or electron-withdrawing
substituents (Me- or F-) on the aromatic ring were explored, and the corresponding products 3x-y were
achieved in good yields with excellent dr and 91%, 74% ee, respectively.
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We also examined some α-amino carbonyl compounds, such as α-aminoacetophenone hydrochloride 8 and
α-aminomalonic acid diethyl ester hydrochloride 9, but no reaction occurred under the standard conditions
(Scheme 3). The possible reason is owing to lower reactivity of these two α-amino carbonyl compounds.
Scheme 3. Reaction of 2a and Other α-Amino Carbonyl Compounds 8 and 9
standard
conditions
O
O
N
No reaction
No reaction
NH2
HCl
a)
b)
+
Ph
Ph
Ph
Ph
Ph
2a
O
8
standard
conditions
O
EtOOC
COOEt
N
+
NH2
HCl
9
2a
O
Moreover, a single crystal of product 3l was obtained, and its absolute configuration was determined to be
(3R,3'R,5'R) by the X-ray crystallographic analysis (See SI, section 1).
On basis of the absolute structure of product 3l and previous reports on the mechanism of dinuclear zinc
catalysis,8,9 a possible catalytic cycle was proposed to explain the chirality transfer in the catalytic asymmetric
reaction (Scheme 4). Treatment of ligand L3d with 2 equivalents of ZnEt2 afforded the dinuclear zinc complex
Ⅰ. Next, the reaction of 3-amino oxindole 1a with complex Ⅰ generated intermediate Ⅱ accompanied by the
formation of 1 equivalent of ethane. Then, β,γ-unsaturated α-keto amide 2a coordinated to both zinc atoms
from the other less hindered face to form Ⅲ, which underwent a Michael reaction to afford the complex Ⅳ.
Next, intermediate Ⅴ and the species Ⅱ were released by a proton exchange with another 3-amino oxindole,
and the catalytic cycle was restarted. Intermediate Ⅴ immediately transformed into its condensation product
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Ⅵ
that was isolated, and characterized. Finally, the product 3a was obtained via an intramolecular
5
6
7
Fridel-Crafts alkylation under acidic conditions.
8
9
Scheme 4. Proposed Chirality Transformation in the Catalitic Asymmetric Reaction
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Ar3
HO
N
Ar4
Ar4
OH
N
Ar3
Ar3
Et
Zn
Ar4
Ar4
O
N
O
N
Ar3
Zn
OH
2 equiv Et2Zn
O
NH2
3 equiv ethane
O
N
I
L3d
Ar3 = p-CF3Ph
Ar4 = p-CH3Ph
1
1 equiv ethane
Ph
N
O
N
Ph
N
NH
O
O
O
Ar3
O
O
Ar4
Ar4
Ar3
Zn Zn
Ph
NH2
Ph
N
Ph
O
spontaneous
O
N
O
N
N
fast
O
N
VI
V
O
2a
N
N
1
Ph
O
TFA
II
Ph
Ph
N
Ph
N
O
N
NH2
Ph
O
H2N
O
N
O
O
Ar3
Ar3
Ar4
Ar4
O
Ar4
Ar4
O
O
O
Ph
Ar3
Ar3
Zn Zn
Zn Zn
O
NH
O
N
O
N
N
N
O
N
3a
III
IV
CONCLUSION
In conclusion, a series of new unsymmetric semi-azacrown ether ligands have been designed and
synthesized. These C1-symmetric ligands show better asymmetric catalytic performance than the
C2-symmetric Azephenol ligands and Prophenol ligands in the new asymmetric Michael/cyclic keto-imine
formation/Friedel-Crafts alkylation reactions of 3-amino oxindoles and β,γ-unsaturated α-keto amides. It is
remarkable that changing the ligand’s skeletons and the electronic nature of aromatic rings in the ligands can
enhance the enantioselectivities of the reaction. An array of chiral 2,5-pyrrolidinyl dispirooxindole containing
two nonadjacent spiro-quaternary chiral centers are achieved in moderate to good yields with good
diastereoselectivities and moderate to excellent enantioselectivities (up to 95% ee). According to the
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experiment results and the absolute structure of product 3l, a possible catalytic cycle is proposed to explain the
origin of the asymmetric induction. The application of these new C1-symmetric ligands to other reactions is
ongoing in our laboratory.
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Experimental Section
General Information. Optical rotation values were measured with instruments operating at λ = 589 nm,
corresponding to the sodium D line at 20 °C. 1H and 13C{1H} NMRspectra were recorded on Bruker AVANCE
400 MHz spectrometer and the chemical shifts are reported in ppm downfield from tetramethylsilane (δ = 0.00
1
ppm) for H NMR and relative to the central CDCl3 resonance (δ = 77.0 ppm) for 13C{1H} NMRspectroscopy.
High−resolution mass spectra (HRMS) were performed on a Q-TOF Micro LC/MS System ESI spectrometer.
The enantiomeric excesses (ee) were determined by HPLC (chiral column; mobile phase hexane/i-PrOH).
Compounds 1a-d,13 4,11 5a (Ar3 = Ph),14a 5b (Ar3 = p-CF3Ph),14b and 78a were synthesized according to the
literature. Compound 5c (Ar3 = p-CH3Ph) were used as purchased.
General Procedure for the Preparation of 6a-c. To a suspension of (S)-5 (3.54 mmol, 1.0 equiv) and
potassium carbonate (1.470 g, 10.62 mmol, 3.0 equiv) in DMF (14 mL) at 0 °C, was added benzylchloride 4
(0.718 g, 3.72 mmol, 1.05 equiv). The reaction mixture was stirred at rt for 16h before phosphate buffer (50 mL)
(pH = 7) and EtOAc (50 mL) were added. The layers were separated and the aqueous phase was extracted
with EtOAc (3 X 150 mL). The combined organic extracts were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to yield an orange residue. The crude product was purified by flash
column chromatography on silica gel (Petroleum ether:EtOAc = 90:10 to 80:20) to yield 6.
(S)-2-hydroxy-3-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-5-methylbenzaldehyde (6a). White solid,
1.12 g, 79% yield, mp 108.7-109.4 oC, [α]D = +35.2 (c =0.65, CHCl3); IR 3349, 2879, 2825, 1644, 1620, 1602,
1491, 1448, 1381, 1318, 1248, 1212, 1099, 1067, 1033, 970, 874, 800, 767, 745, 709, 699, 648, 590, 526 cm-1;
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1H NMR (400 MHz, CDCl3) δ ppm 9.81 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.31-7.24 (m,
4H), 7.20-7.12 (m, 3H), 7.07 (s, 1H), 4.47-4.43 (m, 1H), 3.37 (d, J = 13.6 Hz, 1H), 3.25-3.22 (m, 1H), 3.05 (d, J
= 13.6 Hz, 1H), 2.96-2.89 (m, 1H), 2.29 (s, 3H), 2.17-2.08 (m, 1H), 2.04-1.95 (m, 1H), 1.25 (s, 2H). 13C{1H}
NMR(100 MHz, CDCl3) δ ppm 197.7, 159.1, 148.3, 145.6, 139.4, 133.5, 130.0, 129.6, 129.5, 128.1, 128.0,
127.6, 127.3, 127.1, 121.6, 77.3, 73.7, 55.8, 52.1, 31.1, 21.7, 21.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C26H28NO3+ 402.2064; Found 402.2065.
