Protecting-group directed stereospecific organocatalytic [3+2] cycloadditions: A facile access to chiral spirocyclic oxindoles

Article abstract of DOI:10.3998/ark.5550190.p008.401

An efficient organocatalytic [3+2] cycloaddition between isocyanides and methyleneindolinones, with simultaneous formation of two quaternary stereocenters, for the rapid construction of dihydrospiro[pyrrolidin-3,3'- oxindole] derivatives with high enantiopurity and structural diversity was developed. Furthermore, different protecting group on the nitrogen atom of methyleneindolenones gave rise to a different major diastereoisomer, suggesting a new avenue of great importance to medicinal chemistry and diversity-oriented synthesis. ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.p008.401

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Protecting-group directed stereospecific organocatalytic [3+2]
cycloadditions: a facile access to chiral spirocyclic oxindoles
Bin Tan,a,b Xuan Zhang,c and Guofu Zhong*,a
a College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University,
16 Xuelin St., Hangzhou, ZheJiang 310 036, P. R. China
b Department of Chemistry, South University of Science and Technology of China,
Tangchang Rd., Shenzhen, Guandong 518 055, P. R. China
c Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637 371, Singapore
E-mail: zgf@hznu.edu.cn
Dedicated to Professor Pierre Vogel on the occasion of his 70th birthday
Abstract
An efficient organocatalytic [3+2] cycloaddition between isocyanides and methyleneindolinones,
with simultaneous formation of two quaternary stereocenters, for the rapid construction of
dihydrospiro[pyrrolidin-3,3′-oxindole] derivatives with high enantiopurity and structural
diversity was developed. Furthermore, different protecting group on the nitrogen atom of
methyleneindolenones gave rise to a different major diastereoisomer, suggesting a new avenue of
great importance to medicinal chemistry and diversity-oriented synthesis.
Keywords: Asymmetric catalysis, oxindoles, spirocyclic, organocatalysis, protecting group
Introduction
The spiro[pyrrolidin-3,3′-oxindole] skeleton is commonly presented in a large number of natural
products1-3 as well as medicinally relevant compounds4-6 (Figure 1) and associated with
significant biological activities. For instance, the Spirotryprostain B, isolated from the
fermentation broth of Aspergillus fumigatus, has been proved to render complete inhibition of
the G2/M progression in mammalian tsFT210 cells.7 In light of promising bioactivities, the
therapeutic potential of this attractive heterocyclic spiro motifs has led to a demand for efficient
construction of spiro[pyrrolidin-3,3′-oxindole] ring system with high enantioselectivity.
Page 124
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Figure 1. Some examples of natural occurring and biologically active spirocyclic oxindoles.
Over the past several years, intensive effort has been put into the asymmetric construction of
this type of spirocyclic oxindole skeletons. However, resulting from the spiro structure, only a
few transformations have achieved the goal.8-21 The challenges associated with the
stereocontrolled construction of spirocyclic oxindole core arise from introducing quaternary
carbon stereocenter at C-3 of oxindole,22,23 which is highly sterically congested. As a result, the
direct catalytic enantioselective synthesis of the spirocyclic oxindole structure with two
quaternary carbon chiral centers24,25 remains a daunting challenge.
Page 125
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Figure 2. Structures of cinchona alkaloid derived organocatalysts.
Cinchona alkaloids26-37 and their derivatives (Figure 2) have proven to be powerful
organocatalysts for various organocatalytic38-42 asymmetric C-C bond formations. Recently,
isocyanide has been reported as an efficient nucleophile,43-46 as the α-hydrogen atom is
sufficiently acidic to be deprotonated by cinchona alkaloids. Inspired by this discovery, it is
envisioned that the [3+2] cycloaddition of isocyanide and methyleneindolinone may be promoted
by bifunctional cinchona alkaloid catalysts, leading to a direct stereoselective access to
dihydrospirocyclic oxindoles, which may be easily transformed into the spiro[pyrrolidin-3,3′-
oxindole] derivatives (Scheme 1).
CO2Et
Ph
R
NH
O
O
R
organocatalyst
[3+2] cycloaddition
PG = protecting group
N
Ph
OEt
N
O
NC
O
N
N
H
PG
PG
spiro[pyrrodilin-3,3'-oxindole]
skeleton
Scheme 1. Proposed strategy for construction of spiro[pyrrolidin-3,3′-oxindole] skeletons by
[3+2] cycloaddition between isocyanides and methyleneindolinones.
In this communication, the discovery of the first asymmetric organocatalytic [3+2]
cycloaddition between isocyanide and methyleneindolinone with simultaneously formation of
two quaternary and one tertiary stereocenters is reported for the rapid construction of
Page 126
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
dihydrospiro[pyrrolidin-3,3′-oxindole] derivatives with high enantiopurity and structural
diversity. Furthermore, different protecting group gave rise to different major diastereoisomer,
which suggested a new avenue of great importance to medicinal chemistry and diversity-oriented
synthesis.
Results and Discussion
The initial optimization began with the addition of isocyanide 1a (1.5 equiv) to
methyleneindolinone 2a in CH2Cl2 in the presence of commercially available quinine (catalyst I,
10 mol%) at room temperature. Although the reaction proceeded smoothly, the major product
was separated from a 1.1 to 1 mixture of diastereoisomers in 43% yield with a poor
enantioselectivity (32% ee, Table 1, entry 1). Several other cinchona alkaloids were tested
(catalysts II and III) under the same condition, however, the yield and selectivity were generally
not good (Table 1, entries 2 and 3). Notably, a significant improvement in both diastereo- and
enantioselectivity was observed when cinchona alkaloids containing thiourea scaffolds were
screened (Table 1, entries 4-7). The reactions fully completed within 2 hours and the highest ee
was achieved using catalyst VI, accomplished with good yield (76%) and catalyst VII produced
the opposite enantiomer with comparable ee value. A subsequent solvent screening revealed that
nonpolar solvents are beneficial to this type of reaction, as slight increase in enantioselectivity
and yield was observed in toluene (Table 1, entry 8). There was somewhat drop in ee when only
1.0 equiv of isocyanide 1a was used (Table 1, entry 10). Decreasing the reaction temperature
prolonged the reaction time with no improvement in either enantioselectivity or yield (Table 1,
entry 11). Finally, 5 mol% catalyst loading was found to be better for obtaining high yield and
excellent enantioselectivity (Table 1, entries 12 and 13).
With the optimized condition in hand, the scope of Boc-protected methyleneindolinones was
investigated (Table 2). The presence of both electron withdrawing group and donating group at
the indolinone moiety was all tolerated to afford more than 99% ee (Table 2, entries 1-5).
