Biomedical Engineering Reference
In-Depth Information
CN
1. [Pd(dba)
2
] (5 mol%)
329
(12 mol%)
Ag
3
PO
4
, rt, 40 min
[Pd]
MeO
MeO
MeO
O
O
2. K
2
CO
3
, K
4
[Fe(CN)
6
]
328
78%
N
N
N
O
I
328
330
331
(ee = 72%)
O
O
O
O
F
F
N
PPh
2
PPh
2
O
MeO
steps
N
N
F
F
O
N
N
H
H
329
(-)-Physostigmine
333
(-)-Esermethole
332
SCHEME 9.57
Synthesis of (
)-esermethole
332
and (
)-physostigmine
333
by Zhu and
coworkers.
affords (
S
)-oxindole
containing a cyanomethyl group. For the Pd-catalyzed
reaction, (
S
)-DIFLUORPHOS
331
329
proved to be the most effective ligand that allowed
the formation of
331
in 78%yield and 72%ee. Further steps led to the natural products
(
)-esermethole (
).
The cyclobutane natural products SNF4435 C (
332
) and (
)-physostigmine (
333
339
340
)
found in the extracts of the culture broth of the Okinawan strain of
S. spectabilis
are
reported to exhibit immunosuppressive and multidrug resistance reversal activities.
These compounds thus became the target of several synthetic organic chemists
worldwide. Parker and Lim, for instance, were able to utilize the earlier work of
Trauner and Beaudry [126] by employing a domino Stille reaction/electrocyclization
process to form the cyclobutane ring system. In this approach, the Pd(0)-catalyzed
reaction of vinyl iodide
) and SNF4435 D (
335
with enantiopure trimethyl stannane
334
presumably
affords tetraene
336
[127], which is appropriately set up for the 8
/6
-electrocycliza-
p
p
tion. The reaction afforded SNF4435 C (
339
) and a diastereomer via the
endo
-
transition state
337
(Scheme 9.58). Interestingly, only compound
339
and not
340
is
formed in the reaction via
. This is consistent with the probably nonenzymatic
formation of the compound in nature from their cometabolite spectabilin.
Martin and coworkers prepared the A/B/C-ring system of the indole alkaloid
manzamine A (
338
) through a domino Stille/Diels-Alder reaction [128]. This natural
product, a potent antitumor agent, was isolated from marine sponges of the genera
Haliclona
and
Pellina
found off the coast of Okinawa [129]. At the time, this newly
reported manzamine A ring system was synthetically built up from the enantiopure
vinyl bromide
344
, which was reacted with vinyl tributylstannane in the presence of
Pd(PPh
3
)
4
to afford the intermediate triene
341
. Immediately following this initial
process, an intramolecular Diels-Alder reaction occurs, upon heating, to yield
342
343
as the only product in 68% yield. In this process, three new carbon-carbon bonds
and three new stereogenic centers with excellent induced diastereoselectivity are
achieved. The enantioselective total synthesis of manzamine A (
344
) is completed
through
343
in a total of 21 linear steps (Scheme 9.59).
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