Chiral: N, N ′-dioxide/Co(II)-promoted asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones

Article abstract of DOI:10.1039/c7cc03575f

A chiral N,N′-dioxide/Co(BF₄)₂·6H₂O complex catalytic system has been developed to efficiently catalyze the asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones. The corresponding chiral multisubstituted spiroisoxazolidines with three contiguous quaternary-tertiary stereocenters were obtained in moderate to high yields with excellent dr and ee values (up to 97% yield, >19:1 dr and 98% ee).

Full text of DOI:10.1039/c7cc03575f

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Chiral N,N’-Dioxide/Co(II)-Promoted Asymmetric 1,3-Dipolar
Cycloaddition of Nitrones with Methyleneindolinones †
Dong Zhang, Chengkai Yin, Yuhang Zhou, Yali Xu, Lili Lin,* Xiaohua Liu and Xiaoming Feng*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A chiral N,N’-dioxide/Co(BF4)2·6H2O complex catalytic system has Scheme 1 Reactions of nitrones and methyleneindolinones
been developed to efficiently catalyze the asymmetric 1,3-dipolar
cycloaddition of nitrones with methyleneindolinones. The
corresponding chiral multisubsitituted spiroisoxazolidines with
three contiguous quaternary-tertiary stereocenters were obtained
in moderate to high yields with excellent dr and ee values (up to
97% yield, >19:1 dr and 98% ee).
Five-membered heterocyclic isoxazolidines are important synthetic
intermediates in organic chemistry.1 Undoubtedly, one of the most
convergent ways to synthesize isoxazolidines is the 1,3-dipolar
cycloaddition (1,3-DC) of nitrones with alkenes.2 Numerous chiral
affording more type of products with both spirooxindole and
metal complexes3 and organocatalysts4 have been developed to
isoxazolidine structures and contiguous quaternary−terꢀary
catalyze the reaction, offering optically active isoxazolidines in high
stereocenters in higher efficiency under milder reaction conditions.
efficiency. On the other hand, spirooxindole scaffold is found in a
Initially, the cycloaddition of tert-butyl (E)-3-(2-(tert-butoxy)-2-
large family of natural alkaloids and has been identified as one of
the privileged scaffolds for drug discovery.5
oxoethylidene)-2-oxoindoline-1-carboxylate (1a) and nitrone (2a)
was selected as the model reaction to optimize the reaction
The asymmetric 1,3-DC of nitrones with methyleneindolinones or
conditions. The representative results are summarized in Table 1.
their analogues can afford enantioenriched spiro-[isoxazolidine-
Firstly, various metal salts were investigated by complexing with the
chiral N,N’-dioxide ligand L-PrPr2 in toluene at 30 oC for 24 h. The
3,3’-oxindole] derivatives, which possess both the meaningful
isoxazolidine and spirooxindole moieties. In 2013, Cheng applied a
complex of Ni(OTf)2 afforded the desired cycloaddition product 3a
bisthiourea to realize the asymmtetric 1,3-DC of nitrones with
in good yield and diastereoselectivity, but moderate
methyleneindolinones.6 The catalyst with two thiourea functional
enantioselectivity (87% yield, 85:15 dr, 46% ee, Table 1, entry 1).
groups activated the two reactants in a concerted way through
When the reaction was catalyzed by L-PrPr2/Sc(OTf)3 or L-
multiple-hydrogen-bonds (Scheme 1). In our previous work, it was
PrPr2/Mg(OTf)2, the diastereoselectivity was low albeit with high
found that the chiral N,N’-dioxide/metal complexes can also well
enantioselectivity (Table 1, entries 2 and 3). Comparatively, L-
induce the reactions about methyleneindolinones by coordinating
in a bidentate manner.7 We conceived that this strategy may help
PrPr2/Co(ClO4)2·6H2O complex offered higher activity and better
enantioselectivity (Table 1, entry 4, 90% yield, 68:32 dr, 83% ee).
the competitive coordination of methyleneindolinones to the N,N’-
When the counter ion of Co(II) was examined, the L-
dioxide/metal catalyst in the presence of Lewis basic nitrones and
PrPr2/Co(BF4)2·6H2O complex improved the ee value from 83% to
promote the reaction more efficiently. Herein, we report our efforts
91% (Table 1, entry 5). Next, various ligands were evaluated. Upon
in developing a N,N’-dioxide/Co(BF4)2·6H2O complex system for the
changing the amide moiety of the N,N'-dioxide ligands from 2,6-
asymmetric 1,3-DC between nitrones and methyleneindolinones,
diisopropyl to 2,4,6-triisopropyl group, the ee value was decreased
from 91% to 79% (Table 1, entry 5 vs 6). Decreasing the steric
a.Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China.
