Amino-indanol-catalyzed asymmetric michael additions of oxindoles to protected 2-amino-1-nitroethenes for the synthesis of 3,3′-disubstituted oxindoles bearing α,β-diamino functionality

Article abstract of DOI:10.1021/jo2004378

An organocatalytic asymmetric Michael addition reaction of 3-substituted oxindoles to protected 2-amino-1-nitroethenes has been developed. The reaction is catalyzed by a simple and readily available amino-indanol derivative and affords the desired products in very high yields (up to 99%) with excellent diastereoselectivities (up to >99:1) and very good enantioselectivities (up to 90%). Significantly, this study provides a general catalytic method for the construction of 3,3′-disubstituted oxindoles bearing α,β- diamino functionality as well as vicinal chiral quaternary/tertiary stereocenters. The potential utility of the protocol also had been demonstrated by gram-scale reaction and the versatile conversion of product. Furthermore, On the basis of the comprehensive experimental results and the absolute configuration of one of the Michael adducts, a work model was also proposed to explain the origin of asymmetric induction.

Full text of DOI:10.1021/jo2004378

ARTICLE
pubs.acs.org/joc
Amino-Indanol-Catalyzed Asymmetric Michael Additions of
Oxindoles to Protected 2-Amino-1-nitroethenes for the Synthesis of
3,30-Disubstituted Oxindoles Bearing r,β-Diamino Functionality
Xiong-Li Liu,†,^ Zhi-Jun Wu,‡ Xi-Lin Du,§ Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
†Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
‡Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
§Department of General Surgery, TangDu Hospital, The Fourth Military Medical University, Xi’an 710038, China
^Graduate School of Chinese Academy of Sciences, Beijing 100049, China
S Supporting Information
b
ABSTRACT: An organocatalytic asymmetric Michael addition
reaction of 3-substituted oxindoles to protected 2-amino-1-
nitroethenes has been developed. The reaction is catalyzed by a
simple and readily available amino-indanol derivative and
affords the desired products in very high yields (up to 99%)
with excellent diastereoselectivities (up to >99:1) and very good
enantioselectivities (up to 90%). Significantly, this study pro-
vides a general catalytic method for the construction of 3,30-
disubstituted oxindoles bearing R,β-diamino functionality as
well as vicinal chiral quaternary/tertiary stereocenters. The potential utility of the protocol also had been demonstrated by gram-
scale reaction and the versatile conversion of product. Furthermore, On the basis of the comprehensive experimental results and the
absolute configuration of one of the Michael adducts, a work model was also proposed to explain the origin of asymmetric induction.
’ INTRODUCTION
bearing R,β-diamino functionality as well as vicinal chiral qua-
ternary/tertiary stereocenters, moreover, it should be a signifi-
cant challenge due to the stereocontrol of both the absolute and
relative configurations (Scheme 1).
3,30-Disubstituted oxindole structures are versatile synthetic
motifs for biologically active natural products and pharmaceuti-
cally attractive intermediates.1 In particular, optically active 3,30-
disubstituted oxindoles with R-amino or β-amino functionality
are quite attractive and valuable synthetic targets. Consequently,
substantial catalytic asymmetric approaches for these structural
motifs have been reported in recent years, for example, using
3-substituted oxindoles as nucleophiles addition to imines lead-
ing to R-amino functionality2 and addition to nitroolefins leading
to β-amino functionality (Scheme 1).3 However, in sharp con-
trast, the highly enantioselective and general methods for the
synthesis of 3,30-disubstituted oxindoles with R,β-diamino func-
tionality remains elusive (Scheme 1), despite the indisputable
fact that this kind of structural motif serves as a prominent feature
in some biologically active natural products and several pharma-
ceutically active compounds, such as (þ)-alantrypinone, (ꢀ)-
serantrypinone, and (ꢀ)-lapatin.4 In this context, an efficient
approach for the asymmetric construction of structurally diverse
3,30-disubstituted oxindole scaffolds bearing R,β-diamino func-
tionality is highly desirable. To this end, one conceivable strategy
could be to use the asymmetric conjugate addition reaction of
3-substituted oxindoles with 1,2-diamino-containing Michael accep-
tor, such as protected 2-amino-1-nitroethenes (Scheme 1).5 If that is
indeed the case, we can envision that this process will provide
straightforward access to 3,30-disubstituted oxindole motifs
The Michael addition is certainly one of the most powerful
bond-forming transformations, and the diversity in donors and
acceptors that can be combined is remarkable.6 In this respect,
the application of 3-substituted oxindoles as nucleophile with a
diverse range of Michael acceptors has recently become the focus
of research leading to various oxindoles that incorporate a chiral
quaternary carbon center.3,7 In spite of that significant progress
having been made, the catalytic asymmetric Michael addition of
3-substituted oxindoles to protected 2-amino-1-nitroethenes, a
class of ideal 1,2-diamino-containing Michael acceptor candi-
dates with an easily transformable functional group, has not been
realized so far (Scheme 1). To the best of our knowledge, there is
only one example about the asymmetric Michael addition of
aldehydes to protected 2-amino-1-nitroethenes by Ma and co-
workers.5b In this context, as a continuing effort to develop new
methodology for the construction of complex structural motifs
with organocatalysts,8 we recently realized the first catalytic
asymmetric Michael addition of 3-substituted oxindoles to
protected 2-amino-1-nitroethenes by a very simple and readily
Received: February 27, 2011
Published: April 04, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Strategies for the Synthesis of 3,30-Disubstituted
Oxindoles Bearing R-Amino, β-Amino, or R,β-Diamino
Functionality
Table 1. Screening of Organocatalystsa
available amino-indanol catalyst,9 leading to the formation of a
wide scope of 3,30-disubstituted oxindoles bearing R,β-diamino
functionality with vicinal chiral quaternary/tertiary stereocenters
in up to 99% yield, 90% ee, and >99:1 dr. Herein, we wish to
report our research results on this subject.
entry
1
time (h)
yield (%)b
drc
ee (%)d
1
2
1a
1b
1c
1d
1e
1f
8
8
97
90
96
97
96
97
97
95
97
97
98
28
97
95
89:11
84:16
94:6
98:2
96:4
99:1
94:6
96:4
90:10
94:6
94:6
85:15
94:6
93:7
ꢀ20
41
ꢀ9
3
’ RESULTS AND DISCUSSION
3
8
Our studies commenced with a screen of organocatalysts
derived from cinchona alkaloids (1aꢀg) and chiral 1,2-diamine
compounds (1h,i) by means of the model reaction of 3-benzyl-
oxindole 2a and (Z)-N-(2-nitrovinyl)acetamide (3a) in CH2Cl2
at 0 ꢀC (Table 1, entries 1ꢀ9). These experiments revealed that
the reaction could be catalyzed by 10 mol % catalyst and afforded
4a in excellent yields and good to excellent diastereoselectivities,
but very poor enantioselectivities. However, to our delight,
during the further quest for potential organocatalysts, it was
observed that some simple and readily available amino-indanols
1j,k, and 1m,n catalyzed smoothly the model reaction, affording
4a in excellent yields and diastereoselectivities, particularly with
acceptable enantioselectivity ranging from 58% to 71% ee
(Table 1, entries 10ꢀ11 and 13ꢀ14). We also noted that the
relatively high ee value could be obtained with 1l as catalyst, but
the reactivity was unacceptable (Table 1, entry 12). By compre-
hensive comparison, 1k was designated as the optimal catalyst in
view of the reactivity and diastereo- and enantioselectivity
(Table 1, entry 11).
