Biomedical Engineering Reference
In-Depth Information
O
O
N
O
N
O
AuCl
3
(10 mol%)
CH
3
CN, 40°C, 4.5 h
8
8
N
N
N
N
H
TBSO
TBSO
78%
H
H
125
126
OTBS
OTBS
1.
p
-TsOH, MeCN
2. HPLC purification
(H
2
O/CH
3
CN/TFA)
77%
O
O
O
N
O
N
NH
3
3
steps
N
O
14
NH
3
8
O
8
N
H
N
H
N
O
OH
-
HO
CF
3
CO
2
HO
H
H
(-)-Crambidine
128
127
SCHEME 4.37
Synthesis of (
)-crambidine by Gin and coworkers.
heterocyclic structures, was recently reported by Gin and coworkers in their
elegant total synthesis of (
)-crambidine
128
[35]. Hence, in the presence of
5 mol% of AuCl
3
, 2-aminopyrimidine
125
was added across the internal alkyne to
furnish the tricyclic pyrimidine
in a regio- and stereoselective manner
(Scheme 4.37). The enamine functionality present in
126
126
was used in the next step
for the spiroaminal formation at C8, while the resulting tetracyclic pyrimidinium
127
was converted to (
after three additional steps.
Gold-catalyzed tandem reactions have also been used in total synthesis as
exemplified by the formal synthesis of nitidine
133
achieved by Takemoto and
coworkers. (Scheme 4.38) [36].
Upon treatment with 5mol% of (JohnPhos)AuNTf
2
, alkyne
)-crambidine
128
129
was converted
into the pentacyclic compound
in an excellent 98% yield. The transformation
involved the first hydroamination of the alkyne that led to the formation of inter-
mediate
132
. A subsequent gold-promoted Mukaiyama-type aldol condensation
with the enecarbamate group, followed by elimination of methanol, furnished
131
130
. The reduction of the Boc moiety in
131
into a methyl group finally produced
dihydronitidine
.
Several studies have shown that electrophilic gold species could be used as
catalysts to perform a variety of structural rearrangements. Such a kind of transfor-
mation is frequently encountered in the cycloisomerizations of enynes [31]. The gold-
catalyzed transformation used by Zhang and coworkers in the formal synthesis of
indolizidine 167B
132
, a precursor of nitidine
133
is also a representative example of a skeletal reorganization
(Scheme 4.39) [37]. Indeed, the gold-catalyzed activation of the alkyne in enyne
138
134
allowed the formation of the highly strained cationic species
135
. A subsequent
fragmentation of the azetidine ring furnished an acyl cation
136
, which finally reacted
with the enamine group to produce the bicyclic pyrrole
137
. The synthesis of
indolizidine 167B
138
was achieved after a final hydrogenation step.
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