Enantioselectivity dioxiranes

The enantioselective oxidation of prochiral sulfides with DMD has been achieved by using bovine serum albumin (BSA) as the chiral inductor Moderate to good enan-tioselectivities have been reported in the presence of this protein, for which a typical example is shown in equation 22 . As yet, however, no enantioselective oxidation of a prochiral sulfide has been documented by employing an optically active dioxirane. We have tried the enantioselective oxidation of methyl phenyl sulfide with the dioxirane generated from the ketone 7 (Shi s ketone), but an ee value of only ca 5% was obtained. One major hurdle that needs to be overcome with such enantioselective dioxirane oxidations is the suppression of the background oxidation of the sulfide substrate by Caroate, an unavoidable feature of the in-situ mode. 

The ability of non-C2 symmetric ketones to promote a highly enantioselective dioxirane-mediated epoxidation was first effectively demonstrated by Shi in 1996 [114]. The fructose-derived ketone 44 was discovered to be particularly effective for the epoxidation of frans-olefins (Scheme 17 ). frans-Stilbene, for instance, was epoxidized in 95% ee using stoichiometric amounts of ketone 44, and even more impressive was the epoxidation of dialkyl-substituted substrates. This method was rendered catalytic (30 mol %) upon the discovery of a dramatic pH effect, whereby higher pH led to improved substrate conversion [115]. Higher pH was proposed to suppress decomposition pathways for ketone 44 while simultaneously increasing the nucleophilicity of Oxone. Shi s ketone system has recently been applied to the AE of enol esters and silyl enol ethers to provide access to enantio-enriched enol ester epoxides and a-hydroxy ketones [116]. Another recent improvement of Shi s fructose-derived epoxidation reaction is the development of inexpensive synthetic routes to access both enantiomers of this very promising ketone catalyst [117]. 

Several other attempts at producing highly enantioselective dioxirane-based catalysts for asymmetric epoxidation have been reported [29, 30] of these Armstrong s tropinone-derived a-fiuoroketone was found to be a good mediator (Scheme 1.11)... 

Shi s Highly Enantioselective Dioxirane Epoxidation Mediated by a Fructose-derived Dioxirane... 

Development of chiral, nonracemic dioxiranes for the catalytic enantioselective epoxidation of alkenes 99SL847. 

Enantioselective epoxidation of unfunctionalized alkenes was until recently limited to certain ds-alkenes, but most types of alkenes can now be successfully epoxi-dized with sugar-derived dioxiranes (see Section 9.1.1.1) [2]. Selective monoepox-idation of dienes has thus become a fast route to vinylepoxides. Functionalized dienes, such as dienones, can be epoxidized with excellent enantioselectivities (see Section 9.1.2). 

A number of chiral ketones have been developed that are capable of enantiose-lective epoxidation via dioxirane intermediates.104 Scheme 12.13 shows the structures of some chiral ketones that have been used as catalysts for enantioselective epoxidation. The BINAP-derived ketone shown in Entry 1, as well as its halogenated derivatives, have shown good enantioselectivity toward di- and trisubstituted alkenes. 

Vinyl epoxides are highly useful synthetic intermediates. The epoxidation of dienes using Mn-salen type catalysts typically occurs at the civ-olefin. Epoxidations of dienes with sugar-derived dioxiranes have previously been reported to react at the trans-olefin of a diene. A new oxazolidinone-sugar dioxirane, 9, has been shown to epoxidize the civ-olefin of a diene <06AG(I)4475>. A variety of substitution on the diene is tolerated in the epoxidation, including aryl, alkyl and even an additional olefin. All of these substitutions provided moderate yields of the mono-epoxide with good enantioselectivity. 

Among many other methods for epoxidation of disubstituted E-alkenes, chiral dioxiranes generated in situ from potassium peroxomonosulfate and chiral ketones have appeared to be one of the most efficient. Recently, Wang et /. 2J reported a highly enantioselective epoxidation for disubstituted E-alkenes and trisubstituted alkenes using a d- or L-fructose derived ketone as catalyst and oxone as oxidant (Figure 6.3). 

