Reformatsky-aldol reaction

A catalytic enantioselective vinylogous Reformatsky-aldol reaction exploits iridium catalysis, gives excellent regio-, diastereo-, and enantio-selectivities, and can be carried out with approximately equal facility from the alcohol or aldehyde oxidation level. 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

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. 

The next task was to form the C2-C3 aldol bond stereoselectively. However, asymmetric coupling of acetate derivatives to aldehydes is often accompanied by poor / -induction [89]. Moreover, the C3-C4 bond is particularly sensitive to retro-aldol reaction, especially under basic conditions. In the natural products, this was observed to be the main decomposition reaction. The first total syntheses of epothilones circumvented this problem by constructing this part of the molecule in an indirect manner, e.g., by using reduced forms at Cl or C5. We decided to employ our chromium-Reformatsky methodology, which avoids these problems and allows the direct use of reagents in the correct oxidation state. The non-basic reaction conditions, the intermediacy of a chromium(III) aldolate that is resistant to retro-aldol reaction, and the potential of a direct asymmetric carboxymethyl ( acetate ) transfer favor the use of this method [90]. 

Silylacetals of difluoroketene have an important synthetic potential and constitute an alternative to the Reformatsky reagent generated from ethyl bromodifluoroace-tate." They are prepared by reduction by a bromo-, iodo-di-, or trifluoroacetate in the presence of a trialky Isilylchloride. Despite the fact that they are difficult to prepare, they behave similar to their nonfluorinated analogues (aldolization reactions, conjugated addition, etc.) (Figure 2.27)." ... 

Allyltributyltin, 10 Boron trifluoride etherate, 43 Di-jjL-carbonylhexacarbonyldicobalt, 99 Grignard reagents, 138 Ketenylidenetriphenvlphosphorane, 154 Methoxyamine, 177 Reformatsky reagent, 346 Tin(IV) chloride, 300 Tributylcrotyltin, 10 Aldol reactions General considerations, 202 Directed aldols using imines Norephedrine, 200... 

Highly ry//-selective aldol synthesis from cr-iodo ketones is promoted under aqueous conditions by a distannane system, (BujSnb, Bu2SnF2, and HMPA. Aqueous solutions of acetaldehyde or formaldehyde provide /3-hydroxy ketones.272 The ate complex Li+[//-Bu2Snl ( generated from Lil and -Bu2SnI2 leads to the highest class of syn-diastereoselectivity in the Reformatsky-type reaction (Equation (106)).273... 

In 1993, Corey reported the first synthesis of paeoniflorin.56 The core of paeoniflorin was constructed using a Sml2-mediated Reformatsky-type reaction (Scheme 7.16). Treatment of a-chloronitrile 31 with Sml2 gave cyclobutanol 32 in excellent yield. The sensitivity of cyclobutanol 32 to base precluded the use of more conventional aldol-type cyclisations.56... 

An aldol reaction using the enolate of acetaldehyde and requiring it to react with a ketone is doomed to failure acetaldehyde itself is far too good an electrophile. In the forward synthesis, therefore, this first step was carried out at the ester oxidation level (using a Reformatsky reaction), and the ester was subsequently converted to the aldehyde by a reduction of the kind discussed in Chapter 24. 

There was no problem with selectivity in the second aldol reaction because the aldehyde is not enolizable. The Reformatsky reaction in this sequence illustrates the fact that, of course, aldol-type... 

Refoimatsky Reactions. The Reformatsky reaction of a-halooxazolidinones provides an alternative to the more conventional aldol reaction. Although the traditional zinc-mediated Reformatsky using valine-derived compounds proceeds nonselectively, the Sn modification with 2-bromo-2-methylpropionyloxazolidinone proceeds well (eq 46). In this particular case, however, the geminal dialkyl substiments favor the endocyclic carbonyl acyl transfer of the auxiliary by the aldolate oxygen. 

Related reactions Evans aldol reaction, Mukaiyama aldol reaction, Reformatsky reaction ... 

As shown in Scheme 9-57, the Ci-Cf, ketones 202 and 203 have both been prepared by aldol chemistry. The synthesis of ketone 202 used the Braun auxiliary 204 in a lithium-mediated aldol reaction and afforded adduct 205 in 75% yield and 98% ds [75]. This synthe.sis can be compared with the related Reformatsky reaction of imide 206, again controlled by an auxiliary attached to the enolate... 

Cyclic cobalt-acyl complexes can be deprotonated, and subsequent reaction of these enolates with aldehydes gives predominantly the anti/threo product (Scheme 63). Rhenium-acyl complexes can be deprotonated in the same manner. These lithium enolates can be alkylated or can react with [M(CO)5(OTf)] (M = Re, Mn) to give the corresponding enolates (Scheme Many transition metal enolates of type (21) or (22) are known, - but only a few have shown normal enolate behavior , e.g. aldol reaction, reaction with alkyl halides, etc. Particularly useful examples have been developed by Molander. In a process analogous to the Reformatsky reaction, an a-bromo ester may be reduced with Smia to provide excellent yields of condensation products (Scheme 65) which are generated through intermediacy of a samarium(III) enolate. ... 

Several workers have observed aldol reactions with enolates prepared by reductive removal of an o-heteroatom from a carbonyl compound. The classic example is the Reformatsky reaction, which is reviewed in Volume 2, Chapter 1.8. Dubois and coworkers have employed this method for the preparation of magnesium enolates. An important example from this study, which stimulated much of the subsequent work on aldol stereoselectivity, is shown in equation (21). 

Because the Reformatsky sequence allows the generation of an ester enolate in the presence of an enolizable aldehyde or ketone, it is uniquely suited for intramolecular aldol reactions.- The transformation shown in equation (10) would be difficult to accomplish by conventional base-promoted aldol methods. ... 

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