Squaramide-catalysed asymmetric cascade reactions of 2,3-dioxopyrrolidines with 3-chlorooxindoles

Article abstract of DOI:10.1039/c9ob02663k

A highly efficient method for the enantioselective construction of dispirocyclic compounds has been developed by the squaramide-catalysed asymmetric Michael addition/cyclization cascade reaction of 2,3-dioxopyrrolidines with 3-chlorooxindoles. The corresp

Full text of DOI:10.1039/c9ob02663k

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DOI: 10.1039/C9OB02663K
Journal Name
ARTICLE
Squaramide−catalysed asymmetric cascade reactions of 2,3‐
dioxopyrrolidines with 3‐chlorooxindoles
Jiang‐Bo Wen, and Da‐Ming Du*a
a
Received 00th January 20xx,
Accepted 00th January 20xx
A highly efficient method for the enantioselective construction of dispirocyclic compounds has been developed by the
squaramide‐catalysed asymmetric Michael addition/cyclization cascade reaction of 2,3−dioxopyrrolidines with
DOI: 10.1039/x0xx00000x
3
−chlorooxindoles. The corresponding chiral dispiro[indoline‐3,1'‐cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐triones were
www.rsc.org/
obtained in high yields with excellent stereoselectivities (up to 94% yield, >25:1 dr and >99% ee). Furthermore, a gram‐scale
experiment confirmed the reliability of the current reaction and further effective transformation of the product has been
realized.
of 5‐membered lactams with a four‐carbon heterocyclic ring
8
Introduction
structure with biological interest, has also received attention
because of its pyrrole structural unit. Currently, 2‐
pyrrolidinones are found in many pharmaceuticals (Fig.2,
and in active natural products (Fig.2,
)9. Therefore, there
Recently spirooxindole has been greatly developed in organic
EG
)9
1
synthesis. Especially, spiro‐cyclopropane‐oxindoles, having
HG
significant framework in medicine (Fig. 1), shows important
pharmacological and biological activities, such as anti‐tumours may show some unexpected bioactivity when the spiro‐
2
3
4
5
(
A
), anti‐HIV (
B
), anti‐obesity (
C
), anti‐cancer (
D
) , which has cyclopropane‐oxindoles are combined with 2‐pyrrolidinones.
6
been got tremendous attention from scientists.
Fig. 2 Some natural products and pharmaceuticals comprising the 2‐
pyrrolidinones motifs.
To the best of our knowledge, the most organocatalytic
enantioselective reactions of 2,3‐dioxopyrrolidines are [4+2]
cyclization from 3‐carbonyl and 4‐methylene positions.10 The
Fig. 1 Some pharmaceuticals with the spiro‐cyclopropane‐oxindoles
motifs.
[
2+1] cycloaddition reaction only from 4‐methylene position is
Besides, it is well known that pyrrole is an important building
unit of biomolecules. Correspondingly 2‐pyrrolidinones, a class
11
rare. In 2018, Li and co‐workers obtained enantioenriched
spirocyclopropane compounds by one‐pot method, which
realized the transformation of 2,3‐dioxopyrrolidines from [4+2]
to [2+1] cycloaddition (Scheme 1a). In 2019, Jiang and co‐
7
a.
School of Chemistry and Chemical Engineering
Beijing Institute of Technology
South Zhongguancun Street, Beijing 100081 (P. R. China)
E‐mail: dudm@bit.edu.cn (D.‐M. Du)
12
workers realized asymmetric [3 + 2] cycloaddition of 2,3‐
dioxopyrrolidines (Scheme 1b). Herein, we try to use 3‐
chlorooxindoles to react with 2,3‐dioxopyrrolidines to produce
the target spirocyclic framework (Scheme 1c).
5
http://cce.bit.edu.cn/
Electronic Supplementary Information (ESI) available: Copies of 1H and 13C NMR
spectra of new compounds, and HPLC chromatograms. CCDC 1971523. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2019
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
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Journal Name
screen the catalysts and solvents (Table 1, entriesV1ie–w1A5rt)ic.leTOhnelirnee
are some inorganic bases (Table 1, entri
D
O
e
I
s
: 1
2
0.
–
1
9
03
)
9
a
/C
n
9
d
OB
o
0
r
2
g
6
anic
6
3
K
bases (Table 1, entries 10 and 11) were screened. According to
the results, the organic bases could not show the target product
3
aa with an excellent yield and enantioselectivity. In addition,
compared with inorganic bases, organic bases reduced the
product diasteroselectivity significantly (Table 1, entries 10–11).
In addition, the yield of product is still at an unsatisfactory level.
To our delight, the yield of the reaction significantly improved
4 3
with excellent ee and dr when using NH HCO (Table 1, entry 8).
The base loading of the reaction did not lead to considerable
improvement (Table 1, entries 12–15), according to the screen
results, 0.1 mmol base loading would still the best condition.
Scheme 1 Asymmetric synthesis of 2,3‐dioxopyrrolidine derivatives.
Results and discussion
In the initial study, 2,3‐dioxopyrrolidine 1a and 3‐
chlorooxindole 2a were chosen as model substrates to optimize
the reaction conditions. Firstly, various bases were evaluated in
dichloromethane at room temperature before starting to
Fig. 3 The screened organocatalysts for the reaction.
Consequently, the initial reaction was carried out with
NH HCO (0.1mmol) in CH Cl at room temperature in the
4 3 2 2
Table 1 Screening bases for the model reactiona
presence of cinchona‐derived squaramide catalysts (Fig. 3) to
screen for remaining optimal reaction conditions shown in
Table 2. A series of squaramide catalysts were first screened
(
Table 2, entries 1
catalyst C1, the ee value obtained by the catalysis of C2
or C11 is slightly reduced, but the yield is seriously degraded.
C6 C8 having the epimer configuration to C1 afforded the
opposite enantiomers with unsatisfactory yields and ee values
(Table 2, entries 6 8). Furthermore, a quinine‐derived thiourea

13). As the results display, compared with
b
drc
d
Entry
Slovent
Base
_
Catalyst Yield (%)
ee (%)
,
C5 C10
,
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
33
45
36
50
41
50
53
78
54
54
44
63
70
73
73
19:1
24:1
19:1
19:1
19:1
24:1
16:1
19:1
13:1
3:1
85
78
81
82
90
91
82
95
78
57
36
91
94
93
94
Na
2
CO
3

NaHCO
NaOH
3
K CO
2 3

KHCO
KOH
3
C14 screened in comparison with squaramide C1 showed an
unsatisfactory outcome (Table 2, entry 14). Thus, C1 is still the
best catalyst for the model reaction (Table 2, entry 1). Then, we
optimized the conditions such as solvent and temperature to
get the best result: 87% yield with >25:1 dr and 96% ee (Table
2, entry 24). Meanwhile, the effect of catalyst loading on the
reaction was explored which showed the product yield and ee
decreased slightly regardless of the catalyst loading was
reduced to 2.5mol% or increased to 7.5mol%.
NH
CsCO
Et
DBU
4
HCO
3
3
10
3
N
1
1e
6:1
12
NH
NH
NH
NH
4
HCO
4
HCO
4
HCO
4
HCO
3
3
3
3
24:1
24:1
24:1
19:1
f
g
h
13
14
15
a
Unless otherwise noted, the reactions were carried out with 1a (0.1 mmol),
2
a (0.12 mmol), catalyst (5 mol%) and base (0.1 mmol) in 1.0 mL of CH
2
2
Cl at
room temperature (25 C) for 1.5 h. b Isolated yield after purification by
With the optimized conditions in hand, the substrate scope
of the reaction was explored. First, we set out to investigate the
substrate scope of 3‐chlorooxindoles 2 whose data are collected
column chromatography. Determined by NMR analysis. d Determined by
HPLC analysis. e 0.5 mmol base was used. f 1.5 mmol base was used. g 2.0
c
h
mmol base was used. 3.0 mmol base was used.
in Scheme 2. When some electron‐withdrawing substituents,
2
| J. Name., 2019, 00, 1‐3
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a
such as F, Cl and Br was introduced to the phenyl ring, the Scheme 2 Substrate scope for asymmetric Michael addition reaction.
View Article Online
R1
DOI: 10.1039/C
R
4
9OB02663K
relevant products
enantioselectivities
(
3ab‐ae
(86 92%
>25:1 dr) with moderate to good
91%). However, when Br was introduced to 4‐
)
were obtained in good
O
Cl
C1
O
5
mol%
N
NH4HCO3 (1.0 equiv)
O
R1
+
R3
O
R2


ee) and excellent
N
N
R4
AcOEt, 0
oC, 2 h
N
O
R2
R3
diastereoselectivities (7:1
yields (55
O
1a-t
2a-i
3aa-ta

position of 3‐chlorooxindole, the corresponding product 3af
could be obtained in an obviously decreasing yield and
enantioselectivity. The above results imply that the electronic
property of the substituent on the phenyl ring had an extensive
role in the reactivity. Interestingly, when the benzyl was
introduced to the nitrogen atom of 3‐chlorooxindole, the
product 3ag retained an excellent yield and good
enantioselectivity. In contrast, the yield and ee value of 3ah
decreased slightly due to the introduction of methyl group on
nitrogen atom. Depressingly, when the methyl group was
O
O
O
O
O
NH
NH
NH
NH
NH
N
O
Ph
N
O
Br
Ph
N
O
Cl
Ph
N
O
F
Ph
N
O
Ph
O
O
O
Br
O
O
3
aa, 87%yield,
25:1dr, 96% ee
3ab, 76%yield,
>25:1 dr, 86% ee
3ac, 80%yield,
>25:1 dr, 90% ee
3ad, 91%yield,
24:1 dr, 92% ee
3ae, 55%yield,
>25:1 dr, 89% ee
>
Bn
O
N
Me
O
Me
O
O
O
N
NH
NH
NH
N
O
N
Ph
N
O
Ph
N
O
Me
Ph
N
O
Ph
Ph
O
Br
O
O
O
O
O
3
2
af, 72% yield,
0:1 dr, 59% ee
3ag, 94% yield,
>25:1 dr, 94% ee
3ah, 81% yield,
>25:1 dr, 88% ee
3ai, 71% yield,
7:1 dr, 93% ee
3ba, 84% yield,
>25:1dr, 91% ee
Me
MeO
MeO
OMe
O
Cl
O
O
O
O
NH
NH
NH
NH
NH
MeO
Ph
N
O
Ph
N
O
Ph
N
O
Ph
N
O
N
introduced to the phenyl ring of 2, the product 3ai was obtained
Ph
O
O
O
O
O
O
3ga, 89% yield,
>25:1 dr, 94% ee
with a bad yield and diastereoselectivity.
