Synthesis of planar chiral [2.2]paracyclophane-based amino thioureas and their application in asymmetric aldol reactions of ketones with isatins

Article abstract of DOI:10.1016/j.tetasy.2013.07.023

Several novel [2.2]paracyclophane-based amino thioureas have been designed and synthesized. The [2.2]paracyclophane-based amino thioureas were used as bifunctional catalysts for organocatalytic enantioselective aldol reactions between ketones and isatins,

Full text of DOI:10.1016/j.tetasy.2013.07.023

Tetrahedron: Asymmetry 24 (2013) 1082–1088
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of planar chiral [2.2]paracyclophane-based amino
thioureas and their application in asymmetric aldol reactions
of ketones with isatins
⇑
⇑
Yu Lu, Yudao Ma , Shaobo Yang, Manyuan Ma, Hongju Chu, Chun Song
Department of Chemistry, Shandong University, Shanda South Road No. 27, Jinan 250100, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel [2.2]paracyclophane-based amino thioureas have been designed and synthesized. The
[2.2]paracyclophane-based amino thioureas were used as bifunctional catalysts for organocatalytic enan-
tioselective aldol reactions between ketones and isatins, affording the desired adducts containing a chiral
tertiary alcohol in high yields (up to 92% yield) and with good enantioselectivity (up to 88% ee). This is a
successful example of employing planar chiral [2.2]paracyclophane-based amino thioureas in asymmet-
ric aldol reactions.
Received 14 June 2013
Accepted 24 July 2013
Available online 2 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
and amine center can activate both substrates simultaneously at
defined positions in the transition states.11
The asymmetric aldol reaction is one of the most powerful and
efficient methods for the formation of chiral carbon–carbon
bonds.1 Since List and Barbas first reported the proline catalyzed
cross-aldol reaction of ketones and aldehydes,2 many amine deriv-
atives have been applied to asymmetric cross-aldol reactions.3 In
particular, pyrrolidine-based secondary amines and primary amine
catalysts often complement each other in their ability to activate
different substrates,4 and expand their application to a wide range
of carbonyl compounds via enamine catalysis.5 In 2005, Tomasini
et al. reported the first asymmetric aldol reaction of isatin with
acetone catalyzed by dipeptide-based organocatalysts.1c The
asymmetric aldol condensation of ketones with various isatins
has attracted more and more attention because 3-alkyl-3-hydrox-
yindolin-2-ones produced bearing a stereogenic quaternary center
at C3 and make up the core of many natural products and
pharmaceuticals, with a broad range of biological activities.6,7
Thus, significant efforts have focused on developing efficient
organocatalysts for asymmetric aldol reactions of isatins with
ketones.8
Since planar chiral substituted [2.2]paracyclophanes were first
reported as being used as ligands in asymmetric catalysis in
1997,12 planar chiral molecules, such as ferrocene derivatives and
substituted [2.2]paracyclophanes, have played an important role
in asymmetric catalysis.13 In recent years, a series of planar chiral
ligands based on the [2.2]paracyclophane backbone have been pre-
pared and their applications as rhodium or copper complexes in
highly enantioselective transformations have also been demon-
strated.14 In spite of these efforts, examples of the synthesis and
application of [2.2]paracyclophane-based organocatalysts are
rare.15 Herein we describe the synthesis of several new planar chi-
ral amino thioureas and their application in organocatalytic enan-
tioselective aldol reaction.
2. Results and discussion
Our synthetic route to catalysts 6, 10a, and 10b is described in
Schemes 1 and 2.
Over the past few years, the utilization of chiral ureas/thioureas
and amines has emerged as a viable strategy in the design of effi-
cient organocatalysts for asymmetric organic transformations.
Notable examples include Jacobsen’s ureas/thioureas for a variety
of reactions9 and Takemoto’s amine-thioureas for Michael addition
and aza-Henry reactions.10 A thiourea and an amine moiety could
lead to a class of bifunctional organocatalysts. The double H-bond
2.1. Synthesis of planar chiral amino thiourea derived from
[2.2]paracyclophane
(RP)-4-Bromo-12-formyl[2.2]paracyclophane 2 was synthesized
from racemic 4,12-dibromo[2.2]paracyclophane by the reported
procedure.16,17 Aldehyde 2 was converted into the corresponding
oxime by reaction with hydroxylamine hydrochloride and NaOAc
in ethanol in quantitative yield. Methylation of the oxime with di-
methyl sulfate followed by reduction of borane gave the desired
(RP)-4-aminomethyl-12-bromo[2.2]paracyclophane 3 in excellent
⇑
Corresponding authors. Tel.: +86 531 88361869; fax: +86 531 88565 211.
E-mail addresses: ydma@sdu.edu.cn (Y. Ma), chunsong@sdu.edu.cn (C. Song).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.023

Y. Lu et al. / Tetrahedron: Asymmetry 24 (2013) 1082–1088
1083
subjected to a Pd-catalyzed amination with benzhydrylideneamine
to afford, after hydrolysis by hydrochloric acid, triamino[2.2]para-
cyclophane 5 in satisfactory yield. For the synthesis of amino
thiourea 6, it is necessary to only protect the alkylamino group
in 5. Fortunately, the mono-Boc-protected compound 5 was easy
to obtain directly due to the different reactivity of the two kinds
of amino groups in 5. The remaining amino groups reacted with
3,5-bis(trifluoromethyl)phenyl isothiocyanate to produce, after
removal of the Boc-protecting group with trifluoroacetic acid, the
final product (RP,RP)-6 in good yield (Scheme 1).
Br
CHO
n-BuLi, THF, -78°C
DMF
1. NH2OH·HCl
2. Me2SO4
3. Borane
Br
Br
2
1
3
NH2
N
H
2
NaBH4
Br
Br
Br
4
2.2. Synthesis of planar and central chiral amino thioureas
derived from proline and [2.2]paracyclophane 10a, 10b
1. (BOC)2O
(C6H5)2C=NH
1. (BOC)2O
According to a previously described procedure,19 starting from
N
H
N=C=S
CF3
known
compound
(RP)-4-amino-12-benzhydrylideneami-
2.
2.