Methyleneindolinone derivatives bearing various substituents at the C-C double bond also
participated in the direct [3+2] cycloaddition reactions. Excellent enantioselectivity in up
to >99% ee was generally obtained with ester substituents on the C-C double bond (Table 2,
entries 6 and 7). It was noteworthy that a slight drop in ee (only 98%) with prolonged reaction
time was observed as the ester substituents were replaced by ketones (Table 2, entries 8-10). The
absolute configuration of Boc-protected product 3c was determined by X-ray crystallography
(Figure 3).
Page 127
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Table 1. Catalyst screening and optimization of cycloaddition reaction conditionsa
Entry
1
Catalyst
I
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
Et2O
Time (h) Yield (%) b
dr c
ee (%) d
32
6
5
5
2
2
2
2
2
4
4
5
2
4
43
45
61
67
76
76
74
78
63
71
78
80
75
1.1:1
1.2:1
2.0:1
3.2:1
4.1:1
4.2:1
4.0:1
4.5:1
3.8:1
5.0:1
5.6:1
5.5:1
5.2:1
2
II
49
3
III
IV
V
89
4
95
5
96
6
VI
VII
VI
VI
VI
VI
VI
VI
97
7
97
8
>99
98
9
10 e
11 f
12 g
13 h
toluene
toluene
97
32
toluene
toluene
>99
89
aAll reactions were carried out by using isocyanide 1a (0.15 mmol, 1.5 equiv) and
methyleneindolinone 2a (0.1 mmol, 1.0 equiv) with 10 mol% of catalyst at 23 C. bIsolated yield
c
1
(major isomer). dr determined by crude H-NMR; the relative configuration of the minor
diastereoisomer corresponds to that of compound 5a (see Table 3). dee was determined by chiral
HPLC. eOnly 1.0 equivalent 1a was used. f The reaction was conducted at 0 C. g5 mol% catalyst
was used. h Catalyst loading was 2 mol%.
Page 128
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Figure 3. X-ray crystallography of Boc-protected product 3c.
In the course of cycloaddition between isocyanide and Boc-protected methyleneindolinones,
besides the isolated major isomer, some minor compound was also observed in small amount.
Since the spiro[indoline-3,3′-pyrrolidine] core is of promising biological properties, there is a
high possibility that the minor stereoisomers process unique bioactivities. Therefore, it is a very
great importance for “diversity-oriented synthesis”,47 if the minor isomers could be formed as
major products.
Based on the previous reports48 and our comprehension of this cycloaddition reaction, we
anticipated that changing the electronic and steric properties of the methyleneindolinones by
modification of the protecting group on nitrogen atom might be a promising approach to affect
the diastereoselectivity. Remarkably, a new diastereoisomer49 was obtained as major product by
simply replacing the protecting Boc-group with benzyl group. Several methyleneindolinones
were selected for investigation of the generality of this approach (Table 3). Good yields and
excellent enantioselectivities were obtained with methyleneindolinones bearing various
substituents on the indolinone moiety and C-C double bond. Compared with the Boc-protected
substrates, the reaction with the Bn-protecting group is generally slower and needs double
catalyst loading (10 mol%).
Although the electronic and steric properties of the substrates pay a crucial role to the
stereoselectivity of cycloaddition reaction, from the results of this specific reaction, the steric
hindrance of protecting group is the determinant factor for high diastereoselectivity. For further
understanding the inherent insight, we obtained the structure of a Bn-protected substrate by X-
ray crystallography (see the Supporting material). As one face may be blocked by the presence of
protecting group, leaving one site open for the cycloaddition. Thus, a catalytic activation mode
of the cycloaddtion reactions was proposed (Figure 4).
Page 129
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Table 2. Boc-protected substrates scope of the cycloaddition reactionsa
Entry
R1
OEt
R2
H
3
Time (h) Yield (%) b
dr c
ee (%) d
>99
>99
>99
>99
>99
>99
>99
>99
97
1
2
3a
3b
3c
3d
3e
3f
2
2
2
2
2
2
2
3
3
3
80
75
71
63
72
76
68
64
42
61
5.5:1
5.0:1
5.2:1
4.8:1
5.0:1
5.6:1
4.7:1
4.0:1
2.6:1
4.0:1
OEt
F
3
OEt
Cl
Br
Me
H
4
OEt
5
OEt
6
OMe
OBn
Me
7
H
3g
3h
3i
8
H
9
Ph
H
10
p-Br-C6H4
H
3J
98
a
All reactions were carried out by using isocyanide 1a (0.15 mmol, 1.5 equiv) and
b
methyleneindolinone 2a-2J (0.1 mmol, 1 equiv) with 5 mol% of catalyst VI at 23 C. Isolated
yield (major isomer). c dr determined by crude 1H-NMR. d ee was determined by chiral HPLC.
Further exploration of substrate scope was focused on the variation of isocyanides. Two more the
methyl and benzyl isocyano-esters (1b and 1c) were tested as typical examples (Scheme 2).
Gratifyingly, both reactions proceeded smoothly in high yield and enantioselectivity, further
illustrating the validity and generality of this direct asymmetric cycloaddition.
Scheme 2. Reactions with various isocyanides.
Page 130
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
Table 3. Scope of the [3+2] cycloaddition with Bn-protected substratesa
Entry
R3
OEt
OEt
OEt
OEt
Ph
R4
H
5
Time (h) b Yield (%) b
ee (%) c
98
1
2
3
4
5
5a
5b
5c
5d
5e
2
2
2
2
3
81
67
73
75
63
F
99
Cl
Br
Cl
97
98
>99
aAll reactions were carried out by using isocyanide 1a (0.15 mmol, 1.5 equiv) and
methyleneindolinone 4a-4e (0.1 mmol, 1 equiv) with 10 mol% of catalyst VI at 23 C. bIsolated
1
yield. (Crude H-NMR displayed only one major isomer. However, the product is not very
c
stable, which decreased the isolated yield.) ee was determined by chiral HPLC.
CF3
R'
N
Chiral
Scaffold
S
R''
F3C
N
H
N
H
H
O
O
N
EtO
R
N
R
C
Figure 4. Proposed activation mode of the catalyst and substrates.
Conclusions
An asymmetric organocatalytic [3+2] cycloaddition of isocyanide and methyleneindolinone has
been developed in good yield and excellent enantioselectivity, tolerating a broad range of
substrates. The approach was associated with the formation of two quaternary and one tertiary
carbon stereogenic centers, providing a highly stereoselective solution to the complex
spiro[pyrrolilin-3,3′-oxindole] ring skeleton. Remarkably, two different major diastereoisomers
Page 131
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
can be selectively achieved by choosing different protecting groups on the nitrogen atom of
methyleneindolinones. The success of this strategy opens up new perspectives in the construction
of complex spiro[pyrrolidin-3,3′-oxindole] structure for a rapid access to biologically and
pharmaceutically active candidates.
