L-Pyroglutamic Sulphonamide as Hydrogen-Bonding Organocatalyst: Enantioselective Diels-Alder Cyclization to Construct Carbazolespirooxindoles

Article abstract of DOI:10.1021/acs.joc.7b00733

Hydrogen-bonding organocatalysts L-pyroglutamic sulphonamides were readily synthesized for the first time by fully exploiting the potentials of L-pyroglutamic acid. The newly designed catalyst was successfully applied in catalyzing asymmetric Diels-Alder

Full text of DOI:10.1021/acs.joc.7b00733

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Note
L-pyroglutamic sulphonamide as H-bonding
organocatalyst: Enantioselective Diels-Alder
cyclization to construct carbazolespirooxindoles
Ji-Wei Ren, Jing Wang, Jun-An Xiao, Jun Li, Hao-Yue Xiang, Xiao-Qing Chen, and Hua Yang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
Downloaded from http://pubs.acs.org on June 1, 2017
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L-pyroglutamic sulphonamide as H-bonding organocatalyst:
Enantioselective Diels-Alder cyclization to construct
carbazolespirooxindoles
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Ji-Wei Ren, Jing Wang, Jun-An Xiao, Jun Li, Hao-Yue Xiang,
Xiao-Qing Chen, Hua Yang*
College of Chemistry and Chemical Engineering, Central South University,
Changsha, 410083, P. R. China
e-mail: hyangchem@csu.edu.cn
ABSTRACT: Hydrogen-bonding organocatalysts - L-pyroglutamic sulphonamides were readily
synthesized for the first time by fully exploiting the potentials of L-pyroglutamic acid. The newly
designed catalyst was successfully applied in catalyzing asymmetric Diels-Alder cyclization of
methyleneindolinones with 2-vinyl-1H-indoles to efficiently assemble carbazolespirooxindoles in
excellent stereoselectivity (up to 99% ee, >20:1 dr) and yields (up to 99%). Mechanistic studies
disclosed that the well designed hydrogen-bonding modes between L-pyroglutamic sulphonamide
and substrates were crucial for the stereocontrol in the cyclization.
Organocatalysis has received considerable attention and experienced booming development in
the last decade. Powerful organocatalysts with diverse structural motifs have emerged in a wide
1
range of chemical transformations. In the sense of availability, natural chiral sources such as
amino acid, alkaloid, and sugar mainly constituted the arsenal for developing organocatalysts,
which received extensive modification to meet the needs for the substrates with specific structural
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features.1b-1d Most prominently, L-proline has been amenable to numerous derivatizations to create
2
an array of effective and arguably most frequently used organocatalysts since Barbas’s group
2
e
reported their seminal work on the proline-catalyzed direct asymmetric Aldol reaction. However,
the advance of organocatalysis is facing an inherent hurdle - the restricted availability of chiral
sources. One viable solution could be relied on fully exploiting the potential of currently available
chiral sources through rationally designing the structures of chiral catalysts, which might be one of
top urgent tasks for chemistry community at this stage. Noticeably, pyroglutamic acid, a cheap
chiral feedstock with both enantiomeric forms readily available, was usually used as starting
materials in asymmetric synthesis owing to its salient features including a preset chiral
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stereocenter, five-membered lactam, and carboxylic acid. Encouragingly, the research groups of
4
5
Ye and Smith successfully transformed L-pyroglutamic acid into a variety of N-heterocyclic
carbene catalysts, which showed attractive catalytic activities in activating enal or aldehyde
(Scheme 1). Conceivably, the lactam moiety in pyroglutamic acid offers H-bonding donor and
acceptor simultaneously, which could potentially bind to the substrate through double H-bonding.
Unfortunately, pyroglutamic acid as a privileged double H-bonding partner seemed neglected and
has never been properly appreciated ever since. As a consequence, developing new class of
organocatalyst by fully taking advantage of the structural features of pyroglutamic acid would be
constructive and beneficial to the advance of organocatalysis.
Scheme 1. Development of L-pyroglutamic acid-based organocatalyst
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6
Spirooxindoles, possessing wide spectrum of biological profiles, have gained considerable
synthetic interests by starting from isatins and their derivatives as the building blocks. Notably,
organocatalysis has demonstrated unparalleled capability in the enantioselective construction of
7
spirooxindoles, especially for carbazolespirooxindoles. Despite impressive advances achieved in
this journey, it is highly demanding to develop novel and practical organocatalytic systems which
can effectively target the parent structure of isatin derivatives to escalate the stereocontrol in
enantioselective transformations. Hence, we envisioned that the concurrent presence of lactam
moieties in pyroglutamic acid and isatin are expected to be intimately bound via double
H-bonding. Considering practicality and accessibility, we designed L-pyroglutamic acid
sulphonamide bearing two distinct H-bonding sites, which can be concisely prepared from
inexpensive L-pyroglutamic acid and phenylsulfonamide in one step. Herein, we disclose the
development and application of the first L-pyroglutamic acid-derived H-bonding organocatalyst.
Impressively, the newly developed catalyst demonstrated excellent stereocontrol and catalytic
activity
in
the
asymmetric
Diels-Alder
cyclization
to
construct
the
spiro[tetrahydrocarbazole-3,3′-oxindole] framework,8 which presumably benefited from an
intimate double H-bonding interaction of isatin core with catalyst as well as a H
H-bonding (Scheme 1).
2
O-relay
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Scheme 2. Derivatization of L-pyroglutamic acid for H-bonding organocatalyst
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Following the concept of our design, we prepared L-pyroglutamic acid amide 4 and a series of
sulphonamides 5 with varied electronic and steric effects, in which N-H group of amide or
sulphonamide could provide effective H-bonding site. One-step direct coupling between
L-pyroglutamic acid and aniline 2 or sulphonamide 3 afforded the desired L-pyroglutamic acid
derivatives in reasonable yields (Scheme 2). Notably, due to the aqueous solubility of
L-pyroglutamic acid derivative, the isolated yields for mono-substituted sulphonamide 5a-5d were
relatively low though these reactions proceeded smoothly. According to our previous success on
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the derivatization of L-proline, long hydrophobic alkyl chain - dodecyl group was introduced to
mitigate the problematic solubility of sulphonamide in water, leading to an improved yield (5e). In
addition, more sterically demanding catalyst - 2,4,6-trimethyl analogue was also synthesized in
moderate yield. Subsequently, these designed catalysts were employed to catalyze the D-A
reaction between 2-vinyl-1H-indole 6a and methyleneindolinone 7a (as shown in Table 1). It is
noteworthy that Boc- or Me- protected isatin derivatives were requisite to secure satisfactory
stereoselectivity in the D-A cycloadditions while the unprotected methyleneindolinones were
rarely used.8,11 As can be seen, lactam moiety in 7a is exposed to be bound by its double
H-bonding partner. Initially, in the absence of catalyst, this reaction proceeded in chloroform at
room temperature to give the corresponding cycloadduct - spiro[tetrahydrocarbazole-3,3′
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-
oxindole] 8aa in excellent yield (99%) and diastereoselectivity (>20:1 dr) (entry 1). Then,
L-pyroglutamic acid (1) as well as its amide derivative 4 were tested, leading to faster reaction
with frustrating enantioselectivities (entries 2 and 3). To our delight, use of L-pyroglutamic acid
sulfonamide 5 gave cycloadduct 8aa in excellent yield with moderate enantioselectivity
(58%-66% ee) and excellent diastereoselectivity (>20:1 dr) (entries 4-9). Interestingly, steric and
electronic effects of substituents on the phenyl moiety in 5 had negligible impact on
stereoselectivity. Taking into consideration of solubility in ordinary solvent and the preparative
yield of sulphonamide 5, L-pyroglutamic acid p-dodecylphenylsulfonamide 5e was employed for
further studies. As protic or polar solvents might disturb H-bonding interaction of catalyst with
substrate, various nonpolar solvents were evaluated and chloroform was proven the optimal
solvent in terms of stereoselectivity (entries 10-12 vs 8). Given the spontaneous background
reaction, the concentration of this reaction was diluted to 0.02 M. Satisfyingly, the corresponding
enantioselectivity was significantly improved to 88% ee (entry 13). Finally, the molar ratio of
these two substrates was slightly adjusted, affording the optimum results (yield 99%, 90%
ee, >20:1 dr) with a molar ratio of 6a:7a (2:1) (entry 14). Actually, lower catalyst-loading (10
mol%) was also evaluated in the model reaction. An elongated reaction time (30 h) was needed to
achieve the completion of the reaction and a reduced enantioselectivity (86% ee) and comparable
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yield (99%) for cycloadduct 8aa were obtained (entry 16).
Table 1. Screening the designed catalysts for organocatalytic D-A cyclizationa
Yieldb,c (%)
99
ee (%)
c
Entry Catalyst
none
Solvent
CHCl
Time (h)
30
1
3
0
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1
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
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3
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0
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88
90
85
86
5a
5b
5c
5d
5e
5f
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5e
5e
5e
5e
5e
5e
5e
CH
DCE
toluene
CHCl
CHCl
2
Cl
2
1
1
13d
3
1
4d,e
3
1
5d,f
CHCl
3
1
6d,e,g
CHCl
3
a
Unless otherwise noted, all reactions were carried out using 2-vinyl-1H-indole 6a (0.20 mmol, 1.0 equiv.),
b
methyleneindolinone 7a (0.20 mmol, 1.0 equiv.) and catalyst (0.04 mmol, 20 mol%) in solvent (0.5 mL). Isolated
c
d
e
yields. dr >20:1, determined by HPLC on a chiral stationary phase. Concentration was 0.02 M. Molar ratio of
f
g
6
a:7a was 2:1. Molar ratio of 6a:7a was 1:2. 10 mol% catalyst 5e was added.
