Asymmetric synthesis of congested spiro-cyclopentaneoxindoles via an organocatalytic cascade reaction

Article abstract of DOI:10.1021/jo4008223

Starting from simple alkylidene oxindoles and nitroketones, a highly stereoselective methodology was developed for the synthesis of spiro-cyclopentaneoxindoles with four consecutive stereogenic centers. Using an organocatalytic cascade of Michael and aldol reactions in the presence of a chiral thiourea catalyst products were obtained in moderate to high yields and excellent enantioselectivities. Nitro, ester, and hydroxyl groups were introduced to the spiro ring, which could be used to facilitate further functionalization of the products.

Full text of DOI:10.1021/jo4008223

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Note
Asymmetric synthesis of congested spiro-
cyclopentaneoxindoles via an organocatalytic cascade reaction
Artur Noole, Kaja Ilmarinen, Ivar Jarving, Margus Lopp, and Tõnis Kanger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4008223 • Publication Date (Web): 23 Jul 2013
Downloaded from http://pubs.acs.org on August 5, 2013
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Asymmetric synthesis of congested spiro-
cyclopentaneoxindoles via an organocatalytic cascade
reaction
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Artur Noole, Kaja Ilmarinen, Ivar Järving, Margus Lopp and Tõnis Kanger*
Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618
Tallinn, Estonia
kanger@chemnet.ee
Abstract
Starting from simple alkylidene oxindoles and nitroketones, a highly stereoselective
methodology was developed for the synthesis of spiro-cyclopentaneoxindoles with
four consecutive stereogenic centers. Using an organocatalytic cascade of Michael
and aldol reactions in the presence of a chiral thiourea catalyst products were obtained
in moderate to high yields and excellent enantioselectivities. Nitro, ester and hydroxyl
groups were introduced to the spiro ring, which could be used to facilitate further
functionalization of the products.
A spirooxindole scaffold makes up the core of many natural and synthetic bioactive
compound1, 2, 3, 4 exhibiting a broad range of activities, including antitumor5 and anti-
malarial activity. 6 (Figure 1) For those reasons, the asymmetric synthesis of
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spirooxindoles has received considerable attention (for recent reviews, see references7,
8). However, the formation of spiro rings with multiple consecutive stereocenters still
remains an inspiring and difficult task.9, 10, 11
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The main challenges en route to chiral spirooxindoles are the formation of a
quaternary spiro center and the need to exhibit a stringent control over the
stereochemical outcome of the reaction, as in most cases multiple stereocenters are
formed.
O
HN
N
O
N
OH
H
N
O
O
H
H
O
O
O
HN
N
N
H
N
O
HN
O
O
NO2
O
marcfortine B
Cyclopiamine B
Cintrinadin A
Figure 1. Spirooxindole containing natural products.
Many strategies have been devised for spirooxindole core formation, with the ones
employing alkylidene oxindoles as precursors being most prominent.12 , 13 , 14 , 15
Alkylidene indolinones are activated via the carbonyl group for the initial Michael
addition, effectively delaying the formation of the quaternary center that takes place
during the cyclization step to form the spiro ring. This tactic allows to overcome the
high-energy barrier associated with quaternary center formation, as well as delivering
the chiral induction for the later stages of the cascade by the initial chirality generated
by a Michael addition step.
Among the other spirooxindoles the synthesis of functionalized all-carbon spiro-
cyclopentane derivatives is still a challenge.16,17,18,19 20 More important than the size of
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the cycle is it’s substitution pattern enabling constructing various derivatives of spiro-
cyclopentaneoxindoles with the promising medicinal properties. In a recent paper21
we described a new methodology for the asymmetric synthesis of spiro-
cyclopropyloxindoles22 starting from alkylidene indolinones. Inspired by this work, as
well as recent literature examples and success in our own laboratory in
organocatalytic Michael23, 24, 25, 26, 27 and aldol reactions,28 we set out to develop a new
methodology for the formation of highly substituted spiro-cyclopentaneoxindoles (the
structural core of many natural products) employing alkylidene oxindoles and
nitroketones as precursors. β-Nitroketones 2 with an ethylene bridge between
functional groups, which both can be activated by hydrogen-bonding can act as
versatile substrates for organocatalysis.29 Although, the nucleophilic and electrophilic
sites are present in the same molecule, a sufficiently short linker ensures a suppressed
intramolecular reaction making them ideal building blocks for cascade reactions. With
these considerations, we envisioned a new Michael – aldol cascade using alkylidene
oxindoles and nitroketones leading to the formation of highly functionalized spiro-
cyclopentaneoxindoles (Scheme 1). Nitro, ester and hydroxyl groups in the target
compound are reactive sites for further transformations making obtained spiro-
cyclopentaneoxindoles highly valuable building blocks.
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O2N
Michael
addition
R1
R1
OH
R3
O
R3
NO2
Aldol
reaction
R2
O
R2
O
N
N
Boc
3
Boc
2
1
Scheme 1. Retrosynthetic analysis for spiro-cyclopentaneoxindoles formation.