Pd-DPPF; 110°C
NH2
H2N
no[2.2]paracyclophane 7a,18 the (S)-N-Boc-prolyl group was intro-
duced via a classical coupling between 7a and 8 to generate the
corresponding amide. Deprotection of the benzhydrylideneamino
group by hydroxylamine hydrochloride and NaOAc led to the
isolation of the desired (RP,S)-4-amino-12-(N-Boc-prolinami-
do)[2.2]paracyclophane 9a with excellent chemoselectivity. Finally,
the target product (RP,S)-10a was obtained by a simple reaction
between 9a and 3,5-bis(trifluoromethyl)phenyl isothiocyanate
followed by removal of the Boc-protecting group with TFA. The
(SP,S)-10b was prepared from (SP)-4-amino-12-benzhydrylideneami-
NaOBu-t
F3C
3. HCl
5
3. TFA
S
F3C
F3C
N
H
N
H
N
X =
X
X
H
(RP,RP)-6
Scheme 1. Synthesis of planar chiral amino thiourea 6.
no[2.2]paracyclophane 7b and
8 following the representative
procedure described above (Scheme 2).
O
1.
2.3. Catalytic asymmetric aldol reactions
Cl
N
NH
NH2
8
BOC
N
O
BOC
With these catalysts in hand, we next examined their efficiency
in enantioselective aldol reactions with isatin 11a and acetone 12a
as the model substrates. The results of the catalyst and solvent
optimization are presented in Table 1.
NH2
2. NH2OH·HCl
N=C(Ph)2
7a
F3C
9
It is well known that the addition of small quantities of water to
the organocatalyzed aldol addition of acetone to isatin results in an
increase in the enantioselectivity of the reaction.8g,l We therefore
modified the reported procedure,8g,l with water as an additive, to
evaluate the solvent effects. With CH2Cl2 as the solvent, the reac-
tion was catalyzed by 10a to afford the desired product 13a in
O
N=C=S
1.
NH
N
H
F3C
X
2. TFA
10a
(RP,S)-
Table 1
O
Catalyst and solvent optimizationa
O
NH
NH2
O
N
H
HO
O
20 mol% cat; rt
X
O
N=C(ph)2
O
+
2 equiv. water
N
H
N
H
7b
(SP,S)-10b
11a
12a
13a
F3C
S
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
eec (%)
X =
N
H
N
H
1
2
3
4
5
6
7
8
10a
10a
10a
10a
10a
10a
10a
10a
10a
6
CH2Cl2
Acetone
Methanol
Toluene
Acetonitrile
DME
Dioxane
Ether
THF
48
48
48
48
48
48
48
48
48
96
48
85
68
83
84
79
83
85
86
89
88
60
60
33
20
45
15
43
59
67
76
68
32
F3C
Scheme 2. Synthesis of chiral amino thioureas 10a, 10b.
yield. A one-pot reductive amination of 2 with 3 using NaBH4 as a
reducing agent resulted in the chemoselective formation of the ex-
pected (RP)-bis(12-bromo[2.2]paraclophane-4-methylene)amine 4
in good yield. Not as reported previously by us,18 the Buchwald–
Hartwig amination of 4 under standard conditions failed to give
a satisfactory result. We therefore turned our attention to protect
the amine function of 4 by means of a amine-protecting group,
9
10
11
THF
THF
10b
a
The reaction was carried out with 11a (0.136 mmol), 31 equiv 12a (4.216
mmol), 20 mol % catalyst, (0.0272 mmol), and water (2 equiv) in 1.25 mL of the
specified solvent at room temperature.
b
Isolated yield.
c
Determined by chiral HPLC (Chiralpak IA column) analysis.
tert-butyloxycarbonyl. The Boc-protected compound
4 was

1084
Y. Lu et al. / Tetrahedron: Asymmetry 24 (2013) 1082–1088
Table 3
85% yield and 60% ee (Table 1, entry 1). However inferior yields and
enantioselectivities were obtained when the reaction was con-
ducted in acetone (Table 1, entry 2). Further solvent optimization
(Table 1, entries 3–9) identified THF as the best solvent for this
reaction, in which the ee value was improved to 76% (Table 1, entry
9). With THF as the optimal solvent, catalyst 6 showed a lower cat-
alytic activity with a moderate enantioselectivity of 68% ee (Table 1,
entry 10). However, compared with catalyst 10a, a lower ee value
was given by its diastereoisomer 10b with a mismatched pair of
chiralites (Table 1, entry 11). Screening of catalysts 10a and 10b re-
vealed that the absolute configuration of product 13a was deter-
mined by the central chirality of the catalysts.
In order to obtain better yields and enantioselectivities, we next
investigated the impact of additives on the aldol reaction with 10a
as the catalyst and THF as the solvent (Table 2). These additives led
to lower reaction yields and poor enantioselectivities in contrast to
water (Table 2, entries 1–9). It should be noted that while the reac-
tion time was obviously shortened from 48 to 4 h with PhCO2H as
an additive, the ee value was poor at room temperature (Table 2,
entry 1). Lowering the reaction temperature to ꢀ45 °C, led to only
moderate enantioselectivity being obtained with an extension of
the reaction time (Table 2, entry 10). Among the acids, phenols,
amides, alcohols, and water screened, it appeared that water
(2 equiv) was the most effective additive, achieving the highest
enantioselectivity (Table 2, entry 13). Hence the water loading con-
ditions were also studied, as reported by Tomasini,8l some negative
effects on the enantioselectivity were observed when less or more
water was added (Table 2, entries 11, 12, 14, and 15).
