Synthesis of a Class of Chiral-Bridged Phosphoramidite Ligands and Their Applications in the First Iridium-Catalyzed Asymmetric Addition of Arylboronic Acids to Isatins

Article abstract of DOI:10.1021/acs.joc.5b00595

A series of novel chiral phosphoramidite ligands based on chiral-bridged biphenyl backbones have been prepared conveniently and characterized. The ligands complexed with [IrCodCl]₂ provided the first iridium catalyst system for the asymmetric a

Full text of DOI:10.1021/acs.joc.5b00595

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Article
Synthesis of a class of chiral-bridged phosphoramidite
ligands and their applications in the first iridium-catalyzed
asymmetric addition of arylboronic acids to isatins
Yue Zhuang, Yuwei He, Zihong Zhou, Wang Xia, Chuyu Cheng,
Meng Wang, Bin Chen, Zhongyuan Zhou, Jiyan Pang, and Liqin Qiu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00595 • Publication Date (Web): 23 Jun 2015
Downloaded from http://pubs.acs.org on July 2, 2015
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Synthesis
of
a
class
of
chiral-bridged
phosphoramidite ligands and their applications in the
first iridium-catalyzed asymmetric addition of
arylboronic acids to isatins
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†
†
†
†
†
†
Yue Zhuang, Yuwei He, Zihong Zhou, Wang Xia, Chuyu Cheng, Meng Wang,
†
§
†
,†,‡
Bin Chen, Zhongyuan Zhou, Jiyan Pang and Liqin Qiu*
†
School of Chemistry and Chemical Engineering, South China Sea BioꢀResource
Exploitation and Utilization Collaborative Innovation Center, The Key Laboratory of
Lowꢀcarbon Chemistry & Energy Conservation of Guangdong Province, Sun Yatꢀsen
University, No. 135 Xingangxi Road, Guangzhou 510275, People’s Republic of China
‡
Huizhou Research Institute of Sun Yatꢀsen University, Dayawan, Huizhou, People’s
Republic of China
§
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University,
HK (China)
Fax: (+86)ꢀ20ꢀ8411ꢀ0996; eꢀmail: qiuliqin@mail.sysu.edu.cn
Abstract. A series of novel chiral phosphoramidite ligands based on chiralꢀbridged
biphenyl backbones have been prepared conveniently and characterized. The ligands
complexed with [IrCodCl]
2
provided the first iridium catalyst system for the
asymmetric addition of arylboronic acids to Nꢀprotected isatins with high efficiency.
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When performed in THF/H O at 80℃ with 2 equiv. of the arylboronic acids, the
transformations acquired good to excellent results (up to 98% yield and 95% ee).
INTRODUCTION
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Transition metalꢀcatalyzed asymmetric reactions lie at the core of organic synthesis,
in which design and synthesis of efficient chiral ligands plays a key role. Since
1
Monophos was synthesized in 1994 and employed in asymmetric addition reaction
2
later, a plenty of phosphoramidite ligands were developed for their easy synthesis,
convenient modification and potential applications in many kinds of enantioselective
3
catalytic reactions. Nowadays chiral phosphoramidite compounds have become one
of the most widely used ligands.
Chiral 3ꢀsubstituted oxindoles are common structural motifs which constitute a
useful class of compounds that can be found in various biologically active molecules
4
and natural products. A number of successful methods for 3ꢀhydroxyoxindoles have
5
been developed in recent years, and the formation of quaternary carbon centers via
addition of arylboronic acids to isatins seems to be one of the most useful methods for
efficient construction of this structural scaffold. In 2006，Hayashi and coworkers first
reported the asymmetric addition of arylboronic acids to Nꢀprotected isatins catalyzed
with Rh/(R)ꢀMeOꢀmop complex, achieving high enantioselectivities and excellent
yields. In their paper, a chiral phosphoramidite ligand was also tested, however, the
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obtained enantioselectivity was only 39% ee. Meanwhile, use of a rhodium/chiral
8
H ꢀBINOLꢀderived phosphoramidite as the catalyst afforded 55% ee in the similar
7
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reaction. Recently, several ligands including MeꢀBIPAM,
8
H ꢀBINOLꢀderived
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phosphineꢀoxazoline ligands, chiral NHC and chiral sulfoxide phosphine
complexed with ruthenium, palladium, copper or rhodium were also employed for the
catalysis. However, most of the obtained ee values via these cheaper central metal
catalytic systems such as Ru or Pd are still lower than those with Rh complex.
Relatively economical and efficient catalytic system is warmly expected. Herein, we
disclose the development of a new type of chiral phosphoramidite ligands based on
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chiralꢀbridged biphenyl backbones
and their applications in the first
iridiumꢀcatalyzed asymmetric addition of arylboronic acids to Nꢀprotected isatins.
The addition reactions acquired high yields and good to excellent enantioselectivities.
RESULTS AND DISCUSSION
Scheme 1. Synthesis of ligands 4
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Fig.1. X-ray crystal structure of ligand (S,S,R
a
,S,S)-4a (ORTEP drawing at 30%
ellipsoid probability).
As shown in Scheme 1, synthesis of ligands 4 was quite simple and robust. The key
desymmetrized annulation diphenol intermediates 3aꢀc were readily prepared from
prochiral 2,2,6,6ꢀtetrahydroxyꢀbiphenyl with different chiral bis(mesylate) or
1
3
N
bis(tosylate) by a Williamson synthesis. Following S 2 substitution reaction
mechanism, the central chirality configuration of the etherꢀlinked backbone became
reversed from 2. Meanwhile, perfect chirality transfer from central to axial chirality
was performed and products 3a-c were given in 76%, 53% and 68% yields
14
respectively. Reaction of 3aꢀc with phosphorus trichloride yielded corresponding
intermediates phosphoryl chlorides first. Subsequent addition of the desired amine to
the reaction system in the presence of a base finally acquired the phosphoramidite
ligands 4a-d and 4f-n. Dimethylamineꢀderived phosphoramidite ligand (S,S,R
a
)ꢀ4e
was prepared via another reaction of (S,S,R
a
)ꢀ3b with hexamethylphosphorus triamide
1
(
HMPT). Through a singleꢀcrystal Xꢀray diffraction analysis of ligand (S,S,R ,S,S)ꢀ4a,
a
all its chiral configurations were confirmed (Fig. 1). It is worthy to note that these
ligands are stable enough and can be purified by common silica gel column
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chromatography without special precaution to water or air.
a
Table 1. Metal Sources and Ligands Screening
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b
c
Entry
Metal
Ligand
Yield (%)
Ee (%)
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2
3
4
5
6
7
8
9
Rh(Cod)
Rh(Cod)
[RhNBDCl]2
Pd(OAc)
[IrCodCl]
[IrCodCl]
[IrCodCl]2
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
2
BF
Cl
4
(S,S,R
(S,S,R
a
a
,S,S)ꢀ4a
,S,S)ꢀ4a
86
69
86
81
88
87
53
61
75
84
48
8
14
2
2
(S,S,R ,S,S)ꢀ4a
a
2
(S,S,R
(S,S,R
(S,S,R
a
a
a
,S,S)ꢀ4a
,S,S)ꢀ4a
,R,R)ꢀ4b
8
2
84
15
17
21
10
13
55
76
6
2
(S,S,R )ꢀ4c
a
2
2
2
(S,S,R
(S,S,R
a
a
)ꢀ4d
)ꢀ4e
10
(S,R
a
)ꢀ4f
11
12
13
[IrCodCl]2
(R,R,S ,S,S)ꢀ4g
a
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
2
2
a
(R,R,S ,R,R)ꢀ4h 43
(R
(R
a
)ꢀ5
,S,S)ꢀ6
32
83
14
a
81
a
2
Reaction conditions: 0.2 mmol of Nꢀbenzyl isatin, phenylboronic acid (2 equiv.), [IrCodCl] (1 mol%),
b
ligand (2.2 mol%), KF (2 equiv.), 50℃, 48 h, solvent: THFꢀH
2
O (2 mLꢀ0.1 mL). Yield of isolated
c
product. Determined by chiral HPLC.
