Page 95 - Advanced Organic Chemistry Part B - Reactions & Synthesis

each case the electrophile is an aldehyde. Pay particular attention to the retrosynthetic 67
relationship between the products and the reactants, which corresponds in each case to
Path A (p. 64). We see that the aldol addition reaction provides -hydroxy carbonyl SECTION 2.1
compounds or, more generally, adducts with a hydroxy group to the stabilizing group Aldol Addition and
Condensation Reactions
Z of the carbon nucleophile.

Z OH Z
O
C C R 1 C – +
R 2 R 1 R 2

Note also the stereochemistry. In some cases, two new stereogenic centers are
formed. The hydroxy group and any C(2) substituent on the enolate can be in a syn
or anti relationship. For many aldol addition reactions, the stereochemical outcome of
the reaction can be predicted and analyzed on the basis of the detailed mechanism of
the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic
formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but
with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which
are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of
an amide; reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show
titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3.

2.1.2.1. Aldol Reactions of Lithium Enolates. Entries 1 to 4 in Scheme 2.1 represent
cases in which the nucleophilic component is a lithium enolate formed by kinetically
controlled deprotonation, as discussed in Section 1.1. Lithium enolates are usually
highly reactive toward aldehydes and addition occurs rapidly when the aldehyde is
added, even at low temperature. The low temperature ensures kinetic control and
enhances selectivity. When the addition step is complete, the reaction is stopped by
neutralization and the product is isolated.
The fundamental mechanistic concept for diastereoselectivity of aldol reactions of
lithium enolates is based on a cyclic TS in which both the carbonyl and enolate oxygen
2
are coordinated to the lithium cation. The Lewis acid character of the lithium ion
promotes reaction by increasing the carbonyl group electrophilicity and by bringing
the reactants together in the TS. Other metal cations and electrophilic atoms can play
the role of the Lewis acid, as we will see when we discuss reactions of boron and other
metal enolates. The fundamental concept is that the aldol addition normally occurs
through a chairlike TS. It is assumed that the structure of the TS is sufficiently similar
to a chair cyclohexane that the conformational concepts developed for cyclohexane
rings can be applied. In the structures that follow, the reacting aldehyde is shown with
R rather than H in the equatorial-like position, which avoids a 1,3-diaxial interaction
with the enolate C(1) substituent. A consequence of this mechanism is that the reaction

2
(a) H. E. Zimmerman and M. D. Traxler, J. Am. Chem. Soc., 79, 1920 (1957); (b) P. Fellman and
J. E. Dubois, Tetrahedron, 34, 1349 (1978); (c) C. H. Heathcock, C. T. Buse, W. A. Kleschick,
M. C. Pirrung, J. E. Sohn, and J. Lampe, J. Org. Chem., 45, 1066 (1980).