Catalytic asymmetric peroxidation of α,β-unsaturated nitroalkenes by a bifunctional organic catalyst

Article abstract of DOI:10.1021/ol500677v

A new enantioselective peroxidation of α,β-unsaturated nitroalkenes was realized with an easily accessible acid-base bifunctional organic catalyst derived from cinchona alkaloids. This reaction provides unprecedented easy access to optically active chiral peroxides, as illustrated by the asymmetric synthesis of β-peroxy nitro compounds.

Full text of DOI:10.1021/ol500677v

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Peroxidation of α,β-Unsaturated Nitroalkenes
by a Bifunctional Organic Catalyst
Xiaojie Lu and Li Deng*
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, United States
S
* Supporting Information
ABSTRACT: A new enantioselective peroxidation of α,β-unsaturated nitroalkenes was realized with an easily accessible acid−
base bifunctional organic catalyst derived from cinchona alkaloids. This reaction provides unprecedented easy access to optically
active chiral peroxides, as illustrated by the asymmetric synthesis of β-peroxy nitro compounds.
umerous peroxy natural products have been isolated,
of α,β-unsaturated nitroalkenes.9 It is noteworthy that Lattanzi
once reported the asymmetric peroxidation of α,β-unsaturated
nitroalkenes with TBHP utilizing a proline-derived catalyst.10
Up to 84% ee was obtained with β-aryl nitroalkenes and
TBHP; nevertheless, both the enantioselectivity and yield of
the reactions are highly substrate-dependent. In the sole
example of a reaction with a simple β-alkyl nitroalkene, the
peroxide was reported to be formed in 20% yield and with the
ee value undetermined. The enantioselectivity as well as the
substrates scope of not only nitroalkenes but also hydro-
peroxide remained to be significantly improved to render this
reaction synthetically applicable for the synthesis of peroxy
natural products. Herein, we reported the first highly
enantioselective catalytic asymmetric peroxidation of the
alkyl nitroalkene to prepare the chiral β-hydroperoxy
nitroalkane.
N
and many of them are identified to be highly potent
anticancer, antitumor, and antimalaria compounds.1 Impor-
tantly, the cytotoxicity of the peroxide functionality renders
some of them, such as artemisine and yingzhaosu C (Figure
1), the most effective and widely used antimalarial drugs,
Figure 1. Selected examples of bioactive peroxide natural products.
thereby proving molecules incorporating a peroxide function-
ality in a proper chiral scaffold could provide compounds of
clinical significance.2 This in turn highlights the urgent need
to develop new methods to expand our ability to access chiral
peroxides of a broad structural diversity. To our knowledge,
the creation of a chiral peroxide motif still relies on the
transformation of an optically active precursor designed on an
ad hoc basis.3−7 Thus, enantioselective methods of useful
generality for the transformations of prochiral starting
materials into optically active peroxides are urgently needed.
However, the development of such asymmetric oxidations
stands as a challenging problem in asymmetric synthesis.8
Recently, our group has reported the first catalytic highly
enantioselective peroxidation reaction of α,β-unsaturated
ketones via base-iminium catalysis.8a To extend our
cooperative catalysis approach to the development of highly
enantioselective peroxidation reactions of an electron-deficient
double bond in conjugation with noncarbonyl functionality,
we began to investigate enantioselective peroxidation reactions
We began our investigation employing β-phenyl nitroalkene
1A as the model substrate with cumene hydroperoxide 2a. A
variety of cinchona alkaloid derivatives (Figure 2) were
screened for their ability to promote the aforementioned
model reaction (Table 1). The 6′-OH cinchona alkaloid
Figure 2. Structures of cinchona alkaloids.
Received: March 4, 2014
Published: April 14, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
to partial decomposition of the nitroalkenes via polymer-
ization, as insoluble byproducts were formed during the
reaction. Consequently, a reaction in a reduced concentration
of 0.20 M vs 0.50 M (Table 2, entry 2) was attempted to
avoid polymerization. However, only 64% conversion was
afforded after 96 h with no improvement in isolated yield.
Nonetheless, increasing the amount of cumene hydroperoxide
from 1.5 to 3.0 equiv improved the isolated yield to 51%
(Table 2, entry 3). A further increase of the cumene
hydroperoxide led to a yield of 60% although the
enantioselectivity decreased noticeably (Table 2, entry 4).
