Darzens catalytic asymmetric

S. Arai, T. Shioiri, Catalytic Asymmetric Darzens Condensation under Phase-Transfer-Catalyzed Conditions , Tetrahedron Lett. 1998, 39, 2145-2148. 

Cyclopropanation, Horner-Wadsworth Emmons Reaction, and Darzens Condensation Although induction in the cyclopropanation of alkenes was reported early, this work was disputed [49]. Other reports of cyclopropanations have yielded, at best, low asymmetric inductions [llh,50]. The first example of a catalytic asymmetric Horner-Wadsworth Emmons reaction, which is promoted by a chiral quaternary ammonium salt, was reported recently by the Shioiri group (Scheme 10.10) [51]. The reaction of the prochiral ketone 74 gives optically active a,P-unsaturated ester 76 with 57% ee. 

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... 

Scheme 6.10 Catalytic asymmetric Darzens reaction of a-haloamides.

Asymmetric epoxidation The catalytic asymmetric epoxidation of alkenes has been the focus of many research efforts over the past two decades. The non-racemic epoxides are prepared either by enantioselective oxidation of a prochiral carbon-carbon double bond or by enantioselective alkylidenation of a prochiral C=0 bond (e.g. via a ylide, carbene or the Darzen reaction). The Sharpless asymmetric epoxidation (SAE) requires allylic alcohols. The Jacobsen epoxidation (using manganese-salen complex and NaOCl) works well with ds-alkenes and dioxirane method is good for some trans-alkenes (see Chapter 1, section 1.5.3). 

The Darzens reaction (tandem aldol-intramolecular cyclization sequence reaction) is a powerful complementary approach to epoxidation (see Chapter 5) that can be used for the synthesis of a,P-epoxy carbonyl and a,p-epoxysulfonyl compounds (Scheme 8.32). Currently, all catalytic asymmetric variants of the Darzens reactions are based on chiral phase-transfer catalysis using quaternary ammonium salts as catalysts. 

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). 

Early work on the use of chiral phase-transfer catalysis in asymmetric Darzens reactions was conducted independently by the groups of Wynberg [38] and Co-lonna [39], but the observed asymmetric induction was low. More recently Toke s group has used catalytic chiral aza crown ethers in Darzens reactions [40-42], but again only low to moderate enantioselectivities resulted. 

The classical aza-Darzens reaction (between bromoenolates and imines) has been investigated by several groups in recent years, especially with respect to the design and execution of asymmetric variants. Both stoichiometric and catalytic methods have been studied thus, the reactions between N-Dpp imines and chiral ot-bromoenolates [49] (derived from Oppolzer s sultams Scheme 4.35) and between S-chiral sulfmylimines and achiral bromoenolates [50] (Scheme 4.36) have been reported. 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

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. 

Epoxidations and Darzens Condensations The asymmetric catalytic epoxida-tion of a,p-unsaturated ketones using cinchona alkaloid-derived catalysts was introduced in the 19708. However, high levels of enantioselectivity were achieved only 20 years later, when Lygo, Arai, 2-t94 others P ... 

The condensation of the asymmetric oxazoline (125) and 2-propanone is reported to give the adduct (126 equation 40). The Darzens condensation of aromatic aldehydes with phenacyl halides in the presence of catalytic bovine serum albumin affords epoxy ketones in optical yields as high as 62% ee. ... 

Scheme 16.34 Asymmetric phase-transfer catalytic Darzen reaction of a-halo ketones.

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]. 

Ku JM, Yoo MS, Park HG, Jew SS, Jeong BS. Asymmetric synthesis of a, (3-epoxysulfones via phase-transfer catalytic Darzens reaction. Tetrahedron 2007 63(34) 8099-8103. 

---