Asymmetric Construction of 3,3-Disubstituted Oxindoles Bearing Vicinal Quaternary-Tertiary Carbon Stereocenters Catalyzed by a Chiral-at-Rhodium Complex

Article abstract of DOI:10.1021/acs.joc.7b00793

A highly diastereo- and enantioselective synthesis of 3,3-disubstituted oxindoles bearing vicinal quaternary-tertiary carbon centers is enabled by a chiral-at-rhodium Lewis acid catalyst starting from isatin N-protected ketimines and 2-acyl imidazoles. The excellent results with 93-99% yields, diastereoselectivities of 43:1 to >200:1, and high enantioselectivities of 98.4 to >99% confirm the potential of bis-cyclometalated rhodium catalysts for the development of effective asymmetric transformations.

Full text of DOI:10.1021/acs.joc.7b00793

Note
Asymmetric Construction of 3,3-Disubstituted
Oxindoles Bearing Vicinal Quaternary-Tertiary Carbon
Stereocenters Catalyzed by a Chiral-at-Rhodium Complex
Huihua Lin, Zijun Zhou, Jun Cai, Bowen Han, Lei Gong, and Eric Meggers
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 May 2017
Downloaded from http://pubs.acs.org on May 29, 2017
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Asymmetric Construction of 3,3-Disubstituted Oxindoles Bearing Vicinal
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Quaternary-Tertiary
Carbon
Stereocenters
Catalyzed
by
a
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Chiral-at-Rhodium Complex
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Huihua Lin,a Zijun Zhou,a Jun Cai,a Bowen Han,a Lei Gong,a * and Eric Meggersa,b *
aKey Laboratory for Chemical Biology of Fujian Province and Department of Chemical Biology,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s
Republic of China
bFachbereich Chemie, PhilippsꢀUniversität Marburg, HansꢀMeerweinꢀStrasse 4, 35043 Marburg,
Germany
ꢀ ABSTRACT
A highly diastereoꢀ and enantioselective synthesis of 3,3ꢀdisubstituted oxindoles bearing vicinal
quaternaryꢀtertiary carbon centers is enabled by a chiralꢀatꢀrhodium Lewis acid catalyst, starting
from isatin Nꢀprotected ketimines and 2ꢀacyl imidazoles. The excellent results with 93 to 99%
yields, diastereoselectivities of 43:1 to >200:1 dr, and high enantioselectivities of 98.5 to >99% ee
confirm the potential of bisꢀcyclometalated rhodium catalysts for the development of effective
asymmetric transformations.
ꢀ TABLE OF CONTENTS
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Optical active 3,3ꢀdisubstituted oxindoles are highly valuable building blocks for biologically
active nature products and pharmaceuticals.1 Consequently, their synthesis, in particular catalytic
asymmetric approaches, have attracted significant attention over the past decades.2–7 Of them, the
Mannichꢀtype reaction of isatinꢀderived ketimines with different nucleophiles provides an efficient
route to chiral 3,3ꢀdisubstituted oxindoles containing a 3ꢀamino substituent in addition to adjacent
quaternaryꢀtertiary carbon stereocenters.4 The construction of such stereogenic centers remains a
challenging task in organic synthesis, presumably owing to the steric congestion around the
stereocenters.8 For instance, Guo’s group developed an enantioselective and solventꢀcontrolled
diastereoselective reaction of isatin ketimines with hydroxyacetone by a chiral amino acid
catalyst.4a Wang and coworkers applied a quinidineꢀderived organocatalyst to the first direct
asymmetric vinylogous Mannich reaction of γꢀbutenolides with isatinꢀderived ketimines.4c Silvani’s
group reported the stereoselective addition of trimethylsiloxyfuran to isatinꢀderived benzhydryl
ketimines catalyzed by a chiral phosphoric acid.4e In these cases, although the enantioselectivities
were good to excellent, only very modest diastereoselectivities were achieved. Recently, Wu et. al
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4b
and our group4d reported the highly diastereoselective and enantioselective Mannich reaction of
isatinꢀderived ketimines to build up vicinal quaternaryꢀtertiary carbon centers on the oxindole
scaffold by using a tertiary amineꢀthiourea catalyst and a metalꢀtemplated Brønsted base,
respectively. Despite these advances, strategies to gain command of both the absolute and relative
configuration in one single chemical transformation are still demanded for the synthesis of such
optical active molecules. Herein, we wish to report our progress on utilizing asymmetric catalysts
which draw their chirality exclusively from metalꢀcentered chirality9–11 to catalyze an asymmetric
Mannichꢀtype reaction between 2ꢀacyl imidazoles and isatin Nꢀprotected ketimines (Figure 1). Very
high diastereoselectivities (43:1 – >200:1 dr) and enantioselectivities (98.5 – >99% ee) were
achieved for a variety of substrates (18 examples).
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Figure 1. Previous work and this study on stereoselective synthesis of chiral 3,3ꢀdisubstituted
oxindoles by chiralꢀatꢀmetal catalysts.
We recently developed highly efficient chiral Lewis acid catalysts based on an octahedral
bisꢀcyclometalated chiralꢀatꢀmetal scaffold.10 For example, complex ꢁꢀRhO10c features exclusive
metalꢀcentered chirality which is comprised of a rhodium center, two bidentate benzoxazole ligands
and two substitutionally labile acetonitriles in addition to a hexafluorophosphate counterion (Figure
1). It exhibits high catalytic activity and excellent stereocontrol for a range of asymmetric organic
transformations.10 In order to expand our investigations to other challenging transformations which
desire a control of both the enantioselectivity and diastereoselectivity, the Mannichꢀtype reaction of
2ꢀacyl imidazole 1a with isatin NꢀBoc ketimine 2a was examined in the presence of 5 mol% ꢁꢀRhO
in dichloromethane. Gratifyingly, the desired product 3a was generated, although with a sluggish
rate and with modest stereoselectivities (70% conversion within 75 h, 5.3:1 dr and 79% ee, Table 1,
entry 1). We subsequently optimized the reaction conditions including solvent, catalyst loading,
additives, and temperature. As revealed in entries 2–5, toluene served as the best solvent for the
transformation 1a+2a→3a by providing a 93% conversion in 5 h, 100:1 dr and 97% ee. Further
decrease of catalyst loading to 2 mol% and addition of 4 Å molecular sieves (MS) led to the optimal
conditions, enabling the reaction to be completed within 14 h to afford 3a with 49:1 dr and 98% ee
(entry 7). Moreover, a rhodium benzothiazole derivative ꢁꢀRhS10e (entry 10) and an analogous
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iridium complex ꢁꢀIrO10a (entry 11) developed by us previously were also tested in the system.
Both of them only provided trace amounts of the desired product at the standard conditions,
indicating that the activity of the catalysts in this reaction precisely relied on the chiral environment
and inherent character of the metal center.
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Table 1. Initial Experiments and Optimizationa
cat.
(mol%)
T
t
conv. ee
entry
solvent additives
drd
(°C) (h) (%)b (%)c
(5)
1
2
-RhO
-RhO
-RhO
-RhO
-RhO
-RhO
-RhO
-RhO
-RhO
CH2Cl2
THF
none
none
none
none
none
none
20 75
20 72
70
59
99
11
93
99
96
96
99
<5
<5
<5
79
77
46
5.3:1
18:1
1:1.9
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(5)
(5)
(5)
(5)
(2)
(2)
(2)
(2)
3
MTBE
DMF
20
20 72
20
3
e
e
4
–
–
5
toluene
toluene
5
97 100:1
6
20 14
20 14
96
98
96
99
80:1
49:1
80:1
12:1
7
toluene 4Å MS
toluene 4Å MS
toluene 4Å MS
toluene 4Å MS
toluene 4Å MS
toluene 4Å MS
8
40
0
4
9
96
10
11
12
20 14
20 14
20 14
n.d.e n.d.e
n.d.e n.d.e
n.d.e n.d.e
(2)
-RhS
(2)
-IrO
none
aReaction conditions: 2ꢀacyl imidazole 1a (0.10 mmol), isatin NꢀBoc ketimine 2a (0.15 mmol), the
metal catalyst (2–5 mol%), in the indicated solvent (1 mL) and at the indicated temperature in air.
