Organocatalytic Asymmetric Michael/Cyclization Cascade Reactions of 3-Hydroxyoxindoles/3-Aminooxindoles with α,β-Unsaturated Acyl Phosphonates for the Construction of Spirocyclic Oxindole-γ-lactones/lactams

Article abstract of DOI:10.1021/acs.joc.5b02253

Enantioselective Michael/cyclization cascade reactions of 3-hydroxyoxindoles/3-aminooxindoles with α,β-unsaturated acyl phosphonates by using a cinchonine derived squaramide as the catalyst were developed. A broad range of spirocyclic oxindole-γ-lactones/lactams could be obtained in moderate to excellent yields (up to 98%) with good to excellent diastereo- and enantioselectivities (up to >99:1 dr and 97% ee) under mild conditions. This work represents the first example about the α,β-unsaturated acyl phosphonates for the asymmetric construction of spirocyclic oxindoles.

Full text of DOI:10.1021/acs.joc.5b02253

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Note
Organocatalytic Asymmetric Michael/Cyclization Cascade
Reactions of 3-Hydroxyoxindoles/3-Aminooxindoles
with alpha,beta-Unsaturated Acyl Phosphonates for the
Construction of Spirocyclic Oxindole-gamma-lactones/lactams
Lin Chen, Zhi-Jun Wu, Ming-Liang Zhang, Deng-Feng
Yue, Xiao-Mei Zhang, Xiao-Ying Xu, and Wei-Cheng Yuan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Nov 2015
Downloaded from http://pubs.acs.org on November 9, 2015
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Organocatalytic Asymmetric Michael/Cyclization Cascade Reactions of
3-Hydroxyoxindoles/3-Aminooxindoles with α,β-Unsaturated Acyl Phosphonates
for the Construction of Spirocyclic Oxindole-γ-lactones/lactams
Lin Chen,†,‡ Zhi-Jun Wu,§ Ming-Liang Zhang,†,ІІ Deng-Feng Yue,†,ІІ Xiao-Mei Zhang,† Xiao-Ying
Xu*,† and Wei-Cheng Yuan*,†
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†National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
‡College of Chemistry and Materials Sciences, Guizhou Normal University, Guiyang 550001,
China
§Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
ІІUniversity of Chinese Academy of Sciences, Beijing 100049, China
Table of Contents Graphic
Abstract
Enantioselective
Michael/cyclization
cascade
reactions
of
3-hydroxyoxindoles/3-aminooxindoles with α,β-unsaturated acyl phosphonates by using a
cinchonine derived squaramide as the catalyst were developed. A broad range of spirocyclic
oxindole-γ-lactones/lactams could be obtained in moderate to excellent yields (up to 98%) with
good to excellent diastereo- and enantioselectivities (up to >99:1 dr and 97% ee) under mild
conditions. This work represents the first example about the α,β-unsaturated acyl phosphonates for
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the asymmetric construction of spirocyclic oxindoles.
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Optically active spirocyclic oxindoles are common structural motifs in a variety of
architecturally complex natural products and pharmaceutical moleculars.1 A large number of
elegant synthetic methods for the construction of the privileged spirocyclic scaffolds have been
documented over the past decade.2 In particular, the catalytic asymmetric synthesis of chiral
spirocyclic oxindole-γ-lactones/lactams has attracted the scientists’ great attentions,3 and various
creative strategies have been established, including NHC-catalyzed [3+2] annulations of
α,β-unsaturated aldehydes with isatins3a-d or isatinimines3g-h and Michael/cyclization of
3-hydroxyoxindoles with α,β-unsaturated aldehydes3e or α,β-unsaturated esters.3f However, with a
literature survey, we noticed that using α,β-unsaturated acyl phosphonates as Michael acceptors
for the synthesis of spirocyclic oxindole compounds has not been exploited. In this context,
considering the importance of the spirocyclic oxindoles in pharmaceutical science, it is
conceivable that the development of an efficient method to access structurally diverse spirocyclic
oxindole-γ-lactones/lactams by using α,β-unsaturated acyl phosphonates will be desirable and
meaningful.
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α,β-Unsaturated acyl phosphonates were widely employed in catalytic asymmetric synthesis,4
and commonly played a role as activated ester surrogates for generating ester or amide compounds
by using the lability of the C-P bond (Scheme 1).5 Recently, our group developed a chiral
squaramide catalyzed asymmetric Michael addition of 3-monosubstituted oxindoles to
α,β-unsaturated acyl phosphonates, giving a series of 3,3'-disubstituted oxindole derivatives in
good results.6 On the other hand, 3-hydroxyoxindoles/3-aminooxindoles containing two reactive
sites have been successfully applied in some asymmetric reactions.7 Nevertheless, we also
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demonstrated that 3-hydroxyoxindoles/3-aminooxindoles could serve as a type of special
nucleophiles for the synthesis of 3,3'-disubstituted oxindoles and spirooxindoles.8 In this context,
as part of our ongoing investigations aimed at developing new strategies for the construction of
structurally diverse spirocyclic oxindole compounds,9 we envisioned that a catalytic asymmetric
Michael/cyclization cascade reaction of 3-hydroxyoxindoles/3-aminooxindoles with
α,β-unsaturated acyl phosphonates would be realized under certain asymmetric conditions, and
allowed us to produce a chiral acyl phosphonate intermediate (Scheme 1). Subsequently, this
intermediate will preferentially undergo an intramolecular cyclization reaction via acyl transfer
process, thus leading to a class of spirocyclic oxindole-γ-lactones/lactams (Scheme 1).
Importantly, this work represents the first example of α,β-unsaturated acyl phosphonates used in
catalytic asymmetric reactions for the construction of spirocyclic oxindole compounds. Herein, we
wish to report our studies about this subject.
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Scheme 1. Design strategy for the construction of spirocyclic oxindole-γ-lactones/lactams
Our investigations began with the screening of various chiral bifunctional cinchona alkaloid
derived squaramides 4a-d, as shown in Table 1. The reaction of N-methyl-3-hydroxyoxindole 1a
with diethyl but-2-enoylphosphonate 2a could proceed to completion within 9 h in
dichloromethane (DCM) at 25 °C with 20 mol % catalyst 4a, affording the desired spirocyclic
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oxindole-γ-lactone 3a in 53% yield with >99:1 dr and 92% ee (entry 1). Other squaramides 4b-d
gave comparable results (entries 2-4). By comparison, cinchonine derived squaramide 4d offered
the best results (entry 4). Afterward, a series of solvents including halohydrocarbons, arenes,
ethers and acetonitrile were evaluated (entries 5-11). It was found that acetonitrile was the suitable
solvent and gave the product 3a in 70% yield with >99:1 dr and 94% ee (entry 11). To further
improve the yield, the molar ratio of 1a to 2a was also investigated (entries 12-13). It was
observed that when 2.0 equiv. of 2a was used, the yield increased to 96% without erosion in the
diastereo- and enantioselectivity (entry 13). Unfortunately, trying to reduce the catalyst loading to
10 mol % and 5 mol %, the worse results than that with 20 mol % catalyst were obtained (not
shown). Accordingly, in light of the above surveys, the optimal reaction conditions of 0.1 mmol
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1a and 2.0 equiv. of 2a in 2 mL acetonitrile with 20 mol % of 4d at 25 oC were established.
