Epoxidation of enones

The asymmetric epoxidation of enones with polyleucine as catalyst is called the Julia-Colonna epoxidation [27]. Although the reaction was originally performed in a triphasic solvent system [27], phase-transfer catalysis [28] or nonaqueous conditions [29] were found to increase the reaction rates considerably. The reaction can be applied to dienones, thus affording vinylepoxides with high regio- and enantio-selectivity (Scheme 9.7a) [29]. 

The N-aminoaziridine version7 of the a,/3-epoxyketone->alkynone fragmentation is a possible alternative in situations where the simple tosylhydrazone version6-9 fails. The tosylhydrazone method often gives good yields at low reaction temperatures, but it tends to be unsuccessful with the epoxides of enones that are not cyclic or are not fully substituted at the /5-carbon atom. For example, it has been reported9 that 2,3-epoxycyclohexanone docs not produce 5-hexynal by the tosylhydrazone route. The A-aminoaziridine method can also be recommended for the preparation of acetylenic aldehydes as well as ketones. 

Enders and coworkers <96AG(E)1725> have developed an interesting general one-pot method for the asymmetric epoxidation of enones with oxygen in the presence of diethylzinc and (l ,/ )-N-methylpseudoephedrine (30), which provides a, P - epoxyketones in very high yield and high enantiomeric excess (e.g., 33 —> 34). The actual reactive species is believed to be the chirally modified alkoxy(ethylperoxy)zinc 31, which attacks the si face of the s-cis conformation of the (E) enones (cf. 32). 

Chiral PTC has been used effectively for making intermediates for drugs. Dolling and coworkers have used 8-R, 9-5, N-(p-trifluoromethylbenzyl) cinchonium bromide to carry out an important asymmetric alkylation, giving 95% ee (Starks, 1987). Nucleophilic epoxidations of enones, Darzens reaction, Michael additions, etc. are some examples of reactions rendered asymmetric through chiral PTCs (Nelson, 1999). 

The epoxidation of electron-deficient alkenes, particularly a,P-unsaturated carbonyl compounds, continues to generate much activity in the literature, and this has been the subject of a recent concise review <00CC1215>. Additional current contributions in this area include a novel epoxidation of enones via direct oxygen atom transfer from hypervalent oxido-).3-iodanes (38), a process which proceeds in fair to good yields and with complete retention of... 

The epoxidation of enones with poly-D-leucine is complementary to other strategies. Enders et u/.[8] introduced a new method for the asymmetric epoxidation of a-enones using diethylzinc, oxygen and (1R, lR)-or (IS1, 2S)-N-methylpseudoephedrine as chiral auxiliary. 

Table 4.1 Epoxidation of enones using poly-L-leucine catalyst15 71.

B. Lygo, P. G. Wainwright Phase-Transfer Catalyzed Asymmetric Epoxidation of Enones using N-Anthracenylmethyl-Substituted Cinchona Alkaloids , Tetrahedron 1999, 55,6289-6300. 

To date the most useful and wide ranging reaction catalysed by polyamino acids is the asymmetric epoxidation of enones [22]. 

Table 1. Epoxidation of Enones using Triphasic Conditions ...

Fig. 15 Amines used in conjunction with TRIP for the epoxidation of enones and enals...

A weak base such as glycine added to [HMIMjPFg has also been reported to catalyze a Knoevenagel reaction of malononitrile and benzaldehyde 110). A KOH-treated [BMIMjPFg also provides a suitable medium for the Corey-Chaykovsky epoxidation of enones and cyclopropanation of aldehydes using trimethyl sulfonium iodide (///). 

SCHEME 47. Phase-transfer catalyzed asymmetric epoxidation of enones... 

In 1996, Enders and coworkers reported the asymmetric epoxidation of ( )-enones 91 in the presence of stoichiometric amounts of diethylzinc and (lR,2R)-A-methylpseudo-ephedrine (120) under an oxygen atmosphere to give fraw -epoxides 92 with excellent yields (94-99%), almost complete diastereoselectivity (>98% de) and with very good enantioselectivities (61-92%) (Scheme 54) . For the same reaction Pu and coworkers utilized achiral polybinaphthyl 121 as ligand (in excess) instead of the chiral aminoalcohol. For each substrate, only one diastereomer was formed, but in most cases yields were lower than observed with the Enders system. Enders catalyst shows high asymmetric induction for alkyl-substituted enones (ee 82-92%), but for substrates bearing only aromatic substituents only modest enantioselectivity was obtained (R = R = Ph ... 

An alternative method for the epoxidation of enones was developed by Jackson and coworkers in 1997 , who utilized metal peroxides that are modified by chiral ligands such as diethyl tartrate (DET), (5,5)-diphenylethanediol, (—)-ephedrine, ( )-N-methylephedrine and various simple chiral alcohols. The best results were achieved with DET as chiral inductor in toluene. In the stoichiometric version, DET and lithium tert-butyl peroxide, which was generated in situ from TBHP and n-butyllithium, were used as catalyst for the epoxidation of enones. Use of 1.1 equivalent of (-l-)-DET in toluene as solvent afforded (2/f,35 )-chalcone epoxide in 71-75% yield and 62% ee. In the substo-ichiometric method n-butyllithium was replaced by dibutylmagnesium. With this system (10 mol% Bu2Mg and 11 mol% DET), a variety of chalcone-type enones could be oxidized in moderate to good yields (36-61%) and high asymmetric induction (81-94%), giving exactly the other enantiomeric epoxide than obtained with the stoichiometric system (equation 37). 