3ca, 75% yield,
25:1 dr, >99% ee
3
da, 83% yield,
3ea, 86% yield,
>25:1 dr, 93% ee
3fa, 72% yield,
>25:1 dr, 90% ee
>
>25:1dr, 96% ee
Cl
Br
Table 2 Optimization of reaction conditionsa
Br
O
O
O
O
O
NH
NH
NH
NH
NH
Cl
Cl
Br
Ph
N
O
Ph
N
O
Ph
N
O
Ph
N
O
Ph
N
O
O
O
O
O
O
3
ha, 77% yield,
3ia, 73% yield,
>25:1 dr, 92% ee
3ja, 83% yield,
>25:1 dr, 94% ee
3ka, 77% yield,
>25:1 dr, 95% ee
3la, 84% yield,
24:1 dr, 92% ee
>25:1 dr, 94% ee
F
O2N
F
O2N
O
O
O
O
O
NH
NH
NH
NH
NH
b
drc
16:1
>25:1
24:1
19:1
>25:1
>25:1
>25:1
>25:1
>25:1
24:1
>25:1
16:1
8:2
d
Entry
Slovent
Catalyst
C1
C2
C3
C4
C5
C6
C7
C8
Yield (%)
78
70
75
32
64
70
56
54
82
68
64
22
41
66
87
84
78
75
66
80
69
64
81
87
82
77
74
78
ee (%)
Ph
N
O
Ph
N
O
Ph
N
O
Ph
N
O
Ph
N
O
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
95
91
92
4
O
O
O
O
O
3
>
ma, 81% yield,
25:1 dr, 93% ee
3na, 70% yield,
>25:1 dr, >99% ee
3oa, 87% yield,
>25:1 dr, 85% ee
3pa, 50% yield,
>25:1 dr, 80% ee
3qa, 82% yield,
>25:1 dr, 93% ee
O
O
94
85
78
82
65
90
91
21
53
85
93
93
90
87
84
92
89
86
95
96
93
88
90
92
NH
NH
O
NH
Me
N
O
N
O
Ph
N
O
Br
O
O
O
3
ra, 85% yield,
25:1 dr, 94% ee
3sa, 71% yield,
>25:1 dr, 83% ee
3ta
,
73% yield,
>25:1 dr, 85% ee
>
C9
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
C10
C11
C12
C13
C14
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
a
Reactions were carried out by using 1 (0.1 mmol), 2 (0.12 mmol), catalyst C1
5 mol%) and NH HCO (0.1 mmol) in 1.0 mL of AcOEt at 0 C for 2 h. The dr
values were determined by NMR analysis. The ee values were determined by
(
4
3
HPLC analysis.
13:1
CH
3
CN
>25:1
>25:1
>25:1
24:1
24:1
>25:1
19:1
>25:1
24:1
>25:1
>25:1
>25:1
13:1
1
2
Subsequently, the R and R groups of substrates
1 were
AcOEt
DCE
inspected under the optimized conditions as shown in Scheme
. When phenyl ring included different halogens in the R1
position of 1, the corresponding products 3gana could be
obtained in moderate to good yields with excellent diastereo‐
and enantioselectivities. But the reaction with 2‐chlorophenyl
and 4‐fluorophenyl substrates had lower yields (3ia and 3na).
Unfortunately, the phenyl ring at the R position containing
electron‐withdrawing nitro group was awful to the reaction
CHCl
3
2
toluene
THF
PhCl
e
2
2
2
2
3
4
CH
CH
2
Cl
CN
2
e
e
3
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
1
f
25
g
2
e,h
2
2
7
(
3oa and 3pa). We suspect that it may be due to the excessive
electron withdrawing of the nitro group, which reduces the
reactivity of the reaction. When the phenyl ring at the R1
8e,i
C1
19:1
aUnless otherwise noted, the reactions were carried out with 1a (0.1 mmol),
2
a (0.12 mmol), catalyst (5 mol%) and NH
4
HCO
3
(0.1 mmol) in 1.0 mL of position of the
solvent at room temperature (25 C) for 1.5 h. Isolated yield after corresponding products 3ba
1
contained the methoxy or methyl groups, the
b

fa were obtained with good to
c
d
purification by column chromatography. Determined by NMR analysis.
Determined by HPLC analysis. The reaction was performed at 0 C for 2h.
excellent enantioselectivities. When naphthalene was at the R1
position of 1, the corresponding products 3qa and 3ra could be
obtained with excellent enantioselectivities and good yields. In
addition, the effect of substituents R on the benzene ring
e
f
The reaction was performed at ‒20 C for 4 h. g The reaction was performed
at 50 C for 0.5h. h 2.5 mol% catalyst was used. 7.5 mol% catalyst was used.
i
2
connected to N on the reaction was also explored. It was found
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that the introduction of the electron withdrawing group and the enantioselectivity with the same excellent diasterVeieowsAertlieclcetOivnliitnye
electron donating group resulted in a decrease in the yield and (86% yield and 95% ee, >25:1 dr).
DOI: 10.1039/C9OB02663K
ee value of the products (3sa and 3ta).
Scheme 4 Gram scale synthesis of 3aa
.
Afterwards, we chose 3aa as the starting material to try to
reduce the carbonyl group to a hydroxyl group by NaBH(OAc)
in CH Cl at room temperature. As a result, as shown in Scheme
, we obtained the reduced product 4a in 88% yield with
excellent diastereoselectivity and slightly lower
enantioselectivity (>25:1 dr, 92% ee).
3
2
2
Fig. 4 X‐ray crystal structure of 3ka
.
4
The absolute configuration of the target product was
identified by single crystal X‐ray diffraction analysis of 3ka.13
The absolute configuration of 3ka was determined to be (2’S,
3
R, 3’S) (Fig. 4). The absolute configurations of the other
products were assigned by analogy. By determining the
configuration, we tried to explain the mechanism of the
reaction. The catalyst C1 enhances the electrophilicity of
substrate 1a and activates substrate 2a through hydrogen
bonding. The oxindole–C‐3 of 3‐chlorooxindole completes the
Michael reaction by Re‐face attacking the β‐carbon atom of
substrate 1a. Then, the carbanion (adjacent to the carbonyl
group) produced by the Michael addition reaction attacks the C‐
Scheme 5 Transformations of product 3aa
.
To further explore the universality of the reaction, we
repeated the above reaction using 3‐bromooxindole. To our
surprise, we obtained the diastereomers of 3aa in 80% yield
with 95% ee and >25:1 dr.
4
position of the substrate 1a and removes the chlorine atom to
obtain the product 3aa
.
O
O
F3C
H
N
N
N
H
HN
OMe
C1
O
O
O
N
O
Cl
Ph
NH
N
H
N
H
Ph
O
N
O
Scheme 6 Michael reaction of 2,3‐dioxopyrrolidine with 3‐
bromooxindole.
+
N
N
Ph
H
Ph
O
1a
2a
O
3
aa
O
O
O
Conclusions
N
N
H
H
O
Ph
N
In summary, we have developed a highly enantioselective
Michael addition/cyclization cascade reaction of 2,3‐
dioxopyrrolidines with 3‐chlorooxindoles catalyzed by a chiral
squaramide catalyst derived from quinine. The desired
dispirocyclic products bearing three adjacent chiral centers
were obtained in good to excellent yields (up to 94%) with
excellent stereoselectivities (up to >25:1 dr and >99% ee). The
gram‐scale experiment was also successfully performed with
excellent stereoselectivity. Furthermore, in the further
conversion of the product, we have found that in the presence
N
O
H
N
O
N
O
H
O
Cl
Ph
N
Ph
O
HN
H
Cl
O
N
Ph
H
NH
B
Re-face
attack
A
Scheme 3 Proposed reaction mechanism.