Fig. 2. Ligands (
R
)ꢀ5 and (
R
a
,S,S)ꢀ6.
a
Table 2. Solvents, Bases, and Temperature Screening
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Entry
Metal
Base
Solvent
Yield(%)
Ee(%)
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[IrCodCl]
[IrCodCl]2
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
HKF
EtOH/H
2
O
2
76
66
93
95
97
45
58
92
28
96
37
81
88
83
64
trace
31
54
39
73
<10
27
50
64
82
98
ꢀꢀ
90
90
88
91
88
42.
79
86
71
83
90
90
91
51
72
i
PrOH/H O
t
2
2
2
BuOH/H
THF/H
MTBE /H
2
O
O
2
2
O
[IrCodCl]2
DCM/H O
Dioxane/H O
2
DME/H
DMF/H
xylene/H O
2
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
2
2
2
O
O
2
1
0
[IrCodCl]2
2
11
12
13
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
2
2
THF
THF/H
THF/H
2
2
O
O
K
2
CO
KOH
PO
3
14
15
16
17
18
19
20
21
22
23
[IrCodCl]2
THF/H O
2
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
2
2
K
3
4
THF/H
THF/H
THF/H
2
2
2
O
O
O
t
d
KO Bu
CsF
ND
90
79
88
65
ND
[IrCodCl]2
Cs CO
THF/H O
2
3
2
[IrCodCl]
[IrCodCl]
[IrCodCl]
2
2
2
Et
3
N
THF/H
THF/H
THF/H
2
2
2
O
O
O
LiOH H
DIPEA
KF
KF
KF
KF
KF
KF
KF
2
O
e
[IrCodCl]2
THF/H O
93f
2
[IrCodCl]
[IrCodCl]
[IrCodCl]
[IrCodCl]2
ꢀꢀ
2
2
2
THF/H
THF/H
THF/H
2
2
2
O
O
O
88
90
g
24
25
26
27
h
90i
THF/H O
93
2
j
THF/H
THF/H
THF/H
2
2
2
O
O
O
ꢀꢀ
0
k
2
2
8
9
[IrCodCl]
[IrCodCl]
2
23
17
l
2
ꢀꢀ
67
a
2
Reaction conditions: 0.2 mmol of Nꢀbenzyl isatin, phenylboronic acid (2 equiv.), [IrCodCl] (1 mol%),
b
ligand (2.2 mol%), base (2 equiv.), 50℃, 48 h, solventꢀH
2
O (2 mLꢀ0.1 mL). Yield of isolated product.
c
d
e
f
g
Determined by chiral HPLC. Not determined. 50℃, 48 h, 1 equiv. base. 50℃, 48 h, 3 equiv. base.
h
i
j
6
0℃ 24 h, 1 equiv. base. 70℃, 24 h, 1 equiv. base. 80℃, 24 h, 1 equiv. base. [IrCodCl]
2
was not
k
l
used. Ligand was not used. Base was not used.
After acquiring the new type of ligands 4, we turned into investigation on the
asymmetric addition reaction of Nꢀprotected isatin and phenylboronic acid. At first,
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complexes of ligand (S,S,R
the reaction in the presence of 2.0 equiv. of KF as base at 50°C (Table 1, entries 1ꢀ5).
IrCodCl] as the metal source afforded the best result with the yield up to 88% and
4% ee (Table 1, entry 5). In contrast, both palladiumꢀ and rhodiumꢀcatalyzed
a
,S,S)ꢀ4a with different metal sources were examined for
[
2
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reaction with this ligand showed comparable activities but much lower
enantioselectivities (Table 1, entries 1ꢀ4). To gain insight into this catalytic system, we
then tested the rest of ligands (4b-4h) complexed with [IrCodCl]
comparison with phosphoramidite (S,S,R ,S,S)ꢀ4a bearing a highly bulky
S,S,R ,R,R)ꢀ4b possessing
)ꢀ1ꢀphenylethyl]ꢀamine counterpart provided a slight decrease in the yield and
2
in the reaction. In
a
bis[(S
)ꢀ1ꢀphenylethyl]amine,
ligand
(
a
a
bis[(R
much poorer enantiomeric excess (Table 1, entry 5 vs 6). This may be due to the
considerable effects of matching/mismatching between stereochemical elements of
15
the chiral amine and axial chirality in the ligands. Similar phenomenon also
occurred in the reaction for ligands (R,R,S ,S,S)ꢀ4g and (R,R,S ,R,R)ꢀ4h (Table 1,
a
a
entries 11 vs 12). Analysizing the catalytic results, we found that axial chirality
contrary to the central chiralities of the amine was the matched configuration. Ligands
a
(S,S,R )ꢀ4c-4e only provided moderate yields and very low ee’s of the phenylꢀadduct
(Table 1, entries 7ꢀ9). The results indicated that both larger steric hindrance and
proper central chirality in the amine unit of the phosphoramidite ligand led to higher
enantioselection. Ligand S,R )ꢀ4f derived from enantiomerically pure
)ꢀ1,2ꢀpropanediol as the auxiliary shows two signals in P NMR, because of the
(
a
3
1
(S
two possible diastereomers caused by the phosphorus centre and the
1
C symmetrical
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propyldioxy backbone. It also gave low enantioselectivity in spite of high yield
Table 1, entry 10). As a reference, we also used Feringa’s ( )ꢀBINOLꢀbackbone
ligands ( )ꢀ5 and ( ,S,S)ꢀ6 (Fig. 2) to this model reaction. However, the former
yielded a disappointing result (Table 1, entry 13). The latter provided a slight drop in
the yield and enanoselectivity in comparison with ligand (S,S,R ,S,S)ꢀ4a (Table 1,
entries 14 vs 5), and ligand (S,S,R ,S,S)ꢀ4a was shown to be the most effective for the
(
R
R
a
R
a
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a
a
arylation reaction. To improve the reaction, solvents, bases and temperature were
further optimized, and the results are outlined in Table 2. Conditional experiments
showed that THF, [IrCodCl] , and KF were the best combination for this reaction. It is
2
noticed that, our system does require adding water as a protic source. Without water
the yield of arylation product decreased dramatically from 95% to 37% (Table 2,
2
entries 4 vs 11). While no ligand existed, [IrCodCl] could just catalyze the reaction
with low yield and racemic product (Table 2, entry 28). No base added in the reaction
also acquired moderate enantioselectivity, however, the yield dropped sharply (Table
2, entry 29). Reaction temperature had little effect on enantiomeric excess of the
product but it influenced the yield significantly. When the temperature was raised
from 50
℃
to 80
℃
, the yield increased from 64% to 98% (Table 2, entries 24ꢀ26).
a,b,c,d
Scheme 2. Catalytic asymmetric arylation of isatins with arylboronic acids
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a
Reaction conditions: 0.2 mmol of Nꢀprotected isatins, arylboronic acids (2 equiv.), [IrCodCl]
2
(1
b
a 2
mol%), (S,S,R ,S,S)ꢀ4a (2.2 mol%), KF (1 equiv.), 80℃, 24 h, solvent: THFꢀH O (2 mLꢀ0.1 mL).
c
d
Yield of isolated product. The ee values were determined by chiral HPLC. Data in the brackets
a
represent the results with (R ,S,S)ꢀ6 as the ligand. Other reaction conditions were the same as listed
above.
