Highly enantio-and diastereoselective generation of two quaternary centers in spirocyclopropanation of oxindole derivatives

Article abstract of DOI:10.1002/chem.201203099

Spirocyclopropanes: Only one out of eight possible stereoisomers was obtained in the asymmetric cascade cyclopropanation of alkylidene oxindoles with ethyl 2-chloroacetoacetate. Improved catalyst design ensured that spirocyclopropyl oxindoles featuring tw

Full text of DOI:10.1002/chem.201203099

COMMUNICATION
DOI: 10.1002/chem.201203099
Highly Enantio- and Diastereoselective Generation of Two Quaternary
Centers in Spirocyclopropanation of Oxindole Derivatives.
[
a, b]
[c]
[a]
[b]
Artur Noole,
Natalia S. Sucman, Mikhail A. Kabeshov, Tꢀnis Kanger,
[c] [a]
Fliur Z. Macaev, and Andrei V. Malkov*
Biologically active spirocyclopropane derivatives of in-
doles emerged recently as potent drug candidates. Thus, spi-
rooxindole 1 exhibited nanomolar activity as an HIV-1 non-
nucleoside reverse transcriptase inhibitor on both wild-type
produced various degrees of diastereoselectivity, but so far
were confined to racemic series. More recently, a few exam-
ples of successful asymmetric cyclopropanation of the
[4,11]
parent oxindoles were reported.
[1,2]
and drug-resistant mutant viruses,
type 2 showed promising antitumor activity
effective for treatment of obesity and diabetes (Scheme 1).
whereas compounds of
Organocatalytic approaches to spiro-annulation of oxin-
doles 5 offer a high degree of stereo- and enantiocontrol
and have become extremely popular for the construction of
[3,4]
and were also
[5]
[12–18]
The stereochemistry of these compounds plays a crucial role
in their biological activity.
five- and six-membered spiro-rings.
However, examples
of a direct spirocyclopropanation of indole derivatives
[19]
remain scarce. The major challenge in the synthesis of 3 is
to ensure a stringent control in the formation of the three
contiguous stereocenters, which, in theory, can give rise up
to eight stereoisomers (four diastereomeric pairs of enan-
[20]
tiomers). In a recent report,
spirooxindoles 3, featuring
one quaternary center, were obtained in excellent diastereo-
and enantioselectivities by a cascade cyclopropanation of 5
with bromonitromethane catalyzed by chiral thioureas.
However, for the next member of the homologue series,
1
-bromonitroethane, in which two adjacent quaternary cen-
ters are created, the diastereocontrol dropped dramatically.
[
11]
Furthermore, it has been recently revealed
that in the
3
4
case of spirooxindoles 3, in which R =NO and R =H, the
2
dia ACHUTNRGENNUGs tereo ACHTUNGRTENNUNGm eric composition can be significantly enriched in
Scheme 1. Biologically active spirocyclopropane derivatives of indoles.
favor of the more thermodynamically stable isomer by a
base-catalyzed equilibration. Naturally, this option is not
3
4
In the past, the main strategies for the construction of spi-
rocylopropyl oxindole motif 3 relied either on transition-
metal-catalyzed cylopropanation using diazo oxindoles 4
available for 3 with R , R ¼
6
H, which leaves the issue of
diastereoselectivity in the asymmetric organocatalytic cyclo-
propanation wide open.
A
H
U
T
E
N
N
ACHTUNGTRENNUNG
[1,6–9]
with a suitable alkene partner
noid species to unsaturated oxindoles 5.
or addition of a carbe-
Herein, we focused on developing a formal [2+1] cycload-
dition method for the highly enantio- and diastereoselective
construction of spirocyclopropane oxindoles 3 featuring two
quaternary centers using chiral catalysts 6–9 (Figure 1).
In recent years, a-halo-b-dicarbonyl compounds acquired
a successful track record in asymmetric organocatalytic and
metal-catalyzed cyclopropanations of a,b-unsaturated com-
[
1–3,10]
Both strategies
[
a] A. Noole, Dr. M. A. Kabeshov, Prof. Dr. A. V. Malkov
Department of Chemistry
Loughborough University
Loughborough LE11 3TU (UK)
Fax : (+44)1509-223925
[21,22]
pounds including aldehydes,
the related conjugated ke-
[23,24]
[25]
E-mail: a.malkov@lboro.ac.uk
tones and esters,
and nitroalkenes. The key feature of
[
b] A. Noole, Prof. Dr. T. Kanger
Department of Chemistry
a-halocarbonyl compounds is the dual nucleophilic/electro-
philic reactivity of the a-carbon, which is a prerequisite for
the cascade cyclopropanation.
Tallinn University of Technology
Akadeemia tee 15, Tallinn 12618 (Estonia)
In a background racemic run, oxindole 5a was treated
[
c] N. S. Sucman, Prof. Dr. F. Z. Macaev
Institute of Chemistry
Academiei str. 3, Chisinau 2028 (Moldova)
with ethyl a-chloroacetoacetate 10 in the presence of K CO3
2
in CH Cl at room temperture to afford an equimolar mix-
2
2
ture of all four possible diastereoisomers after 24 h (Table 1,
entry 1). It is worth noting that the same reaction with un-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203099.
Chem. Eur. J. 2012, 18, 14929 – 14933
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14929