In order to demonstrate the preparative utility and
robustness of this reaction, the reaction of 1a and 2a was
performed on a gram‐scale. Under the optimal conditions, the
target product 3aa can be obtained in a slightly lower yield and
3
of NaBH(OAc) , the carbonyl group of 3aa can be reduced to a
hydroxyl group to give product 4a. This cascade reaction may
provide a convenient method for the synthesis of potentially
4
| J. Name., 2019, 00, 1‐3
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bioactive pyrrolidine derivatives in which spiro‐cyclopropane‐ (2'S,3R,3'S)‐6‐Bromo‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
View Article Online
DOI: 10.1039/C9OB02663K
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ab). 3ab was
oxindoles were combined with 2‐pyrrolidinones.
obtained as a white solid (36.1 mg, 76% yield), m.p. 89−91 °C. HPLC
(
Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, t = 34.0 min
minor), t = 20.5min (major); minor diastereoisomer, t = 12.6 min;
= ‒53.9 (c 8.35, CH Cl ):
): δ9.29 (s, 1H, NH), 7.81–7.74 (m, 3H, ArH),
.35–7.31 (m, 5H, ArH), 7.24–7.20 (m, 2H, ArH), 7.16–7.14 (m, 2H,
ArH), 7.03–7.01 (m, 1H, ArH), 4.41 (d, J = 12.4 Hz, 1H, CH ), 4.29 (d, J
12.8 Hz, 1H, CH ):
), 4.09 (s, 1H, CH) ppm; 13C NMR (100 MHz, CDCl
Experimental
R
(
R
R
General Methods: All solvents commercially and available chemicals
were used without further purification. The column chromatography
was performed with silica gel (200−300 mesh) using mixtures of
petroleum ether and ethyl acetate. Melting points were determined
with a XT‐4 melting‐point apparatus without corrected. H NMR
spectra were measured with Bruker Ascend 400 MHz spectrometer,
2
0
8
6% ee for the major diastereoisomer. []
H NMR (400 MHz, CDCl
D
2
2
1
3
7
1
2
=
2
3
δ 194.0, 172.1, 157.3, 141.8, 141.7, 138.2, 129.6, 129.3, 128.8, 128.4,
and chemical shifts were reported in δ (ppm) units relative to
1
3
127.0, 126.3, 125.6, 123.8, 122.4, 119.3, 113.5, 45.8, 43.8, 43.5, 42.9
tetramethylsilane (TMS) as the internal standard. C NMR spectra
were measured at 100 MHz with Bruker Ascend 400 MHz
spectrometer and chemical shifts are reported in δ (ppm) units
relative to tetramethylsilane and referenced to the solvent peak
7
9
+
ppm. HRMS (ESI): m/z calcd for C25
H
18
N
2
O
3
Br [M + H] 473.0495,
8
1
+
found 473.0507; calcd for C25
75.0485.
H
18
N
2
O
3
Br [M + H] 475.0475, found
4
(
3
CDCl , δ(C) = 77.00 ppm, acetone‐d6 δ(C) = 30.83 ppm, DMSO‐d6
1
9
δ(C) = 39.43 ppm). F NMR spectra were measured at 376 MHz with (2'S,3R,3'S)‐6‐Chloro‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
Bruker Ascend 400 MHz spectrometer. Proton coupling patterns are cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ac). 3ac was
described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet obtained as a white solid (34.4 mg, 80% yield), m.p. 178−180 °C. HPLC
(
m). High‐resolution mass spectra were obtained with an Agilent (Daicel Chiralpak IB, n‐hexane/2‐propanol = 80:20, flow rate 1.0
6
520 Accurate‐Mass‐Q‐TOF MS system equipped with an mL/min, detection at 254 nm): major diastereoisomer, t
R
= 14.6 min
electrospray ionization (ESI) source. The enantiomeric excesses were (minor), t = 24.8 min (major); minor diastereoisomer, t
R
R
= 20.1 min;
2
0
determined by chiral HPLC analysis using an Agilent 1200 LC 90% ee for the major diastereoisomer. []
D
2 2
= ‒58.4 (c 7.95, CH Cl ).
1
instrument with Daicel Chiralpak IA, IB, IC or AD‐H columns. Optical
3
H NMR (400 MHz, CDCl ): δ 9.07 (s, 1H, NH), 7.87 (d, J = 8.4 Hz 1H,
rotations were measured with Krüss P8000 polarimeter at the ArH), 7.78 (d, J = 8.4 Hz, 2H, ArH), 7.38–7.34 (m, 5H, ArH), 7.24 (t, J
o
indicated concentration with the units of grams per 100 mL at 20 C = 7.8 Hz, 1H, ArH), 7.17–7.15 (m, 2H, ArH), 7.09 (dd, J
1
2
= 8.4 Hz, J =
using sodium D light.
1.2 Hz, 1H, ArH), 6.87 (d, J = 1.6 Hz, 1H, ArH), 4.43 (d, J = 12.8 Hz, 1H,
1
3
CH
2
), 4.31 (d, J = 12.8 Hz, 1H, CH
): δ 194.0, 172.1, 157.2, 141.6, 141.5, 138.2, 134.6,
29.6, 129.3, 128.8, 128.5, 127.0, 126.0, 123.2, 122.7, 119.3, 110.6,
2
), 4.11 (s, 1H, CH) ppm; C NMR
General procedure for asymmetric Michael addition/cyclization
reaction for synthesis of compound 3
(100 MHz, CDCl
3
1
4
To a dried small bottle were added 2,3‐dioxopyrrolidines
0.1mmol), 3‐chlorooxindoles (0.12 mmol), squaramide
catalyst C1 (5 mol%) and NH HCO (0.1 mmol) in 1.0 mL of AcOEt
at 0 C. The reaction mixture was stirred for 2 h and the progress
1
5.7, 43.8, 43.5, 43.0 ppm. HRMS (ESI): m/z calcd for C25
H
18
N
O
2 3
Cl
(
2
+
[
M + H] 429.1000, found 429.1015.
4
3

(
2'S,3R,3'S)‐6‐Fluoro‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
of the reaction was monitored by TLC analysis (Petroleum
ether/ ethyl acetate = 1:1). After the completion of the reaction,
the crude product mixture was purified by flash column
chromatography on silica (petroleum ether/ethyl acetate = 4:1)
to afford the pure product
prepared using an achiral catalyst.
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ad). 3ad was
obtained as a light yellow solid (37.5 mg, 91% yield), m.p. 163−165 °C.
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
R
= 20.5
R
= 11.4
3. The racemic standard of 3 was
min (minor), t = 14.4 min (major); minor diastereoisomer, t
min; 92% ee for the major diastereoisomer. []
R
20
D
= ‒33.5 (c 12.75,
1
CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 9.01 (s, 1H, NH), 7.90 (dd, J
= 5.6 Hz, 1H, ArH), 7.76 (d, J = 7.6 Hz, 2H, ArH), 7.36–7.32
m, 5H, ArH), 7.22 (t, J = 7.4 Hz, 1H, ArH), 7.17–7.15 (m, 2H, ArH), 6.79
td, J = 9.0 Hz, J = 2.4 Hz, 1H, ArH), 6.57 (dd, J = 8.4 Hz, J = 2.4 Hz,
H, ArH), 4.41 (d, J = 12.8 Hz, 1H, CH ), 4.29 (d, J = 12.8 Hz, 1H, CH ),
.11 (s, 1H, CH) ppm; C NMR (100 MHz, CDCl ): δ 194.0, 172.4,
63.0 (d, J = 245.5 Hz), 157.4, 141.9 (d, J = 11.8 Hz), 138.2, 129.7,
1
=
(
2'S,3R,3'S)‐1'',3'‐Diphenyldispiro[indoline‐3,1'‐cyclopropane‐
8.8 Hz, J
2
2
',3''‐pyrrolidine]‐2,4'',5''‐trione (3aa). 3aa was obtained as a light
(
(
yellow solid (34.3 mg, 87% yield), m.p. 151−153 °C. HPLC (Daicel
Chiralpak IA, n‐hexane/ethyl acetate = 80:20, flow rate 1.0 mL/min,
1
2
1
2
1
4
1
1
2
4
2
2
detection at 254 nm): major diastereoisomer, t
= 40.3 min (major); minor diastereoisomer, t
R
= 52.1 min (minor),
= 45.6 min; 96% ee
13
3
t
R
R
1
3
2
0
1
for the major diastereoisomer. []
D
= ‒15.7 (c 13.0, CH
2
Cl
2
). H NMR
3
4
29.3, 129.2, 128.7, 128.4, 126.9, 126.4 (d, J = 9.7 Hz), 120.2 (d, J =
.8 Hz), 119.2, 109.1 (d, J = 22.2 Hz), 98.7 (d, J = 27.1 Hz), 45.8, 43.6,
(
(
400 MHz, CDCl
d, J = 7.6 Hz, 2H, ArH), 7.34–7.30 (m, 5H, ArH), 7.25–7.16 (m, 4H,
= 7.6 Hz, J = 0.8 Hz, 1H, ArH), 6.79 (d, J = 7.6 Hz, 1H,
ArH), 4.43 (d, J = 12.8 Hz, 1H, CH ), 4.28 (d, J = 12.8 Hz, CH ), 4.14 (s,
H, CH) ppm; C NMR (100 MHz, CDCl ): δ 193.9, 172.1, 157.4, 140.5,
3
): δ 9.01 (s, 1H, NH), 7.94 (d, J = 7.6 Hz 1H, ArH), 7.75
2
2
19
3.5, 42.8 ppm; F NMR (376 MHz, CDCl
3
): δ ‒110.7 ppm. HRMS (ESI):
ArH), 7.11 (td, J
1
2
+
m/z calcd for C25
H
18
N
2
O
3
F [M + H] 413.1296, found 413.1299.