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(S)-2-hydroxy-3-((2-(hydroxybis(4-(trifluoromethyl)phenyl)methyl)pyrrolidin-1-yl)methyl)-5-methylbenzaldehy
de (6b).11b White foam, 1.37 g, 72% yield. [α]D = +31.3 (c =0.83, CHCl3); 1H NMR (400 MHz, CDCl3) δ ppm 9.80
(s, 1H), 7.88 (J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.56-7.52 (m, 4H), 7.20 (d, J = 1.3 Hz, 1H), 7.05 (d, J =
1.7 Hz, 1H), 4.04-4.00 (m, 1H), 3.33 (d, J = 12.8 Hz, 1H), 3.24 (d, J = 12.9 Hz, 1H), 2.94-2.89 (m, 1H),
2.50-2.44 (m, 1H), 2.28 (s, 3H), 1.95-1.84 (m, 1H), 1.66-1.52 (m, 3H).
(S)-2-hydroxy-3-((2-(hydroxydi-p-tolylmethyl)pyrrolidin-1-yl)methyl)-5-methylbenzaldehyde (6c). White foam,
1.14 g, 75% yield, mp 54.3-55 oC, [α]D = +43.2 (c =0.74, CHCl3); IR 2920, 2864, 1648, 1617, 1604, 1508, 1458,
1377, 1263, 1213, 1164, 1098, 1020, 867, 807, 715, 599, 568, 511 cm-1; 1H NMR (400 MHz, CDCl3) δ ppm 9.78
(s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 1.5 Hz, 1H), 7.08-7.02 (m, 5H), 3.98-3.92
(m, 1H), 3.35-3.24 (m, 1H), 2.91-2.85 (m, 1H), 2.45-2.38 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H),
1.96-1.86 (m, 1H), 1.76-1.67 (m, 1H), 1.62-1.51 (m, 2H). 13C{1H} NMR(100 MHz, CDCl3) δ ppm 196.4, 157.6,
145.3, 144.2, 138.6, 135.7, 135.6, 132.0, 128.9, 128.7, 128.6, 128.0, 125.6, 125.4, 120.2, 70.8, 55.4, 53.8, 29.7,
23.8, 21.0, 20.9, 20.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H32NO3+ 430.2377; Found 430.2381.
General Procedure for the Preparation of Ligands 3. To a suspension of aldehyde 6 (1.57 mmol, 1.0
equiv) in EtOH (8.0 mL) was added (S)-pyrrolidin-2-ylbisphenylmethanol 78a (1.73 mmol, 1.1 equiv). The
reaction was stirred at rt for 2 h. NaBH4 (66 mg, 1.73 mmol, 1.1 equiv) was added in one portion and the
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mixture was stirred at rt for additional 3 h before phosphate buffer (50 mL) (pH = 7) and EtOAc (50 mL) were
added. The layers were separated and the aqueous phase was extracted with EtOAc (3 X 100 mL). The
combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to yield a white residue.
The crude product was purified by flash column chromatography on silica gel (Petroleum ether:EtOAc =
20:100) to yield L3 as a white foam.
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2-(((S)-2-(hydroxydiphenylmethyl)azetidin-1-yl)methyl)-6-(((S)-2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)meth
yl)-4-methylphenol (L3a). 0.92 g, 94% yield, mp 78.3-79.1 °C; [α]D = +50.6 (c = 0.66, CHCl3); IR 2953, 1599,
1
1475, 1447, 1032, 988, 866, 745, 697, 637 cm-1; H NMR (400 MHz, CDCl3) δ ppm 7.66 (d, J = 7.8 Hz, 2H),
7.58-7.53 (m, 4H), 7.43 (d, J = 7.6 Hz, 2H), 7.33-7.25 (m, 8H), 7.23-7.09 (m, 4H), 6.58 (s, 1H), 6.52 (s, 1H),
4.37 (s, 1H), 3.94 (s, 1H), 3.33-3.17 (m, 5H), 2.87-2.83 (m, 2H), 2.39-2.35 (m, 1H), 2.28-2.20 (m, 1H), 2.13 (s,
3H), 2.08-1.95 (m, 2H), 1.78-1.51 (m, 4H), 1.21 (m, 1H); 13C{1H} NMR(100 MHz; CDCl3) δ ppm 152.6, 146.5,
129.0, 128.6, 128.3, 128.2, 128.0, 127.4, 127.0, 126.8, 126.7, 126.4, 126.0, 125.95, 124.2, 78.8, 72.7, 71.5,
+
65.8, 58.0, 57.5, 55.1, 50.1, 29.6, 24.1, 20.4, 19.5, 15.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C42H45N2O3
625.3425; Found 625.3427.
2-(((S)-2-(hydroxydi-p-tolylmethyl)pyrrolidin-1-yl)methyl)-6-(((S)-2-(hydroxydiphenylmethyl)azetidin-1-yl)meth
yl)-4-methylphenol (L3b). 0.97 g, 95% yield, mp 83.4-84.1 °C; [α]D = +51.3 (c = 0.67, CHCl3); IR 2970, 1601,
1476, 1447, 1380, 1249, 1159, 1066, 990, 866, 808, 783, 699, 743, 635, 569 cm-1; 1H NMR (400 MHz, CDCl3) δ
ppm 7.57 (d, J = 7.4 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.45-7.39 (m, 5H), 7.32-7.24 (m, 5H), 7.22-7.18 (m, 1H),
7.17-7.14 (m, 1H), 7.10-7.05 (m, 5H), 6.59 (s, 1H), 6.54 (s, 1H), 4.43-4.38 (t, J = 7.9 Hz, 1H), 3.95-3.91 (m, 1H),
3.41 (d, J = 12.8 Hz, 1H), 3.28-3.18 (m, 3H), 3.13-3.09 (d, J = 13.2 Hz, 1H), 2.93-2.80 (m, 2H),2.43-2.35 (m,
1H), 2.28 (s, 3H), 2.26 (s, 1H), 2.24-2.21 (m, 5H), 2.13 (s, 3H), 1.99-1.95 (m, 1H), 1.82-1.74 (m, 1H), 1.65-1.58
(m, 1H), 1.57-1.48 (m, 1H); 13C{1H} NMR(100 MHz; CDCl3) δ ppm 152.7, 146.1, 144.2, 144.1, 143.7, 136.1,
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135.9, 129.0, 128.9, 128.8, 128.6, 128.3, 128.2, 128.1, 127.4, 127.0, 126.8, 126.0, 125.9, 125.72, 125.70,
125.3, 123.9, 122.0, 78.8, 76.6, 75.6, 71.6, 57.9, 57.3, 55.1, 50.0, 29.5, 24.0, 21.0, 20.96, 20.45, 19.5. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C44H49N2O3+ 653.3738; Found 653.3738.
