Asymmetric [3+2] Annulations to Construct 1,2-Bispirooxindoles Incorporating a Dihydropyrrolidine Motif

Article abstract of DOI:10.1002/adsc.201700849

Constructing chiral bispirooxindoles is difficult to achieve but highly attractive owing to their many potential applications in medicinal chemistry. Here we present an asymmetric [3+2] annulation reaction of Morita–Baylis–Hillman carbonates from isatins and isatin-based N-Boc-ketimines under the catalysis of a newly designed multifunctional 4-dimethylaminopyridine-type substance. The reaction shows high γ-regioselectivity, producing highly complex 1,2-bispirooxindoles incorporating a dihydropyrrolidine motif in excellent yields with moderate to outstanding stereoselectivity (dr>19:1, up to >99% ee). This protocol has been expanded to utilize trifluoromethyl-containing ketimines, delivering complicated architectures with fused and spirocyclic frameworks in modest enantioselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201700849

Title: Asymmetric [3+2] Annulations to Construct 1,2-Bispirooxindoles
Incorporating a Dihydropyrrolidine Motif
Authors: Qing He, Wei Du, and Ying-Chun Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700849
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10.1002/adsc.201700849
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric [3+2] Annulations to Construct 1,2-
Bispirooxindoles Incorporating a Dihydropyrrolidine Motif
Qing He,a Wei Du,a and Ying-Chun Chena,b*
a
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, People’s
Republic of China
Fax: (+86)-28-8550-2609; e-mail: ycchen@scu.edu.cn
College of Pharmacy, Third Military Medical University, Chongqing 400038, People’s Republic of China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: Constructing chiral bispirooxindoles is difficult to with moderate to outstanding stereoselectivity (dr >19:1, up
achieve but highly attractive owing to their many potential to >99% ee). This protocol has been expanded to utilize
applications in medicinal chemistry. Here we present an trifluoromethyl-containing
ketimines,
delivering
asymmetric [3+2] annulation reaction of complicated architectures with fused and spirocyclic
MoritaBaylisHillman carbonates from isatins and isatin- frameworks in modest enantioselectivity.
based N-Boc ketimines under the catalysis of the newly
designed multifunctional 4-dimethylaminopyridine-type
Keywords: bispirooxindoles; MoritaBaylisHillman
carbonates; ketimines; [3+2] annulations; tetrasubstituted
stereogenic center; Lewis base catalysis.
substance. The reaction shows high -regioselectivity,
producing
highly
complex
1,2-bispirooxindoles
incorporating a dihydropyrrolidine motif in excellent yields
Isatin-derived N-Boc ketimines are highly
electrophilic reagents that have been widely applied
to construct chiral 3-aminooxindoles[6] and to make
3,2-pyrrolidinylspirooxindole derivatives through
asymmetric [3+2] annulation reactions.[7] On the
other hand, the MoritaBaylisHillman[8] (MBH)
derivatives of isatins have been demonstrated to be
ideal 3C synthons through the formation of
zwitterionic allylic ylides with a Lewis base (LB)
Introduction
Spirocyclic oxindoles incorporating a pyrrolidine
motif are ubiquitous in natural products and synthetic
bioactive substances.[1] Furthermore, the introduction
of another spirocyclic framework into the pyrrolidine
skeleton to construct more complex derivatives,
especially in an adjacent pattern, draws particular
interest, as significant medicinal potentials, such as
anti-mycobacterium tuberculosis bacteria (MTB),
anti-microbial and anti-tumor functions, were
observed (Figure 1).[2] Such scaffolds could be
synthesized by using various cycloaddition or
catalyst, efficiently producing
a
diversity of
spirooxindoles in combination with differently
structured electrophiles.[9] Hence it is predicted that
the possible assembly of isatin-based ketimines and
MBH carbonates of isatins would straightforwardly
yield the desired 1,2-bispirooxindoles incorporating a
dihydropyrrolidine framework, as illustrated in
Scheme 1.
annulation-based
protocols,[3]
while
the
methodologies of making such architectures
asymmetrically are still limited,[4] which is partially
due to the challenge imposed by constructing
adjacent tetrasubstituted stereogenic centers.[5]
Scheme 1. [3+2] Annulation approach to access 1,2-
bispirooxindoles incorporating a dihydropyrrolidine motif.
Results and Discussion
Figure
1.
Representative
bioactive
3,2-
The initial investigation with MBH carbonate 1a and
isatin ketimine 2a resulted in a complex mixture
pyrrolidinylspirooxindoles incorporating an adjacent
spirocyclic motif.
1
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10.1002/adsc.201700849
Advanced Synthesis & Catalysis
DMAP-type catalysts.[11] As summarized in Table 1,
chiral substance C1 also exhibited excellent catalytic
activity but low enantioselectivity (Table 1, entry 4).
O-methyl ether C2 showed poorer enantiocontrol
(Table 1, entry 5). Subsequently, we further modified
the structures of the catalysts. C3 with a morpholine
motif furnished inferior data (Table 1, entry 6).
Interestingly, compound C4 with a hydroxyl group at
3-position of pyrrolidine moiety enhanced the
enantioselectivity significantly, indicating that the
additional hydrogen-bonding interaction is probably
beneficial for the enantiocontrol (Table 1, entry 7).
Moreover, the enantioselectivity was further
improved by using C5 with a (S)-prolinol motif
(Table 1, entry 8). Nevertheless, a very poor ee value
was obtained for C6 with mismatched (S,R)-chirality
(Table 1, entry 9). In addition, catalyst C7 with a
Table 1. Screening conditions for the asymmetric [3+2]
annulation reactions of 1 and 2a.[a]
piperidine-2-methanol motif
delivered
lower
enantioselectivity (Table 1, entry 10). It was also
found that the reaction took longer to complete at 20
C while a better ee was obtained (Table 1, entry 11).
The N-protection group of the MBH carbonate was
further investigated (Table 1, entries 1214), and
high enantioselectivity was observed with an N-
benzyl group (Table 1, entry 13). The solvent effects
were tested as well (Table 1, entries 1517), and the
enantiomerically pure product 3c was produced in
98% yield in PhCF3 (Table 1, entry 17).
Yield[b] ee[c]
Entry R
Cat
DABCO toluene 12
Ph3P toluene 12
Solvent t [h]
[%]
[%]
1
Me/1a
/
/
/
/
/
2
3
4
5
6
7
8
9
Me/1a
Me/1a
Me/1a
Me/1a
Me/1a
Me/1a
Me/1a
Me/1a
Me/1a
DMAP toluene 0.5
3a, 96
toluene 0.5
3a, 98 39
3a, 96 25
3a, 98 35
3a, 98 61
3a, 98 76
3a, 98 15
3a, 98 65
3a, 98 78
3b, 97 85
3c, 98 86
3d, 96 85
3c, 95 91
3c, 98 93
3c, 98 >99
C1
C2
C3
C4
C5
C6
C7
C5
C5
C5
C5
C5
C5
C5
toluene
toluene
toluene
toluene
toluene
toluene
1
4
3
3
3
4
Table 2. Substrate scope of the asymmetric [3+2]
annulations of MBH carbonates 1 and ketimines 2.[a]
10
11[d] Me/1a
12[d] MOM/1b
13[d] Bn/1c
14[d] Boc/1d
15[d] Bn/1c
16[d] Bn/1c
toluene 24
toluene 24
toluene 24
toluene 24
DCE
7
Entry R1
R2
H
t [h] Yield[b] [%] ee[c] [%]
CHCl3
20
1
H
24
3c, 98
>99
17[d] Bn/1c
PhCF3 24
2
3
4
5-Cl
5-Br
5-I
5-NO2
6-Br
7-Cl
5-Me
5-MeO
5,7-Me2
H
H
H
H
H
H
H
H
H
12
11
11
24
48
48
48
48
56
30
3e, 96
3f, 95
3g, 97
3h, 96
3i, 96
3j, 97
95
96
87
88
89
88
[a]
Unless noted otherwise, reactions were performed using
1 (0.11 mmol), 2a (0.1 mmol), catalyst (0.01 mmol) and 4
Å MS (50 mg) in solvent (2 mL) at rt.