Scope of substrates in the asymmeric aldol reactiona
O
O
HO
O
20 mol%
R3
10a
; rt
R2
O
R2
+
O
R3
THF; 2 equiv. H2O
N
N
R1
R1
13a-l
11a-h
12a-c
Entry
R1/R2/R3
H/H/Me
Methyl/H/Me
Trityl/H/Me
H/7-Cl/Me
H/7-F/Me
H/5-Me/Me
H/5-Cl/Me
H/5-F/Me
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
48
48
48
48
48
48
48
48
72
96
72
96
89 13a
87 13b
89 13c
86 13d
85 13e
88 13f
83 13g
92 13h
78 13i
79 13j
79 13k
80 13l
76
25
4
66
60
68
70
88
64
72
58
68
9
H/5-F/Ph
H/5-F/4-CH3OC6H4
H/H/Ph
10
11
12
H/H/4-CH3OC6H4
a
Unless otherwise noted, reactions were carried out with 11 (0.136 mmol), 12
(31 equiv, 4.216 mmol) in THF (1.25 mL) with 20 mol % of catalyst 10a and 2 equiv.
of water at room temperature.
b
Isolated yield.
c
Enantiomeric excesses were determined by chiral HPLC analysis (Chiralpak
IA-H column).
drance of the substituent on the nitrogen of isatin had an impor-
tant influence on the enantioselectivity. The enantiomeric excess
decreased from 76 to 25 to 4 as the size of substituent is increased
from H to Me to trityl (Table 3, entries 1–3). On the other hand, the
electronic properties of the substituent and its position on the isat-
in phenyl ring showed some influence on the enantioselectivities
(Table 3, entries 4–8). For example, the ee value of 5-fluoroisatin
11h (Table 3, entry 8) was much higher than that of 7-fluoroisatin
11e (Table 3, entry 5). Acetone, acetophenone, and p-methoxyace-
tophenone were also examined in the reaction (Table 3, entries 9–
12); the desired products were obtained in good yields (78–80%)
with moderate enantioselectivities (58–72% ee).
Having optimized the reaction conditions, we finally evaluated
the substrate scope with various ketones and isatins. As shown in
Table 3, with acetone as the substrate, various substituted isatins
were applied to this reaction (Table 3, entries 1–8). The steric hin-
Table 2
Additive effect on the reaction of isatin with acetonea
O
O
HO
O
20 mol% 10a; rt
O
O
+
THF; additive
N
H
N
H
2.4. Transition state models for the asymmetric aldol reaction
11a
12a
13a
The absolute configuration of the major enantiomers of 13a–b,
13f–i, and 13k–l was determined to be (S) by comparison of the
specific rotation with the literature data,1b,4b,20 the absolute config-
uration of the major enantiomers of 13c–e and 13j was assigned as
(S) by analogy, and through comparison of the specific rotation and
chiral HPLC elution order, with configurationally defined examples.
The observed absolute configuration of the products was in agree-
ment with the proposed transition state model in which the isatin
is activated by bifurcated H-bonding with the NH of prolinamide as
well as the NH of the thiourea through hydrogen bond interac-
tions,21 while the R group of the enamine formed by reaction of
the 10a pyrrolidine moiety with ketone shields the Si-face of the
carbonyl group of isatin, therefore, the nucleophilic addition of
the enamine to the Re-face of the activated carbonyl group there-
fore leads to the major (S)-product (Fig. 1, model A).
Entry
Additive
Time (h)
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
PhCO2Hc
TFAc
4
48
48
48
48
48
48
48
48
96
48
48
48
48
48
83
79
74
73
80
78
81
75
73
91
85
75
89
77
70
36
50
34
40
54
64
24
36
30
58
40
48
76
35
32
4-Br-phenolc
4-NO2-phenolc/H2Oe
4-NO2-phenolc
4-NO2-phenole
p-Toluenesulfonamidee
Hexafluoroisopropanole
Trifluoroethanole
PhCO2Hc,h
9
10
11
12
13
14
15
None
H2Od
H2Oe
H2Of
H2Og
a
Unless otherwise noted, all reactions for the additive study were conducted
Unlike the planar and central chiral prolinamido thiourea 10a,
when the planar chiral amino thiourea 6 was used as a bifunctional
organocatalyst, a simple transition state model could account for
the stereochemical outcome of the reaction (Fig. 1, model B). The
carbonyl group of isatin was bonded by the NH of the thiourea
and the resulting activated C@O bond is approached by the enam-
ine b-C atom at its Re-face to avoid steric hindrance between the R
group and the isatin aromatic ring, leading to an (S)-configuration
at the newly formed stereogenic center.
using 11a (0.136 mmol), 12a (31 equiv 4.216 mmol), and 20 mol % catalyst loading
of 10a, in 1.25 mL of THF with additive at room temperature, ee was determined by
chiral HPLC (Chiralpak IA colmun) analysis.
b
Isolated yield.
20 mol % additive was used.
1 equiv. of H2O was used.
2 equiv. of additive were used.
3 equiv. of H2O were used.
10 equiv. of H2O were used.
c
d
e
f
g
h
The reaction was performed at ꢀ45 °C.

Y. Lu et al. / Tetrahedron: Asymmetry 24 (2013) 1082–1088
1085
To a mixture of the oxime (100 mg, 0.304 mmol) and K2CO3
(252.1 mg, 1.82 mmol) in acetone (5.0 mL) was added dimethyl
sulfate (0.12 mL, 1.22 mmol). After stirring for 24 h at room tem-
perature, aq ammonia (1.0 mL) was added followed by water
(15 mL). The mixture was extracted with CH2Cl2 (3 ꢁ 10 mL). The
organic phase was washed twice with brine, and dried over MgSO4.
After removal of the solvent under reduced pressure, the residue
was purified by flash column chromatography (petroleum ether/
ethyl acetate = 10:1), to give the corresponding oxime ether
(105.0 mg, 98% yield).
N
H
N
H
NH
N
H
S
S
R
O
PCP
NH
N
R
O
N
F3C
F3C
H
CF3
CF3
In an oven-dried Schlenk flask charged with the oxime ether
(102.0 mg, 0.30 mmol) and anhydrous THF (1.0 mL), the resulting
solution was stirred at 65 °C under argon and borane-methyl sul-
fide (0.75 mmol) was added dropwise via a syringe. The reaction
mixture was stirred for 2 h at 65 °C, and then the solution was
cooled to room temperature. Next MeOH (2.0 mL) was added,
and the mixture was stirred for another 20 min. After the mixture
was taken to dryness by a rotary evaporator, MeOH (5.0 mL) and
2 M hydrochloric acid (5.0 mL) were added to the residue and
the solution was refluxed for 1 h. The mixture was cooled to
25 °C and then basified with NaOH pellets to pH 10. After evapora-
tion under reduced pressure, the residue was extracted with CH2-
Cl2 (3 ꢁ 5.0 mL) and the combined organic phases were washed
with brine and dried over MgSO4. The solvent was removed under
reduced pressure and the crude product was purified by flash chro-
matography (CH2Cl2/ethanol = 15:1) to afford 3 as a white solid
Model A
Model B
Figure 1. Proposed transition state models for the asymmetric aldol reactions.
