Diastereodivergent synthesis of 3-spirocyclopropyl-2-oxindoles through direct enantioselective cyclopropanation of oxindoles

Article abstract of DOI:10.1002/chem.201200655

Falling like dominos: The first direct organocatalytic asymmetric cyclopropanation reaction of oxindole was developed, in which oxindoles were employed as a dinucleophilic C₁ synthon and bromonitroolefins with a dielectrophilic center were used as a C₂ synthon (see scheme). An amino acid based multifunctional catalyst promoted the [2+1] reaction, giving the products in high yields and excellent enantioselectivities. A divergent synthesis of different stereoisomers of 3-spirocyclopropyl-2-oxindoles was achieved. Copyright

Full text of DOI:10.1002/chem.201200655

COMMUNICATION
DOI: 10.1002/chem.201200655
Diastereodivergent Synthesis of ACHTUNTRGNEU3GN -Spirocyclopropyl-2-oxindoles through
Direct Enantioselective Cyclopropanation of Oxindoles
Xiaowei Dou and Yixin Lu*[a]
Oxindoles are structural motifs that are widely present in
oping an enantioselective synthetic method for the direct cy-
natural products and medicinally important agents.[1] In par-
ticular, spirocyclic oxindoles bearing a quaternary stereogen-
ic center at the 3-position possess significant biological pro-
files. In this context, syntheses of 3-spirocyclic oxindoles
bearing a five-[2] or six-membered[3] ring system have been
intensively investigated due to the biological importance of
these molecules. Spirocyclopropyl oxindoles have shown re-
markable biological activities (Scheme 1),[4] and as such are
molecules of high synthetic value.[2c,5] Surprisingly, methods
clopropanation of oxindole substrates.
Asymmetric cyclopropanation reactions have fascinated
organic chemists for decades because the cyclopropane
motif is both synthetically useful and biologically impor-
tant.[9] Well-established synthetic strategies for asymmetric
cyclopropanation include the Simmons–Smith reaction,[10]
transition-metal-catalyzed decomposition of diazoalkanes,[11]
Michael-initiated ring-closure reactions,[12] and many
others.[13] In the past few years, organocatalytic cyclopropa-
nation has emerged as a powerful approach for the construc-
tion of chiral cyclopropanes.[14] However, a direct cyclopro-
panation method to access spirocyclopropyl oxindoles has
yet to be developed. In the reported organocatalytic cyclo-
propanation methods,[14] a-halogenated carbonyl compounds
are commonly utilized as a C1 synthon, which contains a nu-
cleophilic/electrophilic center for the construction of cyclo-
propanes.
From a practical point of view, it would be ideal if simple
oxindoles could be used directly as a C1 synthon for the syn-
thesis of cyclopropyl spirooxindoles. We envisioned that the
employment of oxindoles containing a dinucleophilic center
as a C1 synthon, in combination with a suitable dielectro-
philic C2 synthon (e.g., halogenated nitroolefins), might pro-
vide a straightforward cyclopropanation strategy. In the
presence of a suitable catalyst, oxindole can readily add to
a nitroolefin. After intramolecular proton transfer, an SN2
substitution is expected to generate the cyclopropane core.
Ostensibly, the O-alkylation product[15] may be formed in
addition to the desired C-alkylation product (Scheme 2). It
is noteworthy that utilization of a dinucleophilic C1 synthon
in asymmetric organocatalytic cyclopropanation is unknown,
and the use of halogenated nitroolefins in asymmetric cyclo-
propanation has also not been disclosed. Notably, Connon
and co-workers have described a stereoselective synthesis of
functionalized nitrocyclopropanes by employing nitroolefins
as a reaction component. However, their attempt to utilize
a halogenated nitroolefin in the asymmetric cyclopropana-
tion led to disappointing results.[14f] Herein, we describe the
first direct highly diastereoselective and enantioselective cy-
clopropanation of oxindoles by employing oxindoles as
a readily available C1 synthon and (E)-b-bromo-b-nitroole-
fins as a convenient C2 synthon.
Scheme 1. Bioactive molecules containing a spirocyclopropyl oxindole/in-
doline motif.
for the preparation of 3-spirocyclopropane-2-oxindoles are
very limited.[6] To the best of our knowledge, only one ex-
ample of the enantioselective construction of cyclopropyl
spirooxindoles has been reported recently; Bartoli, Benci-
venni et al. utilized a Michael–alkylation cascade to realize
the enantioselective nitrocyclopropanation of 3-alkylidene
oxindoles.[7] As part of our ongoing efforts towards the effi-
cient creation of quaternary stereogenic centers and chiral
spirooxindole derivatives,[8] we became interested in devel-
[a] X. Dou, Prof. Dr. Y. Lu
Department of Chemistry & Medicinal Chemistry Program
Life Sciences Institute, National University of Singapore
3 Science Drive 3, 117543 (Singapore)
Fax : (+65)6779-1691
We initiated our study by examining the reaction between
N-Boc-protected oxindole 1a and (E)-b-bromo-b-nitrostyr-
ene 2a (Table 1). Tertiary amine–thiourea catalysts[16] were
E-mail: chmlyx@nus.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200655.
Chem. Eur. J. 2012, 18, 8315 – 8319
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8315