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This two-step cascade reaction involves an initial Michael addition of nitronate to
alkylidene oxindole 1, followed by intramolecular cyclization via an aldol reaction. In
the course of the cascade, four consecutive stereogenic centers are formed, two of
which are quaternary. From the outset, it was envisioned, that the reaction could be
catalyzed by bifunctional thiourea or a squaramide catalyst (Figure 2),30, 31, 32 as both
alkylidene indolinones 1 and nitroketones 2 can by activated by hydrogen bonding. It
was deemed necessary for the alkylidene oxindole to bear a protecting group, as this
could provide an additional hydrogen bond acceptor group, as well as increasing the
solubility of the substrate. It is known that the protective group at nitrogen of the
oxindole influences the stereoselectivity of the aldol reaction.33,34 From the synthetic
point of view it was reasonable to use easily removable boc-group. For the generation
of a nitronate, however, the presence of a tertiary amine subunit within the catalyst
was considered to be crucial (deprotonation during nitronate formation).
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Et
Et
N
OMe
OMe
N
NMe2
N
N
H
NH
NH
HN
HN
NH
NH
N
S
N
S
S
NH
O
NH
O
CF3
F3C
CF3
CF3
F3C
F3C
CF3
7
F3C
6
5
4
Figure 2. Catalysts used.
To investigate the proposed cascade, a model reaction between alkylidene oxindole 1a
and nitroketone 2a was chosen (Table 1). Initial optimization experiments were
conducted in toluene at ambient temperature. To our delight, when 10 mol % of
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thiourea 4 catalyst was used, in the presence of two equivalents of nitroketone 2a,
product was isolated in 86% yield with 10:1 diastereomeric ratio and 96% ee (Table 1,
entry 1). Lowering the catalyst loading and excess of nitroketone had a detrimental
effect on the reaction rate and yield (Table 1, entry 2). Squaramide 5 as well as
thioureas 6 and 7, provided inferior results in respect to catalyst 4 (Table 1, entries 3-
6). When solvent was switched from toluene to DCM, however, the reaction rate was
slightly increased with only a minor influence on the stereoselective outcome of the
reaction (Table 1, entry 7).
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TABLE 1. Screening results.a
O2N
MeOOC
*
MeOOC
*
OH
*
O
*
catalyst*
O
O
solvent, r.t.
NO2
N
N
Boc
3aa
Boc
2a
1a
entry
2 (equiv)
catalyst (mol %)
4 (10 mol %)
4 (5 mol %)
5 (5 mol %)
6 (5 mol %)
6 (10 mol %)
7 (10 mol %)
4 (10 mol %)
solvent
time (h)
yield (%)b
d.r.c
10:1
10:1
3:1
ee (%)d
96
1
2
3
4
5
6
7
2
1.2
1.2
1.2
2
toluene
toluene
toluene
toluene
toluene
toluene
DCM
3
20
46
24
3
86
57
29
49
75
71
87
96
82
7:1
-94
-99
-99
95
7:1
2
2
5:1
2
2
10:1
a Reaction conditions: alkylidene oxindole, nitroketone and catalyst were mixed and stirred at RT until
TLC showed full conversion; b isolated yield; c determined by 1H NMR; d determined by chiral HPLC.
With the optimal conditions in hand (1 equiv of 1, 2 equiv. of 2, 10 mol % thiourea 4
in DCM), next we set out to determine the full substrate scope for the reaction
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(Scheme 2). Different alkylidene oxindoles 1 were subjected to the reaction
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7
conditions, both with electron withdrawing and donating groups at the aromatic ring.
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O2N
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EtOOC
OH
Br
O
N
H
Figure 3. X-ray structure of spirooxindole 3ea’ (one of two similar molecules in the
asymmetric unit).
Scheme 2. Substrate scope experiments.a
O2N
R1
R1
OH
R3
O
O
catalyst 4
R2
R2
O
R3
NO2
DCM, r.t.
2-6h
N
N
Boc
Boc
2
1
3
O2N
O2N
EtOOC
O2N
MeOOC
EtOOC
O2N
OH
OH
OH
O
O
O
N
N
N
Boc
Boc
Boc
F
3ca
Yield = 92%
d.r. 10:1/ee = 95%
3ba
Yield = 79%
d.r. 10:1/ee = 97%
3aa
Yield = 87%
d.r. 10:1/ee = 95%
O2N
O2N
O2N
O2N
EtOOC
MeO
OH
EtOOC
Cl
EtOOC
Br
EtOOC
F3CO
OH
OH
OH
O
O
O
O
N
N
N
N
Boc
Boc
Boc
Boc
3ga
Yield = 93%
d.r. 12:1/ee = 98%
3fa
Yield = 94%
3ea
Yield = 94%
d.r. 20:1/ee = 97%
3da
Yield = 85%
d.r. 20:1/ee = 95%
d.r. 20:1/ee = 97%
a Reaction conditions: 1equiv. of alkylidene oxindole 1 (0.15 mmol), 2
equiv. of nitroketone 2 (0.3 mmol) and 10 mol % of catalyst 4 (0.015
mmol) were mixed at ambient temperature in DCM (0.5 mL).
