Asymmetric Epoxidation DOI: 10.1002/anie.200803238 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 Juliµ 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. 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. , MacMillans 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·2 Cl 3 CCO 2 H (10 mol %) at 30 8C in dioxane for 20 h, 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 % 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·2 Cl 3 CCO 2 H (10 mol %) at 32 8C 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] 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·2 F 3 CCO 2 H (10–20 mol %), 50 8C, dioxane, 12–48 h], followed by basic workup of the crude Scheme 1. Catalytic asymmetric hydroperoxidation. [*] C.M. Reisinger, Dr. X. Wang, Prof. Dr. B. List Max-Planck-Institut für Kohlenforschung Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany) Fax: (+ 49) 208-306-2982 E-mail: list@mpi-muelheim.mpg.de [**] This work was supported by the Max Planck Society, the DFG (SPP 1179, Organocatalysis), and the Fonds der Chemischen Industrie (KekulØ 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 under http://dx.doi.org/10.1002/anie.200803238. Communications 8112  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2008, 47, 8112 –8115