Biomedical Engineering Reference
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(b)
Pd(II)-Catalyzed Oxidative Heck Coupling
(Simplified Catalytic Cycle)
(a)
Pd-catalyzed/Mediated Arene Alkenylation
Pd(0)
Heck
(o)
H
X
+
PdX
2
R'
R
catalyst
regeneration
arene
palladation
Pd(0)
X = I, Br, Cl, OTf...
H
X
β
-
H
elimination
R'
R
Pd
R'
X
PdX
1,2-insertion
28
Pd(II)
H
+
R'
R'
R
Oxidative Heck
29
R'
SCHEME 1.9
Pd-catalyzed arene alkenylation.
desired product together with Pd(0), which is reoxidized to Pd(II) in the presence of a
terminal oxidant.
As with other C-H functionalization processes, oxidative Heck reactions tend
to suffer from drawbacks associated with regioselectivity. While similar strategies to
those employed in direct arylation reactions have been developed, these inherently
limit the substrates that may be efficiently coupled [42]. For example, electron-rich
(hetero)arenes, which typically undergo electrophilic palladation with high levels of
selectivity at the most nucleophilic position, have been extensively studied in these
processes. Indeed, furan, thiophene, pyrrole, and indole derivatives have all been
successfully employed [44]. On the other hand, methods using functional groups that
are able to chelate Pd(II) species in order to direct palladation have also been
described [45].
In the past 30 years, several groups have applied Pd(II)-enabled oxidative
carbon-carbon bond formation to natural product synthesis. The examples discussed
in the following section will focus on the use of
stoichiometric palladium
for
heteroarene alkenylation/alkylation that proceed through a common mechanism.
The use of
Pd(II)-catalyzed
oxidative Heck reactions as a synthetic strategy will be
exemplified by Gaunt and coworkers synthesis of rhazinicine (Section 1.9).
The 1978 synthesis of (
) by Trost and coworkers is one of the
earliest examples of Pd(II)-mediated olefin arylation in natural product synthesis [46].
This member of the iboga alkaloid family was rapidly prepared in only four steps
using a simple yet elegant strategy (Scheme 1.10). A boron trifluoride-catalyzed
diastereoselective Diels-Alder reaction of chiral diene
þ
)-ibogamine (
30
31
and acrolein afforded
32
cyclohexene
as a 4:1mixture of diasteromers in 92%yield. Reductive amination of
the latter with tryptamine and subsequent intramolecular Pd(0)-catalyzed allylic
OHC
OHC
OEt
2
(10 mol%)
PhMe
-10°C, 48 h
92%
BF
3
⋅
1. Tryptamine, MgSO
4
PhMe, -10°C to -5°C
2. NaBH
4
, MeOH, 0°C
H
Pd(PPh
3
)
4
(3-6 mol%)
CH
3
CN, 70°C
N
+
O
O
O
H
Ph
OMe
H
O
Ph
OMe
H
Ph
OMe
O
O
33
34
32
(dr = 4:1)
31
PdCl
2
(CH
3
CN)
2
AgBF
4
, Et
3
N
N
N
N
NaBH
4
MeOH, 0°C, 1 h
40-45%
(2 steps)
Pd
Pd
syn
addition
CH
3
CN, rt, 1 h
then 70-75°C, 12 h
indole palladation
H
H
H
H
H
(+)-Ibogamine
30
(er = 4:1)
SCHEME 1.10
Synthesis of (
þ
)-ibogamine by Trost et al.
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