2
2
1
3
1
1
1
C
3
(
2'S,3R,3'S)‐5‐Bromo‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
38.3, 129.8, 129.6, 129.2, 128.7, 128.2, 126.8, 124.94, 124.85, 122.6,
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ae). 3ae was
obtained as a white solid (26.1 mg, 55% yield), m.p. 174−176 °C. HPLC
19.2, 110.0, 46.1, 43.6, 43.5, 42.9 ppm. HRMS (ESI): m/z calcd for
+
25
H
19
N
2
O
3
[M + H] 395.1390, found 395.1390.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2019, 00, 1‐3 | 5
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 6 of 11
ARTICLE
Journal Name
(
Daicel Chiralpak IA, n‐hexane/ethyl acetate = 65:35, flow rate 1.0 (d, J = 8.0 Hz, 2H, ArH), 7.43‐7.34 (m, 6H, ArH), 7.28–7.24 (m, 1H, ArH),
View Article Online
DOI: 10.1039/C9OB02663K
R
mL/min, detection at 254 nm): major diastereoisomer, t = 10.3 min 7.17–7.14 (m, 3H, ArH), 6.94 (d, J = 7.6 Hz, 1H, ArH), 4.51 (d, J = 12.8
(
[
major), t
R
= 15.6 min (minor); 89% ee for the major diastereoisomer. Hz, 1H, CH
2
), 4.31 (d, J = 12.8 Hz, 1H, CH
) ppm; 13C NMR (100 MHz, CDCl
3
2
), 4.17 (s, 1H, CH), 3.30 (s,
): δ 194.0, 169.9, 157.3,
20
1
]
D
= ‒73.7 (c 10.70, CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 8.76 (s, 3H, CH
3
1H, NH), 8.11 (d, J = 1.6 Hz, 1H, ArH), 7.76 (d, J = 7.6 Hz, 2H, ArH), 143.3, 138.4, 129.71, 129.69, 129.2, 128.74, 128.66, 128.2, 126.7,
7
.40–7.31 (m, 6H, ArH), 7.26–7.22 (m, 1H, ArH), 7.16–7.14 (m, 2H, 124.7, 124.2, 122.7, 119.3, 108.1, 45.9, 43.4, 43.3, 42.9, 26.7 ppm.
+
ArH), 6.73 (d, J = 8.4 Hz, 1H, ArH), 4.43 (d, J = 12.8 Hz, 1H, CH
d, J = 12.8 Hz, 1H, CH
), 4.11 (s, 1H, CH) ppm; 13C NMR (100 MHz, 409.1545.
CDCl ): δ 193.9, 171.4, 157.2, 139.4, 138.2, 131.6, 129.7, 129.3, 129.2,
2
), 4.29 HRMS (ESI): m/z calcd for C26
H
21
N
2
O
3
[M + H] 409.1547, found
(
2
3
1
4
4
4
28.8, 128.4, 128.1, 127.0, 126.8, 119.3, 115.5, 111.3, 45.7, 43.9,
(
2'S,3R,3'S)‐6‐Methyl‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
7
9
+
3.4, 43.1 ppm. HRMS (ESI): m/z calcd for C25
H
18
N
2
O
3
1
Br [M + H]
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ai). 3ai was
obtained as a light yellow solid (29.0 mg, 71% yield), m.p. 167−169 °C.
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate
8
+
73.0495, found 473.0504; calcd for C25
75.0475, found 475.0487.
18 2 3
H N O Br [M + H]
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
R
= 21.3
= 11.9
= ‒32.5
(
2'S,3S,3'S)‐4‐Bromo‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
min (minor), t
R
= 15.7 min (major); minor diastereoisomer, t
R
2
0
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3af). 3af was min, t
obtained as a yellow solid (34.1 mg, 72% yield), m.p. 175−177 °C. (c 6.70, CH
R
= 14.2; 93% ee for the major diastereoisomer. []
D
1
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 8.57 (s, 1H, NH), 7.81 (t,
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate J = 7.4 Hz, 3H, ArH), 7.38–7.30 (m, 5H, ArH), 7.24 (t, J = 7.4 Hz, 1H,
.0 mL/min, detection at 254 nm): major diastereoisomer, t = 12.1 ArH), 7.17–7.15 (m, 2H, ArH), 6.94 (d, J = 7.6 Hz, 1H, ArH), 6.71 (s, 1H,
min (minor), t = 18.0 min (major); minor diastereoisomer, t = 10.6 ArH), 4.46 (d, J = 12.8 Hz, 1H, CH ), 4.28 (d, J = 12.8 Hz, 1H, CH ), 4.11
) ppm; 13C NMR (100 MHz, CDCl
): δ 194.0,
1
R
R
R
2
2
2
0
min, t
R
= 15.0 min; 59% ee for the major diastereoisomer. []
D
= ‒ (s, 1H, CH), 2.36 (s, 3H, CH
3
3
1
1
7
9.3 (c 4.30, DMSO). H NMR (400 MHz, CDCl
3
): δ 8.32 (s, 1H, NH), 172.4, 157.4, 140.5, 139.1, 138.4, 130.6, 129.7, 129.2, 128.7, 128.2,
.77 (d, J = 8 Hz, 2H, ArH), 7.39–7.31 (m, 6H, ArH), 7.24–7.19 (m, 3H, 126.8, 124.7, 123.3, 121.9, 119.2, 110.8, 46.1, 43.5, 42.9, 21.6 ppm.
+
ArH), 7.11 (t, J = 8 Hz, 1H, ArH), 6.85 (d, J = 8 Hz, 1H, ArH), 5.58 (s, 1H, HRMS (ESI): m/z calcd for C26
CH), 4.29 (d, J = 12.4 Hz, 1H, CH ), 4.08 (d, J = 12.4 Hz, 1H, CH ), ppm; 409.1550.
C NMR (100 MHz, DMSO‐d6): δ 192.9, 171.1, 157.7, 145.0, 138.8,
30.2, 130.0, 129.5, 129.0, 128.1, 127.4, 126.6, 125.8, 121.3, 120.1,
19.1, 108.9, 46.8, 44.4, 43.7, 37.7 ppm. HRMS (ESI): m/z calcd for
H
21
N
2
O
3
[M + H] 409.1547, found
2
2
1
3
1
1
C
C
(
2'S,3R,3'S)‐1''‐Phenyl‐3'‐(m‐tolyl)dispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ba). 3ba was
obtained as a light yellow solid (34.3 mg, 84% yield), m.p. 149−151 °C.
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate
7
9
+
25
H
H
18
N
N
2
O
O
3
Br [M + H] 473.0495, found 473.0503; calcd for
8
1
+
25
18
2
3
Br [M + H] 475.0475, found 473.0486.
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t = 15.8
R
(
2'S,3R,3'S)‐1‐Benzyl‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
min (minor), t = 12.4 min (major); minor diastereoisomer, t = 14.1
R
R
2
0
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ag). 3ag was min; 91% ee for the major diastereoisomer. []
obtained as a light yellow solid (45.3 mg, 94% yield), m.p. 129−131 °C. CH
D
= ‒30.0 (c 11.35,
): δ 9.18 (s, 1H, NH), 7.92 (d, J = 7.6
1
2
Cl
2
). H NMR (400 MHz, CDCl
3
HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 85:15, flow rate Hz, 1H, ArH), 7.72 (d, J = 8.0 Hz, 2H, ArH), 7.28 (t, J = 7.8 Hz, 2H, ArH),
.0 mL/min, detection at 254 nm): major diastereoisomer, t = 24.9 7.22–7.17 (m, 3H, ArH), 7.13–7.07 (m, 2H, ArH), 6.97 (d, J = 8.4 Hz,
min (major), t = 58.9 min (minor); 94% ee for the major 2H, ArH), 6.73 (d, J = 7.6 Hz, 1H, ArH), 4.42 (d, J = 12.8 Hz, 1H, CH ),
diastereoisomer. [] ) ppm;
CDCl ): δ 7.99 (d, J = 7.2, 1H, ArH), 7.85 (d, J = 8.0 Hz, 2H, ArH), 7.41 ): δ 193.9, 172.0, 157.3, 140.4, 138.4, 138.3,
t, J = 8.0 Hz, 2H, ArH), 7.35–7.24 (m, 10H, ArH), 7.15–7.10 (m, 3H, 130.3, 129.5, 129.2, 129.1, 128.64, 128.57, 126.8, 126.7, 125.0, 124.9,
1
R
R
2
20
1
D
2 2 2 3
= ‒15.5 (c 15.60, CH Cl ). H NMR (400 MHz, 4.29 (d, J = 12.8 Hz, 1H, CH ), 4.10 (s, 1H, CH), 2.29 (s, 3H, CH
1
3
3
C NMR (100 MHz, CDCl
3
(
ArH), 6.88 (d, J = 7.6 Hz, 1H, ArH), 5.05 (d, J = 15.2 Hz, 1H, CH
d, J = 15.6 Hz, 1H, CH ), 4.51 (d, J = 12.8 Hz, 1H, CH
Hz, 1H, CH
), 4.17 (s, 1H, CH) ppm; 13C NMR (100 MHz, CDCl
70.1, 157.3, 142.4, 138.4, 135.6, 129.71, 129.66, 129.2, 128.8, 128.7,
28.6, 128.3, 127.8, 127.4, 126.8, 124.8, 124.3, 122.8, 119.3, 109.1,
2
), 4.90 122.7, 119.2, 109.9, 46.1, 43.6, 43.5, 43.0, 21.4 ppm. HRMS (ESI): m/z
+
(
2
2
), 4.35 (d, J = 12.8 calcd for C26
): δ 194.1,
H
21
N
2
O
3
[M + H] 409.1547, found 409.1554.
2
3
1
1
4
(
2'S,3R,3'S)‐3'‐(2‐Methoxyphenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ca). 3ca was
obtained as a white solid (31.8 mg, 75% yield), m.p. 207−209 °C. HPLC
5.8, 44.2, 43.9, 43.6, 43.0 ppm. HRMS (ESI): m/z calcd for C32
M + H] 485.1860, found 485.1868.
