Biomedical Engineering Reference
In-Depth Information
O
O
O
N
O
OH
N
steps
Rh(II)
Methyl
acrylate
HBr
N
SO
2
Ph
O
N
C
2
H
5
OH
O
+
N
N
-
57
65b
(±)-Camptothecin
71
SCHEME 13.15
Claisen rearrangement in refluxing chlorobenzene to afford the desired rearranged
derivative
66
in 74% overall yield. This transformation is a rare example of a
Claisen rearrangement taking place in a hydroxypyridone system [28d,30]. The
a
-hydroxypyridone
66
was then converted into its triflate derivative under standard
conditions. This was followed by Stille coupling with tetramethyltin to provide
a
-methyl pyridone
67
in 84% yield. In the presence of rhodium(III) chloride in hot
ethanol, compound
67
was rapidly isomerized to olefin
68a
(91%). The success of
this key transformation derives from the carbon symmetry of the
-substituent in
pyridone
67
. Oxidation of
68a
in two steps then selectively generated the Friedl
b
ander
substrate
68b
, which was reacted with
o
-aminobenzaldehyde to give oxoindolizino
quinoline
69
in 73%yield. Ozonolysis of
69
in CH
2
Cl
2
/MeOH at
€
78
C accomplished
selective double bond cleavage in
69
to provide mappicine ketone
70
.
A related synthesis of racemic camptothecin
71
was also carried out by Greene
and coworkers soon thereafter and is similarly based on the isom
unchnone dipole
strategy [31]. The starting point commenced from the readily available hydroxy
pyridone
65b
(Scheme 13.15). Subsequent steps include a Claisen rearrangement
of a functionalized allylic ether, a hindered Heck coupling, and a Friedlander
condensation.
€
13.2.2.
unchnones as Dipoles
Formation and dipolar trapping of the related thioisom
Isothiom
€
unchnone dipole formed by
interaction of rhodium carbenoids derived from diazo thioamides [32] has not been
studied in as much detail as the isom
€
unchnone system [33]. Nevertheless, treatment of
diazo thioamide
72
with a Rh(II) catalyst afforded cycloadduct
73
in 85%yield whose
formation is derived from the intramolecular [3
€
2]-cycloaddition of a mesoionic
dipole intermediate [34]. An alternative method that has also been used to generate
thioisom
þ
unchnones involves treatment of thioamides with bromoacetyl chloride in
the presence of triethylamine [35]. In the case of the
cis
-aryl alkenyl-substituted
piperidinethione
74
, this reaction resulted in the formation of cycloadduct
76
in 85%
yield as a single diastereomer (Scheme 13.16) [34].
The unusual structure of the schizozygane alkaloid family has made them
challenging targets for total synthesis [36]. On the basis of the cycloaddition results
outlined in Scheme 13.16, Padwa and coworkers carried out an approach toward a
synthesis of the isoschizozygane alkaloid (
€
)-isoschizogamine [34]. The assumption
was made that the hexacyclic skeleton of the isoschizozygane alkaloid skeleton could
be prepared from a compound of type
79
by a sequence of enamide protonation,
N
-acyliminium ion cyclization, and lactamization. Enamide
79
may be generated by
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