4
8
5
8
0
6
8
ꢀ15
ꢀ1
ꢀ5
4
7
1g
1h
1i
8
8
8
9
8
10
11
12
13
14
1j
8
68
71
74
58
71
1k
1l
8
30
8
1m
1n
8
a All the reactions were carried out at 0 ꢀC for the specified time, 2a (0.2
mmol), 3a (0.24 mmol), 1 (10 mol %) in CH2Cl2 (4.0 mL).
b Isolated yield. c Diastereoisomeric ratio determined with chiral HPLC
by analysis of the purified product after separating by column chroma-
tography. d Determined by chiral HPLC analysis.
Having identified the best catalyst 1k, optimization of reac-
tion conditions was further investigated. The probe of reaction
temperature was first carried out in CH2Cl2 (Table 2, entries
1ꢀ4). It was observed that ꢀ40 ꢀC was the most ideal
temperature for obtaining the product in view of the yield
and stereoselectivity (Table 2, entry 3). Next, the effect of
various solvents for the Michael addition of 2a to 3a was also
surveyed. It was found that CH2Cl2 is better than the other six
different solvents surveyed (Table 2, entry 3 vs entries 5ꢀ10).
Delightfully, the most desired results (99% yield, 49:1 dr, and
86% ee) could be obtained smoothly in DCE and DCM mixed
solvent (volume ratio 7:1) (Table 2, entry 11). An attempt to
add 100 mg of 4 Å molecular sieves (MS) to the process would
not result in any improvement in the reaction (Table 2, entry 12
vs entry 11). Dilution had no any improvement in the yield, dr,
and ee value, and a slight extension of reaction time was
required (Table 2, entry 13). On the contrary, Michael adduct
4a could be obtained in quantitative yield with 98:2 dr and up to
90% ee after 12 h by increasing the concentration of 3-sub-
stituted oxindole 2a to 0.12 M (Table 2, entry 14). Afterward,
upon further elevating the concentration to 0.24 M, enantios-
electivity was decreased to 82%, albeit without sacrificing the
yield and diastereoselectivity (Table 2, entry 15).
Adopting the reaction conditions described in Table 2, entry
14 as the optimal compromise among the reactivity and diaster-
eo- and enantioselectivity, the generality of the method was
demonstrated by evaluating a variety of 3-substituted oxindoles
and two protected 2-amino-1-nitroethenes (Table 3). 3-Benzyl-
N-Boc-oxindoles 2bꢀi tolerated substitution at any position of
the aromatic ring of the benzyl group, and both electron-donating
and electron-withdrawing functionalities were compatible (Table 3,
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ARTICLE
Table 2. Optimization of Reaction Conditionsa
The absolute configuration of 4k was assigned as (C8R,C9S)
configuration on the basis of the X-ray crystal structure of 4k0,10
prepared from 4k by removal of the Boc group with F3CCOOH
(Scheme 3). As no reaction occurred at the stereogenic center in
4k while removing the Boc group, compound 4k was deduced to
have the same (C8R,C9S) configuration. Meanwhile, the abso-
lute configuration of the other products were assigned by
analogy.
Next, we attempted the versatile conversion of compound 4f
into other functionalized compounds, such as 5, 6, and 7
(Scheme 4). The Pd/C-catalyzed hydrogenation of compound
4f proceeded smoothly in methanol, converting the nitro group
into a primary amine group contained in 5. Then, compound 6
could be obtained in 90% yield with >99:1 dr and 86% ee from 5
via the protection with (Boc)2O (Boc = tert-butoxycarbonyl).
Eventually, we also found that compound 5 could be transformed
into 7 in 62% yield with >99:1 dr and 83% ee via two sequential
steps: deprotecting the Boc group with F3CCOOH and protec-
tion of the amine group with TsCl (Scheme 4).
On the basis of experimental results and the observed absolute
configuration of 4k, we suggest Figure 1 as a proposed working
model. As illustrated in Figure 1, the tertiary amine group of the
catalyst activates the deprotonated enolated oxindole. Simulta-
neously, owing to strong intramolecular hydrogen bonding in
substrate 3a, only the Z isomer is formed; as a result, this
probably facilitates the formation of single hydrogen bonding
interaction between the hydroxyl group of the catalyst and the
nitro group of substrate 3a. Subsequently, the si-face of the 3a
was preferably attacked by the re-face of enolated oxindole,
delivering the desired Michael adduct with (C8R,C9S)
configuration.
entry
solvent
DCM
T (ꢀC) time (h) yield (%)b
drc
ee (%)d
1
2
rt
3
8
98
97
98
31
99
83
75
34
56
44
99
99
98
99
99
98:2
94:6
97:3
96:4
95:5
96:4
94:4
92:8
93:7
85:15
98:2
98:2
98:2
98:2
98:2
62
71
DCM
0
3
DCM
ꢀ40
ꢀ78
ꢀ34
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
15
30
15
15
15
30
30
30
15
15
20
12
10
84
4
DCM
89
5
DCE
81
6
CHCl3
65
7
C6H5Cl
toluene
78
8
65
9
CH3CN
THF
71
10
11
12
13
14
15
44
DCE/DCM
DCE/DCM
DCE/DCM
DCE/DCM
DCE/DCM
86e
85e,f
86 e,g,h
90e,g,i
82e,g,j
a Unless otherwise noted, the reactions were carried out with 2a (0.2
mmol), 3a (0.24 mmol), and 1k (10 mol %) in solvent (4.0 mL).
b Isolated yield. c Diastereoisomeric ratio determined with chiral HPLC
by analysis of the purified product after separating by column chroma-
tography. d Determined by chiral HPLC analysis. DCE/DCM = 7:1
e
(volume ratio). f With 100 mg of 4 Å MS as additive. g 2a (0.24 mmol)
and 3a (0.20 mmol) were used. h 6.0 mL of solvent was used. i 2.0 mL of
solvent was used. j 1.0 mL of solvent was used. DCM = dichloro-
methane; DCE = 1,2-dichloroethane.
’ CONCLUSION
In conclusion, we have developed an organocatalytic metho-
dology for the asymmetric Michael addition of 3-substrated
oxindoles to protected 2-amino-1-nitroethenes in the presence
of a simple amino-indanol derivative. A wide spectrum of 3,30-
disubstituted oxindoles bearing R,β-diamino functionality and
vicinal quaternary/tertiary stereocenters were smoothly obtained
in excellent yields (up to 99%), virtually perfect diastereoselec-
tivities (up to >99:1), and good enantioselectivities (up to 90%).