H
25
N
2
O
3
+
[
(Daicel Chiralpak IC, n‐hexane/2‐propanol = 75:25, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, t
R
0
= 33.1 min
= ‒65.7 (c
2
(
2'S,3R,3'S)‐1‐Methyl‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
(major); >99% ee for the major diastereoisomer. []
D
1
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ah). 3ah was 11.85, CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ8.76 (s, 1H, NH), 8.05 (d,
obtained as a light yellow solid (33.1 mg, 81% yield), m.p. 149−151 °C. J = 7.6 Hz, 1H, ArH), 7.78 (d, J = 8.4 Hz, 2H, ArH), 7.377.31 (m, 3H,
HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate ArH), 7.277.20 (m, 2H, ArH), 7.12 (t, J = 7.6 Hz, 1H, ArH), 7.04 (d, J =
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
R
= 8.2 7.6 Hz, 1H, ArH), 6.946.88 (m, 2H, ArH), 6.83 (d, J = 7.6 Hz, 1H, ArH),
= 7.2 4.29 (d, J = 12.4 Hz, 1H, CH ), 4.01 (d, J = 12.4 Hz, 1H, CH ), 3.83 (s,
= ‒30.9 (c 15.60, 1H, CH), 3.63 (s, 3H, OCH ): δ194.5,
) ppm; 13C NMR (100 MHz, CDCl
min (major), t = 14.9 min (minor); minor diastereoisomer, t
min; 88% ee for the major diastereoisomer. []
CH
R
R
2
2
20
D
3
3
1
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 7.96 (d, J = 7.6, 1H, ArH), 7.84 172.4, 158.0, 157.5, 140.5, 138.5, 131.1, 129.8, 129.2, 128.5, 126.6,
6
| J. Name., 2019, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 11
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
ARTICLE
1
4
4
25.3, 125.2, 122.6, 120.4, 119.3, 117.7, 110.6, 109.7, 55.4, 45.7, (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate 1.0
View Article Online
DOI: 10.1039/C9OB02663K
R
+
4.8, 42.9, 41.4 ppm. HRMS (ESI): m/z calcd for C26
H
21
N
2
O
4
[M + H]
mL/min, detection at 254 nm): major diastereoisomer, t
= 18.8 min
25.1496, found 425.1492.
(minor), t
R
= 13.3 min (major); 94% ee for the major diastereoisomer.
20
1
[
]
D
2 2 3
= 20.9 (c 8.75, CH Cl ). H NMR (400 MHz, CDCl ): δ8.74 (s,
(
2'S,3R,3'S)‐1''‐Phenyl‐3'‐(p‐tolyl)dispiro[indoline‐3,1'‐
1H, NH), 7.92 (d, J = 7.6 Hz, 1H, ArH), 7.78 (d, J = 8.0 Hz, 2H, ArH),
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3da). 3da was 7.36 (t, J = 8.0 Hz, 2H, ArH), 7.317.22 (m, 4H, ArH), 7.137.10 (m,
obtained as a light yellow solid (33.9 mg, 83% yield), m.p. 158−160 °C. 3H, ArH), 6.88 (d, J = 7.6 Hz, 1H, ArH), 4.44 (d, J = 12.8 Hz, 1H, CH ),
2
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 75:25, flow rate
.0 mL/min, detection at 254 nm): major diastereoisomer, t = 28.1
min (minor), t = 22.3 min (major); 96% ee for the major
diastereoisomer. []
CDCl ): δ8.93 (s, 1H, NH), 7.94 (d, J = 7.6 Hz, 1H, ArH), 7.76 (d, J =
13
4
CDCl
1
4
4
.24 (d, J = 12.8 Hz, 1H, CH
2
), 4.08 (s, 1H, CH) ppm; C NMR (100 MHz,
1
R
3
): δ 193.7, 171.9, 157.3, 140.5, 138.2, 134.3, 131.2, 129.2,
28.9, 128.8, 128.1, 126.9, 124.9, 124.6, 122.7, 119.2, 110.1, 45.9,
3.5, 42.7, 42.6 ppm. HRMS (ESI): m/z calcd for C25H N O Cl [M + H]
18 2 3
R
2
0
1
D
2 2
= ‒29.8 (c 12.35, CH Cl ). H NMR (400 MHz,
+
3
29.1000, found 429.1010.
8
7
.0 Hz, 2H, ArH), 7.32 (t, J = 8.0 Hz, 2H, ArH), 7.257.19 (m, 2H, ArH),
.147.04 (m, 5H, ArH), 6.80 (d, J = 8.0 Hz, 1H, ArH), 4.43 (d, J = 12.8
(
2'S,3R,3'S)‐3'‐(2,4‐Dichlorophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ha). 3ha was
obtained as a light yellow solid (35.7 mg, 77% yield), m.p. 176‐178 °C.
Hz, 1H, CH
2
), 4.28 (d, J = 12.4 Hz, 1H, CH
2
), 4.10 (s, 1H, CH), 2.31 (s,
): δ 194.0, 172.1, 157.4,
40.5, 138.3, 138.1, 129.6, 129.4, 129.2, 128.6, 126.8, 126.4, 125.0,
1
3
3
1
1
3 3
H, CH ) ppm; C NMR (100 MHz, CDCl
22.6, 119.2, 109.9, 46.2, 43.6, 43.5, 43.0, 21.2 ppm. HRMS (ESI): m/z HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 75:25, flow rate
+
calcd for C26
H
21
N
2
O
3
[M + H] 409.1547, found 409.1554.
1.0 mL/min, detection at 254 nm): major diastereoisomer, t
min (minor), t = 16.5 min (major); 94% ee for the major
diastereoisomer. []
CDCl ): δ8.99 (s, 1H, NH), 7.94 (d, J = 8 Hz, 1H, ArH), 7.75 (d, J = 8.0
Hz, 2H, ArH), 7.40 (d, J = 2.0 Hz, 1H, ArH), 7.36 (t, J = 8.0 Hz, 2H, ArH),
R
= 26.5
R
20
1
(
2'S,3R,3'S)‐3'‐(4‐Methoxyphenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
D
2 2
= ‒51.5 (c 25.9, CH Cl ). H NMR (400 MHz,
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ea). 3ea was
obtained as a white solid (36.5 mg, 86% yield), m.p. 160−162 °C. HPLC
3
7
7
1
.297.22 (m, 2H, ArH), 7.18 (dd, J
.10 (t, J = 7.4 Hz, 2H, ArH), 6.88 (d, J = 7.6 Hz, 1H, ArH), 4.34 (d, J =
2.8 Hz, 1H, CH ), 4.05 (d, J = 12.8 Hz, 1H, CH ), 3.86 (s, 1H, CH) ppm;
C NMR (100 MHz, CDCl ): δ 193.6, 171.9, 157.2, 140.6, 138.2,
1 2
= 8.0 Hz, J = 2.0 Hz, 1H, ArH),
(Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, t
minor), t = 23.2 min (major); minor diastereoisomer, t
dr, 93% ee for the major diastereoisomer. []
R
= 31.5 min
= 19.6 min;
(
R
R
2
2
1
3
2
0
= ‒28.0 (c 13.3,
2 2 3
CH Cl ). H NMR (400 MHz, CDCl ): δ8.89 (s, 1H, NH), 7.93 (d, J = 7.6,
3
D
1
136.1, 135.2, 132.7, 129.7, 129.2, 129.0, 127.1, 127.0, 126.4, 125.1,
24.3, 122.9, 119.6, 110.1, 45.8, 44.4, 42.5, 41.7 ppm. HRMS (ESI):
1
1
7
6
1
H, ArH), 7.78 (d, J = 8, 2H, ArH), 7.32 (t, J = 8.0 Hz, 2H, ArH), 7.25–
.18 (m, 2H, ArH), 7.11–7.05 (m, 3H, ArH), 6.85 (d, J = 7.6 Hz, 1H, ArH),
+
m/z calcd for C25
H
17
N
2
O
3
Cl
2
[M + H] 463.0611, found 463.0610.
.80 (d, J = 8.8 Hz, 2H, ArH), 4.43 (d, J = 12.8 Hz, 1H, CH
) ppm; 13C NMR (2'S,3R,3'S)‐3'‐(2‐Chlorophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
2.8 Hz, 1H, CH ), 4.07 (s, 1H, CH), 3.70 (s, 3H, OCH
): δ194.0, 172.0, 159.3, 157.5, 140.5, 138.4, 130.9,
29.2, 128.6, 126.7, 125.0, 122.6, 121.4, 119.2, 114.1, 110.0, 55.1,
2
), 4.26 (d, J =
2
3
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ia). 3ia was
obtained as a light yellow solid (31.3 mg, 73% yield), m.p. 153−155 °C.
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 75:25, flow rate
(100 MHz, CDCl
3
1
4
+
6.2, 43.5, 43.4, 43.1 ppm. HRMS (ESI): m/z calcd for C26
H] 425.1496, found 425.1504.