Experimental Section
General. Analytical thin layer chromatography (TLC) was performed using Merck 60 F254
precoated silica gel plate (0.2 mm thickness). Subsequent to elution, plates were visualized using
UV radiation (254 nm) on Spectroline Model ENF-24061/F at 254 nm. Further visualization
was possible by staining with basic solution of potassium permanganate or acidic solution of
ceric molybdate. Flash chromatography was performed using Merck silica gel 60 with freshly
distilled solvents. Columns were typically packed as slurry and equilibrated with the appropriate
solvent system prior to use.
Proton nuclear magnetic resonance spectra (1H NMR) were recorded on Bruker AMX 400
1
spectrophotometer (CDCl3 as solvent). Chemical shifts for H NMR spectra are reported as δ in
units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of
chloroform-d (δ 7.26, singlet). Multiplicities were given as: s (singlet), d (doublet), t (triplet), dd
(double of doublet) or m (multiplets). The number of protons (n) for a given resonance is
indicated by nH. Coupling constants are reported as a J value in Hz. Carbon nuclear magnetic
resonance spectra (13C NMR) are reported as δ in units of parts per million (ppm) downfield
from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.0, triplet).
Enantioselectivities were determined by High performance liquid chromatography (HPLC)
analysis employing a Daicel Chiralpak AD-H or OD-H. Optical rotations were measured in
CH2Cl2 on a Schmidt + Haensdch polarimeter (Polartronic MH8) with a 1.0 mL cell (c given in
g/100 mL). Absolute configuration of the products was determined by X-ray.
High resolution mass spectrometry (HRMS) was recorded on Finnigan MAT 95×P spectrometer.
General experimental procedure for the construction of spirocyclic oxindoles with
organocatalytic [3+2] cycloaddition reactions (3a-3J). To a solution of methyleneindolinone
(0.1 mmol, 1 equiv), and isocyanide (0.15 mmol, 1.5 equiv) in toluene (0.2 mL) was added
catalyst VI (0.005 mmol, 0.05 equiv). The resulting mixture was stirred at room temperature (23
°C). After the reaction completed, the mixture was quenched with water (5 mL) and extracted
with ethyl acetate (2 x 5 mL). The combined organic layer was washed with brine and dried over
Na2SO4. The solvent was then removed under reduced pressure. The product was afforded by
silica gel flash chromatography using gradient elution (EtOAc/Hexane = 1:10 to 1:6).
Page 132
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
1-tert-Butyl
4′,5′-diethyl
(3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro[indoline-3,3′-pyrrole]-1,4′,5′-tricarboxylate
(3a).1H-
NMR (400 MHz, CDCl3) δ 7.93 (d, J 8.0 Hz, 1H), 7.78 (d, J 8.0 Hz, 1H),
7.57 (d, J 7.2 Hz, 1H), 7.41-7.26 (m, 5H), 7.20 (t, J 7.6 Hz, 1H), 4.35-4.22
(m, 2H), 4.18 (s, 1H), 3.88-3.77 (m, 2H), 1.62 (s, 9H), 1.26 (t, J 6.8 Hz,
3H), 0.75 (t, J 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 173.21,
170.73, 168.06, 161.85, 148.79, 141.91, 139.87, 129.71, 128.12, 127.68,
126.83, 126.58, 125.00, 123.97, 114.90, 87.89, 85.08, 70.27, 62.69, 62.50,
61.15, 28.02, 13.90, 13.36. HPLC: Chiralpak AD-H (hexane/i-PrOH = 92/8, flow rate 1 mL/min,
21
λ = 210 nm), tR (major) = 6.7 min, tR (minor) = 9.8 min; >99% ee. [α]D = -9.7 (c = 1.0,
CH2Cl2). HRMS (ESI) calcd for C28H31N2O7 (M+H)+, m/z 507.2131, found 507.2135.
1-tert-Butyl 4′,5′-diethyl 5-fluoro (3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-
CO2Et
Ph
dihydrospiro [indoline- 3,3′-pyrrole]-1,4′,5′-tricarboxylate (3b).1H-
N
EtO2C
NMR (400 MHz, CDCl3) δ 7.96 (dd, J 4.4, 9.2 Hz, 1H), 7.67 (dd, J 2.8,
F
8.4 Hz, 1H), 7.58 (d, J 7.2 Hz, 2H), 7.35 (m, 4H), 7.12 (m, 1H), 4.38-4.27
O
N
Boc
(m, 2H), 4.19 (s, 1H), 3.98-3.84 (m, 2H), 1.63 (s, 9H), 1.30 (t, J 7.2 Hz,
3H), 0.84 (t, J 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 172.86,
3b
170.58, 167.83, 161.41, 161.28, 158.85, 148.73, 141.62, 135.86, 128.16,
Chemical Formula:
C28H29FN2O7
Exact Mass: 524.1959
127.77, 126.80, 125.90, 125.81, 116.32, 116.19, 116.09, 114.46, 114.20,
88.07, 85.30, 70.22, 62.70, 62.65, 61.31, 28.00, 13.90, 13.44. HPLC:
Chiralpak OD-H (hexane/i-PrOH = 97/3, flow rate 1 mL/min, λ = 210
21
nm), tR (minor) = 7.4 min, tR (major) = 9.1 min; >99% ee. [α]D = -16.4 (c = 1.0, CH2Cl2).
HRMS (ESI) calcd for C28H30FN2O7 (M+H)+, m/z 525.2037, found 525.2034.
1-tert-Butyl 4′,5′-diethyl 5-chloro (3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro [indoline- 3,3′-pyrrole]-1,4′,5′-tricarboxylate (3c). H-
1
CO2Et
N
Ph
EtO2C
NMR (400 MHz, CDCl3) δ 7.93 (d, J 8.8 Hz, 1H), 7.84 (d, J 2.0 Hz, 1H),
7.59 (d, J 7.2 Hz, 2H), 7.41-7.28 (m, 5H), 4.39-4.29 (m, 2H), 4.18 (s,
1H), 4.01-3.96 (m, 1H), 3.88-3.84 (m, 1H), 1.63 (s, 9H), 1.32 (t, J 7.2 Hz,
3H), 0.85 (t, J 7.1 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 172.57,
170.32, 167.75, 161.30, 148.60, 141.66, 138.38, 130.53, 129.68, 128.17,
127.79, 126.78, 126.74, 125.80, 116.15, 88.10, 85.48, 69.98, 62.69,
62.68, 61.35, 27.99, 13.96, 13.46. HPLC: Chiralpak AD-H (hexane/i-
Cl
O
N
Boc
3c
Chemical Formula:
C28H29ClN2O7
Exact Mass: 540.1663
PrOH = 95/5, flow rate 1 mL/min, λ = 210 nm), tR (minor) = 9.1 min, tR
21
(major) = 11.6 min; >99% ee. [α]D = 39.0 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for
C28H30ClN2O7 (M+H)+, m/z 541.1742, found 541.1745.