Notably, when the reaction was run in a higher substrate
concentration (0.33 M) and with 3.0 equiv of cumene
hydroperoxide, the chiral peroxide could be produced in 93%
ee and 62% yield (Table 2, entry 5).
With the optimal reaction conditions established, the
reaction scope with respect to the nitroalkenes was
investigated. The aromatic nitroalkenes bearing both the
meta- and para-substituted groups could be transformed into
the corresponding peroxide in good yield and enantioselec-
tivity (Table 3, entries 2−5). Furthermore, substituents of
Table 1. Asymmetric Peroxidation Reaction of α,β-
Unsaturated Nitroalkene 1A with Cumene Hydroperoxide
2a
a
b
c
entry
cat.
solvent
conv (%)
ee (%)
1
Q-4
hexane
hexane
hexane
hexane
hexane
hexane
hexane
33
66
<5
49
50
41
57
60
47
29
<1
12
15
49
nd
70
76
70
90
89
88
68
nd
76
2
Q-5
3
Q-6
4
Q-7a
Q-7b
Q-7c
Q-7d
Q-7d
Q-7d
Q-7d
Q-7d
Q-7d
Q-7d
5
6
7
8
cyclohexane
9
cyclohexane/toluene = 3:1
toluene
10
11
12
13
TBME
CH2Cl2
Table 3. Substrate Scope of α,β-Unsaturated Nitroalkenes 1
with Cumene Hydroperoxide 2a
methylcyclohexane
61
91
a
b
1
The reaction was run with 0.1 mmol of 1A. Determined by H
c
NMR analysis. Determined by HPLC analysis.
afforded good conversion but moderate ee (Table 1, entries
1−2) while Q-6 just decomposed (Table 1, entry 3).
Conceivably, the cumene hydroperoxide might react with
thiourea functionality in the Q-6 catalyst. Our attention was
then turned to cinchona alkaloids bearing other hydrogen
bond donors at the 9-position; thus, a series of 9-sulfonamide
cinchona alkaloids Q-7 were investigated.11 To our
satisfaction, these 9-sulfonamide catalysts were much better
in enantioselectivity (Table 1, entries 4−7). In particular,
catalyst Q-7d could provide the peroxide with 90% ee and
57% conversion after 24 h (Table 1, entry 7). Solvent
screening revealed that methylcyclohexane was the optimal
solvent, affording 91% ee and 61% conversion after 24 h
(Table 1, entry 13).
a
d
entry
1
R
time (h)
yield (%)
ee (%)
e
1
2
3
1A
1B
1C
1D
1E
1F
1G
1H
1I
Ph
80
62
93
4-Me-Ph
3-Me-Ph
4-Br-Ph
3-Br-Ph
4-Cl-Ph
4-F-Ph
120
51
88
90
91
87
96
58
b
4
96
43
b
5
120
43
bf
,
6
7
8
9
96(120)
120(144)
120
52(45)
63(50)
65
94(83)
88(83)
92
bf
,
b
c
4-OMe-Ph
n-C4H9
120
59
83
c
10
11
12
1J
n-C7H15
PhCH2CH2
i-C4H9
120
61
90
c
c
1K
1L
88
67
84
The reaction in methylcyclohexane reached 88% conversion
with 89% ee after 96 h; however, the isolated yield was only
38% (Table 2, entry 1). Probably, the poor yield might be due
100
55
86
a
Unless noted, all the reactions were carried out with 0.2 mmol of
nitroalkene 1. The reactions were run with 0.6 mL of
methylcyclohexane and 0.2 mL of dichloromethane. The reactions
b
c
were run at 0 °C with 1.5 equiv of 2a and 0.4 mL of
methylcyclohexane. It is determined by the HPLC analysis. Absolute
Table 2. Optimization of Asymmetric Peroxidation between
β-Nitrostyrene 1A and Cumene Hydroperoxide 2a
d
e
configuration was determined to be R; for details, see Supporting
f
Information. Results in parentheses were obtained with QD-7d.
