Asymmetric diastereoselective synthesis of spirocyclopropane derivatives of oxindole

Article abstract of DOI:10.1002/ejoc.201402061

A new asymmetric organocatalytic synthesis of spirocyclopropane oxindoles has been developed. The method is based on the Michael addition of N-Boc-protected 3-chlorooxindole to unsaturated 1,4-dicarbonyl compounds, affording trans-substituted spirocyclopropane oxindole derivatives in high diastereo- and enantioselectivity. Copyright

Full text of DOI:10.1002/ejoc.201402061

Job/Unit: O42061
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FULL PAPER
DOI: 10.1002/ejoc.201402061
Asymmetric Diastereoselective Synthesis of Spirocyclopropane Derivatives of
Oxindole
[a]
[a]
[a]
[a]
[a]
ˇ
ˇ
Maksim Oseka, Artur Noole, Sergei Zari, Mario Öeren, Ivar Järving,
Margus Lopp,[a] and Tõnis Kanger*[a]
Keywords: Organocatalysis / Asymmetric synthesis / Cyclization / Michael addition / Small ring systems
A new asymmetric organocatalytic synthesis of spirocyclo-
propane oxindoles has been developed. The method is based
on the Michael addition of N-Boc-protected 3-chlorooxindole
to unsaturated 1,4-dicarbonyl compounds, affording trans-
substituted spirocyclopropane oxindole derivatives in high
diastereo- and enantioselectivity.
Introduction
The synthesis of spirocyclic oxindole derivatives has re-
cently gained considerable attention.[1] This core structure
can be found in many natural and synthetic compounds
exhibiting a diverse range of biological activities, including
antimalarial,[2] anti-HIV,[3] and anticancer activities.[4] Their
medical importance has made them valuable synthetic tar-
gets and has spurred research towards the creation of con-
venient and highly selective methods for their synthesis. The
asymmetric construction of a spirocyclopropane motif is es-
pecially challenging due to the presence of three consecutive
stereogenic centers in the highly strained three-membered
ring. From a stereochemical point of view, the synthesis of
α,β-identically substituted cyclopropane derivatives of ox-
indole is even more complex because of the formation of
an enantiomeric trans-substituted derivative structure with
a nonstereogenic C-3 center, together with an achiral diaste-
reoisomeric cis-isomer with a pseudo-asymmetric center at
C-3 (Figure 1).
Previously, we described the synthesis of spirocyclopro-
pane oxindoles starting from alkylidene oxindoles or 3-
chlorooxindoles.[5] The latter are very useful building blocks
for the creation of all-carbon quaternary centers by cascade
reactions using the dualistic properties of the carbon at the
third position of oxindole. Chlorine increases the acidity of
the C–H bond, making the carbon atom more nucleophilic,
and chloride is also a good leaving group for the nucleo-
philic substitution. Thus, Michael-initiated ring closure
(MIRC)[6] between α,β-unsaturated carbonyl compounds
and 3-chlorooxindole is a straightforward method for spiro-
cyclopropanation of oxindoles. Unsaturated 1,4-dicarbonyl
Figure 1. Stereochemistry of trans- and cis-substituted spirocyclo-
propane oxindoles.
compounds have also been used in MIRC for the prepara-
tion of substituted cyclopropanes,[7] although there are only
few examples of asymmetric reactions.[8] To the best of our
knowledge, there are no reports concerning asymmetric or-
ganocatalytic cyclopropanation on symmetric unsaturated
1,4-diketones.
Results and Discussion
To explore the feasibility of the synthesis of symmetric
spirocyclopropane oxindoles, the cascade reaction between
N-Boc-protected 3-chlorooxindoles 1 and aromatic unsatu-
rated 1,4-diketones 2 was investigated (Scheme 1).
[a] Department of Chemistry, Tallinn University of Technology,
Akadeemia tee 15, 12618 Tallinn, Estonia
E-mail: kanger@chemnet.ee
http://www.chem.ttu.ee/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402061.
Scheme 1. General scheme for the synthesis of spirocyclopropane
oxindoles.
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This reaction cascade is an example of enantioselective
MIRC and consists of a Michael addition followed by an
intramolecular nucleophilic substitution, leading to the for-
mation of cyclopropane derivatives 3. Based on our recent
results in the asymmetric desymmetrization of unsaturated
1,4-diketones,[9] various enantiomeric thiourea, Cinchona
alkaloid, or squaramide catalysts I–V were used to catalyze
reactions (Figure 2).
In our first experiments, an unprotected NH oxindole
as a synthetically preferable starting material was used.[10]
However, due to the insufficient acidity of the hydrogen at
C3, no reaction took place.[11]
N-Boc-protected 3-chlorooxindole 1a reacted smoothly
with unsaturated aromatic 1,4-diketone 2a and provided
spirocyclopropane oxindole 3a in good yield and enantio-
selectivity (Table 1, entry 1). Protecting the oxindole nitro-
gen with an electron-withdrawing group increases the acid-
ity of the C–H bond at C3. On the other hand, it provides
the opportunity for the formation of additional H-bonds
between the catalyst and the substrate. In this model reac-
tion the ratio of spirocyclopropane oxindole 3a, uncyclized
Michael adduct 4a, and achiral compound 5a, together
with the enantiomeric purity of 3a were determined. To fa-
cilitate the purification of the product 3a, the crude mixture
was treated with trifluoroacetic acid (TFA) and the product
was isolated as a free N-H oxindole 3a-NH as a single dia-
stereoisomer (side-products 4a and 5a were identified by
Figure 2. Catalysts used in the study.
1H NMR spectroscopic analysis of the crude mixture). All with Cinchona alkaloid IV, but the poor yield obtained
thiourea-derived catalysts gave quite similar ee values for (21% for 3a) made it unattractive for practical use (Table 1,
the product (Table 1, entries 1, 2 and 5). Squaramide cata- entry 4). The highest yield (70%) was obtained by sacrific-
lyst III was clearly inappropriate for the cyclopropanation. ing enantioselectivity in running the reaction with catalyst
The highest enantio- and diastereoselectivity was achieved II (Table 1, entry 2).
Table 1. Screening of the catalyst and optimization.[a]
Entry Catalyst (mol-%)
Solvent
t [°C]
Time [h]
Ratio 3a/4a/5a[b]
Yield [%][c]
ee [%][d]
N-Boc
N-H
1
2
3
4
5
6
7
8
9
10
I (10)
II (10)
III (10)
IV (10)
V (10)
II (20)
II (10)
II (10)
II (10)
II (10)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CH2Cl2
DCE
r.t.
r.t.
r.t.
r.t.
r.t.
60
r.t.
r.t.
r.t.
4
18
48
48
48
48
18
48
48
48
96
n.d.
61
70
–67
67
n.d.
