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O
O
20 mol % cat.*
Br
CO
2
H
Catalyst =
H
H
H
Me
CHCl
3
, Et
3
N, -30°C
EtO
2
C
CO
2
Et
EtO
2
C
CO
2
Et
92% yield
96% ee
Scheme 2A.23.
Enamine - catalyzed intramolecular α - alkylation of aldehydes.
2A.4. NEW DEVELOPMENTS IN ORGANOCATALYSIS
2A.4.1. Merging Enamine and Iminium Activation: Organocascade Catalysis
[36]
Rapid access to compounds possessing elevated levels of structural complexity remains
a preeminent goal for the chemical sciences. While the total synthesis approach to
molecular complexity has traditionally focused on a “stop and go” sequence of individual
reactions, it is intriguing to consider that biologic systems produce elaborate molecules
in a continuous process, wherein enzymatic transformations are combined in highly
regulated catalytic cascade cycles. A crucial requirement for the success of these pro-
cesses is the capacity of transform-specifi c enzymes to coexist in the same reaction
medium without detrimental interactions. Consideration of the conceptual blueprints of
enzymatic catalysis in the context of organocatalysis has recently led to the development
of a powerful synthetic concept whereby a cascade iminium and enamine activation
sequence leads to highly functionalized products (Scheme 2A.24) [36].
R
O
Me
O
N
R
Nucleophile (Nu)
Im
E
n
H
t
-Bu
Nu
O
Ar
E
Electrophile (E)
Catalyst
Cascade
catalysis
Cascade
product
Scheme 2A.24.
Organocascade catalysis concept.
A demonstration of the power and utility of this cascade hypothesis for the rapid
construction of stereochemical complexity was fi rst illustrated through the enantioselec-
tive synthesis of a series of
- chloroaldehydes (Scheme 2A.25 ) [37] .
Notably, the diastereoselectivity of the second step of this reaction sequence was
almost exclusively catalyst controlled. Additionally, this cascade strategy demonstrated
good latitude in terms of the nucleophilic and electrophilic components by extension to
encompass hydride nucleophiles and fl uoride electrophiles [37]. As such, there is con-
siderable potential for this technology to exceed its original design by increasing the
number of bond-forming events occurring in the organocascade sequence. Indeed, a
triple-cascade sequence, involving an enamine-iminium-enamine relay, was recently
demonstrated by Enders and coworkers (Scheme 2A.26 ) [38] .
β
- aryl,
α