Having the optimal conditions in hand, we sought to examine the substrate tolerance for this
newly developed catalytic system. Firstly, diversely substituted 2-vinyl-1H-indole derivatives 6
were evaluated under the standard conditions (as shown in Table 2). In general, substituents with
different electronic natures at different positions of β-aryl ring were all well tolerated and
excellent diastereoselectivity and good enantioselectivity were thoroughly achieved (entries 2-9).
However, in the presence of strong electron-withdrawing group (-NO ) on the aryl ring, a
2
relatively low yield (60%) was obtained for 8da (entry 4). On the other hand, 2-vinylindoles with
electron-withdrawing or electron-donating groups at C5-position of indole core also gave good
stereochemical outcomes and chemical yields (entries 10-12). In addition, switching phenyl to
methyl at the terminal double bond also afforded high yield and good stereoselectivity (entry 13).
Surprisingly, removal of terminal substituent on the exocyclic double bond significantly reduced
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diastereoselectivity (82:18 dr) and enantioselectivity (61% ee) (entry 14). It is worth mentioning
that higher concentrations and longer reaction durations were required to secure synthetically
useful chemical yields for 8ma and 8na as these reactions were sluggish.
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Table 2. Substrate scope of 2-vinyl-1H-indole 6a
Yieldb
(%)
eec
(%)
Entry
R
R1
H
Time
h)
drc
(
9
9
1
2
3
4
5
6
7
8
9
C
6
H
5
17
15
24
24
15
24
15
15
15
36
36
12
30
48
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
82:18
90
90
(
8aa)
9
9
p-MeC
6
H
4
H
(
8ba)
9
9
p-BrC
6
H
4
H
86
(
8ca)
6
0
p-NO
2
C
6
H
4
H
84
(
8da)
9
9
o-MeC
6
H
4
H
94
(8ea)
8
4
o-BrC
6
H
4
H
>99
94
(8fa)
9
9
m-MeC
6
H
4
H
(8ga)
9
9
m-BrC
6
H
4
H
89
(8ha)
99
m-MeOC
6
H
4
H
90
(
8ia)
99
1
1
1
0
1
2
C
C
C
6
6
6
H
H
H
5
5
5
Cl
Br
MeO
H
89
(
8ja)
99
82
(
8ka)
99
>99
85
(
8la)
13d
14d
Me
H
98
(
8ma)
94
H
61/83
(
8na)
a
Unless otherwise noted, all reactions were carried out using 2-vinyl-1H-indole 6 (0.40 mmol, 2.0 equiv.),
b
methyleneindolinone 7a (0.20 mmol, 1.0 equiv.) and 5a (0.04 mmol, 20 mol%) in CHCl
3
(10 mL). Isolated yields.
c
d
Determined by HPLC on a chiral stationary phase. Concentration of 7a was 0.04 M.
Next, various substituted methyleneindolinones 7 were extensively investigated by reacting
with 2-vinyl-1H-indole 6a and the obtained results are illustrated in Table 3. Gratifyingly,
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methyleneindolinones with a variety of substituents on the phenyl group proceeded the title
reaction in excellent diastereo- and enantioselectivity with high yields (entries 1-7). On the other
hand, alternative electron-withdrawing groups such as benzoyl, cyano, and acetyl were also tested
for methyleneindolinones and the corresponding cycloadduct 8ai-8ak were achieved in excellent
yields (97-99%) with good to excellent enantioselectivities (81% to 94% ee) (entries 8-10).
Moreover, the absolute configuration of cycloadduct 8af was determined by X-ray
crystallographic analysis (see SI for details).
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9
0
Table 3. Substrate scope of methyleneindolinone 7a
R1
b
drc
c
Entry
R
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
5-F
5-Cl
5-Br
CO
2
2
2
2
2
2
2
Et
7
7
99 (8ab)
99 (8ac)
99 (8ad)
99 (8ae)
99 (8af)
99 (8ag)
99 (8ah)
97 (8ai)
99 (8aj)
99 (8ak)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
98
96
94
96
93
89
83
81
94
89
CO
CO
Et
Et
Et
Et
Et
Et
7
5-Me CO
24
10
7
6-Br
7-Br
7-F
H
CO
CO
CO
7
COPh
CN
20
24
12
H
1
0
H
Ac
a
Unless otherwise noted, all reactions were carried out using 2-vinyl-1H-indole 6a (0.40 mmol, 2.0 equiv.),
b
methyleneindolinone 7 (0.20 mmol, 1.0 equiv.) and 5a (0.04 mmol, 20 mol%) in CHCl
3
(10 mL). Isolated yields.
c
Determined by HPLC on a chiral stationary phase.
At this stage, it can be concluded that H-bonding catalyst 5e demonstrated excellent substrate
tolerance in the title reaction, which motivated us to employ more challenging substrate including
7l and 7m to construct multiple all-carbon quaternary stereocenters enantioselectively (Scheme 3).
Disubstituted methyleneindolinone 7l was subjected to the standard conditions, providing 8al in
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high yield (98%) and moderate enantioselectivity (45/83% ee) but low dr (66:34), which was
attributed to poor isomeric ratio of 7l (2:1). Moreover, dicyano methyleneindolinone 7m gave
cycloadduct 8am in moderate yield (62%) with excellent diastereoselectivity (>20:1 dr) and good
enantioselectivity (81% ee).
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Scheme 3. Construction of spirooxindole bearing two vicinal all-carbon quaternary
stereocenters
Aiming at better understanding the interaction mode between catalyst and substrates, various
control experiments were carried out under the optimal conditions (Scheme 4a and 4b). Firstly,
N-protected 2-vinyl-1H-indole 6 or/and N-protected methyleneindolinone 7 were employed in the
title reaction to intentionally mask the hydrogen-bonding sites on these substrates (Scheme 4a).
Not surprisingly, the corresponding cycloadducts 8oa, 8an, and 8on were obtained in markedly
reduced enantioselectivities, though in good chemical yields and diastereoselectivities. These
results suggested that N-H groups in both 2-vinyl-1H-indoles and methyleneindolinones actively
interacted with catalyst 5, having sizeable influence on the observed enantioselectivity. Moreover,
1
this statement was also confirmed through H NMR spectroscopic studies on the mixture of 5e
with 6a or 7a with a molar ratio of 1:1, in which downfield shifts of 0.60 ppm and 0.31 ppm were
induced for the N-H signals in 6a or 7a respectively (see SI for spectra). Besides, effects of water
on this catalytic system were also investigated. Interestingly, removal of water dramatically
degraded the enantioselectivity while addition of water had a negligible impact on chemical yield
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and stereochemical outcomes (Scheme 4b). These results suggested that water played an important
role in the interaction between catalyst and substrate. On the basis of these experimental results, a
plausible catalytic mode is proposed to illustrate the interaction of catalyst 5 with substrates
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Scheme 4c). Presumably, double H-bondings were formed spontaneously between
L-pyroglutamic acid sulphonamide 5 and isatin derivative 7 through the perfectly matched lactam
moieties while 2-vinyl-1H-indole 6 was bound to sulphonamide moiety of catalyst via a H O-relay
2
H-bonding. In this manner, excellent enantioselectivity and diastereoselectivity were achieved
through this privileged interaction mode, which would be fundamental for the further application
of this new class of organocatalyst.
Scheme 4. Control experiments and plausible catalytic mode
In conclusion, we successfully developed a novel class of hydrogen-bonding organocatalyst -
L-pyroglutamic acid sulphonamide. The design of this H-bonding catalyst and its catalytic activity
feature i. Step-economic and highly accessible preparation; ii. New H-bonding platform with
minimal modification of L-pyroglutamic acid; iii. Excellent stereocontrol in catalyzing
asymmetric Diels-Alder cyclization of methyleneindolinones with 2-vinyl-1H-indoles (up to 99%
ee, >20:1 dr), affording carbazolespirooxindoles bearing three contiguous chiral centers with
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one/two quaternary stereocenters. More importantly, the success of this hydrogen-bonding catalyst
would greatly inspire the emergence of versatile L-pyroglutamic acid-based organocatalysts as
well as their broader application in asymmetric synthesis.
10
11
12
13
14
15
16
17
18
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EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all the reagents were purchased from
commercial suppliers and used without further purification. 1H NMR spectra were
recorded at 400 MHz. The chemical shifts were recorded in ppm relative to
tetramethylsilane and with the solvent resonance as the internal standard. Data were
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
1
3
quartet, m = multiplet), coupling constants (Hz), integration. C NMR data were collected
at 100 MHz with complete proton decoupling. Chemical shifts were reported in ppm from
the tetramethylsilane with the solvent resonance as internal standard. Infrared spectra (IR)
were measured by FT-IR apparatus. High resolution mass spectroscopy (HRMS) was
recorded on TOF MS ES+ mass spectrometer and acetonitrile was used to dissolve the
sample. Column chromatography was carried out on aluminum oxide (200-300 mesh). All
the substituted 2-vinyl-1H-indoles were prepared according to the reported protocol.12 All
the substituted methyleneindolinones were prepared according to the reported protocol.13
Typical Experimental Procedure of Glutamic Sulphonamides 5. To a solution of
L-pyroglutamic acid
sulphonamide (6.0 mmol, 1.2 equiv.), DMAP (0.18 g, 1.5 mmol, 0.3 equiv.), and EDCI
1.15 g, 6.0 mmol, 1.2 equiv.) respectively. The mixture was stirred for 72 hours before
1 (0.65 g, 5.0 mmol) in DCM (10 mL) were added benzene
3
(
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
being partitioned between EtOAc (100 mL) and HCl (1 M, 15 mL) at room temperature.
