Catalytic enantioselective peroxidation of α,β-unsaturated ketones

Article abstract of DOI:10.1021/ja802982h

Despite the potential of chiral peroxides as biologically interesting or even clinically important compounds, no catalytic enantioselective peroxidation has been reported. With a chiral catalyst not only to induce enantioselectivity but also to convert a well established epoxidation pathway into a peroxidation pathway, the first efficient catalytic peroxidation has been successfully developed. Employing readily available α,β-unsaturated ketones and hydroperoxides and an easily accessible cinchona alkaloid catalyst, this novel reaction will open new possibilities in the asymmetric synthesis of chiral peroxides. Under different conditions a highly enantioselective epoxidation with the same starting materials, reagents, and catalyst has was also established. Copyright

Full text of DOI:10.1021/ja802982h

Published on Web 06/05/2008
Catalytic Enantioselective Peroxidation of r,ꢀ-Unsaturated Ketones
Xiaojie Lu, Yan Liu, Bingfeng Sun, Brittany Cindric, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received April 23, 2008; E-mail: deng@brandeis.edu
Scheme 1. Mechanism of a Base-Catalyzed Nucleophilic Epoxidation
of R,ꢀ-Unsaturated Ketones
The number of biologically interesting natural products possessing
peroxide structure motifs is substantial and still growing.1 Many peroxy
natural products display antitumor, anticancer, and antiparasite activi-
ties, which are attributed to the propensity of the peroxide to initiate
radical reactions in an iron-rich environment.2 Furthermore, peroxide
natural products such as artemisinin are clinically important antimalaria
drugs. Despite the potential of chiral peroxides as biologically
interesting or even clinically important compounds, synthetic methods
for the preparation of chiral peroxides are highly limited.3–6 In
particular efficient catalytic enantioselective peroxidations are urgently
needed, yet none are available. In fact only a single example of a chiral
auxiliary-directed peroxidation in high diastereoselectivity could be
found in the literature.7 Herein, we wish to report the development of
a highly enantioselective peroxidation of R,ꢀ-unsaturated ketones with
an easily accessible chiral organic catalyst.
The base-promoted reaction of R,ꢀ-unsaturated ketones 1 with
hydroperoxides 2 represents a classic epoxidation reaction. Asymmetric
variants of this epoxidation with both chiral metal and organic catalysts
have also been reported.8–13 It is well-established that the epoxide 3
is formed via a two-step mechanism (Scheme 1); nucleophilic addition
of the hydroperoxide 2 to 1 followed by an intramolecular nucleophilic
substitution of the resulting enolate (5) that breaks the weak peroxide
bond. In principle this epoxidation pathway (1 to 3) could be converted
into a peroxidation pathway (1 to 6) if 5 could be trapped by
protonation, although the overwhelming preference of 5 for the
intramolecular nucleophilic substitution is evident from the lack of
reported peroxidation of R,ꢀ-unsaturated carbonyl compounds.
Although chiral amine-catalyzed nucleophilic epoxidations of R,ꢀ-
unsaturated carbonyl compounds have already been reported,13 we
suspected that a cinchona alkaloid derivative such as 814 could not
only render the nucleophilic addition of the hydroperoxide 2 to the
iminium intermediate 9 enantioselective, but also strongly influence
the partitioning of the peroxyenamine intermediate 10 between the
epoxidation (10 to 11) and the peroxidation (10 to 12) pathways
(Scheme 2). Presumably, owing to steric crash and multipoint binding
interactions between the peroxyenamine intermediate and the covalently
linked cinchona alkaloid, the bond-rotational freedom of the peroxy-
enamine should be hampered, compared to that of the enolate 5 in
Scheme 1. We expected that this conformational rigidity imposed by
8 on the peroxyenamine would diminish its ability to adopt the active
conformation by which the nucleophilic enamine moiety is optimally
aligned relative to the O-O bond for the nucleophilic attack. This in
turn would decelerate the epoxidation. In contrast, with the protonated
quinuclidine as a proton source nearby to facilitate the protonation of
the peroxyenamine, the peroxidation might be accelerated.
Scheme 2. A Proposed Catalytic Cycle for the Reaction of 1 and 2
with Cinchona Alkaloid 8
Particularly noteworthy are the highly enantioselective peroxidations
of R,ꢀ-unsaturated ketones 1 with the R-methoxy isopropyl hydrop-
eroxide 2c (entries 18-23, Table 1). The ability to employ 2c
