Biomedical Engineering Reference
In-Depth Information
B
N
BnO
2
C
H
CO
2
Bn
PhCO
2
H, MgSO
4
Benzene, 70°C
NHBn
R
OHC
H
N
H
CO
2
Me
CO
2
Me
R
180
181a
(R = Me)
181b
(R = CH(OMe)
2
)
181c
(R =
o-
MeOC
6
H
4
)
182
(ee > 99%; de > 95%)
H
B
N
Bn
N
BnO
2
C
BnO
2
C
R
R
N
H
H
CO
2
Me
CO
2
Me
184a
(R = Me, 51%)
184b
(R = CH(OMe)
2
, 41%)
184c
(R =
o-
MeOC
6
H
4
, 74%)
183
N
N
OH
H
N
H
Ph
O
CO
2
Me
H
O
(-)-Strychnine
185
(-)-lochneridine
186
SCHEME 9.31
Synthesis of strychnine
185
by Kuehne and coworkers.
183
rearrangement of this intermediate provides the nine-membered iminium ion
.
In this instance, this aforementioned intermediate
183
then undergoes a second
cyclization to form the enantiopure tetracycle
. The fourfold domino reaction
can be carried out with a range of R groups (as illustrated in aldehyde
181
),
resulting in high ee and dr values. Both vinyl and acetal derivatives of
184
181
have
been applied in the total synthesis of (
)-strychnine, an impressive 14-step
approach from tryptophan
with 5% overall yield (Scheme 9.31). The same
group has also used a similar domino strategy for the synthesis of the natural
product (
180
)[72].
The
Daphniphyllum
family of alkaloids are an assorted series of ring sys-
tems with usually interesting biological activities. The secodaphniphylline natural
products isolated from
Daphniphyllummacropodum
bear a pentacyclic ring system
of which the biosynthesis is proposed to come from squalene. Heathcock reported a
synthesis of the cyclic skeleton of this natural product through a high-yielding
fivefold anionic/pericyclic domino sequence (Scheme 9.32) [73]. This sequence
is initiated through a twofold condensation of the enantiopure dialdehyde
)-lochneridine (
186
187
to
the dihydropyridinium ion
, which then undergoes an intramolecular hetero-
Diels-Alder reaction to give the unsaturated iminium ion
188
. Cyclization of this
iminium ion and [1,5]-hydride shift provides a second iminium ion moiety as
part of compound
189
191
. Hydrolysis of this intermediate upon workup affords the
tetracyclic compound
192
an advanced intermediate to secodaphniphylline (
193
),
in a remarkable 75% yield.
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