Biomedical Engineering Reference
In-Depth Information
O
CO
2
Et
EtO
2
C
Boc
NH
[Cp*Rh(MeCN)
3
][SbF
6
]
2
(5 mol%)
Cu(OAc)
2
⋅
H
2
O (20 mol%), O
2
(1 atm)
t
-AmOH, 60°C, 20 h
74%
HN
1. K
2
CO
3
(10 equiv)
MeOH/DCM (1:1), rt, 12 h (97%)
2. TFA, rt, 30 min (94%)
3. DBU (1.2 equiv)
DMF, 150°C, 19 h (36%)
H
NHBoc
+
H
N
H
N
Ac
Ac
119
120
121
Paullone
118
SCHEME 1.30
Synthesis of paullone by Fagnou and coworkers.
heterocycle
. The resulting Rh(I) species is reoxidized to Rh(III) by an external
oxidant, such as Cu(OAc)
2
, present in stoichiometric quantities or as a cocatalyst
under an atmosphere of O
2
.
Despite the relative infancy of Rh(III)-catalyzed C-H bond functionalization
reactions, the power of this method for the rapid construction of heterocyclic scaffolds
has recently been demonstrated by Fagnou and coworkers in the synthesis of paullone
118
117
(Scheme 1.30) [97], an inhibitor of cyclin-dependent kinases (CDKs) [98]. The
indole core of paullone was formed using a Rh(III)-catalyzed oxidative coupling of
acetanilide with a strategically functionalized internal alkyne [99]. Alkyne
,
readily prepared in four steps in 50% overall yield from
o
-iodoaniline, was coupled
with acetanilide
120
in the presence of [Cp
Rh(MeCN)
3
][SbF
6
]
2
(5 mol%),
copper(II) acetate (20mol%), and molecular oxygen (1 atm) as the terminal oxidant
to provide indole
119
in 74% yield as a single regioisomer. Despite the presence of a
structurally similar
N
-Boc-aniline moiety in
120
, exclusive chemoselectivity was
obtained for acetanilide cyclorhodation, confirming previous results that
N
-Boc-
anilines are not compatible directing groups for this Rh(III) catalyst. From indole
121
121
,
paullone (
) was obtained following a three-step sequence consisting of indole and
aniline deprotections, followed by lactam formation.
118
1.12. CONCLUSION
The development of transition metal-catalyzed transformations taking place at
C-H bonds has provided chemists with a variety of new tools for the efficient
formation of carbon-carbon and carbon-heteroatom bonds. Efforts during the past
decade have led to highly chemoselective reactions with increased functional group
compatibility, making these transformations more amenable to the synthesis of
complex natural products. The syntheses discussed in this chapter highlight
the wealth of methods that have been utilized in this context and demonstrate how
C-H bond functionalization has matured as a field.
Having demonstrated its viability in this context, the future of the discipline will
rely on its successful application in an industrial setting and its ability to truly render
traditional chemical processes more efficient. Examples of the use of direct arylation
(see Section 1.2) in a pharmaceutical context have appeared, proving that some of
these methods are possible on multikilogram scale. Noticeably, Merck Research
Laboratories employed a Pd(0)-catalyzed direct arylation reaction in their synthesis of
GABA
A
agonist
(Scheme 1.31) [100].More recently, the same process department
used a Ru-catalyzed direct arylation reaction to access the biaryl core of anacetrapib
(
122
123
), a target of
interest
for
the treatment of hypercholesterolemia [101].
Search WWH ::
Custom Search