Biomedical Engineering Reference
In-Depth Information
O
O
BnO
N
N
H
N
N
heat
C
2
H
5
OBn
C
2
H
5
O
N
O
MeO
N
Me
MeO
N
N
Me
CO
2
Me
CO
2
Me
116
117
-N
2
O
O
N
N
+
O
C
2
H
5
OBn
O
C
2
H
5
OBn
-
MeO
N
N
H
Me
Me
CO
2
Me
CO
2
Me
MeO
119
(78% from
116
)
118
steps
N
C
2
H
5
OAc
MeO
N
Me
HO
CO
2
Me
(-)-Vindoline
120
SCHEME 13.27
119
was initiated by an intramolecular inverse electron demand Diels-Alder cyclo-
addition of the 1,3,4-oxadiazole
116
with the tethered enol ether. Loss of nitrogen from
the initial Diels-Alder cycloadduct
117
provides the push-pull carbonyl ylide
118
,
which then undergoes a subsequent 1,3-dipolar cycloaddition with the tethered indole.
More important, the diene and dienophile substituents complement and reinforce
the [4
2]-cycloaddition regioselectivity dictated by the linking tether. The relative
stereochemistry in the cycloadduct is controlled by a combination of the dienophile
geometry and an exclusive
endo
indole [3
þ
2]-cycloaddition sterically directed to
the
Re
face opposite to the newly formed fused lactam. This
endo
diastereoselection
for the 1,3-dipolar cycloaddition has been attributed to a conformational (strain)
preference dictated by the dipolarophile tether [52]. Cycloadduct
119
was finally
converted to the natural product vindoline
120
in several additional steps. Extension
of these cascade studies by the Boger group eventually provided for a total synthesis
of the bisindole alkaloids vinblastine and vincristine (Scheme 13.27) [53].
þ
13.2.5.
Intermolecular Azomethine Ylide Cycloadditions
þ
p
[3
-component have been
widely used for the synthesis of natural products containing pyrrolidine rings [54]. A
variety of methods for generating the azomethine ylide dipole, ranging from
2]-cycloaddition involving azomethine ylides as the 4
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