To evaluate the scope of the reaction, we examined different arylboronic acids and
Nꢀprotected isatins under the optimal reaction conditions, and the results are
summarized in Scheme 2. At first, various isatin substrates bearing methylꢀ, benzylꢀ,
1
ꢀtritylꢀ or 1ꢀanthracenꢀ9ꢀylmethyl substituent on their nitrogen atoms were selected
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2
2
2
2
2
2
2
3
3
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3
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3
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5
5
5
5
5
5
5
6
for the reactions with phenylboronic acid. Benzylꢀprotected isatin got the best result,
other Nꢀprotected isatins only acquired small amounts of the corresponding products
with lower ee values (7a-7d). Further experiments showed that 5ꢀsubstituent of the
Nꢀbenzyl protected isatins on the aromatic rings had a significant influence on this
reaction. The addition of phenylboronic acid to Nꢀbenzylꢀ5ꢀchloro or
Nꢀbenzylꢀ5ꢀfluoro isatin all obtained lower enantioselectivities and yields in contrast
with the reaction of nonꢀsubstituted Nꢀbenzylꢀisatin (7s, 7t). Moreover,
Nꢀbenzylꢀ5ꢀmethoxyꢀisatin and free isatin as the substrates achieved hardly any of
arylation products. This displayed the necessity of the Nꢀbenzyl protection in the
catalytic system. Then, impact of boronic acids on the 1,2ꢀaddition reaction was
explored. Arylboronic acids bearing weak electronꢀwithdrawing substituents at paraꢀ
or metaꢀposition afforded corresponding 3ꢀarylꢀ3ꢀhydroxyꢀ2ꢀoxindole derivatives in
high yields with excellent enantioselectivities in the range of 83–95% ees (7e, 7j-7l
and 7r), while introduction of strong electronꢀwithdrawing group to the phenyl ring
led to somewhat decrease of the yields and enantioselectivities (7i, 7m). Interestingly,
metaꢀelectronꢀdonating groups on the arylboronic acids resulted in high yields and
enantioselectivities (7f-7h). However, paraꢀsubstituted arylboronic acids possessing
electronꢀdonating substituents lowered both the yields and enantioselectivities (7n-7q).
Besides, another phenomenon was also noted. Using ligand (Ra,S,S)ꢀ6 instead of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
(S,S,R ,S,S)ꢀ4a, the reactions afforded lower ee’s and yields (7f, 7n, 7o and 7r). This
demonstrates as well the effectiveness of our synthetic ligands. We infer that increase
of the ligands’ rigidity was favorable for the reaction’s stereoselectivity and yield. We
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have
also
examined
other
substrates
such
as
acid
benzaldehyde,
ethyl ester,
2
,2,2ꢀtrifluoroacetophenone,
2ꢀoxoꢀ4ꢀphenylbutyric
N,Nꢀdimethylsulfamoylꢀprotected benzaldimine and chalcone. However, those
substrates reacted with aryl boronic acid in trace or didn’t react under the optimum
conditions.
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58
59
60
In conclusion, a class of novel chiralꢀbridged biphenyl phosphoramidite ligands has
been synthesized on basis of inducing stereochemistry right in the beginning of the
synthetic pathway. Iridiumꢀcatalyzed enantioselective addition of arylboronic acids to
isatins was successfully realized unprecedentedly along with use of the ligands. A
series of chiral 3ꢀarylꢀ3ꢀhydroxylꢀ2ꢀoxindoles were afforded in high yields with up to
95% ee. The match of axial and central chiralities in the ligands showed significant
influence on the reaction. Further applications of these newly developed
phosphoramidite ligands in other asymmetric catalysis are on going in our laboratory.
EXPERIMENTAL SECTION
General Information. Anhydrous 1,4ꢀDioxane, THF and methyl tertꢀbutyl ether
(MTBE) were distilled from sodium and benzophenone before use. Anhydrous
toluene, DMF, DME, Et
3
N, DCM, pyridine, and xylene were refluxed and distilled
t
i
from CaH
2
. Ethanol, BuOH and PrOH were distilled over magnesium turnings.
Reagents were obtained from commercial sources and used directly without further
purification unless otherwise specified. NMR spectra were recorded on a 400 MHz or
300 MHz spectrometer. Optical rotations were measured on a polarimeter and
calibrated with pure solvent as a blank. HRMS were recorded on a ESIꢀQꢀTOF mass
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
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4
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5
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5
5
5
5
6
spectrometer. Enantiomeric excesses (ee) were determined by HPLC using Daicel
Chiralpak ODꢀH, IAꢀ3 or ICꢀ3 column
Preparation of (
R,R,Sa-3c). To a solution of 2,2',6,6'ꢀtetrahydroxybiphenyl 1 (0.8 g, 3.67 mmol) and
Cs CO (3.56 g, 10.93 mmol ) in 120 mL DMF was added a solution of compound
)ꢀ2c (1.00 g, 2.43 mmol) in 100 mL DMF over a period of 4 h at 80 °C under N
S)-[6,6'-(2R,4R-pentadioxy)]-(2,2')-dihydroxy-(1,1')-biphenyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
3
(S
,
S
2
.
The resulting suspension was stirred for 24 h at this temperature. The solvent was
removed under reduced pressure and the obtained crude product was poured into
water and extracted three times with ethyl acetate. The extract was washed
successively with 1 N HCl solution, water and brine. The combined organic layer was
4
separated, dried over MgSO and concentrated in vacuo. Purification of the residue by
flash chromatography to afford a white solid (R,R,S
a
)ꢀ3c. White solid: 0.47 mg, 68%
1
D
7
1
yield; mp 145ꢀ146 °C; [α]
+140 (c = 1.0, CHCl
3
). H NMR (400 MHz, CDCl
3
) δ
7
.20 – 7.14 (m, 2H), 6.72 (d,
J
= 8.1 Hz, 2H), 6.65 – 6.58 (m, 2H), 4.69 – 4.57 (m,
13
2H), 1.36 (d,
J
= 6.5 Hz, 5H), 1.28 (t,
J
3
= 7.1 Hz, 2H). C NMR (101 MHz, CDCl ) δ
+
1
58.6, 153.9, 129.4, 111.1, 110.1, 75.1, 40.8, 22.1. HRMS (ESI) [M+H] : calcd for
+
4
C
17
H
19
O
287.1283, found 287.1279.
General Procedure for the Synthesis of 4. Under N
solution of PCl (0.73 mmol), the corresponding amine (0.73 mmol) and triethylamine
2
atmosphere and at 80℃, a
3
(3.65 mmol) in toluene (20 mL) was stirred for 6 h, then a solution of diol 3 (0.73
mmol) in THF (10 mL) was added into this solution. The resulting suspension was
3
stirred further for 12 h at room temperature. The precipitated Et N·HCl salt was
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filtered off, and the solvent of the filtrate was removed under vacuum. The residue
was then purified by flash column chromatography on silica gel (PE/EA=10/1) to
afford product ligand 4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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32
33
34
35
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37
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39
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42
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44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
R
)-[6,6’-(2
e,g][1,4])-bis((
yield; mp 92ꢀ93 °C; [α]
S S-butadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
,3
[
a
S)-1-phenylethyl)amine ((S,S,R ,S,S)-4a). White solid: 341.1 mg, 89%
2
D
7
1
+42 (c = 1.0 mg/mL,CHCl
3
). H NMR (300 MHz, CDCl
3
) δ
7
4
.37 – 7.24 (m, 2H), 7.16 – 7.04 (m, 11H), 7.00 – 6.87 (m, 3H), 4.67 – 4.48 (m, 2H),
13
.02 – 3.86 (m, 2H), 1.73 (d, J = 7.0 Hz, 6H), 1.42 (d, J = 5.8 Hz, 6H). C NMR (101
MHz, CDCl ) δ 159.2, 152.5, 152.4, 151.4, 142.9, 129.7, 129.2, 128.0, 127.7, 126.6,
3
31
1
18.5, 118.2, 117.5, 116.9, 85.4, 85.2, 52.2, 52.0, 18.9. P NMR (162 MHz, CDCl
3
) δ
+
+
144.69. HRMS (ESI) [M+H] : calcd for C32
)-[6,6’-(2 ,3 -butadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta[e,
g][1,4])-bis((
4
H33NO P 526.2147, found 526.2155.