which could be readily separated by flash chromatography
entry 2). Importantly, the major product showed 96% ee.
(
However, attempted reduction of the catalyst loading to a
more practical 10 mol% level had a detrimental effect on
the reaction rate and selectivity. Therefore, we next turned
[27–29]
[30]
to bifunctional thiourea catalysts 7
and 8,
which
proved successful in the asymmetric spirocyclopropanation
[20]
of 5 with bromonitromethane.
Quinine-derived thiourea 7 (10 mol%, CH Cl , RT, 24 h)
2
2
combined with NaHCO (1 equiv) afforded a 3:1 mixture of
3
the same two diastereoisomers, as with 6, in high enantiose-
lectivity, but a low overall yield (entry 3). To optimize the
reaction efficiency, various solvents and bases were exam-
ined. In toluene (entry 4) and MeCN (entry 7), diastereose-
lectivity dropped significantly to give mixtures of all possible
isomers. The highest enantioselectivity was attained in THF,
though the yield and diastereoselectivity were poor
(
entry 6). Chloroform emerged as a clear winner, showing
Figure 1. Chiral catalysts.
the best overall performance (entry 5). Other inorganic
bases, such as Na CO and CsF (entries 8 and 9), proved
2
3
slightly inferior to NaHCO . Catalyst 8 mirrored the results
[
a]
3
Table 1. Optimization of the reaction conditions.
shown by 7 delivering the same 3:1 mixture of dia
ACHTUNGTRENNUNGs tereo-
AHCTUNGTREGiNNNU somers of the opposite enantiomeric series (entry 10).
It appears that the commonly used commercial catalysts
6
–8 under a variety of experimental conditions exhibited a
similar reactivity pattern favoring formation of two dia-
stereoisomers in a 3:1 ratio at best. Notably, the components
A
H
U
G
R
N
U
G
ACHTUNGTRENNUNG
of this mixture cannot be easily separated by chromatogra-
phy, thus reducing the practical value of the method. Clear-
ly, improvement in the catalyst design was required to over-
come this problem.
A set of experiments revealed that diastereoselectivity
was influenced by the substituents on the aromatic group of
the thiourea catalyst, in particular by those restricting rota-
tion about the CꢀN bond. A major improvement was ach-
Entry
Cat.
Base
Solvent
Yield
d.r.
[%]
ee
[%]
[b]
[b]
[c]
[%]
1
2
3
4
5
6
7
8
9
–
K
–
2
CO
3
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
86
72
48
n.d.
97
54
87
87
76
48
82
25:25:25:25
71:24:5
77:23
n.d.
78:22
63:37
9:31:52:8
74:26
77:23
75:25
n.a.
96:55:12
93:95
n.d.
94:96
97:99
n.d.
89:94
93:95
ꢀ93:ꢀ86
91:94
91:82
87:83
[
d]
6
7
7
7
7
7
7
7
8
9
9
9
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
3
[
e]
toluene
CHCl
THF
3
ieved with catalyst 9 with bulky iPr groups occupying the
ortho positions; the diastereoselectivity soared to 13:1 while
maintaining a good yield and a respectable enantioselectivi-
ty (entry 11). Effectively, only one of eight possible stereo-
isomers was produced! The yield was further improved by
doubling the concentration of the reactants (entry 12),
though using an excess of ethyl a-chloroacetoacetate 10
alone proved detrimental (entry 13).
MeCN
Na
2
CO
3
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
3
3
3
3
3
3
CsF
10
11
12
13
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
93:7
91:9
90:10
[
f]
97
93
[
g]
[
a] Unless stated otherwise, the reactions were carried out on a
0
2
.15 mmol scale as a 0.15m solution at RT for 24 h with 1 equiv of 5a,
equiv of 10, 1 equiv of base and 10 mol% catalyst loading. [b] Yield of
The reaction scope was investigated following the opti-
mized protocol: chloroform as a solvent (0.3m solution), 5
isolated product. [c] Determined by chiral HPLC analyses after deprotec-
tion of tBoc. [d] 1 Equiv of catalyst was used. [e] Complex mixture of all
possible diastereoisomers. [f] 0.3m Solution. [g] 4 Equiv of 10 used.
(
1 equiv), 10 (2 equiv), NaHCO (1 equiv), and 9 (10 mol%)
3
at room temperature. Under these conditions, the reactions
were complete within 24 h (Scheme 2). The substitution pat-
tern in the aromatic ring of the starting oxindoles 5a–f did
not affect the efficacy of the process: the spirocyclopropanes
11a–f were uniformly obtained in high yields and high enan-
tio- or diastereoselectivities.
The reaction is likely to proceed by Michael addition of
the enolate of 10 to the unsaturated amide fragment in 5 to
generate two new stereogenic centers followed by cycliza-
tion to create the final spiro-stereocenter. To shed more
light on the stereoselectivity in each step, symmetrical
protected oxindole 5 was complete in just 1 h and gave a
similar outcome, but we opted for tert-butoxycarbonyl (Boc)
protection, which may benefit stereodifferentiation in the
presence of a chiral controller.
For the enantioselective version, we first tested cinchoni-
dine 6 (Figure 1) as a chiral base (1 equiv, CH Cl , RT).
[
26]
2
2
The reaction produced a 3:1 mixture of two main dia
ACHTUNGTRENNUNGi somers and a minor quantity of a third diastereoisomer,
ACHTUNGTRNENUNGs tereo-
14930
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14929 – 14933

