Reaction of Enolates - Carbohydrates: Tools for Stereoselective Synthesis - page 46

The first type involves the use of enolates derived from acetates bearing a sub-
stituent R 3

H [Eq. (3.1)]. Most often, this substituent is simply a methyl group,
and this class is termed “propionate-type” aldol reactions. Aldol reactions using
simple acetate enolates (R 3

≠

H) are, naturally, called “acetate-type” aldols [Eq.
(3.2)]. This classification is used because propionate-type enolates and simple
acetate enolates behave quite differently in chiral auxiliary-controlled aldol reac-
tions. While many chiral auxiliaries have been shown to effectively control the
stereochemical course of propionate-type aldol reactions, the stereocontrol of an
acetate-type aldol reaction turns out to be far more challenging. As a consequence,
asymmetric acetate aldol reactions have been utilized much less frequently in
the total syntheses of natural products as well as novel biologically active
compounds.

=

3.2
Aldol Alkylation

Virtually all chiral auxiliaries developed so far have been used in the aldol reaction
with more or less success. The use of carbohydrates as chiral auxiliaries has been
scarce in this important transformation and the results obtained cannot compete
with the gold standard in the literature [4]. Carbohydrates suffer historically from
the perception of being highly complex molecules, with too many functional
groups and too many chiral centers, to be of practical utility in stereodifferentiating
processes. Indeed, the first results obtained by the group of Heathcock [5], at the
beginning of the 1980s, seem to reinforce this negative opinion 1) . Condensation
of the lithium enolate of propionate 1 derived from d-fructopyranose with benzal-
dehyde afforded the four diastereoisomers of the aldol adducts 2 with practically
no stereodifferentiation, apart from a small anti/syn preference (Scheme 3.2).

D- fructo

O CMe 2 O CMe 2 CH 3

1) LDA, THF

O -78 °C O

O O

O O

O O OH

O O

2) PhCHO

O O

2

1

Me 2 Me 2

syn : anti (27 : 73)
dr of syn product (17 : 10)
dr of anti product (37 : 36)

Scheme 3.2 Propionate-type aldol reaction using diacetone-D-fructopyranose as chiral

auxiliary.

A detailed study on the same reaction was carried out 15 years later by Costa
et al. , who demonstrated that the low diastereoselectivity obtained is due to the
loss of integrity of the enolate geometry during the reaction, as a consequence of
the various sites to which the lithium cation of the enolate may coordinate [6]. The

1) Even though it is an aldol condensation, we include this example here because of its historical
importance in the development of carbohydrates as chiral auxiliaries in asymmetric synthesis.