Organocatalytic conjugate addition of nitroalkanes to 3-ylidene oxindoles: A stereocontrolled diversity oriented route to oxindole derivatives

Article abstract of DOI:10.1021/jo402099p

An efficient and highly enantioselective Michael addition of nitroalkanes to 3-ylidene oxindoles is described, mediated by thiourea-based bifunctional organocatalysts. The stereochemistry at C_α and C _β centers is perfectly controlled, and the intermediate C-3 enolate is trapped with a second Michael acceptor. The developed one-pot three-component consecutive reactions generate up to four contiguous stereocenters, including the C-3 all-carbon quaternary center, in a perfectly defined configuration. The conversion of the β-nitro oxindole into the corresponding β-amino derivative discloses synthetically useful transformations, exploitable to generate pharmaceutically attractive molecular targets.

Full text of DOI:10.1021/jo402099p

Article
pubs.acs.org/joc
Organocatalytic Conjugate Addition of Nitroalkanes to 3‑Ylidene
Oxindoles: A Stereocontrolled Diversity Oriented Route to
Oxindole Derivatives
Arianna Quintavalla,*,† Francesco Lanza,† Elisa Montroni,†,‡ Marco Lombardo,† and Claudio Trombini†
†Department of Chemistry ‘‘G. Ciamician’’, Alma Mater Studiorum, University of Bologna, Via Selmi, 2, I-40126 Bologna, Italy
‡Consorzio Interuniversitario “CINMPIS”, V. Orabona 4, 70125 Bari, Italy
S
* Supporting Information
ABSTRACT: An efficient and highly enantioselective Michael addition of
nitroalkanes to 3-ylidene oxindoles is described, mediated by thiourea-based
bifunctional organocatalysts. The stereochemistry at Cα and Cβ centers is
perfectly controlled, and the intermediate C-3 enolate is trapped with a second
Michael acceptor. The developed one-pot three-component consecutive reac-
tions generate up to four contiguous stereocenters, including the C-3 all-carbon
quaternary center, in a perfectly defined configuration. The conversion of the
β-nitro oxindole into the corresponding β-amino derivative discloses synthetically
useful transformations, exploitable to generate pharmaceutically attractive
molecular targets.
additions10,12 (Scheme 1, eq 2a) bypass the generation of a
stereolabile tertiary center at C-3, directly assembling the chiral
INTRODUCTION
■
The oxindole scaffold characterizes a large number of natural and
quaternary center at this position. Since the conjugate addition
synthetic compounds with important biological activities1,2
shown in Scheme 1, eq 3 provides a poor control of the C-3
(Figure 1).
stereochemistry, there are very few studies of organocatalytic
Therefore, considerable efforts have been devoted to design
asymmetric intermolecular additions to the β-carbon of 3-ylidene
strategies to synthesize these challenging structures.3 The
oxindoles. Xiao and co-workers13 reported the conjugate
potential medicinal significance of these enantiopure backbones
addition of acetylacetone to 3-ylidene oxindoles, and using
has prompted the development of asymmetric approaches, by
means of chiral metal catalysts4 and, more recently, organo-
nitromethane as a Michael donor, the expected product was
catalysts.5 A main challenge in these approaches is the
obtained in high yield and enantiocontrol at Cα, but in almost
identical amounts of the two diastereoisomers due to lack of
construction of the chiral backbone often containing sequences
of stereocenters, including quaternary centers.6 In particular, a
control at C-3.
As part of our ongoing investigation into the stereoselective
chiral quaternary center at the 3-position of the oxindole ring is a
addition of nitroalkanes to α,β-unsaturated systems14 promoted
structural feature of almost all these bioactive scaffolds. In the
by bifunctional thiourea-based organocatalysts,15 we set out to
past few years a huge number of contributions has been published in
this field. Currently, there are two7 main organocatalytic strategies to
develop the Michael addition of nitroalkanes (1) to 3-ylidene
oxindoles (2) to access highly stereoenriched C-3 β-nitro
address the C-3 all-carbon quaternary stereocenter, which exploit
the electrophilic or nucleophilic character of the selected oxindole
substrate, respectively (Scheme 1).
The first strategy is based on the preliminary nucleophilic
oxindoles (3) (Scheme 2, eq 1). Following a “diversity-oriented
synthesis” (DOS)16 approach, we checked the opportunities
offered by the adducts so generated to create structural
diversification in chiral 3,3′-disubstituted oxindoles.
It is noteworthy that the C-3 β-nitro oxindole core was usually
conjugate addition to exocyclic α,β-unsaturated oxindole
followed by spirocyclization,8,9 as shown in Scheme 1, eq 1.
synthesized by exploiting conjugate additions to nitro-
Alternatively, the nucleophilicity of C-3 is exploited, typically
alkenes4,5,8−11 (Scheme 2, eq 2). Very few authors8j,12a,13
explored the complementary reactivity between nitroalkanes
and 3-ylidene oxindoles, which was exploited in our approach
(Scheme 2, eq 1).
starting from racemic C-3 monosubstituted derivatives10
(Scheme 1, eq 2a). Domino spiroannulations are again possible
when an electrophilic function is present on the C-3 side chain11
(Scheme 1, eq 2b). Spirocyclizations (Scheme 1, eqs 1 and 2b)
are the most frequently exploited approaches, where the chirality
generated in the first step controls the formation of the adjacent
stereocenters. On the other hand, the reported intermolecular
Received: September 22, 2013
© XXXX American Chemical Society
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Figure 1. Representative natural and synthetic bioactive products containing the oxindole skeleton.
Scheme 1. Organocatalytic Strategies Employed To Asymmetrically Generate an All-Carbon Quaternary Stereocenter on the C-3
a
Oxindole Position
a
Abbreviations: Nu = nucleophilic site; E, E1, E2 = electrophilic sites; EWG = electron-withdrawing group; Y = generic substituent.
Scheme 2. Our Asymmetric Approach (Eq 1) to C-3 β-Nitro Oxindole Scaffolds in Comparison with the Most Investigated
Approach in the Literature (Eq 2)
B
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performed on it. However, we were pleased to note that just
slightly lower ees were obtained for unprotected starting material
2a (entry 1). This is a noteworthy result, since most of the
reported reactions work well on N-protected substrates only.
Other bifunctional organocatalysts (II−IX, Table 1) were tested
in the model reaction on substrate 2c, and high conversions in
short reaction times were invariably observed (entries 4−11).
Diastereo- and enantioselectivity did not undergo significant
changes when Cinchona-derived thioureas (II−V) and Take-
moto’s thiourea (VI) were used (entries 4−8). Significant lower
ees were recorded employing Cinchona alkaloids VIII and IX
(entries 10 and 11), and even worse results were obtained with
particularly Jacobsen’s thiourea VII (entry 9). The best results in
terms of reaction rate and stereocontrol were obtained with catalysts
I and VI; thus, further optimization was carried out using the low-
cost, commercially available Takemoto thiourea VI.
RESULTS AND DISCUSSION
■
Initially we focused our attention on the addition of nitro-
methane (1a) to differently N-substituted (E)-ethyl 2-(2-
oxoindolin-3-ylidene)acetates (2a−c) by using the bifunctional
Cinchona-derived organocatalyst I. As summarized in Table 1,
Table 1. N-Protecting Groups and Catalysts Screening in the
Organocatalyzed Asymmetric Conjugate Addition of 1a to 3-
a
Ylidene Oxindoles (2a−c)
The reaction conditions were deeply investigated to under-
stand the effects of nitromethane equivalents, catalyst loading,
solvent, and temperature on both the rate and the stereoselection
of the process. Selected data are summarized in Table 2.
When the amount of nitromethane (entry 1) and the catalyst
loading (entry 2) were individually lowered, and also when they
were simultaneously decreased up to 2.5 equiv of 1a and 2.5 mol %
of VI (entries 3 and 4), we still got excellent results. The reaction
time increased but still was reasonable when 2 equiv of 1a and only
1 mol % of catalyst (entry 5) were used. Some solvents were also
screened, without significant changes in the reaction performance.
Finally we lowered the temperature (entries 6 and 7), but we did not
observe any improvement in the diastereoselection. From these
results we can infer that our reaction system did not allow a
stereoselective C-3 protonation. Indeed the C3−H acidity of 3-alkyl-
substituted oxindoles might be significantly influenced by the
N-protecting group.17 Electron-withdrawing protecting groups
increase the acidity of the C-3 position; for instance, the pKa value
of N-acetyloxindole is around 13. Hence, the N-Boc protection
could favor a C-3 epimerization under our reaction conditions.18
To expand the reaction scope, we applied our protocol to a
variety of 3-ylidene oxindoles (2c−n), and we were delighted to
find that the process tolerated different substitution patterns very
well (Table 3). The employed conditions, representing the best
balance of reaction rate and stereocontrol for the different
substrates, were identified with 5 equiv of 1a and 5 mol % of
catalyst VI. The reactions smoothly proceeded when the
aromatic ring was decorated with both electron-withdrawing
(entries 2−5) and electron-donating (entry 6) groups. In
addition, the substituent position on the ring did not affect the
efficiency of the process (cf. entries 2 and 4 and entries 3 and 5).
The ethyl ester could be replaced by benzyl (entry 7) and
tert-butyl (entry 8) esters. So far, good yields and excellent
enantioselectivities (up to >99% ee) were reached for both
diastereoisomers of the β-nitro indolin-2-ones (3c−j).
b
b
c
entry substrate catalyst time (h) conversn (%)
dr
ee (%)
1
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
I
1.5
1.75
1
92
99
99
91
99
99
99
99
99
99
99
51/49
49/51
55/45
48/52
48/52
55/45
57/43
52/48
54/46
55/45
53/47
93/92
92/93
2
I
3
I
99/>99
d
4
II
1.5
1.75
1.5
1.5
1
97/98
5
III
IV
V
95/96
d
6
97/97
7
98/98
99/>99
59/64
82/86
8
VI
VII
VIII
IX
9
1.5
1.5
2
10
11
d
83/86
a
Reaction conditions: 2 (0.1 mmol), 1a (1 mmol), catalyst (10 mol %),
dichloromethane (DCM, 0.15 mL), room temperature. Determined
by H NMR of the crude mixture. Determined by chiral stationary
phase (CSP) HPLC of 3, isolated as a mixture of two C-3 epimers; ee
b
c
1
Significant changes, mainly in the enantiocontrol, were
observed when, instead of the ester function, aromatic or ali-
phatic groups were located at the exocyclic double bond. For the
phenyl derivative 3k the ee dropped to 60% (Table 3, entry 9)
and the addition of an electron-withdrawing substituent on the
phenyl ring provided even worse results (entry 10). The last
attempt was conducted on introducing an aliphatic group on the
double bond; however, we obtained very poor ees and longer
reaction times (entry 11). The latter data suggested that a crucial
role for the enantioselectivity was played by the presence of an
ester on the 3-ylidene oxindole. According to the dual activation
model19 proposed by Takemoto19a and Deng19b and theoretical
d
values refer to the two C-3 epimers. Opposite enantiomers were
formed.
the employed conditions allowed us to perform reactions much
more quickly than those reported by Xiao13 (90% yield after
15 h), and complete conversions were recorded within only 2 h
with all of the substrates 2a−c (entries 1−3).
As expected, the diastereomeric ratio (dr) was very poor, even
if associated with a high enantiomeric excess (ee) for both of the
diastereoisomers. Since the best enantioselectivity was achieved
for the N-Boc substrate 2c (entry 3), further optimization was
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Table 2. Optimization of the Reaction Conditions for the Organocatalyzed Asymmetric Conjugate Addition of 1a to 3-Ylidene
a
Oxindole 2c
b
b
c
entry
amt of 1a (equiv)
amt of VI (mol %)
T (°C)
time (h)
conversn (%)
dr
ee (%)
1
2
3
4
5
6
7
2.5
10
5
10
1
room temp
room temp
room temp
room temp
room temp
0
1
1.5
1
99
99
99
99
72
99
72
57/43
52/48
53/47
52/48
52/48
49/51
47/53
97/>99
>99/99
99/99
5
2.5
2
2.5
1
2
98/98
5.5
1.5
120
95/95
5
5
>99/>99
>99/>99
5
5
−20
a
b
c
Reaction conditions: 2c (0.1 mmol), catalyst VI, DCM (0.15 mL). Determined by 1H NMR of the crude mixture. Determined by CSP-HPLC of
3c, isolated as a mixture of two C-3 epimers; ee values refer to the two C-3 epimers.
a
Table 3. Organocatalyzed Asymmetric Conjugate Addition of 1a to 3-Ylidene Oxindoles 2c−n
b
c
d
entry
substrate
R1
R2
R3
product
time (h)
yield (%)
dr
ee (%)
99/99
1
2c
2d
2e
2f
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bn
CO2tBu
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
3c
3d
3e
3f
1
3.5
3.5
1.5
1
80
83
72
92
82
89
72
99
52
98
62
57
53/47
60/40
53/47
56/44
59/41
55/45
55/45
57/43
59/41
60/40
69/31
60/40
2
5-Cl
5-Br
6-Cl
7-Br
5-OMe
H
>99/>99
>99/>99
98/98
3
4
5
2g
2h
2i
3g
3h
3i
95/94
6
1
>99/>99
>99/>99
>99/>99
60/64
7
2
8
2j
H
3j
2
9
2k
2l
H
3k
3l
2
10
11
12
H
pNO2Ph
tBu
2
31/33
2m
2n
H
3m
3n
26
2
26/29
H
CO2Et
94/92
a
b
Reaction conditions: 2 (0.1 mmol), 1a (0.5 mmol), catalyst VI (5 mol %), DCM (0.15 mL), room temperature. Yield of isolated product after
c
d
flash chromatography. Determined by 1H NMR of the crude mixture. Determined by CSP-HPLC of products 3, isolated as a mixture of two C-3
epimers; ee values refer to the two C-3 epimers.
a
Table 4. Organocatalyzed Asymmetric Conjugate Addition of Nitroalkanes 1a−f to 3-Ylidene Oxindole 2c
b
c
d
entry
nitroalkane
MeNO2 (1a)
product
time (h)
yield (%)
anti/syn
ee anti (%)
e
1
3c
4b
4b
4b
4c
4d
4e
4f
1
2
80
99/99
e
2
EtNO2 (1b)
78
76/24
99/1
95/5
92/8
91/9
90/10
97/98
f
3
EtNO2 (1b)
48
3
73
>99/>99
>99/>99
>99/>99
>99/>99
>99/>99
4
5
6
7
8
EtNO2 (1b)
71
nPrNO2 (1c)
7
76
MeO2C(CH2)3NO2 (1d)
Ph(CH2)2NO2 (1e)
iPrNO2 (1f)
4
83
4
72
144
traces
a
b
Reaction conditions: 2c (0.1 mmol), 1 (0.5 mmol), catalyst VI (10 mol %), DCM (0.15 mL), 0 °C. Yield of isolated product after flash
c
chromatography. Determined by CSP-HPLC of the crude mixture; the stereochemical notations anti and syn refer to the Cα−Cβ relationship.
d
e
Determined by CSP-HPLC of the products, isolated as a mixture of two C-3 epimers; ee values refer to the two C-3 epimers. Reaction performed
f
at room temperature with 5 mol % of VI. Reaction performed at −10 °C.
calculations performed by Papai,19c the bifunctional organo-
catalyst should simultaneously activate both Michael donor and
acceptor, thus controlling the approach of the nitroalkane to the
3-ylidene oxindole. The oxindole reasonably interacts with the
thiourea moiety via multiple hydrogen bonds, enhancing the
electrophilicity of the reacting carbon center. Concurrently, the
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nitro compound coordinates to the tertiary amine group. The
poor enantiocontrol observed when the methyleneindolinone
was directly connected to an aryl or alkyl group suggests that the
ester moiety affects the coordination between catalyst and
substrate, enabling a high enantiocontrol. On the other hand, the
interaction between the N-Boc carboxyl group and the catalyst,
identified as crucial by many authors,8j,9f,10e,f,k,n,11d,f in our system
seems to be present but not strictly necessary, as evidenced by the
small differences in enantioselectivity recorded for substrates
2a−c (Table 1, entries 1−3).