The electronic nature of an alkylidene oxindole 1 had little to no effect on the
reactivity and selectivity of the reaction. All products were obtained in high yield (79-
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94%) and good to excellent diastereoselectivities (from 10:1 to 20:1) and high
enantioselectivities (Scheme 2). Although, it should be noted that ester moiety was
essential for the successful reaction outcome, as with phenyl, cyano or 4-nitrobenzoyl
groups either no reaction occurred or a complex mixture of products was detected by
TLC.
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The absolute stereochemistry of the product was unambiguously assigned by a single
crystal x-ray diffraction of spiro-cyclopentanoxindole 3ea after the boc-group had
been cleaved (Figure 3). Other compounds in the series were assigned based on
analogy. Taking into account the structural information gained from the x-ray
structure we propose that after the initial Michael addition of the nitronate to
alkylidene oxindole has occurred ester and nitro groups are in trans orientation. The
carbonyl group of the ketone and nitro group are hydrogen-bonded to the catalyst,
efficiently fixing their orientation for the cyclization to proceed stereospecifically.
This ensures a preferred cis-configuration of the nitro and hydroxyl groups in the final
product.
To further expand the substrate scope of our methodology, different nitroketones 2
were synthesized and subjected to the reaction conditions (Scheme 3). A clear
correlation between the size of the substituent R3 and reaction rate, as well as
selectivity, emerged. With the ethyl group as R3, only a slight drop in
diastereoselectivity was observed (d.r. 6:1) as the product was obtained in high yield
and 97% ee for the major isomer. The benzyl substituent proved more challenging as
only moderate selectivity (d.r. 2:1) and yield (51%) were achieved (Scheme 3). The
sterically bulkiest isobutyl group produced product with high d.r. 10:1 but with low
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yield (25 %). Finally, phenyl substituted nitroketone was prepared but under optimal
cascade reaction conditions no product was obtained. It is noteworthy, however, that
in all cases high enantioselectivity was retained.
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Scheme 3. Substrate scope experiments.a
O2N
MeOOC
MeOOC
OH
R3
O
O
catalyst 4
O
R3
NO2
DCM, r.t.
2-24h
N
N
Boc
Boc
2
1
3
O2N
O2N
O2N
MeOOC
MeOOC
MeOOC
OH
OH
OH
Ph
O
O
O
N
N
N
Boc
Boc
Boc
3ad
Yield = 25%
d.r. 10:1/ee = 96%
3ac
Yield = 51%
d.r. 3:1/ee = 97%
3ab
Yield = 86%
d.r. 6:1/ee = 97%
a Reaction conditions: 1equiv. of alkylidene oxindole 1 (0.15 mmol), 2
equiv. of nitroketone 2a (0.3 mmol) and 10 mol % of catalyst 4 (0.015
mmol) were mixed at ambient temperature in DCM (0.5 mL).
In conclusion we have developed a new organocatalytic, highly enantioselective
methodology for the synthesis of spiro-cyclopentaneoxindoles via a Michael – aldol
cascade reaction. During the cascade reaction four consecutive stereogenic centers
were formed, two of which were quaternary. In most cases, high diastereoselectivities
were observed (up to 20:1) which were only diminished when sterically more
demanding nitroketones were employed as reaction substrates. The final product can
be easily unprotected to obtain free spirooxindoles and versatile functional groups
(nitro, hydroxyl and ester) were introduced to the spiro ring, which could easily be
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transformed to other functionalities. This represents a novel strategy for the synthesis
of highly functionalized spirooxindoles with an all-carbon spiro ring.
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Experimental section
General
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Full assignment of H and C chemical shifts is based on the 1D and 2D FT NMR
spectra on a 400 MHz instrument. Solvent peaks (CHCl3/CDCl3 δ=7.26/77.16) were
used as chemical shift references. Chiral HPLC was performed using Chiralcel OD-H,
Chiralpak AD-H and Chiralpak AS-H columns. Mass spectra were recorded by using
Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS spectrometer by
using AJ-ESI ionization. Precoated silica gel 60 F254 plates were used for TLC,
whereas for column chromatography Merck silica gel was used. Commercial reagents
were generally used as received. DCM and EtOAc were distilled from P2O5.
Synthesis of catalysts
Thiourea 6 was commercially available from Strem and used as received. Thioureas 4
and 7 and squaramide 5 were prepared according to literature procedures.353637
Synthesis of starting materials
Methylene indolinones 1a-g were prepared according to literature procedures from
commercially available isatines using a Boc protection – Wittig sequence. 38
Nitroketones 2 were prepared as described by Miyakoshi et al.39
5-methyl-1-nitrohexan-3-one 2d. Synthesis is based on the literature procedure.39 5-
methylhex-1-en-3-one (0.6 g, 5.4 mmol) and sodium nitrite (0.74 g, 10.7 mmol) were
dissolved in THF (2.7 mL). Acetic acid (0.6 mL, 10.7 mmol) was added dropwise and
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left stirring at ambient temperature for overnight. The reaction mixture was extracted
with water/DCM, organics back-extracted with sat NaHCO3 and dryed over MgSO4.