The organic layer was washed with half-saturated brine (3×30 mL), dried over Na
and concentrated in vacuo. The resulting residue was purified via silica gel colunm
chromatography (MeOH/DCM = 1%-5%) to yield sulphonamide
Sulphonamide 5a: White solid (0.46 g, yield 33%); m.p. 84-85 °C; [α]
2
SO ,
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
.
2
0
D
= -41.4 (c = 0.5 in
-1
1
MeOH); IR (KBr) ν 3430, 2921, 1633, 1263, 1010, 896, 843, 812 cm ; H NMR (400 MHz,
DMSO-d ) δ 12.32 (br s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H), 4.04
(dd, J = 9.0, 4.2 Hz, 1H), 2.40 (s, 3H), 2.23-2.33 (m, 1H), 1.99-2.11 (m, 2H), 1.69-1.77 (m, 1H);
6
13C NMR (100 MHz, DMSO-d
6
) δ 177.6, 172.1, 144.9, 136.7, 130.1, 128.0, 56.2, 29.2, 25.0, 21.6;
+
HRMS (TOF-ES+) m/z: [M+Na] calcd for C12
H
14
N
2
O NaS 305.0572, found 305.0570.
4
2
0
Sulphonamide 5b: White solid (0.59 g, yield 40%); m.p. 113-115 °C; [α]
D
= -43.1 (c = 0.5 in
-
1 1
MeOH); IR (KBr) ν 3417, 1656, 1499, 1262, 1148, 836 cm ; H NMR (400 MHz, DMSO-d
.87 (dd, J = 6.8, 2.0 Hz, 2H), 7.76 (s, 1H), 7.14 (dd, J = 6.8, 2.0 Hz, 2H), 4.03 (dd, J = 8.8, 4.0
Hz, 1H), 3.86 (s, 3H), 2.22-2.32 (m, 1H), 1.97-2.11 (m, 2H), 1.68-1.76 (m, 1H); 13C NMR (100
6
) δ
7
MHz, DMSO-d
6
) δ 177.6, 172.1, 163.6, 131.1, 130.4, 114.7, 56.3, 56.2, 29.2, 25.0; HRMS
+
(
TOF-ES+) m/z: [M+Na] calcd for C12
H
14
N
2
O
5
NaS 321.0521, found 321.0514.
Sulphonamide 5c: White solid (0.64 g, yield 41%); m.p. 108-109 °C; [α] 2
0
= -25.6 (c = 0.5 in
D
-1
1
MeOH); IR (KBr) ν 3392, 2867, 1681, 1352, 1260, 1140, 847, 738 cm ; H NMR (400 MHz,
DMSO-d ) δ 12.74 (br s, 1H), 8.45 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 4.07
(dd, J = 9.2, 4.4 Hz, 1H), 2.25-2.34 (m, 1H), 1.98-2.12 (m, 2H), 1.73-1.81 (m, 1H); C NMR (100
6
1
3
MHz, DMSO-d ) δ 177.5, 172.8, 150.8, 144.9, 129.7, 125.0, 56.4, 29.2, 24.9; HRMS (TOF-ES+)
6
+
m/z: [M+Na] calcd for C11
H
11
N
3
O NaS 336.0266, found 336.0264.
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Sulphonamide 5d: White solid (0.45 g, yield 32%); m.p. 111-112 °C; [α]
D
= -39.7 (c = 0.5 in
-1
1
MeOH); IR (KBr) ν 3423, 1634, 1466, 1338, 1186, 899, 848, 760 cm ; H NMR (400 MHz,
DMSO-d ) δ 12.49 (br s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.56-7.60 (m, 1H), 7.41-7.45
m, 2H), 4.08 (dd, J = 9.2, 4.4 Hz, 1H), 2.60 (s, 3H), 2.27-2.36 (m, 1H), 1.97-2.12 (m, 2H),
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
1.72-1.80 (m, 1H); 13C NMR (100 MHz, DMSO-d
) δ 177.5, 172.2, 137.8, 137.4, 134.1, 132.9,
6
+
1
3
30.7, 126.7, 56.2, 29.2, 25.1, 20.0; HRMS (TOF-ES+) m/z: [M+Na] calcd for C12
H
14
N
2
O S
4
05.0572, found 305.0580.
Sulphonamide 5e: White solid (1.22 g, yield 56%); m.p. 32-36 °C ; [α] 2
MeOH); IR (KBr) ν 3403, 2926, 1694, 1595, 1462, 1255, 1142, 1086, 837, 725 cm ; H NMR
400 MHz, CDCl3, mixture of isomers for dodecyl alkyl chain) δ 7.98 (d, J = 8.4 Hz, 2H),
7.26-7.34 (m, 3H), 4.28-4.31 (m, 1H), 2.32-2.49 (m, 3H), 2.06-2.11 (m, 1H), 1.51-1.68 (m, 4H),
.05-1.29 (m, 15H), 0.72-0.88 (m, 6H); 13C NMR (100 MHz, CDCl3, mixture of isomers for
0
= -40.2 (c = 0.5 in
D
-
1 1
(
1
dodecyl alkyl chain) δ 179.8, 171.0, 153.8, 135.7, 128.4, 128.3, 57.8, 46.2, 36.5, 31.8, 31.7, 29.6,
+
29.5, 29.3, 29.1, 27.6, 27.2, 24.5, 22.7, 22.5, 14.0; HRMS (TOF-ES+) m/z: [M+Na] calcd for
C
23
H
36
N
2
4
O NaS 459.2293, found 459.2308.
20
Sulphonamide 5f: White solid (0.93 g, yield 60%); m.p. 137-138 °C; [α]
D
= -38.5 (c = 0.5 in
-1
1
MeOH); IR (KBr) ν 3394, 2981, 1681, 1460, 1340, 1141, 1051, 896, 834 cm ; H NMR (400
MHz, DMSO-d
6
) δ 12.33 (br s, 1H), 7.77 (s, 1H), 7.05 (s, 2H), 4.08 (dd, J = 9.2, 4.4 Hz, 1H), 2.61
13
(
s, 6H), 2.26-2.34 (m, 4H), 1.98-2.11 (m, 2H), 1.70-1.78 (m, 1H); C NMR (100 MHz, DMSO-d
6
)
δ 177.5, 172.6, 143.4, 140.1, 133.6, 132.1, 56.0, 29.2, 25.1, 22.5, 20.9; HRMS (TOF-ES+) m/z:
+
[
M+Na] calcd for C14
H
18
N
2
O NaS 333.0885, found 333.0900.
4
General procedure for synthesis of spirooxindoles 8. 2-Vinyl-1H-indoles 6 (0.40 mmol, 2.0
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equiv.), methyleneindolinones 7 (0.20 mmol, 1.0 equiv.), and catalyst 5e (20 mol%) were
dissolved in regular chloroform without drying (10 mL). After completion of the reaction
(monitored by TLC), organic solvent was removed in vacuo. Then the residue was purified via
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
flash chromatography (EtOAc/PE = 10%-30%) to yield the corresponding product 8.
8
a
20
Spirooxindoles 8aa : White solid (86.8 mg, yield 99%, >20:1 dr, 90% ee); [α]
D
= -89.0 (c = 0.1
1
in CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 8.08 (s, 1H), 8.05 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H),
7
.24-7.29 (m, 2H), 7.02-7.15 (m, 7H), 6.93-6.97 (m, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 7.6
Hz, 1H), 4.43-4.47 (m, 1H), 4.14 (s, 1H), 4.08-4.12 (m, 1H), 3.97-4.05 (m, 1H), 3.72 (dd, J = 16.4,
0.8 Hz, 1H), 3.11 (dd, J = 16.8, 5.6 Hz, 1H), 1.10 (t, J = 7.0 Hz, 3H); HPLC analysis:
CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 6.74 min (major),
1
(
R
19.87 min (minor).
Spirooxindoles 8ba: White solid (89.8 mg, yield 99%, >20:1 dr, 90% ee); m.p. 156-158 °C;
20
); IR (KBr) ν 3356, 2919, 1728, 1699, 1470, 1176, 818, 754, cm-1;
[
α]
1H NMR (400 MHz, DMSO-d
7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.01-7.08 (m, 4H), 6.90-6.98 (m, 3H), 6.84 (t, J = 7.6 Hz,
H), 6.63 (d, J = 7.6 Hz, 1H), 4.32 (q, J = 5.4 Hz, 1H), 4.01-4.09 (m, 1H), 3.90-3.99 (m, 1H), 3.88
(s, 1H), 3.62 (dd, J = 16.4, 11.2 Hz, 1H), 3.03 (dd, J = 16.8, 5.6 Hz, 1H), 2.15 (s, 3H), 1.04 (t, J =
D
= -65.1 (c = 0.1 in CH
2
Cl
2
6
) δ 11.02 (s, 1H), 10.42 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.25 (d, J
=
1
7
1
.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d
) δ 178.6, 172.3, 142.1, 138.2, 136.7, 136.4, 136.0,
6
30.2, 129.0, 128.7, 128.5, 126.9, 125.4, 121.3, 121.0, 119.0, 117.3, 111.4, 109.6, 103.5, 60.7,
+
52.1, 46.3, 42.2, 27.9, 21.0, 14.5; HRMS (TOF-ES+) m/z: [M+Na] calcd for C29
H
26
N
2
O Na
3
473.1841, found 473.1825; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8
mL/min, UV: 254 nm), t
R
= 5.60 min (major), 14.95 min (minor).