(R
S S
R
)-1-phenylethyl)amine ((S,S,R
a
,R,R)-4b). White solid: 325.7 mg, 85%
27
D
1
yield; mp 83ꢀ84 °C; [α]
+354 (c = 1.0 mg/mL,CHCl ). H NMR (400 MHz, CDCl )
3
3
δ 7.39 (t, J = 8.1 Hz, 1H), 7.22 – 7.10 (m, 12H), 7.01 (d, J = 8.1 Hz, 1H), 6.92 – 6.86
m, 2H), 4.57 – 4.43 (m, 2H), 4.01 – 3.92 (m, 2H), 1.70 (d, 6H), 1.43 (dd, J = 5.6, 2.8
(
13
Hz, 6H). C NMR (101 MHz, CDCl
3
) δ 159.4, 159.1, 152.8, 152.7, 151.7, 143.2,
1
29.7, 129.3, 128.0, 128.0, 127.7, 126.6, 118.5, 118.1, 118.1, 117.7, 116.7, 85.4, 85.3,
31
54.3, 54.2, 22.9, 22.8, 18.8, 18.8. P NMR (162 MHz, CDCl ) δ 149.67. HRMS (ESI)
3
+
+
[
M+H] : calcd for C32
)-[6,6’-(2 ,3 -butadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
e,g][1,4])-dibenzylamine ((S,S,R
4
H33NO P 526.2147, found 526.2162.
(R
S S
[
a
)-4c). White solid: 183.8 mg, 73% yield; mp
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2
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
D
7
1
1
–
6
–
58ꢀ159 °C; [α]
+176 (c = 1.0 mg/mL,CHCl
3
). H NMR (400 MHz, CDCl
3
) δ 7.44
7.36 (m, 5H), 7.34 – 7.28 (m, 6H), 7.22 – 7.17 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H),
.90 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.33 (dd, J = 15.1, 7.9 Hz, 2H), 3.97
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
3.89 (m, 2H), 3.58 – 3.44 (m, 2H), 1.42 (dd, J = 13.5, 6.1 Hz, 6H). C NMR (101
MHz, CDCl
3
) δ 159.2, 158.8, 152.2, 152.1, 151.2, 137.9, 129.7, 128.8, 128.3, 127.2,
31
1
18.6, 117.9, 117.9, 117.4, 117.0, 85.3, 85.2, 48.3, 48.1, 18.9. P NMR (121 MHz,
+
+
CDCl
3
) δ 144.30. [M+H] : calcd for C30
,3 -butadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
e,g][1,4])-diisopropylamine ((S,S,Ra)-4d). White solid: 282.9 mg, 78 % yield; mp
4
H29NO P 498.1834, found 498.1851.
(R)-[6,6’-(2S S
[
27
D
1
1
30ꢀ131 °C; [α]
3 3
+64 (c = 1.0 mg/mL,CHCl ). H NMR (400 MHz, CDCl ) δ 7.36 –
7.25 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H), 7.00 – 6.92 (m, 3H), 4.02 – 3.88 (m, 2H), 3.52
13
–
3.41 (m, 2H), 1.43 (dd, J = 6.0, 2.7 Hz, 6H), 1.21 (dd, J = 8.7, 6.9 Hz, 12H). C
NMR (101 MHz, CDCl
3
) δ 159.1, 158.9, 152.7, 152.6, 152.1, 129.6, 129.1, 118.2,
31
1
18.0, 118.0, 117.4, 116.9, 85.3, 85.2, 44.7, 44.6, 24.5, 24.4, 18.9, 18.9. P NMR
+
+
(162 MHz, CDCl
02.1841.
)-[6,6’-(2
e,g][1,4])-dimethylamine ((S,S,R
3 4
) δ 142.20. [M+H] : calcd for C22H29NO P 402.1834, found
4
(R
S,3S-butadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
[
a
)-4e). White solid: 312 mg, 86% yield; mp
27
1
134ꢀ135 °C; [α]
D
+19 (c = 1.0 mg/mL,CHCl ). H NMR (400 MHz, CDCl ) δ 7.35 (t,
3
3
J = 8.1 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.1 Hz,
1H), 6.96 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.02 – 3.84 (m, 2H), 2.63 (d, J
13
=
9.1 Hz, 6H), 1.43 (dd, J = 5.9, 2.9 Hz, 6H). C NMR (101 MHz, CDCl
3
) δ 160.2,
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60.2, 153.7, 129.9, 115.5, 114.5, 114.3, 112.8, 86.1, 34.9, 34.5, 18.8. P NMR (162
+
+
3 4
MHz, CDCl ) δ 147.97. HRMS (ESI) [M+H] : calcd for C18H21NO P 346.1203,
found 346.1208.
)-[6,6’-(2 -propyldioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R
S
2
D
7
[
e,g][1,4])-diisopropylamine ((S,R
a
)-4f). White solid:189.2 mg, 67% yield; [α]
+47
1
(c = 1.0 mg/mL,CHCl
3
). H NMR (400 MHz, CDCl
3
) δ 7.38 – 7.31 (m, 1H), 7.31 –
7
4
3
1
.27 (m, 1H), 7.08 – 7.04 (m, 1H), 7.02 – 6.93 (m, 3H), 4.46 – 4.40 (m, 1H), 4.37 –
.26 (m, 1H), 3.79 (dd, J = 22.4, 11.8 Hz, 1H), 3.52 – 3.40 (m, 2H), 1.38 (dd, J = 6.5,
13
.4 Hz, 3H), 1.21 (td, J = 7.6, 2.9 Hz, 12H). C NMR (101 MHz, CDCl ) δ 159.4,
3
59.2, 159.0, 158.8, 152.6, 152.5, 152.2, 129.8, 129.7, 129.3, 129.2, 118.6, 118.5,
118.3, 118.3, 118.2, 118.2, 117.6, 117.3, 117.3, 80.3, 78.3, 44.7, 44.6, 24.5, 24.5, 24.4,
31
+
1
7.2, 17.2. P NMR (121 MHz, CDCl
3
) δ 151.56, 151.24. [M+H] : calcd for
+
C
21
H
27NO
4
P 388.1672, found 388.1649.
