Asymmetric Reformatsky reaction

Chiral //-hydroxylester 61 cannot be satisfactorily obtained through the reaction between a prochiral ketone and the enolate. It can, however, be synthesized via the chiral ligand-induced asymmetric Reformatsky reaction of ketones (Scheme 8-21). 

In most cases, the Reformatsky reaction is not very stereospecific and mixtures of erythro- and threo-p-hydroxyesters are obtained when asymmetric a-haloesters are used as reagents (equation 79). The erythro threo ratio appears to depend on the solvent polarity and the reaction time. However, it is of current interest to develop highly stereocontrolled asymmetric Reformatsky reactions. To date, high diastereoselectivities could be achieved only in a few cases either by substitution of zinc with other metal... 

Chiral Modification of Achiral Organometallic Reagents. The addition of n-Butyllithium or Ethylmagne-sium Bromide to aldehydes or ketones in the presence of (—)-sparteine resulted in the formation of optically active secondary or tertiary alcohols with 20% ee or lower. Optically active acyl sulfoxides (<15% ee) were obtained by acylation of p-Tolylsulfinylmethyllithium. The asymmetric Reformatsky reaction of ethyl bromoacetate with benzaldehyde proceeds with 95% ee, in an exceptional case (eq 1). ... 

Scheme 4.4 Asymmetric Reformatsky reaction with various ketones using cinchonine as a chiral ligand.

Scheme 4.72 a-Bromo N-acyloxazolidinones 323 and 326-328 as auxiliaries for asymmetric Reformatsky reactions. 

As a kind of nucleophilic addition reaction similar to the Grignard reaction, the Reformatsky reaction can afford useful ft-hydroxy esters from alkyl haloacetate, zinc, and aldehydes or ketones. Indeed, this reaction may complement the aldol reaction for asymmetric synthesis of //-hydroxy esters. 

Asymmetric intramolecular Reformatsky reactions/ The bromoacetates (1) of (3-hydroxy ketones undergo a Reformatsky-type reaction when treated with Sml2 to give (3-hydroxy-8-valerolactones (2). These products are useful in their own... 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

Particularly challenging is the use of chiral ligands in order to impose enan-tiocontrol on a Reformatsky reaction. Although preparatively useful levels of asymmetric induction have been described in the recent literature by using enantiomerically pure amino alcohol ligands43 this reaction has not yet reached a similar level of perfection as the enantioselective addition of other organozinc reagents to aldehydes in the presence of the same type of additives. Some selected examples of stereoselective Reformatsky type reactions which delineate the present state of the art are summarized in Scheme 14.6. 

Analogous asymmetric, samarium Reformatsky reactions of chiral 3-bro-moacetyl-2-oxazolidinones have been described by Fukuzawa.140 For example, reduction of 124 with Sml2 generates a samarium enolate that then reacts with pivalaldehyde to give the a-unbranched (I-hydroxycarboximide 125 in 87% yield and in high diastereoisomeric excess (Scheme 5.89). The reaction is synthetically noteworthy as highly diastereoselective acetate aldol processes are difficult to achieve. Sm(III) ions are likely to play an important role in the... 

Bandraege, S, Josephson, S, Moerch, L, Vallen, S, Asymmetric synthesis of p-hydroxyesters by Reformatsky reactions and amide base mediated condensations, Acta Chem. Scand. Ser. B, 35, 273-277, 1981. 

Reductive cyclizadons of 3-bromoacetoxy aldehydes and ketones promoted by Sml2 afford 3-hydroxyvalerolactones with unprecedented degrees of 1,3-asymmetric induction (equation 57). Numerous attempts at utilizing zinc-mediated intramolecular Reformatsky reactions to access these lactones have failed. The successful development of the Smh-based methodology therefore provides perhaps the most convenient entry to this important class of molecules. ... 

Seven-membered ring lactones can be accessed in excellent yields by the Smia-mediated intramolecular Reformatsky reaction as well. Although several substitution patterns provide exceptional relative asymmetric induction in this process (equation 62), it is clear that high diastereoselectivity cannot be achieved for all substitution patterns in the formation of seven-membered ring lactones. ... 

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