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Spirooxindoles 8ca: White solid (102.3 mg, yield 99%, >20:1 dr, 86% ee); m.p. 140-142 °C;
2
0
[α]
D
= -53.8 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3401, 2924, 1712, 1468, 1326, 1178, 1013, 826, 746
2
-
1 1
cm ; H NMR (400 MHz, DMSO-d
8.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.05-7.09 (m, 4H), 6.96 (t, J = 7.6 Hz, 1H), 6.86 (t, J =
7.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.31-4.35 (m, 1H), 4.01-4.09 (m, 1H), 3.92-3.99 (m, 1H),
6
) δ 11.05 (s, 1H), 10.48 (s, 1H), 7.30-7.36 (m, 3H), 7.25 (d, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
=
3
3
.90 (s, 1H), 3.57 (dd, J = 16.2, 11.0 Hz, 1H), 3.09 (dd, J = 16.6, 5.8 Hz, 1H), 1.04 (t, J = 7.2 Hz,
H); 13C NMR (100 MHz, DMSO-d
) δ 178.2, 172.2, 142.1, 140.6, 136.4, 136.2, 131.3, 131.1,
6
129.9, 128.7, 126.8, 125.4, 121.4, 121.1, 120.3, 119.1,117.4, 111.4, 109.8, 103.6, 60.8, 52.0, 46.0,
+
4
5
2.2, 27.4, 14.5; HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
H
23
N
2
O NaBr 537.0790, found
3
37.0775; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254
= 5.97 min (major), 13.56 min (minor).
nm), t
R
Spirooxindoles 8da: Yellow solid (57.5 mg, yield 60%, >20:1 dr, 84% ee); m.p. 177-178 °C;
20
[α]
D
= -53.2 (c = 0.1 in CH
2
2
Cl ); IR (KBr) ν 3367, 2976, 1725, 1698, 1519, 1468, 1346, 1178,
-
1 1
856, 744 cm ; H NMR (400 MHz, Acetone-d
.0 Hz, 2H), 7.52 (dd, J = 6.8, 2.0 Hz, 2H), 7.39-7.42 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.06-7.12
m, 2H), 6.99-7.03 (m, 1H), 6.91 (td, J = 7.6, 1.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.73 (dd, J =
10.8, 5.6 Hz, 1H), 4.02-4.17 (m, 3H), 3.79-3.86 (m, 1H), 3.25 (dd, J = 16.4, 6.0 Hz, 1H), 1.13 (t, J
6
) δ 10.24 (s, 1H), 9.53 (s, 1H), 8.00 (dd, J = 7.2,
2
(
13
=
7.2 Hz, 3H); C NMR (100 MHz, Acetone-d ) δ 177.5, 171.8, 149.1, 146.8, 141.7, 136.6, 135.4,
6
130.0, 129.4, 128.4, 126.9, 125.5, 122.9, 121.3, 120.9, 118.9, 117.4, 110.9, 109.4, 104.0, 60.4,
+
52.0, 46.0, 42.8, 26.9, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
H
23
N
3
O Na 504.1535,
5
found 504.1526; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV:
54 nm), t = 9.52 min (major), 14.40 min (minor).
2
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
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6
Spirooxindoles 8ea: White solid (90.2 mg, yield 99%, >20:1 dr, 94% ee); m.p. >300 °C; [α] 20
D
=
-
1 1
-
118.1 (c = 0.1 in CH
400 MHz, DMSO-d ) δ 11.04 (s, 1H), 10.59 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz,
H), 7.15-7.17 (m, 1H), 6.93-7.11 (m, 7H), 6.78 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 4.84
(q, J = 5.2 Hz, 1H), 4.03-4.09 (m, 1H), 3.93-3.99 (m, 1H), 3.86 (s, 1H), 3.39-3.46 (m, 1H), 2.99
2
Cl
2
); IR (KBr) ν 3354, 1712, 1470, 1333, 1187, 1028, 741 cm ; H NMR
(
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
3
(
dd, J = 16.4, 5.6 Hz, 1H), 2.35 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, DMSO-d )
6
δ 178.9, 172.4, 142.1, 140.5, 136.9, 136.4, 136.1, 130.6, 130.4, 128.7, 126.9, 126.8, 126.5, 125.7,
124.3, 121.4, 121.0, 119.1, 117.4, 111.4, 109.7, 103.5, 60.8, 52.0, 46.6, 36.8, 28.3, 20.3, 14.5;
+
HRMS (TOF-ES+) m/z: [M+Na] calcd for C29
H
26
N
2
O Na 473.1841, found 473.1826; HPLC
3
analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 5.33 min
R
(major), 16.02 min (minor).
Spirooxindoles 8fa: White solid (86.9 mg, yield 84%, >20:1 dr, >99% ee); m.p. 252-253 °C;
20
[α]
D
= -120.1 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3329, 2916, 1717, 1620, 1466, 1334, 1183, 1018,
2
-1 1
869, 739 cm ; H NMR (400 MHz, Acetone-d
6
) δ 10.20 (s, 1H), 9.59 (s, 1H), 7.38-7.47 (m, 5H),
.15-7.19 (m, 1H), 7.06-7.11 (m, 2H), 6.98-7.03 (m, 2H), 6.83-6.87 (m, 1H), 6.79 (d, J = 8.0 Hz,
H), 5.42 (dd, J = 11.2, 5.6 Hz, 1H), 4.11-4.18 (m, 1H), 4.01-4.07 (m, 2H), 3.63 (dd, J = 16.0,
7
1
11.2 Hz, 1H), 3.15 (dd, J = 16.0, 5.6 Hz, 1H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
Acetone-d ) δ 178.1, 171.6, 141.6, 141.2, 136.6, 135.8, 132.8, 129.8, 128.5, 128.3, 127.8, 127.7,
27.0, 125.3, 125.2, 121.1, 120.9, 118.9, 117.3, 110.9, 109.1, 104.0, 60.3, 52.0, 47.0, 40.6, 27.6,
6
1
+
13.7; HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
23
H N
2
3
O NaBr 537.0790, found 537.0775;
HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
R
=
5.98 min (major), 18.47 min (minor).
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Spirooxindoles 8ga: White solid (90.1 mg, yield 99%, >20:1 dr, 94% ee); m.p. 177-179 °C; [α] 20
D
-1
=
-100.2 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3409, 3219, 2919, 1705, 1468, 1176, 1035, 794, 747 cm ;
2
1H NMR (400 MHz, Acetone-d
6
) δ 10.17 (s, 1H), 9.41 (s, 1H), 7.37-7.40 (m, 2H), 7.29 (d, J = 7.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hz, 1H), 6.96-7.09 (m, 6H), 6.85-6.90 (m, 2H), 6.70 (d, J = 8.0 Hz, 1H), 4.54 (q, J = 5.6 Hz, 1H),
4.11-4.17 (m, 1H), 4.01-4.07 (m, 2H), 3.83 (dd, J = 16.4, 11.2 Hz, 1H), 3.12 (dd, J = 16.0, 5.2 Hz,
1
3
1
1
H), 2.17 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, Acetone-d
6
) δ 178.0, 172.0, 141.8,
41.1, 137.1, 136.6, 136.4, 130.1, 129.6, 128.0, 127.8, 127.3, 127.1, 125.6, 120.9, 120.7, 118.8,
117.2, 110.8, 109.1, 104.0, 60.2, 52.1, 46.5, 42.6, 27.6, 20.5, 13.6; HRMS (TOF-ES+) m/z:
+
[
M+Na] calcd for C29
H
26
N
2
O Na 473.1841, found 473.1845; HPLC analysis: (CHIRALCEL
3
OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 5.43 min (major), 13.11 min
R
(minor).
Spirooxindoles 8ha: White solid (102.8 mg, yield 99%, >20:1 dr, 89% ee); m.p. 165-166 °C;
20
[α]
D
= -65.4 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3396, 2924, 1710, 1620, 1469, 1323, 1179, 877, 746
2
-
1
1
cm ; H NMR (400 MHz, Acetone-d
6
) δ 10.20 (s, 1H), 9.49 (s, 1H), 7.43 (t, J = 1.8 Hz, 1H),
7
1
.38-7.40 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.23-7.26 (m, 2H), 7.06-7.11 (m, 3H), 6.98-7.02 (m,
H), 6.92 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 4.56 (dd, J = 11.2, 5.6 Hz, 1H), 4.10-4.17
(m, 1H), 4.01-4.08 (m, 2H), 3.78 (dd, J = 16.4, 11.2 Hz, 1H), 3.19 (dd, J = 16.4, 5.6 Hz, 1H), 1.13
13
(
t, J = 7.2 Hz, 3H); C NMR (100 MHz, Acetone-d
6
) δ 177.7, 171.9, 143.9, 141.7, 136.6, 135.8,
131.6, 129.8, 129.7(4), 129.7(0), 128.3, 127.8, 127.0, 125.5, 121.5, 121.2, 120.8, 118.8, 117.3,
+
110.9, 109.3, 104.0, 60.3, 52.0, 46.2, 42.4, 27.2, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for
C
28
H
23
N
2
O
3
NaBr 537.0790, found 537.0779; HPLC analysis: (CHIRALCEL OD-H, 30%
i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 5.74 min (major), 11.44 min (minor).