80
–75
48
86
63
65
90
1:0.1:0.2
1:0.9:0.5
1:0.6:0.05
1:0.6:0.2
1:0.4:0.3
1:0.1:0.1
1:0.2:0.2
1:0.2:0.2
1:0.2:0.1
n.d.
21
42
51
57
44
44
59
toluene
[a] Reaction conditions (0.1 mmol scale, 0.2 m solution): 1 (1 equiv.), 2a (1.2 equiv.), NaHCO3 (2 equiv.). [b] Determined by 1H NMR
spectroscopic analysis of the crude mixture. [c] The main product 3a or 3a-NH was isolated as a single diastereoisomer. [d] The ee of 3
was determined by chiral HPLC analysis of the isolated product.
2
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Asymmetric Spirocyclopropane Derivatives of Oxindole
Figure 3. Scope of the reaction. [a] The main product 3 was isolated as a single diastereoisomer. [b] Diastereomeric ratio was determined
by 1H NMR spectroscopic analysis of the crude mixture. [c] The ee was determined by chiral HPLC analysis of the isolated product.
1
[d] Determined by H NMR spectroscopic analysis of the crude mixture. [e] The reaction was stirred for 96 h.
We then turned our attention to further improving the of yield (from 58 to 81%) and enantioselectivity (ee from 75
efficiency of the thiourea II catalyzed cascade reaction to 87%) (Figure 3, compounds 3a–e). Diastereoselectivity
(Table 1, entries 6–9). Increasing temperature and catalyst varied from excellent (Figure 3, compound 3d) to high (Fig-
loading did not improve the yield, instead, the selectivity ure 3, compound 3e). Bromo-substituted oxindole did not
decreased dramatically (Table 1, entry 6). Solvent screening noticeably affect the results of the cascade (Figure 3, com-
revealed that the product 3a-NH could be obtained in mod- pound 3f). However, the reaction between Boc-protected 3-
erate yield in 48 h in all cases, but the best enantio- and chlorooxindole 1a and aliphatic diketone [(E)-hex-3-ene-
diastereoselectivity were obtained in toluene (Table 1, en- 2,5-dione] did not proceed, probably due to the lower elec-
try 7). Decreasing the reaction temperature from room tem- trophilicity of the latter. A similar observation emerged
perature to 4 °C had little influence on stereoselectivity, but from the work of Liao et al. in the case of the addition of 3-
an extended reaction time was required to achieve reason- alkyl-substituted oxindoles to unsaturated 1,4-diketones.[12]
able yield (Table 1, entry 10).
The scope of the reaction was then broadened to include
With optimal conditions in hand [1 (1.2 equiv.), 2 nonsymmetric unsaturated 1,4-dicarbonyl compounds,
(1 equiv.), NaHCO3 (2 equiv.), and II (10 mol-%) in toluene which led to spiro-oxindoles containing two tertiary and
at room temp.], the scope of the reaction was investigated one quaternary center (Figure 3, compounds 3g–j). Al-
first by using various symmetric diketones 2. The obtained though nonsymmetric unsaturated 1,4-diketones have two
compounds and the product parameters are presented in different electrophilic centers for Michael addition, the nu-
Figure 3.
cleophilic attack was regioselective. Two regioisomers of the
Electron-donating or electron-withdrawing substituents intermediate should give different diastereoisomers after in-
in the aromatic ring of the diketones 2 provided products tramolecular cyclization, but only one out of four possible
with two tertiary stereocenters with similar results in terms stereoisomers was formed (Figure 3, compound 3g and 3h).
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Scheme 2. Cyclization of Michael adduct 4c.
Unsaturated keto esters reacted smoothly with 3-chloro- enes,[5a] but the relative stereochemistry of non-cyclized in-
oxindole, but the main product was non-cyclized compound termediate 4c was not determined because during the cycli-
4, which could not be separated from 3 (Figure 3, com- zation the stereogenic center at C3 is lost. Although the
pounds 3i and 3j). Even though only a small amount of 3 racemic product 3c was obtained from the starting materi-
formed, the diastereoselectivity was very high, indicating als in the presence of an inorganic base, no reaction with
that, similar to nonsymmetric 1,4-diketones, Michael ad- non-cyclic intermediate 4c was observed under the same
dition to unsaturated keto esters was also regioselective.
conditions using the same base. This study also suggests
The relative stereochemistry of symmetric spiro-oxind- that the stereochemistry of the final product 3c is deter-
oles 3a–f was determined by 1H NMR spectroscopic analy- mined in the first step of the cascade (Michael addition)
sis, whereas the absolute stereochemistry of one of the prod- because two different chiral organocatalysts II and V af-
ucts, 3c-NH, was determined by vibrational circular dichro- forded the same enantiomer in reaction with non-cyclic in-
ism (VCD) (Figure 4).
termediate 4c, whereas enantiomers of 3c were obtained in
separate reactions with starting materials 1a and 2c.
Conclusions
Herein, we have described the synthesis of spiro-oxind-
oles through asymmetric organocatalytic reaction of sym-
metric unsaturated 1,4-diketones and 3-chlorooxindoles.
This methodology provides products 3a–f with two iden-
tically substituted tertiary stereocenters in moderate yields
and with very high diastereo- and enantioselectivities. In
the case of unsaturated 1,4-keto esters and non-symmetric
diketones, the first conjugated addition is highly regioselec-
tive and provides spiro-oxindoles 3g–j containing two terti-
ary and one quaternary center with excellent diastereoselec-
tivity.
Figure 4. VCD analysis of 3c-NH.
The assigned absolute stereochemistry was interpolated
to other compounds in the series. The relative stereochemis-
try of spiro-oxindoles 3g–j was determined by NOESY
NMR experiments (for details, see the Supporting Infor-
mation).
Experimental Section
General Methods and Materials: Full assignment of 1H and 13C
chemical shifts was based on the 1D and 2D FT NMR spectra
obtained with a Bruker Avance III 400 MHz instrument. Chemical
shifts (δ) are reported in ppm relative to residual solvent signals
(CHCl3: δ = 7.26/77.16 ppm; DMSO: δ = 2.50/39.52 ppm). HRMS
spectra were recorded with an Agilent Technologies 6540 UHD
Accurate-Mass Q-TOF LC/MS spectrometer by using AJ-ESI ion-
ization. Optical rotations were obtained with an Anton Paar GWB
Polarimeter MCP500. Chiral HPLC was performed using a Chi-
ralpak AD-H column. Precoated silica gel 60 F254 plates were used
In an additional experiment, non-cyclic Michael adduct
4c (6:1 mixture of diastereoisomers) was cyclized in the
presence of organocatalysts II or V (Scheme 2). The reac-
tion was very slow, indicating the importance of the cata-
lyst/substrate complex throughout the cascade reaction.
