Alkylation of chiral enolates

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

The counterion of an enolate has a pronounced influence on competing transition states of enolate reactions. The effect is often the result of cation chelation by the carbonyl oxygen atom and one or more additional basic portions of the reactants. For example, alkylation of chiral enolates may lead to more or less diastereomerically pure products and selectivity often depends on the countercation. The importance of the countercation in controlling enolate reaction product distributions requires that the synthetic chemist has at hand stereoselective methods for the preparation of enolate anions with a wide variety of counterions. This chapter is divided into several sections. The 10 following sections describe important current methods for preparing Li, Mg, B, Al, Sn, Ti, Zr, Cu, Zn and other transition metal enolates. 

Aldehyde, Ketone, and Ester Enolates 867 Enolate Regiochemistry 872 The Aldol Condensation 873 Mixed Aldol Condensations 878 Chalcones From the Mulberry Tree to Cancer Chemotherapy 880 The Claisen Condensation 882 Intramolecular Claisen Condensation The Dieckmann Cyclization 884 Mixed Claisen Condensations 885 Acylation of Ketones with Esters 886 Alkylation of Enolates 887 The Acetoacetic Ester Synthesis 889 The Malonic Ester Synthesis 891 Alkylation of Chiral Enolates 893 Enolization and Enol Content 895 a Halogenation of Aldehydes and Ketones 900... 

Alkylation of chiral enolates (Section 20.12) Chiral enolates may undergo alkylation stereoselectively to give product enriched in one enantiomer. 

In conclusion, the asymmetric alkylation of chiral enolates and enamines can be completed with high stereoselectivity affording final products with high optical purity [17], The chiral economy of this and other noncatalytic methods that use chiral auxiliary agents in a stoichiometric quantity depends on their availability and effective recycling in the process. 

Evans DA, Takacs JM. Enantioselective alkylation of chiral enolates. Tetrahedron Lett. 1980 21 4233 236. 

Clark, D.L. and Heathcock, C.H. (1993) Studies on the alkylation of chiral enolates application toward the total synthesis of discodermolide. j. Org. Chem., 58, 5878-5879. 

The first three sections of this chapter describe diastereoselective alkylations of chiral enolates including heteroatom-substituted enolates [15, 20]. Section 3.4 deals with the class of enolate alkylations that have typically been included under the rubric of chiral-auxiliary-controlled processes. As suggested by the term, the auxiliary is only transiently utilized and, following alkylation, is subsequently excised. The facile use of chiral auxiliaries in asymmetric enolate alkylations has played and continues to play a pivotal role in the stereoselective formation of new C-C bonds. After a brief survey of the relatively few developments in catalytic enantioselective enolate alkylations (Section 3.5) [21, 22], selected examples of enolate a-hydroxylations (Section 3.6) [23-25] and a-halogenations (Section 3.7) [26, 27] are covered. The corresponding a-aminations of enolates are discussed in Chapter 10, describing stereoselective formation of a-amino acids. 

There are numerous examples of diastereoselective alkylations of chiral enolates, in which the extant asymmetry of the substrate exerts suitable stereochemical control in the alkylation step [15, 20]. Several useful guiding principles have been determined to aid in predicting the stereochemical outcome. The examples discussed in the following sections have been selected to showcase the power of enolate alkylations for the stereoselective formation of new C-C bonds, as well as to highlight selected historical aspects in the development of the field. 

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