The substrate scope was also extended to the challenging
construction of a quaternary stereocenter on the Cα position. For
this purpose we applied our protocol to substrate 2n,
characterized by a tetrasubstituted exocyclic double bond
(Table 3, entry 12). Once again, the reaction quickly provided
the desired product with high ees for both diastereoisomers.
The next step in our investigation was to explore the use of
higher nitroalkanes as Michael donors (Table 4), with the aim of
introducing a further stereocenter and approaching the structural
complexity of bioactive oxindoles.
Although it was not possible to control the absolute
configuration of the third stereocenter, this limitation can be
turned into an opportunity if we react the β-nitro oxindole 4 with
an electrophile, with the aim of building up an all-carbon C-3
quaternary stereocenter increasing the structural complexity
(Scheme 2, eq 1). With respect to the previously reported
strategies, that employ simple C-3 racemic substrates4a,c,e,5,10
(Scheme 1, eq 2a), our approach consists of reacting a pair of
diastereoisomers (Scheme 1, eq 3). In this perspective, the β-nitro
indolin-2-one scaffold 4 could represent a useful precursor for the
asymmetric synthesis of 3,3′-disubstituted oxindoles with more
substitution variants.
The first attempts were made by exploiting N-phenyl-
maleimide,20 1,1-bis(benzenesulfonyl)ethylene21 and trans-β-nitro-
styrene22 as electrophiles, in the presence of the same thiourea
catalyst used for the preliminary Michael addition. As shown in
Scheme 4, the reaction with N-phenylmaleimide proceeded
smoothly, affording product 6 as a single stereoisomer in good
yield. In this one-pot three-component tandem reaction four
contiguous stereocenters, including the desired C-3 all-carbon
quaternary center, were enantioselectively generated.
We first applied the same conditions optimized for nitro-
methane 1a (Table 4, entry 1). Nitroethane 1b quickly provided
the desired product 4b in good yield and excellent stereocontrol
at Cα, but with modest control of the Cβ stereochemistry (entry 2).
We tried to improve the dr by lowering the temperature, and
pleasingly, the diastereocontrol at −10 °C was almost complete
(entry 3). However, the reaction time was much longer (48 h), so
that the best trade-off between reactivity and stereoselectivity was
reached by employing 10 mol % of catalyst at 0 °C. After 3 h 4b was
obtained in good yield and dr and high ees for each diastereoisomer
(entry 4). The protocol was successfully applied to nitroalkanes
1c−e (entries 5−7). Only the isopropyl derivative 1f did not afford
the corresponding product (entry 8); this was probably due to the
great steric compression at the α-nitro position. Data presented in
Table 4 showed that the configurations of the two stereocenters
directly generated in the conjugate addition were highly defined,
while the C-3 configuration was, as usual, out of control. With the
aim of introducing a quaternary and two tertiary adjacent
stereocenters on the oxindole scaffold, we extended the addition
of nitroethane 1b to substrate 2n (Scheme 3).
To introduce structural diversity, the reactivity of 4b was also
tested in the Michael addition to 1,1-bis(benzenesulfonyl)-
ethylene (Scheme 4). Compound 7, featuring three adjacent
stereocenters, was efficiently isolated with excellent stereoenrich-
ment. With regard to the organocatalyzed conjugate addition of
3-substituted racemic oxindole derivatives to vinyl sulfones, it is
known that good stereocontrol is possible only if an aryl
substituent on C-3 is present, while 3-alkyl oxindoles generally
afford the corresponding adducts in low yields and poor
enantioselectivity. For this reason, Lu and co-workers21a and
Kim and co-workers21b were forced to develop specifically
modified organocatalysts. In our case, thanks to the matched
induction of pre-existing stereocenters and catalyst, the
asymmetric Michael reaction smoothly proceeded on 3-alkyl
oxindole 4b with the readily available Takemoto catalyst VI.
The last application of the hydrogen-bond catalysis involved
the addition of 4b to trans-β-nitrostyrene (Scheme 5), further
confirming the versatility of the β-nitro indolin-2-one scaffold as a
synthetic precursor of optically active 3,3′-disubstituted oxindoles.
One of the advantages of the proposed one-pot tandem
reactions was that a single catalyst sequentially promoted two
different transformations, so that the addition of other catalysts
was not necessary. However, to further expand the opportunities
of structural diversification, we explored a second activation
mode employing covalent amino catalysis for the reaction of 4b
with 2-cyclohexen-1-one10p,11a and with crotonaldehyde.8a,c,d,10j,11c,d
As depicted in Scheme 6, the thiourea VI was easily removed by
means of an acidic workup, allowing us to carry out the
subsequent Michael reaction directly on the crude reaction
mixture containing 4b.
Scheme 3. Organocatalytic Protocol Employed To
Stereoselectively Introduce a Quaternary and Two Tertiary
Adjacent Stereocenters
Primary amine X and secondary amine XI represent the
matched catalysts for the addition of anti-4b to cyclohexenone
and crotonaldehyde, respectively, affording the corresponding
products 9 and 10 in good yields. Once again, 3,3′-disubstituted
oxindoles bearing four contiguous stereocenters were obtained
with good to excellent stereocontrol.
The adduct 5 was obtained in good yield and high ee, and
surprisingly, in this case the two C-3 epimers were not equally
present (dr = 85/15). A possible explanation could be that the
steric crowding and the substituent distribution on the adjacent
stereocenters partially affect the C-3 configuration.
A notable synthetic application of the β-nitro oxindole scaffold
lies in its easy conversion to the corresponding β-amino motif
recognized in many bioactive compounds.1−3 As depicted in
Scheme 7, on reduction with Raney nickel of the β-nitro indolin-
2-one 4b, we quantitatively obtained the expected β-amino
indolin-2-one 11.
Summarizing the first part of this study, we developed an
asymmetric organocatalytic protocol for the conjugate addition
of nitroalkanes to 3-ylidene oxindoles, which efficiently provided
substituted β-nitro indolin-2-ones in good yields and excellent
enantioselectivities. Indeed, up to three stereocenters were
generated one pot, two of them with high stereocontrol.
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Scheme 4. One-Pot Three-Component Tandem Reactions To Access 3,3′-Disubstituted Oxindoles 6 and 7
Scheme 5. One-Pot Three-Component Tandem Reaction To
Access 3,3′-Disubstituted Oxindole 8
Scheme 7. Reducing Agent Dependent Transformations of
β-Nitro Oxindole 4b into β-Amino 11 and β-Hydroxylamino
12 Oxindoles. Stereoconvergent Base-Promoted C-3
Epimerization of β-Amino and β-Hydroxylamino Derivatives
Looking for the best reaction conditions, we tried also
palladium on carbon as a reducing agent and, interestingly, the
pair of observed products was different from those obtained
using Raney nickel. A careful analysis of the HPLC-MS and NMR
spectra allowed us to establish that the palladium catalyst partially
reduces the β-nitro oxindole 4b to the corresponding
β-hydroxylamino oxindole 1223 (Scheme 7). As expected, the
β-amino and the β-hydroxylamino derivatives were both isolated
as mixtures of two C-3 epimers (11a,b and 12a,b, respectively)
but, interestingly, when subjected to basic conditions they con-
verged to a single stereoisomer (Scheme 7). As previously
mentioned about compound 5, the C-3 configuration could be
affected by the stereochemical features and the ability to form
specific interactions of the substituents on Cα and Cβ. In this case,
the greater thermodynamic stability of 11a and 12a acts as a
driving force in the base-promoted stereoconvergent C-3
epimerization.
At last we remark the usefulness of the asymmetric
organocatalytic conjugate addition of nitroalkanes to 3-ylidene
oxindoles reported here in the synthesis of enantioenriched
oxindole and indoline derivatives, potentially exploitable in drug
discovery. For example, the optically active conjugate adduct
Scheme 6. Sequential Synthesis of 3,3′-Disubstituted Oxindoles 9 and 10
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anti-4b (>99% ee) was first reduced and then cyclized to
compound 13, featuring a core structure similar to those of many
important natural products24 (Scheme 8). The absolute
synthetic value of the developed asymmetric Michael addition of
nitroalkanes to 3-ylidene oxindoles, complementary to the most
widely studied reactions present in the literature.
Scheme 8. Synthetic Elaborations on the Optically Active
Conjugate Adduct anti-4b To Obtain the Stereochemically
Different Compounds 13 and 14, Featuring a Natural Core
Structure
EXPERIMENTAL SECTION
■
Materials. All of the chemicals were used as received. Catalysts I−V
were known and prepared according to the literature procedures.26
Compounds 2a,27 2b,c,28 2d−f,h,11f 2i,9f 2j,k,9a,d 2l,9b and 1e29 were
known and prepared according to the literature procedures.
Characterization of Compounds. 1H and 13C NMR spectra were
recorded on a 200 or 400 NMR instrument with a 5 mm probe. All
chemical shifts have been quoted relative to deuterated solvent signals;
chemical shifts (δ) are reported in ppm, and coupling constants (J) are
reported in Hz; HPLC-MS analysis was performed using an HPLC
system coupled with a single-quadrupole mass spectrometer. A
ZOBRAX-Eclipse XDB-C8 column was employed for the chromato-
graphic separation: mobile phase H2O/CH3CN, gradient from 30% to
80% of CH3CN in 8 min, 80% of CH3CN until 25 min, 0.4 mL min−1.
Mass spectrometric detection was performed in full-scan mode from
m/z 50 to 2600: scan time 0.1 s in positive ion mode, ESI spray voltage
4500 V, nitrogen gas 35 psi, drying gas flow 11.5 mL min−1, fragmentor
voltage 20 V. CSP-HPLC analyses were performed using hexane/
2-propanol (n-Hex/IPA) mixtures. Flash chromatography was carried
out using Merck silica gel 60 (230−400 mesh particle size). Thin-layer
chromatography was performed on Merck 60 F254. The [α]D25 values
and the major enantiomers in the following characterization have been
defined with respect to the products obtained with catalyst VI.
Synthesis of (E)-tert-Butyl 7-Bromo-3-(2-ethoxy-2-oxoethylidene)-
2-oxoindoline-1-carboxylate (2g). Ethyl 2-(triphenylphos-
phoranylidene)acetate (1.2 mmol) was added to a solution of 7-bromoindo-
line-2,3-dione (1 mmol, 226 mg) in DCM (4 mL). The reaction mixture
was stirred at room temperature overnight. After the reaction was complete,
the solvent was removed under reduced pressure. The crude mixture was
dissolved in THF (5 mL), DMAP (4-dimethylaminopyridine, 5 mol %)
was added to the solution, and finally, Boc2O (di-tert-butyl dicarbonate,
1.1 mmol) was added. The reaction mixture was stirred at room temperature
for 1 h. Then the solvent was removed under reduced pressure and the
product was purified by flash chromatography on silica gel (cyclohexane/
ethyl acetate 9/1): 95% yield (376 mg), crystalline solid (mp 73−77 °C);
1H NMR (400 MHz, CDCl3) δ 8.66 (dd, J = 7.9 and 1.1 Hz, 1H), 7.59 (dd,
configuration of compound 13 has been determined by
theoretical calculation of its electronic circular dichroism
(ECD) spectrum and of its optical rotation (OR), using the
TD-DFT method (see the Supporting Information).
The possibility of creating stereochemically different scaffolds
starting from the same substrate could be synthetically very
useful, providing a platform of diastereomeric derivatives to
better evaluate the effect of relative stereochemistry on
bioactivity. With this aim, exploiting the acidity on the Cβ
position, we subjected anti-4b to basic conditions (1,5-
diazabicyclo[5.4.0]undec-5-ene, DBU, 30 mol %) and syn-4b was
isolated in good yield without compromising the optical purity. The
previously described reductive protocol25 allowed us to obtain
product 14, characterized by a relative stereochemistry different
from that of compound 13. Thus, the Cα absolute configuration,
controlled by the chiral thiourea during the conjugate addition, is the
only one that remains unchanged, while the stereochemistry at the
other centers can be manipulated by means of stereoconvergent
transformations, depending on the desired target molecule.
J = 8.1 and 1.1 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.94 (s, 1H), 4.34 (q, J = 7.1
Hz, 2H), 1.66 (s, 9H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 27.7, 61.5, 85.8, 106.7, 123.4, 124.6, 125.6, 127.5, 136.2,
137.1, 140.8, 147.6, 164.9, 166.3; HPLC-MS (ESI) tr = 12.7 min; [M+ Na]+
418.2 m/z, [2M + Na]+ 813.2 m/z, 817.2 m/z. Anal. Calcd for
C17H18BrNO5 (395.04): C, 51.53; H, 4.58; N, 3.53. Found: C, 51.37; H,
4.56; N, 3.54.
Synthesis of (E)-tert-Butyl 3-(2,2-Dimethylpropylidene)-2-
oxoindoline-1-carboxylate (2m). Pivalaldehyde (1.2 mmol) was
added to a solution of indolin-2-one (1 mmol, 133 mg) in EtOH (5 mL),
finally piperidine (10 mol %) was added. The reaction was refluxed for
1.5 h, then it was cooled to room temperature and the solvent was
removed under reduced pressure. The product was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 8/2). (E)-3-
(2,2-Dimethylpropylidene)indolin-2-one was dissolved in THF (5 mL),
and then DMAP (5 mol %) was added and finally Boc2O (1.1 mmol).
The reaction mixture was stirred at room temperature for 1 h. After the
reaction was complete, the solvent was removed under reduced pressure and
the product was purified by flash chromatography on silica gel (cyclohexane/
ethyl acetate 9/1): 97% yield (292 mg); crystalline solid (mp 82−86 °C); 1H
NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.78−7.71 (m, 1H),
7.36−7.29 (m, 1H), 7.25 (s, 1H), 7.17 (td, J = 7.7 and 1.2 Hz, 1H), 1.65 (s,
9H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 28.1, 29.1, 32.7, 84.0,
115.0, 120.9, 123.5, 125.5, 126.0, 128.9, 140.0, 149.3, 154.3, 167.0; HPLC-MS
(ESI) tr = 13.4 min; [2M + Na]+ = 625.4 m/z. Anal. Calcd for C18H23NO3
(301.17): C, 71.73; H, 7.69; N, 4.65. Found: C, 71.61; H, 7.71; N, 4.65.
