Biomedical Engineering Reference
In-Depth Information
Pd(OAc)
2
(10 mol%)
P(
t
-Bu)
3
⋅
HBF
4
(20 mol%)
K
2
CO
3
(1.3 equiv)
DMF, 140°C, 1 h
76%
1. NaOH, MeOH/H
2
O, reflux (90%)
2. DPPA, Et
3
N, PhMe, reflux
then aq HCl, 80°C (69%)
3.
CN
Me
CO
2
Me
1. H
2
SO
4
MeOH
2. LiHMDS
MeI, THF
79%
Me
MeO
MeO
MeO
CO
2
Me
Br
H
OMe
, MgSO
4
MeO
Br
MeO
MeO
CH
2
Cl
2
, rt
OHC
OMe
23
24
25
TBSO
Me
Me
OTBS
1. NaBH
4
, MeOH, rt
2. TBAF, THF, rt
3. HBF
4
, then PPh
3
, DIAD
THF, reflux
37%
Me
OMe
MeO
MeO
MeO
DMF, 160°C
52% (2 steps)
N
N
N
OMe
MeO
MeO
MeO
)-Coralydine
22
OMe
27
OMe
26
(
±
TBSO
OMe
OMe
6
π
electro-
cyclization
Me
OTBS
electrocyclic
ring-opening
MeO
N
MeO
OMe
OMe
SCHEME 1.8
Synthesis of (
)-coralydine by Baudoin and coworkers.
DMF at 140
C for 1 h. Following hydrolysis, Curtius rearrangement, and imine
formation, BCB
underwent a tandem thermal electrocyclic ring-opening/6
p
-
electrocyclization to produce dihydroisoquinoline
26
27
. Imine reduction by NaBH
4
produced a 6:1 mixture of diastereomers in favor of the desired
cis
product in nearly
quantitative yield. Isolation of the major diastereomer, TBAF-promoted desilylation,
and subsequent Mitsunobu reaction afforded (
)-coralydine (
22
).
1.5. PALLADIUM(II)-MEDIATED INTRAMOLECULAR
OXIDATIVE ALKENYLATION OF sp
2
C-H BONDS
Discovered in the early 1970s [39], the Mizoroki-Heck reaction has become a
reliable and practical method for the formation of a carbon-carbon bond between an
arene and an olefin [23]. While this reaction is a powerful tool for natural product
synthesis [40], the required use of an aryl (pseudo)halide as one of the coupling
partners leads to additional synthetic operations associated with its preparation, a
challenging task in some situations. The direct coupling of a (hetero)arene
C-H bond with an unfunctionalized alkene, namely, an oxidative Heck process,
represents the chemical ideal in this field (Scheme 1.9a). Initially reported in the late
1960s by Fujiwara and coworkers [41], considerable progress has been made in this
field over the past 40 years; while originally mediated by stoichiometric quantities
of Pd(II), catalytic processes have been developed in which a terminal oxidant, such
as Ag(I), Cu(II), O
2
,
t
-BuOOH, or
t
-BuOOBz, is added to regenerate the active
catalyst [42].
Mechanistic studies have led to a clearer understanding of the Pd(II)-catalyzed
coupling of (hetero)arenes with alkenes [43]. The catalytic cycle is initiated by the
formation of ArPdX intermediate
, generated by the electrophilic substitution of
an sp
2
C-H bond by a cationic Pd(II) species (Scheme 1.9b). Subsequent olefin
coordination and 1,2-migratory insertion (similar to the traditional Heck reaction)
lead to the formation of Pd(II) intermediate
28
29
.
b
-Hydride elimination produces the
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