Table 1. Conditions Optimizationa
entry Cat. Solvent Time (h) yieldb (%)
drc eec (%)
1
2
4a
4b
4c
4d
4d
4d
DCM
DCM
DCM
DCM
CHCl3
DCE
9
9
53 >99:1
46 99:1
92d
93d
94
94
94
93
85
87
94
92
94
94
3
9
39 >99:1
51 >99:1
4
9
5
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53
97:3
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9
55 >99:1
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4d Toluene
4d C6H5Cl
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38
43
94:6
95:5
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6
9
4d
4d
THF
Et2O
3
54 >99:1
41 97:3
70 >99:1
81 99:1
10
11
12e
3
4d CH3CN
4d CH3CN
3
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13f
4d CH3CN
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96
99:1
94
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a
Unless otherwise noted, all reactions were performed with 1a (0.1 mmol), 2a (0.1 mmol)
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b
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and 4 (20 mol %) in solvent (2.0 mL). Isolated yield. Determined by chiral HPLC. d Contrary
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configuration to 3a. e 1a:2a = 1:1.5. f 1a:2a = 1:2. DCE = 1,2-dichloroethane.
With the optimal reaction conditions in hand, the substrate scope was explored, and the
results are summarized in Table 2. Various substituted 3-hydroxyoxindoles 1b-l were examined
by reacting with α,β-unsaturated acyl phosphonate 2a and the desired spirocyclic
oxindole-γ-lactones 3b-l were obtained in 82-98% yields with up to >99:1 dr and 87-95% ee. It
was found that the substituents R1 on N atom of 3-hydroxyoxindoles had slight effects on the
reactivities and stereoselectivities. Both aliphatic and aromatic substituents on N atom of
3-hydroxyoxindoles 1b-g were tolerated, affording the desired spirocyclic oxindole-γ-lactones in
90-98% yields, 97:3-99:1 dr and 87-95% ee (entries 1-6). Gratifyingly, the reaction of
3-hydroxyoxindole 1h without N-protecting group proceeded well to provide spirocyclic
oxindole-γ-lactone 3h in good yield and excellent ee value (entry 7). Furthermore,
electron-donating and electron-withdrawing substituents on the aromatic ring of
3-hydroxyoxindoles with different positions were investigated, and the corresponding products
were obtained in high yields (up to 97% yield) with excellent diastereoselectivities (up to >99:1
dr) and enantioselectivities (up to 95% ee) (entries 8-11). The absolute configuration of the major
isomer 3k was assigned as (C7R, C9R) through the single crystal X-ray analysis (See the
supporting information). The stereochemistry of the other products in Table 2 and Table 3 was
assigned by analogy.10
Table 2. Scope of asymmetric Michael/cyclization cascade reaction of 3-hydroxyoxindoles 1
with α,β-unsaturated acyl phosphonate 2aa
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entry
R1/R2 Time (h)
3
yieldb (%)
drc eec (%)
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iPr/H (1b)
nBu/H (1c)
iBu/H (1d)
Allyl/H (1e)
Bn/H (1f)
30 3b
30 3c
30 3d
16 3e
30 3f
28 3g
28 3h
30 3i
94
96
98
90
98
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94
97:3
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95
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95
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94
99:1
99:1
99:1
99:1
99:1
98:2
Ph/H (1g)
H/H (1h)
Me/5-Me (1i)
Me/5-F (1j)
82 >99:1
89 >99:1
97 >99:1
8
8
8
3j
3k
3l
10 Me/5-Br (1k)
11 Me/6-Cl (1l)
91
99:1
a Unless otherwise noted, all reactions were performed with 1 (0.1 mmol), 2a (0.2 mmol) and 4d
(20 mol %) in CH3CN (2.0 mL). b Isolated yield. c Determined by chiral HPLC.
To further investigate the scope of the asymmetric reaction, we focused on the examinations
of α,β-unsaturated acyl phosphonates 2b-j with 1a as the donor (Table 3). The substituents R4 of
acyl phosphonates were first tested. It was found that substituents R4 of esters only slightly
affected the yields, providing the desired 3a in good to excellent yields with excellent
stereoselectivities (entries 1-3). The introduction of bulky alkyl substituents to the β-position of
α,β-unsaturated acyl phosphonates led to comparable results (entry 4 vs. 3 and entry 5 vs. 1).
However, aromatic groups had obvious effects on the stereoselectivities and furnished the desired
products in good yields with acceptable ee values (entries 6 and 7). This protocol was also
broadened to conjugated unsaturated acyl phosphonate 2i and good result was obtained (entry 8).
In addition, hindered β-disubstituted acyl phosphonate 2j could also react with 1a, but provided
3q in only 33% yield with 89% ee (entry 9).
Table
3.
Scope
of
asymmetric
Michael/cyclization
cascade
reaction
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N-methyl-3-hydroxyoxindole 1a to α,β-unsaturated acyl phosphonates 2a
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entry
R3/R4 Time (h)
3
yieldb (%)
drc eec (%)
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2
3
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7
Me/Me (2b)
Me/iPr (2c)
Me/nBu (2d)
nPr/nBu (2e)
nPr/Me (2f)
24 3a
33 3a
33 3a
35 3m
35 3m
24 3n
24 3o
87
92
97
99:1
94
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94
95
94
71
78
99:1
99:1
94 98:2d
88 96:4d
90 81:19
Ph/Me (2g)
2-furyl/Me (2h)
96
92:8
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9
24 3p
72 3q
88 95:5d
93
89
(2i)
(2j)
33
-
a
Unless otherwise noted, all reactions were performed with 1a (0.1 mmol), 2 (0.2 mmol) and 4d
(20 mol %) in CH3CN (2.0 mL). b Isolated yield. c Determined by chiral HPLC. d Dr values were
determined by 1H NMR analysis of crude reaction mixture.
Inspired by the above-achieved results, we next directed our efforts to the task of
constructing spirocyclic oxindole-γ-lactams. As shown in Table 4, the reaction of 3-aminooxindole
5a with α,β-unsaturated acyl phosphate 2a was conducted in acetonitrile with 4d as the catalyst,
and the desired spirocyclic oxindole-γ-lactam 6a was obtained in poor yield but with good
stereoselectivity (Table 4, entry 1). However, to our delight, replacing acetonitrile with
dichloromethane obviously led to a set of improved results (entry 2). Then, we explored the
generality of the Michael/cyclization cascade reaction with respect to various 3-aminooxindoles 5
and α,β-unsaturated acyl phosphonates 2. Firstly, a variety of 3-aminooxindoles 5b-e bearing
different substituent groups on
N atom were examined by reacting with diethyl
but-2-enoylphosphonate 2a (entries 3-6). It was found that both aliphatic and aromatic substituents
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were tolerated, furnishing the desired products 6b-d in moderate yields (31-60%) with excellent
diastereoselectivities (up to >99:1 dr) and enantioselectivities (96-97% ee) (entries 3-5).