3. Conclusion
In conclusion, several novel [2.2]paracyclophane-based amino
thioureas have been synthesized and successfully applied to asym-
metric aldol reaction of isatins with ketones. The corresponding al-
dol products were obtained in good enantioselectivities (up to 88%
ee) and high yields (up to 92%). Further modification of [2.2]para-
cyclophane-based amino thioureas as well as investigations into
other reaction variants are currently underway in our laboratory.
4. Experimental
4.1. General
(75.6 mg, 80% yield). Mp: 156–158 °C. ½a D20
¼ ꢀ165 (c 0.1, CH2Cl2);
ꢂ
1H NMR (300 MHz, CDCl3) d 1.61 (br s, 2H), 2.76–2.93 (m, 3H),
3.02–3.20 (m, 3H), 3.33–3.46 (m, 2H), 3.59 (br s, 1H), 3.84 (br s,
1H), 6.44–6.54 (m, 4H), 6.65 (s, 1H), 7.00 (s, 1H). 13C NMR
(75 MHz, CDCl3) d 32.8, 33.0, 33.5,35.5, 44.6, 126.6, 127.7, 131.3,
131.6, 133.2, 134.8, 135.3, 136.6, 138.9, 140.1, 141.4, 142.1; HRMS
(ESI): calcd for C17H19BrN (M+H)+ 316.0701, found: 316.0690.
Commercially available reagents were used without further
purification unless otherwise noted. Ketones were obtained from
commercial sources and were distilled or filtered through a plug
of silica gel prior to use. Solvents were reagent grade and purified
by standard techniques. Reactions were stirred magnetically under
an argon atmosphere and monitored by thin layer chromatography
(TLC). Purification of reaction products was carried out by column
chromatography on silica gel. Melting points were recorded on a
melting point apparatus and are uncorrected. Optical rotations
were measured on a polarimeter and are reported in degrees (c
g/100 mL, solvent). 1H and 13C NMR spectra were recorded on a
Bruker AVANCE-300 at 298 K. Chemical shifts are reported in parts
per million (ppm) downfield from tetra-methylsilane (TMS) with
reference to the internal standard for 1H NMR and 13C NMR spec-
tra. HRMS spectra were recorded on an Agilent 100 ABI-API4000
spectrometer. Enantiomeric excess was determined by HPLC on a
Chiralpak IA chiral column using hexane/EtOH or hexane/i-PrOH
as eluents with UV detection at 254 nm.
4.2.2. Preparation of (RP,RP)-bis(12-bromo[2.2]paraclophan-4-yl
methylene)amine 4
An oven-dried Schlenk flask was charged with (RP)-4-amino-
methyl-12-bromo[2.2]paracyclophane 3 (589.2 mg, 1.87 mmol),
(RP)-4-formyl-12-bromo[2.2]paracyclophane
2
(587.2 mg,
1.87 mmol), THF (15 mL), and NaBH4 (991.4 mg, 26.18 mmol).
The mixture was stirred at room temperature for 3 days. Next,
MeOH (15 mL) was added, and the mixture was stirred for another
1 h. After the mixture was evaporated to dryness under vacuum,
MeOH (20 mL) and 12 M hydrochloric acid (10 mL) were added
to the residue, and the resulting solution was refluxed for 1 h.
The reaction mixture was cooled to 25 °C and added to satd aq
NaOH (10 mL). Next, MeOH was removed under reduced pressure,
and the aqueous layer was extracted with CH2Cl2 (3 ꢁ 20 mL). The
combined extract was evaporated on a rotary evaporator, and the
residue was purified by chromatography on silica gel (CH2Cl2/ethyl
acetate = 15:1) to furnish 4 as a white solid (862.7 mg, 75% yield);
4.2. Synthesis of amino thiourea 6 derived from
[2.2]paracyclophane
4.2.1. Preparation of (RP)-4-aminomethyl-12-bromo[2.2]para-
Mp: 188–190 °C; ½a D20
ꢂ
¼ ꢀ91 (c 0.05, CH2Cl2); 1H NMR (300 MHz,
cyclophane 3
CDCl3) d 1.61 (br s, 1H), 2.68–2.84 (m, 6H), 2.97–3.19 (m, 6H),
3.29–3.45 (m, 4H), 3.46 (d, J = 13.2 Hz, 2H), 3.65 (d, J = 13.2 Hz,
2H), 6.45 (dd, J1 = 7.5 Hz, J2 = 1.5 Hz, 2H), 6.48–6.49 (m, 4H), 6.51
(d, J = 7.8 Hz, 2H), 6.56 (s, 2H), 7.03 (d, J = 1.2 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 32.8, 33.2, 33.6, 35.6, 51.8, 126.6, 129.5, 131.6,
133.3, 134.7, 135.3, 137.8, 138.9, 139.2, 139.6, 141.5; HRMS
(ESI): calcd for C34H34Br2N (M+H)+ 616.1038, found 616.1021.
(RP)-4-Bromo-12-formyl[2.2]paracyclophane
2
(200 mg,
0.64 mmol) and NaOAc (262.4 mg, 3.20 mmol) were dissolved in
EtOH (5.0 mL) at 78 °C. Hydroxylamine hydrochloride (177.9 mg,
2.56 mmol) was added to the stirred solution in portions. The mix-
ture was stirred at 78 °C for 2 h. After completion (monitored by
TLC), the solvent was removed under reduced pressure. Water
(10 mL) was added to the residue, and the mixture was extracted
with CH2Cl2 (3 ꢁ 10 mL). The combined CH2Cl2 extract was washed
with brine, dried over anhydrous Na2SO4, and then concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (petroleum ether/ethyl acetate = 5/1) to
afford oxime as a white solid (210.0 mg) in essentially quantitative
yield.
4.2.3. Preparation of (RP,RP)-bis(12-amino[2.2]paracyclophan-
4-yl methylene)amine 5
At first, (RP,RP)-bis(12-bromo[2.2]paraclophan-4-yl methy-
lene)amine 4 (100 mg, 0.163 mmol) and di-tert-butyl pyrocarbon-
ate (0.045 mL, 0.196 mmol) were dissolved in CH2Cl2 (3.0 mL) and
stirred at ambient temperature until the starting material was

1086
Y. Lu et al. / Tetrahedron: Asymmetry 24 (2013) 1082–1088
consumed. The mixture was concentrated to dryness under
vacuum and directly purified by flash column chromatography
(CH2Cl2) to yield 115.0 mg of N-Boc-protected amine (99% yield)
as a white solid.
