Access to 2′,3′-dihydro-1′H-spiro[indoline-3,4′- pyridin]-2-ones via amino acid derived phosphine-catalyzed asymmetric [4+2] annulation with easily available oxindole-derived α,β-unsaturated imines

Article abstract of DOI:10.1016/j.tet.2014.02.052

The phosphine-catalyzed asymmetric [4+2] annulation of vinyl ketones with more easily available oxindole-derived α,β-unsaturated imines has been further developed in the presence of an easily available multifunctional thiourea-phosphine catalyst derived f

Full text of DOI:10.1016/j.tet.2014.02.052

Tetrahedron 70 (2014) 2838e2846
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Access to 20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-ones via
amino acid derived phosphine-catalyzed asymmetric [4þ2]
annulation with easily available oxindole-derived
imines
a,b-unsaturated
*
*
Xiao-Nan Zhang, Xiang Dong, Yin Wei , Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai
200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 January 2014
Received in revised form 13 February 2014
Accepted 14 February 2014
Available online 5 March 2014
The phosphine-catalyzed asymmetric [4þ2] annulation of vinyl ketones with more easily available
oxindole-derived
a,b-unsaturated imines has been further developed in the presence of an easily
available multifunctional thiourea-phosphine catalyst derived from natural amino acid, providing the
enantioselective synthesis of 20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-ones in good yields and
moderate de values with higher enantioselectivities under mild conditions.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric [4þ2] annulation
Chiral phosphines
Organocatalysts
Spirooxindoles
1. Introduction
rapid generation of enantiomerically enriched compounds with
complex molecular structures.7 More recently, several reports
Spirooxindoles are the structural valuable motifs frequently
existing in a variety of pharmacological agents and natural alka-
loids.1 In particular, some spiro heterocyclic oxindoles have drawn
considerable interest in the area of synthetic organic chemistry
and medicinal chemistry since they have various types of bi-
ological activities and the potential clinical significance.2 Although
many synthetic methods have been disclosed for the synthesis of
spirooxindoles,3 their enantioselective preparation with several
chiral centers including the stereogenic carbon at C3 is a still
challenging and demanding task.4 Notably, existing stereoselective
catalytic syntheses of substituted six-membered heterocyclic spi-
rooxindoles from simple substrates and catalysts are very few.5
Thus, the design and development of new and highly enantiose-
lective methods for direct construction of this skeleton is highly
desirable.
about the enantioselective synthesis of spirocyclopenteneox-
indoles via phosphine-catalyzed reactions have been disclosed.8
For example, Zhong, Loh and Chi and their co-workers reported
several novel [4þ2] annulations initiated by
a phosphine-
catalyzed aza-RauhuteCurrier reaction that provides a practical
access to highly functionalized tetrahydropyridines.9 On the basis
of these studies and our previous work on chiral phosphines as
nucleophilic catalysts in asymmetric synthesis,10,11 we have just
reported a phosphine-catalyzed asymmetric [4þ2] annulation of
vinyl ketones with oxindole-derived
a,b-unsaturated imines,
which is the first phosphine-catalyzed enantioselective synthesis
of isatin-based spiro-fused six-membered heterocycle derivatives
in 47e88% yields with 5.0:1e20:1 de values and 87e98% ee
values.12 Since these spiro-fused six-membered heterocycles are
very interesting compounds, herein we wish to report the full
detail of another version of this asymmetric [4þ2] annulation of
The development of nucleophilic phosphine organocatalysis
has seen remarkable progress in recent years,6 and phosphine-
mediated reactions have emerged as a powerful tool for the
vinyl ketones with more easily available oxindole-derived
a,b-
unsaturated imines in the presence of a more common chiral
phosphine catalyst easily derived from amino acid to provide 20,30-
dihydro-10H-spiro[indoline-3,40-pyridin]-2-ones in 54e88% and
moderate de values with higher enantioselectivities (94e99% ee
values in most cases).
* Corresponding authors. Fax: þ86 21 64166128; e-mail addresses: weiyin@mail.
sioc.ac.cn (Y. Wei), Mshi@mail.sioc.ac.cn (M. Shi).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.052

X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
2839
2. Results and discussion
tosyliminoethylidene)indolin-2-one 1 was then explored. Regard-
less of whether R2 is an electron-rich or -deficient aromatic ring,
the reactions proceeded smoothly to give the corresponding an-
nulation products 3gen in moderate to good yields (47e82%) with
good dr values (2.8:1e7.7:1) and excellent ee values (96e99%), re-
spectively (Table 2, entries 6e14). Only in the case of (3E)-1-(3,5-
dimethylbenzyl)-3-((Z)-2-(4-nitrophenyl)-2-tosyliminoethylidene)
indolin-2-one 1m, the corresponding adduct 3m was obtained in
relative lower yield along with relative lower dr value (2.8:1 dr),
perhaps due to the electronic effect (Table 2, entry 13). Using (3E)-
1-(3,5-dimethylbenzyl)-3-((Z)-2-(4-bromophenyl)-2-
We initiated the study by investigating the reaction between
a
more easily available (3E)-1-methyl-3-((E)-2-phenyl-2-
tosyliminoethylidene)indolin-2-one 1a (see Supplementary data)
and methyl vinyl ketone (MVK) 2a using various chiral phosphines
CP1eCP9 (20 mol %) in toluene at room temperature (see Table SI-1
in Supplementary data). Gratifyingly, we found that the more easily
available chiral phosphine CP9 derived from L-valine could produce
the desired product 3a in 74% yield with 6.3:1 dr and 99% ee
(Table SI-1). With the identification of the best catalyst in this re-
action, we next attempted to further optimize the reaction condi-
tions by screening of several solvents, such as THF, CH2Cl2, Et2O, and
CH3CN. The reaction outcomes revealed that toluene was still the
best choice as a solvent, and using 20 mol % CP9 as the catalyst at
room temperature for 2 days gave 3a with the best reaction out-
come, which served as the best conditions in this reaction (Table 1,
entries 1e5).
tosyliminoethylidene)indolin-2-one 1l0, which is the Z-isomer of
(3E)-1-(3,5-dimethylbenzyl)-3-((E)-2-(4-bromophenyl)-2-
tosyliminoethylidene)indolin-2-one 1l as substrate, similar results
were obtained, suggesting that the E or Z-configuration of substrate
1 did not influence the reaction outcomes (Table 2, entry 12). When
R2 is a sterically more bulky 1-naphthalene moiety (R2¼naphtha-1-
yl) or more substituted aromatic group (R2¼2,4-Cl2C6H3), the re-
actions also proceeded efficiently to afford the corresponding
products 3o and 3p in 78 and 87% yields with 6.3:1 and 2.3:1 dr and
equally excellent ee values (Table 2, entries 15e16). Gratifyingly, the
reaction tolerated an aliphatic moiety (R2¼isopropyl) in (3E)-1-
(3,5-dimethylbenzyl)-3-(3-methyl-2-tosyliminobutylidene)indo-
lin-2-one 1q, the corresponding adduct 3q (double bond migrated
product) was obtained in 54% yield along with 8.3:1 dr, albeit in
only 17% ee, perhaps due to the steric influence (Table 2, entry 17).
Using methyl vinyl ketone (2a) as substrate, we next examined its
reactions with substrates 1rev bearing different substituents on
their isatin-based benzene rings, and it was found that all of the
reactions proceeded smoothly to produce the corresponding
products 3rev in good yields (75e83%) along with 5.9:1e7.7:1 dr
and 99% ee values, respectively (Table 2, entries 18e22). Next, the
investigation on the scope of vinyl ketones was continued using 1a
as substrate (Table 2, entries 23e24). When R5 is ethyl group (2b,
R5¼Et), the reaction also proceeded smoothly to give the corre-
sponding annulation product 3v in 64% yield with 4.2:1 dr and 98%
ee (Table 2, entry 23). However, when R5 is phenyl group (2c,
R5¼Ph), the corresponding annulation product could not be
obtained, perhaps due to the easy self-polymerization of 1-
phenylprop-2-en-1-one 2c under the standard reaction condi-
tions (Table 2, entry 24). The absolute configuration of 3l has been
assigned as (3S, 30S)-configuration by X-ray diffraction. The ORTEP
drawing has been shown in Fig. 3 and the CIF data are summarized
in Supplementary data.
Table 1
Optimization of the reaction conditionsa
Entry
Solvent
Time (d)
Yield (%)b
drc
ee (%)d
1
2
3
THF
CH2Cl2
Et2O
CH3CN
Toluene
2
2
2
2
3
72
70
74
48
65
5.0:1
4.5:1
5.9:1
1.3:1
6.3:1
99
93
99
73
99
4
5e
a
Reactions were performed with 1a (0.10 mmol) and 2a (0.30 m mol) in the
presence of 20 mol % of CP9 in solvent (1 mL) at room temperature.
b
Yield of isolated single isomer.
c
Determined by 1H NMR analysis of the crude reaction mixture.
d
Determined by chiral HPLC analysis.
10 mol % of CP9 was used.
e
The 3-substituted 3-hydroxyoxindole unit is encountered in
a large variety of alkaloids and natural products with a wide
spectrum of biological activities.13 An aldol reaction of 3a with 1-
methylindoline-2,3-dione could proceed smoothly to give the cor-
responding product 4a in 67% yield along with 1.7:1 dr value, which
contains not only an isatin-based spiro-fused six-membered het-
erocycle skeleton but also a 3-substituted 3-hydroxyoxindole unit
(Scheme 1). Deprotection of the tosyl of the chiral model product 3a
could also be readily carried out under mild reaction conditions to
produce the absolute configuration maintained imine 5a in 66%
yield (Scheme 2).
Having determined the optimal reaction conditions for the
highly enantioselective synthesis of 3a, we turned our attention to
the scope and limitations of this multifunctional chiral phosphine-
catalyzed asymmetric [4þ2] annulation of vinyl ketones with these
more easily available oxindole-derived a,b-unsaturated imines, and
the results are summarized in Table 2. The synthesis of these
more easily available -unsaturated imines has been shown
a,b
in Supplementary data. Their structures including Z- and E-con-
figuration have been confirmed by X-ray diffraction (Figs. 1 and 2).