Synthesis of (E)-tert-Butyl 3-(1-Ethoxy-1-oxopropan-2-yli-
dene)-2-oxoindoline-1-carboxylate (2n). DMAP (5 mol %) was
added to a solution of indoline-2,3-dione (1 mmol, 147 mg) in THF
CONCLUSION
■
Even though asymmetric processes applied to indoles, oxindoles,
and isatins seem to represent a mature field in organocatalysis, we
demonstrated that still a number of useful reactions and
applications can be disclosed. We carefully examined the Michael
addition of nitroalkanes to 3-ylidene oxindoles and found
optimized conditions to perfectly control the stereochemistry at
Cα and Cβ centers. Under our reaction conditions we had no
chance to stereodefine the C-3 position; however, when the
generated intermediate enolate was trapped with a second
Michael acceptor, an all-carbon quaternary stereocenter was
formed in a perfectly defined configuration. The conversion of
the β-nitro oxindole adduct into the corresponding β-amino
derivative disclosed intriguing and synthetically useful trans-
formations, such as stereoconvergent processes and stereoselective
base-promoted isomerizations. Considering the number of
substrates examined and the number of synthetic transformations
they were subjected to, we believe to have demonstrated the
G
dx.doi.org/10.1021/jo402099p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(5 mL); then Boc2O (1.1 mmol) was added. The reaction mixture was
stirred at room temperature for 1 h. After the reaction was complete, the
solvent was removed under reduced pressure. The crude mixture was
dissolved in DCM (4 mL), and ethyl 2-(triphenylphosphoranylidene)-
propanoate (1.2 mmol) was added. The reaction mixture was stirred at
room temperature overnight. Then the solvent was removed under
reduced pressure and the product was purified by flash chromatography
on silica gel (cyclohexane/ethyl acetate 9/1): 50% yield (166 mg), gum;
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.7 Hz, 1H), 7.36−7.29 (m,
tert-Butyl 3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindo-
line-1-carboxylate (3c): mixture of two diastereoisomers; 80% yield
(30 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8.4 and 2.8 Hz,
2H), 7.41−7.33 (m, 2H), 7.29−7.14 (m, 4H), 5.01 (dd, J = 14.4 and 9.3
Hz, 1H), 4.84 (dd, J = 14.9 and 8.1 Hz, 1H), 4.64 (dd, J = 14.8 and 5.8
Hz, 1H), 4.40 (dd, J = 14.4 and 5.0 Hz, 1H), 4.23−4.06 (m, 6H), 4.04 (d,
J = 3.8 Hz, 1H), 3.99 (d, J = 3.1 Hz, 1H), 1.65 (s, 18H), 1.18 (t, J = 7.1
Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 13.6,
13.8, 28.0, 43.7, 43.9, 45.0, 45.4, 62.2, 62.3, 72.3, 72.4, 84.9, 85.0, 115.3,
115.4, 123.2, 123.5, 123.6, 123.7, 124.7, 124.8, 129.2, 129.5, 140.3, 140.6,
148.77, 148.76, 168.7, 169.2, 172.7, 173.4; HPLC-MS (ESI) tr = 9.9 min,
10.0 min; [M + Na]+ = 401.3 m/z. Anal. Calcd for C18H22N2O7
(378.14): C, 57.14; H, 5.86; N, 7.40. Found: C, 57.02; H, 5.85; N, 7.39.
3-((R)-1-Ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindoline: mixture
of two diastereoisomers; CSP-HPLC: OJ 90/10 n-Hex/IPA for 10 min,
then up to 80/20 in 20 min, 80/20 up to 70 min; flow rate 0.5 mL/min at
room temperature; λ 214 nm; tr(isomer A) = 43.2 min (major), 51.8 min
(minor); tr(isomer B) = 49.5 min (major), 63.9 min (minor).
tert-Butyl 5-chloro-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-
oxoindoline-1-carboxylate (3d): mixture of two diastereoisomers;
83% yield (34 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 5.1
Hz, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.38−7.31 (m, 2H), 7.24−7.20 (m, 2H),
5.00 (dd, J = 14.4 and 9.0 Hz, 1H), 4.91 (dd, J = 14.8 and 7.3 Hz, 1H), 4.78
(dd, J = 14.8 and 6.6 Hz, 1H), 4.46 (dd, J = 14.4 and 5.2 Hz, 1H), 4.22−4.03
(m, 6H), 4.00 (d, J = 4.3 Hz, 1H), 3.93 (d, J = 3.0 Hz, 1H), 1.64 (s, 18H),
1.22−1.09 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 13.68, 13.73, 28.0, 43.7,
44.0, 44.7, 45.2, 62.4, 62.5, 72.2, 72.6, 85.2, 85.3, 116.6, 116.7, 123.7, 123.9,
125.1, 125.8, 129.2, 129.5, 130.2, 130.3, 138.9, 139.1, 148.6, 168.4, 168.6, 171.9,
172.8; HPLC-MS (ESI) tr = 10.7 min; [M + Na]+ = 435.2, 437.3 m/z, [M +
K]+ = 451.2 m/z, [2M + Na]+ = 847.4 m/z. Anal. Calcd for C18H21ClN2O7
(412.10): C, 52.37; H, 5.13; N, 6.79. Found: C, 52.21; H, 5.14; N, 6.78.
5-Chloro-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindo-
line: mixture of two diastereoisomers, gum; 1H NMR (400 MHz,
CDCl3) δ 7.96 (bs, 2H), 7.52−7.48 (m, 1H), 7.33−7.16 (m, 3H), 6.92−
6.76 (m, 2H), 4.99 (dd, J = 14.4 and 9.0 Hz, 1H), 4.84 (dd, J = 14.7 and
8.2 Hz, 1H), 4.65−4.55 (m, 1H), 4.52 (dd, J = 14.5 and 4.9 Hz, 1H), 4.40
(m, 1H), 4.27−4.16 (m, 3H), 4.12−4.05 (m, 2H), 4.02−3.87 (m, 2H),
1.31−1.15 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 13.8, 13.9, 43.1,
43.3, 44.8, 44.9, 62.3, 62.4, 72.1, 72.2, 111.0, 111.1, 124.5, 124.7, 124.9,
124.9, 126.8, 128.0, 128.4, 129.1, 129.3, 129.5, 139.7, 139.9, 168.9, 169.3,
176.0; HPLC-MS (ESI) tr = 7.5 min, 7.6 min; [M + H]+= 313.1 m/z,
[M + Na]+= 335.1 m/z. Anal. Calcd for C13H13ClN2O5 (312.05): C,
49.93; H, 4.19; N, 8.96. Found: C, 49.89; H, 4.20; N, 8.94. CSP-HPLC:
IC 90/10 n-Hex/IPA up to 50 min; flow rate 0.6 mL/min at room
temperature; λ 214 nm; tr(isomer A) = 31.4 min (major), 39.7 min
(minor); tr(isomer B) = 44.2 min (minor), 45.9 min (major).
tertButyl 5-bromo-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-
oxoindoline-1-carboxylate (3e): mixture of two diastereoisomers;
72% yield (33 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.82−7.76 (m,
2H), 7.53−7.45 (m, 2H), 7.40−7.32 (m, 2H), 5.00 (dd, J = 14.4 and 9.0
Hz, 1H), 4.91 (dd, J = 14.8 and 7.3 Hz, 1H), 4.80 (dd, J = 14.8 and 6.6
Hz, 1H), 4.46 (dd, J = 14.5 and 5.1 Hz, 1H), 4.24−4.02 (m, 6H), 4.00 (d,
J = 4.3 Hz, 1H), 3.93 (d, J = 3.0 Hz, 1H), 1.64 (s, 18H), 1.22−1.09 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 13.7, 13.7, 28.0, 43.8, 44.1, 44.7,
45.1, 62.4, 62.5, 72.2, 72.6, 85.2, 85.4, 117.0, 117.0, 117.6, 117.7, 125.5,
126.2, 126.5, 126.7, 132.1, 132.5, 139.4, 139.6, 148.6, 168.4, 168.6, 171.8,
172.7; HPLC-MS (ESI) tr = 10.9 min; [M + Na]+= 479.2, 481.1 m/z.
Anal. Calcd for C18H21BrN2O7 (456.05): C, 47.28; H, 4.63; N, 6.13.
Found: C, 47.13; H, 4.61; N, 6.11.
5-Bromo-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindo-
line: mixture of two diastereoisomers, gum; 1H NMR (400 MHz,
CDCl3) δ 7.79 (bs, 2H), 7.45−7.38 (m, 2H), 7.38−7.29 (m, 2H), 6.84−
6.76 (m, 2H), 4.99 (dd, J = 14.5 and 8.8 Hz, 1H), 4.84 (dd, J = 14.8 and
8.1 Hz, 1H), 4.62 (dd, J = 14.8 and 5.7 Hz, 1H), 4.52 (dd, J = 14.5 and 4.8
Hz, 1H), 4.26−4.18 (m, 4H), 4.12−4.04 (m, 1H), 4.00−3.89 (m, 3H),
1.31−1.14 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 13.8, 13.9, 43.2,
43.3, 44.7, 44.8, 62.3, 62.4, 72.17, 72.23, 111.4, 111.5, 115.5, 127.2,
127.3, 127.6, 127.7, 132.0, 132.2, 140.2, 140.4, 168.9, 169.2, 175.2, 175.7;
HPLC-MS (ESI) tr = 7.7 min; [M + H]+ = 357.1, 359.1 m/z, [M + Na]+ =
379.1, 381.0 m/z. Anal. Calcd for C13H13BrN2O5 (356.00): C, 43.72; H,
2H), 7.09 (t, J = 7.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.66
(s, 9H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 14.0,
17.1, 28.1, 30.9, 62.0, 84.4, 114.9, 120.7, 122.0, 123.4, 123.9, 129.9,
138.8, 141.8, 149.2, 165.7, 169.2; HPLC-MS (ESI) tr = 11.7 min; [M +
Na]+ = 354.2 m/z, [2M + Na]+ = 685.5 m/z. Anal. Calcd for C18H21NO5
(331.14): C, 65.24; H, 6.39; N, 4.23. Found: C, 65.22; H, 6.37; N, 4.22.
General Procedure for the Organocatalyzed Michael
Addition of Nitroalkanes 1 to 3-Ylidene Oxindoles 2. The 3-
ylidene oxindole (0.1 mmol) was added to a solution of catalyst (5 or 10
mol %) in DCM (0.15 mL), and then nitroalkane (0.5 mmol) was added
at room temperature or at 0 °C. The mixture was stirred at the same
temperature, and the conversion was monitored by TLC and 1H NMR.
The crude mixture of the reactions performed at room temperature was
directly purified by flash chromatography on silica gel (cyclohexane/
ethyl acetate 85/15). The crude mixture of the reactions performed at
0 °C was quenched at the same temperature with 2 mL of HCl (1 N) and
extracted with DCM (3 × 2 mL). The organic phases were collected and
dried over Na2SO4, the solvent was evaporated under reduced pressure
without heating, and the product was purified by flash chromatography
on silica gel (cyclohexane/ethyl acetate 85/15). Before CSP-HPLC
analysis, the purified product (0.04 mmol) (and, when necessary, the
crude reaction mixture) was deprotected using 18 equiv of trifluoro-
acetic acid (TFA) in 0.4 mL of DCM. After 45 min the reaction was
quenched with 2 mL of a 0.1 M solution of phosphate buffer (pH 7) and
the aqueous phase was extracted with DCM (2 × 2 mL). The organic
phases were collected and dried over Na2SO4. The solvent was evaporated
under reduced pressure, and the corresponding N-deprotected β-nitro
oxindole was obtained pure and directly injected into CSP-HPLC.
3-((R)-1-Ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindoline (3a):
1
mixture of two diastereoisomers; 85% yield (24 mg), oil; H NMR
(400 MHz, CDCl3) δ 7.93 (bs, 2H), 7.34−7.20 (m, 3H), 7.17 (d, J = 7.5
Hz, 1H), 7.12−7.01 (m, 2H), 6.91 (d, J = 7.8 Hz, 2H), 4.99 (dd, J = 14.5
and 9.4 Hz, 1H), 4.78 (dd, J = 14.8 and 8.9 Hz, 1H), 4.46 (m, 2H), 4.29−
4.14 (m, 4H), 4.14−4.07 (m, 1H), 4.04 (m, 1H), 3.99−3.91 (m, 2H),
1.23 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 13.8, 13.9, 43.0, 43.3, 45.0, 45.1, 62.1, 62.2, 72.0, 72.3, 110.3,
122.9, 123.0, 124.3, 124.4, 124.8, 125.0, 129.2, 129.3, 141.3, 141.6, 169.1,
169.8, 176.5, 176.8; HPLC-MS (ESI) tr = 6.4 min, 6.8 min; [M + H]+ =
279.2 m/z, [M + Na]+ = 301.2 m/z. Anal. Calcd for C13H14N2O5
(278.09): C, 56.11; H, 5.07; N, 10.07. Found: C, 55.91; H, 5.09; N,
10.04. CSP-HPLC: OJ 90/10 n-Hex/IPA for 10 min, then up to 80/20
in 20 min, 80/20 up to 60 min; flow rate 0.5 mL/min at 40 °C; λ 214 nm;
tr(isomer A) = 38.5 min (major), 44.8 min (minor); tr(isomer B) = 42.7
min (major), 53.8 min (minor).
(2R)-Ethyl 2-(1-benzyl-2-oxoindolin-3-yl)-3-nitropropanoate (3b):
1
mixture of two diastereoisomers; 86% yield (32 mg), gum; H NMR
(400 MHz, CDCl3) δ 7.39−7.16 (m, 14H), 7.10−7.01 (m, 2H), 6.84−
6.72 (m, 2H), 5.03−4.88 (m, 5H), 4.80 (dd, J = 14.8 and 8.9 Hz, 1H),
4.52−4.37 (m, 2H), 4.24−4.04 (m, 6H), 4.01 (d, J = 3.7 Hz, 2H), 1.17
(t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 13.7, 13.8, 43.2, 43.4, 44.09, 44.11, 44.5, 44.6, 62.0, 62.1, 72.10,
72.41, 109.5, 122.9, 123.0, 124.0, 124.1, 124.3, 124.5, 127.4, 127.5,
127.88, 127.91, 128.86, 128.87, 129.0, 129.2, 135.40, 135.42, 143.4,
143.6, 169.2, 169.7, 174.4, 174.6; HPLC-MS (ESI) tr = 9.5 min, 9.8 min;
[M + H]+ = 369.2 m/z, [M + Na]+ = 391.2 m/z. Anal. Calcd for
C20H20N2O5 (368.14): C, 65.21; H, 5.47; N, 7.60. Found: C, 65.06; H,
5.47; N, 7.61. CSP-HPLC: IC 90/10 n-Hex/IPA for 10 min, then up to
85/15 in 5 min, 85:15 up to 80 min; flow rate 0.5 mL/min at room
temperature; λ 254 nm. tr(isomer A) = 56.1 min (major), 71.0 min
(minor); tr(isomer B) = 61.2 min (major), 73.6 min (minor).
H
dx.doi.org/10.1021/jo402099p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.67; N, 7.84. Found: C, 43.69; H, 3.68; N, 7.83. CSP-HPLC: IC 90/10 n-
Hex/IPA for 10 min, then up to 80/20 in 10 min, 80/20 for 15 min, then up
to 75/25 in 15 min, 75/25 up to 40 min; flow rate 0.5 mL/min at room
temperature; λ214 nm; tr(isomer A) = 27.7 min (major), 31.3 min (minor);
tr(isomer B) = 32.4 min (major), 33.0 min (minor).