142.5; HRMS (ESI): calcd for C52H44F12N5S2 (M+H)+ 1030.2847,
found 1030.2861.
4.3. Synthesis of planar and central chiral amino thioureas
derived from proline and [2.2]paracyclophane 10a, 10b
In a glovebox, an oven-dried Schlenk flask was charged with the
N-Boc-protected amine (115.1 mg, 0.161 mmol), Pd-DPPF (5.8 mg,
0.5 mol %), benzhydrylideneamine (87.4 mg, 0.483 mmol), sodium
t-butoxide (46.4 mg, 0.483 mmol), and toluene (2.0 mL). The mix-
ture was stirred at 110 °C under nitrogen for 8 h. After the reaction
mixture was cooled to room temperature and diluted with CH2Cl2
(3.0 mL), HOAc was added until the mixture tested pH 6 by an indi-
cator paper. Next, 3 M hydrochloric acid (1.0 mL) was added and
stirred for 4 h at room temperature. After completion (monitored
by TLC), the white precipitate formed was filtered. The filtered so-
lid product was dispersed in ethanol (4.0 mL) and the pH of the
suspension was adjusted to 9 by the addition of a 4 M NaOH aque-
ous solution slowly. The solvent was removed, and the residue was
purified by chromatography on silica gel (CH2Cl2/ethanol 3:1) to
furnish the desired product 5 (47.1 mg, 60% yield) as a white solid.
4.3.1. Preparation of (RP,S)-4-amino-12-(N-Boc-prolinamido)
[2.2]paracyclophane 9a
To
a
solution of (RP)-4-amino-12-benzhydrylideneami-
no[2.2]paracyclophane 7a17 (97.3 mg, 0.242 mmol), and Et3N
(0.51 mL, 3.63 mmol) in anhydrous CH2Cl2 (2.0 mL) at 0 °C was
added N-Boc-(S)-proline chloride 818 (0.14 M in CH2Cl2, 3.46 mL,
0.484 mmol). The mixture was stirred at room temperature under
nitrogen for 8 h. The reaction was quenched by the addition of 10%
aq NaHCO3 (2.0 mL). The organic layer was separated, washed with
satd aq NaHCO3 (2.0 mL), and dried over Na2SO4. After removal of
the solvent in vacuum, the residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 10:1; petroleum
ether/ethyl acetate = 4:1) to afford the desired amide as a yellow
solid (111.7 mg, 77% yield).
Mp: 186–188 °C; ½a D20
ꢂ
¼ ꢀ102 (c 0.1, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d 2.57–2.71 (m, 4H), 2.73–2.81 (m, 3H), 2.89–2.99 (m,
3H), 3.02–3.09 (m, 7H), 3.24–3.29 (m, 2H), 3.40 (d, J = 13.2 Hz,
2H), 3.66 (d J = 13.2 Hz, 2H), 5.38 (d, J = 1.5 Hz, 2H), 6.07 (dd,
J1 = 7.8 Hz, J2 = 1.5 Hz, 2H), 6.27 (d, J = 7.8 Hz, 2H), 6.36 (dd,
J1 = 7.8 Hz, J2 = 1.5 Hz, 2H), 6.54 (d, J = 7.8 Hz, 2H), 7.05 (d,
J = 1.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 32.0, 32.5, 33.1, 33.9,
51.4, 118.4, 122.7, 124.3, 128.0, 131.7, 134.3, 135.6, 137.4, 138.4,
139.5, 141.1, 145.0; HRMS (ESI): calcd for C34H38N3 (M+H)+
488.3066, found 488.3074.
The amide and NaOAc (61.3 mg, 0.745 mmol) were dissolved in
EtOH (5.0 mL) at 45 °C, after which hydroxylamine hydrochloride
(46.6 mg, 0.671 mmol) was added to the stirred solution in por-
tions. The mixture was stirred at 45 °C for 6 h. After completion
(monitored by TLC), the solvent was removed under reduced pres-
sure. Water (10 mL) was then added, and the mixture was ex-
tracted with CH2Cl2 (3 ꢁ 10 mL). The combined CH2Cl2 extract
was washed with brine, dried over anhydrous Na2SO4, and then
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (CH2Cl2; CH2Cl2/ethyl ace-
tate 5:1) to give the product 9a as a white solid (77.0 mg, 95%
4.2.4. Preparation of (RP,RP)-bis(12-(3,5-bis(trifluoro-methyl)-
phenyl thiocarboxamino)[2.2]paracyclophan-4-yl
methylene)amine 6
yield). Mp: 180–181 °C; ½a D20
ꢂ
¼ ꢀ248 (c 0.09, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 1.53 (s, 9H), 1.89–2.05 (m, 2H), 2.51–2.60 (br
s, 1H), 2.62–2.76 (m, 2H), 2.84–3.02 (m, 2H), 3.05–3.15 (m, 2H),
3.17–3.23 (m, 2H), 3.44 (br s, 2H), 3.85 (br s, 2H), 4.55 (s, 1H),
5.77 (s, 1H), 6.07 (d, J = 6.9 Hz, 1H), 6.28–6.33 (m, 2H), 6.52 (d,
J = 7.8 Hz, 1H), 7.81 (s, 1H), 8.73 (br s, 1H); 13C NMR (75 MHz,
CDCl3) d 24.5, 28.1, 28.5, 32.3, 32.5, 32.6, 33.4, 47.5, 61.2, 81.0,
119.0, 120.3, 122.5, 124.2, 129.2, 134.8, 135.5, 136.7, 140.7,
140.9, 146.4, 156.4, 170.1; HRMS (ESI): calcd for C26H34N3O3
(M+H)+ 436.2600, found 436.2589.
To a solution of (RP,RP)-bis(12-amino[2.2]paracyclophan-4-yl
methylene)amine 5 (93.1 mg, 0.191 mmol) in CH2Cl2 (1.5 mL)
was added di-tert-butyl pyrocarbonate (0.05 mL, 0.21 mmol) at
ꢀ5 °C. The mixture was stirred at ꢀ5 °C for 2 h. The crude product
was rapidly purified by flash column chromatography (CH2Cl2/
ethyl acetate 20:1) to afford 112 mg (quantitative yield) of the
mono-Boc-protected 5 as a white solid.