(
S)-[6,6’-(2R,4R-pentadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
[e,g][1,4])-bis((
S)-1-phenylethyl)amine ((R,R,S
a
,S,S)-4g). White solid: 338.3 mg, 86%
27
D
1
yield; mp 102ꢀ103 °C; [α]
ꢀ83 (c = 0.5 mg/mL,CHCl
3
). H NMR (400 MHz, CDCl
3
)
δ 7.37 – 7.28 (m, 1H), 7.22 – 7.15 (m, 9H), 7.10 (t, 2H), 7.00 (t, J = 8.5 Hz, 2H), 6.83
dd, J = 16.0, 8.1 Hz, 2H), 4.79 – 4.66 (m, 2H), 4.53 – 4.44 (m, 2H), 2.09 – 1.89 (m,
(
1
3
2H), 1.70 (d, J = 7.0 Hz, 6H), 1.44 (t, J = 6.4 Hz, 6H). C NMR (101 MHz, CDCl ) δ
3
1
58.2, 158.1, 153.0, 152.9, 152.1, 143.3, 129.1, 128.6, 128.0, 128.0, 127.7, 126.5,
116.1, 116.1, 115.9, 113.1, 111.6, 74.8, 74.4, 54.2, 54.1, 41.5, 22.9, 22.8, 22.6, 22.3.
31
+
+
P NMR (162 MHz, CDCl
3
) δ 148.28. [M+K] : calcd for C33
H
34NO
4
PK 578.1862,
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
found 578.1834.
)-[6,6’-(2 ,4
e,g][1,4])-bis((
(S
R
R
-pentadioxy)]-(1,1’)-biphenyl-(3,5-Dioxa-4-phosphacyclohepta
[
R
)-1-phenylethyl)amine ((R,R,S
a
,R,R)-4h). White solid: 330.5 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
D
7
1
8
4% yield; mp 109ꢀ110 °C; [α]
+59 (c = 1.0 mg/mL,CHCl ). H NMR (400 MHz,
3
CDCl
3
) δ 7.31 – 7.25 (m, 2H), 7.13 (bs, 2H), 6.98 (dd, J = 13.6, 8.2 Hz, 2H), 6.89 (t, J
=
7.5 Hz, 2H), 4.77 – 4.68 (m, 2H), 4.63 – 4.52 (m, 2H), 2.08 – 1.89 (m, 2H), 1.44
13
(dd, J = 6.4, 3.6 Hz, 6H). C NMR (101 MHz, CDCl
3
) δ 158.1, 157.9, 152.6, 152.5,
1
51.9, 143.0, 128.9, 128.5, 128.2, 128.0, 127.7, 127.7, 126.5, 120.8, 118.8, 116.2,
31
116.2, 115.6, 113.3, 111.8, 74.8, 74.5, 52.2, 52.0, 41.7, 22.6, 22.3. P NMR (162
+
+
3 4
MHz, CDCl ) δ 143.28. [M+H] : calcd for C33H35NO P 540.2298, found 540.2299.
General Procedure for the Synthesis of 3-aryl-3-hydroxyoxindoles 7a-7t. Under
an argon atmosphere, a solution of [IrCodCl] (1.34 mg, 0.01 mmol) and
)ꢀ4a (2.2 mg, 0.021 mmol) in THF (1.0 mL) was stirred for 30 min at room
temperature. Isatins (0.20 mmol), arylboronic acids (0.4 mmol) and KF (11.6 mg, 0.1
mmol) were added. The resulting mixture was stirred for 24 h at 80 . Then the
2
a
(S,S,R ,S,S
℃
solvent was evaporated under reduced pressure and the residue was purified by flash
column chromatography on silica gel with petroleum ether/EtOAc as eluent to afford
the desired product.
1-Benzyl-3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (7a) White solid: 61.7 mg,
18
D
1
9
8% yield; mp 132ꢀ133 °C; [α]
3 3
+23 (c = 1.0, CHCl ); H NMR (400 MHz, CDCl )
δ 7.46 – 7.42 (m, 2H), 7.40 – 7.28 (m, 9H), 7.25 (td, J = 7.8, 1.3 Hz, 1H), 7.07 (td, J =
7
.6, 0.9 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.08 (d, J = 15.7 Hz, 1H), 4.87 (d, J = 15.7
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Hz, 1H), 3.41 (s, 1H). C NMR (101 MHz, CDCl
3
) δ 142.6, 140.2, 135.4, 129.7,
1
28.9, 128.7, 128.3, 127.8, 127.3, 125.4, 125.0, 123.6, 109.8, 44.1. HPLC Daicel
Chiralpak ODꢀH column (flow rate 0.5 mL/min,
ee, 13.9 min (minor), 15.6 min (major).
iPrOH/Hex = 20/80, UV 227 nm): 93%
10
11
12
13
14
15
16
17
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19
20
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46
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51
52
53
54
55
56
57
58
59
60
1
-Trityl-3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (7b) White solid: 17.7 mg,
1
D
8
1
1
7
3
1
9% yield; mp 165ꢀ166 °C; [α]
3 3
ꢀ27 (c = 0.5, CHCl ); H NMR (400 MHz, CDCl ) δ
.50 – 7.36 (m, 11H), 7.31 – 7.19 (m, 10H), 7.02 – 6.94 (m, 2H), 6.43 – 6.37 (m, 1H),
13
.27 (s, 1H). C NMR (101 MHz, CDCl
3
) δ 141.8, 129.9, 129.1, 128.7, 128.6, 128.3,
28.3, 127.8, 127.0, 125.4, 125.3, 125.0, 124.4, 123.6, 123.0, 116.2, 108.7, 78.0.
HPLC Daicel Chiralpak ODꢀH column (flow rate 0.5 mL/min,
UV 227 nm): 30% ee, 10.1 min (major), 11.3 min (minor).
iPrOH/Hex = 20/80,
1
-Anthracen-9-ylmethyl-3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one
(7c)
3
D
1
1
White solid: 35.6 mg, 43% yield; mp 169ꢀ170 °C; [α]
+11 (c = 0.4, CHCl
3
); H
NMR (400 MHz, CDCl ) δ 8.54 (s, 1H), 8.46 – 8.41 (m, 1H), 8.12 – 8.06 (m, 1H),
3
7.59 – 7.50 (m, 3H), 7.39 – 7.28 (m, 9H), 7.18 – 7.12 (m, 1H), 6.90 – 6.81 (m, 2H),
13
6
.20 (d,
CDCl
25.2, 124.5, 123.3, 119.1, 112.1, 37.9. HPLC Daicel Chiralpak ICꢀ3 column (flow
J
= 15.5 Hz, 1H), 5.82 (d,
J
= 15.5 Hz, 1H), 3.28 (s, 1H). C NMR (101 MHz,
3
) δ 177.6, 147.1, 138.3, 131.4, 130.8, 129.8, 129.6, 128.5, 127.4, 127.0, 125.3,
1
rate 0.7 mL/min,
min (minor).
iPrOH/Hex = 15/85, UV 227 nm): 30% ee, 21.7 min (major), 28.0
1-Methyl-3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (7d) White solid: 27.7
31
D
1
mg, 58% yield; mp 138ꢀ139 °C; [α]
3
+52 (c = 1.0, CHCl ); H NMR (400 MHz,
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2
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3
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CDCl
3
) δ 7.44 – 7.40 (m, 2H), 7.39 – 7.35 (m, 2H), 7.35 – 7.28 (m, 3H), 7.15 – 7.09
1
3
(m, 1H), 6.94 (d,
J
= 7.8 Hz, 1H), 3.36 (s, 1H), 3.29 (s, 3H). C NMR (101 MHz,
) δ 177.6, 143.5, 140.1, 131.6, 129.9, 128.6, 128.3, 125.4, 125.0, 123.6, 108.7,
PrOH/Hex =
CDCl
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
6.5. HPLC Daicel Chiralpak ODꢀH column (flow rate 0.5 mL/min,
5/85, UV 227 nm): 91% ee, 25.0 min (minor), 31.8 min (major).