9.1 Hz, 1H), 4.84 (dd, J = 14.8 and 8.1 Hz, 1H), 4.64 (dd, J = 14.8 and 5.8
Hz, 1H), 4.35 (dd, J = 14.5 and 4.6 Hz, 1H), 4.25−4.01 (m, 7H), 3.96 (d,
J = 2.8 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 1.64 (s, 18H), 1.22−1.13 (m,
6H); 13C NMR (50 MHz, CDCl3) δ 13.7, 13.8, 28.1, 43.7, 43.9, 45.3,
45.7, 55.6, 55.7, 62.2, 62.3, 72.1, 72.5, 84.66, 84.74, 110.0, 110.2, 113.8,
113.9, 116.3, 116.4, 124.5, 125.0, 133.6, 133.8, 148.8, 156.97, 157.01,
168.7, 169.1, 172.6, 173.4; HPLC-MS (ESI) tr = 9.9 min, 10.2 min; [M +
Na]+ = 431.3 m/z, [2M + Na]+ = 839.6 m/z. Anal. Calcd for
C19H24N2O8 (408.15): C, 55.88; H, 5.92; N, 6.86. Found: C, 55.77; H,
5.93; N, 6.87.
tert-Butyl 6-chloro-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-
oxoindoline-1-carboxylate (3f): mixture of two diastereoisomers;
1
92% yield (38 mg), oil; H NMR (400 MHz, CDCl3) δ 7.98−7.92
(m, 2H), 7.22−7.12 (m, 4H), 5.00 (dd, J = 14.3 and 9.0 Hz, 1H), 4.87
(dd, J = 14.8 and 7.5 Hz, 1H), 4.74 (dd, J = 14.8 and 6.4 Hz, 1H), 4.44
(dd, J = 14.4 and 5.3 Hz, 1H), 4.21−4.04 (m, 6H), 3.98 (d, J = 3.9 Hz,
1H), 3.92 (d, J = 2.7 Hz, 1H), 1.65 (s, 18H), 1.22−1.11 (m, 6H); 13C
NMR (50 MHz, CDCl3) δ 13.7, 13.8, 28.0, 43.8, 44.0, 44.6, 45.0, 62.3,
62.4, 72.3, 72.5, 85.4, 85.5, 116.16, 116.23, 121.7, 122.3, 124.3, 124.5,
124.7, 124.8, 135.1, 135.4, 141.3, 141.5, 148.5, 168.4, 168.8, 172.2,
173.0; HPLC-MS (ESI) tr = 10.9 min; [M + Na]+ = 435.2 m/z,
[2M+Na]+ = 847.4 m/z. Anal. Calcd for C18H21ClN2O7 (412.10): C,
52.37; H, 5.13; N, 6.79. Found: C, 52.16; H, 5.13; N, 6.78.
3-((R)-1-Ethoxy-3-nitro-1-oxopropan-2-yl)-5-methoxy-2-oxoin-
1
doline: mixture of two diastereoisomers, gum; H NMR (400 MHz,
CDCl3) δ 8.45 (bs, 2H), 6.90−6.73 (m, 6H), 4.96 (dd, J = 14.5 and 9.3
Hz, 1H), 4.76 (dd, J = 14.8 and 8.9 Hz, 1H), 4.49−4.35 (m, 2H), 4.29−
4.15 (m, 4H), 4.10 (ddd, J = 8.6, 4.8, and 3.3 Hz, 1H), 4.04−3.92 (m,
3H), 3.79 (s, 3H), 3.78 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1
Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 13.8, 13.9, 43.0, 43.3, 45.5, 45.6,
55.78, 55.84, 62.1, 62.2, 72.0, 72.1, 110.8, 111.6, 111.7, 113.7, 113.8,
126.1, 126.4, 134.6, 134.8, 156.09, 156.14, 169.1, 169.8, 176.5, 176.8;
HPLC-MS (ESI) tr = 5.9 min, 6.2 min; [M + H]+ = 309.2 m/z, [M +
Na]+= 331.2, [2M + Na]+ = 639.3 m/z. Anal. Calcd for C14H16N2O6
(308.10): C, 54.54; H, 5.23; N, 9.09. Found: C, 54.42; H, 5.24; N, 9.12.
CSP-HPLC: OD-H 85:15 n-Hex/IPA for 15 min, then up to 80/20 in
10 min, 80/20 for 10 min, then up to 70/30 in 10 min, 70/30 up to 41 min;
flow rate 0.5 mL/min at room temperature; λ 214 nm; tr(isomer A) =
24.9 min (major), 33.4 min (minor); tr(isomer B) = 31.3 min (minor),
36.3 min (major).
tert-Butyl 3-((R)-1-(benzyloxy)-3-nitro-1-oxopropan-2-yl)-2-ox-
oindoline-1-carboxylate (3i): mixture of two diastereoisomers; 72%
yield (32 mg), oil; 1H NMR (200 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz,
2H), 7.41−6.95 (m, 16H), 5.15 (s, 2H), 5.10 (s, 2H), 5.02 (dd, J = 14.4
and 9.3 Hz, 1H), 4.81 (dd, J = 14.8 and 8.3 Hz, 1H), 4.58 (dd, J = 14.9
and 5.5 Hz, 1H), 4.39 (dd, J = 14.5 and 4.6 Hz, 1H), 4.27−3.93 (m, 4H),
1.64 (s, 9H), 1.63 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 28.0, 43.6,
43.7, 45.0, 45.4, 67.97, 68.02, 72.2, 84.9, 115.4, 115.5, 123.1, 123.3,
123.5, 124.6, 124.7, 128.4, 128.5, 128.6, 128.7, 129.2, 129.4, 134.4, 134.5,
140.2, 140.5, 148.6, 168.7, 169.1, 172.5, 173.2; HPLC-MS (ESI) tr =
11.0 min, 11.2 min; [M + Na]+ = 463.3 m/z, [2M + Na]+ = 903.5 m/z.
Anal. Calcd for C23H24N2O7 (440.16): C, 62.72; H, 5.49; N, 6.36.
Found: C, 62.71; H, 5.48; N, 6.35.
3-((R)-1-(Benzyloxy)-3-nitro-1-oxopropan-2-yl)-2-oxoindoline:
mixture of two diastereoisomers, gum; 1H NMR (400 MHz, CDCl3) δ
8.42 (bs, 2H), 7.39−7.30 (m, 6H), 7.30−7.20 (m, 7H), 7.18 (d, J = 7.5
Hz, 1H), 7.08−6.91 (m, 3H), 6.85 (t, J = 8.4 Hz, 1H), 5.26−5.08 (m,
4H), 5.01 (dd, J = 14.6 and 9.5 Hz, 1H), 4.76 (dd, J = 14.8 and 9.0 Hz,
1H), 4.51−4.38 (m, 2H), 4.16 (m, 1H), 4.10 (m, 1H), 3.98−3.91 (m,
2H); 13C NMR (50 MHz, CDCl3) δ 43.0, 43.3, 44.98, 45.03, 67.8, 67.9,
71.9, 72.3, 110.3, 110.4, 122.96, 122.99, 124.3, 124.4, 124.6, 124.8, 128.4,
128.51, 128.54, 128.6, 128.7, 129.1, 129.3, 134.6, 134.7, 141.2, 141.5,
169.1, 169.7, 176.3, 176.5; HPLC-MS (ESI) tr = 8.4 min, 8.7 min;
[M + H]+ = 341.1 m/z, [M + Na]+ = 363.2 m/z. Anal. Calcd for
C18H16N2O5 (340.11): C, 63.52; H, 4.74; N, 8.23. Found: C, 63.42; H,
4.73; N, 8.22. CSP-HPLC: OJ 90/10 n-Hex/IPA for 10 min, then up to
80/20 in 20 min, 80/20 up to 105 min; flow rate 0.5 mL/min at room
temperature; λ 214 nm; tr(isomer A) = 77.1 min (minor), 90.9 min
(major); tr(isomer B) = 84.8 min (major), 100.9 min (minor).
tert-Butyl 3-((R)-1-(tert-butoxy)-3-nitro-1-oxopropan-2-yl)-2-ox-
oindoline-1-carboxylate (3j): mixture of two diastereoisomers; 99%
yield (40 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.1 Hz,
1H), 7.86 (d, J = 8.1 Hz, 1H), 7.40−7.32 (m, 2H), 7.28−7.14 (m, 4H),
5.06 (dd, J = 14.2 and 9.0 Hz, 1H), 4.88 (dd, J = 14.7 and 8.1 Hz, 1H),
4.69 (dd, J = 14.7 and 6.0 Hz, 1H), 4.49 (dd, J = 14.1 and 5.6 Hz, 1H),
4.15 (ddd, J = 8.9 and 5.7 and 2.9 Hz, 1H), 4.00 (ddd, J = 8.1 and 6.0 and
3.3 Hz, 1H), 3.93 (d, J = 3.2 Hz, 1H), 3.82 (d, J = 2.8 Hz, 1H), 1.65 (s,
9H), 1.64 (s, 9H), 1.30 (s, 9H), 1.19 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ 27.3, 27.5, 28.1, 44.5, 44.9, 45.1, 45.5, 72.9, 73.3, 83.5, 84.8,
115.2, 115.3, 123.5, 123.6, 123.7, 124.3, 124.6, 129.0, 129.3, 140.3, 140.7,
148.9, 167.4, 167.9, 172.8, 173.4; HPLC-MS (ESI) tr = 10.8 min,
11.1 min; [M + Na]+ = 429.4 m/z, [2M + Na]+ = 835.5 m/z. Anal. Calcd
6-Chloro-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindo-
line: mixture of two diastereoisomers, gum; 1H NMR (400 MHz,
CDCl3) δ 8.33 (bs, 2H), 7.19−7.02 (m, 4H), 6.95 (s, 2H), 4.99 (dd, J =
14.4 and 9.0 Hz, 1H), 4.81 (dd, J = 14.7 and 8.3 Hz, 1H), 4.57 (dd, J =
14.7 and 5.5 Hz, 1H), 4.49 (dd, J = 14.4 and 5.1 Hz, 1H), 4.26−4.11 (m,
4H), 4.08 (ddd, J = 8.6 and 5.5 and 3.4 Hz, 1H), 4.01 (m, 1H), 3.93−
3.87 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 13.8, 13.9, 43.1, 43.3, 44.5, 44.6, 62.26, 62.34, 72.1,
72.3, 110.9, 122.9, 123.0, 123.37, 123.42, 125.28, 125.32, 135.0, 135.2,
142.4, 168.9, 169.5, 176.4, 176.7; HPLC-MS (ESI) tr = 7.3 min, 7.7 min;
[M + Na]+ = 335.1 m/z. Anal. Calcd for C13H13ClN2O5 (312.05): C,
49.93; H, 4.19; N, 8.96. Found: C, 49.77; H, 4.18; N, 8.93. CSP-HPLC: IC
90/10 n-Hex/IPA for 35 min, then up to 80/20 in 15 min, 80/20 for 10 min,
then up to 70/30 in 5 min, 70/30 for 5 min, then up to 1/1 in 2 min, 1/1
up to 73 min; flow rate 0.6 mL/min at room temperature; λ 254 nm;
tr(isomer A) = 33.4 min (major), 52.7 min (minor); tr(isomer B) = 44.1 min
(minor), 68.4 min (major).
tert-Butyl 7-bromo-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-
oxoindoline-1-carboxylate (3g): mixture of two diastereoisomers;
82% yield (37 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.56−7.47 (m,
2H), 7.22−7.16 (m, 2H), 7.05 (t, J = 7.8 Hz, 2H), 5.01 (dd, J = 14.4 and
9.0 Hz, 1H), 4.88 (dd, J = 14.9 and 7.5 Hz, 1H), 4.74 (dd, J = 14.9 and 6.4
Hz, 1H), 4.44 (dd, J = 14.4 and 5.1 Hz, 1H), 4.20−4.05 (m, 6H), 4.04 (d,
J = 3.9 Hz, 1H), 3.99 (d, J = 3.2 Hz, 1H), 1.66 (s, 9H), 1.65 (s, 9H), 1.15
(t, J = 7.6 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 13.6, 13.7, 27.7, 43.7, 44.0, 45.2, 45.6, 62.5, 72.3, 72.4, 86.0, 86.1, 106.5,
106.6, 122.6, 122.8, 125.49, 125.54, 127.0, 127.6, 134.0, 134.3, 139.3,
139.5, 147.5, 168.4, 168.6, 173.0, 173.7; HPLC-MS (ESI) tr = 10.5 min;
[M + Na]+ = 479.1, 481.2 m/z. Anal. Calcd for C18H21BrN2O7 (456.05):
C, 47.28; H, 4.63; N, 6.13. Found: C, 47.13; H, 4.64; N, 6.14.
7-Bromo-3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-2-oxoindo-
line: mixture of two diastereoisomers, gum; 1H NMR (400 MHz,
CDCl3) δ 8.07 (bs, 2H), 7.43 (d, J = 3.7 Hz, 1H), 7.41 (d, J = 3.7 Hz,
1H), 7.17 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.00−6.93 (m,
2H), 5.01 (dd, J = 14.4 and 9.0 Hz, 1H), 4.81 (dd, J = 14.8 and 8.4 Hz,
1H), 4.60 (dd, J = 14.8 and 5.5 Hz, 1H), 4.49 (dd, J = 14.5 and 4.6 Hz,
1H), 4.26−3.99 (m, 8H), 1.21 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz,
3H); 13C NMR (50 MHz, CDCl3) δ 13.7, 13.8, 43.2, 43.3, 46.0, 46.2,
62.2, 62.3, 72.1, 72.4, 103.2, 103.3, 123.1, 124.1, 126.30, 126.34, 131.8,
132.0, 140.8, 141.04, 168.8, 169.3, 174.8, 175.2; HPLC-MS (ESI) tr =
7.3 min, 7.6 min; [M + H]+ = 357.2, 359.1 m/z, [M + Na]+ = 379.1, 381.0
m/z. Anal. Calcd for C13H13BrN2O5 (356.00): C, 43.72; H, 3.67; N, 7.84.
Found: C, 43.71; H, 3.68; N, 7.81. CSP-HPLC: IC 85:15 n-Hex/IPA for
15 min, then up to 80/20 in 10 min, 80/20 for 10 min, then up
to 70/30 in 10 min, 70/30 up to 70 min; flow rate 0.5 mL/min at 14 °C; λ
214 nm; tr(isomer A) = 48.4 min (major), 50.7 min (minor);
tr(isomer B) = 57.4 min (major), 66.1 min (minor).
tert-Butyl 3-((R)-1-ethoxy-3-nitro-1-oxopropan-2-yl)-5-methoxy-
2-oxoindoline-1-carboxylate (3h): mixture of two diastereoisomers;
89% yield (36 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 2.9
Hz, 1H), 7.77 (d, J = 2.9 Hz, 1H), 6.90−6.84 (m, 2H), 6.80 (dd, J = 2.6
and 1.1 Hz, 1H), 6.77 (dd, J = 2.6 and 1.2 Hz, 1H), 4.97 (dd, J = 14.5 and
I
dx.doi.org/10.1021/jo402099p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
for C20H26N2O7 (406.17): C, 59.10; H, 6.45; N, 6.89. Found: C, 58.95;
H, 6.44; N, 6.91.
125.4, 129.1, 129.2, 129.4, 129.5, 140.8, 141.3, 142.1, 142.9, 147.6, 147.9,
176.4, 176.7; HPLC-MS (ESI) tr = 7.5 min, 7.6 min; [M + H]+ = 328.3
m/z, [M + Na]+ = 350.1 m/z. Anal. Calcd for C16H13N3O5 (327.09): C,
58.72; H, 4.00; N, 12.84. Found: C, 58.52; H, 4.01; N, 12.85. CSP-
HPLC: IC 85:15 n-Hex/IPA for 20 min, then up to 80/20 in 20 min, 80/
20 up to 52 min; flow rate 0.5 mL/min at room temperature; λ 214 nm;
tr(isomer A) = 39.0 min (minor), 46.8 min (major); tr(isomer B) = 43.0
min (major), 45.5 min (minor).