Page 133
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
1-tert-Butyl 4′,5′-diethyl 5-bromo (3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro[indoline -3,3′-pyrrole]-1,4′,5′-tricarboxylate (3d). 1H-
NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88 (d, J 8.8 Hz, 1H), 7.59-7.54
(m, 3H), 7.39-7.28 (m, 4H), 4.41-4.28 (m, 2H), 4.17 (s, 1H), 4.03-3.95
(m, 1H), 3.90-3.82 (m, 1H), 1.63 (s, 9H), 1.33 (t, J 7.2 Hz, 3H), 0.85 (t, J
7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 172.44, 170.24, 167.73,
161.29, 148.58, 141.66, 138.89, 132.62, 129.51, 128.18, 127.80, 126.78,
126.12, 117.99, 116.55, 88.11, 85.52, 69.88, 62.70, 62.69, 61.37, 27.99,
14.01, 13.48. HPLC: Chiralpak AD-H (hexane/i-PrOH = 97/3, flow rate 1
mL/min, λ = 210 nm), tR (minor) = 15.0 min, tR (major) = 21.0 min;
CO Et
2
Ph
EtO C
N
2
Br
O
N
Boc
3d
Chemical Formula:
BrN O
C
H
28 29
2 7
Exact Mass: 584.1158
21
>99% ee. [α]D = 39.2 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for C28H30BrN2O7 (M+H)+, m/z
585.1236, found 585.1234.
1-tert-Butyl 4′,5′-diethyl 5-methyl (3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-
dihydro-spiro[indoline-3,3′-pyrrole]-1,4′,5′-tricarboxylate (3e). 1H-
NMR (400 MHz, CDCl3) δ 7.82 (d, J 8.4 Hz, 1H), 7.59-7.55 (m, 3H),
7.40-7.31 (m, 4H), 7.20 (d, J 8.3 Hz, 1H), 4.37-4.28 (m, 2H), 4.19 (s, 1H),
3.95-3.78 (m, 2H), 2.37 (s, 3H), 1.63 (s, 9H), 1.31 (t, J 7.2 Hz, 3H), 0.78
(t, J 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 173.27, 170.54, 168.08,
162.05, 148.83, 142.01, 137.50, 134.61, 130.15, 128.11, 127.66, 126.97,
126.82, 123.85, 114.70, 87.83, 84.90, 70.32, 62.61, 62.39, 61.10, 28.03,
21.18, 13.97, 13.38. HPLC: Chiralpak AD-H (hexane/i-PrOH = 95/5, flow
CO Et
2
Ph
EtO C
N
2
Me
O
N
Boc
3e
Chemical Formula:
N O
C
H
29 32
2 7
Exact Mass: 520.2210
rate 1 mL/min, λ = 210 nm), tR (minor) = 8.6 min, tR (major) = 11.5 min; >99% ee. [α]D21 = 15.1
(c = 1.0, CH2Cl2). HRMS (ESI) calcd for C29H33N2O7 (M+H)+, m/z 521.2288, found 521.2289.
1-tert-Butyl 5′-ethyl 4′-methyl (3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-
CO Et
2
Ph
MeO C
1
dihydrospiro[indoline- 3,3′-pyrrole]-1,4′,5′-tricarboxylate (3f). H-
N
2
NMR (400 MHz, CDCl3) δ 7.97 (d, J 8.0 Hz, 1H), 7.71 (d, J 7.6 Hz, 1H),
7.59 (d, J 1.2 Hz, 2H), 7.57-7.33 (m, 5H), 7.23 (t, J 7.6 Hz, 1H), 4.37-
4.26 (m, 2H), 4.22 (s, 1H), 3.38 (s, 3H), 1.64 (s, 9H), 1.29 (t, J 7.2 Hz,
3H). 13C-NMR (100 MHz, CDCl3) δ 172.94, 170.76, 168.65, 161.89,
148.79, 141.71, 139.63, 129.75, 128.17, 127.76, 126.80, 126.37, 124.92,
123.72, 114.97, 88.24, 85.14, 70.25, 62.53, 62.31, 52.05, 28.03, 13.92.
O
N
Boc
3f
Chemical Formula:
N O
Exact Mass: 492.1897
C
H
27 28
2 7
HPLC: Chiralpak AD-H (hexane/i-PrOH = 95/5, flow rate 1 mL/min, λ =
21
210 nm), tR (major) = 11.7 min, tR (minor) = 14.4 min; >99% ee. [α]D
=
-7.5 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for C27H29N2O7 (M+H)+, m/z 493.1975, found
493.1969.
Page 134
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
4′-Benzyl 1-tert-butyl 5′-ethyl (3R,4′S,5′R)-2-oxo-5′-phenyl-4′,5′-dihydrospiro [indoline-
1
3,3′-pyrrole]-1,4′,5′-tricarboxylate (3g). H-NMR (400 MHz, CDCl3) δ
CO Et
2
Ph
BnO C
7.89 (d, J 8.0 Hz, 1H), 7.78 (d, J 7.6 Hz, 1H), 7.57 (d, J 1.4 Hz, 2H),
7.56-7.18 (m, 9H), 6.91 (d, J 6.4 Hz, 2H), 4.87 (d, J 12 Hz, 1H), 4.69 (d,
J 12.0 Hz, 1H), 4.37-4.25 (m, 3H), 1.60 (s, 9H), 1.27 (t, J 7.2 Hz, 3H).
13C-NMR (100 MHz, CDCl3) δ 173.02, 170.68, 167.95, 161.98, 148.62,
141.76, 139.76, 134.39, 129.77, 128.41, 128.37, 128.30, 128.14, 127.72,
126.85, 126.47, 125.05, 123.68, 115.09, 88.01, 84.95, 70.24, 67.35,
62.54, 62.52, 27.99, 13.90. HPLC: Chiralpak AD-H (hexane/i-PrOH =
90/10, flow rate 1 mL/min, λ = 210 nm), tR (major) = 10.8 min, tR (minor)
= 13.2 min; >99% ee. [α]D21 = -9.7 (c = 1.0, CH2Cl2). HRMS (ESI) calcd
N
2
O
N
Boc
3g
Chemical Formula:
N O
C
H
33 32
2 7
Exact Mass: 568.2210
for C33H33N2O7 (M+H)+, m/z 569.2288, found 569.2290.