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c
bConversion determined by H NMR analysis. Ee values of the major diastereomer determined by
d
HPLC analysis on a chiral stationary phase. Dr values determined by HPLC analysis on a chiral
stationary phase. eNot determined.
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We next examined the influence of protection groups of the isatinꢀderivated ketimines on the
catalytic outcomes. As summarized in Table 2, the reaction was strongly dependent on steric and
electronic effects of the Nꢀprotection group. For example, the benzyloxy carbamate (Cbz protection
group) provided a slightly faster reaction rate and higher enantioselectivity (entry 2), while the
electronꢀrich pꢀmethoxyphenyl group (PMP) prevented a conversion to the desired product (entry 3).
Most interestingly, the sterically less demanding methyloxy carbamate led to a significantly
improvement of the reaction rate (94% yield in 2 h) as well as diastereoꢀ and enantioselectivity
(>200:1 dr, >99% ee, entry 4). We found that for substrate 2d, the catalyst loading could be reduced
to 1 mol% while still providing a satisfactory reaction time of 4 hours for 95% yield, 200:1 dr
and >99% ee (entry 5). A further reduction of the catalyst loading to 0.5 and 0.2 mol% resulted in
slightly lower stereoselectivities (entries 6–8).
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Table 2. Comparison of Protection Groups (PG) for the Isatin-Derivated Ketiminesa
entry
PG
cat. (mol%) t(h) yield (%) ee (%)b
drc
49:1
48:1
n.a.e
> 200:1
200:1
55:1
2.4:1
29:1
1d
2
Boc(
)
)
2
2
2
2
1
0.5
0.2
0.2
14
12
12
2
88
96
0
94
95
93
46
94
98
>99
n.a.e
>99
>99
99
2a
Cbz(
2b
3
4
5
6
7
8f
PMP( )
2c
COOMe(
COOMe(
COOMe(
COOMe(
COOMe(
)
)
)
)
)
2d
2d
2d
2d
2d
4
20
64
24
92
98
aReaction conditions: 2ꢀacyl imidazole 1a (0.10 mmol), isatin Nꢀprotected ketimine 2a–d (0.15
b
mmol), metal catalyst (0.2–2 mol%), 4Å MS (5.0 mg), toluene (1 mL) in air. Ee values of the
c
major diastereomer determined by HPLC analysis on a chiral stationary phase. Dr values
d
e
determined by HPLC analysis on a chiral stationary phase. Taken from entry 7 of Table 1. Not
applicable. fCarried out at 40 °C.
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Scheme 1. Scope Regarding 2-Acyl Imidazoles.
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With the optimal conditions and the best protection group for ketimine substrates in hand, we
evaluated the generality of the catalytic reaction with respect to 2ꢀacyl imidazoles and isatin
derivated ketimines. First, a range of 2ꢀacyl imidazoles containing phenyl groups with methyl
substituents at metaꢀ, orthoꢀ or paraꢀposition (products 3e–g), electron withdrawing (product 3h) or
donating (products 3i) groups, a naphthyl moiety (product 3j), and a heteroaromatic ring (product
3k) at the βꢀposition to the 2ꢀacyl imidazoles moiety were established to be nicely compatible in
this reaction (Scheme 1). The products 3d–k were provided in 95 – 99% yield with 76:1 – >200:1
dr and 98.5 – >99% ee. Notably, an Nꢀmethyl protected imidazole (product 3l) required a longer
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reaction time of 36 h, but still provided excellent stereoselectivities. However, the substrate 1j
without an aromatic substituent at the βꢀposition of the 2ꢀacyl imidazole moiety failed to provide
the desired product. Furthermore, Scheme 2 reveals that different aryl substituents were also well
tolerated for the isatinꢀderivated ketimines. In all of the nine examples, the desired products 3n–v
were generated with excellent yields, dr, and ee values.
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Scheme 2. Scope Regarding Isatin-Derivated Ketimines.
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In summary, we have developed a highly diastereoꢀ and enantioselective synthesis of
3,3ꢀdisubstituted oxindoles bearing vicinal quaternaryꢀtertiary carbon centers by using a
chiralꢀatꢀrhodium catalyst. Chiral oxindoles were obtained in 93 – 99% yield, and with 43:1
– >200:1 dr and 98.5 – >99% ee (18 examples), thereby confirming the versatility of our
bisꢀcyclometalated chiralꢀatꢀmetal Lewis acids for asymmetric catalysis.
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ꢀ
EXPERIMENTAL SECTION
General Information. Catalyst ꢁꢀRhO,10c ꢁꢀRhS,10e ꢁꢀIrO,10a 2ꢀacyl imidazoles12 and
Nꢀalkoxycarbonyl ketimines13 were prepared according to published procedures. H and 13C{1H}
1
NMR spectra (proton decoupled) were recorded on a Bruker AM (400 MHz or 500 MHz)
spectrometer at ambient temperature. NMR standards were used as follows: 1H NMR spectroscopy:
δ = 7.26 ppm (CDCl3), 3.31 ppm (CD3OD), 2.05 ppm (CD3COCD3); 13C{1H} NMR spectroscopy:
δ = 77.0 ppm (CDCl3), 49.0 ppm (CD3OD), 29.8 ppm (CD3COCD3). Highꢀresolution mass spectra
were recorded on a Bruker En Apex Ultra 7.0T FTꢀMS instrument using ESI technique (ICR：ion
cyclotron resonance). Elemental analysis was performed on a Vario EL III (Germany).
General Procedure for the Synthesis of 2-Acyl Imidazoles.12 To a solution of Nꢀmethylimidazole
or Nꢀisopropylimidazole (1.2 eq) in anhydrous THF (0.6 M) at –78 °C was added nꢀBuLi (1.2 eq,
2.4 M in hexanes) dropwise. The reaction mixture was stirred at this temperature for 30 min, and
then stirred at room temperature for 30 min. The corresponding Weinreb amide in THF (2.0 M) was
added dropwise to the flask after the reaction mixture was cooled to –78 °C. The reaction mixture
was allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched
with AcOH (6.0 eq) at room temperature and extracted with EtOAc. The organic phase was washed
with aqueous saturated NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
The crude product was subjected to a silica gel flash chromatography (nꢀhexane/EtOAc = 5:1 to 3:1)
to afford the pure substrates.
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1ꢀ(1ꢀIsopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ethanꢀ1ꢀone (1j). 1.25 g, 82% yield, colorless oil; H NMR
(500 MHz, CDCl3) δ (ppm) 7.15 (d, J = 0.7 Hz, 1H), 7.04 (d, J = 0.5 Hz, 1H), 5.43 (hept, J = 6.7 Hz,
1H), 2.55 (s, 3H), 1.32 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 190.7, 142.4,
129.4, 121.0, 49.1, 27.8, 23.4; IR (film): ν (cmꢀ1) 2982, 2934, 2866, 1675, 1463, 1454, 1393, 1371,
1353, 1333, 1258, 1212, 1158, 1134, 1101, 1088, 1051, 953, 916, 770, 716, 666, 624; HRMS (ESI)
m/z calcd for C8H12N2ONa (M+Na)+ 175.0847, found: 175.0851.