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2-(((S)-2-(hydroxydi-p-tolylmethyl)azetidin-1-yl)methyl)-6-(((S)-2-(hydroxydi-p-tolylmethyl)pyrrolidin-1-yl)met
hyl)-4-methylphenol (L3c). 0.99 g, 93% yield, mp 81.0-81.6 °C; [α]D = +52.0 (c = 0.67, CHCl3); IR 2965, 2920,
1
1610, 1509, 1475, 1168, 1098, 1038, 1020, 990, 864, 809, 782, 597, 571 cm-1; H NMR (400 MHz, CDCl3) δ
ppm 7.52 (d, J = 8.1 Hz, 2H), 7.43-7.39 (m, 5H), 7.31-7.29 (m, 2H), 7.11-7.04 (m, 9H), 6.60 (s, 1H), 6.53 (s, 1H),
4.36-4.32 (t, J = 8.0 Hz, 1H), 3.95-3.91 (dd, J = 5.0, 9.1 Hz, 1H), 3.38-3.26 (m, 2H), 3.24- 3.13 (m, 3H),
2.88-2.80 (m, 2H), 2.43-2.36 (m, 1H), 2.28-2.22(m, 14H), 2.13 (s, 3H), 1.98-1.94 (m, 1H), 1.81-1.73 (m, 1H),
1.65-1.55 (m, 1H), 1.53-1.46 (m, 1H); 13C{1H} NMR(100 MHz; CDCl3) δ ppm 152.7, 144.3, 143.8, 143.1, 141.5,
136.5, 136.2, 136.0, 135.8, 129.1, 128.99, 128.97, 128.92, 128.7, 127.4, 125.85, 128.81, 125.7, 124.2, 121.8,
78.6, 76.5, 72.8, 71.4, 58.0, 57.2, 55.1, 50.0, 29.6, 24.0, 21.06, 21.01, 20.98, 20.95, 20.4, 19.5. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C46H53N2O3+ 681.4051; Found 681.4051.
2-(((S)-2-(hydroxybis(4-(trifluoromethyl)phenyl)methyl)pyrrolidin-1-yl)methyl)-6-(((S)-2-(hydroxydi-p-tolylmeth
yl)azetidin-1-yl)methyl)-4-methylphenol (L3d). 1.19 g, 96% yield, mp 81.8-82.3 °C; [α]D = +41.2 (c = 0.67,
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CHCl3); IR 2969, 2867, 1615, 1510, 1477, 1414, 1322, 1161, 1119, 1067, 1016, 815, 770, 596, 572 cm-1; H
NMR (400 MHz, CDCl3) δ ppm 7.88 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.0 Hz, 4H), 7.40
(d, J = 7.8 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.61 (s, 1H), 6.51
(s, 1H), 4.33-4.29 (t, J = 8.0 Hz, 1H), 4.00-3.97 (m, 1H), 3.34 (d, J = 12.5 Hz, 1H), 3.27-3.21 (m, 2H), 3.17-3.11
(m, 2H), 2.86-2.75 (m, 2H), 2.49-2.42 (m, 1H), 2.33-2.24 (m, 8H), 2.13-2.08 (m, 4H), 1.98-1.88 (m, 1H),
1.67-1.57 (m, 2H), 1.47-1.35 (m, 1H); 13C{1H} NMR(100 MHz; CDCl3) δ ppm 152.8, 151.3, 150.2, 142.3, 141.2,
136.9, 136.6, 129.6, 129.1, 129.0, 128.8 (q, J = 32.6 Hz), 128.6 (q, J = 31.1 Hz), 127.5, 126.5, 126.2, 126.0,
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125.9, 125.2 (q, J = 3.8 Hz), 125.0 (q, J = 3.8 Hz), 124.2 (q, J = 271.9 Hz), 124.15 (q, J = 271.9 Hz), 121.1, 78.0,
77.1, 73.2, 70.5, 60.6, 55.6, 54.9, 50.3, 29.8, 23.7, 21.0, 20.9, 20.4, 19.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C46H47F6N2O3+ 789.3485; Found 789.3488.
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2-(((S)-2-(hydroxybis(4-(trifluoromethyl)phenyl)methyl)azetidin-1-yl)methyl)-6-(((S)-2-(hydroxybis(4-(trifluoro
methyl)phenyl)methyl)pyrrolidin-1-yl)methyl)-4-methylphenol (L3e). 1.27 g, 90% yield, mp 81.3-82.1 °C; [α]D
=
+37.2 (c = 0.68, CHCl3); IR 2970, 1731, 1616, 1478, 1413, 1320, 1252, 1161, 1117, 1066, 1016, 830, 770, 733,
667, 602, 512, 471 cm-1; 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J = 8.3 Hz, 2H), 7.67 (t, J = 8.5 Hz, 4H),
7.59-7.54 (m, 8H), 7.48 (d, J = 8.3 Hz, 2H), 6.54 (s, 1H), 6.48 (s, 1H), 4.45-4.41 (t, J = 8.0 Hz, 1H), 4.03-3.99 (m,
1H), 3.38 (d, J = 12.8 Hz, 1H), 3.29 (s, 2H), 3.25-3.19 (m, 2H), 2.96-2.90 (m, 1H), 2.87-2.82 (m, 1H), 2.47-2.40
(m, 1H), 2.16-2.11 (m, 4H), 2.02-1.93 (m, 2H), 1.73-1.62 (m, 2H), 1.59-1.50 (m, 1H); 13C{1H} NMR(100 MHz;
CDCl3) δ ppm 152.4, 150.5, 149.6, 149.3, 147.3, 129.5 (q, J = 32.4 Hz), 129.34 (q, J = 31.5 Hz),129.3, 129.2 (q,
J = 32.3 Hz), 129.0 (q, J = 32.4 Hz), 128.8, 126.3, 126.2, 126.13, 126.11, 125.5, 125.4, 125.38, 125.34, 125.27,
125.2, 124.6 (q, J = 271.6 Hz), 124.02 (q, J = 271.6 Hz), 123.98 (q, J = 271.1 Hz), 123.8, 122.73, 122.67, 121.6,
78.5, 76.4, 72.5, 71.0, 58.5, 57.5, 55.1, 29.6, 23.8, 20.3, 19.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C46H41F12N2O3+ 897.2920; Found 897.2923.
2-(((S)-2-(hydroxydi-p-tolylmethyl)azetidin-1-yl)methyl)-6-(((S)-2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)meth
yl)-4-methylphenol (L3f). 0.94 g, 92% yield, mp 76.4-77.1 °C; [α]D = +50.5 (c = 0.82, CHCl3); IR 3677, 2972,
2895, 1475, 1450, 1403, 1393, 1250, 1224, 1066, 879, 810, 744, 702, 638 cm-1; 1H NMR (400 MHz, CDCl3) δ
ppm 7.67 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.31-7.24 (m, 7H), 7.18-7.00 (m,
7H), 6.60 (s, 1H), 6.52 (s, 1H), 4.32 (t, J = 8.0 Hz, 1H), 3.98-3.94 (m, 1H), 3.28 (s, 2H), 3.21-3.12 (m, 3H),
2.87-2.81 (m, 2H), 2.44-2.37 (m, 1H), 2.29-2.21 (m, 8H), 2.13 (s, 3H), 1.99-1.93 (m, 1H), 1.80-1.72 (m, 1H),
1.65-1.56 (m, 1H), 1.54-1.42 (m, 1H); 13C{1H} NMR(100 MHz; CDCl3) δ ppm 152.6, 147.2, 146.6, 143.0, 141.4,
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136.6, 136.3, 129.2, 129.0, 128.9, 128.6, 128.2, 127.4, 126.6, 126.4, 125.9, 125.8, 124.4, 121.7, 78.7, 76.6,
72.9, 71.4, 58.6, 56.8, 55.1, 50.1, 29.7, 24.0, 21.1, 20.99, 20.4, 19.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C44H49N2O3+ 653.3738; Found 653.3740.