1-tert-Butyl 5′-ethyl 4′-acetyl (3R,4′S,5′S)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro[indoline-3,3′-pyrrole]-1,5′-dicarboxylate (3h). H-NMR
EtO C
2
1
Ph
N
(400 MHz, CDCl3) δ 7.99 (d, J 8.0 Hz, 1H), 7.66 (d, J 7.6 Hz, 1H), 7.50-
7.34 (m, 6H), 7.24-7.21 (m, 2H), 4.42-4.28 (m, 2H), 4.23 (s, 1H), 1.73 (s,
3H), 1.65 (s, 9H), 1.33 (t, J 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ
201.64, 173.05, 171.16, 161.31, 148.60, 141.67, 139.48, 130.08, 128.28,
127.80, 126.74, 126.59, 125.45, 123.18, 115.29, 87.98, 85.45, 71.13,
69.56, 62.52, 30.20, 28.03, 13.91. HPLC: Chiralpak OD-H (hexane/i-
PrOH = 97/3, flow rate 1 mL/min, λ = 210 nm), tR (major) = 17.9 min, tR
O
O
N
Boc
3h
Chemical Formula:
N O
C
H
27 28
2 6
Exact Mass: 476.1947
21
(minor) = 21.6 min; >99% ee. [α]D = 35.2 (c = 1.0, CH2Cl2). HRMS
(ESI) calcd for C27H29N2O6 (M+H)+, m/z 477.2026, found 477.2028.
1-tert-Butyl 5′-ethyl 4′-benzoyl (3R,4′S,5′S)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro[indoline-3,3′-pyrrole]-1,5′-dicarboxylate (3i). H-NMR
EtO2C
N
1
Ph
(400 MHz, CDCl3) δ 7.72 (d, J 7.6 Hz, 1H), 7.56 (d, J 7.2 Hz, 2H), 7.49
(d, J 8.0 Hz, 1H), 7.42-7.28 (m, 7H), 7.21-7.12 (m, 4H), 5.05 (s, 1H),
4.48-4.30 (m, 2H), 1.61 (s, 9H), 1.32 (t, J 7.2 Hz, 3H). 13C-NMR (100
MHz, CDCl3) δ 196.40, 173.54, 171.15, 160.73, 148.23, 142.43, 139.16,
137.37, 133.00, 129.79, 128.33, 128.19, 127.59, 127.28, 127.22, 126.93,
125.07, 122.31, 114.39, 87.91, 84.96, 70.66, 66.77, 62.48, 28.01, 13.88.
HPLC: Chiralpak IC (hexane/i-PrOH = 90/10, flow rate 1 mL/min, λ =
210 nm), tR (major) = 13.8 min, tR (minor) = 29.5 min; 97% ee. [α]D21 = -
O
O
N
Boc
3i
Chemical Formula:
32H30N2O6
Exact Mass: 538.2104
C
7.7 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for C32H31N2O6 (M+H)+, m/z 539.2182, found
539.2183.
Page 135
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
1-tert-Butyl 5′-ethyl 4′-(4-bromobenzoyl) (3R,4′S,5′S)-2-oxo-5′-
phenyl-4′,5′-dihydrospiro- [indoline-3,3′-pyrrole]-1,5′-dicarboxylate
(3J). H-NMR (400 MHz, CDCl3) δ 7.67 (d, J 7.6 Hz, 1H), 7.53 (d, J 8.0
Br
EtO2C
N
Ph
1
Hz, 3H), 7.39-7.33 (m, 6H), 7.26-7.23 (m, 1H), 7.19-7.13 (m, 3H), 4.99
(s, 1H), 4.44-4.31 (m, 2H), 1.63 (s, 9H), 1.31 (t, J 7.2 Hz, 3H). 13C-NMR
(100 MHz, CDCl3) δ 195.40, 173.45, 170.98, 160.61, 148.05, 142.22,
139.11, 136.10, 131.63, 129.99, 128.80, 128.26, 128.19, 127.70, 127.78,
126.87, 125.14, 122.15, 114.47, 87.95, 85.26, 70.58, 66.65, 62.53, 28.02,
13.87. HPLC: Chiralpak AD-H (hexane/i-PrOH = 85/15, flow rate 1
mL/min, λ = 210 nm), tR (major) = 16.9 min, tR (minor) = 26.5 min; 98%
O
O
N
Boc
3j
Chemical Formula:
C32H29BrN2O6
Exact Mass: 616.1209
21
ee. [α]D = -15.9 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for C32H30BrN2O6 (M+H)+, m/z
617.1287, found 617.1284.
1-tert-Butyl 4′-ethyl 5′-methyl (3R,4′S,5′S)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro [indoline-3,3′- pyrrole]-1,4′,5′-tricarboxylate (3k). H-
CO2Me
N
1
Ph
EtO2C
NMR (400 MHz, CDCl3) δ 7.93 (d, J 8.0 Hz, 1H), 7.77 (d, J 7.6 Hz, 1H),
7.57 (d, J 7.2 Hz, 2H), 7.41-7.30 (m, 5H), 7.21 (t, J 7.6 Hz, 1H), 4.20 (s,
1H), 3.87-3.76 (m, 5H) (-CH3 and –CH2 overlap), 1.62 (s, 9H), 0.73 (t, J
7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 173.15, 171.33, 168.13,
161.88, 148.77, 141.75, 139.91, 129.78, 128.22, 127.80, 126.84, 126.53,
125.10, 123.82, 114.91, 87.70, 85.11, 70.38, 62.78, 61.25, 53.34, 28.02,
13.35. HPLC: Chiralpak AD-H (hexane/i-PrOH = 85/15, flow rate 1
mL/min, λ = 210 nm), tR (major) = 6.7 min, tR (minor) = 8.4 min; >99%
O
N
Boc
3k
Chemical Formula:
C27H28N2O7
Exact Mass: 492.1897
21
ee. [α]D = -12.8 (c = 1.2, CH2Cl2). HRMS (ESI) calcd for C27H29N2O7 (M+H)+, m/z 493.1975,
found 493.1972.