considerably increases the synthetic potential of this new catalytic
asymmetric peroxidation, as the corresponding chiral peroxides could
be readily converted to chiral hydroperoxides suitable for further
elaborations (Scheme 3).15 The catalytic asymmetric peroxidation also
provides a new enantioselective route to the chiral ꢀ-hydroxy ketones
as peroxides could be easily reduced to the corresponding alcohol
(Scheme 3).16
Following our observation that the peroxide/epoxide ratio inversely
correlated with the reaction temperature, we performed the reactions
of various R,ꢀ-unsaturated ketones with cumene hydroperoxide (2b)
at elevated temperature (23 or 55 vs 0 °C) to establish conditions for
an asymmetric epoxidation of 1.17 As summarized in Table 2, highly
We then investigated how R,ꢀ-unsaturated ketone 1A reacted with
TBHP (2a) in the presence of 8. We found that, with TFA (20 mol
%) as the additive, the reaction afforded the peroxide 6Aa as the
dominant product in 85% ee (entry 1, Table 1). When performed in
toluene with 30 mol % TFA both the peroxide/epoxide (6/3) ratio and
the enantioselectivity could be improved to an excellent level (entry
2, Table 1). Importantly, the reaction demonstrated considerable scope
for both the R,ꢀ-unsaturated ketones 1 and the hydroperoxides 2.
9
8134 J. AM. CHEM. SOC. 2008, 130, 8134–8135
10.1021/ja802982h CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Peroxidation of R,ꢀ-Unsaturated Ketones 1 with 8a
interesting chiral peroxides. Furthermore, with the same catalyst and
reagents, a highly asymmetric epoxidations of acyclic enones could
be achieved simply by performing the reaction at a higher temperature.
Acknowledgment. We are grateful for financial support from
National Institute of Health (Grant GM-61591). We thank Professor
Jeffrey Agar for his assistance in MS analysis.
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
entry enone peroxide temp (°C) time (h)
6:3b
yield (%) 6 ee (%)c
6
1d
2
1A
1A
1B
1C
1D
1E
1F
1H
1I
1A
1B
1C
1D
1E
1F
1H
1I
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2c
23
23
23
23
23
23
23
23
23
0
0
0
0
0
0
0
0
0
2
4
4
4
4
4
4
4
4
16
12
12
16
12
24
24
24
19
24
24
17
24
24
91:9
92:8
94:6
94:5
nd
85
88
91
85
91
84
90
3
References
4e
5f
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93:7 (95:5)
90:10
86 (90) 93 (90)
6
7
65
90
89
91
89
87
95:5
94:6
8
9f
86:14 (93:7) 64 (77) 94 (88)
10
11
12
13
14
15
16
17
86:14
77:23
88:12
87:13
90:10
89:11
85:15
65:35
77:23
86:14
88:12
95:5
74
70
75
77
82
75
66
55
60
70
62
63
42
60
94
92
92
95
96
94
96
97
92
95
95
95
94
94
18g 1A
19g 1C
20g 1D
21g 1F
22g 1G
23g 1H
0
0
0
0
78:22
95:5
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0
a Unless noted, reactions were run with 0.3 mmol 1, 0.36 mmol 2.
b Determined by 1H NMR. c See Supporting Information (SI). d Reaction
was run with 0.1 mmol 1 and 20 mol % TFA. e Absolute configuration was
established as R (see SI). f The results in parentheses were obtained with
QD-NH2. g Reaction was run with 20 mol % TFA.
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Scheme 3. Synthetic Transformations of Chiral Peroxides 6
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Table 2. Epoxidation of R,ꢀ-Unsaturated Ketones 1 with 8a
entry
enone
temp (°C)
time (h)
6:3b
yield (%) 3
ee (%)c
3
1
1A
1C
1D
1F
1G
1H
23
23
23
55
55
55
72
72
72
24
24
24
1:99
1:99
1:99
32:68
33:67
13:87
88
91
91
55
54
71
97
97
97
97
96
97
2
3d
4
5
6
a Unless noted, reactions were run with 0.3 mmol of 1, 0.36 mmol 2b.
b Determined by 1H NMR analysis. c Entry 1 was determined by HPLC
analysis, others are determined by GC analysis. d Absolute configuration
was assigned as (3R,4S).
enantiomerically enriched epoxides were indeed obtained as the major
product and in synthetically useful yields.18
In summary, by using a chiral catalyst to not only induce enanti-
oselectivity but also to convert a well-established epoxidation pathway
into a peroxidation pathway, we have developed the first highly
enantioselective catalytic peroxidation reaction. Employing readily
available reagents and catalyst, this novel reaction is expected to open
new possibilities in the asymmetric synthesis of the biologically
(17) For an aspartate-catalyzed electrophilic epoxidation, see: Peris, G.; Jakob-
sche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710.
(18) While this manuscript was in preparation, an 8-catalyzed asymmetric
epoxidation of cyclic enone with H2O2 was reported: Wang, X.; Reisinger,
C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070.
JA802982H
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J. AM. CHEM. SOC. VOL. 130, NO. 26, 2008 8135