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2-(((S)-2-(hydroxybis(4-(trifluoromethyl)phenyl)methyl)azetidin-1-yl)methyl)-6-(((S)-2-(hydroxydiphenylmethy
l)pyrrolidin-1-yl)methyl)-4-methylphenol (L3g). 1.12 g, 94% yield, mp 77.3-77.9 °C; [α]D = +39.5 (c = 0.68,
CHCl3); IR 2967, 1615, 1477, 1448, 1413, 1322, 1162, 1067, 1016, 833, 767, 747, 702, 637, 602, 514 cm-1; 1H
NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.4 Hz, 2H), 7.57-7.49 (m, 10H), 7.33-7.27
(m, 4H), 7.19 (t, J = 7.4 Hz, 1H), 6.51 (s, 2H), 4.44 (t, J = 7.8 Hz, 1H), 3.97-3.94 (m, 1H), 3.41 (d, J = 13 Hz, 1H),
3.31-3.18 (m, 4H), 3.01-2.95 (m, 1H), 2.84-2.79 (m, 1H), 2.38-2.31 (m, 1H), 2.10 (s, 3H), 2.07-2.06 (m, 1H),
2.03-1.93 (m, 2H), 1.87-1.79 (m, 1H), 1.71-1.62 (m, 1H), 1.60-1.51 (m, 1H); 13C{1H} NMR(100 MHz; CDCl3) δ
ppm 152.6, 150.1, 147.7, 146.3, 146.1, 129.2 (q, J = 32.5 Hz), 129.1 (q, J = 32.3 Hz), 129.0, 128.6, 128.4,
128.2, 127.4, 126.9, 126.7, 126.3, 126.1, 125.9, 125.3 (q, J = 3.7 Hz), 125.2 (q, J = 3.6 Hz), 124.14 (q, J =
272.0 Hz), 124.13 (q, J = 271.9 Hz), 123.2, 122.4, 79.4, 75.9, 71.9, 71.7, 59.4, 56.2, 55.2, 50.0, 29.5, 24.1, 20.4,
19.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C44H43F6N2O3+ 761.3172; Found 761.3176.
General Procedure for the Synthesis of β,γ-Unsaturated α-Keto Amides 2. To a solution of potassium
salt6j (0.1 mol) in H2O (150 mL) at room temperature was added a solution of concentrated HCl. Then a great
deal of precipitation appeared and the reaction stirred at rt for 4 h. The precipitate was collected by filtration,
washed thrice with distilled water and dried under vacuum to furnish the keto-acid which was used as an
intermediate, without further purification.To a solution of keto-acid (20 mmol) in 30 mL dry CH2Cl2 was added 5
drops DMF followed by the corresponding oxalyl chloride (25 mmol, 1.25 equiv) drop by drop at 0 °C. Then the
reaction was stirred at rt for 4 h. Concentration in vacuo gave the keto acyl chloride which was used as an
intermediate without further purification. To a solution of keto acyl chloride in 30 mL dry DCM at 0 °C was
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added a solution of N-methylbenzeneamine (15 mmol) and Et3N (25 mmol) in 20 mL dry CH2Cl2 by dropping.
The reaction mixture was stirred at room temperature overnight. Then saturated aqueous NaHCO3 (100 mL)
was added and resulting mixture was extracted with dichloromethane (3 × 50 mL). The combined organic layer
was washed with brine (40 mL), dried over Mg2SO4, filtered, evaporated, and purified via column
chromatography on silica gel (eluent: n-pentane/ethyl acetate = 5:1).
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(E)-N-methyl-2-oxo-N,4-diphenylbut-3-enamide (2a). Yellow solid; 3.87 g, 73% yield in three steps; mp 90-92
oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.60 (d, J = 16.3 Hz, 1H), 7.52 (dd, J = 7.0, 2.0 Hz, 2H), 7.40 (td, J =
7.1, 6.2, 3.3 Hz, 3H), 7.32 (dd, J = 8.2, 6.3 Hz, 2H), 7.27 (dd, J = 7.8, 1.5 Hz, 1H), 7.23-7.16 (m, 2H), 6.76 (d, J
= 16.3 Hz, 1H), 3.44 (s, 3H);13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.1, 167.1, 147.5, 141.7, 134.0, 131.31,
129.6, 129.3, 129.1, 129.0, 128.9, 128.7, 128.1, 126.6, 125.4, 123.5, 36.5. IR: 1639, 1678, 1179, 729, 689,
cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16NO2+ 266.1176; Found 266.1179.
(E)-N-methyl-2-oxo-N,4-diphenylbut-3-enamide (2b). Yellow solid; 3.52 g, 63% yield in three steps; mp
127-129oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.60 (d, J = 16.3 Hz, 1H), 7.52 (dd, J = 7.0, 2.0 Hz, 2H), 7.40
(td, J = 7.1, 6.2, 3.3 Hz, 3H), 7.32 (dd, J = 8.2, 6.3 Hz, 2H), 7.27 (dd, J = 7.8, 1.5 Hz, 1H), 7.23-7.16 (m, 2H),
6.76 (d, J = 16.3 Hz, 1H), 3.44 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.6, 167.0, 148.5，147.7,
140.3, 134.4, 131.9, 131.6, 129.9, 129.5, 129.4, 129.2, 129.1, 128.7, 128.4, 128.2, 127.6, 123.9, 44.2, 13.2. IR:
1679, 1646, 1101, 769, 755, 700, 685 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18NO2+ 280.1332;
Found 280.1332.
(E)-N-benzyl-2-oxo-N,4-diphenylbut-3-enamide (2c). Yellow solid; 4.84 g, 71% yield in three steps; mp
117-119 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.62– 7.24 (m,14H), 7.05-7.02 (m, 2H), 6.72 (d, J = 16.36 Hz,
1H), 5.05 (s, 2H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.1, 167.0, 147.6, 140.1, 136.5, 134.0, 131.3,
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129.5, 129.4, 129.1, 128.8, 128.7, 128.7, 128.4, 128.0, 127.9, 123.6, 52.7. IR: 1681, 1640, 1179, 729, 689 cm-1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H20NO2+ 342.1489; Found 342.1488.
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(E)-4-(4-methoxyphenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2d). Yellow solid; 3.72 g, 63% yield in
three steps; mp 90-92 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.56 (d, J = 16.24 Hz, 1H), 7.50-7.47 (m, 2H),
7.34-7.25 (m, 3H), 7.21-7.18 (m, 2H), 6.91 (d, J = 8.68 Hz, 2H), 6.66-6.61 (m, 1H), 3.83 (s, 3H), 3.43 (d, J = 1.4
Hz, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.1, 167.3, 162.3, 147.4, 141.9, 130.6, 129.5, 128.0, 126.7,
126.5, 121.3, 114.6, 55.5, 36.5. IR: 1680, 1639, 1171, 837, 760, 733, 681 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C18H18NO3+ 296.1281; Found 296.1282.
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(E)-N-methyl-2-oxo-N-phenyl-4-(p-tolyl)but-3-enamide (2e). Yellow solid; 3.46 g, 62% yield three steps; mp
93-95 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.56 (d, J = 16.24 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.35-7.18 (m,
7H), 6.72 (d, J = 16.32 Hz, 1H), 3.44 (s, 3H), 2.38 (s, 3H);13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.3, 167.2,
147.7, 142.1, 141.8, 131.4, 129.8, 129.6, 128.8, 128.1, 126.6, 122.6, 36.6, 21.6. IR: 1644, 1594, 1114, 791,
774, 739, 698 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18NO2+ 280.1332; Found 280.1334.