Additionally, 3-aminooxindole 5e, without N-protecting group, could also react with 2a and
afforded the corresponding product 6e in 55% yield with 98:2 dr and 96% ee (entry 6). On the
other hand, a survey of α,β-unsaturated acyl phosphonates was also conducted. α,β-Unsaturated
acyl phosphonate 2b reacting with 5c smoothly afforded 65% yield, albeit with slightly lower
enantioselectivity (entry 7). It was observed that the substituents R3 at the β-position of acyl
phosphonates had slight effect on the yields and enantioselectivities and acceptable results could
be obtained regardless of aliphatic and aromatic groups (entries 8-10). Furthermore, the
conjugated unsaturated acyl phosphonate 2i was found to be compatible for giving 6i with 94% ee
(entry 11). Moreover, when β-disubstituted acyl phosphonate 2j was used as an acceptor, the
expected product 6j was furnished in 35% yield and 85% ee (entry 12).
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Table 4. Scope of the asymmetric Michael/cyclization cascade reaction of 3-aminooxindoles 5
to α,β-unsaturated acyl phosphonates 2a
entry
1 d Me (5a)
R1
R3/R4 Time (h)
6
yieldb (%)
drc ee (%)c
Me/Et (2a)
Me/Et (2a)
Me/Et (2a)
Me/Et (2a)
Me/Et (2a)
Me/Et (2a)
Me/Me (2b)
nPr/Me (2f)
Ph/Me (2g)
2-furyl/Me
(2h)
20 6a
20 6a
29 6b
29 6c
29 6d
29 6e
29 6c
48 6f
48 6g
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51
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96
97
97
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96
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88
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7
8
9
Me (5a)
Et (5b)
Bn (5c)
Ph (5d)
H (5e)
49 >99:1e
60
31
55
65
41
55
98:2
92:8
98:2
98:2
98:2
94:6
Bn (5c)
Bn (5c)
Bn (5c)
10 Bn (5c)
48 6h
51
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11 Bn (5c)
12 Bn (5c)
48 6i
(2i)
31
35
92:8
-
94
85
120 6j
(2j)
8
9
a Unless otherwise noted, all reactions were performed with 5 (0.1 mmol), 2 (0.2 mmol) and
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b
c
d
4d (20 mol %) in DCM (2.0 mL). Isolated yield. Determined by chiral HPLC. Acetonitrile
was used as a solvent. e Dr value was determined by 1H NMR analysis of crude reaction mixture.
Based on our experiment results and the absolute configuration of the major isomer 3k, a
possible reaction mechanism has been tentatively proposed. As shown in Scheme 2, with the dual
activation of catalyst 4d, the 3-hydroxyoxindoles 1 as the Michael donors were enolized by the
tertiary amine moiety. Synchronously, the α,β-unsaturated acyl phosphonates 2 as acceptors were
directed by the squaramide motif through a hydrogen-bonding interaction. And then, the enolized
oxindole (from Si face) would attack the α,β-unsaturated acyl phosphonate (to Re face) to generate
the chiral acyl phosphonate intermediate M. And then, the intermediate M will further undergo an
intramolecular cyclization reaction via acyl transfer process, resulting spirocyclic
oxindole-γ-lactones 3 (Scheme 2).
Scheme 2. A proposed transition state for this transformation
In summary, we have developed a highly enantioselective Michael/cyclization cascade
reaction of 3-hydroxyoxindoles/3-aminooxindoles with α,β-unsaturated acyl phosphonates
catalyzed by a cinchonine derived quaramide catalyst. With this developed protocol, a broad range
of spirocyclic oxindole-γ-lactones/lactams could be obtained in moderate to excellent yields (up to
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97%), with good to excellent diastereo- and enantioselectivities (up to >99:1 dr and 97% ee) under
mild conditions. Notably, this work represents the first example of α,β-unsaturated acyl
phosphonates used in catalytic asymmetric reactions for the generation of spirocyclic
γ-lactones/lactams.
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EXPERIMENTAL SECTION
General Methods. 1H NMR and 13C NMR (300 and 75 MHz, respectively) spectra were recorded
1
in CDCl3. H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with
the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm). Data are reported as
the follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and m =
multiplet), coupling constants (Hz) and integration. 13C NMR chemical shifts are reported in ppm
relative to tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at
77.20 ppm). Melting points were recorded on a Buchi Melting Point B-545.
3-hydroxyoxindoles3e (1a-l), 3-aminooxindoles8a (5a-e) and α,β-unsaturated acyl
phosphonates5a,12 (2a-j) were prepared according to the reported procedures or similarly. Unless
otherwise noted, materials were purchased from commercial suppliers and used without further
purification. All reactions have been carried out with distilled and degassed solvents in oven-dried
glassware.
General procedure for the synthesis of spirocyclic oxindole-γ-lactones 3. Under the
protection of nitrogen, an oven-dried 20 mL reaction tube was charged with 3-hydroxyoxindole 1
(0.1 mmol, 1.0 equiv.), catalyst 4d (0.02 mmol, 20 mol %) and CH3CN (1.0 mL). After 10 min of
o
stirring at 25 C, α,β-unsaturated acyl phosphonate 2 (0.2 mmol, 2.0 equiv.) in CH3CN (1.0 mL)
was added. The stirring was maintained at the same temperature until the total consumption of
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3-hydroxyoxindoles 1 (monitored by TLC). The crude reaction mixture was diluted with CH2Cl2,
and filtered through a pad of silica gel. The solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel (eluted with petroleum ether/ethyl acetate) to
give the desired products 3.
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(2R,3R)-1',3-dimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3a)3e-f. White solid; 22.2
mg, 96% yield; 99:1 dr, 94% ee; The ee was determined by HPLC (Chiralpak OD-H column,
EtOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 11.2 min,
tminor = 14.9 min); 1H NMR (300 MHz, CDCl3) δ 0.99 (d, J = 6.5 Hz, 3H), 2.72 (dd, J = 7.4 Hz, J
= 15.6, 1H), 2.85-2.95 (m, 1H), 3.03 (dd, J = 12.5 Hz, J = 15.5 Hz, 1H), 3.20 (s, 3H), 6.86 (d, J =
7.8 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.40 (td, J = 1.1 Hz, J = 7.8 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 12.6, 26.2, 35.0, 40.2, 86.1, 108.6, 123.5, 124.2, 124.8, 131.2,
144.6, 173.0, 175.4; HRMS (ESI-TOF) calcd. for C13H13NNaO3 [M + Na]+: 254.0788, found
254.0777.
