Communications
DOI: 10.1002/anie.200803238
Asymmetric Epoxidation
Catalytic Asymmetric Hydroperoxidation of a,b-Unsaturated Ketones:
An Approach to Enantiopure Peroxyhemiketals, Epoxides, and
Aldols**
Corinna M. Reisinger, Xingwang Wang, and Benjamin List*
Despite the wealth of enantioselective and catalytic epoxida-
tions of olefins—including those associated with the names of
Juliꢀ and Colonna, Wynberg, Jackson, Sharpless, Jacobsen,
Katsuki, Enders, Shi, and Shibasaki—there is still no general
method for the epoxidation of simple a,b-unsaturated
ketones.[1] Previously described methods often lack scope,
reactivity, and selectivity. Very recently, we introduced a
highly enantioselective epoxidation of cyclic enones using
amines such as 1a and 1b as catalysts and hydrogen peroxide
as the oxidant.[2] Subsequent to our publication and during the
preparation of this manuscript, Deng et al. described a
catalytic asymmetric tert-alkyl peroxidation of enones using
the same catalysts.[3] Here we report our independent studies
leading to a highly enantioselective catalytic hydroperoxida-
tion of simple aliphatic enones with hydrogen peroxide. Our
process delivers enantiopure cyclic peroxyhemiketals, which
are readily converted into either epoxides or aldols.
peroxyhemiketal 3a was formed in 58% yield (Scheme 1).
Along with this cyclic peroxide, which is an intermediate and
common a byproduct in Weitz–Scheffer-type epoxidations,[8]
the expected epoxide 4a was also formed in roughly 30%
Scheme 1. Catalytic asymmetric hydroperoxidation.
Iminium catalysis has been introduced recently as a
powerful strategy for the enantioselective epoxidation of a,b-
unsaturated carbonyl compounds. After pioneering contribu-
tions by Jørgensen et al., MacMillanꢁs group and we have also
reported secondary amine catalysts for the epoxidation of
enals.[4] Continuing our studies on the use of primary amine
catalysts for reactions of a,b-unsaturated ketones,[5] we have
discovered a highly efficient, general, and enantioselective
epoxidation of cyclic enones with hydrogen peroxide using
cinchona alkaloid derived primary amine catalysts 1a and
1b.[2] These powerful and readily made catalysts have
previously found utility in other selected transformations.[6]
In an effort to expand the scope of our epoxidation, we turned
our attention to acyclic aliphatic a,b-unsaturated ketones.
Previously, few asymmetric epoxidation methodologies gave
satisfactory results with this substrate class.[7] Remarkably,
when 2-decenone (2a) was subjected to aqueous hydrogen
peroxide (50 wt%) and the primary amine salt catalyst
1a·2Cl3CCO2H (10 mol%) at 308C in dioxane for 20 h,
yield. Since cyclic peroxyhemiketals are known to be trans-
formed into the corresponding epoxides under basic condi-
tions,[9] basic workup of the product mixture will always
enable quantitative epoxide formation independent of the
initially observed ratio of peroxyhemiketal 3a to epoxide 4a
(see below). Furthermore, reduction of peroxides such as 3a
should provide 3-hydroxy ketones (e.g. 5a).
In preliminary studies we evaluated the scope of the
amine 1a-catalyzed hydroperoxidation. Treating both linear
and branched a,b-unsaturated ketones 2a–e with three
equivalents of aqueous hydrogen peroxide (30 wt%) in the
presence of catalyst 1a·2Cl3CCO2H (10 mol%) at 328C in
dioxane for 36–48 h directly resulted in the formation of
peroxyhemiketals 3a–e in reasonable yields and with high
enantioselectivities (Table 1). In general, the only detected
by-products were the corresponding epoxides 4, which are
easily separated from peroxides 3. Substrates with an
aromatic residue at the double bond and trisubstituted olefins
turned out to be unreactive under our reaction conditions.
The 1,2-dioxolane subunit is present in many natural products
and bioactive molecules, and peroxyhemiketals related to 3
are key intermediates in the synthesis of this structural
motif.[10]
[*] C. M. Reisinger, Dr. X. Wang, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
Fax: (+49)208-306-2982
E-mail: list@mpi-muelheim.mpg.de
We also optimized the reaction conditions for epoxide
formation. Indeed, subjecting linear and branched a,b-
unsaturated ketones to a slightly modified version of the
hydroperoxidation conditions [1.5 equiv aqueous hydrogen
peroxide (50 wt%), 1a·2F3CCO2H (10–20 mol%), 508C,
dioxane, 12–48 h], followed by basic workup of the crude
[**] This work was supported by the Max Planck Society, the DFG (SPP
1179, Organocatalysis), and the Fonds der Chemischen Industrie
(Kekulꢁ fellowship to C.M.R. and Award in Silver to B.L.). We thank
our GC and HPLC departments for their support.
Supporting information for this article is available on the WWW
8112
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 8112 –8115