Filtered, concentrated and purifed by silica gel column chromatography (eluent
petrooleum ether : acetone 20:1) to yield 337 mg (40%) of product as yellow oil. IR ν:
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1
2961, 1717, 1557 cm-1; H NMR (400 MHz, Chloroform-d) δ 4.67 – 4.62 (m, 2H),
3.04 (t, J = 6.0 Hz, 2H), 2.40 (d, J = 7.0 Hz, 2H), 2.26 – 2.12 (m, 1H), 0.95 (d, J = 6.6
13
Hz, 6H). C NMR (101 MHz, CDCl3) δ 205.7, 69.0, 51.9, 38.9, 24.7, 22.6. HRMS
(ESI) calcd for [M+Na]+ (C7H13NO3Na)+ requires m/z 182.0788, found 182.0788.
General procedure for the synthesis of spiro-cyclopentaneoxindoles
Methylene oxindole 1 (0.15 mmol, 1 equiv.), nitroketone 2 (0.3 mmol, 2 equiv.) and
thiourea 4 (10 mol %, 0.015 mmol) were dissolved in DCM (0.5 mL) and stirred at
ambient temperature until TLC showed complete disappearance of the limiting
starting material. Mixture was directly purified by silica gel column chromatography
using a mixture of heptane/EtOAc as eluent. Diastereomeric ratio was determined by
1H NMR and enantioselectivity by chiral HPLC analysis.
1'-(tert-butyl)-5-methyl-(1S,2R,4S,5S)-2-hydroxy-2-methyl-4-nitro-2'-oxospiro-
[cyclopentane-1,3'-indoline]-1',5-dicarboxylate 3aa. Synthesized according to
general procedure from tert-butyl-(E)-3-(2-methoxy-2-oxoethylidene)-2-oxoindoline-
1-carboxylate 1a and 4-nitrobutan-2-one 2a. Product was isolated after silica gel
column chromatography using a mixture of heptane:EtOAc as an eluent in 87 % yield
(55 mg) with d.r. 10/1 and ee 99% that was determined after the cleavage of the boc-
group [Chiralcel AD-H, Hex:iPrOH 80:20, 1 mL/min, 230 nm; major (tR = 9.44 min)
and minor (tR = 8.04 min)]; IR ν: 3497, 2981, 2258, 1783, 1739, 1556 cm-1; 1H NMR
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(400 MHz, Chloroform-d) δ 7.87 (dt, J = 8.2, 0.8 Hz, 1H), 7.47 (ddd, J = 7.5, 1.5, 0.5
Hz, 1H), 7.42 – 7.36 (m, 1H), 7.22 (td, J = 7.6, 1.1 Hz, 1H), 5.55 (ddd, J = 10.4, 6.3,
1.9 Hz, 1H), 4.70 (d, J = 6.3 Hz, 1H), 3.56 (s, 3H), 3.18 (dd, J = 15.3, 10.4 Hz, 1H),
2.61 (dd, J = 15.1, 1.9 Hz, 1H), 2.20 (s, 1H), 1.63 (s, 9H), 1.03 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 175.9, 169.9, 148.8, 140.8, 129.6, 125.2, 124.7, 124.5, 115.2, 85.2,
85.0, 82.4, 65.8, 54.8, 52.9, 43.2, 28.2, 21.6. HRMS (ESI) calcd for [M+Na]+
(C20H24N2O8Na)+ requires m/z 443.1425, found 443.1423.
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1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-7'-fluoro-2-hydroxy-2-methyl-4-nitro-2'-
oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3ba.
Synthesized
according to general procedure from tert-butyl-(E)-3-(2-ethoxy-2-oxoethylidene)-7-
fluoro-2-oxoindoline-1-carboxylate 1b and 4-nitrobutan-2-one 2a. Product was
isolated after silica gel column chromatography using a mixture of heptane:EtOAc as
an eluent in 79 % yield (54 mg) with d.r. 10/1 and ee 97% [Chiralcel AD-H,
Hex:iPrOH 90:10, 1 mL/min, 230 nm; major (tR = 10.01 min) and minor (tR = 11.02
1
min)]; IR ν: 3503, 2983, 2259, 1783, 1743, 1556 cm-1; H NMR (400 MHz,
Chloroform-d) δ 7.31 (dd, J = 7.2, 1.5 Hz, 1H), 7.25 – 7.12 (m, 2H), 5.56 (ddd, J =
10.3, 6.0, 1.7 Hz, 1H), 4.66 (d, J = 5.9 Hz, 1H), 4.12 – 3.93 (m, 2H), 3.22 – 3.10 (m,
1H), 2.69 – 2.60 (m, 1H), 2.25 – 2.20 (m, 1H), 1.59 (s, 9H), 1.09 – 1.01 (m, 6H). 13C
NMR (101 MHz, CDCl3) δ 175.1, 169.1, 148.5 (d, J = 251.0 Hz), 147.1, 128.9 (d, J =
2.2 Hz), 127.5 (d, J = 9.5 Hz), 125.5 (d, J = 7.0 Hz), 120.6 (d, J = 3.5 Hz), 117.7 (d, J
= 20.3 Hz), 85.2 (d, J = 32.7 Hz), 82.6, 66.2 (d, J = 1.7 Hz), 62.1, 54.8, 42.9, 27.7,
21.4, 13.6. HRMS (ESI) calcd for [M+H]+ (C21H26FN2O8)+ requires m/z 453.1668,
found 453.1660.
