Crown asymmetric epoxidation

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Scheme 8.6 Crown ether-catalyzed asymmetric epoxidation.

Chiral monoaza-15-crown-5 derived from D-glucose 92 was shown to be another good catalyst in the asymmetric epoxidation of chalcones with tert-butylhydroper-oxide as the oxidant, with the highest enantioselectivity (94% ee) being reported by Bako (entry 4, Table 11.8) [71]. The tetracyclic C2-symmetric guanidiurn salt 93, which was prepared from (SJ-malic acid by Murphy, also showed excellent enantioselection in the asymmetric epoxidation of chalcone (entry 5) [72]. 

As an application of the modified conditions, the asymmetric synthesis of (7 )-fiuoxetine was demonstrated (Scheme 35.28). Fluoxetine is an antidepressant drug and currently marketed as a racemate. Asymmetric epoxidation of amide 101 under Shibasaki s conditions provided epoxide 102 in 91% yield and 99% ee. Subsequent regionselec-tive reduction with Red-Al in the presence of a crown ether afforded the (3-hydoxyl amide 103, which was converted into (/ )-fluoxetine 104 in two steps. °... 

Makosza and co-workers have reported the preparation of epoxides from a-halo carbanions and ketones, according to the Darzens reaction, under PT conditions, using TEBA72,73 or dibenzo-18-crown-6.74 The ratio of isomers depends on the reaction conditions.75,76 Asymmetric induction has been reported in the Darzens reaction using chiral catalysts.77,78 The use of several chloro carbanions as well as K2C03 and Na2C03 in the solid state has also been studied. 

Promising examples of the catalytic asymmetric Darzens condensation, which yields an epoxide product via carbon-carbon and carbon-oxygen bond formation, have been reported recently by two groups (Scheme 10.11). Toke and co-workers used crown ether 24 in the reaction to form the a,P-unsaturated ketone 78 [38b] with 64% ee, whereas the Shioiri group used the cinchona-derived salt 3a [52], which resulted in 78 with 69% ee. The latter authors propose a catalytic cycle involving generation of a chiral enolate in situ from an achiral inorganic base... 

Bruns and Haufe have described the first examples of a transition metal complex mediated asymmetric ring opening (ARO) of both meso- and racemic epoxides via formal hydro-fluorination [23]. Initial attempts with chiral Euln complexes led to very low asymmetric induction. Opening of cyclohexene oxide 30 with potassium hydrogendifluoride in the presence of 18-crown-6 and a stoichiometric amount of Jacobsens chiral chromium salen complex 29 [24a] finally yielded two products 31 and 32 in a 89 11 ratio and 92% combined yield, the desired product 31 being formed with 55% ee. Limiting 29 to a catalytic amount of 10 mol% led to an increase in the ratio of 31, however, with the enantiomeric excess dropping to 11% (Scheme 5). 

The structural motifs of some excellent chiral crown ethers have been derived from easily accessible natural products. For example, a (+)-camphor-based chiral aza-crown ether 7 was developed and successfully apphed in asymmetric conjugate addition by Brunet [11]. The use of D-glucose-based crown ethers 8 and 9 as chiral phase-transfer catalysts has been intensively studied by Bako and colleagues in the asymmetric Michael addition [12], Darzens condensation [13], and epoxidation [14]. Another carbohydrate-derived chiral crown ether 10 was prepared from chiro-inositol by Aldyama and coworkers, which successfully enabled the enantioselective conjugate addition of N-(diphenylmethylene) glycine tert-butyl ester to several electrophiles [15]. 

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