-5′-Benzyl 1-tert-butyl 4′-ethyl (3R,4′S,5′S)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro [indoline-3,3′- pyrrole]-1,4′,5′-tricarboxylate (3l). H-
CO2Bn
N
Ph
EtO2C
1
NMR (400 MHz, CDCl3) δ 7.91 (d, J 8.0 Hz, 1H), 7.58-7.54 (m, 3H),
7.38-7.29 (m, 7H), 7.26-7.22 (m, 3H), 7.02 (t, J 7.6 Hz, 1H), 5.27 (dd, J
12.6, 24.5 Hz, 2H), 4.22 (s, 1H), 3.84-3.72 (m, 2H), 1.61 (s, 9H), 0.70 (t,
O
N
Boc
13
J 7.2 Hz, 3H). C-NMR (100 MHz, CDCl3) δ 173.14, 170.43, 168.01,
3l
162.00, 148.77, 141.78, 139.82, 135.25, 129.68, 128.42, 128.17, 128.11,
127.94, 127.79, 126.88, 126.52, 124.97, 123.74, 114.88, 87.82, 85.10,
70.32, 67.94, 62.63, 61.22, 28.02, 13.32. HPLC: Chiralpak AD-H
Chemical Formula:
33H32N2O7
Exact Mass: 568.2210
C
(hexane/i-PrOH = 90/10, flow rate 1 mL/min, λ = 210 nm), tR (minor) =
21
14.3 min, tR (major) = 19.4 min; >99% ee. [α]D = -13.4 (c = 0.8, CH2Cl2). HRMS (ESI) calcd
for C33H33N2O7 (M+H)+, m/z 569.2288, found 569.2290.
General procedure for the construction of spirocyclic oxindoles with organocatalytic
[3+2]cycloaddition reactions (5a-3f): To a solution of methyleneindolinone (0.1 mmol, 1
equiv) and isocyanide 1a (0.15 mmol, 1.5 equiv) in DCM (0.2 mL) was added catalyst VI (0.01
Page 136
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
mmol, 0.1 equiv). The resulting mixture was stirred at room temperature (23 °C). After the
reaction completed, the mixture was quenched with water (5 mL) and extracted with DCM (2 x 5
mL). The combined organic layer was washed with brine and dried over Na2SO4. The solvent
was then removed under reduced pressure. The product was afforded by silica gel flash
chromatography using gradient elution (EtOAc/Hexane = 1:10 to 1:6).
Diethyl
1-benzyl
(3R,4′S,5′S)-2-oxo-5′-phenyl-4′,5′-
1
CO2Et
N
dihydrospiro[indoline-3,3′-pyrrole]-4′,5′- dicarboxylate (5a). H-NMR
(400 MHz, CDCl3) δ 7.73 (d, J 1.2 Hz, 2H), 7.71 (s, 1H), 7.56-7.32 (m,
8H), 7.26 (t, J 7.6 Hz, 1H), 7.17 (d, J 7.6 Hz, 1H), 6.98 (t, 7.6 Hz, 1H),
6.80 (d, J 8.0 Hz, 1H), 5.03 (d, J 15.6, Hz, 1H), 4.96 (d, J 15.6, Hz,
1H),4.86 (s, 1H), 4.36 (q, J 7.1 Hz, 2H), 3.67-3.63 (m, 2H), 1.32 (t, J 7.2
Ph
EtO2C
O
N
Bn
13
Hz, 3H), 0.78 (t, J 7.2 Hz, 3H). C-NMR (100 MHz, CDCl3) δ 173.41,
5a
171.56, 167.83, 163.22, 143.64, 138.95, 135.18, 129.88, 128.96, 128.19,
128.09, 127.93, 127.34, 126.81, 126.64, 123.80, 122.98, 109.59, 89.39,
68.51, 62.50, 60.66, 59.18, 44.38, 14.02, 13.49. HPLC: Chiralpak IB
(hexane/i-PrOH = 85/15, flow rate 1 mL/min, λ = 210 nm), tR (minor) =
Chemical Formula:
C30H28N2O5
Exact Mass: 496.1998
10.9 min, tR (major) = 12.6 min; 98% ee. [α]D21 = 58.7 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for
C30H29N2O5 (M+H)+, m/z 497.2076, found 497.2079.
Diethyl 1-benzyl 5-fluoro (3R,4′R,5′R)-2-oxo-5′-phenyl-4′,5′-dihydrospiro[indoline-3,3′-
1
pyrrole]-4′,5′- dicarboxylate (5b). H-NMR (400 MHz, CDCl3) δ 7.68 (d, J 7.6 Hz, 2H), 7.51
(s, 1H), 7.42-7.30 (m, 8H), 6.93 (t, J 8.4 Hz, 2H), 6.67 (q, J 4.0 Hz, 1H), 4.94 (d, J 3.6 Hz, 2H),
4.82 (s, 1H), 4,32 (q, J 7.2 Hz, 2H), 3.67-3.61 (m, 2H), 1.28 (t, J 7.2 Hz, 3H), 0.81 (t, J 7.2 Hz,
3H). 13C-NMR (100 MHz, CDCl3) δ 173.05, 171.31, 167.73, 162.53,
CO2Et
Ph
160.24, 139.57, 138.72, 134.82, 129.00, 128.23, 128.20, 128.03, 127.25,
N
EtO2C
F
126.53, 125.27, 125.18, 116.33, 116.10, 115.27, 115.01, 110.08, 110.01,
89.51, 68.54, 62.52, 59.34, 44.50, 13.97, 13.48. HPLC: Chiralpak OD-H
O
N
(hexane/i-PrOH = 95/5, flow rate 1 mL/min, λ = 210 nm), tR (minor) = 29.6
Bn
min, tR (major) = 40.7 min; 99% ee. [α]D21 = -81.9 (c = 1.1, CH2Cl2). HRMS
5b
(ESI) calcd for C30H28FN2O5 (M+H)+, m/z 515.1982, found 515.1979.
