Preformed metal enolates

The classical aldol addition, which is usually run in protic solvents, is reversible. Most modern aldol methodologies, however, rely on highly reactive preformed metal enolates, whereby proton donors are rigorously excluded. As a consequence, the majority of recent stereoselective aldol additions are performed under kinetic control. Despite this, reversibility and, as a consequence, an equilibration of yrn-aldolates to a t/-aldolates by retro-aldol addition, should not be excluded a priori. 

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... 

The aldol reaction is one of the most fundamental tools in organic chemistry, and it still remains an open field for new ideas and developments504-509. Among the many reviews dedicated to this subject, the reader should refer, for a more referenced survey, to Heathcock7,11 and more recently to Braun s articles510 devoted specifically to the preformed metal enolates of group I—II. The Mannich reaction (the aza-equivalent of the aldol reaction) is a subject on its own and will be only partially treated here. 

In recent organic synthesis, stereoselective aldol condensations has been performed under two different conditions. Under the influence of acid, stabilized enol derivatives, enolsilanes (M = SiMe3), can condense with aldehydes or acetals in a stereoselective fashion [Eq. (12)]. In this reaction the role of the acid is to activate aldehydes or acetals. Alternatively, under basic conditions, the same process can be carried out directly with aldehydes and reactive, preformed metal enolates (M = Li, MgL, ZnL, AIL2, BL2, etc.) of defined geometry. 

The present procedures illustrate general methods for the use of preformed lithium enolates5 as reactants in the aldol condensation6 and for the quenching of alkali metal enolates in acetic anhydride to form enol acetates with the same structure and stereochemistry as the starting metal enolate.7 The aldol product, [Pg.55]

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

A number of reagents are available for transforming carbonyl compounds directly to a-oxygenated products without the preformation of a metal enolate and are discussed in Section 4.1.5. 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

Among the methodologies listed in the introduction to generate the key enol/enolate intermediate, the enantioselective protonations of metal enolates, the so-called preformed enolates, or of their substitutes such as enamines or enol ethers have known, by far, the most intensive research development (Scheme 7.2). 

Our research group independently found a catalytic enantioselective proto-nation of preformed enolate 47 with (S,S)-imide 30 founded on a similar concept (Scheme 5) [51]. The chiral imide 30, which has an asymmetric 2-oxazoline ring and is easily prepared from Kemp s triacid and optically active amino alcohol, is an efficient chiral proton source for asymmetric transformation of simple metal enolates into the corresponding optically active ketones [50]. When the lithium enolate 47 was treated with a stoichiometric amount of the imide 30, (K)-en-riched ketone 48 was produced with 87% ee. By a H-NMR experiment of a mixture of (S,S)-imide 30 and lithium bromide, the chiral imide 30 was found to form a complex rapidly with the lithium salt. We envisaged that a catalytic asym-... 

Various methods using a stoichiometric amount of chiral proton sources or chiral ligands are available for enantioselective protonation of metal enolates e.g., protonation of metal enolates preformed by deprotonation of the corresponding ketones or by allylation of ketenes [6,7,8,9,10,11,13,17,18,19,21,22,25,26, 29,30,31,32,37,40,41,42,43,49,50,53,54,55,56,57,59,60,63], the Birch reduction of a, 3-unsaturated acids in the presence of a sugar-derived alcohol 2... 

Traditionally, aldol reactions were carried out under protic conditions, such that the enolate was formed reversibly (see Volume 2, Chapter 1.5). An added measure of control is possible if one uses a sufficiently strong base that the enolate may be quantitatively formed prior to addition of the electrophile. The renaissance that has occurred in the aldol reaction in the last two decades has been mainly due to the development of methods for the formation and use of preformed enolates. The simplest enolates to prepare are those associated with lithium and magnesium, and there now exists a considerable literature documenting certain aspects of lithium and magnesium enolate aldol chemistry. This chapter summarizes the aldol chemistry of preformed enolates of these Group I and Group II metals. Other chapters in this volume deal with boron enolates, zinc enolates, transition metal enolates and the related chemistry of silyl and stannyl enol ethers. 

The classic case of effective stereocontrol under equilibrating conditions is the House method, wherein the aldol reaction of the preformed lithium enolate is carried out in the presence of coordinating divalent metal ions, such as magnesium and zinc. An example is seen in equation (134). The enolate of phenyl-acetone reacts with propionaldehyde to give 86-90% anti aldol, regardless of the original enolate geometry. Further discussion on zinc endates is found in Volume 2, Chapter 1.8. 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

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... 

Condensation Reactions. Traditionally, intermolecular aldol condensation reactions have been performed under equilibrating conditions using weaker bases than r-BuOK in protic solvents. Since the mid-1970s, new methodology has focused on directed aldol condensations which involve the use of preformed Lithium and (jroup 2 enolates, (Troup 13 enolates, and transition metal enolates. Although examples of the use of f-BuOK in intramolecular aldol condensations are limited, complex diketones... 

Prior to the advent of organocatalysis, the asymmetric direct a-allqtlation reaction was relatively unknown. Classical methods to access a-allq lated carbonyl products required stoichiometric amounts of preformed aldehyde metal enolates. Additionally, side reactions such as aldol, Canizzaro- or Tischenko-type processes diminished the efficiency of these reactions. In this sense the asymmetric intermolecular Sjj2 a-alkylation of aldehydes with simple allq l halides has been a difficult feat to achieve. 

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