Two points particularly noteworthy in this work include the
following: (1) this is the sole example so far for the asymmetric
synthesis of 3,30-disubstituted oxindoles bearing R,β-diamino
functionality; and (2) the simple and readily available amino-
indanol derivative 1k works well for this kind of asymmetric
Michael addition reaction, whereas some analogous organic
bifunctional catalysts derived from cinchona alkaloids or chiral
1,2-diamines are futile to control the enantioselectivity. In
addition, the potential utilities of the protocol also had been
demonstrated by gram-scale reaction and the versatile conver-
sion of product.
entries 1ꢀ8). In these cases, the desired Michael adducts were
generally obtained in excellent yields and diastereoselectivities, with
good ee values ranging from 78% to 89%. Notably, with 1-naphthyl
derivative 2j as donor, excellent yield, dr, and good ee values were
achieved as well (Table 3, entry 9). Similar results were observed with
the thiophene counterpart 2k (Table 3, entry 10). Moreover,
3-alkyloxindole substrates 2lꢀn also showed very high reactivity,
while the corresponding products could be obtained in high yields
and diastereoselectivities and good enantioselectivities after 12 h
under the optimal reaction conditions (Table 3, entries 11ꢀ13).
Furthermore, the oxindole core may also be modified. Thus, both the
benzo moiety (Table 3, entries 14 and 15) and the N-protecting
group were changed (Table 3, entries 16 and 17) as well for giving
access to structurally diverse products. 3-Aryloxindole 2s gave rise to
the corresponding adduct 4s in excellent yield and diastereoselec-
tivity, but with only 55% ee (Table 3, entry 18). On the other hand,
another protecting group also could be incorporated into 2-amino-1-
nitroethene, for example, (Z)-N-(2-nitrovinyl)benzamide (3b) and
2c were subjected to the standard conditions and furnished the
corresponding adduct with acceptable results (Table 3, entry 19).
To exploit the potential of the current catalyst system, the reaction
wasscaleduptousing4.8mmolof2f as the starting material addition
to 3a with 10 mol % of 1k. Product 4f could be obtained smoothly in
93% yield, 95:5 dr, and 82% ee after 12 h, without significant
deleterious effect on the reactivity and stereoselectivity (Scheme 2).
’ EXPERIMENTAL SECTION
General Experimental Procedure for the Asymmetric
Michael Additions of Oxindoles to Protected 2-Amino-1-
nitroethenes Catalyzed by Amino-Indanol. In an ordinary vial
equipped with a magnetic stirring bar, to the mixture of oxindoles 2 (0.24
mmol) and catalyst 1k (0.02 mmol) in 2.0 mL of freshly distilled
CH2ClCH2Cl/CH2Cl2 (7:1) was added protected 2-amino-1-ni-
troethenes 3 (0.2 mmol). The reaction mixture was stirred at ꢀ40 ꢀC
4010
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Table 3. Asymmetric Michael Addition Reaction of a Variety of 3-Substituted Oxindoles to Protected 2-Amino-1-nitroethenesa
ARTICLE
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Table 3. Continued
a Unless otherwise noted, the reactions were carried out with 2 (0.24 mmol), 3 (0.20 mmol), and 1k (10 mol %) in DCE/DCM 2.0 mL (volume ratio =
7:1) at ꢀ40 ꢀC for 12 h. b Isolated yield. c Diastereoisomeric ratio determined with chiral HPLC by analysis of the purified product after separating by
column chromatography. d Determined by chiral HPLC analysis. e The absolute configuration of 4k was determined in view of the X-ray crystal structure
of the derivative 4k0.10 f Run for 48 h. g Run at ꢀ78 ꢀC for 48 h.
for 12 h and was directly loaded onto silica gel and purified by flash
chromatography to give products 4.
7.34ꢀ7.36 (m, 1H), 7.43ꢀ7.45 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ 22.7, 27.9, 42.7, 51.5, 58.0, 75.5, 84.7, 114.6, 124.3, 124.5, 126.3, 127.0,
127.7, 129.0, 129.7, 133.3, 139.6, 148.0, 170.0, 176.1; IR (KBr) ν 3339,
3032, 2931, 1662, 1558, 1245, 841, 752, 567 cmꢀ1; HRMS (ESI) calcd
for C24H27N3NaO6 [M þ Na]þ 476.1792, found 476.1798.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-benzyl-
2-oxoindoline-1-carboxylate (4a): white solid; yield 99%, 98:2 dr,
90% ee, [R]20 þ31.5 (c 1.35, CHCl3); mp 153.3ꢀ155.6 ꢀC; depro-
D
tected the Boc group, the ee was determined by HPLC analysis with a
Chiralpak AD-H column (80/20 hexane/i-PrOH; 1.0 mL/min; λ =
254 nm; tmajor = 9.23 min; tminor = 6.15 min); 1H NMR (CDCl3, 300
MHz) δ 1.48 (s, 9H), 1.82 (s, 3H), 3.16 (d, J = 12.6 Hz, 1H), 3.32 (d, J =
12.6 Hz, 1H), 4.93ꢀ4.96 (m, 2H), 5.54ꢀ5.59 (m, 1H), 6.45 (br s, 1H),
6.70 (d, J = 6.9 Hz, 2H), 6.95ꢀ7.04 (m, 3H), 7.18ꢀ7.21 (m, 2H),
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(4-meth-
ylbenzyl)-2-oxoindoline-1-carboxylate (4b): white solid; yield
93%; 95:5 dr, 83% ee, [R]20D þ23.3 (c 1.63, CHCl3); mp 92.3ꢀ93.9 ꢀC;
deprotected the Boc group, the ee was determined by HPLC analysis
with a Chiralpak AD-H column (80/20 hexane/i-PrOH; 1.0 mL/min;
λ = 254 nm; tmajor = 10.41 min; tminor = 6.44 min); 1H NMR (CDCl3,
4012
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ARTICLE
300 MHz) δ 1.47 (s, 9H), 1.79 (s, 3H), 2.14 (s, 3H), 3.13 (d, J = 12.9 Hz,
1H), 3.27 (d, J = 12.9 Hz, 1H), 4.92ꢀ4.95 (m, 2H), 5.54ꢀ5.58 (m, 1H),
6.57 (d, J = 7.8 Hz, 2H), 6.63ꢀ6.65 (m, 1H), 6.77 (d, J = 7.8 Hz, 2H),
7.18ꢀ7.21 (m, 2H), 7.36ꢀ7.39 (m, 1H), 7.43ꢀ7.46 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 20.8, 22.6, 27.8, 42.3, 51.4, 58.0, 75.5, 84.5, 114.6,
124.3, 124.4, 126.5, 128.4, 128.9, 129.5, 130.1, 136.5, 139.5, 148.0, 170.2,
176.2; IR (KBr) ν 3337, 2981, 1783, 1734, 1668, 1558, 1252, 1150, 1105,
756 cmꢀ1; HRMS (ESI) calcd for C25H29N3NaO6 [M þ Na]þ
490.1949, found 490.1967.