To a stirred solution of mono-Boc-protected 5 (112.2 mg,
0.191 mmol) in anhydrous CH2Cl2 at 30 °C under argon, 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (0.10 mL, 0.573 mmol) was
added dropwise via a syringe, and the reaction mixture was stirred
overnight at 30 °C. After completion (monitored by TLC), the
remaining 3,5-bis(trifluoromethyl)-phenyl isothiocyanate was re-
moved rapidly by flash column chromatography (CH2Cl2/petro-
leum ether 2:1; CH2Cl2/ethyl acetate 50:1) to give the desired
thiourea as a white solid (200.0 mg, 93% yield).
4.3.2. Preparation of (RP,S)-4-(3,5-bis(trifluoromethyl)-phenyl
thiocarboxamino)-12-prolinamido[2.2]paracyclophane 10a
To a stirred solution of 9a (300.1 mg, 0.689 mmol) in anhydrous
CH2Cl2 at 30 °C under argon, 3,5-bis(trifluoromethyl)phenyl isothi-
ocyanate (0.18 mL, 1.03 mmol) was added dropwise via syringe,
and the reaction mixture was stirred overnight at 30 °C. After com-
pletion (monitored by TLC), the remaining 3,5-bis(trifluoromethyl)
phenyl isothiocyanate was removed rapidly by flash column chro-
matography (CH2Cl2/ethyl acetate 25:1) to give the thiourea as a
white solid (462.6 mg, 95% yield).
To a stirred solution of the thiourea (200.6 mg, 0.178 mmol) in
CH2Cl2 (1.5 mL), TFA (1.0 mL) was added and the reaction mixture
was stirred for 30 min at 0 °C. Saturated aqueous sodium carbon-
ate solution was added until the mixture became basic (pH 8).
The mixture was extracted by CH2Cl2 (3 ꢁ 10 mL) and the com-
bined organic phases were washed with brine and dried over
Na2SO4. The solvent was removed under reduced pressure and
the crude product was purified by flash chromatography (CHCl3;
CHCl3/ethyl acetate 15:1) to give the desired product 6 (155.7 mg,
To a stirred solution of the thiourea (462.6 mg, 0.655 mmol) in
CH2Cl2 (3.0 mL), TFA (3.0 mL) was added and the reaction mixture
was stirred for 30 min at 0 °C. Next, satd aq NaHCO3 solution was
added until the stirred mixture tested basic (pH 8). The mixture
was extracted by CH2Cl2 (3 ꢁ 15 mL), and the combined organic
phases were washed with brine and dried over Na2SO4. The solvent
was removed under reduced pressure and the crude product was
purified by flash chromatography (CHCl3/ethanol 15:1) to give
the desired product 10a as a white solid (355.2 mg, 85% yield).
85% yield) as a white solid. Mp: 116–118 °C; ½a D20
¼ ꢀ79 (c 0.07,
ꢂ
CH2Cl2); 1H NMR (300 MHz, CDCl3) d 2.70–3.00 (m, 6H), 3.04–
3.21 (m, 5H), 3.14–3.28 (m, 6H), 3.53–3.91 (m, 2H), 3.99–4.08
(m, 2H), 6.23 (s, 2H), 6.45–6.68 (m, 8H), 7.03 (s, 2H), 7.63 (s,
2H), 7.97 (s, 4H), 9.14 (br s, 2H); 13C NMR (75 MHz, CDCl3) d
32.2, 32.5, 33.8, 34.1, 50.0, 119.0, 121.2 (J = 270.2 Hz), 124.4,
124.8, 127.5, 128.0, 128.4, 131.1, 131.6 (J = 33.8 Hz), 132.0,
132.2, 132.5, 133.3, 134.7, 135.2, 135.7, 136.4, 137.6, 139.9, 140.2,
Mp: 142–144 °C;
½
a 2D0
ꢂ
¼ ꢀ146 (c 0.08, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 1.69–1.83 (m, 2H), 1.99–2.10 (m, 1H), 2.23–
2.36 (m, 2H), 2.78–2.88 (m, 2H), 2.91–3.00 (m, 2H), 3.04–3.16
(m, 4H), 3.25–3.40 (m, 2H), 4.05 (dd, J1 = 9.3 Hz, J2 = 5.1 Hz, 1H),
6.22 (s, 1H), 6.40 (dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 6.54 (d,

Y. Lu et al. / Tetrahedron: Asymmetry 24 (2013) 1082–1088
1087
J = 8.1 Hz, 1H), 6.57 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 6.66 (d,
J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.63(s, 1H), 7.81 (br s, 1H), 8.03 (s,
2H), 9.90 (s, 1H), 9.97 (s, 1H); 13C NMR (75 MHz, CDCl3) d 26.2,
31.3, 32.0, 33.1, 33.2, 34.1, 47.5, 61.3, 118.7, 118.8, 121.2
(J = 277.5 Hz), 121.3, 124.2, 124.9, 127.3, 129.5, 129.8, 131.1,
131.6, 132.0 (J = 35.2 Hz), 132.5, 135.0, 136.2, 136.4, 136.5, 140.1,
141.3, 141.9, 174.1, 179.0; HRMS (ESI): calcd for C30H29F6N4OS
(M+H)+ 607.1966, found 607.1940.
(5:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 21 min,
tminor = 27.9 min.
4.4.4. (S)-7-Chloro-3-hydroxy-3-(2-oxopropyl)indolin-2-one 13d20c
White solid, 86% yield; Mp: 175–177 °C. ½a D20
¼ ꢀ14:5 (c 0.75,
ꢂ
MeOH, 66% ee); enantiomeric excess of 13d was measured by chi-
ral stationary phase HPLC analysis using a Chiralpak IA column
(5:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 33.6 min,
tminor = 37.5 min.