Diastereoisomers of 4c cyclized in the presence of catalyst
II with different rates, and the diastereomeric ratio of reco-
vered 4c changed to 20:1. In the presence of catalyst V, the
ratio remained unchanged. It is known that 3-chlorooxind-
oles afford the syn-product in Michael addition to nitrostyr- for TLC, and Merck silica gel was used for column chromatog-
4
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Asymmetric Spirocyclopropane Derivatives of Oxindole
raphy. Chiral catalysts IV and V were commercially available from
Aldrich or Strem, and I, II and III were prepared according to
reported procedures.[13,14] Commercial reagents were generally used
as received. CH2Cl2 and EtOAc were distilled from P2O5.
(E)-1,4-Bis(4-bromophenyl)but-2-ene-1,4-dione (2a): Obtained as a
tan brown solid in 46% yield according to the general procedure.
1H NMR (400 MHz, CDCl3): δ = 7.97 (s, 2 H, 2ϫ CH), 7.92 (d,
J = 8.7 Hz, 4 H, 4ϫ ArH), 7.68 (d, J = 8.7 Hz, 4 H, ArH, 4ϫ
ArH) ppm.
General Procedure for the Synthesis of N-Boc-Oxindoles: N-Boc-
oxindoles were prepared according to a reported procedure from
commercially available oxindoles.[15] To a solution of the corre-
sponding oxindoles (1 equiv.) in anhydrous THF (0.25 m), Na2CO3
(9 equiv.) and Boc2O (2.5 equiv.) were added at room temperature
and the resulting mixture was stirred at 70 °C for 12 h. The solid
was filtered off and the solvent was evaporated. The crude product
was purified by silica gel column chromatography (heptane/ethyl
acetate, 10:1).
(E)-1,4-Diphenylbut-2-ene-1,4-dione (2b): Obtained as a bright-yel-
low solid in 70% yield according to the general procedure. 1H
NMR (400 MHz, CDCl3): δ = 8.09–8.03 (m, 4 H, 4ϫ ArH), 8.01
(s, 2 H, 2ϫ CH), 7.66–7.60 (m, 2 H, 2ϫ ArH), 7.56–7.49 (m, 4 H,
4ϫ ArH) ppm.
(E)-1,4-Di-p-tolylbut-2-ene-1,4-dione (2c): Obtained as a yellow so-
lid in 45% yield according to the general procedure. 1H NMR
(400 MHz, CDCl3): δ = 8.00 (s, 2 H, 2ϫ CH), 7.97 (d, J = 8.2 Hz,
4 H, 4ϫ ArH), 7.32 (d, J = 8.0 Hz, 4 H, 4ϫ ArH), 2.45 (s, 6 H,
2ϫ ArCH3) ppm.
tert-Butyl 2-Oxoindoline-1-carboxylate: The title compound was
obtained as a pink solid in 70% yield according to the general
procedure. 1H NMR (400 MHz, CDCl3): δ = 7.79 (ddd, J = 8.2,
1.0, 0.5 Hz, 1 H, ArH), 7.30 (dddt, J = 8.4, 7.5, 1.6, 0.9 Hz, 1 H,
ArH), 7.24 (ddd, J = 7.4, 1.4, 0.6 Hz, 1 H, ArH), 7.13 (td, J = 7.5,
1.1 Hz, 1 H, ArH), 3.65 (s, 2 H, CH2), 1.65 (s, 9 H, Boc) ppm.
(E)-1,4-Bis(4-chlorophenyl)but-2-ene-1,4-dione (2d): Obtained as a
bright-yellow solid in 46% yield according to the general pro-
cedure. 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.7 Hz, 4 H,
4ϫ ArH), 7.98 (s, 2 H, 2ϫ CH), 7.51 (d, J = 8.7 Hz, 4 H, 4ϫ
ArH) ppm.
tert-Butyl 5-Bromo-2-oxoindoline-1-carboxylate: The title com-
pound was obtained as a pink solid in 53% yield according to the
general procedure. H NMR (400 MHz, CDCl3): δ = 7.70 (d, J =
8.7 Hz, 1 H, ArH), 7.42 (ddt, J = 8.7, 1.8, 0.8 Hz, 1 H, ArH), 7.39–
7.36 (m, 1 H, ArH), 3.64 (s, 2 H, CH2), 1.63 (s, 9 H, Boc) ppm.
(E)-1,4-Bis(4-nitrophenyl)but-2-ene-1,4-dione (2e): The title com-
pound was prepared by a two-step procedure. In the first step, p-
nitroacetophenone was transformed into p-nitro-α-oxo-benzene-
acetaldehyde by using a reported procedure.[17] In the second step,
p-nitro-α-oxo-benzeneacetaldehyde (375 mg; 2.09 mmol) was
dissolved in anhydrous CH2Cl2 (10 mL), and a solution of
1
General Procedure for the Synthesis of N-Boc-3-chlorooxindoles 1a
and 1b: A solution of corresponding N-Boc-oxindoles (1 equiv.) in
THF (0.7 m) was added over 10 min at –78 °C to a solution of
LiHMDS [generated in situ from nBuLi (1.6 m in hexanes,
2.2 equiv.) and hexamethyldisilazane (2.3 equiv.) in THF (0.5 m) at
0 °C]. The mixture was stirred at –78 °C for 40 min, then N-chloro-
succinimide (1.05 equiv.) was added in one portion. The mixture
was warmed slowly to room temperature and stirred overnight. A
mixture of saturated aqueous NH4Cl and H2O (1:1) was added,
and the mixture was extracted with CH2Cl2. The combined organic
fractions were dried with MgSO4 and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (heptane/ethyl acetate, 7:1).
1-p-nitrophenyl-2-triphenylphosphoranylidene-ethanone
(1.2 g;
2.8 mmol/10 mL) in CH2Cl2 was added dropwise. After 10 min, a
yellow solid started to precipitate. After completion of the reaction,
the mixture was filtered, and the solid was washed with cold chloro-
form. The solid was recrystallized from the mixture of chloroform
and ethyl acetate to give 3e (450 mg, 66% yield). 1H NMR
(400 MHz, DMSO): δ = 8.39 (d, J = 8.9 Hz, 4 H, 4ϫ ArH), 8.31
(d, J = 8.9 Hz, 4 H, 4ϫ ArH), 7.94 (s, 2 H, 2ϫ CH) ppm.
General Procedure for the Synthesis of Nonsymmetric Unsaturated
1,4-Diketones and Keto Esters 2g–j: Prepared by an in situ oxi-
dation-Wittig reaction sequence according to a reported procedure
from the corresponding Wittig reagents and either hydroxyacetone
or methyl glycolate.[18]
tert-Butyl 3-Chloro-2-oxoindoline-1-carboxylate (1a): The title com-
pound was obtained as a red amorphous solid in 49% yield accord-
ing to the general procedure. 1H NMR (400 MHz, CDCl3): δ =
7.85 (d, J = 8.3 Hz, 1 H, ArH), 7.45 (d, J = 7.5 Hz, 1 H, ArH),
7.40 (dddd, J = 8.3, 7.7, 1.4, 0.8 Hz, 1 H, ArH), 7.22 (td, J = 7.6,
1.0 Hz, 1 H, ArH), 5.23 (s, 1 H, CH), 1.64 (s, 9 H, Boc) ppm. 13C
NMR (101 MHz, CDCl3): δ = 169.96, 148.84, 140.09, 130.88,
125.71, 125.25, 124.56, 115.58, 85.28, 52.10, 28.17 ppm. HRMS
(ESI): m/z calcd. for C13H14ClNO3Na+ [M + Na]+ 290.0554; found
290.0566.