either an electron-withdrawing or electron-donating nature on
the aromatic ring were tolerated (Table 3, entries 2−8). For
nitroalkenes of low solubility in methylcyclohexane, the
combined solvent system methylcyclohexane/CH2Cl2 = 3:1
proved to be optimal because additional dichloromethane
assisted in dissolving the solid nitroalkenes (Table 3, entries
4−8). Importantly a variety of aliphatic nitroalkenes were
found to undergo peroxidation in good yields and
enantioselectivity at 0 °C (Table 3, entries 9−12).
concn
(M)
conv
b
a
c
entry 2a equiv
time (h)
(%)
ee (%) yield (%)
1
2
3
4
5
1.5
1.5
3.0
5.0
3.0
0.50
0.20
0.20
0.20
0.33
96
96
88
120
80
88
64
77
78
86
89
92
92
84
93
38
37
51
60
62
To render this asymmetric peroxidation reaction more
synthetically applicable for the synthesis of peroxy natural
product, we investigated the peroxidation of α-alkoxyl
a
b
1
The reaction was run with 0.2 mmol of 1A. Determined by H
NMR analysis. Determined by HPLC analysis
c
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Organic Letters
Letter
hydroperoxides with nitroalkene 1K, as peroxide 3K could be
readily converted to the corresponding β-hydroperoxy nitro-
alkane by treating with acid. A variety of α-alkoxyl
hydroperoxides were synthesized according to literature
reports.12 We first found that the secondary hydroperoxide
2b readily decomposed (Table 4, entry 1). Tertiary α-alkoxyl
With the hydroperoxide 2g, the substrate scope with respect
to nitroalkenes 1 was investigated. A variety of aliphatic
nitroalkenes underwent peroxidation in good yield and
excellent enantioselectivity. Significantly, the addition product
3g could be efficiently transformed to the β-hydroperoxy
nitroalkane 8 with good yield (Table 5). Interestingly, the
peroxidation also took place in 6.1 to 8.3:1 dr, indicating the
peroxidation proceeded not only in high enantioselectivity in
terms of recognizing the enantio topic face of the nitro-
alkenes, but also in resolution of the hydroperoxide 2g with a
significant level of selectivity.
Table 4. Asymmetric Peroxidation of Nitroalkenes with α-
Alkoxyl Hydroperoxide
In summary, we have developed the first catalytic highly
enantioselective peroxidation of both aromatic and aliphatic
nitroalkenes utilizing the easily accessible reagents and
catalysts. Utilizing the hydroperoxide 2g, the first asymmetric
synthesis of chiral β-hydroperoxy nitroalkane was successfully
developed.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details. This material is available free of charge
via the Internet at http://pubs.acs.org.
a
b
c
entry
2
2 (equiv)
time (h)
conv (%)
ee (%)
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
5
2b
2c
2d
2e
2f
1.2
1.2
1.2
1.2
1.2
2.0
1.2
24
48
72
24
24
144
24
0
nd
60
51
nd
nd
89
nd
■
50
60
<5
<5
>95
0
*E-mail: deng@brandeis.edu.
Notes
d
The authors declare no competing financial interest.
6
2g
2h
7
ACKNOWLEDGMENTS
We are grateful for the generous financial support from the
NIH (GM-61591).
a
b
d
■
All the reactions were carried out with 0.1 mmol of nitroalkene.
Determined by H NMR analysis. Determined by HPLC analysis.
6.5:1 dr was observed, and ee was determined after hydrolysis to the
c
1
hydroperoxide.
REFERENCES
■
Table 5. Substrate Scope of Nitroalkene 1 with α-Alkoxyl
Hydroperoxide 2g
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(h)
3g
3g, yield
8, ee
c
8, yield
a
b
entry
1
1, R
(dr)
(%)
(%)
(%)
d
K,
144
6.5:1
80
89
77
homobenzyl
M, n-propyl
I, n-butyl
2
3
4
5
144
144
140
148
6.8:1
6.2:1
8.3:1
6.1:1
81
67
74
68
90
90
85
92
74
75
77
78
J, n-heptyl
L, isobutyl
a
b
d
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Determined by H NMR analysis. Determined by HPLC analysis.
Absolute configuration was determined as S; see Supporting
c
1
Information for details.
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2g was shown to be a suitable reagent giving us >95%
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observed with the bulkier peroxide 2h (Table 4, entry 7).
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