(E)-4-(4-bromophenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2f). Yellow solid; 4.34 g, 63% yield in three
steps; mp 103-105 oC. 1H NMR (400 MHz, CDCl3): δ 7.55- 7.50 (m, 3H), 7.40-7.26 (m, 5H), 7.20-7.17 (m, 2H),
6.77 (d, J = 16.36 Hz, 1H); 3.44 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ 189.6, 166.8, 145.8, 141.7, 132.9,
132.3, 130.0, 129.6, 128.1, 126.5, 125.7, 123.9, 36.6. IR: 1663, 1644,1111, 814, 771 cm-1. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C17H15BrNO2+ 344.0281; Found 344.0282.
(E)-4-(4-chlorophenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2g). Yellow solid; 3.18 g, 53% yield in three
steps; mp 83-86 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.54 (d, J = 16.32 Hz, 1H), 7.46 (d, J = 8.48 Hz, 2H),
7.38-7.26 (m, 5H), 7.20-7.17 (m, 2H), 6.75 (d, J = 16.32 Hz, 1H), 3.44 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3):
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δ (ppm) 189.6, 166.8, 145.7, 141.7, 137.3, 132.5, 129.8, 129.6, 129.4, 128.1, 126.5, 123.8, 36.6. IR: 1661,
1644, 1087, 772, 696 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H15ClNO2+ 300.0786; Found 300.0786.
(E)-4-(4-fluorophenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2h). Yellow solid; 3.57 g, 63% yield in three
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steps; mp 80-82 C. H NMR (400 MHz, CDCl3): δ (ppm) 7.59-7.50 (m, 3H), 7.36-7.26 (m, 3H), 7.19 (d, J =
7.44Hz, 2H), 7.11-7.06 (m, 2H), 6.71 (d, J = 16.32 Hz, 1H), 3.44 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ
(ppm) 189. 8, 167.0, 164.5 (d, J = 253.4 Hz), 146.1, 141.8, 130.8 (d, J = 8.8 Hz), 129.6, 128.1, 126.5, 123.2 (d,
J = 2.2 Hz), 116.3 (d, J = 22.0 Hz), 36.6. IR: 1680, 1639, 1163, 839, 814, 769, 704, 692 cm-1. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C17H15FNO2+ 284.1081; Found 284.1082.
(E)-N-methyl-4-(4-nitrophenyl)-2-oxo-N-phenylbut-3-enamide (2i). Yellow solid; 3.41 g, 55% yield in three
steps; mp 139-141 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.26 (d, J = 8.44 Hz, 2H), 7.70-7.59 (m, 3H)
7.38-7.18 (m, 5H), 6.93 (d, J = 16.32 Hz, 1H), 3.45 (s, 3H). 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 189.2,
166.7, 149.3, 144.0, 142.0, 140.4, 130.1, 129.6, 128.7, 127.1, 126.9, 124.6, 37.1. IR: 1688,1641, 1091, 848,
766, 741, 681 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H15N2O4+ 311.1026; Found 311.1023.
(E)-4-(3,4-dimethylphenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2j). Yellow solid; 4.34 g, 74% yield in
three steps; mp 99.4-100.1 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.55 (d, J = 16.3 Hz, 1H), 7.34-7.24 (m, 5H),
7.20-7.14 (m, 3H), 6.70 (d, J = 16.3 Hz, 1H), 3.44 (s, 3H), 2.28 (d, J = 5.6 Hz, 6H); 13C{1H} NMR(100 MHz,
CDCl3): δ (ppm) 190.4, 167.3, 148.0, 141.8, 140.9, 137.4, 131.7, 130.3, 129.9, 129.6, 128.0, 126.6, 126.5,
122.4, 36.5, 20.0, 19.8. IR: 2921, 1643, 1620, 1594, 1494, 1449, 1423, 1388, 1303, 1254, 1237, 1214, 1198,
1178, 1157, 1073, 1033, 1019, 998, 981, 956, 917, 890, 874, 822, 799, 774, 699, 629, 542, 471 cm-1. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C19H20NO2+ 294.1489; Found 294.1492.
(E)-4-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2k). Yellow solid; 4.52 g, 73% yield
in three steps; mp 89-91oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.50 (d, J = 10.76 Hz, 1H), 7.34-7.27 (m, 3H),
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7.19 (d, J = 5.00 Hz, 2H), 7.03-7.01 (m, 2H), 6.81 (d, J = 5.28 Hz, 1H), 6.59 (d, J = 10.80 Hz, 1H), 6.01 (s,2H),
3.43 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 189.9, 167.2, 150.6, 148.5, 147.3, 141.8, 129.6, 129.3,
128.5, 126.5, 125.8, 125.4, 121.6, 108.7, 106.7, 101.8, 36.5. IR: 1639, 1678, 1179, 729, 689, cm-1 . HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C18H16NO4+ 310.1074; Found 310.1078.
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(E)-4-(3-bromophenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2l). Yellow solid; 3.86 g, 56% yield in three
steps; mp 79-81 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.95 (d, J = 16.32 Hz, 1H), 7.62 (d, J = 7.88 Hz, 1H),
7.56 (d, J = 7.76, 1H), 7.37-7.22 (m, 7H), 6.65 (d, J = 16.32 Hz, 1H), 3.46 (s, 3H); 13C{1H} NMR(100 MHz,
CDCl3): δ (ppm) 190.6, 167.2, 146.2, 141.9, 134.4, 134.0, 132.5, 130.0, 129.8, 128.6, 128.4, 128.3, 127.2,
126.4, 37.0. IR: 1641,1591,1174, 831, 771, 760, 697 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H15BrNO2+ 344.0281; Found 344.0281.
(E)-4-(3-bromophenyl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2m). Yellow solid; 2.90 g, 52% yield in three
steps; mp 75-78 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.58 (d, J = 16.32 Hz, 1H), 7.35-7.26 (m, 6H),
7.25-7.22 (m, 1H), 7.21-7.18 (m, 2H), 6.74 (d, J = 16.32 Hz, 1H), 3.44 (s, 3H), 3.36 (s, 3H); 13C{1H} NMR(100
MHz, CDCl3): δ (ppm) 190.2, 167.1, 147.7, 141.8, 138.8, 134.0, 132.2, 129.6, 129.3, 128.9, 128.0, 126.6, 126.0,
123.3, 36.5, 21.3. IR: 1644,1592,1176, 829, 775, 763, 695 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H18NO2+ 280.1332; Found 280.1333.
(E)-4-(furan-2-yl)-N-methyl-2-oxo-N-phenylbut-3-enamide (2n). Yellow solid; 2.71 g, 53% yield in three steps;
mp 137-139 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.52 (s, 1H), 7.38-7.28 (m, 4H), 7.19 (d, J = 7.72 Hz, 2H),
6.72 (d, J = 3.08 Hz, 1H), 6.67-6.62 (m, 1H), 6.51-6.49 (m, 1H), 3.42 (d, J = 0.72 Hz, 3H). 13C{1H} NMR(100
MHz, CDCl3): δ (ppm) 189.6, 167.0, 150.7, 146.0, 141.8, 132.9, 129.6, 129.3, 128.0, 126.4, 126.4, 120.8, 117.5,
117.5, 113.0, 36.5. IR: 1640, 1618, 1110, 801, 773, 740, 697 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H14NO3+ 256.0968; Found 256.0965.