The epoxidation of enones using chiral phase transfer catalysis (PTC) is an emerging technology that does not use transition metal catalysts. Lygo and To described the use of anthracenylmethyl derivatives of a cinchona alkaloid that are capable of catalyzing the epoxidation of enones with remarkable levels of asymmetric control and a one pot method for oxidation of the aUyl alcohol directly into... 

Ye, J., Wang, Y, Liu, R., Zhang, G., Zhang, Q., Chen, J. and Liang, X. A Highly Enantioselective Phase-transfer Catalyzed Epoxidation of Enones with a mild Oxidant, Trichloroisocyanuric acid. Chem. Commun. 2003, 2714-2715. 

Keiji Maruoka of Kyoyo University reports (J. Am. Chem. Soc. 2004,126, 6844) the development of enantiomerically-pure quaternary ammonium salts (2) that catalyze the epoxidation of enones. The epoxidation of the r-butyl ketone 1 is particularly interesting, as Baeyer-Villiger oxidation would be expected to convert 3 into the ester 4. 

Epoxidation of Enones Using the Superoxide/Dioxygen Reagent. 157... 

Epoxidation of enones on treatment with basic hydrogen peroxide or /-butyl hydroperoxide, or with bleach, might be viewed as another form of trapping the initially produced anion.99 In this case the enol-ate, e.g. (425 Scheme 57), attacks the oxygen of the hydroperoxide to eject hydroxide and yield the epoxy ketone (426)." Finally, the initial anion can also be trapped by a sigmatropic rearrangement, as in... 

One topic where biocatalysis has not scored big successes (yet ) is the epoxidation reaction of alkenes. Against this background, the finding that poly-L-alanine catalyzes the epoxidation of enones such as chalcone, ArjCfOjCH H Ar2, raised plenty of interest (Julia, 1980). By employing hydrogen peroxide and NaOH in a biphasic water-toluene mixture together with poly-L-alanine, 2 K,3, S -epoxychalcone was ob-... 

J. Skidmore, and J. A. Smith, beta-Peptides as catalysts poly-beta-leudne as a catalyst for the Julia-Colonna asymmetric epoxidation of enones, Chem. Commun. 2001, (22), 2330-2331. 

In contrast with metal-complex catalyzed transformations [52], enantioselective organocatalyzed intermolecular conjugate additions of O-nudeophiles seem to be limited to peroxides such as hydrogen peroxide or tert-butyl hydroperoxide. In these reactions the primary addition product, a / -peroxy enolate, reacts further to yield an epoxide (Scheme 4.31). Consequently, reactions of this type are covered in Section 10.2 Epoxidation of Enones and Enoates . 

As discussed in Section 10.1, asymmetric epoxidation of C=C double bonds usually requires electrophilic oxygen donors such as dioxiranes or oxaziridinium ions. The oxidants typically used for enone epoxidation are, on the other hand, nucleophilic in nature. A prominent example is the well-known Weitz-Scheffer epoxidation using alkaline hydrogen peroxide or hydroperoxides in the presence of base. Asymmetric epoxidation of enones and enoates has been achieved both with metal-containing catalysts and with metal-free systems [52-55]. In the (metal-based) approaches of Enders [56, 57], Jackson [58, 59], and Shibasaki [60, 61] enantiomeric excesses > 90% have been achieved for a variety of substrate classes. In this field, however, the same is also true for metal-free catalysts. Chiral dioxiranes will be discussed in Section 10.2.1, peptide catalysts in Section 10.2.2, and phase-transfer catalysts in Section 10.2.3. 

Well-defined peptides of known sequence have been used to shed light on the mechanism of catalysis in the epoxidation of enones with hydrogen peroxide [91, 93-95]. The peptide sequences of the catalysts have been systematically varied and correlated with catalytic activity and selectivity. From the many variations investigated it was concluded (i) that the N-terminal region of the peptides harbors the catalytically active site, and that (ii) a helical conformation is required for the peptide catalysts to be active. The latter conclusion is supported both by the dependence of catalytic activity on chain-length and by IR investigations [91, 94]. NMR data that might aid further elucidation of catalyst structure, interaction with the substrate enones, etc., are, unfortunately, not yet available. 

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

In the metal-free epoxidation of enones and enoates, practically useful yields and enantioselectivity have been achieved by using catalysts based on chiral electrophilic ketones, peptides, and chiral phase-transfer agents. (E)-configured acyclic enones are comparatively easy substrates that can be converted to enantiomeri-cally highly enriched epoxides by all three methods. Currently, chiral ketones/ dioxiranes constitute the only catalyst system that enables asymmetric and metal-free epoxidation of (E)-enoates. There seems to be no metal-free method for efficient asymmetric epoxidation of achiral (Z)-enones. Exocyclic (E)-enones have been epoxidized with excellent ee using either phase-transfer catalysis or polyamino acids. In contrast, generation of enantiopure epoxides from normal endocyclic... 

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