Biomedical Engineering Reference
In-Depth Information
O
MeO
N
Me
R
1
R
1
1. LDA, HMPA/THF, -78°C
2. TMSCl, -78 to 0°C
321
O
R
1
I
O
3. HCl/H
2
O
steps
H
OTIPS
OTIPS
320
322
323
OTIPS
O
(R
1
= )
O
steps
Pd(OAc)
2
(30 mol%)
PPh
3
(60 mol%)
Ag
2
CO
3
Pd
H
O
R
1
R
1
H
H
THF, reflux
6
O
I
OH
OH
OH
326
325
324
12
O
13
H
8
9
steps
10
6
4
HO
2
C
H
OBz
HO
(-)-Scopadulcic acid A
327
SCHEME 9.56
Synthesis of scopadulcic acid A
327
by Overman and coworkers.
containing two sterogenic centers was used, which was generated starting from alkyl
iodide
and reaction
with TMSCl led to the corresponding silyl enol ether, which was carried through the
Ireland-Claisen rearrangement to afford
320
andWeinreb amide
321
to give ketone
322
. Enolization of
322
.
A double Heck reaction using palladium acetate in the presence of triphenyl
phosphane and silver carbonate afforded compound
323
and further on to vinyl iodide
324
326
through the intermediate
325
. In this process, the product containing the B, C, and D rings of the scopadulan
skeleton was generated as a single stereoisomer in 90%yield. The addition of Ag
2
CO
3
was used to suppress the migration of the double bond during the first Heck reaction.
The natural product
327
was then produced from allyl alcohol
326
in further eight
synthetic steps.
Zhu and coworkers recently reported the development of an enantioselective
domino Heck/cyanation reaction as the key step in the total synthesis of (
)-esermet-
hole (
) (Scheme 9.57) [125]. Both compounds,
isolated from the seeds of
Physostigma venenosum
, show excellent inhibition of
acetyl- and butyrylcholinesterase. In this sequence, the achiral aryl halide
332
) and (
)-physostigmine (
333
was
coupled through its unsaturated aniline tether by an intramolecular enantioselective
Heck reaction to afford the alkyl palladium intermediate
328
330
containing a single
stereogenic center. Quenching of
330
with cyanide through addition of K
4
[Fe(CN)
6
]
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