Under the optimal reaction conditions, using MVK (2a) as substrate,
we first examined its reaction with substrates 1bed to investigate
the influence of the protecting group R1 in substrates 1 on this
annulation. It was found that the reactions of 1bed with 2a pro-
ceeded smoothly to give the corresponding products 3bed in good
yields (67e85%) with 5.3:1e8.3:1 drs and 97e99% ees (Table 2,
entries 1e3) and the substrate 1d with 3,5-dimethylbenzyl group
as a protecting group gave the best result. Substrates 1e and 1f were
then tested to elucidate the effect of the protecting group R3 on the
stereoselective induction, and the tosyl group proved to be a good
choice (Table 2, entries 4e5). With the optimal groups R1 and R3
established, the scope of (3E)-1-(3,5-dimethylbenzyl)-3-(2-
The catalytic annulation is postulated to go through a tandem
RauhuteCurrier/SN2-substitution sequence.9,14,15 With the assis-
tance of intermolecular hydrogen bonding, the steric hindrance
between the oxindole-derived a,b-unsaturated imine and the ste-
rically bulky diarylmethyl group of the catalyst plays significant
role in the stereoselectivity (Fig. 4, TS-1). The high diaster-
eoselectivity likely resulted from a favorable SN2 reaction of TS-II
(Fig. 4).
In conclusion, an interesting and useful asymmetric [4þ2] an-
nulation reaction of vinyl ketones with more easily available
oxindole-derived a,b-unsaturated imines has been developed by

2840
X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
Table 2
The substrate scope of [4þ2] annulationa
Entry
Substrate 1
R1
R2
R3
R4
Substrate 2 (R5)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1eh
1f
1g
1h
1ik
1j
Bn
H
C6H5
C6H5
C6H5
C6H5
Ts
Ts
Ts
Nsi
Bsj
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2b (Et)
3b, 67e
3cf, 74e
3d, 85
3e, 44
3f, 78
3g, 79
3h, 82
3i, 72
6.5:1
5.3:1
8.3:1
6.3:1
7.7:1
7.7:1
7.1:1
6.3:1
7.7:1
7.1:1
6.7:1
6.7:1
2.8:1
5.3:1
6.3:1
2.3:1
8.3:1
7.7:1
7.1:1
6.7:1
5.9:1
7.7:1
4.2:1
d
97
99
99
90
99
99
97
97
96
98
98
97
97
96
96
94
17
99
99
99
99
99
98
d
3,5-DMBng
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
3,5-DMBn
C6H5
4-MeC6H4
4-FC6H4
2-CIC6H4
3-CIC6H4
4-CIC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
4-CF3C6H4
Naphtha-1-yl
2,4-Cl2C6H3
Isopropyl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
9
3j, 74
3k, 80
3l, 78
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1k
1ll
m
1l0
3l, 76
1mn
1n
1o
1p
1q
1r
3m, 47
3n, 64
3o, 78
3p, 87
3qo, 54
3r, 75
3s, 76
3t, 78
3u, 75
3v, 83
3w, 64e
Trace
H
5-F
5-Cl
5-Br
5-Me
6-Me
H
1s
1t
1u
1v
1a
1a
H
2c (Ph)
a
Reactions were performed with 1 (0.10 mmol) and 2 (0.30 mmol) in the presence of 20 mol % of CP9 and toluene (1 mL) at room temperature.
Isolated yields.
b
c
d
e
f
Determined by 1H NMR of the crude reaction mixture.
Determined by HPLC analysis.
Yield of single isomer.
An additional Michael addition of substrate 1c with methyl vinyl ketone 2a took place.
3,5-DMBn¼3,5-dimethylbenzyl.
g
h
i
Substrate 1e was isolated as only Z-configuration.
Ns¼Nitrophenylsulfonyl.
j
Bs¼Benzenesulfonyl.
k
l
Substrate 1i was assigned as Z-configuration by X-ray diffraction.
The configuration of 1l has been assigned by X-ray diffraction as E-configuration.
Substrate 1l0 is Z-configuration, which was isolated as the Z-isomer of 1l.
Substrate 1m was isolated as only Z-configuration.
m
n
o
The structure of 3q is listed in the upper right corner of the table, which is a double bond migrated product.
utilizing
a
more easily available multifunctional thiourea-
300 and AM-400 spectrophotometers (75 or 100 MHz) with com-
plete proton decoupling spectrophotometers (CDCl3: 77.0 ppm).
Infrared spectra were recorded on a PerkineElmer PE-983 spec-
trometer with absorption in cmꢀ1. Flash column chromatography
was performed using 300e400 mesh silica gel. For thin-layer
chromatography (TLC), silica gel plates (Huanghai GF254) were
used. Chiral HPLC was performed on a Waters 2487 series with
chiral columns (Chiralpak AD-H, IC-H columns 4.6ꢁ250 mm (Daicel
phosphine catalyst CP9 derived from a common natural amino
acid, which provides the corresponding isatin-based spiro-fused
six-membered heterocycle derivatives with higher ee values com-
pared with our previous work.12 Further efforts are in progress to
develop the use of this reaction in the synthesis of biologically
active molecular complexes.
3. Experimental section
3.1. General remarks
Chemical Ind., Ltd.), Phenomenex Lux 5m Cellulose-1 column
4.6ꢁ250 mm (PC-1, (Phenomenex Ind., Ltd.)) and Phenomenex Lux
5
m
Cellulose-2 column 4.6ꢁ250 mm (PC-2, (Phenomenex Ind.,
Ltd.))). Mass spectra were recorded by ESI and HRMS was measured
on a HP-5989 instrument. Catalysts CP1eCP8, which are known
compounds, were prepared according to the same procedures in
the previous literature and CP9 was prepared in the same way (see
Supplementary data).
Melting points were determined on a digital melting point ap-
paratus and temperatures were uncorrected. Optical rotations were
determined at 589 nm (sodium D line) by using a Perkin-Elmer-341
MC digital polarimeter;
[a]D-values are given in unit of
10 degꢀ1 cm2 gꢀ1. 1H NMR spectra were recorded on a Bruker AM-
300 and AM-400 spectrometer for solution in CDCl3 with tetra-
methylsilane (TMS) as an internal standard; coupling constants J
are given in Hertz. 13C NMR spectra were recorded on a Bruker AM-
Compound (S)-CP9. A white solid; mp 67e68 ꢂC; IR (KBr):
3275, 3051, 2958, 2922, 1532, 1480, 1354, 1264, 1182, 1021, 813, 738,
696 cmꢀ1 1H NMR (400 MHz, CDCl3, TMS):
0.54e0.64 (m, 6H,
2CH3), 1.88e1.96 (m, 1H, CH), 2.17e2.31 (m, 8H, 2CH3þCH2), 4.99
n
;
d

X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
2841
Fig. 3. ORTEP drawing of 3l.
(br, 1H, NH), 5.09 (br, 1H, CH), 5.36 (br, 1H, NH), 6.32 (br, 1H, CH),
7.03e7.16 (m, 8H, ArH), 7.41e7.49 (m, 10H, ArH); 31P NMR (CDCl3,
161.93 MHz, 85% H3PO4):
d
ꢀ24.56; HRMS (ESI) calcd for-
C
33H38N2PSþ1 (MþOH)þ requires 525.2493, found: 525.2487;
[a
]
20 ꢀ23.1 (c 1.00, CHCl2).
D
Fig. 1. ORTEP drawing of 1i.
3.2. Spectroscopic data of the reaction products
3.2.1. (3S,30S)-30-Acetyl-1-methyl-60-phenyl-10-tosyl-20,30-dihydro-
10H-spiro[indoline-3,40-pyridin]-2-one (3a). A colorless solid, 36 mg,
74% yield; mp 94e95 ꢂC; IR (CH2Cl2):
n
2962, 2360, 1711, 1610, 1492,
1470, 1355, 1259, 1167, 1084, 1018, 799, 710, 698, 658 cmꢀ1; 1H NMR
(400 MHz, CDCl3, TMS): 2.02 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.96
d
(dd, 1H, J¼3.2, 11.6 Hz, CH), 3.18 (s, 3H, CH3), 4.37 (dd, 1H, J¼11.6,
14.0 Hz, CH2), 4.70 (dd, 1H, J¼3.2, 14.0 Hz, CH2), 4.92 (s, 1H, ]CH),
6.48 (d, 1H, J¼7.6 Hz, ArH), 6.82 (d, 1H, J¼7.6 Hz, ArH), 6.95 (t, 1H,
J¼7.6 Hz, ArH), 7.20e7.28 (m, 4H, ArH), 7.32e7.38 (m, 4H, ArH), 7.65
(d, 2H, J¼8.4 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d 21.6, 26.5,
28.7, 46.1, 49.1, 52.6, 108.5, 117.8, 122.0, 122.4, 127.6, 127.7, 127.9,
128.5, 128.7, 129.8, 130.3, 136.3, 137.5, 141.4, 144.1, 144.5, 177.0,
203.5; HRMS (ESI) calcd for C28H27N2O4Sþ1 (MþH)þ requires
487.1692, found: 487.1682; enantiomeric excess was determined by
HPLC with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼24.04 min,
tmajor¼26.22 min; ee% >99%; [
a
]
20 þ161.4 (c 1.00, CH2Cl2)].
D
3.2.2. (3S,30S)-30-Acetyl-1-benzyl-60-phenyl-10-tosyl-20,30-dihydro-
10H-spiro[indoline-3,40-pyridin]-2-one (3b). A colorless solid, 38 mg,
67% yield; mp 95e96 ꢂC; IR (CH2Cl2):
n
3058, 2922, 1708, 1609,
1488, 1466, 1355, 1267, 1166, 1106, 1090, 986, 955, 815, 753, 734,
709, 697, 658 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
2.03 (s, 3H,
d
CH3), 2.48 (s, 3H, CH3), 3.03 (dd,1H, J¼2.8,11.6 Hz, CH), 4.42 (dd,1H,
J¼11.6, 14.0 Hz, CH2), 4.73 (dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.85 (d, 1H,
J¼16.0 Hz, CH2), 4.90 (d, 1H, J¼16.0 Hz, CH2), 4.95 (s, 1H, ]CH), 6.51
(d, 1H, J¼7.6 Hz, ArH), 6.67 (d, 1H, J¼7.6 Hz, ArH), 6.91 (t, 1H,
J¼7.6 Hz, ArH), 7.13 (t, 1H, J¼7.6 Hz, ArH), 7.21e7.25 (m, 6H, ArH),
7.31e7.36 (m, 6H, ArH), 7.65 (d, 2H, J¼8.0 Hz, ArH); 13C NMR
Fig. 2. ORTEP drawing of 1l.