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Preparation of ketimines. In an ovenꢀdried Schlenk tube under argon atmosphere, isatin (2.00
mmol) and Nꢀcarbomethoxyꢀtriphenylphosphinimine (2.20 mmol) were placed. After an addition of
anhydrous 1,4ꢀdioxane (2.00 mL), the mixture was heated at 120 °C for 5 h. After that, additional
Nꢀcarbomethoxyꢀtriphenylphosphinimine (1.32 mmol) was added into the reaction mixture at room
temperature, and the system was degassed via freezeꢀpumpꢀthaw for three cycles. After the mixture
was thoroughly degassed, the mixture was sealed and heated at 120 °C for additional 8 h, then
cooled down to room temperature. After evaporation of the volatile organic solvent, the crude
residue was purified by flash chromatography (silica gel, nꢀhexane/EtOAc = 3:1), and then
recrystallized from nꢀhexane/EtOAc.
Methyl (Z)ꢀ(1ꢀmethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2d). 218 mg, 50% yield, orange solid,
mp 128–130 °C; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.61 (s, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.09 (t,
J = 7.2 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.18 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 162.5, 157.2, 154.5, 148.1, 135.8, 124.5, 123.6, 118.8, 109.4, 53.8, 26.1; IR (film):
ν (cmꢀ1) 2957, 2359, 1959, 1738, 1721, 1612, 1471, 1434, 1372, 1333, 1277, 1260, 1240, 1185,
1155, 1123, 1097, 1016, 982, 895, 879, 792, 751; HRMS (ESI) m/z calcd for C11H10N2O3Na
(M+Na)+ 241.0584, found: 241.0583.
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Methyl (Z)ꢀ(1ꢀethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2e). 200 mg, 43% yield, red solid, mp
114–116 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.56 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.03 (t, J =
6.8 Hz, 1H), 6.83 (d, J = 7.7 z, 1H), 3.90 (s, 3H), 3.68 (d, J = 6.8 Hz, 2H), 1.22(t, J = 7.0 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 162.5, 156.7, 154.7, 147.2, 135.7, 124.5, 123.2, 118.7,
109.4, 53.6, 34.8, 12.3; IR (film): ν (cmꢀ1) 2086, 1736, 1615, 1470, 1358, 1253, 1185, 1100,
987,751, 462; HRMS (ESI) m/z calcd for C12H12N2O3Na (M+Na)+ 255.0740, found: 255.0738.
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Methyl (E)ꢀ(1ꢀbenzylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2f). 324 mg, 55% yield, orange solid,
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mp 102–104 °C; H NMR (500 MHz, CDCl3) δ (ppm) 7.54 (s, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.26–
7.13 (m, 5H), 6.96 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.78 (s, 2H), 3.88 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ (ppm) 162.5, 157.3, 154.5, 147.4, 135.7, 134.4, 128.9, 128.0, 127.4,
124.6, 123.6, 118.9, 110.4, 53.9, 44.0; IR (film): ν (cmꢀ1) 2069, 1737, 1616, 1470, 1435, 1354, 1250,
1182, 1100, 1002, 462; HRMS (ESI) m/z calcd for C17H15N2O3 (M+H)+ 295.1077, found: 295.1077.
Methyl (E)ꢀ(1,5ꢀdimethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2g). 162 mg, 35% yield, red solid,
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mp 142–144 °C; H NMR (500 MHz, CDCl3) δ (ppm) 7.34 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.66
(d, J = 7.9 Hz, 1H), 3.87 (s, 3H), 3.09 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 162.6, 157.3, 154.8, 145.9, 136.2, 133.3, 124.9, 118.7, 109.2, 53.7, 26.1, 20.7; IR (film): ν
(cmꢀ1) 2922, 1959, 1729, 1676, 1620, 1601, 1494, 1422, 1359,1334, 1269, 1241, 1212, 1150, 1113,
1013, 914, 880, 820, 757, 727, 546, 458; HRMS (ESI) m/z calcd for C12H12N2O3Na (M+Na)+
255.0740, found: 255.0740.
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Methyl (E)ꢀ(1,7ꢀdimethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2h). 214 mg, 46% yield, red solid,
mp 148–150 °C; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.40 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.90 (t,
J = 7.5 Hz, 1H), 3.88 (s, 3H), 3.38 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
162.5, 157.8, 154.5, 145.6, 139.5, 123.4, 122.2, 121.2, 119.3, 53.58, 29.30, 18.40; IR (film): ν (cmꢀ1)
2953, 1737, 1682, 1604, 1453, 1364, 1326, 1265, 1211, 1125,1084, 1040, 918, 875, 854, 790, 771,
734, 604, 534, 511; HRMS (ESI) m/z calcd for C12H12N2O3Na (M+Na)+ 255.0740, found: 255.0736.
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Methyl (E)ꢀ(5ꢀmethoxyꢀ1ꢀmethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2i). 238 mg, 48% yield,
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maroon solid, mp 174–176 °C; H NMR (500 MHz, CDCl3) δ (ppm) 7.20 (s, 1H), 7.05 (d, J = 7.3
Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H), 3.80 (s, 3H), 3.17 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 162.4, 157.3, 156.4, 155.0, 141.9, 121.7, 119.4, 110.2, 109.3, 55.8, 53.8, 26.1; IR
(film): ν (cmꢀ1) 2360, 1787, 1743, 1722, 1676, 1640, 1631, 1552, 1530,1491, 1468, 1433, 1414,
1383, 1359, 1290, 1268, 1239, 1222, 1195, 1163, 1113, 1027, 998, 897, 878, 824, 805, 572, 460;
HRMS (ESI) m/z calcd for C12H12N2O4Na (M+Na)+ 271.0689, found: 271.0687.
Methyl (E)ꢀ(5ꢀchloroꢀ1ꢀmethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2j). 162 mg, 32% yield, red
solid, mp 149–151 °C; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.53 (s, 1H), 7.41 (dd, J = 8.3, 1.9 Hz,
1H), 6.74 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.13 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
161.9, 156.7, 153.6, 146.4, 135.2, 129.2, 124.3, 120.0, 110.6, 53.9, 26.2; IR (film): ν (cmꢀ1) 2921,
1959, 1741, 1683, 1613, 1483, 1462, 1434, 1356, 1240, 1198, 1179, 1113, 1074, 1013, 905, 879,
825, 807, 727, 662, 559, 538, 460; HRMS (ESI) m/z calcd for C11H9ClN2O3Na (M+Na)+ 275.0194,
found: 275.0194.
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Methyl (E)ꢀ(5ꢀbromoꢀ1ꢀmethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2k). 238 mg, 40% yield, red
solid, mp 140–142 °C; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.67 (s, 1H), 7.59 (dd, J = 8.3, 1.9 Hz,
1H), 6.74 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 3.16 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
161.9, 156.5, 153.4, 146.8, 138.1, 127.1, 120.3, 116.2, 111.0, 53.9, 26.2; IR (film): ν (cmꢀ1) 2922,
2851, 1958, 1741, 1683, 1611, 1552, 1531, 1481, 1463, 1434, 1354, 1324, 1267, 1242, 1197, 1178,
1111, 1013, 901, 877, 457; HRMS (ESI) m/z calcd for C11H9BrN2O3Na (M+Na)+ 318.9689, found:
318.9687.
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Methyl (E)ꢀ(5ꢀfluoroꢀ1ꢀmethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2l). 165 mg, 35% yield, red
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solid, mp 122–124 °C; H NMR (500 MHz, CDCl3) δ (ppm) 7.34 (s, 1H), 7.21 (td, J = 8.7, 2.6 Hz,
1H), 6.80 (dd, J = 8.6, 3.7 Hz, 1H), 3.94 (s, 3H), 3.19 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 162.1, 160.3, 158.3, 154.1, 144.2, 122.1 (d, J = 24.3 Hz), 119.9, 111.8 (d, J = 24.1 Hz), 110.3
(d, J = 7.5 Hz), 53.9, 26.2; IR (film): ν (cmꢀ1) 3067, 2957, 1739, 1682, 1622, 1489, 1437, 1360,
1336, 1276, 1243, 1210, 1159, 1108, 1055, 1013, 922, 882, 835, 795, 761, 723, 680, 548, 506, 461;
HRMS (ESI) m/z calcd for C11H9FN2O3Na (M+Na)+ 259.0489, found: 259.0489.