5[d]
6[d]
7[d]
8[e]
9
[b] Yield of isolated product.
[c]
Determined by HPLC analysis using a chiral stationary
phase; 1H NMR analysis indicated dr >19:1.
[d] At 20 C.
3k, 96 (72) 79 (98)
3l, 96
3m, 97
3n, 98
3o, 96
3p, 96
3q, 98
3r, 95
3s, 97
3t, 97
3u, 97
75
76
95
94
98
79
87
78
88
97
10
11
12
13
H
5-Me
under the catalysis of 1,4-diazabicyclo[2.2.2]octane
(DABCO) in toluene at room temperature (Table 1,
entry 1), while no apparent conversion was observed
in the presence of Ph3P (Table 1, entry 2), probably
because of the bulky tetrahedral feature of the ylide
intermediate, inhibiting the formation of the
congested 1,2-bispirooxindole structure.[10] In contrast,
planar 4-dimethylaminopyridine (DMAP) showed
very high catalytic activity and the -regioselective
[3+2] annulation product 3a with the desired 1,2-
bispirooxindole skeleton was isolated in an almost
quantitative yield with exclusive diastereoselectivity
(Table 1, entry 3). Subsequently, we explored the
asymmetric version by employing some chiral
H
H
5-MeO 30
5,7-Me2 36
5-Cl
5-Br
5-I
14[d] 5-Cl
15[d] 5-Cl
16[d] 5-Cl
17[d] 5-Cl
72
55
48
56
40
6-Br
H
18[f]
H
[a]
Unless noted otherwise, reactions were performed using
1 (0.11 mmol), 2 (0.1 mmol, R3 = Me), catalyst C5 (0.01
mmol) and 4 Å MS (50 mg) in PhCF3 (2 mL) at 20 C.
[b] Yield of isolated product.
[c]
Determined by HPLC analysis using a chiral stationary
phase; 1H NMR analysis indicated dr >19:1.
2
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10.1002/adsc.201700849
Advanced Synthesis & Catalysis
[d] In CHCl3 at 40 C.
incorporating
spirocyclic
frameworks
were
[e] Data in parentheses were obtained after recrystallization.
[f] R3 = Bn.
synthesized in excellent yields with moderate
enantioselectivity (Table 3, entries 15) which can be
greatly improved through recrystallization (Table 3,
entries 1 and 5). It was noted that the chiral DABCO-
based catalytic system appeared no to be compatible
with the current asymmetric reactions.[13a]
With the optimized catalytic conditions in hand,
the scope and limitations of the new asymmetric
reaction were further explored (Table 2). Excellent
yields were obtained overall. An array of MBH
carbonates 1 with different electron-withdrawing
groups on the aryl ring resulted in high to outstanding
enantioselectivity in the reactions with ketimine 2a
(Table 2, entries 27), while some reaction conditions
were tuned accordingly (Table 2, entries 57).
Nevertheless, the MBH carbonates 1 with electron-
donating groups showed lower reactivity and only
moderate enantiocontrol (Table 2, entries 810). In
addition, the optical purity could be improved
through recrystallization (Table 2, entry 8).
Substrates 2 with electron-donating substituents
provided the corresponding [3+2] products 3np in
excellent enantioselectivity (Table 2, entries 1113),
while lower enantiocontrol was observed for the
ketimines 2 bearing electron-withdrawing groups,
even at lower temperature (Table 2, entries 1417).
In addition, ketimine 2 with a bigger N-benzyl group
also underwent the annulation smoothly (Table 2,
entry 18).
bispirooxindole 3c
Table 3. Asymmetric [3+2] annulations of MBH
carbonates 1 and CF3-containing hemiaminals 4.[a]
Entry
1[d]
R1
H
R2
H
Yield[b] [%]
5a, 90 (70)
ee[c] [%]
73 (96)
CF3-containing spirooxindole 5b
2
3
4
H
Me
Cl
H
5b, 92
5c, 94
5d, 91
5e, 92 (74)
76
60
61
74 (98)
Figure 2. X-ray crystal structures of enantiopure 3c and 5b.
Cl
Me
Cl
5[d]
H
The absolute configuration of the chiral [3+2]
annulation products 3c and 5b was unambiguously
determined by X-ray crystallographic analysis, as
outlined in Figure 2.[15] Thus, the other chiral
products were assigned by analogy.
A plausible catalytic mechanism of the asymmetric
annulation reaction is proposed in Scheme 2. Catalyst
C5 attacks MBH carbonate 1c to form the
zwitterionic allylic ylide I, which subsequently
attacks ketimine 2a from the Re-face with the
possible assistance of a hydrogen-bonding interaction
between the hydroxyl group of the pyrrolidine moiety
and the N-Boc group, affording intermediate II.
Finally, product 3c is generated after cyclization and
the release of the catalyst C5.
[a]
Reactions were performed using 1 (0.11 mmol),
hemiaminal 4 (0.1 mmol), catalyst C5 (0.01 mmol),
benzoic acid (0.04 mmol) and 4 Å MS (50 mg) in CHCl3
(1 mL) at 5 C for 7296 h.
[b] Yield of isolated product.
[c] Determined by HPLC analysis using a chiral stationary
phase; 1H NMR analysis indicated dr >19:1.
[d] Data in parentheses were obtained after recrystallization.
To further investigate the current chiral catalyst
system, the [3+2] annulation reactions between isatin-
based MBH carbonates 1 and trifluoromethyl (CF3)-
containing ketimines, generated in situ from the
hemiaminal precursors 4, were examined.[12,13] As
summarized in Table 3, the annulations proceeded
smoothly under the similar catalytic conditions using
the catalytic amounts of benzoic acid as the imine
formation promoter.[14] An array of products 5
3
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10.1002/adsc.201700849
Advanced Synthesis & Catalysis
Such substances may be potentially benefiting in
medicinal chemistry.
