Asymmetric synthesis of 3-spirocyclopropyl-2-oxindoles via intramolecular trapping of chiral aza-ortho-xylylene

Article abstract of DOI:10.1039/c3cc45369c

Chiral aza-ortho-xylylene intermediates were efficiently generated from 3-chloro-3-substituted oxindole precursors. The first intramolecular trapping of chiral aza-ortho-xylylene intermediates led to a highly asymmetric synthesis of 3-spirocyclopropyl-2-oxindoles.

Full text of DOI:10.1039/c3cc45369c

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Asymmetric synthesis of 3-spirocyclopropyl-
2-oxindoles via intramolecular trapping of chiral
aza-ortho-xylylene†
Cite this: Chem. Commun., 2013,
49, 9224
Received 16th July 2013,
Accepted 8th August 2013
Xiaowei Dou, Weijun Yao, Bo Zhou and Yixin Lu*
DOI: 10.1039/c3cc45369c
www.rsc.org/chemcomm
Chiral aza-ortho-xylylene intermediates were efficiently generated from
We hypothesize that an efficient intramolecular trapping of
3-chloro-3-substituted oxindole precursors. The first intramolecular chiral aza-ortho-xylylene intermediates may represent a general
trapping of chiral aza-ortho-xylylene intermediates led to a highly approach to access chiral spirooxindole scaffolds. One apparent
asymmetric synthesis of 3-spirocyclopropyl-2-oxindoles.
advantage of this method is that the final optically enriched
products are constructed via intramolecular diastereoselective
Spirocyclic oxindoles bearing a quaternary stereogenic center at processes, which are obviously much easier to control. To
the 3-position are challenging molecules of significant biological realize our proposed synthesis, we reasoned 3,3-disubstituted
importance. In the past decade, tremendous efforts have been oxindoles bearing a halogen atom and a tethered nucleophilic
directed toward asymmetric construction of 3-spirocyclic oxindoles moiety at the 3-position could serve as the crucial chiral aza-
bearing a five or six-membered ring system. Among spirocyclic ortho-xylylene precursor. Treatment with base is anticipated to
oxindoles of other ring sizes, 3-spirocyclopropane-2-oxindoles yield the aza-ortho-xylylene intermediate, and the subsequent
represent another important class, however, their syntheses are intramolecular trapping then leads to the formation of chiral
much less studied. As part of our ongoing research towards spirooxindole motifs (Scheme 1).
asymmetric creation of biologically important molecules bearing
For the construction of oxindoles containing a chlorine atom
a quaternary stereogenic center,1 we became interested in at the 3-quaternary chiral center, 3-chlorooxindoles seem to be
developing general approaches for the asymmetric preparation ideal starting materials (Scheme 2). Various 3-chlorooxindoles
of spirooxindole structural motifs.
could be readily derived from nitroolefins,7 a method reported
The aza-ortho-xylylene intermediate was proposed and
experimentally proved in 1960s,2 and synthetic methods making
use of this type of intermediate were well documented in literature.3
On the other hand, asymmetric reactions employing aza-ortho-
xylylene intermediates are rare. To date, only a handful of recent
reports have described such applications. Stoltz disclosed a copper-
mediated asymmetric process via putative ortho-azaxylylene to
access oxindoles with C3 all-carbon quaternary stereocenters.4
Krische proposed that an aza-ortho-xylylene intermediate was
involved in his synthesis of 3-tert-prenylated oxindoles.5 Yuan
reported an enantioselective construction of 3,3-disubstituted
oxindoles, in which he also utilized key aza-ortho-xylylene
intermediates.6 All these examples employed carbon or heteroatom
nucleophiles to react with aza-ortho-xylylene intermediates, in
an intermolecular fashion. To the best of our knowledge, an
intramolecular variant is not known.
Scheme 1 Creation of spirooxindoles via intramolecular trapping of aza-ortho-
xylylene.
Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543.