H
21
N
2
O
4
[M
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
R
= 38.8
R
= 24.5
+
min (minor), t = 21.0 min (major); minor diastereoisomer, t
R
2
0
min; 92% ee for the major diastereoisomer. []
CH
D
= ‒66.7 (c 9.95,
(
3
2'S,3R,3'S)‐3'‐(3,4‐Dimethoxyphenyl)‐1''‐phenyldispiro[indoline‐
,1'‐cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3fa). 3fa was
1
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 8.80 (s, 1H, NH), 7.99 (d, J = 7.6
Hz, 1H, ArH), 7.77 (d, J = 8.0, 2H, ArH), 7.43–7.35 (m, 3H, ArH), 7.32–
.20 (m, 4H, ArH), 7.16–7.10 (m, 2H, ArH), 6.89 (d, J = 7.6 Hz, 1H, ArH),
.37 (dd, J = 12.8 Hz, J = 1.6 Hz, 1H, CH ), 4.09 (dd, J = 12.8 Hz, J
.6 Hz, 1H, CH ), 3.95 (s, 1H, CH) ppm; C NMR (100 MHz, CDCl ): δ
93.8, 172.0, 157.3, 140.6, 138.3, 135.4, 131.9, 129.9, 129.8, 129.2,
28.8, 127.7, 126.9, 126.7, 125.1, 124.6, 122.8, 119.6, 110.0, 45.9,
18 2 3
4.4, 42.7, 42.6 ppm. HRMS (ESI): m/z calcd for C25H N O Cl [M + H]
obtained as a light yellow solid (29.9 mg, 72% yield), m.p. 150–152 °C.
HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 65:35, flow rate
7
4
1
1
1
4
4
1
2
2
13
1
2
=
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
min (minor), t = 15.2 min (major); 90% ee for the major
diastereoisomer. []
CDCl ): δ9.09 (s, 1H, NH), 7.93 (d, J = 7.6, 1H, ArH), 7.75 (d, J = 8.0
Hz, 2H, ArH), 7.32 (t, J = 8.0 Hz, 2H, ArH), 7.257.18 (m, 2H, ArH), 7.09
R
= 20.0
2
3
R
2
0
1
D
2 2
= ‒21.1 (c 8.7, CH Cl ). H NMR (400 MHz,
3
+
29.1000, found 429.1012.
(
6
td, J
1
= 7.8 Hz, J
2
= 0.8 Hz, 1H, ArH), 6.86 (d, J = 7.6 Hz, 1H, ArH),
), 4.32 (d, J = 12.8
), 3.75 (s, 3H, OCH
.796.72 (m, 3H, ArH), 4.46 (d, J = 12.8 Hz, 1H, CH
2
(
2'S,3R,3'S)‐3'‐(3‐Bromophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ja). 3ja was
obtained as a white solid (39.2 mg, 83% yield), m.p. 182−184 °C. HPLC
Daicel Chiralpak IC, n‐hexane/ethyl acetate = 75:25, flow rate 1.0
Hz, 1H, CH
ppm; C NMR (100 MHz, CDCl
1
2
), 4.09 (s, 1H, CH), 3.81 (s, 3H, OCH
3
3
)
1
3
3
): δ 194.0, 171.9, 157.4, 149.00,
48.97, 140.3, 138.3, 129.2, 128.7, 126.8, 125.1, 124.9, 122.7, 122.3,
21.8, 119.3, 112.8, 111.1, 109.8, 56.0, 55.8, 46.3, 43.8, 43.5, 43.3
(
1
+
mL/min, detection at 254 nm): major diastereoisomer, t = 21.6 min
ppm. HRMS (ESI): m/z calcd for C27
H
23
N
2
O
5
[M + H] 455.1601, found
R
4
55.1617.
(minor), t
R
= 18.3 min (major); 94% ee for the major diastereoisomer.
20
1
[
]
D
= ‒21.0 (c 7.60, CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ8.66 (s,
1
H, NH), 7.91 (d, J = 7.6 Hz, 1H, ArH), 7.78 (d, J = 8.4, 2H, ArH), 7.43
(
2'S,3R,3'S)‐3'‐(4‐Chlorophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
(
d, J = 8.0 Hz, 1H, ArH), 7.38–7.34 (m, 3H, ArH), 7.30–7.18 (m, 3H,
ArH), 7.14–7.10 (m, 2H, ArH), 6.89 (d, J = 7.6 Hz, 1H, ArH), 4.47 (d, J =
2.8 Hz, 1H, CH ), 4.28 (d, J = 13.2 Hz, 1H, CH ), 4.11 (s, 1H, CH) ppm;
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ga). 3ga was
obtained as a white solid (38.2 mg, 89% yield), m.p. 170‐172 °C. HPLC
1
2
2
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J. Name., 2019, 00, 1‐3 | 7
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 8 of 11
ARTICLE
Journal Name
13C NMR (100 MHz, CDCl
1
1
3
): δ 193.6, 171.8, 157.3, 104.5, 138.2, 132.7, (376 MHz, CDCl
): δ ‒111.8 ppm. HRMS (ESI): m/z calcd for
F [M + H] 413.1296, found 413.1D3O10I:.10.1039/C9OB02663K
3
View Article Online
+
C
25
H
18
N
2
O
3
32.0, 131.4, 130.1, 129.2, 128.9, 128.5, 126.9, 124.9, 124.4, 122.8,
22.5, 119.3, 110.1, 45.8, 43.5, 42.6, 42.3 ppm. HRMS (ESI): m/z calcd
+
for C25
H
18
N
2
1
O
3
Br [M + H] 473.0495, found 473.0500; calcd for (2'S,3R,3'S)‐3'‐(4‐Fluorophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
8
+
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3na). 3na was
obtained as a light yellow solid (28.9 mg, 70% yield), m.p. 156−158 °C.
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate
C
25
H
18
N
2
O
3
Br [M + H] 475.0475, found 475.0483.
(
2'S,3R,3'S)‐3'‐(2‐Bromophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
R
1.0 mL/min, detection at 254 nm): major diastereoisomer, t = 11.2
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ka). 3ka was
obtained as a light yellow solid (36.5 mg, 77% yield), m.p. 167−169 °C.
HPLC (Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate
min (major); minor diastereoisomer, t
R
= 8.3 min; >99% ee for the
20
1
major diastereoisomer. []
MHz, CDCl
D
= ‒37.2 (c 7.50, CH
2
Cl
2
). H NMR (400
3
): δ 8.99 (s, 1H, NH), 7.91 (d, J = 7.6, 1H, ArH), 7.74 (d, J =
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
min (minor), t = 14.5 min (major); minor diastereoisomer, t
min; 95% ee for the major diastereoisomer. []
R
= 22.7 8.0 Hz, 2H, ArH), 7.34–7.30 (m, 2H, ArH), 7.26–7.14 (m, 4H, ArH),
R
R
= 16.8 7.11–7.08 (m, 1H, ArH), 7.00 (t, J = 8.6 Hz, 2H, ArH), 6.84 (d, J = 8.0
2
0
= ‒81.3 (c 5.17, Hz, 1H, ArH), 4.42 (d, J = 12.8 Hz, 1H, CH
2
), 4.22 (d, J = 12.8 Hz, 1H,
CH ), 4.08 (s, 1H, CH) ppm; C NMR (100 MHz, CDCl ): δ 193.8, 171.7,
D
1
3
1
CH
Hz, 1H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH), 7.58 (dd, J
Hz, 1H, ArH), 7.33 (t, J = 7.8 Hz, 2H, ArH), 7.26–7.18 (m, 4H, ArH),
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 9.07 (s, 1H, NH), 7.97 (d, J = 7.6
2
3
1
3
1
1
1
62.5 (d, J = 246.6 Hz), 157.3, 140.3, 138.3, 131.5 (d, J = 8.2 Hz),
1
= 7.6 Hz, J = 1.6
2
4
29.3, 128.8, 126.9, 125.3 (d, J = 3.3 Hz), 125.0, 124.6, 122.8, 119.3,
2
19
15.8 (d, J = 21.7 Hz), 109.9, 46.0, 43.5, 42.9, 42.7 ppm; F NMR
7
.15–7.08 (m, 2H, ArH), 6.87 (d, J = 7.6 Hz, 1H, ArH), 4.35 (d, J = 12.8
(376 MHz, CDCl
3
): δ ‒112.9 ppm. HRMS (ESI): m/z calcd for
1
3
Hz, 1H, CH
2
), 4.04 (d, J = 12.8 Hz, 1H, CH
): δ193.8, 171.9, 157.3, 140.5, 138.3, 133.1,
32.2, 130.1, 129.3, 129.2, 128.9, 127.2, 126.9, 125.7, 125.2, 124.6,
2
), 3.89 (s, 1H, CH) ppm; C
+
C
25
H
18
N
2
O
3
F [M + H] 413.1296, found 413.1307.
NMR (100 MHz, CDCl
3
1
1
(
2'S,3R,3'S)‐3'‐(3‐Nitrophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
22.8, 119.7, 109.9, 46.2, 44.8, 44.4, 42.9 ppm. HRMS (ESI): m/z calcd
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3oa). 3oa was
+
for C25
H
18
N
2
1
O
3
Br [M + H] 473.0495, found 473.0505; calcd for
obtained as a white solid (38.3 mg, 87% yield), m.p. 174−176 °C. HPLC
8
+
C
25
H
18
N
2
O
3
Br [M + H] 475.0475, found 475.0485.
(
Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, t = 24.9 min
= 15.8 min (major); 85% ee for the major diastereoisomer.
R
(
2'S,3R,3'S)‐3'‐(4‐Bromophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
(minor), t
R
2
0
1
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3la). 3la was []
D
2 2 3
= ‒18.2 (c 11.65, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.94 (s,
H, NH), 8.07–8.05 (m, 2H, ArH), 8.87 (d, J = 7.6, 1H, ArH), 7.71 (d, J
1
=
7
obtained as a white solid (39.8 mg, 84% yield), m.p. 162−164 °C. HPLC
Daicel Chiralpak IC, n‐hexane/ethyl acetate = 80:20, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, t = 45.4 min
= 37.5 min (major); 92% ee for the major diastereoisomer.