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1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-2-hydroxy-2-methyl-4,5'-dinitro-2'-oxospiro-
[cyclopentane-1,3'-indoline]-1',5-dicarboxylate 3ca. Synthesized according to
general procedure from tert-butyl-(E)-3-(2-ethoxy-2-oxoethylidene)-5-nitro-2-
oxoindoline-1-carboxylate 1c and 4-nitrobutan-2-one 2a. Product was isolated after
silica gel column chromatography using a mixture of heptane:EtOAc as an eluent in
92 % yield (66 mg) with d.r. 10/1 and ee 95% [Chiralcel AD-H, Hex:iPrOH 90:10, 1
mL/min, 230 nm; major (tR = 12.73 min) and minor (tR = 8.13 min)]; IR ν: 3502,
2983, 1791, 1765, 1740, 1557, 1526 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 8.34
(d, J = 2.5 Hz, 1H), 8.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 5.51 (ddd,
J = 10.5, 6.4, 1.8 Hz, 1H), 4.72 – 4.58 (m, 1H), 4.04 (qd, J = 7.1, 3.4 Hz, 1H), 3.89
(dq, J = 10.7, 7.1 Hz, 1H), 3.16 (dd, J = 15.5, 10.3 Hz, 1H), 2.57 (dd, J = 15.5, 1.8 Hz,
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1H), 2.39 (s, 1H), 1.57 (s, 9H), 1.04 – 0.91 (m, 6H). C NMR (101 MHz, CDCl3) δ
174.9, 168.9, 148.3, 146.0, 144.7, 127.1, 125.7, 121.2, 115.0, 86.3, 85.1, 82.8, 65.4,
62.4, 55.7, 43.8, 28.2, 21.6, 13.8. HRMS (ESI) calcd for [M+K]+ (C21H25N3O10K)+
requires m/z 518.1172, found 518.1169.
1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-2-hydroxy-2-methyl-4-nitro-2'-oxo-5'-
(trifluoromethoxy)spiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
Synthesized according to general procedure from tert-butyl-(E)-3-(2-ethoxy-2-
oxoethylidene)-2-oxo-5-(trifluoromethoxy)indoline-1-carboxylate 1d and 4-
3da.
nitrobutan-2-one 2a. Product was isolated after silica gel column chromatography
using a mixture of heptane:EtOAc as an eluent in 85 % yield (66 mg) with d.r. 20/1
and ee 95% [Chiralcel AD-H, Hex:iPrOH 90:10, 1 mL/min, 230 nm; major (tR = 5.41
min) and minor (tR = 4.77 min)]; IR ν: 3496, 2983, 1787, 1739, 1557 cm-1; 1H NMR
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(400 MHz, Chloroform-d) δ 7.90 (d, J = 8.9 Hz, 1H), 7.41 – 7.38 (m, 1H), 7.29 – 7.21
(m, 1H), 5.56 (ddd, J = 10.3, 6.2, 1.8 Hz, 1H), 4.60 (d, J = 6.2 Hz, 1H), 4.10 (dq, J =
10.8, 7.1 Hz, 1H), 3.94 (dq, J = 10.8, 7.1 Hz, 1H), 3.20 (dd, J = 15.4, 10.4 Hz, 1H),
2.61 (dd, J = 15.3, 1.8 Hz, 1H), 2.26 (s, 1H), 1.62 (s, 9H), 1.06 (s, 3H), 1.02 (t, J = 7.1
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Hz, 3H). C NMR (101 MHz, CDCl3) δ 175.2, 169.1, 148.6, 145.9 (d, J = 2.2 Hz),
139.2, 127.4, 122.1, 120.58 (d, J = 257.4 Hz), 118.7, 115.9, 85.4, 85.1, 82.7, 65.8,
62.1, 55.3, 43.5, 28.2, 21.6, 13.7. HRMS (ESI) calcd for [M+Na]+ (C22H25F3N2O9Na)+
requires m/z 541.1402, found 541.1408.
1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-5'-bromo-2-hydroxy-2-methyl-4-nitro-2'-
oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3ea.