3-((R)-1-(tert-Butoxy)-3-nitro-1-oxopropan-2-yl)-2-oxoindoline:
mixture of two diastereoisomers, syrup; 1H NMR (400 MHz, CDCl3) δ
8.06 (bs, 2H), 7.32−7.25 (m, 2H), 7.25−7.19 (m, 2H), 7.11−7.03 (m,
2H), 6.95−6.88 (m, 2H), 5.00 (dd, J = 14.2 and 9.3 Hz, 1H), 4.80 (dd,
J = 14.7 and 9.1 Hz, 1H), 4.46 (ddd, J = 14.2 and 12.1 and 5.0 Hz, 2H),
4.08−3.96 (m, 2H), 3.91 (d, J = 3.5 Hz, 1H), 3.81 (d, J = 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 43.9, 44.0, 45.00, 45.2, 72.3, 73.1, 109.9,
tert-Butyl 3-((S)-3,3-dimethyl-1-nitrobutan-2-yl)-2-oxoindoline-1-
carboxylate (3m): mixture of two diastereoisomers; 62% yield (22 mg),
gum; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.3 Hz, 1H), 7.79 (d,
J = 8.2 Hz, 1H), 7.38−7.11 (m, 6H), 4.71−4.47 (m, 4H), 3.82 (s, 1H),
3.74 (s, 1H), 3.05 (ddd, J = 10.4 and 4.7 and 1.7 Hz, 1H), 2.86 (m, 1H),
1.65 (s, 18H), 1.13 (s, 18H); 13C NMR (50 MHz, CDCl3) δ 28.1, 28.3,
28.6, 33.7, 34.1, 45.3, 45.4, 48.0, 49.7, 73.7, 74.1, 84.4, 84.5, 115.0, 115.6,
123.3, 124.0, 124.4, 124.5, 127.4, 128.4, 128.8, 139.8, 140.8, 149.0, 149.1,
174.0, 175.7; HPLC-MS (ESI) tr = 10.8 min, 11.2 min; [M + Na]+ =
385.2 m/z, [2M + Na]+ = 747.7 m/z. Anal. Calcd for C19H26N2O5
(362.18): C, 62.97; H, 7.23; N, 7.73. Found: C, 62.95; H, 7.24; N, 7.74.
3-((S)-3,3-Dimethyl-1-nitrobutan-2-yl)-2-oxoindoline: mixture of
two diastereoisomers, amorphous solid; 1H NMR (400 MHz, CDCl3) δ
8.32 (bs, 1H), 8.22 (bs, 1H), 7.31−7.16 (m, 4H), 7.13−6.98 (m, 2H),
6.95−6.81 (m, 2H), 4.74−4.47 (m, 4H), 3.72 (s, 1H), 3.66 (s, 1H), 3.06
(ddd, J = 9.9 and 4.9 and 1.7 Hz, 1H), 2.90 (ddd, J = 8.6 and 5.1 and 1.8
Hz, 1H), 1.14 (s, 18H); 13C NMR (50 MHz, CDCl3) δ 28.4, 28.5, 33.7,
34.1, 45.4, 47.1, 48.8, 74.2, 74.6, 109.8, 110.3, 122.3, 122.7, 123.9, 125.1,
126.1, 128.3, 128.6, 129.1, 140.8, 141.8, 177.6, 179.5; HPLC-MS (ESI)
tr = 7.8 min, 8.4 min; [M + H]+ = 263.1 m/z, [M + Na]+ = 285.2 m/z,
[2M + H]+ = 525.3 m/z. Anal. Calcd for C14H18N2O3 (262.13): C,
64.10; H, 6.92; N, 10.68. Found: C, 63.88; H, 6.94; N, 10.70. CSP-
HPLC: IC 90/10 n-Hex/IPA for 15 min, then up to 80/20 in 10 min,
80/20 for 10 min, then up to 70/30 in 5 min, 70/30 for 5 min, then up to
1/1 in 1 min, 1/1 up to 53 min; flow rate 0.5 mL/min at room
temperature; λ 254 nm; tr(isomer A) = 31.5 min (major), 39.2 min
(minor); tr(isomer B) = 45.9 min (major), 47.7 min (minor).
tert-Butyl 3-((R)-1-Ethoxy-2-methyl-3-nitro-1-oxopropan-2-yl)-2-
oxoindoline-1-carboxylate (3n): mixture of two diastereoisomers; 57%
yield (22 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.92−7.78 (m, 2H),
7.59 (d, J = 7.6 Hz, 1H), 7.41−7.29 (m, 2H), 7.22−7.12 (m, 2H), 7.04
(d, J = 7.6 Hz, 1H), 5.38 (d, J = 13.2 Hz, 1H), 5.15 (d, J = 13.2 Hz, 2H),
4.97 (d, J = 12.4 Hz, 1H), 4.46−4.33 (m, 4H), 3.95 (s, 1H), 3.94 (s, 1H),
1.65 (s, 9H), 1.64 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 6.8 Hz,
3H), 1.13 (s, 6H); 13C NMR (50 MHz, CDCl3) (major isomer) δ 13.9,
14.6, 28.1, 49.1, 49.9, 62.2, 80.0, 85.1, 115.0, 122.6, 124.6, 125.1, 129.4,
140.8, 148.6, 171.6, 172.8; HPLC-MS (ESI) tr = 10.8 min; [M + Na]+ =
415.4 m/z, [2M + Na]+ = 807.5 m/z. Anal. Calcd for C19H24N2O7
(392.16): C, 58.16; H, 6.16; N, 7.14. Found: C, 58.08; H, 6.18; N, 7.15.
3-((R)-1-Ethoxy-2-methyl-3-nitro-1-oxopropan-2-yl)-2-oxoindo-
line: mixture of two diastereoisomers, gum; 1H NMR (400 MHz,
CDCl3) δ 7.68 (bs, 1H), 7.57 (bs, 1H), 7.40−7.19 (m, 3H), 7.09−6.94
(m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.46 (d, J =
13.2 Hz, 1H), 5.17 (d, J = 12.8 Hz, 1H), 5.15 (d, J = 13.2 Hz, 1H), 4.93
(d, J = 12.8 Hz, 1H), 4.48−4.34 (m, 4H), 3.85 (s, 2H), 1.41 (t, J = 7.2 Hz,
3H), 1.37 (t, J = 7.2 Hz, 3H), 1.13 (s, 6H); 13C NMR (100 MHz,
CDCl3) (major isomer) δ 14.1, 14.3, 48.4, 49.5, 62.2, 79.8, 109.8, 122.9,
124.3, 125.2, 129.2, 141.4, 171.9, 175.7; HPLC-MS (ESI) tr = 6.7 min,
7.4 min; [M + H]+ = 293.3 m/z, [M + Na]+ = 315.2 m/z, [2M + Na]+ =
607.4 m/z. Anal. Calcd for C14H16N2O5 (292.11): C, 57.53; H, 5.52; N,
9.58. Found: C, 57.51; H, 5.54; N, 9.56. CSP-HPLC: IC 90/10 n-Hex/
IPA for 10 min, then up to 80/20 in 5 min, 80/20 for 15 min, then up to
70/30 in 15 min, 70/30 up to 47 min; flow rate 0.5 mL/min at room
temperature; λ 214 nm; tr(isomer A) = 23.2 min (major), 29.0 min
(minor); tr(isomer B) = 35.3 min (minor), 41.6 min (major).
110.0, 122.9, 122.8, 124.4, 124.5, 125.2, 125.4, 129.0, 129.2, 141.1, 141.6,
167.8, 168.7, 176.2, 176.3; HPLC-MS (ESI) tr = 7.3 min, 7.9 min; [M +
H]+ = 251.1 m/z. Anal. Calcd for C11H10N2O5 (250.06): C, 52.80; H,
4.03; N, 11.20. Found: C, 52.74; H, 4.01; N, 11.23. CSP-HPLC: OJ 90/
10 n-Hex/IPA for 10 min, then up to 80/20 in 20 min, 80/20 up to 56 min;
flow rate 0.5 mL/min at room temperature; λ 214 nm; tr(isomer A) =
27.6 min (major), 38.4 min (minor); tr(isomer B) = 33.0 min (major),
52.2 min (minor).
tert-Butyl 3-((S)-2-nitro-1-phenylethyl)-2-oxoindoline-1-carboxy-
late (3k): mixture of two diastereoisomers; 52% yield (20 mg), gum; 1H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.0 Hz,
1H), 7.35−7.08 (m, 10H), 7.08−6.95 (m, 5H), 6.63 (d, J = 7.5 Hz, 1H),
5.43−5.29 (m, 2H), 5.12 (dd, J = 13.9 and 7.9 Hz, 1H), 4.92 (dd, J = 13.1
and 9.0 Hz, 1H), 4.25 (td, J = 7.6 and 3.8 Hz, 1H), 4.03 (m, 1H), 3.92 (d,
J = 3.7 Hz, 1H), 3.80 (d, J = 7.8 Hz, 1H), 1.65 (s, 18H); 13C NMR (100
MHz, CDCl3) δ 27.99, 28.01, 45.5, 46.0, 48.2, 48.7, 75.7, 77.1, 84.5, 84.6,
114.9, 115.0, 123.9, 124.1, 124.3, 124.4, 124.6, 124.8, 128.0, 128.2, 128.4,
128.48, 128.53, 128.7, 128.8, 129.0, 134.1, 135.2, 140.2, 140.4, 148.5,
148.6, 173.5, 173.9; HPLC-MS (ESI) tr = 10.6 min; [M + Na]+ = 405.2
m/z. Anal. Calcd for C21H22N2O5 (382.15): C, 65.96; H, 5.80; N, 7.33.
Found: C, 65.87; H, 5.81; N, 7.32.
3-((S)-2-Nitro-1-phenylethyl)-2-oxoindoline: mixture of two dia-
stereoisomers, amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.33−
7.00 (m, 14H), 6.93−6.85 (m, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.67 (d, J =
7.7 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.48 (dd, J = 13.1 and 6.7 Hz, 1H),
5.35 (dd, J = 13.7 and 7.3 Hz, 1H), 5.14 (dd, J = 13.7 and 8.0 Hz, 1H),
4.92 (dd, J = 13.1 and 9.1 Hz, 1H), 4.29 (dt, J = 7.7 and 4.0 Hz, 1H), 4.01
(m, 1H), 3.84 (d, J = 3.9 Hz, 1H), 3.73 (d, J = 8.3 Hz, 1H); 13C NMR (50
MHz, CDCl3) δ 44.5, 45.3, 47.9, 48.6, 75.8, 77.5, 109.8, 110.0, 122.4,
122.5, 124.4, 125.4, 126.26, 126.32, 128.0, 128.1, 128.40, 128.45, 128.50,
128.53, 128.8, 134.9, 136.0, 141.2, 141.5, 177.4, 177.5; HPLC-MS (ESI)
tr = 7.6 min; [M + H]+ = 283.3 m/z, [M + Na]+ = 305.3 m/z. Anal. Calcd
for C16H14N2O3 (282.10): C, 68.07; H, 5.00; N, 9.92. Found: C, 67.94;
H, 5.00; N, 9.96. CSP-HPLC: IC 90/10 n-Hex/IPA for 10 min, then up
to 80/20 in 5 min, 80/20 for 15 min, then up to 70/30 in 5 min, 70/30
up to 36 min; flow rate 0.5 mL/min at room temperature; λ 230 nm;
tr(isomer A) = 25.0 min (minor), 26.8 min (major); tr(isomer B) = 29.7
min (major), 31.7 min (minor).
tert-Butyl 3-((S)-2-nitro-1-(4-nitrophenyl)ethyl)-2-oxoindoline-1-
carboxylate (3l): mixture of two diastereoisomers; 98% yield (42 mg),
1
gum; H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 2H), 8.00
(d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H),
7.40−7.30 (m, 2H), 7.30−7.17 (m, 6H), 7.16−7.07 (m, 1H), 6.85 (d, J =
7.6 Hz, 1H), 5.42−5.22 (m, 3H), 4.97 (dd, J = 13.4 and 9.5 Hz, 1H), 4.37
(ddd, J = 8.5 and 6.8 and 3.9 Hz, 1H), 4.32−4.23 (m, 1H), 3.98 (d, J =
3.8 Hz, 1H), 3.88 (d, J = 6.7 Hz, 1H), 1.58 (s, 18H); 13C NMR (50 MHz,
CDCl3) δ 27.97, 28.00, 45.1, 45.5, 48.1, 48.5, 75.4, 85.1, 115.2, 115.4,
123.3, 123.6, 123.7, 123.8, 124.4, 124.5, 124.7, 129.2, 129.3, 129.5, 129.6,
140.0, 140.5, 141.5, 142.4, 147.7, 147.9, 148.2, 148.3, 172.8, 173.4;
HPLC-MS (ESI) tr = 10.7 min; [M + Na]+ = 450.2 m/z, [2M + Na]+ =
877.7 m/z. Anal. Calcd for C21H21N3O7 (427.14): C, 59.01; H, 4.95; N,
9.83. Found: C, 58.85; H, 4.94; N, 9.81.
3-((S)-2-Nitro-1-(4-nitrophenyl)ethyl)-2-oxoindoline: mixture of
two diastereoisomers, amorphous solid; 1H NMR (400 MHz, CDCl3)
δ 8.12 (d, J = 8.9 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.91 (bs, 1H), 7.38−
7.23 (m, 6H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.01 (t, J =
7.6 Hz, 1H), 6.87−6.80 (m, 2H), 6.70 (d, J = 7.8 Hz, 1H), 5.41−5.26 (m,
3H), 4.97 (dd, J = 13.3 and 9.4 Hz, 1H), 4.41 (ddd, J = 8.3 and 6.9 and
4.0 Hz, 1H), 4.27 (dt, J = 9.4 and 6.7 Hz, 1H), 3.90 (d, J = 3.9 Hz, 1H),
3.81 (d, J = 6.9 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 44.3, 44.9, 47.8,
48.3, 75.4, 76.6, 110.2, 110.4, 122.9, 123.0, 123.6, 123.9, 124.3, 125.0,
tert-Butyl 3-((2R,3S)-1-ethoxy-3-nitro-1-oxobutan-2-yl)-2-oxoin-
doline-1-carboxylate (anti-4b): mixture of two diastereoisomers;
1
71% yield (28 mg), gum; H NMR (400 MHz, CDCl3) δ 7.84 (t, J =
8.6 Hz, 2H), 7.39−7.29 (m, 4H), 7.17 (t, J = 7.7 Hz, 2H), 5.67 (dq, J =
9.9 and 6.8 Hz, 1H), 5.30 (dq, J = 9.2 and 6.3 Hz, 1H), 3.99−3.91 (m,
4H), 3.91−3.84 (m, 1H), 3.80 (dd, J = 9.3 and 4.1 Hz, 1H), 3.74 (d, J =
4.3 Hz, 1H), 3.62 (d, J = 4.0 Hz, 1H), 1.78 (d, J = 6.5 Hz, 3H), 1.64
J
dx.doi.org/10.1021/jo402099p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 21H), 0.99 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 13.5, 13.6, 18.1, 18.9, 28.0, 28.1, 44.1, 45.3, 50.6,
51.5, 61.8, 61.8, 79.5, 81.8, 84.5, 84.7, 115.1, 115.2, 123.4, 123.7, 124.0,
124.4, 124.5, 124.6, 129.1, 129.3, 140.4, 140.5, 148.9, 149.1, 167.9, 168.1,
172.8, 172.9; HPLC-MS (ESI) tr = 10.3 min, 10.4 min; [M + Na]+ =
415.3 m/z. Anal. Calcd for C19H24N2O7 (392.16): C, 58.16; H, 6.16; N,
7.14. Found: C, 57.98; H, 6.18; N, 7.14.
C22H28N2O9 (464.18): C, 56.86; H, 6.08; N, 6.03. Found: C, 56.69; H,
6.08; N, 6.05.
(2R,3S)-1-Ethyl 6-methyl 3-nitro-2-(2-oxoindolin-3-yl)-
1
hexanedioate: mixture of two diastereoisomers, gum; H NMR (400
MHz, CDCl3) δ 7.71−7.50 (bs, 2H), 7.34−7.20 (m, 4H), 7.05 (t, J = 8.0
Hz, 2H), 6.90−6.81 (m, 2H), 5.68−5.59 (m, 1H), 5.41−5.29 (m, 1H),
4.05−3.92 (m, 4H), 3.86 (dd, J = 10.0 and 4.4 Hz, 1H), 3.74 (dd, J = 9.2
and 4.4 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 3H), 3.59 (d, J = 4.4 Hz, 1H), 3.51
(d, J = 4.4 Hz, 1H), 2.54−2.39 (m, 6H), 2.28−2.20 (m, 2H), 1.03−0.94
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 13.6, 13.7, 27.4, 27.7, 29.9,
30.4, 43.9, 44.9, 49.4, 49.7, 51.9, 61.8, 61.9, 83.5, 86.1, 109.6, 109.7,
122.6, 122.9, 124.5, 124.9, 125.2, 125.3, 129.0, 129.1, 141.2, 141.4,
168.0, 168.4, 171.9, 171.9, 175.7, 175.9; HPLC-MS (ESI) tr = 7.3 min;
[M + H]+ = 365.3 m/z, [M + Na]+ = 387.2 m/z, [2M + Na]+ = 751.5
m/z. Anal. Calcd for C17H20N2O7 (364.13): C, 56.04; H, 5.53; N, 7.69.
