Catalytic asymmetric epoxidation of cyclic enones

Article abstract of DOI:10.1021/ja801181u

A highly enantioselective epoxidation of cyclic enones with hydrogen peroxide has been developed that is catalyzed by chiral primary amine salts. Copyright

Full text of DOI:10.1021/ja801181u

Published on Web 04/19/2008
Catalytic Asymmetric Epoxidation of Cyclic Enones
Xingwang Wang, Corinna M. Reisinger, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received February 17, 2008; E-mail: list@mpi-muelheim.mpg.de
Table 1. Catalyst Investigation
Enantioselective catalytic epoxidations of olefins provide
chiral epoxides of central importance to various branches of
chemistry.1 While there are powerful solutions for several
different classes of olefins,2 a highly enantioselective epoxidation
of simple cyclic enones has to our knowledge not been
described. Here we report a practical solution to this important
problem. We found that cyclic enones are readily epoxidized
with excellent enantioselectivity upon treatment with hydrogen
peroxide and a catalytic amount of a chiral primary amine salt.
Previously reported asymmetric epoxidations of cyclic R,ꢀ-
unsaturated ketones using cinchona alkaloid-derived quaternary
ammonium salt catalysts,3 poly(amino acid) catalysts,4 or
stoichiometric chiral hydroperoxides5 gave only poor or moder-
ate enantioselectivities with most cyclic enones. Recently,
secondary amine catalysts and their salts have been used in
enantioselective Weitz-Scheffer-type epoxidations of R,ꢀ-
unsaturated aldehydes via iminium catalysis.6 An extension to
R,ꢀ-unsaturated ketones appeared attractive to us, and we were
particularly encouraged by recent applications of primary amine
salts in the iminium catalysis of enone substrates.7 For example,
we have developed a highly enantioselective conjugate reduction
of enones with Hantzsch ester catalyzed by an R-amino acid
ester/chiral phosphate salt.8
Inspired by these studies, we investigated our previously used
valine salts 1a and 1b for the epoxidation of cyclohexenone
(2a) with 1.5 equiv of hydrogen peroxide (50% w/w in H2O)
(eq 1 in Table 1). The epoxidation reaction to 3a proceeded
smoothly, but the enantioselectivity was only moderate (Table
1, entries 1 and 2). We next shifted our attention to diamine
salts, expecting such bifunctional catalysts to possibly activate
both the enone substrate via iminium ion formation and
hydrogen peroxide via general base catalysis. Indeed, C2-
symmetric TFA salts 1c and 1d gave promising results (entries
3 and 4). Gratifyingly, (1R,2R)-1,2-diphenylethane-1,2-diamine
(DPEN) salts 1e-i proved to be both active and highly
enantioselective catalysts. The best result in this series was
achieved with DPEN-mono-TRIP salt 1g (entry 7) although
even TFA salt 1e (entry 5) gave high yield and enantioselec-
tivity. 9-Amino cinchona alkaloid9 salts 1j and 1k, which have
recently been used in primary iminium catalysis,7 have also been
investigated and gave excellent results. Especially, 9-amino-9-
deoxyepiquinine salt 1j proved to be both highly active and
enantioselective (entry 10).
entry
cat
conv (%)a
erb
entry
cat
conv (%)a
erb
1
2
3
4
5
1a
1b
1c
1d
1e
73
92
93
71
95
62:38
44:56
82:18
38:62
6
7
8
9
1f
1g
1h
1i
92
98
91
49
82
94:6
c
96:4
92:8
90:10
4:96
c
c
10
1j
95:5
a Determined by GC with external standard. b Determined by chiral
GC. c Absolute configuration [2R,3R] of 3a with catalysts 1g was
determined from its optical rotation.3a
In the case of ꢀ-substituted cyclohexenones, quinine-derived
catalyst 1j proved to be particularly suitable (entries 6-11).
As expected, quinidine-derived catalyst 1k gave the opposite
enantiomer with equally high enantioselectivities (entry 12).
2-Cycloheptenones turned out to be excellent substrates, fur-
nishing high yields of essentially enantiopure epoxides (entries
14-16). In contrast, 2-cyclopentenone exhibited lower reactivity
to give epoxide 3o, which to our knowledge for the first time
was obtained in good enantioselectivity (entry 17). R-Substituted
enones were unreactive under the reaction conditions. Consistent
with this and the fact that the corresponding nonprotonated
amines 1 as well as quinine itself are much less active and
enantioselective (see Supporting Information), we propose the
reaction to proceed via iminium ion A. The second basic amine
Having identified two useful catalysts (1g and 1j) for the
epoxidation of cyclohexenone (2a), scope and limitations of our
new epoxidation reaction were investigated next (for a detailed
comparison of catalysts 1e, 1g, and 1j with different substrates,
see Supporting Information). Indeed, treating different cyclic
enones 2 with aqueous hydrogen peroxide (1.5 equiv) in the
presence of the catalytic amine salts (10 mol %) at 30-50 °C
in dioxane for 20-48 h gave the corresponding R,ꢀ-epoxyke-
tones 3 in good yields and excellent enantioselectivities in almost
all cases studied (Table 2). In addition to cyclohexenone itself,
a number of different substituted cyclohexenones could be
converted with excellent results, including the natural product
isophorone (entry 5) and a cyclohexenedione (entry 13).
site of the catalyst may organize the transition state by directing
the attack of hydrogen peroxide toward one enantioface of the
double bond.
Pretransition state assembly A resembles structures proposed
by Yamaguchi et al. and by Taguchi et al. in their pioneering
studies on asymmetric iminium catalysis with proline-derived
9
6070 J. AM. CHEM. SOC. 2008, 130, 6070–6071
10.1021/ja801181u CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Preliminary Scope of the Epoxidation of Enonesa
of R,ꢀ-unsaturated ketones as well as the development of even
more efficient catalysts and a more detailed mechanistic
understanding. Our work adds to a growing number of
conceptually interesting reactions that are catalyzed by primary
amine salts, combining iminium and Brønsted acid catalysis.7,11
Acknowledgment. We thank the DFG (Priority Program
Organocatalysis SPP1179), the Max-Planck-Society, Novartis
(Young Investigator Award to B.L.), AstraZeneca (Award in
Organic Chemistry to B.L.), and the Fond der Chemischen
Industrie (Kekule´ fellowship to C.M.R. and Silver Award to
B.L.). We also thank our GC and HPLC departments for their
support, and Nolwenn Martin and Simone Marcus for technical
assistance.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and GC and HPLC
traces. This material is available free of charge via the Internet at
http://pubs.acs.org.
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a Reactions with catalyst 1j and 1k (1g) were performed on a 1.0
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secondary amine catalysts.10 Our current studies focus on
expanding the scope of this catalytic asymmetric epoxidation
JA801181U
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