Biomedical Engineering Reference
In-Depth Information
O
H
CO
2
Bn
H
CO
2
Bn
H
CO
2
Bn
H
O
1. Ac
2
O, Et
3
N, cat DMAP
CH
2
Cl
2
, rt, 45 min
2. Pyridine, THF, rt, 15 min
then Pb(OAc)
4
in AcOH
-78°C to rt
3. NaBH
4
, aq NaOH
72% (4 steps)
Na
2
PdCl
4
(1.1 equiv)
NaOAc (1.1 equiv)
AcOH, rt, 72 h
O
25 steps
4.0%
H
H
H
H
HO
O
O
HO
HO
H
H
H
H
HON
O
N
N
OH
HO
AcO
23
O
O
O
O
O
HO
H
AcO
Pd
OH
HO
O
Cl
79
(prepared in 3 steps and 82% yield
from Oleanolic Acid)
O
HO
HO
Me
OH
2
O
80
81
HO
HO
O
OH
OH
OH
OH
N
Lobatoside E
78
AcO
Pd
Cl
N
SCHEME 1.20
Synthesis of lobatoside E by Yu and coworkers.
The oxidation of allylic sp
3
C-H bonds by palladium(II)-based systems has
been a method of interest for over 40 years [70,71]. These reactions are typically
carried out using catalytic Pd(OAc)
2
in combinationwith a stoichiometric amount of a
terminal oxidant, for example, benzoquinone, MnO
2
,orO
2
. Although traditional
stoichiometric methods have now been replaced by milder catalytic conditions, many
limitations, especially concerning regioselectivity, still restrict the application of this
process in total synthesis. For example, terminal alkenes usually undergo competitive
Wacker oxidation processes, while internal alkenes typically give mixtures of
regioisomeric allylic acetates (Scheme 1.21a). Some of these problems are currently
being addressed, notably through the development of new catalytic systems incor-
porating novel ligands that significantly alter product distributions [72]. Mechanis-
tically, catalyst coordination to the alkene is believed to direct selective C-H bond
cleavage, generating
p
-allyl Pd(II) intermediate
(Scheme 1.21b). Carbon-oxygen
bond formation yields both corresponding products and Pd(0), which is in turn
reoxidized to Pd(II) in the presence of a terminal oxidant.
In 2006, White and coworkers reported a novel method for the preparation
of macrocycles employing an allylic C-H bond oxidation strategy [73]. Based on
their Pd(OAc)
2
/sulfoxide-catalyzed benzoquinone-promoted regioselective allylic
oxidation system [72a,b], a wide range of 14- to 19-membered macrolides were
prepared in synthetically useful yields (Scheme 1.22a). Mechanistic investigations
revealed that this reaction proceeds through the formation of a
p
-allyl Pd-carboxylate
complex, with C-O bond formation occurring via an inner sphere pathway (reductive
82
(a)
Challenges
(b)
Simplified Catalytic Cycle
cat. Pd(II)
stoich (o)
AcOH
H
OAc
H
R
R
(o)
Pd(OAc)
2
+
+
R
OAc
O
R
R
R'
Pd(0)
terminal alkenes
Wacker oxidation by-products
OAc
AcO
H
AcO
cat. Pd(II)
stoich (o)
H
R
R'
Pd
OAc
OAc
+
OAc
R
R'
R
R'
+
R
R'
R
R'
AcOH
82
R
R'
internal alkenes
mixture of regioisomers
SCHEME 1.21
Pd(II)-catalyzed allylic C-H oxidation.
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