4.93ꢀ4.96 (m, 2H), 5.53ꢀ5.57 (m, 1H), 6.21ꢀ6.32 (m, 1H),
6.48ꢀ6.51 (m, 2H), 6.84ꢀ6.86 (m, 2H), 7.18ꢀ7.21 (m, 2H),
7.38ꢀ7.44 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.0, 22.7, 27.9,
42.7, 51.5, 58.0, 75.6, 84.6, 114.5, 124.3, 124.4, 126.5, 126.7, 127.6, 127.7,
129.0, 130.4, 133.1, 137.3, 139.6, 148.0, 169.9, 176.2; IR (KBr) ν 3380,
3034, 1785, 1736, 1558, 1252, 1149, 706 cmꢀ1; HRMS (ESI) calcd for
C25H29N3NaO6 [M þ Na]þ 490.1949, found 490.1965.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(3,5-di-
methylbenzyl)-2-oxoindoline-1-carboxylate (4d). white solid;
yield 92%; >99:1 dr, 82% ee, [R]20 þ26.2 (c 1.75, CHCl3); mp
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(3-methyl-
benzyl)-2-oxoindoline-1-carboxylate (4c). white solid; yield
D
171.4ꢀ173.6 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak OJ-H column (90/10 hexane/i-PrOH;
1.0 mL/min; λ = 254 nm; tmajor = 33.31 min; tminor = 41.97 min); 1H
95%; 96:4 dr, 89% ee, [R]20 þ50.1 (c 1.40, CHCl3); mp 162.1ꢀ
D
164.5 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak AD-H column (90/10 hexane/
i-PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 27.45 min; tminor
15.95 min); H NMR (CDCl3, 300 MHz) δ 1.50 (s, 9H), 1.76 (s,
3H), 2.08 (s, 3H), 3.11 (d, J = 12.6 Hz, 1H), 3.26 (d, J = 12.6 Hz, 1H),
=
1
Scheme 2. The Asymmetric Michael Addition Reaction of 2f
to 3a in Gram-Scale
Figure 1. Proposed working model for the asymmetric Michael addi-
tion of 3-substituted oxindoles to protected 2-amino-1-nitroethene.
Scheme 3. Transformation of 4k to 4k0 and the X-ray Crystallographic Structure of 4k0
Scheme 4. Transformation of 4f to Other Compounds
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NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.77 (s, 3H), 2.02 (s, 6H), 3.08
(d, J = 12.6 Hz, 1H), 3.22 (d, J = 12.6 Hz, 1H), 4.91ꢀ5.01 (m, 2H),
5.55ꢀ5.59 (m, 1H), 6.28 (s, 2H), 6.65 (s, 1H), 6.80ꢀ6.84 (m, 1H),
7.17ꢀ7.21 (m, 2H), 7.34ꢀ7.37 (m, 1H), 7.44ꢀ7.47 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 20.8, 22.6, 27.8, 42.6, 51.3, 58.0, 75.5, 84.4, 114.3,
124.3, 124.4, 126.6, 127.5, 128.4, 128.7, 133.0, 137.0, 139.5, 147.9, 170.2,
176.3; IR (KBr) ν 3325, 2926, 1786, 1736, 1559, 1251, 1148, 841,
759 cmꢀ1; HRMS (ESI) calcd for C26H31N3NaO6 [M þ Na]þ
504.2105, found 504.2112.
(CDCl3, 75 MHz) δ 22.7, 27.9, 42.3, 51.4, 55.4, 55.6, 58.1, 75.5, 84.7,
110.4, 112.5, 114.8, 122.1, 124.2, 124.4, 125.6, 126.6, 129.0, 139.8, 148.0,
169.9, 176.2; IR (KBr) ν 3341, 2979, 1784, 1733, 1557, 1516, 1261,
1150, 1027, 766 cmꢀ1; HRMS (ESI) calcd for C26H31N3NaO8 [M þ
Na]þ 536.2003, found 536.2024.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(2-fluo-
robenzyl)-2-oxoindoline-1-carboxylate (4i). white solid; yield
99%; 97:3 dr, 85% ee, [R]20 þ16.3 (c 1.50, CHCl3); mp 153.1ꢀ
D
155.3 ꢀC; deprotected the Boc group, the ee was determined by HPLC
analysis with a Chiralpak AD-H column (80/20 hexane/i-PrOH;
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(2-meth-
oxybenzyl)-2-oxoindoline-1-carboxylate (4e). white solid;
1
1.0 mL/min; λ = 254 nm; tmajor = 11.14 min; tminor = 6.91 min); H
yield 95%; 97:3 dr, 84% ee, [R]20 ꢀ17.4 (c 1.75, CHCl3); mp
NMR (CDCl3, 300 MHz) δ 1.54 (s, 9H), 1.78 (s, 3H), 3.25 (d, J = 13.2
Hz, 1H), 3.41 (d, J = 13.2 Hz, 1H), 4.86ꢀ4.90 (m, 2H), 5.50ꢀ5.56 (m,
1H), 6.36ꢀ6.38 (m, 1H), 6.72ꢀ6.77 (m, 1H), 6.81ꢀ6.86 (m, 2H),
7.12ꢀ7.13 (m, 1H), 7.15ꢀ7.19 (m, 2H), 7.39ꢀ7.43 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 22.7, 27.9, 34.7, 51.6, 57.3, 75.4, 84.9, 114.3, 115.0
(d, JCF = 22.6 Hz), 121.0 (d, JCF = 15.2 Hz), 123.5 (d, JCF = 3.5 Hz),
124.4, 124.8, 125.7, 129.1, 129.3, 131.3 (d, JCF = 3.7 Hz), 139.3, 148.1,
160.5 (d, JCF = 245.3 Hz), 170.0, 176.2; IR (KBr) ν 3275, 2950, 1763,
1725, 1661, 1558, 1153, 1101, 750, 702 cmꢀ1; HRMS (ESI) calcd for
C24H26FN3NaO6 [M þ Na]þ 494.1698, found 494.1705.
D
138.1ꢀ139.9 ꢀC; deprotected the Boc group, the ee was determined
by HPLC analysis with a Chiralpak OD-H column (80/20 hexane/
i-PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 23.45 min; tminor = 15.55 min);
1H NMR (CDCl3, 300 MHz) δ 1.60 (s, 9H), 1.66 (s, 3H), 3.08 (d, J =
13.2 Hz, 1H), 3.47 (d, J = 13.2 Hz, 1H), 3.58 (s, 3H), 5.04ꢀ5.12 (m,
2H), 5.33ꢀ5.53 (m, 1H), 5.73ꢀ5.92 (m, 1H), 6.60 (d, J = 8.4 Hz, 1H),
6.64ꢀ6.69 (m, 1H), 6.75 (d, J = 7.2 Hz, 1H), 7.00ꢀ7.17 (m, 4H), 7.49
(d, J = 8.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.7, 28.1, 35.8, 51.6,
54.7, 57.3, 75.6, 84.7, 110.0, 114.1, 119.9, 122.4, 123.5, 125.5, 126.5,
128.6, 128.7, 131.5, 139.4, 148.5, 157.2, 169.5, 176.7; IR (KBr) ν 3339,
3055, 2934, 1783, 1733, 1557, 1250, 1150, 755 cmꢀ1; HRMS (ESI)
calcd for C25H29N3NaO7 [M þ Na]þ 506.1898, found 506.1922.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(3-meth-
oxybenzyl)-2-oxoindoline-1-carboxylate (4f). white solid; yield
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(naph-
thalen-1-ylmethyl)-2-oxoindoline-1-carboxylate (4j). white
solid; yield 94%; 97:3 dr, 86% ee, [R]20 þ41.4 (c 1.50, CHCl3); mp
D
121.1ꢀ124.2 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak AD-H column (80/20 hexane/i-PrOH;
1.0 mL/min; λ = 254 nm; tmajor = 11.30 min; tminor = 8.25 min); 1H NMR
(CDCl3, 300 MHz) δ 1.32 (s, 9H), 1.72 (s, 3H), 3.58 (d, J = 13.2 Hz, 1H),
3.95 (d, J = 13.2 Hz, 1H), 5.13ꢀ5.16 (m, 2H), 5.73ꢀ5.77 (m, 1H),
6.32ꢀ6.34 (m, 1H), 6.80 (d, J = 7.2 Hz, 1H), 7.03ꢀ7.06 (m, 3H),
7.23ꢀ7.43 (m, 4H), 7.56 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.88
(d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.7, 27.7, 38.1, 51.6,
57.9, 75.7, 84.4, 114.3, 123.9, 124.3, 124.4, 124.6, 125.4, 125.6, 126.4, 128.0,
128.2, 128.3, 128.9, 129.7, 131.7, 133.4, 139.5, 147.8, 170.0, 176.5; IR (KBr)
ν 3339, 2980, 1784, 1735, 1558, 1251, 1149, 1100, 772 cmꢀ1; HRMS (ESI)
calcd for C28H29N3NaO6 [M þ Na]þ 526.1949, found 526.1964.
