Biomedical Engineering Reference
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Fmoc
N
O
Fmoc
N
O
MeO
2
C
1. Et
2
NH, THF, 0°C to rt, 3 h
then PhH, reflux, 2 h
2.
m
CPBA, THF, 0°C to rt
then NaOMe, MeOH, reflux, 45 min
3. Benzoyl peroxide (30 mol%)
O
2
, THF, 60-65°C, 18 h
4. Et
3
N, MsCl, THF, 0°C to rt, 2 h
MeO
2
C
O
H
N
N
O
N
Pd(OAc)
2
(1 equiv)
O
2
(1 atm)
THF/H
2
O/AcOH (1:1:1)
rt, 36-48 h
29%
N
O
H
H
H
H
Me
Me
Me
Me
Me
(+)-Austamide
38
Me
40
39
10%
PdX
2
X
H
CO
2
Me
CO
2
Me
MeO
2
C
MeO
2
C
NR
1,2-migratory
insertion
ring
expansion
NR
NR
NR
H
39
X
X
Me
PdX
Pd(0)
HX
H
H
H
Me
Me
Me
H
Me
Me
Me
XPd
Me
41
42
43
44
SCHEME 1.12
Synthesis of (
þ
)-austamide by Baran and Corey.
Several important observations were made during the development of the key
Pd-mediated cyclization reaction, which provided valuable mechanistic insight. First,
acetic acid appeared to play a crucial role in the reaction since no cyclized product was
observed in its absence. When the reaction was performed with C2 chloromercurated
indole as the cyclization precursor, an increase in reaction rate was observed. From
these results, a reaction pathway involving C-H bond cleavage via electrophilic
palladation of indole
at C2 was proposed, followed by 1,2-migratory insertion,
much like the Heck-type processes involved in the synthesis of (
40
þ
)-ibogamine (
30
)
þ
35
and (
). Owing to the use of a very polar reaction medium,
the authors proposed that the heterolysis of palladated intermediate
)-paraherquamide B (
occurred to
produce cationic intermediate
43
. Ring expansion via migration of the electron-rich
indole moiety followed by elimination of HX would provide
39
. Alternatively, one
could imagine that
42
39
could be obtained from
42
via
b
-hydride elimination, followed
by reprotonation and ring expansion.
The antiviral marine alkaloid dragmacidin F (
) has piqued the interest of the
synthetic community due to both its intriguing pyrazinone core and its complex [3.3.1]-
bridged ring system [53]. Stoltz and coworkers applied a Pd(II)-mediated oxidative
Heck cyclization to prepare the latter moiety in their synthesis of this natural product in
2004 (Scheme 1.13) [54]. Starting from commercially available (-)-quinic acid,
pyrrole
45
was prepared in seven steps (32% overall yield). Addition of a stoichio-
metric quantity of Pd(OAc)
2
and 2 equiv of DMSO as a ligand to a solution of
46
in
tert
-butanol and acetic acid yielded the desired [3.3.1]-bicyclic compound in 74%
yield after stirring for 10 h at 60
C. Surprisingly, all attempts to form this carbon-
carbon bond using a traditional Heck reaction (i.e., from the corresponding
3-bromopyrrole starting material) were met with starting material decomposition or
synthetically unacceptable product mixtures. Efforts were also made to render this
process catalytic in palladium via the addition of a stoichiometric terminal oxidant to
the reaction mixture. Unfortunately, this led to both starting material and product
decomposition, presumably through an oxidative pathway.
The transformation of pyrrole
46
47
50
proceeded in good yield
over a four-step sequence, including a diastereoselective hydrogenation of the
exocyclic alkene, a methyl ether formation, a regioselective bromination, and a
subsequent metal-halogen exchange. With
to boronic ester
50
in hand, a regioselective Suzuki
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