(2R,3R)-1'-isopropyl-3-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3b). Colorless
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oil; 24.4 mg, 94% yield; 97:3 dr, 87% ee; [α]D = +54.8 (c = 0.73, CHCl3); The ee was
determined by HPLC (Chiralpak OJ-H column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ =
254 nm, major diastereomer: tmajor = 6.9 min, tminor = 7.5 min); 1H NMR (300 MHz, CDCl3) δ 0.99
(d, J = 6.5 Hz, 3H), 1.48 (dd, J = 4.6 Hz, J = 7.0 Hz, 6H), 2.70 (dd, J = 7.6 Hz, J = 15.7 Hz, 1H),
2.78-2.89 (m, 1H), 3.01 (d, J = 12.3 Hz, J = 15.7 Hz, 1H), 4.47-4.56 (m, 1H), 6.99 (d, J = 7.9 Hz,
1H), 7.10 (t, J = 7.5 Hz, 1H), 7.33-7.39 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 12.4, 19.1, 19.5,
34.9, 40.7, 44.3, 85.8, 110.0, 122.9, 124.4, 125.2, 130.8, 143.2, 172.7, 175.6; HRMS (ESI-TOF)
calcd. for C15H17NNaO3 [M + Na]+: 282.1101, found 282.1094.
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(2R,3R)-1'-butyl-3-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3c). Colorless oil;
26.2 mg, 96% yield; 99:1 dr, 94% ee; [α]D20 = +64.0 (c = 0.79, CHCl3); The ee was determined by
HPLC (Chiralpak AD-H column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tmajor = 6.8 min, tminor = 8.9 min); 1H NMR (300 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz,
3H), 1.00 (d, J = 6.5 Hz, 3H), 1.32-1.44 (m, 2H), 1.60-1.70 (m, 2H), 2.72 (dd, J = 7.4 Hz, J = 15.7
Hz, 1H), 2.84-2.93 (m, 1H), 3.02 (dd, J = 15.6 Hz, J = 12.5 Hz, 1H), 3.54-3.63 (m, 1H), 3.71-3.80
(m, 1H), 6.86 (d, J = 7.8 Hz, 1H), 7.12 (td, J = 0.8 Hz, J = 7.6 Hz, 1H), 7.33-7.41 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 12.6, 13.7, 20.0, 29.4, 35.0, 39.8, 40.3, 86.0, 108.9, 123.2, 124.3, 124.9,
131.1, 144.0, 172.9, 175.6; HRMS (ESI-TOF) calcd. for C16H19NNaO3 [M + Na]+: 296.1257,
found 296.1254.
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(2R,3R)-1'-isobutyl-3-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3d). Colorless oil;
26.7 mg, 98% yield; 99:1 dr, 95% ee; [α]D20 = +68.3 (c = 0.96, CHCl3); The ee was determined by
HPLC (Chiralpak AD-H column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
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diastereomer: tmajor = 6.9 min, tminor = 11.6 min); H NMR (300 MHz, CDCl3) δ 0.96 (dd, J = 1.7
Hz, J = 6.7 Hz, 6H), 1.02 (d, J = 6.5 Hz, 3H), 2.05-2.17 (m, 1H), 2.72 (dd, J = 7.3 Hz, J = 15.6 Hz,
1H), 2.84-2.97 (m, 1H), 3.03 (dd, J = 15.5 Hz, J = 12.5 Hz, 1H), 3.36 (dd, J = 7.3 Hz, J = 13.9 Hz,
1H), 3.59 (dd, J = 7.7 Hz, J = 14.0 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 7.12 (td, J = 0.8 Hz, J = 7.6
Hz, 1H), 7.33-7.40 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 12.8, 20.2, 20.2, 27.0, 35.0, 40.1, 47.7,
85.9, 109.1, 123.2, 124.3, 124.8, 131.1, 144.5, 173.3, 175.5; HRMS (ESI-TOF) calcd. for
C16H19NNaO3 [M + Na]+: 296.1257, found 296.1253.
(2R,3R)-1'-allyl-3-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3e). Colorless oil;
23.2 mg, 90% yield; 99:1 dr, 93% ee; [α]D20 = +57.5 (c = 0.79, CHCl3); The ee was determined by
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HPLC (Chiralpak AD-H column, EtOH/hexane = 50/50, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tmajor = 6.1 min, tminor = 10.5 min); 1H NMR (300 MHz, CDCl3) δ 1.02 (d, J = 6.5 Hz,
3H), 2.73 (dd, J = 7.1 Hz, J = 15.5 Hz, 1H); 2.84-2.97 (m, 1H), 3.03 (dd, J = 15.4 Hz, J = 12.5 Hz,
1H); 4.19 (dd, J =5.3 Hz, J = 16.4 Hz, 1H), 4.43 (dd, J = 5.1 Hz, J = 16.4 Hz, 1H), 5.20-5.26 (m,
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2H), 5.75-5.87 (m, 1H), 6.85 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 7.0 Hz, 1H), 7.34-7.39 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 12.6, 34.9, 40.3, 42.3, 86.0, 109.5, 117.9, 123.5, 124.3, 124.7, 130.7,
131.1, 143.7, 172.8, 175.5; HRMS (ESI-TOF) calcd. for C15H15NNaO3 [M + Na]+: 280.0944,
found 280.0940.
(2R,3R)-1'-benzyl-3-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3f). White solid;
30.1 mg, 98% yield; 99:1 dr, 95% ee; [α]D20 = +48.5 (c = 0.78, CHCl3); Mp: 145.1-146.3 ºC; The
ee was determined by HPLC (Chiralpak AD-H column, EtOH/hexane = 50/50, flow rate 1.0
mL/min, λ = 254 nm, major diastereomer: tmajor = 9.1 min, tminor = 37.4 min); 1H NMR (300 MHz,
CDCl3) δ 1.06 (d, J = 6.5 Hz, 3H), 2.76 (dd, J = 7.3 Hz, J = 15.6 Hz, 1H), 2.90-2.98 (m, 1H), 3.07
(dd, J = 15.5 Hz, J = 12.5 Hz, 1H), 4.74 (d, J = 15.7 Hz, 1H), 5.02 (d, J = 15.7 Hz, 1H), 6.74 (d, J
= 7.8 Hz, 1H), 7.10 (td, J = 0.8 Hz, J = 7.7 Hz, 1H), 7.25-7.37 (m, 7H); 13C NMR (75 MHz,
CDCl3) δ 12.8, 35.0, 40.3, 43.9, 86.0, 109.7, 123.5, 124.3, 124.7,127.2, 127.9, 128.9, 131.1, 135.0,
143.7, 173.2, 175.5; HRMS (ESI-TOF) calcd. for C19H17NNaO3 [M + Na]+: 330.1101, found
330.1090.