Chemical Formula:
C30H27FN2O5
Exact Mass: 514.1904
Diethyl
1-benzyl
5-chloro
(3R,4′R,5′R)-2-oxo-5′-phenyl-4′,5′-
dihydrospiro [indoline-3,3′-pyrr ole]-4′,5′-dicarboxylate (5c). 1H-NMR
(400 MHz, CDCl3) δ 7.69 (d, J 7.2 Hz, 2H), 7.51 (s, 1H), 7.42-7.27 (m,
10H), 7.63 (d, J 8.4 Hz, 1H), 4.93 (s, 2H), 4.80 (s, 1H), 4.35-4.27 (m, 2H),
3.70-3.58 (m, 2H), 1.28 (t, J 7.2 Hz, 3H), 0.81 (t, J 7.2 Hz, 3H). 13C-NMR
(100 MHz, CDCl3) δ 172.77, 171.28, 167.71, 162.36, 142.66, 138.81,
134.63, 132.68, 130.02, 129.04, 128.25, 128.19, 128.08, 127.22, 126.47,
125.68, 115.67, 110.98, 89.48, 68.17, 62.53, 60.96, 59.65, 44.42, 13.98,
13.51. HPLC: Chiralpak OD-H (hexane/i-PrOH = 90/10, flow rate 1
CO Et
2
Ph
EtO C
N
2
Cl
O
N
Bn
5c
Chemical Formula:
ClN O
C H
30 27
2 5
Exact Mass: 530.1608
Page 137
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
mL/min, λ = 210 nm), tR (minor) = 19.4 min, tR (major) = 25.1 min; 97% ee. [α]D21 = -17.5 (c =
1.1, CH2Cl2). HRMS (ESI) calcd for C30H28ClN2O5 (M+H)+, m/z 531.1687, found 531.1683.
Diethyl
1-benzyl
5-bromo
(3R,4′R,5′R)-2-oxo-5′-phenyl-4′,5′-
1
CO2Et
N
dihydrospiro[indoline-3,3′-pyrrole]-4′,5′-dicarboxylate (5d). H-NMR
(400 MHz, CDCl3) δ 7.68 (d, J 7.2 Hz, 2H), 7.51 (s, 1H), 7.42-7.27 (m,
8H), 7.21-7.18 (m, 2H), 6.67 (d, J 8.4 Hz, 1H), 4.93 (s, 2H), 4.80 (s, 1H),
4.34-4.29 (m, 2H), 3.68-3.60 (m, 2H), 1.28 (t, J 7.2 Hz, 3H), 0.81 (t, J 7.2
Ph
EtO2C
Br
O
N
Bn
13
Hz, 3H). C-NMR (100 MHz, CDCl3) δ 172.88, 171.29, 167.71, 162.38,
142.16, 138.77, 134.66, 129.77, 129.03, 128.46, 128.25, 128.19, 128.07,
127.34, 127.22, 126.48, 125.33, 110.46, 89.50, 68.26, 62.53, 59.56, 44.46,
13.98, 13.48. HPLC: Chiralpak OD-H (hexane/i-PrOH = 90/10, flow rate
1 mL/min, λ = 210 nm), tR (minor) = 19.5 min, tR (major) = 26.6 min;
5d
Chemical Formula:
30H27BrN2O5
Exact Mass: 574.1103
C
21
98% ee. [α]D = -25.5 (c = 1.0, CH2Cl2). HRMS (ESI) calcd for
C30H28BrN2O (M+H)+, m/z 575.1182, found 575.1180.
Ethyl 4′-benzoyl-1-benzyl 5-chloro (3R,4′R,5′S)-2-oxo-5′-phenyl-
EtO2C
N
Ph
4′,5′-dihydrospiro[indoline -3,3′-pyrrole]-5′-carboxylate (5e). 1H-
NMR (400 MHz, CDCl3) δ 7.71-7.85 (m, 2H), 7.51-7.47 (m, 4H), 7.36-
7.27 (m, 8H), 7.16-7.06 (m, 4H), 6.53 (d, J 8.4 Hz, 1H), 5.97 (s, 1H),
5.02 (d, J 15.6 Hz, 1H), 4.82 (d, J 15.6 Hz, 1H), 4.38-4.31 (m, 2H), 1.28
(t, J 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 195.52, 173.45,
172.23, 162.32, 141.55, 138.30, 138.14, 134.64, 133.47, 129.57, 128.98,
128.69, 128.65, 128.32, 128.24, 128.05, 128.00, 127.01, 126.51, 124.69,
110.25, 91.07, 69.53, 62.69, 57.79, 50.84, 44.33, 13.95. HPLC:
Cl
O
O
N
Bn
5e
Chemical Formula:
C34H27ClN2O4
Exact Mass: 562.1659
Chiralpak AD-H (hexane/i-PrOH = 80/20, flow rate 1 mL/min, λ = 210 nm), tR (major) = 22.5
21
min, tR (minor) = 43.5 min; >99% ee. [α]D = -44.7 (c = 1.2, CH2Cl2). HRMS (ESI) calcd for
C34H28ClN2O4 (M+H)+, m/z 563.1738, found 563.1735.
Acknowledgements
Financial support from the National Natural Science Foundation of China (NSFC-21373073) and
the Program for ChangJiang Scholars and Innovative Research Team in Chinese University (IRT
1231) is gratefully acknowledged. G.Z. appreciated a QianJiang Scholar from ZheJiang Province
in China.
References
1. Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36.
http://dx.doi.org/10.1002/anie.200390048
Page 138
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
2. Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
http://dx.doi.org/10.1002/anie.200701342
PMid:17943924
3. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
http://dx.doi.org/10.1002/ejoc.200300050
4. Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc. 2007, 129, 1020.
http://dx.doi.org/10.1021/ja067552n
PMid:17263369
5. Ding, K.; Lu, Y; Nikolovska-Koleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Roller, P.
P.; Tomita, Y.; Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130.
http://dx.doi.org/10.1021/ja051147z
PMid:16028899
6. Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R. S.; Qiu, S.; Nikolovska-Coleska,
Z.; Ding, K.; Wang, G.; Chen, J.; Bernard, D.; Zhang, J.; Lu, Y.; Gu, Q.; Shah, R. B.; Pienta,
K. J.; Ling, X.; Kang, S.; Guo, M.; Sun, Y.; Yang, D.; Wang, S. Proc. Natl. Acad. Sci. U.S.A.
2008, 105, 3933.
http://dx.doi.org/10.1073/pnas.0708917105
PMid:18316739 PMCid:PMC2268798
7. Nicolaou, K. C.; Snyder, S. A. Proc. Natl. Acad. Sci. USA, 2004, 101, 11929.
http://dx.doi.org/10.1073/pnas.0403799101
PMid:15302925 PMCid:PMC514411
8. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
http://dx.doi.org/10.1002/1521-3773(20020517)41:10<1650::AID-ANIE1650>3.0.CO;2-B
9. Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396.
http://dx.doi.org/10.1021/ja075335w
PMid:17880222 PMCid:PMC2615581
10. Chen, X.; Wei, Q.; Luo, S.; Xiao, H.; Gong, L. J. Am. Chem. Soc. 2009, 131, 13819.
http://dx.doi.org/10.1021/ja905302f
PMid:19736987
11. Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marinetti, A. Chem.-Eur. J. 2010, 16,
12541.