R
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Spirooxindoles 8ia: White solid (93.0 mg, yield 99%, >20:1 dr, 90% ee); m.p. 98-100 °C; [α] 20
D
=
-
1
-74.7 (c = 0.1 in CH
Cl
2 2
); IR (KBr) ν 3418, 3214, 2986, 1737, 1683, 1464, 1180, 1032, 745 cm ;
1H NMR (400 MHz, Acetone-d
6
) δ 10.17 (s, 1H), 9.44 (s, 1H), 7.37-7.40 (m, 2H), 7.30 (d, J = 7.6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1H), 6.98-7.10 (m, 4H), 6.89 (td, J = 7.6, 1.2 Hz, 1H), 6.82-6.84 (m, 2H), 6.72 (d, J = 7.6 Hz,
1H), 6.60-6.63 (m, 1H), 4.56 (q, J = 5.6 Hz, 1H), 4.10-4.18 (m, 1H), 3.99-4.07 (m, 2H), 3.83 (dd,
1
3
J = 16.4, 11.6 Hz, 1H), 3.67 (s, 3H), 3.15 (dd, J = 16.8, 6.0 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, Acetone-d ) δ 178.1, 172.0, 159.3, 142.8, 141.8, 136.6, 136.3, 130.1, 128.8,
6
128.0, 127.1, 125.6, 121.0, 120.9, 120.7, 118.8, 117.2, 114.3, 112.2, 110.8, 109.1, 103.9, 60.2,
+
5
4
4.3, 52.1, 46.4, 42.7, 27.6, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for C29
H
26
N
2
O Na
4
89.1790, found 489.1772; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8
= 6.37 min (major), 15.79 min (minor).
mL/min, UV: 254 nm), t
R
2
0
Spirooxindoles 8ja: White solid (92.9 mg, yield 99%, >20:1 dr, 89% ee); m.p. 186-188 °C; [α]
D
=
-102.4 (c = 0.1 in CH
2
2
Cl ); IR (KBr) ν 3441, 3246, 2907, 1737, 1701, 1617, 1472, 1147, 860,
-1 1
807, 752 cm ; H NMR (400 MHz, Acetone-d
6
) δ 10.39 (s, 1H), 9.44 (s, 1H), 7.39 (d, J = 5.6 Hz,
H), 7.38 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.23-7.25 (m, 2H), 7.03-7.13 (m, 5H), 6.88 (td, J = 7.6,
.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.57 (dd, J = 11.2, 5.6 Hz, 1H), 4.14-4.22 (m, 1H),
1
1
4.01-4.09 (m, 2H), 3.82 (dd, J = 16.4, 11.2 Hz, 1H), 3.16 (dd, J = 16.4, 5.6 Hz, 1H), 1.15 (t, J =
1
3
7
1
.2 Hz, 3H); C NMR (100 MHz, Acetone-d ) δ 177.9, 171.8, 141.8, 141.0, 138.4, 135.0, 129.9,
6
28.7, 128.2, 128.1, 127.9, 126.7, 125.6, 124.1, 121.0, 120.7, 116.7, 112.2, 109.2, 104.0, 60.4,
+
52.0, 46.1, 42.6, 27.5, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
23
H N
2
O NaCl
3
493.1295, found 493.1274; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8
mL/min, UV: 254 nm), t
R
= 5.46 min (major), 8.14 min (minor).
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Spirooxindoles 8ka: White solid (101.9 mg, yield 99%, >20:1 dr, 82% ee); m.p. 181-182 °C;
2
0
[α]
D
= -118.0 (c = 0.1 in CH
2
2
Cl ); IR (KBr) ν 3439, 2906, 1737, 1699, 1616, 1471, 1147, 859,
-
1 1
8
1
05, 751 cm ; H NMR (400 MHz, Acetone-d
6
) δ 10.41 (s, 1H), 9.44 (s, 1H), 7.54 (d, J = 2.0 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H), 7.35 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.23-7.25 (m, 2H), 7.19 (dd, J = 8.8, 2.0
Hz, 1H), 7.03-7.13 (m, 4H), 6.88 (td, J = 7.6, 0.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.57 (dd, J =
1.6, 6.0 Hz, 1H), 4.15-4.23 (m, 1H), 4.00-4.08 (m, 2H), 3.82 (dd, J = 16.4, 11.2 Hz, 1H), 3.16 (dd,
1
13
J = 16.8, 5.6 Hz, 1H), 1.16 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, Acetone-d
141.8, 140.9, 138.2, 135.2, 129.9, 128.8, 128.7, 128.1, 127.9, 126.7, 125.6, 123.3, 121.1, 119.8,
12.7, 111.7, 109.2, 103.9, 60.4, 52.0, 46.1, 42.6, 27.4, 13.6; HRMS (TOF-ES+) m/z: [M+Na]+
calcd for C28 NaBr 537.0790, found 537.0765; HPLC analysis: (CHIRALCEL OD-H,
6
) δ 177.9, 171.7,
1
H
23
N
2
O
3
30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 5.51 min (major), 8.06 min (minor).
R
Spirooxindoles 8la: White solid (91.9 mg, yield 99%, >20:1 dr, >99% ee); m.p. 173-174 °C;
20
[α]
D
= -117.8 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3386, 2903, 1697, 1479, 1174, 1019, 840, 805, 751
2
-
1 1
cm ; H NMR (400 MHz, Acetone-d
6
) δ 10.00 (s, 1H), 9.40 (s, 1H), 7.23-7.31 (m, 4H), 7.09-7.13
(m, 2H), 7.02-7.06 (m, 2H), 6.85-6.90 (m, 2H), 6.73 (dd, J = 8.8, 2.4 Hz, 1H), 6.69 (d, J = 7.6 Hz,
1H), 4.58 (dd, J = 11.2, 5.6 Hz, 1H), 4.14-4.22 (m, 1H), 3.98-4.06 (m, 2H), 3.81-3.85 (m, 1H),
3.77 (s, 3H), 3.11 (dd, J = 16.4, 5.6 Hz, 1H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
Acetone-d ) δ 178.0, 172.0, 153.9, 141.8, 141.2, 137.0, 131.6, 130.1, 128.7, 128.0, 127.9, 127.5,
26.6, 125.6, 121.0, 111.4, 110.3, 109.1, 103.9, 99.7, 60.2, 54.9, 52.1, 46.4, 42.7, 27.6, 13.8;
6
1
+
HRMS (TOF-ES+) m/z: [M+Na] calcd for C29
H
26
N
2
O Na 489.1790, found 489.1768; HPLC
4
analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
R
= 6.69 min
(major), 20.05 min (minor).
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Spirooxindoles 8ma: White solid (73.4 mg, yield 98%, >20:1 dr, 85% ee); m.p. 141-142 °C;
2
0
[α]
D
= -55.6 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3422, 2922, 1701, 1622, 1459, 1180, 865, 802, 743
2
-
1 1
cm ; H NMR (400 MHz, DMSO-d
6
) δ 10.94 (s, 1H), 10.47 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.18-7.24 (m, 2H), 6.99-7.05 (m, 2H), 6.87-6.94 (m, 3H), 3.94 (s, 1H), 3.81-3.93 (m, 2H),
1
3
2.99-3.04 (m, 1H), 2.81-2.87 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H); C NMR
100 MHz, DMSO-d ) δ 178.6, 171.9, 142.7, 136.5, 135.6, 131.0, 128.7, 127.1, 124.9, 121.6,
20.8, 118.8, 117.9, 111.3, 109.9, 103.7, 60.5, 52.4, 44.4, 32.0, 28.0, 16.3, 14.3; HRMS (TOF-ES+)
(
6
1
+
m/z: [M+Na] calcd for C23
H
22
N
2
O Na 397.1528, found 397.1511; HPLC analysis: (CHIRALCEL
3
OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
minor).
Spirooxindoles 8na: Major diastereomer: white solid (55.8 mg, yield 77%, 61% ee); m.p.