94%; 98:2 dr, 84% ee, [R]20 ꢀ88.7 (c 1.38, CHCl3); mp 112.2ꢀ
D
114.9 ꢀC; deprotected the Boc group, the ee was determined by HPLC
analysis with a Chiralpak AD-H column (80/20 hexane/i-PrOH;
1
1.0 mL/min; λ = 254 nm; tmajor = 11.64 min; tminor = 7.52 min); H
NMR (CDCl3, 300 MHz) δ 1.50 (s, 9H), 1.79 (s, 3H), 3.12 (d, J = 12.6
Hz, 1H), 3.29 (d, J = 12.6 Hz, 1H), 3.54 (s, 3H), 4.90ꢀ4.94 (m, 2H),
5.54ꢀ5.56 (m, 1H), 6.20ꢀ6.21 (m, 2H), 6.31 (d, J = 7.5 Hz, 1H),
6.58ꢀ6.61 (m, 1H), 6.87ꢀ6.92 (m, 1H), 7.20ꢀ7.23 (m, 2H),
7.42ꢀ7.45 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 22.6, 27.7, 42.6,
51.4, 54.8, 57.8, 75.4, 84.6, 113.3, 114.3, 114.6, 122.0, 124.1, 124.3, 126.3,
128.6, 129.0, 134.6, 139.6, 147.9, 158.8, 169.8, 175.9; IR (KBr) ν 3336,
2929, 1788, 1668, 1560, 1253, 1166, 1040, 757, 697 cmꢀ1; HRMS (ESI)
calcd for C25H29N3NaO7 [M þ Na]þ 506.1898, found 506.1902.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(4-meth-
oxybenzyl)-2-oxoindoline-1-carboxylate (4g). white solid;
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-2-oxo-3-
(thiophen-2-ylmethyl)indoline-1-carboxylate (4k). white so-
lid; yield 94%; 94:6 dr, 84% ee, [R]20 þ27.6 (c 1.25, CHCl3); mp
D
158.1ꢀ160.3 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak OD-H column (85/15 hexane/i-PrOH;
1.0 mL/min; λ = 254 nm; tmajor = 23.97 min; tminor = 20.68 min); 1H
NMR (CDCl3, 300 MHz) δ 1.54 (s, 9H), 1.82 (s, 3H), 3.38 (d, J = 14.1
Hz, 1H), 3.59 (d, J = 14.1 Hz, 1H), 4.75ꢀ7.81 (m, 2H), 5.46ꢀ5.53 (m,
1H), 6.24ꢀ6.27 (m, 1H), 6.52 (d, J = 3.0 Hz, 1H), 6.68ꢀ6.71 (m, 1H),
6.94 (d, J = 5.1 Hz, 1H), 7.20ꢀ7.32 (m, 2H), 7.41 (d, J = 7.2 Hz, 1H),
7.55 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.8, 28.0, 36.6,
51.5, 57.6, 75.3, 84.9, 114.9, 124.2, 124.8, 125.0, 126.2, 126.3, 127.6,
129.5, 134.7, 140.1, 148.2, 170.0, 175.7; IR (KBr) ν 3285, 2980, 1785,
1756, 1558, 1148, 1203, 1105, 767, 701 cmꢀ1; HRMS (ESI) calcd for
C22H25N3NaO6S [M þ Na]þ 482.1356, found 482.1363.
yield 94%; 96:4 dr, 78% ee, [R]20 þ44.1 (c 1.50, CHCl3); mp
D
161.4ꢀ163.2 ꢀC; deprotected the Boc group, the ee was determined
by HPLC analysis with a Chiralpak AD-H column (80/20 hexane/i-
PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 13.95 min; tminor = 7.69 min);
1H NMR (CDCl3, 300 MHz) δ 1.50 (s, 9H), 1.76 (s, 3H), 3.10 (d, J =
12.9 Hz, 1H), 3.26 (d, J = 12.9 Hz, 1H), 3.65 (s, 3H), 4.90ꢀ4.94 (m,
2H), 5.51ꢀ5.55 (m, 1H), 6.24ꢀ6.28 (m, 1H), 6.51 (d, J = 8.7 Hz, 2H),
6.61 (d, J = 8.7 Hz, 2H), 7.18ꢀ7.25 (m, 2H), 7.40ꢀ7.43 (m, 2H); 13C
NMR (CDCl3, 75 MHz) δ 22.7, 27.9, 41.9, 51.4, 55.0, 58.1, 75.6, 84.7,
113.2, 114.7, 124.2, 124.5, 125.5, 126.5, 129.0, 130.7, 139.6, 148.0, 158.6,
169.9, 176.2; IR (KBr) ν 3275, 2930, 1785, 1735, 1557, 1513, 1251,
1149, 1106, 1033, 838, 754 cmꢀ1; HRMS (ESI) calcd for C25H29-
N3NaO7 [M þ Na]þ 506.1898, found 506.1913.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(2-eth-
oxy-2-oxoethyl)-2-oxoindoline-1-carboxylate (4l). colorless
oil; yield 92%; 94:6 dr, 74% ee, [R]20 þ25.7 (c 1.88, CHCl3);
D
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(3,4-di-
methoxybenzyl)-2-oxoindoline-1-carboxylate (4h). white so-
deprotected the Boc group, the ee was determined by HPLC analysis
with a Chiralpak OJ-H column (80/20 hexane/i-PrOH; 0.8 mL/min;
λ = 254 nm; tmajor = 29.45 min; tminor = 38.05 min); 1H NMR (CDCl3,
300 MHz) δ 0.95 (t, J = 7.2 Hz, 3H), 1.62 (s, 9H), 1.83 (s, 3H), 3.01 (d,
J = 16.2 Hz, 1H), 3.18 (d, J = 16.2 Hz, 1H), 3.79ꢀ3.87 (m, 2H),
4.31ꢀ4.39 (m, 1H), 4.75ꢀ4.53 (m, 1H), 5.25ꢀ5.28 (m, 1H), 6.78 (d,
J = 9.6 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.25ꢀ7.36 (m, 2H), 7.75 (d, J =
8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.5, 22.6, 28.0, 39.8, 52.0,
52.9, 61.0, 74.4, 85.1, 115.0, 123.6, 124.7, 125.7, 129.6, 140.1, 148.5,
168.5, 170.6, 175.5; IR (KBr) ν 3338, 2982, 2934, 1730, 1669, 1253,
lid; yield 95%; 95:5 dr, 81% ee, [R]20 þ35.1 (c 1.50, CHCl3); mp
D
134.1ꢀ136.8 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak AD-H column (80/20 hexane/i-PrOH;
1
1.0 mL/min; λ = 254 nm; tmajor = 14.06 min; tminor = 8.22 min); H
NMR (CDCl3, 300 MHz) δ 1.49 (s, 9H), 1.77 (s, 3H), 3.10 (d, J = 12.6
Hz, 1H), 3.26 (d, J = 12.6 Hz, 1H), 3.53 (s, 3H), 3.72 (s, 3H), 4.91ꢀ4.94
(m, 2H), 5.51ꢀ5.55 (m, 1H), 6.08 (s, 1H), 6.25ꢀ6.35 (m, 2H), 6.51 (d,
J = 8.1 Hz, 1H), 7.20ꢀ7.23 (m, 2H), 7.41ꢀ7.44 (m, 2H); 13C NMR
4014
dx.doi.org/10.1021/jo2004378 |J. Org. Chem. 2011, 76, 4008–4017

The Journal of Organic Chemistry
ARTICLE
1150, 1030, 841, 775, 680 cmꢀ1; HRMS (ESI) calcd for C21H27N3NaO8
[M þ Na]þ 472.1690, found 472.1708.
