Chemistry Reference
In-Depth Information
This extraordinary result was well received by the synthetic community; however, the
underlying activation mode was not exploited outside of this initial intramolecular aldol
reaction for more than 30 years. Indeed, it was not until the ingenious work of List,
Lerner, and Barbas in 2000 that the utility of enamine catalysis truly came to fruition
via application to a variety of carbonyl
- functionalization reactions. The fi rst example
of modern enamine chemistry arose through a catalytic asymmetric aldol reaction
(Scheme 2A.11 ) [20] .
α
O
OH
O
30 mol % cat.*
O
Catalyst =
H
CO
2
H
H
R
R
DMSO, 23°C
54-97% yield
60-96% ee
Scheme 2A.11.
List, Lerner, and Barbas's proline-catalyzed catalytic asymmetric aldol reaction.
Mechanistically, enamine catalysis might be better described as a bifunctional cataly-
sis as the amine catalyst typically interacts with an aldehyde or ketone substrate to form
an enamine while simultaneously engaging an electrophilic reaction partner via either
hydrogen bonding or electrostatic attraction. This general mode of activation has now
been exploited in a wide range of enantioselective carbonyl α - functionalization pro-
cesses, a selection of which is presented below.
2A.3.1. Asymmetric Aldol and Aldol - Type Reactions
Following the work of List, Lerner, and Barbas [20], enamine-catalyzed enantioselective
aldol reactions received considerable attention [1,21]. Although several novel catalyst
structures can be utilized, many aldol processes can be performed using commercially
available, and inexpensive, proline as the requisite organocatalyst allowing high effi -
ciency and enantioselectivity. Of particular note was the intermolecular aldehyde-alde-
hyde crossed aldol reaction, a transformation that previously had only been accomplished
within the realm of enzymatic catalysis (Scheme 2A.12) [22].
This procedure was elaborated further by MacMillan and co-workers to generate a
two-step carbohydrate synthesis based on the enamine-catalyzed aldol dimerization of
α - oxyaldehydes, followed by a Mukaiyama - aldol - cyclization event. This protocol gener-
ated a series of differentially substituted hexoses in high yield, with excellent levels of
diastereoselectivity and enantiopurity (Scheme 2A.13 ) [23] .
List reported the related three-component Mannich reaction of acetone, anisidine,
and a range of aldehydes to furnish β - PMP - protected aminoketones (Scheme 2A.14 )
[24]. The process could be extended to α-oxyketones, the products of which can be
readily converted to valuable amino alcohol building blocks.
Barbas and co-workers later reported an extension of this methodology to allow the
direct synthesis of aldehyde-aldehyde Mannich derivatives in a one-pot operation
(Scheme 2A.15 ) [25] .