E-mail: chmlyx@nus.edu.sg
Scheme 2 Asymmetric synthesis of spirocyclopropyl oxindoles from nitroolefins
via an aza-ortho-xylylene intermediate.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc45369c
c
9224 Chem. Commun., 2013, 49, 9224--9226
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more than 30 years ago but did not draw much attention from anticipated to effectively promote the projected conjugate
the synthetic community. Reaction of 3-chlorooxindoles with addition through cooperative interactions with both substrates.
suitable electrophiles creates oxindoles with the desired quaternary When quinine-derived 4 was used, the reaction was fast, however,
stereogenic center. Such oxindoles are precursors for the sub- the stereoselectivities were modest (entry 1). We next chose to
sequently in situ generated chiral aza-ortho-xylylene and the employ our recently developed amino acid incorporating multi-
final spirooxindole products, if the chiral unit tethering the functional catalysts.10 To our delight, all the multifunctional
potential nucleophilic site is carefully designed and properly catalysts could efficiently promote the reaction, affording the
positioned. It would be ideal if the electrophilic partners were desired products in high yields and with very high diastereo-
latent nucleophiles for the intramolecular trapping at a later stage. selectivities. Incorporation of a silylated L-threonine backbone11
In this regard, nitroalkenes appear to be an excellent choice. The into the catalyst structure resulted in a series of new catalysts,
asymmetric conjugate addition of 3-chlorooxindoles to nitroolefins essential for further improvement of the enantioselectivity.
is expected to proceed smoothly, and such a conjugate addition Catalyst 9 which contains an O-TBDPS-L-threonine moiety,
would have to proceed in a highly diastereoselective and enantio- turned out to be the best catalyst (entry 6). When the reaction
selective manner to install the required chirality for further trans- was performed in the presence of 5 mol% 9 at 0 1C under
formation. The nitroalkane adducts can be readily activated for the optimized reaction conditions, adduct 3a was obtained in 98%
intramolecular trapping of chiral aza-ortho-xylylene to create yield, with >25: 1 dr and 97% ee (entry 8).
spiro structural motifs. It is noteworthy that the above proposed
Having obtained oxindoles with a 3-chlorinated quaternary
reaction sequence creates chiral spirocyclopropyl oxindoles, with center with excellent stereochemical control, we next proceeded
nitroolefins employed as sole starting materials, which make the to find conditions for the generation of the key chiral aza-ortho-
method attractive and practical. Herein, we document the first xylylene intermediate, and the subsequent intramolecular trap-
intramolecular trapping of chiral aza-ortho-xylylene precursors ping for the creation of spirocyclopropyl oxindoles (Table 2).
for enantioselective and diastereoselective construction of We reasoned that the basicity of the base utilized is of crucial
3-spirocyclopropyl-2-oxindoles.
importance, therefore, our first goal was to identify a suitable
To start our investigation, we examined the conjugate addition base which triggers the effective formation of the aza-ortho-
of 3-chlorooxindoles to nitroolefins,8 in the presence of various xylylene intermediate. No desired product was observed when
tertiary amine–thiourea catalysts (Table 1). For the selection of 3a was treated with triethylamine in toluene (entry 1). Switching
organic catalysts, we focused on bifunctional tertiary amine reaction medium to a more polar solvent, e.g. DMSO, led to the
catalysts containing a Brønsted acid moiety,9 which are formation of a trace amount of the desired product (entry 2).
DBU, which was used in the literature examples for a similar
purpose,4 led to extensive decomposition (entry 3). Inorganic
bases were tested next. The use of K2CO3 was ineffective, again
the starting material decomposed, and so was the use of
Na2CO3 in different solvents (entries 4–6). When NaHCO3 was
employed, the results were promising; product was obtained in
moderate yield, and excellent diastereoselectivity and enantio-
selectivity were retained for the cyclopropyl oxindole 10a
Table 1 Conjugate addition of 3-chlorooxindole 1a to nitroolefin 2a catalyzed
by different organic catalystsa
Table 2 Base-induced formation of an aza-ortho-xylylene intermediate and
spirooxindole 10aa
Entry
Cat.
