Biomedical Engineering Reference
In-Depth Information
Ph
Ph
TMS
Li
O
O
O
H
O
Li
MeO
OMe
O
H
91
CO
2
t
-Bu
O
+
O
O
t
-Bu
Ar
H
t
-BuO
2
C
CO
2
t
-Bu
89
90
92
OH
O
O
HO
TMS
H
steps
CO
2
t
-Bu
O
O
H
N
CO
2
t
-Bu
O
O
93
(-)-Lycorine
94
SCHEME 9.17
Synthesis of lycorin
94
by Tomioka and coworkers.
used as an emetic [32]. Moreover, the compound also has antiviral activity and can
induce apoptosis. Tomioka and coworkers have now developed an enantioselective
domino approach toward (
)-lycorine
(94)
and (
)-2-
epi
-lycorine (Scheme 9.17) [33].
In their synthesis, reaction of the double Michael acceptor
90
containing two enoate
moieties with the aryllithium derivative
89
obtained from the corresponding aryl
bromide in the presence of the chiral ligand
91
led to the substituted cyclohexane
derivative
99% ee after recrystallization). In this
domino process, a Michael reaction initially took place to afford
93
in 88% yield and 92% ee (
H
92
as an intermediate
that then underwent a second Michael addition to provide
93
. Further transformations
of
93
led to the desired alkaloid
94
.
is a steroid with remarkable selective antiproliferative
properties and an IC
50
value of 1.8 nM. It is the most active member of the cortistatin
family and was isolated from the sponge
Corticium simplex
by Kobayashi and
coworkers [34]. In 2008, two groups, the group of Nicolaou [35] and the group of
Baran [36], addressed the total synthesis of
(
þ
)-Cortistatin A
(99)
and both used a domino process for
their approach. Baran and coworkers started from readily available prednisone
99
,
whereas Nicolaou and coworkers began with a commercially available monocyclic
system. Nicolaou and coworkers used a domino oxa-Michael addition/aldol/
dehydration process for the synthesis of (
(100)
þ
)-cortistatin A
(99)
starting from
95
using
basic conditions. The desired ABCD ring framework
(98)
of
99
was obtained in 52%
yield, whereby
can be assumed as intermediates (Scheme 9.18).
Sorensen and coworkers also reported a stereocontrolled synthesis of a complex
pentacycle embodying the molecular architecture of the cortistatin class of natural
products starting from (
96
and
97
)-Hajos-Wiechert ketone using a domino oxidative
dearomatization/ether formation/nitrile oxide cycloaddition reaction [37].
(
S
)-Camptothecin
þ
is awell-known anticancer agent that was isolated from
Camptotheca acuminata
by Wall and coworkers in 1966 [38]. It inhibits the
topoisomerase I, which is important for the cleavage and reforming of DNA strands
during the replication process just as the topoisomerase II [39]. In the treatment of
cancer, camptothecin
(101)
(101)
has been replaced by irinotecan and topotecan [40].
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