Biomedical Engineering Reference
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hand, platinum decomplexation was facilitated by the addition of potassium cyanide
(140 equiv). Separation of the resulting diastereomers by reverse-phase preparative
HPLC and subsequent auxiliary removal afforded
77
in 96% ee, which was readily
converted to (
)-rhazinilam (
71
).
1.8. PALLADIUM(II)-ENABLED CARBON-OXYGEN BOND
FORMATION AT sp
3
C-H BONDS
The selective transformation of simpleC-Hbonds into carbon-heteroatombonds is a
much sought after process due to its significant potential to facilitate functional group
installation in complex organic syntheses. C-H oxidation is of particular interest due
to the high degree of oxygenation contained in several classes of natural products and
the versatility of these derivatives as synthetic intermediates. Historically, this field
has been focused on the conversion of methane to methanol, a very simple yet highly
attractive transformation. More recently, efforts have been focused on the oxidation
of C-H bonds in more complex systems, with Pd(II) and Pt(II) catalysts being
efficiently utilized.
As is common to most C-H bond functionalization processes, site selectivity
poses a significant challenge to the application of C-H bond oxygenation in natural
product synthesis. Two principal strategies have been employed to overcome this
hurdle. Lewis basic functional groups found within the substrate have been used to
chelate the metal center and direct cyclometalation to effect site-specific C-H bond
functionalization. This general concept is discussed in Section 1.6. A second
strategy involves the functionalization of allylic C-H bonds, which is believed to
proceed via alkene coordination to the metal and directed intramolecular C-H bond
cleavage (see below).
In 1985, Baldwin and coworkers published an insightful report on the use of
cyclopalladation reactions for the functionalization of unactivated methyl C-H
bonds [67]. This study revealed that a carefully designed oxime-directed Pd(II)-
based system could selectively oxidize a single methyl C-H bond within a complex
natural product. Since then, Baldwin's method has been applied to the synthesis of
several natural product targets [68], including lobatoside E (
) [69], a member of
the cyclic bisdesmosides family. Yu and coworkers envisioned that the C23
hydroxyl group in the pentacyclic triterpene core of lobatoside E could arise from
the selective oxidation of oleanolic acid, a highly abundant natural triterpene
(Scheme 1.20). To this effect, oleanolic acid derivative
78
, containing a chelating
oxime functional group, was prepared. Addition of Na
2
PdCl
4
(1.1 equiv) and
sodium acetate (1.1 equiv) in acetic acid (0.02M) yielded complex
79
80
after 72 h
of stirring at room temperature. Compound
was further transformed into an
O
-
acetylated pyridine-ligated complex since intermediates of this type had previously
been demonstrated to readily oxidize when treated with Pb(OAc)
4
[67]. Subsequent
reductive workup with NaBH
4
, required to remove Pd(II) salts coordinated to the
product, afforded
80
). The complete selectivity for C-H
oxidation of the equatorial methyl group can be explained by its coplanar arrange-
ment with the oxime directing group.
81
in good yield (72% from
79
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