Synthesized
according to general procedure from tert-butyl-(E)-5-bromo-3-(2-ethoxy-2-
oxoethylidene)-2-oxoindoline-1-carboxylate 1e and 4-nitrobutan-2-one 2a. Product
was isolated after silica gel column chromatography using a mixture of
heptane:EtOAc as an eluent in 94 % yield (72 mg) with d.r. 20/1 and ee 97%
[Chiralcel AD-H, Hex:iPrOH 90:10, 1 mL/min, 230 nm; major (tR = 8.39 min) and
minor (tR = 5.85 min)]; IR ν: 3496, 2981, 1785, 1738, 1556 cm-1; 1H NMR (400 MHz,
Chloroform-d) δ 7.70 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.45 (dd, J = 8.7,
2.1 Hz, 1H), 5.48 (ddd, J = 10.3, 6.2, 1.8 Hz, 1H), 4.54 (d, J = 6.1 Hz, 1H), 4.05 (dq, J
= 10.8, 7.1 Hz, 1H), 3.87 (dq, J = 10.8, 7.1 Hz, 1H), 3.12 (ddd, J = 15.4, 10.3, 1.3 Hz,
1H), 2.55 (dd, J = 15.3, 1.7 Hz, 1H), 2.16 (d, J = 1.1 Hz, 1H), 1.55 (s, 9H), 1.01 –
0.93 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 174.9, 169.0, 148.5, 139.7, 132.3,
128.0, 127.6, 117.6, 116.5, 85.2, 85.1, 82.6, 65.6, 62.0, 55.1, 43.2, 28.1, 21.5, 13.6.
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HRMS (ESI) calcd for [M+Na]+ (C21H25BrN2O8Na)+ requires m/z 535.0686, found
535.0687.
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1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-5'-chloro-2-hydroxy-2-methyl-4-nitro-2'-
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oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3fa.
Synthesized
according to general procedure from 1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-5'-bromo-2-
hydroxy-2-methyl-4-nitro-2'-oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
1f and 4-nitrobutan-2-one 2a. Product was isolated after silica gel column
chromatography using a mixture of heptane:EtOAc as an eluent in 94 % yield (66 mg)
with d.r. 20/1 and ee 97% [Chiralcel AD-H, Hex:iPrOH 90:10, 1 mL/min, 230 nm;
major (tR = 7.67 min) and minor (tR = 5.69 min)]; IR ν: 3499, 2982, 1786, 1738, 1556
cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 2.2
Hz, 1H), 7.30 (dd, J = 8.7, 2.3 Hz, 1H), 5.49 (ddd, J = 10.3, 6.1, 1.8 Hz, 1H), 4.54 (d,
J = 6.1 Hz, 1H), 4.05 (dq, J = 10.7, 7.1 Hz, 1H), 3.87 (dq, J = 10.7, 7.1 Hz, 1H), 3.12
(ddd, J = 15.3, 10.3, 1.2 Hz, 1H), 2.55 (dd, J = 15.4, 1.6 Hz, 1H), 2.15 (d, J = 1.2 Hz,
13
1H), 1.55 (s, 9H), 1.04 – 0.89 (m, 6H). C NMR (101 MHz, CDCl3) δ 175.1, 169.1,
148.7, 139.3, 130.2, 129.5, 127.4, 125.3, 116.2, 85.3, 85.2, 82.7, 65.7, 62.1, 55.3,
43.4, 28.2, 28.2, 21.6, 13.7. HRMS (ESI) calcd for [M+Na]+ (C21H25ClN2O8Na)+
requires m/z 491.1191, found 491.1193.
1'-(tert-butyl)-5-ethyl-(1S,2R,4S,5S)-2-hydroxy-5'-methoxy-2-methyl-4-nitro-2'-
oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3ga.
Synthesized
according to general procedure from (E)-ethyl 2-(5-methoxy-2-oxoindolin-3-
ylidene)acetate 1g and 4-nitrobutan-2-one 2a. Product was isolated after silica gel
column chromatography using a mixture of heptane:EtOAc as an eluent in 93 % yield
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(65 mg) with d.r. 12/1 and ee 98% [Chiralcel OD-H, Hex:iPrOH 95:5, 1 mL/min, 230
nm; major (tR = 15.57 min) and minor (tR = 20.66 min)]; IR ν: 2984, 2254, 1789,
1739, 1556 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J = 8.9 Hz, 1H), 7.03
(d, J = 2.7 Hz, 1H), 6.89 (dd, J = 8.9, 2.7 Hz, 1H), 5.55 (ddd, J = 10.4, 6.1, 1.8 Hz,
1H), 4.61 (d, J = 6.1 Hz, 1H), 4.10 (dq, J = 10.8, 7.2 Hz, 1H), 3.90 (dq, J = 10.8, 7.1
Hz, 1H), 3.82 (s, 3H), 3.16 (ddd, J = 15.3, 10.4, 1.6 Hz, 1H), 2.61 (dd, J = 15.2, 1.8
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Hz, 1H), 2.23 (d, J = 1.6 Hz, 1H), 1.61 (s, 9H), 1.05 – 0.97 (m, 6H). C NMR (101
MHz, CDCl3) δ 175.8, 169.4, 156.9, 148.9, 134.0, 126.9, 116.0, 114.0, 111.1, 85.3,
84.7, 82.6, 66.1, 61.9, 55.8, 54.9, 43.1, 28.2, 21.6, 13.7. HRMS (ESI) calcd for
[M+Na]+ (C22H28N2O9Na)+ requires m/z 487.1687, found 487.1692.