(100 MHz, CDCl3, TMS): d 21.6, 28.8, 44.2, 46.2, 49.2, 52.7, 109.6,

2842
X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
Ts
Ts
N
Ph
N
O
Ph
O
HO
N
Et2NH
+
O
O
MeOH, r.t.
O
O
N
N
O
N
4a, 67% yield, 1.7:1 dr
Scheme 1. Aldol reaction of 3a with 1-methylindoline-2,3-dione.
3a
20
Ts
N
tminor¼38.92 min, tmajor¼46.64 min; ee%¼98%; [
a
]
þ57.9 (c 1.00,
D
N
N
Ph
Ph
CH2Cl2)].
TFA/thioanisole, r.t.
3.2.4. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-60-phenyl-10-tosyl-
O
O
O
20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one (3d). A color-
O
N
less solid, 50 mg, 85% yield; mp 95e96 ꢂC; IR (CH2Cl2):
n
2921, 1710,
1609, 1488, 1466, 1355, 1167, 1091, 988, 812, 756, 736, 710, 698,
659 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
2.00 (s, 3H, CH3), 2.23
5a, 66% yield, 98% ee
3a, 99% ee
d
Scheme 2. Deprotection of the tosyl of product 3a.
(s, 6H, 2CH3), 2.48 (s, 3H, CH3), 3.00 (dd,1H, J¼2.8,12.0 Hz, CH), 4.43
(dd, 1H, J¼12.0, 14.0 Hz, CH2), 4.71 (dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.79
Fig. 4. Proposed transition state.
117.9, 122.1, 122.5, 127.4, 127.6, 127.7, 127.8, 127.9, 128.57, 128.63,
128.7, 129.8, 130.3, 135.8, 136.4, 137.5, 141.5, 143.2, 144.5, 177.0,
203.5; HRMS (ESI) calcd for C34H31N2O4Sþ1 (MþH)þ requires
563.2005, found: 563.1990; enantiomeric excess was determined
(s, 2H, CH2), 4.96 (s, 1H, ]CH), 6.51 (d, 1H, J¼7.6 Hz, ArH), 6.71 (d,
1H, J¼7.6 Hz, ArH), 6.86 (s, 1H, ArH), 6.90e6.95 (m, 3H, ArH), 7.14 (t,
1H, J¼7.6 Hz, ArH), 7.21e7.29 (m, 3H, ArH), 7.33e7.37 (m, 4H, ArH),
7.66 (d, 2H, J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d 21.2,
by HPLC with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/
21.6, 28.8, 44.2, 46.1, 49.2, 52.4,109.6, 117.9, 122.1, 122.4, 125.1, 127.6,
127.7, 127.8, 128.5, 128.6, 129.2, 129.8, 130.3, 135.6, 136.3, 137.5,
138.2, 141.4, 143.3, 144.4, 176.9, 203.4; HRMS (ESI) calcd for
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼43.48 min,
tmajor¼73.92 min; ee%¼97%; [
a]
20 þ161.3 (c 1.00, CH2Cl2)].
D
C
36H35N2O4Sþ1 (MþH)þ requires 591.2318, found: 591.2305; en-
3.2.3. (3S,30S)-30-Acetyl-1-(3-oxobutyl)-60-phenyl-10-tosyl-20,30-di-
antiomeric excess was determined by HPLC with a Chiralcel AD-H
hydro-10H-spiro[indoline-3,40-pyridin]-2-one (3c). A colorless solid,
column
[
l
¼214 nm; eluent: hexane/isopropanol¼70/30; flow
40 mg, 74% yield; mp 97e98 ꢂC; IR (CH2Cl2):
n
2923, 2854, 1710,
1609, 1489, 1466, 1356, 1166, 1091, 992, 812, 754, 711, 698,
658 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
2.06 (s, 3H, CH3), 2.16
rate: 0.60 mL/min; tminor¼38.30 min, tmajor¼51.64 min; ee%¼99%;
[a
]
20 þ114.7 (c 1.00, CH2Cl2)].
D
d
(s, 3H, CH3), 2.49 (s, 3H, CH3), 2.85e2.95 (m, 2H, CH2), 2.98 (dd, 1H,
J¼3.2, 11.6 Hz, CH), 3.81e3.88 (m, 1H, CH2), 3.95e4.02 (m, 1H, CH2),
4.34 (dd, 1H, J¼11.6, 14.0 Hz, CH2), 4.70 (dd, 1H, J¼3.2, 14.0 Hz, CH2),
4.89 (s, 1H, ]CH), 6.48 (dd, 1H, J¼2.0, 7.6 Hz, ArH), 6.92e6.95 (m,
2H, ArH), 7.20e7.32 (m, 6H, ArH), 7.36 (d, 2H, J¼8.0 Hz, ArH), 7.64
3.2.5. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-10-((4-nitrophenyl)
sulfonyl)-60-phenyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-
one (3e). A colorless solid, 27 mg, 44% yield; mp 117e118 ꢂC; IR
(CH2Cl2):
n
2923, 2854, 1711, 1608, 1531, 1488, 1348, 1171, 1090, 855,
2.05 (s, 3H, CH3),
740, 697 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
d
(d, 2H, J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d
21.6, 28.7,
2.25 (s, 6H, 2CH3), 3.44 (dd, 1H, J¼2.8, 11.6 Hz, CH), 4.48 (dd, 1H,
J¼11.6, 13.6 Hz, CH2), 4.76e7.87 (dd, 3H, CH2), 4.79 (s, 2H,
CH2þCH2), 5.02 (s, 1H, ]CH), 6.77 (d, 1H, J¼7.6 Hz, ArH), 6.87 (s, 1H,
ArH), 6.96 (s, 2H, ArH), 7.02e7.10 (m, 6H, ArH), 7.19e7.26 (m, 2H,
ArH), 7.73 (d, 2H, J¼8.8 Hz, ArH), 8.23 (d, 2H, J¼8.8 Hz, ArH); 13C
30.2, 34.8, 39.9, 46.0, 48.8, 52.9, 108.9, 117.6, 122.1, 122.3, 127.6,
127.7, 127.8, 128.5, 128.7, 129.8, 130.3, 136.2, 137.4, 141.4, 143.0,
144.5, 177.2, 203.5, 206.9; HRMS (ESI) calcd for C31H31N2O5Sþ1
(MþH)þ requires 543.1954, found: 543.1934; enantiomeric excess
was determined by HPLC with a Chiralcel AD-H column [
eluent: hexane/isopropanol¼70/30; flow rate: 0.60 mL/min;
l
¼214 nm;
NMR (100 MHz, CDCl3, TMS): d 21.3, 29.1, 44.3, 46.4, 49.4, 54.6,
109.8, 118.3, 122.5, 123.0, 124.0, 125.3, 127.9, 128.3, 128.91, 128.95,

X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
2843
129.0, 129.4, 130.1, 135.5, 136.0, 138.4, 140.8, 143.3, 145.6, 150.1,
176.5, 203.3; HRMS (ESI) calcd for C35H32N3O6Sþ1 (MþH)þ requires
622.2012, found: 622.2011; enantiomeric excess was determined
by HPLC with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼26.78 min,
20
tmajor¼36.06 min; ee%¼97%; [
a
]
þ122.0 (c 1.00, CH2Cl2)].
D
by HPLC with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼42.06 min,
3.2.9. (3S,30S)-30-Acetyl-60-(2-chlorophenyl)-1-(3,5-dimethylbenzyl)-
20
tmajor¼57.80 min; ee%¼90%; [
a
]
þ169.62 (c 1.00, CH2Cl2)].
10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one (3i). A
D
colorless solid, 45 mg, 72% yield; mp 110e111 ꢂC; IR (CH2Cl2):
n
3.2.6. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-60-phenyl-10-(phe-
nylsulfonyl)-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3f). A colorless solid, 45 mg, 78% yield; mp 106e107 ꢂC; IR
2921, 1711, 1609, 1488, 1466, 1435,1355, 1265, 1167, 1109, 1091, 1033,
991, 883, 860, 814, 756, 735, 704, 686, 661 cmꢀ1 1H NMR
(400 MHz, CDCl3, TMS): 1.97 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.44
;
d
(CH2Cl2):
n
2922, 2854,1713,1610,1488, 1466, 1447,1357, 1170,1091,
1.99 (s, 3H,
(s, 3H, CH3), 3.03 (br, 1H, CH), 4.45 (dd, 1H, J¼11.6, 14.0 Hz, CH2),
4.63e4.66 (m, 1H, CH2), 4.73 (d, 1H, J¼15.6 Hz, CH2), 4.86 (d, 1H,
J¼15.6 Hz, CH2), 4.92 (s, 1H, ]CH), 6.70 (d, 1H, J¼8.0 Hz, ArH),
6.83e6.88 (m, 2H, ArH), 6.92e6.99 (m, 3H, ArH), 7.13e7.37 (m, 7H,
757, 728, 693 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
d
CH3), 2.24 (s, 6H, 2CH3), 2.99 (dd, 1H, J¼2.8, 12.0 Hz, CH), 4.46 (dd,
1H, J¼12.0, 13.6 Hz, CH2), 4.72 (dd, 1H, J¼2.8, 13.6 Hz, CH2), 4.79 (s,
2H, CH2), 4.97 (s, 1H, ]CH), 6.57 (d, 1H, J¼7.2 Hz, ArH), 6.71 (d, 1H,
J¼8.0 Hz, ArH), 6.86 (s, 1H, ArH), 6.89e6.95 (m, 3H, ArH), 7.15 (t, 1H,
J¼8.0 Hz, ArH), 7.20e7.33 (m, 5H, ArH), 7.54e7.58 (m, 2H, ArH),
7.65e7.69 (m, 1H, ArH), 7.76 (d, 2H, J¼8.4 Hz, ArH); 13C NMR
ArH), 7.64 (br, 2H, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d 21.1,
21.6, 29.0, 44.3, 45.3, 49.2, 109.7, 119.0, 122.3, 122.6, 125.2, 126.1,
127.7, 128.7, 129.2, 129.5, 129.6, 131.6, 135.6, 136.3, 138.3, 143.4,
176.5, 203.5; HRMS (ESI) calcd for C36H34ClN2O4Sþ1 (MþH)þ re-
quires 625.1928, found: 625.1923; enantiomeric excess was de-
(100 MHz, CDCl3, TMS):
d 21.2, 28.9, 44.2, 46.1, 49.2, 52.6, 109.6,
117.9, 122.1, 122.5, 125.1, 127.70, 127.73, 127.76, 128.6, 128.7, 129.2,
130.2, 133.3, 135.5, 137.3, 138.3, 139.3, 141.4, 143.3, 176.8, 203.4;
HRMS (ESI) calcd for C35H33N2O4Sþ1 (MþH)þ requires 577.2161,
found: 577.2155; enantiomeric excess was determined by HPLC
termined by HPLC with a Chiralcel AD-H column [
l
¼214 nm;
eluent: hexane/isopropanol¼70/30; flow rate: 0.70 mL/min;
tminor¼32.91 min, tmajor¼62.82 min; ee%¼96%; [
a]
20 þ147.8 (c 1.00,
D
CH2Cl2)].
with a Chiralcel IC column [
l
¼230 nm; eluent: hexane/iso-
propanol¼60/40; flow rate: 0.60 mL/min; tminor¼86.17 min,
3. 2.10. (3S, 30S)-30-Acetyl-60-(3-chlorophenyl)-1-(3, 5-
dimethylbenzyl)-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyr-
idin]-2-one (3j). A colorless solid, 46 mg, 74% yield; mp 94e95 ꢂC;
20
tmajor¼123.57 min; ee%¼99%; [
a]
þ139.9 (c 1.00, CH2Cl2)].