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(E)-N-methyl-2-oxo-N-phenyl-4-(thiophen-2-yl)but-3-enethioamide (2o). Yellow solid; 2.22 g, 41% yield in
three steps; mp 135-137 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.72 (d, J = 15.96 Hz, 1H), 7.48-7.06 (m, 8H),
6.59 (d, J = 15.92 Hz, 1H), 3.41 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (pp m) 189.4, 167.0, 141.8, 139.6,
132.9, 130.4, 129.6, 128.6, 128.1, 126.5, 122.1, 36.6. IR: 1639, 1678, 1179, 729, 689, cm-1 . HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H14NO2S+ 272.0740; Found 272.0743.
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(E)-N-methyl-4-(naphthalen-2-yl)-2-oxo-N-phenylbut-3-enamide (2p). Yellow solid; 3.22 g, 51% yield in three
steps; mp 137-139 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.95 (s, 1H), 7.87-7.73 (m, 4H), 7.65-7.61 (m, 1H),
7.56-7.49 (m, 2H), 7.35-7.20 (m, 4H), 6.88 (d, J = 16.24 Hz, 1H), 3.46 (s, 3H);13C{1H} NMR(100 MHz, CDCl3): δ
(ppm) 190.0, 167.1, 147.5, 141.8, 134.7, 133.2, 131.6, 131.2, 129.6, 128.9, 128.8, 128.1, 127.8, 127.8, 129.9,
126.6, 123.6, 123.5, 36.6. IR: 1641, 1612, 1109, 855, 814, 752, 697 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C21H18NO2+ 316.1332; Found 316.1332.
(E)-N-(4-methoxyphenyl)-N-methyl-2-oxo-4-phenylbut-3-enamide (2q). Yellow solid; 3.60 g, 61% yield in
three steps; mp 99-101 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59-7.55 (m, 1H), 7.53-7.51 (m, 2H),
7.42-7.38 (m, 3H), 7.11 (d, J = 8.84 Hz, 2H), 6.82 (d, J = 8.84 Hz, 2H), 6.72 (d, J = 16.36 Hz, 1H), 3.76 (s, 3H),
3.39 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.7, 167.3, 159.2, 147.4, 134.3, 134.1, 131.3, 129.1,
127.7, 128.2, 123.6, 114.7, 55.4, 36.8. IR: 1641, 1591, 1174, 830, 771, 762, 700 cm-1. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C18H18NO3+ 296.1281; Found 296.1284.
(E)-N-methyl-2-oxo-4-phenyl-N-(p-tolyl)but-3-enamide (2r). Yellow solid; 3.41 g, 61% yield in three steps; mp
108-110 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.61-7.50 (m, 3H), 7.43-7.36 (m, 3H), 7.09 (dd, J = 8.24 Hz,
4H), 6.77-6.72 (m, 1H), 3.41 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.4, 167.2, 147.4,
139.1, 138.1, 134.1, 131.3, 130.2, 129.1, 128.7, 126.5, 123.6, 36.6, 21.1. IR: 1677, 1639, 1089, 825, 762 cm-1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18NO2+ 280.1332; Found 280.1333.
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(E)-N-(4-fluorophenyl)-N-methyl-2-oxo-4-phenylbut-3-enamide (2s). Yellow solid; 2.44 g, 43% yield in three
steps; mp 80-82 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.55-7.50 (m, 3H), 7.39-7.35 (m, 2H), 7.34-7.26 (m,
3H), 7.20-7.17 (m, 2H), 6.76 (d, J = 16.36 Hz, 1H), 3.43 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 190.0,
166.9, 161.8 (d, J = 247.3 Hz), 147.8, 137.7 (d, J = 3.1 Hz), 133.9, 131.4, 129.1, 128.8, 128.6 (d, J = 8.7 Hz),
123.4, 116.5 (d, J = 22.7 Hz), 36.8. IR: 1660, 1643, 1112, 840, 814, 765, 684 cm-1. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H15FNO2+ 284.1081; Found 284.1085.
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(E)-N-(4-chlorophenyl)-N-methyl-2-oxo-4-phenylbut-3-enamide (2t). Yellow solid; 3.36 g, 56% yield in three
steps; mp 92-94 oC. 1H NM R (400 MHz, CDCl3): δ (ppm) 7.54 (d, J = 10.84 Hz, 1H), 7.46 (d, J = 5.60 Hz, 1H),
7.38-7.28 (m, 5H), 7.18 (d, J = 4.96 Hz, 2H), 6.74 (d, J = 10.88 Hz, 1H), 3.44 (s, 3H); 13C{1H} NMR(100 MHz,
CDCl3): δ (ppm) 189.6, 166.8, 145.8, 141.7, 137.3, 132.5, 129.9, 129.6, 128.4, 128.1, 126.5, 123.8, 36.6. IR:
1647,1618,1115,875,766 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H15ClNO2+ 300.0786; Found
300.0783.
(E)-N-(4-bromophenyl)-N-methyl-2-oxo-4-phenylbut-3-enamide (2u). Yellow solid; 2.89 g, 42% yield in three
steps; mp 107-109 oC. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.63-7.58 (m, 1H), 7.55-7.53 (m, 2H), 7.46-7.39 (m,
5H), 7.07 (d, J = 8.28 Hz, 1H), 6.81 (d, J = 16.28 Hz, 1H), 3.41 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm)
189.7, 166.8, 147.9, 141.0, 133.9, 132.8, 131.5, 129.1, 128.8, 128.2, 123.3, 121.9, 36.6. IR: 1678, 1641, 835,
827, 762, 710 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H15BrNO2+ 344.0281; Found 344.0286.
(E)-4-(benzo[d][1,3]dioxol-5-yl)-N-(4-chlorophenyl)-N-methyl-2-oxobut-3-enamide (2v). Yellow solid; 2.74 g,
o
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40% yield in three steps; mp 107.2-107.8 C. H NMR (400 MHz, CDCl3): δ (ppm) 7.51 (d, J = 16.2 Hz, 1H),
7.31-7.26 (m, 2H), 7.13-7.03 (m, 4H), 6.83 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 16.2 Hz, 1H), 6.03 (s, 2H), 3.40 (s,
3H); 13C{1H} NMR(100 MHz, CDCl3): δ (ppm) 189.5, 167.0, 150.8, 148.5, 147.6, 140.5, 133.8, 129.8, 128.4,
127.8, 126.0, 121.3, 108.8, 106.8, 101.8, 36.6. IR: 1655, 1639, 1618, 1596, 1489, 1450, 1360, 1259, 1216,
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1092, 1033, 974, 927, 854, 809, 805, 771, 732, 548 cm-1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C18H14ClNNaO4+ 366.0504; Found 366.0506.
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General procedure for the Preparation of products 3. In a flame-dried Schlenk tube, a solution of
diethylzinc (50 μL, 1.0 M in hexane) was added to a solution of the chiral ligand L3d (9.2 mg, 10 mol%) in dry
CH3CN/CH2Cl2 (1/1, 2.5 mL) under nitrogen. The mixture was stirred at room temperature for 30 min. Then
Et3N (0.325mmol), 3-amino oxindole hydrochloride 1 (0.25 mmol), and β,γ-unsaturated α-keto amide 2 (0.275
mmol) were added to the mixture successively. The mixture was stirred at -45 °C until the starting material was
completely consumed (monitored by TLC). The solvent is evaporated to give the residue. Then the
trifluoroacetic acid (1 mL) and CH2Cl2 (1mL) was added to the residue, and the mixture was stirred at room
temperature for 0.5 h. Then the mixture was quenched with sat. aq NaHCO3 (15 mL) and extracted with CH2Cl2
(2 × 10 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude product was purified by column chromatography (CH2Cl2/acetone = 35/1)
to give the pure product 3.