selected to promote the predicted reaction. As HBr would
be generated during the reaction process, a stoichiometric
amount of (NH4)2CO3 was used as an HBr scavenger be-
cause (NH4)2CO3 could capture the released HBr and not
induce undesired background reactions.[17] Cinchona alka-
loid derived compounds 5 and 6 promoted the reaction effi-
ciently, furnishing three diastereomers 3a, 3a’[18] and 4a in
high yields with excellent enantioselectivities, but with very
poor diastereoselectivities (Table 1, entries 1 and 2). To fur-
ther improve the results, we chose to employ our recently
developed amino acid incorporating multifunctional cata-
lysts.[8c] All of the multifunctional catalysts could efficiently
promote the reaction, affording the desired C-alkylation
products 3a, 3a’ and 4a in high yields. Fine tuning of the
side-chain structure of the amino acid moiety in the catalysts
led to the formation of 3a and 4a with excellent enantio-
and diastereoselectivity. However, the selectivity between
3a and 4a remained poor (Table 1, entries 3–9). Gratifying-
ly, further extensive additive and solvent studies[19] resulted
in promising results; when the reaction was performed in
chloroform in the presence of 5 ꢁ molecular sieves, cyclo-
propyl spirooxindole 3a was obtained in good yield and ex-
cellent ee (Table 1, entry 10).
Scheme 2. Organocatalytic approaches to cyclopropanes and cyclopropyl
spirooxindoles. a) The previously reported approach to organocatalytic
cyclopropanation. b) The synthesis of cyclopropyl spirooxindoles, em-
ploying dinucleophilic and dielectrophilic synthons.
The substrate scope was investigated next (Table 2). Both
the oxindole and the bromonitroolefin could
be varied, and cyclopropyl spirooxindoles 3
were obtained in good diastereomeric ratios
Table 1. The direct asymmetric cyclopropanation reaction of oxindole 1a.[a]
and excellent enantioselectivities (Table 2,
entries 1–10). When alkyl bromonitroolefin
2q was employed, a product with high ee
was obtained, although only in moderate
yield and poor diastereoselectivity (Table 2,
entry 11). When the reaction was performed
on a larger scale, similar results were ob-
tained (Table 2, entry 12).
Having stereoselectively obtained spirocy-
clopropanes 3, our next task was to devise
a diastereodivergent approach to selectively
access cyclopropanes 4. It is well-established
that activated cyclopropanes can be readily
opened by nucleophiles,[20] we therefore con-
Entry
Catalyst
Yield [%][b]
3a/3a’/4a[c]
ee [%][d]
3a/3a’
4a
sidered the possibility of converting 3 into 4
1
2
3
4
5
6
7
8
5
6
95
97
82
85
95
95
97
98
98
98
28:58:14
44:44:12
46:12:42
43:14:43
45:6:49
45:5:50
39:4:57
52:6:42
53:5:42
67:9:24
90:93
88:93
n.d.
n.d.
80
87
85
86
86
92
92
through
a cyclopropane opening–closing
process. We reasoned that the employment
of a suitable nucleophile may lead to the
opening of the cyclopropane ring in 3a, and
the highly stabilized oxindole enolate makes
opening at the a-position of the nitro group
favorable, and the subsequent ring closure
may yield 4a (Scheme 3).
7a
7b
7c
7d
7e
7 f
7g
7g
57:n.d.
75:n.d.
72:n.d.
78:n.d.
85:n.d.
96:n.d.
97:n.d.
97:n.d.
9
10[e]
90
The feasibility of converting 3a into 4a in
the presence of a number of Lewis bases
was studied (Table 3). When diisopro-
[a] Reactions were performed with 1a (0.05 mmol), 2a (0.06 mmol), (NH4)2CO3
(0.05 mmol), and the catalyst (0.005 mmol, 10 mol%) in toluene (1.0 mL) at room
temperature for 3 h. Products 3a and 3a’ were obtained as a mixture, and product 4a
was easily separated from 3a and 3a’ by column chromatography. [b] Combined isolat-
ed yield of the three stereoisomers. [c] Determined by 1H NMR analysis. [d] Deter-
AHCTUNGTRENNpGUN ylethylamine (DIPEA) was used, only
a trace amount of 4a was observed, suggest-
ing the importance of the nucleophilicity of
the promoting base (Table 3, entry 1). Both
mined by HPLC analysis on
a chiral stationary phase (n.d.: not determined).
[e] CHCl3 (1.0 mL) was used as the solvent and molecular sieves (5 ꢁ, 10 mg) were
added.
8316
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 8315 – 8319

