Enone epoxidation, phase transfer catalyst

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. 

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [17]. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [18]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the tx,/ -epoxy ketone 28 in >99.5% ee (Scheme 10). 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

Fig. 12.10 Chiral phase-transfer catalysts for enone epoxidation.

Scheme 12.14 Enone epoxidation with dual function phase-transfer catalyst 26.

Epoxidation of Enones and a, 3-Unsaturated Sulfones Using Cinchona-Based Chiral Phase-Transfer Catalysts... 

Later on, Liang and coworkers successfully employed trichloroisocyanuric acid (TCCA) as a new type of stoichiometric oxidant for the asymmetric epoxidation of acyclic enones in the presence of 10 mol% of catalyst 4 (Scheme 5.6) [9]. The desired epoxy ketones were obtained in good yields (69-93%) with high enantioselectivities (73-93% ee) under nonaqueous solid-liquid conditions [9b]. In this reaction, TCCA reacts with an inorganic base (KOH) to form a hypochlorite salt, which is transferred to the organic phase by the phase-transfer catalyst and oxidizes... 

The same kind of associative event lies at the heart of the catalytic asymmetric epoxidation of enones using the interesting binaphthyl derived spiro ammonium salt 33, which serves as a phase transfer catalyst as well as chiral auxiliary. Using sodium hypochlorite in a biphasic system, this catalyst mediates the high-yielding epoxidation of a variety of electron-deficient trisubstituted and trara-disubstituted olefins with excellent enantioselectivity, as represented by the conversion of enone 34 to the corresponding epoxy ketone 35 <04JA6844>. 

Nucleophilic oxidation of electron-deficient alkenes is another route to epoxides. For example, reaction of enones with hydrogen peroxide and sodium hydroxide provides epoxides in good yield. The first attempt to turn this into an asymmetric transformation utilised the benzylchloride salt of quinine as a chiral phase transfer catalyst but only moderate enantioselectivity was obtained (55% with... 

The epoxidation of conjugated double bonds also proceeds smoothly with the Oxone-acetone system, as illustrated by eq 9. The conversion of water-insoluble enones can be accomplished with this method using CH2CI2 as a cosolvent and a quaternary ammonium salt as a phase-transfer catalyst. However, a more convenient procedure utilizes 2-butanone both as a dioxirane precursor and as an immiscible cosolvent (eq 10). No phase-transfer agent is required in this case. 

SCHEME 35.29. Asymmetric epoxidation of enones 106 using cinchonidine-derived, phase-transfer catalyst 105. 

Taylor and co-workers employed an asymmetric phase-transfer-catalyzed epoxidation as the key step in the synthesis of (+)-manumycin and revised the structural assignment for the natural antibiotic (—)-manumycin (Scheme 35.31). Using A-benzylcinchonidinium chloride 111 as the phase-transfer catalyst, asymmetric epoxidation of cw-enone 112 provided epoxide 113 in 32% yield (82% based on recovered 112) and 89% ee (>99% ee after recrystallizations). Epoxide 113 was finally transformed into... 

General experimental procedure for the asymmetric epoxidation of enones using a phase-transfer catalyst To a mixture of enone (3.0 mmol), phase-transfer catalyst (0.15 mmol) in toluene (70 mL) at room temperature was added dropwise a solution of NaOCl in water (15 wt%, 9.0mmol) and a solution of KOH in water (12M, 1 mL). The mixture was stirred at room temperature... 

Besides the success obtained in the epoxidation of enones by either phase transfer catalysts or polyamino acid derivatives, there was not any example of the related reaction with aldehydes 13. Recently, chiral amine 22 was deployed as a soluble catalyst for the enantioselective epoxidation of a, 3-unsaturated aldehydes 13 to give the expected epoxide 55 (Scheme 4.9). 

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]. 

Direct phase-transfer catalysed epoxidation of electron-deficient alkenes, such as chalcones, cycloalk-2-enones and benzoquinones with hydrogen peroxide or r-butyl peroxide under basic conditions (Section 10.7) has been extended by the use of quininium and quinidinium catalysts to produce optically active oxiranes [1 — 16] the alkaloid bases are less efficient than their salts as catalysts [e.g. 8]. In addition to N-benzylquininium chloride, the binaphthyl ephedrinium salt (16 in Scheme 12.5) and the bis-cinchonidinium system (Scheme 12.12) have been used [12, 17]. Generally, the more rigid quininium systems are more effective than the ephedrinium salts. 

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... 

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... 

The asymmetric epoxidation of electron-deficient olefins, particularly a,/3-enones, including the use of chiral metal hydroperoxides, asymmetric phase-transfer methods, polyamino acid catalysts, and the chiral dioxiranes, has been reviewed <2000CC1215>. 

A variation of the Sharpless asymmetric epoxidation is to employ chiral hydroperoxides. The chiral iminium salt 89 has moderate enantiocontrol for epoxidation. Quatemized cinchona alkaloids can serve as chiral catalyst and phase-transfer agents in epoxidation of enones with NaOCl. Enones are also epoxidized by oxygen in the presence of diethylzinc and A-methylpseudoephedrine, whereas IZj-enones are submitted to enantioselective epoxidation by t-BuOOH-O-PrO),Yb and the BINOL 90. 

Quite recently, one of the most efficient phase-transfer-catalyzed epoxidation methods for chalcone-type enones was developed by the Park-Jew group [11], A series of meta-dimeric cinchona PTCs with modified phenyl linkers were prepared. Among this series, the 2-fluoro substituted catalyst 5, exhibited unprecedented activity and enantioselectivity for the epoxidation of various trans-chalcones in the... 

Reaction with alkaline peroxide (or hypochlorite) and a chiral catalyst allows the asymmetric epoxidation of enones. Excellent asymmetric induction has been achieved using metal-chiral ligand complexes, such as those derived from lanthanides and (/ )- or (5)-BlNOL. Alternatively, phase-transfer catalysis using ammonium salt derivatives of Cinchona alkaloids, or the use of polyanuno acid... 

The importance of chiral epoxy-ketones is becoming increasingly recognized as physiologically active natural products, as metabolic intermediates, and as chiral synthons. Cyclohex-2-enones (1) have been transformed into optically active epoxycyclohexanones (2) using t-butylhydroperoxide in toluene, to which catalytic quantities of solid sodium hydroxide and the chiral catalyst quininium benzyl chloride were added, under phase-transfer conditions. In the unsubstituted case the yield is 60% with enantiomeric excess of 20% as determined by n.m.r. Substituents at C(2), C(3), and C(4) block the epoxidation reaction but compounds with gem-dimethyl groups at C(5) and C(6) are readily converted. 

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