(E)-1-Phenylpent-2-ene-1,4-dione (2g): Obtained as a light-yellow
solid in 88% yield according to the general procedure. 1H NMR
(400 MHz, CDCl3): δ = 8.02–7.95 (m, 2 H, 2ϫ ArH), 7.70 (d, J =
15.8 Hz, 1 H, CH), 7.66–7.60 (m, 1 H, ArH), 7.55–7.49 (m, 2 H,
2ϫ ArH), 7.09 (d, J = 15.7 Hz, 1 H, CH), 2.44 (s, 3 H, CH3) ppm.
(E)-1-(4-Nitrophenyl)pent-2-ene-1,4-dione (2h): Obtained as a light-
yellow solid in 78% yield according to the general procedure. 1H
NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.8 Hz, 2 H, 2ϫ ArH),
8.14 (d, J = 8.9 Hz, 2 H, 2ϫ ArH), 7.66 (d, J = 15.7 Hz, 1 H, CH),
7.14 (d, J = 15.7 Hz, 1 H, CH), 2.46 (s, 3 H, CH3) ppm.
tert-Butyl 5-Bromo-3-chloro-2-oxoindoline-1-carboxylate (1b): The
title compound was obtained as a red amorphous solid in 12%
yield according to the general procedure. 1H NMR (400 MHz,
CDCl3): δ = 7.77 (d, J = 8.7 Hz, 1 H, ArH), 7.60–7.54 (m, 1 H,
ArH), 7.52 (ddd, J = 8.7, 2.1, 0.7 Hz, 1 H, ArH), 5.20 (d, J =
(E)-Methyl-4-oxo-4-(p-tolyl)but-2-enoate (2i): Obtained as an
1
orange solid in 85% yield according to the general procedure. H
1.0 Hz, 1 H, CH), 1.63 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 15.6 Hz, 1 H, CH), 7.91
CDCl3): δ = 169.07, 148.66, 139.11, 133.86, 128.76, 126.48, 118.13, (d, J = 8.2 Hz, 2 H, 2ϫ ArH), 7.31 (d, J = 8.0 Hz, 2 H, 2ϫ ArH),
117.29, 85.71, 51.36, 28.16 ppm. HRMS (ESI): m/z calcd. for 6.88 (d, J = 15.5 Hz, 1 H, CH), 3.84 (s, 3 H, OCH3), 2.43 (s, 3 H,
C13H13BrClNO3Na+ [M + Na]+ 367.9660; found 367.9674.
ArCH3) ppm.
General Procedure for the Synthesis of Symmetric Unsaturated 1,4- (E)-Methyl-4-(4-chlorophenyl)-4-oxobut-2-enoate (2j): The title
Diketones 2a–d: Synthesized by Friedel–Crafts acylation reaction
according to a reported procedure from the corresponding substi-
tuted benzenes and fumaryl chloride.[16]
compound was obtained as a yellow solid in 87% yield according
to the general procedure. 1H NMR (400 MHz, CDCl3): δ = 7.94
(d, J = 8.7 Hz, 2 H, 2ϫ ArH), 7.87 (d, J = 15.5 Hz, 1 H, CH),
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7.48 (d, J = 8.7 Hz, 2 H, 2ϫ ArH), 6.89 (d, J = 15.5 Hz, 1 H, CH),
3.85 (s, 3 H, OCH3) ppm.
8.0, 1.4 Hz, 1 H, oxindole-H), 7.15 (td, J = 7.7, 1.0 Hz, 1 H, oxind-
ole-H), 4.45 (d, J = 8.1 Hz, 1 H, CH), 4.16 (d, J = 8.1 Hz, 1 H,
CH), 1.57 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, CDCl3): δ =
191.7, 190.0, 169.8, 149.0, 140.4, 136.7, 136.2, 134.2, 133.8, 129.0,
128.9, 128.8, 128.7, 124.8, 123.2, 122.1, 115.2, 85.0, 41.4, 40.8, 40.3,
28.2 ppm. HRMS (ESI): m/z calcd. for C29H25NO5Na+ [M +
Na]+ 490.1625; found 490.1639.
General Procedure for the Asymmetric Synthesis of Spirocycloprop-
ane Oxindoles 3a–j: Unsaturated 1,4-dicarbonyl compound 2
(1 equiv., 0.1 mmol), N-Boc 3-chlorooxindole
1 (1.2 equiv.,
0.12 mmol), NaHCO3 (2 equiv., 16.8 mg, 0.2 mmol) and thiourea
II (10 mol-%, 6.0 mg) were dissolved in toluene (0.5 mL) and
stirred at room temp. for 48 h. The progress of the reaction was
monitored by NMR spectroscopy. Upon completion of the reac-
tion, the mixture was directly purified by silica gel column
chromatography (heptane/ethyl acetate). The diastereomeric ratio
was determined by 1H NMR spectroscopic analysis of the crude
mixture and the enantiomeric purity was determined by chiral
HPLC analysis.