-Benzyl-3-hydroxy-3-(3-chlorophenyl)-1,3-dihydro-indol-2-one (7e) White
i
1
1
3
D
1
1
solid: 59.3 mg, 85% yield; mp 138ꢀ139 °C; [α]
MHz, CDCl ) δ 7.41 (s, 1H), 7.37 – 7.17 (m, 10H), 7.04 (t,
d, = 7.7 Hz, 1H), 5.01 (d, = 15.5 Hz, 1H), 4.79 (d, = 15.5 Hz, 1H), 4.41 (s, 1H).
C NMR (75 MHz, CDCl ) δ 177.5, 142.6, 135.5, 134.8, 131.7, 131.2, 130.2, 129.8,
129.0, 128.6, 128.1, 127.5, 127.0, 126.5, 125.1, 124.9, 124.1, 122.9, 111.3, 109.1,
4.5. HPLC Daicel Chiralpak IAꢀ3 column (flow rate 0.5 mL/min, PrOH/Hex =
20/80, UV 227 nm): 83% ee, 17.5 min (major), 19.5 min (minor).
+24 (c = 0.7, CHCl
3
); H NMR (300
3
J
= 10.8, 4.2 Hz, 1H), 6.79
(
J
J
J
13
3
4
i
1
-Benzyl-3-hydroxy-3-m-tolyl-1,3-dihydro-indol-2-one (7f) White solid: 62.51
3
D
1
1
mg, 95% yield; mp 155ꢀ156 °C; [α]
3
+54 (c = 0.6, CHCl ); H NMR (300 MHz,
CDCl
3
) δ 7.40 – 7.27 (m, 5H), 7.27 – 7.15 (m, 5H), 7.11 (d,
J
= 5.8 Hz, 1H), 7.03 (t,
J
= 7.5 Hz, 1H), 6.78 (d,
J
= 7.8 Hz, 1H), 5.05 (d,
J
= 15.6 Hz, 1H), 4.81 (d,
J
= 15.6
13
Hz, 1H), 3.67 (s, 1H), 2.33 (s, 3H). C NMR (75 MHz, CDCl
3
) δ 177.9, 142.8, 140.4,
138.5, 135.7, 132.1, 129.8, 129.3, 129.1, 128.7, 128.0, 127.6, 126.1, 125.2, 123.8,
22.6, 109.9, 78.3, 44.4, 22.0. HPLC Daicel Chiralpak IAꢀ3 column (flow rate 0.7
1
mL/min,
minor).
i
PrOH/Hex = 15/85, UV 227 nm): 90% ee, 16.3 min (major), 18.4 min
(
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-Benzyl-3-hydroxy-3-(3-methoxyphenyl)-1,3-dihydro-indol-2-one (7g) White
3
D
0
1
solid: 66.9 mg, 97% yield; mp 157ꢀ158 °C; [α]
3
+69 (c = 0.6, CHCl ); H NMR (300
MHz, CDCl
3
) δ 7.35 – 7.27 (m, 4H), 7.27 – 7.18 (m, 4H), 7.06 – 6.99 (m, 2H), 6.91 (d,
= 7.7, 1.7 Hz, 1H), 6.84 (dd, = 8.2, 2.5 Hz, 1H), 6.78 (d, = 7.8 Hz, 1H), 5.05 (d,
= 15.6 Hz, 1H), 4.81 (d, = 15.6 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 1H). C NMR (75
) δ 176.2, 158.5, 141.3, 140.5, 134.2, 130.4, 128.5, 128.4, 127.6, 126.5,
26.1, 123.7, 122.3, 116.3, 112.7, 109.8, 108.5, 76.8, 54.1, 43.0. HPLC Daicel
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
J
J
J
13
J
MHz, CDCl
3
1
Chiralpak IAꢀ3 column (flow rate 0.7 mL/min,
ee, 30.5 min (major), 33.8 min (minor).
iPrOH/Hex = 10/90, UV 227 nm): 91%
1
-Benzyl-3-hydroxy-3-biphenyl-3-yl-1,3-dihydro-indol-2-one (7h) White solid:
3
D
0
1
71.9 mg, 92% yield; mp 164ꢀ165 °C; [α]
3
+57 (c = 0.5, CHCl ); H NMR (400 MHz,
CDCl
7.31 (m, 7H), 7.30 – 7.23 (m, 1H), 7.07 (t,
.14 (d, = 15.6 Hz, 1H), 4.82 (d, = 15.6 Hz, 1H), 3.86 (d,
NMR (101 MHz, CDCl
29.1, 128.9, 128.7, 127.8, 127.4, 127.4, 127.3, 127.1, 125.0, 124.1, 124.1, 123.7,
3
) δ 7.65 (d, J = 5.5 Hz, 1H), 7.58 – 7.52 (m, 3H), 7.47 – 7.42 (m, 4H), 7.40 –
J
= 7.5 Hz, 1H), 6.84 (d,
J
= 7.9 Hz, 1H),
13
5
J
J
J
= 5.0 Hz, 1H). C
3
) δ 177.7, 142.6, 141.6, 140.9, 140.8, 135.5, 131.8, 129.8,
1
+
+
109.8, 78.1, 44.1. HRMS (ESI) [M+Na] : calcd for C27
14.1482. HPLC Daicel Chiralpak ICꢀ3 column (flow rate 0.7 mL/min,
20/80, UV 227 nm): 92% ee, 16.6 min (major), 18.9 min (minor).
H21NO
2
Na 414.1470, found
4
iPrOH/Hex =
1
-Benzyl-3-hydroxy-3-(3-methoxycarbonylpheny)-1,3-dihydro-indol-2-one (7i)
3
D
0
1
White solid: 55.2 mg, 74% yield; mp 148ꢀ149 °C; [α]
+55 (c = 0.5, CHCl
3
); H
NMR (400 MHz, CDCl
3
) δ 8.14 (s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.7 Hz,
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2
2
2
2
2
2
3
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3
3
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1
H), 7.58 – 7.52 (m, 1H), 7.45 (t,
J
= 7.8 Hz, 1H), 7.39 – 7.25 (m, 6H), 7.11 – 7.04 (m,
H), 6.85 (d,
J
= 7.8 Hz, 1H), 5.09 (d,
J
= 15.6 Hz, 1H), 4.89 (d,
J = 15.6 Hz, 1H),
13
.93 (d,
J
= 3.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ 177.3, 166.7, 155.7, 142.6,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
40.7, 135.3, 131.2, 131.2, 130.7, 130.1, 129.8, 129.7, 129.6, 129.0, 128.9, 127.9,
27.3, 126.5, 125.0, 123.8, 121.9, 120.1, 116.3, 110.0, 52.2, 44.2, 29.7. HRMS (ESI)
+
+
[
4
M+Na] : calcd for C23H19NO Na 396.1206, found 396.1207. HPLC Daicel
Chiralpak IAꢀ3 column (flow rate 0.5 mL/min,
ee, 23.4 min (major), 25.7 min (minor).
iPrOH/Hex = 20/80, UV 227 nm): 83%
1
-Benzyl-3-hydroxy-3-(4-fluorophenyl)-1,3-dihydro-indol-2-one (7j) White
30
D
1
solid: 62.6 mg, 94% yield; mp 145ꢀ146 °C; [α]
3
+34 (c = 0.6, CHCl ); H NMR (400
MHz, CDCl
3
) δ 7.43 – 7.37 (m, 2H), 7.36 – 7.23 (m, 7H), 7.13 – 6.99 (m, 3H), 6.83 (d,
13
J
= 7.8 Hz, 1H), 5.05 (d,
NMR (101 MHz, CDCl ) δ 177.5, 162.7 (d,
31.4, 130.0, 128.9, 127.9, 127.4 (d, = 8.3 Hz), 127.3, 125.0, 123.7, 115.6 (d,
J
= 15.6 Hz, 1H), 4.84 (d,
J
= 15.6 Hz, 1H), 3.73 (s, 1H). C
3
J = 247.3 Hz), 142.6, 136.0, 135.9, 135.3,
1
J
J
=
19
+
3
21.7 Hz), 109.9, 44.1. F NMR (377 MHz, CDCl ) δ ꢀ113.78. HRMS (ESI) [M+Na] :
+
calcd for C21
H16FNO
2
Na 356.1057, found 356.1067. HPLC Daicel Chiralpak IAꢀ3
column (flow rate 0.7 mL/min, iPrOH/Hex = 15/85, UV 227 nm): 92% ee, 16.5 min
(major), 20.0 min (minor).