Experimental Section
1H NMR spectra were recorded at 400 MHz or 600 MHz
(Varian) and 13C NMR spectra were recorded at 100 MHz
or 150 MHz (Varian). Chemical shifts are reported either
in ppm downfield from CDCl3 (δ = 7.26 ppm) for 1H NMR,
or relative to the central CDCl3 resonance (δ = 77.0 ppm)
for 13C NMR. Coupling constants are given in Hz. Optical
rotations were measured at 589 nm at 20 ºC. Enantiomeric
excess was determined using HPLC analysis on Chiralpak
ID, IE, IF, AD-H and Chiralcel OD-H columns. ESI-HR-
MS was recorded on a Waters SYNAPT G2. TLC was
performed on glass-backed silica plates. Column
chromatography was performed using silica gel (200300
mesh), eluting with ethyl acetate and petroleum ether. All
other chemicals were used without purification as
commercially available. Toluene, THF, ethyl acetate
(EtOAc), petroleum ether, dichloromethane (DCM) and
MeCN were freshly distilled before use.
General procedure for asymmetric [3+2]
annulations
Scheme 2. Proposed catalytic mechanism of the
MBH carbonate 1 (0.11 mmol), ketimine 2 (0.1 mmol),
catalyst C5 (4.6 mg, 0.01 mmol) and 4 Å MS (50 mg) were
stirred in trifluorotoluene (2.0 mL) at –20 C (or in CHCl3
at –40 C). The reaction was monitored by TLC analysis.
After the reaction was complete, the solution was
concentrated and the residue was purified by flash
chromatography on silica gel (ethyl acetate/petroleum
ether = 1:9 to 1:5) to afford the chiral product 3.
asymmetric [3+2] annulation reaction.
After removal of the N-Boc group of product 3c,
the
enamine
moiety
could
be
reduced
diastereoselectively with Et3SiH in the presence of
BF3Et2O, giving the more useful pyrrolidine
derivative 6 in a moderate yield with slightly reduced
enantiopurity (Scheme 3).[16]
The asymmetric [3+2] annulations of MBH carbonates 1
and CF3-containing hemiaminals 4: MBH carbonate 1
(0.11 mmol), hemiaminal 4 (0.1 mmol), catalyst C5 (4.6
mg, 0.01 mmol), benzoic acid (4.9 mg, 0.04 mmol) and 4
Å MS (50 mg) were stirred in CHCl3 (1.0 mL) at 5 C. The
reaction was monitored by TLC analysis. After the reaction
was complete, the solution was concentrated and the
residue was purified by flash chromatography on silica gel
(ethyl acetate/petroleum ether = 1:10 to 1:4) to afford the
chiral product 5.
Scheme 3. Transformations of [3+2] product 3c.
tert-Butyl
(3R,3'R)-1''-benzyl-4'-cyano-1-methyl-
2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-3',3''-
indoline]-1'-carboxylate (3c): yield: 52.2 mg (98%);
white solid; [α]D20 = –134.9 (c = 1.10 in CHCl3); >99% ee,
determined by HPLC analysis [Daicel chiralpak ID, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
Conclusion
1
(minor) = 23.84 min, t (major) = 33.48 min]; H NMR
We have investigated an asymmetric [3+2]
annulation reaction of isatin-derived MoritaBaylis
Hillman carbonates and isatin-derived N-Boc
ketimines. A newly developed catalysis of chiral 4-
(400 MHz, CDCl3): δ = 8.12(s, 0.32H), 8.00 (s, 0.15H),
7.58–7.52 (m, 2H), 7.35–7.31 (m, 1H), 7.19–7.10 (m, 4H),
7.04–6.97 (m, 2H), 6.65 (d, J = 7.2 Hz, 1H), 6.55 (d, J =
6.8 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 16.0 Hz,
1H), 4.31 (d, J = 16.0 Hz, 1H), 2.90 (s, 3H), 1.46 (s, 3H),
1.01 (s, 6H); 13C NMR (150 MHz, CDCl3): δ = 172.3,
172.1, 149.5, 149.3, 149.1, 144.2, 143.5, 134.4, 130.6,
130.1, 128.6, 127.3, 126.9, 126.5, 126.3, 123.2, 123.1,
121.8, 113.7, 109.5, 108.4, 108.1, 90.7, 84.3, 83.5, 74.7,
65.4, 43.9, 27.9, 27.3, 25.9; ESI-HR-MS: m/z = 555.1998,
calcd. for (C32H28N4O4 + Na)+: 555.2003.
dimethylaminopyridine-type
substance
with
additional hydrogen-bonding groups appears to be
efficient in constructing a diversity of 1,2-
bispirooxindoles with excellent yields, exclusive
diastereoselectivity and moderate to remarkable
enantioselectivity. The protocol was further expanded
to an [3+2] annulation reaction between Morita
BaylisHillman carbonates and trifluoromethyl-
substituted ketimines which generated in situ from
the corresponding hemiaminals in the presence of
acid additives, affording architectures with vicinal
tetrasubstituted stereogenic centers with excellent
diastereoselectivity and moderate enantioselectivity.
tert-Butyl (3R,3'R)-1''-benzyl-5''-chloro-4'-cyano-1-
methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3e): yield: 54.4 mg (96%);
20
white solid; [α]D = 38.6 (c = 1.05 in CHCl3); 95% ee,
determined by HPLC analysis [Daicel chiralpak ID, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
1
(minor) = 19.96 min, t (major) = 33.15 min]; H NMR
(400 MHz, CDCl3): δ = 8.12 (s, 0.31H), 7.99 (s, 0.15H),
7.54 (s, 2H), 7.377.34 (m, 1H), 7.207.16 (m, 1H),
7.137.09 (m, 3H), 7.027.00 (m, 1H), 6.696.67 (m, 1H),
6.536.51 (m, 2H), 6.30 (d, J = 8.4 Hz, 1H), 5.07 (d, J =
4
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10.1002/adsc.201700849
Advanced Synthesis & Catalysis
16.0 Hz, 1H), 4.31 (d, J = 16.0 Hz, 1H), 2.96 (s, 3H), 1.46
(s, 3H), 1.01 (s, 6H); 13C NMR (150 MHz, CDCl3): δ =
172.0, 171.9, 149.9, 149.7, 149.0, 144.1, 142.1, 133.9,
130.6, 130.3, 128.8, 127.5, 127.2, 126.6, 126.4, 123.9,
123.5, 123.3, 122.8, 113.5, 110.5, 108.5, 108.3, 90.2, 84.6,
83.7, 74.7, 65.3, 44.1, 27.9, 27.3, 26.0; ESI-HR-MS: m/z =
589.1617, calcd. for (C32H27ClN4O4 + Na)+ : 589.1613.