(2S,3S)-tert-Butyl 2,3-Bis(4-methylbenzoyl)-2Ј-oxospiro[cycloprop-
ane-1,3Ј-indoline]-1Ј-carboxylate (3c): (E)-1,4-di-p-tolylbut-2-ene-
1,4-dione (2c; 1 equiv., 0.1 mmol), N-Boc 3-cholrooxindole 1a
(1.2 equiv., 0.12 mmol), NaHCO3 (2 equiv., 16.8 mg, 0.2 mmol),
and thiourea II (10 mol-%, 6.0 mg) were dissolved in toluene
(0.5 mL) and stirred at room temp. for 96 h. Product was isolated
as a single diastereoisomer in 64% yield (32 mg) as a pink solid
with dr 10:1 (1H NMR analysis of crude material) and ee 77% for
the major isomer [Chiralpak AD-H; Hex/iPrOH, 9:1; 1 mL/min;
20 °C; 230 nm; tR = 17.9 (major), 22.1 (minor) min]. [α]2D5 = +209.4
(2S,3S)-tert-Butyl 2,3-Bis(4-bromobenzoyl)-2Ј-oxospiro[cycloprop-
ane-1,3Ј-indoline]-1Ј-carboxylate (3a): The title compound was syn-
thesized according to the general procedure from N-Boc 3-chloro-
oxindole 1a and (E)-1,4-bis(4-bromophenyl)but-2-ene-1,4-dione
(2a). Product was isolated as a single diastereoisomer in 67% yield
(42 mg) as a reddish solid with dr 10:1 (1H NMR analysis of crude
material) and ee 86% for the major isomer [Chiralpak AD-H; Hex/
iPrOH, 9:1; 1 mL/min; 25 °C; 230 nm; tR = 18.5 (major), 24.0
(minor) min]. [α]2D5 = +180.8 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 1 H, oxindole-H), 7.83
(d, J = 8.6 Hz, 2 H, 2ϫ ArH), 7.67 (d, J = 8.5 Hz, 2 H, 2ϫ ArH),
7.58 (d, J = 8.6 Hz, 2 H, 2ϫ ArH), 7.53 (d, J = 8.5 Hz, 2 H, 2ϫ
ArH), 7.34 (td, J = 8.0, 1.3 Hz, 1 H, oxindole-H), 7.30 (dd, J =
7.8, 1.3 Hz, 1 H, oxindole-H), 7.15 (td, J = 7.6, 1.1 Hz, 1 H, oxind-
ole-H), 4.35 (d, J = 8.0 Hz, 1 H, CH), 4.08 (d, J = 8.0 Hz, 1 H,
CH), 1.57 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, CDCl3): δ =
190.7, 189.0, 169.7, 148.8, 140.4, 135.3, 134.9, 132.4, 132.3, 130.3,
130.1, 129.8, 129.3, 129.3, 124.9, 122.7, 122.0, 115.4, 85.3, 41.3,
40.5, 40.0, 28.2 ppm. HRMS (ESI): m/z calcd. for
C29H23Br2NO5Na+ [M + Na]+ 645.9835; found 645.9847.
1
(c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.88 (d, J =
8.2 Hz, 2 H, 2ϫ ArH), 7.87 (ddd, J = 8.2, 1.0, 0.5 Hz, 1 H, oxind-
ole-H), 7.73 (d, J = 8.2 Hz, 2 H, 2ϫ ArH), 7.34 (ddd, J = 7.7, 1.3,
0.5 Hz, 1 H, oxindole-H), 7.30 (ddd, J = 8.2, 7.7, 1.4 Hz, 1 H,
oxindole-H), 7.23 (d, J = 7.9 Hz, 2 H, 2ϫ ArH), 7.18 (d, J =
7.9 Hz, 2 H, 2ϫ ArH), 7.13 (td, J = 7.7, 1.1 Hz, 1 H, oxindole-H),
4.42 (d, J = 8.1 Hz, 1 H, CH), 4.13 (d, J = 8.1 Hz, 1 H, CH), 2.37
(s, 3 H, ArCH3), 2.36 (s, 3 H, ArCH3), 1.56 (s, 9 H, Boc) ppm. 13C
NMR (101 MHz, CDCl3): δ = 191.3, 189.7, 169.9, 149.0, 145.2,
144.7, 140.4, 134.3, 133.9, 129.6, 129.6, 129.0, 128.8, 128.7, 124.8,
123.4, 122.1, 115.2, 84.9, 41.2, 40.9, 40.4, 28.1, 21.9, 21.8 ppm.
HRMS (ESI): m/z calcd. for C31H29NO5Na+ [M + Na]+ 518.1938;
found 518.1948.
tert-Butyl 3-Chloro-3-(1,4-dioxo-1,4-di-p-tolylbutan-2-yl)-2-oxoind-
oline-1-carboxylate (4c): Obtained as a side product in the synthesis
of 3c. Compound 4c (8.5 mg, 16%) was isolated as a red solid with
dr 5:1 (1H NMR analysis of crude material). For the main isomer:
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.2 Hz, 2 H, 2ϫ
ArH), 7.89–7.84 (m, 3 H, 2ϫ ArH, oxindole-H), 7.45 (dd, J = 7.6,
0.8 Hz, 1 H, oxindole-H), 7.31–7.27 (m, 1 H, oxindole-H), 7.26–
7.23 (m, 2 H, 2ϫ ArH), 7.19 (d, J = 7.9 Hz, 2 H, 2ϫ ArH), 7.05
(td, J = 7.6, 1.0 Hz, 1 H, oxindole-H), 5.48 (t, J = 5.3 Hz, 1 H,
CH), 4.50 (dd, J = 18.7, 5.0 Hz, 1 H, CH2), 3.34 (dd, J = 18.7,
5.6 Hz, 1 H, CH2), 2.40 (s, 3 H, ArCH3), 2.35 (s, 3 H, ArCH3),
1.70 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, CDCl3): δ = 198.3,
196.8, 171.8, 149.2, 144.8, 144.6, 139.3, 133.7, 133.0, 130.7, 129.5,
129.5, 129.2, 128.8, 127.8, 125.0, 123.9, 115.7, 85.0, 64.1, 50.7,
37.3, 28.3, 21.8, 21.8 ppm. HRMS (ESI): m/z calcd. for
C31H3OClNO5Na+ [M + Na]+ 554.1705; found 554.1709.
[(2S,3S)-2Ј-Oxospiro(cyclopropane-1,3Ј-indoline)-2,3-diyl]bis[(4-
bromophenyl)methanone] (3a-NH): To a stirred solution of 3a
(30 mg, 0.049 mmol) in chloroform (5 mL) was added trifluoro-
acetic acid (0.5 mL) at 0 °C. After stirring for 1 h at room temp.
the mixture was concentrated to give the pure product (30 mg,
quant) as a white solid. 1H NMR (400 MHz, DMSO): δ = 10.78
(s, 1 H, NH), 7.80 (d, J = 8.7 Hz, 2 H, 2ϫ ArH), 7.73 (d, J =
8.7 Hz, 2 H, 2ϫ ArH), 7.70 (d, J = 8.6 Hz, 2 H, 2ϫ ArH), 7.62
(d, J = 8.6 Hz, 2 H, 2ϫ ArH), 7.21 (td, J = 7.7, 1.2 Hz, 1 H,
oxindole-H), 7.05 (d, J = 7.4 Hz, 1 H, oxindole-H), 6.94 (td, J =
7.6, 0.9 Hz, 1 H, oxindole-H), 6.89 (d, J = 7.7 Hz, 1 H, oxindole-
H), 4.38 (d, J = 7.8 Hz, 1 H, CH), 4.06 (d, J = 7.8 Hz, 1 H,
CH) ppm. 13C NMR (101 MHz, DMSO): δ = 191.1, 190.4, 172.1,
142.6, 135.1, 134.9, 132.2, 132.0, 130.0, 129.8, 128.6, 128.4, 127.9,
123.6, 121.9, 121.7, 110.1, 38.3, 38.1 ppm. HRMS (ESI): m/z
C24H15Br2NO3Na+ calcd. for [M + Na]+ 545.9311; found 545.9311.