determined by HPLC analysis with a Chiralpak OD-H column (80/20
hexane/i-PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 12.77 min;
1
tminor = 19.84 min); H NMR (CDCl3, 300 MHz) δ 1.93 (s, 3H),
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-butyl-2-
oxoindoline-1-carboxylate (4m). white solid; yield 91%; 97:3 dr,
80% ee, [R]20D þ24.6 (c 2.00, CHCl3); mp 75.4ꢀ77.1 ꢀC; deprotected
the Boc group, the ee was determined by HPLC analysis with a
Chiralpak OD-H column (80/20 hexane/i-PrOH; 1.0 mL/min; λ =
254 nm; tmajor = 14.46 min; tminor = 6.86 min); 1H NMR (CDCl3, 300
MHz) δ 0.75 (t, J = 7.2 Hz, 3H), 0.75ꢀ0.78 (m, 1H), 0.88ꢀ1.21 (m,
1H), 1.15ꢀ1.23 (m, 2H), 1.61 (s, 9H), 1.68 (s, 3H), 1.89ꢀ2.06 (m, 2H),
4.71ꢀ4.79 (m, 2H), 5.28ꢀ5.36 (m, 1H), 6.35ꢀ6.38 (m, 1H),
7.16ꢀ7.21 (m, 1H), 7.25ꢀ7.33 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 13.5, 22.5, 22.6, 25.8, 28.0, 35.7, 52.0,
56.2, 75.2, 85.2, 114.6, 124.0, 124.8, 127.3, 128.9, 139.5, 148.5, 169.9,
3.26 (d, J = 12.6 Hz, 1H), 3.42 (d, J = 12.6 Hz, 1H), 4.73ꢀ4.78 (m, 2H),
5.53ꢀ5.57 (m, 1H), 6.43 (d, J = 7.2 Hz, 1H), 6.44ꢀ6.55 (m, 1H), 6.80
(d, J = 6.9 Hz, 2H), 6.87 (d, J = 6.9 Hz, 2H), 7.04ꢀ7.19 (m, 5H),
7.38ꢀ7.44 (m, 3H), 7.53ꢀ7.55 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ 22.9, 41.9, 51.7, 57.4, 75.6, 109.4, 110.0, 123.1, 123.8, 124.6, 126.5,
126.8, 126.9, 127.1, 127.7, 127.8, 128.5, 128.6, 129.1, 129.3, 129.6, 130.0,
133.5, 134.0, 143.9, 170.2, 175.7; IR (KBr) ν 3281, 2924, 1710, 1664,
1556, 1376, 1240, 1109, 756, 698 cmꢀ1; HRMS (ESI) calcd for
C25H23N3NaO4 [M þ Na]þ 452.1581, found 452.1591.
(R)-3-((S)-1-Acetamido-2-nitroethyl)-3-benzyl-2-oxoindo-
lin-1-ylpropionate (4r). white solid; yield 99%; 96:4 dr, 80% ee,
176.8; IR (KBr) ν 3297, 2959, 1785, 1736, 1558, 1150, 763, 694 cmꢀ1
;
[R]20 þ29.0 (c 2.50, CHCl3); mp 158.9ꢀ162.3 ꢀC; the ee was
D
HRMS (ESI) calcd for C21H29N3NaO6 [M þ Na]þ 442.1949, found
determined by HPLC analysis with a Chiralpak AD-H column (90/10
442.1952.