D
3.2.7. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-60-(p-tolyl)-10-tosyl-
IR (CH2Cl2):
852, 791, 738, 706, 685 cmꢀ1
2.01 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.48 (s, 3H, CH3), 3.07 (dd,
n
2920, 1713, 1610, 1487, 1466, 1356, 1168, 1091, 994,
20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one (3g). A color-
;
1H NMR (400 MHz, CDCl3, TMS):
less solid, 48 mg, 79% yield; mp 109e110 ꢂC; IR (CH2Cl2):
n
2921,
1713, 1609, 1488, 1466, 1356, 1167, 1106, 1091, 1021, 988, 818, 762,
745, 708, 693, 661 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
2.00 (s,
d
1H, J¼2.8, 11.6 Hz, CH), 4.40 (dd, 1H, J¼11.6, 14.0 Hz, CH2), 4.70
(dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.77 (d, 1H, J¼15.6 Hz, CH2), 4.82 (d,
1H, J¼15.6 Hz, CH2), 5.00 (s, 1H, ]CH), 6.63 (d, 1H, J¼7.6 Hz,
ArH), 6.73 (d, 1H, J¼8.0 Hz, ArH), 6.87 (s, 1H, ArH), 6.93e6.96 (m,
3H, ArH), 7.14e7.26 (m, 5H, J¼8.0 Hz, ArH), 7.36 (d, 2H, J¼7.6 Hz,
ArH), 7.63 (d, 2H, J¼7.6 Hz, ArH); 13C NMR (100 MHz, CDCl3,
d
3H, CH3), 2.24 (s, 6H, 2CH3), 2.33 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.97
(dd, 1H, J¼2.8, 11.6 Hz, CH), 4.41 (dd, 1H, J¼11.6, 14.0 Hz, CH2), 4.70
(dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.79 (s, 2H, CH2), 4.92 (s, 1H, ]CH),
6.46 (d, 1H, J¼7.6 Hz, ArH), 6.70 (d, 1H, J¼7.6 Hz, ArH), 6.86 (s, 1H,
ArH), 6.90 (t, 1H, J¼7.6 Hz, ArH), 6.95 (s, 2H, ArH), 7.05 (d, 2H,
J¼8.0 Hz, ArH), 7.14 (t, 1H, J¼7.6 Hz, ArH), 7.24 (d, 2H, J¼8.0 Hz,
ArH), 7.36 (d, 2H, J¼8.4 Hz, ArH), 7.66 (d, 2H, J¼8.4 Hz, ArH); 13C
TMS):
d 21.3, 21.6, 28.9, 44.3, 46.0, 49.3, 52.7, 109.8, 118.7, 122.2,
122.6, 125.2, 126.0, 127.5, 127.8, 128.5, 128.8, 129.1, 129.3, 129.9,
130.0, 133.7, 135.5, 136.2, 138.3, 139.2, 140.2, 143.4, 144.8, 176.8,
203.3; HRMS (ESI) calcd for C36H34ClN2O4Sþ1 (MþH)þ requires
625.1928, found: 625.1916; enantiomeric excess was determined
NMR (100 MHz, CDCl3, TMS): d 21.2, 21.3, 21.6, 28.9, 44.2, 46.2, 49.3,
52.4, 109.6, 117.2, 122.1, 122.4, 125.2, 127.6, 127.9, 128.5, 128.6, 129.2,
129.8, 130.5, 134.8, 135.6, 136.4, 138.3, 138.5, 141.4, 143.3, 144.4,
177.0, 203.5; HRMS (ESI) calcd for C37H37N2O4Sþ1 (MþH)þ requires
605.2474, found:605.2454; enantiomeric excess was determined by
by HPLC with a Chiralcel AD-H column [
flow rate:
l
¼214 nm; eluent:
hexane/isopropanol¼70/30;
0.70
mL/min;
20
tminor¼24.40 min, tmajor¼32.84 min; ee%¼96%; [
a
]
þ131.8 (c
D
HPLC with a Chiralcel AD-H column [
l¼214 nm; eluent: hexane/
1.00, CH2Cl2)].
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼45.23 min,
20
tmajor¼84.98 min; ee%¼99%; [
a]
þ135.4 (c 1.00, CH2Cl2)].
3. 2.11. (3S, 30S)-30-Acetyl-60-(4-chlorophenyl)-1-(3, 5-
dimethylbenzyl)-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyr-
idin]-2-one (3k). A colorless solid, 50 mg, 80% yield; mp 96e97 ꢂC;
D
3.2.8. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-60-(4-fluorophenyl)-
10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one (3h). A
IR (CH2Cl2):
987, 837, 727, 706, 689 cmꢀ1
2.00 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.50 (s, 3H, CH3), 2.99 (dd, 1H,
n
2920, 1712, 1609, 1488, 1466, 1356, 1167, 1090, 1014,
colorless solid, 50 mg, 82% yield; mp 104e105 ꢂC; IR (CH2Cl2):
n
;
1H NMR (400 MHz, CDCl3, TMS):
2922, 1712, 1608, 1508, 1488, 1466, 1356, 1222, 1168, 1106, 1091,
1014, 987, 843, 765, 708, 693 cmꢀ1 1H NMR (400 MHz, CDCl3,
TMS): 2.00 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.49 (s, 3H, CH3), 3.00
d
;
J¼2.8, 12.0 Hz, CH), 4.40 (dd, 1H, J¼12.0, 13.6 Hz, CH2), 4.69 (dd, 1H,
J¼2.8, 13.6 Hz, CH2), 4.79 (s, 2H, CH2), 4.96 (s, 1H, ]CH), 6.50 (d, 1H,
J¼7.6 Hz, ArH), 6.72 (d, 1H, J¼8.0 Hz, ArH), 6.86 (s, 1H, ArH),
6.90e6.95 (m, 3H, ArH), 7.15 (t, 1H, J¼8.0 Hz, ArH), 7.20 (d, 2H,
J¼8.4 Hz, ArH), 7.27 (d, 2H, J¼8.4 Hz, ArH), 7.38 (d, 2H, J¼8.0 Hz,
ArH), 7.65 (d, 2H, J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d
(dd, 1H, J¼2.8, 11.6 Hz, CH), 4.41 (dd, 1H, J¼11.6, 14.0 Hz, CH2), 4.71
(dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.79 (t, 2H, J¼16.8 Hz, CH2), 4.92 (s, 1H,
]CH), 6.51 (d, 1H, J¼7.6 Hz, ArH), 6.72 (d, 1H, J¼8.0 Hz, ArH), 6.86
(s, 1H, ArH), 6.89e6.95 (m, 5H, ArH), 7.15 (t, 1H, J¼7.6 Hz, ArH),
7.28e7.32 (m, 2H, ArH), 7.37 (d, 2H, J¼8.0 Hz, ArH), 7.64 (d, 2H,
d
21.2, 21.6, 28.8, 44.2, 46.0, 49.2, 52.3, 109.7, 118.2, 122.0, 122.5,
J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d
21.2, 21.6, 28.9,
125.1, 127.8, 127.9, 128.7, 128.9, 129.2, 129.9, 130.0, 134.4, 135.5,
136.0, 136.1, 138.3, 140.4,143.3,144.7, 176.8, 203.3; HRMS (ESI) calcd
for C36H34ClN2O4Sþ1 (MþH)þ requires 625.1928, found: 625.1910;
enantiomeric excess was determined by HPLC with a Chiralcel PC-2
44.3, 46.1, 49.3, 52.5, 109.7, 114.8 (d, J¼21.6 Hz), 117.8, 122.1, 122.5,
125.2, 127.8, 128.8, 129.3, 129.5 (d, J¼8.5 Hz), 129.9, 130.2, 133.6 (d,
J¼3.0 Hz), 135.6, 136.3, 138.3, 140.5, 143.4, 144.7, 162.9 (d,
J¼246.7 Hz), 176.9, 203.4; 19F NMR (376 MHz, CDCl3, CFCl3):
column [
l
¼230 nm; eluent: hexane/isopropanol¼70/30; flow rate:
20
d
ꢀ112.93; HRMS (ESI) calcd for C36H34FN2O4Sþ1 (MþH)þ requires
0.70 mL/min; tminor¼28.34 min, tmajor¼74.26 min; ee%¼98%; [
a]
D
609.2223, found: 609.2210; enantiomeric excess was determined
þ213.7 (c 1.00, CH2Cl2)].

2844
X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
3. 2.12. (3S, 30S)-30-Acetyl-60-(4-bromophenyl)-1-(3, 5-
dimethylbenzyl)-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyr-
idin]-2-one (3l). A colorless solid, 52 mg, 78% yield; mp 113e114 ꢂC;
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼24.38 min,
20
tmajor¼38.68 min; ee%¼96%; [
a]
þ332.0 (c 1.00, CH2Cl2)].