4.3.3. Preparation of (SP,S)-4-(3,5-bis(trifluoromethyl)-phenyl
thiocarboxamino)-12-prolinamido[2.2]paracyclo-phane 10b
Compound (SP,S)-10b was prepared from (SP)-4-benzhydrylid-
ene amino-12-amino[2.2]paracyclophane 7b following the repre-
sentative procedure described as above. White solid, Mp: 142–
4.4.5. (S)-7-Fluoro-3-hydroxy-3-(2-oxopropyl)indolin-2-one 13e
White solid, 85% yield; Mp: 185–187 °C. ½a D20
¼ ꢀ13:1 (c 0.67,
ꢂ
MeOH, 60% ee). 1H NMR (300 MHz, DMSO-d6) d 2.00 (3H, s), 3.08
(d, J = 16.8 Hz, 1H), 3.35 (d, J = 17.1 Hz, 1H), 6.10 (s, 1H), 6.89–
6.95 (m, 1H), 7.06–7.12 (m, 2H), 10.71 (s, 1H); 13C NMR (75 MHz,
DMSO-d6). d 30.3, 50.2, 72.56, 72.6, 115.9, 116.1, 119.6, 122.0,
122.1, 129.4, 129.6, 134.6, 134.7, 144.7, 147.9, 177.9, 205.1. HRMS
(ESI): calcd for C11H10FNO3 (M+Na)+ 246.0542, found 246.0561;
C11H11FNO3 (M+H)+ 224.0723, found 224.0719. Enantiomeric ex-
cess of 13e measured by chiral stationary phase HPLC analysis
using a Chiralpak IA column (5:1 hexane/EtOH at 0.5 mL/min,
20 °C), tmajor = 49.6 min, tminor = 31.6 min.
144 °C; ½a 2D0
ꢂ
¼ þ86 (c 0.1, CH2Cl2); 1H NMR (300 MHz, CDCl3)
1.91–1.96 (m, 2H), 2.20–2.41 (m, 3H), 2.80–2.93 (m, 3H), 3.09–
3.38 (m, 7H), 4.03 (dd, J1 = 8.7 Hz, J2 = 4.8 Hz, 1H), 6.14 (s, 1H),
6.41 (d, J = 7.8 Hz, 1H), 6.53–6.59 (m, 2H), 6.66 (d, J = 7.8 Hz, 1H),
7.56 (s, 1H), 7.64 (s, 1H), 7.82 (br s, 1H), 8.04 (s, 2H), 9.92 (s, 1H),
10.07 (s, 1H); 13C NMR (75 MHz, CDCl3) d 26.7, 31.0, 32.0, 33.3,
33.4, 34.1, 47.5, 61.0, 118.8, 121.3, 121.5 (J = 271.1 Hz), 124.32,
124.9, 127.4, 129.8, 129.9, 131.6, 132.0 (J = 33.8 Hz), 132.4, 132.5,
135.1, 136.3, 136.5, 140.2, 141.3, 141.7, 173.9, 179.1; HRMS
(ESI): calcd for C30H29F6N4OS (M+H)+ 607.1966, found 607.1977.
4.4.6. (S)-5-Methyl-3-hydroxy-3-(2-oxopropyl)indolin-2-one 13f8f
White solid, 88% yield; Mp: 161–163 °C; ½a D20
¼ ꢀ13:3 (c 0.61
ꢂ
4.4. General experimental procedure for the enantioselective
aldol reaction
MeOH, 68% ee); enantiomeric excess of 13f was measured by
chiral stationary phase HPLC analysis using
a Chiralpak IA
column (5:1 hexane/EtOH at 0.5 mL/min, 20 °C), tmajor = 23.4 min,
tminor = 27.1 min.
To a mixture of catalyst (0.0272 mmol, 20 mol %), isatin 11
(0.136 mmol), and the specified additive in THF (1.25 mL) was
added carbonyl compound 12 (4.216 mmol) at room temperature.
After stirring for 48 h at room temperature, the solvent was re-
moved under reduced pressure to give a residue which was di-
rectly purified by column chromatography on silica gel to afford
the aldol product. The enantiomeric excess was determined using
HPLC on a Chiralpak IA chiral column, with UV detection at
254 nm.
4.4.7. (S)-5-Chloro-3-hydroxy-3-(2-oxopropyl)indolin-2-one 13g20a
White solid, 83% yield; Mp: 158–160 °C. ½a D20
¼ ꢀ15:1 (c 0.47
ꢂ
MeOH, 70% ee); enantiomeric excess of 13g was measured by
chiral stationary phase HPLC analysis using
a Chiralpak IA
column (5:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 31.2 min,
tminor = 54.0 min.
Analytical characteristics for compounds 13a–b, 13d, 13f–13i,
and 13k–13l were in agreement with previously reported spectra
and properties.1b,4b,8f,20
4.4.8. (S)-5-Fluoro-3-hydroxy-3-(2-oxopropyl)indolin-2-one
13h1b
White solid, 92% yield; Mp: 183–185 °C; ½a D20
¼ ꢀ40:1 (c 0.71
ꢂ
MeOH, 88% ee); enantiomeric excess of 13h was measured by chi-
ral stationary phase HPLC analysis using a Chiralpak IA column
(5:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 32.1 min,
tminor = 52.9 min.
4.4.1. (S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-one 13a1b
White solid, 89% yield; Mp: 168–170 °C. ½a D20
¼ ꢀ21:3 (c 0.90,
ꢂ
MeOH, 76% ee); enantiomeric excess of 13a was measured by chi-
ral stationary phase HPLC analysis using a Chiralpak IA column
(4:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 21.1 min;
tminor = 28.0 min.
4.4.9. (S)-5-Fluoro-3-hydroxy-3-(2-oxo-2-phenylethyl)-indolin-
2-one 13i1b
White solid, 78% yield; Mp: 172–173 °C; ½a D20
¼ ꢀ47:8 (c 0.75
ꢂ
4.4.2. (S)-1-Methyl-3-hydroxy-3-(2-oxopropyl)indolin-2-one
MeOH, 64% ee); enantiomeric excess of 13i was measured by chiral
13b8f
stationary phase HPLC analysis using a Chiralpak IA column (5:1
White solid, 87% yield; Mp: 153–155 °C; ½a D20
ꢂ
¼ ꢀ4:4 (c 0.65,
hexane/EtOH
at
0.5 mL/min,
20 °C),
tmajor = 62.0 min,
MeOH, 25% ee); enantiomeric excess of 13b was measured by chi-
ral stationary phase HPLC analysis using a Chiralpak IA column
(5:1 hexane/EtOH at 0.5 mL/min, 20 °C), tmajor = 23.4 min,
tminor = 27.1 min.
tminor = 110.6 min.