Found: C, 55.83; H, 5.53; N, 7.68. CSP-HPLC: IC 80/20 n-Hex/IPA for
10 min, then up to 75/25 in 5 min, 75/25 for 25 min, then up to 65/35 in
15 min, 65/35 up to 67 min; flow rate 0.5 mL/min at room temperature;
λ 254 nm; tr(isomer A) = 26.8 min (major), 33.3 min (minor);
tr(isomer B) = 34.5 min (minor), 63.1 min (major).
tert-Butyl 3-((2R,3S)-1-ethoxy-3-nitro-1-oxo-4-phenylbutan-2-yl)-
2-oxoindoline-1-carboxylate (anti-4e): mixture of two diaster-
eoisomers; 72% yield (34 mg), amorphous solid; 1H NMR (400
MHz, CDCl3) δ 7.88−7.78 (m, 2H), 7.39−7.24 (m, 12H), 7.22−7.13
(m, 4H), 5.86 (ddd, J = 4.4 and 8.4 and 10.4 Hz, 1H), 5.46 (dt, J = 2.8
and 10.4 Hz, 1H), 3.98−3.84 (m, 6H), 3.67 (d, J = 4.0 Hz, 1H), 3.53
(d, J = 2.8 Hz, 1H), 3.45 (dd, J = 2.8 and 14.4 Hz, 1H), 3.32 (dd, J = 10.8
and 14.4 Hz, 1H), 3.28−3.16 (m, 2H), 1.66 (s, 9H), 1.65 (s, 9H), 0.97 (t,
J = 7.2 Hz, 3H), 0.95 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
13.4, 13.5, 28.0, 28.1, 39.0, 39.1, 44.2, 45.6, 49.8, 50.7, 61.9, 62.0, 84.6,
84.7, 85.7, 89.2, 115.1, 115.2, 123.0, 123.7, 123.8, 124.4, 124.6, 124.7,
127.7, 127.8, 128.8, 128.8, 128.9, 128.9, 129.0, 129.1, 129.3, 134.1, 135.1,
140.4, 140.5, 148.9, 168.0, 168.0, 172.4, 172.9; HPLC-MS (ESI) tr =12.1min,
12.4 min; [M + Na]+ = 491.3 m/z, [2M + Na]+ = 959.6 m/z. Anal. Calcd
for C25H28N2O7 (468.19): C, 64.09; H, 6.02; N, 5.98. Found: C, 64.02; H,
6.00; N, 6.00.
3-((2R,3S)-1-Ethoxy-3-nitro-1-oxobutan-2-yl)-2-oxoindoline: mix-
1
ture of two diastereoisomers, amorphous solid; H NMR (400 MHz,
CDCl3) δ 8.10 (bs, 1H), 8.01 (bs, 1H), 7.34−7.19 (m, 4H), 7.12−7.01
(m, 2H), 6.94−6.83 (m, 2H), 5.62 (dq, J = 9.6 and 6.9 Hz, 1H), 5.36 (dq,
J = 8.6 and 6.6 Hz, 1H), 4.08−3.96 (m, 4H), 3.90 (dd, J = 9.6 and 4.4 Hz,
1H), 3.77 (dd, J = 8.5 and 5.2 Hz, 1H), 3.70 (d, J = 4.4 Hz, 1H), 3.60
(d, J = 5.2 Hz, 1H), 1.77 (d, J = 6.6 Hz, 3H), 1.62 (d, J = 6.9 Hz, 3H),
1.02, (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 13.67, 13.72,
17.4, 18.7, 44.0, 44.8, 49.8, 50.4, 61.68, 61.73, 79.5, 81.6, 109.8, 109.9,
122.5, 122.8, 124.6, 125.2, 125.3, 125.4, 128.9, 129.0, 141.2, 141.4, 168.3,
168.7, 176.3; HPLC-MS (ESI) tr = 6.9 min, 7.0 min; [M + H]+ = 293.3
m/z, [M + Na]+ = 315.2 m/z, [2M + Na]+ = 607.4 m/z. Anal. Calcd for
C14H16N2O5 (292.11): C, 57.53; H, 5.52; N, 9.58. Found: C, 57.39; H,
5.51; N, 9.55. CSP-HPLC: IC 90/10 n-Hex/IPA for 10 min, then up to
80/20 in 5 min, 80/20 for 20 min, then up to 75/25 in 15 min, 75/25 up
to 53 min; flow rate 0.5 mL/min at room temperature; λ 214 nm;
tr(isomer A) = 24.4 min (major), 31.5 min (minor); tr(isomer B) = 39.8
min (minor), 47.0 min (major).
tert-Butyl 3-((2R,3S)-1-ethoxy-3-nitro-1-oxopentan-2-yl)-2-oxoin-
doline-1-carboxylate (anti-4c): mixture of two diastereoisomers; 76%
yield (31 mg), gum; 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 8.0 Hz,
2H), 7.40−7.22 (m, 4H), 7.20−7.12 (m, 2H), 5.62 (ddd, J = 10.8 and 7.3
and 5.8 Hz, 1H), 5.16 (ddd, J = 10.3 and 8.3 and 5.0 Hz, 1H), 3.92 (q, J =
7.1 Hz, 2H), 3.89−3.81 (m, 3H), 3.77 (dd, J = 10.3 and 3.0 Hz, 1H), 3.62
(d, J = 4.3 Hz, 1H), 3.54−3.47 (m, 1H), 2.19−2.05 (m, 2H), 2.00−1.89
(m, 2H), 1.65 (s, 18H), 1.08 (t, J = 7.3 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H),
0.95 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 9.6, 10.5, 13.4, 13.5, 26.3, 26.6, 28.0, 28.1, 44.0, 45.6, 49.9,
50.8, 61.76, 61.78, 84.5, 84.6, 85.4, 88.9, 115.0, 115.1, 123.1, 123.6,
123.9, 124.4, 124.6, 124.7, 129.1, 129.2, 140.4, 140.5, 148.9, 149.1, 167.9,
168.1, 172.6, 172.9; HPLC-MS (ESI) tr = 10.9 min, 11.0 min; [M + Na]+ =
429.2 m/z. Anal. Calcd for C20H26N2O7 (406.17): C, 59.10; H, 6.45; N,
6.89. Found: C, 59.04; H, 6.43; N, 6.92.
3-((2R,3S)-1-Ethoxy-3-nitro-1-oxopentan-2-yl)-2-oxoindoline:
mixture of two diastereoisomers, gum; 1H NMR (400 MHz, CDCl3) δ
8.14 (bs, 2H), 7.39−7.17 (m, 4H), 7.14−6.98 (m, 2H), 6.95−6.81 (m,
2H), 5.60 (ddd, J = 10.6 and 8.4 and 4.7 Hz, 1H), 5.25−5.12 (m, 1H),
4.00−3.80 (m, 5H), 3.73 (dd, J = 9.9 and 3.7 Hz, 1H), 3.56 (d, J = 4.4 Hz,
1H), 3.45 (d, J = 3.7 Hz, 1H), 2.24−2.05 (m, 2H), 2.05−1.87 (m, 2H),
1.11−1.05 (m, 3H), 1.02 (t, J = 7.3 Hz, 3H), 0.99−0.91 (m, 6H); 13C
NMR (50 MHz, CDCl3) δ 9.7, 10.5, 13.5, 13.6, 26.2, 26.3, 44.1, 45.4,
49.3, 49.7, 61.6, 61.7, 85.5, 88.9, 109.9, 110.0, 122.5, 122.7, 124.4, 124.9,
125.3, 125.4, 128.9, 129.0, 141.6, 141.7, 168.2, 168.7, 176.7, 177.0;
HPLC-MS (ESI) tr = 7.8 min, 7.9 min; [M + H]+ = 307.3 m/z, [M +
Na]+ = 329.1 m/z, [2M + Na]+ = 635.5 m/z. Anal. Calcd for
C15H18N2O5 (306.12): C, 58.82; H, 5.92; N, 9.15. Found: C, 58.65; H,
5.91; N, 9.17. CSP-HPLC: IC 90/10 n-Hex/IPA for 10 min, then up to
80/20 in 5 min, 80/20 for 20 min, then up to 75/25 in 15 min, 75/25 up
to 58 min; flow rate 0.5 mL/min at room temperature; λ 230 nm;
tr(isomer A) = 21.9 min (major), 27.9 min (minor); tr(isomer B) = 32.6
min (minor), 51.0 min (major).
(2R,3S)-1-Ethyl 6-methyl 2-(1-(tert-butoxycarbonyl)-2-oxoindolin-
3-yl)-3-nitrohexanedioate (anti-4d): mixture of two diastereoisomers;
83% yield (39 mg), oil; 1H NMR (400 MHz, CDCl3) δ 7.91−7.79 (m,
2H), 7.40−7.28 (m, 4H), 7.22−7.13 (m, 2H), 5.70−5.60 (m, 1H),
5.41−5.26 (m, 1H), 4.06−3.92 (m, 3H), 3.92−3.77 (m, 1H), 3.72 (s,
3H), 3.70 (s, 3H), 3.65 (d, J = 4.0 Hz, 1H), 3.53 (d, J = 2.4 Hz, 1H),
2.60−2.19 (m, 8H), 1.65 (s, 18H), 0.98 (t, J = 7.2 Hz, 3H), 0.93 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 13.4, 13.5, 27.8, 27.9, 28.0,
28.1, 29.8, 30.3, 44.0, 45.4, 49.9, 50.7, 51.9, 61.9, 62.0, 83.5, 84.5, 84.7,
86.3, 115.1, 115.2, 123.6, 123.7, 124.4, 124.5, 124.6, 124.7, 129.1, 129.3,
140.4, 140.5, 148.9, 149.0, 167.7, 167.8, 171.8, 172.5, 172.8; HPLC-MS
(ESI) tr = 11.2 min; [M + Na]+ = 487.3 m/z. Anal. Calcd for
3-((2R,3S)-1-Ethoxy-3-nitro-1-oxo-4-phenylbutan-2-yl)-2-oxoin-
1
doline: mixture of two diastereoisomers, amorphous solid; H NMR
(400 MHz, CDCl3) δ 8.12−7.89 (bs, 2H), 7.40−7.21 (m, 13H), 7.17 (d,
J = 7.6 Hz, 1H), 7.13−7.00 (m, 2H), 6.96−6.82 (m, 2H), 5.88−5.79 (m,
1H), 5.53 (dt, J = 2.8 and 10.0 Hz, 1H), 4.08−3.92 (m, 4H), 3.90 (dd, J =
2.0 and 9.6 Hz, 1H), 3.82 (dd, J = 4.0 and 9.2 Hz, 1H), 3.63 (d, J = 4.0
Hz, 1H), 3.52 (d, J = 4.0 Hz, 1H), 3.43 (dd, J = 3.6 and 14.8 Hz, 1H),
3.35 (dd, J = 10.0 and 14.4 Hz, 1H), 3.27−3.10 (m, 2H), 1.06 (t, J = 7.6
Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 13.6,
13.7, 38.5, 39.0, 44.3, 45.3, 49.3, 49.7, 61.8, 61.9, 85.8, 89.1, 110.0, 110.2,
122.6, 122.9, 124.5, 124.7, 124.8, 125.3, 127.6, 127.7, 128.8, 128.8, 128.9,
128.9, 129.0, 129.1, 134.4, 135.3, 141.4, 141.6, 168.3, 168.6, 176.3,
176.6; HPLC-MS (ESI) tr = 9.1 min, 9.2 min; [M + H]+ = 369.4 m/z,
[M + Na]+ = 391.2 m/z, [2M + Na]+ = 759.5 m/z. Anal. Calcd for
C20H20N2O5 (368.14): C, 65.21; H, 5.47; N, 7.60. Found: C, 65.15; H,
5.48; N, 7.59. CSP-HPLC: IC 90/10 n-Hex/IPA for 15 min, then up to
80/20 in 10 min, 80/20 for 15 min, then up to 70/30 in 10 min, 70/30
for 5 min, then up to 1/1 in 5 min, 1/1 up to 76 min; flow rate 0.5 mL/min
at room temperature; λ 214 nm; tr(isomer A) = 27.2 min (major), 45.7 min
(minor); tr(isomer B) = 39.8 min (minor), 70.0 min (major).
tert-Butyl 3-((2R,3S)-1-ethoxy-2-methyl-3-nitro-1-oxobutan-2-yl)-
2-oxoindoline-1-carboxylate (5): major diastereoisomer; 72% yield
(29 mg), syrup; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H),
7.35 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.0 (d, J = 6.8 Hz, 1H),
5.50 (q, J = 6.8 Hz, 1H), 4.41−4.30 (m, 2H), 4.23 (s, 1H), 1.96 (d, J = 7.2
Hz, 3H), 1.65 (s, 9H), 1.36 (t, J = 6.8 Hz, 3H), 1.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 15.8, 15.8, 28.1, 48.9, 51.4, 62.2, 85.1, 88.5,
115.0, 124.1, 124.7, 129.2, 129.7, 140.7, 148.7, 170.6, 172.7; HPLC-MS
(ESI) tr = 11.6 min; [M + Na]+ = 429.4 m/z; [α]D25 = 19° (c = 0.48,
CH2Cl2). Anal. Calcd for C20H26N2O7 (406.17): C, 59.10; H, 6.45; N,
6.89. Found: C, 59.04; H, 6.45; N, 6.91.
3-((2R,3S)-1-Ethoxy-2-methyl-3-nitro-1-oxobutan-2-yl)-2-oxoin-
1
doline: major diastereoisomer, syrup; H NMR (400 MHz, CDCl3) δ
7.68 (bs, 1H), 7.05−6.97 (m, 2H), 6.90−6.84 (m, 2H), 5.59 (q, J = 6.4 Hz,
K
dx.doi.org/10.1021/jo402099p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 4.40−4.31 (m, 2H), 4.12 (s, 1H), 1.95 (d, J = 6.4 Hz, 3H), 1.37
(t, J = 7.2 Hz, 3H), 1.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 13.9,
15.7, 15.8, 48.6, 50.7, 62.0, 88.2, 109.7, 123.0, 124.8, 129.0, 129.1, 141.3,
175.6, 178.5; HPLC-MS (ESI) tr = 8.2 min; [M + H]+= 307.3 m/z, [M +
Synthesis of (R)-tert-Butyl 3-((2R,3S)-1-Ethoxy-3-nitro-1-ox-
obutan-2-yl)-3-((S)-2-nitro-1-phenylethyl)-2-oxoindoline-1-
carboxylate (8). (E)-tert-Butyl 3-(2-ethoxy-2-oxoethylidene)-2-oxoin-
doline-1-carboxylate (2c; 0.1 mmol, 31.7 mg) was added to a solution of
VI (10 mol %) in DCM (0.15 mL), and then nitroethane 1b (0.5 mmol)
was added at 0 °C. The mixture was stirred at the same temperature until
complete conversion (about 4.5 h). The solvent and the excess of 1b
were quickly removed under vacuum (without heating), DCM (0.3 mL)
was added, and trans-β-nitrostyrene (0.2 mmol) was finally added at
−40 °C. The conversion was monitored by TLC and 1H NMR (90% of
conversion after 24 h). The reaction mixture was quenched with 2 mL of
HCl (1 N) and extracted with ethyl acetate (3 × 2 mL). The organic
phases were collected and dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the product was purified by
flash chromatography on silica gel (cyclohexane/ethyl acetate 9/1): 76%
25
Na]+= 329.1 m/z; [α]D = 13° (c = 0.13, CH2Cl2). Anal. Calcd for
C15H18N2O5 (306.12): C, 58.82; H, 5.92; N, 9.15. Found: C, 58.58; H,
5.92; N, 9.16. CSP-HPLC: IC 90/10 n-Hex/IPA for 10 min, then up to
80/20 in 5 min, 80/20 up to 25 min; flow rate 0.5 mL/min at room
temperature; λ 214 nm; tr(major isomer) = 14.5 min (major), 17.8 min
(minor).
