Reaction of Enolates - Carbohydrates: Tools for Stereoselective Synthesis - page 45

3

Reaction of Enolates
Noureddine Khiar, Inmaculada Fernández, Ana Alcudia, Maria Victoria García and
Rocío Recio

3.1
Introduction

The aldol reaction is one the best known and widely employed methods for the
stereoselective buildup of carbon-carbon bonds [1]. Within the different approaches
developed so far, the chiral auxiliary-based aldol reaction is the best-studied trans-
formation and is well understood in terms of the reaction mechanism. While, in
principle, a stoichiometric auxiliary could be used in various ways in the aldol
reaction, the consensus is that the chiral-directing group should be incorporated
into the (enolate) nucleophile. Although uncommon, there are examples where
the chiral auxiliary is in the electrophilic component [2]. The chiral auxiliary-based
aldol reaction has reached such efficiency and reliability that it is employed in
innumerable syntheses of active pharmaceutical ingredients (APIs) needed for
preclinical and early clinical studies on a multi-kilogram scale [3]. The main
reasons for this are that diastereoselective aldol reactions are generally more
robust in terms of scale than catalytic processes, and isomeric byproducts
are diastereomer of the desired product, which can easily be removed from the
mixture.
In an aldol reaction, one C-C bond and up to two stereogenic centers can be
formed in a single chemical step. Aldol reactions can be categorized in two major
families based on the structure of the enolate component (Scheme 3.1).

O

R 2 O

O

HO

R 2 R 1

Enolizatio n

R 3

R 1

syn or anti (Eq 3.1)

XR

Propionate-type Aldol

XR

R 3

O

R 2 O

O

HO

R 2 R 1

Enolizatio n

X = O, N, S (Eq 3.2)

Acetate-type Aldol

R 1 XR

XR

Scheme 3.1

Types of aldol reaction.