hexane/i-PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 23.52 min; tminor
=
15.80 min); 1H NMR (CDCl3, 300 MHz) δ 1.24ꢀ1.37 (m, 3H), 1.77 (s,
3H), 3.20 (d, J = 12.6 Hz, 1H), 3.34 (d, J = 12.6 Hz, 1H), 4.17ꢀ4.31 (m,
2H), 4.95 (d, J = 6.9 Hz, 2H), 5.50ꢀ5.56 (m, 1H), 6.69ꢀ6.75 (m, 3H),
6.95ꢀ7.03 (m, 3H), 7.21ꢀ7.26 (m, 2H), 7.46ꢀ7.49 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 14.0, 22.5, 42.5, 51.8, 58.0, 63.4, 75.3, 114.6, 124.5,
124.7, 126.4, 127.1, 127.8, 129.1, 129.6, 133.2, 139.2, 149.7, 170.3, 176.0;
IR (KBr) ν 3266, 2927, 1789, 1663, 1554, 1284, 1239, 1162, 1027, 765,
701 cmꢀ1; HRMS (ESI) calcd for C22H23N3NaO6 [M þ Na]þ
448.1479, found 448.1495.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-2-oxo-3-
propylindoline-1-carboxylate (4n). white solid; yield 93%; 80%
ee, 96:4 dr, [R]20 þ79.9 (c 1.31 CHCl3); mp 93.1ꢀ96.2 ꢀC; depro-
D
tected the Boc group, the ee was determined by HPLC analysis with a
Chiralpak OD-H column (80/20 hexane/i-PrOH; 1.0 mL/min; λ =
254 nm; tmajor = 22.22 min; tminor = 8.93 min); 1H NMR (CDCl3, 300
MHz) δ 0.74ꢀ0.79 (m, 4H), 0.82ꢀ0.87 (m, 1H), 1.59 (s, 9H), 1.69 (s,
3H), 1.86ꢀ1.95 (m, 2H), 4.68ꢀ4.77 (m, 2H), 5.29ꢀ5.36 (m, 1H),
6.64ꢀ6.67 (m, 1H), 7.14ꢀ7.19 (m, 1H), 7.25ꢀ7.34 (m, 2H),
7.65ꢀ7.70 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.8, 17.2, 22.4,
27.9, 38.1, 52.0, 56.3, 75.1, 85.1, 114.6, 123.9, 124.8, 127.2, 128.8, 139.4,
148.4, 170.2, 176.8; IR (KBr) ν 3280, 2964, 1784, 1732, 1558, 1149,
754 cmꢀ1; HRMS (ESI) calcd for C20H27N3NaO6 [M þ Na]þ
428.1792, found 428.1809.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-(3,5-di-
methylphenyl)-2-oxoindoline-1-carboxylate (4s). white solid;
yield 92%; >99:1 dr, 55% ee, [R]20 ꢀ87.8 (c 1.63, CHCl3); mp
D
114.2ꢀ117.1 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak AD-H column (80/20 hexane/i-PrOH;
1.0 mL/min; λ = 254 nm; tmajor = 5.91 min; tminor = 5.21 min); 1H NMR
(CDCl3, 300 MHz) δ 1.67 (s, 9H), 2.31 (s, 6H), 4.51ꢀ4.56 (m, 1H),
5.02ꢀ5.10 (m, 1H), 6.05ꢀ6.14 (m, 1H), 6.15ꢀ6.23 (m, 1H), 6.94 (s,
1H), 7.11 (s, 2H), 7.15ꢀ7.21 (m, 1H), 7.25ꢀ7.31 (m, 1H), 7.64ꢀ7.71
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.4, 22.6, 28.0, 52.0, 60.9,
75.8, 85.4, 114.4, 123.8, 124.8, 125.1, 128.5, 128.8, 130.2, 136.4, 138.6,
139.2, 148.5, 169.8, 176.0; IR (KBr) ν 3283, 2925, 1785, 1734, 1556,
1250, 1150, 1095, 841, 757, 702 cmꢀ1; HRMS (ESI) calcd for
C25H29N3NaO6 [M þ Na]þ 490.1949, found 490.1951.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-benzyl-
5-fluoro-2-oxoindoline-1-carboxylate (4o). white solid; yield
90%; >99:1 dr, 87% ee, [R]20 þ38.9 (c 1.63, CHCl3); mp 114.2ꢀ
D
116.1 ꢀC; deprotected the Boc group, the ee was determined by
HPLC analysis with a Chiralpak AD-H column (80/20 hexane/i-PrOH;
1.0 mL/min; λ = 254 nm; tmajor = 9.57 min; tminor = 11.36 min); 1H NMR
(CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.83 (s, 3H), 3.17 (d, J = 12.6 Hz, 1H),
3.36 (d, J = 12.6 Hz, 1H), 4.83ꢀ5.00 (m, 2H), 5.54ꢀ5.57 (m, 1H), 6.73 (d,
J = 6.9 Hz, 2H), 6.88ꢀ6.91 (s, 1H), 6.96ꢀ7.05 (m, 3H), 7.14 (d, J = 9.6 Hz,
1H), 7.31ꢀ7.36 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 22.5, 27.8, 42.6,
51.5, 58.2, 75.1, 84.8, 111.9 (d, JCF = 24.6 Hz), 115.5 (d, JCF = 22.8 Hz), 115.9
(d, JCF = 8.0 Hz), 127.1, 127.8, 128.4 (d, JCF = 8.2 Hz), 129.5, 133.1, 135.5,
147.8, 160.0 (d, JCF = 242.6 Hz), 170.7, 175.8; IR (KBr) ν 3283, 2925, 2854,
1785, 1734, 1556, 1479, 1250, 1150, 1095, 1037, 841, 757 cmꢀ1; HRMS
(ESI) calcd for C24H26FN3NaO6 [M þ Na]þ 494.1698, found 494.1704.
(R)-tert-Butyl-3-((S)-1-acetamido-2-nitroethyl)-3-benzyl-
5-methyl-2-oxoindoline-1-carboxylate (4p). white solid; yield
(R)-tert-Butyl-3-((S)-1-benzamido-2-nitroethyl)-3-(3-me-
thylbenzyl)-2-oxoindoline-1-carboxylate (4t). white solid; yield
85%; 86:14 dr, 72% ee, [R]20 þ26.6 (c 2.13, CHCl3); mp 102.2ꢀ
D
104.3 ꢀC; deprotected the Boc group, the ee was determined by HPLC
analysis with a Chiralpak OD-H column (80/20 hexane/i-PrOH;
1.0 mL/min; λ = 254 nm; tmajor = 21.66 min; tminor = 16.96 min); 1H
NMR (CDCl3, 300 MHz) δ 1.53 (s, 9H), 2.10 (s, 3H), 3.20 (d, J = 12.6
Hz, 1H), 3.38 (d, J = 12.6 Hz, 1H), 4.95ꢀ4.99 (m, 2H), 5.70ꢀ5.76 (m,
1H), 6.55 (d, J = 5.4 Hz, 2H), 6.87 (d, J = 6.3 Hz, 1H), 6.89ꢀ6.93 (m,
2H), 7.14ꢀ7.18 (m, 2H), 7.29ꢀ7.33 (m, 2H), 7.42ꢀ7.51 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 21.0, 27.9, 42.6, 52.2, 58.0, 75.5, 84.6, 114.7,
124.3, 124.4, 126.2, 126.7, 126.9, 127.3, 127.5, 127.7, 128.3, 128.5, 128.8,
129.1, 130.5, 131.8, 133.2, 133.5, 137.3, 139.7, 148.1, 167.5, 176.0; IR
(KBr) ν 3342, 2937, 1784, 1734, 1558, 1487, 1251, 1149, 1038, 931,
770 cmꢀ1; HRMS (ESI) calcd for C30H31N3NaO6 [M þ Na]þ
552.2105, found 552.2111.
92%; 95:5 dr, 80% ee, [R]20 þ42.0 (c 1.68, CHCl3); mp
D
132.1ꢀ133.9 ꢀC; deprotected the Boc group, the ee was determined
by HPLC analysis with a Chiralpak OD-H column (80/20 hexane/i-
PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 17.90 min; tminor = 13.90 min);
1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.79 (s, 3H), 2.36 (s, 3H),
3.13 (d, J = 12.6 Hz, 1H), 3.29 (d, J = 12.6 Hz, 1H), 4.90ꢀ4.93 (m, 2H),
5.51ꢀ5.58 (m, 1H), 6.55 (d, J = 10.2 Hz, 1H), 6.68 (d, J = 7.2 Hz, 2H),
6.94ꢀ7.06 (m, 4H), 7.22 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 21.1,
22.7, 27.9, 42.6, 51.6, 57.9, 75.5, 84.4, 114.4, 124.5, 124.6, 126.3, 126.9,
127.6, 127.7, 129.4, 129.6, 133.4, 134.2, 137.1, 148.0, 170.0, 176.2; IR
(R)-tert-Butyl-3-((S)-1-acetamido-2-aminoethyl)-3-(3-me-
thoxybenzyl)-2-oxoindoline-1-carboxylate (5). To a stirred
solution of compound 4f (483 mg, 1 mmol) in CH3OH (20 mL) was
added Pd/C (w/w 10%, 212 mg, 20 mol %) at room temperature. The
reaction mixture was stirred under H2 atmosphere (1 atm) for 8 h at
room temperature. Then, it was filtered through Celite and washed with
ethyl acetate. The filtrates were concentrated and purified by column
chromatography (hexane/ethyl acetate 2:1) to give 5 as a white solid
(KBr) ν 3328, 3034, 1779, 1663, 1555, 1186, 1120, 819, 699 cmꢀ1
.