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(3R,3'R,5'R)-1,1''-dimethyl-3'-phenyldispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione (3a). White
solid. mp 220.5-221 °C. 87 mg, 85% yield, >20:1 dr (determined by 1H NMR), 89% ee, HPLC (Chiral IA cloumn),
i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 15.56 min, t (major) = 11.52 min.
[α]D20 = +128.5 (c = 0.56, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.16–8.14 (m, 1H), 8.08 (d, J = 7.0 Hz, 1H),
7.37-7.33 (m, 1H), 7.23-7.20 (m, 1H), 7.12-7.07 (m, 2H), 7.05-6.96 (m, 5H), 6.88 (d, J = 7.7 Hz, 1H), 6.50-6.48
(m, 1H), 4.40-4.35 (dd, J = 5.8, 14.5 Hz, 1H), 3.32-3.25 (m, 4H), 3.10 (s, 3H), 2.85 (brs, 1H), 2.35-2.30 (dd, J =
5.9, 12.3 Hz, 1H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.4, 178.7, 142.5, 142.2, 135.1, 134.7, 131.0, 129.0,
128.6, 127.7, 127.5, 127.2, 125.6, 124.0, 123.6, 123.0, 108.2, 107.6, 73.4, 69.5, 56.0, 42.2, 26.6, 26.3. IR:
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3359, 2921, 1705, 1610, 1492, 1470, 1371,1346, 1120, 1089, 1078, 1025, 748,708 cm-1. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C26H24N3O2+ 410.1863; Found 410.1865.
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(3R,3'R,5'R)-1''-ethyl-1-methyl-3'-phenyldispiro[indol-ine-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione
(3b).
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White solid. mp 152.7-153.2 °C. 87 mg, 82% yield, >20:1 dr (determined by 1H NMR), 54% ee, HPLC (Chiral IC
cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 36.55 min, t (major) = 22.90
min. [α]D20 = +144.8 (c = 0.84, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.16-8.14 (m, 1H), 8.09 (d, J = 7.2 Hz,
1H), 7.35-7.31 (m, 1H), 7.22-7.18 (m, 1H), 7.10-7.06 (m, 2H), 7.04-6.96 (m, 5H), 6.89 (d, J = 7.2 Hz, 1H),
6.49-6.47 (m, 1H), 4.41-4.36 (dd, J = 5.8, 14.4 Hz, 1H), 3.84-3.80 (m, 2H), 3.32-3.26 (m, 1H), 3.10 (s, 3H),
2.34-2.29 (dd, J = 5.8, 12.3 Hz, 1H), 1.32-1.29 (m, 3H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.0, 178.7, 142.2,
141.6, 135.1, 134.9, 131.0, 129.0, 128.6, 127.7, 127.5, 127.2, 125.6, 124.2, 123.4, 122.9, 108.4, 107.6, 73.4,
67.5, 55.9, 42.3, 35.2, 26.3, 12.7. IR: 3357, 2913, 1703, 1610, 1487, 1465, 1369, 1349, 1119, 1080, 1024, 751,
694 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H26N3O2+ 424.2020; Found 424.2024.
(3R,3'R,5'R)-1''-benzyl-1-methyl-3'-phenyldispiro[indo-line-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione
(3c).
White solid. mp 198.3-198.8 °C. 99.5 mg, 82% yield, >25:1 dr (determined by 1H NMR), 70% ee, HPLC (Chiral
IA cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 14.25 min, t (major) =
11.36 min. [α]D20 = +137.6 (c = 1.06, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.18-8.16 (m, 1H), 8.12-8.09 (m,
1H), 7.31-7.23 (m, 5H), 7.21-7.15 (m, 2H), 7.11-6.97 (m, 7H), 6.77-6.75 (m, 1H), 6.49-6.47 (m, 1H), 5.02-4.92
(m, 2H), 4.43-4.38 (dd, J = 5.8, 14.4 Hz, 1H), 3.39-3.33 (m, 1H), 3.09 (s, 3H), 2.53 (brs, 1H), 2.39-2.35 (dd, J =
5.8, 12.2 Hz, 1H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.6, 178.7, 142.3, 141.6, 135.6, 135.1, 134.7, 131.0,
128.94, 128.87, 128.7, 127.75, 127.72, 127.6, 127.2, 125.6, 124.1, 123.7, 123.0, 109.3, 107.7, 73.5, 67.6, 55.9,
44.2, 42.5, 26.3. IR: 3359, 2920, 1705, 1612, 1486, 1466, 1454, 1349, 1256, 1189, 1157, 1080, 1026, 754, 739,
697 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H28N3O2+ 486.2176; Found 486.2183.
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(3d). White solid. mp 167.3-168.2 °C. 81 mg, 74% yield, >20:1 dr (determined by H NMR), 89% ee, HPLC
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(major) = 14.96 min. [α]D20 = +163.6 (c = 1.05, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 6.4 Hz, 1H),
8.07 (d, J = 7.2 Hz, 1H), 7.36-7.31 (m, 1H), 7.22-7.18 (m, 1H), 7.13-7.06 (m, 2H), 6.89-6.86 (m, 3H), 6.57-6.49
(m, 3H), 4.34-4.29 (dd, J = 5.7, 14.5 Hz, 1H), 3.65 (s, 3H), 3.27-3.18 (m, 4H), 3.09 (s, 3H), 2.84 (brs, 1H),
2.31-2.26 (dd, J = 5.8, 12.2 Hz, 1H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.5, 178.8, 158.6, 142.5, 142.3, 134.8,
131.2, 129.0, 128.6, 127.1, 125.6, 124.0, 123.6, 122.9, 113.1, 108.2, 107.7, 73.4, 67.4, 55.5, 55.1, 42.6, 26.6,
26.3. IR: 3348, 2921, 2851, 1715, 1699, 1611, 1514, 1490, 1467, 1371, 1346, 1245, 1121, 1080, 1020, 840,
744, 694 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H26N3O3+ 440.1969; Found 440.1972.
(3R,3'R,5'R)-1,1''-dimethyl-3'-(p-tolyl)dispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione (3e). White
solid. mp 163.4-164.7 °C. 86 mg, 81% yield, 17:1 dr (determined by 1H NMR), 79% ee, HPLC (Chiral IA
cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 15.79 min, t (major) = 11.19
min. [α]D20 = +179.6 (c = 0.90, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.15 (m, 1H), 8.07 (d, J = 7.2 Hz, 1H),
7.36-7.32 (m, 1H), 7.23-7.19 (m, 1H), 7.13-7.06 (m, 2H), 6.88-6.81 (m, 5H), 6.51 (d, J = 6.8 Hz, 1H), 4.37-4.32
(dd, J = 5.8, 14.4 Hz, 1H), 3.29-3.22 (m, 4H), 3.10 (s, 3H), 2.84 (brs, 1H), 2.32-2.28 (dd, J = 5.8, 12.2 Hz, 1H),
2.15 (s, 3H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.5, 178.8, 142.5, 142.3, 136.7, 134.8, 132.0, 131.2, 129.0,
128.6, 128.4, 127.4, 125.6, 124.0, 123.6, 122.9, 108.2, 107.6, 73.4, 67.4, 55.7, 42.5, 26.6, 26.3, 21.0. IR: 3348,
2923, 1708, 1611, 1491, 1468, 1372, 1346, 1118, 1083, 818, 749, 694 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C27H26N3O2+ 424.2020; Found 424.2024.