1-Benzyl-3-hydroxy-3-(4-chlorophenyl)-1,3-dihydro-indol-2-one (7k) White
30
D
1
solid: 65.6 mg, 94% yield; mp 147ꢀ148 °C; [α]
+25 (c = 0.5, CHCl
3
); H NMR (300
= 7.5 Hz, 1H),
= 15.6 Hz, 1H), 4.35 (s, 1H).
MHz, CDCl
3
) δ 7.40 – 7.24 (m, 10H), 7.23 – 7.19 (m, 1H), 7.04 (t, J
6
.81 – 6.76 (m, 1H), 5.00 (d,
J
= 15.6 Hz, 1H), 4.78 (d,
J
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C NMR (75 MHz, CDCl
3
) δ 177.6, 142.6, 139.0, 135.5, 134.4, 131.7, 130.1, 129.1,
1
28.9, 128.1, 127.5, 127.2, 125.1, 124.0, 110.1, 110.0, 44.4. HPLC Daicel Chiralpak
IAꢀ3 column (flow rate 0.5 mL/min,
min (major), 26.2 min (minor).
iPrOH/Hex = 20/80, UV 227 nm): 93% ee, 21.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
-Benzyl-3-hydroxy-3-(4-trifluoromethoxyphenyl)-1,3-dihydro-indol-2-one (7l)
3
D
0
1
White solid: 50.2 mg, 63% yield; mp 109ꢀ110 °C; [α]
NMR (400 MHz, CDCl ) δ 7.45 (t, = 5.7 Hz, 2H), 7.39 – 7.25 (m, 7H), 7.20 (d,
= 7.8 Hz, 1H), 5.05 (d, = 15.6 Hz, 1H), 4.85 (d, = 15.6 Hz,
H), 3.87 (s, 1H). C NMR (101 MHz, CDCl ) δ 177.3, 149.1, 142.5, 138.8, 135.2,
3
+33 (c = 0.5, CHCl ); H
3
J
J =
8
1
1
.4 Hz, 2H), 6.84 (d,
J
J
J
13
3
31.3, 130.1, 129.0, 127.9, 127.3, 127.1, 125.0, 123.8, 120.4 (q,
J
= 255.9 Hz), 121.0,
) δ ꢀ57.79. HPLC Daicel Chiralpak
iPrOH/Hex = 20/80, UV 227 nm): 94% ee, 17.2
19
110.0, 77.6, 44.1. F NMR (377 MHz, CDCl
3
IAꢀ3 column (flow rate 0.5 mL/min,
min (major), 21.4 min (minor).
1
-Benzyl-3-hydroxy-3-(4-trifluoromethylphenyl)-1,3-dihydro-indol-2-one
3
D
0
(7m) White solid: 19.9 mg, 26% yield; mp 145ꢀ146 °C; [α]
+48 (c = 0.5, CHCl
= 8.3 Hz, 2H), 7.39
= 7.5 Hz, 1H), 6.85 (d, = 7.9 Hz, 1H),
= 15.6 Hz, 1H), 4.30 (s, 1H). C NMR (101 MHz,
CDCl ) δ 177.2, 144.2, 142.5, 135.2, 131.3, 130.2 (q, = 32.2 Hz), 130.2, 129.0,
3
);
1
3
H NMR (400 MHz, CDCl ) δ 7.60 (d, J = 8.3 Hz, 2H), 7.52 (d, J
– 7.31 (m, 5H), 7.31 – 7.23 (m, 2H), 7.08 (t,
.05 (d, = 15.6 Hz, 1H), 4.84 (d,
J
J
13
5
J
J
J
3
1
28.0, 127.3, 125.9, 125.6 (q,
J
= 3.8 Hz), 125.0, 124.0 (q,
J
= 270.4 Hz), 123.9,
19
+
110.0, 77.9, 44.2. F NMR (377 MHz, CDCl
3
) δ ꢀ62.66. HRMS (ESI) [M+Na] :
+
calcd for C22
H
16
F
3
NO
2
Na 406.1025, found 406.1024. HPLC Daicel Chiralpak IAꢀ3
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2
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3
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3
4
4
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4
4
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4
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5
5
5
5
5
5
5
5
5
5
6
column (flow rate 0.5 mL/min, iPrOH/Hex = 20/80, UV 227 nm): 80% ee, 14.9 min
(major), 16.9 min (minor).
1
-Benzyl-3-hydroxy-3-p-tolyl-1,3-dihydro-indol-2-one (7n) White solid: 63.1 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
D
0
1
9
6% yield; mp 155ꢀ156 °C; [α]
+28 (c = 0.5, CHCl ); H NMR (300 MHz, CDCl )
3
3
δ 7.36 – 7.26 (m, 7H), 7.26 – 7.18 (m, 2H), 7.15 (d,
Hz, 1H), 6.77 (d, = 7.8 Hz, 1H), 4.94 (dd,
s, 3H). C NMR (75 MHz, CDCl ) δ 178.0, 142.7, 138.2, 137.5, 135.7, 132.2, 129.8,
29.5, 129.1, 127.9, 127.5, 125.6, 125.2, 123.8, 109.9, 78.3, 44.4, 21.6. HPLC Daicel
J
= 8.4 Hz, 2H), 7.03 (t,
J
= 7.5
J
J = 66.3, 15.6 Hz, 2H), 3.33 (s, 1H), 2.34
13
(
3
1
Chiralpak ODꢀH column (flow rate 0.5 mL/min,
ee, 14.8 min (minor), 16.1 min (major).
iPrOH/Hex = 20/80, UV 227 nm): 82%
1-Benzyl-3-hydroxy-4-biphenyl-4-yl-1,3-dihydro-indol-2-one (7o) White solid:
30
D
1
6
8.0 mg, 87% yield; mp 169ꢀ170 °C; [α]
+19 (c = 0.5, CHCl
3
); H NMR (300 MHz,
CDCl
3
) δ 7.62 – 7.56 (m, 4H), 7.53 – 7.49 (m, 2H), 7.46 (t,
J
= 7.5 Hz, 2H), 7.39 –
7
.31 (m, 6H), 7.31 – 7.25 (m, 2H), 7.16 – 7.03 (m, 1H), 6.84 (d,
J
= 7.9 Hz, 1H), 5.10
1
3
(d,
J
= 15.6 Hz, 1H), 4.89 (d,
J
= 15.6 Hz, 1H), 3.41 (s, 1H). C NMR (75 MHz,
CDCl
3
)δ 177.6, 142.7, 141.3, 140.6, 139.1, 135.4, 131.5, 129.9, 128.8, 127.9, 127.5,
127.3, 127.1, 125.8, 125.0, 123.7, 109.9, 100.0, 77.9, 44.1. HPLC Daicel Chiralpak
ICꢀ3 column (flow rate 0.7 mL/min,
min (major), 22.8 min (minor).