(2R,3R)-3-methyl-1'-phenyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3g). White solid;
27.0 mg, 92% yield; 99:1 dr, 95% ee; [α]D20 = +74.9 (c = 0.91, CHCl3); Mp: 183.2-184.1 ºC; The
ee was determined by HPLC (Chiralpak AD-H column, EtOH/hexane = 50/50, flow rate 1.0
mL/min, λ = 254 nm, major diastereomer: tmajor = 6.3 min, tminor = 12.3 min); 1H NMR (300 MHz,
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CDCl3) δ 1.14 (d, J = 6.4 Hz, 3H), 2.76 (dd, J = 6.2 Hz, J = 14.6 Hz, 1H), 2.93-3.10 (m, 2H), 6.84
(d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.31-7.46 (m, 5H), 7.51-7.56 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 12.6, 34.8, 40.9, 86.1, 109.9, 124.0, 124.5, 126.3, 128.6, 129.8, 129.8, 131.0,
133.3, 144.4, 172.4, 175.4; HRMS (ESI-TOF) calcd. for C18H15NNaO3 [M + Na]+: 316.0944,
found 316.0931.
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(2R,3R)-3-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3h). Colorless oil; 20.5 mg,
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94% yield; 98:2 dr, 95% ee; [α]D = +53.1 (c = 0.71, CHCl3); The ee was determined by HPLC
(Chiralpak OJ-H column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tmajor = 9.9 min, tminor = 6.5 min); 1H NMR (300 MHz, CDCl3) δ 1.07 (d, J = 6.3 Hz,
3H), 2.75 (dd, J = 6.4 Hz, J = 14.6 Hz, 1H), 2.86-3.03 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 7.11 (t, J
= 7.5 Hz, 1H), 7.31-7.36 (m, 2H), 8.63 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.6, 34.9, 40.4,
86.5, 110.7, 123.5, 124.5, 125.1, 131.2, 141.6, 175.5, 175.7; HRMS (ESI-TOF) calcd. for
C12H11NNaO3 [M + Na]+: 240.0631, found 240.0627.
(2R,3R)-1',3,5'-trimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3i). Colorless oil;
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20.0 mg, 82% yield; >99:1 dr, 93% ee; [α]D = +60.4 (c = 0.87, CHCl3); The ee was determined
by HPLC (Chiralpak OD-H column, EtOH/hexane = 15/85, flow rate 1.0 mL/min, λ = 254 nm,
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major diastereomer: tmajor = 7.7 min, tminor = 8.7 min); H NMR (300 MHz, CDCl3) δ 0.98 (d, J =
6.5 Hz, 3H), 2.34 (s, 3H), 2.71 (dd, J = 7.4 Hz, J = 15.7 Hz, 1H), 2.83-2.92 (m, 1H), 3.02 (dd, J =
15.6 Hz, J = 12.5 Hz, 1H), 3.17 (s, 3H), 6.74 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H) 7.18 (d, J = 10.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 12.6, 21.0, 26.2, 35.0, 40.2, 86.2, 108.4, 124.7, 125.0, 131.3,
133.2, 142.1, 173.0, 175.6; HRMS (ESI-TOF) calcd. for C14H15NNaO3 [M + Na]+: 268.0944,
found 268.0935.
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(2R,3R)-5'-fluoro-1',3-dimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3j). White
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solid; 22.1 mg, 89% yield; >99:1 dr, 95% ee; [α]D = +77.0 (c = 0.73, CHCl3); Mp: 212.5-213.3
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ºC; The ee was determined by HPLC (Chiralpak OD-H column, iPrOH/hexane = 30/70, flow rate
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1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 7.3 min, tminor = 8.0 min); H NMR (300
MHz, CDCl3) δ 0.99 (d, J = 6.5 Hz, 3H), 2.72 (dd, J = 7.5 Hz, J = 15.5 Hz, 1H), 2.81-2.90 (m,
1H), 3.01 (dd, J = 15.4 Hz, J = 12.1 Hz, 1H), 3.18 (s, 3H), 6.80 (dd, J = 3.9 Hz, J = 9.2 Hz, 1H),
7.08-7.14 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 12.5, 26.3, 34.7, 40.4, 85.8, 109.4 (d, J = 7.9
Hz), 112.5 (d, J = 25.1 Hz), 117.5 (d, J = 23.4 Hz), 126.3 (d, J = 8.0 Hz), 140.4, 159.5 (d, J =
241.6 Hz), 172.8, 175.1; HRMS (ESI-TOF) calcd. for C13H12FNNaO3 [M + Na]+: 272.0693, found
272.0689.
(2R,3R)-5'-bromo-1',3-dimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3k). White
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solid; 30.2 mg, 97% yield; >99:1 dr, 95% ee; [α]D = +57.2 (c = 0.76, CHCl3); Mp: 206.3-207.2
ºC; The ee was determined by HPLC (Chiralpak AD-H column, EtOH/hexane = 50/50, flow rate
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1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 6.6 min, tminor = 12.4 min); H NMR (300
MHz, CDCl3) δ 0.99 (d, J = 6.4 Hz, 3H), 2.72 (dd, J = 7.1 Hz, J = 15.3 Hz, 1H), 2.82-2.93 (m,
1H), 2.99 (dd, J = 15.2 Hz, J = 12.3 Hz, 1H), 3.17 (s, 3H), 6.75 (d, J = 8.3, 1H), 7.47 (d, J = 1.7,
1H), 7.52 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 12.5, 26.3, 34.7, 40.2,
85.6, 110.1, 116.0, 126.7, 127.5, 133.9, 143.5, 172.5, 175.0; HRMS (ESI-TOF) calcd. for
C13H12BrNNaO3 [M + Na]+: 331.9893, found 331.9879.
(2R,3R)-6'-chloro-1',3-dimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3l). White
solid; 24.1 mg, 91% yield; 99:1 dr, 94% ee; [α]D20 = +37.4 (c = 0.78, CHCl3); Mp: 159.3-159.9 ºC;
The ee was determined by HPLC (Chiralpak OD-H column, EtOH/hexane = 15/85, flow rate 1.0
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mL/min, λ = 254 nm, major diastereomer: tmajor = 8.6 min, tminor = 10.1 min); 1H NMR (300 MHz,
CDCl3) δ 0.98 (d, J = 6.5 Hz, 3H), 2.72 (dd, J = 7.3 Hz, J = 15.5 Hz, 1H), 2.82-2.92 (m, 1 H), 3.00
(dd, J = 15.4 Hz, J = 12.3 Hz, 1H), 3.18 (s, 3H), 6.86 (d, J = 1.7 Hz, 1H), 7.11 (dd, J = 1.8 Hz, J =
8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 12.5, 26.3, 34.8, 40.2, 85.5,
109.5, 123.1, 123.4, 125.2, 137.1, 145.7, 173.0, 175.1; HRMS (ESI-TOF) calcd. for
C13H12ClNNaO3 [M + Na]+: 288.0398, found 288.0387.