D
IR (CH2Cl2):
1091, 1010, 820, 712, 683, 659 cmꢀ1
TMS): 2.01 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.51 (s, 3H, CH3), 2.99
n
2921, 1713, 1677, 1610, 1488, 1466, 1357, 1168, 1106,
3.2.15. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-60-(naphthalen-1-
yl)-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3o). A colorless solid, 50 mg, 78% yield; mp 106e107 ꢂC; IR
;
1H NMR (400 MHz, CDCl3,
d
(dd, 1H, J¼2.8, 11.6 Hz, CH), 4.39 (dd, 1H, J¼11.6, 14.0 Hz, CH2), 4.69
(dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.79 (s, 2H, CH2), 4.96 (s, 1H, ]CH),
6.50 (d, 1H, J¼7.2 Hz, ArH), 6.72 (d, 1H, J¼8.0 Hz, ArH), 6.87 (s, 1H,
ArH), 6.90e6.95 (m, 3H, ArH), 7.15 (t, 1H, J¼7.2 Hz, ArH), 7.20 (d, 2H,
J¼8.4 Hz, ArH), 7.35e7.39 (m, 4H, ArH), 7.64 (d, 2H, J¼8.4 Hz, ArH);
(CH2Cl2):
1091, 1015, 803, 776, 759, 706, 690 cmꢀ1
CDCl3, TMS): 2.09 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.22 (s, 6H,
n
3060, 2922, 1713, 1609, 1488, 1466, 1355, 1185, 1168,
;
1H NMR (400 MHz,
d
2CH3), 3.44 (dd, 1H, J¼2.4, 11.2 Hz, CH), 4.65e4.71 (m, 1H,
CH2), 4.77e4.86 (m, 2H, CH2), 4.94 (dd, 1H, J¼2.4, 13.6 Hz,
CH2), 5.05 (s, 1H, ]CH), 6.71e6.74 (m, 3H, ArH), 6.84 (s, 1H,
ArH), 6.95 (s, 2H, ArH), 7.02e7.20 (m, 5H, ArH), 7.26e7.48 (m,
4H, ArH), 7.59 (d, 1H, J¼8.0 Hz, ArH), 7.66e7.34 (m, 2H, ArH);
13C NMR (100 MHz, CDCl3, TMS):
d 21.3, 21.7, 28.9, 44.3, 46.1, 49.2,
52.4, 109.8, 118.3, 122.1, 122.6, 122.7, 125.2, 127.9, 128.8, 129.2, 129.3,
129.97, 130.04, 131.0, 135.5, 136.1, 136.5, 138.3, 140.5, 143.4, 144.8,
176.8, 203.4; HRMS (ESI) calcd for C36H34BrN2O4Sþ1 (MþH)þ re-
quires 669.1423, found: 669.1405; enantiomeric excess was de-
13C NMR (100 MHz, CDCl3, TMS):
d 21.19, 21.25, 29.1, 44.3, 44.8,
49.5, 54.4, 109.6, 118.2, 122.5, 122.7, 124.7, 125.1, 125.3, 125.5,
126.3, 127.0, 127.6, 128.5, 128.7, 128.9, 129.2, 129.4, 130.6, 131.5,
132.8, 133.5, 135.60, 135.62, 138.2, 140.2, 143.0, 143.3, 176.8,
203.8; HRMS (ESI) calcd for C40H37N2O4Sþ1 (MþH)þ requires
641.2474, found: 641.2468; enantiomeric excess was de-
termined by HPLC with a Chiralcel AD-H column [
l
¼230 nm;
eluent: hexane/isopropanol¼70/30; flow rate: 0.70 mL/min;
tminor¼45.30 min, tmajor¼62.34 min; ee%¼98%; [
a]
20 þ114.8 (c 1.00,
D
CH2Cl2)].
termined by HPLC with a Chiralcel PC-2 column [
l
¼230 nm;
3.2.13. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-60-(4-nitrophenyl)-
eluent: hexane/isopropanol¼70/30; flow rate: 1.00 mL/min;
20
10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3m)
tminor¼12.51 min, tmajor¼28.87 min; ee%¼96%; [
a
]
þ265.8 (c
D
and (3R,30R)-30-acetyl-1-(3,5-dimethylbenzyl)-60-(4-nitrophenyl)-10-
1.00, CH2Cl2)].
tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one (3m0). A
colorless solid, 30 mg, 47% yield; IR (CH2Cl2):
1598, 1519, 1487, 1343, 1167, 1090, 855, 715, 683, 659 cmꢀ1; 1H NMR
(400 MHz, CDCl3, TMS): 1.99 (s, 3H, CH3), 2.23 (s, 6H, 2CH3), 2.52
n
2922, 2837, 1714,
3.2.16. (3S,30S)-30-Acetyl-60-(2,4-dichlorophenyl)-1-(3,5-
dimethylbenzyl)-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyr-
idin]-2-one (3p). A colorless solid, 58 mg, 87% yield; mp
d
(s, 3H, CH3), 2.94e2.97 (m, 1H, CH), 4.43 (dd, 1H, J¼12.0, 14.0 Hz,
CH2), 4.64 (dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.75e4.84 (m, 2H, CH2), 5.11
(s, 1H, ]CH), 6.51 (d, 1H, J¼7.6 Hz, ArH), 6.75 (d, 1H, J¼8.0 Hz, ArH),
6.87 (s, 1H, ArH), 6.91e6.96 (m, 3H, ArH), 7.16e7.20 (m, 1H, ArH),
7.43 (d, 2H, J¼8.0 Hz, ArH), 7.54 (d, 2H, J¼8.8 Hz, ArH), 7.69 (d, 2H,
J¼8.0 Hz, ArH), 8.13 (d, 2H, J¼8.8 Hz, ArH); 13C NMR (100 MHz,
106e107 ꢂC; IR (CH2Cl2):
n
2920, 1712, 1608, 1586, 1486, 1466, 1355,
1265, 1167, 1100, 989, 864, 814, 761, 735, 691, 661 cmꢀ1 1H NMR
(400 MHz, CDCl3, TMS): 1.97 (s, 3H, CH3), 2.25 (s, 6H, 2CH3), 2.47
;
d
(s, 3H, CH3), 3.01 (br, 1H, CH), 4.43 (dd, 1H, J¼11.6, 14.0 Hz, CH2),
4.62e4.65 (m, 1H, CH2), 4.74 (d, 1H, J¼15.6 Hz, CH2), 4.87 (d, 1H,
J¼15.6 Hz, CH2), 4.93 (s, 1H, ]CH), 6.72 (d, 1H, J¼8.0 Hz, ArH),
6.79e6.83 (m, 1H, ArH), 6.87 (s, 1H, ArH), 6.97 (s, 2H, ArH),
7.14e7.33 (m, 6H, ArH), 7.64 (br, 2H, ArH); 13C NMR (100 MHz,
CDCl3, TMS) :
d 21.2, 21.3, 21.66, 21.73, 28.9, 29.0, 44.3, 44.6, 45.5,
45.9, 49.3, 50.4, 50.9, 51.9, 109.88, 109.92, 119.2, 120.7, 122.1, 122.6,
123.19, 123.28, 123.31, 124.7, 125.1, 125.3, 127.87, 127.88, 128.0, 128.1,
128.5, 129.0, 129.3, 129.5, 129.6, 130.14, 130.18, 134.7, 135.0, 135.4,
135.6, 138.3, 138.4, 139.59, 139.63, 142.0, 143.4, 144.1, 144.6, 145.0,
145.2, 147.61, 147.63, 175.6, 176.4, 203.0, 204.4 (a mixture of 3m and
3m0); HRMS (ESI) calcd for C36H34N3O6Sþ1 (MþH)þ requires
636.2168, found: 636.2141; enantiomeric excess of 3m was de-
CDCl3, TMS):
d 21.2, 21.6, 28.9, 44.3, 45.2, 49.2, 109.7, 119.4, 122.3,
122.6, 125.2, 126.5, 127.6, 128.8, 129.2, 129.6, 132.2, 134.1, 135.5,
135.9, 138.2, 143.3, 176.3, 203.3; HRMS (ESI) calcd for
C
36H33Cl2N2O4Sþ1 (MþH)þ requires 659.1538, found: 659.1538;
enantiomeric excess was determined by HPLC with a Chiralcel AD-
H column [
l
¼214 nm; eluent: hexane/isopropanol¼70/30; flow
termined by HPLC with a Chiralcel PC-1 column [
l
¼230 nm; eluent:
rate: 0.70 mL/min; tminor¼30.81 min, tmajor¼80.20 min; ee%¼94%;
hexane/isopropanol¼70/30;
flow rate:
tminor¼18.86 min, tmajor¼33.60 min; ee%¼97%; [
0.70
mL/min;
[a
]
20 þ149.4 (c 1.00, CH2Cl2)].
D
a
]
20 þ82.76 (c 1.00,
D
CH2Cl2)].