Synthesis of (S)-tert-Butyl 3-((R)-2,5-Dioxo-1-phenylpyrroli-
din-3-yl)-3-((2R,3S)-1-ethoxy-3-nitro-1-oxobutan-2-yl)-2-ox-
oindoline-1-carboxylate (6). (E)-tert-Butyl 3-(2-ethoxy-2-oxoethyli-
dene)-2-oxoindoline-1-carboxylate (2c; 0.1 mmol, 31.7 mg) was added
to a solution of VI (10 mol %) in DCM (0.15 mL), and then nitroethane
1b (0.5 mmol) was added at 0 °C. The mixture was stirred at the same
temperature until complete conversion (about 4.5 h). The solvent and
the excess of 1b were quickly removed under vacuum (without heating),
DCM (0.3 mL) was added, and N-phenylmaleimide (0.2 mmol) was
1
yield (41 mg), syrup. Major diastereoisomer: H NMR (400 MHz,
CDCl3) δ 7.88−7.82 (m, 1H), 7.65−7.41 (m, 3H), 7.23−7.15 (m, 2H),
7.10−6.97 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 5.37−5.23 (m, 2H), 4.52−
4.36 (m, 3H), 4.17 (dd, J = 3.2 and 10.4 Hz, 1H), 4.13 (d, J = 6.8 Hz,
1H), 1.64 (d, J = 7.2 Hz, 3H), 1.63 (s, 9H), 1.39 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 14.0, 17.8, 28.0, 50.0, 51.9, 55.8, 62.9, 75.1,
81.6, 85.1, 114.8, 115.2, 123.7, 124.4, 124.6, 126.3, 127.9, 128.4, 129.1,
129.8, 132.8, 139.8, 147.8, 168.9, 174.2; HPLC-MS (ESI) tr = 12.1 min;
[M + Na]+ = 564.3 m/z, [2M + Na]+ = 1105.7 m/z; [α]D25 = 16° (c =
0.91, CH2Cl2). Anal. Calcd for C27H31N3O9 (541.21): C, 59.88; H, 5.77;
N, 7.76. Found: C, 59.65; H, 5.77; N, 7.77. The absolute configuration of
the stereocenters generated in the addition of trans-β-nitrostyrene was
not experimentally determined, but it was indicated on the basis of that
obtained with the same catalyst promoting the same reaction on similar
substrates.22b
1
finally added at 0 °C. The conversion was monitored by TLC and H
NMR until full conversion (1.5 h). The crude reaction mixture was
directly purified by flash chromatography on silica gel (cyclohexane/
1
ethyl acetate 9/1): 81% yield (46 mg), gum; H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 8.4 Hz, 1H), 7.48−7.37 (m, 4H), 7.27−7.25
(m, 1H), 7.20−7.13 (m, 3H), 5.95−5.85 (m, 1H), 4.89 (d, J = 4.8 Hz,
1H), 3.87−3.81 (m, 3H), 2.92 (dd, J = 9.2 and 18.0 Hz, 1H), 2.11 (dd,
J = 5.2 and 18.0 Hz, 1H), 1.69 (s, 9H), 1.64 (d, J = 7.2 Hz, 3H), 0.94
(t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 13.6, 18.6, 28.1, 30.7,
42.0, 52.0, 52.8, 61.6, 79.0, 85.4, 115.7, 123.8, 124.4, 125.1, 126.4, 129.0,
129.2, 130.7, 131.1, 140.7, 144.6, 148.4, 168.2, 173.1, 174.4, 174.7;
HPLC-MS (ESI) tr = 10.9 min; [M −Boc + H]+ = 466.4 m/z, [M+H2O]+ =
583.4 m/z; [α]D25 = 107° (c = 0.71, CH2Cl2). Anal. Calcd for C29H31N3O9
(565.21): C, 61.59; H, 5.52; N, 7.43. Found: C, 61.49; H, 5.54; N, 7.40.
The absolute configuration of the stereocenters generated in the addition of
N-phenylmaleimide was not experimentally determined, but it was indicated
on the basis of that obtained with the same catalyst promoting the same
reaction on similar substrates.20
Synthesis of (R)-tert-Butyl 3-(2,2-Bis(phenylsulfonyl)ethyl)-3-
((2R,3S)-1-ethoxy-3-nitro-1-oxobutan-2-yl)-2-oxoindoline-1-
carboxylate (7). (E)-tert-Butyl 3-(2-ethoxy-2-oxoethylidene)-2-oxoin-
doline-1-carboxylate (2c; 0.1 mmol, 31.7 mg) was added to a solution of
VI (10 mol %) in DCM (0.15 mL), and then nitroethane 1b (0.5 mmol)
was added at 0 °C. The mixture was stirred at the same temperature until
complete conversion (about 4.5 h). The solvent and the excess of 1b
were quickly removed under vacuum (without heating), toluene
(0.6 mL) was added, and 1,1-bis(benzenesulfonyl)-ethylene (0.2 mmol)
was finally added at −10 °C. The conversion was monitored by TLC and
1H NMR until full conversion (overnight). The reaction mixture was
Synthesis of (S)-tert-Butyl 3-((2R,3S)-1-Ethoxy-3-nitro-1-ox-
obutan-2-yl)-2-oxo-3-((R)-3-oxocyclohexyl)indoline-1-carboxy-
late (9). (E)-tert-Butyl 3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-
carboxylate (2c; 0.1 mmol, 31.7 mg) was added to a solution of VI
(10 mol %) in DCM (0.15 mL), and then nitroethane 1b (0.5 mmol)
was added at 0 °C. The mixture was stirred at the same temperature until
complete conversion (about 4.5 h). The reaction mixture was quenched
with 2 mL of HCl (1 N) at 0 °C and extracted with DCM (3 × 2 mL).
The organic phases were collected and dried over Na2SO4. The solvent
was evaporated under reduced pressure (without heating), and the
crude mixture was directly used in the next transformation. Catalyst
X·3HCl (10 mol %), triethylamine (30 mol %), and benzoic acid
(20 mol %) were dissolved in toluene (0.3 mL). After the mixture was
stirred at room temperature for 10 min, 2-cyclohexen-1-one
(0.12 mmol) was added followed by the addition of crude 4b dissolved
in toluene (0.3 mL). The mixture was stirred at room temperature for
48 h. The crude reaction mixture was directly purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 85/15): 65%
yield (32 mg), gum; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz,
1H), 7.41 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 6.4 Hz, 1H), 7.20 (t, J = 6.8 Hz,
1H), 5.46−5.39 (m, 1H), 4.16 (d, J = 5.2 Hz, 1H), 3.95−3.87 (m, 2H),
2.45−2.33 (m, 3H), 2.10−2.03 (m, 2H), 1.90−1.78 (m, 2H), 1.66 (s,
9H), 1.58−1.46 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 13.6, 18.2, 24.0, 25.6, 28.1, 40.7,
42.3, 43.1, 52.7, 54.8, 61.7, 79.4, 85.0, 115.1, 124.4, 124.8, 126.1, 129.6,
140.7, 148.6, 168.2, 175.1, 208.7; HPLC-MS (ESI) tr = 10.7 min; [M −
Boc + H]+ = 389.3 m/z, [M + H2O]+ = 506.5 m/z, [2M + Na]+ = 999.8
quenched with 2 mL of HCl (1 N) at 0 °C and extracted with ethyl
acetate (3 × 3 mL). The organic phases were collected and dried over
Na2SO4. The solvent was evaporated under reduced pressure, and the
product was purified by flash chromatography on silica gel (cyclo-
1
hexane/ethyl acetate 8/2): 68% yield (48 mg), syrup; H NMR (400
MHz, CDCl3) δ 7.99−7.93 (m, 3H), 7.79 (d, J = 7.2 Hz, 2H), 7.73−7.66
(m, 2H), 7.61−7.50 (m, 5H), 7.44 (t, J = 7.6 Hz, 1H), 7.27−7.24 (m,
1H), 5.16−5.09 (m, 1H), 4.41 (dd, J = 3.2 and 6.0 Hz, 1H), 4.13 (d, J =
5.2 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 2.94 (dd, J = 5.6 and 16.0 Hz, 1H),
2.85 (dd, J = 2.8 and 16.0 Hz, 1H), 1.64 (s, 9H), 1.38 (d, J = 6.8 Hz, 3H),
1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 13.6, 17.4, 28.1,
29.6, 50.9, 55.9, 61.8, 79.2, 79.4, 84.8, 116.0, 124.7, 125.6, 126.2, 128.9,
129.0, 129.7, 130.1, 131.0, 134.5, 134.9, 135.6, 137.7, 140.7, 148.8, 168.0,
174.3; HPLC-MS (ESI) tr = 11.9 min; [M-Boc+H]+ = 601.3 m/z, [M +
25
m/z; [α]D = −13° (c = 1.02, CH2Cl2). Anal. Calcd for C25H32N2O8
(488.22): C, 61.46; H, 6.60; N, 5.73. Found: C, 61.35; H, 6.59; N, 5.75.
The absolute configuration of the stereocenters generated in the
addition of 2-cyclohexen-1-one was not experimentally determined, but
it was indicated on the basis of that obtained with the same catalyst
promoting the same reaction on similar substrates.10p
25
H2O]+ = 718.4 m/z; [α]D = 8° (c = 0.54, CH2Cl2). Anal. Calcd for
Synthesis of (S)-tert-Butyl 3-((2R,3S)-1-Ethoxy-3-nitro-1-ox-
obutan-2-yl)-2-oxo-3-((R)-4-oxobutan-2-yl)indoline-1-carboxy-
late (10). To a solution of catalyst XI (20 mol %) and crude product 4b
(0.1 mmol, prepared as described for product 9) in DCM (1 mL) at
−40 °C were added benzoic acid (20 mol %) and then crotonaldehyde
(0.15 mmol). After it was stirred at the same temperature for 24 h, the
reaction mixture was quenched with 2 mL of HCl (1 N) at 0 °C and
C33H36N2O11S2 (700.18): C, 56.56; H, 5.18; N, 4.00. Found: C, 56.38;
H, 5.17; N, 4.01. The absolute configuration of the stereocenter
generated in the addition of 1,1-bis(benzenesulfonyl)ethylene was not
experimentally determined, but it was indicated on the basis of that
obtained with the same catalyst promoting the same reaction on similar
substrates.21b
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extracted with DCM (3 × 2 mL). The organic phases were collected and
dried over Na2SO4. The solvent was evaporated under reduced pressure,
and the crude mixture was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 9/1): 71% yield (33 mg), gum; mixture of
two diastereoisomers; 1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 2.0
Hz, 1H), 9.61 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.43−7.32
(m, 4H), 7.20 (t, J = 7.6 Hz, 2H), 5.50−5.43 (m, 1H), 5.30−5.23 (m,
1H), 4.13 (d, J = 5.6 Hz, 1H), 4.12 (d, J = 5.6 Hz, 1H), 3.99−3.88 (m,
4H), 2.86−2.77 (m, 2H), 2.65 (d, J = 16.4 Hz, 1H), 2.53 (d, J = 17.6 Hz,
1H), 2.23 (ddd, J = 2.8, 10.8, and 14.0 Hz, 1H), 2.08 (ddd, J = 2.4 and
10.4 and 12.4 Hz, 1H), 1.66 (s, 18H), 1.53 (d, J = 6.8 Hz, 3H), 1.51
(d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H), 0.96
(d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 13.6, 13.7, 15.0, 18.1, 28.1, 32.6, 33.2, 45.4, 45.7, 53.0, 53.0,
54.7, 61.7, 61.8, 79.3, 79.9, 84.8, 84.9, 115.0, 115.1, 124.3, 124.4, 124.5,
124.7, 126.3, 126.3, 129.5, 140.3, 140.6, 148.6, 148.7, 168.1, 168.3, 175.5,
175.7, 199.5, 200.0; HPLC-MS (ESI) tr = 10.7 min; [M − Boc + H]+ =
363.4 m/z, [M + H2O]+ = 480.4 m/z, [M + Na]+ = 485.3 m/z, [2M +
Na]+ = 947.8 m/z. Anal. Calcd for C23H30N2O8 (462.20): C, 59.73; H,
6.54; N, 6.06. Found: C, 59.68; H, 6.52; N, 6.08. The absolute
configuration of the stereocenters generated in the addition of
crotonaldehyde was not experimentally determined, but it was indicated
on the basis of that obtained with the same catalyst promoting the same
reaction on similar substrates.8c
mixture was purified by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate 1/1): 90% yield, 68 mg, oil.
(R)-tert-Butyl 3-((2R,3S)-1-ethoxy-3-(hydroxyamino)-1-oxobutan-
2-yl)-2-oxoindoline-1-carboxylate (12a): 1H NMR (400 MHz,
CDCl3) δ 7.64 (bs, 1H), 7.28−7.23 (m, 1H), 7.15−7.06 (m, 1H),
7.02−6.97 (m, 2H), 4.44−4.37 (m, 1H), 4.27 (d, J = 9.6 Hz, 1H), 3.94−
3.76 (m, 2H), 3.20 (dd, J = 10.0 and 8.4 Hz, 1H), 1.54 (s, 9H), 1.44
(d, J = 5.6 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 13.5, 18.3, 28.4, 42.2, 48.8, 55.7, 61.5, 80.5, 118.9, 125.0, 127.3, 128.5,
129.7, 136.9, 153.4, 168.3, 169.4; HPLC-MS (ESI) tr = 7.0 min; [M −
Boc + H]+ = 279.4 m/z, [2M + Na]+ = 779.6 m/z; [α]D25 = −5° (c =
0.67, CH2Cl2). Anal. Calcd for C19H26N2O6 (378.18): C, 60.30; H, 6.93;
N, 7.40. Found: C, 60.28; H, 6.91; N, 7.39.
(S)-tert-Butyl 3-((2R,3S)-1-ethoxy-3-(hydroxyamino)-1-oxobutan-
2-yl)-2-oxoindoline-1-carboxylate (12b): 1H NMR (400 MHz,
CDCl3) δ 7.74 (bs, 1H), 7.32−7.27 (m, 1H), 7.18−6.99 (m, 3H),
4.31−4.18 (m, 3H), 3.97−3.91 (m, 1H), 2.87 (t, J = 8.4 Hz, 1H), 1.53 (s,
9H), 1.47 (d, J = 5.6 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 14.1, 19.0, 28.4, 50.5, 51.3, 56.6, 62.1, 80.3, 118.6, 124.6,
128.2, 128.4, 129.7, 137.2, 153.7, 169.3, 171.4; HPLC-MS (ESI) tr =
25
7.6 min; [M − Boc + H]+ = 279.2 m/z, [2M + Na]+ = 779.6 m/z; [α]D
=
8° (c = 0.93, CH2Cl2). Anal. Calcd for C19H26N2O6 (378.18): C, 60.30; H,
6.93; N, 7.40. Found: C, 60.10; H, 6.94; N, 7.39.