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(2R,3R)-1'-methyl-3-propyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3m). Colorless oil;
24.4 mg, 94% yield; 98:2 dr, 95% ee; [α]D20 = +36.8 (c = 0.80, CHCl3); The ee was determined by
HPLC (Chiralpak AD-H column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
diastereomer: tmajor = 6.7 min, tminor = 9.4 min); 1H NMR (300 MHz, CDCl3) δ 0.79 (t, J = 7.1 Hz,
3H), 1.12-1.25 (m, 3H), 1.38-1.45 (m, 1H), 2.70-2.84 (m, 2H), 2.92-2.99 (m, 1H), 3.19 (s, 3H),
6.86 (d, J = 7.8 Hz, 1H), 7.14 (td, J = 0.8 Hz, J = 7.6 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.40 (td, J
= 1.2 Hz, J = 7.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 21.3, 26.2, 30.3, 33.7, 45.3, 85.5,
108.6, 123.5, 124.2, 125.2, 131.1, 144.4, 173.2, 175.5; HRMS (ESI-TOF) calcd. for C15H17NNaO3
[M + Na]+: 282.1101, found 282.1094.
(2R,3S)-1'-methyl-3-phenyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3n) 3f. White solid;
26.4 mg, 90% yield; 81:19 dr, 71% ee; The ee was determined by HPLC (Chiralpak AD-H column,
EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 8.0 min,
tminor = 10.5 min); 1H NMR (300 MHz, CDCl3) δ 2.81 (s, 3H), 2.91 (dd, J = 7.9 Hz, J = 16.7 Hz,
1H), 3.82 (dd, J = 16.7 Hz, J = 13.7 Hz, 1H), 4.07 (dd, J = 7.9 Hz, J = 13.7 Hz, 1H), 6.66 (d, J =
7.8 Hz, 1H), 6.92 (d, J = 7.7 Hz, 2H), 7.15-7.23 (m, 4H), 7.38 (td, J = 1.2 Hz, J = 7.7 Hz, 1H),
7.54 (dd, J = 0.51 Hz, J = 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 25.8, 32.2, 51.0, 86.4, 108.6,
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123.5, 124.1, 124.8, 127.5, 128.3, 128.4, 131.3, 132.1, 144.3, 172.6, 174.7; HRMS (ESI-TOF)
calcd. for C18H15NNaO3 [M + Na]+: 316.0944, found 316.0934.
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(2R,3S)-3-(furan-2-yl)-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3o) . White
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solid; 27.2 mg, 96% yield; 92:8 dr, 78% ee; The ee was determined by HPLC (Chiralpak AD-H
column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 8.5
min, tminor = 15.2 min); 1H NMR (300 MHz, CDCl3) δ 2.98 (dd, J = 7.5 Hz, J = 17.0 Hz, 1H), 3.00
(s, 3H), 3.70 (dd, J = 17.0 Hz, J = 13.4 Hz, 1H), 4.14 (dd, J = 8.4 Hz, J = 13.3 Hz, 1H), 6.02 (d, J
= 3.2 Hz, 1H); 6.22 (dd, J = 1.8 Hz, J = 3.2 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 7.15-7.20 (m, 2H),
7.41 (td, J = 1.1 Hz, J = 7.8 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 26.1,
32.2, 44.5, 84.6, 107.8, 108.7, 110.5, 123.5, 124.1, 124.6, 131.3, 142.5, 144.3, 147.6, 172.4, 174.1;
HRMS (ESI-TOF) calcd. for C16H13NNaO4 [M + Na]+: 306.0737, found 306.0726.
(2R,3S)-3-((E)-hept-1-en-1-yl)-1'-methyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3p).
Colorless oil; 27.6 mg, 88% yield; 95:5 dr, 93% ee; [α]D20 = -15.5 (c = 0.71, CHCl3); The ee was
determined by HPLC (Chiralpak AD-H column, EtOH/hexane = 30/70, flow rate 1.0 mL/min, λ =
254 nm, major diastereomer: tmajor = 5.1 min, tminor = 7.9 min); 1H NMR (300 MHz, CDCl3) δ 0.81
(t, J = 7.1 Hz, 3H), 0.96-1.04 (m, 2H), 1.08-1.25 (m, 4H), 1.77-1.91 (m, 2H), 2.74 (dd, J = 7.9 Hz,
J = 16.6 Hz, 1H), 3.15 (s, 3H), 3.23 (dd, J = 16.6 Hz, J = 12.8 Hz, 1H), 3.33-3.42 (m, 1H), 5.18
(dd, J = 7.6 Hz, J = 15.3 Hz, 1H), 5.27-5.34 (m, 1H), 6.81 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 7.5 Hz,
1H), 7.36-7.41 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.3, 26.1, 28.4, 30.7, 32.0, 33.7,
49.0, 85.5, 108.5, 122.5, 123.4, 124.1, 124.7, 131.0, 137.3, 144.4, 173.0, 175.3; HRMS (ESI-TOF)
calcd. for C19H23NNaO3 [M + Na]+: 336.1570, found 336.1558.
(R)-1',3,3-trimethyl-3H-spiro[furan-2,3'-indoline]-2',5(4H)-dione (3q). Colorless oil; 8.1 mg,
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AD-H column, EtOH/hexane = 25/75, flow rate 1.0 mL/min, λ = 254 nm, tmajor = 10.0 min, tminor
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9.4 min); 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 3H), 1.29 (s, 3H), 2.38 (d, J = 16.7 Hz, 1H), 3.19
(s, 3H), 3.41 (d, J = 16.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.36-7.43(m,
2H); 13C NMR (75 MHz, CDCl3) δ 21.4, 26.0, 26.2, 41.6, 43.2, 88.5, 108.7, 122.3, 122.7, 127.0,
131.0, 144.9, 174.8, 175.7; HRMS (ESI-TOF) calcd. for C14H15NNaO3 [M + Na]+: 268.0944,
found 268.0940.
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General procedure for the synthesis of spirocyclic oxindole-γ-lactams 6. An oven-dried
20 mL reaction tube was charged with 3-aminooxindoles 5 (0.1 mmol, 1.0 equiv.), catalyst 4d
o
(0.02 mmol, 20 mol %) and CH2Cl2 (1.0 mL). After 10 min of stirring at 25 C, α,β-unsaturated
acyl phosphonate 2 (0.2 mmol, 2.0 equiv.) in CH2Cl2 (1.0 mL) was added. The stirring was
maintained at the same temperature until the total consumption of 3-aminooxindoles 5 (monitored
by TLC). The crude reaction mixture was diluted with CH2Cl2, and filtered through a pad of silica
gel. The solvent was removed under reduced pressure and the residue was purified by
chromatography on silica gel (eluted with petroleum ether/ethyl acetate) to give the desired
products 6.
1,3'-dimethyl-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6a). Colorless oil;
13.1 mg, 51% yield; 98:2 dr, 96% ee; [α]D20 = +21.0 (c = 0.47, CHCl3); The ee was determined by
HPLC (Chiralpak OD-H column, EtOH/hexane = 10/90, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tmajor = 10.0 min, tminor = 10.9 min); H NMR (300 MHz, CDCl3) δ 0.94 (d, J = 6.3
Hz, 3H), 2.62-2.74 (m, 2H), 2.81-2.93 (m, 1H), 3.25 (s, 3H), 6.90 (d, J = 7.8 Hz, 1H), 7.07-7.16
(m, 2H), 7.36 (td, J = 1.4 Hz, J = 7.7 Hz, 1H), 9.01 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.4,
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26.4, 37.4, 38.6, 68.4, 108.7, 122.1, 123.3, 126.8, 129.9, 143.9, 159.4, 172.9, 176.1; HRMS
(ESI-TOF) calcd. for C14H14N2NaO3 [M + Na]+: 281.0897, found 281.0891.