3.2.17. (3S,50S)-50-Acetyl-1-(3,5-dimethylbenzyl)-20-(propan-2-
ylidene)-10-tosylspiro[indoline-3,40-piperidin]-2-one (3q). A color-
3.2.14. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-10-tosyl-60-(4-(tri-
fluoromethyl)phenyl)-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-
2-one (3n). A colorless solid, 42 mg, 64% yield; mp 100e101 ꢂC; IR
less solid, 30 mg, 54% yield; mp 91e92 ꢂC; IR (CH2Cl2):
n
2920,
1701, 1611, 1489, 1467, 1359, 1325, 1155, 1091, 1036, 959, 814, 755,
739, 674 cmꢀ1 1H NMR (400 MHz, CDCl3, TMS):
1.20 (s, 3H,
;
d
(CH2Cl2):
n
2922, 1711, 1610, 1488, 1466, 1356, 1322, 1166, 1122, 1110,
CH3), 1.86 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.27 (s, 6H, 2CH3), 2.44 (s,
3H, CH3), 3.17 (d, 1H, J¼11.6 Hz, CH2), 3.54 (dd, 1H, J¼3.2 Hz,
10.8 Hz, CH), 3.61 (d, 1H, J¼11.6 Hz, CH2), 4.01 (dd, 1H, J¼8.4,
10.8 Hz, CH2), 4.56 (dd, 1H, J¼3.2, 8.4 Hz, CH2), 4.82 (d, 1H,
J¼15.2 Hz, CH2), 4.89 (d, 1H, J¼15.2 Hz, CH2), 6.76 (d, 1H, J¼7.6 Hz,
ArH), 6.90 (m, 3H, ArH), 7.01 (t, 1H, J¼7.6 Hz, ArH), 7.18 (t, 1H,
J¼7.6 Hz, ArH), 7.35 (d, 2H, J¼8.4 Hz, ArH), 7.74 (d, 1H, J¼7.6 Hz,
ArH), 7.90 (d, 2H, J¼8.4 Hz, ArH); 13C NMR (100 MHz, CDCl3,
1066, 1017, 842, 739, 709, 698, 677, 661 cmꢀ1
;
1H NMR (400 MHz,
CDCl3, TMS): 2.00 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.49 (s, 3H, CH3),
3.04 (dd, 1H, J¼2.8, 11.6 Hz, CH), 4.42 (dd, 1H, J¼11.6, 14.0 Hz, CH2),
4.70 (dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.75e4.84 (m, 2H, CH2), 5.04 (s,
1H, ]CH), 6.58 (d, 1H, J¼7.6 Hz, ArH), 6.73 (d, 1H, J¼7.6 Hz, ArH),
6.87 (s, 1H, ArH), 6.93e6.97 (m, 3H, ArH), 7.17 (td, 1H, J¼2.4, 7.6 Hz,
ArH), 7.36 (d, 2H, J¼7.6 Hz, ArH), 7.43 (d, 2H, J¼8.4 Hz, ArH), 7.48 (d,
2H, J¼8.4 Hz, ArH), 7.63 (d, 2H, J¼8.0 Hz, ArH); 13C NMR (100 MHz,
TMS):
d 21.3, 21.6, 21.8, 21.9, 28.5, 43.5, 44.8, 46.0, 48.1, 50.9, 108.7,
CDCl3, TMS):
d
21.2, 21.5, 28.9, 44.3, 46.0, 49.3, 52.3, 109.8, 119.6,
122.7, 124.9, 126.6, 126.8, 127.6, 128.1, 129.3, 129.7, 129.8, 130.6,
135.8, 137.0, 138.4, 142.9, 143.9, 176.9, 206.6; HRMS (ESI) calcd for
122.1, 122.6, 124.7 (q, J¼3.5 Hz), 125.2, 127.9, 128.9, 129.3, 129.9,
130.0, 135.5, 135.93, 135.94, 138.3, 140.3, 141.1 (q, J¼1.1 Hz), 143.4,
C
33H37N2O4Sþ1 (MþH)þ requires 557.2474, found: 557.2467; en-
144.9, 176.6, 203.2; 19F NMR (376 MHz, CDCl3, CFCl3):
d
ꢀ62.47;
antiomeric excess was determined by HPLC with a Chiralcel AD-H
HRMS (ESI) calcd for C36H34FN2O4Sþ1 (MþH)þ requires 609.2223,
column [
l
¼214 nm; eluent: hexane/isopropanol¼70/30; flow
found: 609.2210; enantiomeric excess was determined by HPLC
rate: 0.70 mL/min; tminor¼16.97 min, tmajor¼61.33 min; ee%¼17%;
20
with a Chiralcel AD-H column [
l¼214 nm; eluent: hexane/
[a]
D
þ2.27 (c 1.00, CH2Cl2)].

X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
2845
3.2.18. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-5-fluoro-60-phenyl-
10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one (3r). A
n
2918, 1708, 1599, 1493, 1446, 1355, 1336, 1265, 1184, 1167, 1117,
1090, 1022, 988, 812, 778, 734, 709, 698, 659 cmꢀ1 1H NMR
(400 MHz, CDCl3, TMS): 2.00 (s, 3H, CH3), 2.23e2.25 (m, 9H,
;
colorless solid, 46 mg, 75% yield; mp 114e115 ꢂC; IR (CH2Cl2):
n
d
2922, 2854,1712, 1608, 1492, 1447, 1356,1337, 1264, 1167, 1089, 990,
851, 814, 781, 736, 710, 699, 659 cmꢀ1 1H NMR (400 MHz, CDCl3,
TMS): 2.09 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.51 (s, 3H, CH3), 2.85
(dd, 1H, J¼2.8, 11.6 Hz, CH), 4.40 (dd, 1H, J¼11.6, 14.0 Hz, CH2),
4.77e4.82 (m, 3H, CH2þCH2), 4.93 (s, 1H, ]CH), 5.93e5.95 (m, 1H,
ArH), 6.57e6.60 (m, 1H, ArH), 6.81 (td, 1H, J¼8.8, 2.4 Hz, ArH), 6.87
(s, 1H, ArH), 6.93 (s, 2H, ArH), 7.26e7.32 (m, 3H, ArH), 7.38e7.42 (m,
4H, ArH), 7.68 (d, 2H, J¼8.4 Hz, ArH); 13C NMR (100 MHz, CDCl3,
3CH3), 2.49 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.91 (dd, 1H, J¼2.4,
11.6 Hz, CH), 4.39e4.45 (m, 1H, CH2), 4.71e4.76 (m, 3H, CH2þCH2),
4.97 (s, 1H, ]CH), 6.24 (s, 1H, ArH), 6.58 (d, 1H, J¼8.0 Hz, ArH), 6.85
(s, 1H, ArH), 6.92e6.94 (m, 3H, ArH), 7.24e7.29 (m, 3H, ArH),
7.37e7.39 (m, 4H, ArH), 7.68 (d, 2H, J¼7.2 Hz, ArH); 13C NMR
;
d
(75 MHz, CDCl3, TMS):
d 21.0, 21.1, 21.6, 28.8, 44.1, 46.2, 49.2, 52.2,
109.3, 118.3, 122.8, 125.0, 125.2, 127.5, 127.7, 127.9, 128.5, 128.9,
129.1, 129.8, 130.2, 131.8, 135.6, 137.6, 138.1, 140.9, 141.1, 144.3, 176.8,
203.4; HRMS (ESI) calcd for C37H37N2O4Sþ1 (MþH)þ requires
605.2474, found: 605.2482; enantiomeric excess was determined
TMS):
d
21.2, 21.5, 28.7, 44.3, 46.4, 49.5, 52.1, 110.0 (d, J¼22.9 Hz),
110.2 (d, J¼6.1 Hz), 114.7 (d, J¼23.1 Hz), 117.6, 125.1, 127.7, 127.8,
127.9, 128.8, 129.3, 130.0, 132.0 (d, J¼7.7 Hz), 135.3, 136.1, 137.3,
138.3, 139.2 (d, J¼1.9 Hz), 141.8, 144.9, 159.0 (d, J¼239.8 Hz), 176.8,
by HPLC with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/
isopropanol¼70/30; flow rate: 0.70 mL/min; tminor¼25.51 min,
203.1; 19F NMR (376 MHz, CDCl3, CFCl3):
d
ꢀ102.32; HRMS (ESI)
tmajor¼46.50 min; ee% >99%; [
a
]
20 þ130.3 (c 1.00, CH2Cl2)].
D
calcd for
C
36H34FN2O4Sþ1 (MþH)þ requires 609.2223, found:
609.2202; enantiomeric excess was determined by HPLC with
3.2.22. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-6-methyl-60-phe-
nyl-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3v). A colorless solid, 50 mg, 83% yield; mp 105e106 ꢂC; IR
a
Chiralcel AD-H column
[
l
¼214 nm; eluent: hexane/iso-
propanol¼70/30; flow rate: 0.70 mL/min; tminor¼27.90 min,
20
tmajor¼44.60 min; ee%¼99%; [
a]
þ162.3 (c 1.00, CH2Cl2)].
(CH2Cl2):
1027, 987, 846, 814, 778, 710, 699, 659 cmꢀ1
CDCl3, TMS): 2.00 (s, 3H, CH3), 2.24 (s, 6H, 2CH3), 2.27 (s, 3H, CH3),
n
2921, 1713, 1617, 1495, 1447, 1356, 1226, 1167, 1120, 1091,
D
;
1H NMR (400 MHz,
3.2.19. (3S,30S)-30-Acetyl-5-chloro-1-(3,5-dimethylbenzyl)-60-phe-
nyl-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3s). A colorless solid, 48 mg, 76% yield; mp 108e109 ꢂC; IR
d
2.49 (s, 3H, CH3), 2.96 (dd, 1H, J¼2.8, 11.6 Hz, CH), 4.41 (dd, 1H,
J¼11.6, 14.0 Hz, CH2), 4.69 (dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.77 (s, 2H,
CH2), 4.95 (s,1H, ]CH), 6.38 (d, 1H, J¼7.2 Hz, ArH), 6.54 (s, 1H, ArH),
6.73 (d, 1H, J¼7.2 Hz, ArH), 6.86 (s, 1H, ArH), 6.94 (s, 2H, ArH),
7.22e7.29 (m, 3H, ArH), 7.33e7.37 (m, 4H, ArH), 7.66 (d, 2H,
(CH2Cl2):
1118, 1090, 989, 848, 813, 775, 710, 698, 658 cmꢀ1
(400 MHz, CDCl3, TMS): 2.10 (s, 3H, CH3), 2.23 (s, 6H, 2CH3), 2.53
n
2921,1712,1677,1607,1484,1446,1428,1355,1265,1166,
;
1H NMR
d
(s, 3H, CH3), 2.74 (dd, 1H, J¼2.8, 12.0 Hz, CH), 4.40 (dd, 1H, J¼12.0,
14.0 Hz, CH2), 4.76 (s, 2H, CH2), 4.78 (dd, 1H, J¼2.8, 14.0 Hz, CH2),
4.92 (s, 1H, ]CH), 6.16 (d, 1H, J¼2.4 Hz, ArH), 6.58 (d, 1H, J¼8.4 Hz,
ArH), 6.86 (s, 1H, ArH), 6.93 (s, 2H, ArH), 7.07 (dd, 1H, J¼2.4, 8.4 Hz,
ArH), 7.27e7.32 (m, 3H, ArH), 7.41e7.44 (m, 4H, ArH), 7.70 (d, 2H,
J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d 21.2, 21.6, 21.8,
28.9, 44.1, 46.1, 49.0, 52.3, 110.4, 118.2, 121.8, 123.1, 125.0, 127.3,
127.6, 127.7, 127.8, 128.5, 129.1, 129.8, 135.7, 136.3, 137.5, 138.2, 138.9,
141.2, 143.4, 144.4, 177.2, 203.6; HRMS (ESI) calcd for
C
37H37N2O4Sþ1 (MþH)þ requires 605.2474, found: 605.2471; en-
J¼8.4 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d
21.2, 21.7, 28.6,
antiomeric excess was determined by HPLC with a Chiralcel PC-2
44.3, 46.3, 49.2, 51.9, 110.6, 117.5, 122.4, 125.0, 127.6, 127.7, 127.8,
127.9,128.4,128.8,129.3,130.1,132.0,135.1, 135.9,137.5,138.4,141.8,
142.0, 145.0, 176.7, 203.0; HRMS (ESI) calcd for C36H34ClN2O4Sþ1
(MþH)þ requires 625.1928, found: 625.1924; enantiomeric excess
column
[
l
¼230 nm; eluent: hexane/isopropanol¼70/30; flow
rate: 0.70 mL/min; tminor¼25.05 min, tmajor¼51.90 min; ee%¼99%;
[a
]
20 þ119.8 (c 1.00, CH2Cl2)].