1'-(tert-butyl)-5-methyl-(1S,2R,4S,5S)-2-ethyl-2-hydroxy-4-nitro-2'-
oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3ab.
Synthesized
according to general procedure from tert-butyl-(E)-3-(2-methoxy-2-oxoethylidene)-2-
oxoindoline-1-carboxylate 1a and 1-nitropentan-3-one 2b. Product was isolated after
silica gel column chromatography using a mixture of heptane:EtOAc as an eluent in
86 % yield (56 mg) with d.r. 6/1 and ee 97% [Chiralcel AD-H, Hex:iPrOH 90:10, 1
mL/min, 230 nm; major (tR = 11.87 min) and minor (tR = 7.41 min)]; IR ν: 3502,
2980, 1784, 1739, 1556 cm-1; 1H NMR (400 MHz, Chloroform-d) δ 7.86 (dt, J = 8.1,
0.8 Hz, 1H), 7.48 (dd, J = 7.5, 1.3 Hz, 1H), 7.42 – 7.35 (m, 1H), 7.22 (td, J = 7.6, 1.1
Hz, 1H), 5.58 (ddd, J = 10.5, 6.6, 2.0 Hz, 1H), 4.71 (d, J = 6.5 Hz, 1H), 3.57 (s, 3H),
3.13 – 3.04 (m, 1H), 2.58 (dd, J = 15.3, 1.9 Hz, 1H), 2.06 (d, J = 1.6 Hz, 1H), 1.63 (s,
13
9H), 1.54 – 1.42 (m, 1H), 1.12 – 0.99 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H). C NMR
(101 MHz, CDCl3) δ 176.0, 169.9, 148.8, 140.9, 129.6, 125.6, 124.7, 124.4, 115.3,
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85.2, 85.1, 85.0, 66.0, 55.1, 52.9, 41.0, 28.2, 28.2, 27.66, 7.7. HRMS (ESI) calcd for
[M+Na]+ (C21H26N2O8Na)+ requires m/z 457.1581, found 457.1587.
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oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3ac.
Synthesized
according to general procedure from tert-butyl-(E)-3-(2-methoxy-2-oxoethylidene)-2-
oxoindoline-1-carboxylate 1a and 4-nitro-1-phenylbutan-2-one 2c. Product was
isolated after silica gel column chromatography using a mixture of heptane:EtOAc as
an eluent in 51 % yield (38 mg) with d.r. 3/1 and ee 97% for major isomer [Chiralcel
OD-H, Hex:iPrOH 95:5, 1 mL/min, 230 nm; major (tR = 15.72 min) and minor (tR =
17.51 min)]; IR ν: 3494, 2982, 2258, 1785, 1742, 1555 cm-1; For the major isomer: 1H
NMR (400 MHz, Chloroform-d) δ 7.80 – 7.75 (m, 1H), 7.51 (dd, J = 7.5, 1.3 Hz, 1H),
7.33 (td, J = 7.9, 1.4 Hz, 1H), 7.20 – 7.13 (m, 5H), 7.09 – 7.03 (m, 1H), 6.97 – 6.92
(m, 2H), 5.49 (ddd, J = 10.4, 6.4, 1.7 Hz, 1H), 4.68 (d, J = 6.4 Hz, 1H), 3.51 (s, 3H),
3.34 – 3.24 (m, 1H), 2.69 – 2.63 (m, 1H), 2.24 – 2.17 (m, 1H), 2.01 (s, 1H), 1.59 (s,
13
9H). C NMR (101 MHz, CDCl3) δ 176.0, 169.8, 148.8, 140.8, 134.4, 130.1, 129.5,
128.9, 128.2, 127.6, 125.8, 125.3, 115.0, 85.1, 84.9, 83.9, 65.3, 55.5, 52.9, 42.4, 40.5,
28.3. HRMS (ESI) calcd for [M+Na]+ (C26H28N2O8Na)+ requires m/z 519.1738, found
519.1740.
1'-(tert-butyl)-5-methyl-(1S,2R,4S,5S)-2-hydroxy-2-isobutyl-4-nitro-2'-
oxospiro[cyclopentane-1,3'-indoline]-1',5-dicarboxylate
3ad.