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1-ethyl-3'-methyl-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6b). Colorless
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oil; 13.3 mg, 49% yield; >99:1 dr, 97% ee; [α]D = +15.2 (c = 0.32, CHCl3); The ee was
determined by HPLC (Chiralpak OD-H column, EtOH/hexane = 5/95, flow rate 1.0 mL/min, λ =
1
254 nm, tmajor = 12.0 min, tminor = 13.1 min); H NMR (300 MHz, CDCl3) δ 0.95 (d, J = 6.3 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 2.63-2.73 (m, 2H), 2.81-2.92 (m, 1H), 2.70-3.88 (m, 2H), 6.91 (d, J
= 7.9 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.35 (td, J = 1.4 Hz, J = 7.8 Hz,
1H), 9.01 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.4, 12.5, 35.0, 37.4, 38.6, 68.3, 108.7, 122.3,
123.1, 127.0, 129.8, 143.0, 159.4, 172.5, 176.1; HRMS (ESI-TOF) calcd. for C15H16N2NaO3 [M +
Na]+: 295.1053, found 295.1045.
1-benzyl-3'-methyl-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6c). White
solid; 20.0 mg, 60% yield; 98:2 dr, 97% ee; [α]D20 = +23.1 (c = 0.43, CHCl3); Mp: 189.5-190.5 ºC;
The ee was determined by HPLC (Chiralpak AD-H column, EtOH/hexane = 20/80, flow rate 1.0
mL/min, λ = 254 nm, tmajor = 28.9 min, tminor = 67.4 min); 1H NMR (300 MHz, CDCl3) δ 1.00 (d, J
= 6.3 Hz, 3H), 2.69-2.78 (m, 2H), 2.92 (dd, J = 14.8 Hz, J = 18.8 Hz, 1H); 4.97 (s, 2H), 6.74 (d, J
= 7.8 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 6.6 Hz, 1H), 7.22 (dd, J = 1.2 Hz, J = 7.7 Hz,
1H), 7.29-7.35 (m, 5H), 9.06 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.7, 37.5, 38.8, 44.2, , 68.4,
109.8, 122.2, 123.3, 126.8, 127.2, 127.7, 128.8, 129.8, 135.1, 143.1, 159.5, 173.1, 176.1; HRMS
(ESI-TOF) calcd. for C20H18N2NaO3 [M + Na]+: 357.1210, found 357.1204.
3'-methyl-2,5'-dioxo-1-phenylspiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6d). White
solid; 10.0 mg, 31% yield; 92:8 dr, 96% ee; [α]D20 = +8.9 (c = 0.63, CHCl3); Mp: 229.9-231.5 ºC;
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The ee was determined by HPLC (Chiralpak AD-H column, iPrOH/hexane = 30/70, flow rate 1.0
mL/min, λ = 254 nm, major diastereomer: tmajor = 10.4 min, tminor = 9.4 min); 1H NMR (300 MHz,
CDCl3) δ 1.12 (d, J = 6.0 Hz, 3H), 2.71-2.84 (m, 2H), 2.92 (dd, J = 15.1 Hz, J = 18.5 Hz, 1H),
6.83 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H),
7.39-7.46 (m, 3H), 7.54 (t, J = 7.2 Hz, 2H), 9.07 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.5, 37.5,
38.9, 68.5, 109.9, 122.4, 123.7, 126.6, 126.7, 128.6, 129.7, 129.8, 133.9, 144.2, 159.6, 172.7,
176.0; HRMS (ESI-TOF) calcd. for C19H16N2NaO3 [M + Na]+: 343.1053, found 343.1042.
3'-methyl-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6e). Colorless oil; 13.4
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mg, 55% yield; 98:2 dr, 96% ee; [α]D = +24.4 (c = 0.46, CHCl3); The ee was determined by
HPLC (Chiralpak AD-H column, iPrOH/hexane = 30/70, flow rate 1.0 mL/min, λ = 254 nm, major
1
diastereomer: tmajor = 12.7 min, tminor = 15.8 min); H NMR (300 MHz, CDCl3) δ 1.04 (d, J = 6.3
Hz, 3H), 2.63-2.76 (m, 2H), 2.84 (dd, J = 14.4 Hz, J = 18.3 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 7.07
(t, J = 7.4 Hz, 1H), 7.14 (d, J = 6.7 Hz, 1H), 7.29 (td, J = 1.4 Hz, J = 7.8 Hz, 1H), 7.92 (s, 1H),
9.04 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 12.6, 37.4, 38.7, 68.7, 110.4, 122.5, 123.3, 127.3,
129.9, 140.9, 159.6, 174.5, 176.0; HRMS (ESI-TOF) calcd. for C13H12N2NaO3 [M + Na]+:
267.0740, found 267.0737.
1-benzyl-2,5'-dioxo-3'-propylspiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6f). Colorless
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oil; 14.9 mg, 41% yield; 98:2 dr, 93% ee; [α]D = +13.7 (c = 0.61, CHCl3); The ee was
determined by HPLC (Chiralpak AD-H column, iPrOH/hexane = 10/90, flow rate 1.0 mL/min, λ =
1
254 nm, major diastereomer: tmajor = 31.8 min, tminor = 29.9 min); H NMR (300 MHz, CDCl3) δ
0.78 (t, J = 7.0 Hz, 3H), 1.02-1.12 (m, 2H), 1.33-1.43 (m, 2H), 2.52-2.63 (m, 1H), 2.74 (dd, J =
7.8 Hz, J = 17.1 Hz, 1H), 2.87 (dd, J = 12.8 Hz, J = 17.1 Hz, 1H), 4.92 (d, J = 15.8 Hz, 1H), 4.99
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(d, J = 15.7 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 7.06 (td, J = 0.6 Hz, J = 7.5 Hz, 1H), 7.17 (d, J =6.5
Hz, 1H), 7.23 (dd, J = 1.2 Hz, J = 7.7 Hz, 1H), 7.27-7.34 (m, 5H), 9.05 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 13.8, 21.0, 30.3, 36.0, 44.0, 44.2, 68.1, 109.7, 122.2, 123.3, 127.2, 127.3, 127.8,
128.8, 129.8, 135.2, 143.2, 159.5, 173.3, 176.0; HRMS (ESI-TOF) calcd. for C22H22N2NaO3 [M +
Na]+: 385.1523, found 385.1519.