7.6, 2H, ArH), 7.55 (d, J = 7.6, 1H, ArH), 7.49–7.45 (m, 1H, ArH),
.33–7.17 (m, 4H, ArH), 7.08 (td, J
(
1
= 7.6 Hz, J
2
= 0.8 Hz, 1H, ArH), 6.86
), 4.24 (d, J = 12.8
), 4.15 (s, 1H, CH) ppm; C NMR (100 MHz, CDCl ): δ 193.4,
R
(d, J = 7.6 Hz, 1H, ArH), 4.44 (d, J = 12.8 Hz, 1H, CH
2
(
[
minor), t
R
1
3
Hz, 1H, CH
2
3
2
0
1
]
D
2 2 3
= ‒10.3 (c 10.80, CH Cl ). H NMR (400 MHz, CDCl ): δ 8.78 (s,
1
1
71.6, 157.2, 148.1, 140.5, 138.1, 136.1, 132.0, 129.6, 129.2, 129.0,
27.0, 124.9, 124.1, 123.2, 122.8, 119.4, 110.2, 45.6, 43.5, 42.6, 41.5
1
7
2
6
1
1
1
H, NH), 7.91 (d, J = 7.6 Hz, 1H, ArH), 7.78 (d, J = 8.0 Hz, 2H, ArH),
.44 (d, J= 8.4 Hz, 2H, ArH), 7.36 (t, J = 7.8 Hz, 2H, ArH), 7.30–7.22 (m,
H, ArH), 7.12 (t, J = 7.6 Hz, 1H, ArH), 7.05 (d, J = 8.4 Hz, 2H, ArH),
+
ppm. HRMS (ESI): m/z calcd for C25
40.1248.
H
18
N
3
O
5
[M + H] 440.1241, found
4
.88 (d, J = 7.6 Hz, 1H, ArH), 4.43 (d, J = 12.8 Hz, 1H, CH
2
), 4.23 (d, J =
): δ
2.8 Hz, 1H, CH
2
), 4.06 (s, 1H, CH) ppm; 13C NMR (100 MHz, CDCl
3
(
2'S,3R,3'S)‐3'‐(4‐Nitrophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
93.7, 171.9, 157.3, 140.5, 138.2, 131.9, 131.5, 129.2, 128.9, 128.7, cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3pa). 3pa was
26.9, 125.0, 124.5, 122.8, 122.4, 119.2, 110.1, 45.9, 43.5, 42.6 ppm. obtained as a light yellow solid (22.0 mg, 50% yield), m.p. 175−177 °C.
+
HRMS (ESI): m/z calcd for C25
H
O
18
N
2
1
O
3
Br [M + H] 473.0495, found HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate
8
+
R
1.0 mL/min, detection at 254 nm): major diastereoisomer, t = 27.3
4
4
73.0505; calcd for C25
75.0488.
H
18
N
2
3
Br [M + H] 475.0475, found
min (minor), t
diastereoisomer. []
CDCl ): δ 8.64 (s, 1H, NH), 8.17 (d, J = 8.8 Hz, 2H, ArH), 7.90 (d, J = 7.6,
H, ArH), 7.75 (d, J = 7.6, 2H, ArH), 7.41–7.34 (m, 4H, ArH), 7.31–7.23
m, 2H, ArH), 7.12 (td, J = 7.6 Hz, J = 0.8 Hz, 1H, ArH), 6.92 (d, J = 7.6
Hz, 1H, ArH), 4.45 (d, J = 12.8 Hz, 1H, CH ), 4.23 (d, J = 12.8 Hz, 1H,
), 4.16 (s, 1H, CH) ppm; C NMR (100 MHz, CDCl ): δ 193.3, 171.4,
R
= 20.6 min (major); 81% ee for the major
2
0
1
D
2 2
= +3.6 (c 13.80, CH Cl ). H NMR (400 MHz,
3
(
2'S,3R,3'S)‐3'‐(3‐Fluorophenyl)‐1''‐phenyldispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ma). 3ma was
obtained as a white solid (33.4 mg, 81% yield), m.p. 143−145 °C. HPLC
Daicel Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, t = 16.6 min
= 11.0 min (major); 93% ee for the major diastereoisomer.
2 2 3
= ‒32.4 (c 5.90, CH Cl ). H NMR (400 MHz, CDCl ): δ 9.12 (s,
H, NH), 7.90 (d, J = 7.6 Hz, 1H, ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH),
.31–7.17 (m, 5H, ArH), 7.08 (t, J = 7.6 Hz, 1H, ArH), 6.96–6.90 (m, 3H,
1
(
1
2
2
(
1
3
CH
2
3
R
1
1
57.1, 147.7, 140.4, 138.1, 137.1, 130.9, 129.3, 129.2, 127.1, 125.1,
24.1, 123.8, 123.0, 119.2, 110.1, 45.7, 43.5, 42.5, 41.9 ppm. HRMS
(
[
minor), t
R
2
0
1
]
D
+
(ESI): m/z calcd for C25
H
18
N
3
O
5
[M + H] 440.1241, found 440.1248.
1
7
(
2'S,3R,3'S)‐3'‐(Naphthalen‐1‐yl)‐1''‐phenyldispiro[indoline‐3,1'‐
2
ArH), 6.83 (d, J = 7.6 Hz, 1H, ArH), 4.43 (d, J = 12.8 Hz, 1H, CH ), 4.27
1
3
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3qa). 3qa was
obtained as a light yellow solid (36.5 mg, 82% yield), m.p. 180−182 °C.
HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate
1.0 mL/min, detection at 254 nm): major diastereoisomer, t
min (minor), t = 13.8 min (major); 93% ee for the major
diastereoisomer. []
(
d, J = 12.8 Hz, 1H, CH
2
), 4.07 (s, 1H, CH) ppm; C NMR (100 MHz,
1
CDCl
3
): δ 193.7, 171.8, 162.6 (d, J = 245.6 Hz), 157.3, 140.4, 138.2,
32.0 (d, J = 7.9 Hz), 130.2 (d, J = 8.3 Hz), 129.2, 128.9, 126.9, 125.5
d, J = 2.5 Hz), 125.0, 124.5, 122.8, 119.3, 116.9 (d, J = 22.2 Hz),
15.3 (d, J = 20.9 Hz), 110.0, 45.9, 43.4, 42.7, 42.6 ppm; F NMR
3
3
1
(
4
2
R
= 22.0
2
19
R
1
2
0
1
D
2 2
= ‒40.0 (c 10.70, CH Cl ). H NMR (400 MHz,
8
| J. Name., 2019, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 11
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
ARTICLE
CDCl
Hz, 2H, ArH), 7.62 (d, J = 7.6 Hz, 2H, ArH), 7.49 (d, J = 8.0 Hz, 1H, ArH),
.43–7.35 (m, 3H, ArH), 7.30–7.25 (m, 4H, ArH), 7.19–7.14 (m, 2H,
ArH), 6.77 (d, J = 7.6 Hz, 1H, ArH), 4.39 (d, J = 12.8 Hz, 1H, CH ), 4.33
) ppm; C NMR (100 MHz,
): δ 194.2, 172.2, 157.4, 140.6, 138.1, 133.8, 132.1, 129.2, 129.1,
3
): δ 8.74 (s, 1H, NH), 8.04 (d, J = 7.6 Hz, 1H, ArH), 7.84 (t, J = 8.6 Procedure for synthesis of compound 4a: The product 3aa (0.1
View Article Online
DOI: 10.1039/C9OB02663K
3
mmol) was dissolved in DCM (1.0 mL) and NaBH(QAc) (0.4 mmol, 4
7
equiv) was added. The reaction solution was stirred at room
temperature for 1.5 hours. The progress of the reaction was
monitored by TLC analysis (petroleum ether/ ethyl acetate = 2:1).
After the completion of the reaction, the reaction mixture was
concentrated under reduced pressure and the residue was purified
by silica gel column chromatography (petroleum ether/ethyl acetate
2
1
3
(
s, 1H, CH), 4.10 (d, J = 12.8 Hz, 1H, CH
2
CDCl
3
1
28.8, 128.6, 127.1, 126.9, 126.0, 125.4, 125.04, 124.95, 124.7, 122.8,
122.2, 119.4, 110.1, 46.3, 44.0, 43.4, 42.1 ppm. HRMS (ESI): m/z calcd
+
for C29
H
21
N
2
O
3
[M + H] 445.1547, found 445.1541.
=
3:1) to give pure compound 4a.