Spirocyclopropanation of Oxindoles
COMMUNICATION
Scheme 2. Cyclopropanation of oxindoles 5 with 2-chloroacetoacetate
(
10).
3
(
-chloroacetylacetone (12) and dimethyl chloromalonate
13) were examined (Scheme 3).
-Chloroacetylacetone (12) exhibited reactivity virtually
3
identical to 10 furnishing 14a–f in high yield and with high
level of stereocontrol. The lower diastereomeric ratios ob-
served in the case of 14c and d resulted from the reversed
diastereoselectivity in the racemic series, in which the minor
isomers were formed predominantly. Chloromalonate 13
proved the least reactive of the three halodicarbonyl re-
agents. Under identical conditions, the reaction required
Scheme 3. Cyclopropanation of oxindoles 5 with 3-chloroacetylacetone
(
12; 24 h) and dimethylchloromalonate (13; 48 h).
stereogenic centers thus formed are not “adjusted” in the
later stages of the reaction. The spirocenter is created in the
second cyclization step, which in the case of 11 occurs
through intermediate A (Scheme 4). In this step, both cata-
lysts 7 and 9 proved equally competent ensuring Si facial se-
lectivity for the major diastereoisomer (the opposite enan-
tiomer was formed in the case of 8). It can be speculated
that in the CꢀC bond-forming event, the catalyst brings the
48 h to reach completion. The reduced reactivity appears to
have a beneficial effect on the diastereoselectivity: the re-
spective spirooxindoles 15a, d, and e were formed as virtual-
ly single diastereoisomers, though in slightly lower enantio-
selectivity.
Dissecting the cyclopropanation cascade into two separate
steps provides a useful insight into the role of the new cata-
lyst 9 in attaining efficient stereodifferentiation. NOE NMR
experiments revealed that the two diastereoisomers of 14a
differ by configuration of their single tertiary center in the
cyclopropane ring, which is created in the first Michael addi-
tion step (for establishment of the relative configuration of
diastereoisomers, see Supporting Information). Taking into
account that catalyst 7 afforded 14a in only a 3:1 diastereo-
meric ratio (5a + 12, yield 58%, 43 h), the new catalyst 9
appears to have significantly enhanced enantioselectivity of
the Michael addition. Similarity in the enantio- and dia-
two reactants together: the thiourea motif binds to the oxin-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
stereo
2 also indicates that Michael addition of 10 to 5 proceeds
with remarkable diastereocontrol, since the configuration of
ACHTUNGTRENNUNGs elective outcome exhibited by chiral 10 and achiral
1
Scheme 4. Facial selectivity in the spirocyclopropanation step (only nucle-
ophilic attack from the Si face takes place).
Chem. Eur. J. 2012, 18, 14929 – 14933
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14931

A. V. Malkov et al.
Acknowledgements
We thank RSC for the International
Joint Project grant JP090309 and
TUT for travel fellowiship to AN. We
acknowledge COST-ORCA action
(
CM0905) for creating networking
and exchange opportunities.
Keywords: asymmetric
catalysis · cascade reactions ·
cyclization · organocatalysis ·
spiro compounds
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1
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Chem. Eur. J. 2012, 18, 14929 – 14933

Spirocyclopropanation of Oxindoles
COMMUNICATION
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439.
Published online: October 30, 2012
Chem. Eur. J. 2012, 18, 14929 – 14933
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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