6.546.52 (m, 3H), 5.08 (d, J = 16.2 Hz, 1H), 4.26 (d, J =
16.2 Hz, 1H), 2.94 (s, 3H), 1.45 (s, 3H), 1.01 (s, 6H); 13C
NMR (150 MHz, CDCl3): δ = 172.2, 172.0, 149.7, 149.5,
149.0, 144.9, 144.2, 133.8, 130.4, 128.8, 128.2, 127.5,
126.6, 126.3, 124.6, 124.0, 123.3, 120.9, 113.5, 112.9,
108.6, 108.4, 90.2, 84.6, 83.7, 74.5, 65.1, 44.0, 27.9, 27.3,
26.1; ESI-HR-MS: m/z
=
633.1108, calcd. for
(C32H2779BrN4O4 + Na)+ : 633.1111; m/z = 635.1093, calcd.
for (C32H2781BrN4O4 + Na)+ : 635.1094.
tert-Butyl (3R,3'R)-1''-benzyl-5''-bromo-4'-cyano-1-
methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3f): yield: 58.0 mg (95%);
tert-Butyl (3R,3'R)-1''-benzyl-7''-chloro-4'-cyano-1-
methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3j): yield: 55.0 mg (97%);
20
white solid; [α]D = +41.8 (c = 1.00 in CHCl3); 96% ee,
determined by HPLC analysis [Daicel chiralpak ID, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
white solid; [α]D = 180.7 (c = 1.10 in CHCl3); 88% ee,
20
1
(minor) = 21.01 min, t (major) = 35.97 min]; H NMR
determined by HPLC analysis [Daicel chiralpak AD-H, n-
(600 MHz, CDCl3): δ = 8.11 (s, 0.55H), 7.99 (s, 0.33H),
7.68 (d, J = 1.8 Hz, 1H), 7.557.52 (m, 1H), 7.367.33 (m,
1H), 7.267.24 (m, 1H), 7.197.17 (m, 1H), 7.137.10 (m,
2H), 7.016.99 (m, 1H), 6.686.67 (m, 1H), 6.536.52 (m,
2H), 6.25 (d, J = 8.4 Hz, 1H), 5.05 (d, J = 15.6 Hz, 1H),
4.31 (d, J = 15.6 Hz, 1H), 2.96 (s, 3H), 1.46 (s, 3H), 1.02
(s, 6H); 13C NMR (150 MHz, CDCl3): δ = 171.9, 171.7,
149.9, 149.7, 149.0, 144.1, 142.5, 133.9, 133.5, 130.3,
129.9, 128.8, 127.5, 126.6, 126.4, 123.8, 123.3, 115.9,
113.5, 111.0, 108.5, 108.3, 90.2, 84.6, 83.7, 74.7, 65.2,
44.0, 28.0, 27.3, 26.0; ESI-HR-MS: m/z = 633.1108, calcd.
for (C32H2779BrN4O4 + Na)+ : 633.1112; m/z = 635.1093,
calcd. for (C32H2781BrN4O4 + Na)+ : 635.1097.
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
1
(major) = 10.63 min, t (minor) = 12.11 min]; H NMR
(600 MHz, CDCl3): δ = 8.11(s, 0.55H), 7.98 (s, 0.27H),
7.52 (d, J = 7.2 Hz, 1H), 7.457.41 (m, 1H), 7.337.30 (m,
1H), 7.177.10 (m, 4H), 6.99 (t, J = 7.8 Hz, 1H),
6.896.87 (m, 1H), 6.706.69 (m, 1H), 6.566.55 (m, 2H),
5.17 (d, J = 10.2 Hz, 1H), 5.03 (d, J = 10.2 Hz, 1H), 2.94
(s, 3H), 1.44 (s, 3H), 1.00 (s, 6H); 13C NMR (150 MHz,
CDCl3): δ = 172.8, 172.0, 149.6, 149.4, 148.9, 144.0,
139.7, 136.4, 133.3, 130.4, 128.5, 126.7, 126.3, 125.7,
125.5, 124.8, 124.0, 123.7, 123.3, 115.4, 113.5, 108.5,
108.3, 90.5, 84.5, 83.7, 74.9, 64.9, 45.2, 27.9, 27.3, 26.1;
ESI-HR-MS: m/z = 589.1613, calcd. for (C32H27ClN4O4 +
Na)+: 589.1619.
tert-Butyl
(3R,3'R)-1''-benzyl-4'-cyano-5''-iodo-1-
methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
tert-Butyl
(3R,3'R)-1''-benzyl-4'-cyano-1,5''-
3',3''-indoline]-1'-carboxylate (3g): yield: 64.0 mg (97%); dimethyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
20
white solid; [α]D = +62.7 (c = 1.05 in CHCl3); 87% ee,
determined by HPLC analysis: [Daicel chiralpak AD-H, n-
hexane/i-PrOH = 80/20, 1.0 mL min1, λ = 254 nm]: t
3',3''-indoline]-1'-carboxylate (3k): yield: 52.5 mg (96%);
white solid; []D20: 71.3 (c = 1.15 in CHCl3); 79% ee,
determined by HPLC analysis [Daicel chiralpak ID, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
1
(minor) = 18.86 min, t (major) = 21.97 min]; H NMR
1
(400 MHz, CDCl3): δ = 8.11 (s, 0.28H), 7.99 (s, 0.15H),
7.84 (s, 1H), 7.547.52 (m, 1H), 7.457.43 (m, 1H),
7.367.32 (m, 1H), 7.207.16 (m, 1H), 7.137.09 (m, 2H),
7.017.00 (m, 1H), 6.686.67 (m, 1H), 6.52 (d, J = 6.8 Hz,
2H), 6.15 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 16.0 Hz, 1H),
4.30 (d, J = 16.0 Hz, 1H), 2.96 (s, 3H), 1.46 (s, 3H), 1.01
(s, 6H); 13C NMR (150 MHz, CDCl3): δ = 171.9, 171.5,
149.9, 149.7, 149.0, 144.1, 143.2, 139.4, 135.4, 133.9,
130.3, 128.8, 127.5, 126.5, 126.3, 126.2, 124.0, 123.3,
113.5, 111.5, 108.5, 108.3, 90.1, 85.6, 84.6, 83.7, 74.8,
65.0, 44.0, 27.9, 27.3, 26.0; ESI-HR-MS: m/z = 681.0969,
calcd. for (C32H27IN4O4 + Na)+: 681.0971.
(minor) = 19.61 min, t (major) = 28.22 min]; H NMR
(400 MHz, CDCl3): δ = 8.10 (s, 0.36H), 7.99 (s, 0.16H),
7.577.55 (m, 1H), 7.357.31 (m, 2H), 7.167.08 (m, 3H),
7.006.96 (m, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.65 (d, J =
7.6 Hz, 1H), 6.54 (d, J = 6.8 Hz, 2H), 6.26 (d, J = 8.0 Hz,
1H), 5.05 (d, J = 16.0 Hz, 1H), 4.30 (d, J = 16.0 Hz, 1H),
2.91 (s, 3H), 2.27 (s, 3H), 1.46 (s, 3H), 1.01 (s, 6H); 13C
NMR (150 MHz, CDCl3): δ = 172.1, 172.1, 149.4, 149.2,
149.1, 144.1, 141.0, 134.5, 132.7, 130.8, 130.1, 128.5,
128.5, 127.4, 127.2, 126.4, 126.3, 124.1, 123.0, 121.7,
113.8, 109.2, 108.1, 90.8, 84.2, 83.4, 74.8, 65.4, 43.8, 27.9,
27.3, 25.8, 20.9; ESI-HR-MS: m/z = 569.2159, calcd. for
(C33H30N4O4 + Na)+: 569.2158.
