Asymmetric Darzens reaction

Yan s group has used the camphor-based chiral thioamide 62 in asymmetric Darzens reactions (Scheme 1.21) [32]. The addition of the titanium enolate of 62 to... 

Table 1.10 Chiral reagent 75 in asymmetric Darzens reactions. Ph Ph...

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. 

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. 

Table 1.12 Cinchona alkaloid-derived phase-transfer catalysts for asymmetric Darzens reactions.

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. 

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%. 

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... 

Scheme 24. The proposed mechanism of asymmetric Darzens reaction.

S. Arai, Y. Shirai, T. Ishida, T. Shioiri, Phase-Transfer-Catalyzed Asymmetric Darzens Reactions , Tetrahedron... 

Scheme 3.1 Asymmetric Darzens reaction using chloroketones.

Scheme 6.10 Catalytic asymmetric Darzens reaction of a-haloamides.

A complementary approach to similar products involved the asymmetric Darzens reaction of a-chloro ketones such as 29 with aldehydes. The cinchoninium salt 2f allowed the epoxide 30 to be prepared with reasonably high enantiomeric excess (Scheme 11) [19]. 

A somewhat more successful approach to asymmetric Darzens reactions has been observed in the reaction of a-halosulfones with aldehydes under phase-transfer conditions <07T8099>. The reaction of an a-chlorosulfone with benzaldehyde in the presence of quinine derived phase-transfer catalyst 11, provides the epoxide in excellent yield with very good enantioselectivity. The use of RbOH as the base was crucial to both yield and enantioselectivity. 

Aral, S., Shirai, Y., Ishida, T., Shioiri, T. Phase-transfer-catalyzed asymmetric Darzens reaction. Tetrahedron 1999, 55, 6375-6386. 

Aral, S., Shioiri, T. Asymmetric Darzens reaction utilizing chloromethyl phenyl sulfone under phase-transfer catalyzed conditions. Tetrahedron 2002, 58,1407-1413. 

Diltiazem (9) is an antihypertensive drug. It has prompted a number of studies to find an asymmetric Darzen reaction that can be performed at scale, but, to... 

The asymmetric Darzens reaction of a-chlorocycloalkanones using quatemized cinchona alkaloids as phase-transfer catalyst and LiOH as base in BU2O at room temperature is usually high yielding. However, the moderate ee is disappointing. 

Scheme 16.36 Asymmetric Darzen reaction using bifunctional PTC catalysts.

A phase-transfer-catalysed asymmetric Darzens reaction of cyclic a-chloro ketones has been reported. ... 

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