Methyl (E)ꢀ(6ꢀchloroꢀ1ꢀmethylꢀ2ꢀoxoindolinꢀ3ꢀylidene)carbamate (2m). 212 mg, 42% yield,
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yellow solid, mp 146–148 °C; H NMR (500 MHz, CDCl3) δ (ppm) 7.53 (s, 1H), 7.05 (d, J = 7.7
Hz, 1H), 6.84 (d, J = 1.6 Hz, 1H), 3.92 (s, 3H), 3.17 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 162.1, 157.1, 153.3, 149.1, 141.9, 125.4, 123.7, 117.1, 110.2, 53.8, 26.2; IR (film): ν (cmꢀ1)
2921, 1959, 1740, 1679, 1611, 1491, 1434, 1370, 1310, 1265, 1237, 1201, 1185, 1104, 1077, 1012,
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984, 911, 884, 852, 827, 805, 731, 602, 577, 468; HRMS (ESI) m/z calcd for C11H9ClN2O3Na
(M+Na)+ 275.0194, found: 275.0195.
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General Procedure for the Catalytic Reaction of 2-Acyl Imidazoles with Ketimines. To a
solution of ꢁꢀRhO catalyst (0.2–2.0 mol%) in anhydrous toluene was added 2ꢀacyl imidazole 1a–j
(0.100 mmol) and 4Å MS (5.00 mg) in a brown glass vial. The mixture was stirred at 20 °C for 30
min, then ketimine 2a–m (0.150 mmol) was added. The reaction mixture was stirred at 20 °C for
the indicated time. Upon completion, the mixture was purified by flash chromatography on silica
gel (nꢀhexane/EtOAc = 4:1 to 1:1) to afford product 3a–v.
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tertꢀButyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2ꢀoxoin
dolinꢀ3ꢀyl)carbamate (3a). 43.0 mg, 88% yield, white solid, mp 147–149 °C; 98% ee, 49:1 dr
(HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 85:15–75:25 in 15 min with a linear gradient elution,
flow rate: 0.80–0.50 mL/min in 15 min, 30 °C, 254 nm, major diastereomer: tr(major) = 12.4 min,
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tr(minor) = 16.1 min); [α]D = –17.1 (c = 1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ (ppm) 7.19
(s, 1H), 7.18–7.04 (m, 8H), 6.86 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 7.1 Hz, 1H), 6.55 (d, J = 7.7 Hz,
1H), 5.53 (s, 1H), 5.38 (hept, 1H), 2.82 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.27 (d, J = 6.7 Hz, 3H),
1.11 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 189.1, 175.6, 154.2, 143.9, 143.0, 132.5,
130.8, 130.0, 128.8, 127.9, 127.6, 125.0, 122.1, 121.7, 107.6, 79.9, 64.9, 55.2, 49.6, 28.0, 25.9, 23.7,
23.4. IR(film): ν (cm−1) 2966, 2924, 1722, 1691, 1678, 1613, 1493, 1469, 1454, 1392, 1255, 1165,
1090, 1023, 799, 750, 701; HRMS (ESI) m/z calcd for C28H32N4O4Na (M+Na)+ 511.2316, found:
511.2316.
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Benzyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2ꢀoxoindol
inꢀ3ꢀyl)carbamate (3b). 50.2 mg, 96% yield, white solid, mp 141–143 °C; >99% ee, 48:1 dr (HPLC:
Chiralpak IB, nꢀhexane/iꢀPrOH = 60:40–80:20 in 15 min with a linear gradient elution, flow rate:
0.40 mL/min, 30 °C, 254 nm, major diastereomer: tr(minor) = 21.2 min, tr(major) = 24.1 min);
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[α]D = –43.3 (c = 1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (s, 1H), 7.18 (s, 6H),
7.15–6.96 (m, 6H), 6.85 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 7.0 Hz, 1H), 6.55 (s, 1H), 5.52 (s, 1H), 5.38
(hept, J = 6.5 Hz, 1H), 4.84 (s, 2H), 2.83 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.5 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 189.1, 175.3, 155.0, 144.0, 142.8, 132.4, 130.7, 130.0,
129.1, 128.3, 128.0, 128.0, 127.9, 127.7, 127.0, 125.1, 122.2, 121.8, 107.8, 66.9, 64.9, 55.0, 49.6,
26.0, 23.6, 23.3; IR(film): ν (cm−1) 3347, 2962, 2924, 2852, 1723, 1675, 1613, 1493, 1470, 1765,
1394, 1374, 1317, 1257, 1127, 1091, 1026, 828, 745, 698, 560; HRMS (ESI) m/z calcd for
C31H30N4O4Na (M+Na)+ 545.2159, found: 545.2161.
Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2ꢀoxoindol
inꢀ3ꢀyl)carbamate (3d). 42.4 mg, 95% yield, white solid, mp 135–137 °C; >99% ee, >200:1 dr
(HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 12.6 min, tr(major) = 14.5 min); [α]D = –40.0 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CDCl3) δ (ppm) 7.73 (s, 1H), 7.21 (s, 1H), 7.20–7.16 (m, 1H), 7.16–7.12 (m, 2H),
7.12–7.04 (m, 4H), 6.85 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 5.50
(s, 1H), 5.38 (hept, J = 6.6 Hz, 1H), 3.45 (s, 3H), 2.86 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.28 (d, J =
6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ (ppm) 189.1, 175.4, 155.5, 144.0, 142.9, 132.4, 130.7,
130.0, 129.2, 128.0, 127.7, 126.9, 124.9, 122.3, 121.8, 107.7, 64.8, 54.9, 52.1, 49.6, 26.1, 23.7, 23.3;
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IR(film): ν (cm−1) 3350, 2962, 2925, 1724, 1676, 1614, 1493, 1470, 1456, 1394, 1375, 1318, 1256,
1195, 1128, 1090, 1025, 917, 798, 750, 700, 630, 540, 518; HRMS (ESI) m/z calcd for
C25H26N4O4Na (M+Na)+ 469.1846, found: 469.1847
.
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Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀ(oꢀtolyl)ethyl)ꢀ1ꢀmethylꢀ2ꢀoxoind
olinꢀ3ꢀyl)carbamate (3e). 45.6 mg, 99% yield, white solid, mp 132–134 °C; >99% ee, >200:1 dr
(HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 90:10, flow rate: 0.80 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 16.1 min, tr(major) = 17.7 min); [α]D = –32.3 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CD3OD) δ (ppm) 7.53 (s, 1H), 7.27 (dd, J = 16.5, 8.0 Hz, 2H), 7.16–7.06 (m, 2H),
7.05–6.93 (m, 2H), 6.86 (t, J = 7.3 Hz, 2H), 6.63 (d, J = 7.3 Hz, 1H), 5.82 (s, 1H), 5.46 (hept, J =
6.6 Hz, 1H), 3.50 (s, 3H), 3.02 (s, 3H), 2.03 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 6.7 Hz,
3H); 13C{1H} NMR (126 MHz, CD3OD) δ (ppm) 191.0, 178.3, 157.6, 145.1, 143.9, 140.6, 132.2,
131.6, 131.0, 130.3, 130.1, 129.2, 129.0, 126.2, 126.1, 124.4, 123.2, 109.4, 66.4, 52.7, 50.9, 50.4,
26.6, 23.6, 23.5, 20.1; IR(film): ν (cm−1) 3354, 3110, 3055, 2961, 2926, 1724, 1664, 1613, 1493,
1470, 1394, 1311, 1254, 1194, 1163, 1128, 1091, 1055, 1023, 962, 937, 917, 837, 783, 753, 689,
629, 560, 540, 500; HRMS (ESI) m/z calcd for C26H29N4O4 (M+H)+ 461.2183, found: 461.2183
.
Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀ(mꢀtolyl)ethyl)ꢀ1ꢀmethylꢀ2ꢀoxoind
olinꢀ3ꢀyl)carbamate (3f). 45.1 mg, 98% yield, white solid, mp 163–165 °C; >99% ee, 76:1 dr
(HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 70:30, flow rate: 0.80 mL/min, 30 °C, 254 nm, major
diastereomer: tr(major) = 9.4 min, tr(minor) = 18.9 min); [α]D20 = –30.0 (c = 1.0, CH2Cl2); 1H NMR
(500 MHz, CD3COCD3) δ (ppm) 7.63 (s, 1H), 7.61 (s, 1H), 7.25 (t, J = 7.8 Hz, 2H), 7.15 (s, 1H),
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7.05–6.93 (m, 3H), 6.93–6.87 (m, 1H), 6.86 (s, 1H), 6.73 (d, J = 7.7 Hz, 1H), 5.68 (s, 1H), 5.46
(hept, J = 6.6 Hz, 1H), 3.43 (s, 3H), 2.85 (s, 3H), 2.13 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H), 1.37 (d, J =
6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CD3COCD3) δ (ppm) 189.5, 175.8, 155.8, 145.5, 143.6,
137.6, 133.5, 132.1, 130.5, 129.6, 129.2, 128.6, 128.5, 128.1, 126.3, 123.7, 122.1, 108.3, 65.5, 57.1,
52.0, 50.3, 26.1, 23.6, 23.4, 21.3; IR(film): ν (cm−1) 3348, 2961, 2925, 1724, 1675, 1614, 1493,
1469, 1394, 1374, 1315, 1256, 1195, 1128, 1091, 1030, 907, 868, 799, 777, 754, 734, 699, 632, 540,
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503; HRMS (ESI) m/z calcd for C26H28N4O4Na (M+Na)+ 483.2003, found: 483.2004
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Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀ(pꢀtolyl)ethyl)ꢀ1ꢀmethylꢀ2ꢀoxoind
olinꢀ3ꢀyl)carbamate (3g). 44.2 mg, 96% yield, white solid, mp 165–167 °C; >99% ee, >200:1 dr
(HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm, major
diastereomer: tr(minor) = 13.5 min, tr(major) = 15.0 min); [α]D20 = –40.1 (c = 1.0, CH2Cl2);1H NMR
(500 MHz, CD3COCD3) δ (ppm) 7.76–7.51 (m, 2H), 7.25 (t, J = 7.2 Hz, 2H), 7.14 (s, 1H), 7.01–
6.87 (m, 5H), 6.73 (d, J = 7.9 Hz, 1H), 5.69 (s, 1H), 5.46 (hept, J = 6.6 Hz, 1H), 3.43 (s, 3H), 2.87
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(s, 3H), 2.20 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H), 1.36 (d, J = 6.7 Hz, 3H); C{1H} NMR (126 MHz,
CD3COCD3) δ (ppm) 189.7, 175.9, 155.8, 145.5, 143.6, 138.2, 131.3, 130.6, 130.5, 129.6, 128.9,
128.6, 126.3, 123.7, 122.1, 108.4, 65.6, 56.8, 52.0, 50.3, 26.1, 23.6, 23.4, 20.9; IR(film): ν (cm−1)
3348, 2962, 2924, 1725, 1675, 1613, 1493, 1469, 1394, 1374, 1317, 1257, 1194, 1127, 1091, 1024,
917, 834, 752, 703, 686, 601, 560, 539, 489; HRMS (ESI) m/z calcd for C26H29N4O4 (M+H)+
461.2183, found: 461.2192
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Methyl((R)ꢀ3ꢀ((R)ꢀ1ꢀ(4ꢀbromophenyl)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoethyl)ꢀ1ꢀmethylꢀ
2ꢀoxoindolinꢀ3ꢀyl)carbamate (3h). 52.0 mg, 99% yield, white solid, mp 134–136 °C; 98.5% ee,
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98:1 dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm,
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major diastereomer: tr(major) = 10.9 min, tr(minor) = 13.5 min); [α]D = –73.1 (c = 1.0, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ (ppm) 7.69 (s, 1H), 7.24 (s, 1H), 7.21 (t, J = 8.2 Hz, 3H), 7.15 (s,
1H), 6.94 (d, J = 8.3 Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.61 (d, J = 7.8 Hz,
1H), 5.51 (s, 1H), 5.36 (hept, J = 6.6 Hz, 1H), 3.45 (s, 3H), 2.86 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H),
1.29 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 188.4, 175.2, 155.5, 144.1,
142.8, 132.3, 131.4, 130.8, 130.1, 129.4, 126.5, 124.9, 122.5, 122.4, 122.0, 107.9, 64.5, 54.5, 52.2,
49.7, 26.1, 23.7, 23.3; IR(film): ν (cm−1) 3338, 3055, 2962, 2926, 2853, 1725, 1675, 1614, 1489,
1470, 1413, 1393, 1374, 1354, 1313, 1258, 1194, 1148, 1128, 1090, 1028, 1012, 918, 791, 753, 735,
702, 637, 617, 579, 540, 529, 488; HRMS (ESI) m/z calcd for C25H25BrN4O4Na (M+Na)+ 547.0951
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found: 547.0952
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N
iPr
N
MeO
O
NHCO2Me
O
N
3i
Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)ꢀ1ꢀmethy
lꢀ2ꢀoxoindolinꢀ3ꢀyl)carbamate (3i). 46.2 mg, 97% yield, white solid, mp 162–164 °C; 99% ee,
160:1 dr (HPLC: Chiralpak ASꢀH, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm,
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major diastereomer: tr(major) = 22.5 min, tr(minor) = 42.4 min); [α]D = –50.4 (c = 1.0, CH2Cl2);
1H NMR (500 MHz, CD3COCD3) δ (ppm) 7.62 (d, J = 5.8 Hz, 2H), 7.25 (dd, J = 9.9, 4.5 Hz, 2H),
7.15 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.96 (t, J = 7.3 Hz, 1H), 6.75 (t, J = 12.0 Hz, 1H), 6.67 (d, J =
8.8 Hz, 2H), 5.67 (s, 1H), 5.46 (hept, J = 6.6 Hz, 1H), 3.69 (s, 3H), 3.43 (s, 3H), 2.88 (s, 3H), 1.49
(d, J = 6.6 Hz, 3H), 1.35 (t, J = 10.1 Hz, 3H); 13C{1H} NMR (126 MHz, CD3COCD3) δ (ppm)
189.7, 176.0, 160.3, 155.9, 145.6, 143.6, 132.5, 130.5, 129.7, 128.6, 126.3, 125.4, 123.7, 122.1,
113.7, 108.4, 65.4, 56.3, 55.4, 52.0, 50.3, 26.2, 23.6, 23.4; IR(film): ν (cm−1) 2917, 1959, 1724,
1674, 1612, 1511, 1468, 1394, 1255, 1180, 1091, 1029, 830, 560; HRMS (ESI) m/z calcd for
C26H28N4O5Na (M+Na)+ 499.1952, found: 499.1958
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iPr
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O
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NHCO2Me
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3j
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Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ1ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀoxoethyl)ꢀ1ꢀmethylꢀ
2ꢀoxoindolinꢀ3ꢀyl)carbamate (3j). 47.2 mg, 95% yield, white solid, mp 137–139 °C; 98.6% ee,
138:1 dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 70:30, flow rate: 0.80 mL/min, 30 °C, 254 nm,
major diastereomer: tr(minor) = 9.9 min, tr(major) = 11.7 min); [α]D20 = –40.1 (c = 1.0, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ (ppm) 7.74 (s, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.57 (dd, J = 19.3, 9.3 Hz,
3H), 7.39–7.27 (m, 2H), 7.27–7.15 (m, 3H), 7.12 (s, 1H), 6.83 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 7.1
Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 5.69 (s, 1H), 5.39 (hept, J = 6.5 Hz, 1H), 3.45 (s, 3H), 2.80 (s,
3H), 1.42 (d, J = 6.5 Hz, 3H), 1.24 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
189.1, 175.4, 155.6, 144.0, 142.8, 132.8, 132.7, 130.2, 130.0, 129.9, 129.2, 128.3, 128.2, 127.3,
127.1, 127.0, 126.1, 125.8, 125.0, 122.3, 121.9, 107.8, 64.8, 55.1, 52.1, 49.6, 26.1, 23.6, 23.3;
IR(film): ν (cm−1) 2917, 1959, 1724, 1674, 1612, 1511, 1468, 1394, 1255, 1180, 1091, 1029, 830,
560, 439; HRMS (ESI) m/z calcd for C29H28N4O4Na (M+Na)+ 519.2003, found: 519.2004.
Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀ(thiophenꢀ3ꢀyl)ethyl)ꢀ1ꢀmethylꢀ2ꢀ
oxoindolinꢀ3ꢀyl)carbamate (3k). 44.3 mg, 98% yield, white solid, mp 161–163 °C; >99% ee, 120:1
dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm, major
diastereomer: tr(minor) = 9.4 min, tr(major) = 13.0 min); [α]D20 = –96.3 (c = 1.0, CH2Cl2); 1H NMR
(500 MHz, CD3COCD3) δ (ppm) 7.82 (s, 1H), 7.68 (s, 1H), 7.28 (td, J = 7.7, 1.0 Hz, 1H), 7.25–7.16
(m, 2H), 7.07 (t, J = 5.8 Hz, 2H), 6.96 (t, J = 7.4 Hz, 1H), 6.84–6.69 (m, 2H), 5.85 (s, 1H), 5.45
(hept, J = 6.6 Hz, 1H), 3.43 (s, 3H), 2.90 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (126 MHz, CD3COCD3) δ (ppm) 188.8, 175.7, 155.8, 145.6, 143.7, 133.6, 130.6,
130.2, 129.8, 128.3, 126.3, 125.7, 124.6, 124.1, 122.1, 108.5, 65.1, 52.5, 52.1, 50.4, 26.2, 23.7, 23.2;
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1259, 1195, 1149, 1128, 1090, 1029, 914, 829, 754, 734, 701, 679, 647, 560, 540, 509; HRMS (ESI)
m/z calcd for C23H25N4O4S (M+H)+ 453.1591, found: 453.1593
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Methyl((R)ꢀ1ꢀmethylꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀmethylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ2ꢀoxoindolinꢀ
3ꢀyl)carbamate (3l). 39.3 mg, 94% yield, white solid, mp 149–151 °C; >99% ee, >200:1 dr
(HPLC: Chiralpak ASꢀH, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 28.5 min, tr(major) = 35.2 min); [α]D = –60.7 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CD3COCD3) δ (ppm) 7.67 (s, 1H), 7.37 (s, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.25 (td,
J = 7.7, 0.9 Hz, 1H), 7.16 (t, J = 7.1 Hz, 1H), 7.13–7.02 (m, 5H), 6.97 (t, J = 7.5 Hz, 1H), 6.71 (d, J
= 7.8 Hz, 1H), 5.68 (s, 1H), 4.00 (s, 3H), 3.43 (s, 3H), 2.82 (s, 3H); 13C{1H} NMR (126 MHz,
CD3COCD3) δ (ppm) 189.1, 175.8, 155.8, 145.5, 144.4, 133.5, 131.4, 129.9, 129.7, 129.5, 128.6,
128.4, 128.2, 126.4, 122.2, 108.4, 65.5, 56.7, 52.0, 36.5, 26.1; IR(film): ν (cm−1) 3338, 2960, 2921,
2850, 1959, 1723, 1676, 1613, 1493, 1471, 1402, 1374, 1321, 1259, 1158, 1127, 1091, 1026, 916,
828, 752, 700, 633, 604, 560, 540, 522; HRMS (ESI) m/z calcd for C23H22N4O4Na (M+Na)+
441.1533, found: 441.1534
.
N
iPr
N
O
Ph
NHCO2Me
O
N
Et
3n
Methyl((R)ꢀ1ꢀethylꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ2ꢀoxoindolin
ꢀ3ꢀyl)carbamate (3n). 42.8 mg, 93% yield, white solid, mp 115–117 °C; 98.6% ee, >200:1 dr
(HPLC: Chiralpak ODꢀH, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 14.1 min, tr(major) = 19.3 min); [α]D = –62.9 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.23 (s, 1H), 7.19 (dd, J = 8.8, 6.6 Hz, 1H), 7.16 (s,
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1H), 7.15–7.08 (m, 1H), 7.04 (d, J = 4.3 Hz, 4H), 6.88 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H),
6.60 (d, J = 7.8 Hz, 1H), 5.54 (s, 1H), 5.36 (hept, J = 6.7 Hz, 1H), 3.59 (dq, J = 14.2, 7.0 Hz, 1H),
3.44 (s, 3H), 3.26 (dq, J = 14.2, 7.1 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 6.7 Hz, 3H), 0.70
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 188.8, 174.7, 155.4, 143.3, 143.2,
132.3, 130.9, 130.0, 129.1, 128.0, 127.6, 126.9, 125.1, 122.2, 121.6, 107.8, 64.5, 55.2, 52.1, 49.6,
34.4, 23.8, 23.3, 11.8; IR(film): ν (cm−1) 3348, 2964, 2932, 1721, 1676, 1613, 1489, 1467, 1456,
1393, 1372, 1321, 1259, 1236, 1195, 1133, 1096, 1039, 990, 918, 798, 744, 700, 631, 551, 524, 490,
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434; HRMS (ESI) m/z calcd for C26H28N4O4Na (M+Na)+ 483.2003, found: 483.2000
.
Methyl((R)ꢀ1ꢀbenzylꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ2ꢀoxoindol
inꢀ3ꢀyl)carbamate (3o). 50.2 mg, 96% yield, white solid, mp 163–165 °C; 98.6% ee, 114:1 dr
(HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 13.3 min, tr(major) = 25.5 min); [α]D = –86.2 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.23 (s, 1H), 7.21–7.16 (m, 2H), 7.16–7.07 (m, 7H),
7.04 (td, J = 7.7, 1.2 Hz, 1H), 6.93–6.73 (m, 4H), 6.39 (d, J = 7.8 Hz, 1H), 5.64 (s, 1H), 5.38 (hept,
1H), 4.76 (d, 1H), 4.48 (d, J = 16.1 Hz, 1H), 3.46 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.7
Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 189.1, 175.7, 155.5, 143.5, 143.1, 135.5, 132.4,
131.0, 130.1, 129.1, 128.5, 128.1, 127.9, 127.1, 126.9, 126.8, 125.0, 122.4, 121.9, 109.1, 64.7, 55.1,
52.2, 49.7, 44.1, 23.8, 23.3; IR(film): ν (cm−1) 3338, 2960, 2921, 2850, 1723, 1676, 1613, 1493,
1471, 1402, 1374, 1321, 1259, 1158, 1127, 1091, 1026, 916, 828, 752, 700, 560; HRMS (ESI) m/z
calcd for C31H30N4O4Na (M+Na)+ 545.2159, found: 545.2160.
