Chemistry Reference
In-Depth Information
O
O
O
O
N
3
Catalytic peptide (2.5 mol %)
TMSN
3
,
t-
BuCO
2
H, PhCH
3
N
R
N
R
48
47
O
tBu
O
tBu
H
O
H
O
N
N
HN
HN
COBHN
COBHN
Me
Me
O
O
N
N
a-Np
a-Np
R
N
N
50
49
Bn
Bn
45-85% ee (2000)
71-92% ee (2002)
Scheme 2B.9.
tion about hydrogen bond-mediated enantioselective base organocatalysis. The develop-
ment of effi cient base catalysts [35-38], including those derived from cinchona alkaloids
[35-37], is a topic of continuing interest.
The evolvement of hydrogen bond-mediated enantioselective acid and base catalysis,
in parallel to similarly remarkable development in other forms of organocatalysis [1],
has established two broadly useful concepts in asymmetric synthesis. The respective yet
complementary roles played by these two types of catalysis in asymmetric electrophile-
nucleophile reactions logically raise the question: “Can acid and base catalysis be suc-
cessfully coupled to perform powerful bifunctional asymmetric catalysis with a small
molecule?” As described below, this is not the fi rst visit to this fascinating question by
organic chemists. However, this time, the outcome is different.
2B.3. ACID - BASE BIFUNCTIONAL CATALYSIS BY SMALL CHIRAL
ORGANIC MOLECULES
Highly enantioselective reactions have been realized with bifunctional organic catalysts
that activate and orient the nucleophiles via the formation of a catalyst-substrate
complex through a covalent bond linkage. This is exemplifi ed by the Morrita-Baylis-
Hillman reactions with
iso
- cuperidine
51
[19a] and the direct aldol reaction with proline
54
[39] (Scheme 2B.10 ). Catalysts
51
and
54
promote these reactions through the syn-
ergistic cooperation of acid catalysis with nucleophilic catalysis [19a] and enamine cataly-
sis [39], respectively. Consequently, the presence of certain functional groups in the
nucleophiles, such as the aldehyde, is a prerequisite for the operation of these bifunc-
tional organocatalysts.
In contrast, asymmetric acid-base bifunctional organocatalysis can be applied to both
electrophiles and nucleophiles bearing various functional groups. In fact, the potential
of such bifunctional catalysis has been long recognized. Extensive and systematic inves-
tigations with the goal of achieving effi cient asymmetric reactions had been carried out