HRMS (ESI) calcd for C25H29N3NaO6 [M þ Na]þ 490.1949, found
490.1970.
N-((S)-1-((R)-3-Benzyl-2-oxo-1-phenylindolin-3-yl)-2-ni-
troethyl)acetamide (4q). white solid; yield 83%; 92:8 dr, 64% ee,
[R]20 þ20.0 (c 1.50, CHCl3); mp 65.2ꢀ67.8 ꢀC; the ee was
D
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The Journal of Organic Chemistry
ARTICLE
1
(412 mg, 91% yield). Mp 114.1ꢀ116.9 ꢀC; H NMR (CDCl3, 300
MHz) δ 1.35 (s, 9H), 1.43 (s, 3H), 3.00 (d, J = 6.3 Hz, 2H), 3.36 (d, J =
12.3 Hz, 1H), 3.63 (d, J = 12.3 Hz, 1H), 3.76 (s, 3H), 5.06ꢀ5.11 (m,
1H), 6.85 (d, J = 7.2 Hz, 2H), 6.95 (s, 1H), 7.05 (d, J = 7.2 Hz, 1H),
7.14ꢀ7.27 (m, 3H), 7.33ꢀ7.35 (m, 2H), 7.54ꢀ7.57 (m, 1H), 10.51
(br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 22.1, 28.2, 42.3, 45.8,
52.8, 55.3, 55.6, 81.7, 114.0, 115.2, 123.3, 128.2, 128.6, 128.8, 129.4,
131.5, 135.2, 136.3, 137.1, 156.9, 159.7, 169.9, 170.6; IR (KBr) ν
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: yuanwc@cioc.ac.cn.
’ ACKNOWLEDGMENT
We are grateful for financial support from the National Natural
Science Foundation of China (No. 20802074) and the National
Basic Research Program of China (973 Program) (2010CB833300).
3274, 3060, 2977, 1702, 1490, 1368, 1158, 1053, 726, 612 cmꢀ1
;
HRMS (ESI) calcd for C25H31N3NaO6 [M þ NaO]þ 492.2105,
found 492.2120.
(R)-tert-Butyl-3-((S)-1-acetamido-2-(tert-butoxycarbonyl-
amino)ethyl)-3-(3-methoxybenzyl)-2-oxoindoline-1-carbo-
xylate (6). To a stirred solution of compound 5 (1.0 mmol) in CH3CN
(25 mL) was added (Boc)2O (4.0 mmol) at room temperature. After the
mixture was stirred for 12 h at room temperature, the mixture was
concentrated in vacuo and purified by silica gel column chromatography
(hexane/ethyl acetate = 2/1) to afford 6 (497 mg, 90% yield). Colorless
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oil, >99:1 dr, 86% ee, [R]20 ꢀ88.7 (c 1.38, CHCl3); the ee was
D
determined by HPLC analysis with a Chiralpak AD-H column (80/20
hexane/i-PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 4.58 min; tminor
=
1
4.27 min); H NMR (CDCl3, 300 MHz) δ 1.50 (s, 9H), 1.52 (s,
9H), 1.59 (s, 3H), 3.14 (d, J = 5.7 Hz, 2H), 3.46 (d, J = 12.6 Hz, 1H),
3.59 (d, J = 12.6 Hz, 1H), 3.78 (s, 3H), 5.11ꢀ5.18 (m, 1H), 6.82 (d, J =
2.1 Hz, 1H), 6.84ꢀ6.85 (m, 1H), 6.92 (br s, 2H), 7.00 (d, J = 7.5 Hz,
1H), 7.22 (d, J = 7.8 Hz, 1H), 7.27ꢀ7.33 (m, 3H), 7.58 (d, J = 2.1 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 22.3, 27.5, 28.2, 42.4, 46.5, 51.7,
54.1, 55.1, 80.9, 86.0, 114.0, 115.5, 123.2, 127.6, 128.8, 128.9, 129.4,
130.9, 135.3, 136.0, 136.3, 150.7, 156.8, 159.6, 170.7, 171.1; HRMS
(ESI) calcd for C30H39N3NaO8 [M þ NaO]þ 592.2629, found
592.2639.
N-((S)-1-((R)-3-(3-Methoxybenzyl)-2-oxoindolin-3-yl)-2-
(4-methylphenylsulfonamido)ethyl)acetamide (7). Compound 5
(0.5 mmol) was dissolved in F3CCOOH (1.3 mL) at 0 ꢀC, and the
solution was stirred for about 30 min at 0 ꢀC. It was then concentrated
in vacuo to afford the crude product. To a solution of the crude pro-
duct (0.56 mmol) in dry CH2Cl2 (5 mL) at 0 ꢀC was added Et3N
(1.40 mmol) under an argon atmosphere. The resulting mixture was
stirred at 0 ꢀC for 10 min, then a solution of TsCl (0.84 mmol) in dry
CH2Cl2 (1.5 mL) was added dropwise. The resulting solution was
stirred at 0 ꢀC for 30 min, then allowed to warm to room temperature;
stirring was then continued for about 4 h. The reaction mixture was
concentrated in vacuo and purified by silica gel column chromatogra-
phy (hexane/AcOEt = 10/1) to afforde7 (62%). White soild; >99:1 dr,
83% ee, [R]20D ꢀ5.7 (c 1.5, CHCl3); mp 128.4ꢀ131.9 ꢀC; the ee was
determined by HPLC analysis with a Chiralpak AD-H column (80/20
hexane/i-PrOH; 1.0 mL/min; λ = 254 nm; tmajor = 11.95 min; tminor
=
9.28 min); 1H NMR (CDCl3, 300 MHz) δ 1.83 (s, 3H), 2.42 (s, 3H),
3.05ꢀ3.23 (m, 3H), 3.56 (s, 3H), 3.74 s, 1H), 5.07 (s, 1H), 6.36ꢀ6.41
(m, 2H), 6.61 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.92ꢀ7.12
(m, 4H), 7.25ꢀ7.36 (m, 3H), 7.79 (d, J = 7.5 Hz, 2H), 9.08 (br s, 1H),
9.57 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.6, 22.9, 40.9, 51.3,
53.5, 54.9, 57.4, 110.1, 112.8, 114.8, 122.4, 122.5, 124.0, 128.4, 128.5,
129.5, 129.6, 129.7, 130.0, 136.1, 141.1, 144.8, 158.6, 172.4, 180.1;
HRMS (ESI) calcd for C27H29N3NaO6S [M þ NaO]þ 546.1669,
found 546.1680.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, detailed spectral data for products, and X-ray crystal
structure (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
ARTICLE
(8) (a) Liao, Y.-H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.;
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(10) The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 813793. These
data can be obtained free of charge from the Cambridge Crystallographic
Data Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.
cam.ac.uk/conts/retrieving.html.
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