Organocatalytic enantioselective peroxidation of ketimines derived from isatins

Article abstract of DOI:10.1021/acs.orglett.5b00805

The first catalytic enantioselective addition of hydroperoxides to ketimines derived from isatins has been developed. Excellent yields and enantioselectivities were observed for the reaction of various ketimines with peroxides using a cinchona alkaloid su

Full text of DOI:10.1021/acs.orglett.5b00805

Letter
pubs.acs.org/OrgLett
Organocatalytic Enantioselective Peroxidation of Ketimines Derived
from Isatins
Shuichi Nakamura* and Shun Takahashi
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya
466-8555, Japan
S
* Supporting Information
ABSTRACT: The first catalytic enantioselective addition of hydroperoxides to ketimines derived from isatins has been
developed. Excellent yields and enantioselectivities were observed for the reaction of various ketimines with peroxides using a
cinchona alkaloid sulfonamide catalyst. Both enantiomers of products could be obtained by using pseudoenantiomeric chiral
catalysts. The obtained product can be converted to optically active α-amino hydroperoxide.
ptically active peroxide-containing compounds and their
derivatives have been proven to be useful chiral building
peroxides in excellent yields with high enantioselectivities.7,8
Although such pioneering studies exist, there are no reports to
challenge the difficulty of the enantioselective addition of
hydroperoxides to ketimines.9,10 On the other hand, the
reaction of ketimines derived from isatins has attracted much
attention, because the reaction affords α-amino peroxides
having a 2-oxindole backbone, which is an important structural
motif in biologically active compounds.11 However, only little
attention has been paid to the enantioselective addition of
heteroatoms to ketimines. We recently reported the first
enantioselective reactions of ketimines with some heteroatom
nucleophiles, such as phosphites12 and thiols,13 and we also
developed novel catalysts derived from cinchona alkaloids.14
Herein, our ongoing interest was extended to the enantiose-
lective addition of hydroperoxides to various ketimines using
our original chiral catalysts derived from cinchona alkaloids
(Figure 2).
O
blocks for the preparation of pharmaceutical targets,1 such as
antimalarial2 and anticancer drugs.3 Furthermore, chiral α-
amino peroxide moieties can be found in natural products, such
as verruculogen1a and D-luciferin dioxetanone (Figure 1).4
Figure 1. Natural compounds having an α-amino peroxide structure.
Therefore, their synthetic importance has prompted consid-
erable interest to develop the asymmetric synthesis of chiral α-
amino peroxides, although catalytic enantioselective synthesis
of these compounds remains a considerable challenge.5
One of the most efficient methods for the preparation of
chiral α-amino peroxides is the enantioselective addition of
hydroperoxides to imines.6 Antilla and co-workers reported the
first enantioselective synthesis of chiral α-amino peroxides by
the reaction of hydroperoxides with N-acylimines derived from
aldehydes using chiral phosphoric acids to give chiral α-amino
Figure 2. Enantioselective synthesis of α-amino peroxides through the
addition of hydroperoxides to ketimines.
Received: March 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
First, we examined the reaction of ketimines derived from
isatins 1 with cumene hydroperoxide 2a in the presence of
chiral organocatalysts 3,4 derived from various cinchona
alkaloids in toluene. The results are shown in Table 1.
pyridinesulfonyl, 2-thiophensulfonyl, 8-quinolinesulfonyl, and
8-quinolinecarbonyl groups afforded product 5. The best
enantioselectivity and reactivity were obtained in the reaction
using 4e having an 8-quinolinesulfonyl group (Table 1, entries
6−10). We also examined the reaction using 8-quinoline-
sulfonylated catalysts 4g−i, prepared from quinine, quinidine,
and cinchonine (Table 1, entries 11−13). The reaction using
4g also afforded product 5 with excellent enantioselectivity
(Table 1, entry 11).15 The reaction using 4h and 4i afforded
product 5 with good enantioselectivity having an opposite
stereochemistry than that using 4e (Table 1, entries 12−13).
The catalyst loading of 4e was successfully reduced to 1 mol %,
although the reactivity and enantioselectivity were gradually
reduced (Table 1, entries 14 and 15). The reaction could be
carried out in an open flask to give product 5 in high yield with