tert-Butyl (3R,3'R)-1''-benzyl-4'-cyano-1-methyl-5''-
nitro-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3h): yield: 55.5 mg (96%);
tert-Butyl (3R,3'R)-1''-benzyl-4'-cyano-5''-methoxy-
1-methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3l): yield: 54.0 mg (96%);
20
white solid; [α]D = +29.9 (c = 1.05 in CHCl3); 88% ee,
20
determined by HPLC analysis [Daicel chiralpak AD-H, n-
white solid; [α]D = 40.8 (c = 1.40 in CHCl3); 75% ee,
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
determined by HPLC analysis [Daicel chiralpak AD-H, n-
1
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
(minor) = 9.39 min, t (major) = 12.65 min]; H NMR (600
1
MHz, CDCl3): δ = 8.47 (s, 1H), 8.16 (s, 0.47H), 8.10 (dd, J
= 9.0 Hz, J = 2.4 Hz, 1H), 8.03 (s, 0.24H), 7.557.51 (m,
1H), 7.387.36 (m, 1H), 7.227.19 (m, 1H), 7.157.13 (m,
2H), 7.057.03 (m, 1H), 6.696.68 (m, 1H), 6.556.50 (m,
3H), 5.13 (d, J = 16.2 Hz, 1H), 4.40 (d, J = 16.2 Hz, 1H),
2.92 (s, 3H), 1.47 (s, 3H), 1.03 (s, 6H); 13C NMR (150
MHz, CDCl3): δ = 172.4, 171.5, 150.3, 150.0, 149.0,
148.8, 144.1, 143.8, 133.2, 130.6, 129.0, 127.9, 127.4,
126.7, 126.4, 123.6, 123.4, 123.0, 122.9, 113.2, 109.4,
108.8, 108.5, 89.4, 85.0, 84.1, 74.5, 64.9, 44.3, 27.9, 27.3,
26.2; ESI-HR-MS: m/z = 600.1854, calcd. for (C32H27N5O6
+ Na)+: 600.1861.
(minor) = 10.00 min, t (major) = 11.87 min]; H NMR
(600 MHz, CDCl3): δ = 8.11 (s, 0.41H), 7.99 (s, 0.26H),
7.607.55 (m, 1H), 7.347.32 (m, 1H), 7.187.15 (m, 2H),
7.127.09 (m, 2H), 7.016.97 (m, 1H), 6.676.65 (m, 2H),
6.546.53 (m, 2H), 6.27 (d, J = 8.4 Hz, 1H), 5.13 (d, J =
16.2 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 3.75 (s, 3H), 2.94
(s, 3H), 1.46 (s, 3H), 1.01 (s, 6H); 13C NMR (150 MHz,
CDCl3): δ = 172.2, 172.1, 156.1, 149.5, 149.3, 149.1,
144.2, 136.7, 134.5, 132.5, 130.2, 128.6, 127.3, 126.7,
126.4, 123.2, 122.9, 116.3, 113.7, 113.0, 112.8, 110.1,
108.4, 108.1, 90.8, 84.4, 83.5, 74.8, 65.8, 55.8, 44.0, 27.9,
27.3, 26.0; ESI-HR-MS: m/z = 585.2108, calcd. for
(C33H30N4O5 + Na)+: 585.2111.
tert-Butyl (3R,3'R)-1''-benzyl-6''-bromo-4'-cyano-1-
methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3i): yield: 58.7 mg (96%);
tert-Butyl
(3R,3'R)-1''-benzyl-4'-cyano-1,5'',7''-
trimethyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3m): yield: 54.4 mg
20
white solid; [α]D = 98.2 (c = 1.10 in CHCl3); 89% ee,
20
determined by HPLC analysis [Daicel chiralpak ID, n-
(97%); white solid; [α]D = 63.2 (c = 1.00 in CHCl3);
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
76% ee, determined by HPLC analysis [Daicel chiralpak
AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254
nm]: t (major) = 6.55 min, t (minor) = 8.29 min]; 1H NMR
(400 MHz, CDCl3): δ = 8.10 (s, 0.36H), 7.97 (s, 0.17H),
7.507.45 (m, 1H), 7.337.30 (m, 1H), 7.297.26 (m, 1H),
1
(minor) = 17.30 min, t (major) = 23.99 min]; H NMR
(600 MHz, CDCl3): δ = 8.11 (s, 0.50H), 7.98 (s, 0.29H),
7.557.54 (m, 1H), 7.417.39 (m, 1H), 7.367.34 (m, 1H),
7.207.12 (m, 4H), 7.016.99 (m, 1H), 6.696.68 (m, 1H),
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700849
Advanced Synthesis & Catalysis
7.177.10 (m, 3H), 6.916.88 (m, 1H), 6.736.69 (m, 2H),
6.476.46 (m, 2H), 5.16 (d, J = 17.2 Hz, 1H), 4.24 (d, J =
17.2 Hz, 1H), 2.95 (s, 3H), 2.25 (s, 3H), 1.94 (s, 3H), 1.45
(s, 3H), 1.00 (s, 6H); 13C NMR (150 MHz, CDCl3): δ =
173.1, 172.4, 149.2, 144.0, 139.1, 136.7, 135.1, 132.6,
130.1, 128.7, 126.7, 125.5, 125.4, 125.0, 124.2, 123.1,
122.5, 119.4, 113.9, 108.3, 108.0, 91.4, 84.2, 83.3, 75.0,
64.9, 45.1, 27.9, 27.3, 25.9, 20.6, 18.3; ESI-HR-MS: m/z =
583.2316, calcd. for (C34H32N4O4 + Na)+: 583.2319.
13C NMR (150 MHz, CDCl3): δ = 171.6, 171.4, 149.7,
149.4, 148.8, 142.6, 142.1, 134.0, 130.8, 130.3, 130.2,
128.8, 127.7, 127.1, 126.7, 126.5, 125.6, 124.5, 123.1,
113.3, 110.6, 109.5, 109.3, 90.5, 85.0, 84.1, 74.4, 64.2,
44.2, 28.0, 27.4, 26.2: ESI-HR-MS: m/z = 623.1223, calcd.
for (C32H26Cl2N4O4 + Na)+: 623.1224.
tert-Butyl (3R,3'R)-1''-benzyl-5-bromo-5''-chloro-4'-
cyano-1-methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-
pyrrole-3',3''-indoline]-1'-carboxylate (3r): yield: 61.3
20
tert-Butyl (3R,3'R)-1''-benzyl-4'-cyano-1,5-dimethyl-
2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-3',3''-
indoline]-1'-carboxylate (3n): yield: 53.6 mg (98%);
mg (95%); white solid; [α]D = +159.4 (c = 0.90 in
CHCl3); 87% ee, determined by HPLC analysis [Daicel
chiralpak AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL min1,
λ = 254 nm]: t (major) = 6.46 min, t (minor) = 9.84 min];
1H NMR (400 MHz, CDCl3): δ = 8.10 (s, 0.31H), 7.96 (s,
0.25H), 7.747.69 (m, 1H), 7.517.47 (m, 2H), 7.217.12
(m, 4H), 6.69 (d, J = 6.4 Hz, 2H), 6.54 (d, J = 7.6 Hz, 1H),
6.426.40 (m, 1H), 5.11 (d, J = 16.0 Hz, 1H), 4.33 (d, J =
16.0 Hz, 1H), 2.94 (s, 3H), 1.48 (s, 4H), 1.06 (s, 5H); 13C
NMR (150 MHz, CDCl3): δ = 171.6, 171.3, 149.7, 149.4,
143.0, 142.1, 134.0, 133.1, 130.8, 129.7, 129.3, 128.9,
127.7, 127.1, 126.5, 125.9, 124.8, 123.1, 115.9, 113.3,
110.6, 110.0, 109.8, 90.5, 85.0, 84.1, 74.2, 65.3, 44.2, 28.0,
27.4, 26.1; ESI-HR-MS: m/z = 667.0718, calcd. for
(C32H2679BrClN4O4 + Na)+: 667.0719; m/z = 669.0698,
calcd. for (C32H2681BrClN4O4 + Na)+: 669.0695.