(1s,2R,3S)-tert-Butyl
2,3-Bis(4-methylbenzoyl)-2Ј-oxospiro[cyclo-
propane-1,3Ј-indoline]-1Ј-carboxylate (5c): Obtained as a side prod-
uct in the synthesis of 3c. Compound 5c (4.3 mg, 9%) was isolated
as a white solid. 1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J =
8.0 Hz, 1 H, oxindole-H), 7.84 (d, J = 8.2 Hz, 4 H, 4ϫ ArH), 7.39
(td, J = 7.9, 1.3 Hz, 1 H, oxindole-H), 7.23 (td, J = 7.5, 1.0 Hz, 1
H, oxindole-H), 7.21 (d, J = 8.0 Hz, 4 H, 4ϫ ArH), 7.03 (dd, J =
7.5, 0.8 Hz, 1 H, oxindole-H), 3.61 (s, 2 H, 2ϫ CH), 2.38 (s, 6 H,
2ϫ ArCH3), 1.54 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, CDCl3):
δ = 189.3, 167.6, 149.6, 144.2, 140.3, 134.4, 129.4, 128.9, 128.7,
127.2, 124.4, 118.1, 115.5, 84.4, 42.9, 36.7, 28.2, 21.9 ppm. HRMS
(ESI): m/z calcd. for C31H29NO5Na+ [M + Na]+ 518.1938; found
518.1940.
(2S,3S)-tert-Butyl
2,3-Dibenzoyl-2Ј-oxospiro[cyclopropane-1,3Ј-
indoline]-1Ј-carboxylate (3b): Synthesized according to the general
procedure from N-Boc 3-chlorooxindole 1a and (E)-1,4-di-
phenylbut-2-ene-1,4-dione (2b). The product was isolated as a sin-
gle diastereoisomer in 58% yield (27 mg) as a pink solid with dr
10:1 (1H NMR analysis of crude material) and ee 75% for the
major isomer [Chiralpak AD-H; Hex/iPrOH, 9:1; 1 mL/min; 25 °C;
230 nm; tR = 12.27 (major), 18.8 (minor) min]. [α]2D5 = +387.2 (c =
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.01–7.96 (m, 2
H, 2ϫ ArH), 7.89 (d, J = 8.1 Hz, 1 H, oxindole-H), 7.86–7.81 (m,
[(2S,3S)-2Ј-Oxospiro(cyclopropane-1,3Ј-indoline)-2,3-diyl]bis(p-tolyl-
2 H, 2ϫ ArH), 7.59–7.51 (m, 2 H, 2ϫ ArH), 7.48–7.42 (m, 2 H, methanone) (3c-NH): To a stirred solution of 3c (30 mg, 0.06 mmol)
2ϫ ArH), 7.42–7.35 (m, 3 H, 2ϫ ArH, oxindole-H), 7.32 (td, J = in chloroform (5 mL) was added trifluoroacetic acid (0.5 mL) at
6
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Date: 17-04-14 18:03:31
Pages: 9
Asymmetric Spirocyclopropane Derivatives of Oxindole
0 °C. After stirring for 1 h at room temp. the mixture was concen-
trated to give pure product (23 mg, quant) as a white solid. 1H
NMR (400 MHz, CDCl3): δ = 8.42 (s, 1 H, NH), 7.85 (d, J =
7.98 (m, 2 H, 2ϫ ArH), 7.86–7.82 (m, 2 H, 2ϫ ArH), 7.80 (d, J
= 8.7 Hz, 1 H, oxindole-H), 7.63–7.52 (m, 3 H, 2ϫ ArH, oxindole-
H), 7.50–7.38 (m, 5 H, 4ϫ ArH, oxindole-H), 4.46 (d, J = 8.1 Hz,
8.2 Hz, 2 H, 2ϫ ArH), 7.72 (d, J = 8.2 Hz, 2 H, 2ϫ ArH), 7.31 1 H, CH), 4.13 (d, J = 8.1 Hz, 1 H, CH), 1.55 (s, 9 H, Boc) ppm.
(d, J = 7.6 Hz, 1 H, oxindole-H), 7.22 (td, J = 7.8, 1.0 Hz, 1 H,
oxindole-H), 7.15 (d, J = 8.2 Hz, 2 H, 2 ϫ ArH), 7.14 (d, J =
8.1 Hz, 2 H, 2ϫ ArH), 7.01 (td, J = 7.7, 0.9 Hz, 1 H, oxindole-H),
6.90 (d, J = 7.8 Hz, 1 H, oxindole-H), 4.38 (d, J = 7.9 Hz, 1 H,
13C NMR (101 MHz, CDCl3): δ = 191.4, 189.6, 169.0, 148.8, 139.5,
136.6, 136.0, 134.3, 134.0, 132.0, 129.0, 129.0, 128.9, 128.7, 125.4,
125.3, 117.9, 116.8, 85.4, 41.2, 40.9, 40.4, 28.1 ppm. HRMS (ESI):
m/z calcd. for C29H24Br1NO5Na+ [M + Na]+ 568.0730; found
CH), 4.14 (d, J = 7.9 Hz, 1 H, CH), 2.34 (s, 3 H, ArCH3), 2.33 (s, 568.0748.
3 H, ArCH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 190.5, 189.1,
(1S,2S,3S)-tert-Butyl 2-Acetyl-3-benzoyl-2Ј-oxospiro[cyclopropane-
172.2, 143.9, 143.5, 140.2, 133.2, 132.7, 128.5, 128.4, 127.7, 127.5,
127.4, 123.5, 121.7, 121.6, 109.2, 39.9, 38.6, 37.8, 20.7 (2ϫ C) ppm.
HRMS (ESI): m/z calcd. for C26H21NO3Na+ [M + Na]+ 418.1414;
found 418.1425.
1,3Ј-indoline]-1Ј-carboxylate (3g): Synthesized according to the ge-
neral procedure from N-Boc-3-chlorooxindole 1a and (E)-1-phen-
ylpent-2-ene-1,4-dione (2g). The product was isolated as a single
diastereoisomer in 53% yield (21 mg) as a pink solid with drϾ 20:1
(1H NMR analysis of crude material) and ee 72% for the major
isomer [Chiralpak AD-H; Hex/iPrOH, 8:2; 1 mL/min; 25 °C;
230 nm; tR = 10.1 (major), 7.7 (minor) min]. [α]2D5 = +181.9 (c =
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J =
8.2 Hz, 1 H, oxindole-H), 7.80–7.75 (m, 2 H, 2ϫ ArH), 7.52 (tt, J
= 7.0, 1.2 Hz, 1 H, ArH), 7.42–7.32 (m, 4 H, 2ϫ ArH, 2ϫ oxind-
ole-H), 7.20 (td, J = 7.6, 0.9 Hz, 1 H, oxindole-H), 3.91 (d, J =
8.1 Hz, 1 H, CH), 3.77 (d, J = 8.1 Hz, 1 H, CH), 2.29 (s, 3 H,
COCH3), 1.55 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, CDCl3): δ
= 200.2, 189.8, 169.7, 149.0, 140.5, 136.0, 133.9, 129.1, 128.9, 128.6,
124.8, 122.9, 122.3, 115.3, 85.0, 43.4, 41.1, 40.4, 32.1, 28.1 ppm.