Synthesized
according to general procedure from tert-butyl-(E)-3-(2-methoxy-2-oxoethylidene)-2-
oxoindoline-1-carboxylate 1a and 5-methyl-1-nitrohexan-3-one 2d. Product was
isolated after silica gel column chromatography using a mixture of heptane:EtOAc as
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an eluent in 25 % yield (17 mg) with d.r. 10/1 and ee 96% for major isomer [Chiralcel
OD-H, Hex:iPrOH 95:5, 1 mL/min, 230 nm; major (tR = 12.35 min) and minor (tR =
1
6.80 min)]; IR ν: 3512, 2958, 2873, 2258, 1786, 1739, 1556 cm-1; H NMR (400
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MHz, Chloroform-d) δ 7.90 – 7.83 (m, 1H), 7.47 (dd, J = 7.5, 1.3 Hz, 1H), 7.41 (td, J
= 7.9, 1.4 Hz, 1H), 7.23 (td, J = 7.6, 1.0 Hz, 1H), 5.58 (ddd, J = 10.5, 6.6, 1.9 Hz,
1H), 4.66 (d, J = 6.6 Hz, 1H), 3.56 (s, 3H), 3.17 (ddd, J = 15.3, 10.5, 1.6 Hz, 1H),
2.67 (dd, J = 15.2, 2.0 Hz, 1H), 2.05 (d, J = 1.8 Hz, 1H), 1.64 (s, 9H), 1.34 – 1.24 (m,
2H), 0.92 – 0.89 (m, 1H), 0.83 (dd, J = 15.1, 6.6 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 176.0, 169.9, 148.8, 140.9, 129.6, 125.6, 124.8, 124.3, 115.4, 85.4, 85.3,
85.0, 66.7, 54.6, 52.9, 43.0, 41.8, 28.2, 24.4, 24.3, 24.1. HRMS (ESI) calcd for
[M+K]+ (C23H30N2O8K)+ requires m/z 501.1634, found 501.1630.
Methyl-(1S,2R,4S,5S)-2-hydroxy-2-methyl-4-nitro-2'-oxospiro[cyclopentane-1,3'-
indoline]-5-carboxylate 3aa’. Title compound was prepared for the determination of
enantiomeric purity of spiro-oxindole 3aa by treatment with TFA at ambient
temperature. Ee 99% [Chiralcel AD-H, Hex:iPrOH 80:20, 1 mL/min, 230 nm; major
(tR = 9.44 min) and minor (tR = 8.04 min)]; IR ν: 3421, 2989, 1730, 1699, 1546 cm-
1;1H NMR (400 MHz, methanol-d4) δ 7.48 (ddd, J = 7.6, 1.3, 0.6 Hz, 1H), 7.28 (td, J
= 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.6, 1.1 Hz, 1H), 6.92 (dt, J = 7.8, 0.8 Hz, 1H), 5.54
(ddd, J = 10.5, 6.3, 1.9 Hz, 1H), 4.73 (d, J = 6.2 Hz, 1H), 3.52 (s, 3H), 3.13 (dd, J =
14.9, 10.5 Hz, 1H), 2.61 – 2.51 (m, 1H), 1.00 (s, 3H). 13C NMR (101 MHz, MeOD) δ
180.8, 172.1, 144.0, 129.7, 129.1, 127.2, 123.1, 110.4, 86.3, 82.3, 67.3, 55.1, 52.8,
44.7, 21.2. Elemental analysis for C15H16N2O6: required (C, 56.25 %; H, 5.04 %; N,
8.75 %), found (C, 56.12 %; H, 5.06 %; N, 8.72 %).
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Ethyl-(1S,2R,4S,5S)-5'-bromo-2-hydroxy-2-methyl-4-nitro-2'-oxospiro-
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[cyclopentane-1,3'-indoline]-5-carboxylate 3ea’. Title compound was prepared by
treatment of oxindole 3ea (0.13 mmol, 66 mg) with TFA (50 equiv, 6.4 mmol, 0.5
mL) in DCM (5 mL) at ambient temperature (reaction monitored by TLC). Product
was isolated after silica gel column chromatography using a mixture of
heptane/EtOAc as an eluent to afford 52 mg (yield = 98%) of product as white solid
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o
(mp = 168-170 C). Product was used to grow a single crystal for x-ray diffraction.
Optical rotation for the enantipure compound (single crystal): [α] = -142.3 (c = 0.07,
1
MeOH). IR ν: 3419, 2990, 1733, 1698, 1544 cm-1; H NMR (400 MHz, Chloroform-
d) δ 8.11 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.1 Hz, 1H), 6.81 (d, J =
8.2 Hz, 1H), 5.56 (ddd, J = 10.2, 6.3, 1.8 Hz, 1H), 4.62 (d, J = 6.3 Hz, 1H), 4.14 –
3.95 (m, 2H), 3.19 (dd, J = 15.3, 10.4 Hz, 1H), 2.59 (dd, J = 15.4, 1.9 Hz, 1H), 2.35
(s, 1H), 1.12 – 1.03 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 178.3, 169.5, 140.8,
132.2, 129.3, 128.8, 115.6, 111.3, 85.1, 82.2, 65.8, 62.1, 54.6, 43.4, 21.6, 13.8. HRMS
(ESI) calcd for [M+H]+ (C16H18BrN2O6)+ requires m/z 413.0343, found 413.0341.
Acknowledgments. The authors thank the Estonian Science Foundation (grant
No. 8289), the Ministry of Education and Research (grant no. 0140060s12), EU
European Regional Development Fund (3.2.0101.08-0017) for financial support.
Supporting Information
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Copies of H and C NMR spectra, HPLC chromatograms, crystallographic data of
compound 3ea. This material is available free of charge via the Internet at
http://pubs.acs.org.
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