R
= 6.10 min (major), 9.05 min
(
2
1
51-252 °C; [α] 20
D
= -82.8 (c = 0.1 in CH
Cl
2 2
); IR (KBr) ν 3375, 2941, 1733, 1700, 1620, 1464,
) δ 10.96 (s, 1H), 10.71 (s, 1H), 7.22 (d,
-1
1
297, 1023, 916, 742 cm ; H NMR (400 MHz, DMSO-d
6
J = 8.0 Hz, 1H), 7.14-7.18 (m, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.90-6.95 (m, 2H), 6.70-6.81 (m, 3H),
3
2
.69 (dd, J = 14.4, 7.2 Hz, 2H), 3.27 (dd, J = 12.0, 4.4 Hz, 1H), 2.85-2.98 (m, 2H), 2.30-2.37 (m,
13
H), 0.81 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, DMSO-d
6
) δ 180.4, 171.8, 142.6, 136.6, 136.4,
132.4, 128.6, 125.3, 125.0, 121.7, 121.0, 118.9, 117.5, 111.3, 109.6, 107.8, 60.3, 51.0, 47.7, 22.7,
+
2
2.1, 13.8; HRMS (TOF-ES+) m/z: [M+Na] calcd for C22
H
20
N
2
O Na 383.1372, found 383.1361;
3
HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
7.53 min (minor), 17.74 min (major). Minor diastereomer: White solid (12.1 mg, yield 17%, 83%
ee); m.p. 232-233°C; [α] 20
= -143.8 (c = 0.02 in CH Cl ); IR (KBr) ν 3392, 2925, 1709, 1617,
R
=
D
2
2
-1
1
1
465, 1172, 1022, 814, 757, 734 cm ; H NMR (400 MHz, CDCl ) δ 8.18 (br s, 1H), 8.02 (br s,
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H), 7.34 (d, J = 8.4 Hz, 2H), 7.15-7.22 (m, 2H), 7.06-7.10 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.87
(t, J = 7.6 Hz, 1H), 4.58 (s, 1H), 3.79-3.87 (m, 2H), 3.02-3.11 (m, 1H), 2.89 (dd, J = 16.0, 4.0 Hz,
1
3
1H), 2.35-2.42 (m, 1H), 1.93-1.98 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl )
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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39
40
41
42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ 181.3, 170.5, 140.6, 136.2, 133.5, 130.2, 128.5, 127.3, 125.7, 122.2, 121.8, 119.8, 119.6, 110.6,
+
109.7, 106.1, 60.6, 51.0, 44.8, 31.4, 19.7, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for
C
22
H
20
N
2
3
O Na 383.1372, found 383.1389; HPLC analysis: (CHIRALCEL AD-H, 30%
i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
R
= 10.28 min (minor), 12.03 min (major).
Spirooxindoles 8ab: White solid (90.5 mg, yield 99%, >20:1 dr, 98% ee); m.p. 266-268 °C;
2
0
[α]
D
= -67.5 (c = 0.1 in CH
2
2
Cl ); IR (KBr) ν 3423, 3211, 2908, 1706, 1479, 1183, 1030, 888, 828,
-1
1
7
44 cm ; H NMR (400 MHz, Acetone-d ) δ 10.19 (s, 1H), 9.44 (s, 1H), 7.37-7.42 (m, 2H),
6
7.27-7.29 (m, 2H), 7.13-7.16 (m, 2H), 7.07-7.10 (m, 3H), 6.99-7.02 (m, 1H), 6.81-6.86 (m, 1H),
6.68-6.71 (m, 1H), 4.57 (dd, J = 11.4, 5.8 Hz, 1H), 4.13-4.20 (m, 1H), 4.07-4.12 (m, 2H), 3.82 (dd,
13
J = 16.4, 11.6 Hz, 1H), 3.16 (dd, J = 16.4, 6.0 Hz, 1H), 1.17 (t, J = 6.8 Hz, 3H); C NMR (100
MHz, Acetone-d
) δ 177.8, 172.0, 158.1 (d, 1JC-F = 234 Hz), 140.8, 138.0, 136.6, 136.2, 131.9 (d,
6
3JC-F = 8 Hz), 128.7, 128.0, 127.0, 126.8, 120.8, 118.8, 117.3, 114.2 (d, 2JC-F = 23 Hz), 113.3 (d,
2JC-F = 25 Hz), 110.9, 109.7 (d, 3JC-F = 8 Hz), 103.6, 60.4, 52.7, 46.3, 42.7, 27.4, 13.6; HRMS
+
(TOF-ES+) m/z: [M+Na] calcd for C28
H
23
N
2
3
O NaF 477.1590, found 477.1575; HPLC analysis:
(
CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
R
= 5.57 min (major),
12.58 min (minor).
2
0
Spirooxindoles 8ac: White solid (93.0 mg, yield 99%, >20:1 dr, 96% ee); m.p. 274-275 °C; [α]
D
=
-96.4 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3433, 3216, 2910, 1738, 1699, 1456, 1308, 1145, 827, 754,
2
-1
1
7
04 cm ; H NMR (400 MHz, Acetone-d ) δ 10.19 (s, 1H), 9.55 (s, 1H), 7.38 (d, J = 6.4 Hz, 1H),
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
.38 (s, 1H), 7.26-7.30 (m, 3H), 7.14-7.18 (m, 2H), 7.07-7.11 (m, 3H), 6.99-7.03 (m, 1H), 6.72 (d,
J = 8.4 Hz, 1H), 4.55 (dd, J = 11.2, 5.6 Hz, 1H), 4.09-4.19 (m, 2H), 4.08 (s, 1H), 3.82 (dd, J =
1
3
16.4, 11.6 Hz, 1H), 3.17 (dd, J = 16.6, 5.6 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Acetone-d ) δ 177.5, 172.0, 140.8, 140.7, 136.6, 136.2, 132.1, 128.6, 128.1, 127.9, 127.0, 126.9,
6
125.8(1), 125.7(6), 120.9, 118.9, 117.2, 110.9, 110.4, 103.6, 60.5, 52.5, 46.2, 42.7, 27.4, 13.7;
+
HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
H
23
N
2
3
O NaCl 493.1295, found 493.1295; HPLC
analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 5.50 min
R
(major), 11.63 min (minor).
Spirooxindoles 8ad: White solid (102.7 mg, yield 99%, >20:1 dr, 94% ee); m.p. 276-277 °C;
20
[α]
D
= -100.0 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3433, 3210, 2909, 1736, 1698, 1457, 1173, 1145,
2
-1 1
825, 752, 704 cm ; H NMR (400 MHz, Acetone-d
Hz, 1H), 7.37-7.41 (m, 2H), 7.26 (d, J = 7.6 Hz, 2H), 7.23 (dd, J = 8.4, 2.0 Hz, 1H), 7.16 (t, J =
.2 Hz, 2H), 7.07-7.11 (m, 2H), 6.99-7.03 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.54 (dd, J = 11.2, 5.6
Hz, 1H), 4.10-4.19 (m, 2H), 4.08 (s, 1H), 3.81 (dd, J = 16.4, 11.2 Hz, 1H), 3.17 (dd, J = 16.4, 5.6
6
) δ 10.20 (s, 1H), 9.57 (s, 1H), 7.43 (d, J = 2.0
7
13
Hz, 1H), 1.19 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, Acetone-d
6
) δ 177.4, 172.0, 141.1, 140.7,
136.6, 136.2, 132.5, 130.8, 128.6, 128.5, 128.1, 127.0, 126.9, 120.9, 118.9, 117.2, 113.1, 110.9,
+
103.6, 60.5, 52.5, 46.2, 42.7, 27.4, 13.7; HRMS (TOF-ES+) m/z: [M+Na] calcd for
C
28
H
23
N
2
O
3
NaBr 537.0790, found 537.0768; HPLC analysis: (CHIRALCEL OD-H, 30%
i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 5.55 min (major), 11.76 min (minor).
R
2
0
Spirooxindoles 8ae: White solid (90.0 mg, yield 99%, >20:1 dr, 96% ee); m.p. 269-270 °C; [α]
D
=
-90.2 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3446, 3221, 2920, 1737, 1685, 1493, 1458, 1181, 826, 740,
2
-1
1
700 cm ; H NMR (400 MHz, Acetone-d ) δ 10.15 (s, 1H), 9.29 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H),
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.24-7.26 (m, 2H), 7.05-7.13 (m, 5H), 6.97-7.01 (m, 1H), 6.86 (dd, J = 8.0, 0.8 Hz, 1H), 6.58 (d, J
=
7.6 Hz, 1H), 4.54 (dd, J = 11.2, 5.6 Hz, 1H), 4.03-4.16 (m, 2H), 4.03 (s, 1H), 3.83 (dd, J = 16.4,
1.6 Hz, 1H), 3.13 (dd, J = 16.6, 5.8 Hz, 1H), 2.24 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR
100 MHz, Acetone-d ) δ 178.0, 172.1, 141.3, 139.3, 136.6, 136.3, 130.1, 130.0, 128.7, 128.2,
1
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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60
(
6
127.9, 127.1, 126.6, 126.1, 120.7, 118.8, 117.2, 110.8, 108.8, 104.1, 60.2, 52.1, 46.5, 42.7, 27.6,
+
20.3, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for C29
H
26
N
2
O Na 473.1841, found 473.1829;
3
HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t =
R
5.49 min (major), 13.00 min (minor).
Spirooxindoles 8af: White solid (101.8 mg, yield 99%, >20:1 dr, 93% ee); m.p. 278-279 °C;
20
[α]
D
= -84.8 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3366, 2922, 2922, 1722, 1702, 1604, 1452, 1329,
2
-1 1
1184, 847, 809, 746 cm ; H NMR (400 MHz, Acetone-d
8.0 Hz, 2H), 7.24 (d, J = 7.6 Hz, 3H), 7.12-7.16 (m, 2H), 7.07-7.10 (m, 3H), 6.98-7.02 (m, 1H),
.89 (d, J = 2.0 Hz, 1H), 4.57 (dd, J = 11.2, 6.0 Hz, 1H), 4.13-4.19 (m, 1H), 4.03-4.09 (m, 2H),
3.81 (dd, J = 16.4, 11.2 Hz, 1H), 3.16 (dd, J = 16.6, 5.6 Hz, 1H), 1.16 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, Acetone-d ) δ 177.6, 171.9, 143.5, 140.8, 136.6, 136.2, 129.4, 128.6, 128.0,
27.4, 127.0, 126.8, 123.7, 121.1, 120.8, 118.9, 117.3, 112.2, 110.9, 103.7, 60.4, 52.1, 46.1, 42.6,
6
) δ 10.19 (s, 1H), 9.56 (s, 1H), 7.39 (t, J
=
6
6
1
+
27.4, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
37.0764; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254
nm), t = 5.89 min (major), 15.98 min (minor).