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Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1,5ꢀdimethylꢀ2ꢀoxoi
ndolinꢀ3ꢀyl)carbamate (3p). 45.1 mg, 98% yield, white solid, mp 179–181 °C; >99% ee, 105:1 dr
(HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 80:20, flow rate: 0.50 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 24.3 min, tr(major) = 26.3 min); [α]D = –78.7 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.21 (s, 1H), 7.18–7.13 (m, 1H), 7.12 (s, 1H), 7.11–
7.06 (m, 3H), 6.97 (d, J = 7.8 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 6.40 (s, 1H), 5.45 (s, 1H), 5.39
(hept, J = 13.2, 6.8 Hz, 1H), 3.46 (s, 3H), 2.86 (s, 3H), 2.13 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.29
(d, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 189.2, 175.3, 155.6, 142.9, 141.6,
132.6, 131.0, 130.8, 129.9, 129.4, 128.0, 127.6, 126.8, 125.9, 122.2, 107.4, 64.9, 54.9, 52.1, 49.6,
26.1, 23.7, 23.3, 21.1; IR(film): ν (cm−1) 3356, 2962, 2922, 2852, 1722, 1675, 1622, 1604, 1499,
1455, 1393, 1366, 1316, 1258, 1196, 1136, 1090, 1026, 918, 853, 804, 742, 700, 672, 623, 552, 520;
HRMS (ESI) m/z calcd for C26H28N4O4Na (M+Na)+ 483.2003, found: 483.2000. Anal. Calcd (%)
for C26H28N4O4: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.85; H, 6.30; N, 11.92.
Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1,7ꢀdimethylꢀ2ꢀoxoi
ndolinꢀ3ꢀyl)carbamate (3q). 43.3 mg, 94% yield, white solid, mp 142–144 °C; 98.4% ee, 90:1 dr
(HPLC: Chiralpak ODꢀH, nꢀhexane/iꢀPrOH = 70:30, flow rate: 0.50 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 14.1 min, tr(major) = 22.5 min); [α]D = –34.6 (c = 1.0, CH2Cl2); H
NMR (500 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.21 (s, 1H), 7.18–7.14 (m, 1H), 7.13 (s, 1H), 7.12–
7.05 (m, 4H), 6.90 (d, J = 7.6 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H), 5.43 (s,
1H), 5.38 (hept, J = 13.3, 6.7 Hz, 1H), 3.46 (s, 3H), 3.13 (s, 3H), 2.36 (s, 3H), 1.43 (d, J = 6.6 Hz,
3H), 1.28 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 189.1, 176.3, 155.6, 142.9,
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141.7, 132.9, 132.5, 130.9, 129.9, 128.0, 127.6, 127.5, 122.7, 122.2, 121.6, 119.3, 64.4, 55.1, 52.1,
49.6, 29.6, 23.7, 23.3, 18.9; IR(film): ν (cm−1) 3349, 2962, 2926, 1720, 1676, 1603, 1491, 1456,
1394, 1367, 1343, 1317, 1259, 1196, 1149, 1122, 1073, 1052, 1035, 919, 821, 777, 744, 702, 636,
597, 560, 542, 507; HRMS (ESI) m/z calcd for C26H28N4O4Na (M+Na)+ 483.2003, found:
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483.2004
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Methyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ5ꢀmethoxyꢀ1ꢀmethyl
ꢀ2ꢀoxoindolinꢀ3ꢀyl)carbamate (3r). 46.7 mg, 98% yield, white solid, mp 133–135 °C; >99% ee,
173:1 dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm,
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major diastereomer: tr(minor) = 11.1 min, tr(major) = 14.5 min); [α]D = –81.8 (c = 1.0, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ (ppm) 7.76 (s, 1H), 7.21 (s, 1H), 7.18–7.05 (m, 6H), 6.71 (dd, J =
8.4, 2.4 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 5.45 (s, 1H), 5.39 (hept, J = 13.2, 6.6 Hz,
1H), 3.54 (s, 3H), 3.47 (s, 3H), 2.87 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 189.3, 175.2, 155.7, 155.1, 142.8, 137.5, 132.6, 130.8,
130.0, 128.1, 128.0, 127.8, 122.3, 114.1, 111.9, 108.1, 65.1, 55.4, 54.6, 52.16, 49.6, 26.2, 23.7, 23.3;
IR(film): ν (cm−1) 3349, 2961, 1721, 1673, 1603, 1496, 1467, 1456, 1435, 1394, 1369, 1288, 1258,
1208, 1130, 1088, 1037, 918, 852, 803, 741, 700, 648, 523; HRMS (ESI) m/z calcd for
C26H28N4O5Na (M+Na)+ 499.1952, found: 499.1948
.
Methyl((R)ꢀ5ꢀchloroꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2
ꢀoxoindolinꢀ3ꢀyl)carbamate (3s). 45.7 mg, 95% yield, white solid, mp 136–138 °C; 98.8% ee,
43:1 dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm,
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major diastereomer: tr(minor) = 9.3 min, tr(major) = 14.2 min); [α]D20 = –64.8 (c = 1.0, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ (ppm) 7.67 (s, 1H), 7.22 (s, 1H), 7.18–7.14 (m, 2H), 7.12 (s, 1H), 7.10
(d, J = 4.8 Hz, 3H), 6.68 (s, 1H), 6.51 (d, J = 8.3 Hz, 1H), 5.48 (s, 1H), 5.39 (hept, 1H), 3.47 (s, 3H),
2.84 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 188.8, 175.1, 155.6, 142.7, 142.6, 132.0, 130.6, 130.1, 129.0, 128.7, 128.2, 127.8, 127.2,
125.6, 122.4, 108.6, 64.9, 54.8, 52.3, 49.7, 26.2, 23.6, 23.4; IR(film): ν (cm−1) 3342, 2962, 2925,
1727, 1674, 1611, 1490, 1465, 1394, 1365, 1299, 1260, 1195, 1132, 1103, 1026, 973, 918, 836, 738,
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700, 642, 621, 560, 546, 522; HRMS (ESI) m/z calcd for C25H25N4O4ClNa (M+Na)+ 503.1457
found: 503.1456
,
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Methyl((R)ꢀ5ꢀbromoꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2
ꢀoxoindolinꢀ3ꢀyl)carbamate (3t). 51.5 mg, 98% yield, white solid, mp 159–161 °C; >99% ee, 49:1
dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 70:30, flow rate: 0.80 mL/min, 30 °C, 254 nm, major
diastereomer: tr(minor) = 8.1 min, tr(major) = 11.5 min); [α]D20 = –67.4 (c = 1.0, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ (ppm) 7.68 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.18–7.14 (m, 1H),
7.14–6.98 (m, 5H), 6.79 (s, 1H), 6.47 (d, J = 8.2 Hz, 1H), 5.47 (s, 1H), 5.39 (hept, J = 13.1, 6.5 Hz,
1H), 3.47 (s, 3H), 2.84 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ (ppm) 188.7, 174.9, 155.6, 143.1, 142.7, 132.0, 131.9, 130.6, 130.1, 129.0,
128.3, 128.2, 127.8, 122.4, 114.6, 109.1, 64.8, 54.8, 52.3, 49.7, 26.2, 23.6, 23.3; IR(film): ν (cm−1)
3343, 2962, 2926, 1727, 1675, 1609, 1488, 1466, 1456, 1394, 1363, 1298, 1260, 1195, 1133, 1101,
1053, 1026, 971, 918, 858, 808, 740, 700, 638, 620, 565, 533; HRMS (ESI) m/z calcd for
C25H25N4O4BrNa (M+Na)+ 547.0951, found: 547.0952
.