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(3R,3'R,5'R)-3'-(4-bromophenyl)-1,1''-dimethyldispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione (3f).
White solid. mp 167.7-168.3 °C. 90 mg, 74% yield, > 20:1 dr (determined by 1H NMR), 68% ee, HPLC (Chiral
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IA cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 17.86 min, t (major) =
15.25 min. [α]D20 = +116.2 (c = 1.32, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 6.9 Hz, 1H), 8.04 (d, J
= 7.2 Hz, 1H), 7.36-7.32 (m, 1H), 7.22-7.07 (m, 5H), 6.88-6.83 (m, 3H), 6.53 (d, J = 7.4 Hz, 1H), 4.33-4.28 (dd,
J = 5.7, 14.4 Hz, 1H), 3.26-3.18 (m, 4H), 3.11 (s, 3H), 2.83 (brs, 1H), 2.32-2.28 (dd, J = 5.8, 12.2 Hz, 1H).
13C{1H} NMR(100 MHz, CDCl3) δ 179.2, 178.5, 142.5, 142.2, 134.5, 134.2, 130.8, 130.7, 129.2, 129.1, 128.9,
125.6, 123.9, 123.6, 123.1, 121.2, 108.3, 107.9, 73.2, 67.4, 55.4, 42.4, 26.6, 26.3. IR: 3348, 2923, 1707, 1612,
1490, 1468, 1372, 1346, 1119, 1078, 1010, 837, 749, 693 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C26H23BrN3O2+ 488.0968; Found 488.0973.
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(3R,3'R,5'R)-3'-(4-chlorophenyl)-1,1''-dimethyldispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione (3g).
White solid. mp 185.7-186.3 °C. 93 mg, 84% yield, > 20:1 dr (determined by 1H NMR), 65% ee, HPLC (Chiral
IA cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 16.87 min, t (major) =
14.21 min. [α]D20 = +123.2 (c = 1.21, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.9 Hz, 1H), 8.04 (d, J
= 7.2 Hz, 1H), 7.37-7.32 (m, 1H), 7.23-7.19 (m, 1H), 7.15-7.10 (m, 2H), 7.01-6.99 (m, 2H), 6.91-6.86 (m, 3H),
6.53 (d, J = 7.4 Hz, 1H), 4.35-4.30 (dd, J = 5.8, 14.4 Hz, 1H), 3.28-3.18 (m, 4H), 3.11 (s, 3H), 2.82 (brs, 1H),
2.33-2.28 (dd, J = 5.8, 12.2 Hz, 1H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.3, 178.5, 142.5, 142.2, 134.5, 133.7,
133.0, 130.7, 129.1, 128.91, 128.89, 127.9, 125.6, 123.9, 123.6, 123.1, 108.3, 107.9, 73.3, 67.4, 55.3, 42.4,
26.6, 26.3. IR: 3348, 2921, 2851, 1706, 1611, 1468, 1491, 1372, 1346, 1120, 1083, 834, 750, 693 cm-1. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C26H23ClN3O2+ 444.1473; Found 444.1477.
(3R,3'R,5'R)-3'-(4-fluorophenyl)-1,1''-dimethyldispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione (3h).
White solid. mp 159.7-160.2 °C. 88 mg, 82% yield, > 20:1 dr (determined by 1H NMR), 70% ee, HPLC (Chiral
IA cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 15.81 min, t (major) =
12.67 min. [α]D20 = +169.1 (c = 0.98, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.2 Hz, 1H), 8.05 (d, J
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= 7.2 Hz, 1H), 7.36-7.32 (m, 1H), 7.22-7.19 (m, 1H), 7.14-7.06 (m, 2H), 6.95-6.86 (m, 3H), 6.74-6.69 (m, 2H),
6.51 (d, J = 7.1 Hz, 1H), 4.36-4.31 (dd, J = 5.7, 14.4 Hz, 1H), 3.27-3.18 (m, 4H), 3.10 (s, 3H), 2.83 (brs, 1H),
2.33-2.28 (dd, J = 5.8, 12.2 Hz, 1H). 13C{1H} NMR(100 MHz, CDCl3) δ 179.3, 178.6, 161.8 (d, J = 245.9 Hz),
142.5, 142.2, 134.6, 130.9, 129.1 (d, J = 2.7 Hz), 129.0 (d, J = 7.9 Hz), 128.8, 125.5, 124.0, 123.6, 123.0, 114.6
(d, J = 21.3 Hz), 108.3, 107.7, 73.4, 67.4, 55.3, 42.4, 26.6, 26.3. IR: 3348, 2930, 1708, 1611, 1509, 1491, 1468,
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1347, 1372, 1224, 1119, 1083, 835, 746, 694 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H23FN3O2
428.1769; Found 428.1773.
(3R,3'R,5'R)-1,1''-dimethyl-3'-(4-nitrophenyl)dispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione
(3i).
White solid. mp 199.2-201.1 °C. 75 mg, 66% yield, 22:1 dr (determined by 1H NMR), 43% ee, HPLC (Chiral IA
cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 33.72 min, t (major) = 25.53
min. [α]D20 = +85.4 (c = 0.79, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 6.7 Hz, 1H), 8.05 (d, J = 7.3
Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.38-7.35 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7.08 (m, 4H), 6.89 (d, J = 7.6 Hz,
1H), 6.53 (d, J = 7.2 Hz, 1H), 4.47-4.42 (dd, J = 5.7, 14.3 Hz, 1H), 3.33-3.26 (m, 4H), 3.13 (s, 3H), 2.87 (brs,
1H), 2.41-2.36 (dd, J = 5.8, 12.2 Hz, 1H). 13C{1H} NMR(100 MHz, CDCl3) δ 180.0, 178.1, 147.0, 143.0, 142.5,
142.0, 134.2, 130.2, 129.3, 128.4, 125.5, 123.9, 123.7, 123.3, 122.9, 108.4, 108.0, 73.4, 67.6, 55.4, 42.2, 26.6,
26.4. IR: 3348, 2924, 1715, 1614, 1511, 1491, 1469, 1373, 1343, 1119, 1082, 858, 746, 694 cm-1. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C26H23N4O4+ 455.1714; Found 455.1718.
(3R,3'R,5'R)-3'-(3,4-dimethylphenyl)-1,1''-dimethyldispiro[indoline-3,2'-pyrrolidine-5',3''-indoline]-2,2''-dione
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(3j). White solid. mp 159.3-160.5 °C. 78 mg, 72% yield, >60:1 dr (determined by H NMR), 84% ee, HPLC
(Chiral IA cloumn), i-PrOH/n-Hexane = 20/80, Flow rate: 1.0 mL/min, λ = 254 nm, t (minor) = 10.75 min, t
(major) = 9.49 min. [α]D20 = +210.0 (c = 1.33, in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.17 (m, 1H), 8.08-8.06
(m, 1H), 7.35-7.31 (m, 1H), 7.22-7.18 (m, 1H), 7.09-7.07 (m, 2H), 6.86 (d, J = 7.7 Hz, 1H), 6.77-6.75 (m, 2H),
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