4.4.10. (S)-5-Fluoro-3-hydroxy-3-(2-(4-methoxyphenyl)-2-oxoethyl)
indolin-2-one 13j
White solid, 79% yield; Mp: 170–172 °C; ½a D20
¼ ꢀ52:6 (c 0.82
ꢂ
4.4.3. (S)-1-Trityl-3-hydroxy-3-(2-oxopropyl)indolin-2-one 13c
MeOH, 72% ee). 1H NMR (300 MHz, DMSO-d6) d 3.52–3.57 (d,
J = 17.4 Hz, 1H), 3.83 (s, 3H), 4.03 (d, J = 17.7 Hz, 1H), 6.14 (s, 1H),
6.78 (q, 1H), 6.95–7.03 (m, 3H), 7.19 (dd, 1H) 7.87 (d, 2H), 10.25
(s, 1H); 13C NMR (75 MHz, DMSO-d6); d 45.8, 56.0, 73.8, 110.4,
110.5, 111.8, 112.2, 114.3, 115.1, 115.5, 129.6, 130.7, 134.1,
134.2, 139.6, 156.7, 159.8, 163.8, 178.9, 195.2; HRMS (ESI): calcd
for C17H15FNO4 (M+H)+ 316.0985, found 316.0995; enantiomeric
excess of the 13j was measured by chiral stationary phase HPLC
White solid, 89% yield; Mp: 210–212 °C; ½a D20
¼ ꢀ2:4 (c 0.93,
ꢂ
MeOH, 4% ee). 1H NMR (300 MHz, CDCl3) d 2.14 (s, 3H), 2.98 (d,
J = 16.5 Hz, 1H), 3.14 (d, J = 16.5 Hz, 1H), 3.59 (br s, 1H), 6.28–
6.31 (m, 1H), 6.90–6.95 (m, 2H), 7.17–7.28 (m, 10H), 7.48–7.50
(m, 6H); 13C NMR (75 MHz, CDCl3) d 31.4, 49.8, 73.8, 74.5, 116.4,
122.6, 123.0, 126.9, 127.7, 128.5, 129.4, 129.6, 141.9, 143.5,
177.8, 206.5. HRMS (ESI): calcd for C30H25NO3 (M+Na)+ 470.1732,
found 470.1719. Enantiomeric excess of 13c was measured by chi-
ral stationary phase HPLC analysis using a Chiralpak IA column
analysis using
a Chiralpak IA column (1:1 hexane/EtOH at
0.5 mL/min, 20 °C), tmajor = 22.6 min, tminor = 45.3 min.

1088
Y. Lu et al. / Tetrahedron: Asymmetry 24 (2013) 1082–1088
4.4.11. (S)-3-Hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one 13k1b
Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 9286–9288; (g) Zuend, S. J.;
Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358–15374; (h) Veitch, G. E.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 7332–7335; (i) Reisman, S. E.;
Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198–7199; (j)
Lalonde, M. P.; McGowan, M. A.; Rajapaksa, N. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 2013, 135, 1891–1894.
White solid, 79% yield; Mp: 173–175 °C; ½a D20
¼ ꢀ45:7 (c 0.47
ꢂ
MeOH, 58% ee); enantiomeric excess of 13k was measured by chi-
ral stationary phase HPLC analysis using a Chiralpak IA column
(1:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 17.2 min,
tminor = 27.4 min.
10. For Takemoto’s amine thioureas for catalysis, see: (a) Okino, T.; Nakamura, S.;
Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625–627; (b) Hoashi, Y.; Okino, T.;
Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032–4035; (c) Inokuma, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413–9419; (d) Yamaoka,
Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686–6687; (e)
Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593–601; (f) Takasu, K.; Azuma, T.;
Takemoto, Y. Tetrahedron Lett. 2010, 51, 2737–2740; (g) Inokuma, T.; Takasu,
K.; Sakaeda, T.; Takemoto, Y. Org. Lett. 2009, 11, 2425–2428; (h) Sakamoto, S.;
Inokuma, T.; Takemoto, Y. Org. Lett. 2011, 13, 6374–6377.
11. Li, X.; Zhang, Y. Y.; Xue, X. S.; Jin, J. L.; Tan, B. X.; Liu, C.; Dong, N.; Cheng, J. P.
Eur. J. Org. Chem. 2012, 9, 1774–1782.
12. Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am.
Chem. Soc. 1997, 119, 6207–6208.
4.4.12. (S)-3-Hydroxy-3-(2-(4-methoxyphenyl)-2-oxoethyl) indolin-
2-one 13l20b
White solid, 80% yield; Mp: 181–183 °C; ½a D20
¼ ꢀ83:5 (c 0.86
ꢂ
MeOH, 68% ee); enantiomeric excess of the 13l was measured by
chiral stationary phase HPLC analysis using a Chiralpak IA column
(1:1 hexane/i-PrOH at 0.5 mL/min, 20 °C), tmajor = 23.8 min,
tminor = 46.3 min.
13. For planar chiral paracyclophanes in asymmetric catalysis, see: (a) Dahmen,
S.; Bräse, S. J. Am. Chem. Soc. 2002, 124, 5940–5941; (b) Wu, X. W.; Zhang, T.
Z.; Yuan, K.; Hou, X. L. Tetrahedron: Asymmetry 2004, 15, 2357–2365; (c)
Bräse, S.; Höfener, S. Angew. Chem., Int. Ed. 2005, 44, 7879–7881; (d)
Whelligan, D. K.; Bolm, C. J. Org. Chem. 2006, 71, 4609–4618; (e)
Rozenberg, V.; Sergeeva, E.; Hopf, H. In Modern Cyclophane Chemistry;
Gleiter, R., Hopf, H., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 435; (f)
Aly, A. A.; Brown, A. B. Tetrahedron 2009, 65, 8055–8089; (g) Jiang, B.; Lei, Y.;
Zhao, X. L. J. Org. Chem. 2008, 73, 7833–7836; (h) Paradies, J. Synthesis 2011,
23, 3749–3766; (i) Gibson, S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1,
1256–1269; (j) Hermanns, N.; Dahmen, S.; Bolm, C.; Bräse, S. Angew. Chem.,
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Acknowledgments
Financial support from the National Natural Science Foundation
of China (Grant No. 20671059) and Shandong Province Natural Sci-
ence Foundation (ZR2011BM013) is gratefully acknowledged.
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