Reformatsky reaction, enantioselective

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

The earliest enantioselective Reformatsky reaction was reported in 1973.52 Compound (-)-spartein was used as the chiral ligand, but the reaction gave rather low yield. Almost 20 years later, in 1991, Soai and Kawase53 reported an enantioselective Reformatsky reaction in which chiral amino alcohol 58 or 59 was used as the ligand. Aliphatic and aromatic //-hydroxy esters were obtained with moderate to good yields. 

Pini et al.54 and Mi et al.55 reported the promotion of the enantioselective Reformatsky reaction by using stoichiometric and/or catalytic amounts of amino alcohols. Moderate yields were obtained. 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

Nucleophilic additions to (cyclohexadienone)Fe(CO)3 complexes (218) occur in a dia-stereospecific fashion (Scheme 56)197. For example, the Reformatsky reaction of ketone (218a) affords a simple diasteromeric alcohol product19715. The reduction of (1-carbo-methoxycyclohexa-l,3-dien-5-one)Fe(CO)3 (218b) to give 219 has been utilized in the enantioselective synthesis of methyl shikimate. In a similar fashion, cycloadditions of (2-methoxy-5-methylenecyclohexa-l,3-diene)Fe(CO)3 (220) occur in a diastereospecific fashion198. 

TABLE 2. Chiral ligand-promoted enantioselective Reformatsky reactions... 

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, (g) ees of up to 92% have been achieved in the /i-amino ester product, using a recyclable A-methylcphedrinc as auxiliary. A nickel(II) salt and dimethylzinc are employed the latter serves as dehydrating agent, reductant, and coordinating metal. 

The first enantioselective one-pot, three-component imino Reformatsky reactions q have been reviewed 98 (—)-A, A-Dimethylami noisoborneol has been found to be an excellent ligand for the enantioselective addition of Reformatsky reagents to aromatic and aliphatic aldehydes 99 Enantioselectivities up to 93% ee have been obtained with sulfur-containing aldehydes. 

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. 

Table 19 Indium-mediated enantioselective Reformatsky reaction. Reproduced with permission from the Royal Society of Chemistry...

Difluoroester enolates are available by reduction of halodifluoroacetates with zinc metal [40]. Although the reaction of O-trimethylsilyl difluoroesterenolates with carbonyl compounds leads to the same reaction products as the analogous Reformatsky reaction [41] (Scheme 2.203), use of chiral catalysts results in additions with much greater enantioselectivity [42] (Scheme 2.204). 

Alkynylzinc addition to ArCHO can also be carried out in the presence of 3, whereas the disilyl derivative 4 catalyzes enantioselective Reformatsky reaction on ketones (with ee up to 90%)" which operates by a ftee radical mechanism (requiring air to initiate the reaction). 

In more recent work, germanium catalysts such as GeClq gave a highly diastereoselective Reformatsky reaction favoring the syn diastereomer.228 Another syn selective reaction was reported using TiCl2 and Cu.229 Enantioselective Reformatsky reactions have also used chiral amino alcohols as additives.220... 

Other types of multicomponent reactions have also been successfully developed, such as the first practical three-component imino-Reformatsky reaction, and a pseudo-three-component reaction between allenes and isocyanates, providing excellent levels of enantioselectivity. Finally, excellent results were described for several novel enantioselective tandem sequences. For example, very high enantioselectivities were reached in tandem Michael/ intramolecular cyclisation sequences, as well as in a remarkable multicat-alytic Michael sequence occurring between enones, alkynes, and DIBAL, which stereoselectively afforded a range of chiral p-alkenyl ketones bearing an all-carbon-substituted quaternary stereogenic centre in excellent enantioselectivities. 

A short review covers recent advances in the catalytic enantioselective Reformatsky reaction, while highlighting significant current challenges, and the diastereoselective 0 Reformatsky has also been reviewed (61 references). NHC s catalyse Reformatsky 0 reaction of aldehydes with -TMS-carbonyls, to give -hydroxycarbonyl compounds. ... 

Cozzi, R G., Rivalta, E. (2006). First enantioselective one-pot, three-component imino Reformatsky reaction. Pure and Applied Chemistry, 78, 287-291. 

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