http://dx.doi.org/10.1002/chem.201001791
PMid:20853298
12. Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212.
http://dx.doi.org/10.1021/ja206517s
PMid:21842900
13. Tan, B.; Hernandez-Torres, G.; Barbas, C. F., III, J. Am. Chem. Soc. 2011, 133, 12354.
http://dx.doi.org/10.1021/ja203812h
PMid:21780763
14. Peng, J.; Huang, X.; Jiang, L.; Cui, H.; Chen, Y. Org. Lett. 2011, 13, 4584.
Page 139
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
http://dx.doi.org/10.1021/ol201776h
PMid:21815615
15. Tan, B.; Candeias, N. R.; Barbas, C. F., III. Nat. Chem. 2011, 3, 473.
PMid:21602863
16. Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 4672.
http://dx.doi.org/10.1021/ja110147w
PMid:21395245
17. Tan, B. Hernandez-Torres, G.; Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 12354.
http://dx.doi.org/10.1021/ja203812h
PMid:21780763
18. Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 7837.
http://dx.doi.org/10.1002/anie.201102094
PMid:21728218
19. Jia, Z.; Jiang, H.; Li, J.; Gschwend, B.; Li, Q.; Yin, X.; Grouleff, J.; Chen, Y.; Jorgensen, K.
A. J. Am. Chem. Soc. 2011, 133, 5053.
http://dx.doi.org/10.1021/ja1112194
PMid:21405125
20. Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Wang, R. Angew. Chem., Int. Ed. 2011, 50, 9124.
http://dx.doi.org/10.1002/anie.201104216
PMid:21919145
21. Tan, B.; Zeng, X.; Leong, W. W. Y.; Shi, Z.; Barbas, C. F., III.; Zhong, G., Chem.-Eur. J.
2012, 18, 63.
http://dx.doi.org/10.1002/chem.201103449
PMid:22162076
22. Bui, T.; Candeias, N. R.; Barbas, C. F., III, J. Am. Chem. Soc. 2010, 132, 5574.
http://dx.doi.org/10.1021/ja101032j
PMid:20356308
23. He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 16620.
http://dx.doi.org/10.1021/ja906821y
PMid:19886657
24. Quaternary Stereocenters. Challenges and Solutions in Organic Synthesis (Eds.: Christoffers,
Baro, J. A.), Wiley-VCH, Weinheim, 2006.
25. Douglas,C. J.; Overman, L. E. Proc. Natl. Acad. Sci. USA, 2004, 101, 5363.
http://dx.doi.org/10.1073/pnas.0307113101
PMid:14724294 PMCid:PMC397386
26. Tian, S.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621.
http://dx.doi.org/10.1021/ar030048s
PMid:15311961
27. Li, H.; Wang, Y.; Tang, L.; Deng, L., J. Am. Chem. Soc. 2004, 126, 9906.
Page 140
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
http://dx.doi.org/10.1021/ja047281l
PMid:15303849
28. Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
http://dx.doi.org/10.1039/b508833j
PMid:16136258
29. McCooey, S. H.; Connon. S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
http://dx.doi.org/10.1002/anie.200501721
PMid:16136619
30. Vakulya, B.; Varga, S.; Csampai, A.; Soos, T., Org. Lett. 2005, 7, 1967.
http://dx.doi.org/10.1021/ol050431s
PMid:15876031
31. Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128,
4932.
http://dx.doi.org/10.1021/ja056565i
PMid:16608309
32. Tan, B.; Chua, P. J.; Li, Y.; Zhong, G. Org. Lett. 2008, 10, 2437.
http://dx.doi.org/10.1021/ol8007183
PMid:18489178
33. Tan, B.; Shi, Z.; Chua, P. J.; Zhong,G. Org. Lett. 2008, 10, 3425.
http://dx.doi.org/10.1021/ol801246m
PMid:18616339
34. Tan, B.; Chua, P. J.; Zeng, X.; Lu, M.; Zhong, G. Org. Lett. 2008, 10, 3489.
http://dx.doi.org/10.1021/ol801273x
PMid:18630924
35. Tan, B.; Zhang, X.; Chua, P. J.; Zhong, G. Chem. Commun. 2009, 779.
http://dx.doi.org/10.1039/b813915f
PMid:19322439
36. Tan,B.; Lu,Y.; Zeng, X.; Chua, P. J.; Zhong, G. Org. Lett. 2010, 12, 2682.
http://dx.doi.org/10.1021/ol1007795
PMid:20469881
37. Wu,Y.; Singh, R. P.; Deng, L. J. Am. Chem. Soc., 2011, 133, 12458.
http://dx.doi.org/10.1021/ja205674x
PMid:21766859 PMCid:PMC3156085
38. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
http://dx.doi.org/10.1002/anie.200400650
PMid:15455437
39. List, B. Chem. Commun. 2006, 819.
http://dx.doi.org/10.1039/b514296m
PMid:16479280
Page 141
©ARKAT-USA, Inc.

Issue in Honor of Prof. Pierre Vogel
ARKIVOC 2014 (iii) 124-142
40. Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
http://dx.doi.org/10.1002/anie.200704684
PMid:18421733
41. Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
http://dx.doi.org/10.1002/anie.200705523
PMid:18666089
42. Barbas, C. F., III. Angew. Chem., Int. Ed. 2008, 47, 42.
http://dx.doi.org/10.1002/anie.200702210
PMid:17943929
43. Ito, Y.; Samura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405.
http://dx.doi.org/10.1021/ja00280a056
44. Song, J.; Guo, C.; Chen, P.; Yu, J.; Luo, S. ; Gong, L. Chem.-Eur. J. 2011, 17, 7786.
http://dx.doi.org/10.1002/chem.201100636
PMid:21618634
45. SladoJevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D. J. J. Am. Chem. Soc. 2011, 133, 1710.
http://dx.doi.org/10.1021/ja110534g
PMid:21247165
46. Wang, L.; Bai, J.; Peng, L.; Qi, L.; Jia, L.; Guo, Y.; Luo, X.; Xu, X.; Wang, L. Chem.
Commun. 2012,48, 5175.
http://dx.doi.org/10.1039/c2cc30746d
PMid:22517246
47. Tan, D. Nat. Chem. Biol. 2005, 1, 74.
http://dx.doi.org/10.1038/nchembio0705-74
PMid:16408003
48. Kissane, M.; Maguire, A. Chem. Soc. Rev. 2010, 39, 845.
http://dx.doi.org/10.1039/b909358n
PMid:20111795
49. We only determined the relative configuration of the Bn-protected products based on 2D
NMR (NOESY).
Page 142
©ARKAT-USA, Inc.