t [h]
Yieldb [%]
drc
4 : 1
19 : 1
23 : 1
20 : 1
24 : 1
>25 : 1
>25 : 1
>25 : 1
eed [%] Entry
Base
Solvent
Yieldb [%]
drc
eed [%]
e
1
2
3
4
4
5
6
7
8
9
9
9
2
1
2
2.5
1
1
5
8
94
90
85
91
97
99
98
98
68
74
84
75
94
95
97
97
1
2
3
4
5
6
7
8
9
Et3N
Et3N
DBU
K2CO3
Na2CO3
Na2CO3
NaHCO3
NaN3
Toluene
DMSO
DMSO
DMSO
DMSO
CH2Cl2
DMSO
DMSO
DMSO
—
—
—
—
—
—
—
>25 : 1
>25 : 1
>25 : 1
—
—
—
—
—
—
97
97
97
Trace
f
—
—
f
5
Trace
—
47
88
93
6
7e
8e, f
HCO2Na
a
Reactions were performed with 1a (0.1 mmol), 2a (0.12 mmol) and
the catalyst (0.01 mmol) in toluene (1.0 mL) at room temperature. b Isolated
Reactions were performed with 3a (0.05 mmol) and base (0.15 mmol) in
b
a
yield. Determined by 1H NMR analysis of the crude products. Deter- the solvent specified (0.5 mL) at room temperature for 12 h. Isolated
c
d
mined by HPLC analysis on a chiral stationary phase, ee values of the major yield. Determined by 1H NMR. Determined by HPLC analysis on a
c
d
isomers. e 5 mol% 9 was used. Reaction was performed at 0 1C.
chiral stationary phase. No reaction. Starting material decomposed.
f
e
f
c
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Table 3 Asymmetric synthesis of spirocyclopropyl oxindoles 10a
this communication to the asymmetric preparation of spiro-
cyclic oxindoles of other ring sizes.
Notes and references
1 For our recent examples, see: (a) F. Zhong, X. Han, Y. Wang and
Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837; (b) X. Han, Y. Wang,
F. Zhong and Y. Lu, J. Am. Chem. Soc., 2011, 133, 1726; (c) J. Luo,
H. Wang, X. Han, L.-W. Xu, J. Kwiatkowski, K.-W. Huang and Y. Lu,
Angew. Chem., Int. Ed., 2011, 50, 1861; (d) F. Zhong, G.-Y. Chen and
Y. Lu, Org. Lett., 2011, 13, 82; (e) C. Liu, Q. Zhu, K.-W. Huang and
Y. Lu, Org. Lett., 2011, 11, 2638; ( f ) X. Han, S.-X. Wang, F. Zhong
and Y. Lu, Synthesis, 2011, 1859; (g) C. Liu, X. Dou and Y. Lu, Org.
Lett., 2011, 13, 5248; (h) F. Zhong, X. Han, Y. Wang and Y. Lu, Chem.
Sci., 2012, 3, 1231; (i) G.-Y. Chen, F. Zhong and Y. Lu, Org. Lett.,
2012, 14, 3955; ( j) F. Zhong, W. Yao, X. Dou and Y. Lu, Org. Lett.,
2012, 14, 4018; (k) F. Zhong, J. Luo, G.-Y. Chen, X. Dou and Y. Lu,
J. Am. Chem. Soc., 2012, 134, 10222; (l) J. Luo, H. Wang, F. Zhong,
J. Kwiatkowski, L.-W. Xu and Y. Lu, Chem. Commun., 2012, 48, 4707;
(m) F. Zhong, X. Dou, X. Han, W. Yao, Q. Zhu, Y. Meng and Y. Lu,
Angew. Chem., Int. Ed., 2013, 52, 943; (n) X. Dou and Y. Lu, Org.
Biomol. Chem., 2013, 11, 5217.
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L. McCullagh, J. Am. Chem. Soc., 1966, 88, 1580; (c) R. L. Hinman and
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3 For a review, see: (a) K. Wojciechowski, Eur. J. Org. Chem., 2001,
3587. For selected examples, see: (b) H. Steinhagen and E. J. Corey,
Angew. Chem., Int. Ed., 1999, 38, 1928; (c) Q.-Q. Yang, C. Xiao,
L.-Q. Lu, J. An, F. Tan, B.-J. Li and W.-J. Xiao, Angew. Chem., Int.
Ed., 2012, 51, 9137.