Fax: (+)86 28 85418249 E-mail: lililin@scu.edu.cn; xmfeng@scu.edu.cn
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here].
See DOI: 10.1039/x0xx00000x
hindrance from 2,6-diisopropyl to phenyl group, the ee value was
decreased sharply from 91% to 63% (Table 1, entry 5 vs 7). When
the backbone of the ligand was investigated, it was found that L-
proline derived L-PrPr2 was superior to both L-pipecolic acid derived
L-PiPr2 and L-ramipril derived L-RaPr2 (Table 1, entry 5 vs entries 8
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the reaction conditions
Table 2 Substrate scope of methyleneindolinones 1a
Yieldb
(%)
87
70
78
90
88
91
86
90
80
56
70
84
97
eed
(%)
46
70
79
83
91
79
63
87
77
67
79
94
98
Entrya Ligand Metal salt
Solvent
drc
1
2
3
L-PrPr2 Ni(OTf)2
L-PrPr2 Sc(OTf)3
L-PrPr2 Mg(OTf)2
Toluene
Toluene
Toluene
85:15
70:30
50:50
68:32
66:34
64:36
80:20
67:33
50:50
70:30
60:40
90:10
96:4
4
5
6
7
8
9
10
11
12
13e
L-PrPr2 Co(ClO4)2·6H2O Toluene
L-PrPr2 Co(BF4)2·6H2O Toluene
L-PrPr3 Co(BF4)2·6H2O Toluene
L-PrPh Co(BF4)2·6H2O Toluene
L-PiPr2 Co(BF4)2·6H2O Toluene
L-RaPr2 Co(BF4)2·6H2O Toluene
L-PrPr2 Co(BF4)2·6H2O THF
L-PrPr2 Co(BF4)2·6H2O CH2Cl2
L-PrPr2 Co(BF4)2·6H2O EtOAc
L-PrPr2 Co(BF4)2·6H2O EtOAc
ent-
L-PrPr2
14e
Co(BF4)2·6H2O EtOAc
96
97:3
-96
a Unless otherwise noted, all reactions were carried out with 1a (0.1 mmol),
2a (0.11 mmol), ligand/metal salt (1:1, 10 mol%) in indicated solvent (1.0
mL) under N2 at 30 °C for 24 h. b Isolated yield. c The diastereoselectivities
a Unless otherwise noted, all reactions were carried out with 1 (0.1
mmol), 2a (0.11 mmol), L-PrPr2/Co(BF4)2·6H2O (1:1, 10 mol%) in EtOAc
(1.0 mL) under N2 at 0 °C. b Isolated yield. c The diastereoselectivities
were determined by HPLC analysis. d Determined by chiral HPLC analysis.
e
d
were determined by 1H NMR spectra. Determined by chiral HPLC
The reaction was performed at 0 °C for 72 h.
analysis.
and 9). Subsequently, the solvent effect was examined. No positive
effect was found when THF or CH2Cl2 was used as the solvent (Table
1, entries 10 and 11). Fortunately, when the reaction was
performed in EtOAc, the diastereoselectivity increased to 90:10
(Table 1, entry 12). By lowering the reaction temperature to 0 oC
and prolonging the reaction time to 72 h, the product was obtained
in 97% yield with 96:4 dr and 98% ee (Table 1, entry 13). Besides,
the ent-L-PrPr2/Co(BF4)2·6H2O complex could also promote the
reaction efficiently, affording a similar good result. (Table 1, entry
13 vs 14). Therefore, the optimal reaction conditions were
estabilished as L-PrPr2/Co(BF4)2·6H2O (1:1, 10 mol% ) in EtOAc at 0
oC for 72 h.
(Table 2, 3j-3k).
Subsequently, the scope of nitrones was investigated. Electron
withdrawing or electron donating subsitituent (R3) on the phenyl
ring had no obvious effect on the diastereo- and enantioselectivity.