high enantioselectivity (Table 1, entry 16).
Table 1. Enantioselective Addition of Cumene
Hydroperoxide 2a to Ketimines 1a−c Derived from Isatins
a
Using Various Chiral Organocatalysts 3,4
The scope and limitations of the addition of 2a to various
ketimines 1a,d−l using 5 mol % of 4e were investigated. The
results are summarized in Table 2. The reaction of imines 1d,e
Table 2. Enantioselective Addition of Cumene
Hydroperoxide 2a to Various Ketimines 1a,d−m Using 4e
b
run
1
cat.
product
time (h)
yield (%)
ee (%)
1
1a
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
3a
3b
4a
4a
4a
4b
4c
4d
4e
4f
5
5
5
6
7
5
5
5
5
5
5
5
5
5
5
5
12
48
36
48
48
36
12
36
12
36
12
36
36
60
72
36
94
75
96
48
94
74
91
91
90
11
99
94
99
98
90
99
12
67
88
67
79
88
36
60
97
0
2
entry
1
R
product
yield (%)
ee (%)
3
4
1
1a
1d
1e
1f
H
5
99
99
95
90
99
90
81
97
90
87
97
97
96
97
96
97
95
96
97
96
5
2
5-Me
5-MeO
5-F
8
6
3
9
7
4
10
11
12
13
14
15
16
8
5
1g
1h
1i
5-Cl
9
6
5-Br
10
11
12
13
7
5-NO2
6-Cl
4g
4h
4i
97
8
1j
c
85
9
1k
1l
6-Br
c
67
10
7-F
d
14
4e
4e
4e
96
91
97
e
15
f
16
bearing an electron-donating methyl or methoxy group gave the
corresponding products 8,9 in high yield with high
enantioselectivity (Table 2, entries 2 and 3). Electron-deficient
imines 1f−l having fluoro, chloro, or bromo groups were
tolerable in these reaction conditions, giving products 10−16
with high enantioselectivity (Table 2, entries 4−10). Chemical
yield was excellent in most cases.16 To our knowledge, this is
the first example of the enantioselective synthesis of α-amino
peroxides from a reaction with ketimines.9f
The reaction of ketimines 1a with other hydroperoxides 2b
and 2c17 using 4e also gave products 17,18 in high yield with
high enantioselectivity (Scheme 1).
We next examined the removal of an alkyl group on peroxide
in 18. Treatment of 18 with Amberlyst 15E as an acidic resin in
CH2Cl2 afforded α-amino hydroperoxide 19 in high yield
(Scheme 2).
a
Reaction condition: ketimine 1 (0.03 mmol), 2a (3.0 equiv), 3,4 (10
b
c
mol %), and toluene (0.06 M) were used. Isolated yield. Opposite
enantiomer was obtained. 4e (2 mol %) was used. 4e (1 mol %) and
2a (5.0 equiv) were used. The reaction was carried out in an open
flask using 5 mol % of 4e.
d
e
f
Although the reaction of N-Cbz-N′-benzyl isatinimine 1a
with 2a using cinchonidine 3a or 9-amino-9-deoxy-epi-
cinchonidine 3b afforded product 5 in high yield with low or
moderate enantioselectivity (Table 1, entries 1 and 2), the
reaction using N-tosylated 9-amino-9-deoxy-epi-cinchonidine
4a gave 5 in high yield with good enantioselectivity (Table 1,
entry 3). In order to improve the reactivity and enantiose-
lectivity, we attempted the reaction of various substituted
ketimines with 2a. However, the reaction of ketimines derived
from N-Boc-N′-benzyl isatin 1b or N-Cbz-N′-methyl isatin 1c
gave products 6,7 with lower enantioselectivity than that from
the reaction using 1a (Table 1, entries 4 and 5). We next
investigated the effect of the catalyst structure on stereo-
selectivity. The reaction using various N-substituted 9-amino-9-
deoxy-epi-cinchonidines 4b−f having 1-naphthalenesulfonyl, 2-
In order to improve synthetic efficiency, we next examined
the one-pot synthesis of α-amino peroxides through the aza-
Wittig reaction and hydroperoxide addition reaction (Scheme
3). Although Ph3PO remained in the reaction mixture, the
hydroperoxide addition reaction afforded product 5 in high
yield with high enantioselectivity.
B
DOI: 10.1021/acs.orglett.5b00805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
afforded products with high enantioselectivity. Further studies
focusing on the scope of the asymmetric reaction using novel
organocatalysts are currently under investigation and will be
reported in due course.
Scheme 1. Enantioselective Addition of Hydroperoxides 2b,c
with 1a
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra and experimental procedures for all
new compounds. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00805.
Scheme 2. Transformation of 18 to α-Amino Hydroperoxide
19
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: snakamur@nitech.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by Grants-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from MEXT (26105727).
Scheme 3. One-Pot Synthesis of α-Amino Peroxide
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D
DOI: 10.1021/acs.orglett.5b00805
Org. Lett. XXXX, XXX, XXX−XXX