Entry
10, R/R0
tb [h]
Yieldc [%]
drd
eee [%]
1
2
3
4
5
6
7
8
10a, H/C6H5
8
8
91
95
92
90
92
95
96
91
81
93
74
77
82
86
89
41
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
97
95
92
91
92
92
99
94
86
99
95
95
97
98
99
95
10b, H/2-Br–C6H4
10c, H/3-Br–C6H4
10d, H/3-Cl–C6H4
10e, H/4-Cl–C6H4
10f, H/4-F–C6H4
10g, H/2-Me–C6H4
10h, H/4-OMe–C6H4
10i, H/4-CN–C6H4
10j, H/1-naphthyl
10k, H/2-furyl
10l, H/2-thienyl
10m, 5-Br/C6H5
10n, 6-Cl/C6H5
10o, 5-Cl/2-Br–C6H4
10p, phenethyl
12
16
10
12
22
20
8
20
18
18
10
12
12
24
9
10
11
12
13
14
15
16f
a
Reactions were performed with 1 (0.1 mmol), 2 (0.12 mmol) and 9
(0.005 mmol) in toluene (1.0 mL) at 0 1C for the time specified, and then
with HCO2Na (0.3 mmol) in DMSO (1.0 mL) at room temperature for
b
c
d
12 h. Reaction time for the first step. Isolated yield. Determined by
1H NMR analysis of the crude products. Determined by HPLC analysis
e
f
on a chiral stationary phase, ee values of the major isomers. 10 mol%
9 was used, and the first step was performed at room temperature.
4 (a) S. Ma, X. Han, S. Krishnan, S. C. Virgil and B. M. Stoltz, Angew.
Chem., Int. Ed., 2009, 48, 8037; (b) S. Krishnan and B. M. Stoltz,
Tetrahedron Lett., 2007, 48, 7571.
5 C. D. Grant and M. J. Krische, Org. Lett., 2009, 11, 4485.
6 (a) Y.-H. Liao, Z.-J. Wu, W.-Y. Han, X.-M. Zhang and W.-C. Yuan,
Chem.–Eur. J., 2012, 18, 8916; (b) J. Zuo, Y.-H. Liao, X.-M. Zhang and
W.-C. Yuan, J. Org. Chem., 2012, 77, 11325.
7 (a) P. Demerseman, J. Guillaumel, J.-M. Clavel and R. Royer, Tetrahedron
Lett., 1978, 23, 2011; (b) J. Guillaumel, P. Demerseman, J.-M. Clavel and
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(entry 7). Suspecting that the decomposition is likely due to the
undesired retro-Michael reaction, we next employed less basic
NaN3 and HCO2Na to further improve the results. Gratifyingly,
employing these bases, 10a was obtained in high yield as a
single diastereomer and with 97% ee (entries 8 and 9).
With the optimized reaction conditions in hand, we next
explored the generality of our method for cyclopropyl oxindole
synthesis (Table 3). Different aryl nitroolefins could be
employed (entries 1–12). The reaction was also applicable to
3-chlorooxindoles containing different aromatic moieties
(entries 13–15). Moreover, an alkyl nitroolefin could also be
employed, and the desired product was obtained with excellent
diastereoselectivity and enantioselectivity, although the yield
was moderate (entry 16).
In conclusion, we have disclosed an efficient generation of
chiral aza-ortho-xylylene intermediates and their subsequent
intramolecular trapping for the synthesis of highly optically
enriched 3-spirocyclopropyl-2-oxindoles. It is noteworthy that
the use of chiral aza-ortho-xylylene intermediates for an intra-
molecular reaction is unprecedented. A general implication of
this report is that various spirocyclic oxindole structures may be
accessible by using the approach documented herein, if one
can judiciously choose electrophilic partners and catalytic
systems. We are currently applying the concept illustrated in
¨
8 For a recent report, see: A. Noole, I. Jarving, F. Werner, M. Lopp,
A. Malkov and T. Kanger, Org. Lett., 2012, 14, 4922.
´
9 For reviews, see: (a) C. Palomo, M. Oiarbide and R. Lopez, Chem. Soc.
Rev., 2009, 38, 632; (b) Z. Zhang and P. R. Schreiner, Chem. Soc. Rev.,
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11 (a) L. Cheng, X. Han, H. Huang, M. W. Wong and Y. Lu, Chem.
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Chem., 2007, 5, 1018; (c) X. Wu, Z. Jiang, H.-M. Shen and Y. Lu, Adv.
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F. Zhong and Y. Lu, Chem.–Eur. J., 2012, 18, 13945. Also see ref. 1a, h
and m. For review, see: (h) S.-X. Wang, X. Han, F. Zhong, Y. Wang
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c
9226 Chem. Commun., 2013, 49, 9224--9226
This journal is The Royal Society of Chemistry 2013