The corresponding products 3l-3v were obtained in 73-95% yields,
12:1 to >19:1 dr, 91-99% ee (Table 3, entries 1-11). Significantly,
heterofuryl-substituted nitrone 2w was proved a suitable candidate
in our case, the corresponding desired product 3w was obtained in
72% yield, >19:1 dr and 95% ee (Table 3, entry 12), to our
knowledge, heteroaryl-substituted nitrones have never been
applied in the metal Lewis acid catalyzed 1,3-dipolar cycloaddition
of electron-deficient olefins before. It is worth to mention that the
aliphatic nitrone substrate 2x was also well tolerated in this
catalytic system, delivering the desire product 3x in 98% yield,
90:10 dr and 92% ee (Table 3, entry 13). On the other hand, various
substituents (R4) were also examined, the electronic character and
the position of the substituents on the phenyl ring had a slight
effect on the reaction. Electron-deficient subsitituents showed
better reactivities and selectivities than that of electron donating
subsitituents (Table 3, entries 14-17). In addition, N-methyl nitrone
With the optimized conditions in hand, the substrate scope was
then evaluated. As shown in Table 2, methyleneindolinones with
either electron withdrawing or electron donating substituent (R1)
on the phenyl ring of the oxindole could be smoothly converted to
the corresponding cycloaddition products in good yields with
excellent ee values (Table 2, 3b-3i). When the steric hindrance of
ester group was decreased from tert-butyl group to methyl or
isopropyl group, the corresponding products could also be obtained
in good to excellent yields with excellent dr and good ee values
2 | J. Name., 2012, 00, 1-3
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Table 3 Substrate scope of nitrone 2
Fig. 1 The operando IR experiments
Entry
Yieldb
(%)
eed
(%)
97
98
99
93
95
91
96
99
94
98
R3
R4
drc
a
1
2
3
4
5
6
7
8
4-FC6H4
4-ClC6H4
3-BrC6H4
4-IC6H4
4-NCC6H4
4-F3CC6H4
2,3-Cl2C6H3
4-MeC6H4
4-MeOC6H4
2-Naphthyl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
95 (3l)
83 (3m)
76 (3n)
73 (3o)
75 (3p)
78 (3q)
82 (3r)
88 (3s)
74 (3t)
90 (3u)
>19:1
>19:1
>19:1
12:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
Table 4 Control experimentsa
9
10
Yieldb
eec
(%)
--
--
N.D.
0
0
0
40
65
98
Entry R1
Pg
1
drc
11
C6H5
87 (3v)
>19:1
99
(%)
N.R.
N.R.
12
30
26
18
74
72
97
1
2
3
4
5
6
7
8
C6H5
Boc
Boc
Boc
Me
Bn
H
Ac
Cbz
Boc
1ad
1ae
1af
1ag
1ah
1ai
1aj
1ak
1al
--
--
12
13e
14
15
16
17
18f
2-furyl
Cyclohexyl
C6H5
C6H5
C6H5
C6H5
C6H5
72 (3w)
98 (3x)
75 (3y)
96 (3z)
95 (3aa)
>19:1
9:1
>19:1
>19:1
>19:1
9:1
95
92
97
99
91
91
95
t-Bu
Bz
N.D.
N.D.
N.D.
N.D.
70:30
64:36
96:4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-MeC6H4 85 (3ab)
Me 45 (3ac)
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
C6H5
C6H5
16:1
a Unless otherwise noted, all reactions were carried out with 1a (0.1
mmol), 2 (0.11 mmol), L-PrPr2/Co(BF4)2·6H2O (1:1, 10 mol%) in EtOAc (1.0
mL) under N2 at 0 °C for 72 h. b Isolated yield. c The diastereoselectivities
9
a
Unless otherwise noted, all reactions were carried out with 1 (0.1
were determined by 1H NMR spectra. Determined by chiral HPLC
d
mmol), 2a (0.11 mmol), L-PrPr2/Co(BF4)2·6H2O (1:1, 10 mol%) in EtOAc
(1.0 mL) under N2 at 0 °C for 72 h. b Isolated yield. c Determined by chiral
HPLC analysis.
analysis. e Reaction time 88 h. f Reaction time 5 days.