20
white solid; [α]D = 53.3 (c = 1.15 in CHCl3); 95% ee,
determined by HPLC analysis [Daicel chiralpak AD-H, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
1
(major) = 6.08 min, t (minor) = 11.55 min]; H NMR (600
MHz, CDCl3): δ = 8.11 (s, 0.42H), 7.99 (s, 0.26H),
7.547.53 (m, 1H), 7.397.34 (m, 1H), 7.197.16 (m, 1H),
7.137.11 (m, 4H), 7.037.00 (m, 1H), 6.54 (m, 3H),
6.406.38 (m, 1H), 5.16 (d, J = 16.2 Hz, 1H), 4.28 (d, J =
16.2 Hz, 1H), 2.88 (s, 3H), 2.16 (s, 3H), 1.47 (s, 3H), 1.01
(s, 6H); 13C NMR (150 MHz, CDCl3): δ = 172.3, 172.0,
149.6, 149.1, 143.6, 141.7, 134.6, 132.9, 130.5, 130.3,
128.6, 127.2, 127.1, 126.8, 126.1, 124.1, 123.1, 121.8,
113.8, 109.4, 108.2, 108.0, 90.7, 84.3, 83.4, 74.8, 65.4,
43.8, 27.9, 27.3, 25.9, 20.9; ESI-HR-MS: m/z = 569.2159,
calcd. for (C33H30N4O4 + Na)+: 569.2155.
tert-Butyl (3R,3'R)-1''-benzyl-5''-chloro-4'-cyano-5-
iodo-1-methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-
pyrrole-3',3''-indoline]-1'-carboxylate (3s): yield: 67.2
tert-Butyl (3R,3'R)-1''-benzyl-4'-cyano-5-methoxy-1-
methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
20
mg (97%); white solid; []D = +171.1 (c = 1.00 in
3',3''-indoline]-1'-carboxylate (3o): yield: 54.0 mg (96%); CHCl3); 78% ee, determined by HPLC analysis [Daicel
20
white solid; [α]D = 37.9 (c = 1.20 in CHCl3); 94% ee,
determined by HPLC analysis [Daicel chiralpak AD-H, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
chiralpak AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL min1,
λ = 254 nm]: t (major) = 6.20 min, t (minor) = 8.92 min];
1H NMR (600 MHz, CDCl3): δ = 8.09 (s, 0.43H), 7.96 (s,
0.33H), 7.89 (s, 0.5H), 7.84 (s, 0.4H), 7.697.65 (m, 1H),
7.517.50 (m, 1H), 7.237.19 (m, 3H), 7.13 (d, J = 7.8 Hz,
1H), 6.68 (s, 2H), 6.456.43 (m, 1H), 6.416.37 (m, 1H),
5.12 (d, J = 15.6 Hz, 1H), 4.33 (d, J = 15.6 Hz, 1H), 2.96
(s, 3H), 1.48 (s, 4H), 1.06 (s, 5H); 13C NMR (150 MHz,
CDCl3): δ = 171.6, 171.1, 149.7, 149.5, 148.7, 143.7,
142.2, 139.1, 135.2, 134.7, 134.0, 130.8, 128.9, 128.9,
127.7, 127.1, 126.5, 126.1, 125.0, 123.1, 113.3, 110.6,
110.3, 90.4, 85.5, 85.0, 84.1, 74.1, 65.2, 44.2, 28.0, 27.4,
1
(major) = 9.45 min, t (minor) = 15.71 min]; H NMR (400
MHz, CDCl3): δ = 8.11 (s, 0.31H), 7.99 (s, 0.16H), 7.54 (d,
J = 7.6 Hz, 1H), 7.217.12 (m, 5H), 7.047.00 (m, 1H),
6.866.84 (m, 1H), 6.606.54 (m, 3H), 6.436.41 (m, 1H),
5.13 (d, J = 16.0 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.60
(s, 3H), 2.89 (s, 3H), 1.47 (s, 3H), 1.04 (s, 6H); 13C NMR
(150 MHz, CDCl3): δ = 172.4, 171.9, 156.2, 149.5, 149.2,
143.7, 137.4, 134.6, 130.6, 128.7, 127.3, 127.0, 126.2,
125.1, 123.2, 121.8, 116.0, 115.5, 113.7, 113.0, 112.8,
109.4, 108.7, 90.9, 84.4, 83.5, 75.1, 65.5, 55.9, 43.9, 28.0,
27.4, 26.0; ESI-HR-MS: m/z = 585.2108, calcd. for
(C33H30N4O5 + Na)+: 585.2112.
26.1; ESI-HR-MS: m/z
=
715.0579, calcd. for
(C32H26ClIN4O4 + Na)+: 715.0581.
tert-Butyl (3R,3'R)-1''-benzyl-6-bromo-5''-chloro-4'-
cyano-1-methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-
pyrrole-3',3''-indoline]-1'-carboxylate (3t): yield: 62.6
tert-Butyl
(3R,3'R)-1''-benzyl-4'-cyano-1,5,7-
trimethyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
3',3''-indoline]-1'-carboxylate (3p): yield: 53.8 mg (96%); mg (97%); white solid; [α]D20 = +49.1 (c = 1.05 in CHCl3);
20
white solid; [α]D = 91.1 (c = 1.30 in CHCl3); 98% ee,
determined by HPLC analysis [Daicel chiralpak IC, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
88% ee, determined by HPLC analysis [Daicel chiralpak
AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254
1
nm]: t (major) = 7.62 min, t (minor) = 11.46 min]; H
1
(minor) = 11.23 min, t (major) = 15.53 min]; H NMR
NMR (400 MHz, CDCl3): δ = 8.10 (s, 0.28H), 7.96 (s,
0.25H), 7.50 (s, 1H), 7.407.34 (q, J = 8.0 Hz, 1H), 7.24
(s, 3H), 7.157.06 (m, 2H), 6.84 (s, 1H), 6.596.58 (m,
2H), 6.38 (d, J = 7.2 Hz, 1H), 5.11 (d, J = 16.0 Hz, 1H),
4.31 (d, J = 16.0 Hz, 1H), 2.95 (s, 3H), 1.46 (s, 4H), 1.05
(s, 5H); 13C NMR (150 MHz, CDCl3): δ = 171.8, 171.7,
149.7, 149.4, 145.3, 142.1, 133.9, 130.9, 128.9, 127.9,
127.8, 127.5, 127.1, 126.4, 126.0, 124.5, 124.3, 123.2,
122.8, 113.3, 112.2, 111.8, 110.6, 90.3, 85.0, 84.1, 74.4,
65.2, 44.2, 28.0, 27.4, 26.2; ESI-HR-MS: m/z = 667.0718,
calcd. for (C32H2679BrClN4O4 + Na)+: 667.0719; m/z =
669.0698, calcd. for (C32H2681BrClN4O4 + Na)+: 669.0696.