Wang and Shi have published a detailed study of their fructose-based dioxirane epoxidation catalyst system with hydroxyalkene substrates. The ees obtained were highly pH dependent. The lower enantioselectivity obtained at low pH is attributed to the substantial contribution of direct epoxidation by Oxone. The results obtained with... 

A high catalyst loading (typically 20-30 mol%) is usually required for the epoxidation with ketone 26 because Baeyer-Vilhger oxidation presumably decomposes the catalyst during the epoxidation. The fused ketal moiety in ketone 26 was replaced by a more electron-withdrawing oxazohdinone (32) and acetates (33) with the anticipation that these replacements would decrease the amount of decomposition via Baeyer-Villiger oxidation (Fig. 8) [71, 72]. Only 5 mol% (1 mol% in some cases) of ketone 32 was needed to get comparable reactivity and enantioselectivity with 20-30 mol% of ketone 26 [71]. Since dioxiranes are electrophilic reagents, they show low reactivity toward electron-deficient olefins, such as a, 3-unsaturated esters. Ketone 33, readily available from ketone 26, was found to be an effective catalyst towards the epoxidation of a, 3-unsaturated esters [72]. 

The enantioselective epoxidation of prochiral alkenes with an aldehyde dioxirane was achieved by Bez and Zhao . ... 

The dioxirane epoxidation of a prochrral alkene will produce an epoxide with either one new chirality center for terminal alkenes, or two for internal aUcenes. When an optically active dioxirane is nsed as the oxidant, expectedly, prochiral alkenes should be epoxi-dized asymmetrically. This attractive idea for preparative purposes was initially explored by Curci and coworkers in the very beginning of dioxirane chemistry. The optically active chiral ketones 1 and 2 were employed as the dioxirane precursors, but quite disappointing enantioselectivities were obtained. Subsequently, the glucose-derived ketone 3 was used, but unfortunately, this oxidatively labile dioxirane precursor was quickly consumed without any conversion of the aUcene . After a long pause (11 years) of activity in this challenging area, the Curci group reported work on the much more reactive ketone... 

A novel approach to achieve high regioselectivity was recently developed by Yang and coworkers, in which the in-situ-generated dioxirane functionality, contained within the substrate, oxidizes the secondary 5c-h bond rather than the more reactive tertiary yc-H bond, due to a favorable concerted transition state (equation 31). A limitation of this method, however, is that the ketone unit has to be incorporated into the substrate molecule at the appropriate position, normally a rather unpractical and cumbersome task. Moreover, such a process is necessarily stoichiometric in practice and, thereby, it lacks appeal since nowadays catalytic enantioselective oxyfunctionalizations are in vogue ... 

Unlike epoxidations, the enantioselective CH oxidation is still a virgin field in dioxirane chemistry. The first (and to date only ) enantioselective C—H oxidation has been reported for vic-diols. Thus, the oxidation with the fructose-derived dioxirane of ketone 7 (Shi s ketone) yields the optically active a-hydroxy ketones in ee values of up to 75% °. A typical example of this asymmetric CH oxidation is shown in equation 32 °. 

These few cases indisputably illustrate the synthetic value of such enantioselective CH insertions, a challenging area of dioxirane chemistry that demands more intensive research activity. For that purpose more reactive and more effective chiral dioxiranes must be designed. 

Chiral dioxirane that was also generated in situ from the corresponding ketone and Oxone was first used for catalytic asymmetric epoxidation by Curd et al., although enantioselectivity was low [7], Later, Yang et al. disclosed that this approach had a bright prospect if used with a combination of Oxone and chiral ketone 3 [8]. Ketone 3 is converted into the corresponding dioxirane in situ, which epoxidizes olefins (Scheme 6B.5). 

The chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity of heteroatom oxidations, epoxidations and CH insertions by dioxiranes have been reviewed.26 The selective ring-opening reactions of epoxides at high pressures have been reviewed (in Japanese).27... 

---