2ac was also tested. The reactivity was moderate, but the
diastereo- and enatioselectivity were excellent (45% yield, 16:1 dr,
95% ee, Table 3, entry 18). The absolute configuration of product 3a
was determined to be (3R, 3’R, 5’R) by X-ray crystallography
analysis8 and others were assigned to be the same by comparing
the Cotton effect of the CD spectra with that of 3a.
concerted way.
Next, the control experiments were carried out under the
standard reaction condition. As exhibited in Table 4, when the
substituent R1 was electron donating phenyl group or tert-butyl
group, the reaction did not occur (Table 4, entries 1 and 2). When
the substituent R1 was electron-deficient benzoyl group, the
reaction occurred in a low activity (Table 4, entry 3). These results
suggested that the electron property of R1 influenced the reaction
reactivity a lot. On the other hand, the coordination effect of the
protecting group was investigated, when the substrates 1ag, 1ah
and 1ai which have no metal coordination site on respective
protecting group were carried out in the reaction, almost all of
them afforded the desire products in low activities without any
enantioselectivities (Table 4, entries 4 - 6). In contrast, N-acetyl
protected 1aj and N-benzoxycarbonyl protected 1ak gave the desire
products in moderate yields, dr and ee values (Table 4, entries 7
and 8). Changing the protecting group with tert-butyloxycarbonyl,
the reactivity, diastereoselectivity and enatioselectivity sharply
improved, affording the corresponding product in 97% yield
with >19:1 dr and 98% ee (Table 4, entry 9). It indicated that the
protecting group on the nitrogen atom of the substrates which has
a coordination ester site and large steric hindrance was crucial for
both the activation and stereo control.
To evaluate the synthetic potential of the catalytic system, a
gram-scale synthesis of 3a was carried out. As shown in Scheme 2,
catalyzed by 10 mol% L-PrPr2/Co(BF4)2·6H2O complex, 4.0 mmol 1a
and 4.4 mmol 2a transformed smoothly to 3a in 91% yield (1.97 g)
with >19:1 dr and 98% ee.
Scheme 2 Gram-scaled version of the reaction
To gain some insight into the reaction mechanism, operando IR
experiments and control experiments were performed. Firstly, the
reaction between 1a and 2a was monitored by the operando IR
spectrometer (Fig. 1). It can be seen clearly from the figure that the
amount of product increased with the consuming of starting
materials and no intermediates were observed in the process.
Hence, we speculated that the reaction might proceed in a
On the basis of the experimental results, our previous work9 and
the absolute configuration of the products, a possible transition-
state model was proposed. As illustrated in Scheme 3, the four
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(l) J. L. Hu, L. J. Wang, H. Xu, Z. W. Xie, Y. Tang, Org. Lett., 2015,
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Scheme 3 Crystal structure of 3a and the proposed transition-state
model
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oxygens in the ligand and the oxygen atoms of both amide and the
N-Boc in the methyleneindolinone coordinated with the Co (II) to
form an octahedral complex. The Si face of the
methyleneindolinone was shielded by the 2,6-diisopropylphenyl
group of the ligand. Therefore, the nitrone would attack from the
Re face to afford the product with (3R, 3’R, 5’R) configuration,
which was coincident with the X-ray crystallographic analysis.
In summary, we have developed an efficient chiral N,N’-
dioxide/Co(BF4)2·6H2O complex catalytic system for the asymmetric
1,3-DC between nitrones and methyleneindolinones. A range of
optically active products bearing both spirooxindole and
isoxazolidine structures with three contiguous stereocenters were
obtained in good yields with excellent diastereo- and
enantioselectivity. The synthetic potential of this methodology was
demonstrated by a gram-scale synthesis. Furthermore, a possible
transition-state model was proposed to explain the stereochemistry.
Further applications of the catalysts are underway in our laboratory.
We appreciate the National Natural Science Foundation of
China (Nos: 21572136 and 21432006) for financial support.
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DOI: 10.1039/C7CC03575F
A chiral N,N’ꢀDioxide/Co(BF4)2·6H2O complex catalytic system has been developed to efficiently
catalyze the asymmetric 1,3ꢀdipolar cycloaddition of nitrones with methyleneindolinones. The
corresponding chiral multisubsitituted spiroisoxazolidines with three contiguous
quaternaryꢀtertiary stereocenters were obtained in high yields with excellent dr and ee values.