(600 MHz, CDCl3): δ = 8.09 (s, 0.48H), 7.98 (s, 0.34H),
7.50 (d, J = 7.8 Hz, 1H), 7.187.17 (m, 2H), 7.147.10 (m,
3H), 7.027.00 (m, 1H), 6.866.84 (m, 1H), 6.546.52 (m,
2H), 6.406.38 (m, 1H), 5.14 (d, J = 9.6 Hz, 1H), 4.24 (d,
J = 9.6 Hz, 1H), 3.11 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H),
1.46 (s, 3H), 1.04 (s, 6H); 13C NMR (150 MHz, CDCl3): δ
= 172.6, 172.4, 149.5, 149.2, 143.6, 139.3, 139.1, 134.7,
134.2, 132.6, 130.5, 128.5, 127.3, 127.0, 126.2, 125.1,
123.0, 122.0, 119.3, 113.9, 109.4, 90.6, 84.2, 83.3, 74.6,
65.6, 43.9, 29.3, 28.0, 27.3, 20.6, 18.6; ESI-HR-MS: m/z =
583.2316, calcd. for (C34H32N4O4 + Na)+: 583.2315.
tert-Butyl (3R,3'R)-1''-benzyl-5,5''-dichloro-4'-cyano-
1-methyl-2,2''-dioxo-1'H-dispiro[indoline-3,2'-pyrrole-
tert-Butyl
(3R,3'R)-1,1''-dibenzyl-4'-cyano-2,2''-
dioxo-1'H-dispiro[indoline-3,2'-pyrrole-3',3''-indoline]-
3',3''-indoline]-1'-carboxylate (3q): yield: 58.9 mg (98%); 1'-carboxylate (3u): yield: 59.0 mg (97%); white solid;
20
white solid; [α]D = +74.4 (c = 1.25 in CHCl3); 79% ee,
determined by HPLC analysis [Daicel chiralpak AD-H, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
[α]D20 = –20.7 (c = 0.56 in CHCl3); 97% ee, determined by
HPLC analysis [Daicel chiralpak ID, n-hexane/i-PrOH =
60/40, 1.0 mL min1, λ = 254 nm]: t (minor) = 22.11 min, t
1
1
(major) = 6.54 min, t (minor) = 9.39 min]; H NMR (400
(major) = 37.61 min]; H NMR (400 MHz, CDCl3): δ =
MHz, CDCl3): δ = 8.10 (s, 0.31H), 7.96 (s, 0.26H),
7.607.55 (m, 1H), 7.51 (s, 1H), 7.337.31 (m, 1H),
7.227.13 (m, 4H), 6.69 (d, J = 6.8 Hz, 2H), 6.606.58 (m,
1H), 6.426.40 (m, 1H), 5.10 (d, J = 16.0 Hz, 1H), 4.34 (d,
J = 16.0 Hz, 1H), 2.95 (s, 3H), 1.48 (s, 4H), 1.06 (s, 5H);
8.14(s, 0.54H), 8.01 (s, 0.26H), 7.59–7.55 (m, 2H), 7.17–
7.13 (m, 2H), 7.11–7.08 (m, 2H), 6.98–6.92 (m, 6H), 6.53–
6.41 (m, 6H), 5.16–5.09 (m, 1.57H), 4.98 (d, J = 16.4 Hz,
0.33H), 4.43 (d, J = 15.6 Hz, 0.28H), 4.29 (d, J = 16.0 Hz,
1H), 4.15 (d, J = 15.6 Hz, 0.58H), 1.48 (s, 3H), 1.00 (s,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700849
Advanced Synthesis & Catalysis
6H); 13C NMR (100 MHz, CDCl3): δ = 172.4, 172.1,
149.3, 149.0, 143.8, 143.7, 134.2, 130.6, 130.2, 128.6,
127.7, 127.3, 127.2, 126.5, 126.2, 124.3, 123.7, 123.1,
122.3, 113.7, 109.7, 109.4, 90.6, 84.4, 83.7, 74.8, 65.8,
43.9, 43.8, 28.0, 27.3; ESI-HR-MS: m/z = 631.2316, calcd.
for (C38H32N4O4 + Na)+: 631.2311.
30.5 Hz), 63.3, 44.6, 21.2; ESI-HR-MS: m/z = 544.0913,
calcd. for (C27H18F3N3O3S + Na)+: 544.0911.
(1R,9bS)-1'-Benzyl-5'-chloro-2'-oxo-9b-
(trifluoromethyl)-9bH-spiro[benzo[d]pyrrolo[1,2-
b]isothiazole-1,3'-indoline]-2-carbonitrile
5,5-dioxide
(5e): yield: 49.8 mg (92%); white solid; [α]D20 = +20.6 (c =
0.50 in CHCl3); 74% ee, determined by HPLC analysis
[Daicel chiralpak AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL
min1, λ = 254 nm]: t (minor) = 9.46 min, t (major) = 11.80
min]; 1H NMR (400 MHz, CDCl3): δ = 7.857.83 (m, 1H),
7.707.66 (m, 2H), 7.59 (s, 1H), 7.43 (dd, J = 8.4 Hz, J =
1.6 Hz, 1H), 7.337.27 (m, 4H), 7.137.11 (m, 2H),
6.966.92 (m, 2H), 4.64 (dd, J = 46.8 Hz, 15.2 Hz, 2H);
13C NMR (150 MHz, CDCl3): δ = 170.6, 145.2 (d, J = 1.5
Hz), 142.4, 136.5, 134.3, 134.0, 132.5, 131.7, 129.6, 129.0,
128.6, 128.4, 128.0, 125.7120.0 (q, J = 284.7 Hz), 123.9,
122.6, 121.9, 111.2, 111.2, 101.2, 78.678.0 (q, J = 30.9
Hz), 63.2, 44.8; ESI-HR-MS: m/z = 564.0367, calcd. for
(C26H15ClF3N3O3S + Na)+: 564.0370.
(1R,9bS)-1'-Benzyl-2'-oxo-9b-(trifluoromethyl)-9bH-
spiro[benzo[d]pyrrolo[1,2-b]isothiazole-1,3'-indoline]-2-
carbonitrile 5,5-dioxide (5a): yield: 45.7 mg (90%); white
20
solid; [α]D = 3.3 (c = 0.30 in CHCl3); 73% ee,
determined by HPLC analysis [Daicel chiralpak AD-H, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
1
(minor) = 12.61 min, t (major) = 15.81 min]; H NMR
(400 MHz, CDCl3): δ = 7.82 (d, J = 8.0 Hz, 1H), 7.697.63
(m, 2H), 7.57 (s, 1H), 7.477.43 (m, 1H), 7.317.22 (m,
5H), 7.157.14 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.92 (d,
J = 7.6 Hz, 1H), 4.64 (dd, J = 57.6 Hz, 15.6 Hz, 2H; 13C
NMR (150 MHz, CDCl3): δ = 171.0, 144.9 (d, J = 0.9 Hz),
143.9, 136.5, 134.4, 134.2, 132.3, 131.6, 128.9, 128.8,
128.2, 128.1, 128.1, 125.8120.1 (q, J = 284.6 Hz), 124.1,
124.0, 122.5, 120.2, 111.4, 110.2, 101.8, 78.477.8 (q, J =
30.0 Hz), 63.2, 44.7(t, J = 5.1 Hz); ESI-HR-MS: m/z =
530.0757, calcd. for (C26H16F3N3O3S + Na)+: 530.0756.
