Chemistry Reference
In-Depth Information
to provide the reader with a glimpse of the “state of the art” developments in this area.
Due to a space constraint and the vast amount of literature already accumulated on this
topic, the authors could only strive to accomplish these goals by highlighting select lit-
erature reports. This review thus refl ects the authors' personal view of what is important
in this area.
2B.2. HIGHLY ENANTIOSELECTIVE ACID AND BASE CATALYSIS BY
MONOFUNCTIONAL ORGANIC CATALYSTS
2B.2.1. The Emergence of Highly Enantioselective Acid Catalysts
Most organic reactions are electrophile-nucleophile reactions and, therefore, can be
promoted with metallic and organic catalysts as either an acid or a base. Merely a decade
ago, metal-based chiral Lewis acids provided the only proven and broadly applicable
approach for the activation of electrophiles for asymmetric reactions [3]. Although
organic molecules containing hydrogen bond donors had already been reported to be
competent catalysts for various organic transformations, a highly enantioselective chiral
variant was not yet established [4,5]. A decisive breakthrough in asymmetric catalytic
reactions with an organic acid catalyst came in 1998 when Jacobsen and coworkers
discovered that chiral urea and thiourea derivatives, such as
3
, promoted highly enanti-
oselective Strecker reactions with a broad range of aryl and alkyl imines
1
and HCN
(Scheme 2B.1) [6]. The scope of the reaction was subsequently extended to methyl aryl
ketoimines [7], and furthermore, the mechanism of the chiral urea- and thiourea-cata-
lyzed Strecker reactions was investigated by kinetic studies, NMR, and computational
studies [4]. Results from these studies formed the basis for a mechanistic proposal in
which the activation of the imine by the urea or thiourea functionality of
3
through
hydrogen - bonding interactions was the salient feature [4,8] .
Subsequent studies from the Jacobsen group established effi cient enantioselective
Mannich reactions (Scheme 2B.3) of silylketene acetals
9
with
N
- Boc aromatic imines
8A
and hydrophosphonylation of
8A
(Scheme 2B.2), thereby demonstrating that the
scope of both the electrophiles and the nucleophiles could be expanded [9]. These results
provided compelling indications of chiral urea and thiourea derivatives as generally
applicable organic acid catalysts for asymmetric synthesis [4] .
Importantly, highly enantioselective chiral organic acid catalysts featuring other
hydrogen bond donor functionalities, such as guanidine
14
[10] , alcohols
21
and
14
[11] ,
and amidinium ion
25
[12], were developed (Scheme 2B.4). Each of these pioneering
studies introduced a new class of highly enantioselective acid catalysts to asymmetric
synthesis in the infant stage of chiral acid organocatalysis. Consequently, they each
contributed in a unique way to the establishment of acidic catalysis by organic molecules
as a broadly useful concept for the activation of electrophiles in asymmetric reactions.
Without a doubt, however, the results from Jacobsen's systematic synthetic and mecha-
nistic studies of chiral urea- and thiourea-catalyzed reactions have played a leading role
in shaping the concept of enantioselective acid organocatalysis into one of the corner-
stones of enantioselective organocatalysis. It should be noted that the further develop-
ment and expansion of this concept is currently a topic of intense interest in catalytic
asymmetric synthesis [4], and new classes of powerful chiral acid catalysts, such as chiral
phosphoric acids, continue to emerge [13].
