Metal enolates mixed aldol reaction

An approach has recently been made in which asymmetric aldol reactions are performed without the need for preformed metal enolates.1 In 2000, List and co-workers reported that the cyclic amino acid L-proline is an effective catalyst for the asymmetric aldol reaction of acetone with a variety of aromatic and aliphatic aldehydes2 (Scheme 2.3a). When L-proline was mixed with acetone... 

A number of methods have been developed to bring about the directed aldol reaction between two different carbonyl compounds to give a mixed-aldol product. Most of them proceed from the preformed enolate or silyl enol ether of one of the components. With enolates, a number of metal counterions have been used and the best results have been obtained with lithium or boron enolates, although zinc or transition-metal enolates have found widespread use. For example, the aldol reaction of acetone with acetaldehyde under basic aqueous conditions is inefficient... 

Dialkylzinc derivatives are inert towards conjugated enones (e.g. 181) in hydrocarbon or ethereal solvents. The discovery that a conjugate addition can be promoted by Cu(I) salts in the presence of suitable ligands L (e.g. sulphonamide 182) opened a new route to zinc enolates (e.g. 183), and hence to the development of three-component protocols, such as the tandem 1,4-addition/aldol addition process outlined in equation 92186. If the addition of the aldehyde is carried out at —78 °C, the single adduct 184 is formed, among four possible diastereomeric products. The presence of sulphonamide is fundamental in terms of reaction kinetics its role is supposed to be in binding both Cu(I) and Zn(II) and forming a mixed metal cluster compound which acts as the true 1,4-addition catalyst. 

The Ivanov reaction (Scheme 5.1) is an early example of an aldol addition reaction that proceeded selectively. There has been an enormous amount of work done in this area, and only a small amount of the developmental work will be covered here. A large number of chiral auxiliaries and catalysts have been developed, but we will concentrate on only a few, which suffice to provide an understanding of the structural factors that influence selectivity. The transition structures presented in the following discussion are oversimplifications, in that the enolate and its metal are represented as monomers, when in fact they are not [2-4]. On the other hand, much of the available data may be rationalized on the basis of these structures, so the simplification is justified in the absence of detailed structural and configurational information about mixed aggregate transition structures. 

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