HRMS (ESI): m/z calcd. for C24H23NO5Na+ [M + Na]+ 428.1468;
found 428.1476.
(2S,3S)-tert-Butyl 2,3-Bis(4-chlorobenzoyl)-2Ј-oxospiro[cyclo-
propane-1,3Ј-indoline]-1Ј-carboxylate (3d): Synthesized according to
the general procedure from N-Boc-3-chlorooxindole 1a and (E)-
1,4-bis(4-chlorophenyl)but-2-ene-1,4-dione (2d). The product was
isolated as a single diastereoisomer in 81% yield (43 mg) as a pink
solid with dr 20:1 (1H NMR analysis of crude material) and ee
87 % for the major isomer [Chiralpak AD-H; Hex/iPrOH, 9:1;
1 mL/min; 25 °C; 230 nm; tR = 16.9 (major), 19.7 (minor) min].
[α]2D5 = +257.4 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ
1
= 7.91 (d, J = 8.7 Hz, 2 H, 2ϫ ArH), 7.89 (d, J = 7.9 Hz, 1 H,
oxindole-H), 7.75 (d, J = 8.6 Hz, 2 H, 2 ϫ ArH), 7.40 (d, J =
8.7 Hz, 2 H, 2 ϫ ArH), 7.36 (d, J = 8.6 Hz, 2 H, 2 ϫ ArH),
7.34–7.29 (m, 2 H, 2ϫ oxindole-H), 7.15 (td, J = 7.7, 0.9 Hz, 1 H,
oxindole-H), 4.36 (d, J = 8.0 Hz, 1 H, CH), 4.09 (d, J = 8.0 Hz,
1 H, CH), 1.57 (s, 9 H, Boc) ppm. 13C NMR (101 MHz, CDCl3):
δ = 190.4, 188.8, 169.7, 148.8, 140.9, 140.4, 140.4, 134.8, 134.5,
130.2, 130.0, 129.3, 129.3, 129.2, 124.9, 122.7, 122.0, 115.4, 85.2,
41.3, 40.5, 40.0, 28.1 ppm. HRMS (ESI): m/z calcd. for
C29H23Cl2NO5Na+ [M + Na]+ 558.0845; found 558.0859.
(1S,2S,3S)-tert-Butyl 2-Acetyl-3-(4-nitrobenzoyl)-2Ј-oxospiro[cyclo-
propane-1,3Ј-indoline]-1Ј-carboxylate (3h): Synthesized according to
the general procedure from N-Boc-3-chlorooxindole 1a and (E)-1-
(4-nitrophenyl)pent-2-ene-1,4-dione (2h). The product was isolated
as a single diastereoisomer in 62% yield (28 mg) as a red solid with
drϾ 20:1 (1H NMR analysis of crude material) and ee 68% for the
major isomer [Chiralpak AD-H; Hex/iPrOH, 8:2; 1 mL/min; 25 °C;
230 nm; tR = 12.8 (major), 37.6 (minor) min]. [α]2D5 = +261.4 (c =
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J =
8.8 Hz, 2 H, 2ϫ Ar), 7.96–7.90 (m, 3 H, 2ϫ Ar, oxindole-H), 7.41
(ddd, J = 8.3, 7.6, 1.4 Hz, 1 H, oxindole-H), 7.32 (dd, J = 7.7,
0.9 Hz, 1 H, oxindole-H), 7.22 (td, J = 7.6, 1.0 Hz, 1 H, oxindole-
H), 3.91 (d, J = 8.0 Hz, 1 H, CH), 3.75 (d, J = 8.0 Hz, 1 H, CH),
2.30 (s, 3 H, COCH3), 1.55 (s, 9 H, Boc) ppm. 13C NMR
(101 MHz, CDCl3): δ = 199.7, 188.8, 169.7, 150.7, 148.7, 140.4,
140.3, 129.5 (2ϫ C), 125.0, 124.2, 122.3, 122.2, 115.5, 85.3, 43.3,
41.0, 39.8, 32.0, 28.1 ppm. HRMS (ESI): m/z calcd. for
C24H22N2O7Na+ [M + Na]+ 473.1319; found 473.1319.
(2S,3S)-tert-Butyl 2,3-Bis(4-nitrobenzoyl)-2Ј-oxospiro[cyclopropane-
1,3Ј-indoline]-1Ј-carboxylate (3e): Synthesized according to the ge-
neral procedure from N-Boc-3-chlorooxindole 1a and (E)-1,4-bis-
(4-nitrophenyl)but-2-ene-1,4-dione (2e). The product was isolated
as a single diastereoisomer in 60% yield (33 mg) as a light-orange
solid with dr 9:1 (1H NMR analysis of crude material) and ee 87%
for the major isomer [Chiralpak AD-H; Hex/iPrOH, 8:2; 1 mL/
min; 25 °C; 230 nm; tR = 53.5 (major), 61.2 (minor) min]. [α]2D5
=
1
+222.2 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.29
(d, J = 8.9 Hz, 2 H, 2ϫ ArH), 8.25 (d, J = 8.9 Hz, 2 H, 2ϫ ArH),
8.12 (d, J = 8.9 Hz, 2 H, 2ϫ ArH), 7.97 (d, J = 8.9 Hz, 2 H, 2ϫ
ArH), 7.90 (d, J = 8.2 Hz, 1 H, oxindole-H), 7.38 (ddd, J = 8.3,
7.6, 1.4 Hz, 1 H, oxindole-H), 7.32 (dd, J = 7.8, 0.8 Hz, 1 H, oxind-
ole-H), 7.18 (td, J = 7.7, 1.1 Hz, 1 H, oxindole-H), 4.41 (d, J =
7.8 Hz, 1 H, CH), 4.17 (d, J = 7.8 Hz, 1 H, CH), 1.56 (s, 9 H,
Boc) ppm. 13C NMR (101 MHz, CDCl3): δ = 190.3, 188.4, 169.4,
151.0, 150.8, 148.5, 140.6, 140.5, 140.1, 129.9, 129.8, 129.6, 125.1,
124.3, 124.2, 122.0, 121.8, 115.7, 85.6, 41.8, 40.3, 40.2, 28.1 ppm.
HRMS (ESI): m/z calcd. for C29H23N3O9Na+ [M + Na]+ 580.1327;
found 580.1342.