Synthetic transformations
(3S,3'S,4'S)-1''-Benzyl-1-methyl-2,2''-
dioxodispiro[indoline-3,2'-pyrrolidine-3',3''-indoline]-
4'-carbonitrile (6): Product 3c (53.2 mg, 0.1 mmol) was
dissolved in DCM (1 mL), and TFA (0.15 mL) was added.
Then the solution was stirred at ambient temperature for 5
h. The mixture was diluted with CH2Cl2 (10 mL) and
neutralized with saturated NaHCO3. The aqueous solution
was extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were dried over MgSO4 and concentrated
under reduced pressure. The residue was dissolved in
DCM (1 mL), and Et3SiH (0.64 mL, 4 mmol) and
BF3Et2O (0.52 mL, 4 mmol) were added in sequence at 0
°C. The mixture was stirred for additional 24 h. After
completion, the solvent was evaporated under reduced
pressure and the residue was subjected to column
chromatography with petroleum ether/EtOAc (4:1) as the
eluent to give product 6: yield: 32.5 mg (75%); white solid;
(1R,9bS)-1'-Benzyl-8-methyl-2'-oxo-9b-
(trifluoromethyl)-9bH-spiro[benzo[d]pyrrolo[1,2-
b]isothiazole-1,3'-indoline]-2-carbonitrile
5,5-dioxide
(5b): yield: 48.0 mg (92%); white solid; [α]D20 = 3.8 (c =
0.21 in CHCl3); 76% ee, determined by HPLC analysis
[Daicel chiralpak AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL
min1, λ = 220 nm]: t (minor) = 11.03 min, t (major) =
1
14.66 min]; H NMR (600 MHz, CDCl3): δ = 7.71 (d, J =
8.4 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.48 (d,
J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.307.29 (m,
3H), 7.257.22 (m, 1H), 7.15 (d, J = 6.6 Hz, 2H), 6.94 (d,
J = 7.8 Hz, 1H), 6.84 (s, 1H), 4.68 (dd, J = 111.6 Hz, 15.6
Hz, 2H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3): δ =
171.2, 146.0, 144.9 (d, J = 2.2 Hz), 143.9, 134.3, 134.0,
133.4, 131.5, 129.4, 129.0, 128.1, 128.1, 128.0, 128.0,
127.4, 127.3118.7 (q, J = 284.3 Hz), 124.0, 122.2, 120.3,
111.5, 110.4, 101.8, 78.477.5 (q, J = 30.0 Hz), 63.2,
44.7(t, J = 3.8 Hz), 21.8; ESI-HR-MS: m/z = 544.0913,
calcd. for (C27H18F3N3O3S + Na)+: 544.0922.
20
[α]D = 185.6 (c = 0.23 in CHCl3); >19:1 dr; 96% ee,
determined by HPLC analysis [Daicel chiralpak AD-H, n-
hexane/i-PrOH = 60/40, 1.0 mL min1, λ = 254 nm]: t
1
(minor) = 17.41 min, t (major) = 22.68 min]; H NMR
(400 MHz, CDCl3): δ = 7.31 (dd, J = 11.2, 8.0 Hz, 2H),
7.26–7.20 (m, 4H), 7.11–7.07 (m, 3H), 6.96 (t, J = 7.6 Hz,
1H), 6.84 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H),
6.52 (d, J = 8.0 Hz, 1H), 4.92 (dd, J = 27.2, 16.0 Hz, 2H),
4.66 (dd, J = 9.6, 8.0 Hz, 1H), 4.14–4.09 (m, 1H), 4.00 (dd,
J = 11.2, 7.6 Hz, 1H), 3.68 (brs, 1H), 3.07 (s, 3H); 13C
NMR (150 MHz, CDCl3): δ = 175.4, 174.3, 144.0, 143.5,
134.6, 130.4, 129.7, 128.7, 127.6, 127.1, 124.2, 123.8,
123.1, 123.1, 122.9, 122.2, 109.8, 108.5, 74.0, 61.9, 49.1,
43.8, 36.7, 25.7; ESI-HR-MS: m/z = 435.1816, calcd. for
(C27H22N4O2 + H)+: 435.1819.
(1R,9bS)-1'-Benzyl-5',8-dichloro-2'-oxo-9b-
(trifluoromethyl)-9bH-spiro[benzo[d]pyrrolo[1,2-
b]isothiazole-1,3'-indoline]-2-carbonitrile
5,5-dioxide
(5c): yield: 54.1 mg (94%); white solid; [α]D20 = +30.3 (c =
0.60 in CHCl3); 60% ee, determined by HPLC analysis
[Daicel chiralpak AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL
min1, λ = 220 nm]: t (minor) = 6.94 min, t (major) = 10.22
min]; 1H NMR (400 MHz, CDCl3): δ = 7.837.81 (m, 1H),
7.737.71 (m, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.407.26
(m, 4H), 7.147.12 (m, 2H), 7.08 (s, 1H), 6.83 (d, J = 8.4
Hz, 1H), 4.71 (dd, J = 64.4 Hz, 15.6 Hz, 1H); 13C NMR
(150 MHz, CDCl3): δ = 170.7, 144.9 (d, J = 1.8 Hz), 142.3,
141.3, 135.1, 133.5, 133.3, 131.9, 130.9, 129.9, 129.4,
128.3, 127.1, 125.5119.8 (q, J = 284.6 Hz), 124.1, 123.9,
121.5, 111.8, 110.9, 101.7, 78.277.6 (q, J = 31.4 Hz),
63.4, 45.0; ESI-HR-MS: m/z = 597.9977, calcd. for
(C26H14Cl2F3N3O3S + Na)+: 597.9980.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21572135 and 21125206).
(1R,9bS)-1'-Benzyl-5'-methyl-2'-oxo-9b-
(trifluoromethyl)-9bH-spiro[benzo[d]pyrrolo[1,2-
References
b]isothiazole-1,3'-indoline]-2-carbonitrile
5,5-dioxide
(5d): yield: 47.5 mg (91%); white solid; [α]D20 = +5.5 (c =
0.22 in CHCl3); 61% ee, determined by HPLC analysis
[Daicel chiralpak AD-H, n-hexane/i-PrOH = 60/40, 1.0 mL
min1, λ = 220 nm]: t (minor) = 14.02 min, t (major) =
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201700849
Advanced Synthesis & Catalysis
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8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700849
Advanced Synthesis & Catalysis
Nishino, T. Furuta, K. Kan, M. Sato, M. Yamanaka, T.
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[15] CCDC 1559688 (3c) and 1559689 (5b) contain the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
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10.1002/adsc.201700849
Advanced Synthesis & Catalysis
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Asymmetric [3+2] Annulations to Construct 1,2-
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