(
2'S,3R,3'S)‐3'‐(Naphthalen‐2‐yl)‐1''‐phenyldispiro[indoline‐3,1'‐
(
2'S,3R,3'S,4''S)‐4''‐Hydroxy‐1'',3'‐diphenyldispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ra). 3ra was
obtained as a white solid (37.8 mg, 85% yield), m.p. 172−174 °C. HPLC
cyclopropane‐2',3''‐pyrrolidine]‐2,5''‐dione (4a). 4a was obtained as
(
Daicel Chiralpak IA, n‐hexane/ethyl acetate = 75:25, flow rate 1.0 a white solid (34.9 mg, 88% yield), m.p. 165–167 °C. HPLC (Daicel
mL/min, detection at 254 nm): major diastereoisomer, t
R
= 30.6 min Chiralpak IC, n‐hexane/ethyl acetate = 70:30, flow rate 1.0 mL/min,
(
[
minor), t
R
= 33.8 min (major); 94% ee for the major diastereoisomer. detection at 254 nm): major diastereoisomer, t = 13.2 min (minor),
R
20
1
]
D
= +7.8 (c 9.95, CH
2
Cl
2
). H NMR (400 MHz, CDCl
3
): δ 9.31 (s, 1H,
20
t
+
R
= 22.1 min (major); 92% ee for the major diastereoisomer. []
D
=
NH), 7.94–7.92 (m, 1H, ArH), 7.70–7.66 (m, 5H, ArH), 7.62 (s, 1H, ArH),
.43–7.35 (m, 2H, ArH), 7.22–7.15 (m, 3H, ArH), 7.13–7.04 (m, 3H,
ArH), 6.64–6.62 (m, 1H, ArH), 4.33 (ABq, J= 12.8 Hz, 2H, CH ), 4.20 (s,
): δ 193.9, 172.2, 157.4, 140.5,
1
15.5 (c 15.50, CH
2
Cl
2
). H NMR (400 MHz, acetone‐d6): δ9.84 (s,
7
1
H, NH), 7.68–7.64 (m, 3H, ArH), 7.33–7.29 (m, 2H, ArH), 7.23–7.17
2
(
m, 4H, ArH), 7.14–7.10 (m, 3H, ArH), 7.03–6.99 (m, 2H, ArH), 5.87 (d,
J = 6.4, 1H, OH), 4.66 (d, J = 6.4, 1H, CH), 4.05 (d, J = 11.6 Hz, 1H, CH ),
), 3.85 (s, 1H, CH) ppm; C NMR (100 MHz,
acetone‐d6): δ175.3, 174.0, 144.1, 141.2, 134.1, 131.9, 130.6, 130.3,
1
3
1
1
1
4
4
H, CH) ppm; C NMR (100 MHz, CDCl
3
38.3, 133.1, 132.8, 129.2, 129.0, 128.7, 128.4, 127.8, 127.7, 127.1,
27.0, 126.8, 126.5, 126.4, 125.0, 124.8, 122.7, 119.2, 110.1, 46.2,
21 2 3
3.7, 43.6, 43.0 ppm. HRMS (ESI): m/z calcd for C29H N O [M + H]
2
1
3
3.96 (d, J = 11.2 Hz, 1H, CH
2
+
1
4
3
30.1, 128.9, 128.8, 126.5, 124.2, 123.4, 121.5, 111.3, 72.3, 47.9,
3.6, 40.2, 39.7 ppm. HRMS (ESI): m/z calcd for C25H N O [M + H]
21 2 3
97.1547, found 397.1552.
45.1547, found 445.1551.
+
(
2'S,3R,3'S)‐3'‐Phenyl‐1''‐(o‐tolyl)dispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3sa). 3sa was
obtained as a light yellow solid (29.2 mg, 71% yield), m.p. 158−160 °C. 1'',3'‐Diphenyldispiro[indoline‐3,1'‐cyclopropane‐2',3''‐
HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 70:30, flow rate pyrrolidine]‐2,4'',5''‐trione (6a). 6a was obtained as a white solid
.0 mL/min, detection at 254 nm): major diastereoisomer, t = 20.7 (31.6 mg, 80% yield), m.p. 185–187 °C. HPLC (Daicel Chiralpak IA, n‐
min (major), t = 43.6 min (minor); 83% ee for the major
diastereoisomer. []
CDCl ): δ 8.74 (s, 1H, NH), 8.01 (d, J= 7.6, 1H, ArH), 7.30–7.27 (m, 5H,
ArH), 7.25‐7.23 (m, 2H, ArH), 7.15–7.13 (m, 4H, ArH), 6.86 (d, J = 8.0
Hz, 1H, ArH), 4.29 (d, J = 13.6 Hz, 1H, CH ), 4.13 (d, J = 13.2 Hz, 1H,
CH ), 4.08 (s, 1H, CH), 2.25 (s, 3H, CH ) ppm; C NMR (100 MHz,
CDCl ): δ 194.3, 172.0, 157.9, 140.5, 136.2, 134.7, 131.5, 129.7, 129.6,
29.1, 128.7, 128.6, 128.2, 127.1, 125.6, 125.1, 124.9, 122.7, 110.0,
1
R
R
hexane/ethyl acetate = 60:40, flow rate 1.0 mL/min, detection at 254
2
0
1
D
2 2
= ‒ 32.1 (c 12.90, CH Cl ). H NMR (400 MHz,
nm): major diastereoisomer, t
= 8.3 min (major), t
= 12.2 min
R
R
3
20
(minor); 95% ee for the major diastereoisomer. []
D
= ‒71.3 (c 27.3,
1
CH
2 2
Cl ). H NMR (400 MHz, acetone‐d6): δ8.90 (s, 1H, NH), 8.10 (d,
2
J = 1.6 Hz, 1H, ArH), 7.75 (d, J = 8 Hz, 2H, ArH), 7.38–7.32 (m, 7H, ArH),
.25–7.21 (m, 1H, ArH), 7.16–7.14 (m, 2H, ArH), 6.70 (d, J = 8.4, 1H,
ArH), 4.42 (d, J = 12.8, 1H, CH), 4.28 (d, J = 12.8 Hz, 1H, CH ), 4.10 (s,
H, CH) ppm; C NMR (100 MHz, acetone‐d6): δ194.0, 171.6, 157.3,
139.5, 138.3, 131.7, 129.7, 129.3, 128.8, 128.5, 128.1, 127.0, 126.9,
1
3
2
3
7
3
2
1
4
[
1
3
1
6.5, 46.0, 44.6, 43.5, 18.1 ppm. HRMS (ESI): m/z calcd for C26
H
21
N
2
O
3
+
M + H] 409.1547, found 409.1539.
1
19.3, 115.5, 111.4, 45.7, 43.9, 43.5, 43.1 ppm. HRMS (ESI): m/z calcd
+
for C25
H
19
N
2
O
3
[M + H] 395.1390, found 395.1395.
(
2'S,3R,3'S)‐1''‐(4‐Bromophenyl)‐3'‐phenyldispiro[indoline‐3,1'‐
cyclopropane‐2',3''‐pyrrolidine]‐2,4'',5''‐trione (3ta). 3ta was
obtained as a light yellow solid (34.6 mg, 73% yield), m.p. 172−174 °C.
HPLC (Daicel Chiralpak IA, n‐hexane/ethyl acetate = 65:35, flow rate
Conflicts of interest
There are no conflicts of interest to declare.
1
.0 mL/min, detection at 254 nm): major diastereoisomer, t
min (major), t = 12.3 min (minor); 85% ee for the major
diastereoisomer. []
CDCl ): δ 8.58 (s, 1H, NH), 7.93 (d, J = 7.6 Hz, 1H, ArH), 7.71 (d, J = 9.2
Hz, 2H, ArH), 7.47 (d, J = 8.8 Hz, 2H, ArH), 7.34–7.31 (m, 3H, ArH),
R
= 9.2
R
2
0
1
D
2 2
= ‒ 40.5 (c 15.50, CH Cl ). H NMR (400 MHz,
3
Acknowledgements
The authors are grateful for financial support from the National
), Natural Science Foundation of China (NSFC) (grant number
2
7
1
4
1
1
.27–7.25 (m, 1H, ArH), 7.17–7.09 (m, 3H, ArH), 6.88 (d, J = 8.0 Hz,
H, ArH), 4.43 (d, J = 12.8 Hz, 1H, CH ), 4.24 (d, J = 12.8 Hz, 1H, CH
.14 (s, 1H, CH) ppm; 13C NMR (100 MHz, CDCl
2
3
): δ 193.4, 171.9, 21272024). We also thank the Analysis & Testing Center of
57.3, 140.4, 137.4, 132.2, 129.7, 129.4, 128.8, 128.7, 128.4, 125.0,
24.7, 122.8, 120.6, 120.0, 109.9, 46.1, 43.7, 43.4, 42.8 ppm. HRMS
Beijing Institute of Technology for measure the NMR and mass
spectra.
7
9
+
(
ESI): m/z calcd for C25
73.0504; calcd for C25
75.0479.
H
18
N
2
O
3
Br [M + H] 473.0495, found
8
1
+
4
4
H
18
N
2
O
3
Br [M + H] 475.0475, found
Notes and references
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Synth. Catal., 2017, 359, 3341‐3346; (b) S. Du and J. Zhou, G.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2019, 00, 1‐3 | 9
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Page 10 of 11
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crystallographic data for this paper. These data can be
DOI: 10.1039/C9OB02663K
obtained free of charge from The Cambridge Crystallographic
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0 | J. Name., 2019, 00, 1‐3
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Page 11 of 11
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB02663K
Graphic Abstract
Squaramide−catalysed asymmetric cascade reactions of
,3-dioxopyrrolidines with 3-chlorooxindoles
2
Jiang-Bo Wen and Da‐Ming Du*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology,
Beijing 100081, People’s Republic of China.
R1
O
Cl
R3
N
5
mol% C1
NH HCO (1.0 equiv)
O
R1
4
3
O
R2
+
O
N
Ph
o
N
AcOEt, 0 C, 2 h
R3
N
Ph
O
R2
O
O
H
F3C
28 examples
up to 94% yield
up to >99% ee, >25:1dr
N
N
H
HN
OMe
C1
N
A highly efficient squaramide-catalysed asymmetric Michael addition/cyclization
cascade reaction of 3-chlorooxindoles with 2,3-dioxopyrrolidines has been
developed and the corresponding chiral spirocompounds was obtained in high yields
with excellent stereoselectivities.