Darzens Reactions with Chiral Catalysts

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

Of course, the most practical and synthetically elegant approach to the asymmetric Darzens reaction would be to use a sub-stoichiometric amount of a chiral catalyst. The most notable approach has been the use of chiral phase-transfer catalysts. By rendering the intermediate etiolate 86 (Scheme 1.24) soluble in the reaction solvent, the phase-transfer catalyst can effectively provide the enolate with a chiral environment in which to react with carbonyl compounds. 

The Darzens reaction can also proceed in the presence of a chiral catalyst. When chloroacetophenone and benzaldehyde are subjected to asymmetric Darzens reaction, product 89 with 64% ee is obtained if chiral crown ether 88 is used as a phase transfer catalyst (Scheme 8-30).69... 

Asymmetric induction using catalytic amounts of quininium or A-methyl-ephedrinium salts for the Darzen s reaction of aldehydes and ketones with phenacyl halides and chloromethylsulphones produces oxiranes of low optical purity [3, 24, 25]. The chiral catalyst appears to have little more effect than non-chiral catalysts (Section 12.1). Similarly, the catalysed reaction of sodium cyanide with a-bromo-ketones produces epoxynitriles of only low optical purity [3]. The claimed 67% ee for the phenyloxirane derived from the reaction of benzaldehyde with trimethylsul-phonium iodide under basic conditions [26] in the presence of A,A-dimethyle-phedrinium chloride was later retracted [27] the product was contaminated with the 2-methyl-3-phenyloxirane from the degradation of the catalyst. 

Synthesis of Optically Active Epoxides. Alkaloids and alkaloid salts have been successfully used as catalysts for the asymmetric synthesis of epoxides. The use of chiral catalysts such as quinine or quinium benzylchloride (QUIBEC) have allowed access to optically active epoxides through a variety of reaction conditions, including oxidation using Hydrogen Peroxide (eq 5), Darzens condensations (eq 6), epoxidation of ketones by Sodium Hypochlorite (eq 7), halohydrin ring closure (eq 8), and cyanide addition to a-halo ketones (eq 9). Although the relative stereochemistry of most of the products has not been determined, enan-tiomerically enriched materials have been isolated. A more recent example has been published in which optically active 2,3-epoxycyclohexanone has been synthesized by oxidation with t-Butyl Hydroperoxide in the presence of QUIBEC and the absolute stereochemistry of the product established (eq 10). ... 

The first catalytic asymmetric version of the Darzens reaction was achieved in 1978 by J. Hummelen and H. Wynberg [41]. The treatment of p-chlorobenzaldeh ydc and phenacylchloride with the strong base NaOH in the presence of the benzyl quini-nium chloride 86 as a chiral catalyst (6 mol%) afforded the trans-chalcone epoxide 98 in 68% yield. However, the optical yield achieved was only in the range of 7-9% ee (Scheme 8.33). 

Aldehydes can also be converted to enantioenriched chiral epoxides through the Darzens reaction. Thus, haloimides (e.g., 47) react with benzaldehyde in the presence of a novel phase transfer catalyst 45 derived from BINOL to give 1,2-disubstituted epoxides in good yields with... 

Optically active a, -epoxy stdfones. - The Darzens reaction of ethyl methyl ketone with chloromethyl / -tolyl sulfone in a two-phase system in the presence of chiral ammonium salts such as N-ethylephedrinium bromide results in a,/3-epoxy sulfones with 0-2.57o optical yields. However, if the supported catalyst (1) is used, optical yields of up to 23% can be obtained as in the example formulated in equation (I). On the other hand, the reaction is slower when the catalyst is supported. The presence of a hydroxy group jS to the nitrogen atom of the catalyst is essential for asymmetric induction. 

At the same time, Antilla et al. developed a vaulted biphenanthrol (VAPOL)-based magnesium phosphate 20b mediated asymmetric aza-Darzens reaction for the synthesis of chiral aziridine derivatives. The catalyst was prepared in an identical procedure to the previously described process with VAPOL-derived phosphate and magnesium fert-butoxide, and applied in the enantioselective aza-Darzens reaction of N-benzoyl imines 23 and ot-chloro-1,3-diketone 24. The process formed a series of substituted aziridines 25 bearing various substituents at the aromatic ring, with good... 

The reaction of diazoacetamides with aldehydes in the presence of chiral Ti(OiPr)4/ (R)-BINOL (l,l -bis-2-naphthol) catalyst leads to trans-(2-amidocarbonyl)oxiranes with high stereoselectivities (>95% ee) and thus can be regarded as an asymmetric catalytic Darzens reaction [11]. 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

The Darzens condensation is an old methodology for the construction of a,p-epoxy carbonyl compounds 49 with control of two formed stereogenic centers. This reaction includes an aldol reaction (C-C bond formation), which normally requires stoichiometric amounts of base to achieve good yields. Only phase transfer catalysts, usually chiral ammonium halides have shown to be efQdent to perform this transformation in a catalytic and enantioselective form. 

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