Diastereodivergent Synthesis of 3-Spirocyclopropyl-2-oxindoles
Table 2. The substrate scope of the direct cyclopropanation reaction.[a]
COMMUNICATION
Entry t [h] Product (R, R’)
Yield [%][b] 3/3’[c]
ee [%][d]
Scheme 3. Conversion of 3a into 4a through a nucleophilic-catalyst-initi-
ated cyclopropane ring opening–closing process.
1[e]
2[e]
3[e]
4[e]
5
12
12
24
72
36
24
36
36
12
12
36
12
3a (H, Ph)
72
81
75
63
76
68
60
72
68
87:13
81:19
97
90
3c (H, 3-BrC6H4)
3d (H, 4-BrC6H4)
3g (H, 2-FC6H4)
3h (H, 4-FC6H4)
3 f (H, 4-ClC6H4)
3i (H, 2-MeC6H4)
3j (H, 4-MeC6H4)
3s (6-Cl, Ph)
81:19[f] 95
86:14[f] 96
82:18[f] 97
82:18[f] 98
nium enolate intermediate[21] (Scheme 3, A: Nu=DABCO)
was observed in mass spectra taken during the reaction.
With an effective method for the creation of 4a from 3a
in hand, we proceeded to prepare cyclopropanes 4a directly
from oxindoles 1a and bromonitroolefins 2a (Scheme 4).
The reaction was carried out in a stepwise fashion. By using
the reaction conditions we had established previously
(Table 1, entry 9), a mixture of 3a and 3a’ was isolated (3a/
3a’=53:5, 3a 97% ee), and 4a was obtained in 92% ee.
DABCO was then introduced to effect the conversion of 3a
into 4a. The 3a/3a’ mixture was subjected to epimerization
by treatment with DABCO; 3a was converted into 4a with
preservation of the ee value (97% ee), and 3a’ remained un-
changed during the epimerization process. Finally, 4a was
obtained in 82% overall yield and 95% ee (Table 4,
entry 1). It should be noted that the final product 4a was de-
rived from two sources, that is, through the direct cyclopro-
panation reaction and through epimerization from 3a. Thus,
the ee value obtained in this reaction sequence differs slight-
ly from the result given in Table 2.
6
7
>20:1
97
8
88:12[f] 98
9[e]
88:12
92:8
57:43
85:15
93
99
93
95
10
3o (6-Cl, 2-BrC6H4) 45
3q (H, phenethyl)
3a (H, Ph)
11
46
68
12[e,g]
[a] Reactions were performed with
1
(0.05 mmol),
2
(0.06 mmol),
(NH4)2CO3 (0.05 mmol), and 7g (0.005 mmol, 10 mol%) in CHCl3
(1.0 mL) at room temperature. [b] Isolated yield of 3 and 3’. [c] Deter-
mined by 1H NMR analysis. [d] The ee value of 3, determined by HPLC
analysis on a chiral stationary phase. [e] Molecular sieves (5 ꢁ, 10 mg)
were added. [f] Two diastereoisomers could be separated by silica gel
column chromatography. [g] Reaction was performed with 0.5 mmol of
oxindole 1.
Table 3. Lewis base initiated conversion of 3a into 4a.[a]
By following the same procedure described for the prepa-
ration of 4a, the substrate scope of the synthesis of cyclo-
propyl spirooxindoles 4 was investigated (Table 4). Consis-
tently high chemical yields and excellent diastereo- and
enantioselectivities were obtained for a wide range of aryl
bromonitroolefins (Table 4, entries 1–13). Variation of the
substituents on the oxindole ring was also tolerated
(Table 4, entries 14 and 15). Alkyl bromonitroolefins were
suitable for the reaction; high ee values, chemical yields, and
moderate diastereoselectivities were obtained (Table 4, en-
tries 16 and 17) for these reagents. The reaction was also re-
producible on a larger scale (Table 4, entry 18).
Entry
Base
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
DIPEA
Et3N
DMAP
DABCO
PPh3
12
6
24
6
24
6
trace
42
47
73
–
–
94
95
95
–
quinine
22
86
[a] Reactions were performed with 3a (0.05 mmol) and the base
(0.05 mmol) in THF (0.5 mL) at room temperature. [b] Isolated yield.
[c] Determined by HPLC analysis on a chiral stationary phase.
triethylamine and dimethylaminopyridine (DMAP) could
promote conversion of 3a into 4a without affecting the ee
values, however, the yields were unsatisfactory (Table 3, en-
Deprotection of the final products could be easily
achieved by treating them with trifluoroacetic acid (TFA) in
dichloromethane (Scheme 5). The absolute configurations of
products 3 and 4 were assigned based on the X-ray crystallo-
graphic analysis of a single crystal of de-Boc 3o and product
4b, respectively.
In summary, we have developed the first direct asymmet-
ric cyclopropanation reaction of oxindoles. In our cyclopro-
panation strategy, we employed oxindoles with a dinucleo-
philic center as a C1 synthon, and used bromonitroolefins,
containing a dielectrophilic center, as a unique C2 synthon.
We believe that the cyclopropanation strategy reported
herein will find widespread applications in synthetic organic
chemistry. By using DABCO as a nucleophilic catalyst, a ste-
reochemically retentive conversion of different diastereo-
tries 2 and 3). 1,4-DiazabicycloACTHNUGTRNEUNG[2.2.2]octane (DABCO) was
found to be the most effective promoter, leading to the for-
mation of 4a in good yield, and the enantiomeric excess of
the product was maintained (Table 3, entry 4). Triphenyl-
phosphine, however, was found to be completely ineffective
(Table 3, entry 5). A chiral base (quinine) was also tested in
the epimerization process. However, 4a was obtained in
very poor yield and with decreased ee (Table 3, entry 6). It
is noteworthy that 3a’ remained unchanged in the epimeri-
zation process of 3a. We believe that the conversion of 3a
into 4a was initiated by the nucleophilic attack of the nucle-
ophilic amine on the cyclopropane ring because the ammo-
Chem. Eur. J. 2012, 18, 8315 – 8319
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8317