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iPr
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NHCO2Me
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3u
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Methyl((R)ꢀ5ꢀfluoroꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2ꢀ
oxoindolinꢀ3ꢀyl)carbamate (3u). 45.5 mg, 98% yield, white solid, mp 154–156 °C; >99% ee, 119:1
dr (HPLC: Chiralpak ASꢀH, nꢀhexane/iꢀPrOH = 80:20, flow rate: 1.0 mL/min, 30 °C, 254 nm,
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major diastereomer: tr(minor) = 20.2 min, tr(major) = 33.3 min); [α]D = –19.3 (c = 1.0, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (s, 1H), 7.22 (s, 1H), 7.18–7.04 (m, 6H), 6.88 (td, J = 8.9,
2.5 Hz, 1H), 6.50 (dd, J = 8.4, 3.8 Hz, 2H), 5.50 (s, 1H), 5.39 (hept, 1H), 3.47 (s, 3H), 2.85 (s, 3H),
1.45 (d, J = 6.6 Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 188.9,
175.2, 159.5, 157.6, 155.6, 142.7, 140.0, 132.1, 130.6, 130.1, 128.2, 127.8, 122.4, 115.3 (d, J = 23.6
Hz), 113.4 (d, J = 25.5 Hz), 108.1 (d, J = 8.0 Hz), 65.0, 54.8, 52.2, 49.7, 26.2, 23.7, 23.4; IR(film):
ν (cm−1) 3344, 2963, 2926, 1725, 1674, 1621, 1494, 1467, 1455, 1394, 1370, 1298, 1259, 1197,
1165, 1122, 1088, 1026, 979, 917, 812, 741, 701, 674, 625, 559, 524, 440; HRMS (ESI) m/z calcd
for C25H25N4O4FNa (M+Na)+ 487.1752, found: 487.1753
.
Methyl((R)ꢀ6ꢀchloroꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀphenylethyl)ꢀ1ꢀmethylꢀ2
ꢀoxoindolinꢀ3ꢀyl)carbamate (3v). 46.7 mg, 97% yield, white solid, mp 105–107 °C; >99% ee, 53:1
dr (HPLC: Chiralpak IA, nꢀhexane/iꢀPrOH = 70:30, flow rate: 0.90 mL/min, 30 °C, 254 nm, major
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diastereomer: tr(minor) = 6.8 min, tr(major) = 8.9 min); [α]D = –33.2 (c = 1.0, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ (ppm) 7.68 (s, 1H), 7.22 (d, J = 0.6 Hz, 1H), 7.18–7.04 (m, 6H), 6.83 (dd, J =
8.0, 1.8 Hz, 1H), 6.64 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 5.49 (s, 1H), 5.37 (hept, 1H),
3.46 (s, 3H), 2.85 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ (ppm) 188.9, 175.4, 155.6, 145.3, 142.8, 135.0, 132.1, 130.6, 130.1, 128.2, 127.9,
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125.9, 125.4, 122.4, 121.8, 108.5, 64.5, 54.8, 52.24, 49.7, 26.2, 23.7, 23.4.; IR(film): ν (cm−1) 3346,
2962, 2926, 1729, 1675, 1610, 1495, 1465, 1394, 1371, 1296, 1260, 1195, 1133, 1074, 1026, 967,
917, 892, 842, 796, 737, 701, 647, 620, 577, 518; HRMS (ESI) m/z calcd for C25H25N4O4ClNa
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(M+Na)+ 503.1457, found: 503.1455
.
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tertꢀButyl((R)ꢀ3ꢀ((R)ꢀ2ꢀ(1ꢀisopropylꢀ1Hꢀimidazolꢀ2ꢀyl)ꢀ2ꢀoxoꢀ1ꢀ(thiophenꢀ3ꢀyl)ethyl)ꢀ1ꢀmethylꢀ
2ꢀoxoindolinꢀ3ꢀyl)carbamate (3w, for crystallization). 48.5 mg, 98% yield, white solid, mp 161–
163 °C; >99% ee, 30:1 dr (HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 90:10, flow rate: 1.0 mL/min,
25 °C, 254 nm, major diastereomer: tr(major) = 16.7 min, tr(minor) = 24.7 min); [α]D20 = –92.3 (c =
1
1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ (ppm) 7.36 (s, 1H), 7.23 (s, 1H), 7.18 (t, J = 7.8 Hz,
1H), 7.14 (s, 1H), 7.00 (dd, J = 4.5, 3.1 Hz, 1H), 6.96 (s, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.82–6.69 (m,
2H), 6.57 (d, J = 7.7 Hz, 1H), 5.67 (s, 1H), 5.38 (hept, J = 6.6 Hz, 1H), 2.84 (s, 3H), 1.44 (d, J = 6.6
Hz, 3H), 1.29 (d, J = 6.7 Hz, 3H), 1.09 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 188.3,
175.5, 154.1, 143.8, 142.9, 132.4, 130.0, 129.4, 128.8, 127.6, 125.6, 124.6, 123.7, 122.3, 121.6,
107.5, 79.8, 64.7, 50.9, 49.5, 27.9, 25.9, 23.6, 23.3; IR(film): ν (cm−1) 3357, 3111, 3055, 2975, 2928,
1721, 1675, 1614, 1494, 1470, 1393, 1373, 1353, 1322, 1256, 1165, 1126, 1090, 1023, 962, 918,
829, 752, 726, 701, 679, 648, 560, 540, 514, 488, 463; HRMS (ESI) m/z calcd for C26H30N4O4SNa
(M+Na)+ 517.1880, found: 517.1880.
Catalytic Asymmetric Reaction in 0.8 mmol Scale. To a solution of ꢁꢀRhO catalyst (6.64 mg,
0.00800 mmol, 1.0 mol%) in anhydrous toluene was added 2ꢀacyl imidazole 1b (194 mg, 0.800
mmol) and 4Å MS (40.0 mg) in a brown glass vial. The mixture was stirred at 20 °C for 30 min,
then ketimine 2d (262 mg, 1.20 mmol) was added. The reaction mixture was stirred at 20 °C for 5 h.
After that, the resulting mixture was purified by flash chromatography on silica gel
(nꢀhexane/EtOAc= 4:1 to 1:1) to afford product 3e (361 mg, 98% yield) as a white solid.
Enantiomeric excess and diasteromeric ratio were established by HPLC analysis, >99% ee, >200:1
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dr (HPLC: Chiralpak IB, nꢀhexane/iꢀPrOH = 90:10, flow rate: 0.80 mL/min, 30 °C, 254 nm, major
diastereomer: tr(minor) = 17.5 min, tr(major) = 18.8 min); [α]D20 = –32.3 (c =1.0, CH2Cl2).
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ꢀ
AUTHOR INFORMATION
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Corresponding Authors
*Eꢀmail: gongl@xmu.edu.cn, meggers@chemie.uniꢀmarburg.de.
ꢀ
ACKNOWLEDGMENT
We are grateful for financial support from the National Natural Science Foundation of China
(grant nos. 21572184 and 21472154), the Natural Science Foundation of Fujian Province of China
(grant no. 2017J06006), and the Fundamental Research Funds for the Central Universities (grant no.
20720160027).
ꢀ
ASSOCIATED CONTENT
Supporting Information. NMR spectra, HPLC traces and Xꢀray crystal structure. This material is
available free of charge via the Internet at http://pubs.acs.org. Crystallographic data for compound
3w has been deposited with the Cambridge Crystallographic Data Centre (CCDC) under deposition
number 1541214.
ꢀ
REFERENCES
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(5) For the construction of contiguous quaternaryꢀquaternary carbon centers through
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(6) For selected examples of other catalytic asymmetric Michaelꢀtype reactions of
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(7) For selected examples on the synthesis of chiral 3,3ꢀdisubstituted oxindoles containing
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