Spirooxindoles 8ag: White solid (102.0 mg, yield 99%, >20:1 dr, 89% ee); m.p. 271-272 °C;
H
23
N
2
3
O NaBr 537.0790, found
5
R
2
0
[α]
D
= -55.4 (c = 0.1 in CH
2
2
Cl ); IR (KBr) ν 3434, 2978, 1711, 1612, 1457, 1335, 1178, 782, 739
-1
1
cm ; H NMR (400 MHz, Acetone-d ) δ 10.20 (s, 1H), 9.58 (s, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.30
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(
d, J = 7.2 Hz, 1H), 7.23-7.27 (m, 3H), 7.06-7.15 (m, 4H), 6.99-7.03 (m, 1H), 6.87 (t, J = 7.8 Hz,
1
H), 4.56 (dd, J = 11.0, 5.6 Hz, 1H), 4.12-4.17 (m, 1H), 4.11 (s, 1H), 4.02-4.06 (m, 1H), 3.80 (dd,
1
3
J = 16.4, 11.2 Hz, 1H), 3.18 (dd, J = 16.6, 5.6 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H); C NMR (100
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, Acetone-d ) δ 177.2, 171.8, 141.2, 140.8, 136.6, 136.1, 131.8, 131.0, 128.6, 128.0, 127.0,
6
126.9, 124.7, 122.6, 120.9, 118.9, 117.3, 110.9, 103.6, 101.7, 60.4, 53.5, 46.3, 42.8, 27.4, 13.6;
+
HRMS (TOF-ES+) m/z: [M+Na] calcd for C28
H
23
N
2
O NaBr 537.0790, found 537.0783; HPLC
3
analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 6.42 min
R
(major), 8.57 min (minor).
Spirooxindoles 8ah: White solid (90.8 mg, yield 99%, >20:1 dr, 83% ee); m.p. 266-268 °C;
20
[α]
D
= -85.9 (c = 0.1 in CH
2
2
Cl ); IR (KBr) ν 3368, 3306, 2910, 1717, 1645, 1494, 1333, 1192,
-1 1
859, 776, 737 cm ; H NMR (400 MHz, Acetone-d
Hz, 2H), 7.23-7.26 (m, 2H), 7.07-7.17 (m, 5H), 6.99-7.03 (m, 1H), 6.90-6.93 (m, 2H), 4.58 (dd, J
11.2, 5.6 Hz, 1H), 4.13-4.18 (m, 1H), 4.10 (s, 1H), 4.02-4.06 (m, 1H), 3.82 (dd, J = 16.4, 11.2
Hz, 1H), 3.17 (dd, J = 16.6, 5.6 Hz, 1H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
Acetone-d ) δ 177.4, 171.9, 147.7, 145.3, 140.8, 136.6, 136.1, 133.1, 128.9, 128.6, 128.0, 126.8,
21.7, 121.6, 120.8, 118.9, 117.3, 114.8, 110.9, 103.7, 60.4, 52.7, 46.2, 42.8, 27.3, 13.6; HRMS
6
) δ 10.19 (s, 1H), 9.83 (s, 1H), 7.40 (t, J = 7.2
=
6
1
+
(TOF-ES+) m/z: [M+Na] calcd for C28
H
23
N
2
3
O NaF 477.1590, found 477.1599; HPLC analysis:
(CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
R
= 5.71 min (major),
8
.80 min (minor).
2
0
1
Spirooxindoles 8ai: White solid (90.9 mg, yield 97%, >20:1 dr, 81% ee); m.p. 167-168 °C; [α]
D
-
=
-112.9 (c = 0.1 in CH
2 2
Cl ); IR (KBr) ν 3421, 3372, 2923, 1691, 1622, 1468, 1209, 807, 749 cm ;
1H NMR (400 MHz, Acetone-d
6
) δ 10.16 (s, 1H), 9.46 (s, 1H), 7.81-7.83 (m, 2H), 7.54-7.59 (m,
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H), 7.43 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.27-7.29 (m, 2H), 7.08-7.12 (m, 2H),
.95-7.06 (m, 3H), 6.81-6.86 (m, 2H), 6.73-6.77 (m, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.53 (td, J =
.6, 1.2 Hz, 1H), 5.34 (s, 1H), 4.67 (dd, J = 11.4, 6.0 Hz, 1H), 3.92 (dd, J = 16.2, 11.4 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
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22
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24
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26
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37
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
.20 (dd, J = 16.6, 5.8 Hz, 1H); 13C NMR (100 MHz, Acetone-d
) δ 200.9, 178.4, 141.7, 141.2,
6
138.9, 136.7, 136.5, 132.9, 129.3, 128.8, 128.6, 128.2, 127.8, 127.7, 127.0, 126.6, 126.4, 120.6,
20.5, 118.5, 117.0, 110.8, 108.9, 105.4, 52.7, 44.8, 42.8, 27.7; HRMS (TOF-ES+) m/z: [M+Na]+
calcd for C32 Na 491.1735, found 491.1756; HPLC analysis: (CHIRALCEL OD-H, 30%
1
H
24
N
2
O
2
i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 6.08 min (major), 13.85 min (minor).
R
2
0
Spirooxindoles 8aj: White solid (77.7 mg, yield 99%, >20:1 dr, 94% ee); m.p. 261-262 °C; [α]
D
-1
1
=
-110.5 (c = 0.1 in CH
Cl
2 2
); IR (KBr) ν 3366, 2879, 1702, 1621, 1458, 1180, 752, 703 cm ; H
NMR (400 MHz, Acetone-d
6
) δ 10.37 (s, 1H), 9.57 (s, 1H), 7.61 (t, J = 8.0 Hz, 2H), 7.44-7.46 (m,
H), 7.25-7.28 (m, 2H), 7.08-7.18 (m, 6H), 6.97 (td, J = 7.6, 0.8 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H),
.58 (s, 1H), 3.97 (dd, J = 10.2, 5.8 Hz, 1H), 3.74 (dd, J = 16.6, 10.2 Hz, 1H), 3.27 (dd, J = 16.8,
1
4
13
6.0 Hz, 1H); C NMR (100 MHz, Acetone-d
6
) δ 176.6, 141.7, 140.3, 136.7, 135.8, 129.2, 128.6,
1
4
28.4, 128.0, 127.0, 126.3, 126.1, 121.4, 121.2, 119.3, 118.5, 117.3, 111.1, 109.3, 101.0, 51.1,
+
4.5, 32.4, 27.5; HRMS (TOF-ES+) m/z: [M+Na] calcd for C26
H
19
N ONa 412.1426, found
3
412.1411; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254
nm), t = 6.54 min (major), 25.13 min (minor).
Spirooxindoles 8ak: White solid (80.8 mg, yield 99%, >20:1 dr, 89% ee); m.p. 234-236 °C;
R
2
0
[α]
D
= -75.0 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3404, 2921, 1704, 1620, 1468, 1350, 1161, 741, 701
2
-
1 1
cm ; H NMR (400 MHz, DMSO-d
6
) δ 11.01 (s, 1H), 10.48 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23
(d, J = 8.0 Hz, 1H), 6.92-7.13 (m, 9H), 6.82 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 4.20-4.23
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13
(
m, 2H), 3.59 (dd, J = 16.2, 11.4 Hz, 1H), 3.05 (dd, J = 16.6, 5.8 Hz, 1H), 2.00 (s, 3H); C NMR
100 MHz, DMSO-d ) δ 209.4, 178.8, 142.0, 141.3, 136.4, 129.5, 128.9, 128.4(0), 128.3(5), 127.1,
26.9, 125.7, 121.2, 120.9, 119.0, 117.6, 111.4, 109.7, 104.4, 52.3, 51.1, 42.5, 33.5, 27.8; HRMS
(
6
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(TOF-ES+) m/z: [M+Na] calcd for C27
H
22
N
2
O Na 429.1579, found 429.1559; HPLC analysis:
2
(CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
8.89 min (minor).
Spirooxindoles 8al: Major diastereomer: white solid (60.1 mg, yield 65%, 45% ee); m.p.
