Biomedical Engineering Reference
In-Depth Information
some copper sources, ligands, and a representative panel of bond formation are
highlighted.
3.3.4. Applications in the Synthesis of Complex
Bioactive Molecules
While Buchwald-Hartwig cross-coupling reactions were used in the total synthesis
of natural and bioactive compounds just after their discovery, the Ullmann-type
reactions were employed only in the last years as softer and more convenient
protocols have appeared. Owing to the lower cost of copper and copper-based
catalytic systems, such protocols constitute an interesting substitute for palladium
and a powerful tool, which is illustrated by its growing application in total synthesis.
In fact, in some cases, copper can replace palladium with the same or even better
selectivities and yields. In this section, the authors aim to give an overview of some
representative examples. A more complete and detailed review on Cu-mediated
cross-couplings in total syntheses was recently published by Evano and
coworkers [48].
3.3.5. C-N Bond Formation
3.3.5.1. Aryl amination Aromatic halides and primary amines were success-
fully used in copper-catalyzed coupling reactions to build complex natural and
nonnatural compounds (Scheme 3.23).
Ma and coworkers used a cross-coupling between valine
51
and aryl iodide
52
to prepare the protein kinase C inhibitor benzolactam V8 [49]. The synthesis of
lotrafiban (SB-214857), a glycoprotein IIb/IIIa receptor antagonist, by Hayes and
R
NH
2
Ar
NH
X
R
Ar
R = alkyl; Ar = Aryl; X = I, Br
O
I
OH
NH
OH
HN
CO
2
H
OH
7 steps
MeN
CuI, K
2
CO
3
DMA, 90°C
86%
H
2
N
CO
2
H
51
52
53
Benzolactam V8
HO
2
C
O
CuI,
n-
Bu
4
NOH
MeCN, reflux
(55%)
HN
NMe
NH
HN
N
HO
2
C
N
N
N
O
H
CuI, K
2
CO
3
DMF-H
2
O, 100°C
(72%)
NH
HClH
⋅
N
SB-214857
Martinellic acid
SCHEME 3.23
Selected examples of Cu-mediated arylation of primary amines.
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