We have developed an unprecedented highly enantioselective catalytic peroxidation of enals. of chiral 1 2 and 1 2 thereby facilitating the biological and medicinal chemistry studies of peroxy natural products. A large number of biologically interesting peroxy natural products contain either a 1 2 (7) or 1 2 (1-6) bearing an acetylester substituent and two or more stereocenters (Scheme 1).1 It is particular noteworthy that many of these perxoy natural products have been identified to be highly potent anticancer agents.1 2 A general enantioselective approach toward these structural motifs would greatly facilitate the biological and medicinal chemistry studies of peroxy natural products. However to our knowledge such a synthetic approach has not yet been established.3 4 The presence of non-adjacent stereocenters in these chiral 1 2 and 1 2 and the general lack of asymmetric Morroniside peroxidations of broad substrate scope render the efficient stereoselective constructions of such motifs an outstanding challenge not only in synthetic strategy development but also in methodology development.3c 5 Scheme 1 Representative Peroxy Natural Products and Our General Strategy to Synthesize These Molecules We envision that an asymmetric peroxidation of α β-unsaturated aldehydes 12 followed by an oxidation of the aldehyde to the acid derivatives would provide an attractive route toward β-peroxy acid derivatives 10 (Scheme 1). Asymmetric functionalization of 10 at either carbon 4 or 5 5 followed by a cyclization with a nucleophilic attack Morroniside by the hydroperoxide would generate 8 or 9.6 This strategy could provide a general approach toward chiral Morroniside 1 2 and 1 2 motifs thereby facilitating the total synthesis of a broad range of peroxy natural products. Critical to the implementation of this strategy is the development of a general and highly enantioselective nucleophilic peroxidation of enal 12 that is highly general with respect to the β-alkyl substituent. In this manuscript we wish to report the realization of such an unprecedented asymmetric peroxidation and the application of this new reaction to the development of a stereocontrolled concise and flexible route for the construction of the connected oxidoreductase) in mammalian cells.7c Notably these bioactivities have been attributed to the CNOT10 presence of common dioxane-tetrahydrofuran bicyclic core structure.7b As shown in our retrosynthetic analysis (Scheme 2) the stereochemically dense core 20 was to be constructed Morroniside by an acid-promoted unprecedented hydroperoxide-initiated epoxide-opening cascade from the bis(epoxy)hydroperoxide 21. Intermediate 21 would be prepared from intermediate 22 via the newly developed asymmetric peroxidation of the epoxyenal 22 followed by a Shi epoxidation of the trans-olefin. The epoxyenal 22 could be prepared from known compounds epoxyiodide 25 and vinyliodide 24. Overall the four stereocenters in Morroniside 20 were to be created from the 19-catalyzed asymmetric peroxidation a Shi olefin epoxidation and D-aspartic acid. Scheme 2 Retrosynthesis for the Core Structre of (+)- Stolonoxides C and D Our synthesis commenced from the coupling of epoxyiodide 25 available from D-aspartic acid via four simple operations in 58% overall yield and 99% ee 10 with trans-alkenyliodide 24 (Scheme 3).11 24 was first allowed to react with isopropylmagnesium chloride to generate the trans-alkenylmagnesium chloride 12 which then coupled with epoxyiodide 25 to form 26 in THF. Through considerable optimizations we found the use of a stoichiometric amount of CuI and 4.0 equivalents of HPMA was required for the reaction to proceed with high chemoselectivity in favor of the desired coupling reaction. Otherwise the nucleophilic ring opening of the terminal epoxide became the dominant reaction.13 Deprotection of 26 was readily accomplished and the resulting alcohol 27 was converted into the α β-unsaturated ester 28 when subjected to a Dess-Martin oxidation followed by a Wittig olefination. Reduction of unsaturated ester 28 by DIBAL followed by an oxidation the allylic alcohol thus afforded the key enal intermediate 22. Catalytic asymmetric peroxidation of 22 with α-methoxydiphenyl hydroperoxide 14d applying the optimal condition described previously (Table 1) readily afforded the desired β-peroxyaldehyde which was immediately subjected to sodium chlorite and then TMSCHN2 to form ester 30 in 57% yield over three steps. Importantly the key peroxidation.