Y. Lu and X. Dou
Table 4. Direct diastereoselective synthesis of cyclopropyl spirooxindoles
4.[a]
Entry
Product (R, R’)
Yield [%][b]
d.r.[c]
ee [%][d]
Scheme 5. Removal of the Boc protecting group.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[e]
17[e]
18[f]
4a (H, Ph)
82
92
84
80
85
81
88
71
90
72
77
74
86
91
95
69
82
93
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4:1
95
94
95
96
95
94
94
96
90
95
97
96
94
98
97
92
91
96
4b (H, 2-BrC6H4)
4c (H, 3-BrC6H4)
4d (H, 4-BrC6H4)
4e (H, 2-ClC6H4)
4 f (H, 4-ClC6H4)
4g (H, 2-FC6H4)
4h (H, 4-FC6H4)
4i (H, 2-MeC6H4)
4j (H, 4-MeC6H4)
4k (H, 1-naphthyl)
4l (H, 2-naphthyl)
4m (H, 2,4-ClC6H3)
4n (5-Cl, 2-BrC6H4)
4o (6-Cl, 2-BrC6H4)
4p (H, isobutyl)
4q (H, phenethyl)
4o (6-Cl, 2-BrC6H4)
uation of the prepared cyclopropyl spirooxindoles is also un-
derway.
Acknowledgements
We are grateful for generous financial support from the National Univer-
sity of Singapore (R-143-000-469-112) and GSK–EDB (R-143-000-491-
592).
Keywords: asymmetric synthesis
·
cyclopropanation
·
domino reactions · organocatalysis · oxindole
3:1
>20:1
[a] Reactions were performed with
1
(0.05 mmol),
2
(0.06 mmol),
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achieved the highly diastereodivergent and enantioselective
synthesis of 3-spirocyclopropyl-2-oxindoles, which are a class
of compounds of great biological significance. Currently, we
are extending this novel cyclopropanation approach to the
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Diastereodivergent Synthesis of 3-Spirocyclopropyl-2-oxindoles
COMMUNICATION
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ing Information for details. For
an excellent review on the uses of
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Rev. 2007, 107, 5596–5605.
Received: February 27, 2012
Revised: April 5, 2012
Published online: June 4, 2012
Chem. Eur. J. 2012, 18, 8315 – 8319
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8319