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1-benzyl-2,5'-dioxo-3'-phenylspiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde (6g). White
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solid; 21.8 mg, 55% yield; 94:6 dr, 88% ee; [α]D = -57.9 (c = 0.67, CHCl3); Mp: 85.5-86.3 ºC;
The ee was determined by HPLC (Chiralpak AD-H column, EtOH/hexane = 30/70, flow rate 1.0
mL/min, λ = 254 nm, major diastereomer: tmajor = 15.1 min, tminor = 34.5 min); 1H NMR (300 MHz,
CDCl3) δ 2.92 (dd, J = 7.5 Hz, J = 16.8 Hz, 1H), 3.75 (dd, J = 16.8 Hz, J = 13.8 Hz, 1H), 3.96 (dd,
J = 7.5 Hz, J = 13.8 Hz, 1H), 4.39 (d, J = 16.1 Hz, 1H), 4.86 (d, J = 16.1 Hz, 1H), 6.45 (d, J = 7.7
Hz, 1H), 6.52 (d, J = 7.1 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 7.06-7.24 (m, 7H), 7.33 (d, J = 7.5 Hz,
1H), 7.39 (dd, J = 1.0 Hz, J = 6.9 Hz, 1H), 9.16 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 34.8, 43.8,
49.1, 69.5, 110.0, 122.1, 123.2, 126.3, 126.4, 127.2, 128.2, 128.5, 128.6, 128.6, 130.0, 132.0,
134.5, 143.1, 159.4, 172.6, 175.5; HRMS (ESI-TOF) calcd. for C25H20N2NaO3 [M + Na]+:
419.1366, found 419.1360.
1-benzyl-3'-(furan-2-yl)-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde
(6h).
White solid; 19.6 mg, 51% yield; 99:1 dr, 95% ee; [α]D20 = -51.5 (c = 0.85, CHCl3); Mp: 73.2-74.1
ºC; The ee was determined by HPLC (Chiralpak AD-H column, iPrOH/hexane = 30/70, flow rate
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1.0 mL/min, λ = 254 nm, major diastereomer: tmajor = 16.0 min, tminor = 21.8 min); H NMR (300
MHz, CDCl3) δ 2.97 (dd, J = 8.0 Hz, J = 17.2 Hz, 1H), 3.64 (dd, J = 17.2 Hz, J = 13.3 Hz, 1H),
4.02 (dd, J = 7.9 Hz, J = 13.3 Hz, 1H), 4.63 (d, J = 15.9 Hz, 1H), 4.90 (d, J = 15.9 Hz, 1H), 6.05
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(d, J = 3.3 Hz, 1H), 6.27 (dd, J = 1.9 Hz, J = 3.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.96-7.00 (m,
2H), 7.13 (t, J = 6.6 Hz, 1H), 7.21-7.28 (m, 5H), 7.31 (dd, J = 0.8 Hz, J = 6.6 Hz, 1H), 9.13 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 34.2, 42.9, 44.0, 68.0, 108.7, 109.9, 110.5, 122.1, 123.3, 126.6,
126.9, 127.4, 128.7, 130.0, 134.8, 142.9, 143.2, 147.5, 159.4, 172.3, 174.7; HRMS (ESI-TOF)
calcd. for C23H18N2NaO4 [M + Na]+: 409.1159, found 409.1153.
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1-benzyl-3'-((E)-hept-1-en-1-yl)-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde
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(6i). Colorless oil; 12.9 mg, 31% yield; 92:8 dr, 94% ee; [α]D = -1.0 (c = 0.35, CHCl3); The ee
was determined by HPLC (Chiralpak IA column, EtOH/hexane = 20/80, flow rate 1.0 mL/min, λ =
1
254 nm, major diastereomer: tmajor = 12.2 min, tminor = 15.1 min); H NMR (300 MHz, CDCl3) δ
0.85 (t, J = 7.0 Hz, 3H), 0.97-1.23 (m, 6H), 1.76-1.89 (m, 2H), 2.71-2.78 (m, 1H), 3.10-3.26 (m,
2H), 4.87 (d, J = 15.9 Hz, 1H), 4.99 (d, J = 15.9 Hz, 1H), 5.19-5.37 (m, 2H), 6.70 (d, J = 7.8 Hz,
1H), 7.08 (td, J = 0.9 Hz, J = 7.5 Hz, 1H), 7.19-7.26 (m, 2H), 7.28-7.38 (m, 5 H), 9.09 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 14.0, 22.4, 28.5, 31.0, 32.3, 36.0, 44.1, 47.5, 68.3, 109.7, 122.2, 122.3,
123.2, 126.6, 127.1, 127.6, 128.8, 129.7, 135.1, 137.7, 143.1, 159.5, 173.0, 175.8; HRMS
(ESI-TOF) calcd. for C26H28N2NaO3 [M + Na]+: 439.1992, found 439.1972.
1-benzyl-3',3'-dimethyl-2,5'-dioxospiro[indoline-3,2'-pyrrolidine]-1'-carbaldehyde
(6j).
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Colorless oil; 12.1 mg, 35% yield; 85% ee; [α]D = +64.6 (c = 0.63, CHCl3); The ee was
determined by HPLC (Chiralpak AD-H column, iPrOH/hexane = 30/70, flow rate 1.0 mL/min, λ =
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254 nm, major diastereomer: tmajor = 12.3 min, tminor = 10.3 min); H NMR (300 MHz, CDCl3) δ
1.08 (s, 3H), 1.21 (s, 3H), 2.45 (d, J = 16.7 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 4.89 (d, J = 15.8
Hz, 1H), 5.01 (d, J = 15.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 7.02 (td, J = 0.9 Hz, J = 7.6 Hz, 1H),
7.15 (d, J = 7.5 Hz, 1H), 7.22 (dd, J = 1.2 Hz, J = 7.7 Hz, 1H), 7.27-7.35 (m, 5H), 9.09 (s, 1H);
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13C NMR (75 MHz, CDCl3) δ 22.2, 26.7, 40.4, 44.2, 44.6, 71.2, 110.0, 122.3, 123.6, 125.2, 127.2,
127.7, 128.8, 129.7, 135.1, 143.5, 159.8, 174.3, 176.3; HRMS (ESI-TOF) calcd. for
C21H20N2NaO3 [M + Na]+: 371.1366, found 371.1359.
ASSOCIATED CONTENT
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Supporting Information
Copies of 1H, 13C NMR and HPLC spectra for the products, and single crystal X-ray
crystallography data for product 3k. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xuxy@cioc.ac.cn; yuanwc@cioc.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for the financial support from NSFC (No. 21372217), the CAS western light
program, and Sichuan Youth Science and Technology Foundation (2013JQ0021, 2015JQ0041).
REFERENCES
1. For selected reviews, see: (a) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36.
(b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (c) Galliford, C. V.; Scheidt, K.
A. Angew. Chem., Int. Ed. 2007, 46, 8748. (d) Trost, B. M.; Brennan, M. K. Synthesis 2009,
3003.
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2. For selected reviews, see: (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,
1381. (b) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (c) Franz, A. K.; Hanhan, N.
V.; Ball-Jones, N. R. ACS Catal. 2013, 3, 540. (d) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas,
III, C. F. ACS Catal. 2014, 4, 743.
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3. For selected examples on the catalytic asymmetric synthesis of chiral spirocyclic
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10. See the Supporting Information for more details of crystallographic data and the CCDC
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