Page 93 - Advanced Organic Chemistry Part B - Reactions & Synthesis

The aldol reaction is also important in the synthesis of more complex molecules and 65
in these cases control of both regiochemistry and stereochemistry is required. In most
cases, this is accomplished under conditions of kinetic control. In the sections that SECTION 2.1
follow, we discuss how variations of the basic mechanism and selection of specific Aldol Addition and
Condensation Reactions
reagents and reaction conditions can be used to control product structure and stereo-
chemistry.
The addition reaction of enolates and enols with carbonyl compounds is of broad
scope and of great synthetic importance. Essentially all of the stabilized carbanions
mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as
the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the
carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized
carbanions and ylides undergo this reaction. In the next section we emphasize the
fundamental regiochemical and stereochemical aspects of the reactions of ketones and
aldehydes.

2.1.2. Control of Regio- and Stereoselectivity of Aldol Reactions
of Aldehydes and Ketones
The synthetic utility of the aldol reaction depends on both the versatility of
the reactants and the control of the regio- and stereochemistry. The term directed
aldol addition is applied to reactions that are designed to achieve specific regio-
1
and stereochemical outcomes. Control of product structure requires that one reactant
act exclusively as the nucleophile and the other exclusively as the electrophile. This
requirement can be met by pre-forming the nucleophilic enolate by deprotonation, as
described in Section 1.1. The enolate that is to serve as the nucleophile is generated
stoichiometrically, usually with lithium as the counterion in an aprotic solvent at low
temperature. Under these conditions, the kinetic enolate does not equilibrate with
the other regio- or stereoisomeric enolates that can be formed from the ketone. The
enolate gives a specific adduct, provided that the addition step is fast relative to proton
exchange between the nucleophilic and electrophilic reactants. The reaction is under
kinetic control, at both the stage of formation of the enolate and the addition step.
Under other reaction conditions, the product can result from thermodynamic
control. Aldol reactions can be effected for many compounds using less than a
stoichiometric amount of base. In these circumstances, the aldol reaction is reversible
and the product ratio is determined by the relative stability of the various possible
products. Thermodynamic conditions also permit equilibration among the enolates
of the nucleophile. The conditions that lead to equilibration include higher reaction
temperatures, protic or polar dissociating solvents, and the use of weakly coordinating
cations. Thermodynamic conditions can be used to enrich the composition in the most
stable of the isomeric products.
Reaction conditions that involve other enolate derivatives as nucleophiles have
been developed, including boron enolates and enolates with titanium, tin, or zirconium
as the metal. These systems are discussed in detail in the sections that follow, and
in Section 2.1.2.5, we discuss reactions that involve covalent enolate equivalents,
particularly silyl enol ethers. Scheme 2.1 illustrates some of the procedures that have
been developed. A variety of carbon nucleophiles are represented in Scheme 2.1,
including lithium and boron enolates, as well as titanium and tin derivatives, but in

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T. Mukaiyama, Org. React., 28, 203 (1982).