D
was determined by HPLC with a Chiralcel AD-H column [
l¼214 nm;
3.2.23. (3S,30S)-1-Methyl-60-phenyl-30-propionyl-10-tosyl-20,30-dihy-
dro-10H-spiro[indoline-3,40-pyridin]-2-one (3w). A colorless solid,
eluent: hexane/isopropanol¼70/30; flow rate: 0.70 mL/min;
tminor¼27.30 min, tmajor¼39.95 min; ee% >99%; [
a
]
20 þ164.2 (c 1.00,
32 mg, 64% yield; mp 61e62 ꢂC; IR (CH2Cl2):
n
3057, 2936, 1712,
1610, 1492, 1470, 1360, 1168, 1085, 967, 816, 754, 710, 698,
655 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS):
D
CH2Cl2)].
d
0.90 (t, 3H, J¼7.2 Hz,
3.2.20. (3S,30S)-30-Acetyl-5-bromo-1-(3,5-dimethylbenzyl)-60-phe-
nyl-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3t). A colorless solid, 52 mg, 78% yield; mp 110e111 ꢂC; IR
CH3), 2.18e2.28 (m, 1H, CH2), 2.41e2.50 (m, 4H, CH3þCH2), 3.00
(dd, 1H, J¼2.8, 11.6 Hz, CH), 3.19 (s, 3H, CH3), 4.38 (dd, 1H, J¼11.6,
14.0 Hz, CH2), 4.69 (dd, 1H, J¼2.8, 14.0 Hz, CH2), 4.91 (s, 1H, ]CH),
6.47 (d, 1H, J¼7.6 Hz, ArH), 6.82(d, 1H, J¼8.0 Hz, ArH), 6.94 (t, 1H,
J¼7.6 Hz, ArH), 7.19e7.32 (m, 6H, ArH), 7.36 (d, 2H, J¼8.0 Hz, ArH),
(CH2Cl2):
1091, 989, 846, 811, 775, 735, 709, 698, 658 cmꢀ1
(400 MHz, CDCl3, TMS): 2.10 (s, 3H, CH3), 2.23 (s, 6H, 2CH3), 2.55
n
2921,1712,1604,1481,1446,1423,1355,1337,1265,1166,
;
1H NMR
d
7.64 (d, 2H, J¼8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3, TMS):
d 7.3,
(s, 3H, CH3), 2.69 (dd, 1H, J¼2.8, 11.6 Hz, CH), 4.41 (dd, 1H, J¼11.6,
14.4 Hz, CH2), 4.76e4.81 (m, 3H, CH2þCH2), 4.92 (s, 1H, ]CH), 6.33
(d, 1H, J¼1.6 Hz, ArH), 6.54 (d, 1H, J¼8.8 Hz, ArH), 6.86 (s, 1H, ArH),
6.92 (s, 2H, ArH), 7.22 (dd, 1H, J¼2.0, 8.4 Hz, ArH), 7.29e7.34 (m, 3H,
ArH), 7.42e7.45 (m, 4H, ArH), 7.71 (d, 2H, J¼8.0 Hz, ArH); 13C NMR
21.6, 26.5, 34.3, 46.3, 49.1, 51.9, 108.5, 117.9, 122.0, 122.4, 127.6, 127.7,
127.9, 128.5,128.7,129.8,130.5,136.4,137.5, 141.4,144.1, 144.4,177.2,
206.3; HRMS (ESI) calcd for C29H29N2O4Sþ1 (MþH)þ requires
501.1848, found: 501.1839; enantiomeric excess was determined by
HPLC with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/
(100 MHz, CDCl3, TMS):
d
21.2, 21.9, 28.6, 44.3, 46.2, 49.1, 51.9, 111.1,
isopropanol¼80/20; flow rate: 0.70 mL/min; tminor¼29.81 min,
114.8, 117.5, 125.0, 125.1, 127.7, 127.8, 127.9, 128.8, 129.3, 130.2, 131.3,
132.4, 135.1, 135.9, 137.5, 138.4, 141.9, 142.5, 145.0, 176.6, 202.9;
HRMS (ESI) calcd for C36H34BrN2O4Sþ1 (MþH)þ requires 669.1423,
found: 669.1404; enantiomeric excess was determined by HPLC
tmajor¼40.92 min; ee%¼98%; [
a
]
20 þ156.9 (c 1.00, CH2Cl2)].
D
3.2.24. (3S,30S)-30-(2-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ace-
tyl)-1-methyl-60-phenyl-10-tosyl-20,30-dihydro-10H-spiro[indoline-
3,40-pyridin]-2-one (4a). A white solid, 65 mg, 67% yield; IR
with a Chiralcel AD-H column [
l
¼214 nm; eluent: hexane/iso-
propanol¼70/30; flow rate: 0.70 mL/min; tminor¼32.49 min,
(CH2Cl2):
1169, 1090, 1020, 973, 814, 754, 697 cmꢀ1
CDCl3, TMS): 2.44 (s, 1.8H, 0.6CH3), 2.50 (s, 3H, CH3), 2.54 (d, 0.6H,
n
2953, 2923, 2853, 1720, 1613, 1494, 1459, 1376, 1259,
tmajor¼46.88 min; ee% >99%; [
a]
20 þ147.9 (c 1.00, CH2Cl2)].
;
1H NMR (400 MHz,
D
d
3.2.21. (3S,30S)-30-Acetyl-1-(3,5-dimethylbenzyl)-5-methyl-60-phe-
nyl-10-tosyl-20,30-dihydro-10H-spiro[indoline-3,40-pyridin]-2-one
(3u). A colorless solid, 45 mg, 75% yield; mp 95e96 ꢂC; IR (CH2Cl2):
J¼16.8 Hz, 0.6CH2), 2.78 (d, 1H, J¼16.8 Hz, CH2), 2.88 (d, 1H,
J¼16.8 Hz, CH2), 3.00e3.08 (m, 5.2H, CH3þCHþ0.6CHþ0.6CH2),
3.14e3.16 (m, 6.6H, CH3þ0.6CH3þ0.6CH3), 3.95 (s, 1H, OH),

2846
X.-N. Zhang et al. / Tetrahedron 70 (2014) 2838e2846
Soc. Rev. 2012, 41, 7247e7290; (c) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112,
6104e6155 For the original papers, see: (d) Ramachary, D. B.; Venkaiah, C.;
Krishna, P. M. Org. Lett. 2013, 15, 4714e4717; (e) Mao, H.; Lin, A.; Tang, Y.; Shi, Y.;
Hu, H.; Cheng, Y.; Zhu, C. Org. Lett. 2013, 15, 4062e4065; (f) Zhu, G.; Sun, W.;
Wu, C.; Li, G.; Hong, L.; Wang, R. Org. Lett. 2013, 15, 4988e4991; (g) Tessier, J. D.;
O’Bryan, E. A.; Schroeder, T. B. H.; Cohen, D. T.; Scheidt, K. A. Angew. Chem. 2012,
124, 5047e5051 Angew. Chem., Int. Ed. 2012, 51, 4963e4967.; (h) Jiang, X.; Cao,
Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am. Chem. Soc. 2010, 132, 15328e15333.
4. (a) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003e3025; (b) Zhou, F.; Liu, Y.;
Zhou, J. Adv. Synth. Catal. 2010, 352, 1381e1407; (c) Trost, B. M.; Cramer, N.;
Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396e12397; (d) Chen, X.; Wei, Q.;
Luo, S.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819e13825; (e) Wei,
Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008e1011; (f) Dounay, A. B.; Overman, L. E.
Chem. Rev. 2003, 103, 2945e2964.
4.29e4.37 (m, 2.2H, CH2þ0.6CH2þ0.6OH), 4.44e4.54 (m, 1.6H,
CH2þ0.6CH2), 4.89 (s, 1H, ]CH), 4.91 (s, 0.6H, 0.6CH]), 6.49e6.54
(m, 1.6H, ArHþ0.6ArH), 6.68 (d, 0.6H, J¼7.6 Hz, 0.6ArH), 6.76 (d, 1H,
J¼7.6 Hz, ArH), 6.80e6.93 (m, 4.8H, 3ArHþ1.8ArH), 6.96e7.01 (m,
2.6H, 2ArHþ0.6ArH), 7.18e7.36 (m, 14.4H, 9ArHþ5.4ArH), 7.53 (d,
1.2H, J¼8.4H, 1.2ArH), 7.59 (d, 2H, J¼8.4 Hz, ArH); 13C NMR
(100 MHz, CDCl3, TMS):
d 21.58, 21.62, 26.27, 26.31, 26.4, 26.5, 45.1,
45.3, 46.6, 47.8, 49.0, 49.2, 52.1, 53.2, 73.8, 74.2, 108.58, 108.59,
108.61, 108.64, 117.1, 117.2, 122.36, 122.39, 122.6, 122.8, 123.0, 123.1,
123.6, 123.7, 127.51, 127.56, 127.68, 127.70, 127.76, 127.86, 128.52,
128.54, 128.9, 129.0, 129.3, 129.5, 129.68, 129.75, 129.88, 129.94,
136.1, 137.39, 137.43, 141.65, 141.72, 143.2, 143.4, 143.7, 144.0, 144.5,
5. For recent important reviews, see: (a) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K.
Org. Biomol. Chem. 2012, 10, 5165e5181.
144.5, 175.2, 175.6, 176.0, 204.9, 206.2; HRMS (ESI) calcd for
6. For important reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34,
535e544; (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035e1050; (c) Marinetti, A.; Voituriez, A. Synlett 2010, 174e194.
7. For reviews, see: (a) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985e1990;
(b) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biji, A. T. Acc. Chem. Res.
2006, 39, 520e530; (c) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37,
1140e1152.