R
= 6.70 min (major),
1
224-225 °C; [α] 20
= 49.9 (c = 0.1 in acetone); IR (KBr) ν 3397, 2982, 1728, 1616, 1464, 1266,
D
-1
1
9
2
13, 760, 706 cm ; H NMR (400 MHz,Acetone-d
6
) δ 10.37 (s, 1H), 9.89 (s, 1H), 7.72-7.74 (m,
H), 7.48 (d, J = 7.6 Hz, 1H), 7.33-7.41 (m, 4H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 6.93-7.06 (m, 4H),
1
3
6.83-6.87 (m, 1H), 4.56 (dd, J = 12.0, 5.6 Hz, 1H), 3.47-3.67 (m, 4H), 0.80 (t, J = 7.0 Hz, 3H); C
NMR (100 MHz, Acetone-d ) δ 174.7, 164.5, 141.4, 139.5, 136.8, 134.8, 130.2, 129.3, 129.1,
28.2, 127.8, 126.9, 125.1, 121.8, 121.5, 119.1, 117.6, 115.7, 111.1, 109.5, 106.7, 61.9, 57.5, 54.5,
6
1
+
42.5, 12.7; HRMS (TOF-ES+) m/z: [M+Na] calcd for C29
H
23
N
3
O Na 484.1637, found 484.1655;
3
HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
.37 min (major), 11.35 min (minor). Minor diastereomer: white solid (30.3 mg, yield 33%, 83%
ee); m.p. 272-273 °C; [α] 20
= 297.0 (c = 0.05 in acetone); IR (KBr) ν 3358, 2919, 1695, 1621,
R
=
7
D
-
1 1
1
7
456, 1227, 1009, 853, 743 cm ; H NMR (400 MHz, Acetone-d
6
) δ 10.53 (s, 1H), 9.71 (s, 1H),
.65 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.23-7.25 (m, 2H),
7.07-7.18 (m, 6H), 6.94-6.98 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.76 (dd, J = 12.0, 5.6 Hz, 1H),
.38-4.42 (m, 1H), 4.25-4.30 (m, 1H), 3.95-4.02 (m, 1H), 3.17 (dd, J = 16.8, 5.6 Hz, 1H), 1.26 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, Acetone-d
) δ 175.1, 167.2, 142.6, 139.2, 137.3, 136.4,
4
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29.2, 129.0, 127.9, 127.1, 127.0, 125.5, 125.2, 121.5, 119.5, 117.4, 116.6, 111.3, 109.6, 109.5,
+
00.9, 62.9, 56.2, 51.0, 42.6, 26.2, 13.5; HRMS (TOF-ES+) m/z: [M+Na] calcd for
C
29
H
23
N
3
3
O Na 484.1637, found 484.1625; HPLC analysis: (CHIRALCEL OD-H, 30%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
35
36
37
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t
R
= 6.20 min (major), 24.56 min (minor).
Spirooxindoles 8am: White solid (51.7 mg, yield 62%, >20:1 dr, 81% ee); m.p. 229-230 °C;
2
0
[α]
D
= 145.1 (c = 0.05 in acetone); IR (KBr) ν 3383, 1719, 1619, 1455, 1321, 1186, 749, 700,
-1
1
4
82 cm ; H NMR (400 MHz, Acetone-d ) δ 10.64 (s, 1H), 10.28 (s, 1H), 7.67-7.69 (m, 2H),
6
7.47-7.58 (m, 5H), 7.42 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.16-7.21 (m, 1H), 7.05-7.09
m, 1H), 6.75-6.79 (m, 1H), 6.14 (d, J = 8.0 Hz, 1H), 5.28 (dd, J = 12.0, 5.2 Hz, 1H), 3.82 (dd, J =
7.2, 12.0 Hz, 1H), 3.52 (dd, J = 17.2, 5.2 Hz, 1H); 13C NMR (100 MHz, Acetone-d
) δ 175.0,
142.9, 137.1, 136.8, 135.6, 130.9, 129.1(4), 129.0(5), 129.0, 127.0, 126.6, 124.9, 122.8, 121.9,
19.5, 117.6, 113.4, 113.0, 111.4, 110.6, 103.3, 53.7, 47.7, 41.0, 26.1; HRMS (TOF-ES+) m/z:
(
1
6
1
+
[
M+H] calcd for C27
H
19
4
N O 415.1559, found 415.1572; HPLC analysis: (CHIRALCEL OD-H,
30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 6.95 min (minor), 11.78 min (major).
R
2
0
Spirooxindoles 8oa: White solid (90.2 mg, yield 86%, >20:1 dr, 12% ee); m.p. 253-255 °C; [α]
D
=
-2.7 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3371, 2982, 1717, 1616, 1465, 1170, 845, 803, 743, 698,
2
-
1 1
cm ; H NMR (400 MHz, DMSO-d
6
) δ 10.44 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.27-7.33 (m, 3H),
.20-7.24 (m, 1H), 6.99-7.15 (m, 11H), 6.83 (td, J = 7.6, 0.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H),
.45 (d, J = 2.0 Hz, 2H), 4.38-4.42 (m, 1H), 3.96-4.10 (m, 3H), 3.54 (dd, J = 16.4, 11.2 Hz, 1H),
7
5
1
3
3.17 (dd, J = 16.8, 6.0 Hz, 1H), 1.06 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, DMSO-d
6
) δ 178.3,
1
1
72.2, 142.1, 141.1, 138.8, 137.8, 136.9, 129.9, 129.0, 128.9, 128.6, 128.4, 127.5, 127.2, 126.7,
25.3, 121.3(4), 121.2(8), 119.6, 117.6, 110.3, 109.7, 104.1, 60.8, 51.9, 46.3, 46.1, 42.5, 26.8, 14.5;
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HRMS (TOF-ES+) m/z: [M+Na] calcd for C35
H
30
N
2
O Na 549.2154, found 549.2144; HPLC
3
analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 6.94 min
R
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0
8a
20
Spirooxindoles 8an : White solid (104.6 mg, yield 99%, >20:1 dr, 28% ee); [α]
D
= -14.5 (c =
1
0.1 in CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
) δ 8.05 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.35 (dd, J =
7
6
.6, 0.4 Hz, 1H), 7.24-7.31 (m, 3H), 7.12-7.15 (m, 3H), 7.07-7.11 (m, 3H), 6.96-7.05 (m, 4H),
.89 (td, J = 7.6, 0.8 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 4.71 (d, J = 15.6
Hz, 1H), 4.58 (dd, J = 10.8, 6.0 Hz, 1H), 4.13-4.17 (m, 1H), 4.10 (s, 1H), 4.00-4.04 (m, 1H), 3.84
(
dd, J = 16.4, 11.2 Hz, 1H), 3.15 (dd, J = 16.4, 6.0 Hz, 1H), 1.13 (t, J = 7.0 Hz, 3H); 13C NMR
100 MHz, CDCl ) δ 176.6, 172.4, 142.6, 140.1, 136.2, 135.7(2), 135.6(6), 129.3, 128.9, 128.6,
(
3
128.2, 128.0, 127.6, 127.5, 126.9, 125.5, 121.9, 121.5, 119.5, 117.9, 110.9, 108.8, 104.6, 60.9,
+
5
5
2.3, 46.2, 43.7, 42.7, 27.3, 14.2; HRMS (TOF-ES+) m/z: [M+Na] calcd for C35
H
30
N
2
O Na
3
49.2154, found 549.2133; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8
= 7.51 min (minor), 9.22 min (major).
mL/min, UV: 254 nm), t
R
2
0
Spirooxindoles 8on: White solid (99.8 mg, yield 81%, >20:1 dr, 3% ee); m.p. 187-188 °C; [α]
D
=
0 (c = 0.1 in CH
2
Cl ); IR (KBr) ν 3426, 2920, 1704, 1608, 1461, 1361, 1168, 916, 841, 746, 697
2
-
1 1
cm ; H NMR (400 MHz, Acetone-d
6
) δ 7.45 (d, J = 7.6 Hz, 1H), 7.25-7.38 (m, 9H), 7.21 (d, J =
.2 Hz, 2H), 7.14-7.16 (m, 2H), 7.02-7.12 (m, 6H), 6.91-6.95 (m, 1H), 6.69 (d, J = 8.0 Hz, 1H),
.54 (d, J = 3.2 Hz, 2H), 4.88 (d, J = 2.0 Hz, 2H), 4.66-4.70 (m, 1H), 4.16-4.20 (m, 1H), 4.04-4.09
7
5
(m, 2H), 3.74-3.81 (m, 1H), 3.20-3.25 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
Acetone-d ) δ 176.2, 171.9, 142.8, 140.7, 138.5, 137.6, 137.0, 136.5, 129.2, 128.8, 128.6, 128.5,
28.1, 127.9, 127.5, 127.3, 127.0, 126.9, 126.7, 126.3, 125.3, 121.6, 120.9, 119.2, 117.5, 109.6,
6
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08.8, 104.2, 60.4, 51.9, 46.7, 45.9, 43.1, 42.5, 26.7, 13.6; HRMS (TOF-ES+) m/z: [M+Na] calcd
for C42
H
36
N
2
O
3
Na 639.2624, found 639.2633; HPLC analysis: (CHIRALCEL OD-H, 30%
i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), t = 10.04 min (minor), 15.20 min (major).
R
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ASSOCIATED CONTENT
Supporting Information
X-ray structural data for compound 8af (CIF)
Copies of NMR spectra and HPLC analysis spectra of all compounds (PDF)
AUTHOR INFORMATION
Corresponding author
*e-mail:hyangchem@csu.edu.cn
ORCID
Hua Yang: 0000-0002-5518-5255
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the National Natural Science Foundation of
China (21276282 & 21576296) and Central South University.
REFERENCES
(1) (a) James, T.; Gemmeren, M.; List, B. Chem. Rev. 2015, 115, 9388. (b) Volla, C. M. R.;
Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390. (c) Moyano, A.; Rios, R. Chem. Rev.
2
2
011, 111, 4703. (d) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed.
008, 47, 6138. (e) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (f) Enders, D.;
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