Biomedical Engineering Reference
In-Depth Information
CO
2
H
H
O
O
O
OH
2
(30 mol%)
Me
Me
+
Me
Me
H
Me
DMSO, acetone
97%
Me
Me
5
6
7
(ee = 96%)
SCHEME 6.2
Proline-catalyzed intermolecular aldol reaction.
Me
O
N
Me
Me
Ph
N
H
.
HCl
H
10
(5 mol%)
+
CHO
+
Ph
Ph
O
MeOH, H
2
O, 23°C, 21 h
99% (
exo/endo = 1.3
:1)
Ph
CHO
8
9
exo
-11
(ee = 93%)
endo
-12
(ee = 93%)
SCHEME 6.3
Diels-Alder reaction mediated by MacMillan's catalyst.
6.2. CARBON-CARBON BOND FORMATION
6.2.1. Direct Aldol Reaction
The aldol reaction is one of the most fundamental and important transformations in
organic synthesis. This carbon-carbon bond forming reaction has been widely
investigated with various substrates and catalysts [5]. MacMillan and Northrup
reported a proline-catalyzed
anti
-aldol reaction of various aldehydes to afford the
corresponding
a
-methyl
b
-hydroxy aldehydes
13
15
with excellent enantioselec-
tivities (Scheme 6.4) [6]. They eventually extended the reaction to an
a
-alkoxy
aldehyde to provide
a
,
b
,
g
-trioxy aldehyde
-
in both high yield and high enantio-
meric excess [7]. Since proline is normally used in polar solvents such as DMSO and
DMF, Hayashi et al. developed a combined proline-surfactant organocatalyst
16
and
performed a cross-aldol reaction in the presence of water to afford the
anti
-adduct
17
18
predominantly [8].
Callipeltoside C (
) is a 12-membered ring macrolide bearing a 6-deoxysugar
that exhibits cytotoxic activity against human bronchopulmonary NSCLC-N6 cell
lines [9]. In their synthesis of callipeltoside C, MacMillan and coworkers employed
the proline-catalyzed aldol reaction for the construction of both the sugar moiety
19
20
and the C1-C9 unit
(Figure 6.1).
Thus, the proline-mediated aldol between chiral aldehyde
21
22
and propanal (
23
)
gave the corresponding
with a high stereoselectivity
(Scheme 6.5). A diastereoselective addition of propargyl zinc bromide to the latter
then afforded diol
b
-hydroxy aldehyde
24
25
, which was eventually converted to the desired C1-C9 unit
21
after several transformations, including a homologation [10].
Aldol dimerization of
a
-siloxy acetaldehyde
26
followed by aMukaiyama aldol
of the resulting aldehyde
27
with enol ether
28
and spontaneous cyclization furnished
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