Biomedical Engineering Reference
In-Depth Information
O
O
N
N
+
CO
2
t
-Bu
O
Rh(II)
O
CO
2
t
-Bu
-
N
Me
MeO
N
Me
O
N
2
O
MeO
MeO
CO
2
Me
OMe
MeO
O
99
100
97%
O
O
N
N
N
O
O
O
O
BF
3
·
OEt
2
CO
2
t
-Bu
O
70%
N
N
O
N
O
H
H
Me
H
OH
Me
MeO
2
C
Me
CO
2
Me
(±)-Aspidophytine
103
102
101
SCHEME 13.23
compounds, related to and possibly derived from an aspidosperma-type alkaloid
precursor
104
. A possible biogenetic pathway to the kopsifolines from
104
could
involve an intramolecular epoxide ring-opening, followed by loss of H
2
O as shown in
Scheme 13.24. The interesting biological activity of these compounds, combinedwith
their fascinating and synthetically challenging structure, makes them attractive
targets for synthesis.
Using the metal-catalyzed domino reaction as a key step, the heterocyclic
skeleton of the kopsifolines could eventually be built by a 1,3-dipolar cycloaddition of
a push-pull carbonyl ylide dipole derived from
a
-diazo keto ester
107
across the
indole
-bond. Ring-opening of the resulting cycloadduct
108
followed by a reductive
dehydroxylation step produced the critical silyl enol ether
109
necessary for the final
F-ring closure. The facility and the stereoselectivity of the key cycloaddition reaction
were investigated in more detail using some model substrates. It was found that
the heterocyclic skeleton of the kopsifoline alkaloid family
110
could readily be
constructed by the proposed sequence of reactions outlined in Scheme 13.25 [50].
The isolation of
108
as a single diastereomer was rationalized by recognizing that
the indole moiety approaches the dipole from the least sterically encumbered
position. Ring-opening of the resulting cycloadduct
108
followed by a reductive
dehydroxylation step resulted in the formation of the silyl enol ether
109
necessary for
the final F-ring closure of the kopsifoline skeleton (i.e., formation of
110
).
p
D
H
H
N
N
N
H
OH
O
E
H
+
F
C
18
A
B
16
CO
2
Me
N
N
CO
2
Me
N
CO
2
Me
H
R
R
H
R
104
(R = H or OMe)
105
Kopsifolines
106
(R = H or OMe)
SCHEME 13.24
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