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(4.0 equiv) in the presence of Ag
2
O (1.1 equiv) in DMF at 90
C to afford
in 82-
86% yield. Following methanesulfonic acid-mediated cyclohexane ring closure to
afford
67
, a second cyclopalladation reaction was performed. Treatment of
67
with
PdCl
2
in the presence of NaOAc in freshly distilled glacial acetic acid at 70
C
afforded
66
as a 6:1 mixture of diastereomers. The stereochemical outcome of this
transformation appears to indicate a preference for the isopropyl group to occupy the
pseudo-equatorial position, predisposing the
anti
-methyl group to react with palla-
dium due to its accessibility (pseudo-equatorial as well). Methoxycarbonylation of
68
68
by addition of CO (35-40 atm) and methanol yielded
69
, which was directly
converted to lactam
via acidic hydrolysis of the chelating auxiliary. After
recrystallization and three additional synthetic operations, the core of teleocidin
B4
70
62
was obtained.
1.7. PLATINUM(II)-MEDIATED ALKANE
DEHYDROGENATION
While the discussion has thus far focused on the formation of carbon-carbon bonds,
C-H bond functionalization has also been investigated in the context of alkane
dehydrogenation [1e,62]. These reactions typically occur at electrophilic Rh, Ir, Re,
and Pt centers as a two-step process consisting of a C-H bond cleavage generating a
metal-carbon bond, followed by a
b
-hydride elimination generating the desired
alkene (Scheme 1.17
)
. The release of H
2
gas entropically favors these reactions, yet
most dehydrogenation processes are overall thermodynamically disfavored due to the
high energetic cost associated with the cleavage of sp
3
C-H bonds (endothermic
process). In the past, reactions were carried out under extreme temperatures
(
500
C) or in the presence of a sacrificial alkene as an H
2
acceptor to render
these processes more favorable, thus making dehydrogenation not amenable to total
synthesis. However, milder techniques to drive the reaction equilibrium toward
product formation have been developed, including the removal of H
2
gas from the
reaction mixture or the use of photochemical rather than thermal energy.
Rhazinilam, rhazinal, and rhazinicine, three members of the
Aspidosperma
family of natural products, have received significant attention from the synthetic
community due to their ability to interfere with tubulin polymerization, making them
potential anticancer agents. More specifically, their intriguing structure, consisting of
an axially chiral nine-membered lactam ring containing a heterobiaryl unit, has made
them excellent candidates for the application of C-H functionalization reactions.
In fact, several independent syntheses have been reported using such strategies.
Remarkably, these efforts utilize very different transformations at C-H bonds,
demonstrating the power of this method in natural product synthesis
(Scheme 1.18) [63-66]. Representative syntheses will be discussed in the next section
H
H
[M]
cat [M]
+
H
2
C
-
H bond cleavage
β
-H elimination
H
SCHEME 1.17
Transition metal-catalyzed alkane dehydrogenation.
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