8. (a) Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marinetti, A. Chem.dEur. J.
2010, 16, 12541e12544; (b) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem. Soc.
2011, 133, 4672e4675; (c) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem. 2011,
123, 7983e7987 Angew. Chem., Int. Ed. 2011, 50, 7837e7841; (d) Zhong, F.; Han,
X.; Wang, Y.; Lu, Y. Chem. Sci. 2012, 3, 1231e1234.
9. (a) Shi, Z.; Tong, Q.; Leong, W. W. Y.; Zhong, G. Chem.dEur. J. 2012, 18,
9802e9806; (b) Shi, Z.; Yu, P.; Loh, T.-P.; Zhong, G. Angew. Chem. 2012, 124,
7945e7949 Angew. Chem., Int. Ed. 2012, 51, 7825e7829; (c) Jin, Z.; Yang, R.; Du,
Y.; Tiwari, B.; Ganguly, R.; Chi, Y. R. Org. Lett. 2012, 14, 3226e3229.
10. (a) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005e1018; (b) Shi, M.; Chen, L.-H.
Chem. Commun. 2003, 1310e1311; (c) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem.
Soc. 2005, 127, 3790e3800; (d) Zhang, X.-N.; Deng, H.-P.; Huang, L.; Wei, Y.; Shi,
M. Chem. Commun. 2012, 8664e8666; (e) Zhang, X.-N.; Shi, M. ACS Catal. 2013,
3, 507e512; (f) Yang, Y.-L.; Peng, C.-K.; Shi, M. Org. Biomol. Chem. 2011, 9,
3349e3358; (g) Deng, H.-P.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2011, 1956e1960;
(h) Deng, H.-P.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2012, 183e187; (i) Deng, H.-P.;
Wei, Y.; Shi, M. Adv. Synth. Catal. 2012, 354, 783e789; (j) Yang, Y.-L.; Zhang, Z.;
Zhang, X.-N.; Wang, D.; Wei, Y.; Shi, M. Chem. Commun. 2013, http://dx.doi.org/
10.1039/C3CC46470A
20
C
37H34N3O6Sþ1 (MþH)þ requires 648.2168, found: 648.2174; [
a]
D
þ148.3 (c 1.00, CH2Cl2).
3.2.25. (3S,30S)-30-Acetyl-1-methyl-60-phenyl-30,50-dihydro-20H-
spiro[indoline-3,40-pyridin]-2-one (5a). A colorless solid, 22 mg, 66%
yield;mp133e134 ꢂC;IR(CH2Cl2):
n
3057, 2927,1703,1611,1494,1471,
1421, 1349, 1262, 1172, 1091, 1041, 802, 753, 733, 693 cmꢀ1; 1H NMR
(400 MHz, CDCl3, TMS): 2.01 (s, 3H, CH3), 2.78e2.83 (m, 1H, CH2),
d
2.91 (dd,1H, J¼18.0,1.6Hz, CH2), 3.21 (s, 3H,CH3), 3.34(dd,1H, J¼10.8,
7.6 Hz, CH), 4.39 (dd,1H, J¼17.6, 5.2 Hz, CH2), 4.46e4.54 (m,1H, CH2),
6.84(d,1H, J¼8.0 Hz, ArH), 7.05 (t,1H, J¼7.6Hz, ArH), 7.10e7.11 (m, 1H,
ArH), 7.26e7.39 (m, 4H, ArH), 7.73e7.76 (m, 2H, ArH); 13C NMR
(100 MHz, CDCl3, TMS): d 26.1, 30.3, 35.1, 44.5, 48.5, 52.3,108.2,121.4,
122.4, 126.0, 128.2, 128.6, 129.9, 131.6, 138.8, 143.8, 162.1, 177.6, 206.7;
HRMS (ESI) calcd for C21H21N2Oþ2 1 (MþH)þ requires 333.1603, found:
333.1599; enantiomeric excess was determined by HPLC with
a
Chiralpak AD-H column;
l
¼214 nm; eluent: hexane/iso-
propanol¼70/30; flow rate: 0.5 mL/min; tminor¼27.55 min,
tmajor¼36.72 min; ee%¼98%; [
a
]
20 þ185.8 (c 1.00, CH2Cl2).
D
11. For selected references of chiral phosphines as organocatalysts, see: (a) Matsui,
K.; Takizawa, S.; Sasai, H. Synlett 2006, 761e765; (b) Cowen, B. J.; Miller, S. J. J.
Am. Chem. Soc. 2007, 129, 10988e10989; (c) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J.
Am. Chem. Soc. 2011, 133, 1726e1729; (d) Fang, Y.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 5660e5661; (e) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org.
Lett. 2009, 11, 1927e1930; (f) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang,
X. J. Am. Chem. Soc. 1997, 119, 3836e3837; (g) Voituriez, A.; Panossian, A.;
Acknowledgements
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), the National Basic Research Program of
China (973)-2010CB833302, and the National Natural Science
Foundation of China for financial support (21072206, 21102166,
20472096, 21372241, 21302203, 20672127, 21121062 and
20732008).
ꢀ
Fleury-Bregeot, N.; Retailleau, P.; Marinetti, A. J. Am. Chem. Soc. 2008, 130,
14030e14031; (h) Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H. Angew. Chem.
2010, 122, 9919e9923 Angew. Chem., Int. Ed. 2010, 49, 9725e9729; (i) Steurer,
M.; Jensen, K. L.; Worgull, D.; Jøgensen, K. A. Chem.dEur. J. 2012, 18, 76e79; (j)
Fujiwara, Y.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 12293e12297; (k) Xiao, H.;
Chai, Z.; Zheng, C.; Yang, Y.; Liu, W.; Zhang, J.; Zhao, G. Angew. Chem. 2010, 122,
4569e4572 Angew. Chem., Int. Ed. 2010, 49, 4467e4470; (l) Zhong, F.; Luo, J.;
Chen, G.-Y.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2012, 134, 10222e10227; (m) Zhong,
F.; Chen, G.-Y.; Han, X.; Yao, W.; Lu, Y. Org. Lett. 2012, 14, 3764e3767; (n) Zhao,
Q.; Han, X.; Wei, Y.; Shi, M.; Lu, Y. Chem. Commun. 2012, 970e972; (o) Han, X.;
Zhong, F.; Wang, Y.; Lu, Y. Angew. Chem. 2012, 124, 791e794 Angew. Chem., Int.
Ed. 2012, 51, 767e770.
Supplementary data
Spectroscopic data and chiral HPLC traces of the compounds
shown in Tables 1 and 2 and Schemes 1 and 2, the detailed de-
scriptions of experimental procedures for the preparation of imine
substrates and the crystal structures of 1i (929404), 1l (CCDC
917363) and 3l (CCDC 918762). This material is available free of
charge via the Internet at the website. Supplementary data related
to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.02.052
12. Zhang, X.-N.; Cheng, G.-Q.; Dong, X.; Wei, Y.; Shi, M. Adv. Synth. Catal. 2013, 355,
3351e3357.
13. Hibino, S.; Choshi, T. Nat. Prod. Rep. 2001, 18, 66e87.
14. For reviews of the Rauhut-eCurrier reaction, see: (a) Aroyan, C. E.; Dermenci,
A.; Miller, S. J. Tetrahedron 2009, 65, 4069e4084 For the intramolecular Rauhut-
Currier reaction, see: (b) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129,
256e257; (c) Aroyan, C. E.; Dermenci, A.; Miller, S. J. J. Org. Chem. 2010, 75,
ꢀ
ꢀ
5784e5796; (d) Marques-Lopez, E.; Herrera, R. P.; Marks, T.; Jacobs, W. C.;
Kǒnning, D.; Figueiredo, R. M.; Christmann, M. Org. Lett. 2009, 11, 4116e4119;
(e) Wilson, J. E.; Sun, J.; Fu, G. C. Angew. Chem. 2010, 122, 165e167 Angew. Chem.,
Int. Ed. 2010, 49, 161e163; (f) Wang, X.-F.; Peng, L.; An, J.; Li, C.; Yang, Q.-Q.; Lu,
L.-Q.; Gu, F.-L.; Xiao, W.-J. Chem.dEur. J. 2011, 17, 6484e6491; (g) Gong, J.-J.; Li,
T.-Z.; Pan, K.; Wu, X.-Y. Chem. Commun. 2011, 1491e1493; (h) Zhang, X.-N.; Shi,
M. Eur. J. Org. Chem. 2012, 6271e6279; (i) Takizawa, S.; Nguyen, T. M.; Gross-
mann, A.; Enders, D.; Sasai, H. Angew. Chem. 2012, 124, 5519e5522 Angew.
Chem., Int. Ed. 2012, 51, 5423e5426; (j) Zhang, D.-H.; Shi, M. ChemistryOpen
2012, 1, 215e220; (k) Yuan, W.; Wei, Y.; Shi, M. ChemistryOpen 2013, 2, 63e68.
15. For the intermolecular RauhuteCurrier reaction, see: (a) Zhong, C.; Chen, Y.;
Petersen, J. L.; Akhmedov, N. G.; Shi, X. Angew. Chem. 2009, 121, 1305e1308
Angew. Chem., Int. Ed. 2009, 48, 1279e1282; (b) Zhao, Q.-Y.; Pei, C.-K.; Guan, X.-
Y.; Shi, M. Adv. Synth. Catal. 2011, 353, 1973e1979.
References and notes
1. (a) Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.; EI-Bady, S. M. Bioorg. Med.
Chem. 2004, 12, 2483e2488; (b) Marti, C.; Carreia, E. M. Eur. J. Org. Chem. 2003,
2209e2219; (c) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122,
5666e5667.
2. (a) Kumari, G.; Nutan; Modi, M.; Gupta, S. K.; Singh, R. K. Eur. J. Med. Chem. 2011,
46, 1181e1188; (b) Lo, M. M.-C.; Newmann, C. S.; Nagayams, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2005, 127, 10130e10131; (c) Vintonyak, V. V.;
Warburg, K.; Kruse, H.; Grimme, S.; Hubel, K.; Rauth, D.; Waldmann, H. Angew.
Chem. 2010, 122, 6038e6041 Angew. Chem., Int. Ed. 2010, 49, 5902e5905.
3. For reviews on spirooxindole synthesis, see: (a) Honga, L.; Wang, R. Adv. Synth.
Catal. 2013, 355, 1023e1052; (b) Dalpozzo, R.; Bartolib, G.; Bencivenni, G. Chem.