Procedure for the Stereoconvergent Epimerization to 12a. A
diastereomeric mixture of 12a and 12b (dr = 60/40; 0.1 mmol, 37.8 mg)
was dissolved in EtOH (0.7 mL), and NaHCO3 (10 drops of a saturated
solution) was added. The reaction mixture was stirred at room
temperature for 48 h, and the conversion was monitored by 1H NMR.
After completion, water (3 mL) was added to the mixture, and it was
extracted with ethyl acetate (3 × 3 mL). The organic phases were
collected and dried over Na2SO4. The solvent was evaporated under
reduced pressure, and compound 12a was obtained pure (90% yield,
34 mg, oil).
Synthesis of tert-Butyl 3-((2R,3S)-3-Amino-1-ethoxy-1-oxo-
butan-2-yl)-2-oxoindoline-1-carboxylate (11a,b). Compound 4b
(0.38 mmol, 149 mg) was dissolved in EtOH (5.5 mL), Raney nickel (6
drops of the commercially available suspension in water) was added, and
the reaction mixture was stirred at room temperature under an H2
balloon overnight. Then it was filtered and washed with ethyl acetate and
DCM. The solvent was removed under reduced pressure, and the
diastereomeric mixture of 11a and 11b (dr = 54/46) was obtained pure:
1
95% yield (131 mg), oil; mixture of two diastereoisomers; H NMR
Synthesis of ((2S,3R,3aR)-2,8-Dimethyl-2,3,3a,8-
tetrahydropyrrolo[2,3-b]indol-3-yl)methanol (13). anti-4b
(0.2 mmol, 78.5 mg) was dissolved in EtOH (3 mL), Raney nickel
(4 drops of the commercially available suspension in water) was added, and
the reaction mixture was stirred at room temperature under an H2 balloon
overnight. Then the mixture was filtered and washed with ethyl acetate
and DCM. The solvent was removed under reduced pressure, and the
diastereomeric mixture of 11a and 11b (dr = 54/46) was obtained pure.
The crude mixture was dissolved in acetone (1.5 mL), and K2CO3
(0.4 mmol) was added. The reaction mixture was stirred at 50 °C for
24 h, and the conversion was monitored by 1H NMR. After completion,
the solvent was removed, the residue was dissolved in water (5 mL), and
this solution was extracted with DCM (3 × 6 mL). The organic phases
were collected and dried over Na2SO4. The solvent was evaporated
under reduced pressure, and the crude product 11a was dissolved in
THF (5 mL). LiAlH4 (2 mmol) was added, and the mixture was heated
at 75 °C for 2 h. It was cooled to room temperature and quenched with
ethyl acetate (6 mL) and then H2O (1.2 mL). The resulting mixture was
filtered through Celite and washed with ethyl acetate and MeOH. The
filtrates were concentrated under reduced pressure, and the residue was
purified by flash chromatography on silica gel (DCM/MeOH 20/1),
providing compound 13: 72% yield over three steps, 31 mg, amorphous
solid; 1H NMR (400 MHz, CD3OD) δ 7.14 (t, J = 8.0 Hz, 1H), 7.01 (d, J =
7.2 Hz, 1H), 6.70−6.66 (m, 2H), 3.72 (d, J = 8.0 Hz, 1H), 3.64 (dd, J = 12.0
and 4.0 Hz, 1H) 3.60 (dd, J = 12.0 and 4.0 Hz, 1H), 3.59−3.53 (m, 1H),
2.80 (s, 3H), 2.10−2.04 (m, 1H), 1.26 (d, J = 6.0 Hz, 3H); 13C NMR (100
MHz, CD3OD) δ 21.8, 30.8, 47.2, 52.6, 54.6, 62.4, 111.7, 118.1, 125.3,
128.8, 129.2, 149.3, 179.7; HPLC-MS (ESI) tr = 2.2 min; [M + H]+ = 217.1
m/z, [M+H2O+H]+ = 235.3m/z, [M+Na]+ = 239.1 m/z;[α]D25 =−14°
(c = 0.45, MeOH). Anal. Calcd for C13H16N2O (216.13): C, 72.19; H, 7.46;
N, 12.95. Found: C, 72.16; H, 7.43; N, 12.99.
(400 MHz, CDCl3) δ 7.73 (bs, 2H), 7.31−7.22 (m, 4H), 7.18 (d, J = 6.8
Hz, 1H), 7.14−7.09 (m, 2H), 7.04 (t, J = 7.2 Hz, 1H), 6.43 (bs, 2H),
4.29 (d, J = 10.8 Hz, 2H), 4.24−4.16 (m, 2H), 3.98−3.84 (m, 2H), 3.28
(dd, J = 8.8 and 10.0 Hz, 1H), 3.09 (dd, J = 8.8 and 10.0 Hz, 1H), 1.53 (s,
9H), 1.52 (s, 9H), 1.44 (d, J = 6.0 Hz, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.25
(t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 13.6, 14.1, 21.3, 21.6, 28.4, 45.2, 47.4, 50.4, 51.0, 52.6, 54.4, 61.3, 61.8,
80.1, 80.3, 124.5, 124.7, 125.0, 126.7, 127.7, 128.1, 128.2, 137.1, 137.2,
151.0, 153.8, 169.5, 170.0, 171.8, 175.2; HPLC-MS (ESI) tr = 7.4 min,
8.0 min; [M − Boc + H]+ = 263.3 m/z, [M + H]+ = 363.4 m/z,
[2M + Na]+ = 747.7 m/z. Anal. Calcd for C19H26N2O5 (362.18): C,
62.97; H, 7.23; N, 7.73. Found: C, 62.84; H, 7.22; N, 7.72.
Procedure for the Stereoconvergent Epimerization to (R)-
tert-Butyl 3-((2R,3S)-3-Amino-1-ethoxy-1-oxobutan-2-yl)-2-ox-
oindoline-1-carboxylate (11a). The diastereomeric mixture of 11a
and 11b (dr = 54/46; 0.1 mmol, 36.2 mg) was dissolved in acetone
(0.6 mL), and K2CO3 (0.2 mmol) was added. The reaction mixture was
stirred at 50 °C for 24 h, and the conversion was monitored by 1H NMR.
After completion, the solvent was removed, the residue was dissolved in
water (3 mL), and this solution was extracted with DCM (3 × 3 mL).
The organic phases were collected and dried over Na2SO4. The solvent
was evaporated under reduced pressure, and compound 11a was
1
obtained pure: 95% yield, 34 mg, oil; H NMR (400 MHz, CDCl3) δ
7.71 (bs, 1H), 7.31−7.27 (m, 2H), 7.18 (d, J = 6.8 Hz, 1H), 7.12 (t, J =
7.2 Hz, 1H), 6.22 (bs, 1H), 4.28 (d, J = 10.4 Hz, 1H), 4.24−4.16 (m,
2H), 3.97−3.90 (m, 1H), 3.09 (dd, J = 10.8 and 8.0 Hz, 1H), 1.52 (s,
9H), 1.44 (d, J = 6.0 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 14.1, 21.6, 28.4, 47.4, 51.0, 54.3, 61.8, 80.1, 124.6, 125.0,
127.6, 128.2, 128.4, 137.2, 153.7, 171.8, 175.2; HPLC-MS (ESI) tr = 8.0 min;
[M − Boc + H]+ = 263.1 m/z, [M + H]+ = 363.2 m/z, [2M + Na]+ = 747.2
25
m/z; [α]D = 34° (c = 0.99, CH2Cl2). Anal. Calcd for C19H26N2O5
(362.18): C, 62.97; H, 7.23; N, 7.73. Found: C, 62.77; H, 7.24; N, 7.76.
Synthesis of 12a,b. Compound 4b (0.2 mmol, 78.5 mg) was
dissolved in MeOH (3.5 mL), and Pd on C (20% w/w) was added. The
reaction mixture was stirred at room temperature under an H2 balloon
overnight. Then it was filtered and washed with ethyl acetate and DCM.
The solvent was evaporated under reduced pressure, and the crude
Synthesis of tert-Butyl 3-((2R,3R)-1-Ethoxy-3-nitro-1-oxobu-
tan-2-yl)-2-oxoindoline-1-carboxylate (syn-4b). anti-4b
(0.1 mmol, 39 mg) was dissolved in DCM (0.4 mL), and DBU (1,5-
diazabiciclo[5.4.0]undec-5-ene, 30 mol %) was added. The reaction
mixture was stirred at room temperature for 24 h, and the conversion
was monitored by 1H NMR. The solvent was evaporated under reduced
M
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pressure, and the crude reaction mixture was directly purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 9/1): 70%
yield, 27.5 mg, gum; mixture of two diastereoisomers (dr = 70/30); 1H
NMR (400 MHz, CDCl3) δ 7.89−7.82 (m, 2H), 7.38−7.27 (m, 3H),
7.21−7.12 (m, 3H), 5.33−5.23 (m, 2H), 4.13 (dd, J = 2.4 and 10.0 Hz,
1H), 4.05 (q, J = 6.8 Hz, 2H), 3.96−3.85 (m, 4H), 3.81 (s, 1H), 1.75
(d, J = 7.2 Hz, 3H), 1.67−1.64 (m, 21H), 1.08 (t, J = 7.2 Hz, 3H), 0.91
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 13.4, 13.6, 17.9, 18.4,
28.1, 44.4, 44.6, 49.1, 49.4, 61.8, 62.0, 80.9, 81.6, 84.8, 84.9, 115.3, 115.4,
123.5, 123.6, 123.7, 124.6, 124.6, 129.2, 129.4, 140.2, 140.5, 148.9,
168.6, 169.6, 173.0, 173.2; HPLC-MS (ESI) tr = 10.3 min, 10.4 min;
[M − Boc + H]+ = 293.3 m/z, [M + H2O]+ = 410.3 m/z, [M + Na]+ =
415.3 m/z. Anal. Calcd for C19H24N2O7 (392.16): C, 58.16; H, 6.16; N,
7.14. Found: C, 58.06; H, 6.18; N, 7.15. To check the optical purity of
compound syn-4b, it was deprotected as previously described and
injected in CSP-HPLC.
ASSOCIATED CONTENT
* Supporting Information
Text, tables, and figures giving details of the determination of the
relative and absolute configurations, 1H and 13C NMR spectra of
new compounds, and CSP-HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.Q.: arianna.quintavalla@unibo.it.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
■
3-((2R,3R)-1-Ethoxy-3-nitro-1-oxobutan-2-yl)-2-oxoindoline:
amorphous solid, mixture of two diastereoisomers (dr = 76/24), the
signals of the major isomer have been described; 1H NMR (400 MHz,
CDCl3) δ 7.82 (bs, 1H), 7.30−7.25 (m, 2H), 7.08 (t, J = 7.2 Hz, 1H),
6.90 (d, J = 8.0 Hz, 1H), 5.25−5.17 (m, 1H), 4.11 (q, J = 6.8 Hz, 2H),
3.91 (dd, J = 2.8 and 10.0 Hz, 1H), 3.87 (d, J = 2.8 Hz, 1H), 1.59 (d, J =
6.4 Hz, 3H), 1.13, (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
13.8, 17.8, 44.3, 48.4, 61.9, 81.5, 110.0, 122.9, 124.7, 124.9, 129.1, 140.9,
170.3, 176.0; HPLC-MS (ESI) tr = 7.0 min; [M + H]+ = 293.3 m/z,
[M + Na]+ = 315.2 m/z, [2M + Na]+ = 607.4 m/z. Anal. Calcd for
C14H16N2O5 (292.11): C, 57.53; H, 5.52; N, 9.58. Found: C, 57.35; H,
5.51; N, 9.62. CSP-HPLC: IC 90/10 n-Hex/IPA for 10 min, then up to
80/20 in 5 min, 80/20 for 20 min, then up to 75/25 in 15 min, 75/25 up
to 47 min; flow rate 0.5 mL/min at room temperature; λ 214 nm;
tr(major isomer) = 25.4 min (minor), 34.0 min (major); tr(minor
isomer) = 28.6 min (major), 42.7 min (minor).
Synthesis of ((2R,3R,3aS)-2,8-Dimethyl-2,3,3a,8-
tetrahydropyrrolo[2,3-b]indol-3-yl)methanol (14). syn-4b
(0.1 mmol, 39 mg) was dissolved in EtOH (2 mL), Raney nickel
(3 drops of the commercially available suspension in water) was added,
and the reaction mixture was stirred at room temperature under an H2
balloon overnight. Then it was filtered and washed with ethyl acetate and
DCM. The solvent was removed under reduced pressure, and the
β-amino oxindole 15 was obtained pure as an oil. The crude 15 was
dissolved in THF (3 mL), LiAlH4 (1 mmol) was added, and the mixture
was heated at 75 °C for 2 h. The mixture was cooled to room
temperature and quenched with ethyl acetate (4 mL) and then H2O
(0.8 mL). The resulting mixture was filtered through Celite and washed
with ethyl acetate and MeOH. The filtrates were concentrated under
reduced pressure, and the residue was purified by flash chromatography
on silica gel (DCM/MeOH 20/1), providing compound 14: 76% yield
over two steps, 16.5 mg, amorphous solid.
(S)-tert-Butyl 3-((2R,3R)-3-amino-1-ethoxy-1-oxobutan-2-yl)-2-
oxoindoline-1-carboxylate (15): 1H NMR (400 MHz, CDCl3) δ 7.73
(bs, 1H), 7.32−7.23 (m, 2H), 7.15−7.08 (m, 2H), 5.88 (bs, 1H), 4.32
(d, J = 10.0 Hz, 1H), 4.28−4.13 (m, 3H), 3.64 (dd, J = 8.8 and 9.2 Hz,
1H), 1.54 (s, 9H), 1.30−1.26 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
14.1, 18.0, 28.4, 43.5, 49.0, 51.7, 61.6, 80.0, 124.6, 127.6, 128.0, 128.1,
128.5, 137.4, 153.7, 171.2, 176.2; HPLC-MS (ESI) tr = 7.7 min; [M −
Boc + H]+ = 263.3 m/z, [M + H]+ = 363.4 m/z; [α]D25 = 19° (c = 1.69,
CH2Cl2). Anal. Calcd for C19H26N2O5 (362.18): C, 62.97; H, 7.23; N,
7.73. Found: C, 62.77; H, 7.21; N, 7.72.
((2R,3R,3aS)-2,8-Dimethyl-2,3,3a,8-tetrahydropyrrolo[2,3-b]-
indol-3-yl)methanol (14): 1H NMR (400 MHz, CD3OD) δ 7.14 (t, J =
7.6 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.72−6.65 (m, 2H), 3.95−3.88 (m,
1H), 3.75 (dd, J = 7.6 and 10.8 Hz, 1H) 3.66 (d, J = 6.4 Hz, 1H), 3.56
(dd, J = 7.6 and 10.4 Hz, 1H), 2.81 (s, 3H), 2.54−2.47 (m, 1H), 1.22 (d,
J = 6.8 Hz, 3H); 13C NMR (50 MHz, CD3OD) δ 16.0, 30.8, 47.0, 51.3,
60.8, 111.6, 117.9, 124.0, 128.0, 129.2, 149.3, 180.1; HPLC-MS (ESI)
tr = 2.1 min; [M + H2O + H]+ = 235.3 m/z, [2M + Na]+ = 455.5 m/z;
[α]D25 = 15° (c = 0.15, MeOH). Anal. Calcd for C13H16N2O (216.13):
C, 72.19; H, 7.46; N, 12.95. Found: C, 72.16; H, 7.45; N, 13.00.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Miur-Rome (PRIN
20099PKPHH_004), Fondazione del Monte di Bologna e
Ravenna, and COST Action CM0905 “Organocatalysis”.
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