iPrOH/Hex = 20/80, UV 227 nm): 83% ee, 16.6
1
-Benzyl-3-hydroxy-3-(4-tertbutylphenyl)-1,3-dihydro-indol-2-one (7p) White
3
D
0
1
solid: 63.0 mg, 85% yield; mp 135ꢀ136 °C; [α]
3
+30 (c = 0.5, CHCl ); H NMR (300
MHz, CDCl
3
) δ 7.35 (d,
J
= 0.9 Hz, 3H), 7.34 – 7.28 (m, 6H), 7.26 – 7.23 (m, 1H),
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.22 – 7.18 (m, 1H), 7.04 (t,
J
= 7.5 Hz, 1H), 6.77 (d,
J
= 7.8 Hz, 1H), 5.04 (d,
J =
13
5.6 Hz, 1H), 4.83 (d, = 15.7 Hz, 1H). C NMR (75 MHz, CDCl
J
3
) δ 177.9, 151.5,
42.8, 137.3, 135.6, 131.8, 129.9, 129.1, 127.9, 127.5, 125.8, 125.3, 123.7, 110.0,
09.9, 78.1, 44.4, 34.9, 31.6. HPLC Daicel Chiralpak ICꢀ3 column (flow rate 0.7
10
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mL/min,
minor).
-Benzyl-3-hydroxy-3-(4-phenoxyphenyl)-1,3-dihydro-indol-2-one (7q) White
iPrOH/Hex = 20/80, UV 227 nm): 83% ee, 52.6 min (major), 55.6 min
(
1
30
D
1
solid: 59.4 mg, 73% yield; mp 138ꢀ139 °C; [α]
3
+30 (c = 0.5, CHCl ); H NMR (400
MHz, CDCl ) δ 7.43 – 7.23 (m, 11H), 7.17 – 7.06 (m, 2H), 7.05 – 6.97 (m, 3H), 6.81
3
(d,
J
= 7.8 Hz, 1H), 5.06 (d,
J
= 15.7 Hz, 1H), 4.86 (d,
J = 15.7 Hz, 1H), 3.45 (s, 1H).
1
3
C NMR (101 MHz, CDCl
3
) δ 177.6, 157.6, 156.7, 142.6, 135.4, 134.7, 131.5, 129.9,
1
29.8, 128.9, 127.8, 127.3, 127.0, 125.0, 123.6, 119.2, 118.7, 109.8, 44.1. HRMS (ESI)
+
+
[M+H] : calcd for C27
H
22NO
3
408.1594, found 408.1598. HPLC Daicel Chiralpak
PrOH/Hex = 20/80, UV 227 nm): 86% ee, 20.4
ICꢀ3 column (flow rate 0.5 mL/min,
min (major), 23.1 min (minor).
i
1
-Benzyl-3-hydroxy-3-(3,4-fluorophenyl)-1,3-dihydro-indol-2-one (7r) White
3
D
0
1
solid: 59.6 mg, 85% yield; mp 137ꢀ138 °C; [α]
MHz, CDCl ) δ 7.41 – 7.23 (m, 8H), 7.18 – 6.99 (m, 3H), 6.84 (d,
5.03 (d, = 15.6 Hz, 1H), 4.82 (d,
77.2, 151.5 (dd, = 247.3, 12.7 Hz), 149.9 (dd,
+39 (c = 0.5, CHCl
3
); H NMR (400
3
J
= 7.7 Hz, 1H),
1
3
J
J = 15.6 Hz, 1H). C NMR (101 MHz, CDCl ) δ
3
1
J
3
J
J
= 247.6, 12.6 Hz), 142.4, 137.3 (d,
= 4.2 Hz), 135.2, 131.2, 130.2, 129.0, 128.0, 127.3, 124.9, 123.9, 121.6 (dd, J = 6.5,
19
.7 Hz), 117.4 (d,
J
= 17.5 Hz), 115.1 (d,
J
= 18.8 Hz), 110.0, 44.1. F NMR (377
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5
5
5
5
5
5
5
6
+
MHz, CDCl
3
) δ ꢀ136.44, ꢀ136.50, ꢀ138.07, ꢀ138.13. HRMS (ESI) [M+Na] : calcd for
+
C
21
H
15
F
2
NO
2
Na 374.0963, found 374.0970. HPLC Daicel Chiralpak IAꢀ3 column
(
flow rate 0.5 mL/min, iPrOH/Hex = 10/90, UV 227 nm): 95% ee, 26.7 min (major),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2.3 min (minor).
1
-Benzyl-5-fluoro-3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (7s) White solid:
3
D
0
1
3
1.9 mg, 48% yield; mp 151ꢀ152 °C; [α]
+11 (c = 0.3, CHCl
3
); H NMR (400 MHz,
CDCl
3
) δ 7.50 – 7.30 (m, 9H), 7.29 (s, 1H), 7.05 (dd,
J
= 7.6, 2.6 Hz, 1H), 6.94 (td,
J
J
=
=
8.8, 2.6 Hz, 1H), 6.73 (dd, = 8.6, 4.0 Hz, 1H), 5.07 (d,
J
J
= 15.7 Hz, 1H), 4.87 (d,
13
15.7 Hz, 1H), 3.50 (s, 1H). C NMR (101 MHz, CDCl ) δ 177.6, 159.6 (d,
J
=
3
2
41.5 Hz), 139.7, 138.4, 135.1, 133.2 (d,
J
= 7.6 Hz), 129.0, 128.8, 128.6, 127.9,
= 23.7 Hz), 113.1 (d, = 24.9 Hz), 110.51 (d, = 7.9 Hz),
) δ ꢀ118.89. HPLC Daicel Chiralpak IAꢀ3 column
iPrOH/Hex = 20/80, UV 227 nm): 77% ee, 16.0 min (minor),
127.3, 125.2, 116.1 (d,
J
J
J
19
4
4.2. F NMR (377 MHz, CDCl
3
(flow rate 0.5 mL/min,
1
7.1 min (major).
1-Benzyl-5-chloro-3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (7t) White solid:
30
D
1
3
4.9 mg, 50% yield; mp 157ꢀ158 °C; [α]
+98 (c = 0.3, CHCl
3
); H NMR (400 MHz,
= 8.4, 2.1 Hz, 1H),
= 15.7 Hz, 1H), 3.48 (s,
1H). C NMR (101 MHz, CDCl ) δ 177.3, 141.1, 139.6, 134.9, 133.2, 129.7, 129.0,
CDCl
3
) δ 7.45 – 7.31 (m, 9H), 7.30 – 7.28 (m, 2H), 7.22 (dd,
= 8.4 Hz, 1H), 5.06 (d, = 15.7 Hz, 1H), 4.87 (d,
J
6
.73 (d,
J
J
J
1
3
3
1
29.0, 128.9, 128.7, 128.0, 127.3, 125.5, 125.2, 110.8, 44.2. HPLC Daicel Chiralpak
IAꢀ3 column (flow rate 0.5 mL/min,
min (major), 21.7 min (minor).
i
PrOH/Hex = 20/80, UV 227 nm): 76% ee, 18.0
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Supporting Information
1
13
31
a
Crystallographic data (CIF file) of (S,S,R ,S,S)ꢀ4a. H, C and P NMR spectra and
HPLC chromatograms for all described compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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ACKNOWLEDGEMENTS
We would like to thank Special Financial Fund of Innovative Development of Marine
Economic Demonstration Project (GD2012ꢀD01ꢀ001), Guangdong Provincial Natural
Science Foundation (S2011010001305) and Dayawan District Science and
Technology Program (201202002) for financial support.
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