(1R,2S,3S)-1Ј-tert-Butyl 2-Methyl-3-(4-methylbenzoyl)-2Ј-oxospiro-
[cyclopropane-1,3Ј-indoline]-1Ј,2-dicarboxylate (3i): Synthesized ac-
cording to the general procedure from N-Boc-3-chlorooxindole 1a
and (E)-methyl-4-oxo-4-(p-tolyl)but-2-enoate (2i). The product was
isolated as an inseparable mixture (13 mg) of 3i (drϾ 20:1) and one
of the diastereoisomers of 4i with ratio 1.2:1 (1H NMR analysis of
crude material). 1H NMR (400 MHz, CDCl3): δ (mixture of 3i and
4i, normalized to 3i) = 7.97–7.90 (m, 3.48 H, ArH 4i, oxindole-H
4i, oxindole-H 3i), 7.68 (d, J = 8.2 Hz, 2 H, 2ϫ ArH 3i), 7.52 (dd,
J = 7.8, 0.9 Hz, 1 H, oxindole-H 3i), 7.44 (dd, J = 7.7, 1.1 Hz, 0.8
H, oxindole-H 4i), 7.43–7.37 (m, 1.9 H, 2ϫ oxindole-H 4i), 7.30
(d, J = 8.0 Hz, 1.7 H, 2ϫ ArH 4i), 7.22 (tdd, J = 7.6, 3.6, 1.0 Hz,
2 H, 2ϫ oxindole-H 3i), 7.17 (d, J = 8.0 Hz, 2 H, 2ϫ ArH 3i), 4.26
(dd, J = 10.5, 2.7 Hz, 0.8 H, CH 4i), 3.94 (dd, J = 17.4, 10.5 Hz, 0.9
H, CH2 4i), 3.82 (d, J = 8.1 Hz, 1 H, CH 3i), 3.80 (dd, J = 17.4,
2.7 Hz, 0.8 H, CH2 4i), 3.72 (s, 3 H, OCH3 3i), 3.52 (d, J = 8.1 Hz,
1 H, CH 3i), 3.45 (s, 2.5 H, OCH3 4i), 2.43 (s, 2.4 H, ArCH3 4i),
(2S,3S)-tert-Butyl 2,3-Dibenzoyl-5Ј-bromo-2Ј-oxospiro[cyclo-
propane-1,3Ј-indoline]-1Ј-carboxylate (3f): Synthesized according to
the general procedure from N-Boc-3-chlorooxindole 1b and (E)-
1,4-diphenylbut-2-ene-1,4-dione (2b). The product was isolated as
a single diastereoisomer in 59% yield (32 mg) as a light-orange
solid with dr 8:1 (1H NMR analysis of crude material) and ee 71%
for the major isomer [Chiralpak AD-H; Hex/iPrOH, 9:1; 1 mL/
min; 25 °C; 230 nm; tR = 9.7 (major), 13.1 (minor) min]. [α]2D5
+215.5 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.03–
=
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O42061
/KAP1
Date: 17-04-14 18:03:31
Pages: 9
T. Kanger et al.
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2.36 (s, 3 H, ArCH3 3i), 1.67 (s, 8.4 H, Boc 4i), 1.54 (s, 9 H, Boc
3i) ppm. HRMS (ESI): m/z for 3i: calcd. for C25H25NO6Na+ [M +
Na]+ 458.1574; found 458.1576. HRMS (ESI): m/z for 4i: calcd. for
C25H26ClNO6Na+ [M + Na]+ 494.1341; found 494.1341.
(1R,2S,3S)-1Ј-tert-Butyl 2-Methyl-3-(4-chlorobenzoyl)-2Ј-oxospiro-
[cyclopropane-1,3Ј-indoline]-1Ј,2-dicarboxylate (3j): Synthesized ac-
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and (E)-methyl-4-(4-chlorophenyl)-4-oxobut-2-enoate (2j). The
product was isolated as an inseparable mixture (44 mg) of 3j (drϾ
20:1) and two diastereoisomers of 4j with ratio 2:1.5:1 (1H NMR
1
analysis of crude material). H NMR (400 MHz, CDCl3): δ (mix-
ture of 3j and 4j, normalized to 3j) = 8.01–7.90 (m, 4.5 H), 7.88
(d, J = 8.2 Hz, 0.6 H, oxindole-H 4j), 7.71 (d, J = 8.6 Hz, 2 H, 2ϫ
ArH 3j), 7.55 (dd, J = 7.6, 1.3 Hz, 0.6 H, oxindole-H 4j), 7.50 (dd,
J = 7.9, 1.3 Hz, 1 H, oxindole-H 3j), 7.49–7.37 (m, 5.9 H), 7.34 (d,
J = 8.6 Hz, 2 H, 2ϫ ArH 3j), 7.25–7.17 (m, 2.2 H), 4.25 (dd, J =
10.5, 2.7 Hz, 0.8 H, CH 4j), 4.20 (dd, J = 9.3, 3.5 Hz, 0.6 H, CH
4j), 3.98–3.86 (m, 1.4 H, CH2 4j), 3.83–3.74 (m, 1.37 H, CH2 4j),
3.79 (d, J = 8.0 Hz, 1 H, CH 3j), 3.72 (s, 3 H, OCH3 3j), 3.49 (d,
J = 8.0 Hz, 1 H, CH 3j), 3.44 (s, 2.3 H, OCH3 4j), 3.43 (s, 1.6 H,
OCH3 4j), 1.66 (s, 7.2 H, Boc 4j), 1.66 (s, 5.3 H, Boc 4j), 1.54 (s, 9
H, Boc 3j) ppm. HRMS (ESI): m/z for 3j: calcd. for
C24H22ClNO6Na+ [M + Na]+ 478.1028; found 478.1030. HRMS
(ESI): m/z for 4j: calcd. for C24H23Cl2NO6Na+ [M + Na]+
514.0795; found 514.0800.
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Supporting Information (see footnote on the first page of this arti-
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assignment of 5c, 3h, and 3c-NH. 1H and 13C NMR spectra, chiral
HPLC chromatograms, and computational details.
ˇ
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The authors thank the Estonian Ministry of Education and Re-
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Development Fund (3.2.0101.08-0017) for financial support.
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Received: February 12, 2014
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42061
/KAP1
Date: 17-04-14 18:03:31
Pages: 9
Asymmetric Spirocyclopropane Derivatives of Oxindole
Small Ring Systems
ˇ
ˇ
Symmetrically substituted trans-isomers of
spirocyclopropane oxindole were obtained
in high ee through asymmetric organocata-
lysis, whereas the racemic cis-isomer was
only formed as a minor product.
M. Oseka, A. Noole, S. Zari, M. Öeren,
I. Järving, M. Lopp, T. Kanger* ....... 1–9
Asymmetric Diastereoselective Synthesis of
Spirocyclopropane Derivatives of Oxindole
Keywords: Organocatalysis / Asymmetric
synthesis / Cyclization / Michael addition /
Small ring systems
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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